CA2109992A1

CA2109992A1 - Phthalazinone derivatives

Info

Publication number: CA2109992A1
Application number: CA002109992A
Authority: CA
Inventors: Wilhelm Kump
Original assignee: Individual
Current assignee: Novartis AG
Priority date: 1992-11-27
Filing date: 1993-11-25
Publication date: 1994-05-28
Also published as: JPH06228108A; IL107749A0; KR940011448A; AU5184293A; ZA938847B; CN1095714A; EP0600831A1

Abstract

Abstract Phthalazinone derivatives The invention relates to compounds of formula I

(I) wherein A1 and A2 are hydrogen; unsubstituted or substituted lower alkyl, lower alkenyl or lower alkynyl; heterocyclyl-lower alkyl; acyl; lower alkylsulfonyl; or arylsulfonyl; or together are unsubstituted or substituted lower alkylene;
Ar1 and Ar2 are aryl, heteroaryl or unsubstituted or substituted cycloalkyl;
X is oxygen or sulfur; and Q is a divalent radical of the formula , which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y is oxygen or sulfur, and RA and RB are hydrogen, unsubstituted or substituted lower alkyl or acyl; or Q is a divalent radical of the formula

Description

2las~s~ , Phtha1azinone denvatives The invention relates to compounds of formula I, A, rl C
Al-N~ `N--RA

A2- N ~--Q
Ar2 wherein Al and A2 each, independently of the other, hydrogen, unsubstituted or substituted lower alkyl, unsubsdtuted or substituted lower alkenyl, unsubstituted or subsdtuted lower aL~cynyl, heterocyclyl-lower alkyl, acyl, lower alkylsulfonyl or alylsulfonyl, or Al and A2 ~ogether are unsubstituted o~ substituted lower alkylene;
Arl and Ar2 are each, independently of the other, aryl, heteroaryl or unsubstituted or substituted cycloalkyl;
X is oxygen or sulfi~r, and C N
Q is a divalent radical of the foqmula y/ R . which is bonded by its Y~arlying carbon atom to the Q-binding carbon atom of the benzene ring and by its RB-ca~Tying nitrogen atom to the RA-carrying r,itrogen atom in fonnula I, wherein Y, independently of X, is oxygen or sulfbr and RA and RB are each, independently of ~e other, hydrogen, unsubstituted or substi~uted lower aL~cyl or acyl;
or ~-C=N ~-~
Q is a d~valent radical of the formula H . which is bonded by its carbon atom to ~:~
the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen a~om in formula I, where~n RA has one of the meanings mentioned with the excep~on of acyl;

2~09~92 to salts thereof if salt-forming groups are present, and to tautomers thereof if tautomer-isable groups are present; to processes for the preparation of those compounds, to pharma-ceutical compositions comprising those compounds and to the use of those eompounds in the therapeutic treatment of the human or animal body or for the preparation of pharma-ceutical compositions.

The general terms used hereinbefore and hereinafter preferably have the following meanings within the scope of this applieation:

The term "lower" denotes a radieal having up to and ineluding 7, especially up to and ineluding 4, and mare espeeially having 1 to 3 earbon atoms, unless speeified otherwise. ~;

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

Lower alkenyl has from 2 to 7, preferably from 3 to 7, but especially 3 or 4 earbon atoms and is e.g. allyl or erotyl.

Lower allcynyl has from 2 to 7, preferably from 3 to 7, but especially 3 or 4 carbon atoms and is e.g. propyn-l- orpropyn-2-yl or 2-butyn-1-yl.

Substitutedlower allcyl is preferably lower allcyl as def~ned above whieh is substituted by up to 4, preferably up to 2, radieals seleeted from amino, as in amino-methyl, -ethyl, -propyl or -butyl; mono- or di-lower alkylamino wherein the lower allcyl radieal is mono-or di-substituted by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower al~ylamino, di-lower alkylamino, mereapto, lower aLlcylthio, lower alkylsulfinyl, lower aL~ylsulfonyl, earboxy, lower aL~coxycarbonyl, carbamoyl, N-lower aL~ylearbamoyl, N,N-di-lower alkylearbamoyl and/or by eyano, but is preferably unsubsti-tuted, sueh as aminomethyl, aminoethyl, aminopropyl or aminobutyl; cycloalkylamino, phenyl-lower alkylamino or phenylamino; aeylamino, e.g. lower aLlcanoylamino, phenyl-lower aLIcanoylamino or phenylearbonylalnino ( - benzoylamino); hydroxy, as in hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl; lower aL~coxy wherein the lower aL~yl radieal is mon~ or di-substituted by hydroxy, lower aL~coxy, phenyl-lower aLIcoxy, lower aLkanoyloxy, halogen, amino, lower alkylamino, di-lower aL~ylamino, mercapto, lower alkylthio, lower aL~cylsulfinyl, lower aL~ylsulfonyl, carboxy, lower aLIcoxycarbonyl, carbamoyl, N-lower aLkylcarbamoyl, N,N-di-lower aL~ylcarbamoyl and/or by cyano, but is ~10 9f~ 9~

preferably unsubstituted; phenyl-lower alkoxy; acyloxy, especially lower alkanoyloxy;
mercapto; lower alkylthio wherein the lower alkyl radical is mono- or di-substituted by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, ha10gen, amino, lower aL~cylamino, di-lower aL~cylamino, mercapto, lower aLkylthio, lower aLkylsulfinyl, lower alkylsulfonyl, carboxy, lower aL~oxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl and/or by cyano, but is preferably unsubstituted; phenyl-lower alkylthio; acylthio, especially lower alkanoylthio; carboxy, as in carboxy-methyl, -ethyl or -propyl; esterified carboxy, e.g. lower aLlcoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, especially in methoxy- or ethoxy-carbonyl-methyl, -ethyl or -propyl, or phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl; cyano;
carbarnoyl, as in carbamoylmethyl, carbamoylethyl or carbamoylpropyl; N-lower aLl~yl-carbamoyl; N,N-di-lower alkylcarbamoyl; N-hydroxycarbamoyl; N-phenylcarbamoyl;
thiocarbamoyl; N-lower alkylthiocarbamoyl; N,N dilower alkylthiocarbamoyl; ureido;
ureido substituted at one or both nitrogen atoms by lower aL~yl, aryl or by aryl-lower aL~yl, especially 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower aLlcylureido, 1- or 3-phenylureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-phenyl-lower aLkylureido, e.g.
3-lower allcylureido, such as 3-methyl- or 3-ethyl-ureido, especially in 3-methyl- or 3-ethyl-ureido-methyl, -ethyl or -propyl; thioureido; thioureido substituted at one or both nitrogen atoms by lower aL~yl, aryl or by aryl-lower alkyl, especially 1- or 3-mono-, 1,3-or 3,3~i- or 1,3,3-tri-lower alkylthioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3-or 3,3-di- or 1,3,3-tri-phenyl-low alkylthioureido, e.g. 3-lower alkylthioureido, such as ~ , 3-methyl- or 3-ethyl-thioureido, especially in 3-methyl- or 3-ethyl-thioureido-methyl, :
-ethyl or -propyl; hydrazino; hydrazino subs~ted at one or both nitrogen atoms by lower - ~
alkyl, aryl or by aryl-lower alkyl, especially 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri- ~ ~ -lower alkylhydrazino, 1- or 2-phenylhydrazino; 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-phenyl-lower alkylhydrazino, e.g. 2,2-di-lower aL~cylhydrazino, such as 2,2~imethyl- or 2,2-diethyl-hydrazino; amidino, as in amidino-methyl, -ethyl or -propyl; amidino substi-tuted at one or both nitrogen atoms by lower aL~cyl, alyl or by aryl-lower alkyl, especially N1- or N2-mono-, Nl,N2- or N1,N1-di- or Nl,Nl,N2-tri-lower aL~cylamidino, N1- or N2-phenylamidino, Nl- or N2-mono-, Nl,N2- or Nl,Nl-di- or Nl,N1,N2-tri-phenyl-lower aLkyl-amidino, e.g. Nl,Nl-di-lower alkylamidino, such as Nl,Nl-dimethyl- or N1,N1-diethyl- -amidino; guanidino, as in guanidino-methyl, -ethyl or -propyl; guanidino substituted at one, two or all three nitrogen atoms by lower alkyl, aryl or by aryl-lower aLIcyl, especially 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 alkyl- or -phenyl-lower alkyl-guanidino, especially 3,3-di-lower aL~cylguanidino, such as 3,3-dimethylguanidino or 3,3- ;

21~92 diethylguanidino; oxo which is not bonded to the carbon atom that is bonded to the Al- or A2-carrying nitrogen, as in 2-oxopropyl or 3-oxo-n-butyl; thioxo; imino; lower alkylimino;
acylimino, especially lower aLl~anoylimino, such as acetylimino; hydroxyimino (H0-N=), as in hydroxyiminomethyl (H0-N=CH-), hydroxyimino-ethyl or -propyl; lower aLlcoxy-imino, such as methoxyimino; hydrazono, as in hydrazono-methyl, -ethyl or -propyl; N-mono- or N,N-di-lower alkylhydrazono; N-acylhydrazono, especially N-lower aLlcanoyl-hydrazono, such as acetylhydrazono, or 10wer aL~oxycarbonylhydrazono, such as tert-but-oxycarbonylhydrazono; lower alkylthioimino, such as methyl- or ethyl-thioimino, especially in methylthioimino- or ethylthioimino-methyl, -ethyl or -propyl; and aryl, especially unsubstituted phenyl or phenyl o-, m- or p-substituted by a radical selected from - -lower alkyl, such as methyl or ethyl, hydroxy, lower alkoxy, such as methoxy, halogen, such as fluorine or iodine, carboxy, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano, or pentafluorophenyl, e.g. in benzyl. Preferably, lower aLIcyl is linear and is termina11y substituted by one of the said substituents. ~-Substituted lower alkenyl is preferably lower alkenyl as defined above, especially having from 3 to 7, more especially 3 or 4 carbon atoms, which is subsdtuted by up to 4 radicals, but preferably by one radical, selected from the substituents mentioned in the definition of substituted lower al~yl. In the case of certain subsdtuents, tautomers are possible by alternadon of the double bond. For example hydroxy, mercapto or N-bonded subsdtuents that still have a free hydrogen atom at the bonding nitrogen atom can tautomerise by bonding to a carbon atom of a triple bond to form oxo and thioxo and imino compounds respecdvely; subsdtuents bonded by nitrogen to a double bond, such as hydroxyimino or hydrazono, can also tautomerise when they are present in conjugadon with a double bond ~ ~
in the lower alkenyl radical; such compounds can also exist in tautomeric equilibria ~ j Preferred subsdtuted lower alkenyl radicals are those in which there is no tautomerism, ~-that is to say where e.g. hydroxy, mercapto or N-bonded subsdtuents that sdll have a free -~
hydrogen atom at the bonding nitrogen atom are not bonded to a carbon atom in the lower aL~enyl radical from which a double bond originates, and/or where subsdtuents bonded by - - -nitrogen to a double bond, such as hydroxyimino or hydrazono, are not in conjugadon with ~ -a double bond in the lower alkenyl radical. Preferred to subsdtuted lower aL~enyl, however, is unsubsdtuted lower aLIcenyl A1 andlor A2, especially when bonded by a saturated carbon atom. ;

Subsdtuted lower aL~ynyl is preferably lower aLkynyl as defined above, especially having from 3 to 7, more especially 3 or 4 carbon atoms, which is substituted by up to 4 radicals, -~1~(3~)'3~

but preferably by one radical, selected from the substituents mentioned in the definition of substituted lower alkyl. Analogously to the definition of tautomers and tautomeric equi-libria for substituted lower alkenyl, corresponding tautomers and tautomeric equilibria may also exist for substituted lower alkynyl. Preferred to substituted lower alkynyl is unsubstituted lower alkynyl Al and/or A2, especial1y when bonded by a saturated carbon atom.

Heterocyclyl-lower alkyl is one of the above-mentioned lower alkyl radicals, preferably methyl, ethyl or n-propyl, which is substituted, preferably at the terminal carbon atom, by heterocyclyl, which is especially a saturated, partially saturated or unsaturated single ring that is bonded by a ring nitrogen atom and contains from 3 to 7, especially from 5 to 7, ring atoms which may include, in addidon to the bonding nitrogen atom, up to two further hetero atoms selected from nitrogen, sulfur and/or oxygen; is present as a single ring or may be up to twice, but preferably once, benzofused, cyclopenta-, cyclohexa- or cyclo-hepta-fused; and may be unsubstituted or substituted especially by lower alkyl, lower aLlsa-noyl, hydroxy, lower aLtcoxy~ halogen, cyano and/or by trifluoromethyl, e.g. pyrrolyl, 2,5-dihydropy~Tolyl, pyIrolinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyra~olidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1,3,4-triazolyl, tetrazobl, such as 1- or 2-tetrazolyl, - ~ -telrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, te¢ahydro-isothiazolyl, indolyl, isoindolyl, benzimidazolyl, piperidinyl, piperazin-l-yl, morpholino, thio-morpholino, S,S-dioxothiomorpholino, 1,2~ihydro- or 1,2,3,~tetrahydro-quinolyl, or 1,2-dihydr~ or 1,2,3,4-tetrahydro-isoquinolyl, the said radicals being unsubstituted or substituted as above, especially by lower aL~yl, e.g. in 4-lower aLlcyl-piperazin-l-yl, such as 4-methyl- or 4-ethyl-piperazin-1-yl, or by lower aL~canoyl, e.g. in 4-lower alkanoyl-piperazin-l-yl, such as 4-acetyl-piperazin-1-yl.

Acyl is a radical of an unsubstituted or substituted lower aLkanecarboxylic acid (lower alkyl-(C=O)-) or lower alkanethiocarboxylic acid (lower aL~cyl-(C=S)-) bonded by a i -carbonyl or thiocarbonyl group, the substituents being selected, preferably each independ-ently of the others, from one or more radicals, especially up to three radicals, from the ~ -~roup consisting of hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, such as fluorine, chlorine or bromine, amino, lower alkylamino, di-lower alkyl- - -amino, mercapto, lower aL~ylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxy, lower aL~coxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl,phenyl, naphthyl, such as 1- or 2-naphthyl, fluorenyl, such as 9-fluorenyl, phenyl or naphthyl each substituted by halogen, such as fluorine or chlorine, trifluoromethyl, :, - . : , . . . , ~ :

2~09~

hydroxy, lower alkoxy andlor by cyano, and cyano; a radical of an unsubstituted or substituted arylcarboxylic acid bonded by a carbonyl or thiocarbonyl group, prefcrably selected from benzoyl or naphthylcarbonyl each unsubstituted or substituted by halogcn, such as fluorine or chlorinc, trifluoromethyl, hydroxy, lower alkoxy and/or by cyano;
carbamoyl or thiocarbamoyl; the radical of an N-substituted carbamic acid or thiocarbamic acid bonded by its aminocarbonyl group or aminothiocarbonyl group, respectively, in which the N-atom is preferably substituted by one or two radica1s sclccted from lower alkyl and substitutcd lower aL~cyl, substituted lowcr alkyl being substitutcd especially by the substituents mentioned above for substituted lower aLlcanecarboxylic acids, and prcferably being subsdtutcd by up to three, but especially by onc, of those subsdtuents; or the radica1 of a semiester of carbonic acid bondcd by its carbonyl group, which radical is prefcrably sclected from lower aL~coxycarbonyl and subsdtutcd lower all~oxycarbonyl, there being present preferably up to three, and is especially one, of the subsdtuents as defined above for subsdtutcd lower alkanecarboxylic acids, and isespecially lowcr aLkanoyl, halo-lower alkanoyl, such as trifluo~ or trichloro-acctyl, phenyl-lower alkanoyl, such as phenylacotyl, benzoyl, carbamoyl, N-mono- or N,N-di- ~;
Iower alkylcarbamoyl, N-mon~ or N,N-bis-(hydroxy-lower alkyl)carbamoyl, thio- -carbamoyl, N-mono- or N,N-di-lower alkylthiocarbamoyl, N-mono- or N,N-bis-(hydroxy-lower alkyl)thiocarbamoyl, lowcr al~oxycarbonyl, such as tert-butoxycarbonyl, ~ ~ ~
or phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl. Acyl is especially lower ~ -aLlcanoyl, amino-lower alkanoyl, such as aminoacetyl, carbamoyl or thiocarbamoyl. In prefer~d compounds of formula I, acyl may be omitted from the definidon of RA and RB
in favour of the other definitions.

Lower alkanoyl is preferably formyl, acetyl, propionyl, n-butyryl, pivaloyl or valeroyl, especially formyl, acetyl or propionyl.

Halogen is especially fluorine, chlorine, bromine or iodine, more especially fluorine or iodine.

Lower aLlcylsulfonyl (= lower aLlcyl-SO2-) is preferably methane- or ethane-sulfonyl.

Arylsulfonyl (= aryl-SOr) preferably contains an aryl radical as defined below and is especially benzenesulfonyl or benzenesulfonyl substituted in the benzene radical by lower aL~yl, lower alkoxy, hydroxy, halogen andJor by aifluoromethyl, but preferably by one of the said radicals, e.g. toluenesulfonyl, such as ~toluenesulfonyl.

2 1 0 9 t~

Lower aLIcylene which is formed by Al and A2 together is unbranched, has especially from 1 to 4, more especially 2 or 3, carbon atoms, and is unsubstituted or substituted by one or more, preferably up to 3, especially one, substituent(s) selected from lower aL~cyl, such as methyl or ethyl, amino, amino-lower aLl~yl, such as amino-methyl, -ethyl or -propyl, mono- or di-lower aLkylamino, mono- or di-lower alkylamino-lower alkyl, wherein the lower aLI~yl radical is mono- or di-subsdtuted by hydroxy, lower aLkoxy, phenyl-lower aLkoxy, lower aLkanoyloxy, halogen, amino, lower aLtcylamino~ di-lower allcylamino, mercapto, lower aLkylthio, lower aL~cylsulfinyl, lower alkylsulfonyl, carboxy, lower aL~coxycarbonyl, carbamoyl, N-lower aL~cylcarbamoyl, N,N-di-lower aL~cylcarbamoyl and/or by cyano, but is preferably unsubstituted, cycloaL~ylarnino, cycloalkylamino-lower alkyl, phenyl-lower allylamino, phenyl-lower aLIcylamino-lower alkyl, phenylamino, phenylamino-lower alkyl, acylamino, e.g. Iower alkanoylamino, phenyl-lower alkanoyl-amino or phenylcarbonylamino ( - benzoylamino), acylamino-lower alkyl, e.g. lower aLI~anoylamino-lower aLkyl, phenyl-lower aL~canoylamino-lower aL~cyl or phenylcarbonyl-amino-lower alkyl ( - benzoylatnino-lower aL~cyl), hydroxy, hydroxy-lower aLkyl, e.g.
hydroxymethyl, hydroxyethyl or hydroxypropyl, lower aL~oxy or lower aL~oxy-loweralkyl, wherein the terminal lower aL~cyl radical is mono- or di-substituted by hydroxy, lower aL~oxy, phenyl-lower aLt~oxy, lower alkanoyloxy, halogen, amino, lower allcyl-amino, di-lower alkylamino, mercapto, lower alkylthio, lower aLIcylsulfmyl, lower aL~cylsulfonyl, carboxy, lower aLIcoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, - ~ ~ -N,N-di-lower aL~ylcarbamoyl andlor by cyano, but is preferably unsubstituted, e.g.
2-methoxy- or 2-ethoxy-ethoxy-lower aLIcyl, phenyl-lower alkoxy, such as benzyloxy, phenyl-lower aL~coxy-lower aLIcyl, such as 2-benzyloxyethyl, acyloxy, especially lower aL~anoyloxy, acyloxy-lower alkyl, especially lower aL~canoyloxy-lower aL~cyl, such as 2-acetoxyethyl, mercapto, mercap~lower alkyl, e.g. mercaptomethyl or mercaptoethyl, lower aL~cylthio or lower alkylthio-lower aL~cyl wherein the terrninal lower alkyl radical is ~-mono- or di-substituted by hydroxy, lower aLlcoxy, phenyl-lower aLl~oxy, lower alkanoyl-oxy, halogen, amino, lower aLkylamino, di-lower aL~cylamino, mercapto, lower alkylthio, lower aL~cylsulfinyl, lower aL~cylsulfonyl, carboxy, lower aLtcoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano, but is preferably unsubstituted, e.g. 2-methylthio- or 2-ethylthio-ethylthio-lower aLcyl, phenyl-lower aL1cylthio, such as benzylthio, phenyl-lower aLkylthio-lower aLtcyl, such as 2-benzyl-thio-ethyl, acylthio, especially lower aLtcanoylthio, acylthio-lower aLkyl, especially lower aL~anoylthio-lower aL~cyl, such as 2-acetyldlioethyl, carboxy, carboxy-lower aL~cyl, such as carboxymethyl, esterified carboxy, e.g. lower aL~coxycarbonyl, such as methoxycarbonyl, . . , ~ . , .

~1~'3~9~

ethoxycarbonyl or tert-butoxycarbonyl, esterified carboxy-lower alkyl, e.g. Iower alkoxy-carbonyl-lower aL~yl, such as methoxycarbonylmethyl, ethoxycarbonylmethyl or tert-but-oxycarbonylmethyl, or phenyl-lower aLlcoxycarbonyl-lower alkyl, such as benzyloxycar-bonylmethyl, cyano, cyano-lower aLkyl, carbamoyl, carbamoyl-lower aLlcyl, such as carbamoyl-methyl, -ethyl or -propyl, N-lower aLlcylcarbamoyl, such as N-methyl- or N-ethyl-carbamoyl-methyl, -ethyl or -propyl, N,N-di-lower aLlcylcarbamoyl, N-lower alkylcarbamoyl-lower aLkyl, N,N-di-lower aLlcylcarbamoyl-lower aLlcyl, N-hydroxy-carbamoyl, N-hydroxycarbamoyl-lower aLlcyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower aL~yl, thiocarbamoyl, thiocarbamoyl-lower aLlcyl, N-lower aLlcylthiocarbamoyl, N-lower alkylthiocarbamoyl-lower aLlcyl, N,N-di-lower aL~ylthiocarbamoyl, N,N-di-lower aLkylthiocarbamoyl-lower alkyl, ureido, ureido-lower alkyl, ureido or ureido-lower aLlcyl each substituted at one or both nitrogen atoms by lower alkyl, aryl or by aryl-lower aL~cyl, especially 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower alkylureido, 1- or 3-phenyl- - ~
ureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-phenyl-lower aL~cylureido, e.g 3-lower ~ -aL~ylureido, such as 3-methyl- or 3-ethyl-ureido, 1- or 3-mono-, 1,3-di- or 3,3-di- or 1,3,3-tri-lower allcylureido-lower alkyl, 1- or 3-phenylureido-lower aL~yl, 1- or 3-mono-, ~ ~ -1,3- or 3,3-di- or 1,3,3-tri-phenyl-lower alkylureido-lower alkyl, e.g. 3-lower alkyl- -ureido-lower alkyl, such as 3-methyl- or 3-ethyl-ureido-lower alkyl, especially 3-methyl-or 3-ethyl-ureido-methyl, -ethyl or -propyl, thioureido, thioureido-lower aL~yl, thioureido or thioureido-lower aLIcyl subsdtuted at one or both nilrogen atoms by lower alkyl, aryl or by aryl-lower all~rl, especially 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-lower alkyl-thioureido, 1- or 3-phenylthioureido, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-phenyl~
lower alkylthioureido, e.g. 3-lower alkylthioureido, such as 3-methyl- or 3-ethyl-thio- -ureido, 1- or 3-mono-, 1,3-di- or 3,3-di- or 1,3,3-tri-lower alkylthioureido-lower aL~yl, 1- -.
or 3-phenylthioureido-lower aLIcyl, 1- or 3-mono-, 1,3- or 3,3-di- or 1,3,3-tri-phenyl-lower a1kylthioureido-lower alkyl, e.g. 3-lower alkylthioureido-lower alkyl, such as 3-methyl- or 3-ethyl-thioureido-lower alkyl, especially 3-methyl- or 3-ethyl-thioureido-methyl, -ethyl or -propyl, hydrazino, hydrazino-lower alkyl, such as hydrazino-methyl, -ethyl or -propyl, hydrazino or hydrazino-lower aLkyl substituted at one or both nitrogen atoms by lower aL~yl, aryl or by aryl-lower aL~cyl, especially 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-lower aLlcylhydrazino, 1- or 2-phenylhydrazino, 1- or 2-mono-, 1,2- or 2,2-di- or 1,2,2-tri-phenyl-lower alkylhydrazino, e.g. 2,2-di-lower aLIcylhydrazino, such as 2,2-dimethyl- or 2,2-diethyl-hydrazino, 1- or 2-mono-, 1,2- or 2,2~i- or 1,2,2-tri-lower aL~cyl-hydrazino-lower alkyl, 1- or 2-phenylhydrazino-lower alkyl, 1- or 2-mono-, 1,2- or 2,2-di-or 1,2,2-1ri-phenyl-lower alkylhydrazino-lower alkyl, e.g. 2,2-di-lower alkylhydrazino-lower aL~yl, such as 2,2-dimethyl- or 2,2-diethyl-hydrazino-lower aL~yl, amidino, 210~
9.

amidino-lower allcyl, such as amidino-methyl, -ethyl or -propyl, amidino or arnidino-lower aL~yl substituted at one or both nitrogen atoms by lower allcyl, aryl or by aryl-lower allcyl, especially Nl- orN2-mono-, Nl,N2- or Nl,NI-di- or Nl,Nl,N2-tri-lower allcylamidino, Nl-or N2-phenylamidino, Nl- or N2-mono-, Nl,N2- or Nl,NI-di- or Nl,Nl,N2-tri-phenyl-lower allcylarnidino, e.g. Nl,Nl-di-lower aLIcylamidino, such as Nl,Nl-dimethyl- or Nl,NI-diethyl-amidino, Nl- or N2-mono-, Nl,N2- or Nl,NI di- or Nl,Nl,N2-tri-lower allcyl-amidino-lower allcyl, Nl- or N2-phenylamidino-lower alkyl, Nl- or N2-mono-, Nl,N2- or Nl,NI-di- or Nl,NI,N2-tri-phenyl-lower aUcylamidino-lower allcyl, e.g. Nl,NI-di-lower allcylamidino-lower allcyl, such as Nl,NI-dimethyl- or Nl,NI-diethyl-amidino-lower allcyl, guanidino, guanidino-lower aUcyl, such as guanidino-methyl, -ethyl or -propyl, guanidino or guanidino-lower allcyl substituted at one, two, or all three nitrogen atoms by lower allcyl, aryl or by aryl-lower allcyl, especially 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 allcyl- or -phenyl-lower aUcyl-guanidino, especially 3,3-di-lower allcylguanidino, such as 3,3-dimethylguanidino or 3,3-diethylguanidino, 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 j2,3,3- or 1,1,3,3-tetra-orl,1,2,3,3-penta-lowerallcyl-or-phenyl-lowerallcyl-guanidino-loweraUcyl, :
cspeciaUy 3,3-di-lower aUcyl-guanidino-lower allyl, such as 3,3-dimethylguanidino-lowa allcyl or 3,3-diethylguanidino-lowa aUcyl, oxo, oxo-lower allcyl, especially lower aUcanoyl, such as formyl, acetyl or propionyl, thioxo, thioxo-lower allcyl, imino, imino-lower aUcyl, lower aUcylimino, lowa aUcylimino-lower aUcyl, acylimino, especially lower aLtianoyl-imino, such as acetylimino, acylimino-lower allcyl, especially lower allcanoylimino-lower aUcyl, such as acetylimin~lowa aUcyl, hydroxyimino, hydroxyimino-lower allcyl, such as hydroxyiminomethyl, hydroxyiminoethyl or hydroxyiminopropyl, lower allcoxyimino or lowa aUcoxyimino-lower alkyl, such as methoxyimino or methoxyimino-lower allcyl,hydrazono, hydrazono-lower aUcyl, such as hydrazGnomethyl, hydrazonoethyl or hydra-zonopropyl, N-mono- or N,N-di-lowa aUcylhydrazono, N-mono- or N,N-di-lower allcyl- -hydrazono-lower allcyl, N-acylhydrazono, especiaUy N-lower allcanoylhydrazono, such as acetylhydrazono, or lower aUcoxycarbonylhydrazono, such as tert-butoxycarbonylhydra-zono, N-acylhydrazono-lowa allcyl, especiaUy N-lower allcanoylhydrazono-lowa alkyl, such as acetylhydrazono-lowa aUcyl, or lowa aL~coxycarbonylhydrazono-lowa allcyl, such as tert-butoxycarbonylhydrazono-lowa allcyl, lower allcylthioimino, such as methyl- or ethyl-thioimino, and lowa allcylthioimino-lower allcyl, such as methyl- or ethyl-thio-imino-lower allcyl, especially methyl- o~ ethyl-thioimino-methyl, -ethyl or -propyl.
Aryl is preferably phenyl or naphthyl, such as 1- or 2-naphthyl. The phenyl and naphthyl , " ; ~ , . A; , ~

