CN1931869B - Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use - Google Patents
Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use Download PDFInfo
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- CN1931869B CN1931869B CN2005100296270A CN200510029627A CN1931869B CN 1931869 B CN1931869 B CN 1931869B CN 2005100296270 A CN2005100296270 A CN 2005100296270A CN 200510029627 A CN200510029627 A CN 200510029627A CN 1931869 B CN1931869 B CN 1931869B
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- China
- Prior art keywords
- deoxidation
- fluoro
- compound
- pyrimidine
- ketone
- 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.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- -1 N-substituted pyrrolidinyl Chemical group 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims description 39
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical class COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000007127 saponification reaction Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 235000010755 mineral Nutrition 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 229950001891 iprotiazem Drugs 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 18
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 238000000034 method Methods 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 12
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 229960002949 fluorouracil Drugs 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 6
- 210000002784 stomach Anatomy 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- 230000004060 metabolic process Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
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- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
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- 229940002612 prodrug Drugs 0.000 description 2
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- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 2
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
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Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a compound of the general formula (I) and medicinal salt thereof, wherein R1 and R2 are independently selected from hydrogen, C[1-6] straight-chain or branched-chain alkyl, phenyl and phenyl optionally substituted by C[1-6] alkyl or C[1-6] alkoxy; the condition is that at least one group in the R1 and R2 is not hydrogen; X represents O or S; R3 is selected from hydrogen, C[1-6] straight-chain or branched-chain alkyl, phenyl and phenyl optionally substituted by C[1-6] alkyl or C[1-6] alkoxy; R4 and R5 are independently selected from hydrogen or two (C[1-6]) alkyl amido, the condition is that at least one group in the R4 and R5 is not hydrogen; or R4 and R5 can be combined into a ring and form N-substituted pyrrolidinyl or N-substituted piperdine, and the substituted group is selected from C[1-3] alkyl. The present invention also relates to a preparation process of the compound. The present invention further relates to a medicine composition containing the compound or its medicinal salt and the application of the compound or its medicinal salt in preparation of antitumor medicine.
Description
Technical field
The present invention relates to have antitumor and 5 '-deoxidation-5-fluorine cytidine analog derivative antiviral activity, the invention still further relates to the purposes of the described compound of preparation method in pharmacy of this compounds
Background technology
5 FU 5 fluorouracil has been widely used in the treatment of kinds of tumors because of its selectivity and lower untoward reaction preferably since nineteen fifty-seven is synthesized.Yet the 5 FU 5 fluorouracil major part is an intravenous injection, the administration inconvenience.For making things convenient for the patient to use, developed prodrug---the 5 '-'-Deoxy-5-fluorouridine that is fit to oral prodrug 5 FU 5 fluorouracil already.But oral 5 '-'-Deoxy-5-fluorouridine has certain intestines toxicity, and therefore, its suitable prospect is wideless.
Under technical field be sought after developing the prodrug of 5 FU 5 fluorouracil, this compounds itself should no cytotoxicity, but in vivo the effect of enzyme down metabolism be that 5 FU 5 fluorouracil is brought into play antitumor action.Further be that described compound also should have the good curing selectivity.
Summary of the invention
But an object of the present invention is to provide no cytotoxicity own, in vivo enzyme effect down metabolism be the 5 '-deoxidation-5-fluorine cytidine analog derivative of 5 FU 5 fluorouracil.
Another object of the present invention provides the preparation method of described 5 '-deoxidation-5-fluorine cytidine analog derivative.
A further object of the present invention provides the application of described 5 '-deoxidation-5-fluorine cytidine analog derivative in preparing antitumor or antiviral.
The object of the invention realizes by following design: a kind of compound or pharmaceutically acceptable salt thereof with following formula (I):
Wherein, R is selected from
-XR
3Or
Group;
Wherein:
R
1And R
2Be independently selected from hydrogen, C
1-6Straight or branched alkyl, phenyl and randomly by C
1-6Alkyl or C
1-6The phenyl that alkoxyl group replaces; Condition is R
1And R
2In at least one group is arranged for hydrogen;
X represents O or S;
R
3Be selected from hydrogen, C
1-6Straight or branched alkyl, phenyl and randomly by C
1-6Alkyl or C
1-6The phenyl that alkoxyl group replaces;
R
4And R
5Be independently selected from hydrogen or two (C
1-6) alkylamino, condition is R
4And R
5In at least one group is arranged for hydrogen;
Perhaps R
4And R
5Can combine into ring, form the pyrrolidyl of N-replacement or the piperidines that N-replaces, described substituting group is selected from C
1-3Alkyl.
The preferred compound of the present invention is as follows:
Wherein, R is selected from
-XR
3With
Group;
Another aspect of the present invention relates to the preparation method of above-mentioned 5 '-deoxidation-5-fluorcytidines, and its route of synthesis is as follows:
Wherein X, R
1, R
2, R
3, R
4And R
5Definition the same.
Starting material compound (A) but the reference literature similar approach obtains [Chinese Journal of Pharmaceuticals such as Dong Hui, 33:108 (2002)].
1. at first, (A) becomes ester with acylating agent with compound, gets the compound of general formula (B).Described acylating agent is C
1-6Alkane acyl chlorides or C
1-6Alkanoic acid anhydride, C
6-10Aroyl chloride or C
6-10Aroyl chloride or acid anhydrides that aromatic acid acid anhydride, contraposition halogen replace, preferred acylating agent is selected from Acetyl Chloride 98Min., diacetyl oxide, propionyl chloride, propionic anhydride and Benzoyl chloride.Solvent for use is to contain single halogen of acid binding agent or polyhalid alkane, aromatic hydrocarbons, second cyanogen, DMF etc. or its mixed solvent, and described acid binding agent is pyridine, triethylamine, salt of wormwood or yellow soda ash.Preferred solvent is the mixed solution of polyhalohydrocarbon and pyridine.
