NO133197B - - Google Patents

Description

The present invention relates to an analogous method for the production of pharmacologically active isothioureas of the formula .„1

NO

and salts thereof where

X^" is hydrogen or lower alkyl,

X 2 is hydrogen or lower alkylthio,

n is from 2 to 5,

R is hydrogen, lower alkyl, phenyl, phenylethyl, hydroxyphenylethyl or benzyl, and

R 2 is lower alkyl, allyl, propargyl or (CI^) Z where m is from 1 to 3 and Z is phenyl, optionally substituted with hydroxy or halogen,

hydroxy, dialkylamino, cyano, carboxy or

1 2

phenoxy, or R can together with R and the adjacent carbon, nitrogen and sulfur atoms form a thiazoline or thiazolinone ring.

It has long been assumed that many of the physiologically active substances in the animal body during their action come into contact with certain specific places known as receptors. Histamine is a compound that is believed to work in this way, but as histamine's effects fall within more than one type, it is believed that there is more than one histamine receptor type. Histamine's mode of action, which is blocked by drugs commonly called "antihistamines" (of which mepyramine is a typical example), is thought to involve a receptor as indicated by Ash and Schild (Brit. J. Pharmac. Chemother. 1966, 27, 427 ) as H-l. The isothioureas produced according to the present invention are characterized in that they act on histamine receptors other than the H-1 receptor. They are thus used to inhibit certain histamine reactions which are not inhibited by the above-mentioned antihistamines. According to the present invention, isothioureas are denoted by the formula I, it being understood that the structure of the nucleus is such that the bond between the carbon and nitrogen atoms can just as well be represented as a double bond. Provided that tautomerism affects the compounds mentioned in this description, the numbering of the core has been modified accordingly.

The compounds produced according to the invention thus have the general formula:

where X is hydrogen or lower alkyl,

2

X is hydrogen or lower alkylthio,

n is from 2 to 5,

R 1 is hydrogen, lower alkyl, phenyl, phenylethyl, hydroxyphenylethyl or benzyl, and

R is lower alkyl, allyl, propargyl or (CH2)mZ where m is from 1 to 3 and Z is phenyl, optionally substituted with hydroxy or halogen;

hydroxy, dialkylamino, cyano, carboxy or

1 2

phenoxy, or R can together with R and the adjacent carbon, nitrogen and sulfur atoms form a thiazoline or thiazolinone ring^

and the method is characterized in that a thiourea of the formula

NHR

12 1

wherein X , X , n and R have the aforementioned meanings,

2' 2 is treated with a compound of the formula R Y, where R ' has

2 1 2

same meaning as R stated above when R and R together with adjacent carbon, nitrogen and sulfur atoms do not form a thiazoline or thiazolinone ring, and R 2' has the meaning of a haloethyl or acetic acid residue when R 1 and R 2 together with adjacent carbon , nitrogen or sulfur atoms form a thiazoline-respectively thiazolinone ring,

or when R 1 and R 2 together with adjacent carbon, nitrogen and sulfur atoms form a thiazoline ring, that an amine of the formula

1 2

in which X , X and n have the same meaning as mentioned above, is treated with 2-methylmercapto-2-thiazoline.

Specific compounds which are particularly useful include: N-3-(4(5)-imdazolyl/-propyl-S-ethylisothiourea, N-3-Z4(5)-imidazolyl7-propyl-S-(2-phenylethyl)-isothiourea, N-3-/<4>~(5)-imidazolyl7-propyl-S-propargyl isothiourea, and N-4-//^( 5) - imidazolyl/butyl-S-methylisothiourea f.

The starting material of formula III

1 2 in which X, X and n have the same meanings as in formula I, is produced by one compound of formula II,

1 2

in which X , X and n have the same meaning as formula I, is reacted with an isothiocyanate of the formula R 3 NCS, where R 3 is an alkyl group with 1-4 carbon atoms, aryl, aralkyl or benzoyl.

In the case where R 3 is benzoyl, hydrolysis leads to the corresponding compounds where R 3 is hydrogen, which compounds can alternatively be formed directly from the amines of formula II

by reaction at an elevated temperature with ammonium or an alkali metal thiocyanate.

The compounds of formula III, where R 3 is hydrogen, an alkyl group with 1-4 carbon atoms, phenyl, phenethyl, hydroxyphenethyl or benzyl, are hitherto unknown compounds. Treatment of the compounds of formula III, where R 3 is hydrogen, an alkyl group with 1-4 carbon atoms, phenyl, phenethyl, hydroxyphenethyl or

2 2

benzyl with the compound R Y, where R has the same meaning as in formula I, and Y is halogen or hydroxy, leads to the isothioureas of formula I. This reaction is normally carried out on the halogen acid addition salt of the compounds of formula III and/or in the presence of halogen acid, which, when Y is halogen, will usually have the formula HY. The reaction will normally be carried out in a suitable solvent such as an alcohol, e.g. ethanol, dimethylformamide or acetone.

An alternative method for preparing certain compounds of formula I from the amines of formula II comprises treating the latter with an alkylthio compound, e.g. with 2-methylmercapto-2-thiazoline which is described in example 24.

As stated earlier, the isothioureas in question normally exist and are produced as addition salts with acids. Such addition salts include those with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, picric acid and maleic acid, and as described in a number of the following examples, the addition salt with one of these acids can easily be converted into the addition salt with another. Such a conversion can take place using ion exchange methods. A particularly favorable method, which also in many cases causes purification to a sufficient extent to enable the resulting solution to

ning of the addition salt is used for pharmacological determinations, includes the formation of the picrate salt and conversion from there to the chloride salt.

As stated above, the subject isothioureas have been shown to have pharmacological action in the animal body as antagonists to certain effects of histamine which are not blocked by "antihistamines", such as mepyramine.

It has e.g. has been shown to selectively inhibit the histamine-stimulated secretion of gastric acid from the light-exposed stomachs of rats anesthetized with urethane at doses from 8 to 256 micromol per kg. Similarly, the action of these compounds and products can in many cases be demonstrated by their antagonism to the actions of histamine on other tissues which, according to the above-mentioned report by Ash and Schil, are not H-1 receptors. Examples of such tissues are irradiated isolated guinea pig heart, isolated right atrium of guinea pig and isolated rat uterus.

The invention is illustrated, but not limited in any way, by the following examples.

EXAMPLE 1

Preparation of S-methyl-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea-dihydroiodide. (i) 4(5)-2-chloroethylimidazole hydrochloride (200 g) was dissolved in dimethylformamide (600 ml) and the solution treated with charcoal and filtered. The filtrate was added little by little to a stirred suspension of sodium cyanide (176 g) in dimethylformamide (2.25 liters), and the mixture was kept at 130-135°C. The addition took 35 minutes, and then the temperature was held at 135°C for 5 minutes. After cooling in an ice bath to 10°C, suspended solids were filtered off and washed with dimethylformamide. The filtrate was concentrated under reduced pressure, and traces of dimethylformamide were removed with p-xylene (2 x 200 mL). The dry residue was dissolved in distilled water (500 ml) and transferred to a 1-liter extraction apparatus (volume including washing liquids now 750 ml) and extracted continuously with isopropyl acetate. The extracts were dried over magnesium sulfate, treated with charcoal and concentrated to a small volume. Cooling gave 4(5)-(2-cyanoethyl)-imidazole (106 g), mp 71-74°C.

Alternative conditions for the synthesis of 4(5)-(2-cyanoethyl)-imidazole are as follows:

A solution of 4(5)-(2-chloroethyl)-imidazole hydrochloride (136 g)

in water (500 ml) was added with stirring to a solution of sodium cyanide (420 g) in water (1.65 L). The obtained mixture

was heated to 60-65°C for 20 hours. After cooling, the solution was treated with charcoal, filtered and concentrated under reduced pressure. The dry residue was extracted with hot ethyl acetate (5 L), and the extracts were treated with charcoal and concentrated under reduced pressure to give 4(5)-(2-cyanoethyl)-imidazole (61 g), mp 70-71°C . A pure sample of the base, melting point 71-73°C, was prepared by recrystallization in isopropyl acetate. A sample of the hydrochloride, melting point 118-120°C, was prepared by acidification with dry hydrogen chloride in ether.

