HK1005875B - N-oxycarbonyl substituted 5'-deoxy-5-fluorocytidines - Google Patents
N-oxycarbonyl substituted 5'-deoxy-5-fluorocytidines Download PDFInfo
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- HK1005875B HK1005875B HK98105008.2A HK98105008A HK1005875B HK 1005875 B HK1005875 B HK 1005875B HK 98105008 A HK98105008 A HK 98105008A HK 1005875 B HK1005875 B HK 1005875B
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Description
The present invention relates to N⁴-(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine derivatives, and a pharmaceutical composition containing the same for treating tumors.
More particularly, the present invention relates to N⁴-(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine derivatives represented by the general formula (I),
wherein R¹ is n-propyl, n-butyl, n-pentyl, isopentyl, neopentyl, 3,3-dimethylbutyl, n-hexyl, 2-ethylbutyl, phenylethyl, and cyclohexylmethyl; and R is a hydrogen atom or a radical easily hydrolyzable under physiological conditions,
as well as hydrates or solvates of the compounds of the general formula (I), and a pharmaceutical composition containing the same with excellent pharmacokinetic profiles for treating tumors with high safety margin.
It is known that many precursors of 5-fluorouracil (5-FU) are useful as antitumor agents, but in general their bioconversion efficiency is still insufficient for the treatment of patients suffering from tumors and they cause intestinal toxicities and immunosuppressive toxicities, which are their major and dose limiting toxicities.
USP 4,966,891 discloses precursors of 5-FU which are improved in the above mentioned aspect of bioconversion efficiency and toxicities. They are converted to 5'-deoxy-5-fluorocytidine (5'-DFCR) by acylamidases, to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase, and then to 5-FU by pyrimidine nucleotide phosphorylase in vivo which is preferentially localized in the liver, small intestin and tumor tissues. During intensive studies on the pharmacokinetic profiles of the precursors of 5-FU, particularly of N⁴-(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine derivatives, the inventors found that certain specific precursors are selectively converted into 5'-DFCR by an acylamidase isozyme that is preferentially located at the liver but not the other organs of humans, and exhibited more improved pharmacokinetic profiles than the other compounds tested. The further studies based on the above findings enabled the inventors of the present invention to identify that the specific N⁴-(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine derivatives (hereinafter referred to as N⁴-(substituted-oxycarbonyl)-5'-DFCR) represented by the above mentioned general formula (I) have selectively improved pharmacokinetic profiles in monkeys, viz. 4 to 7 times higher maximum concentration (Cmax) of 5'-DFUR and 4 times larger higher area under the curve (AUC) of 5'-DFUR in blood than the other compounds, and less intestinal toxicity.
The term "a radical easily hydrolyzable under physiological condition" preferably signifies acetyl, propionyl, benzoyl, toluoyl, β-alanyl, valyl, and the like.
Preferred N⁴-(substituted-oxycarbonyl)-5'-DFCRs of the present invention are:
- 5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine,
- N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine,
- 5'-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine,
- 5'-deoxy-5-fluoro-N⁴-(hexyloxycarbonyl)cytidine,
- 5'-deoxy-5-fluoro-N⁴-(isopentyloxycarbonyl)cytidine,
- 5'-deoxy-5-fluoro-N⁴-(neopentyloxycarbonyl)cytidine,
- 5'-deoxy-N⁴-[(3,3-dimethylbutoxy)carbonyl]-5-fluorocytidine,
- 5'-deoxy-N⁴-[(2-ethylbutoxy)carbonyl]-5-fluorocytidine,
- N⁴-[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine,
- 5'-deoxy-5-fluoro-N⁴-[(2-phenylethoxy)carbonyl]cytidine,
- 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine,
- 2',3'-di-O-acetyl-N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine,
- 2',3'-di-O-benzoyl-N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine,
- 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine,
- 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(isopentyloxycarbonyl)-cytidine,
- 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(hexyloxycarbonyl)-cytidine,
- 2',3'-di-O-acetyl-5'-deoxy-N⁴-[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,
- 2',3'-di-O-acetyl-N⁴-[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine,
- 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-[(2-phenylethoxy)-carbonyl]cytidine,
Among the above compounds, particularly preferred N⁴-(substituted-oxycarbonyl)-5'-DFCRs of the present invention are:
- 5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine,
- 5'-deoxy-5-fluoro-N⁴-(isopentyloxycarbonyl)cytidine,
- 5'-deoxy-5-fluoro-N⁴-(hexyloxycarbonyl)cytidine,
- 5'-deoxy-N⁴-[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,
- 5'-deoxy-5-fluoro-N⁴-(neopentyloxycarbonyl)cytidine,
- 5'-deoxy-N⁴-[(3 ,3-dimethylbutoxy)carbonyl]-5-fluorocytidine,
- 5'-deoxy-5-fluoro-N⁴-[(2-phenylethoxy)carbonyl]cytidine,
- N⁴-[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine, especially
- N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine,
- 5'-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine,
The N⁴-(substituted-oxycarbonyl)-5'-DFCRs represented by the general formula (I) as well as their hydrates or solvates can be prepared by a reaction of a compound represented by the general formula (II),
wherein R⁴ is a hydroxy-protecting radical such as acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl, and the like,
with a compound represented by the general formula (III),
R¹OCOCl (III)
wherein R¹ is the same as defined above,
followed, if necessary, by removal of a protecting radical.