2. with general formula (B) compound and 1,2,4-triazole (C) condensation obtains general formula (D) compound.Described condensing agent is phosphorus oxychloride or tribromo oxygen phosphorus preferably; Acid binding agent is pyridine, triethylamine preferably; Preferably single halogen of solvent or polyhalid alkane, second cyanogen.
3. general formula (D) compound is replaced or disubstituted amine (NR with single
1R
2) reaction, saponification gets the compound of general formula (E) then.Preferably be selected from ether, benzene, tetrahydrofuran (THF), single halogen or polyhalid alkane, dioxane, second cyanogen with the solvent that replaces the amine reaction, best solvent is polyhalid alkane or dioxane.Saponification reaction reagent is selected from sodium alkoxide, ammoniacal liquor of mineral alkalis such as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom or the like.The saponification reaction solvent is selected from Fatty Alcohol(C12-C14 and C12-C18), water and their combination of 1-4 carbon atoms such as methyl alcohol, ethanol, propyl alcohol, Virahol.
4. with general formula (D) compound and alcohol or mercaptan (HXR
3) reaction, saponification gets the compound of general formula (F) then.Be selected from ether, benzene, tetrahydrofuran (THF), single halogen or polyhalid alkane, dioxane, second cyanogen or its combination with the solvent of alcohol or thiol reactant, preferred solvent is polyhalid alkane or dioxane or its combination.
With the reaction of general formula (D) compound and strong aqua, saponification then with N, the disubstituted dimethylacetal of N-react the compound of general formula (H).Be selected from ether, benzene, tetrahydrofuran (THF), single halogen or polyhalid alkane, dioxane, second cyanogen with the solvent of strong aqua reaction, preferred solvent is polyhalid alkane and dioxane.Saponification reaction reagent is selected from sodium alkoxide, the ammoniacal liquor of mineral alkalis such as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or 1-4 such as sodium methylate, a sodium ethylate carbon atom.The saponification reaction solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), as methyl alcohol, ethanol, propyl alcohol, Virahol, water, and their combination.With N, the solvent of the disubstituted dimethylacetal reaction of N-is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane, preferred solvent is methyl alcohol, ethanol, ether.
When needing, compound of the present invention can be prepared as the form of pharmaceutical salts according to ordinary method.Comprise its inorganic acid salt and organic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid; Organic acid includes, but is not limited to acetate, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid.
Another aspect of the present invention relates to the pharmaceutical composition that contains described compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
Described pharmaceutically acceptable carrier can be chosen according to the practice of affiliated technical field, obtains the composition of solid form or liquid form.
Another aspect of the present invention relates to described compound or the application of its pharmacy acceptable salt in the medicine of preparation anti-tumor activity.
Described tumour comprises the cancer that esophagus, stomach, intestines, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain or central nervous system take place, perhaps thyroid carcinoma, leukemia, Hokdkin disease, lymphoma or myelomatosis.
Compound or pharmaceutically acceptable salt thereof of the present invention can be avoided the intestines toxicity of 5 '-'-Deoxy-5-fluorouridine, and high in more normally organizing with the concentration of its metabolism involved enzyme (dThdPase) in tumor tissues.Therefore, have again with compound of the present invention or its medicinal medicine of making and to treat selectivity preferably, such medicine can be thought very promising antitumour drug.
Embodiment
Below in conjunction with embodiment the present invention is described in detail, but the following example should not regarded limitation of the scope of the invention as.
Embodiment 1
Preparation 5 '-deoxidation-5-fluoro-N
4-methylcytidine (compound 1)
A, 2 ', 3 '-two-O-acetyl-5 '-'-Deoxy-5-fluorouridine (Formula B compound, wherein R
6Be ethanoyl)
Reference literature method (Chinese Journal of Pharmaceuticals such as Dong Hui, 33:108 (2002)) obtains starting raw material 5 '-'-Deoxy-5-fluorouridine (compd A).Get 2g (8.1 mmole) compd A and be dissolved in the 40ml anhydrous pyridine, drip 1.8ml (18 mmole) aceticanhydride, stirred overnight at room temperature.Adding 5ml methyl alcohol then continues to stir the solution evaporate to dryness 15 minutes.Solid is dissolved in the 40ml methylene dichloride, washes with 10% sodium bicarbonate aqueous solution of 40ml, and water is used methylene dichloride 10ml * 2 extractions again.Combined dichloromethane liquid, anhydrous sodium sulfate drying filters evaporate to dryness.Residue 10ml ethyl alcohol recrystallization gets white solid 2.4g, yield 90%, 187 to 189 ℃ of fusing points.
B, 1-(2 ', 3 '-two-O-acetyl-β-D-5 '-desoxyribofu-base)-4-(1,2, the 4-triazol-1-yl)-pyrimidine-2-(1H)-ketone (general formula D compound, wherein R
6Be ethanoyl)
Get 6.4g (93 mmole) 1,2, the 4-triazole adds in the 150ml anhydrous acetonitrile, and ice bath is cooled to below 5 ℃, agitation and dropping 2.0ml (21 mmole) phosphorus oxychloride and 15ml (108 mmole) triethylamine, and then stirred 30 minutes.Remove ice bath, add 2.4g (7.3 mmole) 2 ', 3 '-two-O-acetyl-5 '-'-Deoxy-5-fluorouridine, 20 ℃ were stirred 2 hours.In 5% sodium bicarbonate aqueous solution of solution impouring 120ml, with methylene dichloride 75ml * 2 extractions.Reclaim organic solvent, residue can not purifiedly be directly used in next step reaction.With silica gel H post layer separate white solid 2.2g, yield 80%, 128 to 130 ℃ of fusing points.
