HU197214B - Process for producing pharmaceutical compositions containing 3-etoxycarbonyl-1,6-dimetil-4-oxo-6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidinium-methosulfate as active component for preventing and treating gastrointestinal damages - Google Patents

Abstract

Prevention and cure of gastrointestinal damage comprises administering adequate doses to patients of racemic or optically active: 3-ethoxy- carbonyl-1,6-di methyl-4-oxo-6,7,8,9-tetra hydro- 4-H-pyrido- (1,2,-e)-pyrimidiniku metho-sulphate.

Description

BACKGROUND OF THE INVENTION The present invention relates to a method for preventing and treating gastrointestinal lesions in humans and animals as racemic or optically active 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1 , 2-a] for the preparation of a pharmaceutical composition containing pyrimidinium methosulfate.

3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridole, 2-a] pyrimidinium methosulfate

the. ) Methylating 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine, or

b. ) By reduction of 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate, or

c. ) Converting 3-carboxy-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate to the corresponding ethyl ester, or

d. ) May be prepared by cyclization of 2-methyl-6-oxo-1- [3 '- (1'-roethylamino-2'-ethoxycarbonyl-3'-oxo) -propenyl] -piperidine in a known manner (Hungarian Patent Nos. 156,119 and 158,085). Arzneim. Forschung 1972, 22, 815-952).

As used herein, the term "known manner" encompasses procedures known from the prior art to the day of priority.

The active ingredient of the present invention is marketed as an analgesic under the name PROBON ⁸ , particularly for the treatment of chronic musculoskeletal and surgical pain. Like all analgesics, it has an anti-inflammatory effect.

Unexpectedly, we have found that ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidinium methosulfate 10-1200 mg / kg In the dosage range, the entire gastrointestinal tract provided protection and cure for damage caused by chemical or exogenous and endogenous agents, both in preventive and curative treatments.

The most commonly used anti-inflammatory agents are known to cause gastrointestinal damage (Table id) [Trends in Pharm. Sci., 5, 156 (1984)].

drug Frequency of ulcer formation in the stomach Frequency of other damage to the gastrointestinal system acetyl sza- licilsav +++ ++++ benoxaprofen + ++ fenoprofen +++ ++++ flufenamic ++ +++ ibuprofen ++ +++ indomethacin +++ ++++ ketoprofen ++ +++ naproxen + ++ phenylbutazone + ++++ piroxicam +++ ++++ sulindac + +++

+ means: damage occurs in 0.1-5.0% of cases

++ meaning: damage occurs at -10.0% the cases 5,0- +++ meaning: damage occurs in -15.0% the cases 10,0- ++++ meaning: damage the cases more than 20.0% live

acetylsalicylic acid: 2-Acetoxybenzoic acid

benoxaprofen: 2- (4-chlorophenyl) -a-methyl-5-benz oxazolecetsav fenoprofen: 2- (3-phenoxyphenyl) -propionic acid flufenamic: 2 - [(3- / trifluoromethyl / phenyl) amino amino] benzoic acid ibuprofen: 2- [4- (2-methyl profile) phenyl] -propi- acid indomethacin: 1- (4-Chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid ketoprofen: 2- (3- (benzoyl) -phenyl) -propionic acid naproxen: (+) -2- (6-methoxy-2-naphthyl) -propionic acid phenylbutazone: 3,4-dioxo-l, 2-diphenyl-4-butilpi- razolidin piroxicam: 4-Hydroxy-2-methyl-t-2-pyridinyl-2β-1,2-benzothiazine-3-carboxamide-1,1-dioxide sulindac: 1 - [(4- / Methylsulfinyl / phenyl) methylene] -1'-tin-η-3-acetic acid

In view of the above, it is surprising that PROBON®, as an anti-inflammatory agent, does not cause gastrointestinal damage but, on the contrary, has a cytoprotective effect.

The compounds used so far in therapy exert their effects only in the narrow area of the gastrointestinal system.

