DE2114563A1 - Substituted 6 phenyl imidazo square bracket to 2.1 square bracket to thiazole - Google Patents

Description

American Cyanamid Company, Wayne, New Jersey, V.St.Ä.

Substituted 6 -phenyl-imidazo ^ 2,1-b / thiazoles

The invention relates to new dl and 1 compounds of the formula

wherein R is a hydrogen atom, a C -C lower alkyl radical or a -COR- group. means in which R-, a hydrogen atom or a lower CC ₃ -Allyi radical, and their pharmaceutically acceptable salts. The invention relates to a new process for the preparation of these compounds and the use of these compounds for the treatment of helia thiasis in warm-blooded animals.

109842/1986

A range of 6-substituted imidazo ^ 2, l-b / -thiazoles is in U.S. Patents 3,274,209 and 3,364,112 generally described. The use of these compounds as anthelmintics is also suggested and there are Values given for several compounds.

It has now been found that an effective and safe control of whipworms in warm-blooded animals with a selected group of dl and! compounds of the formula

wherein R is a hydrogen atom _{f is} a lower C -C ₄ radical or a group COR ^, in which R_ is a hydrogen atom or a lower C -C 4 -alkyl radical, and

denotes a single or double bond, and

pharmaceutically acceptable acid addition salts thereof can be achieved. These salts can include the hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like Be salts.

According to the invention, a suitable anilide, for example 3'-acetylacetanilide, 3'-acetylformanilide or 3'-acetylpropionanilide in an inert solvent such as methylene chloride, chloroform, carbon tetrachloride or the like dissolved and with bromine, chlorine or the like to the corresponding 3'-chloro- or 3'-bromoacetylacetanilide, -formanilide or -propionanilide, which is used in the following Reaction scheme denoted by formula I, implemented,

109842/1985

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Treatment of the anilide of formula I with an equimolar Amount of 2-aminothiazole or 2-amino-2-thiazoline in an inert solvent such as methylene chloride, Chloroforxa. Acetone, lithyl acetate or the like at a temperature between about 20 and 75 degrees C provides the 3 '- ^ (2-imino-4-thiazolin-3-yl) acety1 / acetanilide-, formanilide or propionanilide hydrochloride or hydrobromide salt of the formula II. This salt is at least the theoretical i-lenge of an alkali borohydride in the presence of a lower alcohol such as methanol, ethanol, butanol, isopropanol, a mixture of water and lower alcohols or the like and then treated with an organic Acid or a hydrohalic acid with formation of the Hydroxyäthylacetanilidhydrohalogenids of the formula IVB acidified. It has also been found that the iminothiazolinyl anilide hydrohalide of formula II with acetic anhydride in the presence of an inert solvent such as acetic acid and an alkali acetate at a temperature between about 50 and 120 degrees C to deia 2-acetyliminothiazolinyl anilide of the formula III can be implemented, which is obtained by reacting «lit an alkali borohydride and then Acidification can easily be converted into the thiazolinyl anilide hydrohalide of the formula IVA. The reaction conditions used are similar to those used for treating the compounds of formula II with alkali borohydride.

The cyclization of the thiazolinyl anilide hydrohalide (formula IV) is carried out by reacting the compound with Thionyl chloride at a temperature between about 40 and 75 degrees C and treating the reaction product with acetic anhydride at about 50 to 140 degrees C. The reaction product is then dissolved in hydrochloric acid and mixed with ammonium hydroxide or an alkali hydroxide, whereby the dihydroimidazothiazolylacetanilide of the formula V is obtained will. If this product is then treated with perchloric acid, the perchlorate salt of formula V is obtained.

109842/1985

21H563

The cyclization of compounds of the formula IV can also be carried out by reaction with concentrated sulfuric acid and then Treatment of the reaction product with a strong base, for example ammonium hydroxide or alkali hydroxide, can be achieved. This reaction yields the tetrahydroimidazothlazolylacetanilide free base of the formula V. The treatment of the imidazothiazolylacetanilide of the formula V with hydrochloric acid or hydrobromic acid at reflux temperature gives the aminophenylimidazothiazole dihydrohalide of formula VII.

The compound of the formula VII can advantageously also be made from 2,3,5,6-Tetrahydro-6- (m-nitrophenyl) imidazo / 2,1-b / -thiazole hydrochloride (VI) by reacting this compound with stannous chloride and hydrochloric acid at a higher temperature, for Example between about 60 and 100 degrees C. The product obtained is then treated with an alkali hydroxide neutralized, and the mixture is treated with an alcoholic hydrogen halide solution.

The m-aminophenyl compound of the formula VII as free Base can be converted into the corresponding formanilide of VIII by reaction with formic acid. the Reaction can be carried out in the presence of an inert solvent, for example toluene, or in formic acid alone will. In general, the reaction is carried out at a temperature between 50 and 125 degrees C, however, a range of 75 to 100 degrees C is usually preferred.

The formanilide (VIII) is then treated with lithium aluminum hydride in the presence of an inert solvent such as tetrahydrofuran at a temperature between about 25 and 75 degrees C and vorzugsv / else AO to 50 degrees C. The m-methylaminophenylimidazothiazole of the formula IX is then obtained.