(Found: C 45.5%, H 5.1%, N 26.7%

C6H?N3HC1 requires: C 45.7%, H 5.1%, N 26.7%).

(ii) A solution of 4(5)-(2-cyanoethyl)-imidazole (61 g) in absolute alcohol (600 ml) was saturated with ammonia gas at -20°C.

The solution obtained was hydrogenated over Raney nickel catalyst (about 4 g) at a pressure of 100 atmospheres for 4 hours at a temperature of 135-145°C. After cooling, filtering and treating with charcoal, the solution was concentrated under reduced pressure to give 4(5)-3-aminopropylimidazole (74 g)

as a low-melting solid. For purification, the amine (61 g) was dissolved in a solution of sodium bicarbonate (82 g) in water (1.6 liters) and N-carbethoxyphthalmid (122 g) was added over 1/2 hour. After stirring for 1 1/2 hours, the solid precipitate was isolated, washed with water and dried. Recrystallization in aqueous ethanol gave 4(5)-(3-phthalimidopropyl)-imidazole. A pure sample prepared by further recrystallization in aqueous ethanol had a melting point of 160-162°C.

(Found: C 65.6%, H 5.2%, N 16.7% C14H13N3°2 requires: C 65/9%, H 5.1%, N 16.5%).

Hydrolysis with 5N hydrochloric acid for 16 hours followed by removal of phthalic acid gave 4(5)-(3-aminopropyl)-imidazole dihydrochloride, mp 156-158°C (from ethanol/ether).

(Found: C 36.6%, H 6.8%, N 21.1%, Cl 35.7%, C6H11N32HC1 requires: c 36.4%, H 6.6%, N 21.2%, Cl 35 .8%).

Treatment with sodium ethoxide in ethanol gave pure 4(5)-(3-aminopropylD-imidazole (42 g).

iii) A solution of benzoyl isothiocyanate (65.2 g) in chloroform was slowly added to a solution of 4(5)-(3-aminopropyl)-imidazole (50.0 g) in chloroform (1.5 L). The resulting solution was heated under reflux for 2 hours and concentrated under reduced pressure. The residue was dissolved in ethanol and added to an excess of distilled water, causing precipitation of a white solid. Recrystallization from ethyl acetate gave N-benzoyl-N'-[3-4-(5-imidazolyl)-propyl]-thiourea (44 g), mp 145-148°C.

(Found: C 58.5%, H 5.6%, N 19.5%, S 10.9%

<C>14<H>16N4OS requires: c 58.3%, H 5.6%, N 19.4%, S 11.1%).

Additional material (13.5 g), mp 138-142°C was prepared from the mother liquor.

(iv) The benzoylthiourea (47 g) was added with stirring to a solution of potassium carbonate (13.8 g) in water (800 ml) at 60-70°C. Subsequent heating at this temperature for 1 hour gave a clear solution, which was treated with charcoal and

concentrated to a small volume. Cooling gave N-[3-(5(5)-imidazolyl)-propyl]-thiourea (23 g), m.p. 149-150°C, as a colorless solid. Analytical pure material with the same m.p. was prepared by recrystallization from water.

(Found: C 45.9%, H 6.7%, N 30.6%, S 17.6% C7H12N4S requires: C 45.6%, H 6.6%, N 30.4%, S 17, 4%).

(v) Aqueous hydroiodic acid (64/66%, 12 mL) was added dropwise with stirring to a cooled suspension of N-[3-(4(5)-imidazolyl)-propyl]-thiourea (20.0 g) in absolute ethanol (200ml). The addition of an excess of anhydrous ether precipitated a solid, which was filtered off and washed with ether to give the hydrogen iodide salt (29.2 g), mp 135-136°C as a yellow solid. (Found: C 21.2%, H 4.0%, N 17.8%, S 10.2% <C>7<H>12<N>4S"HI requires: c 26.9%, H 4 .2%, N 17.9%, S 10.3%) (vi) Methyl iodide (21 g) was added to a methanolic solution of N-[3-(4(5)-imidazolyl)-propyl]-thiourea hydrogen iodide [ prepared from the base (20.3 g)]. The solution was heated under reflux for 1 hour and then concentrated under reduced pressure. Recrystallization of the residue in isopropyl alcohol/ether gave S-methyl-N-[3-(4(5)-imidazolyl )-propyl]-isothiourea dihydrogen iodide (35.0 g), mp 107-109°C.

(Found: C 21.2%, H 3.7%, N 12.1%, S 7.0%, I 56.0% C8<H>1<4N>4S'2HI teever: C 21.2% , H 3.6%, N 12.3%, S 7.1%, I 55.9%)

EXAMPLE 2

Preparation of S-ethyl-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea-dihydrogen iodide and sulfate. (i) Ethyl iodide (12.5 g) was added to a solution of N-[3-(4(5)-imidazolyl)-propyl]-thiourea hydrogen iodide (23.0 g) in absolute ethanol (250 ml) containing water ( 2 ml). The solution obtained was heated under reflux for 4 hours and concentrated under reduced pressure. Recrystallization of the residue in ethanol/ether gave S-ethyl-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen iodide (31.5 g), mp 113-114°C. (Found: C 23.2%, H 3.9%, N 11.9%, S 7.1%, I 54.2% <CgH>16N4S,2HI requires: C 23.1%, H 3.9 % N 12.0%, S 6.9%, I 54.2%). (ii) A solution of S-ethyl-N-[3-(4(5)-imidazolyl)-propyl]-iso-thiourea dihydrogen iodide (20 g) in water was passed down a funnel made of Amberlite ion exchange resin IRA 401 (S04 — shape, 250 ml). After elution with water, the eluate was concentrated under reduced pressure. Recrystallization of the residue in water/isopropyl alcohol gave S-ethyl-N-[3-(4(5)-imidazolyl)-propyl]-iso-thiouronium sulfate (14.0 g), mp 184-186°C.

(Found: C 34.7%, H 5.9%, N 18.1%, S 20.4% <C>9<H>16N4S,H2S04 requires: c 34.8%, H 5.9%, N 18.1%, S 20.6%).

EXAMPLE 3

Preparation of S-(n-propyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen iodide

n-Propyl iodide (1.7 g) was added to a solution of N-[-(4(5)-imidazolyl)-propyl]-thiourea hydrogen iodide (3.11 g) in n-propyl alcohol (50 ml) containing water (2 ml). The resulting solution was heated under reflux for 18 hours and concentrated under reduced pressure. Recrystallization of the residue in n-propyl alcohol/ethyl acetate gave S-(n-propyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen iodide (3.2 g), mp 102- 104°C.

(Found: C 24.9%, H 4.1%, N 11.6%, S 6.8% C10H18N4S'2HI requires: c 24.9%, H 4.2%, N 11.6%, S 6.7%).

EXAMPLE 4

Preparation of S-isopropyl-N-[3-(4(5)-imidazolyl-propyl-iso-thiourea f dihydrogen iodide.

Isopropyl iodide (1.3 g) was added to a solution of N-[3-(4(5)-imidazolyl)-propyl]-thiourea hydrogen iodide (2.33 g) in isopropyl alcohol (30 mL) containing water (2 mL). The resulting solution was heated under reflux for 76 hours and concentrated under reduced pressure. Recrystallization of the residue in isopropyl alcohol/ethyl acetate gave S-isopropyl-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen iodide (1.5 g), mp 60°C (approx.)

