CH619703A5 - Process for the preparation of novel optionally ring-substituted cycloalkano[b]thiophene ureas or thioureas and use thereof - Google Patents

Description

The invention relates to a process for the preparation of new, optionally ring-substituted cycloalkano- [b] -55 -thiophene-ureas or -thioureas of the formula III.1

n - c - niir ,.

2nd

or

• nhr,

619703

4th

wherein X is oxygen or sulfur, Y is hydrogen, C ^ alkyl or halogen, Z is hydrogen or C ^ alkyl, Ri is hydrogen or C ^ alkyl, R ;, hydrogen, Cj. ^ - alkyl, C3_6-cycloalkyl , Allyl, 2-propynyl, hydroxyl, C1_ (i-alkoxy, allyloxy, methallyloxy, 2-butenyloxy, methoxymethyl, phenoxy, CH2-CH2-OH, -CH2 - CH20-CH3, -CH2-CH2- S-CH3, -CH2-CH (ORj) 2, -CH2-CF3, -CH2-CN, -CH2-C02R1; -NH-COaRi,

O O

ii ii

-c-rj, -c-cc13,

he

P-

c-nh-j e

"ch.-,

0

nh-c-nh-ch ^ -

means, where n is 0, 1 or 2 and Q, if n is 0, is hydrogen, 3,4-methylenedioxy, 2-, 3- or 4-methoxy, 4-ethoxy, 4-chloro, 4-butoxy, 4-methylthio, 2,4-dimethyl, 2,4-dimethoxy, 2,4-dichloro, 4-nitro or 2-methyl-4-bromo, if n is 1, is hydrogen, 4-chloro, 4- Represents meth-oxy or 3,4-methylenedioxy and, if n is 2, is hydrogen, R3 is hydrogen or C 1 -C 4 -alkyl and U is a divalent radical of the formula

40 h

] ^ C = 0, ° the

OH

Ri

Rb means, where R4 and R3, which are the same or different, represent 45 hydrogen or C 1-4 alkyl.

It is also possible to prepare the cis and trans isomers if U is the radical of the formula —CHOH— or the optical isomers of the new compounds of the formula I or II.

The process according to the invention is characterized in that one molar equivalent of a compound of the formula

nhr.,

respectively.

(III)

(IV)

5

619703

or an acid addition salt thereof in water or an inert organic solvent at a temperature of

0 to 100 ° C with 1 to 1.5 molar equivalents of a compound of the formula

R2NCX

implemented or for the preparation of compounds of the formula

1 or II, in which Ra and R3 are hydrogen, a molar equivalent of an acid addition salt of a corresponding compound of the formula III or IV in an aqueous medium at a pH of 5 to 7 and at a temperature of 10 to 80 ° C with 1 to 1 , 5 molar equivalents of a compound of the formula

MeNCX

where Me means sodium or potassium, and the product is isolated.

In preferred compounds obtainable according to the invention, the symbol R2 represents hydrogen, C 1-4 -alkyl, Cs-o-cycloalkyl, allyl, 2-propynyl, hydroxyl, C 1-4 -alkoxy, allyloxy, methallyloxy, 2-butenyloxy, methoxymethyl, phenoxy, -CH2-CH2-OH, -CHjjCHCORì) ,, -CH2-CF3, -CH2-CN, -NH-C02Ri,

x

TT

nh-c-nhr,

(IIa)

io where U for

■ ^ ch2,

: CHOH or

; C = 0

stands and R2 stands for hydrogen, C ^ alkyl, allyl, Ci_4-alkoxy, 2-propynyl, methoxymethyl or hydroxyl. 15 Particularly preferred compounds of the formula I correspond to the formula x

h nh-c-nhr,

25th

(Ia)

O

O

where U for

-C-R ,, -C-CCL.

; CH2,

; CHOH or

; c = 0

-cil, -,

-ch2-,

or where Q, if n is 0, 4-chloro, 3,4-methylenedioxy, 2-, 3- or 4-methoxy, 4-ethoxy, 4-butoxy, 4-methylthio, 2,4-dimethyl, 2, 4-dichloro, 4-nitro or 2-methyl-4-bromo means if n is 1, is hydrogen or 4-methoxy and, if n is 2, is hydrogen.

The cycloalkano- [b] -thie-nylureas obtainable according to the invention can be present in the form of the ice and the trans isomers and in the form of racemic mixtures or the optically active isomers.

According to the definition of U, the compounds obtainable according to the invention are further divided into three separate subclasses, i.e. Compounds in which U is a divalent radical of the formula

H

; C = 0, ^: C ^ or

OH

R *

r.,

means.

Those compounds of the formula I and II in which Z is hydrogen, Y is hydrogen or bromine and U is a radical of the formula -CO-, -CHOH-or -CH.- are preferred.

Particularly preferred compounds of the formula II correspond to the formula

30th

stands and R2 is hydrogen, C ^ alkyl, allyl, C ^ alkoxy, 2-propynyl, methoxymethyl or hydroxyl.

The preferred and particularly preferred compounds of the formulas I and II defined above can be present in the form of the ice and trans isomers and in the form of racemic mixtures or in the form of the optically active isomers.

