Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-12
2003-11-11
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252160, C514S261100, C514S275000, C544S237000, C544S254000, C544S262000, C544S322000, C544S323000
Reexamination Certificate
active
06645965
ABSTRACT:
The present invention relates to compounds and their compositions to be used in the hypertension therapy and prophylaxis. More specifically it relates to the use of said hypertensives for systemic and local use, in particular for the cardiovascular area. More specifically the present invention relates to new antihypertensive compounds having an improved performance.
The known compounds of the prior art used in the hypertension treatment generally have a limited efficacy. The hypertension treatment is usually carried out by administering to the patient the antihypertensives in association with other medicines active on the vascular system, such as for instance calcium-antagonists, diuretics, beta-blockers, ACE inhibitors. For example the antihypertensive antagonists of the angiotensin (ex. Losartan), the calcium antagonists (ex. dihydropyridines), diuretics (for example thiazidic derivatives, direct and undirect vasodilators (ex. Minoxidil, Zaprinast) are not able when used alone to assure the therapy success.
It is necessary moreover to point out that some antihypertensives cause side effects for the respiratory apparatus, such as bronchoconstriction, dyspnea. For instance the antihypertensive used in the angina pectoris and cardiac arrhythmias treatment, for instance Timolol and Propanolol, give said side effects.
Other antihypertensives induce vasodilatation through phosphodiesterases inhibition and show side effects for various apparatuses (gastrointestinal, cardiovascular, ocular, etc.) See for instance Sildenafil and Zaprinast.
The need was felt to have available compositions active in the hypertension pathology treatment for systemic and local use, in particular of the cardiovascular area, with improved therapeutic profile. In particular the need was felt, moreover, to have available antihypertensive medicines having a beta-blocking or antiphosphodiesterasic action with lower side effects.
The Applicant has unexpectedly and surprisingly found compounds and pharmaceutical compositions usable in the treatment of the hypertension pathologies for systemic and local use, particularly of the cardiovascular area, with improved therapeutic profile, and without the side effects of the known hypertensive medicines.
It is an object of the present invention nitrate salts of compounds having an antihypertensive activity, or pharmaceutical compositions thereof, for systemic and local use, particularly to be used for the cardiovascular area, said compounds being characterized in that they contain least a reactive group capable to be salified, said compounds being selected from the following classes:
Class (A1b):
R
A1
=—O with R
III
A1
free valence, so as to form in combination with the carbon atom in 5 position a ketone group, R
A1
together with R
I
A1
and the carbon atoms in 4 and 5 position of the heterocyclic ring in the compound of formula (A1b), with R
IV
A1
and R
III
A1
free valences, forms the aromatic ring having 6 carbon atoms containing a —COOH group:
R
I
A1
=H, Cl;
R
I
A1
with R
A1
, R
IV
A1
, R
III
A1
and the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b) forms the aromatic ring containing a COOH group (IXc), R
I
A1
with R
IV
A1
and with the carbon atom in 4 position of the heterocyclic ring of formula (A1b) forms the following saturated ring having five carbon atoms:
R
II
A1
=—(CH
2
)
3
—CH
3
, —O—CH
2
—CH
3
;
R
III
A1
=H, free valence,
R
III
A1
free valence with R
IV
A1
free valence forms a double bond between the carbon atoms in 4 and 5 position in the heterocyclic ring of formula (A1b),
R
III
A1
with R
IV
A1
, R
IV
A1
and the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b) forms the aromatic ring containing a —COOH group (IXc);
R
IV
A1
=free valence, R
IV
A1
along with R
I
A1
with the carbon atom in 4 position of the heterocyclic ring of formula (A1b) forms the saturated ring having five carbon atoms (IXd)
R
IV
A1
with R
III
A1
, R
I
A1
and the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b) forms the aromatic ring containing a —COOH group (IXc),
R
IV
A1
with R
III
A1
both free valences form a double bond between the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b);
known as Valsartan;
Class (A2):
the precursors of this class are the following ones: 1 (2H)-phthalazinone hydrazone (Hydralazine); 6-(1-piperidiny-1)-2,4-pyrimidinediamine 3-oxide (Minoxidil); 1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazol [4,3-d]pyrimidin-5-yl)-4-etoxyphenyl]sulphonyll-4-methyl-piperazine (Sildenafil), 2-(2-propyloxyphenyl)-8-azapurin-6-one (Zaprinast);
Class (A3):
R
I
B1
and R
II
B1
, equal to or different from each other, are H, CH
3
,
In the formula (XId) t=0, 1.
