JPS608282A - Benzo-1,2-thiazine-1,1-dioxide derivative, manufacture and medicine - 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: 0=O-R1 (wherein R is a lower alkyl group having 1 to 4 carbon atoms, R1 is a straight or branched alkyl group having 1 to 5 carbon atoms, preferably a t-butyl group) , Ar is an aromatic group or 1 to 3 O, S
, N, etc., preferably 2-
pyridyl or 2-deazolyl group) and its addition salts with pharmaceutically acceptable acids.

Preferred specific examples of the compound represented by the general formula (I) of the present invention include 4-pivaloyloxy-2-methyl-2H
-1,2-benzothiazine-6-[N-(2-pyridyl)-carboxamide)-1,1-dioxide, 4-bivaloyluogycy 2-methyl-2H-1,2-benzothiazine-3-(N- (2-thiazolyl)-carboxamide)-1,1-dioxide is mentioned.

In U.S. Pat. No. 3,591,584, a series of novel compounds of 3-ami7carbonyl-1,2-benzothiazine-1,1-dioxides with a heterocyclic residue on the nitrogen atom of the amino group were first described. Reported.

Compounds of this type have analgesic and anti-inflammatory properties and have been used in the treatment of rheumatoid arthritis, although some of them cause side effects, particularly gastrointestinal disturbances in patients. However, such impairment is common with other non-steroidal anti-inflammatory drugs.

The inventors previously obtained Italian patent application No. 19486A/8
No. 2 (filed on February 5, 1982), and the novel 4-hydroxy-2
-Methyl-2H-1,2-benzothiazine-5(N-(
An ester of 2-pyridyl)-carboxamide 1,1-dioxide has been prepared and its pharmacological properties have been investigated.

Since such new derivatives have more or less the same properties as the starting compounds, it was simply concluded that local administration would be more preferable since they would show a real therapeutic benefit.

As a result of further intensive studies, the present inventors found that the 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3
-(xi-(2-pyridyl)-carboxamide)-1,
The hydroxyl group at position 4 of 1-dioxide is
The present inventors discovered that by esterifying IA with a substituent group, a new compound having an anti-inflammatory effect and an extremely excellent anti-inflammatory effect could be obtained, and the present invention was completed.

The new derivatives represented by the general formula (1), especially those in which the hydroxyl group at the 4-position is esterified with a t-butyl group, maintain substantially the same anti-inflammatory effect and have a pronounced ulcer-forming effect. The therapeutic index (ther
apeutic 1ndex) of the starting compound.
25 times higher.

The compounds described in said patents can be obtained by various methods of preparation, and other similar compounds can be found from the prior art.

Such a production method is shown below using a reaction formula.

OHQ) 1 OH (wherein R and R1 are, for example, a methyl group, R2 is, for example, a hydrogen atom, an alkyl group, a heterotetraaromer, etc.: Journal of Medical Chemistry, 14 (12)
, 1171 (1971).

Other methods for producing ikezu have been described in the patents or literature, but to date no method has been found to have significant advantages over the aforementioned methods.

Therefore, another object of the present invention is the general formula (I
) The object of the present invention is to provide an excellent new method for producing the compound shown in the following.

According to the present invention, the compound represented by the general formula (I) of the present invention is prepared according to the scheme shown below. ! m is done.

However, in the formula, R-, R1 and Ar are the same as above, X and X! 8+4 atoms, such as 0/ or I3r
shows.

0 (■) (To) He (X) (To) 0RI (To) Kari) (I) The main feature of the novel method of the present invention is that from the 5-atom derivative, the 3rd position is already an N-heterocyclic ring. This means that a 10-membered ring substituted with a carboxamide group is obtained.

Next, the method of the present invention shown in the above diagram will be explained in more detail.

The starting materials (dI and (b)) can be commercially available, or can also be produced according to known methods.

In fact, the compound (to) is a sodium salt dissolved in water.
Completely neutralize with mineral acid, filter unreacted material if necessary, and remove p.
It can be obtained by acidifying with H1-0 and filtering the compound (Vl).

