NO166328B

NO166328B - PROCEDURE FOR THE PREPARATION OF CARBOXYLAL CHOYDIPE Peptides.

Info

Publication number: NO166328B
Application number: NO893332A
Authority: NO
Inventors: William J Greenlee
Original assignee: Merck & Co Inc
Priority date: 1982-06-07
Filing date: 1989-08-18
Publication date: 1991-03-25
Also published as: NO166328C; NO893332L; NO893332D0

Description

Fremstilling og farmasøytisk bruk av nye carboxyalkyldipeptider såvel som derivater og analoger derav, er blitt beskrevet i Europa-patentsøknad 12 401. Forbindelsene beskrevet i angitte Europa-patentsøknad er anvendbare som omdannende enzyminhibitorer og som antihypertensive midler. The production and pharmaceutical use of new carboxyalkyl dipeptides, as well as derivatives and analogues thereof, has been described in European patent application 12 401. The compounds described in said European patent application are useful as converting enzyme inhibitors and as antihypertensive agents.

Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av carboxyalkyldipeptider av den type som er beskrevet i den ovenfor angitte Europa-patentsøknad. Fremgangsmåten ifølge oppfinnelsen er således rettet mot fremstilling av carboxyalkyldipeptider av formel: The present invention relates to a method for the production of carboxyalkyl dipeptides of the type described in the above-mentioned European patent application. The method according to the invention is thus aimed at producing carboxyalkyl dipeptides of the formula:

hvori R er aryl, som eventuelt er substituert med lavere alkyl, lavere alkoxy, halogen, en heterocyklisk gruppe som eventuelt er substituert med halogen, dihalogen, lavere alkyl, hydroxy, lavere alkoxy, acylamino, halogen-lavere alkyl; hvori aryl betyr fenyl, nafthyl eller bifenyl, og den heterocykliske gruppe betyr indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, kinolinyl, isokinolinyl og benzothienyl, R1 er lavere alkyl med 1 til 4 carbonatomer; -NH-X- er alanin? glycin; isoleucin; leucin; lysin; fenylalanin; valin; wherein R is aryl optionally substituted with lower alkyl, lower alkoxy, halogen, a heterocyclic group optionally substituted with halogen, dihalogen, lower alkyl, hydroxy, lower alkoxy, acylamino, halo-lower alkyl; wherein aryl means phenyl, naphthyl or biphenyl, and the heterocyclic group means indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl and benzothienyl, R 1 is lower alkyl of 1 to 4 carbon atoms; -NH-X- is alanine? glycine; isoleucine; leucine; lysine; phenylalanine; valine;

Y er alanin; glycin; isoleucin; leucin; lysin; fenylalanin; prolin; valin; og Y is alanine; glycine; isoleucine; leucine; lysine; phenylalanine; proline; valine; and

farmasøytisk akseptable salter derav; pharmaceutically acceptable salts thereof;

Foretrukne er forbindelser av formel I: Preferred are compounds of formula I:

R er aryl, som eventuelt er substituert med lavere alkyl, lavere alkoxy, halogen; R is aryl, which is optionally substituted with lower alkyl, lower alkoxy, halogen;

R^, -NH-X- og Y er som ovenfor definert. R 1 , -NH-X- and Y are defined as above.

Mere foretrukne forbindelser av formel I er slike hvori: R er fenyl; More preferred compounds of formula I are those wherein: R is phenyl;

R^ er ethyl; og R 1 is ethyl; and

-NH-X og Y er som ovenfor definert. -NH-X and Y are defined as above.

De mest foretrukne er forbindelser av formel I hvori: R er fenyl; Most preferred are compounds of formula I wherein: R is phenyl;

R^ er ethyl; R 1 is ethyl;

-NH-X er alanin; og -NH-X is alanine; and

Y er prolin. Y is proline.

De foretrukne forbindelser av formel I innbefatter også farmasøytisk akseptable salter derav. The preferred compounds of formula I also include pharmaceutically acceptable salts thereof.

