IE42039B1 - Substituted tetrahydrobenzothiophenes - Google Patents

Abstract

The novel compounds correspond to the formula: 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

This invention relates to novel substituted tetrahydrobenzothiophenes. The compounds of the present invention are cycloalkano ώ] thienylurea compounds represented by formulae (1) and (11) below: (1) (Π) wherein Z is hydrogen or ((^-C^alkyl; Y is hydrogen, ((q-C^alkyl, halogen, cyano, nitro, acetyl, acetylamino or the moiety RpNHCONH-; Rp Rg, Rp Rg, Rg, R^q and Rp are each individually hydrogen or ((^-C^alkyl; M and U are each individually divalent moieties of the formulae: \=0, 'CHOH, / / or wherein R4 and Rg are each individually hydrogen or (CpC^Jalkyl and with the proviso that M and U may not be the same except when both are ^/r4rS; ' A is a moiety of the formula R, X I1 II _ N —c—W ' 43039 which is bonded to the 4-, 5- or 7- position in formula (1) and to the 4-, 5-, or 8- position in formula (II) with the proviso that when A is bonded to tlie 5-position then M and U cannot be I ι and wherein X is a divalent radical selected from oxa(=0), thia(=S) and =N-R-|; W is selected from (C^-C^) alkylthio and a moiety of the formula with the proviso that W is (C^-C^) alkylthio only when 10 X is =N-R-j and W may not be when X is -Ν-Ri and wherein R2 and R3 are selected from the members set forth in the following table I: TABLE I *2r3 hydrogen hydrogen alJjyi Cj-C^2 alkyl C2-C4 cycloalkyl C3-Cg cycloalkyl C3-Cg allyl allyl methallyl 2-propynyl 2-butenyl 2-propynyl hydroxy -HcH2)n - alkoxy C^-Cg * allyloxy methallyloxy - 2-butenyloxy ι methoxymethyl phenoxy -ch2-ch2-oh -ch2-ch2-o-ch3 - -ch2-ch2-s-ch3 . -CBj-03(0¾¾ -ch2-cf3 -ch2-cn -CHz-CO^ -NH-COnR-, 0 J 1 II -0-¾ 0 0 -C-CCl3 - 4 42039 Table I - Continued R2R3 o -_, @0 U- ch2- qLL- ch2- υό 0 II NH-C-NH-CH,- u5 (οΊ -CH2-CH2- jgH(CH2)n- 430 3» ·> wherein, in Table I, Rj is as hereinabove defined, n is 0, 1 or 2, and Q is any one of the substituents listed in Table II belqw: TABLE II Q n = 0 n = 1 n = 2 hydrogen, hydrogen hydrogen 3,4-methylenedioxy ‘ 4-chloro 2(3 or 4)-methoxy 4-methoxy 4-ethoxy 4-chloro 4-butoxy 4-methylthio 2.4- dimethyl 2.4- dimethoxy 2.4- dichloro 4-nitro 2-methyl-4-bromo 3,4-methylenedioxy and further, when substituent A is represented by the formula: wherein and X are as hereinabove defined, and taken together with the associated Nitrogen 1s morpholino, piperidino, pyrrolidin -1-yl, 4-phenylpiperazin-l-y1, '4-(4-methoxyphenyl)piperazin -1-yl, 4-carbethoxypiperazin -Τ-yl, 4-oxopiperazin -1-yl, 1,2,3,4-tetrahydroquinolin.-1-yl or.the moiety of the formula: 'ΛΑ'®;6 J with respect to the compounds when M or U is I J^CHOH in formulae (I) and (II) hereinabove, hereinafter the 5 terms cis. and trans refer to the configuration of the hydroxyl group with respect to substituent A as defined hereinabove. The cycloalkano£bj thienylurea compounds defined by formulae (I) and (II) may be in the form of racemic mixtures or they may be optically active isomers Τθ thereof.

A preferred group of compounds within the scope of formulae (I) and (II) are represented as follows: wherein substituent A may be attached to the 4, 5 or 7(8) carbon of the cycloalkyl ring and is represented by the formula j X •I ../¾ -NH-C-N ^R3 wherein X is oxygen or sulfur and R2 and Rj taken together with the nitrogen to which they are attached are morpholino, pyrrolidin-l-yl, 4-phenylpiperazin —1-yl, 4-(4-methoxyphenyl) pi perazi n —1-yl, 1,2,3,4-tetrahydroqui no1i n — 1-yl or the moiety of the formula: and the optically active isomers thereof.

Another preferred group of compounds within . the scope of formulae (I); and (II) may be defined as ' followsi wherein A may be attached to the 4,5 or 7(8) carbon of the cycloalkyl ring and is represented by the formula: R, X ' I II ' ‘ -N—C—W wherein is hydrogen or alkyl C1-Ci}, X is oxygen, sul5 fur or NR^, W, is NR^Rj or alkylthio C^-C^ with the proviso that W is alkylthio C-^-C^ only when X is NR^ and W may not be NRjR^ when X is NR^, and the remaining substituents are as hereinabove defined.

When substituent A in the preferred group of compounds mentioned lo above is represented by the formula: x -NR1-C-NR2R3 , wherein R^ is hydrogen or alkyl C^-C^ and X is oxygen or sulfur then R^ and R^ preferably represent members independently selected from the groups listed in Table III 15 below: .,4 20 39 TABLE . III r2 R3 hydrogen hydrogen alkyl C^-Cg allyl C1-C4 5 cycloalkyl C3-C5 cycloalkyl C3~Cg allyl allyl methallyl 2-butenyl 2-propynyl 2-propynyl 10 hydroxy alkoxy G^-Cg allyloxy methallyloxy 2-butenyloxy 15 methoxymethyl phenoxy -ch2-ch2-oh -CH2-CH(ORp2 -ch2-cp3 20 -ch2-cn -nh-co2r1 0 II -C-Rj^ 0 II -C-CC13 43039 Table III Continued R2 *3 0 θθ Lojl—ch2- U-ch2- ai (CH2>n- - wherein and n are as hereinabove defined and Q is selected from the group consisting of the substituents listed in Table IV below: $203® TABLE -IV Q n - 0 n = 1 n = 2 4-chloro 3.4- methylenedioxy 2(3 or 4)-methoxy 4-ethoxy 4-butoxy 4-methylthio 2.4- dimethyl 2.4- dichloro 4-nitro 4-methyl-4-bromo hydrogen 4-methoxy hydrogen and wherein M and ,0 are as defined above; and Y and Z representmembers independently listed in Table V below.

TABLE V.

Y Z hydrogen fluoro chloro bromo iodo alkyl C^-C^ nitro CH3CONH- RjNHCONH- hydrogen alkyl C1-C4 LX The thus defined formulae (I) and (II) cycloalkano[b]thienylurea compounds may be the cis and trans i somers when M ,or U i s and racemic mixtures, or the optically active isomers thereof.

It is recognized that the compounds of the present invention may be further divided into three distinct subclasses according to the definition of M and U; i.e., when M is ^?C=O, ^CHOH or ^CR^-Rg and U is ^C=0, ^tCHOH or ''ICR.R- with the above-mentioned proviso and consequently the hereinafter described preferred groups of formulae (I) and (II) cycloalkane[b]thienylurea compounds also may be further divided into three distinct subclasses.

Another group of preferred compounds, repre15 sented by the formulae (lb) and Ub) are defined as follows: wherein Y is hydrogen or bromine; R^ to R.^, M, 0 ahd A are as defined above, with the provisos that A has to be in the4 or 7 position in formulae (lb) and in the 4 or 8 position in formula (lib), and when A is in 4 position, u cannot be ^CR^R^ when R^ and R5 are (Ci-C^)al kyl and that Rg and Rg or R-^θ and R^ cannot be (C-j-C^Jalkyl similarly when A is in the 7 Or 8 position M cannot be ^jCR^R^ when R^ and R^ are (¾ -C^)al kyl and and R? cannot be (C-|-¾ )al kyl; substituent A being repre5 sented by the formulas wherein R^ is hydrogen or (C-C^) al kyl; X is oxygen, sul10 fur or NR^; W is or (C-|-C^) alkyl thio; with the proviso that W is (CpC^) alkylthio only when X is NR^ and W cannot be NR2R3 when X is NR^.

When substituent A in the group of preferred compounds of formulae (Ib and lib) is represented by the formula R. ' X I1 II /¾ —N-C N Xr3 wherein R^ is as defined hereinabove and X is oxygen or sulfur then R2 and R3 preferably represent members independently listed in Table VI below: 43039 TABLE VI R2R3 hydrogen hydrogen alkyl C-^-Cg alkyl C3~C4 cycloalkyl C3-C4 cycloalkyl C3-Cg any! ( allyl 2-propynyl 2-propynyl hydroxy alkoxy Cj^-Cg methoxymethyl phenoxy <0>(CH2)n- 4-methoxypheny1 U-c„2- wherein n is 0, 1 or 2; the thus defined formulae (Ib) and (lib) cycloalkano[b]thienylurea compounds may be the cis and trans isomers when M and U is Xiniii ^CHOH and can be racemic mixtures of the optically active isomers thereof. Among the more preferred compounds are those cycloalkano[b]thienylureas represented by the structure (lc) below: wherein M is / or sulfur; and R2 and R3;CHOH or /C=O; X is oxygen represent members independently 43039 listed in Table VII below: TABLE VIT «2 r3 5 hydrogen < alkyl C^-Cg hydrogen alkyl C1-C4 10 allyl alkoxy C^-C^ 2-propynyl methoxymethyl hydroxy The thus defined formula (lc) cycloalkanol[b]thienylurea compounds may be the cis and trans isomers when M is CHOH and can be racemic mixtures, or the optically active isomers thereof.

AnoLner more preferred group of cycloalkano[b] · thienylurea compounds is represented by formula (lie) below: X R ll ^K2 NH-C-N (He) wherein ϋ is ^CH2, ^>CHOH or ^>C=O; X is oxygen or sulfur; and R2and Rg represent members listed in Table VIII below.

TABLE VHI r2 R3 hydrogen alkyl C^-Cg allyl alkoxy C1-C4 2-propynyl methoxymethyl hydroxy | hydrogen alkyl C2-C4 The thus defined formula (lie) cycloalkano[b]thienylurea compounds may be the cis and trans isomers 'Wijen U.is ^CHOH, and can be racemic mixtures, or the optically active isomers thereof.

An especially preferred group of cycloalkano[b]15 thienylurea compounds is represented by formula (Id) below: wherein ϋ is ^>CHOH or ^5c=O; X is oxygen Or sulfur; and R2 and Rg represent members from the groups list20 ed in Table IX below.

TABLE IX r2 «3 hydrogen hydrogen alkyl C^-Cg alkyl C1-C4 allyl alkoxy C1~C4 2-propynyl methoxyme thyl hydroxy The thus defined formula (Id) eyeloalkano[b] thienylurea compounds may be the cis and trans isomers when U is CHOH and ban be racemic mixtures, or the optically active isomers thereof.

This invention also relates to methods for the 15 preparation of the above-identified cycloalkane[b]thienylurea compounds, which may be racemic mixtures, the cis and trans isomers, when M or U is ^CHOH or the ootically active isomers thereof.

In accordance with this invention, formulae 20 (I) and (II) cycloalkanotb]thienylurea compounds wherein M, U, A, R^ to and Y and Z are defined as above with the above-mentioned provisos, can be prepared by reacting a hereinafter formula (Ie) or (lie) cycloalkano[b]thiophenamine or an acid-addition salt thereof with an ap25 propriately substituted hereinafter formula (III) isocyanate or isothiocyanate.

The reaction can be carried out using approximately equimolar amounts of the isocyanate or isothiocyanate and the amine or amine acid salt; however, it is generally preferable to employ from 5% to 50% excess of the isocyanate or isothiocyanate wherein the cycloalkano ring does not contain a hydroxyl group. The reaction can be conducted at atmospheric or superatmospheric pressure at a temperature in the range of 0°c. to 100°C., but is preferably conducted at atmospheric pressure at 0°C. to 70eC. in the presence of an organic solvent.

Suitable organic solvents include aprotic aromatic solvents suoh as benzene, toluene and xylene; chlorinated hydrocarbon solvents such as methylene chloride, chloroform and diehloroethane; ethers such as tetrahydrofuran, diethyl ether, dimethoxyethane, diethylene glycol dimethyl ether, and dioxane; lower alkyl Cj-G4 ketones such as acetone, methyl ethyl ketone, methyi butyl ketone t and methyl isobutyl ketone, or mixtures of said solvents.

When the above reaction is carried out using a cycloalkanotb]thiophenamine aoid salt, it is desirable to add an acid acceptor to the reaction mixture. Suitable acid.acceptors include trialkylamines such as triethylamine, trimethylamine, or pyridine; alkali metal carbonates, bicarbonates and hydroxides such as sodium and potassium carbonate, bicarbonate and hydroxide; alkaline earth metal carbonates such as calcium carbonate, and strong basic ion exchange resins, and aqueous alkali in a 2-phase system using an immiscible hydrocarbon solvent, such as benzene or toluene, or a chlorinated hydrocarbon, such as chloroform or diehloroethane.

