The present invention relates to novel benzothiazine-1,1-dioxide derivatives. These benzothiazine-1,1-dioxide derivatives have a high hyaluronidase-inhibiting activity and accordingly can be used in drugs such as anti-inflammatory agent, anti-allergic agent and the like.

BACKGROUND OF THE INVENTION 
(1) Field of the Invention 
The present invention relates to novel benzothiazine-1,1-dioxide 
derivatives having an excellent pharmacological action, a process for 
producing said derivatives, and pharmaceutical compositions comprising 
said derivatives. 
(2) Description of the Prior Art 
Various types of anti-inflammatory agents have heretofore been proposed and 
clinically used. Of them, man in number and typical are adrenocortical 
steroid-like compounds and cyclooxygenase-inhibiting substances, and these 
compounds and substances suppress inflammation, i.e. inflammatory edema 
induced by vasodilation and increased capillary permeability, irrespective 
of the causes. 
However, the adrenocortical steroid-like compounds show adrenal 
dyscorticism induced by abnormal physiological disturbances, and the 
cyclooxygenase-inhibiting substances show gastropathy due to the 
suppression of biosynthesis of gastric mucosa-protecting substance (e.g. 
prostaglandin E.sub.2) as well as a strong adverse effect deviated from 
this general drug effect. 
SUMMARY OF THE INVENTION 
Hence, it is an object of the present invention to provide a novel compound 
which has an anti-inflammatory action, etc. without showing adverse 
effects (dyscorticism, gastropathy, etc.) as seen in the conventionally 
used adrenocortical steroid-like compounds and simple 
cyclooxygenase-inhibiting substances. 
The present inventors had previously reported that hyaluronidase takes part 
in inflammation and allergy, and hyaluronidase-inhibiting agents have a 
possible anti-inflammatory and anti-allergic activities [Japanese Journal 
of Inflammation, Vol. 4 No. 4, p. 437 (1984)]. As a result of further 
study on this matter, the present inventors found that particular 
benzothiazine-1,1-dioxide derivatives have a strong inhibitory action on 
hyaluronidase and accordingly are useful as drugs such as 
anti-inflammatory agent, anti-allergic agent and the like. 
Accordingly, the present invention relates to benzothiazine-1,1-dioxide 
derivatives represented by the general formula (I): 
##STR1## 
and/or the general formula (II): 
##STR2## 
(in the formulas (I) and (II), R.sub.1 is a carboxyl group or a tetrazoyl 
group, and R.sub.2 and R.sub.3, which can be the same or different, are 
each an atom or substituent selected from the group consisting of a 
hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a cyano 
group, a trifluoromethyl group, a mercapto group, a lower alkyl group, a 
lower alkoxy group, a lower alkylcarbonyl group, a lower alkylcarbonyloxy 
group and a lower thioalkoxy group), or pharmacologically acceptable salts 
thereof. 
The present invention further relates to a process for producing a 
benzothiazine-1,1-dioxide derivative represented by the above mentioned 
general formula (I) and/or (II) or a pharmacologically acceptable salt 
thereof, which process comprises a step of condensing 
4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid or a 
derivative thereof represented by the general formula (III): 
##STR3## 
(in the formula (III), R.sub.4 is an atom or substituent selected from the 
group consisting of a hydroxyl group, an alkoxy group, an aryloxy group, 
an N-oxysuccinimido group, a halogen atom and a group capable of forming 
an acid anhydride with a neighboring carbonyl (CO) group], with an aniline 
derivative represented by the general formula (IV): 
##STR4## 
[in the formula (IV), R.sub.1 is a carboxyl group or a tetrazoyl group, 
and R.sub.2 and R.sub.3, which may be the same or different, are an atom 
or substituent selected from the group consisting of a hydrogen atom, a 
halogen atom, a hydroxyl group, a nitro group, a cyano group, a 
trifluoromethyl group, a mercapto group, a lower alkyl group, a lower 
alkoxy group, a lower alkylcarbonyl group, a lower alkylcarbonyloxy group 
and a lower thioalkoxy group] in an inert solvent. 
