Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-10
2004-07-27
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S263400, C514S263210, C514S263200, C514S263220, C514S263230, C544S061000, C544S118000, C544S277000
Reexamination Certificate
active
06767906
ABSTRACT:
The invention relates to 2-amino-6-anilino-purine derivatives and to processes and novel intermediates for their preparation, pharmaceutical formulations which comprise such derivatives, and the use of these derivatives as medicaments.
The invention relates to 2-amino-6-anilino-purine derivatives of the formula I
in which q is 1-5,
R
1
is
&agr;)—S(═O)
k
—NR
6
R
7
, in which
k is 1 or 2,
wherein under the proviso that R
6
and R
7
cannot be simultaneously hydrogen
&agr;1) R
6
, R
7
can be identical or different from one another and represent an aliphatic, carbocyclic, heterocyclic, carbocyclic-aliphatic or heterocyclic-aliphatic radical; hydrogen or lower aliphatic acyl; or
&agr;2) R
6
and R
7
together are a substituted or unsubstituted alkylene or alkenylene radical, in which 1-3 C atoms can be replaced by oxygen, sulfur or nitrogen;
&bgr;) N-(aryl lower alkyl)carbamoyl;
&ggr;) a radical of the formula —NH—S(═O)
i
—R
8
, in which
i is 1 or 2,
R
8
is an aliphatic, carbocyclic or heterocyclic radical; or
&dgr;) a radical of the formula —NH—C(═O)—R
9
, in which
R
9
is alkoxy, aryloxy, alkenyl, alkynyl, heterocyclyl alkynyl, aryl alkynyl, heteroaryl alkynyl, alkynyloxy or aryl alkynyloxy, which in each case is unsubstituted or substituted;
where, if more than one radical R
1
is present in the molecule, these can be identical or different from one another,
R
2
is hydrogen, carbamoyl or N-lower alkyl-carbamoyl,
R
3
is a lower aliphatic radical, which is unsubstituted or substituted by hydroxy, lower alkoxy, amino, lower alkylamino or N,N-di-lower alkylamino and
a) R
4
is hydrogen, amino, phenylamino, lower alkylamino, hydroxyl, phenoxy, lower alkoxy, acyl having 1-30 C atoms, a substituted aliphatic hydrocarbon radical having not more than 29 C atoms, a substituted carbocyclic or carbocyclic-aliphatic radical having not more than 29 C atoms or a heterocyclic or heterocyclic-aliphatic radical having not more than 20 C atoms and not more than 9 heteroatoms and
R
5
, independently of R
4
, is as defined above for R
4
, with the exception of hydrogen, or
b) R
4
and R
5
together are a substituted or unsubstituted alkylene or alkenylene radical having in each case not more than 15 C atoms, in which 1-3 C atoms can be replaced by oxygen, sulfur or nitrogen,
and their salts.
Unless stated otherwise, in the present disclosure organic radicals designated “lower” contain not more than 7, preferably not more than 4, carbon atoms.
q is preferably 1-3, as a rule 1 or 2, preferably 1. Only if it is possible for steric reasons, can q also be 4 or 5. If q is 1, R
1
is, for example, in the 3 position or, preferably, in the 4 position.
If R
1
represents —S(═O)
k
—NR
6
R
7
, k can be 1 or 2. Preferably k is 2.
Halogen is, for example, fluorine, chlorine, bromine or iodine. Preferably it is fluorine or chlorine.
An aliphatic radical R
6
or R
7
is an unsubstituted or substituted alkyl or in each case mono- or polyunsaturated alkenyl or alkynyl radical having in each case not more than 20 C atoms, i.e. an unsubstituted or substituted C
1
-C
20
alkyl, C
2
-C
20
alkenyl or C
2
-C
20
alkynyl radical. As a rule, these radicals, including their substituents, have not more than 16, in particular not more than 12, and especially not more than 8, C atoms. Preferably, the aliphatic radical is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, 3-methylbutyl, n-pentyl, 4-methyl-n-pentyl, n-hexyl, 5-methyl-n-hexyl, n-heptyl, 6-methyl-n-heptyl, n-octyl, 7-methyl-n-octyl, n-nonyl, 8-methyl-n-nonyl, n-decyl or 9-methyl-n-decyl. Most preferably, the aliphatic radical is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 3-methylbutyl, n-heptyl or n-octyl. The alkenyl radical is, for example, allyl, propenyl, isopropenyl, 2- or 3-methallyl and 2- or 3-butenyl. The alkynyl radical is, for example, propargyl or butynyl. In corresponding unsaturated radicals, the double bond is located, in particular, in a position higher than the &agr; position to the free valency.