The compounds represented by the above general formula (II) can be prepared by 2',3'-di-O-acylation or silylation of 5'-deoxy-5-fluorocytidine [J. Med. Chem., 22, 1330 (1979)] as described in USP 4,966,891 or by direct coupling of 5-fluorocytosine with 1,2,3-tri-O-acetyl-5-deoxyribofuranose according to the procedure similar to that described in the literature [Synthesis, 748 (1981)].
The reaction of the compound of the above general formula (II) with the compound of the above general formula (III) can be carried out in a solvent such as pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane and the like in the presence of acid acceptor such as triethylamine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, lutidine and the like. The reaction can be carried out at a temperature between 0 and 30°C.
The protecting radical may, if necessary, be removed after the reaction by the procedures known to those skilled in the art [Protective Groups in Organic Synthesis, John Wiley & Sons, New York, Can. J. Chem., 49, 493 (1971) and USP 4,966,891], e.g. by basic or acidic hydrolysis.
The compounds of the above general formula (I) can exist as unsolvated as well as solvated forms, including hydrated forms. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product. Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained during, for example, crystallization.
N⁴-(Substituted-oxycarbonyl)-5'-DFCR derivatives represented by the general formula (I) as well as hydrates or solvates of the compounds of the general formula (I) prepared by the present invention exhibit activity against human colon cancer CXF280 and gastric cancer GXF97 xenografts, mouse colon 26 carcinoma, mouse Lewis lung carcinoma, and the like in mice over a very wide range of dosages both orally and parenterally and are useful as antitumor agents. They are efficiently converted to 5'-DFCR by an acylamidase isozyme, to 5'-DFUR by cytidine deaminase and then to the active metabolite 5-FU by pyrimidine nucleoside phosphorylase.
The present invention further relates to a pharmaceutical composition, particularly for the treatment of tumors characterized by containing a compound of the above general formula (I).
The N⁴-(substituted-oxycarbonyl)-5'-DFCRs of the present invention can be administered orally or non-orally to human beings by various conventional administration methods. Moreover, the N⁴-(substituted-oxycarbonyl)-5'-DFCRs according to the present invention are used singly or formulated with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration such as, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene-glycols or petroleum jelly. The pharmaceutical composition can be made up in a solid form (e.g. as tablets, dragees, enteric coating tablets, granulars, enteric coating granulars, suppositories, capsules or enteric capsules) in a semi-solid form (e.g. as salves) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical composition may be sterilized and/or may contain further adjuvants such as preserving, stabilizing, setting or emulsifying agents, flavor-improving agents, salts for variation of the osmotic pressure or substances acting as buffers. The pharmaceutical composition can be prepared in a conventional manner.
The N⁴-(substituted-oxycarbonyl)-5'-DFCRs according to the present invention can be used alone or as mixtures of two or more different N⁴-(substituted-oxycarbonyl)-5'-DFCRs and the amount of the N⁴-(substituted-oxycarbonyl)-5'-DFCRs is about 0.1 to 99.5%, preferably 0.5 to 95% based on the weight of the pharmaceutical composition.
The pharmaceutical composition according to the present invention may be formulated in a combination with other conventional antitumor agent.
Susceptibility to acylamidase of the N⁴-(substituted-oxycarbonyl)-5'-DFCRs of the present invention and their pharmacokinetic profiles in the monkey are shown as follows:
The N⁴-(substituted-oxycarbonyl)-5'-DFCRs of the present invention were incubated with crude extracts of monkey and human liver in the presence of an inhibitor of cytidine deaminase, tetrahydrouridine (0.4 mM) at 37°C for 60 min. Thereafter, the product 5'-DFCR was separated by HPLC and the enzyme susceptibility was calculated from the amount of the product. As Table 1 shows, the compounds provided in the present invention were highly susceptible to the human liver acylamidase, suggesting that they are efficiently biotransformed to 5'-DFCR in human. Table 1.
| Susceptibility to monkey and human acylamidase in the liver | ||
| 11 | 20 | 71 |
| 12 | 29 | 190 |
| 13 | 47 | 220 |
| 14 | 32 | 74 |
| 15 | 23 | 210 |
| 16 | 33 | 210 |
| 17 | 22 | 160 |
| 20 | 19 | 320 |
| 21 | 26 | 82 |
| 22 | 43 | 110 |
| 24 | 18 | 64 |
| 25 | <13 | 160 |
| 26 | 20 | 560 |
| 27 | 59 | 110 |
| 28 | 25 | 52 |
| 29 | 22 | 50 |
The compounds of the present invention were orally administered into groups of 2 to 5 cynomolgous monkeys (3-4 kg). At various times after the administration, plasma was taken for determination of blood concentrations of intact molecules and their active metabolite 5'-DFUR.
Metabolites in the plasma were separated by HPLC and their concentrations were calculated. As Table 2 shows, the compounds of the present invention gave high levels in Cmax and AUC of the active metabolite 5'-DFUR in the plasma. These results indicate that the compounds provided in the present invention can be effectively utilized for the treatment of various tumors in human beings. Table 2.
| Pharmacokinetic Profiles in Monkeys | ||
| 10 | 1.44 | 2.03 |
| 11 | 1.57 | 2.06 |
| 12 | 2.10 | 2.90 |
| 13 | 1.50 | 1.96 |
| 14 | 1.80 | 2.40 |
| 15 | 2.60 | 2.89 |
| 16 | 1.40 | 2.52 |
| 17 | 1.65 | 2.66 |
| 28 | 1.00 | 1.40 |
| 29 | 2.00 | 2.09 |
The antitumor activities of the compounds of the present invention are shown as follows:
CXF280 tumor (about 2 x 2 mm piece) was implanted subcutaneously into BALB/c nu/nu mice (21 - 22 g) on day 0. When tumor volume became 100 mm³ on day around 14, the compounds of the present invention were orally administered daily for 3 weeks. At one day after the last treatment, tumor volume was calculated.
