CN1004756B - Process for preparing compounds - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof are described. Also described are processes for the preparation of compounds of formula (I) and formulations thereof, and their use as medicaments, for example for the treatment of gastric acid secretion. The compound of formula (I) is: in the formula, R₁、Ｒ₂、Ｒ₃、Ｒ₄X and R_cAre all the same as defined in the specification.

Description

The preparation method of chemical compound

The pharmaceutical preparation that the invention relates to the manufacture method of some noval chemical compounds and contain this chemical compound.

From such as United States Patent (USP) 2,585,155 and 3,541,060; French Patent (FRP) 1,003,821 and 2,037,001; And German OLS1; learn in 949,615: various benzothiazoles-2-sulfinylamines can be used as vulcanization accelerator, from european patent application 5129 and 80602, UK Patent Application 2; 314; learn some 2-(pyridylmethyl sulfinyls in 523) the benzimidazole useful as drug, and from Swiss Patent 623,582, West Germany OLS2; 548; 340 and French Patent (FRP) 2,392,021 in learn some 2-(heterocyclic methyl sulfinyls) benzimidazole.

According to the present invention, we provide the production method of (I) formula chemical compound and pharmaceutically acceptable salt thereof, and described (I) formula chemical compound is:

（Ⅰ）

Rc is separated by 1,2,3,4 or 5 other atom and SO group in the formula nucleophilic nitrogen, oxygen or sulfur,

R ₁, R ₂, R ₃And R ₄Can be identical or different, each is hydrogen, halogen, alkoxyl, alkyl, fluoro-alkyl, alkanoyl, RS(O naturally) n-,-NO ₂,-N(R) ₂-NHCOR, perhaps-COOH or its ester or amide,

Except top given implication, R ₁, R ₂, R ₃And R ₄In adjacent a pair of substituent group also can form jointly-(CH ₂) the x-chain, perhaps the carbon atom that is connected with them forms hexa-atomic undersaturated carbocyclic ring or azacyclo-jointly,

X equals 3,4 or 5,

N equals 0,1 or 2,

X is oxygen, sulfur or NR ₁₅,

R ₁₅Be hydrogen ,-COR ,-COOR or the alkyl that replaced by-OCOR arbitrarily,

R is hydrogen, phenyl or the alkyl that replaced by phenyl arbitrarily, and phenyl itself is replaced by alkyl arbitrarily,

Condition is: ⅰ) Rc is not-CH ₂CH ₂-morpholino,

ⅱ) when Rc is the nitrogen nucleophile that is stated from aryl or the heteroaryl, R ₁₅Be not-the COR group, R wherein is the alkyl that is unsubstituted,

ⅲ) when X be NR ₁₅The time, Rc does not comprise undersaturated azacyclo-, and said azacyclo-is neither that a) replaced or unsubstituted amino replaced, neither be by b) group replaced the support of N-oxygen, and

ⅳ) when x be NR ₁₅The time, Rc does not comprise the alkyl that piperidyl replaced through alkyl replaces arbitrarily or halogen replaces arbitrarily.

Described method comprises:

A) respective compound of selective oxidation (VI) formula:

Ⅵ

R wherein ₁, R ₂, R ₃, R ₄, X is identical with above-mentioned definition with Rc,

B) by means of making R ₁₅Respective compound and R for (I) formula of hydrogen ₁₅Z reaction (R wherein ₁₅Be the group outside the hydrogen of above-mentioned definition, Z is good leaving group), production X is NR ₁₅, and R ₁₅Be (I) formula chemical compound of group outside the hydrogen of above-mentioned definition, perhaps

C) utilization has one-NO ₂The method of (I) formula respective compound selective reduction of base, production has one-NH ₂(I) formula chemical compound of base,

And at needs or in case of necessity, make (I) formula chemical compound that obtains change its pharmaceutically acceptable salt into, it is perhaps opposite,

Oxidizing process a) can be under reaction condition in inert certain solvent and carries out, and for example carries out in ethyl acetate, dichloromethane, chloroform or its mixture.This reaction is preferentially selected for use and is being lower than room temperature, for example-20 ℃+carry out under 10 ℃ of temperature.In the presence of suitable catalyst, for example in the presence of the vanadyl acetylacetonate compound, this suitable oxidant that uses in reacting is peracid, for example between chloro benzylhydroperoxide or t-butyl hydrogen peroxide.

At process b) in, said good leaving group can be example with the halogen, in the presence of certain alkali and under about 15 to 30 ℃ of temperature, this reaction can be to be in the inert solvent under the reaction condition to be carried out, and for example carries out in dimethyl formamide.

At process c) in, this selective reduction reaction for example can for example use hydrazine and Raney nickel to carry out electronation under alkali condition, but with catalytic reduction for well, for example use Pto ₂Catalyst and ethanol are as reaction medium.

Can the known traditional method of utilization itself, for example make the method for (VII) formula chemical compound and the reaction of (VIII) formula chemical compound, make (VI) formula chemical compound, said (VII) formula chemical compound is:

（Ⅶ）

R in the formula ₁, R ₂, R ₃, R ₄Define as above with X, said (VIII) formula chemical compound is:

Z-Rc

Rc defines as above in the formula, and Z is good leaving group, for example halogen (chlorine).

Can be at acid acceptor, for example potassium carbonate exists down, in suitable solution, for example at N, carries out this reaction in the dinethylformamide.

(VII) formula and (VIII) formula chemical compound are known substance, perhaps can be prepared with known traditional method own by known compound.The application requires in No. 85/09406 file of that part UK Patent Application of its priority, for the production that is used for above-mentioned reaction raw material, has done more fully and has introduced.

The pharmaceutically acceptable salt of (I) formula chemical compound comprises the salt that generates with suitable organic acid or mineral acid, for example the salt that generates with halogen acids, sulphuric acid, alkanesulfonic acid, tartaric acid or citric acid.When (I) formula chemical compound have-when COOH or other acidic-group, we also provide the salt that generates with suitable organic base or inorganic base, for example with the salt of ammonium, alkali metal, alkaline-earth metal, alkylamine and generation, benzimidazole nucleus itself is tart, therefore can generate salt with aforesaid suitable alkali.

(I) formula chemical compound and pharmaceutically acceptable salt thereof are suitable for, because they have pharmaceutically active on one's body animal, because these materials can stop or the gastric acid inhibitory secretory action, for example at＜U.S. physiology magazine〉(" AmJPhysiol. ", 1982,243(6), show in the test of being discussed on G505-510), so their particularly suitables.(I) formula chemical compound also can be used for the intermediate of synthetic other chemicals.

According to proof, these noval chemical compounds can be used for stoping or the gastric acid inhibitory secretory action, and/or be used for the treatment of and be usually directed to the secretory disease of excess stomach acid, for example sudden or recurrent peptic ulcer, duodenal ulcer, gastric ulcer, dyspepsia, duodenitis, the Zollinger-Ellison Cotard, reflex esophagitis and for example treating because of the upper gastrointestinal curing ulcer erosion causes bleeding, particularly do not relate to hemorrhage under the situation when trunk, these chemical compounds also can be treated because of using NSAID (non-steroidal anti-inflammatory drug) to cause, gastritis or dyspepsia, prevention tonicity ulcer causes serious patient or burn patient gastrointestinal hemorrhage, for sour aspiration syndrome (the MondelsonShi comprehensively demonstrate,proves) patient of critical days, prevention causes patient's cyclic hemorrhage because of the hemorrhagic peptic ulcer before carrying out general anesthesia, and reduce patient because of leukemia, graft-versus-host disease or serious hepatic disease cause hemorrhage chance, whether above-mentioned disease is no matter relevant with the gastric acid secretion effect of process, all can obtain medical treatment.

For purposes above-mentioned, the dosage of prescribe medicine is decided on used chemical compound, prescribe medicine mode and required treatment certainly, but in general, at U.S. physiology magazine (" AmJPhysiol. ", 1982,243(6), illustrate in the test in G505-510), when the following pharmaceutical quantities of these chemical compounds is 16 ^-*To 10 ^-4During M, obtained gratifying result.For the people, clothes dosage was about 1 to 3000 milligram in verified total day, preferentially selected the 5-500 milligram for use, was preferably about 10～200 milligrams, and these dosage can be divided into 1 to 6 time and take being under the releasing pattern every day.Therefore, the presented in unit dosage form that is suitable for taking comprises from about 1 milligram to 600 milligrams this chemical compound, these chemical compounds also should with solid-state or liquid pharmaceutically acceptable diluent, carrier or mixed with excipients.

(I) formula chemical compound and pharmaceutically acceptable salt thereof have such advantage, promptly compare with the chemical compound with similar structures, when taking by digestive tract, easier absorption, less to the gastrointestinal zest, the toxicity effect of paying is little, activity is higher, and is more stable for gastric acid.

As the nucleopilic reagent of the part among the radicals R c, to be split up into by 4 atoms and SO group, preferably by 2 or 3 atoms separately, these atoms are carbon atom preferably.Nucleopilic reagent as a part among the radicals R c, be under common physiological condition, for example at PH under about condition of 7.4 to 1, can show that group of its nucleophilicity, and the nucleophilicity under this condition is bigger than water, and this nucleopilic reagent preferably also is alkaline, and its protonated degree is relevant with PH, even but under very low PH condition, also always have a large amount of unprotonated nucleopilic reagents.

