JPS5883626A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:A highly safe anti-inflammatory agent, containing 2-benzylaminopyrimidine or a pharmacologically acceptable salt thereof as an active constituent, having improved anti-inflammatory action, and exhibiting remarkable analgesic and antipyretic action with low toxicity. CONSTITUTION:An anti-inflammatory agent containing 2-benzylaminopyrimidine of the formula or a pharmacologically acceptable salt thereof, e.g. hydrochloride, hydrobromide or citrate, as an active constituent. The compound has improved anti-inflammatory action and exhibits remarkable analgesic and antipyretic action on pains and pyrexia due to the inflammation and low toxicity. The safety is much higher than aspirin, and flufenamic acid. The compound of the formula in about 5-80wt%, preferably about 40-60wt% concentration may be contained in the agent as the active constituent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel anti-inflammatory agent, and more particularly to an anti-inflammatory agent containing a pharmaceutically acceptable salt thereof represented by the following formula as an anti-inflammatory agent. Regarding drugs.

The snow-benziaminopyridine represented by the above formula (1') has been well known for a long time as a substance having antihistamine action. The present inventor conducted various studies on the pharmacological effects of 2-benzylaminopyridine ζdine of the above formula (1), and as a result,
Now, as an anti-inflammatory agent, 2-benzylaminotrimidine of formula (1) has a superior anti-inflammatory effect than the standard aspirin (especially the anti-inflammatory effect is large at the initial stage of administration),
Moreover, it was discovered that the toxicity was much lower than that of aspirin, and therefore it was a safer anti-inflammatory agent than aspirin, leading to the completion of the present invention.

The superiority of the anti-inflammatory agent according to the present invention 1F: The effect can be demonstrated by the following animal experiments.

〔Test method〕

(1) Suppressive effect on carrageenan edema (rat) After measuring the left hind paw of the rat by the constant volume syringe water replacement method, a 9 l-carrageenan solution (a 5 d/rat) was injected subcutaneously into the left paw, A constant volume t#I was determined over time. The test drug (29G gum arabic bath solution) was prepared for 30 minutes before injection of carrageenan.
Orally administered at 60% prior to carrageenin injection.
/ Rats were orally challenged with water gold. From the measured constant volume, the edema rate and drug inhibition rate at each measurement time were calculated according to the following formula VC. Also, Sol! of each drug! Litekfimd is calculated from the suppression rate at each measurement time to floating birch suppression ψ.
- Calculated by the Wilaosos method. The results are shown in Table 1 of the t-T period.

V attack: fixed volume before carrageen injection Fixed volume after Yt nicaragenin injection E#: Average edema rate of control group Et: average edema rate of drug administration group $9s-Unable to calculate confidence limits.

Actual rate Known anti-inflammatory agent 1% Measurement of pain J value by Ra*dalj-8alitte method (rats) The drug was orally administered to rats, and after a minute of SO, a l-carrageenan solution αlW/ Rats were injected with pain in both legs over time +@*tRavhd*1l
It was measured using a -8alitto pressurizing device (manufactured by Ugo Baaila). The analgesic coefficient was calculated using the following formula for either the inflamed foot or the non-inflamed foot. The results are shown in Table 2 below.

(Note) (b))! - Gum arabic solution (6) Ratio of inflamed feet to non-inflamed feet (6) Known analgesics (centrally acting) (3) Antipyretic effect on yeast fever (rat) Thermistor thermometer (Methl N5IF, newly manufactured by Natsume Seisakusho) )
After measuring +ii Al m k of rats using !
0-Beer yeast suspension 1al1 body weight 100 fl □ was subcutaneously injected, and 16 hours later, animals whose body temperature steadily increased (about 1° C. or more) were selected and the drug (gum arabic solution) was orally administered.

Rectal temperature was measured over time, and a graph showing the change in average rectal temperature for each administration group over time was created from the obtained test results.
The amount tl of each drug required to lower the rectal temperature by 2°C was calculated by the area method. The results are shown in Table 3 below.

