Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-05-03
2002-08-13
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S330000, C530S331000
Reexamination Certificate
active
06432921
ABSTRACT:
The present invention relates to non-slow-binding thrombin inhibitors, a process for the preparation of said inhibitors, pharmaceutical compositions containing the same, and the use of these thrombin inhibitors as antithrombotic agents.
BACKGROUND OF THE INVENTION
Much attention has been focused on inhibition of thrombin as potential anticoagulants. Inhibitors of the enzyme thrombin, a key serine protease within the blood coagulation cascade, have for some time been considered as potential candidates for anticoagulant prophylaxis and therapy. In particular the multiple roles played by thrombin in its actions on coagulation factors, circulating blood components, and the cells of the vessel wall makes it a particularly attractive target in a variety of pathological states. Moreover, limitations associated with currently employed anticoagulants, in particular the occurrence of bleeding complications, necessitate the search for more specifically-acting agents.
Many peptide(-like) serine protease inhibitors have been disclosed, amongst which are transition state inhibitors of thrombin. Many of these latter compounds, however, are slow-binding inhibitors. The use of slow-binding inhibitors of thrombin is open to criticism. In vivo, thrombin is constantly generated in plasma and thrombin inhibitors primarily function by slowing thrombin formation through inhibiting thrombin-mediated amplification steps. To slow down such an amplification cascade, a non-slow-binding inhibitor would be preferable. A larger dose of a slow-binding inhibitor would be needed to achieve the same effect, with a correspondingly increased risk of side-effects.
Relevant thrombin inhibitors are disclosed by Brady et al., Bioorganic & Medicinal Chemistry, 3 (1995), 1063-78 wherein D-Phe-Pro-Arg-amide and D-Phe-Pro-Lys-X derivatives have been disclosed, X being a ketoester or amine. These compounds are disclosed to be slow-binding thrombin inhibitors, and likewise these compounds are excluded from the present invention. In the search for non-slow-binding thrombin inhibitors Jones et al., J. Enzyme Inhibition, 9 (1995), 43-60 attempted to obtain improvement by using D-Cha-Pro-Lys-COOH derivatives. However, although these derivatives proved to be more potent thrombin inhibitors, they still exhibit slow-binding properties.
In a recent attempt to obtain potent non-slow-binding thrombin inhibitors Lewis et al., Thrombosis and Haemostasis, 74(4) (1995), 1107, prepared Me-D-Phe-Pro-Lys-X derivatives, X being carboxyamide or carboxylic acid. These compounds, among which specifically disclosed Me-D-Phe-Pro-Lys-COOH, are classified as slow-binding inhibitors. This compound therefore does not fulfill the requirements of the present invention and is excluded from protection.
A thrombin inhibitor with an alkyl-substituted lysine is disclosed in U.S. Pat. No. 5,523,308. In earlier references other Phe-Pro-Lys sequences are described, for example by Iwanowicz et al. in Bioorganic & Medicinal Chemistry Letters, 2 (1992), 1607-12, which discloses D-Phe-Pro-Lys-X derivatives, X being i.a. a ketoester. Such compounds may also be described as slow-binding thrombin inhibitors.
Other types of peptides for inhibition of different serine proteases are also disclosed. Tsutsumi et al. in J. Med. Chem., 37 (1994), 3492-3502 described peptide-like compounds having thiazole and benzothiazole C-terminal ends. It was found that such thiazole derivatives are 300 times more potent than the corresponding thiophene analogues. It was further posited that C-terminal heterocyclic groups would provide a critical hydrogen-bond interaction with the histamine of the protease prolyl endopeptidase. Although it was further suggested that this feature may well be capable of extension to other serine proteases, thrombin proteases were not specifically mentioned. The mechanistic explanation of Tsutsumi was later challenged by Edwards et al. in J. Med. Chem., 38 (1995), 76-85, but also these authors found that elastase inhibitors of the type D-Phe-Val-Pro-Val-X, X being thiazole and benzothiazole, are non-slow-binding inhibitors of the relevant serine protease. These authors suggest the development of peptidyl &agr;-ketoheterocycles as inhibitors of other serine proteases as well.
