GB2361425A

GB2361425A - Thiourea rodenticide

Info

Publication number: GB2361425A
Application number: GB0009278A
Authority: GB
Inventors: Charles Leslie Hodgkinson
Original assignee: Sorex Ltd
Current assignee: Sorex Ltd
Priority date: 2000-04-17
Filing date: 2000-04-17
Publication date: 2001-10-24
Anticipated expiration: 2020-04-17
Also published as: GB2361425A8; GB2361425B; GB0009278D0

Abstract

A rodenticide comprises a thiourea of the formula <EMI ID=1.1 HE=46 WI=87 LX=735 LY=803 TI=CF> <PC>wherein X, Y and Z are independently selected from N(R<SP>2</SP>), O, C(R<SP>3</SP>) (R<SP>4</SP>), or S,<BR> ```and wherein R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> independently are optionally present and, when present, are independently selected from H, halogen, alkyl, aryl, alkoxy and aryloxy,<BR> ```and wherein the thiourea group is substituted at one or more of positions 4 to 7 and n is 1 to 4,<BR> ```and wherein R<SP>1</SP> is substituted at one or more other of the positions 4 to 7 and is selected from H, halogen, alkyl, aryl, alkoxy and aryloxy.

Description

2361425 THIOUREAS This invention relates to thiourea compounds and in

particular to thiourea compounds of heterocyclic compounds which are useful as rodenticides.

Thiourea compounds have been used for the control of many types of pests and ANTU (alpha-naphthyl thiourea) has been used commercially as a rodenticide. However, it has been found that ANTU has an impurity which is carcinogenic. Furthermore, the compound also has an effect whereby sublethal doses give some tolerance to the target species and have an antifeeding property.

J. Pharmacol, 90,260-270 (1947) discloses that the toxicity of thioureas is at its highest when the thiourea group is singly substituted with an aromatic ring. DE 818049 discloses that a compound with an extra nitrogen between the phenyl ring and the thiourea has a high toxicity, but is relatively unstable.

Thioureas, especially ANTU, are known to act on specific cells within the lungs. This action involves oxidation of the sulphur atom and then acylation of sites within the cells causing cell death. This in turn causes a build up of fluid in the lung which is probably the cause of death. This mode of action and the tolerance effect induced by non-lethal doses make these compounds especially attractive as rodenticides, this being due to the humaneness of their action and the fact that non-lethal doses can build up tolerance in larger animals.

The applicant has found a series of compounds which have a high toxicity and fewer unwanted properties. Thus, according to a first aspect of the present invention, there is provided a thiourea of the formula H 4 3 X 4 H2NyN 2 6 z S n 7 (R')m 2 wherein X, Y and Z are independently selected from N(R 2), 0, C(R 3)(R4), or S, and wherein R 2, R 3, and R 4 are independently optionally present and, when present, are independently selected from H, halogen, alkyl, aryl, alkoxy and aryloxy, and wherein the thiourea group is substituted at one or more of positions 4 to 7 and n is 1 to 4, and wherein R1 is substituted at one or more other of the positions 4 to 7 and is selected from H, halogen, alkyl, aryl, alkoxy and aryloxy.

In the present context, "halogen" is preferably taken to mean F, Cl, Br, or 1. When R1, R 2, R 3 and/or R4 are alkyl, they are preferably selected from Cj_ 4 alkyls, when they are aryls they are preferably selected from phenyl or substituted phenyl. Similarly, when they are alkoxy, they are preferably selected from C1_4 alkoxy compounds and when they are aryloxy they are preferably selected from phenyl or substituted phenyl aryloxy compounds.

Preferably n is 1. It has been found that particularly preferred compounds are obtained when the thiourea group is substituted at position 5 or 7. The ring containing X, Y and Z may be heterocyclic and is preferably such that the thiourea of the present invention is an indazole. In such an embodiment, when the thiourea is substituted at the 5-position, the N atom at the 1 -position is preferably attached to a hydrogen atom. Thus, particularly preferred compounds are indazol-5-yl thiourea.

N H2NyH N S N H 3 and indazol-7-yl thiourea:

\\II N N H NH NH2 and 1 -methyl indazol-7-yl thiourea:

N N Me NH H2 According to a second aspect of the present invention, there is provided a rodenticide comprising the thiourea.

The rodenticide may, for example, be extruded, moulded or compressed into any shape, and may be in the form of a liquid, gel, paste, foam or bait or any other rodenticidal presentation.

According to a further aspect of the present invention, there is provided the use of a thiourea as a rodenticide.

Example 1 Preparation of N-N -H-indazol-7-yi) Thiourea 7-Nitro indazole (34.3mmol) was added to 10% palladium on charcoal (0.5gm) and IMS (200ml) in a 1L stainless steel autoclave. The vessel was pressurised with 30 atmospheres of hydrogen and agitated at 40C for 3 hours. After cooling and cracking, the mixture was filtered and the solvent 4 removed to give 1 H-indazol-7-amine as a dark solid (M. pt 1 51-1530C, 3.4gm, 74%).

