JPS61161281A - 1,2-benzothiazine-3-carboxamide derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is 5-chloro-3-methyl-2-pyridyl, 3,5-dichloro-6-methyl-2-pyridyl, 4-propyl-2-pyridyl, etc.; R2 is lower alkyl). EXAMPLE:4-Hydroxy-2-methyl-N-( 5-chloro-3-methyl-2-pyridyl )-2H-1, 2-benzothia zine-3-carboxamide-1,1-dioxide. USE:An anti-inflammatory agent. It is a low-toxic compound having low side effects such as digestive tract disorder, and useful for the remedy of inflammation of mammals. PREPARATION:The compound of formula I can be produced by condensing 1,2-benzoxazine-3-carboxylic acid of formula II or its reactive derivative with e.g. an acid chloride, acid anhydride or the amine of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention is directed to 1,2-benzothiazine-3 useful as a medicine.
- Regarding carboxamide derivatives, more specifically 4-hydroxy-2-methyl-N-substituted- having anti-inflammatory effect
2H-1,2-benzothiazine-3-carboxamide
1. Regarding age oxide.

Background of the Invention In recent years, as non-steroidal anti-inflammatory agents, a new type of so-called oxicam-based compound having a benzothiazine skeleton has been used instead of the classic phenylacetic acid-based, phenylpropionic-based compounds having a carboxyl group. Chemicals have appeared (Japanese Patent Publication No. 51-42114, Japanese Patent Publication No. 33075-1975, Japanese Patent Publication No. 92976-1980,
JP-A-57-14589, JP-A-57-140785
No., Japanese Patent Publication No. 57-139076). Among these compounds, some have been found to have stronger anti-inflammatory effects than their predecessors (eg, piroxicam, stoxicam).

Problems to be Solved by the Invention However, even with the above-mentioned conventional oxicam compounds, there remains a problem to be solved in that they have strong side effects such as gastrointestinal disorders, which can be said to be fateful for conventional non-steroidal anti-inflammatory drugs.

Means for Solving the Problems In view of the above technical situation, the present inventors conducted various studies, discovered a new anti-inflammatory oxicam compound with few side effects, and completed the present invention.

Accordingly, it is an object of the present invention to provide such pharmaceutically useful anti-inflammatory compounds.

The present invention is based on the general formula CI) H (wherein R1 is 5-chloro-3-methyl-2-pyridyl, 3,5-dichloro-6-methyl-2-pyridyl, 4-
Propyl-2-hy+)dyl, 3.5-cyclolo4.6
-Simethyl-2-pyridyl, 3-benzyloxy-2-
Pyridyl, 3,5-dichloro-4-methyl-2-pyridyl, 2,4-dimethy/I/-6-pyrimidyl, 1,3-
Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidyl, 4,5-dihydrothiazol-2-yl, 5-nitrothiazol-2-yl, 1.3
．． 4-thiadiazol-2-yl, 5-mercapto-1
, 3,4-thiadiazol-2-yl, pyrazole-3
-yl, benzimidazol-2-yl, 4-methylbenzothiazol-2-yl or 3,5-dichloro-2
-pyridyl, and R1 represents lower alkyl. ) The present invention relates to a 1,2-benzothiazine-3-carboxamide derivative represented by:

The lower alkyl group for R1 in the above general formula (I) includes methyl, ethyl, propyl, i-propyl, n-1
C1-C such as 4- or 5ec-butyl, pentyl group
6 alkyl groups are mentioned.

