AU593384B2 - Depilating compounds and compositions - Google Patents

Description

r 4 ^^aia« 7WW.

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority 591,19,) kA 14 p* At A Related Art: APPLICANT'S REFERENCE: PH 34036/AU Name(s) of Applicant(s): Imperial Chemical Industries PLC t< Address(es) of Applicant(s): .4 Imperial Chemical House, Millbank, London SW1P 3JF, UNITED KINGDOM.

Address fur Service is: PHILLIPS ORMONDE FITZPATRICK SPatent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Complete Specification for the invention entitled: DEPILATING COMPOUNDS AND COMPOSITIONS Our Ref 67751 POF Code: 1453/1453 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): 6003q/1 1 la TITLE: DEPILATING COMPOUNDS AND COMPOSITIONS This invention relates to depilating compounds and compositions, and in particular it relates to compositions which are useful for chemically depilating animals following oral ingestion, and which contain certain 4-pyridone derivatives.

The removal of animal hair, most notably the removal of fleece from sheep, is a major industry. Traditionally, this has been done by skilled hand labour, but this has been augmented more recently by a variety of machines. However, the costs of manual and mechanical means of hair removal, both in terms of labour and process costs, and damage and discomfort to the animal, has been high, and there has consequently been an upsurge of interest in the use of chemical agents which renders the hair more easily removable. A number of patent applications covering defleecing agents for sheep have been filed, for example Australian Patent No. 492923 and Australian Patent Appli.ations Nos. 11737/76 and 73659/81.

According to this invention, there is provided a 4pyridone compound of the formula I:- 11 o c-44 I wherein R 1 is a phenyl or thienyl radical substituted with one or more substituents selected from halogen atoms, amino, carbamoyl, carboxy, cyano and nitro radicals, 1-6C alkyl, halogenoalkyl and alkoxy radicals, (1-6C alkoxy)carbonyl radicals, mono (1-6C alkyl)carbamoyl radicals, 1-6C alkylamino, halogenoalkoxy and alkanoylamino radicals, and di(l-6C alkyl)amino and di(l-6C alkyl)carbamoyl radicals, and R 2 R3, R 4 and R 5 are independently selected from hydrogen and halogen atoms, amino and cyano radicals, e-6C alkyl, halogenoalkyl, alkoxy and alkylthio radicals, (1-6C alkoxy)carbonyl and mono(l- -2- 6C alkyl)carbamoyl radicals.

In the 4-pyridone compound of the formula I, a suitable value for R 2

R

3

R

4 or R 5 when any of them is halogen, or for the halogen substituent in R 1 is, for example, a fluorine, chlorine, bromine or iodine atom, and especially a fluorine, chlorine or bromine atom.

A suitable value for R 2

R

3

R

4 or R 5 when any of them is 1-6C alkyl, or for an alkyl substituent in R1 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl or hexyl radical.

A suitable value for R 2

R

3

R

4 or R 5 when :any is a 1-6C halogenoalkyl radical, or for a halogenoalkyl *fi substituent in R 1 is for example, a chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, trifluoromethyl, 1- or 2-chloroethy, 1-or 2-fluoroethyl, 1,2-dichloroethyl, 1,2difluoroethyl, 1,1,2- or 2,2,2-trichloroethyl, 1,1,2 or 2,2,2trifluoroethyl, 1-chloro-2,2-difluoroethyl, 2- or 3chloropropyl, 2,2,3,3,3-pentafluoropropyl, or 2,2,3,3tetrachloro-4,4,4-trifluorobutyl radical.

A suitable value for R 2

R

3

R

4 or R 5 when any is a '4 1-6C alkoxy radical, or for an alkoxy substituent in R1, is, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy radical.

25 A suitable value for R 2

R

3

R

4 or R 5 when any is a 4 4 '1-60 alkylthio radical is, for example, a methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1methylbutylthio, l-ethylbutylthio, 2-methylbutylthio, pentylthio or hexythio radical.

A suitable value for R 2

R

3

R

4 or R 5 when any is a (1-6C alkoxy)carbonyl radical, or for an alkoxycarbonyl substituent in R1, is, for example, a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or pentyloxycarbonyl radical.

t r i, i i: -3o 99 o o 99 9 S iS*# A suitable value for R 2

R

3

R

4 or R 5 when any is a mono-(l-6C alkyl) carbamoyl radical or for a mono-(l-6C alkyl)carbamoyl substituent in R 1 is, for example, a methylcarbamoyl, ethylcarbamoyl, propyicarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl or hexylcarbamoyl radical.