The percent inhibition of tumor growth given in Table 3 above was calculated from the formula: V₀ = volume of tumor before treatment was started, T= volume of the tumors from the treated group, C =volume of the tumor from the control group.
As Table 3 shows, the compounds provided in the present invention were safely administered without causing intestinal toxicity and were much more effective than 5-FU.
Antitumor activity of a representative compound (Example 13), of the present invention, was measured as follows. Mice (CDF₁) were subcutaneously inoculated with colon 26 carcinoma (10⁶ cells) on day 0. The compound was administered daily for 7 times from day 21 when the animals became cachectic. One day after the last treatment, tumor weight gain, carcass weight gain, adipose tissue weight, concentrations of glucose and the acute phase reactant IAP (immunosuppressive acidic protein) in the serum were measured. As Table 4 shows, mice treated with vehicle were abnormal in cachexia parameters such as adipose tissue weight, serum glucose and IAP levels, whereas treatment with the compound of Example 13 suppressed tumor growth and improved cachexia.
The toxicity (LD₅₀) of the representative compounds (Example 13,14, and 17) of the present invention was examined by oral administration daily for 21 days in mice. The representative LD₅₀ values obtained from the experiments were more than 500 mg/kg/day.
A dosage per day to a patient of the N⁴-(substituted-oxycarbonyl)-5'-DFCRs of the present invention may be varied depending upon his weight and state to be remedied, but generally is in the range of 0.5 to 500 mg per 1 kg of weight, preferably about 2 to 200 mg. It should be noted that the compound of the invention can be expected to have 3-5 times higher activity than those of the compounds disclosed in USP 4,966,891 in humans, when taking into consideration of the data of Cmax and AUC of 5'-DFUR after oral administration of the present compounds in monkeys. From the same reason, the compounds of the present invention can be expected to show sufficient activity at the 3-5 times lower dosage than those of the compounds of said U.S. Patent. The present invention can provide a pharmaceutical composition for treating tumors with high safety margin.
The following Examples are intended to illustrate the present invention in more detail, but are not intended to limit its scope in any manner.
5'-Deoxy-5-fluorocytidine (50 mg) was dissolved in dry pyridine (1.3 ml). To the solution was added acetic anhydride (39 ml) with stirring at 0°C. The reaction mixture was stirred for 3 hours at 0°C. After removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and ice cooled water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The resudie was purified by silica gel column chromatography (dichloromethane/methanol=9/1 as an eluent) followed by recrystallization from isopropanol to give 37 mg of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine : 191.5-193°C, FAB-MS m/z 330 (MH⁺).
A solution of sodium iodide (3.6 g) and chlorotrimethylsilane (794 ml) in dry acetonitrile (15 ml) was stirred with molecular sieves 0.4 nm (4Å) (200 mg) at 0°C for 5 min (colorless sodium chloride deposited during stirring). 1,2,3-Tri-O-acetyl-5-deoxy-β-D-ribofuranose (2.0 g) was added and the mixture was stirred at 0°C for 30 min. Then, a solution of the trimethylsilylated 5-fluorocytosine, freshly prepared from 5-fluorocytosine (1.12 g), in dry acetonitrile (5 ml) was added at 0°C and stirring was continued for 3 h at room temperature. The mixture was filtered, the filtrate was concentrated in vacuo, and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution. The aqueous layer was extracted with CH₂Cl₂/MeOH (10:1). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography using CH₂Cl₂/MeOH (15:1) as an eluent, followed by recrystallization from isopropanol to give 1.24 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine.
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (2 g) in CH₂Cl₂ (15 ml) and dry pyridine (983 ml) was added dropwise n-propyl chloroformate (957 ml) with stirring and cooling on ice bath. After stirring for 30 min at room temperature, the mixture was evaporated to dryness under reduced pressure. The residue was partitioned between ether and saturated aqueous solution of sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered.
The filtrate was evaporated to give 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine (2.5 g) : EI-MS m/z 415(M⁺); ¹H-NMR(d₆-DMSO) δ 0.92 (3H, t, J=7.3 Hz), 1.37 (3H, d, J=6.3 Hz), 1.63 (2H, sex, J=7.3 Hz), 4.06-4.14 (3H, m), 5.11 (1H, t, J=6.3 Hz), 5.47 (1H, d.d., J=4.6 & 6.3 Hz), 5.81 (1H, d, J=4.6 Hz), 8.31 (1H, br. s), 10.63 (1H, br. s)
The following compounds were obtained according to a manner analogous to that of Example 1 (R¹ and R are the same with those in the general formula (I)). The compound of Example 9 was prepared from the known 2',3'-di-O-benzoyl-5'-deoxy-5-fluorocytidine (USP 4,966,891) by the similar manner to that of Example 1.
To a solution of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine (2.5 g) in CH₂Cl₂ (17 ml) was added dropwise 1N NaOH (17 ml) with stirring and cooling with ice bath. After stirring for 1 hr at 0°C, MeOH (0.9 ml) was added to the mixture. And pH of the reaction mixture was adjusted to 6 by the addition of concentrated HCl and partitioned. The aqueous layer was extracted with a mixed solvent of CH₂Cl₂/MeOH(95/5) successively (40 ml x 10). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solution was evaporated, and the residue was crystallized from ethyl acetate to give 5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine as colorless crystals (1.6 g, y. 79.8%) : mp. 125-126.5° C; EI-MS m/z 331 (M⁺).