(Burger's Medical Chemistry, 4th Edition, Vol. 2, pp. 835-853; and Volume 3, pp. 361-406 and 507-534; John Wiley and Sons, 1979-1981).

Particularly noteworthy is the fact that PROBON® has anti-ulcer properties not only in the stomach but also in the rest of the intestinal tract. Cimetidine, which is widely used, only protects the stomach lining, not the intestine.

Indomethacin, which is mainly used for the treatment of inflammatory joint, muscular and soft-tissue disorders, is known to have a number of side effects such as central nervous system symptoms, gastrointestinal symptoms, allergic reactions, haematological symptoms, and the like. The usual dose is up to 150-200 mg daily. Further increases in volume do not increase the therapeutic effect, but side effects are increased.

To reduce or eliminate the adverse side effects of Indomethacin, the active substance Synergistic Anti-Inflammatory Drug with Probon and Indomethacin has been selected, especially for the treatment of patients with mild to moderate musculoskeletal disorders. (European Patent Specification No. 0091,179). * (Note: This product is not commercially available.) According to this publication, Probon has a favorable effect on the absorption and elimination properties of Indomethacin, thereby reducing the therapeutic dose of Indomethacin to such a low level that no adverse side effects of Indomethacin can occur. .

The decrease in side effects is thus attributable to the reduced amount of Indomethacin.

No. 0 091 179. The European patent specification makes no mention or suggestion of the cytoprotective effect of Probon.

The cytoprotective activity of the compound of the invention is demonstrated by the following pharmacological results. Cimetidine (1-cyano-2-methyl-3- [2 - ((5-methylimidazol-4-yl) methylthio) ethyl] guanidine hydrochloride) was used as reference substance in the experiments. In some cases, atropine was also included in the experiments. «

The efficacy of the compound against damage in male and female Sprague-Dawley CFY rats weighing 140-170 grams is shown in Table 1 in 0.5 ml of hydrochloric acid ethanol (containing 2 ml of concentrated hydrochloric acid per 100 ml). There were 10 to 10 animals per group. The animals were acclimatized to 21 + 1 ° C for 4 days prior to the experiments while being free to eat food and water. The animals were allowed to drink only water for 24 hours prior to the experiments.

The animals were given orally 0.5 ml of hydrochloric acid ethanol, and after two hours, the animals were decapitated, the stomach was opened and the severity of the lesions was determined as follows: 0: intact mucosa, 1:

ulcer or erosion less than 1 mm, ulcer size 2: 1-2 mm, ulcer 3: 3-4 mm, ulcer 4: 4-5 mm, ulcer greater than 5: 5 mm. The test substance was administered 40 minutes before oral administration, and 10 minutes before the alcohol administration after sub-cutaneous administration. The results are

Table 1 shows.

No. 1 spreadsheet

Effect of 3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate, cimetidine and atropine on gastrointestinal damage by hydrochloric acid in rats

Compound Dosage way Dose mmol / kg lesions severity number Control (methyl cellulose) 3.4 ± 0.6 4.4 0.9 + group 3-Ethoxycarbonyl-1,6-dimethyl-4- -oxo- 6,7,8,9- te trachi d ro- 4 ff-pir time- [L, 2-a] pyridinium methosulfate po 2.26x10-1 0.6 + 0.1 0.6 0.2 + cimetidine po 2.97X1O- ¹ 3.2 0.3 + 3.8 0.4 + sc 2.97 + 10- ¹ 3.7 0.4 + 5.0 0.6 + atropine po 3.46x10- ' 3.2 0.4 + 3.7 0.3 + sc ³ 3.46xl0- 3.0 0.5 + 3.6 0.4 +

If the above experimental setting was modified so that the experimental animals received 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] for 4 consecutive days. The dose of pyrimidinium methosulfate shown in Table 1 and 40 minutes after the last dose of 0.5 ml of ethanolic hydrochloric acid did not show any changes in the gastric mucosa of the brain (Table 2).