A suitable value for a 1-6C alkylamino substituent in

R

1 is, for example, a methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino or hexylamino radical.

A suitable value for a 1-6C halogenoalkoxy substituent in Rl is, for example, a fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 1-or 2-fluoroethoxy, 1- or 2-chloroethoxy, 1,1- or 1,2-difluoroethoxy, 1,1- or 1,2-diclloroethoxy, 1,1,2-, 15 1,2,2- or 2,2,2-trifluoroethoxy, 2-or 3-fluoropropoxy or 2.2.3,3,3-pentafluoropropoxy radical.

A suitable value for a 1-6C alkanoylamino substituent in R 1 is, for example, a formamido, acetamido, propionamido, butyramido, isobutyramido, valeramido, isovaleramido or 20 hexanamido radical.

A suitable value for a di-(l-6C alkyl)amino substituent in R 1 is, for example, a dimethylamino, ethylmethylamino, diethylamino, dipropylamino, methylpropylamino, ethylpropylamino, dibutylamino, dihexylamino 25 or hexylmethylamino radical.

A suitable value for a di-(l-6C alkyl)carbamoyl substituent in RI is, for example, a dimethylcarbanoyl, ethylmethylcarbamoyl, diethylcarbamoyl, methylpropylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl or hexylmethylcarbamoyl radical.

A preferred group of compounds of the invention comprises compounds of the formula I wherein R2, R3, R 4 and R are hydrogen and Rl is a phenyl or thienyl radical at least one substituent selected from the group consisting of halogen atoms, nitro radicals, and 1-40 alkyl, alkoxy, halogenoalkyl and 999 9t 9 99 9

I

i 'j ru~LC~2;; -4halogenoalkoxy radicals, provided that at least one of such substituents is a halogen atom or a 1-4C halogenoalkyl radical, and that when R 1 is a phenyl radical one such substituent is in a meta-position thereof.

A more preferred group of compounds of the invention, comprises compounds of the formula I wherein R 1 is a phenyl radical bearing a chlorine or bromine atom or a trifluoromethyl radical as a meta-substituent therein, and a particularly preferred group comprises compounds in which R 1 is a dichlorophenyl or tribromophenyl radical.

Particular preferred compounds of the invention are 1t (3,4-dichlorobenzyl)-4-pyridone, l-(3,5-dichlorobenzyl)-4- 1ft pyridone, l-(3-chloro-4-fluorobenzyl)-4-pyridone, 1-(3,5dibromobenzyl)-4-pyridone, l-(3,4,5-tribromobenzyl)-4-pyridone and 1-[3,5-bis(trifluoromethyl)benzyl]-4-pyridone.

The novel 4-pyridone derivative of the invention may be manufactured by processes known per se for the manufacture of chemically analogous compounds. Thus, the following processes, wherein R 1

R

2

R

3

R

4 and R 5 have the meaning given above, are 20 provided as a further feature of the inventionsa) the reaction of 4-pyridonae (which may alternatively be S" described as tautmeric 4-hydroxypyridine), of the formula:with an alkyl halide of the formula X.CH2R 1 wherein X is a halogen atom, in the presence of a base; the reaction of 4-pyrone of the formulasg2-

F

3

IZ

of the formula NH 2

.CH

2 RI; or reaction of a 4-methylpyridinium salt of the with an amine C) the formula:a, It I

I

r t I II ~rI ~j3 (113 I G

(IV)

ELf.

wherein Y- is an anion, with a lower alkyl nitrite in the presence of a base; or d) the hydrogenolysis of a halogen compound of the formula:hit a a ii a ~h

I

I

I$4*II

I

K 2 1 3 C' CA, P I the reaction of a 4-hydroxypyridine silyl ether of the r. -6formular- 3 p 3

(VI)

wherein R is a lower alkyl radical, which may be the same or different, with an alkyl halide of the formula X.CH 2

R

1 wherein S, X is a halogen; or .t f) the reaction of a 4-halogenopyridinium salt of the formula:- X N- C-(VII) yt t wherein X and Y have the meanings defined above, with dimethylsulphoxide.

In process a suitable base is, for example, sodium S 25 hydride.

In process the anion Y is suitably a halide ion.

A suitable lower alkyl nitrite is, for example, one of 1 to 6 carbon atoms, for example pentyl nitrite, and a suitable base is an alkali metal 1-6C alkoxide, for example sodium methoxide or i sodium ethoxide.