The following compounds were obtained according to a manner analogous to that of Example 10 (R¹ and R are the same with those in the general formula (I)).
(not according to the present invention)
5'-Deoxy-5-fluorocytidine (2.5 g) was dissolved in dry pyridine (20 ml). To the mixture, trimethylsilyl chloride (3.4 ml) was added dropwise at 0°C, and stirred for 30 min at room temperature. To the reaction mixture, cyclohexyl chloroformate (2.0 ml) was added in one portion at 0°C. After stirring of the mixture for 1 hour at room temperature, pyridine was evaporated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO₃ and ether. The organic layer was washed with brine, dried over anhydrous MgSO₄ and concentrated under reduced pressure. To the residue were added citric acid (2.0 g) and methanol (50 ml). The mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue was dissolved in CH₂Cl₂/MeOH (95:5) and neutralized by aqueous NaOH. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH₂Cl2/MeOH (20:1) as an eluent, followed by recrystallization from ethyl acetate to give N⁴-(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocytidine (3.47g: 92% yield) : mp. 134-136°C, FAB-MS m/z 372(MH⁺).
The following compounds (not according to the present invention) were obtained according to a manner analogous to that of Example 19 (R¹ and R are the same with those in the general formula (I)).
5'-Deoxy-2',3'-di-O-acetyl-5-fluorocytidine (1.5 g) and dry pyridine (0.74 ml) were dissolved in dry dichloromethane (15 ml). To the mixture, toluene solution of neopentyl chloroformate (3 eq.) was added dropwise at 0°C, and stirred at room temperature for 1 hr. After the solvent was removed under reduced pressure, the residue was partitioned between ether and saturated aqueous solution of sodium carbonate. The organic layer was successively washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(neopentyloxycarbonyl)cytidine as pale yellow oil. This crude product was dissolved in ethanol (15 ml) and cooled on ice-bath. Then 1N aqueous sodium hydroxide solution was added dropwise while maintaining the temperature below 15°C. After the addition was completed, the reaction mixture was neutralized with conc. hydrochloric acid at 0°C. The solution was concentrated under reduced pressure, and the concentrate was partitioned between water and a mixed solution of CH₂Cl₂/MeOH (95:5). The aqueous layer was back-extracted with CH₂Cl₂/MeOH (95:5) ten times (20 ml each). All organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂/MeOH (20:1) as an eluent to give 5'-deoxy-5-fluoro-N⁴-(neopentyloxycarbonyl)cytidine (1.37 g: 84% yield) as amorphous powder: FAB-MS m/z 360 (MH⁺); 1H-NMR (d₆-DMSO) δ 0.93 (9H, s), 1.31 (3H, d,J=6.3Hz), 3.68 (1H,q,J=5.9Hz), 3.81 (2H, br. s), 3.87-3.92 (1H, m), 4.04-4.09 (1H, m), 5.05 (1H,d,J=5.9Hz), 5.41 (1H, br. d, J=5.3Hz), 5.67 (1H,dd,J=1.3,3.6Hz), 8.04 (1H, br. s), 10.53 (∼1H, br. s).
was obtained according to a manner analogous to that of Example 28 except that 3,3-dimethylbutyl chloroformate was used as the acylating agent:amorphous powder (71% yield); FAB-MS m/z 374 (MH⁺); ¹H-NMR (d₆-DMSO) δ 0.93 (9H, s), 1.31 (3H,d,J=6.3Hz), 1.55 (2H,t,J=7.3Hz), 3.68 (1H,q,J=5.9Hz), 3.84-3.93 (1H, m), 4.03-4.09 (1H, m), 4.15 (2H,t,J=7.3Hz), 5.05 (1H,d,J=5.9Hz), 5.40 (1H, br, d,J=5.3Hz), 5.67 (1H,dd,J=1.3,4.0Hz), 8.00 (1H, br. s), 10.53 (∼1H, br. s).
The following examples illustrate pharmaceutical preparations containing a compound provided by the present invention.
Interlocking gelatin capsules each containing the following ingredients were manufactured in a manner known per se:
| N⁴-(Butoxycarbonyl)-5'-deoxy-5-fluorocytidine | 100 mg |
| Corn starch | 20 mg |
| Titanium dioxide | 385 mg |
| Magnesium stearate | 5 mg |
| Film | 20 mg |
| PEG 6000 | 3 mg |
| Talc | 10 mg |
| 543 mg |
Tablets each containing the following ingredients were manufactured in a manner known per se:
| N⁴-(Butoxycarbonyl)-5'-deoxy-5-fluorocytidine | 100 mg |
| Lactose | 25 mg |
| Corn starch | 20.2 mg |
| Hydroxypropylmethyl cellulose | 4 mg |
| Magnesium stearate | 0.8 mg |
| Film | 10 mg |
| PEG 6000 | 1.5 mg |
| Talc | 4.5 mg |
| 166 mg |
Dry parenteral dosage forms were manufactured in a manner known per se:
- (1) A total 5 g of N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine was dissolved in 75 ml of distilled water, the solution was subjected to a bacteriological filtration, and then divided aseptically into 10 sterile vials. The solution was then freeze-dried to yield 500 mg of sterile dry solid per vial.
- (2) Clean N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine in the amount of 500 mg per vial or ampoule was sealed in the receptacle and heat-sterilized.
The above dry dosage forms were reconstituted before use by adding a suitalble sterile aqueous solvent such as water for injection or isotonic sodium chloride or 5% dextrose for parenteral administration.
