BE884846A - 2-PHENYLIMIDAZO (2,1-B) BENZOTHIAZOLE DERIVATIVES - Google Patents

Description

       

    <EMI ID = 1.1>

  
benzothiazole represented by formula I

  

  <EMI ID = 2.1>


  
  <EMI ID = 3.1>

  
different, each represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a nitroso group, an amino group, a carboxy group, a nitrile group, a carbamoyl group, a sulfamoyl group, a group lower alkyl, hydroxy lower alkyl, lower alkoxy group, phenyl lower alkoxy group, lower carboxyalkoxy group, lower alkoxycarbonyl group lower alkoxy, lower alkoxycarbonyl group, acyloxy group, lower alkylthio group, lower alkylsulfinyl group , a lower alkyl sulfonyl group, a lower alkoxysulfinyl group, a lower alkoxysulfonyl group, a mono or di alkylamino group

J

  
  <EMI ID = 4.1>

  
cents which can combine with each other to form a benzene ring or a lower alkylenedioxy group; R4,

  
  <EMI ID = 5.1>

  
each have a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a nitroso group, an amino group, a thiocyanate group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a lower alkoxy carboxy group, a lower alkoxy lower alkoxycarbonyl group, an acyloxy group, a lower alkylthio group, a lower alkylsulfinyl group,

  
a lower alkylsulfonyl group, a mono or di group

  
  <EMI ID = 6.1>

  
represented by the formula

  

  <EMI ID = 7.1>


  
  <EMI ID = 8.1>

  
dotted line represents the existence or absence of a double

  
  <EMI ID = 9.1>

  
  <EMI ID = 10.1>

  
a nitro group, a lower alkyl group or a lower alkoxy group, the dotted line represents existence

  
  <EMI ID = 11.1>

  
represents the above group other than a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a lower alkyl group or a lower alkoxy group; and (2) R6 is a bromine atom or a group.

  
  <EMI ID = 12.1>

  
hydrogen atom or a halogen atom and (3) R6 is a

  
  <EMI ID = 13.1>

  
above other than a hydrogen atom or a nitro group, and their salts.

  
  <EMI ID = 14.1>

  
above is meant a straight or branched carbon chain having 1-5 carbon atoms. Consequently, the lower alkyl radical of the lower alkyl group, of the hydroxy lower alkyl group, of the lower mono or di alkylamino group, of the lower alkyl group, of the lower alkylsulfinyl group, of the lower alkylsulfonyl group

  
  <EMI ID = 15.1>

  
methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, etc. Likewise, the lower alkoxy radical of the lower alkoxy group, of the lower alkoxy phenyl group, of the lower alkoxy carboxy group, of the lower alkoxy lower alkoxycarbonyl group, and of the lower alkoxycarbonyl group is in practice a methoxy group, an ethoxy group, a propoxy group. , a butoxy group, etc.

  
Similarly, as the acyl radical of the acylamino group and of the acyloxy group, mention may be made of a lower alkanoyl group such as the formyl group, the acetyl group, the propionyl group, the butyryl group, etc., an aromatic acyl group such as

  
  <EMI ID = 16.1>

  
oxalo (-COCOOH), carbamoyl group, tetrazol-5ylcarbonyl group, methanesulfonyl group, ethanesulfonyl group, etc.

  
The halogen atoms are illustrated by the fluorine atom, the chlorine atom, the iodine atom and the bromine atom.

  
In addition, as a dioxy alkylene group formed by combination

  
  <EMI ID = 17.1>

  
methylenedioxy, an ethylenedioxy group, etc.

  
The compounds of the general formula 1 represented above object of the. present invention form addition salts with acids or form, depending on the type of substituents, the salts with bases. The present invention encompasses the pharmaceutically acceptable salts of the compounds of general formula I and examples of these salts are the acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, nitric acid , sulfuric acid, etc., or an organic acid such as acid

  
  <EMI ID = 18.1>

  
with the bases formed according to the type of the substituent in the

  
  <EMI ID = 19.1>

  
niac and the salts with organic bases such as methylamine, ethylamine, diethylamine, trimethylamine, triethylamine, pyridine, picoline, arginine, lysine, etc.

  
  <EMI ID = 20.1>

  
  <EMI ID = 21.1>

  
[2,1-b] benzothiazole, 2- (4-nitrophenyl) -3-nitroimidazo-

  
  <EMI ID = 22.1>

  
or phenyl) -3- (nitro or nitroso) -5,6,7 or 3- (methoxy or methyl) imidazo [2, 1-b] benzothiazole, 2- (4-nitro-phenyl or phenyl) -

  
  <EMI ID = 23.1>

  
(Chem. Abstr., 71, 124309t (1969)), 2- (4-methoxy-phenyl) imidazo [2, 1-bjbenzothiazole (Chem. Abstr., 72, 100606g (1970)), 2- (4 -bromophenyl, 4-chlorophenyl or phenyl) -3- (bromo or

  
  <EMI ID = 24.1>

  
(1972)). However, there is no indication in these des-. reviews on 'the uses of these compound as medicines.

  
1

  
  <EMI ID = 25.1>

  
  <EMI ID = 26.1>

  
formula

  

  <EMI ID = 27.1>


  
  <EMI ID = 28.1>

  
  <EMI ID = 29.1>

  
feel antihistamine activity. Namely different

  
  <EMI ID = 30.1>

  
as described above but it was not known that compounds of this type were effective in an immunity system and possessed a powerful immunoregulatory action.

  
On the other hand, the compounds of the present invention have

  
  <EMI ID = 31.1>

  
antiallergic, antiasthmatic agents, antirheumatic agents, anticancer agents, therapeutic agents of autoimmune disease and as suppressants of rejection during tissue transplantation and skin grafting,

  
The compounds of the present invention have an immunoregulatory action but are classified into those having an immunosuppressive action and those having an immunostimulatory action.

  
The compounds of the present invention exhibiting an immunosuppressive action which possess a cell-mediated immunity suppressing activity, for example by suppressing the delayed type hypersensitivity reaction of which the type is

  
  <EMI ID = 32.1>

  
proteins are useful as antiallergic agents, anti rheumatic agents, autoimmune disease therapeutics

  
and as suppressants of the rejection phenomenon during transplantations of tissues and skin grafts. In particular, these compounds are useful as hypersensitive agents of the delayed type and as antirheumatic agents. Namely, so far, only steroids are known as antiallergic agents in particular as hypersensitive agents of the delayed type.

  
This is true with regard to anti-rheumatic drugs.

  
However, when steroids are used for a long time, they cause a serious secondary action and cause what is called steroid addiction and therefore it has been desired to develop antiallergic and antirheumatic agents of a non-steroidal type giving less

  
side reactions.

  
  <EMI ID = 33.1>

  
Persistence of the potent delayed type can be used in place of these steroids. In addition, they can be used together with steroids, which results in a reduction in the amount of steroids used.

  
  <EMI ID = 34.1>

  
immunosuppressive and also showing suppression of

  
formation of humoral antibodies, for example an action of

  
  <EMI ID = 35.1>

  
antiallergic agents since they suppress production. of the IgE antibody which is the main object of immediate hypersensitivity.

  
The compounds of the present invention having an immunostimulatory action and having an activity increasing

  
  <EMI ID = 36.1>

  
both the delayed type hypersensitivity reaction

  
so . that an activity of blastogenesis of lymphocytes and an activity increasing the formation of humoral antibodies, as well as the activity increasing antibodies in the blood, are useful as anticancer and anti-tumor agents as well as anti-rheumatic and therapeutic agents against hepatitis chronic.

