CA2129179A1 - Trisubstituted pyrimido[5,4-d]pyrimidines for modulating multi-drug resistance, pharmaceutical compositions containing these compounds and processes for their preparation - Google Patents

Trisubstituted pyrimido[5,4-d]pyrimidines for modulating multi-drug resistance, pharmaceutical compositions containing these compounds and processes for their preparation

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Publication number
CA2129179A1
CA2129179A1 CA002129179A CA2129179A CA2129179A1 CA 2129179 A1 CA2129179 A1 CA 2129179A1 CA 002129179 A CA002129179 A CA 002129179A CA 2129179 A CA2129179 A CA 2129179A CA 2129179 A1 CA2129179 A1 CA 2129179A1
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Canada
Prior art keywords
group
piperidino
denotes
methyl
morpholino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002129179A
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French (fr)
Inventor
Armin Heckel
Uwe Bamberger
Annerose Mauz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
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Dr Karl Thomae GmbH
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Publication of CA2129179A1 publication Critical patent/CA2129179A1/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Abstract Pyrimido Pyrimidine Compounds The invention relates to compounds of formula I

Description

~` 2~29i79 ~; .;

61490.578 Pyrimido Pyrimidine ~ompounds This invention relates to novel trisubstituted pyrimido-[5,4 d]pyrimidines, processes for their preparation, pharmaceutical compositions containing them and their use in modulating multi-drug resistance.

Chemotherapy for malignant diseases has proved to be a successful cure only in a few cases. Any resistance present at the start of the treatment or occurring during therapy obstructs therapeutic success. The cause and manifestation of such resistance takes many forms.
However a pleiotropic resistance is frequently observed which is not restricted to specific chemical or pharmacological groups of active substances and which is usually based on the transportation of active substances out of tumour cells, leading to a reduced i~ntracellular accumulation of the active substance.

A clinically significant mechanism of pleiotropic resistance, which to date has been investigated most thoroughly, is based on the expression of the transport protein gpl70 (P-glycoprotein) in the membrane of tumour cells (see Ferguson and Cheng, Critical Issues Relating to Clinical Drug Resistance, Cancer Bulletin 41: 7-13 (1989)). This transport protein has a specificity for lipophilic substances and thus influences the intracellular concentration of cytostatics (which are currently of clinical importance) of the vinca-alkaloid category, of anthracyclin antibiotics, of epipodophylotoxins and of other natural substances (see van der Bliek and Borst, Multidrug Resistance, Advances in Cancer Research 52: 165-203 (1989)).

It has now been found that certain novel trisubstituted j 2~29~79 , .

pyrimido[5,4-d]pyrimidines have valuable properties particularly a sensitising e~fect on resistant tumours in chemotherapy.

Thus viewed from one aspect the present invention provides compounds of formula I

Rc ~ N R
N ~ ~ a N ~N

b (wherein Ra denotes a pyrrolidino, piperidino or hexamethyleneimino group in which a methylene group in the 3-position of a pyrrolidino group or in the 3- or 4-position of a piperidino or hexamethyleneimino group is replaced by a ~CR1-A-(R2NR3)-, >CO- or >(R40-C-OR5)- group or by a group of formula . .

~--R6 ~ I
R

(wherein A denotes a carbon-nitrogen bond or a C13-alkylene .
group;

R1 denotes a hydrogen atom or a Cl3-alkyl group;

R2 denotes a hydrogen atom or a C13-alkyl group optionally substituted by a phenyl group;

R3 denotes a hydrogen atom or an optionally phenyl-substituted C14-alkyl group wherei-n the phenyl group is ~ 212~79 .~

optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by Cl3-alkyl or Cl3-alkoxy groups, wherein the substituents may be identical or different, or R3 denotes a Cl4-alkyl group substituted by a carboxy, alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or by two phenyl groups, whilst the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms, or R3 denotes a C24-alkyl group optionally substituted in the 2-, 3- or 4-position by a hydroxy, amino, alkylamino or dialkylamino group, whilst the above-mentioned alkyl moieties may each contain 1 to 3 carbon atoms, /
or R3 denotes a Cl3-alkoxycarbonyl group, or R2 and R3 together with the nitrogen atom between them denote a cycloalkyleneimino group having 3 to 7 ring members, or a morpholino, thiomorpholino, l-oxido-thiomorpholino or l,l-dioxido-thiomorpholino group;
R4 and R5 independently represent Cl3-alkyl groups, or R4 and R5 together denote a C23-n-alkylene group;
R6 denotes a hydrogen atom or a Cl3-alkyl group; and R7 denotes a hydrogen atom, or a Cl3-alkyl or phenyl group); and Rb and Rc independently denote a cyclic alkyleneimino or alkenyleneimino group having 5 to 7 ring members to which a l,4-butadienyl bridge is optionally attached via the 2-, 3- or 3-, 4-positions, and which is optionally monosubstituted by a methylenedioxy group or mono-, di-2~179 or trisubstituted by fluorine, chlorine or bromine atomsor by alkyl, alkoxy, amino, alkylamino, dialkylamino or alkanoylamino groups, wherein the alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms and the alkanoyl moiety may contain 2 or 3 carbon atoms and the substituents may be identical or different, or R~ and Rc may each denote a morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino or (RBNRg)- group, or Rc may also represent an optionally phenyl-substituted C13-alkoxy or C13-alkylthio group;

R8 denotes a hydro~en atom or a C14-alkyl group optionally substituted by a phenyl, cyano, carboxy or alkoxycarbonyl group or in the 2-, 3- or 4-position by an amino, alkylamino, dialkylamino, alkanoylamino, benzoylamino or phenylsulphonylamino group, wherein the above-mentioned alkyl, alkoxy and alkanoyl moieties may each contain 1 to 3 carbon atoms and the phenyl nucleus in each case is optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by C13-alkyl or C13-alkoxy groups and the substituents may be identical or different; and Rg denotes a hydrogen atom, or a C14-alkyl group optionally substituted by a phenyl or naphthyl group, wherein the phenyl and naphthyl group may each be mono or disubstituted by fluorine, chlorine or bromine atoms or by alkyl, alkoxy, amino, alkylamino or dialkylamino groups, (wherein the substituents may be identical or different and each alkyl and alkoxy moiety may contain 1 to 3 carbon atoms), or Rg denotes a C15-alkanoylamino or anthracenyl group);

` ~` 2~2~179 and the iso~ers, isomer mixtures and salts thereof.

In particular, compounds of ~ormula I where Ra represents a ~CO- or ~(R90-C-OR5)- group are valuable intermediate products for the preparation of the other compounds of ~ormula I which have valuable pharmacological properties.

Examples of the definitions of the groups given hereinbefore include:

for Ra: 3-amino-piperidino, 4-methylamino-piperidino, 4-dimethylamino-piperidino, 4-ethylamino-piperidino, 4-diethylamino-piperidino, 4-(N-methyl-ethylamino)-piperidino, 4-n-dipropylamino-piperidino, 4-benzylamino-piperidino, 4-(N-methyl-benzylamino)-piperidino, 4-(N-ethyl-benzylamino)-piperidino, 4-(N-isopropyl-benzylamino)-piperidino, 4-pyrrolidino-piperidlno, 4-piperidino-piperidino, 4-(2,2-di-phenyl-ethyl)-piperidino, 4-(3,3-diphenyl-propyl)-piperidino, 4-carboxymethylamino-piperidino, 4-methoxycarbonylamino-piperidino, 4-ethoxycarbonylamino-piperidino, 4-n-propoxycarbonylamino-piperidino, 4-dimethylaminocarbonylmethylamino-piperidino, 4-(2-dimethylaminocarbonylethyl-amino)-piperidino, 4-(3-dimethylaminocarbonylpropyl-amino)-piperidino, 4-diethylaminocarbonylmethylamino-piperidino, 4-(2-diethylaminocarbonylethyl-amino)-piperidino, 4-(3-diethylaminocarbonylpropyl-amino)-piperidino, 4-di-n-propylaminocarbonylmethylamino-piperidino, 4-(2-di-n-propylaminocarbonylethyl-amino)-piperidino, 4-(3-di-n-propylaminocarbonylpropyl-amino)-piperidino-, 4-(N-carboxymethyl-methylamino)-piperidino-, 4-(N-methoxycarbonyl-methylamino)-piperidino, 4-(N-ethoxycarbonyl-methylamino)-piperidino, 4-(N-n-propoxy-carbonyl-methylamino)-piperidino, 4-(N-dimethylaminocarbonylmethyl-methylamino)-piperidino, 4-2~29~79 [N-(2-dimethylaminocarbonylethyl)-methylamino]-piperidino, 4-[N-(3-dimethylaminocarbonylpropyl)-methylamino]-piperidino, 4-(N-diethylaminocarbonylmethyl-methylamino)-piperidino, 4-[N-(2-diethylaminocarbonylethyl)-methylamino]-piperidino, 4-[N-(3-diethylaminocarbonylpropyl)-methylamino]-piperidino, 4-(N-di-n-propylaminocarbonyl-methyl-methylamino)-piperidino, 4-[N-(2-di-n-propylaminocarbonylethyl)-methylamino]-piperidino, 4-[N-(3-di-n-propylaminocarbonylpropyl)-methylamino]-piperidino, 4-(N-carboxymethyl-ethylamino)-piperidino, 4-(N-methoxycarbonyl-ethylamino)-piperidino, 4-(N-ethoxycarbonyl-ethylamino)-piperidino, 4-(N-n-propoxycarbonyl-ethylamino)-piperidino, 4-(N-dimethyl-aminocarbonylmethyl-ethylamino)-piperidino, 4-[N-(2-dimethylaminocarbonylethyl)-ethylamino]-piperidino, 4-[N-(3-dimethylaminocarbonylpropyl)-ethylamino]- ..
piperidino, 4-(N-diethylaminocarbonylmethyl-ethylamino)-piperidino, 4-[N-(2-diethylaminocarbonylethyl)-ethylamino]-piperidino, 4-[N-(3-diethyl-aminocarbonylpropyl)-ethylamino]-piperidino, 4-(N-di-n-propylaminocarbonylmethyl-ethylamino)-piperidino, 4-[N-(2-di-n-propylaminocarbonylethyl)-ethylamino]-piperidino, 4-[N-(3-di-n-propylaminocarbonylpropyl)-ethylamino]-piperidino, 4-(N-carboxymethyl-isopropylamino)-piperidino, (4-(N-methoxycarbonyl- ~:
n-propylmethylamino)-piperidino, 4-(N-ethoxycarbonyl-n- : :
propylamino)-piperidino, 4-(N-n-propoxycarbonyl-isopropylamino)-piperidino, 4-(N-dimethylaminocarbonylmethyl-n-propylamino)-piperidino, 4-[N-(2-dimethylaminocarbonylethyl)-n-propylamino]-piperidino, 4-[N-(3-dimethylaminocarbonylpropyl)-n-propylamino]-piperidino, 4-(N-diethylaminocarbonylmethyl-n-propylamino)-piperidino, 4-[N-(2-diethylaminocarbonylethyl)-n-propylamino]-piperidino, 4-[N-(3-diethylaminocarbonylpropyl)-isopropylamino]-piperidino, 4-(N-di-n-propylaminocarbonylmethyl-isopropylamino)-piperidino, 4-[N-(2-di-n-propylaminocarbonylethyl)-n-propylamino]-piperidino, 4-[N-(3-di-n-propyl-aminocarbonylpropyl)-n-propylamino]-piperidino, 4-[N-(2-aminoethyl)-amino]-piperidino, 4-[N-(2-methyl.amino-ethyl)-amino]-piperidino, 4-[N-(2-ethylaminoethyl)-amino]-piperidino, 4-[N-(2-isopropylamino-ethyl)-amino]-piperidino, 4-[N-(2-dimethylamino-ethyl)-amino]-piperidino, 4-[N-(2-diethylamino-ethyl)-amino]-piperidino, 4-[N-(2-di-n-propylamino-ethyl)-amino]-piperidino, 4-[N-(3-amino-propyl)-amino]-piperidino, 4-[N-(3-methylamino-propyl)-amino]-piperidino, 4-[N-(3-ethylamino-propyl)-amino]-piperidino, 4-[N-(3-isopropylamino-propyl)-amino]-piperidino, 4-[N-(3-dimethylamino-propyl)-amino]-piperidino, 4-[N-(3-diethylamino-propyl)-amino]-piperidino, 4-[N-(3-di-n-propylamino-propyl)-amino~-piperidino, 4-[N-(2-aminoethyl)-methylamino]-piperidino, 4-[N-(2-methylamino-ethyl)-methylamino]-piperidino, 4-[N-(2-ethylamino-ethyl)-methylamino~-piperidino, 4-[N-(2-isopropylamino-ethyl)-methylamino]-piperidino, 4-[N-(2-dimethylamino-ethyl)-methylamino]-piperidino, 4-[N-(2-diethylamino-ethyl)-methylamino]-piperidino, 4-[N-(2-di-n-propylamino-ethyl)-methylamino]-piperidino, 4-[N-(3-amino-propyl)-methylamino]-piperidino, 4-[N-(3-methylamino-propyl)-methylamino]-piperidino, 4-[N-(3-ethylamino-propyl)-methylamino]-piperidino, 4-[N-(3-isopropylamino-propyl)-methylamino]-piperidino, 4-[N-(3-dimethylamino-propyl)-methylamino]-piperidino, 4-[N-(3-diethylaminopropyl)-methylamino]-piperidino, 4-[N-(3-di-n-propylaminopropyl)-methylamino]-piperidino, 4-[N-(2-amino-ethyl)-ethylamino]-piperidino, 4-[N-(2-methylamino-ethyl)-ethylamino]-piperidino, 4-[N-(2-ethylamino-ethyl)-ethylamino]-piperidino, 4-[N-(2-isopropylamino-ethyl)-ethylamino]-piperidino, 4-[N-(2-dimethylamino-ethyl)-ethylamino]-piperidino, 4-[N-(2-diethylamino-ethyl)-ethylamino]-piperidino, 4-[N-(2-di-n-propylamino-ethyl)-ethylamino]-piperidino, 4- [N- (3-aminopropyl)-ethylamino]-piperidino, 4- [N- (3-methylamino-propyl)-ethylamino]-piperidino, 4-[N-(3-ethylamino-propyl)-ethylamino]-piperidino, 4-[N-(3-isopropylamino-propyl)-ethylamino]-piperidino, 4-[N-(3-dimethylamino-propyl)-ethylamino]-piperidino, 4-[N-(3-diethylamino-propyl)-ethylamino~-piperidino, 4-[N-(3-di-n-propylamino-propyl)-ethylamino]-piperidino, 4-[N-(2-amino-ethyl)-n-propylamino]-piperidino, 4-[N-(2-methylamino-ethyl)-isopropylamino]-piperidino, 4-[N-(2-ethylamino-ethyl)-isopropylamino]-piperidino, 4-[N-(2- -isopropylamino-ethyl)-n-propylamino]-piperidino, 4-[N-(2-dimethylamino-ethyl)-n-propylamino]-piperidino, 4-[N-(2-diethylamino-ethyl)-n-propylamino]-piperidino, 4-[N-(2-di-n-propylamino-ethyl)-n-propylamino]-piperidino, 4-[N-(3-amino-propyl)-n-propylamino]-piperidino, 4-[N-(3-methylamino-propyl)-n-propylamino]-piperidino, 4-[N-(3-ethylamino-propyl)-n-propylamino]-piperidino, 4-[N-(3-isopropylamino-propyl)-n-propylamino]-piperidino, 4-[N-(3-dimethylamino-propyl)-n-propylamino]-piperidino, 4- ~:
[N-(3-diethylamino-propyl)-n-propylamino]-piperidino, 4-[N-(3-di-n-propylamino-propyl)-n-propylamino]-piperidino, 3-amino-pyrrolidino, 3-methylamino-pyrrolidino, 3-dimethylamino-pyrrolidino, 3-diethylamino-pyrrolidino, 3-amino-hexamethyleneimino, 4-amino-hexamethyleneimino, 3-methylamino-hexamethyleneimino, 4-methylamino-hexamethyleneimino, 3-dimethylamino-hexamethyleneimino, 4-dimethylamino-hexamethyleneimino, 3-diethylamino-hexamethyleneimino and 4-diethylamino-hexamethyleneimino group, for Rb and Rc: pyrrolidino, piperidino, hexa-methyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino, ~,1-dioxido-thiomorpholino, 1,2,3,4-tetrahydro-isoquinolino, 1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolino, methylamino, ethylamino, n-` `~`` 2~2917~

