JPS6067421A - Antiulcer - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention This invention relates to orally administered agents having antiulcer, antispasmodic and local anesthetic effects.

(Prior Art) Many medicines are used to treat ulcer disease.
These drugs are mainly included in the group of so-called histamine-H2-receptor blockers, such as cimetidine and its derivatives, virentzebine, and also other derivatives included in the group of anxiolytics (3,=+payasi, etc.) Ar
zneim 5Forseha 31°679.198
1), included in the group of intestinal anti-inflammatory agents, such as carbenoxolone [F, Tarnok: Dru
gs Exp, C11n, Rea, 5 +157
．． 1979], and progelmid CS, E.

Miederer et al.: Drugs,
Exp.

Cl1n, Res, 5, 205.1979) 1, as well as paraneurolytic agents and cholinergic inhibitors, such as oxyphenonium bromide, glomonoselinium bromide,
Drotaperinium chloride, xopociminium bromide, or atropinium chloride P1 optionally additionally contains natural compounds, such as Glycyr
rhiza Glabra) or compounds of the polyisozolenoid type P (M, Murakami et al.: Arzne
im, Forsch, 31°799.1981). In addition, local anesthetic oxesacaine [J,
Seifert%: Proc, S
occult Exp, Biol, Med.

109.664.1962] is used as an antacid suspension or in admixture with Glo-In [F, Sve
c): Farmakodynamika 1tekov
I.

5loral< Academy of 5cieit
ce Eratislava.

1953).

The disadvantage of conventionally used compounds is that they have side effects, such as cimetidine and its derivatives, which damage the helmet mucosa [rJL Guslandi: I
nt, J, C11n, Pharmaceutical.

18, 140, 1980), has an unfavorable effect on motility, and has weak or no full 12 effect (V, -) 2sec (Jiraaek):F'
armakotherap.

zpravy no. 4, 43, 1980 J.

(Structure of the Invention) The above-mentioned drawbacks of the present invention are based on the following formula: It is removed by an orally administered agent having anti-inflammatory, antispasmodic and local anesthetic effects, which contains an eA acid or a salt with an organic acid as an active ingredient together with a physiologically harmless carrier and/or an antacid component. Ru.

(Specific description of the composition) The active ingredient of the medicament of this invention, namely trans-2-(1-pyrrolidinylcis and hexyl ester of 3-n-pentyloxycarbanylic acid, or its hydrochloride) has a local anesthetic effect. It is a known compound produced in connection with the investigation of carbanyl derivatives (Czechoslovak Patent Nos. 125,666 and 1126,102). Having both general membrane-stabilizing, local anesthetic and antispasmodic effects and maintaining full efficacy at low PM are important and proven prerequisites for anti-ulcer efficacy.

The medicament of this invention exhibits higher anti-ulcer effect than conventional medicaments under experimental conditions caused by acute fatigue,
- It has a remarkable protective effect even after multiple administrations. This medicine has already known local anesthetic and sedative effects (p, specs, etc.: Farm, obzor
45, 355, 1976).

Nature, occurrence, development and connection of local anesthetic effects in low pH media 1. Strength, after-effects and storage, activity on the acidic side (S, Stole, etc.: Brat, Le
k.

Li5ty 70, 297.1978), low acute toxicity immediately after oral administration, low side effects, and toxicity measured after one month of administration fully meet the conditions for the treatment of helmet ulcers.

The active ingredients of the medicament of this invention, namely trans-2-(1-pyrrolidinyl)cyclohexyl ester of 3-n-pentyloxycarbanylic acid i, o mgAg and 1
0.0g was administered to Wistar rats, and 30 minutes later, acute fatigue due to swimming began, and this fatigue was given three times for 30 minutes each at 90-minute intervals. It showed a significant protective effect on the size and ulcer incidence index after gastric disease. When administered once to rats at doses of 10 ng and 10 ng of the active ingredient of the present invention under the above conditions, the incidence of ulcers was reduced by 27% and 33%, respectively, compared to control animals. , 2ri7
5 kg and 10 10 second doses reduced the number of animals with ulcers by 30% and 37 cm, respectively. The average size of the lesions on the helmet after single or repeated administration of the active fraction of this invention was significantly smaller depending on the dose. Under the same experimental conditions, oxesacaine, used as a control, did not affect the size after gastropathy, but rather increased it.

The active compounds of the invention caused a supra-reduction in the ulcerogenic index in a comparative test with oxesacaine, atrobin and a control. Only a dose of 101 g was effective in repeated administration. In contrast, oxesacaine did not affect or increased the ulcerogenic index.