The above reaction may be graphically illustrated as follows; 43039 wherein X is oxygen or sulfur; R^ to Ζ, Y, M and U are as broadly defined hereinabove, with the above-mentioned proviso.

Formula (I) and (II) cycloalkano[b]thienylurea compounds, wherein R2 and R3 are hydrogen may be advan10 tageously prepared from the above-identified (Ie) or (lie) amine or its acid salt, by reacting said amine with an approximately equimolar amount of sodium or potassium cyanate or thiocyanate; however it is generally preferable to emply 5% to 50% excess of the cyanate or thiocy5 anate wherein the cycloalkano ring does not contain a hydroxy group. The reaction can be conducted under the conditions described above in detail. Suitable solvents include water, polar solvents such as Cj-Cg alcohols, tetrahydrofuran, dioxane, ethyleneglycol dimethyl ether, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone and mixtures thereof; in the pH range of 5 to 7 and preferably at pH 6 and at 1O°C to 80°C.

The above reaction may be graphically illustrated as follows; 1 (I) (II) wherein X is oxygen or sulfur; R, to R Ζ, Y, M and 11» U are as defined above in relation to formulae I and II, with the above-metioned proviso.

Formula (I) and (IX) cycloalkano[b]thienylurea compounds ean also be prepared by reacting approximately equimolar amounts of an appropriately substituted hereinafter formula (If) or (Ilf) cycloalkano[b]thienyl isocyanate or thiocyanate and an appropriately substituted I^RgNH amine or its acid salt. The reaction can be graphically illustrated as follows: Wherein X is oxygen or sulfur; R^ to R^^ Z and Y are 25 as defined above; the group -NCX may be on the 4, 5 or position of (If) and on the 4, 5 or 8 position of (Ilf), with the proviso that M is ^CR^NCX instead of ^CR4A and ϋ is ^CR4NCX instead of ^>CR4A as defined broadly above, and when -NCX is in the 5 position M can30 not be ^>CR4NCX and U cannot be ^CR4NCX, and with the further proviso that the cycloalkano ring does not contain a hydroxyl group.

Xn practice, the reaction is usually conducted with a slight excess (i.e. up to 20% excess) of the iso5 cyanate or isothiocyanate in the presence of a solvent, such as described above. Although the reaction may be conducted at superatmospheric pressure and temperatures as high as 100°C., it is generally preferable to conduct the reaction at atmospheric pressure at a temperature between O’C. and 8O’C. When a R2R3NH amine acid salt is used it is most beneficial to introduce into the reaction mixture an acid acceptor such as described above.

When an aqueous or a C^-C3 alcoholic ammonia or amine solution is used in the above reaction sequence, then the formula (I) and (II) cycloalkano[b]thienylurea compounds are obtained, wherein R·^ is hydrogen; R2 and R3 are as defined above.

Preparation of the isocyanates (If) and (Ilf), utilized in the above reaction, are readily accomplished by reacting the appropriate cycloalkano[b]thiophenamines or their acid salt with phosgene, preferably under anhydrous conditions, e.g., a blanket of inert gas such as nitrogen. The reaction is initially carried out at a temperature between about O’C. to 40°C., preferably 10“C. to 20°C., and then heated to between about 50°C. and 100°C, and preferably to from 60°C. to 80°C, The reaction is usually also conducted in the presence of an organic solvent such as benzene, toluene or xylene.

The isothiocyanates (If) and (Ilf) can be pre30 pared by reacting the appropriate cycloalkano[bjthiophen23 amines with equimolar amounts of carbon disulfide, triethylamine, and a carbodiimide represented by the formula: G-N-C=N-G where G is cyclohexyl, cycloheptyl, or (^,765) alkyl. This reaction is generally conducted in the presence of a solvent such as tetrahydrofuran or an ether such as diethyl ether, at a temperature from -10eC. to +25°C. The product can be isolated by distillation or by dry-column chromatography, and the reaction may be illustrated as follows: Wherein M is CR^NHj in structure (Ie) and (lie) and CR^NCS in structures (If) and (Ilf) instead of CR^A respectively; U is CR^Nt^ in (Ie) and (lie) and CR NCS in (If) and (Ilf) and that the cycloalkano 4 group can only have one NH2 or NCS group; the NH2 and 4203 NCS group may be in the 4, 5 or 7 position of (le) and (If),’respectively, and in the 4, 5 or 8 position of (He) and (Ilf), respectively and G is cyclohexyl, cyclo heptyl, or C^-Cg alkyl.

Alternatively, the formulae (If) and (Ilf) iso thiocyanates can be prepared by the reaction of 1,1'-thiocarbonyldiimidazole with (Ie) and (lie) cycloalkano » [b]thiophenamines in the presence of chloroform at ambient temperature. The reaction may be illustrated as fol lows: Wherein to R^ Z and Y are defined as above: M is 30 ^>CR4NH2 in structures (Ie) and (lie) and ^CR4NCS in 420 39 structures (If) and (Ilf) instead of respectively; U is CR4NH2 in (Ie> and (He) and CRjNCS in (If) and (Ilf) and that the cycloalkano ring can only have one NH2 or NCS group; the NH2 and NCS group may be in the 4, 5 or 7 position of (Ie) and (If), respectively, and in the 4, 5 or 8 position of (lie) and (Ilf), respectively.

Advantageously, type (I) and (II) eyeloalkano[b]thienylurea compounds, wherein M or U ί s a c=0 group, can be prepared from the corresponding type (I) or (II) compounds, wherein R to R , M, U, Z and Y are 1 3 defined as above with the proviso that R2 cannot be hydroxyl and with the further proviso that M Or U cannot be C=0 by an oxidation reaction, comprising reacting a type (I) or (II) compound of the formulae: (I) (XI) with a 2 to 8 mole. equivalent and preferably with a 4 to 5 mole equivalent of an oxidixing agent selected from ceric ammonium nitrate, silver oxide, chromic anhydride or sodium bichromate, at a temperature from 0°C to 100°C., and preferably 20°C to 60°C., in a solvent selected from aqueous solutions of acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, which may contain nitric acid, phosphoric acid or perchloric acid or chromic anhydride26 -acetic anhydride followed by hydrolysis. The hereinbefore described reaction yields type (1) and (II) compounds wherein the cycloalkano ring contains a 4 or 7(8) oxo group.

Furthermore, the above type (I) and (XI) cycloalkano [b]thienylurea compounds, wherein M or U is a 0=0 group, can also be prepared by the above-mentioned oxidative process from the compounds graphically illustrated as follows; (a) (b) wherein M and U are selected from^CHj and CHOH with the proviso that M cannot be the same as U; the NH-CHO group may be in the 4 or 7 position of structure (a) and or θ position of structure (b); R to R,, are as deo 11 fined above. On completion of oxidation step, the resulting oxo compounds are hydrolyzed in a dilute mineral acid. The thus obtained amine acid salts are then reacted with an alkali metal cyanate or thiocyanate at pH 5 to 7 as hereinbefore described in detail, to yield the desired type (I) or (II) ureas or thioureas.

The corresponding 4 or 7(8) hydroxy (cis and trans isomers as defined above) analogs are prepared from the corresponding type (I) or (II) compounds where M or U can be only ^)C=0 , by reduction with equimolar or excess amounts of sodium borohydride, at a temperature v4 2 Ο 3 9 _ range between from 0°C to 75°C., and preferably 20°C to 40°C., in C-|-C3 alcohols to afford a mixture of the cis and trans isomers.

All of the hereinbefore described preparation of type (I) and (II) cycloalkano[§thienylurea compounds yields racemic (dl) mixtures. g Should the optically active isomers of type (I) and (II) compounds be desired, these may be conveniently obtained by the resolution of the racemic (dl) amines (Ie) or (lie) with (R) -(+)- and (S)-(-)-N- benzoylglutamic acids, respectively in sequence, and using the thus obtained optically active amines (Ie) or (lie) in one of the hereinbefore described reactions leading to type (I) or (II) cycloalkanol[b)thienylurea compounds of the present invention.

Compounds of formula (I) and (II) wherein A is -- N — C—S — R where R is (C^-C^jalkyl and R·] is H or (C^-C^)al kyl, can be made by a process comprising alkylating one mole ρπιι -i va 1 pnf nf a rnmnniind nf fhp -FnrniiilAp with from 1 to 1.5 mole equivalents of an inorganic acid ester of a C^-C^ alkanol in a solvent inert to the reaction at 0° to 75°C. for a period of time sufficient for a substantial degree of alkylation to take place. The inorgani acid ester is preferably selected from (C^-C4)alkyl bromides, (C-|-C4)alkyl iodides and di (C^-C4)alkyl sulfates. b Certain intermediate compounds used in the preparation of the formulae I and II compounds of this invention are believed to be novel per se. These compounds have the following formulap: wherein R-| Y and Z are as defined above in relation to formulae I and II Compounds of this invention are useful as growth-promoting agents for animals such as poultry, fur-bearing and farm animals, and the use of said compounds for this purpose provides the added advantage of improving feed conversion for said animals., As used herein, the term f'eed conversion means the ratio of unit weight of feed per unit weight of gain and improvement in feed conversion means increased weight gain for a given unit of feed consumed.

In practice, a growth-promoting amount of a formula (I or II) cycloalkano[bj/thienylurea or an optically active isomer is administered to a host animal usually in, or with, the animal's feed. However, said compound may also be administered as a subcutaneous implant under the skin of said animal or as a parenteral injection. When administered in the feed of e.g. chickens, turkeys, sheep, cattle and goats, usually 0.0001% to 0.08% by weight, and preferably 0.001% to 0.04% by weight of the formula (I or II) urea is effective for increasing growth rate and improving feed conversion. The formula (I or II) urea may be added to the animal feed in the form of a pre-mix comprising 10 to 99% by weight of edible carrier and 1 to 30% by weight of the urea when administered to said animals as a parenteral injection or subcutaneous implant, usually in amounts that will supply O.OOlmg. to 0.2mg. and preferably 0.005mg. to O.lOmg. per kg. of body weight per day of the active compound, will produce the desired improvement in weight gain and enhance food conversion.

In tests conducted with day old chicks, if was found, that from 1 ppm to 9 ppm of 4,5,6,7-tetrahydrobenzo[bl thien-4-ylurea administered in the chick feed produced a 3.3% to 6.6% improvement in weight gain over untreated controls, and likewise produced a 2.7% to 4.7% improvement in feed conversion.

Compounds of this invention are also useful as herbicidal agents. Said compounds are effective for controlling undesirable broadleaf and grass weeds when applied to soil containing seeds of said undesirable weeds, or when applied to the foliage of such plants. Usually 5 pounds to 15 pounds, and preferably 8 pounds to 10 pounds per acre of the active compound, is sufficient to provide control of the undesirable plants.

The invention is illustrated by the Examples which follow and which describe the preparation of representative compounds as well as animal growth testing data on typical compounds of the invention (Examples 32, 66 and 67). Examples 17-19, 21, 23, 24, 27, 28, 30, 33, 36, 37, 54 and 61 relate to the preparation of intermediates.

EXAMPLE 1 Preparation of 1-methyl-3-(4,5,6,7-tetrahydrobenzo [b]thien-4-yl)urea A mixture of 1.89 grams (0.01 mole) of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. of dry benzene is stirred while 1.05 grams (0.01 mole) of triethylamine and 01.7 ml. (excess) of methyl isocyanate are added successively. Addition of the latter gives rise to an exotherm, and the mixture becomes very pasty. The mixture is kept at 45°C. for one hour, and after cooling to room temperature, the solid is collected, washed thoroughly with benzene and then with water. On drying, this gives 1.7 grams (81%) of product, melting point 183°C. to 186°C. Recrystallization from acetone gives 1.23 grams, melting point 187.5°C. to 189°C. jb On a 0.05 mole scale, the crude yield is 83% (9.15 grams), and the product melts at 181eC. to 186°C. Recrystallization from acetone gives 6.5 grams, melting point 184.5°C. to 187°C.

EXAMPLE 2 Preparation of l-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl) urea In the manner described in Example 1, ethyl isocyanate is allowed to react with 4,5,6,7-tetrahydrobenzo [b] thiophen-4-amine hydrochloride to afford 10.1 grams of l-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. 2a Recrystallization of the crude product from 2-propanol-water (9/1) affords crystals which are dissolved in chloroform and washed successively with IN sulfuric acid, water and saturated sodium bicarbonate solution. This gives the desired product, melting point 184°C. to 188.5°C. 3Q after evaporation of the chloroform.

\ · .. Zf.. · - · .

EXAMPLE 3 Preparation of l-isopropyl-3-(4,5,6,7-tetrahydrobenzo [b]-4-yl) urea~ i. In a nitrogen atmosphere, 5.35 grams of 4,5,6,75 -tetrahydrobenzo[b]thiophen-4-amine is stirred in 100 ml. of diethyl ether, and 3.57 grams of isopropyl isocyanate in 40 ml. of diethyl ether is slowly added to afford crystalline product. The mixture is stirred for an additional 0.5 hour and then filtered after Standing overnight to give 8.3 grams, melting point 223°C. to 226°C., of l-isopropyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

EXAMPLE 4 Preparation of l-(n-hexyl)~3-(4,5,6,7-tetrahydrobenzo[b]tiiien-4-yl)urea In the manner described in Example 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is allowed to react with n-hexyl isocyanate to give l-(n-hexyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 122°C. to 124 °C.