109842/1985

Furthermore, according to the invention, 1-6- (m-aminophenyl) -2,3,5,6-tetrahydroimidazc / 2,1-b / thiazole dihydrochloride by separation of racemic dl-2,3 , 5,6-tetrahydro-6- (m-nitrophenyl) -imidazo ^, 1-b / thiazole with d-tartaric acid to form the 1-base-d-tartrate salt, which is then converted into the free base and then into the 1-isomer 1-6- (m-nitrophenyl ) -2,3,5,6-tetrahydroiraidazo / 2, lb / thiazole hydrochloride is converted, obtained. Reduction of 1-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo ^ 2.1b / thiazole hydrochloride with stannous chloride in hydrochloric acid gives the desired 1-6- (m-aminophenyl) -2.3 , 5,6-tetrahydroimidazo £ 2,1-b / -thiazole dihydrochloride. This response is shown below.

VI

^SnC1 2 χ

HCl 7

HCl

1-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo £ 2, l-b_ / ~ thiazole hydrochloride and d-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo ^, l-b_ / thiazole hydrochloride.

2HCl

1-6 · (m-aminophenyl) -2,3,5,6-tetrahydroimidazo ^ 2, l-b_ykhlmsol dihydrochloride and d-6 - (m-aminophenyl) -2, 3,5,6 t "tr * hydroimidaao / 2, lb ^ / thiazole dihydrochloride.

The reactions described above show the following reaction chemistry

109842/1986 owqinal

21U583

Reaction former

/ XV-XOCH.

HCOR

.

or '$ // vy_cocH ₂ -x + f ^N

3 ·

X = Br

CH CO H KOCOCH

1"

¹ HCOR.

UIA R = CH HA R = CH

Rr>

1. NaBH ₁

. HX HB RX ³

CH, Br ³

1. NaBH ₁

2. HX

¹ N-CH ₂ CH-OH

• NHCOR

.HX

IVA R ₂ = COCH,

R ₅ = CH ₃ '

. ^ JL I Br__

IVB R ₉ = H

X · ⁵ s Cl ⁵

SOCl / DMF

a. ac ω

3. OH

or

-Ίϋ33Α2 / 1965

OH

cry- HCOR.

.X

VA R = CH

X = perchloric acid

VB R = CH, r? = missing

.HX VIA X = d-tartrate

SnCl,

HCl

(1-base D-acid salt) VIB X = Cl

(1-isomer)

2HX VIIA X = Cl

VIIB X = Cl

1. GH

2. HCO ₂ H VIIC X = Cl

1-isomer VIID X = Cl

109842/1985 d isomer

VII

ν-

1. LiAlH ₁

2. HX

NHCHO VIIIA

.2HX IXA X = Cl

NHCH.

109842/1985

21H563

wherein R ₂ denotes a hydrogen atom or an acetyl group, R- denotes a hydrogen atom or a lower C -C ~-alkyl radical, X denotes perchlorate, chlorine or bromine and a single or double bond.

The compounds according to the invention are effective anthelmintics for the treatment of helminthiasis in Warm-blooded animals.

The compounds are in at very low dosages, for example 1 to about 10 mg / kg body weight highly effective and are preferably used in doses of 1.5 to 5.0 mg / kg body weight of warm-blooded animals applied. They have the advantage that they contain all of the major gastrointestinal nematodes, viz Effectively remove ascarids, hookworms, whipworms and tapeworms. To their known relatives they have the advantage that they are used against whipworms, a group of helminths that have hitherto been extremely difficult was to fight, are very effective. You can fight helminthiasis at laboratory, agricultural Farm animals, domestic animals and wild animals kept in captivity are used and are particularly beneficial for the treatment of helminthiasis in canids.

The active compounds can advantageously be administered orally or parenterally. Oral administration can take place in the form of tablets, pills, capsules, boluses, impregnating agents, liquid preparations or in the feed. When the compounds are used parenterally, they will generally be dissolved in a pharmaceutically acceptable carrier, for example distilled water, polyethylene glycol or the like , adjusted to a pH between 3.5 and 6.5 and administered by subcutaneous or intramuscular injection.

109842/1988

-ίο- 21H563

The following examples explain details of the preparation of compounds according to the invention and the test of representative compounds against helminths in warm-blooded animals.

Example 1 Preparation of 3'-Bromoacetylacetanilide (IA)

A solution of 110.0 g (0.62 moles) of 3'-acetylacetanilide in 2400 ml of chloroform is added dropwise with stirring to a solution of 33.0 ml (102.9 g; 0.644 mol) Bromine in 240 ml of chloroform was added. The solution is stirred for one hour and the resulting precipitate is filtered off, washed with ether and dried. By stirring the solid in a large Volume of water, an oily precipitate forms, which crystallizes on further stirring. The solid is filtered off and washed with water and then with 2-propanol. The dried product weighs 148.34 g and is recrystallized from 2-propanol to the product with a melting point of 108.5 to 110 degrees C.

