CA2109993A1

CA2109993A1 - Substituted derivatives of diaminophthalimide

Info

Publication number: CA2109993A1
Application number: CA002109993A
Authority: CA
Inventors: Uwe Trinks; Peter Traxler
Original assignee: 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: CN1102643A; EP0600830A1; JPH06199786A; AU5184393A

Abstract

Abstract Substituted derivatives of diaminophthalimide There are described compounds of the formula I

Description

-1- 2~9393 Substituted derivatives of diaminophthalimide The invention relates to compound~ of the formula I

A, r Al- N~C
A2-N~ N-R

Ar2 X ' .
in which Al and A2 independently of one another are substituted lower alkyl, substituted ::
. lower alke~yl, substituted lower alkynyl or hyd ogcn, where maximally one oE the radica1s Al and A2 can be hydrogen, or Al and ~2 togcther are lower alkylene substituted by substituents other than lower all~yl and other than hydroxyl; Arl and Ar2 indcpcndcndy of ono another are aryl, heteroaryl or unsubstituted or substituted cycloalkyl, thc group C~- is -C(~ C(d)~ H2- or -C(~ R2), where Rl and R~ independendy of ono another are hydrogcn or lower al~yl, and R i8 hydrogen, lower alkyl, aIyl-lower aLltyl, aryl, amino, hydroxyl or lower alkoxy, salts thereof if salt-folming groups arc present, and/or ~mon thereof if tautomerizable radicals are present, processes for the prcparation of those compounds, pharmacoutical preparadons which contain these compounds, and the uso of those compounds for the therapeutic treatment of the human or animal body or for the production of pharmaceutical preparations.

In tho context of the present application, the general tenns used aboYc and below preferab!y have tho following meanings:

The prefîx "lower" designates a radical having not mo¢e than 7, in par~cular not mo~e than 4, and especially having l to 3 carbon atoms, if no~ing is stated otherwise.

. Lower alkyl is preferably n-propyl, iso~ropyl, n-butyl, isobutyl, sec-butyl, te~t-butyl, , .

-2- 210~9~3 n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl or n-propyl.

Lower alkenyl has 2 to 7, preferably 3 to 7, in partieular 3 or 4, carbon atoms, and is, e.g.
allyl or crotyl.

Lower aL~ynyl has 2 to 7, preferably 3 to 7, in particular 3 or 4, carbon atoms, and is, e.g.
propyn-l- or propyn-2-yl or 2-butyn-1-yl.

Substituted lower alkyl h preferably lower alkyl as defined above, which is substituted by not more than 4, preferably not more than 2, radieals seleeted from amino, as inarninomethyl, -ethyl, -propyl or -butyl, mono- or di-lower-alkylamino, in which the lower alkyl radieal is monosubstituted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower aLIcoxy, lower aL~canoyloxy, halogen, amino, lower aL~cylamino, di-lower alkylamino, mereapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxyoarbonyl, earbamoyl, N-lower alkylearbamoyl, N,N-di-lower aL~cylcarbamoyl and/or eyano or is preferably unsubstituted, sueh as aminomethyl, aminoethyl, aminopropyl or aminobutyl, eyeloalkylamino, phenyl-lower alkylamino or phenylamino, aeylamino, o.g. lower alkanoylamino, sueh as aeetylamino, phenyl-lower alkanoylamino or phonylearbonylamino ( - benzoylamino), hydroxyl, as in hydroxymethyl, hydroxyethyl or hydroxypropyl, lower allcoxy, in whieh the lower allcyl radieal is monosubstituted or disubstituted by hydroxyl, lower al~oxy, phenyl-lower al~oxy, lower alkanoyloxy,halogon, amino, lower aL~ylamino, di-lower alkylamino, mereapto, lower alkylthio, lower alkylsulfinyl, lowor alkylsulfonyl, earboxyl, lower a1koxyearbonyl, earbamoyl, N-lower aL~ylearbamoyl, N,N-di-lowor al~ylearbamoyl and/or eyano or is preferably unsubstituted, phonyl-lower alkoxy, aeyloxy, in partieular lower a1kanoyloxy, mereapto;lower al~ylthio, in whieh tho lower alkyl radieal is monosubstituted or disubstituted by hydroxyl, lower aLkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lowor alkylamino, di-lower al~ylamino, mereapto, lower aL~ylthio, lower aL~ylsulfinyl, lower aLkylsulfonyl, carboxyl, lower aLt~oxycarbonyl, carbamoyl, N-lower alkylearbamoyl, N,N-di-lower aLlcyl-carbamoyl and/or eyano or is preferably unsubstituted, phenyl-lower alkylthio, aeylthio, in particular lower aL~anoylthio, earboxyl, as in earboxymethyl, -ethyl or -propyl, esterified earboxyl, e.g. lower aL~coxyearbonyl, such as methoxyearbonyl, ethoxyearbonyl or tert-butoxyearbonyl, especially in methoxy- or ethoxyearbonyl-methyl, ~thyl or -propyl, or phenyl-lower alkoxyearbonyl, such as benzyloxyearbonyl, cyano, carbamoyl, as in earbamoylmethyl, earbamoylethyl or earbamoylpropyl, N-lower aLtcylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, thiocarbamoyl, 2~9~9~

N-lower aLkylthiocarbamoyl, N,N-di-lower alkylthiocarbamoyl, ureido. ureido substituted on one or both ni~ogen atoms by lower iaLkyl, aryl or aryl-lower iaLkyl, in par~icular 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 aLIcylureiido, e.g. 3-lower aLcylureido, such as 3-methyl- or 3-ethylureido, especially in ureido-, 3-methyl- or 3-ethyl-ureido-methyl, -ethyl or -propyl, thioureido, thioureido substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, in particular 1- or 3-mono-, 1,3- or 3,3-di-or 1,3,3-tri-lower aLlcylthioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3- or 3,3-di-or 1,3,3-triphenyl-lower aLlcylthioureido, e.g. 3-lower aLkylthioureido, such as 3-methyl- or 3-ethylthioureido, cspecially in thioureido-, 3-methyl- or 3-ethylthioureido-methyl, -ethyl `
or -propyl, hydrazino, hydrazino substituted on one or both nitrogen atoms by lower aL~yl, aryl or aryl-lower alkyl, in particular 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower alkyl-hydrazino, 1- or 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl-lower aL~ylhydrazino, e.g. 2,2-di-lower alkylhydrazino, such as 2,2-dimethyl- or 2,2-diethyl-hydrazino, amidino, as in amidinomethyl, -ethyl or -propyl, amidino 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,Nl-di- or Nl,Nl,N2-tri-lower alkylamidino, Nl- or N2-phenyl-amidino, Nl- or N2-mono-, Nl,N2-, Nl,Nl-di- or Nl,Nl,N2-triphonyl-lower alkylamidino, o.g~ Nl,Nl-di-lowcr alkylamidino, such as Nl,Nl-dimethyl- or Nl,Nl-diethylamidino, guanidino, as in guanidinomethyl, -ethyl or -propyl, guanidino substituted on one, two or all three nitrogen at~ms by lower alkyl, aryl or aryl-lower aL~yl, 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-, 112,3-, 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-dimethylguanidino or 3,3-dicthyl-guanidino, oxo which is not bonded to carbon which is bonded to the nitrogen cafrying A
or A2, as in 2-oxopropyl or 3-oxo-n-butyl, thioxo, imino, lower alkylimino, acylimino, in pardculaf lower alkanoylimino, such as aceqlimino, hydroxyimino ~HO-N--), as in hydroxyiminomethyl (HO-N=CEl-), hydroxyimin~ethyl or -propyl, lower a1koxyimino,such as methoxyimino, hydrazono, as in hydrazono-methyl, -ethyl or -propyl, N-mono- or N,N~i-lowcr aLIcylhydrazono, N-acylhydrazono, in particular N-lower aL~canoyl-hydrazono, such as acetyLhydrazono or lower alkoxycarbonylhydrazono, such as tert-butoxycarbonylhydrazono, lower alkylthioimino, such as methyl- or ethylthioimino, especially in methylthioimino- or ethylthioimino-methyl, -ethyl or -propyl, and heterocyclyl, in which heterocyclyl is defined as bclow for heterocyclyl-lower alkyl.
Preferably, lower alkyl is linear and terminally substituted by one of the substituents mentioned.

` 210~3 Substituted lower aLIcenyl is preferably lower alkenyl as defmed above, in particular having 3 to 7, especially 3 or 4, carbon atoms, which is substituted by not more than 4 radicals, preferably one radical, selected from the substituents mentioned in the definition of substituted lower aL~cyl. In the case of certain substituents, tautomers are possible by interaction with the double bond. Thus, hydroxyl, mercapto or N-bonded substituents which also have a free hydrogen on the bonding nitrogen tautomerize on bonding to a carbon atom of a tTiple bond to oxo, thioxo or imino compounds; substituents bonded via nitrogen by a double bond, such as hydroxyimino or hydrazono can likewise tautomerize when they are conjugated to a double bond in the lower alkenyl radical, compounds of this type can also be present in tautomeric equilibriums. Preferred substituted lower alkenyl radicals are those in which no tautomerism occurs, i.e. where e.g. hydroxyl or N-bonded substituents, which also have a free hydrogen on the bonding nitrogen, are not bonded in the lower alkenyl radical to a carbon atom from which a double bond commences, andlor where substituents bonded ~ia nitrogen by a double bond7 such as hydroxyimino orhydrazono, are not conjugated to a double bond in the lower aL~cenyl radical. Unsubstituted lower aL~cenyl Al and/or A2, such as 3-allyl, i8 prefer~ed to substituted lower alkenyl.

Substituted lower aL~ynyl is preferably lower alkynyl as defined above, in particular having 3 to 7, especially 3 or 4, carbon atoms, which is subsdtuted by not more than 4 radical8, preferabb ono radical, selected from the substituents mentionod in the def~nition of 9ubstitutod lower alkyl. Analogously to the dofinition of tautomers and tautomeric equilibriums for substituted lower alkenyl, corresponding tautomers and tautomeric cquilibriums can also be present for substituted lower aL~cynyl. Unsubstituted lower alkynyl Al and/or A2 is preferred to substituted lower alkynyl.

Heterocyclyl-lower aLkyl is one of the abovementioned lower alkyl radicals, preferably methyl, ethyl or n-propyl, which, preferably on the torminal carbon atom, is ~ubstituted by heterocyclyl, which is primalily a saturated, partially saturated or unsaturatod single ring which is bonded via a ring nitrogen atom and contains 3 to 7, primarily 5-7, ring atoms, where apart from the bonding nitrogen atom additionally up to two further hetero atoms can be present, selected from nitrogen, sulfur and/or oxygen; present as a single ring or fused to not more than two, p~ferably one, benzene, cyclopentane, cyclohexane orcycloheptane ring; and can be unsubstituted or subsdtuted in particular by lower aLIcyl, lower alkanoyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, e.g.
pyrrolyl, 2,5~ihydropyrro1yl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolinyl, 2109~3 pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1,3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroiso-thiazolyl, indolyl, isoindolyl, benzimidazolyl, piperidinyl, piperazin-l-yl, morpholino, thiomorpholino, S,S-dioxothiomoIpholino, 1,2-dihydr~ or 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydro- or 1,2,3,4-tetrahydroisoquinolyl, where the radicals mentioned are unsubstituted or substituted as above, in particular by lower aL~cyl, e.g. in 4-lower aLlcyl-piperazin-l-yl, such as 4-methyl- or 4ethyl-piperazin-1-yl, or by lower aL~anoyl, e.g. in 4-lower aL~canoylpiperazin-l-yl, such as 4-acetylpiperazin-1-yl.

Lower alkylene substituted by substituents apart from lower alkyl or hydroxyl, which is formed from Al and A2 tog~ther, is unbranched, in particular has 1 to 4, preferably 1 to 3, carbon atoms and is substituted by one or more, preferably not mot~ than 3, in particular one, substituent selected from amino, amino-lower aL~cyl, such as aminomethyl, -ethyl or -propyl, mono- or di-lower aL~ylamino, mono- or di-lower alkylamino-lower aLIcyl, in which the lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower alkoxy, phenyl~lower a1koxy, lower aL~canoyloxy, halogenj amino, lower aL~cylamino, di-lower allcylamino, mercapto, lower alkylthio, lower aL1cylsul~myl, lower aL~ylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower aL~cyl-carbamoyl and/or cyano or is preferably unsubstitutod, cycloalkylamino, cycloalkylamino~lower alkyl, phonyl-lower aL~ylamino, phcnyl-lower aL~ylamino-lower alkyl, phenylamino, phcnylamino-lower al~yl, acylamino, e.g. Iowcr aLlcanoylamino, phonyl-lower a11canoylamino or phenylcarbonylamino ( - benzoylamino), acylamino-lower alkyl, o.g. Iower allcanoylamino-lower alkyl, phenyl-lower alkanoylamlno-lower alkyl or phenylcarbonylamino-lower alkyl ( - benzoylamino-lower aL~yl), hydroxy-lowcr alkyl, e.g. hydroxymethyl, hydroxyethyl or hydroxypropyl, lower alkoxy or lowcr alkoxy-lower alkyl, in which tho terminal lowcr alkyl radical is monosubstituted or di9ubstituted by hydroxyl, lower alkoxy, phcnyl-lowcr alkoxy, lowcr alkanoyloxy,halogen, amino, lower alkylamino, di-lower allcylamino, mercapto, lower alkylthio, lowcr alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower aL~coxycarbonyl, carbamoyl, N-lower a~ylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or cyano or is preferably unsubstitutedt e.g. 2-methoxy- or 2-ethoxy-ethoxy-lower alkyl, phenyl-lower alkoxy, such as benzyloxy, phenyl-lower aL~coxy-lower alkyl, such as 2-benzyloxyethyl, acyloxy, in particular lower alkanoyloxy, acyloxy-lower alkyl, in particular lower alkanoyloxy-lower aLIcyl, such as 2-acetoxyethyl, mercapto, mercapto-lower aL~yl, e.g. mercaptomethyl or mercaptocthyl, lower alkylthio or lower alkylthio-lower alkyl, in which the terminal lower alkyl radical is monosubstituted or disubstituted by hydroxyl, lower aL~coxy, phenyl-lower aLkoxy, lower - 6 ~ 9 ~ 9 3 alkanoyloxy, halogen, amino, lower alkylamino, di-lowes alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower aL~ylcarbamoyl and/or cyano or is preferably unsubstituted, e.g. 2-methylthio- or 2-ethylthio-ethylthio-lower alkyl, phenyl-lower aLIcylthio, such as benzylthio, phenyl-lower aLt~yl~io-lower a1kyl, such as 2-benzylthioethyl, acylthio, in particular lower alkanoylthio, acylthio-lower aL~yl, in particular lower a1kanoylthio-lower atkyl, such as 2-acetylthioethyl, carboxyl, carboxy-lower alkyl, such as carboxymethyl, esterified carboxyl, e.g. lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, esterified carboxy-lower alkyl, e.g. lower alkoxycarbonyl-lower alkyl, such as methoxy-carbonylmethyl, ethoxycarbonylmethyl or tert-butoxycarbonylmethyl, or phenyl-lower aLkoxycarbonyl-lower alkyl, such as benzyloxycarbonylmethyl, cyano, cyano-lower alkyl, carbamoyl, carbamoyl-lower aL~cyl, such as carbamoylmethyl, -ethyl or -propyl, N-lower aLkylcarbamoyl, such as N-methyl- or N-ethyl~carbamoylmethyl, -ethyl or -p~pyl, N,N-di-lower a~ylcarbamoyl, N-lower a~ylcarbamoyl-lower alkyl, N,N-di-lower a~yl-carbamoyl-lower a~yl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower a~yl, N-phonylcarbamoyl, N-phenylcarbamoyl-lower a~yl, thiocarbamoyl, thio-carbamoyl-lower a~yl, N-lower a~ylthiocarbamoyl, N-lower a~ylthiocarbamoyl-lower~yl, N,N-di-lower a~ylthiocarbamoyl, N,N-di-lower a~ylthiocarbamoyl-lower a~yl, ureido, ureido-lower ~yl, ureido or ureido-lower a~yl substituted on one or both' nitrogen atoms by lower a~yl, aryl or atyl-lower a~yl, in panicular 1- or 3- mono-, 1,3-or 3,3~- or 1,3,3-tri-lower a~ylureido, 1- or 3-phenylureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower a~ylureido, e.g. 3-lower a~ylureido, such as 3-methyl- or 3-ethylureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower a~ylureido-lower a~yl, 1-or 3-phcnylureido-lower a~yl, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower a~ylureido-lower a~l, e.g. 3-lower a~ylureldo-lower a~yl, such as 3-methyl- or 3-othylurei~lower a~yl, especiatly 3-methyl- or 3-ethylureidomethyl, -ethyl or -propyl, thioureido, thioureido-lower a~yl, thioureido or thioureido-lower a~yl substituted on one or both nit~gen atoms by lower a~yl, aryl or aryl-lower a~yl, in panicular 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower ~ylthioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower a~ylthioureido, e.g. 3-lower a~ylthioureido, such 3-methyl- or 3-ethylthioureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower a~ylthio-ureido-lower a~yl, 1- or 3-phenylthioureido-lower a~yl, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-triphenyl-lower ~ylthioureido-lower ~yl, e.g. 3-lower a~ylthioureido-lowera~yl, such as 3-methyl- or 3-ethylthioureido-lower a~yl, es~ia~y 3-methyl- or 3-ethyl-thioureidomethyl, ~thyl or -propyl, hydrazino, hydrazino-lower a~yl, such as ::
2 ~ 3 ~:

hydrazinomethyl, -ethyl or -propyl, hydrazino or hydrazino-lower aL~cyl substituted on one or both nitrogen atoms by lower aLkyl, aryl or aryl-lower aL~yl, in particular 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower aLkylhydrazino, 1- dr 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-triphenyl-lower aL~ylhydrazino, e.g. 2,2~i-lower alkylhydrazino, such as 2,2-dimethyl- or 2,2-diethylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or1,2,2-tri-lower alkylhydraz~no-lower aLlcyl, 1- or 2-phenylhydrazino-lower aLlcyl, 1- or 2-mono-, 1,2- or 2,2 di- or 1,2,2-triphenyl-lower aL~ylhydrazino-lower aL~cyl, e.g. ~ -2,2-di-lower alkylhydrazino-lower alkyl, such as 2,~-dimethyl- or 2,2-diethyl-hydrazino-lower aL~cyl, amidino, amidino-lower alkyl, such as amidinomethyl, -ethyl or -propyl, amidino or amidino-lower alkyl substituted on one or both nitrogen atoms by lower aL~yl, aryl or aryl-lower a1~cyl, in particular Nl- or N2-mono-, Nl,N2- or Nl,Nl-di- or Nl,Nl,N2-tri-lower aL~cylamidino, Nl- or N2-phenylamidino, Nl- or N2-mono-, Nl,N2-, Nl,Nl-di- or Nl,NI,N2-triphenyl-lower aL~cylamidino, e.g. Nl,NI~i-lower alkylamidino, such as Nl,NI-dimethyl- or Nl,NI-diethylamidino, Nl- or N2-mono-, Nl,N2- or Nl,Nl-di-or Nl,NI,N2-tri-lower alkylamidino-lower aLIcyl, Nl- or N2-phenylamidino-lower aL~yl, Nl- or N2-mono-, Nl,N2-, Nl,Nl-di- or Nl,Nl,N2-triphenyl-lower alkylamidino-lower alkyl, o.g. Nl,Nl-di-lower alkylamidino-10wer aLkyl, such as Nl,Nl-dimethyl- or Nl,Nl-di-ethylamidino-lower aL~cyl, guanidino, guanidino-lower alkyl, such as guanidinomethyl, -ethyl or -propyl, guanidino or guanidino-lower alkyl substituted on one, two or all three nitrogen atoms by lower allcyl, aryl or alyl-lower aLlcyl, 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 1,1,2,3j3-ponta-lower al~yl- or -phenyl-lower alkyl guanidino, in particular 3,3-di-lower alkylguanidino, such as 3,3-dimethylguanidino or 3,3-diethyl-guanidino, 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 aLl~yl- or -phenyl-lower aLIcylguanidino-lower aL~cyl, in particular 3,3-di-lower aL~cylguanidino-lower alkyl, such as 3,3-dimethylguanidino-lower alkyl or 3,3-diethylguanidino-lower aLlcyl, oxo, oxo-lower alkyl, in particular lower alkanoyl, such as formyl, acetyl or propionyl, thioxo, thioxo-lower alkyl, imino, imino-lower aLlcyl, lower aL~ylimino, lower alkyl-imino-lower alkyl, acylimino, in particular lower a1kanoylimino, such as acetylimino, acylimino-lower aL~yl, in particular lower aL~anoylimino-lower aL~cyl, such as acetyl-imino-lower alkyl, hydroxyimino, hydroxyimino-lower aL~cyl, such as hydroxyimino-methyl, hydroxyiminoethyl or hydroxyiminopropyl, lower alkoxyimino or lower aL~coxy-imino-lower alkyl, such as methoxyimino or methoxyimino-lower aL~cyl, hydrazono,hydrazono-lower alkyl, such as hydrazonomethyl, hydrazonoethyl or hydrazonopropyl, N-mono- or N,N-di-lower alkylhydrazono, N-mono- or N,N-di-lower aL~cyl--- 8 - 2 i ~ 3 hydrazono-lower aLtcyl, N-acylhydrazono, in par~cular N-lower alkanoylhydrazono, such as acetylhydrazono, or lower aL~coxycarbonylhydrazono, such as tert-butoxycarbonyl-hydrazono, N-acylhydrazono-lower alkyl, in particular N-lower aL~canoylhydrazono-lower alkyl, such as acetylhydrazono-lower a11yl, or lower alkoxycarbonylhydrazono-lower alkyl, such as tert-butoxycarbonylhydrazono-lower aLlcyl, lower aLkylthioimino, such as methyl- or ethylthioimino, and lower alkylthioimino-lower alkyl, such as methyl- or ethyl-thioimino-lower alkyl, especially methyl- or ethylthioiminomethyl, -ethyl or -propyl.
:
In the definition of the group -(C=X)-, -(C=0)-, -(C=S)- and -CH2- are preferred, in particular-(C-~)- and -(C=S)-, especially -(C=0)-.

Aryl is preferably phenyl or naphthyl, such as 1- or 2-naphthyl. The phenyl and naphthyl radicals can be unsubstituted or substituted, in pardcular as indicated in the following for phenyl. Aryl is preferably phenyl which is unsubstituted or substituted by one or more, preferably not more than 5, in particular one or two, especially one, in particular present in the p-positdon or, in the caso of halogen, especially fluorine, as subsdtuents not more than 5, substituents from the group consisdng of hydrocarbyl, e.g. lower alkyl, lower alkenyl, lower alkyny1, lower alkylene ~inked to two adjacent C atoms), cyeloalkyl, phenyl-lower alkyl or pheny1; substituted hydrocarbyl, e.g. Iower alkyl which is substituted e.g. by hydroxyl, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower allcylamino, mercapto, lower alkylthio, lower alkylsulf1nyl, lower allcylsulfonyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-lowcr alkylcarbamoyl, N,N-di-lower allcylcarbamoyl and/or cyano; hydroxyl; etherified hydroxyl, e.g. lower alkoxy, halo-lower aL~coxy, phenyl-lowa alkoxy, phenoxy, lower alkenyloxy, halo-lowa alkenyloxy, lower alkynyloxy or lower aLIcylenedioxy (!inked to two adjacent C atoms);
estai~led hydroxyl, e.g. Iowa alkanoyloxy, phenyl-lowa alkanoyloxy or phenylcarbonyloxy ( = benzoyloxy); mercapto; ethaified mercapto which may be oxidized, e.g. Iower alkylthio, phenyl-lower allcylthio, phenylthio, lower alkylsulfinyl [-S(=0)-lower alkyl], phenyl-lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl [-S(02)-lower aLlcyl], phenyl-lowa aLkylsulfonyl or phenylsulfonyl; halogen, nitro, amino;
monohydrocarbylamino, e.g. lower aLlcylatnino, cycloaL~cylamino, phenyl-lowa aLkyl-amino or phenylamino; dihydt~carbylamino, e.g. di-lower alkylamino, N-lowa aL~cyl-N-phenylatnino, N-lower aLkyl-N-phenyl-lower aLt~ylamino, lower aLkyleneatnino or lower aLkyleneatnino interrupted by -~, -S- or -NR" (in which R" is hydrogen, lower aLkyl or acyl, e.g. lower alkanoyl); acylamino, e.g. Iower alkanoylamino, phenyl-lower alkanoylamino or phenylcarbonylamino ( ^ benzoylamino); acyl, e.g. lower aLkanoyl, :
..

g phenyl-lower aLkanoyl or phenylcarbonyl (= benzoyl); carboxyl; esterified carboxyl, e.g.
lower alkoxycarbonyl; amidated carboxyl, e.g. carbamoyl, N-lower aLkylcarbamoyl,N,N-di-lower alkylcarbamoyl, N-hydroxycarbarnoyl or N-phenylcarbamoyl; cyano, phosphoryloxy substituted on the phosphorus by two radicals seleceed independendy of one another from hydroxyl, lower aLkoxy or phenyl-lower aLkoxy, such as benzyloxy, or phosphoryloxy substituted on the phosphorus by phenylene-1,2-dioxy (i.e. a radical of the O--P--O
çoTmula a~ I `, in which Q~ and Q2 independendy of one another are a~
hydrogen, lower aL~yl orphenyl-lower aL~yl, or in which Ql and Q2 together are ortho-phcnylene), sulfo (S03H); esterified sulfo, e.g. lowcr aLtcoxysulfonyl; and amidated sulfo, e.g. sulfamoyl (SO2NH2), N-lower alkylsulfamoyl, N,N-di-lower aL~cylsulfamoyl or N-Phenylsulfamoyl; where phenyl groups occurring in the substituents are in each case unsubstituted or substituted by lower aL~yl, lower alkoxy, hydroxyl, halogen and/or trifluormethyl; primarily aryl is unsubsdtuted phenyl or pentafluorophenyl or phenyl or pentafluorophenyl which is o-, m- or p-subsdtuted by a radical selected from lower aL~cyl, such as methyl or ethyl, hydroxyl, lower alkoxy, such as methoxy, halogen, such as fluorine or iodine, carboxyl, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxy-carbonyl, and cyano.

Lowcr aL~ylene, linked to two adjaccnt C atoms of a benzene ring, is preferably C3-C4alkyleno, c.g. 1,3-propylene or 1,4-butylenc.

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

Lower alkyleneamino is preferably C4-C7- and in partlcular C4-Csalkyleneamino, e.g.
piperidino. Lower aL~yleneamino interrupted by -O-, -S- or -NR"- is preferably such a C4-C7- and in pardcular C4-Csalkyleneamino in which a ring carbon atom is teplaced by the corresponding hetero group, and is in pardcular morpholino, thiomorpholino, piperazino or 4-lower-alkyl- or 4-lower aL~canoylpiperazino.

Acyl is preferably lower alkanoyl, halo-lower alkanoyl, such as trifluo~ or trichloroacetyl, aryl-lower aL~canoyl, e.g. phenyl-lower aL~canoyl, such as phenylacetyl, arylcarbonyl, such as phenylcarbonyl, where aryl in the two last-mentioned cases is 2~ 93 defined as above with the exception that acyl substituents occurring in the last-mentioned aryl radicals ar~ preferably selected from lower aLkanoyl, phenyl-lower alkanoyl and phenylcarbonyl, or is lower alkoxycarbonyl, such as tert-butoxycarbonyl, oq phenyl-lower aLtcoxycarbonyl, such as benzyloxycarbonyl. Acyl is primarily lower alkanoyi.

