JPS5899489A - Benzothienothiazine derivative and pharmaceutical composition containing the same - Google Patents

Abstract

NEW MATERIAL:4-Hydroxy-2-methyl-N-( 6-halogeno-2-pyridyl )-2H-[1]benzothieno-[2,3-e]-1,2-thazine-3-carboxamide, 1,1-dioxide of formulaI(X is halogen) and its salt. EXAMPLE:4-Hydroxy-2-methyl-N-( 6-chloro-2-pyridyl )-2H-[1]benzothieno-[2,3- e]-1,2-thiazine-3-carboxamide 1,1-dioxide. USE:Antiphlogistic agent having durable effect and low toxicity and troubles in the digestive tracts. PROCESS:The derivative of formulaIcan be prepared by the condensation reaction of the ester of formula II (R is 1-4C lower alkyl) with the aminopyridine compound of formula III (X is halogen) in an inert solvent such as xylene.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to benzochenothiazine derivatives represented by the general formula (1) (wherein X represents a halogen atom) and its conventional compounds,
Aspirin, ibuprofen, etc. have been known as anti-inflammatory, analgesic, and antipyretic agents, but recently, indomethacin, diclofenac sodium, etc., which have excellent anti-inflammatory effects, have been frequently used. However, these drugs have drawbacks such as strong side effects such as toxicity and gastric disorders, and lack of long-lasting effects. Therefore, benzothiazine-based piroxicam is being developed as a new type of anti-inflammatory agent with improved properties (for example, Av7ywQ
m-pea, ac (26, (7), 1300-130
3 (1976)), the generic name "oxicam" has been given to this family of compounds. However, although piroxicam also has excellent anti-inflammatory effects and long-lasting effects, it still causes gastric disorders that are typical of anti-inflammatory drugs, and is not much different from indomethacin or diclofenac sodium. Another oxicam, isoxicam, is also in development. However, although this compound has less toxicity and gastrointestinal disturbances, its anti-inflammatory activity is weaker than that of piroxicam (e.g. Reference Apyui AC Nine-ai, 5 256 (1999)).
75)).

Further, compounds belonging to this group include 4-hydroxy-2-methyl-N-(2-pyridyl)-214-(1)
Benzocheno(2,s-e)-1,2-thiazine-
An anti-inflammatory agent represented by 3-carboxamide 1,1-dioxide (hereinafter referred to as Compound-I) is known (Japanese Unexamined Patent Publications No. 55-35086 and No. 56-2991). However, as an anti-inflammatory agent, characteristics have not been sufficiently described.

The present inventors synthesized a number of compounds and investigated their physiological activities in detail in order to find drugs with strong anti-inflammatory activity, long-lasting effects, and low toxicity and gastrointestinal disorders. As a result, we succeeded in discovering various characteristics required as an anti-inflammatory agent in the compound represented by general formula (1).

Preparation of the compounds of the invention can be accomplished by several methods. For example, esters represented by general formula (2) (wherein R represents a lower alkyl group having 1 to 4 carbon atoms) and amino acids represented by general formula (3) (wherein X represents a halogen atom) Obtained by condensation reaction with pyridines. This reaction can be carried out, for example, by heating both components in an inert, high-boiling solvent such as xylene. In this case, in order to shorten the reaction time, it is advantageous to use the amine component in a stoichiometric excess of the ester component, and to set the reaction temperature at 100° or higher and as high as possible up to the boiling point of the solvent used. Reaction time is 4-3
0 hours, usually in the range of 8 to 20 hours. Also, the product-
Generally, it crystallizes and precipitates by cooling the reaction solution, so it is possible to separate it by another method and then purify it by washing and recrystallizing.

The compound of the present invention represented by the general formula (1) (hereinafter X=C1
In the case of , the compound is abbreviated as -ol, and when :go=p, the compound is abbreviated as the compound-F. ) as anti-inflammatory agents are detailed in Examples 3 to 7, and the experimental results are summarized in Tables 1 and 2. Data for control drugs Compound-I (indomethacin and diclozenaf sodium) are also described.

Table-1 * Literature value: Applied Pharmaceutical Landfill, (6), 1285 (1972
)※※Literature value: Nippon Yakurishi et al. 319 (1973) Table 2 From the results in Table 1, the characteristics of the compound of the present invention represented by general formula (1) can be evaluated as follows.

The ability of the compound of the present invention to inhibit carrageenan edema, that is, the potency of its action against acute inflammation, is between the conventional anti-inflammatory agents indomethacin and diclozenaf sodium and the new type of compound-H.

However, the dose that causes gastric disorder is higher than that of any of the comparative drugs, and therefore the therapeutic index is 4 to 5 times different. It can also be said that it is a compound with extremely low acute toxicity and a very high stability range. Compound-H has an excellent stability range, but its therapeutic index is comparable to that of conventional anti-inflammatory drugs, and it causes severe gastric irritation.

