Acylated 4-amidino- and 4-guanidinobenzylamines for the inhibition of plasma kallikrein

Abstract

The invention relates to the use of acylated 4-amidino- or 4-guanidinobenzylamine in accordance with the general formula I P4-P3-P2-P1  (I) where P4 is a monosubstituted or polysubstituted or unsubstituted benzylsulfonyl group, P3 is a monosubstituted or polysubstituted or unsubstituted, natural or unnatural α-amino acid or α-imino acid in the D configuration, P2 is a monosubstituted or polysubstituted or unsubstituted, natural or unnatural α-amino acid or α-imino acid in the L configuration, and P1 is a monosubstituted or polysubstituted or unsubstituted 4-amidino- or 4-guanidinobenzylamine group, for inhibiting plasma kallikrein (PK), factor XIa and factor XIIa, in particular for preventing the activation of coagulation at synthetic surfaces and for systemic administration as anticoagulants/-antithrombotic agents, in particular for preventing the activation of coagulation at synthetic surfaces for the purpose of averting thromboembolic events.

1 . (canceled) 
     
     
         2 . An acylated 4-amidinobenzylamine or 4-guanidinobenzylamine according to formula I
   P4-P3-P2-P1  (I),
   or a salt thereof,   wherein   P4 is a monosubstituted or polysubstituted or unsubstituted benzylsulfonyl group;   P3 is a monosubstituted or polysubstituted, unnatural α-amino acid residue or α-imino acid residue in the D configuration, or a monosubstituted, polysubstituted, or unsubstituted, natural α-amino acid residue or α-imino acid residue in the D configuration, wherein,
 when P3 has a structure according to the following formula: 
   
       
         
           
           
               
               
           
         
         
           R 2  is not an unsubstituted branched alkyl radical having 1-6 C atoms; 
         
         P2 is (a) a monosubstituted or polysubstituted natural or unnatural α-amino acid residue or α-imino acid residue in the L configuration, wherein the substituent at substituted P2 is a substituted or unsubstituted, branched or linear aralkyl radical having 1-10 C atoms, or P2 is (b) Asp, hGlu, Dap, Dap(Z), Lys, Lys(Z), Arg, Thr, Thr(Bzl), Ser(Bzl), hSer(Bzl), Phe or hPhe; and 
         P1 is a monosubstituted or polysubstituted or unsubstituted 4-amidinobenzylamine or 4-guanidinobenzylamine group;
 wherein a linker group is optionally and additionally coupled to P4 or P2; 
 wherein 
 (a) the linker group, when present, together with the substituent on P4 or P2, is of formula II
   U—Z—Y—X—  (II),
 
 
 wherein
 U is H 2 N—, HOOC—(CH 2 ) n —CO—NH—, HOOC—, H 2 N—(CH 2 ) n —NH—CO— or HS—, and Z is —(CH 2 ) n —, —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, wherein
 n=1 to 10, 
 d=1, 2, 3 or 4, 
 v is an integer from 1 to 1000, 
 m=0, 1, 2, 3 or 4, and k=0 or 1; 
 
 U is CH 3 —O—, and Z is —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k — or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v —O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, wherein
 d=1, 2, 3 or 4; 
 v is an integer from 1 to 1000; 
 m=0, 1, 2, 3 or 4; and 
 k=0 or 1; or 
 
 U and Z are absent; 
 Y is —CO—NH—, —NH—CO—, —SO 2 —NH—, —NH—SO 2 —, —S—S—, or —S—, or, if U and Z are absent, Y is H 2 N—, HOOC—, HS—, HO—, or halogenated alkyl; and 
 X is absent, —(CH 2 ) n —, wherein n=0, 1, 2, 3, or 4, or —(CH 2 ) n —O—, wherein n=1, 2, 3 or 4, and wherein, when X is —(CH 2 ) n —O— linked to P4, X is bonded to the benzyl radical by way of the oxygen atom; or 
 
 (b) the linker group, when present, together with P2, is of formula III: 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 q is 0, 1, 2, 3, 4 or 5, and 
 D is U—Z—Y—, 
 wherein
 U is H 2 N—, HOOC—(CH 2 ) n —CO—NH—, HOOC—, H 2 N—(CH 2 ) n —NH—CO— or HS—, and Z is —(CH 2 ) n —, —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v —O—(CH 2 ) m —(NH—CO—CH 2 —CH 2 ) k —, wherein 
  n=1 to 10, 
  d=1, 2, 3 or 4, 
  v is an integer from 1 to 1000, 
  m=0, 1, 2, 3 or 4, and k=0 or 1; 
 U is CH 3 —O—, and Z is —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH) k — or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v —O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, wherein 
  d=1, 2, 3 or 4; 
  v is an integer from 1 to 1000; 
  m=0, 1, 2, 3 or 4; and 
  k=0 or 1; or 
 U and Z are absent; 
 Y is —CO—NH—, —NH—CO—, —SO 2 —NH—, —NH—SO 2 —, —S—S—, or —S—, or, if U and Z are absent, Y is H 2 N—, HOOC—, HS—, HO—, or halogenated alkyl; 
 
 
           wherein optionally two linker groups of two compounds of formula I join together to form a single connector, each of the two linker groups independently having the structure of formula II or formula III; 
           wherein each substituent at the substituted P4, P3, and P1 is: 
         
         (a) a halogen, 
         (b) a substituted or unsubstituted, branched or linear alkyl radical having 1-6 C atoms, or a substituted or unsubstituted, branched or linear aralkyl radical having 1-10 C atoms, or 
         (c) hydroxyl, amino, cyano, amidino, guanidino, methyloxycarbonyl, benzyl, benzyloxycarbonyl, aminomethyl, glutarylamidomethyl, succinylamidomethyl, oxyalkylcarbonyl, carboxyl, carboxymethyl, carboxyethyl group, where appropriate esterified with a lower alkyl radical or oxyalkylcarbonyl, carboxyl, carboxymethyl, or carboxyethyl which is present as unsubstituted amide or amide which is substituted by an alkyl or aryl group; 
         wherein
 the sulfur atom of the benzylsulfonyl group of P4 is linked to the α-amino or α-imino group of P3, 
 the carbon atom of the carbonyl group of P3 is bonded to the α-amino or α-imino group of P2 or, when α-amino or α-imino group is absent in P2, to the β-amino or β-imino group of P2, and 
 the nitrogen atom of benzylamine of P1 is linked to the C-terminal carbonyl group of P2. 
 
       
     
     
         3 . The compound as claimed in  claim 2 , wherein the linker group is additionally coupled to P4 or P2, with the linker group being coupled to P4 by way of said substituent or coupled directly to a functional group of P2. 
     
     
         4 . The compound as claimed in  claim 2 , wherein the compound comprises the linker group coupled to P4. 
     
     
         5 . The compound as claimed in  claim 3 , wherein, if the linker group is coupled to P4, P2 is glycine, alanine, or serine. 
     
     
         6 . The compound as claimed in  claim 3 , wherein the linker group is coupled to P2, and P2 is of formula III. 
     
     
         7 . The compound as claimed in  claim 2 , wherein said acylated 4-amidinobenzylamine or 4-guanidinobenzylamine is according to formula V, 
       
         
           
           
               
               
           
         
         wherein q=0 or 1; 
         R 1  is: 
         (a) hydrogen, 
         (b) a halogen, 
         (c) a substituted or unsubstituted, branched or linear alkyl radical having 1-6 C atoms, 
         (d) a hydroxyl, amino, cyano, amidino, guanidino, methyloxycarbonyl, benzyl, benzyloxycarbonyl, aminomethyl, glutarylamidomethyl, succinylamidomethyl, and an oxyalkylcarbonyl, carboxyl, carboxymethyl or carboxyethyl group, where appropriate esterified with a lower alkyl radical, oxyalkylcarbonyl, carboxyl, carboxymethyl or carboxyethyl which is present as unsubstituted amide or amide which is substituted by an alkyl or aryl group, or 
         (e) a group of formula (II):
   U—Z—Y—X—  (II),
 
 wherein
 U is H 2 N—, HOOC—(CH 2 ) n —CO—NH—, HOOC—, H 2 N—(CH 2 ) n —NH—CO— or HS—, and Z is —(CH 2 ) n —, —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v —O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, wherein
 n=1 to 10, 
 d=1, 2, 3 or 4, 
 v is an integer from 1 to 1000, 
 m=0, 1, 2, 3 or 4, and k=0 or 1; 
 
 U is CH 3 —O—, and Z is —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —OCH 2 ) k — or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v —O—(CH 2 ) m —(NH—CO—CHO—CH 2 ) k —, wherein
 d=1, 2, 3 or 4; 
 v is an integer from 1 to 1000; 
 m=0, 1, 2, 3 or 4; and 
 k=0 or 1; or 
 
 U and Z are absent; 
 Y is —CO—NH—, —NH—CO—, —SO 2 —NH—, —NH—SO 2 —, —S—S—, or —S—, or,
 if U and Z are absent, Y is H 2 N—, HOOC—, HS—, HO—, or halogenated alkyl; 
 
 X is absent, —(CH 2 ) n —, wherein n=0, 1, 2, 3, or 4, or —(CH 2 ) n —O—, wherein n=1, 2, 3 or 4, and wherein, when X is —(CH 2 ) n —O— linked to P4, X is bonded to the benzyl radical by way of the oxygen atom; 
 
