Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-31
2001-04-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S257000, C514S278000, C514S294000, C544S284000, C544S294000, C546S018000
Reexamination Certificate
active
06211189
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds which are aminospiropiperidine quinazoline 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).
WO 97/14686 discloses, amongst other compounds, aminospiropiperidine quinazoline derivatives of the following formula:
wherein R
3
represents various substituents, for use as pharmaceuticals. The treatment or prophylaxis of inflammatory conditions is disclosed as a particular pharmaceutical use.
DISCLOSURE OF THE INVENTION
According to the present invention, there is provided a compound of formula (I)
wherein:
R
1
and R
2
independently represent hydrogen, C1 to 6 alkyl, C2 to 6 alkenyl, C2 to 6 alkynyl, C1 to 6 alkoxy, C1 to 6 alkylthio, halogen, hydroxy, trifluoromethyl or amino;
R
3
represents one or more substituents independently selected from hydrogen, C1 to 6 alkyl, C2 to 6 alkenyl, C2 to 6 alkynyl, C1 to 6 alkoxy, C1 to 6 alkylthio, halogen, hydroxy, trifluoromethyl, amino, cyano, nitro, trifluoromethoxy, methanesulphonyl, sulphamoyl, —NR
4
R
5
, —COOR
6
, —CONR
7
R
8
, benzyloxy, phenyl, or a 5-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 5-membered heterocyclic aromatic ring is optionally substituted, the optional substituents being C1 to 6 alkyl, halogen, cyano, nitro, hydroxy, C1 to 6 alkoxy, trifluoromethyl and trifluoromethoxy;
R
4
, R
5
and R
6
independently represent hydrogen or C1 to 6 alkyl;
R
7
and R
8
independently represent hydrogen, C1 to 6 alkyl or phenyl, which phenyl is optionally substituted by one or more groups independently selected from C1 to 6 alkyl, halogen, cyano, nitro, hydroxy, C1 to 6 alkoxy, trifluoromethyl and trifluoromethoxy;
X represents —(CH
2
)
n
—, wherein n represents zero or 1; and
A represents an aromatic carbocyclic ring or a 5- or 6-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 pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.
The compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers, racemates and tautomers have the advantage that they are potent inhibitors of the inducible isoform of the enzyme nitric oxide synthase (iNOS) present in macrophages.
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 in formula (I) represents a benzo ring.
Preferably, R
1
in formula (I) represents hydrogen. Alternatively, it is preferred that R
1
in formula (I) represents fluoro.
Preferably, R
2
in formula (I) represents fluoro.
In another preferred embodiment, n in formula (I) has a value of zero.
Particular compounds of the invention include:
(R*R*)-4′-amino-5′-fluoro-1,3,4,10a-tetrahydrospiro[pyrido[2,1-a]isoindole-2,2′(1′H)quinazoline]-6-one;
(R*S*)-4′-amino-5′-fluoro-1,3,4,10a-tetrahydrospiro[pyrido[2,1-a]isoindole-2,2′(1′H)quinazoline]-6-one;
(R*R*)-4-amino-5-fluoro-3b′,4′,6′,7′-tetrahydrospiro[quinazoline-2,5′(2H,9′H)-thieno[3,2-a]indolizine]-9′-one;
(R*S*)-4-amino-5-fluoro-3b′,4′,6′,7′-tetrahydrospiro[quinazoline-2,5′(2H,9′H)-thieno[3,2-a]indolizine]-9′-one;
(R*R*)-4-amino-5-fluoro-6′,7′,9′,9a-tetydrospiro[quinazoae-2,8′(2H,4′H)-thieno[2,3-a]indolizine]-4′-one;
(R*S*)-4-amino-5-fluoro-6′,7′,9′,9a′-tetrahydrospiro[quinoline-2,8′(2H,4′H-thieno[2,3-a]indolizine]-4′-one;
(R*R*)-4′-amino-7-chloro-5′-fluoro-1,3,4,10b-tetrahydrospiro[pyrido[2,1-a]isoindole-2,2′(1′H)-quinazoline]-6-one;
(R*S*)-4′-amino-7-chloro-5′-fluoro-1,3,4,10b-tetrahydrospiro[pyrido[2,1-a]isoindole-2,2′(1′H)-quinazoline]-6-one;
(R*R*)-4′-amino-8-chloro-5′-fluoro-1,3,4,10b-tetrahydrospiro[pyrido[2,1-a]isoindole-2,2′(1′H)-quinazoline]-6-one;
(R*S*)-4′-amino-8-chloro-5′-fluoro-1,3,4,10b-tetrahydrospiro[pyrido[2,1
Hamley Peter
Pimm Austen
Tinker Alan
AstraZeneca UK Limited
Nixon & Vanderhye
Shah Mukund J.
Truong Tamthom N.
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