The process according to the invention can be carried out by reacting approximately equimolar amounts of the isocyanate 40 or isothiocyanate of the formula R, NCX and the compound of the formula III or IV or the acid addition salt thereof. If the cycloalkane ring does not contain a hydroxyl group, it is preferred to work with a 5- to 50% excess of isocyanate or iso-45 thioeyanate. The reaction can be carried out at atmospheric pressure or at elevated pressure, but is preferably carried out at atmospheric pressure and at a temperature of 0 to 70 ° C. in the presence of an organic solvent.

Suitable organic solvents are aprotic aro-50 matic solvents, such as benzene, toluene or xylene; Chlorinated hydrocarbons, such as methylene chloride, chloroform or dichloroethane: ethers, such as tetrahydrofuran, diethyl ether, dimethoxyethane, dimethylene glycol, dimethyl ether or di-oxane; Ketones having alkyl groups of 1 to 4 carbon atoms, such as acetone, methyl ethyl ketone, methyl butyl ketone or methyl isobutyl ketone; or mixtures of these solvents.

If the reaction with the compound of the formula RoNCX is carried out using an acid addition salt of the compound of the formula III or IV, then it is best to work in the presence of an acid acceptor. Suitable acid acceptors are trialkylamines, such as triethylamine, trimethylamine or pyridine; Alkali carbonates such as sodium * or potassium carbonate; Alkaline earth carbonates, such as calcium carbonate; and strongly basic ion exchange resins 65 and an aqueous alkali in a two-phase system containing an immiscible hydrocarbon solvent such as benzene or toluene or a chlorinated hydrocarbon such as chloroform or dichloroethane.

619703

6

The new compounds obtainable according to the invention are suitable as growth-promoting agents for animals, such as poultry, fur animals or agricultural livestock, the use of these compounds for this purpose giving the additional advantage that better conversion of feed is achieved in the animals. The term "feed conversion" as used herein means the ratio of the weight unit of feed to the increase in weight by one unit of weight, where an improvement in feed conversion means an increased weight gain for a given amount of feed consumed.

The method according to the invention for improving the feed efficiency and increasing the growth rate of warm-blooded animals is characterized in that the animals are orally administered an effective amount of a new compound of the formula I or II.

The supplementary feed according to the invention for increasing the growth rate of poultry, fur animals and farm animals is characterized in that it contains 70 to 99% by weight of an edible carrier material and 1 to 30% by weight of a new compound of the formula (I) or (II) contains.

In practice, the animals can be given a growth-promoting amount of a new compound of formula (I) or III) or an optically active isomer thereof in or with the feed. However, the compound can also be implanted under the animal's skin or administered by parenteral injection. When introducing the compounds obtainable according to the invention into the feed of chickens, turkeys, sheep, cattle, goats and the like, normally about 0.0001 to 0.08% by weight, preferably 0.001 to 0.04% by weight, is the Compound of formula (I) or (II) sufficient to increase the rate of growth and to improve feed conversion. When the products are injected parenterally or implanted subcutaneously, the desired improvement in weight gain and increased feed conversion are achieved when the active compound is used in an amount of about 0.001 to 0.2 mg daily, preferably in an amount of 0.005 to 0.10 mg administered per kg of the animal's body weight.

Tests carried out on 1-day-old chickens had shown that by adding 1 to 9 ppm 4,5,6,7-tetrahydro-benzo- [b] -thien-4-yl - urea in the chicken feed can achieve an improvement in weight gain of 3.3 to 6.6% and an increase in feed conversion of 2.7 to 4.7% compared to the untreated control animals.

The compounds obtainable according to the invention are also suitable as herbicidal compositions. Thus, they are suitable for controlling the undesired broad-leaved weeds and the grass weeds if they are applied to the soil containing the seeds of the undesired weeds or to the foliage of these plants. It is usually sufficient to control the undesirable plants if the active compound is applied in an amount of about 5.60 to 16.8 kg / ha, preferably in an amount of about 11.2 kg / ha.

example 1

Preparation of l-methyl-3- (4,5,6,7-tetrahydrobenzo- [bJ - thien-4-yl) urea

While stirring, a mixture of 1.89 g (0.01 mol) of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine-hydrochloride in 20 ml of dry benzene is gradually added 1 , 05 g (0.01 mol) of triethylamine and 1.7 ml (excess) of methyl isocyanate. The addition of the latter compound leads to an exothermic reaction, whereupon the mixture becomes very pasty. You leave the mixture during one

Hour at 45 ° C, recover the solid after cooling to room temperature and then wash it well with benzene and finally with water. Drying gives 1.7 g (81%) of the product, which has a melting point of 183 to 5 186 ° C. Recrystallization from acetone gives 1.23 g of the product with a melting point of 187.5 to 189 ° C.

When working on a 0.05 mole scale, the crude product yield is 83% (9.15 g), which melts at 181 ° C to 186 ° C. The recrystallization of this material from acetone gives 6.5 g of the product with a melting point of 184.5 to 187 ° C.

Example 2

15 Preparation of l-ethyl-3- (4,5,6,7-tetrahydrobenzo- [bJ - thien-4-yl) urea

In the manner described in Example 1, ethyl isocyanate is reacted with 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-20 amine hydrochloride, 10.1 g of l-ethyl-3- (4 , 5,6,7 - tetrahydrobenzo- [b] thien-4-yl) urea. The recrystallization of the crude product from an isopropanol / water mixture (9/1) gives crystals, which are dissolved in chloroform and washed successively with 1N sulfuric acid solution, water 25 and saturated sodium bicarbonate solution. After evaporating the chloroform, the desired product is obtained with a melting point of 184 to 188.5 ° C.

