Claims
- 1. Benzimidazoles corresponding to the formula (I) ##STR73## wherein the pyridazinone ring is attached in the 5- or 6-position of the benzimidazole ring and R.sup.1 stands for a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group, R.sup.2 stands for a hydrogen atom, a straight chained or branched C.sub.1 to C.sub.4 alkyl group, a C.sub.1 to C.sub.4 alkoxy group, a hydroxy group, a halogen atom, an amino group or a nitro group, m has the value 2 or 3 and n stands for an integer with a value from 1 to 6, and the pharmaceutically acceptable salts thereof.
- 2. A pharmaceutical preparation comprising a benzimidazole as claimed in claim 1, together with at least one inert, pharmaceutically acceptable carrier or diluent.
- 3. A benzimidazole according to claim 1, wherein said benzimidazole is N.sup.1 -[3-(imidazol-4-yl)propyl]-N.sup.2 -[3-[5-(4-methyl -6-oxo-1,4,5,6-tetrahydropyridazin-3yl)-1H-benzimidazol-2-yl] propyl]-guanidine or pharmaceutically acceptable salts thereof.
- 4. A benzimidazole according to claim 1, wherein said benzimidazole is 6-[2-(2-aminoethyl)-1H-benzimidazol-5-yl]-4,5-dihydro -5-methyl-3(2H)-pyridazinone or pharmaceutically acceptable salts thereof.
- 5. A benzimidazole according to claim 1, wherein said benzimidazole is N.sup.1 -[3-(imidazol-4-yl)propyl]-N.sup.2 -[2-[5-(4-methyl -6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1H-benzimidazol -2-yl]ethyl]-guanidine or pharmaceutically acceptable salts thereof.
- 6. A benzimidazole according to claim 1, wherein said benzimidazole is N.sup.1 -[3-(imidazol-4-yl)propyl]-N.sup.2 -[4-[5-(4-methyl -6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1H-benzimidazol -2yl]butyl]-guanidine or pharmaceutically acceptable salts thereof.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 3734083 |
Oct 1987 |
DEX |
|
DESCRIPTION
This is a division of application Ser. No. 168,273, filed Mar. 15, 1988, now U.S. Pat. No. 4,957,920.
The treatment of cardiac insufficiency by means of medicaments has for almost 200 years been based on the use of digitalis glycosides such as digoxin and digitoxin because these were the only substances available which had an inotropic increasing action and therefore provided the only possibility of treating the cause of cardiac failure, namely the insufficient contractibility of the heart.
The quest for digitalis substitutes initially led to the sympathomimetic drugs, but these have numerous serious disadvantages, such as undesirable chronotropic and arrhythmogenic side effects and lack of availability in a suitable form for oral administration. In the last ten years, numerous substances have been found in rapid succession which produce a positive inotropic effect, i.e. a contractibility enhancing effect by inhibiting the phosphodiesterases of the heart muscle cells, in particular phosphodiesterase type III (PDE III). Examples of these PDE inhibitors are amrinone (J. R. Benotti et al, N. Engl. J. Med. 299, 1373 (1978)), milrinone (A. A. Alousi et al, J. Cardiovasc. Pharmacol 5, 792 (1983)) and the benzimidazole derivative pimobendane (J. C. A. von Meel, Arzneim-Forsch. 35, 284 (1985)). These substances, however, also have undesirable side effects due to the mechanisms of their action, such as thrombocytopaenia or gastrointestinal disturbances.
It is therefore an object of the present invention to find new, effective, positive inotropic substances which do not act by the mechanism of phosphodiesterase inhibition.
The present invention solves this problem.
