CS195276B2 - Method of preparing cycloalkano/b/thieny lureas - Google Patents

Abstract

The novel compounds correspond to the formula: <IMAGE> in which X, Y, Z, R1, R2, R3 and U have the meanings given in Claim 1. They are prepared by a) reacting one mol equivalent of a compound of the formula I or II, in which the -NR1-CX-NHR1 radical is replaced, or its acid addition salts with 1 to 1.5 mol equivalents of R2NCX or b) reacting one mol equivalent of an acid addition salt of a compound of the formula I or II, in which R2 and R3 denotes hydrogen and the -NR1-CX-NHR2 radical is replaced by -NHR1, with 1 to 1.5 mol equivalents of a compound of the formula MeNCX, in which Me denotes sodium or potassium, and isolating the product. The reaction (a) is carried out in water or an inert organic solvent at 0 to 100 DEG C. The reaction (b) is carried out in aqueous medium at pH = 5 to 7 and 10 to 80 DEG C. The novel compounds of the formulae I and II are administered orally to warm-blooded animals to improve the extent of the feed effect and to increase the growth rate. A supplementary feed for increasing the growth rate of poultry, fur-bearing animals and agricultural productive animals contains 70 to 99% by weight of an edible carrier and, as the remainder, a novel compound of the formula I or II.

Description

The invention relates to a process for the preparation of cycloalkano- (b) thienylureas of the formula I

2-butenyloxy, methoxymethyl, phenoxy, —CH2 — CH2 — OH, —СНз — CH2 — О — СНз, —CH2 — CH2 — S — СНз, —CH2 — CH (OR1) 2, —CH2 — CF3, —CH2— CN, —CH2 — CO2R1, —NH — CO2R1, wherein Z is hydrogen or (C1-C4) alkyl, Y is hydrogen, halogen, cyano, and U is > C = O, > CHOH, n is 1 or 2, X is oxygen or sulfur, R 1 is hydrogen or C 1 -C 4 alkyl, and R 2 is:

hydrogen, C 1 -C 6 alkyl, C 2 -C 8 cycloalkyl, allyl, C 1 -C 6 cycloalkyl.

methallyl,

2-Butenyl,

2-propynyl, hydroxy, C 1 -C 6 alkoxy, allyloxy, methallyloxy,

O

II -С-R /,

ITjLcHj-, ζΧΛ-ΝΗ-

195278

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with an equimolecular up to 50% molar excess of sodium or potassium cyanate or thiocyanate in an aqueous medium at pH 5-7 and at a temperature of 10 ° C to 80 ° C and the product isolated.

Another preferred compound of formula wherein m is 0, 1 or 2 and Q is selected from the group consisting of when n = 0 hydrogen, 4-chloro, 3,4-mithylenedioxy, 2 (3 or 4) methoxy 4-ethoxy, 4-butoxy, 4-methylthio, 2,4-dimethyl, 2,4-dimethoxy, 2,4-dichloro, 4-nitro and 2-methyl-4-bromo; when n = 1 hydrogen, 4-chloro, 4-methoxy and 3,4-methylenedioxy; when n = 2 hydrogen.

Compounds of formula I are prepared by reacting one mole equivalent of a compound of formula II

Λ1 ^(CH 2> n, wherein R 1, Z, Y, U and n are as defined above with 1 'to 1.5 mol equivalents of the compound of formula III

RžNCX '. (III), wherein X and Rž are as defined above in an organic solvent inert to the reactants at a temperature of 0 ° C to 100 ° C.

Preferably, the compound of formula II is used in the form of an acid addition salt and the reaction is carried out in the presence of an acid acceptor. .

Preferred compound of formula

wherein X 1 is oxygen or sulfur is prepared by reacting a compound of formula

with an equimolar to 50 mol% excess of sodium or potassium cyanate or thiocyanate in an aqueous medium at pH 5-7 and at a temperature of 10-80 ° C and the product is isolated. The above cycloalkano (b) thienylureas can be in the form of cis- or transisomers and in the form of racemic mixtures or in the form of optically active isomers.