The thus obtained intermediate (to)) is then converted into a compound (
4). The compound can be produced by using a commercially available product or by a known production method.

The reaction between intermediate (vl) and compound (4) is from 0 to 80°a
1 Preferably carried out at room temperature to the boiling point of the solvent used,
stoichiometric or catalytic amounts of base and/or if necessary
In the presence of acid acceptors (B), such as aliphatic, aromatic or heterocyclic t-amines, alkali or alkaline earth metal hydroxides or carbonates, alkali metal bicarbonates, acetates, hydrides, amides or alkoxides. Let's do it.

(As β-1 for sl, commonly used ones can be used, such as benzene, toluene,
Acetone, chloroporum, 1,2-dichloro-ethane,
Dimethylformamide, water, methylene chloride, etc. can be used. The reaction may also be carried out in a bilayer solvent using water and the above-mentioned solvents. In some cases, the reagent used in excess may itself act as a solvent.

The reaction is also catalyzed by (0), e.g. nIJ receptor receptor).
The reaction may be carried out in the presence of a base, a quaternary ammonium salt or a phosphonium salt (particularly in a two-layer reaction), an alkali iodide, cuprous iodide, etc. as described above.

Intermediate (g) is reacted with sodium methoxide in dimethyl sulfoxide, and the heat generation during the reaction is checked to ensure that the reaction temperature does not exceed the range of 5° to 35°. The intermediate (3) thus obtained can be prepared by addition with a mineral acid (HXI), preferably hydrochloric acid, by adding an acid to a solution of said intermediate (3) in a solvent which precipitates the preformed salt. Salt it.

The intermediate thus obtained is converted into an acyl halide (R1
00X) or carboxylic acid anhydride ('(R100)20
) and the above-mentioned solvent (S) (excluding water) at a temperature of 0 to 70°0. On this occasion,
The catalyst (0) described above may also be used, but is often unnecessary in this case. At the end of the reaction, the intermediate is isolated,
Immediately add stoichiometric amounts of base CB) and/or solvent (
S) to obtain the compound Fuchi).

The intermediate abyss) is finally converted into a solvent (S) in the presence of a base (E).
) and in the presence or absence of catalyst (0), 0 to 1
00°C 1 React with the sample iRx preferably at room temperature 0 In the reaction, a lower alcohol can be used as a solvent, and the final product compound (
1) can be crystallized.

Moreover, compound CI) uses compound (3) as a starting material,
It can also be produced according to the reaction shown below.

l (In the formula, R, R1 and Ar are the same as above, R2 is a lower alkyl group, X is a halogen, for example 01zBr, and (B), (S), (0) are the same as above.) Intermediate ( 3
) in the presence of base (B), solvent (S) and catalyst (0)
RX in the presence or absence of 0 to 100°0, preferably at room temperature. The intermediate thus obtained (
XF/), for example, 'T syl halide bonic acid (R1-
000H) or carboxylic acid ester (R100OR2
) to react. However, the base (B), solvent (S) and catalyst (0) are the same as above. Also suitable are acid catalysts, such as mineral acids such as sulfuric acid, phosphoric acid, hydrochloric acid and the like.

The reaction is preferably carried out between 0 and 100°a, preferably between room temperature and 60°a or the boiling point of the solvent used.

The final product, Compound (I), is crystallized from a solvent such as alcohol, ether, methylene chloride, acetone, etc., or a mixture thereof.

Compound (1) obtained by vaporization may be further treated with various pharmaceutically acceptable acids, such as inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, or such as oxalic acid, maleic acid, etc. addition salts with organic acids such as , fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid.

Such a salt can be easily produced by a known method. For example, a compound (I ) to the solution.

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (a) Production of intermediate (capital) 0.06 mol of intermediate (W) dissolved in 200 ml of fishing rod was placed in a beaker with a capacity of 500 mj, and when it was completely dissolved, 1N hydrochloric acid was added little by little. , until completely neutral as checked by indicator or pH meter. The reaction mixture was left under stirring for about 30 minutes and any solid formed was removed.