This invention relates to benzimidazoles corresponding to the general formula I ##STR4## in which the pyridazinone ring is attached in the 5- or 6-position of the benzimidazole ring and R.sup.1 denotes a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group; R.sup.2 denotes a hydrogen atom, a straight chained or branched C.sub.1 to C.sub.4 alkyl group, a C.sub.1 to C.sub.4 alkoxy group, a hydroxy group, a halogen atom, an amino group or a nitro group: A stands for a hydrogen atom or a group of the formula wherein R.sup.3 denotes a hydrogen atom or an optionally substituted C.sub.1 to C.sub.4 alkyl group or a C.sub.1 to C.sub.4 alkoxy group and B denotes a cyano group, a benzoyl group or a phenyl sulphonyl group, or A stands for a group of the formula ##STR5## in which m has the value 2 or 3; and n stands for an integer with a value from 1 to 6, and to the physiologically acceptable salts thereof.
In the general formula 1, R.sup.1 denotes a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group. Examples of such straight chained or branched C.sub.1 to C.sub.4 alkyl groups are the methyl, ethyl, n-propyl, isopropyl, n-butyl and sec-butyl group, the methyl group being preferred. R.sup.2 stands for a hydrogen atom, a straight chained or branched C.sub.1 to C.sub.4 alkyl group as defined above with reference to R.sup.1, a C.sub.1 to C.sub.4 alkoxy group, for example a methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy group, a hydroxy group, a halogen atom, for example a fluorine, chlorine or bromine atom, an amino group or a nitro group. When R.sup.2 stands for a halogen atom, it is preferably a chlorine atom. Compounds in which R.sup.2 is a hydrogen atom are particularly preferred.
A stands for a hydrogen atom or for a group of the formula ##STR6## wherein R.sup.3 denotes a hydrogen atom, an optionally substituted C.sub.1 to C.sub.4 alkyl group, for example a methyl, ethyl, n-propyl, isopropyl or n-butyl group, or a C.sub.1 to C.sub.4 alkoxy group. If the C.sub.1 to C.sub.4 alkyl group is substituted, it is preferably mono- or disubstituted with a halogen atom, e.g. a chlorine, bromine or iodine atom, or with a C.sub.1 to C.sub.4 alkoxy group, for example an ethoxy or methoxy group, and/or an aryl group, preferably a phenyl group, but an unsubstituted C.sub.1 to C.sub.4 alkyl group is particularly preferred, especially the methyl group.
The symbol A may also stand for a group of the formula ##STR7## in which R.sup.3 has the same meaning as defined above and B stands for a cyano group, a benzoyl group or a phenyl sulphonyl group, preferably a cyano group.
The symbol A may also stand for a group of the formula ##STR8## wherein R.sup.3 again has the meanings defined above.
Lastly, A may stand for a group of the formula ##STR9## wherein m has the value 2 or 3, preferably the value 3.
The symbol n in all cases stands for an integer with a value from 1 to 6, preferably 2, 3 or 4. Compounds in which n has the value 3 are particularly preferred.
One preferred group of compounds according to the invention is characterized in that R.sup.1 in the general formula I stands for a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group, in particular a methyl group, R.sup.2 and A each stand for a hydrogen atom and n stands for an integer with a value from 1 to 6, in particular the number 3.
Another preferred group of compounds according to the present invention is characterized in that in the general formula I, R.sup.1 stands for a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group, in particular a methyl group, R.sup.2 stands for a hydrogen atom, A stands for a group of the formula ##STR10## wherein R.sup.3 denotes a hydrogen atom, an optionally substituted C.sub.1 to C.sub.4 alkyl group or a C.sub.1 to C.sub.4 alkoxy group and n represents an integer with a value from 1 to 6, in particular 3.
Yet another preferred group of compounds according to the present invention is characterized in that in the general formula I, R.sup.1 stands for a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group, in particular a methyl group, R.sup.2 stands for a hydrogen atom, A denotes a group of the formula ##STR11## wherein R.sup.3 denotes a hydrogen atom or an optionally substituted C.sub.1 to C.sub.4 alkyl group and B denotes a cyano group, a benzoyl group or a phenyl sulphonyl group, and n represents an integer with a value from 1 to 6, in particular 3.