propylamino, isopropylamino, dimethylamino,diethylamino, di-n-propylamino, di-isopropylamino, benzylamino, 4-fluoro-benzylamino, 4-chloro-benzylamino, 4-bromo-benzylamino, 4-methyl-benzylamino, 4-methoxy-benzylamino, naphth-1-yl-methylamino, naphth-2-yl-methylamino, 4-fluoro-naphth-1-yl-methylamino, 4-chloro-naphth-1-yl-methylamino, 4-bromo-naphth-2-yl-methylamino, 4-methyl-naphth-2-yl-methylamino, 4-methoxy-naphth-1-yl-methylamino, 4-dimethylamino-naphth-2-yl-methylamino, N-benzyl-methylamino, N-(4-fluoro-benzyl)-methylamino, N-(4-chloro-benzyl)-methyl-amino, N-(4-bromo-benzyl)-methylamino, N-(4-methyl-benzyl)-methylamino, N-(4-methoxy-benzyl)-methylamino, N-(naphth-1-yl-methyl)-methylamino, N-(naphth-2-yl-methyl)-methylamino, N-(4-fluoro-naphth-1-yl-methyl)-methylamino, N-(4-chloro-naphth-1-yl-methyl)-methylamino, N-(4-bromo-naphth-2-yl-methyl)-methylamino, N-(4-methyl-naphth-2-yl-methyl)-methylamino, N-(4-methoxy-naphth-1-yl-methyl)-methylamino, N-(4-dimethyl-amino-naphth-2-yl-methyl)-methylamino, N-benzyl-ethylamino, N-(4-fluoro-benzyl)-ethylamino, N-(4-chloro-benzyl)-ethylamino, N-(4-bromo-benzyl)-ethylamino, N-(4-methyl-benzyl)-ethylamino, N-(4-metho~y-benzyl)-ethylamino, N-(naphth-1-yl-methyl)-ethylamino, N-(naphth-2-yl-methyl)-ethylamino, N-(4-fluoro-naphth-1-yl-methyl)-ethylamino, N-(4-chloro-naphth-1-yl-methyl)-ethylamino, N-(4-bromo-naphth-2-yl-methyl)-ethylamino, N-(4-methyl-naphth-2-yl-methyl)-ethylamino, N-(4-methoxy-naphth-1-yl-methyl)-ethylamino, N-(4-dimethylamino-naphth-2-yl-ethyl)-methylamino, N-benzyl-n-propylamino, N-(4-fluoro-benzyl)-n-propylamino, N-(4-chloro-benzyl)-n-propylamino, N-(4-bromo-benzyl)-n-propylamino, N-(4-methyl-benzyl)-n-propylamino, N-(4-methoxy-benzyl)-n-propylamino, N-(naphth-1-yl-methyl)-n-propylamino, N-(naphth-2-yl-methyl~-n-propylamino, N-(4-fluoro-naphth-1-yl-methyl)-n-propylamino, N-(4-chloro-naphth-1-yl-methyl)-n-propylamino, N-(4-bromo-.... . , ... . ... . ~. . . - --``` 2129179 naphth-2-yl-methyl)-n-propylamino, N-(4-methyl-naphth-2-yl-methyl)-n-propylamino, N-(4-methoxy-naphth-1-yl-methyl)-n-propylamino, N-(4-dimethylamino-naphth-2-yl-ethyl)-n-propylamino, N-benzyl-isopropylamino, N-(4-~luoro-benzyl)-isopropylamino, N-(4-chloro-benzyl)-isopropylamino, N-(4-bromo-benzyl)-isopropylamino, N-(4-methyl-benzyl)-isopropylamino, N-(4-methoxy-benzyl)-isopropylamino, N-(naphth-1-yl-methyl)-isopropylamino, N-(naphth-2-yl-methyl)-isopropylamino, N-(4-fluoro-naphth-1-yl-methyl)-isopropylamino, N-(4-chloro-naphth-l-yl-methyl)-isopropylamino, N-(4-bromo-naphth-2-yl-methyl)-isopropylamino, N-(4-methyl-naphth-2-yl-methyl)-isopropylamino, N-(4-methoxy-naphth-1-yl-methyl)-isopropylamino, N- (4-dimethylamino-naphth-2-yl-ethyl)-isopropylamino, N-(2-phenyl-ethyl)-amino, N-(3-phenyl- :~
propyl)-amino, N- (2-phenyl-ethyl)-methylamino, N- (3-phenyl-propyl)-methylamino, N-(2-phenyl-ethyl)-ethylamino, N- (3-phenyl-propyl)-ethylamino, N- (2-phenyl-ethyl)-n-propylamino, N-( 3-phenyl-propyl)-n-propylamino, N-(2-phenyl-ethyl)-isopropylamino, N-(3-phenyl-propyl)-isopropylamino, N- (2-cyano-ethyl)-amino, N- (3-cyano-propyl)-amino, N-(2-amino-ethyl)-amino, N-(2-methylamino-ethyl)-amino, N-(2-dimethylamino-ethyl)-amino, N-(2-diethylamino-ethyl)-amino, N-(2-di-n-propylamino-ethyl)-amino, N-(2-diisopropylamino-ethyl)-amino, N- (2-acetylamino-ethyl)-amino, N- (2-propionylamino-ethyl)-amino, N-(2-benzoylamino-ethyl)-amino, N-(2-benzenesulphonylamino-ethyl)-amino, N-( 2-toluenesulphonylamino-ethyl)-amino, N-( 2-cyano-ethyl)-methylamino, N-(3-cyano-propyl)-methylamino, N-(2-amino-ethyl)-methylamino, N-(2-methylamino-ethyl)-methylamino, N-(2-dimethylamino-ethyl)-methylamino, N-(2-diethylamino-ethyl)-methylamino, N-( 2-di-n-propylamino-ethyl)-methylamino, N-(2-diisopropylamino-ethyl)-methylamino, N-(2-acetylamino-ethyl)-methylamino, N-(2-propionylamino-ethyl)-methylamino, N-( 2-ben20ylamino-ethyl)-methylamino, N-(2-benzenesulphonylamino-ethyl)-`~ 2t2~17~

methylamino, N-(2-toluenesulphonylamino-ethyl)-methylamino, N-(2-cyano-ethyl)-ethylamino, N-(3-cyano-propyl)-ethylamino, N-(2-amino-ethyl)-ethylamino, N-(2-methylamino-ethyl)-ethylamino, N-(2-dimethylamino-ethyl)-ethylamino, N-(2-diethylamino-ethyl)-ethylamino, N-(2-di-n-propylamino-ethyl)-ethylamino, N-(2-diisopropylamino-ethyl)-ethylamino, N-(2-acetylamino-ethyl)-ethylamino, N-(2-propionylamino-ethyl)-ethylamino, N-(2-benzoylamino-ethyl)-ethylamino, N-(2-benzenesulphonylamino-ethyl)-ethylamino, N-(2-toluenesulphonylamino-ethyl)-ethylamino, N-(2-cyano-ethyl)-n-propylamino, N-(3-cyano-propyl)-isopropylamino, N-(2-amino-ethyl)-n-propylamino, N-(2-methylamino-ethyl)-n-propylamino, N-(2-dimethylamino-ethyl)-isopropylamino, N-(2-diethylamino-ethyl)-n-propylamino, N-(2-di-n-propylamino-ethyl)-n-propylamino, N-(2-diisopropylamino-ethyl)-n-propylamino, N-(2-acetylamino-ethyl)-n-propylamino, N-(2-propionylamino-ethyl)-n-propylamino, N-(2-benzoylamino-ethyl)-n-propylamino, N-(2-benzenesulphonylamino-ethyl)-n-propylamino, N-(2-toluenesulphonylamino-ethyi)-isopropylamino, N-(2-cyano-ethyl)-benzylamino, N-(3-cyano-propyl)-benzylamino, N-(2-amino-ethyl)-benzylamino, N-(2-methylamino-ethyl)-benzylamino, N-(2-dimethylamino-ethyl)-benzylamino, N-(2-diethylamino-ethyl)-benzylamino, N-(2-di-n-propylamino-ethyl)-benzylamino, N-(2-diisopropylamino-ethyl)-benzylamino, N-(2-acetylamino-ethyl)-benzylamino, N-(2-propionylamino-ethyl)-benzylamino, N-(2-benzoylamino-ethyl)-benzylamino, N-(2-benzenesulphonyl-amino-ethyl)-benzylamino, N-(2-toluenesulphonylamino-ethyl)-benzylamino, N-carboxymethyl-amino, N-methoxycarbonylmethyl-amino, N-ethoxycarbonylmethylamino, N-isopropoxycarbonylmethyl-amino, N-(2-carboxy-ethyl)-amino, N-(2-methoxycarbonyl-ethyl)-amino, N-(2-ethoxycarbonyl-ethyl)-amino, N-(2-n-propoxycarbonyl-ethyl)-amino, N-(3-carboxy-propyl)-amino, N-(3-methoxycarbonyl-propyl)-amino, N-(3-:` ::

