CN1191240C - Nitrogen monoxide synthase inhibitor, its preparation method and application - Google Patents

Abstract

The present invention relates to a novel compound with a general formula (I), wherein R1 represents hydrogen, chlorine, bromine, methyl or methoxy groups; R2 represents hydrogen, the alkyl of C1 to C4 or phenyl; R3 represents the alkyl of C1 to C4, allyl, benzyl or substituted benzyl; X represents nitrogen or sulfur. The present invention also discloses a preparation method of the compound with the general formula (I), a medical composition containing the I and a use thereof for treating septic shock, enteritis, rheumarthritis, diabetes, cerebral ischemic injury, presenile dementia, etc.

Description

Nitric oxide synthase inhibitors and its production and use

Technical field

The present invention relates to new isothiourea class compound, their preparation method, the medicinal compositions that contains these compounds and their medical use, particularly as the purposes of nitric oxide synthase inhibitors.

Background technology

Septic shock is present intractable disease, does not still have active drug clinically, and mortality ratio is high.Some disease such as sacroiliitis does not still have good medicine at present.Wherein the excessive NO that is produced by iNOS catalysis is the major reason that causes septic shock and inflammation, and therefore, exploitation iNOS inhibitor has the potential therapeutic value to these diseases.

Obtaining many progress in research aspect the no inhibitor in recent years, wherein, the compound that contains the isothiourea structure have preferably NOS suppress active (Southan GJ, Szabo C.Biochem Pharmacol.1996,51:383-394).1997, (Shearer BG such as Shearer BG, et al.J Med Chem.1997,40 (12): 1901-1905) report S-ethyl-N-substituted-phenyl isothiourea has stronger NOS restraining effect, and nNOS had selectivity, but they are eliminated rapidly in vivo, have influenced its using value.

Summary of the invention

The present invention is on the basis of no inhibitor research in the past, selecting the N-phenyl isothiourea is parent nucleus, introduce (replacement) benzimidazolyl-2 radicals-sulfydryl in the contraposition of phenyl again with ring-type isothiourea structure, or its bioisostere (replacement) benzothiazole-2-sulfydryl, a series of new isothiourea class compounds have been designed and synthesized, through preliminary pharmacology test, The compounds of this invention all has certain NOS to suppress active.

The isothiourea class compound of (replacement) benzo miaow of a series of containing (thiophene) azoles-2-sulfydryl that the present invention designs and synthesizes, general formula is as follows:

R wherein ₁Can represent hydrogen, chlorine, bromine, methyl or methoxy; R ₂Expression hydrogen, C _1-4Alkyl or phenyl; R ₃Expression C _1-4Alkyl, allyl group or (replacement) benzyl; X represents nitrogen or sulphur.

Preferred compound is: R ₁Expression hydrogen, chlorine or methoxyl group; R ₂Expression hydrogen, methyl, propyl group or phenyl; R ₃(substituting group can be 2-Cl, 2-Br, 2-CN, 2-NO for expression methyl, ethyl, normal-butyl, allyl group, benzyl or substituted benzyl ₂, 4-Cl, 4-Br, 4-CN, 4-NO ₂.3,4-methylene-dioxy); X represents nitrogen or sulphur.

More preferred compound is: R ₁Expression hydrogen or methoxyl group, R ₂Expression methyl or n-propyl, R ₃Expression methyl, ethyl, normal-butyl, benzyl or 4-cyano group benzyl.

According to the present invention, pharmacy acceptable salt comprises the acid salt that forms with following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid, Phenylsulfonic acid

The compound of above-mentioned general formula and pharmacy acceptable salt thereof can be:

S-methyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea hydriodate (I-1)

S-ethyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea hydriodate (I-2)

S-normal-butyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea hydriodate (I-3)

S-allyl group-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea hydrobromate (I-4)

S-benzyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-5)

S-p-chlorobenzyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-6)

S-is to cyano group benzyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea hydrobromate (I-7)

S-is to nitrobenzyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea hydrobromate (I-8)

S-(3, the 4-dimethoxy-benzyl)-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-9)

S-(3, the 4-methylenedioxy benzyl)-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-10)

S-methyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-11)

S-ethyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydriodate (I-12)

S-normal-butyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydriodate (I-13)

S-allyl group-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydrobromate (I-14)

S-benzyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-15)

S-p-chlorobenzyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-16)

S-is to cyano group benzyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydrobromate (I-17)

S-is to nitrobenzyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydrobromate (I-18)

S-(3, the 4-methylenedioxy benzyl)-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-19)

S-methyl isophthalic acid-methyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-20)

S-ethyl-1-methyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-21)

S-normal-butyl-1-methyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-22)

S-methyl isophthalic acid-n-propyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-23)

S-ethyl-1-n-propyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-24)

S-normal-butyl-1-n-propyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-25)

S-methyl isophthalic acid-phenyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-26)

S-ethyl-1-phenyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-27)

S-normal-butyl-1-phenyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiourea (I-28)

S-allyl group-1-phenyl-4-[3-(benzimidazolyl-2 radicals-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-29)

S-methyl isophthalic acid-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydriodate (I-30)

S-ethyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-31)

S-normal-butyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-32)

S-allyl group-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-33)

S-benzyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-34)

S-is to cyano group benzyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-35)

S-is to nitrobenzyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydrobromate (I-36)

S-methyl isophthalic acid-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydriodate (I-37)

S-ethyl-1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-38)

S-normal-butyl-1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-39)

S-allyl group-1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea (I-40)

S-methyl isophthalic acid-methyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiourea (I-41)

S-normal-butyl-1-methyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiourea (I-42)

S-benzyl-1-methyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-43)

S-ethyl-1-n-propyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiourea (I-44)

S-normal-butyl-1-n-propyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiuronium salts hydrochlorate (I-45)

S-ethyl-1-phenyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiourea (I-46)

S-normal-butyl-1-phenyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] isothiourea (I-47)

S-methyl isophthalic acid-methyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] isothiourea (I-48)

S-normal-butyl-1-methyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] isothiourea (I-49)

S-is to nitrobenzyl-1-methyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] isothiourea hydrobromate (I-50)

S-ethyl-1-n-propyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] isothiourea (I-51)

S-normal-butyl-1-n-propyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] isothiourea (I-52)

The preparation method of general formula (I) compound is as follows:

Work as R ₂Be hydrogen, R ₃During for the alkyl of C1-4, allyl group, benzyl or substituted benzyl, the preparation method is as follows:

Work as R ₂Be C _1-4Alkyl or phenyl, R ₃During for C1-4 alkyl, allyl group, benzyl or substituted benzyl, the preparation method is as follows:

Wherein X represents nitrogen or sulphur, and solvent orange 2 A is an aprotic polar solvent, and solvent B is acetone or acetonitrile, and solvent C is acetone, C _1-4Alcohol, acetonitrile or N, dinethylformamide, Y represents halogen.

The preferred acetonitrile of aprotic polar solvent, Nitromethane 99Min., nitroethane, N among the above-mentioned preparation method, dinethylformamide or methyl-sulphoxide.

The pharmacology test result shows, the compound of general formula (I) and pharmacy acceptable salt thereof all have in various degree restraining effect to iNOS in the macrophages in vitro, therefore, formula (I) compound and pharmacy acceptable salt thereof can be used for the treatment of the clinical disease relevant with the iNOS inhibitor.These illnesss comprise septic shock, enteritis, rheumatic arthritis, diabetes, cerebrum ischemia damage and presenile dementia etc.

The pharmacologically active testing method of part of compounds is as follows: get 10 of Kunming kind female mices, abdominal injection 2% talcum powder suspension 0.4ml/ only, behind the 48h, abdominal injection BCG (bacille Calmette-Guerin vaccine, bacillus calmette-guerin) 0.4ml and rTNF10 ten thousand units behind the 5d, put to death the dislocation of mouse cervical vertebra, the HBSS solution of 37 ℃ of preheatings of abdominal injection 5ml is immediately gently rubbed belly 3～5min.With 75% alcohol disinfecting skin of abdomen, cut off an osculum, sucking-off intraperitoneal liquid, use again 1ml HBSS solution (Hank ' s balanced salt solution withoutCa ²⁺, Mg ²⁺) the flushing abdominal cavity once.The liquid and the washing fluid of sucking-off are merged, be transferred in the centrifuge tube of silication, the centrifugal 5min of 10000rpm abandons supernatant liquor, and the cell of precipitation is resuspended with the DMEM substratum of 25ml preheating, be transferred in (1ml/ hole) on the 24 porocyte culture plates, and 37 ℃, 5%CO ₂After cultivating 4h, the visible adherent scavenger cell of microscopically.The careful DMEM substratum that goes in the culture hole of inhaling along the HBSS solution 1ml/ hole of 37 ℃ of preheatings of hole wall adding, adds every hole 0.1mol/L L-arginine gently then, LPS 20ug, rTNF100 unit, the every hole of dosing holes adds the 10ul soup, and control wells adds the 10ul solvent.37 ℃, 5%CO ₂Cultivate 20h, culture supernatant 500ul is got in every hole ,-70 ℃ of preservations.

