Claims
- 1. A serine protease inhibitor of the formula (XX),J—D—E—N(R′)1—Q (XX) wherein Q has the formula wherein the substructure is a structure selected from wherein X is O or S;X′ being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof; (R′)1 is H or (1-4C)alkyl; J is H, optionally substituted D,L α-hydroxyacetyl, (R′)2, (R′)2—O—C(O)—, (R′)2—C(O)—, (R′)2—SO2—, (R′)7OOC—(CH(R′)3)p—SO2—, (R′)7OOC—(CH(R′)3)p—, (R′)32NCO—(CH(R′)3)p—, Het-CO—(CH(R′)3)p—, or an N-protecting group, wherein (R′)2 is selected from (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl and (3-12C)cycloalkyl, which groups may optionally be substituted with (3-12C)cycloalkyl, (1-6C)alkoxy, oxo, OH, COOH, CF3 or halogen, and from (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl groups of which may optionally be substituted with (1-6C)alkyl, (3-12C)cycloalkyl, (1-6C)alkoxy, OH, COOH, CF3, or halogen; each group (R′)3 is independently H or has the same meaning as (R′)2, (R′)7 has the same meaning as (R′)3 or is Het-(1-6C)alkyl or Het-(2-6C)alkynyl; and Het is a 4-, 5- or 6-membered heterocycle containing one or more heteroatoms selected from O, N or S; p is 1, 2 or 3; D is a bond, an amino-acid of the formula —NH—CH[(CH2)qC(O)OH]—C(O)— or an ester derivative thereof and q is 0, 1, 2 or 3, —N((1-12C) alkyl)—CH2—CO—, —N((2-12C)alkenyl)—CH2—CO—, —N((2-12C)alkynyl)—CH2—CO—, —N(benzyl)—CH2—CO—, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a L- or D-amino acid having a hydrophobic, basic or neutral side chain, which amino acid may optionally be N-(1-6C) alkyl substituted; or J and D together are the residue (R′)4(R′)5N—CH(R′)6—C(O)—, wherein (R′)4 and (R′)5 independently are (R′)2, (R′)2—O—C(O)—, (R′)2—C(O)—, (R′)2—SO2—, (R′)7OOC—(CH(R′)3)p—SO2—, (R′)7OOC—(CH(R′)3)p—, H2NCO—(CH(R′)3)p—, or an N-protecting group, or one of (R′)4 and (R′)5 is connected with (R′)6 to form a 5- or 6-membered ring together with “N—C” to which they are bound, which ring may be fused with an aliphatic or aromatic 6-membered ring; and (R′)6is a hydrophobic, basic or neutral side chain; E is an L-amino acid with a hydrophobic side chain, serine, threonine, a cyclic amino acid, or E is —N(R′)3—CH2—C(O)— or the fragment wherein t is 2, 3, or 4, and W is CH or N, or E—N(R′)1 taken together form the fragment wherein u is 1, 2 or 3; or a prodrug thereof.
- 2. The compound of claim 1 having the formula (XX), wherein E is an L-amino acid with a hydrophobic side chain, serine, threonine or —N(R′)3—CH2—C(O)— or wherein E—N(R′)1 taken together form the fragment
- 3. The compound of claim 1 having the formula (XX), whereinJ is as previously defined; D is a bond, an amino-acid of the formula —NH—CH[(CH2)qC(O)OH]—C(O)— or an ester derivative thereof and q being 0, 1, 2 or 3, —N((1-6C)alkyl)—CH2—CO—, —N((2-6C)alkenyl)—CH2—CO—, —N(benzyl)—CH2—CO—, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, which amino acid may optionally be N-(1-6C)alkyl substituted; or J and D together are the residue (R′)4(R′)5N—CH(R′)6—C(O)—; and E is a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C)alkyl, (1-6C)alkoxy, benzyloxy or oxo, or E is —(R′)3—CH2—C(O)— or the fragment
- 4. The compound of claim 3, whereinJ is H, 2-hydroxy-3-cyclohexyl-propionyl-, 9-hydroxy-fluorene-9-carboxyl, (R′)2, (R′)2—SO2—, (R′)7OOC—(CH(R′)3)p—SO2—, (R′)7OOC—(CH(R)3)p—, (R′)32N—CO—(CH(R′)3)p—, Het-CO—(CH(R′)3)p— wherein Het contains as a heteroatom at least a nitrogen atom which is bound to CO, or an N-protecting group, wherein (R′)2 is selected from (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl which groups may optionally be substituted with (1-6C)alkoxy; each group (R′)3 is independently H or has the same meaning as (R′)2; (R′)7 has the same meaning as (R′)3 or is morpholino-(1-6C)alkyl or morpholino-(2-6C)alkynyl; D is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, which amino acid may optionally be N-(1-6C)alkyl substituted; or J and D together are the residue (R′)4(R′)5N—CH(R′)6—C(O)—.
- 5. The compound of claim 4, whereinJ is H, (R′)2—SO2—, (R′)7OOC—(CH(R′)3)p—, (R′)12N—CO—(CH(R′)3)p—, D is a bond, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or J and D together are the residue (R′)4(R′)5N—CH(R′)6—C(O)—, wherein at least one of (R′)4 and (R′)5 is (R′)7OOC—(CH(R′)3)p— or (R′)2—SO2— and the other independently is (1-12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-12C)cycloalkyl, (7-15 C)aralkyl, (R′)2—SO2— or (R′)7OOC—(CH(R′)3)p—, and (R′)6 is a hydrophobic side chain.
- 6. A pharmaceutical composition comprising the compound of claim 1 and pharmaceutically suitable auxiliaries.
- 7. A process for preparing a pharmaceutical composition, comprising mixing together a compound of claim 1 with pharmaceutically acceptable auxiliaries.
- 8. A method of treating or preventing thrombosis or thrombosis-related diseases in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 1.
Priority Claims (1)
Number |
Date |
Country |
Kind |
97201227 |
Apr 1997 |
EP |
|
Parent Case Info
This application is a 371 of PCT/EP98/02455, filed Apr. 21, 1998.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/EP98/02455 |
|
WO |
00 |
10/19/1999 |
10/19/1999 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO98/47876 |
10/29/1998 |
WO |
A |
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5519036 |
Himmelsbach |
May 1996 |
|
Foreign Referenced Citations (4)
Number |
Date |
Country |
0 555 824 A1 |
Aug 1893 |
EP |
WO 9208709 |
May 1992 |
WO |
WO 9216549 |
Oct 1992 |
WO |
WO 9513274 |
May 1995 |
WO |