In the formula (XIe) YB
B1
can have the following meanings:
in the formula (XIf) Z=H, —OCH
3
;
in the formula (A3):
X
IB
1
=—O—, —S—;
n and m, equal to or different from each other, are 0, 1;
in the formula (XIp):
S
1
=H, CN, OCH
3
, CH
3
, —CH
2
—CH
3
, —O—CH
2
—CONH—CH
3
, —COCH
3
, —CO—(CH
2
)
2
—CH
3
, —O—CH
2
—CH═CH
2
, —CH
2
—CH═CH
2
, cyclopentyl, or
S
2
=H, CH
3
, Cl, —SOCH
3
, —CONH
2
;
S
1
with S
2
and the carbon atoms in 2 and 3 position of the C
6
aromatic ring of the same radical (XIp) forms the following ring:
wherein:
[
(*)
atom adjacent to the aromatic ring of the formula XIp
VII
]
B=—CH
2
—, —NH—, —CH═CH—,
(*)
—CO—CH
2
—;
A=—O—,
(*)
—CH
2
—CH(OH)—,
(*)
—O—CH
2
—,
(*)
—S—CH
2
—, —CH
2
—CH
2
—, —CH
2
—,
A is a tertiary carbon atom and contemporaneously W1 is free valence so as to form a double bond —CH═CH— between A and the carbon atom in 1′ position,
A in the ring having 5 atoms (XIp
VII
) is a tertiary carbon atom containing a substituent such that with the carbon atom in 1′ position and with one of the two W1 or W2 radicals, the other radical being free valence, forms an aromatic ring having 6 carbon atoms according to the following formula:
W1=H, free valence, when W1 is free valence and A is a tertiary carbon atom as above defined, a double bond between A and the carbon atom in 1′ position is formed,
W1 together with W2, the carbon atom in 1′ position and the substituent A forms an aromatic ring having 6 carbon atoms;
W2=free valence, H, OH, —CH
3
, —ONO
2
, —O which with W1=free valence and the carbon atom in 1′ position forms a ketone group,
W2 together with W1, the carbon atom in 1′ position and the substituent A forms an aromatic ring having 6 carbon atoms; S
3
=H, F, Cl, OH, NO
2
,—CH
2
—CO—NH
2
—(CH
2
)
2
—OCH
3
, —NH—COCH
3
, —CH
2
—O—CH
2
—CH
2
—O—CH(CH
3
)
2
, —CH
2
—CH
2
—COOCH
3
, —NH—CO—N(C
2
H
5
)
2
, —NH—CO—(CH
2
)
2
—CH
3
, —NH—SO
2
—CH
3
—NH—CO—NH—[cyclohexyl], —CH
2
—CH
2
—O—CH
2
—[cyclopropyl];
S
4
=H, Cl, —CH
2
—CH
2
— which with the carbon atoms in 1 and 6 position of the aromatic ring of the same radical (XIp) and with X
B1
in the formula (A3) equal to oxygen, being contemporaneously m n=1 and R
VII
B1
free valence, forms the following ring:
S
4
is a tertiary carbon atom which with the carbon atoms in 1 and 6 position of the aromatic ring of the radical (XIp), and with the following components of the formula (A3): the carbon atom —|C|
n
—(n=1), the radical X
B1
equal to oxygen (m=1), and R
VII
B1
with R
V1
B1
free valences, forms the following ring:
R
VI
B1
=H, free valence;
R
VII
B1
=H, free valence;
Other compounds belonging to this class are the following: 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl] benzamide (Labetalol), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl] piperazine (Terazosin), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl) piperazine (Prazosin);
Class (A4):
the following groups of compounds belong to this class:
(A4a):
&bgr;-[(2-methylpro
Arent Fox Kintner & Plotkin & Kahn, PLLC
Nicox S.A.
Raymond Richard L.
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