Claims (7)
- Compounds represented by the general formula (I), wherein R¹ is n-propyl, n-butyl, n-pentyl, isopentyl, neopentyl, 3,3-dimethylbutyl, n-hexyl, 2-ethylbutyl, phenylethyl, and cyclohexylmethyl;and R is a hydrogen atom or a radical easily hydrolyzable under physiological conditions, as well as hydrates or solvates of the compounds of the general formula (I).
- N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine.
- 5'-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine.
- The compounds5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine,5'-deoxy-5-fluoro-N⁴-(hexyloxycarbonyl)cytidine,5'-deoxy-5-fluoro-N⁴-(isopentyloxycarbonyl)cytidine,5'-deoxy-5-fluoro-N⁴-(neopentyloxycarbonyl)cytidine,5'-deoxy-N⁴-[(3,3-dimethylbutoxy)carbonyl]-5-fluorocytidine,5'-deoxy-N⁴-[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,N⁴-[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine,5'-deoxy-5-fluoro-N⁴-[(2-phenylethoxy)carbonyl]cytidine,2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(propoxycarbonyl)cytidine,2',3'-di-O-acetyl-N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine,2',3'-di-O-benzoyl-N⁴-(butoxycarbonyl)-5'-deoxy-5-fluorocytidine,2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(pentyloxycarbonyl)cytidine,2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(isopentyloxycarbonyl)cytidine,2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-(hexyloxycarbonyl)cytidine,2',3'-di-O-acetyl-5'-deoxy-N⁴-[(2-ethylbutyl)oxycarbonyl]-5-fluorocytidine,2',3'-di-O-acetyl-N⁴-[(cyclohexylmethoxy)carbonyl]-5'-deoxy-5-fluorocytidine,2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N⁴-[(2-phenylethoxy)-carbonyl]cytidine.
- A process for producing the compounds according to claims 1-4 which comprises reacting a compound represented by the general formula (II), wherein R⁴ is a hydroxy-protecting radical, with a compound represented by the general formula (III), R¹OCOCl (III) wherein R¹ is the same as defined above, and, if necessary, removing the protecting radicals.
- A pharmaceutical composition, particularly for the treatment of tumors characterized by containing a compound of the general formula (I), as in claim 1, or a hydrate or solvate of the compound of the general formula (I), as an active ingredient.
- The use of the compounds of claims 1-4 for the manufacture of an antitumor agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP92121538 | 1992-12-18 | ||
| EP92121538 | 1992-12-18 |
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| Publication Number | Publication Date |
|---|---|
| HK1005875B true HK1005875B (en) | 1999-01-29 |
| HK1005875A1 HK1005875A1 (en) | 1999-01-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK98105008A HK1005875A1 (en) | 1992-12-18 | 1998-06-05 | N-oxycarbonyl substituted 5'-deoxy-5-fluorocytidines |
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| Country | Link |
|---|---|
| US (1) | US5472949A (en) |
| EP (1) | EP0602454B1 (en) |
| JP (1) | JP2501297B2 (en) |
| KR (1) | KR100347218B1 (en) |
| CN (1) | CN1035617C (en) |
| AT (1) | ATE137244T1 (en) |
| AU (1) | AU671491B2 (en) |
| BG (1) | BG61485B1 (en) |
| BR (1) | BR9305089A (en) |
| CA (1) | CA2103324C (en) |
| CZ (1) | CZ284788B6 (en) |
| DE (1) | DE69302360T2 (en) |
| DK (1) | DK0602454T3 (en) |
| EE (1) | EE03086B1 (en) |
| ES (1) | ES2086856T3 (en) |
| FI (1) | FI112365B (en) |
| GE (1) | GEP20074251B (en) |
| GR (1) | GR3020286T3 (en) |
| HK (1) | HK1005875A1 (en) |
| HR (1) | HRP931430B1 (en) |
| HU (2) | HU218291B (en) |
| IL (1) | IL108000A0 (en) |
| IS (1) | IS4108A (en) |
| LT (1) | LT3115B (en) |
| LV (1) | LV10625B (en) |
| MY (1) | MY109282A (en) |
| NO (1) | NO300066B1 (en) |
| NZ (1) | NZ250414A (en) |
| PH (1) | PH30168A (en) |
| PL (1) | PL174100B1 (en) |
| RO (1) | RO112619B1 (en) |
| RU (2) | RU2458932C2 (en) |
| SA (1) | SA93140409B1 (en) |
| SI (1) | SI9300648B (en) |
| SK (1) | SK281403B6 (en) |
| SV (1) | SV1993000080A (en) |
| TW (1) | TW372239B (en) |
| UA (1) | UA39158C2 (en) |
| UY (1) | UY23697A1 (en) |
| YU (1) | YU49411B (en) |
| ZA (1) | ZA939293B (en) |
Families Citing this family (87)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5476932A (en) * | 1994-08-26 | 1995-12-19 | Hoffmann-La Roche Inc. | Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives |
| EP0882734B1 (en) * | 1997-06-02 | 2009-08-26 | F. Hoffmann-La Roche Ag | 5'-Deoxy-cytidine derivatives |
| NZ330360A (en) * | 1997-06-02 | 1999-03-29 | Hoffmann La Roche | 5'-deoxy-cytidine derivatives, their manufacture and use as antitumoral agents |