(Found: C 27.5%, H 4.8%, N 10.6%, S 6.0% C1QH18N4S,2HI + 10%

iso-C3H?0H requires: C 27.4%, H 4.8%, N 10.8%, S 6.2%)

EXAMPLE 5

Preparation of S-(n-butyl)-N-[3-(4(5)-imidazolyl)-propyl]- iso-thiourea dihydrobromide (i) Aqueous hydrobromic acid (49%, 3.6 mL) was added dropwise with stirring to a cooled suspension of N-[3-(4(5)-imidazolyl)-propyl]-thiourea (6.0 g) in absolute ethanol (200 ml). Addition of excess anhydrous ether precipitated a solid, which was isolated and washed with ether to give the hydrobromide salt (8.4 g), mp 163-164°C. (ii) The solution prepared by adding n-butyl bromide (1.7 g) to N-[3-(4(5)-imidazolyl)-propyl]thiourea hydrobromide (3.2 g) in absolute ethanol (25 ml) containing water (2ml)

was heated under reflux for 72 hours. Concentration followed by recrystallization from isopropyl alcohol gave S-(n-butyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrobromide

(2.8 g), mp 162-163°C.

(Found: C 32.8%, H 5.6%, N 14.1%, S 8.0%, Br 39.8% <C>llH20N4S'2Hgr requires: C 32'9% H 5.5% , N 13.9%, S 8.0%, Br 39.7%)

EXAMPLE 6

Preparation of S-(n-hexyl)-N-[3-(4-(5)-imidazolyl)-propyl]-isothiourea dihydrobromide

The solution prepared by the addition of n-hexyl bromide (1.9 g) to N-[3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide (3.0 g) in absolute ethanol (25 ml) containing water (1 ml ) was heated under reflux for 20 hours. Concentration followed by recrystallization from isopropyl alcohol/ether gave S-(n-hexyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrobromide

(4.3 g), mp 159-161°C.

(Found: C 36.5%, H 6.2%, N 13.2%, S 7.3%, Br 37.2% C13H24N4S,2HBr requires: C 36.3%, H 6.1%, N 13.0%, S 7.5%, Br 37.2%)

EXAMPLE 7

Preparation of S-allyl-N-[3-(4(5)-imidazolyl)-propyl-isothiourea dihydrobromide

The solution prepared by adding allyl bromide (0.97 g)

to N-[3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide

(2.0 g) in absolute ethanol (20 mL) containing water (1 mL) was heated under reflux for 3.5 h. Concentration followed by recrystallization from isopropyl alcohol gave S-allyl-N-[3-(4(5)-imidazolyl)-propyl]-isothiourinide dihydrobromide (2.11 g), mp 114-116°C.

(Found: C 31.2%, H 4.8%, N 14.4%, S8.1%, Br 41.1% <C>10<H>16N4S'2HBr requires:C 31/1%/ H 4.7%, N 14.5%, S8.3%, Br 41.4%)

EXAMPLE 8

Preparation of S-propargyl-N-[3-(4(5)-imidazolyl)-propyl-isothiourea dihydrobromide

The solution prepared by adding propargyl bromide (2.4 g) to N-[3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide

(5.0 g) in absolute ethanol (40 mL) containing water (2.5 mL)

was heated under reflux for 2 hours. Concentration followed by recrystallization from ethanol gave S-propargyl-N-[3-(4(5)-imidazolyl)-propyl-isothiourea dihydrobromide (5.4 g), mp 166-167°C.

(Found: C 31.4%, H 4.1%, N14.4%, S 8.4%, Br 41.6% C10H14N4S'2HBr requires: c 31'3%' H 4' 2%' N14' 6%' S 8'4%' Br 41'6%)•

EXAMPLE 9

Preparation of S-benzyl-N-[3-(4(5)-imidazolyl)-propyl-isothiourea f dihydrobromide

The solution prepared by adding benzyl bromide (1.7 g)

to N-[3-(4(5)-imidazolyl)-propyl]-1-iourea hydrobromide

(2.7 g) in ethanol (30 mL) was heated under reflux for 2 1/2 h. Concentration followed by recrystallization from ethanol/isopropyl alcohol gave S-benzyl-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrobromide (3.8 g), mp 201-202°C.

(Found: C 38.5%, H 4.7%, N12.8%, S 7.6%, Br 36.9% <C>14H18N4S'2HBr requires: C38.6%, H 4.6%, N12.9%, S 7.4%, Br 36.6%).

EXAMPLE 10

Preparation of S-(m-hydroxybenzyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrobromide

A solution of m-hydroxybenzyl alcohol (0.88 g) and N-[3-(4(5)-imidazolyl)-propyl-thiourea (1.3 g) in aqueous hydrobromic acid (49%, 10 mL) was heated under reflux for 2.5 hours. Concentration followed by recrystallization in ethanol/isopropyl alcohol gave S-(m-hydroxybenzyl)-N-[3-(4(5)-imidazolyl)-propyl-1-isothiourea dihydrobromide in two portions: 0.66 g, mp 192-194°c, and 0.53 g, mp 191-192°C.

(Found: C 37.4%, H 4.3%, N 12.1%, Br 35.0%, S7.1% C14H18N4OS,2HBr requires: c 37.2%, H4.5%, N 12, 4%, Br 35.3%, S7.l%)

EXAMPLE 11

Preparation of S-(p-chlorobenzyl)-N-[3-(4(5)-imidazolyl)-propyl-isothiourea dihydrochloride

The solution prepared by adding p-chlorobenzyl chloride

(1.3 g) to N-[3-(4(5)-imidazolyl)-propyl-thiourea (1.5 g) in 2N hydrochloric acid (25 ml) containing acetone (15 ml) was heated under reflux for 2 1/2 hour. Concentration followed by recrystallization from ethanol/isopropyl alcohol gave S-(p-chloro-benzyl)-N-[3-(4(5)-imidazolyl)-propyl-isothiourea dihydrochloride (2.5 g), mp 217-219° C.

(Found: C 43.7%, H4.8%, N 14.5%, Cl 28.1%, S8.8% <C>14<H>1?N4C1 S,2HC1 requires: C 44.0% , H5.0%, N 14.7%, Cl 27.9%, S 8.4%)

EXAMPLE 12

Preparation of S-(2-phenylethyl)-N-[3-(4(5)-imidazolyl)propyl]-isothiourea dihydrobromide

The solution prepared by adding 2-phenylethyl bromide

(1.6 g) to N-[3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide (2.2 g) in absolute ethanol (30 ml) containing water

(1 ml) was heated under reflux for 18 hrs. Concentration followed by recrystallization from ethanol/isopropyl alcohol gave S-(2-phenylethyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrobromide (3.0 g), mp 179-181°C .

(Found: C 39.9%, H 5.1%, N 12.5%, S 7.2%, Br 35.7% C15<H>20<N>4<S>'2HBr requires: c 40 .0%, H 4.9%, N 12.4%, S 7.1%, Br 35.5%)

EXAMPLE 13

Preparation of S-(2-phenoxyethyl)-N-[3-(4(5)-imidazolyl)-propyl-1-isothiourea dihydrobromide.

The solution prepared by adding 2-phenoxyethyl bromide (2.0 g) to N-[3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide (2.6 g) in absolute ethanol (30 ml) containing water

(1 ml) was heated under reflux for 48 hrs. Concentration followed by recrystallization from isopropyl alcohol/ether afforded S-(2-phenoxyethyl)-N-[3-(4(5)-imidazolyl)-propyl-1-isotropin dihydrobromide (3.5 g), m.p. 153 -156°C.