Analysis calculated for

Calculated: C 46.90; H 3.94; Br 31.20; N 5.47; Found: C, 47.12; H 3.94; Br 31.21; N 5.47.

Example 2

Production of 3 '- ^ (2-imino-4-thiazolin-3-yl) acetyl / - acetanilide-hydrobromide (IIA)

A solution of 64.8 g (0.253 moles) of 3'-bromoacetylacetanilide (Example 1) and 25.3 grams (0.253 moles) of 2-aminothiazole

109842/1985

21U563

in 450 ml of acetone is heated to 50 to 60 degrees C for 2 hours heated «The deposited product is filtered off, washed with acetone and dried to give 58.74 g of crude product net, which after recrystallization from methanol / ether gives product with a melting point of 225 degrees (decomposition).

Anal. ber. for

C 43.83; H 3.96; Br 22.43; N 11.80; S 9.00; Found: C 43.90; H 4.21; Br 22.21; N 11.73; S 8.69.

Example 3

Production of 3 '- ^ (2-Iinino-3-thiazolidinyl) acetyl / - acetanilide-hydrobromide (IIB)

A solution of 5.12 grams (0.020 moles) of 3'-bromoacetylacetanilide in 70 ml of acetone is stirred to a solution of 2.04 g (0.020 mol) of 2-amino-2-thiazoline in Given 30 ml of acetone. The mixture is stirred for 1.5 hours and then the precipitate is filtered off, washed with acetone and dried to 6.00 g of a white solid, which upon recrystallization delivers product from water with a melting point of 275 to 277 degrees C.

Anal. for C _{,, H 1} , .BrN-O ₀ S:

C 43.58; H 4.50; Br 22.31; N 11.73; S 8.95; Found: C, 43.99; H 4.66; Br 22.51; N 11.72; S 9.14.

1098 42/1985

Example 4

Making 3 ' -jjL- ((Acetylimino) - »« S-thiazolin-S-yj / -

acetylacetanilide (IIIA)

A mixture of 35.6 g (0.10 mol) 3 '- / 2-ImInO ^ -thiazolin-3-yl) acetyl / acetanilide hydrobromide (Example 2), 11.8 g (0.12 mol) potassium acetate, 150 ml acetic anhydride and 150 ml Acetic acid is stirred under reflux for one hour. The mixture is cooled to 50 degrees C and filtered, and the filtrate is evaporated under reduced pressure. The residue is subjected to an azeotropic distillation treatment with toluene, then triturated with 2-propanol and filtered to give 25.8 g of crude product which upon recrystallization from aqueous acetic acid Provides product with a melting point of 224 to 226 degrees C.

Anal. for C ₁₅ H ₁₅ N ₃ O ₃ S:

C 56.77; H 4.76; N 13.24; S 10.10. Found: C, 56.88; H 4.77; N 13.16; S 9.90.

Example 5

Production of 3'-2- ^ 2- (acetylimino) -4-thiazolin-3-yl / - -l-hydroxyäthylacetanilid-hydrobromid (IVA)

A mixture of 3.2 g (0.01 mole) 3 '- ^ 2- (acetylimino) -4 thiazolin-3-yl / acetylacetanilide (Example 4) in 30 ml To 95 percent ethanol, 0.30 g (0.0078 mol) of sodium borohydride are added while stirring. The mixture is stirred for 2.5 hours, poured into water and acidified with acetic acid. The solution is reduced under Pressure evaporated and the residue becomes

109842/1985

from dilute hydrobromic acid to give 2.25 g of product crystallizes, which when recrystallized from water yields product with a melting point of 228 degrees C (decomposition).

.Anal. calc. for C ₁ , H _1Q BrN_0 _o S:

13 Io ό J.

C 45.00; H 4.53; Br 19.96; N 10.50; S 8.01; Found: C 45.11; H 4.81; Br 20.16; N 10.57; S 7.74.

Example 6

Production of 3 '- / 1-hydroxy-2- (2-imino-3-thiazolidinyl) - ethy1 / acetanilide hydrochloride (IVB)

A slurry of 63.47 g (0.177 moles) 3 '- ^ (2-ImInO-S-thiazolidiny-acetyl / acetanilide hydrobromide (Example 3) in 1 liter of 95 percent ethanol, which is kept at 5 degrees C, is added while stirring with 5.70 g (0.15 mol) Sodium borohydride added. After stirring for 40 minutes, a further 4.10 g of sodium borohydride are added, and the mixture is acidified with hydrochloric acid and evaporated under reduced pressure. The residue will partitioned between chloroform and dilute aqueous ammonium hydroxide. Two more chloroform extracts are combined with the first, washed with brine, dried (sodium sulfate) and to an oil evaporated. Treatment with acetone yields 26.77 g (48%) of melting point white crystalline hydrochloride 235 to 237 degrees C.

Analysis calculated for

Calculated: C 49.44; H 5.74; Cl 11.23; N 13.31; S 10.15; Found: C 49.87; H 5.27; Cl 11.51; N 13.25; S 10.40.

