the procedure of synthesizing the formula ( 1 ) compound is as follows : add formula ( 2 ) compound , formula ( 3 ) compound and anhydro - dimethylbenzene into a dry flask , mix with heating until reflux ; reflux for a certain period of time , and then introduce nitrogen gas to remove methanol resulted from the reaction ; continue reflux for several hours , then cool down , and put the reaction mixture in the refrigerator to crystallize the solid ; filter the solid by vacuum ; wash the solid with an appropriate amount of organic solvent ; let the solid dry to obtain the formula ( 1 ) compound . the formula ( 1 ) compounds have important bioactivities . the pharmacodynamic experiments have shown that the formula ( 1 ) compound has substantial effects in inhibiting dimethylbenzene induced mouse ear swelling , chemical stimulus induced pain , and carrageenan induced rat foot swelling . furthermore , the experiments have shown evident relationship between the dosage and effectiveness . these compounds can inhibit induced primary and secondary inflammations of rats on a dosage dependent basis . in comparison to the representative medicine of the same class , meloxicam , the formula ( 1 ) compounds have less side effects in causing rat stomach ulcer . the formula ( 1 ) compounds have enhanced therapeutic effect and reduced side effects . the ld 50 ( the single dosage causing 50 % death of the testing animals ) by oral and abdominal administration is in the range of from 200 to 500 mg / kg . the formula ( 1 ) compounds or their pharmaceutically acceptable salts or solvates can be combined with commonly used auxiliary or carriers to produce anti - inflammatory and analgesic pharmaceutical composition . this pharmaceutical composition can be in the form of injection solution , tablet or capsule . [ 0018 ] fig1 is the obtained curve showing the effect on the carrageenan induced rat foot swelling model , wherein the abscissa indicates time ( hour ), and the y - axis indicates the extent of the swelling . the present invention is further described in detail with following examples . add the compound ( 2 ) ( 1 . 5 g , 0 . 005 mol ), 2 - amido - 5 - methyl thiazole ( compound 3 ) ( 0 . 75 g , 0 . 0065 mol ) and dimethylbenzene ( 180 ml ) into a 500 ml dry tri - neck round bottom flask ; reflux with mixing under nitrogen atmosphere for ten hours , then cool down the reaction mixture ; filter to obtain 1 . 2 g yellow crystal of 6 - chlorine - 4 - hydroxy - 2 - methyl - n -[ 2 -( 5 - methyl ) thiazolyl ]- 2h - thieno -[ 2 , 3 - e ]- 1 , 2 - thiazine - 3 - formamide - 1 , 1 - dioxide , mp . : 245 ˜ 250 ° c . ; ms ( m / z ): 392 , 374 , 328 , 141 , 115 ; 1 hnmr ( dmso - d 6 ): δ 2 . 328 ( d , 3h , j = 6 ), 2 . 937 ( s , 3h ), 7 . 364 ( s , 1h , j = 6 ), 7 . 678 ( s , 1h ); 13 cnmr ( dmso - d 6 ) 165 . 528 , 163 . 503 , 155 . 943 , 138 . 012 , 136 . 395 , 134 . 720 , 124 . 305 , 122 . 572 , 111 . 559 , 38 . 320 , 11 . 664 . divide the mice randomly into five groups , with each team consisting of ten mice . the five groups are respectively the blank control group , the positive medicine control ( meloxicam ) group , and the testing groups which use low , medium and high dosages of the compound of example 1 . the mice of the positive medicine group were fed orally with 8 mg / kg meloxicam , and the mice of the three testing groups were fed with 2 mg / kg ( low ), 4 mg / kg ( medium ) and 8 mg / kg ( high ), respectively , the compound synthesized in example 1 . dimethylbenzene was used to induce ear swelling of the mice . the inhibition rate of the positive medicine group was 43 %, and the inhibition rate of the low , medium and high dosage testing groups were 56 %, 67 % and 81 %, respectively , which were significantly different from the blank control group ( p & lt ; 0 . 