C, 5 '-deoxidation-5-fluoro-N
4-methylcytidine (compound 1)
Get 3.5g (10 mmole) 1-(2 ', 3 '-two-O-acetyl-β-D-5 '-desoxyribofu-base)-4-(1,2, the 4-triazol-1-yl)-pyrimidine-2-(1H)-ketone joins in the mixed solution of 10ml aqueous methylamine solution and 30ml dioxane, stirring at room 1h, evaporate to dryness.Add 60ml tetrahydrofuran (THF), 50ml methyl alcohol and 12.5ml water then successively.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12.5ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.Elimination resin, solution evaporate to dryness, residue get white solid 2g, yield 80%, fusing point: 96 to 98 ℃ through the silicagel column purifying.
1H-NMR (DMSO-d
6) δ (ppm): 1.26 (3H, d, 4 '-CH
3), 2.80 (3H, s, N-CH
3), 3.64 (1H, d, 3 '-H), 3.79 to 3.82 (1H, m, 4 '-H), 3.97 (1H, d, 2 '-H), 4.96 (1H, d, OH), 5.25 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.68 (1H, d, CHCF), 8.02 (1H, s, NH).
Embodiment 2
Preparation 5 '-deoxidation-5-fluoro-N
4-ethyl cytidine (compound 2)
Get 3.5g (10 mmole) 1-(2 ', 3 '-two-O-acetyl-β-D-5 '-desoxyribofu-base)-4-(1,2, the 4-triazol-1-yl)-pyrimidine-2-(1H)-ketone and join in the mixed solution of 5ml ethamine and 30ml dioxane stirring at room 1h, evaporate to dryness.Add 60ml tetrahydrofuran (THF), 50ml methyl alcohol and 12.5ml water then successively.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12.5ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.Elimination resin, solution evaporate to dryness, residue get white solid 2.3g, yield 85%, fusing point: 100 to 102 ℃ through the silicagel column purifying.
1H-NMR (DMSO-d
6) δ (ppm): 1.10 (3H, t, N-CH
2CH
3), 1.28 (3H, d, 4 '-CH
3), 3.00 to 3.10 (2H, m, N-CH
2), 3.66 (1H, d, 3 '-H), 3.80 to 3.83 (1H, m, 4 '-H), 3.99 (1H, d, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.70 (1H, d, 1 '-H), 7.71 (1H, d, CHCF), 8.05 (1H, s, NH).
Embodiment 3
Preparation 5 '-deoxidation-5-fluoro-N
4-propyl group cytidine (compound 3)
According to the described method of implementing 2, replace ethamine with propylamine, get white solid 5 '-deoxidation-5-fluoro-N
4-propyl group cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.90 (3H, t, N-CH
2CH
2CH
3), 1.27 (3H, d, 4 '-CH
3), 1.40 to 1.45 (2H, m, N-CH
2CH
2CH
3), 3.00 to 3.08 (2H, m, N-CH
2), 3.65 (1H, d, 3 '-H), 3.80 to 3.84 (1H, m, 4 '-H), 3.95 (1H, d, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.71 (1H, d, 1 '-H), 7.72 (1H, d, CHCF), 8.10 (1H, s, NH).
Embodiment 4
Preparation 5 '-deoxidation-5-fluoro-N
4-butyl cytidine (compound 4)
According to the described method of implementing 2, replace ethamine with butylamine, get white 5 ' thick-deoxidation-5-fluoro-N
4-butyl cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.87 (3H, t, N-CH
2CH
2CH
2CH
3), 1.27 to 1.32 (5H, m, 4 '-CH
3And N-CH
2CH
2CH
2CH
3), 1.47 to 1.52 (2H, m, N-CH
2CH
2CH
2CH
3), 3.32 to 3.39 (2H, m, N-CH
2), 3.63 to 3.65 (1H, m, 3 '-H), 3.79 to 3.84 (1H, m, 4 '-H), 3.98 to 3.99 (1H, m, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.68 (1H, d, CHCF), 8.05 (1H, s, NH).
Embodiment 5
Preparation 5 '-deoxidation-5-fluoro-N
4-sec.-propyl cytidine (compound 5)
According to the described method of implementing 2, replace ethamine with Isopropylamine, get white solid 5 '-deoxidation-5-fluoro-N
4-sec.-propyl cytidine.40 to 42 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.07 to 1.27 (9H, m, 4 '-CH
3And N-CH (CH
3)
2), 3.33 to 3.40 (1H, m, N-CH), 3.79 to 3.82 (1H, m, 3 '-H), 3.96 to 3.99 (1H, m, 4 '-H), 4.19 to 4.23 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.24 (1H, d, OH), 5.67 (1H, d, 1 '-H), 7.68 (1H, d, CHCF), 7.84 (1H, s, NH).
Embodiment 6
Preparation 5 '-deoxidation-5-fluoro-N
4-isopentyl cytidine (compound 6)
According to the described method of implementing 2, replace ethamine with isobutylcarbylamine, get white liquid 5 '-deoxidation-5-fluoro-N
4-isopentyl cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.86 to 0.89 (6H, m, N-CH (CH
2CH
3)
2), 1.14 to 1.16 (4H, m, N-CH (CH
2CH
3)
2), 1.29 (3H, d, 4 '-CH
3), 3.43 to 3.46 (1H, m, N-CH), 3.65 to 3.69 (1H, m, 3 '-H), 3.91 to 3.94 (1H, m, 4 '-H), 4.10 to 4.11 (1H, m, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.70 (1H, d, 1 '-H), 7.70 (1H, d, CHCF), 8.06 (1H, s, NH).