  
The compounds of the present invention exhibit a suppressive action in the test of passive cutaneous anaphylaxis
(PCA); which means that the compounds of the present invention have an antiallergic action and are useful as antiallergic and antiasthmatic agents.

  
In addition, since the compounds of the present invention exhibit very low toxicity, these compounds can be used as medicaments for the various uses described above.

  
The drug compositions containing the compounds of the present invention as the main compound are formulated in the usual manner using the usual formulation carriers and excipients. The drugs can be administered orally in the form of tablets, pills, capsules, granules, etc. or they can be administered parenterally as injections such as intravenous injections, intramuscular injections, etc. or in the form of aerosols, suppositories, etc.

   The doses of the drugs are suitably determined in each case, taking into account the symptom, the age of the patient, the distinction between the sexes, etc. but are usually from
50 - 500 mg per day for an adult in the case of oral administration and 20 - 300 mg per day for an adult in the case of parenteral administration and are administered in two or three doses per day .

  
The compounds of the present invention are prepared by any of the following methods: (A) Cyclization:

  

  <EMI ID = 37.1>


  
in which A represents a carbonyl group or a group

Y

  
represented by -CH- (in which Y represents a halogen atom).

  
Examples of the halogen atom represented by Y are the iodine atom, the bromine atom, the chlorine atom, etc.

  
In the above reaction, there is a reaction using the starting material in which A is a carbonyl group and a reaction using the starting material in which A is the

Y

  
group represented by -CH-. Namely, in the case of the preparation of the 2-phenylimidazo [2,1-b] benzothiazole derivative represented by the general formula (Ia)
  <EMI ID = 38.1>
   <EMI ID = 39.1>

  
used as starting material while in the case of the preparation of the derivative of 2-phenyl-2,3-dihydroimidazo

  
  <EMI ID = 40.1>

  

  <EMI ID = 41.1>


  
the compound (IIb) in which A is the group represented by y
-CH- is used as the starting material.

  
The previous reaction -is usually carried out in a solvent and as the solvent used in this case there are, for example, methanol, 'ethanol, isopropanol, methoxy-

  
  <EMI ID = 42.1>

  
cellosolve, Diglyme, ethyl acetate, acetonitrile, chloroform, carbon tetrachloride, etc. The reaction is carried out under heating, preferably under heating at reflux.

  
On the other hand, the second reaction is usually carried out in a solvent in the presence of a base under heating,

  
preferably under reflux heating. Practical examples

  
  <EMI ID = 43.1>

  
organic such as alcohols (methanol, ethanol, etc.) chloromethane, dichloromethane, chloroform, tetra-

  
  <EMI ID = 44.1>

  
water or mixtures thereof. As the base used in the reaction, there are mineral bases such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium acetate, sodium acetate, etc., and organic bases such as the <EMI ID = 45.1>

  
etc. Pyridine, etc. can also be used as a solvent.

  
In this case, when the starting material (II) in which

  
  <EMI ID = 46.1>

  
it is hydrolysed during the reaction to form the compound
(I) correspondent of the present invention in which one at

  
  <EMI ID = 47.1>

  
In addition, the starting materials (lla) and (Ilb) are produced according to the following reaction principles and can be used in the reactions without being isolated.

  

  <EMI ID = 48.1>
 

  
(B) Hydrolysis:

  
The compound of the present invention represented by the general formula (1) having a hydroxy group, a carboxy group or an amino group can be prepared by hydrolyzing the compound having an acyloxy group, a lower alkoxycarbonyl group or an acylamino group in the usual manner .. Namely, the compound of formula (I) in which at least one of

  
  <EMI ID = 49.1>

  
  <EMI ID = 50.1>

  
is an acyloxy group under an alkaline condition in the usual manner. The compound of formula (I) in which at least

  
  <EMI ID = 51.1>

  
lower alkoxy can be prepared by hydrolyzing the compound

  
  <EMI ID = 52.1>

  
lower carbonyl or a lower alkoxycarbonyl group lower alkoxy under an alkaline condition in the usual manner and the compound of formula (I) in which at least one

  
  <EMI ID = 53.1>

  
can be prepared by hydrolyzing the compound in which at

  
  <EMI ID = 54.1>

  
lower alkoxy under an alkaline condition in the usual manner. Likewise the compound of formula (I) in which at

  
  <EMI ID = 55.1>

  
carboxy group, such as a bxaloamido group (-NHCOCOOH) can be prepared by hydrolyzing the compound having a lower alkoxycarbonyl group, for example the compound having

  
  <EMI ID = 56.1>

  
be prepared by hydrolyzing the compound in which at least

  
  <EMI ID = 57.1>

  
acid in the usual manner.

  
(C) Alkoylation

  
The compound of the present invention represented in the formula <EMI ID = 58.1>

  
phenyl-lower alkoxy, a lower alkoxycarbonyl group, lower alkoxy, a dioxy-lower alkylene group, a lower alkoxycarbonyl group, a mono- or di- group

  
  <EMI ID = 59.1>

  
posed having a hydroxy group, a carboxy group or an amino group by reacting the compound with a corresponding alkylating agent in the usual manner. To know,

  
  <EMI ID = 60.1>

  
is a lower alkoxy group or an alkoxycarbonyl group. lower-lower alkoxy can be prepared by alkylating the-

  
  <EMI ID = 61.1>

  
hydroxy with a corresponding alkylating agent such as a lower alkyl halide or a lower alkoxycarbonyl halide in the usual manner. The compound in

  
  <EMI ID = 62.1>

  
lower can be prepared by alkylating the compound in

  
  <EMI ID = 63.1>

  
corresponding alkylating agent such as a lower phenylalkyl halide in the usual manner, and the compound

  
  <EMI ID = 64.1>

  
are combined with each other to form a lower dioxyalkyl group can be prepared by alkylating the compound

  
  <EMI ID = 65.1>

  
with a corresponding alkylating agent such as

  
  <EMI ID = 66.1>

  
even, the compound of the present invention represented by the

  
  <EMI ID = 67.1>

  
  <EMI ID = 68.1>

  
  <EMI ID = 69.1>

  
carboxy by reacting the compound with an agent

  
corresponding alkylation such as a lower alkyl halide in the usual manner, and the compound of formula CI) -.

  
  <EMI ID = 70.1> corresponding in the usual way. In addition, the compound of formula (I) in which at least one of R; at R6 is a lower mono- or di-alkylamino group can be prepared by

  
  <EMI ID = 71.1>

  
an amino group with a corresponding alkylating agent such as a lower alkyl halide in the usual manner.

  
(D) Acylation:

  
The compound of the present invention having the formula

  
  <EMI ID = 72.1>

  
acyloxy or an acylamino group can be prepared by acylating

  
  <EMI ID = 73.1>

  
hydroxy or an amino group with a corresponding acylating agent such as an acyl halide or an acid anhydride in the usual manner.
(E) Amide formation:

  
  <EMI ID = 74.1>

  
having one or more carbamoyl groups can be prepared by placing in the amide form the compound having a carboxy group or a lower alkoxycarbonyl group in the usual manner. Namely, the compound of formula (I) in

  
  <EMI ID = 75.1>

  
be prepared by reacting the compound in which at

  
  <EMI ID = 76.1>

  
lower alkoxycarbonyl with ammonia in the usual manner and the compound of formula (I) in which at least one

  
  <EMI ID = 77.1>

  
carbamoyl, for example the compound having an oxamido group (-NHCOCONH2) can be prepared by reacting the

  
  <EMI ID = 78.1>

  
acylamino having a carboxy group or a lower alkoxycarbonyl group such as an ethoxalylamido group

  
  <EMI ID = 79.1>

  
  <EMI ID = 80.1>

  
The compound of the present invention having the general formula (I) in which R6 is a halogen atom can be prepared by halogenation of the compound of formula (I) in

  
  <EMI ID = 81.1>

  
  <EMI ID = 82.1>

  
sulfuryl and the bromo-succinic acid imide in the usual manner.