| US6005098A (en) * | 1998-02-06 | 1999-12-21 | Hoffmann-La Roche Inc. | 5'deoxycytidine derivatives |
| HUP0103640A3 (en) * | 1998-09-25 | 2003-01-28 | Warner Lambert Co | Chemotherapy of cancer with acetyldinaline in combination with gemcitabine, capecitabine or cisplatin |
| US20070122481A1 (en) * | 1998-11-02 | 2007-05-31 | Elan Corporation Plc | Modified Release Compositions Comprising a Fluorocytidine Derivative for the Treatment of Cancer |
| US20080113025A1 (en) * | 1998-11-02 | 2008-05-15 | Elan Pharma International Limited | Compositions comprising nanoparticulate naproxen and controlled release hydrocodone |
| SK12242002A3 (en) * | 2000-02-28 | 2003-02-04 | Aventis Pharma S. A. | A composition comprising camptothecin and a pyrimidine derivative for the treatment of cancer |
| WO2001076581A1 (en) * | 2000-04-11 | 2001-10-18 | Sayuri Yamada | Curcumin compositions |
| KR100631754B1 (en) * | 2000-08-09 | 2006-10-09 | 주식회사 코오롱 | N-alkyloxycarbonyl-5-fluorocytosine derivatives and preparation method thereof |
| KR100730768B1 (en) * | 2000-08-09 | 2007-06-21 | 코오롱생명과학 주식회사 | 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-carboxylic acid and its derivatives and preparation methods thereof |
| GB0113374D0 (en) * | 2001-06-04 | 2001-07-25 | Jerram Clare | Washing line umbrella |
| NZ533940A (en) * | 2002-01-14 | 2007-06-29 | Novartis Ag | Combinations comprising epothilones and anti-metabolites |
| CA2477088A1 (en) | 2002-02-22 | 2003-10-02 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| CA2506085A1 (en) * | 2002-11-15 | 2004-06-03 | Ronald Lynn Merriman | Combination chemotherapy comprising a mek inhibitor and capecitabine for treating cancer |
| EP1631278A4 (en) * | 2003-05-20 | 2006-09-20 | Aronex Pharmaceuticals Inc | Combination chemotherapy comprising capecitabine and a liposomal platinum complex |
| SI1689404T1 (en) * | 2003-11-13 | 2009-02-28 | Pharma Mar Sau | Combination of et-743 with 5-fluorouracil pro-drugs for the treatment of cancer |
| DK1706414T3 (en) * | 2003-12-22 | 2008-10-13 | Hoffmann La Roche | Process for Fluorocytidine Derivatives |
| DK1848414T3 (en) | 2005-02-03 | 2011-07-25 | Gen Hospital Corp | Process for the treatment of gefitinib-resistant cancer |
| WO2006103187A2 (en) * | 2005-04-01 | 2006-10-05 | F. Hoffmann-La Roche Ag | Method for administration of capecitabine |
| NZ587586A (en) | 2005-07-18 | 2012-04-27 | Bipar Sciences Inc | Treatment of cancer |
| ES2384267T3 (en) | 2005-07-21 | 2012-07-03 | Nuvo Research Ag | Stabilized chlorite solutions in combination with fluoropyrimidines for cancer treatment |
| AU2006311877A1 (en) | 2005-11-04 | 2007-05-18 | Wyeth Llc | Antineoplastic combinations with mTOR inhibitor, herceptin, and/orHKI-272 |
| DK3184526T3 (en) | 2005-12-13 | 2019-01-14 | Incyte Holdings Corp | PYRROLO [2,3-D] PYRIMIDINE DERIVATIVES AS A JANUS-KINASE INHIBITOR |
| US20100160442A1 (en) * | 2006-07-18 | 2010-06-24 | Ossovskaya Valeria S | Formulations for cancer treatment |
| US20080085310A1 (en) * | 2006-10-06 | 2008-04-10 | Maria Oksana Bachynsky | Capecitabine rapidly disintegrating tablets |
| CN100425617C (en) * | 2006-10-31 | 2008-10-15 | 浙江海正药业股份有限公司 | Fluoropyrimidine compound carbalkoxylation method |
| ITMI20070435A1 (en) | 2007-03-05 | 2008-09-06 | Innovate Biotechnology Srl | 2 ', 3'-DI-O-acyl-5-FLUORONUCLEOSIDI |
| MX2009011255A (en) * | 2007-04-20 | 2009-11-23 | Reddys Lab Ltd Dr | Process for preparing capecitabine. |
| WO2008145403A1 (en) * | 2007-06-01 | 2008-12-04 | Synthon B.V. | Processes related to making capecitabine |
| DK2740731T3 (en) | 2007-06-13 | 2016-04-11 | Incyte Holdings Corp | CRYSTALLINE SALTS OF JANUSKINASEINHIBITOREN (R) -3- (4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-CYCLOPENTYLPROPANNITRIL |
| US7842675B2 (en) * | 2007-09-15 | 2010-11-30 | Protia, Llc | Deuterium-enriched capecitabine |
| WO2009042064A2 (en) * | 2007-09-21 | 2009-04-02 | Nektar Therapeutics Al, Corporation | Oligomer-nucleoside phosphate conjugates |
| US8022216B2 (en) | 2007-10-17 | 2011-09-20 | Wyeth Llc | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
| KR101013312B1 (en) * | 2007-11-19 | 2011-02-09 | 한미홀딩스 주식회사 | Method for preparing capecitabine and method for preparing β-anomer-enhanced trialkyl carbonate compound |
| AR064165A1 (en) | 2007-12-06 | 2009-03-18 | Richmond Sa Com Ind Y Financie | A PROCEDURE FOR THE PREPARATION OF CAPECITABIN AND INTERMEDIARIES USED IN THIS PROCEDURE |
| WO2009088989A1 (en) * | 2008-01-03 | 2009-07-16 | Plus Chemicals, S.A. | Process for the preparation of capecitabine |
