IE914423A1

IE914423A1 - Novel compounds

Info

Publication number: IE914423A1
Application number: IE442391A
Authority: IE
Original assignee: Beecham Group Plc
Priority date: 1990-12-20
Filing date: 1991-12-18
Publication date: 1992-07-01
Also published as: PT99888A; GB9027721D0; MX9102730A; AU9114291A; ZA919941B; WO1992011274A1

Abstract

Compounds of formula (I), wherein R<1> optionally protected hydroxy or methoxy, R<2> is hydrogen or 4'-( alpha -L-oleandrosyl)- alpha -L-oleandrosyloxy, and -Y- is a C1-3 alkylene group optionally substituted by one or more organic radicals, are useful in the treatment of helminthiasis.

Description

The present invention relates to novel anthelmintic compounds, to processes for their production, to pharmaceutical formulations containing them, and to their use in human or veterinary medicine.

The milbemycins and avermectins are a group of macrolide antibiotics which have been prepared by the cultivation of microorganisms and are described in inter alia GB-A-1,390,336, J. Antibiotics 29(3) , 76-14 to 76-16 and 29 (6), 76-35 to 76-42, GB-A-2 170 499, EP-A-0 073 660 and EP-A-0 204 421. They have anthelmintic activity. Further anthelmintically active milbemycins and avermectins are described in GB-A-2 176 180, EP-A-0 212 867, EP-A-0 237 339, EP-A-0 241 146, EP-A-0 214 731, EP-A-0 194 125, EP-A-0 170,006, and US-A-4,285, 963.

The compounds disclosed in the above references include compounds of formula (A): (A) is wherein Ra is methoxy or hydroxy, is hydrogen, Rc is pentanoyloxy, heptanoyloxy, or 2-methylhexanoyloxy, and Rd is methyl or ethyl; or Ra is methoxy or hydroxy, R^3 is hydrogen, Rc is 2-methylbutanoyloxy, B3117 -22,4-dimethylpent-2-enoyloxy, or 2,4-dimethylpentanoyloxy, and is methyl or ethyl, with the proviso that when is ethyl, Ra is hydroxy and Rc is 2,4-dimethylpentanoyloxy; or Ra is methoxy or hydroxy, Rb is the group of formula: (4'-(a-L-oleandrosyl)-α-L-oleandrosyloxy), Rc is hydroxy, and R^ is 1-methyl propyl.

EP-A-0 325 462 (USSN 299,933) describes the compound of 15 formula (B), which has been designated VM48130; absolute configuration of the compounds (B) is believed to be as follows: The and of formulae (A) OH B3117 -3The present invention provides compounds of formula (I) (I) hydrogen or 4'-(a-L-oleandrosyl)-α-L-oleandrosyloxy, and -Y- is a Cj-3 alkylene group optionally substituted by one or more organic radicals.

Suitable protecting groups for hydroxy include TBDMS (t-butyldimethylsilyl), and acyl. Further suitable protecting groups are described in, for example, ''Protective Groups in Organic Synthesis'' Theodora W. Greene, Wiley-Interscience 1981 Ch 2, 10-86. . 2 .

Preferably, R is hydroxy and R is hydrogen.

Organic radicals may advantageously be selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heterocyclyl, mono-, bi- and tri-cycloalkyl, mono-, bi- and tri-cycloalkenyl and aralkyl.

As used herein alkyl includes straight and branched C^^q, more especially C-^-^, particularly C^-g alkyl, and alkenyl and alkynyl include straight and branched C2-20' more especially C2"12, particularly C2~g alkenyl and alkynyl.

B3117 -4The alkylene group Y, or an alkyl, alkenyl or alkynyl moiety herein, including such moieties present as optional substituents on Y,may optionally be substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, alkylthio, oxo, halogen, trifluoromethyl, and optionally substituted amino.

When used herein the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, cl_6 alkyl, aryl, C-^-g alkoxy, halo substituted (C-^-g) alkyl, hydroxy, amino, nitro, carboxy, C-^-g alkoxycarbonyl, C^-g alkoxycarbonyl-(C-^-g)-alkyl, C^-g alkylcarbonyloxy, or C^-g alkylcarbonyl groups.

The term 'heterocyclyl' includes saturated, unsaturated and aromatic single or fused rings comprising up to four hetero atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three halogen, Cj^-g alkyl, C^-g alkoxy, halo-(C-^-g)-alkyl, hydroxy, amino, carboxy, C^-g alkoxycarbonyl, C^-g alkoxycarbonyl(C^-g) alkyl, aryl or oxo groups.