Embodiment 7
Preparation 5 '-deoxidation-5-fluoro-N
4-allyl group cytidine (compound 7)
According to the described method of implementing 2, replace ethamine with allylamine, get white solid 5 '-deoxidation-5-fluoro-N
4-allyl group cytidine.145 to 147 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.27 (3H, d, 4 '-CH
3), 3.64 to 3.66 (1H, m, 3 '-H), 3.80 to 3.82 (1H, m, 4 '-H), 3.93 to 3.97 (2H, m, N-CH
2), 3.99 to 4.02 (1H, m, 2 '-H), 4.96 to 5.19 (3H, m, OH and N-CH
2CH=CH
2), 5.24 (1H, d, OH), 5.70 (1H, d, 1 '-H), 5.83 to 5.93 (1H, m, N-CH
2CH=CH
2), 7.69 (1H, d, CHCF), 8.05 (1H, s, NH).
Embodiment 8
Preparation 5 '-deoxidation-5-fluoro-N
4-phenyl cytidine (compound 8)
According to the described method of implementing 2, replace ethamine with aniline, get yellow solid 5 '-deoxidation-5-fluoro-N
4-phenyl cytidine.117 to 120 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.28 (3H, d, 4 '-CH
3), 3.63 (1H, d, 3 '-H), 3.80 to 3.82 (1H, m, 4 '-H), 3.99 (1H, d, 2 '-H), 4.96 (1H, d, OH), 5.26 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.07 to 7.73 (6H, m, CHCF and Ar-H), 8.05 (1H, s, NH).
Embodiment 9
Preparation 5 '-deoxidation-5-fluoro-N
4-phenmethyl cytidine (compound 9)
According to the described method of implementing 2, replace ethamine with benzene methanamine, get white solid 5 '-deoxidation-5-fluoro-N
4-phenmethyl cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.26 (3H, d, 4 '-CH
3), 3.64 to 3.67 (1H, m, 3 '-H), 3.80 to 3.82 (1H, m, 4 '-H), 3.98 to 4.00 (1H, d, 2 '-H), 4.54 to 4.55 (2H, m, N-CH
2), 4.96 (1H, d, OH), 5.25 (1H, d, OH), 5.68 (1H, s, 1 '-H), 7.23 to 7.34 (5H, m, Ar-H), 7.75 (1H, d, CHCF), 8.61 (1H, t, NH).
Embodiment 10
Preparation 5 '-deoxidation-5-fluoro-N
4-p-methoxyphenyl cytidine (compound 10)
According to the described method of implementing 2,, get yellowish brown solid 5 '-deoxidation-5-fluoro-N so that methyl oxyaniline is replaced ethamine
4-p-methoxyphenyl cytidine.Fusing point: 113 to 115 ℃.
1H-NMR (DMSO-d
6) δ (ppm): 1.28 (3H, d, 4 '-CH
3), 3.65 to 3.67 (1H, m, 3 '-H), 3.74 (3H, s, OCH
3), 3.80 to 3.83 (1H, m, 4 '-H), 3.98 to 4.01 (1H, d, 2 '-H), 4.96 (1H, d, OH), 5.25 (1H, d, OH), 5.68 (1H, s, 1 '-H), 6.91 to 7.55 (4H, m, Ar-H), 7.76 (1H, d, CHCF), 8.51 (1H, t, NH).
Embodiment 11
Preparation 5 '-deoxidation-5-fluoro-N
4, N
4-methylcytidine (compound 11)
According to the described method of implementing 2, replace ethamine with dimethylamine, get white solid 5 '-deoxidation-5-fluoro-N
4, N
4-dimethyl cytidine.143 to 144 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.27 (3H, d, 4 '-CH
3), 3.06 (6H, s, N-(CH
3)
2), 3.66 (1H, d, 3 '-H), 3.77 to 3.82 (1H, m, 4 '-H), 3.96 to 3.97 (1H, m, 2 '-H), 4.96 (1H, d, OH), 5.25 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.69 (1H, d, CHCF), 8.02 (1H, s, NH).
Embodiment 12
Preparation 5 '-deoxidation-5-fluoro-N
4, N
4-diethyl cytidine (compound 12)
According to the described method of implementing 2, replace ethamine with diethylamine, get white solid 5 '-deoxidation-5-fluoro-N
4, N
4-diethyl cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.16 (6H, t, N-(CH
2CH
3)
2), 1.27 (3H, d, 4 '-CH
3), 3.00 to 3.03 (4H, m, N-(CH
2CH
3)
2), 3.65 (1H, d, 3 '-H), 3.79 to 3.82 (1H, m, 4 '-H), 3.96 to 3.97 (1H, m, 2 '-H), 4.96 (1H, d, OH), 5.25 (1H, d, OH), 5.66 (1H, d, 1 '-H), 7.69 (1H, d, CHCF), 7.95 (1H, s, NH).
