Pyrimidine nucleus-containing compound and a medicament...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C540S600000, C514S217060, C514S228200, C514S232500, C514S234800, C544S291000, C544S062000, C544S082000, C544S116000

Reexamination Certificate

active

06339089

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pyrimidine nucleus-containing compound such as a thienopyrimidine derivative or a quinazoline derivative which is useful for pharmacotherapeutically ameliorating arterial blood oxygen partial pressures (PaO
2
) in hypoxemic patients and those patients who are under oxygen inhalation treatment due to acute respiratory insufficiency.
BACKGROUND ART
While broncodilators, antiphlogistics, cardiac insufficiency treating agents, antitussives, etc. have been used currently as neosotropic agents for treating respiratory insufficiency diseases, there is no effective medicaments for patients suffering from hypoxemia such as chronic obstructive pulmonary disease (COPD).
DISCLOSURE OF THE INVENTION
Under such circumstances, medicaments for enhancing and ameliorating PaO
2
values caused to be lowered by respiratory diseases have been in demand. Further, these diseases are often accompanied by increase in the arterial blood CO
2
partial pressure (PaCO
2
) in addition to drop in PaO
2
, and in such cases medicaments having PaCO
2
lowering actions in addition to PaO
2
enhancing actions have been necessitated.
The present inventors made intensive studies in search of medicaments which ameliorate blood oxygen partial pressure in hypoxemia to find that a pyrimidine nucleus-containing compound such as a thienopyrimidine derivative or a quinazoline derivative to be described later is useful for prophylaxis and therapy of hypoxemia incidental to respiratory diseases.
The compound of the present invention has actions to enhance respiratory functions in the lungs and to increase PaO
2
by redistribution of bloodstream based mainly on hypoxemic pulmonary vasoconstriction (HPV) enhancing actions or to increase ventilation and respiration rate whereby to increase PaO
2
and also to reduce PaCO
2
.
The compound of the present invention relates to a pyrimidine nucleus-containing compound represented by the formula (I):
wherein ring A represents the ring of the formula (a):
in which R
1
is a nitro group, an amino group, a substituted amino group or a halogen atom, or the ring of the formula (b):
in which R
1′
is an alkyl group, an alkenyl group, a phenyl group, a nitro group, an amino group, a substituted amino group or a halogen atom;
R
2
and R
4
independently represent a hydrogen atom, an alkyl group or an alkenyl group; and
R
3
and R
5
independently represent an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, a cycloalkyl group, an adamantyl group, a pyridylmethyl group, a furylmethyl group, a thienylmethyl group, a cinnamyl group, an acyl group, an alkoxycarbonyl group, a substituted alkyl group, a substituted carbamoyl group or a substituted amino group; or
either R
2
and R
3
or R
4
and R
5
, together with the nitrogen atom to which they are attached, may form a 4 to 7-membered saturated heteromonocyclic ring which may be substituted;
with the proviso that at least one of R
2
to R
5
is an alkenyl group,
or acid addition salts thereof.
That is, the pyrimidine nucleus-containing compound of the present invention relates to a quinazoline derivative represented by the formula (II):
or acid addition salts thereof, or a thienopyrimidine derivative represented by the formula (III):
or acid addition salts thereof.
The alkyl group by which ring A (R
1′
) may be substituted may preferably be a C
1
-C
6
alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl and n-hexyl. In particular, R
1′
may preferably be methyl, ethyl or propyl substituting at the 7-position of the thienopyrimidine ring.
The alkenyl group by which ring A (R
1′
) may be substituted may preferably be a C
3
-C
6
alkenyl group, for example, allyl, cis-2-butenyl, trans-2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 4-pentenyl, cis-2-pentenyl, trans-2-pentenyl, cis-2-hexenyl, trans-2-hexenyl and 1,4-pentadien-3-yl.
The substituted amino group by which ring A (R
1
, R
1′
) may be substituted may preferably be a mono- or di-C
1
-C
3
alkylamino group, for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino or mono- or diallylamino.
The halogen atom by which ring A (R
1
, R
1′
) may be substituted includes a fluorine, chlorine, bromine or iodine atom.
The alkyl group regarding R
2
to R
5
may preferably be a C
1
-C
20
alkyl group, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl and n-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
The alkenyl group regarding R
2
to R
5
may preferably be C
3
-C
6
alkenyl group, for example, allyl, cis-2-butenyl, trans-2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 4-pentenyl, cis-2-pentenyl, trans-2-pentenyl, cis-2-hexenyl, trans-2-hexenyl and 1,4-pentadien-3-yl.
With respect to the substituent group regarding R
3
and R
5
, the alkynyl group includes, for example, 2-propynyl, 2-butynyl, 2-pentynyl, 2-heptynyl; the aralkyl group includes, for example, benzyl, phenetyl, 1-naphthylmethyl and 2-naphthylmethyl, preferably benzyl; the cycloalkyl group, which may preferably be a C
3
-C
6
cycloalkyl group, includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the adamantyl group includes, for example, 1-adamantyl, 2-adamantyl; the pyridylmethyl group includes, for example, 2-pyridylmethyl and 3-pyridylmethyl; the furylmethyl group includes, for example, furfuryl and 3-furylmethyl; the thienylmethyl group includes, for example, 2-thienyl and 3-thienylmethyl; the acyl group, which may preferably be a C
1
-C
6
aliphatic acyl group, includes, for example, formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl; the alkoxycarbonyl group, which may preferably be a C
1
-C
6
alkoxycarbonyl group, includes, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 2-methylpropyloxycarbonyl, t-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl; the substituted alkyl group includes, for example, alkoxy-, amino-, carbamoyl-, hydroxy- or halo-substituted alkyl, for example, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 3-methoxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,3-dihydroxypropyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-carbamoylethyl, 3-carbamoylpropyl, 2-(N-methylcarbamoyl)ethyl, 3-(N-ethylcarbamoyl)propyl, 2-(N-allylcarbamoyl)ethyl, 2-(piperazinocarbonyl)ethyl, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl; the substituted carbamoyl group, which may preferably be a C
1
-C
9
linear alkyl- or alkenyl-carbamoyl, a C
3
-C
8
cycloalkyl- or cycloalkenyl-carbamoyl, an arylcarbamoyl or a heteromonocyclic ring-containing carbamoyl group, includes, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, t-butylcarbamoyl, n-butylcarbamoyl, nonylcarbamoyl, cyclohexylcarbamoyl, allylcarbamoyl, 1-pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-thiomorpholinocarbonyl; and the substituted amino group, which may preferably be a mono- or di-C
1
-C
6
alkyl-amino group or a heteromonocyclic ring containing amino group, includes, for example, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, heptylamino, dimethylamino, diethylamino, dipropylamino, 1-pyrrolidino, piperidino, morpholino, 1-thiomorpholinyl. substituted amino group, which may preferably be a mono- or di-C
1
-C
6
alkyl-amino group or a heteromonocyclic ring-containing amino group, includes, for example, methylamino, ethylamino, propylamino, t-butylamino, pentylamino, heptylamino, dimethylamino, diethylamino, dipropylamino, 1-pyrrolidino, piperidino, morpholino, 1-thiomorpholinyl.
The 4 to 7-membered saturated heteromonocyclic ring formed by R
2
and R
3
or R
4
and R
5
together with the nitrogen atom to which they are attached includes, for example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidiny

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