WO2009041841A1 - Peptide-platinum complexes, method for preparation and use the same - Google Patents
Peptide-platinum complexes, method for preparation and use the same Download PDFInfo
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- WO2009041841A1 WO2009041841A1 PCT/PL2008/000068 PL2008000068W WO2009041841A1 WO 2009041841 A1 WO2009041841 A1 WO 2009041841A1 PL 2008000068 W PL2008000068 W PL 2008000068W WO 2009041841 A1 WO2009041841 A1 WO 2009041841A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
Definitions
- the present invention relates to novel peptide-platinum complexes, to their preparation, pharmaceutical composition and to use the same as medicament for treatment of tumors, especially in the form of infusions, intravenous injections or implants.
- the main used compounds include cisplatin or analogs thereof.
- platinum complexes such as cisplatin has been shown to be effective in the treatment of most advanced forms of tumors (Rosenberg, Cancer 1985, 55, 2303 2316; Prestayko et al., Cancer Treat. Rev. 1979, 6, 17 39).
- the present invention provides the new peptide-platinum complexes of the general formula I: Tyr-D-Ala-Gly-Phe-NH-NH ⁇ -Phe ⁇ - AA-PtX 2 wherein:
- AA is a residue of methionine, cysteine, histidine, 1,3-diaminebutanoic acid or 1,4- diaminepentanoic acid,
- X is halogen, or pharmaceutically acceptable salts thereof.
- Cl is preferred halogen.
- Tyr denotes tyrosine, preferably L-tyrosine
- D-AIa denotes D-alanine
- GIy denotes glycine
- Phe denotes phenylalanine, preferably L-phenylalanine.
- Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, lactic acid, malonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like
- organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, lactic acid, malonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like.
- the present invention further relates to a method for the preparation of the new peptide-platinum complexes of general formula I, as defined above, comprising reacting peptide of general formula V: Tyr-D-Ala-Gly-Phe-NH-NH ⁇ — Phe «— AA, optionally in the form of an acid addition salt, with Pt(II) compound.
- the obtained product may be, if necessary, converted into a desired pharmaceutically acceptable salt by a conventional method.
- Pt(II) compound can be, for example, haloplatinate(II).
- the reaction is preferably carried out in an aqueous medium.
- the essential feature of the method according to the invention is that the amino acid residues of methionine, cysteine or histidine chemically linked to an opioid peptide, as shown by formulae II to IV, are the elements which directly complexes platinum.
- the intermediate complexing peptide of formula V may be prepared by routine amino acids addition. It is novel compound. The method for the preparation of the opioid peptide was described by Lipkowski et al. Bioorg. Med. Chem. Lett. 1999, 2763-2766.
- Novel peptide-platinum complexes are effective in the chemotherapy of tumors and they also exhibit analgesic effect, thereby simultaneously they control a pain associated with chemotherapy and neoplastic lesions.
- the present invention also provides a pharmaceutical composition for the treatment of tumors comprising as an active ingredient the novel peptide-platinum complexes of general formula I, as defined above, or their pharmaceutically acceptable salts and a therapeutically acceptable carrier.
- the compounds are preferably formulated in a suitable pharmaceutical composition using known additions such as a therapeutically acceptable carrier, diluent or auxiliaries.
- the invention relates to novel peptide-platinum complexes of formula I, defined above, or to their pharmaceutically acceptable salts for use in the treatment of tumors with simultaneous complete or partial blocking a conduction of the pain impulses as the result of affinity to the opioid receptors of peptide complexes.
- Novel compounds can take the form of intravenous infusions, subcutaneous implant or implant into body tissues that ensures the best access of released novel peptide-platinum complex to a site of treatment.
- Novel compounds can be administered singly as a substance or as an ingredient of multi-drugs composition of medicaments used in the therapy.
- the affinity to opioid receptors was evaluated accordingly to the test described by Misicka at al. in Life Sciences 51, 1025, 1992.
- Affinity test Homogenate of a rat brain is saturated with a standard of the opioid ligand, then the tested compound is added and amount of labeled compound displaced with the tested compound is measured.