Embodiment 13
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(methoxyl group)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 13)
Get 3.5g (10 mmole) 1-(2 ', 3 '-two-O-acetyl-β-D-5 '-desoxyribofu-base)-4-(1,2, the 4-triazol-1-yl)-pyrimidine-2-(1H)-ketone joins in the mixed solution of 50ml anhydrous methanol and 5ml anhydrous triethylamine, refluxed evaporate to dryness 30 minutes.Add 60ml tetrahydrofuran (THF), 50ml methyl alcohol and 12.5ml water then successively.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12.5ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue are dissolved in the 100ml methylene dichloride, use the 100ml water washing.Tell organic layer, use anhydrous MgSO
4Drying is filtered the organic solvent evaporate to dryness.Through the silicagel column purifying, get white solid 2.3g, yield 89%, 183 to 185 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.31 (3H, d, 4 '-CH
3), 3.68 to 3.69 (1H, d, 3 '-H), 3.86 to 3.93 (1H, m, 4 '-H), 3.94 (3H, s, OCH
3), 4.05 (1H, s, 2 '-H), 4.94 (1H, s, OH), 5.27 (1H, s, OH), 5.69 (1H, d, 1 '-H), 8.03 (1H, d, CHCF).
Embodiment 14
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(oxyethyl group)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 14)
According to the described method of implementing 13, replace anhydrous methanol with dehydrated alcohol, get white solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(oxyethyl group)-5-fluoro-pyrimidine-2-(1H)-ketone.
1H-NMR (DMSO-d
6) δ (ppm): 1.25 (3H, t, OCH
2CH
3), 1.30 (3H, d, 4 '-CH
3), 3.68 to 3.69 (1H, d, 3 '-H), 3.86 to 3.89 (1H, m, 4 '-H), 3.90 to 3.94 (2H, m, OCH
2), 4.03 (1H, s, 2 '-H), 4.96 (1H, d, OH), 5.27 (1H, d, OH), 5.69 (1H, d, 1 '-H), 8.03 (1H, d, CHCF).
Embodiment 15
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(propoxy-)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 15)
According to the described method of implementing 13, replace anhydrous methanol with propyl alcohol, get white solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(propoxy-)-5-fluoro-pyrimidine-2-(1H)-ketone.
1H-NMR (DMSO-d
6) δ (ppm): 0.95 (3H, t, OCH
2CH
2CH
3), 1.27 (3H, d, 4 '-CH
3), 1.30 to 1.35 (2H, m, OCH
2CH
2CH
3), 3.66 to 3.67 (1H, d, 3 '-H), 3.86 to 3.90 (1H, m, 4 '-H), 3.92 to 3.94 (2H, m, OCH
2), 4.00 to 4.01 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.27 (1H, d, OH), 5.69 (1H, d, 1 '-H), 8.00 (1H, d, CHCF).
Embodiment 16
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(n-butoxy)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 16)
According to the described method of implementing 13, replace anhydrous methanol with propyl carbinol, get white solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(n-butoxy)-5-fluoro-pyrimidine-2-(1H)-ketone.
1H-NMR (DMSO-d
6) δ (ppm): 0.89 (3H, t, OCH
2CH
2CH
2CH
3), 1.29 to 1.35 (5H, m, 4 '-CH
3And OCH
2CH
2CH
2CH
3), 1.47 to 1.50 (2H, m, OCH
2CH
2CH
2CH
3), m, OCH
2), 3.66 to 3.67 (1H, d, 3 '-H), 3.86 to 3.88 (1H, m, 4 '-H), 3.94 to 3.98 (2H, m, OCH
2), 4.00 to 4.02 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.28 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.95 (1H, d, CHCF).
Embodiment 17
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(isopropoxy)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 17)
According to the described method of implementing 13, replace anhydrous methanol with Virahol, get white solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(isopropoxy)-5-fluoro-pyrimidine-2-(1H)-ketone.
1H-NMR (DMSO-d
6) δ (ppm): 1.17 to 1.28 (6H, m, OCH (CH
3)
2), 1.33 (3H, d, 4 '-CH
3), 3.72 to 3.74 (1H, m, 3 '-H), 3.90 to 3.92 (1H, m, 4 '-H), 3.92 to 3.95 (1H, m, OCH), 4.19 to 4.21 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.24 (1H, d, OH), 5.67 (1H, d, 1 '-H), 7.88 (1H, d, CHCF).
Embodiment 18
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(phenoxy group)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 18)
According to the described method of implementing 13, replace anhydrous methanol with phenol, make solvent with dioxane, get gray solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(phenoxy group)-5-fluoro-pyrimidine-2-(1H)-ketone.
1H-NMR (DMSO-d
6) δ (ppm): 1.29 (3H, d, 4 '-CH
3), 3.66 to 3.67 (1H, m, 3 '-H), 3.85 to 3.89 (1H, m, 4 '-H), 4.01 to 4.05 (1H, d, 2 '-H), 4.96 (1H, d, OH), 5.25 (1H, d, OH), 5.68 to 5.69 (1H, m, 1 '-H), 7.27 to 7.73 (6H, m, CHCF and Ar-H).