Suitably the heterocyclic ring comprises from 4 to 7 ring atoms, preferably 5 to 6 atoms.

The term 'halogen' refers to fluorine, chlorine, bromine and iodine .

As used herein mono-, bi- and tri-cycloalkyl include C3-2O' especially C^-·^, more especially C^-θ, groups, and mono-, bi- and tri-cycloalkenyl include C4~2qz especially C4-12, more especially Cg-θ groups. When any organic radical comprises a mono-, bi- or tri-cycloalkyl or mono-, bi- or tri-cycloalkenyl moiety, that moiety may be substituted as set out above for alkyl, alkenyl, and alkynyl, and/or by one or more substituents selected from the group consisting of B3117 — 5— methylene and alkyl. Bicyclic and tricyclic groups may be fused or bridged and are preferably attached via a carbon atom which is common to two rings.

Any two substituents on -Y- may be taken together with the carbon atom(s) to which they are attached to designate a cycloalkyl, cycloalkenyl, aryl or heterocyclyl group which may optionally be substituted as set out above.

The compound or mixture of compounds according to the invention is suitably provided in substantially pure form, for example at least 50% pure, suitably at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight. An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.

The compounds of the invention have parasiticidal properties, for example against nematodes such as Trichostrongylus colubriformis, and are useful for the treatment of helminthiasis in animals such as mammals, including humans and domesticated animals (including farm animals).

Accordingly the present invention also provides a compound according to the invention, for use in the treatment of the human or animal body, especially for treating endo- and ectoparasitic infestations and particularly for treating helminthiasis of domestic and farm animals.

B3117 -6The term helminthiasis encompasses those diseases of man and animals caused by infestation with parasitic worms such as Strongyles, Ascarids, hookworms lungworms, filarial worms and whipworms. The compound may also be used against nematodes occurring in the soil or parasitic to plants.

The compounds of the invention are also active against Arthropods. The phylum Arthropoda comprises insects - such as biting flies, lice, bugs, beetles and fleas - and arachnids - such as mites and ticks.

Thus, a broad aspect of the invention provides a method of eradicating arthropod or nematode infestations, which method comprises applying a compound according to the invention or a derivative thereof to the arthropods or nematodes or to their environment.

The present invention thus provides a pesticidal composition comprising a compound according to the invention or a derivative thereof together with a suitable carrier or excipient, such as an aerosol formulation.

The present invention also provides a pharmaceutical or veterinary composition comprising a compound according to the invention or a pharmaceutically acceptable derivative thereof together with a pharmaceutically or veterinarily acceptable carrier or excipient.

The present invention also provides a method of treatment or prophylaxis of endo- and ectoparasitic infestations, especially helminthiasis, of animals (including birds and fish) , especially humans and domesticated mammals, which comprises administering an effective non-toxic amount of a compound according to the invention or a pharmaceutically acceptable derivative thereof, or a composition according to the invention, to a patient in need thereof.

B3117 -7The composition according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other anthelmintics.

In suitable formulations the drug may be administered to animals orally (as a paste, drench, bolus, capsule or tablet), parenterally, percutaneously, as a food additive (eg granules, pellets or powder), or may be prepared as an aerosol spray formulation.

The compounds of the invention may be formulated as a mixture with each other and/or with other anthelmintics, insecticides, acaricides or other pharmacologically active substances .

Suitably the composition consists of sufficient material to provide a dose of from 0.001 to lOOmg of active ingredient per kg of animal body weight per dose, more suitably 0.01 to lOmg/kg per dose.

A composition according to the invention may suitably contain from 0.1% by weight, preferably from 1.0 to 60% by weight, of the compound according to the invention (based on the total weight of the composition), depending on the method of administration.

It will be appreciated that, in some cases, it will be advisable to repeat the dosing of the infected or potentially infected human or animal with the compound of the invention according to conventional dosage regimes used with anthelmintics.

Compounds of formula (I) may be prepared by treating a compound of formula (II): B3117 -3' ι 9 wherein R and R are as defined above, with a compound of formula X-Y-X , wherein X and X are the same or different and each is a leaving group, or, in the case when Y is optionally substituted methylene, X and X1, together with the carbon atom to which they are attached, form a carbonyl group, and R^ is hydrogen or C^_g alkyl.

The reaction is typically carried out at ambient temperature in an organic solvent such as dichloromethane in the presence of a suitable acid catalyst such as p-toluenesulphonic acid.

Suitable leaving groups include Cg-g alkoxy.

