Substituted nitrogen heterocyclic derivatives and...

Details Substituted nitrogen heterocyclic derivatives and... Substituted nitrogen heterocyclic derivatives and...

2001-07-12

2003-04-22

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S244000, C544S276000, C544S277000, C546S118000

Reexamination Certificate

active

06552192

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to new purine and pyrazolopyrimidine derivatives and their deaza analogues and to their use in suitable utilities, especially diagnostic and therapeutic methods.
It relates, in particular, to purine derivatives and their inhibitory effect with respect to cyclin-dependent kinase proteins, abbreviated cdks and also with an inhibitory effect with respect to viruses and immunostimulation. Purine analogues as cdk inhibitors are disclosed for example in WO 97/16452, WO 98/05335 and WO/9720842. The teaching of these patents includes 2,6,9-trisubstituted and less substituted purine derivatives only.
DESCRIPTION OF RELATED ART
Tetrasubstituted purines are disclosed in WO 98/01448 in which substituents are short hydrocarbonyl chains, usually represented by hydrogen. Substituents at C6 represents hydrogen or amine optionally substituted by one or two hydrocarbon groups; substituents at C8 are hydroxy, mercapto, acyloxy or oxycarbonyl substituted by aliphatic alkyl only. Nucleotide analogues containing phosphonate groups are diclosed for example in U.S. Pat. Nos. 4,659,825; 4,724,233; 5,124,051; 5,302,585; 5,208,221; 5,352,786; 5,356,886;.5,142,051; in EP publication numbers 269,947; 481,214; 630,381; 369,409; 454,427; 618,214; 398,231; 454,427; 468,119; 481,119; 481,214; 434,450 and in WO 95/07920; WWO 094/03467, WO96/33200 and WO94/03467. Typical purine base is adenine, 2,6-diaminopurine and guanine. The purine bases may include the deaza analogues thereof 6,9-Substituted and 2,6,9-trisubstituted purines and related analogues are disclosed in WO 96/33200. 2,8,9-, 6,8,9-Trisubstituted and 2,6,8,9-tetrasubstituted purines and tri- and tetrasubstituted pyrazolopyrimidines and their deaza analogues have not yet been described.
SUMMARY OF THE INVENTION
It is an object of this invention to provide anticancer, antiviral, neurodepresssive and immunosuppressive compounds having improved selectivity and efficiency index, i.e. that are less toxic yet more efficacious than analogues known heretofore.
The invention concerns substituted nitrogen heterocyclic derivatives of the formula I
wherein,
A is a divalent group selected from the ensemble consisting of
Z is N or CH, provided that at least one Z being N;
R2 and R6 are independent of one another, represent H, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, cycloheteroalkyl alkyl or R6′—X wherein
X is an —NH—, —N(C
1
-C
6
-alkyl)-, —O— or —S— moiety;
R6′ is H, alkyl, substituted alkyl, acyl, amido, sulfo, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, arylalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl, heteroalkyl, cycloalkyl alkyl and cycloheteroalkyl alkyl;
R8 is halogen, hydroxyl, amino, carboxyl, cyano, nitro, amido, sulfo, sulfamido, carbamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl or R8′—X wherein X is —NH—, —N(alkyl)-, —O— or —S— moiety and
R8′ is according to any one of the substituents defined above for R2′ or R6′.
R9 is alkyl, substituted alkyl, acyl, carboxyl, amido, sulfamino, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, heteroalkylcycloalkyl alkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, arylalkyl, heteroarylalkyl, heteroalkyl or —B—R9′— wherein
B is —CH
2
—, —(CH
2
)
2
—, —CH(CH
3
)CH
2
—, —CH(CH
2
F)CH
2
—, —CH(CH
2
OH)CH
2
—, or the groups of the following structure,
 wherein the left hand bond is linked to nitrogen of 5-membered ring of compounds of the formula I;
R4 and R5, that are independent of one another, represent hydrogen, hydroxyl, halogen, amino, acyloxy substituent having 1-5 carbon atoms, alkoxy substituent having 1-5 carbon atoms, alkylmercapto substituent having 1-5 carbon atoms, alkylamino substituent having 1-5 carbon atoms and dialkylamino in which each alkyl substituent has 1-5 carbon atoms;
R7 and R10, that are independent of one another, represent H or alkyl substituent having 1-10 carbon atoms;
R9 is —(CH
2
)
n
—R9′, wherein n=1-2 and the
R9′ is —X(CH
2
)
m
Y wherein
X is —O—, —S—, —NH— or —N (alkyl)- substituent having 1-6 carbon atoms;
m=1-2;
Y is carboxyl, amido, sulfo, sulfamino, hydroxyl, carboxyl, mercapto, carbylmercapto, amino, alkylamino, carbamino—PO(OH)
2
, —PO(O—C
1
-C
6
-alkyl)
2
, —PO(NH—C1-C6-alkyl)
2
, PO(O—C
1
-C
6
-alkyl)(NH—C1-C6-alkyl), —PO(OH)(O—C
1
-C
6
-alkyl); —PO(OH)(NH—C
1
-C
6
-alkyl) or —(CH
2
CHD)—R9′, wherein
R9′, X, m and Y are as defined above and
D is alkyl, substituted alkyl, —PO(OH)
2
, —PO(OH)(O—C
1
-C
6
-alkyl), —PO(OH)(NH—C
1
-C
6
-alkyl).
The above not yet defined generic group having meanings as introduced in the following legend:
“halogen” refers to fluorine, bromine, chlorine, and iodine atoms;
“alkyl” refers to
a branched or unbranched alkyl group having 1-6 carbon atoms,
a branched or unbranched alkenyl group having 1-6 carbon atoms,
a branched or unbranched alkinyl group having 1-6 carbon atoms;
“substituted alkyl” refers to a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and having substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl. These substituent generic groups having the meanings being identical with the definitions of the corresponding groups as defined in this legend;
“carbyloxy” denotes the group —OR
a
, where R
a
is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this, legend;
“carbylmercapto” denotes the group —SR
b
, where R
b
is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend;
“sulfo” denotes the group —SO
3
R
c
, where R
c
is
hydrogen,
a branched or unbranched alkyl group having 1-6 carbon atoms,
a branched or unbranched alkenyl group having 1-6 carbon atoms,
a branched or unbranched alkinyl group having 1-6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl, whereas these generic groups have meanings which are identical with the definitions of the corresponding groups as defined in this legend;
“sulfamino” denotes the group —NHSO
3
R
d
, wherein R
d
is
hydrogen,
a branched or unbranched alkyl group having 1-6 carbon atoms
a branched or unbranched alkenyl group having 1-6 carbon atoms,
a branched or unbranched alkinyl group having 1-6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl, whereas these generic substituents have meanings which are identical with definitions of the corresponding groups as defined in this legend;
“acyl” denotes the group —C(O)R
e
, where R
e
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend;
“aryloxy”

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