  
(G) Nitration:

  
The compound of the present invention having the general formula (I) in which R6 is a nitro group can be prepared by nitration of the compound of formula (I) in which

  
  <EMI ID = 83.1>

  
with a nitrating agent such as nitric acid in the usual manner.

  
(H) Formation of the nitroso radical:

  
The compound of the present invention representing the general formula CI) in which R &#65533; is a nitroso group can be prepared by reacting the compound of formula (I) in which R6 is a hydrogen atom with an agent for forming the nitroso radical such as nitrous acid in the usual manner.

  
(I) Reduction:

  
The compound of the present invention having the general formula (I) having an amino group or a lower hydroxyalkyl group can be prepared by reducing the, compound

  
  <EMI ID = 84.1>

  
The lower or a lower alkoxycarbonyl group of the usual nanier. Namely, the compound of formula (I) in

  
  <EMI ID = 85.1> prepared by reducing the compound in which at least one of

  
  <EMI ID = 86.1>

  
  <EMI ID = 87.1>

  
is a lower hydroxyalkyl group can be prepared

  
  <EMI ID = 88.1>

  
is a lower alkanoyl group or a lower alkoxycarbonyl group in the usual manner.

  
(J) Formation of the lower thioalkyl radical:

  
The compound of the present invention having the formula

  
  <EMI ID = 89.1>

  
lower can be prepared by reacting the compound of formula (I) in which R6 is a hydrogen atom with an agent for forming a lower thioalkyl radical such as a sulfinyl lower alkyl halogen in the usual manner .

  
(K) Oxidation:

  
The compound of the present invention having the formula

  
  <EMI ID = 90.1>

  
a lower sulfinylalkyl group or a lower sulfonylalkyl group can be prepared by oxidizing the compound of

  
  <EMI ID = 91.1>

  
thio-lower alkyl in the usual manner.

  
The desired compounds of formula (I) thus prepared are isolated and purified by a conventional chemical operation usually used in the art such as recrystallization, extraction, various chromatographies, etc.

  
Next, the experimental results indicating the excellent pharmacological effect of the compounds of the present invention are indicated below.

  
Activity for delayed type hypersensitivity in mice:

  
Seven-week-old ICR-SCL mice (Assoc. Coopérative Agricole Shizuoka) were sensitized by brushing

  
0.1 ml of a 7% picryl chloride solution in absolute ethanol on the shaved abdomen. In this case the solution was used under heating to prevent the picryl chloride from precipitating. After a seven-day sensitization period, the mice were compared by brushing 0.02 ml of a 1% picryl chloride solution in olive oil inside each ear. The thickness of the ear was measured with a dial thickness gauge. The increase in the thickness of the ear was calculated as the difference between the value measured before the basting and 24 hours after it. The test compounds were administered orally between day 0 and day 3 after immunization. The results are given in Table 1.

  

  <EMI ID = 92.1>
 

  

  <EMI ID = 93.1>
 

  
1 EXAMPLE 1

  

  <EMI ID = 94.1>


  
To 150 ml of anhydrous acetonitrile were added 4.5 g of 2-aminobenzothiazole and 6.8 g of m-chlorophenacyl bromide and the mixture was heated to 65-75 [deg.] C for one hour under brewing. After completion of the reaction, the reaction mixture was cooled, the crystals formed were collected by filtration, washed with acetonitrile and dried to provide 8.5 g of white hydrobromide crystals

  
  <EMI ID = 95.1>

  
Then 8.5 g of hydrobromide crystals were heated to reflux in 75 ml of methylcellosolve. After completion of the reaction, the reaction mixture was cooled to

  
  <EMI ID = 96.1>

  
added to the reaction mixture, whereby white crystals are formed. The reaction mixture was further cooled with ice and the crystals formed were collected by filtration and recrystallized from ethanol to

  
  <EMI ID = 97.1>

  

  <EMI ID = 98.1>


  
  <EMI ID = 99.1>

  
following compounds EXAMPLE 2

  

  <EMI ID = 100.1>


  
Melting point: 177-180 [deg.] C

  
Elementary analysis for C15H9N2IS:

  

  <EMI ID = 101.1>


  
EXAMPLE 3

  

  <EMI ID = 102.1>


  
Melting point: 178-179 [deg.] C

  
  <EMI ID = 103.1>

  

  <EMI ID = 104.1>


  
EXAMPLE 4

  

  <EMI ID = 105.1>


  
Melting point: 177-179 [deg.] C

  
  <EMI ID = 106.1>

  

  <EMI ID = 107.1>
 

  
  <EMI ID = 108.1>

  

  <EMI ID = 109.1>


  
Melting point: 195-197 [deg.] C

  
  <EMI ID = 110.1>

  

  <EMI ID = 111.1>


  
EXAMPLE 6

  

  <EMI ID = 112.1>


  
Melting point: 198-199 [deg.] C

  
  <EMI ID = 113.1>

  

  <EMI ID = 114.1>


  
EXAMPLE 7

  

  <EMI ID = 115.1>


  
Melting point: 161-163 [deg.] C Elemental analysis for C19H12N2S:

  

  <EMI ID = 116.1>


  
EXAMPLE 8

  

  <EMI ID = 117.1>


  
Melting point: 248 [deg.] C

  
  <EMI ID = 118.1>

  

  <EMI ID = 119.1>


  
EXAMPLE 9

  

  <EMI ID = 120.1>


  
Melting point: 223 [deg.] C

  
  <EMI ID = 121.1>

  

  <EMI ID = 122.1>


  
EXAMPLE 10
  <EMI ID = 123.1>
 Fusion point . 243-245 [deg.] C

  
  <EMI ID = 124.1>

  

  <EMI ID = 125.1>


  
EXAMPLE 11

  

  <EMI ID = 126.1>


  
Melting point: 161-162 [deg.] C

  
  <EMI ID = 127.1>

  

  <EMI ID = 128.1>


  
EXAMPLE 12

  

  <EMI ID = 129.1>


  
Melting point: 224-226 [deg.] C

  
  <EMI ID = 130.1>

  

  <EMI ID = 131.1>


  
EXAMPLE 13
  <EMI ID = 132.1>
 Melting point: 220 [deg.] C

  
  <EMI ID = 133.1>

  

  <EMI ID = 134.1>


  
EXAMPLE 14

  

  <EMI ID = 135.1>


  
Melting point: 293-295 [deg.] C

  
  <EMI ID = 136.1>

  

  <EMI ID = 137.1>


  
EXAMPLE 15

  

  <EMI ID = 138.1>


  
Melting point: 193-195 [deg.] C

  
  <EMI ID = 139.1>

  

  <EMI ID = 140.1>


  
EXAMPLE 16

  

  <EMI ID = 141.1>


  
Melting point: 186-188 [deg.] C <EMI ID = 142.1>

  

  <EMI ID = 143.1>


  
EXAMPLE 17

  

  <EMI ID = 144.1>


  
Melting point: 209 [deg.] C

  
  <EMI ID = 145.1>

  

  <EMI ID = 146.1>


  
EXAMPLE 18

  