The furnace solution was acidified to pH 1-0, and the precipitated compound (b) was filtered, washed with water, and dried under reduced pressure (yield 65-9
0%). The obtained compound (NMR spectrum,
It was investigated by spectrum, UV spectrum and elemental analysis.

(1>) Production of intermediate (g) Stirrer, thermometer, reflux condenser, dropping funnel, external automatic humidity control device (external: Lthen
In a flask with a capacity of 11 with a nostatic bath, 0.25 mol of intermediate (b) and 237 mol of potassium carbonate were added.
, 200m/ of water was added. The reaction mixture was heated to 50°C and after heating for 25 minutes, 8.5% of tetrabutylammonium hydrogen sulfate was added. was added and then the reaction mixture was heated at 50°0.
Intermediate (2) stirred for 8 hours, added 20Qml of benzene, and dissolved in 250ml of benzene with rapid stirring.
0.6 mol was added portionwise over 20 minutes. The resulting reaction mixture was then refluxed for 70 min, cooled to room temperature, the organic and inorganic layers were separated, and the resulting organic layer was washed with a small amount of acidic water, 1N KOH and finally water to neutralize it. . The benzene layer was dried for 2003 minutes, and then the solvent was evaporated under reduced pressure to obtain the desired intermediate (g) composition (yield 60-80%).

The product was further crystallized using a suitable solvent and investigated by NMR spectra, ER spectra and elemental analysis.

(Q) Preparation of intermediate (to) Anhydrous DMSO 10 in a 500 mj flask equipped with stirrer, thermometer, dropping funnel and external cooling device.
0 m/s Add 0.2 mol of the intermediate (g) obtained in (b) above, and add 0.2 mol of anhydrous DMS0100 m/s with rapid stirring.
Sodium methoxide suspended in 21.5. was added over a period of 1 hour. At this time, the internal humidity is 60°
I tried not to exceed C.

After the addition was complete, the reaction mixture was stirred for 20 minutes, acidified with 5N hydrochloric acid, and extracted with chloroform.

After drying, the 7oo form layer was evaporated and the resulting intermediate (
Dissolve the residual liquid of 3) in ethanol, add o0cteethanolic hydrochloric acid to make the hydrochloride, and obtain the desired hydrochloride intermediate (
XI) was obtained (yield 66-67%).

This often does not require crystallization. The resulting intermediate (3) was investigated by NMR spectroscopy, ER spectroscopy and elemental analysis.

(d) Production of intermediate (XI[) The intermediate (XOo
, 15 mol of anhydrous 1,2-dichloroethane and the reaction mixture was stirred at room temperature for 15 minutes, then cooled to 2-6°C, and 0.16 mol of an acyl halide of formula a(am3)3aoat was added. Added all at once.

The reaction mixture was stirred at 0-5 °C for 60 min, then at ca.
Raise the temperature to 2000 over 0 minutes, then about 60
The temperature was raised to 60-70°C over a period of minutes. During the heating operation, MCI continued to occur for about 3 hours.

After the reaction was completed, the reaction mixture was cooled to room temperature, and the obtained intermediate (c) was filtered. This intermediate (2) is about 200 mz
of water for 10 minutes with rapid stirring under cooling.
The pH was adjusted to 7.5 with %KOH. The suspension was stirred for about 2 hours, and the desired intermediate (XI!l) obtained was filtered, recrystallized from Improper Tools, and analyzed by NMR spectrum, engineering R spectrum, and elemental analysis. fi'7J peta (yen 78-92%).