Lower alkanoyl is preferably for nyl, acetyl, propionyl, n-butyryl, pivaloyl or valeroyl, in particular forrnyl, acetyl or propionyl.

E~ste~ified carboxyl is preferably lower aL~oxycarbonyl such as methoxycarbonyl,ethoxycarbonyl or tert-butoxycarbonyl, hal~lower alkoxycarbonyl, fluorenyl-, naphthyl-or phenyl lower alkoxycarbonyl, such as fluorenylmethoxycarbonyl or benzyloxycarbonyl.

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

Cycloal~yl i8 preferably C3~C~- and in particular Cs-C7cycloalkyl, which is intended to moan that it contains 3 to 8 or 5 to 7 ring carbons respectively, and is e.g. cyclopentyl, cyclohoxyl or cyclohepql. Thc cycloalkyl radicals mentioncd can also be substituted, e.g.
by lowcr al~yl or hydroxyl.

Halogen is in particular fluorine, chlodne andlor bromine, but can also be iodine.

R i8 prcferably selccted from all the abovementioned meanings apart ~om aryl and is in parlicular hydrogcn.

Hetcroaryl is an unsaturatcd hoterocyclic radical and is preferably linked via a ring carbon atom. It is in parlicular a 5- or ~membe~ed ring having not more than 3 he~o atoms selec~ed from N, O and S, especially N, e.g. imidazolyl, triazolyl, pyridyl, pyrimidinyl or triazinyl, and very especially pyridyl. These radicals can be unsubstitutcd or substituted e.g. by lower alkyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl.

Pyridyl is e.g. 2-, 3- or ~pyridyl.

Imidazolyl is e.g. 2- or 4(5)-imidazolyl.

-Il- 2109~93 Triazolyl is e.g. 1,2,4-triazol-3- or -4-yl or 1,2,3-triazol-4-yl.

Pyrimidinyl is e.g. 2-, 4- or 5-pyrimidinyl.

Triazinyl is e.g. 1,3,5-triazin-2-yl.

If thioxo is mentioned as a substituent above or below, this is not present bonded to terminal methyl (i.e. not in thioaldehydes).

Salts of co npounds according to the invention having salt-forming groups aro primarily pharrnaceudcally utilizablc, non-toxic salts. For example, compounds of tho formula I can forrn acid addidon salts with basic groups, such as prirnary, secondary or tertiary amino groups, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. acetic acid, fumaric acid or methanesulfonic acid, or with amino acids, such as argininc or Iysine. Compounds of the formu1a I having an acidic group, e.g. carboxyl, sulfo or phospho, form e.g. metal or ammonium salts, such as alkali metal and alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, as well as ammonium salts with arnmonia or suitablo organic amines, such as lower alkylamines, e.g. triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis(~hydroxyethyl)amine or t~s(2-hydroxy-othyl)amino, basic aliphadc osters of carboxylic acids, e.g. 2-diethylaminoethyl4-aminobonzoate, lower al~ylenoarnines, e.g. l-ethylpiperidine, cycloal~ylamines, o.g.
dicyclohoxylamino, or bonzylaminos, e.g. N,N'-dibenzylethylenodiamine, dibenzylamino or benzyl-B-phonethylamine. Compounds of the formula I having an acidic and a basic group can also bo present in the form of internal salts, i.e. in zwitterionic form.

Salts of the compounds according to the invendon also include complexes of compounds of the formula I with transitdon metal ions, e.g. copper, cobalt, pladnum or manganese.

For isoladon or purificadon, pharmaceutically unsuitable salts, e.g. picrates o~perchlorates, can also be used. For therapcudc administradon, only the pharmaceutically utilizable, non-toxic salts are suitable, which are therefore preferred.

The compounds of the formula I of the prescnt invention can be present as individual isomers or isomer mixtures, if several isomers are possible. When unsymmetrically ~; substituted double bonds or rings are present, e.g. in the case of substituted lower aLl~enyl : , . ,.

- l2-Al or A2, the cis- and/or the trans-form can be present, in the case of double-bonded nitrogen on ring systems, such as in hydroxyimino, for example the syn- or the anti-form.
Asymmetrically substituted carbon atoms can be present in the (S)-, (R)- or (R,S)-forrn.
When corresponding structural requirements are present, isomer mixtures (such asracemates or diastereomer mixtures), pure diastereomers or pure enan~omers can therefore be present.

If tautomers of the compounds of the present invention can be present, be it in pure form or in equilibrium with other tautomers, these are likewise emb~aced in the definitions above and below. Tautomerizable groups are present e.g. if hydrogen is bonded to O or N
which are bonded to a carbon atom from which a double bond commences, which makes possible keto/enol or imine/enamine tautomerism. 'rhis is the case, for example, for those compounds of the formula I which contain thioureido o~ guanidino radicals or substituted derivativcs thereof as defined above having at least one hydrogen atom on a nitrogen atom. It is also possible that the tautomeric forms are present in equilibrium, for example in solutions. All tautomers of this type, whose occurrence is familiar to the person skilled in the art, aré likewise embraced in the present invention. Prefelred compounds of the formula I or their sa1ts are those which are present in only one tautomeric form or in which one tautomeric form strongly predominates.

Tho compounds according to tho invcntion have useful, in particular phannacologically utilizable, properties. In particular they exhibit specific inhibitory actions which are of pharrnacological interest. Primarily, they act as protein tyrosine kinase inhibitors and oxhibit o.g. a potent inhibition of the tyrosino kinase activity of the rcceptor for epidermal growth factor ~EGE7) and of c-erbB2 kinase. These rceptor-specific enzyme activities play a key role in signal transmission in a plurality of mammalian cells including human cells, in particular of epithelial cells, colls of the immune system and cells of the central and peripheral nervous system. The EGF-induced activation of the rcceptor-associated protein tyrosine kinase (EGF-R-PIK) is, in various types of cells, a prerequisite for cell division and thus for the proliferation of a cell populadon. The replicadon of these cells is thus inhibited by addidon of EGF rcceptor-spccific tyrosine kinase inhibitors.

Tho inhibidon of the EGF receptor-specific protcin tylosine ldnase (EGF-R-PIK) can be detected e.g. by the method of E. McGlynn et al. (see Europ. J. Biochem. 207, 265-275 (1992)). The compounds according to the invention inhibit the enzyme activity to an extent of 50% (ICso), preferably in concentrations from about O.Ol IlM or higher, in 9 ~ 3 particular at 10-8 to 1o-3 M, especially at 10-6 to 104 M. They additionally likewise exhibit in the micromolar range, preferably at 5 x 1~7 to 10-3 M, in particular at 1~5 to 10-3 M, e.g. also an inhibition of the cell growth of an EGF-dependent cell line, for example the epidermoid mouse keratinocyte cell 1ine. In order to measure this inhibition of cell growth, the EGF-stimulated cell proliferadon of epidermal BALB/MK keratino ytes is used (description of the process in Meyer, T. et al., Int. J. Cancer ~, 851 (1989. These cells are dependent on the presence of EGF to a great extent for proliferation (Weissmann, B.
E., Aaronson, S. A, Cell ~, 599 (1983)). To carry out the test, BALB/MK cells (10,000/depression) are transferred to 9~hole microtitre plates and incubated overnight.
The test substances (dissolved in DMSO) are added in various concentradons (in serial dilutions) so that the final 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 go through at least three cell division cycles. The growth of the MK
cells is measured by means of Methylene Blue staining. ICso values are defined as the concentration of the particular test substance which leads to a 50% decrease relative to control cultures without inhibitor.

In addition to or instead of EGP-R PIK, the compounds according to the invention also inhibit other tyrosine kinases which are involved in the signal transmission mediated by trophic factors, e.g. the abl kinase, kinases from the family of the src kinases and the c-erbB2 kinase (H13R-2) family, and also serine/threonine kinases, e.g. protein kinaso C, which all play a part in growth regulation and transformation in mammalian cells, including human cells.

Tho inhibition of c-erbB2 tyrosine kinase (HER-2) can be detected e.g. analogously to the method of E. Mc(}lynn et al. (see Europ. J. Biochem. 207, 265-275 (1992)) used for EGP-R-PIK. The c-erbB2 kinase can be isolated according to known protocols and its activity determined, e.g. according to T. Alciyama et al., Science 232, 1644 (1986). or preferably according to P.M. Guy et al. (see J. Biol. Chem. ~, 13851-13856 (1992)).

The compounds according to the invendon are thus also suitable for inhibidon of the processes mediated by dlese and related tyrosine kinases.

The andtumour acdviq in vivo is tested, for example, using human epithelial cellcarcinoma A431 (ATCC No. CRL 1555), which is transplanted into female BALB/c nude mice (Bomholtgard, Denmark). For the experiments, tumours of diameter of about 1 cm3 ~iO9~

occurring in vivo are obtained from the animals under sterile condidons by excision.
These tumours are homogenized, suspended in 10 volumes (w/v) of phosphate-buffered saline and injected s.c. (0.2 mlimouse, e.g. 106 ce~ls/mouse) into the left flank of the animals. Treatment with a test substance is initiated 5 to 8 days after transplantation, when the diameter of the tumours is 4 to 5 mm. The particular test substance (for example dissolved in ~)Lauroglycol (1,2-propylenglycol-monolaurate, mixture of both constitution isomers, Gattefossé S.A., Saint Priest, France), ~Gelucire (glycerides and partial polyglycerides of fatty acids, Gattefossé S.A., Saint Priest, France) or sesame seed oil), is admiDistered p.o. daily f~r 15 successive days. Tumour growth is determined by monitoring the vertical tumour diameter, and the tumour volume is determined according to the formula ~ x L x D2/6 (L = length, D = diameter of the tumour vertically to the tumour axis). The results can be expressed in per cent as treatment/conttol (T/C).
~, .. .
The compounds according to the invention are therefore usoful e.g. in the treatment of beni8n or malignant t~unours. They are able to cause tumour regression and to prevent motastatic spread of tumours and tho growth of micrometastases; In particular, they can be used in epidermal hypelproliferadon (psoriasis), in the treatment of neoplasms of epithelial character, e.g. carcinomas of the breast, and in leukaemias. The compounds can additionally be employed in the treatment of disorders of the immune system and of inflammations if protcin kinases are involved in these disorders. The compounds can a1so be used in ~e treatment of disorders of the central or peripheral nervous system if signal transmission by protoin kinases is involved. Finally, the compounds of the ptesent in~ention also have antimicrobial properties, which make them suitable e.g. for the treatment of disorders which are caused by bacteria, such as Salmonella typhimuIium, viruses, such as Vaccinia virus, and other microbes which interact with protein lcinases reacdng to g~owth factors.

Compounds according to the invention can be used both on their own and in combination with other pharmacologically active substances, e.g. together with (a) inhibitors of the enzymes of polyamine synthesis, (b) inhibitors of protein kinase C, (c) inhibitors of other tyrosine kinases, (d) cytokines, (e) negadve gro~,vth regulators, e.g. TGP-,B orlFN-,B, (f) aromatase inhibitors, (g) antioestlogens or (h) cytostatics.

In the groups of compounds of the fo~mula I mendoned in the following, general definidons, e.g. of substituents, can be replaced independendy of one other by more specific definidons mentioned above in the general definitions.

3~

The invention relates in particular to compounds of the formula I in which Al and A2 independently of one another are hydrogen, branched or preferably linear lower alkyl, which is substituted by not more than 2 radicals, preferably one radical, selected from amino, mono- or di-lower alkylamino, cycloaL~ylamino, phenyl-lower alkylamino, phenylamino, lower aL~anoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, hydroxyl, lower aL~coxy, phenyl-lower aLl~oxy, lower aLkanoyloxy, mercapto, lower aLtcylthio, phenyl-lower aLlcylthio, lower aLkanoylthio, carboxyl, lower aLIcoxycarbonyl, phenyl-lower aL~oxycarbonyl, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N~i-lower aL~ylcarbamoyl, N-hydroxycarbamoyl, N-phonylcarbamoyl, ~iocarbamoyl, N-lower alkylthiocarbamoyl, N,N~i-lower alkylthiocarbamoyl, ureido, ureido substituted on one or both nitrogen atoms by lower aL~cyl, aryl or aryl-lower alkyl, thioureido, thioureido substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, hydrazmo, hydrazino substituted on one or both nitrogen atoms by lower aL~yl, aryl or aryl-lower alkyl, amidino, amidino substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, guanidino, guanidino substituted on one, two or all three nitrogon atoms by lower ~lkyl, aryl or aryl-lower a1kyl, oxo which is not bonded to the carbon which is bonded to the nitrogon car~ying Al or A2, or thioxo, imino, lower al~yl-~ imino, lowcr allcanoylimino, hydroxyimho, lowerallcoxyimho, hydrazono, N-mono- or N,N-di-lower alkylhydrazono, N-lowcr alkanoylhyd azono, lowor alkoxycarbonyl-hydrazono, and lower alkylthioimino, preferably terminally, or heterocyclyl-lower al~yl, in which hotorocyclyl is pyrrolyl, 2,5-dihydropyrrolyl, pylTolinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, tctrahydrooxazolyl, to~rahydroisoxazolyl, tetrahydrothiazolyl, tctrahydroisothiazolyl, indolyl, isoindolyl, benzimidazolyl, pipolidhyl, piperazin-l-yl, morpholino, thiomorpholino, S,S-dioxothio-morpholino, 1,2-dihydr~ or 1,2,3,4tetrahydroquinolyl, or 1,2~ihydr~ or 1,2,3,4-tetrahydroisoquinolyl which is terminally bonded to the lower alkyl radical and is unsubstituted or substituted by lower alkyl, lower alkanoyl, hydroxyl, lowa alkoxy, . halogen, cyano and/or trifluoromethyl, where maximally one of thc radicals Al and A2 is hydrogen, or in which A~ and A2 together arc lower alkylene, which is substituted by not morc than 3 substituents selected iiom amino, amino-lower.alkyl, mono- or di-lowcr alkylamino, mono- or di-lower a1kylamino-lower aLcyl, cycloalkylamino, cycloalkylamino-lowcr al~yl, phenyl-lower aLkylamino, phenyl-10wer a1kylamino-lower alkyl, phenylamino, phenylamino-lower alkyl, lower aL~canoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoylamino-lower a1kyl, phenyl-lower allcanoylamino-lower alkyl, phenylcarbonylamino-lower aL~cyl, hydroxy-lower aL~cyl, lower 9~

aLIcoxy, lower aLI~oxy-lower aL~cyl, lower aLI~oxy-lower aLkoxy, lower aLt~oxy-lower aLIcoxy-lower aL~cyl, phenyl-lower aL~oxy, phenyl-lower aLlcoxy-lower aLkyl, lower aLkanoyloxy, lower aLI~anoyloxy-lower alkyl, mercapto, mercapto-lower aLIcyl, lower alkylthio, lower aLIcylthio-lower aLI~yl, lower allylthio-lower aLIcylthio-lower alkyl, phenyl-lower aLIcylthio, phenyl-lower aL~ylthio-lower aL~cyl, lower aL~canoyl~io, lower aLkanoylthio-lower aLkyl, carboxyl, carboxyl-lower aLkyl, lower aL~oxycarbonyl, lower aLI~oxycarbonyl-lower alkyl, phenyl-lower aL~coxycarbonyl-lower alkyl, cyano, ...
cyano-lower allcyl, carbamoyl, carbamoyl-lower aL~cyl, N-lower aL~cylcarbamoyl, N,N-di-lower aLkylcarbamoyl, N-lower aLIcylcarbamoyl-lower aLkyl, N,N-di-lower aL~cyl-carbamoyl-lower alkyl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower aL~cyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower alkyl, thiocarbamoyl, thio-carbamoyl-lower alkyl, N-lower alkylthiocarba noyl, N-lower alkylthiocarbamoyl-lower alkyl, N,N-di-lower aLlcylthiocarbarnoyl, N,N-di-lower aLI~ylthiocarbamoyl-lower alkyl, urcido, ureido-lower alkyl, ureido or ureido-lower alkyl substituted on one or both nitrogen atoms by lower alkylj aryl or aryl-lower aLIcyl, thioureido, thioureido-lower alkyl, thioureido or thioureido-lower aL~yl substituted on one or both nitrogen atoms by lower allyl, aTyl or.aryl-lower aL~cy1, hydrazino, hydrazino-lower alkyl, hydrazino orhydrazino lowcr a1~yl substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lowor allcyl, amidino, amidino-lower alkyl, amidino or amidino-lower aLkyl substitutcd on one or both nitrogen atoms by lower aLlcyl, aryl or aryl-lower alkyl, guanidinoj guanidino-lower aLlcyl, guanidino or guanidino-lower aLlcyl substituted on one, two or all threc nitrogen atoms by lower aLIcyl, aryl or aryl-lower alkyl, oxo, oxo-loweralkyl, thioxo, thioxo-lower alkyl, imino, imino-lower alkyl, lower alkylimino, Iower alkylimino-lower aL~cyl, lower aL~anoylimino, lower alkanoylimino-lower alkyl, hydroxyimino, hydroxyimino-lower alkyl, lower aLcoxyimino, lower aL~oxyimino-lower alkyl, hydrazono, hydrazono-lowcr alkyl, N-mono- or N,N-di-lower-aL1cylhydrazono, N-mono- or N,N-di-lower alkylhydrazono-lower alkyl, N-lower aLIcanoylhydrazono, lower alkoxycarbonylhydrawno, N-lower alkanoylhydrazono-lower aLkyl, lower-aLIcoxy-carbonylhydrazono-lower aL~cyl, lower aL~cylthioimino and lower aL~cylthioimin~lower aLkyl Arl and Ar2 independently of one another are aryl, imidazolyl, triazolyl, pyridyl, pyrimidinyl and triazinyl, which are unsubsdtuted or subsdtuted by lower aLkyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, or cycloalkyl which is unsubstituted or substituted by lower alkyl or hydroxyl; the group -C(=X~ is -(C=O)-, C(=S)- or -CH2-;
and R is hydrogen, lower aL~cyl, amino, hydroxyl or lower alkoxy; where (if possible, independently of otherradicals which correspond to one of these generic terms) F' ~

2109~93 aryl is unsubstituted or substituted phenyl or naphthyl, in which the substituents are selected from one or more subs~ituents from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent C atoms), cycloalkyl, phenyl-lower alkyl or phenyl; lower alkyl, which is substituted by hydroxyl, lower aLkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower aLIcylamino, di-lower aL~cylamino, mercapto, lower aL~ylthio, lower aLIcylsulf1nyl, lower aL~ylsulfonyl, carboxyl, lower alkoxyearbonyl, carbamoyl, N-lower aL~cylcarbamoyl, N,N-di-lower aL~cylcarbamoyl and/or cyano; hydroxyl; lower alkoxy, halo-lower aLIcoxy, phenyl-lower aLIcoxy, phenyloxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy or lower alkylene-dioxy (linked to two adjacent C atoms); lower alkanoyloxy, phenyl-lower aLkanoyloxy, phenylearbonyloxy; mercapto; lower aLkylthio, phenyl-lower alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower a1kylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenyl-lowêr aLkylsulfonyl, phenylsulfonyl; halogen, nitro, amino; lower alkylamino, eyeloalkylamino, phenyl-lower alkylamino, phenylamino; di-lower alkylamino, N-lower alkyl-N-phenylamino, N-lower aLkyl-N-phenyl-lower aL~cylamino, lower alkyleneamino, lower ~L~noylamino, phenyl-lower alkanoylamino, phenylearbonylamino, lower alkanoyl, phenyl-lower alkanoyl; phenylcarbonyl; carboxyl; lower alkoxycarbonyl;earbamoyl, N-lower alkylearbamoyl, N,N-di-lower alkylearbarnoyl, N-hydroxyearbamoyl, N-phenylearbamoyl; eyano, phosphoryloxy substituted on the phosphorus by two radieals seleeted independen~y of one another from hydroxyl, lower alkoxy or phenyl-loweralkoxy, sueh as benzyloxy, or phosphoryloxy substituted on the phosphorus by phonylene-1,2~ioxy, sulfo; lower alkoxysulfonyl; sulfarnoyl, N lower aL~ylsulfamoyl, N,N-di-lower alkylsulf~unoyl and N-phenylsulfamoyl, where phenyl groups oeeurnng in the substituents are in each ease unsubsdtuted or substituted by lower alkyl, lower alkoxy, hydroxyl, halogen and/or trifluoromethyl; and in whieh . . eyeloalkyl is C3-C8eyeloalkyl, in partielar eyelopentyl, eyelohexyl or eyeloheptyl;

and pharmaeeutieally utilizable salts of these eompounds if salt-forming groups are present.

Preferred eompounds of the formula I are those in whieh Al and A2 independendy of one another are selected from hydrogen and lower alkyl which is substituted by not more than 2 radieals, preferably one radical, seleeted from amino, mon~ or di-lower alkylamino, lower alkanoylamino, sueh as aeetylamino, hydroxyl, carboxyl, lower aLtcoxyearbonyl, phenyl-lower alkoxycarbonyl, carbamoyl, N-lower alkylearbamoyl, N,N-di-lower alkyl-~z~o~3 carbamoyl, ureido, ureido substituted on one or both nitrogen atoms by lower alkyl, thioureido, thioureido substituted on one or both nitrogen atoms by lower aL~cyl, amidino, amidino substituted on one or both nitrogen atoms by lower aLIcyl, guanidino, guanidino substituted on one, two or all three nitrogen atoms by lower allyl, oxo which is not bonded tO the carbon which is bonded to the ni~rogen carrying Al or A2, hydroxyimino, lower aL~oxyimino, hydrazono, N-mono- or N,N-di-lower aL~cylhydrazono, N-lower alkanoylhydrazono, lower aL~oxycarbonylhydrazono and lower alkylthioimino, wheremaximally one of the two radicals Al and A2 can be hydrogen, or Al and A2 together are lower aL~ylene which is substituted by one or not more than 3, preferably one substituent, selected from amino, amino-lower aL~yl, mono- or di-lower aL~cylamino, mono- or di-lower aL~ylamino-lower aLkyl, hydroxy-lower alkyl, carboxyl, carboxyl-lower alkyl, .
lower aL~oxycarbonyl, lower alkoxycarbonyl-lower alkyl, phenyl-lower aL~coxy-carbonyl-lowér alkyl, carbamoyl, carbamoyl-lowa aLtcyl, N-lower alkylcarbamoyl, ;
N,N-di-lower allcylcarbamoyl, N-lower aL~ylcarbamoyl-lower aL~cyl, N,N-di-lowcr aL~cyl-carbamoyl-lower alkyl, ureido, ureido-lower aL~yl, ureido or ureido-lower allyl :
substituted on one or both nitrogen atoms by lowcr allcyl, thiourcido, thioureido-lower alkyl, thioureido or thioureido-lowcr alkyl substituted on one or both nitrogen atoms by lower.alkylj amidino, amidino-lower alkyl, amidino or amidino-lower aL~yl substituted on one or both nitrogen atoms by lower alkyl, guanidino, guanidin~lower alkyl, guanidino or guanidino-lowcr alkyl substituted on one, two or all three nitrogen atoms by lower aLlcyl, oxo, oxo-lower aL~cyl, hydroxyimino, hydroxyimino lower alkyl, lower aL~oxyimino, 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 aLIcanoyl-hydrazono, lower alkoxycarbonylhydrazono, N-lower alkanoylhydrazono-lower aLI~yl, lower.allcoxycarbonylhydrazono-lower alkyl, lower alkylthioimino and lower aLlcylthio-imino-lower alkyl; Arl and Ar2 are phenyl which is unsubstituted or substituted by a substituent selected from trifluoromethyl, hydroxyl, lower aLt~oxy, ha10-lower aL~oxy, phenyl-lower aL~oxy, phenoxy, lower a1kanoyloxy, phenyl-lower aL~canoyloxy, phenyl-. carbonyloxy, cyano, sulfo and sulfamoyl or not more than ffve times by halogen, the group -(C-X)- is -(C~ or -(C=S)-, and R is hydrogen or lower a1kyl, and pharmaceutically utilizable salts thereof if salt-forrning groups are present.

More highly preferred compounds of the fo~mula I are those in which Al and A2 independently of one another are hydrogen or lower aL~cyl which is substituted by a radical selected from amino, as in aminomethyl, 2-aminoethyl, 3-aminopropyl or 4aminobutyl, lower aLl~anoylamino, as in 3-acetylaminopropyl, carbamoyl, as in carbarnoylmethyl, 9~93 2-carbamoylethyl or 3-carbamoylpropyl, ureido, as in 3-ureidopropyl, ureido substituted on one or both nitrogen atoms by lower aLkyl, e.g. lower aL~cylureido, as in 3-methylureido- or 3-ethylureido-methyl, -ethyl or -propyl, thioureido as in 3-thioureidopropyl, thioureido substituted on one or both nitrogen atoms by lower aL~cyl, e.g. 3-lower alkylthioureido, as in 3-methyl- or 3-ethylthioureidomethyl, -ethyl or -propyl, amidino, as in amidinomethyl, -ethyl or -propyl, guanidino, as in guanidinomethyl, -ethyl or -propyl, and lower alkylthioimino, as in methylthioimino- or ethylthioimino-methyl, -ethyl or -propyl, where maximally one of the radicals Al and A2 can be hydrogen, or in which Al and A2 together are lower alkylene which is substituted by a substituent selected from amino, amino-lower aLlcyl, such as aminomethyl, 2-aminoethyl or 3-aminopropyl, hydroxy-lower alkyl, such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl, carboxyl, carboxy-lower aL~yl, such as carboxymethyl, lower aLkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, lower aL~coxycarbonyl-lower alkyl, such as methoxycarbonylmethyl, ethoxycarbonylmethyl or tert-butoxycarbonyl-methyl, lower aLIcanoyl, such as formyl, acetyl or propionyl, hydroxyimino, hydroxy-imillo-lower alkyl, such as hydroxyiminomcthyl, 1- or 2-hydroxymethyliminoethyl or 1-, 2- or 3-hydroxyiminopropyl, hydrazono and hydrazono-lower alkyl, such as hydrazono-methyl, 1- or 2-hydrazonoethyl or 1-, 2- or 3-hydra~onopropyl, especially ethylene or (altemati~rely or supplementary to ethylene) methylene which is substituted in the l-position by one of the amino-lower al~yl, hydroxy-lower alkyl, carboxyl, lowcr aLlcoxy-carbonyl, lowcr alkanoyl, hydroxyimino-lower al~yl or hydrazono-lower alkyl radicals mentioned; Arl and Ar2 arc phenyl or 4-halophenyl, e.g. ~fluorophenyl; the group-(C-X)- is -(C=O~; and R is hydrogen, and pharmaccutically utilizable salts thereof if salt-forming groups are present.

l~ven more highly preferred compounds of the ~ormula I are those in which Al and A2 independently of one another are 2~aminoethyl, 3-aminopropyl, ~aminobutyl, 3-aceql-aminopropyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2-(3-me~ylureido)ethyl, 2-(3-ethylureido)ethyl, 3-ureidopropyl, 3-thioureidopropyl, 3-(3-methylureido)propyl, 3-(3-ethylureido)propyl, 2-(3-methylthioureido)ethyl, 2-(3-ethylthioureido)ethyl, 3-(3-methylthiourcido)propyl, 3-(3-ethylthioureido)propyl, 2-amidinoethyl, 3-amidino-propyl, 2-guanidinoethyl, 3-guanidinopropyl, 3-(N-methylthioimino)propyl or hydrogen, where maximally one of the radicals Al and A2 can be hydrogen, or in which Al and A2 together are ethylene or (alternatively or supplementary to ethylene) me~ylene which is subsdtuted in the l-position by aminomethyl, 3-aminopropyl, hydroxymethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propionyl, hydroxyiminomethyl or hydrazonomethyl;

~109~93 Arl and Ar2 independendy of one another are phenyl or 4~fluorophenyl, where Arl and Ar2 preferably have the same meaning; the group -(C=X)- is -(C=O)-; and R is hyd~ogen, and phannaceutically udlizable salts thereof if salt-forrning groups are present.