`` 2~29179 ethoxycarbonyl-propyl)-amino, N-(3-isopropoxycarbonyl-propyl)-amino, N-carboxymethyl-methylamino, N-(methoxycarbonyl-methyl)-methylamino, N-(ethoxycarbonyl-ethyl)-methylamino, N-(isopropoxycarbonylmethyl)-methylamino, N-(2-carboxy-ethyl)-methylamino, N-(2-methoxycarbonyl-ethyl)-methylamino, N-(2-ethoxycarbonyl-ethyl)-methylamino, N-(2-n-propoxycarbonyl-ethyl)-methylamino, N-(3-carboxy-propyl)-methylamino, N-(3-methoxycarbonyl-propyl)-methylamino, N-(3-ethoxycarbonyl-propyl)-methylamino, N-(3-isopropoxycarbonyl-propyl)-methylamino, N-(carboxymethyl)-ethylamino, N-(methoxycarbonylmethyl)-ethylamino, N-(ethoxycarbonylmethyl)-ethylamino, N-(isopropoxycarbonylmethyl)-ethylamino, N-(2-carboxy-ethyl)-ethylamino, N-(2-methoxycarbonyl-ethyl)-ethylamino, N-(2-ethoxycarbonyl-ethyl)-ethylamino, N-(2-n-propoxycarhonyl-ethyl)-ethylamino, N-(3-carboxy-propyl)-ethylamino, N-(3-methoxycarbonyl-propyl)-ethylamino, N-(3-ethoxycarbonyl-propyl)-ethylamino, N-(3-isopropoxycarbonyl-propyl)-ethylamino, N-(carboxymethyl)-n-propylamino, N-(methoxycarbonylmethyl)-n-propylamino, N-(ethoxycarbonylmethyl)-n-propylamino, N-(isopropoxycarbonylmethyl)-isopropylamino, N-(2-carboxy-ethyl)-n-propylamino, N-(2-methoxycarbonyl-ethyl)-isopropylamino, N-(2-ethoxycarbonyl-ethyl)-n-propylamino, N-(2-n-propoxycarbonyl-ethyl)-n-propylamino, N-(3-carboxypropyl)-n-propylamino, N-(3-methoxycarbonyl-propyl)-isopropylamino, N-(3-ethoxycarbonyl-propyl)-n-propylamino, N-(3-isopropoxycarbonyl-propyl)-n-propylamino, N-(carboxymethyl)-benzylamino, N-(methoxycarbonylmethyl)-benzylamino, N-(ethoxycarbonylmethyl)-benzylamino, N-(isopropoxycarbonylmethyl)-benzylamino, N-(2-carboxy-ethyl)-benzylamino, N-(2-methoxycarbonyl-ethyl)-benzylamino, N-(2-ethoxycarbonyl-ethyl)-benzylamino, N-(2-n-propoxycarbonyl-ethyl)-benzylamino, N-(3-carboxy-., . . . . ~ . : . ., . :, ~:

2129~79 propyl)-benzylamino, N-(3-methoxycarbonyl-propyl)-benzylamino, N-(3-ethoxycarbonyl-propyl)-benzylamino, N-(3-isopropoxycarbonyl-propyl)-benzylamino, N-anthracen-9-yl-amino, N-(anthracen-9-yl)-methylamino, N-(anthracen-9-yl)-ethylamino, N-(anthracen-9-yl)-n-propylamino, N-(anthracen-9-yl)-isopropylamino, N-(anthracen-9-yl)-benzylamino, 5-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl, 6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl, 7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl, 6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinolin-2-yl, 5-acetamido-1,2,3,4-tetrahydro-isoquinolin-2-yl and 5-propionylamino-1,2,3,4-tetrahydro-isoquinolin-2-yl groups and for Rc: additionally methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 2-phenylethoxy, 3-phenylethoxy, methylthio, ethylthio, n-propylthio, isopropylthio, benzylylthio, 2-phenylethylthio and 3-phenylethylthio group.

Preferred compounds according to the invention include those of formula I wherein:
.

Ra denotes a pyrrolidino or piperidino group wherein a methylene group in the 4-position is replaced by a >CRl-A-(R2NR3~-, >CO- or >(R40-C-ORs)- group or by a group of formula ~ 1 ~7 (wherein A denotes a carbon-nitrogen bond or a methylene group;

2129~ 79 Rl denotes a hydrogen atom;
R2 denotes a hydrogen atom, or a methyl or ethyl group;
R3 denotes a hydrogen atom, or R3 denotes a Cl3-alkyl group optionally substituted by a phenyl, carboxy, methoxycarbonyl, dimethylamino or dimethylaminocarbonyl group or by two phenyl groups, or R3 denotes a C23-alkyl group which is substituted in the 2- or 3-position by a dimethylamino group, or R3 denotes a Cl3-alkoxycarbonyl group, or R2 and R3 together with the nitrogen atom between them denote a pyrrolidino or piperidino group;
R4 and R5 together denote an ethylene group;
R6 denotes a hydrogen atom; and R7 denotes a phenyl group);

Rb denotes a dialkylamino group wherein each alkyl moiety may contain 1 to 3 carbon atoms, or Rb denotes a methylamino group substituted at the nitrogen atom by a benzyl or naphthyl group, or Rb denotes a piperidino, morpholino or 1,2,3,4-tetrahydro-isoquinolyl group; and Rc denotes a benzylamino group (optionally substituted at the nitrogen atom by a Cl3-alkyl group) optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by a methyl or methoxy group -~ 2129179 and may be substituted in the alkyl moiety by a phenyl, carboxy, methoxycarbonyl, ethoxycarbonyl or cyano group, or in the 2- or 3-position by an amino, acetylamino, benzoylamino or p-toluenesulphonylamino group, or Rc may represent a naphthylamino group (optionally methyl-substituted at the nitrogen atom) optionally substituted in the naphthyl nucleus by a methoxy or dimethylamino group, or Rc may represent a 1,2,3,4-tetrahydro-isoquinolyl group optionally substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, methylenedioxy or acetamido group, or Rc may represent a morpholino, N-methyl-cyclohexylmethylamino or benzyloxy group, and the isomers and salts thereof.

Particularly preferred compounds according to the invention are those of formula I wherein:

Ra denotes a piperidino group in which a methylene group in the 4-position is replaced by a >CRl-A-(R2NR3)- group (wherein A denotes a carbon-nitrogen bond or a methylene group;
R1 denotes a hydrogen atom;
R2 denotes a hydrogen atom, or a methyl or ethyl group;
R3 denotes a hydrogen atom, or R3 denotes a C23-alkyl group substituted by two phenyl groups, ` ' 212917~

or R3 denotes a Cl3-alkyl group optionally substituted in the 2- or 3-position by a dimethylamino group, or R3 denotes a methoxycarbonyl group, or R2 and R3 together with the nitrogen atom between them represent a piperidino group);

Rb denotes a dimethylamino group in which a methyl group is substituted by a ben~yl or naphthylmethyl group, or Rb denotes a piperidino or morpholino group; and Rc denotes a dimethylamino group in which a methyl group is substituted by a benzyl group (optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by a methyl or methoxy group) or by a naphthylmethyl group, or Rc denotes a 1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl, 1,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinolinyl, morpholino or N-(3-benzoylamino-propyl)-benzylamino group, wherein the groups Rb and R~ are different, and the salts and isomers thereof.

Viewed from a different aspect the invention provides a process for preparing the compounds of the invention, said process comprising at least one of the following steps:
a) reacting a compound of formula II

` ` 212~

Rc N~

N (II) Rb (wherein Rb and Rc are as hereinbefore defined and Z denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, or a phenoxy or methylsulphonyl group) with a compound of formula III
Ra - H (III) (wherein Ra is as hereinbefore defined);

b) (to prepare compounds of formula I wherein Ra denotes a >CH-(R2NR3)- group) reductively aminating a compound of formula IV
Rc N ~ ~ a ~ ~ N (IV) Rb i (wherein Rb and Rc are as hereinbefore defined and Ral denotes a pyrrolidino, piperidino or hexamethyleneimino group, wherein the methylene group in the 3-position of the pyrrolidino group or in the 3- or 4-position of the piperidino or hexamethyleneimino group is replaced by a >CO- group) with an amine of formula V

~29179 H - R2NR3 (V) (wherein R2 and R3 are as hereinbefore defined);

c) hydrolysing a compound of formula I which contains an >(R40COR5)- group into a corresponding carbonyl compound of formula I;

d) hydrolysing a compound of formula I which contains an alkoxycarbonyl group into a corresponding carboxy compound of formula I;

e) esterifying or amidating a compound of formula I
which contains a carboxy group into a corresponding compound of formula I which contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group;

f) o~idising a compound of formula I which contains a thiomorpholino group into a corresponding 1-oxido-thiomorpholino compound of formula I;

g) oxidising a compound of formula I which contains a thiomorpholino or 1-oxido-thiomorpholino group into a corresponding 1,1-dioxido-thiomorpholino compound of formula I;

h) performing a process as defined in any one of steps ~ `~
(a) to (g) on a corresponding protected compound and subsequently removing the protecting group used; and i) converting a compound of formula I into a salt thereof.

The reaction of step (a) is conveniently carried out in an inert solvent such as acetone, methylethylketone, ` --` 2129173 tetrahydrofuran, dioxane, chlorobenzene, dimethylformamide or dimethylsulphoxide, optionally in the presence of an inorganic base, e.g. sodium carbonate or potassium hydroxide, or a tertiary organic base, e.g.
triethylamine or pyridine, whilst the latter may simultaneously serve as solvent, and optionally in the presence of a reaction accelerator such as a copper salt, a corresponding amine-hydrohalide or alkali metal halide, at temperatures between 0 and 150C, but preferably at temperatures between 20 and 120C.
However, the reaction may also be carried out without a solvent or in an excess of the compound of formula III.

The reductive amination of step (b) is conveniently carried out in a solvent such as methanol, ethanol, tetrahydrofuran or dioxane, preferably in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride, preferably at ambient temperature or in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium/charcoal, under a hydrogen pressure of 1 to 5 bar. -~

The optional subsequent hydrolysis of steps (c) and (d) is preferably carried out in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100C, preferably at the boiling temperature of the reaction mixture.

The optional subsequent esterification and/or amidation of step (e) is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimeth~lformamide, benzene, toluene, chlorobenzene, :. ~ ,. . . . - - .. -`; 2~291~9 tetrahydrofuran, benzenettetrahydrofuran or dioxane or, particularly advantageously, in a corresponding alcohol or amine as solvent, optionally in the presence of an acid such a~ hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutylchloroformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pen~oxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbo-diimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and, in addition, optionally in the presence of 4-dimethylaminopyridine, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, expediently at temperatures between 0 and 150C, preferably at temperatures between 0 and 80C.

The optional subsequent oxidation of steps (f) and (g) is preferably carried out in a solvent or mixture of solvents, e.g. in water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulphuric acid or trifluoroacetic acid, conveniently at temperatures between -80 and 100C depending on the oxidising agent used.

To prepare a corresponding 1-oxido compound of formula I
the oxidation is conveniently carried out with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50C, or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium -`` 2~291~

acetate, with N-bromo-succinimide in ethanol, with tert.butyl-hypochlorite in methanol at -80 to -30C, with iodobenzodichloride in aqueous pyridine at o to 50C, with nitric acid in glacial acetic acid at 0 to 20C, with chromic acid iIl glacial acetic acid or acetone at 0 to 20C and with sulphurylchloride in methylene chloride at -70C, and the resulting thioether-chlorine complex is conveniently hydrolysed with aqueous ethanol.

To prepare a corresponding l,l-dioxido compound of formula I from a corresponding l-oxido compound the oxidation is carried out conveniently with one or more equivalents of the oxidising agent used, or from a corresponding thio compound, preferably with two or more equivalents of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid/acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100C or in acetone at 0 to 60C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures of between 0 and 60C, with nitric acid in glacial acetic acid at o to 20C, with chromic acid or potassium permanganate in glacial acetic acid, water/sulphuric acid or acetone at 0 to 20C.

