Integrin receptors antagonists
View Patent ↗The invention relates to novel compounds which bind to integrin receptors, and to the preparation thereof and the use thereof as drugs.
1. A compound of the formula I
B—G—L I
where B, G and L have the following meanings:
L is a structural element of the formula I L
—U—T I L
where
T is COOH, COO—C 1-8 -alkyl or COO-benzyl, and
—U— is —(X L ) a —(CR L 1 R L 2 ) b — or ═CR L 1 —,
where
a is 0 or 1,
b is 0, 1 or 2,
X L is CR L 3 R L 4 or oxygen
R L 1 , R L 2 , R L 3 and R L 4
are, independently of one another, hydrogen, a halogen radical, a branched or unbranched, optionally substituted C 1 –C 4 -alkyl, C 1 –C 4 -alkoxy radical, or in each case independently of one another, two radicals R L 1 and R L 2 or R L 3 and R L 4 or, where appropriate, R L 1 and R L 3 together are an optionally substituted 3- to 7-membered cycloalkyl radical
G is
where
the structural element G can be incorporated in both orientations, and where structural element G is connected to structural element L or B via X G wherein X G , is carbon and where the rings fused on the 7-membered ring of the structural element G are optionally substituted,
B is a structural element of the formula I B
A—E— I B
where A and E have the following meanings:
A is a structural element selected from the group of structural elements of the formulae I A 1 , I A 4 , I A 7 , I A 8 , I A 14 :
and
where
m is 1, 2 or 3
R A 1 and R A 2
are, independently of one another, hydrogen, CN, halogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl or CO—C 1 –C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C 3 –C 7 -cycloalkyl radical or a radical CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 , CO—NR A 15 R A 16 or SO 2 NR A 15 R A 16 or the two R A 1 and R A 2 radicals together are a fused-on, optionally substituted 5- or 6-membered, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three heteroatoms selected from the group of O, N and S,
R A 13 and R A 13 *
are, independently of one another, hydrogen, CN, halogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 –C 7 -cycloalkyl radical or a CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 or CO—NRA 15 R A 16 radical,
where
R A 14 is hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, alkylene-C 1 –C 4 -alkoxy, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
R A 15 and R A 16 ,
are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, CO—C 1 –C 6 -alkyl, SO 2 —C 1 –C 6 -alkyl, COO—C 1 –C 6 -alkyl, arylalkyl, COO-alkylene-aryl, SO 2 -alkylene-aryl or hetarylalkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, aryl, CO-aryl, SO 2 -aryl, hetaryl or CO-hetaryl radical,
R A 3 and R A 4
are, independently of one another, hydrogen, —(CH 2 ) n —(X A ) j —R A 12 , or the two radicals together are a 3-to 8-membered, saturated, unsaturated or aromatic N heterocyclic system which may additionally contain two other identical or different heteroatoms O, N or S, it being possible for the ring optionally to be substituted or for another, optionally substituted, saturated, unsaturated or aromatic ring to be fused onto this ring,
where
n is 0, 1, 2 or 3,
j is 0 or 1,
X A is —SO 2 —, —S—, —O—, —CO—, —O—CO—, —CO—O—, —CO—N(R A 12 )—, —N(R A 12 )—CO—, —N(R A 12 )—SO 2 — or —SO 2 —N(R A 12 )— and
R A 12 is hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, —O-alkylene-aryl or —O-aryl radical, an amino radical with primary or, where appropriate, secondary or tertiary Substitution, an optionally C 1 –C 4 -alkyl- or aryl-substituted C 2 –C 6 -alkynyl or C 2 –C 6 -alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, C 3 –C 7 -cycloalkyl, aryl or hetaryl radical, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted, or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring,
R A 6 and R A 6 *
are hydrogen, a branched or unbranched, optionally substituted C 1 –C 4 -alkyl, —CO—O—C 1 –C 4 -alkyl, arylalkyl, —CO—O-alkylene-aryl, —CO—O-allyl, —CO—C 1 –C 4 -alkyl, —CO-alkylene-aryl, C 3 –C 7 -cycloalkyl or —CO-allyl radical or the two radicals R A 6 and R A 6 * in the structural element I A 7 together are an optionally substituted, saturated, unsaturated or aromatic heterocyclic system which may, in addition to the ring nitrogen, contain up to two further different or identical heteroatoms O, N, S,
R A 7 is hydrogen, —OH, —CN, —CONH 2 , a branched or unbranched, optionally substituted C 1 –C 4 -alkyl, C 1 –C 4 -alkoxy, C 3 –C 7 -cycloalkyl or —O—CO—C 1 –C 4 -alkyl radical, or an optionally substituted arylalkyl, —O-alkylene-aryl, —O—CO-aryl, —O—CO-alkylene-aryl or —O—CO-allyl radical, or the two radicals R A 6 and R A 7 together are an optionally substituted, unsaturated or aromatic heterocyclic system which may, in addition to the ring nitrogen, contain up to two further different or identical heteroatoms O, N, S,
