LOW-MOLECULAR SERINE PROTEASES INHIBITORS COMPRISING POLYHYDROXY-ALKYL AND POLYHYDROXY-CYCLOALKYL RADICALS
The invention relates to novel amidines and quanidines, the production and use thereof and the use thereof as trypsine-type serine protease competitive inhibitors, especially thrombine and compliment proteases CIs and C1r. The invention also relates to pharmaceutical compositions which contain said compounds as active ingredients, in addition to the use of the compounds as thrombine inhibitors, anticoagulants, compliment inhibitors and anti-inflammatory agents. The novel compositions are characterised by the linkage of a serine protease inhibitor having amidine or guanidine functions with an alkyl radical having two or more hydroxyl functions, whereby said alkyl radical is derived from sugar derivates. Several sugar structural components or components derived from sugar can therefore be linked to each other. Said principle of linking sugar derivates enables oral active compounds to be obtained.
1 . A compound of the general formula (I)
A-B-D-E-G-K-L (I),
in which
A stands for H, CH 3 , H-(R A1 )i A
in which
R A1 denotes
in which
R A2 denotes H, NH 2 , NH—COCH 3 , F, or NHCHO,
R A3 denotes H, or CH 2 OH,
R A4 denotes H, CH 3 , or COOH,
i A is 1 to 20,
j A is 0, 1, or 2,
k A is 2 or 3,
l A is 0 or 1,
m A is 0, 1, or 2,
n A is 0, 1, or 2,
the groups R A1 being the same or different when i A is greater than 1,
B denotes
A-B stands for
or for a neuraminic acid radical or N-acetylneuraminic acid radical bonded through the carboxyl function,
in which
R B1 denotes H, CH 2 OH, or C 1-4 alkyl,
R B2 denotes H, NH 2 , NH—COCH 3 , F, or NHCHO,
R B3 denotes H, C 1-4 alkyl, CH 2 —O—(C 1-4 alkyl), COOH, F, NH—COCH 3 , or CONH 2 ,
R B4 denotes H, C 1-4 alkyl, CH 2 —O—(C 1-4 alkyl), COOH, or CHO, in which latter case intramolecular acetal formation may take place,
R B5 denotes H, C 1-4 alkyl, CH 2 —O—(C 1-4 alkyl), or COOH,
k B is 0 or 1,
l B is 0, 1, 2, or 3 ( l B≠0 when A=R B1 =R B3 =H, m B= k B=0 and D is a bond),
m B is 0, 1, 2, 3, or 4,
n B is 0, 1, 2, or 3,
R B6 denotes C 1-4 alkyl, phenyl, or benzyl, and
R B7 denotes H, C 14 alkyl, phenyl, or benzyl,
D stands for a bond or for
in which
R D1 denotes H or C 1-4 alkyl,
R D2 denotes a bond or C 1-4 alkyl,
R D3 denotes
in which
l D is 1, 2, 3, 4, 5, or 6,
R D5 denotes H, C 1-4 alkyl, or Cl, and
R D6 denotes H or CH 3 ,
and in which a further aromatic or aliphatic ring can be condensed onto the ring systems defined for R D3 ,
R D4 denotes a bond, C 1-4 alkyl, CO, SO 2 , or —CH 2 —CO,
E stands for
in which
k E is 0, 1, or 2,
l E is 0, 1, or 2,
m E is 0, 1, 2, or 3,
n E is 0, 1, or 2,
p E is 0, 1, or 2,
R E1 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, C 3-8 cycloalkyl having a phenyl ring condensed thereto, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6 alkyl, OH, O—C 1-6 alkyl, F, Cl, and Br,
R E1 may also denote R E4 OCO—CH 2 — (where R E4 denotes H, C 1-12 alkyl, or C 1-3 alkylaryl),