- the anti-tumor activity was evaluated in the proliferation test. This test consists in counting proliferating tumor cells contained in culture comprising the tested compounds (and medium). The novel compounds resulted in distinct reduction of proliferation of the tumor cells T98G-human glioblastoma (about 50% after 4 days in comparison with the standard).
- Proliferation test for assessment of the effect of peptides on cell growth T98G cells were seeded into 35 mm diameter culture dishes (3xl05/dish) and peptides dissolved in medium were added at the concentration lO ⁇ M or 20 ⁇ M. Cell numbers were measured every day from day 4 by harvesting the cells using 0.25% trypsin-0.02% EDTA and counting in a hemacytometer chamber.
- Boc-Tyr-D-Ala-Gly-Phe-NH-NH ⁇ -Phe-NH 2 is coupled with Boc protected amino acids: Boc-Met-OH, Boc-Cys-OH and Boc-His-OH.
- Boc-Tyr-D-Ala-Gly-Phe-NH-NH ⁇ Phe ⁇ -Met-Boc, Boc-Tyr-D-Ala-Gly-Phe-NH- NH ⁇ -Phe ⁇ -Cys-Boc and Boc-Tyr-D-Ala-Gly-Phe-NH-NH ⁇ -Phe ⁇ His-Boc are prepared. Double-sided Boc protecting group is then removed from all peptides.
- the crude product is purified by a high performance liquid chromatography on C 18 column using system of solvents A and B H 2 O/ ACN: 0.05% TFA in H 2 O (A) and 0.05% TFA in ACN (B).
- ACN - acetonitrile, TFA - trifluoroacetic acid Tyr-D-Ala-Gly-Phe-NH-NH*-Phe ⁇ -Met(N,5)PtCl 2
- the crude product is purified by a high performance liquid chromatography on Ci g column using system of solvents A and B H 2 O/ACN: 0.05% TFA in H 2 O (A) and 0.05% TFA in ACN (B).
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Abstract
The novel peptide-platinum complexes of the general formula I: Tyr-D-Ala-Gly-Phe-NH-NH<- Phe<- AA-PtX2, wherein AA is a residue of methionine, cysteine, histidine, 1,3-diaminebutanoic acid or 1,4-diaminepentanoic acid, X is halogen or pharmaceutically acceptable salts thereof are disclosed. Also provided is a method for preparation of novel complexes comprising reacting peptide of general formula V: Tyr-D-Ala-Gly-Phe-NH-NH<- Phe<- A with Pt(II) compound. Using novel complexes as a medicament for treatment of tumors, showing simultaneously analgesic activity is also described.
Description
PEPTIDE-PLATINUM COMPLEXES, METHOD FOR PREPARATION AND
USE THE SAME
TECHNICAL FIELD
The present invention relates to novel peptide-platinum complexes, to their preparation, pharmaceutical composition and to use the same as medicament for treatment of tumors, especially in the form of infusions, intravenous injections or implants. BACKGROUND ART
While the treatment of tumors is still insufficiently effective, the use of platinum compounds resulted in a great improvement of chemotherapy efficiency. The main used compounds include cisplatin or analogs thereof. The use of platinum complexes such as cisplatin has been shown to be effective in the treatment of most advanced forms of tumors (Rosenberg, Cancer 1985, 55, 2303 2316; Prestayko et al., Cancer Treat. Rev. 1979, 6, 17 39).
However, known platinum compounds used up to the present induce a number of adverse reactions including vomiting, nephrotoxicity, neurotoxicity (Sleijfer et al., Pharm Weekbl Sci. 1985, 7, 237 244) and in particular a high level of pain. Side effects associated with the use of the known compounds necessitate heavy limiting their doses. Therefore, an application of various different novel compounds have been proposed, see, for example, US Patent No. 7,208,611.
There is a need for novel methods to control a pain associated with chemotherapy. The unique compounds reported here do this.