Example 3

30 Preparation of l-isopropyl-3- (4,5,6,7-tetrahydrobenzo- [b] - 4-yl) urea

5.35 g of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine in 100 ml of di-35 ethyl ether are stirred under a nitrogen atmosphere and 3.57 g of isopropyl isocyanate in 40 ml of diethyl ether are slowly added, with a crystalline product is obtained. The mixture is stirred for a further half an hour, then left to stand overnight and then filtered off, 8.3 g of l-isopropyl-3- (4,5,6,7-tetrahydro-4o benzo [b] thiene being obtained -4-yl) urea with a melting point of 223 to 226 ° C.

Example 4

Preparation of l- (n-hexyl) -3- (4,5,6,7-tetrakydrobenzo- [b] -45-thien-4-yl) urea

In the manner described in Example 1, 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine with n-hexyl isocyanate is added to l- (n-hexyl) -3- (4.5 , 6,7-tetrahydrobenzo- [b] -50-thien-4-yl) urea. Melting point = 122 to 124 ° C.

Example 5

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

55

In a similar manner to that described in Example 1, 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine-hydrochloride is reacted with cyclohexyl isocyanate in dry tetrahydro-furan, 7 g of l-cyclohexyl -3- (4,5,6,7-tetrahydro-6o benzo [b] thien-4-yl) urea with a melting point of 222 to 225 ° C.

Example 6

Preparation of 4,5,6,7-tetrahydrobenzo- [b] thien-4-yl-65 urea

It is added with stirring at about 15 ° C. to a mixture of 50 g of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine-hydro-

7

619703

chloride (real about 45 g, based on a purity of 90%) in 100 ml of water dropwise a solution of 23.1 g of potassium cyanate in 100 ml of water. When the addition is complete, the mixture is slowly warmed to 70 to 75 ° C. and kept at this temperature for one hour. Then the mixture is cooled and the white solid is filtered off and washed with water. The solid is air dried, pulverized and washed with acetonitrile. Drying gives 37.3 g of the crude product which, after treatment with about 1200 ml of hot acetone, gives 11.45 g of the title compound with a melting point of 200 to 204 ° C.

In a similar manner, 2-methyl- and 3-methyl-4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl-urea are prepared, giving products which are obtained at 232 to 233 ° C. and melt at 227 to 230 ° C (decomposition). If N-methyl-4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine hydrochloride is used, l-methyl-1- (4,5,6,7-tetrahydrobenzo- [ b] -thien - 4-yl) urea, which melts at 151.5 to 154.5 ° C.

Example 7

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

9.48 g of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine hydrochloride are stirred in 100 ml of dry tetrahydrofuran and 6.06 g of triethylamine are added. After stirring for 15 to 30 minutes, 5.23 g of ethyl isothiocyanate in 20 ml of dry tetrahydrofuran are added dropwise and the mixture is heated to 50 ° C. for 2 hours. The mixture is then cooled and filtered, after which the filter cake is washed with hexane. The filtrate is evaporated to dryness and poured onto ice. The oil is extracted with ether and the extract is washed with a 1N sulfuric acid solution, with water and with a saturated sodium bicarbonate solution. The ether extract is dried and evaporated to dryness to give an oil. This oil crystallizes in ether and gives l-ethyl-3- (4,5,6,7-tetrahydrobenzo - [b] -thien-4-yl) thiourea, which melts at 106 to 112 ° C.

Similarly, by using methyl isothiocyanate, butyl isothiocyanate or cyclohexyl isothiocyanate, 1-methyl-, 1-butyl- or l-cyclohexyl-3- (4,5,6,7 - tetrahydro-benzo- [b] -thien-4-yl) -thiourea.

Example 8

a) Preparation of (-) - 4,5,6,7-tetrahydrobenzo- [b] -thio-

phen-4-ammonium- (R) -N-benzoyl-glutamate (starting material)

A mixture of 8.04 g of (R) - (+) - N-benzoyl-glutamic acid, 1.92 g of acetic acid and 80 ml of water is heated on a steam bath until a solution is obtained. 9.80 g of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine are gradually added to this hot solution with stirring. To completely convert the amine, use about 2 ml of ethanol for rinsing. Then the mixture is allowed to cool to room temperature and is left to stand overnight. The mixture is then cooled in a refrigerator and filtered to obtain the crystals, after which the filter cake is washed several times with water. Drying gives 9.27 g of the title salt with a melting point of 192 to 194 ° C.

[œ] sL = -9.39 °, t «] ^ 3u = -44.6 °, [a] 305 = -71.4 ° at c = 4.475 in acetic acid.

The original filtrate is concentrated to a small volume under reduced pressure and partitioned between diethyl ether and an aqueous sodium hydroxide solution.

The aqueous phase is extracted with ether and the like. combines this ether extract with the first ether fraction. The ether solution is then dried over magnesium sulfate u. after evaporation to dryness, the amine is added, with stirring 5 to a hot solution of 8.04 g '(S) - (-) - N-benzoyl-glutamic acid in 1.92 g acetic acid and 80 ml water . Rapid crystallization occurs and after heating for 10 minutes on a steam bath, the mixture is allowed to cool in a refrigerator. The crystals io are collected, washed with water and dried and give 11.1 g of (+) - 4,5,6,7-tetrahydrobenzo- [b] - thiophene-4-ammonium- (S) -N-benzoyI -glutamate salt, which melts at 192 to 193.5 ° C.