The concrete nucleopilic reagent that can mention comprises in the oxygen, thioether of pyridine-N-oxide or phenolic hydroxyl group or the sulfur in the thiophenol or its parent, for example sulfur in the monothioester.But what we preferentially used is nitrogen nucleophile (wherein nitrogen-atoms neutral).Our concrete preferred nitrogen nucleophile is oxime, hydrazine, pyridine, and what override used is amido.Amido can at random be substituted, for example by the R of following provisions ₉And R ₁₀Group replaces, and amido preferably is stated from aromatic ring and fastens, and for example is stated from the phenyl ring.

The radicals R c that can mention comprises by formula:

-c（R ₁₆R ₁₇）y-（CR _1＊R _1＊）z-R _X

The group of representative, y can be identical or different with z in the formula, respectively does for oneself 0,1 or 2; R ₁₆, R ₁₇, R ₁₈And R ₁₉Can be identical or different, each is hydrogen or alkyl naturally, R _XBe the ring of representing by (II), (III), (IV) or (V) formula:

And when y+z is non-vanishing, R _XCan be-NR _*, R ₁₀, R ₅, R ₆, R ₇And R ₈Be from being R in the above ₁, R ₂, R ₃And R ₄Choose in the group of defined,

R ₉And R ₁₀Can be identical or different, respectively do for oneself hydrogen, alkyl, phenyl or cycloalkyl, each can be replaced arbitrarily by phenyl in these groups, and phenyl self is replaced arbitrarily by alkyl institute,

Perhaps R ₉And R ₁₀In, one can define as above, and another can be-OR ₁₁Perhaps-NR ₁₂R ₁₃, perhaps

R ₉And R ₁₀The nitrogen-atoms that is connected with them can form one jointly may also contain 0,1 or 2 other heteroatomic 4 to 8 yuan of undersaturated or saturated ring, and this ring can have one or more substituent R ₁, and

R ₁₁, R ₁₂And R ₁₃Can be identical or different, alkyl, cycloalkyl, alkanoyl, phenyl or the pyridine radicals representing hydrogen separately, replaced arbitrarily by halogen or quilt=O,

Perhaps R ₉Be as defined above except can not with R ₁₀Form the group of ring, and R ₈And R ₁₀With nitrogen-atoms and R ₈Form one and may also contain other 0,1 or 2 heteroatomic saturated quaternary to octatomic ring with the carbon atom on the ring that nitrogen-atoms is connected is common, this ring can have one or more substituent R ₁,

A representative is connected to five yuan or six-membered heterocycle or thia ring on this molecule remainder by ring carbon atom,

Y is N or C,

When y was N, W was O-, when y is C W be-OH or-SR ₁₄, and R ₁₄Be hydrogen, phenyl, cycloalkyl, alkanoyl or the alkyl that replaced arbitrarily by benzene.

The scheme that we select is, at R ₁, R ₂, R ₃And R ₄In have one and at least at R ₅, R ₆, R ₇And R ₈In to have a substituent group at least be not hydrogen, work as R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇Perhaps R ₈During for halogen, said halogen can be chlorine or fluorine.

Work as R ₁To R ₈, R, X, R ₉, R ₁₀, R ₁₁, R ₁₂, R ₁₃, R ₁₄, R ₁₅, R ₁₆, R ₁₇, R ₁₈Perhaps R ₁₉In, when any substituent group representative being arranged or comprising carbon-containing group, we select to contain the group that is equal to or less than 10 carbon atoms, preferably select to contain the group that is equal to or less than 6 carbon atoms.

The R that we specifically select for use ₉And R ₁₀, contain 1 or 2 carbon atom.

Work as R ₉And R ₁₀When the nitrogen-atoms that is connected with them formed ring jointly, this ring can contain other nitrogen, oxygen and/or sulphur atom.The ring that we select is piperidine ring or morpholino ring.

The ring A that we select for use is an aromatic ring.The example of the ring A that can mention is thiophene and pyrazoles, and what preferentially use is pyrimidine or pyridine.

Substituent R ₅To R ₇Number, obviously can not surpass the number that has the position of substitution on the ring A.

Work as R ₁To R ₃In when having substituent group to represent ester, we select C for use ₁To C ₆Alcohol, for example the ester group that is generated with alkanol is worked as R ₁To R ₂In when having substituent group to represent amide, they can be for example unsubstituted amide or by monoalkyl or the amide that replaced by two alkyl.

Work as R ₁To R ₄Perhaps R _*To R _*In adjacent a pair of substituent group when forming chain jointly, the chain that we select is:

-CH=CH-CH=CH-or-(CH ₂) ₄-,

Specify radicals R ₁To R ₄Comprise hydrogen, methoxycarbonyl, phenylcarbonyl group, methyl, chlorine, methoxyl group, OF ₃, NO ₂, tolysulfonyl and-NH ₂, perhaps at R ₁To R ₄In adjacent a pair of substituent group can form jointly-the CH=CH-CH=CH-chain,

The y that we select for use is o, and z is 0 or 1, the R that we select for use ₁₆, R ₁₇, R ₁₈And R ₁₉Being H or methyl, preferably all is H.

The specified acyclic radicals R c that can mention is:

-CH ₂CH ₂N(CH ₃) ₁With-CH ₂CH ₂N(CH ₃) C ₆H ₅

Specified radicals R ₅To R ₁Comprise hydrogen, methyl, chlorine, propyl group, methoxyl group and butyl.

Work as R ₉And R ₁₀When nitrogen-atoms on the ring that is connected with them and carbon atom formed ring jointly, the ring that we select was a piperidine ring, for example N-methyl piperidine ring.

Specified radicals X is NH, O, S, N-acetyl group, NCH ₂OCO-tertiary butyl, NCOO-ethyl and N-methyl.

Specified radicals R ₁₄It is acetyl group.

Some (VI) formula chemical compound is a noval chemical compound, and the present invention also provides these noval chemical compounds.Y+z is greater than zero (VI) formula chemical compound, especially R _XThose chemical compounds that are (III) formula ring have special significance.

According to the present invention, we also provide contains (preferably with small scale) (I) formula chemical compound or its pharmaceutical acceptable salt as the medical composition of active component, wherein is mixed with pharmaceutically acceptable excipient, diluent or carrier.The excipient, diluent or the carrier that are suitable for for example have: use lactose, starch, Talcum or stearic acid in tablet and dragee; In soft gelatin capsule, use tartaric acid or lactic acid; In suppository, use natural or hardened oils or wax; For injection (intramuscular injection or intravenous injection) agent or coloclysis water, use surfactant and antiseptic, these chemical compounds also can be put in poison through skin, for example make ointment.(I) formula chemical compound or pharmaceutically acceptable salt select preferentially that to have mass median diameter be 0.01 to 10 micron for use.The chemical compound of this granularity can for example be sieved with sieve in case of necessity with the method preparation of grinding or milling.These compositionss also can contain suitable preservatives, stabilizing agent, wetting agent, solubilizing agent, sweetener, coloring agent and aromatizing agent.Need, these compositionss can be made the maintenance releasing pattern.

In case of necessity, these chemical compounds can with antacid buffer agent, for example make form of mixtures and put in poison jointly.

The compositions that we select for use designs to such an extent that can be digested and assimilated or rectum absorbs, and discharges its content at enteral.The compositions that we specifically select for use is unaffected by the gastrointestinal acidic moiety time, for example the casing preparation.

(I) formula chemical compound has optically active, and can it be separated into their optical isomer with known traditional method itself, therefore, the present invention provides these chemical compounds with the form of its optical isomer or its mixture (for example its racemic mixture).

By the following example explanation the present invention, but but be not limited, in these embodiments, temperature is meant Celsius temperature.

Embodiment 1

N, N-dimethyl-2-(1H-benzimidazolyl-2 radicals-Ji sulfinyl methyl)-aniline

A) N, N-dimethyl-2-(1H-benzimidazolyl-2 radicals-Ji sulphomethyl)-aniline

Dissolving 8.18 gram 2-Dimethylaminobenzene methyl chloride hydrochlorates are handled with 5.4 gram 2-mercaptobenzimidazoles and 11.0 gram Anhydrous potassium carbonates in the 100ml anhydrous dimethyl formamide, at room temperature stir resulting mixture overnight.This reactant mixture is injected water, use ethyl acetate extraction, extract is used dried over mgso after washing.Evaporate this solvent, make this residue recrystallization, obtained the cream-colored solid of 5.68 grams with toluene.As eluent, wash product from the thin layer chromatography post with dichloromethane-ethyl acetate (9: 1), obtained colorless solid, fusing point is 158-160 °.

Elementary analysis:

Detected value: C, 68.05; H, 6.09; N, 15.1; S, 11.34(%)

C ₁₆H ₁₇N _*The theoretical value of S: C, 67.8; H, 6.01; N, 14.85; S, 11.31(%).

B) N-dimethyl-2-(1H-benzimidazolyl-2 radicals-Ji sulfinyl methyl)-aniline

Product 1.0 gram in a) step is dissolved among the 30ml dichloromethane, stirs this solution down at 0 °, in add within a few minutes at least in batches 0.67 gram 98% between the chloro benzylhydroperoxide.This reactant mixture was stirred 0.5 hour, wash with saturated sodium bicarbonate aqueous solution, use the salt water washing then, dry, evaporate this solvent, from the thin layer chromatography post this residue is washed as eluent with dichloromethane-ethyl acetate (7: 3), obtained 0.6 gram colorless solid, fusing point is 120-121 °.