Embodiment 19
Preparation 5 '-deoxidation-5-fluoro-thio uridine (compound 19)
Get 3.5g (10 mmole) 1-(2 ', 3 '-two-O-acetyl-β-D-5 '-desoxyribofu-base)-4-(1,2, the 4-triazol-1-yl)-pyrimidine-2-(1H)-ketone and be suspended in the 100ml second eyeball, stir Dropwise 5 ml thioacetic acid down, stirred overnight at room temperature.Solution is washed with 250ml saturated sodium bicarbonate solution and 250ml saturated common salt with 250ml methylene dichloride dilution back.The organic layer anhydrous Na
2SO
4Drying concentrates.In the mixed solution of anhydrous triethylamine, refluxed evaporate to dryness 30 minutes.Solid residue adds 60ml tetrahydrofuran (THF), 50ml methyl alcohol and 12.5ml water successively.Be chilled to 0 ℃, add the 2N sodium hydroxide solution of 12.5ml, stir and be neutralized to about pH=7 with 732 type Zeo-karbs after 10 minutes.The elimination resin, solution evaporate to dryness, residue are dissolved in the 100ml methylene dichloride, use the 100ml water washing.Tell organic layer, use anhydrous MgSO
4Drying is filtered the organic solvent evaporate to dryness.Through the silicagel column purifying, get faint yellow solid 2g, yield 80%, 180 to 182 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.34 (3H, d, 4 '-CH
3), 3.71 to 3.73 (1H, d, 3 '-H), 3.86 to 3.93 (1H, m, 4 '-H), 4.05 to 4.08 (1H, m, 2 '-H), 4.94 (1H, s, OH), 5.26 (1H, s, OH), 5.69 (1H, d, l '-H), 7.56 (1H, d, CHCF), 9.80 (1H, s, NH).
Embodiment 20
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(ethylmercapto group)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 20)
According to the described method of implementing 19, replace thioacetic acid to get yellow solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(ethylmercapto group)-5-fluoro-pyrimidine-2-(1H)-ketone with sulfur alcohol.
1H-NMR (DMSO-d
6) δ (ppm): 1.21 (3H, t, SCH
2CH
3), 1.31 (3H, d, 4 '-CH
3), 2.91 to 2.94 (2H, m, SCH
2), 3.60 to 3.62 (1H, d, 3 '-H), 4.00 to 4.02 (1H, m, 4 '-H), 4.10 to 4.12 (1H, s, 2 '-H), 4.96 (1H, d, OH), 5.28 (1H, d, OH), 5.69 to 5.72 (1H, m, 1 '-H), 8.05 (1H, d, CHCF).
Embodiment 21
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(rosickyite base)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 21)
According to the described method of implementing 19, replace thioacetic acid to get yellow solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(rosickyite base)-5-fluoro-pyrimidine-2-(1H)-ketone with propylmercaptan.
1H-NMR (DMSO-d
6) δ (ppm): 0.96 (3H, t, SCH
2CH
2CH
3), 1.26 (3H, d, 4 '-CH
3), 1.90 to 1.55 (2H, m, SCH
2CH
2CH
3), 2.90 to 2.98 (2H, m, SCH
2), 3.66 (1H, d, 3 '-H), 3.88 to 3.89 (1H, m, 4 '-H), 3.95 to 3.99 (1H, m, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.73 (1H, d, 1 '-H), 7.74 (1H, d, CHCF).
Embodiment 22
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(butylthio)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 22)
According to the described method of implementing 19, replace thioacetic acid to get yellow solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(butylthio)-5-fluoro-pyrimidine-2-(1H)-ketone with butyl sulfhydryl.
1H-NMR (DMSO-d
6) δ (ppm): 0.92 (3H, t, SCH
2CH
2CH
2CH
3), 1.28 to 1.32 (5H, m, 4 '-CH
3And SCH
2CH
2CH
2CH
3), 1.86 to 1.90 (2H, m, SCH
2CH
2CH
2CH
3), 2.88 to 2.92 (2H, m, SCH
2), 3.62 to 3.65 (1H, m, 3 '-H), 3.81 to 3.84 (1H, m, 4 '-H), 3.98 to 4.00 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.24 (1H, d, OH), 5.70 (1H, d, 1 '-H), 7.64 (1H, d, CHCF).
Embodiment 23
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(iprotiazem base)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 23)
According to the described method of implementing 19, replace thioacetic acid to get yellow solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(iprotiazem base)-5-fluoro-pyrimidine-2-(1H)-ketone with isopropyl mercaptan.
1H-NMR (DMSO-d
6) δ (ppm): 1.31 to 1.36 (9H, m, 4 '-CH
3And SCH (CH
3)
2), 2.90 to 2.92 (1H, m, SCH), 3.75 to 3.78 (1H, m, 3 '-H), 3.96 to 3.98 (1H, m, 4 '-H), 4.20 to 4.23 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.24 (1H, d, OH), 5.69 (1H, d, 1 '-H), 7.70 (1H, d, CHCF).
Embodiment 24
Preparation 1-(5 '-deoxidation-β-D-ribofuranose)-4-(thiophenyl)-5-fluoro-pyrimidine-2-(1H)-ketone (compound 24)
According to the described method of implementing 19, replace thioacetic acid to get yellow solid 1-(5 '-deoxidation-β-D-ribofuranose)-4-(thiophenyl)-5-fluoro-pyrimidine-2-(1H)-ketone with thiophenol.
1H-NMR (DMSO-d
6) δ (ppm): 1.25 (3H, d, 4 '-CH
3), 3.64 (1H, d, 3 '-H), 3.85 to 3.87 (1H, m, 4 '-H), 3.99 to 4.01 (1H, m, 2 '-H), 4.95 (1H, d, OH), 5.26 (1H, d, OH), 5.71 (1H, d, 1 '-H), 7.04 to 7.63 (6H, m, CHCF and Ar-H).
Embodiment 25
Preparation 5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine (compound 25)
A.5 '-deoxidation-5-fluoro-cytidine (compound G)
According to the described method of implementing 2, replace ethamine with strong aqua, get white solid 5 '-deoxidation-5-fluoro-cytidine.192 to 193 ℃ of fusing points.
