Claims
- 1. A compound of formula III: ##STR16## wherein R.sup.1 is hydrogen or optionally protected hydroxy; R.sup.2 is alkoxy, optionally protected hydroxy, oxo or C.sub.1-6 alkyl or C.sub.2-6 alkenyl O-substituted oximino; R.sup.3 is hydrogen, optionally protected hydroxy, or a group 4'-(a-L-oleondrosyl)-a-L-oleandroxylloxy or a-L-oleandrosyloxy wherein the terminal hydroxy group is optionally protected.
- 2. A process for the preparation of a compound of formula (III) as defined in claim 1, which process comprises treating a compound of formula V: ##STR17## with an acid catalyst to effect Beckmann rearrangement, wherein X is hydrogen or a sulphonyl group, R.sup.1 to R.sup.3 are as defined in claim 1, R.sup.8 is hydrogen or optionally protected hydroxy, and R.sup.9 is methyl, ethyl, 1-methyl propyl or (Z) but-2-en-2-yl, with the provision that (a) if R.sup.1 is optionally protected hydroxy, then R.sup.3 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is (Z) but-2-en-2-yl, (b) if and only if R.sup.3 is not hydrogen then R.sup.9 is 1-methyl propyl, (c) if R.sup.3 is not hydrogen, then R.sup.8 is optionally protected hydroxy, (d) if R.sup.9 is (Z) but-2-en-2-yl and R.sup.8 is optionally protected hydroxy, then R.sup.1 is hydrogen and R.sup.2 is optionally hydroxy, and (e) is R.sup.2 is not methoxy or optionally protected hydroxy, then R.sup.1, R.sup.3 and R.sup.8 are hydrogen and R.sup.9 is (Z) but-2-en-2-yl.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 8725679 |
Nov 1987 |
GBX |
|
| 8818374 |
Aug 1988 |
GBX |
|
| 8824763 |
Oct 1988 |
GBX |
|
Parent Case Info
This application is a continuation of application Ser. No. 265,509, filed 11/1/88, now abandoned.
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 U.S. Pat. No. 4,285,963.
The compounds disclosed in the above references include compounds of formula (A): ##STR2## wherein R.sup.a is methoxy or hydroxy, R.sup.b is hydrogen, R.sup.c is hydrogen, pentanoyloxy, heptanoyloxy, or 2-methylhexanoyloxy, and R.sup.d is methyl or ethyl, with the proviso that when R.sup.c is hydrogen, R.sup.e is methoxy; or R.sup.a is methoxy or hydroxy, R.sup.b is hydrogen, R.sup.c is 2-methylbutanoyloxy, 2,4-dimethylpent-2-enoyloxy, or 2,4-dimethylpentanoyloxy, and R.sup.d is methyl or ethyl, with the proviso that when R.sup.d is ethyl, R.sup.a is hydroxy and R.sup.c is 2,4-dimethylpentanoyloxy; or R.sup.a is methoxy or hydroxy, R.sup.b is the group of formula: ##STR3## (4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy), R.sup.c is hydroxy, and R.sup.d is 1-methyl propyl.
EP-A-0 254 583 (U.S. Ser. No. 076,274) describes compounds of formula (B): ##STR4## wherein R.sup.e is hydrogen or E 2-methyl 2-butenoyloxy, and R.sup.f is methoxy or hydroxy, with the proviso that when R.sup.e is E 2-methyl 2-butenoyloxy, R.sup.f is methoxy.
The microorganism from which the compounds of formula (B) were obtained has also been found to produce compounds of formula (C) ##STR5## wherein R.sup.g and R.sup.h are as set out in the following table:
The absolute configuration of the compounds of formulae (A) to (D) is believed to be as follows: ##STR7##
We have now discovered that it is possible to prepare novel compounds from starting materials having a hydroxy substituent at the C-22 position, and that these compounds are useful s anthelmintically active compounds.