15 [«]« !. = + 12.2 °, [a] 430 = + 42.7 °, [«]," = + 82 ° at c = 435 in acetic acid.

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

-yl urea

20 8.8 g of the (R) - (+) - N-benzoyl-glutamic acid salt of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine are added to an ice in a separating funnel / Water mixture and adds 3.5 g of sodium hydroxide in 55 ml of water. The mixture is shaken until a solution is obtained and then extracted twice with diethyl ether. The ether extracts are washed with a saturated sodium chloride solution and, after the addition of ice, the mixture is extracted with 2.36 ml of concentrated hydrochloric acid in 25 ml of water. Then you treat the acid layer with 30 2.29 g of potassium cyanate in 30 ml of water at 20 ° C. After stirring for one hour, the mixture is heated for half an hour and then cooled. The product is filtered off, washed with water and dried and gives 2.75 g of (-) - 4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl-urea 35 with a melting point of 218.5 to 221.5 ° C.

[«] = 89 = -63.2 °, [a] 43 (i = -149.9 °, [a] 305 = -271.5 °.

The salt of 4,5,6,7-tetrahydrobenzo- [b] -thiophene-4-amine and (S) - (-) - N-40-benzoyl-glutamic acid are treated in a similar manner in the above manner and receives (+) - 4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl-urea with a melting point of 218 to 220 °.

[a] ^ 9 = + 60 °, [a] 43 (i = + 149.8 °, [a] 305 = + 272.5 °.

45

Example 9

Preparation of 4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl - urea so 19.9 g of 4,5,6,7-tetrahydro-benzo- [b] - are cooled in a flask thiophene-4-amine and slowly add a solution of 12 ml of 12N hydrochloric acid in 50 ml of water. A solution of 11.7 g of potassium cyanate in 80 ml of water 55 is then added over the course of 2 hours at about 20 ° C. The mixture is stirred for one hour at room temperature and then warmed to 60 ° C., after which it is left at this temperature for half an hour. After standing overnight at room temperature, the product is isolated, washed with water and 21 g 60 of the title compound are obtained with a melting point of 206 to 209 ° C.

Example 10

Preparation of 2-chloro-4,5,6,7-tetrahydrobenzo- [b] thien-65 -4-yl urea

The desired 2-chloro-4,5,6,7-tetrahydro-benzo [b] thien-4-yl urea is prepared in the manner given in Example 9.

619703

8th

way, by reacting 2-chloro-4,5,6,7-tetrahydrobenzo- [b] - thiophene-4-amine in situ with hydrocyanic acid. The product melts at 194 to 198 ° C.

Example 11

The compounds listed in Table I below are obtained using the procedures given in Examples 3 and 5 using the appropriate amines (in diethyl ether as solvent) or amine hydrochloride (in tetrahydrofuran as solvent) and the appropriate isocyanates or isothiocyanates.

10th

h h h h

h h h h h h

h h h h

h h h h h h

h h h h

h h h h h h

O

O

O

O s s

s

TABLE I

-n-CioHo

"0

-ch2-ch2

-ch2ch2-oh

-n-C8H17

t> -

-ch2ch = ch2

-ch2- / oV?

.NHR,

Y Z

Ri x

ra

Reaction solvent

Melting point ° C

H

H

-CH.3

o n-hexyl

ether

70.5-74.5

H

H

-ch3

s

ethyl

ether

104-107

-ch3

H

H

s

ethyl

THF

118-121

-ch3

H

H

0

ethyl

THF

209-211

-ch.

H

H

o sec-butyl

THF

182.5-185

-ch3

H

H

o n-hexyl

THF

118-120

H

-chs

H

s

ethyl

THF

120.5-123.5

H

-cha

H

o sec-butyl

THF

197-198

H

-chj,

H

o n-hexyl

THF

148-150

H

H

H

O

-chzCH = ch2

THF

175-176

H

H

H

O

-ch2co2c2h5

THF

147-149

Ether ether ether

Ether thf

Ether thf thf thf thf

219-221 109-111

122-125

279-283 01

140-154 66-69

125-129 101-103

123-127

-ch,

9

TABLE I (continued)

619703

Ri x

r,

Reaction solvent

Melting point ° C

H

H

h h

h h h

h h

h h

h h

h h

h h

h h

h h

h cha h

H

-ch3

h h

-cha h

H

-cha h

h cha h

h h

-chj,

h h

-cha h

H

-cha h

H

-ch9

H

-chs

-ch3

H

-ch3

-CHs h

-ch3

-ch,

H

-CHa

-ch3

h h

H

H

H

H

H

H

H

H

H

H

H

h h

H

H

H

H

H

H

H

h h

o o

o o o o o s o o o s o o s o o

o o o o o o o o

Cl

-CH2-C = CH

<ô): och3

-oc2h5

-och2-ch = ch2

-0-n-CeHia

-C2H5

-2-C4Hn

-c2h5

H

-n-CeHls H

-c2h5

-2-C4H9 -n-C ,, H13

-c2h5 -2-c4h9

Cl

H

-n-C4H9 -CH2CN -CH2-CH2-OCH3 -CH2CH2-S-CH3

-ch.