| US20090311335A1 (en) * | 2008-06-12 | 2009-12-17 | Scott Jenkins | Combination of a triptan and an nsaid |
| SI2310011T1 (en) | 2008-06-17 | 2013-10-30 | Wyeth Llc | Antineoplastic combinations containing hki-272 and vinorelbine |
| BRPI0916694B1 (en) | 2008-08-04 | 2021-06-08 | Wyeth Llc | use of neratinib in combination with capecitabine to treat erbb-2 positive metastatic breast cancer, kit and product comprising the same |
| EP2370414A4 (en) * | 2008-12-02 | 2012-11-14 | Reddys Lab Ltd Dr | Preparation of capecitabine |
| WO2010063080A1 (en) * | 2008-12-05 | 2010-06-10 | Commonwealth Scientific And Industrial Research Organisation | Amphiphile prodrugs |
| CA2755789C (en) | 2009-04-06 | 2016-01-19 | Wyeth Llc | Treatment regimen utilizing neratinib for breast cancer |
| FR2945211A1 (en) | 2009-05-06 | 2010-11-12 | Sanofi Aventis | ANTITUMOR COMBINATION COMPRISING CABAZITAXEL AND CAPECITABINE |
| AU2010249443B2 (en) | 2009-05-22 | 2015-08-13 | Incyte Holdings Corporation | 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octane- or heptane-nitrile as JAK inhibitors |
| CN102858791A (en) * | 2009-07-23 | 2013-01-02 | 台湾神隆股份有限公司 | Process for producing fluorocytidine derivatives |
| WO2011067588A1 (en) | 2009-12-04 | 2011-06-09 | Generics [Uk] Limited | Cyclic sulphinyl esters of cytidine |
| WO2011104540A1 (en) * | 2010-02-24 | 2011-09-01 | Generics [Uk] Limited | One step process for the preparation of capecitabine |
| AU2011224484A1 (en) | 2010-03-10 | 2012-09-27 | Incyte Holdings Corporation | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
| SI2835053T1 (en) | 2010-03-12 | 2016-09-30 | Genzyme Corporation | Combination therapy for treating breast cancer |
| MY161078A (en) | 2010-05-21 | 2017-04-14 | Incyte Holdings Corp | Topical formulation for a jak inhibitor |
| CN102260309B (en) * | 2010-05-24 | 2014-10-22 | 重庆福安药业(集团)股份有限公司 | Method for preparing high-purity capecitabine |
| EP2640723A1 (en) | 2010-11-19 | 2013-09-25 | Incyte Corporation | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors |
| CN102558262A (en) * | 2010-12-23 | 2012-07-11 | 天津泰普药品科技发展有限公司 | Preparation method of high-purity capecitabine |
| KR20140040819A (en) | 2011-06-20 | 2014-04-03 | 인사이트 코포레이션 | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
| CN102266303A (en) * | 2011-07-07 | 2011-12-07 | 程雪翔 | Capecitabine medicinal composition and preparation method thereof |
| UA111854C2 (en) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS |
| CN102516338B (en) * | 2011-12-09 | 2014-04-02 | 海南锦瑞制药股份有限公司 | Capecitabine compound, pharmaceutical composition and preparation method thereof |
| TWI560195B (en) * | 2012-01-13 | 2016-12-01 | Pharmaessentia Corp | Novel synthesis of 5-deoxy-5'-fluorocytidine compounds |
| PH12020551186B1 (en) | 2012-11-15 | 2024-03-20 | Incyte Holdings Corp | Sustained-release dosage forms of ruxolitinib |
| JP6397831B2 (en) | 2013-03-06 | 2018-09-26 | インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ | Method for producing JAK inhibitor and intermediate thereof |
| KR20160045081A (en) | 2013-08-07 | 2016-04-26 | 인사이트 코포레이션 | Sustained release dosage forms for a jak1 inhibitor |
| TW201529074A (en) * | 2013-08-20 | 2015-08-01 | Incyte Corp | Survival benefit in patients with solid tumors with elevated C-reactive protein levels |
| EP2883959A1 (en) | 2013-12-13 | 2015-06-17 | Plasmia Biotech, S.L. | Enzymatic production of cytosinic nucleoside analogues |
| CN103897006A (en) * | 2013-12-18 | 2014-07-02 | 吉林修正药业新药开发有限公司 | Preparation method of capecitabine isomer |
| EP3151864B1 (en) | 2014-06-09 | 2020-08-05 | Lipomedix Pharmaceuticals Ltd. | Combination therapy comprising a liposomal prodrug of mitomycin c and radiotherapy |
| CN104530164A (en) * | 2014-12-31 | 2015-04-22 | 辰欣药业股份有限公司 | Synthesis technology for capecitabine |
| KR20160117060A (en) | 2015-03-31 | 2016-10-10 | 이승주 | Baby table |
| CN105646625B (en) * | 2015-12-29 | 2019-06-11 | 江苏吴中医药集团有限公司 | A kind of preparation method of capecitabine |
| ES2914123T3 (en) | 2017-01-09 | 2022-06-07 | Shuttle Pharmaceuticals Inc | Selective histone deacetylase inhibitors for the treatment of a human disease |
| US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
| TR201702500A2 (en) * | 2017-02-20 | 2017-07-21 | Anadolu Ueniversitesi | THE USE OF SERANIB-2 IN THE TREATMENT OF LUNG CANCER AND BREAST CANCER |
| US10435429B2 (en) | 2017-10-03 | 2019-10-08 | Nucorion Pharmaceuticals, Inc. | 5-fluorouridine monophosphate cyclic triester compounds |
| WO2019113487A1 (en) | 2017-12-08 | 2019-06-13 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