Compounds of formula (II) may be obtained from compounds of formula (III) : (III) substituent of an avermectin or milbemycin, such as those set out above for compounds of formulae (A) and (B), as shown below: B3117 It will be appreciated that the -OR4 substituent at the C21 position forms part of an acetal group. Therefore it can be exchanged for other -OR4 substituents by treatment with HOR4/H+.

Compounds of formula (III) are naturally occurring or can be obtained from naturally occurring compounds, such as compounds of formulae (A) and (B), by hydrolysis of an acyloxy substituent at position C23.

The acyloxy group may be hydrolysed by conventional methods such as base hydrolysis eg. NaOH/MeOH, enzymatically using a hydrolase, or by treatment with a suitable hydride reducing agent eg.diisobutylaluminium hydride (DIBAL).

It will be appreciated that the process of the invention can be applied to essentially any starting material avermectin or milbemycin having hydroxy or protected hydroxy (such as acyloxy) at each of positions C22 and C23. Furthermore the compounds of formulae (A), (B) and (I) to (III) can be modified using techniques which are well known in the art and are described in, for example, Natural Products Reports 3_(2) [1986] 87 et seq. and Macrolide Antibiotics [1984]Ch.l4, 553 et seq. Thus, a particular aspect of the invention provides any milbemycin or avermectin of partial formula (i), as well as a process for its preparation which comprises treating a mibemycin or avermectin of partial formula (ii) with a compound of formula X-Y-X^.

B3117 Compounds of formulae further aspect of the (II) and (ii) are novel and form a invention.

The following Example illustrates the present invention. (IA) is the compound of formula (I) wherein R^ is hydroxy, R is hydrogen, and -Y- is the group and intermediate (IIA) is the compound of formula (II) wherein 9 R is hydroxy and R is hydrogen.

B3117 -11Example (a) Synthesis of the 23OH derivative of VM 48130 Diisobutylaluminium hydride (DIBAL, 1.5M in toluene, 1.2 ml, 1.80 mmol) was added dropwise (over ca 10 mins) to a solution of VM 48130 (300 mg, 0.45 mmol) in dry tetrahydrofuran (20 ml) under nitrogen and at -50°C. T.L.C. analysis of the mixture after 30 mins showed complete reaction. The reaction mixture was quenched by the careful addition of 1 M ammonium chloride solution (5 ml) then allowed to warm to room temperature. 2 M Hydrochloric acid (40 ml) was added to the solution extracted with ethyl acetate (3 x 40 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate (40 ml), dried over magnesium sulphate (anhydrous) and concentrated in vacuo.

The crude product was purified by flash chromatography on silica gel (using ethyl acetate as eluent) to provide the 23OH derivative of VM 48130 (189 mg, 70%). i^cn.m.r. (dg-Acetone : 172.5, 142.4, 141.4, 137.7, 134.4, 134.9, 124.8, 124.4, 121.8, 120.8, 119.3, 101.0, 81.5, 81.2, 81.0, 78.0, 74.7, 69.0, 68.9, 68.5, 68.2, 49.1, 46.6, 40.2, 37.5, 36.7, 36.5, 35.1, 22.7, 19.8, 15.6, 13.6, 13.1 and 11.0m/z(FAB) ; 623(MNa+). (b) Synthesis of (IIA) To a solution of the 23OH derivative of VM 48130 (200 mg, 0.33 mmol) in methanol (10 ml) at room temperature was added in one portion sodium metaperiodate (150 mg, 0.70 mmol).

T.l.c. analysis after 3.5 hours showed complete reaction.