Very preferred compounds of the fo~mula I are those in which Al and A2 independendy of one another are 2-aminoethyl, 3-aminopropyl, 2-carbamoyle~yl, 3-ureidopropyl, 3-(3-methylureido)propyl, 3-dlioureidopropyl or hydrogen, where maximally one of the radicals Al and A2 can be hydrogen, or in which Al and A2 together are ethylene or (alternatively or supplementary to ethylene) methylene which is substituted in the l-position by aminomethyl, hydroxymethyl, carboxyl, methoxycarbonyl, propionyl, hydroxyiminomethyl or hydrazonomethyl; Arl and Ar2 are phenyl; the group -(C--X)- is -(CzO)-; and Ris hydrogen, and pharmaceudcaUy udlizable salts thereof if salt-foIming groups are present.

Of all the proviously mentioned compounds of the formula I, in each case those are very primarily preferred in which one of the two radicals Ai and A2 is hydrogen, the other lower alkyl which is unsubstituted or subsdtuted by one of the subsdtuents mentioned in each case; or in which Al and A2 together are a lower al~yleno which is subsdtuted by one of tho substitucnts mendoned in cach case; while the other radicals have the meanings mendoned, pharmaceudcally udlizable salts thereof if salt-forming groups are present, and tautomer~ thercof if tautomerizable groups are present.

The in~endon relates especiaUy to the specific compounds described in tho o%amples and to pharmaceutically udlizable salts thereof.

The compounds of the formula I can be prepared in a manner known per se, e.g. by a) reacdng a carboxylic acid of the formula II

Arl Al--N ~,D~CH
I 11 ~
A2- N ~~COOH
Ar2 in which Arl, Ar2, Al and A2 are as defined in formula I, or a reactive acid derivative 2109~3 thereof with an amino compound of the formula m H2N-R (m) :

in which R is as defined in formula L functional groups in ~e s~ng materials which are not intended to participate in the reaction if necessary being present in protected for n, and protective groups present being removed, o~

b) to prepare compounds of the formula I in which Al and A2 together are methylene gubstituted by esterified carboxyl or lower atlcanoyl, reacting a compound of the formula XI ' Ar1--NH~
Ar2--NI~N - R ~XI) in which Arl, Ar2, X and R arc as defined for compounds of the formula I, with an atdehyde of the formuta Xll R~-CHO (X~

in which Ro i5 estified carboxyl or lower a1kanoyl, or a reactive derivative thereof, functionat groups in the stardng matcriats which are not intended to participate in the roaction if necessary being present in protectçd foIm, and protective groups present being removed, and, if desired, conveIting an obtainable compound of the formuta I into anothercompound of the formula I andlor converting an obtainable salt into thc free compound o.r into another 8alt, and/or converting an obtainable free compound of the formula I into a salt and/or scparating an obtainable mixturc of isomeric compounds of the formula I into the individual isomers.

In the following more detaited description of the process, the symbols Arl, Ar2, Al, A2, X, R, Rl and R2 in each case are as defined in formutae I and ~ and, if nothing is stated .~
`: " ' `

2.~9393 otherwise, the radicals R3 and R4 are aryl, aTyl-lower alkyl or lower aLkyl.

Process a): Formation of an imide The carboxylic acids of the formula II are present either with ~ee carboxyl groups, or as `
reactive derivatives (where one or preferably both carboxyl g~oups can be deIivatized), for example as esters derived from the free carboxyl compound, e.g. as activated esters, as a reactive anhydride, or additionally as a reactive cyclic amide. The reactive de~ivatives can also be forrned in situ.

Esters of compounds of the formula I~ are preferably those of the formula II' Ar Al--N~COOR3 "
I~ 11 (~') A2 N'--COOR4 Ar2 in which Arl, Ar2, Al and A2 aro as defined in formula I and R3 and R4 independently of one another aT~ aryl, o.g~ 4-nih~phenyl, aryl-lower al~yl, e.g. benzyl, or lower a1kyl, such as methyl.

Activated esters of compounds of tho formula II arc in particular esters which are unsaturated on the linking carbon atom of the esterifying radical, e.g. of the v~nyl cster type, such as vinyl estcrs (obtainable e.g. by transcsterification of an appr~pnate estcr with vinyl acetate; activated vinyl ester method), carbamoyl estcrs (obtainable e.g. by treating the concsponding acid with an isoxazolium reagent; 1,2~xazolium or Woodward method), or l-lower alkoxyvinyl esters (obtainable e.g. by treating the co~responding acid with a lower alkoxyaceqlene; ethoxyacetylene method), or esters of the amidino type, such as N,N' disubstituted amidino esters (obtainable e.g. by treating the corresponding acid with a suitable N,N'-disubstituted carbodiimide, e.g. N,N'-dicyclohexylcarbodiimidc;
carbodiimide method), or N,N'~isubstituted amidino esters (obtainable c.g. by treating the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, in particular phenyl esters substituted by electron-wi~drawing substituents (obtainable e.g. by treating the corresponding acid with a suitably substituted phenol, e.g.
4-nitIophenol, ~methylsulfonylphenol, 2,4,5-trichloqophenol, 2,3,4,5,~pentachlorophenol ~iO9993 or 4-phenyldiazophenol in the presence of a condensing agent, such as N,N'-dicyclo-hexylcarbodiimide; activated aryl ester method), cyanomethyl esters (obtainable e.g. by treating the corresponding acid with chloroacetonitrile in the presence of a base;
cyanomethyl ester method), thioesters, in par~cular unsubs~tuted or substituted phenylthio esters, e.g. by nitro (obtainable e.g. by treating the corresponding acid with unsubsdtuted or substituted thiophenols, e.g. by nitro, inter alia with the aid of the anhydride or carbodiimide method; activated thioester method), or in particular amino or amido esters (obtainable e.g. by treating the co~esponding acid with an N-hydroxyamino or N-hydroxyamido compound, e.g. N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide, l-hydroxybenzo-tdazole or 3-hydroxy-3,~dihydro-1,2,3-benzo triazin~one, e.g. by the anhydride or carbodiimide method; activated N-hydroxy ester method).

Anhydrides of acids of the formula II can be internal anhydrides or mixed anhydrides of those acids, e.g. anhydrides with inorganie acids, sueh as aeid halides, in partieular acid ehloddes (obtainablo e.g. by treating the eorresponding acid with thionyl chloride, phosphorus pentaehloride or oxalyl ehlorido; aeid ehlorido method), azidos (obtainable o.g. from a eoITosponding aeid ester via the eorresponding hydrazide and treatment thereof with nitrous aeid; azide method), anhydrides with earbonie aeid hemiesters, o.g. earbonie aeid lower alkyl hemiestçrs (obtainable e.g. by treating the eorresponding aeid with lower alkyl ebloroformates or with a l-lower alkoxyearbonyl-2-lower al~oxy-1,2 dihydro-quinoline; mi~ced ~al~yl earbonie anhydride method), or anhydrides with dihalogenated, in partieular diehlorinated, phosphorie aeid (obtainable e.g. by treating the eorresponding aeid with phosphorus oxyehloride; phosphorus oxyehloride method), anhydridos with other phosphorie aeid derivadves (e.g. those whieh ean be obt~ned using phenyl N-phenyl-phosphoramidoehloridate or by reaedon of allcylphosphoramides in the presonee of sulfonie anhydrides and/or raeemization-suppressing addidves, sueh as N-hydroxy-benzotriazole, or in the presenee of diethyl eyanophosphonate) or wieh phosphorous acid derivadves, or anhydrides with organie aeids, sueh as mixed anhydrides with organie earboxylie aeids (obtainable e.g. by treadng the eorresponding aeid with an unsubsdtuted or subsdtuted lower alkane- or phenyl-lower alkaneearboxylie aeid halide, e.g.
phenylaeeql, pivaloyl or trifluoroaeeql ehloride; mixed earboxylie anhydride method) or with organie sulfonie aeids (obtainable e.g. by Ireadng a salt, such as an alkali metal sa1t, of the corIesponding acid with a suitable organic sulfonyl halide, such as lower al~ane- or aryl-, e.g. methane- or p-toluenesulfonyl chloride; mixed sulfonic anhydride method) and also symmetrical anhydrides (obtainable e.g. by eondensadon of the colTesponding acid in '3 the presence of a carbodiimide or of l-diethylaminopropyne; symmetdcal anhyd~idemethod). Internal anhydrides can preferably be prepared from a free dicarboxylic acid of the formula Il by reaction with acid anhydrides of the formula (X), Rs-(C=O)-O-(C=O)-Rs', in which Rs and R5' independently of one another are hydrogen or lower alkyl, but not both hydrogen, in particular acetic anhydride.

Anhydrides of carboxylic acids of the formula II are preferably internal anhydrides of the forrnula IV

Arl O

~0 ( ) A2--N~/
Ar2 in which Al, A2, Arl and Ar2 a~e as defLned in formula I.

Suitablo cyclic amides are in parlicular amides with five-membered diazacycles of aromatic character, such as amides with imidawles, e.g. imidawle (obtainable e.g. by treating the corresponding acid with N,N'-carbonyldiimidawle; imidawle method), or pyrawle, e.g. 3,5-dimethylpyrawle (obtainable e.g. via the acid hydrazide by treating with acetylacetone; pyrawlide method).

As mentioned, derivadves of carboxylic acids which are used as acylating agents can also be formed in situ. For instance, N,N'-disubstituted amidino esters can be formed h situ by reacting tho mixturo of the stardng material of the formula m and the acid of the formula II used as the acyladng agent in the presenco of a suitaWe N,N'-disubsdtuted carb~
diimide, e.g. N,N'-cyclohexylcarbodiimide, for example in the presence of a suitable base, such as triethylamine. Addidonally, amino or amido esters of the acids used as acylating agents can be formed in the presence of the stardng material of the formula III to be acylated by reacdng the mixture of the corresponding acid and amino star~ing materials in the presence of an N,N'-disubsdtuted carbodiimide, e.g. N,N'-dicyclohexylcarbodiimide, and of an N-hydroxyamine or N-hydroxyamide, e.g. N-hydroxysuccinimide, if desired in the presence of a suitable base, e.g. 4 dimethylaminopyridine. ~ addition activation in situ can be achieved by reaction with N,N,N',N'-tetraalkyluronium compounds, such as -25- 2~993 O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexailuorophosphate. Finally, phosphoric anhydrides of the carboxylic acids of the formula II can be prepared in situ by reacting an alkylphosphoramide, such as hexamethylphosphoramide, in the presence of a sulfonic anhydride, such as 4-toluenesulfonic anhydride, with a salt, such as a tetrafluoborate, e.g. sodium tetrafluoborate, with another derivative of hexamethyl-phosphoramide, such as benzotriazol-l-ylo~cytris(dimethylamino)phosphonium hexa-fluoride, preferably in the presence of a racemization-suppressing additive, such as N-hydroxybenzotriazole.

The reaction for the preparation of an amide bond can be carried out in a manner known per se, for example as described for condensation reactions in standard texts, such as "Houben-Weyl, Methoden der organischen Chemie" CHouben-Weyl, Methods of Organic Chemistry], 4th Edition, Volume 15/II (1974), Volume IX (1955) Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Pepddes" (E. Gross and J. Meienhofer, eds.), Volumes 1 and 2, Academic E'ress, London and New York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Splinger-Verlag, Berlin 1984.

Tho reaction of a compound of the formula II' in accordance with the aminolysis of phthalic acid diesters with ammonia or primaTy amines, which is known per se, ispreferred. The reaction proceeds with activated diaryl phthalates, e.g. the di(p-nitrophenyl) ester, normally at room temperature, but with di-lower aLlcyl esters usually only at high tomperatures. The Teaction of di-lower alkyl esters in solvents, in particular in a highboiling alcohol, e.g. a diol, such as ethylene glycol, or alternatively glycerol, at normal pressure and temperaturos i~om 100 to 150C, e.g. of about 120C, or the reaction of the lower alkyl esters with ammonia or the amine of the formula m in question at the ~ ` .
same temperaturcs in the presence of a solvent, for example of an alcohol, e.g. a lower alkanol, such as methanol or ethanol, or additionally in the absence of a solvent, in an autoclave at elevated pressure, is particularly preferred. Preferably, the dimethyl ester is used as the phthalic acid diester.

If, apart from the radicals -a)OR3 and -COOR4 in the compounds of the fonnula II', still furthèr esterified carboxyl radicals are present as substituents, e.g. present in a lower alkoxycarbonyl-lower alkyl as Al and/or A2 or in a lower alkylene substituted by lower alkoxycarbonyl and/or lower alkoxycarbonyl-lower alkyl, which is for ned from Al and A2 together, these can be converted to the corresponding amides in the reaction with ammonia, lower allylamines, di-lower alkylamines, hydroxylamine or phenylamine ~1~9~

(preferably in the same batch virtually simultaneously with the radicals -CO(:)R3 and -C00~4)-The reaction corresponding to the aminolysis of phthalic anhydrides of the formula IV
with compounds of the formula m [ammonia or primary amines (lower aLkylarnine, aryl-lower aL~ylamine, arylamine, hydrazine (protected on an N atom), hydroxylamine or lower alkyloxyamine)], which is known per se, which preferably takes place at relatively high temperatures or with hexamethyldisilazane and methanol at room temperature [Davis, Peter D. and Bit, Rino A., Tetrahedron Lett. 31, 5201-5204 (1990)] is also preferred.

The protective groups for functional groups in starting materials whose reaction should be avoided, in particular carboxyl, amino, hydroxyl, mercapto and sulfo groups, in particular include those proteetive groups (conventional proteeting groups) which are customa~ily used in the synthesis of pepdde compounds, but also of cephalosporins and penicillins and also nueleie aeid derivatives and sugars. These protective groups can a1ready be present in tho precursors and should proteet the funcdonal groups in question against undesired side reaetions such as acylations, etherifications, esterifieations, oxidations, solvolysis etc. In certain cases, the proteetive groups can moreover effect a selective, for example stereoseleetivo, course of reaedon. It is charaeterisdc of proteedve groups that they can bo removod easily, i.e. without undesired sido reactions, for example solvolytically, reductively, photolytically or alternadvely enzymatically, e.g. even under physiological conditions. It is also characterisdc of proteedve groups that they are not present in the final substances.
.: ,;
Tho protection of functional groups by such protective groups, the protective groups themselves, and their removal reactions are described, for example, in standard texts such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in Th. W. Creene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in '~he Pepddes"; Volume 3 (1~. Gross and J. Meienhofer, eds.), Academic Press, London and New York 1981, in "Methoden der organischen Chemie"
lMethods of Organic Chemistry], Houben-Weyl, 4th Edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide,Proteine" lAmino acids, Pepddes and Proteins], Verlag Chemie, Weinhdm, DeerfieldBeach and Basle 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Mono-saccharide und Derivate" [Chemistry of the Carbohydrates: Monosaccharides and '2~1~9l~3 Derivatives], Georg Thieme Verlag, Stuttgart 1974.

A carboxyl group is protected e.g. as an ester group which is selectively cleavable under mild conditions. A carboxyl group protected in esterified form is primarily esterified by a lower group, which is preferably branched in the l-posidon of the lower aL~yl group or substituted in the 1- or 2-position of the lower alkyl group by suitable substituents.

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

A protected carboxyl group which is esterified by a lower aLlcyl group which is branched in the l-position of the lower aL~yl group is, for example, tert-lower alkoxycarbonyl, e.g.
tert-butoxycarbonyl.

A protected earboxyl group which i8 esterified by a lower alkyl group which is substituted in tho 1- or 2 posidon of she lower alkyl group by suitable substituents is, for example, arylmothoxycarbonyl ha~ing one or two aryl radicals, in which aryl is phenyl which is unsubsdtuted or mon~, di- or trisubsdtuted e.g. by lowor alkyl, e.g. tert-lower aLkyl, such as tert~butyL lower alkoxy, o.g. methoxy, hydroxyl, halogon, e.g. chlorine, and/or nitro, for oxamplo benzyloxycarbonyl, bonzyloxycarbonyl subsdtuted by the substdtuents montioned, o.g. 4nitrobenzyloxycarbonyl or 4methoxybonzyloxycarbonyl, diphenyl-mothoxycarbonyl or diphenylmethoxycarbonyl substituted by the subsdtuents mentioned.
e.g. di-(4-methoxyphenyl)methoxycarbonyl, and also carboxyl esterified by a lower alkyl group, where the lower alkyl group is substituted by suitablo substituents in the 1- or ~position, such as l-lower alkoxy-lower allcoxycarbonyl, e.g. methoxymethoxycarbonyl, ~;
l-mothoxyothoxycarbonyl or l-ethoxyethoxycarbonyl, l-lower alkylthio-lower alkoxy-earbonyl, e.g. l-methylthiomethoxyearbonyl or l-ethylthioethoxyearbonyl, aroylmethoxy-carbonyl, in which the aroyl group is benzoyl which is unsubstituted or substituted, for example, by halogen, such as bromine, e.g. phenacyloxycarbonyl, 2-halo-lower a1koxy-carbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxy-carbonyl, and also 2-(trisubstituted silyl) lower alkoxycarbonyl, in which the substituents independently of one another are each an aliphatic, araliphadc, cycloaliphatdc or aromatic hydrocarbon radical which is unsubstituted or substituted, e.g. by lower aL~cyl, lower alkoxy, aryl, halogen and/or nitro, for example lower aL~cyl, phenyl-lower alkyl, cycloa11~yl or pnenyl which is unsubstdtuted or subsdtuted as above, e.g. 2-tri-lower alkylsilyl-lower aL~oxycarbonyl, such as 2-tri-lower aL~cylsilylethoxycarbonyl, e.g. 2-tlimethylsilylethoxy-21~99~3 carbonyl Qr 2-(di-N-butylmethylsilyl)ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.

A carboxyl group is also protected as an organic silyloxycarbonyl jgroup. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, e.g. tri-methylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can also be substituted by two lower aL~cyl groups, e.g. methyl groups, and an amino or carboxyl group of a second molecule of the formula I. Compounds having such protective groups can be prepared e.g. using dimethylchlorosilane as a silylating agent.

A carboxyl group is also protected in the form of an internal ester having a hydroxyl group at a suitable distanee, e.g. in the ~-position, to the earboxyl group present in the molecule, i.e. in the form of a laetone, preferably of a ~-lactone.

A proteeted earboxyl greup is preferably tert-lower alkoxycarbonyl, e.g. tert-butoxy-earbonyl, benzyloxyearbonyl, ~nitrobenzyloxyearbonyl, 9-fluorenylmethoxyearbonyl or tiphenylme~oxyearbonyl, or a earboxyl group proteeted in the form of a laetone, in partieular of a ~-lactono.

Proteeted earboxyl is set free aeeording to eustomary proeesses, e.g. the proeesses mentioned in tho abovementioned standard texts about proteetive gTWpS.
.
Thus, proteeted earboxyl, e.g. tert-lower alkoxyearbonyl, lower alkoxyearbonyl substituted in the 2-posidon by a trisubstituted silyl group or in the l-position by lower alkoxy or lower alkylthio, or unsubstituted or substituted diphenylmethoxyearbonyl ean be eonverted into free earboxyl by treating with a suitable aeid, sueh as formie aeid, hydroehlorie aeid or tri~uoroaeetie aeid, if dosired with addition of a nueleo~hilie eompound, sueh as phenol or anisole. Unsubstituted or substituted benzyloxyearbonyl ean be set free e.g. by means of hydrogenolysis, i.e. by treating with hydrogen in the presenee of a metaUie hydrogenation eatalyst, sueh as a paUadiurn eatalyst. Addidonally, suitably substituted benzyloxyearbonyl, such as ~nitrobenzyloxyearbonyl, ean also be eonverted into free earboxyl by reiduetion, e.g. by treating wi~h an alkali metal dithionite, sueh as sodium dithionite, or with a redueing metal, e.g. zine, or a redueing metal salt, sueh as a ehromium(LI) salt, e.g. ehromium(lI) ehloride, eustomarily in the presence of a hydrogen donor whieh, together with the metal, ean produce raseent hydrogen, such as an aeid, primarily a suitable earboxylie acid, such as a lower aL~canecarboxylic aeid which is 21099~

unsubsdtuted or substituted, e.g. by hydroxyl, e.g. acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or ~aric acid, or of an alcohol or thiol, water preferably being added. By treating with a reducing metal or metal salt, as described above, 2-hal~lower-aLIcoxycarbonyl (if desired after conversion of a 2-bromo-lower aLIcoxycarbonyl grwp into a corresponding 2-iodo-lower aLkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into free carboxyl.
Aroylmethoxycarbonyl can likewise be cleaved by treating with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenoxide or sodium iodide. 2-~risubsdtuted silyl) lower aL~oxycarbonyl, such as 2-tri-lower aL~ylsilyl-lower a1~oxycarbonyl, can also be cleaved by treating with a salt of hydrofluoric acid producing the fluoride anion, such as an aLlcali metal fluoride, e.g. sodium fluoride or potassium fluoride, if desired in the presence of macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, e.g. tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprodc, polar solvent, such as dimethyl sulfoxide or N,N~dimethylacetamide. As organic silyloxycarbonyl, such as tri-lower alkylsilyloxy-carbonyl, e.g. trimethylsilyloxycarbonyl, protected carboxyl can be set free, as doscribed above, in a customary manner by solvolysis, e.g. by treating with water, an alcohol or aeid, or addidonally fluoride. Estorified carboxyl can also be set free enzymadcally, for oxample by esterases or suitable pepddases, o.g. esterified arginine or lysine, such as Iy8ine methyl ester, by means of trypsin. As an intemal ester, such as a ~y-lactone, protected carboxyl can be set free by hydrolysis in the presence of a hydroxide containing base, such as of aL~aline earth metal hydroxide or in pardcular of an alkali metal hydroxide, e.g. NaOH, KOH or LiOH, particularly LiOH, the correspondingly protected hydroxyl ~oup being simultaneously set free.

A protected amino group is protected by an amino protecdve g~oup, e.g. in the form of an acylamino, arylmethylamino, etherifled mercaptoamino, 2-acyl-lower aL~-l-enylamino or silylamino group or as an azido group.

In an acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid ha~ing e.g. not more than 18 carbon atoms, in particular a lower alkanecarboxylic acid which is unsubsdtuted or substituted, e.g. by halogen or aryl, or of benzoic acid which is unsubsdtuted or subsdtuted, e.g. by halogen, lower alkoxy or nitro, or preferably of a carbonic acid hemiester. Such acyl groups are prefesably lower aL~anoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, e.g. 2-haloacetyl, such as 2-chloro, ~ ,, 'X~

21~99~3 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl which is unsubstituted or substituted by, e.g. by halogen, lower aL~oxy or nitro, such as benzoyl, 4-chlorobenzoy~, 4-methoxybenzoyl or 4-nitrobenzoyl, lower allcoxycarbonyl, lower aL~oxycarbonyl which is preferably branched in the l-position of the lower aL~yl radical or substituted in the l- or 2-position, e.g. tert-lower aL~coxycarbonyl, such as tert-butoxycarbonyl, arylmethoxy-carbonyl having one, two or three aryl radicals which are phenyl which is unsubstituted, mono- or polysubstituted e.g. by lower aL~yl, in particular tert-lower aLkyl, such as tert-butyl, lower a1~oxy, such as methoxy, hydroxyl, halogen, such as chlorine, and/or nitro, e.g. benzyloxycarbonyl, 4nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl,9-fluorenylmethoxycarbonyl or di-(4methoxyphenyl)methoxycarbonyl, aroylmethoxy-carbonyl, in which the aroyl group is preferably benzoyl which is unsubstituted or substituted, e.g. by halogen, such as bromine, e.g. phenacyloxycarbonyl, 2-hal~lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo-ethoxycarbonyl, 2-(trisubstituted silyl)-lower aL~oxycarbonyl, e.g. 2-tri-lower aLtcyl-silyl-lower alkoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methylsilyl)ethoxycarbonyl, or triarylsilyl-lower alkoxycarbonyl, e.g. 2-triphenylsilyl-ethoxycarbonyl.

In an arylmethylamino group, e.g. a mono-, di- or in particular triarylmethylamino group, the aryl radicals are in particular unsubstituted or substituted phenyl radicals. Such groups are o.g. bonzyl-, diphenylmethyl- or in particular tritylamino.
`:
In an etheri~led mercaptoamino group, the mercapto group i8 primarily present as a substituted arylthio or aryl-lower allcylthio, in which aryl is, for exa nple, phcnyl which is unsubstituted or substituted, e.g. by lower alkyl, such as methyl or tert-butyl, lower a1koxy, such as methoxy, halogen, such as ch10rine, and/or nitro, e.g. 4nitrophenylthio.

In a 2-acyl-lower-aL~-l-enyl radical which can be used as amino protecdve group, acyl is e.g. the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid which is unsubstituted or subsdtuted, e.g. by lower all~yl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, andlor nitro, or in particular of a carbonic acid hemiester, such as a carbonic acid lower alkyl hemiester. Conesponding protecdve groups are primarily l-lower alkanoyl-lower aL~ en-2-yl, e.g. l-lower alkanoylprop-l-en-2-yl, such as 1-acetylprop-l-en-2-yl, or lower alkoxycarbonyl-lower allc-l-en-2-yl, e.g. lower alkoxycarbonylprop-l-en-2-yl, such as l-ethoxycarbonyl-prop-l-en-2-yl.

~1~99~3 A silyla nino group is, for example, a tri-lower alkylsilylamino group, e.g. tlimethylsilyl-amino or tert-butyldirnethylsilylamino. The silicon atom of the silylamino group can also only be substituted by two lower alkyl groups, e.g. methyl groups, and the amino group or carboxyl group of a second molecule of the formula I. Compounds containing such protective groups can be prepared e.g. using the corresponding chlorosilanes, such as dimethylchlorosilane, as silylating agents.
, . :
An amino group can also be protected by conversion into the protonated forrn; suitable acid anions are especially those of strong inorganic acids, such as of sulfuric acid, phosphoric acid or hydsohalic acids, e.g. the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino protective groups are lower allcoxycarbonyl, phenyl-lower aL~coxy-carbonyl, fluorenyl-lowa aLlcoxycarbonyl, 2 lower alkanoyl-lower alk-1-en-2-yl or lower aL~oxycarbonyl-lower alk-l-en-2-yl, e.g. tert-butoxycarbonyl or benzyloxycarbonyl.

Bivalent amino psotectivc groups, such as mono- or disubstituted methylidene groups, such as l~lower alkoxy ~for example mothmy or ethoxy)-lower dkylidene (for exarnple othylidene or l-n-butylidene), e.g. =C(CH3)(0C2HS), and also o.g. =C(CH3)2 or -CH-phenyl, and, in pasticular, bisacyl radicals, o.g. the phthalyl radical, which together with the nitrogen atom to be psotected forms a lH-isoindole-1,3(2~-dione (phthalimido group), ase also preferred.