EXAMPLE 5 Preparation of l-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien- 4-yl) urea In a similar manner, as described in Example 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochlor25 ide is allowed to react with cyelohexyl isocyanate in dry tetrahydrofuran to afford 7 grams of 1-oyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 222°C. to 225°C.

EXAMPLE 6 Preparation of l-methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea A mixture of 5 grams of methoxyamine hydrochlor5 ide in 60 ml. of methylene chloride is cooled to about °C., and 6 grams of triethylamine in 15 ml. of methylone chloride ,is added’. After 20 minutes, 5.38 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate in 20 ml. of methylene chloride is added over 20 minutes at 15°C. to 20°C. After stirring for an hour, the mixture is ( filtered, and the filtrate is washed with water and then aqueous sodium bicarbonate solution. The solution is dried and evaporated to afford a white solid. The solid is recrystallized from acetone-hexane to afford 5.1 grams, melting point 138.5°C. to 141°C., of 1-methoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.

Similarly, l-ethoxy-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea and 1-butoxy-3-(4,5,6,7-tetrahydrobenzo [b] thien-4-yl) urea are prepared by using ethoxyamine hydrochloride and n-butoxyamine hydrochloride, respectively, in place of methoxyamine hydrochloride.

EXAMPLE 7 Preparation of l-(benzyloxy)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea In the manner described in Example 6, 0-benzyl hydroxyamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to afford 1-(benzyloxy)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is recrystallized from 95% ethyl alcohol-methyl isobutyl ketone. The product melts at 96.5°C. to 99°C. 43039 EXAMPLE 8 Preparation of l-hydroxy-l-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl) urea In the manner described in Example 6, N-methyl5 hydroxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to afford 1-hydroxy-1-methyl-3(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, which is recrystallized from acetone-hexane-ether to give crystals, with melting point 98°C. to 102 °C.

EXAMPLE 9 Preparation of l-methoxy-l-methyl-3-(4,5,6,7-tetrahydro benzo [bj thien-4-yl) urea Following the procedure described in Example 6, Ν,Ο-dimethyl hydroxylamine hydrochloride and 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate are allowed to react to give l-methoxy-l-methyl-3-(4,5,6,7-tetrahydrobenzo [b] thien-4-yl) urea, which is crystallized from acetone-hexane-ether to give product melting at 60°C» to 62.5°C.

EXAMPLE 10 Preparation of 4,5,6,7-tetrahydrobenzo [h.]thien-4-y lurea A mixture of 50 grams of amine hydrochloride (about 45 grams real, based on 90% purity) in 100 ml. of water is.stirred at about 15°C., and a solution of 23.1 grams of potassium cyanate in 100 ml. of water is added dropwise. After completion of the addition, the mixture is warmed slowly to 70°C. to 75°C. and held for an hour. The mixture is cooled, and the white solid is collected by filtration and washed with water. The solid is air34 -dried, pulverized, and washed with acetonitrile. On drying, this gives 37.3 grams of crude product, which on treatment with about 1200 ml. of hot acetone gives 11.45 grams, melting point 200°C. to 204°C. of the title compound.

Similarly, 2-methyl- and 3-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea are prepared to give produots melting at 23?-233°C. and 227-230°C. (dec.), respectively. When N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is used, 1-methyl-1'-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 151.5-154.5°C,, is obtained.

EXAMPLE 11 Preparation of l-phenethyl-3-(4,5,6,7-tetrahydrobenzotb]thien-4-yl)urea~ A mixture of 3.82 grams of phenethylamine in 100 ml. of diethyl ether under nitrogen atmosphere is allowed to react with 5.38 grams of 4,5,6,7-tetrahydrobenzo[bJthien-4-yl isocyanate in 25 ml. of diethyl ether via dropwise addition of the latter solution. After stirring an hour at room temperature, the mixture is filtered and washed with ether to give 7.9 grams, melting point 163°C. to 166°C.,lof 1-phenethyl-3-(4,5,6,7-tetrahydrObenzo[b]thien-4-yl)urea.

In a similar memner, methylamine, ethylamine, isopropylamine, n-hexylamine and cyclohexylamine are allowed to react With the aforementioned isocyanate to afford Ι-methyl-, Ι-ethyl-, 1-isopropyl-) 1-hexyl- and 1-cyclohexyl-3-(4,5,6,7tetrahydrobenzo[b)thien-4-ylurea.

EXAMPLE 12 Preparation of 1,l-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea A solution of 6.27 grains of 4,5,6,7-tetrahydro5 benzo[b]thien-4-yl isocyanate in 200 ml. of diethyl ether is charged with gaseous dimethylamine introduced via a capillary tube with stirring. After 0.5 hour of bubbling, the gas flow is terminated, and the mixture is evaporated to dryness to give a solid residue. This is crys10 tallized from acetone-hexane-ether to give 1,1-dimethy1-3-(4,5,6,7-tetrahydroben2o[b]thien-4-yl)urea melting at 117°C. to 120°C.

The identical product is obtained when 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is allowed to react with equivalent amounts (or excess) of dimethylcarbamoyl chloride and triethylamine in dimethylformamide. The reaction mixture is stirred for several hours and theft filtered. The filtrate is evaporated to dryness and the residue is purified by crystallization from acetone-hex20 ane to afford the title compound.

EXAMPLE 13 Preparation of l-benzyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl) ureaIn the manner described in Example 6, except for the use of diethyl ether instead of methylene chloride, l-benzyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yi)urea is obtained by allowing benzylamine and 4,5,6,7-tetrahydrobenzo [b] thien-4-yl isocyanate to react. The product melts at 211°C. to 214°C.

The title compound is also obtained by allowing - 36 43039 ν ι I benzyl isocyanate to react with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in ether.

EXAMPLE 14 Preparation of l-hydroxy-3-(4,5,6,7-tetrahydrobenzotb]thien-4-yl)urea ~ The above compound is prepared in the manner described in Example 6, by allowing 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate to react with hydroxylamine hydrochloride in the presence of triethylamine. The product melts at 158.5°C. to 160.5°C.

EXAMPLE 15 Preparation of N-(4,5,6,7-tetrahydrobenzo[b)thien-4-yl) -4-morphollnecarboxamide—— In the manner outlined in Example 6, except 15 for using diethyl ether instead Of methylene chloride, 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is allowed to react with morpholine to give N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-4-morpholinecarboxamide, which melts at 152°C. to 154°C.

EXAMPLE 16 Preparation of 2-bromo-4,5,6,7-tetrahydrobenzo[bJthien-4-ylurea_2A sample of 7.84 grams of 4,5,6,7-tetrahydrobenzo(b)thien-4-ylurea is dissolved in 72 ml. of acetic acid, and 24 ml* of water is added. Bromine (2.3 ml. or 7.05 grams) in 32 ml. of acetic acid is added dropwise. The mixture is stirred at room temperature for 0.5 hour, and then 7.23 grams of sodium acetate in 40 ml. of water is added. An additional 120 ml. of water is added and stirring is continued for 0.5 hour. The white solid is collected, washed with water and cold sodium acetate solution to give 9.8 grams, melting point 206.5°C. to 209.5°C., of 2-bromo-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.

EXAMPLE 17 Preparation of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine A sample of 54.3 grams of N-formyl-4,5,6,7-tetrahydrobenzo [b]thiophen-4-amine is stirred in 270 ml. of acetic acid and 90 ml. of Water. Bromine (53 grams) in 120 ml. of acetic acid is added gradually. After stirring for 0.5 hour at room temperature, 61.5 grams of sodium acetate in 225 ml. of water is added. More water is added, and the mixture is extracted with ether. Methylene chloride is added to the ether solution to prevent crystallization, and the solution is evaporated to dryness. The residue is crystallized from acetone-hexane· -ether to afford 61 grams, melting point 104°C. to 108°C. of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo [b]thiophen-4-amine.

EXAMPLE 18 Preparation of 2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b] thiophen-4-amine A mixture -of 40.9 grams of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, 16.2 grams of cuprous cyanide and 47 ml. of dry dimethylformamide is heated at reflux temperature for 4 hours, and then cooled to about 60°C. and poured into 270 ml. of water. The mixture is extracted with toluene several times, and the toluene extracts are washed with 1.2N hydrochloric acid and saturated sodium chloride, respectively. On drying, 5.7 grains of crude product is obtained. The aqueoue mother liquor is treated with 97.3 grams of ferric chloride hexahydrate and 30 ml. of concentrated hydrochloric acid and shaken. It is then extracted with toluene several times, and the extracts are washed further with 1.2N hydrochloric acid, saturated sodium bicarbonate solution and brine, respectively. On drying and evaporation of toluene, an additional 2.5 grams of product is obtained. The two crops are combined and recrystallized from acetone-hexane to afford 4.8 grams of 2-oyano-N-formyl-4,5,6,7-tetrahydrobenso[b]thiophen-4-amine, melting point 131°C. to 134°C.

EXAMPLE 19 Preparation of 2-cyano-4,5,6,7-tetrahydrobenzo[bjthiophen-4-amine hydrochloride .

A mixture of 4.8 grams of 2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 70 ml. of IN hydrochloric acid Ib refluxed for an hour and evaporated to dryness to afford 4.7 grams of 2-cyano-4,5,6,7-tetrahydrobenzo [b]thiophen-4-amine hydrochloride, melting point 241°C. to 246°C.(dec.).

EXAMPLE 20 Preparation of 2-cyano-4,5,6,7-tetrahydrobenzo[b]thien-4-yiurea The desired product, 2-oyano-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, is prepared in the manner described in Example 10 by allowing 2-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-4-amine hydrochloride to react with potassium cyanate. The crude product melts at 210°C, to 214°C., and the product which is recrystallized from nitromethane melts at 209°C. to 213°C.

EXAMPLE 21 Preparation of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thio_phen-4-amine_“_ A sample of 11.4 grams 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 150 ml. of chloroform at about 10°C., and 6.1 ml. of sulfuryl chloride is added dropwise. The mixture is stirred for 3.5 hours at room temperature, and then about 20 ml. of 50% sodiuitt hydroxide solution is added gradually to dissolve the suspended solid. The mixture is then poured into water and extracted with chloroform twice. The extracts are dried, evaporated to dryness, and the resi15 due is distilled to give 7.4 grams of 2-chloro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine, boiling point 94 °C. to 98°C/o.5 Torr.

EXAMPLE 22 Preparation of 2-chloro-4,5/6/7-tetrahydrobenzo[b]thien_-4-yl-urea_ The desired product, 2-chloro-4,5,6,7-tetrahydrobenzo [b]thien-4-ylurea, is prepared in the manner described in Example 31 by allowing 2-chloro-4,5,6,7-tetrahydrobenzO[b]thiophen-4-amine to react with hydrocyanic acid in situ. The product melts at 194eC. to 198°C.

EXAMPLE 23 Preparation of N-(2-acetyl-4,5,6,7-tetrahydrobenzo[b] thien-4-yl)acetamide N-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-430 amine (19.5 grams) is stirred in 300 ml. of methylene - 40 42039 chloride in a nitrogen atmosphere, and 17 ml. of acetyl chloride is added. The mixture is cooled to about 10°C., and 28.1 ml.' of stannic chloride is added slowly. After stirring for 1.5 hours at room temperature, the mixture is cooled to about 10eC., and 450 ml. of 1.2N hydrochloric acid is added. The mixture is shaken, and the methylene chloride solution is separated and washed with IN hydrochloric acid, followed by saturated sodium bicarbonate solution. On drying and evaporating to dryness, crystals are obtained. Recrystallization from acetone-hexane gives 15.4 grams, melting point 167.5°C. to 172°c., of N-(2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide.

EXAMPLE 24 Preparation of 2-acety1-4,5,6,7-tetrahydrobenzotb]thio'phen-4-amine hydrochloride ~ The product from Example 23 (7.25 grams) is heated with 90 ml. of IN hydrochloric aoid at reflux temperature for 8.5 hours and cooled. The mixture is diluted with water and extracted with methylene chloride.

The aqueous layer is then evaporated to dryness using 2-propanol for facilitating removal of water. This gives 4.85 grams of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophene-amine hydrochloride.

EXAMPLE 25 Preparation of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl-urea_2 A sample of 6.3 grams of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is dissolved in 35 ml. of water and cooled to 15®C, A solution - 41 43039 of 2.64 grams of potassium cyanate in 35 ml. of water is added, and after 0.5hour the mixture is heated at 70°C. for about 40.minutes. The mixture is cooled, and the solid is collected and washed with water. On drying, .55 grams, melting point 218°C. to 220°C., of 2-acetyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is obtained.

EXAMPLE 26 Preparation of 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[blthien-4-yl)thiourea A sample of 9.48 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is stirred in 100 ml. of dry tetrahydrofuran, and 6.06 grams of triethylamine is added. After stirring for 15 to 30 minutes, .23 grams of ethyl isothiocyanate in 20 ml. of dry tet15 rahydrofuran is added dropwise, and the mixture is heated for 2 hours at 50°C. The mixture is cooled and filtered, and.the filter cake is washed with hexane. The filtrate is evaporated to dryness and poured on ice.