SUMMARY OF THE INVENTION
The present invention relates to the surprising finding that the teachings of Edwards, Tsutsumi and others can also be applied to thrombin inhibitors. The application of the C-terminal heterocycles to the compounds as disclosed by Lewis, Jones and Brady provide potent thrombin inhibitors having non-slow-binding properties to thrombin. Moreover, many of these compounds show improved biological half-lifes and oral bioavailability.
The invention therefore relates to non-slow-binding thrombin inhibitors of the formula:
A—B—C-Lys-D
wherein
A is H, 2-hydroxy-3-cyclohexyl-propionyl-, R
1
, R
1
—O—CC—, R
1
—CO— , R
1
—SO
2
—, —(CHR
2
)
n
COOR
3
, or an N-protecting group, wherein
R
1
is selected from —(1-6C)alkylene-COOH, (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substituted with (1-6C)alkyl, (2-12C)alkoxy, hydroxy, or halogen;
R
2
is H or has the same meaning as R
1
;
R
3
is selected from H, (1-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16C)aralkenyl, the aryl group of which may be substituted with (16C)alkyl, (2-12C)alkoxy, hydroxy, or halogen;
n is an integer of 1 to 3;
B is a bond, L-Asp or an ester derivative thereof, Leu, norLeu, —N(benzyl)—CH
2
—CO—, —N(2-indane)—CH
2
—CO—, D-1-Piq, D-3-Piq, D-Tiq, Atc or a D-amino acid having a hydrophobic aromatic side chain;
C is Azt, Pro, Pec, norLeu(cyclo)Gly, or an amino acid of one of the formulae —N[(3-8C)cycloallkyl]-CH
2
—CO— or —N(benzyl)-CH
2
—CO—;
D is selected from COOH, tetrazole, oxazole, thiazole and benzothiazole;
or A and C have the aforesaid meanings, B is D—(3-8C)cycloalkylalanine, and D is tetrazole, oxazole, thiazole or benzothiazole;
or a prodrug thereof,
or a pharmaceutically acceptable salt thereof;
with the exception of the compound Me-D-Phe-Pro-Lys-COOH.
The compounds of the present invention are useful for treating and preventing thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. The compounds of the invention may also be used as anticoagulants in extracorporeal blood circuits, as necessary in dialysis and surgery. The compounds of the invention may also be used as in vitro anticoagulants.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds according to this invention are the compounds wherein D is COOH. In addition, preferably A is H, (1-12C)alkyl, —CO—(7-15C)aralkyl, —SO
2
—(1-12C)alkyl, —SO
2
—(6-14C)aryl, or —SO
2
(7-15C)aralkyl; B is a bond, L-Asp, norLeu, D-1-Piq, or D-Phe; and C is Pro, norLeu(cyclo)Gly, or —N-cyclopentyl—CH
2
—CO—. More preferred are the non-slow-binding thrombin inhibitors wherein A is —SO
2
-benzyl, B is a bond, and C is norLeu(cyclo)Gly, or wherein A is —SO
2
-ethyl, B is D-Phe, and C is Pro; or wherein A is hydrogen, B is D-1-Piq, and C is Pro.
Other preferred compounds according to the invention are those wherein D is oxazole or thiazole. Further, preferably A is H, (1-12C)alkyl, 2-hydroxy-3-cyclohexyl-propionyl-, —CO—(CH
2
)
n
COOH, —CO—(7-15C)aralkyl, —SO
2
—(6-14C)aryl, —SO
2
—(7-15C)aralkyl, —SO
2
—(1-12C)alkyl, —(CHR
2
)
n
COOR
3
, R
2
being H or (1-12Calkyl) and R
3
being H, (1-12C)alkyl or benzyl; and C is Pro, norLeu(cyclo)Gly, or —N[(3-8C)cycloalkyl]-CH
2
—CO—. Particularly preferred are the n
Adang A. E. P.
Grootenhuis P. D. J.
Peters J. A. M.
van Boeckel C. A. A.
Akzo Nobel N.V.
Borin Michael
Rothwell Figg Ernst & Manbeck p.c.
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