DISCLOSURE OF INVENTION
Unexpectedly, it has been found that the complex of opioid peptide and platinum maintaining both analgesic activity of peptide and therapeutic properties of platinum may be prepared. The present invention provides the new peptide-platinum complexes of the general formula I:
Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<- AA-PtX2 wherein:
AA is a residue of methionine, cysteine, histidine, 1,3-diaminebutanoic acid or 1,4- diaminepentanoic acid,
X is halogen, or pharmaceutically acceptable salts thereof.
Cl is preferred halogen.
Individual amino acids residues are marked in three-letter codes: Tyr denotes tyrosine, preferably L-tyrosine, D-AIa denotes D-alanine, GIy denotes glycine, Phe denotes phenylalanine, preferably L-phenylalanine.
The compounds of general formula I may be shown by formula Ia.
Ia Preferred compounds within the scope of formula I and Ia are those of formulae
II to IV:
II
III
IV or pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, lactic acid, malonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like.
The present invention further relates to a method for the preparation of the new peptide-platinum complexes of general formula I, as defined above, comprising reacting peptide of general formula V: Tyr-D-Ala-Gly-Phe-NH-NH<— Phe«— AA, optionally in the form of an acid addition salt, with Pt(II) compound. The obtained product may be, if necessary, converted into a desired pharmaceutically acceptable salt by a conventional method. Pt(II) compound can be, for example, haloplatinate(II).
The reaction is preferably carried out in an aqueous medium.
The essential feature of the method according to the invention is that the amino acid residues of methionine, cysteine or histidine chemically linked to an opioid peptide, as shown by formulae II to IV, are the elements which directly complexes platinum. This
is also shown by scheme: Tyr-D-Ala-Gly-Phe-NH-NH<— Phe<— AA-PtCl2 , wherein: AA = Met, Cys, His, 1,3-diaminebutanoic acid or 1 ,4-diaminepentanoic acid represents Pt(II) complexing fragment and Tyr-D-Ala-Gly-Phe-NH-NH<— Phe represents an opioid peptide. The intermediate complexing peptide of formula V may be prepared by routine amino acids addition. It is novel compound. The method for the preparation of the opioid peptide was described by Lipkowski et al. Bioorg. Med. Chem. Lett. 1999, 2763-2766.
Novel peptide-platinum complexes are effective in the chemotherapy of tumors and they also exhibit analgesic effect, thereby simultaneously they control a pain associated with chemotherapy and neoplastic lesions.
The present invention also provides a pharmaceutical composition for the treatment of tumors comprising as an active ingredient the novel peptide-platinum complexes of general formula I, as defined above, or their pharmaceutically acceptable salts and a therapeutically acceptable carrier.
Before administration the compounds are preferably formulated in a suitable pharmaceutical composition using known additions such as a therapeutically acceptable carrier, diluent or auxiliaries.
Other aspect of the invention includes the provision of novel peptide-platinum complexes of formula I, defined above, or their pharmaceutically acceptable salts for use in the treatment of tumors.
Particularly, the invention relates to novel peptide-platinum complexes of formula I, defined above, or to their pharmaceutically acceptable salts for use in the treatment of tumors with simultaneous complete or partial blocking a conduction of the pain impulses as the result of affinity to the opioid receptors of peptide complexes.
Novel compounds can take the form of intravenous infusions, subcutaneous implant or implant into body tissues that ensures the best access of released novel peptide-platinum complex to a site of treatment.
Novel compounds can be administered singly as a substance or as an ingredient of multi-drugs composition of medicaments used in the therapy.
To better illustrate the present invention, there are provided the examples showing the method for the preparation of the new peptide-platinum complexes, characteristic of their affinity to the opioid receptors and anti-tumor properties. The
scope of the present invention should not be limited to the content of the examples below.
The affinity to opioid receptors (δ and μ) was evaluated accordingly to the test described by Misicka at al. in Life Sciences 51, 1025, 1992. Affinity test: Homogenate of a rat brain is saturated with a standard of the opioid ligand, then the tested compound is added and amount of labeled compound displaced with the tested compound is measured.
The anti-tumor activity was evaluated in the proliferation test. This test consists in counting proliferating tumor cells contained in culture comprising the tested compounds (and medium). The novel compounds resulted in distinct reduction of proliferation of the tumor cells T98G-human glioblastoma (about 50% after 4 days in comparison with the standard).
