JPS58148819A - Anti-inflammatory, antipyretic and analgesic agent containing theobromine derivative as active constituent - Google Patents

Abstract

PURPOSE:An anti-inflammatory, antipyretic and analgesic agent containing a specific theobromine derivative, e.g., 1- 3- 4-m,p-dichlorophenylpiperazinyl-(1) -n- propyl theobromine, and an acid addition salt thereof as active constituents. CONSTITUTION:An anti-inflammatory, antipyretic and analgesic agent containing a theobromine derivative expressed by formulaI R is H or lower alkyl; Z is formula IV or V (X1, X2, Y1 and y2 are H, lower alkyl, lower alkoxyl, CF3 or halogen); n is an integer 2-10 and an acid addition salt thereof as active constituents. The compound expressed by formulaIis administered in a dose of preferably about 3-100mg per day orally or parenterally, intramuscularly, subcutaneously or intravenously, etc. and used as the above-mentioned drug. The compound can be prepared by reacting a compound expressed by formula II (X is halogen or p-toluenesulfonyloxy) with a compound expressed by formula III.

Description

Detailed Description of the Invention The present invention provides an anti-inflammatory drug containing a theobromine derivative as an active ingredient.
Regarding antipyretics and analgesics. More specifically, the general formula [wherein R represents a hydrogen atom or a lower alkyl group].

a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a halogen atom, respectively), or a group represented by a hydrogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, respectively or a halogen atom).

n is an integer from 2 to 10] and its acid addition salt as active ingredients.
Regarding antipyretics and analgesics.

In the above general formula [■], u, Xr, X!
, Yt, and the lower alkoxy group seen in the definitions of Yt are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl and ethyl.

n-propyl, isopropyl, isobutyl, l-methylpropyl + tert-butyl, n-pentyl.

It means an alkyl group such as 1-ethylpropyl, isoamyl, n-hexyl group, or an alkoxy group based thereon. In addition, halogen atoms specifically include chlorine, bromine,
It means iodine and fluorine.

Furthermore, the compound CI) of the present invention can be easily converted into an acid addition salt by reacting with a pharmacologically acceptable inorganic or organic acid. Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and examples of organic acids include maleic acid, fumaric acid, succinic acid, acetic acid, malonic acid, citric acid, and benzoic acid. I can do it.

The present inventors have conducted intensive research on the usefulness of the theopromine derivative [I] as a medicine, and have discovered that it has unexpectedly excellent analgesic, antipyretic, and antiinflammatory effects, and has developed the present invention. It is completed.

That is, the theopromine derivative of the compound of the present invention has a structure that is significantly different from that of conventionally used antipyretic analgesics and antiinflammatory agents.

Therefore, the compounds of the present invention are useful as anti-inflammatory and antipyretic analgesics.

Compound (I) of the present invention can be produced by nine different methods, and one commonly used method is as follows.

[II) [11) and H
l[1] (In the formula, X means a halogen atom or a para-toluefsulfonyloxy group, and R, Z and n have the above-mentioned meanings.) That is, a compound represented by the general formula [formula].

The compound represented by the general formula [111) is reacted to obtain the compound [I] of the present invention.

This reaction can be carried out without any solvent or from lower alcohols such as methanol, ethanol, propatool, and impropatol, benzenes such as benzene, toluene, and xylene, and ethers such as ethyl ether and tetrahydrofuran. A solvent can be appropriately selected and used.

Although the reaction proceeds at room temperature, it is preferable to heat the solvent to the boiling point for the first reaction. This can be done even more smoothly.

Next, the effects and toxicity of the compounds of the present invention will be shown in experimental examples.

Experimental Example 1, Experimental Method (1) Analgesic Effect ■ Acetic Acid Writing Method When a 0.7% acetic acid solution was intraperitoneally injected at 0.1 m//1 QII into ddY male mice (body weight 20-25 f), the hindlimb Wri based on stretching
Suppression of thing syndrome was used as an index of analgesic effect. Fifty minutes after oral administration of the compounds of the present invention and control drugs shown below, acetic acid was injected, and the number of Wriing Syndromes was observed for 15 minutes thereafter. Note that the Litchf 1eld-Wi 1 coxon method 2) was used to calculate the 5096 effective density (kJ) so).

