Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-19
2001-10-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S231000, C544S278000
Reexamination Certificate
active
06303613
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds which are aminopyrimidine derivatives. The invention also concerns related aspects including processes for the preparation of the compounds, compositions containing them and their use as pharmaceuticals. There are also provided chemical intermediates useful for the production of the compounds.
BACKGROUND OF THE INVENTION
Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes—constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep. Med. Chem., 1996, 31, 221-230).
DISCLOSURE OF THE INVENTION
According to the invention, there is provided a compound of formula (I):
wherein
R
1
represents hydrogen, alkyl C1 to 6, alkoxy C1 to 6, halogen or trifluoromethyl;
R
2
represents hydrogen or alkyl C1 to 6;
A represents a five membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S; or a six membered heterocyclic aromatic ring containing 1 to 3 nitrogen atoms;
(i) R
3
represents phenyl, a six membered heterocyclic aromatic ring containing 1 to 3 nitrogen atoms, or a five membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S, which phenyl or heterocyclic aromatic ring may be optionally substituted by alkyl C1 to 6, alkenyl C2 to 6, alkynyl C2 to 6, alkoxy C1 to 6, halogen, hydroxy, alkylthio C1 to 6, cyano, trifluoromethyl, nitro or a group —NR
5
R
6
;
and R
4
, R
5
and R
6
independently represent hydrogen or alkyl C1 to 6; or
(ii) R
3
represents alkyl C1 to 8, alkenyl C2 to 8 or alkynyl C2 to 8;
and R
4
represents hydrogen or alkyl C1 to 6; or
(iii) R
3
and R
4
together represent (CH
2
)
a
.Z.(CH
2
)
b
, Z representing N(COOR
7
), wherein R
7
represents alkyl C1 to 6 or haloalkyl C1 to 6, or R
7
represents a group (CH
2
)
n
YR
9
wherein n represents an integer from 2 to 5, Y represents O, S or a bond and R
9
represents alkyl C1 to 6 optionally substituted by halogen or nitro, or R
9
represents phenyl optionally substituted by alkyl C1 to 6, halogen or nitro; and
a and b independently represent an integer 1 to 3, provided that a+b is 3 or 4; or
(iv) R
3
and R
4
together represent (CH
2
)
a
.Z.(CH
2
)
b
, Z representing N(COR
8
), wherein R
8
represents phenyl, a six membered heterocyclic aromatic ring containing 1 to 3 nitrogen atoms or a five membered heterocyclic aromatic ring containing 1 to 3 heteroatoms which may be the same or different and are selected from O, N and S, which phenyl or heterocyclic aromatic ring may be optionally substituted by alkyl C1 to 6, alkoxy C1 to 6, halogen, nitro, cyano, trifluoromethyl, alkylsulphonyl C1 to 6 or aminosulphonyl; and
a and b independently represent an integer 1 to 3, provided that a+b is 3 or 4,
or pharmaceutically acceptable salts, enantiomers, racemates and tautomers thereof.
The invention further provides a process for the preparation of such compounds or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.
According to the invention there is also provided a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, for use as a medicament.
Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial.
A more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
According to the invention, there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.
More particularly, there is also provided a method of treating, or reducing the risk of, inflammatory disease in a person suffering from or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.
The compounds of the present invention may also be used advantageously in combination with a second pharmaceutically active substance, particularly in combination with a selective inhibitor of the inducible isoform of cyclooxygenase (COX-2). Thus, in a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in combination with a COX-2 inhibitor for the treatment of inflammation, inflammatory disease and inflammatory related disorders. And there is also provided a method of treating, or reducing the risk of, inflammation, inflammatory disease and inflammatory related disorders in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof in combination with a COX-2 inhibitor.
Preferably, A represents a thieno ring. Especially preferred embodiments are where the compound of formula (I) is a thieno[2,3-d]pyrimidine or a thieno[3,2-d]pyrimidine.
In another preferred embodiment, A represents a pyrido ring. Especially preferred embodiments are where the compound of formula (I) is a pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[3,4-d]pyrimidine or pyrido[4,3-d]pyrimidine. Pyrido[3,2-d]pyrimidine compounds of formula (I) are the most preferred.
Preferably, R
3
represents phenyl, cyclopropyl, ethyl, thiazolyl, ethynyl or furanyl.
In another preferred embodiment, wherein R
3
and R
4
are in accordance with option (iii) in formula (I), Z represents N(COOC
2
H
5
), and a and b each has a value of 2.
Especially preferred compounds of the invention include:
7-amino-4,5-dihydro-5-phenylthieno[3,2-d]pyrimidine;
5-cyclopropyl-4,5-dihydro-7-aminothieno[3,2-d]pyrimidine;
5-ethyl-4,5-dihydro-7-aminothieno[3,2-d]pyrimidine;
5-(2-thiazolyl)-4,5-dihydro-7-aminothieno[3,2-d]pyrimidine;
5-(2-furyl)-4,5-dihydro-7-aminothieno[3,2-d]pyrimidine;
7-amino-4,5-dihydro-5-ethynylthieno[3,2-d]pyrimidine;
ethyl 7′-aminospiro[piperidine-4,5′(4′H)-thieno[3,2-d]pyrimidine]-1-carboxylate;
ethyl 4′-amino-3′-chlorospiro[piperidine-4,6′(7′H)-thieno[2,3-d]pyrimidine]-1-carboxylate;
4′-amino-(4-cyanobenzoyl)-spiro[piperidine-4,2′-(1′H)-(pyrido[3,2-d]pyrimidine)];
4′-amino-(2-thienoyl)-spiro[piperidine-4,2′-(1′H)-(pyrido[3,2-
McInally Thomas
Tinker Alan
Astrazeneca AB
Balasubramanian Venkateraman
Nixon & Vanderhye
Raymond Richard L.
LandOfFree
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