Amino-ketone solid support templates

• US 6,117,940 A
• Filed: 10/16/1998
• Issued: 09/12/2000
• Est. Priority Date: 10/17/1997
• Status: Expired due to Fees

• Current Assignee: Advanced Syntech LLC A Kentucky Limited Liability Corporation
• Original Assignee: Advanced Syntech LLC A Kentucky Limited Liability Corporation
• Inventors: Mjalli, Adnan M. M.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US09/174,521
• Time in Patent Office: 697 Days
• Field of Search: 525/54.11, 525/54.21, 525/55, 525/153, 525/157, 525/257, 525/259, 436/111, 436/128
• US Class Current: 525/54.11
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 241/18 Oxygen or sulfur atoms
• CPC Class Codes: C07D 243/14 1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
• CPC Class Codes: C08F 290/06 Polymers provided for in subclass C08G
• CPC Class Codes: C08F 290/065 Polyamides; Polyesteramides; Polyimides
• CPC Class Codes: C08G 65/33317 heterocyclic
• CPC Class Codes: Y10T 436/173845 Amine and quaternary ammonium
• CPC Class Codes: Y10T 436/200833 Carbonyl, ether, aldehyde or ketone containing

Abstract

A solid support template for solid phase synthesis of amino group containing compounds is provided that comprises amino-ketone core compounds of the general formula:

A-L-NH(CR.sub.1 R.sub.2).sub.n COR.sub.3

linked to appropriate insoluble substrates to create solid support templates having the general formula:

Polymer-X-L-NH(CR.sub.1 R.sub.2).sub.n COR.sub.3

where L is a multifunctional monomer carrying a first functional group that forms a covalent bond with X and a second functional group comprising an amine and L, R₁, R₂ and R₃ are selected from the group consisting of alkyl, alkyl-aryl, alkenyl, alkenyl-aryl groups having up to 6 carbon atoms and substituted forms thereof. The amino-ketone templates are useful for the solid phase synthesis of compounds such as the imidazoles, benzodiazepines, pyrazines, and steroid mimics.

Claims

1. A solid phase reaction component for the production of an amino containing chemical compound in a reaction media, said solid phase reaction component comprising an amino-ketone core compound linked to a polymer substrate, said reaction component being insoluble in said reaction media.

2. The solid phase reaction component of claim 1 having the formula:

space="preserve" listing-type="equation">Polymer-X-L-NH(CR.sub.1 R.sub.2).sub.n COR.sub.3

wherein;

n=1 or 2;

X is a moiety that forms a covalent bond to join said polymer and said amino-ketone core compound;

L is a multifunctional monomer carrying a first functional group that forms a covalent bond with X and a second functional group comprising an amine and L, R₁, R₂ and R₃ are selected from the group consisting of alkyl, alkyl-aryl, alkenyl, alkenyl-aryl groups having up to 6 carbon atoms and substituted forms thereof.

3. The solid phase reaction component of claim 2 wherein said polymer is selected from the group of organic polymers consisting of polystyrene, polypropylene, polyethylene glycol, polyacrylamide, cellulose and combinations thereof.

4. The solid phase reaction component of claim 2 wherein said polymer is a composite of inorganic and organic substrates.

5. The solid phase reaction component of claim 4 wherein said polymer is a composite consisting of polyacrylamide supported within a matrix of kieselghuhr particles.

6. The solid phase reaction component of claim 2 wherein X is selected from the functional group consisting of oxygen, an ester, an amide, sulfur, silicon, and carbon.

7. The solid phase reaction component of claim 2 wherein substituents of the substituted forms of L, R₁, R₂ and R₃ are selected from the group consisting of H, chloro, fluoro, bromo, iodo, nitro, cyano, and amino radicals, alkyloxy, alkyloxy aryl, aminocarbonyl, aminocarbonylalkyl-aryl, thioalkyl, thioalkyl-aryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, alkylsulfonamide aryl, alkylsulfoxide aryl, alkylsulfone aryl, alkyl aminocarbonylamino alkyl, alkyl aminocarbonylamino alkyl aryl, C1-C6 alkyloxycarbonyl alkyl, alkyloxycarbonyl alkyl aryl, carboxyalkyl, carboxyalkyl aryl carbonylalkyl, carbonylalkyl aryl, alkyloxycarbonylamino alkyl, alkyloxycarbonylamino alkyl aryl, Guanidino, alkylCOOH, alkylCONH2, alkenylCOOH, alkenyl CONH2 groups and said alkyl and aryl groups contain up to 6 carbon atoms.

8. The solid phase reaction component of claim 7 wherein said aryl group is mono, di- and tri-substituted and said aryl group is selected from the group consisting of phenyl, biphenyl, 2-naphthyl, 1-naphthyl, pyridyl, furyl, thiophenyl, indolyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benthiazolyl, and benzoxazolyl.