Proliferation test: for assessment of the effect of peptides on cell growth T98G cells were seeded into 35 mm diameter culture dishes (3xl05/dish) and peptides dissolved in medium were added at the concentration lOμM or 20μM. Cell numbers were measured every day from day 4 by harvesting the cells using 0.25% trypsin-0.02% EDTA and counting in a hemacytometer chamber.
MODES FORCARRYING OUT THE INVENTION Synthesis of complexing peptides
Boc-Tyr-D-Ala-Gly-Phe-NH-NH<-Phe-NH2 is coupled with Boc protected amino acids: Boc-Met-OH, Boc-Cys-OH and Boc-His-OH.
(Boc - tertbutyloxycarbonyl).
Boc-Tyr-D-Ala-Gly-Phe-NH-NH^Phe<-Met-Boc, Boc-Tyr-D-Ala-Gly-Phe-NH- NH^-Phe<-Cys-Boc and Boc-Tyr-D-Ala-Gly-Phe-NH-NH^-Phe^His-Boc are prepared. Double-sided Boc protecting group is then removed from all peptides.
Deblocking Boc: IN HCl in acetic acid or ethyl acetate is added and after 20 minute cold diethyl ether is added to precipitate the product
Dihydrochloride peptide products 2HClxTyr-D-Ala-Gly-Phe-NH-NH^Phe<-Met- NH2; 2HClxTyr-D-Ala-Gly-Phe-NH-NH<-Phe^Cys-NH2, 2HClxTyr-D-Ala-Gly-
Phe-NH-NH<— Phe<— HiS-NH2 precipitated from the reaction mixture with diethyl ether
are filtered off and the compounds for complexing reaction with K2[PtCl4] salt having stated below physico-chemical data and formulae VI - VIII are obtained:
VI Tyr-D-Ala-Gly-Phe-NH-NH÷-Phe^Met
M = 748.3 Da, [M + 2HC1] = 820.3 Da
ESI MS [M + H+] Calculated: 749.3 Da, Found: 749.1 Da
[M + Na+] Calculated: 771.8 Da, Found: 772 Da
[M + 2H+] /2 Calculated: 375.2 Da, Found: 375 Da
RP HPLC column C12 tR= 5.36 min
RP HPLC column Cl 8 tR= 9.6 min
VII Tyr-D-Ala-Gly-Phe-NH-NH^-Phe^Cys
M = 720.3 Da, [M + 2HC1] = 792.3 Da [M + H+] Caculated: 721.3 Da, Found: 721.1 Da
[M + 2H+] /2 Calculated: 361.1 Da, Found: 361 Da RP HPLC column Cl 8 tR= 6.7 min
68
VIII Tyr-D-Ala-Gly-Phe-NH-NH÷-Phe^-His
M = 754.35 Da, [M + 2HC1] = 826.3 Da [M + H+] Calculated: 755.35 Da, Found: 755.3 Da,
[M + 2H+] /2 Calculated: 378.18 Da, Found: 378 Da. RP HPLC column C12 tR= 3.9 min RP HPLC column Cl 8 tR= 8.2 min
Example 1. Preparation of Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Met(S,N)PtCI2
(structural formula II) and its properties.
74 mg (1.7XlO-4 M) Of K2[PtCl4] is added to the solution of 133 mg (lJxlO"4 M) of 2HClxTyr-D-Ala-Gly-Phe-NH-NH^Phe^Met in 10 ml of distilled water. The resulting suspension is stirred at room temperature for 3 days. After filtering off a precipitate, the filtrate is evaporated to dryness using an evaporator and a crude product is obtained. Yield: 94 mg (56%).