109842/1985

Example production of S'-iS ^

ypacetanilide perchlorate (VA)

A mixture of 6.00 g (0.015 moles) 3'-2- / 2- (acetylimino) 4-thiazolin-3-yl / -l-hydroxyethylacetanilide hydrobromide (Example 5) in 90 ml of dry DIiF (dimethylformamide) is added dropwise with stirring with 2.0 g (0.017 mol) Thionyl chloride added. The mixture is stirred for 2 hours at 50 to 55 degrees C, then cooled to 25 degrees C. and stirring is continued while 1.17 g (0.0099 mol) of thionyl chloride is added dropwise. the The mixture is stirred at 25 degrees C for 30 minutes and then at 50 to 55 degrees C for one hour. The mix will cooled and filtered, and the piltrate confused? evaporated at reduced pressure. After 1.5 hours The residue is refluxed in 100 ml of acetic anhydride, the acetic anhydride is distilled off under reduced pressure. The residue is dissolved in dilute hydrochloric acid, filtered, with concentrated ammonium hydroxide made alkaline and extracted twice with methylene chloride. The combined organic layers are extracted with dilute hydrochloric acid, and the product is extracted again with base in methylene chloride. The dried methylene chloride solution is evaporated to an oil which is converted into the perchlorate salt which, after recrystallization from 95 percent ethanol, yields product with a melting point of 185 - 187 degrees C.

Analysis calculated for C ₁₃ H _{14 ClN 3} O ₅ S:

Calculated: C 43.39; H 3.92; Cl 9.85; N 11.68; S 8.91; Found: C, 43.37; H 3.82; Cl 9.90; N 11.50; S 8.82.

1098 * 2/1985

- ¹⁵ "21U563

Example 8

Preparation of 3 ¹ - (2,3,5,6-Tetrahydroimidazo ^ 2, lb / - thiazol-6-yl) -acetanilide (VB)

5.00 g (0.0158 mol) of 3 ' - {X -hydroxy-2- (2-dynyl) ethyl / acetanilide hydrochloride (Example 6) are added in small portions to 15 ml of concentrated sulfuric acid over 0.5 hours. The orange solution is stirred for an additional hour, poured onto ice and made alkaline with concentrated ammonium hydroxide. The aqueous phase is extracted twice with chloroform and the combined organic layers are washed with water and brine, dried (sodium sulfate) and evaporated in vacuo to give 3.76 g of an oil. Recrystallization from ether gives 3.32 g (80% crude yield) of fine white crystals, which are recrystallized from 2-propanol to give a product with a melting point of 164 to 166 degrees C.

Analysis calculated for C ₁₃ H ₁₅ N ₃ OS:

Calculated: C 59.74; H 5.79; N 16.08; S 12.27; Found: C 59.93; H 5.85; N 15.96; S 12.49.

Example 9

Preparation of 6- (m-aminophenyl) -5,6-dihydroimidazo- [2, 1-b / thiazole dihydrochloride (VIIA)

2.80 g (0.0078 mole) 3 '- (5,6-dihydroimidazo ^ 2, l-b / thiazol-6-yl) acetanilide perchlorate (Example 7) are in the free

109842/1985

Base transferred and then dissolved in 15 ml of 6N hydrochloric acid. The solution is stirred under reflux for 1.6 hours and then evaporated under reduced pressure. The residue is subjected to an azeotropic distillation treatment with 2-propanol subjected and then from 95 percent ethanol / 2-propanol recrystallized to 1.69 g (75%) of crystalline product with a melting point of 242 to 244 degrees C.

Anal. for C ₁₁ H ₁₃ Cl ₂ N ₃ S:

C 45.54; H 4.52; Cl 24.43; N 14.48; S 11, O5; Found: C 45.39; H 4.66; Cl 24.26; N 14.27; S 10.83.

Example 10 Preparation of 6- (πι-

imidazo / 2,1-b / thiazole dihydrochloride (VIIB)

A solution of 1.00 g (0.0038 mol) of 3 '- (2,3,5,6-tetrahydroimidazo ^ 2, l-b / thiazol-6-yl) acetanilide (Example 8) in 17 ml of 6N hydrochloric acid is refluxed for 2.5 hours warmed and then left to stand overnight at room temperature. The solution is concentrated under reduced pressure, made alkaline with concentrated aqueous sodium hydroxide with cooling and then with 3 portions Chloroform extracted. The combined organic layers are washed with brine, dried (Sodium sulfate) and evaporated to 0.84 g of an oil, m-aminotetramisole free base. The oil is in dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution and Recrystallization of the residue from 2-propanol gives 0.91 g (81%) of a cream-colored solid with a melting point 198 to 201 degrees C (decomposition).