The reaction may be carried out using approximately equimolar amounts of isocyanate or isothiocyanate and amine or amine salt, and acid, although it is generally preferred to use an excess of isocyanate or isothiocyanate of 5 to 50% wherein the cycloalkane ring does not contain a hydroxyl group. The reaction may be carried out at, but not limited to, atmospheric pressure or positive pressure, at a temperature in the range of 0 ° C to 100 ° C. preferably carried out at atmospheric pressure at a temperature of from 0 ° C to 70 ° C in the presence of an organic solvent.

Suitable solvents are aprotic aromatic solvents such as benzene. toluene and xylene; chlorinated hydrocarbons such as methyl chloride, chloroform and dichloroethane; an ether such as tetrahydrofuran, diethyl ether; dimethoxyethane, dimethylene glycol, dimethyl ether or dioxane; C 1 -C 4 lower alkylene ketones such as acetone, methyl ethyl ketone, methyl butyl ketone and methyl isobutyl ketone, or a mixture of these solvents.

When cycloalkano (b) thiophenamine salts are used in the above reaction, X is preferably oxygen or sulfur is prepared by reacting a compound of the formula and adding an acid acceptor to the reaction mixture. Suitable acid acceptors are trialkylamines such as triethylamine, trimethylamine, pyridine and the like; carbonates. alkali metals such as sodium and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; and strongly basic ion exchange resins, and suitable alkalis in a 2-phase system using an immiscible hydrocarbon solvent such as benzene or toluene, or a chlorinated hydrocarbon such as chloroform or dichloroethane.

The compounds of the invention are useful as animal growth stimulants, such as poultry, fur animals and farm animals, and the use of said compounds for this purpose has the advantage of improving feed conversion for said animals; and in improving feed conversion is meant a weight increase, increment _'from a given unit of feed consumed. .

In practice, cyclopalkano (b) thienyl urea of the formula I or an optically active growth-promoting isomer is administered to the animals, usually with or without feed. However, said compounds may be administered as a subcutaneous implant under the skin of said animal or as a parenteral injection. When administered to poultry feed у, turkeys, sheep, cattle, goats and the like. Is generally an effective amount of 0.0001 · ·% to 0.08 wt.%, Preferably 0.001 θ / · ¹ to 0.04% by weight urea of formula I to increase and improve conversion feed. When administered to said animals, the active compounds as parenteral injections or subcutaneous implants are administered in an amount of about 0.001 mg to 0.2 mg, preferably 0.005 mg to 0.10 mg per kg body weight per day, and the desired weight gain is achieved. increase and increase feed conversion. ·

In tests conducted with one day old chickens, it was found that 1-9 ppm of 4,5,6,7-tetrahydrobezo (b) thien-4-ylurea fed to chickens caused 3.3 to 6.6% of the weight gain and also provides 2.7% to 4.7% improvement in feed conversion.

The compounds of the invention are also useful as herbicidal compositions; They are effective for controlling undesirable broadleaf and grass weeds when applied to soil containing seeds of said undesired weed or applied to foliage of such plants. Usually, 5.60 kg / ha to 16.8 kg / ha, preferably 9 kg / ha to 11.2 kg / ha are suitable for such control of undesirable plants.

The invention is further elucidated in the Examples, in which test data of the compounds of the invention are also given.

Example 1 Preparation of 1-methyl-3- (4,5,6,7-tetrahydrobenzo (b) -thien-4-yl) urea

A mixture of 4,5,6,7-tetrahydrobenzo (b) thiophen-4-amine hydrochloride (1.89 g, 0.01 mol) in dry benzene (20 ml) was stirred while 1.05 g (0.01) was gradually added. mole) of triethylamine and 1.7 ml (excess) of methylene cyanate. The last preparation causes an exothermic reaction and the mixture becomes very pasty. The mixture was kept at 45 ° C for one hour and after cooling to room temperature the solid was removed, washed thoroughly with benzene and then with water. After drying, 1.7 g (81%) of the product is obtained, m.p. 183-186 ° C. Recrystallization from acetones gave 1.23 g, mp 187.5-189 ° C.

