Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-20
2001-02-27
Davenport, Avis M. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S009100, C514S011400, C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C514S018700
Reexamination Certificate
active
06194380
ABSTRACT:
This invention relates to a promoting agent for bone formation which comprises a peptide or polypeptide containing the amino acid sequence consisting of ArgGlyAsp (hereinafter referred to as RGD sequence) in the molecule. Further, the invention relates to a prophylactic and therapeutic method for bone fracture utilizing a promoting agent for bone formation comprising the peptide or polypeptide containing the said RGD sequence. Also, the invention relates to a novel cyclic peptide containing the said RGD sequence. And further, it relates to a promoting agent for bone formation which comprises a compound represented by the general formulae (IX), (X), (XI) and (XII).
Bone is composed of outer cortical bone and inner trabecular bone. The function of bone in living body is to maintain a given shape as a skeleton and to store various inorganic substances such as calcium, phosphoric acid and the like. Bone may apparently appear to be a tissue with less variability, but actually old bone is adsorbed and instead new bone is formed. This is usually referred to as bone reformation. The bone reformation can be accomplished by coupling of osteoclasts controlling bone adsorption with osteoblasts controlling bone formation as both can primarily participate in therein. It has been recently elucidated that the function of osteoblasts is not limited to bone formation solely, but it is related to differentiation and activation of osteoclasts and osteoblasts may play a role as a control center in cellular bone reconstruction.
Those diseases generally referred to as bone metabolism diseases may include osteoporosis, Behget disease, osteomalacia, hyperostosis and osteopetrosis. Among them, osteoporosis is the most frequently developed disease and frequency of its occurrence appears to increase with senescence so that the diagnosis and effective therapy thereof have been earnestly desired.
The bone metabolism diseases mean those diseases wherein bone cells have specific metabolic abnormalities in any bone tissues. The present inventors have made earnest studies to find out a promoting factor for bone formation using a cultural assay and finally completed this invention.
Integrin may participate in the interaction between cells and cells or between cells and extracellular matrices and play an important role in wound healing, development, immunization, hemostasis or metastasis. Integrin superfamily is an &agr;,&bgr;-heterodimer group found on the cell surface and may combine extracellular ligands and cytoskeleton. All integrins are heterodimers and each sub-unit is extracellular by 90% and may have a long membrane permeable domain and a short intracellular domain. The extracellular domain is bound with the extracellular matrices or ligands of the cell surface, while the intracellular domain is bound with cytoskeleton proteins. Bone matrices such as osteopontin, bone sialoglycoproteins, thrombospondin, fibronectin and vitronectin are found in bone and all proteins have been found to have the RGD sequence. Recently, osteoclasts have been found to have integrin &agr;V&bgr;3 and &agr;2&bgr;1 in the cell membrane surface (Davies J. et al., J. Cell Biol., Vol.1, 109, p.1817, 1989 and Zambonin Z. A. et al., Connect. Tissue Res., Vol.20, p.143, 1989). From the facts that bone absorption by osteoclasts can be inhibited by the action of an antibody to integrin (Davies J. et al., J. Cell Biol., Vol.109, p.1817, 1989), that bone absorption by rat osteoclasts can be inhibited by synthetic GRGDSP peptide (GlyArgGlyAspSerPro)(Horton M. A. et al., Exp. Cell Res., Vol.195, p.368, 1991), and further that echstatin, a protein derived from snake venom and having the RGD sequence and a platelet aggregation inhibiting activity, a synthetic GdRGDSP peptide and a cyclic synthetic GPenGRGDSPCA peptide can inhibit bone absorption by mouse osteoclasts and GdRGDSP peptide can inhibit the formation of tartaric acid-resistant and phosphatase-positive multinuclear osteoclasts (Gabri V. D. P. et al., J. Bone Miner. Res., Vol.9, p.1021, 1994), it is suggested that recognition and adhesion of bone matrices by integrin and related cytoskeleton does deeply participate in the development of bone absorption function of osteoclasts.
