Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-11
2003-12-02
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06657070
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a novel process of producing chirally pure &agr;-amino acids and N-sulfonyl &agr;-amino acids. Compounds of the present invention are useful for a variety of purposes, including for use in pharmaceutical compositions.
A variety of techniques have been described for production of a preferred enantiomer from &agr;-amino acids. More efficient means for producing chirally pure target compounds are needed.
SUMMARY OF THE INVENTION
In one aspect, the present invention comprises a process for preparing chirally pure S-enantiomers &agr;-amino acids.
In a further aspect, a process is provided for preparing chirally pure S-enantiomers of 2-aminoalcohols, aldehydes and oximes.
In yet another aspect, a process is provided for preparing chirally pure S-enantiomers of N-sulfonyl a-amino acids.
In a further aspect, a process is provided for preparing chirally pure N-sulfonyl 2-aminoalcohols, aldehydes and oximes.
These and other aspects of the invention will be apparent to one of skill in the art upon reading of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to a process for the preparation of chiral &agr;-amino acids.
In another aspect, the present invention provides a process for the resolution of chiral N-sulfonyl &agr;-amino acids.
Both processes of the invention produce chirally pure compounds which can be converted to suitable target compounds, including the corresponding 2-aminoalcohols or N-sulfonyl 2-aminoalcohols, aldehydes and oximes, among other desirable target compounds.
As used herein, the term “chirally pure” refers to compounds which are in 100% S-enantiomeric form as measured by chiral high performance liquid chromatography (HPLC). Other methods of measuring chiral purity include conventional analytical methods, including specific rotation, and conventional chemical methods. However, the technique used to measure chiral purity is not a limitation on the present invention.
As used herein, the term “pharmaceutically useful” refers to compounds having a desired biological effect, whether as a therapeutic, immune stimulant or suppressant, adjuvant, or vaccinal agent. Similarly, a variety of compounds which are suitable for use in non-pharmaceutical applications, e.g., a diagnostic, a marker, among others may be produced by the method of the invention. However, other pharmaceutically useful compounds may be produced by this method.
The compounds produced by the present invention and any target compounds into which they are converted can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with organic and inorganic acids such as acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, mallic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids, and mixtures thereof. Other salts include salts with alkali metals or alkaline earth metals, such as sodium (e.g., sodium hydroxide), potassium (e.g., potassium hydroxide), calcium or magnesium.
These salts, as well as other compounds produced by the method of the invention may be in the form of esters, carbamates and other conventional “pro-drug” forms, which, when administered in such form, convert to the active moiety in vivo. In one desirable embodiment, the prodrugs are esters. See, e.g., B. Testa and J. Caldwell, “Prodrugs Revisited: The “Ad Hoc” Approach as a Complement to Ligand Design”, Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).
Both natural and unnatural &agr;-amino acids, natural and unnatural 2-aminoalcohols, and intermediates thereof, may be prepared according to the present invention. Typically, &agr;-amino acids are characterized by the formula (NH
2
)(CHR.)(COOH), in which R, is an aliphatic radical. The a-amino acids prepared according to the invention can be converted to N-sulfonyl &agr;-amino acids and other desired compounds. Such other desired compounds include, without limitation, the corresponding 2-aminoalcohols, aldehydes, oximes, and pharmaceutically acceptable salts, hydrates, and prodrugs thereof. Similarly, both natural and unnatural N-sulfonyl &agr;-amino acids, natural and unnatural N-sulfonyl 2-aminoalcohols, and intermediates thereof, may be prepared according to the present invention. Thus, the N-sulfonyl &agr;-amino acids described herein can be readily reduced to 2-aminoalcohols, or converted to the corresponding aldehydes, oximes, and pharmaceutically acceptable salts, hydrates, and prodrugs thereof, using techniques known to those of skill in the art.
For example, chirally pure a-amino acids produced according to the method of the invention and having the formula (R)
2
CH(CH
2
)
n
CH(CO
2
H)NH-R′ can readily be converted to chirally pure 2-aminoalcohols. In another example, chirally pure N-sulfonyl &agr;-amino acids produced according to the invention and having the formula (R)
2
CH(CH
2
)
n
CH(CO
2
H)NH—S(O)
2
R′ are readily converted to N-sulfonyl 2-aminoalcohols of the formula (R)
2
CH(CH
2
)
n
CH(CH
2
OH)NH
2
R′. Suitably, in the above formulae, n is 0 to about 10; R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, CH
2
cycloalkyl, CH
2
-3-indole, CH(loweralkyl)-2-furan, CH(loweralkyl)-4-methoxyphenyl, CH(loweralkyl)phenyl, or CH(OH)-4-SCH
3
-phenyl; and R′ is selected from among H, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, heterocycle, substituted heterocycle, phenyl, substituted phenyl, benzyl, substituted benzyl, cycloalkyl, and substituted cycloalkyl, among other suitable groups. In another example, an N-sulfonyl 2-aminoalcohol having the formula (R)
2
CH(CH
2
)
n
CH(CH
2
OH)NH—S(O)
2
-2-C
4
H
2
S-5-Cl is prepared using the method of the invention. However, the chirally pure compounds produced by the methods of the present invention are not limited by the above formulae.
The term “alkyl” is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms, preferably one to eight carbon atoms and, most preferably, one to six carbon atoms; as used herein, the term “lower alkyl” refers to straight- and branched-chain saturated aliphatic hydrocarbon groups having one to six carbon atoms; “alkenyl” is intended to include both straight- and branched-chain alkyl group with at least one carbon—carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms; “alkynyl” group is intended to cover both straight- and branched-chain alkyl groups with at least one carbon—carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms.
The terms “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as just described having from one to three substituents selected from the group including halogen, CN, OH, NO
2
, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, substituted alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term “aryl” is used herein to refer to a carbocyclic aromatic system, which may be a single ring, or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, and indane.
The term “substituted aryl” refers to aryl as just defined having one to four subst
Howson and Howson
Lambkin Deborah C.
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