210~f~

radicals may be unsubsdtuted or may be subsdtuted especially as indicated in the follow-ing for phenyl. Aryl is preferaUy phenyl which is unsubstituted or substituted by one or more, preferably up to 5, especially one or two, and more especially by one subsdtuent especially in the p-posidon or, in the case of halogen, especially fluorine, by up to S
subsdtuents from the group consisdng of hydrocarbyl, e.g. Iower alkyl, lower alkenyl, lower aLlcynyl, lower aLlcylene (linked to two adjacent carbon atoms), cycloalkyl, phenyl-lower alkyl or phenyl; subsdtuted hydrocarbyl, e.g. Iower alkyl, which is substituted, e.g., by hydroxy, lower aL~coxy, phenyl-lower aLkoxy, lower alkanoyloxy, halogen, amino, lower aLIcylamino, di-lower aLlcylamino, mercapto, lower aL~ylthio, lower aL~cylsulfinyl, lower alkylsulfonyl, carboxy, lower aLlcoxycarbonyl, carbamoyl, N-lower aLlcylcarbamoyl, N,N-di-lower aLlcylcarbamoyl and/or by cyano; hydroxy; etherified hydroxy, e.g. lower aL~coxy, halo-lower aL1coxy, phenyl-lower alkoxy, phenoxy, lower aL~cenyloxy, halo-lower alkenyloxy; or lower aL~ynyloxy; lower alkylenedioxy (linked to two adjacent carbon atoms); esterified hydroxy, e.g. Iower aLlcanoyloxy, phenyl-lower aL~canoyloxy or phenyl-carbonyloxy ( - benzoyloxy); mercapto; etherified mercapto which may or may not be -oxidised, e.g. Iower alkylthio, phenyl-lower alkylthio, phenylthio, lower aL~ylsulfinyl ~-S(=O)-Iower aLlcyl], phenyl-lower alkylsulfinyL phenylsulfinyl, lower aLlcylsulfonyl [-S(02)-lower aLl~yl], phenyl-lower alkylsulfonyl or phenylsulfonyl; halogen; nitro; amino;
monohydrocarbylamino, e.g. Iower alkylamino, cycloalkylamino, phenyl lower aLlcyl-amino orphenylamino; dihydrocarbylamino, e.g. di-lower al~ylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl lower aL~ylamino, lower alkyleneamino or lower aL~cyleneamino intenupted by -O-, -S- or -NR" (wherein R" is hydrogen, lower alkyl or acyl, e.g. Iower alkanoyl); acylamino, e.g. Iower aL~anoylamino, phenyl-lower al~anoyl-amino or phenylcarbonylamino ( - benzoylamino); acyl, e.g. Iower aLlcanoyl, phenyl-lower aLkanoyl or phenylcarbonyl (= benzoyl); carboxy; esterified carboxy, e.g. lower aLlcoxycarbonyl; amidated carboxy, e.g. carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower aLlcylcarbamoyl, N-hydroxycarbamoyl or N-phenylcarbamoyl; cyano; phosphoryl-oxy substituted at the phosphorus atom by two radicals selected independendy of one another from hydroxy, lower alkoxy and phenyl-lower aL~coxy, such as benzyloxy, or phos-phoryloxy substituted at the phosphorus atom by phenylene-1,2-dioxy (that is to say a Il , . . .
O--P--O
radical of the formula al O ~, wherein Ql and Q2 are each, independently of Q/ ~
the other, hydrogen, lower alkyl or phenyl-lower allyl, or Ql and Q2 together are ortho- :
phenylene); sulfo (SO3H); esterified sulfo, e.g. lower allcoxysulfonyl; and amidated sulfo, ,. .

- 11 - z~ ~f,~l3(,~

e.g. sulfamoyl (-SO2NH2), N-lower aL~ylsulfamoyl, N,N-di-lower a1kylsulfamoyl or N-phenylsulfamoyl; phenyl groups present in the subsdtuents each being unsubstituted or subsdtuted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl. Aryl is especially unsubsdtuted phenyl, phenyl o-, m- or p-subsdtuted by a radical selected from lower aL~yl, such as methyl or ethyl, hydroxy, lower alkoxy, such as methoxy, halogen, such as fluorine or iodine, carboxy, lower aLlcoxycarbonyl, such as methoxy- or ethoxy-carbonyl, and cyano, or is pentafluo~ophenyl.

Lower alkylene linked to two adjacent carbon atoms of a benzene ring is preferab1y C3-C4alkylene, e.g. 1,3-propylene or 1,4-butylene.

Lower alkylenedioxy linked to two adjacent carbon atoms is preferably Cl-C2aL~ylene-dioxy, e.g. methylene- or 1,2-ethylene-dioxy.

Lower aLlcyleneamino is preferably C4-C7- and especially C4-Cs-alkyleneamino, e.g. pip-eridino. Lower alkylcneamino intcrrupted by ~, -S- or -NR'- is preferably such a C4-C7-and especially CrC5-aLlcyleneamino in which a ring carbon atom has been rcplaced by the corresponding hetero group, and is especially morpholino, thiomorpho1ino, piperazino or 4-lower alkyl- or 4-lower aLlcanoyl-piperazino. --Hetcroaryl is an unsaturated heterocyclic radical and is preferably linked by a ring carbon atom. It is especially a 5- or ~membcred ring having up to threc hetero atoms selected from N, O and S, especially N, e.g. imidazolyl, triazolyl, pyridyl, pyrimidinyl or triazinyl, ~ ~ -especially pyridyl. Those radicals may bc unsubsdtuted or subsdtuted e.g. by lower alkyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl.

Pyridyl is e.g. 2-, 3- or 4-pyridyl.

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

Triazolyl is e.g. 1,2,4-triazol-3- or -4-yl or 1,2,3-triazol-4-yl.

PyrimWnyl is e.g. 2-, 4- or S-pyrimidinyl.

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

2~09~92 Heteroaryl is especially 2-, 3- or 4-pyridyl, 2-, 4- or S-pyrimidinyl or 1 ,3,5-triazin-2-yl.

Cycloalkyl is preferably C3-C8- and especially C5-C7-cycloaL~yl, indicating that it contains from 3 to 8 and from 5 to 7 ring carbon atoms respectively, and is, e.g. cyc10-pentyl, cyclohexyl or cycloheptyl. The said cycloalkyl radicals may also be substituted e.g. by lower aLkyl or hydroxy or also by halogen, such as fluorine or chlorine.
(1) ~2) The divalent radical Q is either a divalent radical of the fo~mula ~ C--N ~
I/ ~
B
which is bonded by its Y-carrying carbon atom [arrow (1)] to the Q-binding carbon atom of the benzene ring and by its RB~arrying nitrogen atom [a~row (2)] to the RA-carrying nitrogen atom in forrnula I, wherein Y, independently of X, is oxygen or sulfur, so that corresponding compounds of forrnula I have the fo~nula IA

Arl 11 Al-N~ `N' A
l I (IA) A2-N' ~ ~C,N~R
Ar2 Y

wherein the radicals are as defined for compounds of formula I, or exist as tautomers thereof, as described hereinafter; or a divalent radical of the forrnula ~ ~ -(1) (2) -C = N , which is bonded by its carbon atom ~arrow (1)] to the Q-bindin~g H -:
carbon atom of the benæne ring and by its nitrogen atom [arrow (2)] to the RA~arrying nitrogen atom in formula I, so that corresponding compounds of formula I have the formula IB

_13_21~92 Arl 11 Al- N ~ ~ N ' A
l I (IB) A2-N' ~ ~C~N
Ar2 H

wherein the radicals have the meanings already given.

In the definition of each of the individual groups -(C=X)- and -(C=Y)- as -(C=O)- or -(C=S)-, preference is given to -(C=O)-.

The compounds of formula IA wherein RA and RB are each hydrogen, and ~e compounds of formula IB wherein RA is hydrogen are preferred, the remaining radicals in both cases being as defined for compounds of formula I.

Where reference is made hereinbefore and hereinafter to thioxo, that substituent is not bonded to terminal methyl.

Salts of compounds according to the invention having salt-forming groups are especially pharrnaceutically acceptable~ non-toxic salts. Por example, compounds of formula I
having basic groups, e.g. primary, secondary or tertiary amino groups (also in hydrazino or hydrazono) may form acid addition salts 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 arginine or lysine. Compounds of formula I having an acidic group, for example a -carboxy, sulfo or phospho group, form e.g. metal or ammonium salts, such as alkali metal ~ -and aL~caline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, such as lower alkyl-amines, e.g. triethylamine, hydroxy-lower al;kylamines, e.g. 2-hydroxyethylamine, bis(2-hydroxyethyl)amine or tris(2-hydroxyethyl)amine, basic aliphatic esters ofcarboxylic acids, e.g. ~arninobenzoic acid 2-diethylaminoethlyl ester, lower alkylene-amines, e.g. l-ethylpiperidine, cycloaLIcylamines, e.g. dicyclohexylamine, or benzyl- ~-arninesj e.g. N,N'-dibenzylethylenediamine, dibenzylamine or benzyl-~-phenethylamine.
Compounds of fonnula I having an acidic and a basic group may also be in the form of internal salts, that is to say in zwitterionic form.

, : ~ - -:

210999~

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

For the purposes of isoladon or purificatdon it is also possible to use pharmaceutically unacceptable salts, e.g. picrates or perchlorates. Only the phannaceutically acceptable, non-toxic salts are used therapeutically and these are therefore preferred.

The compounds of formula I of the present invendon may be in the form of individual isomers or in the form of mixtures of isomers in those cases where several isomers are possible. Where asymmetrically substituted double bonds or rings are present, e.g. in substituted lower alkenyl Al or A2, the cis and/or the trans form may be present, and in the case of doubly bonded nitrogen in ring systems, as in hydroxyimino, for example the syn-or the and-form may be present. Asymmetrically substituted carbon atoms may be in the (S)-, (R)- or (R,S)-form. When appropriate structural prerequisites are met, mixtures of isomers (such as racemates or diastereoisomeric mixtures), pure diastereoisomers or pure enantiomers may accordingly be present.

Where it is possible for tautomers of compounds of the present invention to exist, whether in pure form or in equilibrium with other tautomers, those tautomers are also included in the definitions given hereinbefoPv and hereinafter. TautomeTisable groups exist, e.g., if a hydrogen atom is bonded to an O, S or N atom that is bonded to a carbon atom from which a double bond originates, allowing imine/enan~ine or (~io-)keto/enol tautomerism, as the case may be. That applies, for example, in compounds of fMmula I that contain thioureido or guanidino radicals or derivatives thereof substituted as defined above having at least one hydrogen atom at a nilrogen atom. In parlicular tautomers may be present if one of the radicals RA and RB in compounds of foqmula I is hydrogen whilst the other has one of the meanings mentioned with the exception of hydrogen: if, in compounds of formula IA, RA
is hydrogen, X is oxygen and RB is one of the mentioned radicals other than hydrogen, then preferentially that hydrogen migrates, with the simultaneous migration of the double bond, to X (-(C=X)-NH-NRB'- (wherein RB' has the meanings given for RB with the exception of hydrogen) then becomes -(C-XH)=N-RB'- in formula 1), and if, in com-pounds of formula IA. RB is hydrogen, Y is oxygen and RA is one of the mentionedradicals other than hydrogen, then preferentially that hydrogen migrates, with ~e simultaneous n~igration of the double bond, to Y (-NRA'-NH-(C=Y)- (wherein RA' has the meanings given for RA with the exception of hyd~gen) then becomes -NRA'-N=(C-YH)-, . ", !,. .:: :` ` ' )'3!1'3'~

in formula I). It is also possible for tautomeric forms to be present in equilibrium, for example in solutions. All such tautomers, the occulrence of which is familiar to the person skilled in the art, are also included. Preferred tautomeAsable compounds of formula I are those which exist in only one tautomeric form or in which one tautomerAc form strongly predominates.

All hitherto investigated compounds of formula LA wherein Y is oxygen, RA is one of the mentioned radicals other than hydrogen and RB is hydrogen are in the tautomeric form of formula IC

Arl ~
Al-N~ C`N~R A' A2-N~c~N (IC) Ar2 Y--H

wherein Y is oxygen, RA' is one of the radicals mentioned for RA other than hydrogen and the rernaining radicals have the meanings given. Analogous situations may also exist in ~ - -corresponding compounds wherein Y is sulfur.

The compounds according to the invention have valuable, especia11y pharm~cologically useful, properties. In particular they exhibit specific inhibitoTy actions which are of pharmacological interest. They act especially as tyrosine protein ldnase inhibitars and ~ -exhibit e.g. a strong inhibition of the tyrosine kinase ac~vity of the receptor for the epidermal growth factor tEGF) and c-erbB2 kinase. Those Teceptor^specific enzyme activ~
ities play a key role in the signal transmission in a large number of mammal cells, ~ -including human cells, especially epithelial cells, cells of the immune syst~m and cells of the central and peripheral nervous system. The EGF-induced activation of the receptor-associated tyrosine protein kinase (EGF-R-TPK~ is in vaTious types of cells a prerequisite for cell division and thus for proliferation of a cell population. The addition of EGF~
receptor-specific tyrosine kinase inhibitors therefore inhibits the prolifera~on of those ~ -cells.

The inhibition of EGF-receptor-specific tyrosine protein kinase tEGF-R-TPK) can be demonstrated e.g. by the method acco~ding to E. McGlynn et aL (see Europ. J. Biochem.

.. ~ . - , ~ ~ , - , , 2~0999'~

207, 265-275 (1992)). The compounds of the invendon inhibit the enzyme acdvity by 50 % (ICso) especially in concentradons of approximately 0.01 ,uM or above, more especially from 10-7 to 10-3M, e.g. from 1.2 x 10-6 to 104M. They furthermore exhibit, likewise in the micromolar range, especially from lo-7 to 10-3M, more especially from 1 x lo-6 to 104M, e.g. also an inhibidon of the cell growth of an EGP-dependent cell line, for example the epidermoid mouse keratinocyte cell line. EGF-sdmulated cell proliferadon of epidermal BALB/MK-keratinocytes is used to measure that inhibidon of cdl growth (process described in Meyer, T., et aL, Int. J. Cancer 43, 851 (1989)). Por proliferation, those cells rely to a great extent on the prescnce of EGP (Weissmann, B. E., Aaronson, S.
A, Cell ~, 599 (1983). In order to carry out the test, BALB~MK-cells (10 000/well) are transferred to 96-well microtitre platcs and incubated overnight. The test substances ~dissolvod in DMSO) are addod in various concentrations (in series of diludons) such that the final concentradon of DMSO does not cxceed 1 %. After the addidon, the plates are incubated for three days during which time the control cultures without test substancc arc ablo to undergo at least threc cell division cyclcs. The growth of the MK cells is mcasured by means of methylene bluc staining. ICs0-values are defined as that concentradon of the respective test substance which results in a 50 % decrease compared with the control cultures without inhibitor.

In addition to or instead of EGF-R-TPK, the compounds according to the invention also ~ -inhibit other tyrosine kinascs that are involvod in signal transmission modiated by trophic factors, e.g. abl kinasc (ICSo down to approximately 10-7 M), kinases from the family of the src kinases (ICSo down to approxitnatcly 10~ M) and c-erbB2 kinase (HER-2), and also se~ine/threonine kinases, e.g. p~tein kinæ C ~down to 10~ M), all of which play a part in growth regulation and transformadon in mammal cells, including human cells.

The inhibidon of c-erbB2 tyrosine kinase ~ER-2) can be demonstratod e.g. analogously to the method used for EGF-R-TPK according to E. McGlynn _ aL (see Europ. J. Bi~chem. 207, 265-275 (1992)). c-erbB2 kinase can be isolated and its acdvity determined ac-cording to known protocols e.g. according to T. Akiyama _ al., Science 232, 1644 (1986).
or preferably according toP. M. Guy et al. (see J. Biol. Chem. 267, 13851-13856 (1992)).

The compounds according to the invention are thus also suitable for the inhibition of the processes mediated by those and related tyr~sine kinases.

The and-tumour acdvity in vivo is tested, for example, using human epithelial cell -17- ~10~9~, carcinoma A431 (ATCC No. CRL 1555), which is transplanted into hair1ess female BALB/c mice (Bomholtgard, Denmark). For the experiments, tumours occur ing in vivo of approximately 1 cm3 diameter are removed from the anima1s by excision under sterile conditions. The tumours are homogenised, suspended in 10 volumes (w/v) of phosphate-buffered saline and injectcd s.c. (0.2 mUmouse, e.g. 106 cells/mouse) into the left flank of the animals. Treatment with a test substance is commenced 5 to 8 days after transplant-ation when the diameter of the tumours measures 4 to 5 mm. The test substance [for example dissolved in ~9Lauroglycol (1,2-p~pylene glycol monolaurate, mixture of both constitutional isomers; Gattefossé S.A., Saint Priest, France), ~9Gelucire (glycerides and ~
partial polygiycerides of fatty acid; Gattefosse S.A., Saint Priest, France) or sesame oil] is --administered p.o. daily for 15 successive days. The tumour growth is ascertained by -monitoring the vertical tumour diameter, and the tumour volume is calculated in accord- -ance with the formula 7~ x L x D2/6 (L = length, D = diameter of the tumour at right angles -~
to the tumour axis). The tesults can be given as a treatment/control (T/C) quotient as a -percentage .

The compounds according to the invendon are therefore useful, for example, in the treat-ment of benign or malignant tumours. They are capable of causing tumour regression and ~ n of preventing tumour metastasis and the growth of micrometastases. In pardcular they can be used in the case of epidermal hyperprolifetadon (psoriasis), in the treatment of neoplasia of an epithelial nature, e.g. mammary carcinomas, and in the case of Ieukaemias. -Tiae compounds can furdlermo~e be used in the treatment of those disorders of tbe immune system and those inflammadons in which protein kinases are involved. The cornpounds can also be used in the treatment of disotders of the central or peripheral nervous system -in which signal transmission by protein kinases is involved. Lasdy, the compounds of the present invention also have andmicrobial pr~perdes, making them suitable, e.g., for the treatment of disorders caused by bacteria, such as Salmonella typhimurium, viruses, such as Vaccinia virus, and other microhs that interact with protein kinases responsive to growth factors.

The compounds according to the invention may be used alone or in combination with other pharmacologically acdve 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) negative growth regulators, e.g. TGF-B or IFN-B, (f) aromatase -inhibitors, (g) anti-oestrogens or (h) cytostadc agents.
~ :-'~ ' -18- 21099!3~

In the groups of compounds of formula I mentioned in the following, general definitions, for example of substituents, can be replaced, independently of one another, by more specific definitions mentioned in the general defimitions.

Preference is given to compounds of formula I wherein Al and A2 are each, independently of the other, hydrogen; lower alkyl; subsdtuted lower aLIcyl, which is substituted by up to 2 radicals selected from amino, mono- or di-lower aLkylamino wherein the lower alkyl radical is mono- or di-substituted by hydroxy, lower alkoxy, phenyl-lower aL~oxy, lower aL~anoyloxy, halogen, amino, lower aL~ylarnino, di-lower aLlcylamino, mercapto, lower aL~cylthio, lower alkylsulfinyl, lower aLIcylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower aLlcylcarba noyl, N,N-di-lower aL~cyl-carbamoyl and/or by cyano but is preferably unsubstituted, C3-C8cycloaL~cylamino, phenyl-lower alkyla nino, phenylamino, lower aL~anoylamino, phenyl-lower aL~canoyl-amino, phenylcarbonylamino, hydroxy, lower aL~coxy wherein the lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl Al or A2 but is preferably unsubstituted, phenyl-lower aL~oxy, lower aL~anoyloxy, mercapto, lower aLkyl-thio wherein the lower alkyl radical is mon~ or di-substituted as above in di-lower aLlcylamino-lower alkyl Al or A2 but is preferably unsubstituted, phenyl-lower aLkylthio, lower alkanoylthio, carboxy, lower allcoxycarbonyl, phenyl-lowa alkoxycarbonyl, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower aL~ylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower allylthiocarbamoyl, N,N-di-lower aLIcylthio-carbamoyl, ureido, ureido subs~tuted at one or both nitrogen atoms by lower alkyl, thio-ureido, thioureido substituted at one or both nitrogen atoms by lower aL~yl, hydrazino, hydrazino subsdtuted at one or both nitrogen atoms by lower alkyl, amidino, amidino substituted at one or both nitrogen atoms by lower alkyl, guanidino, guanidino substituted at one, two or all three nitrogen atoms by lower aLkyl, oxo which is not bonded to the carbon atom that is bonded to the Al- or A2-carrying nitrogen atom, thioxo, imino, lower alkylimino, lower aLl~anoylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono-or N,N-di-lower alkylhydrazono, N-lower aL~canoylhydrazono, lower alkoxycarbonyl-hydrazono and lower alkylthioimino; lower alkenyl or lower alkynyl each of which is sub-sdtuted by one of the radicals mendoned for substituted lower alkyl Al and/or A2 but is preferably unsubsdtuted; heterocyclyl-lower alkyl wherein heterocyclyl is a radical selected from pyrrolyl, 2,5-dihydropyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyraz-olinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1,3,4-triawlyl, tetrawlyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetra-hydro-isothiawlyl, indolyl, isoindolyl, benzimidazolyl, piperidinyl, piperazin- l-yl, - 19 - ~ 3 ~ ~

morpholino, thiomorpholino, S,S-dioxothiomorpholino, 1,2-dihydro- or 1,2,3,4tetra-hydro~uinolyl and 1,2-di- or 1,2,3,~tetra-hydroisoquinolyl, which radical is unsubstituted or is substituted especially by lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl, is bonded by a ring nitrogen atom and is bonded ~ .
terminally to the lower alkyl; lower alkanoyl; halo-lower alkanoyl; phenyl-lower aLl~anoyl;
benzoyl; carbamoyl; N-mono- or N,N-di-lower aLlcylcarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)carbamoyl; thiocarbamoyl; N-mono- or N,N-di-lower aL~cylthio- ~:
carbamoyl; N-mono- or N,N-bis-(hyd~oxy-lower aLlcyl)thiocarbamoyl; lower aL~oxy- -: .
carbonyl; phenyl-lower aLlcoxycarbonyl; lower alkylsulfonyli benzenesulfonyl or benzene- . -~
sulfonyl subsdtuted in the benzene radical by lower aLlcyL lower alkoxy, hydroxy, halogen .: -andtor by trifluoromethyl, preferably by one of the radicals mendoned; ~ -or ~ -Al and A2 together form lower alkylene which is unsubsdtuted or subsdtuted by up to three subsdtuents selected from lower al~yl, amino, amino-lower alkyl, mono- or di-lower ~s - :
alkylamino, mono- or di-lower aL~ylamino-lower alkyl, wherein the terminal lower aL~yl radical is mono- or di-subsdtuted as above in di-lower alkylamino-lower alkyl Al or A2 but is preferably unsubsdtuted, C3-C8cycloalkylamino; C3-C8cycloalkylamino-loweralkyl, phenyl-lower aLlcylamino, phenyl-lower alkylamino-lower alkyl, phenylamino, phcnylamino.-lower alkyl, lower alkanoylamino, phenyl-lower allcanoylamino, phenyl-carbonylamino, lower alkanoylamino-lowcr alkyl, phenyl-lowcr al~anoylamino-loweraLltyl, phcnylcarbonylamino-lower alkyl, hydt~xy, hydmxy-lower alkyl, lower aL~oxy or lower allcoxy-lower aL~cyL wherein the terminal lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl Al or A2 but is preferably unsubsdtuted, phenyl-lower alkoxy, phenyl-lower alkoxy-lower alkyl, lower alkanoyloxy, ::: :
lower aLIcanoyloxy-lower allcyl, mercapto, mcrcapto-lower al~yl, lower alkylthio or lower aL~ylthio-lower alkyl, wherein the terminal lower aLlcyl radical is mono- or di-subsdtuted :~
as above in di-lower alkylatnino-lower alkyl Al or A2 but is preferably unsubstituted, phenyl-lower alkylthio, phenyl-lower alkylthio-lower aL~yl, lower aLlcanoylthio, lower :
allcanoylthio-lower aLlcyl, carboxy, carboxy-lower aL~yl, lower a1koxycarbonyl, lower aLcoxycarbonyl-lower alkyl, phenyl-lower alkoxycarbonyl-lower alkyl, cyano, cyano-lower alkyl, carbamoyl, carbamoyl-lower alkyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl-lower alkyl, N,N-di-lower aL~cylcarbamoyl-lower alkyl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower aL~cyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower alkyl, thiocarbamoyl, thiocarbamoyl-lower aL~cyl, N-lower alkylthiocarbamoyl, N-lower aL~cylthiocarbamoyl-lower aL~cyl, N,N~i-lower alkylthio- - s carbamoyl, N,N-di-lower alkylthiocarbamoyl-lower aL~cyl, ureido, ureido-lower aL~cyl, -20- 210999~

ureido or ureido-lower alkyl substituted at one or both nitrogen atoms by lower allcyl, thioureido, thioureido-lower aLkyl, thioureido or thioureido-lower aLkyl substituted at one or both nitrogen atoms by lower aLlcyl, hydrazino, hydrazino-lower alkyl, hydrazino or hydrazino-lower aLlcyl substituted at one or both nitrogen atoms by lower aL~cyl, amidino, amidino-lower alkyl, amidino or amidino-lower allcy1 substituted at one or both nitrogen atoms by lower alkyl, guanidino, guanidino-lowa alkyl, guanidino or guanidino-lower alkyl substituted at one, two or all three nitrogen atoms by lower alkyl, oxo, oxo-lower aUcyl, thioxo, thioxo-lower aL~cyl, imino, imino-lower aL~cyl, lower aL~cylimino, lower aL~ylimino-lower alkyl, lower alkanoylimino, lower aLkanoylimino-lower alkyl, hydroxy-imino, hydroxyimino-lower aLlcyl, lower aL~oxyimino, lower aLlcoxyimino-lower alkyl, hydrazono, hydrazono-lower alkyl, N-mono- or N,N-di-lower alkylhydrazono, N-mono- or NtN-di-lower alkylhydrazono-lower aLlcyl, N-lower aL~anoylhydrazono, lower alkoxy-carbonylhydrazono, N-lower aL~anoylhydrazono-lower aLlcyl, lower aLlcoxycarbon hydrazono-lower aLkyl, lower al~ylthioimino and lower alkylthioimino-lower aL~yl;
Arl and Ar2 are each, independently of the other, unsubstituted phenyl; phenyl o-, m- or p-subsdtuted by a radical selected from lower alkyl, such as methyl or ethyl, hydroxy, lower alkoxy, such as methoxy, halogen, such as fluorine or iodine, carboxy, lower aLlcoxycaTbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano; pentafluoro-phenyl; heteroaryl bonded by a ring nitrogen atom and selected from imidazolyl, triazolyl, pyridyl, pyNnidinyl and triazinyl, which are unsubsdtuted or subsdtuted by lower allcyl, hydroxy, lower allcoxy, halogen, cyano and/or by trifluoromethyl; or C3-C8cycloalkyl which is unsubstituted or subsdtuted by lower alkoxy or by hydroxy;
X is oxygen or sulfi~r, and C N
Q is a divalent radical of the formula y/ h . which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benæne ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur and RA and RB are each, independently of the other, hydrogen; unsubsdtuted or subsdtuted lowa alkyl as defimed above for Al and A2, especially unsubstituted lower alkyl or lower aLlcyl substituted by up to two radicals selected from amino, mono- or di-lower aLIcyl-amino, hydroxy and lower alkoxy; lower alkanoyl; halo-lower alkanoyl; phenyl-lower alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-di-lower aL~cylcarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)carbamoyl; thiocarbamoyl; N-mono- or N,N-di-lower alkylthiocarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)thiocarbamoyl; lower ~ --21- 2~999~

aLlcoxycarbonyl; or phenyl-lower aLlcoxycarbonyl; or Q (as alternative or further meaning of Q with reference to the last-mentioned divalent C=N
radical) is a divalent radical of the formula H ~ which is bonded by its carbon atom to dhe Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-car ying nitrogen atom in formula I, wherein . -RA is unsubsdtuted or subsdtuted lower aL~yl, preferably as defined above;
salts thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

Strong preference is given to compounds of formula I wherein Al and A2 are each, independendy of the odher, hydrogen; lower aLlcyl; substituted lower ~ -aL~yl which is substituted by up to 2 radicals, but preferably by one radical, selected from amino, mono- or di-lower alkylamino, hydroxy, lower alkoxy, carboxy, lower alkoxy~
carbonyl, phenyl-lower alkoxycaTbonyl, cyano, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower aL~cylcarbamoyl, ureido, ureido subsdtuted at one or both nitrogen atoms by lower aLlcyl, thioureido and diioureido subsdtuted at one or both nitrogen atoms by lower . - -alkyl; lower alkenyl; or lower alkynyl; or . -Al and A2 togedher form lower alkylene, which is unsubsdtuted or substituted by lower aL~cyl, amino, amino-lower aL~yl, mono- or di-lower aL~ylamino, hydroxy, hydroxy-lower aL~yl, lower alkoxy, lower alkoxy-lower alkyl, carboxy, carboxy-lower alkyl, lower - -aL~coxycarbonyl, lower- al~oxycarbonyl-lower aLlcyl, cyano, cyano-lower aL~yl, carbamoyl, carbamoyl-lower alkyl, N-lower alkylcarbamoyl, N,N-di-lower a11cylcarbamoyl, N-lower t alkylasrbamoyl-lower alkyl, N,N-di-lower alkylcarbamoyl-lower aLl~yl, thiocarbamoyl, - -dhiocarbamoyl-lower alkyl, N-lower aLlcyldliocarbamoyl, N-lower aL~cyldhiocarbamoyl-lower aLtcyl~ N,N-di-lower alkylthiocarbamoyl, N,N-di-lower aLkylthiocarbamoyl-lower aLkyl, ureido, ureido-lower alkyl, ureido or ureido-lower aLlcyl substituted at one or both :-nitrogen atoms by lower allcyl, thioureido, thioureido-lower aLlcyl or by thioureido or thio~
ureido-lower aL~cyl substituted at one or both nitrogen atoms by lower aL~cyl;
Arl and Ar2 are each, independently of the other, unsubstituted phenyl; phenyl o-, m- or p-subsdtuted by a radical selected from lower alkyl, such as methyl or ethyl, hydroxy, lower aLkoxy, such as methoxy~ halogen, such as fluorine or iodine, carboxy, lower aLkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and cyano; pentafluoro-phenyl; or C3-C8cycloaLl~yl; but preferably each represents the same radical;
Xisoxygenorsulfur;and ~:

- 22- 2~. 0 9 9 ~ ~.