The present invention furthermore relates to pharmaceutical compositions 
comprising, as an active ingredient, a benzothiazine-1,1-dioxide 
derivative represented by the above mentioned general formula (I) and/or 
(II) and/or a pharmacologically acceptable salt thereof, and having a 
hyaluronidase-inhibiting activity.

DETAILED DESCRIPTION OF THE INVENTION 
Firstly, detailed description is made on the benzothiazine-1,1-dioxide 
derivative which is the novel compound of the present invention. 
As mentioned above, the compound is represented by the general formula (I): 
##STR5## 
and/or the general formula (II): 
##STR6## 
The compound of the present invention is defined by these two general 
formulas because the compound ordinarily consists of two tautomers 
represented by the general formulas (I) and (II). Besides the mixture of 
these two tautomers represented by the general formulas (I) and (II), the 
compound may further be a single compound represented by the general 
formula (I) or (II) isolated from the mixture. 
The compound of the present invention also includes a pharmacologically 
acceptable salt obtained from the compound of the general formula (I) 
and/or the compound of the general formula (II) by a conventional method. 
As specific examples of the pharmacologically acceptable salt, there can 
be addition salts of inorganic salts such as sodium salt, potassium salt 
and the like. 
With respect to the substituents in the general formulas (I) and (II), 
R.sub.1 is restricted to a carboxyl group or a tetrazoyl group. The reason 
is that as is clear from Examples which follow, the compound of the 
general formula (I) and/or (II) exerts a hyaluronidase-inhibiting action 
only when R.sub.1 is a carboxyl group or a tetrazoyl group. 
R.sub.2 and R.sub.3 may be the same or different and can each take one of 
the various substituents defined above. The "lower alkyl" in the above 
definition denotes an alkyl group represented by the general formula 
C.sub.n H.sub.2n+1 --(n=1-6) of straight chain or branched chain with 1-6 
carbon atoms. The "lower alkoxy" denotes an alkoxy group represented by 
the general formula C.sub.n H.sub.2n+1 O--(n=1-6) of straight chain or 
branched chain with 1-6 carbon atoms. 
The compound of the present invention having a strong inhibitory action 
against inflammatory enzyme and hyaluronidase is useful for relaxation of 
the pain caused by disorders such as immediate type allergy, arthritis, 
rheumatic arthritis and the like and other inflammatory diseases, and 
accordingly is an effective drug. 
When R.sub.1 in the compound of the present invention represented by the 
general formula (I) and/or the general formula (II) is replaced with 
alkoxycarbonyl group, this ester may also have the same activity since it 
can be hydrolyzed in vivo to exert the drug effect. 
Description is made on the process of the present invention for producing a 
benzothiazine-1,1-dioxide derivative or a salt thereof. 
In the production process of the present invention, there are used, as 
starting materials, 4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3- 
carboxylic acid or a derivative thereof represented by the general formula 
(III): 
##STR7## 
[in the formula (III), R.sub.4 is an atom or substituent selected from the 
group consisting of a hydroxyl group, an alkoxy group, an aryloxy group, 
an N-oxysuccinimido group, a halogen atom and a group capable of forming 
an acid anhydride with a neighboring carbonyl (CO) group] and an aniline 
derivative represented by the general formula (IV): 
##STR8## 
[in the formula (IV), R.sub.1 is a carboxyl group or a tetrazoyl group, 
and R.sub.2 and R.sub.3, which can be the same or different, are an atom 
or substituent selected from the group consisting of a hydrogen atom, a 
halogen atom, a hydroxyl group, a nitro group, a cyano group, a 
trifluoromethyl group, a mercapto group, a lower alkyl group, a lower 
alkoxy group, a lower alkylcarbonyl group, a lower alkylcarbonyloxy group 
and a lower thioalkyoxy group]. 