Get above-mentioned preservation sample, melt under the room temperature, press kit method and measure NO content.The content of NO in the sample is represented the activity of iNOS in the scavenger cell.By the NO content of dosing holes and the NO content of control wells, be calculated as follows the active percentage that suppresses of iNOS:

By the iNOS maximum inhibition of 3 concentration medicines, calculate the IC of each medicine with the Logit method ₅₀Value.

Above pharmacologically active testing method reference literature reported method (Zhu D.Y., Li R., Liu G.Q.etal..Life Sci, 1999,65 (14): PL221-231).

Part of compounds pharmacology test result is as follows:

Compound IC ₅₀(mol/L) Compound IC ₅₀(mol/L)

Aminoguanidine 2.3 * 10 ^-6I-21 8.9 * 10 ^-5

I-1 9.1×10 ^-6 I-22 ＞10 ^-5

I-2 2.2×10 ^-6 I-23 1.2×10 ^-6

I-3 6.7×10 ^-6 I-24 7.9×10 ^-6

I-4 8.5×10 ^-6 I-25 3.3×10 ^-6

I-5 1.3×10 ^-5 I-26 3.6×10 ^-5

I-6 9.3×10 ^-6 I-27 8.1×10 ^-6

I-7 2.2×10 ^-5 I-28 7.5×10 ^-6

I-8 8.7×10 ^-6 I-29 2.1×10 ^-5

I-9 1.8×10 ^-5 I-30 3.0×10 ^-7

I-10 8.7×10 ^-6 I-31 3.2×10 ^-7

I-11 4.0×10 ^-5 I-32 5.0×10 ^-7*

I-12 7.7×10 ^-6 I-33 6.2×10 ^-6

I-13 7.7×10 ^-5 I-34 4.4×10 ^-7*

I-14 3.9×10 ^-5 I-35 1.6×10 ^-7*

I-15 8.2×10 ^-5 I-36 6.5×10 ^-6

I-16 3.4×10 ^-5 I-37 6.5×10 ^-5

I-17 9.1×10 ^-5 I-38 1.9×10 ^-6*

I-18 3.4×10 ^-5 I-39 8.7×10 ^-8*

I-19 2.1×10 ^-5 I-40 1.1×10 ^-6*

I-20 6.6×10 ^-6

Aminoguanidine: positive control drug, the iNOS selective depressant is in the III phase clinical study stage at present, is used for the treatment of diabetes.

The pharmaceutical composition of a kind of treatment and NO synthase inhibitor diseases associated wherein contains general formula (I) compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutical composition can be a dosage form conventional on the technology of pharmaceutics such as tablet, capsule, injection.

Embodiment

The preparation example of part active compound is as follows:

Fusing point is measured with b shape melting point tube, and medium is a methyl-silicone oil, and thermometer is not proofreaied and correct; Ultimate analysis is measured with CarloErba 1106 type elemental analysers; IR spectrum Nicolet Impact 410 type determination of infrared spectroscopy, the KBr compressing tablet; ¹HNMR finishes (mark in the TMS) with JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser; MS measures with Nicolet2000 type Fourier transform mass spectrometer and HP 1100 type mass spectrographs.

Example 1

S-methyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea hydriodate (I-1)

2-(4-nitrophenylsulfenyl) benzoglyoxaline (III-1):

With 2-mercaptobenzimidazole 9.5g (63.3mmol), anhydrous acetonitrile 60ml, powdered sodium hydroxide 2.53g (63.3mmol), p-Nitrophenyl chloride 9.98g (63.3mmol) and PEG-400 1.0g add in the pressure bottle, place 120 ℃ of oil baths to react 28h under the induction stirring, cooling, suction filtration, cold acetonitrile washing secondary is washed to pH7 again, get yellow solid (III-1) 15.1g (87.9%), 185～186 ℃ of mp.

¹HNMR(90MHz，CDCl ₃+DMSO-d ₆)，δ(ppm)：7.17～7.32(2H，m，ArH)，7.47～7.62(4H，m，ArH)，8.04～8.20(2H，m，ArH)

2-(4-amino-benzene sulfenyl) benzoglyoxaline (IV-1):

Reduced iron powder 10g (179mmol) and 95% ethanol 200ml are added in the three-necked bottle, drip 10%HCl 8.4ml under the mechanical stirring, behind the 10min, add compound (III-1) 11.3g (41.7mmol), be warming up to 55 ℃, reaction 4h transfers pH8.5～9.5 with 40%NaOH, add activated carbon decolorizing 10min, suction filtration while hot, iron mud concentrates with 95% washing with alcohol secondary, filtrate decompression, get light yellow crystal (IV-1) 9.3g (92.5%), 234～237 ℃ of mp.

¹HNMR(90MHz，CD ₃COCD ₃)，δ(ppm)：5.11(3H，brs，NH)，6.68～6.78(2H，m，ArH)，7.04～7.14(2H，m，ArH)，7.32～7.41(4H，m，ArH)

1-benzoyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] thiocarbamide (V-1):

Ammonium thiocyanate 2.36g (31.0mmol) and anhydrous propanone 20ml are added in the three-necked bottle, in 5min, splash into Benzoyl chloride 3.54g (25.2mmol) under the mechanical stirring, behind the backflow 20min, slowly drip compound (IV-1) 5.0g (20.7mmol) and the suspension that anhydrous propanone 50ml forms, continue backflow 12h, cooling, suction filtration, use acetone and water washing successively, get yellow solid (V-1) 8.2g (97.8%), 216～218 ℃ of mp.

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：5.64(1H，s，NH)，6.91～8.16(13H，m，ArH)，11.5(1H，s，-C ₆H ₅-NH-CS-)，12.9(1H，s，-NH-CO-C ₆H ₅)

N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] thiocarbamide (VI-1)

With compound (V-1) 8.1g (200mmol), THF 90ml, 2mol/L NaOH 22ml mixes, and stirring and refluxing 5.5h removes THF under reduced pressure, add water 22ml, reacting liquor while hot filters through gac, and filtrate is transferred pH8.5 with 1mol/LHCl, suction filtration, wash faint yellow solid (VI-1) 4.6g (76.5%), 196～198 ℃ of mp.

IR (cm ^-1): 3340,3265,3169 (NH), 3075,3052 (ArH), 1619,1587,1518,1495 (C=C, C=N), 1404 (imidazoles), 813 (ArH replaces two), 744 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：7.08～7.23(2H，m，ArH)，7.14～7.53(8H，m，ArH+NH ₂)，9.83(2H，brs，NH)

MS(LC/MSD(+)70V，m/z)：323.0([M+Na] ⁺)，301.1([M+H] ⁺，base?peak)

Compound (VI-1) 0.6g (2.0mmol) and anhydrous propanone 8ml are mixed, and dropping methyl iodide 0.375ml under stirring (0.855g, 6.0mmol), backflow 6h, cooling, suction filtration, washing with acetone gets light yellow crystal (I-1) 0.8g (90.5%), 186～187 ℃ of mp.

IR (cm ^-1): 3300 (NH), 3126～2710 (NH ₃ ⁺), 3098 (ArH), 2953,2835 (CH), 1704 (C=N), 1629,1583,1552 (C=C, C=N), 1425,1403 (imidazoles), 748 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：2.12(3H，s，-S-CH ₃)，7.15～7.68(8H，m，ArH)，7.68～9.60(4H，br， ⁺NH ₃+NH)

MS(SCI?70eV，m/z)：315(M+1)，298(M-16)，284，142(base?peak)

Anal(C ₁₅H ₁₄N ₄S ₂·HI；C％，H％，N％)：Req?40.73，3.42，12.67?Found?40.56，3.50，12.44

Example 2

S-ethyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea hydriodate (I-2)

With compound (VI-1) and iodoethane (mol ratio 1: 3) is raw material, and the method for similar compound (I-1) gets light yellow crystal (I-2,54.8%), 148～150 ℃ of mp.

IR (cm ^-1): 3443,3407 (NH), 3135～2835 ( ⁺NH ₃), 3082 (ArH), 2977,2930 (CH), 1628,1546,1524 (C=C, C=N), 1426,1403 (imidazoles), 1269 (SCH ₂-), 749 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：1.38(3H，t，J＝7.33Hz，-S-CH ₂-CH ₃)，3.30(2H，q，J＝7.08Hz，-S-CH ₂-)，7.16～7.58(8H，m，ArH)，7.58～9.80(4H，br， ⁺NH ₃+NH)

MS(SCI?70eV，m/z)：329(M+1)，312(M-16)，284，254，242(base?peak)

Anal(C ₁₆H ₁₆N ₄S ₂·HI；C％，H％，N％)：Req?42.11，3.75，12.28?Found?41.89，3.84，12.06

Example 3

S-normal-butyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea hydriodate (I-3)

With compound (VI-1) and iodo-n-butane (mol ratio 1: 3) is raw material, and the method for similar compound (I-1) gets light yellow crystal (I-3,62%), 176～177 ℃ of mp

IR (cm ^-1): 3149～2734 ( ⁺NH ₃), 3077 (ArH), 2958,2928 (CH), 1627,1587,1544,1516 (C=C, C=N), 1422,1407 (imidazoles), 1269 (SCH ₂-), 737 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：0.95(3H，t，J＝6.48Hz，-S-(CH ₂) ₃-CH ₃)，1.33～1.77(4H，m，-S-CH ₂-CH ₂CH ₂-CH ₃)，3.26(2H，t，J＝7.02Hz，-S-CH ₂-)，7.14～7.67(8H，m，ArH)，7.7～10.0(4H，br， ⁺NH ₃+NH)