The following are listed as specific compounds of the present invention. (The numbers in parentheses indicate compound numbers used in this specification.) ■4-Hydroxy-2-methyl-N-(5-riIff
O-3-methyl-2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide l,1-dioxide (Ia) ■4-hydroxy-2-methyl-N-(3,5-dichloro-6-methyl -2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (Ib) ■4-hydroxy-2-methyl-N-(4-propyl-
2-pyridyl) -2H-1,2-benzothiazine-3
-Carboxamide 1,1 dioxide (Ic) ■4-Hydroxy-2-methyl-N-(3,5-dichloro-4,6-', ;methyl-2-pyridyl)-2H-1
,2-benzothiazine-3-carboxamide 1,1-dioxide (Id) -di- ■4-hydroxy-2-methyl-N-(3-benzyloxy-2-pyridyl)-2H-1,2-benzothiazine-3- Carboxamide 1,1-dioxide (Ie) ■4-hydroxy-2-methyl-N-(3,5-dichloro-4-methyl-2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 11, 1-dioxide (If) ■4-Hydroxy-2-methyl-N-(2,4-dimethyl-6-pyrimidyl)-28-1,2-benzothiazine-3-carboxamide 1,1-dioxide (Ig) ■4 -Hydroxy-2-methyl-N-(1,3-dimethyl-2,4-dioxy-1,2,3,4-tetrahydro-6-pyrimidyl)-2H-1,2-benzothiazine-
3-Carboxamide 1,1-dioxide (Ih) ■4-Hydroxy-2-methyl-N-(4,5-dihydrothiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-di Oxide (I
+) (04-hydroxy-2-methyl-N-(5-nitrothiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1 dioxide (I
, i) 04-hydroxy-2-methyl-N-(1,3,4-thiadiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (I
k) ◎4-hydroxy-2-methyl-N-(5-mercapto-1,3,4-thiadiazol-2-yl)-2H-1
,2-benzothiazine-3-carboxamide 1,1-
Dioxide (Il) 04-hydroxy-2-methyl-N-(pyrazole-3
-yl)-2H-1,2-benzothiazin-3-carboxamide 1,1-dioxide (1m) 04-hydroxy-2-methyl-N-(benzimidazol-2-yl) -2T(-1,2- Benzothiazine-3-carboxamide 1,1-dioxide (In) 04-hydroxy-2-methyl-N-(4-methylbenzothiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1 -dioxide (I
o) o4-hydroxy-2-methyl-N-(3,5-dichloro-2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (
Ip) Various methods can be employed to produce the compound of the present invention, but a typical method can be represented by the following chemical formula.

(and) (I) or a reactive derivative thereof (in the formula 3, R2 is the same as defined above), i.e. 1,2-benzoxazine-3-carboxylic acid of formula (6) or a reactive derivative thereof and an amine ), the desired 1,2-benzoxazine-3-carboxamide derivative (I) can be synthesized.

In the above synthesis method, free carboxylic acid (II) may be directly condensed with an amine (e.g., heated condensation in the presence of an appropriate solvent), but it is generally preferable to use a reactive derivative of carboxylic acid OD. . Such reactive derivatives include acid halides (e.g. acid chloride, acid bromide), acid anhydrides [(e.g. acetic acid, isovaleric acid, mesylic acid, p-
anhydride with toluic acid; alkyl haloformes such as ethoxycarbonyl chloride); DCC (dicyclohexylcarbodiimide); water-soluble DCC: gEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), Phosphate esters such as phenylhumesphite; acid anhydrides derived using ethoxyacetylene, enamine, etc.], active esters (e.g. lower alkyl esters such as methyl ester and ethyl ester)
Phenol, p-=)lophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol,
Thiophenol, p-nitrothiophenol phenyl ester; benzyl ester), active 77 species (
Examples include acid amide derived using carbonyldiimidazole), and other known reagents used in the field of peptide synthetic chemistry may also be employed.

Further, the corresponding phosphoric acid and the like may be used as a reactive derivative of the raw material amine.

This condensation reaction is generally carried out in the presence of a solvent. Such a solvent is preferably a solvent that does not directly participate in the reaction, such as ethers such as tetrahydrofuran and dioxane, DMF, and DMSO.

Chloroform, dichloromethane, hirisine, benzene,
Examples include toluene, xylene, ethyl acetate, and mixtures thereof. The reaction temperature is usually -20℃~200℃
The reaction time is usually about 30 minutes to 72 hours.

The target compound obtained by the above condensation reaction is collected by means known per se (eg, extraction, distribution, recrystallization, reprecipitation, column chromatography). The collected compound can be converted into a salt form according to a conventional method, and such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid;
Examples include salts with organic acids such as acetic acid, lactic acid, methanesulfonic acid, cabsylic acid, citric acid, fumaric acid, and tartaric acid.

Therefore, such salts are also included as compounds of the present invention.

When the compound of the present invention is used as a medicine, the administration form may be oral or parenteral.

In the case of oral administration, the compound of the present invention or the salt itself may be administered, but usually appropriate additives are added and tablets, tablets, etc.
It is administered in the form of powders, granules, capsules, syrups, etc. These additives include dezopun, lactose,
Known formulation ingredients such as diluents such as cellulose, disintegrants or compounding agents; lubricants such as magnesium stearate can be selected.

In the case of parenteral administration, injections and rectal administration are typical preparations, for example, the compound of the present invention or the above salt and an injection solvent (e.g. distilled water, propylene glycol), oils and fats (e.g.
It is dissolved or suspended in cocoa butter, polyoxyethylene sorbitan fatty acid ester), etc., and a surfactant (
Example: nonionic surfactant such as polysorbate 80)
is used with the addition of.