In the reactions described hereinbefore, reactive groups such as hydroxy, amino, alkylamino or carbonyl groups may be protected by means of conventional protecting groups which are removed by cleaving after the reaction.

For example, the protective group for a hydroxy group may be a trimethylsilyl, acetyl, ben~oyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, the protecting group for an amino, alkylamino or imino group may be an acetyl, benzoyl, ethoxycarbonyl or .

.: ,. : -~. . -~ 2129179 benæyl group and the protecting group for a carbonyl group may be a 1,3-dioxane or 1,3-dioxolane group.

The optional subsequent cleaving of the protecting group is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably cleaved hydrogenolytically, e.g.
using hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

Moreover, the compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with organic or ~ -inorganic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

In addition, the new compounds of formula I thus obtained, if they contain a carboxy group, may if desired subsequently be converted into the salts thereof with organic or inorganic bases, more particularly for pharmaceutical use into the physiologically acceptable ` ` 21~917~

salts thereof. Examples of such bases lnclude sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of formulae II to V used as starting materials in the process of the invention are known in some cases or may be obtained by conventional methods.

Thus, for example, the compounds of formulae II and IV
are obtained by step-wise substitution of the chlorine atoms of 2,4,8-trichloro-pyrimido[5,4-d]pyrimidine (see DE-C-l 116 676).

As mentioned above, the compounds of the invention have valuable properties. Thus, the compounds of formula I, wherein Ra denotes a pyrrolidino, piperidino or hexamethvleneimino group, in which a methylene group in the 3-position of a pyrrolidino group or in the 3- or 4-position of a piperidino or hexamethyleneimino group is replaced by a >CO- or >(R40COR5)- group, are valuable intermediate products for preparing other compounds of formula I which have valuable pharmacological properties, particularly a sensitising effect on resistant tumours during chemotherapy.

For example, the sensitising effect of the following compounds:

A = 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine, B = 2-[4-(N-methoxycarbonyl-amino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido-[5,4-d]pyrimidine, C = 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-\ 212~73 .

- 2~ -methyl-amino)-4-piperidino-pyrimido[5,4-d]-pyrimidine, D = 8-(N-benzyl-N-methyl-amino)-2-[4-(piperidino)-piperidin-l-yl]-4-morpholino-pyrimido[5,4-d]-pyrimidine, E = 2-[4-(N,N-dimethylaminomethyl)-piperidino]-8-[N-(naphth-1-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine, F = 4-(N-benzyl-methyl-amino)-2-[4-(N,N-dimethylamino)-piperidino]-8-morpholino-pyrimido[5,4-d]pyrimidine, G = 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine, H = 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(naphth-1-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine, : :

I = 2-~4-(2,2-diphenylethylamino)-piperidino]-4-~N-~:`
benzyl-N-methyl-amino)-8-morpholino-pyrimido-[5,4-d]pyrimidine, J = 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N-(3-benzoylaminopropyl)-amino]-4-morpholino-pyrimido-[5,4-d]pyrimidine and K = 2-[4-(N,N-dimethylamino)-piperidino]-4-[N-(naphth-1-yl-methyl)-N-methyl-amino]-8-morpholino-pyrimido-~5,4-d]pyrimidine was tested on cells resistant to adriamycin as follows:
Proliferating, adriamycin-resistant S 180 mouse sarcoma ` `" 2~29173 cells were cultivated for six days in the presence of various concentrations of test ~ubstance.
Concentrations of the test substances with a cytotoxic or cytosta~ic effect were indicated by reduced cell growth or by the cells dying off. The end point of the assay is the number of living cells per culture which is determined indirectly, making use of the property of vital cells to reduce the dye MTT [= 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] to coloured formazane. The IC50 denotes the concentration of a test substance which reduces the number of vital cells per culture vessel to 50% of the untreated control.

The test substances were tested both in the absence of adriamycin and also in the presence of a quantity of adriamycin which does not have a proliferation-inhibiting effect under the culture conditions.
Therefore, two IC50 values were obtained for each test substance, one in the presence of adriamycin (IC50 ADR), the other in the absence of adriamycin (IC50). The difference in the logarithms (to the base ten) of the two IC50 values: ~ = lgIC50-lgIC50 ADR is a measure of the increase in the cytotoxicity of the test substance brought about by adriamycin.

Test procedure:

Exponentially growing adriamycin-resistant or adriamycin-sensitive S 180 cells were plated out in 96-well flat-bottomed microtitre dishes at a rate of 2000 cells per well in 100 ~l of growth medium (RPMI-1640 containing 10% foetal calf serum). The culture dishes were incubated in an incubator at 37C, 5% C02 at 100%
relative humidity. After 24 hours, 50 ~l of growth medium containing various concentrations of test substance and 50 ~l of growth medium with or without `` 212~179 adriamycin were added to each well. Following a further 6-day cultivation period, 50 ~l of tetrazolium salt solution [5 mg of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide per ml of phosphate-buffered saline solution, diluted 1:5 (v/v) with RPMI-1640 before use] were pipetted into each well. After 4 days' incubation the culture medium was carefully suction filtered and the formazane formed intracellularly was solubilised with 150 ~l of uimethylsulphoxide per well.
The dishes were briefly shaken and the optical density was measured at 570 nm with a photometer such as a Dynatech MR-600 apparatus. The formation of the coloured formazane by reduction of the tetrazolium salt is proportional to the number of living cells. The averages of three measurements were used to calculate the IC50 values (dilution stage: 1:2).

IC50 [~g/ml] lg ICso Substance Adriamycin in ng/ml IC50 100 ng Adriamycin , _ O 100 A 1 0.3 0.53 B 10 1.0 1.00 C 2 0.3 0.82 D 3 0.3 1.00 E 3 0.1 1.48 F 3 0.3 1.00 G 3 0.1 1.48 H 3 0.1 1.48 I 10 0.3 1.52 ~ 3 0.1 1.48 K 3 0.1 1.48 .

The compounds of the invention thus exhibit marked sensitisation to adriamycin-resistant sarcoma cells and are therefore suitable for use, optionally in conjunction with a chemotherapeutic agent, for sensitising tumours which are resistant to chemotherapy, : ~ - : : .

2~2~179 i.e. their resistance to the particular chemotherapy is removed and in this way remission of the tumours resistant to these substances is brought about.
Examples of chemotherapeutic agents include vinca alkaloids such as vinblastin, vincristin or vindesin, epipodophyllotoxins such as VP16 or anthracyllin-antibiotics such as daunorubicin, doxorubicin or bleomycin, colchicin, mitoxantron, taxol, taxotere, mithramycin or mitomycin.

The eompounds of the invention, in conjunetion with a ehemotherapeutic agent, thus prevent therapy-resistant tumour cell sub-populations from surviving therapy and causing a relapse.

Viewed from a further aspeet the invention thus provides a pharmaceutical composition eomprising a compound of formula I or a physiologically aceeptable salt thereof together with at least one physiologieally aeceptable carrier or excipient and optionally together with one or more ehemotherapeutie agent.

Viewed from a still further aspeet the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufaeture of a medieament for use in sensitising therapy-resistant tumour cells during ehemotherapy.

Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human, pre~erably mammalian body to sensitive therapy-resistant tumour cells during chemotherapy, said method eomprising administering to said body a eompound of formula I or a physiologieally acceptable salt thereof.

The compounds of the invention are well tolerated, since administration of compound G, for example, in a dose of . .:- . - - -: :: :

2~29~79 100 mg/kg i.v. in mice did not lead to any detectable toxic side effects~

The compounds according to the invention are preferably administered separately and, appropriately, some days (e.g. one or two days) before the administration of a chemotherapeutic agent or in conjunction with a chemotherapeutic agent administered in the usual dose;
the dose of the pyrimido[5,4-d]-pyrimidine used is between 1 and 50 mg/kg o~ body weight per day, preferably between 3 and 20 mg/kg of body weight per day, divided up into 1 to 4 single doses. However, the drug is preferably administered by infusion.

For combined administration with a suitable chemotherapeutic agent an intravenous preparation such as an ampoule preparation is suitable; for separate administration, earlier administration or parallel administration, preparations in the form of plain or coated tablets, suspensions, syrups, capsules or suppositories are suitable.

For example, on the basis of the administration protocols known from the literature for the natural products u~ed in the chemotherapy of neoplastic diseases (see Goodman and Gilman's, The Pharmacological Basis of Therapeutics, Macmillan Publishing Company, New York, 7th Edition, pages 1240-1247 and 1277-1289 (1985)) the first administration of a compound of the invention or a physiologically acceptable acid addition salt thereof conveniently takes place before or together with administration of the chemotherapeutic agent used, or before or together with administration of a combination of several chemotherapeutic agents (see DeVita et al. in "Cancer, Principles & Practice o~ Oncology", 2nd Edition, J. B. Lippincott Company Philadelphia).

., . ~ , . . .. . . . . . , . -` 2~2~179 Further doses of a compound of the inventlon or a physiologically acceptable acid addition salt thereof may be given by oral route or, again, by intravenous route depending on the circumstances.

A combined preparation which is suitable for i.v.
administration according to the invention thus usefully contains 1 to 25 mg/kg, preferably 1 to 20 mg/kg of body weight of a compound of the invention or a pnysiologically acceptable acid addition salt thereof and a suitable chemotherapeutic agent or a combination of various suitable chemotherapeutic agents.

The Examples which follow are intended to illustrate the invention:

` '`` 2~2~79 Preparation of the starting compounds:

Example I

2,8-Dichloro-4-morpholino-pyrimido[5,4-d]pyrimldine 9 g o~ 2,4,8-Trichloro-pyrimido[5,4-d]pyrimidine are suspended in 70 ml of acetone and 3.3 g of morpholine in 10 ml of acetone are added at 0C. The reaction mixture is stirred for one hour whilst cooling with ice and then poured onto 100 ml of water. The precipitate formed is suction filtered, washed with water and dried in a desiccator.
Yield: 9.5 g (81 ~ of theory).
Rf value: 0.96 (silica gel; cyclohexane/ethyl acetate =
2:1) The following are prepared analogously:

2,8-dichloro-4-diethylamino-pyrimido[5,4-d]pyrimidine Rf value: 0.45 (silica gel; methylene chloride) 2,8-dichloro-4-[N-(naphth-1-yl-methyl)-N-methyl-amino]-pyrimido[5,4-d]pyrimidine 2,8-dichloro-4-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-pyrimido[5,4-d]pyrimidine 2,8-dichloro-4-piperidino-pyrimido[5,4-d]pyrimidine Rf value: 0.66 (silica gel; cyclohexane/ethyl acetate =
2:1) 2,4-dichloro-4-(N-methyl-benzylamino)-pyrimido[5,4-d]pyrimidine Rf value: 0.5 (silica gel; cyclohexane/ethyl acetate =
2:1) ` ``` 2129~79 Example II

2-Chloro-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimidoLs,4-d]pyrimidine 1 g (3.2 mMol) of 2,8-dichloro-4-morpholino-pyrimido[5,4-d]pyrimidine is dissolved in 15 ml of acetone and 1.9 g (8.1 mMol) of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline in a little acetone is added at ambient temperature. After 3 hours' stirring, the mixture is poured onto 20 ml of water and the precipitate is suction filtered and dried.
Yield: 1.2 g (83 ~ of theory), Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate =
2:1) The following are prepared analogously:

8-(N-benzyl-N-methyl-amino)-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.60 (silica gel; cyclohexane/ethyl acetate =
2 : 1 ) 2-chloro-4-morpholino-8-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-pyrimido[5,4-d]pyrimidine Rf value: 0.50 (silica gel; cyclohexane/ethyl acetate =
2:1) 2-chloro-8-[N-(4-methoxy-benzyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 157-158C

2-chloro-8-[N-(4-methyl-benzyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine ` -"' 2~2~17g Melting point: 156-157C

2-chloro-8-[N-(4-chloro-benzyl)-N-methyl-amino]-4-morpholino-pyrimidoC5,4-d]pyrimidine Melting point: 149-151C

2-chloro-8-(N-cyclohexylmethyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 98-100C

2-chloro-4-morpholino-8-[N-(naphth-2-yl-methyl)-N-methyl-amino]-pyrimido[5,4-d]pyrimidine Melting point: 132-134C

2-chloro-8-[N-(4-methoxy-naphth-1-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 131-135C

2-chloro-8-[~-(4-N,N-dimethylamino-naphth-1-yl-methyl)-N-methylamino]-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 145-148C

2-chloro-8-[N-(naphth-1-yl-methyl)-N-methylamino]-4-piperidin-1-yl-pyrimido[5,4-d]pyrimidine Rf value: 0.62 (silica gel; cyclohexane/ethyl acetate =
2:1) 2-chloro-8-(N-benzyl-N-ethyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 108-110C

2-chloro-4-morpholino-8-(3-phenylpropylamino)-pyrimido[5,4-d]pyrimidine Melting point: 100-102C

2-chloro-4-morpholino-8-(2-phenylethylamino)-pyrimido[5,4-d]pyrimidine - -'` 2~2317~1 Melting point: 141-143C

2-chloro-8-(cyclohexylmethylamino)-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 125-127C

8-benzylamino-2-chloro-4-morpholino-pyrimido-[5,4-d]pyrimidine Melting point: 148-151C

2-chloro-8-(4-methyl-benzylamino)-4-morpholino-pyrimido-[5,4-d]pyrimidine Melting point: 180-182C -.