MS(SCI?70eV，m/z)：357(M+1)，284，242，184，57(base?peak)

Anal(C ₁₈H ₂₀N ₄S ₂·HI；C％，H％，N％)：Req?44.63，4.37，11.57?Found?44.36，4.55，11.29

Example 4

S-allyl group-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea hydrobromate (I-4)

With compound (VI-1) and allyl bromide 98 (mol ratio 1: 1.2) is raw material, and the method for similar compound (I-1) gets light yellow crystal (I-4,35.6%), 184～186 ℃ of mp

IR (cm ^-1): 3444 (NH), 3140～2710 ( ⁺NH ₃), 2970 (CH), 1635,1582,1554 (C=C, C=N), 1423,1403 (imidazoles), 1269 (SCH ₂-), 745 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.07(2H，d，J＝6.75Hz，-S-CH ₂-)，5.23～5.57(2H，m，＝CH ₂)，5.7～6.1(1H，m，-S-CH ₂-CH＝CH ₂)，7.25～7.80(8H，m，ArH)，8.78(4H，brs， ⁺NH ₃+NH)

MS(SCI?70eV，m/z)：341(M+1)，324(M-16)，284(base?peak)，242

Anal(C ₁₇H ₁₆N ₄S ₂·HBr；C％，H％，N％)：Req?48.46，4.07，13.30?Found?48.13，4.09，13.17

Example 5

S-is to cyano group benzyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea hydrobromate (I-7)

With compound (VI-1) with to cyano-benzyl bromide (mol ratio 1: 1.2) is raw material, and the method for similar compound (I-1) gets crude product, gets white crystal (I-7,60.5%), 182～184 ℃ of mp with recrystallizing methanol

IR (cm ^-1): 3461,3289 (NH), 3110～2770 ( ⁺NH ₃), 3062 (ArH), 2955 (CH), 2237 (CN), 1636,1583,1553,1500 (C=C, C=N), 1440,1401 (imidazoles), 1267 (SCH ₂-), 738 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.76(2H，s，-S-CH ₂-)，7.15～7.92(12H，m，ArH)，7.92～10.8(4H，br， ⁺NH ₃+NH)

MS(LC/MSD(+)70V，m/z)：416.1([M+H] ⁺，base?peak)

Anal(C ₂₂H ₁₇N ₅S ₂·HBr；C％，H％，N％)：Req?53.23，3.65，14.11?Found?52.96，3.63，13.78

Example 6

S-is to nitrobenzyl-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea hydrobromate (I-8)

With compound (VI-1) with to nitro bromobenzyl (mol ratio 1: 1.2) is raw material, and the method for similar compound (I-1) gets light yellow crystal (I-8,87.2%), 186～188 ℃ of mp

IR (cm ^-1): 3380,3276 (NH), 3168～2700 ( ⁺NH ₃), 3072 (ArH), 2967,2851 (CH), 1624,1600,1577 (C=C, C=N), 1520,1342 (NO ₂), 1413 (imidazoles), 1267 (SCH ₂-), 855 (ArH replaces two), 746 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.78(2H，s，-S-CH ₂-)，5.69(4H，br，+NH ₃+NH)，7.14～7.30(4H，m，ArH)，7.48～7.78(6H，m，ArH)，8.07～8.26(2H，m，ArH)

MS(LC/MSD(+)70V，m/z)：436.1([M+H] ⁺，base?peak)

Anal(C ₂₁H ₁₈BrN ₅O ₂S ₂；C％，H％，N％)：Req?48.84，3.51，13.56?Found?48.68，3.49，13.16

Example 7

S-(3, the 4-methylenedioxy benzyl)-N-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiuronium salts hydrochlorate (I-10)

With compound (VI-1) and 3,4-methylene-dioxy benzyl chloride (mol ratio 1: 1.2) is a raw material, the method for similar compound (I-1), crude product, with anhydrous methanol refining white crystal (I-10,53.1%), 192～193 ℃ of mp

IR (cm ^-1): 3430 (NH), 3140～2765 ( ⁺NH ₃), 3070 (ArH), 2949,2893 (CH), 1651,1590,1559,1502,1488 (C=C, C=N), 1417,1403 (imidazoles), 1269 (SCH ₂-), 1249,1039 (ArOR), 822 (ArH replaces two), 747 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.59(2H，s，-S-CH ₂-)，5.99(2H，s，-O-CH ₂-O-)，6.82～7.65(11H，m，ArH)，7.65～10.2(4H，br，+NH ₃+NH)

MS(ESI(+)70V，m/z)：457.0([M+Na] ⁺)，435.1([M+H] ⁺，base?peak)

Anal(C ₂₂H ₁₈N ₄O ₂S ₂·HCl；C％，H％，N％)：Req?56.10，4.07，11.90?Found?55.89，3.87，11.64

Example 8

S-methyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-11)

2-(4-oil of mirbane sulfydryl) benzothiazole (III-2):

2-mercaptobenzothiazole 7.7g (46.0mmol), anhydrous acetonitrile 37ml, powdered sodium hydroxide 1.9g (47.5mmol), p-Nitrophenyl chloride 7.25g (46.0mmol) and PEG-400 0.9g are added in the pressure bottle, place 120 ℃ of oil baths to react 20h under the induction stirring, cooling, suction filtration, cold acetonitrile washing secondary, wash with water again to pH7, get orange solid (III-2) 11.1g (83.6%), 114～116 ℃ of mp

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：7.35～7.50(2H，m，ArH)，7.70～7.98(4H，m，ArH)，8.17～8.30(2H，m，ArH)

2-(4-amino-benzene sulfydryl) benzothiazole (IV-2):

Reduced iron powder 6.9g (123mmol) and 95% ethanol 150ml are added in the three-necked bottle, drip 10%HCl 6ml under the mechanical stirring, behind the 10min, add compound (III-2) 8.4g (29.1mmol), be warming up to 55 ℃, reaction 3.5h transfers pH8.5～9.5 with 40%NaOH, add activated carbon decolorizing 10min, suction filtration while hot, iron mud concentrates with 95% washing with alcohol secondary, filtrate decompression, light yellow crystal (IV-2) 6.9g (91.7%), mp110～111 ℃

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.56(2H，brs，NH ₂)，6.68～6.77(2H，d，ArH)，7.11～7.43(4H，m，ArH)，7.60～7.80(2H，m，ArH)

1-benzoyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] thiocarbamide (V-2):

Ammonium thiocyanate 3.3g (43.4mmol) and anhydrous propanone 20ml are added in the three-necked bottle, in 5min, drip Benzoyl chloride 6g (42.7mmol) under the mechanical stirring, behind the backflow 20min, slowly drip the solution that compound (IV-2) 11g (42.6mmol) and anhydrous propanone 130ml form, continue backflow 6.5h, cooling, suction filtration, use acetone and water washing successively, get faint yellow solid (V-2) 16.8g (93.7%), 191～193 ℃ of mp

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：7.25～8.02(13H，m，ArH)，9.11(1H，brs，-C ₆H ₅-NH-CS-)，12.89(1H，brs，-CS-NH-CO-)

N-[4-(benzothiazole-2-sulfydryl) phenyl] thiocarbamide (VI-2):

With compound (V-2) 5.0g (11.9mmol) and 10%NaOH 50ml mixing, in 80 ℃ of reaction 3.5h, add water 100ml under stirring, cooling, suction filtration, water washing gets faint yellow solid (VI-2) 3.2g (85%), 158～160 ℃ of mp

IR (cm ^-1): 3416,3234,3156 (NH), 3058,3041 (ArH), 2981 (CH), 1616,1572,1500 (C=C, C=N), 1424 (thiazoles), 811 (ArH replaces two), 758 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：7.25～7.50(4H，m，ArH)，7.58～7.86(6H，m，ArH+NH ₂)，9.98(1H，brs，NH)

MS(LC/ESI(+)/MSD?70V，m/z)：340.0([M+Na] ⁺)，318.0([M+H] ⁺，base?peak)

Compound (VI-2) 0.6g (1.89mmol) and anhydrous propanone 10ml are mixed, and adding methyl iodide 0.53ml under stirring (1.21g, 8.52mmol), backflow 7h, cooling, suction filtration, washing with acetone gets white crystal, above-mentioned white crystal is dissolved in DMF 5ml, through activated carbon filtration, filtrate is transferred pH9 with 5%NaOH, cooling, suction filtration, water and cold acetone washing successively, get white solid (I-11) 0.4g (63.8%), 112～115 ℃ of mp

IR (cm ^-1): 3349,3285 (NH ₂), 3062 (ArH), 2925,2897 (CH), 1639,1574 (C=C, C=N), 1425 (thiazoles), 863 (ArH replaces two), 753 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：2.42(3H，s，-S-CH ₃)，3.61(2H，br，NH ₂)，7.05～7.82(8H，m，ArH)

MS(EI?70eV，m/z)：331(M ⁺)，284(base?peak)，257，241，167

Anal(C ₁₅H ₁₃N ₃S ₃；C％，H％，N％)：Req?54.35，3.95，12.68?Found?54.22，4.03，12.49

Example 9

S-ethyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] isothiourea hydriodate (I-12)