The above preparations can be manufactured by known methods such as those described in the 10th edition of the Japanese Pharmacopoeia General Rules for Preparations.

Effect The compound of the present invention is a low-toxic compound with few side effects such as gastrointestinal disorders, and is useful as a medicine such as an anti-inflammatory agent for inflammation in mammals such as humans, monkeys, dogs, rabbits, rats, and mice.

The dose of the compound of the present invention for adult human beings varies depending on the route of administration, but is usually about 5 to 500 kg per dose, preferably about 10 to 200 kg, depending on the patient's age, symptoms, body weight, It is preferable to increase or decrease the dose as appropriate depending on your medical history and other factors.

Example (1) - (11 Compound (La) - (Ip) c
Production D (4-hydroxy-2-methyl-N-(5-
Chlor-3-methyl-2-pyridyl)-2H-1,2-
Benzothiazine-3-carboxamide 1,1-dioxide (Ia) 4-hydroxy-2-methyl-2I (-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide (hereinafter abbreviated as rBcMJ). )0.5.li
+, 2-amino-5-chloro-3-methylpyridine 0.
Nitrogen gas was introduced into a mixture of 6 g of dry xylene and 30 g of dry xylene for 5 minutes while stirring, and then heated under reflux for 16.5 hours. After the reaction, the produced solid was separated and extracted with hot chloroform. The remaining yellow crystals obtained by distilling off the solvent from the extract were recrystallized from acetonitrile to give 0.1 g (1
4.2%).゛Melting point 227-228°C (decomposition) NMR spectrum (d, -DMSO) δ: 2.2
8 (3H, S, Ar-CH5), 2.90 (3H
, S, N-CH5).

7.5-8.5 (7B, m, ArHan (I C
0NH).

IR spectrum (sha, ') m-1: 3100,290
0,1630°1540.1390,1330,116
0,760,570° The following compounds (Ib to Ip) were obtained using BGM and various amines in the same manner as in the above example.

(2) 4-hydroxy-2-methyl-N-(3,5-dichloro-6-methyl-2-pyridyl)-2H-1,2-
Benzothiazine-3-carboxamide 1,1-dioxide (Ib) Melting point 178-180.5°C (decomposition) Yield 15.6%N
MR spectrum (CD C13) δ: 2.62 (3H
, S , Ar-CH,), 2.97 (3H,S,N-
CH5), 7.3-&2(5H,m,ArH), 8.7
0 (1B, broad, C0NH).

IR spectrum inkstone g branch) zl: 3300, 1610,
1580°1555.1490,1420,1350,
1150,1170,5700(3)4-hydroxy-
2-Methyl-N-(4-propyl-2-pyridyl)-2
H-1,2-benzothiazine-3-carboxamide 1
,1-dioxide (Ic) Melting point 163-164°C Yield 31.9% NMR spectrum (CDC13) δ: 0.98 (3Jt, J==7
Hz, CHs), 1.3-2. I C2H,
m, CAI,).

2.67 (2H,t, J=7H2,CH,), l
9 3 (3H, S.

N-CH,), 6.89 (IH, dd, pyridine nucleus 3H) + 7.5-8.4 (6H, m, ArH),
9.08 (IH, broad.

C0NHn.

kBr-x.

IR spectrum (max)”, 3100, 2900
゜1600.1520,1420,1350,1300
,1170,760°620.570°(4)4-hydroxy-2-methyl-N-(3,5-dichloro-4,6-dimethyl-2-pyridyl)-2H-1
,2-benzothiazine-3-carboxamide 1,1-dioxide (Id) Melting point 163-165°C Yield 15. o% NMR spectrum (CD(J, )δ: 2.47 (3H.

S, Ar-CH8), 2.55 (3H, S, Ar
CH,), 2.90 (3H,S,N-CH,),
7.3-8.2 (4H, m, ArH).

8, 70 (IH, broad, CONH).

kBr-z.

IR spectrum () cm, 37002900a
X 1615.15B0, 150Q, 1350, 1260.
1180. Boo.