On a 0.05 mol scale, the crude yield is 83 percent of the raw material (9.15 g) and the product melts at 181-186 ° C. Recrystallization from acetone gave 6.5 g, mp 184.5-187 ° C.

Example 2

Preparation of 1-ethyl-3- (4,5,6,7-tetrahydro-benzo (b) -thien-4-yl) -urea

In the manner described in Example 1, ethyl isocyanate was reacted with 4,5,6,7-tetrahydrobenzo (b) -thiophen-4-amine hydrochloride to obtain 10.1 g of 1-ethyl-3- (4,5,6,7). -tetrahydrobenzo (b) thlen-4-yl) urea.

Recrystallization of the crude product from 2-propanol / water (9/1) gave crystals which were dissolved in chloroform and washed with 1N sulfuric acid, water, and saturated sodium bicarbonate solution. 184 DEG-188.5 DEG C. is obtained after evaporation of the chloroform.

Example 3

Preparation of 1-isopropyl-3- (4,5,6,7-tetrahydro-benzo (b) thien-4-yl) urea

5.35: g · 4.5, 6,7-tetrahydrobenzo [b] thiophen-4-amine was stirred under nitrogen in 100 ml of diethyl ether and 3.57 g of isopropyl isocyanate in 40 µl of diethyl ether was added slowly to obtain crystalline product. the ^mixture! was stirred for further 0.5 hrs., and then filtered after standing overnight, 8.3 g of 1-isopropyl-3- (4,5,6,7-tetrahydro-benzo (b) thien-4- yl) urea.

Example 1 a d 4 '. ·

Preparation of 1-cyclohexyl-3- (4,5,6,7-tetrahydrobenzo (b) thien-4-yl) urea

In the manner described in Example 1, 4,5,6,7-tetrahydrobenzo [b] thiophen-4-amine is reacted with n-hexylisocyanate to give 1- (n-hexyl) -3- (4,5,6,7) m.p. 122-124 ° C; - tetrahydrobenzo (b) thien-4-yl) urea;

Example 5

Preparation of 1-cyclohexyl-3- (4,5,6,7-tetrahydrobenzo (b) thien-4-yl) urea

The same. by the method of Example 1, 4,5, a, 7-tetrbhydrobenzo (b) thlofen-4-amine hydrochloride was reacted with cyclohexyl isocyanate in dry tetrahydrofuran to give 7 g of 1-cyclohexyl-3- (4). 5,6,7-etrahydrobenzzo (b) thien-4-yl) urea, m.p. 222-225 ° C.

Example 6

Preparation of 4,5,6,7-tetrahydrobenzo (bthien-ylureas)

A mixture of 50 g of amine hydrochloride (about 45 g indeed based on 90% purity) in 100 ml of water is stirred at about 15 ° C and a solution of 23.1 g of potassium cyanate in 100 ml of water is added dropwise. After the addition was complete, the mixture was slowly warmed to 70-75 ° C and held for an hour. The mixture was cooled and the white solid was removed by filtration and washed with water. The solid was air dried, ground and washed with acetone / tril. After drying, 37.3 g of crude product are obtained, which after treatment with 1200 ml of hot acetone gives 11.45 g of the title compound, m.p. 200-204 ° C.

Similarly, 2-methyl and 3-methyl-4,5,6,7-tetrahydrobenzo (b) thten-4-ylurea were prepared to give the products melting at 232-233 ° C, respectively. Mp 227-230 ° C. . When N-methyl-4,5,6,7-tetrazolobenzo (b) thiophen-4-amine hydrochloride is used, 1-methyl-1- (4,5,6,7-tetrahydrobenzo (b)) is obtained. thien-4-yl) urea, m.p. 151-154.5 ° C.

