Synthesis of peptide analogues

• US 4,242,256 A
• Filed: 06/29/1979
• Issued: 12/30/1980
• Est. Priority Date: 03/15/1977
• Status: Expired due to Term

• Current Assignee: Michael Szelke, Robert Sharpe
• Original Assignee: Michael Szelke, Robert Sharpe
• Inventors: Szelke, Michael, Sharpe, Robert
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/053,519
• Time in Patent Office: 550 Days
• Field of Search: 260/112.5 R, 562/567, 562/568, 562/571, 562/442, 562/560, 562/561, 562/556
• US Class Current: 530/328
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07F 9/5407 Acyclic saturated phosphonium compounds

Abstract

Compounds being analogues of a dipeptide in which the nitrogen atom of the linking amide group of the dipeptide is replaced by trivalent group ##STR1## and in which, optionally, the carbonyl function of this linking group is replaced by the divalent group --CH₂ -- are of value in the synthesis of isosterically modified peptides.

Claims

1. A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula:

##STR10## by a trivalent group ##STR11## to thereby obtain a dipeptide analogue of the formula (I);

##STR12## wherein R is hydrogen, or a monofunctional organic group, or a bond to the group --CH(R⁵)-- forming a cyclic group ##STR13## NR¹ R² is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R⁴)-- forming a cyclic group ##STR14## COR³ is a carboxyl group or a derivative thereof, R⁴ and R⁵ are the same or different side chain residues of an α

-amino aicd, or R⁴ is a divalent group bonded to the group R¹ R² N--, or R⁵ is a divalent organic group bonded to the group ##STR15## which comprises;

reacting a ketone of the formula (II);

##STR16## wherein A is an amine-protecting group, with zinc, to obtain a compound of formula (III);

##STR17## reacting the compound of formula (III) with a compound of the formula ##STR18## wherein Z is a group capable of acting as a leaving group in a nucleophilic substitution reaction, and B is a carboxy-protecting group to obtain a compound of the formula ANR² --CHR⁴ --COCHRCHR⁵ --COB;

removing the amine- and carboxy-protecting groups if necessary, thereby obtaining a compound of the formula (I).

4. A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula:

##STR40## by a trivalent group ##STR41## and for replacing the carbonyl group of said linking amide group by a methylene group --CH₂ --, to thereby obtain a dipeptide analogue of the formula (I);

##STR42## which comprises;

preparing a dipeptide analogue of formula (II);

##STR43## according to the process of any of claims 1 or 2, wherein the symbols A, R¹, R², R³, R⁴, R⁵, and B have the meaning given in said claims;

reducing said compound of formula (II) to a compound of formula (III);

##STR44## removing the amino- and carboxy-protecting groups if necessary, thereby obtaining a compound of formula (I).

5. A process of preparing a polypeptide analogue which comprises:

preparing a dipeptide analogue of formula (I);

##STR45## by the process of any of claims 1 or 2, wherein R¹, R², R³, R⁴, R⁵ R have the meanings given in said claims,

adding at least one α

-amino acid or a polypeptidyl residue comprising a sequence of α

-amino acids to the amino terminus or to the carboxy terminus or to both, of said dipeptide analogue.

6. A process of preparing a polypeptide analogue which comprises:

preparing a dipeptide analogue of formula (I);

##STR46## by the process of claim 4, wherein R¹, R², R³, R⁴, R⁵ and R have the meanings given in said claims,

adding at least one α

-amino acid or a polypeptidyl residue comprising a sequence of α

-amino acids to the amino terminus or the carboxy terminus or to both, of said dipeptide analogue.

8. The method of any of claims 1, 2 or 3 wherein R⁴ and R⁵ are the same or different side chain residues of an α

-amino acid selected from the group consisting of α

-alanine, β

-alanine, arginine, asparagine, aspartic acid, 3,5-dibromotyrosine, cystine, cysteine, dopa, N-formyl glycine, glycine, glutamic acid, glutamine, histidine, hydroxylysine, hydroxyproline, 3,5-diiodotyrosine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, pyroglutamic acid, hydroxyproline, serine, spinacin, threonine, thyroxine, tryptophan, tyrosine and valine.

9. The method of any of claims 1, 2 or 3 wherein said amine-protecting group A is selected from the group consisting of benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, amyloxycarbonyl, biphenylisopropoxycarbonyl, o-nitrophenylsulfonyl, phthaloyl, and p-butoxycarbonyl.

10. The method of any of claims 1 or 2 wherein said carboxy protecting group B is selected from the group consisting of C₁ -C₄ alkyl esters, amides, N-substituted amides, benzyl esters and t-butylester.