The starting material of the general formula (III) is obtained by a known 
method, for example, a method described in J. Med. Chem. Vol. 14, 1171 
(1971). With respect to the R.sub.4 in the general formula (III), the 
alkoxy group is preferably a straight chain or branched chain alkoxy group 
of 1-6 carbon atoms; the halogen atom is preferably a chlorine atom, an 
iodine atom or a bromine atom; the aryloxy group is preferably a phenoxy 
group, a mono-, di- or trinitrophenoxy group or the like. 
With respect to the compound of the general formula (IV) as another 
starting material, some of such compounds are available commercially, and 
others can be synthesized by a known method. 
In order to provide the objective compound of the general formula (I) and 
the objective compound of the general formula (II) with 
hyaluronidase-inhibiting activity, it is necessary to use the starting 
compound of the general formula (IV) wherein R.sub.1 is a carboxyl group 
or a tetrazoyl group, i.e. an aminobenzoic acid derivative or a 
(tetrazo-5-yl)aniline. 
The reaction of the compound of the general formula (III) with the compound 
of the general formula (IV) is effected in an inert solvent. As the inert 
solvent, there are preferably used, for example, one or more aromatic 
hydrocarbon solvents such as dry benzene, toluene, xylene and the like. 
Other proper organic solvents ma also be used. The compound of the general 
formula (III) and the compound of the general formula (IV) are used in 
proportions of preferably 1 mole and 0.1-10 moles, more preferably 1 mole 
and 0.5-2.5 moles, respectively. By reacting them in said solvent, there 
takes place a condensation reaction such as dehydration, alcohol removal 
or dehydrohalogenation, and thereby an objective compound of the general 
formula (I) and/or an objective compound of the general formula (II) can 
be obtained. When the condensation reaction gives a volatile alcohol as a 
by-product, the reaction mixture is subjected to distillation when hot, so 
as to distil off the alcohol and thereby an objective compound can be 
easily isolated as a residue. 
When it is difficult to distil off the by-produced alcohol, the objective 
compound can be isolated and purified by a column chromatography which is 
used in synthetic chemistry, for example, a column chromatography using a 
silica gel, activated carbon, a polyamide, cellulose or the like. 
The objective compound can also be obtained by subjecting the compound of 
the general formula (III) and the compound of the general formula (IV) to 
a condensation reaction with a condensing agent such as 
dicyclohexylcarbodiimide or the like. The objective compound can also be 
obtained by other condensation reaction which is useful in organic 
synthesis, such as an acid anhydride method, an acid halide method, a 
phosphazo method or the like. 
Then, description is made on the pharmaceutical composition of the present 
invention. 
The pharmaceutical composition of the present invention is characterized by 
comprising, as an active ingredient, a benzothiazine-1,1-dioxide 
derivative represented by the general formula (I) and/or the general 
formula (II) and/or a pharmacologically acceptable salt thereof, and 
having a hyaluronidase-inhibiting activity. As mentioned above, this 
hyaluronidase-inhibiting activity is expressed when the substituent 
R.sub.1 in the compound of the general formula (I) and/or the general 
formula (II) is a carboxyl group or a tetrazoyl group. Thus, the 
pharmaceutical composition of the present invention comprises an active 
ingredient having a hyaluronidase-inhibiting activity and is effective for 
relaxation of the pain caused by diseases such as immediate type allergy, 
arthritis, rheumatic arthritis and the like and other inflammatory 
diseases. 
When the pharmaceutical composition of the present invention is 
administered to patients with the above diseases as a remedy, the dose has 
no particular restriction and varies depending upon the type of diseases, 
the disease conditions, age, health condition and body weight of patient, 
the frequency of administration, the expected effect and the type of the 
concurrently prescribed drug, if any. However, the dose is about 5-1,000 
mg, preferably about 10-500 mg in terms of active ingredient, per adult 
per day, and it is administered orally or parenterally one or more times 
per day. When the pharmaceutical composition of the present invention is 
used as a remedy particularly for various inflammatory diseases or 
allergic diseases, the dose is within the above range. Ordinarily, 
however, the dose is preferably about 10-500 mg, more preferably about 
30-300 mg per adult per day. 