R E2 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, indolyl, tetrahydropyranyl, tetrahydrothiopyranyl, diphenylmethyl, dicyclohexylmethyl, C 3-8 cycloalkyl having a phenyl ring condensed thereto, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6 alkyl, OH, O—(C 1-6 alkyl), F, Cl, and Br, and may also denote CH(CH 3 )OH or CH(CF 3 ) 2 ,
R E3 denotes H, C 1-6 alkyl, C 3-4 cycloalkyl, aryl, heteroaryl, C 3-8 cycloalkyl having a phenyl ring condensed thereto, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6 alkyl, OH, O—(Cl 1-6 alkyl), F, Cl, and Br,
the groups defined for R E1 and R E2 may be interconnected through a bond, the
groups defined for R E2 and R E3 may also be interconnected through a bond,
R E2 may also denote COR E5 (where R E5 denotes OH, O—(C 1-6 alkyl), or O—(C 1-3 alkylaryl)), CONR E6 R E7 (where R E6 and R E7 denote H, C 1-6 alkyl, or C 0-3 alkylaryl), or NR E6 R E7 ,
E may also stand for D-Asp, D-Glu, D-Lys, D-Orn, D-His, D-Dab, D-Dap, or D-Arg,
G stands for
where l G is 2, 3, 4, or 5, and one of the CH 2 groups in the ring is replaceable by O, S, NH, N(C 1-3 alkyl), CHOH, CHO(C 1-3 alkyl), C(C 1-3 alkyl) 2 , CH(C 1-3 alkyl), CHF, CHCl, or CF 2 ,
in which
m G is 0, 1, or 2,
n G is 0, 1, or 2,
p G is 0, 1, 2, 3, or 4,
R G1 denotes H, C 1-6 alkyl, or aryl,
R G2 denotes H, C 1-6 alkyl, or aryl,
and R G1 and R G2 may together form a —CH═CH—CH═CH— chain,
G may also stand for
in which
q G is 0, 1, or 2,
r G is 0, 1, or 2,
R G3 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, or aryl,
R G4 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, or aryl (particularly phenyl or naphthyl),
K stands for
NH—(CH 2 ) n K-Q K
in which
n K is 0, 1, 2, or 3,
Q K denotes C 2-6 alkyl, whilst up to two CH 2 groups may be replaced by O or S,
Q K also denotes
in which
R K1 denotes H, C 1-3 alkyl, OH, O—C( 1-3 alkyl), F, Cl, or Br,
R K2 denotes H, C 1-3 alkyl, O—(C 1-3 alkyl), F, Cl, or Br,
X K denotes O, S, NH, N—(C 1-6 alkyl),
Y K denotes ═CH—,
═N—, or
Z K denotes ═CH—,
═N—, or
U K denotes ═CH—,
═N—, or
V K denotes ═CH—,
═N—, or
W K denotes
but in the latter case L may not be a guanidine group,
n K is 0, 1, or 2,
p K is 0, 1, or 2,
q K is 1 or 2,
L stands for
in which
R L1 denotes H, OH, O—(C 1-6 alkyl), O—(CH 2 ) 0-3 -phenyl, CO—(C 1-6 alkyl), CO 2 —(C 1-6 alkyl), or CO 2 —(C 1-3 alkylaryl),
and the tautomers thereof, stereoisomers thereof, salts thereof with pharmacologically acceptable acids or bases, and the prodrugs thereof.
2 . A compound of the general formula (I)
A-B-D-E-G-K-L (I),
in which
A stands for H or H—(R A1 )i A
in which
R A1 denotes
in which
R A4 denotes H, CH 3 , or COOH,
i A is 1 to 6,
j A is 0, 1, or 2,
k A is 2 or 3,
m A is 0, 1, or 2,
n A is 0, 1, or 2,
the groups R A1 being the same or different when i A is greater than 1;
B denotes
A-B stands for
in which
R B1 denotes H or CH 2 OH,
R B2 denotes H, NH 2 , NH—COCH 3 , or F,
R B3 denotes H, CH 3 , CH 2 —O—(C 1-4 alkyl), or COOH,
R B4 denotes H, C 1-4 alkyl, CH 2 —O—(C 1-4 alkyl), COOH, or CHO, in which latter case intramolecular acetal formation may take place,
R B5 denotes H, CH 3 , CH 2 —O—(C 1-4 alkyl), or COOH,
k B is 0 or 1,
l B is 0, 1, 2, or 3 ( l B≠0 when A=R B1 =R B3 =H, m B= k B=0, and D is a bond),
