(19)                        European Patent Office

                                                                                                                                                    (11) Publication number: 0 166 287

                                                                                                                                                                                                           A1     

 

(12)                                                               EUROPEAN PATENT APPLICATION

 

(21) Application number:    85107104.3                                                                                                                                                             (51)Int.Cl.4 C07 D 401/12, C07 D 491/04

                                                                                                                                                                                         A 61 K 31/44      

(22) Filing date: June 6, 1985

 

(30)         Priority:  June 16, 1984 CH 2899/84

                June 16, 1984 CH 2901/84

 

 

 

 

 

 

(43)         Publication date

                of the application: January 2, 1988

                  Patent Gazette 86/1

 

 

 

 

 

(84)         Designated contracting states:

                AT BE CH DE ES FR GB FR IT LI LU NL SE

 

(71)         Applicant: Byk Gulden Lomberg Chemische Fabrik GmbH, Byk-Gulden-Strasse 2, D-7750 Konstanz (DE)

 

(72)         Inventor: Kohl, Bernhard, Dr., Heinrich-v.-Tettingen Strasse 35a, D-7750 Konstanz 19 (DE)

                Inventor: Sturm, Ernst, Dr., In de Reben 1, D-7750 Konstanz 19 (DE)

                Inventor: Klemm, Kurt, Prof, Dr., Im Weinberg 2, D-7753 Allensbach (DE)

                Inventor: Riedel, Richard, Dr., Salmannsweillergasse 36, D-7750 Konstanz (DE)

                Inventor: Figala, Volker, Dr., Am Hochfirst 2, D-7753 Allensbach 4 DE)

Inventor: Rainer, Georg, Dr., Josef-Anton-Feuchtmayer-Strasse 7, D-7750 Konstanz (DE)

                Inventor: Schaefer, Hartmann, Dr., Zum Purren 27, D-7750 Konstanz 16 (DE)

                Inventor: Senn-Bilfinger, Jörg, Dr., Säntisstrasse 7, D-7750 Konstanz (DE)

 

(54)         Dialkoxypyridines, Process for their Preparation, their Application and Medicinal Products thereof

 

(57)         Dialkoxypyridines of the general formula I

                                                                                             [see formula]

where R1 denotes a 1-3C-alkyl group, which is completely or predominantly substituted by fluorine, or a chlorodifluoromethyl; and

R1' denotes hydrogen, halogen, trifluoromethyl, a 1-3C-alkyl group or a 1-3C-alkoxy group, which may or not be completely or predominantly substituted by fluorine; or

R1 and R1', together and with the inclusion of the oxygen atom, to which R1 is bonded, denote a 1-2C-alkylene dioxy group, which may or not be completely or partially substituted by fluorine, or a chlorotrifluoroethylenedioxy group,

R3 denotes a 1-3C-alkoxy group,

one of the groups R2 and R4 denotes a 1-3C-alkoxy group and the other denotes a hydrogen atom or a 1-3C-alkyl group, and

n denotes the numbers 0 or 1,

 

and salts thereof are new compounds with interesting pharmacological properties.

 

                                                                                              ---------------

                                                                                            ACTORUM AG

 

287EP                                                                                                                                                                                       0166287

                                                                                                     -48-

                                                                                                                                                                                                        5853

                                                                                    Industrial Applicability

 

The dialkoxypyridines of the general formula I and their salts exhibit useful pharmacological properties that render them useful for industrial purposes. They significantly inhibit the secretion of gastric acid in warm blooded animals and, in addition, exhibit an excellent protective action on the stomach and intestines of warm blood animals. This protective action on the stomach and intestine is observed even upon administering doses that are below the doses inhibiting the secretion of acid. In addition, the inventive compounds are distinguished by the absence of significant side effects and by a wide therapeutic range.

 

In this context the concept "protection of the stomach and intestine" is defined as the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as gastric ulcer, duodenal ulcer, gastritis and stomach irritation caused by hyperacidity or medicinal products), which can be caused (for example, by certain anti-inflammatory agents and antirheumatic agents), chemicals (for example, ethanol), gastric acid or stress situations.

 

Another advantage of the inventive compounds is their comparatively high chemical stability.

 

Surprisingly the inventive compounds are clearly superior with regard to their excellent properties to the prior art compounds. On the basis of these properties, the dialkoxypyridines and their pharmacologically compatible salts are quite suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of diseases of the stomach and intestine and those diseases that result from an excess secretion of gastric acid.

0166287

287EP                                                                                                                                                                     5853

-49-

Therefore, another subject matter of the invention relates to the inventive compounds for application in the treatment and/or prophylaxis of the aforesaid diseases.

 

Similarly the invention relates to the application of the inventive compounds for manufacturing medicinal products that are used for the treatment and/or prophylaxis of the aforesaid diseases.

 

Another subject matter of the invention relates to medicinal products that contain one or more dialkoxypyridines of the general formula I and/or their pharmacologically compatible salts.

 

The medicinal products are prepared by methods that that are well-known by the person skilled in the art. As medicinal products, the pharmacologically active compounds (= active substances), according to the invention, are used either as such or preferably in combination with suitable pharmaceutical adjuvants or substrates in the form of tablets, coated tablets, capsules, suppositories, plaster (for example, TTS), emulsions, suspensions or solutions, where the content of the active substance ranges advantageously from 0.1 to 95%.

 

The adjuvants and/or substrates that are suitable for the desired formulations of the medicinal products are known to the specialist skilled in the art. Solvents, gelling agents, suppository bases, inactive substances for tablets and other active substance vehicles as well as antioxidants, dispersing agents, emulsifiers, antifoaming agents, flavor correctants, preservatives, solubilizing agents, colorants or, in particular, permeation promoters and complexing agents (for example, cyclodextrins) are used.

 

The active substances can be administered orally, parenterally or percutaneously.

 

In general, it has proven to be advantageous in human medicine to administer the active substance(s) - in the case of oral administration - in a daily dose ranging from approximately 0.01 to approximately 20, preferably from 0.05 to 5, in particular from 0.1 to 1.5 mg/kg of body weight, optionally in the form of several, preferably 1 to 4, individual doses to obtain the desired results.

0166287

287EP                                                                                                                                                                     5853

 

-50-

 

In the case of parenteral treatment, similar and/or (in particular in the case of intravenous administration of the active substance), usually smaller doses are effective. The requisite optimal dose and method of administrating the active substances can be easily determined by any person skilled in this particular art.

 

If the inventive compounds and/or salts are to be used for treatment of the aforementioned diseases, the pharmaceutical formulations may or may not contain one or more pharmacologically active constituents from other groups of medicinal products, like antacids, for example aluminum hydroxide and magnesium aluminate; tranquilizers, such a benzodiazepines, for example diazepam; spasmolytics, such as bietamiverine and camylofin; anticholinergics, such as oxyphencyclimine and phencarbamide; local anesthetics, such as tetracaine and procaine; and optionally also enzymes, vitamins or amino acids.

 

In this context, special emphasis in placed especially on the combination of the inventive compounds with other drugs, which inhibit acid secretion, such as H2 blockers (for example, cimetidine and ranitidine) and, furthermore, with so-called peripheral anticholinergics (for example, pirenzepine, telenzepine and zolenzepine) and with gastrin antagonists, with the goal of intensifying the main action in the additive or superadditive sense and/or eliminating or decreasing the side effects.