As the dosage form, there can be mentioned, for example, powders, parvules, 
granules, tablets, capsules, suppositories, injections, etc. These dosage 
forms can be prepared using ordinary vehicles, adjuvants, additives and 
the like by an ordinary method. 
That is, when a solid form for oral administration is prepared, the active 
ingredient is mixed with vehicles and, if necessary, binders, 
disintegrants, lubricants, colorants, flavoring substances, etc. and the 
mixture is made into tablets, coated tablets, granules, powders, capsules 
or the like by an ordinary method. 
As the vehicle, there are, for example, lactose, corn starch, white sugar, 
glucose, sorbitol, crystalline cellulose, silicon dioxide and the like; as 
the binder, there are, for example, a polyvinyl alcohol, a polyvinyl 
ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth gum, 
gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinyl 
pyrrolidone and the like; as the disintegrant, there are used, for 
example, starch, agar, a gelatin powder, crystalline cellulose, calcium 
carbonate, sodium hydrogencarbonate, calcium citrate, dextrine, pectin and 
the like; as the lubricant, there are used, for example, magnesium 
stearate, talc, a polyethylene glycol, silica, a hardened vegetable oil 
and the like; as the colorant, there can be used those officially allowed 
substances only for use in drugs; and as the flavorings, there are used a 
cocoa powder, menthol, aromatic acid(s). peppermint oil, borneol, a 
cinnamon powder and the like. If necessary, the tablets and granules may 
be coated with sugar, gelatin or other appropriate coating material. 
When injections are prepared, the active ingredient is mixed with a 
pH-adjusting agent, a buffering agent, a stabilizer, a solubilizer, etc. 
if necessary, and the mixture is made into intravenous injections by an 
ordinary method. 
EXAMPLES 
Next, Examples of the present invention are described. 
Synthesis Example 1 
To 6.0 g of a compound of the formula (III). i.e. 
4-hydroxy-2-methyl-3-methoxycarbonyl-2H-,1,2-benzothiazine-1,1-dioxide was 
added 3.8 g of a compound of the formula (IV), i.e. 
2-(tetrazo-5'-yl)aniline. The mixture was refluxed for 24 hours in 80 ml 
of o-xylene to effect a condensation reaction. 
The insoluble materials were collected by filtration while the reaction 
mixture was hot, followed by washing with o-xylene. The residue was 
recrystallized from dioxane-water to obtain 7.5 g of 
4-hydroxy-2-methyl-N-[2'-(tetrazo-5"-yl)phenyl]-2H-1,2-benzothiazine-3-car 
boxamido-1,1-dioxide (this corresponds to the compound No. 1 in Table 1). 
Melting point: 256-258.degree. C. 
Elemental analysis (wt. %) 
Calculated for C.sub.17 H.sub.14 N.sub.6 O.sub.4 : C 52.25, H 3.54. 
Found: C 51.30, H 3.56. 
Synthesis Examples 2-15 
The following benzothiazine-1,1-dioxide derivatives were obtained by 
basically the same procedure as described in Synthesis Example 1 except 
that various aniline derivatives different from that of Synthesis Example 
1 were used as a compound of the formula (IV). 