1) r(endershot, L, C, and
Forsaith, J.; J., Pharmac.
ol, exp, 'rher, , 125+ 23
7 (1959) 2) Li tcnfield, Jr., J. T., and
vVi 1coxon.

F; J, Pharmacol, exp, Th
erap, 96 + 99 (1949) ■ Pradykinin-induced nociceptive reaction 3.4) S, D, male rats (body weight 250-3509) in which a polyethylene tube was inserted into the common carotid artery in advance were used. The analgesic effect was examined using symptoms such as flexion of the right forelimb, right rotation of the head, and standing up as indicators of pain response.

3) Takeshi Abe, Taketoshi Kaneko, Hiroshi Takagi 1111tt, 6
7゜9-14 (1971) 4) Blane, (j, F, J, Pharm
a, Pharmacol, 19°367 (19
67) (2) Antipyretic effect S, D, male rats weighing 250 to 300 f were subcutaneously injected with 2++J/animal suspension of dried yeast to induce fever, and 4 hours later, the compound of the present invention as a test compound and a control were administered. The drug was administered orally. The rectal temperature of the rat was measured over time, and the dose that would reduce fever by 1°C or more at the peak of action of the test compound was determined.

The compound of the present invention as a test compound was weighed with a weight of 300 f.
Thirty minutes after oral administration to istar rats, 0.05 gLl of 1% carrageenan solution was injected into the rat's heel, and the volume of the heel was measured after 3 hours to calculate the edema rate, which was 430% of the inhibition rate compared to the control group. The effective dose (EDII) was calculated.

5) Vinegar, L Ctal; J.
Pharmacol, exp.

Ther, 166, 96 (1969) (4) Acute Toxicity Acute toxicity was investigated using ddY strain male mice and S, D strain male rats, and 50% lethality 1 (Lose) was calculated. For mice, 10 mice were administered at each dose and observed for 3 days after administration of one compound of the present invention. In rats, 5 animals of each dose were used and observed for 7 days.

2. Test compound Compound A: 1- (3-(4-m, p-dichlorophpentylpiperazinyl-11j) -n-propyl)
Theopromine compound B: l (2(4(J, m-dimethylphenylpiperazinyl-(11)-ethyl j-thio compound C:
1-(3-[4-0-chlorophenylbiperanonyl-(11)-n-propyl)-theopromine 2HC/ Compound D: 1-(4-(4-<J-methoxyphenylpiperazinyl-(11) )-a-butyl)-thio compound g
: l (4-(4-p-fluorophenylpiperazinyl-(1ton-n-butyl)theopromine-2HC/ compound?: 1-(4-(4-m, p-dichlorophenylpiperazinyl-fl)) - n-butyl)-
Theopromine 2l-IC/Compound G: l-(5-(4-m-methylphenylpiperazinyl-fil)-o-pentyl)-theopromine 2HCV In the above structural formula, 'rb means 1 formula and Hl means.

Control lid I Nimepyrizole...4-Methoki/-2
-(5-methoxy-3-methylpyrazol-1-yl)
-6-Methylpyrimidine vs. ssn: thearamide...-4-((5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl)-1-piperazineethanolis drug I! I: Perisoxal...3-(1-Hydroxy2-piperidinoethyl)-5-phenylisoxazole 3 Experimental results l) Analgesic effect and acute toxicity Table 1 shows analgesic effect (El) in mice. ) and the %lethal dose (Lm). ) and safety margin (LIJ5°/k'
i-'so).

From Table 1, it is clear that the compound group of the present invention has a stronger analgesic effect (5 to 90 times more) than the control drug, and also has a wide safety margin.

Furthermore, Table 2 shows the analgesic effect in rats (HD, 0) and 50
96 Lethal dose (LD, ) and safety margin (Lose/ED)
s. )showed that.

From Table 2, it is clear that the compound group of the present invention has a stronger analgesic effect (4 to 8 times) compared to the control drug.

2) Antipyretic action As a result of studying Compound A, which is a representative compound of the present invention, 1 ml for reducing fever by 1°C or less at the peak of action.
kgP, (J, ) Ha401'v/9P, U,
There was a time. This is the control drug I40■/kgP, (J,
, Control drug II 40"IP/9)', (J, ,
Control drug III l 6019/9)'.

0, it can be seen that the force is the same or about four times stronger.

3) Anti-inflammatory effect The results are shown in Table 3.

