Patent ID: 6136984
Filing Date: 2000-10-24
Classification: B01J,C07D

Abstract:
A method for preparing a compound of formula I ##STR25## wherein A is a hydrogen atom or a group of formula ##STR26## wherein R.sup.5 is alkylene optionally substituted with hydrogen, alkyl, aryl, heteroaryl, alkoxy, aryloxy, cyano, hydroxy, dialkylamino, arylalkylamino, diarylamino or halogen;R.sup.6 is hydrogen, alkyl optionally substituted with hydroxy, halogen, cyano, alkoxy, aryloxy, dialkylamino, arylalkylamino or diarylamino; or aralkyl;R.sup.5 and R.sup.6 may be covalently linked to each other by a covalent bond or an additional alkylene group R.sup.5, thereby giving rise to a fragment of the type shown below ##STR27## wherein n and m are integers between 0 and 15; R.sup.7 is hydrogen, alkyl, alkyl substituted with hydroxy, alkoxy, aryloxy, alkylthio, arylthio, dialkylamino, arylalkylamino or diarylamino; aralkyl, aryl, aryl substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl;R.sup.1 is hydrogen, alkyl optionally substituted with hydroxy, halogen, cyano, alkoxy, aryloxy, dialkylamino, arylalkylamino or diarylamino; or aralkyl;R.sup.1 may be covalently linked to A, R.sup.5, R.sup.6 and/or R.sup.7, in which case --R.sup.1 --A-- or --R.sup.1 --R.sup.5 -- represents low alkylene, unsubstituted or substituted with alkyl, hydroxy, alkoxycarbonyl, alkoxy or dialkylamino, --R.sup.1 --R.sup.6 -- represents ethylene or propylene, unsubstituted or substituted with alkyl, hydroxy, alkoxy or dialkylamino, and/or --R.sup.1 --R.sup.7 -- represents methylene, propylene or butylene unsubstituted or substituted with alkyl, hydroxy, alkoxycarbonyl, alkoxy or dialkylamino;R.sup.2 is alkyl optionally substituted with aryl, heteroaryl, alkoxy, aryloxy, cyano, dialkylamino, arylalkylamino, diarylamino or halogen;aryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl;heteroaryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; andR.sup.3 is cyano, nitro, --CO--R' or --C(OH)--R', R' being alkyl, alkyl substituted with halogen, aryl, aryl substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl or heteroaryl; or --SO.sub.2 R"", R"" being alkyl or substituted or unsubstituted aryl,R.sup.4 is hydrogen or COZ, Z being substituted or unsubstituted alkyl, aryl, arylamino or alkylamino; and pharmaceutically acceptable salts thereof;the method comprising the steps of:(a) attachment of a compound having a free or protected primary or secondary amino group of the formula A--NH--R.sup.1 to a substrate (S) via a chemical bond or linker (L), optionally followed by a deprotection step, for generating a substrate-bound free primary or secondary amine of the formula S--L--A'--N(R.sup.1)H,wherein R.sup.1 is as defined above,A' is a chemical bond or a group of formula ##STR28## wherein R.sup.5, R.sup.6 and R.sup.7 are as defined above;R.sup.5 and R.sup.6 may be covalently linked to each other by a covalent bond or an additional alkylene group R.sup.5, thereby giving rise to a fragment of the type shown below ##STR29## wherein n and m are as defined above; (b) acylation of the substrate-bound free primary or secondary amine of the formula S--L--A'--N(R.sup.1)H with a cyanoacetic acid derivative of the structure NC--CH.sub.2 --COX, wherein X is a hydroxy group or a leaving group;(c) reaction of the resulting substrate-bound amide of the formula S--L--A'--N(R.sup.1)--CO--CH.sub.2 --CN wherein R.sup.1 is as defined above, with an aliphatic or aromatic isothiocyanate of the structure R.sup.2 --NCS wherein R.sup.2 is as defined above, in the presence of a base;(d) alkylation of the resulting substrate-bound intermediate of the formula S--L--A'--N(R.sup.1)--CO--C(CN).dbd.C(NHR.sup.2)--SH with an alkylating agent of the structure R.sup.3 --CH.sub.2 --X, wherein R.sup.3 is as defined above and X is a leaving group for nucleophilic displacement, under neutral or acidic conditions, followed by treatment with a base, in order to prepare a compound of formula II ##STR30## wherein S, L, A', R.sup.1, R.sup.3 and R.sup.4 are as defined above; and R.sup.2 is alkyl optionally substituted with aryl, heteroaryl, alkoxy, aryloxy, cyano, hydroxy, dialkylamino, arylalkylamino, diarylamino or halogen;aryl optionally substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; heteroaryl optionally Substituted with alkyl, aryl, heteroaryl, halogen, alkoxy, aryloxy, dialkylamino, alkylarylamino, diarylamino, halogen, cyano, alkoxycarbonyl or aminocarbonyl; and pharmaceutically acceptable salts thereof; and(e) subjection of the resulting substrate-bound compound of formula II to cleavage conditions in order to prepare the compound of formula I.