IE44846B1

IE44846B1 - Tetrahydrobenzothiophenes

Info

Publication number: IE44846B1
Application number: IE238676A
Authority: IE
Original assignee: American Cyanamid Co
Priority date: 1975-11-04
Filing date: 1976-10-28
Publication date: 1982-04-21
Also published as: IN144699B; IL50683A; PL112081B1; YU268576A; NZ182324A; AR229075A1; IT1066301B; SU685153A3; IE44846L; PL193437A1; ES452988A2; YU40654B; CU34625A; DD128921A6; DK497676A

Abstract

Process for the production of new ones

Description

This invention relates to novel 4,5,6,7 - tetrahydro - 7 oxo(oxy)benzo£bJ- thiopen - 4 - amine compounds, to processes for their preparation, and to their use for improving feed efficiency and enhancing growth rate of animals. The invention is a modification of or improvement in that forming the subject of our Patent Specification No. 42039.

The compounds of this invention have the formula: (I) wherein R^ is hydrogeri; R2 is hydrogen, C^-Cg alkanoyl, 10 halo-substituted Cy_g alkanoyl or •i 4 S 4 6 3,4-dichloro, chloro, methyl, methoxy or taker, together with the associated nitrogen wherein Y is hydrogen, nitro; or R, anu R„ ι 2 represent a cycli: imido selected from succinimido, maleiiaido, b phthalimido and 1,2,3,6-tetrchyJrophthslimido; I<2 is oxo or hydroxy, with the proviso that when R^ is oxo then Rg is not hydrogen or formyl; X is chlorine, bromine or iodine, and n is 0 except when Rj and Rg are ^oti’ hydrogen when n is ϋ or 1.

The invention includes the- optical isomers of the compounds of formula I as well as racemic mixtures thereof, and 'when R3 is hydroxyl the racemic mixture and optical isomers of the cis and trans isomers thereof, wherein the term cis and trans refer to the configuration of the 7-hydroxy group with respect to the 4-amino group. 846 A preferred embodiment of the present invention consists of those compounds of formula (I) wherein R-j is hydrogen; R2 is C^-Cg alkanoyl or halo-substituted C-j-Cg alkanoyl; and when R^ and R^ are taken together with the associated nitrogen they represent phthalimido.

Among the compounds Qf the invention are: N-acety1-4,5,6,7-tetrahydro-7-oxobenzcf b]thiophen-4-amine; . . N-propionyl-4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine; N-i sobutyl-4 ,5,=6,7-tetrahydro-7-oxobenzc{ b] thi ophen-4-arai ne; N-pivaloyl-4,5,6,7-tetrahydro-7-bxobenzofbjthiophen-4-amine; N-trichloroacetyl-4,5,6,7-tetrahydro-7-oxobenzoQbJthiophen-4-amine;. and 4,5,6,7-tetrahydro-7-oxobenzorb]thiophen-4-yl)phthalimide.

This invention further relates to methods of preparation of the above-described-formula (I), 4,5,6,7 - tetrahydro - 7 - oxy(oxy)benzo15 [Jb] thiophen - 4 - amine compounds, hereinbelow described and exemplified in detail.

The novel formula (I) tetrahydro - 7 - oxobenzo £bj thiophen - 4 - amine compounds of the present invention wherein R3 is oxo may be prepared from the corresponding formula (II) 4,5,6,7-- tetrahydrobenzo[b]thiophen - 4 - amines by an oxidation reaction which may be graphically illustrated as follows: wherein R-, and R? are as defined above. ? 4 4 4 8 4 5 In general, a formula (II) amine is reacted with a 2 to 8 mole equivalent, preferably with a 2 to 5 mole equivalent, of an oxidizing agent selected from ceric ammonium nitrate, ceric sulfate silver oxide, chromic anhydride and sodium bichromate at a temperature from 0°C. to 100°C., preferably 20°C. to 60°C., in a solvent selected from aqueous solutions of acetic acid, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, which may contain nitric acid, phosphoric acid or perchloric acid, or chromic anhydride - acetic anhydride, followed by hydrolysis. Other oxidizing agents such as persulfates, may also be used in the above oxidation reaction if so desired.