1098A2 / 198B

-17- 211A563

Example 11

Production of 6- (m-aminophenyl) -2,3,5,6-tetrahydroimidazo / 2,1-b / thiazole dihydrochloride (VIIB)

A slurry, cooled to 5 degrees C, of 22.57 g (0.10 mol) of stannous chloride dihydrate in 35 ml of concentrated hydrochloric acid is stirred all at once with 7.14 g (0.025 mol) of 6- (m-nitrophenyl) -2.3, 5,6-tetrahydroimidazo l_2 , 1-b / thiazole hydrochloride added. The reaction is allowed to proceed for 30 minutes at 40 degrees C and then heated to 75 to 80 degrees C for 3 hours. The reaction mixture is poured onto ice, neutralized with aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to give the free base as a yellow oil. The free base is dissolved in methanol and treated with excess hydrogen chloride solution in 2-propanol. Evaporation of the solvent and treatment of the oily residue with acetonitrile gives 5.08 g (68% yield) of crude product, which is recrystallized from 95 percent ethanol to a white solid with a melting point of 202-205 degrees C.

Anal. ber. for

C 45.21; H 5.17; N 14.38; S 10.97; Cl 24.27. Found: C, 44.80; H 5.60; N 14.08; S 11.07; Cl 24.07.

ORIGINAL INSFBCTED

crack

21H563

Example 12

Manufacture of 3 '- (2,3,5,6-Tetrahydroimidazo ^ 2, lb / - thiazol-6-yl) formanilide (VIIIA)

Method A;

A mixture of 3.29 g (0.015 mol) of free 6- (m-aminophenyl) -2,3,5,6-tetrahydroimidazo / 2,1-b / thiazole base (obtained by treating the dihydrochloride salt with base), 5g of 90 percent formic acid and 45 ml Toluene is stirred in an oil bath while it is slowly distilled. The first water-containing distillate goes over at 76 to 92 degrees C. The temperature rises to 105 degrees C. After two more distillations with The total reaction time is 4 hours with 45 ml of toluene and 5 g of 90 percent strength formic acid. The residue will partitioned between aqueous potassium carbonate and chloroform, the aqueous layer is extracted with chloroform, and the combined organic layers are washed with water, dried (magnesium sulfate) and under reduced pressure The pressure was removed from the solvent to give a white solid. Trituration with acetonitrile and recrystallization from ethanol gives product with a melting point of 177 to 179 degrees C.

Method B:

14.5 g (0.0664 mol) of the free base are dissolved in 75 ml of 97 to 100 percent formic acid, and the Solution is heated on the steam bath for 2 hours. The excess formic acid is collected in a rotary evaporator distilled off under reduced pressure. The syrupy residue is dissolved in water. After addition a little methylene chloride and crushed ice will do this

OWGINAt WSPECTED

109342/1995

Two-phase system and stirred with Kaliuiacarbonatlösung made alkaline. Most of the product crystallizes and is insoluble in both phases. This faction is filtered off and washed with water and acetonitrile. A small amount of product is dried by evaporation (Potassium carbonate) obtained methylene chloride phase, bringing the total yield to 11.15 g (0.045 mol, 60%) is brought; Melting point 176 to 178 degrees C.

Example 13

Production of 2,3,5,6-tetrahydro-6- (m-methylamlnophenyl) - imidazo ^ 2,1-b / thiazole dihydrochloride (IXA)

A 1.15 g (0.030 mole) lithium aluminum hydride slurry in 80 ml of dry tetrahydrofuran, 5.00 g (0.0203 mol) of 3 '- (2,3,5,6-tetrahydroimidazo £ 2,1-b / -thiazol-6-yl) formanilide is added with stirring (Example 12) at a rate that kept the temperature at 40 to 45 degrees C. will. The reaction mixture is then stirred at room temperature for 3 hours and at 40 to 50 degrees C. for 30 minutes. After the reaction mixture has cooled, 1.8 ml of water are carefully added dropwise and then 2 ml of 15 percent aqueous Sodium hydroxide added. The mixture is filtered and the filter cake is washed with tetrahydrofuran. Evaporate the solvent gives an oil that is dissolved in methanol and mixed with a hydrogen chloride solution in 2-propanol is acidified. The precipitate is filtered off and yields 4.18 g (67% yield) of crude product obtained from methanol is recrystallized and has a melting point of 229 to 231 degrees C.

Anal. for C ₁₀ H ₁ , N-SCl:

C 47.06; H 5.60; N 13.72; S 10.47; Cl 23.15; Found: C, 46.82; H 5.56; N 13.60; S 10.40; Cl 23.16.

109842 / 198B

Example 14

Production of 1-2,3,5,6-tetrahydro-6- (m-nitrophenyl) ■ imidazo / 2,1-b / thiazole hydrochloride (VIA)

Method A:

28.58 g (0.10 mol) of dl-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo / 2,1 -b / thiazole hydrochloride (Example 11) are converted to the free base. A mixture of the free base, 15.0 g (0.10 mol) of d-tartaric acid and 520 ml of 95 percent ethanol is heated on the steam bath and allowed to cool to 30 degrees C. The deposited salt is filtered off, washed with ethanol and dried to give 15.4 g (77%) of the 1-base d-acid salt with a melting point of 181 to 182 degrees C (decomposition); / alpha /, -58.1 degrees (c = 7.7, H ₃ O). Twice recrystallization from 90 percent ethanol gives an analytically pure sample with a melting point of 182 degrees C (decomposition); / alpha / _d -60.3 degrees (c = 7.5, H ₃ O).