C N
Q is a divalent radical of the formula y/ h . which is bonded by its Y-carrying carbon atom to the Q binding carbon atom of the benzene ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur, and RA and RB are each, independently of the other, hydrogen; unsubstituted lower aLtcyl or lower aLkyl substituted by a radical selected from amino, mono- or di-lower alkylamino, hydroxy and lower aL~oxy; lower alkanoyl; carbamoyl; N-mono- or N,N-di-lower aLkyl-carbamoyl; N-mono- or N,N-bis-~hydroxy-lower alkyl)carbamoyl; thiocarbamoyl;
N-mono- or N,N-di-lower alkylthiocarbamoyl; N-mono- oq N,N-bis-(hydroxy-lower aLIcyl)thiocarbamoyl; lower all~oxycarbonyl; or phenyl-lower aLI~oxycarbonyl; orQ (as alternative or further meaning of Q with reference to the last-mentioned divalent C=N
radical) is a divalent radical of the formula H . which is bonded by its carbon atom to the Q-binding catbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein RA is unsubstituted or substituted lower aLlcyl~ preferably as defined above;
salts thereof if salt-forming groups are present, and tautomers thereof if tautomeIisable groups are present.

Greater preference is given to compounds of formula LA, wherein Al and A2 are each, independendy of the other, hydrogen or lower aL~yl, or Al and A2 together are lower alkylene, especially ethylene; Arl and Ar2 are each, independently of the other, unsubstituted phenyl or phenyl substituted in the o-, m- or p-position, especially in the p-position, by halogen or by lower aLIcyl; ~ -X and Y are ea~h, independendy of the other, oxygen or sulfur, but preferably each - ~ :
represents ~e same one of the said radicals, especially oxygen; and RA and 1~B are each, independently of the other, hydrogen, lower alkyl, hydroxy-lower alkyl, such as 2-hydroxyethyl, carbamoyl or thiocarbamoyl;
and tautomers thereof if tautomerisable groups are present. -Greater preference is given also to compounds of formula IB, wherein Al and A2 are each, independendy of the other, hydrogen or lower aL~yl, or Al and A2 together are lower aL~cylene, especially ethylene;
Arl and Ar2 are each, independendy of the other, unsubstituted phenyl; phenyl substituted in the o-, m- or p-position, especially in the p-position, by halogen or by lower alkyl; or -23- 21(3~'3~
cyclohexyl which is unsubstituted or substituted by lower aL~cyl, such as methyl or ethyl, hydroxy or by halogen, such as fluorine or chlorine;
X is oxygen or sulfur, especially oxygen; and RA is hydrogen, lower aLky1, hydroxy-lower alkyl, such as 2-hydroxyethyl, carbamoyl or thiocarbamoyl; -and tautomers thereof if tautomerisable groups are present. If Y is oxygen, RA is one of the last-mentioned radicals other than hydrogen and RB is hydrogen, then preferendally the tautomeric fonn of fonnula IC having the cor esponding substituents is present.

Special preference is given to compounds of formula IA wherein A1 and A2 are hydrogen, Arl and Ar2 are each, independently of the othcr, a radical selected from phenyl, 4fluoro- - ~ - -phenyl and ~methylphenyl, but preferably each represents the same one of the said radicals, X and Y are each, independently of the other, oxygen or sulfur, but arc especially each - - --oxygen, and RA and RB are each, independendy of thc other, hydrogen, methyl, 2-hydroxyethyl or caIbamoyl; '~and tautomers thcIeof if tautomerisable groups are present. If Y is oxygen, RA is one of ~- -the last-mentioned radicals othcr dhan hydrogen and RB is hydrogen, prcferentially the tautomeric fonn of formula IC having the corresponding substituents is present. -Special preference is given also to compounds of formula IB wherein Al and A2 are hydrogen, Arl and Ar2 are each, independently of thc other, a radical selected from phenyl and cyclo- ~ -hexyl, X is oxygen or sulfur, especially oxygen, and RA is hydrogen.

Of all the compounds of for nula I mentioned hereinbefore, there are more especialb ~ ;
preferred those wherein Al and A2 are hydrogen; or one of the two radicals Al and A2 is hydrogen and the other falls under the definition of unsubstituted lower aL~cyl or lower alkyl substituted by one of the mentioned substituents;
or Al and A2 together are a radical which falls under the definitions of unsubstituted lower -~

-~

210~992 . 24 -alkylene and lower aL~cylene substituted by one of the mentioned substituents, especially unsubstituted lower alkylene;
whilst the remaining radicals have the meanings given, pharmaceutically acceptable salts thereof if salt-forming groups are present, and tautomcrs thereof if tautomerisable groups are present.

Most espesialliy preferred of all the compounds mentioned hereinbefore are those of fo~snula IA wherein each of the radicals RA and RB is hydrogen and the romaining radicals have the meanings given, or compounds of fonnula IB wherein the radicals havo the meanings given, saks thereof if salt-forming groups arc present, and tautomers thercof if tautomerisablc groups are present.

Most strongly prcferred arc the individual compounds of formula I mentioned in the Examples, salts thereof if salt-forming g~oups are present, and tautomers thereof if tautomerisable groups are present, and the prosesses mentioned therein for the prcparadon thercof; or pharmaceutical compositions comprising those compounds as active -ingredient, those compounds for use in a therapeutic method for the treatment of the human or animal body and the usc of those compounds in the therapeudc treatment of the ' human or animal body or for the preparadon of a pharmaceudcal composidon for the treat-ment of protein kinase~ependent disorders.

The compounds of formula I can be obtained according to pmsesses known ~ se, forexample as follows~

a) for the preparadon of a compound of formula I wherein Q is a divalent radical of the ~-C N
formula y/ b . which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benæne ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in fo~mula I wherein Y, independendy of X, is oxygen or sulfur, and RA and RB are each, independently of the other, hydrogen, unsubsdtuted or substituted lower alkyl or acyl and the remaining radicals have the meanings given, a dicarboxylic acid of formula n 2 ~ 0 9 ~ .3 ~.

Arl Al-N~,~C--OH
ll (II) A2- N ~ C--OH
Ar2 wherein Al, A2, Arl and Ar2 have the meanings given, or a reactive deIivative thereof wherein the radicals are as defined for compounds of formula I, is reacted with a hydra2ine compound of formula m RA NH NH RB (m) wherein RA and RB are as defined for compounds of formula I, it being possible for the compounds of formulae I~ and/or m also to be used in the fonn of salts if salt-forming groups are present, and functional groups in compounds of formulae II and/or m that are not to take part in the reaction if necessary being in protected fonn, and any protec~ing groups present are removed, or ) for the pr~paration of a compound of fo~nula I wherein Q is a divalent radical of C=N
formula H , which is bonded by its carbon atom t~ the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-calIying nitrogen atom in forrnula I
wherein RA is unsubstituted or substituted lower alkyl, : -a formylbenzoic acid derivative of fonnula ~, A,rl Al--N ~ C ~ H
A2--N ~ C--H
Ar2 ~:

wherein the radicals are as last defined, o~ a reactive derivauve thereof, is reacted with a ` ~ .
compound of f~rmula XIV, ~ - :

~. .. . - -- 26 - 2 ~ 9 '~ '~

RA NH NH2 (XIV) wherein RA is as last defined, any funcdonal groups that are not to take part in the reacdon if necessary being protected, and any protecdng groups present are removed, and, if desired, as additiona1 process steps, an obtainable compound of formula I is converted into a different compound of formula I, and/or an obtainable salt is converted into the free compound or into a different salt, and/or an obtainable free compound of formula I is converted into a salt and/or an obtainable mixture of isomers of compounds of formula I is separated into its isomers.

In the following more detailed description of the processes, the symbols Al, A2, Arl, Ar2, X, Y. RA and RB are each as defined for compounds of formula I unless specified otherwise.
.-More detailed descriPdon of the processes:

Process a) (Diamide formation) Dicarboxylic acids of formula II exist in free form or especially in the form of reactive derivatives in which one or both, but preferably both, carboxy groups may have been derivatised, for example in the form of an activated acid derivative or a reactive internal anhydride. The reacdve derivatives may also be formed in situ. The nvo carboxy groups -may be reacted simultaneously or in succession. Preferably, in that manner compounds of ~ -formula are obtained wherein RA and RB have the meanings given with the excepdon of acyl; from resulting compounds of formula I wherein RA and/or RB are hydrogen, it is then possible using additional process steps (see below) to obtain compounds of formula I
wherein RA andlor RB are acyl. Those compounds may also be obtained by reacting protected derivatives of formula III wherein one of the radicals RA and RB is acyl whilst in - -place of the other there is a protecting group. After removal of the protecting group the freed nitrogen atom, which carries a hydrogen atom, may then in a further reacdon step be reacted with the sdll underivatised second carboxy group. It is also possible for a compound of formula II protected at a carboxy radical to be reacted with a compound of formula III, followed by removal of the carboxy-protecdng group and renewed reaction to form a phthalazinedione derivadve.

~ . . .... : ~

-27- 2109~

The free carboxylic acid of for nula II may be activated, especially also in situ, for example by a strong acid, such as a hydrohalic, sulfuric, sulfonic or carboxylic acid or an acidic ion exchanger, e.g. hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, an unsubstituted or substituted, e.g. halo-substituted, aLIcanecarboxylic acid, or by an acid of formula II, preferably using an excess of the acid of formula II, if necessary with the water of reaction being bound by water-binding agents, with removal of the water of reaction by azeotropic distillation or with extracdve esterification, by an acid anhydride, especially an inorganic acid anhydride, for example a carboxylic acid anhydride, e.g. a lower aLkanecarboxylic acid anhydride (with the exception of formic acid anhydride), such as acetic anhydride, or by a suitable activadon or coupling reagent of the type listed hereinafter.

Acdvating and coupling reagents that may be used for activating carboxylic acids of formula II in situ are especially carbodiimides, e.g. a N,N'-di-CI-C4aL~cyl- or N,N'-di-Cs-C7cycloalkyl-carbodumide, such as diisopropylcarbodiimide or N,N'-dicyclohexyl- -carbodiimide, advantageously with the addition of an activation catalyst, such as N-hydroxysuccinimide or unsubstituted or subsdtuted, e.g. halo-, Cl-C7alkyl- or Cl-C7-alkoxy-substituted, N-hydroxy-benzotriazole or N-hydroxy-S-norbornene-2,3-dicarb-oxamide, Cl-C4alkylhaloformate, e.g. isobuql chloroformate, suitable carbonyl compounds, e.g. N,N-carbonyldiimidazole, suitable 1,2-oxazolium compounds, e.g. 2- ~ -ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate or 2-tert-buql-5-methyl-isoxazolium per-chlorate, suitable acylamino compounds, e.g. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro- -~ -quinoline, or suitable phosphoryl cyanamides or azides, e.g. diethylphosphoryl cyanamide ~ ~ ~
or diphenylphosphoryl azide, and also triphenylphosphine disulfide or l-Cl-C4alkyl-2- - -halopyAdinium halides, e.g. l-methyl-2-chloropyAdinium iodide.
. .
An activated acid derivadve is, for example, a compound of formula IIa A, rl --Al- N ~ C--Zl ¦¦ (IIa) A2- N~ 11--Z2 Ar2 -wherein Zl and/or Z2 are hydroxy or especially reactively activated hydr~xy, a maximum 2:l0~9~

of one of the two radicals Zl and Z2 being hydroxy. Z1 and/or Z2 may preferably be an azido group (obtainable, for example, by reaction of a corresponding acid ester by way of the corresponding hydrazide and treatment thereof with nitrous acid); halogen, especially chlor,ne or bromine (obtainable, for example, by reacdon with an organic acid halide, especially with an oxalyl dihalide, such as oxalyl dichloride, or especially with an inorganic acid halide, e.g. with an acid halide of phosphorus or sulfur, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride or thionyl bromide);
cyanomethoxy; phenoxy substituted in the o-, m- and/or p-position(s) by electron-attracdng subsdtuents, such as nit o, chlorine or fluorine, e.g. nitrophenoxy, such as 4nitrophenoxy or 2,4~initrophenoxy, or polyhalophenoxy, such as pentachlorophenoxy (which may be prepared, e.g., by treatment of the co~responding acid with chloroaceto-nitrile in the presence of a base, or by reaction of the acid with the corresponding phenol, e.g. nitrophenol or polyhalophenol, in the presence of a condensation agent, such as N,N'-dicyclohexylcarbodiimide); or an asymmetric acid anhydride, which may be obtained, for example, by the acdon of a salt, e.g. an aL~cali meta1 salt, such as the sodium or potassium salt, of an acid of formula II or of its reacdon partner, preferably of a lower ~ -aLlcanecarboxylic acid, such as acedc acid, on a respecdve complementary acid halide, : -especially in the case of reacdon with a salt of a carboxylic acid of formula II a carboxylic acid halide, e.g. chloride, or in the case of reacdon of a carboxylic acid halide of forrnula -IIa wherein Zl and Z2 are halogen, e.g. chlorine or bromine, with a salt of a lower alkane-carboxylic acid, especially sodium or potassium acetate. Zl and Z2 are preferably halogen, -such as chlorine or bromine, 4-nitrophenoxy or acyloxy, e.g. Iower alkanoyloxy, such as acetoxy.
-Internal anhydrides of dicarboxylic acids of formula II are especially those of formula IIb Arl O

A2 N~
Ar2 wherein Al~ A2, Arl and Ar2 are as defined for formula I. Those anhydrides are suitable on reacdon with compounds of formula III especially for the preparation of compounds of : `
2 1 ~ 2 formula I wherein RA and RB have the meanings given with the exception of acyl. The reaction takes place preferably in inert solvents, for example ethers, e.g. di-lower alkyl ethers, such as diethyl ether, or cyclic ethers, such as dioxane or tetrahydrofuran, in alcohols, such as methanol or ethanol, or in N,N-di-lower a1kylcarboxylic acid amides, such as dimethylformamide or dimethyl acetamide, at temperatures of from 0 C to the reflux temperature, preferably of from 40 C to the reflux temperature, e.g. at from approximately 50 C to approximately 67 C or a lower reflux temperature, if nccessary in the presence of a protective gas, such as nitrogen or argon. Internal anhydrides of formula IIb are the especially prcferred acid dedvatives of compounds of formula II. -If RA and/or RB in a starting matedal of formula III are acyl, the reaction is ca~ied out - -especially advantageously with a reacdve compound of formula II wherein Zl and Z2 are halogen, e.g. chlorine or bromine, in the presence of a strong base, such as an alkaline earth metal hydride, e.g. sodium hydride, preferably in an inert solvent, e.g. an acid amide, such as dimcthylformamide or l,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinonc, at ~ -temperatures of from 0 to 50 C, e.g. at room temperature.

A starting matedal of formula II is obtainable, for example, by hydrolysing a dicarboxylic ~-acid ester of formula IV

Ar Al--N ~ a)OR

A2--N ~COOR2 Ar2 ~ -wherein Rl and R2 are lower alkyl, especially methyl, and the remaining radicals have the meanings given, preferably in an acidic or aL~aline medium. For example, the hydrolgsis of a compound of formula IV 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 or potassium hydroxide, in a mixture of water and ethanol or methanol, at preferred temperatures of from 0 C to the reflux temperature of the reaction mixture in question, especially from approximately 60 C to the reflux temperature. The reaction is conducted especially preferably with the exclusion of oxygen, for example under a protective gas, such as argon or nitrogen. If the lower aLlcyl radicals Rl and/or R2 at the bonding carbon atom are branched, acid hydrolysis is also possible, for example using sulfuric acid or a hydrohalic 210~.'3~ ~

acid, such as hydrochloric acid. The compounds of formula II may also be prepared from analogues of compounds of formula IV that contain carboxy-protecting groups, forexample those mentioned hereinafter, instead of Rl andtor R2, by means of removal of the protecting groups. Ana10gues of compounds of formula IV that contain carboxy-protecting groups instead of Rl and/or R2 are obtained, for example, by using below, instead of the compounds of formula V, analogous compounds that contain a carboxy-protecting group instead of Rl and/or R2 (which compounds may be pIepared analogously to compounds of formula V) from which the compounds that contain carboxy-protecting groups instead of Rl and/or R2 and are analogous to the compounds of formula IV are produced by reactions analogous to those described below for compounds of formula IV themselves. By the removal of prol~:cting groups from resuldng analogues of compounds of formula IV under suitable condidons, preferably those mendoned hereinafter for the removal of protecting groups, it is possible to obtain the compounds of formula II.

A starting material of formula IV is prepared, e.g. by reacdng a cyclohexadiene of - -- - -formula V - ~ ~
, ~
Me3SiO COORl JU` (V), Me3SiO COOR2 wherein Me is methyl (alternatively other lower alkyl radicals may be present) and wherein Rl and R2 are as defined for compounds of formula IV, with an aniline of formula VI
AHN-Ar (VI) wherein A is especially hydrogen, unsubstituted or substituted lower aL~cyl, unsubstituted or subsd-tuted lower alkenyl, unsubsdtuted or subsdtuted lower alkynyl, heterocyclyl-lower aL~yl, acyl, lower aL~ylsulfonyl or arylsulfonyl, as defined above for Al or A2, and Ar is aryl, heteroaryl or unsubsdtuted or subsdtuted cycloalkyl, as defined above for Ar or Ar2, or with a dianilino-lower aL~cylene compound of formula VI' ' ~: :, ' ' 2~.~9992 Arl-NH-K-NH~Ar2 (VI~) wherein Arl and Ar2 are as defined for compounds of formula I, e.g. are phenyl, and K is substituted or, preferably, unsubstituted lower aL~ylene, as defined hereinbefore for unsubstitueed or substituted lower alkylene formed by Al and A2 together, with acid catalysis, for exarnple in a lower alkanecarboxylic acid, such as acetic acid, at temperatures of from 80 C to the reflux temperature, e.g. from 100 to approximately 140 C, [see. Matlin, Stephen A. and Barron, Kenneth, J. Chem. Res. Synop. 8, 24~247 (1990)]. Functional gTOUpS present in the stardng materials that are not to take part in the reaction are, if necessary, protected. Any protecting groups present may be removed in a suitable reaction step. Protecting groups, their inlroducdon and their removal are described hereinafter. Substituents at the radicals Ar may also be introduced, after the condensation, by methods of classical aromatic and heterocyclic chemistry or by enzymatic methods (e.g. 4-hydroxyladon).

The preparadon of compounds of formula V, which is carried out, e.g., by way of a Diels-Alder reaction from a 2,3-bis(tri-lower alk!ylsilyloxy)butadiene and an acetylenedicarb-oxylic acid di-lower aL~cyl ester, is also described in the quoted liteTature source (Matlin _ O and may be ca~Tied out in a manner analogous to that described therein.

To prepare asymmetric compounds of formula IV wherein Al and A2 and/or Arl and Ar2 are different, for example compounds of formula V may be reacted with two different compounds of formula VI - e.g. stepwise - and the desired compounds of formula IV
isolated by chromatographic separation, e.g. on silica gel.

FurtheImore, to prepare compounds of formula IV wherein the radicals have the meanings given with the exception of unsubstituted or substituted lower aLIcylelle foImed by Al and A2 together, for example compounds of foImula IV with hydrogen instead of Al and A2 may be 1) reacted with a reagent of formula VII ~-., W3-L (VII) wherein -32- ~.~099.'3~

W3 is unsubstituted or substituted lower aLlcy1, unsubstituted or subsdtuted lower alkenyl, unsubstituted or substituted lower aL~cynyl or heterocyclyl-lower aL~cyl, as defincd herein-before in the definition of A1 and/or A2, and when W3 iS substituted lower alkenyl or sub-stituted lower aL~ynyl, L is preferably bonded to a carbon atom from which a muldplc bond does not originate and is so selected that the reaction by substitution occurs more rapidly than does the addition to the multiple bond; and L is a nucleofugal group, preferably toluenesulfonyloxy or halogen, such as chlorine, bromine or iodine, or, if the radical W3 contains 2 or more carbon atoms, oxa (-O-) or thia (-S-) which is bonded to two vicinal carbon atoms (forming an oxirane or thiirane which reacts during the alkylation, which is cartied out especially in the presence of a strong base, such as lithium diisopropylamide, sodium amide or, especially, sodium hydride, at temper~tures of from 50 C to the boiling point of the reaction mixture, e.g. at from 80 to 100 C, in an acid amide, such as dimethylformamide, or a urea derivative, such as 1,3-dimethyl-3,4,5,~tetrahydro-2(1H)-pyrimidinone (DMPU), and during subsequent hydrolysis to yield a 2-hydroxy- or 2-mercapto-lower alkyl group), or aza (-NH-) which is bonded to two vicinal carbon atoms (forming an azirane which reacts during the reaction, which is carried out especially in the presence of a strong base, such as lithium diiso-propylamide, sodium amide or, especially, sodium hydlide, at temperatures of from 50 C
to the boiling point of the reaction mixture, e.g. at from 80 to 100 C, in an acid amide, such as dimethylformamide, or a urea derivative, such as 1,3~imethyl-3,4,5,~tetrahydro-2(1H)-pyrimidinone (DMPU), and during subsequent hydrolysis to yield a 2-amino-lower ~ ~
alkyl g~up), functional groups in the star~ng materials that are not to take part in the ~ -reaction being present in free form or in protccted form, and any protecting groups present are removed, if necessary, in suitable reacdon steps.

The reaction is carried out preferably in the presence of a strong base, such as an aLl~ali metal hyd~ide, e.g. sodiu n hydride, an aLcali metal arnide, such as sodium amide, or an alkali metal di-lower alkylamide, such as lithium diisopropylamide, especially sodium - -~
hyd~ide or sodium amide, which may be added, for example, in the form of a dispersion in oil, using an equimolar amount of the base with respect to the molar amount of the compound of formula IV having a hydrogen atom instead of each of Al and A2, or using ~-an excess of the base, for example from 1 to 5 times the molar amount, especially once or twice the molar amount, at temperatures of from room temperature to the reflux temper-ature of the reaction mixture, especially from approximately 80 to approximately 100 C, - -in an aprotic, especially polar, solvent, such as an acid amide, e.g. dimethylformamide, 1,3-dimethyl-3,4,5,~tetrahydro 2(1H)-pyrimidinone (DMPU) or hexamethylphosphoric ~ ~, '!. : - - :~ . . , . . . :, ' ~ . : ., . ~ ..... . .

33 210~9~

acid triamide, or a mixture of such solvents, in the presence or absence of protective gas, such as argon or nitrogen, the ammonia formed when the base used is an alkali metal amide being removed by applying a vacuum, e.g. of from 0.1 to 100, especially from 0.5 to 10, torr; and/or 2) reacted with an acid of formula VII', W3~-L~ (VII') wherein W3' iS acyl, lower alkylsulfonyl or arylsulfonyl, as mendoned above in the def~nidon of Al andlor A2, or with a leacdve derivative thereof, L' being hydroxy or a radical as defined hereinbefore for Zl in a compound of formula IV, especially halogen, under conditions analogous to those described for the reaction of a compound of fonnula II with a compound of formula m.

If a compound of formula I is to be prepared wherein only one of the radicals Al and A2 has the meanings given above with the exception of hydrogen, whilst the other ishydrogen, the reacdon is carried out with a molar amount of the compound of formula VII
or VII' which corresponds preferably to from 0.2 to 2 times the molar amount, e.g. from 1 to 1.6 times the molar amount, of the compound of formula IV having hydrogen instead of Al and A2. If each of the two hydrogen atoms in the compound of formula IV wherein A
and A2 are hydrogen is to be replaced by a radical other than hydrogen mentioned in the -~
definition of Al and A2, then preferably an excess, e.g. a 2- to 10-fold, especially an approximately t~vo- to th~ee-fold, excess of the compound of formula VII or VII' is used. ~ ~

The compounds of formulae V, VI, VI', VII and VII' are known, are commercially ~ -available or may be prepared according to processes that are known ~ se.