  <EMI ID = 147.1>


  
  <EMI ID = 148.1>

  
  <EMI ID = 149.1>

  

  <EMI ID = 150.1>


  
EXAMPLE 19

  

  <EMI ID = 151.1>


  
  <EMI ID = 152.1> 9

  
  <EMI ID = 153.1>

  

  <EMI ID = 154.1>


  
EXAMPLE 20

  

  <EMI ID = 155.1>


  
Melting point: 256-258 [deg.] C <EMI ID = 156.1>

  

  <EMI ID = 157.1>


  
EXAMPLE 21

  

  <EMI ID = 158.1>


  
Melting point: 267-269 [deg.] C

  
  <EMI ID = 159.1>

  

  <EMI ID = 160.1>


  
EXAMPLE 2 2

  

  <EMI ID = 161.1>


  
melting point above 300 [deg.] C 1

  
  <EMI ID = 162.1>

  

  <EMI ID = 163.1>


  
EXAMPLE 23

  

  <EMI ID = 164.1>


  
Melting point: 287-289 [deg.] C

  
  <EMI ID = 165.1>

  

  <EMI ID = 166.1>


  
EXAMPLE 24

  

  <EMI ID = 167.1>


  
Melting point above 300 [deg.] C

  
  <EMI ID = 168.1>

  

  <EMI ID = 169.1>


  
EXAMPLE 25

  

  <EMI ID = 170.1>


  
Melting point 234-236 [deg.] C <EMI ID = 171.1>

  

  <EMI ID = 172.1>


  
EXAMPLE 26

  

  <EMI ID = 173.1>


  
  <EMI ID = 174.1>

  

  <EMI ID = 175.1>


  
EXAMPLE 27

  

  <EMI ID = 176.1>


  
Melting point: 264-266 [deg.] C

  
  <EMI ID = 177.1>

  

  <EMI ID = 178.1>


  
EXAMPLE 28

  

  <EMI ID = 179.1>


  
Melting point: 267-269 [deg.] C

  
  <EMI ID = 180.1>

  

  <EMI ID = 181.1>
 

  
EXAMPLE 2 9

  

  <EMI ID = 182.1>


  
  <EMI ID = 183.1>

  
  <EMI ID = 184.1>

  

  <EMI ID = 185.1>


  
EXAMPLE 30

  

  <EMI ID = 186.1>


  
  <EMI ID = 187.1>

  

  <EMI ID = 188.1>


  
EXAMPLE 31

  

  <EMI ID = 189.1>


  
Melting point: 160-162 [deg.] C

  
  <EMI ID = 190.1>
  <EMI ID = 191.1>
 EXAMPLE 32

  

  <EMI ID = 192.1>


  
Melting point: 310-312 [deg.] C (decomposed)

  
  <EMI ID = 193.1>

  

  <EMI ID = 194.1>


  
EXAMPLE 33

  

  <EMI ID = 195.1>


  
Melting point: 232 [deg.] C

  
  <EMI ID = 196.1>

  

  <EMI ID = 197.1>


  
EXAMPLE 34

  

  <EMI ID = 198.1>


  
Melting point: 232 [deg.] C

  
  <EMI ID = 199.1>

  

  <EMI ID = 200.1>


  
EXAMPLE 35
  <EMI ID = 201.1>
 melting point: 194 [deg.] C

  
  <EMI ID = 202.1>

  

  <EMI ID = 203.1>


  
EXAMPLE 36

  

  <EMI ID = 204.1>


  
Melting point: 146 [deg.] C

  
  <EMI ID = 205.1>

  

  <EMI ID = 206.1>


  
EXAMPLE 37

  

  <EMI ID = 207.1>


  
Melting point: 262-264 [deg.] C

  
  <EMI ID = 208.1>

  

  <EMI ID = 209.1>


  
EXAMPLE 38

  

  <EMI ID = 210.1>


  
Melting point: 154-156 [deg.] C <EMI ID = 211.1>

  

  <EMI ID = 212.1>


  
EXAMPLE 39

  

  <EMI ID = 213.1>


  
Melting point: 234 [deg.] C

  
  <EMI ID = 214.1>

  

  <EMI ID = 215.1>


  
EXAMPLE 40

  

  <EMI ID = 216.1>


  
Melting point: 306 [deg.] C

  
  <EMI ID = 217.1>

  

  <EMI ID = 218.1>


  
EXAMPLE 41

  

  <EMI ID = 219.1>


  
To 50 ml of acetonitrile, 10 g of 2-aminobenzothiazole and 7 g of α-bromopropiophenone were added and the mixture was heated at reflux for 3 days. After cooling the reaction mixture, the precipitated 2-aminobenzothiazole hydrobromide was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of chloroform and then 100 ml of acetate

  
  <EMI ID = 220.1>

  
formed was collected and concentrated under reduced pressure. The residue obtained was subjected to chromatography on a column of silica gel and then the product was eluted using chloroform as eluent to give 1.5 g

  
  <EMI ID = 221.1>

  

  <EMI ID = 222.1>


  
Following the same procedure as above, the following compounds were prepared.

  
EXAMPLE 42

  

  <EMI ID = 223.1>


  
Melting point: 82-84 [deg.] C

  
  <EMI ID = 224.1>

  

  <EMI ID = 225.1>


  
EXAMPLE 43
  <EMI ID = 226.1>
   <EMI ID = 227.1>

  
Elementary analysis for C29H22N202S:

  

  <EMI ID = 228.1>


  
EXAMPLE 44

  

  <EMI ID = 229.1>


  
  <EMI ID = 230.1>

  

  <EMI ID = 231.1>


  
EXAMPLE 45

  

  <EMI ID = 232.1>


  
  <EMI ID = 233.1>

  

  <EMI ID = 234.1>


  
EXAMPLE 46
  <EMI ID = 235.1>
 Melting point: 235 [deg.] C

  
  <EMI ID = 236.1>

  

  <EMI ID = 237.1>


  
EXAMPLE 47

  

  <EMI ID = 238.1>


  
Melting point: 149 [deg.] C

  
  <EMI ID = 239.1>

  

  <EMI ID = 240.1>


  
EXAMPLE 48

  

  <EMI ID = 241.1>


  
Following the same procedure as in Example 1, using 3.6 g of 2-amino-6-methoxybenzothiazole and 6 g of

  
  <EMI ID = 242.1>

  
dihydrobenzothiazole. The white crystals were heated at reflux in 150 ml of methylcellosolve for 3 hours. After cooling the reaction mixture, the crystals formed were collected by filtration and the filtrate was concentrated under reduced pressure to form a solid. The crystals recovered above were combined with the solid material and after adding 30 ml of a saturated solution of sodium hydrogencarbonate to it, the product was extracted with 300 ml of chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 2.5 g of

  
  <EMI ID = 243.1>

  
zole.

  
  <EMI ID = 244.1>

  

  <EMI ID = 245.1>


  
EXAMPLE 49

  

  <EMI ID = 246.1>


  
To 70 ml of methyl ethyl ketone were added 7 g of 2-aminobenzothiazole and 10 g of o-methoxyphenacyl bromide and the mixture was heated at reflux for 10 hours. The reaction mixture was filtered while hot to recover the precipitated crystals. The crystals were washed with methyl ethyl ketone and dried to provide 3.0 g of

  
  <EMI ID = 247.1>

  
having a melting point of 263-265 [deg.] C.