The oil is extracted with ether, and the extract is wash20 ed with IN sulfuric acid, water, and saturated sodium bicarbonate solution. The ether extract is dried and evaporated'to dryness to afford an oil. This oil crystallizes in ether to afford 1-ethyl-3-(4,5,6,7-tetrahydrob.enzo [b]thien-4-ylJthiourea, melting point 106°C. to 112°C.

Similarly, use of methyl isothiocyanate, butyl isothiocyanate and cyclohexyl isothiocyanate affords 1-methyl·-, 1-butyl- and 1-cyclohexy1-3-(4,5,6,7-tetrahydrobenzo [b]thien-4-yl)thioureas.

EXAMPLE 27 Preparation of 4,5>6,7-tetrahydrobenzo[b3thiophen-4-amine A sample (61.2 grams) of 4,5,6,7-tetrahydrobenzo [b] thiophen- 4 -amine hydroohloride is suspended in 150 ml. of water, and about 400 ml. of 10% aqueous ammonium hydroxide is added to the mixture. The alkaline mixture is then extracted twice with ether, and after drying the ethereal solution is evaporated tc dryness.

The amine is then distilled to give 40.9 grams, boiling point 100»C. to 102°C. at 3 Torr., of 4,5,6,7-tetrahydrobenzo(b]thiophen-4-amine.

EXAMPLE 28 Preparation of (-)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ammonium (R)-N-benzoyl glutamate , A mixture of 8.04 grams of (R)-(+)-N-benzoyl glutamic acid.in 1.92 grams 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 grams of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added gradually. About 2 ml. of ethanol is used in the transfer as a rinse for the amine. The mixture is then allowed to cool to room temperature and to stand overnight.

The mixture is cooled in a refrigerator, filtered to collect the crystals, and the filter cake is washed with water several times. Oh drying, this gives 9.27 grams of the title salt, melting point 192°C. to 194»C.; [al”9 -9.39», [«]436 -44.6», (α]365 -71.4» at c4.475 in acetic acid.

The original filtrate is concentrated under reduced pressure to a small volume and partitioned be- 43 tween diethyl ether and aqueous sodium hydroxide. The aqueous base is extracted with ether, and this ether extract is combined with the first ether fraction. This is then dried over magnesium sulfate, evaporated to dry5 ness to afford the recovered amine, and the amine is added to a stirred, hot solution of 8.04 grams of (S)-(-)-N-benzoyl glutamic acid in 1.92 grams of acetic acid and 80 ml. of water. Crystallization occurs rapidly, and after 10 minutes of heating on a steam bath, the mixture is allowed to cool in a refrigerator. The crystals are. collected, Washed with water and dried to afford 11.1 grams of (+)-4,5,6,7-tetrahydrobenzo(b]thiophene-4-ammonium (S)-N-benzoyl glutamate salt, melting point 192°C. to 193.5°C.; (alggg +12.2°, +42.7°, [^355 + 82° at c = 4.35 in acetic acid.

EXAMPLE 29 Preparation of (-)-4,5,6,7-tetrahydrobenzo[b)thien-4-ylurea The salt (8.8 grams of 4,5,6,7-tetrahydrobenzo20 [b)thiophen-4-amine (R)-(+)-N-benzoyl glutamic acid) is added to ice water mixture is a separatory funnel, and 3.5 grams of sodium hydroxide in 55 ml. of water is added. The mixture is shaken until a solution is obtained, and then is extracted with diethyl ether twice. The ether extracts are washed with saturated sodium chloride Solution, and with ice added the mixture is extracted with 2.36 ml. of concentrated hydrochloric acid in 25 ml. of water. The acid layer is then treated with 2.29 grams of potassium cyanate in 30 ml. of water at 20°C. After stirring for an hour, the mixture is heated to 0.5 hour - 44 42039 and cooled- The product is collected by filtration, washed with water, and dried to give 2.75 grams, melting point 218.5’C. to 221.5°C.; [a]g|9 -63.2°, [a]43g -149.9°, [a]jgg -271.5°, of (-) 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.

Similarly, the salt of 4,5,6,7-tetrahydrobenzo-[b]thiophen-4-amine and (S)-(-)-N-benzoyl glutamic acid is treated in the above manner to afford (+)-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point 218°C·. to 220°C.,< la]||9 +60°, (a]436 +149.8°, [a)365 +272.5°.

EXAMPLE 30 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl iso cyanate ~ A sample of 47.6 grams of 4,5,6,7-tetrahydrobenzo [b]thiophen-4-amine hydrochloride is stirred in 150 ml. of water, and 350 ml. of 10% sodium hydroxide is added. The mixture is shaken and extracted with benzene twice. The extract is dried and evaporated to dryness to afford the amine, which is stored under nitrogen. The amine is then added dropwise to 866 ml. of 12.5% phosgene solution (benzene) in nitrogen atmosphere at 20°C* After stirring for an hour at room temperature, the mixture is gradually heated to 60°C. and kept at this temperature for 7 hours. The mixture is cooled to room temperature and evaporated to dryness to afford a residue, which is distilled to give 22.4 grams, boiling point 98°C. to 101°C/0.6 Torr., of 4,5,6,7-tetrahydrobenzo[bjthien-4-yl isocyanate.

EXAMPLE 31 Preparation of 4,5,6,7-tetrahydrobenzo[b)thien-4-ylurea X A sample of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (19.9 grams) is cooled in a flask, and a Solution of 12 ml. of 12N hydrochloric acid in 50 ml. of water is slowly added. Subsequently, at about 20”C., a solution of 11.7 grams of potasstium cyanate in 80 ml. of water is added in 0.5 hour. The mixture is stirred at room temperature for one hour and then warmed to 60°C. and kept at this temperature for 0.5 hour. After standing Overnight at room temperature, the product is collect10 ed and washed with water to afford 21 grams, melting point 206°C. to 209°C.

EXAMPLE 32 Mouse Growth Regulant Tests CFI female mice from Carworth Farm ate receiv15 ed when they are six weeks old. They are housed ten to a cage in air-conditioned rooms (72°F. to 76°F.) with automatically controlled lights, 14 hours on and 10 hours off. The basal diet used in these studies is Purina Laboratory Chow (see description below), which is Supplied ad libitum. Water is also allowed ad libitum.

Thirteen days after arrival, the mice are weighed in groups of ten and assigned at random to the different treatments. The concentration of the different compounds in the diet is indicated in the following Tables.

Twelve days later the mice are weighed again and the experiment terminated. At least three cages (30 mice) of untreated controls are included'in each test. Test data are provided in Table XI below wherein data are reported as percent weight gain over controls. The following is a description of the diet to which the growth promot46 ing compounds are added.

DIET GUARANTEED ANALYSIS Crude protein not less than.............23.0% Crude fat not less than................. 4.5% Crude fiber not more than............... 6,0% Ash not more than....................... 9.0% INGREDIENTS Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground extruded corn, ground oat groats, soybean meal, dehydrated alfalfa meal, cane molasses, animal fat preserved with BHA, vitamin Bn, supplement, calcium pantothenate, choline chloride, folic acid, riboflavin supplement, brewers' dried yeast, thiamin, niacin, vitamin A supplement, D activated plant sterol, vitamin E supplement, calcium carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, iron oxide, manganous oxide, cobalt carbonate, copper oxide, zinc oxide. rt - 47 ib 42039 W ti ω flj 4J Φ Xl H ρ σ» ti 3Ή e f-l CD Ή 4J I G-P craw G) ϋ O •Η M Ei XJ Φ 3 & Φ λΙμ 5 — m ο M n Ό rt fi β 0 .. 0 H P rt O rd 0 ε «Ρ·Η - 48 42039 Table χ - Continued - 50 I Table X - Continued Table X - Continued Table X - Continued Table X - Continued - 54 1 Table X - Continued - 55 1-. 43039 - 56 43039 Table X - Con-tinged - 57 42039 - 58 I Table X - Continued •P x: to tn tri -rt Φ ω s Ό C -P H fi fi φ ο Φ g Λ ϋ-rt g rt fi Ο Φ < ta w w Φ Φ Φ U Eh ati «Μ φ φ >ί·ΡΛ fi rt 44 Φ O •rt 04 tfl JS Φ (ri 44 CU ,-. φ £'J5.3 oca c ffl nJ fr Cn A! < e H *rt Φ & ra O fi D H «rt O 44 (fl &i3 Ο M O ft C 0 ra λ u ra +> ffl h C 0 ffl ffl M > > U O •H μ h c Ο (8-H ffl B 18 Table X..a - Continued - 61 ) 43039 Table 43039 Table X..a - Continued - 61 I able - 62 4203 1 EXAMPLE 33 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isothiocyanate A sample (47.5 grains) of 4,5,6,7-tetrahydrobenzo 5 [b]thiophen-4-amine hydrochloride is stirred in methylene chloride-water and 5% sodium hydroxide solution is added gradually until the pH is about 10. The methylene chloride layer is removed and the aqueous layer is extracted with methylene chloride. The organic layers are combin10 ed, dried over magnesium sulfate, and evaporated to dryness to afford the oily amine. The amine is stirred in 500 ml. of ethyl acetate under nitrogen atmosphere and .4 grams of triethylamine is added. After about 15 minutes, 20.9 grams of carbon disulfide is added to af15 ford a copius precipitate. An additional 200 ml. of ethyl acetate is added and the solid is pulverized with a spatula. After an hour of stirring, 51.5 grams of dicyclohexyl carbodiimide is added and stirring is continued for an overnight period. Subsequently, the mixture is heated at about 50°c. for 2 hours and cooled. The solid is removed by filtration and washed with ethyl acetate. The filtrate is evaporated to afford a mixture of solid and mostly oil. The solid is removed by filtration after ether is added. The ether filtrate is evap25 orated to dryness to afford the crude isothiocyanate, which is purified by chromatography on a dry-column of silica gel using 65/35 (volume/volume) of petroleum ether/methylene chloride.

EXAMPLE 34 Preparation of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)piperidinethiocarboxamide In 50 ml. of tetrahydrofuran, 5.85 grams of 5 4,5,6,7-tetrahydrobenzo[f]thien-4-yl isothiocyanate is stirred and 2.81 grams of piperidine is added. An exotherm is observed and the temperature rises to about 40°C. to 50°C. After 2.5 hours, the mixture is heated at reflux temperature for 3.5 hours. After stirring overnight, the mixture is evaporated to dryness to afford a sticky yellow-brown solid. Ether is added to this material and the off-white, insoluble product is collected. The crude product, 5.25 grams, melts at 102°C. to 104°C.

EXAMPLE 35 The following compounds set forth in Table XI below are prepared by using the methods described in Example 3 and Example 5 and using the corresponding amines (diethyl ether solvent) or amine hydrochlorides (tetra20 hydrofuran solvent) with the appropriate isocyanates or isothiocyanates. - 64 43039 TABLE XI. 43039 4> ♦So PM Φ Φ O' U C O' •H QJ •P *0 K Φ β r4 in ro O' O KT to O' K Ol 09 ro CO tO tn o O' OJ H rd OJ H H O' H H H to r*4 ( I 1 ί 1 1 •H 1 1 1 J σ\ OJ o\ f*. CO *4* 0 © ro to tn © OJ CO OJ O' ^a· o to Ol «-Ί r4 OJ i-4 r4 H H ι—I β Ο «Ρ Ή β •μ φ ϋ > Φ Η ’ Ο ω Μ Φ Λ •Ρ Φ Μ Φ Λ •Ρ Φ Λ +1 ω fo Φ fo fo fo a Λ a a 53 e< 4J E< E< e< φ ο» Ο OOOMOWWW Table XI - Continued a a a aaaaaaaa aa a asaaaaaw aa a aaaaaaaa - 66 I 43039 Table XT ' - Continued Table XI - Continued - 70 42039 Table XI - Continued 43039 Table XI - Continued -Cl CH,C1O 216-217 d O O Λ ® V tn M C tn •d V 4J >0 rd 2-5 σ\ CO . CO1 O tn Ci P*· rd rd <*) rd rd rd a CJ H | rd I 1 tn 1 m 1 C* 1 ci 1 a Ci c* o rd ci rd rd rd Cl rd rd m Cl in m © Ci ci Ci Ci 1 1 1 1 rd H ci o m * © Ci Ci Ci CJ Table XI - Continued - 73 I Table XI - Continued EXAMPLE 36 Preparation of 4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophen-4-amine hydrochloride 2,3-Dimethyl-6,7-dihydro-5H-benzo[b]thiophen-4-one is prepared in the manner described by Napier and Chu [International Journal of Sulfur Chemistry, A, 62-64 (1971) ]. This ketone is converted to 4-formylamino-4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophene by the method described by Kloetzel, Little, and Pish [Journal of Organic Chemistry, 18, 1511-1515 (1953)]. Hydrolysis of this formamido derivative is accomplished by using the method described in Example 19 to afford 4,5,6,7-tetrahydro-2,3-dimethylbenzo[b]thiophen-4-amine hydrochloride.1 3-Methyl-6,7-dihydro-5H-benzo[b]thiophen-4-one is prepared similarly and converted to 3-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride by the above sequence. ί EXAMPLE 37 Preparation of 2-methyl·—' 4,. 5,6,7-tetrahydrobenzo [b] thiophen-4-amine hydrochloride 2-Methylthiophene is converted to 2-methyl-6,7-dihydro-5H-benzo[b]thiophen-4-one by the method described by Fieser and Kennelly [Journal American Chemical Society, 57, 1611 (1935)]. This ketone is further converted to 2-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride by the methods cited in Example 36. .

