Thienopyrimidines

Details Thienopyrimidines Thienopyrimidines

2000-05-26

2002-07-16

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S267000, C544S250000, C544S278000

Reexamination Certificate

active

06420368

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 or Hal, where one of the radicals R
1
or R
2
is always ≠H,
R
1
and R
2
together are also alkylene having 3-5 C atoms,
R
3
, R
4
in each case independently of one another are H, A, OA or Hal,
R
3
and R
4
together are also alkylene having 3-5 C atoms, —C—CH
2
—CH
2
—, —C—CH
2
—C— or —O —CH
2
—CH
2
—O—,
X is R
5
or R
6
, which is monosubstituted by R
7
,
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, or is —C
6
H
4
—(CH
2
)
m
—,
R
6
is cycloalkylalkylene having 6-12 C atoms,
R
7
is COOH, COOA, CONH
2
, CONHA, CON(A)
2
or CN,
A is alkyl having 1 to 6 C atoms,
Hal is F, Cl, Br or I,
m is 1 or 2, and
n is 0, 1, 2 or 3,
and their physiologically acceptable salts.
Pyrimidine derivatives are disclosed, for example, in EP 201 188 or WO 93/06104.
The invention is 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 show a 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 ascertaining their IG
50
values (concentration of the inhibitor which is needed in order to achieve a 50% inhibition of the enzyme activity). To carry out the determinations, enzymes isolated by known methods can be used (e.g. W. J. Thompson et al., Biochem. 1971, 10, 311). To carry 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 effective as inhibitors of phenylephrine-induced contractions in cavernous body preparations of hares. This biological action can be demonstrated, for example, by 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 production 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, characterized in that
a) a compound of the formula II
in which
R
1
, R
2
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
3
, R
4
and n have the meanings indicated, 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 by converting a compound of the formula I into one of its salts.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, X, L and n 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
or R
6
radical which is monosubstituted by R
7
.
R
5
is a linear or branched alkylene radical having 1-10, preferably 1-8, C atoms, the alkylene radical preferably being, 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.
R
6
is cycloalkylalkylene having 6-12 C atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexyl-propylene or cyclohexylbutylene.
One of the radicals R
1
and R
2
is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R
1
and R
2
are also together preferably propylene, butylene or pentylene.
Hal is preferably F, Cl or Br, but also I.
The radicals R
3
and R
4
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, 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
7
is preferably, for example, COOH, COOCH
3
, COOC
2
H
5
, CONH
2
, CON(CH
3
)
2
, CONHCH
3
or CN.
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 relates in particular 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 Id, which correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which
in Ia
X is R
5
or R
6
, which is substituted by COOH or COOA;
in Ib
R
1
, R
2
in each case independently of one another are H, A or Hal, where at least one of the radicals R
1
and R
2
is always ≠H,
R
3
and R
4
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
or R
6
, which is substituted by COOH or COOA;
in Ic
R
1
, R
2
in each case independently of one another are H, A or Hal, where at least one of the radicals R
1
and R
2
is always ≠H,
R
3
, R
4
in each case independently of one another are H, A, OA or Hal,
R
3
and R
4
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
or R
6
, which is substituted by COOH or COOA,
n is 1 or 2,
in Id
R
1
, R
2
in each case independently of one another are H, A or Hal, where one of the radicals R
1
and R
2
is always ≠H,
R
1
and R
2
together are also alkylene having 3-5 C atoms,
R
3
, R
4
in each case independently of one another are H, A, OA or Hal,
R
3
and R
4
together are also —O—CH
2
—O—,
X is R
5
which is monosubstituted by R
7
,
R
5
is linear or branched alkylene having 1 to 10 C atoms, or —C
6
H
4
—CH
2
—,
R
7
is COOH or COOA,
A is alkyl having 1 to 6 C atoms,
Hal is F, Cl, Br or I,
m is 1 and
n is 1 or 2.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the liter

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