Furthermore, from the results in Table 2, the effect of the compound of the present invention represented by general formula (1) on adjuvant arthritis, that is, chronic inflammation, is that Compound-0e is equivalent to or greater than the comparative drug, but Compound- F is slightly inferior. However, in terms of therapeutic index against chronic inflammation, both compounds are superior to the comparators. Again, the therapeutic index of Compound-H is smaller than that of indomethacin, indicating no usefulness as a new type of anti-inflammatory agent.

Furthermore, as shown in Example 4, all of the compounds of the present invention were found to have anti-inflammatory effects equivalent to or longer than Compound-H in terms of durability.

Based on the above, when clinically applying the compound of the present invention represented by the general formula (]), it should be a drug with a high safety margin that maintains a strong anti-inflammatory effect, and which occurs frequently with non-steroidal anti-inflammatory drugs. It can be said that this drug has an extremely low risk of causing side effects such as gastric disorders.

The administration form of the compound of the present invention may be oral preparations such as tablets, capsules, powders, granules, etc., depending on the disease state and site of manifestation.
Alternatively, it is appropriately selected from suppositories, liquids, ointments, and injections such as intravenous and intramuscular injections. Among these, oral preparations and suppositories are particularly preferred. Dosage per adult per day is 1-100? yLfI, preferably in the range of 5 to 60 mg, typically taken once a day.

Next, the method of the present invention will be further explained by examples.

However, the method of this invention is not limited to the following examples.

Example 1 4-hydroxy-2-methyl-N-(6-chloro-2-
pyridyl)-2H-(1)benzocheno(2,3-e)
-Synthesis of 1,2-thiazine-3-carboxamide 1,1-dioxide (1) 2-amino-6-chloropyridine: 29 containing 100.6 g (0,68 mol) of 2,6-dichloropyridine
500 ml of thiammonia aqueous solution was heated to 190°0 in a 14 autoclave and reacted for 5.5 hours with stirring. - After cooling overnight, the precipitate was filtered once and washed with ice water. This was then dissolved in 500 ml of dichloromethane and the resulting solution was washed with 400 ml of water, dried and concentrated under reduced pressure to give the pale yellow title compound 6 as a residue.
2.8 g (71.8 g) was obtained.

Melting point near 3°C Thin layer chromatography: R1=o, 36 (solvent 0HzOJ
z: Et(l(=25:1)(2)4-hydroxy-2-methyl-N-(6-chloro-2-pyridyl)-2H-(1)-benzocheno(2j7e)-1,
2-77 gin-3-carboxamide 1,1-dioxide: 3-carbomethoxy-4-hydroxy-2-methyl-2
4.9 g of H-(1)benzocheno(2,3-e)-1,2-thiazine 1,1-dioxide and 70 g of 2-7mino-6-chloropyridine were added to 150 ml of xylene, and the mixture was heated at reflux temperature for 14 hours. Stirred.

After cooling the resulting reaction mixture and removing xylene under reduced pressure, the residue was washed with methanol and chloroform. The crude crystals were recrystallized from a mixed solvent of N,N-dimethylformamide and ethanol to obtain the title compound 3.7.
I got a 9.

Melting point = 238-240'O (decomposition) Elemental analysis value: 01yHx20A'N5O4Sz 01 (0#N8 Theoretical value (4) 48,40 2.86 8.40 9.
96 15.20 Actual value ((a) 48,69 2.75
85210.02 15.2ONMR(δ蒲″693
1m) = 302 (3H1s), 6.9~7.1 (I
H, m), 75-8.5 (7H, m), 11.1 (IH, 8) Example 2 4-hydroxy-2-methyl-N-(6-fluoro-2
-pyridyl)-2H-(1)benzochenoC2,5-e
) -j, 2-thiazine-6-carpoxyamide 1,
Synthesis of 1-dioxide (1) 2-amino-6-fluoropyridine: 48 ml of 29thiammonium aqueous solution containing 4.75 g of 2,6-difluoropyridine was heated to 150°0 in an autoclave and stirred for 45 minutes. I got a reaction. - After standing overnight, the precipitate was separated and washed with ice water. This product was then dissolved in 50 ml of dichloromethane, the resulting solution was washed with 40 ml of water, dried, and concentrated under reduced pressure. 3.4 g (75%) of the compound was obtained.

Melting point = 56-58°0 (2) 4-hydroxy-2-methyl-N-(6-fluoro-2-pyridyl)-2H-(1) Benzocheno(2,
3-e)-1,-2-thiazine-3-carboxamide 1,1-dioxide: 6-carbomethoxy-4-hydroxy-2-methyl-2
H-(1)benzocheno(2,3-e)-1,2-thiazine 1,1-dioxide 4.59 and 2-amino-6-fluoropyridine 2.4!
A! and stirred at reflux temperature for 9 hours. □The obtained reaction mixture was cooled, and the precipitated crystals were separated. This product was recrystallized from a mixed solvent of N,N-dimethylbormamide-ethanol to obtain 3.8 g of the title compound.

Melting point: 250-251°G (decomposition) Elemental analysis value @ 017”12FN30482 and shite HF
N5 Theoretical value (%9 50,362.9B 4.69 1
036 15.82 calculated value (@ 50.33 2,
82 4.61 10.27 j5.658.4 (8
H, m), 11.12 (IH, 8) Example 6 The anti-inflammatory effect by carrageenan edema method was assayed as follows. The compound to be tested was suspended in a 0.2% carboxymethylcellulose solution and orally administered to 7 male wiriln+ rats (0.5 ml, 17,100 g body weight).

