Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-21
2003-05-20
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S139000
Reexamination Certificate
active
06566524
ABSTRACT:
FIELD OF INVENTION
The present invention relates to methods of preparing amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids. More particularly, the invention relates to the solid phase synthesis of substituted amino-tetrahydroisoquinoline-sulfonamide hydroxamic acids using a solid support. The invention also relates to methods of preparing combinatorial libraries of amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids.
BACKGROUND ART
The amino-substituted-tetrahydroisoquinoline-carboxylates (amino-substituted-TIQ-carboxylates) and related compounds, such as amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids (amino-substituted-TIQ-sulfonamide hydroxamic acids), are useful in numerous pharmaceutical applications. Such compounds have been useful in treatment of degenerative joint disorders, disorders of the connective tissue, ulcerations, atherosclerosis, stenosis, inflammation, carcinomatosis, anorexia, and septic shock. Thus, it is desirable to generate amino-substituted-TIQ-sulfonamide hydroxamic acids for testing as potential drug candidates. The acceleration of drug discovery has generated growing demands for efficient synthetic methods to produce therapeutic candidates. Preferably the methods are suitable for use in generating combinatorial libraries.
Schudok, U.S. Pat. No. 5,962,471, teach substituted 6- and amino-substituted-tetrahydroisoquinoline-carboxylates suitable for therapy of disorders involving increased activity of matrix-degrading metalloproteinases. Schudok teaches a method of synthesizing substituted amino-substituted-TIQ-3-(N-hydroxy)carboxamides by successively treating substituted amino-substituted-TIQ-carboxylates with ethyl chloroformate, N-methylmorpholine and O-trimethylsilylhydroxylamine. Thouin et al.,
Tetrahedron Letters,
41:457-460 (2000) teach the synthesis of hydroxamic acids by the nucleophilic displacement of carboxylates from oxime resins using hydroxylamine in a methanol:chloroform solution, and disclose hydroxamic acids prepared using proline, phenylalanine and alanine.
There is a need for facile and efficient methods for the synthesis of amino-substituted-TIQ-sulfonamide hydroxamic acids. It is desirable that the methods conveniently produce combinatorial libraries of compounds.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide novel methods of preparing amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids. It is also an object of the invention to provide novel methods of preparing combinatorial libraries of amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids.
In accordance with one aspect of the invention, there are provided methods of preparing amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids having the structure:
wherein R
1
is an alkyl, an aryl, a heterocyclic moiety, an amide, a sulfonamide, a urea, a thiourea, or an alcohol, and R
2
is an aryl, a hetero-aromatic ring or a hydrocarbocycle. The methods comprise the steps of providing an orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate attached to a solid support; attaching the R
1
group to the amino-substituted of the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate; removing the protecting group from the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate to form a deprotected, R
1
-substituted amino-substituted-tetrahydroisoquinoline-carboxylate, reacting the deprotected, R
1
-substituted amino-substituted-tetrahydroisoquinoline-carboxylate with a sulfonyl chloride having the structure R
2
SO
2
C1 to form an intermediate attached to a solid support; and cleaving the intermediate from the solid support to form an amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acid.
In accordance with another aspect of the invention, there are provided methods of preparing amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids comprising the steps of providing an orthogonally protected amino-substitutent-tetrahydroisoquinoline-carboxylate attached to a solid support; attaching a moiety selected from the group consisting of amides, sulfonamides, ureas, thioureas, alcohols, alkyls and mixtures thereof to the amino-substituent of the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate; removing the protecting group from the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate to form a deprotected amino-substituted-tetrahydroisoquinoline-carboxylate; reacting the amino-substituted-tetrahydroisoquinoline-carboxylate with a sulfonyl chloride to form an intermediate attached to a solid support; and cleaving the intermediate from the solid support to form an amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acid.
In accordance with yet another aspect of the invention, there are provided methods of preparing a combinatorial library of amino-substituted-tetrahydroisoquinoline sulfonamide hydroxamic acids having the structure:
wherein R
1
is alkyl, aryl, heterocyclic moiety, amide, sulfonamide, urea, thiourea, or alcohol, and R
2
is aryl, hetero-aromatic ring or hydrocarbocycle. The methods comprise the step of providing a support-bound orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate. The methods further comprise the steps of attaching a first R
1
group to a first portion of the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate and attaching a second R
1
group to a second portion of the orthogonally protected amino-substituted-tetrahydroisoquinoline carboxylate, deprotecting the first and second portions of the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate to form first and second deprotected amino-substituted-tetrahydroisoquinoline-carboxylates; attaching a first R
2
group to the ring nitrogen of the first deprotected amino-substituted-tetrahydroisoquinoline to form a first support-bound intermediate and attaching a second R
2
group to the ring nitrogen of the second deprotected amino-substituted-tetrahydroisoquinoline to form a second support-bound intermediate; and cleaving the first and second support-bound intermediates from the solid support to form first and second amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acids. When the first and second R
1
groups are the same, then the first and second R
2
groups are different, and when the first and second R
2
groups are the same, then the first and second R
1
groups are different. The first and second portions of the protected amino-substituted-tetrahydroisoquinoline-carboxylate may be separated prior to attachment of the R
1
group, for example by partitioning the orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate into at least a first orthogonally protected amino-substituted-tetrahydroisoquinoline-carboxylate and a second orthogonally protected-amino-substituted-tetrahydroisoquinoline-carboxylate.
In accordance with another aspect of the invention, there are provided methods of preparing an amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acid comprising the steps of providing an amino-substituted-tetrahydroisoquinoline intermediate attached to a solid support and having the structure:
wherein R
1
and R
2
are defined above, and W represents a solid support; and cleaving the amino-substituted-tetrahydroisoquinoline intermediate from the solid support with a cleaving composition comprising NH
2
ON a, NH
2
OH and methanol to form an amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acid.
In accordance with yet another aspect of the invention, there are provided methods of preparing amino-substituted-tetrahydroisoquinoline-sulfonamide hydroxamic acid comprising the steps of providing amino-substituted-tetrahydroisoquinoline-carboxylate attached to a solid support; reacting the ring nitrogen of the amino-substituted-tetrahydroisoquinoline-carboxylate with a sulfonyl chloride to form an in
Liu Song
Rennells William Martin
Davis Zinna Northington
Kozlowski Holly D.
The Procter & Gamble Co.
Upite David V.
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