(Found: C 38.4%, H 4.7%, N 11.9%, S6.8%, Br 34.1% C15H20<N>4<OS>'2HBr requires: c 38/6% H4, 8%, N 12.0%, S6.9%, Br 34.3%)

EXAMPLE 14

Preparation of S-[2-(N,N-dimethylamino)-ethyl-N-[3-(4(5)-imidazolyl)-propyl-1-isothiourea trihydrobromide

A solution of 2-(N,N-dimethylamino)-ethanol (0.89 g) and N-[3-(4(5)-imidazolyl)-propyl-thiourea (1.84 g) in 48% aqueous hydrobromic acid ( 15 ml) was heated under reflux for 20 h. Concentration followed by repeated recrystallization in ethanol/ether gave the product as a hygroscopic trihydrobromide (1.3 g).

(Found: C 26.7%, H 4.9%; N 13.9%, S 6.5% <C>ll<H>21<N>5<S>,3HBr requires: c 26.5% , H 4.9%, N 14.1%, S 6.4%)

EXAMPLE 15

Preparation of S-[3-(N,N-dimethylamino)-propylI-N-[3-(4(5)-imidazolyl)-propyl]- isothiourea trihydrobromide

A solution of 3-(N,N-dimethylamino)-propanol (1.55 g) and N-[3-(4(5)-imidazolyl)-propyl]-thiourea (2.76 g) in 48% aqueous hydrobromic acid (30 ml) was heated under reflux for 20 hrs. Concentration followed by repeated precipitation of the residue in ethanol/ether gave the product as a hygroscopic trihydrobromide (5.9 g), m.p. 90°C (approx.).

(Found: C 28.1%, H 5.5%, N 13.1%, S 6.0% <C>12H23<N>5<S>'3HBr requires: c 28.1%, H 5, 1%, N 13.6%, S 6.0%)

EXAMPLE 16

Preparation of S-(carboxynrethyl)-N-[3-(4(5)-imidazolyl)-propyl1-isothiourea dihydrobromide

A solution of N-[3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide (2.0 g) in dimethylformamide (25 mL) containing bromoacetic acid (1.05 g) was kept at 10°C for 16 hours. The addition of excess ether forte to the precipitation of an oil,

which crystallized after treatment with cold ethanol to give S-(carboxymethyl)-N-[3-(4(5)-imidazolyl)-propyl 1-isothiourea dihydrobromide (2.0 g), mp 146-147°C.

(Found: C 21.0%, H 4.0%, N 13.9%, S 7.9%, Br 39.4% <C>9<H>14N402S,2HBr requires:C 26.8%, H 4.0%, N 13.9%, S 7.9%, Br 39.6%)

EXAMPLE 17

Preparation of 2-[3-(4(5)-imidazolyl)-propylamino]-thiazolin-4-one-dihydrobromide

A solution of N-[3-(4(5)-imidazolyl-propyl-thiourea hydrobromide (2.65 g) in dimethylformamide (30 mL) containing bromoacetic acid (1.39 g) was kept at room temperature for 20 hours. of ether excess forte to precipitation of a

oil, which crystallized after treatment with ethanol. The resulting solid (1.3 g, m.p. 229-231°C) was recrystallized from aqueous ethanol to give 2-[3-(4(5)-imidazolyl)-propylamino]-thiazolin-4-one dihydrobromide ( 0.9 g), melting point 230-232°C.

(Found: C 28.3%, H 3.6%, N 14.4%, S 8.3%, Br 41.1% CgH12N4OS,2HBr requires: C 28.0%, H 3.7%, N 14.5%, S 8.3%, Br 41.4%)

EXAMPLE 18

Preparation of N,S-dimethyl-N'-f3-(4(5)-imidazolyl)-propyl-isothiourea dihydrogen iodide and dihydrochloride. (i) Methyl isothiocyanate (3.5 g) was slowly added to a solution of 4(5)-(3-aminopropyl)-imidazole (6.0 g) in chloroform (50 ml). The resulting solution was heated under reflux for 1 hour and concentrated under reduced pressure,

which gave N-methyl-N'-[3-(4(5)-imidazolyl)-propyl-thiourine-

substance f as a semi-solid substance.

An analytically pure sample was prepared by treatment with hydrogen chloride, recrystallization of the salt in ethanol/ether followed by treatment with aqueous potassium carbonate. Recrystallization in water gave the pure base with melting point 135-137°C.

(Found C 48.4%, H 7.1%, N 28.0%, S 15.9%

CgH14N4S requires: C 48.5%, H 7.1%, N 28.3%, S 16.2%).

(ii) The crude thiourea (4.8 g) was converted to its iodide salt with 66% hydroiodic acid (2.7 ml). It was dissolved in methanol (50 ml), methyl iodide (3.42 g) was added,

and the solution was heated under reflux for 2 hours. Concentration gave an oil, which crystallized on contact with nitromethane/ether. Further recrystallization from nitromethane/ether gave pure N,S-dimethyl-N'-[3-(4(5)-imidazolyl)-propyl-isothiourea dihydrogen iodide (8.2 g), mp 143-145°C.

(Found: C 23.1%, H 3.7%, N 11.9%, S 6.8% CgH16N4S,2HI requires: C 23.1%, H 3.9%, N 12.0%, S 6.9%).

(iii) Prepare the crude isothiourea hydrogen iodide salt as described above from N-methyl-N'-[3-(4(5)-imidazolyl)-propyl]-thiourea hydrogen iodide (13 g) and methyl iodide (8.5 g)

in methanol was converted to its picrate (23.8 g) m.p. 187-189°C. Treatment with hydrochloric acid and removal of picrin-

acid in the usual manner followed by recrystallization of the product in isopropyl alcohol/hexane gave N,S-dimethyl-N'-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrochloride (3.6 g) m.p. 194-196° C.

(Found: C 38.1%, H 6.4%, N 19.4%, S 10.9%, Cl 24.9%

CgH16N4S,2HCl requires: C 37.9%, H 6.2%, N 19.6%, S 11.2%, Cl 24.9%).

EXAMPLE 19

Preparation of S-ethyl-N-methyl-N'-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen in odide

Crude N-methyl-N'-[3-(4(5)-imidazolyl)-propyl]-thiourea hydrogen iodide prepared as described in Example 21 from 4(5)-(3-aminopropyl)-imidazole (6.0 g ) was dissolved in absolute ethanol (100 mL) containing water (2 mL). Ethyl iodide (8.75 g) was added and the solution heated under reflux for 23 hours. Concentration followed by recrystallization from ethanol/ether/ethyl acetate gave S-ethyl-N-methyl-N'-[3-(4(5)-imidazolyl)propyl]-isothiourea dihydrogen iodide (4.5 g), mp 134-135°C

(Found: C 25.0%, H 4.4%, N 11.6%, S 6.9%, I 52.5% <C>10<H>18N4S' 2HI requires: c 24.9%, H 4.2%, N 11.6%, S 6.7%, I 52.6%)

EXAMPLE 20

Preparation of N-ethyl-S-methyl-N'-[3-(4(5)-imidazolyl)-propyl]-isothiouronium sulfate (i) Ethyl isothiocyanate (4.2 g) was added slowly to a solution of 4(5) -(3-aminopropyl)-imidazole (6.0 g) in acetonitrile (25 mL). The resulting solution was heated under reflux for 2 hours, during which time a white solid precipitated. After cooling, the white solid was isolated and washed with acetonitrile to give N-ethyl-N'-[3-(4(5)-imidazolyl)-propyl-thiourea (8.9 g), mp 145-148°C .

(Found: C 51.2%, H 7.8%, N 26.6%, S 15.1% <C>9<H>16<N>4S requires: c 50.9%, H 7.6 %, N 26.4%, S 15.1%).

(ii) The thiourea (4.0 g) was converted to its hydrogen iodide salt and reacted with methyl iodide in accordance with the method described in Example 21. The crude product produced was directly converted to its sulfate using Amberlite ion exchange resin IRA 401 (SO₂<->). Recrystallization from ethanol/isopropyl alcohol gave N-ethyl-S-methyl-N<1->[3-(4(5)-imidazolyl)-propyl]-isothiouronium sulfate (1.0 g), mp 151-153°C).