B.N, the dinethylformamide dimethylacetal
The new methyl-sulfate that steams in 63g (0.5mol) dehydration back is added 36.5g (0.5mol) exsiccant N, in the dinethylformamide.Under agitation be heated to about 75 ℃, this temperature maintenance 3 hours, cooling is stand-by in icy salt solution then.27g (0.5mol) sodium methylate is suspended in 30 to 60 ℃ the sherwood oil of 200ml, cryosel is bathed cooling and is slowly dripped the mixed solution for preparing previously down, keeps below the temperature-5 ℃.Dropwise, continue to stir the elimination solid 0.5 hour.104 to 106 ℃ of cuts are collected in the clear liquor distillation, get colourless liquid 40g, yield 65%.
C.5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine (compound 25)
2.5g (10 mmole) 5 '-deoxidation-5-fluoro-cytidine adds 40ml methyl alcohol, stirs slowly to drip 1.8ml (13 mmole) N, dinethylformamide dimethylacetal down.After the stirring at room 2 hours, solid filtering is washed with ethanol and ether successively, and drying gets white solid 2.7g, yield 90%, fusing point: 204 to 205 ℃.
1H-NMR (DMSO-d
6) δ (ppm): 1.46 (3H, d, 4 '-CH
3), 3.18 and 3.0 (6H, 2s, N-CH
3* 2), 3.90 to 3.92 (1H, m, 3 '-H), 4.18 to 4.20 (1H, m, 4 '-H), 4.27 to 4.29 (1H, d, 2 '-H), 5.80 to 5.82 (1H, d, 1 '-H), 7.88 (1H, d, CHCF), 8.65 (1H, s, N=CH).
Embodiment 26
Preparation 5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine (compound 26)
According to the described method of implementing 25, with N, N-diethylformamide dimethylacetal replaces N, and the dinethylformamide dimethylacetal gets white solid 5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine, fusing point: 164 to 166 ℃.
1H-NMR (DMSO-d
6) δ (ppm): 1.14 to 1.22 (6H, 2t, CH
2CH
3* 2), 1.29 (2H, d, 4 '-CH
3), 3.52 to 3.59 (4H, m, N-CH
2CH
3* 2), 3.65 to 3.66 (1H, m, 3 '-H), 3.84 to 3.86 (1H, m, 4 '-H), 4.01 (1H, s, 2 '-H), 4.90 (1H, s, OH), 5.33 (1H,, OH), 5.70 (1H, s, 1 '-H), 7.82 (1H, d, CHCF), 8.66 (1H, s, N=CH).
Embodiment 27
Preparation 5 '-deoxidation-5-fluoro-N
4-((dipropyl amido) methylene radical) cytidine (compound 27)
According to the described method of implementing 25, with N, N-dipropyl methane amide dimethylacetal replaces N, and the dinethylformamide dimethylacetal gets white solid 5 '-deoxidation-5-fluoro-N
4-((dipropyl amido) methylene radical) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.90 to 0.95 (6H, m, N-CH
2CH
2CH
3* 2), 1.22 to 1.26 (6H, 2t, N-CH
2CH
2CH
3* 2), 1.28 (2H, d, 4 '-CH
3), 3.50 to 3.54 (4H, m, N-CH
2CH
2CH
3* 2), 3.64 to 3.66 (1H, m, 3 '-H), 3.88 to 3.89 (1H, m, 4 '-H), 4.01 to 4.03 (1H, m, 2 '-H), 4.90 (1H, s, OH), 5.33 (1H,, OH), 5.70 (1H, s, 1 '-H), 7.80 (1H, d, CHCF), 8.65 (1H, s, N=CH).
Embodiment 28
Preparation 5 '-deoxidation-5-fluoro-N
4-((dibutyl amino) methylene radical) cytidine (compound 28)
According to the described method of implementing 25, with N, N-dibutyl formamide dimethylacetal replaces N, and the dinethylformamide dimethylacetal gets white solid 5 '-deoxidation-5-fluoro-N
4-((dibutyl amino) methylene radical) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 0.87 to 0.89 (6H, m, N-CH
2CH
2CH
2CH
3* 2), 1.27 to 1.35 (7H, m, 4 '-CH
3And N-CH
2CH
2CH
2CH
3* 2), 1.49 to 1.54 (2H, m, N-CH
2CH
2CH
2CH
3* 2), 3.50 to 3.60 (4H, m, N-CH
2CH
2CH
2CH
3* 2), 3.63 to 3.65 (1H, m, 3 '-H), 3.50 to 3.55 (1H, m, 4 '-H), 3.98 to 3.99 (1H, m, 2 '-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.68 (1H, d, 1 '-H), 7.78 (1H, d, CHCF), 8.68 (1H, s, N=CH).
Embodiment 29
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine (compound 29)
According to the described method of implementing 25, replace N with N-crassitude dimethylacetal, the dinethylformamide dimethylacetal gets white solid 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine, 198 to 200 ℃ of fusing points.
1H-NMR (DMSO-d
6) δ (ppm): 1.28 (3H, d, 4 '-CH
3), 1.97 to 2.04 (2H, m), 3.01 to 3.05 (5H, m), 3.50 to 3.54 (2H, m), 3.66 to 3.70 (1H, m, 3 '-H), 3.83 to 3.87 (1H, m, 4 '-H), 4.01 to 4.05 (1H, m, 2 '-H), 4.88 (1H, d, OH), 5.18 (1H, d, OH), 5.70 to 5.71 (1H, d, 1 '-H), 7.71 (1H, d, CHCF).
Embodiment 30
Preparation 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) piperidines subunit) cytidine (compound 30)
According to the described method of implementing 25, replace N with N-methyl piperidine dimethylacetal, the dinethylformamide dimethylacetal gets white solid 5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) piperidines subunit) cytidine.