As is clear from Table 3, the compound group of the present invention is 10-251N
It showed anti-inflammatory effect at i/kg.

Table 3 As is clear from the above experimental examples, the theophylline derivative of the compound of the present invention has strong analgesic, antipyretic, and antiinflammatory effects, and is useful as an antiinflammatory, antipyretic, and analgesic agent. is extremely valuable.

When the compound of the present invention is used as an anti-inflammatory, antipyretic, or analgesic agent, it is administered orally or parenterally (intramuscularly, subcutaneously, intravenously, etc.). The dosage varies depending on the disease, severity of symptoms, age, etc., and is not particularly limited.
Usually about 1 to 1000 μ per day for adults, preferably about 3
~1ooINi.

In order to formulate a compound of the present invention, it is formed into a dosage form such as a tablet, m-granule, tk tablet, capsule, injection, herbal medicine, etc. by a conventional method in the technical field of pharmaceutical preparation.

That is, when preparing an oral solid preparation, the main drug is an excipient, and if necessary, a binder and a disintegrant.

Lubricant 1 After adding coloring agents, flavoring agents, etc., it is made into tablets, coated tablets, granules, powders, capsules, etc. by a conventional method.

Examples of excipients include lactose and cornstarch.

White sugar, glucose, sorbitol, crystalline cellulose, etc.
Examples of binders include polyvinyl alcohol, polyvinyl ether, and ethyl cellulose.

Methylcellulose, gum arabic, tragacanth.

Gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., and disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc. Examples of lubricant materials include magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc.; and colorants that can be added to pharmaceuticals.
What is f0T is used as a flavoring agent.

Cocoa powder, peppermint, aromatic acid, peppermint oil, cybernetic acid.

Cinnamon powder etc. are used. Of course, these tablets and A-granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.

When preparing an injection, add PI (adjusting agent, buffering agent, stabilizer, preservative, etc.) to the main drug as necessary, and prepare the preparation for subcutaneous, intramuscular, or intravenous injection using a conventional method.

A synthesis example of the present invention is given below.

Synthesis Example 1 Lomine 1-(4-bromo-n-butyl)theopromine 9.5f
, ortho, meta-dimethylphenylpiperazine 3.8f
, and triethylamine4. Of is stirred under reflux in toluene for 13 hours. The triethylamine hydrochloride is removed and the filtrate is extracted with dilute hydrochloric acid.

The mixture is made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer is washed with water and dried with anhydrous potassium carbonate. The solvent was distilled off, and the resulting crude crystals were recrystallized with methyl cellosolve to give the title 1-(4-(4-ortho, meta-dimethylphenylpiperazinyl-[11]-n-butyl)-theopromy/). 379 (yield 43.64%) is obtained.

Melting point = 134-135°C Elemental analysis value: HN as Cx5HstUtN* Theoretical value (%') 65.05 7.61 19.8
0 Actual value (95') 65,11 7.72 19
．． 46 Synthesis Example 2 l-(5-promo n-pentyl) theopromy/7,9
f, 50 g of N-benzhydrylbiperanone.

and triethylamine 4y are stirred under reflux for 17,930 hours. The subsequent operations were carried out in the same manner as in Synthesis Example 1, and the obtained crude crystals were converted into hydrochloride by a conventional method. Recrystallize from isopropyl alcohol to obtain the title 1'-(5
-(4-Benzhydrylpiperazinyl-!11)-n-
pentyl)-theobromi/·hydrochloride (4.9y (yield 4)
09%).

Melting point: 262-264℃ (decomposition) Elemental analysis value: Cy* Hsa Ot Ns ・2 H
HN as CI Theoretical value C%) 60,93 6.71 14.71 Actual value (%) 60,57 7.15 14.65 Synthesis example 3
5f, N-orthomethoxyphenylpiperazine 38y,
and triethylamine 4.09 in toluene 11.5
Stir at reflux for an hour. Thereafter, the same treatment as in Synthesis Example 1 is performed to obtain crude crystals. Purified by silica gel chromatography,
The title 1-(7-(4-ortho-methoxyphenylpiperazinyl-fi+)-n-heptyl)-theopromine t
ay (yield 49.1%).

