Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support

• US 5,288,514 A
• Filed: 09/14/1992
• Issued: 02/22/1994
• 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): Pal, Asok
• Assistant Examiner(s): ACHUTAMURTHY, PONNATHAPURA N
• Application Number:
  US07/944,469
• Time in Patent Office: 526 Days
• Field of Search: 427/2, 530/334, 530/335, 530/337, 530/345
• US Class Current: 435/4
• 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 synthesis of therapeutically useful compounds. The invention provides a rapid approach for combinatorial synthesis and screening of libraries of derivatives of therapeutically important classes of compounds such as benzodiazepines, prostaglandins and β-turn mimetics. In order to expediently synthesize a combinatorial library of derivatives based upon these core structures, 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. A method of making a plurality of benzodiazepines on a substrate comprising the steps of:

coupling substituted amino benzophenones to a substrate, said substituted amino benzophenones comprising protecting groups;

removing said protecting groups from said amino benzophenones to form amino benzophenones having amino active sites;

coupling a plurality of amino acid derivatives to said amino active sites; and

cyclizing molecules resulting from the step of coupling said plurality of amino acid derivatives, whereby a plurality of benzodiazepines are formed on said substrate.

2. The method as recited in claim 1 further comprising the step of alkylating the benzodiazepines.

3. The method as recited in claim 1 wherein the step of coupling substituted amino benzophenones to a substrate further comprises the steps of:

coupling the substituted amino benzophenones to acid-cleavable linkers;

and coupling the acid-cleavable linkers to the substrate.

4. The method as recited in claim 3 wherein the linkers are coupled to the substituted amino benzophenone before the linkers are coupled to the substrate.

5. The method as recited in claim 3 wherein the linkers are coupled to the substrate before the linkers are coupled to the substituted amino benzophenone.

6. The method as recited in claim 1 wherein the step of coupling substituted amino benzophenones to a substrate further comprises the steps of:

activating a first region of the substrate;

coupling a first substituted amino benzophenone to said first region;

activating a second region of the substrate; and

coupling a second substituted amino benzophenone to said second region.

7. The method as recited in claim 2 wherein the step of coupling substituted amino benzophenones to a substrate further comprises the steps of:

activating a first region of the substrate;

coupling a first substituted amino benzophenone to said first region;

activating a second region of the substrate; and

coupling a second substituted amino benzophenone to said second region.

8. The method as recited in claim 1 wherein the step of coupling a plurality of amino acid derivatives further comprises the steps of:

treating one portion of the amino benzophenones having amino active sites with a first amino acid;

and treating a second portion of the amino benzophenones having amino active sites with a second amino acid, whereby a mixture of coupled benzophenone derivatives is formed on said substrate.

9. The method as recited in claim 2 wherein the step of coupling a plurality of amino acid derivatives further comprises the steps of:

treating one portion of the amino benzophenones having amino active sites with a first amino acid;

and treating a second portion of the amino benzophenones having amino active sites with a second amino acid, whereby a mixture of coupled benzophenone derivatives is formed on said substrate.

10. The method as recited in claim 1 wherein the step of removing said protecting groups from said amino benzophenones further comprises the steps of:

removing one portion of said protecting groups from said amino benzophenones, whereby a mixture of protected and deprotected amino benzophenones is produced;

coupling an amino acid derivative to where said protecting group has been removed; and

removing a second portion of said protecting groups from said amino benzophenones.

11. The method as recited in claim 2 wherein the step of removing said protecting groups from said amino benzophenones further comprises the steps of:

removing one portion of said protecting groups from said amino benzophenones, whereby a mixture of protected and deprotected amino benzophenones is produced;

coupling an amino acid derivative to where said protecting group has been removed; and

removing a second portion of said protecting groups from said amino benzophenones.

12. The method as recited in claim 2 wherein the step of alkylating the cyclized molecules further comprises the steps of:

treating one portion of the cyclized molecules with a first alkylating agent;

and treating a second portion of the cyclized molecules with a second alkylating agent, whereby a mixture of alkylated molecules is formed on said substrate.

13. The method as recited in claim 7 wherein the step of alkylating the cyclized molecules further comprises the steps of:

treating one portion of the cyclized molecules with a first alkylating agent;

and treating a second portion of the cyclized molecules with a second alkylating agent, whereby a mixture of alkylated molecules is formed on said substrate.

14. The method as recited in claim 11 wherein the step of alkylating the cyclized molecules further comprises the steps of:

treating one portion of the cyclized molecules with a first alkylating agent;

and treating a second portion of the cyclized molecules with a second alkylating agent, whereby a mixture of alkylated molecules is formed on said substrate.

15. The method as recited in claim 3 wherein linkers are selected from the group consisting of:

4-(4-(5-chloro-2-fluorenylmethoxycarbonylamino-benzoyl)-phenoxymethyl)phenoxyacetic acid and 4-benzoyl-6-chloro-3-fluorenylmethoxycarbonylaminobenzoyloxymethyl-phenoxyacetic acid.

16. The method as recited in claim 2 wherein the alkylated benzodiazepines are selected from the group consisting of:

7-chloro-1,3-dihydro-5-(4-hydroxyphenyl)-1,3-dimethyl-(2H)1,4-benzodiazepin-2-one;

7-chloro-1,3-dihydro-5-(4-hydroxyphenyl)-1-ethyl-3-methyl-(2H)1,4-benzodiazepin-2-one;

1-allyl-7-chloro-1,3-dihydro-5-(4-hydroxyphenyl)-3-methyl-(2H)1,4-benzodiazepin-2-one;

7-chloro-1,3-dihydro-5-(4-hydroxyphenyl)-1-ethyl-3-(4-hydroxyphenylmethyl)-(2H)1,4-benzodiazepin-2-one;

8-carboxy-7-chloro-1,3-dihydro-1,3-dimethyl-5-phenyl-(2H)1,4-benzodiazepin-2-one;

7-chloro-1,3-dihydro-1-ethyl-5-(4-hydroxyphenyl)-3-isopropyl-(2H)1,4-benzodiazepine-2-one;

7-chloro-1,3-dihydro-3-carboxymethyl-1-ethyl-5-(4-hydroxyphenyl)-(2H)1,4-benzodiazepine-2-one;

8-carboxy-7-chloro-1,3-dihydro-1-methyl-5-phenyl-3-phenylmethyl-(2H)1,4-benzodiazepine-2-one;

8-carboxy-7-chloro-1,3-dihydro-3-methyl-5-phenyl-1-phenylmethyl-(2H)1,4-benzodiazepine-2-one; and

7-chloro-1,3-dihydro-1-ethyl-5-(4-hydroxyphenyl)-1-ethyl-3-(4-aminobutyl)-(2H)1,4-benzodiazepine-2-one.

17. The method as recited in claim 3 wherein said acid-cleavable linkers are selected from the group consisting of allyl 2-(4-hydroxymethylphenoxy) acetate and allyl 2-(4-bromomethylphenoxy) acetate.

18. The method of claims 1 or 3, wherein said coupling of substituted benzophenones to a substrate comprises coupling the phenyl rings of said benzophenones to said substrate.