The corresponding 7-hydroxy (cis and trans isomer, as defined above) analogues may be prepared from the corresponding type (Ia) compounds, by reducing with equimolar or excess amounts of sodium borohydride, at a temperature range from 0°C. to 75°C., preferably 20°C to 40°C., in Cg-Cj alcohols to afford a mixture of the cis and trans isomers. The above reaction may be graphically illustrated as follows: 4 8 4 6 ι ι I I - (Ia) wherein R^ and Rg are as defined above.

The novel 4,5,6,7 - tetrahydro - 7 - oxo(oxy)benzojj)Jthiophen 4 - amine compound of formulae la and Ib, obtained by the procedures hereinabove described, are racemic mixtures.

Should the optically active isomers of said compounds be desired, the racemic mixture of 4,5,6,7 - tetrahydrobenzo[b]thiophen - 4 amine (V) is initially treated with (R) - (+) - N - benzoylglutamic acid to afford a salt with the (+) - 4,5,6,7 - tetrahydrobenzo[b]thiophen 10 4 - amine. It is not necessary to employ more than one mole of the resolving acid for each 2 moles of the racemic amine, as a cheaper acid, preferably acetic acid, can be substituted for the balance of the required * * 8 The compounds of this invention are useful as growth promoting agents for animals such as poultry, fur-bearing and farm animals and their use for this purpose has the added advantage of improving feed conversion for said animals. The term feed 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.

Thus, a growth-promoting amount of a formula (I) 4,5,6,7 tetrahydro - 7 - oxo(oxy)benzoj_b]thiophen - 4 - amine or an optically active isomer thereof may be administered to a host animal in, or with, the animal's feed. In this connection, the invention provides an animal feed premix for improving feed efficiency and enhancing the growth rate of animals, which comprises from 70% to 99% by weight of an edible carrier and from 1% to 30% by weight of a compound of formula (I). Such 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 said animals, usually 0.00012 to 0.082 by weight, and preferably 0.001% to 0.04% by weight of formula (I) amine, is effective for increasing growth rate and improving feed conversion. When administered as a parenteral injection or subcutaneous implant, usually in amounts that will supply 0.005 mg., to 0.2 mg., preferably 0.001 mg. to 0.10 mg. 448 4® per kg. of body weight per day of the active compound, it will produce the desired improvement in weight gain and enhance food conversion.

Compounds of the present invention are also useful for the preparation of.animal growth regulating and herbicidal urea compounds .5 by a number of alternative routes, as set forth in the following paragraphs.

A-formula I amine, except when R-j and Rg are both hydrogen, is hydrolyzed in dilute mineral acid and the resulting 4,5,6,7 - tetrahydro --7 - oxo(dxy)benzorb] - thiophen - 4 - amine of formula (III) is reacted with an equimolar or excess (5% to 50%) amount of sodium or potassium cyanate at a temperature in the range of 0°C. to 100°C., preferably 0°C. to 70°C., in the presence of a solvent selected from water, C^-Cg alcohols, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, methyl ethyl ketone or mixtures thereof in the pH range of 5 to 7, and preferably at pH 6. The above reaction may be graphically illustrated as follows:8 '2 (IV) wherein Rg represents oxo or hydroxy. The formula IV compounds obtained are the racemic mixtures and the cis and trans isomers thereof, wherein Rg is hydroxyl.

A formula III amine may also be reacted with an isocyanate of the formula : R-NCO under conditions similar to those described above to yield a formula IV substituted urea of the structure 448^6 wherein Rg is as defined above and R represents a substituent, such as alkyl, alkoxy, benzyl, phenyl and substituted phenyl, selected to enhance the biological activity and/or to impart suitable physical properties to said urea.