Lavere alkylgruppene innbefatter rettkjedede, for-grenede og umettede hydrocarbonradikaler med 1-6 carbonatomer slik som methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. Aralkyl- og heteroaralkylgruppene har fra 1 til 6 carbonatomer i alkyl-delen og innbefatter benzyl, fenethyl, 3,3-difenylpropyl, 3-indolylmethyl. Halogen betegner klor, brom, jod eller fluor. Hvor aryl fremkommer i radikalene, betegner dette fenyl, nafthyl eller bifenyl. Heteroaryl innbefatter indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, kinolinyl, isokinolinyl og benzothienyl. Acylamino angir lavere alkanoylamino og aroylaminogrupper som acetylamino og benzyl-amino. The lower alkyl groups include straight-chain, branched and unsaturated hydrocarbon radicals with 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl. The aralkyl and heteroaralkyl groups have from 1 to 6 carbon atoms in the alkyl part and include benzyl, phenethyl, 3,3-diphenylpropyl, 3-indolylmethyl. Halogen denotes chlorine, bromine, iodine or fluorine. Where aryl appears in the radicals, this denotes phenyl, naphthyl or biphenyl. Heteroaryl includes indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl and benzothienyl. Acylamino denotes lower alkanoylamino and aroylamino groups such as acetylamino and benzylamino.

Fremgangsmåten ifølge foreliggende oppfinnelse er kjennetegnet ved at en forbindelse av formel The method according to the present invention is characterized in that a compound of formula

omsettes med et dipeptidbenzylester-hydroklorid under dannelse av en beskyttet dipeptidester; angitte ester under-kastes katalytisk hydrogenering, hvorpå den dannede dipeptidester behandles med acetonnitril og maleinsyre under dannelse av forbindelser av formel I som S,S,S-stereoisomere maleatsalter. is reacted with a dipeptide benzyl ester hydrochloride to form a protected dipeptide ester; specified ester is subjected to catalytic hydrogenation, after which the formed dipeptide ester is treated with acetonitrile and maleic acid to form compounds of formula I as S,S,S-stereoisomeric maleate salts.

Fremgangsmåten ifølge oppfinnelsen illustreres i det etterfølgende reaksjonsskjerna hvori de foretrukne reaktanter er angitt for lettere å illustrere fremgangsmåten ifølge oppfinnelsen . The method according to the invention is illustrated in the subsequent reaction core in which the preferred reactants are indicated to more easily illustrate the method according to the invention.

Som vist i reaksjonsskjemaet omsettes ethyl- fb -benzoyl-acrylat II (fremstilt ved methoden ifølge W. Koga, Nippon Kagaku Zasshi, 7_6. 1053-6 (1955 ) ) med L-alanin-L-prolin-benzylester-hydroklorid HI i nærvær av ethanol og natriumbicarbonat under dannelse av beskyttet dipeptidester IV . Denne dipeptidester IV behandles deretter med ethanol og Raney-Nickel-katalysator (R.H. Mitchell, et. al, Tetrahedron Lett., 2A, 2637 (1980)) under dannelse av dipeptidester V. Behandling av V med maleinsyre tilveiebringer I som S,S,S-stereoisomermaleatsaltet. As shown in the reaction scheme, ethyl-fb-benzoyl-acrylate II (prepared by the method according to W. Koga, Nippon Kagaku Zasshi, 7_6. 1053-6 (1955) ) is reacted with L-alanine-L-proline-benzyl ester hydrochloride HI in the presence of ethanol and sodium bicarbonate to form protected dipeptide ester IV. This dipeptide ester IV is then treated with ethanol and Raney-Nickel catalyst (R.H. Mitchell, et. al, Tetrahedron Lett., 2A, 2637 (1980)) to form dipeptide ester V. Treatment of V with maleic acid affords I as S,S, The S-stereoisomer maleate salt.