In compounds of formula VII, lower aLkyl (or lower alkenyl or lower aL~cynyl) W3 iS
preferably unsubstituted or substituted by protected amino, especially as in protected amino-lower alkyl, e.g. phthalimido-lower alkyl, such as phthalimidopropyl; mono-lower alkylamino protected for example by lower alkoxycarbonyl, such as tert-butoxycarbonyl, and unsubstituted or substituted as above (and in that case if necessary protected at the substituents) in the mon~lower aLl~yl radical, especially as in correspondingly protected and substituted mon~lower aL~cylamin~lower aL1cyl; di-lower aLIcylamino unsubstituted or 210~992 subsdtuted as defined above (and in that case if necessary protected at subsdtuents) in the two N-lower aL~cyl radicals, especial1y as in corresponding unsubstituted or substituted di-lower aLlcyla nino-lower alkyl; N-protected cycloalkylamino, especia11y as in N-pro-tected cycloalkyla nino-lower alkyl; N-protected phenyl-lower alkylamino, especially as in N-protected phenyl-lower alkylamino-lower aL~yl; N-protected phenylamino, espccially as in N-protected phenylamino-lower alkyl; acylamino, as in acylarnino-lower allcyl; pro-tected hydroxy, especially as in hydroxy-lower alkyl in which the hydroxy group is in pro-tected form; lower alkoxy wherein the terrninal lower alkyl radical is unsubstdtuted or substituted as above (and in that case if necessary with protected substituents), as in corresponding substituted protected or unsubstituted lower aL~oxy-lower aL~cyl; phenyl-lower alkoxy, especially as in phenyl-lower alkoxy-lower aLlcyl; acyloxy, especially as in acyl-lower allcoxy-lower aLkyl; protected mercapto, especially as in mercapto-lower aLlcyl wherein the mercapto group is in protected form; lower alkylthiowherein the terminal lower aL~cyl radical is unsubstituted or subsdtuted as above (if necessary with protected substituents); especially as in correspondingly subsdtuted protected or unsubstituted lower aLlcylthio-lower a~yl; phenyl-lower alkylthio, as in phenyl-lower aL~ylthio-lower alkyl;
acylthio, as in acylthio-lower alkyl; protected carboxy, as in protected carboxy-lower alkyl; esterified carboxy, as in esterified carboxy-lower aL~cyl; cyano, as in cyano-lower all~yl; oxo, as in oxo-lowcr alkyl (if necessary protected by acetal formation, e.g. with ;
lower alkanols, especially ethane-1,2-diol, it being possible for the protecdng group to be removed at the desi~ed stage by hydrolysis in the presence of an acid, such as acedc acid or sulfuric acid~; andJor thioxo, especially as in thioxo-lower alkyl with the excepdon of thioxomethyl (if necessaTy protected by thioacetal formadon, e.g. with lower alkylmer- -captans, such as ethane-1,2-dithiol, it being possible for the protecting group to be removed at a suitable point by hydrolysis in the presence of an acid, such as acedc acid or sulfuric acid), or heterocyclyl, as in heterocyclyl-lower alkyl which is, if necessary, protected. - --- -.
If there is used instead of a compound of formula VII a corresponding compound wherein -a halogen atom is present in the radical W3 (which in this case is unsubsdtuted or subsd-tuted lower alkyl as defined above for A1 and A2) in addition to one of the mentioned nucleofugal radicals L, then the corresponding unsubsdtuted or substituted lower aLkenyl -compound may be obtained by the eliminadon of hydrogen halide in the presence of the ;
base used for the reacdon, e.g. sodium amide, which is employed for example in excess, under the above-mendoned reaction condidons. In an analogous manner a compound with an unsubstituted or substituted lower aLkynyl group may be obtained from a corresponding 2~0999~ ~

analogue of the compound of formula VII wherein two furtha ha10gen atoms are present in addition to one of the mentioned nucleofugal radicals L.

In obtainabb compounds of formula IV, carboxy groups that are present as substituents in Al and/or A2 may be converted into carbamoyl, N-mono- or N,N-di-lower alkylcarbamo-yl, N-hydroxycarbamoyl or N-phenylcarbamoyl groups (also into N-aryl- and N-aryl-lower aL~yl-carbamoyl groups), for example by reaction with ammonia, a lower aLlcyl-amine or a di-lower aL~ylaminc, hydroxylamine or phenylamine, in the presence of a condensation agent, e.g. acarbodiimide, such as dicyclohexylcarbodiimidb, or apolar derivative thereof, in a polar organic solvent, such as ethanol, or in the presence of a N,N'-carbonyldiazolide, such as N,N'-dicarbonylimidazole (see H. A. Staab, Angew.
Chem. 74, 407423 (1962)) in an inert organic solvent, e.g. a chlorinated hydrocarbon, such as methylene chloride or chloroform, or in an ether, such as diethyl ether, tetrahydro-furan or dioxane, by way of the cQrresponding carboxylic acid azolide. In that manner the corresponding compounds of formula IV are obtained wherein Al and/or A2 contain -carbamoyl, N-mono- or N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl or N-phenyl- ~-carbamoyl. Corresponding thiocarbamoyl, N-mono-lower alkylthiocarbamoyl or N,N~i- ~ ~ -lower aUcylcarbamoyl substituents in Al and A2 may be obtained from carboxy by conversion into a carbonyl halide, e.g. with an inorganic acid halide, such as phosphorus trichloride, phosphQrus pentachloride or thionyl chloride, or with an organic acid halide, ~ ~ ;
such as oxalyl dichlQride, and subsequent reaction e.g. with phosphorus pentachlotide, hydrogen sulfide and ammonia, a lower alkylamine or an N,N-di-lower alkylamine.

In compounds of formula IV wherein A1 and/or A2 are e.g. a hydroxy-lower alkyl radical, ~ -the hydroxy group may be converted by nucleophilic subsdtudon into a free hydrazino group or a hydrazino g~up N-subsdtuted by lower alkyl, aryl and/Qr by aryl-lower aL~cyl - -or into a guanidino group or a guanidino group N-subsdtuted by lower aL~cyl, aryl and/or by aryl-lower alkyl. For example, a hydroxy compound may be converted by reacdon with an aromadc sulfonic acid or an acdvated derivadve thereof, such as a correisponding aromadc sulfonic acid halide, e.g. toluenesulfonic acid halide, such as toluenesulfonic acid chloride, into the corresponding ester of the aromadc sulfonic acid, in the absence or, preferably, in the presence of a suitable base, e.g. a terdary nitrogen base, such as triethyl-amine or N-methylmorpholine. The ester may then be reacted with hydrazine, guanidine or a correspondingly subsdtuted derivadve or a salt thereof, in which protecdng groups may also be present, under the condidons of nucleophilic subsdtutdon, preferably in the presence of an organic solvent, e.g. an alcohol, such as methanol, ethanol or tnfluoro-2109~2 ethanol, a ketone, such as acetone, a nitrile, such as acetonitrile, an ester, such as ethyl acetate, an ether, such as diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane, an acid amide, such as dimethylformamide, a bisaUcanesulfine, such as dimethyl sulfoxide, an aryl alcohol, such as phenol, or also water, or a mixture of those solvents, where appropriate (e.g. for the reaction of aryl-bonded nitrogen) in an inert organic solvent, such as dimethylformamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid-inone, with the addition of a strong base, such as sodium amide or sodium hydride. If necessary, any protecting groups present are removed. A compound of formula IV is obtained wherein Al and/or A2 contain substituents selected from hydrazino, hydrazino substituted at one or both nitrogen atoms by lower aUcyl, aryl or by aryl-lower aUcyl, guanidino and guanidino substituted at one, two or aU three nitrogen atoms by lower aUcyl, aryl or by aryl-lower alkyl. Those compounds of formula IV wherein substituents selected from hydrazino and hydrazino substituted at the terminal N-atom by lower alkyl, aryl and/or by aryl-lower aUcyl are present may also be obtained starting from a corresponding oxo compound of formula IV by reaction thereof with a nitrogen base selected from hydrazine and hydrazine mono- or di-subsdtuted at one of the two nitrogen atoms by lower alkyl, aryl and/or by aryl-lower alkyl, as described hereinafter for the reaction of an oxo compound with a nitrogen base, and subsequent reduction of a resulting corres-ponding imino compound, preferably by catalytic hydrogenation with selective hydrogen-ation catalysts, especiaUy in the presence of paUadium on solid carriers, e.g. on carbon, in polar organic or organic-aqueous solvents or solvent mixtures, especially in ethers, e.g. -cyclic ethers, such as tetrahydrofuran or dioxane, or in alcohols, such as lower aUcanols, -e.g. methanol or ethanol, or mixtures thereof, e.g. a methanoVtetrahydrofuran mixture, at temperatures of from -20 to 60 C, e.g. from 0 to 40 C, such as at room temperature.

In compounds of foqmula IV wherein Al and/or A2 are e.g. a cyano-lower aLl~yl radical, cyano groups may be converted into carbamoyl or N-lower aUcylcarbamoyl groups in ~ -compounds of forrnula IV e.g. by partial hydrolysis according to a Graf-Ritter reaction or via imino-lower aUcyl ester salts. The conditions for the hydrolysis of the cyano inter- -~
mediate may be so selected that the reaction is discontinued ae the amide stage. For that purpose hydrolysis with acids is especially suitable, there being suitable e.g. 80% sulfuric - - -acid (with heating), polyphosphoric acid (at 110-150 C), hydrobromic acid/glacial acetic -~ -acid (room temperature, formic acid or without a solvent), hydrogen chloride gas in ethereal solutdon followed by the addidon of water or aqueous hydrochloric acid, or boron -halides. It is also possible by means of the Graf-Ritter reaction to prepare N-mono~
aL~cylated amides of formula IV from the corresponding nitriles. For that purpose the ~ -~ -37 2109~9~

nitriles are reacted in the presence of a strong acid, especially 85-90% sulfuric acid, or polyphosphoric acid, formic acid, boron trifluoride or other Lewis acids, but not a1uminium chloride, with compounds that are capable of forming carbenium ions in the acidic medium, that to say e.g. with olefins or alcohols. The imino-lower allcyl esters of formula IV are obtained e.g. by the acid-catalysed addition of alcohols to the nitrile precursors. The addition may a1ternatively be catalysed by bases, e.g. alcoholates, such as sodium methoxide. If, instead of alcohols, corresponding mercaptans are used, for exarnple in the presence of nitrogen bases, such as triethylamine or N-methylmorpholine, ~ -then the corresponding imino-lower aLlcylthio esters are obtained. In accordance with a Pinner cleavage by thermal decomposition of the imho ester salts at temperatures above approximately 80 C, the carbamoyl derivatives are obtained from the imino-lower aL~cyl -esters, and the c~responding thiocarbamoyl derivatives are obtained from the i nino-lower alkylthio esters. The thiocarbamoyl compounds may also be obtained directly by reacting cyano groups with hydrogen sulfide analogously to partial hydrolysis, for example h the presence of terliary amines, such as triethylamhe.

A compound of forrnula lV wherein Al and/or A2 are e.g. an amidino-lower alkyl or an ~ ;
amidino-lower aL~yl substituted at a nitrogen atom by up to two radicals selected f~m lower alkyl, aryl and afyl-lower allcyl may be prepared by reacting a correspondhg imin~lower alkyl ester or imino-lower allcylthiol ester precursor (in the form of an acid addition salt, e.g. -(C=NH) OC2HS . HCI or -C(=NH)-SC2HS HI respectively, prepared as described above from a correspondhg cyano compound) with ammonia or the corres-ponding lower alkyl-, aryl- or aryl-lower alkyl-amine. The cyano precursors may be converted, for example also by reacdon with an alkali metal amide, or by reaction with a corresponding ammonium salt, e.g. a correspondhg ammonium halide, into the free,mon~ or di-substituted amidines. Compounds of formula IV wherein Al and/or A2 contain an amidino subsdtuted at each of the two nitrogen atoms by aryl, aryl-lower aL~yl or by lower aL~cyl may be prepared from compounds (which may be prepared in an analogous manner to that desclibed above for lower alkylcarbamoyl) wherein carbamoyl N-substituted by lower alkyl, aryl or by aryl-lower alkyl is present instead of carbamoyl as subsdtuent in Al and/or A2 in formula IV, e.g. by reactdon with POCI3 or PCls to form the corresponding imide acid chlorides (e.g. -(C=NH-lower aL~yl)-Cl) which, after reaction with ammonia or a primary or secondary amine, yield subsdtuted arnidines of formula IV
(see Chem. Abstr. 81, 91186a (1974)).

In an obtainable compound of formula IV, amino groups present as substituents in A

-38- 21099~

and/or A2 may be converted into ureido or into ureido substituted at one or each of the two nitrogen atoms by one radical selected from lower aLlcyl, aryl and aryl-lower alkyl by reacting a compound of formula IV wherein e.g. Al and/or A2 are amino-lower alkyl or -N-mono-lower alkylamin~lower alkyl, or wherein there is an arylamino-lower aLlcyl and/or an aryl-lower alkylamino-lower alkyl instead of one or each of the radicals A1 and A2 (which may be prepared, e.g., by reacting a compound of formula IV having hydrogen instead of Al or A2 with an analogue of a compound of formula VII that contains, in addition to the nucleofugal group L, a further nucleofugal group, e.g. halogen, under conditions analogous to those for the reacdon of a compound of formula IV havinghydrogen instcad of Al and/or A2, again using analogous reacdon condidons and subsd- -~
tudon of the second nucleofugal radical either by an arylaminc or an aryl-lower al~yl-amine; or, starting from a compound of formula IV wherein Al and/or A2 are a hydroxy- -lower al~yl radical, by converling the hydroxy group into a nucleofugal radical, e.g. by treatment with an a~matic s~fonic acid halide, such as toluenesulfonic acid chloride, and - --then ~dng that nucleofugal r~ical with an arylamine or an aryl-lower a~ylamine under conditions an~ogous to those for the reacdon of a compound of formula IV having hydrogen instead of Al an~or A2 with a compound of formula V~), with a lower a~yl, - - -~
aryl or aryl-lower a~yl isocyanate or N-protected isocyanatc (e.g. benzyl isocyanate), -prcferably in an ether, e.g. a cyclic ether, such as tetrahyd~furan, at preferred temper-atures of from -~ to ~ C, espe~ly app~ximately at room temperature, funcdonal groups that are not to ta~e part in the reacdon being p~tect~ if necessary, and any protecdng g~ups present are removed in a suitable reacdon step.
. " ' - '~: -In an analogous manner, amino g~ups present as subsdtuents in Al and/or A2 in compounds of formula IV may be con~erted into thioureido or into thioureido subsdtuted at one or each of the two nit ogen atoms by one radical selected ~m lower a~yl, aryl and ~-aryl-lower a~yl, by using cresponding thiois~yanates instead of isocyanates.

Compounds of formula IV whe~in Al an~or A2 are e.g. a ureido-lower a~yl subsdtuted at the terminal nitrogen atom by 2 radicals selected f~m lower a~yl, aryl and aryl-lower ~ -a~yl may be prepared, for example, by reacdng a corresponding amino-lower ~yl ~
compound of formula IV with phosgene or an analogue thereof, e.g. a N,N'-carbonyl- ~ -diazolide, such as N,N'-carbonyldiimidazole (see H. A. Staab, Angew. Chem. 74, 407-423 `
(1962, and then reac~ng the resuldng chlorocarbonyl- or azolidocarbonyl-amino compound with ammonia substituted by 2 radicals selected from lower a~yl, aryl and aryl-lower a~yl, or reacting the corresponding amino-lower a~yl compound of 39 ~1~9992 formula IV with the reacdon product of ammonia substituted by 2 radicals selected from lower alkyl, aryl and aryl-lower aLkyl with phosgene or an analogue thereof, e.g a N,N'-carbonyldiazolide, such as N,N'-carbonyldiimidazole, to obtain the correspondingly substituted ureido compound. The reactions are preferably carried out in inert solvents, especially chlorinated hydrocarbons, such as methybne chloride or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxane, or acid amidbs, such as dimethyl-formamide, at temperatures of from -20 C to the reflux temperature, especially from 0 to 3o C

Compounds of formula IV wherein Al and/or A2 contain e.g. a thioureido-lower alkyl - -radical substituted at the terminal nitrogen atom by 2 radicals selected from lower allcyl, aryl and aryl-lower alkyl may be prepared in an analogous manner, for example byreacting a corresponding amino-lower alkyl compound of formula IV with thiophosgene or an analogue thereof, e.g. a N,N'-thiocarbonyldiazolide, such as N,N'-thiocarbonyl-diimidazole (see. H. A. Staab, Angew. Chem. ~, 407-423 (1962)), and then reacting the resulting chlorothiocarbonyl- or azolidothiocarbonyl-amino compound with ammoniasubstituted by 2 radicals selected from lower al~yl, aryl and aryl-lower aLkyl, or conversely reacting a corresponding amino-lower alkyl compound of formula IV with the reaction product of ammonia substituted by 2 radicals selected from lower aL~yl, aryl and aryl-lower alkyl with thiophosgene or an analogue thereof, e.g. a N,N'-thiocarbonyl-diazolide, such as N,N'-thiocarbonyldiimidazob.

In a compound of formula IV, e.g. a hydroxy-lower aL~cyl radical Al andJorA2 may be oxidised to yield the corresponding oxo compound. In the case of primary alcohols, the use of selective oxidising agents is necessary for that purpose, e.g. potassium ferrate (K2FeO4) in aqueous solvents and pyrolusite in organic solvents, tert-butyl chromate, pyridinium dichromate or especially pyridinium chlorochromate in inert organic solvents, e.g. chlorinated hydrocarbons, such as dichloromethane or chloroform. The reaction takes place preferably at temperatures of from -20C to the reflux temperature, e.g. at approx- ~ -imately from 0 to 40 C In the case of secondary alcohols, the oxidatdon may also be carried out with less selecdve oxidising agents, such as chromic acid, dichromate/sulfunc acid, dichromateJglacial acetic acid, nitric acid, pyrolusite, selenium dioxide or dimethyl sulfoxide in the presence of oxalyl chloride, in water, in aqueous or organic solvents, such as halogenated hydrocarbons, e.g. methylene chloride, or carboxylic acid amides, such as dimethylformarnide, preferably at temperatures of from -50 C to the reflux temperature, especially from -10 to 50 C. A compound of formula IV is obtained wherein the radical 210~992 Al and/or A2 carry oxo.

Compounds of formula IV wherein Al andlor A2 contain imino, lower aLkylimino, acyl-imino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower alkyl- ;
hydrazono and/or N-acylhydrazono, e.g. as subsdtuents in a substituted lower alkyl radical, may be prepared from corresponding oxo compounds of formula IV, either after isoladon of the oxo compound or, preferably, by the direct further use thereof as a crude product, for example after partial concentradon by evaporation to remove the solvent in ~ -which the oxidation (which is preferably carried out as desc ibed immediately above) of a ~ -hydroxy compound to an oxo compound is carried out. -Thus an oxo compound may be converted into a corresponding imino derivatdve by reac-don with a nitrogen base selected from ammonia, lower aLkylamines, hydroxylamine, lower alkoxyamine, hydrazine, N-mono- or N,N-di-lower aLkylhydrazine and N-acyl- - ~ ~
hydrazine. The reacdon condidons correspond to the condidons customary for the reaction - -of carbonyl compounds with nitrogen bases, the nitrogen base being used, for example, in -the form of a salt of an acid, e.g. a hydrohalic acid, such as hydrogen fluoride, hydrogen chloride, hyd~gen bromide or hydrogen iodide, especially hydrogen chloride, sulfuric ~ -acW or a hydrogen sulfato, such as an alkali metal hydrogen sulfate, e.g. sodium hydrogen ; - -sulfate, phosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, e.g. an alka1i metal hydrogen phosphateor 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, especially a carboxylic acid, such -as a lower alkanecarboxylic acid unsubsdtuted or subsdtuted in the lower alkyl radical preferably by halogen, such as fluorine or iodine, e.g. acetic acid, chloroacedc acid, dichloroacedc acid or trifluoro- or trichloro-acedc acid, or a sulfonic acid, such as a lower alkylsulfonic acid, e.g. methanesulfonic acid, ethanesulfonic acid or ethanedisulfonic acid, or an arylsulfonic acid, such as benzene- or naphthalene-sulfonic acid or naphthalene-l,S-disulfonic acid; it being possible also for a salt of one of the mendoned nitrogen bases with an acid to be prepared in ~, especially by liberadng the weak acid from the corres-ponding salt of a readily voladle weak acid, such as a lower alkanecarboxylic acid, e.g.
acedc acid, or especially carbonic acid or hydrogen carbonate, that can be liberated by a ~ ~-strong acid, such as sulfuric acid or especially one of the mendoned hydrohalic acids; in water (in the presence or absence of surfactants), in 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 sulfoxide, or di-lower allcyl-lower aL~canoyl--41- 2~9~

amides, such as dimethylformamide, in organic solvents, such as alcohols, e.g. methanol or ethanol, di-lower aLlcyl sulfoxides, such as dimethyl sulfoxide, di-lower alkyl-lower alkanoylamides, such as dimethylformamide, or in adequately inert nitriles, such as aceto-nitrile, or in a mixture of such organic solvents, or without a solvent in a melt, preferably in an alcohol solution, such as in methanol, ethanol or especially isopropanol; pteferably at temperatures of from -20 C to the reflux temperature of the reacdon mixture in the presence of a solvent, or in the case of melts up to 220 C, especially at temperatures of from 0 to 50 C in the presence of a solvent, more especially at approximately room temperature.

An oxo compound of formula IV may be converted into a corresponding thioxo compound, for example by reaction with phosphorus pentasulfide or, preferably, aphosphorus pentasulfide substitute, such as Laweson's reagent (= 2,4-bis(4-methoxy-phenyl)-2,4-dithioxo-1,3,2,Wthiaphosphetane), the reaction being carried out in an inert organic solvent, for example in a halogenated hydrocarbon, such as dichloromethane, at temperatures of from 30 C to the reflux temperature, especiaUy under reflux.

A compound of formula IV wherein Al and/or A2 contain acylimino subsdtuents, e.g. as substituents in a substituted lower aL~yl radical, may be obtained from a corresponding imino starting material by reaction thereof with a free acid that contains the acyl radical, for example in the presence of a condensation agent, such as a carbodiimide, e.g. dicyclo- --hexylcarbodiimide, or with an acdvated acid derivadve thereof, e.g. a carboxylic acid halide, where appropriate in the presence of a suitable base, e.g. a tertiary amine, as already defined, preferably with the exclusion of moisture.
, , Compounds of formula IV wherein Al and/or A2 carry lower aL~ylthioimino substituents, e.g. in subsdtuted lower alkyl, may preferably be prepared by reacting a corresponding imino st~rting material of formula IV with a lower aLlcylsulfenyl halide (which may be prepared, e.g., from a sulfenic acid with hydrogen halide or by chlorolysis, bromolysis or iodolysis of a corresponding organo sulfur compound, it being possible for the preparadon also to be carried out in ~a)- especially a lower alkylsulfenyl halide, such as methyl~
sulfenyl chloride, preferably using a salt of the imino compound or in the presence of an aL~cali hydroxide, such as sodium or potassium hydroxide, preferably in organic solvents, e.g. hydrocarbons, such as heptane, ethers, such as diethyl ether, dioxane or tetrahydro-furan, or carboxylic acid amides, such as dimethylformamide, at preferred temperatures of from 0 C to the reflux temperature, especially from 0 to 30 C.

:, ' - ' -42- 2:109~
;". ':
Even if not explicitly mentioned in the paragraphs re1ating to the preparation of a compound of formula IV, a compound of formula IV wherein Al and/or A2, in addition to or instead of substituted lower alkyl, are selected from substituted lower alkcnyl and substituted lower alkynyl, may be prepared where appropriate and expedient by prepar-ation p~cesses analogous to those described for a compound of formula IV having sub!.d-tuted lower aL~cyl radicals.

A compound of formula IV wherein Al and/or A2 are e.g. heterocyclyl-lower aLkyl may be obtained frnm a corresponding compound of formula IV wherein at least one of the - -substituents Al and A2 is hydrogen, or from a corresponding analogue having hydrogen instead of each of Al and A2, preferably by reaction with a compound of formula VIII
heterocyclyl-lower alkyl-L" (Vm) wherein heterccyclyl-lower alkyl is as defined above and L" is a nucleofugal group as ~ -~
defined hereinbefore for L in compounds of formula VII, with nucleophilic subsdtudon of the nucleofugal group L". The reaction condidons preferably correspond to those condidons mendoned for the allcyladon reacdon with a compound of formula VII in the -~
presence of a st~ng base. ;~

To prepare compounds of formula IV wherein Al and A2 together are unsubstituted or substituted lower al~ylene, for example a compound of for nula IV having hydrogen instead of Al and A2 is reacted with a bisalkyladng reagent of formula IX ~ ~ -,'. ' , .
L,-B-L2 (IX) '~

wherein B is unsubsdtuted or substituted lower alkylene as a divalent radical bonded in each case by one of its carbon atoms (which radical is unsubstituted or, for example, subsdtuted by the subsdtuents, preferably one of those subsdtuents, mendoned in the definidon of subsd-tuted lower alkyl formed by Al and A2 together) and Ll and L2 are each, independen~y of the other, a nucleofugal group as described above for L in the definidon of compounds of formula VII, those funcdonal groups in the stardng materials that are not to take part in the reacdon being protected if necessary by protecdng groups that are removed in a suitable reacdon ~ , 43 2l~9~2 step. The preferred pr~tecting groups, their introduction and their removal have been mentioned hereinbefore.

Ll is preferably a nucleofugal group, especially aliphatica11y or aromadcally substituted sulfonyloxy, e.g. methanesulfonyloxy or p-toluenesulfonyloxy (tosyloxy), halogen, such as chlorine, bromine or iodine, or cyano, whilst L2, if a lower alkylene radical B contains two or more carbon atoms, may be oxa (~-) or thia (-S-) which is bonded to two vicina1 carbon atoms (forming an oxirane or thiirane which reacts during the alkylation, which is carried out especially in the presence of a strong base, such as lithiusn diisopropylamide, sodium amide or, especially, sodium hydride, at temperatures of from 50C to the boiling point of the reaction mixture, e.g. at from 80 to 100 C, in an acid amide, such as dimethylformamide, and during subsequent hydr~lysis to yield a 1-hydroxy- or 1-mer-capto-lower alkybne group), or aza (-NH-) which is bonded to two vicinal carbon atoms (forming an azirane which reacts during the alkylation, which is carried out especially in the presence of a strong base, such as lithium diisopropylamide, sodium amide or, especially, sodium hydridc, at temperatures of from 50C to the boiling point of the reaction mixture, e~g. at from 80 to 100 C, in an acid amidc, such as dimethylformamide, and during subse~uent hydrolysis to yicld a 1-amino-lower alkylene group).

The reaction is preferably carried out under the reaction conditions described as being preferred for the reaction of a compound of formula IV having a hydrogen atom instead of each of Al and A2 with a compound of formula VII.

It is also possible for L1 and L2 together to be oxo bonded to the terminal carbon atom of ~-B (the compound of formu1a IX is then an aldehyde) or for them each to be lower alkoxy (the compound of formula IX is then an acetal). Preferably, B in compounds of formula II
is in that case selected from esterified carboxymethylene, such as lower aLlcoxycarbonyl-methylene, and lower alkanoylmethylene. The reaction takes place, for example, in the presence of an acid, e.g. a hydrohalic acid, such as hydrochloric acid, or, preferably, in the presence of a Lewis acid, especially SnCl2 (e.g. as a hydrate), in a suitable solvent or solvent mixture, e.g. an ether, such as a di-lower alkoxy-lower alkane, espe ially 1,2-di-methoxyethane, at prefer ed temperatures of from 0 to 50 C, e.g. at approximately room temperature, if necessary with the addition of water.

The compound of formula IX is preferably used in equimolar amount or in excess with respect to the compound of formula IV having a hydrogen atom instead of each of Al and ~;

21039~

A2, especially in 1 to 3 times the molar amount, e.g. 1 to 1.5 times the molar amount, such as approximately 1.2 times the molar amount. The strong base used for the reaction is preferably employed in excess with respect to the compound of formula IV that contains a hydrogen atom instead of each of Al and A2, especially in 2 to 10 times the molar amount, for example in 2 to 3 times the molar amount.

The reaction may be carAed out in such a manner that the nucleofugal groups L1 and L2 are substituted virtually simultaneously in one stage, or the nucleofugal groups Ll and L2 may be substituted in succession in different stages.