Compound (VI-2) 0.5g (1.58mmol) and anhydrous propanone 8ml are mixed, and adding iodoethane 0.64ml under stirring (1.24g, 7.94mmol), backflow 8h, cooling, suction filtration, washing with acetone gets pale yellow crystals (I-12) 0.65g (87.2%), 163～165 ℃ of mp

IR (cm ^-1): 3255～2771 ( ⁺NH ₃), 3065,3049 (ArH), 2924,2825 (CH), 1625,1581,1519 (C=C, C=N), 1423 (thiazoles), 1227 (SCH ₂-), 758 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：1.42(3H，t，J＝7.47Hz，-CH ₂CH ₃)，3.35(2H，q，J＝7.32Hz，-S-CH ₂-CH ₃)，7.23～7.50(4H，m，ArH)，7.76～7.85(4H，m，ArH)，9.53(3H，brs， ⁺NH ₃)

MS(SCI?70eV，m/z)：346(M+1)，300，284，258，241，156(base?peak)

Anal(C ₁₆H ₁₅N ₃S ₃·HI；C％，H％，N％)：Req?40.59，3.41，8.88?Found?40.32，3.46，8.64

Example 10

S-benzyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiuronium salts hydrochlorate (I-15)

With compound (VI-2) and benzyl chloride is raw material (mol ratio 1: 1.2), and the method for similar compound (I-12) gets faint yellow solid, uses the anhydrous methanol recrystallization, gets off-white color crystal (I-15,64.3%), 155～157 ℃ of mp

IR (cm-1): 3458,3382,3085～2790 (NH, ⁺NH ₃), 3058 (ArH), 2982,2931 (CH), 1638,1581,1555 (C=C, C=N), 1428 (thiazoles), 1235 (SCH ₂-), 753 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.75(2H，s，-S-CH ₂-)，7.37～7.47(9H，m，ArH)，7.74～7.84(4H，m，ArH)，10.2(3H，br， ⁺NH ₃)

MS(ESI(+)70V，m/z)：430.0([M+Na] ⁺)，408.0([M+H] ⁺，base?peak)

Anal(C ₂₁H ₁₇N ₃S ₃·HCl·H ₂O；C％，H％，N％)：Req?54.59，4.36，9.09?Found?54.94，4.38，8.91

Example 11

S-p-chlorobenzyl-N-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiuronium salts hydrochlorate (I-16)

With compound (VI-2) and 4-chlorobenzyl chloride is raw material (mol ratio 1: 2.5), and the method for similar compound (I-12) gets off-white color crystal (I-16,80%), 157～158 ℃ of mp

IR (cm ^-1): 3456,3393 (NH), 3099～2767 ( ⁺NH ₃), 3056 (ArH), 2981,2937 (CH), 1637,1584,1556 (C=C, C=N), 1426 (thiazoles), 1233 (SCH ₂-), 839 (ArH replaces two), 753 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：4.75(2H，s，-S-CH ₂-)，7.27～7.53(8H，m，ArH)，7.72～7.98(4H，m，ArH)，10.2(3H，br， ⁺NH ₃)

MS(ESI(+)70V，m/z)：442.0([M+H] ⁺，base?peak)

Anal(C ₂₁H ₁₇ClN ₃S ₃·HCl·0.5H ₂O；C％，H％，N％)：Req?51.74，3.93，8.62?Found51.67，3.95，8.32

Example 12

S-methyl isophthalic acid-methyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea (I-20)

1-methyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] thiocarbamide (VII-1):

Compound (IV-1) 4.0g (16.6mmol) and dehydrated alcohol 60ml are mixed, add Trapex 2.0g (27.4mmol), stirring and refluxing 11h, activated carbon decolorizing, filtrate suitably concentrates, it is an amount of to add ethyl acetate, cooling, suction filtration, ethyl acetate washing, get light yellow solid (VII-1) 4.5g (86.3%), 194～196 ℃ of mp.

IR (cm ^-1): 3337,3174 (NH), 3050 (ArH), 2961 (CH), 1581,1550,1527,1491 (C=C, C=N), 1411 (imidazoles), 827 (ArH replaces two), 748 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：3.05(3H，d，-NH-CH ₃)，6.56(2H，br，-HNCSNH-)，7.11～7.26(2H，m，ArH)，7.40～7.57(6H，m，ArH)，9.38(1H，brs，NH)

MS(LC/MSD(+)70V，m/z)：353.0([M+K] ⁺)，337.1([M+Na] ⁺)，315.0([M+H] ⁺，base?peak)

MS(EI?70eV，m/z)：284，283，282(base?peak)，241，224

Anal(C ₁₅H ₁₄N ₄S ₂·0.5H ₂O；C％，H％，N％)：Req?55.70，4.67，17.32?Found?55.75，4.47，17.56

Compound (VII-1) 0.3g (0.95mmol) and anhydrous propanone 6ml are mixed, add methyl iodide 0.18ml (0.41g under the induction stirring, 2.86mmol), backflow 7h, column chromatography for separation (eluent: benzene: ethyl acetate: triethylamine=9: 1: 0.5), get white solid (I-20) 0.15g (47.9%), 180～182 ℃ of mp

IR (cm ^-1): 3378 (NH), 3030 (ArH), 2956 (CH), 1600,1578,1482 (C=C, C=N), 1408 (imidazoles), 837 (ArH replaces two), 750 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：2.31(3H，s，-S-CH ₃)，2.96(3H，s，-N-CH ₃)，6.92～7.02(2H，m，ArH)，7.11～7.25(4H，m，ArH)，7.39～7.58(4H，m，ArH+NH)

MS(EI?70eV，m/z)：328(M ⁺)，281(base?peak)，265，240，149

Anal(C ₁₆H ₁₆N ₄S ₂；C％，H％，N％)：Req?58.51，4.91，17.06 Found?58.38，4.86，16.82

Example 13

S-methyl isophthalic acid-n-propyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea (I-23)

1-n-propyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] thiocarbamide (VII-2):

With compound (IV-1) and isothiocyanic acid n-propyl (mol ratio 1: 1.66) is raw material, and the method for similar compound (VII-1) gets light yellow solid (VII-2,91.5%), 186～188 ℃ of mp

IR (cm ^-1): 3261 (NH), 3051 (ArH), 2960,2930,2871 (CH), 1607,1578,1551,1493 (C=C, C=N), 1406 (imidazoles), 752 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：0.95(3H，t，J＝7.33Hz，-NH-CH ₂CH ₂CH ₃)，1.40～1.75(2H，m，-NH-CH ₂-CH ₂-CH ₃)，3.45(2H，m，-NH-CH ₂-)，7.08～7.19(2H，m，ArH)，7.43～7.52(6H，m，ArH)，9.29(1H，brs，NH)

MS(LC/MSD(+)70V，m/z)：365.1([M+Na] ⁺)，343.1([M+H] ⁺，base?peak)

Anal(C ₁₇H ₁₈N ₄S ₂；C％，H％，N％)：Req?59.62，5.30，16.36?Found?59.62，5.49，16.24

With compound (VII-2) and methyl iodide (mol ratio 1: 3) is raw material, the method of similar compound (I-20), column chromatography for separation (eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=3: 1: 0.3), get white crystal (I-23,48.0%), mp is 168～171 ℃.

IR (cm ^-1): 3348 (NH), 2956,2867 (CH), 1598,1579,1483 (C=C, C=N), 1412 (imidazoles), 1270 (SCH ₂-), 751 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：0.96(3H，t，J＝7.08Hz，-NCH ₂CH ₂CH ₃)，1.45～1.70(2H，m，-N-CH ₂CH ₂-CH ₃)，2.31(3H，s，-S-CH ₃)，3.32(2H，t，J＝7.33Hz，-S-CH ₂-CH ₂-)，6.92～7.02(2H，m，ArH)，7.11～7.25(4H，m，ArH)，7.40～7.58(4H，m，ArH+NH)

MS(EI?70eV，m/z)：356(M ⁺)，341，309(base?peak)，265，252，240，224，149

Anal(C ₁₈H ₂₀N ₄S ₂；C％，H％，N％)：Req?60.64，5.65，15.72?Found?60.35，5.42，16.05

Example 14

S-normal-butyl-1-n-propyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea (I-25)

With compound (VII-2) and iodo-n-butane (mol ratio 1: 3) is raw material, the method of similar compound (I-20), column chromatography for separation (gradient elution agent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=3～1: 1: 0.15～0.1), get white solid (I-25,57.3%), mp is 86～89 ℃.