(e) Production of compound (I) The intermediate (Xllll) obtained in the above (d) was placed in a reaction vessel with a capacity of 100 m/m equipped with a stirrer, a thermometer, and a dropping funnel.
．． 12 mol, 400 mj of ethanol, and 100 mj of water were added. The reaction mixture was stirred for 15 minutes, 120 ml of 1N NaOH solution was added and stirred again for 20 minutes at room temperature. Then, 0.68 mol of methyl chloride was added dropwise over about 25 minutes. The 18 If reaction was allowed to proceed at room temperature, and the resulting precipitate was filtered, washed with water, and then dried. Yield was 65-90%. The obtained target compound has an NMR spectrum,
W-beta by spectra and elemental analysis.

Example 2 (a) Preparation of intermediate (XIV) from intermediate (3) The same procedure as in Example 1 was carried out. The product (XIV) with a yield of 45-8% was investigated by NMR spectroscopy, EMR spectroscopy and elemental analysis.

(b) Production of compound (I) Total capacity of stirrer, thermometer, reflux condenser, dropping funnel, and external automatic temperature control device: 1000 m417
) 7 Lasco intermediate (XIV) 0,13? +v-le,
Anhydrous 1,2-dichloroethane 300mz and triethylamine 6.9. and then heat the reaction mixture to 50°C.
heated to. 2〇 (OH3)3Co 0.099 mol of acyl halide represented by C1 was dissolved in dichloroethane 15
The diluted solution was added dropwise into m4 over 20 minutes. A slight heat generation was observed during dripping. Further 50°C after completion of dripping
Stirring was continued for 20 minutes. Then triethylamine6.
8. was added, stirred again at 50°O for 15 minutes, and then
．． A solution containing 0.099 mol of the above acyl halide in 15 mJ of 2-dichloroethane was added dropwise over about 20 minutes.

At the end of the second drop, the temperature was 50°C.
Hold for 0 min, then the reaction mixture was cooled to 50°C and filtered to remove the solid product (triethylamine hydrochloride).

The furnace solution was washed twice with 200mj of water, twice with 20[]mj of 0,5N NaOH solution, and then washed with water to neutralize it. The solution in 1,2-dichloroethane was dried over Na25O, and the solvent was evaporated under vacuum until an oil formed.

The oil immediately became solid and could be dissolved successfully in ethyl ether. The resulting suspension was filtered and washed with ethyl ether to yield a solid. This product did not require recrystallization and was dried as is (yield 75-90%)
. The obtained compound was investigated by NMR spectrum, ER spectrum and elemental analysis.

In the vaporization example, Ar of the raw material compound (to) is 2-
When pyridyl is used, 4-pivaloyloxy-2-methyl-2H-1,2- represented by formula (XV)
When benzothiazine-5-[N-(2-pyridyl)-carboxamide]-1,1-dioxide is used where Ar is 2-thiazolyl, it is represented by formula (XM) 4
-pivatetrayloxy-2-methyl-2H-1,2-benzothiazine-5-(li-(2-thiazolyl)carboxamide)1,1-dioxide was changed. Next, their characteristic values are shown.

0((1!H3)3 Idumi 0(01(3)3 [Compound (XV)) White crystalline powder, mp 152-154°001■-Kotaji vector analysis (6 eyelids, in CD043): ( δ value; p
Door) 9.0 (e, Broad, Mobile-B)l-),
8.35-8.15 (m, 2H = H-5 of pyridine ring
, H-6), 8.0-7.4 (m, 5H (4 adamatic + n-3 of pyridine ring)ls7.3-6.9 (
m, 11 (=H-4 of pyridine ring), 3.05 (gl
, 9(=-N-OH3), 1-4[8S9H=O(OH
3) 3') m spectrum analysis (Dr): (am)6
700-5150 (broad), 2980 (weak), 1760.1680.1530.1455.165
0.13 beats, 1090.765 elemental analysis value 8C3°H2
□N305S Theoretical value (support): 057.82 H5,095N10
．． 11 Actual value ($): 057.69 H5,087N
10.28 [Compound (No. 1)] White creamy powder, mp 175-177°C0
C01) I-N spectrum analysis (6[Z, 0DOj3
Medium); (δ value: ppm) 11.1-9.9CB, Broad 1H, Mopil → Stop-), 8.0-7.55 (m
, 4a1 aromatic), 7.5 and 7.0 (I
2 H doublets 1. T -z 4Hz = 2H thiazolyl), 6.0 (oS 5H-N-C1■3), 1.4 (e
, 5+a=-o(OH3)3) Ball spectrum analysis (KB
r) s (am-1) Shame 80-6220 (Broad), 2980 (Week), 1760.1675.1
560.1560.1350.1180.760.72
0 elemental analysis value = 0□8H engineering, N30. S Theoretical value: 051.29 H4,54N9.97 Actual value (%): a 51.20 u 4.46 u
10. C11 Next, the present invention will be explained in more detail with reference to $-type kjJ examples and pharmacological test examples, but the present invention is not limited to these test examples.

