Pyrimidine derivatives and processes for the preparation...

Details Pyrimidine derivatives and processes for the preparation... Pyrimidine derivatives and processes for the preparation...

1999-04-01

2001-06-26

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S262000

Reexamination Certificate

active

06251911

ABSTRACT:

The invention relates to 4-amino-1H-pyrazolo[3,4]pyrimidine derivatives and intermediates and to processes for the preparation thereof, to pharmaceutical formulations comprising such derivatives, and to the use of those derivatives as medicaments.
The invention relates to 4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives of formula I
wherein m is an integer from 0 up to and including 3,
v is 0 or 1,
R is hydrogen or lower alkyl,
R
1
is halogen, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl, or lower alkyl that is unsubstituted or substituted by halogen, cyano, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl or by N,N-di-lower alkyl-carbamoyl, it being possible when several phenyl substituents R
1
are present for those substituents to be identical or different from one another, and
a) R
2
is hydrogen and R
3
is
&agr;) a radical of formula II
wherein Y is oxygen or sulfur and
R
4
is
&agr;&agr;) an alkyl radical that is unsubstituted or substituted by amino, lower alkanoylamino, benzoylamino, benzyloxycarbonylamino, lower alkoxycarbonylamino, phenylamino or by benzylamino and that contains, including the substituents, from 4 to 20 carbon atoms,
&agr;&bgr;) phenylamino, benzylamino, naphthylamino, pyridylmethylamino, or alkylamino having from 4 to 11 carbon atoms, or
&agr;&ggr;) phenyl, or monocyclic heterocyclyl bonded via a carbon atom and having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur, any phenyl radicals present in the radical R
4
being unsubstituted or substituted by one or more radicals selected from nitro, amino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, halogen, cyano, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, methylenedioxy and lower alkyl, it being possible when several phenyl substituents are present for those substituents to be identical or different from one another,
&bgr;) unsubstituted alkyl having from 5 to 12 carbon atoms or lower alkyl substituted by
&bgr;&agr;) unsubstituted or lower-alkyl-substituted monocyclic heterocyclyl having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur,
&bgr;
62
) phenyl substituted by
i) phenyl,
ii) unsubstituted or chloro-substituted phenoxy or iii) unsubstituted or lower-alkyl-substituted monocyclic heterocyclyl having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur,
&bgr;&ggr;) naphthyl,
&bgr;&dgr;) cycloalkyl having from 3 to 8 ring members that is unsubstituted or substituted by lower alkyl or by lower alkoxycarbonyl, or
&bgr;&egr;) amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzyloxycarbonylamino, lower alkoxycarbonylamino, benzoyl amino, phenylamino, benzylamino, ureido, N
3
-phenyl-ureido, N
3
-lower alkyl-ureido, N
3
,N
3
-di-lower alkyl-ureido, amino-lower alkanoylamino, (lower alkoxycarbonylamino-lower alkanoyl)-amino, (benzy)oxycarbonylamino-lower alkanoyl)-amino, prolyl-amino, (N-lower alkoxycarbonyl-prolyl)-amino, N
3
-lower alkyl-thio-ureido, N
3
-phenyl-thioureido, cyano, guanidino, amidino, toluenesulfonylamino, lower alkanesulfonylamino or unsubstituted or lower-alkyl-substituted monocyclic heterocyclylcarbonylamino having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur,
radicals mentioned in section &bgr;&egr;) that contain a phenyl radical being unsubstituted or substituted in the phenyl radical by halogen, cyano, nitro, amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino, hydroxy, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkyl-carbamoyl or by lower alkyl, or
&ggr;) a radical of formula III
