Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-07-28
2001-06-05
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S298000, C544S358000, C544S360000, C544S382000
Reexamination Certificate
active
06242600
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel 2-piperazinone-1-acetic acid derivatives which are useful for a medicine, or a salt thereof and to a pharmaceutical composition for inhibiting cell-adhesion comprising these derivatives as effective components.
BACKGROUND ART
As the factors participating in adhesion to the extracellular substrate of animal cells, there have been known fibronectin, vitronectin, osteopontin, collagen, thrombospondin, fibrinogen, von willebrand factor, etc. These proteins include tripeptide sequence of -Arg-Gly-Asp- as cell recognition site. This tripeptide is recognized by at least one protein belonging to the receptors integrins, which are heterodimeric proteins consisting of sub-units combined to two membranes [Science, 238, 491 (1987)].
Structurally related integrin receptors, which recognize the amino acid sequence -Arg-Gly-Asp-, are known to express at the extracellular surface glycoprotein of platelets, endothelial cells, leucocyte, lymphocyte, monocyte and granulocyte. Compounds having the amino acid sequence -Arg-Gly-Asp- are competitively bound to the site to be bound with intracellular adhesive factors to thereby inhibit the binding of intracellular adhesive factors. As such substances for inhibiting intracellular adhesion, there has been known, for example, H-Gly-Arg-Gly-Asp-Ser-Pro-OH.
When blood vessels are injured, platelets are activated with, for example, endothelial collagens, which causes binding of fibrinogen to platelets, i.e. platelet aggregation, to form thrombus. The interaction between platelets and fibrinogen takes place through GP IIb/IIIa, this being an important characteristic feature of platelet aggregation. Cell adhesion-inhibiting substances can inhibit platelet aggregation due to substances causing platelet aggregation such as thrombin, epinephrine, ADP and collagen.
Besides, cell-adhesion inhibiting substances are expected to be useful as drugs for suppression of metastasis of tumor cells (inhibition of fixed adhesion at the site where the tumor cells are migrated).
Linear or cyclic peptides containing the amino acid sequence, -Arg-Gly-Asp- (RGD) have been known as cell-adhesion inhibiting substances [Journal of Biological Chemistry (J. Biol. Chem.), 262, 17294 (1987) and Japanese published unexamined patent application No. 174797/1990, among others].
And, non-peptide compounds having an anti-thrombotic action are disclosed in Japanese published unexamined patent application No. 264068/1992 and EPA 505868. Further, compounds having pyridyl-piperazine or pyridazinyl-piperazine, which have an anti-thrombotic action, are disclosed in WO 96-24581. And, such drugs as aspirin, heparin and ticlopidine are known to show undesirable side effects such as prolongation of bleeding time. As known platelet aggregation inhibiting substances which are slight in the action of prolonging bleeding time, cyclic peptide derivatives are described in the Japanese publication of translations of International patent application No. 509551/1994.
DISCLOSURE OF INVENTION
These known peptide derivatives mentioned above are not satisfactory in the potency of their activity, and their oral absorbability is not satisfactory from the practical viewpoint. Besides, since these peptide derivatives are hydrolyzed with enzymes including aminopeptidase, carboxypeptidase or various types of endopeptidase, e.g. serine protease, their stability in a solution containing these enzymes or in a living body is not satisfactory. Therefore, for clinical application of these peptide derivatives, there are problems still to be solved.
And, in the non-peptide compounds having an anti-thrombotic action, compounds having higher potency and being durable for a longer period as compared with the above-mentioned known compounds having an antithrombotic action have been sought for.
Further, the known platelet aggregation inhibiting substances which are slight in the action of prolonging bleeding time are far from being satisfactory in the durability of the action and oral absorbability. Therefore, such compounds as showing longer durability and capable of being administered orally have been sought for.
The present inventors diligently made extensive studies and, as a result, they succeeded in synthesizing a compound or a salt thereof [hereinafter, referred to as Compound (I)], whose characteristic feature in the chemical structure lies in having a basic heterocyclic group at terminals of substituents at 4-positions of the 2-piperazinone ring, represented by the formula (I)
wherein the ring A is a basic 5- to 7-membered heterocyclic group which may be substituted; the ring B is a divalent 5- to 7-membered nitrogen containing heterocyclic group which may be substituted or a divalent 5- to 7-membered cyclic hydrocarbon group which may be substituted; Y is an optionally substituted methylene group; R
1
is a hydrogen atom, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted hydrocarbon group which may be bound through a carbonyl group, a thio group, a sulfinyl group or a sulfonyl group; R
2
is a hydrogen atom or an optionally substituted hydrocarbon group; R
3
is an optionally esterified or amidated carboxyl group; and D is a lower alkyl group substituted with an optionally esterified carboxyl group; a compound or a salt thereof [hereinafter, referred to as Compound (I-1)]represented by the formula (I-1)
wherein the ring A
1
is a basic 5- to 7-membered aromatic heterocyclic group which may be substituted; the ring B is a divalent 5- to 7-membered nitrogen containing heterocyclic group which may be substituted or a divalent 5- to 7-membered cyclic hydrocarbon group which may be substituted; Y
1
is an optionally substituted imino group; R
1
is a hydrogen atom, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted hydrocarbon group which may be bound through a carbonyl group, a thio group, a sulfinyl group or a sulfonyl group; R
2
is a hydrogen atom or an optionally substituted hydrocarbon group; R
3
is an optionally esterified or amidated carboxyl group; and D is a lower alkyl group substituted with an optionally esterified carboxyl group; and a compound or a salt thereof [hereinafter, referred to as Compound (I-2)] represented by the formula (I-2)
wherein the ring A
2
is a piperidyl group which may be substituted; the ring B
1
is a phenylene group which may be substituted; Y
1
is an optionally substituted imino group; R
1
is a hydrogen atom, an optionally substituted hydroxy group, an optionally substituted amino group or an optionally substituted hydrocarbon group which may be bound through a carbonyl group, a thio group, a sulfinyl group or a sulfonyl group; R
2
is a hydrogen atom or an optionally substituted hydrocarbon group; R
3
is an optionally esterified or amidated carboxyl group; and D is a lower alkyl group substituted with an optionally esterified carboxyl group, and further found that these compounds thus synthesized unexpectedly possess a potent and durable platelet aggregation inhibiting action. Based on this finding, the present invention was accomplished.
More specifically, the present invention relates to
(1) the compound (I);
(2) the compound (I-1);
(3) the compound (I-2);
(4) a compound of the above (1),
wherein the ring A is a basic 5- to 7-membered heterocyclic group containing, besides carbon atoms, 1 to 3 hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom, which may have 1 to 5 substituents selected from the class consisting of (1) a C
1-6
alkyl group, (2) a C
2-6
alkenyl group, (3) a C
2-6
alkynyl group, (4) a C
3-8
cycloalkyl group, (5) a C
3-8
cycloalkenyl group, (6) a C
7-12
aralkyl group, (7) a C
6-10
aryl group, (8) a C
1-6
alkoxy group, (9) a phenoxy group, (10) a C
1-6
alkanoyl group, (11) a benzoyl group, (12) a C
1-6
alkanoyloxy group, a benzoyloxy group, (13) a carboxyl group, (14) a C
1-6
alkoxy-carbonyl group, (15) a carbamoyl group, (16) a
Tamura Norikazu
Terashita Zen-ichi
Chao Mark
Patel Sudhaker B
Raymond Richard L.
Riesen Philippe Y.
Takeda Chemical Industries Ltd.
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