11. The method of any of claims 1 or 2 wherein said leaving group Z is selected from the group consisting of p-toluene sulphonate and bromide.

12. The method of any of claims 1, 2 or 3 which comprises removing the amino-protecting group A by acid hydrolysis.

15. The method of claim 4 wherein said reduction of said compound of formula (II) is carried out by HSCH₂ CH₂ SH followed by treatment with Raney nickel.

16. The method of claim 4, wherein said reduction of said compound of the formula (II) is carried out by a stepwise reduction which comprises:

converting the grouping --COB, to a group --COOH;

reducing the keto group to an alcohol;

activating said alcohol group by transforming said alcohol group into a mesylate or tosylate thereof; and

selectively reducing the activated alcohol group with a hydride reagent.

2. A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula:

##STR19## by a trivalent group ##STR20## to thereby obtain a dipeptide analogue of the formula (I);

##STR21## wherein R is hydrogen, or a monofunctional organic group, or a bond to the group --CH(R⁵)-- forming a cyclic group ##STR22## NR¹ R² is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R⁴)-- forming a cyclic group ##STR23## COR³ is a carboxy group or a derivative thereof, R⁴ and R⁵ are the same or different side chain residues of an α

-amino acid, or R⁴ is a divalent group bonded to the group R¹ R² N--, or R⁵ is a divalent organic group bonded to the group ##STR24## which comprises;

reacting a compound of formula (II);

##STR25## with triphenylphosphine and a mild base to obtain an ylide of formula (III);

##STR26## reacting the ylide of formula III with a compound of the formula ##STR27## wherein Z is a group capable of acting as a leaving group in a nucleophilic substitution reaction, and B is a carboxy-protecting group, and then

cleaving the C--P bond, to thereby obtain a compound of formula (IV);

##STR28## removing the amine- and carboxy-protecting group if necessary; and

thereby obtaining a compound of formula (I).

13. The method of claim 2 wherein said mild base is Na₂ CO₃ /H₂ O/C₂ H₅ OCOCH₃.

14. The method of claim 2 wherein said cleavage of said C--P bond is carried out by electrolysis.

3. A method for isosterically replacing the nitrogen atom of the linking amide group of a dipeptide of the formula:

##STR29## by a methylene group --CH₂ --, and for replacing the carbonyl group of said linking amide group by a methylene group --CH₂ --, to thereby obtain a dipeptide analogue of the formula (I);

##STR30## wherein NR¹ R² is an amino group, or an imino group or derivative thereof, bonded to the group --CH(R⁴)-- forming a cyclic group ##STR31## COR³ is a carboxy group or derivative thereof, R⁴ is the side chain residue of an α

-amino acid, or R⁴ is a divalent group bonded to the group R¹ R² N--, which comprises;

reacting an amino acid derivative selected from the group consisting of amino acid halide, amino acid imidazolylamide and amino acid anhydride, of the formula (II);

##STR32## wherein A is an amine-protecting group, and Q is selected from the group consisting of halogen atom ##STR33## group and oxocarbonyl-containing group, with diazomethane to obtain an α

-diazomethyl compound of formula (III);

##STR34## reacting said compound of formula (III) with a catalyst and an alcohol of formula R⁶ OH wherein R⁶ is a C₁ -C₆ alkyl group, to yield an ester of formula (IV);

##STR35## transforming the ester of formula (IV) to an α

-diazomethyl ketone of formula (V);

##STR36## reacting said α

-diazomethyl ketone of formula (V) with a catalyst and an alcohol to yield an ester of formula (VI);

##STR37## transforming said ester of formula (VI) to an α

-diazomethyl ketone of formula (VII);

##STR38## reacting said α

-diazomethyl ketone of formula (VII) with a catalyst and an alcohol R⁶ OH to yield an ester of formula (VIII);

##STR39## removing the amino protecting group and transforming the carboxy ester to a group COR³ if necessary;

thereby obtaining a dipeptide analogue of formula (I).

7. A process of preparing a polypeptide analogue which comprises:

preparing a dipeptide analogue of formula (I);

##STR47## by the process of claim 3, wherein R¹, R², R³ and R⁴ have the meanings given in said claim;

adding at least one α

-amino acid or a polypeptidyl residue comprising a sequence of α

-amino acids to the amino terminus or to the carboxy terminus or to both, of said dipeptide analogue.

17. A dipeptide analogue of the formula:

##STR48##

18. A polypeptidue analogue of the formula:

##STR49##

19. A polypeptidue analogue of the formula:

##STR50##