One hour after administration of the test drug, 0.1 ml of a solution of carrageenan, which is known as an inflammatory agent, was injected subcutaneously into the right sole of the rat's foot. Six hours after the injection of carrageenan, the rats were sacrificed with ether, the ankle joints of both legs were cut, and the difference in weight was determined to calculate the edema suppression rate of the test drug relative to the control group (administered only the solvent).

The edema suppression rate is calculated using the following formula.

For each test drug, the ED50 value was determined and compared.

The experimental results are shown in the second column of Table-1.

Example 4 The durability of the anti-inflammatory effect by the carrageenan edema method was tested as follows.

ED for each test drug at 1 hour and 6 hours before administration, with carrageenin injection as the reference (0 hours)
The durability of the anti-inflammatory effect was examined by calculating the 50 value. As an indicator of the durability of anti-inflammatory effect, the 6-hour pre-administration ED5o/
The value of the ratio of ED ao administered 1 hour before was used. That is,
The closer this value is to 1, the better the sustainability is. The experimental method was the same as in the example. The results are shown in Table-3.

Table-6 Example 5 A? The anti-inflammatory effect by the Juvant arthritis method was assayed as follows.

Mycσ%c,i for SD male and female rats (8 weeks old)
4←b Temple C-J-A, i Cells at 0ゝ4mV [1
, 1 ml of liquid paraffin was injected into the skin of the right hind foot to relieve arthritis.

I woke up. Thereafter, the progress of disease onset was observed, and the body weight and swelling of the non-injected paw were measured two weeks later, and experimental groups were created so that the tumor rate, body weight, and date of onset were equal.

The test drug suspended in a solution of carboxymethyl cellulose was administered to the thus obtained homogeneous experimental group once a day for 7 days.
Orally administered for 1 day. During this period, body weight and sleepiness of the non-injected paw were measured orally.

ED30 was determined from the degree of suppression of swelling rate for 7 days compared to the control group to which only the solvent was administered.

The swelling rate was calculated using the following formula.

The ED30 value obtained for each test drug in the left hind shin volume before bacterial injection is shown in the second column of Table 2.

Example 6 Gastric Disorder Test in Rats Groups of 5 to 7 8-week-old W.L.4ia4 male rats were used. After fasting for 18 hours, each test drug was orally administered,
The animals were killed by decapitation 6 hours later. The helmet was removed, and after injecting 10ml of physiological saline, it was fixed with 5ml of neutral formalin solution. After about 10 minutes, a large incision was made and gastric disorder 1. In particular, observe the presence or absence of erodion,
Dose U to generate 50 thierodione by Non's method
D5. was calculated using the Lhi Kano11L4MuWLIGσ2 Hori method and is shown in the third column of Table-1.

Example 7 Acute toxicity was evaluated as follows.

Using ddy male mice (5 mice per group), the test drug suspended in 0.2% carboxymethyl cellulose was added in 2 ml/o.
After oral administration at a ratio of 1:9, observation was performed for 7 days, and the LD50 value was estimated based on the mortality rate on the final day.

The experimental results are shown in the fifth column of Table-1.

Example 8 Tablet composition containing compound -O4: Compound "06 10""4 Cornstarch 270mg Polyvinylpyrrolidone -15??+4 Stearin-plated magnesium -5mg Total 500yn-1 The above ingredients were compressed into tablets using a tablet machine.

Example 9 Capsule composition containing Compound-O4: Compound-Ol 10rrhg
Corn starch 23[]mf lactose 50yn4magnesium stearate 10mII was filled into hard gelatin capsules to prepare capsule size 11.

Example 10 20 ml of fine powder of suppository compound-cl containing compound-C4 was suspended in 5 ml of O, D, O (manufactured by Nisshin Oil Co., Ltd., medium chain fatty acid triglyceride) and filled into a soft gelatin capsule membrane. I got a suppository.

Patent applicant: Mitsui Toatsu Chemical Co., Ltd. Continuation of page 1 0 shots Mikio Kumakura 2141 Togo, Mobara City 0 shots clear by Takuo Nakano 2231-20 Kamigocho, Totsuka-ku, Yokohama City

Claims (1)

[Claims] (1) 4-hydroxy-2-methyl-N-(6-halogeno-2-pyridyl)-2H- represented by general formula (1) (wherein, X represents a halogen atom) (1) Benzocheno C
2,3-e)'-1,2-thiazine-6-ka (in the formula,
X represents a halogen atom) 4-hydroxy-2-methyl-N-(6-halogeno-2-pyridyl)-2H-(1']benzocheno(2,3-e)-1,2-thiazine A pharmaceutical composition containing -ro-carboxamide 1,1-dioxamide and its salt with a physiologically acceptable inorganic or organic base. (5) Claim 4 for use as an anti-inflammatory agent. The pharmaceutical composition described in Section 1.