wherein R
5
is carboxy-lower alkanoylamino, benzyloxycarbonylamino, ureido, N
3
-phenyl-ureido, N
3
-(chloro-phenyl)-ureido, N
3
-(lower alkoxy-phenyl)-ureido, N
3
-lower alkyl-ureido, N
3
,N
3
-di-lower alkyl-ureido, N
3
-lower alkyl-thioureido, amino-lower alkanoyl-amino, (lower alkoxycarbonylamino-lower alkanoyl)-amino, (benzyloxycarbonylamino-lower alkanoyl)amino, prolyl-amino, (N-lower alkoxycarbonyl-prolyl)-amino, hydroxy-lower alkanoyl-amino, di-lower alkylamino-methyleneamino, succinimido, phthalimido, guanidino or amidino,
&dgr;) unsubstituted or lower-alkyl-substituted monocyclic heterocyclyl bonded via a ring carbon atom and having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur, or
&egr;) lower alkanesulfonyl or unsubstituted or lower-alkyl-substituted benzenesulfonyl, or
b) R
2
and R
3
together are
di-lower alkylamino-methyleneamino, or a substituted or unsubstituted alkylene or alkenylene radical having up to 15 carbon atoms, wherein from 1 to 3 carbon atoms may have been replaced by oxygen, sulfur or nitrogen,
and salts, solvates and tautomers thereof.
The general terms used hereinabove and hereinbelow preferably have the following meanings within the scope of the present Application:
The term “lower” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4, and more especially 1 or 2, carbon atoms.
When m is 0, the phenyl ring does not carry any substituents R
1
. Preferably, m is an integer from 0 up to and including 2. When m is 1, the phenyl substituent R
1
is primarily in the 4-position, i.e. in the para-position, or especially in the 3-position, i.e. in the meta-position.
When m is 2, the two phenyl substituents R
1
are preferably in the 3- and 4-positions.
When v is 0, the (R
1
)
m
phenyl radical is bonded directly to the nitrogen atom in the 4-position of the 1H-pyrazolo[3,4-d]pyrimidine derivative.
Halogen R
1
is fluorine, bromine, iodine or preferably chlorine.
Lower alkoxy R
1
is, for example, methoxy.
Lower alkanoyloxy R
1
is, for example, acetoxy.
Lower alkoxycarbonyl R
1
is, for example, methoxycarbonyl.
N-Lower alkyl-carbamoyl R
1
is, for example, N-methyl-carbamoyl.
Amino- or cyano-substituted lower alkyl R
1
is, for example, —(CH
2
)
x
—NH
2
or —(CH
2
)
x
—CN, respectively, wherein x is in each case from 1 to 4.
Unsubstituted or lower-alkyl-substituted monocyclic heterocyclyl having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur is preferably bonded via a ring carbon atom, for example pyridyl, such as 2-, 3- or 4-pyridyl, lower alkyl-pyridyl, such as 2-methyl-pyrid-6-yl, lower alkyl-pyridinium-yl, such as N-methyl-pyridinium-4-yl, thienyl, such as 3-thienyl, thiazolyl, such as 2- or 5-thiazolyl, pyrrolyl, such as 2-pyrrolyl, N-lower alkyl-pyrrolyl, such as N-lower alkyl-pyrrol-2-yl, imidazolyl, such as 2- or 4-imidazolyl, furyl, such as 2- or 3-furyl, tetrazolyl, such as 5-tetrazolyl, or lower alkyl-tetrazolyl, such as 2-lower alkyl-tetrazol-5-yl.
Unsubstituted or lower-alkyl-substituted monocyclic heterocyclylcarbonylamino having 5 or 6 ring members and from 1 to 4 ring hetero atoms selected from nitrogen, oxygen and sulfur preferably contains one of the above-mentioned heterocyclyl radicals and is, for example, furoylamino, such as especially 2-furoylamino.
Amidino is a radical of the formula —C(═NH)—NH
2
.
Guanidino is a radical of the formula —NH—C(═NH)—NH
2
.
Ureido is a radical of the formula —NH—C(═O)—NH
2
.
N
3
-Lower alkyl-ureido is a radical of the formula —NH—C(═O)—NH-lower alkyl, preferably N
3
-ethyl-ureido.
N
3
,N
3
-Di-lower alkyl-ureido is a radical of the formula —NH—C(═O)—N(lower alkyl)
2
.
N
3
-Phenyl-ureido is a radical of the formula —NH—C(═O)—NH-phenyl.
N
3
,N
3
-Diphenyl-ureido is a radical of the formula —NH—C(═O)—N(phenyl)
2
.
Thioureido i

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