According to the present invention there is provided a compound of formula (I): ##STR8## wherein R.sup.1 is hydrogen or optionally protected hydroxy; R.sup.2 is alkoxy, optionally protected hydroxy, oxo or optionally O-substituted oximino; R.sup.3 is hydrogen, optionally protected hydroxy, or a group 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy or .alpha.-L-oleandrosyloxy wherein the terminal hydroxy group is optionally protected; one of R.sup.4 and R.sup.5 is hydrogen and the other is methyl; and one of R.sup.6 and R.sup.7 is hydrogen and the other is methyl; with the proviso that (a) when R.sup.1 is optionally protected hydroxy, R.sup.3 is hydrogen, and (b) when R.sup.2 is not methoxy or optionally protected hydroxy, R.sup.1 and R.sup.3 are both hydrogen.
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.
Suitable substituents for an oxime are as set out in EP-A-O 288 205. Compounds of the present invention having at least one oxo group may be converted to a corresponding optionally O-substituted oxime by conventional means, for example by reaction with optionally O-substituted hydroxylamine, for example in the form of the hydrochloride, in a suitable solvent such as aqueous methanol, typically at ambient temperatures. Once formed an O-substituted oxime may be reacted with a suitable O-acylating or O-alkylating agent. The compound may exist as syn or anti isomers or mixtures thereof. Suitable etherifying substituents for an oxime include C.sub.1-6 alkyl and C.sub.2-6 alkenyl.
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 TrichostronqVlus 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, 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 (e.g. 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 0.01 to 100 mg of active ingredient per kg of animal body weight per dose, more suitably 1.0 to 100 mg/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.
A further aspect of the invention provides a process for the preparation of a compound of formula (I), which process comprises the acid catalysed cyclisation of a compound of formula (II): ##STR9## wherein R.sup.1 to R.sup.7 have the values set out above, and R.sup.14 is hydrogen or lower alkyl, more particularly C.sub.1-3 alkyl.
It should be appreciated that the configuration at C21 of the compound of formula (I) will be subject to thermodynamic control (as discussed e.g. by P. Deslongchamps et al, Canadian J. Chem. [1981] 59, 1105): it is believed that the epimer in which the configuration at C21 is as in the naturally occurring compounds of formulae (A), (B) and (C) is normally thermodynamically favoured.
Compounds of formula (II) may be obtained from compounds of formula (III): ##STR10## wherein R.sup.1 to R.sup.3 are as defined above, via the routes shown in Scheme I below: ##STR11##
Notes
The compounds of formula (III) are novel and form a further aspect of the invention.
Compounds of formula (III) can be prepared by cleaving the 21-22 carbon-carbon bond of a precursor having a hydroxy substituent on C22, such as compounds of formulae (A), (B), (C) and (D).
Thus, a process for the preparation of a compound of formula (III) comprises subjecting a compound of formula (IV): ##STR12## to 21-22 carbon-carbon bond cleavage, wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above with respect to formula (I), R.sup.8 is hydrogen or optionally protected hydroxy, and R.sup.9 is methyl, ethyl, 1-methyl propyl or (Z) but-2-en-2-yl, with the proviso that (a) if R.sup.1 is optionally protected hydroxy, then R.sup.3 is hydrogen, R.sup.8 is hydrogen, and R.sup.9 is (Z) but-2-en-2-yl, (b) if and only if R.sup.3 is not hydrogen then R.sup.9 is 1-methyl propyl, (c) if R.sup.3 is not hydrogen, then R.sup.8 is optionally protected hydroxy, (d) if R.sup.9 is (Z) but-2-en-2-yl and R.sup.8 is optionally protected hydroxy, then R.sup.1 is hydrogen and R.sup.2 is optionally protected hydroxy, and (e) if R.sup.2 is not methoxy or optionally protected hydroxy, then R.sup.1, R.sup.3 and R.sup.8 are hydrogen and R.sup.9 is (Z) but-2-en-2-yl.
Particular protecting groups for R.sup.1 and R.sup.8 when they are protected hydroxy include those present in the naturally occurring compounds of formulae (A) to (C) above.
Those skilled in the art will appreciate that acyl can readily be removed, for example by base hydrolysis, and compounds of formula (I) wherein R.sup.1 is hydroxy or protected hydroxy, wherein the protecting group may or may not be acyl, R.sup.2 is methoxy or optionally protected hydroxy, and R.sup.3 is hydrogen, are thus readily derivable from the corresponding compounds of formulae (B) and (C) wherein R.sup.1 is a naturally occurring acyloxy group.