An amine of formula (III) where Rg is oxo,* may be reacted with phosgene, preferably under anhydrous.conditions, under a blanket of inert gas such as nitrogen. The reaction is initially carried out at a temperature from 0°C. to 40°C., preferably 10°C to 20°C., and then heated to from 50°C to -100°C., preferably from 60°C. to 80°G. to yield the isocyanate of formula (V): wherein Rg is oxo. This reaction is usually conducted in the presence of an organic solvent such as benzene, toluene or xylene. The thus obtained isocyanate of formula (V) is then reacted with an equimolar or excess (5% to 50%) amount of an amine of the formula TO HN \ R. to yield a formula IV urea of the structure: wherein Rg is as defined above; R^ and Rg represent substituents, such as alkyl, alkoxy, benzyl and aryl groups, selected to favourably enhance the biological activity and/or physical properties of said urea. For the preparation of compounds of formula IV, wherein Rg is hydroxyl, the corresponding oxo compounds are conveniently reduced with sodium borohydride in C-j-Cg alcolols.

An amine of formula (III) wherein Rg is oxo, may also be reacted with equimolar amounts of carbon disulfide, triethylamine and a carbodiimide represented by the formula: 6-N = C = N-G wherein G is cyclohexyl, cycloheptyl and C^-Cg alkyl to produce the corresponding thiophene (V). This reaction is generally conducted in the presence of a solvent such as tetrahydrofuran, ethyl acetate, or an ether such as diethyl ether, at a temperature from -10° to +80°C, and preferably from -10° to +50°C. The above reaction may be graphically illustrated as follows: wherein G is cyclohexyl, cycloheptyl or C^-Cg alkyl. ι 4 8 4 6 The thus obtained animal growth promoting urea compounds of formula IV are the racemic mixtures of the cis and trans isomers when Rg is hydroxyl; unless, of course, the reaction sequence leading to said ureas is started with the resolved (d or 1_) formula (III) amines.

The invention is illustrated by the Examples set forth below.

Examples 3 and 28 relate to the preparation of intermediates, while Example 27 illustrates the use of a compound of this invention in the preparation of a urea derivative thereof.

Example 1 Preparation of N-Acetyl-4,5,6,7-tetrahydro-710 oxobenzo[b]thiophen-4-amine A solution of·2.15 g of N - acetyl - 4,5,6,7 tetrahydrobenzo) b J thiophen - 4 - amine in 12 ml of acetic acid is stirred and 3.04 g of chromium tri oxide in 13.6 ml of acetic anhydride is added in 15 minutes at 10°C to 15°C. After an hour at 20°C, 20 ml of water is added and the mixture is allowed to stand overnight. Additional water (50 ml) is added, the mixture is saturated with sodium chloride and extracted with tri chloromethane (100, 150 and 50 ml volumes). The combined extract is washed with brine and then with water. The water wash is extracted with tri chloromethane and the extract is combined with the main tri chloromethane extract. Evaporation of the extract affords a yellow-green residue, which after trituration with ether gives 1.32 g of the title compound, m.p. 160°C to 164°C.

Example 2 Preparation of N-trichloroacetyl-4,5,6,7- tetrahydro-7oxobenzofjy thiophen-4-annne Into 2 equivalents of trichloroacetic anhydride,. 1 equivalent of 4,5,6,7 - tetrahydrobenzo[bjthiophen - 4 - amine is added to afford the amide, which is collected and dried. The N - trichloroacetyl 4,5,6,7 - tetrahydrobenzo[bj thiophen - 4 - amine melts at 80°C to 86°C. This material is then oxidized in the general manner described in Example T but using ceric ammonium nitrate as oxidizing agent to afford the title product, m.p. 167°C to 171°C.

Example 3 Preparation of N-chloroacetyl-4,5,6,7tetrahydrobenzoQbJthiophen-4-ami ne A mixture of 7.59 g of 4,5,6,7 - tetrahydrobenzo^b]thiophen 4 - amine hydrochloride is stirred in 60 ml of dry tetrahydrofuran and 10.1 g of triethylamine in 20 ml of dry tetrahydrofuran is added.

After stirring under a nitrogen atmosphere for 15 minutes, 3.5 ml or 5.25 g of chloroacetyl chloride in 30 ml of dry tetrahydrofuran is added dropwise, while the temperature is maintained at 30°C to 40°C. After an hour of stirring, the mixture is filtered, the filter cake is washed with tetrahydrofuran, and the filtrate is evaporated to dryness.