Embodiment 2

Method and the suitable raw material of use with record among the embodiment 1 can prepare following compounds:

A) 2-(2-pyridylmethyl sulfo-) benzoxazole ⅰ), fusing point is 46-47 °,

ⅱ .2-(2-pyridylmethyl sulfinyl) benzoxazole,

Detected value: C, 60.31%; H, 4.02%; N, 10.91%; S, 12.36%;

C ₁₃H _1*N ₂O ₂The theoretical value of S: C, 50.5%; H, 3.88%;

N，10.9%;S，12.4%。

B) 2-(4-methoxyl group-3 ⅰ), 5-dimethyl-2-pyridylmethyl sulfo-) benzoxazole, fusing point 127-128 °.

ⅱ .2-(4-methoxyl group-3,5-dimethyl-2-pyridylmethyl sulfo-) benzoxazole, fusing point 103-105 °.

C) 2-(4-methoxyl group-3 ⅰ), 5-dimethyl-2-pyridylmethyl sulfo-) benzoxazole, fusing point 124-125 °.

ⅱ) 2-(4-methoxyl group-3,5-dimethyl-2-pyridine radicals methanesulfinyl) benzothiazole, fusing point 142-142.5 °.

D) 5-chloro-2-(2-pyridylmethyl sulfo-) benzoxazole ⅰ), fusing point 84-85 °.

ⅱ) 5-chloro-2-(2-pyridylmethyl sulfinyl) benzoxazole, fusing point 91-93 °.

E) 2-(2-pyridylmethyl sulfo-) benzoxazole-5-carboxylate methyl ester ⅰ), fusing point 85-87 °.

ⅱ) 2-(2-pyridylmethyl sulfinyl) benzoxazole-5-carboxylate methyl ester, fusing point 87-90 °.

F) benzothiazole 2-(2-pyridylmethyl sulfo-ⅰ)), fusing point 52-53 °.

ⅱ) 2-(2-pyridylmethyl sulfinyl) benzothiazole, fusing point 106-108 °.

G) N ⅰ), N-dimethyl-2-(5,6-dimethyl-1H-2-benzimidazolyl sulphomethyl) aniline, fusing point 144-146 °.

ⅱ) N, N-dimethyl-2-(5,6-dimethyl-1H-2-benzimidazolyl sulfinyl methyl) aniline, fusing point is 141-142 °.

H) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and N, N, 4-trimethylaniline, fusing point 159-161 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N, 4-trimethylaniline, fusing point 133-134 °.

I) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and 4-chloro-N, N-dimethyl-aniline, fusing point 148-151 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and 4-chloro-N, N-dimethyl-aniline, fusing point 148-151 °.

J) 2-(5-chloro-1H-2-benzimidazolyl sulphomethyl ⅰ))-and N, N-dimethyl-aniline, fusing point 49-52 °.

ⅱ) 2-(5-chloro-1H-2-benzimidazolyl sulfinyl methyl)-and N, N-dimethyl-aniline, fusing point 121-123 °.

K) 2-(5 ⅰ), 6-two chloro-1H-2-benzimidazolyl sulphomethyls)-N, accelerine, fusing point 128-130 °.

ⅱ) 2-(5,6-two chloro-1H-2-benzimidazolyl sulfinyl methyl)-N, N-dimethyl-aniline, fusing point 147-149 °.

L) 2-(2-Dimethylaminobenzene ylmethyl sulfo-ⅰ))-and 1H-benzimidazole-5-carboxylate methyl ester, fusing point 127-129 °.

ⅱ) 2-(2-dimethylaminophenyl methylsulfinyl)-and 1H-benzimidazole-5-carboxylate methyl ester, 130 ° of fusing points (decomposition).

M) N ⅰ), N-dimethyl-2-(5-methyl isophthalic acid H-2-benzimidazolyl sulphomethyl) aniline, fusing point 141-143 °.

ⅱ) N, N-dimethyl-2-(5-methyl isophthalic acid H-2-benzimidazolyl sulfinyl methyl) aniline, fusing point 50-52 °.

N) 2-(2-(1-piperidyl)-phenyl methyl sulfo-ⅰ))-and the 1H-benzimidazole, fusing point 171-172 °.

ⅱ) 2-(2-(1-piperidyl)-phenyl methyl sulfinyl)-and the 1H-benzimidazole, fusing point 160-161 °.

O) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and N, N-diethylaniline, fusing point 127-128 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N-diethyl-aniline, 109 ° of fusing points.

P) 2-(2-(5-methoxyl group-1H-benzimidazolyl) sulphomethyl ⅰ))-and N, N-dimethyl-aniline, mass spectrum: M ⁺329.

ⅱ) 2-(2-(5-methoxyl group-1H-benzimidazolyl) sulfinyl methyl)-and N, N-dimethyl-aniline.

Detected value: C, 60.36%; H, 5.81%; N, 11.89%;

S，9.69%。

C ₁₇H ₁₉N ₅O ₂S. ¹/ ₇CH ₂Cl ₂Theoretical value: C, 60.30%;

H，5.65%;N，12.30%;S，9.38%，

G) 2-(2-benzothiazolyl sulphomethyl ⅰ))-and N, N-dimethyl-aniline, fusing point 47-48 °.

ⅱ) 2-(2-benzothiazolyl sulfinyl methyl)-and N, N-dimethyl-aniline, fusing point 72-73 °.

R) 2-(5-Trifluoromethyl-1 H-2-benzimidazolyl sulphomethyl ⅰ))-and N, N-dimethyl-aniline, fusing point 50-51 °.

ⅱ) 2-(5-Trifluoromethyl-1 H-2-benzimidazolyl sulfinyl methyl)-and N, accelerine, fusing point 50-51 °.

S) N ⅰ), N-dimethyl-2-(5-nitro-1H-2-benzimidazolyl sulphomethyl)-aniline, fusing point 146-148 °.

ⅱ) N, N-dimethyl-2-(5-nitro-1H-2-benzimidazolyl sulfinyl methyl)-aniline, fusing point is 105-106 ° (dextrorotation).

T) phenyl ketone (2-(2-N, N dimethylamine base phenyl methyl sulfo-)-1H-5-benzimidazolyl ⅰ)), 62 ° of fusing points.

ⅱ) (2-(2-N, N dimethylamine base phenyl methyl sulfinyl)-1H-5-benzimidazolyl) phenyl ketone, 74 ° of fusing points.

U) 2-(5 ⅰ), 6-dimethoxy-1H-2-benzimidazolyl sulphomethyl)-N, N-dimethyl-aniline, fusing point 93-95 °.

ⅱ) 2-(5,6-dimethoxy-1H-2-benzimidazolyl sulfinyl methyl)-N, N-dimethyl-aniline, fusing point 142-144 °.

V) ⅰ) 5-(1H-2-benzimidazolyl sulphomethyl)-and N, N, 2-trimethyl-4-pyrimidinamine, fusing point 174.5-176 °.

ⅱ) 5-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N, 2-trimethyl-4-pyrimidinamine, fusing point 189-190.5 °.

W) N ⅰ), N-dimethyl-2-(4-Trifluoromethyl-1 H-2-benzimidazolyl sulphomethyl)-aniline, fusing point 93-95 °.

ⅱ) N, N-dimethyl-2-(4-Trifluoromethyl-1 H-2-benzimidazolyl sulfinyl methyl)-aniline, fusing point 129-130 °.

X) N-(2-(1H-2-benzimidazolyl sulfo-) ethyl ⅰ))-and N-methyl-aniline, fusing point 115-117 °.

ⅱ) N-(2-(1H-2-benzimidazolyl sulfinyl) ethyl)-and N-methyl-aniline, fusing point 148-149.5 °.

Y) N ⅰ), N-dimethyl-2-(1H-2-naphtho-(2,3-d) imidazole radicals sulphomethyl)-aniline, 178 ° of fusing points (dextrorotation).

ⅱ) N, N-dimethyl-2-(1H-2-naphtho-(2,3-d) imidazole radicals sulfinyl methyl)-aniline, 129 ° of fusing points (dextrorotation).

Z) aniline 2-(2-(1H-benzimidazolyl) sulfinyl ⅰ)), shrinks down at 160 ° by fusing point 202-203 °.

Embodiment 3

2-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N-dimethyl-6-propyl group-aniline

A) 2-methoxyl group-3-propylbenzoic acid

1.9 gram 2-methoxyl group-3-propylbenzoic acid methyl ester are dissolved in the 300ml methanol.Be added in the aqueous solution that is dissolved with 16.6 gram sodium hydroxide in the 100ml water, reflux and heated this mixture 3 hours down.Evaporating solvent is with this mixture of dilute hydrochloric acid acidify.With this product of 800ml ethyl acetate extraction, water washing, dried over mgso, evaporating solvent then.With the brown oil that hot pentane extraction obtains, make the chemical compound of 25.9 gram subheads, be yellow solid, fusing point is 55-58 °.

