Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1995-06-05
2002-03-26
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S450000, C536S007100, C549S264000
Reexamination Certificate
active
06362168
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to antiparasitic agents and in particular to compounds related to the avermectins and milbemycins but having a novel substituent group at the 25-position and to a process for their preparation.
The avermectins are a group of broad spectrum antiparasitic agents referred to previously as the C-076 compounds. They are produced by fermenting a strain of the microorganism
Streptomyces avermitilis
ATCC 31267, 31271 or 31272 under aerobic conditions in an aqueous nutrient medium containing inorganic salts and assimilable sources of carbon and nitrogen. The morphological and cultural properties of the strains ATCC 31267, 31271 and 31272 are described in detail in British Patent Specification No. 1573955 which also describes the isolation and the chemical structure of the eight individual components which make up the C-076 complex. The milbemycins are structurally related macrolide antibiotics lacking the sugar residues at the 13-position. They are produced by fermentation, for example as described in British Patent Specification No. 1390336 and European Patent Application publication No. 0170006.
In our European Patent Application publication No. 0214731, published Mar. 18, 1987, the counterpart of U.S. application Ser. No. 886,867, filed Jul. 16, 1986, we disclose that by adding certain specified carboxylic acids, or derivatives thereof, to the fermentation of an avermectin producing organism it is possible to obtain novel compounds, related to the avermectins but having an unnatural substituent group at the 25-position in place of the isopropyl or sec-butyl group which is normally present.
The novel compounds produced are characterised in that the substituent group at the 25-position is alpha-branched i.e. the carbon atom attached to the C-25 ring position is a secondary carbon atom linked to two further carbon atoms.
In our co-pending U.S. patent application Ser. No. 107,825, filed Oct. 13, 1987, we describe and claim new mutant strains of the microorganism
Streptomyces avermitilis
lacking branched-chain 2-oxo acid dehydrogenase activity. Said strains have been deposited in the American Type Culture Collection, Rockville, Md. under the designations
Streptomyces avermitilis
ATCC 53567 and ATCC 53568.
SUMMARY OF THE INVENTION
We have now discovered that, by using these new mutant strains of
Streptomyces avermitilis
it is possible to obtain a further range of novel avermectin derivatives, not previously obtainable, wherein the C-25 substituent is linked by an unbranched (primary) carbon atom. The novel compounds are highly active antiparasitic agents having particular utility as anthelmintics, ectoparasiticides, insecticides and acaricides. The compounds can be subjected to conventional chemical transformation reactions to obtain further novel semi-synthetic derivatives. Thus, according to the present invention there are provided compounds having the formula (I):
wherein
X represents a single or a double bond; R
1
is H or OH; provided that when X is a single bond, R
1
is H or OH, and when X is a double bond, R
1
is absent;
R
2
is H, C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, alkoxy-alkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group, wherein any of said alkyl, alkoxy alkenyl or alkynyl groups may be substituted by one or more halo atoms; or a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl group, either of which may be substituted by methylene or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may be substituted by one or more C
1
-C
4
alkyl groups or halo atoms; or a group of the formula SR
5
wherein R
5
is C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo, or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
R
3
is hydrogen or methyl;
and R
4
is H or a 4′-(alpha-L-oleandrosyl)-alpha-L-oleandrosyloxy group of the formula
with the proviso that when R
4
and R
1
are both H and the double bond is absent, R
2
is not H or CH
3
.
In the above definition, alkyl groups containing 3 or more carbon atoms may be straight or branched chain. Halo means fluoro, chloro, bromo or iodo.
The C-076 complex comprises eight distinct but closely related compounds described as C-076 A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. The “a” series of compounds refers to the natural avermectin wherein the 25-substituent is (S)-sec-butyl and the “b” series to those wherein the 25-substituent is isopropyl. The designations “A” and “B” refer to avermectins wherein the 5-substituent is methoxy or hydroxy, respectively, and the numeral “1” refers to avermectins wherein a double bond is present at the 22-23 position, and numeral “2” to avermectins having a hydrogen at the 22-position and hydroxy at the 23 position.
In this application, the “a” and “b” identifiers have been dropped. Identifiers A1, A2, B1 and B2 have been retained to refer to non-natural avermectins having the structural features corresponding to those of the natural avermectins as noted above.
Preferred compounds of the formula (I) are those wherein R
4
is 4′-(alpha-L-oleandrosyl)-alpha-L-oleandrosyloxy.
Also preferred are compounds of the formula (I) wherein R
2
is SR
5
and R
5
is methyl or ethyl.
In another group of preferred compounds R
2
is methyl, isopropyl or sec-butyl.
In a further group of preferred compounds R
2
is branched C
3
-C
8
alkyl group substituted by one or more halo atoms, particularly 1-(trifluorome thyl) ethyl.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the invention the compounds of formula (I) wherein R
1
is OH and the double bond is absent or wherein the double bond is present and R
1
is absent and R
4
is 4′-(alpha-L-oleandrosyl)-alpha-L-oleandrosyloxy are prepared by fermenting a
Streptomyces avermitilis
mutant organism ATCC 53567 or 53568, as described in U.S. patent application Ser. No. 107,825, in the presence of the appropriate carboxylic acid of the formula R
2
CH
2
CO
2
H, wherein R
2
is as previously defined, or a salt, ester, or amide thereof or oxidative precursor therefor. The acid is added to the fermentation either at the time of inoculation or at intervals during the fermentation. Production of the compounds of formula (I) may be monitored by removing samples from the fermentation, extracting with an organic solvent and following the appearance of the compound of formula (I) by chromatography, for example using high pressure liquid chromatography. Incubation is continued until the yield of the compound of formula (I) has been maximised, generally for a period of from 12 to 16 days.
A preferred level of each addition of the carboxylic acid or derivative thereof is between 0.05 and 4.0 grams per litre. The best yields of the compounds of formula (I) are obtained by gradually adding the acid to the fermentation, for example by daily additions of the acid or derivative thereof over a period of several days. The acid may be added as a salt, such as the sodium or ammonium salt, or as an ester, such as the methyl or ethyl ester or as an amide, but is preferably added as the free acid. Alternative substrates which may be used in the fermentation are derivatives which are oxidative precursors for the carboxylic acids; thus, for example suitable substrates would be alcohols of the formula R
2
(CH
2
)
n
OH or amine derivatives of the formula R
2
(CH
2
)
n
NH
2
, wherein n is 2, 4 or 6, substituted lower alkanoic acids of the formula R
2
(CH
2
)
n
CO
2
H wherein n is 3 or 5 or aldehydes of the formula R
2
(CH
2
)
n
CHO wherein n is 1, 3 or 5 and R
2
is as previously defined. The media used for the fermentation may be a conventio
Dutton Christopher J.
Gibson Stephen P.
Lee Shih-Jen E.
Benson Gregg C.
Peselev Elli
Pfizer Inc.
Richardson Peter C.
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