B3117 IE 914423 2 The suspension was cooled to 0°C and sodium borohydride (80 mg, 2.1 mmol) was added. After 10 mins the mixture was allowed to warm to room temperature and stirred for a further 30 mins. The mixture was then concentrated in vacuo to ca 3 ml. This was then diluted with EtOAc (80 ml), washed successivley with 2 M hydrochloric acid (40 ml) and saturated aqueous sodium hydrogen carbonate (40 ml) , dried over magnesium sulphate (anhydrous) and the solvent removed in vacuo. The crude product weas purified by silica gel preparative t.l.c. using Petrol : Ethyl acetate (1 : 2) as eluant to give (IIA) (37.5 mg, 24%). 13Cn.m.r. (CDC13) : 173.4, 142.7, 139.4, 137.7, 137.2, 123.4, 120.5, 120.2, 118.0, 96.9, 80.1, 79.2, 69.0, 68.7, 68.3, 68.2, 67.1, 48.4, 45.6, 36.6, 36.3, 35.9, 34.5, 22.3, 19.8 and 15.5 m/z(FAB) : 499 (MNa+). (c) Synthesis of (IA) To a solution of (IIA) (24 mg, 50.4 gmol) in dichloromethane (3 ml) at RT was added 2,2-dimethoxypropane (0.5 ml, 4.07 mmole) and a catalytic amount of p-toluenesulphonic acid. After 4h the mixture was diluted with saturated aqueous sodium hydrogen carbonate (20 ml) and extracted with dichloromethane (2 x 20 ml). The organic layers were dried over magnesium sulphate (anhydrous) and solvent removed in vacuo. The crude product (24 mg) was purified by preparative thin layer chromatography (silica-gel) using l:2-hexane: ethyl acetate as eluant. This provided 9 mg (34%) of (IA) . 13C nmr: 173.61, 142.82, 139.57, 137.96, 137.15, 123.45, 120.73, 120.27, 118.02, 111.54, 104.24, 80.20, 79.23, 75.12, 69.14, 68.69, 68.50, 67.69, 48.48, 45.72, 38.25, 36.17, 36.00, 34.50, 27.04, 26.69, 22.29, 29.92 and 15.48. m/z (FAB): 539 (MNa+).

Claims

1. A compound of formula (I): . 1 7 wherein R is optionally protected hydroxy or methoxy, R is hydrogen or 4'-(a-L-oleandrosyl)-α-L-oleandrosyloxy, and -Y- is a Ci_3 alkylene group optionally substituted by one or more organic radicals.

2. A compound according to Claim 1, wherein is hydroxy and R is hydrogen. 25

3. A compound according to Claim 1 or 2, wherein Y is the group -C (CH^^ - .

4. A compound according to any preceding claim, for use in the treatment of the human or animal body.

5. A compound according to any one of Claims 1 to 3, for use in the treatment of helminthiasis. B3117 IE 914423 14

6. Use of a compound according to any one of Claims 1 to 3 for the manufacture of a medicament for use in the treatment of helminthiasis.

7. A method of treatment or prophylaxis of endo- and ectoparasitic infestations of animals, which comprises administering an effective non-toxic amount of a compound according to any one of Claims 1 to 3, or a pharmaceutically 10 acceptable derivative thereof, to a patient in need thereof.

8. A method of eradicating arthropod or nematode infestations, which method comprises applying a compound according to any one of Claims 1 to 3, or a derivative 15 thereof, to the arthropods or nematodes or to their environment.

9. A pesticidal composition comprising a compound according to any one of Claims 1 to 3 or a derivative 20 thereof together with a suitable carrier or excipient.

10. A pharmaceutical or veterinary composition comprising a compound according to any one of Claims 1 to 3, or a pharmaceutically acceptable derivative thereof, together 25 with a pharmaceutically or veterinarily acceptable carrier or excipient.

11. A process for preparing a compound of formula (I) as defined in Claim 1, which comprises treating a compound of 30 formula (II): B3117 15 wherein and R 2 are as defined in Claim 1, with a compound 1 1 of formula X-Y-X , wherein X and X are the same or different and each is a leaving group, or, in the case when Y is optionally substituted methylene, X and X^, together with the carbon atom to which they are attached, form a 20 carbonyl group, and R 4 is hydrogen or C-^_g alkyl.

12. A compound of formula (II) as defined in Claim 11.

13. A milbemycin or avermectin of partial formula (i): B3117 wherein Y is as defined in Claim 1.

14. 15 14. A process for the preparation of a compound of formula (i) as defined in Claim 13, which comprises treating a compound of formula (ii): B3117 -17IE 914423 with a compound of formula X-Y-x\ wherein X and are the same or different and each is a leaving group, or, in the case when Y is optionally substituted methylene, X and X 1 , together with the carbon atom to which they are attached, 5 form a carbonyl group, and R 4 is hydrogen or C|_g alkyl.

15. A compound of formula (ii) as defined in Claim 14.

16. A compound of formula (I) given and defined in Claim 1, substantially as hereinbefore described and exemplified.

17. Use according to Claim 6, substantially as hereinbefore described .

18. A pesticidal composition according to Claim 9, substantially as hereinbefore described.

19. A pharmaceutical or veterinary composition according to Claim 10, substantially as hereinbefore described.

20. A process for preparing a compound of formula (I) given and defined in Claim 1, substantially as hereinbefore described and exemplified.

21. A compound of formula (I) given and defined in Claim 1, whenever prepared by a process claimed in Claim 11 or 20.

22. A compound as claimed in any one of Claims 12, 13 or 15, substantially as hereinbefore described.