No. 2 spreadsheet

Effect of 3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4A-pyrido [1,2-a] pyrimidinium methosulfate on Gastrointestinal Damage to Hydrochloric Alcohol in Four-Day Pretreatment in Rats

Compound Dosage way Daily dose mmoles / kg body weight lesions severity number Control (methyl cellulose) 3.510.6 6.2U.1 3-ethoxycarbonyl-1,6-dimethyl-4- oxo-6,7,8,9-tetrahydro-pyrido-4Zf - [l, 2-a] pyrimidinium methosulfate po 5.52X10- ¹ 0:00 0:00

3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate has been shown to have cimetidine and atropine reference compounds as an external anti-inflammatory agent. Table 3 below.

In the experiments, groups of 10 Sprague-Dawley CFY rats of both sexes, each weighing 140-170 g, were dosed orally with 24 hours of fasting and the test compound was decapitated after 4 hours. Determination of gastrointestinal damage was performed according to Adami's method with 0: intact mucosa, 1: small number of punctate hemorrhages, 2: 1-5 small ulcer, 3: large number of small ulcer or 1-2 larger ulcer, 4: numerous larger ulcer indicates formation. (Arch. Int. Pharmacodin, 147, 113-145, 1964).

The data in the table show that while cimetidine and atropine did not affect all ulcers, 3-ethoxycarbonyl-1,6-dimethyl-435-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2- Pyrimidinium methosulfate was effective in preventing ulcer formation in all ulcer models.

No. 3 spreadsheet

Effect of 3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine methoBZulfate, Cimetidine and Atropine on Gastrointestinal Damage to Various Anti-Inflammatory Agents in Rats

Compound

Control (methylcellulose) 3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate

cimetidine

atropine

Adagoláe way Dose mmol / kg Severity of lesion Indomethacin Naproxen Zomepyrac 20 75 mg / tskg p.o. dosing 75 2.810.4 1.810.3 2.5 ± 0.4 po 5.52110 ^-1 0.2 + 0:04 0.310.07 0.H0.02 p.o. 0.99x10 ^-1 0.0 0.310.06 2.510.3 po 1.98110 ^-1 2.310.4 po 3.46x10-3 0.0 1.210.3 0.0 po ³ 6.92xl0- 1.310.3

3-Ethododecarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate has been found not only in the stomach but also in other areas of the gastrointestinal tract. and heals the damage. The effect on intestinal ulcer formation was investigated in a group of ten Sprague-Dawley CFY rats compared to cimetidine and atropine.

Indomethacin was used as the damaging agent as in the previous experiments.

Test compound (cimetidine, atropine and 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate) the animals received it for four consecutive days until the damaging agent (indomethacin) was administered once, on the second day. During the experiment, the animals were free to consume food and water. After the fourth day, the intestinal lesions after killing the animals and then opening the abdomen were determined by the Tsumori method (J. Pharm. D. 1980, 3, 659-660). Outside index 0 to 4 means 0: intact mucosa, 1: 1-3 minor ulcer or erosion, 2: 1-5 ulcer or erosion, 3:

more than 5 ulcers, or 1-3 perforated ¹ ulcer, 4: numerous perforated ulcers. In addition to determining mortality and length of the small intestine from the pyloric to the small intestine, weights of animals and frequency of ascites were also determined.

The control group I received neither protective nor harmful material. Control group U received only the harmful substance (indomethacin). Control A. group II, besides the harmful substance, cimetidine, while the control group IV.

group received atropine. Group V received 4-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrabidro-4H-pyrido [1,2-a] pyrimidinium methosulfate besides the damaging agent for four days. The results of the tests are shown in Figure 4.

which is found to occur only in the group treated with 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyridinium methosulfate. protective effect in all tested parameters.