______________________________________ 
Compound 
No. Name of compound 
______________________________________ 
2 4-Hydroxy-2-methyl-N-(2'-carboxyphenyl)-2H-1,2- 
benzothiazine-3-carboxamido-1,1-dioxide 
3 4-Hydroxy-2-methyl-N-(2'-carboxy-4'-chlorophenyl)- 
2H-1,2-benzothiazine-3-carboxamido-1,1-dioxide 
4 4-Hydroxy-2-methyl-N-(2'-carboxy-5'-chlorophenyl)- 
2H-1,2-benzothiazine-3-carboxamido-1,1-dioxide 
5 4-Hydroxy-2-methyl-N-(2'-carboxy-3'-methylphenyl)- 
2H-1,2-benzothiazine-3-carboxamido-1,1-dioxide 
6 4-Hydroxy-2-methyl-N-(2'-carboxy-4'-methylphenyl)- 
2H-1,2-benzothiazine-3-carboxamido-1,1-dioxide 
7 4-Hydroxy-2-methyl-N-(2'-carboxy-4'-hydroxy- 
phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1- 
dioxide 
8 4-Hydroxy-2-methyl-N-(2'-carboxy-6'-hydroxy- 
phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1- 
dioxide 
9 4-Hydroxy-2-methyl-N-(2'-carboxy-5'-nitro- 
phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1- 
dioxide 
10 4-Hydroxy-2-methyl-N-(3'-carboxyphenyl)-2H-1,2- 
benzothiazine-3-carboxamido-1,1-dioxide 
11 4-Hydroxy-2-methyl-N-(4'-carboxyphenyl)-2H-1,2- 
benzothiazine-3-carboxamido-1,1-dioxide 
12 4-Hydroxy-2-methyl-N-(3'-carboxy-6'-chlorophenyl)- 
2H-1,2-benzothiazine-3-carboxamido-1,1-dioxide 
13 4-Hydroxy-2-methyl-N-(3'-carboxy-2'-hydroxy- 
phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1- 
dioxide 
14 4-Hydroxy-2-methyl-N-(3'-carboxy-4'-hydroxy- 
phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1- 
dioxide 
15 4-Hydroxy-2-methyl-N-(4'-carboxy-5'-hydroxy- 
phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1- 
dioxide 
______________________________________ 
The melting points and mass spectral data of the above obtained compound 
Nos. 2-15 are shown in Table 1, together with those of the compound No. 1 
obtained in Synthesis Example 1. 
TABLE 1 
__________________________________________________________________________ 
No. 
R.sub.1 R.sub.2 
R.sub.3 
Yield (%) 
m.p. (.degree.C.) 
MS (m/e) 
__________________________________________________________________________ 
1 2'-(tetrazo-5"-yl) 
H H 84 256-258 
398 
2 2'-COOH H H 78 259-262 
374 
3 2'-COOH 4'-Cl 
H 76 262-265 
408 
4 2'-COOH 5'-Cl 
H 65 264-268 
408 
5 2'-COOH 3'-CH.sub.3 
H 52 210-213 
388 
6 2'-COOH 4'-CH.sub.3 
H 84 228-235 
388 
7 2'-COOH 4'-OH 
H 31 289-291 
372 (M.sup.+ --H.sub.2 O) 
8 2'-COOH 6'-OH 
H 43 251-255 
390 
9 2'-COOH 5'-NO.sub.2 
H 69 284-288 
419 
10 3'-COOH H H 93 289-298 
374 
11 4'-COOH H H 86 &gt;290 374 
12 3'-COOH 6'-Cl 
H 95 282-286 
408 
13 3'-COOH 2'-OH 
H 91 273-275 
390 
14 3'-COOH 4'-OH 
H 60 275-278 
390 
15 4'-COOH 5'-OH 
H 41 238-241 
390 
__________________________________________________________________________ 
Next, the pharmacological actions of the compound of the present invention 
are described by way of Pharmacological Tests. 
Pharmacological Test 1 
Effect on hyaluronidase activity 
0.8 mg/ml of a hyaluronidase (a product of Sigma Co.) taken from bovine 
testicles was used as an enzyme. Test compounds (compound Nos. 1, 2, 4, 7, 
8, 9 and 13) were dissolved at various concentrations in a 1 M acetate 
buffer (pH 3.5) and heated at 37.degree. C. for 20 minutes. Then, calcium 
chloride was added to each of the resulting solutions so that the calcium 
chloride concentration became 5 mM, and each of the resulting mixtures was 
heated at 37.degree. C. for 20 minutes. 
Thereto was added potassium hyaluronate so that its concentration in the 
buffer became 2.4 mg/ml, and the mixture was heated at 37.degree. C. for 
40 minutes. 