EXAMPLE 38 Preparation of 1-methyl-3-(4,5,6,7-tetrahydrobenzo [b]thien-7-yl)urea 4,5-Dihydro-6H-benzo[b]thiophen-7-one is prepared by the method of MacDowell and Greenwood [Journal of Heterocyclic Chemistry, /, 44 (1965)J and converted to 4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine hydrochlor5 ide, melting point 209°C. to 212°C., by the methods cited in Example 36. The'amine hydrogen· chloride salt is then treated with potassium cyanate in the manner described in Example 10 to afford 4,5,6,7-tetrahydrobenzo[b]thien-7-ylurea, melting point 211°C. to 213 °C.

Conversion of the amine salt to l-methyl-3-(4,~ ,6,7-tetrahydrobenzo[b]thien-7-yl)urea, melting point 192°C. to 195°C. is accomplished by using the procedure of Example 7.

EXAMPLE 39 Preparation of 2-nitro -4,5,6,7-tetrahydrobenzo[b].thien-4-ylurea Acetic anhydride (30.8 ml.) is cooled to -10°C. to -12 °C. and to the stirred solution is added dropwise 70% nitric acid (4 g. or 44.5 mmol). Over a period of 0.5 hour, N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine (7.24 grams or 40 mmol) is added and the mixture is allowed to warm to room temperature over 2.5 hours and poured onto ice-water mixture (200 ml.). After stirring overnight, the sticky solid is filtered off and washed well with water. The air-dried, dark, sticky solid is triturated with ether ('-'-'20 ml.). and the resulting nitro compound is filtered and washed with ether (10 ml.). The product, 2-nitro-N-formy1-4,5,6,7-tetrahydrobenzo [b]thiophen-4-amine, melts at 116°C. to 120°C. and weighs 3.25 grams.

Hydrolysis of the above formamide is accomplished by the method described in Example 19 to afford 2-nitro-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrogen chloride, melting point ^>2 60 °C; infrared spectrum shows NOj bands at 1520 cm”'' and 1335 cm”'” Conversion of the amine hydrogen chloride salt to 2-nitro-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is accomplished by the method described in Example 10. It melts at 211°C. with decomposition after recrystallization for MeOH^ EXAMPLE 40 Preparation of l-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydrobenzo [b]thien-4-yl) urea By the method of Kloetzel, Little, and Pish [Journal of Organic Chemistry, 18, 1511 (1953)], 4,5,6,7-tetrahydro-4-methylbenzo[b]thiophen-4-ol is prepared and dehydrated with fused sodium hydrogen sulfate by heating to afford 6,7-dihydro-4-methylbenzo[b]thiophene, boiling point 75°/0.9 Torr. This olefin (3 grams) is stirred with 3.9 grams of silver isocyanate in 50 ml. of dry ether under N2 atmosphere at -10eC. and 5.07 grams of iodine is added. After stirring for 1.25 hour at -10°C. to 0°C. and then at 10°C to 15°C. for 1.5 hours, the mixture is filtered over diatomaceous earth and the filter cake is washed with ether thoroughly. The filtrate is then treated with 2 ml. of 40% aqueous methyl amine to afford 1.62 grams, melting point 122°C. to 123°C., of l-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydrobenzo[b]thi en—4-yl)urea.

EXAMPLE 41 Preparation of 1-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo [b]thien-4-yl)urea Deiodination of l-methyl-3-(5-iodo-4-methyl5 -4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea is accomplished by treating a methanol mixture of this compound with Palladium on carbon and magnesium oxide in a P'aar hydrogenator at 50 psig. After uptake of the hydrogen is completed, the mixture is filtered through diatomaceous . earth and filtrate is evaporated to dryness to afford l-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 135°C. to 145°C.

EXAMPLE 42 Preparation of l-methyl-3-(5,6„7,8-tetrahydro-4H-cyclohepta [b] thien-'4-y1 )urea “ -:5,6,7,8-Tetrahydro-4H-cyclohepta[b]thiophen-4-one is converted to N-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)formamide, melting point 164°C. to 166°C.> by method described in Example 36 (second reference).

Hydrolysis of the formamide is accomplished by the method described in Example 19 to afford 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride, melting point 233°C. to 236°C. dec. The amine hydrochloride is then converted to l-methyl-3-(5,6,7,8-tetrahydro-4H25 -cyclohepta[b]thien-4-yl)urea, melting point 220°C. to 222°C., by the method described in Example 35 using THF as solvent. -t b similarly, l-ethyl-3- (5,6,7,.8-tetrahydro-4H-cycloheptafbjthien-4- yl) -2-thiourea with melting point 117°C. to 120°C. is obtained.

EXAMPLE 43 Preparation of 7,7-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea By the method described in Example 36 (first reference), 7,7,-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-one is prepared and converted to 7,7-dimethy1-4,5,6.7- tetrahydrobenzo [b]thiophen-4-amine hydrochloride, melting point 211.5°C. to 215°C., by the remaining methods described in Example 36. The amine hydrochloride is converted to 7,7-dimethy1-4,5,6,7-tetrahydrobenzo [b]thien-4-ylurea, melting point 184°C. to 189°C. dec., by the method described in Example 10.

EXAMPLE 44 Preparation of 6,6-dimethy1-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea By the method described in Example 36 (first reference), 6,6-dimethy1-4,5,6,7-tetrahydrobenzo[b]thiophen-4-one is prepared and converted to 6,6-dimethyl-4,5,6.7- tetrahydrobenzo[b]thiophen-4-amine hydrochloride (melting point ^>300 °C.) by the two remaining methods cited in Example 36. The amine hydrochloride is then converted to 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point 174°C. to 178’C.,by the method outlined in Example 10.

EXAMPLE 45 Preparation of l-methyl-3-(5-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea Diisopropylamine (7.3 grams or 72 mmol) is cooled and stirred in 60 ml. of dry tetrahydrofuran (THF) and 45 ml. (72 mmol) of 1.6N n-butyl lithium in hexane is added at <^-5°C. Five minutes later a solution of 4,5,6,7-tetrahydrobenzo(b]thiophen-4-one, 12 grams of 60 mmol in 30 ml. of THF) is added dropwise at 0°C. to -10°C. After stirring for 30 minutes at room temperat5 ure, 38 grams (270 mmol) of methyl iodide is added at <^30 °C. After stirring for 40 hours at room temperature, 100 ml. of water is added and the THF is removed in vacuo. The residue is extracted with 3x50 ml. of methylene chloride and the combined extracts are washed with 50 ml. of 2N hydrochloric acid, 50 ml. of IM sodium carbonate, and 50 ml. of brine, respectively. The solution is dried (magnesium sulfate) and evaporated in vacuo to afford 9.46 grams of light brown oil. The oil is purified by chromatography on a silica-gel dry column using 1:1 hexane/methylene chloride to afford 6.9 grams of -methyl-4,5,6,7-tetrahydrobenzo[b)thiophen-4-one. This ketone is converted to 5-methyl-4,5,6,7-tetrahydrobenzo[b] thiophen-4-amine hydrochloride by the method cited in Example 36 and then the amine hydrochloride is con20 verted to l-methyl-3-(5-methyl-4,5,6,7-tetrahydrobenzo[bjthien-4-yl)urea, melting point 173°C. to 182°C., by the method described in Example 7.

Similarly, alkylation of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-one with ethyl iodide, propyl iodide, and butyl iodide affords the corresponding 5-alkyl ketones, which are converted in the above manner to l-methyl-3-(5-ethyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-methyl-3-(5-propyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, and 1-methy1-3-(5-buty1-4,5,6,7-tetrahydrobenzo30 [b]thien-4-yl)urea, respectively.

EXAMPLE 46 Preparation of l-(methoxymethyl)-3-(4,5,6,7-tetrahydrobenzo [b] thien-4-yl) urea In 150 ml. of methanol, 8.24 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea is stirred and 2.1 grams of sodium hydroxide pellets followed by 2.31 grams of paraformaldehyde in 50 ml. of methanol are added. The mixture is heated at reflux for 10 hours and cooled to afford crystals which are collected. The filtrate is evaporated to dryness and the residue is washed with water to afford 6.7 grams of solid. Recrystallization of the combined fractions from acetone-hexane gives 5.3 grams of 1-(methoxymethyl)-3-(4,5,6,7-tetrahydrobenzo [b]thien-4-yl)urea, melting point 160°C. to 162°C.

EXAMPLE 47 Preparation of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl thiourea_2 A mixture of 13.21 grams of l-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea in 100 ml. of 10% sodium hydroxide solution is heated to reflux for 10 minutes and cooled. The solid is collected and dissolved in 95% ethanol and the solution is evaporated to afford 9 grams of white solid. Recrystallization of this solid from chloroform/hexane affords 8.13 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl thiourea, melting point 129ec. to 131°c.

EXAMPLE 48 Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea A sample of 6 grams of 4,5,6,7-tetrahydrobenzo81 42039 [b]thien-4-ylurea is dissolved in 375 ml. of 50% aqueous acetic acid and 75 grams of ceric ammonium nitrate is added in portions over a 10 minute period with stirring at 25®C. to 35°C. The pale-orange solution is stirred for another 5 minutes and 100 ml. of water is added.

The solution is extracted twice with ethyl acetate (450 ml. and 350 ml.) and the combined extracts are washed with 100 ml. of water. The organic extract is evaporated to dryness in vacuo and the brown residue is crystal10 lized from methanol to afford 2.37 grams of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea, melting point 237°C. to 238°C. dec. Recrystallization from methanol affords purified product, melting point 245°C. to 246°C. dec.

Similarly, 1-methy1-3-(4,5,6,7-tetrahydro-715 -oxobenzo[b]thien-4-yl)urea, l-ethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)urea, l-n-hexyl-3-(4,5,6,7tetrahydro-7-oxobenzo[b]thien-4-yl)urea, l-n-dodecyl-3-(4,5,6,7-tetrahydro-7-oxobenzotb]thien-4-yl)urea, and l-phenyl-3-(4,5,6,7-tetrahydro-7-oxobenzo tb]thien-4-yl20 urea, 4,5,6,7-tetrahydro-4-oxobenzo[b]thien-7-ylurea, 1-methy1-3-(4,5,6,7-tetrahydro-4-oxobenzo[bJthien-4-yl)urea and the optically active isomers of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylureas are also prepared by the above procedure starting with the corresponding ureas Substitution of the ceric ammonium nitrate with silver oxide, chromic anhydride or sodium dichromate also affords the above mentioned 7-oxo compounds. Chromic anhydride followed by hydrolysis, also affords the 7-oxo compounds. The above-mentioned 7-oxo derivatives are also prepared by oxidising their correa- 82 ponding 7-hydroxycycloalkano[b]thien-4-ylurea in the same manner.

EXAMPLE 49 Preparation of and separation of 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea into the cis -trans isomers 7-Keto-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea (0.5 grams, 2.38 mm) is suspended in ethanol (50 ml.) and to the stirred solution is added solid sodium borohydride (0.5 grams, 13.2 mm). After stirring overnight the mixture is treated cautiously with 5% aqueous acetic acid (20 ml.). After stirring 15 minutes the solvent is removed, the residue dissolved in a small volume of methanol and percolated through a 1-1/2' x 13/4 silica gel dry column eluting with 20% methanolic methylene chloride. The resulting gum is crystallized from ethyl acetate/methanol to afford 66 mg. (13% Y) of the more polar (L.L.C) alcohol (B), melting point 194°C. to 197°C. The mother liquor material is separated into its two major components 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea by high pressure liquid chromatography on Spherosil XOA 400 using the solvent systems hexane (1800 ml.)/methanol (425)/ chloroform (1000) (flow rate <**13 ml./min.). This procedure affords the less polar alcohol A (29 mgs. 6% yield, melting point 162°C. to 169°C. (methanol/ethyl acetate), and the more polar alcohol B (50 mg., 10% yield), melting point 197°C. to 198°C.

EXAMPLE 50 Preparation of 2,4-bis[3'-methylureido]-4,5,6,7-tetrahydrobenzofb]thiophene 2-Nitro-4-amino-4,5,6,7-tetrahydrobenzo[b]thio83 42039 phene hydrochloride (0.5 grams, 2.13 mmol) is dissolved in concentrated hydrochloric acid (4.3 ml.). The stirred solution is treated with stannous chloride dihydrate (2.56 grams, 11.35 mmol) added in portions over a minute period (solution becomes hot). The brown solution is stirred for 3 hours, added to ice/water (20 ml.), made alkaline with 10¾ sodium hydroxide and the turbid solution extracted 3 times with methylene chloride (total volume ω 100 ml.). The combined methylene chloride extracts are washed once with brine (20 ml.), dried (sodium sulfate)and evaporated to afford a gum.