The residue is then triturated with water and the title compound, m.p. T15°C to 119°C, is collected and washed with water and hexane. i 4 8 d 6 Examples_ 4 to 25 The following compounds,exemplified by structure 13, are prepared by following the method oTTximple 2. The corresponding starting materials, exemplified by structure A, are prepared by the methods of either Example 2 or Example 3.

Example JI 4 cci3 5 CHgCl 6 CHClg 7 cf3 8CH2CH3 9 ch(ch3)2 10 CH2-C(CH3)3 11 (ch2)4ch3 12 -C6H5 13 4-chlorophenyl 14 2-chlorophenyl 15 3-chlorophenyl 16 4-nitrophenyl 17 3-nitrophenyl 18 2-nitrophenyl 19 4-methoxyphenyl 20 2-methoxyphenyl 21 3-methox;yphenyl 22 2-methylphenyl 23 3-methylphenyl 24 4-methylphenyl 25 3,4-dichlorophenyl ι4846 Example 26 Preparation of N-(4,5,6,7-tetrahydro-7oxobenzo[bjthien-4-yl)phthalimide In 50 ml of toluene, 5 g of 4,5,6,7 - tetrahydrobenzofVjthiophen - 4 - ylamine, 4.84 g of phthalic anhydride, and 0.5 ml of triethylamine are heated at reflux to azeotropically remove water. After the distillation of water is completed, the mixture is cooled, the crystals are collected and washed with ether to afford N - (4,5,6,7 tetrahydrobenzo|”b]thien - 4 - yl) phthalimide, m.p. 166°C to 167.5°C. Oxidation of this compound by the method of Example 2 affords the title compound, ro.p. 163°C to 166°G.

Similarly, use of maleic anhydride, cis - 1,2,3,6 tetrahydrophthalic anhydride, and succinic anhydride in place of phthalic anhydride affords N - (4,5,6,7 - tetrahydro -7oxoberizoQjjthien - 4 - yl) maleimide, -cis - 1,2,3,6 - tetrahydrophthalimide and - succinimide, respectively.

Example 27 Preparation of 4,5,6,7 - tetrahydro-7-oxobenzo[bjthien - 4 - ylurea A sample of 18.95 g. of N - acetyl - 4,5,6,7 - tetrahydro - 7 oxobenzojji]- thiophen - 4 - amine is heated to reflux temperature with 6N hydrochloric acid for 4 hours. The mixture is cooled, filtered through glass wool to remove tars and the tars are washed twice with 75 ml of water. The combined washes and filtrate is washed with di chloromethane and then evaporated to dryness in vacuo. The residue is dissolved in 75 ml of water and a solution of 12.5 g of potassium 4484 6 cyanate in 35 ml of water is added rapidly. After stirring overnight, the product is collected by filtration and washed with water and then with methanol. This affords 7.7 g of the title compound, m.p. 231°C to 234°C dec.

Example 28 Preparation of (-) N-acetyl-4,5,6,7-tetrahydrobenzojJ)]thiophen-4-amine A solution in toluene of (i) 4,5,6,/ - tetrahydrobenzoj bjthiophon - 4 - amine is stirred under a nitrogen atmosphere and acetic anhydride is added. The mixture is then heated to reflux and water is removed by azetroping. After water no longer is distilled over, the mixture is cooled and the title compound is collected and washed with toluene.

Example 29 Preparation of (-) N-acetyl-4,5,6,6-tetrahydro-7-oxobenzob j -thiophen-4-ami ne Hie ceric ammonium nitrate oxidation of (-) N - acetyl 15 4,5,6,7 - tetrahydrobenzoi bjthiophen - 4 - amine by the method of Example 2 affords the title compound. m.p. 130°C to 136°C, I al·24 = - 144.4°C, C = 0.514 in acetic acid. 4 8 46 Example 30 Mouse Growth Regulant Tests CFI female mice froni Carworth Farm are received when they are 6 weeks old. They are housed TO 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. Hater is also allowed ad libitum.

Thirteen days after arrival·, the mice are weighed in groups of and assigned at random to the different treatments. The concentration of the different compounds in the diet is indicated in the following Table, Twelve days later the mice are weighed again and the experiment terminated. At least 3 cages (30 mice) of untreated controls are included in each test. Test data are provided in the Table below wherein data are reported as percent weight gain over controls. The following is a description of the diet to which the growth promoting compounds are added.