2-chloro-8-(4-methoxy-benzylamino)-4-morpholino-pyrimido~5,4-d]pyrimidine Melting point: 156-158C

8-(N-benzyl-N-methyl-amino)-2-chloro-4-diethylamino-pyrimido[5,4-d]pyrimidine Oil, R~ value: 0.52 (silica gel; methylene chloride) 2-chloro-8-[N-(naphth-1-yl-methyl)-N-methylamino]-4- :~
morpholino-pyrimido[5,4-d]pyrimidine Oil, Rf value: 0.42 (silica gel; cyclohexane/ethyl acetate = 2:1) 2-chloro-4-morpholino-8-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-pyrimido[5,4-d]pyrimidine Oil, Rf value: 0.40 (silica gel; cyclohexane/ethyl acetate = 2:1) 8-(N-benzyl-N-methyl-amino)-2-chloro-4-piperidino-pyrimido[5,4-d]pyrimidine Oil, R~ value: 0.79 (silica gel; cyclohexane/ethyl acetate = 2:1) 2~2~179 8-benzyloxy-2-chloro-4-morpholino-pyrimido-[5,4-d]pyri~.idine R~ value: 0.45 (silica gel; cyclohexane/ethyl acetate =
2:1) 2-chloro-4,8-bis(morpholino)-pyrimido[5,4-d]pyrimidine Rf value: 0.16 (silica gel; methylene chloride/methanol =
3 9 : 1 ) 8-(N-benzyl-N-ethyloxycarbonylmethyl-amino)-2-chloro-4-piperidino-pyrimido[5,4-d]pyrimidine From N-benzylglycinethylester and 2,8-dichloro-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 87-91C

8-[N-benzyl-N-(2-cyanoethyl)-amino]-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine From 3-benzylaminopropionitrile and 2,8-dichloro-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 108-112C

8-[N-(anthracen-9-yl)-N-methyl-amino]-2-chloro-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.91 (silica gel; methylene chloride/methanol = . .
9 : 1 ) 8-(N-benzyl-N-isopropyl-amino)-2-chloro-4-morpholino-pyrimido[S,4-d]pyrimidine Rf value: 0.64 (silica gel; cyclohexane/ethyl acetate =
2:1) 2-chloro-8-dibenzylamino-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.62 (silica gel; cyclohexane/ethyl acetate =
2:1) -chloro-4-(N-benzyl-N-methyl-amino)-8-morpholino-` "`` 212~79 pyrimido[5,4-d]pyrimidine Rf value: 0.52 (silica gel; cyclohexane/ethyl acetate =
2:1) 2-chloro-8-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.71 (silica gel; methylene chloride/methanol =
9 : 1 ) 2-chloro-8-(isoindolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.9 (silica gel; methylene chloride/methanol =
9 : 1 ) 2-chloro-8-(5-methoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.66 (silica gel; cyclohexane/ethyl acetate =
2:1) 2-chloro-8-benzylthio-4-morpholino-pyrimido-[5,4-d]pyrimidine Rf value: 0.72 (silica gel; methanol/methylene chloride =
50:1) 2-chloro-8-(5-acetylamino-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Rf value: 0.55 (silica gel; methylene chloride/methanol =
9:1) 2-chloro-8-(6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Melting point: 194-197C

2-chloro-8-(6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine ` ``` 212~179 Prepared from 2-chloro-8-(6,7-dihydroxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine by alkylation with bromochloromethane in dimethylformamide.
Melting point: 187-189C

`-` 212~17~

Preparation of the end products:

Example 1 2-[4-(N,N-Dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine 1.2 g (2.7 mMol) of 2-chloro-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine are dissolved in 20 ml of dioxane, 1.4 g (11 mMol) of 4-dimethylamino-piperidine are added and the mixture is refluxed for 4 hours. Then the solution is poured onto water and the product is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is purified by chromatography over a silica gel column with methylene chloride/methanol/ammonia = 30:1:0.1.
Yield: 0.5 g (36 ~ der Theorie), Melting point: 125C
C28H38N8O3 (534.67) Calc.: C 62.90 H 7.16 N 20.96 Found: 62.82 7.26 20.72 The following are prepared analogously:

(1) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-methylamino)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 50 ~ of theory, Melting point: 98C
C25H34NsO (462.60) Calc.: C 64.91 H 7.41 N 24.23 Found: 64.77 7.52 24.18 . -.
(2) 2-[4-(N,N-dimethylamino)-piperidino]-8-(1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-~` 212~179 pyrimido[5,4-d]pyrimidine-oxalate Yield: 20 % of theory Melting point: 145C
C26H3~N8O x (COOH)2 (564.65) Calc.: C 59.56 H 6.43 N 19.84 Found- 59.57 6.69 19.68 (3) 2-[4-(N,N-dimethylamino)-piperidino3-8-[N-(4-methoxy-benzyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 33.8 % of theory, Melting point: 109-110C
C26H36N8O2 (492.63) Calc.: C 63.39 H 7.37 N 22.75 Found: 63.14 7.34 22~44 (4) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(4-methyl-benzyl)-N-methylamino]-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 33 % of theory, Melting point: 234-235C
C26H36N8O x 0.5H2O (485.64) Calc.: C 64.30 H 7.68 N 23.08 Found: 64.12 7.65 22.83 (5) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(4-chloro-benzyl)-N-methylamino]-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 51.7 % of theory, Melting point: 215-220C
C2sH33ClNs (497.05) Calc.: C 60.41 H 6.69 N 22.55 Found: 60.42 6.69 22.33 (6) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(naphth-2-yl-methyl)-N-methylamino]-4-morpholino-pyrimido[5,4-d]-pyrimidine :.. ~ . .:. . :

` ``` 2~L2~17~

Yield: 57.5 ~ of theory, Melting point: 114-117C
C2gH36Nso (512.66) Calc.: C 67.94 H 7.08 N 21.86 Found: 67.8g 7.11 21.69 t7) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(4-methoxy-naphth-l-yl-methyl)-N-methyl-amino~-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 54.4 ~ of theory, Melting point: 130-132C
C30H38N8O2 x 0.5H2O (551.70) Calc.: C 65.31 H 7.12 N 20.31 Found: 65.32 7.01 20.19 (8) 2-[4-(N,N-dimethylamino)-piperidino]-3-[N-(4-N,N-dimethylamino-naphth-l-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 35.2 ~ of theory, Melting point: 170C
C31H41NgO xH2O (573.74) Calc.: C 64.90 H 7.55 N 21.97 Found: 64.57 7.47 21.87 (9) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-ethylamino)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 79 % of theory, Oil, Rf value: 0.25 (silica gel; ethyl acetate/methanol/
ammonia = 8:2:0.5) C26H36NsO (476.63) Calc.: C 65.52 H 7.61 N 23.51 Found: 65.51 7.74 23.59 (10) 2-[4-(N,N-dimethylamino~-piperidino]-8-[N-(naphth-1-yl-methyl)-N-methylamino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 67 ~ of theory, :. ~ . . ' ' ' . : ' . - . ' ' . ' ~ . .' ' ."

` `` 212~179 -- ~o Melting point: 146-148C
C2gH36Nso (512.66) Calc.: C 67.94 H 7.08 N 21.86 Found: 67.96 7.20 21.47 (11) 2-[4-(N,N-dimethylamino)-piperidino]-8-(3-phenylpropyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 56 % of theory, Melting point: 82-84C
C26H36N8O (476.63) Calc.: C 65.52 H 7.61 N 23.51 Found: 64.92 7.65 22.72 (12) 2-[4-(N,N-dimethylamino)-piperidino]-8-(2-phenylethyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 68 % of theory, Melting point: 115-117C
C2sH34Ns (462.60) Calc.: C 64.91 H 7.41 N 24.22 Found: 64.60 7.36 24.16 ~;

(13) 2-[4-(N,N-dimethylamino)-piperidino]-8-(cyclohexylmethylamino)-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 58 ~ of theory, Melting point: 110-112C
C24H3sNs (454.62) Calc.: C 63.41 H 8.42 N 24.65 Found: 63.13 8.59 24.71 (14) 2-[4-(N,N-dimethylamino)-piperidino]-8-benzylamino-4-morpholino-pyrimido~5,4-d]pyrimidine Yield: 58 ~ of theory, Melting point: 148-150C
C24H32Ns (448.58) l29~79 Calc.: C 64.26 H 7.19 N 24.98 Found: 63.89 7.25 23.89 (15) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(4-methylbenzyl)-amino]-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 47 ~ of theory, Melting point: 142-144C
C25H34NsO (462.60) Calc.: C 64.91 H 7.41 N 24.22 Found: 64.86 7.52 24.32 (16) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(~-methoxybenzyl)-amino]-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 55 ~ of theory, Melting point: 124-126C
C25H34N8O2 (478.60) Calc.: C 62.74 H 7.16 N 23.41 Found: 62.30 7.30 23.32 (17) 8-(N-benzyl-N-methyl-amino)-2-[4-(piperidino)- ;
piperidin-1-yl]-4-morpholino-pyrimido[5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 4-piperidino-piperidine Yield: 54 ~ o~ theory, Melting point: 106C
C28H3sNsO (502.67) Calc.: C 66.91 H 7.62 N 22.29 Found: 67.02 7.85 22.33 (18) 8-(N-benzyl-N-methyl-amino)-2-[4-(N,N-dimethylaminomethyl)-piperidino]-4-morpholino-pyrimido[5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 4-(N,N-dimethylaminomethyl)-piperidine ` 2~29179 Yield: 30.6 ~ of theory, Melting point: 145-147C
C26H36NsO (476.63) Calc.: C 65.52 H 7.61 N 23.51 Found: 65.24 7.70 23.59 (19) 8-(N-benzyl-N-methyl-amino)-4-morpholino-2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-on-8-yl)-pyrimido[5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one Yield: 47 % of theory, Melting point: 203-205C
C31H3sNg02 (565.68) Calc.: C 65.82 H 6.24 N 22.28 Found: 65.35 6.59 22.39 ' (20) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-diethylamino-pyrimido[5,4-d]pyrimidine Melting point: 145-148C
Yield: 23.8 % of theory, Melting point: 160-162C
C2sH36N8 (448.62) Calc.: C 66.93 H 8.09 N 24.98 Found: 66.85 8.05 25.30 (21) 2-[4-(N,N-dimethylamino)-piperidino]-4-[N-(naphth-1-yl-methyl)-N-methyl-amino]-8-morpholino-pyrimido[5,4-d]pyrimidine Yield: 78 % of theory, Melting point: 124-126C
C2gH36Nso (512.66) Calc.: C 67.94 H 7.08 N 21.86 Found: 68.00 7.21 21.76 (22) 2-[4-(N,N-dimethylamino)-piperidino]-4-(1,2,3,4-. .. .. . . . .. . .

~ . - : ... .