Another preferred group of compounds according to the present invention is characterized in that R.sup.1 stands for a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group, in particular a methyl group, R.sup.2 stands for a hydrogen atom, A denotes a group of the formula ##STR12## wherein R.sup.3 stands for a hydrogen atom or an optionally substituted C.sub.1 to C.sub.4 alkyl group, and n represents an integer with a value from 1 to 6, preferably 3.
Lastly, another preferred group of the compounds according to the present invention is characterized in that in the general formula I, R.sup.1 stands for a hydrogen atom or a straight chained or branched C.sub.1 to C.sub.4 alkyl group, in particular a methyl group, R.sup.2 denotes a hydrogen atom, A stands for a group of the formula ##STR13## in which m has the value 2 or 3, and n represents an integer with a value from 1 to 6, in particular 3.
The following are specific examples of preferred compounds: 6-2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone; N.sup.1 -[3-(imidazol-4-yl)propyl]-N.sup.2 -[3-[5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1H-benzimidazol -2-yl]propyl]-guanidine; 6-2-(2-aminoethyl)-1H-benzimidazol -5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone; N.sup.1 -[3-(imidazol-4-yl)propyl]-N.sup.2 -[2-[5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1H-benzimidazol-2-yl]ethyl]guanidine; 6-2-(4-aminobutyl)-1H-benzimidazol-5-yl]-4,5-dihydro -5-methyl-3(2H)-pyridazinone and N.sup.1 -[3-(imidazol-4-yl) propyl]-N.sup.2 -[4-5-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin -3-yl)-1H-benzimidazol-2-yl]butyl]-guanidine and their physiologically acceptable salts.
The compounds according to the invention are prepared by a process which is characterized in that
The compounds according to the invention corresponding to the general formula I may be prepared by several different process variations as follows:
1) compounds corresponding to the general formula I in which R.sup.1, R.sup.2 and n have the meanings indicated above and A stands for a hydrogen atom are obtained
The compounds obtained by the different process variations are isolated and purified in conventional manner, for example by recrystallization, chromatographic procedures etc.
The compounds obtained by the different process variations may optionally be converted into their physiologically acceptable salts. These salts may be obtained, for example, by a reaction with mineral acids such as hydrochloric, hydrobromic hydriodic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulfuric acid or with organic acids such as formic acid, acetic acid, propionic acid, phenyl acetic acid, tartaric acid, citric acid, fumaric acid, methane sulphonic acid, embonic acid, etc.
The compounds according to the invention corresponding to the general formula I may be present as a series of tautomeric forms or in several stereoisomeric forms. This invention therefore covers not only the salts and hydrates of the compounds of general formula 1 described above but also all tautomeric and stereoisomeric forms.
The compounds according to the invention may be formulated in any desired manner for administration. The invention therefore also covers pharmaceutical preparations containing at least one compound according to the invention for use in human of veterinary medicine. Such pharmaceutical preparations may be conventionally prepared with the aid of one or more pharmaceutically acceptable carriers or diluents.
The compounds according to the invention may therefore be formulated for oral, buccal, topical, parenteral or rectal administration.
For oral administration, the pharmaceutical preparation may be in the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by the conventional methods with the aid of acceptable diluents.
For buccal administration, the pharmaceutical preparation may be in the form of tablets or sachets formulated in the conventional manner.
The compounds according to the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be prepared in single dose form as ampoules or in multiple dose containers with added preservative.
The pharmaceutical preparations may assume forms such as suspensions, solutions or emulsions in oily or aqueous carriers and they may contain formulating auxiliaries such as stabilizers and/or suspending or dispersing agents.
Alternatively, the active ingredient may be present in powder form to be reconstituted with a suitable carrier such as sterile, pyrogen free water before use.
The compounds according to the invention may also be formulated as rectal preparations, for example suppositories or retention enemas, which may contain, for example, conventional suppository excipients such as cocoa butter or other glycerides.
For topical application, the compounds according to the invention may be formulated in the conventional manner as ointments, creams, gels, lotions, powders or sprays.