In process the hydrogenolysis is preferably carried out in the presence of a catalyst, for example platinum or palladium.

In process the lower alkyl radicals R are preferably of 1 to 6 carbon atoms, for example methyl or ethyl r 7 radicals.

The halogen compound of the formula V, which is used as the starting material in process is obtained by reacting 4-pyridone with thionyl chloride to form the >N.SOC1 derivative, which is reacted with an aldehyde RICHO to form the required halogeno compound All of the above process a) to f) are carried out in a suitable inert diluent or solvent, and may be accelerated or completed by carrying out the reaction at an elevated temperature, which may often conveniently be the boiling point of the diluent or solvent.

ft 4 According to a further feature of this inve. ion, there is provided a depilating composition, for administration to animals, comprising as the effective component thereof at least one 4-pyridone compound as defined above.

The composition of the invention may be administerd to animals by any convenient means, but oral administration is preferred and for this route, the composition is usually formulated as a liquid aqueous suspension or a gelatine capsule.

In addition to water, the dispersion may comprise a co-solvent to assist in the dispersion of the compound. A typical example of a suitable co-solvent is ethoxylated castor oil; this is used in water at a rate sufficient to give a 1 to 20%, preferably a S4%, w/v solution. Other typical ingredients such as antifoams S 25 (to prevent foaming during manufacture) may be included in artrecognised quantities. The compound itself is present to the extent that a dose of from 1 to 500mg. of compound per kg animal body weight, preferably 5 to 250mg/kg., may conveniently be given.

Preparation of suitable depilatory compositions may be carried out by any of the formulations which include conventional excipients and diluents.

The invention is illustrated, but not limited, by the following Examples.- Eu -8- Example 1 4-Pyridone (4-hydroxypyridine), (2.5g) was dissolved Sin dimethylformamide (DMF), and added to a stirred suspension of sodium hydride (1.28g of a 50% dispersion) in a mixture of equal parts of toluene and DMF. The mixture effervesced and produced a slight exotherm. 3,4-Dichlorobenzyl chloride (3.5ml) was added, and the reaction mixture was stirred for 1 hour, then poured into water. The preci itated solid was filtered off, and recrystallised first from methanol, then from chloroform, to give l-(3,4-dichlorobenzyl)-4-pyridone as a white solid, m.p.

71-74 0 c.

Example 2 A solution of 3,4,5-tribromotoluene (7.0g, 21 mmole), N-bromosuccinimide (3.78g, 21 mmole) and benzoyl peroxide (O.lg) in carbon tetrachloride (80ml) was heated under reflux and irradiated with a sunlight lamp for 1 hour. After cooling, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to leave a tan coloured solid (9.8g) which consisted of the starting material, 3,4,5-tribromobenzyl bromide and l-dibromomethyl-3,4,5-tribromobenzene (1:2.1 by NMR spectroscopy).

A solution of crude 3,4,5-tribromobenzyl bromide (9.8g) and 4-pyridone sodium salt (6.0g) in dimethylformamide (10ml) was stirred at room temperature under nitrogen for 16 S 25 hours. The mixture was then poured into iced water (100ml) and stirred for 0.5 hours, and the resultant solid was filtered off and washed successively with water (50ml) and ether (2 x to give l-(3,4,5-tribromobenzyl)-4-pyridone, m.p. 2110C.

Example 3 A solution of 3,5-bis(trifluoromethyl)benzyl bromide (9.4g, 30.8 mmole) and 4-pyridone sodium salt (7.0g) in dimethylformamide (20ml) was stirred under nitrogen at room temperature for 16 hours. The mixture was poured into iced water (100ml) and stirred for 0.5 hours, and the resultant solid was filtered off and washed successively with water (50ml) and

I

9 ether (2 x 50ml) to give l-[3,5-bis(trifluoromethyl)benzyl]-4pyridone.

Example 4 To a solution of 3,4,5-tribromotoluene (8.4g) in carbon tetrachloride (75ml) was added N-bromosuccinimide and benzoyl peroxide (60mg). The mixture was heated at reflux in the presence of light, and further portions of benzoyl peroxide were added periodically, until the reaction was complete The reaction mixture was cooled to room temperature and filtered, and the filtrate was evaporated to yield a mixture of products including the desired 3,4,5tribromobenzyl bromide as determined by 1H NMR spectroscopy).

