Amino amides, peptides and peptidomimetics

• US 20040010162A1
• Filed: 04/01/2003
• Published: 01/15/2004
• Est. Priority Date: 04/01/2002
• Status: Active Grant

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Yao, Xin, Petasis, Nicos A.
• Granted Patent: US 6,946,542 B2
• Time in Patent Office: Days
• US Class Current: 564/138
• CPC Class Codes: C07C 231/12 by reactions not involving the formation of carboxamide groups
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Synthetic methods and compounds involving amino amides, peptides and peptidomimetics. Amino amide derivatives are prepared via the one-step three-component reaction of a glyoxamide, an amine, and an organoboron derivative. Conversion of the product to another glyoxamide intermediate allows the iterative use of this chemistry for the synthesis of peptides and peptidomimetics.

Claims

1. A method for preparing an amino amide, the method comprising:

providing an amine derivative of formula 1

 

wherein;

R¹ and R² are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy, provided that R¹ and R² can be connected together forming a ring;

converting amine derivative 1 to a compound of formula 2

wherein;

Rw is hydrogen, alkyl, aryl, heteroaryl;

contacting the compound of formula 2 with an amine derivative of formula 3 and an organoboron compound of formula 4 to form a reaction mixture

 

wherein;

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl;

Ra and Rb are independently selected from a group consisting of hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy, provided that Ra and Rb can be joined together forming a ring; and

X and Y are independently selected from a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that X and Y can be joined together forming a ring; and

allowing the reaction mixture to react to form an amino amide of formula 5

2. The method of claim 1, further comprising:

converting the amino amide of formula 5 to an amino amide of formula 6

 

wherein;

R⁴ is hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, or alkoxy.

3. The method of claim 1, wherein:

one of R¹, R², R³, Ra, Rb, Rw, X and Y is connected to a polymeric chain or other solid phase material.

4. The method of claim 1, wherein:

the amino amide of formula 5 is formed as a member of a combinatorial library.

5. The method of claim 3, wherein:

the amino amide of formula 5 is formed as a member of a combinatorial library.

23. A combinatorial library including a plurality of compounds, one or more of the plurality of compounds in the combinatorial library being prepared by the process of claim 1.

27. The method of claim 1, wherein:

Rw is hydrogen.

6. A method for preparing a peptide, the method comprising:

providing an amino amide derivative of formula 6

 

wherein;

R¹, R² and R⁴ are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy, provided that two or more of R¹, R² and R⁴ can be connected together forming one or more rings;

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl or allenyl; and

Rw is hydrogen, alkyl, aryl, heteroaryl;

converting the amino amide derivative of formula 6 to a compound of formula 7

 

wherein;

Rw′

is hydrogen, alkyl, aryl, heteroaryl;

contacting the compound of formula 7 with an amine of formula 8 and an organoboron compound of formula 9 to form a reaction mixture

 

wherein;

R⁵ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl;

Rc and Rd are independently selected from a group consisting of hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino, acylamino, sulfonylamino, and alkoxy, provided that Rc and Rd can be joined together forming a ring; and

X and Y are independently selected from a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that X and Y can also be joined together forming a ring; and

allowing the reaction mixture to react to form a peptide of formula 10

7. The method of claim 6, further comprising:

converting the peptide of formula 10 into to a peptide of formula 11

 

wherein;

R⁶ is hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, or alkoxy.

8. The method of claim 6, wherein:

one of R¹, R², R³, R⁴, R⁵, Rc, Rd, Rw, X or Y is connected to a polymeric chain or other solid phase material.

9. The method of claim 6, wherein:

the peptide of formula 10 is formed as a member of a combinatorial library.

10. The method of claim 8, wherein:

the peptide of formula 10 is formed as a member of a combinatorial library.

24. A combinatorial library including a plurality of compounds, one or more of the plurality of compounds in the combinatorial library being prepared by the process of claim 6.

28. The method of claim 6, wherein:

one or more of Rw and Rw′

are hydrogen.

11. A method for preparing a peptidomimetic compound, the method comprising:

providing an amino amide or peptide derivative of formula 6

 

wherein;

R¹, R², and R⁴ are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy; and

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl, provided that R¹, R², R³ and R⁴ can be connected together forming one or more rings;

contacting the amino amide or peptide derivative of formula 6 with a 1,2 dicarbonyl compound of formula 13 and an organoboron compound of formula 12 to form a reaction mixture

 

wherein;

Rw is hydrogen, alkyl, aryl or heteroaryl.

R⁷ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl;

R⁸ is hydrogen, alkyl, alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy;

X and Y are independently selected from a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that X and Y can be joined together forming a ring; and

allowing the reaction mixture to react to form a compound of formula 14

12. The method of claim 11, wherein:

one of R¹, R², R³, R⁴, R⁷, R⁸, Rw, X or Y is connected to a polymeric chain or other solid phase material.

13. The method of claim 11, wherein:

the compound of formula 14 is formed as a member of a combinatorial library.

14. The method of claim 12, wherein:

the compound of formula 14 is formed as a member of a combinatorial library.

25. A combinatorial library including a plurality of compounds, one or more of the plurality of compounds in the combinatorial library being prepared by the process of claim 11.

29. The method of claim 11, wherein:

Rw is hydrogen.

