GB2143128A - Antineoplastic organogermanium compounds - Google Patents
Antineoplastic organogermanium compounds Download PDFInfo
- Publication number
- GB2143128A GB2143128A GB08416634A GB8416634A GB2143128A GB 2143128 A GB2143128 A GB 2143128A GB 08416634 A GB08416634 A GB 08416634A GB 8416634 A GB8416634 A GB 8416634A GB 2143128 A GB2143128 A GB 2143128A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- group
- compounds
- antineoplastic
- antineoplastic agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/30—Germanium compounds
Abstract
An antineoplastic composition containing an organogermanium compound of the general formula: <IMAGE> wherein A represents a hydrogen atom, a lower alkyl group such as a methyl or ethyl group or a phenyl group, B represents a hydrogen atom, or a lower alkyl group such as a methyl or ethyl group and Z represents a hydroxyl or amino group.
Description
SPECIFICATION
Antineoplastic agent
BACKGROUND OF THE INVENTION
Field of the Invention:
The present invention relates to antineoplastic agent containing an organogermanium compound as a principal ingredient.
Description of the Prior Art
Germanium (Ge), which is a metal and known as a homologue of carbon, has semiconductive effect like silicon (Si) as a special property and, in addition, it has been studied in this aspect for a long time.
Recently the studies of organogermanium compounds have been advanced and the results thereof have been reported and they have attracted public attention in various technical fields, particularly medical field. For example, it is well known in the medical and pharmaceutical fields that carboxyethylgermanium sesquioxide of the formula (GeCH2CH2COOH)203, has quite excellent physiological effects such as strong hypotensive and antineoplastic effects and it is free from toxicity or adverse reaction.
Further, compounds analogous to the sesquioxide type compounds represented by above mentioned carboxyethylgermanium sesquioxide have been studied intensively. A sesquisulfide type compounds (Ge-C-C-CO-)2S3 having the same structure as that of the above compound, except that oxygen atoms bonded alternately with germanium atoms to make the compound as a reticulate, macromolecular compound are replaced with sulfur atoms having similar bonding properties, has been synthesized by one of the inventors of the present invention. This type of compounds and a process for the preparation thereof have been applied for patent (see Japanese Patent Application No.
203090/1982). Though the mechanism of the physiological activity of the sesquioxide type compounds have not fully been elucidated yet, it has been believed generally that those effects are realized by the germanium-oxygen bond contained in the structure. Therefore, it is expected that sesquisulfide type compounds having the same structure as that of the sesquioxide type compounds except that the oxygen atom in the reticulate bond is replaced with a sulfur atom which is a homologue of oxygen have also excellent physiological activities.
After intensive investigations made under these circumstances, the inventors of the present invention have found that some of the organogermanium compounds of sesquisulfide type have quite strong antineoplastic effects. The present invention has been completed on the basis of this finding.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an antineoplastic agent which comprises as a principal ingredient an organogermanium compound of the general formula:
wherein A represents a hydrogen atom, a lower alkyl group which as a methyl or ethyl group, or a phenyl group, B represents a hydrogen atom or a lower alkyl group such as a methyl or ethyl group and
Z represents a hydroxyl or amino group.
Detailed Description of the Preferred Embodiments
The antineoplastic agent of the present invention contains an organogermanium compound of the general formula (I) as the principal ingredient as described above. This type of compound has a fundamental structure comprising a germylpropionic acid derivative containing a germanium atom and a propionic acid residue having an oxygen-containing functional group CO-Z. In this molecular compound, above germylpropionic acid derivative and sulfur atoms are bonded alternately in a ratio of 2/3. The substituent A in the above general formula (I) is a hydrogen atom, a lower alkyl group such as a methyl, ethyl, propyl or isopropyl group or a substituted phenyl group. The substituent B is a hydrogen atom or a lower alkyl group as mentioned in the substituent A.The substituent A is arranged in ct-position and substituent B is B-position, to the germanium atom, respectively.