"-O

2 '0' -nh-co2ch8

o thf

Ether ch2c12

ch2c12

CHaCl ^

Ether thf thf thf h2o thf h2o thf thf thf thf thf thf h2o ch2ci2

thf

ether

ether

Ether ether ch.oh ch2c12

chocl,

137-144

188-189

223-226

90-94

70-73

54-57

209-211

181-184

116-118.5

234.5-236.5

111-121

225-227

121-125

197-198

148-150

153-157

181-183.5

203-209

233-237 159-161 179-181 142-144 128-130

183-185 183-186

278-279

171-172 234-237

619703

10th

TABLE I (continued)

Ri

R «

Reaction solvent

Melting point ° C

H

H

H H H H H

H H

H

H

H

H

H

H

H

H

H

H H H H H

H H

H

H

H

H

H

H

H

H

H

H H H H H

H H

H

H

H

H

H

H

H

O

O

O O O O O

O O

O

O

O

O

O

O

-ch.

M

-CH2CFc -t-butyl

2 © "

-ch2 - <(;> - ci

-CH2CH (OCHa) 2

W '0C2H5

K9} - °° 1H9

- <®-och3

- ° - / o

CH2C12

ch2ci2

ch2ci2 ch2ci2 ch2ci2 ch2ci2 ch2ci2

ch2ci2 ch2ci2

CH2C12

ch2ci.

ch2ci2

CH "C1,

CH2C1,

CHoCL

CH, C1 "

201-204

192-195

188-191 208-211 .187-192 216-217 125-128

175-178 231-234

241-242.5

242-245

200-204

221-225

183-186

223-226

159-161

11

619703

Example 12

Preparation of 7,7-dimethyl-4,5,6,7-tetrahydrobenzo [b] thien-4-yl urea

According to the method of Napier and Chu [International Journal of Sulfur Chemistry A, 1, pp. 62 to 64 (1971)], 7,7-dimethyl-4,5,6,7-tetrahydrobenzo- [b] -thio- phen-4-one and uses the Kloetzel method,

Little and Fish, J. Org. Chem. 18, 1511-1515 (1953) into the 4-formylamino compound which, by heating with 1N hydrochloric acid for 1 hour, gives 7,7-dimethyl-4,5,6,7-- tetrahydrobenzo- [b] -thiophene-4-amine hydrochloride is hydrolyzed, which melts at 211.5 to 215 ° C. The amine hydrochloride is converted according to the procedure of Example 6 into 7,7-dimethyl-4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl-urea, which is at 184 to 189 ° C melts with decomposition.

Example 13

Preparation of 5,6,7,8-tetrahydro-4H-cyclohepta- [b] thien-4-yl urea

According to the method of Example 6, 5,6,7,8 - tetrahydro-4H-cyclohepta- [b] -thiophene-4-amine hydrochloride is converted into 5,6,7,8-tetrahydro-4H-cyclohepta- [ b] -thien-4-yl urea, which melts at 217 ° C with decomposition.

Example 14

The compounds specified below are obtained by reacting 4,5,6,7-tetrahydro-7-oxobenzo- [b] thio-phen-4-amine hydrochloride with compounds of the general formula R2NCX in the presence of an equimolar amount of tri ethylamine in solvents such as aromatic solvents, chlorinated solvents, ethers, C 1-4 lower alkyl ketones or mixtures thereof, preferably in methylene chloride, tetrahydrofuran or benzene.

product

r2ncx

R2

x

Mp (° C)

chanco cha ~

0

212-215

c2h5nco c2h5-

0

188-190

cci3c-nco

II

O

M

ii o

ii c13c-c-

0

185-188

cch5ch2nco c0h5ch2-

0

-

c2h5ncs c2h6-

s

-

(ch3) äCH-nco

(ch3) 2ch-

0

188-190

ch2 = ch-ch2-nco ch2-ch-ch2-

0

171-174

Trial 1

The following studies serve to evaluate the growth promoting properties of 4,5,6,7-tetrahydro-benzo- [b] -thien-4-yl-ureas against chicks.

In these studies, chicks 1 day old are used, which are placed in heated cages and supplied with food and water ad libitum. In each examination, 5 male and 5 female chicks are used per cage and 3 cages per treatment. The treatment consists of a basic feed, which is mixed with 1, 3 or 9 ppm of the compound to be examined. The chicks are weighed at the beginning and at the end of the examination. Feed consumption is determined during the study period, which is 13 days from the start of the day the chicks are 1 day old. The composition of the basic feed used and the results obtained are given below.

Basic kitchen food ground yellow corn

53.45%

Soy flour (49%)

28.0

Menhaden fish meal (60%)

5.0

Corn flour (60%)

5.0

dehydrated alfalfa flour (17%)

2.0

stabilized fat

4.0

Dicalcium phosphate

1.2

ground limestone

0.5

Sodium chloride

0.3

Tra-Min No. 3 *

0.05

Vitamin premix * *

0.5

100.00

** Vitamin premix for 1 ton

D, L-methionine

453.6 g

BHT

113.6

Vitamin A (30,000 units / g)

100.0

Vitamin Ds (200,000 units / g)

5.0

Vitamin E (44 093 units / kg)

45.4

Riboflavin

4.0

Niacinamide

25.0

Calcium pantothenate

8.0

Vitamin K (menadione)

1.0

Folic acid (parvo [10%])

13.0

Choline chloride (50%)

908.0

Vitamin B12 (Proferm, 44 mg / kg)

227.0

Corn oil

50.0

finely ground corn

2582.4

4536.0

* Tra-Min No. 3

Result in 0.454 kg / t

Manganese 12.50%

62.5 ppm

Iron 6.00%

30.0

Zinc 5.00%

25.0

Copper 0.65%

3.25

Iodine 0.35%

1.75

Cobalt 0.25%

1.25

Calcium 15.30% min.