In compounds of formula IX, B is preferably unsubstituted lower aLI~ylene or lower aLIcylene substituted by one or more, especially one, of the following substituents: lower aL~cyl, protected amino or amino-lower alkyl, e.g. phthalimido or phthalimido-lower aL~yl, such as phthalimidopropyl, or mono-lower alkylarnino or mono-lower aL~cylamino-lower aL~yl protected, for example, by lower aLIcoxycarbonyl, such as tert-butoxycarbonyl, and unsubstituted or substituted in the mono-lower aL~cyl radical as above (and in that case, if --necessary, protected at the subsdtuents), di-lower alkylamino or di-lower alkylamino-lower alkyl unsubstituted or substit~ted as defined above in both N-lower alkyl radicals (and in that case, if necessary, protected at the substituents), N-protected cycloalkylamino or cycloaL~yla nino-lower alkyl, N-protected phenyl-lower alkylamino or phenyl-lower aLIcylamino-lower allcyl, N-protected phenylamino or phenylamino-lower alkyl, acylamino or acylarnino-lower alkyl, hydroxy (possible in addition to the definition of substituted lower aLIcylene forrned by Al and A2 in intennediates) or hydroxy-lower alkyl in which the hydroxy group is in protected form, lower alkoxy or lower aLIcoxy-lower aL~cyl wherein the terminal lower aLkyl radical is unsubstituted or substituted as above (and in that case, if necessary, by protected substituents), phenyl-lower aLtcoxy or phenyl-lower allcoxy-lower aLkyl, acyloxy or acyloxy-lower aL~cyl, mercapto or mercapto-lower a~cyl wherein the mer-capto group is in protected fonn, lower aLcylthio or lower aLkylthio-lower aL~cyl wher~in -the tern~inal lower aL~cyl radical is unsubstituted or substituted as above (and in that case, if necessary, by protected substituents), phenyl-lower aL~cylthio or phenyl-lower aL~ylthi~
lower aL~cyl, acylthio or acylthio-lower alkyl, protected carboxy or carboxy-lower aL~cyl, esterified carboxy or carboxy-lower aL~yl, cyano or cyano-lower alkyl, oxo or oxo-lower alkyl (if necessary protected by acetal formation, e.g. with a lower aL~canol, especially with ethane-1,2~diol, it being possible for the protecting group to be removed at the desired stage by hydrolysis in ~e presence of an acid, such as acetic acid or sulfuric acid), or thioxo or thioxo-lower aLlcyl (if necessary protected by thioacetal formation, e.g. with a ~: `
2~09992 lower alkylmercaptan, such as ethane-1,2-dithiol, it being possible for the protecting group to be removed at a suitable point by hydrolysis in the presence of an acid, such as acetic acid or sulfuric acid).

In obtainable compounds of formula IV, carboxy in a carboxy or carboxy-lower alkyl group (which is present in a substituted lower a~ylene formed by Al and A2 together) may be converted into carbamoyl, N-mono- or N,N-di-lower a~ylcarbamoyl, N-hydroxy-carbamoyl or N-phenylcarbamoyl (also into N-aryl- and N-aryl-lower alkyl-carbamoyl groups), for example by reaction with ammonia, a lower a~ylamine or a di-lower a~yl-amine, hydroxylamine orphenylamine (also an N-aryl- or N-aryl-lower a~yl-amine), or with a salt thereof in each case, in the presence of a condensation agent, e.g. a carbo-diimide, such as dicyclohexylcarbo~mide, or a polar derivative thereof, in a polar organic solvent, such as ethanol, or a N,N'-carbonyl diazolide, such as N,N'-dicarbonylimidazole (see H. A. Staab, Angew. Chem. 74, ~23 (1962)) in an inert organic solvent, e.g. a chlorinated hyd~carbon, such as methylene chloride or chloroform, or in an ether, such as diethyl ether, tetrahydrofuran or dioxane, by way of the corresponding carboxylic acid -azolidc. In that manner a corresponding compound of formula IV is obt~ed having substituted lowcr a~ylene formed by A1 and A2, which is substituted by carbamoyl, N- ~ , mono- or N,N~-lower a~ylcarbamoyl, N-hydroxycarbamoyl and/or by N-phenylcarba- ~ -moyl. A corresponding thiocarbamoyl substituent in substituted lower a~ylene formed by - -- -Al ~d A2 r~y bc obtained from carboxy by conversion into a carbonyl halide, e.g. with an inorganic acid halidc, such as phosphorus trichl~ide, phosphorus pentachloride or thionyl chloride, or with an organic acid halide, such as oxalyl dichloride, and subsequent reacdon e.g. with phosphorus pentachloridc, hydrogen su~ide and ammonia, a lowera~ylamine or a di-lower a~ylamine, hy~xylamine or phenylamine.

In compounds of formula ~ wherein a subsdtuted lower a~ylene formed by Al and A2 -together is subsdtuted by hydroxy and/or by hydroxy-lower a~yl, the hydroxy group!may be converted by nucleophilic substitution into a hydrazino group, a hydrazino group - ~ - -N-subsdtuted by lower a~yl, aryl an~or by aryl-lower a~yl, a guanidino group, or a guanidino group N-subsdtuted by lower a~yl, aryl and/or by aryl-lower a~yl. For example, hyd~xy may be converted by reacdon with an aromadc sulfonic acid or an ~ ~ -activated derivadve thereof, such as the corresponding aromatic sulfonic acid halide, e.g. a toluenesulfonic acid halide, such as toluenesulfonic acid chloride, in the absence or, preferably, the presence of a suitable base, e.g. a tertiary nitrogen base, such as triethyl-amine or N-methylmorpholine, into hy~xy esterified by the cor~sponding aromatic ~ . . .
.. . .

2:109~

sulfonic acid, and then that ester may be reacted with hydrazine, guanidine, a colres-pondingly substituted derivative thereof or a salt thereof, in which protecting groups may also be present, under the conditions of a nucelophilic substitution, preferably in the presence of an organic solvent, e.g. an alcohol, such as methanol, ethanol or trifluoro-ethanol, a ketone, such as acetone, a nitrile, such as acetonitrile, an ester, such as ethyl acetate, an ether, such as diethyl ether, ethylene glycol dimethy1 ether, tetrahydnofuran or dioxane, an acid amide, such as dimethylformamide, a bisalkanesulfine, such as dimethyl sulfoxide, an aryl alcohol, such as phenol, or also water, or a mixture of those solvents, if necessary (e.g. for the reaction of aryl-bonded nitrogen) in an inert organic solvent, such as dimethylformamide or 1,3-dimethyl-3,4,5,~tetrahydro 2(1H)-pyrimidinone, with the addition of a stnong base, such as sodium amidc or sodium hydride. Where appropriate and expedient, any protccting groups present arc rcmoved. A compound of formula lV is obtained whercin Al and A2 together form a substituted lower alkylene with substituents selected from hydrazino, hydrazino subsdtutcd at one or both nitrogcn atoms by lower alkyl, aryl or by aryl-lower alkyl, guanidino and guanidino substitutcd at one, two or all three nitrogen atoms by lower alkyl, aryl or by aryl-lower alkyl.

In compounds of formula IV whcrein Al and A2 together form a lowcr a1kylene substi-tuted by cyano and/or by cyano-lower alkyl, cyano groups may bc converted, e.g. by partial hydrolyds according to a Graf-Rittcr rcacdon, or by way of imino-lowcr alkyl ester salts, into carbamoyl groups or N-lower a1kylcarbamoyl groups in compounds of formula ~ -IV. The conditions for the hy~olyds of the cyano intcrmediate may be so sclected that the reaction is discontinued at the amide stage. For that purpose hydrolysis with acids is especia~y suitable, thcrc being suitable e.g. 80 % sulfuric acid (with heating), polyphos-phoric acid (at 11~150 C), hydrogen b~midc/glacial acctic acid (room temperature, formic acid or without a solvent), HCl gas in ethercal solution fo~owed by the addition of ~ -water or aqueous hydrochloric acid, or boron halides. It is possible by means of the Graf-Ritter rcaction to preparc N-monoa~ylated amides of formula ~ from the corrcsponding -nitr~es. Por that purpose the nitr~es arc reacted in the presence of a strong acid, especially 85-~ % su~ic acid, orpolyphosphoric acid, formic acid, boron trifluoride or other ~ ~
Lewis acids, but not aluminium chloride, with compounds that are capable of forming - -carbenium ions in the acidic medium, that is to say e.g. with olefins or alcohols. The ~ -imino-lower a~yl esters of formula ~ arc obtained e.g. by the acid-catalysed addition of -~cohols to the cyano compounds (in the form of salts). That addition may altematively be catalysed by bases, e.g. alcoholates such as sodium methoxide. ~, instead of alcohols, corresponding mercaptans are used, for example in ~e presence of nitrogen bases, such as -n- 2~09992 triethylamine or N-methylmorpholine, then the corresponding imino-lower alkylthio esters are obtained. In accordance with a Pinner cleavage by thermal decomposition of the imino ester salts at temperatures above approximately 80 C, the carbamoyl derivadves are obtained from the imino-lower aLIcyl esters, and the corresponding thiocarbamoyl deriva-dves are obtaincd from the imino-lower alkylthio esters. The thiocarbamoyl compounds may also be obtained directly by reacdng cyano groups with hydrogen sulfide analogously to partial hydrolysis, for example in the presence of tertiary nitrogen bases, such as triethylamine.

Compounds of formula IV wherein a subsdtuted lower alkylene formed by Al and A2 together is subsdtuted by amidino, amidino-lower alkyl, amidino subsdtuted at a nitrogen atom by up to two radicals selected from lower alkyl, aryl and aryl-lower alkyl, and/or by amidino-lower alkyl subsdtuted at a nitrogen atom by up to two radicals selected from lower allcyl, aryl and aryl-lower al~yl, may be prepared by reacting an imino-lower alkyl ester or imino-lower a11cylthiol ester (in the form of an acid addition salt, e.g. --(C=NEI)-OC2HS-HCl or -C(=NH)-SC2HS-HI respecdvely), which has been prepared as above from corresponding cyano or cyano-lower alkyl statdng materials, with ammonia or corresponding primary or secondary lower aL~yl-, aryl- and/or aryl-lower aL~cyl-amines. -~
The corresponding cyano procursors may be converted, for example also by reaction with an aL~ali metal amide, or by reacdon with a primary or secondary ammonium salt, e.g. a prirna~y or secondary ammonium halide, into the corresponding free, mono- or di-sub-sdtuted amidines. Compounds of formula IV wherein Al and A2 together are a subsdtuted ~ -lower alkylene which caTries as subsdtuent an amidino or amidino-lower al~yl substituted at each of the two nitrogen atoms by aryl, aryl-lower aL~cyl or by lower allcyl, may also be - -prepared from the corresponding compounds (which may be prepared as described above for lower alkylcarbamoyl) wherein carbamoyl N-substituted by lower alkyl, aryl or by aryl-lower alkyl is present in formula IV, e.g. by reaction with POCl3 or PCls to form the ;~
corresponding imide acid chlorides (e.g. -~C-NH-lower alkyl)-Cl) which, afterreaction ~ ~
with ammonia or a corresponding amine, yield subsdtuted amidines of formula IV (see ~-- ~- - - - -Chem. Abstr. 81, 91186a (1974)).

In obtainable compounds of fortnula IV, amino radicals present in amino and/or amino-lower alkyl radicals (which are present as substituent in a substituted lower alkylene formed by Al and A2 together) may be converted into ureido, ureido-lower aL~yl or ureido or ureido-lower aL~yl subsdtuted at one or each of the two nitrogen atoms by one radical selected from lower aLIcyl, atyl and aryl-lower aL~cyl by reacting a corresponding amino -48- 21~9992 compound of formula IV in which amino radicals are present, such a compound in which N-mono-lower alkylamino radicals are present or such a compound in which arylamino or aryl-lower alkylamino stands in place of amino (which may be prepared, e.g, by reacdng compounds of formula IV wherein the subsdtuted lower alkylene formed by A1 and A2 together contains hydroxy which is converled by esterification, e.g. by reacdon with an aromatic sulfonic acid halide, such as toluenesulfonic acid chloride, into a nucleofugal radical, e.g. aromadc sulfonyloxy, analogously to the reacdon of compounds of formula IV having hydrogen instead of A1 and A2 with compounds of formula VII with nucleophilic subsdtudon of the nucleofugal aromadc sulfonyloxy either with an arylaJnine or an aryl-lower alkylamine), with a lower alkyl, aryl or a~yl-lowa alkyl isocyanate or an N-protected isocyanate (e.g. benzyl isocyanate), preferably in an ether, e.g. a cyclic ether, such as tetrahydrofuran, at prefared temperatures of from -20 to 60 C, especially approximately at room temperature, functional g~oups that are not to take part in the reactdon being protectcd if necessary, and, if desired, any protecting groups present are removed. ~- -In an analogous manner, amino groups in compounds of formula IV (which are present as subsdtuent in a subsdtuted lower alkylene formed by Al and A2 together) may be ~- -conveIted into thioureidoorinto tbioureido subsdtuted atone oreach of the two nitrogen atoms by one radical selected from lower allcyL aryl and aryl-lower alkyl by using corres- ~ -ponding thioisocyanates instead of the isocyanates.

Compounds of formula IV that contain as substituent in a subsdtuted lower alkylene fo¢med by A1 and A2 togeth ureido and/or ureido-lower alkyl subsdtuted at the terminal nitrogen atom by up to two radicals selected from lower alkyl, aryl and aryl-lower alkyl may be prepaled, for example, by reacdng a corresponding amino compound of formula IV with phosgene or an analogue thereof, e.g. a N,N'-carbonyldiazolide, such as N,N'~
carbonyldiimidazole (see H. A. Staab, Angew. Chem. 74, 407~23 (1962)), and then !
~ing the resulting chlorocarbonyl- or azolidocarbonyl-amino compound with ammonia subsdtuted by up to 2 radicals selected from bwer allcyl, aryl and aryl-lower alkyl, or conversely reacdng a corresponding amino compound of formula IV with the reacdonproduct of ammonia subsdtuted by up to 2 radicals selected from lower aLkyl, aryl and aryl-lower aLlcyl with phosgene or an analogue thereof, e.g. a N,N'-carbonyldiazolide, such as N,N'-carbonyldiimidazole, to obtain the correspondingly subsdtuted ureido compound. The reacdons are preferably carried out in inert solvents, especially chlor-inated hydrocarbons, such as methylene chloride or chloroform, ethers, such as diethyl 210~

ether, tetrahydrofuran or dioxane, or acid amides, ~uch as dimethylformamide, at temp-eratures of from -20 C to the reflux temperature, especia11y from 0 to 30 C. If, instead of an amino compound of formula IV, an analogue is used in which mono-lower alkylamino, arylamino and/or aryl-lower alkylamino are present, it is also possible to obtain a corre sponding compound of formula IV wherein up to three subsdtuents selected from lower aL~cyl, aryl and aryl-lower alkyl are present at the two nitrogen atoms of ureido groups Compounds of formula IV wherein a subsdtuted lower alkylene formed by Al and A2 contains as subsdtuent thioureido-lower alkyl substdtuted at the terminal nitrogen atom by 2 radicals selected from lower aIkyl, aryl and aryl-lower alkyl may be prepared in an analogous manner, forexample by reacdng a corresponding amino compound of formula IV with thiophosgene or an analogue thereof, e.g a N,N'-thiocarbonyldiazolide, such as N,N'-thiocarbonyldiimidazole (see ~ A Staab, Angew Chem 74, 407-423 (1962), and then reacdng the resuldng chlorothiocarbonyl- or azolidothiocarbonyl-amino-compound with ammonia subsdtuted by 2 radicals selected from lower aL~yl, aryl and ~ ~ -aryl-lower alkyl, or convcrsely reacting a corresponding amino compound of formula IV -with the reacdon p~duct of ammonia substituted by 2 radicals selected from lower alkyl, aryl and aryl-lower alkyl with thiophosgene or an analogue thereof, e.g. a N,N'-thio-carbonyldiazolide, such as N,N'-thiocarbonyldiimidazole. ~ ~ -Compounds of formula IV wherein a substituted lower alkylene formed by Al and A2contains as substdtuent hydroxy and/or hydroxy-lower alkyl may be oxidised to ces- ~ -ponding oxo compounds, ~ the case of primary alcohols the use of selective oxidising agents is necessary for that purpose, e.g. potassium ferrate (K2FeO4) in aqueous solvents and pyrolusite in organic solvents, tert-butyl chromatc, pyridinium dicluomate or especially pyridinium chlorochromate in inert organic solvents, e.g. chlorinated hydro-carbons, such æ dichloromethane or chloroform. The reaction takes place preferably at temperatures of from -20 C to the reflux temperature, e.g. at approximately from 0 to 40 C. In the case of secondary alcohols, thc oxidation may also be carried out using less selective oxidising agents, such as chromic acid, dichromate/sulfuric acid, dichromate/-glacial acedc acid, nitric acid, pyrolusite and selenium dioxide. Compounds of formula IV
are obtained wherein a subsdtuted lower alkylene formed by A1 and A2 together has been substituted by oxo.

A compound of formula IV wherein a substituted lower alkylene formed by Al and A2 together contains one or more substituents selected from imino, lower aLkylimino, acyl-so- 2lo99~2 imino, hydroxyimino, lower aLkoxyimino, hydrazono, N-mono- or N,N-di-lower aL~yl-hydrazono, N-acylhydrazono and a lower alkyl subsdtuted by imino, lower alkylimino, acylimino, hydroxyimino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower alkylhydrazono and/or by N-acylhydrazono may be prepared from a corresponding oxo compound of formula IV, either after isolation of the oxo compound or, preferably, by the direct further use thereof as a crude product, for example after pardal concentradon by evaporation to remove the solvent in which the oxidatdon of a hydroxy compound to the oxo compound is earried out, which is effected, for example, as described immediately above.

Thus the oxo eompounds may be eonverted into the corresponding imino derivadves by reacdon with nitrogen bases selected from ammoda, lower alkylamines, hydroxylamine, lower aL~coxyamine, hydrazine, N-mono- or N,N~i-lower aLIcylhydrazine and N-acyl-hydrazine. The reaetion eonditions eorrespond to the conditdons eustomary for the reaetdon of a earbonyl eompound with a dtrogen base, the nitrogen base being used, for example, in the fonn of a salt of an acid, e.g. a hydrohalie aeid, sueh as hydrogen fluoride, hydrogen ehloride, hydrogen bromide or hydrogen iodide, espeeially hydrogen ehloride, sulfurie ~ -aeid or a hydrogen sulfate, sueh as an alkali metal hydtogen sulfate, e.g. sodium hydrogen sulfate, phosphoric aeid, a hydrogen phosphate or a dihydrogen phosphate, e.g. an aL~
metal hydrogen phosphate or dihydrogen phosphate, such as sodium hydrogen phosphate, disodimn hydrogen phosphate, potassium hydrogen phosphate or dipotassium hydrogen phosphate, or in the form of a salt with an organie acid, espeeially a carboxylic acid, sueh as a lower alkanecarboxylie acid unsubstituted or subsdtuted in the lower alkyl radieal preferably by halogen, sueh as fluoIine or iodine, e.g. acede aeid, ehloroaeetde aeid, diehloloacede aeid or tlifluoro- or triehloro-acede aeid, or with a sulfonie aeid, sueh as a lower alkylsulfode aeid, e.g. methanesulfonde aeid, ethanesulfonie acid or ethane-disulfonie aeid, or an arylsulfonie acid, such as benzene- or naphthalene-sulfonic acid or naphthalene-1,5-disulfonie acid; it being possible also for a salt of one of the mendoned nitrogen bases to be prepared with an aeid in s , especially by liberating the weak aeid from the eorresponding salt of a readily voladle weak aeid, such as a lower alkane-carboxylic aeid, e.g. aeedc aeid, or espeeially earbonic acid or hydrogen earbonate, that can be liberated by a sttong aeid, such as sulfurie aeid or espeeially one of the mentioned hydrohalie aeids; in water, in aqueous solvent mixtures, sueh as a mixture of water with one or more aleohols, e.g. methanol, ethanol or isopropanol, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, or di-lower alkyl-lower aLkanoylamides, such as dimethyl-formamide, in organie solvents, such as aleohols, e.g. methanol or ethanol, di-lower aLkyl -Sl- 2109992 sulfoxides, such as dimethyl sulfoxide, di-lower alkyl-lower alkanoylamides, ~uch as dimethylformamide, or in adequately inert nitriles, such as acetonitrile, a mixture of such organic solvents, or without a solvent in a melt, preferably in an alcoholic soludon, such as in methanol, ethanol or especially isopropanol; preferably at temperatures of from -20 C to the reflux temperature of the reaction mixture in the presence of a solvent, or in the case of melts up to 220 C, especially at temperatures of from 0 to 50 C in the presence of a solvent, more cspecially at approximately room temperature.

A compound of foQmula IV wherein a substituted lower al~ylene formed by Al and A2 together contains acylimino and/or acylimino-lower alkyl as subsdtuent may be obtained from a corresponding imino compound by reacdon with a corresponding free acid that - - - - -contains the acyl radical, for example in the presence of a condensation agent, such as a ~ -carbodiimide, e.g. dicyclohexylcarbodiimide, or an activated acid derivative thcreof, e.g. a carboxylic acid halide, where appropriate in the presenoe of a suitable base, e.g. a tertiary ~ - -amine as already defined, preferably with the exclusion of moisture.

Compounds of formuia IV wherein lower alkylene formed by Al and A2 together carries lower alkylthioimino substituents may preferably be prepared by reacting a corresponding imino star~ng material of formula IV with a lower alkylsulfenyl halide (which may be prepar~ e.g., from a sulfenic acid with hydrogcn halide or by chlorolysis, bromolysis or iodolysis of a corresponding organosulfur compound, it being possible for the preparation also to be carried outin ~a), especiaUy a lower alkylsulfenyl halide, such as methyl-sulfenyl chloridle, preferably using a salt of the imino compound or in the presence of an alkali hydroxide, such as sodium or potassium hydroxide, preferably in organic solvents, - -e.g. hydrocarbons, such as heptane, ethers, such as diethyl ether, dioxane or tetrahydro~
furan, or carboxylic acid amides, such as dimethylformamide, at preferred temperatures of - - -from 0 C to the reflux temperature, especiaUy from 0 to 30 C. ~ -:
Compounds of formula II are obtained from the obt~unable compounds of formula IVpreferably by hydrolysis, e.g. in acidic or alkaline medium. Preferably the hydrolysis of the compound of formula IV 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 or potassium -hydroxide, in a mixture of water and ethanol or methanol, at preferred temperatures of from 0 C to the reflux temperature of the reaction mixture in question, especially approx-imately from 40 C to the reflux temperature. The reaction is calried out especially preferably with the exclusion of oxygen, for example under a protective gas, such as argon , ',"-'.''-.~,`''~

-52- 21 0~9,'3~

or nitrogen.

Compounds of formulae IIa and IIb may be prepared from the compounds of formula II.

The preparation of a compound of formula IIa is cat~ied out, for example, as described above.

Internal anhydrides of formula llb may be prepared, fo~ example, from a free dicarboxylic acid of formula II by reaction with an acid anhydride of formula X
:. ~
R3-(C=O)-~(C=O)-R3' (X) ~ -wherein R3 and R3~ are each, independendy of the other, hydrogen or lower alkyl, but a~e not each hydrogen, especially acetic anhydride.

The staning materials of f~mula m are known, are commercially avaUable or may beprepated accor~ing to p~ocesses hlown per se.

Compounds of formula m wherein one or both of ~e radicals RA and RB are unsubstituted or substituted lower alkyl may be prepared, for example, by reacting a compound of formula XI
RA~_Q ~) wherein RA' is unsubstituted or substituted lower alkyl, as defined in formula I for RA. and Q is a leaving group with a compound of formula XII -wherein RB is as defined for compounds of formula I, or reacting a compound of formula Xl' 53 21~9~

~B~Q (XI') wherein RB' has the same meanings as RA' in compounds of formula XI and Q has the same meaning as in compounds of formula XI
with a compound of formula XII', RA NH NH2 (XII') wherein RA is as defined for compounds of formula I.

The reaction is carried out under the conditions of a first or second order nucleophilic substitution. l~or example a compound of fonnula XI or XI' wherein Q is a leaving group with high polarisability of the electron shell, e.g. bromine or iodine, may be reacted in a polar aprodc solvent, e.g. acetone, acetonitrile, nitromethane, dimethyl sulfoxide or dimethylfo¢mamide. The reaction may also be carried out in water to which, if necessary, an organic solvent, e.g. ethanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamlde or acetone, bas been added as solubiliser. The substitution reacdon is carried out where approprlate at reduced or elevated temperature, e.g. in a temperatuIe range of from approximately 40 C to approximately 100 C, preferably from approximately -10 C tO
approximately 50 C, and wh~re appropnate under an inert gas, e.g. a nitrogen or argon atmosphere.

Acyl RA and/or RB may be introduced, for example, by the reacdon of acids of ~e formulae RA"-OH or RB"-OH, wherein RA" and ~B" each have the meanings given for acyl RA or RB- or reacdve derivatives thereof, e.g. anhydrides, ~nitrophenyl esters O} acid halides, such as chlorides or bromides, with free hydrazine or one of the compounds of ~ -formulae XII or XII' under acyladon conditions analogous to those described for the reacdon of compounds of for nula II or reactdve derivatives thereof with compounds of formula m, but if RA" and/or RB" is the radical of a semiester of carbonic acid, only reacdve derivadves are suitable, prepared, for example, from the corresponding alcohol -and phosgene; for the introducdon of carbamoyl or an acyl radical of an N-mono-subsdtuted carbamic acid or a thiocarbamoyl or N-monosubsdtuted thiocarbamoyl radical, - - ~ -on the other hand, reaction with an N-substituted isocyanate or an N-protected isocyanate (e.g. benzyl isocyanate from which carbamoyl may be obtained by removal of the benzyl -protecting group) or corresponding thioisocyanates is especially suitable, which reaction is carried out preferably in an ether, e.g. a cyclic ether, such as tetrahydrofuran, at prefelTed ~-'-: ..','~
' ~- ' temperatures of from -20 to 60 C, especially approximately at room temperaturc, and for the introduction of N-disubstituted carbamoyl or thiocarbamoyl, for example reaction of hydrazine or the corresponding compounds of formulae XII or XII' with phosgene or analogues thereof, e.g~ N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole (see H. A. Staab, Angew. Chem. 74, 407-423 (1962)), or the corresponding thio ana1Ogues, such as thiophosgene etc., and subsequent reaction of the resulting chloro(thio)carbonyl-or azolido(thio)carbonyl-amino compounds with the corresponding ammonia substituted by 2 radicals, is suitable, or conversely reacdon of thc hydrazine compounds of formulae XII or XII' with the reaction product of ammonia substituted by 2 radicals with (thio)phosgene or analogues thereof, e.g. N,N'-(thio)carbonyldiazolidbs, such as N,N'-carbonyldiirnidazo1e, is suitable; the reactdon is preferably carried out in inert solvents, especiaUy chlorinated hydrocarbons, such as methybnc chloride or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxane, or acid amides, such as dimethylform-amidb, at temperatures of from -20 C to the reflux tcmperature, especially from 0 to Compounds of formulae XII or X~' whcrein RA or RB are as dbfined for compounds of formula I with the exccption of hydrogen, may in an analogous maoner be aUcylated to introducc the complernentaly radical RB' or RA' or acylated to introduce the comple-mentary radical RB or RA

Frec hydrazine ~also in the form of a salt) may also be reacted with the simultaneous imro-- ~-ducdon Of RA and RB-Compounds of formulae XI and XI' are known, are commerciaUy available or can be ~ ~ -prepared according to processes lcnown ~ sc. Substituents in substituted lower aUcyl RA' ~:
and/or RB' may be introduced andlor modified for example by methods analogous to those described for the subsdtution or modificatdon of the lower aUcyl radical in the preparadon of compounds of formula IV ca~ying subsdtuted lower allcyl Al and/or A2. It is also possible for a protected hydroxy group to be present in the starting materials instead of Q
which group is if necessary first (after removal of the protecting group) converted into a leaving group, for example with toluenesulfonyl chloride etc.

All remaining starting materials are known, are commercially available or can be prepared according to processes known ~ se.

2.1~9992 A11 of the starting materials mentioned (that is to say starting materials or intermediates) may if necessary be protected at funcdonal groups that are not to take part in the described reactions, any protecting groups present being removed at a suitable point in time. Result-ing compounds of formula I having protecting groups may be converted into the free compounds of formula I by removal of the protecting groups or may be subjected to the additional process steps mentioned hereinafter.