The test compound is 4 represented by the formula (XV) of the present invention.
-bivaloyluogycy 2-methyl-2H-1,2-benzothiazine-3-(N-(2-pyridylnocarboxamide)-1,1-dioxide (hereinafter referred to as 0HF1021) and the formula (XW) of the present invention 4-Bivaloyl-2-methyl-2H-1,2-benzothiazine-5-(N-(2-thiazolylcarboxamide)-
1,1-dioxide (hereinafter referred to as OHF 1047)
was used. In addition, as a comparative example, oxicam
4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-(N-(2-pyridyl)carboxamide)-i,i-dioxide (hereinafter referred to as Acute toxicity was investigated by administering the test compound by mouth to mice (SPF).

The test animals were fasted from food for 18 hours after the start of the test, and were given only water ad libitum. The test compound was suspended in 1% carboxymethyl cellulose. L from the test results
The D5o value was calculated and the results are shown in Table 1.

Table 1 (Anti-inflammatory effect on transplanted carrageenan edema 1 Male Orl
:0D (SD) rats, body weight 17o-2o59, were used.

Before the start of the test, test animals were allowed to acclimate to constant temperature and humidity conditions for at least one week, fasted for 18 hours before the start of the test, given only water ad libitum, and randomly divided into groups of 54.
(4 different doses were administered for each compound). Control group animals received vehicle only.

The tests were as follows: (1) Piroxicam vs. 0HF1021 (2) Piroxicam vs. 0HF1047, GHF1109
and 0HF1115.

The test compounds were administered orally at different doses and
C.N. (Winter O.A.) et al. (Proc.

Soc, Rbcp, Biol, Mad, 111
．． 544 (1962)), 1%
Carrageenin solution (physiological solution)
One hour after administration of the test compound, a subplanter (5ub solution) of 0.1-
We investigated the effect on edema caused by accompaniment with (S. plantar). The paw volume of test animals administered the test compound was measured using Lucy Bee (L) immediately before and at various times after administration of the inflammatory drug (carrageenan).
euce p, ) (Arch, Engineering, Phar
macodym, 156-1257 (1962))
A water-mercury plethysmometer (pl
etismometer). ED the results:.

It is expressed as a value and shown in Table 2. The ED3o value is the AU between the administration group of each test compound and each control group.
Logarithmic regress (% dose)/(edema suppression) calculated from the ratio of the average value of O (area under the drug concentration curve indicating an increase in stepping volume)
ion ) 0 (gastric disorder) calculated based on the straight line In the test animals used in the anti-inflammatory effect test, gastric ulcer formation was visually observed 7 hours after administration of the test compound to examine gastric disorder.

For each test animal, a logarithmic attenuation line of dose - 1 tumor size (mm) was calculated, and the UD3 value was calculated based on this. The UD3 value obtained in this way indicates that the total size of the gastric ulcer is 5 m.
This is the dose required to reach m. The obtained results are shown in the second
Shown in the table.

From the results shown in Tables 1 and 2 above, the following was discovered. In short, QHF1021 has an extremely superior anti-inflammatory effect compared to the comparative example piroxicam, and surprisingly, it has at least 10 times less ulcerogenic activity than the comparative example. , toxicity is also about 6
5% lower.