A protected amino group is set fr~e in a maMer known per se and, despending on the type of the protective groups, in various manners, preferably by means of solvolysis or reduction. Lower aL~oxycarbonylamino, such as test-butoxycarbonylamino, can be cleaved in the presence of acids, for example mineral acids, e.g. hydsohalic acid, such as hydrochlosic acid or hydrobromic acid, in pasticular hydrobromic acid, or of sulfuric or phosphosic acid, preferably of hydrochloric acid, in polar solvents, such as water or a carboxylic acid, such as acetic acid, or ethers, preferably cyclic ethers, such as dioxane, 2-halo-lower aL~coxycarbonylarnino (if desired after conversion of a 2-brom~lower aLkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroyl-methoxycasbonylamino or ~nitrobenzyloxycarbonylamino can be cleaved e.g. by treating with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acedc acid. Aroylmethoxycarbonylamino can also be cleaved by treadng -32- 21099~

with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenoxide, and 4-nitrobenzyloxycarbonylamino can also be cleaved by ~eating with an aL~ali metal, for example sodium dithionite. lJnsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-(trisubstituted silyl)-lower alkoxycarbonylamino, such as 2-tri-lower aL~ylsilyl-lower aL~coxycarbonylamino, can be cleaved by treating with a suitable acid, e.g. formic or trifluoroacetic acid, unsubstituted or substituted benzyloxy-carbonylamino, e.g. by means of hydrogenolysis, i.e. by treating with hydrogen in the presence of a suitable hydrogenation catalyst, such as of a palladiwn catalyst, preferably in polar solvents, such as di-lower aLtcyl-lower aLkanoylarnides, e.g. dimethylforrnamide, ethers, such as cyclic ethers, e.g. dioxane, or alcohols, such as methanol, ethanol or propanol, methanol being particularly preferred, unsubstituted or substituted tliarylmethyl-amino or formylamino, eg. by treating with an acid, such as mineral acid, e.g. hydrochloric aeid, or an organic acid, e.g. formic, acetic or trifluoroacetic acid, if desired in the presence of water, and an amino group protected as silylamino can be set free e.g. by means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, e.g.
2-ehloroaeetyl, can be set free by treating with thiourea in the presence of a base, or with a thiolate salt, sueh as an alkali metal thiolate of the thiourea,, and subsequent solvolysis, such as aleoholysis or hydrolysis, of the resultant substitudon product. An amino group protected by 2 (trisubsdtuted silyl)-lower allcoxycarbonyl, such as 2-tri-lower a1kyl-silyl-loweralkoxycarbonyl, can also be converted into the free amino group by treating with a salt of hydrofluorie acid yielding fluo~ide anions such as indicated in coMection with the release of an appr~pTiately protected carboxyl group. Silyl, such as tamethylsilyl, bonded direedy to a hetero atom, such as nitrogen, can likewise be removed by means of fluoride ions. The removal of the phthalyl group can be carTied out e.g. by means of hydrazino hydrate or by means of an acid, eg. of a mineral acid, such as hydrochloric acid, or of an organie aeid, sueh as aeetie acid1 if desired in the presence of organic solvents, o.g. methanol or tetrahydrofuran.

Amino protected in the form of an azido group is converted into free amino e.g. by reducdon, for oxample by catalydc hydrogenation with hydrogen in the pTesence of a hydrogenation catalyst, such as platinum oxide, palladium c¢ Raney nickel, by reduction by means of mercapto compounds, such as dithiothreitol or mercaptoethanol, or alternatively by treating 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, e.g. dichloromethane, or alternatively in water oq a mixtu~e of water and an organic solvent, such as an alcohol or dioxane, at about 20C to 25C, or alternatively 2109~93 :
with cooling or hea~ng.

A hydroxyl group can be protected, for example, by an acyl group, e.g. unsubstituted lower a1kanoyl or lower aLIcanoyl which is substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or in particular by an acyl radical of a carbonic acid hemiester mentioned for p~otected amino gzoups. A preferred hydroxyl protective group is, for example, 2,2,2-trichloroethoxycarbonyl, 4nitrobenzyloxycarbonyl, di- or triphenyl-methoxycarbonyl. A hydroxyl group can additionally be protected by tri-lower aL~cylsilyl, e.g. trimethylsilyl, triisopropylsilyl or tert-butyl dimethylsilyl, an easily removable etherifying group, e.g. an a1kyl group, such as tert-lower alkyl, e.g. tert-butyl, an oxa- or a thiaaliphadc or -cycloaliphatic, in particular 2-oxa- or 2-thiaaliphatic or -cycloaliphatic, hydrocarbon radical, forexarnple l-lower alkoxy-lower alkyl or l-lower alkylthio-lower alkyl, such as methoxymethyl, l-methoxyethyl, l-ethoxyethyl, methylthiomethyl, l-methylthioethyl or l-ethylthioethyl, or 2-oxa- or 2-thiacycloaL~cyl having 5-7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, a thia analogue thereof or by l-phenyl-lower alkyl, such as benzyl, diphenylmethyl or trityl, where the phenyl radicals can be substituted, for example, by halogen, e.g. chlorine, lower alkoxy, e.g. methoxy, and/or nitro.

Two, in par~cular, adjacent hydroxyl groups occluring in a molecule or an adjacent hydroxyl and amino group, can be protected, for example, by bivalent protective groups, such as a mothylcne group which is preferably substituted, for example by one or two lower al~yl radicals or oxo, e.g. by unsubstituted or substituted allcylidene, e.g. lower alkylidene, such as isopropylidene, cycloaL~cylidene, such as cyclohexylidene, a carbonyl group or benzylidene.

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

A protected hydroxyl group is preferably protected by tri-lower allcylsilyl or as a lactone, in pardcular by tert-butyl-dimethylsilyl.

A mercapto group can in pardcular be protected by S-alkylation with unsubsdtuted or substituted allcyl radicals, silylation, thioacetal formation, S-acylation or by the formation of asymmetric disulfide g~oups. Prefe~ed mercapto protective groups are, for example, benzyl which is unsubstituted or substituted in the phenyl radical, e.g. by methoxy or nitro, such as 4-methoxybenzyl, diphenylmethyl which is unsubstituted or substituted in the phenyl radical, e.g. by methoxy, such as di-(~methoxyphenyl)methyl, triphenylmethyl, pyridyldiphenylmethyl, trimethylsilyl, benzylehiomethyl, tetrahydropyranyl, acylamino-methyl, such as acetamidomethyl, is~buty~ylacetamidomethyl or 2-chloroacetamid~
methyl, benzoyl, benzyloxycarbonyl or aL~cyl-, in particular lower aL~cylaminocarbonyl, such as ethylaminocarbonyl, and also lower aLkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfQ

A hydroxyl or macapto group protected by a suitable acyl group, a tri-lower alkylsilyl group or by unsubstituted or substituted l-phenyl-lower aL~yl is set free analogously to an appropriately protected amino group. A hyd~oxyl or mercapto group protected by 2,2-dichloroacetyl is æt freo e.g. by basic hydrolysis atld a hydroxyl or mercapto group proteeted by tert-lower-alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloa1iphatic hydrocarbon radieal is set free by acidolysis, e.g. by treating with a mineral acid or a strong earboxylie aeid, e.g. trifluoroacetie aeid. Mereapto protected by pyridyldiphenyl-mothyl ean be set free e.g. by mercury(II) salts at pH 2-6 or by zine/aeetie aeid or eleetrolytie rcduetion, acetamidomethyl and iso-butyrylamidomethyl ean be set free e.g.
by reaedon with mercury(I~ salts at pH 2-6, 2-ehloroaeetamidomethyl ean be set free e.g.
by l~piperidinothioearboxamido, and S-ethylthio, S-tert-butylthio and S-sulfo can be se~
free e,g. by thiolysis with thiophenol, thioglycolie aeid, sodium thiophenoxide or 1,4~dithiothreitol. Two hydroxyl groups or an adjacent amino and hydroxyl group, which are togoth¢r proteeted by means of a bivalent protective group, preferably ¢.g. a methylene group whieh is monosubstituted or disubstitut¢d by lower aL1cyl, sueh as by lower alkylidono, e.g. isopropylidene, eyeloalkylidene, e.g. eyelohexylidene, or benzylidene, ean be set free by aeidic solvolysis, preferably in the presence of a mineral aeid or of a strong organie aeid. A tri-lower allcylsilyl g~oup is likewise removed by acidolysis, e.g. by mineral aeid, preferably hydrofluorie acid, or a strong earboxylie aeid. ~Halo-lower aLkoxyearbonyl is removed by the abovemendoned redueing agents, e.g. redueing metal, sueh as zine, redueing metal salts, sueh as ehromiumaI) salts, or by sulfur eompounds, for example sodium dithionite or preferably sodium sulfide and earbon disulfide. E~sterified hydroxyl groups, e.g. lower alkanoyloxy, sueh as aeetyloxy, can also be set free by esterases, and acylated amino, for example, by suitable peptidases.

A sulfo group can be proteeted for example by lower alkyl, e~g. methyl or ethyl, by phenyl or as a sulfonamide, for example as an imidazolide.

2 1 0 ~ 3 A sulfo group protected as the sulfonic acid ester or sulfonamide is set free, for example, by acidic hydrolysis, e.g. in the presen~e of mineral acid, or preferably by basic hydrolysis, e.g. using aL~cali metal hydroxide or alkali metal carbonate, for example sodium carbonate.

If necessary, oxo is protected during acetal formadon, e.g. with lower aL~anols, in particular with ethane-1,2-diol, it being possible to remove the pr~tective group at a desiIed stage by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid, and if necessary thioxo-lower alkyl is protected by thioacetal formadon, e.g. with lower alkylmercaptans~ such as ethane-1,2-dithiol, it being possible to remove the protective group at the suitable time by hydrolysis in the presence of an acid, such as acedc acid or sulfuric acid.

Thè temperatures for the release of the protected functional groups are preferably between -80 and 100C, especially betwoen -20 and 50C, e.g. between 10 and 35C, such as in the region of room temperature OT at roflux temperature.

In thG presence of so~rer~ll protected functional groups, if desired, the protective groups can be selectcd such that more than one such g~oup can be removed simultaneously, for exampb by aeidolysis, such as by treadng with tdfluoroacedc acid, or with hydrogen and a hydrogenatlon eatalyst, such as a palladium~rbon eatalyst. Conversely, the g~oups ean also be seleeted sueh that they eannot all be remo~red simultaneously, but in the desired ~equenee, the eolre~onding intermediates being obtained.

The stardng materials of the formula II' are prepated e.g. by reacdng a eyelohex~diene of the formula V

Me3SiO COOR3 Il 11 (V) Me3SiO~ COOR4 in whieh Me is methyl (other lower ~l~yl groups could altematively be present) and in wbieh R3 and R4 are as defined for compounds of the formula II', with an aniline of the fo~mula VI

9 9~ ~ -AHN-Ar (VI) in which A is in particular hydrogen or substituted lower allyl, substituted lower aLkenyl, substituted lower aLkynyl or heterocyclyl-lower aL~cyl, such as defined above for Al or A2, and in which Ar is aryl, heteroaryl or unsubstituted or substitl ted cycloaL~cyl, such as defined above for Arl or Ar2, with acid catalysis [see Matlin, Stephen A. and Barron, Kenneth, J. Chem. Res. Synop. ~, 24~247 (1990)]. In ~he star~ng materials, functional groups which are not intended to participate in the rcaction are protected if necessary. If necessary, protective groups present are removed in a suitable reac~on stage. Protective groups, their introduction and their removal have already been described above.
Substituents on thc radicals Ar can also bc introduced aftcr the condensation by methods of classical aromatic or heterocyclic chemistry or enz)nnatic methods (e.g.
4-hydroxylation) .

The preparation of the compounds of the formula V is carried out e.g. via a Mels-Alder reaction from a 2,3-bis(tri-lower alkyldlyloxy)butadiene and a di-lower aL~yl acotylenedicarboxylate, is likewise describcd in the literature indicated (Matlin et al.) and can be c~ied out analogously to the manner described there.

To propare unsymmetrical compounds of the formula II', in which Al and A2 and/or Arl and Ar2 are different, compounds of the formula V, for example, can be reacted with two different compounds of the formula VI - e.g. stepwise - and the desired compounds of the formula ~' isolated by a chromatographic separation, e.g. on silica gel.

E urthormore, to prepare compounds of the formula ~' in which ~e radica1s are as dofined apart f~om lower alkylene formed from Al and A2 together and substituted by substituents other than lower allyl or hydroxyl, for example compounds of the f~mula Il' in which, instead of Al and A2, hydrogen is present, are reacted with a reagent of the formula V~
Alk-L (VII) in which Alk is substituted lower aL~cyl, substituted lower aL~cenyl, substituted lower al~ynyl or heterocyclyl-lower alkyl, as mentioned above in the definition of Al and/or A2, where L in the case of substituted lower alkenyl or substituted lower aL~cynyl, is preferably bonded to a carbon atom from which no muldple bond commences, and is selected such 2109~3 that the reaction takes place more rapidly by substitution than the addition to the multiple bond; and L is a nucleofugie group, preferably aliphatic- or aromatic-substituted sulfonyloxy, e.g. methanesulfonyloxy or p-toluenesulfonyloxy (tosyloxy), halogen, in particular chlorine, bromine or iodine, or cyano, or in the case where the radical AL~
contains two or more carbon atoms, is oxa (-O-) or thia (-S-), which is bonded to two vicinal carbon atoms (an oxirane or thiirane being formed which during alkylation, which is in particular carried out 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, e.g. at 80 to 100C, in an acid arnide, sueh as dimethylformamide, or a urea derivative, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (I)MPU), and during subsequent hydrolysis reacts with the formation of a 2-hydroxy- or 2-mereapto-lower alkyl group), or aza(-NH-), which is bonded to two vicinal carbon atoms (an azirane being formed, which during reaction, which is carried out, in pardeular, in the preænee of a strong base, sueh as lithium diisopropylamide, sodium amide or especially sodium hydride, at temperaturvs between 50C and the boiling point of the reaedon mixture, e.g. at 80 to 100C, in an acid amide, sueh as dimethylfo~mamide, or a urea deri~advej sueh as 1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidinone (DMPU), and during subsequent hydrolysis reaets with the formadon of a 2-amino-lower al~yl group), funedonal groups in starting materials whieh are not intended to partieipate in the reaedon being present in free or proteeted form, and proteedve groups present if neeessary being removed in suitable reaedon steps.

The reaedon preferably takes plaee in the presenee of a strong base, sueh as an alkali metal hydride, e.g. sodium hydride, an al~ali metal amide, sueh as sodium amide, or an aL~ali metal di-lower alkylamide, sueh as lithium diisopropy1amide, in partieular of sodium hydride or sodium amide, whieh ean be added e.g. as a dispersion in oil, in pardeular using an equimolar amount or an exeess of the base, for example 1 to S times the molar amount, especially 1 to 2 tdmes the molar amount, relative to the molar amount of the compound of the formula II' in whicb instead of Al and A2 one hydrogen atom is present in eaeh ease, at temperatures between room temperature and the reflux temperature of the reacdon mixture, in particular bet~,veen about 80 and about 100C, in aprotdc, in pardcular polar, solvents, sueh as acid amides, e.g. dimethylforma~nide, 1,3-di-methyl-3,4,5,~tetrahydro-2(1H)-pyrimidinone (DMPU) or hexamethylphosphoramide, or mixtures of such solvents, in the presence or absence of protective gas, such as argon or nitrogen, where if alkali metal amides are used as bases, resultant ammonia is removed by applying a vacuum, e.g from 0.1 to 100, in particular from O.S to 10 mm Hg.

-38- 21099~3 ~

If compounds of the formula I are to be prepared in which only one of the radicals Al and A2 is defined as above apart from hydrogen, while the other is hydrogen, the reaction is carried out using a molar amount of the compound of the formula VII, which preferably corresponds to 0.2 to 2 dmes the molar a nount, e.g. 1 to 1.6 times the molar amount, reladve to the molar amount of the compound of the formula II' in which, instead of Al and A2, hyd~ogen is present. If both hydrogen atoms in the compound of the formula II' in which, instead of Al and A2 hydrogen is present, are replaeed by the radicals mendoned in the definition of Al and A2 apart from hydrogen, an-excess, e.g. a 2- to 10-, in particular an about 2- to 3-fold excess of the compound of the formula VII is preferably employed.

The eompounds of the formula V, VI and VII are knownj eommercially available, or can be prepared by processes known per se.

In the eompounds of the formula VII, ALlc is preforably substituted by protected amino, in particular as protected amino-lower alkyl, e.g. phthalimido or phthalimido-lower a1kyl, sueh as phthalimidopropyl, or lower alkanoylamino-lower alkyl, such as 3-acetylaminopropyl, for example by lower alkoxyearbonyl, such as tort butylox~rearbonyl, mono-lower allcylamino whieh is protected and unsubstituted in the mono-lowa-alltyl radieal or subsdtutod as above (and then if neeessary protected on the 8ubsdtuonts); in pardeular in corrrespondingly protected and substitutod mono-lower aL~tylamino-lower alkyl; di-lower aL~cylsmino whieh is unsubstituted in the two N-lower alkyl radieal8 or subsdtuted as defined above (and then if necessary protected on substituents); in partieular in colrespondingly unsubstituted or substituted di-lower aL~ylamino-lower alkyl; N-protected cyeloalkylamho, in partieular in N-protectedeycloalkylamho-lower allcyl; N-protected phenyl-loweral~ylamino, in partieular in N~proteeted phenyl-lower alkylamino-lower aL~yl; *proteeted phenylamino in partieular in N-proteeted phenylamino-lower aL~cyl; aeylamino, sueh as in aeylamino-lower a1kyl;
proteeted hydroxyl, in particular in hydroxyl-lower alkyl, in whieh the hydroxyl group is present in protected form; lower alkoxy, in whieh the terminal lower allyl radieal is unsubstituted or substituted as above (and then if neeessary with protected substituents), such as in eorresponding substituted protected or unsubstituted lower aLtcoxy-lower allyl;
phenyl-lower allcoxy, in paTtieular in phenyl-lower aL~oxy-lower aLkyl; aeyloxy, in partieular in acyl-lower alkoxy-lower alkyl; proteeted mercapto, in particular in mercapto-lower alkyl, in whieh the mereapto group is present in protected form; lower alkylthio, in which the terminal lower alkyl radieal is unsubstituted or substituted as above 39 æ10~9~'~

(and then if necessary with protected substituents), in particular in correspondingly substituted protected or unsubstituted lower alkylthio-lower aLl~yl; phenyl-lower aLkylthio, such as in phenyl-lower aLIcylthio-lower aL~cyl; acylthio, such as in acylthio-lower aL~yl, protected earboxyl, sueh as in protected earboxy-lower aL~yl; esterified earboxyl, sueh as in esterified earboxy-lower aLkyl; cyano, sueh as in eyano-lower alkyl; oxo, such as in oxo-lower aLI~yl (if necessaTy protected by acetal formation, e.g. with lower aL~canols, in particular with ethane-l ,2-diol, it being possible to remove the protective group in the desired step by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid);
thioxo, in particular in thioxo-lower a11cyl (if necessary protected by thioacetal formation, e.g. with lower aL~cylmereaptans, such as ethane-1,2-dithiol, it being possible to remove the proteetive group at a suitable time by hydrolysis in the presence of an aeid, such as aeetie aeid or sulfurie aeid); arld/or heteroeyelyl, sueh as in heteroeyelyl-lower aLkyl whieh is proteeted if neeessary.

If, instoad of a eompound of the formula VII, a eorresponding compound is used in which a halogen atom is present on the radieal ALk, which here is lower aLlcyl substituted as defined above for A1 and A2, additionally to ono of the nueleofugie radieals L mentioned, tho eorresponding substituted lower alkenyl eompound ean be obtained by elimination of hydrogen halide in the presenee of the base used for reaetion, e.g. of sodium amide, which o.g. is employed in exeess, under the abovemçntionedreaetion eonditions. Analogously, eorresponding substituted lower alkynyl radieals ean be obt~uned from analogues of the eompound of the formula VII, in whieh two further halogen atoms are prosent additionally to one of the nueleofugie radieals L mentioned.

In eompounds of the formula II' obt~unable, earboxyl groups whieh are present in Al and/or A2 as a substituent ean be eonverted into earbarnoyl, N-mono- or N,N-di-lower alkylearbamoyl, N-hydroxyearbarnoyl or N-phenylearbamoyl groups (also into N-aryl and N-aryl-lower alkylcarbamoyl groups), for example by reaetion with ammonia, a lower alkylamine or a di-lower alkylamine, hydroxylamine or phenyla nine, in the presence of a eondensing agent, e.g. a earbodiimide, sueh as dieyelohexylearbodumide or a polar derivative thereof, in polar organie solvents, such as ethanol, or in the presence of an N,N'-earbonyldiazolide, such as N,N'-dicarbonylimidazole (cf. H. A. Staab, Angew.
Chem. 74, 407~23 (1962)) in inert organic solvents, e.g. chlo~inated hydroearbons, such as diehloromethane or ehloroform, or in ethers, sueh as diethyl ether, tetrahydrofuran or dioxane, via the corresponding earboxylie acid azolide. The corresponding compounds of the formula II' in whieh Al and/or A2 eontains earbamoyl, N-mono- or N,N-di-lower 21~99~ ~

alkylcarbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl are thus obtained.
Corresponding thiocarbamoyl substituents in Al and A2 can be obtained from carboxyl by conversion into a carbonyl halide, e.g. with an inorganic acid halide, such as phosphorus trichloride, phosphorus pentachlo~ide or thionyl chloride, or an organic acid halide, such as oxalyl chloride, and subsequent reaction e.g. with phosphorus pentachloride, hydrogen suffide and ammonia or the amines mentioned.

In compounds of the formula II' in which Al and/or A2 are e.g. a hydroxy-lower aLkyl, the hydroxyl group can be converted by nucleophilic substitution into a hydrazino group or hydrazino group whieh is N-substituted by lower alkyl, aryl and/or aryl-lower aL~yl, a guanidino group or a guanidino group which is N-substituted by lower aL~cyl, aryl and/or aryl-lower aL~cyl. For example, a hydroxy compound can be converted into the eorresponding ester of the aromadc sulfonic aeid by reaetion with aromade sulfonic acids or aedvated derivadves thereof, sueh as the eorresponding aromatic sulfonyl halides, e.g.
toluenesulfonyl halides, sueh as toluenesulfonyl ehloride, in the absenee or preferably presenee of suitable bases, e.g. tertia~y nitrogen bases, sueh as triethylamine or N-methyl norpholine, and these esters then reaeted with hydrazine, guanidine, the appropriately subsdtuted defivadves, or salts thereof, it also being possible for proteetive groups to be present, under the eondidons of nueleophilie subsdtution, preferably in the presenee of organie solvents, e.g. aleohols, sueh as methanol, ethanol or trifluoIoethanol, ketones, sueh as aeetone, nitriles, sueh as aeetonitrile, esters, such as ethyl acetate, ethers, sueh as diethyl ethor, ethylene glyeol dimethyl ether, tetrahydrofuran or dioxane, aeid amidesj sueh as dimethylformamide, bisa1kanesulfines, sueh as dimethyl sulfoxide, aryl aleohols, sueh as phenol, or alternatively of water, or mixtures of these solvents, if desired (e.g. for the reaedon of nitrogen bonded to aryl) in ineft organic solvents, siueh as dimethylformamide or 1,3-dimethyl-3,4,5,~tetrahydro-2(1H) pyrimidinone, with theaddition of strong bases, sueh as sodium amide or sodium hydride. If neeessary, proteedve groups present are femoved. Compounds of the formula II' are obtained in whieh Al and/or A2 eontains substdtuents seleeted from hydrazino, hydrazino substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower aL~yl, guanidino or guanidino subsdtutcd on one, two or all three nitrogen atoms by lower alkyl, aryl or aryl-lower aLkyl.
Those eompounds of the formula II' in whieh subsdtuents seleeted from hydrazino and hydrazino substituted on the ter ninal N atom by lower aL~cyl, aryl and/or aryl-lower alkyl are present, ean also be obtained star~ng from a eorresponding oxo eompound of the formula II' by reaedon thereof with nitrogen bases such as hydrazine ~r hydrazine subsdtuted up to 2 dmes on one of the two N atoms by lower aL~yl, aryl and/or aryl-lower .. . . ., . ~ . ,.. .. . ., ............. ; . , .,. i,.. ~ .. , - ... .. . - , -aLkyl, as described further below for the reaction of an oxo compound with ni~ogen bases and subsequent reduction of a corresponding imino compound obtained, preferably by catalytic hydrogenation with selective hydrogenation catalysts, in particular in the presence of palladium on solid support materials, e.g. on carbon, in polar organic or organic-aqueous solvents or solvent mixtures, in particular in ethers, e.g. cyclic ethers, such as tetrahydrofuran or dioxane, or in alcohols, such as lower aL~anols, e.g. methanol or ethanol, or mixtures thereof, e.g. methanol/tetrahydrofuran mixtures, at temperatures between -20 and 60C, preferably between 0 and 40C, e.g. at about room temperature.

In compounds of the formula II' in which Al and/or A2 is, e.g. a cyano-lower alkyl, cyano groups can be convertedinto carbamoyl or N-lower alkylcarbamoyl groups in compounds of the fonnula Il', by partial hydrolysis, in the sense of a Graf-Ritter reacdon, or via imino-lower aLtcyl ester salts. The condidons in the hydrolysis of the cyano intermediate can be sclected such that the reaction is terminated at the amide stage. For this purpose, hydrolysis wirh acids is particularly suitable, e.g. 80% sulfuric acid (with heating), polyphosphoric acid (at 110-150C), hydrobromic acid/glacial acedc acid (room tcmperature, formic acid or without solvent), HCl gas in ethereal soludon followed by the addition of water or aqueous hydrochloric acid, or boron halides being suitable. The prcparation of N-monoalkylated amides of the formula II' from the corresponding nitriles al80 t~es placo with the aid of the Graf-Ritter reaction. ~or this purpose, the nitriles are reactcd, in tho presence of a strong acid, especially 85-90% sulfuric acid, or alternadvely polyphosphoric acid, formic acid, boron trifluoride or other Lcwis acids, but not aluminium chloridc, with compounds which can fonn carbcnium ions in the acidic medium, e.g. with olefins or alcohols. The imino-lower aL~cyl esters of the formula II' are obtained e.g. by acid-catalyzed additiol~ of alcohols onto the nitrile precursors. This addidon can altematively be catalyzed by bascs, e.g. alkoxides, such as sodium methoxide. If, instoad of alcohols, co~rcsponding mercaptans are employed, for example in the presence of nitrogen bases, such as triethylamine or N-methylmorpholine, the corresponding imino-lower alkyl thioesters arc obtained. The carbamoyl derivadves are obtained from the imino-lower alkyl esters and the corresponding thiocarbamoyl derivadves from the imino-lower aL~cyl thioesters in the sense of a Pinner cleavage by thermal decomposition of the imino ester salts at temperatures above about 80C. The thiocarbamoyl compounds can als~ be obtained directly by reaction of cyano groups with hydrogen sulfide analogously to the partial hydrolysis, for example in the presence of tertiary amines, such as triethylamine.

~9993 Compounds of the formula II' in which Al andlor A2 is e.g. an amidino-lower aLkyl or an amidino-lower aLkyl substituted on one nitrogen atom by not more than two radicals selected from lower alkyl, aryl and aryl-lower aLIcyl, can be prepared as described above by reaction of a corresponding imin~lower allyl ester or imino-lower alkyl thioester precursor (as the acid addition salt, e.g. -(C=NH)-OC2Hs . HCl or -C(=NH)-SC2Hs . HI, prepared as described above from a corresponding cyano compound) by reacting with ammonia or the corresponding amines. The cyano precursors can also be converted into the corresponding free, mono- or disubstituted amidines, for example, by reaction with an alkali metal amide, or by reaction with a primary or secondary ammonium salt, e.g. a primary or secondary ammonium halide. Compounds of the formula II' in which Al and/or A2 contain an amidino substituted on each two nitrogen atoms by aryl, aryl-lower aLltyl or lower alkyl, can be prepared from the compounds (which can be preparedanalogously to the method described above for lower aLkylcarbamoyl), in which informula II, instead of carbamoyl, carbamoyl which is N-subsdtuted in Al and/or A2 by lower alkyl, aryl or aryl-lower aL1cyl is contained as a substituent e.g. by reaction with POCl3 or PCls in the corresponding imido acid chlorides (e.g. -(C-NH-lower a1kyl)-CI), which, after reaction with ammonia or a primary or secondary arnine yield substituted amidines of the formula II' (cf. Chem. Abstr. ~, 91186a (1974)).