18.35% max.

5

io

15

20th

25th

30th

35

40

45

50

55

60

65

619703

12

Chick test mean chick weight gain after 13 days (g)

Dose experiment percentage

(ppm) 1928 1929 1930 1931 Average improvement

1.

control

-

189

175

180

188

183

• -

2nd

4,5,6,7-T etrahydro-

1

181

193

182

200

189

3.3

3rd

benzo- [b] thien-4-

3rd

199

186

197

198

195

6.6

4th

-yl urea

9

190

198

191

191

193

5.5

mean weight gain in kg / kg of feed during the 13 days

1.

control

-

1.54

1.52

1.46

1.48

1.50

-

2nd

4,5,6,7-tetrahydro-

1

1.48

1.45

1.49

1.44

1.46

2.7

3rd

benzo- [b] thien-4-

3rd

1.47

1.40

1.44

1.40

1.43

4.7

4th

-yl urea

9

1.45

1.45

1.46

1.40

1.44

4.0

Trial 2

Growth promotion and feed efficiency ratings in sheep that have received an implant containing the compound to be investigated

In order to investigate the effect of a 4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl-urea compound on sheep, Wether lambs are statistically divided into groups of 6 in enclosures. The sheep are weighed and provided with food and water ad libitum. The feed is weighed daily and the unused feed from the previous day is collected and weighed. The test lambs are provided with the same non-drug-containing feed as the control animals, but are given one or more subcutaneous implants in the base of the ears, which contain the compound to be examined. The formulation of the implant used is given below. After the six-week treatment period, the lambs are weighed again and the total feed consumed is calculated.

In these investigations, six groups of six lambs are used per treatment, of which each animal is administered approximately 11 to 105 mg of the investigating compound.

Table II shows the mean weight gains over the six weeks, while Table III shows the weight gains in kg / kg of feed. From these values it can be seen that the lambs who have been implanted with 11 mg or 99 mg of the compound to be examined show a weight gain of about 10% compared to the untreated control animals 6 weeks after the implantation. Feed utilization during this period compared to the untreated control animals is also improved by about 5%.

Lamb feed o / o ground corn cobs

15.0

ground yellow corn

48.0

Soy flour (49%)

10.0

dehydrated alfalfa flour

15.0

molasses

10.0

iodized salt

0.5

Dicalcium phosphate

1.0

Premix

0.5

100.0

Premix for 1 ton g

Tra-Min No. 3 <D

454

Vitamin A (30,000 units / g)

133

Vitamin D3 (200,000 units / g)

5

Corn oil

100

ground corn

3848

4540

fl> Tra-Min No. 3 =

«/»

calcium

21.00

manganese

12.50

iron

6.00

zinc

5.00

copper

0.65

iodine

0.35

cobalt

0.25

13

619703

Pellet implant 4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl urea 11.0 mg glyceryl-12-hydroxystearate 10.50 mg

Magnesium stearate

0.50 mg 22.00 mg

TABLE II

mean weight gain over 6 weeks, kg / lamb

treatment

Number of drug implants (a)

1

2nd

Repetitions 3 4 5

6

medium

control

0

8.50

8.70

9.93

6.50

7.03

6.75

7.90

4,5,6,7-tetrahydrobenzo

1

11.25

9.32

9.20

8.63

8.05

6.68

8.86

- [b] -thien-4-yl urea

9

10.83

9.60

8.75

7.20

8.53

7.20

8.69

(a) Average weight: 22 mg each

Composition: 50% active ingredient + 50% carrier material

TABLE III

average weight gain in kg / kg feed per enclosure

treatment

Number of drug implants (a)

1

Repetitions 3 4 5

medium

control

0

7.88

6.77

7.41

8.82

9.18

8.16

8.04

4,5,6,7-T etrahydro-

1

6.63

6.58

7.41

8.21

8.05

8.49

7.57

- [b] -thien-4-yl urea

9

6.51

6.75

7.80

8.38

7.56

7.97

7.49

(a) Average weight: 22 mg each

Composition: 50% active ingredient 4- 50% carrier material

Trial 3

Investigation of the growth regulating effect on mice

The female mice (CFI) are obtained from the car worth farm at 6 weeks of age. They are caged in groups of 10 animals that are in air-conditioned rooms [22.2 to 24.4 ° C (72 to 76 ° F)] that are automatically lit for 14 hours and kept dark for 10 hours. The basic diet used in these studies is a Purina laboratory feed (Purina Laboratory Chow), the composition of which is given below and which is given ad libitum, as is water which is also added ad libitum.

Thirteen days after arrival, the mice are weighed in groups of 10 animals and statistically selected for various treatments. The concentration of the various compounds in the feed is given in the following tables. The mice are weighed again 12 days later and the experiment is ended. At least 3 cages with untreated control mice (30 mice) are used in each examination. The test results are given in the following Table IV, which shows the values for the percentage weight gain compared to the control animals.