The gum is dissolved in methylene chloride (10 ml.) and ether (10 ml.) and the stirred solution treated with a solution of methyl isocyanate (0.5 grams, 8.8 mmol) in ether (10 ml.), added over a 10-minute period. The mixture is stirred overnight, then evaporated to dryness and the residue recrystallized from hot methanol to afford 230 mg. (38% yield) of 2,4-bis [3'-methylureido]-4,5,6,7-tetrahydrobenzo[b]thiophene melting point 233°C. to 234°C.

EXAMPLE 51 Preparation of 5,6,7,8-tetrahydro-4H-cyclohepta(b]thien-4-ylurea A sample of 5,6,7,8-tetrahydro-4H-cyclohepta[b]25 -thiophen-4-amine hydrochloride is converted to 5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea, melting point 217°C. dec., by the method of Example 10.

EXAMPLE 52 Preparation of l-(methoxymethyl)-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea By the method described in Example 46, a sample of 5,6,7,8,-tetrahydro-4H-cyclohepta[b]thien-4-ylurea is converted to l-(methoxymethyl)-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea, melting point 197°C. to 201°C. dec.

EXAMPLE 53 Preparation of N-formyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine ~ In the manner described in Example 48, N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is oxidized with ceric ammonium nitrate to afford N-formyl-4,5,6,7tetrahydro-7-oxobenzo[b]thiophen-4-amine, melting point 118°C. to 120°C. dec.; this product is extracted from the reaction mixture with methylene chloride. The use of chromic anhydride in acetic anhydride followed by hydrolysis also affords the identical product.

EXAMPLE 54 Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride In the manner described in Example 36, N-formy 1-4 ,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine is hydrolyzed with 2N hydrochloric acid/ethanol to afford 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride, melting point 230°C. to 232°C. dec.

EXAMPLE 55 Preparation of 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate and urea Conversion of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride to 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate is accomplished by heating a toluene mixture of the hydrochloride at reflux temperature while phosgene is introduced. After the mixture becomes less cloudy, it is cooled and filtered. Evaporation of the filtrate affords the crude 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate; IR maximum = 2250 cm-1' Addition of NH^/MeOH solution to this isocyanate affords 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea.

EXAMPLE 56 The following compounds are prepared by allowing 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride to react with RNCX in the presence of an equimolar quantity of. triethylamine in solvents such as aromatic solvents, chlorinated hydrocarbons, ethers, low er alkyl C^-C4 ketones, or mixtures thereof.

RNCXR Product X ch3nco ch3- 0 20 c2h5nco c2h5- 0 cci3^-nco 0 C13C-C- 0C6H5CH2NCO c6h5c§2- 0 c2h5ncsc2H5“ s 25 ch3o-ch2nco ch3-o-ch2- 0 ch3o-ch2ncs ch3-o-ch2- s CHgO-^O^-NCOch3-- 0 EXAMPLE 57 The following compounds are prepared by reacting 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl isocyanate with the appropriate amines in inert solvents, as described before in Example 35.

Product AminesR1R2 nh2-och3 H -och3 nh2-oh H -OH ch3nh-oh -CH3 -OH ch3nh-och3 -ch3 -och3 ch2=ch-ch2-nh2 H -ch2-ch=»ch2 ch=c-ch2-nh2 H -ch2-c=ch (CH3)2NH -ch3 -ch3 c6h5ch2nh2 H -ch2-c6h5 c2h5nh2 Hc2h5 n-C4HgNH2 H -n-C4H9 CH3C-NH2 H 0 -c-ch3 <5)-ch2-nh2 H -cb2^) CH2-NH2 H -ch2 -O ch3^ CH-NHch3^ 2 H -ch(ch3)2 EXAMPLE 58 By the method described in Example 49, the following compounds are prepared as cis and trans mixtures from their corresponding keto precursors: Optically active isomers of 7-hydroxy-4,5,6,7-tetrahydrobenzo tb]thien-4-ylurea, l-methyl-3-{7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-ethyl-3- (7-hydroxy-4,5,6,7-tetrahydrobenzo tb]thien-4-yl)urea, 1,1-dimethy1-3-(7-hydroxy-4,5,6,7-tetrahydrob:enzo tb] thien10 -4-yl)urea, l-methoxy-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-methyl-l-methoxy-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)rea, l-hydroxy-3-{7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 1-hydroxy-l-methyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo15 [b]thien-4-yl)urea, 1-methoxymethyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, l-allyl-3-(7-hydroxy-4,5,6,7-tetrahydroben2o[b]thien-4-yl)-urea, 1-(2-propynyl)-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, 5,6,7,8-tetrahydro-4H-8-hydroxycyclohepta[b]20 thien-4-ylurea, 4-hydroxy-4,5,6,7-tetrahydrobenzo[bjthien-7ylurea, and 1-Isopropyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-yl) Urea are also prepared.

EXAMPLE 59 Preparation of 5,6,7,8-tetrahydro-4H-8-oxocyqlohepta[b]thieh-4-ylurea ~ A sample of 5,6,7,8-tetrahydro-4H-cyclohepta[b]25 thien-4-ylurea is oxidized with ceric ammonium nitrate in the manner described in Example 48 to afford 5,6,7,8-tetrahydro-4n-8-oxocyclopheta[b]thien-4-ylurea, melting point 246eC. to 248°C. dec. - 88 42039 EXAMPLE 60 Preparation of l,2-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)2-thiopseudourea In 100 ml. of methanol, 2.3 ml. of methyl iodide 5 and 7.1 grams of l-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)thiourea is stirred at room temperature for 4 days. The solvent is evaporated in vacuo and the residual oil is heated and stirred in ethyl acetate to afford crystals. The crystals are collected and recrystallized from chloroform/hexane and then from chloroform/benzene to afford 2.5 grams, melting point 145°C. to 148°C., and 6.53 grams, melting point 143°C. to 145°C., of 1,2-dimethy 1-3- (4,5,6,7-tetrahydrobenzo[b]thien-4-yl)-2-thiopseudourea by d r i o d i d e.

Similarly, the hydrochloride and hydrobromide salts are prepared by using methyl chloride and methyl bromide, respectively.

Substitution of l-butyl-3-(4,5,6,7-tetrahydrobenzo [b]thien-4-yl)thiourea in the above example affords l-butyl-2-methyl-3-(4,5,6,7-tetrahydrobenzo[blthien-4-yl)-2-thiopseudourea hydriodide melting point 131°C. to 133 °C. 831) Example 61 Preparation of 5-keto-4,5,6,7tetrahydrobenzofb] thiophene 6,7-DiKydrobenzo[b]thiophene (3.3 grams, 24.3 . ' - . mmol) xs dxssolfyed xh methylene chlorxde (250 ml.) and '· the solution is cooled to -25 °C. and solid 85% m-chloroperbenzoic acid (6.19 grams, 30.5 mmol) is added with shaking. The mixture is allowed to stand in the refrigerator (3-7°C.) for 3 days. The solution is washed With saturated sodium bicarbonate (3 x 100 ml.) and water (100 ml.), and dried over sodium sulfate. It is then evaporated to afford a brown semi-solid which is assumed to be a mixture Of epimeric hydroxy-m-chlorobenzoates (589 grams, 79% yield); 3500, 1730 cm-1·· S 15 The mixture of hydroxy-m-chlorobenzoates (5.89 . grams, 19.1 mmol) is refluxed for one hour With 95% ethanol (160 ml.) and 20% sulfuric acid (160 ml.). The bulk of the ethanol is removed in vacuo and the solution extracted three times with methylene chloride (3 x 150 ml.).

The extracts are combined and washed with saturated sodium bicarbonate (2 x 150 ml.), brine (150 ml.), dried (Na2SO^) and evaporated to afford a gum (3.8 grams).

The gum is chromatographed on a dry column (SiOg 3’ x 1 3/4) (methylene chloride eluent) to furnish the required *nujol is a trade mark - 90 420 ketone as a light brown oil (0.95 gram, 33% yield, neat max 1725)· EXAMPLE 62 Preparation of 1-methy1-3-(4,5,6,7-tetrahydrobenzo[b]thien-5-yl) urea -Keto-4,5,6,7-tetrahydrobenzo[b]thiophene (0.95 grams, 6.25 mmol) is stirred overnight at room temperature with ethanol (10 ml.), methoxyamine hydrochloride (1.05 grams, 12.6 mmol) and 10% sodium hydroxide (2.5 ml. 6.25 mmol). Saturated sodium bicarbonate (25 ml.) is added and the ethanol is removed in vacuo. The residual solution is extracted twice with methylene chloride (total volume 75 ml.) and the methylene chloride layers combined, washed with water (25 ml.), dried (sodium sulfate), and evaporated to afford the methoxirne as a brown oil (1.06 grams, 94% yield); 9^^ 1650 (weak) 1060.

The crude methoxirne (1.06 grams, 5.85 mmol) is stirred with tetrahydrofuran (7 ml.). The cooled mixture is treated with borane in THF (15 ml., 15 mmol) (temp20 erature kept below 10°C.). The mixture is refluxed for 4 hours, cooled to 15°C., and water (1 ml.) is added, followed by 20% potassium hydroxide (10 ml,). After refluxing for one hour, the THF is removed in vacuo and the residue extracted twice with methylene chloride (tot25 al volume 100 ml.). The extracts are combined, washed brine (20 ml.), dried (Na2SO4), and evaporated to afford a colorless oil (700 mg.). The oil dissolved in ether (10 ml.) and treated with a solution of methyl isocyanate (0,7 gram, 12.3 mmol) in ether (10 ml.). The mix30 ture is stirred overnight and filtered. The cake is washed with ether (5 ml.) and air-dried to afford the title compound as a white solid (430 mg., 35% yield), melting poing 154-158°C. Recrystallization from aqueous methanol affords the analytical specimen, melting point 167-169 °C.

Similarly, when methyl isocyanate is replaced with ethyl isocyanate, n-hexyl isocyanate, dimethylcarbamoyl chloride, or allyl isothiocyanate, 1-ethyl, l-(n-hexyl), and l/l-dimethyl-3-(4,5,6,7-tetrahydrobenzo[b]10 thien-5-yl)ureas, and l-allyl-3-(4,5,6,7-tetrahydrobenzo(b]thien-5-yl)thiourea are obtained.

EXAMPLE 63 A sample of 6,7-dihydrobenzo[b]thiophene is stirred in the cold In 96% sulfuric acid containing 4-6 mole equivalents of urea. After 1 hour the mixture is poured on ice and the organic phase is removed. Evaporation of the orgahic phase to dryness in vacuo affords 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.

EXAMPLE 64 A 1 gram sample of 4-hydroxy-4,5,6,7-tetrahydrobenzo [b]thiophene is stirred in the cold for several hours in thionyl chloride (5 ml·.) and the mixture is evaporated to dryness. The crude 4-chloro-4,5,6,7-tetrahydrobenzo [b] thiophene is then added to a mixture of urea (1-5 mole-equivalents) in dimethylformamide and diisopropyl ethylamine. The mixture is warmed, after several hours, to 50°C. and after 4 hours is poured on ice and ' the product, 4,5,6,7-tetrahydrobenzo[h]thien-4-ylurea, ' is collected by filtration. - 92 42039 EXAMPLE 65 A sample of 6,7-dihydrobenzo[b]thiophene is stirred with silver isocyanate and iodine as described in Example 40 and the resulting product, 5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is treated with concentrated ammonia solution to afford 5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea. This latter product is then reduced in the manner described in Example 41 to afford 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea.

The following products are also obtained by reacting 5-iodo-4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate with R2R3NH to afford the corresponding iodo ureas, which are then hydrogenated in the above manner to give compounds of the formula: Ro R2 H -CH3 H -C2H5 H -CH(CH3)2 -ch3 -ch3 H -OH H -°CH3 -ch3 -OH -ch3 -och3 4 2 0 39 When allyl amine and 2-propynyl amine are used to give 1-allyl or 1-(2-propynyl)-3(5-iodo-4,5,6,7-tetrahydrobenzo (b]thien-4-yl) urea, the resulting iodo ureas are deiodinated with tributyl tin hydride (BUgSnH). This reducing agent (BUgSnH) can also be used to deiodinate these aforementioned iodo ureas, while use of Zn/HCl to give the desired ureas and polymeric material.

EXAMPLE 66 The following tests were conducted to evaluate 10 the ability of 4,5 > 6,7-tetrahydrobenzo[b]thien-4-ylurea to promote growth in chicks.

In these tests day-old chicks are placed in heated cages and. given feed and water ad libitum. Ih each test there are 5 male and 5 female chicks per cage and three cages per treatment are used. Treatments consist of a basal diet plus 1,3 or 9 ppm. of test compound. The chicks are weighed at the beginning and end of the experiment. Peed consumption is determined for the experimental period which is 13 days beginning when the chicks are one day old. The basal diet employed and results obtained are reported below.