m B is 0, 1, 2, or 3,
n B is 0, 1, 2, or 3,
R B6 denotes C 1-4 alkyl, phenyl, or benzyl, and
R B7 denotes H, C 1-4 alkyl, phenyl, or benzyl,
D stands for a bond or for
in which
R D1 denotes H or C 1-4 alkyl,
R D2 denotes a bond or C 1-4 alkyl,
R D3 denotes
R D4 denotes a bond, C 1-4 alkyl, CO, SO 2 , or —CH 2 —CO,
E stands for
in which
k E is 0, 1, or 2,
m E is 0, 1, 2, or 3,
R E1 denotes H, C 1-6 alkyl, or C 3-8 cycloalkyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6 alkyl, OH, and O—C 1-6 alkyl,
R E2 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, tetrahydropyranyl, diphenylmethyl, or dicyclohexylmethyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-6 alkyl, OH, O—(C 1-6 alkyl), F, Cl, and Br, and may also denote CH(CF 3 ) 2 ;
R E3 denotes H, C 1-6 alkyl, or C 3-8 cycloalkyl,
R E2 may also denote COR E5 (where R E5 denotes OH, O—C 1-6 alkyl, or O—(C 1-3 alkylaryl)), CONR E6 R E7 (where R E6 and R E7 denote H, C 1-6 alkyl, or C 0-3 alkylaryl respectively), or NR E6 R E7 ;
E may also stand for D-Asp, D-Glu, D-Lys, D-Orn, D-His, D-Dab, D-Dap, or D-Arg;
G stands for
where l G is 2, 3, or 4, and one of the CH 2 groups in the ring is replaceable by O, S, NH, N(C 1-3 alkyl), CHOH, or CHO(C 1-3 alkyl);
in which
m G is 0, 1, or 2;
n G is 0, or 1;
K stands for
NH—(CH 2 ) n K-Q K
in which
K is 1 or 2,
Q K denotes
in which
R K1 denotes H, C 1-3 alkyl, OH, O—(C 1-3 alkyl), F, Cl, or Br,
R K2 denotes H, C 1-3 alkyl, O—(C 1-3 alkyl), F, Cl, or Br,
X K denotes O, S, NH, N—(C 1 alkyl),
Y K denotes ═CH—,
═N—, or
Z K denotes ═CH—,
═N—, or
U K denotes ═CH—,
═N—, or
and
L stands for
in which
R L1 denotes H, OH, O—(C 1-6 alkyl), or CO 2 —(C 1-6 alkyl),
and the tautomers thereof, stereoisomers thereof, salts thereof with pharmacologically acceptable acids or bases, and the prodrugs thereof.
3 . A compound of the general formula (I)
A-B-D-E-G-K-L (I),
in which
A stands for H or H—(R A1 )i A
in which
R A1 denotes
in which
R A4 denotes H, or COOH,
i A is 1 to 6,
j A is 0 or 1,
k A is 2 or 3,
n A is 1 or 2,
the groups R A1 being the same or different when i A is greater than 1;
B denotes
R B3 denotes H, CH 3 , or COOH,
R B4 denotes H, CH 3 , COOH, or CHO, in which latter case intramolecular acetal formation may take place,
k B is 0 or 1,
l B is 1, 2, or 3,
m B is 0, 1, 2, or 3,
n B is 1, 2, or 3,
D stands for a bond
E stands for
in which
m E is 0 or 1,
R E2 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, phenyl, diphenylmethyl, or dicyclohexylmethyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-4 alkyl, OH, O—CH 3 , F, and Cl;
G stands for
where l G is 2, 3, or 4 and one of the CH 2 groups in the ring is replaceable by O, S, NH, or N(C 1-3 alkyl),
in which
n G is 0 or 1;
K stands for
NH—CH 2 -Q K
in which
Q K denotes
in which
R K1 denotes H, CH 3 , OH, O—CH 3 , F, or Cl,
X K denotes O, S, NH, N—CH 3 ,
Y K denotes ═CH—,
or ═N—,
Z K denotes ═CH—,
or ═N—; and
L stands for
in which
R L1 denotes H, OH, or CO 2 —(C 1-6 alkyl),
and the tautomers thereof, stereoisomers thereof, salts thereof with pharmacologically acceptable acids or bases, and the prodrugs thereof.