B) N-(1,1-dimethyl-2-ethoxy)-2-methoxyl group-3-propylbenzene amide

25.3 gram 2-methoxyl group-3-propylbenzoic acids are dissolved in the 400ml anhydrous methylene chloride, make it under reflux temperature, to heat 3 hours, under room temperature, stirred 14 hours then with the 17ml thionyl chloride.Evaporating solvent, (the air bath temperature is 135 ° with Kugelruhr equipment product of distillation; 0.35mmHg), make the faint yellow oily thing of 24.1 grams.This grease is dissolved in the 200ml anhydrous methylene chloride; 0 ° of following and N ₂In the atmosphere, gradually it is joined in dichloromethane (200ml) solution of the 2-amino-2-methyl propanol (20.2 gram) under stirring.Under the room temperature this reactant mixture was stirred 18 hours.With 300ml chloroform extraction product, with the washing of 150ml dilute hydrochloric acid, wash successively with 150ml sodium bicarbonate solution and 100ml saline then, use dried over mgso at last.After the evaporating solvent, with cyclohexane extraction crystallization subhead chemical compound, obtained 20.4 gram white solids, fusing point is 95-96.5 °.

C) 4,5-dihydro-2-(2-methoxyl group-3-propyl group phenyl)-4,4-two first base oxazoles

In the step b) 20.4 gram product is placed the 200ml anhydrous methylene chloride, stir and be cooled to 0 °.Add the 17ml thionyl chloride, stirred this reactant mixture 2 hours under the room temperature.Evaporating solvent and thionyl chloride are handled residue with ether.In this solid, add entry, with diluted sodium hydroxide solution this mixture that alkalizes.With this product of 500ml extracted with diethyl ether,, use dried over mgso then with the water washing of 150ml salt.Evaporating solvent is used the thin layer chromatography purified product, and as eluent, (135 ° of air bath temperature 0.7mmHg), have obtained 17 gram subhead chemical compounds, are colorless oil with the distillation of Kugelruhr equipment then with ethyl acetate-petroleum ether (1: 9).

D) 2-(4,5-dihydro-4, H-dimethyl-oxazole-2-yl)-N, N-dimethyl-6-propyl group-aniline

In the 120ml anhydrous tetrahydro furan, add the 9ml dimethylamine, mixture is cooled to-15 °, in N ₂Stir under the atmosphere, add 81ml simultaneously, the hexane solution of 1.6M n-BuLi.Stirred this reactant mixture 40 minutes down at-16 °, add step c) product 16 grams that are dissolved in the 100ml anhydrous tetrahydro furan, warm this mixture stirred 20 hours then to room temperature.Water stops the reaction of this reactant mixture, and with 500ml ethyl acetate extraction product, dried over mgso is used in the water washing of 100ml salt then.Evaporating solvent, (the air bath temperature is 135 °, 0.25mmHg), has obtained 16.4 gram subhead chemical compounds, is flaxen grease with the distillation of Kugelruhr equipment then.

E) 2-dimethylamino-3-propylbenzene methanol

In the step d) 17.3 gram product is dissolved in the 480ml2M dilute hydrochloric acid, and in the heating down 20 hours that refluxes, evaporating solvent is used the phosphorus pentoxide dried residue.The product that obtains is dissolved in the 500ml anhydrous tetrahydro furan, and the Yu Bingzhong cooling is stirred under the blanket of nitrogen, adds the tetrahydrofuran solution of 300ml 1M monoborane-oxolane simultaneously).Stirred this reactant mixture 68 hours under the room temperature, use the methanol cessation reaction then, evaporating solvent with this product of ethyl acetate extraction, is used 150ml sodium bicarbonate solution and the water washing of 150ml salt in succession, uses dried over mgso then.Evaporating solvent, (the air bath temperature is 156 ° with Kugelruhr equipment product of distillation; 1.0mmHg), obtained 13.2 gram subhead chemical compounds, be flaxen grease.

F) 2-chloromethyl-6-propyl group-N, the accelerine hydrochlorate

Product in the step e) 13.1 grams are dissolved in the 50ml anhydrous methylene chloride, are cooled to 0 °, stirring adds the 6ml thionyl chloride down, refluxes and heats this mixture 1.5 hours down.Evaporating solvent adds ethereal hydrochloric acid, collects product, then with the absolute ether development, has obtained 6.8 gram subhead chemical compounds, is cream-colored solid.

Mass spectrum: m/e211/213.

G) 2-(1H-2-benzimidazolyl sulphomethyl)-and N, N-dimethyl-6-propyl group-aniline

Utilize among the embodiment 1 a) method, the product of step f) is converted into subhead chemical compound (fusing point is 147-150 °).

H) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N-dimethyl-6-propyl group-aniline

Utilize b among the embodiment 1) method, the product of step g) is converted into subhead chemical compound (fusing point is 145-147.5 °).

Embodiment 4

According to the method for record among the embodiment 3, use suitable raw material can prepare following compounds:

A) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and 4-methoxyl group-N, N-dimethyl-aniline, fusing point 144-145 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and 4-methoxyl group-N, N-dimethyl-aniline, fusing point 130-131 °.

B) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and N-ethyl-N-propyl group-aniline, 121 ° of fusing points.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and N-ethyl-N-propyl group-aniline, 114 ° of fusing points.

C) 2-(2-(4-morpholinyl) phenyl methyl sulfo-ⅰ))-and 1H-aniline, 170 ° of fusing points.

ⅱ) 2-(2-(4-morpholinyl) phenyl methyl sulfinyl)-and 1H-aniline, fusing point 74-76 °.

Embodiment 5

2-(1,2,3,4-tetrahydrochysene-1,6-dimethyl quinoline-8-ylmethyl sulfinyl)-the 1H-benzimidazole

A) 1,2,3,4-tetrahydrochysene-6-methylquinoline

With the 6-methylquinoline (5.16 the gram, 36mmole) and pyridine-monoborane complex (13.2ml 144mmole) places 75ml acetic acid, stirred 18 hours under the room temperature, stir down, handle this product mixture with the 30ml diluted hydrochloric acid aqueous solution, alkalization then (use earlier 40%NaHCO, after use NaHCO ₃, to PH8), use ethyl acetate extraction three times.Water washs the organic facies that merges three times, uses dried over sodium sulfate then, and evaporating solvent has obtained brown oil.Purified with thin layer chromatography, made eluent, obtained the subhead chemical compound, be low melting point (4.7 grams, 67%) solid with petroleum ether (boiling point 40-60 °)-ether (3: 1), ^m/ _eThe 147(base peak).

B) 1,2,3,4-tetrahydrochysene-1,6-dimethyl quinoline

3.8 gram (25.8mmole) 6-methyl tetrahydroquinolines are dissolved in the 75ml anhydrous methylene chloride, handle, stirred 20 hours under the room temperature with 5.2 gram (3.5mmole) fluoboric acid trimethyl oxonium salts.This mixture is injected saturated sodium bicarbonate aqueous solution, and inclining organic layer.With chloroform extraction water layer twice, wash the organic facies twice of merging with water, use Na ₂SO ₄Drying, evaporation has obtained yellow oil.Purify with thin layer chromatography, make eluant, made the subhead chemical compound, be faint yellow oily with petroleum ether (boiling point 40-60 °)-ether (5: 1).

^m/ _z161 (molecular weight (MW)=base peak), 160,146,145,144,131,117,91,77.

C) 1,2,3,4-tetrahydrochysene-1,6-dimethyl quinoline-8-carboxyl aldehyde

Stir down in ice bath, at N ₂(2.1 grams in anhydrous dimethyl formamide 10.3mmole) (7ml) solution, dropwise add the 1.17ml(1.982 gram, 12.5mmole) phosphoryl chloride phosphorus oxychloride in the product of step b) under the atmosphere.Reactant mixture is heated to 120 ° (momently), remain on then 80 ° following 2 hours.Cool off this mixture, inject rare NaHCO ₃In the aqueous solution, with ethyl acetate extraction three times, wash the organic facies three times of merging with water, dried over sodium sulfate is evaporated to and obtains 960 milligrams of subhead chemical compounds (49%), is yellow oily.

The m/Z189(m.W.=base peak), 172,160,144,132,117,105,91.

Proton magnetic resonance (PMR) (HNMR) (CDCl ₃) acetaldehyde is at δ 10.06.

D) 1,2,3,4-tetrahydrochysene-8-methylol-1,6-dimethyl quinoline

1.5 gram (7.94mmole) products of step c) are dissolved in the ethanol, at least 10 minutes, add 300 milligrams of (7.94mmole) sodium borohydrides while stirring under the room temperature in batches.This mixture of restir 20 minutes is injected in the water, uses ethyl acetate extraction three times, washes the organic facies twice of merging with water, through Na ₂SO ₄The evaporation of dry back has obtained 1.41 gram (93%) subhead chemical compounds, is flaxen viscosity oily.

^m/ _z(single tetramethylsilane (TMS) derivant) 263(MW), the 248(base peak), 172,73.

E) 1,2,3,4-tetrahydrochysene-8-chloromethyl-1,6-dimethyl quinoline hydrochlorate

With d) product 1.4 gram (7.33mmole) in step is dissolved in the 10ml anhydrous benzene, stirs down in psychrolusia in batches with the 0.8ml(1.31 gram, and 11mmole) thionyl chloride is handled.This mixture is warmed to room temperature (2 hours), is heated to 50 ° (1 hours) afterwards, and then cooling, and handle with the 2ml ethereal hydrochloric acid, be evaporated to dried, the brown solid that obtains with the ether development, filtering, obtain 1.73 gram (96%) subhead chemical compounds, is filbert solid.