Active compounds of this invention, antacids, combinations of active compounds of this invention with aluminum phosphate and pectin: 1ilj acid agents (Glu I), active compounds of this invention and
What about commercially available agents containing aluminum hydroxide cells? Experiments under the same conditions show that the combination of the active compounds of the invention and Glu I most strongly inhibits ulcer formation; The size of the stomach disease decreased by 73% and 78%, respectively. ZmgAcg
Even after repeated administration of 5 doses of each drug and 5 doses of 1Q myylcg, the above combination was the most effective, reaching an inhibition of 80 degrees. As a control always rat body weight 176
5 ml of distilled water was administered per g. The effect of the combination was also most pronounced for C in the d111 constant of the ulceration index value.

In determining the acute toxicity of the active compounds of this invention, the following L
D5o values (Ir9/kg) were obtained.

Animal species Intravenous Subcutaneous-M intracavitary Oral H mouse 1
3 125 57.5 815 Wistarrat 12
4 289 72.5 1070 rabbits 29 150
4fi,5-guinea pig 732-0,11nfjAC9,1,Q hVJ/9 and 10
1lIN9 (7) Administration - 1 to ji Tewistar rats
In the toxicity sleep test when administered orally for several months,
No symptoms of zen effect were observed in either l or body weight. However, in the most urgent type 2 administration f1,
In some cases the weight gain was lower than the average daily weight gain. There was no significant difference in body N increase at the end of the experiment. In the analysis of all the organs tested, adrenal gland and kidney function increased only in a septic manner depending on the dose. Blood status did not show any signs of toxic effects; in fact, red blood cell counts and hemoglobin levels were better after the experiment than at the start of the Eiken test.

Biochemical parameters also show no signs of toxic effects. Histological test! In the bag, the findings of t'+ cannot be distinguished from the control group by 8. Vacuolar dystrophy and other types of dystrophy of a reversible nature that are expected to return to normal after removal of the induction wound occasionally occur.

Local stimulation trials with intradermal administration and intracutaneous administration of 5171 did not show any abnormal stimulation effects.

The medicaments of this invention are prepared by dissolving a suitable salt of the active compound in water or other pharmaceutically acceptable liquid and semi-liquid bases, or by dissolving the base of the active compound in a suitable bath agent, if desired, especially an ether. In particular, they can be prepared and, furthermore, customary auxiliary compounds can be chilled and formulated into solid pharmaceutical forms, such as tablets. In liquid medicines, the usual stabilizing additives are added, such as phosphate buffers, emulsifiers (Sorbimacrodal), suspension or emulsion stabilizers (e.g. cellulose esters, hydrated silica, bentonite, etc.) In case of solid pharmaceuticals, for example #
Powder, lactose, methylcellulose, gelatin, dextrin, stearinated magnesium, microcrystalline cellulose, etc. can be added.

From the expected daily dose, the amount of base in the medicine should be reduced by 1 to 5
0η range, destruction, decomposition, etc.? Not performed.

The starting active compounds of this invention are as described above in Czechoslovak patents Nos. 125,666 and 126.102.
It can be manufactured by the method of No.

The medicament of this invention can be administered to humans in the usual dosage forms, such as solid, semi-liquid or liquid, for ulcers of all symptoms, or even for nervous back pain, from 10 to 20,011 Q per day.
k. It can be administered in several doses if desired. Similarly, the agents of the invention can be used as veterinary medicine, for example for inhibiting neurological damage to the gastric mucosa in commercial animals.

The following examples are two specific examples of dosage forms of this invention.

However, the scope of the present invention is not limited to the scope of this example.

Example 1. 10 g of tablets with anti-ulcer effect contain 10.9 g of lactose, 138 g of lactose. F'
of starch and this is mixed with the desired amount of starch aqueous glue i.
Tighten the grip. This (VV obtained by granulating and homogenizing the kelp)
Add C2y magnesium stearate, and the diameter is about 5r.
Am 11 (compressed into 1 total approximately 2501n90 tablets).

One tablet corresponds to 10 ttq of active compound.

Similarly, 5 #1] active ingredient? It is also possible to produce tablets with

Example 2. Active compound of anti-crush injection suspension 501119 sound 20rn! , dissolved in distilled or deionized water, and this? , 14.55. li
of aluminum hydroxide and 4.90.9 of magnesium hydroxide. This is how you made one? The suspension contains 1119 of the active compound in 5-1, 291 mg of water, 1 of aluminum chloride, and 92
111p(7) contains hydroxide magnesia ramula.

Patent Applicant Sueno ()/Power f') J Amia Viet Patent Attorney Kazuyuki Nishi Patent Attorney Baseboard Product Patent Attorney Akiyuki Yamaguchi Patent Attorney Masaya Nishiyama

Claims (1)

[Claims] 3-n-pentyloxycarbanylic acid notra7s-2-(1-e loricinyl)cyclohexyl ester, or its pharmaceutically acceptable salts with non-'43Am or organic acids, as an active ingredient, An orally administered agent having antiulcer action, antispasmodic action, and local anesthetic action, comprising a carrier and/or an antacid component that is naturally acceptable.