R A 8 is hydrogen, a branched or unbranched, optionally substituted C 1 –C 4 -alkyl, CO—C 1 –C 4 -alkyl, SO 2 —C 1 –C 4 -alkyl or CO—O—C 1 –C 4 -alkyl radical or an optionally substituted aryl, CO-aryl, SO 2 -aryl, CO—O-aryl, CO-alkylene-aryl, SO 2 -alkylene-aryl, CO—O-alkylene-aryl or alkylene-aryl radical,
R A 9 and R A 10
are, independently of one another, hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C 3 –C 7 -cycloalkyl radical or a CO—O—R A 14 , O—R A 14 , S—R A 14 , NR A 15 R A 16 or CO—NR A 15 R A 16 radical, or the two R A 9 and R A 10 radicals in the structural element I A 14 together are a 5- to 7-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals,
Z 5 is NR A 8 , oxygen or sulphur,
and
E is a spacer structural element which connects structural element A to structural element G covalently, wherein the spacer structural element E is composed of two to four partial structural elements selected from the group of E 1 and E 2 , the partial structural elements being linked in any sequence, and E 1 and E 2 having the following meanings:
E 1 is a partial structural element of the formula I E1
—(X E ) i —(CH 2 ) c —CR E 1 R E 2 —(CH 2 ) d —(Y E ) l — I E1
and
E 2 is a partial structural element of the formula I E2
(NR E 3 ) e —(CR E 4 R E 5 ) f —(Q E ) k —(CR E 6 R E 7 ) g —(NR E 8 ) h — I E2
where
c, d, f and g
are, independently of one another, 0, 1 or 2,
e, h, i, k and l,
are, independently of one another, 0 or 1,
X E and Q E
are, independently of one another, CO, CO—NR E 9 , S, SO, SO 2 , SO 2 NR E 9 , CS, CS—NR E 9 , CS—O, CO—O, O—CO, O, ethynyl, CR E 10 —O—CR E 11 , CR E 10 R E 11 —, C(═CR E 10 R E 11 ), CR E 10 ═CR E 11 —, CR E 11 (OR E 12 )—CR E 11 , CR E 10 —CR E 11 (OR E 12 ) or an optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S,
Y E is —CO—, —NR E 9 —CO—, —SO—, —SO 2 —, —NR E 9 —SO 2 —, —CS—, —NR E 9 —CS—, —O—CS— or —O—CO—
R E 1 , R E 2 , R E 4 , R E 5 , R E 6 and R E 7
are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical, a —(CH 2 ) w —R E 13 radical, an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, O-aryl or O-alkylene-aryl radical, or, independently of one another, in each case two radicals R E 1 and R E 2 or R E 4 and R E 5 or R E 6 and R E 7 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic system,
where
w is 0,1,2, 3 or 4,
R E 3 , R E 8 and R E 9
are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, CO—C 1 –C 6 -alkyl, CO—O—C 1 –C 6 -alkyl or SO 2 —C 1 –C 6 -alkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, CO—O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO 2 -aryl, CO-hetaryl or SO 2 -alkylene-aryl radical,
R E 10 and R E 11
are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
R E 12 is hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
R E 13 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, -arylalkyl, —O-alkylene-aryl or —O-aryl radical, an amino radical with primary or, where appropriate, secondary or tertiary substitution, be an optionally C 1 –C 4 -alkyl- or aryl-substituted C 2 –C 6 -alkynyl or C 2 –C 6 -alkenyl radical, a C 5 –C 12 -bicycloalkyl, C 6 –C 18 -tricycloalkyl radical, a CO—O—R A 14 radical, or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, C 3 –C 7 -cycloalkyl, aryl or hetaryl radical, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring, wherein the optional substituents are selected from the group consisting of —NO 2 , —NH 2 , —OH, —CN, —COOH, —O—CH 2 —COOH, halogen, a branched or unbranched, C 1 –C 4 -alkyl, C 1 –C 4 -haloalkyl —CO—O—C 1 –C 4 -alkyl, C 3 –C 6 -cycloalkyl, C 1 –C 4 -alkoxy, C 1 –C 4 -alkylthio, —NH—CO—O—C 1 –C 4 -alkyl, —O—CH 2 —COO—C 1 –C 4 -alkyl, —NH—CO—C 1 –C 4 -alkyl, —CO—NH—C 1 –C 4 -alkyl, —NH—SO 2 —C 1 –C 4 -alkyl, —SO 2 —NH—C 1 –C 4 -alkyl, —N(C 1 –C 4 -alkyl) 2 , —NH—C 1 –C 4 -alkyl, —SO 2 —C 1 –C 4 -alkyl —NH—CO-aryl, CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylene-aryl, —NH—SO 2 -aryl, SO 2 —NH-aryl, —CO—NH-benzyl, —NH—SO 2 -benzyl, —SO 2 —NH-benzyl, —SO 2 —NR 2 R 3 or —CO—NR 2 R 3 , where the radicals R 2 and R 3 , independently of one another, have the meaning of R L 5 , or the two radicals R 2 and R 3 together are a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, contains up to three other different or identical heteroatoms O, N, S, and optionally two radicals substituting this heterocyclic system together are a fused or saturated, unsaturated or aromatic carbocyclic or heterocyclic system which contains up to three different or identical heteroatoms O, N, S, and the ring can optionally be substituted or another, optionally substituted ring can be fused onto this ring or a physiologically tolerated salt, enantiomerically pure, diastereomerically pure or tautomeric form thereof.