Example 7

Preparation of 2-cyano-4,5,6,7-tetrahydrobenzo- (b) thien-4-urea

The desired product, 2-to-yes-4,5,6,7-tetrahydro-benzo (b) thten-4-yl-urea, was prepared as described in Example 6 by reaction of 2-cyano-4,5,6,7-tetrahydrobent of (b) of thiophen-4-amine with potassium cyanate. The crude product melts at 210 DEG-214 DEG C. and the product is recrystallized. from nitromethane, melting at 209 to 213 degrees Celsius.

Example 8

Preparation of 2-Chloro-4,5,6,7-tetrahydro-benzo (b) rien-4-ylurea The desired product 2-chloro-4,5,6,7-tetrahydro-dibenzenol-4-yl-urea is prepared as described in of Example 13 by reaction of 2-chloro-4,5,6,7-tetrahydrobenzo (b) thiophen-4-amine with hydrocyanic acid in situ. The product melts at 194-198 ° C.

Example 9

Preparation of 2-acetyl-4,5,7-tetrahydro-benzo (b) thien-4-urea

Sample 6.3 · g of hydrochloride · 2-acetyl-4,5, Octeteahytobenzo (b) thiophen-4-amine is dissolved in 35 ml of water and cooled to 15 ° C. A solution of 2.64 g of potassium cyanate in 35 ml of water is added and after 0.5 h the mixture is heated at 70 ° C for 40 minutes. The mixture was cooled and the solid was collected and washed with water. Drying gave 5.55 g of 2-tert-1,4,5,6,7-tetrahydro-benzo [b] heen-a-yl-urea, m.p. 218-220 ° C.

Example 1 and U o

Preparation of 1-ethyl-3- (4,5,6,7-tetrahydrobenzo (b) thien-4-yl) thiourea

Sample 9, 48 g of 4,5,6,7-etrahydrobenzo (b) thlofen-4-thymine hydrochloride are stirred in 100 ml of trra-drofurtn and 6.06 g of rrlethlamine are added. After stirring for 15-30 minutes, 5.23 g of ethylsulfonyl chloride in 20 ml of dry terra-drofuran are added dropwise and the mixture is heated at 50 ° C for 2 hours. The mixture was cooled and filtered and the filter cake was washed with hexane. The filtrate was evaporated to dryness and placed on ice. The oil was extracted with ether and the extract was washed with 1N sulfuric acid, water and saturated sodium bicarbonate solution. The ether extract was dried and evaporated to dryness to give an oil. The oil crystallized in ether to give 1-ethyl-3 (4,5,6,7-trtrahydrobenzo (b) thien-4-yl) thiourea, m.p. 106-112 ° C.

Similarly, using methyl isothiocyanate, butyl isothioctan and cycloeexyl isorhioctetin yields 1-methyl-, 1-butyl- and 1-cyclohexyl-S- (4,5,6,7-etherhydro-benzo (b) -hien-4-yl) urea.

Příklaaii

Preparation of (-) - 4,5,6,7-tetrahydrobenzo (b) -telophen-4-ammonium · (R) -N-benzo-1-glutamate

A mixture of 8.04 g of R- (+) - N -benzoylgluramic acid in 1.92 g of acetic acid and 80 ml of water is heated on a steam bath until a solution is obtained. This hot solution is stirred while 9.80 g of 4,5,6,7- [beta] -hydrobenzo (b) thiophen-4-amine is added gradually. About 2 ml of ethanol is used as tap-off for the amine. The mixture was then allowed to cool to room temperature and allowed to stand overnight. The mixture is cooled in a refrigerator, filtered to separate crystals, and the filter cake is washed several times with water. Drying gave 9.27 g of the title salt, mp 192-194 ° C; (a539 ²⁵ -9.39 ^o , (αφϊβ · —44.6 °; -71.4 ° C, at c = 4.475 in acetic acid).

The original filtrate was concentrated from reduced pressure to a small volume and partitioned between diethyl ether and aqueous sodium hydroxide.