After the termination of the reaction, the amount of the substrate 
hydrolyzed was determined at 585 nm using the Elson-Morgan's procedure, 
from which there were determined the effects of each test compound at 
various concentrations on the normal enzymatic reaction. 
The results are shown in FIG. 1. The solid circles along the ordinate 
indicate piroxicam, and the open deltas indicate 
4-hydroxy-2-methyl-N-(phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1-dioxa 
ne as discussed below. 
It has become clear from the results of FIG. 1 that the compound of the 
present invention has an excellent inhibitory action against 
hyaluronidase. 
In this test, there was also examined Piroxicam which is an inhibitor for 
cyclooxygenase. Although this drug belongs to benzothiazine-1,1-dioxide 
derivatives, it showed no effect on hyaluronidase activity at a 
concentration range of 0.01-0.3 mM employed in the test. Further, 
4-hydroxy-2-methyl-N-(phenyl)-2H-1,2-benzothiazine-3-carboxamido-1,1-dioxi 
de showed no effect either in the same concentration range. 
It has become clear from this test that the R.sub.1 of the 
benzothiazine-1,1-dioxide derivative represented by the general formula 
(I) and/or the general formula (II) must be a carboxyl group or a 
tetrazoyl group in order for the derivative to show a 
hyaluronidase-inhibiting action. 
It has also become clear that the hyaluronidase-inhibiting activity of the 
present compound is very high considering that the "50% enzyme inhibition" 
concentration of Tranilast [which is an anti-allergic agent and also a 
hyaluronidase-inhibiting agent reported by the present inventors in Chem. 
Pharm. Bull., 33 (9), 3738 (1985)] is about 0.23 mM. 
Pharmacological Test 2 
Action against rat plantar edema induced by carrageenin 
Male Sprague-Dawley rats weighing 200-250 g were injected s.c. 
(subcutaneously) with 0.1 ml of carrageenin into the subplantar region of 
the right hind paw. 60 minutes before the carrageenin administration, a 
test compound (compound No. 1) had been administered p.o. (orally). The 
compound No. 1 showed a noticeably high inhibitory action against edema in 
an administration amount of 200 mg per kg of rat body weight, as compared 
with the control where only the carrageenin solution was administered. 
That is, as shown in FIG. 2, in 30 minutes after the carrageenin 
administration, the swelling percent is 8.0% in the compound No. 1, while 
it is 18.2% in the control. Therefore, the inhibition of the compound No. 
1 reached 54% in 30 minutes after the carrageenin administration. About 
the same inhibition (%) was seen also in 1, 1.5, 2 and 3 hours after the 
carrageenin administration. Thus, the anti-inflammatory effect of the 
compound of the present invention was proven in this animal test. 
Pharmacological Test 3 
Action on histamine liberation from fat peritoneal mast cells by 
concanavalin A 
This test was effected in accordance with the method of R. P. Siraganian 
[J. Immunol., 114, 886 (1974)]. That is, a Locke solution containing 
phosphatidylserine, a test compound and a suspension of rat peritoneal 
mast cells was heated for 20 minutes at 37.degree. C. Incidentally, the 
concentrations of phosphatidylserine and the test compound in the Locke 
solution were 3.0 .mu.g/ml and 0.2 mM, respectively. A concanavalin A 
solution was added to the Locke solution, and the mixture was subjected to 
a reaction for 10 minutes at 37.degree. C. After ice-cooling, the reaction 
mixture was subjected to centrifugation for 10 minutes at 4.degree. C. 
Both the supernatant and the precipitate were measured for histamine 
content by the method of Shore et al. [J. Exp. Ther., 127, 182 (1959)] to 
determine a ratio of histamine liberated. The results are shown in Table 
2. As seen in Table 2, the compounds of the present invention showed an 
inhibitory action against the normal histamine liberation reaction without 
using any test compound. 