The protecting groups for functional groups in starting materials the reaction of which is to be avoided, cspecially c~rboxy, amino, hydroxy, mcrcapto and sulfo groups, include cspeciaUy those protocting groups (convcntional protecting groups) which are customarily used in the synthesis of peptide compounds, and also in the synthesis of cephalosporins and penicillins as well as nucleic acid derivativcs and sugars. Those protecting groups may already be prescnt in the precursors and arc intended to protect the functional groups in question against undesired secondary reacdons, such as acylation, etherification, ester-if ication, oxidation, solvolysis, etc.. In certain cases the protecting groups can additionally cause the reactions to proceed selccdvely, for example stereoselecdvely. It is a character-isdc of protecdng groups that thoy can be removed easily, i.e. without undesired secondary reactions taking place, for examplc by solvolysis, Ieducdon, photolysis, and also enzymat-ically, for examplc also under physiological condidons. It is also characterisdc of protecting groups that they are not present in the end products. - - ~ -, ~
The protecdon of funcdonal groups by such protecting groups, the protecdng groups them-selves and the reacdons for their removal are described, for cxample, in standard works such as J. P. W. McO nie, "Protecdve Groups in Organic Chemistry", Plenum ~ress, - -London and New York 1973, in Th. W. Greene, "Protecdvc Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", Volumc 3 ~3. Gross and J. Meienhofer, eds.), Academic Press, London and Ncw Yor~ 1981, in "Methoden dcr organischcn Chemie", --Houben-Weyl, 4th edition, Volume 151l, Georg Thieme Verlag, Stuttgart 1974, in H.~D.
Jakubke and H. Jescheit, "Aminosauren, Pepdde, Proteine" ("Amino acids, pepddes,proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basle 1982, and in Jochcn ~ ~ -Lehmann, "Chemic der Kohlenhydrate: MonosacchaTide und Derivate" ("The Chemistryof Carbohydrates: monosaccharides and derivatives"), Georg Thieme Verlag, Stuttgart 1974.
~ ..
A carboxy group is protected, for example, in the form of an ester group which can be cleaved selectively under mild conditions. A carboxy group protected in esterified form is -56- 210.~9~

esterified especially by a lower alkyl group that is preferably branched in the l-position of the lower aL~cyl group or substituted in the 1- or 2-position of the lower aLkyl group by suit-able substituents.

A protected carboxy group esterified by a lower alkyl group is, for example, methoxy-carbonyl or ethoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group that is branched in the l-position of the lower alkyl group is, for example, tert-lower aLIcoxycarbonyl, for example tert-butoxycarbonyl.

A protected carboxy group esterified by a lower allyl group that is substituted in the 1- or 2-position of the lower alkyl group by suitable substituents is, for example, arylmethoxy-carbonyl having one or two aryl radicals, wherein aryl is phenyl that is unsubstituted or mono-, di- or tri-substituted, for example, by lower aL~yl, for example tert-lower aLlcyl, such as tert-butyl, lower aL~coxy, for example methoxy, hydroxy, halogen, for example ~ -chlorine, and/or by nitro, for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the mentioned substituents, for example 4nitrobenzyloxycarbonyl or 4-methoxy-benzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by the mentioned substituents, for example di(~methoxyphenyl)methoxycarbonyl, and also carboxy esterified by a lower aL~yl group, the lower alkyl group being substituted in the 1-or 2-position by suitable substituents, such as l-lower aLt~oxy-lower aL~coxycarbonyl, for example methoxymethoxycarbonyl, l-methoxyethoxycarbonyl or l-ethoxyethoxy-carbonyl, l-lower alkylthio-lower alkoxycarbonyl, for example l-methylthiomethoxy- -carbonyl or l~thylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloro-ethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, as well as 2-(tri-substi-tuted silyl~lower aL~coxycarbonyl wherein the substituents are each independently of the others an aliphatic, araliphatic, cycloaliphatic or aromadc hydrocarbon radical ehat is unsubstituted or substituted, for example, by lower alkyl, lower aLkoxy, aryl, halogen and/or by nitro, for example lower aL~cyl, phenyl-lower alkyl, cycloaLkyl or phenyl each of which is unsubstituted or substituted as above, for example 2-tri-lower aL~ylsilyl-lower aL~coxycarbonyl, such as 2-tri-lower aL~ylsilylethoxycarbonyl, for example 2-trimethyl-silylethoxycarbonyl or 2-(di-n-butyl-methyl-silyV-ethoxycarbonyl, or 2-triarylsilylethoxy-carbonyl, such as triphenylsilylethoxycarbony1.

.. . , . ... . . . . , ... . - .. -- .- , .. .. , ... .. ... ,.. . . ..... ,, . ,.. . -, , , ' i '.r' .~,~ ' ' ' -57- 21~9992 A carboxy group is also protected in the fonn of an organic silyloxycarbonyl group. An erganic silyloxycarbonyl group is, for examp1e, a tri-lower alkylsilyloxycarbonyl groùp, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can also be subsdtuted by two lower atkyl groups, for example methyl groups, and an amino group or carboxy group of a second molecule of formula I. Compounds having such protecdng groups can be prepa~ed, for example, using corresponding halosilanes, such as dimethylchlorosilane, as silylating agents.

A carboxy group is also protected in the form of an internal ester by a hydroxy group that is present in the molecule at a suitable distance from the carboxy group, for example in the lr-position reladve to the carboxy group, i.e. in the form of a lactone, preferably a ^t-lactone.

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

Protected carboxy is fIeed according to customary processes, e.g. the processes mendoned in the standard wa~s concerning protecting groups mentdoned above.
,~".' -', ,.' -For example, protected carboxy, for example tert-lower allcoxycarbonyl, lower alkoxy- - ~
carbonyl substituted in the 2-posidon by a trisubstituted silyl group or in the 1-position by ~ ~ -lower alkoxy or by lower alkylthio, or unsubstituted or substituted diphenylmethoxy- ~ --carbonyl can be converted into free carboxy by treatment with a suitable acid, such as -formic acid, hydrogen chloride or tdfluoroacetic acid, where appropriate with the addidon of a nucleophilic compound, such as phenol or anisole. Unsubsdtuted or substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, i.e. bytreatment with hydrogen in the presence of a metal hydrogenadon catalyst, such as a ~ ~
palladium catalyst. In addidon, suitably subsdtuted benzyloxycarbonyl, such as ~nitro ~ ~ -benzyloxycarbonyl, can be converted into free carboxy also by reducdon, for example by treatment with an alkali metal dithionite, such as sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal salt, such as a chromium(II) salt, for example chromium(lI) chloride, customarily in the presence of a hydrogen-yielding agent that, together with the metal, is capable of producing nascent hydr~gen, such as an acid, 58 21~9~92 especially a suitable carboxylic acid, such as an unsubstituted or substituted, for example hydroxy-substituted, lower alkanecarboxylic acid, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, ~chloromandelic acid or tartaric acid, or in the presence of an alcohol or thiol, wata preferably being added. By treatment with a reducing metal or metal salt, as described above, 2-halo-lower aLlcoxy-carbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lowa aLlcoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into frec carboxy. Aroylmethoxycarbonyl can be cleaved also bytreatment with a nucleophilic, prefcrably salt-forming, rcagent, such as sodium thio-ph~nolate or sodium iodide. 2-(tri-subsdtuted silyl)-lower aL~coxycarbony1, such as 2-tri-lower alkylsilyl-lower al~oxycarbonyl, can be converted into free carboxy also by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an aL~ali metal fluoride, for example sodium or potassium fluoride, where appropriate in the presence of a macrocyclic polyether ("crown ether"~, or with a fluoride of an organic quaternary base, such as tetra-lower allcylammonium fluoqide or tri-lower aL~ylaryl-lower aLlcylammonium fluoride, for example tetraethylammonium fluoride or tetrabutyl-ammonium fluoride, in the presence of an aprodc, polar solvent, such as dimethylsulfoxide or N,N-dimethylacetamide. Carboxy protected in the form of organic silyloxy-carbonyl, such as tri-lower aL~cylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, can be ~eed in customary manner by solvobsis, for example by treatment with water, an alcohol or an acidi or, furthermore, a fluoride, as described above. Esterified carboxy can also be freed enzymadcally, for example by means of esterases or suitable peptidases, for example esterified arginine or Iysine, such as Iysine methyl ester, using trypsin. Carboxy protected in the form of an internal ester, such as ~-lactone, can be freed by hydrolysis in the presence of a hydroxide-containing base, such as an aL~aline earth metal hydroxide or especially an alkali metal hydroxide, for example NaOH, KOH or LiOH, especially LiOH, the correspondingly protected hydroxy group being freed at the same time.

A protected amino group is protected by an amino-protecting group, for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-l-enylamino or silylamino group or in the form of an azido group In an acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid having, for examplé, up to 18 carbon atoms, especially an unsubstituted or substituted, for example halo- or aryl-substituted, lower aL~canec~rboxylic acid or an unsubstituted or subsdtuted, for example halo-, lower allcoxy- or nitro-subsdtuted, benzoic acid, or, 59 21.~'~992 preferably, of a carbonic acid semiester. Such acyl groups are prefcrably lower alkanoyl.
such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, for example 2-halo-acetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, unsubsdtuted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoyl, such as benzoyl, 4chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower aL~coxycarbonyl, preferably lower aLlcoxycarbonyl that is branched in the l-posidon of the lower allcyl radical or suitably substituted in the 1- or 2-positdon, for example tert-lower aLkoxycarbonyl, such as tert-butoxycarbonyl, arylnethoxycarbonyl having one, two or three aryl radicals which are phenyl that is unsubsdtuted or mono- or poly-substituted, for example, by lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower aLlcoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by nitro, for example benzyloxy-carbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxy-carbonyl or di(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl wherein thearoyl group is preferably benzoyl that is unsubsdtuted or subsdtuted, for example, by halogen, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxy- -carbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodo ethoxycarbonyl, 2-(tri-subsdtuted silyl)-lower alkoxycarbonyl, for example 2-tri-lower aLkylsilyl-lower allcoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl- - -methyl-silyl~ethoxycarbonyl, or triarylsilyl-lower allcoxycarbonyl, for example 2-tri-phenylsilylethoxycarbonyL ~ -~
:~ :
In an aryhnethylamino group, for example a mono-, di- or especially tri-arylmethylamino ~ -~
group, the aryl Iadicals are especially unsubstituted or subsdtuted phenyl radicals. Such groups are, for example, benzyl-, diphenylmethyl- or especially trityl-amino. ~;
- - ~
In an etherified mercaptoamino group the mercapto group is especially in the form of -subsdtuted arylthio or aryl-lower alkylthio, wherein aryl is, for example, phenyl that is unsubstdtuted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, andlor by nitro, for example ~ ~ -~nitrophenylthio.

In a 2-acyl-lower alk-l-enyl radical that can be used as an amino-protecdng group, acyl is, for example, the corresponding radical of a lower aLl~anecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower aLkyl semiester. - ;

''~

.60- 2109992 Corresponding protecting groups are especially 1-lower alkanoyl-lower alk-1-en-2-yl, for example 1-lower aLkanoylprop-l-en-2-yl, such as 1-acetylprop-1-en-2-yl, or lower alkoxy-carbonyl-lower alk-1-en-2-yl, for example lower allcoxycarbonylprop-1-en-2-yl, such as 1-ethoxycarbonylprop-1-en-2-yl.

A silylamino group is, for example, a tri-lower alkylsilylamino group, for example tnmethylsilylamino or tert-butyl-dimethylsilylamino. The silicon atom of the silylamino group can also be substituted by ody two lower allcyl groups, for example methyl groups, and by the amino group or carboxy group of a second mokcule of formula I. Compounds having such protecting groups can be prepared, for example, using corresponding chloro silanes, such as dimethylchlorosilane, as silylating agents.

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

Preferred amino-protocting groups are lower alkoxycarbonyl, phenyl-lower alkoxycar-bonyl, fluorenyl-lower alkoxycarbonyL 2-lower alkanoyl-lower alk-1-en-2-yl and lower aUcoxycarbonyl-lower alk-1-en-2-yl, especially tert-butoxycarbonyl and benzyloxy-carbonyl.

Also preferred are divalent amino-protecting groups, such as mono- or di-subsdtuted methylidene groups, such as l-lower al~o~cy(far example methoxy or ethoxy)-lower alkyl-idene (for exarnple ethylidene or l-n-butylidene), e.g. =C(CH3)(0C2HS), and also e.g.
~(CH3)2 o~ =CEl-phenyl, and especially bisacyl radicals, e.g. the phthalyl radical, which together with the nitrogen atom to be protected forms a lH-isoindole-1,~(2H~dione (phthalirnido group).

A protected amino group is freed in a manner known per se and, according to the nature of the protccdng groups, in various ways, preferably by solvolysis or reduction. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, can be cleaved in the presence of acids, for example mineral acids, for example a hydrogen halide, such as hydrogen chloride or hydrogen bromide, especially hydrogen bromide, or sulfuric or phosphoric acids, preferably hydrogen chloride, in polar solvents, such as water or a carboxylic acid, such as acetic acid, or ethers, preferably cyclic ethers, such as dioxane, and 2-halo-lower 2103~9~

alkoxycarbonylamino (where appropriate after conversion of a 2-bromo-lowcr alkoxy-carbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), and aroyl-methoxycarbonylamino or ~nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable reducing agent, such as zinc in the presence of a suitaUe carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can be cleavcd also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and ~nitrobcnzyloxycarbonylamino also by treatment with an allcali mcta1 ~ -dithionite, for example sodium dithionite. Unsubstituted or substituted diphenylmethoxy-carbonylamino, tert-lower alkoxycarbonylamino or 2-(tri-substitutcd silyl)-lower alkoxy-carbonylamino, such as 2-tri-lowcr alkylsilyl-lower aL~oxycarbonylamino, can be cleaved by treatment with a suitablc acid, for cxampb formic acid or trifluoroacetic acid; ~ ~ -unsubstituted or substituted benzyloxycarbonylamino can be cleaved, for example, by -~
means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable - ~ -hydrogenation catalyst, such as a palladium catalyst, preferably in polar solvents, such as di-lower a~yl-lower a~oylamides, for cxample dimethylformamide, ethers, such as cyclic ethers, for example dioxane, or alcohols, such as methanol, ethanol or propanol, methanol being cspccia~y prefer~ unsubstituted or substituted triarylmethylamino or -formylamino can be clcaved, for cxamplc, by treatment with an acid, such as a mincral acid, for exampb hyd~chloric aci~ or an organic acid, for examplc formic, acedc or trifluoroacetic acid, where appropriate in the presence of water, and an amino group ~ - ~
protccted in the form of silylamino can bc freed, for example, by means of hyd~lysis or ~ -a1coholysis. An amino g~up protected by 2-haloacetyl, for example 2-chloroacetyl, can be f~ by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an a~i metal thiolate of thiourea, and subscquent solvolysis, such as alcoholysis or - -hydrolysis, of thc resulting substitution product. An amino group protected by 2-(tri-substituted silyl~lower a~oxycarbonyl, such as 2-tri-lower alkylsilyl-lower a~oxy~
carbonyl, can be converted into the free amino group also by treatment with a salt of ~ ~ ~
hydrofluoric acid that yields fluoride anions, as h~dicated above in connection with the - -freeing of a correspondingly p~tected carboxy gt~up. Likewise, silyl, such as trimethyl-silyl, bonded ~recdy to a hetero atom, such as nit~gen, can be removed using fluoride ions. The removal of the phdhalyl g~up can be effected e.g. by means of hydrazine hydrate or by means of an acid, e.g. a mineral acid, such as hydrochloric acid, or an ~ -organic acid, such as acetic acid, where appropriate in the presence of organic solvents, e.g. methanol or tetrahydrofuran.
Amino protected in the form of an azido group is converted into free amino, for example, - 62 - 2 1 ~

by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, by reduction using mercapto compounds, such as dithiothreitol or mercaptoethanol, or by treatment with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried ou~ in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or in water or in a mixture of water and an organic solvent, such as an alcohol or dioxane, at approximately from 20C to 25C, or with cooling or heating.

A hydroxy group can be protected, for example, by an acyl group, for examplc lower alkanoyl that is unsubstituted or substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or especially by an acyl radical of a carbonic acid semiester mentioned for protected a nino groups. A preferred hydroxy-protecting group is, for example, 2,2,2-trichloroethoxycarbonyl, ~nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or triphenylmethoxycarbonyl. A hydroxy group can also be protected by tri-lower alkylsilyl, for example trimcthylsilyl, triisopropylsilyl or tert-butyl-dimethylsilyl, a readily removable etherifying group, for example an alkyl group, such as tert-lower aL~yl, for example tert-butyl. an oxa- or a thia-aliphatic or -cycloaliphatic, especially 2-oxa- or 2-thia-aliphatic or-cycloaliphatic, hydrocarbon radical, for example 1-lower alkoxy-lower aLlcyl or 1-lower alkylthio-lower al~yl, such as methoxyrnethyl, l-methoxyethyl, 1-cthoxy-ethyl, methylthiomethyl, l-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cyclo-alkyl having from S to 7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding tbia analogue, and also by l-phenyl-lower aU~yl, such as benzyl, diphenyl-methyl or trityl, wherein the phenyl radicals can be subsdtuted, for example, by halogen, for example chlonne, lower alkoxy, f example methoxy, and/or by nitro.

Two hydroxy groups, especia11y adjacent hydroxy groups, occurring in a molecule, or a hydroxy group and an amino group that are adjacent to one another, can be protected, for example, by divalent protecdng groups, such as a methylene group that is preferably substituted, for example, by one or two lower aL~yl radicals or by oxo, for example unsub-stituted or substituted alkylidene, for example lower alkylidene, such as isopropylidene, --cycloaL~cylidene, such as cyclohexylidene, a carbonyl group or benzylidene.

A hydroxy group in a position adjacent to a carboxy group can be protected by the ~ -formation of an internal ester (lactone), especially a ~-lactone. -Preference is given to a protected hydr~xy group protected by tri-lower aL~ylsilyl or in the `:

-63- 2~ 0~;'3!,2 form of a lactone, especially by tert-butyl-dimethylsilyl.

A mercapto group can be protected especially by S-aLkyladon with unsubstituted or substi-tuted alkyl radicals, by silylation, by thioacetal formation, by S-acylation or by the fonnadon of asymmetric disulfide groupings. Preferred mercapto-protecting groups are, for example, benzyl that is unsubstituted or substdtuted in the phenyl radical, for example by methoxy or by nitro, such as 4-methoxybenzyl, diphenylmethyl that is unsubstituted or subsdtuted in the phenyl radical, for example by methoxy, such as di(4-methoxyphenyl)-methyl, triphenylmethyl, pyridyldiphenylmethyl, trimethylsilyl, benzylthiomethyl, tetrahydropyranyl, acylaminomethyl, such as acetamidomethyl, isobutyrylacetamido-methyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or aL~cyl-, especially lower alkyl-aminocarbonyl, such as ethylaminocarbonyl, and also lower alkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfo. --A hydroxy or mercapto group protected by a suitable acyl group, by a tri-lower aLlcylsilyl group or by unsubstdtuted or subsdtuted l-phenyl-lower allyl is freed analogously to a correspondingly protected a nino group. A hydroxy or mercapto group protected by 2,2-di-chloroacetyl is freed, for example, by basic hydrolysis, and a hydroxy or mercapto group protected by t~rt-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or 2-oxa- or 2-thia-cycl~
aliphatic hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid~ Mercapto protected by pyridyldiphenylmethyl can be freed, for example, using mercury(~) salts at - -pH 2-6 or by zinc/ace~c acid or by electrolytic reduction; mercapto protected by acet-amidomethyl and isobutyrylamidomethyl can be freed, for example, by reaction with mercuryaI) salts at pH 2-6; mercapto protected by 2-chloroacetamidomethyl can be freed, for example, using l-piperidino~hiocarboxamide; and S-ethylthio, S-tert-butylthio and S-sulfo can be freed, for example, by thiolysis with thiophenol, thioglycolic acid, sodium thio~henolate or 1,4-dithiothreitol. Two hydroxy groups or an amino group and a hydroxy group adjacent to one another which are together protected by means of a divalent protect-ing group, preferably, for example, by a methylene group mono- or di-substituted by lower aLkyl, such as lower allcylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be freed by acid solvolysis, especially in the presence of a mineral acid or a strong organic acid. A tri-lower aLIcylsilyl group is likewise removed by acidolysis, for example by a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. 2-Halo-lowa aL~coxycarbonyl is removed using the above-mentioned reducing agents, for example a reducing metal, such as zinc, or reducing metal ~ -2 ~ o rl ~ 9 ,~

salts, such as ch~omium(II) salts, or by sulfur compounds, for example sodium dithionite or preferably sodium sulfide and carbon disulfide, Esterified hydroxy groups, for example lower aLI~anoyloxy, such as acetoxy, can be freed also by osterases, and acylated amino, for example, by suitable peptidases A sulfo group can be protected, for example, by lower allcyl, e g methyl or ethyl, by phenyl, or in the form of a su1fonamide, for example an imidazolide A sulfo group protected in the form of a sulfonic acid ester or sulfonamide is freed, for example, by acid hydrolysis, e.g. in the presence of a mineral acid, or preferably by basic -hydrolysis, e g. with an alkali metal hyd~xide or alkali metal carbonatc, for example sodium carbonate Oxo is if neccssary protected by acetal formadon, e.g. with lower alkanols, especially with ethanc-1,2-diol, it being possible for the protecting group to be rcmoved at the dcsired stage by hydrolysis in the prcsencc of an acid~ such as acctic acid or sulfuric acid, and thioxo-lowcr alkyl is if necessary protected by thioacetal fonnadon, e.g. with lower aLkyl-mercaptans, such as ethane-1,2~ithiol, it being possible for the p~tecting group to be rcmoved at a suitable point by hydrolysis in the presence of an acid, such as acedc acid or sulfuric acid.

The tcmperatures for frecing the protectcd funcdonal groups are preferably from -80 to 100C, especially from -20 to 50C, for example from 10 to 35C, such as in the region of room tcmperaturc or at reflux tcmperature.
: ..
When scvd protected funcdonal groups are prcsent, if dcsired the protecting groups can bc so selected that morc than one such gl~DUp can be removed simultaneously, for example ~ ~ -by acidolysis, such as by treatment with tlifluoroacedc acid, or with hydrogen and a hydrogenadon catalyst, such as a palladium-on-carbon catalyst. Conversely, the groups can also bc so sclectcd that thcy cannot all be removed simultaneously, but rather can be removed in a desired sequence, the coIIesponding intermediates being obtained Process b) (Cyclisation of 2-formylbenzoic acid derivadves with hydrazines) Formylbenzoic acid derivatives of formula XIII are in free form or especially in the form of reacdve derivadves in which either the carboxy group or the formyl group, or both, may 2 .l. a ~

be derivatised. The forrnyl group and the carboxy group may be reacted simultaneously or in succession, possibly also in different batches, with the compound of formula XIV.

The carboxy group may be present, for example, in the form of an acdvated acid group, e.g. in the form of an anhydride or of a derivative wherein, instead of the carboxy group, a radical Zl-(C=O)- is present in which Zl is reactively activated hydroxy as defined above for compounds of formula IIa.

In a reactdve compound of formula XIII, the fo~myl group may be present in reactively derivadsed form, for example in acetal form, especially in the fo~n of di-lower allcoxy-methyl, such as dimethoxymethyl or diethoxyethyl, as bis(aryl-lower alkoxy)methyl, for example dibenzyloxymethyl, or as lower aLIcylenedioxymethyl, such as ethylene-1,2-dioxymethyl.

The reaction condidons co~espond to the general reacdon condidons mentioned hereinafter. --Preferably, a reacdve derivative of a compol~nd of fonnula XIII is used which has the formula XIIIa Arl 1l -A,- N ~,C~ (Xma) Ar2 HO H

wherein E is hydrogen or lower alkyl and the remaining radicals have the meanings given. The reaction of a compound of formula XIIIa is preferably carried out in an inert solvent, e.g. an ether, especially a di-lower aLlcyl ether, such as diethyl ether, or more especially a cyclic ether, such as tetrahydrofuran or especially dioxane, preferably at elevated pressure in a pressure tube, at preferred temp- -eratures of from 50 to 150 C, preferably at approximately 120 C. Preferably, the hydrazine compound of fo~mula XIV is present in excess with respect to the compound of formula xm, for example in a 1.1- to 10-fold molar excess.
: -' . ' .

-66- 21~

In the starting materials of formula XIII and reactive derivatives thereof and in thc starting materials of forrnula XIV, functional groups that are not to take part in the reaction arc if necessary present in protected form. The protecting groups and their in~duction are as described under process a). The removal of protecting groups is carried out also prefcrably in accordance with the methods described under process a~.

The starting materials of formula XIII can be prepared according to processes known se. For example, they may be prepared from a compound of formula IV, which may be prepared as described abovc and whercin thc radicals have the meanings givcn above, by reaction with ammonia or a lower allylamine and subsequent reduction of the resulting compounds to yield compounds of formula XIIIa The reaction with ammonia or a lowcr alkylamine (aminolysis) is caIried out at tcmpcra-tures of from 10 to 150 C, preferably at from 100 to 150 C. Preference is given to the reaction of di-lower alkyl esters of formula IV, especially in a high-boiling alcohol, e.g. a diol, such as cthylcne glycol, or in another solvent, c.g. a lower aL~canol, such as methanol or ethanol, or in the absence of solvents, in an autoclave at elevated pressure.
In that manner phthalimidc derivatives of formula XV, ,Ar Al--N~ /N - E (XV) Ar2 are obtained wherein Al, A2, Arl, Ar2 and E have the meanings given. The reduction of those compounds is carried out, for example, with suitable complex hydrides, especially with lithium aluminium hydride, in suitable solvents, preferably in ethers, such as di-lower alkyl ethers or cyclic ethers, such as dioxane or especially tetrahydrofuran, at preferred temperatures of from O to 50 C, especially approximately at room temperature, the complex hydride preferably being used in excess, for example in a 1.1- to 10-fold molar excess with respect to the compound of formula XV. In that manner the cyclic 2-formyl-ben~oic acid derivatives of foImula XIIIa are obtained.
~ .:

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

-67- ~ d'~

Provided that the compounds of formula XI~ do not eontain hydrolysis-sensitive funher substituents that would result in undesired products, free compounds of formula xm can be obtained from compounds of formula Xma under suitable conditions by removal of the -NH-E radical (freeing of the carboxy group) under conditions known Per se for hydro-lysis, e.g. in the presence of aqueous lyes, e.g. in the presence of alkaline earth metal -hydroxides, such as sodium hydroxide or potassium hydroxide; or in the presence of aeids, such as hydrohalic acids, e.g. hydrochlorie acid, sulfurie aeid or phosphorie acid, -~
espeeially weak acids, sueh as acetic acid or fonnic acid; in the presence or absenee of ~ -further solvents, such as tetrahydrofuran or dimethylformamide, at temperatures of from O C to tho reflux temperature, e.g. approximately from 20 to 50 C.

The free compounds can then be eonvened aeeording to processes known Per se intofunher reactive derivatives. For example the formyl radical may be eonvened into aeetal form with lower allcyl aleohols, such as methanol or ethanol, with aryl-lower alkyl aleohols, such as benzyl aleohol, or with diols, sueh as ethane-1,2-diol (ethylene glyeol) (preferably with acid catalysis, e.g. in the prescnee of toluenesulfonic acid, sulfurie acid, -phosphorie aeid, a hydrohalie aeid, sueh as hydroehloIie aeid, or a haloacede aeid, sueh as ~ ~-trifluoro- or triehlor~aeedc aeid; in suitable solvents, e.g. aromatie solvents, such as - -benzene, toluene or xylene, or in halogenated hydroearbons, such as chlorofonn, triehlo¢o - ~ ~
ethylene or diehloromethane, at ele~ated temperatures, e.g. under reflux), andlor the ~ - ;
earboxy group may be eonver~cd into an aeti~ated form, for example as deseribed under ~ - -process a) for reaetive star~ng materials of formula IIa.

The appropriate sequence and suitabk reaetion eonditions are familiar to the person - -skilled in the art; functional groups that are not to take part in the reactions are if necessary to be protected.
.
The star~ng materials of formula XIV are known or ean be prepared analogously to the starting eompoundls of formula m.

Additional Process steps~

Compounds of formula I can be conver~d in a manner known ~ se into other compounds of formula I.

21~99~'~

It is possible to carry out the said conversions individually, or alternatively to select suitable combinadons of the individual conversions, that is to say to carry out two or more conversions with a compound of formula I. Functdona1 groups in stardng materials of formula I and other stardng materials that are not to take part in the reacdon in quesdon are, if necessary, in protected form. The protecdng groups are removed at suitable points in dme. The introducdon of the protecdng groups, the protectdng groups themsdves and their removal are as described hereinbefore.