Method B:

A solution of 0.05 moles of free d, 1-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo / 2, lb / thiazole base (prepared from 14.30 g (0.050 moles) of the corresponding hydrochloride ) in 200 ml of hot ethanol, 3.75 g (0.025 mol) of d-tartaric acid are added all at once. The mixture is briefly refluxed and then allowed to cool to room temperature. The precipitate is filtered off, washed with absolute ethanol and dried to 7.95 g (79.7%) of the 1-base d-acid salt with a melting point of 184 ° C .; / alpha / _d -56.2 degrees (c = 6.8, H ₂ O).

1098A2 / 1985

Example 15

Isolation of 1-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo ^ 2, l-b / thiazole hydrochloride (VIB)

The conversion of 10.4 g of 1-base-d-tartrate salt into the free base and treatment of an ethanolic solution of the free base with hydrogen chloride solution in 2-propanol gives 7.05 g of 1-6- (m-nitrophenyl) -2.3, 5,6-tetrahydroimidazo ^ 2, lb / -thiazole hydrochloride from melting point 209 to 210 degrees C; ^ alpha / _d = -96.9 degrees (c = 6.7, H ₃ O). Recrystallization twice from ethanol gives the practically pure product; _< / alpha / _d - 99.4 degrees (c = 6.4, H ₃ O).

Example 16

Production of 1-6- (m-aminophenyl) -2,3,5,6-tetrahydro imidazo ^, 1-b / thiazole dihydrochloride (VIIC)

According to the procedure described for the reduction of 6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo ^ 2,1-b / thiazole hydrochloride, 14.98 g (0.0524 mol) 1-2.3 , 5,6-Tetrahydro-6- (m-nitrophenyl) imidazo / 2,1-b / thiazole hydrochloride (Example 14) obtained 11.03 g of the free base as an oil. The free base is dissolved in methanol and acidified with hydrogen chloride solution in 2-propanol, giving 9.97 g (68% yield) of white crystalline product with a melting point of 273 to 276 degrees C; ^ alpha / ^ ⁵ - 78.5 degrees (c = 10; H ₃ O). An analytically pure sample with a melting point of 276.5 to 279 degrees C. is obtained by recrystallization from water / 2-propanol.

Anal. ber. for

C 45.21; H 5.17; N 14.38; S 10.97; Cl 24.27; Found: C, 45.23; H 5.19; N 14.34; S 11.08; Cl 24.17.

109842/1985

-22- 21U563

Example 17

Production of d-2,3,5,6-tetrahydro-6- (m-aminophenyl) - imidazo ^, 1-b / thiazole dihydrochloride (VIID)

Following the procedure of Example 16, 14.00 g (0.0491 mol) of d-6- (m-nitrophenyl) -2,3,5,6-tetrahydroimidazo- 12, 1-b / thiazole hydrochloride (from d, 1 -6- (m-nitrophenyl) -2,3,5, ö-tetraliydroimidazo ^, 1-b / thiazole hydrochloride and 1-tartaric acid obtained) 12.75 g (89%) recrystallized d-6- (m-aminopheny1) - 2,3,5,6-tetrahydroimidazo ^ 2,1-b / -thiazole dihydrochloride obtained from melting point 277 to 278 degrees C; / alpha / p +84.6 degrees (c = 9.9, H ₂ O).

Anal .: Found: C 45.39; H 5.21; N 14.47; S 11.19; Cl 24, O5.

Example 18

Female albino mice are each infected with about 20 infectious larvae of Nematospiroides dubius. This species of nematode is a representative example of the economically important trichostrongylid worms of ruminants and other host animals, and of nematodes in general. Twenty-two days after infection, groups of four randomly selected mice containing adult specimens of N. dubius are given single oral doses of solutions or suspensions of test compounds in 0.4 ml of water per 20 g of mouse. Treated mice and, in each test, 4 randomly chosen groups of untreated mice are sacrificed 26 or 27 days after infection. The number of worms in the small intestine of each mouse is determined by microscopic examination. Average worm counts are calculated for each treated group and for the untreated control animals, and the

109842/1985

Effectiveness in percent is determined according to the usual formula given below:

mean number of worms in control animals; mean number of worms in treated animals ; mean number of worms in control animals

X 100.

The following Table I shows results obtained with the method described above from representative tests with dl-m-aminotetramisole, 6- (m-aminopheny1) -2,3,5,6-tetrahydroimidazc / 2,1-b / thiazole dihydrochloride. Each result in Table I corresponds to a group of treated mice. The overall results show that the approximate dose that will eliminate 50% of the worms, ie the ED ₅₀ , is 1.0 mg / kg. For a compound of the tetramisol type, this is an unusually high activity.

10 9 8 4 2/1985

Table I.

Effectiveness of dl-antinotetramisole against N-. dubius for a single oral dose

middle

Dose effective-

% Effectiveness per group,%

100, 100, 100 100

100, 100 100

100, 100-, 100, 100, 100 (100, 100) 100

2.0 77, 78, 82, 82, 83, 88, 92, 98 85

1.25 80, 82 81

1.00 29, 29, 49, 57, 59, 77 50

0.5 2, 6, 8

109842/1985

Example 19

Values obtained by the method described above (Example 18) for the unsubstituted dl-tetramisole in mice against N. dubius show an ED ₅₀ of about 9 mg / kg (Table II). So m-aminotetramisole is about nine times as active as tetramisole. The doses required to achieve an effectiveness of 85 to 88% also show an effect of the m-amino compound about eight times better.