The present inventors had previously reported that known anti-allergic 
agents, for example, Tranilast shows, at 0.3 mM, an inhibition of about 
20% in the same reaction of histamine liberation from rat peritoneal mast 
cells by concanavalin A and thereby expresses an anti-allergic action 
[Chem. Pharm. Bull., 33 (9), 3738 (1985)]. As compared with that of 
Tranilast, the tested compounds of the present invention definitely show a 
very high activity, and this activity can lead to suppress allergic 
reaction effectively. 
Pharmacological Test 4 
Action on rat 48-hour homologous PCA reaction 
Male SD rats weighing 200-250 g were injected with 0.1 ml of a rat anti-egg 
albumin serum diluted with a physiological saline solution, intradermally 
at the back in order to passively sensitize the rats. After 48 hours, 0.5 
ml of 1% Evans Blue containing 5 mg of antigen (egg albumin) was 
administered intravenously. After 30 minutes, each rat was sacrificed by 
bleeding and the skin was peeled off. Then, the amount of the coloring 
material in the lesion was determined by the method of Katayama et al. 
[Microbial. Immunol., 122 (2), 89 (1987)]. Incidentally, each test 
compound had been administered orally 60 minutes before the antigen 
administration. 
The results are shown in Table 3. 
The compound No. 1 of the present invention showed a higher suppressive 
action than the control (Tranilast). 
Thus, the anti-allergic action of the compound of the present invention was 
proven in this animal test. 
Pharmacological Test 5 
Action on gastropathy 
The compound No. 1 of the present invention and two known cyclooxygenase 
inhibitors, i.e. Indometacin and Piroxicam were examined for action on rat 
gastric mucosa. That is, the compound No. 1, Indometacin or Piroxicam was 
administered orally to male SD rats (body weight: 200-250 g) which had 
been fasted for 24 hours. After the administration, the rats were allowed 
to no food and no water for 48 hours. Then, the stomach of each rat was 
removed under ether anesthesia and fixed with formalin. The resulting 
stomach was incised and the length of the mucous ulcer generated in the 
glandular portion of the stomach was measured using a dissecting 
microscope (magnification of 10). The results are shown in Table 4. No 
ulcer was seen in any of the rats to which the compound No. 1 of the 
present invention had been administered in an amount of 100, 300 or 500 
mg/kg. 
Meanwhile, when Piroxicam was administered, all the rats formed severe 
ulcer in an administration amount of 100 mg/kg, and 3 out of the 5 rats 
tested died and the surviving 2 rats formed very severe ulcer in an 
administration amount of 300 mg/kg. When Indometacin was administered, all 
the rats formed very serious ulcer in an administration amount of 50 
mg/kg. 
This test proved that the compound of the present invention causes no 
gastropathy. 
TABLE 2 
______________________________________ 
Inhibition 
Test compound 
Inhibition (%) 
Test compound 
(%) 
______________________________________ 
No. 1 93.9 No. 7 86.0 
No. 2 81.3 No. 8 83.7 
No. 3 65.0 No. 9 106.5 
No. 4 85.1 No. 10 90.7 
No. 5 85.2 No. 11 60.3 
No. 6 63.0 
______________________________________ 
TABLE 3 
__________________________________________________________________________ 
Amount Amount of colorant 
administered 
Administration 
which leaked out 
Suppression 
Test compound 
(mg/kg) 
route (.mu.g/site) 
(%) 
__________________________________________________________________________ 
Control -- p.o. 9.7 .+-. 1.9 
-- 
No. 1 200 p.o. 3.4 .+-. 1.3 
65.1 
No. 2 200 p.o. 6.8 .+-. 2.3 
29.3 
__________________________________________________________________________ 
TABLE 4 
__________________________________________________________________________ 
Amount Number of 
administered 
Administration 
rats in 
Ulcer index 
Test compound 
(mg/kg) 
route one group 
mean S.E. 
