Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-03
2004-08-24
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...
C544S250000
Reexamination Certificate
active
06780867
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
and R
2
are each, independently of one another, H, A, OH, OA, NO
2
or Hal,
R
1
and R
2
together are alternatively alkylene having 3-5 carbon atoms, —O—CH
2
—CH
2
—, —CH
2
—O—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
X is mono-R
5
-substituted R
3
or R
4
,
R
3
is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH
2
groups may be replaced by —CH═CH— groups, O, NH or NA,
R
4
is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,
R
5
is O(CH
2
)
n
COOH, O(CH
2
)
n
COOA, O(CH
2
)
n
CONH
2
, O(CH
2
)
n
CONHA, O(CH
2
)
n
CONA
2
or O(CH
2
)
n
CN, S(O)
m
(CH
2
)
n
COOH, S(O)
m
(CH
2
)
n
COOA, S(O)
m
(CH
2
)
n
CONH
2
, S(O)
m
(CH
2
)
n
CONHA, S(O)
m
(CH
2
)
n
CONA
2
or S(O)
m
(CH
2
)
n
CN,
m is 0, 1 or 2,
n is 1 or 2,
A is alkyl having 1 to 6 carbon atoms, and
Hal is F, Cl, Br or I, and their physiologically acceptable salts and/or solvates.
Pyrimidine derivatives are disclosed, for example, in WO 99/55708, EP 934321, EP 201 188 or WO 93/06104.
The invention had the object of finding novel compounds having valuable properties, in particular those which can used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts and/or solvates have very valuable pharmacological properties and are well tolerated.
In particular, they exhibit specific inhibition of cGMP phosphodiesterase (PDE V).
Quinazolines having a cGMP phosphodiesterase-inhibiting activity are described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106(1994).
The biological activity of the compounds of the formula I can be determined by methods as described, for example, in WO 93/06104. The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by measuring their IC
50
values (concentration of the inhibitor needed to achieve 50% inhibition of the enzyme activity).
The determinations can be carried out using enzymes isolated by known methods (for example W. J. Thompson et al., Biochem. 1971, 10, 311). The experiment can be carried out using a modified batch method of W. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228).
The compounds are therefore suitable for the treatment of illnesses of the cardiovascular system, in particular cardiac insufficiency, and for the treatment and/or therapy of impotence (erectile dysfunction).
The compounds are furthermore suitable for the treatment of angina, high blood pressure, high pulmonary pressure, congestive heart failure, atherosclerosis, conditions involving reduced passage through heart vessels, peripheral vascular diseases, strokes, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders.
The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.
The compounds are effective as inhibitors of phenylephrine-induced contractions in corpus cavernosum preparations of rabbits. This biological action can be demonstrated, for example, by the method described by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993).
The inhibition of the contraction demonstrates the effectiveness of the compounds according to the invention for the therapy and/or treatment of impotence.
The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active ingredients.
The invention accordingly relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to Claim
1
and their salts,
characterised in that
a) a compound of the formula II
in which
X is as defined above,
and L is Cl, Br, OH, SCH
3
or a reactive esterified OH group, is reacted with a compound of the formula III
in which
R
1
and R
2
are as defined above,
or
b) a radical X in a compound of the formula I is converted into another radical X by, for example, hydrolysing an ester group to a COOH group or converting a COOH group into an amide or into a cyano group,
and/or in that a compound of the formula I is converted into one of its salts.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, X and L are as defined under the formulae I, II and III, unless expressly stated otherwise.
A is alkyl having 1-6 carbon atoms.
In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.
A is furthermore alkenyl having 2-6 carbon atoms, for example vinyl or propenyl.
A is furthermore a halogenated alkyl radical, such as, for example, trifluoromethyl.
X is a mono-R
5
-substituted R
3
or R
4
radical.
R
3
is a linear or branched alkylene radical having 1-10 carbon atoms, where the alkylene radical is preferably, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, hexylene, 1-, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methylpropylene, 1-ethyl-2-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene. R
3
is furthermore, for example, but-2-enylene or hex-3-enylene Very particular preference is given to methylene, ethylene, propylene or butylene.
R
4
is cycloalkylalkylene having 5-12 carbon atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. R
4
is alternatively cycloalkyl, preferably having 5-7 carbon atoms. Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
R
5
is preferably, for example, OCH
2
COOH, OCH
2
COOA, S(O)
m
CH
2
COOH or S(O)
m
CH
2
COOA.
Hal is preferably F, Cl or Br, but also I.
The radicals R
1
and R
2
may be identical or different and are preferably located in the 3- or 4-position of the phenyl ring. They are, for example, in each case independently of one another, H, OH, alkyl, F, Cl, Br or I or together are alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are preferably also in each case alkoxy, such as, for example, methoxy, ethoxy or propoxy.
The term solvates is taken to mean hydrates or, for example, alcoholates.
For the entire invention, all radicals which occur more than once may be identical or different, i.e. are independent of one another.
Accordingly, the invention relates in particular to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above, Some preferred groups of compounds may be expressed by the following sub-formulae la to lf, which conform to the formula I and in which the radicals not designated in greater detail are as defined under the formula I, but in which
in Ia X is R
3
which is substituted by O(CH
2
)
n
COOH, O(CH
2
)
n
COOA, O(CH
2
)
n
CONH
2
, O(CH
2
)
n
CONHA, O(CH
2
)
n
CONA
2
or O(CH
2
)
n
CN, S(O)
m
(CH
2
)
n
COOH, S(O)
m
(CH
2
)
n
COOA, S(O)
m
(CH
2
)
n
CONH
2
, S(O)
m
(CH
2
)
n
CONHA, S(O)
m
(CH
2
)
n
CONA
2
or S(O)
m
(CH
2
)
n
CN;
in Ib R
1
and R
2
are each, independently of one another, Hal, OH or OA,
X is R
3
which is substituted by O(CH
2
)
n
COOH, O(CH
2
)
n
COOA, S(O)
m
(CH
2
)
n
COOH or S(O)
m
(CH
2
)
n
COOA;
in Ic R
1
and R
2
are each, independently of one another, Hal, OH or OA,
X is R
3
which is substituted by O(CH
2
)
n
COOH, O(CH
2
)
n
COOA, S(O)
m
(CH
2
)
n
COOH or S(O)
m
(CH
2
)
n
COOA,
R
3
is methylene, ethylene or propylene;
in Id R
1
and R
2
are each, independently of one another, Hal, OH or OA,
R
1
and R
2
together are alkylene hav
Beier Norbert
Christadler Maria
Eggenweiler Hans-Michael
Jonas Rochus
Schelling Pierre
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
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