The following is a description of the feed 45 in which the growth promoting compounds are added.

Lining

Guaranteed analytical values: 50 raw protein, no less than raw fat, no less than raw fiber, no more than ash, no more than

55

23.0% 4.5% 6.0% 9.0%

Components:

Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, milled extruded corn, 60 oat meal, soybean meal, dehydrated alfalfa meal, cane molasses, preserved with butylhydroxyanisole animal fat, vitamin Bi2 additive, Kalziumpanto-naphthenate, choline chloride, folic acid , Riboflavin additive, dried brewer's yeast, thiamine, niacin, vitamin A additive, D-activated plant sterol, vitamin E additive, calcium carbonate, dicalcium phosphate, iodized salt, iron (III) ammonium citrate, iron oxide, manganese (II) oxide , Cobalt carbonate, copper oxide and zinc oxide.

619703

14

table iv

Effect of 4,5,6,7-tetrahydrobenzo- [b] -thien-4-yl-ureas as animal growth-promoting agents. The values determined in mice are given as a percentage weight gain compared to the control animals.

z-

Y-

Ri X. ! X! (S-n-c-n

R;

• P-i1

Dose in ppm in feed x

Y Z

Ri

* 2 *

Ra '

Weight gain compared to the control animals in ° / o

50

o h

h h

h h

50.1

400

o h

h h

h h

119.6

50

0

h h

h h

-cha

61.8

200

o h

h h

h h

134.2

50

o h

h h

H

-c2h5

40.3

200

0

h h

h h

-c2h5

87.6

400

o h

h h

-och h

68.6

400

0

h h

H

-oh h

102.0

400

o h

h h

H

-ch (ch3) 2

88.0

400

o h

h h

-ch2CH2- {o)

H

72.3

400

o h

h h

-CH2- (C ^

H

32.4

400

s h

h h

H

-c2h5

54.6

400

O

Br h

h h

H

76.3

400

O

Cl h

h h

H

4.8

400

o h

h h

-n-C0H1B

H

14.5

400

O

H

H

-ch3

H

H

27.2

400

0

-cha

H

H

H

H

7.6

400

s

H

h h

■ cha,

H

88.5

400

O

H

H

H

H

(left-turning isomer)

H

122.5

400

O

H

H

H

-ch2ch = ch2

H

48.4

400

O

H

H

H

H

-ch3

134

400

O

H

H

h h

-c2h5

87.6

400

O

H

H

H

H

-ch (ch3) 2

88

400

0

h h

H

h n-hexyl

14.5

400

O

H

H

H

H

-ch2c8h5

32.4

400

O

H

H

H

H

-CH2ch2cgh5

72.3

400

s

H

H

H

H

-CA

54.6

15

619703

TABLE IV (continued)

Dose in ppm in the feed

X

Y

Z

Ri

R2 '

V

Weight gain compared to the control animals in%

400

O

H

H

-CH *

H

H

27.2

400

O

H

H

H

H

-CH2-CH = CH2

48.4

400

s

H

H

H

H

-CH,

88

400

400

400

400

400

400

o o

h h

h h

h h

h h h h

400

S

H

H

H

H

400

S

H

H

H

H

400

O

H

H

H

H

400

s

H

H

H

H

400

s

H

H

H

H

400

s

H

H

H

H

400

0

H

H

H

H

200

O

H

H

H

H

400

O

H

H

H

H

400

0

H

H

H

H

400

O

H

H

H

H

400

O

H

H

H

H

400

O

H

H

H

H

400

O

H

H

H

H

h h h h h h h h h h h h h h h

V

h n-

-cr2-ch2- <P>

-n-butyl

-CH2-CH2-OH

-n-C8H17

-ch2-ch = ch2

-ch2-c = ch

-n-butyl

-ch2-o-ch3 -ch2cn Cl ci

-nh-cooch,

-ch2-nh-c0-nh

ÒU

- <^ Coh3

-ch2-ÇÎ]

-ck2 - ^>

- <5) —ci

! - ^ ° ch3

-ch

43

11

15

75 3

16

32

60 82 25 102

12

18 18 29

78 39 48 21 16

619 703 16

TABLE IV (continued)

Dose in ppm in the feed

X

Y

Z

Ri

R2 '

Weight gain compared to the control animals in%

400

O

h h

h h

i

O

Sr.

41

400

o h

h h

H

-ch2-h @ n

46

400

o h

h h

H

-ch2cf3

19th

400

o h

h h

H

-ch2-cl

1

400

o h

h h

H

-ch2-ch (och3) 2

22

400 O H H H H 31

400 O H H H H

400 O H H H H

400 OH H H - (()) - 0c "h

- <5) -oc2h

400

o h

h h

9

400

o h

h h

-Oh

102.9

400

o h

h h

-ochg

68.5

400

o h

h h

-oc2h5

61

400

o h

h h

H

-o-ch2-ch = ch2

5

400

O

H

H

H

H

-O-n-C0Hls

29

400

O

Br

H

H

H

H

76.3

400

O

Cl

H

H

H

H

4.8

400

O

-ch3

H

H

H

H

7.6

400

O

-ch,

H

H

-2-butyl h

2nd

400

O

H

-ch3

H

H

H

26

400

O

H

-ch3

H

-n-hexyl

H

21st

400

O

-CH,

"chg

H

-2-butyl

H

3rd

400

O

-en,

-ch3

H

H

H

0

• V *

17th

TABLE V

619703

Efficacy of cycloalkano- [b] thienylurea compounds as animal growth promoters. The test results determined on mice are given as a percentage weight gain compared to the control animals.