IR (cm ^-1): 3363 (NH), 3059 (ArH), 2957,2928,2876 (CH), 1597,1577 (C=C, C=N), 1413 (imidazoles), 1268 (SCH ₂-), 750 (ArH, adjacent two replace)

¹HNMR(90MHz，CD ₃COCD ₃+CDCl ₃)，δ(ppm)：0.84～1.01(6H，m，-NCH ₂CH ₂CH ₃+-SCH ₂CH ₂CH ₂CH ₃)，1.15～1.80(6H，m，-SCH ₂CH ₂CH ₂CH ₃+-NCH ₂CH ₂CH ₃)，2.79(2H，t，J＝7.32Hz，-SCH ₂CH ₂-)，3.32(2H，t，J＝7.32Hz，-N-CH ₂-CH ₂-)，6.82～6.92(2H，m，ArH)，7.07～7.17(2H，m，ArH)，7.39～7.92(6H，m，ArH+NH)

MS(EI?70eV，m/z)：398(M ⁺)，342，308，282，265(base?peak)，240，224，150

Anal(C ₂₁H ₂₆N ₄S ₂；C％，H％，N％)：Req?63.28，6.58，14.06?Found?63.53，6.70，14.17

Example 15

S-methyl isophthalic acid-phenyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] preparation of isothiourea (I-26)

1-phenyl-3-[4-(benzimidazolyl-2 radicals-sulfydryl) phenyl] thiocarbamide (VII-3):

Compound (IV-1) 3.0g (12.4mmol) and anhydrous acetonitrile 50ml are mixed, add thiocarbanil 2.8g (20.7mmol), stirring and refluxing 20h, cooling, suction filtration, the acetonitrile washing gets faint yellow solid (VII-3) 4.2g (89.6%), mp 210～212C

IR (cm ^-1): 3259 (NH), 3028 (ArH), 2956,2873 (CH), 1589,1539 (C=C, C=N), 1408 (imidazoles), 751 (ArH, adjacent two replace)

¹HNMR(300MHz，DMSO-d ₆+CD ₃COCD ₃)，δ(ppm)：7.60～7.64(3H，m，ArH)，7.78～7.84(2H，m，ArH)，8.0～8.10(6H，m，ArH)，8.20～8.25(2H，m，ArH)，10.3(3H，m，NH)

MS(LC/MSD?ESI(+)70V，m/z)：399.2([M+Na] ⁺)，377.2([M+H] ⁺，base?peak)

Compound (VII-3) 0.3g (0.80mmol) and anhydrous propanone 5ml are mixed, add methyl iodide 0.15ml (0.34g under the induction stirring, 2.40mmol), back flow reaction 10.5h, column chromatography for separation (eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=2: 1: 0.1), get ecru crystal (I-26) 0.1g (32.1%), 82～84 ℃ of mp.

IR (cm ^-1): 3380 (NH), 3054 (ArH), 2958,2926,2869 (CH), 1689,1620,1577,1491 (C=N, C=C), 1432 (imidazoles), 1268 (SCH ₂-), 832 (ArH replaces two), 743 (ArH, adjacent two replace), 694 (ArH, single replacements)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：2.37(3H，d，-SCH ₃)，6.84～7.01(3H，m，ArH)，7.12～7.15(2H，m，ArH)，7.25～7.29(2H，m，ArH)，7.34～7.51(4H，m，ArH)，7.61～7.62(1H，m，ArH)，7.74～7.76(1H，m，ArH)，8.80～8.94(1H，d，NH)，12.5(1H，br，NH)

MS(LC/MSD?ESI(+)70V，m/z)：413.3([M+Na] ⁺)，391.3([M+H] ⁺，base?peak)

Anal(C ₂₁H ₁₈N ₄S ₂；C％，H％，N％)：Req?64.59，4.65，14.35?Found?64.45，5.01，14.03

Example 16

S-methyl isophthalic acid-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea hydriodate (I-30)

1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] thiocarbamide (VII-4)

With compound (IV-2) 3.0g (11.6mmol) and dehydrated alcohol 60ml mixed dissolution, add Trapex 1.70g (23.2mmol) under the induction stirring, backflow 16h, activated carbon decolorizing, filtrate decompression reclaims solvent, add ethyl acetate 3ml, normal hexane 6ml, cooling, suction filtration, get off-white color crystal (VII-4) 3.3g (85.7%), 150～152 ℃ of mp.

IR (cm ^-1): 3296,3179 (NH), 2995 (CH), 1593,1575,1545,1526,1458 (C=C, C=N), 983 (thiazoles), 758 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：3.14(3H，d，J＝4.64Hz，HNCH ₃)，6.53(1H，br，NH)，7.24～7.41(4H，m，ArH)，7.47～7.88(4H，m，ArH)，8.51(1H，brs，NH)

MS(LC/MSD(-)70V，m/z)：330.0([M-H] ^-，base?peak)

MS(EI?70eV，m/z)：300，299(base?peak)，267，258，241，166

Anal(C ₁₅H ₁₃N ₃S ₃；C％，H％，N％)：Req?54.35，3.95，12.68?Found?54.47，3.95，12.99

Compound (VII-4) 0.33g (1.0mmol) and anhydrous propanone 6ml are mixed, add methyl iodide 0.19ml (0.43g under the induction stirring, 3.03mmol), backflow 14h, evaporation section acetone, cooling, suction filtration gets the off-white color crystal, use the methanol/acetone recrystallization, get white crystal (I-30) 0.25g (53.0%), 192～194 ℃ of mp.

IR (cm ^-1): 3044 (ArH), 2977,2870 (CH), 2840～2750 ( ⁺NH ₂), 1611,1588,1502,1488 (C=C, C=N), 1425,1007 (thiazoles), 763 (ArH, adjacent two replace)

¹HNMR(90MHz，DMSO-d ₆+CDCl ₃)，δ(ppm)：2.72(3H，s，-S-CH ₃)，3.2(3H，s，-N-CH ₃)，7.30～7.49(4H，m，ArH)，7.58～7.88(4H，m，ArH)，9.45(2H，br， ⁺NH ₂)

MS(EI?70eV，m/z)：345(M ⁺)，298(base?peak)，282，265，257，240，167

Anal(C ₁₆H ₁₅N ₃S ₃·HI；C％，H％，N％)：Req?40.59，3.41，8.88?Found?40.57，3.25，9.05

Example 17

S-ethyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-31)

Compound (VII-4) 0.33g (1.0mmol) and anhydrous propanone 6ml are mixed, add iodoethane 0.24ml (0.46g under the induction stirring, 2.95mmol), backflow 15h, column chromatography for separation (eluent: hexanaphthene: ethyl acetate: triethylamine=2: 1: 0.1), get white crystal (I-31) 0.2g (55.6%), 121～123 ℃ of mp.

IR (cm ^-1): 3267 (NH), 3070 (ArH), 2970,2920 (CH), 1608,1574,1525,1480,1461 (C=C, C=N), 1409,1190 (SCH ₂-), 1006 (thiazoles), 835 (ArH replaces two), 754 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：1.26(3H，t，J＝7.57Hz，-S-CH ₂CH ₃)，2.72(2H，q，J＝7.32Hz，-S-CH ₂CH ₃)，2.96(3H，s，N-CH ₃)，4.60(1H，br，NH)，6.97～7.07(2H，m，ArH)，7.20～7.39(2H，m，ArH)，7.57～7.90(4H，m，ArH)

MS(EI?70eV，m/z)：359(M ⁺)，342，302，298(base?peak)，282，257，241，167

Anal(C ₁₇H ₁₇N ₃S ₃；C％，H％，N％)：Req?56.79，4.77，11.69?Found?56.63，4.81，11.76

Example 18

S-normal-butyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-32)

With compound (VII-4) and iodo-n-butane (mol ratio 1: 3) is raw material, and the method for similar compound (I-31) gets white crystal (I-32,64.5%), 136～138 ℃ of mp.

IR (cm ^-1): 3287 (NH), 2927 (CH), 1607,1578,1514,1480,1454 (C=C, C=N), 1425,1008 (thiazoles), 1409,1191 (SCH ₂-), 838 (ArH replaces two), 758 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：0.89(3H，t，J＝6.35Hz，-S-CH ₂CH ₂CH ₂CH ₃)，1.20～1.70(4H，m，-SCH ₂₁CH ₂CH ₂CH ₃)，2.69(2H，t，J＝6.83Hz，-S-CH ₂-)，2.96(3H，s，N-CH ₃)，4.50(1H，br，NH)，6.96～7.10(2H，m，ArH)，7.20～7.45(2H，m，ArH)，7.54～7.89(4H，m，ArH)

MS(EI?70eV，m/z)：387(M ⁺)，331，298，282，257，164(base?peak)

Anal(C ₁₉H ₂₁N ₃S ₃；C％，H％，N％)：Req?58.88，5.46，10.84?Found?59.11，5.52，11.03

Example 19

S-benzyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-34)

With compound (VII-4) and benzyl chloride (mol ratio 1: 1.2) is raw material, the method of similar compound (I-31), column chromatography for separation (gradient elution agent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=4～3: 1: 0.15), get off-white color crystal (I-34,65.4%), mp is 158～161 ℃.

IR (cm ^-1): 3310 (NH), 2957,2927,2870 (CH), 1606,1575,1514,1481 (C=C, C=N), 1424,1009 (thiazoles), 1191 (SCH ₂-), 839 (ArH replaces two), 761 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：2.90(3H，s，N-CH ₃)，3.96(2H，s，S-CH ₂-)，4.50(1H，br，NH)，6.97～7.07(3H，m，ArH)，7.22～7.39(6H，m，ArH)，7.55～7.88(4H，m，ArH)

MS(EI?70eV，m/z)：421(M ⁺)，364，297(base?peak)，281，269，254，241，163

Anal(C ₂₂H ₁₉N ₃S ₃；C％，H％，N％)：Req?62.67，4.54，9.97?Found?62.42，4.56，9.85

Example 20

S-is to cyano group benzyl-1-methyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-35)

With compound (VII-4) with to cyano-benzyl bromide (mol ratio 1: 1.2) is raw material, the method of similar compound (I-31), column chromatography for separation (gradient elution agent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=3～1.5: 1: 0.15), get white crystal (I-35,74.1%), mp is 122～125 ℃.