  
Then 3 g of hydrobromide were added to a mixture of
50 ml of chloroform and 20 ml of 10% ammonia and after stirring the mixture for 20 minutes at room temperature, the layer of chloroform formed was recovered. The chloroform layer obtained was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to form white solids which were recrystallized from <EMI ID = 248.1>

  

  <EMI ID = 249.1>


  
EXAMPLE 50

  

  <EMI ID = 250.1>


  
  <EMI ID = 251.1>

  
benzothiazole and 12 g of o-acetoxyphenacyl bromide and the mixture was heated at reflux for 3 hours. After

  
  <EMI ID = 252.1>

  
cooled, precipitated 2-aminobenzothiazole hydrobromide

  
was removed by filtration and the filtrate was concentrated under reduced pressure and then toluene was added to the residue whereby crystals precipitated. The crystals were collected by filtration and dried to provide 3.5 g of white crystals of 2-imino-3- (o-hydroxybenzoylmethyl) 2,3-dihydrobenzothiazole.

  
  <EMI ID = 253.1>

  
alcoholic hydrochloric acid to form the hydrochloride which was heated with 50 ml of methylcellosolve and treated as in Example 1 to give 1.6 g of white crystals.

  
  <EMI ID = 254.1> <EMI ID = 255.1>

  

  <EMI ID = 256.1>


  
EXAMPLE 51

  

  <EMI ID = 257.1>


  
A solution of 6.8 g of 2-aminobenzothiazole and 7.2 g of

  
  <EMI ID = 258.1>

  
ethyl ketone was heated at reflux for 3 hours. After cooling the reaction mixture, 50 ml of ether were added to the reaction mixture, the precipitates formed were removed by filtration and the mother liquor was concentrated under reduced pressure. The residue formed was dissolved in

  
  <EMI ID = 259.1>

  
solution was acidified by addition of an ethanolic hydrochloric acid solution. The crystals formed were collected by filtration, dried and then heated to reflux.

  
  <EMI ID = 260.1>

  
reaction mixture was basified by addition of concentrated ammonia and then cooled to form crystals which were collected by filtration and recrystallized from tetrahydrofuran-n-hexane to give 1 g of 2- (2,4-

  
  <EMI ID = 261.1>

  

  <EMI ID = 262.1>
 

  
Following the same procedure as above, the following compound was prepared.

  
EXAMPLE 52

  

  <EMI ID = 263.1>


  
Melting point: 235 [deg.] C

  
  <EMI ID = 264.1>

  

  <EMI ID = 265.1>


  
EXAMPLE 53

  

  <EMI ID = 266.1>


  
After having heated under reflux 4 g of 2-imino hydrochloride

  
  <EMI ID = 267.1>

  
40 ml of chloroform and 9 ml of thionyl chloride for 2 hours, the reaction mixture was concentrated under reduced pressure to provide 4.2 g of crude hydrochloride crystals

  
  <EMI ID = 268.1>

  
product were added 50 ml of chloroform, 50 ml of water

  
and 5 g of sodium hydrogen carbonate and the mixture was heated to reflux for 3 hours. After completion of the reaction, the chloroform layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a tacky material. The sticky material was treated with a hydrochloric acid-ethanol mixture and the white solids thus obtained were

  
  <EMI ID = 269.1> <EMI ID = 270.1>

  
benzothiazole.

  
Nuclear magnetic resonance spectrum (D &#65533; -DMSO)

  

  <EMI ID = 271.1>


  
  <EMI ID = 272.1>

  
) dihydrobenzothiazole used above as a raw material was prepared in the following manner:

  
In 100 ml of ethanol, 7.5 g of 2-imino-3-phenacyl-2,3-dihydrobenzothiazole hydrobromide were suspended and after the suspension had cooled to 0-5 [deg.] C, 1.2 g of

  
  <EMI ID = 273.1>

  
suspension and the mixture was stirred for one hour. The reaction mixture was mixed with 5 ml of water and concentrated under reduced pressure. The residue was extracted with toluene and the extract was washed with water, dried over anhydrous magnesium sulfate and then the solvent was distilled off to give a tacky product. The sticky product was dissolved in ethanol and a hydrochloric acid-ethanol mixture was added to the solution.

  
  <EMI ID = 274.1>

  
EXAMPLE 54

  

  <EMI ID = 275.1>


  
In a solution of 2.5 g of potassium hydroxide in

  
  <EMI ID = 276.1> brewed for one hour at 40-50 [deg.] C, whereby the additive was completely dissolved. Then, 3 ml of acetic acid were gradually added dropwise to the reaction mixture under stirring, whereby crystals precipitated. The crystals were collected by filtration, washed with water and then methanol and dried for

  
  <EMI ID = 277.1>

  
thiazole.

  
Melting point: 296-298 [deg.] C

  
  <EMI ID = 278.1>

  

  <EMI ID = 279.1>


  
Following the above procedure, the following compounds were prepared.

  
EXAMPLE 55

  

  <EMI ID = 280.1>


  
Melting point: 285-286 [deg.] C

  
Elementary analysis for C16H12N202S:

  

  <EMI ID = 281.1>


  
EXAMPLE 56
  <EMI ID = 282.1>
 Melting point: 261-263 [deg.] C

  
  <EMI ID = 283.1>

  

  <EMI ID = 284.1>


  
EXAMPLE 57

  

  <EMI ID = 285.1>


  
  <EMI ID = 286.1>

  

  <EMI ID = 287.1>


  
  <EMI ID = 288.1>

  

  <EMI ID = 289.1>


  
Melting point: 287-290 [deg.] C (decomposed)

  
  <EMI ID = 290.1>

  

  <EMI ID = 291.1>


  
EXAMPLE 59

  

  <EMI ID = 292.1>


  
Melting point: 253-255 [deg.] C <EMI ID = 293.1>

  

  <EMI ID = 294.1>


  
EXAMPLE 60

  

  <EMI ID = 295.1>


  
2.2 g of a 15 ml mixture of 20% aqueous potassium hydroxide solution and 50 ml of methanol were added

  
  <EMI ID = 296.1>

  
the mixture was heated at reflux for 30 minutes. After completion of the reaction, 4 ml of acetic acid was added to the reaction mixture and the crystals precipitated

  
were collected by filtration, washed successively with water, methanol and ethanol, and dried to provide 1.7

  
  <EMI ID = 297.1>

  

  <EMI ID = 298.1>


  
By following the above procedure, the following compounds have

  
  <EMI ID = 299.1>

  
EXAMPLE 61

  

  <EMI ID = 300.1>


  
Melting point: 255 [deg.] C.