@Table 3: #Antipyretic effect rate on maternal fever Known antipyretics (4) Mouse Vinegar 2 Stretching inhibitory drug was orally administered to mice, and 30 minutes later α6 thiacetic acid-physiological saline α1
Administered intraperitoneally at mI/body [10f'. The number of times each mouse developed stretching was measured for 10 to 20 minutes after administration of the acetic acid-physiological saline solution. The average number of stretching for each treatment group was compared with that of the control group.
'A test was carried out, and the stretching inhibition rate was calculated by Kiji Shimo. The results are below! It is shown in Table 4.

XI@0 Motoichi P〈α01 (6) Minimum lethal dose After completing various tests, animals were observed for 3 days to see if they died, and the minimum lethal t was determined. The results are shown in Table 5 below.

mouse: (Note) (b)) O8 corresponds to the administration port.

(-Safety factor: Minimum lethal dose (MLD) of each drug and me-
Suppression amount (10,.) or ratio (MLD/ID,...
) was sought. The results are shown in Table 6 of the manure.

As is clear from the data in Tables 1 to 6 showing the above test results, 2-benzylaminodessudine according to the present invention has excellent anti-inflammatory effects (Table 1), pain associated with inflammation and It also exhibits remarkable analgesic and antipyretic effects against fever (Tables 2 to 4), and is also less toxic (Table 5) compared to control standards (aspirin, flufenamic acid, aminopyrine, pentazocine). It has a much better safety factor
It has significant characteristics in that it is extremely suitable as an anti-inflammatory agent.

In accordance with the present invention - pendylaminopyridine or a pharmaceutically acceptable salt thereof can be administered orally or parenterally. For administration, the above active ingredients are combined with conventional liquid or solid pharmaceutically acceptable organic or inorganic diluents or carriers or excipients.
Appropriate dosage forms, such as solid forms such as tablets, coated tablets, capsules, semi-open tablets, granules, fine granules, or solutions;
It is possible to formulate liquid forms such as suspensions, emulsions, syrups, etc.

The following six examples can be given as diluents, carriers, or excipients suitable for such preparations.

Excipients: starch and modified starches, flower seeds, sandalwood,
Crystalline cellulose, - calcium hydrogen phosphate, etc.; Binder: carboxymethyl cellulose and other cells 0
Varnish derivatives, algine #salts, gelatin, polyvinylpyrrolidone, etc.; Lubricants such as magnesium nistearate, calcium stearate, talc, etc.; Disintegrants: agar, calcium carbonate, sodium hydrogen carbonate,
Calcium carboxymethyl cellulose, etc. e-powder: D-sorbitol, I resolpe) 8G.

Aluminum monostearate, etc.; Diluent (water, ethanol, monosilog, glucose solution, etc.)

is the active ingredient in such formulations! - Benzyl az-nobilimidine is most commonly used in its free base form,
Alternatively, it may be used in the form of a pharmaceutically acceptable salt. Examples of salts that can be used include inorganic acid salts such as hydrochloride, bromate, and sulfate, and acetate, phosphate, and citric acid. Examples include organic acid salts such as salts and fumarates.

The above formulations can be sterilized and/or e.g.
Preservatives (e.g. benzyl alcohol, methyl palaubenzoate, propyl benzoate, etc.), stabilizers (e.g. sodium bisulfite, ascorbic acid, citric acid, sodium bicarbonate, boric acid, etc.) , wetting agents (e.g. glycerin, etc.), emulsifiers (e.g. egg yolk lecithin, soybean lecithin, etc.), tonicity agents (e.g. sodium chloride, sodium citrate, glucose, mannitol, etc.), suspending agents (e.g. gum arabic) , numbering agent (
(cherry flavor, etc.), odorants, and other adjuvants.

Thus, the formulations of the present invention can generally contain the active ingredient at a concentration of about 5 to about 80%, preferably about 40 to about 60% by weight, depending on its dosage form. .