For oral administration, a suitable daily dose of compounds according to the invention may be divided into one to four doses with a total of from 5 mg to 1 g per day, depending on the condition of the patient. In some cases it may be necessary to deviate from the quantities mentioned above, depending on the individual response to the active ingredient or the nature of its formulation and the time or time interval of administration. In some cases, it may be sufficient to use less than the minimum quantity stated above while in other cases it may be necessary to exceed the upper limit.
The benzimidazoles according to the invention corresponding to the general formula 1 combine good oral availability with interesting pharmacological properties, especially cardiovascular effects, in particular positive inotropic and blood pressure lowering effects. They show an excellent cardiotonic activity in numerous pharmacological standard models, for example in vitro in the isolated, perfused Langendorff heart or in vivo on narcotized guinea pigs, where they produce a marked increase in contractibility.
a) Method
The arrangement of Langendorff was modified according to P. R. Beckett (J. Pharm. Pharmacol. 22, 818 (1970)) and R. M. Abel and R. L. Reis (Circ. Res. 27, 961 (1970)) to determine the haemodynamic effects of the compounds according to the invention on isolated, perfused guinea pig hearts. The spontaneously beating guinea pig hearts were catheterized in the left ventricle and perfused with solutions of the test substances in physiological saline solution/ethanol (9:1) at concentrations of 10.sup.-4 to 10.sup.-8 mol/1 at a constant perfusion pressure of 60 mm Hg.
b) Measured Values
a) Method
The animals were narcotized with urethane (1 5 g/kg). The trachea was cannulated for volume controlled respiration. The two carotid arteries were then exposed operatively. A Tip catheter (3F) was introduced through the right carotid artery and moved forwards through the ascending aorta into the left ventricle while the pressure was continuously recorded. Successful passage through the aortic valves is recognized by the typical left ventricular pressure curve. A thermistor probe (3F, F. Edwards) is pushed forwards into the aortic arch through the left carotid for thermodilution. The thermistor probe also has a lumen for the recording of arterial blood pressure. A catheter is passed through the right jugular vein to be placed in front of the right auricle for application of the cold injectate (0.2 ml of 0.9% NaCl, 15.degree. C). The ECG is recorded in the first shunt. All substances are dissolved in physiological saline solution and infused through the left jugular vein (infusion volume 0.02 ml/min). The drug is applied after haemodynamic stabilization and under .beta.-blockage (metoprolol 2 mg/kg i.m.). All circulatory parameters are continuously registered on a direct recorder. The pulse frequency is calculated from the ECC, the contractibility (dp/dt) is calculated from the volume curve and the volumetric cardiac output per unit time is calculated from the thermodilution curve.
b) Measured Values______________________________________ Maximum percentage changes compared with initial values Dose Contract- BloodExample (.mu.g/kg/ ility Pressure CardiacNumber min) dp/dt sys. Frequency______________________________________1 10 +38% -25% +20%6 10 +97% -15% +17%Pimo- 10 +10% -51% +3%bendane(Compari-son)______________________________________
The inhibitory action of the compounds according to the invention on phosphodiesterase was tested on phosphodiesterase type III obtained from ox heart (Sigma Chemie, BRD) by the methods of W. Diederen and H. Weisenberger (Arzneim.-Forschung 31, 177 (1981)) (Method A) and of M. A. Appleman and W. L. Terasaki (Advances in Cyclic Nucleotide Research, volume 5, Raven Press, New York (1975), page 153) (Method B). The table shows the percentage inhibition of PDE-III activity.______________________________________ Concentration (mol/l) 10.sup.-7 10.sup.-6 10.sup.-5 10.sup.-4______________________________________Example 1 Method A 0 0 7 10 Method B 0 0 0 4Pimobendane Method A 7 15 30 --(comparison) Method B -- 5 19 57______________________________________
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4923869 |
Poucher et al. |
May 1990 |
|
Divisions (1)
|
Number |
Date |
Country |
| Parent |
168273 |
Mar 1988 |
|
Patent Grant
5039675