IR (cm ^-1): 3294 (NH), 2970 (CH), 2227 (CN), 1609,1573,1511,1480 (C=C, C=N), 1423,1006 (thiazoles), 1191 (SCH ₂-), 838 (ArH replaces two), 756 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：2.89(3H，s，N-CH ₃)，4.02(2H，s，S-CH ₂-)，4.70(1H，br，NH)，6.94～7.04(2H，m，ArH)，7.21～7.45(4H，m，ArH)，7.55～7.87(6H，m，ArH)

MS(LC/ESI(+)/MSD?70V，m/z)：469.0([M+Na] ⁺)，447.0([M+H] ⁺，base?peak)

MS(SCI?70eV，m/z)：413，297(base?peak)，281，269，241，163

Anal(C ₂₃H ₁₈N ₄S ₃；C％，H％，N％)：Req?61.85，4.06，12.54?Found?61.46，4.06，12.40

Example 21

S-ethyl-1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-38)

1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] thiocarbamide (VII-5):

With compound (IV-2) and isothiocyanic acid n-propyl (mol ratio 1: 2.5) is raw material, and anhydrous acetonitrile is a solvent, and the method for similar compound (VII-4) gets light yellow solid (VII-5,82.7%), 122～124 ℃ of mp.

IR (cm ^-1): 3253,3173 (NH), 3068,2956,2930 (CH), 1605,1597,1542,1523,1459 (C=C, C=N), 1004 (thiazoles), 833 (ArH replaces two), 757 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：0.94(3H，t，J＝7.56Hz，-HN-CH ₂CH ₂CH ₃)，1.52～1.77(2H，m，-NH-CH ₂CH ₂CH ₃)，3.60(2H，q，J＝6.84Hz，-HN-CH ₂-)，6.51(1H，br，NH)，7.24～7.47(4H，m，ArH)，7.63～7.89(4H，m，ArH)，8.63(1H，brs，NH)

MS(LC/MSD(-)70V，m/z)：358.0([M-H] ^-，base?peak)

MS(EI?70eV，m/z)：300，299(base?peak)，267，258，241，166

Anal(C ₁₇H ₁₇N ₃S ₃；C％，H％，N％)：Req?56.79，4.77，11.69?Found?56.57，4.79，11.55

With compound (VII-5) and iodoethane (mol ratio 1: 2.6) is raw material, the method of similar compound (I-31), column chromatography for separation (eluent: hexanaphthene: ethyl acetate: triethylamine=2: 1: 0.1), get light yellow crystal (I-38,58.0%), mp is 102～105 ℃.

IR (cm ^-1): 3284 (NH), 2964,2927 (CH), 1606,1576,1519,1481 (C=C, C=N), 1423,1007 (thiazoles), 1248 (SCH ₂-), 838 (ArH replaces two), 759 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：0.96(3H，t，J＝7.57Hz，N-CH ₂CH ₂CH ₃)，1.27(3H，t，J＝7.57Hz，SCH ₂CH ₃)，1.49～1.74(2H，m，N-CH ₂CH ₂CH ₃)，2.73(2H，q，J＝7.32Hz，S-CH ₂-)，3.33(2H，t，J＝7.08Hz，N-CH ₂-)，4.60(1H，br，NH)，6.96～7.06(2H，m，ArH)，7.19～7.45(2H，m，ArH)，7.56～7.89(4H，m，ArH)

MS(EI?70eV，m/z)：387(M ⁺)，358，326，284(base?peak)，257，241，167

Anal(C ₁₉H ₂₁N ₃S ₃；C％，H％，N％)：Req?58.88，5.46，10.84?Found?58.62，5.72，10.67

Example 22

S-normal-butyl-1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-39)

With compound (VII-5) and iodo-n-butane (mol ratio 1: 3) is raw material, the method of similar compound (I-31), column chromatography for separation (eluent: hexanaphthene: ethyl acetate: triethylamine=2: 1: 0.1), get light yellow crystal (I-39,60.1%), mp is 92～95 ℃.

IR (cm ^-1): 3351 (NH), 2964,2929,2871 (CH), 1606,1577,1479 (C=C, C=N), 1425,1006 (thiazoles), 1249 (SCH ₂-), 839 (ArH replaces two), 757 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：0.89(3H，t，J＝6.84Hz，S-CH ₂CH ₂CH ₂CH ₃)，0.96(3H，t，J＝6.83Hz，N-CH ₂CH ₂CH ₃)，1.20～1.80(6H，m，SCH ₂CH ₂CH ₂CH ₃+NCH ₂CH ₂CH ₃)，2.69(2H，t，J＝7.33Hz，SCH ₂-)，3.33(2H，t，J＝7.32Hz，NCH ₂-)，4.70(1H，br，NH)，6.97～7.10(2H，m，ArH)，7.19～7.47(2H，m，ArH)，7.56～7.89(4H，m，ArH)

MS(EI?70eV，m/z)：415(M ⁺)，359，326，299，284(base?peak)，257，241，167

Anal(C ₂₁H ₂₅N ₃S ₃；C％，H％，N％)：Req?60.68，6.06，10.11?Found?60.49，6.22，9.94

Example 23

S-allyl group-1-n-propyl-3-[4-(benzothiazole-2-sulfydryl) phenyl] preparation of isothiourea (I-40)

With compound (VII-5) and allyl bromide 98 (mol ratio 1: 2.5) is raw material, the method of similar compound (I-31), column chromatography for separation (eluent: hexanaphthene: ethyl acetate: triethylamine=2: 1: 0.1), get light yellow crystal (I-40,60.0%), mp is 90～92 ℃.

IR (cm ^-1): 3292 (NH), 2966,2928 (CH), 1606,1575,1513,1480 (C=C, C=N), 1424,1010 (thiazoles), 837 (ArH replaces two), 758 (ArH, adjacent two replace)

¹HNMR(90MHz，CDCl ₃)，δ(ppm)：0.96(3H，t，J＝7.08Hz，N-CH ₂CH ₂CH ₃)，1.42～1.73(2H，m，NCH ₂CH ₂CH ₃)，3.23～3.44(4H，m，NCH ₂-+SCH ₂-)，4.75(1H，br，NH)，5.14～5.35(2H，m，＝CH ₂)，5.67～6.10(1H，m，SCH ₂CH＝)，6.96～7.06(2H，m，ArH)，7.20～7.47(2H，m，ArH)，7.57～7.88(4H，m，ArH)

MS(EI?70eV，m/z)：399(M ⁺)，384，342，284，257，241，167(base?peak)

Anal(C ₂₀H ₂₁N ₃S ₃；C％，H％，N％)：Req?60.11，5.30，10.52?Found?59.88，5.46，10.43

Example 24

S-methyl isophthalic acid-methyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] preparation of isothiourea (I-41)

2-(4-nitrophenylsulfenyl)-5-methoxyl group benzo imidazoles (III-3):

With 2-sulfydryl-5-methoxyl group benzo imidazoles 10g (0.056mol), p-Nitrophenyl chloride 8.8g (0.056mol), anhydrous acetonitrile 50ml, sodium hydroxide powder 2.2g (0.056mol), PEG-600 1g adds in the pressure bottle successively, sealing is reacted 30h under 120 ℃ of left and right sides induction stirring of outer temperature, be chilled to room temperature, suction filtration, cold acetonitrile is washed, khaki solid (III-3) 13.5g (79.9%), mp:145～150 ℃

2-(4-amino-benzene sulfenyl)-5-methoxyl group benzo imidazoles (IV-3):

Iron powder 6.8g (0.12mol) is mixed with 95% ethanol 135ml, add 10%HCl 5.7ml again, add compound (III-3) 6.9g (0.028mol) behind the mechanical stirring 10min, finish, temperature is 60 ℃ in being warming up to, behind the reaction 9h, drip 40% sodium hydroxide solution, add an amount of activated carbon to pH8～9, stir 15min, suction filtration while hot, filtrate decompression concentrates, cooling, suction filtration gets crude product, with re-crystallizing in ethyl acetate (adding a small amount of vat powder), light brown crystal (IV-3) 2.9g (52%), mp:147～148 ℃.

1-methyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] thiocarbamide (VII-6):

Compound (IV-3) 1.7g (6.27mmol) and dehydrated alcohol 20ml are mixed, stir adding Trapex 0.54g (7.40mmol) down, backflow 15h, cooling, suction filtration, crude product ethyl alcohol recrystallization, light yellow crystal (VII-6) 1.7g (79.1%), mp:186～188 ℃.