 
         R 2  is: 
         (a) hydrogen, 
         (b) a substituted branched, substituted linear, or unsubstituted linear alkyl radical having 1-6 C atoms, or 
         (c) a hydroxyl, amino, cyano, amidino, guanidino, methyloxycarbonyl, benzyl, benzyloxycarbonyl, aminomethyl, glutarylamidomethyl, succinylamidomethyl, and an oxyalkylcarbonyl, carboxyl, carboxymethyl or carboxyethyl group, where appropriate esterified with a lower alkyl radical, oxyalkylcarbonyl, carboxyl, carboxymethyl or carboxyethyl which is present as unsubstituted amide or amide which is substituted by an alkyl or aryl group; 
         R 3  together with P2 is 
         (a) a monosubstituted or polysubstituted natural or unnatural α-amino acid residue or α-imino acid residue in the L configuration, wherein the substituent at substituted P2 is a substituted or unsubstituted, branched or linear aralkyl radical having 1-10 C atoms, 
         (b) P2 is Asp, hGlu, Dap, Dap(Z), Lys, Lys(Z), Arg, Thr, Thr(Bzl), Ser(Bzl), hSer(Bzl), Phe, or hPhe, or 
         (c) a group of formula (III): 
       
       
         
           
           
               
               
           
         
         
           wherein
 q is 0, 1, 2, 3, 4 or 5, and 
 D is U—Z—Y—, 
 wherein
 U is H 2 N—, HOOC—(CH 2 ) n —CO—NH—, HOOC—, H 2 N—(CH 2 ) n —NH—CO— or HS—, and Z is —(CH 2 ) n —, —(CH 2 ) d —[O—CH 2 —CH 2 ]O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —CH 2 ) k —, wherein 
  n=1 to 10, 
  d=1, 2, 3 or 4, 
  v is an integer from 1 to 1000, 
  m=0, 1, 2, 3 or 4, and k=0 or 1; 
 U is CH 3 —O—, and Z is —(CH 2 ) d —[O—CH 2 —CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k — or —(CH 2 ) d —[O—CH(CH 3 )—CH 2 ] v O—(CH 2 ) m —(NH—CO—CH 2 —O—CH 2 ) k —, wherein 
  d=1, 2, 3 or 4; 
  v is an integer from 1 to 1000; 
  m=0, 1, 2, 3 or 4; and 
  k=0 or 1; or 
 U and Z are absent; 
 Y is —CO—NH—, —NH—CO—, —SO 2 —NH—, —NH—SO 2 —, —S—S—, or —S—, or, 
 if U and Z are absent, Y is H 2 N—, HOOC—, HS—, HO—, or halogenated alkyl; 
 
 
         
         and 
         R 4  is: 
         (a) hydrogen, 
         (b) a substituted or unsubstituted, branched or linear alkyl radical having 1-6 C atoms, or 
         (c) a hydroxyl, amino, cyano, amidino, guanidino, methyloxycarbonyl, benzyl, benzyloxycarbonyl, aminomethyl, glutarylamidomethyl, succinylamidomethyl, and an oxyalkylcarbonyl, carboxyl, carboxymethyl or carboxyethyl group, where appropriate esterified with a lower alkyl radical, oxyalkylcarbonyl, carboxyl, carboxymethyl, or carboxyethyl which is present as unsubstituted amide or amide which is substituted by an alkyl or aryl group; 
         or 
         each of R 1  and R 3  is independently and optionally a linker group, with the linker group being coupled to P4 by way of a substituent as defined for R 1  or coupled directly to a functional group of P2. 
       
     
     
         8 . The compound as claimed in  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein n=1 to 8, and q=0 or 1. 
       
     
     
         9 . The compound as claimed in  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein n=1 to 1000, r=0 to 3 and q=0 or 1. 
       
     
     
         10 . The compound as claimed in  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
         wherein
 p=0, 1, 2 or 3, 
 q=0 or 1, 
 n=1 to 1000, 
 m=1 to 3. 
 
       
     
     
         11 . The compound as claimed in  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein n=0 to 5; 
       
         
           
           
               
               
           
         
       
       wherein n=0 to 9; 
       
         
           
           
               
               
           
         
       
       wherein n=1 to 6; 
       
         
           
           
               
               
           
         
       
       wherein n=0 to 3; 
       
         
           
           
               
               
           
         
       
       wherein n=0 to 3 and m=0 to 1000; 
       
         
           
           
               
               
           
         
       
       wherein n=1 to 1000; or 
       
         
           
           
               
               
           
         
       
       wherein n=1 to 3 and m=1 to 1000; wherein q, in each case, is 0 or 1. 
     