It may be then considered that the adhesion of cell matrices between osteoblasts and bone matrices would be caused by the adhesion mechanism via collagen and fibronectin in the bone matrices and &bgr;1 integrin of osteoblasts. Also, it would be possible in the adhesion mechanism between heterocytes that the cell adhesion of osteoblasts with osteoclasts can be performed via fibronectin as both &bgr;3 integrin of osteoclasts and &bgr;1 integrin in osteoblasts may be a receptor for fibronectin. However, it has not yet been suggested that the disintegrin family including echstatin or kistrin (William R. G. et al., Protein Science, Vol.2, p.1749, 1993) and the RGD peptide show a promoting action for bone formation.
It is the object of this invention to provide a promoting agent for bone formation, a therapeutic method for bone formation and a process for preparing a promoting agent for bone formation.
Bone formation can be promoted by administering a peptide or polypeptide containing the RGD sequence in the molecule or a biologically acceptable salt thereof to patients. The peptides or polypeptide containing the RGD sequence in the molecule may illustratively include kistrin, echstatin, a peptide represented by Gly-Arg-Gly-Asp-Ser (hereinafter referred to as GRGDS (SEQ ID NO: 1)), a compound represented by the general formula (I)
wherein R
1
, R
2
, R
3
, R
4
, R
5
and R
6
may be the same or different and each represents one selected from the group consisting of a hydrogen atom; an alkyl group of 1-8 carbon atoms optionally substituted with one selected from the group consisting of a hydroxy group, a carboxy group, a cycloalkyl group of 3-10 carbon atoms optionally substituted with a hydroxy group, and an aryl group of 6-12 carbon atoms optionally substituted with a hydroxy group ; a cycloalkyl group of 3-10 carbon atoms optionally substituted with hydroxy group and an aryl group of 6-12 carbon atoms optionally substituted with a hydroxy group, R7 and R8 may be the same of different and each represents a group selected from the group consisting of a hydroxy group, an alkoxy group of 1-8 carbon atoms, an alkenyloxy group of 2-12 carbon atoms, a cycloalkyloxy group of 3-10 carbon atoms and an aryloxy group of 6-12 carbon atoms, and X represents S or SO
2
and a compound represented by the general formula (II)
wherein R
9
, R
10
, R
11
and R
12
may be the same or different and each represents one selected from the group consisting of a hydrogen atom, an alkyl group of 1-8 carbon atoms, a cycloalkyl group of 3-10 carbon atoms and an aryl group of 6-12 carbon atoms optionally substituted with a hydroxy group, R
13
, R
14
and R
15
may be the same or different and each represents a group selected from the group consisting of a hydroxy group, an alkoxy group of 1-8 carbon atoms, an alkenyloxy group of 2-12 carbon atoms, a cycloalkyloxy group of 3-10 carbon atoms and an aryloxy group of 6-12 carbon atoms, and X represents S or SO.
And, this invention provides a new compound represented by the formula (II).
Also, this invention is directed to a therapeutic method for promoting bone formation which comprises administering to patients a compound represented by the general formula (IX)
wherein R
16
represents —N(R
20
)
2
,—C(═NH)—NH
2
, —NH—C(═NH)—NH
2
or —CO—NH—C(═NH)—NH
2
(in which R
20
independently represents a hydrogen atom or an alkyl group of 1-4 carbon atoms optionally substituted with a phenyl group), R
17
represents a hydrogen atom or an alkyl group of 1-4 carbon atoms optionally substituted with a phenyl group, R
18
represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenyl group optionally substituted with a methoxy group or —COR
21
(in which R
21
represents —OH, —NH
2
, —NH—(CH
2
)
2
-phenyl, an alkoxy group of 1-3 carbon atoms, a benzyloxy group, Pro or Aoc), R
19
rep
Baron Roland
Gadek Thomas R.
Inazu Mizuho
Kitamura Kazuyuki
Knolle Jochen
Bierman, Muserlian and Lucas
Davenport Avis M.
Hoechst Marion Roussel
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