In compounds of the formula II' obtainable, amino groups which are present as a substituent in Al and/or A2 can be con~rerted into ureido or ureido substituted on one or both nitrogen atoms by up to one radical in each case selected from lower aL~yl, aTyl and aryl-lowa alkyl, by reacting compounds of the fonnula II', in which e.g. Al and/or A2 is amino-lower alkyl or N-mono-lower alkylamino-lower alkyl, or in which instead of one or both of the radicals Al and A2, an arylamino-lower allcyl and/or an aryl-lower ~Llcyl-amino-lower alkyl is present (can be prepared e.g. by reacdon of compounds of the formula II', in which instead of Al or A2 hydrogen is present, with analogues of the compounds of the formula VII, which apart from the nuclcofugic group L contain a further nucleofugic group, e.g. halogen, under conditions ana10gous to the reaction of compounds of the fonmula ~', in which instead of Al andlor A2 hydrogcn is present, with fresh use of analogous conditdons and substitution of the second nucleofugic radical either by an arylamine or an aryl-lower alkylamine, or of compounds of the formula II', in which Al and/or A2 are a hydroxy-lower alkyl, by converting ~e hydroxyl group into a nucleofugic radical, e.g. by treatment with an aromatic sulfonyl halide, such as toluenesulfonyl chloride, and then reacting this with an arylamine or aryl-lower aLkylamine under conditions analogous to the reaction of compounds of the fonnula II', in which instead of ælo~

Al and/or A2 hydrogen is present, with compounds of the fonnula VII), with a lower allyl, aryl or aIyl-lower aLkyl isocyanate or N-protected isocyanate (e.g. benzyl isocyanate), preferably in an ether, e.g. a cyclic ether, such as tetrahydrofuran, at preferred temperatures between -20 and 60C, in particular at about room temperature, where functional groups which are not intended to participate in the reaction are protected if necessary, and protectivo groups present are removed in a suitable reaction step.

Analogously, in compounds of the forrnula II' amino groups which ale present in Al and/or A2 as a subsdtuent, can be converted into thioureido or thioureido substituted on one or both nitrogen atoms by up to one radical selected from lower aL~yl, aryl or aryl-lower alkyl in each case, by using corresponding thioisocyanates instead of the isocyanates.

Compounds of the formula II' in which Al and/or A2 are, e.g. a ureido-lower aL~cyl substituted on the terminal nitrogen by 2 radicals selected from lower aLkyl, aryl and aryl-lower alkyl, can be prepared, for example, by reacting corresponding amino-lower alkyl compounds of the formula II' with phosgene or analogues thercof, e.g.
N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole (cf. H.A. Staab, Angew.
Chem. ~, 407423 (1962)), and then reacting the resulting chlo~ocarbonyl- or azo}idocarbonyl-amino compounds with ammonia substituted by 2 radicals selected from lowor allcyl, aryl and a~yl-lower alkyl, or conversely reacting the corresponding amino lower a1kyl compounds of the formula II' with tho reaction product of ammonia substituted by 2 radicals selected from lower alkyl, aryl and aryl-lower a1kyl, with phosgene or analogues thcreof, c.g. the N,N'-carbonyldiazolides, such as N,N'-carbonyldi-imidazole, to obtain the correspondingly substituted ureido compounds. The reactions are preferably calried out in inert solvents, in particular chlorinated hydrocarbonsj such as dichloromethane or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxanc, or acid amides, such as dimethylformamide, at temperatures between -20C and the reflux temperature, in particular between 0 and 30C.

Compounds of the formula Il', in which Al and/or A2 contain e.g. a thioureido lower a1kyl substituted on the terminal nitrogen by 2 radicals selected from lower alkyl, aryl and aryl-lower alkyl, can be prepared in an analogous manner, for example, by reacting corresponding amino-lower alkyl compounds of the fo~mula II' with thiophosgene or analogues thereof, e.g. N,N'-thiocarbonyldiazolides, such as N,N'-thiocarbonyl-diimidazole (cf. H.A. Staab, Angew. Chem. 74, 4~7-423 (1962)), and then Teacting the 9~3 resulting chlorothiocarbonyl- or azolidothiocarbonylamino compounds with ammoniawhich is substituted by 2 radicals selected from lower alkyl, aryl and aryl-lower aLkyl~ or conversely, reacting the corresponding amino-lower aL~cyl compounds of the formula II' wi~h the reaction product of ammonia substituted by 2 radicals selected from lowel aLIcyl, aryl and aryl-lower aLIcyl, with thiophosgene or analogues thereof, e.g. the N,N'-thio-carbonyldiazolides, such as N,N'-tbiocarbonyldiimidazole.

In compounds of the formula II', a hydroxy-lower alkyl Al and/or A2 e.g. can be oxidized to the corrcsponding oxo compound. In the case of primary alcohols, the use of selective oxidizing agents is ncccssary for this purposc, e.g. of potassium ferratc (K2FeO4) in aqueous solvents and manganese dioxide in organic solvents, tert-butyl chromate,pyr~dinium dichromate or in particular pyridinium chlorochromate in inert organic solvents, e.g. chlorinated hydrocarbons, such as dichlor~methane or chloroform. The reaction prefcrably takcs placc at temperatures between -20C and the reflux temperature, o.g. at about 0 to 40C. In the case of secondary alcohols oxidadon can additionally be car~iod out using less selective oxidizing agents, such as chromic acid, dichromate/sulfuric acid, dichromate/glacial acetic acid, nitric acid, manganese dioxide, selenium dioxide or dimethyl sulfoxide in tho presenco of oxalyl chloride, in water, a~ueous or organic solvents, such as halogenated hydrocarbons, e.g. dichloromethane, or carboxamides, such as dimethylformamide, prefcrably at temperatures between -50C and reflux temperature, in particular between -10 and 50C. Compounds of the formula II' are obtained in which the radical Al and/or A2 carries oxo.

Compounds of the formula II' in which Al and/or A2 contain imino, lower alkylimino, acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower aL~ylhydrazono andlor N-acylhydrazono, e.g. as subsdtuents in a subsdtuted lower aL~yl, can be prepared from corresponding oxo compounds of the formula ~', either aftcrisolation of the oxo compounds or preferably by their direct reuse as a crude product, for exarnple after partial evaporation to remove the solvent, in which the oxidation (preferably carried out as last descIibed) of a hydroxy to an oxo compound.

Thus, an oxo compound can be converted by reaction with nit ogen bases selected from ammonia, lower alkylamines, hydroxylamine, lower a11coxyamine, hydrazine, N-mono- o~
N,N-di-lower aLkylhydrazine and N-acylhydrazine into a corresponding imino derivative.
The reaction condidons correspond here to the customary conditions for the reaction of carbonyl compounds with nitrogen bases, the nitrogen base being used, for example, as a ~9~

salt of an acid, e.g. of a hydrohalic acid, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, particularly preferably hydrochloric acid, of sulfuric acid or a hydrogen sulfate, such as an aLl~ali metat hydrogen sulfate, e.g. sodium hydrogen su1fate, of phosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, e.g. of an aLkali metal hydrogen phosphate or dihydrogen phosphate, such as sodium hydrogenphosphate, disodium hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen phosphate, or as a salt with an organic acid, in particular with a caTboxylic acid, such as a lower alkanecarboxylic acid which is unsubstituted in the lower aLkyl radical or substituted, preferably by halogen, such as fluorine or iodine, e.g. acetic acid, chloroacetic acid, dichloroacetic acid or trifluoro- or trichloroacetic acid, or with a sulfonic acid, such as a lower aLkylsulfonic acid, e.g. methanesulfonic acid, ethanesulfonic acid orothanedisulfonic acid, or an arylsulfonic acid, such as benzcne- or naphthalenesulfonic acid or naphthalene-1,5-disulfonic acid; it atso being possible to prepare a salt of one of the abovementioned nit~ogen bases with an acid first ~, especially from the corresponding salt of an easity volatile weak acid which can be driven off by a strong acid, such as sulfuric acid or, primarity, one of the hydrohalic acids mentioned, such as a lower alkanecarboxylic acid, e.g. acetic acid, or in particular carbonic acid or hydrogen carbonate, by driving off the weak acid; the reaction taking place in water (in the presence or absence of surfactants), an aqueous solvent mixture, such as a mixture of water with one or more alcohols, e.g. methanol, ethanol or isopropanol, di-lower alkyl sulfoxides, such as dimethyl sutfoxide, or di-lower aLIcyl-lower allcanoylamides, such as dimethyl-formamide, organic solvents, such as a1cohols, e.g. methanol or ethanol, di-lower aLtcyl sulfoxides, such as dimothyl sulfoxide, di-lower alkyl-lower alkanoylamides, such as dimethylformamide, or in sufficiently inert nitrites, such as acetonitrite, a mixture of such organic solvents, or without solvent in a melt, preferably in an alcoholic solution, such as in methanol, ethanol or in particutar isopropanol; preferably at temperatures between -20C and the reftux temperature of the reaction mixture in the prescnce of a solvent, in the case of melting up to 220C, in particular at temperatures from 0 to 50C in the presence of a solvent, especially at about room temperature.

Oxo compounds of the formula II' obtainable in such a way can be converted into the corresponding thioxo compounds, for example by reaction with phospho~us pentasulfide or preferably phosphorus pentasulfide substitutes, such as Laweson's reagent (=
2,4-bis(~methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane), the reaction being carried out in inert organic solvents, for example in a halogenated hydrocarbon, such as dichloromethane, at temperatures from 30C up to the reflux temperature, in par8cular ~109~3 under reflux.

Compounds of the formula II', in which Al and/or A2 contain acylamino substituents, e.g.
as substituents in a substituted lower aLkyl, can be obtained from cQrresponding imino starting materials by reaction thereof with a free acid which contains the acyl radical to be introduced, for example in the presence of condensing agents, such as carbodiimides, e.g.
dicyclohexylcarbod1imide or with an acdvated acid derivadve thereof, e.g. a carboxylic acid halide, if appropriate in the presence of a s~itable base, e.g. a tertiary amine, as already defined, preferably with the exclusion of moisture.

Compounds of the folmula I~' in which A~ and/or A2 carry lower alkylthioimino substituents, e.g. on substituted lower alkyl, can prcfcrably bc prepared by reacting corrcsponding imino starting materials of the formula II' using lower alkylsulfenyl halides (which can be prepared e.g. from sulfenic acids using hydrogen halidcs or chlo~olysis, bromolysis or iodolysis of corresponding organosulfur compounds, it also being possible for the preparation to be car icd out in situ), in particular lower alkcnylsulfcnyl halides, such as methylsulfcnyl 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, e.g. hydrocarbons, such as heptane, ethers, such as diothyl cther, dioxane or tetrahydrofuran, or carboxamides, such as dimethylformamide, at preferrod temperatures ~etween OgC and reflux temperature, in particular between 0 and 30C.

In this place, it may be expressly noted that compounds of the formula II' in which A
and/or A2, additionally to or instead of substituted lower allcyl, are selected from substitutcd lower a1kenyl and subsdtuted lower alkynyl, even when these are not explicitly mentioned in the sections for the preparation of compounds of the formula II', can be prepared in an efficient and expedient manner using analogous preparadon processes as described for the compounds of the formula II' containing substituted lowera1kyl radicals.

Compounds of the fonnula II' in which Al and/or A2 is e.g. heterocyclyl-lower aLkyl can be obtained from corresponding compounds of the fonnula II' in which at least onc of the substituents Al and A2 is hydrogen or from corresponding analogues in which instead of Al and A2 hydrogen is in each case present, preferably by reaction with compounds of the fonnula vm 2~ 3 Heterocyclyl-lower aLtcyl-L' (VIII) in which heterocyclyl-lower alkyl is as defined above and L' is a nucleofugic g~up, as defined above for L in compounds of the fofmula VII, with nucleophilic substitu~on of the nucleofugic group L'. The reaction condidons coqTespond here preferably to ~e condidons in the presence of a strong base mendoned under the allyladon reacdon wi~h compounds of the formula VII.

To prepate compounds of the formula II' in which Al and A2 together are lower alkylene which is substituted by substituents other than lower alkyl or hydroxyl, compounds of the formula II', for example, in which"nstead of Al and A2, hydrogen is present, are reacted with an alkyladng reagent of the fonnula IX

Ll-B-L2 :
in whieh B is a substituted lower al~ylene as a bi~alent radical (for example substituted by the substituents montioned in tho def~nition of substituted lower alkylene formed together from Al and A2, and additionally lower alkyl and/or hydtoxyl, whieh are possible as wbstituents in~intennediates), and in whieh Ll and L2 independently of one another are a nueleofugie gr~up, as desclibed abovo forL in the definition of compounds of the formula VIIj whero if noeossary those funetional groups in the statting materials whieh are not intondod to partieipate in the reaclion are protoeted by proteetive groups whieh ate removod in a suitable reaetion step. The preferred proteetive groups, their inttoduetion and their temoval were mentioned above.

Ll i~ preforably a nueleofugie gtoup, in pattieulat aliphatie - or atomatie - substituted sulfonyloxy, e.g. methanesulfonyloxy or p-toluenesulfonyloxy (tosyloxy), halogen, sueh as ehlorine, bromine or iodino, or eyano, while L2, if a lower allcylene radieal B eontains two or more carbon atoms, can be oxa (-0~) or thia (-S-), whieh is bonded to two vieinal earbon atoms (an oxirane ot thiirane being formed whieh reaets during alkyladon, whieh is earried out in pattieularin the presenee of a strong base, sueh as lithium diiso~opylamide, sodiurn amide or espeeially sodium hydride, at temperatures between 50C and the boiling point of the reaction mixture, e.g. at 80 to 100C, in an aeid amide, sueh as dimethylformamide, and during subsequent hydrolysis with fonnation of a l-hydroxy- or l-mercapto-lower alkylene group), or aza (-NH-), whieh is bonded to two vieinal carbon atoms (an azirane being formed, which reaets during aL~yladon, whieh in pardeular takes 21~9~93 place 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, e.g. at 80 to 100C, in an acid amide, such as dimethylformamide, and during subsequent hydrolysis with formation of a l-amino-lower alkylene group).

It i9 also possible that Ll and L2 together are oxo which is bonded to the terminal carbon of B (the compound of the formula IX is then an aldehyde), or are in each case lower aL~oxy (the compound of the fonnula IX is then an acetal). Preferably, B in compounds of the formula ~ is then selected from esterified carboxymethylene, such as lower aLkoxyearbonylmethylene, or lower alkanoylmethylene. The reaction takes place, for example, in the presenee of acids, e.g. hydrohalie acids, sueh as hydrochloric aeid, or preferably in the presenee of Lewis acids, in parlicular SnCl2 (e.g. as the hydrate), in suitable solvents or in solvent mixtures, e.g. ethers, such as di-lower alkoxy-lower allcanes, in partieular l,~dimethoxyethane, at prefer~ed temperatures between 0 and 50C, e.g. at about room temperature, if necessary with addition of water.

The reacdon is preferably earried out under the reaction conditions whieh are described as preferr~d for the reaction of eompounds of the formula II' in whieh, instead of Al and A2, a hydrogen atom is in eaeh ease present, with eompounds of the formula VII.

The eompound of the formula ~C is preferably employed in the equimolar amount or in an oxeoss relativo to the eompound of the formula ~', in whieh, instead of Al and A2, a hydrogen atom is in eaeh ease present, in panieular in the 1- to 3-times molar amount, e.g.
tho 1- to 1.5-times molar amount, sueh as tho about 1.2-timos amount. The strong base omployod is preferably omployed in an oxeess relative to tho eompound of the formula II', in whieh, instead of Al and A2, a hydrogen atom i~ in eaeh ease present, in partieular in tho 2 to 10-times molar amount, e.g. in the 2- to 3-times molar amount.

The reaetion ean be eanied out such that the nueleofugie groups Ll and L2 are substituted virtually simultaneously in one batch, or the nucleofugic groups Ll and L2 ean be substituted successively.

In the eompounds of the formula IX, B is preferably lower alkylene which is substituted by one or more of the following substituents: proteeted amino or amino-lower alkyl, e.g.
phthalirnido or phthalimido-lower alkyl, sueh as phthalimidopropyl, or for example by lower alko~cycarbonyl, such as tert-butoxyearbonyl, mono-lower alkylamino or .

21~93 mono-lower aLkylamino-lower allyl which is protected and unsubstituted or substituted as above in the mon~lower aLkyl radical (and then protected on the substituents if necessary), di-lower aLlcylamino or di-lower allylamino-lower allyl which is unsubstituted or substituted as above in the two N-lower alkyl radicals (and then protected on the substituents if necessary), N-protected cycloaL~cylamino or cycloallylamino-lower aLkyl, N-protected phenyl-lower aL~cylamino or phenyl-lower aLIcylamino-lower alkyl, N-protected phenylamino or phenylamino-lower aL~yl, acylamino or acylamino-loweraLIcyl, hydroxyl (additionally possible in intermediates to the definition of substituted lower aL~cylene formed from Al and A2) or hydroxy-lower aL~cyl, where the hydroxy group is present protected, lower aL~oxy or lower aL~coxy-lower aLkyl, in which the terminal lower alkyl radical is present unsubstituted or substituted as above (and then if necessary with pmtected substituents), phenyl-lower alkoxy or phenyl-lower aL~oxy-lower alkyl, aeyloxy or acyloxy-lower aLIcyl, mercapto or mercapto-lower aL~cyl, in which the mercapto group is present in protected form, !ower alkylthio or lower alkylthio-lower aLkyl, in which the terminal lower aLIcyl radical is present unsubstituted or substituted as above (and then if necessary with protected substituents), phenyl-lower aLkylthio or phenyl-lower alkylthio-lower alkyl, acylthio or acylthio-lower alkyl, pmteeted earboxyl or earboxy-lower alkyl, esterified earboxyl or earboxy-lower aL~yl, cyano or cyano-lower alkyl, oxo or oxo-lower alkyl (if necessary protected by acetal formation, e.g. with lower alkanols, in pa~ticular with ethane-1,2-diol, it being possible for the pmtective group to be romoved in the desired step by hydrolysis in the presence of an acid, such as acedc acid or sulfurie aeid), or thioxo or thioxo-lower aLIcyl (if necessary protected by thio~cetal formation, e.g. with lower aLIcylmereaptan~, such as ethane-1,2-dithiol, it being possible for the protective group to be removed at a suitable time by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid).

In compounds of the formula II' obtainable, earboxyl (in a earboxy or carboxy-lower allcyl group whieh is present in a substituted lower aL~cylene formed from Aland A2 together) ean be converted into earbamoyl, N-mono- or N,N-di-lower-alkylearbarnoyl, N-hydroxy-earbamoyl or N-phenylearbamoyl (also in~o N-aryl- and N-aryl-lower-aLIcylcarbamoyl groups), for example by reaction with ammonia, a lower aLlcylamine or a di-lower aL~yl-amine, hydroxylamine or phenylarnine, or in eaeh ease a salt thereof, in the presence of a condensing agent, e.g. a carbodiimide, such as dicyclohexylcarbodiimide or a polar derivative thereof, in polar organie solvents, such as ethanol, or an N,N'-carbonyl-diazolide, such as N,N'-dicarbonylimidazole (ef. H.A. Staab, Angew. Chem. 74, 407-423 (1962)) in inert organic solvents, e.g. chlorinated hydr~carbons, such as diehloromethane - ~10~9'3 - so or chloro~orm, or in ethers, such as diethyl ether, tetrahydrofuran or dioxane, via the corresponding carboxylic acid azolide. Corresponding compounds of the formula lI' are thus obtained in which a substituted lower aL~ylene formed from Al and A2 together is present, which is substituted by carbamoyl, N-mono- ~r N,N-di-lower-alkylcarbamoyl, N-hydroxycarbamoyl and/or N-phenylcarbarnoyl. Corresponding thiocarbamoyl substituents in substituted lower aL~cylene formed from Al and A2 together can be obtained from carboxyl by conversion into a carbonyl halide, e.g. using an inorganic acid halide, such as phosphorus trichloride, phosphorus pentachloride or thionyl chloride, or an organic acid halide, such as oxalyl chloride, and subsequent reaction e.g. with phosphorus pentachlorido, hydrogen sulfide and ammonia, primaty or secondary amines.

In compounds of the formula II' in which a substituted lower aLlcylene formed from Al and A2 togother is substituted by hydroxyl and/or hydroxy-lower aL~yl, the hydroxy group can be converted by nucleophilic substitution into a hydrazino group or hydrazino group N-substituted by lower alkyl, aryl and/or aryl-lower al~yl, or a guanidino group or a guanidino group N-substituted by lower allcyl, aryl and/or atyl-lower aL~cyl. For example, hydroxyl can be converted by reaction with aromatic 8ulfonic acids or activated derivatives thereof, such as tho corresponding atomatic sulfonyl halides, e.g. toluene-sulfonyl halidesj such as toluenesulfonyl chloride, in the absence or preferably, presence of suitablo basos, o.g. tortiaty nitrogen basos, such as triethylamine or N-methyl-morpholino, into hydroxyl esterifiod by the corresponding aromatic sulfonic acid and then this oster can be reacted with hydrazino, guanidinc, the correspondingly substituted derivative9 or salts thereof, * also being possible forprotecdvc groups to h present, under the conditions of nucleophilic substitution, preferably in the presence of organic solvent8, o.g. alcohol8, such as methanol, ethanol or trifluoroethanol, ketones, such as acetone, nitrilos, such as acetonitrile, esters, such as ethyl acetate, ethers, such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane, acid amides, such as d~nethyl-formamide, bisaL~anesulfines, such as dimethyl sulfoxide, aryl alcohols, such as phenol, or alternadvely of water, or mixtures of these solvents, if necessary (e.g. for the reaction of nitrogen bonded to aryl) in ;nert organic solvents, such as dimethylformamide or1,3-dimethyl-3,4,5,~tetrahydro-2(1H)-pynrnidinone, with addition of strong bases, such as sodium amide or sodium hydride. If necessary, protecdve groups present are removed.
Compounds of the formula II' are obtained in which Al and A2 togetha form a substituted lower allylene containing subsdtuents selected from hydrazino, hydrazino substituted on one or both nitrogen atoms by lower alkyl, a~yl or aryl-lower-aLkyl, guanidino and guanidino substituted on one, two or all three nitrogen atoms by lower alkyl, aryl or 21~9~93 :

aTyl-lower allcyl.

In compounds of the formula II' in which Al and A2 together form a lower aLkylene which is substituted by cyano andJor cyano-lower aL~cyl, cyano groups can be converted e.g. by par~sal hydrolysis, in the sense of a Graf-Ritta reaction, or via imino-lower alkyl ester salts into carbarnoyl or N-lower-allcylcarbamoyl groups in compounds of the formula II'.
The conditions in the hydrolysis of the cyano intermediate can be selected such that the reaction is terminated at the amide stage. Por this purpose, hydrolysis with acids is particularly suitable e.g. 80% su1furic acid (with heating), polyphosphoric acid (at 110-150C), hydrobromic acid/glacial acetic acid (room temperature, fo~mic aeid or without solvent), HCI gas in ethereal solution followed by the addition of water or aqueous hydmehlorie acid, or boron halides being suitable. The preparation of N-monoaL~cylated amides of the formula II' from the corresponding nitriles takes place with the aid of the Graf-Ritter reaetion. For this purpose, the nitriles are reaeted, in the presenco of a strong acid, espeeially 85-90% sulfuric aeid, or alternatively polyphosphoric aeid, formic aeid, boron trifluorido or other Lewis aeids, but not aluminium ehlorido, with compounds whieh ean form earbenium ions in the aeidie medium, e g. with olefins or aleohols. The imino-lower-alkyl esters of the formula II' aro obtained e g. by aeid-eatalyzed addition of aleohols onto tho nitrile preeursors (as salts) This addition ean alternatively be eatalyzed by bases, e.g. allcoxides, sueh as sodium methoxide. If, instead of aleohols, eorresponding mereaptans aro employed, for oxample in the presence of nitrogen bases, sueh as triethylamine or N-methylmorpho1ine, the eorresponding imino-lower aL~yl thioesters are obtained. ~he earbamoyl derivatives are obtained from tho imino-lower aL~yl esters and tho eorresponding thiocarbamoyl derivadves from the imino-lower alkyl thioesters in the sense of a Pinner eleavage by thermal decomposition of tho imino ester salts a~ temperatures above about 80C. The thiocarbamoyl compounds ean also be obtained direedy by reaetion of eyano groups with hydrogen sulfide analogously to the partial hydrolysis, for example in the presence of tertiary nitrogen bases, sueh as triethylamine.

Compounds of the formula II' in whieh a substituted lower a1kylene fonned from Al and A2 together is substituted by amidino, amidino-lower a1kyl, amidino substituted on a nitrogen atom by up to two radicals selected from lower alkyl, aryl and aryl-lower alkyl and/or amidino-lower alkyl substituted on a nitrogen atom by up to two radicals selected from lower aL~yl, aryl and aryl-lower alkyl, can be converted by ~action of the imino-lower alkyl ester or imino-lower aL~ylthio esters prepared as above from ~ ` ;` i . J ~ :

2~9~3 corresponding cyano or cyano-lower-aLIsyl s~ing compounds (as acid addition salts, e.g.
-(C=NH)-OC2Hs.HCl or -Ct=NH)-SC2Hs-HI) by reacting with ammonia, primary or secondary amines. 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 or secondary ammonium salt, e.g. a primary or secondary ammonium halide. Compounds of the formula II' in which Al and A2 together are a substituted lower aL~cylene which carries on each two nitrogen atoms amidino or amidino-lower aL~cyl substituted by aryl, aryl-lower alkyl or lower alkyl as substituents can be prepared from the corresponding compounds (which can be prepared as described above for lower aL~ylcarbamoyl) in which in formula II' carbarnoyl which is N-substituted by lower alkyl, aryl or aryl-lower alkyl is present, e.g. by reaction with POC4 or PCls in tho corresponding imido acid chlorides (o.g. ~(C--NH-lower-alkyl)-Cl), which after reaction with ammonia or a primary or secondary amine yield substituted amidines of the formula II (cf. Chem. Abstr. 81, 91186a (1974)).

In compounds of the foImula II' obtainable, amino radicals occurnng in amino and/or amino~lower al~yl Iadieals (which are present as a subsdtuent in a subsdtuted lower al~yleno formed from Al and A2 together) can be converted into ureido, ureido-lower alkyl or ureido or ureido lower alkyl, subsdtuted on one or both nitrogen atoms by up to ono radieal in eaeh ease seleeted from lower alkyl, an~l or ~-lower alkyl, by reaeting eorresponding amino compounds of tho formula ~' in whieh amino radieals are present, those in whieh N-mono-lower alkylamino radicals are present or those in which, instead of amino, arylamino or aryl-lower-alkylamino is present (whieh can be prepared e.g. by reaedon of compounds of the formula II' in whieh the subsdtuted lower alkylene fo~med from Al and A2 together contains hydroxyl, whieh is eonverted by esterificadon, e.g. by roaction with aromatie sulfonyl halide, sueh as toluenesulfonyl ehloride, into a nueleofugie radieal, e.g. a~omatde sulfonyloxy, analogously to the reaetion of eompounds of the formula I~' in which, instead of Al and A2, hydrogen is present, with eompounds of the formula VII with nueleophilic substitutdon of the nucleofugie aromatdc sulfonyloxy dther with an arylamine or an aryl-lower alkylamine), with a lower alkyl, aryl or aryl-lower a1~yl isoeyanate or an N-proteeted isocyanate (e.g. benzyl isocyanate), preferably in an ether, e.g. a cyelic ether, such as tetrahydrofuran, at prefer~ed temperatures between -20 and 60C, in particular at about room temperature, functdonal groups which are not intended to panicipa~e in the reaetion being proteeted if necessary, and protective groups present being removed if desired.