01 ), as shown in table 1 . divide the rats randomly into five groups , with each group consisting of ten rats . the five groups are the blank control group , the positive medicine control group ( meloxicam 4 mg / kg ), and the testing groups which use low , medium and high dosages of the compound of example 1 . use carrageenan induced inflammation to cause rat plantar swelling . the rats of the testing groups took 1 mg / kg ( low ), 2 mg / kg ( medium ) and 4 mg / kg ( high ), respectively , of the compound synthesized in example 1 . 2 - 6 hours after induced inflammation , the plantar swelling rate of the testing groups was significantly different from that of the blank control group ( p & lt ; 0 . 01 - 0 . 001 ). furthermore , the compound ( 1 ) is substantially more effective than the positive medicine meloxicam ( see table 2 and fig1 ). the mice in testing groups were orally fed with 2 mg / kg , 4 mg / kg and 8 mg / kg of the compound synthesized in example 1 . the chemical stimuli induced pain ( acetic acid body twist reaction ) of the mice in the testing groups were significantly different from that of the blank control group ( p & lt ; 0 . 01 - 0 . 001 ). the percentage of body twist for the 2 mg / kg ( low ), 4 mg / kg ( medium ) and 8 mg / kg ( high ) groups were 90 %, 80 % and 60 %. in comparison to the percentage of body twist ( 100 %) of the positive medicine meloxicam ( 8 mg / kg ), the compound synthesized in example 1 was substantially more effective ( see table 3 ). the rats in the testing groups orally took 1 mg / kg ( low ), 2 mg / kg ( medium ) and 4 mg / kg ( high ) of the compound synthesized in example 1 , and showed dosage dependent inhibition of the primary and secondary inflammation induced by adjuvant . the compound synthesized in example 1 showed substantial inhibition of the rat foot swelling at eighteen hours , twenty fourth hours , third days , eighth days and nineteen days after inflammation being induced , which was significantly different from the blank control group , p & lt ; 0 . 01 . the compound synthesized in example 1 was substantially more effective in comparison to meloxicam ( see table 4 ). it was observed that among the rats which took orally 1 mg / kg ( low ), 2 mg / kg ( medium ) and 4 mg / kg ( high ) the compound synthesized in example 1 continuously for four successive days , the occurring rate of ulcer increased with increased dosage , with corresponding ulcer occurring rate of 0 %, 30 % and 80 %, respectively . in comparison with 4 mg / kg meloxicam , which had the ulcer occurring rate of 100 %, the compound synthesized in example 1 had less side effect ( p & lt ; 0 . 01 , see table 5 ). select the compound synthesized in example 1 , which meet pharmaceutical preparation standard , as the raw material , and sieve the raw material . mix 8 weight units of the compound of example 1 , 100 weight units of mannitol and 40 weight units of peg - 400 homogeneously ; add injection use water and mix ; then add 1 mol / l naoh solution with mixing until ph was 9 . 45 . add active carbon , mix for twenty minutes at room temperature , then separate the active carbon . then add injection use water to obtain a final concentration of the compound synthesized in example 1 of about 4 mg / ml , and mix it homogeneously . filter with 0 . 