As mentioned above, the characteristics of the compounds of the present invention, such as extremely low ulcer-forming effect, which is the most serious side effect of nonsteroidal anti-inflammatory drugs, and excellent anti-inflammatory effects, make them suitable for therapeutic use. It is extremely advantageous and shows unexpected superiority when compared with the results obtained with other shellfish derivatives tested at the same time.

Small fruit, 0HF1047 or 4-hydroxy-2-methyl-2H-1,2-benzothiazine-6-(N-(2-
The pivalic acid ester of (thiazolyl)-carpoxamide)-i,i-dioxide (hereinafter referred to as sudoXican) showed only a very low anti-inflammatory effect. On the other hand, the sharp compound Stoxicam was tested as a reference example (Wismann E.H.
Em Wholesale E, H), Ombarzino G.G. (Lo
mbardino J, G, ): [oxicam,
Novel non-steroidal anti-inflammatory drug (Oxicams-A)
, novelfurnily of Non-5t
eroidal Anti-inflammator
y Drug8) j zEur, J, RhGu
matol, engineering 11fla, rrm,, 4 to 4)),
'28o (1981) showed an anti-inflammatory effect comparable to that of piroxicam. Therefore, in this case, the medicinal efficacy was significantly impaired, at least by forming the drug into the form of pivalic acid ester.

0HF1109 and OHF'1115 also have excellent anti-inflammatory effects, but no improvement in resistance was observed (on the other hand, the n-butyryl ester of piroxicam (!HF1115
was slightly more ulcerogenic and had a relative therapeutic index of 1.43 and 1.50, respectively, which was slightly higher than that of piroxicam.

(Other pharmacological effects of 0HF1021) 0HF of the present invention
In other tests that directly compared 0HF1021 with the comparative example viroshicam, it was found that 0HF1021 had excellent analgesic and antipyretic effects in addition to anti-inflammatory effects. Transplant edema caused by nyscutin in rats, erythema caused by ultraviolet light (er7thema) in guinea pigs
Phenylquinone-induced torsion (wri) in L mice
When we calculated the ratio of ED50 values for the fever caused by brewer's yeast in the ``thing'' test and in rats, we found that 0HF
1021 is 1.52.0.49 respectively compared to the comparative example
．． The values were 0.72 and 0.71 times higher. Also cHF
102i and Comparative Example showed almost the same effect on adjuvant arthritis in rats.

The results of the pharmacological tests shown above show that GHF1024 has anti-inflammatory effects that are practically superior to piroxicam, and the side effects are clearly lower (approximately 1/6 of the comparative example).
It was shown that

The present invention further relates to a medicament containing the compound (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. The medicament of the present invention is acceptable as at least one medicament. It may also contain excipients.

The medicament of the present invention can be administered orally, parenterally, or locally, and can be administered in capsules, tablets, or similar forms, respectively.
The following formulations, suppositories, vials, and creams are administered in the form of gels.

To formulate oral preparations containing tl', the active ingredient is mixed with excipients in the form of a solid powder, such as lactose, sugar, sorbitol, mannitol, potato, cereal (cerθa1) or corn. It may be mixed with starch or amylopectin, cellulose or gelatin derivatives, and may further contain lubricants such as talc, polyethylene glycol, silica, magnesium or calcium stearate.

In the case of tablets, they may be prepared according to methods known in the art.

In the case of hard gelatin capsules, granules of the active ingredient are combined with solid powdered excipients such as lactose, sucrose, sorbitol, mannitol,
It may contain starch, cellulose or gelatin derivatives as described above, and may also contain stearic acid, magnesium stearate, or talc.

Rectal formulations containing unit doses may be in a form containing the active ingredient and a neutral fat-protecting acid (eg, fatty acid glycerol) or a water-soluble or self-emulsifying excipient (eg, a polyethylene glycol mixture).

