Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-01
2004-02-17
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S328000
Reexamination Certificate
active
06693102
ABSTRACT:
The present invention relates to new chemical compounds which stimulate soluble guanylate cyclase, their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
One of the most important cellular transmission systems in mammals is cyclic guanosine monophosphate (cGMP). Together with nitrogen monoxide (NO) which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO/cGMP system. The guanylate cyclases catalyse the biosynthesis of cGMP from guanosine triphosphate (GTP). The representatives of this family known hitherto can be divided into two groups according to structural features and according to the nature of the ligands: the particulate guanylate cyclases, which can be stimulated by natriuretic peptides, and the soluble guanylate cyclases, which can be stimulated by NO. The soluble guanylate cyclases consist of two subunits and very highly probably contain one haem per heterodimer, which is a part of the regulatory centre. This has a central importance for the activation mechanism. NO can bind to the iron atom of the haem and thus markedly increase the activity of the enzyme. Haem-free preparations on the other hand, cannot be stimulated by NO. CO is also able to attack at the central iron atom of the haem, where the stimulation by CO is markedly lower than that by NO.
Owing to the formation of cGMP and the regulation of phosphodiesterases, iron channels and protein kinases resulting therefrom, guanylate cyclase plays a crucial role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission, and in diseases which are based on a disturbance of the abovementioned processes. Under pathophysiological conditions, the NO/cGMP system may be suppressed, which can lead, for example, to high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, cardiac insufficiency, thromboses, stroke and myocardial infarct.
An NO-independent possibility of treatment for diseases of this type, which is targeted at influencing the cGMP signal pathway in organisms, is a promising approach on account of the high efficiency and low side effects which are to be expected.
For therapeutic stimulation of the soluble guanylate cyclase, hitherto exclusively compounds such as organic nitrates have been used, whose action is based on NO. This is formed by bioconversion and activates the soluble guanylate cyclase by attacks on the central iron atom of the haem. Besides the side effects, the crucial disadvantages of this manner of treatment includes the development of tolerance.
In recent years, a few substances have been described which stimulate soluble guanylate cyclase directly, i.e. without prior release of NO, for example 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1, Wu et al., Blood 84 (1994), 4226; Mülsch et al., Br. J. Pharmacol. 120 (1997), 681), Fatty acids (Goldberg et al., J. Biol. Chem. 252 (1977), 1279), diphenyliodonium-hexafluorophosphate (Pettibone et al., Eur. J. Pharmacol. 116 (1985), 307), isoliquiritigenin (Yu et al., Brit. J. Pharmacol. 114 (1995), 1587) and various substituted pyrazole derivatives (WO 98/16223).
Furthermore, pyrazolopyridine derivatives have been described as stimulators of soluble guanylate cyclase in WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO 00/06569 and WO 00/21954. In these patent applications, pyrazolopyridines are also described which have a pyrimidine radical in the 3 position. Compounds of this type have a very high in vitro activity with respect to the stimulation of soluble guanylate cyclase. However, it has been seen that these compounds have some disadvantages with respect to their in vivo properties, for example their behaviour in the liver, their pharmacological behaviour, their dose-response relationship or their metabolization pathway.
It was therefore the object of the present invention to provide further pyrazolopyridine derivatives which act as stimulators of soluble guanylate cyclase, but which do not have the abovementioned disadvantages of the compounds from the prior art.
This object is achieved according to the present invention by the compounds according to claim 1. These new pyrazolopyridine derivatives are distinguished by a pyrimidine radical in the 3 position which has a certain substitution pattern, namely a pyridine radical in the 5 position of the pyrimidine ring and an amino group in the 4 position of the pyrimidine ring.
Specifically, the present invention relates to the compounds of the formula (I)
in which
R
1
represents 4-pyridinyl or 3-pyridinyl;
R
2
represents H, NH
2
or halogen;
and salts, isomers and hydrates thereof.
According to an alternative embodiment the present invention relates to the compounds of the formula (I), wherein
R
1
represents 4-pyridinyl or 3-pyridinyl;
R
2
represents H, NH
2
or Cl;
and salts, isomers and hydrates thereof.
According to a further alternative embodiment the present invention relates to the compounds of the formula (I), wherein
R
1
represents 4-pyridinyl or 3-pyridinyl;
R
2
represents H;
and salts, isomers and hydrates thereof.
The compounds of the formula (I) according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts, for example, are those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can likewise be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
The compounds according to the invention can be present in tautomeric forms. This is known to the person skilled in the art, and forms of this type are likewise included by the scope of the invention.
The compounds according to the invention can furthermore occur in the form of their possible hydrates.
Halogen in the context of the present invention represents fluorine, chlorine, bromine and iodine.
The compounds of the formula (I) according to the invention can be prepared by the reaction of the compound of the formula (II)
A) with a compound of the formula (III)
where
R
1
is as defined above;
if appropriate in an organic solvent, with heating to give the compound of the formula (I);
or
B) with a compound of the formula (IV)
where
R
1
is as defined above;
in an organic solvent under heating to compounds of the formula (V)
where
R
1
is as defined above;
subsequently with a halogenating agent to compounds of the formula (VI)
where
R
1
is as defined above;
R
2
represent halogen;
and finally with aqueous ammonia solution under heating and elevated pressure.
The compound of the formula (II) can be prepared according to the following reaction scheme:
The compound of the formula (II) is obtainable in a multi-stage synthesis from the sodium salts of ethyl cyanopyruvate, which is known from the literature (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934, 512, 97). By reaction thereof with 2-fluorobenzylhydrazine with heating and under a protective gas atmosphere in an ine
Alonso-Alija Cristina
Dembowsky Klaus
Feurer Achim
Flubacher Dietmar
Lang Dieter
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