Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-10
2004-09-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S267000
Reexamination Certificate
active
06787548
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,
X is R
4
, R
5
or R
6
, which is monosubstituted by R
7
,
R
4
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,
R
5
is cycloalkyl or cycloalkyl alkylene having 5-12 C atoms,
R
6
is phenyl or phenylmethyl,
R
7
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, B3r or I,
where at least one of the radicals R
1
or R
2
is OH,
and their physiologically acceptable salts.
Pyrimidine derivatives have been 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 exhibit 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 the ascertainment 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 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 the phenylephrine-induced contractions in corpus cavernosum preparations of 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. In addition, they can 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,
characterized in that
a) a compound of the formula II
in which
X has the meaning 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 hydrolysing an ester group to a COOH group or converting a COOH group into an amide or into a cyano group
or
c) in a compound of the formula I, a radical R
1
and/or R
2
is converted into another radical R
1
and/or R
2
by converting an alkoxy group into a hydroxyl group,
and/or 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
, R
6
, R
7
, 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
4
, R
5
or R
6
radical which is monosubstituted by R
7
.
R
4
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
4
is furthermore, for example, but-2-enylene or hex-3-enylene. Ethylene, propylene or butylene is very particularly preferred.
R
5
is cycloalkylalkylene having 5-12 C atoms, preferably, for example, cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexyl-propylene or cyclohexylbutylene. R
5
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, alkoxy, hydroxyl, F, Cl, Br or I. Preferably, they are independently of one another Hal and hydroxyl. At least one of the radicals R
1
and R
2
is hydroxyl.
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 whole 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
4
, phenyl or phenylmethyl, which is substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN;
in Ib
R
1
, R
2
in each case independently of one another are H, A, OH, OA or Hal,
X is R
4
, phenyl or phenylmethyl, which is substituted by COOH, COOA, CONH
2
, CONA
2
, CONHA or CN;
where at least one of the radicals R
1
and R
2
is OH;
in Ic
R
1
, R
2
in each case independently of one another are H, A, OA or Hal,
X is alkylene having 2-5 C atoms, cyclohexyl, phenyl or phenylmethyl, which is monosubstituted by R
7
,
R
7
is COOH or COOA,
A is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I,
where at least one of the radicals R
1
and R
2
is OH;
in Id
R
1
is Hal,
R
2
is OH,
X is alkylene having 2-5 C atoms, cyclohexyl, phenyl or phenylmethyl, which is monosubstituted by R
7
,
R
7
is COOH or COOA,
A is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I,
and their physiologically acceptable salts.
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 literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
In the compounds of the formula II or III, R
1
, R
2
, R
3
, R
4
, X and n have the meanings indicated, in particular the preferred meanings indicated.
If L is a reactive esterified OH group, this is preferably alkylsulfonylo
Christadler Maria
Jonas Rochus
Kluxen Franz-Werner
Schelling Pierre
Merck Patent Gesellschaft mit beschränkter Haftung
Millen White Zelano & Branigan P.C.
Raymond Richard L.
LandOfFree
Thienopyrimidines as phosphodiesterase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Thienopyrimidines as phosphodiesterase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thienopyrimidines as phosphodiesterase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3218613