M/Z209/11(MW), the 174(base peak), 158,145,131,119,91.

F) 2-(1,2,3,4-tetrahydrochysene-1,6-diformazan yl-quinoline-8-ylmethyl sulfo-)-the 1H-benzimidazole

According to a) method among the embodiment 1, with e) product of step is converted into subhead chemical compound (fusing point 85-88 °, dextrorotation).

G) 2-(1,2,3,4-tetrahydrochysene-1,6-diformazan yl-quinoline-8-ylmethyl sulfinyl)-the 1H-benzimidazole

According to b among the embodiment 1) method, with f) the rapid product of step is converted into subhead chemical compound (fusing point 112-113 °).

Embodiment 6

According to the method for describing among the embodiment 5, utilize suitable raw material can prepare following compounds:

A) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and N, N, 3,4,5-pentamethyl-aniline, fusing point 161.5-162.5 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N, 3,4,5-pentamethyl-aniline, fusing point 122-123 °.

B) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and 4-methoxyl group-N, N, 3,5-tetramethyl aniline, fusing point 157-158 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and 4-methoxyl group-N, N, 3,5-tetramethyl aniline, fusing point 138-139 °.

C) 2-(1H-2-benzimidazolyl sulphomethyl ⅰ))-and N, N-dimethyl-4-(1,1-dimethyl ethyl)-aniline, fusing point 166-167 °.

ⅱ) 2-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N-dimethyl-4-(1,1-dimethyl ethyl)-aniline, 130 ° of fusing points.

Embodiment 7

2-(1-(2-dimethylaminophenyl) ethyl sulfinyl)-the 1H-benzimidazole

A) 1-(2-dimethylaminophenyl)-ethanol

Be used in the 2-bromo-N in the 60ml absolute ether, accelerine (10.0 gram) and magnesium (1.4 gram) and iodine (crystallization) preparation Grignard reagent.This reagent is cooled to 0 °, under blanket of nitrogen, stirs, within least 30 minutes, dropwise add absolute ether (20ml) solution of acetaldehyde (3.34ml).0 ° is stirred after 1 hour down, this mixture is warmed to room temperature.Add ammonium acetate solution after 2 hours.Separate two layers after 10 minutes.With this water layer of extracted with diethyl ether, the ether layer extract that merge of water and salt water washing in succession, dry and be evaporated to and obtain the residual buff oily thing of 7.5 grams.After thin layer chromatography is purified (making eluent with ether-petroleum ether (1: 1)), made required product 3.7 grams, be the light yellow oil.

Nuclear magnetic resonance, NMR (CDC1 ₃) δ 7.2m(4H) 6.8 broadbands (1H) 5.12q(1H) 2.73S(6H) 1.55d(3H)

B) 2-(1-(2-dimethylaminophenyl)-ethylenebis dithiocarbamate)-the 1H-benzimidazole

Cooling 2-(2-dimethylaminophenyl in ice bath)-and anhydrous benzene (50ml) solution of ethanol (3.6 gram), dropwise add the 1.75ml thionyl chloride, after stirring 1 hour, this mixture is warmed to room temperature, continue stirring 2 hours.Concentrate this mixture in a vacuum, with benzene azeotropic.Leach this residue with the 50ml anhydrous dimethyl formamide, stir, in this solution, add anhydrous dimethyl formamide (30ml) solution of 2-mercaptobenzimidazole (3.22 gram), add 7.5 gram potassium carbonate then.At room temperature stir this mixture 18 hours, and be injected into then in the water of brackish water, use ethyl acetate extraction.Water and saline wash the extract of merging in succession, and drying obtains the filbert solid of 6.1 grams after the evaporation.After thin layer chromatography is purified, make 3.4 gram products, be light yellow solid.

Nuclear magnetic resonance, NMR (CDC1 ₃): 5.22q(1H δ 7.0-7.7m(8H))

2.95S（6H）1.80d（＊H）

C) 2-(1-(2-dimethylaminophenyl)-ethyl sulfinyl)-the 1H-benzimidazole

With 3 gram c) product of step is dissolved in the 350ml ethyl acetate, is cooled to-20 °, adds ethyl acetate (50ml) solution of metachloroperbenzoic acid (1.83 gram).Stir after 1 hour, in vacuum, concentrate this mixture.The natural gum that obtains is dissolved in the minimum dichloromethane, feed the thin layer chromatography post then,, obtained raw material 1.5 grams of recovery and two kinds of diastereomers of title compound with 1: 1 ether-petroleum ether eluting, 437 milligrams of the diastereomers of polarity minimum, fusing point 119-120 °; 298 milligrams of the diastereomers of polarity maximum, fusing point 103-105 °.

Embodiment 8

2-(1H-benzimidazolyl-2 radicals-Ji sulfinyl methyl)-the benzenethiol acetas

A) 2-methylol thiophenol

3.08 gram thiosalicylic acids are dissolved in the 20ml anhydrous tetrahydro furan,, stir, under blanket of nitrogen, monoborane tetrahydrofuran complex solution (tetrahydrofuran solution of 40ml 1M) is dropwise being added wherein at least within an hour with ice-cooled.Under 0 °, this mixture was stirred 1 hour.Dropwise add methanolic hydrochloric acid till stopping foaming.This mixture is injected water, use ethyl acetate extraction.Successively with dilute hydrochloric acid, water and salt water washing acetic acid ethyl acetate extract, dry then, evaporation obtains being subhead chemical compound 2.9 grams of yellow oily.

Nuclear magnetic resonance, NMR (CDC1 ₃): 4.75S(2H δ 7.1-7.5m(4H))

3.69bS（1H）2.05bS（1H）

B) 2,2 '-the two benzyl alcohol of dithio

19 gram 2-methylol thiophenol solution and 100ml alkali alumina were dissolved in the common mechanical agitation of the solution that obtains in the 400ml ethanol 48 hours, aerating oxygen meanwhile, remove by filter aluminium oxide, and wash with hot ethanol, remove by filter ethanol and evaporation, the residue alcohol crystal has obtained 9.33 gram subhead chemical compounds, the * crystal form that is white in color, fusing point 136-138 °.

C) 2,2 '-the two phenyl methyl chlorides of dithio

500 milligram 2,2 of cooling in water-bath '-the two benzyl alcohol of dithio, Dropwise 35 0 μ l thionyl chloride.In at least 45 minutes, stir this mixture frequently, remove excessive thionyl chloride in a vacuum,, obtained jonquilleous 570mg subhead chemical compound, be rubber-like with benzene azeotropic.

Nuclear magnetic resonance, NMR (CDC1 ₃): 4.72S(4H δ 7.2-7.9m(8H))

D) 2-(2,2 '-the two phenyl methyl sulfo-s of dithio)-the 1H-benzimidazole

In the 3ml anhydrous dimethyl formamide, add 547mg potassium carbonate and 570mg2,2 '-the two phenyl methyl chlorides of dithio, in this mixture, add anhydrous dimethyl formamide (5ml) solution of 2-mercaptobenzimidazole (510mg).Under the room temperature, this mixture was stirred 3 days, inject water then, collecting precipitation washes this solid with water, is dissolved in the dichloromethane then.Dry this solution, and in vacuum, concentrate.After purifying, the thin layer column chromatography method obtained the be white in color subhead chemical compound of solid, shaped of 260mg.

Nuclear magnetic resonance, NMR (CDC1 ₃): 4.60S(4H δ 7.1-7.6m(16H)).

E) 2-(1H-benzimidazolyl-2 radicals-Ji sulphomethyl)-the benzenethiol acetas

Stirring is through ice-cooled 2-(2,2 '-the two phenyl methyl sulfo-s of dithio)-suspension of 1H-benzimidazole (11.5 gram) in ethanol (200ml), add the 806mg sodium borohydride in meanwhile at least 30 minutes in batches.This mixture was further stirred 60 minutes, meanwhile be warmed to room temperature.Under the room temperature, stir this mixture 2 hours, use the alcohol hydrochloric acid acidify, stirred 10 minutes, then this mixture is injected sodium bicarbonate solution, use ethyl acetate extraction.Successively water and this extract of salt water washing are dry then and concentrated in a vacuum.Residue is dissolved in the anhydrous dimethyl formamide (80ml), adds 7.5 gram sodium bicarbonate.This mixture is cooled to 0 °, slowly adds the 6.0ml acetic anhydride.Make this mixture reach room temperature, placed 18 hours.Be injected in the water, use ethyl acetate extraction.Water and salt water washing ethyl acetate, drying and evaporation then successively.Make 3.1 gram crude products through the thin layer chromatography purification.With making the crystalline subhead chemical compound of the 1.5 colourless * of gram after the ethyl acetate crystallization, fusing point is 134-138 °.

F) 2-(1H-benzimidazolyl-2 radicals-Ji sulfinyl methyl)-the benzenethiol acetas

According to b among the embodiment 1) method, with e) product of step is converted into title compound, fusing point is 65-68 °.