  
  <EMI ID = 301.1>

  

  <EMI ID = 302.1>


  
EXAMPLE 62

  

  <EMI ID = 303.1>


  
Melting point: above 300 [deg.] C

  
Elementary analysis for C16 ilio N20 3s

  

  <EMI ID = 304.1>


  
EXAMPLE 63

  

  <EMI ID = 305.1>


  
Melting point: above 300 [deg.] C

  
  <EMI ID = 306.1>

  

  <EMI ID = 307.1>


  
EXAMPLE 64

  

  <EMI ID = 308.1>


  
Melting point: above 300 [deg.] C <EMI ID = 309.1>

  

  <EMI ID = 310.1>


  
EXAMPLE 65

  

  <EMI ID = 311.1>


  
In 2.0 ml of water were suspended 2.08 g of

  
  <EMI ID = 312.1>

  
and then, after adding 10 ml of a normal sodium hydroxide solution to the suspension, the mixture was stirred for 3 hours at room temperature. Insoluble matter was removed by filtration and acetic acid was added to the filtrate to form crystals which were collected by filtration, washed with water and dried to provide 1.1 g of 2- (p- chlorophenyl) -3-oxaloamido-

  
  <EMI ID = 313.1>

  

  <EMI ID = 314.1>


  
EXAMPLE 66
  <EMI ID = 315.1>
 To a mixture of 30 ml of 2N hydrochloric acid and 20 ml of

  
  <EMI ID = 316.1>

  
during 2 hours. The reaction mixture was concentrated under reduced pressure to form solids which were recrystallized from ethanol to provide 4.2 g of

  
  <EMI ID = 317.1>

  

  <EMI ID = 318.1>


  
EXAMPLE 67

  

  <EMI ID = 319.1>


  
To a mixture of 100 ml of concentrated hydrochloric acid and
300 g of methylcellosolve were added 8.5 g of

  
  <EMI ID = 320.1>

  
reaction mixture was cooled to form crystals which were collected by filtration. The crystals were suspended in 200 ml of methylcellosolve and after having basified the suspension by adding concentrated ammonia, 80 ml of water were added to the mixture followed by cooling, whereby crystals precipitated. The precipitated crystals were collected by filtration and

  
  <EMI ID = 321.1>

  
benzothiazole.

  
Melting point: 161-163 [deg.] C <EMI ID = 322.1>

  

  <EMI ID = 323.1>


  
EXAMPLE 68

  

  <EMI ID = 324.1>


  
To 40 ml of methyl ethyl ketone were added 2.6 g of

  
  <EMI ID = 325.1>

  
ethyl monobromacetic acid and 1.5 g carbonate

  
of potassium and the mixture was heated at reflux overnight. After completion of the reaction, the reaction mixture

  
was cooled, the insolubles were removed by filtration and the filtrate was concentrated under reduced pressure to provide solids which were recrystallized

  
from toluene-n-hexane to provide 1.8 g of 2- (p-ethoxy-

  
  <EMI ID = 326.1>

  

  <EMI ID = 327.1>


  
By following the above procedure the following compound was prepared.

  
EXAMPLE 69
  <EMI ID = 328.1>
 Melting point: 114-116 [deg.] C

  
  <EMI ID = 329.1>

  

  <EMI ID = 330.1>


  
EXAMPLE 70

  

  <EMI ID = 331.1>


  
1.8 g of 3-amino-2 (p-chlorophenyl) were dissolved in a mixture of 15 ml of pyridine and 15 ml of methylene chloride

  
  <EMI ID = 332.1>

  
of ethyloxalyl chloride in 10 ml of methylene chloride was added dropwise to the solution at temperatures below 5 [deg.] C. The temperature of the mixture was raised to ambient temperature and, after stirring the mixture for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was extracted with 400 ml of ethyl acetate and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to form crystals which were collected and recrystallized at from ethanol to give 1.72 g of

  
  <EMI ID = 333.1>

  

  <EMI ID = 334.1>


  
Following the above procedure, the following compound was prepared.

  
EXAMPLE 71

  

  <EMI ID = 335.1>


  
Melting point: 238-241 [deg.] C

  
  <EMI ID = 336.1>

  

  <EMI ID = 337.1>


  
EXAMPLE 72

  

  <EMI ID = 338.1>


  
1.2 g of

  
  <EMI ID = 339.1>

  
at 3 - 10 [deg.] C and then the mixture was stirred for one hour at room temperature. To the reaction mixture was added 100 ml of water and then the product was extracted with a mixture of 25 ml of toluene and 25 ml of ethyl acetate. The extract was washed with water and then an aqueous solution of sodium hydrogencarbonate, dried over

  
anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.2 g of white crystals of 2- (m-formamido-

  
  <EMI ID = 340.1>

  

  <EMI ID = 341.1>
 

  
EXAMPLE 73

  

  <EMI ID = 342.1>


  
  <EMI ID = 343.1>

  
drop 9 drop a solution of 1.2 g of ethyl chlorocarbonate in 5 ml of methylene chloride at temperatures below 10 [deg.] C. Then the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to form crystals which were collected and recrystallized

  
from ethanol to provide 1.56 g of 2- (p-chloropheny &#65533; <EMI ID = 344.1>

  

  <EMI ID = 345.1>


  
  <EMI ID = 346.1>

  

  <EMI ID = 347.1>


  
  <EMI ID = 348.1>

  
benzothiazole in 3 ml of acetic anhydride and 10 ml of pyridine was stirred overnight at 80 [deg.] C. The reaction mixture was concentrated under reduced pressure and the residue formed was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using a 10: 3 mixture of toluene and ethyl acetate as eluent and the crystals obtained were recrystallized from a mixture of toluene and n -hexane to provide 1.35 g of 2- (m-acetoxyphenyl) imidazo

  
  <EMI ID = 349.1>

  

  <EMI ID = 350.1>


  
EXAMPLE 75

  

  <EMI ID = 351.1>


  
  <EMI ID = 352.1>

  
of p-toluyle in 10 ml of tetrahydrofuran at temperatures below 10 [deg.] C and the mixture was stirred overnight

  
at room temperature. The reaction mixture was mixed with 100 ml of toluene, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixture of toluene

  
  <EMI ID = 353.1>

  
  <EMI ID = 354.1>

  

  <EMI ID = 355.1>


  
EXAMPLE 76

  

  <EMI ID = 356.1>


  
  <EMI ID = 357.1>

  
[2,1-bJbenzothiazole were added 50 ml of methylcellosolvi and 10 ml of 30% ammonia and after mixing the mixture for one hour at room temperature, the crystals formed were recovered by filtration, washed successively with chloroform and then methanol and dried to provide

  
  <EMI ID = 358.1>

  
thiazole.

  
Melting point: above 300 [deg.] C

  
  <EMI ID = 359.1>

  

  <EMI ID = 360.1>


  
  <EMI ID = 361.1>

  

  <EMI ID = 362.1>


  
  <EMI ID = 363.1>

  
3.2 g of 2- (m-methoxycarbonylphenyl) imidazo- were added <EMI ID = 364.1>

  
of the mixture, the precipitated crystals were collected by filtration, washed with chloroform and dried to provide

  
  <EMI ID = 365.1>

  
benzothiazole.

  
Melting point: 261 [deg.] C

  
  <EMI ID = 366.1>

  

  <EMI ID = 367.1>


  
EXAMPLE 78

  

  <EMI ID = 368.1>


  
While vigorously stirring a mixture of a solution of

  
  <EMI ID = 369.1>

  
50 ml of chloroform and 30 ml of a saturated aqueous solution of sodium hydrogencarbonate, a solution of 1.2 g of bromine in 5 ml of chloroform was gradually added dropwise to the mixture at room temperature. Then the chloroform layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to form solids. The solid product was recrystallized from a mixture of toluene and

  
  <EMI ID = 370.1>

  

  <EMI ID = 371.1>
 

  
Following the above procedure, the following compounds were prepared.