760.630° (5) 4-hydroxy-2-methyl-N-(3-benzyloxy-2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1 dioxide (Ie
) Melting point: 215-223°C (decomposition) Yield: 46.2cm NMR
Spectrum (d, -DMSO) δ: 2.80 (
3B,S,N-CH,), 5.37 (2H,S,
CH,), 6.9-8.3(13,H,,m,ArH
and C0NH), 1570 (IH, broad,
0H) kBr-1°IR spectrum ()cm, 3450,3000
゜max 1600.1560, 1430, 1380, 1330,
1310,1180°1030.760,740 (6) 4-hydroxy-2-methyl-N-(3,5-dichloro-6-methyl-2-pyridyl)-2H-1,2-
Benzothiazine-3-carboxamide 1,1-dioxide (If) Melting point 222-227°C (decomposition) Yield 35.1-NMR
Spectrum (CDC4) δ: 2. ．． 52 (3H
,S.

N-CH5), 2.9 7 (3H, S, N-C
H5), 7.4-8.2 (4H, m, ArH)
, 8.32 (IH,S, pyridine nucleus 2H).

8.9 5 (IH, S, C0NH), 1 3.1
3 (IH,S,0I()kBr-1.

IR spectrum ()cm, 33501640ax 1570.1500,1430,1330,1150,
840,760°690.640 (7) 4-hydroxy-2-methyl-N -(2,4-
dimethyl-6-pyrimidyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (
Ig) Melting point 207-208°C (decomposition) Yield 35.8% NMR
Spectrum (CDCIIs + do DMSO)
δ: 2, 48 (3H, S, CHs) t z58
(3HtS+CHs C2,88(3H,S,N-CH
3), 7.5-8.3 (5H, m, ArH) kB
r-1°IR spectrum (n1ax)ffi, 325J
3100°1650.1510,1380,1320,
1150,850,770(8)4-hydroxy-2-
Methyl-N-(1,3-dimethyl-2,4-dioxy-
1,2,3,4-tetrahydro-6-pyrimidyl)-2
H-1,2-benzothiazine-3-carboxamide 1
,1-dioxide (Ih) Melting point 290-290.5℃ Yield 13.2% NMR spectrum (d, -DMSO) δ: 3.05 (3'f
(,S,N-CH,), 3.32 (3H,S,
N-CI(,), 3.6 7 (3H,S,N-
CIH, ), 7.67-8.6 7 (5H, m
, ArHand C0NB) kBr-1.

IR spectrum ()cm, 2950, 1700°max 1640.1600, 1350, 1280, 1170,
850,780° (9) 4-hydroxy-2-methyl-
N-(4,5-dihydrothiazol-2-yl)-2H
-1,2-benzothiazine-3-carboxamide 1,
1-dioxide (Ii) Melting point 300°C Yield 28.2% NMR spectrum (da DMSO) δ: 3.05
(3H,S,N-CH5), 3.62 (2H,t
, J=7Hz, CH,).

4, 45 (2H, t, J=7Hz, CH, L 7.5
-8.5 (5H.

m, ArHand C0NH) kBr-1°IR spectrum () cm * 3400, 1655°max 1580.1550, 1380, 1340.1170,
840,780004-hydroxy-2-methyl-N-
(5-nitrothiazol-2-yl) -2H-1,2
-Benzothiazine-3-carboxamide 1,1-dioxide (Ij) Melting point 246.5-247°C Yield 632% NMR spectrum (d6-DMSO) δ: 2.82 (3H, S, N-
CH5), 7.6-8.2 (5H, m, ArHa
nd C0NH), 8.6 5 (LH, 81 thiazole nucleus IH) kBr ~1・IR spectrum ()α, 3200, 3100°m
ax 1630.1590, 1520, 1470, 1350,
1300,1170°810.770,730 ■4-Hydroxy-2-methyl-N-(1,3,4-thiadiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide ( I
k) Melting point 238-239°C (decomposition) Yield 3Z8% NMR spectrum (d, -DMSO) δ: 2.85 (3H,
S, N-CH3), 7.5-8.2 (5H, m,
ArHand C0NH), 9.03 (IH,S
, thiadiazole nucleus IH)kBr-1゜IR spectrum ()cm, 3200, 2800゜
ax 1590.1510, 1320, 1280, 1170,
830,760g a4-hydroxy-2-methyl-N-
(5-mercapto-1,3,4-thiadiazole-2-
yl)-2H1+2-benzothiazine-3-carboxamide 1,1-dioxide (I i) Melting point 221-2
28°C (decomposition) Yield 80.9% NMR spectrum (d
a DMSO) δ: 2.80 (3H, S, N
-CH, ), 7.5-8.2 (5H,m, ArH
and C0NH) kBr-1°IR spectrum ()cm, 3250,3100
゜max 2850.1640, 1600, 1550, 1460,
1350,1300°1260.760 034-hydroxy-2-methyl-N-(pyrazole-
3-yl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (1m) Melting point 22
1-222℃ yield 48.6% NMR spectrum (d,
-DMSO) δ: 2.83 (3H,S,N-OH
,), 6.47-8.17 (8I(,m,ArH
and C0NH), 10.55 (IH, bro
ad, 0H) kBr-1.