In the case of injections for parenteral administration, pharmaceutically acceptable sterile liquids, such as water or aqueous polyvinylbitetraridone solutions, or oils, such as peanut oil, can be used as excipients, and if necessary. It also contains stabilizers and/or buffers. The active ingredient can be dissolved in liquid and sterilized on a filter before filling into vials, or suitably lyophilized. If lyophilized, the liquid vial of the injection may be added to the packaging on the day of packaging to reconstitute the solution at the time of use.

In the case of suppositories and injections, a local anesthetic can be added to the excipient if necessary.

The unit dosage of the medicament of the present invention is 10 to 20 as the active ingredient.
0mp, and the number of administrations per day is preferably once.

To formulate topical preparations, J1a-base (fa(H
-ba'') t'l't forms flU, fc such as petrolatum, paraffin oil, lanolin, etc. can be used, and also self-emulsifying M excipients such as alcohols, lipids, polyethylene glycols, ethers or esters of fatty acids. or to prepare salves, ointments, and gels of hydrophilic colloids using different polymers such as carboxyvinyl polymers, sodium carboxymethylcellulose, methylcellulose, Methocel gelatinized in water,
Ethanol, propylene glycol, glycerol, polyethylene glycol, etc. are used.

Appropriate antibiotics such as parabens, phenol derivatives, quaternary ammonium salts, etc. may be added to topical preparations such as those described above.

The concentration of the active ingredient in the topical formulation can vary within a range of 100 volts.

Next, the present invention will be explained in more detail with reference to prescription examples, but the present invention is not limited to these prescription examples.

(Gelatin hard capsule for iD administration) y aaF1021 50 40 60 Microcrystalline cellulose 37.565 30 (Avicel ■
) outside rated 105 98 8
Calcium 4 phosphate (Thcompress ■) Talli 6.54 6.1 5.73 Magnesium stearate 0.96 0.9 0.77 Thcompress 5
In order to prepare 1,000 pieces, each of the above-mentioned ingredients was used in a proportion corresponding to the amount of the active ingredient, and the preparation was carried out according to the method shown below.

That is, the raw materials were passed through a sieve, placed in a powder mixer, and homogenized. The mixture was passed through an auperculum machine (
hard gel capsules or oporcs using an operculum-machine).
ula). The weight of the composition containing the active ingredient in one capsule was 180 m9.

(Suppositories for rectal administration) 9 0HF1021 60 60 100 Semi-synthetic glypeptide 1570 1540 1500 (Litepsol ■) To prepare 5000 suppositories, use the above ingredients in proportions according to the amount of active ingredient. It was formulated according to the method shown below.

That is, a mass of excipient was melted at 40°C and the active ingredient was incorporated into the molten excipient using a suitable disperser. The resulting mass was cooled to 66° O and poured into PvQ or aluminum valves (valvθ) with a volume of 1,8 ml each under stirring.

The weight of the suppositories dispensed into each bulb was 1.69, solidified and the containers were appropriately sealed.

(Cream for topical administration (cream of oil-water emulsion)) Ri0HF1021 2 5 Octyldodecanol 77 (RiutanOl G@) Liquid triglyceride 08 6 6 (Miritol 218 ■) Polyoxyethylene cetostear 22 Lyrualcohol (emalgin (-1g1n) B/B2■) Propylene glycol 55 Carboxyvinyl polymer 11 (carbopol 940■) Phenocombin> (Fenocombin■) 11 hydroxylation) +
Jum Appropriate amount Appropriate amount (adjusted to pH 5.5) Purified water Total amount 100g Total amount 100g To prepare 5 kg of cream, each of the above-mentioned ingredients was used in a ratio according to the concentration of the active ingredient according to the method shown below.

It was neutralized to give ptt5.5. Ingredients and lipids obtained
・Collect the powder in a suitable casting and melt it at 70°O.

The solution was made up to 800U.

The mixture was poured onto the Mizui lipid layer while homogenizing with a suitable emulsifier. The resulting emulsion was then cooled to 4,000 ℃, and the hydroglycol suspension of the active ingredient was added thereto. The emulsion was finally stabilized by adding a gel of carboxyvinyl polymer and dispersed with a suitable JN stirrer. The pH was adjusted to 5.5.