~ 212~179 tetrahydro-isoquinolin-2-yl)-8-morpholino-pyrimido[5,4-d]pyrimidine Yield: 81 ~ of theory, Melting point: 49-53C
C26H34N8O (474.61~
Calc.: C 65.80 H 7.22 N 23.61 Found: 65.61 7.34 23.46 (23) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-methylamino)-4-piperidino-pyrimido[5,4-d]pyrimidine Yield: 50 ~ of theory, C26H36N8 (460.63) Calc.: C 67.80 H 7.88 N 24.32 Found: 67.39 8.15 24.27 (24) 2-[4-(N,N-dimethylamino)-piperidino]-4,8-bis~N-benzyl-amino)-pyrimido[5,4-d]pyrimidine Yield: 71 % of theory, Melting point: 143-145C
C27H32N8 (468.61) Calc.: C 69.20 H 6.88 N 23.91 Found: 69.48 6.87 23.89 (25) 8-benzyloxy-2-[4-(N,N-dimethylamino)-piperidino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 19 % of theory, Melting point: 186-188C
C24H3lN7O2 (449.56) Calc.: C 64.12 H 6.95 N 21.81 Found: 64.23 6.96 21.69 (26) 2-~4-(N,N-dimethylamino)-piperidino]-4,8-bis(morpholino)-pyrimido[5,4-d]pyrimidine Yield: 26 % of theory, Melting point: from 140C
C2lH32N8O2 x H2O (446.56) Calc.: C 56.48 H 7.67 N 25.09 ` ~`` 212~179 Found: 56.62 7.53 24.89 (27) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-ethoxycarbonylmethyl-amino)-4-morpholino-pyrimidoC5,4-d]pyrimidine Yield: ~7 ~ of theory Melting point: 112-115C
C28H38N8O3 (534.67) Calc.: C 62.90 H 7.16 N 20.96 Found: 63.04 7.07 21.02 (28) 2-~4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N- `
(2-cyano-ethyl)-amino]-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 89 ~ of theory, Melting point: 45-47OC
C27H3sNs (501.64) Calc.: C 64.65 H 7.03 N 25.13 Found: 64.63 7.10 25.38 (29) 2-[4-(N,N-dimethylaminomethyl)-piperidino]-8-[N-(naphth-1-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 21 ~ of theory, Melting point: 158C
C3~H38N8O (526.69) Calc.: C 68.42 H 7.27 N 21.27 Found: 68.55 7.48 21.05 (30) 2-~4-(N,N-dimethylaminomethyl)-piperidino]-8-[N-(naph~h-1-yl-methyl)-N-methyl-amino]-4-piperidino-pyrimido[5,4-d]pyri~idine Yield: 41 ~ of theory, Melting point: 150-151C
C31H40N8(524.72) Calc.:C 70.96 H 7.68 N 21.36 Found:71.04 7.44 21.68 , ~ , : , , ~
: ,-.. :. : . . :- .

` '` 212~179 (31) 4-(N-benzyl-N-methyl-amino)-2-[4-(N,N-dimethylamino)-piperidino]-8-morpholino-pyrimido[5,4-d]pyrimidine Yield: 47 % of theory, Melting point: 122C
C25H34NsO (462.60) Calc.: C 64.91 H 7.41 N 24.23 Found: 64.93 7.60 24.29 (32) 8-[N-(anthracen-9-yl)-N-methyl-amino]-2-[4-(N,N-dimethylamino)-piperidino]-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 18 % of theory, ~-Melting point: 168C
C33H38NsO (562.72) Calc.: C 70.44 H 6.81 N 19.91 Found: 70.20 6.88 19.46 (33) 2-[4-(N-methoxycarbonyl-amino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 24 % of theory, Melting point: 110C
C26H34N8O3 (506.61) Calc.: C 61.64 H 6.76 N 22.12 Found: 61.47 6.91 22.17 (34) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-cyclohexylmethyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 19 ~ of theory, Melting point: 210-212C
C25H4oNsO x 0.5 H2O (477.66) Calc.: C 62.86 H 8.65 N 23.46 Found: 62.76 8.41 23.53 (35) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-` ` 212~79 - ~6 -isopropyl-amino)-~-morpholino-pyrimido[5,4-d]pyrimidine-oxalate Yield: 38 ~ of theory, Melting point: 122-125C
C27H3aN8O x (COOH)2 (580.69) Calc.: C 59.98 H 6.94 N 19.30 Found: 59.74 7.17 19.50 (36) 8-dibenzylamino-2-[4-(N,N-dimethylamino)-piperid no]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 47 % of theory, Melting point: 163C
C31H3~NsO (538.70) Calc.: C 69.12 H 7.11 N 20.80 Found: 69.01 7.06 20.34 (37) 2-(4-pyrrolidino-piperidin-1-yl)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine-oxalate From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 4-pyrrolidino-piperidine Yield: 57 % of theory, Melting point: 131-134C
C27H3sNs x (COOH)2 (578.67) Calc.: C 60.19 H 6.61 N 19.36 Found: 59.97 6.95 19.13 (38) 2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 8-aza-1,4-dioxaspiro-[4,5]decane Yield: 58 % of theory, Melting point: 143C
C25H31N7O3 (477.58) Calc.: C 62.88 H 6.54 N 20.53 ..... .. , .. ,., , ~.... ~ . ~ ... ,.... -.
: . - . ~ ~ .,.. :,.,:, .. . . . : : - - - -:
.. :.. -. .... :.:.: :. ~ .. . ............ . . ~ - : . .

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

`' 2~29179 Found: 62.89 6.62 20.47 (39~ 2-[4-(N,N-dimethylamino)-piperidino]-8-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 16 % of theory, Melting point: 106C
C28H40NsO3 (536.68) Calc.: C 62.66 H 7.51 N 20.88 Found: 62.63 7.33 20.92 (40) 2-[4-(N,N-dimethylamino)-piperidino~-8-(isoindolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 52 % of theory, Melting poi~t: 195-197C
C25H32NsO (460.59) Calc.: C 65.19 H 7.00 N 24.33 Found: 64.90 6.59 23.75 (41) 2-[4-(N,N-d~methylaminomethyl)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 16 % of theory, Melting point: 67C
C29H40N8O3 x 3H2O x (COOH)2 (692.77) Calc.: C 53.75 H 6.98 N 16.17 Found: 53.91 6.85 15.54 (42) 2-[4-(N,N-dimethylaminomethyl)-piperidino]-8-(5-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 32 % of theory, Melting point: 143C
C27H36NsO2 (504.64) Calc.: C 64.26 H 7.19 N 22.20 Found: 64.24 7.51 22.71 . .: .: ~, .. .

(43) 2-(8-aza-1,4-dioxaspiro[4,5]decan-~-yl)-8-(6,7-dimethoxy-1,2 ~,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine R~ value: 0.65 (si.lica ~el; methylene chloride/methanol = 9:1) (44) 2-[4-(N,N-dimethylamino)-piperidino]-8-benzylthio-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 30 % of theory, Melting point: 165C
C24H3lN70S (465.63) Calc.: C 61.91 H 6.71 N 21.06 Found: 62.03 6.71 20.79 (45) 2-[4-(N,N-dimethylamino)-piperidino]-8-(5-acetylamino-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine Yield: 73 % of theory, Melting point: 195c C28H97Nso2 (531.67) Calc.: C 63.26 H 7.01 N 23.71 Found: 63.12 6.95 23.94 (46) 2-[4-(N,N-dimethylamino)-piperidino]-ô-(6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine Yield: 57 % of theory, Melting point: 194-197C
C26H3~NsO3 (506.61) Calc.: C 61.64 H 6.76 N 22.12 Found: 60.ô6 6.93 21.95 (47) 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 91 % of theory, '~ ','' ' ''. . ,,' "' ' ' " "',.' , . ~; : . : ' ' '. . ' .'' ' ' ' ' .. '`. '' "_ ' ' ' ```` 2~ 2~179 Melting point: 99-101C
C27H34Ns3 (518.62) Calc.: C 62.53 H 6.61 N 21.61 Found: 62.05 6.63 21.19 (48) 2-C4-(N,N-dimethylamino)-pyrrolidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[s,4-d]pyrimidine Yield: 77 ~ of theory, Melting point: 173-174C
C27H36NsO3 (520.69) Calc.: C 62.29 H 6.97 N 21.52 Found: 62.08 7.15 21.30 E~ampl~ 2 2-[4-(N,N-diethylamino)-piperidino)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine 1.73 g of 2-(4-oxo-piperidin-1-yl)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine are dissolved in 20 ml of methanol and 20 ml of dioxane and mixed with 0.293 g of diethylamine. To this solution are added 0.31 g of sodium cyanoborohydride and 0.24 g of glacial acetic acid and the mixture is stirred for 7 hours at ambient temperature. Then the reaction mixture is stirred into 100 ml of water and made alkaline with 2N
sodium hydroxide solution. This solution is extracted with ethyl acetate, the organic phase is separated off, dried and evaporated down. The product is purified over a silica gel column with ethyl acetate/methanol/ammonia =
7:3:0.15.
Yield: 570 mg (29 ~ of theory) Oil C27H38NsO (490.66) Calc.: C 66.09 H 7.81 N 22.84 Found: 66.29 7.82 22.95 .. ~ . ~ - . ...... . . .

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

` ' 2~2917~

The following are prepared analogously:

(1) 2-(4-benzylamino-piperidino)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 90 ~ of theory, Melting point: 103-106C
C30H36Nso (524.67) Calc.: C 68.68 H 6.92 N 21.36 Found: 68.39 7.02 21.24 (2) 8-(N-benzyl-N-methyl-amino)-2-(4-ethylamino-piperidino)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 65 % of theory, Melting point: 92-94C
C2sH34NsO (462.60) Calc.: C 6~.91 H 7.41 N 24.22 Found: 64.95 7.61 24.56 (3) 2-[4-(2,2-diphenylethylamino)-pipe.ridino]-4-(N-benzyl-N-methylamino)-8-morpholino-pyrimido[5,4-d]pyrimidine Yield: 61 % of theory, Melting point: 106-108C
C37H42Ns (614.80) Calc.: C 72.29 H 6.89 N 18.23 Found: 71.92 6.98 18.00 (4) 2-[4-(3,3-diphenylpropylamino)-piperidino]-4-(N-benzyl-N-methylamino)-8-morpholino-pyrimido[5,4-d]-pyrlmldlne Yield: 52 % of theory, Melting point: 56-58C
C38H44NsO (628.83) Calc.: C 72.58 H 7.05 N 17.82 Found: 72.53 7.13 18.21 (5) 2-[4-(N',N'-dimethylcarbamoylmethyl-N-methylamino)-piperidino]-8-(N-ben2yl-N-methyl-amino)-4-morpholino--,:. -: : : : :.. : .. .. . .

. , . .: .

~ 2:12~17~

pyrimido[5,4-d]pyrimidine From 2-(4~oxo-piperidin-1-yl)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and N-methyl~lycine-(N',N'-dimethyl)-amide.
Yield: 60 % o~ theory Oil C28H39NgO2 (533.68) Calc.: C 63.02 H 7.37 N 23.62 Found: 62.94 7.50 23.72 (6) 2-(4-amino-piperidino)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine-oxalate Yield: 24 % of theory, Melting point: 204C (decomp.) C23H30N8O x (COOH)2 (524.58) Calc.: C 57.24 H 6.15 N 21.36 Found: 57.17 6.31 21.53 (7) 2-[4-[N-[2-(N',N'-dimethylamino)-ethyl]-N-methyl-amino]-piperidino3-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 60 % of theory Oil C28H4lNgO2 (519.70) Calc.: C 64.71 H 7.95 N 24.26 Found: 64.84 8.05 24.42 (8) 2-[4-(N-methylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 31 % of theory, Melting point: 94C
C27H36N8O3 (520.64) Calc.: C 62.29 H 6.97 N 21.52 Found: 62.23 7.02 21.62 (9) 2-(4-aminopiperidino)-8-(6,7-dimethoxy-1,2,3,4-`i. ~ ~' ' . . . ' .