The aqueous bases were extracted with ether and this ether extract was combined with the first ether fraction. This was then dried over magnesium sulfate, evaporated to dryness, and the amine was recovered, which was added to a stirred hot solution of 8.04 g of (S) - (N-benzoylglutamic acid in 1.92 g of acetic acid and 80 ml of water). Crystallization proceeds rapidly and after 10 minutes heating on a steam bath, the mixture is allowed to cool in a refrigerator.

The crystals were collected, washed with water and dried to give 11.1 g of (+) -4,5,6,7-tetrahydrobenzo (b) thiophene-4-ammonium (S) -N-benzoylglutamate, m.p. 192-193, 5 ° C; (0:) ⁵ 5892 + 12.2 °, (a) 436 + 42.7 °, (a ^ + a '82 ° C at c = 4.35' in acetic acid.

Example 12

Preparation of (-) -4,5,6,7-tetrahydrobenzo (b) -thien-4-ylurea

The salt (8.8 g of 4,5,6,7-tetrahydro-benzo (b) -thiophen-4-amine (R) - (+) - N -benzoylglutamic acid) was added to a mixture of water and ice in a separatory funnel and added. with 3,5 g of sodium hydroxide in. 55 ml of water. The mixture was shaken until a solution was obtained and then extracted twice with ether. Etherové. The extracts were washed with saturated brine and extracted with 2.36 ml of concentrated hydrochloric acid in 25 ml of water. The acidic layers were then treated with 2.29 g of potassium cyanate in 30 ml of water at 20 ° C. After stirring for 1 hour, the mixture was heated for half an hour and cooled.

The product was collected by filtration, washed with water and dried; 2.75 g, m.p. 218.5-221.5 ° C; (ajsei) ²⁵ - 63.2, (α) 436 - 149.9, (a) 365 - 271.5 °, (-) 4,5,6,7-tetrahydrobenzo- (b) thi-4-tylurea.

Similarly, the salt of 4,5,6,7-etrahydrobenzo (b) thiophen-4-amine and (S) - (-) - N-benzoylglutamic acid are treated as above to give (+ j-4,5,6). , 7-tetrahydrobenzo (b) ttUen-4-yl-urea, melting point 218-220 ° C (Al] + 589 ²⁵ 60 (a) 436 + 149.8 °, (a) 365 + 272.5 °.

Example 13

Preparation of 4,5,6,7-tetrahydrobenzo (b) thien-4-ylureas

A sample of 4,5,6,7-tetrahydrobenzo (b) thiophen-4-amine (19.9 g) was cooled in a flask and a solution of 12 mL of 12 N hydrochloric acid in 50 mL of water was added slowly. Later, at about 20 degrees Celsius, a solution of 11.7 g of potassium cyanate in 80 ml was added at half an hour. water. The mixture was stirred at room temperature for one hour and then heated to 60 ° C for half an hour. After standing overnight at room temperature, the product was collected and washed with water to give 21 g, mp 206-209 ° C.

Mouse growth control assays.

CFI female mice from the Carworth Farm six weeks old were admitted. They were put in a cage in a tempered room at 22.2 to 24.4 ° C (72 to 76 ° F) with automatic light control, ten hours on, 10 hours off. The basal diet used in these studies is “Purina Laboratory Choro”. (see description below), which is administered ad libitum. Water is also allowed at will.

Thirteen days after the start, the mice were weighed in groups of ten and randomly assigned to different treatments. The concentration of the different compounds in the diet is shown in the following tables. Twelve days later they were; the mice are weighed again and the experiment interrupted. At least three cages (30 mice) of control mice. . who did not serve a diet were included in each experiment. The data are shown in Table XI as percent weight gain relative to control. The following is a description of the diet to which increment enhancing compounds are added.