Fremgangsmåten ifølge oppfinnelsen tilveiebringer således en enkel, effektiv og økonomisk måte for å syntetisere forbindelser av formel I ettersom utgangsmaterialene og hovedreaktantene enten lett kan fremstilles eller er kommer-sielt tilgjengelige. I en foretrukken utførelsesform kan diesteren IV fremstilles for lagring og transport og kan deretter omdannes til enten monoestersaltet eller en forbindelse av formel I. The process according to the invention thus provides a simple, efficient and economical way to synthesize compounds of formula I as the starting materials and the main reactants can either be easily prepared or are commercially available. In a preferred embodiment, the diester IV can be prepared for storage and transport and can then be converted to either the monoester salt or a compound of formula I.

Oppfinnelsen illustreres nærmere i det etterfølgende eksempel. The invention is illustrated in more detail in the following example.

Eksempel Example

N-( l- carboethoxy- 3- fenylpropyl)- L- alanyl- L- prolin 3,12 g (10 mmol) L-alanyl-L-prolin-benzylester-hydroklorid kombineres med 2,04 g (10 mmol) ethyl-j2>-benzoyl-acrylat, 0,84 g (10 mmol) natriumbicarbonat og 20 ml absolutt ethanol, og blandingen omrøres deretter ved romtemperatur i 24 timer. Blandingen filtreres deretter, hvorpå 2 ml vann og W-7 Raney-nikkel-katalysator (R.H. Mitchell, et at., Tetrahedron Lett., 21, 2637 (1980)) tilsettes, og blandingen hydrogeneres ved 21,09 kg/cm 2 i 24 timer. Etter filtrering for å fjerne katalysatoren og konsentrering til tørrhet taes residuet opp i acetonitril og filtreres. Til filtratet tilsettes en acetonitrilløsning inneholdende en halvmolarekviva-lent av maleinsyre, og etter omrøring i 1 time oppsamles det faste materiale, skylles med acetonitril og tørkes under N-(l-carboethoxy-3-phenylpropyl)-L-alanyl-L-proline 3.12 g (10 mmol) L-alanyl-L-proline benzyl ester hydrochloride is combined with 2.04 g (10 mmol) ethyl- β-benzoyl acrylate, 0.84 g (10 mmol) of sodium bicarbonate and 20 ml of absolute ethanol, and the mixture is then stirred at room temperature for 24 hours. The mixture is then filtered, whereupon 2 ml of water and W-7 Raney nickel catalyst (R.H. Mitchell, et al., Tetrahedron Lett., 21, 2637 (1980)) are added, and the mixture is hydrogenated at 21.09 kg/cm 2 in 24 hours. After filtration to remove the catalyst and concentration to dryness, the residue is taken up in acetonitrile and filtered. An acetonitrile solution containing a half-molar equivalent of maleic acid is added to the filtrate, and after stirring for 1 hour the solid material is collected, rinsed with acetonitrile and dried under

dannelse av maleatsaltet. formation of the maleate salt.

Claims

Process for the production of carboxylalkyldi-

peptides of formula

where R is aryl, which is optionally substituted with lower alkyl, lower alkoxy, halogen, a heterocyclic group which is optionally substituted with halogen, dihalogen, lower alkyl, hydroxy, lower alkoxy, acylamino, halogen-lower alkyl; wherein aryl means phenyl, naphthyl or biphenyl, and the heterocyclic group means indolyl, thienyl, imidazolyl, furyl, benzimidazolyl, pyridyl, quinolinyl, isoquinolinyl and benzothienyl, R 1 is lower alkyl of 1 to 4 carbon atoms; -NH-X- is alanine; glycine; isoleucine; leucine; lysine; phenylalanine; valine;

Y is alanine; glycine; isoleucine; leucine; lysine; phenylalanine; proline; valine; and

pharmaceutically acceptable salts thereof; characterized in that a compound of formula

is reacted with a dipeptide benzyl ester hydrochloride to form a protected dipeptide ester; specified ester is subjected to catalytic hydrogenation, after which the formed dipeptide ester is treated with acetonitrile and maleic acid to form compounds of formula I as S,S,S-stereoisomeric maleate salts.