Table 4

Effect of cimetidine, atropine and 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate on intestinal ulcer induced by indomethacin in rat

Dose Pusz- Ulcer Ulcer intestinal length Body weight Ascitus mg / needle- elöfordu- index cm become. (G) occurrence / kg MEMORANDUM Lasa decrease (-) examined by chromium release % frequent- their number increased frequent % dás (+) %

Control group I. (methylcellosolve 10 ml / kg bw) 0 0 0 118.8 + 17 (+) 9.1 ± 1.2 0 control II. group indomethacin, p.o. 15 30 100 3.4 0.4 + 80.7 + 12 (-) 18.112.5 80 control III. group indomethacin, p.o. 15 20 100 3.3510.4 76H0 (-) 16.512.3 90 - «- cimetidine, s.c. control ARC. group indomethacin, p.o. 4x25 15 15 70 2.H0.25 97 ± 13 (-) 18.012.6 100 + atropine Group V indomethacin, p.o. 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate, p.o. 4x1 15 4x50 10 40 1.0 + 0:15 110 + 18 (+) 2.0 ± 0.3 10

-510

Treatment of 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium metasulphate with standard pharmaceutical forms (capsules, tablets, dragees) such as suppositories, suppositories, injections, etc.), the active ingredient content of which may vary from 10 to 500 mg, depending on the presentation. The daily or divided dose may vary from 10 to 1200 mg depending on the condition, age and severity of the disease and the mode of administration.

In the case of oral administration, the daily dose may vary from 10 to 1200 mg, preferably from 100 to 800 mg.

3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyridinidine-methosulfate is also useful in veterinary therapy for the treatment and prevention of gastrointestinal lesions. The daily or divided dose may vary from 10 to 500 mg / kg depending on the animal species and the severity of the lesions. The administration may be carried out by incorporation into feed or in the form of capsules, tablets, dragees, suppositories or injections.

Further details of our process are set forth in the Examples, but are not limited to the Examples.

Examples

Example 1: 100 mg, 200 mg and 300 mg capsules:

1200 g of 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinium methosulfate 4 g of ariabel yellow 38.90 C.I. 77,492, 4 g of polyoxyethene-6000 (DAB, 7-GFR), 12 g of betaine hydrochloride (pH. Hg. VI), 12 g of titanium dioxide C.I. 77,891 (USP XX), 20 g aerosil 300 ((USP XX), 27.2 g methyl cellulose (USP XX), 32 g aerosil R-972 (USP XX), 83.6 g talc (USP XX), and 196 g Mixture of microcrystalline cellulose (NF XV, USP XX) was homogenized in the usual manner and the wet granulate prepared with 100 g of stearin (USP XX) using 200 ml of isopropanol and 65.2 g of Luviscol VA 64 (vinyl pyrrolidone-vinyl acetate copolymer) was hard filled into gelatin capsules with a suitable filling device.

Example 2: 100 mg, 200 mg and

300 mg dragee:

Instead of encapsulation, the granules prepared as described in Example 1 were compressed into tablets of the desired weight using a tablecloth extraction apparatus and then film-coated using a mixture of isopropanol-methylene chloride in a manner known per se.

Example 3: 100 mg, 200 mg and 300 mg tablets:

The granules prepared as described in Example 1 are compressed into tablets of the desired weight using a suitable tabletting machine.

Claims (2)

PATENT CLAIMS CLAIMS 1. A process comprising as an active ingredient 3-ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4 H -pyrido [1,2-a] pyrimidinium methosulfate. The preparation of a pharmaceutical composition which is prepared in a manner known per se 3-Ethoxycarbonyl-1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,1a] pyrimidinium methosulfate is mixed with fillers, diluents and other excipients commonly used in the pharmaceutical industry, and is gastrointestinal. It is used to prevent damage to the therapy and pharmaceutical compositions Ké ₄ 5 sift out. 2. The method of claim 1, wherein the active ingredient is formulated as a tablet, dragee, capsule, suppository or injection.