22 μm micropore membrane in accordance with the aseptic operation in a class 100 laminar flow super - clean room . upon passing the qualification examination , fill the composition into 6 ml brown sealing bottles under aseptic condition and insert venting rubber stopper . put the bottles in a lypholyser , freeze , after three hours apply vacuum ; sublimation - drying for 24 hours , then seal and cover the stopper with the aluminum cover . package the sealing bottles after quality assurance check . every sealing bottle contained 8 mg the compound of example 1 . [ 0028 ] table 2 effects upon the carrageenan induced rat foot swelling ( n = 10 , x ± s ) dosage change in the foot volume at certain hours after giving the carrageenan group ( mg / kg ) one hour two hours three hours four hours five hours six hours blank control — 0 . 41 ± 0 . 18 0 . 70 ± 0 . 20 1 . 08 ± 0 . 21 1 . 20 ± 0 . 24 1 . 23 ± 0 . 24 1 . 24 ± 0 . 29 group meloxicam 4 . 0 0 . 39 ± 0 . 15 0 . 55 ± 0 . 21 0 . 57 ± 0 . 33 ** 0 . 70 ± 0 . 34 ** 0 . 89 ± 0 . 33 * 0 . 82 ± 0 . 39 * low 1 . 0 0 . 25 ± 0 . 15 0 . 56 ± 0 . 27 0 . 66 ± 0 . 34 ** 0 . 76 ± 0 . 28 ** 0 . 83 ± 0 . 28 ** 0 . 83 ± 0 . 25 ** medium 2 . 0 0 . 24 ± 0 . 11 * 0 . 39 ± 0 . 17 ** 0 . 63 ± 0 . 54 ** 0 . 70 ± 0 . 25 *** 0 . 79 ± 0 . 25 ** 0 . 80 ± 0 . 21 ** high 4 . 0 0 . 29 ± 0 . 20 0 . 37 ± 0 . 22 ** 0 . 50 ± 0 . 20 *** 0 . 59 ± 0 . 30 *** 0 . 60 ± 0 . 31 *** 0 . 64 ± 0 . 24 ** [ 0029 ] table 3 analgesic effects upon the body twist reaction induced by acetic acid dosage numbers of occurrence of percentage of group ( mg / kg ) body twist ({ overscore ( x )} ± s ) body twist (%) blank control — 44 . 22 ± 21 . 200 100 group meloxicam 8 . 0 18 . 11 ± 14 . 37 ** 100 high 8 . 0 2 . 78 ± 3 . 49 *** 60 medium 4 . 0 10 . 78 ± 8 . 15 ** 80 low 2 . 0 14 . 78 ± 6 . 38 ** 90 [ 0030 ] table 4 effects upon the adjuvant induced rat foot swelling ( x ± s , n = 10 ) rate of the change in the volume of left and right feet at certain time after dosage giving adjuvant group ( mg / kg ) 18 hours 24 hours 3 days 8 days 19 days blank control — 0 . 86 ± 0 . 17 0 . 96 ± 0 . 10 1 . 00 ± 0 . 13 1 . 12 ± 0 . 09 1 . 10 ± 0 . 12 group meloxicam 4 . 0 0 . 78 ± 0 . 13 0 . 76 ± 0 . 20 * 0 . 75 ± 0 . 14 ** 0 . 76 ± 0 . 23 *** 0 . 99 ± 1 . 29 low 1 . 0 0 . 77 ± 0 . 28 0 . 75 ± 0 . 24 * 0 . 74 ± 0 . 28 ** 0 . 75 ± 0 . 29 ** 0 . 97 ± 0 . 19 medium 2 . 0 0 . 62 ± 0 . 10 ** 0 . 60 ± 0 . 10 *** 0 . 61 ± 0 . 13 *** 0 . 60 ± 0 . 14 *** 0 . 69 ± 1 . 10 high 4 . 0 0 . 65 ± 0 . 08 ** 0 . 65 ± 0 . 12 ** 0 . 53 ± 0 . 13 *** 0 . 63 ± 0 . 16 *** 0 . 72 ± 1 . 12 [ 0031 ] table 5 effects on causing rat gastric mucosa ulcer dosage number of the ulcer occurring rate group ( mg / kg ) animals ( unit ) (%) blank control — 10 0 group meloxicam 4 10 100 high 4 10 80 medium 2 10 30 low 1 10 0 while the present invention has been described in detail and pictorially shown in the accompanying drawings , these should not be construed as limitations on the scope of the present invention , but rather as an exemplification of preferred embodiments thereof . it will be apparent , however , that various modifications and changes can be made within the spirit and the scope of this invention as described in the above specification and defined in the appended claims and their legal equivalents .
the present invention is related to a type of thienothiazine compounds having molecular structure of formula and their pharmaceutically acceptable salts or solvates . the present invention is also related to the method of producing the formula compound , an anti - inflammatory and analgesic pharmaceutical composition containing the formula compound , and the method of using the formula compound to prepare anti - inflammatory and analgesic medicine .