4 . A compound of the general formula (I)
A-B-D-E-G-K-L (I),
in which
A stands for H or H—(R A1 )i A
in which
R A1 denotes
in which
R A4 denotes H, or COOH,
i A is 1 to 6,
j A is 0 or 1,
k A is 2 or 3,
n A is 1 or 2,
the groups R A1 being the same or different when i A is greater than 1;
B denotes
A-B stands for
in which
R B3 denotes H, CH 3 , or COOH,
R B4 denotes H, CH 3 , COOH, or CHO, in which latter case intramolecular acetal formation may take place,
k B is 0 or 1,
l B is 1, 2, or 3,
m B is 0, 1, 2, or 3,
n B is 1, 2, or 3,
R B6 denotes C IA alkyl, phenyl, or benzyl, and
R B7 denotes H, C 1-4 alkyl, phenyl, or benzyl,
D stands for
in which
R D1 denotes H or C 1-4 alkyl,
R D2 denotes a bond or C 1-4 alkyl,
R D3 denotes
in which
R D4 denotes a bond, C 1-4 alkyl, CO, SO 2 , or —CH 2 —CO, and
R D6 denotes H or CH 3 ,
E stands for
in which
m E is 0 or 1,
R E2 denotes H, C 1-5 alkyl, or C 3-8 cycloalkyl, which groups may carry up to three identical or different substituents selected from the group consisting of C 1-4 alkyl, OH, O—CH 3 , F, and Cl;
G stands for
where l G is 2, 3, or 4 and one of the CH 2 groups in the ring is replaceable by O, S, NH, or N(C 1-3 alkyl),
in which
n G is 0 or 1;
K stands for
NH—CH 2 -Q K
in which
Q K denotes
in which
R K1 denotes H, CH 3 , OH, O—CH 3 , F, or Cl,
X K denotes O, S, NH, N—CH 3 ,
Y K denotes ═CH—,
or ═N—,
Z K denotes ═CH—,
or ═N—,
L stands for
in which
R L1 denotes H, OH, or CO 2 —(C 1-6 alkyl),
and the tautomers thereof, stereoisomers thereof, salts thereof with pharmacologically acceptable acids or bases, and the prodrugs thereof.
5 . A compound of the general formula (I)
A-B-D-E-G-K-L (I),
in which
A stands for H or H—(R A1 )i A
in which
R A1 denotes
in which
i A is 1 to 6,
j A is 0 or 1,
n A is 1 or 2,
the groups R A1 being the same or different when i A is greater than 1;
B denotes
in which
l B is 1, 2, or 3,
m B is 1 or 2,
D stands for a bond,
E stands for
in which
m E is 0 or 1,
R E2 denotes H, C 1-6 alkyl, C 3-8 cycloalkyl, phenyl, diphenylmethyl, or dicyclohexylmethyl,
the building block E preferably exhibiting D configuration,
G stands for
building block G preferably exhibiting L configuration,
K stands for
NH—CH 2 -Q K
in which
Q K denotes
L stands for
in which
R L1 denotes H, OH, or CO 2 —(C 1-6 alkyl),
and the tautomers thereof, stereoisomers thereof, salts thereof with pharmacologically acceptable acids or bases, and the prodrugs thereof.
6 . A compound of the general formula (I)
A-B-D-E-G-K-L (I),
in which
A stands for H or H-(R A1 )i A
in which
R A1 denotes
in which
R A4 denotes H, or COOH,
i A is 1 to 6,
j A is 0 or 1,
k A is 2 or 3,
n A is 1 or 2,
the groups R A1 being the same or different when i A is greater than 1;
B denotes
A-B stands for
in which
R B3 denotes H, CH 3 , or COOH,
R B4 denotes H, CH 3 , COOH, or CHO, in which latter case intramolecular acetal formation may take place,
k B is 0 or 1,
l B is 1, 2, or 3,
m B is 0, 1, 2, or 3,
n B is 1, 2, or 3,
R B6 denotes C 1-4 alkyl, phenyl, or benzyl, and
R B7 denotes H, C 1-4 alkyl, phenyl, or benzyl,
D stands for
in which
R D1 denotes H,
R D2 denotes a bond or C 1-4 alkyl,
R D3 denotes
R D4 denotes a bond, C 1-4 alkyl, CO, SO 2 , or —CH 2 —CO, and
E stands for
in which
m E is 0 or 1,
R E2 denotes H, C 1-6 alkyl, or C 3-8 cycloalkyl, which groups may carry up to three identical or different substituents selected from the group consisting of F and Cl;
G stands for
where l G is 2
in which
n G is 0,
K stands for
NH—CH 2 -Q K
in which
Q K denotes
in which
X K denotes S,
Y K denotes ═CH—, or ═N—,
Z K denotes ═CH—, or ═N—,
L stands for
in which
R L1 denotes H, or OH,
and the tautomers thereof, stereoisomers thereof, salts thereof with pharmacologically acceptable acids or bases, and the prodrugs thereof.
7 . A medicinal drug comprising at least one compound of claim 1 .
8 . A method of using one or more compounds of claim 1 for the preparation of medical drugs for the treatment or prophylaxis of diseases which can be alleviated by inhibition of one or more serine proteases.
9 . A method as defined in claim 8 , wherein the serine protease for a compound is thrombin.
10 . A method as defined in claim 8 , wherein the serine protease for a compound is C1s or C1r.