2. A compound as claimed in claim 1 , wherein the spacer structural element E used is a structural element of the formula I E1E2
—E 2 —E 1 — I E1E2
and E 1 and E 2 have the following meanings:
E 1 is a partial structural element of the formula I E1
—(X E ) i —(CH 2 ) c —CR E 1 R E 2 —(CH 2 ) d —(Y E ) l — I E1
and
E 2 is a partial structural element of the formula I E2
—(NR E 3 ) e —(CR E 4 RE 5 ) f —(Q E ) k —(CR E 6 RE E 7 ) g —(NR E 8 ) h — I E2
where
c, d, f and g
are, independently of one another, 0, 1 or 2
e, h, i, k and l
are, independently of one another, 0 or 1,
X E and Q E
are, independently of one another, CO, CO—NR E 9 , S, SO, SO 2 , SO 2 NR E 9 , CS, CS—NR E 9 , CS—O, CO—O, O—CO, O, ethynyl, CR E 10 —O—CR E 11 , CR E 10 R E 11 , C(═CR E 10 R E 11 ), CR E 10 CR E 11 , CR E 10 (OR E 12 )—CR E 1 , CR E 11 —CR E 11 —(OR E 12 ) or an optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S,
YE is —CO—, —NR E 9 —CO—, —SO—, —SO 2 —, —NR E 9 —SO 2 —, —CS—, —NR E 9 —CS—, —O—CS— or —O—CO—
R E 1 , R E 2 , R E 4 –R E 5 , R E 6 and R E 7
are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical, a —(CH 2 ) w —R E 13 radical, an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, O-aryl or O-alkylene-aryl radical, or, independently of one another, in each case two radicals R E 1 and R E 2 or R E 4 and R E 5 or R E 6 and R E 7 together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic system,
where
w is 0, 1, 2, 3 or 4,
R E 3 , R E 8 and R E 9
are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, CO—C 1 –C 6 -alkyl, CO—O—C 1 –C 6 -alkyl or SO 2 —C 1 –C 6 -alkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, CO—O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO 2 -aryl, CO-hetaryl or SO 2 -alkylene-aryl radical,
R E 10 and R E 11
are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical,
R E 12 is hydrogen, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 2 –C 6 -alkenyl, C 2 –C 6 -alkynyl or alkylene-cycloalkyl radical or an optionally substituted C 3 –C 7 -cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, and
R E 13 is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C 1 –C 6 -alkyl, C 1 –C 4 -alkoxy, arylalkyl, —O-alkylene-aryl or —O-aryl radical, an amino radical with primary or, where appropriate, secondary or tertiary substitution, an optionally C 1 –C 4 -alkyl- or aryl-substituted C 2 –C 6 -alkynyl or C 2 –C 6 -alkenyl radical, a C 5 –C 12 -bicycloalkyl, C 6 –C 18 tricycloalkyl radical, a CO—O—R A 14 radical, or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, C 3 –C 7 -cycloalkyl, aryl or hetaryl radical, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted, or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring, wherein the optional substituents are selected from the group consisting of —NO 2 , —NH 2 , —OH, —CN, —COOH, —O—CH 2 —COOH, halogen, a branched or unbranched, C 1 –C 4 -alkyl, C 1 –C 4 -haloalkyl —CO—O—C 1 –C 4 -alkyl, C 3 –C 6 -cycloalkyl, C 1 –C 4 -alkoxy, C 1 –C 4 -alkylthio, —NH—CO—O—C 1 –C 4 -alkyl, —O—CH 2 —COO—C 1 –C 4 -alkyl, —NH—CO—C 1 –C 4 -alkyl, —CO—NH—C 1 –C 4 -alkyl, —NH—SO 2 —C 1 –C 4 -alkyl, —SO 2 —N H—C 1 –C 4 -alkyl, —N(C 1 –C 4 -alkyl) 2 , —NH—C 1 –C 4 -alkyl, —SO 2 —C 1 –C 4 -alkyl —NH—CO-aryl, CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylene-aryl, —N H—SO 2 -aryl, SO 2 —N H-aryl, —CO—N H-benzyl, —N H—SO 2 -benzyl, —SO 2 —NH-benzyl, —SO 2 —NR 2 R 3 or —CO—NR 2 R 3 , where the radicals R 2 and R 3 , independently of one another, have the meaning of R L 5 , or the two radicals R 2 and R 3 together are a 3 to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, contains up to three other different or identical heteroatoms O, N, S, and optionally two radicals substituting this heterocyclic system together are a fused or saturated, unsaturated or aromatic carbocyclic or heterocyclic system which contains up to three different or identical heteroatoms O, N, S, and the ring can optionally be substituted or another, optionally substituted ring can be fused onto this ring.
3. A pharmaceutical preparation for oral or parenteral use, comprising at least one compound as claimed in claim 1 in addition to conventional pharmaceutical excipients.