A solution of 4-pyridone (105g) and sodium methoxide (54g) in methanol (350ml) was stirred at room temperature overnight. The reaction mixture was concentrated, allowed to partially solidify, then diluted with ether (50ml). The solid was collected by filtration and dried to yield 4-hydroxypyridine sodium salt (llOg).

A solution of crude 3,4,5-tribromobenzyl bromide (13.6g) and 4-pyridone sodium salt (5.9g) in N,Ndimethylformamlde (20ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and the precipitate was collected by filtration and washed with water.

The solid was stirred in ether, the product was collected by S* filtration and dried to yield l-(3,4,5-tribromobenzyl)-4pyridone as white crystals from ethanol/water, mp 213 0

C

Example 4-Pyridone (1.46g) was dissolved in ethanol containing sodium hydroxide (0.60g). The mixture was stirred at room temperature for lh, then treated with 3,4-dic,hlorobenzyl chloride and stirring was continued for a further lh.

The reaction mixture was diluted with water, and the precipitate was filtered off and washed with water. The solid was stirred in ether and the product was collected by filtration and dried to afford l-(3,4-dichlorobenzyl)-4-pyridone (2.29g) as tan crystals, nip Examples 6-19 The general process described in Examples 4 and 5 was repeated, using the appropriately-substituted benzyl halide (or, in the case of Example 13, 5-chiorothenyl chloride) to give the following compounds 1 C r 1 25 I '6 7 8 9 10 11 12 13 14 15 16 17 18 19 3-chiorophenyl 3 ,5-dichlorophenyl 3, 5-dibromophenyl 3-chloro-4-fluorophenyl 3 ,5-bis( trifluoromethyl)pheny'L 2 ,3-dichlorophenyl 3-t rifluoromethyiphenyl 5-chiorothenyl 3 ,4-dibromo-5-nitrophenyl 3, 5-dibromo-4-methoxyphenyl 3 ,5-dibromo--4-chlorophenyl pentafluorophenyl 3-bromo-4-e thoxy-5-ni trophenyl 3,4 ,5-trichlorophenyl I I I (a) 1 75 1 I 178 1 1 110 1 1 142 1 149 1 117 I 1 123 1 1 140 1 1 198 1 I 223 1 1 185 1 I 77 1 I 185 1 4 I I ~II I

I

411*11

I

NMR in D 6 -acetone: 8 5.20(2H,s); 6.20(2H,d); 7.4(4H,m); 7.75(2H,d).

DS34036 SF22 JDA/IIELe 01 Sep 87

Claims (8)

1. A 4-pyridone compound of the formulao- ~2g 0 -c~ wherein Rl is a phenyl at thienyl radical substituted with one at mote substituents selected from halogen atoms, amino, carbamoyl, carboxy, cyano and nitro radicals, 1-6C alkyl, halogenoalkyl and alkoxy radicals, (1l-6C alkoxy)carbonyl radicals, mono(l-6C alkyl)carbamoyl radicals, 1-6C alkylamino, halogenoalkoxy and alkanoylamino radicals, and di(l-6C alkyl)amino and di(l-6C alkyl)carbamoyl radicals, and R 2 R 3 R 4 and R 5 are independently selected from hydrogen and halogen atoms, amino and cyano radicals, 1-6C alkyl, halogenoalkyl, alkoxy and alkylthio radicals, (1-6C alkoxy)carbonyl and mono(l- 6C alkyl)carbamoyl radicals.