Chick Basal Diet Ground yellow corn 53.45 Soybean oil meal (49%) 28,0 Menhaden fish meal (60%) 5.0 Corn gluten meal (60%) 5.0 Dehydrated alfalfa meal (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 POR 1-TON DL methionine 453.6 grams BHT 113.6 Vitamin A (30,000 u/g) 100.0 Vitamin D, (200,000 u/g) 5.0 Vitamin E (20,000 u/lb.) 45.4 Riboflavin 4.0 Niacinamide 25.0 Ca. Pantothenate 8.0 Vitamin K (menadione) 1.0 Parvo (10%), folic acid 13.0 Choline chloride (50%) 908.0 Proferra (20 mg./lb.), B12 227.0 Corn oil 50.0 Fine ground corn 2582.4 4536.0 lb./Ton Furnishes *Tra-Min No. 3 Manganese 12.50 % 62.5 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. 43039 -Ρ c ρ β) c ε φ φ ο > k ο φ h 0< ε Η Ρ C φ ε Ρ ΪΗ Φ a σ Ρ<*· φ ε > a φ a P c P Φ c ε κ\ ω m , Φ φ c— ¢- o I Β · o > 1 • » • Κλ to in >4 0 cm ti ti Φ 04 CL E H i o to tn ti* Κ\ Ch in m • in ti ti ti co xi Ch i* • • « * Ρ Ρ Η P P P P P □0 Ο 30 P P 33 ti o o co Ο Ολ Ch tn ti ti ti Ρ CM Ρ P o\ • • · * P P P P P Ο CM >- P o so Ch ti to 00 X) Ch P m ti ti ti* ti Ρ ι—ί Ρ P c Ch * • · • Φ P P P P P ε P S4 c Φ Α m to co P a σ CM in o n Ch co O\ ti X CM in ti- ti- ti «—ι ι-1 p r-l Q w Ch « • · « X. P P P P P TO Φ. Φ Γ_, PM co ti co s· in σ\ P Ch o >3 CM in ti ti ti co CO Ch σι ti Ch • B · * «Η Ρ P P Ό P P P P P A P Φ P >—» hO Φ s 1 ρ m Ch ti > a l p tn ch k Φ a Φ P'— > < 1 0 1 0 k t fn I I res I P 1 Of-i 1 Ρ c P s>Pk 0 ·» JS L—ί 1 ti Φ 0 »—j i ti Η ω ti o C Φ s b ω ti o c φ Ρ * $H N G) Jh P P ' ·. k N φ k C tnp cp 3 ti c LAP CP 3 0 •ν Φ Φ Λ P Φ 0 * Φ Φ J3 P ο xt P .Q P >J Jh P_I o tiPOP >» , . » , • • , • Η cm m ti P w tn ti - 96 42039 EXAMPLE 67 Growth Enhancement and Feed Efficiency Evaluations in Sheep Given an Implant Containing Test Compound To determine the effect of a 4,5,6,7-tetrahydrobenzo [b]thien-4-ylurea compound on sheep, Wether lambs are randomly allotted to pens in groups of six. The sheep are weighed and permitted food and water ad libitum. The feed is weighed daily, and uneaten feed from the previous day is collected and weighed. Test lambs receive the same unmedicated diet as control animals, but test animals receive one or more subcutaneous implants containing test compound at the base of the ear. The formulation of the implant used is given below. At the end of the six-week treatment period, the lambs are again weighed, and total feed consumed is calculated.

In these tests, six replicates of six lambs each per treatment are used and each animal receives from about 11 mg. to 105 mg. of test compound.

Average six-week weight gains are presented in Table XIII and feed per pound of gain is presented in Table XIV. From these data it can be seen that lambs implanted with 11 mg. or 99 mg. of test compound showed approximately a 10% increase in weight gain over untreated controls six-weeks after implantation. Feed utilization for the same period was also improved by about 5% over untreated controls.

’ LAMB DIET Ground Corn Cob 15.0 Ground Yellow Corn 48.0 Soybean Oil Meal (49%) 10.0 Dehydrated Alfalfa Meal 15.0 Molasses 10.0 iodized Salt 0.5 Dicalcium Phosphate 1.0 Premix '0.5 i'o'o.o PREMIX· FOR ONE'TON Tra-Min No. 3^1^ 454 grams Vitamin A (30,000 μ/g) 133 grams Vitamin Da (200,000 μ/g) 5 grams Corn Oil 100 grams Ground Corn 3S48grams (i) Tra-Min No. 3: Calcium .21.00% Manganese 12.505$ Iron 6.00% Zinc 5· 00$$ Copper 0.65% Iodine 0.355$ Cobalt 0.25% Pellet Implant ^jSjOjT-TetrahydrobenzotbJthien- ' 11.0 mg. 4-ylurea Glyceryl 12-hydroxystearate 10.50 mg.

Magnesium stearate 0.50 mg. 22.00 mg. - 98 42039 Average 6-Week Weight Gain (kg.)/iamb 0 co σ σι a) co < • • • b- co co m co 0 l·- ω OJ co » • • 10 to C— m in 0 0 LP m • • t— co 50 G 0 m O 0 m CO OJ •H sr • • » P s 10 X) t •H H K\ 0 n fl O*i IU ri m • 4 P5 σι σ co o OJ 0 0- m CO Oj • • co σ σ 0 IP m σ GJ :o r-4 • • • co r-i 0 H H X ri w P ω c a ri 0 r—i cn fc r-i 0 0, ε H I 1 ri ri r—, rtj fc Pjfc P L._J P ri Ο H c r4 P N >> ri 0 1 C 1 R fc t- ri-iT P P n£i 1 ri c co 0 c ct, 0 fc ri fc 0 στ» ·η Eh ·» x: o ri ri ba ε GJ GJ P J3 taO •ri ri ri P ri t: •ri § fc fl fl < ril fc 1) •H fc O s in + bD fc Ό § in c •H P H (fl & Ξ O ϋ 420 39 c φ Αι >4 Φ α ti ο \ Ό Φ Φ ii Φ Φ S ι Φ φ hO ti $4 Φ > < > < ο 30 7.57 σ\ «5Γ fr- 10 σ\ S- γΗ σ\ φ • * * 3Q 30 t- 20 ιη φ Η ο ιη ιη > * 1 σ 30 t- CM (Η X C X) CM κ\ ο «55* • • • •Η 30 30 χ> 4-5 Η γ-4 γΗ ο rH «=Τ st X) ft m * ·- • { Φ fr- ο C Ρπ fr- 30 m l·- m t- CM • • - · Φ φ φ 30 m Γ< » ω ιη ί-4 • • c- φ <ρ <β ft Ο «Ρ 3 tec φ 3 ti . ο r-4 σ\ •Q Sh Μ SOB 3 ε & Η ί 1 ti φ Φ 3£> Μ •Plh3 Ρ Φ 0 rt C r-4 Ρ !Ί >3 Φ Ο 1 C ι ε Sh fr- Φ«=Γ «μ μ Λ .2 1 ti C φ 0 c Φ Ο •k Jh φ k ϋ ΙΛΌ Η » >»£ -=r£p Λ ϋ ti φ Φ •Η Η ti Φ ω ιη s CM CM «Ρ £2 hO •Η Φ Φ •μ «ί ε •Η X Ο ?4 α α < hO Μ Ό Ο ιη w ο α ε ο ο til

Claims (8)