IR (cm ^-1): 3338 (NH), 3175,3147 (ArH), 1545,1527,1490,1410 (C=C, C=N), 1153 (C-O-C), 825 (ArH replaces two)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：2.93(3H，d，NCH ₃)，3.77(3H，S，OCH ₃)，6.77～7.49(7H，m，ArH)，7.76(1H，brs，NH)，9.57(1H，brs，NH)，12.48(1H，brs，NH)

MS(ESI(+)70V，m/z)：367([M+Na] ⁺)，345.1([M+H] ⁺，base?peak)

Anal(C ₁₆H ₁₆N ₄OS ₂；C％，H％，N％)：Req?55.79，4.68，16.26?Found?55.55，4.68，15.94

Compound (VII-6) 0.3g (0.875mmol) and anhydrous acetonitrile 5ml are mixed, stir and add methyl iodide 0.37g (2.62mmol) down, backflow 7h, column chromatography for separation [eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=1: 1.5: 0.125] gets white solid (I-41).mp：70～72℃。

IR(cm ^-1)：3412(NH)，2928(CH)，1607，1578，1481，1409(C＝C，C＝N)，1200，1153(C-O-C)

¹HNMR(300MHz，DMSO-d ₆)，δ(ppm)：2.30(3H，s，SCH ₃)，2.77(3H，d，NCH ₃)，3.76(3H，s，OCH ₃)，6.61～7.44(7H，m，ArH)，12.48(2H，brs，NH)

MS(SCI?70eV，m/z)：359([M+1] ⁺)，311(M-SCH ₃)，195(base?peak)

Anal(C ₁₇H ₁₈N ₄OS ₂；C％，H％，N％)：Req?56.96，5.06，15.63?Found?57.24，5.55，14.48

Example 25

S-normal-butyl-1-methyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] preparation of isothiourea (I-42)

With compound (VII-6) 0.3g (0.875mmol), anhydrous propanone 5ml and butyl iodide 0.48g (0.3ml) mix, backflow 8h, column chromatography for separation [eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=1: 1.5: 0.125] gets white crystalline thing (I-42).mp：74～76℃。

IR (cm ^-1): 3392,3218 (NH), 3043 (ArH), 2952 (CH), 1610,1577,1481,1407 (C=C, C=N), 1269 (SCH ₂), 1198,1152 (C-O-C), 835 (ArH replaces two)

¹HNMR(300MHz，CD ₃COCD ₃)，δ(ppm)：0.86(3H，t，CH ₃)，1.36(2H，m，CH ₂)，1.52(2H，m，CH ₂)，2.82(2H，t，SCH ₂)，2.88(3H，s，NCH ₃)，3.79(3H，s，OCH ₃)，6.77～6.92(4H，m，ArH)，7.36～7.48(3H，m，ArH)

MS(LC/ESI(+)MSD?70eV，m/z)：423.1([M+Na] ⁺)，401.1([M+H] ⁺，base?peak)

Anal(C ₂₀H ₂₄N ₄OS ₂；C％，H％，N％)：Req?59.97，6.04，13.99?Found?59.72，6.21，13.74

Example 26

S-ethyl-1-n-propyl-3-[4-(5-methoxyl group benzo imidazoles 2-sulfydryl) phenyl] preparation of isothiourea (I-44)

1-n-propyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] thiocarbamide (VII-7):

Compound (IV-3) 1.5g (5.54mmol) and dehydrated alcohol 20ml are mixed, stir adding propyl isothiocyanide 0.67g (9.2mmol) down, backflow 22h.Remove ethanol under reduced pressure, add acetic acid ethyl dissolution, drip an amount of normal hexane then, cooling, suction filtration, off-white color solid (VII-7) 1.1g (53.4%), mp:144～148 ℃

IR (cm ^-1): 3360 (NH), 3193 (ArH), 2960,2929 (CH), 1533,1491,1402 (C=C, C=N), 1154 (C-O-C), 826 (ArH replaces two)

¹HNMR(300MHz，DMSO-d ₆)，δ(ppm)：0.93(3H，t，CH ₃)，1.62(2H，m，CH ₂)，3.56(2H，t，NCH ₂)，3.85(3H，s，OCH ₃)，6.80～7.68(7H，m，ArH)，7.80(1H，brs，NH)，9.58(1H，brs，NH)

MS(ESI(+)70V，m/z)：395.0([M+Na] ⁺)，373.1([M+H] ⁺，base?peak)

Anal(C ₁₈H ₂₀N ₄OS ₂；C％，H％，N％)：Req?58.04，5.41，15.04?Found?58.31，5.55，14.86

With compound (VII-7) 0.3g (0.806mmol), anhydrous propanone 5ml and iodoethane 0.63g (0.36ml) mix, backflow 5h, column chromatography for separation [eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=2: 1: 0.1] gets white powder (I-44).mp：146～148℃。

IR (cm ^-1): 3454 (NH), 3043, (ArH), 2954 (CH), 1606,1580,1479 (C=C, C=N), 1165 (C-O-C), 822 (ArH replaces two)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：0.88(3H，t，CH ₃)，1.15(3H，t，CH ₃)，1.56(2H，m，CH ₂)，2.81(2H，q，SCH ₂)，3.20(3H，m，NCH ₂)，3.76(3H，s，OCH ₃)，6.75～7.44(7H，m，ArH)，12.41～12.45(1H，m，NH)

MS(LC/ESI(+)MSD?70eV，m/z)：423.1([M+Na] ⁺)，401.1([M+H] ⁺，base?peak)

Anal(C ₂₀H ₂₄N ₄OS ₂；C％，H％，N％)：Req?59.96，6.04，13.99?Found?60.12，6.14，14.13

Example 27

S-ethyl-1-phenyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] preparation of isothiourea (I-46)

1-phenyl-3-[4-(5-methoxyl group benzo imidazoles-2-sulfydryl) phenyl] thiocarbamide (VII-8):

Compound (IV-3) 1.8g (6.64mmol) and anhydrous acetonitrile 20ml are mixed, stir adding thiocarbanil 1.04g (7.77mmol) down, backflow 18h.Be chilled to room temperature, suction filtration is used the acetonitrile thorough washing, gets khaki solid (VII-8) 1.4g (yield 52%).

¹HNMR(300MHz，DMSO-d6)，δ(ppm)：3.54(3H，s，OCH ₃)，6.56～7.28(7H，m，ArH)，7.35～7.38(5H，m，ArH)，9.19-9.23(1H，m，NH)，9.62(1H，brs，NH)

MS(ESI(+)70V，m/z)：429.1([M+Na] ⁺)，407.0([M+H] ⁺)，

293.0(base?peak)

Anal(C ₁₈H ₂₀N ₄OS ₂；C％，H％，N％)：Req?62.04，4.46，13.78?Found?61.82，4.61，13.47

With compound (VII-8) and iodoethane (mol ratio 1: 5) is raw material, and the method for pressing similar compound (I-41) is synthetic.Through column chromatography for separation [eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=1: 1.5: 0.1], get faint yellow oily thing (I-46).mp：166～170℃。

IR (cm-1): 3402 (NH), 2930 (CH), 1621,1576,1491 (C=C, C=N), 1152 (C-O-C), 824 (ArH replaces two)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：1.16(3H，t，CH3)，2.86(2H，q，SCH ₂)，3.81(3H，s，OCH ₃)，6.75～7.74(12H，m，ArH)，9.20～9.23(1H，m，NH)，12.33～12.38(1H，m，NH)，12.46～12.50(1H，m，NH)

Anal(C ₂₃H ₂₂N ₄OS ₂；C％，H％，N％)：Req?63.57，5.10，12.89?Found?63.42，4.99，13.17

Example 28

S-methyl isophthalic acid-methyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] preparation of isothiourea (I-48) is to chloroacetanilide (VIII):

P-Chlorobenzoic acid amide 51.2g (0.4mol) is added in the 120ml Glacial acetic acid, be warming up to 60 ℃ under stirring, solid is molten entirely, slowly drip aceticanhydride 46.4g (0.44mol), drip off back backflow 1h, put the cold analysis crystalline substance, suction filtration, sherwood oil is washed, and gets white, needle-shaped crystals (VIII) 62g (yield 91%).Mp:175～176 ℃ (literature value: 177～179 ℃).

Adjacent nitro is to chloroacetanilide (IX):

Compound (VIII) 51g (0.3mol) is dissolved in the 120ml aceticanhydride, and ice bath is cooled to below 15 ℃, slowly drips nitrosonitric acid 5ml, temperature is lower than 15 ℃ in keeping, and drips to finish to stir 2h, in reaction solution impouring 900ml frozen water, suction filtration, washing gets yellow solid (IX) 60g (yield 93%).

Ortho-nitro-parachloroaniline (X):

Compound (IX) 64g (0.3mol) is dropped among the 55% sulfuric acid 180ml, the about 0.5h of reflux, to the solid completely dissolve, after cold slightly with in the reaction solution impouring 700ml frozen water, transfer pH to 8～9 with 10% sodium hydroxide, place a few hours, filter, get orange red solid (X) 46.6g (yield 90%).Mp:104 ℃ (literature value: 117～119 ℃)

To chlorine o-phenylendiamine dihydrochloride (XI):

Compound (X) 4g (0.023mol) is dropped among the 95% ethanol 50ml, add 0.3g palladium charcoal, catalytic hydrogenation waits that stopping to inhale hydrogen filters reaction solution rapidly, and filtrate is transferred pH2～3 with dense HCl, be concentrated into then dried, must pink solid (XI) 4.5g (yield 75%).

2-sulfydryl-5-chloro benzimidazole (XII):

Sodium hydroxide 2.3g (0.056mol) is thrown in 95% ethanol 40ml and water 8ml, after the stirring and dissolving in dripping dithiocarbonic anhydride 1.3ml (0.022mol) below 36 ℃, finish and stir 0.5h, add compound (XI) 4g (0.019mol) then, reflux 12h, reaction finishes and is chilled to 70 ℃, add activated carbon decolorizing 15min, filtered while hot, filtrate adds 65 ℃ of hot water 100ml, transfer pH8 with 36% acetic acid, leave standstill a few hours, suction filtration, washing, a small amount of alcohol is washed, and gets light brown solid (XII) 2.8g (yield 81%).

