Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-06-04
2004-01-27
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06683051
ABSTRACT:
This application claims the benefit of PCT/EP99/06654, filed Sep. 9, 1999, which claims priority to German application 198 42 415.9, filed Sep. 16, 1998.
The invention relates to a novel pharmaceutical preparation comprising cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) and/or one of its physiologically acceptable salts and at least one chemotherapeutic agent and/or one of its physiologically acceptable salts and/or an angiogenesis inhibitor and/or one of its physiologically acceptable salts.
This novel preparation can be used to control pathologically angiogenic disorders, thromboses, myocardial infarct, coronary heart disease, arteriosclerosis, tumours, osteoporosis, inflammations and infections.
The invention was based on the object of providing novel medicinal products in the form of pharmaceutical preparations which have better properties than known medicinal products used for the same purposes.
This object has been achieved by the finding of the novel preparation.
Cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) is disclosed in EP 0 770 622 and acts in particular as integrin inhibitor, in particular inhibiting the interactions of the &agr;
v
, &bgr;
3
or &bgr;
5
integrin receptors with ligands, such as, for example, the binding of fibrinogen to the &agr;
v
&bgr;
3
integrin receptor. The compound shows particular activity in the case of the integrins &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, &agr;
IIb
&bgr;
3
and &agr;
v
&bgr;
1
, &agr;
v
&bgr;
6
and &agr;
v
&bgr;
8
.
This effect can be detected, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990).
The present invention is to be regarded as a selection invention in relation to EP 0 770 622.
WO 98/14192 mentions pharmaceutical products which comprise combinations of non-peptide vitronectin receptor antagonists with chemotherapeutic agents. The effect of an antiangiogenesis therapy combined with a chemotherapy is described by J. Folkman in Nature Medicine 1, 27-30 (1995).
The efficacy of cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) in combination with a chemotherapeutic agent can be shown in Lewis lung carcinoma system. The Lewis lung carcinoma is only inadequately influenced by conventional chemotherapeutic agents (Y. Kakeji and B. A. Teicher, Invest. New Drugs 15: 39-48 (1997)). The method for delaying tumour growth is carried out in analogy to Kakeji (F. Mitjans et al., J. Cell Sci. 108: 2825-2838 (1995)).
The invention further relates to a pharmaceutical preparation comprising cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) and/or one of its physiologically acceptable salts and at least one chemotherapeutic agent and/or one of its physiologically acceptable salts.
The invention relates in particular to a pharmaceutical preparation as described, characterized in that a chemotherapeutic agent from a group consisting of
a) alkylating agents,
b) antibiotics,
c) antimetabolites,
d) biologicals and immunomodulators,
e) hormones and antagonists thereof,
f) mustard gas derivatives,
g) alkaloids,
h) inhibitors of matrix metalloproteinases (MMP inhibitors),
i) protein kinase inhibitors,
k) others is employed.
Examples of preferred alkylating agents are busulfan, carboplatin, carmustine, cisplatin, cyclophosphamide, dacarbazine, ifosfamide or lomustine.
Examples of preferred antibiotics are bleomycin, doxorubicin (Adriamycin), idarubicin or plicamycin.
Examples of preferred antimetabolites are sulfonamides or folic acid antagonists such as, for example, also 5-fluorouracil (5-FU), mercaptopurine, methotrexate or thioguanine or 5-FU with calcium folinate (leucovorin).
Examples of preferred biologicals and immunomodulators are interferon a2 A, interleukin2 or levamisole.
Examples of preferred hormones and antagonists thereof are flutamide, goserelin, mitotane or tamoxifen.
Examples of preferred mustard gas derivatives are melphalan, carmustine or nitrogen mustard.
Examples of preferred alkaloids are the taxanes such as docetaxel or paclitaxel, also etoposide, vinblastine or vinovelbine [sic].
Other chemotherapeutic agents mean those which cannot be assigned to the above groups, such as, for example, altretamine, cladribine, gemcitabine, leucovorin, levamisole, pentostatin or irinotecan.
Among inhibitors of matrix metalloproteinases (MMP inhibitors), which are also described, for example, by M. Wittaker [sic] et al. in
Current Opinion in Drug Discovery
&
Development
1, 157-164 (1998), the following compounds are preferred, for example baltimastat (BB-94), marimastat (BB-2516), BB-3644, ilomastat, metastat, AG-3340, BAY-12-9566, AE-941
eovastat, CGS-27023A, RS-113456, RS-130830, Ro-32-3555, Ro-31-9790, CT-1746, CT-1418, D-1927, D-2163.
Protein kinase inhibitors are described, for example, by G. McMahon et al. in
Current Opinion in Drug Discovery
&
Development
1, 131-146 (1998) and by L. M. Strawn et al. in
Exp. Opin. Invest. Drugs
7, 553-573 (1998). In the preparations according to the invention, the following receptor tyrosine kinase inhibitors are specifically preferred:
CGP 79787, SU-101 (HWA 486, leflunomide, Arava), SU-5416, SU-5271 (PD-153035), PD-173074, SU-6668, ZD-1839, CP-358774.
The preparations according to the invention also include so-called prodrug derivatives of the angiogenesis inhibitors and/or of the chemotherapeutic agents, i.e. compounds which are modified with, for example, alkyl or acyl groups, sugars or oligopeptides and are rapidly cleaved in the body to give the active compounds according to the invention. The prodrug derivatives include, for example, also the chemotherapeutic agent capecitabine which is the prodrug of 5-FU, as described, for example, in Inpharma No. 1142, 13-14 (1998).
Particular preference is given to a pharmaceutical preparation as described, characterized in that a chemotherapeutic agent from a group consisting of docetaxel, paclitaxel, carboplatin, cisplatin, 5-FU and calcium folinate, irinotecan, cyclophosphamide, carmustine, doxorubicin, vinorelbine, goserelin or gemcitabine is employed.
The use of gemcitabine in tumour treatment is described, for example, by B. J. Braakhuis et al. in Semin-Oncol. 1995 August; 22 (4 Suppl.11): 42-6 or by R. M. Mohammed et al. in Pancreas 1998 January; 16(1): 19-25.
The invention further relates to a pharmaceutical preparation comprising cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) and/or one of its physiologically acceptable salts and gemcitabine and/or one of its physiologically acceptable salts.
The invention further relates to a pharmaceutical preparation comprising cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) and/or one of its physiologically acceptable salts and at least one angiogenesis inhibitor and/or one of its physiologically acceptable salts.
Preferred angiogenesis inhibitors are described, for example, in Table 1 in WO 9741844.
Particular preference is given to &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
integrin inhibitors, for example the compounds mentioned in EP 0 770 622.
The novel pharmaceutical preparation can be produced by converting cyclo(Arg-Gly-Asp-D-Phe-NMe-Val) and/or one of its physiologically acceptable salts and at least one chemotherapeutic agent and/or one of its physiologically acceptable salts and/or an angiogenesis inhibitor and/or one of its physiologically acceptable salts, into a suitable daily dosage form together with at least one solid, liquid or semiliquid excipient or ancillary substance. The preparations obtained in this way can be employed as medicinal products in human or veterinary medicine, in particular for the treatment of tumours. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral, sublingual or rectal), parenteral or topical (for example transdermal) administration and do not react with the compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol acetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc, cellulose. Particularly used for oral administration are tablets, coated tablets, capsules, syrups, suspensions or drops, for rectal admi
Goodman Simon
Haunschild Jutta
Jonczyk Alfred
Perschl Astrid
Rösener Sigrid
Carlson Karen Cochrane
Merck Patent GmbH
Snedden Sheridan
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