21~
- ~3 -Analogously, in compounds of the formula II' arnino groups which are present as a substituent in a substituted lower aL~cylene formed from Al and A2 together can be converted into thioureido or thioureido substituted on one or both nitrogen atoms by up to one radical in each case selected from lower aLt~yl, arvl or arvl-lower alkyl, by using corresponding thioisocyanates instead of the isocyanates.

Compounds of the formula II', in which ureido and/or ureido-lower aL~yl subsdtuted on the tcrminal nitrogen by ~wo radicals sel~cted from lower aL~yl, aryl and aryl-lower aLIcyl is prcscnt as a substituent in a substituted lowa aL~ylene formed from Al and A2 together, can be prepared, for example, by reacting corresponding amino compounds of the foqmula II' with phosgene or ana10gues thereof, e.g. N,N'-carbonyldiazolides, such as N,N'-curbonyldiimidazolo (cf. H.A. Staab, Angew. Chem. 74, 407-423 (1962)), and then reacting the resulting chlorocarbonyl- or azolidocarbonylamino compounds with ammonia substituted by 2 radicals selected from lower alkyl, aryl and aryl-lower alkyl, or convorsdy reacting the corresponding amino compounds of the formula II' with thGrcaction product of ammonia substitutcd by 2 radicals selected from lower alkyl, aryl and aryl-lower alkyl with phosgcne or analogucs thereof, e.g. the N,N'-carbonyldiazolides, such as N,N'-carbonyldiirnida~ole, to obtain thc cor espondingly substituted ureido compounds. The reactions are preferably canied out in inert solvents, in particular chlorinated hydrocarbons, such as dichloromethane or chloroform, ethers, such as diethyl other, tetrahydrofuran or dioxane, or acid amides, such as dimcthylformamide, attomperatures botwoon -20C and reflux temperature, in particular botween 0 and 30C.

Compounds of tho formula II', in which thioureido-lower alkyl substitutcd on the terminal nitrogen by 2 radicals selected fmm lower aL~yl, aryl and aryl-lower aL~yl is present as a substituent in a subsdtuted lower al~ylene formed from Al and A2, can be prepared in an analogous manner, for cxample, by reacting corresponding amino compounds of the formula II' with thiophosgene or analogues thereof, e.g. N,N'-thiocarbonyldiazolides, such as N,N'-thioc&rbonyldiimidazole (cf. H.A. Staab, Angew. Chem. 74, 407~23 (1962)), and thes~ reacting the resulting chlorothiocarbonyl- or azolidothiocarbonylamino compounds with ammonia substituted by 2 radicals selected from lower aLIcyl, aryl and aryl-lower aLkyl, or conversely reacting the coIresponding amino compounds of the formula II' with the ~:action pmduct of ammonia substituted by 2 radicals selected from lower aLkyl, aryl and aryl-lower alkyl with thiophosgene or analogues thereof, e.g. the N,N'-thiocarbonyldiazolides, such as N,N'-thiocarbonyldiimidazole.

2~9~3 A compound of the formula II' in which hydroxyl and/or hydroxy-lower-alkyl is present as substituent in a subsdtuted lower allylene fonned from Al and A2 together can be oxidized tO a corresponding oxo compound. In the case of primary alcohols the use of selective oxidizing agents is necessary for this purpose, e.g. of 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, e.g. chlorinated hydrocarbons, such as dichloromethane or chloroform. The reaction preferably takes place at temperatures bet veen -20C and reflux temperature, e.g.
at about 0 to 40~C. In the case of secondary alcohols, the oxidation can additionally be carried out using less selective oxidizing agents, such as chromic acid, dichromate/sulfuric aeid, dichromate/glacial acetie acid, nitric acid, manganese dioxide and selenium dioxide.
Compounds of the formula II' are obta~ned in which a substituted lower alkylene formed from Al and A2 together is substituted by oxo.

Compounds of the fonnula II' in which one or more substituents selected from imino, lower alkylimino, acylamino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono, N-acylhydrazono and a lower al~yl substituted by imino, lowor aL1cylimino, acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower-alkylhydrazono and/or N-acy1hydrazono, are present in a substiluted lower alkyleno formed from At and A2 together, can be prepared from corresponding oxo compourids of the formula ~', dther aftor isoladon of tho oxo compounds or preferably by their direct reuse as a crudo product, for example after pardal ovaporadon to remove the solvent, in which the oxidation of a hydroxy compound to the oxo compound is carriod out, which takes place, for example, as last described.

Thus, tho oxo compounds can be converted into the coIresponding imino derivatives by reaction with ni~ogen bases selected from ammonia, hwer alkylamines, hydroxylamine, lower alkoxyamine, hydrazine, N-mono- or N,N-di-lower-alkylhydrazine and N-acylhydrazine. The Ieacdon condidons are the condidons convendonally used for the reaction of carbonyl compounds with nitrogen bases, using, for example, the nilrogen base in the form of a salt of an acid, for oxample of a hydrohalic acid, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydliodic acid, particularly preferably hydrochloric acid, of sulfmic acid or of a hydrogen sulfate, such as an alkali 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 particular with a carboxylic acid, such as a lower alkanecarboxylic acid which is unsubstituted in the lower allyl ~dical or substituted in the lower aLkyl radical, preferably by halogen, such as fluorine or iodine, for example acetic acid, chloroacetic acid, dichloroacetic acid or trifluor~ or ~ichloroacetic acid, or a sulfonic acid, such as a lower aL~anesulfonic acid, for example methanesulfonic acid, ethanesulfonic acid or e~anedisulfonic acid, or an arylsulfonic acid, such as benzene- or naphthalenesulfonic acid or naphthalene-1,5-disulfonic acid; it also being possible for a sa1t of one of the abovemendoned nitrogen bases with an acid to be prepared only in situ, especially from the eorresponding salt of a readily volatile weak acid, such as a lower aL~anecar~oxylie acid, for example acetie acid, or, in particular, carbonic acid or hydrogen earbonate, which ean be replaced by a strong acid, such as sulfuric aeid or, primarily, one of the abovementioned hydrohalie acids; the reaction taking place in water, an aqueous solvent mixture, sueh as a mixture of water with one or more aleohols, for example mothanol, ethanol ol isopropanol, di-lower-alkyl sulfoxides, sueh as dimethyl sulfoxide, or di-lower alkyl-lower a1kanoylamides, sueh as dimethylformamide, organie solvents, sueh as aleohols, for examplo methanol or ethanol, di-lower-aL~cyl sulfoxides, sueh as dimethyl sulfoxide, di~lower aL~yl-lower-alkanoylamidesi sueh as dimethylformamide, or insuffieiontly inert nitriles, sueh as acotonitrilo, a mixture of sueh otganie solvents, or without solvents in a molt, preferably in an aleoho1ie solution, sueh as methanol, ethanol or, in partieular, isopropanol; preferably at tomperatures botween -20C and the reflux temperature of tho teaetion mixture in tho presenee of a solvont, and melts up to 220C, in partieular at temperatures from 0 to 50C, in the presenee of a solvent, mainly at approximatoly room tomperature.

Compounds of the formula II' in whieh aeylimino and/or aeylimino-lower aLkyl is present as a subsdtuent in a subsdtutod lower aLlcylene formed from Al and A2 ean bo obtained from the eoIresponding imino eompounds by reaedon with the eo~responding freo aeids whieh eontain the aeyl radieal, for example in the presonee of eondensing agents, sueh as earbodiimides, e.g. dieyelohexylearbodiimide, or aedvated aeid deirivatives thereof, e.g.
earboxylie aeid halides, if dosired in the presoneo of a suitable base, e.g. of a tertiary amine, sueh as alteady defined, preferably with exelusion of moisture.

Compounds of the formula II' in which lower alkylene foqmed from Al and A2 together ea ries lower allylthioimino subsdtuents ean preferaUy be prepared by reacting eorresponding imino starting materials of the formula II' using lower alkylsulfenyl ha1ides 2 ~ 3 (which can be prepared e.g. from sulfenic acids using hydrogen halides or chlorolysiss bromolysis or iodolysis of corresponding organosulfur compounds, it also being possible for the preparation to be carried out in SitU), in parlicular lower aL~enylsulfenyl 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, e.g. hydrocarbons, such as heptane, ethers, such as diethyl ether, dioxane or tetrahydrofuran, or carboxamides, such as dimethylformamide, at preferred temperatures between 0C and reflux temperature, in par~cular between 0 and 30C.

The compounds of the formula II are preferably obtained from the compounds of the formula I~' oStainable by hydrolysis, e.g. in an acidic or alkaline medium. Preferably, the hydrolysis of the compound of the formula II' is carried out in an aqueous alcoholic solution of a hydroxy base, e.g. with a solution of an alkali metal hydroxide, such as sodium hydrox1de or potassium hydroxide, in a mixture of water and ethanol or methanol, at preferred temperatures from 0C up to the reflux temperature of the corresponding reaction mixture, in pa~icular between about 60C andreflux temperature. The reaction is panicularly preferably carriodout with the exclusion of oxygen, for oxample under protecdvo gas, such as argon or nitrogen.

Tho star~ng materials of the formula IV are preferably prepared by reacting a compound of tho fonnula II, as dofined abovo, with an acid anhydride of the formula X

R5-(C~)~O-(czo)-Rs (X) in which R5 and R~' indopondendy of one another are hydrogen or lower alkyl, but not both hydrogen, for example in the presence or preferably absence of further suitable solvents, at preferred temperatures between 0C and reflux temperature, e.g. at 40 to 60C.

The other staning materials are knownj commercially available or can be prepared by known processes.

Process b) Fonnadon of aminals In compounds of the formulae XI and XII, if functional groups are present which are not intended to participate in the reaction these g~oups are protected if necessary, preferably ; ; - ~ .,, J

~`Q9~3 by the protective groups given in process a). The removal of ~e protective groups in the resulting compounds is ca~ied OUt, if necessary, by the methods likewise mentioned in process a).

A reactive derivadve of an aldehyde of the fonnula XII is in particular a coIresponding acetal of the formula XIIa Ro-CH(-O~)2 (~a) in which Ro is as defined and G is lower alkoxy, such as methoxy or ethoxy, or in which the two radicals -O-G together are lower alkylenedioxy, such as ethylene-1,2-dioxy.

The reacdon prcferably takes place in the presence of acids, e.g. hydrohalic acids, such as hydrochloric acid, or sulfuric acid, or in parlicular in the presence of Lewis acids, especially SnCI2 (o.g. as the hydrate), in suitable solvcnts or solvent mixtures, e.g. ethers such as di-lower alkoxy-lower alkanes, in pardcular in 1,2-dimethoxyethane, at preferred tomperatures between 0 and 50C, e.g. at about room temperature, if necessary with additlon of water.

The star~ng compounds of the formu1a ~ or XIla aTe known, commerciaUy available or can bo prepaTed by proccsses known per se.

The starling materia1s of the formu1a Xl can be prepared ~nalogously to the methods described in p~cess a) from analogues of compounds of the formula ~' or IV in which, instead of Al and A2, a hydrogen atom is present in each case (can be prepared è.g. from compound8 of the fonnula ~t and of the formula VI, in which A is hydrogen and the other radicals havo the given meanings, by tho methods mendoned and if desiled by the corresponding intermediates), by reacdon with compounds of the fo~nula m. ~or example, they can be prepared as described in ~P 0 516 588 (Applicatdon Numbor 92 810 38S).

Conversions:

Compounds of the formula I can bo converted into other compounds of the formula I in a manner known per se.

2 ~ 3 It is possible to carry out the conversions mentioned individually, or else also to selece suitable combinations, i.e. to carry out two or more conversions widl a compound of the formula I. Functional groups in starting materials of the formula I and other starting materia1s which are not intended to participate in the particular reaction are present, if necessary, in protected form. The protective groups are removed at suitable times. The introduction of the protective groups, the protective groups themselves and their removal are as described above.

For example, a compound of the formula I in which the group -C(=X)- is -C(-~)- can be reacted with a suitable reagent so that another compound of the formula I in which the group -C(zX)- is -C(zS)-, -CHr or -C(=CRlR2)- is obtained. A suitable reagent for the conversion of -C(zO)- into -C(=S)- is e.g. the Lawesson reagent ~= 2,~bis(~methoxy~
phenyl)-2,4dithioxo-1,3,2,4dithiaphosphetane), the reaction being carried out, for examplo, in a halogenatod hydrocarbon, such as dichloromethane, at temperatures from 30C up to reflux temperature, in particular at reflux temperature. To convert -C(=O)- into -CH2, for oxamplo, the systems LiAlH4te~hydrofuran or zinc amalgam/HCUethanol are suitable. The conversion of -C(=O)- into -C(=CRlR2)- is carried out e.g. by reaction wid a strong base, e,g, LDA (lithium diisopropylamide) and then a Grignard reagent of the formula HCRIR2M~ Hat = halogen, e.g. iodine).

Purthelmore, o.g, compounds of tho formu1a I in which R is hydrogcn can be converted into othor compounds of tho formula I in which R is lowcr a1kyl or aryl-lower alkyl by alkylation, o,g. using lowor aL~cyl or aryl lowcr aL~cyl halides, by treatmcnt with suitablc bases, for example sodium hydrido or potassium tert-butoxidc.

Compounds of the formula I in which one of the radicals Al and A2 is hydrogcn can be convorted into othe,r compounds of thc foImula I in which nonc of the radicals Al and A2 is any longer hydrogen by reaction with suitable rcagcnts.

To introducc Al or A2 = subsdtuted lowcr dkyl, e.g. treatment with the basc LDA and subsequen¢ rcaction with a substituted di-lower alkyl ethcr or a substitutcd lower aL~yl halidc is suitable. Under these conditions, a group -N(-R)- = -NH- which may be pTesent in the molccule is allcylated only slighdy or not at all. Substituted lower alkyl here is defined as for the corresponding radical Al andlor A2 in compounds of the formula I.

Compounds of the formula I in which Arl and/or Ar2 is aryl, in particular phenyl or 2i~9~3 naphthyl, which is substituted by halogen, pre~erably br~mine, can be converted into the corresponding derivatives, in which one or all of the halogen atoms present in aryl Ar and/or Ar2 are replaced by cyano, for example by reaction with a cyanide sa1t of a transition metal, 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 alkyl-lower alkanecarboxamide, e.g. dimethylformamide, without or with subsequent addition of a catalyst, e.g. of a transidon metal halide, such as iron~II) chloride, in aqueous solution (seealsoRosenmundetal.,Ber.52, 1749(1916);vonBraunetal.,Ann.488, 111(1931).

In compounds of the formula 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 with the introduction of one or more nitro groups, for example under customary conditions for the introduction of a nitro group in aromatics, e.g.
with eoneentrated or lOO~o nitrie acid at temperatures between 0 and 100C, preferably betwoen 10 and 40C, in an inert solvent, e.g. an organic acid anhydride, such as acetie anhydride. If several different produets are formed here with a different position and numbor of nitro groups, these can be separatet by customary methods, for example by column chromatography.
.
A nitro substituent of the radicals Aq and/or Ar2 can be reduced to amino, e.g. by hydrogenation under customary condidons, e.g. by hydrogenadon in the presence of a hydrogenadon cat~lyst suitable for the selecdve reduetion of nitro groups, sueh as Raney niekel, in an inert solvent, e.g. a eyclie or aeyclic ether, such as tetrahydrofuran, under normal pressure or at an increased pressure of up to S bar.

Compounds of the for,mula I containing etherified hydroxy groups, for exarnplç cont~ning lower aL~oxy radicals as subsdtuents within Arl andlor Ar2 or on Al and/or A2 can be eonverted into the corresponding hydroxy-subsdtuted compounds of the formula I by ether cleavage. The ether cleavage is carried out under condidons known per se, for example in th~ presenee of hydrohalie acids, such as hydrobromic acid or hydriodic aeid, in the presenee or absence of solvents, such as carboxylic acids, e.g. lower alkanecarboxylic aeids, sueh as acetic acid, at temperatures bet veen 20C and the reflux temperature of the reaction mixture, or pIeferably under mild conditions using boron halides, in particular boron tribromide, in an inert solvent, such as a chlorinated hydrocarbon, e.g.
dichloromethane or chloroform, at temperatures between -80 and 0C, in pardcularbetween -50 and -20C.

2~099~3 Compounds of the formula I in which Al and/or A2 or substituted lower aLkylene formed from these two radicals together contain hydroxy radicals e.g. in hydroxy-lower aL~cyl A
and/or A2 or l-hydroxy-lower aLI~ylethylene formed from Al and A2 together, can be converted into the corresponding imino compounds, such as hydroxyimino compounds, by oxidation to the corresponding carbonyl compounds and reaction with hydroxylamine or a salt thereof or other amino compounds taking place directly subsequently or only after the isolation of the carbonyl compound. The other substituents, reagents and preferred reaction conditions are found in the description of the preparation of compounds of the fonnula II, in which imino, lower alkylimino, acylimino, hydroxyimino, lower aL~coxy-imino, hydrazono, N-mono- or N,N-di-lower aL~cylhydrazono and/or N-acylhydrazono is present as a substitucnt in substituted lower allylene formed from Al and A2 together, from coqTesponding oxo compounds of the formula II, where instead of the oxo compounds of tho formula ~ those of the formula I are to be employed.

Compounds of the formula I in which hydroxyimino is present as a substituent in Al and/or A2 or lowor alkylene formed from these two radicals together can be reacted with hydrogcnadon to give the corresponding amino compounds. The hydrogenation here is preferably carried out catalydca11y using selectivc hydrogenation catalysts, in particular in the presence of palladium on solid support materials, e.g. on carbon, in polar organic or organic-aqueous solvents or solvent mixtures, in particular in ethers, e.g. cyclic ethers, such as tetrahydrofuran or dioxane, or in alcohols, e.g. Iower alk~mols, such as methanol or ethanol, or mixtures thereof, e.g. in methanollte~rahydrofuran mixtures, at temperatures between -20 and 60C, preferably between 0 and 40C, o.g. at about room temperature.

In compounds of the forrnula I containing primary hydroxy groups, for example those compounds of the formula I in which substituted lower alkyl, l~wer a1~enyl or lower alkynyl Al andlor A2 contain primary hydroxy g oups, such as in hydroxyethyl, or in which a substituted lower alkylene formed from Al and A2 together i8 present, which contains hydroxy-lower alkyl, such as hydroxymethyl, as a subsdtuent, pnirnary hydroxyl groups can be oxidized to coTresponding carboxyl or carboxy-lower alkyl radicals, for example by oxidadon with chromic acid, dichromate/sulfuric acid, nitric acid, manganese dioxide or potassium permanganate, preferably with potassium permanganate in neutral or alkaline medium, e.g. in aqueous alcoholic solution, at prefe~red temperatures between -20 and 50C, in particular between 0C and room temperatore. Corresponding carboxy-subsdtuted compounds of the formula I are obtained.

21~9~3 In compounds of the forrnula I in which a substituted lower alkyl Al and/or A2 contains carboxyl, such as in carboxymethyl Al and/or A2, or in which a substituted lower aL~cylene formed from Al and A2 together is present, which contains carboxyl or carboxy-lower aLIcyl as a substituent, for example in those compounds which are prepared by the last-described process from compounds of the forrnula I containing primary hydroxy groups, carboxy groups can be converted into the corresponding lower a1koxycarbonyl groups by reacdon with diazomethane (yields methoxycarbonyl) or with lower atkanols, such as methanol or ethanol. The reacdon with diazomethane is catried out, for example, in aqueous alcoholic solution, e.g. in water/methanol or preferably in ether, in the presence of an ethereal solution of diazomethane, e.g. diazomethane in diethyl ether, at temperatures between 20 and 30C, e.g. bet~veen 0C and room temperature. The reaction with lower alkanols is preferably catried out in the presence of condensing agents, such as carbodiimides, e.g. dicyclohexylcarbodiimide, in the lower alkanol in quesdon, to which a further inert organic solvent, preferably dimethylforrnamide or dimethylacetamide, can be added, at temperatures bet veen 0 and reflux temperature, preferably between 10 and 40C. Corresponding lower al~oxycarbonyl compounds of the formula I are obtained.
Conversoly, in a compound of the formula I esterified carboxyl (in pardcutar lower alkoxycarbonyl, such as cthoxycarbonyl, for example as a subsdtuent of lower aL~cylene fonned from Al and A2 together in formuta I) can be convcrted into free carboxyl, for example by hydrolysis h the presence of water and acids, such as hydrohatic acids, e.g.
hydrochtoric acid, or sutfuric acid, or suitable Lowis acids, such as SnCl2, atso in the presence of 8uitablo solvents, in parlicular ethers, e.g. di-lower atkoxy-lower alkanes, such as 1,2~1imethoxyethano, at preferred temperatures of between 0 and 50C, e.g. at about room temperature, if necessary under protective gas, such as argon or nitrogen. Atso posdble is the release of carboxyl by biochemicat methods such as hydrolysis with esterases in suitable buffer systems.

Compounds of thc formuta I in which hydroxyl and/or hydroxy-lower aL~yl is present as a subsdtuent in a substituted lower alkylene formed ~om Al and A2 together can be oxidized to a corresponding oxo compound. In the case of primary alcohols, the use of selectivc oxidizing agents is necessary for this purpose, e.g. of potassium ferrate (K2FeO4) in aqueous solvents and also manganese dioxide in organic solvents, tert-butyl chromate, pyridinium dichromate or in particular pyridinium chlorochromate in inert otganic solvents, e.g. chlorinated hydrocarbons, such as dichloromethane or chloroform. The reaction preferably takes place at temperatures between -20C and reflux temperature, e.g.

2~9$93 at about 0 to 40C. In the case of secondary alcohols, the oxidation can additionally be ~ "
carried out with less selective oxidizing agents, such as chromic acid, dichromate/sulfuric acid, dichromate/glacial acetic acid, r~itric acid, manganese dioxide, selenium dioxide or dimethyl sulfoxide in the presence of oxalyl chloride, in water, aqueous or organic ~ .
solvents, such as halogenated hydrocarbons, e.g. dichloromethane, or carboxamides, such as dimethylformamide, preferaWy at temperatures between -50C and reflux temperature, in particular between -10 and 50C. Compounds of the fonnula I are obtained in which substituted lower alkylene formed from Al and A2 together is substituted by oxo.
Compounds of the formula I in which one or more substituents selected from imino, lower alkylimino, acylimino, hydroxyimino, lower aLlcoxyimino, hydrazono, N-mono- or N,N-di-lower aLtcylhydrazono, N-acylhydrazono and lower alkyl substituted by imino, lower alkylimino, acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower alkylhydrazono.and/or N-acylhydrazono in a substituted lower alkylene formcd from Al and A2 together can bo prepared from corresponding oxo compounds of tho fortnula.I, eithcr after isolation of the oxo compounds or preferably by their direct rcusc as a crudo product, for example after partial evapo~tion to remove the solvent in which the oxidation.of a hydroxy compound to the oxo compound is carried out, which takes placo, for example, as last described.

Thus, the oxo compounds can be converoed into the corresponding imino derivatives by reaction with nitrogen bases selected from ammonia, lower alkylamines, hydroxylamine, lower alkoxyamine, hydrazine, N-mono- or N,N-di-lowor alkylhydrazine and N-acyl-hydrazine. The reaction condidons are the condidons convendonally used for the reacdon of carbonyl compounds with nitrogen bases, using, for example, the nitrogen.base in the form of a salt of an acid, for example of a hydrohalic acid, such as hydrofluwic 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 phospho~ic 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 particular with a carboxylic acid, such as a lower alkanecarboxylic acid which is unsubstituted in the lower aL1cyl radical or substituted in the lower alkyl radical, preferably by halogen, such as fluorine or iodine, e.g. acetic acid, chloroacetic acid, dichloroacetic acid or trifluoro- or trichloroacetic acid, or a sulfonic acid, such as a lower aLlcanegulfonic 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 aLIcanecarboxylic 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, primarily one of the abovementioned hydrohalic acids; the reaction taking place in water (in the presence or absence of surfactants), 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 aL~canoylamides, 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 alkanoylamidos, such as dimethylformamide, or in sufflciently inert nitriles, such as acetonitrile, a mixture of such organic solvents, or without solvents in a melt, preferably in an alcholic 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, and melts up to 220C, in particular at temperatures from 0 to 50C, in tho presonce of a solvent, mainly at about room temperature.

Freo compounds of tho formula I having sa1t-forming groups and obtainable according to tho process can bo converted into their salts in a manner hlown per se, compounds having basic properties e.g. by treating with acids or suitablo dorivatives thereof, compounds having acidic proporties e.g. by treating with bases or suitable derivatives thereof.

Mixtures of isomers obtainable according to the invention can be separated into individual isomers in a manner known per se, diastereomers -8- by partition betweon multi-phase solvent mixtures, recrystallization and/or chromatographic separadon, for example on silica gel, racemates e.g by formadon of salts with optically pure salt-forming reagents, separadon of the diastereomer mixture thus obtainable, e.g. by means of fractional crystallizatlon, and subsequent release of the desired pure enantiomers, or by chromatography on optically active column materials.

The abovementioned reactions can be carried out under reaction conditions known per se, in the absence or customarily the presence of solvents or diluents, preferably those which are inert to the reagents used and dissolve these, in the absence or presence of catalysts, 2109~93 condensing agents or neutralizing agents, depending on the type of reaction ar.d/or reaction participants, at reduced, normal or elevated temperature, e.g. in the temperature ;
range f~om about -80C to about 200C, preferably from about -20C to about 150C, e.g.
at room temperature up to reflux temperature, on melting at up to 220C, under atmospheric pressure or in a closed vessel, if desired under pressure, e.g. at the pressure which is formed in the reaction mixture under the reaction conditions in a closed tube, and/or in an inert atmosphere, e.g. under argon or nitrogen. The reaction conditions specifically mentioned in each case are prefe~red.

Solvents and diluents are, for example, water, alcohols, e.g. lower alkaL~canols, such as methanol, ethanol or propanol, diols, sueh as ethylene glycol, triols, such as glycerol, or aryl aleohols, sueh as phenol, aeid amides, e.g. earboxamides, such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-3,4,5,~tetrahydro-2(1H)-pyrim-idinone (DMPU), or amides of inorganic acids, such as hexamethylphosphora nide, ethers, o.g. eyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl other or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower aL~canes, o.g. dichloromethane or chloroform, ketones, such as acetone, nitriles, such as aeotonitrile, aeid anhydridos, sueh as aeetie anhydride, esters, sueh as ethyl aeetate, bisalkanesulfines, sueh as dimothyl sulfoxide, nitrogen heteroeyeles, sueh as pyridine, hydrocarbons, e.g. lower alllanes, sueh as heptane, or aromaties, sueh as benzene or toluene, or mixtures of these solvents, it being posdble to select the suitable solvent in each easo for the abovementioned roactions.