Dose in ppm in the feed

Connection r, *

Weight gain compared to the controls in%

400

nh-co-nh-r-î

i i

• s-x

CB3 Ciï3

-CH,

15

400

h-co-nh-ro * cho

-CH,

39

400 400

400

400 50 * 100 * 200 * 400 *

C1S

trans nh-conh-rJ

<JH-CO-NH-R3l

NH-CO-NH-R-l! -

I .1

H

110

H

99

-ch3

41

-c2h5

40

H

54

-ch2-o-chs

10th

H

134

H

112

H

108

H

117

H

105

* 5 cages of 10 mice were examined per dose.

v

Claims (9)

619703 2nd PATENT CLAIMS 1. Process for the preparation of new, optionally ring-substituted cycloalkano-rb] -thiophene-ureas or -thioureas of the formula fl x, which improve the feed efficiency and the growth rate of animals I1 II n — c — nhr0 or (i) (ii) where X is oxygen or sulfur, Y is hydrogen, C, _4-alkyl or halogen, Z is hydrogen or Cj_4-alkyl, R4 is hydrogen or C ^ -alkyl, R2 is hydrogen, C1_12-alkyl, C3.0-cycloalkyl, allyl , 2-propynyl, hydroxyl, C1_0-alkoxy, allyloxy, methallyloxy, 2-butenyloxy, methoxymethyl, phenoxy, -CH2-CH2-OH, -CH2-CH20 - CH3, -CH2-CH2-S-CH3, - CH2-CH (OR1) 2, -CH2-CF3, -CH2-CN, -CH.-CO ^ j, -NH-CO ^, 25th o o ii ii -C-R ,, -C-CC1, O- ■ ch2-, c 0 c-nh-3 ■ CIL 0 > ih-c-nh-ch2- "N ■ cii2-, : n> 0H2-CIV ede * O- (CH0) -2 'n means, where n is 0, 1 or 2 and Q, if n is 0, is hydrogen, 3,4-methylenedioxy, 2-, 3- or 4-methoxy, 4-ethoxy , 4-chloro, 4-butoxy, 4-methylthio, 2,4-dimethyl, 2,4-dimethoxy, 2,4-dichloro, 4-nitro or 2-methyl-4 - bromo, if n is the Number 1 means hydrogen, 4-chloro, 4-methoxy or 3,4-methylenedioxy and, if n is 2, is hydrogen, R3 is hydrogen or C1_4-alkyl and U is a divalent radical of the formula ; C = 0, H OH or Ri Riî 55 60 means, wherein R4 and R5, which are the same or different, represent 65 hydrogen or C1_4-alkyl, characterized in that one has a molar equivalent of a compound of the formula 3rd 619703 or an acid addition salt thereof in water or an inert organic solvent at a temperature of 0 to 100 ° C with 1 to 1.5 molar equivalents of a compound of the formula r2ncx or for the preparation of compounds of the formula I or II, in which R2 and R3 are hydrogen , a molar equivalent of an acid addition salt of a corresponding compound of the formula III or IV in an aqueous medium at a pH of 5 to 7 and at a temperature of 10 to 80 ° C with 1 to 1.5 molar equivalents of a compound of the formula MeNCX where Me means sodium or potassium, and the product is isolated. 2. The method according to claim 1, characterized in that the compound of the formula III or IV is used in the form of an acid addition salt and the reaction with the compound of the formula R2NCX is carried out in the presence of an acid acceptor. 3. The method according to claim 2, characterized in that one carries out the reaction in an aromatic hydrocarbon or a chlorinated hydrocarbon as a solvent in the presence of an aqueous solution of sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate or potassium hydroxide as an acid acceptor. 4. The method according to any one of claims 1 to 3, characterized in that the eis and trans isomers when U is the rest of the formula -CHOH-, or the optical isomers of the new compounds of the formula I or II. 5. A method for improving the feed efficiency and increasing the growth rate of warm-blooded animals, characterized in that the animals are orally administered an effective amount of a new compound of formula I or II. 15 6. The method according to claim 5, characterized in that the compound in the feed is administered in an amount of 0.0001 to 0.08% by weight, based on the feed. 7. The method according to claim 5 or 6, characterized in that one draws the eis and trans isomers when U is the The rest of the formula -CHOH- means, or the optical isomers of the new compounds of formula I or II used. 8. Supplementary feed to increase growth 25 speed of poultry, fur animals and farm animals, characterized in that it contains 70 to 99 wt .-% of an edible carrier material and 1 to 30 wt .-% of a new compound of formula I or II. 9. co-feed according to claim 8, characterized in that it is an ice or trans isomer when U is the rest of the Formula -CHOH- means or contains an optical isomer of a new compound of formula I or II. 35 From US Pat. No. 3,776,924 compounds with herbicidal activity are known which have the formula 40 45 correspond, where W is ^ CH2, ^: CH-Q, -S-, ^; S (0) n so (where n is from zero to 2) or ^ NR, Z is O or S, x is zero is to 6 and R, R1 and Q are hydrogen or various substituents.