Diet guaranteed analysis crude protein no less than 23.0% crude fat no less than 4.5% raw fiber no. more than 6,0% ash not more than 9,0%

Folders

Meat and bone meal, dried. skimmed milk, wheat germ meal, fish meal, animal liver, dried. beet pulp,. ground extruded grain, ground. oats, groats, soy meal, dehydrated alpha meal, reed molasses, animal fat with BHA, calcium B12 supplement, choline chloride, folic acid, ⁴ riboflavin, dried yeast, thiamine vitamin A supplement, D activated plant sterol, vitamin E supplement calcium carbonate, dicalcium phosphate, iodized salt,. ammonium citrate, iron oxide, manganese oxide, cobalt carbonate. copper oxide, zinc oxide.

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Table XI

Effect of 4,5,6,7-tetrahydrobenzo (b) thien-4-ylureas as an animal growth promoting agent given as a percentage of the weight gain relative to controls using mice as test animals

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Example 14

The following compounds of Table XII are further prepared using the methods described in Example 3 and Example 5 and using the corresponding amines - (diethyl ether solvent) or amine hydrochlorides (tetrahydrofuran solvent) with the appropriate isocyanates or isothiocyanates. .

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Example 15

Preparation of 1-methyl-3- (4,5,6,7-fetrahydrobenzo (b) thlen-7-yl) urea

4,5-dihydro-6H-benzo (b) thiophene was prepared by the method of Mac Dowell and Greenwood (Journal of Heterocyclic Chemistry, 2, 44, 1965) and converted to 4,5,6,7-tetrahydro-4H-dihydrochloride. Melting point: 209-212 ° C (heating in 1N hydrochloric acid and evaporation to dryness). The salt is then treated with potassium cyanate as described in Example 6 to give 4,5,6,7-etrahydrobenzo (b) thien-7-ylurea, m.p. 211-213 ° C.

Conversion of the amine salt to 1-methyl-3- (4,5,6,7-tetrahydro-benzo (b) thien-7-yl) urea, m.p. 192-195 ° C, can be carried out in a manner known per se.

Example 16 .....................

Preparation of 2-nitro-N-formyl-4,5,6,7-tetrahydro-benzo (b) thien-4-yl-ureas.

Acetic anhydride (30.8 mL) was cooled to -10 to -12 ° C and 70% nitric acid (4 g or 44.5 mol) was added to the stirred solution. After 0.5 h, Nbformyl-4,5,6,7-betrab hydrobenzoyl (b) thiophene-4-amine (7.24 g or 40 mmol) was added and the mixture was allowed to warm to room temperature over 2.5 h and poured. to blend! ice-water (200 mL). After stirring overnight, the solid was filtered and washed well with water. The air-dried, dark, sticky solid was triturated with ether (~ 20 mL) and the nitro salt formed. was washed with ether (10 mL). Přodff, ·. ' 2-nitro-N-formyl-4,5,6,7- (4-thiophet-4-amine) melts at 116-120 ° C; and weighs 3.25 g.

Known hydrolysis of said formamide affords 2- [2- (4-chloro-4,5-ethoxy) -hydrobenzene (b) thienyl] -amine hydrochloride, m.p. 260 ° C; infrared spectrum shows NO 2 bands at 1520 cm -1 and 1335 cm -1.

The conversion of said amine hydrochloride to 2-nitro-4,5,6,7-tetrahydro-benoo (b) -thien-4-yl-urea was carried out as described in Example 6. It melts at 211 ° C with decomposition after recrystallization from MeOH.

Example 17 ...............

Preparation ₁ 7,7-dlmθthylt4,5,6 bθtrahydrot 7-benzo (b) thien-4-yl-urea

7,7-α1πιβ04γ1-4,5,6,7-ββββ1 (b) -thiophen-4-one was prepared by the method of Napler and Chu [Interaational Journal of Sulfur Chemlstry, A, 1, 62-64]. (1971)]. This ketone is converted to N- (7,7-dl-methyl-4,5,4,7-betrate hydrobenzo (b) thien-4-yl) -formamide which is hydrolyzed - - to hydrochloride - 7,7- dimethyb4,5,4,7btetrbhydrob7hzo (bth (ofen-4-biphenyl, m.p. 2111.5-215 ° C) as described by Kizil, Little and Fish - [Journal of Organic Chemistry, 18, 1511 The amine hydrochloride is stirred in water and a small molar excess (5-10%) of KOCN in water is slowly added and the mixture is heated at 70-75 ° C for one hour and then cooled. The title compound is then collected by filtration and washed with water and acetonitrile, m.p. 184-189 ° C.

