Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-07-29
2004-08-17
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S262000
Reexamination Certificate
active
06777419
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
, R
2
in each case independently of one another are H, A, OH, OA or Hal,
R
1
and R
2
together are also alkylene having 3-5 C atoms, —O—CH
2
—CH
2
—, —CH
2
—O—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
R
3
, R
4
in each case independently of one another are H or A,
X is R
5
, R
6
or R
7
monosubstituted by R
8
,
R
5
is linear or branched alkylene having 1-10 C atoms, in which one or two CH
2
groups can be replaced by —CH═CH— groups, O, S or SO,
R
6
is cycloalkyl or cycloalkylalkylene having 5-12 C atoms,
R
7
is phenyl or phenylmethyl,
R
8
is COOH, COOA, CONH
2
, CONHA, CON(A)
2
or CN,
A is alkyl having 1 to 6 C atoms and
Hal is F, Cl, Br or I,
and their physiologically acceptable salts and solvates.
Pyrimidine derivatives are disclosed, for example, in EP 201 188 and WO 93/06104.
The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability.
In particular, they exhibit specific inhibition of cGMP phosphodiesterase (PDE V).
Quinazolines having 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 such as are described, for example, in WO 93/06104. The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by the determination of their IC
50
values (concentration of the inhibitor which is needed in order to achieve a 50% inhibition of the enzyme activity).
For carrying out the determinations, enzymes isolated according to known methods can be used (e.g. W. J. Thompson et al., Biochem. 1971, 10, 311). For carrying out the experiments, a modified batch method of W. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228) can be used.
The compounds are therefore suitable for the treatment of disorders of the cardiovascular system, in particular of cardiac insufficiency, and for the treatment and/or therapy of potency disorders (erectile dysfunction).
The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.
The compounds are efficacious as inhibitors of the phenylephrine-induced contractions in corpus cavernosum preparations from hares.
This biological action can be demonstrated, for example, according to the method which is described by F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993). The inhibition of the contraction shows the efficacy of the compounds according to the invention for the therapy and/or treatment of potency disorders.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further pharmaceutical active compounds.
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,
which is characterized in that
a) a compound of the formula II
in which
R
3
, R
4
and X have the meanings indicated,
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
have the meanings indicated, or
b) in a compound of the formula I, a radical X 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 a compound of the formula I is converted into one of its salts.
Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, X and L have the meanings indicated in the formulae I, II and III, if not expressly stated otherwise.
A is alkyl having 1-6 C atoms.
In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 C 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.
X is an R
5
, R
6
or R
7
radical monosubstituted by R
7
.
R
5
is a linear or branched alkylene radical having 1-10 C 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
5
is furthermore, for example, but-2-enylene or hex-3-enylene.
A CH
2
group in R
5
can preferably be replaced by oxygen. Ethylene, propylene, butylene or CH
2
—O—CH
2
is very particularly preferred.
R
6
is cycloalkylalkylene having 5-12 C atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene.
R
6
is also cycloalkyl preferably having 5-7 C atoms.
Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.
Hal is preferably F, Cl or Br, but also I.
The radicals R
1
and R
2
can be identical or different and are preferably in the 3 or 4 position of the phenyl ring. They are, for example, in each case independently of one another, H, alkyl, OH, F, Cl, Br or I or together alkylene, such as, for example, propylene, butylene or pentylene, furthermore ethylenoxy, methylenedioxy or ethylenedioxy. Preferably, they are also in each case alkoxy, such as, for example, methoxy, ethoxy or propoxy.
The radical R
8
is preferably, for example, COOH, COOA such as, for example, COOCH
3
or COOC
2
H
5
, CONH
2
, CON(CH
3
)
2
, CONHCH
3
or CN, but in particular COOH or COOA.
It applies to the entire invention that all radicals which occur a number of times can be identical or different, i.e. are independent of one another.
Accordingly, the invention in particular relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ia to If, which correspond to the formula I and in which the radicals not designated in greater detail have the meanings indicated in the formula I, but in which
in Ia X is R
5
substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN, or is phenyl or phenylmethyl;
in Ib R
1
and R
2
together are alkylene having 3-5 C atoms, —O—CH
2
—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
X is R
5
substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN, or is phenyl or phenylmethyl;
in Ic R
1
, R
2
in each case independently of one another are H, A, OH, OA or Hal,
R
1
and R
2
together are also alkylene having 3-5 C atoms, —O—CH
2
—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
X is R
5
substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN, or is phenyl or phenylmethyl;
in Id R
1
, R
2
in each case independently of one another are H, A, OH, OA or Hal,
R
1
and R
2
together are also alkylene having 3-5 C atoms, —O—CH
2
—CH
2
—, —O—CH
2
—O— or —O—CH
2
—CH
2
—O—,
X is alkylene having 2-5 C atoms, which is monosubstituted by R
8
, or cyclohexyl, phenyl or phenylmethyl,
R
3
is alkyl having 1-6 C atoms,
R
4
is alkyl having 1-6 C atoms,
R
8
is COOH or COOA,
A is alkyl having 1 to 6 C atoms,
Hal is F, Cl, Br or I;
in Ie R
1
, R
2
in each case independently of one another are H, A, OH, OA or Hal,
R
1
and R
2
together ar
Beier Norbert
Christadler Maria
Eggenweiler Hans-Michael
Jonas Rochus
Schelling Pierre
Berch Mark L.
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
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