  
EXAMPLE 79

  

  <EMI ID = 372.1>


  
Melting point: 178-180 [deg.] C

  
  <EMI ID = 373.1>

  

  <EMI ID = 374.1>


  
EXAMPLE 80

  

  <EMI ID = 375.1>


  
  <EMI ID = 376.1>

  

  <EMI ID = 377.1>


  
EXAMPLE 81

  

  <EMI ID = 378.1>


  
Melting point: 239 [deg.] C

  
  <EMI ID = 379.1>

  

  <EMI ID = 380.1>
 

  
EXAMPLE 82

  

  <EMI ID = 381.1>


  
Melting point: 144 [deg.] C

  
  <EMI ID = 382.1>

  

  <EMI ID = 383.1>


  
EXAMPLE 83

  

  <EMI ID = 384.1>


  
  <EMI ID = 385.1>

  
  <EMI ID = 386.1>

  

  <EMI ID = 387.1>


  
EXAMPLE 84

  

  <EMI ID = 388.1>


  
Melting point: 219 [deg.] C

  
  <EMI ID = 389.1>

  

  <EMI ID = 390.1>
 

  
EXAMPLE 85

  
  <EMI ID = 391.1>

  
In 100 ml of methylene chloride were dissolved 2 g of

  
  <EMI ID = 392.1>

  
  <EMI ID = 393.1>

  
potassium carbonate and 1.8 g of iodine, the mixture was stirred overnight, vigorously, at room temperature. The crystals formed were collected by filtration

  
  <EMI ID = 394.1>

  

  <EMI ID = 395.1>


  
EXAMPLE 86

  

  <EMI ID = 396.1>


  
  <EMI ID = 397.1>

  
thiazole in 40 ml of methylene chloride was added a solution of 0.95 g of sulfuryl chloride in 5 ml of methylene chloride and after stirring for 10 minutes,

  
40 ml of a 10% aqueous solution of potassium hydrogen carbonate were added to the mixture followed by stirring. The organic layer formed was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to form crystals which were recrystallized from ethanol to give 1.4 g of

  
  <EMI ID = 398.1>

  

  <EMI ID = 399.1>


  
Following the above procedure, the following compound was prepared.

  
EXAMPLE 87

  

  <EMI ID = 400.1>


  
Melting point: 180 [deg.] C

  
  <EMI ID = 401.1>

  

  <EMI ID = 402.1>


  
EXAMPLE 88

  

  <EMI ID = 403.1>


  
To 30 ml of chloroform were added 1.35 g of 2- (m-acetoxy-

  
  <EMI ID = 404.1>

  
succinimide and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated 1 under reduced pressure and the residue was washed with ether

  
  <EMI ID = 405.1>

  
been brewed for 30 minutes at room temperature. To the reaction mixture was added acetic acid to acidify the mixture and then 50 ml of water was added to the mixture to form crystals which were collected by filtration and recrystallized from a mixture of methylcellosolve and water to give 1.2 g of 3-bromo-2- (m-hydroxy-

  
  <EMI ID = 406.1>

  

  <EMI ID = 407.1>


  
EXAMPLE 89

  

  <EMI ID = 408.1>


  
After cooling 30 ml of fuming nitric acid between <EMI ID = 409.1>

  
The mixture was poured into ice water and the crystals formed were collected by filtration and recrystallized from acetic acid to give 2.2 g of 2- (p-chloro-

  
  <EMI ID = 410.1>

  
Melting point: 180-183 [deg.] C <EMI ID = 411.1>

  

  <EMI ID = 412.1>


  
EXAMPLE 90

  

  <EMI ID = 413.1>


  
To 700 ml of acetic acid were added 14 g of 2- (p-chloro-

  
  <EMI ID = 414.1>

  
sodium nitrite, under stirring, at room temperature, the mixture was stirred for 3 hours. Then 500 ml of water was added to the mixture and the crystals thus formed were collected by filtration and washed with water and then

  
  <EMI ID = 415.1>

  

  <EMI ID = 416.1>


  
EXAMPLE 91

  

  <EMI ID = 417.1>


  
  <EMI ID = 418.1>

  
that, 6 g of zinc powder were gradually added &

  
  <EMI ID = 419.1>

  
insoluble matter was removed by filtration and 3 drops of concentrated sulfuric acid were added to the filtrate to form a precipitate. After filtering off the precipitate, 20 ml of concentrated sulfuric acid was added to the mother liquor and the mixture was left to stand overnight. The crystals formed were collected by filtration and added to a mixture of ethyl acetate and water. After adding potassium carbonate to it and stirring, the ethyl acetate layer formed was recovered, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to form crystals which have been recovered and recrystallized

  
from toluene to give 2.3 g of 3-amino-2- (p-chloro-

  
  <EMI ID = 420.1>

  

  <EMI ID = 421.1>


  
EXAMPLE 92

  

  <EMI ID = 422.1>


  
  <EMI ID = 423.1>

  
ethanol, 1 g of sodium borohydride was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and 900 ml of chloroform was added to the residue. After removing the insoluble matter formed, the residue was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was recrystallized from isopropyl alcohol

  
  <EMI ID = 424.1>

  

  <EMI ID = 425.1>


  
EXAMPLE 93

  

  <EMI ID = 426.1>


  
  <EMI ID = 427.1>

  
methylsulfinyl chloride ethane obtained from 4 g of dimethyl disulfide and 5.2 g of sulfuryl chloride under ice cooling. Then, the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then the residue was extracted with 200 ml of chloroform. The extract

  
  <EMI ID = 428.1>

  
sodium and then water, dried over sodium sulfate. anhydrous magnesium and concentrated under reduced pressure. The

  
  <EMI ID = 429.1>

  

  <EMI ID = 430.1>
 

  
EXAMPLE 94

  

  <EMI ID = 431.1>


  
To a solution of 1.5 g of 2- (p-chlorophenyl) -3-methylthioimidazo [2,1-b] benzothiazole in 50 ml of chloroform were added 1.7 g of m-chloroperbenzoic acid and the mixture a been brewed overnight at room temperature. The reaction mixture was washed with a 5% aqueous solution of sodium hydrogencarbonate and then water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methyl-

  
  <EMI ID = 432.1>

  
thiosulfinylimidazo [2, 1-b] benzothiazole.

  
Melting point: 185-187 [deg.] C (decomposed)

  
  <EMI ID = 433.1>
  <EMI ID = 434.1>
 EXAMPLE 95

  

  <EMI ID = 435.1>


  
  <EMI ID = 436.1>

  
stirring vigorously, a solution of 1.6 g of bromine in 5 ml of chloroform was added dropwise to the mixture. Then, the chloroform layer formed was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Residual solids were subjected to silica gel column chromatography and the product was eluted using a mixture of chloroform and ethyl acetate to give 0.8 g of 3-bromo-7-

  
  <EMI ID = 437.1>

  

  <EMI ID = 438.1>


  
EXAMPLE 96

  

  <EMI ID = 439.1>


  
To a solution prepared by adding 0.2 g of lithium aluminum hydride to 20 ml of tetrahydrofuran cooled to 0-5 [deg. C] was gradually added dropwise a solution of 1.2 g

  
  <EMI ID = 440.1>

  
10 ml of tetrahydrofuran and the mixture was further stirred for 10 minutes at 0-5 [deg.] C. After gradually adding 5 ml of 10% acetic acid to the reaction mixture, 50 ml of ethyl acetate was added to the mixture and the product was extracted. The extract was dried over anhydrous magnesium sulfate and concentrated to give 10 g of solids which were recrystallized from isopropanol to give

  
  <EMI ID = 441.1>

  
Melting point: 159 [deg.] C

  
Elementary analysis for C16H12N20S.

  

  <EMI ID = 442.1>
 

  
Following the same procedure, the compound illustrated in the following Example was prepared.

  
EXAMPLE 97

  

  <EMI ID = 443.1>


  
Melting point: 132 [deg.] C

  
  <EMI ID = 444.1>

  

  <EMI ID = 445.1>


  
Following the same procedure as in Example 1, the following compounds were prepared.