It will further be appreciated that 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyl may readily be removed or partly removed, for example by acid hydrolysis, and compounds of formula (I) wherein R.sup.3 is optionally protected hydroxy, or .alpha.-L-oleandrosyloxy, wherein the terminal hydroxy group is optionally protected, may thus readily be derived from the compounds of formula (A) wherein R.sup.b is 4-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyloxy.
In a preferred process of the invention, R.sup.1 is hydrogen, R.sup.2 is methoxy or hydroxy, R.sup.3 and R.sup.8 are hydrogen, and R.sup.9 is (Z) but-2-en-2-yl.
Processes for cleaving the 21-22 carbon-carbon bond will typically include oxidation of the C22 hydroxy group to a ketone, conversion of the ketone to a corresponding oxime, and effecting rearrangement of the oxime under Beckmann conditions. The Beckmann rearrangement is discussed in "The Chemistry of the carbon-nitrogen double bond" Ed. Saul Patai Wiley-Interscience 1970, 408.
The oxidation will typically be carried out using DMSO/oxalyl chloride (Swern oxidation), or a chromium based oxidizing agent such as pyridinium chlorochromate (PCC), with protection of hydroxy groups elsewhere as necessary, for example using TBDMS.
The oxime may then be prepared by any conventional means, for example by reaction with optionally O-substituted hydroxylamine, for example in the form of the hydrochloride, in a suitable solvent such as aqueous methanol, typically at ambient temperatures.
The oxime may be used directly in the Beckmann rearrangement or may first be converted to a more reactive derivative, for example by sulphonylation with an appropriate sulphonylating agent such as a sulphonic anydride or sulphonyl halide, advantageously in the presence of a little of the corresponding sulphonic acid.
The Beckmann rearrangement is typically effected using an acid catalyst such as PPSE (polyphosphoric acid silyl ether). Where the oxime has been activated, for example by sulphonylation, mildly acidic work-up conditions can be used to effect the rearrangement
In any or all of the above processes, sensitive groups may if necessary be protected using protecting groups which are conventional in the art.
It should be appreciated that in the presence of an alcohol the valerolactone compound of formula (III) will exist in equilibrium with the corresponding ring opened ester.
Those skilled in the art will appreciate that the process of the invention can be applied to essentially any milbemycin or avermectin having a hydroxy (or oxo or oxime) group present at the C22 position. Furthermore, the compounds of formulae (I) and (III) can be further modified using techniques which are in themselves 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. 14, 553 et seq. Thus, a broad aspect of the invention provides any milbemycin or avermectin of partial formula (i) hereinbelow, as well as a process for its preparation which comprises effecting acid-catalysed cyclisation of a milbemycin or avermectin of partial formula (ii) hereinbelow: ##STR13## wherein R.sup.4 to R.sup.7 and R.sup.14 have the values set out above.
A further broad aspect of the invention provides a milbemycin or avermectin of partial formula (v) hereinbelow, as well as a process for its preparation which comprises effecting 21-22 carbon-carbon bond cleavage of a milbemycin or avermectin having a hydroxy (or oxo or oximino) substituent at the C22 position: ##STR14##
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4285963 |
Arison et al. |
Aug 1981 |
|
Foreign Referenced Citations (13)
| Number |
Date |
Country |
| 0073660 |
Mar 1983 |
EPX |
| 0074758 |
Mar 1983 |
EPX |
| 0170006 |
Feb 1986 |
EPX |
| 0214731 |
Jul 1986 |
EPX |
| 0194125 |
Sep 1986 |
EPX |
| 0204421 |
Dec 1986 |
EPX |
| 0212867 |
Mar 1987 |
EPX |
| 0237339 |
Sep 1987 |
EPX |
| 0241146 |
Oct 1987 |
EPX |
| 0288205 |
Oct 1988 |
EPX |
| 0254853 |
Jan 1989 |
EPX |
| 1390336 |
Apr 1975 |
GBX |
| 2170499 |
Aug 1986 |
GBX |
Non-Patent Literature Citations (2)
| Entry |
| J. Antibiotics, 29 (3), 76-14-76-15 (1976). |
| J. Antibiotics, 29 (6), 76-35-76-42 (1976). |
Continuations (1)
|
Number |
Date |
Country |
| Parent |
265509 |
Nov 1988 |
|
Patent Grant
5055596