9. The solid phase reaction component of claim 7 suitable for the synthesis by solid phase reaction of imidazoles, indoles, thiazoles, diazepines, pyrazines, sulfonamides, ureas, pyridines, piperindines, steroids, mimimcs and the like having the formula:

space="preserve" listing-type="equation">Polymer-X-L-NH(CR.sub.1 R.sub.2).sub.n COR.sub.3.

10. The solid phase reaction component of claim 7 suitable for the synthesis by solid phase reaction of imidazoles, indoles, thiazoles, diazepines, pyrazines, sulfonamides, ureas, pyridines, piperindines, steroids, mimimcs and the like having the formula:

space="preserve" listing-type="equation">Polymer-X-L-NHCR.sub.1 R.sub.2 COR.sub.3.

11. The solid phase reaction component of claim 7 suitable for the synthesis by solid phase reaction of highly functionalized imidazoles having the formula:

##STR28##

12. The solid phase reaction component of claim 7 suitable for the synthesis by solid phase reaction of highly functionalized diazepines having the formula:

where R5 and R6 may be joined as a ring system or may be separate.

13. The solid phase reaction component of claim 2 wherein said polymer is selected from the group of inorganic polymers consisting of kieselghur, silica gel, and controlled pore glass and polymeric organic substrates consisting of polystyrene, polypropylene, polyethylene glycol, polyacrylamide and cellulose.

14. A method for the solid phase production of an amino containing compound in a reaction media comprising the steps of:

a. forming a solid phase support template comprising an amino-ketone core compound linked to a polymer substrate, said reaction template being insoluble in said reaction media and having the formula

space="preserve" listing-type="equation">Polymer-X-L-NH(CR.sub.1 R.sub.2).sub.n COR.sub.3

wherein;

n=1 or 2;

X is a moiety that forms a covalent bond to join said polymer and said amino-ketone core compound;

L is a multifunctional monomer carrying a first functional group that forms a covalent bond with X and a second functional group comprising an amino group and L, R₁, R₂ and R₃ are selected from the group consisting of alkyl, alkyl-aryl, alkenyl, alkenyl-aryl groups having up to 6 carbon atoms and substituted forms thereof;

b. reacting said solid phase support template in said reaction media to form a reaction product comprising said desired amino containing compound linked to said resin;

c. cleaving said reaction product; and

d. separating said desired amino containing compound from said reaction media.

15. The method of claim 14 wherein said desired amino containing compound is an imidazole that proceeds in accordance with the following solid phase reaction:

##STR29##

16. The method of claim 14 wherein said desired amino containing compound is a benzodiazepine derivative that proceeds in accordance with the following solid phase reaction:

17. The method of claim 14 wherein said desired amino containing compound is an imidazole-diazepinone derivative that proceeds in accordance with the following solid phase reaction:

18. The method of claim 14 wherein said desired amino containing compound is a pyrazine derivative that proceeds according to the following reaction:

19. The method of claim 14 wherein said desired amino containing compound is a steroid mimic that proceeds according to the following reaction:

20. The method of claim 14 wherein said desired amino containing compound is 2-(3-benzyl-2-oxo-5-phenyl-2H-pyrazin-1-yl)-N-hydroxy-propionamide and said solid phase support has the formula:

21. The method of claim 14 wherein said desired amino containing compound is N-hydroxy-2-(5-oxo-2-phenyl-1,5-dihydrobenzo[e][1,4]diazepin-4-yl)-propionamide and said solid phase support has the formula:

22. The method of claim 14 wherein said desired amino containing compound is 3-(1-methyl-2-oxo-2-phenyl-ethylamino)-propionic acid and said solid phase support has the formula:

23. The method of claim 14 wherein said desired amino containing compound is 2-(1-carboxy-2-phenyl-ethyl)-1-oxo-phenyl-1,2-dihydro-pyrizinol[1,2-b]isoquinolin-5-ylium trifluoro-acetate and said solid phase support has the formula:

24. The method of claim 14 wherein said desired amino containing compound is 3-(2,4-diphenyl-imidazole-1-yl)-N-methyl-propionamide and said solid phase support has the formula:

25. The method of claim 14 wherein said desired amino containing compound is N-hydroxy-3-[2-(4-methanesulfonyl-phenyl)-4-phenyl-imidazol-1-yl]-propionamide.

26. The method of claim 14 wherein said desired amino containing compound is 3-(2-{1-[3-(4-methoxy-phenyl)-uriedo]-2phenyl-ethyl}-4-phenyl-imidazol-1-yl)-N-methyl-propionamide.

27. The method of claim 14 wherein said desired amino containing compound is 8-benzyl-2-phenyl-4,5,7,8-tetrahydr-1,3a,7-triaza-azulen-6-one.

28. The method of claim 14 wherein said desired amino containing compound is 3-(2-benzo[1,3]dioxol-5-yl-5-oxo-1,5-dihydro-benzo[e][1,4]diazepin-4-yl)-N-methyl-propioamide.

29. The method of claim 14 wherein said desired amino containing compound is selected fromthe group having the formulae: