Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-17
2001-04-24
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S417000
Reexamination Certificate
active
06221894
ABSTRACT:
BACKGROUND OF THE INVENTION
Nodulosporic acid and two related components are antiparasitic agents and ectoparasiticidal agents isolated from the fermentation culture of Nodulisporium sp. MF-5954 (ATCC 74245). These three compounds have the following structures: nodulisporic acid (compound A)
29,30-dihydro-20,30-oxa-nodulisporic acid (compound B)
31-hydroxy-20,30-oxa-29,30,31,32-tetrahydro-nodulisporic acid (compound C)
SUMMARY OF THE INVENTION
This invention relates to new acaricidal, antiparasitic, insecticidal and anthelmintic agents related to the nodulisporic acids, to processes for their preparation, compositions thereof, their use in the treatment of parasitic infections, including helminthiasis, in human and animals, and their use in the treatment of parasitic infections in plants or plant products.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a compound having the formula I:
or a pharmaceutically acceptable salt thereof, wherein R
X
is selected from the group consisting of:
CH
2
CH
2
CF
3
, C(CH
3
)
2
CO
2
CH
3
, C(CH
3
)
2
CO
2
CH
2
CH
3
, C(CH
3
)
2
CON(CH
3
)
2
, C(CH
3
)
2
CONHCH
2
CF
3
, C(CH
3
)
2
CON(CH
3
)CH
2
CH
3
, CH(CH
2
F)
2
, C(CH
2
F)
2
CO
2
CH
3
, C(CH
3
)
2
CH
2
F, C(CH
2
F)
3
, and C(CH
2
F)
2
CH
3
; or R
X
is a group derived from an amine selected from the group consisting of 1,1 -dimethylpropylamine, 1,1-dimethylprop-2-enylamine, 3,4,4-trichlorobut-3-enylamine, 1,1,2-trimethylprop-2-enylamine, 1,1-dimethyl-2-trifluoromethylprop-2-enylamine, 3-methyoxypropylamine, 1,1-dimethylbutylamine, 4,4,4-trifluorobutylamine, 2,2,3,3,3-pentafluoropropylamine, 3,3,4,4,4-pentafluorobutylamine, 5,5,5-trifluoropentylamine, 1-fluoromethyl-2-fluoroethylamine, 1-methyl-2,2,2-trifluoroethylamine, 2-fluoromethyl-3-fluoropropylamine, 1,1-dimethyl-2,2,2-trifluoroethylamine, 2,2-difluoropropylamine, 3,3-difluorobutylamine, 2,2-difluorobutylamine, 2-methyl-3,3,3-trifluoropropylamine, 2,2,3,3,4,4,4-heptafluorobutylamine, 2,2-difluoro-3-methylbutylamine, 2-methyl-3,3,3-trifluoropropylamine, 3-methylbutylamine, 1,1-dimethyl-2-oxo4,4,4-trifluorobutylamine, 1,1-dimethyl-2-oxo-5,5,5-trifluoropentylamine, 1,1,3-trimethyl-2-oxobutylamine, 1,1,3,3-tetramethyl-2-oxobutylamine, propyl 2-amino-2-methylpropanoate, isopropyl 2-amino-2-methylpropanoate, phenyl 2-amino-2-methylpropanoate, 1,1-bis(fluoromethyl)-2-oxo-4,4,4-trifluorobutylamine, 1,1-bis(fluoromethyl)-2-oxo-3,3-dimethylbutylamine, 2-amino-2,2-bis(fluoromethyl)-(N-methyl-N-ethyl)acetamide, ethyl 2-amino- 2,2-bis(fluoromethyl)acetate, propyl 2-amino-2,2-bis(fluoromethyl)acetate, isopropyl 2-amino-2,2-bis(fluoromethyl)acetate, phenyl 2-amino-2,2-bis(fluoromethyl)acetate, 1,1-dimethyl-2-oxopropylamine, 1,1-dimethyl-2-oxobutylamine, 1,1,3-trimethyl-2-oxobutylamine, &agr;,&agr;-dimethyl-&bgr;-oxophenethylamine, 2,3-dimethyl-3-hydroxy-2-butylamine.
The present invention provides in another aspect pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. Such compositions may further comprise one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.
The present invention provides in another aspect a method for treating parasitic diseases in a mammal which comprises administering an antiparasitic amount of a compound of Formula I. The treatment may further comprise co-administering one or more other active ingredients such as anthelmintic agents, insect regulators, ecdosyne agonists and fipronil.
The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is intended to include all possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and all possible geometric isomers.
In addition, the present invention includes all pharmaceutically acceptable salts thereof. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N
−
-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
Compounds of the present invention are named based on the trivial name of the parent compound, nodulisporic acid (compound A).
Compounds of the present invention are prepared from nodulisporic acid (Compound A) which in turn is obtained from the fermentation culture of Nodulisporium sp. MF-5954 (ATCC 74245). The description of the producing microorganism, the fermentation process, and the isolation and purification of the three nodulisporic acids are disclosed in U.S. Pat. No. 5,399,582, issued Mar. 21, 1995, which is hereby incorporated by reference in its entirety.
Compounds of formula I are prepared from the corresponding carboxylic acid using standard amide-forming reagents known to those skilled in the art. The reaction is carried out using at least one equivalent of an amine nucleophile, H
2
NR
X
, although preferably ten to one hundred equivalents of amine nucleophiles are employed. Amide-forming reagents include, but are not restricted to, dicyclohexylcarbodiimide, 1-(3diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl), diisopropylcarbodiimide, benzotriazol- 1-yloxy-tris(dimethylamino)phosphonium hexafluorphosphate (BOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), chloro-tris-pyrrolidino-phosphonium hexafluorophosphate (PyCloP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), diphenylphosphoryl azide (DPPA), 2-(1H-benzotriazole-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-N,N,N′,N′-bis(pentamethylene)uronium hexafluorophosphate and 2-chloro-1-methylpyridinium iodide. The amide-forming reactions may be facilitated by the optional addition of N-hydroxybenzotriazole or N-hydroxy-7-aza
Fisher Michael H.
Meinke Peter T.
Shih Thomas L.
Lee Shu M.
Merck & Co. , Inc.
Oswecki Jane C.
Rose David L.
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