WO1992011274A1

WO1992011274A1 - Novel compounds

Info

Publication number: WO1992011274A1
Application number: PCT/GB1991/002285
Authority: WO
Inventors: Roderick John Dorgan; Nigel Hussain
Original assignee: Beecham Group Plc
Priority date: 1990-12-20
Filing date: 1991-12-19
Publication date: 1992-07-09
Also published as: GB9027721D0; IE914423A1; MX9102730A; PT99888A; AU9114291A; ZA919941B

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

Novel Compounds

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 19(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):

wherein R^a is methoxy or hydroxy, R^b is hydrogen, R^c is pentanoyloxy, heptanoyloxy, or 2-methylhexanoyloxy, and R^d is methyl or ethyl; or R^a is methoxy or hydroxy, R is hydrogen, R^c is 2-methylbutanoyloxy, 2,4-dimethylpent-2-enoyloxy, or 2,4-dimethylpentanoyloxy, and R^d is methyl or ethyl, with the proviso that when R^d is ethyl, R^a is hydroxy and R^c is 2,4-dimethylpentanoyloxy; or R^a is methoxy or hydroxy, R^b is the group of formula:

(4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy), R^c is hydroxy, and R is 1-methyl propyl.

EP-A-0 325 462 (USSN 299,933) describes the compound of formula (B), which has been designated VM48130;

The absolute configuration of the compounds of formulae (A) and (B) is believed to be as follows:

The present invention provides compounds of formula (I) :

wherein R¹ is optionally protected hydroxy or methoxy, R² is hydrogen or 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy, and -Y- is a C_{1- 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.

Preferably, R¹ is hydroxy and R² 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_{1 -20}, more especially C₁ -₁₂, particularly C₁ -₆ alkyl, and alkenyl and alkynyl include straight and branched C_2-20, ^more especially C₁ -₁₂, particularly C₂-₆ alkenyl and alkynyl. The 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, rι~_Q alkyl, aryl, C₁ -₆ alkoxy, halo substituted ( C₁ -₆) alkyl, hydroxy, amino, nitro, carboxy, C₁ -₆ alkoxycarbonyl, C₁ -₆

alkoxycarbonyl- ( C₁ -₆) -alkyl, C₁ -₆ alkylcarbonyloxy, or C₁ -₆ 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, C₁ -₆ alkyl, C₁ -₆ alkoxy, halo-(C₁ -₆)-alkyl, hydroxy, amino, carboxy, C₁ -₆ alkoxycarbonyl, C₁ -₆ alkoxycarbonyl ( C₁ -₆) 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 C₃-₂₀, especially C₃-₁₂, more especially C₄-₈, groups, and mono-, bi- and tri-cycloalkenyl include C₄~2_Q, especially C₄-₁₂, more especially Cc-g groups. When any organic radical comprises a mono-, bi- or tri-cycloalkyl or mono-, bi- cr 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 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. The 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. The 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 100mg 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 or. 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):

wherein R¹ and R² are as defined above, with a compound of formula X-Y-X¹, wherein X and X¹ 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 R⁴ is hydrogen or C_{1- 6} 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-toluene- sulphonic acid.

Suitable leaving groups include C_{1- 6} alkoxy.

Compounds of formula (II) may be obtained from compounds cf formula (III):

wherein R¹ and R² are as defin^κed above and R³ is a C25 substituent of an avermectin or milbemycin, such as those set out above for compounds of formulae (A) and (B), as shown below:

(i) NaIO₄/MeOH/RT

(ii) NaBH₄/0°C 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 KOR⁴/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) [1986187 et seq. and Macrolide Antibiotics [1984]Ch.14, 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-X¹.

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

The following Example illustrates the present invention. (IA) is the compound of formula (I) wherein R¹ is hydroxy, R² is hydrogen, and -Y- is the group -C(CH₃)₂-, and intermediate (IIA) is the compound of formula (II) wherein R¹ is hydroxy and R² is hydrogen.

Example

(a) Synthesis of the 230H 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 230H derivative of VM 48130 (189 mg, 70%).

¹³Cn.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 11.0 ^m/z(FAB) : 623 (MNa⁺) .

(b) Synthesis of (IIA)

To a solution of the 230H 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. 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. (CDCl₃) : 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, 68.7,568.3, 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 μmol) in dichloromethane (3 ml) at RT was added 2,2-dimethoxypropane (0.5 ml, 4.07 mmole) and a catalytic amount of p_-toluenesulρhonic 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) :

wherein R¹ is optionally protected hydroxy or methoxy, R² is hydrogen or 4'-(α-L-oleandrosyl)-α-L-oleandrosyloxy, and

-Y- is a C_{1- 3} alkylene group optionally substituted by one or more organic radicals.

2. A compound according to Claim 1, wherein R¹ is hydroxy and R² is hydrogen.

3. A compound according to Claim 1 or 2, wherein Y is the group -C(CH₃)₂-.

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.

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 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 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 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 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 formula (II):

wherein R¹ and R² are as defined in Claim 1, with a compound of formula X-Y-X¹, wherein X and X¹ 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 R⁴ is hydrogen or C_{1- 6} alkyl.

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

13. A milbemycin or avermectin of partial formula (i)

wherein Y is as defined in Claim 1.

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):

with a compound of formula X-Y-X¹, wherein X and X¹ 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 R⁴ is hydrogen or C_{1- 6} alkyl.

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