| ES2983284T3 (en) | 2018-01-09 | 2024-10-22 | Shuttle Pharmaceuticals Inc | Selective histone deacetylase inhibitors for the treatment of human diseases |
| WO2019139920A1 (en) | 2018-01-10 | 2019-07-18 | Nucorion Pharmaceuticals, Inc. | Phosphor(n)amidatacetal and phosph(on)atalcetal compounds |
| WO2019143860A1 (en) * | 2018-01-19 | 2019-07-25 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
| US11427550B2 (en) | 2018-01-19 | 2022-08-30 | Nucorion Pharmaceuticals, Inc. | 5-fluorouracil compounds |
| CN112105608B (en) | 2018-01-30 | 2023-07-14 | 因赛特公司 | Process for the preparation of (1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-one) |
| SMT202400306T1 (en) | 2018-03-30 | 2024-09-16 | Incyte Corp | Treatment of hidradenitis suppurativa using jak inhibitors |
| JP2022517352A (en) | 2019-01-11 | 2022-03-08 | リポメディックス・ファーマシューティカルズ・リミテッド | Liposomal Compositions and Production Methods Containing Liposomal Prodrugs of Mitomycin C |
| AU2020315394A1 (en) | 2019-07-17 | 2022-02-17 | Nucorion Pharmaceuticals, Inc. | Cyclic deoxyribonucleotide compounds |
| CN115605492B (en) | 2020-04-21 | 2025-09-16 | 配体制药股份有限公司 | Nucleotide prodrug compounds |
| US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
| AU2021331658A1 (en) | 2020-08-31 | 2023-03-30 | Emory University | 5'-substituted nucleoside monophosphates, prodrugs thereof, and uses related thereto |
| WO2023177894A1 (en) | 2022-03-18 | 2023-09-21 | Ideaya Biosciences, Inc. | Combination therapy comprising a mat2a inhibitor and an antimetabolite agent |
| EP4382093B1 (en) | 2022-12-05 | 2025-08-27 | a Fine House S.A. | Oral suspensions comprising capecitabine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1135258A (en) * | 1979-06-15 | 1982-11-09 | Richard D'souza | Process for the preparation of 5'deoxy-5-fluorouridine |
| DE3587500T2 (en) * | 1984-12-04 | 1993-12-16 | Lilly Co Eli | Tumor treatment in mammals. |
| CA1327358C (en) * | 1987-11-17 | 1994-03-01 | Morio Fujiu | Fluoro cytidine derivatives |
-
1993
- 1993-11-12 AU AU50690/93A patent/AU671491B2/en not_active Expired
- 1993-11-15 TW TW082109533A patent/TW372239B/en not_active IP Right Cessation
- 1993-11-17 CA CA002103324A patent/CA2103324C/en not_active Expired - Lifetime
- 1993-11-23 HR HR92121538.0A patent/HRP931430B1/en not_active IP Right Cessation
- 1993-12-01 EP EP93119349A patent/EP0602454B1/en not_active Expired - Lifetime
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- 1993-12-01 AT AT93119349T patent/ATE137244T1/en active
- 1993-12-01 DK DK93119349.4T patent/DK0602454T3/en active
- 1993-12-01 ES ES93119349T patent/ES2086856T3/en not_active Expired - Lifetime
- 1993-12-07 SA SA93140409A patent/SA93140409B1/en unknown
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- 1993-12-10 HU HU9303525A patent/HU218291B/en active Protection Beyond IP Right Term
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- 1993-12-13 CZ CZ932731A patent/CZ284788B6/en not_active IP Right Cessation
- 1993-12-14 FI FI935616A patent/FI112365B/en not_active IP Right Cessation
- 1993-12-14 US US08/167,392 patent/US5472949A/en not_active Expired - Lifetime
- 1993-12-15 PH PH47455A patent/PH30168A/en unknown
- 1993-12-15 RO RO93-01706A patent/RO112619B1/en unknown
- 1993-12-15 YU YU77993A patent/YU49411B/en unknown
- 1993-12-16 BG BG98304A patent/BG61485B1/en unknown
- 1993-12-16 RU RU93056196/04A patent/RU2458932C2/en active Protection Beyond IP Right Term
- 1993-12-16 KR KR1019930027962A patent/KR100347218B1/en not_active Expired - Lifetime
- 1993-12-16 MY MYPI93002726A patent/MY109282A/en unknown
- 1993-12-16 RU RU2012134029/04A patent/RU2493162C1/en not_active IP Right Cessation
- 1993-12-16 JP JP5342812A patent/JP2501297B2/en not_active Expired - Fee Related
- 1993-12-16 BR BR9305089A patent/BR9305089A/en not_active Application Discontinuation
- 1993-12-17 IS IS4108A patent/IS4108A/en unknown
- 1993-12-17 UY UY23697A patent/UY23697A1/en not_active IP Right Cessation
- 1993-12-17 LV LVP-93-1347A patent/LV10625B/en unknown
- 1993-12-17 UA UA93004687A patent/UA39158C2/en unknown
- 1993-12-17 LT LTIP1627A patent/LT3115B/en not_active IP Right Cessation
- 1993-12-17 SV SV1993000080A patent/SV1993000080A/en not_active Application Discontinuation
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1994
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1995
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1996
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1998
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