Embodiment 9

2-((1-acetyl group-1H-benzimidazolyl-2 radicals-yl) sulfinyl methyl)-benzenethiol acetas

A) 2-((1-acetyl group-1H-benzimidazolyl-2 radicals-yl) sulphomethyl)-benzenethiol acetas

With 1 gram 2-(2,2 '-the two phenyl methyl sulfo-s of dithio)-the 1H-benzimidazole is dissolved in the 20ml ethanol O ° and N ₂Gas stirs down, adds the 70mg sodium borohydride, stirs this mixture 2 hours.With this solution of alcohol hydrochloric acid acidify, stirred 5 minutes, inject sodium bicarbonate solution, use ethyl acetate extraction.Successively use sodium bicarbonate solution, water and this ethyl acetate of salt water washing, dry then and evaporation.The grease that obtains is dissolved in the anhydrous dimethyl formamide, adds 1.86 gram sodium bicarbonate.At N ₂Stir this mixture under the atmosphere, be cooled to 0 °.Dropwise add the 1.75ml acetic anhydride, 0 ° was stirred this solution 1 hour down.This mixture is injected water, use ethyl acetate extraction.Water and salt water washing extract, drying and evaporation then successively.Purify through thin layer chromatography, made 370mg colorless solid shape subhead chemical compound.Nuclear magnetic resonance, NMR (CDC1 ₃): 7.25-7.5m(5H δ 7.7m(3H))

4.66S（2H）2.78S（3H）

2.45S（3H）。

B) 2-((1-acetyl group-1H-benzimidazolyl-2 radicals-yl)-sulfinyl methyl)-benzenethiol acetas

According to b among the embodiment 1) method, a) product of step is converted into title compound, fusing point 99-102 °.

Embodiment 10

2-(1H-2-benzimidazolyl sulfinyl)-and N, the N-dimethyl amine

At N ₂In atmosphere and the ice-water-bath, with 2-(2-(N, the N dimethylamine base) ethylenebis dithiocarbamate)-3H-benzimidazole (1.7 grams, 7.7mmole) * vanadio (III) acetylacetonate (200mg) and t-butyl hydrogen peroxide (1.5 grams, 70% aqueous solution, 1.05 gram, 11.6mmole) place anhydrous methylene chloride, at N ₂The common stirring 3 hours in atmosphere and the ice-water-bath.After 2 hours 40 minutes, add a vanadyl acetylacetonate (200mg) again, this mixture is evaporated to dried (at room temperature on the rotary evaporator), carry out thin layer chromatography immediately and purify, use chloroform-methanol (5: 1) as eluent.

Resulting title compound (700mg, 38%) is faint yellow oily thing.

Proton magnetic resonance (PMR) (CDC1 ₃, 360MH ₂) δ 7.7(m, 2H); 7.34(m, 2H; 3.52(m, 1H); 3.35(m, 1H); 2.97(m, 1H); 2.81(m, 1H); 2.35(2,6H).

Embodiment 11

3-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N-dimethyl-2-pyridine amine

A) 2-dimethylamino-3-picolinic acid ethyl ester

14.9 gram 2-chloro-3-picolinic acid ethyl esters are placed the 100ml anhydrous tetrahydro furan, under 0 °, handle with the 15ml dimethylamine while stirring, at room temperature stirred this reactant mixture then 20 hours.Evaporation removes desolvates, and product 400ml ethyl acetate extraction is used the 100ml sodium bicarbonate aqueous solution, and then with the water washing of 100ml salt, reuse dried over mgso.Evaporating solvent, product distills (137 ° of air bath temperature with Kugelruhr equipment; 1.1mmHg), obtain 15.4 gram subhead chemical compounds, be faint yellow oily.

B) 2-dimethylamino-3-piconol

The product of 7.8 gram step a) is dissolved in the 150ml anhydrous tetrahydro furan 0 ° and N ₂Under the atmosphere, while stirring to wherein adding 44.2ml, the diethyl ether solution of 1M lithium aluminium hydride gradually.Reflux and heated this mixture 1.5 hours down, use the frozen water stopped reaction then.With 500ml ethyl acetate extraction product, (2 * 100ml) washing secondaries, dried over mgso boils off solvent to saline then.(the air bath temperature is 105 ° with the distillation of Kugelruhr equipment; 0.4mmHg) product, obtain 5.65 the gram faint yellow oily the subhead chemical compound.

C) 3-chloromethyl-2-(N, N dimethylamine base) pyridine hydrochloride

With the 3.25ml thionyl chloride, at 0 ° and N ₂Be added drop-wise under the atmosphere in anhydrous methylene chloride (100ml) solution of the step b) product (5.65 gram) under stirring.Warm this reactant mixture heated 1.5 hours under refluxing then to room temperature.Steaming desolventizes, and with this product of methylbenzene azeotropic, develops with ether then.The residue solid that is white in color weighs 7.16 grams, is the subhead chemical compound, fusing point 190-192 °.

D) 3-(1H-2-benzimidazolyl sulphomethyl)-and N, N-dimethyl-2-pyridine amine

According to a) method among the embodiment 1, the product of step c) is converted into the subhead chemical compound, fusing point 106-109 °.

E) 3-(1H-2-benzimidazolyl sulfinyl methyl)-and N, N-dimethyl-2-pyridine amine

According to b among the embodiment 1) method, the product of step d) is transformed into the subhead chemical compound, fusing point 124-126 °.

Embodiment 12

2-(1H-2-benzimidazolyl sulfinyl methyl)-phenol

A) 2-(1H-2-benzimidazolyl sulphomethyl)-phenol

In at least 20 minutes, with the 16ml thionyl chloride drop to stir down in anhydrous benzene (60ml) suspension of ice-cooled 2-salicylic alcohol (24.8 restrain).Solution is warmed to room temperature, and at room temperature kept 1 hour.Concentrate this mixture in the vacuum, obtain 2-chloro-methyl phenol crude product.

Under blanket of nitrogen, in anhydrous dimethyl formamide (200ml) solution of the 2-mercaptobenzimidazole that stirs (16 gram), add 35 gram potassium carbonate, stirred this mixture 20 minutes.Thick 2-chloro-methyl phenol is dissolved in the 80ml anhydrous dimethyl formamide, and it is added in the said mixture.Under the room temperature this mixture was stirred 20 hours, pour into and contain in the brinish water, use ethyl acetate extraction, the acetic acid ethyl ester extract that water and salt water washing successively merges, dry then and evaporation.After purifying, thin layer chromatography obtained 4.5 gram white solids.Use the ethyl acetate crystallization, make the subhead chemical compound that 1.5 grams are colourless * crystal form.Nuclear magnetic resonance, NMR (CDC1 ₃) δ 7.46bs(2H), 7.2m(5H), 6.99d(1H), 6.89t(1H), 4.47s(2H).

B) 2-(1H-2-benzimidazolyl sulfinyl methyl)-phenol

In chloroform (30ml) solution of ice-cooled (2-hydroxyphenyl)-methyl sulfo--1H-benzimidazole (100mg), add ice-cold between-dichloromethane (10ml) solution of chlorine benzylhydroperoxide (72mg).0 ° was stirred this mixture 1 hour down, is warmed to room temperature then.After 3 hours, dilute this mixture, successively use sodium bicarbonate aqueous solution, sodium metabisulfite solution and water washing, concentrate in a vacuum then, obtain title compound 75mg, be colorless solid with chloroform.Nuclear magnetic resonance, NMR (dimethyl sulfoxide (DMSO)) δ 7.8m(2H) 4.53dod(2H 6.9m(2H 7.5m(4H))).

Embodiment 13

2-(2-pyridylmethyl sulfinyl-N-oxide)-1H-benzimidazole

A) 2-chloromethylpyridine-N-oxide

2-chloromethyl pyridine hydrochloride (1.64 gram) aqueous solution is alkalized with sodium bicarbonate, with chloroform extraction (2 * 15ml).Water and this chloroform of salt water washing, drying and filtration then successively.Stir this solution under the blanket of nitrogen, in at least 20 minutes, add 1.81 gram metachloroperbenzoic acids in batches, stir after 18 hours under the room temperature, this mixture is poured in the saturated sodium bicarbonate solution, use chloroform extraction, concentrate the chloroform extract that merges in the vacuum, obtained being the subhead chemical compound of yellow oily, solidify meter 1.31 grams through placing this material.Nuclear magnetic resonance, NMR (CDC1 ₂) δ 8.3m(1H) 7.7m(1H) 7.3m(2H) 4.86S(2H).

B) 2-(2-pyridylmethyl sulfo--N-oxide))-the 1H-benzimidazole

According to a) method among the embodiment 1, a) product in step is converted into the subhead chemical compound, fusing point 148-151 °.

C) 2-(2-pyridylmethyl sulfinyl-N-oxide)-1H-benzimidazole

According to b among the embodiment 1) method, the product of step b) is converted into title compound, fusing point 183-184 ° (dextrorotation).

Embodiment 14

(2-(2-dimethylaminophenyl methylsulfinyl)-1H-benzimidazole-1-yl) methyl-2,2-dimethyl propylene acid esters

Under 25 °; with 2-(1H-2-benzimidazolyl sulfinyl methyl)-N; accelerine (1.5 grams; 5mM) with chloromethyl pivalate (1ml; 6.9mM) contain Anhydrous potassium carbonate (1.4 the gram; 10.0mM) anhydrous dimethyl formamide (20ml) solution, stirred 16 hours, with mixture reaction here in the 50ml water; with ethyl acetate (3 * 100ml) extractions; with saline (2 * 25ml) washing organic faciess, dried over mgso, filtration; evaporation; obtain yellow oil, purify, make eluent with dichloromethane-ethyl acetate (5: 1) with thin layer chromatography.Evaporate required eluent, obtain yellow oil, solidify through placing.Develop this solid matter with pentane, filter, dry in a vacuum, obtain 1.2 gram products, fusing point is 70-71 °.