On account of the closo relationship between the eompounds of the fo mula I and their precursors in free form and in the fonn of salts andlor tautomers, above and below the free eompounds and starting materials are also eorrespondingly and expediently if desired to be understood as meaning the eorresponding salts or free compounds and/or tautomers if the eompounds eontain one or more salt-forming groups, e.g. basie groups, sueh as amino or imino groups, also those which are bonded to not more than one unsaturated earbon atom, such as the groups -NAlArl and/or -NA2Ar2 on the C atom of the eentral phenyl ring radical, in which Arl and Al and/or Ar2 and A2 are not bondcd via an unsaturated earbon atom, and/or acidic groups, such as carboxyl or sulfo (SO3H), and/or tautomerizable groups. If, in eonneedon with starting materials and eompounds of the formula I above and below a substituent, a eompound, a tautomer, a salt, subsdtuents, eompounds,tautomers or salts are mentioned, this is, if meaningful and expedient, to be understood as meaning "one or more" independently of the use of the singular or plural. ~ neeessary, 2 ~ 3 starting materials can also be present in protected form, if meaningful and expedient, protective groups being removed at suitable times. Protective groups and their removal are in particular def~ned as above.

The compounds or their salts can also be obtained as hydrates, or their crystals can include e.g. the solvent used for crystallization.

In the process of the present invention, preferably those starting materials are employed which lead to the compounds described as particularly useful.

The invention also relates to those embodiments of the process in which the reaction is carried out starting from a compound obtainable in any desired process step as an intermediate and the missing process steps are carried out, or in which a starting material ;
is fonned under the reacdon conditions or is used in the form of a derivative, e.g. of a salt thereof.

Sequcnces and reaction conditions of all the reactions described are preferably to be solected as is to be regarded as corresponding and expedient for the person skilled in the ar~.

Tho present invention 1ikewise includes novd intermediates. This applies in particular for the intermediates of the formula II and those of the formula II', which are defined as above. The intermediate compounds of the formula II and of the formula II' montioned in the oxampbs are particularly preferred.

The present invendon also relates to pharmaceudcal preparations which contain compounds of tho formula I as an active ingredient. Pardcularly preferred preparations are thoso for enteral, in particular Gral, and also for parenteral administration. The preparadons contain the acdve ingredient on its own or preferably together with a pharmaceudcally udlizable carrier. The dose of the acdve ingredient depends on the disease to be treated, and on tho species, age thereof, wdght and individual condidon, and on the manner of administradon.

A pharmaceudcal composidon is preferred which is suitable for administradon to amammal, in pardcular a human, who suffers from a disorder which responds to inhibition of a protein kinase, for example psoriasis or a tumour, comprising an amount of a 21~9~93 compound of the formula I or a salt thereoft if salt-forming groups are present, effilcacious for the inhibition of the protein kinase, together w;~ at least one phannaceutically acceptable ca~rier.

The pharmaceutical preparations contain from about 5% to about 95% of the activeingredient, single-dose administration forms preferably containing from about 20% to about 90% and non-single-dose administration foIms preferably containing about 5% tO
about 20% of active ing~edient. Dose unit forms, such as coated tablets, tablets or capsules, contain from about 0.05 g to about 1.0 g of the active ingredient.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. Thus, pharmaceutical compositions for oral administration can be obtahed by combining the acdve ingredient with one or more solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired, to give tablets or coated tablet cores, opdonally by addidon of addidonal auxiliaries.

Suitable carriers ~e in panicu1ar fillers, such as wgar, e.g. lactose, sucrose, mannitol or so¢bitol, cellulose preparadons and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, e.g. maize, wheat, nce or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose andhr polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the abovemondoned starches, and also carboxymethyl starch, crosslinked polyvinylpyrrolidone, or a1ginic acid or a salt thereof, such as sodium alginate. Addidonal auxiliaries are primarily flow condidoners and lubIicants, e.g. silicic acid~ talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or deri~adves thereof.

Coated tablet cores can be provided with suitable coadngs, if desired enteric-coated, inter alia concentrated sugar solutions which, if desired contain poly~rinylpyrrolidone~ talc, gum arabic, polyethylene glycol and/or dtanium dioxide, coating soludons in suitable organic solvents or solvent mu~tures or, for the preparadon of enteric-coated coadngs, soludons of suitable cellulose preparadons, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, being used. Colourants or pigments, e.g. for idendfication or for characterization of various active ingledient doses, can be added to tablets or coated tablet coatings.

210~3 Orally adminsterable pharmaceutical compositions are also hard gelatin capsules, and also soft, closed capsules of gelatin and a softener, such as glycerol or sorbitol. The hard gelatin capsules can contain the active ingredient in the form of granules, e.g. in a mixture with fillers, such as maiæ starch, binders andlor lubricants, such as talc or magnesium stearate, and, if desired, of stabilizers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquid auxiliaries, e.g. fatty oils, Lauroglycol (Gattefossé S. A., Saint Priest, France), Gelucir (Gattefossé S. A., Saint P~iest, France) or sesame oil, paraffin oil or liquid polyethylene glycols, such as PEG 300 or 400, or fatty acid ostors of lower alkyl glycols, if desired with addidon of stabilizer andJor detergent.

Purther ~ral administration folms are e.g. syrups prepared in a customary manner, which contain the active ingredient e.g. in suspended form and in a concentradon of about 5% to ~0%, preferably about 10%, or in a simi1ar concentration which results in a suitable single dose on measuring out 5 or lO ml. In addition e.g. powdered or liquid concentrates for the preparadon of shakes, e.g. in milk, are also possible. Such concentrates can also be packed in singlo dose amounts.

Possible rcctally administerable pharmaceudcal preparadons are e.g. suppositories, which consist of a combination of the active compound with a suppository base. Sui~able suppodtory bases are o.g. natural or synthotic triglyceridos, paraffin hydrocarbons, polyothylono glycols or higher a1kanols.

Por parenteral administration, aqueous soludons of an active ingredient in water-soluble form, o.g. of a water-soluble salt, or aqueous injccdon suspensions which contiain viscodty-increasing substances, e.g. sodiurn carboxymethylcellulose, sorbitol and/or dextran and if desired stabili~ers are primarily suitable. In dlis case, the active compound, if desired together with auxiliaries, can also be present in the fo~m of a Iyophilisate and can be brought into solution before parenteral administration by addition of suitable solvents.

Soludons, as are used e.g. for parcntcral administradon, can also be administered as infusion solutions.

The invendon likewise relates to a process for the treatment of the abovemendoned disease condidons, in pardcular those which respond to inhibidon of protein kinases. The 2109~93 compounds of the present invention can be administered prophylactically o~
therapeutically, preferably in an amount effec~Live against the diseases mentioned to a mammal, e.g. a human, who needs a trea~nent of dlis type, the compounds preferably being used in the form of pharmaceutical preparations. In the case of a body weight of about 70 kg, a daily dose of 1 mg to 5000 mg, e.g. of about 0.1 g to about 5 g, preferably of about 0.5 g to about 2 g, of a compound of the present invention is adrninistered here.

The following examples illustrate the present invention; temperatures are given in degrees Celsius. The following abbreviations are used: abs. = absolute (anhydrous); TLC = thin layer chromatogram; DM~ = dimethylformamide; DMPU = 1,3-dimethyl-3,4,~,6-tetra-hydro-2(1H)-pyrimidinone ("dimethylpyrourea"); ether = diethyl ether, FAB-MS = fast atom bombardment mass spectroscopy; satd~ = saturated; lH-NMR = proton nuclear magnctic resonancc; HV = high vacuum;conc. = concentrated; cryst. = crystalline; RT =
room temporature; m.p. = melting point; TH~7 = tetrahydrofuran; torr = pressure unit (1 torr corresponds to a 1 mm mercury column). Quantitative ratios of solvent/eluent mixtures relate, if not stated otherwise, to volume ratios (v/v).

ExamPlo 1: 5.8-DiPhenvl-5.8-diaza-6-hvdroxvm~thvl-5.6.7.8-tetrahvdro-naphthalene-2.3-dicarboximide A suspen~ion of 230 mg (0.7 mmol) of dimethyl 5,8-diphenyl-5,8-diaza-6~hydroxy-mothyl-5,6,7,8-tetrahydronaphthalenc-2,3-dicarboxylate in 8 ml of ethylenc glycol is heated to 124; ammonh gas is passed with stir ing for 24 h. The reaction mixture is cooled, treated with saturated sodium chloride soludon and oxtracted with ethyl acetate.
The ethyl acet~lte phases are successively washed th~ dmes with water and once with satd, sodium chloride solution, driedwith sodium sulfate and cvaporated. The evaporation residue is applied to silica gel with dichloromethane and chromatographed. Usingdichloromethane, the by-products arc first removed, and the product fractions are cluted using hcxanc/ethyl acctate 2:1, combined and evaporated. The evaporadon residue is crystallized from ethyl acetatc/hexane. The dtle compound isobtained in the form of orange crystals, m.p. 268, FAB-MS: 386~M++~.
The starting materials arv prepared as follows:

a) methvl 5.8-diphenvl-5~8-diaza-~hvdroxvmethvl-5.6.7.8-te~ahvdro-naphthalene-2.3-dicarboxvlate 96 mg (2.2 mmol) of sodium hydride (60% dispersion in oil) are added under argon to a 2109~3 solution of 377 mg ~1 mmol) of dimethyl 4,5-dianilinophthalate in 10 ml of DMF abs. A
solution of 96 ~1 (1.2 mmol) of epichlorohydrin in 2 ml of DMF abs. is added dropwise at RT, and the reaction mixture is heated to 100C and stirred for 12 h. The reaction mixture is cooled, the solvent is evaporated, the black residue is dissolved in dichloromethane and the solution is washed with water, dIied with sodium sulfate and evaporated. Theevaporation residue is chromatographed on silica-gel using ethyl acetate/hexane 1:2, and the product fractions are combined and evaporated. The title compound is thus obtained as a slightly yellow powder, m.p. 68, FAB-MS: 433 [M++H~.

b) Dimethvl 4.5-dianilinonhthalate A solution of 5.6 g (15 mmol) of ciimethyl 4,5-bis(tnmethylsilyloxy)cyclo-hexya-1,4-diene-1,2-dicarboxylate and 5.5 ml (60 mmol) of aniline in 60 ml of glacial acetic acid is boiled under reflux for 4 h. The reaction mixture is cooled, the solvent is evaporatcd, the dark-brown residue is dissolved in dichloromethanc and the solution is washed successively wi~ 20 ml of lN HCl, 50 ml of satd. NaHCO3 solution and ~rice with 20 ml of water, dried using sodium sulfate and ovaporated. The crude product is rccrystallized from cthanol. In this manner, thc title compound is obtained in the form of yellow crystals, m.p. 178, FAB-MS: 377 [~H].

c) I;)imethvl 4.5-bis(trimcthvlsilvloxv~cvclohexa-l.~diene-1.2-dicarboxvlate A solution of 7.1 g (50 mmol) of dimcthyl acctylenedicarboxylate in 30 ml of toluene is added drop visc under argon to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy~1,3-butadiene (95%) and the mixture is then boilcd at reflux for 19 h. The reaction mixturc is coobd, the solvent is evaporated and the residue is distilled in a high vacuum (0.1 mbar, 12~127). In this manner, the tide compound is obtained as a yollow, highly viscous oil, lH-NMR (~DC13): ~; a 0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).
.

Example 2: 4-(3-Aminopropvl)-4.5-dianilinoPhthalimidc Analogously to Example 1, 44 mg (0.1 mmol) of dimethyl 4(3-aminoproPyl)-A,5-di-anilinophthalate in 4 ml of ethylene glycol are heated to 120, ammonia gas being passed in with stirring for 24 h. The reacdon mixture is cooled, treated with conc. sodium chloride solution and extracted with ethyl acetate. The ethyl acetate phases aresuccessively washed three times with water and once with satd. sodium chloIide solution, dried widl sodium sulfate and evaporated. The evaporation residue is chromatographed on silica gel using dichloromethanelmethanol 10:1, and dhe product fractions are combined and evaporated. In this manner, dhe dde compound is obtained in the form of yellow 21~9~93 crystals, FAB-MS: 387 [M~+~I].
The sta~ng materials are prepared as follows;

a) D;methvl 4-(3-aminopropyl)-4.5-dianilinophthalate 39 mg (0.78 mmol) of hydrazine hydrate are added under argon in one portion to asolution of 186 mg (0.33 mmol) of dimethyl 4,5-dianilino~(3-[N-phthalîmidopropyl]) phthalate in 15 ml of THP and the reaction mixture is heated under reflux for 22 h. The reaction mixture is cooled to 40, treated with 200 ,ul of conc. hydrochloric acid and heated to 70 for 2 minutes, cooled to room temperature and filte~ed. The filtrate is evaporated, and the residue is partitioned between ethyl acetate and water. The water yhase is separated, rendered basic with 2N sodium hydroxide solution and extracted a further two tin~es with ethyl acetate. The organic phases are combined, dried with sodium sulfate and evaporated. The residue is chromatographed on silica gel using dichloromothane/methanol 10:1 and the product fractions are evaporated and dried under high vacuum. In this manner? the tit1e compound is obtained in the form of a pale ye11ow foam, l~AB-MS: 434 [M~+H], lH-N~ ((3D30D): 7.6 (s, lH),7.3 (t, 2H),7.15 (m, 6H),6.75 (m, 3H), 3.8 (d, 6H), 3.65 (t,2H), 2.7 (t, 2H), 1.85 (m, 2H).

b) Methvl 4.$-D1anilino-4-(3-rN-DhthalimidoproPYll~ Dhthalatc 6~ mg (1.5 mmol) of sodium amido (cryst.) are added 1mder nitogen to a solution of 377 mg ( 1 mmol) of dimethyl 4,S di~nilino phthalate ~Example 1 b) in lS ml of DMPU abs.
Tho reaction mixtmo is hoatod to 40 and a vacuum of l toIr is applied for 30 min. It is then pressurized with nitrogen and 402 mg (1.5 mmol) of N-(3-bromopropyl)phthalimide are added. The reaction mixture is heated to 100C and stirred for 2 h. Thc rcaction mixture is cooled, treated with water and cxtracted three times with ethyl acetatc. Thc organic phascs are combined, washed with watcr, dried using sodium sulfatc and evaporated. The evaporadon residue is chromatographed on silica gel using ethyl acetate/hexane 1:1, and the product fhctions are combined and evaporated. In this manner, the tdtle compound is obtained in the form of pale ycllow crystals, m.p. 182-183, FAB-MS: 564 [M~+~.

ExamPle 3: 4-(3-r3-McthvlureidolProPvl)-4.5-dianilinoPhthalimidc Analogously to Example 1, 50 mg (0.1 mmol) of dimcthyl 4(3-[3-methyl-ureido]propyl)-4,5-dianilinophthalate in 4 ml of ethylene glycol are heated to 120, ammonia gas being passed in with stirring for 24 h. The reaction mixture is cooled, treated 21~9~93 with conc. sodium chloride solution and extracted with ethyl acetate. The ethyl acetate phases are successively washed three times with water and once with satd. sodiumchloride solution, dried using sodium sulfate and evaporate~ The evaporation residue is chromatographed in silica gel using ethyl acetate/methanol 50:1, and the product fractions are combined and evaporated. In this manner, the tide compound is obtained in the form of a yellow foam, FAB-MS: 444 ~M+~, TLC (silica gel, ethylace~tte/methanol 20:1)Rf'0.40.
The stardng material is prepared as follows:

a) Dimethvl 4-(3-r3-methvlureidolpropvl)~.S-dianilinophthalate A solution of 43 mg (0.1 mmol) of dimethyl 4-(3-aminopropyl)~,5-dianilinophdlalate (Example 2 a) in 15 ml of THP is treated with 9 ,ul (0.15 mmol) of methyl isocyanate and the mixture is stirred at RT for 2 h. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and the solution is washed successively wtth lN HCl and water, dried with sodium sulfate and cvaporated. In this manner, the title compound is obtained in the form of ycllow crystals, I?AB-MS: 490 [M++Hl, TLC (silica gel, dichlormethane~methanol 7:3) RF0.85.

Exam~le 4: 4-(2-Aminoethvl~-4.5-dianilinoDhthalimide Analogously to Examplc 1, 44 mg (0.1 mmol3 of dimethyl 4(2-aminoethyl)-4,5-di-anilinophthalate in 4 ml of ethylene glycol arc heatcd to 120, ammonia gas being passed in with sdrling for 24 h, Tlte reacdon m1xture is cooled, treatcd with conc. sodium chloride soludon and extracted with ethyl acetate. Tlte ethyl acetate phases aresuccossively washed thrcc timcs with water and oncc with satd. sodium chloride soludon, dried with sodium sulfatc and evaporated. The evaporation residue is chromatographcd on silica gel using dichloromethane/methanol 10:1, and dte product fractions are combined and evaporated. In dhis manner, the tide compound is obtained in the form of yellow crystals, FAB-MS: 373 [M++H].
Tlte star~ng material is prepared as follows:

a) Dimetltvl 4-(2-aminoethvl)-4,5-dianilinophthalate 48 mg (1.1 mmol) of sodium hydride (60% dispersion in oil, Fluka, Switzerland) are added under argon to a solution of 377 mg (1 mmol) of dimetltyl 4,5~ianilinophthalate (Example 1 b) in 10 ml of DMF abs. A solution of 62 Ill (1.2 mmol) of aziridine in 2 ml of DMF abs. is added dropwise at RT, and the reaction mixture is heated to 100C and stirred for 4 h. The reacdon mixture is cooled, the solvent is evaporated, the black residue is dissolved in dichloromethane and the solution is washed with water, dried with sodium sulfate and evaporated. The evaporation residue is chromatographed on silica gel using dichloromethane/methanol 10:1, and the product fractions are combined, evaporated and dried under high vacuum. In this manner, the title compound is obtained in the forrn of a slightly yellow foam, FAB-MS: 419 [M++~.

Example 5: 4-(3-CarbamoY!ethY1)4.5-dianilinoPhthalimide Analogously to Example 1, 46 mg (0.1 mmol) of dimethyl (4-(3-methoxycarbonylethyl)-4,5-dianilinophthalate in 4 ml of ethylene glycol are heated to 120C, ammonia gas being passed in with stirring for 24 h. The reaction mixture is cooled, treated with conc. sodium chloride solution and extracted with e`thyl acetate. The ethyl acetate phases are successively washed three times with water and once with satd.
sodium chloride soludon, dried with sodium sulfate and evaporated. The evaporadon residue is chromatographedon silica gel using ethyl acetatethexane 1:1, and the product fractions arc combincd and cvaporated. In this manncr, the dde compound is obtained in the form of yellow crystals, PAB-MS: 416 [M~+H].

Tho starting material is prcpared as follows:

a) DimethYI 4-(3-methvloxYcarbonvlethvl~-4.5~ianilinoDhthalate 48 mg (1.1 mmol) of sodium hydridc 60% dispersion in oil, Pluka, Switzerland) are added undcr argon to a soludon of 377 mg (1 mmol) of dimethyl 4,5-dianilinophthalate (Example 1 b) in 10 ml of DMF abs. A solution of 134 ~Ll (1.2 mmol) of medhyl 3-bromopropionatc (Pluka, Switzerland) in 2 ml of DMP abs. is added dropwise at RT, and thc rcacdon mixture is heated to 100C and sdrred for 12 h. The reaction mixturv is cooled, the solvent is evaporated, the Uack residue is dissolved in dichloromethane and the solution is washed with water, dried with sodium sulfate and evaPorated. Theovaporation residue is chromatographed on silica gel using dichloromethane/methanol 10:1, and tho product fractions aro combined, evaporated and dried in a high vacuum. In this manner, the title compound is obtained in the form of slightly yellow crystals, PAB-MS: 463 lM++H].

Example 6: 5.8-DiPhenvl-5.8-diaza-6-hvdroximinomethvl-5.6.7~8-tetrahYdro-naphthalene-2.3-dicarboximide A solution of 386 mg (1 mmol) of 5,8-diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetra-hydronaphthalene-2,3~icarboximide ~Example 1) in 20 ml of abs. dichloromethane is treaeed with 323 mg (1.5 mmol) of pyridinium chlorochromaee (Fluka, Switzerland) in 20 ml of abs. dichloromethane and ehe mixeure is seirred ae RT for 2 h. 20 ml of diethyl ether is then added, and the mixture is filtered through Celite~ (filter aid based on kieselguhr, Fluka, Switzerland) and washed with~ dichlo~omethane/ether 1:1. The filtrate is concentrated to 20 ml in a cold water bath, ehe residue is treated with 20 ml of methanol and a solution of 70 mg (1.0 mmol) of hydroxylamine hydrochloIide in 20 ml of methanol is added. The reaction mixture is stured at RT for 18 h, then evaporated and chromatographed on silica gel using ethyl acetatelhexane 1:1. The product fractions are evaporated and d~ied in a high vacuum. The title compound is thus obtained in the form of orange crystals.

Example 7: 6-AminomethYl 5.8-diphenyl-S.8-diaza~5.6.7.8-tetrahYdro-naphthalene-2.3-dicarboximide A soludon of 40 mg (Ql mmol) of 5,8-diphenyl-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tctrahydronaphthalene-2,3-dicarboximide (Examplo 1) in 5 ml of methanol and 2 ml of TE~ is hydrogenated on Pd/C using hydTogen. The reaction mixture is f~tered from the catalyst and washed with methanol, and the filtrate is conccntrated. In this manner, thc dtlo compound is obtained in thc form of yellow crystals, ~AB^MS: 385 [M~+~l.

ExamDlo 8:
S,8-Diphonyl-5,~-diaza-5,6,7,8-tetrahydronaphthalene-2,3~icar~oximide-6-carboxylic acid is prepared from dhe tide compound of Example 1 (by oxidation widh KMnO4).

ExamPlo 9: StaIting from l~xample 8, methyl 5,8~iphenyl-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3~icarboximid~6-carboxylate is prepa~ed (udng diazomethane).

Exam~le 10: Sear~ng f~om Example 8, ethyl 5,8~iphenyl-5,8-diaza-5,6,7,8-tetrahydro-naphthaleno-2,3-dicarboximide-6-carboxylate is prepared (using ethanoVdicyclo-hexylcarbodiimide) .

ExamPle 11: 5,8-Diphenyl-5,8-diaza-6-hydrazonomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide is prepared analogously to l~xample 6 (by reaction with pyridinium chlorochromate and subsequent reaction with hydrazine).

210~3 Example 12: The follo ving are prepared analogously to one of the abovementionedexamples and/or the processes mentioned:

(a) 5,8-Bis(~fluorophenyl)-5,8-diaza-6-hydroxymethyl-5,6,7,8-eetra hydro-naphthalene-2,3 -dicarboximide (b) 4-(3-Aminopropyl)-4,5-bis(4-fluoroanilino)phthalimide (c) 4-(3-Methylaminopropyl)~,S-dianilinophthalimide (from Example 2a by reaction with methyl iodide and further reaction of the dimethyl 4(3-methylaminopropyl)-4,5-dianilino-phthalate analogously to Example 2) (d) ~(3-Aminoethyl)-4,5-bis(4-fluoroanilino)phthalimide (e) 4(3-Carbamoylpropyl)-4,5-bis(4-fluoroanilino)phthalimide (f) 5,8-Bis(4-fluorophenyl)-5,8-diaza-~hydroximinomethyl-5,6,7,8-tetra-hydro-naphthalene-2,3-dicarboximide.
(g) 6-Aminomethyl-5,8-bis(4fluorophenyl)-5,8-diaza-5,6,7,8-tetra-hydro-naphthalene-2,3-dicarboximide (h) 5,8-Bis(4~fluorophenyl)-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboximide--6-carboxylic acid (i) Methyl 5,8-bis(4fluorophenyl)-5,8~iaza-5,6,7,8-tetra-hydro-naphthalcne-2,3-dicarboximid-~carboxylate (j) Ethyl 5,8-bis(4fluorophcnyl)-5,8-diaza-5,6,7,8-tetra- ;
hydro-naphthalene-2,3-dicarboximid-6-carboxylate (k) 5,8-Bis(4-fluorophenyl)-5,8-diaza-~hydrazonomcthyl-5,6,7,8-tetra-hydro-naphthalenc-2,3-dicarboximide (1) 4(3-Amidinopropyl)-4,5-dianilinophthalimidc (m) 4-(3-Mcthylthioiminopropyl)-4,5-dianilinophthalimide (n) 4-(3-Carbamoylpropyl)-4,5-dianilinophthalimidc (o) 4(3-Urcidopropyl)-4,5-dianilinophthalimide (p) 4-(3-[3-Ethylureido]propyl)-4,5-dianilinophthalimide (q) 4(3-Aminobutyl)-4,5-dianilinophthalimidc (r) 4-(3-[3-Methylthiourcido]ethyl)-4,5-dianilinophthalimide (s) 4-(3-~N'-Ethylthiourcido]ethyl)4,5-dianilinophthalimide tt~(3-r3-MethvlthioureidolProPvl)4.5-dianilino~hthalimide and (u) 4-(3-rthioureidolDro~vl)-4,5-dianilinophthalimide Analogously to Exarnple 1, 180 mg (0.36 mol) of dimethyl 4-(3-[3-methylthioureido]propyl-4,5-dianilinophthalate in 5 ml of ethylene glycol are 2~99~3 heated to 120C, ammonia gas being passed in with stilling for 24 h. The reaction mixture is cooled, treated with concentrated sodium chloride solution and extracted with ethyl acetate. The ethyl acetate phases are successively washed three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and evaporated. The evaporation residue is chromatographed on silica gel using dichloromedhane/methanol 60:1, and the product fractions eluting first are combined and evaporated. In this manner, the tide compound (t) is obtained in the fo~m of a yellow foam, FAB-MS: 460 [M+~, TLC (silica gel, dichloromethane/me~anol 10:1) Rf~0.50. The fractions eluting after this are combined and evaporated In this manner, the title compound (u) is obta~ned in the form of a yellow foam, PAB-MS: 446 [M++Hl, TLC ~silica gel, dichloro-methane/methanol 10:1) Rf~0.39.
The stardng material is preparvd as follows:

a) Dimethvl 4-(3-~3-methvlthioureidol~ro~vl)-4.5-dianilinophthalate A solution of 220 mg (0.5 mmol) of dimethyl 4-(3-aminopropyl)4,5~ianilino~hthalate (Example 2 a) in S ml of dichloromethane is treated with 70 ~1 (1 mmol) of methyl isothiocyanate and sti~Ted at RT for 4 h. The leaction mLsture is evaporated and the ovaporation re8idue is cluomatographed on silica gel using ethyl acetate. The product fractions are combined and evaporated. In this manner, the title compound is obtained in tho fonrs of a yellow foam, ~AB-MS: 507 pM+~, TLC (siUca gel, dichloromethane/methanol 10:1) Rf=0.68.

