Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-02
2002-05-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S011400, C530S318000, C540S454000, C540S460000, C540S467000
Reexamination Certificate
active
06384026
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to macrocyclic compounds and their derivatives and to methods for synthesizing and using these compounds.
BACKGROUND OF THE INVENTION
Substantial effort has been expended by a wide variety of entities in attempting to develop highly effective pesticides, particularly insecticides and/or insect repellents which are capable of eradicating or controlling arthropods, such as insects, that contaminate stored food, for example, fruits, vegetables, grains, and the like; that destroy ornamental and agricultural plants, crops, and trees; or that attack, harm, or annoy humans and animals. Particularly bothersome for humans and animals are blood-sucking insects, such as mosquitoes, fleas, and lice, and anthropods, such as ticks. These insects, in addition to being an annoyance, are also potentially harmful due to their ability to transmit diseases.
One approach has been to develop poisons which kill the insects. However, in many instances, insects have developed resistance to the pesticides (possibly by “natural selection”) or are able to detect and avoid poisons. Furthermore, many poisons have undesirable effects on human and other animal life, and therefore uses thereof have often been regulated or forbidden.
Moreover, some insects, like the common German or house cockroach (Blattela germanica) and the American cockroach (Periplaneta americana), when killed by pesticides and left in areas that cannot be reached or cleaned, have been identified as a significant allergen in house dust. It has been estimated that 10-15 million people in the United States are allergic to cockroaches. Since dead cockroaches in unreachable areas emit the allergen, poisons are ineffective in such situations. Still further, simply the presence of such insects in areas inhabited or occupied by humans is highly undesirable.
In an attempt to avoid the problems posed by the use of insect poisons and to meet the consumer demand, various insect repellent formulations have been developed. However, many such formulations incorporate active ingredients which are highly toxic to humans and to many animals. Consequently, the usable concentration of these toxic chemicals must be reduced, typically to the point of rendering the resulting formulation ineffective in providing the desired repulsive effect. Moreover, many such repellent materials are toxic and others are foul smelling, discoloring, or both. These adverse properties seriously limit their utility in many situations. Insect repellent formulations which have enjoyed commercial success, for example those containing N,N-diethyl-m-toluamide (“DEET”), have been few in number.
Insect pupae, given that they generally cannot crawl, run, or fly, should be vulnerable to predation. However, many benefit from concealment and camouflage, or from mechanical means of defense. It has been discovered that in some cases insect pupae are protected chemically. For example, pupae of coccinellid beetles (genus Epilachna) bear a dense coating of glandular hairs, as shown in
FIG. 1
, that secrete oily droplets which are repulsive to insects. Likewise, the Mexican bean beetle (
E. varivestis
) secretes azamacrolides, which are lactones with a single nitrogen atom incorporated into a ring of 15 or 16 members, as shown in FIG.
2
.
Thus, a need continues to exist for new insect repellents, preferably ones which, unlike DEET, are based on naturally occurring products and which have greater repellent activity against a broader group of insect types, reduced toxicity, longer lasting effects, improved physical characteristics, reduced staining characteristics, and improved stability. The present invention is directed toward meeting this need.
SUMMARY OF THE INVENTION
The present invention is related to an isolated macrocycle having the formula:
where d is an integer from 0 to about 100; A, B, and each D are the same or different and are selected from the group consisting of
wherein each R
1
is the same or different and is a bivalent alkylene moiety; each R
2
is the same or different and is a bivalent alkylene moiety; and each R
3
is the same or different and is selected from the group consisting of a hydrogen atom and an alkyl moiety.
The present invention also relates to a method of preparing a macrocycle having the formula:
where d is an integer from 0 to about 100; A, B, and each D are the same or different and are selected from the group consisting of
where each R
1
is the same or different and is a bivalent alkylene moiety; each R
2
is the same or different and is a bivalent alkylene moiety; and each R
3
is the same or different and is selected from the group consisting of a hydrogen atom and an alkyl moiety. The method includes providing an isolated linear compound having the formula:
where f is an integer from 0 to about 100; E and each F are the same or different and have the formula:
where each R
4
is the same or different and is a bivalent alkylene moiety; each R
5
is the same or different and is selected from the group consisting of a hydrogen atom and an alkyl moiety; each R
6
is the same or different and is a bivalent alkylene moiety; each X is the same or different and is hydrogen or an amine protecting group; Y
1
is a hydrogen atom or an alcohol protecting group; and Y
2
is an OH group or an carboxylic acid protecting group. The method further includes cyclizing the linear compound under conditions effective to produce a macrocycle, wherein A, B, and each D are the same or different and have the formula:
The present invention further relates to an isolated linear compound having the formula:
where f is an integer from 0 to about 100; E and each F are the same or different and have the formula:
where each R
4
is the same or different and is a bivalent alkylene moiety; each R
5
is the same or different and is selected from the group consisting of a hydrogen atom and an alkyl moiety; each R
6
is the same or different and is a bivalent alkylene moiety; each X is the same or different and is hydrogen or an amine protecting group; Y
1
is a hydrogen atom or an alcohol protecting group; and Y
2
is an OH group or an carboxylic acid protecting group.
The macrocycles of the present invention or combinations thereof can be used as a substantially pure substance or as a component in compositions or formulations of substances to repel insects or arthropods from the proximity and/or the surfaces of plants, fruits and vegetables, and animals. Further, the macrocycles of the present invention or combinations thereof can be used as a substantially pure substance or as a component in compositions or formulations of substances to repel insects or arthropods from desired locations, such as dwelling structures, particularly in locations where food is stored. The macrocycles of the present invention can also be used to disrupt arthropod mating.
Further, the macrocycles of the present invention or combinations thereof can be used as a substantially pure substance or as a component in compositions or formulations of substances in medicinal applications, particularly as neurotoxins.
REFERENCES:
patent: 4996315 (1991-02-01), Speranza et al.
patent: 5532231 (1996-07-01), Rosenberg
Bradshaw et al., Aza-Crown Macrocycles John Wiley & Sons., Inc., pp. 352,353, 1993.*
Habermehl, “Neurotoxins from Amphibians,”Toxicon, 29:1165-1166 (1991).
Benoit, “Mechanism(s) of Action of Neurotoxins Acting on the Inactivation of Voltage-Gated Sodium Channels,”C. R. Soc. Biol., 192:409-436 (1998).
Brown, “Insights on the Voltage-Sensitive Sodium Channel: The Batrachotoxin Connection,”Toxicon, 27:21-22 (1989).
Gusovsky et al., “Interaction of Pumiliotocin B With an ‘Alkaloid-Binding Domain’ on the Voltage-Dependent Sodium Channel,”Molecular Pharmacology, 42:1104-1108 (1992).
Tang et al., “Effects of Besipirdine at the Voltage-Dependent Sodium Channel,”Br. J. Pharmacol., 116:2468-2472 (1995).
Myers et al., “Conus Peptides as Chemical Probes for Receptors and Ion Channels,”Chem. Rev., 93:1923-1936 (1993).
Schröder et al., “Combinatorial Chemistry in
Eisner Thomas
Farmer Jay J.
Schroeder Frank C.
Smedley Scott R.
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