(Found: C 37.0%, H 6.5%, N 17.4%, S 19.4% °10H18N4S'H2S04 requires: c 37.0%, H 6.2%, N 17.3%, S 19.8%).

EXAMPLE 21

Preparation of N,S-diethyl-N'-[3-(4(5)-imidazolyl)-propyl]-i sothiouronium sulfate

N-ethyl-N'-[3-(4(5)-imidazolyl)-propyl]-thiourea (4.0 g) was reacted with ethyl iodide using a method similar to that described in Example 23, which to finally gave N,S-diethyl-N'-[3-(4(5)-imidazolyl)-propyl]-i sothiouronium sulfate (3.0 g).

(Found: C 39.2%, H 6.8%, N 16.5% °11<H>20<N>4S' H2S04 requires: c 39.0%, H 6.6%, N 16.5 %).

EXAMPLE 2 2

Preparation of N-(n-butyl)-S-methyl-N'-[3-(4(5)-imidazolyl)-propyl]-isothiourein dihydrochloride

(in). The reaction of n-butyl isothiocyanate (9.2 g) with 4(5)-(3-aminopropyl)-imidazole (10.0 g) in acetonitrile (50 ml) in accordance with the method described in Example 23 gave N-(n -butyl)-N'-[3-(4(5)-imidazolyl)-propyl]-thiourea (19 g). An analytically pure sample, melting point 93-98°C, was prepared by recrystallization in aqueous isopropyl alcohol. (Found: C 54.7%, H 8.5%, N 23.5%, S 13.3% C11<H>20N4S requires: c 55.0%, H 8.4%, N 23.3% , S 13.3%). (ii) The thiourea (6.4 g) was reacted with an excess of methyl iodide, and the product produced was then converted to a hydrochloride salt via a picrate intermediate (melting point 150-151°C) using a method similar to that in example 21 described. Recrystallization of the final product in ethanol/ether gave N-(n-butyl)-S-methyl-N'-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrochloride (3.3 g), m.p. 152 -155°C.

(Found C 44.0%, H 7.6%, N 17.2%, S 9.8%, Cl 21.5% <C>12<H>22<N>4<S>'2HC1 requires: c 44/°%/ H 7.4%, N 17.1%, S 9.8%, Cl 21.7%)

EXAMPLE 2 3

Preparation of S-methyl-N-phenyl-N'-[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen iodide (i) The reaction of phenyl isothiocyanate (3.25 g) with 4(5)-(3- aminopropyl)-imidazole (3.0 g) in acetonitrile (10 ml) in accordance with the method described in Example 23 gave N-phenyl-N'-[3-(4(5)-imidazolyl)-propyl]-thiourea. (ii) The thiourea was treated with 66% aqueous hydroiodic acid (2.4 ml) in methanol, and the produced hydroiodine salt was reacted with excess methyl iodide in methanol for 18 hours. Concentration followed by repeated precipitation from isopropyl alcohol/chloroform/ether finally gave S-methyl-N-phenyl-N<1->[3-(4(5)-imidazolyl)-propyl]-isothiourea dihydrogen iodide as a highly hygroscopic solid ( 4.0 g).

(Found: C 31.4%, H 3.8%, N 10.8%, S 5.7%, I 47.8% C14H18N4S'2HI requires: c 31.7%, H 3.8%, N 10.6%, S 6.0%, I 47.9%).

EXAMPLE 2 4

Preparation of 2-[3-(4(5)-imidazolyl)-propyl]-amino-2-thiazoline-hydrogen in odide

A solution of 2-methylmercapto-2-thiazoline hydrogen iodide (2.6 g) and 4(5)-(3-aminopropyl)-imidazole (1.3 g) in ethanol (20 mL) was heated under reflux for 5 1/2 hour. Concentration followed by recrystallization from ethanol/methanol gave 2-[3-(4(5)-imidazolyl)-propyl]-amino-2-thiazoline hydrogen jpdide (1.79 g), mp 208-210°C.

(Found: C 31.8%, H 4.3%, N 16.4% S 9.3%, I 37.6% CgH14N4S, HI requires: C 32.0%, H 4.5%, N 16 .6%, S 9.5%, I 37.5%).

EXAMPLE 25

Preparation of S-methyl-N-[4-(4(5)-imidazolyl)-butyl-isothiouronium sulfate (i) Senzoyl isothiocyanate (7.5 g) was added dropwise to a solution of 4(5)-(4-aminobutyl )-imidazole (4.8 g) in chloroform (350 ml) containing a small amount of ethanol (1.6 g), and the mixture was refluxed for 3 hours and then concentrated under reduced pressure. The residue was dissolved in hot ethanol, and then distilled water was added, until precipitation of an oil began. The mixture, after storage at 0°C for 16 hours, contained a granular solid, which was collected and crystallized in 10% aqueous ethanol, yielding the thiocyanate salt of N-benzoyl-N<1->[4-(4(5)-imidazolyl )-butyl]-thiourea as colorless crystals (5.0 g), mp 139-140°C.

(Found: C 53.6%, H 5.4%, N 19.3%, S 17.2%

C15H18N4OS,HCNS requires: c 53.2%, H 5.3%, N 19.4%, S 17.7%).

Additional material (1.64 g), mp 139-141°C, was prepared from the mother liquor.

(i i) N-benzoyl-N'-[4-(4(5)-imidazolyl)-butyl]-thiourea f-hydrothiocyanate (1.5 g) was added with stirring to 2.5N potassium hydroxide (30 ml) at 65 -70°C. After 15 minutes, the mixture was cooled, acidified with dilute hydrochloric acid and after 2 hours at 5°C the precipitated benzoic acid was filtered off. The filtrate

was made basic with anhydrous potassium carbonate and concentrated to dryness under reduced pressure to give a residue which was extracted

hardened with hot ethanol. The extract was concentrated to 5 ml and cooled, yielding colorless crystals. The latter formed after recrystallization in water (9 ml) N-[4-(4(5)-imidazolyl)-butyl]-thiourea (0.7 g) with a melting point of 166-167°C.

(Found: C 48.7%, H 7.1%, N 28.2%, S 16.0% <C>8<H>1<4N>4S requires: c 48.5%, H 7.1 %, N 28.3%, S 16.2%). (iii) A solution of N-[4-(4(5)-imidazolyl)-butyl]-thiourine substance f (0.6 g) in methanol (10 ml) containing 55% aqueous hydroiodic acid (0.4 g) and methyl iodide (0.94 g) was heated under reflux for 4 hours. The mixture was concentrated, and the residue was dissolved in water and converted to its sulfate by passing it through an ion exchange resin (Amberlite, IRA 401, SO 2 - ) and eluting with water. Concentration and crystallization in ethanol/ether gave S-methyl-N-[4-(4(5)-imidazolyl)-butyl]-isothiouronium sulfate (0.7 g), mp 199-201°C.

(Found: C 35.4%, H 6.1%, N 18.1%, S 20.1% <C>9<H>16<N>4S,H2S<0>4 requires: c 34.8 %, H 5.9%, N 18.1%, S 20.6%).

The product was further characterized as its picrate, melting point 195-196°C.

