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US 5,962,337 AGranted
Combinatorial 1,4-benzodiazepin-2,5-dione library
AssigneePharmacopeia, Inc.
InventorMichael H. J. Ohlmeyer
Life of this patent
Estimating the term…
Abstract
A method has now been found of synthesizing a combinatorial library of 1,4-benzodiazepin-2,5-diones on solid supports via an aza-Wittig ring closure, said compounds optionally encoded with tags, and to the use of this library in assays to discover biologically active compounds, and, optionally, to cleave 1,4-benzodiazepin-2,5-diones therefrom.
Claims14
A method of synthesizing a 1,4-benzodiazepin-2,5-dione which comprises:
- a. attaching an amino-protected .alpha.-aminoacid or an amino-protected N-alkyl .alpha.-aminoacid to a solid support via its carboxyl group to form a resin linked amino-protected .alpha.-aminoacid or amino-protected N-alkyl .alpha.-aminoacid;
- b. cleaving an amino protecting group from said resin linked amino-protected .alpha.-aminoacid or amino-protected N-alkyl .alpha.-aminoacid to provide a resin linked .alpha.-aminoacid or N-alkyl .alpha.-aminoacid;
- c. acylating said resin linked .alpha.-aminoacid or N-alkyl .alpha.-aminoacid with a 2-azidobenzoyl chloride to form a resin linked N-(2-azidobenzoyl)aminoacid;
- and
- d. cyclizing said resin linked N-(2-azidobenzoyl)aminoacid via aza-Wittig ring closure to provide a resin linked 1,4-benzodiazepin-2,5-dione.
2 more elements
A method of synthesizing a 1,4-benzodiazepin-2,5-dione which comprises:
- a. attaching an amino-protected .alpha.-aminoacid to a solid support via its carboxyl group to form a resin linked amino-protected .alpha.-aminoacid;
- b. cleaving an amino protecting group from said resin linked amino-protected .alpha.-aminoacid to provide a resin linked .alpha.-aminoacid;
- c. reductively alkylating said linked .alpha.-aminoacid with an aldehyde and a reducing agent to provide a resin linked N-alkyl .alpha.-aminoacid;
- d. acylating said resin linked N-alkyl .alpha.-aminoacid with a 2-azidobenzoyl chloride to form a resin linked N-(2-azidobenzoyl)aminoacid;
- and
- e. cyclizing said resin linked N-(2-azidobenzoyl)aminoacid via aza-Wittig ring closure to provide a resin linked 1,4-benzodiazepin-2,5-dione.
3 more elements
A method of synthesizing, 1,4-benzodiazepin-2,5-diones of the formulae:
- which comprises:
- a) reacting a resin-linked .alpha.-amino ester of the formula:
- ##STR59## wherein .sub.S is a solid support and R.sup.11 is hydrogen or benzyloxy, suspended in an aprotic, polar solvent and an excess of a soluble organic base with an excess of a substituted 2-azidobenzoyl chloride of the formula:
- ##STR60## wherein X.sup.1 and X.sup.2 are hydrogen or methoxy, to produce a resin-linked N-(2-azidobenzoyl)amino ester;
- b) suspending said resin-linked ester in an involatile solvent and treating said suspension with an excess of a trivalent phosphorus reagent at 80-140.degree. C. for 2-24 hr. to produce a resin-linked 1,4-benzodiazepin-5-one of the formula:
- ##STR61## and c) suspending said resin-linked 1,4-benzodiazepin-5-one in an acidic solution at room temperature for 1-24 hr. to produce a 1,4-benzodiazepin-2,5-dione of the formula:
- ##STR62##
4 more elements
A method of synthesizing a 1,4-benzodiazepin-2,5-dione of the formula:
- which comprises:
- a) reacting a resin-linked .alpha.-amino ester of the formula:
- ##STR63## wherein .sub.S is a solid support, suspended in an aprotic, polar solvent and an excess of a soluble organic base with an excess of a substituted 2-azidobenzoyl chloride of the formula:
- ##STR64## wherein X.sup.1 and X.sup.2 are hydrogen, to produce a resin-linked N-(2-azidobenzoyl)amino ester;
- b) suspending said resin-linked ester in an involatile solvent and treating said suspension with an excess of a trivalent phosphorus reagent at 80-140.degree. C. for 2-24 hr. to produce a resin-linked 1,4-benzodiazepin-5-one of the formula:
- ##STR65## and c) suspending said resin-linked 1,4-benzodiazepin-5-one in an acidic solution at room temperature for 1-24 hr. to produce a 1,4-benzodiazepin-2,5-dione of the formula:
- ##STR66##
4 more elements
A compound of the formula:
A compound of the formula:
- wherein
- .sub.S is a solid support;
- R.sup.11 is hydrogen or benzyloxy;
- and
- X.sup.1 and X.sup.2 are hydrogen or methoxy.
2 more elements
Dependencies are inferred from the claim text.