The compound from above (3,4gm, 25.5mmol) was stirred in acetonitrile (75ml) and treated with 1.05 equivalents of freshly prepared benzoylisothiocyanate. The mixture was refluxed for 1 hour, cooled and the product filtered off, washed with water and dried to give N7benzoyi-N'-(lHindazol-7-yl) thiourea (M. pt = 230-232'C, 7.24gm, 96%).

A suspension of the above (7.24gm, 24.4mmol) in IMS (125ml) was treated with sodium hydroxide (1.1 equivalents) in water (60mis). The mixture was refluxed for 90 minutes, cooled and evaporated to one third volume. Water (50ml) was added to the residue and the product removed by filtration. The product was then recrystallised from IMS/Toluene as an off-white solid (M. pt 203-204-C, 1.7gm, 36%).

1H NMR (DIVISO, 6 in ppm) 7.1(m,1H), 7.2(m,IH), 7.6(m,1H), 8.1(s,1H), 7.0-8.0(broad, 2H), 9.6(s,11-1), 13.0(s,lH).

IMS refers to Industrial Methylated Spirits which is 'an industrial solvent that is a mixture of mainly ethanol denatured with some methanol and higher alcohols.

Example 2 Preparation of N-O -Methyl-1 H-Indazol-7-yl) Thiourea 2-Methyl-6-nitroaniline (40gm, 0.263mole) was dissolved in acetic acid (1.8L) and cooled to 150C. Sodium nitrite (18.2gm) in water (60mi) was added and the mixture stirred and kept below 250C. The reaction was stood for 3 days and an impurity was filtered off. The filtrate was evaporated to dryness and the residue was treated with water and the product filtered off, washed with water and recrystallised from toluene (M. pt = 177-179'C. 31gm, 72%).

The compound from above (30.8gm, 0.189mole) in water (720ml) was treated with sodium hydroxide (33gm) in water (11 Oml) and warmed to 80'C. Dimethyl sulphate (68gm) was added over 30 minutes whilst the temperature was allowed to drop to 650C. The mixture was then stirred at 65'C for 2 hours, cooled and the mixture filtered. The I and 2 methyl isomers were separated by column chromatography (eluent - dichloromethane/hexane) and recrystallisation from iso-octane gave 1-methyl-7-nitro-lH-indazole (M. pt = 93-970C, 3.2gm, 9.6%). This was treated as in Example 1 to give the title compounds (M. pt = 210-212C, 0.96gm).

1H NIVIR (DIVISO, 6 in ppm) 4.1(s,31-1), 7.11(m,21-1), T.7 (m,1H), 7.08.0(broad, 2H), 8.0(s,1H), 9.5(s,111-1).

Example 3 Preparation of N-(1 -H-indazol-5-yi) Thiourea 5-Aminoindazole (13.3gm, 0.1mole) was added to a freshly prepared solution of benzoyl thiocyanate (from benzoyl chloride (14.1gm, 0.1mole) and ammonium thiocyanate (8.5gm, 0. 11 mole)) in acetone (1 50ml). The mixture was refluxed for 40 minutes, cooled and filtered. The solid was washed with acetone and dried to give a white solid (24.3gm, 82%).

The compound from above (6gm, 0.02mole) was added to a solution of potassium hydroxide (2.4gm, 0.04mole) in water (80ml). The mixture was then refluxed for 4 hours and allowed to cool. The solid was filtered off and dried to give the produce as a white solid, M. pt 240-244'C (3.1 gm, 80.6%) Example 4

The LD50 results were obtained against wistar rats by intubation of a solution of the compounds in triethanolamine/polyethylene glycol 200 (9:1).

6 Table 1 (Selected thiourea compounds) Formula Name LD50 (mg/Kg) C8H,oN2S Benzyl thiourea >25 Cj5H12N4SO 3-Benzoyl 1 -Indazol-5-yl thiourea 25 C71-17CIN2S 2-Chlorophenyl thiourea 15 C8HjON2SO 4-Methoxyphenyl thiourea 15 C7H8N2S Phenyl thiourea 10 C,,H,oN2S Alpha-Naphthyl thiourea (ANTU) 10 C12HI2N2S 2-Methyl Naphth-1-yl thiourea 7 CjoHqN3S Quinolin-5-yl thiourea 5 C8HjON2S 2-Methylphenylthiourea 3 C8H8N4S lndazol-7-yl thiourea 3 C8H8N4S Indazol-5-yl thiourea 3 CqHjoN4S 1 -Methyl I ndazol-7-yl thiourea 2 "LD50" is the dosage at which 50% of the rats tested die.