` ' 2~29~79 tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 22 % of theory, Melting point: 236-238C
C26H34N8O3 (506.61) Calc.: C 61.64 ~ 6.76 N 22.12 Found: 62.16 6.60 22.20 (10) 2-~4-(N,N-diethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine Yield: 4 ~ af theory, Melting point: 122C
C30H42N8O3 (562.72) Calc.: C 64.03 H 7.62 N 19.91 Found: 63.91 7.38 20.02 (11) 2-[4-(morpholin-4-yl)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine Yield: 58 ~ of theory, Melting point: 83C
C30H40N8O4 1576-70) Calc.: C 62.48 H 6.99 N 19.43 Found: 62.01 7.21 19.62 (12) 2-[4~ oxidothiomorpholin-4-yl)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 40 ~ of theory, Melting point: 113C
C30H40Ns4S (608.77) Calc.: C 59.14 H 6.62 N 18.41 Found: 59.10 6.62 18.59 : :: ' ~: - . : - : . - : `: . - . : `:

` ~'` 212~7~

Example 3 8-IN-Benzyl-N-methyl-amino)-4-morpholino-2-(4-oxo-piperidin-1-yl)-pyrimido[5,4-d]pyrimidine 0.8 g of 2-(8-aza-1,4-dioxaspiro[4,5]decan-8-yl)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine are stirred in 40 ml of lN HCl for 20 minutes at ambient temperature and then stirred for 10 minutes over a steam bath. ~fter cooling, the mixture is made slightly basic with sodium hydroxide solution, extracted with ethyl acetate and the organic phase, having been washed with water and dried over sodium sulphate, is evaporated down n vacuo. The residue obtained is triturated with ether.
Yield: 0.6 g (82 ~ of theory), C23H27N7O2 (433.53) Calc.: C 64.~2 H 6.28 N 22.62 Found: 64.35 6.10 22.41 The following is prepared analogously:

8-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-oxo-piperidin-1-yl)-4-morpholino-pyrimido[5,4-d]-pyrimidine Rf value: 0.16 (silica gel; ethyl acetate/cyclohexane =
2 : 1 ) Yield: 76 ~ of theory Example 4 2-[4-(Carboxymethylamino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine sodium salt 0.5 g of 2-[4-(methyloxycarbonylmethylamino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine are stirred in 10 ml of 2~2~17~

methanol and 1 ml of lN NaOH over a steam bath for about 15 minutes. The mixture is then evaporated down ln vacuo, triturated with water and the product obtained is suction filtered and dried.
Yield: 0.3 ~ (62 ~ of theory), Melting point: 166-169C
C2sH32N~O3 (492.59) Calc.: C 60.96 H 6.55 N 22.75 Found: 60.78 6.07 22.77 The following is prepared analogously:

(1) 2-[4-~N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-carboxymethyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine Yield: 79 % of theory, Melting point: 151-155C
C25H32N8O3Na (514.56) Calc.: C 58.24 H 6.26 N 21.73 Found: 58.95 6.07 21.77 Example S

2-[4-(N,N-Dimethylamino)-piperidino]-8-[N-benzyl-N-(3-benzoylaminopropyl)-amino]-4-morpholino-pyrimido[5,4-d]-pyrimidine 0.75 g of 2-[4-(N,N-dimethylamino)-piperidino]-B-[N-benzyl-N-(3-aminopropyl)-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine are dissolved in 8 ml of methylene chloride and mixed with 0.24 g of benzoyl chloride and 0.3 g of triethylamine in 2 ml of methylene chloride. The reaction mixture is stirred for 12 hours at ambient temperature and then extracted three times with water. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed over a silica gel column , - - - . . . -r - . ........
; . ' , `::
: . . ' ' ' .:~ , ',: ' :: ' ~ .-``` 212~7~

using methylene chlorlde/methanol = 7:3.
Yield: 0.7 g (77 ~ of theory) Oil C34H43Ns2 (fi09.78) Calc.: C 66.97 H 7.11 N 20.67 Found: 66.85 6.98 20.71 The following compounds are obtained analogously:

(l) 8-[N-benzyl-N-(3-acetylaminopropyl~-amino]-2-[4-(N,N-dimethylamino)-piperidino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 69 ~ of theory, Melting point: 165-167C
C29H4lNgO2 (547.71~
Calc.: C 63.60 H 7.54 N 23.02 Found: 63.33 7.68 23.20 (2) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N-(3-toluenesulphonamidopropyl)-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine Yield: 77 ~ of theory, Melting point: 86-89C
C34H4sNsO3s (659.86) Calc.: C 61.89 H 6.87 N 19.10 S 4.87 Found: 61.79 6.91 18.92 5.28 Example 6 8-[N-Benzyl-N-(3-aminopropyl)-amino]-2-[4-(N,N-dimethylamino)piperidino]-4-morpholino-pyrimido[5,4-d]-pyrimidine 4 g of 8-[N-benzyl-N-(2-cyano-ethyl)-amino]-2-[4-(N,N-dimethylamino)-piperidino]-4-morpholino-pyrimido[5,4-d]pyrimidine are treated with hydrogen in 200 ml of ethanolic ammonia and in the presence of 0.8 g of Raney nickel. After the calculated amount of hydrogen has been taken up the catalyst is filtered off, the filtrate is evaporated down ln Y~s~ and the residue obtained i9 purified over a silica gel column with methylene chloride/methanol/ammonia = 7:3:0.15.
Yield: 2 g (50 ~ of theory), Melting point: 102-105C
C27H3sNsO (505.67) Calc.: C 64.13 H 7.77 N 24.93 Found: 64.39 8.00 25.04 -: . - - . - .

~ . - . - . . -: .

` -"` 2~2~179 Example I

Coated tablets containing 75 m~ of 2-[4-tN,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine 1 tablet core contains:
Active substance 75.0 mg Calcium phosphate 93.0 mg Corn starch 35.5 mg Polyvinylpyrrolidone 10.0 mg Hydroxypropylmethylcellulose 15.0 mg Magnesium stearate 1.5 mg 230.0 mg Preparation:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylm~thylcellulose and half the specified amount of magnesium stearate. Using a tablet making machine, compressed tablets about 13mm in diameter are produced which are then rubbed through a 1.5 mm mesh screen on a suitable machine and mixed with the remaining magnesium stearate. These granules are compressed in a tablet making machine to form tablets of the desired shape.
Weight of core: 230 mg Punch: 9 mm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose.
The finished film coated tablets are glazed with beeswax.
Weight of film-coated tablet: 245 mg . . . , . ;. : , ~

` ```` 212~17~

E~ample II

Tablets containing 100 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]-pyrlmlcllne Composition:
1 tablet contains:
Active substance 100.0 mg Lactose 80.0 mg Corn starch 34.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 2.0 mg 220.0 mg Pre~aration process:

The active substance, lactose and starch are mixedtogether and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist mass has been screened (2.0 mm mesh size) and dried in a rack dryer at 50C it is screened again (1.5 mm mesh size) and the lubricant is added. The mixture produced is formed into tablets.
Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.

.. :: . .. .: ~ .:

` ``` 2~ 2~79 Example LII

Tablets containing 150 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]-pyrimidine Composition:
1 tablet contains:
Active substance 150.0 mg Powdered lactose 89.0 mg Corn starch 40.0 mg Colloidal silica 10.0 mg Polyvinylpyrrolidone 10.0 mg Magnesium stearate 1.0 mq 300.0 mg Preparation:

The active substance mixed with lactose, corn starch andsilica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a 1.5 mm mesh screen.

The granules dried at 45~C are rubbed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are compressed from the mixture.
Weight of tablet: 300 mg Punch: 10 mm, flat .
,~ . : :::: . ;
~ ~ . . . .

21291 7~

Fxample IV

Hard gelatin capsules containing 150 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine . -1 capsule contains:
Active substance 150.0 mg Dried corn starch about 180.0 mg Powdered lactose about 87.0 mg Magnesium stearate 3.0 mg about 320.0 mg Pre~aration:

The active substance is mixed with the excipients, passed through a 0.75 mm mesh screen and homogeneously mixed in a suitable apparatus.

The final mixture is pac~ed into size 1 hard gelatin capsules.
Capsule contents: about 320 mg Capsule shell: size 1 hard gelatin capsule.

Example V

Suppositories containing 150 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido-[5,4-d]pyrimidine 1 suppository contains:
Active substance 150.0 mg Polyethyleneglycol 1500 550.0 mg Polyethyleneglycol 6000 460.0 mg . . ,. ~ ~ ~ : :
: - . .-. ~ - . ., -`- ` 2~2~179 Polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg Preparation:

After the suppository mass has been melted, the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

Example VI

Suspension containing 50 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]-pyrimidine 100 ml of suspension contain:
Active substance 1.0 g Sodium salt of carboxymethylcellulose 0.2 g Methyl p-hydroxybenzoate 0.05 g Propyl p-hydroxybenzoate 0.01 g Sucrose 10.0 g Glycerol 5.0 g 70~ Sorbitol solution 50.0 g Flavouring 0.3 g Distilled water ~ 100 ml Preparation:

Distilled water is heated to 70C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring.
After the additio~. and dissolution of the sugar, ` ``~ 2~L2~179 sorbitol solution and flavouring, the suspension is evacuated with stirring.
5 ml of suspension contain 50 mg of active substance.

E~m~

Ampoules containing 10 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]-pyrimidine Composition:
Active substance 10.0 mg 0.01 N hydrochloric acid q.s.
Twice distilled water ~ 2.0 ml Preparation process:

The active substance is dissolved in the required amountof 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.
Sterilisation is carried out by heating to 121C for 20 minutes.

Example VIII

Ampoules containing 50 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-- --isoquinolin-2-yl)-4-morpholino-pyrimido~5,4-d]pyrimidine -Composition:
Active substance 50.0 mg 0.01 N hydrochloric acid q.s.
Twice distilled water ad 10.0 ml `--` 212~179 Preparation process:

The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules.
Sterilisation is carried out by heating to 121C for 20 minutes.

Dry ampoules containing 10 mg of doxorubicin and 10 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine Composition of the dry ampoule:

Doxorubicin 10.0 mg Active substance 10.0 mg Preparation process:

The two active substances are dissolved in the required amount of 0.01 N HCl, filtered sterile and lyophilysed.

The solvent ampoule contains 5 ml of saline solution.

Before use the lyophilysate is dissolved in th~ sterile physiological saline solution.

`- :"` 212917~

Example X

Dry ampoules containing 50 mg of doxorubicin and 50 mg of 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido~5,4-d]pyrimidine Composition of the dry ampoule:

Doxorubicin 50.0 mg Active substance 50.0 mg Preparation process:

The two active substances are dissolved in the required amount of 0.01 N HCl, filtered sterile and lyophilysed.

The solvent ampoule contains 25 ml of saline solution.

Before use the lyophilysate is dissolved in the sterile physiological saline solution.

Clearly, all other compounds of the invention may be used as active substances in the galenic preparations described above.

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

Claims (13)

1. Compounds of formula I
(I) (wherein Ra denotes a pyrrolidino, piperidino or hexamethyleneimino group in which a methylene group in the 3-position of a pyrrolidino group or in the 3- or 4-position of a piperidino or hexamethyleneimino group is replaced by a >CR1-A-(R2NR3)-, >CO- or >(R4O-C-OR5)- group or by a group of formula (wherein A denotes a carbon-nitrogen bond or a C13-alkylene group;

R1 denotes a hydrogen atom or a C1-3-alkyl group;

R2 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a phenyl group;

R3 denotes a hydrogen atom or an optionally phenyl-substituted C1-4-alkyl group wherein the phenyl group is optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by C1-3-alkyl or C1-3-alkoxy groups, wherein the substituents may be identical or different, or R3 denotes a C1-4-alkyl group substituted by a carboxy, alkoxycarbonyl, cyano, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group or by two phenyl groups, whilst the above-mentioned alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms, or R3 denotes a C2-4-alkyl group optionally substituted in the 2-, 3- or 4-position by a hydroxy, amino, alkylamino or dialkylamino group, whilst the above-mentioned alkyl moieties may each contain 1 to 3 carbon atoms, or R3 denotes a C1-3-alkoxycarbonyl group, or R2 and R3 together with the nitrogen atom between them denote a cycloalkyleneimino group having 3 to 7 ring members, or a morpholino, thiomorpholino, 1-oxido-thiomorpholino or 1,1-dioxido-thiomorpholino group;
R4 and Rs independently denote C1-3-alkyl groups, or R4 and R5 together denote a C2-3-n-alkylene group;
R6 denotes a hydrogen atom or a C1-3-alkyl group; and R7 denotes a hydrogen atom, or a C1-3-alkyl or phenyl group); and Rb and Rc independently denote a cyclic alkyleneimino or alkenyleneimino group having 5 to 7 ring members to which a 1,4-butadienyl bridge is optionally attached via the 2-, 3- or the 3-, 4-positions, and which is optionally monosubstituted by a methylenedioxy group or mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl, alkoxy, amino, alkylamino, dialkylamino or alkanoylamino groups, wherein the alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms and the alkanoyl moiety may contain 2 or 3 carbon atoms and the substituents may be identical or different, or Rb and Rc may each denote a morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino or (R8NR9)- group, or Rc may also denote an optionally phenyl-substituted C1-3-alkoxy or C1-3-alkylthio group;