For example, a compound of formula I in which carbonyl groups are present in acyl substituents may be reacted with a suitable reagent so as to produce a different compound of formuh I that contains a thiocarbonyl group instead of the corresponding carbonyl group. Suitable reagents for the conversion of -C(=O)- into -C(=S)- are e.g. phosphorus pentasulfide or preferably phosphorus pentasulfide substdtutes, e.g. Lawesson's reagent (=
2,4bis(4methoxyphenyl)-2,4dithioxo-1,3,2,4dithiaphosphetane), the reactdon beingcarried out, for example, in a halogenated hydrocarbon, such as dichloromethane, at temp-eratures of from 30 C to the reflux temperature, especially at the reflux tempeMture.

Compounds of formula I wherein one of the radicals Al and A2 is hydrogen may be converted by reacdon with suitable reagents into different compounds of formula I
wherein neither of the radicals Al and A2 is hydrogen. ;

A suitable method of introducing Al or A2 representing unsubstdtuted or subsdtuted lower - ~ -al~yl is e.g. treatment with the base lithium diisopropylamide (IDA) and subsequent reacdon with an unsubstituted or subsdtuted di-lower alkyl ether or with an unsubstituted or subsdtuted lower alkyl halide. Substdtuted lower alkyl is in this case as defined for the corresponding radical Al and/or A2 in compounds of formula I.
"
Compounds of formula I wherein at least one of the radicals Arl and Ar2 is phenyl may be converted by hydrogenadon into compounds of formula I that contain a cyclohexyl radical instead of the phenyl radical or radicals. The hydrogenadon is ca~ried out preferably in the presence of a catalyst that allows selecdve hydrogenadon of aromadc double bonds, for example when amide groups that are not to be reacted are present, especially a catalyst of heavy metal oxides, such as a Rh(III)/Pt(VI) oxide catalyst according to Nishimura (S.
Nishimura, Bull. Chem. Soc. Japan ~, 566 (1960), in suitable solvents, especially water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, or preferably in the presence of PtO2 in lower aLkanecarboxylic acids, such as .~
. ~

21099~2 acetic acid, at temperatures of from 0 C to the reflux temperature or up to lS0 C, preferably at from 10 to 50 C, e.g. at room temperature, and at hydrogen pressures of from 1 to 50 bar, e.g. approximately at normal pressure.

Compounds of formula I wherein Arl and/or Ar2 are aryl, especially phenyl or naphthyl, substituted by ha1Ogen, preferably bromine, may be converted into the corresponding derivatives in which one or all of the halogen atoms present in aryl Arl and/or Ar2 have been replaced by cyano, for example by reaction with a cyanide salt of a transition metal, especially CuCN, at temperatures of from 50 to 150 C, preferably from 60 to 140 C, in an ine~ polar solvent, such as a N,N-di-lower alkyl-lower alkanecarboxylic acid amide, e.g. dimethylformamide, without or with the subsequent addition of a catalyst, e.g. a transidon metal halide, such as iron(m) chloride, in aqueous solution (see also Rosenmund et aL, Ber. ~, 1749 (1916); von Braun _ aL, Ann. 488, 111 (1931).

In compounds of formula I the radicals Arl and/or Ar2 that are unsubstituted or substituted aryl, especia1ly unsubsdtuted phenyl or naphthyl, may be nitrated independendy of one - --another, with the introducdon of one or more nitro groups, for example under customary conditions for the introducdon of a nitro group into aromatic compounds, e.g. with concentrated or 100 % nitric acid at temperatures of from 0 to 100C, preferably from 10 to 40 C, in an inert solvent, e.g. an organic acid anhydride, such as acetic anhydride. If several different products are obtained with different posidons of and numbers of nitro groups, then dhose may be separated according to conventional methods, for example by column chromatography. ~ ~

Nitro substdtuents in the radicals Arl and/or Ar2 may be reduced to amino groups, for ~ ` -example by hydrogenation under customary conMtions, e.g. by hydrogenation in thepresence of a hydrogenadon catalyst suitable for the selective reduction of nitro groups, such as Raney nickel, in an inert solvent, e.g. a cyclic or acyclic ether, such as tetrahydr~
furan, under normal pressure or at a pressure of up to S bar.

Compounds of formula I ~,vith etherified hydroxy groups, for example lower aL~oxy radicals, as substituents in Arl and/or Ar2 or at Al and/or A2 may be converted by ether cleavage into the corresponding hydroxy-substituted compounds of formula I. The ether cleavage is ca~ied out under conditions known ~ se, for example in the presence of hydrohalic acids, such as hydrogen bromide or hydrogen iodide, in the presence or absence of solvents, such as carboxylic acids, e.g. lower alkanecarboxylic acids, such as -70- 2~9~

acetic acid, at temperatures of from 20 C to the reflux temperature of the reaction mixture, or preferably under mild conditions with boron halides, especially boron tribromide, in an inert solvent, such as a chlorinated hydrocarbon, e.g. methylene chloride or chloroform, at temperatures of from -80 to 0 C, especially from -50 to -20 C.

Compounds of formula I that contain hydroxy e.g. in Al, A2 and/or substituted lower alkylene formed by those two radicals together, may be converted, by oxidadon to the corresponding carbonyl compounds and by reaction, carried out immediately afterwards or only after isolation of the carbonyl compound, with hydroxylamine or a salt thereof or with fur~er amino compounds, into the corresponding imino compounds, such as thecorresponding hydroxyimino compounds. The further substituents, reagents and preferred reaction conditions may be found in the description of the preparation of compounds of formula IV wherein imino, lower alkylimino, acylimino, hydroxyimino, lower alkoxy-imino, hydrazono, N-mono- or N,N-di-lower aL~cylhydrazono and/or N-acylhydrazono is present as substituent in substituted lower alkylene formed by Al and A2 together, from corresponding oxo compounds of formula IV, oxo compounds of formula I being usedinstead of the oxo compounds of formula lV.
.: :. '~
Compounds of formula I that contain hydroxyimino as substituent in Al andlor A2 or contain a lower alkylene formed by those two radicals together may be converted by hydrogenation into the corresponding amino compounds. The hydrogenation is preferably carried out catalytically using selecti~e hydrogenation catalysts, especially in the presence of palladium on solid carriers, e.g. on carbon, in polar organic or organic-aqueous solvents or solvent mixtures, especially in ethers, e.g. cyclic ethers, such as tetrahydrofuran or dioxane, or in alcohols, e.g. lower alkanols, such as methanol or ethanol, or mixtures thereof, e.g. in methanoVte~ahydrofuran mixtures, at temperatures of from -20 to 60 C, preferably from 0 to 40 C, e.g. approximately at room temperature.

In compounds of formula I having primary hydroxy groups, for exarnple compounds of formula I in which subsdtuted lower alkyl, substituted lower alkenyl or substituted lower aL~cynyl Al and/or A2 contain primary hydroxy groups, as in hydroxyethyl, or in which Al and A2 together form a substituted lower aLkylene that contains hydroxy-lower aLIcyl, such as hydroxymethyl, as substituent, primary hydr~xy groups may be oxidised to corres-ponding carboxy or carboxy-lower alkyl radicals, for example by oxidation with chromic acid, dichromate/sulfuric acid, nitric acid, pyrolusite or potassium permanganate, preferably with potassium permanganate in a neutral or aLlcaline medium, e.g. in an 21~9~

aqueous alcoholic solution, at preferred temperatures of from -20 to 50 C, especially from 0 C to room temperature. Corresponding carboxy-substituted compounds of forrnula I are obtained.

In compounds of formula I in which a substituted lower aLkyl Al and/or A2 contains carboxy, as in carboxymethyl Al and/or A2, or in which Al and A2 together form a subsd-tuted lower allylene that contains carboxy or carboxy-lower alkyl as substituent, for example in such compounds which are prepared in accordance with the last-de~cribed process from compounds of formula I having primary hydroxy groups, carboxy groups may be converted by reaction with diazo-lower aLl~anes, such as diazomethane (yielding methoxycarbonyl), or with lower alkanols, such as methanol or ethanol, into the corres-ponding lower aL~coxycarbonyl groups. The reaction with diazomethane is car~ied out, for example, in aqueous-alcoholic solution, e.g. in water/methanol, or preferably in an ether, in the presence of an ethereal solution of diazomethane, e.g. diazomethane in diethyl ether, at temperatures of from -20 to 30 C, e.g. from 0 C to room temperature. The reaction with lower aL~canols is preferably calTied out in the presence of condensation agents, such as carbodiimides, e.g. dicyclohexylcarbodiimide, in the relevant lower alkanol to which a further inert organic solvent, preferably dimethylformamide or dimethyl acetamide, may have been added, at temperatures of from 0 to the reflux temperature, preferably from 10 to 40 C. Corresponding lower aLl~oxycarbonyl compounds of formula I are obtained.

A compound of fonnula I wherein a substituted lower alkylene formed by Al and A2together contains hydroxy and/or hydroxy-lower alkyl as substituents may be oxidised to a corresponding oxo compound. In the case of primary alcohols the use of selectiveoxidising agents is necessary for that puIpose, e.g. potassium ferrate (K2FeO4) in aqueous solvents and pyrolusite in organic solvents, tert-butylchromate, pyridinium dichromate or especially pyridiniurn chlorochrornate in inert organic solvents, e.g. chlorinated hydrocarbons, such as dichloromethane or chlorofo~m. The reaction is carried out prefer-ably at temperatures of from -20 C to the reflux temperature, e.g. at approximately from 0 to 40 C. ~ the case of secondaIy alcohols, the oxidation may also be carried out using less selective oxidising agents, such as chromic acid, dichromate/sulfuric acid,dichromate/glacial acetic acid, nitric acid, pyrolusite, selenium dioxide or dimethyl sulfoxide in the presence of oxalyl chloride, in water or in aqueous or organic solvents, such as halogenated hydrocarbons, e.g. methylene chloride, or carboxylic acid amides, such as dimethylformamide, preferably at temperatures of from -50 C tO reflux temp-erature, especially from -10 to 50 C. Compounds of formula I are obtained wherein -72- 2~99g~

substituted lower alkylene formed by Al and A2 together and/or substituted mcthyl Z are substituted by oxo.

Compounds of formula I wherein a substituted lower alkylene formed by Al and A2 together contains one or more substituents selected from imino, lower alkylimino, acyl-imino, hydroxyimino, lower aL~coxyimino, hydrazono, N-mono- or N,N di-lowcr aL~cyl-hydrazono, N-acylhydrazono and lower alkyl substituted by imino, lower aLkylimino, acylimino, hydroxyimino, lower aL~oxyimino, hydrazono, N-mono- or N,N-di-lowcr aL~cylhydrazono and/or by N-acylhydrazono, and/or compounds of forrnula I wherein Z is methyl substituted by imino, lower alkylimino, acylimino, hydroxyimino, lower ~ ~ ~
aL~oxyimino, hydrazono, N-mono- or N,N-di-lower aLIcylhydrazono or by N-acyl- - - - -hydrazono, may be prepared from corresponding oxo compounds of foImula I, either after isolation of the oxo compounds or, preferably, by the direct further use thereof in the form of a crude product, for example after partial concentration by evaporation to remove the solvent in which the oxidation of a hydroxy compound to the oxo compound is carried out, which is effected, for example, as described immediately above.

Thus the oxo compounds may be converted into the corresponding imino deriva~ves by reaction with nitrogen bases selected from ammonia, lower alkylamines, hydroxylamine, lower alkoxyamine, hydrazine, N-mono- or N,N-di-lower aL~cylhydrazine and N-acyl-hydrazine. The reaction conditions cQ~respond to the conditions customary for the reaction of a carbonyl compound with a nitrogen base, the nitrogen base being used, for example, in the f~m of a salt of an acid, e.g. a hydrohalic acid, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide or hydrogen iodide, especially hydrogen chloride, sulfuric acid or a hydrogen sulfate, such as an aL~ali metal hydrogen sulfate, e.g. sodium hydrogen sulfate, phosphoric acid, a hydrogen phosphate or a dihydrogen phosphate, e.g. an alkali meta1 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, especially a carboxylic acid, such as a lower alkanecarboxylic acid unsubstituted or substituted in the lower aL~cyl radical preferably by halogen, such as fluorine or iodine, e.g. acetic acid, chloroacetic acid, dichloroacetic acid or trifluor~ or trichloro-acetic acid, or with a sulfonic acid, such as a lower alkylsulfonic acid, e.g. methanesulfonic acid, ethanesulfonic acid or ethane-disulfonic acid, or an arylsulfonic acid, such as benzene- or naphthalene-sulfonic acid or naphthalene-1,5-disulfonic acid; it being possible for a salt of one of the mentioned nitrogen bases be prepared with an acid in situ, especially by libera~ng the weak acid from ~ .-~. :. ~,.

- 73 - ~ 9 9 9 ~

the corresponding salt of a readily volatile weak acid, such as a lower alkanecarboxylic acid, e.g. acetic acid, or especially carbonic acid or hydrogen carbonate, that can be liberated by a strong acid, such as sulfuric acid or especially one of the mendoned hydrohalic acids; in water (in the presence or absence of surfactants), in 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 sulfoxide, or di-lower alkyl-lower alkanoylamides, such as dimethylformamide, in organic solvents, such as alcohols, e.g. methanol or ethanol, di-lower alkyl sulfoxides, such as dimethyl sulfoxide, di-lower alkyl-lower alkanoylamides, such as dimethylformamide, or in adequately inert nitribs, such as acetonitrile, a mixture of such organic solvents, or without a solvent in a melt, preferably in an alcoholic solutdon, such as in methanol, ethanol or especially isopropanol; preferably at temperatures of from -20 C to the reflux temperature of the reaction mixture in the presence of a solwnt, or in the case of melts up to 220 C, especially at temperatures of *om 0 to 50 C in the presence of a solvent, more especially approximately at room temperature.

Free compounds of formula I having salt-forming properties obtainable in accor~ance with the process can be converted in a manner known ~r se into their salts, compounds having basis properlies e.g. by treatment with acids or suitable derivatives thereof, and compounds with acidic properlies e.g. by treatment with bases or suitable delivatives thereof.

Mixtures of isomers obtainable in accordance with the invention can be separated into the individual isomers in a mannerknown ~r se, diastereoisomers e.g. by partitioningbetween multi-phase solvent mixtures, recrystallisation and/or chromatographic separa-don, for example on silica gd, and racemates e.g. by the formation of salts with optically pure salt-forming reagents and separation of the so-obtainable diastereoisomeric mixture, e.g. by means of fractional crystallisation, or by chromatography on optically active -~
column materials.

General reaction conditions:

The above-mentioned reactions can be carried out under reaction conditions that are hlownperse, in the absence orcustomarily in the presence of solvents or diluents, prefer-ably those solvents and diluents that are inert towards dle reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents or neulralising ~74~ 210999?, agents, depending on the nature of the reaction and/or the reactants at reduced, normal or elevated temperature, e.g. in a temperature range of from approximately -80C toapproximately 250C, preferably from approximately -20C to approximately 150C, for example from room tempeMture to the reflux temperature, or in the case of melts at up to 220C, under atmospheric pressure or in a closed vessel, if desired under pressure, for example at the pressure produced in the reaction mixture under the reaction eonditions in a closed tube, and/or in an inert atmosphere, e.g. under an argon or nitrogen atmosphere.
The reaction eonditions speeifically mentioned are preferred.

Solvents and diluents are, for example, water, aleohols, for example lower aLlcanols, such as methanol, ethanol or propanol, diols, sueh as ethylene glyeol, triols, such as glyeerol, or aryl alcohols, sueh as phenol, aeid amides, for example carboxylic acid amides, such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-dinone (DMPU), or amides of inorganic acids, such as hexamethylphosphoric acid tri-amide, ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or aeyelic ethers, sueh as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, sueh as hal~lower aLIcanes, for example methylene ehloride or ehloroform, ketones, such as aeetone, nitriles, sueh as aeetonitIile, acid anhydrides, such as acetic anhydride, esters, sueh as ethyl aeetate, bisaLIcane sulfines, sueh as dimethyl sulfoxide, nitrogen hetero-eyeles, sueh as pyridine, hydrocarbons, for example lower aL~canes, sueh as heptane, or aromatie eompounds, such as benzene or toluene, or mixtures of those solvents, it being possible to seleet the partieular solvents that are suitable for eaeh of the above-mentioned reaetions.
.~
In view of the elose relationship between the eompounds of formula I and the precursors thereof in free form and in the form of salts and/or tautomers, hereinbefore and hereinafter any reference to the free compounds and starling materials or the salts and/or tautomers -thereof should be understood as including the corresponding salts or free compounds -and/or tautomers, respectively, as appropriate and expedient, provided that the compounds contain one or more salt-forming groups, e.g. basic groups, such as amino or imino - -groups, and also those that are bonded at not more than one unsaturated carbon atom, such - ~
as the groups -NAlArl and/or -NA2Ar2 at the carbon atom of the central phenyl ring ~ ~ -wherein Ar1 and Al and/or Ar2 and A2 are not bonded by way of an unsaturated carbon -atom, and/or acidic groups, such as carboxy or sulfo (SO3H), and/or tautomerisable groups. In eonneetion with starting materials, intermediates or eompounds of formula I, any reference made hereinbefore and hereinafter to a substituent, a compound, a tautomer 21099~

or a salt, or to substituents, compounds, tautomers or salts, is to be understood, irrespective of whether the singular or the plural is used, as meaning "one or more" as appropriate and expedient. Starting materials may also be used in protected form, where necessary, appropriate and expedient, it being possible for the protecdng groups to be removed at suitable dmes. Prote dng groups, their introducdon and their removal are especially as defined above under process a).

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

In the process of the present invendon the starting materials used are preferably those that result in the compounds described at the beginning as being preferred.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carned out, or in which a starting material is formed under thc reacdon condidons o,r is used in the form of a derivadvc, for example a salt, thereof.

Thc sequence and reacdon conditions of a11 thc described reactions are preferably to be so selected as considered appropriate and expedieM to the person skilled in the art.
,,~ -Pharmaceudcal Composidons and Processes:

The present invention relates also to pharmaceudcal composidons comprising compounds of formula I as acdve ingredient. Especially preferred are composidons for enteral, especiaUy oIal, or parenteral administradon. The compositions comprise the acdveingredient on its own or, preferably, together with a pharmaceudcal~y acceptable carrier.
The dose of the acdve ingriient depends on the disease to be treated, and on the species, age, weight and individual condidon, as well as the method of administration. -~
-.. ~
Preferred is a pharmaceutical compositdon that is suitable fo,r administration to a warm- ~ -blooded atumal, especially man, suffering from a disease that responds to the inhibidon of a protein kinase, for example pso~iasis or a tumour, comprising an amount of a compound of formula I, or of a salt thereof if salt-forming groups are present, tha~ is effecdve in the inhibition of the protein kinase, together with at least one phannaceudcally acceptable carrier.

210~

The phaImaceutical compositions comprise from approximately 5 % to approximately95 % active ingredient, dosage forms that are in single dose form preferably comprising from approximately 20 % to approximately 90 % active ingredient, and dosage forms that are not in single dose form preferably comprising from approximately 5 % to approx-imately 20 % active ingredient. Unit dose forms, such as dragées, tablets or capsules, comprise from approximately 0.05 g to approximately 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning,dissolving or lyophilising processes. For example pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with one or more solid carriers, where necessary granulating a resulting mixture and processing the mixture or the granules, if desired or appropriate with the addidon of additional excipients, to form tablets or dragée cores.

Suitable carriers are especially fillers, such as sugars, e.g. lactose, saccharose, mannitol or sorbitol, cellulose preparatians and/or calcium phosphates, e.g. tricalcium phosphate or ~ -calcium hydrogen phosphate, and binders, such as starches, e.g. corn, wheat, rice or potato ~ - -starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose -and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above- ~ -mentioned starches, and also carboxymethyl starch, crosslinked polyvinylpyrrolidone or alginic acid or a salt thereof, such as sodium alginate. Additional excipients are ~specially - ~ ;-flow conditioners and lubricants, e.g. si1icic acid, talc, steanc acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives the~eof. ~ -Dragée cores may be provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinyl- -pyrr~lidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable - ~ ~-organic solvents or solvent mixtures, or, for the preparation of enteIic coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropyl-methylcellulose phthalate. Dyes or pigrnents may be added to the tablets or dragée ~-coatings, e.g. for identificadon purposes or to indicate different doses of active ingredient.

Orally administrable pharmaceutical compositions are also dry-filled capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticiser, such as . .

- 77 ~ 0 $ rJ ~ ~

glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders and/or glidants, such as talcum or magnesium stearate, and, where appropriate, stabilisers. In soft capsules, the active ingredient is prcferably dissolved or suspended in suitable liquid excipients, e.g. fatty oils, ~9Lauroglycol (Gattefossé S.A., Saint Priest, France), ~Gclucire (Gattefossé S.A., Saint Priest, France) or sesame oil, paraffin oil or liquid polyethylene glycols, such as PEG 300 or 400 (Fluka, Switzerland), to which stabilisers or detergents may also be added.

Other oral forms of administration are, for example, syrups prepared in customary manner that comprise the acdve ingrodient e.g. in suspended form and in a concentradon of - -approximately from 5 % to 20 %, preferably approximately 10 %, or in a similar concen- ~ ~ -tradon that provides a suitable singb dose when administer~d, for example, in measures of 5 or 10 ml. Also suitable, for example, are powdered or liquid concentrates for preparing shal~es, e.g. in milk. Such concentrates can also be packed in single~ose quanddes.

Suitable rectally adrninistrable pharmaceudcal compoddons are e.g. suppositories that consist of a combinadon of the acdve ingredient with a suppository base. Suitable suppos-itory bases are e.g. natural or synthedc triglycerides, paraffn hydrocarbons, polyethylene glycols or higher alkanols.

For parenteral administration there are suitable, cspecially, aqueous solutions of an active ingredient in water-soluble form, e.g. in the form of a water-soluble salt, or aqueous injecdon suspensions that comprise viscosity-increasing substances, e.g. sodium carboxy-methylcellulose, sorbitol and/or dextran, and, where appropriate, stabilisers. The active ingredient, where appropriate together with excipients, may also be in the form of a lyophilisate and may be made into a solution prior to parenteral administradon by the addition of suitable solvents.

Soludons as used e.g. for parenteral administradon may also be used as infusion soludons.

The invendon relates also to a method of treadng the above-mendoned pathalogicalcondidons, especially those responsive to an inhibidon of protein kinases. The compounds of the present invendon may be administered prophylacdcally or therapeudcally, preferably in an amount that is effecdve against the mendoned diseases, to a warm-blooded animal, e.g. man, requiring such treatment, preferably in the form of pharma--78 - 21~ 9 r~ ~ ~

ceutical compositions. For a body weight of approximately 70 kg a daily dose of from I mg to 5000 mg, e.g. from approximately 0.1 g to approximately 5 g, preferably from approximately 0.5 g to approximately 2 g, of a compound of the present invention is administered.

The following Examples illustrate the present invention; temperatures are given in degrees Celsius. The following abbreviations are used: calc. = calculated; ether = diethyl ether;
FAB-MS = Fast Atom Bombardment Mass Spectroscopy; PD-MS = Field Desorption Mass Spectroscopy; sat. = saturated; mbar = unit of pressure (1 mbar = 1 hectopascal);
IH-NMR = proton nuclear magnetic resonance; m.p. = melting point.

Unless specified other vise, the ratios given for solventteluant mixtures relate to volume (vtv).

Example 1: 6.7-Dianilino-2H.3H-phthalazine-1.4-dione - ~
1.2 g of 4,5-dianilinophthalic anhydride are heated under reflux for 90 min in 60 ml of ~ -tetrahydrofuran with 1.2 g of hydrazine hydrate. The reaction mixtuue is then concentrated by evaporation in vacuo and the evaporation residue is crystallised three times from methanoVether to yield the title compound in the form of colourless crystals, m.p.

C2oH,6N4O2: molecular weight calc. 344, found 344 (FD-MS). ~ -The star~ng materials are prepared as follows: ~ ~ -a)4.5-Dianilinophthalicanhydride ~ ~ -A solution of 2 g of 4,5-dianilinophthalic acid in acetic anhydride is heated for 30 min at 60 C, a strong yellow colouring appearing. After concentra~on by evaporation yellow crystals of 4,5-dianilinophthalic anhydride remain, which are recrystallised from acetone/-ether and then have a melting point of 19~197C -C20H,4N2O3: molecular weight calc. 330, found 330 (FD-MS). ~ ~-..
b) 4.5-Dianilinophthalic acid 4,5-Dianilinophthalie acid dimethyl ester (3.05 g) in a mixture of methanol (500 ml) and lN sodium hydroxide solution (100 ml) is heated under reflux for 2 hours with the exclusion of oxygen. The methanol is subsequently evaporated off in vacuo and the alkaline solution of the reaction product is acidified with hydrochloric acid. The 4,5-di~

2~0~

anilinophthalic acid rapidly precipitates in crystalline form and, after recrystallisation fr~m methylene chloride, is obtained in the form of faintly yellowish pointed prisms which melt at 169C with decomposition.
C2oHl6N2O4: molecular weight calc. 348, found 348 (FD-MS).

c) 4,5-Dianilinophthalic acid dimethyl ester A soludon of 5.6 g (15 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-di-carboxylic acid dimethyl ester and 5.5 ml (60 mmol) of aniline in 60 ml of glacial acetic acid is boilcd under reflux for 4 hours. The reacdon mixture is cooled, the solvent is evap-orated off, the darlc-brown residue is dissolved in dichloromethane and the solutdon is washed in succession with 20 ml of lN HCI, 50 ml of sat. NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporadon. The crude p~oduct is recrystallised from ethanol. In that manner the dtle compound is obtained in the fonn of yellow crystals, m.p. 178, FAB-MS: 377 [M~+H].

d) 4.5-Bis(tlimethylsilyloxv)cvclohexa-1.4-diene-1.2-dicarboxYlic acid dimethvl ester Under argon, a solution of 7.1 g (50 mmol) of acetylenedicarboxylic acid dimethyl ester (E;luka, Switzerland) in 30 ml of toluene is added dropwise to 12.5 g (50 mmol) of 2,3-bis-(trimethylsilyloxy)-1,3-butadiene (Aldrich, Federal Republic of Germany) (9596) and then the mixture is boiled for 19 hours under reflux condidons. The reacdon mixture is cooled, the solvent is evaporated off and the residue is distilled under a high vacuum (0.1 mbar, 124127). In that manner the dtle compound is obtained in the form of a highly viscous yellow oil, lH-NMR (CDC13): ~ = 0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).

