Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
2001-03-26
2004-09-21
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S002600, C514S016700, C514S017400, C514S018700, C514S019300, C530S330000, C530S345000, C562S553000, C562S445000, C570S123000
Reexamination Certificate
active
06794492
ABSTRACT:
BACKGROUND OF THE INVENTION
Perfluoroalkyl iodide compounds have been known for some time. It has been observed that iodonium salts having a fluoroalkyl and an aryl group are strong alkylation agents with useful reaction chemistry.
Recently, it has been reported that fluorine-containing amino acids have been actively investigated in view of their high potential for biological studies and medical applications. See “The First Fluoroalkylation of Amino Acids and Peptides in Water Utilizing the Novel lodonium Salt (CF
3
SO
2
)
2
NI(Ph)CH
2
CF
3
”, DesMarteau and Montanari. Synthetic routes to fluorinated amino acids normally involve several steps using fluorinated building blocks, mostly obtained by the conversion of carbon heteroatoms to C—F bonds. A more direct approach involves fluoroalkylations. Cysteine and related amino acids and peptides can be alkylated by alkyl halides or esters if both the substrate and alkylating reagant can be solubilized in mixed water organic solvents or in liquid ammonia. The novel iodonium salts disclosed in the above referenced publication are generally stable to water.
Other investigators have reported that hypervalent iodine compounds are useful reagants or reactive intermediates. See Umemoto and Gotoh, “Synthesis, Properties, and Reactivity of (1H, 1H-Perfluoroalkyl)- and (1H-Perfluoro-1-alkenyl)aryliodonium Triflates and Their Analogs”. The hypervalent iodines may carry fluoro-alkyl or alkenyl groups, and they have shown useful properties in part because of the high electronegativity of the fluoro groups. However, many of these reaction schemes are sensitive to the presence of water, and therefore could not be expected to be useful in biological applications or other aqueous applications of peptide chemistry.
Unfortunately, most reaction schemes to prepare di-peptides or long peptide chains using amino acids have the added difficulty that an unprotected —COOH group of the amino acid will react readily with the adjacent nitrogen of the N-alkyl amino acid. Thus, in many cases it is impossible to provide for coupling of one amino acid with another amino acid because an unprotected —COOH is reactive. Typically, it has been required in the past to convert the —COOH group to an ester group having an alkyl R attached so that the amino acid molecule will not condense with itself, as shown below:
A chemistry reaction scheme that facilitates the reaction or combination of amino acids with each other to form dipeptides or polypeptides, in a way that does not require the —COOH group to be first converted to an ester as shown above, would be very useful. A reaction sequence or compound that is capable of deactivating the nitrogen group (i.e. the —NH) in an amino acid, such as that set forth below, would be highly desirable.
Preferably, such a group or composition would reduce the reactivity of the —NH group in the molecule above such that it does not react as quickly, thereby facilitating the formation of di-peptides, polypeptides, and so forth. The —NH needs to be deactivated so that the —COOH group does not condense with the —NH group within one amino acid, but instead reacts in a desirable manner to form compounds having more than one amino acid in sequence.
SUMMARY OF THE INVENTION
Surprisingly, it has been discovered that certain fluorinated compounds may be successfully used as reaction agents in accomplishing the polymerization of useful amino acids structures into peptides. Novel lipophilic building blocks that can be used with amino acids have been discovered. Fluorinated methyl groups have been found to be particularly useful.
Compounds and reaction schemes have been discovered that may provide a lipophilic moiety which is more readily absorbed across the blood brain barrier, making them particularly useful for biological applications as applied to pharmaceutically active compounds of many types. For example, many proteins involved in osteoporosis, arthritis, and cancer may be reacted with compounds containing fluoro groups (i.e. —CF
3
; —CH
2
—CF
3
, and the like) to produce altered structures that are more lipophilic than their fully H-saturated counterparts, providing more biological mobility, more stability, and increased biological activity.
Certain compounds have been found to be useful as biological building blocks to generate many types of pharmaceutically useful and active compounds. These building blocks avoid the unintentional or undesirable condensation of an amine group with an adjacent —COOH group, thereby allowing for combination of amino acid and similar compounds to be coupled together in a way that promotes biological activity.
In one application of the invention, a compound having the generic formula below is provided:
in which the R
1
and R
2
group is selected from the group consisting of: alkyls, hydrogen, aryls, aromatic compounds, amines, sulfur-containing alkyl groups, sulfur-containing aryl groups, and heterocyclic compounds; and R
2
. In many applications, the R group will be chosen so as to provide a compound having an amino acid base structure. Further, the compound above may be reacted to form a dipeptide, a tripeptide, or a multi-peptide structure having biological activity. These structures may be incorporated into animal or human proteins having biological application.
In another aspect of the invention, the di-peptide having the chemical formula:
is shown, in which R
1
, R
2
, and R
3
each are selected from the group consisting of: alkyls, hydrogen, aryls, aromatic compounds, amines, sulfur-containing alkyl groups, sulfur-containing aryl groups, and heterocyclic compounds.
In yet another aspect of the invention, a peptide or peptide chain having the generic structure set forth below is disclosed:
In the above embodiment of the invention, the R
1
, R
2
, R
3
and R
4
groups are independently selected from the group consisting of: alkyls, hydrogen, aryls, aromatic compounds, amines, sulfur-containing alkyl groups, sulfur-containing aryl groups, and heterocyclic compounds. A repeating sequence denoted by a long chain peptide having multiple -n groups is provided, and -n may have a value of as little as 1 to as much as several hundred thousand.
In other aspects of the invention, the novel compounds having fluorinated carbon atoms could be used in forensic applications for tagging or providing a chemical signature on compounds for later detection by mass spectrometry, or other analytical techniques. For example, it would be possible to prepare novel fluorine and iodine containing analogs of compounds known to bind brain receptors. Fluorine could be introduced as a 2,2,2-trifluoroethyl group. A methoxy or methylenedioxy functionality on an aromatic ring could provide for rapid iodination. Using this method, it would be possible to “tag” or chemically identify compounds so that if and when they are later used to manufacture drugs or illegal substances, analytical chemical techniques could be used to confirm the source of the starting materials. This could assist providing linking evidence in narcotics enforcement.
In biological and medical applications, this “tagging” procedure could be used to follow the course of compounds as they traverse the blood brain barrier, and determine by radioiodine imaging and similar techniques the location of substances that have been introduced into a human or animal. Thus, medical investigators and researchers could use the compounds of this invention to choose an appropriate fluorinated material among a wide variety made by the alkylation methods disclosed herein.
In some applications, it would be possible and desirable to take biological material from an individual, fluorinate carbon atoms in a preselected manner, and then re-introduce the material, facilitating a measure of the accumulation of such materials in the body and various locations within the body.
Further, other compounds containing a —CF
3
group have been found to have anti-cancer activity. In particular, dipeptides of tyrosine/isoleucine with a —CF
3
group attached to a nitrogen (—NH) group are found to have a
DesMarteau Darryl
Montanari Vittorio
Clemson University
Dority & Manning P.A.
Low Christopher S. F.
Lukton David
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