Example 18 .j

Preparation of 4,6-Dimethyl-4,5,6,7-betraldehyde (b) thlen-4-ylurea ^!

6,6--11 Methyl-4,5,6,7-tetrahydro-lbobenzo (b) -thiophene-4-one was prepared by the method of Napier and Chu [International Journal of Sulfur Chemistry, A, 1, 62-64 (1971)]. This ketone is then converted to N-4,6-dimethyl-4,5,4,7tetrahydrobenzo [b] thien-4-yl] formamide which is hydrolyzed to 6,6-dimethylmethyl-4,5-hydrochloride. (4) thiophene-4-amine (m.p. &gt; 300 ° C) according to the method described in Little 107 [107] by Little and Fish [Journal] of Organic Chemistry, 18, 1511- 1515 (19-8-)].

The amine hydrochloride was stirred in water and a small molar excess (5-10%) of KOCN in water was added. The mixture was heated at 70-75 ° C for 1 hour, cooled and the product collected by filtration. The filter cake is washed thoroughly with water and dried; 174 DEG-178 DEG C. 4,6-dimethyl-4,5,6,7-tetrahydrobenzo (b) 1H-4-yl-urea is obtained.

Example 19 ·

Preparation of 5,6,7,8-Tetrahydro-4-H-cyclohept-beta (b) 1H-4-yl-urea. '

A sample of 5,6,7,8-tetrahydro-4H-cyclohapta (b) thiophent-4-amine hydrochloride is converted to 5,4,7,8-betahydro-4H-cyclohepta (b) thlen-4-ylurea, m.p. 217 DEG. C, as described in Example 6.

Example 20

The following compounds are prepared by reacting 4,5,8,7-betramhydrothiazole (b) -thiophen-4-amine hydrochloride with RNCX in the presence of an equimolar amount of tri7thiamine in solvents such as aromatic solvents, chlorinated hydrocarbons, ethers, lower alkyl C1-C4 ketones or mixtures thereof.

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Example 21

The following tests were performed to assess the ability of 4,5,6,7-tetrahydrobenzo (b) thlen-4-ylurea to promote growth of chickens.

In these experiments, one day old chick is placed in a heating cage and fed and water is given to them at will. In each experiment, there are 5 males and 5 females per cage and three cages are used for treatment. Treatment consists of a basal diet plus 1.3 or 9 ppm of the test compound. The chicks weigh at the beginning and end of the experiment. Food consumption is determined for an experimental period that is 13 days from the start when the chicks are one day old. The basal diet used and the results are shown below.

Basal diet of chickens

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⁺ tra- min No. 3 ^{+ +} vitamin premix 0.05 0.5 100.00 ^{+ +} Vitamin mixture per ton DL methienin 453.6 g BHT 113.6 g Vitamin A (30,000 j / g) 100.0 g Vitamin D3 (200,000 J / g) 5.0 g Vitamin E (44,093 j / kg) 45,4 g riboflavin 4.0 g niacinamide 25,6 g Ca panthothenate 8,0 g Vitamin K (menadione) 1.0 g parvo (10%), folic acid 13,0 g Choline chloride (50 %) 908.0 g vitamin B12 (proferm, 44 mg / kg 227.0 g corn oil ? 50; 0 g fine ground corn 2,582.4 g 4,536.0 g ⁺ tra-min # 3 0,454 kg / tonne manganese 12.50% 62.5 ppm iron 6,00% 30.0 ppm zinc 5,00% 25.0 ppm copper 0.65% 3.25 ppm iodine 0.35% 1.75 ppm cobalt 0.25% 1.25 ppm calcium 15.30 min. 1835 max.