R8 denotes a hydrogen atom or a C1-4-alkyl group optionally substituted by a phenyl, cyano, carboxy or alkoxycarbonyl group or in the 2-, 3- or 4-position by an amino, alkylamino, dialkylamino, alkanoylamino, benzoylamino or phenylsulphonylamino group, wherein the above-mentioned alkyl, alkoxy and alkanoyl moieties may each contain 1 to 3 carbon atoms and the phenyl nucleus in each case may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by C1-3-alkyl or C1-3-alkoxy groups and the substituents may be identical or different; and R9 denotes a hydrogen atom, or a C1-4-alkyl group optionally substituted by a phenyl or naphthyl group, wherein the phenyl and naphthyl group may each be mono-or disubstituted by fluorine, chlorine or bromine atoms or by alkyl, alkoxy, amino, alkylamino or dialkylamino groups, (wherein the substituents may be identical or different and each alkyl and alkoxy moiety may contain 1 to 3 carbon atoms), or Rg denotes a C1-5-alkanoylamino group or anthracenyl group);
and the salts thereof.
2. Compounds as claimed in claim 1 wherein Ra denotes a pyrrolidino or piperidino group in which a methylene group in the 4-position is replaced by a >CR1-A-(R2NR3)-, >CO- or >(R4O-C-OR5)- group or by a group of formula (wherein A denotes a carbon-nitrogen bond or a methylene group;

R1 denotes a hydrogen atom;

R2 denotes a hydrogen atom, or a methyl or ethyl group;

R3 denotes a hydrogen atom, or R3 denotes a C1-3-alkyl group optionally substituted by a phenyl, carboxy, methoxycarbonyl, dimethylamino or dimethylaminocarbonyl group or by two phenyl groups, or R3 denotes a C2-3-alkyl group which is substituted in the 2- or 3-position by a dimethylamino group, or R3 denotes a C1-3-alkoxycarbonyl group, or R2 and R3 together with the nitrogen atom between them denote a pyrrolidino or piperidino group;
R4 and R5 together denote an ethylene group;
R6 denotes a hydrogen atom; and R7 denotes a phenyl group);

Rb denotes a dialkylamino group wherein each alkyl moiety may contain 1 to 3 carbon atoms, or Rb denotes a methylamino group substituted at the nitrogen atom by a benzyl or naphthyl group, or Rb denotes a piperidino, morpholino or 1,2,3,4-tetrahydro-isoquinolyl group; and Rc denotes a benzylamino group (optionally substituted at the nitrogen atom by a C1-3-alkyl group) optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by a methyl or methoxy group and in the alkyl moiety by a phenyl, carboxy, methoxycarbonyl, ethoxycarbonyl or cyano group, or in the 2- or 3-position by an amino, acetylamino, benzoylamino or p-toluenesulphonylamino group, or Rc may represent a naphthylamino group (optionally methyl-substituted at the nitrogen atom) optionally substituted in the naphthyl nucleus by a methoxy or dimethylamino group, or Rc may represent a 1,2,3,4-tetrahydro-isoquinolyl group optionally substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, methylenedioxy or acetamido group, or Rc may represent a morpholino, N-methyl-cyclohexylmethylamino or benzyloxy group, and the salts thereof.
3. Compounds as claimed in any one of the preceding claims wherein Ra denotes a piperidino group in which a methylene group in the 4-position is replaced by a >CR1-A-(R2NR3)- group (wherein A denotes a carbon-nitrogen bond or a methylene group;
R1 denotes a hydrogen atom;
R2 denotes a hydrogen atom, or a methyl or ethyl group;
R3 denotes a hydrogen atom, or R3 denotes a C2-3-alkyl group substituted by two phenyl groups, or R3 denotes a C1-3-alkyl group optionally substituted in the 2- or 3-position by a dimethylamino group, or R3 denotes a methoxycarbonyl group, or R2 and R3 together with the nitrogen atom between them represent a piperidino group);

Rb denotes a dimethylamino group in which a methyl group is substituted by a benzyl or naphthylmethyl group, or Rb denotes a piperidino or morpholino group; and Rc denotes a dimethylamino group in which a methyl group is substituted by a benzyl group (optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by a methyl or methoxy group) or by a naphthylmethyl group, or Rc denotes a 1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl, 1,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinolinyl, morpholino or N-(3-benzoylamino-propyl)-benzylamino group, wherein the groups Rb and Rc are different;
and the salts thereof.
4. Compounds as claimed in claim 1 being:

(a) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]-pyrimidine, (b) 2-[4-(N-methoxycarbonyl-amino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido-
[5,4-d]pyrimidine, (c) 2-[4-(N,N-dimethylamino)-piperidino]-8-(N-benzyl-N-methyl-amino)-4-piperidino-pyrimido[5,4-d]pyrimidine, (d) 8-(N-benzyl-N-methyl-amino)-2-[4-(piperidino)-piperidin-l-yl]-4-morpholino-pyrimido[5,4-d]pyrimidine, (e) 2-[4-(N,N-dimethylaminomethyl)-piperidino]-8-[N-(naphth-1-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine, (f) 4-(N-benzyl-N-methyl-amino)-2-[4-(N,N-dimethylamino)-piperidino]-8-morpholino-pyrimido[5,4-d]pyrimidine, (g) 2-[4-(N,N-dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4-morpholino-pyrimido[5,4-d]pyrimidine, (h) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-(naphth-1-yl-methyl)-N-methyl-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine, (i) 2-[4-(2,2-diphenylethylamino)-piperidino]-4-(N-benzyl-N-methyl-amino)-8-morpholino-pyrimido-[5,4-d]pyrimidine, (j) 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N-(3-benzoylaminopropyl)-amino]-4-morpholino-pyrimido-[5,4-d]pyrimidine, (k) 2-[4-(N,N-dimethylamino)-piperidino]-4-[N-(naphth-1-yl-methyl)-N-methyl-amino]-8-morpholino-pyrimido-[5,4-d]pyrimidine, and the salts thereof.

5. 2-[4-(N,N-Dimethylamino)-piperidino]-8-(6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl)-4 morpholino-pyrimido[5,4-d]pyrimidine and the salts thereof.
6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable salt of a compound as claimed in any one of claims 1 to 5.
7. A pharmaceutical composition containing a compound as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.
8. A pharmaceutical composition as claimed in claim 7, characterised in that it additionally contains a chemotherapeutic agent.
9. A process for the preparation of a compound as claimed in claim 1, said process comprising at least one of the following steps:
a) reacting a compound of formula II

(II) (wherein Rb and Rc are as defined in any one of claims 1 to 5 and Z denotes a leaving group) with a compound of formula III

Ra - H (III) (wherein Ra is as defined in any one of claims 1 to 5);

b) (to prepare compounds of formula I wherein Ra denotes a >CH-(R2NR3)- group) reductively aminating a compound of formula IV

(IV) (wherein Rb and Rc are as defined in claims 1 to 5 and Ra' denotes a pyrrolidino, piperidino or hexamethyleneimino group in which the methylene group in the 3-position of the pyrrolidino group or in the 3- or 4-position of the piperidino or hexamethyleneimino group is replaced by a >CO- group) with an amine of formula V
H - R2NR3 (V) (wherein R2 and R3 are as defined in claims 1 to 5);

c) hydrolysing a compound of formula I which contains an >(R4OCOR5)- group into a corresponding carbonyl compound of formula I;

d) hydrolysing a compound of formula I which contains an alkoxycarbonyl group into a corresponding carboxy compound of formula I;

e) esterifying or amidating a compound of formula I
which contains a carboxy group into a corresponding compound of formula I which contains an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group;

f) oxidising a compound of formula I which contains a thiomorpholino group into a corresponding 1-oxido-thiomorpholino compound of formula I;

g) oxidising a compound of formula I which contains a thiomorpholino or 1-oxido-thiomorpholino group into a corresponding 1,1-dioxidothiomorpholino compound of formula I;

h) performing a process as defined in any one of steps (a) to (g) on a corresponding protected compound and subsequently removing the protecting group used; and i) converting a compound of formula I into a salt thereof.
10. Use of a compound as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition for sensitising resistant tumours.
11. A method of treatment of the human or non-human animal body to sensitise therapy-resistant tumour cells during chemotherapy comprising administering to said body a compound of formula I as claimed in claim 1 or a physiologically acceptable salt thereof.
12. A compound of formula I as defined in claim 1 substantially as herein disclosed in any one of the Examples.
13. Each and every novel compound, composition, process, use and method as herein disclosed.
CA002129179A 1993-08-02 1994-07-29 Trisubstituted pyrimido[5,4-d]pyrimidines for modulating multi-drug resistance, pharmaceutical compositions containing these compounds and processes for their preparation Abandoned CA2129179A1 (en)

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DEP4325900.6 1993-08-02
DE4325900A DE4325900A1 (en) 1993-08-02 1993-08-02 Trisubstituted pyrimido[5,4-d]pyrimidines for the modulation of multi-drug resistance, medicaments containing these compounds and processes for their production

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AU (1) AU683888B2 (en)
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CA (1) CA2129179A1 (en)
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TW414798B (en) * 1994-09-07 2000-12-11 Thomae Gmbh Dr K Pyrimido (5,4-d) pyrimidines, medicaments comprising these compounds, their use and processes for their preparation
DE19608653A1 (en) * 1996-03-06 1997-09-11 Thomae Gmbh Dr K Pyrimido [5,4-d] pyrimidines, medicaments containing these compounds, their use and processes for their preparation
US6331543B1 (en) 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use
USRE37234E1 (en) * 1996-11-01 2001-06-19 Nitromed, Inc. Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses
US5958926A (en) 1996-11-01 1999-09-28 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
US6472425B1 (en) 1997-10-31 2002-10-29 Nitromed, Inc. Methods for treating female sexual dysfunctions
CN1984660B (en) * 2003-07-03 2010-12-15 美瑞德生物工程公司 4-arylamino-quinazolines as activators of aspartic acid specificity cysteine protease and inducers of apoptosis
US8309562B2 (en) * 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
DE102004002557A1 (en) * 2004-01-17 2005-08-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of substituted pyrimido (5,4-d) pyrimidines for the treatment of respiratory diseases
US8258145B2 (en) * 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
CA2592900A1 (en) 2005-01-03 2006-07-13 Myriad Genetics Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof

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EP0023559B1 (en) * 1979-07-03 1984-09-19 Dr. Karl Thomae GmbH 2-(perhydro-1,4-diazino)-pyrimido(5,4-d)pyrimidines, their preparation and medicaments containing them
DE2931573A1 (en) * 1979-08-03 1981-02-26 Thomae Gmbh Dr K AGENT TO CONTROL THE GROWTH OF CANCER CELLS AND THEIR PRODUCTION
DE3049207A1 (en) * 1980-12-27 1982-07-29 Dr. Karl Thomae Gmbh, 7950 Biberach NEW TRISUBSTITUTED PYRIMIDO (5,4-D) PYRIMIDINE, THEIR PRODUCTION AND USE AS A MEDICINAL PRODUCT
DE3423092A1 (en) * 1984-06-22 1986-01-02 Dr. Karl Thomae Gmbh, 7950 Biberach NEW 8-ALKYLTHIO-2-PIPERAZINO-PYRIMIDO (5,4-D) PYRIMIDINE, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
DE3833392A1 (en) * 1988-10-01 1990-04-05 Thomae Gmbh Dr K Use of pyrimido[5,4-d]pyrimidines for preventing primary and secondary resistance in chemotherapy and pharmaceuticals containing these compounds

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IL110509A (en) 1998-01-04
FI943574A0 (en) 1994-08-01
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HUT70957A (en) 1995-11-28
AU683888B2 (en) 1997-11-27
AU6881394A (en) 1995-02-09
SK91594A3 (en) 1995-04-12
IL110509A0 (en) 1994-10-21
EE9400255A (en) 1996-02-15
ZA945689B (en) 1996-02-01
CN1106405A (en) 1995-08-09
HU9402253D0 (en) 1994-09-28
DE4325900A1 (en) 1995-02-09
EP0645390A1 (en) 1995-03-29
TW251286B (en) 1995-07-11
RU94028278A (en) 1996-08-27
JPH0789963A (en) 1995-04-04
NO301479B1 (en) 1997-11-03
NO942853D0 (en) 1994-08-01
NO942853L (en) 1995-02-03
US5618814A (en) 1997-04-08
BG98931A (en) 1995-09-29
KR950005828A (en) 1995-03-20
PL304512A1 (en) 1995-02-06
FI943574A (en) 1995-02-03
RO113557B1 (en) 1998-08-28
CZ184594A3 (en) 1995-02-15

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