Example 2: 6.7-Bis(4fluoroanilinol-2H3H-Phthalazine-1.4dione 0.60 g of 4,5-bis(4-fluoroaoilino)phthalic anhydride in 30 ml of tetrahydrofuran is heated under reflux for 90 min with 0.60 g of hydrazine hydrate, the reacdon mixture is then concentrated by evaporation in vacuo and the evaporation residue is repeatedly crystal-lised from methanol. The dtle compound is obtained in the form of fine white prisms, m.p.
16~-168 C.
Elemental analysis: C20Hl4F2N4O2 (380.35):
calc.: C 63.16%, H 3.71%, N 14.73%;
found: C 62.88% H 3.98% N 14.77%
The starting materials are prepared as follows:

-80- 21~9~g2 a) 4,5-Bis(4-fluoroanilino)phthalic anhydride Bis(4-fluoroanilino)phthalic acid dimethyl ester (2 g) is hydrolysed analogously to Example 1 b) with aqueous methanolic sodium hydroxide solution. The resulting free dicarboxylie aeid is eonverted analogously to Example 1 a), without further purification, directly into the anhydride using acetic anhydride (heatdng at 50 C until anhydride forma-tion is complete, then concentradon by evaporatdon and filtratdon of the evaporation --residue, which has been dissolved in ethyl aeetate, through a small amount of silica gel in order to remove dark impuritdes). The resultdng 4,5-bis(4-fluoroanilino)phthalic anhydride ~-is obtained from ethyl acetate/ether in the form of shiny yellow crysta1s, m.p. 225-227 C.
C2~HI2N2F2O3: moleeular weight calc. 366, found 366 (FD-MS).
b)4.5-Bis(4-fluoroanilino)Dhthalicaciddimethvlester ,, , ~
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-diearboxylie aeid dimethyl ester (Example ld) and 2.3 ml (24 mmol) of 4-fluoroaniline in -60 ml of glacial aeede acid is boiled under reflux conditions for 2 hours. The reacdon mixture is cooled, the solvent is evaporated off, the dark-brown residue is dissolved in dichloromethane and the solutdon is washed in succession with 20 ml of lN HCI,50 ml of -~
sat. NaHCO3 and t vice with 20 ml of water, dried with sodium sulfate and eoncentrated ---by evaporation. The evap~ratdon residue is ehromatographed on siliea gel with ethyl aeetate/hexane 2:1, and the produet fraetions are eoneentrated by evaporation and reerystallised from ethyl aeetate~exane. In that manner the title eompound is obtained in - -the form of yellow erystals. lH-NMR (CDCl3): ~ - 7.40 (s, 2H),7.10-6.80 (m, 8H), 5.70 (br s, 2H), 3.83 (s, 6H). ; ~ -Example 3: 6.7-Bis(4-methylaniliQ)-2H3H-phthalazine-lA-dione The title eompound is obtained analogously to the reaction deseribed in Example 1 by reacting 0.56 g of 4,5-bis(4-methylanilino)phthalic anhydride with 0.6 g of hydrazine -hydrate in 50 ml of tetrahydrofuran. The tide compound is erystallised from methanol in the form of colourless, finely fdted needles, m.p. c. 170 C. ~
C22H2oN402: molecular weight eale. 372, found 372 (E;D-MS). ~ ~-The starting materials are prepared as follows:

a) 4.5-Bis(4-methvlanilino)phthalic anhvdride 4,5-Bis(4-methylanilino)phthalic acid dimethyl ester (4.45 g, 0.011 mol) is heated under reflux with 50 ml of 2M sodium hydroxide solution and 1000 ml of methanol under a -81- 210~

nitrogen atmosphere. The mixture is then concentrated to 300 ml, acidif1ed with SM HCI
and the dicarboxylic acid formed is extracted repeatedly with ethyl acetate. The combined extracts are dried (disodium sulfate) and concentrated by evaporation. The brownish evaporation residue is dissolved in acedc anhydride and heated for 10 minutes at 40 C.
The solution is concentrated by evaporadon and the residue is purified by filtration over silica gel (solvent ethyl acetatefhexane 1:1). 4,5-Bis(4methylanilino)phtha1ic anhydride is obtained in the form of a strongly yellow-coloured filtrate. After concentradon by evaporation the residuc is crystallised from diethyl ether to yield the title compound: m.p.
221-223 C; C22H28N203: molecular weight calc. 358, found 358 (E7D`-MS).

b) 4.5-Bis(4-methylanilino)phthalic acid dimethvl ester The dde compound is obta,ined analogously to Example 1 c) stardng from 23.1 g (60.8 mmoV of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4diene-1,2-dicarboxylic aciddimethyl estcr and 22.7 g (0.21 mol) of 4-toluidine. The dde compound is obtained from ethyl acetatelether in the form of shiny ycllowish crystal platelets, m.p. 170-172 C.

Example 4: 6.7-Dianilino-2.3-dimethyl-2H~N-phthalazine-1.4-dione 0.250 g of 4,5-dianilinophthalic anhydride (Example 1 a) are heated for 14 hours at 80 C
with 0.110 g of N,N'-dimcthylhydrazine dihydrochloride (Pluka, Switzerland) and 0.2155 g of ethyldiisopropylamine in 50 ml of dimethylformamide. The reacdon mixture is then concentrated by evaporadon in vacuo. The evaporadon residue is separated by chromatography on silica gd. Using hexane/ethyl acetate 2:1 a yellow impurity isremoved. The major por~ion is eluted with ethyl acetate/methanol 9:1. After concentradon of the eluate by evaporation, the tide compound is obtained from medhanoVether in the form of colourless crystals, m.p. 217-218 C.
C22H2oN4O2: molecular weight calc. 372, found 372 (PD-MS) Example 5: 6,7-Dian lino-4hydroxy-2-méthyl-?H-phthalazin-l-one The dtle compound is obtained analogously to the process described in Example 1 by headng Q20 g of 4,5-dia,nili,nophthalic anhydride (Example 1 a) with excess N-methyl-hydrazine (0.20 g; Fluka, Switzerland) in 30 ml of tetrahydrofuran for 90 min Crystallisadon from tetrahydrofuran/ether yields colourless crystals, m.p. 27~278 C.
C2,Hl8N402: molecular weight calc. 358, found 358 (FD-MS).

Example 6: 2-Aminothiocarbonyl-6~7-dianilino~-hydroxv-2H-phtha1azin-1-one A soludon of 0.250 g of 4,5~ianilinophthalic anhydride (Example 1 a) and 0.069 g of 2.~0!3'~!32 ,, thiosemicarbazide (E~luka, Switzerland) in 70 ml of methanol is heated under rcflux for 3 hours. The yellowish solid that has precipitated from thc reacdon mixturc after that dme is filtered off and is crystallised twice from dimothylformamidc. The dtle compound is obtained in dhe form of pale-yellowish crysta1s, m.p. 230-232 C.
C2lHl7N502S: molecular weight calc. 403, found 403 ff~D-MS).

Example7: 6.7-dianilino~hydroxY-2-(2-hvdroxycthvl)-2H-phdlalazin-1-one The tide compound is obtained analogously to the process described in Example 1 by heating 0.23 g of 4,5-dianilinophthalic anhydlide (Example 1 a) widh excess 2-hydroxy- ~ ~ -ethylhydrazine (Q12 g) in 50 ml of tetrahydrofuran for2 hours.
C22H2oN403: molecular weight calc. 388, found 388 (E~D-MS).

Example 8: 6.7-Dianilino-2H-Phthalazin-1-one A solution of 6,7~ianilino-3-hydroxy-2H-phthalazin-1-one (0.078 g, 0.235 mmol) in dioxane (10 ml) is hea~ed in a pressure tube with hydrazine hydrate (0.1 ml, approximately 2 mmol) for 4 hours at 120 C. The reaction mixture is concentrated by evaporadon and then purified on silica gel with the eluantedhyl acetatelhexane 2:1 to yield a material of RfO.35 (thin layer chromatography on silica gel 60, Merck, Darmstadt) which, after ~ -crystallisadon tw ce from diethyl edher, yields dhe pure dtle compound having a meldng - -point of 25~255 C with partial decomposidon (cream-coloured platelets). C~116N40, molecular weight calc. 328, found 328 (E~MS).
The starting material is prepared as follows: ~ -a) 4.5-Bis(anilino)phthalimide A suspension of 230 mg (0.7 mmol) of 4,5-bis(aoilino)phthalic acid dimethyl ester (Example 1 c in 23 ml of ethylene glycol is heated to 120; with stilTing, ammonia gas is passed tbrough for a period of 24 hours. The reaction mixture is cooled and ext~actedwith ethyl acetate. The ethyl acetate phases are washed in succession three times witb water -and oncc with sat. sodium chloride soludon, dried with sodium sulfate and concentrated by evaporadon. Tbe evaporadon residue is chromatographed on silica gel with dichloro metbane/metbanol 40:1, and tbe product fracdons are combined and concentrated byevaporation to yield the title compound in the form of yellow crystals, m.p. 215-217, FAB-MS: 330 [M++Hl.

21 09~92 b) 6.7-Dianilino-3-hvdroxY-2H-phthalazin-l~ne Solid lithium aluminium hydride (a total of 0.34 g, 8.9 mmol) is added in porlions, with stirring, to a soludon of 4,5-bisanilino-phthaLimide (0.493 g, 1.49 mmol) in tetrahyd~
furan (150 ml), the originally strongly yellow-coloured soludon then being only fdndy yellowish. Water and sufficient citric acid soludon to produce a pH of approximately 4.5 are then addW. The mixture is filtered through ~Celite (filtering aid based on diatomaceous earth, Fluka, Switzerland), and subsequently washed with tetrahydrofuran and ethyl acetate, and then the filtrate is extracted with ethyl acetate. After drying and concentradng by evaporadon, an amorphous lacquer remains, which crystallises on tritura-tion with a small amount of ethyl acetate. In that manner faintly yellowish crystals of the title compound are obtained which are ~ ystallised from methanoVether for purification purposes, m.p. from 220 C (decomp.); C2~ 7N302, molecular weight calc. 331, found 331 (FD-MS).
Exampb 9 (A2 6-Anilino-7-cyclohexYlamino-2H-~hthalazin-l-one and (B~

6.7-dicyclohexYlamino2H-phthalazin-l-one : -6,7-Dianilino-2H-phthalazin-l-one (E~ample 8; 0.092 g, 0.028 mmol) is hydrogenated for 24 hours in glacial acedc acid (10 ml) with platinum dioxide ~2; 0.002 g). The material resulting from the hydrogenation is separated into two components by chromatography on silica gd with the eluant ethyl acetatefhexane 1:1. The more rapidly migrating substance is crystallised ~om is~propyl alcohoVdietbyl ether to givo colourless hexagonal crystals having a molting point of 265-266 C (title compound (A)), C2~jH22N40: molecular weight calc. 334, found 335 ~+H~+ (FAB-MS). The substance eluted later, which migrates a little more slowly, crgslalli~ on concentradon of its soludon by evaporation; after washing the crystals with diethyl ether the title compound (B), m.p. 285 C, is obtained in the form of colourloss crysta1s; C2~H28N40, molecular weight calc. 340, found 341 (M+H)+ (FAB-MS). -~
.
Example 10: Capsules 5000 capsules each comp~ising 0.25 g of active ingredient, e.g. one of the compounds prepared in Examples 1 to 9, are prepared~
.,'~-','' Composition active ingredient 1250 g talc . 180 g wheat starch 120 g magnesium stearate 80 g lactose 20 g Method: The pulverulent substances are f~rced through a sieve having a mesh size of 0.6 mm and mixed together. A 033 g portion of the mixture is introduced into each gelatine capsule using a capsule-filling machine.

Claims

1. A compound of formula I, (I) wherein A1 and A2 are each, independently of the other, hydrogen, unsubstituted or substituted lower alkyl, unsubstituted or substituted lower alkenyl, unsubstituted or substituted lower alkynyl, heterocyclyl-lower alkyl, acyl, lower alkylsulfonyl or arylsulfonyl, orA1 and A2 together are unsubstituted or substituted lower alkylene;
Ar1 and Ar2 are each, independently of the other, aryl, heteroaryl or unsubstituted or substituted cycloalkyl;
X is oxygen or sulfur, and Q is a divalent radical of the formula , which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benzene ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur and RA and RB are each, independently of the other, hydrogen, unsubstituted or substituted lower alkyl or acyl;
or Q is a divalent radical of the formula H , which is bonded by its carbon atom to the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein RA has one of the meanings mentioned with the exception of acyl;

a salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

2. A compound of formula I according to claim 1, wherein RA and, if present, RB are each hydrogen and the remaining radicals are as defined, a salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

3. A compound of formula I according to claim 1, wherein Al and A2 are each, independently of the other, hydrogen; lower alkyl; substituted lower alkyl, which is substituted by up to 2 radicals selected from amino, mono- or di-lower alkylamino wherein the lower alkyl radical is mono- or di-substituted by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkyl-carbamoyl and/or by cyano or is unsubstituted, C3-C8cycloalkylamino, phenyl-lower alkylamino, phenylamino, lower alkanoylamino, phenyl-lower alkanoylamino, phenyl-carbonylamino, hydroxy, lower alkoxy wherein the lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl A1 or A2 or is unsubstituted, phenyl-lower alkoxy, lower alkanoyloxy, mercapto, lower alkylthio wherein the lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl Al or A2 or is unsubstituted, phenyl-lower alkylthio, lower alkanoylthio, carboxy, lower alkoxy-carbonyl, phenyl-lower alkoxycarbonyl, cyano, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, thiocarbamoyl, N-lower alkylthiocarbamoyl, N,N-di-lower alkylthiocarbamoyl, ureido, ureido substituted at one or both nitrogen atoms by lower alkyl, thioureido, thioureido substituted at one or both nitrogen atoms by lower alkyl, hydrazino, hydrazino substituted at one or both nitrogen atoms by lower alkyl, amidino, amidino substituted at one or both nitrogen atoms by lower alkyl, guanidino, guanidino substituted at one, two or all three nitrogen atoms by lower alkyl, oxo which is not bonded to the carbon atom that is bonded to the A1- or A2-carrying nitrogen, thioxo, imino, lower alkylimino, lower alkanoylimino, hydroxy-imino, lower alkoxyimino, hydrazono, N-mono- or N,N-di-lower alkylhydrazono, N-lower alkanoylhydrazono, lower alkoxycarbonylhydrazono and lower alkylthioimino; loweralkenyl or lower alkynyl each of which is substituted by one of the radicals mentioned for substituted lower alkyl A1 and/or A2 or is unsubstituted; heterocyclyl-lower alkyl wherein heterocyclyl is a radical selected from pyrrolyl, 2,5-dihydropyrrolyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1,3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetrahydro isothiazolyl, indolyl, isoindolyl, benz-imidazolyl, piperidinyl, piperazin-1-yl, morpholino, thiomorpholino, S,S-dioxothio-morpholino, 1,2-dihydro- or 1,2,3,4-tetrahydro-quinolyl and 1,2-di- or 1,2,3,4-tetra-hydro-isoquinolyl, which radical is unsubstituted or is substituted by lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl, is bonded by a ring nitrogen atom and is bonded terminally to the lower alkyl; lower alkanoyl; halo-lower alkanoyl; phenyl-lower alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-di-lower alkyl-carbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)carbamoyl; thiocarbamoyl;
N-mono- or N,N-di-lower alkylthiocarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)thiocarbamoyl; lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl; lower alkyl-sulfonyl; benzenesulfonyl; or benzenesulfonyl substituted in the benzene radical by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or A1 and A2 together form lower alkylene which is unsubstituted or substituted by up to three substituents selected from lower alkyl, amino, amino-lower alkyl, mono- or di-lower alkylamino, mono- or di-lower alkylamino-lower alkyl, wherein the terminal lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl A1 or A2 or is unsubstitNted, C3-C8cycloalkylamino, C3-C8cycloalkylamino-lower alkyl, phenyl-lower alkylamino, phenyl-lower alkylamino-lower alkyl, phenylamino, phenylamino-lower alkyl, lower alkanoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoylamino-lower alkyl, phenyl-lower alkanoylamino-lower alkyl, phenylcarbonyl-amino-lower alkyl, hydroxy, hydroxy-lower alkyl, lower alkoxy or lower alkoxy-lower.
alkyl, wherein the terminal lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl A1 or A2 or is unsubstitNted, phenyl-lower alkoxy, phenyl-lower alkoxy-lower alkyl, lower alkanoyloxy, lower alkanoyloxy-lower alkyl, mercapto, mercapto-lower alkyl, lower alkylthio or lower alkylthio-lower alkyl, wherein the terminal lower alkyl radical is mono- or di-substituted as above in di-lower alkylamino-lower alkyl A1 or A2 or is unsubstituted, phenyl-lower alkylthio, phenyl-lower alkylthio-lower alkyl, lower alkanoylthio, lower alkanoylthio-lower alkyl, carboxy, carboxy-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, phenyl-lower alkoxycarbonyl-lower alkyl, cyano, cyano-lower alkyl, carbamoyl, carbamoyl-lower alkyl, N-lower alkyl-carbamoyl, N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl-lower alkyl, N,N-di-lower alkylcarbamoyl-lower alkyl, N-hydroxycarbamoyl, N-hydroxycarbamoyl-lower alkyl, N-phenylcarbamoyl, N-phenylcarbamoyl-lower alkyl, thiocarbamoyl, thiocarb-amoyl-lower alkyl, N-lower alkylthiocarbamoyl, N-lower alkylthiocarbamoyl-lower alkyl, N,N-di-lower alkylthiocarbamoyl, N,N-di-lower alkylthiocarbamoyl-lower alkyl, ureido, ureido-lower alkyl, ureido or ureido-lower alkyl substituted at one or both nitrogen atoms by lower alkyl, thioureido, thioureido-lower alkyl, thioureido or thioureido-lower alkyl substituted at one or both nitrogen atoms by lower alkyl, hydrazino, hydrazino-lower alkyl, hydrazino or hydrazino-lower alkyl substituted at one or both nitrogen atoms by lower alkyl, amidino, amidino-lower alkyl, amino or amidino-lower alkyl substituted at one or both nitrogen atoms by lower alkyl, guanidino, guanidino-lower alkyl, guanidino or guanidino-lower alkyl substituted at one, two or all three nitrogen atoms by lower alkyl, oxo, oxo-lower alkyl, thioxo, thioxo-lower alkyl, imino, imino-lower alkyl, lower alkyl-imino, lower alkylimino-lower alkyl, lower alkanoylimino, lower alkanoylimino-lower alkyl, hydroxyimino, hydroxyimino-lower alkyl, lower alkoxyimino, lower alkoxyimino-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 are each, independently of the other, unsubstituted phenyl; phenyl o-, m- or p-substituted by a radical selected from lower alkyl, hydroxy, lower alkoxy, halogen, carboxy, lower alkoxacarbonyl and cyano; pentafluarophenyl; heteroaryl bonded by a ring nitrogen atom and selected from imidazolyl, triazolyl, pyridyl, pyrimidinyl and triazinyl, which are unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl; or C3-C8cycloalkyl which is unsubstituted or substituted by lower alkoxy or by hydroxy;
X is oxygen or sulfur, and Q is a divalent radical of the formula , which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benzene ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur and RA and RB are each, independently of the other, hydrogen; unsubstituted or substituted lower alkyl as defined above for A1 and A2; lower alkanoyl; halo-lower alkanoyl; phenyl-lower alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-di-lower alkylcarbamoyl; N-mono-or N,N-bis-(hydroxy-lower alkyl)carbamoyl; thiocarbamoyl; N-mono- or N,N-di-lower alkylthiocarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)thiocarbamoyl; loweralkoxycarbonyl; or phenyl-lower alkoxycarbonyl; or Q is a divalent radical of the formula , which is bonded by its carbon atom to the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein RA is unsubstituted or substituted lower alkyl, preferably as defined above;
a salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

4. A compound of formula I according to claim 3, wherein Q is a divalent radical of the formula , which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benzene ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur and RA and RB are each, independently of the other, hydrogen; unsubstituted or substituted lower alkyl as defined above for A1 and A2; lower alkanoyl; halo-lower alkanoyl; phenyl-lower alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-di-lower alkylcarbamoyl; N-mono-or N,N-bis-(hydroxy-lower alkyl)carbamoyl; thiocarbamoyl; N-mono- or N,N-di-lower alkylthiocarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)thiocarbamoyl; loweralkoxycarbonyl; or phenyl-lower alkoxycarbonyl; and the remaining radicals are as defined, a salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

5. A compound of formula I according to claim 3, wherein Q is a divalent radical of the formula , which is bonded by its carbon atom to the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen atom in formula I, and the remaining radicals are as defined, a salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

6. A compound of formula I according to claim 1 wherein A1 and A2 are each, independently of the other, hydrogen; lower alkyl; substituted lower alkyl which is substituted by up to 2 radicals selected from amino, mono- or di-lower alkylamino, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxy-carbonyl, cyano, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, ureido, ureido substituted at one or both nitrogen atoms by lower alkyl, thioureido and thioureido substituted at one or both nitrogen atoms by lower alkyl; lower alkenyl; or lower alkynyl; or A1 and A2 together form lower alkylene, which is unsubstituted or substituted by lower alkyl, amino, amino-lower alkyl, mono- or di-lower alkylamino, hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, carboxy, carboxy-lower alkyl, lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkyl, cyano, cyano-lower alkyl, carbamoyl, carbamoyl-lower alkyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-lower alkylcarbamoyl-lower alkyl, N,N-di-lower alkylcarbamoyl-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 at one or both nitrogen atoms by lower alkyl, thioureido, thioureido-lower alkyl or by thioureido or thio-ureido-lower alkyl substituted at one or both nitrogen atoms by lower alkyl;
Ar1 and Ar2 are each, independently of the other, unsubstituted phenyl; phenyl o-, m- or p-substituted by a radical selected from lower alkyl, hydroxy, lower alkoxy, halogen, carboxy, lower alkoxycarbonyl and cyano; pentafluorophenyl; or C3-C8cycloalkyl; but preferably each represents the same radical;
X is oxygen or sulfur, and Q is a divalent radical of the formula , which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benzene ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur, and RA and RB are each, independently of the other, hydrogen; unsubstituted lower alkyl or lower alkyl substituted by a radical selected from amino, mono- or di-lower alkylamino, hydroxy and lower alkoxy; lower alkanoyl; carbamoyl; N-mono- or N,N-di-lower alkyl-carbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)carbamoyl; thiocarbamoyl;
N-mono- or N,N-di-lower alkylthiocarbamoyl; N-mono- or N,N-bis-(hydroxy-lower alkyl)thiocarbamoyl; lower alkoxycarbonyl; or phenyl-lower alkoxycarbonyl; or Q is a divalent radical of the formula , which is bonded by its carbon atom to the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein RA is unsubstituted or substituted lower alkyl as defined above;
a salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

7. A compound of formula I according to claim 1 having the formula IA
(IA) wherein A1 and A2 are each, independently of the other, hydrogen or lower alkyl, or A1 and A2 together are lower alkylene;
Ar1 and Ar2 are each, independently of the other, unsubstituted phenyl or phenyl substi-tuted in the o-, m-, or p-position by halogen or by lower alkyl;
X and Y are each, independently of the other, oxygen or sulfur; and RA and RB are each, independently of the other, hydrogen, lower alkyl, hydroxy-lower alkyl, carbamoyl or thiocarbamoyl;
and tautomers thereof if tautomerisable groups are present.

8. A compound of formula I according to claim 1 having the formula IB

(IB) wherein A1 and A2 are each, independently of the other, hydrogen or lower alkyl, or A1 and A2 together are lower alkylene;
Ar1 and Ar2 are each, independently of the other, unsubstituted phenyl; phenyl substituted in the o-, m- or p-position by halogen or by lower alkyl; or cyclohexyl which is unsubsti-tuted or substituted by lower alkyl, hydroxy or by halogen;
X is oxygen or sulfur; and RA is hydrogen, lower alkyl, hydroxy-lower alkyl, such as 2-hydroxyethyl, carbamoyl or thiocarbamoyl;
and tautomers thereof if tautomerisable groups are present.

9. A compound of formula IA according to claim 7, wherein A1 and A2 are hydrogen, Ar1 and Ar2 are each, independently of the other, a radical selected from phenyl, 4-fluoro-phenyl and 4-methylphenyl, X and Y are each, independently of the other, oxygen or sulfur, and RA and RB are each, independently of the other, hydrogen, methyl, 2-hydroxyethyl or carbamoyl;
and tautomers thereof if tautomerisable groups are present.

10. A compound of formula IB according to claim 8 wherein A1 and A2 are hydrogen, Ar1 and Ar2 are each, independently of the other, a radical selected from phenyl and cyclo-hexyl, X is oxygen or sulfur, and RA is hydrogen.

11. A compound according to claim 1, wherein A1 and A2 are hydrogen; or one of the two radicals A1 and A2 is hydrogen and the other falls under the definition of unsubstituted lower alkyl or lower alkyl substituted by one of the mentioned substituents;
or A1 and A2 together are a radical which falls under the definitions of unsubstituted lower alkylene and lower alkylene substituted by one of the mentioned substituents, whilst the remaining radicals have the meanings given, a pharmaceutically acceptable salt thereof if salt-forming groups are present, and tautomers thereof if tautomerisable groups are present.

12. A compound of formula I according to claim 1 named 6,7-dianilino-2H,3H-phthalazine-1,4-dione.

13. A compound of formula I according to claim 1 named 6,7-bis(4-fluoroanilino)-2H,3H-phthalazine-1,4-dione.

14. A compound of formula I according to claim 1 named 6,7-bis(4-methylanilino)-2H,3H-phthalazine-1,4-dione.

15. A compound of formula I according to claim 1 named 6,7-dianilino-2,3-dimethyl-2H,3H-phthalazine-1,4-dione.

16. A compound of formula I according to claim 1 named 6,7-dianilino-4-hydroxy-2-methyl-2H-phthalazin-1-one.

17. A compound of formula I according to claim 1 named 2-aminothiocarbonyl-6,7-dianilino-4-hydroxy-2H-phthalazin-1-one.

18. A compound of formula I according to claim 1 named 6,7-dianilino-4-hydroxy-2-(2-hydroxyethyl)-2H-phthalazin-1-one.

19. A compound of formula I according to claim 1 named 6,7-dianilino-2H-phthalazin-1-one.

20. A compound of formula I according to claim 1 named 6-anilino-7-cyclohexylamino-2H-phthalazin-1-one.

21. A compound of formula I according to claim 1 named 6,7-dicyclohexylamino-2H-phthalazin-1-one.

22. A pharmaceutical composition comprising a compound of formula I or a pharma-ceutically acceptable salt of such a compound having at least one salt-forming groups according to any one of claims 1 to 3, together with a pharmaceutically acceptable carrier.

23. A pharmaceutical composition according to claim 22 which is suitable for administration to a warm-blooded animal suffering from a disease responsive to inhibition of a protein kinase, comprising a compound of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group according to any one of claims 1 to 3, in an amount that is effective in the inhibition of the protein kinase, together with at least one pharmaceutically acceptable carrier.

24. The use of a compound of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group according to any one of claims 1 to 21 for the preparation of a pharmaceutical composition.

25. The use according to claim 24 of a compound of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group according to any one of claims 1 to 21 for the preparation of a pharmaceutical composition for use against diseases responsive to inhibition of tyrosine protein kinases.

26. The use according to claim 24 of a compound of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group according to any one of claims 1 to 27 for the preparation of a pharmaceutical composition for use against diseases responsive to inhibition of the action of EGF-receptor kinase.

27. The use according to claim 24 of a compound of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group according to any one of claims 1 to 21 for the preparation of a pharmaceutical composition for the treatment of diseases responsive to inhibition of tyrosine protein kinases or serine/threonine kinases.

28. The use of a compound of formula I or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group according to any one of claims 1 to 21 for inhibition of EGF-receptor-associated tyrosine protein kinase.

29. The use of a compound of formula I of a pharmaceutically acceptable salt of such a compound having at least one salt forming group according to any one of claims 1 to 3 for the treatment of diseases that are responsive to inhibition of protein kinase.

30. A method of treating warm-blooded animals suffering from diseases responsive to inhibition of protein kinase, comprising the administration to a warm-blooded animal requiring such treatment of a compound of formula I or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, according to claim 1, in a dose that is effective in the treatment of such diseases.

31. A process for the preparation of a compound of formula I according to claim 1 wherein a) for the preparation of a compound of formula I wherein Q is a divalent radical of the formula , which is bonded by its Y-carrying carbon atom to the Q-binding carbon atom of the benzene ring and by its RB-carrying nitrogen atom to the RA-carrying nitrogen atom in formula I, wherein Y, independently of X, is oxygen or sulfur, and RA and RB are each, independently of the other, hydrogen, unsubstituted or substituted lower alkyl or acyl and the remaining radicals have the meanings given, a dicarboxylic acid of formula II

(II) wherein A1, A2, Ar1 and Ar2 have the meanings given, or a reactive derivative thereof wherein the radicals are as defined for compounds of formula I, is reacted with a hydrazine compound of formula III
RA-NH-NH-RB (III) wherein RA and RB are as defined for compounds of formula I, it being possible for the compounds of formulae II and/or III also to be used in the form of salts if salt-forming groups are present, and functional groups in compounds of formulae II and/or III that are not to take part in the reaction if necessary being in protected form, and any protecting groups present are removed, or b) for the preparation of a compound of formula I wherein Q is a divalent radical of formula , which is bonded by its carbon atom to the Q-binding carbon atom of the benzene ring and by its nitrogen atom to the RA-carrying nitrogen atom in formula I

wherein RA is unsubstituted or substituted lower alkyl, a formylbenzoic acid derivative of formula XIII

(XIII) wherein the radicals are as last defined, or a reactive derivative thereof, is reacted with a compound of formula XIV

RA-NH-NH2 (XIV) wherein RA is as last defined, any functional groups that are not to take part in the reaction if necessary being protected, and any protecting groups present are removed, and, if desired, as additional process steps, an obtainable compound of formula I is converted into a different compound of formula I, and/or an obtainable salt is converted into the free compound or into a different salt, and/or an obtainable free compound of formula I is converted into a salt and/or an obtainable mixture of isomers of compounds of formula I is separated into its isomers.