15. A method for preparing a peptidomimetic compound, the method comprising:

providing an amino amide or peptide derivative of formula 6

 

wherein;

R¹, R², and R⁴ are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy; and

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl, provided that R¹, R², R³ and R⁴ can be connected together forming one or more rings;

converting the amino amide or peptide derivative of formula 6 to a compound of formula 7

 

wherein;

Rw is hydrogen, alkyl, aryl or heteroaryl.

contacting the compound of formula 7 with an amino carbonyl compound of formula 16 and an organoboron compound of formula 15 to form a reaction mixture

 

wherein;

R⁹ and R¹¹ are independently selected from a group consisting of alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl;

R¹⁰ is hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, or alkoxy;

R¹² is selected from a group consting of;

hydrogen, alkyl, alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy, provided that R¹⁰, R¹¹ and R¹² can be connected together forming one or more rings;

X and Y are independently selected from a group consisting of;

hydroxy, alkoxy, aryloxy, amino, alkylamino, or dialkylamino;

X and Y can also be joined together forming a ring; and

allowing the reaction mixture to react to form a compound of formula 17

16. The method of claim 15, wherein:

one of R¹, R², R³, R⁴, R⁹, R¹⁰, R¹¹, R¹², Rw, X or Y is connected to a polymeric chain or other solid phase material.

17. The method of claim 15, wherein:

the compound of formula 17 is formed as a member of a combinatorial library.

18. The method of claim 16, wherein:

the compound of formula 17 is formed as a member of a combinatorial library.

26. A combinatorial library including a plurality of compounds, one or more of the plurality of compounds in the combinatorial library being prepared by the process of claim 15.

30. The method of claim 15, wherein:

Rw is hydrogen.

19. A method for preparing a combinatorial library including a plurality of compounds, the method comprising:

providing one or more amine derivatives of formula 1

 

wherein;

R¹ and R² are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy, provided that R¹ and R² can be connected together forming a ring;

converting the one or more amine derivatives 1 to compounds of formula 2

 

wherein;

Rw is hydrogen, alkyl;

aryl, heteroaryl;

contacting the compounds of formula 2 with one or more amine derivatives of formula 3 and organoboron compounds of formula 4 to form one or more reaction mixtures

 

wherein;

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl;

Ra and Rb are independently selected from a group consisting of hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy, provided that Ra and Rb can be joined together forming a ring; and

X and Y are independently selected from a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that X and Y can be joined together forming a ring; and

allowing the reaction mixtures to react to form a combinatorial library including one or more amino amides of formula 5

20. A method of preparing a combinatorial library including a plurality of compounds, the method comprising:

providing one or more amino amide derivatives of formula 6

 

wherein;

R¹, R² and R⁴ are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy, provided that two or more of R¹, R² and R⁴ can be connected together forming one or more rings;

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl or allenyl; and

Rw is hydrogen, alkyl, aryl, heteroaryl;

converting the amino amide derivatives of formula 6 to one or more compounds of formula 7

 

wherein;

Rw′

is hydrogen, alkyl, aryl, heteroaryl;

contacting the compounds of formula 7 with one or more amines of formula 8 and organoboron compounds of formula 9 to form one or more reaction mixtures

 

wherein;

R⁵ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl;

Rc and Rd are independently selected from a group consisting of hydrogen, alkyl, allyl, benzyl, aryl, heteroaryl, acyl, sulfonyl, amino, acylamino, sulfonylamino, and alkoxy, provided that Rc and Rd can be joined together forming a ring; and

X and Y are independently selected from a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that X and Y can also be joined together forming a ring; and

allowing the reaction mixtures to react to form one or more peptides of formula 10

21. A method of preparing a combinatorial library including a plurality of compounds, the method comprising:

providing one or more amino amides or peptide derivatives of formula 6

 

wherein;

R¹, R², and R⁴ are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy; and

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl, provided that R¹, R², R³ and R⁴ can be connected together forming one or more rings;

contacting the amino amides or peptide derivatives of formula 6 with one or more 1,2 dicarbonyl compounds of formula 13 and organoboron compounds of formula 12 to form one or more reaction mixtures

 

wherein;

Rw is hydrogen, alkyl, aryl or heteroaryl.

R⁷ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl;

R⁸ is hydrogen, alkyl, alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy;

X and Y are independently selected from a group consisting of hydroxy, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, provided that X and Y can be joined together forming a ring; and

allowing the reaction mixtures to react to form one or more compounds of formula 14

22. A method of preparing a combinatorial library including a plurality of compounds, the method comprising:

providing one or more amino amides or peptide derivatives of formula 6

 

wherein;

R¹, R², and R⁴ are independently selected from a group consisting of hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, and alkoxy; and

R³ is alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, or allenyl, provided that R¹, R², R³ and R⁴ can be connected together forming one or more rings;

converting the amino amides or peptide derivatives of formula 6 to one or more compounds of formula 7

 

wherein;

Rw is hydrogen, alkyl, aryl or heteroaryl.

contacting the compounds of formula 7 with one or more amino carbonyl compounds of formula 16 and organoboron compounds of formula 15 to form one or more reaction mixtures

 

wherein;

R⁹ and R¹¹ are independently selected from a group consisting of alkyl, aryl, heteroaryl, allyl, alkenyl, alkynyl, and allenyl;

R¹⁰ is hydrogen, alkyl, allyl, alkenyl, aryl, heteroaryl, acyl, sulfonyl, amino, alkylamino, dialkylamino, acylamino, sulfonylamino, or alkoxy;

R¹² is selected from a group consting of;

hydrogen, alkyl, alkenyl, aryl, heteroaryl, amino, alkylamino, dialkylamino, hydroxyamino, alkoxyamino, hydroxyl, alkoxy, aryloxy or heteroaryloxy, provided that R¹⁰, R¹¹ and R¹² can be connected together forming one or more rings;

X and Y are independently selected from a group consisting of;

hydroxy, alkoxy, aryloxy, amino, alkylamino, or dialkylamino;

X and Y can also be joined together forming a ring; and

allowing the reaction mixtures to react to form one or more compounds of formula 17