The substituent Z with reference to the oxygen-containing functional group is a hydroxyl group (-OH) or an amino group (-N H2). Therefore, the organogermanium compounds being used as the principal ingredient of the antineoplastic agent of the present invention include, for example, the following compounds:
The organogermanium compounds having above mentioned structure may be synthesized by various processes.For example, a process disclosed in the specification of the above Japanese Patent
Laid-Open No. 203090/1982 comprises addition of trichlorogermane HGeCI3 to an acrylic acid derivative (II) to form a trichlorogermylpropionic acid derivative (III), reaction of this derivative (III) with hydrogen sulfide in the presence of a base under an anhydrous condition to form a trimercapto compound (IV) and intermolecular removing of hydrogn sulfide from this trimercapto compound (IV), according to the following reaction scheme:
wherein the symbols A, B and Z have the same meaning as referred above.
It is preferable in some of the compounds, especially when the substituent Z is NH2, to start with a substituted or unsubstituted acrylic acid [a compound of the formula (II) in which Z = -OH], instead of a substituted acrylamide [a compound of the formula (II) in which Z is NH2], because the amide is generally expensive and not easily available in commerce and undesirable side reactions may occur while the addition reaction thereof with the trichlorogermane proceeds, as shown in the following reaction scheme:
In both of the above mentioned processes, the trimercapto compound (IV) formed by the reaction with hydrogen sulfide may be either isolated not.
The organogermanium compounds of the general formula (I), including the compounds (1 ) to (7) obtained by the above process are generally colorless, transparent crystals. The antineoplastic agent of the present invention containing the organogermanium compound as the principal ingredient may be formulated into tablets, powder, granule, capsules, and the like by a known method.
The antineoplastic agent of the present invention formulated as above is administered to patients bearing various tumors to inhibit the growth of carcinoma or to overcome the same. However, it is difficult to confirm the pharmacological effects of the antineoplastic effects of the present invention by actually administering them to the patient, since various problems are involved in such a test The doses and effects of them were, therefore, proved by biological experiments.
An organogermanium compound was suspended in water and administered perorally to mice, to
which 1 x 106 IMC carcinoma cells had been transplanted subcutaneously, for a given period of time.
The antineoplastic agents of the present invention inhibited the growth of the IMC carcinoma well as shown in Table (1).
TABLE 1
Number Wt. Ratio + Number Wt. of cardnoma | Inhibition Compound Dose Wt Ratio * of mice (average + S.D) rate (%) | t value P Control > \ 20 1A9+0.53 10 10 0.0258 10 1.29 + 0.34 - 1.082 (1) 2 0.0052 ~ 10 1.56 + 0.56 13.6 0.335 50 0.1205 10 1.03+0.31 31 2.427 * (2) 10 0.0241 10 1.06 + 0.39 29 2.276 * 2 0.0048 10 1.10+0.32 26.0 2.130 * 10 10 0.0241 10 1.08+0.29 28 2.270 * (3) 2 0.0048 10 1.06 + 0.39 29 2.269 * 100 100 0.2257 10 1.17 + 0.51 21 1.578 (4) 10 0.0226 10 1.30+oat 0.40 13 0.997 50 50 0.0928 10 1.19 + 0.67 20 1.339 (5) 2 0.0037 10 1.63 + 0.76 0.589 50 50 0.1299 10 1.23+0.46 17 1.320 (6) 2 0.0052 10 1.22+0.31 18 1.481 25 0.0466 10 0.65 + 0.31 56 4.608 ** (7) 5 0.0093 10 0.76 + 0.32 49 3.987 ** 1 0.0019 10 1.17 + 0.48 21 1.606 * Dose/chemical formula wt. of each compound * = P < 0.05 ** = P < 0.01
It is true that the weight of the carcinoma after the administration of (GeCH2CH2COOH)203, which was mentioned above as a typical example of the sesquioxide type compounds in the amount of 100 mg/kg/day is 0.95, but the amount ratio (dose/chemical formula weight) was high as about 0.3215. Thus, it is apparent that the antineoplastic agents of the present invention inhibit the growth of the IMC carcinoma remarkably.
The physiological mechanism of a tumor in human bodies is quite complicated, since various factors are concerned therewith. From the results shown in Table (1), it is expected that when an antineoplastic agent of the present invention containing the compound (7) as the principal ingredient is administered to human in a dose of 1 mg/kg/day (50 mg/day for human weighing 50 kg), an inhibition rate equivalent to that obtained in the mice will be obtained.As the dose of the above mentioned sesquioxide compounds being used practically for the treatment of cancer is about 500 to
2000 mg/day, and, the LDso value, depending on the kind of the organo germanium compound, of the
compound (7) is as large as 560 mg/day, therefore, even the upper limit of the dose will be far lower than the LDsol and the antineoplastic agent of the present invention which can be administered perorally
can be used for the treatment of tumors in human bodies.
The following examples will further illustrate the present invention.
EXPERIMENTAL EXAMPLE 1
Synthesis of organogermanium compound:
(1) Synthesis of compound (1)
25.2 g (0.1 mol) of 2-carboxyethyltrichlorogermane Cl3GeCH2CH2COOH was dissolved in 200 ml
of anhydrous benzene. 24 g (0.1 mol) of anhydrous pyridine was added to the solution and the mixture was stirred. Then, dry hydrogen sulfide gas was introduced therein for 60 min. Benzene was removea carefully from the resulting oily product and then the residue was dissolved in 100 ml of methanol. The solution was added to 300 ml of purified water and crystals thus formed were recrystallized from methanol to obtain 16.8 g of 2-carboxyethylgermanium sesquisulfide (1) (GeCH2CH2COOH)2S3 in the form of colorless plate. Yield was 86.7%.
Melting point: 2000C (calculated from DTA spectrum)
Solubilities: easily soluble in DMSO, dioxane, THF and acetone.
Elementary analysis as Ge2C6H,004S3: Ge C H S
calculated: 37.44 18.61 2.62 24.83
found: 37.21 18.69 2.68 24.89
IR (KBr, cm-l) 3420, 1707,425 NMR (dioxane-d8, a)1.97, 2.57 (2) Synthesis of compounds (2) to (7):
These compounds were synthesized in the same manner described above. The physical properties of the compounds (2) to (5) are shown in Table (2) and those of the compounds (6) and (7) are shown in
Table (3).
TABLE 2
Elementary analysis Compound calcd./found m.p. IR (KBr, cm-1) Solvent NMR (#) Yield Ge C H S 34.92 23.13 3.40 23.16 185(dec) 3450, 2960, 1705, 1405, CD3OD 1.36(3H,d,J=7Hz,-CH-CH3), 5.77 (2) 1240, 1220, 610, 425 2.08~2.95(3H,m,-CH-CH2) 35.45 23.17 3.39 23.34 34.92 23.13 3.40 23.15 196(dec) 3450, 2980, 1705, 1465, CD3OD 1.38(3H,d,J=7.5Hz,CH=CH3), 93.8 (3) 1420, 1245, 760, 425 2.03(2H,m,J=45Hz,Ge-CH2), 35.20 22.29 3.45 22.96 2.94(1H,m,J=29Hz,CH=CO) 32.73 27.07 4.09 21.68 235(dec) 3400, 2960, 1700, 1445, CD3OD 1.37(3H,dd,J=12Hz,CO-CH-CH3), 72.1 (4) 1225, 820, 680, 600, 425 1.37(3H,dd,J=12Hz,Ge-CH-CH3), 32.50 27.13 4.02 21.92 2.18(1H,m,J=28.5Hz,CH-CO), 2.80(1H,m,J=28.5Hz,Ge-CH) 26.90 40.06 3.36 17.82 265(dec) 3450, 3040, 2850, 1710 CD3OD 3.00(2H,d,J=8Hz,CH2-CO), (5) 1600, 1410, 1230, 700, 425 94.1 26.41 40.32 3.54 17.86 3.55(1H,t,J=16Hz,Ge-CH-), 7.25(5H,m,-C6H5) TABLE 3
Elementary analysis Compound calcd./found m.p. IR (KBr, cm-1) Solvent NMR (#) Yield Ge C H N S 37.66 18.69 3.14 7.27 24.94 203(dec) 3300, 3200, 1665, DMF-d7 1.97(2H,t,J=15Hz,Ge-CH2), 27.5 (6) 1400, 1020, 600, 2.50(2H,t,J=15Hz,CH2-CO), 38.00 18.86 3.20 7.08 24.90 210(dec) 425 7.10(2H,d,J=60Hz,-NH2) 27.00 40.20 3.75 5.21 17.89 3450, 3350, 3200, DMF-d7 2.43(1H,t,J=14Hz,Ge-CH), 81.8 (7) 1660, 1600, 1400, 3.05(2H,d,J=7Hz,CH2-CO), 27.26 40.34 3.93 5.18 17.66 765, 700, 420 7.23(5H,m,-C6H5) EXPERIMENTAL EXAMPLE 2
Tumor-suppressing effects of the antineoplastic agents of the present invention:
Female CDF, mice of 9 weeks old were used. Each group consisted of 10 mice but control group consisted of 20 mice. 1 x 108 lMC carcinoma cells were transplanted to each of them subcutaneously.
From the next day, an antineoplastic agent of the present invention containing the organogermanium compound of the general formula (I) as the principal ingredient was administered perorally in a dose of the organogermanium compound of 1 to 100 mg/kg/day for 5 days and then the administration was stopped for one day. This cycle was repeated three times. Two days after the final administration, the mice were sacrificed and the carcinoma in each mouse was weighed to obtain the results shown in
Table (1).
Claims (5)
1. An antineoplastic agent which comprises as a principal ingredient an organogermanium compound of the general formula:
wherein A represents a hydrogen atom, a lower alkyl group or a phenyl group, B represents a hydrogen atom or a lower alkyl group and Z represents a hydroxyl or amino group.
2. An antineoplastic agent as claimed in claim 1, wherein A is a methyl or ethyl group.
3. An antineoplastic agent as claimed in claim 1 or claim 2, wherein B is a methyl or ethyl group.
4. An antineoplastic agent as claimed in any of the preceding claims, formulated as tablets, powder, granules or capsules.
5. An antineoplastic agent as claimed in claim 1 and substantially as hereinbefore described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58125726A JPS6016924A (en) | 1983-07-11 | 1983-07-11 | Antineoplastic agent |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8416634D0 GB8416634D0 (en) | 1984-08-01 |
GB2143128A true GB2143128A (en) | 1985-02-06 |
GB2143128B GB2143128B (en) | 1987-05-20 |
Family
ID=14917251
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08416634A Expired GB2143128B (en) | 1983-07-11 | 1984-06-29 | Antineoplastic organogermanium compounds |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPS6016924A (en) |
CH (1) | CH661661A5 (en) |
DE (1) | DE3425404A1 (en) |
FR (1) | FR2549066B1 (en) |
GB (1) | GB2143128B (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2158070A (en) * | 1984-04-25 | 1985-11-06 | Asai Germanium Res Inst | Antioxidant |
GB2190835A (en) * | 1984-12-18 | 1987-12-02 | Asai Germanium Res Inst | Resistance imparting agent for cold syndrome |
FR2600251A1 (en) * | 1986-06-18 | 1987-12-24 | Asai Germanium Res Inst | OSTEOBLAST ACTIVATOR MEDICINES CONTAINING ORGANOGERMANIC COMPOUNDS |
US4772628A (en) * | 1985-12-28 | 1988-09-20 | Asai Germanium Research Institute | Organogermanium compound and antitumor agent composed mainly of this compound |
GB2211410A (en) * | 1987-10-29 | 1989-07-05 | Asai Germanium Res Inst | Germanium compounds for reducing nephrotoxicity of cyclosporin |
GB2211411A (en) * | 1987-10-29 | 1989-07-05 | Asai Germanium Res Inst | Germanium compounds for improving reduced functions of organs caused by inhibited blood circulation |
US4973553A (en) * | 1987-09-09 | 1990-11-27 | Asai Germanium Research Institute | Salt or organogermanium compound and medicine containing the same |
GB2233898A (en) * | 1989-07-20 | 1991-01-23 | Asai Germanium Res Inst | Ophthalmic compositions containing organo-germanium compounds |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01117801A (en) * | 1987-10-29 | 1989-05-10 | Asai Gerumaniumu Kenkyusho:Kk | Washing and preserving solution for separated organ |
JP2652556B2 (en) * | 1988-08-29 | 1997-09-10 | 株式会社浅井ゲルマニウム研究所 | Organic germanium compound and method for producing the same |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1257225A (en) * | 1968-03-29 | 1971-12-15 | ||
EP0016444A1 (en) * | 1979-03-15 | 1980-10-01 | Asai Germanium Research Institute | Method and agent for inducing an interferon |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4271084A (en) * | 1978-03-01 | 1981-06-02 | Ryuichi Sato | Germanium-containing organic polymer and the process for the production of the same |