(Found: C 37.6%, H 3.2%, N 20.6%, S 4.8% C9H16N4S'2C6H3N3°7 requires: c 37*6%, H 3.3%, N 20.9% , S 4.8%). ;EXAMPLE 26 ;Preparation of S-methyl-N-[2-(4(5)-imidazolyl)ethyl]-isothiourea f dihydrogen in odide ;(i) A solution of benzoyl isothiocyanate (32.6 g) in chloroform was added to a solution of histamine (22.2 g) in chloroform (300 ml). The resulting solution was heated at reflux temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in the minimal volume of dimethylformamide and added to an excess of distilled water to give N-benzoyl-N'-[2-(4(5)-imidazolyl)-ethyl]-thiourea (39 g), mp ;159- 160°C. The pure substance with melting point 162-163.5°C was prepared by recrystallization in ethanol/ethyl acetate. The monohydrochloride had a melting point of 20l-202°C. (Found: C 49.8%, H 4.9%, N 17.8%, Cl 11.3%, S 10.3% <C>13<H>14N4OS,HCl requires: c 50.2%, H 4.9%, N 18.0%, Cl 11.4%, S 10.3%) (ii) The benzoylthiourea (17.45 g) was dissolved in 2.5N potassium hydroxide (600 ml) and the solution was heated • during reverse for 1/2 hour. After cooling and acidification with hydrochloric acid followed by removal of benzoic acid by filtration, the filtrate was made basic with solid potassium carbonate. After concentration under reduced pressure, the dry residue was extracted several times with hot absolute alcohol. The combined alcoholic extracts were concentrated and the residue crystallized in a minimal amount of water to give N-[2-(4(5)-imidazolyl)-ethyl]-thiourea (7.5 g), mp 170-173°C. The monohydrochloride had a melting point of 100°C (approx.). (Found: C 34.1%, H 5.6%, N 26.5%, S 14.8% C6H1QN4S, HC1,.0.25 H20 requires: C 34.1%, H 5.5%, N 26.5%, S 15.2%) (iii) The thiourea (10.0 g) was converted to its hydrogen iodo salt (mp 156-158°C) and reacted with methyl iodide in methanol in accordance with that in example 1 described method. Recrystallization from isopropyl alcohol gave S-methyl-N-[2-(4(5)-imidazolyl)-ethyl]-isothiourea dihydrogen iodide (13.0 g), mp 158-159°C. ;(Found: C 19.3%, H 3.0%, N 12.8%, S 7.4%, I 57.8% C7H12N4S,2HI requires: c 19/1%/ H 3.2%, N 12.7%, S 7.3%, I 57.7%). ;EXAMPLE 27 ;Preparation of S-(2-phenylethyl)-N-[2-(4(5)-imidazolyl)-ethyl]-isothiourea dihydrobromide ;Aqueous hydrobromic acid (49%, 0.7 ml) was added dropwise with stirring to a cooled suspension of N-[2-(4(5)-imidazolyl)-ethyl]-thiourea (0.9 g) in ethanol. On addition of the ether excess, the hydrobromide salt was precipitated, after which it was redissolved in absolute alcohol (20 ml) containing water (1 ml). 2-Phenylethyl bromide (1.0 g) was added and the resulting solution heated under reflux for 24 hours. Recrystallization of the product in isopropyl alcohol gave S-(2-phenylethyl)-N-[2-(4(5)-imidazolyl)-ethyl]-isothiourea dihydrobromide (1.0 g), mp 170-171°C. ;(Found: C 38.8%, H 4.7%, N 13.0%, S 7.5%, Br 36.8% <C>14<H>18N4S'2HBr requires:C 38.6% , H 4.6%, N 12.9%, S 7.4%, Br 36.6%) ; EXAMPLE 28 ; Preparation of N, S- dimethyl- N' -[ 2-( 4( 5)- imidazolyl )-ethyl]-iso-thiourea f dihydrogen in odide (i) Methyl isothiocyanate (11 g) was reacted with histamine (16.7 g) in chloroform in accordance with the procedure described in Example 21. N-methyl-N'-[2-(4(5)-imidazolyl)-ethyl]-thiourea was isolated as its hydrochloride salt (28.5 g), mp 134-136°C. (ii) The hydrogen iodide salt was prepared from the hydrochloride (4.7 g) via the base intermediate and reacted with methyl iodide (2.8 g) in methanol in accordance with the method described in Example 21. Recrystallization of the product in ethanol/ether gave N,S-dimethyl-N<1->[2-(4(5)-imidazolyl)-ethyl]-iso-thiourea dihydrogen iodide (4.2 g), mp 193-195°C . ;(Found: C 21.5%, H 3.5%, N 12.5%, S 7.1%, I 56.0% C8H14N4S,2HI requires: C 21.2%, H 3.6%, N 12.3%, S 7.1%, I 55.9%). ;EXAMPLE 29 ;Preparation of S-(2- hydroxyethyl)- N-[ 3-( 4( 5)-imidazolyl)-propyl1- in sothiouronium sulfate ;The solution prepared by adding 2-bromoethanol (1.9 g) to N- [3-(4(5)-imidazolyl)-propyl-thiourea hydrobromide (4.0 g) in absolute ethanol (35 ml) containing water (1 ml) was heated under reflux for 20 hours. Treatment of the crude product with picric acid gave S-(2-hydroxyethyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiouronium dipicrate (5.2 g), mp 145-147°C. ;(Found: C 36.9%, H 3.1%, N 20.3%, S 4.7% ;C9H16N4OS'2C6H3N3°7 requires: c 36.7%, H 3/2%, N 20, 4%, S 4.7%). The picrate was converted to the corresponding hydrochloride in the usual way using hydrochloric acid. This was finally converted to S-(2-hydroxyethyl)-N-[3-(4(5)-imidazolyl)-propyl]-isothiouronium sulfate (1.9 g) (IRA 401 SO 4 ), which was obtained like a glass. ;(Found: C 33.8%, H 5.9%, N 18.0% CgH16N4OS,0.9 H2S04: C 34.1%, H 5.7%, N 17.7%). EXAMPLE 30 Preparation of S-methyl-N-benzyl-N'-[3-(4(5)-imidazolyl)-propyl]-i sothiouronium sulfate (i) A solution of 4(5)-(3-aminopropyl) -imidazole (1.25 g) in absolute alcohol (10 mL) was added slowly with stirring to carbon disulfide (20 mL). An oil was formed which little by little crystallized. After filtration and washing with ether, the solid (1.5 g, mp 125-130°C) was recrystallized twice from water to give N-[3-(4(5)-imidazolyl)-propyl]-dithiocarbamic acid ( 0.43 g), melting point 130-134°c. ;(Found: C 41.7%, H 5.5%, N 1.1%, S 31.3% ;C7H11N3S2 ' requires: c 41/8%/ H 5.5%, N 20.9%, S 31.9%). (ii) A solution of this compound (1.0 g) in methanol (5 ml) containing methyl iodide (0.71 g) was stirred at room temperature for 1 hour. Concentration under reduced pressure followed by addition of ether gave a solid cream (1.43 g). Recrystallization from ethanol/ether gave S-methyl-N-[3-(4(5)-imidazolyl)-propyl]-dithiocarbamate hydrogen iodide (0.64 g), mp 112.5-113.5°C. ;(Found: C 28.0%, H 4.1%, N 12.3%, S 18.7%, I 36.9% <C>8<H>13N3S22HI requires: c 28>°% H 4 ,1%, N 12.2%, S 18.7%, I 37.0%). ;(iii) This compound (10.4 g) was added to a stirred mixture of benzylamine (3.2 g) and potassium carbonate (2.1 g) in water (30 ml) and stirring was continued for 3 hours at reflux - the temperature. After cooling, water (50 mL) was added and the mixture was extracted with chloroform (4 x 200 mL). Concentration of the dried extracts gave an oil, which after recrystallization in ethanol/ether gave colorless needles (5.5 g, m.p. 122-125°C). Recrystallization of a portion (2.8 g) of this solid in ethanol/water gave N-benzyl-N'-[3-(4(5)-imidazolyl)-;propyl]-thiourea (2.3 g), melting point 126-127°C. ;(Found: C 61.5%, H 6.7%, N 20.7%, S 11.7% <C>14<H>18N4S requires: c 61/3%, H 6.6%, N 20.4%, S 11.7%). (iv) N-benzyl-N'-[3-(4(5)-imidazolyl)-propyl]-thiourea (2.74 g) was converted to its hydrogen iodide salt and reacted with methyl iodide (1.41 g) in accordance with the method described in example 1. The product produced was passed through a soyle of ion exchange resin Amberlite IRA-401 (S04 ). Recrystallization finally in aqueous methanol gave S-methyl-N-benzyl-N1 - ;[3-(4(5)-imidazolyl)-propyl]-isothiouronium sulfate as the hemihydrate (1.88 g), mp 139-140° C. ;(Found: C 45.7%, H 5.7%, N 14.4%, S 16.1% C15<H>20N4S/H2S<0>4'0.5H2° requires: c 45.6% , H 5.9%, N 14.2%, S 16.2%) ; EXAMPLE 31 ; Preparation of S- benzyl- N-( n-butyl)- N'-[ 3-( 4( 5)- imidazolyl )-propyl]- i sothiouronium sulfate; N-(n-butyl)-N'-[3-(4(5)-imidazolyl3-propyl]-thiourea (6.2 g) was converted to its hydrobromide salt and reacted with benzyl bromide ( 13.7 g) in accordance