Tricyclic nitrogen heterocycles as PDE IV inhibitors

Details Tricyclic nitrogen heterocycles as PDE IV inhibitors Tricyclic nitrogen heterocycles as PDE IV inhibitors

1999-12-10

2002-07-09

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S912000

Reexamination Certificate

active

06417190

ABSTRACT:

The invention relates to the use of tricyclic nitrogen heterocycles of general formula I
as pharmaceutical compositions with an inhibiting effect on PDE IV, wherein the groups R
1
, R
2
and R
3
may have the meanings given in the following part of the description and in the claims.
BACKGROUND OF THE INVENTION
Cyclic nucleotide-phosphodiesterases (PDEs) bring about degradation of the second messenger cAMP and cGMP to 5′-AMP and 5′-GMP. The second messenger cAMP and cGMP trigger the activation of protein kinases and hence the phosphorylation of proteins. By hydrolysing cAMP and cGMP to form the inactive nucleotides 5′-AMP and 5′-GMP, PDEs prevent the activation of the protein kinases. Phosphodiesterases are divided up into different classes of PDE isoenzymes, depending inter alia on their different substrate specificities, different kinetic properties, etc. The family of the PDE I isoenzymes is activated by means of the intracellular receptor protein for Ca
2+
ions kalmodulin (Ca
2+
/kalmodulin-stimulated PDE). PDE II isoenzymes are cGMP-stimulated phosphodiesterases with little affinity for cAMP and cGMP. The family of the PDE III isoenzymes (cGMP-inhibited) is characterised by a high affinity for cAMP and cGMP. Type IV phosphodiesterases (PDE IV) mean cAMP-specific PDEs which have a high affinity for cAMP but a low affinity for cGMP. PDE V isoenzymes are cGMP-specific while having a low affinity for CAMP.
PDE inhibitors influence the concentration of intracellular cAMP and cGMP. Of particular interest is the selective inhibition of type IV phosphodiesterase which leads to an increase in the concentration of intracellular cAMP.
Type IV phosphodiesterase (PDE) inhibitors are known from the prior art. One of the most prominent examples of the compounds which selectively inhibit the PDE IV isoenzyme is rolipram which has the following chemical structure.
PDE IV inhibitors cause vasodilatation (reduction in the tone of the smooth muscle), have a partial positive inotropic effect and also have anti-inflammatory properties. Accordingly, PDE IV inhibitors may have a therapeutic effect in the treatment and prophylaxis of diseases in which the above effects caused by increasing the cAMP concentration are expected and desirable.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found-that tricyclic heterocycles of general formula (I) wherein the groups R
1
, R
2
and R
3
are as hereinafter defined are selective inhibitors of type IV phosphodiesterase.
The invention consequently relates to the use of tricyclic nitrogen heterocycles of general formula I
as pharmaceutical compositions with a PDE IV inhibiting activity, wherein
R
1
denotes C
1
-C
5
-alkyl, C
5
-C
6
-cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms, selected from the group comprising oxygen and nitrogen;
R
2
denotes C
1
-C
5
-alkyl or C
2
-C
4
-alkenyl;
R
3
denotes C
1
-C
5
-alkyl, which may optionally be substituted by C
1
-C
4
-alkoxy,
C
5
-C
6
-cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms, selected from the group comprising oxygen and nitrogen,
C
5
-C
6
-cycloalkyl or phenyl or benzyl optionally substituted by C
1
-C
4
-alkoxy, optionally in the form of their racemates, enantiomers; in the form of their diastereomers and mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable addition salts thereof.
It is preferable to use the compounds of general formula (I) as described above, wherein
R
1
may denote C
1-4
-alkyl, C
5-6
-cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl or phenyl;
R2 may denote C
1-4
-alkyl or C
2-4
alkenyl;
R3 may denote C
1-4
-alkyl which may optionally be substituted by C
1-4
-alkoxy, C
5-6
-cycloalkyl, phenoxy, (C
1-4
-alkoxy)phenyloxy, piperazine or pyrrole, or R3 may denote C
5-6
-cycloalkyl, or phenyl or benzyl optionally substituted by C
1-4
-alkoxy,
optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable acid addition salts thereof.
It is also preferable to use compounds of general formula (I) as described above, wherein
R
1
denotes ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, N-morpholinyl or phenyl;
R
2
denotes ethyl, propyl, allyl or butenyl;
R
3
denotes ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or N-pyrrolylmethyl,
optionally in the form of their racemates, enantiomers, in the form of their diastereomers and mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable addition salts thereof.
It is particularly preferred to use compounds of general formula (I) as described above, wherein
R
1
denotes ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;
R
2
denotes ethyl or n-propyl;
R
3
denotes ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl,
optionally in the form of their racemates, enantiomers, in the form of their diastereomers and mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable addition salts thereof.
If desired, the compounds of general formula (I) may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid. Suitable acids for this purpose include, for example, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. It is also possible to use mixtures of the abovementioned acids.
Suitable alkyl groups (including those which are part of other groups) are branched and unbranched alkyl groups with 1 to 5 carbon atoms, such as: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. butyl, tert.-butyl, n-pentyl, iso-pentyl or neo-pentyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may be used for the abovementioned groups.
Examples of cycloalkyl groups with 5 or 6 carbon atoms include cyclopentyl or cyclohexyl. Examples of 5- or 6-membered, saturated or unsaturated heterocyclic rings which may contain one or two heteroatoms selected from the group comprising oxygen and nitrogen, include: furan, tetrahydrofuran, tetrahydrofuranone, &ggr;-butyrolactone, &agr;-pyran, &ggr;-pyran, dioxolane, tetrahydropyran, dioxane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine, pyrazolidine.
The compounds of general formula (I) may be prepared analogously to the method described in the prior art for some examples of the compounds of general formula (I) described hereinbefore (Tenor et al.,
Chem. Ber
. Vol. 97 (1964) S. 1373-1382), the contents of which are hereby referred to.
The present invention is directed not only to the application mentioned at the beginning but also to the use of the above compounds of general formula (I) for preparing pharmaceutical compositions for the treatment or prevention of diseases in which the selective inhibition of the PDE IV enzyme is indicated.
The present invention also relates to the use of compounds of general formula (I) for the treatment or prevention of diseases in which a therapeutically desirable effect can be achieved by increasing the concentration of intracellular cAMP. Accordingly, the present invention is directed to the use of compounds of general formula (I) according to the above definitions for increasing the concentration of intracellular cAMP. The use of the compounds o

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