2-(4-nitrophenylsulfenyl)-5-chloro benzimidazole (III-4):

With compound (XII) 4g (0.022mol), anhydrous acetonitrile 30ml, powdered sodium hydroxide 0.9g (0.023mol); parachloronitrobenzene 3.4g (0.022mol) and PEG-600 1ml add in the pressure bottle, fill the N2 protection, react 42h under the induction stirring in 120 ℃ of oil baths; cooling, suction filtration, filtrate concentrates; place; suction filtration, cold acetonitrile are washed 3 times, are washed to neutrality again; get yellow solid (III-4) 3g (yield 45%), mp:186～167 ℃ 2-(4-amino-benzene sulfenyl)-5-chloro benzimidazole (IV-4):

Reduced iron powder 1.6g (0.029mol) and 95% ethanol 40ml are mixed, stir and add 10%HCl1.1ml down, add compound (III-4) 2g (6.65mmol) behind the 10min, be warming up to 60 ℃ of reaction 4h, 40 ℃ of reaction Bi Lengzhi, transfer pH8～9 with 40% sodium hydroxide, activated carbon decolorizing 10min, suction filtration while hot, iron mud is washed twice with 95% ethanol, filtrate slightly concentrates, and is directly used in next step reaction.

1-methyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] thiocarbamide (VII-9):

Trapex is added in the previous step reaction gained solution (mol ratio 1: 1.17), and back flow reaction 10h separates out a large amount of solids, suction filtration, ethanol is washed, pale yellow powder (VII-9) 1.3g (yield 87%), mp:218～220 ℃

IR (cm ^-1): 3350 (NH), 3178,3147 (ArH), 1545,1527,1491,1396 (C=C, C=N), 826 (ArH replaces two)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：2.93(3H，s，NCH ₃)，7.15～7.60(7H，m，ArH)，7.87(1H，brs，NH)，9.79(1H，brs，NH)，12.80(1H，brs，NH)

MS(ESI(+)70V，m/z)：371.0([M+Na] ⁺)，349.1([M+H] ⁺，base?peak)

Anal(C ₁₅H ₁₃N ₄S ₂Cl；C％，H％，N％)：Req?51.64，3.76，16.06?Found?51.76，3.59，15.79

Compound (VII-9) 0.3g (0.86mmol) and anhydrous propanone 5ml are mixed, add methyl iodide 0.16ml (2.58mmol) under the induction stirring, reflux 8h, reaction solution is through column chromatography for separation [eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=1.5: 1: 0.1], faint yellow solid (I-48), mp:86～88 ℃.

IR:(cm ^-1): 3393,3234 (NH), 3019 (ArH), 2924 (CH), 1608,1576,1479,1409 (C=C, C=N), 837 (ArH replaces two)

¹HNMR(300MHz，CDCl ₃)，δ(ppm)：2.67(3H，s，SCH ₃)，3.05(3H，s，NH ₃)，7.10～7.16(3H，m，ArH)，7.38～7.50(4H，m，ArH)

MS(ESI(+)70V，m/z)：385.0([M+Na] ⁺)，363.0([M+H] ⁺，base?peak)

Anal(C ₁₆H ₁₅N ₄S ₂Cl；C％，H％，N％)：Req?52.95，4.17，15.44?Found52.79，4.22，15.23

Example 29

S-(4-nitrobenzyl)-1-methyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] preparation of isothiourea hydrobromate (I-50)

Compound (VII-9) 0.2g (0.52mmol) and anhydrous propanone 4ml are mixed, add under the induction stirring nitro bromobenzyl 0.37g (1.7mmol), backflow 9h, cooling, suction filtration, acetone is washed, off-white color solid (I-50), mp:210～212 ℃

IR:(cm ^-1): 3437 (NH), 3068 (ArH), 2933 (CH), 1607,1582,1531 (C=C, C=N), 858 (ArH replaces two)

¹HNMR(300MHz，DMSO-d ₆)，δ(ppm)：3.05(3H，s，NCH ₃)，4.63(2H，s，S-CH ₂-Ph)，7.22～7.66(9H，m，ArH)，8.23～8.25(2H，m，ArH)，9.80(1H，brs，NH)

MS(ESI(+)70V，m/z)：506.1([M+Na] ⁺)，484.0([M+H] ⁺，base?peak)

Anal(C ₂₂H ₁₈N ₅S ₂ClO ₂·2HBr；C％，H％，N％)：Req?40.92，3.12，10.84Found?40.89，3.06，10.54

Example 30

S-ethyl-1-n-propyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl] preparation 1-n-propyl-3-[4-(5-chloro benzimidazole-2-sulfydryl) phenyl of isothiourea (I-51)] thiocarbamide (VII-10):

Press the method for similar compound (VII-9), will prepare compound (IV-4) gained solution and propyl isothiocyanide reaction (mol ratio 1: 2.5), faint yellow solid (VII-10), mp:180～182 ℃

IR (cm ^-1): 3366 (NH), 3193 (ArH), 2962 (CH), 1581,1533,1491,1394 (C=C, C=N), 827 (ArH replaces two)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：0.89(3H，t，CH ₃)，1.55(2H，m，CH ₂)，3.42(2H，s，NCH ₂)，7.15～7.58(7H，m，ArH)，7.95(1H，brs，NH)，9.68(1H，brs，NH)，12.80(1H，brs，NH)

MS(ESI(+)70V，m/z)：399.1([M+Na] ⁺，base?peak)，377([M+H] ⁺)

Compound (VII-10) 0.2g (0.53mmol) and anhydrous propanone 5ml are mixed, stir and add iodoethane 0.21ml (2.63mmol) down, reflux 9h, reaction solution is through column chromatography for separation [eluent: sherwood oil (60～90 ℃): ethyl acetate: triethylamine=2: 1: 0.2], faint yellow solid (I-51), mp:56～58 ℃.

IR (cm ^-1): 3439 (NH), 3068 (ArH), 2960,2927 (CH), 1610,1577,1479,1400 (C=C, C=N), 835 (ArH replaces two)

¹HNMR(500MHz，DMSO-d ₆)，δ(ppm)：0.88(3H，t，CH ₃)1.15(3H，t，CH ₃)，1.56(2H，m，CH ₂)，2.81(2H，m，CH ₂)，3.20(2H，q，SCH ₂)，3.33(2H，s，NCH ₂)，6.77～7.49(7H，m，ArH)，12.61(1H，brs，NH)

MS(ESI(+)70V，m/z)：405.1([M+H] ⁺，base?peak)

Anal(C ₁₉H ₂₁N ₄S ₂Cl；C％，H％，N％)：Req?56.35，5.23，13.83?Found?56.01，5.29，13.68

Claims (8)

1, the compound of general formula (I) or its pharmacy acceptable salt:

R wherein ₁Expression hydrogen, chlorine, bromine, methyl or methoxy; R ₂Expression hydrogen, C _1-4Alkyl or phenyl; R ₃Expression C _1-4Alkyl, allyl group, benzyl or substituted benzyl; X represents nitrogen or sulphur;

The substituting group of above-mentioned described substituted benzyl is: 2-Cl, 2-Br, 2-CN, 2-NO ₂, 4-Cl, 4-Br, 4-CN, 4-NO ₂, 3,4-methylene-dioxy, 3,4-dimethoxy.

2, compound according to claim 1, wherein R ₁Expression hydrogen, R ₂Expression hydrogen, R ₃The expression ethyl, X represents nitrogen.

3, compound according to claim 1, wherein R ₁Expression hydrogen, R ₂The expression n-propyl, R ₃The expression normal-butyl, X represents sulphur.

4, according to each described compound or its pharmacy acceptable salt among the claim 1-3, pharmacy acceptable salt is the acid salt that forms with following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid, Phenylsulfonic acid.

5, the preparation method of the general formula of claim 1 (I) compound may further comprise the steps:

Work as R ₂Be hydrogen, R ₃Be C _1-4Alkyl, allyl group, benzyl or during substituted benzyl, the preparation method is as follows:

Work as R ₂Be C _1-4Alkyl or phenyl, R ₃Be C _1-4When alkyl, allyl group, benzyl or substituted benzyl, the preparation method is as follows:

R wherein ₁Such as claim 1 definition,

Wherein X represents nitrogen or sulphur, and solvent orange 2 A is an aprotic polar solvent, and solvent B is acetone or acetonitrile, and solvent C is acetone, C _1-4Alcohol, acetonitrile or N, dinethylformamide, Y represents halogen;

The substituting group of substituted benzyl is: 2-Cl, 2-Br, 2-CN, 2-NO ₂, 4-Cl, 4-Br, 4-CN, 4-NO ₂, 3,4-methylene-dioxy, 3,4-dimethoxy.

6, method according to claim 5, wherein aprotic polar solvent is acetonitrile, Nitromethane 99Min., nitroethane, N, dinethylformamide or methyl-sulphoxide.

7, a kind of pharmaceutical composition wherein contains general formula (I) compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.

8, each defined compound or its pharmacy acceptable salt purposes in preparation NO synthase inhibitor among the claim 1-4.