The crude product is purified by a high performance liquid chromatography on C18 column using system of solvents A and B H2O/ ACN: 0.05% TFA in H2O (A) and 0.05% TFA in ACN (B). (ACN - acetonitrile, TFA - trifluoroacetic acid) Tyr-D-Ala-Gly-Phe-NH-NH*-Phe^-Met(N,5)PtCl2
M = 1013.23 Da, [M + HCl] = 1049.21 Da [M + H+] Caculated: 1014.23 Da, Found: 1014.3 Da, [M-(C1>H+] Calculated: 979.27 Da, Found: 979.23 Da. RP HPLC column C12 tRi = 8.73 min, X91 = 9.28 RP HPLC column Cl 8 tR= 10.9 min
The compound shows an affinity to μ type opioid receptors on a level corresponding with morphine (Ki=6.2 nM) and slightly lower affinity to the δ type opioid receptors (Ki=104nM).
In the test of tumor cells proliferation of glioblastoma the compound in concentration of 20mM/L reduced the amount of cell fission to 50% of that occured in control culture.
Example 2. Preparation of Tyr-D-Ala-Gly-Phe-NH-NH^-Phe^Cys(S,N)PtCl2
(structural formula III) and its properties 8.6 mg (2xlO"5M) of K2[PtCl4] is added to the solution of 15 mg of (2xlO'5M)
2HClxTyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Cys in 2 ml of distilled water. Precipitate is formed. The suspension is stirred at room temperature for 6 days. After filtering off a precipitate, the filtrate is evaporated to dryness and 15.3 mg of a contaminated product is obtained in the form of yellow crystalline precipitate. Yield: 15.3 mg. The crude product is purified by a high performance liquid chromatography on C18 column using system of solvents A and B H2(VACN: 0.05% TFA in H2O (A) and 0.05% TFA in ACN (B).
M = 985.2 Da, [M + HCl] = 1021.2 Da [M + Na+] Calculated: 1008.19 Da, Found: 1008.06 Da, [M-(Cr)+H+] Calculated: 951.23 Da, Found: 951.42 Da [M-(2C1")+H+] Calculated: 915.26 Da, Found: 914.47 Da. RP HPLC column C18 tR= 13.1 min
The compound shows an affinity to μ type opioid receptors on a level corresponding with morphine (Ki=7.9nM), and slightly lower affinity to the δ type opioid receptors (Ki=90nM).
In the test of tumor cells proliferation of glioblastoma the compound in concentration of 20mM/L reduced the amount of cell fission to 50% of that occured in control culture.
Example 3. Preparation of Tyr-D-Ala-Gly-Phe-NH-NH-Phe-His(N,N)PtCl2
(structural formula IV) and its properties
43 mg (LIxIO"5 M) Of K2[PtCl4] is added the solution of 79 mg (UxIO"5 M) 2HClxTyr-D-Ala-Gly-Phe-NH-NH<-Phe<-His in 7 ml of distilled water. Pale-beige precipitate is formed. The suspension is stirred at room temperature for 4 days. After filtering off a precipitate, the filtrate is evaporated to dryness using an evaporator and a crude product is obtained. Yield: 92 mg (92%). The crude product is purified by a high performance liquid chromatography on Ci g column using system of solvents A and B H2O/ACN: 0.05% TFA in H2O (A) and 0.05% TFA in ACN (B). HCl*Tyr-D-Ala-Gly-Phe-NH-NH^Phe^His(N,iV)PtCl2
M = 1019.26 Da, [M + HCl] = 1057.28 Da [M + H+] Calculated: 1020.26 Da, Found: 1020.25 Da, [M-(C1")+H+] Calculated: 984.28Da, Found: 984 Da. RP HPLC column C12 tR1 = 6.61 min, tw = 6.76 min RP HPLC column Cl 8 tR= 10.2 min
The compound shows an affinity to μ type opioid receptors on a level corresponding with morphine (11.2nM) and slightly lower affinity to the δ type opioid receptors (Ki=I 12nM).
In the test of tumor cells proliferation of glioblastoma the compound in concentration of 20mM/L reduced after 4 days the amount of cell fission to 50% of that occured in control culture.
Claims
1. A peptide-platinum complex of the general formula I: Tyr-D-Ala-Gly-Phe-NH- NH^Phe«-AA-PtX2 wherein:
AA is a residue of methionine, cysteine, histidine, 1,3-diaminebutanoic acid or 1,4- diaminepentanoic acid, X is halogen or a pharmaceutically acceptable salt thereof.
