Methods for processing chemical compounds having reactive functional groups

• US 6,942,966 B1
• Filed: 09/06/1996
• Issued: 09/13/2005
• Est. Priority Date: 01/11/1995
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Cook, Phillip Dan
• Primary Examiner(s): Celsa, Bennett
• Assistant Examiner(s): Epperson, Jon D.
• Application Number:
  US08/709,160
• Time in Patent Office: 3,294 Days
• Field of Search: 435/7.1, 436/501, 436/518, 530/333, 530/334, 540472-474
• US Class Current: 435/6.12
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 515/08 Bridged systems

Abstract

Novel macrocyclic compounds are constructed to include large cyclic structures that are interrupted by at least one ring system. Each interrupting ring system includes two bridgehead atoms. Bridgehead atoms are bonded to one or more bridges that interconnect one or more ring systems thereby forming a large cyclic structure. Located in each bridge are two or more nitrogenous moieties that are derivatized with chemical functional groups. The ring systems can include further nitrogenous moieties, either as ring atoms or on pendant groups attached to the ring. These can also be derivatized with chemical functional groups. The totality of the chemical functional groups imparts certain conformational and other properties to the macrocyclic compounds. In accordance with certain embodiments of the invention, libraries of such macrocyclic compounds are prepared utilizing permutations and combinations of the chemical functional groups and the nitrogenous moieties to build complexity into the library.

Claims

1. A synthetic process comprising the steps of:

providing a first chemical compound having a first functional group and a second functional group, said first chemical compound comprising a macrocyclic compound having a cyclic structure that is interrupted with at least one pyridine or triazine ring system, said pyridine or triazine ring system having two bridgehead atoms, each bridgehead atom being connected to at least one bridge containing at least three nitrogens, wherein each of said first functional group and said second functional group independently includes one of said three nitrogens;

placing a blocking group on said first finctional group;

reacting said second functional group with a first reagent pool comprising at least four different chemical compounds, thereby forming a first mixture of adducts having covalent bonds between said second functional group and said chemical compounds of said first reagent pool;

deblocking said first functional group, thereby forming a first mixture of deblocked compounds;

reacting at least a portion of said first mixture of deblocked compounds with a first reagent consisting essentially of a second chemical compound, thereby forming a mixture of products having covalent bonds between said first functional group and said second chemical compound.

2. The process of claim 1 further comprising dividing said first mixture of deblocked compounds into at least two portions before said reaction with said first reagent.

3. The process of claim 1 further comprising testing at least a portion of said mixture of products in a biological assay.

4. The process of claim 1 wherein said first chemical compound has at least a third functional group.

5. The process of claim 4 further comprising reacting said at least third functional group with a second reagent pool comprising a plurality of chemical compounds, thereby forming a second mixture of adducts having covalent bonds between said at least third functional group and said chemical compounds of said second reagent pool.

6. The process of claim 5 wherein said reaction of said at least third functional group is performed before said deblocking of said first functional group.

7. The process of claim 5 further comprising testing at least a portion of said mixture of products in a biological assay.

8. The process of claim 4 further comprising placing a blocking group on said at least third functional group.

9. The process of claim 8 wherein said first chemical compound has at least a fourth functional group.

10. The process of claim 9 further comprising reacting said at least fourth functional group with a third reagent pool comprising a plurality of chemical compounds, thereby forming a third mixture of adducts having covalent bonds between said at least fourth functional group and said chemical compounds of said third reagent pool.

11. The process of claim 10 wherein said reaction of said at least fourth functional group is performed before said deblocking of said first functional group.

12. The process of claim 10 further comprising testing at least a portion of said mixture of products in a biological assay.

13. The process of claim 12 further comprising deblocking said at least third functional group, thereby forming a second mixture of deblocked compounds.

14. The process of claim 13 further comprising reacting at least a portion of said second mixture of deblocked compounds with a fourth reagent pool comprising a plurality of chemical compounds, thereby forming a fourth mixture of adducts having covalent bonds between said at least third functional group and said chemical compounds of said fourth reagent pool.

15. The process of claim 14 wherein said reaction of said at least third functional group is performed before said deblocking of said first functional group.

16. The process of claim 14 further comprising testing at least a portion of said mixture of products in a biological assay.

17. The process of claim 13 further comprising reacting at least a portion of said second mixture of deblocked compounds with a second reagent consisting essentially of a third chemical compound, thereby forming a second mixture of products having covalent bonds between said at least third functional group and said third chemical compound.

18. The process of claim 17 further comprising testing at least a portion of said second mixture of products in a biological assay.

19. The process of claim 1 wherein said first reagent pool comprises at least six different chemical compounds.

20. The process of claim 1 wherein at least one chemical compound of said reagents and reagent pools includes a reactive moiety capable of forming a covalent bond with a nitrogen.

21. The process of claim 1 wherein at least one of said three nitrogens belongs to an amine, hydroxylamine, amide, hydrazide, carbamate, urea, hydrazine, sulfonamide, sulfanamide or sulfinamide.

22. The process of claim 1 wherein said ring system is pyridine, 1,3,5-triazine, a-triazine, or as-triazine.

23. The process of claim 20 wherein at least one of said reactive moieties is an aldehyde, ketone, acid, acid halide, halide, acid anhydride, isocyanate, isothiocyanate, chloroformate or activated ester.