JPS5935916B2 (en) * | 1981-06-09 | 1984-08-31 | 紀博 柿本 | Organic germanium compound and its manufacturing method |
JPS58174391A (en) * | 1982-04-07 | 1983-10-13 | Daiichi Yakuhin Sangyo Kk | Tetrakis(1-(n-carboxymethylcarbamoyl)ethylmercapto) germane and preparation thereof |
-
1983
- 1983-07-11 JP JP58125726A patent/JPS6016924A/en active Granted
-
1984
- 1984-06-29 GB GB08416634A patent/GB2143128B/en not_active Expired
- 1984-07-10 DE DE19843425404 patent/DE3425404A1/en active Granted
- 1984-07-10 CH CH3344/84A patent/CH661661A5/en not_active IP Right Cessation
- 1984-07-11 FR FR8411038A patent/FR2549066B1/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1257225A (en) * | 1968-03-29 | 1971-12-15 | ||
EP0016444A1 (en) * | 1979-03-15 | 1980-10-01 | Asai Germanium Research Institute | Method and agent for inducing an interferon |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2158070A (en) * | 1984-04-25 | 1985-11-06 | Asai Germanium Res Inst | Antioxidant |
US5071873A (en) * | 1984-04-25 | 1991-12-10 | Asai Germanium Research Institute | Antioxidant |
GB2190835B (en) * | 1984-12-18 | 1990-06-06 | Asai Germanium Res Inst | Resistance imparting agent for cold syndrome of low pulmonary function patients |
GB2190835A (en) * | 1984-12-18 | 1987-12-02 | Asai Germanium Res Inst | Resistance imparting agent for cold syndrome |
US4772628A (en) * | 1985-12-28 | 1988-09-20 | Asai Germanium Research Institute | Organogermanium compound and antitumor agent composed mainly of this compound |
FR2600251A1 (en) * | 1986-06-18 | 1987-12-24 | Asai Germanium Res Inst | OSTEOBLAST ACTIVATOR MEDICINES CONTAINING ORGANOGERMANIC COMPOUNDS |
US4973553A (en) * | 1987-09-09 | 1990-11-27 | Asai Germanium Research Institute | Salt or organogermanium compound and medicine containing the same |
GB2211410A (en) * | 1987-10-29 | 1989-07-05 | Asai Germanium Res Inst | Germanium compounds for reducing nephrotoxicity of cyclosporin |
US4919917A (en) * | 1987-10-29 | 1990-04-24 | Asai Germanium Research Institute Co., Ltd. | Agent for reducing nephrotoxicity caused by cyclosporin administration |
US5006553A (en) * | 1987-10-29 | 1991-04-09 | Asai Germanium Research Institute Co., Ltd. | Agent for improving reduced functions of organs caused by inhibited blood circulation |
GB2211410B (en) * | 1987-10-29 | 1991-06-12 | Asai Germanium Res Inst | Organogermanium compounds for reducing the nephrotoxicity caused by cyclosporin administration |
GB2211411B (en) * | 1987-10-29 | 1991-07-10 | Asai Germanium Res Inst | Organogermanium compounds for improving the reduced function of organs caused by inhibited blood circulation |
GB2211411A (en) * | 1987-10-29 | 1989-07-05 | Asai Germanium Res Inst | Germanium compounds for improving reduced functions of organs caused by inhibited blood circulation |
GB2233898A (en) * | 1989-07-20 | 1991-01-23 | Asai Germanium Res Inst | Ophthalmic compositions containing organo-germanium compounds |
US5118679A (en) * | 1989-07-20 | 1992-06-02 | Asai Germanium Research Institute Co., Ltd. | Agent for preventing and treating opacity of lens |
GB2233898B (en) * | 1989-07-20 | 1993-06-16 | Asai Germanium Res Inst | Agent for preventing and treating opacity of the lens |
Also Published As
Publication number | Publication date |
---|---|
JPS6158449B2 (en) | 1986-12-11 |
JPS6016924A (en) | 1985-01-28 |
GB2143128B (en) | 1987-05-20 |
DE3425404A1 (en) | 1985-01-31 |
GB8416634D0 (en) | 1984-08-01 |
CH661661A5 (en) | 1987-08-14 |
FR2549066A1 (en) | 1985-01-18 |
DE3425404C2 (en) | 1987-03-05 |
FR2549066B1 (en) | 1988-07-15 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20030629 |