     
         12 . The compound as claimed in  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       wherein n=0 to 4 and m=10 to 1000; 
       
         
           
           
               
               
           
         
       
       wherein n=1 to 4, p=2 to 4 and m=1 to 1000; 
       
         
           
           
               
               
           
         
       
       wherein n=1 to 3 and m=10 to 1000; 
       
         
           
           
               
               
           
         
       
       wherein m=10 to 1000; or 
       
         
           
           
               
               
           
         
       
       wherein m=10 to 1000; and
 wherein q is 0 or 1. 
 
     
     
         13 . The compound as claimed in  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
         wherein D-Ser(tBu) in position 3 is optionally replaced with D-Cha or D-Phe, and succinyl at P2 is optionally replaced with glutaryl; 
       
       
         
           
           
               
               
           
         
         wherein D-Cha in position P3 is optionally replaced with D-Phe or D-Ser(tBu); 
         or 
       
       
         
           
           
               
               
           
         
         wherein D-Cha in position P3 is optionally replaced with D-Phe or D-Ser(tBu). 
       
     
     
         14 . The compound as claimed in  claim 2 , wherein, in formula I,
 P4 carries a radical R at the aromatic radical,   P3 is D-Ser, D-Ser(tBu), D-Phe, or D-Cha, and   P2 is a natural or unnatural amino acid Aaa,   wherein
 R is H—; 4-, 3-, or 2-COOH; 4-, 3-, or 2-COOMe; 4-, 3-, or 2-AMe; 4-, 3-, or 2-glutaryl-AMe; or 4-, 3-, or 2-CN; and 
 Aaa is Asp, hGlu, Dap, Dap(Z), Lys, Lys(Z), Arg, Thr(Bzl), Ser(Bzl), hSer(Bzl), Phe, or hPhe. 
   
     
     
         15 . The compound as claimed in  claim 14 , wherein,
 when P3 is D-Ser,
 Aaa is Dap, Dap(Z), Lys, Lys(Z), Ser(Bzl), Phe, or hPhe, and R is H; 
   when P3 is D-Ser(tBu),
 Aaa is Gin, Dap, Dap(Z), Lys, Lys(Z), Arg, Thr(Bzl), Ser(Bzl), hSer(Bzl), Phe, or hPhe, and R is H; 
   when P3 is D-Cha,
 Aaa is Lys or Glu, and R is H; 
   or   when Aaa is —NH—CH—[CH 2 —CH 2 —CO—NH—(CH 2 ) 3 —[O—(CH 2 ) 2 ] 3 —CH 2 —NH 2 ]—CO—,
 R is H. 
   
     
     
         16 . The compound as claimed in  claim 2 , wherein the substituent at substituted P2 is a substituted or unsubstituted, branched or linear aralkyl radical having 1-10 C atoms. 
     
     
         17 . A compound of formula I:
   P4-P3-P2-P1  (I),
   wherein   P1 is unsubstituted 4-amidinobenzylamine; and   (1) P4 is unsubstituted benzylsulfonyl,
 P3 is D-Ser or D-Ser(iBu), and 
 P2 is Asp, GIn, hGlu, Dap, Dap(Z), Lys, Lys(Z), Arg, Thr, Thr(Bzl), Ser(Bzl), Phe, or hPhe; 
   (2) P4 is benzylsulfonyl substituted with 4-COOH or 4-COOMe,
 P3 is D-Ser, and 
 P2 is Ser; 
   (3) P4 is benzylsulfonyl substituted with 4-CN,
 P3 is D-Ser, and 
 P2 is Pro; 
   (4) P4 is unsubstituted benzylsulfonyl,
 P3 is D-Cha, and 
 P2 is Glu, Lys, or Lys(Z); or 
   (5) P4 is benzylsulfonyl substituted with 3-CN, 3-aminomethyl, or 3-(Glut-NHCH 2 ),
 P3 is D-Cha, and 
 P2 is Pro; 
   wherein the sulfur atom of the benzylsulfonyl group of P4 is linked to the α-amino group of P3,
 the carbon atom of the carbonyl group of P3 is bonded to the α-amino group of P2 or, when P2 is hSer, to the n-amino group of P2, and 
 the nitrogen atom of benzylamine of P1 is linked to the C-terminal carbonyl group of P2. 
   
     
     
         18 . The compound as claimed in  claim 17 , wherein P4 is unsubstituted benzylsulfonyl. 
     
     
         19 . The compound as claimed in  claim 18 , wherein P3 is D-Ser. 
     
     
         20 . The compound as claimed in  claim 19 , wherein P2 is hPhe. 
     
     
         21 . A compound: 
       
         
           
           
               
               
           
         
         or a salt thereof.