Solid phase and combinatorial synthesis of compounds on a solid support

• US 5,545,568 A
• Filed: 12/02/1993
• Issued: 08/13/1996
• Est. Priority Date: 09/14/1992
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Ellman, Jonathan A.
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US08/161,677
• Time in Patent Office: 985 Days
• Field of Search: 427/2.1, 427/2.13, 427/2.11, 427/2.12, 427/2.23, 436/518, 436/531, 436/501, 435/7.1
• US Class Current: 506/15
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00432 Photolithographic masks
• CPC Class Codes: B01J 2219/00454 by chemical cleavage from the solid support
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00504 Pins
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00592 Split-and-pool, mix-and-divide processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00711 Light-directed synthesis
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C07C 405/00 Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• CPC Class Codes: C07D 243/24 : Oxygen atoms
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C40B 50/14 : Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: C40B 80/00 : Linkers or spacers specially adapted for combinatorial chemistry or libraries, e.g. traceless linkers or safety-catch linkers

Abstract

Methods, compositions, and devices for synthesizing combinatorial libraries of various useful compounds, such as benzodiazepines, prostaglandins, β-turn mimetics and glycerol-derived drugs is described. In order to expediently synthesize such combinatorial libraries of derivatives based upon these core structures, a general methodology for the solid phase synthesis of these derivatives is also provided. This disclosure thus also describes an important extension of solid phase synthesis methods to nonpolymeric organic compounds.

Claims

1. An array comprising a plurality of benzodiazapines at selected, known positions on a substrate wherein each of said benzodiazapines is substantially pure within each of said selected locations and has a composition different than selected other benzodiazapines on said substrate.

2. The array of claim 1, wherein said substrate comprises amino-derivatized polyethylene pins.

3. A method of synthesizing benzodiazapines and analogs thereof on a solid substrate, comprising the steps of:

(a) coupling a first compound selected from the group consisting of an unsaturated carbocyclic compound, a unsaturated heterocyclic compound or a carbocyclic compound, to a substrate, said first compound including a first substituent selected from the group consisting of acyl halide or organometallic, and a second substituent selected from the group consisting of amino, protected amino, nitro, halogen, hydroxyl, azide, --OSO₂ R, --OR, --SR, hydrogen, alkyl, aryl, heteroaryl, substituted alkyl, substituted aryl, substituted heteroaryl and --N═

NAr where R is alkyl and Ar is aromatic;

(b) reacting said first compound with a second compound selected from the group consisting of an unsaturated carbocyclic compound, a unsaturated heterocyclic compound or a carbocyclic compound, under conditions effective to form a ketone, said second compound including a first substituent selected from the group consisting of acyl halide or organometallic, and a second substituent selected from the group consisting of amino, substituted amino, nitro, halogen, hydroxyl, azide, --OSO₂ R, OR, --SR, hydrogen, alkyl, aryl heteroaryl, substituted alkyl, substituted aryl or substituted heteroaryl and --N═

NAr where R is alkyl and Ar is aromatic;

provided that if said first compound includes an acyl halide substituent, then said first substituent of said second compound is organometallic and vice versa, and further provided that one of said second substituents of either of said compounds must be selected from the group consisting of amino, substituted amino, nitro, halogen, hydroxyl, azide,--OSO₂ R, --OR, --SR, and --N═

NAr where R is alkyl and Ar is aromatic and be located adjacent said first substituent;

(c) forming a free amine;

(d) coupling an amino acid derivative to said free amine to form an amide; and

(e) cyclizing said amide to form support-bound benzodiazapines or benzodiazapine analogs.

4. The method of claim 3, wherein said organometallic substituent is selected from the group consisting of trialkyltin or triaryltin.

5. The method of claim 4, wherein said first compound is a substituted aryltrimethyltin, and said second compound is a substituted aryl chloride.

7. The method of claim 3, wherein said substrate comprises amino-derivatized pins.

8. The method of claim 3, further comprising the step of cleaving said benzodiazapine from said support.

9. The method of claim 3, further comprising the step of reacting said amide with a compound having the formula RX, wherein R is selected from the group consisting of alkyl, aryl, or heteroaryl, and X is halogen.

6. The method of claim 6, wherein said amino acid derivative is an acyl fluoride amino acid derivative.