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To determine the effect of 4,5,6,7-tetrahydrobenzo (b) thlen-4-ylureas on sheep, they are randomly selected lambs for pens in groups of 6. Sheep are weighed and feed and water allowed at will. The unused feed from the previous day is collected and weighed Experimental animals receive the same feed as the control animals, but the experimental animals receive one or more subcutaneous implants containing the test compound at the bottom of the ear. and the total feed consumed is calculated.

In these experiments, six replicates of six lambs were used for treatment and each animal received about 11 mg to 105 mg of the test compound.

The average of the six-week increment is given in Tab. XIII and the increase in kg / kg of feed is given in Table XIV. From these data, it can be seen that lamb implanted with 11 mg or 99 mg of the test compound showed an approximately 10% increase in weight gain over the untreated controls six weeks after implantation. Feed utilization was also improved at the same time by about 5% over untreated controls.

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Claims (5)

OBJECT OF THE INVENTION A process for the preparation of cycloalkano (b) thienylureas of the general formula I wherein Z. is hydrogen or alkyl of 1 to 4 carbon atoms, Y is hydrogen, halogen, cyano, U is &gt; C = O, > CHOH, n is 1 or 2, X is oxygen or sulfur, R1 is. hydrogen or alkyl with '1 ^to' the fourth the carbon atoms and R 2 are: " •hydrogen, 2-butenyloxy,. . alkyl 'C1-C12' methoxymethyl, - C3-C6 cycloalkyl, phenoxy, allyl, —CH2 — CH2 —OH, methallyl,. —CH2 — CH2 —O — CH3 2-Butenyl, —CH2 — CH2 — S — CH3. 2-propynyl, —CH2 — CH (OR 1) 2, hydroxy, —CH2 — CF3, C 1 -C 6 alkoxy. —CH2 — CN, allyloxy, —CH2 — CO2R1, methallyloxy, —NH — CO2R1, wherein m is 0, 1 or 2 and Q. is selected from the group consisting of when n = 0 hydrogen, 4-chloro, 3,4-methylenedioxy, 2 (3 or 4) methoxy, 4-ethoxy, 4-butoxy, 4-methylthio, 2,4-dimethyl, 2,4 dimethoxy, 2,4- (chloro, 4-nitro and 2-methyl-4) -bromo; when n = 1 hydrogen, 4 * chloro, 4-methoxy and 3,4-methylenedioxy; when n - 2 hydrogen. characterized in that one mole equivalent of the compound of formula (II) is reacted И5276 Wherein R 1, Z, У, U and n are as defined above with 1 to 1.5 mol equivalents of the compound of formula III RzNCX (III), wherein X and Rz are as defined above in an organic solvent inert to k ^; reactants at 0 to 100 ° C. 2. A process according to claim 1, wherein the compound of formula II is used in the form of an acid addition salt and the reaction is carried out in the presence of an acid acceptor. 3. A process according to claim 2 wherein the reaction is carried out in an aromatic hydrocarbon or chlorinated hydrocarbon solvent in the presence of an acid acceptor selected from the group consisting of sodium or potassium bicarbonate, carbonate or hydroxide. 4. The process of item 1 for preparing a compound of formula X II Where X is oxygen or sulfur, characterized in that a compound of the formula is reacted With an equimolar to 50% molar excess of sodium or potassium cyanate or thloocyanate in an aqueous medium at pH 5-7 and at 10-80 ° C and the product isolated. 5. A process according to claim 1 for the preparation of a compound of the formula wherein X is oxygen or sulfur, characterized in that the compound of the formula is reacted with an equimolar to 1 mole. 50% molar excess of sodium or potassium cyanate or thloocyanate in aqueous medium at pH 5-7 and 10-80 ° C and the product isolated.