Prepared with similar methods:

1.2-(2-the dimethylaminophenyl methylsulfinyl)-and 1H-1-benzimidazole carboxylic acid, ethyl ester semihydrate, fusing point 75-77 °.

(2.2-1-methyl-(1H-2-benzimidazolyl sulfinyl methyl))-N, accelerine, mass spectrum: ^m/ _e313.

Embodiment 15

N, N-dimethyl-2-(5-(4-aminomethyl phenyl sulfonyl)-1H-2-benzimidazolyl sulfinyl methyl) aniline

A) 5-(4-aminomethyl phenyl sulfonyl)-1H-benzimidazolyl-2 radicals (3H)-thioketone

With 2.6 gram 4-tosyl benzene-1, the 2-diamidogen is dissolved in the 50ml dimethyl formamide, handles 18 hours with 6ml Carbon bisulfide under 60 ° and the blanket of nitrogen, in refrigerative solution impouring frozen water, has obtained the subhead chemical compound of yellow mercury oxide shape, and fusing point is 200 °.

B) N, N-dimethyl-2-(5-(4-aminomethyl phenyl sulfonyl)-1H-2-benzimidazolyl sulphomethyl) aniline

According to a) method among the embodiment 1, a) step product is converted into the subhead chemical compound, 81 ° of fusing points.

C) N, N-dimethyl-2-(5-(4-aminomethyl phenyl sulfonyl)-1H-2-benzimidazolyl sulfinyl methyl) aniline

According to b among the embodiment 1) method, with b) product of step is converted into title compound, 85 ° of fusing points.

Embodiment 16

Method according to similar to Example 15 has prepared following compounds:

A) 2-(4 ⅰ), 7-dimethoxy-1H-2-benzimidazolyl sulphomethyl)-N, N-dimethyl-aniline, fusing point 142-144 °.

ⅱ) 2-(4,7-dimethoxy-1H-2-benzimidazole sulfinyl methyl)-N, accelerine, 61 ° of fusing points.

Embodiment 17

2-(1H-2-benzimidazolyl sulfinyl methyl) aniline

A) N-(2-hydroxymethyl phenyl)-2,4,6-triethylbenzene sulfonamide

N in ice bath ₂Under the atmosphere, with 2-(((2,4, the 6-trimethylphenyl) sulfonyl) amine) anhydrous tetrahydro furan (80ml) solution of benzoic acid (5.0 gram) stirred, handled with diborane-tetrahydrofuran complex (17.3ml1M solution).Under the room temperature this reactant mixture was stirred 3 hours, add diborane-tetrahydrofuran complex (17.3ml, 1M solution) again after being cooled to 0 °, at room temperature continuous stirring is spent the night.Reactant mixture is cooled to 0 ° once more, adds diborane-tetrahydrofuran complex (17.3ml, 1M solution) again, at room temperature stirred continuously 3 hours, and added dilute hydrochloric acid continuously, this mixture of dilute with water, use ethyl acetate extraction, after water washing, use dried over mgso.Evaporating solvent has obtained the required product of 4.0 grams, is oily.Its structure confirms through nuclear magnetic resonance, NMR and mass spectrum.

B) N-(2-chloromethyl phenyl)-2,4, the 6-trimethylbenzene sulfonamide

Be dissolved in the anhydrous dichloroethanes of 80ml a) going on foot product 4.0 grams, handle with the 1.15ml sulphinyl chlorine while stirring under the room temperature, after this reactant mixture was stirred 5 hours, add the 0.1ml sulphinyl chlorine again, continuation is stirred and is spent the night.Then this reactant mixture is poured in the water, separated organic layer, use the washed with dichloromethane water layer, merge organic solution, use dried over mgso, steaming desolventizes and has obtained 4.06 and restrain the subhead chemical compound that is faint yellow oily.

C) N-(2-(1H-2-benzimidazolyl sulphomethyl) phenyl)-2,4, the 6-trimethylbenzene sulfonamide

With b) step products 4.06 grams and 1.9 grams 1,3-dihydro-2H-benzimidazolyl-2 radicals-thioketone stirred 3 hours in the 70ml anhydrous dimethyl formamide with Anhydrous potassium carbonate 2.1 grams.This reactant mixture is poured in the water, filtered the product of collecting precipitation, the water thorough washing obtains the required product of 4.39 grams after the drying, be flaxen powder, fusing point 202-203 °.

D) aniline 2-(1H-2-benzimidazolyl sulphomethyl)

At room temperature, use 29ml methanesulfonic acid treatment step c while stirring) product 3.87 gram and 4.83ml methyl phenyl ethers anisoles.This peony reactant mixture was stirred 27 hours, slowly pour in the excess bicarbonate aqueous solution, use ethyl acetate extraction, use the salt water washing then, drying, steaming desolventizes, making eluent with dichloromethane-ethyl acetate (4: 1) washes residue from the thin layer chromatography post, having obtained the required product of 1.43 grams, is the fulvescent solid, 270 ° of fusing points (solidifying again after 139 ° of fusings).

E) aniline 2-(1H-2-benzimidazolyl sulfinyl methyl)

According to embodiment 1 in b) mode that method is identical, oxidation d) product of step, with the title compound that has obtained being fluffy colorless solid shape behind the ethyl alcohol recrystallization, 177 ° of fusing points (dextrorotation).

Embodiment 18

2-(5-amino-1H-2-benzimidazolyl sulfinyl methyl)-and N, accelerine

Under 1 atmospheric pressure, in containing 0.4 gram PtO ₂150ml ethanol in, make 2.2 gram N, N-dimethyl-2-(5-nitro-1H-2-benzimidazolyl sulfinyl methyl) aniline hydrogenation 24 hours.Remove catalyst, in a vacuum evaporating solvent.With chromatography (SiO ₂Methanol-ethyl acetate of/1: 10) the purification residue has obtained title compound, and fusing point is 156-157 ° (dextrorotation).

Embodiment 19

2-(1H-2-benzimidazolyl sulfinyl methyl)-N-cyclohexyl-methylphenylamine

A) benzaldehyde 2-(N-cyclohexyl-N-methyl-amino)

Stir down, reflux 8.68 adjacent Fluorobenzaldehyde .s of gram and 11.9 gram N-methylcyclohexylamines are 5.5 hours in the 70ml dimethyl formamide that contains 14.49 gram potassium carbonate.Cooled reactant mixture is poured in the dilute hydrochloric acid, used chloroform extraction.Divide water-yielding stratum, with the potassium carbonate alkalization, use chloroform extraction, then through water washing, dry and evaporation has obtained 11.8 gram subhead chemical compounds.Mass spectrum: M ⁺217,174 ° of boiling points.

B) benzyl alcohol 2-(N-cyclohexyl-N-methylamino)

According to embodiment 5d) method reduction step product a), obtained the subhead chemical compound.Mass spectrum: M ⁺219,148 ° of boiling points.

C) 2-(1H-2-benzimidazolyl sulphomethyl)-N-cyclohexyl-N-methyl-aniline

According to the method for embodiment 5, with b) product of step is converted into the subhead chemical compound, fusing point 165-166 °.

D) 2-(1H-2-benzimidazolyl sulfinyl methyl)-N-cyclohexyl-N-methyl-aniline

According to b among the embodiment 1) method, with o) product of step is converted into title compound, fusing point 132-133 °.

The test of pesticide effectiveness

A portion

Once adopted Berglindh T, Obrink KJ is at Acta, Physiol.Scand, the rabbit gastric gland test method of narrating among 1976.96150-159 and 97 401-414 is measured the activity (with data) of some chemical compounds in No. 85106252, the Chinese patent application.Simultaneously also once with the activity of discloseder chemical compounds in EPA45200 of this method mensuration tool similar structures.

(ⅰ) 2-[2-pyridine radicals methanesulfinyl]-benzimidazole, Timoprazole.This chemical compound is disclosed in West Germany OLS2, and 548,340 and French Patent (FRP) 2,392, embodiment 1 in 021, page 2 the 11st row in the Swiss Patent 623,582, and publish the 8th page of the 34th row in EP45200, embodiment 1,2,3 and 4, and the 22nd page the 2nd row (claim 9).

(ⅱ) 2-[2-pyridine radicals methanesulfinyl]-1-methyl-benzimidazole, see also Deutsche Bundespatent prospectus 2,548; 340 and the embodiment 14 of French Patent (FRP) 2,392,021; the 9th page of the 7th row of page 2 the 25th row of Swiss Patent 623,582 and EP45200 and the 22nd page the 13rd capable.