with the method described in Example 25. The product prepared was passed through a column of ion exchange resin Amberlite IRA 401 (SO 4 ). Concentration of the aqueous eluate gave S-benzyl-N-(n-butyl)- N'-[3-(4(5)-imidazolyl)-propyl]-isothiouronium sulfate as a hygroscopic solid (4.0 g). ;(Found: C 50.2%, H 6.6%, N 13, 4%, S 14.6% C18H26N4S,H2S04 requires: C 50.5%, H6.6%, N 13.1%, S15.0%). ;EXAMPLE 32 ;Preparation of N,S-dimethyl-N' - 5-[4(5)-imidazolyl-pentyl"] lisothiouronium sulfate (i) A mixture of 1-bromo-7-phthalimidoheptan-2-one (60.0 g) and formamide (360 ml) was heated at 180 - 185°C for 2 hours. After removal of excess formamide by distillation under reduced pressure, the residue was hydrolyzed by heating (under reflux) with 5N hydrochloric acid (1.8 liters) for 18 hours. After cooling to 0°C and filtering to remove phthalic acid, the filtrate was concentrated under reduced pressure, and the residue extracted with hot ethanol and concentrated again. The amine hydrochloride residue was converted to the free base by passing through Amberlite ion exchange resin IRA 401 (OH<->) and eluting with methanol. The base produced was converted to the picrate with picric acid (82.5 g) in water. The picrate was recrystallized several times from water to give 4(5)-(5-aminopentyl)-imidazole di-picrate (55 g), mp 209-211°C. An analytically pure sample had a melting point of 210 - 211°C (from nitromethane). ;(Found: c 39^2%, H 3.3%, N 20.3% <C>8<H>15<N>3'<2C>6<H>3°7 requires: C 39.3 %, H 3.5%, N 20.6%). ;The picrate was treated with hydrochloric acid in the usual manner to give the amine dihydrochloride (24.6 g), which was finally converted to 4(5)-(5-aminopentyl)-imidazole (15.3 g), mp 45-48° C, by passing through an ion exchange resin Amberlite IRA 401 (0H~). (ii) A solution of methyl isothiocyanate (2.92 g) and 4(5)-(5-aminopentyl)-imidazole (6.13 g) in acetonitrile (40 ml) was heated under reflux for 3 hours. Cooling followed by recrystallization from acetonitrile gave N-methyl-[5-(4(5)-imidazolyl)-pentyl]-thiourea (5.3 g), mp 108-109°C. ;(Found: C 53.2%, H 8.1%, N 25.1% C10H18N4S ' requires: C 53.1"/ °, H 8.0%, N 24.8%). ;(iii) The thiourea (2.26 g) was converted to its hydrogen iodo salt and reacted with methyl iodide (1.42 g) in accordance with the method described in Example 21. The product prepared was converted directly to its sulfate using Amberlite ion exchange resin IRA 401 (SO^ ). Recrystallization from methanol/ether gave N,S-dimethyl-N<1->[5-(4(5)-imidazolyl)-pentyl]-isothiouronium sulfate (2.2 g), mp 220-221 °C. ;(Found: C 39.2%, H 6.8%, N 16.7%, S 18.8% <C>11<H>20N4S'H2S04 ^ ever: c 39.0%, H 6.6%, N 16.6%, S 19.0%). ;EXAMPLE 33 ;S-(2-phenylethyl)-N-[4-(4(5)-imidazolyl)butyl]isothiourea-dihydrobromide (in ) Aqueous hydrobromic acid (49%, 0.53 mL) was added slowly to a solution of N-[4-(4(5)-imidazolyl)butyl]thiourine (2.0 g) in absolute ethanol. ether gave the hydrobromide salt (2.68 g), m.p. 194-197° C. (ii) A solution of the hydrobromide salt (2.5 g) and excess d of 2-phenylethyl bromide in aqueous ethanol was heated under reflux for 17 h. Concentration and recrystallization from isopropyl alcohol-ether gave S-(2-phenylethyl)-N-[4-(4(5)-imidazolyl)butyl]isothiourea dihydrobromide (2.6 g), m.p. ;214-215°C. ;Found: c 41.3%, H 5.2%, N 12.1%, S 6.8%, Br 34.2. C16H22N4S-2HBr requires: c 41?4%? H 5.2%, N 12.1%, S 6.9%, ;Br 34.4%). EXAMPLE 34 Preparation of N,S-dimethyl-N1-[4-(4(5)-imidazolyl)butyl] in sot iour inst of f. dihydro iodine. (i) 4(5)-(4-Aminobutyl)imidazole (15.0 g, containing about 12 w/w% ethanol) was dissolved in hot acetonitrile (100 mL). The solution was filtered, methyl isothiocyanate (7.3 g) was added, and the resulting solution was heated under reflux for 1 1/2 hours. After concentration, the remaining oil was triturated several times with hot isopropyl acetate, which gave the thiourea in crystalline form. ;Recrystallization from acetonitrile-isopropyl acetate gave N-methyl-N'-[4-(4(5)-imidazolyl)butyl]thiourea in two portions: 14 g, melting point 125-126°C and 2.5 g, melting point 123- 124°C. Analytical pure material, mp 127-128°C, was obtained by further recrystallization from acetonitrile followed by recrystallization from water. ;(Found: C 51.2, H 7.8, N 26.2, S 14.9%. ;CgH16N4S required: C 50.9, H 7.6, N 26.4, S 15.1%) ;(ii) A solution of 4(5)-(4-aminobutyl)imidazole (32.0 g containing about 4 w/w% ethanol) and methyl isothiocyanate (17.5 g) in ethanol (300 mL) was heated up under reflux for 0.5 hours. Concentration to half volume and addition to isopropyl acetate (400 ml) gave the product in two portions (32 g, m.p. 128-129°C, 10 g, m.p. 125-128°C). Recrystallization from water gave the analytically pure product, m.p. 129-130°C. (iii) The thiourea (1.5 g) was converted to its hydroiodide salt and reacted with methyl iodide using the method described in Example 1 to form N,S-dimethyl-N<1->[4-(4( 5)-imidazolyl)butyl]-isothiourea, dihydroiodide (1.2 g), m.p. 155-157°C (from nitromethane); (Found: C 24.8, H 4.2, N 11.4, S 6, 7 <C>10H18<N>4S-2HI requires: c 24'8' H 4.2, N 11.6 and S 6.7). ;EXAMPLE 3 5 ;Preparation of S- methyl- N-(2-phenylethyl)- N'-[ 4( 4( 5)- imidazolyl) butyl1- isothiourea, dihydroiodide ; (i) 4(5)-(4- aminobutyl)-imidazole (2.5 g containing 8 wt/wt% ethanol) was reacted with 2-phenylethyl isothiocyanate (2.71 g) by a method similar to that described in example 37. The product obtained was converted to its maleate salt with maleic acid in ethyl acetate. Recrystallization from isopropyl alcohol-ether gave N-(2-phenylethyl)-N'-[4-(4(5)-imidazolyl)butyl]thiourea maleate (2.8 g), mp 124-126°C. ;(Found: C 57.5, H 6.4, N 13.5, S 7.5% C16H22N4S-C4H3°4 requires: c 57'4/ H 6.3, N 13.4, S 7.7 %). (ii) The thiourea was converted to its hydroiodide salt and reacted with methyl iodide using the method described in Example 1 to form the title compound. EXAMPLE 3 6 Preparation of S-methyl-N-(2-(p-hydroxyphenyl)ethyl)-N'-(4-(4(5)-imidazoly1)butyl)isothiourea f,dihydroiodide. (i) Tyramine hydrochloride (4.4 g) was converted to its base with sodium (0.6 g) in ethanol. A solution prepared from ba sen in ethanol (200 ml) and water (6.5 ml) was added to a solution prepared from mercuric acetate (5.7 g) in ethanol (100 ml) containing water (3.3 ml). The resulting solution was diluted with some water (3.5 mL) and slowly added to carbon disulfide (65 mL) under reflux. After addition, heating was continued for 3 hours, the mixture was filtered from mercury sulfide and the filtrate was concentrated under reduced pressure. The residue was extracted with acetonitrile, filtered and the filtrate concentrated to p-hydroxyphenylethyl isothiocyanate as a pale yellow oil. This was immediately then dissolved in ethanol and 4-4(5)-aminobutylimidazole (2.2 g) was added. The solution was heated for 4 hours under reflux and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel using ethyl acetate as eluent. The product obtained was recrystallized twice from isopropyl alcohol to give N-(2-(p-hydroxyphenyl)ethyl)-N'-(4-(4(5)-imidazolyl)butyl)thiourea (2.1 g ), melting point 170-172°C. ;(Found: C 60.5, H 7.1, N 17.5, S, 10.1%. C16H22N4OS required: c 60.4, H 7*0' N 17.6, S, 10.1% ). (ii) The thiourea was converted to its hydroiodide salt and reacted with methyl iodide using the method described in Example 1 to form the title compound.