1. A compound of the following formulae: A (I) or (II) wherein Z is hydrogen or (C^-C 4 )alkyl*, Y is hydrogen,. (C-|-C 4 )alkyl; halogen, cyano, nitro, acetyl, acetylamino or the moiety R^-NHCONH-; R^, Rg, R?, Rg, R g , R^q and R 1;l are each individually hydrogen or (C-j-C^alkyl; M and U are each individually divalent moieties of the formulae: ;c=o, ,CHOH, -c /R4 / c ^r 5 or A\a Is wherein R 4 and Rg are each individually hydrogen or (CpC 4 )alkyl and with the proviso that M and U may not be the same except when both are ^CR 4 R 5 ; A is a moiety of the formula: RiX I II -N-C-W which is bonded to the 4-, 5-, or 7-position in formula (I) and to the 4-, 5-, or 8-position in formula (II) with the proviso that when A is bonded to the 5-position then and U cannot be ^CR 4 A? and wherein X is a 101 divalent radical selected from oxa (¢0), thia (=S) and =N-R^; W is selected from (Cj.· C/palkylthio and a moiety of the formula with the proviso that W is (C,-¾) alkylthio onl R« R« Ά . /2 when X is and W may not be when X is »N-: and wherein R 2 and R^ are selected fro$ the group consisting of the members'set forth in the following table r 2 R 3 hydrogen, hydrogen, alkyl Cq-Ci 2 , alkyl C1-C4, cycloalkyl C 3 -Cg, cycloalkyl Cg-Cg, allyl, allyl, methallyl, 2-butenyl, 2-propynyl, 1 hydroxy, alkoxy Οχ-Cg, allyloxy, methallyloxy,. 2-butenyloxy, methoxymethyl, phenoxy, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -S-CH 3 , -CH 2 ~CH(0R 3 ) 2 , -CH 2 -CF 3 , -ch 2 -cn, -CH 2 “GO 2 R2, -nh-co 2 r 1 , 2-propynyl and ζ> 2 > η -, 102 103 wherein n is'0, 1, or 2 and Q is selected from the members set forth' in the following table Q When n = 0 when n = 1 1 'when n = 2 hydrogen, hydrogen, hydrogen 4-chloro, 4-chloro, 3,4-methylenedioxy, 4-methoxy and 2(3 or 4)-methoxy, 4-ethoxy, 4-butoxy, 3,4-methylenedioxy 4-methylthio, 2.4- dimethyl, 2.4- dimethoxy, 2.4- dichloro, 4-nitro and 2-methy1-4-bromo 1 104 or R 2 and R 3 taken together with the associated Nitrogen is selected from morpholino, piperidino, pyrrol i di n-1-yl, 4-phenyl pi perazi n-l-yl, 4-carbethoxypi perazi n-1-yl, 4-oxopiperazin-l-yj, 4-(4-methoxyphenyl )pi perazi n-1-yl, 1,2,3,-45 tetrahydroquinol in-l-yl and the moiety of the formula: or a cis or trans isomer thereof when M or U is ^CHOH or an optical isomer thereof. 10 2. The compound according to Claim 1, 4, 5, 6, 7tetrahydrobenzoQbJ thien-4-ylurea. 3. An optical isomer of the compound according to Claim 2. 4. The compound according to Claim 1, l-methyl-3(4,5,6,7-tetrahydrobenzo £b]thien-4-yl)urea. 15 5. The compounc according to Claim 1, 1-methoxy-lmethy1-3-(4,5,6,7-tetrahydrobenzo[b] thien-4-yl)urea. b. The compound according to Claim 1, l-ethyl-3(4,5,6,7-tetrahydrobenzo[b] thien-4-yl )urea. 7. The compound according to Claim 1, 1-methoxy 30 -3-(4,5,6,7-tetrahydrobenzo [b] thien-4-yl)urea. 105 8. The compound· according to Claim 1, 1-hydroxyl-methyl-3-(4,5,6,7-tetrahydrobenzoCbi thien-4-yl)urea. 9. The compound according to Claim 1, l-hydroxy-3(4,5,6,7-tetrahydrobenzoE3 thien-4-yl )urea. 10. The compound according to Claim 1, 1-methoxymethyl -3-(4 3 5,6,7-tetrahyd'rohenzoLb] thien-4-yl )urea. 11. The compound according to Claim 1, 1 -(2-propynyl) -3-(4,5,6,7-tetrahydrobenzo jl·] thien-4-yl)urea. 12. The compound according to Claim 1, l-allyl-3(4,5,6,7-tetrahydrobenzo Eb] thien-4-yl)urea. 13. The compound according to Claim 1, l-isopropyl-3(4,5,6,7-tetrahydrobenzo[bj thien-4-yl )urea. 14. The compound according to Claim 1, 1,l-dimethyl-3(4,5,6,7-tetrahydrobenzo03 thien-4-yl)urea. 15. The compound according to Claim 1, 4, 5, 6,7tetrahydro-7-oxobenzo 03 -thien-4-ylurea. 16. An optical isomer of the compound according to Claim 15. 17. The compound according to Claim 1, l-methyl-3(4,5,6,7-tetrahydr.o-7-oxobenzo[b] thien-4-yl )urea. 18. The compound according to Claim 1, 1-ethyl -3-(4,5,6,7-tetrahydro-7-oxobenzo jjo) thien-4-yl )urea. 19. The compound according to Claim 1, 1-methoxymethyl -3-(4,5,6,7-tetrahydro-7-oxobenzo [b] thien-4-yl)urea. 20. The compound according to Claim 1, 1-(2-propynyl) -3-(4,5,6,7-tetrahydro-7-oxobenzo 03 thien-4-yl)urea. 21. The compound according to Claim 1, l-allyl-3(4,5,6,7-tetrahydro-7-oxobenzoCbJ thien-4-y1) urea. 22. The compound according to Claim 1, 1-methoxy-lmethyl-3-(4,5,6,7-tetrahydro-7-oxobenzo [b] thien-4-yl)urea. 106 23. The compound according to Claim 1, l-hydroxy-3(4,5,6,7-tetrahydro-7-oxobenzo [b] thien-4-y1)urea. 24. The compound according to Claim 1, 1-hydroxy-lmethyl -3-(4,5,6,7-tetrahydro-7-oxobenzo[bj thien-4-yl)urea. 5 25. The compound according to Claim 1, l-methoxy-3(4,5,6,7-tetrahydro-7-oxobenzo jJS] thi en-4-yl )urea. 26. The compound according to Claim 1, l,l-dimethyl-3(4,5,6,7-tetrahydro-7-oxobenzo D>1 thien-4-yl)urea. 27. The compound according to Claim 1, T-isopropyl-310 (4,5,6,7-tetrahydro-7-oxobenzo [b] thien-4-yl)urea. 28. The compound according to Claim 1, 7-hydroxy-4,5,6,7tetrahydrobenzo [b], thi en-4-yl urea. 29. The cis or trans isomer of the compound according to Claim 28 or an optical isomer thereof. 30. The compound according to Claim 1, l-methyl-3(7-hydroxy-4,5,6,7-tetrahydrobenzo IH thien-4-yl)urea. 31. The compound according to Claim 1, l-ethyl-3(7-hydroxy-4,5,6,7-tetrahydrobenzo [S]thien-4-yl)urea. 32. The compound according to Claim 1, 1,1-dimethyl 20 -3-(7-hydroxy-4,5,6,7-tetrahydrobenzo [b]thien-4-yl)urea. 33. The compound according to Claim 1, 1-methoxymethy1-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo [b] thien-4-yl)urea. 34. The compound according to Claim 1, 1 -isopropyl-3(7-hydroxy-4,5,6,7-tetrahydrobenzo [b] thien-4-yl)urea. 25 35. The compound according to Claim 1, 1 -(2-propynyl) -3-{7-hydroxy-4,5,6,7-tetrahydrobenzo M thien-4-yl)urea. 36. The compound according to Claim 1, l-allyl-3(7-hydroxy-4,5,6,7-tetrahydrobenzo [bj thien-4-yl)urea. 37. The compound according to Claim 1, l-methoxy-3□ Q (7-hydroxy-4,5,6,7-tetrahydrobenzo[bj thien-4-yl)urea. 107 1. 38. The compound according to Claim 1, 1-methoxy-1methyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo[b] thien-4-yl)urea. 39. The compound according to Claim 1, l-hydroxy-3(7-hydroxy-4,5,6,7-tetrahydrobenzo[’b] thien-4-yl )urea. 5 40. The compound according to Claim 1, 1-hydroxy-lmethyl-3-(7-hydroxy-4,5,6,7-tetrahydrobenzo [b] thien-4-yl)urea. 41. A compound of the formula wherein X is sulfur or oxygen; γ is hydrogen, halogen, 10 cyano, alkyl C-j-C^ or acetyl; Z is hydrogen or alkyl C-j-C^; R-j is hydrogen or alkyl Cj-C 4 ; Rg is hydrogen, alkyl C-j-C-jg, cycloalkyl C 3 -C g , allyl, methallyl, 2-butenyl, hydroxy, or alkoxy C-j-C 4 ; 15 R 3 is hydrogen, alkyl C-|-C 4 , cycloalkyl C 3 -C g or 108 n is 1 or 2; or is taken together and is morpholino, piperidino or pyrrolidin-1-yl; or ah optical isomer thereof. 5 42. A compound of the following formulae wherein Rp Y and Z are as defined in Claim 1, or an optical isomer thereof. 43. The compound according to Claim 42, N-formyl10 4,5,6,7-tetrahydro-7- oxobenzo 03 thiophen-4-amine, or an optical isomer thereof. 44. A process for the preparation of compounds of formula (I) and' formula (II) as defined in Claim 1 except that A is a moiety of the formula: 109 ' 42039 R. X I 1 II — N— c— NH-Rwherein X is oxygen or sulfur and R^ and R 2 are as defined in Claim 1 comprising reacting one mole equivalent of a compound of the formulae: wherein all substituents are as defined in Claim 1 with from about one to about 1.5 mole equivalents of a compound of the formula: r 2 ncx wherein X is oxygen or sulfur and Rj is as defined in Claim 1 in an organic solvent inert to the reactants at a temperature of from 0 u C. to 100°C. for a period of time sufficient for a substantial degree of addition to take place. •45· A process according to Claim 4.4 wherein the amine is in the form of an acid addition salt and said reaction is carried out in the presence of an acid acceptor. 46. A process according to Claim 44 wherein the amine is in the form of an acid addition salt and said reaction is carried out in an aromatic hydrocarbon or chlorinated hydrocarbon solvent and in the presence of an acid acceptor selected from sodium or potassium-bicarbonate, - carbonate, or hydroxide no . present is an aqueous solution. 47. A process for the preparation of compounds of formula (Xi. and formula (II) as defined in Claim 1 except that A is a moiety of the formula: X / K 2 wherein X is oxygen or sulfur and R^, and R^ are as defined in Claim 1 comprising reacting one mole equivalent of a compound of the formulae: wherein all substituents are as defined in Claim 1, with from about one to about l.b mole equivalents of a compound of the formula: wherein Rj and R^ are as defined in Claim 1, in an organic solvent inert to the reactants at a temperature of from 0°C to 100°C. for a period of time sufficient for a substantial degree of addition to take place. 48. A process according to Claim 47 wherein the amine is in the form of an acid addition salt and said reaction is conducted in the presence of an acid acceptor. 49. A process for the preparation of compounds of the formulae: 111 wherein X is ( oxygen or sulfur and R^, R 2 , Rg, Y, and Z are as defined in Claim 1, comprising oxidizing one mole equivalent of a compound of the formulae: wherein R^, Rg, Rg, X, Y, and Z are as hereinabove defined and ϋ is -Cfig or ^CHOH with from 2 to 8 mole equivalents of an oxidizing agent selected from ceric ammonium nitrate, 'silver 10 oxide, chromic anhydride and sodium dichromate in the presence of an aqueous solution of a solvent selected from acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimeenoxyethane and diethylene glycol dimethyl ether wherein said solutions may contain 15 nitric acid, phosphoric acid, or perchloric acid, or chromic anhydride, in acetic anhydride at a temperature -of from 0°C. to 100°C. for a period of time suffice lent for a substantial degree of oxidation-to take place. 50- A process according to Claim 49 wherein 20 4 to 5 mole equivalents of an oxidizing agent is used at a temperature range of from 20°C to 60°C. 51. A process for the preparation of compounds 112 of the formulae: wherein Rp Y, and Z are as defined in Claim 1, comprising oxidizing one mole equivalent of a compound of the formulae: I wherein Rp Y, and Z are as hereinabove defined and U is -CH 2 - or /CHOH with from 2 to 8 mole equivalents of an oxidizing agent selected from the ceric ammonium nitrate, silver oxide, chromic anhydride and sodium dichromat^ ' in the presence of an aqueous solution of a solvent selected from acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, wherein said solutions may contain nitric acid, phosphoric acid, or perchloric acid, or chromic anhydride, or in acetic anhydride at a temperature of from 0°C. to 100°C. for a period of time sufficient for a substantial degree of oxidation to take place. 52. A process according to Claim 5] wherein 4 to 5 mole equivalents of an oxidizing agent are used at a temperature range from 20°C to 60°C. .113 53. A process for the preparation of compounds of the formulae: :. x x R 2 -N cis and trans OH cis and trans wherein R^, R 2 , R 3 , Y and Z are as defined in Claim 1 and X is oxygen or sulfur comprising reducing one mole equivalent of a compound of the formulae: *2 Wherein R^, R 2 , R 3 , X, Y, and Z are as hereinabove defined, with an equimolar excess of sodium borohydride in a C^-Cg alkanol solvent at a temperature of from 0°C to 75°C. for a period of time sufficient for a substantial degree of reduction to take place. 54. A process according to Claim 53 wherein the temperature range is 20° to 40°C. 55. A process for the preparation of a compound of the formula: 114 wherein X is oxygen or sulfur comprising reacting a compound of the formula: with an equimolar to 50% molar excess of sodium or poI tassium cyanate or thiocyanate in an aqueous medium at pH 5-7 at a temperature of 10°C. to 80°C. and recovering said product.! 56. wherein X is pound of the for the preparation of a comA process pound of the oxygen or sulfur comprising reacting a com- with an equimolar to 50% molar excess of sodium or potassium cyanate or thiocyanate in an aqueous medium at pH 5-7 at a temperature of 10°C. to 80°C. and recovering said product. A process for the preparation of a compound of the formula: 115 wherein R 2 is hydrogen, ((^-Cg) alkyl, allyl, alkoxy,

2. -propynyl, methoxymethyl or hydroxy and R g is hydrogen or (C r C 4 ) alkyl, comprising reacting a compound of 5 the formula: · in an aromatic solvent selected from benzene, toluene, xylene and a mixture of the isomers of xylene with phosgene at reflux, recovering the resultant 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4*yl isocyanate, reacting said isocyanate in a C^-Cg alkanol solvent with an excess amount of an amine of the formulas wherein R 2 and Rg are as defined hereinabove, and recov1 5 ering said product. 5g / A process for the preparation of a compound of the formula: comprising reacting a compound of the fonnula: 116 IH-CHO 42038 » » with 2 to 8 equivalents of an oxidizing agent selected from ceric ammonium nitrate, silver l oxide, chromic! anhydride and sodium bichromate in the presence of an aqueous solution of a solvent selected from acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether wherein said solutions may contain nitric acid, phosphoric acid, or perchloric acid, or chromic anhydride in acetic anhydride at a temperature from 0°C. to 100°C. 59.. A process for the preparation of a compound of the formula; wherein X is oxygen or sulfur and R 2 and R^ are each independently selected from' hydrogen and (C-j-Cg.)- alkyl comprising reacting a compound of the formula; wherein X, R 2 , and R 3 are as hereinabove defined with 2 to 8 mole equivalents of an oxidizing agent selected 117

3. 4ZU3U from ceric ammonium nitrate, chromic anhydride and sodium dichromate in the presence of an aqueous solution of a solvent selected from acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, wherein said solutions may contain nitric acid, phosphoric acid, or perchloric acid or chromic.anhydride, in acetic anhydride at a temperature of from 0°C to: 100°C. 50 A orocess for the preparation of compounds of formula (I) and formula (II) as defined in Claim 1 except that A is a moiety of the formula: wherein R is (Cj-C^) alkyl and R 1 is hydrogen or C-|_ 4 alkyl 15 ' comprising alkylating one mole equivalent of a compound of the formulae: 48039 wherein all substituents are as defined in Claim 1, • t. with from one to 1.5 mole equivalents of an inorganic acid ester of a C-,-C^ alkanol in a solvent inert to the reactants at a temperature of from 0°C to 75°C. for a period of time sufficient for a substantial degree of alkylation to take place. 61. A process according to Claim 60, wherein the inorganic acid ester is selected from (C-C 4 )a1kyl bromides, (C]-C 4 ) alkyl iodides and di (0·|-0 4 ) alkyl sulfates. 62. A method for improving feed efficiency and enhancing the growth rate of animals comprising administering to said animals an effective amount of a compound according to any one of Claims 1-43. 63. A method according to Claim 62, wherein the compound is orally or parenterally administered to said animal. 64., A method according to Claim 63, wherein said compound is orally administeroid to said animals in an amount equivalent to from 0.0001% to 0.08% by weight of the animal feed. . · 65. A method according to,'Claim 63, wherein said compound is parenterally administered.as one or more subcutaneous implants beneath the skin of said animal , said implants being sufficient to provide a daily drug release of from 0.001 mg. to 0.2 mg. of said compound per kg. of animal body weight. 66. An animal feed composition for improving feed efficienty and enhancing the growth rate of animals, comprising: a nutritionally balanced animal feed containing a compound according to any one of Claims 1-43. 119 67. An animal feed composition according to Claim 60, wherein the compound is present in an. amount from 0.0001% ' to’ 0.08% by weight of the feed. 68. An animal feed premix for enhancing the growth rate

4. 5 of animals, comprising from 70% to 99% by weight of an edible carrier and from 1% to 30%'by weight of a compound i according to any one of Claims 1-43. 69. A compound according to Claim 1, Claim 41 or Claim 42 and substantially as described in any one of

5. 10 Examples 1-16, 20, 22, 25, 26, 29, 31, 34, 35, 38-53, 55 to 60 and 62-65 herein. 70. A process for preparing a compound according to Claim 1, Claim 41 or Claim 42 and substantially as described in any one of Examples 1-16, 20, 22, 25, 26,

6. 15 29, 31, 34, 35, 38-53, 55 to 60 and 62-65 herein. 71. A compound according to Claim 1, Claim 41 or Claim 42 whenever prepared by a process according to any one of Claims 44-61 or Claim 70. 72. A method for improving feed efficiency and

7. 20 enhancing the growth rate of animals according to Claim 62 and substantially as described in either of Examples 66 and 67 herein. 73. An animal feed composition according to Claim 66 and substantially as described in either of Examples

8. 25 66 or 67 herein.