2. A peptide-platinum complex according to claim 1, which is compound selected from the group consisting of compound of formula II, compound of formula III and compound of formula IV:
II
III 
IV
3. A method for the preparation of a peptide-platinum complex of general formula I as defined in claim 1, comprising reacting peptide of general formula V: Tyr-D-Ala- Gly-Phe-NH-NH<— Phe*— AA, optionally in the form of an acid addition salt, with Pt(II) compound.
4. A pharmaceutical composition for the treatment of tumors comprising an active ingredient and a therapeutically acceptable carrier, characterised in that the active ingredient is a peptide-platinum complex of general formula I as defined in claim 1.
5. A peptide-platinum complex of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof for use in the treatment of tumors.
6 The peptide-platinum complex according to claim 5 for use in the form of intravenous infusions, subcutaneous implant or implant into body tissues.
7. The peptide-platinum complex according to claim 5 for use as a substance or as an ingredient of multi-drugs composition of medicaments used in the therapy.
8. The peptide-platinum complex according to claim 5 selected from the group consisting of compound of formula II, compound of formula III and compound of formula IV.
9. A peptide-platinum complex of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof for use in the treatment of tumors with simultaneous complete or partial blocking a conduction of the pain impulses as the result of affinity to the opioid receptors of peptide complex.
10. The peptide-platinum complex according to claim 9 for use in the form of intravenous infusions, subcutaneous implant or implant into body tissues.
11. The peptide-platinum complex according to claim 9 for use as a substance or as an ingredient of multi-drugs composition of medicaments used in the therapy.
12. The peptide-platinum complex according to claim 9 selected from the group consisting of compound of formula II, compound of formula III and compound of formula IV.
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|---|---|---|---|
| PLP383412 | 2007-09-24 | ||
| PL383412A PL208164B1 (en) | 2007-09-24 | 2007-09-24 | New peptide complexes of platinum, the manner of obtaining them, pharmaceutical composition and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699847A (en) * | 2017-01-04 | 2017-05-24 | 陕西慧康生物科技有限责任公司 | Method for purifying argireline at low cost |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014943A2 (en) * | 2002-08-13 | 2004-02-19 | Lipkowski Andrzej W | Biphalin derivates and their analgesic applications |
| US20060205677A1 (en) * | 2005-02-23 | 2006-09-14 | Xenoport, Inc. | Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use |
| US20070010427A1 (en) * | 2005-07-07 | 2007-01-11 | Cancure Laboratories, Llc | Use of one or more metal carriers to selectively kill mammalian cells |
-
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- 2007-09-24 PL PL383412A patent/PL208164B1/en unknown
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- 2008-09-23 WO PCT/PL2008/000068 patent/WO2009041841A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014943A2 (en) * | 2002-08-13 | 2004-02-19 | Lipkowski Andrzej W | Biphalin derivates and their analgesic applications |
| US20060205677A1 (en) * | 2005-02-23 | 2006-09-14 | Xenoport, Inc. | Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use |
| US20070010427A1 (en) * | 2005-07-07 | 2007-01-11 | Cancure Laboratories, Llc | Use of one or more metal carriers to selectively kill mammalian cells |
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| Title |
|---|
| LIPKOWSKI A W ET AL: "Biological activity of fragments and analogues of the potent dimeric opioid peptide, biphalin", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 9, no. 18, 20 September 1999 (1999-09-20), pages 2763 - 2766, XP004179967, ISSN: 0960-894X * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699847A (en) * | 2017-01-04 | 2017-05-24 | 陕西慧康生物科技有限责任公司 | Method for purifying argireline at low cost |
| CN106699847B (en) * | 2017-01-04 | 2020-08-14 | 陕西慧康生物科技有限责任公司 | Method for purifying hexapeptide at low cost |
Also Published As
| Publication number | Publication date |
|---|---|
| PL383412A1 (en) | 2009-03-30 |
| PL208164B1 (en) | 2011-03-31 |
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