EXAMPLE 37

Preparation of N,S- dimethyl- N'-( 4-( 2- methylthio- 4( 5) imidazolyl) butyl) isothiourea, dihydroiodide (i) A solution of 4(5)-(4-aminobutyl) imidazol-2- thione (6 g) in methanol (200 mL) saturated with hydrogen chloride was refluxed for 3 h and then concentrated in vacuo. The resulting solid was recrystallized from ethanol to give 2-methyl-4(5)-(4-aminobutyl)imidazole dihydrochloride,

(5.6 g), m.p. 181-182°C. The latter (4.5 g) was neutralized with sodium hydroxide (1.4 g) in ethanol (100 ml) at 0°C, the mixture was then filtered from sodium chloride, refluxed for 2 h with methyl isothiocyanate (1.46 g) and finally concentrated under reduced pressure. The resulting solid was extracted with isopropanol (3 x 100 mL) at 50°C

and the combined extracts were cooled to 0°C. The material that crystallized out was isolated and recrystallized from 85% ethanol, which gave the analytically pure product, m.p. 185-186°C.

(Found: C 46.6, H 7.2, N 21.6, S 24.6,

<C>10<H>18N4S2 requires: c 46.5, H 7.0, N 21.7, S 24.8). (ii) The thiourea was converted to its hydroiodide salt and reacted with methyl iodide using the method described in Example 1 to form the title compound.

EXAMPLE 38

Preparation of N,S-dimethyl-N'-(4-(4-methyl-S-imidazolyl)butyl)isothiourea-dihydroiodide

(i) 1-bromomethyl-2'-thienyl ketone (160 g) was added dropwise with stirring over 90 minutes to formamide (2.35 L) at 180°±5°C under a nitrogen atmosphere. After 3.5 hours at this temperature, the mixture was set aside overnight and excess formamide removed under reduced pressure. The residue was dissolved in 10% hydrochloric acid (300 ml), treated with charcoal, filtered, and the filtrate was basified to pH 10 with 10% sodium hydroxide. The precipitated solid was collected, washed with water and recrystallized from ethanol and then twice from isopropyl acetate to give 4-methyl-5-(2'-thienyl)-imidazole (43 g) as white needles, m.p. 174-6°C. (Found: C 58.7%, H 17.3%, N 17.3%, S 19.8%. C8H8N2S requires= c 58.5%, H 4.9%, N 17.1%, S 19 .5%). (ii) 4-methyl-5-(2'-thienyl)imidazole (4.5 g) was dissolved in ethanol (50 ml) and converted to the nitrate salt, m.p. 168°C (decomposition) upon the addition of nitric acid.

The nitrate salt (21.0 g) was added portionwise to stirred, concentrated sulfuric acid (420 ml) at 4-6°C over 30 min. After 1 hour at 0-5°C, the mixture was poured onto ice and basified to pH 9 with 40% sodium hydroxide solution, keeping the temperature below 40° C. The precipitated solid was isolated and added to boiling water (600 mL), stirred for 10 min and filtered hot. Several recrystallizations from aqueous dimethylformamide gave 4-methyl-5 -(5'-nitro-2'-thienyl)imidazole as a yellow solid (12.0 g), mp 275-280°C.

(Found: C 46.1, H 3.3, N 20.2, S 15.2, C8H?N302S requires: C 45.9, H 3.4, N 20.1, S 15.4).

(iii) 4-methyl-5-(5<1->nitro-2<1->thienyl)imidazole (2.1 g) dissolved in a mixture of ethanol (25 ml), water (25 ml) and ammonium hydroxide ( 5.6, 0-88, 10 ml). Raney nickel (50 g) was added and the suspension was stirred and heated under reflux for 18 hours. Filtration and concentration gave a residual oil, which was dissolved in ethanol and treated with picric acid (5.2 g) in ethanol. Recrystallization from water gave 4-methyl-5-(4-aminobutyl)imidazole, dipicrate. (iv) A solution of methyl isothiocyanate (2.92 g) and 4-methyl-S-(4-aminobutyl)imidazole (6.13 g, obtained from the picrate by treatment with hydrochloric acid followed by basification) in ethanol was heated under reflux for 3 hours. Concentration followed by crystallization gave N-methyl-N'-(4-(4-methyl-5-imidazolyl)butyl)thiourea. (v) The thiourea was converted to its hydroiodide salt and reacted with methyl iodide using the method described in Example 1 to form the title compound.

Claims (1)

Analogy method for the preparation of pharmacological active isothioureas of the formula and salts thereof where X<1> is hydrogen or lower alkyl, X 2 is hydrogen or lower alkylthio, n is from 2 to 5, R is hydrogen, lower alkyl, phenyl, phenylethyl, hydroxyphenylethyl or benzyl, and R 2 is lower alkyl, allyl, propargyl or (CH2)m<Z >where m is from 1 to 3 and Z is phenyl, optionally substituted with hydroxy or halogen, hydroxy, dialkylamino, cyano, carboxy or 1 2 phenoxy, or R can together with R and the the adjacent carbon, nitrogen and sulfur atoms form a thiazoline or thiazolinone ring, characterized in that a thiourea of the formula \TTTn 12 1 wherein X , X , n and R have the aforementioned meanings, , 21 2 is treated with a compound of the formula R Y, where R has the same meaning as R 2 stated above when R 1 and R 2 together with adjacent carbon, nitrogen and sulfur atoms does not form a thiazoline or thiazolinone ring, and R 2 1 has the meaning of a haloethylene or acetic acid residue when R 1 and R 2 together with adjacent carbon, nitrogen and sulfur atoms form a thiazolinone ring, 1 1 2 <!> or when R and R together with adjacent carbon-, nitrogen and sulfur atoms form a thiazoline ring, that an amine of the formula where X<1> t X<2> and n have the same meaning as mentioned above, treated with 2-methylmercapto-2-thiazoline.