The cream was packaged in flexible aluminum tubes or other suitable packaging layers for topical administration.

Special 1 Creation 11 (Person Giesi Pharmaceutina Esse, continuation of page 1 ■Int, C1,' Identification code Internal serial number (C0
7D 417. /12 277:00 7330-4 C 279:00 ) 7330-4C 0 Inventor Flavio Villani Republic of Italy Parma Via Palermo 30

Claims (1)

[Claims] 1 General formula (■): (wherein, R is a lower alkyl group having 1 to 4 carbon atoms, R1 is a straight or branched alkyl group having 1 to 5 carbon atoms, and Ar is an aromatic group. or a heteroaromatic monocyclic or picitalic residue containing 1 to 3 heteroatoms such as O, S, N, etc.). 2 Claim 1, wherein R1 is a t-butyl group
Compounds described in Section. 3. The compound according to claim 1 or 2, wherein the Ar is 2-pyridyl or 2-thiazolyl group. 44-pivaloyloxy-2-methyl-2H-1゜2-
The compound according to claim 1, which is benzothiazine-3-(N-(2-pyridyl)-carboxamide)-1,1-dioxide. 54-pivaloyloxy-2-methyl-2H-i. 2-benzothiazine-3-(N-(2-thiazolyl)-
The compound according to claim 1, which is carboxamide)-1,1-dioxide. 6 Formula ((capital): %Formula% (In the formula, or a halogen atom, Ar is an aromatic group or 1-
A heteroaromatic monocyclic or picitalic residue containing three heteroatoms such as O, S, N, etc.
A compound represented by the general formula (g): 0 (wherein Ar is the same as above) is obtained by reacting with a compound represented by the formula aO:H (wherein Ar is the same as in nu), and the derivative or its (t addition j47
'l' means to esterify the sand group of water 1 with an acylating agent and finally alkylate the nitrogen atom at the 2-position.
General formula (I) with ¥ character: 0=O-R1 (in the formula, 1R is a lower alkyl group having 1 to 4 carbon atoms, R1 is a straight or branched alkyl group having 1 to 5 carbon atoms, and Ar is as defined above) method for producing the compound shown in (same). 7 Claim 6, wherein R1 is a t-butyl group
Manufacturing method described in section. 8. The manufacturing method according to claim 6 or 7, wherein the Ar is a 2-pyridyl or 2-thiazolyl group. 9 The compound represented by the general formula (IX) is converted into a compound represented by the general formula (3).
) in the presence of sodium methoxide and dimethyl sulfoxide at 60-65°
7. The manufacturing method according to claim 6, wherein the reaction is carried out at a temperature of C or less. 10. The production method according to claim 6, characterized in that the esterification reaction is carried out in the presence or absence of a solvent, a base, or a catalyst at a temperature of 0 to 100°0, preferably at room temperature. 11 General formula (I): (wherein, R is a lower alkylated group having 1 to 4 carbon atoms, R1 is a straight or branched alkyl group having 1 to 5 carbon atoms, and Ar is an aromatic group or 1 to 3 carbon atoms (a heteroaromatic monozylic or picitalic residue containing a heteroatom such as 0.81N) or a pharmaceutically acceptable salt thereof as an active ingredient, and has analgesic and anti-inflammatory effects. . 12. The medicament according to claim 11, wherein R1 is a t-butyl group. 13. The medicament according to claim 11 or 12, wherein the Ar is 2-pyridyl or 2-penzolyl group. 14 Contains 10 to 200 mg of the compound represented by the general formula (I) per unit dose and is administered orally, rectally or parenterally in the form of capsules, optionally coated tablets, suppositories or vials. The medicament according to claim 11. 15. The medicament according to claim 12, which contains the compound represented by formula (1) at a concentration of 1 to 10% and is administered locally in the form of a cream or gel.