Administration th of the active ingredient according to the present invention, its administration method 1' (
4, but generally per adult person per day, for oral administration, from about α25 to about λat, preferably from about asf to about 1. It can be set to Off. However, the above administration ta
, is a tentative guideline, and the nature of the human or animal to be administered;
It is of course possible to administer doses exceeding the above lower or upper limit depending on the severity of the symptoms, administration interval, etc.

Incidentally, the benzylaminopyridine or its pharmaceutically acceptable salt used as an active ingredient in the present invention is a known compound as described above, and can be produced according to a known method. A specific example of the method is described below as a complete reference.

2-chloropyrindine 1 & ISfkm water ethanol 16
Dissolve 0 mal and add 1747 fl of benzilua to it 6
Heat to reflux for an hour. After cooling, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. ether@
is dehydrated with anhydrous sodium sulfate and the ether is distilled off under reduced pressure to obtain 2-benzylaminopyridine dine as a white crystal, which is reconsolidated from absolute ethanol (
Yield 801G).

One point: 81.1S-11! 'C Elemental analysis value: CoHllN.

Calculated value: c'rtat, HaOO*, 7V! 2491
G real? IIJ1[:CTa51%, ff5.9596,
N2'! , 63 IR (KB de, 3-' value): 3200
% l 590.1570%152G Reference N! : 710 t1 of l-benzylaminopyrimidine bromate-benzylaminopyrimidine was dissolved in absolute ethanol, 9.8ft of hydrogen bromide-acid was added thereto, and the mixture was stirred at room temperature for several minutes. The solvent was removed under reduced pressure, and the residue was recrystallized from an ether/ethanol mixture to obtain 2-benzylaminopyrimidine bromate as white needles (yield e
o %) as Melting point: 116-1.111℃ Elemental analysis 'Il: CoHoNm' HB calculation f
l: C4 64cm, H45456, Nl 579 actual measurement j
ii: C49, 92%, #4.8311, NIL57 1R (KBr, 1-1 value): 3!20.2750°16
4G, 15411,1826゜Example 1: Capsule formulation〉 Main drug: 2-benzylaminopyrimidine 121Sq, 2s0119 Excipient: Corn starch IV 1! jty, 11sq lubricant nystearin beak magnesium 3q, 1s19 total t(
(per 1 kaguseru)! 50q, 450q main nest 2
-Add excipients to benzylaminopyrimidine, make the powder into granules, add a lubricant and fill it into one hard cell.

Implementation IFN! : Tablet prescription> Main drug:! -Benzyla Z nopyrimidine 12! &η, 250'9 excipients:
Crystalline cellulose! 5q, 40qI: Corn starch 25q, ! 5ql = flower species
54ql, 54q Disintegrating agent: Lucium carboxymethylcellulose 13q, 20ql Binder: Hydroxyglopyl cellulose say, Lubricating agent: Magnesium sterophosphate 3q, 4K Total amount (per tablet) 2sOag, 400q Main drug An excipient, a disintegrant, and a binder are added to 2-benzylaminopyridine to form back-tilt granules that are evenly mixed, and then a lubricant is added to form a compressed tablet. Further, if necessary, an appropriate coating (eg, hydroxyglobil methylcellulose, shellac, etc.) can be added to the resulting tablets.

Example 3: Suspension formulation> (1 as base Dispersant: carboxymethylcellulose sodium 3q Preservative: sorbic acid 2q Stabilizer = 11!Hydrogen sulfate) 17 Um 1q Buffer dihydrogen diphosphate Sodium a5q buffer Sodium diphosphate-hydrogen α2q sweetener: Kozue Seishaku 1i
@ 00 q Flavoring agent: Cherry flavor
014 Diluent: Purified water 1d as whole tone
After dissolving and dispersing sweeteners, dispersants, buffers, preservatives, stabilizers, and flavoring agents in Kozue Seisui, the main drug is uniformly dispersed to form a suspension.

Claims (1)

[Scope of Claims] An anti-inflammatory agent characterized by containing an active ingredient of snow-pendylaonopyrimidine or a pharmaceutically acceptable salt thereof represented by the formula t-V.