2. A compound as claimed in claim 1 wherein R 1 is a phenyl or thienyl radical substituted with one or more substituents selected from fluorine, chlorine, bromine and iodine atoms, and methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, tert-butyl, isobutyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, trifluoromethyl, 1- and 2-chloroethyl, I- and 2-fluoroethyl, l,2-"dichloroethyl, 1,2-difluoroethyl, 1,1,2- and 2,2,2-trichioroethyl, 1,1,2 and 2,2,2-trifluoroethyl, 1-chloro--2,2-difluoroethyl, 2- and 3- chloropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrachloro- 4,4,4-trifluorobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s!ec-butoxy, tert-butoxy, pentyloxy, hexyloxv, methoxycarbonyl, ethoxycArbomyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbomyl, pentyloxycarbonyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, -12- isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, methylamino, ethylamino, propylamino, isopropylamino, butylamino, pentylamino, hexylamino, fluoromethoxy, chioromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, trichioromethoxy, 1- and 2- fluoroethoxy, 1- and 2-chioroethoxy, 1,1- and 1,2- difluoroethoxy, 1,1- and 1,2-dichioroethoxy, 1,2,2- and 2,2,2-trifluoroethoxy, 2- and 3-fluoropropoxy, 2,2,3,3,3- pentafluoropropoxy, formamido, acetamido, propionamido, butyramido, isobutyramido, valeramido, isovaleramido, hexanamido, dimethylamino, ethylmethylamino, diethylamino, TI I dipropylamino, methylpropylamino, ethyipropylamino, a Cr dibutylamino, dihexylamino, hexylmethylamino, dimethylcarbamoyl, ethylmethylcarbamoyl, diethylcarbamoyl, methyipropylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl and hexylmethylcarbamoyl radicals, and R 2 R 3 R 4 and R 5 are each selected from fluorine, chlorine, bromine and iodine atoms, and methyl, ethyl, propyl, isopopyl, butyl, sec- butyl, tert-butyl, isobutyl, pentyl, hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, trifluoromethyl, 1- and 2-chioroethyl, 1- and 2-fluoroethyl, 1,2-dichioroethyl, 1,2-difluoroethyl, 1,1,2- and 2,2,2-trichioroethyl, 1,1,2 and 2,2,2-trifluoroethyl, l-chloro-2,2-difluoroethyl, 2- and 3- chioropropyl, 2,2,3,3,3-pentafluoropropyl, 2,2,3,3-tetrachloro-- 4,4,4-trifluorobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s.ec-butoxy, tert-butoxy, pentyloxy, hexyloxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1- methylbutylthio,. l-ethylbutylthio, 2-methylbutylthio, pentylthio, hexythio, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl ,methylcarbamoyl, ethy3.carbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl and hexylcarbamoyl radicals.

3. A compound as claimed in claim 1 wherein R 2 R 3 R 4 and R5 are all hydrogen, and RI is a phenyl or thienyl radical w 13 bearing at least one substituent selected from the group consisting of halogen atoms, nitro radicals, and 1-4C alkyl, alkoxy, halogenoalkyl and halogenoalkoxy radicals, provided that at least one of such substituents is a halogen atom or a 1-4C halogenoalkyl radical, and that when R 1 is a phenyl radical one such substituent is in a meta-position thereof.

4. A compound as claimed in claim 1, 2 or 3 wherein R 1 is a phenyl radical bearing a chlorine or bromine atom or a trifluoromethyl radical as a meta-substituent therein.

5. A compound as claimed in claim 4 wherein R 1 is a dichlorophenyl or tribromophenyl radical. S

6. A compound as claimed in claim 1 which is selected t i from the group consisting of l-(3,4-dichlorobenzyl)-4-pyridone, i' l-(3,5-dichlorobenzyl)-4-pyridone, l-(3-chloro-4-fluorobenzyl)- 4-pyridone, l-(3,5-dibromobenzyl)-4-pyridone, 1-(3,4,5- tribromobenzyl)-4-pyridone and 1-[3,5-bis(trifluoro- methyl)benzyl]-4-pyridone.

7. A process for the manufacture of a 4-pyridone compound, as claimed in claim 1, which comprises:- 20 a) the reaction of 4-pyridone (which may alternatively be described as tautmeric 4-hydroxypyridine), of the formula:- 2 R 3 with an alkyl halide of the formula X.CH 2 R 1 wherein X is a halogen atom, in the presence of a base; r A I 14 b) the reaction of 4-pyrone of the formula:- 0 (III) with an amine of the formula NH 2 .CH 2 R1; or c) the reaction of a 4-methylpyridinium salt of the formula:- 15 C3-A- ^2H (IV) R4- wherein Y- is an anion, with a lower alkyl nitrite in the presence of a base; or Sd) the hydrogenolysis of a halogen compound of the t formula:- 0- (v) e) the reaction of a 4-hydroxypyridine silyl ether of the 1 k 15 formula 2 R3 C (VI) wherein R is a lower alkyl radical, which may be the same or different, with an alkyl halide of the formula X.CH 2 R 1 wherein X is a halogen; or f) the reaction of a 4-halogenopyridinium salt of the formula:- 3 wherein X and Y have the meanings defined above, with dimethylsulphoxide.

8. A depilating composition, for administration to animals, comprising as the effective component thereof at least one 4-pyridone compound as claimed in claim 1. DATED: 15 September 1987 W 4 PHILLIPS ORMONDE FITZPATRICK Attorneys for: Imperial Chemical Industries PLC DC34036 01 Sep 87