Table II

% Effectiveness of dl-tetramisole against N. dubius in a single oral dose

middle

Dose effective-

mg / kg% effectiveness per group /%

20 96, 96, 98, 99, 99, 100 98

16 74, 91, 92, 94 88

12 60, 62, 68, 73 66

10 49, 58, 63, 67, 70, 74, 77, 77, 79, 83 70

8 28, 33, 33, 39 33

6 0, 0, 0, 0, 19, 24 7

109842/1986

-26- 21H563

Example 20

Acute oral toxicity values for the compounds described above and several analogous compounds for mice in various individual oral doses were obtained by conventional methods (Table III). These m-amino and substituted m-amino analogs of tetramisole are considerably more toxic than tetramisole, consistent with their higher anthelmintic activity. However, all compounds, including tetramisole, have a similar chemotherapeutic index, that is, a ratio of LD ₅₀ ZED ₅₀ , from 10 to 20. All compounds are well tolerated at doses required to completely remove worms.

1Q0842 / 198 &

Tabel Oral toxicity of various tetramisols to mice

mg / kg

Phenyl substituent

Steroid isomer dose mg / kg

none m-NH, m-NH-HCO m-NH-CH, m-NH-CO-CH.

dl

dl dl

dead / animals in total

dl

5 »6-dihydro m-NH ₂ ^a

dl

300 200 150

100 50 40 20 15 10 4-5

LD

ED

50 50

10/10

15/20

8/30

1/10

approx.

approx.

_{: r>} approx.

4/4 10/12 7/14 2/29 0/8

4/5 3/9 2/10 0/12

12/13
1/10

0/4
0/8

30th

3
10

2/5 0/4

0/4

100

7 14

>

3-4

> 10 1.5

a.

all other compounds are 2,3,5,6-Tetrahydroimida «othiiyBole.

Example 21

Using the method of Example 18, the approximate EDcQ values for a single oral dose against N. dubius were determined Mice determined for tetramisole and analogs thereof with various substituents on the phenyl ring (Table IV). the Is surprisingly high activity of dl-m-aminotetramisole attributed to its Laevo component. The activity against tetraamisole is not only due to an amino group, but also increased by various substituted amino groups in the m-position. Identical substituents in the The p- or o-positions, as well as other types of substituents in the m-position, give less activity as tetramisole. Particularly noteworthy is the higher quantitative activity compared to the m-nitro analogs.

109842/1985

Table IV

21U563

Comparison of the oral effectiveness of different tetramisols

against N. dubius

stereo
isomer salt dl HCl dl 2HCl 1 2HCl d 2HCl dl base 1 base d base

base

dl 2HCl 1 2HCl dl base dl HCl 1 HCl d HCl dl HClO dl 2HCl dl dl HBr dl HCl

Phenyl substituent

(H)

NH ₂ NH ₂ NH ₂

NH-HCO NH-HCO NH-HCO

NH-CO-CH

NH-CH ₃ NH-CH

N = C = S N0 "

ED,

OH

OCH

CH,

meta 9 1

0.75 10

4 7

20th

para

20th

> 50

15th —— 12th HO > 30 > 200 25th - 1.5 _ -

as base ortho

> 100

S indicates inactivity at the indicated dose

This compound is a 5,6-dihydroimidazothiazole; Everyone others are 2,3,5,6-Tetrahydr © compounds

109842/1985

Example 22

Dogs infected with mature adult whipworms (Trichuris vulpis) are taken orally or subcutaneously treated various single or double doses of unsubstituted or substituted tetramisole analogs (Table V) Whipworms that come off in the feces are collected for several days, along with the whipworms that are still there are determined in necropsia. The effectiveness in Percent is determined in these "critical" tests. The m-amino analogs have a surprisingly higher one Activity as unsubstituted tetramisole at oral or subcutaneous doses that are not acceptable for dogs are toxic. Trichuris is a species of uraatoden that is one Resists combat with most known anthelmintics in well-tolerated doses. Taxonomically related Nematodes, for example Trichinella and Capillaria also insensitive to most anthelmintics.

109842/1985

or

Tab 1 1 e

Comparison of oral / subcutaneous (SC) activity against mature specimens of Trichuris vulpis

in dogs

Stereo- nwfta-phe- maximum
Isomer nylsubsti-non-lethal

tuent dose for dogs, % effectiveness oral at mg / kg % effectiveness SC at mg / kg

mg / kg 5 2.5 1.25 20 15 10 5 2.5 1.25

oral SC
dl H> 20 25 (> 10 mg / kg) ^a

IH 30 - "100 _Y 43 _v

(2) ^X (2) ^X

- '' dl NH ₅ 7.5 5 98 99

P ² (2)

°° 1 NH "10 M 100 100

2 ~ ^w ~ ;;; ^ - 100 72

ro (2)

2 8th - ( 92 (3) (2 2) 50 100 100 (7) (3) ) (2) y

^ dl NH-HCO 7.5> 5 100 83

^OT 1 NH-HCO / 2.5 100 M6 _V

(2) (M) ^b

dl NH-CH ₃ > 10 30 100 94 29

a. other values in () indicate the number of dogs when it is more than 1. % Effectiveness refers to all worms (lost and present) in all dogs at the given dose.