(v) 4-(3-[3-Ethylthioureido]propyl)-4,5-dianilinophthalimide (w) 4-(3-Guanidinylethyl)-4,5-dianilinophthalimide (x) 4-(3-Guanidinylpropyl)-4,5-dianilinophtha1imide (y) 4-(3-Amidinopropyl)-4,5-bis(4fluoroanilino)phthalimide (z) 4-(3-Methylthioiminopropyl)-4,5-bis(4-fluoroanilino)phthalimide Example 13: The following are prepared analogously to the abovementioned examples and/or the processes mentioned:

(a) 4-(3-Carbamoylpropyl)4,5-bis(4fluoroanilino)phthalimide (b) 4-(3-Ureidopropyl)-4,5-bis(4-fluoranilino)phthalimide (from the ti~e compound of Example 2a) by reaction with carbonyldiimidazole and then with ammonia) (c) 4-~3-Thioureidopropyl)-4,5-bis(4-fluoroanilino)phthalimide -76- 2109~93 (d) 4-(3-[3-Methylureido]ethyl)~,S-bis(4-fluo~oanilino)phdlalimide (e) 4-(3-[3-Ethylureido3ethyl)-4,5-bis(4-fluoroanilino)phthalimide (f) 4-(3-[3-Methylureido]propyl)-4,5-bis(4fluoroanilino)phthalimide (g) 4-(3-[3-Ethylureido]propyl)-4,5-bis(~fluoroanilino)phthalimide (h) 4-(3-AminobutyV-4,5-bis(~fluoroanilino)phthalimide (i) 4-(3-[3-Methylthioureido]ethyl)-4,5-bis(~fluoroanilino)phthalimide (j) ~(3-[3-Ethylthioureido]ethyl)-4,5-bis(4fluoroani1ino)phtha1imide (k) 4-(3-[3-Methylthioureido]propyl)-4,5-bis(4-fluoroanilino)phthalimide (1) 4-(3-[3-Ethylthioureido]propyl)-4,5-bis(4-fluoroanilino)phthalimide (m) 4-(3-Guanidinylethyl)-4,5-bis(4-fluoroanilino)phthalimide :
(n) 4(3-Guanidinylpropyl)-4,5-bis(4-fluoroanilino)phthalimide.
:
l~xample 14: The following is prepared analogously to one of the examples mentioned andlor the processes mentioned:

(A) 4-~3-AcetYlaminoProPvlw~5~iarilinoDhthalimide:

Analogously to E~xample 1, 200 mg (0.46 mmol) of 4-(3-acetylaminopropyl)-4,5-dianilino-phthalic anhydridc in 10 ml of ethylenc glycol is hcated at 120, ammonia gas being passed in with sti~ing for 3 h. The rcaction mixture is cooled, treated with concentrated sodium chloride solution and exlracted with ethyl acctate. The cthyl acetate phases are successively washed thrcc timcs with water and once with saturated sodiurn chloride solution, dried with sodium sulfate and evaporated. The evaporation residue is chromatographed on silica gel using ethyl acetate, and the product fractions are combinéd and evaporated. In this manner, the title compound is obtained in the form of a yellow foam, ~ 429 lM++H], TLC (silica gel, ethyl acetate) RfC0.30.

The star~ng material is prepared as follows:

a) ~(3-AcetYlaminoDropYl)-4.5-dianilinophthalic anhYdride A suspension of 390 mg (0.9 mmol) of dimethyl ~(3-aminopropyl)-4,5-dianilinophthalate (Example 2a), 500 mg of sodium hydroxide, 10 mg of sodium ascorbate, 25 ml of 2Nsodium hydroxide solution and 10 ml of methanol is s~ed at reflux under argon for 16 h.
The ~eaction mixture is adjusted to pH 1 using lN hydrochloric acid and concentrated on a rotary evaporator. The residue is digested with acetone, ~lteIed and sucked dry, treated ``~ 2109~3 with S0 ml of acetic anhydride and heated to 70C during the course of 2 h. The yellow suspension is filtered and the filtrate is evaporated. The evaporation residue is chromatographed on silica gel using ethyl acetate, and the product fractions are combined and evaporated. In this manner, dle tide compound is obtained in the fo~m of a yellow oil, FAB-MS: 430 [M~+~q, TLC (silica gel, e~yl acetate) Rf'0.38.

(B) 4-(3-Acetylaminopropyl)4,5-bis(4-fluoroanilino)phd alimide.

Example 15: (A) 1.3-Mphenvl-2-edhvloxvcarbonvl-2.3-dihYdrobenzimidazo~e-5.6-di- ~ `
carboximide and (B) 1,3-diphenyl-2-carboxv-2 3-dihYdrobenzimidazole-5 6-dicarbox-imide 2 mg of tin(II~ chloride hydrate and 1000 ~,ll (5.5 mmol) of ethyl diethoxyacetate (Fluka, Switzerland) are added under argon to a solution of 330 mg (1 mmol) of 4,5-dianilinophthalimide in 5 ml of dimethoxyethane. The reaction mixture is stirred at RT
for 16 h and filtered, the filtrate is adsorbed and chromatographed on silica gel using ethyl acetate/hexane 1:2. The product fracdons which are eluted first are evaporated, and the residuo i8 recrystalliud from ethyl acetate/hexane and dried in a high vacuum. ~ this manner, the title compound (A) is obtained in the form of golden yellow crystals, PAB-MS: 414 [M++E~, DC (silica gel, ethyl acctate/hexane 2:1) Rf'0.23. The product fractions which are then eluted are evaporated, and the residue is recrystallized from ethyl acetate/hexane and dTied in a high vacuum. In this manner, the title compound (B) is obtained in the form of golden yellow lustrous crystals, PAB-MS: 368 [M++HI, DC (silica gel, ethyl acetatelhexane 2:1) E40.15.
The stardng material is prepared as follows:
, a) 4.5-Bis(anilino)Dhthalimide A suspension of 230 mg (0.7 mmol) of dimethyl 4,5-bis(anilino)phthalate in 23 ml of ethylene glycol is heated to 120; ammonia gas is passed through with sturing for 24 h.
The reaction mixture is cooled and exlracted with ethyl acetate. The ethyl acetate phases are successively washed three times with water and once with sat~ sodium chloride soludon, dried with sodium sulfate and evaporated. The cvaporation residue is chromatographed on silica gd using dichloromethane/methanol 40:1, and theproductfractions are combined and evaporated. In this manner, the title compound is obtained in the form of yellow crystals, m.p. 215-217, FAB-MS: 330 [M~+Hl.
b) Dimethvl 4.5-bis(tIimethv!silvloxv~cvclohexa-1.4-diene-1.2-dicarboxvlate :

2iO9993 A soludon of 7.1 g (50 mmol) of dimethyl acetylenedicarboxylate in 30 ml of toluene is added dropwise under argon to 12.5 g (50 mmol) of 95% 2,3-bis(tTimethylsilyl-oxy)-1,3-butadiene and the mixture is then boiled at reflux for 19 h. The reacdon mixture is cooled, the solvent is evaporated and the residue is distilled in a high vacuum (0.1 mbar, 124-127). In this manner, the title compound is obtained as a yellow, highly viscous oil, IH-NMR (CDCl3): ~ = 0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H~.

c) Dimethvl 4~5-bis(anilino)~hthalate ~ ;
A solution of 5.6 g (15 mmol) of dimethyl 4,5-bis(trimethylsilyloxy)cyclohexa-1,4diene--1,2-dicarboxylate and 5.5 ml (6û mmol) of aniline in 60 ml of glacial acedc acid is boiled at reflux for 4 h. The reaction mixture is cooled, the solvent is evaporated, the dark brown residue is dissolved in dichloqomethane and the solution is washed successively with 20 ml of lN HCl, 50 ml of satd. NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and evaporated. The crude product is recrystallized from ethanol. In this manner, the title compound is obtained in the form of yellow crystals, m.p. 178, FAB-MS: 377 [M~+H].
Exam~le 16: 5000 capsules are prepared which each contain 0.25 g of active ingredient, o.g. ono of the compounds prepated in Examples 1-15:

Composition Active ingredient1250 g Talc 180 g Wheat starch 120 g Magnesium stearate80 g Lactose 20 g Process: The powdered substances are forced through a sieve with a mesh width of 0.6 mm and mixed. Portions of 0.33 g each of the mixture are filled in gelatin capsules by means of a capsule-911ing machine.

Claims

1. A compound of the formula I

(I) in which A1 and A2 independently of one another are substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl or hydrogen, where maximally one of the radicals A1 and A2 can be hydrogen, or A1 and A2 together are lower alkylene substituted by substituents other than lower alkyl and other than hydroxyl; Ar1 and Ar2 independency of one another are aryl, heteroaryl or unsubstituted or substituted cycloalkyl, the group -C(=X)- is -C(=O)-, -C(=S)-, -CH2- or -C(=CR1R2), where R1 and R2 independently of one another are hydrogen or lower alkyl, and R is hydrogen, lower alkyl, aryl-lower alkyl, aryl, amino, hydroxyl or lower alkoxy, salts thereof if salt-forming groups are present, and/or tautomers thereof if tautomerizable radicals are present.

2. A compound of the formula I according to claim 1, in which A1 and A2 independency of one another are hydrogen, lower alkyl which is substituted by up to 2 radicals selected from amino, mono- or di-lower alkylamino, cycloalkylamino, phonyl-lower alkylamino, phenylamino, lower alkanoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, hydroxyl, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, lower alkanoylthio, carboxyl, lower alkoxycarbonyl, phenyl lower alkoxycarbonoyl, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-hydroxycarbonyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower alkylthiocarbamoyl, N,N-di-lower alkylthiocarbamoyl, ureido, ureido substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, thioureido, thioureido substituted on one or both nitrogen atoms by lower alkyl, aryl of aryl-lower alkyl, hydrazino, hydrazino substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, amidino, amidino substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, guanidino, guanidino 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 alkyl-imino, lower alkanoylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower alkylhydrazono, N-lower alkanoylhydrazono, lower alkoxycarbonyl-hydrazono, and lower alkylthioimino, or heterocyclyl-lower alkyl, in which heterocyclyl is pyrrolyl, 2,5-dihydropyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrawlidinyl, triazolyl, tetrazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, indolyl, isoindolyl, benzimidazolyl, piperidinyl, piperazin-1-yl, morpholino, thiomorpholino, S,S-dioxothiomorpholino, 1,2-dihydro- or 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydro- or 1,2,3,4-tetrahydroisoquinolyl which is terminally bonded to the lower alkyl radical and is unsubstituted or substituted by lower alkyl, lower alkanoyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, where maximally one of the radicals A1 and A2 is hydrogen, or in which A1 and A2 together are lower alkylene, which is substituted by not more than 3 substituents selected from amino, amino-lower alkyl, mono- or di-lower alkylamino, mono- or di-lower alkylamino-lower alkyl, cycloalkylamino, cycloalkyl-amino-lower alkyl, phenyl-lower alkylamino, phenyl-lower alkylamino-lower alkyl,phenylamino, phenylamino-lower alkyl, lower alkanoylamino, phenyl-lower alkanoyl-amino, phenylcarbonylamino, lower alkanoylamino-lower alkyl, phenyl-lower alkanoyl-amino-lower alkyl, phenylcarbonylamino-lower alkyl, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkoxy-lower alkoxy-lower alkyl, phenyl-lower alkoxy, phenyl-lower alkoxy-lower alkyl, lower alkanoyloxy, lower alkanoyloxy-lower alkyl, mercapto, mercapto-lower alkyl, lower alkylthio, lower alkyl-thio-lower alkyl, lower alkylthio-lower alkylthio-lower alkyl, phenyl-lower alkylthio, phenyl-lower alkylthio-lower alkyl, lower alkanoylthio, lower alkanoylthio-lower alkyl, carboxyl, carboxyl-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-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 alkylcarbarnoyl-lower alkyl, N,N-di-lower alkylcarbamoyl-lower alkyl, N-hydroxy-carbamoyl, N-hydroxycarbamoyl-lower alkyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower alkyl, thiocarbamoyl, thiocarbamoyl-lower alkyl, N-lower alkylthiocarbamoyl, N-lower alkylthiocarbamoyl-lower alkyl, N,N-di-lower alkylthiocarbamoyl, N,N-di-lower alkylthiocarbamoyl-lower alkyl, ureido, ureido-lower alkyl, ureido or ureido-lower alkyl substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, thioureido, thioureido-lower alkyl, thioureido or thioureido-lower alkyl substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, hydrazino, hydrazino-lower alkyl, hydrazino or hydrazino-lower alkyl substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, amidino, amidino-lower alkyl, amidino or amidino-lower alkyl, substituted on one or both nitrogen atoms by lower alkyl, aryl or aryl-lower alkyl, guanidino, guanidino-lower alkyl, guanidino or guanidino-lower alkyl substituted 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 alkanoylimino-lower alkyl, hydroxyimino, hydroxyimino-lower alkyl, lower alkoxyimino, lower alkoxy-imino-lower alkyl, hydrazono, hydrazono-lower alkyl, N-mono- or N,N-di-lower-alkyl-hydrazono, N-mono- or N,N-di-lower alkylhydrazono-lower alkyl, N-lower alkanoyl-hydrazono, lower alkoxycarbonylhydrazono, N-lower alkanoylhydrazono-lower alkyl,lower-alkoxycarbonylhydrazono-lower alkyl, lower alkylthioimino and lower alkylthio-imino-lower alkyl; Ar1 and Ar2 independently of one another are aryl, imidazolyl, triazolyl, pyridyl, pyrimidinyl and triazinyl, which are unsubstituted or substituted by lower alkyl, hydroxyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, or cycloalkyl which is unsubstituted or substituted by lower alkyl or hydroxyl; the group -C(-X)- is -(C-O)-, -C(=S)- or -CH2-; and R is hydrogen, lower alkyl, amino, hydroxyl or lower alkoxy; where aryl is unsubstituted or substituted phenyl or naphthyl, in which the substituents are selected from one or more substituents from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent C atoms), cycloalkyl, 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, lower alkynyloxy or lower alkylene-dioxy (linked to two adjacent C atoms); lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy; mercapto; lower alkylthio, phenyl-lower alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenyl-lower alkylsulfonyl, phenylsulfonyl; halogen, nitro, amino; lower alkylamino, cycloalkylamino, phenyl-lower alkylamino, phenylamino; di-lower alkylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, lower alkanoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl; phenylcarbonyl; carboxyl; lower alkoxycarbonyl;carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl; cyano, phosphoryloxy substituted on the phosphorus by two radicals selected independently of one another from hydroxyl, lower alkoxy or phenyl-lower alkoxy, such as benzyloxy, or phosphoryloxy substituted on the phosphorus by phenylene-1,2-dioxy, sulfo; lower alkoxysulfonyl; sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl and N-phenylsulfamoyl, where phenyl groups occurring in the substituents are in each case unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxyl, halogen and/or trifluoromethyl; and in which cycloalkyl is C3-C8cycloalkyl, and pharmaceutically utilizable salts of these compounds if salt-forming groups are present.

3. A compound of the formula I according to claim 1, in which A1 and A2 independently of one another are selected from hydrogen and lower alkyl which is substituted by not more than 2 radicals selected from amino, mono- or di-lower alkylamino, lower alkanoylamino, hydroxyl, carboxyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, ureido, ureido substituted on one or both nitrogen atoms by lower alkyl, thioureido, thioureidosubstituted on one or both nitrogen atoms by lower alkyl, amidino, amidino substituted on one or both nitrogen atoms by lower alkyl, guanidino, guanidino substituted on one, two or all three nitrogen atoms by lower alkyl, oxo which is not bonded to the carbon which is bonded to the nitrogen carrying A1 or A2, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower alkylhydrazono, N-lower alkanoylhydrazono, lower alkoxy-carbonylhydrazono and lower alkylthioimino, where maximally one of the two radicals A1 and A2 can be hydrogen, or A1 and A2 together are lower alkylene which is substituted by one or not more than 3 substituents selected from amino, amino-lower alkyl, mono- or di-lower alkylamino, mono- or di-lower alkylamino-lower alkyl, hydroxy-lower alkyl, carboxyl, carboxyl-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, phenyl-lower alkoxycarbonyl-lower alkyl, carbamoyl, carbamoyl-lower alkyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl-lower alkyl,N,N-di-lower alkylcarbamoyl-lower alkyl, ureido, ureido-lower alkyl, ureido or ureido-lower alkyl substituted on one or both nitrogen atoms by lower alkyl, thioureido, thioureido-lower alkyl, thioureido or thioureido-lower alkyl substituted on one or both nitrogen atoms by lower alkyl, amidino, amidino-lower alkyl, amidino or amidino-lower alkyl substituted on one or both nitrogen atoms by lower alkyl, guanidino, guanidino-lower alkyl, guanidino or guanidino-lower alkyl substituted on one, two or all three nitrogen atoms by lower alkyl, oxo, oxo-lower alkyl, hydroxyimino, hydroxy-imino-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 alkoxy-carbonylhydrazono, N-lower alkanoylhydrazono-lower alkyl, lower alkoxycarbonyl-hydrazono-lower alkyl, lower alkylthioimino and lower alkylthioimino-lower alkyl; Ar1 and Ar2 are phenyl which is unsubstituted or substituted by a substituent selected from trifluoromethyl, hydroxyl, lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy,phenoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy, cyano, sulfo and sulfamoyl or not more than five times by halogen, the group -(C=X)- is -(C=O)- or -(C=S)-, and R is hydrogen or lower alkyl, and pharmaceutically utilizable salts thereof if salt-forming groups are present.

4. A compound of the formula I according to claim 1, in which A1 and A2 independently of one are hydrogen or lower alkyl which is substituted by a radical selected from amino, lower alkanoylamino, carbamoyl, ureido, ureido substituted on one or both nitrogen atoms by lower alkyl, thioureido, thioureido substituted on one or both nitrogen atoms by lower alkyl, amidino, guanidino and lower alkylthioimino, where maximally one of the radicals A1 and A2 can be hydrogen, or in which A1 and A2 together are lower alkylene which is substituted by a substituent selected from amino, amino-lower alkyl, hydroxy-lower alkyl, carboxyl, carboxy-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, lower alkanoyl, hydroxyimino, hydroxyimino-lower alkyl, hydrazono and hydrazono-lower alkyl; Ar1 and Ar2 are phenyl or 4-halophenyl; the group -(C=X)- is -(C=O)-; and R
is hydrogen, and pharmaceutically utilizable salts thereof if salt-forming groups are present.

5. A compound of the formula I according to claim 1, in which A1 and A2 independently of one another are 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 3-acetylaminopropyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2-(3-methylureido)ethyl, 2-(3-ethylureido)ethyl, 3-ureidopropyl, 3-thioureidopropyl, 3-(3-methylureido)propyl, 3-(3-ethylureido)propyl, 2-(3-methylthioureido)ethyl, 2-(3-ethylthioureido)ethyl, 3-(3-methylthioureido)propyl, 3-(3-ethylthioureido)propyl, 2-amidinoethyl, 3-amidinopropyl, 2-guanidinoethyl, 3-guanidinopropyl, 3-(N-methylthioimino)propyl or hydrogen, where maximally one of the radicals A1 and A2 can be hydrogen, or in which A1 and A2 together are methylene or ethylene which is substituted in the 1-position by aminomethyl, 3-aminopropyl, hydroxymethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propionyl, hydroxyimino-methyl or hydrazonomethyl; Ar1 and Ar2 independently of one another are phenyl or 4-fluorophenyl, the group -(C=X)- is -(C=O)-; and R is hydrogen, and pharmaceutically utilizable salts thereof if salt-forming groups are present.

6. A compound of the formula I according to claim 1, in which A1 and A2 independently of one another are 2-aminoethyl, 3-aminopropyl, 2-carbamoylethyl, 3-(3-methylureido)propyl, or hydrogen, where maximally one of the radicals A1 and A2 can be hydrogen, or in which A1 and A2 together are methylene or ethylene which is substituted in the 1-position by aminomethyl, hydroxymethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, propionyl, hydroxyiminomethyl or hydrazonomethyl; Ar1 and Ar2 are phenyl; the group -(C-X)- is -(C=O)-; and R is hydrogen, and pharmaceutically utilizable salts thereof if salt-forming groups are present.

7. 5,8-Diphenyl-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarbox-imide of the formula I according to claim 1.

8. 4-(3-Aminopropyl-5,8-ianilinophthalimide of the formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

9. 4-(3-[3-Methylureidolpropyl)-4,5-dianilinophthalimide of the formula I according to claim 1.

10. 4-(2-Aminoethyl)-4,5-dianilinophthalimide of the formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

11. 4-(3-Carbamoylethyl)-4,5-dianilinophthalimide of the formula I according to claim 1.

12. 5,8-Diphenyl-5,8-diaza-6-hydroximinomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide of the formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

13. 6-Aminomethyl-5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide of the formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

14. 5,8-Diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide-6-carboxylic acid of the formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

15. Methyl 5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarbox-imide-6-carboxylate of the formula I according to claim 1.

16. Ethyl 5,8-diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarbox-imide-6-carboxylate of the formula I according to claim 1.

17. 5,8-Diphenyl-5,8-diaza-6-hydrazonomethyl-5,6,7,8-tetrahydronaphthalene-2,3-di-carboximide of the formula I according to claim 1, or a pharmaceutically acceptable salt thereof.

18. 4-(3-Acetylaminopropyl)-4,5-dianilinophthalimide of the formula I according to claim 1.

19. 4-(3-[3-Methylthioureido]propyl)-4,5-dianilinophthalimide of the formula I according to claim 1.

20. 4-(3-Thioureidopropyl)-4,5-dianilinophthalimide of the formula I according to claim 1.

21. 1,3-Diphenyl-2-ethyloxycarbonyl-2,3-dihydrobenzimidazole-5,6-dicarboximide of the formula I according to claim 1.

22. 1,3-Diphenyl-2,3-dihydrobenzimidazole-5,6-dicarboximide of the formula I
according to claim 1, or a pharmaceutically acceptable salt thereof.

23. A compound of the formula I according to claim 1 selected from 5,8-bis(4-fluoro-phenyl)-5,8-diaza-6-hydroxymethyl-5,6,7,8-tetrahydro-naphthalene-2,3 dicarboximide, 4-(3-aminopropyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-methylaminopropyl)-4,5-di-anilinophthalimide, 4-(3-aminoethyl)-4,5-bis(4-fluoroanilino)phthalimide, 4(3-carbamoylpropyl)-4,5-bis(4-fluoroanilino)phthalimide, 5,8-bis(4-fluorophenyl-5,8-diaza--6-hydroxy-2,3-dicarboximide, 6-aminomethyl-5,8-bis(4-fluorophenyl)-5,8-diaza--5,6,7,8-tetrahydro-naphthalene-2,3-dicarboximide, 5,8-bis(4-fluorophenyl)-5,8-diaza--5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide-6-carbonylic acid, methyl 5,8-bis(4-fluorophenyl)-5,8-diaza-5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide--6-carboxylate, ethyl 5,8-bis(4-fluorophenyl)-5,8-diaza-5,6,7,8-tetrahydro-naphthalene-2,3-dicarboximide-6-carboxylate, 5,8-bis(4-fluorophenyl)-5,8-diaza--6-hydrazonomethyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboximide, 4-(3-amidino-propyl)-4,5-dianilinophthalimide, 4-(3-methylthioiminopropyl)-4,5-dianilinophthalimide, 4-(3-carbamoylpropyl)-4,5-dianilinophthalimide, 4-(3-ureidopropyl)-4,5-dianilino-phthalimide, 4-(3-[3-ethylureido]propyl)-4,5-dianilinophthalimide, 4-(3-aminobutyl)-4,5-dianilinophthalimide, 4-(3-[3-methylthioureido]ethyl)-4,5-dianilinophthalimide, 4-(3-[N'-ethylthioureido]ethyl)-4,5-dianilinophthalimide, 4-(3-[3-ethylthioureido]-propyl)-4,5-dianilinophthalimide, 4-(3-guanidinylethyl)-4,5-dianilinophthalimide, 4-(3-guanidinylpropyl)-4,5-dianilinophthalimide, 4-(3-amidinopropyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-methylthioiminopropyl)-4,5-bis(4-fluoroanilino)-phthalimide, 4-(3-carbamoylpropyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-ureido-propyl)-4,5-bis(4-fluoranilino)phthalimide, 4-(3-thioureidopropyl)-4,5-bis(4-fluoroanilino)phthalimide 4-(3-[3-methylureido]ethyl)-4,5-bis(4-fluoroanilino)-phthalimide, 4-(3-[3-ethylureido]ethyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-[3-methylureido]propyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-[3-ethylureido]propyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-aminobutyl)-4,5-bis(4-fluoroanilino)-phthalimide, 4-(3-[3-methylthioureido]ethyl)-4,5-bis(4-fluoranilino)phthalimide, 4-(3-[3-ethylthioureido]ethyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-[3-methylthio-ureido]propyl)-4,5-bis(4-fluoroanilino)phthalimide, 4-(3-[3-ethylthioureido]propyl)-4,5-bis(4-fluoranilino)phthalimide, 4(3-guanidinylethyl)-4,5-bis(4fluoranilino)-phthalimide, 4-(3-guanidinylpropyl)-4,5-bis(4-fluoroanilino)phthalimide and 4-(3-acetylaminopropyl)-4,5-bis(4-fluoroanilino)phthalimide, and pharmaceutically acceptable salts thereof if salt-forming groups are present.

24. A pharmaceutical preparation containing a compound of the formula I or a pharmaceutically utilizable salt of such a compound having at least one salt-forming group, according to any one of claims 1 to 3, together with a pharmaceutically utilizable carrier.

25. A pharmaceutical composition which is suitable for administration to a mammal who suffers from a disorder which responds to inhibition of a protein kinase, comprising an amount effective for inhibition of the protein kinase of a compound or a pharmaceutically utilizable salt of such a compound having at least one salt-forming group, of the formula I
according to any one of claims 1 to 3, together with at least one pharmaceutically acceptable carrier.

26. The use of a compound of the formula I or of a pharmaceutically utilizable salt of such a compound having at least one salt-forming group, according to any one of claims 1 to 3, for the production of pharmaceutical preparations for the treatment of diseases which respond to inhibition of protein tyrosine kinases or serine/threonine kinases.

27. The use of a compound of the formula I or of a pharmaceutically utitizable salt of such a compound having at least one salt-forming group, according to any one of claims 1 to 3, for thc inhibition of EGP receptor-associated protein tyrosine kinase.

28. A method for the treatment of mammats suffering from those disorders which respond to inhibition of protein ldnase, comprising the administration of a dose of a compound of the formula I or of a pharmaceutically utilizable salt of such a compound having at least one salt-forming group, which is effective for the treatment of these disorders, according to claim 1 to a mammal needing this treatment.

29. A process for the preparation of a compound of the formula I according to claim 1, which comprises a) reacting a carboxylic acid of the formula II

(II) in which Ar1, Ar2, A1 and A2 are as defined in formula I, or a reactive acid derivative thereof with an amino compound of the formula m H2N-R (III) in which R is as defined in formula I, functional groups in the starting materials which are not intended to participate in the reaction if necessary being present in protected form, and protective groups present being removed, or b) to prepare compounds of the formula I in which A1 and A2 together are methylene substituted by esterified carboxyl or lower alkanoyl, reacting a compound of the formula XI

(XI) in which Ar1, Ar2, X and R are as defined for compounds of the formula I, with an aldehyde of the formula XII

R0-CHO (XII) in which R0 is esterified carboxyl or lower alkanoyl, or a reactive derivative thereof, functional groups in the starting materials which are not intended to participate in the reaction if necessary being present in protected form, and protective groups present being removed, and, if desired, converting an obtainable compound of the formula I into anothercompound of the formula I and/or converting an obtainable salt into the free compound or into another salt, and/or converting an obtainable free compound of the formula I into a salt and/or separating an obtainable mixture of isomeric compounds of the formula I into the individual isomers.

30. A compound of the formula II

(II) in which Al and A2 independently of one another are substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl or hydrogen, it only being possible for maximally one of the radicals Al and A2 to be hydrogen, or Al and A2 together are lower alkylene substituted by substituents other than lower alkyl and other than hydroxyl; and Ar1 and Ar2 independently of one another are aryl, heteroaryl or unsubstituted or substituted cycloalkyl, salts thereof if salt-forming groups are present, and tautomers thereof if tautomerizable groups are present

31. A compound of the formula II' (II') in which A1 and A2 independently of one another are substituted lower alkyl, substituted lower alkenyl substituted lower alkynyl or hydrogen, it being possible for maximally one of the radicals Al and A2 to be hydrogen, or Al and A2 together are lower alkylene which is substituted by substituents other than lower alkyl and other than hydroxyl; Ar1 and Ar2 independently of one another are aryl, heteroaryl or unsubstituted or substituted cycloalkyl and R3 and R4 independently of one another are aryl, aryl-lower alkyl or lower alkyl, salts thereof if salt-forming groups are present, and tautomers thereof if tautomerizable groups are present.