Melting point: 97-98℃ Elemental analysis value 'Ct* k43m 'Js Theoretical value as Ns (%) 64.08 7.74 17.94
Actual value (%) 63,90 7.67 18.01
Synthesis Example 4 l-(2-(4-halermethquinphenylbibe 1-(
2-bromoethyl) theopromine 6.99° para-methoxyphenylpiperazine 3.89 and triethylamine 4. Of is stirred in benzene under reflux. Remove the triethylamine hydrochloride and extract the liquid with dilute hydrochloric acid.

The mixture is made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform layer is washed with water and dried with anhydrous potassium carbonate.

The solvent was distilled off, and the resulting crude crystals were recrystallized from methanol to give the title 1-(2-(4-para-methoxyphenylpiperazinyl=1)ethyl)-theopromine 4,'l (yield: 6
1.396) is obtained.

Melting point: 157-159°C Elemental analysis value: Cto H2S (H as Js Ne
N Theoretical value (%) 60.27 6.59 21.09 Actual value (%) 60.46 6.43 21.15
Synthesis Example 5 l-(3-promo n-propyl) theopromine 7.2
y, ortho-methylphenylpiperazine 35y and triethylamine 4. Of is stirred under reflux in benzene solvent for 16 hours. Thereafter, the treatment was carried out in the same manner as in Synthesis Example 4, and the obtained crude crystals were recrystallized from ethanol to obtain the title 1-(3-[4-ortho-methylphenylpiperazinyl-(11) -n-
7' oral pill) - Theopromine 6.3f! (Yield 91,
3%).

Melting point = 152-154°C Elemental analysis value: I-I as Cn H2S Ut Ns
N Theoretical value (%) 63.60 7.13 21.20 Actual value (96) 63.40 7.20 21.31 Synthesis example 6 l-(4-promo n-butyl) theopromine 7.5y
, parachlorobenzylhomopiperazine 4.52 and triethylamine 4, Oy are stirred under reflux in a benzene solvent. Thereafter, the same treatment as in Synthesis Example 4 was carried out.

Isopropyl ether is added to the obtained oil and left to cool with water to crystallize. The obtained crude crystals were recrystallized from ethanol to obtain the title 1-(4-(4-para-chlorobenzylhomopiperazinyl-il+)-n-butyl)-theopromine5. El (675% yield) is obtained.

Melting point near 1~73℃ Elemental analysis value: Czs Hat (Jt Ns HN as Cl Theoretical value (%) 60,17 6.82 18.3
1 Actual value (%) 59.94 6.86 18.
43 Synthesis Example 7 l-(5-bromo-n-pentyl)theopromine 7,L
3.5 g, 4-piperidone ethylene ketal and 4.0 y of triethylamine are stirred in a benzene solvent under reflux. The reaction mixture is then washed with water and dried over anhydrous potassium carbonate. After distilling off the solvent, the obtained crude crystals were recrystallized from acetone and isopropyl ether to obtain the title 1-(5
-[4-(piperidone ethylene ketal)yl-(11
)-n-pentyl)-theopromine 539 (yield 69.
0%).

Melting point = 95-96℃ Elemental analysis value HN as CIIH1lU4NS Theoretical value (%) 58.29 7.48 17.88
Actual value (96) 58,06 7.54 1102
Synthesis Example 8~. The compounds shown in Table 4 were obtained by a method similar to that of Synthesis Example 1.

Next, Examples 1 and 2 will describe specific examples of formulations for carrying out the present invention.

Example 1 Tablet 1-(3-[4-rn, p-dichlorophenylpiperazinyl fill-rhopropyl)theobromine 10
．． 0 parts lactose 535
Microcrystalline cellulose 18.0 Corn starch 180 Calcium stearate 05 According to the usual method, the above ingredients are mixed, made into fine granules, and compressed to form one tablet of 100 cm.
tablets.

1-(5-(4-m-methylphenylpiperazinyl-f
il)-n-pentyl)-theopromine-211C/
10.0 parts lactose
70.0 Corn starch 20.0 Patent application for manufacturing 100 to 100 capsules according to the above formulation according to the conventional method - Artificial Formula Company

Claims (1)

[Claims] (11-. General formula [In the formula, R represents a hydrogen atom or a lower alkyl group, respectively. Atom, lower alkyl group (meaning a lower alkoxy group, trifluoromethyl group, or halogen atom). n is 2~
Indicates an integer of lO. ] An anti-inflammatory, antipyretic, and analgesic agent containing the theobromine derivative represented by and its acid addition salt as an active ingredient.