> means inactive at the specified dose b. mean dose 1.5 (1.25-1.75)

x. total dose administered twice a day ___ »,

ν - ^

* ' a single dose for 2 dogs, otherwise the entire dose twice a day cn

Claims (1)

Claims
Racemates and levo isomers of compounds of the formula wherein R is a hydrogen atom, a lower C.-C.-alkyl radical or a group COR ₃ in which R _{3 is} a hydrogen atom or a lower C.-CU-alkyl radical, and ■■■ denotes a single or double bond, and pharmaceutically acceptable ones Acid addition salts. 2. Compound according to claim 1, characterized in that that R is a lower alkyl radical having 1 to 4 carbon atoms means. 3. A compound according to claim 1, characterized in that R denotes the methyl radical. 4. A compound according to claim 1, characterized in that R is the group -COH. 5. A compound according to claim 1, characterized in that R denotes the group -COR ₃ , in which R is a lower alkyl radical having 1 to 3 carbon atoms. 6. A compound according to claim 5, characterized in that R ₃ denotes the methyl radical. Method for combating gas / crointestinal Nematodes / n JiWdnnbBütern ^^^ aduifch cj ^ ennabichnet that a MmatocideViWfige a ^ '^ erbinduftg the formula 1098A2 7 198B BR 21U563 S / NH ί
R. in which R is a water atom, a lower C -C alkyl radical or a group 'Is alkyl, and denotes a single or double bond, or a pharmaceutically acceptable one Acid addition salts thereof administered. 8. VerfahrA according to claim 7, characterized in that that the compound is administered orally in an amount of 1 to 10 mg / kg body weight / of the animal. 9. The method according to claim 7, characterized in that that the compound is administered parenterally in an amount of 1 to 10 mgfkg of the body weight of the animal. 10. The method according to claim 7, characterized in that lf- (m-aminophenyl) -2,3,5,6-tetrahydroimidazo- £ 2,1-by-thlazole dihydrochloride is administered. 11. The method according to claim 7, characterized in that that one 3 · | (2,3,5,6-Tetrahydroimidazo ^ 2, l-b / -thiazol-6-yl) -formaniliü or the 1-isomer thereof administered. 12. The method according to claim 7, characterized in that that 6l- (ra-methylaminophenyl) -2,3,5,6-tetrahydroimidazo- ^ 2,1-b / tlj Lazole dihydrochloride or the 1-isomer thereof administered, 109842/1986 br -34-21U563 Process for the preparation of racemates and 1-isomers of compounds of the formula NH Ί R wherein R is a hydrogen atom, a lower C -C. -alkyl radical or a group ~ COR_, in which R _{3 is} a hydrogen atom or a lower C ₁ -C ₃ -Al] Cyl radical, and their pharmaceutically acceptable salts, characterized in that a compound of the formula wherein X is a pharmaceutically acceptable anion with stannous chloride in the presence of an acid HX at a temperature between 60 and 100 degrees C converts »the mixture obtained is treated with an aqueous alkali metal hydroxide and the product from the reaction treated with an alcoholic solution of an acid HX to give the corresponding Amiη to produce the desired case with formic acid at a temperature between about 50 and 125 degrees C to the corresponding aldehyde: can be converted, de »- nit LH-aluminum aluminum hydride in the presence of an inert organic Solvent at a temperature between about 25 and 75 degrees C can be implemented, the mixture thus produced mixed with an aqueous base, the solvent separates from the mixture, and if the acid salt 1 098Λ 2/1 98 5 br -35-21H563 it is desired to acidify the remaining product with an acid having a pharmaceutically acceptable anion to generate the corresponding methylamino compound. Process for the preparation of a compound according to Claim 1, in which R denotes the group COR-, in which R _{3 is} as defined above »characterized in that a compound of the formula \\ * ^HX NHCOR wherein R- is a hydrogen atom or the group -COR- and X denotes an anion which reacts with (a) concentrated sulfuric acid and the product thus produced with an alkali hydroxide treated or (b) reacts with thionyl chloride at a temperature between 40 and 75 degrees C, the reaction product at 50 to 140 degrees C treated with acetic anhydride, excess acetic anhydride removed from the product thus produced and the acidic solution treated with an alkali hydroxide. Process according to claim 1, characterized in that a compound in which R is the group -COR ₃ , in which R- is as defined above, by reaction with a strong acid at a temperature between 60 and 125 degrees C, treatment of the product thus produced is converted into the corresponding amine with an alkali hydroxide and acidification of the product obtained with an acid having a pharmaceutically acceptable anion. 109842/1 9, B.