__________________________________________________________________________ 
No. 1 100 p.o. 5 0 
300 p.o. 4 0 
500 p.o. 5 0 
Piroxicam 
100 p.o. 5 14.4 .+-. 8.0 
300 p.o. 2* 65.5 .+-. 33.5 
Indometacin 
50 p.o. 5 42.8 .+-. 8.7 
__________________________________________________________________________ 
*Ulcer index was determined on 2 surviving rats of the 5 rats tested. 
Toxicity Test 1 
The compound of the present invention was further tested for acute toxicity 
by intravenous injection using male ddy mice. There was no death when the 
compound No. 1 of the present invention was administered in an amount of 
10-500 mg/kg (each group consisted of 10 mice). 
Thus, the compound of the present invention showed a very strong inhibitory 
action against hyaluronidase (which is an inflammatory enzyme), and 
exhibited suppressive effects for edema induced by carrageenin, liberation 
of histamine from rat peritoneal mast cells by concanavalin A, and rat 
homologous PCA reaction. 
Further, no gastropathy and no substantial adverse effect were seen both 
macroscopically and microscopically when the compound of the present 
invention was administered to a test animal in an amount exceeding the 
level at which the efficacy is expressed. 
Therefore, the compound of the present invention is useful as a drug for 
relaxation of the pain caused by diseases such as arthritis, rheumatic 
arthritis and the like and other inflammatory diseases and also for 
relaxation of diseases such as bronchial asthma, nasal allergy and other 
diseases caused by allergic reaction. 
Next, there are shown Preparation Examples of the pharmaceutical 
composition of the present invention. 
Preparation Example 1 
Tablets 
______________________________________ 
Compound No. 1 of the present invention 
50 g 
Lactose 10 g 
Corn starch 30 g 
Crystalline cellulose 8 g 
Hydroxypropyl cellulose 1 g 
Magnesium stearate 1 g 
100 g 
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Procedure 
There was mixed the compound No. 1 of the present invention, lactose, corn 
starch and crystalline cellulose. Thereto was added a solution of 
hydroxypropyl cellulose dissolved in 30 mol of water, and the resulting 
mixture was kneaded thoroughly. The kneaded material was passed through a 
20-mesh sieve to obtain granules. The granules were dried and then mixed 
with magnesium stearate. The mixture was made into tablets each of 100 mg. 
Preparation Example 2 
Capsules 
______________________________________ 
Compound No. 1 of the present invention 
100 g 
Lactose 100 g 
Corn starch 50 g 
Crystalline starch 47 g 
Magnesium stearate 3 g 
300 g 
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Procedure 
The above ingredients were mixed thoroughly and encapsulated by 300-g 
portions to obtain capsules. 
Preparation Example 3 
Granules 
______________________________________ 
Compound No. 1 of the present invention 
100 g 
Lactose 470 g 
Corn starch 400 g 
Hydroxypropyl cellulose 30 g 
1000 g 
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Procedure 
There were mixed the compound No. 1 of the present invention, lactose and 
corn starch. Thereto was added a solution of hydroxypropyl cellulose 
dissolved in 400 ml of water, and the mixture was kneaded thoroughly. The 
kneaded material was passed through a 29-mesh sieve to obtain pellets. The 
pellets were dried and then uniformalized in size to obtain granules. 
Preparation Example 4 
Suppositories 
______________________________________ 
Compound No. 1 of the present invention 
50 g 
Macrogol 4000 200 g 
Macrogol 1500 50 g 
300 g 
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Procedure 
Macrogols 4000 and 1500 were melted on a water bath. Thereto was added a 
fine powder of the compound No. 1 of the present invention. The mixture 
was stirred until the powder was dispersed uniformly. The dispersion was 
poured into a suppository mold to obtain suppositories. 
As described in detail above, there have been provided, according to the 
present invention, benzothiazine-1,1-dioxide derivatives having a 
hyaluronidase-inhibiting activity and useful as an active ingredient of 
drug, as well as a process for producing said derivative. 
There have also been provided pharmaceutical compositions comprising the 
above compounds as an anti-inflammatory agent or an anti-allergic agent.