IR spectrum (max)z, 3400,16
30°1570.1480,1340,1280.11
80.770Qe 4-hydroxy-2-methyl-N-
(benzimidazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (In) Melting point 300°C or higher Yield 31.9% NMR spectrum (d, -DMSO) δ: 3 .07(
3H,S,N-CH3), 7.0-s, 6
(IOH, m, ArHandCONB) kBr-1°IR spectrum () crn, 3200, 1665°ma
x 1570.1340,1240,1150,900,7
80054-Hydroxy-2-methyl-N-(4-methylbenzothiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (10) Melting point 227-228°C or higher Yield 33.6% NMR spectrum (d6-DMSO) δ: 2.57 (3H, S,
Ar-CH8), l88 (3H,S,N-CH,
L'y, 0-8, 3 (8B, m, ArHand
C0NH)kBr-1°IR spectrum ()cfn, 3250, 1610°ma
x 1590.1520, 1480, 1340, 1260,
1160,840゜αQ4-hydroxy-2-methyl-N-(3,5-dichloro-2-pyridyl)-2H-1
,2-benzothiazine-3-carboxamide 1,1-
Dioxide (Ip) Melting point 191-193.5℃ or higher Yield 17.6% NMR
Spectrum (CDCz8) δ: 2.97 (3H,
S.

N-OH, ), 7.4-8.8 (sH,m, Ar
H), s, 35 (IH, d, J=2) (Z, pyridine nucleus 2H), 8.93 (IH, broad.

C0NH), 13.10 (IH, S, 0H) kB
r-1°IR spectrum ()cm, 3300,1610
, 1580aX , 1555, 1490, 1420, 1350, 1270
, 1180, 1160° 830.760, 710 When the compound of the present invention is used, for example, as an anti-inflammatory agent, it can be used, for example, in the following formulation.

Preparation Example (Tablet) Compound (I) 50 ■ Lactose 20 ■ Starch 5 Q mV Cellulose 5 rng Binder Appropriate Lubricant Appropriate The above composition is mixed and compressed according to a conventional method to produce a tablet.

Effect of the invention Examples of pharmacological tests on the compounds of the present invention are listed below.

Anti-inflammatory effect test using carrageenan edema method (experimental method) SlC-8D fibrous runt (5 weeks old, weight 14l40-
16O to the sample [compound of the present invention (1) and pyroki 3igm
(manufactured by Company A, suspended in physiological saline) 0.075 m, 1 was injected subcutaneously into the right hind leg. The foot condition was measured every hour after the injection using the mercury method, and the edema suppression rate (18
%) was calculated. The control group was a group to which only the aqueous solution of gum arabic was orally administered.

For the oral administration group, autopsy was performed after the above test was completed to observe the presence or absence of gastrointestinal disorders.

(Results) Table 1 shows the measurement results of the edema suppression rate. The above autopsy (
As a result of pathological observation of the gastrointestinal tract, etc., no gastrointestinal disorder was observed in the group administered with the compound of the present invention, but intestinal ulcers were observed on the side of the body in the group administered with piroxicam. .

The data in the first coating above is 2-! of each sample. , or 4-1Kf
The figure shows the maximum edema suppression rate 4 hours after administration.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1) (In the formula, R_1 is 5-chloro-3-methyl-2-pyridyl, 3-5 dichloro-6-methyl-2- Pyridyl, 4-
Propyl-2-pyridyl, 3,5-dichloro-4,6-
Dimethyl-2-pyridyl, 3-benzyloxy-2-pyridyl, 3,5-dichloro-4-methyl-2-pyridyl, 2,4-dimethyl-6-pyrimidyl, 1,3-dimethyl-2,4-dioxy -1,2,3,4-tetrahydro-6-pyrimidyl, 4,5-dihydrothiazole-2-
yl, 5-nitrothiazol-2-yl, 1,3,4-
Thiadiazol-2-yl, 5-mercapto-1,3,
4-thiadiazol-2-yl, pyrazol-3-yl, benzimidazol-2-yl, 4-methylbenzothiazol-2-yl or 3,5-dichloro-2-pyridyl, and R_2 represents a lower alkyl group. represent. ) A 1,2-benzothiazine-3-carboxamide derivative represented by: