GB2388595A - Novel 3-substituted-4-hydroxycoumarins - Google Patents

Abstract

Rodenticidal compounds of formula (I) <EMI ID=1.1 HE=47 WI=95 LX=430 LY=569 TI=CF> <PC>and stereoisomers and salts thereof, wherein R is hydrogen, alkyl, cycloalkyl, cycloketonyl, cycloamino, -(CHR<7>)nCOR<5>, -(CHR<7>)nCO2R<5>,-(CHR<7>)n-O2CR<5>, -(CHR<7>)nCONR<5>R<6>, -(CHR<7>)nNR<5>COR<6>,-(CHR<7>)nC(=NH)NR<5>R<6>,-(CHR<7>)n-C I N, or -(CH<7>)nNR<5>R<6>; R<1>, R<2>, R<3> and R<4> are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxyl, nitro, cycloalkyl, S(O)n-alkyl, S(O)n-haloalkyl, optionally substituted aryl, benzoyl, -C I N, -SC I N, -CO2R<5>, -CONR<5>R<6>, -NR<5>R<6>, - NR<5>COR<6>, or -N3, or R<1> and R<2> together represent 5 halogen substituents; Y is oxygen, sulphur, -(CH2)n-, alkenylene, alkynylene, -(CH2)p-O-(CH2)p-, -O(CH2)p-, -(CH2)pO-, -O(CH2)pO-, -S(CH2)p-, -(CH2)pS-, SO(CH2)p-, -(CH2)pSO-, SO2(CH2)p-, -(CH2)pSO2-, -SO-, -SO2-, -CO2-, or -CONH-; X is oxygen or sulphur; m is 0 or 1; n is 0, 1, or 2; each p is independently 1 or 2; R<5> and R<6> are each independently hydrogen, alkyl, hydroxyalkyl, amine, benzyl or optionally substituted aryl, or R<5> and R<6> join to form a cycloalkyl ring, or when R is -(CHR<7>)nCOR<5>, the C=O group of R and the OH group attached to the 4-position of the coumarin ring system join to form a hemiketal; and R<7> is hydrogen or alkyl; with the proviso that when m is 0, X is oxygen, and R<1> R<2>, R<3> and R<4> are all hydrogen, R is other than methyl or -CH2COCH3, and when m is 1, X and Y are both oxygen, and R<1>, R<2>, R<3> and R<4> are all hydrogen, R is other than methyl.

Description

GO 2388595 A continuation (72) Inventor(s): Alan John Whittle Joseph John

Swanborough David Rees Parry Raymond Leo Sunley (74) Agent and/or Address for Service: Malcolm John Houghton Syngenta Limited, PO Box 3538, Intellectual Property Department, Jeaiotts Hlil Research Centre, BRACKNELL, Berks, RG42 6YA, United Kingdom I

- 1 NOVEL COMPOUNDS

This invention relates to novel compounds useful as rodenticides and as human and veterinary medicinal agents, to chemical processes useful for their preparation, to compositions comprising them and to a method of killing rodents or reducing a population of s rodents using the compositions.

According to one aspect of the present invention there is provided a compound of formula (1) or a stereoisomer or a salt thereof, wherein R is hydrogen, alkyl, cycloalkyl, cycloketonyl, cycloamino, (CHR7)nCOR5, (CHR7)nCO2R5, -(CHR7)n-O2CR5, (CHR7)nCoNR5R6, -(CHR7)D NR5COR6, 1 0 (CHR7)nC(=NH)NR5R6, -(CHR7)n-C--N. or ^(CH7)nNR5R6; R', R2, R3 and R4 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxyl, nitro, cycloalkyl, S(O)nalkyl, S(O)n-haloalkyl, optionally substituted aryl, benzoyl, -CON, -SCAN, -CO2R5, -CoNR5R6, -NR5R6, - NR5CoR6, or -N3, or Rat and R2 together represent 5 halogen (e.g. 5 fluorine or 5 5 chlorine) substituents; Y is oxygen, sulphur, -(CH2)p-, alkenylene, alkynylene, -(CH2)p-O-(CH2)p-, -C) (CH2)p-, -(CH2)pO-,-O(CH2)pO-,-S(CH2)p-,-(CH2)pS-,-SO(CH2)p-,-(CH2)pSo-'So2(CH2)p-, -(CH2)pSO2-, -SO-, -SO2-, -CO2-, or -CONH-; X is oxygen or sulphur; 20 m is O or 1; nisO, 1,or2; each p is independently I or 2; Rs and R6 are each independently hydrogen, alkyl, hydroxyalkyl, amino, benzyl or optionally substituted aryl, or Rs and R6 join to form a cycloalkyl ring, or when R is 25 -(CHR7)nCoRs, the C=0 group of R and the OH group attached to the 4-position of the coumarin ring system Join to form a herniketal; and R7 is hydrogen or alkyl; with the proviso that when m is 0, X is oxygen, and R', R2, R3 and R4 are all hydrogen, R is other than methyl or -CH2COCH3, and when m is 1, X and Y are both oxygen, and R, R2, 30 R3 and R4 are all hydrogen, R is other than methyl.

When any one or more of R. R', R2, R3, R4, R5, R6 and R7 is alkyl, or contains an alkyl moiety, it can be straight or branched chain, and is preferably C'-6 alkyl, even more (

2 - preferably Cl 4 alkyl, for example, methyl, ethyl, n-propyl, sopropyl, n-butyl, sec-butyl, tso-butyl, t-butyl, _-pentyl, or_-hexyl.

When any one or more of R. Rat, R2, R3 and R4 is cycloalkyl, or R5 and Ret join to form a cycloalkyl ring, cycloalkyl is preferably C3.6 cycloalkyl for example, cyclopropyl or 5 cyclobutyl. When any one or more of R. R', R2, R3 and R4 is alkoxy, or contains an alk:oxy moiety, it can be straight or branched chain, and is preferably C'-6 alkoxy, for example, methoxy, ethoxy, propoxy or butoxy.

When any one of R', R2, R3 and R4 is alkenyl or alkynyl, it is preferably C2 6 alkenyl or lo C2 6 alkynyl, for example, vinyl, allyl, ethynyl or propargyl.

When any one or more of R., R2, R3, and R4 is haloalkyl, it is preferably Con haloalkyl, and may contain one or more halogen atoms, preferably chlorine, fluonne, or bromine, for example, trifluoromethyl, trifluoroethyl or pentafluoroethyl.

When any one or more of Rat, R2, R3 and R4 is ha]oalkoxy, it is preferably C'-6 IS haloalkoxy, and may contain one or more halogen atoms, preferably chlorine, fluorine, or bromine, for example, trifluoromethoxy, trifluoroethoxy or pentafluoroethoxy.

When R is cycloketonyl, it is a cyclic ketone rmg, preferably a 3-6 membered ring, for example, cyclopentanone or cyclohexanone.

When R is alkylamino or dialkylamino, or contains such a moiety, it is preferably C, 20 alkylamino or di-C-alkylamino, for example methylamino, dimethylarnJno, ethylamino or diethylamino. When R is cycloamino it is a cyclic amine, preferably with a 3-6 membered ring, for example, piperidine or pyrrolidine. The cyclic amine may also contain a further heteroatom, such as oxygen or another nitrogen. Examples of such compounds are morpholine, oxaziran, 2s oxazolidine and piperazine.

When R is -(CHR7)nCOR5, the C=0 group of R and the OH group attached to the 4 position of the coumarin ring system may join to form a hemiketal; i.e. the C of the C=0 group and the O of the OH group are joined by a single bond. Examples of this are to be found in Compounds Nos 85-87 of Table 1. In Compound 85, R is (CHR7)nCOR5, n is 0 30 and R5 is hydrogen. In Compound 86 and 87, R is -(CHR7)nCoR5, n is 1 and R5 and R7 are both hydrogen When any one or more of R', R2, R3 and R4 is halogen, it is preferably fluorine, chlorine, bromine, or iodine.

When any one or more of Rl, R2, R3, R4, R5 and R6 is aryl, it is preferably phenyl. It can also be heteroaryl, preferably with a 5- or 6membered ring containing 0, N or S as the heteroatom, for example, pyridine, pyrrolyl, furyl or thienyl.

When any one or more of Rat, R2, R3, R4, Rs and R6 is substituted aryl, preferred 5 substituents are halogen, for example, fluorine, chlorine or bromine, C,-6 alkyl, nitro, cyano, S-alkyl containing up to 6 carbon atoms, SO-alkyl containing up to 6 carbon atoms, SO2-alkyl containing up to 6 carbon atoms, C'-6 alkoxy, C'-6 haloalkyl or C-6 haloalkoxy.

When any one or more of R. Ret, R2, R3 and R4 is -CoR5, or contains such a moiety, R5 Is preferably Cal 6 alkyl.

ID When any one or more of R. Rat, R2, R3 and R4 is -CO2R5 or -O2CR5. or contains such a moiety, R5 is preferably hydrogen or C'.6 alkyl.

When any one or more of R. Rt, R2, R3 and R4 is -CONR5R6 or NR5CoR6, or contains such a moiety, Rs and R6 are preferably each independently hydrogen or C,^ alkyl.

R7 is preferably hydrogen or methyl.

5 For the avoidance of doubt, by -N3 we mean a triazo group.

When Y is alkenylene, it is preferably C2 6 alkenylene, for example, CH=CH- or -CH2CH=CH-, and when Y is alkynylene, it is preferably C2 6 alkyd nylene, for example, -C-C-.

Particularly preferred are compounds where R', R3 and R4 are hydrogen; R2 is 20 hydrogen or halogen, preferably bromine, Y is oxygen, -OCH2-, -CH2or -(CH:)2-, when m is 1, ormisO; end Xis oxygen.

In a preferred aspect there is provided a compound of formula (I) wherein R is hydrogen, C' 4 alkyl, cyano(C 4)alkyl, Cs 6 cycloketonyl, piperidino, pyrrolidinyl, morpholino, di(C, 4)alkylamino, CI.4 alkylcarbonyl(C 2) alkyl, hydroxy(C' 4)alkylarnino, C' 4 2s alkylamino, C, 4 alkoxycarbonyl, C, 4 alkylarninocarbonyl, carboxy, N,N pentamethyleneamidino, piperidinocarbonyl, benzylarninocarbonyl, arninocarbonyl, Can alkylaminocarbonylmethyl, carboxyrnethyl, hydrazinocarbonylmethyl or piperidinocarbonylmethyl or R joins with the OH group attached to the 4position of the cournarin ring to form the group -C(O)O- or -CH2C(0)0-; Rt is hydrogen or halo (especially 30 2- or 3- fluoro, chloro or bromo); R2 which is in the 4- or 5- position (preferably the 4 position), is hydrogen, halogen, hydroxy, C' 4 alkyl, Cat 4 alkoxy, C'.4 haloalkyl, C.4 haloalkoxy, C'4 alkylthio, C'.4 haloalkylthio, cyano, cyanomethyl, hydroxyrnethyl, C2.4 a!keny!, C-,,, a!kVny!, I-,A:lkyl!fnyl; (I! A alkylsulfonyl acetamido. amino.

- 4 - di(C, 4)alkylamino, di(CI 4)alkylaminocarbonyl or benzoyl, or Rat and R2 together represent pentahalo (especially pentafluoro); R3 and R4 are both hydrogen; X is oxygen; m is O or 1; and when m is 1 Y is ethenylene.

5 The compounds of formula (I) exist as R/S enantiomers around the acarbon atom.

When Y is -SO(CH2)p-, -(CH2)pSO-, or -S(O)-, or any of Ri, R2 and R3, is SO-alkyl, the compounds of formula (I) exist as enantiomers and diastereoisomers. Furthermore, when Y is alkenylene, the compounds of formula (I) may also exist in the cis or bans forms. The scope of the present invention is to be understood to embrace all single isomeric forms of the lo compounds of formula (I) and all mixtures thereof, including raceme mixtures.

The compounds of formula (I) may also be prepared as salts, for example, sodium or potassium salts.

Examples of compounds according to the invention are those presented in Table I and stereoisomers and salts thereof.

TABLE I

Compound No R R R2 R3 R4 X 1 piperidino H H H H O 2 pyrrolidinyl H H H H O 3 -N(CH3)z H H H H O 4 morpholino H H H H O 5 -N(CH3)2 H 4-Br H H O 6 pperdino H H H H O 7 -CH2COCH3 H 4-Br H H O 8 2-cyclohexanonyl H 4-Br H H O 9 2-cyclohexanonyl H H H H O 10 H H H H H O

11 -C(CH3)3 H 4-Br H H O 12 H H 4-Br H H O 13 -CH(CH3)2 H 4-Br H H O 14 CH3 H 4-Br H H O 15 mopholino H 4-Br H H O 16 -NH(CH2)2OH H H H H O

17 -NH(CH22OH H 4-Br H H O 18 -NHCH(CH3)2 H 4-Br H H O 19 -NH2 H 4-Br H H O 20 -N(CH2)2CH3 H 4-Br H H O 21 morpholino H 4-OCHF2 H H O 22 morpholino 2-Cl 4-Cl H H O 23 -CH2COCH3 H H H H O

24 -CH2COCH2CH3 H 4-Br H H O 25 2-cyclopentanonyl H 4-Br H H O 26 -CH(CH3) COCH2CH3 H 4-Br H H O 27 -CH2COCH3 H 4-OCH3 H H O

- 6 - TABLE I (continued) Compound R Rl R2R3 R4 X No. 28 -CH2COCH3 H 4CF3H H O

29 -CH2COCH3 H 4-OCH(CH3)2 H H O

30 -CH(CH3)COCH3 H 4-Br H H O 31 -CH2COCH3 H 4-F H H O

32 -CH2COCH3 H 4-CH3 H H O

33 -CH2COCH3 H 4-CN H H O

34 -CH2COCH3 H 4-OCF3 H H O

35 -CH2COCH3 H 4-OCHF2 H H O

36 -CH2COCH3 H 4-1 H H O

37 -CH2COCH3 H 4-SCHF2 H H O

38 -CH2COCH3 H 4-CH=CH2 H H O

39 -CH2COCH3 H 4-SO2CH3 H H O

40 -CH2COCH3 H 4-NHCOCH3 H H O

41 -CH2COCH3 H 4-CHF2 H H O

42 -CH2COCH3 H 4-N(CH3)2 H H O

43 -CH2COCH3 H 4-SCH2CF3 H H O

44 -CH2COCH3 H 4-OCH2CF3 H H O

45 -CH2COCH3 H 4-C_CH H H O

46 -CH2COCH3 H 4-SCF3 H H O

47 -CH2COCH3 H 4-OCH2CH3 H H O

48 -CH2COCH3 H 4-CH2CN H H O

49 -CH2COCH3 H 4-CH2OH H H O

50 -CH2COCH3 H 4-CH2CH3 H H O

51 -CH2COCH3 H 4-SCH3 H H O

52 -CH2COCH3 H 4-OH H H O

53 -CH2COCH3 H 4-SOCH3 H H O

54 -CH2COCH3 H 4-C(CH3)3 H H O

- 7 TABLEI(continued Compound No. R R R2 R3 R X 55 -CH2COCH3 H 4-> 0H2 H H O

56 -CH2COCH3 H 4-OC(CH3)3 H H O

57 -CH2COCH3 H 4-CH(CH3)2 H H O

58 -CH2COCH3 H 4-CON(CH3)2 H H O

59 -CH2COCH3 3-F 5-F H H O

60 -CH2COCH3 2-C1 4-CI H H O

61 -CH2COCH3 2-CI H H H O

62 -CH2COCH3 3-C1 5-CI H H O

63 -CH2COCH3 2,3,4,5,6-F H H O

64 -CH2COCH3 H 4-COC6Hs H H O 65 -CH2COCH3 3-Br H H H O 66 -CH2COCH3 H 4OCF2CHF2 H H O

67 -CH2COCH3 H 4-OCH2CF2- H H O

CHF2 68 H H H H H O -CH=

CH 69 -CH2CH3 H 4-Br H H O 70 -CN H 4^Br H H O 71 -CO2C2Hs H 4-Br H H O 72 -CONHC(CH3)3 H 4-Br H H O 73 -CO2H H 4-Br H H O 74 -C(=NH)NCsHo* H 4- Br H H O 75 -CONCsHo* H 4-Br H H O 76 -CONHCH2C6Hs H 4-Br H H O 77 - CONH2 H 4-Br H H O 78 -CH2COhnHC(CH3)3 H H H H O

8 - TABLE I (continued) Compound No. R R1 R2 R3 R4 X Y 79 - CH2CO2H H H H H O

80 -CH2CO2H H 4-Br H H O 81 -CH2CONHN(CH3)2 H H H H O

82 -CH2CONHC(CH3h H 4-Br H H O 83 -CH2CO2C2H5 H 4-Br H H O 84 CH:CONCsHo* H 4-Br H H O 85) 5 86) see structures listed under"Chemical formulae" 87) * NC5H'o is piperidino The melting points of compounds 7, 11, 12, 14, 71, 73, 74' 76, 78, 79, 85 and 86 are given in the Examples. Other melting points are: Compound No. Melting Point ( C) 5 116-120

13 104-108

61 112-114

62 122.5-123.5

63 167.5-168.5

66 199-201

69 188-190

70 286-290

72 2548:256.8

75 98- 105

77 206-208.4

80 140-150

81 198.4-201.6

82 246-246.8

83 163.8-166.0

( - 9 -

84 136.1-138.5

87 186.4-188.2

Compounds of formula (I) when X is oxygen may be prepared by reaction of 4-hydroxycoumarin with an appropriate side chain. Examples of procedures suitable for the preparation of compounds of formula (I) are shown in Schemes I to VI. Further details of 5 procedures suitable for the preparation of compounds according to the invention may be found in the Examples.

Compounds of formula (I) where R Is CHR7nCOR5, in which R5, R7 and n have the meanings given before, may be prepared by treating a Mannich base of formula (1), where R is an N-hnked amino group, typically an N-lmked cyclic amino group such as piperidino or lo morpholino, with a ketone H(CHR7)n CoR5 at a temperature of from 50 C to 200C, for example from SO C to 60 C. The Mannich base may be prepared by reacting 4- hydroxycoumarin with an amine, usually piperidine or morpholine, and the appropriate aldehyde of formula (XII) in a suitable solvent, such as dichloromethane, at ambient temperature. Similar methods are described in more detail in the chemical literature - see, 5 for example, US-A-2789986.

Compounds of formula (I) exert powerful anticoagulant activity. They may therefore be suitable for use in appropriate doses as therapeutic anticoagulants for medicinal and veterinary use. Administration of the compounds for such usage is normally in the form of a therapeutic composition comprising a compound of formula (I) as hereinbefore defined, or a 20 theraeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier or diluent.

The compounds of formula (I) are particularly useful as rodenticides and for the control of rodent populations. In such use, the compounds of formula (I) are normally formulated into compositions comprising a rodenticidally effective amount of a compound of 2s formula (I) as hereinbefore described and an inert carrier or diluent.

The compositions of the present invention may be used against a wide range of rodent pests, including the following commensal species: Rattus species, particularly _attus norveeicus (Norway or Brown rat), Rattus rattus (Black rat), Rattus argentiventer (Cotton or Ricefield rat); Mus species, particularly Mus musculus (House mouse); as well as

so non-commensal species which occur particularly as pests of agricultural crops or stored produce in various parts of the world such as for example voles of the family Cricetidae

( - 10 -

including Microtus spp. such as M. agrestis, and Arivicola spp. such as A. terrestris, rats and mice of the family Muridae, including Apodemus spp. such as A. sylvaticus, Acomys caharinus, Akc,don spp., Arvicanthis nlotica, Holochilus braziliensis, Mastomys natalensis, Mus booduga, Mus platvthrix, Neotoma spp., Peromvscus spp., Rattus exulans, Rattus s meltada, Rattus tiomanicus, Sigmodon hispidus and other rodents such as Nesokia indica, Tatera indica, Spermophilus spp., Meriones spp., Eutamias spp., Citellus spp., Bandicota spp., Cricetus cricetus, Ondatra zbetheca, and Myocastor coypus, although this is not intended to be an exhaustive list.

The rate of active ingredient in the rodenticidal composition of the present invention 0 which s effective is dependent on the inherent activity of the selected compound, the sze of the rodent and on susceptibility of the rodent. Thus, the rodenticidally effective rate of active ngredient can vary greatly but generally wi11 be from 0.01 mg/kg to 200 mg/kg and preferably from 0.05 mg/kg to 100 mg/kg for commensal rodents. The rodentcidal composition of the present inventon generally contains from 0.5 to 2000 parts per million of 5 the compound of fomula (1), preferably from 0.5 to 500 parts per million.

Rodenticidal compositions according to the invention are preferably in the form of bait compositions. The rodenticidal bait composition of the present invention may be formulated in accordance with procedures well known in the art and using any suitable bait base which 20 constitutes an edible carrier, for example, meat by-products, fats, bone meal or ground, whole or cut cereal grains such as wheat and wheat by-products, oatmeal, ground or cracked com, soybean products or rice. Any grain can be the base of such a composition. The bait composition may be formulated as for example, a drinking composition, a tracking powder, pellets, wax blocks or wax pellets, rrucro-encapsulated granules, wick devices or may simply 25 be added to the food base eg, whole or cracked wheat grains. The wax blocks or wax pellets use a cereal base such as wheat combined with wax to produce a more weather resistant bait.

Oats and maize are also often used, and it is sensible to produce baits that are similar in content to the natural food of the target rodent. lquid baits are used in dry environments such as seed stores, where there is abundant alternative food but little free water. Fatty 30 rodenticidal bait compositions are regularly made with inert ingredients such as peanut butter, other nut butters, milk solids, animal fats and vegetable oils.

Tracking powders are composed of rodenticidal compounds dispersed in powdered solids. Virtually any powder can be used, including talc, chalk, ground clays, flour, nut shell flour, and powdered stone.

Toxic materials mixed with an inert base material such as a dust or gel are termed 5 contact preparations. These are placed in the harbourages or runways so that the rodent's pelage becomes covered in the composition. The toxicant is then ingested during the grooming process.

Rodenticidal compositions in drinking water comprise suspensions or dispersions of the compounds.

0 Micro-encapsulation of the toxic material has the beneficial effect of further delaying the onset of toxic symptoms so that the animal does not associate the effect with the treatment and therefore the animal will feed on the bait again. Mcro-encapsulation also serves to increase the palatability of the composition. The active ingredient may be microencapsulated by known techniques, for example co-acervation of gelatin and/or gum 5 arable or interracial condensation polymerization using various polymers such as polyurea or polyamides. The bait ingredients generally include but are not limited to a base, hardening agents and optionally, a palatability agent/attractant and a colouring agent. The base can be any cereal flour or meal such as for example, wheatflour, oatflour, maizeflour or riceflour, and 20 the hardening agents include, for example, kaolin, talc, diatomaceous earth and mineral fillers, for example, porcelain (pharmaceutical grade). When the base is a cereal flour or a bait it should be of a quality acceptable for food. A palatability agent/attractant may be added to the bait composition to increase the attraction of the bait. The particular agent depends on the target species, for example, protein hydrolysate, powdered milk, monosodium 25 glutamate, sugar or sucrose may be used for attracting field rodents. Similarly, other agents

can be included such as, an aversive agent, for example, graphite as a bird aversive agent, preserving agents, for example, chlorinated phenols, a moisture retaining agent, for example, polyethylene glycol. Colouring agents may be included to indicate the nature of the active ingredient, for example, Prussian Blue, Rubine toner or Acid Red 9.

30 The invention further provides a method of killing or reducing a population of rodents which comprises supplying to a locus frequented by the rodents a rodenticidally effective amount of a rodenticidal composition comprising an inert carrier and as active ingredient a

- 12 rodenticidally effective concentration of a compound of formula (1) wherein the meanings of R. Rat, R2, R3, R4, R5, R6, R7, X, m and n are as defined above.

The rodenticidal composition may also take the form of a powder or liquid concentrate of the active ingredient for local formulation in the form of a bait.

5 The invention is illustrated by the following Examples in which percentages are by weight and the following abbreviations are used: GC = gas chromatography; NMR - nuclear magnetic resonance; s = singlet; d = doublet; triplet; q = quartet; m = multiplet; g = grammes; CDCI3 = deuterochloroform; DMSO = dimethylsulphoxide; or = fnfra red spectrometry; TLC - thin layer chromatography.

lo Chemical shifts (a) are measured in parts per million from tetramethyl solace. CDCI3 was used as solvent unless otherwise stated.

Preparation 1 This preparation illustrates the preparation of 1-(4'-Bromobiphenyl4-yl)-ethanol (II) Sodium horohydride (0 91g) was added to a stirred suspension of 5 1-(4'-bromo-biphenyl4-yl)-ethanone (m) (Preparation 6) (4.40g) in ethanol (80ml). The reaction mixture was stirred at the ambient temperature for a period of 1.5 hours, then heated at 50 C (bath) for a period of l hour. TLC (silica plates, ethyl acetate/hexane 1:2 as eluent) showed the absence of starting material. After cooling to the ambient temperature the reaction mixture was poured into water (200ml). The white precipitate so formed was 20 collected by filtration at the pump, washed with water and dried under suction to give 1-(4'-bromo-biphenyl-4-yl)-ethanol as a white solid (3.33g). OH NMR (CDC13) 7.52-7.58 (dx2,4H); 7.42-7.47 (dx2,4H); 4.96 (d-d,lH): 1.88 (d,lH) ; 1.55 (d,3H).

Preparation 2 This preparation illustrates the preparation of 1-(4'-Bromobiphenyl4-yl)-2,2-dimethy]-propan-1-ol (IV) 25 n-Butyl lithium (14.5ml of a 2.5M solution in hexane) was added dropwise to a stirred solution of 4, 4'dibromobiphenyl (9.36g) in tetrahydrofuran (90ml) under a nitrogen atmosphere over a period of 30 minutes maintaining the reaction temperature below -65 C.

After the addition was complete, the reaction was stirred at -5 C for a period of 2 hours. Trimethyl acetaldehyde (3.12g) was added dropwise to the stirred reaction mixture 30 over a period of 15 minutes maintaining the reaction temperature below -65 C. The reaction mixture was allowed to warm to the ambient temperature overnight. TLC (silica plates, ethyl acetate/hexane, 1:1 as eluent) showed only a trace of starting material. The reaction mixture was poured onto ice and acid with dilute hydrochloric acid then extracted into ethyl acetate

( - 13

(2x60ml). The combined organic phases were washed with brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed by evaporation under reduced pressure to give 1-(4'-bromo-biphenyl-4-yl)-2,2dimethyl-propan-1-ol plus minor impurities as a pale yellow coloured oil which solidified on standing to give a white waxy solid (8.25g). OH 5 NMR (CDCl3) 0 7.3-7.6(m,SH); 4.43(s,1H); 1.85(b,1H); 0.95(s,9H).

Preparation 3 This preparation illustrates the preparation of 4-(4'-Bromobiphenyl-4-yl)-but-3-en-2-one (V).

A solution of potassium hydroxide (O.Olg) in water (lml) was added dropwise to a stinted suspension of 4'-bromo-biphenyl-4-carbaldehyde (Preparation S) (1.78g) in acetone 0 (lOml) over a period of 2 minutes. The reaction mixture was stirred at the ambient temperature for a period of 3 hours then allowed to stand overnight. TLC (silica plates, chloroform as eluent) showed the absence of starting material. The solid that had precipitated was collected by filtration at the pump, dissolved in dichloromethane (SOrnl), the solution was dried over anhydrous magnesium sulphate, filtered, and the solvent removed by 5 evaporation under reduced pressure to give 4-(4'-bromo-biphenyl-4-yl)-but-3-en-2-one as a yellow crystalline solid (1.70g). OH NMR (CDCl3) 7.65-7.4(m,9H); 6. 76(d,1H); 2.40(s,3H). Preparation 4 This preparation illustrates the preparation of 4,4'-dihydroxy-,3,3'-(4"'-bromo-biphenyl4"-yl)-methylene his (coumarin) (VI).

20 A solution of 4'bromo-biphenyl-4-carbaldehyde (Preparation S) (2.61g) dissolved in ethanol (lOOml) with warming was added to a solution of 4hydroxycoumarin (3.24g) dissolved in ethanol (50cm3) with warning. The stirred reaction mixture was heated under reflex for a period of 16 hours. TLC (silica plates, ethyl acetate eluent) showed the absence of starting material. The reaction mixture was allowed to cool to the ambient temperature 25 and the precipitate that had formed was collected by filtration at the pump, washed with ethanol and dried under vacuum to give (VI) as an off-white solid (4.91g). OH NMR (CDC13): 11.55(s,1H); 11. 35(s,1H); 8.05(m,2H); 7.25-7.78(m,14H); 6.12(s,1H).

Preparation 5 This preparation illustrates the preparation of 4-(4'bromophenyl)-benzaldehyde (VII).

30 4,4'-Dibromobiphenyl (25.0g) was dissolved in dry tetrahydrofuran (220ml), and the solution cooled to -70 C in a dry ice/acetone bath, under a nitrogen atmosphere. A solution of n-butyl lithium in hexane (2.5 molar, 39ml), was added dropwise at -65 C to -70 C, the solutio,. st;,,ed or hours, then N-fo..y! mnrrhnl!ne!!.S,i added layer In minutes at this

- 14 temperature. After stirring for 20 minutes, the reaction was allowed to slowly warm to room temperature, stirred for 30 minutes, then evaporated to dryness under reduced pressure. The residue was stirred under dilute (approximately 0.7M) hydrochloric acid, then filtered and thoroughly water- washed. After air drying, the product was triturated with hexane to give s l9.0g of aldehyde of 93% strength by GC, the remainder being the dibromobiphenyl starting material. Further purification is readily effected by column chromatography. NMR (CDCI3): 10.05(s,1H); 7.4-8.0(m,8H, aromatic protons).

Preparation 6 This illustrates the preparation of 1-(4'-Bromo-biphenyl4yl)-ethanone (III).

Aluminium chloride (6.00g) was added to a stirred solution of acetyl chloride (2.83g) in lo dichloromethane (40ml). The reaction mixture was stirred at the ambient temperature for a period of 0.5 hours then heated under reflux for a period of l hour. The reaction mixture was allowed to cool to the ambient temperature and a solution of 4-bromobiphenyl (4.66g) in dichloromethane (lOrrd) was added portonwise over a period of to minutes. The stirred reaction mixture was heated under reflex for a period of l hour, then allowed to stand at the 5 ambient temperature overnight. TLC (silica plates, ethyl acetate/hexane, 1:2 as eluent) showed the absence of starting material. The solvent was removed by evaporation under reduced pressure, yielding a green solid this was added cautiously to ice/water (50ml), the beige coloured solid so formed was collected by filtration at the pump, washed with water until acid free and dried under vacuum to give 1-(4'-bromo-biphenyl-4-yl)-ethanone as a 20 beige coloured solid (5.44g). OH NMR (CDCI3) 6. 8.02(d,2H); 7.64(d,2H); 7.53(d,2H); 7.46(d,2H); 2.62(s,3H).

EXAMPLE 1

3-[1-(4'-Bromobiphenyl-4-yl)-ethyl]-4-hydroxy-coumarin (Vm: Compound No l4 of Table I) 2s 4-Hydroxycoumarin (1.62g) and 1-(4'-bromo-biphenyl-4-yl) -ethanol (Preparation 1) (2.77g) were treated with glacial acetic acid (50ml). The stirred reaction mixture was warmed until solution was obtained. Concentrated sulphuric acid (10 drops) was added and the stirred reaction mixture was heated to reflux for a period of 2 hours TLC (silica plates, ethyl acetate/hexane 1:2 as eluent) showed the absence of starting material. After cooling to the 30 ambient temperature the reaction mixture was poured into water (250ml).

The off-white precipitate so formed was collected by filtration at the pump, washed with water until acid free and dried under vacuum. Recrystallisation from toluene gave 3-[1-(4'-bromo-biphenyl-4-yl)-ethyl4hydroxycoumarin as a white solid (2.38g). M.Pt

- 15 -

219-222 C. tH NMR (CDCI3): 9.75(b,1H); 7.94(d,1H); 7.2-7.55(m,1H); 4.72(q, 1H); 1.75(d,3H). A general procedure for preparing compound (VIII) is outlined in reaction Scheme I. EXAMPLE 2

5 3-[1-(4'-Bromo-biphenyl-4-yl)-2,2-dimethyl-propyl]-4-hydroxy coumarin (IX: Compound No. 11 of Table I).

4-Hydroxycoumarin (972mg) and 1-(4'-bromo-biphenyl-4-yl)-2,2-dimethyl propan-1-ol (Preparation 2) (1.92g) were mixed together and heated with stirring under a nitrogen atmosphere at 210 C (bath) for a period of 1 hour. TLC (silica plates, ethyl acetate/hexane 0 l:l as eluent) slowed the absence of starting material. After cooling to the ambient temperature the reaction mixture was triturated in ethyl acetate, the solid was collected by filtration at the pump and the solvent was removed from the filtrate by evaporation under reduced pressure to give a yellow coloured gum. This was purified by column chromatography on silica gelethylacetateexane 1:1 2:1 aseluentto give 15 3-[1-(4'-bromo-biphenyl4yl)-2,2-dimethyl-propyll-4-hydroxy coumarin as a white solid (135mg). M. Pt 196-8 C. IH NMR (CDCI3): 7.68(m,3H); 7.4-7.6(m,5H); 7.42(d,2H); 7.2-7. 33(m,2H); 6.62(b,1H); 4.70(s,1H); 1.28(s,9H). A general procedure forpreparing compound (IX) is outlined in reaction Scheme n.

EXAMPLE 3

20 3-[1-(4'-bromo-biphenyl-4-yl)-3-oxo-butyl]-4-hydroxy coumarin (X: Compound No. 7 of Table I).

Piperidine (2 drops) was added to a stiTed suspension of 4-hydroxy coumarin (80mg) and 4-(4'-bromo-biphenyl-4-yl)-but-3-en-2-one (Preparation 3) (lSOmg) in dioxane (2ml). The strred reaction mixture was heated under reflux for a perod of 4 hour. TLC (silica plates, 25 ethyl acetate/hexane, I:1 as eluent) showed the absence of starting material. After cooling to the ambient temperature the reaction mixture was poured into ice/water, the pale yellow coloured precipitate so formed was collected by filtration at the pump, washed with water and dried under vacuum. Preparative thin layer chromatography (silica plates, ethyl acetateexane,1: 1 as eluent) gave 3-[1 -(4'-bromo-biphenyl4-yl)-3-oxo- butyl-4-hydroxy 30 coumarn as a white solid (60mg), which exists as a mixture of tautomers. M.Pt 196-l99C.

H NMR (CDCI3): 8.0-7.8(3xd,lH); 7.6-7.2(m,11H); 4.72-4.28 and 4.20(3xdd, 1H); 3.88(dd); 3.42(s), 3.33(dd), 2.6-2.35(m); 2.05-1.95(m); 2.30, 1.72 and 1.68(3xs,3H). A general procerl're for,nrenanng compound (X! is outlined in reacton Scheme III.

- 16 EXAMPLE 4

3-(4'-Bromo-biphenyl4-ylmethyl)-4-hydroxy coumarin (XI: Compound No. I 2 of Table 1)

Sodium cyanoborohydride (0.70g) was added portionwise over a period of 5 minutes to a 5 stirred suspension of 4,4'dihydroxy-3,3-(4"'-bromobiphenyl-4"-yl)-methylene his coumarin (Preparation 4) (3.12g) in methanol (50ml). The reaction mixture was heated under reflex for 6 hours, then allowed to cool to the ambient temperature and further sodium cyanoborohydnde (0.70g) was added. The stirred reaction mixture was heated under reflux for a period of 48 hours, TLC (silica plates, ethyl acetate/hexane, 1:1 as eluent) showed only 0 a trace of starting material to be present. The reaction mixture was allowed to cool to the ambient temperature and was poured into ce/water (250ml) the white sohd so fanned was removed by filtration at the pump. The filtrate was acidified with dilute hydrochloric acid and the precipitate so formed was collected by filtrate at the pump, washed with water until acid free and dried under vacuum. The product was purified by trituration in hot glacial 5 acetic acid followed by trituration in chloroform to give 3-(4'-bromo-biphenyl4ylmethyl)4-hydroxy coumarin as a white solid (1.37g). M.Pt 284-292 C. OH NMR (CDCI3 + d6 DMSO): o 7.98(d,1H); 7.25-7.6(m,1 IH); 4.02(s,2H). A general procedure for preparing compound (XI) is outlined in reaction Scheme IV.

EXAMPLE 5

20 This Example illustrates the preparation of 3-(4'-bromobiphen-4-yl)-2, 3-dihydro-2 oxo4H-furo[3,2-c][l]benzopyran4-one (Compound No.85 of Table I) and derivatives thereof (Compounds Nos. 71, 73 and 76 of Table I).

2-(4'-Bromobiphen-4-yl), 2-(4-hydroxycoumar-3-yl) acetonitrile 3-(4'Bromobiphen-4-yl), dimethylamino methyl3-4-hydroxy coumarn (3.66gms) and ethanol (40mls) were added to a solution of sodium cyanide (2.0gms) in water (7mls). The mixture was refluxed for 3 hours, cooled and concentrated to remove most of the ethanol.

Water was added to the residue with Meting and the mixture extracted with ethyl acetate.

30 The combined extracts were washed with brine, dried over MgSO4 and concentrated to give the nitrite (2.96gms) as a yellow solid melting at 286-290 C with decomposition.

IR (Nujol): Peak at 2240cm-'.

- 17 -

NMR (CDCI3 + drop of d6-DMSO): 5.98 (s,lH); 7.05-7.15 (dd,2H); 7.28-7.40 (m, 5H); 7.50 (d, 2H); 7.61 (d, 2H); 8.10 (dd, 1H).

2-Amino-3-(4'-bromobiphen4-yl)-4H-furo[3,2-c] [ l]benzopyran-4-one A mixture of 2-(4'-bromobiphen4-yl), 2-(4-hydroxycoumar-3-yl) acetonitrile (4.50gms) and acetic acid (lSOrnls) was heated at 100 C for 2/ hours, stood overnight and the insoluble solid formed was collected, washed with a little acetic acid and sucked dry. This solid was stirred with ethyl acetate (600mls) for 1/: hours and some Insoluble material removed.

lo Concentration of the filtrate gave the product as a yellow solid (2. 68gms) melting at 186.3 188.7 C.

IR (Nujol): Peaks at 3314 and 3400cm'.

NMR (CDC13): 4.41 (bs, 2H); 7.28-7.32 (m, 1H); 7.42 (d, 2H); 7.49 (d, 2H); 7.58 (d, 2H); 7.65 (m,4H); 7.77 (dd, 1H).

3-(4'-Bromobiphen-4-yl)-2,3-dihydro-2-oxo-4H-furo[3,2-c] [ l]benzopyran-4one (X[I: Compound No.85 of Table I) Concentrated HC1 (1.5mls) was added to 2-amino-3-(4'-bromobiphen-4-yl)-4H-furo[3,2 20 c][l]benzopyran4-one (1. 20gms) in acetic acid (8mls) and the mixture heated at 80 C for 10 minutes. After cooling, water was added to the mixture and the precipitated solid was collected, washed with water and dried. The lactone melted at 268.0-272.8 C with decomposition. IR (Nujol): Strong peaks at 1833 and 1728cm'.

2s Now (d6-DMSO): 5.38 (s, 1H); 7.36-7.68 (m,lOH); 7.77 (t, IH); 7.85 (t, 1H).

Ethyl 2-(4'-Bromobiphen-4-yl), 2-(4-hydroxycoumar-3-yl) acetate (XIII: Compound No.71 of Table I)

30 A mixture of 3-(4'-bromobiphen4-yl)-2,3-dihydro-2-oxo4H-furof 3,2-c][1] benzopyran4 one (0.75gms), pyridine (Smls) and ethanol (Smls) was briefly heated to obtain a clear solution and then stood overnight. By TLC the reaction was incomplete so more ethanol (amiss was added and the solution refluxed for IS minutes, cooled and added dropwise to

( - 18 -

cold, stirred 2M HCI. Stirring was continued for 15 minutes and the precipitate collected, washed with water and dried. The crude product (0. 81gms) was purified by dissolving in the minimum volume of toluene and adding hexane. Some insolubles appeared rapidly; these were removed. Subsequently, a gum separated. The supernatents were decanted from this s gum and after standing crystals were deposited. These were filtered, washed with hexane and dried to give the ester (0.37gms) melting at 148.3149.2 C.

IR (Nujol): Strong peaks at 1624, 1691 cm.

NMR (CDC13): 1.37 (I, 3H); 4.35 (q, 2H); 5.78 (s, 1H); 7.30 (dt, 2H); 7. 40 (d, 2H); 7.40 7.60 (m, 7H); 7.98 (dd, 1H).

0 Further ester was obtained from the filtrate and from the gum.

2-(4'-Bromobiphen-4-yl), 2-(4-hydroxycoumar-3-yl) acetic acid (XIV: Compound No.73 of Table I)

Aqueous NaHCO3 (l.Oml) was added to a suspension of 3-(4'-bromobiphen-4yl)-2,3 5 dihydro-2-oxo-4H-furo[3,2-c][l]benzopyran-4-one (0.70gm) in pyridine (lOmls) and the mixture was stiTed at RT. After 20 minutes a clear yellow solution was formed. This was stood overnight and added dropwise to glacial acetic acid with stimug. After a further 30 minutes stimng, water was added and stimng continued for another 30 minutes. The supernatents were decanted from the precipitated gum. The gum did not crystallise so it was 20 dissolved in aq. NaHCO3, some nsolubles removed and aq. HOAc added dropwise untl precipitation was complete. The solid was collected, washed with water and dried. The crude product was redissolved in aq. NaHCO3 and the solution washed with CHzCl2 and then added dropwise to HOAc. The precipitate was collected and reprecpitated once more from aq. NaHCO3 with HOAc, etc. to give the acid (0.42gms) melting at 88-89.7 C, 25 resolidifying and remelting with decomposition at 253.6-256.6 C.

IR (Nujol): Strong peaks at 1665, 1611 cm NMR (d6-DMSO): 5.16 (s, 1H); 7. 29 (m, 2H); 7.42 (d, 2H); 7.55-7.69 (m, 8H); 7.90 (dd, 1H). 30 N-Benzyl 2(4'-Bromobiphen-yl), 2-(4-hydroxycoumar-3-yl) acetamide (XV: Compound No. 76 of Table 1)

- 19 Benzylamine (0.125gm) was added to a suspension of the 3-(4'bromobiphen-4-yl)-2,3 dihydro-2-oxo-4H-furo[3,2-c][1]benzopyran-4-one (0. 50gms) in pyridine (4mls), the mixture was stirred for 10 minutes and then stood overnight. The mixture was poured into 2M HCI, stirred for '/' hour and the precipitate collected, washed with water and sucked dry. The s crude product was purified by chromatography on silica eluting with hexane containing an increasing proportion of EtOAc (two - 30o). The appropriate fractions were combined and concentrated to give the amide (0. 47gms) melting at 259.9-262.8 C.

IR (Nujol): Strong peaks at 1600, 1620, 1660, 1670, 3276 cm'.

NMR (CDCI3): 4.55 (dd, 2H); 5.78 (s, 1H); 7.20-7.60 (m,16H); 8.00 (dd, 2H) ; 14.59 (s, 1H).

A general procedure for preparing compounds (XII), (Xm) and (XV) is outlined in reaction Scheme V. EXAMP1 F 6

2-(4'-Bromobiphen-4-yl), 2-(4-hydroxycoumar-3-yl) N,N-pentamethylene acetarnidine (XVI: 5 Compound No.74 of Table 1) Piperidine (15mls) was added dropwise to a solution of 2-(4'-bromobiphen-4-yl), 2-(4 hydroxycoumar-3-yl) acetonitrile (2.60gms: prepared as described in Example 5) in pyridine (15n1s). The mixture was stirred for 10 minutes, stood overnight and poured slowly into 20 ice/water with stimng. Stirring was continued for a further 1/ hour. The mixture was then carefully brought to pH 7 with dilute HCI. The precipitated solid was collected, washed with water and sucked dry. The crude product was added to EtOAc (300mls) whereupon an insoluble gum formed. The supernatents were decanted and the gum was washed with more EtOAc and then triturated with hexane containing a little EtOAc to give the amidine 25 (1.28gms) as a pale green solid melting at 169.2-173.8 C.

NMR (d6-DMSO): 1.54 (m, 6H); 2.95 (m, 4H); 5.65 (s, 1H); 7.01-7.15 (m, 2H) ; 7.35 (dt, 1H); 7.39-7.6B (m, 8H); 7.78 (dd, 1H).

A general procedure for preparing compound (XVI) is outlined in reaction Scheme V. 30 EXAMPLE 7

This Example illustrates the preparation of 4-(biphen-4-yl)-2,5-dioxodihydropyrano[3,2 c]benzopyran (CBmpound No.86 of Table I) and {lerivatives thereof (Compound Nos. 78 and 79 ^f Tab!e I>.

! - 20

2-Amino4-(biphen-4-yl)-3-ethoxycarbonyl-S-oxo-pyrano[3,2-c]4H] benzopyran Ethyl alpha-cyano-4-phenyl cyclamate (5.54gms) was added to a solution of 4-hydroxy 5 coumarin (3.24gms) in dry pyridine (25mls) and the suspension was briefly warmed to obtain a clear solution. After 1 day at RT the solution was seeded and within an hour a virtually solid mass was obtained. This was stood overnight, then broken up and dilute HCI added with stirring. The solid was collected, washed with water followed by a small volume of methanol and sucked dry. The crude product weighed 8. 94gms. A sample recrystallized 0 from methanol melted at 159.g-161.4 C.

IR (Nujol): Peaks at 3419, 3280,1708,1689, 1653cm'.

NMR (CDC13): 1.19 (I, 3H); 4.08 (m, 2H); 4.98 (s, 1H); 6.47 (brs, 2H); 7. 85 (d, 1H); 7.21 7.60 (m, 12H).

IS 2-lmino4-(biphen4-yl)-S-oxo-dihydropyrano[3,2-c]benzopyran-3carboxylic acid A suspension of crude 2-amino4-(biphen-4-yl)-3ethoxycarbonyl-5-oxo-pyrano[3,2-c][4H] benzopyran (6.39gms) in ethanol (30mls) and 2N NaOH (40mls) was stirred at RT for 70 minutes during which time most of the solid dissolved. The remaining insolubles were no removed; the filtrate was diluted and citric acid added until no further precipitate was fanned. The mixture was stirred at RT for 2 hours and the white solid collected, washed with water and sucked dry. The crude acid (5.84gms) was used directly in the next stage.

IR (Nujol): Peaks at 336O, 1670, 160Scm'.

25 4-(Biphen-4-yl)-2,5-dioxo-dihydropyrano[3,2-c]benzopyran (XVIII: Compound No. 86 of Table I)

A solution of crude 2-imino-4-(biphen-4-yl)-5-oxo-dhydropyrano[3,2cbenzopyran-3 carboxylic acid (5.84gms) in glacial HOAc (33mls) and concentrated HCI (S.Smls) was 30 immersed in a hot oil bath (ca 120 C) for 15 minutes. Initial brisk evolution of gas was observed. The flask was removed from the oil-bath and water (ca 10mls) added to the still hot solution. A solid mass was obtained within 2 minutes. Excess water was then added and the mixture stirred at RT for an hour. The pale yellow solid was collected, washed with

- 21 water and sucked dry. NMR of the crude product (4.99gms) showed a mixture of the required lactone (ca 15%) and the corresponding ringopened acid.

A paste of the crude product from above and acetic anhydride (13mls) was immersed in an 5 oil-bath (ca 180 C) and stirred. After 8 minutes a clear reducing solution was obtained.

Heating was continued for a further 5 minutes. After a few minutes cooling the solution began to crystalline. It was stood at RT 40 minutes and water added. The resulting mixture was vigorously stirred for an hour and the white solid collected, washed with water and dried. The lactone (4.74gms) melted at 200.4-202.2 C.

0 IR (Nujol): Peaks at 1792, 171O, 1642, 1605cm-.

NMR (CDCl3): 3.17-3.27 (m, 2H); 4.58 (dd, 1H); 7.23-7.68 (m, 12H); 7.94 (dd, 1H).

A sample recrystallized from toluene had melting point of 203.8-205.8 C 3(Biphen-4-yl)-3-(4-hydroxy coumar-3-yl) propionic acid (XVII: Compound No. 79 of Table I) Saturated NaHCO3 solution (0.8mls) was added to a solution of 4-(biphen-4-yl)-2,5-dioxo 20 dihydropylano[3,2-c]benzopyran (0.75gms) in pyridine (8mls). The solution was stirred for 2 hours, stood for 9 days and added dropwise to aqueous citric acid solution. The precipitated solid was collected, washed with water and sucked dry. This crude product was dissolved in NaHCO3 solution (ca 60mls), some insolubles were removed and the product reprecipitated with citric acid as before. The product was further purified by redissolving in 25 NaCOa, washing the solution sequentially with CH2CI2 and hexane and reprecipitating etc to give the acid (0.61gms) melting at 137.4-139.2 C, resolidifying and remelting at 199.4 201.4 C with decomposition.

IR (Nujol): Peaks at 1707, 1676, 161 acme.

NMR (CDCI3 + drop d6-DMSO): 3.26 (q,lH); 3.42 (q, 1H); 5.04 (t, 1H); 7.177.60 (m, 12H); 30 8.02 (d, 1H).

N-tert butyl 3-(Biphen-4-yl)-3-(4-hydroxy coumar-3-yl) propionamide (XIX: Compound No.?8 of Table l)

( - 22

Tertiary butylamine (0.16gms) was added to a wand solution of 4-(biphen-4yl)-2,5-dioxo dihydropyrano[3,2-c]benzopyran (0.74gms) in dry pyridine (6mls) and the mixture stood at RT 3 days during which time some crystals separated. The mixture was warmed to 5 redissolve the crystals and added dropwise to 2N HCI (ca lOOmls). The precipitated crude product was collected, washed with water, sucked dry and recrystallized from ethanol (ca 120mls) to give the amide (0.4ggms) melting at 239.6-240.6 C with frothing.

IR (Nujol): Peaks at 3306, 1685, 1620, 1601cm.

NMR (CDCl3 + drop d6-DMSO): 1.14 (s, 9H); 2.99 (dd, lH); 3.29 (dd, 1H); 4. 98 (dd, 1H); 0 7.20-7.59 (m, 12H); 7.81 (s, 1H); 8.02 (dd, 1H); 13.58 (brs, 1H).

A general procedure for preparing compounds (XVn), (XVIII) and (X1X) is outlined in reaction Scheme Vl.

EXAMPLE 8

5 This example illustrates a number of different bait formulations.

Ingredients Wt % A. This composition may be used as a powder or may be compressed into pellets.

Active ingredient 0.00005 to 0.2 20 Preserving agent 0.005% Hydrophobic agent (wax) 5.0 Rodent attractant 2.5 Powdered sohd 4.5 Moisture retaining agent 0.5 as Visible dye 0.25 Cereal flour up to 100.0 B. Active ingredient 0.005 toO.05 Inert ingredients 5.0 30 Cereal flour 90. 0 Rodent attractant up to 100.0 C. This composition is formulated into a wax block.

- 23 Active ingredient 0.001 to 0.1 Moisture retaining agent 0.05 Cereal flour 55.0 Rodent Attractant 5.0 5 Visible dye 0.25 Hydrophobic agent (wax) up to 100.0 D. This composition is a liquid concentrate.

Active ingredient up to 4.0 to Oil up to 100.0 E. This composition is a powder concentrate.

Active ingredient up to 0.1 Mineral oil 10.0 5 Kaolin up to 100.0 EXAMPLE 9

This example demonstrates a range of bait formulations suitable for use in the method of the present invention.

Ingredients Wt % A. Active ingredient 0.005 Chlorinated phenols 0.005% (preserving agent) Synthetic wax 5.0 25 (hydrophobic agent) Protein hydrolysate 2.5 (rodent attractant) Powdered chalk 4.5 Polyethylene glycol 0.5 30 (moisture retaining agent) Prussian blue 0.25 (visible dye) Wheat meal up to 100.0

r - 24 B. Active ingredient 0.05 Vegetable oil 5.0 Maize meal/oat meal 90. 0 5 mixture (3:1) Sucrose up to 100.0 C. Active ingredient 0.015 Monosodium glutamate 0.5 0 Sugar 2.0 Kaolin 2.0 Rubine toner trace Wheatmeal up to lOO 15 D. Active ingredient 0.02 Polyethylene glycol 0.05 Maize meal 55.0 Sucrose 5.0 Prussian Blue 0.25 20 Paraffin wax up to 100. 0 E. Active ingredient l.O Vegetable oil up to lOO.O 25 F. Active ingredient 0.1 Mineral oil l O.0 Kaolin up to 100.0 EXAMPLE 10

30 This example illustrates the rodenticidal activity of compounds according to the invention. Test animals of the strain Rattus norvegicus were acclimatised in solid bottomed cages under hygienic conditions with free access to food and water for seven days prior to treatment, at a

( 25 temperature of 20 + 2 C and ambient humidity and under controlled airflow. Lighting was controlled to provide a 12 hour light/dark cycle. Test animals were chosen within an age range of 6-10 weeks and a weight range of 150-300g. Following the acclimatization period, the test subjects were marked for individual identification and provided with a laboratory diet s for a 6 day conditioning period.

Each test substance was applied orally by intubation at a rate of 250mg/kg body weight to two male test subjects. Clinical observations were made twice within 24 hours of dosing, then daily. Observed mortalities are recorded in Table II.

- 26 -

TABLE II

Compound No. (from Table I) Observed mortality 5 2/2 6 2/2 7 2/2 8 2/2 10 1/2

1 1 2/2

12 2/2

17 2/2

1 8 2/2

19 2/2

20 2/2

26 2/2

30 2/2

37 2/2

47 2/2

50 2/2

s5 1/2 58 1/2

61 2/2

62 2/2

63 2/2

79 1/2

80 2/2

81 1/2

82 2/2

- 27 -

CHEMICAL FORMULAE

(IN DESCRIPTION)

OH R {0 (Y)mR' 1 R3R2

HO 8 L(Y)m - ><R) (la) NOJ O <' B

1'::undNo86 HC 87

*! - 28

SCHb I NaBH, EtOH AICI3, DCM 1 > Br Br OO OH

-I Got CH3CO2H, H2SO4

Br (Vat) SCHEME 11

Br 61 1) nBuLi, THE:/ :1 2) \|' CHO Br TV) OH lo}

- 29 SCHEME 111

Br I CHO

1) nBuLi, THE Acetone [; N 1 KOH, H2O BrCHO (Vu) Br o (V) I, OH -l 1 OH O

Sr Piperidine (cat) (X) OH O

( - 30

Br SCHEME IV 3

Br OH:1 (Vl) I I OH < OH

to 1 (Vu) - i CHO NaBH3CN Br OH Br OH

( - 31

SCHEME V

OH NMe2 :00 NaCN in EtOH/H2O Br HN <: OH ON OH

1 1 Piperidne l l (XV') in pyridne ' 00 00

Br Br Heath HOAc NH2 .: Conc HCI in AcOH | Br O o f' get, (X,) Heat with EtOH / \ Br in pyridine / \ \ Benzylamine \ in pyridine OH COOED NaHC03 in pyridine or \ (Xlil) OH COOH Br { ((xv) (XIV) Br s

- 32 SCME VI

OH COOE':O

Warm in Pyridine O:,3 | NaOH / EtOH / H2O H COOH 4,COOH

Ol c HCI in HOAc 1 _ 1. Aq NaHCO3 in Pyridine at RT Heat in Ac2O 2. Acidify l o t-Butylam no 7 In pyridine H CONH(t-Bu) 'I 5 (xvi') (XIX)

Claims (6)

- 33 CLAIMS

1. A compound of formula (I) OH R R4 (

or a stereoisomer or salt thereof, wherein R is hydrogen, alkyl, cycloalkyl, cycloketonyl, cycloarnino, -(CHR7)nCOR5, -(CHR7)DCo2R5, (CHR7)n-02CR5, lo -(C7)nCoNRsR6, -(CHR7),,NR5CoR6, -(CHR7)nC(=NH)NR5R6-,(CHR7)o-C--N. or -(CH7)nNR5R6; R', R2, R3 and R4 are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, hydroxyl, nitro, cycloalkyl, S(O)n-alkyl, S(O)nhaloalkyl, optionally substituted aryl, benzoyl, -C--N, -SC-N, -Co:R5, CoNR5R6, -NR5R6, - NR5COR6, or -3, or R and R2 together 5 represent 5 halogen substituents; Y is oxygen, sulphur, -(CH2)n-, alkenylene, alkynylene, -(CH2)p-O-(CH2)p-, -O(CH2)p-, -(CH2)pO-, -O(CH2)pO-, -S(CH2)p, -(CHz)pS-, -So(CH2)p-' -(CH2)pSo-, -So2(cH2)p-, -(CH2)pSO2-, -SO-, -SO2, -CO2-, or-CONH-; X is oxygen or sulphur; 20 misOor 1; nisO, 1,or2; each p s independently 1 or 2; R5 and R6 are each independently hydrogen, alkyl, hydroxyalkyl, amine, benzyl or optionally substituted aryl, or R5 and R6 join to form a cycloalkyl ring, or when R is 25 -(CHR7)nCoRs, the C=0 group of R and the OH group attached to the 4-position of the coumarin ring system join to form a hemiketal; and R7 is hydrogen or alkyl;

i - 34 with the proviso that when m is 0, X is oxygen, and R', R2, R3 and R4 are all hydrogen, R is other than methyl or -CH2COCH3, and when m is 1, X and Y are both oxygen, and Rat, R2, R3 and R4 are all hydrogen, R is other than methyl.

5

2. A compound according to claim 1 wherein R', R3 and R4 are all hydrogen; R2 is hydrogen or halogen, Y is oxygen, -OCH2-, -CH2- or -(CH2) 2- when m is 1, or m is 0; and X is oxygen.

3. A compound according to claim 1 wherein R is hydrogen. C.

4 alkyl, cyano(C'.4)alkyl, 0 C56 cycloketonyl, piperidino, pyrrolidinyl, morphohno, di(C' 4)alkylamino, C' 4 alkylcarbonyl(C 2)alkyl, hydroxy(C 4)alkylamino, Ci 4 alkylamino, C, 4 alkoxycarbonyl, C, 4 alkylaminocarbonyl, carboxy, N,N-pentamethyleneamidino, piperidinocarbonyl, benzylaminocarbonyl, amnocarbonyl, C'.4 alkylaminocarbonylmethyl, carboxymethyl, hydrazinocarbonylmethyl or 5 piperidinocarbonylmethyl or R joins with the OH group attached to the 4-position of the coumarin ring to form the group -C(O)O- or -CH2C(O)O-; R' is hydrogen or halo; R2 which is in the 4- or 5position is hydrogen, halogen, hydroxy, C 4 alkyl, C 4 alkoxy, C, 4 haloalkyl, C, 4 haloalkoxy, C.4 alkylthio, Ci.4 haloalkylthio, cyano, cyanomethyl, hydroxymethyl, C2.4 alkenyl, C2 4 alkynyl, C, 4 alkylsulfinyl, C4 o alkylsulfonyl, acetamido, arnlno, di(C, 4)alkylamino, di(C, 4)alkylaminocarbonyl or benzoyl, or R' and R2 together represent pentahalo; R3 and R4 are both hydrogen; X is oxygen; m is 0 or 1; and when m is I Y is ethenylene.

25 4. A process for preparing a compound of formula (I) wherein X is oxygen which comprises reacting a 4-hydroxycoumarm with a compound of formula (Ila):

- 35 -

I R3 HO 8 (Y)m:: (I la) under acidic conditions.

5. A rodenticidal composition comprising a rodenticidally effective amount of a s compound of formula (I) as defined in claim 1 and an inert carrier or diluent.

6. A method of killing or reducing a population of rodents which comprises supplying to a locus frequented by the rodents a rodenticidally effective amount of a compound of formula (I) as defined in claim 1.