Guaranteed Analysis Crude protein not less than --- 23.0% 20 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 Β·^ supplement, calcium pantothenate, choline cholide, 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. 4 8 4 6 TABLE Effectiveness of 4,5,6,7-tetrahydro-7-oxo(oxy)benzoi bJthiophen-4-amines As Animal Growth Promoting Agents Reported as Percent Weight Over Controls Using Mice as the Test Animal

Claims

1. C L A IHS

1. A compound of the formula (I) wherein Rj is hydrogen; Rg is hydrogen, C-j-Cg alkanoyl, 5 halo-substituted (η-Cg alkanoyl or wherein Y is hydrogen, 3,4-dichloro, chloro, methyl, methoxy or nitro or R-| and Rg taken together with the associated nitrogen represent a cyclic amide selected from succinimido, maleimido, phthalimido and 1,2,3,6 - tetrahydrophthalimido; Rg is oxo or hydroxy, with the proviso that when Rg is oxo then Rg is not hydrogen or formyl; 5 X is chlorine, bromine or iodine; and n is 0 except when R-| and Rg are both hydrogen when n is 0 or 1.

2. N - Acetyl - 4,5,6,7 - tetrahydro - 7 - oxobenzo|_b J thiophen - 4 - amine.

3. N - Propionyl - 4,5,6,7 - tetrahydro - 7 10 oxobenzoj b j thi ophen - 4 - amine.

4. N - Isobutyryl - 4,5,6,7 - tetrahydro - 7 - oxobenzo[b jthiophen - 4 - amine.

5. N - Pivaloyl - 4,5,

6. ,7 - tetrahydro - 7 - oxobenzcf bjthiophen - 4 - amine. 15 6. N - Trichloroacetyl - 4,5,6,7 - tetrahydro - 7 oxobenz

7. N - (4,5,6,7 - Tetrahydro - 7 - oxobenzoQbJthien 4 - yl)phthalamide.

8. A process for the preparation of a compound as defined in 20 Claim 1, which comprises oxidizing 1 mole equivalent of a compound of the formula: 4 4 8 4 θ I - wherein R^ and Rg are as defined in Claim 1 with from 2 to 8 mole equivalents of an oxidizing agent selected from ceric ammonium nitrate, ceric sulfate, silver oxide, chromic anhydride and 5 sodium diehromate 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, perchloric acid or chromic anhydride in acetic anhydride at a temperature of from 10 0°C to 100°C for a period of time sufficient for a substantial degree of oxidation tp take place.

9. A process according to Claim 8, wherein 2 to 5 mole equivalents of ah oxidizing agent is used at a temperature range of 20°C to 60°C.

10. A method for improving feed efficiency and enhancing the growth 15 rate of animals, which comprises administering to said animals an 4 4 8 4 6 effective amount of a compound according to any one of Claims 1-7.

11. A method according to Claim 10, wherein said compound is administered to said animals in an amount equivalent to from 0.0001% to 0.08% by weight of the animal feed. 5

12. A method according to Claim 10, wherein said compound is parenterally administered as one or more subcutaneous implants beneath the skin of said animal and said implants being sufficient'to provide a daily drug release of from 0.0005 mg to 0.2 mg of said compound per kg of animal body weight. 10

13. An animal feed composition for improving feed efficiency and enhancing the growth rate of animals, which comprises a nutrionally balanced animal feed containing from 0.0001% to 0.08% by weight of a compound according to any one of Claims 1-7.

14. An animal feed permix for improving feed efficiency and enhancing 15. The growth rate of animals, which comprises from 70% to 99% by weight of an edible carrier and from 1% to 30% by weight of a compound according to any one of Claims 1-7.

15. A compound according to Claim 1 and substantially as described in any one of Examples 1, 2, 4 - 26 and 29 herein. 20

16. A process for preparing a compound according to Claim 1, substantially as described in any one of Examples 1, 2, 4 - 26 and 29 herein.

17. A compound according to Claim 1, whenever prepared by a process according to any one of Claims 8, 9 or 16.