The above information shows that the preferred compounds are those where the thiourea group is attached to a single aromatic moiety and that this moiety is preferably an indazole group. The indazole group was then further substituted with alkyl groups as shown in the table below and the following results were obtained:

4 3 6 1 2 7 1 7 1 2 3 4 5 6 7 LD50 NH N TU 10 NH N TU 7 NH N TU 3 NIA N TU 10 NH N TI) 3 NH N Me TU 10 NH N Me TU 5 NH N TU Me 5 NMe N TU 15 NMe N TU 2 Where TU is a thiourea group and Me is a methyl group.

It can be seen that compounds according to the invention are as effective as, and in many cases better than, other compounds when used as rodenticides.

Claims

8 CLAIMS

A thiourea of the formula H 4 3 1 5 4 x H2NyN 5r 2 6 z S n _ 7 1 (R')m wherein X, Y and Z are independently selected from N(R 2), 0, C(R') (R 4), or S, and wherein R 2, R 3 and R 4 independently are optionally present and, when present, are independently selected from H, halogen, alkyl, aryl, alkoxy and aryloxy, and wherein the thiourea group is substituted at one or more of positions 4 to 7 and n is 1 to 4, and wherein R1 is substituted at one or more other of the positions 4 to 7 and is selected from H, halogen, alkyl, aryl, alkoxy and aryloxy.

2. A thiourea according to claim 1, wherein n is 1.

3. A thiourea according to claim 1 or 2, wherein the thiourea group is substituted at position 5.

4. A thiourea according to any preceding claim, wherein the thiourea group is substituted at position 7.

5. A thiourea according to any preceding claim, wherein the ring comprising X, Y and Z is heterocyclic.

9 6. A thiourea according to any preceding claim which is an indazole. 7. A thiourea having the formula N H2N.yH S N H 8. A thiourea having the formula / N N H NH NH2 9. A thiourea having the formula N N MM e NH2 10. A rodenticide comprising a thiourea according to any preceding claim.

11. A rodenticide according to claim 10 which is extruded, moulded or compressed into any shape.

I 12. A rodenticide according to claim 10 or 11 which is in the form of a liquid, gel, paste, foam or bait.

13. The use of a thiourea according to any one of claims 1 to 9 as a rodenticide.

- 1 14. A thiourea substantially as hereinbefore described with reference to the accompanying examples.

Amendments to the claims have been filed as follows A rodenticide comprising a thiourea of the formula H 4 3 x 1-1211 Y 2 Y 6., z / S n 7 RI wherein X, Y and Z are independently selected from N(R 2)'0' C(R 3) (R 4), or S, and wherein R 2, R 3 and R 4 independently are optionally present and, when present, are independently selected from H, halogen, alkyl, aryl, alkoxy and aryloxy, and wherein the thiourea group is substituted at one or more of positions 4 to 7 and n is 1 to 4, and wherein R1 is substituted at one or more other of the positions 4 to 7 and is selected from H, halogen, alkyl, aryl, alkoxy and aryloxy.

2. A rodenticide according to claim 1, wherein n is 1. 3. A rodenticide according to claim 1 or 2, wherein the thiourea group is substituted at position 5.

4. A rodenticide according to any preceding claim, wherein the thiourea group is substituted at position 7.

5. A rodenticide according to any preceding claim, wherein the ring comprising X, Y and Z is heterocyclic.

6. A rodenticide according to any preceding claim which is an indazole. 7. A rodenticide comprising a thiourea having the formula N H2N Y' N S N H 8. A rodenticide comprising a thiourea having the formula N / N H NH NH2 9. A rodenticide comprising a thiourea having the formula N / N Me NH NH2 10. A rodenticide according to any preceding claim which is extruded, moulded or compressed into any shape.

)5 11. A rodenticide according to claim 10 which is in the form of a liquid, gel, paste, foam or bait.

12. Use of a thiourea of the formula H 4 3 1 5 x H2N 4 4 Y 2 6 z S n 7 1 RI as a rodenticide, wherein X, Y and Z are independently selected from N(R 2), 0, C(R') (R 4), or S, and wherein R 2, R 3 and R 4 independently are optionally present and, when present, are independently selected from H, halogen, alkyl, aryl, alkoxy and aryloxy, and wherein the thiourea group is substituted at one or more of positions 4 to 7 and n is 1 to 4, and wherein R' is substituted at one or more other of the positions 4 to 7 and is selected from H, halogen, alkyl, aryl, alkoxy and aryloxy.

13. Use according to claim 12, wherein n is 1.

14. Use according to claim 12 or 13, wherein the thiourea group is substituted at position 5.

15. Use according to any one of claims 12 to 14, wherein the thiourea group is substituted at position 7.

16. Use according to any one of claims 12 to 15, wherein the ring comprising X, Y and Z is heterocyclic.

17. Use according to any one of claims 12 to 16, wherein the thiourea is an indazole.

18. Use of a thiourea having the formula N H2NyH S N / N H as a rodenticide.

19. Use of a thiourea having the formula \'\, N N H N, NH2 as a rodentcide.

20. Use of a thiourea having the formula N N Me PJH 2 as a rodenticide.

21. A rodenticide substantially as hereinbefore described with reference to the accompanying examples.