Unsaturated radicals are those which contain one or more, in particular conjugated and/or isolated, multiple bonds (double bonds and/or triple bonds). The term cyclic radicals also encompasses aromatic radicals, for example those in which at least one 6-membered carbocyclic or one 5- to 8-membered heterocyclic ring contains the maximum number of non-cumulative double bonds. Carbocyclic radicals in which at least one ring is present as a 6-membered aromatic ring (i.e. benzene ring) are called aryl radicals.
The substituted aliphatic radical R
6
or R
7
can carry one or more identical or different radicals. Depending on the nature of the substituents, these can be attached via a single or multiple bond or linked in spiro form. Substituents are, for example, halogen, such as chlorine, fluorine, bromine or iodine, amino, lower alkylamino, di-lower alkylamino, &ohgr;-amino-lower alkylamino, lower alkanoylamino, aroylamino, such as, benzoylamino, hydroxylamino, hydroxylamino, lower alkoxy-amino, aryloxyamino, such as, phenyloxyamino, amino-cyclohexyl-amino-, amino-phenyl-amino-, carbamoyl-amino (ureido, —NH—C(═O)—NH
2
), (N-lower alkyl-carbamoyl)-amino (—NH—C(═O)—NH-lower alkyl), (N-[&ohgr;-amino-lower alkyl]-carbamoyl)-amino (—NH—C(═O)—NH-lower alkyl-NH
2
), (N-phenyl-carbamoyl)-amino (—NH—C(═O)—NH-phenyl), thio, lower alkylthio, such as methylthio, thiocarbamoyl (—C(═S)—NH
2
), thioureido (—NH—C(═S)—NH
2
), N-lower alkyl-thioureido (—NH—C(═S)—NH-lower alkyl), N-phenyl-thioureido (—NH—C(═S)—NH-phenyl), guanidino, N-lower alkyl-guanidino, carboxyl, lower alkoxycarbonyl, aryloxycarbonyl, such as, phenyloxycarbonyl, benzyloxycarbonyl, hydroxylaminocarbonyl, aminoacyl-amino, carbamoyl, amidino (—C[═NH]—NH
2
), cyano, hydroxy, lower alkoxy, aryloxy, such as, phenyloxy, aminocarbonyl-oxy (—O—C[═O]—NH
2
), oxo, aminosulfonyl and lower alkylsulfonyl-amino. One preferred substituent is hydroxy. Another preferred substituent is lower alkoxy.
A carbocyclic radical R
6
or R
7
is, in particular, a mono-, bi- or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radical, or a corresponding aryl radical. Preferred radicals are those having not more than 14, in particular 10, ring carbon atoms and 3- to 8-, preferably 3- to 7-, especially 3 and 6-membered rings, it also being possible for them to carry one or more, for example two, acyclic radicals, for example those mentioned above, and in particular the lower alkyl radicals, or further carbocyclic or heterocyclic radicals.
Cycloalkyl radicals contain, in particular, from 3 up to and including 10 C atoms, preferably from 3 up to and including 6 C atoms, and are independently from each other, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, as well as bicyclo[2.2.2]octyl, 2-bicyclo[2.2.1]heptyl and adamantyl, which can also be substituted by 1, 2 or more, for example, lower alkyl radicals, in particular methyl radicals. Preferably cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkenyl is, for example, one of the monocyclic cycloalkyl radicals already mentioned which carries a double bond in the 1, 2 or 3 position.
An aryl radical is, in particular, a phenyl, or furthermore a naphthyl, such as 1- or 2-naphthyl, a tetrahydronaphthyl, a biphenylyl, such as, in particular, 4-biphenylyl, and moreover also an anthryl, fluorenyl and azulenyl, as well as their aromatic analogues having one or more saturated rings. Aryl radicals which carry acyclic radicals, such as lower alkyl, are, in particular,
o
-,
m
- and
p
-tolyl und xylyl radicals with methyl radicals in various sites.
Unless stated otherwise, carbocyclic and heterocyclic radicals above and below can be substituted once or more than once, for example twice or three times, in particular by halogen, lower alkyl, lower alkoxy, aryloxy, lower alkoxycarbonyl, trifluoromethyl, hydroxy, nitro, imidazolyl, morpholiny
Brill Wolfgang Karl-Diether
Capraro Hans-Georg
Caravatti Giorgio
Furet Pascal
Imbach Patricia
Berch Mark L.
Dohmann George R.
McNally Lydia T.
Novartis AG
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