  
EXAMPLE 98

  

  <EMI ID = 446.1>


  
'anointed with fusion. 130-132 [deg.] C

  
  <EMI ID = 447.1>

  

  <EMI ID = 448.1>


  
EXAMPLE 99

  

  <EMI ID = 449.1>


  
Melting point: 220-222 [deg.] C <EMI ID = 450.1>

  

  <EMI ID = 451.1>


  
EXAMPLE 100

  

  <EMI ID = 452.1>


  
Melting point: 261-263 [deg.] C

  
  <EMI ID = 453.1>

  

  <EMI ID = 454.1>


  
EXAMPLE 101

  

  <EMI ID = 455.1>


  
Melting point: 210-212 [deg.] C

  
  <EMI ID = 456.1>

  

  <EMI ID = 457.1>


  
EXAMPLE 102

  

  <EMI ID = 458.1>


  
  <EMI ID = 459.1> <EMI ID = 460.1>

  

  <EMI ID = 461.1>


  
Following the same procedure as in Example 75, the following compound was prepared.

  
e

  
EXAMPLE 103

  

  <EMI ID = 462.1>


  
Melting point: 215 [deg.] C

  
  <EMI ID = 463.1>

  

  <EMI ID = 464.1>


  
Following the same procedure as in Example 60, the following compound was prepared.

  
EXAMPLE 104

  

  <EMI ID = 465.1>


  
  <EMI ID = 466.1>

  

  <EMI ID = 467.1>
 

  
EXAMPLE 105

  

  <EMI ID = 468.1>


  
To 50 ml of ethanol were added 500 mg of 7-amino-2-phenyl-

  
  <EMI ID = 469.1>

  
260 mg of potassium carbonate and, while stirring vigorously, the mixture was heated at reflux for two days. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was extracted with

  
50 ml of ethyl acetate and the extract was washed with water, dried over anhydrous magnesium sulfate and then the extract was concentrated under reduced pressure. The residue

  
was subjected to chromatography on a column of silica gel (eluent: toluene: ethyl acetate in the ratio 4: 1) and the crystals obtained were recrystallized from

  
  <EMI ID = 470.1>

  

  <EMI ID = 471.1>


  
  <EMI ID = 472.1>

  

  <EMI ID = 473.1>


  
  <EMI ID = 474.1>

  
  <EMI ID = 475.1>

  
  <EMI ID = 476.1> was heated at reflux for 2 hours and then the insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was mixed with 50 ml of water and extracted with 50 ml of ethyl acetate. The ethyl acetate layer formed was collected, dried over anhydrous magnesium sulfate and then the solvent was distilled off to give an oily product. The oily product was dissolved in 20 ml of a

  
  <EMI ID = 477.1>

  
ether were added to the solution and then the white crystals formed were collected by filtration to give 2.0 g of 2- [m- (N, N-dimethyl) phenyl] imidazo dihydrochloride

  
  <EMI ID = 478.1>

  

  <EMI ID = 479.1>



    

Claims (1)

 <EMI ID = 480.1> characterized in that it is represented by the formula I  <EMI ID = 481.1> 1  <EMI ID = 482.1> different, each represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a nitroso group, an amino group, a carboxy group, a nitrile group, a carbamoyl group, a sulfamoyl group, a group lower alkyl, hydroxy lower alkyl, lower alkoxy group, phenyl lower alkoxy group, lower carboxyalkoxy group, lower alkoxycarbonyl group lower alkoxy, lower alkoxycarbonyl group, acyloxy group, lower alkylthio group, lower alkylsulfinyl group , a lower alkyl sulfonyl group, a lower alkoxysulfinyl group, a lower alkoxysulfonyl group, a mono or di alkylamino group  <EMI ID = 483.1> cents that can combine with each other to form a  <EMI ID = 484.1> R5 and R, which may be the same or different, represent  <EMI ID = 485.1> hydroxy group, nitro group, nitroso group, amino group, thiocyanate group, lower alkyl group, hydroxy lower alkyl group, lower alkoxy group, carboxy lower alkoxy group, lower alkoxycarbonyl group lower alkoxy, group acyloxy, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a mono or lower alkylamino group, an acylamino group or a group represented by the formula  <EMI ID = 486.1> ; and the line in dotted represents the existence or absence of a double bond; however when R2, R3 and R4 are all an atom  <EMI ID = 487.1> a nitro group, a lower alkyl group or a lower alkoxy group, the dotted line represents the existence of a double bond, and (1) R6 is a hydrogen atom, R represents the above group other than a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a lower alkyl group or an alkoxy group  <EMI ID = 488.1> thiocyanate, R1 represents the above group other than a  <EMI ID = 489.1>  <EMI ID = 490.1> above other than a hydrogen atom or a nitro group.  <EMI ID = 491.1> characterized in that it consists of a salt of the new derivative according to claim 1.  <EMI ID = 492.1> according to claim 1, characterized in that it is 2- (m-hydroxyphenyl) imidazo [2,1-bjbenzothiazole.  <EMI ID = 493.1> according to claim 1, characterized in that it is 2- (o-hydroxyphenyl) imidazo [2,1-b] benzothiazole.  <EMI ID = 494.1> according to claim 1, characterized in that it is 2- (p-hydroxyphenyl) imidazo-  <EMI ID = 495.1> 5 according to claim 1, characterized in that it is 2- (m-nitrophenyl) imidazo-  <EMI ID = 496.1> i according to claim 1, characterized in that it is 2- (3-chloro-4-hydroxyphenyl) -  <EMI ID = 497.1> according to claim 1, characterized in that it is 2- (3,5-dichloro-4-hydroxy-  <EMI ID = 498.1> according to claim 1, characterized in that it is 7-hydroxy-2- (p-hydroxy-  <EMI ID = 499.1> characterized in that the benzothiazole derivative represented by the formula is cyclized  <EMI ID = 500.1>  in which A represents a carbonyl group or a group Y represents by -CH- (in which Y represents an atom  <EMI ID = 501.1> different, each represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a nitroso group, an amino group, a carboxy group, a nitrile group, a carbamoyl group, a sulfamoyl group, a group lower alkyl, hydroxy lower alkyl, lower alkoxy group, phenyl lower alkoxy group, lower carboxyalkoxy group, lower alkoxycarbonyl group lower alkoxy, lower alkoxycarbonyl group, acyloxy group, lower alkylthio group, lower alkylsulfinyl group , a lower alkylsulfonyl group, a lower alkoxysulfinyl group, a lower alkoxysylfonyl group, a mono or di lower alkylamino group, or an acylamino group; two adjacent R, R2 and R3 which can combine with each other to form a  <EMI ID = 502.1>  <EMI ID = 503.1> each have a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a nitroso group, an amino group, a thiocyanate group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, an inner alkoxy carboxy group, a lower alkoxy lower alkoxycarbonyl group, an acyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a mono or lower alkylamino group, an acylamino group or a group represented by the formula  <EMI ID = 504.1> ; and the line in dotted line represents the existence or absence of a double  <EMI ID = 505.1> 3 hydrogen, R5 is a hydrogen atom, a halogen atom a nitro group, a lower alkyl group or a lower alkoxy group, the dotted line represents the existence  <EMI ID = 506.1> represents the above group other than a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a nitro group, a lower alkyl group or a lower alkoxy group; and (2) R6 is a bromine atom or a group  <EMI ID = 507.1> hydrogen atom or a halogen atom and (3) R6 is a  <EMI ID = 508.1> above other than a hydrogen atom or a nitro group and then, if necessary, hydrolysis, alkyl, acyl, trans-  <EMI ID = 509.1> nitroso, reduced, forms into lower alkylthio or oxidizes the product.