Method

The preparation of gastric gland:

Basically the method for narrating in Acta.Physiol.Scand.1976.96150-159 by people such as Berglindh prepares isolating rabbit gastric gland.This method comprises from arteria gastrica carries out rabbit stomach vascular perfusion, strikes off and shred separated gastric mucosa, and the gastric mucosa that shreds was carried out collagenase digesting 60-90 minute.Collect gastric gland then and allow it filter, remove coarse fragments through nylon cloth.Again gastric gland is placed on and contains NaCl132.4mM, KCl5.4mM, NaH ₂PO ₄5.0mM, MgSO ₄1.2mM, CaCl ₂1.0mM, cultivate in the medium of glucose 10mM and 1mg/ml gelatin, 37 ℃ of cultivation temperature, medium pH is 7.4.

The mensuration of acid secretions:

Measure in the gastric gland by the method that people such as Berglindh narrate in Acta.Physiol.Scand.1976.97 401-414 ¹⁴C-labelling aminophenazone intake, the sour secretions under the record in the prepared separation gastric gland.

Aminophenazone aggregation in the gastric gland is represented the gastric acid secretion thing in the gland.Reference fluid contains 10 ^-6M ¹⁴The C-aminophenazone.After the culture period, with the gastric gland centrifugalize, remove supernatant and with the gastric gland drying, weigh, and be dissolved in 10% the sodium lauryl sulphate.Calculate supernatant and gastric gland sample respectively with scintillation counter.Calculate in the gastric gland in method described in the Acta.Physiol.Scand.1976.97403 with people such as Berglindh ¹⁴C-labelling aminophenazone aggregation.

Experimental record:

In the presence of the test compounds of 1mM dibutyryl ring AMP and desire research, with gastric gland constant temperature culture 45 minutes.The test compounds of free radical is dissolved in the methanol.The final concentration of methanol in culture medium is 1%, aminophenazone assembled ratio do not have influence.Record each test compounds down produces 50% inhibitory action (ED to the aminophenazone aggregation in the gastric gland ₅₀) time concentration (in the micromole).

The activity of test compounds is high more, and required initiation 50% inhibiting concentration is low more.

Result of the test:

Gained the results are shown in table 1

Conclusion:

The above results shows that the activity of No. 85106252 chemical compounds of the Chinese patent application of being tested in the test of rabbit gastric gland is than the control compound height of prior art.

B portion

The absolute acid stability of No. 85106252 chemical compounds of Chinese patent application and prior art chemical compound (Omeprazole) when adopting follow procedure to record pH=3.

Program

Desire the stock solution of test compounds with 1mg chemical compound and the preparation of 1ml acetonitrile.This stock solution is divided into ten parts 0.1ml solution, and respectively adds 0.9ml 0.1M formates buffer (pH=3).Chromatography (methanol/ammonium acetate mobile phase) with routine is analyzed each part test solution, and the interval that injects post is 14 minutes.With ultraviolet absorption spectrum monitoring moiety test compounds disappearance required time, moiety chemical compound disappearance required time is long more, and the absolute acid stability of this chemical compound is high more.

The result

Result of the test is shown in following table 2

Table 2

Chinese patent application 1/2, pH=3

85106252 sample times (branch)

Number

2k 37.0

2o 216.0

2q 98.0

2s 72.0

2t 62.0

2u 310.0

2w 122.0

2x 1000.0

3 1000.0

4c 1000.0

11 300.0

14 20.0

15 72.0

16 280.0

Omeprazole 6.0

Annotate: the Omeprazole structural formula

Conclusion

These results show: the chemical compound of tested Chinese patent application 85106252 is much more stable than known Omeprazole chemical compound under the acid situation of pH=3.Therefore this data shows that the ability of the anti-gastric acid of these oral administration of compound can be better.

Claims (38)

1, produce the method for (I) formula chemical compound or its pharmaceutically-acceptable salts, the structural formula of said (I) formula chemical compound is:

（Ⅰ）

Wherein Rc is formula-(CR ₁₆R ₁₇) y-(CR ₁₈R ₁₉) the represented group of z-Rx, y can be identical or different with z in the formula, respectively does for oneself 0,1 or 2, R ₁₆, R ₁₇, R ₁₈And R ₁₉Can be identical or different, each is hydrogen or alkyl naturally, and Rx is by (III), the represented ring of (IV) or (V) formula,

And when y+z was not 0, Rx can be-NR ₉R ₁₀,

R ₉And R ₁₀Can be identical or different, respectively do for oneself hydrogen, alkyl, phenyl or cycloalkyl, wherein each can be replaced arbitrarily by phenyl, and phenyl itself can be replaced arbitrarily by alkyl institute,

Perhaps at R ₉And R ₁₀In, one can define as above, and another can be-OR ₁₁Perhaps-NR ₁₂R ₁₃, perhaps

R ₉And R ₁₀With the nitrogen-atoms that is attached thereto together, can form and may also contain 0,1 or 2 heteroatomic, saturated or undersaturated quaternary to octatomic ring, this ring can have one or more substituent R ₁, and

R ₁₁, R ₁₂And R ₁₃Can be identical or different, represent hydrogen separately, by halogen or by=0 alkyl, cycloalkyl, alkanoyl, phenyl or the pyridine radicals that replaces arbitrarily,

Perhaps R ₉Be top definition except can not with R ₁₀Form those groups outside the ring, and R ₈And R ₁₀Be connected with nitrogen-atoms and R ₈Ring on nitrogen-atoms and carbon atom form quaternary jointly to octatomic ring, can also contain 0,1 or 2 other hetero atom on this ring, and can have one or more substituent R ₁,

A representative is connected to five yuan or six-membered heterocycle or thia ring on this molecule remainder by a ring carbon atom,

Y is N or C,

When y was N, W was O-, when y was C, W was-OH or-SR ₁₄, and

R ₁₄Be hydrogen, phenyl, cycloalkyl, alkanoyl or the alkyl that replaced arbitrarily by phenyl,

R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, and R ₈Can be identical or different, each is hydrogen, halogen, alkoxyl, alkyl, fluoro-alkyl, alkanoyl, phenylcarbonyl group RS(O naturally) n-,-NO ₂,-N(R) ₂,-NHCOR, perhaps-COOH or its ester or amide,

Or except top given implication, R ₁, R ₂, R ₃, and R ₄In adjacent a pair of substituent group also can form jointly-(CH ₂) the x-chain, perhaps the carbon atom that is connected with them forms hexa-atomic undersaturated carbocyclic ring or azacyclo-jointly,

X equals 3,4 or 5,

N equals 0,1 or 2,

X is oxygen, sulfur or NR ₁₅,

R ₁₅Be hydrogen ,-COR ,-COOR or the alkyl that replaced by-OCOR arbitrarily,

R is hydrogen, phenyl or the alkyl that replaced by phenyl arbitrarily, and phenyl itself is replaced by alkyl arbitrarily,

Condition is: ⅰ) Rc is not-CH ₂CH ₂-morpholino,

ⅱ) when Rc is the nitrogen nucleophile that is stated from aryl or the heteroaryl, R ₁₅Be not-the COR group, R wherein is the alkyl that is unsubstituted,

ⅲ) when x be NR ₁₅The time, Rc does not comprise through the alkyl that piperidyl replaced that alkyl replaces arbitrarily or halogen replaces arbitrarily,

ⅳ) when x be NH, when Rc was the ring of formula III, y was 0, z is 1, R ₉And R ₁₀All be methyl, R ₁, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, R ₁₈And R ₁₉Respectively be hydrogen, R ₂Not NH ₂,

Comprising:

A) respective compound of selective oxidation (VI) formula:

Ⅵ

R wherein ₁, R ₂, R ₃, R ₄, X is identical with above-mentioned definition with Rc,

B) by means of making R ₁₅Respective compound and R for (I) formula of hydrogen ₁₅Z reaction (R wherein ₁₅Be the group outside the hydrogen of above-mentioned definition, Z is good leaving group), production X is NR ₁₅, and R ₁₅, and R ₁₅Be (I) formula chemical compound of group outside the hydrogen of above-mentioned definition, perhaps

C) utilization has one-NO ₂The method of (I) formula respective compound selective reduction of base, production has one-NH ₂(I) formula chemical compound of base,

And, (I) formula chemical compound that obtains is transformed into its pharmaceutically acceptable salt necessary or when needing, perhaps opposite.

2, in accordance with the method for claim 1, wherein work as R ₁To R ₈In arbitrary group and R, X, R ₉, R ₁₀, R ₁₁, R ₁₂, R ₁₃, R ₁₄, R ₁₅, R ₁₆, R ₁₇, R ₁₈Perhaps R ₁₉Representative or when containing carbon-containing group, this group contain 10 or less than 10 carbon atoms.

3, according to claim 1 or 2 described method, wherein R ₉And R ₁₀Respectively contain 1 or 2 carbon atom.

4, according to claim 1 or 2 described method, wherein R ₁And R ₄Be hydrogen, methoxyl group-carbonyl, phenylcarbonyl group, methyl, chlorine, methoxyl group, CF ₃, NO ₂, tolysulfonyl or-NH ₂, perhaps at R ₁To R ₄In the common one-CH=CH-CH=CH-chain that forms of adjacent a pair of substituent group.

5, according to claim 1 or 2 described methods, wherein y is o, and z is o or 1,

R ₁₆, R ₁₇, R ₁₈, and R ₁₉Be H or methyl, R ₅To R ₈Be hydrogen, methyl, chlorine, propyl group, methoxyl group or butyl, and

X is NH, O, S, N-acetyl group, NCH ₂OCO-tertiary butyl, NCOO-ethyl or N-methyl.