1H-NMR (DMSO-d
6) δ (ppm): 1.30 (3H, d, 4 '-CH
3), 1.97 to 2.14 (4H, m), 3.05 to 3.08 (5H, m), 3.52 to 3.56 (2H, m), 3.68 to 3.70 (1H, m, 3 '-H), 3.85 to 3.88 (1H, m, 4 '-H), 4.02 to 4.05 (1H, m, 2 '-H), 4.86 (1H, d, OH), 5.16 (1H, d, OH), 5.70 to 5.71 (1H, d, 1 '-H), 7.73 (1H, d, CHCF).
Experimental example
The anti-tumor activity test of The compounds of this invention
Compound of the present invention has been carried out the tumor cell proliferation inhibition test.Test method adopts conventional mtt assay.
Cell strain is selected TGC-007 (A549, lung cancer) for use, TGC-043 (HCT116, colorectal carcinoma), TGC-019 (MCF-7, mammary cancer), TGC-039 (BEL-7402, liver cancer).The concentration of used four kinds of cells is all 5 * 10 in the experiment
6/ ml.
Sample preparation: the 110.8mg medicine is placed in the sterilization mortar, add the moistening suspending agent of doing of 50ul tween-80 (account for final drug solution cumulative volume 1%), add 0.5% Xylo-Mucine (CMC-Na) solution 7.72ml again, be ground into suspension and use with the physiological saline preparation.Concentration is respectively: (the CMC suspendible is irritated stomach to embodiment 13, and dosage is that 1 mmole/kg), compound concentration is 10.4mg/ml, gets 90mg medicine 8.65ml CMC liquid suspendible; (the CMC suspendible is irritated stomach to embodiment 25, and dosage is that 1 mmole/kg), compound concentration is 12mg/ml, gets 97.8mg medicine 8.15ml CMC liquid suspendible; (the CMC suspendible is irritated stomach to embodiment 26, and dosage is that 1 mmole/kg), compound concentration is 13.12mg/ml, gets 111mg medicine 8.46ml CMC liquid suspendible; (the CMC suspendible is irritated stomach to embodiment 29, and dosage is 1 mmole/kg): compound concentration is 13.04mg/ml, gets the 106mg medicine with 8.13ml CMC liquid suspendible.
The antineoplastic medicine capecitabine of listing is made positive control, and dosage l mmole/kg irritates stomach behind the CMC liquid suspendible.
Compound concentration is 14.36mg/ml, gets 110.8mg medicine 7.72ml CMC liquid suspendible.
The negative control group medication: compound method is the same, does not only add medicine when grinding.Administration volume=0.5ml/20g.
Animal is adopted BALB/CA-nu mouse (20-24g), Chinese Academy of Sciences's Shanghai Experimental Animal Center.
The 540nm-630nm reading is carried out in the MTT experiment according to tubular fibre measurement operation rules.Sc represents subcutaneous vaccination, and ip represents the abdominal cavity inoculation.
Table 1 test compounds is to the inhibiting rate (%) of tumour cell
Above experimental result shows that compound of the present invention has good antineoplastic activity, and a plurality of compound activities are higher than the marketed drug capecitabine, so The compounds of this invention or its medicinal salts can be used to prepare antitumor drug.
Claims (11)
1. compound or pharmaceutically acceptable salt thereof with following formula (I):
Wherein, R is selected from-XR
3Or
Group;
Wherein:
X represents O or S;
R
3Be selected from hydrogen, C
1-6Straight or branched alkyl, phenyl and randomly by C
1-6Alkyl or C
1-6The phenyl that alkoxyl group replaces;
R
4And R
5Be independently selected from hydrogen or two (C
1-6) alkylamino, condition is R
4And R
5In at least one group is arranged for hydrogen;
Perhaps R
4And R
5Can combine into ring, form the pyrrolidyl of N-replacement or the piperidines that N-replaces, described substituting group is selected from C
1-3Alkyl.
2. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R
1, R
2, XR
3, R
4And R
5Be selected from:
3. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound is selected from:
1-(5 '-deoxidation-β-D-ribofuranose)-4-(methoxyl group)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(oxyethyl group)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(propoxy-)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(n-butoxy)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(isopropoxy)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(phenoxy group)-5-fluoro-pyrimidine-2-(1H)-ketone;
5 '-deoxidation-5-fluoro-thio uridine;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(ethylmercapto group)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(rosickyite base)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(butylthio)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(iprotiazem base)-5-fluoro-pyrimidine-2-(1H)-ketone;
1-(5 '-deoxidation-β-D-ribofuranose)-4-(thiophenyl)-5-fluoro-pyrimidine-2-(1H)-ketone;
5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-((dipropyl amido) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-((dibutyl amino) methylene radical) cytidine;
5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine; Or
5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) piperidines subunit) cytidine.
4. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound is selected from:
1-(5 '-deoxidation-β-D-ribofuranose)-4-(methoxyl group)-5-fluoro-pyrimidine-2-(1H)-ketone;
5 '-deoxidation-5-fluoro-N
4-((dimethylin) methylene radical) cytidine
5 '-deoxidation-5-fluoro-N
4-((diethylin) methylene radical) cytidine; Or
5 '-deoxidation-5-fluoro-N
4-(2-(1-methyl) pyrrolidylidene) cytidine.
5. as the preparation method of the arbitrary described compound or pharmaceutically acceptable salt thereof of claim 1-4, comprising:
(a) make compound (B) with
React, get the compound of general formula (D):
(c) make Compound D and HXR
3Reaction, saponification then obtains general formula F compound:
(d) make compound (D) and NH
3Reaction obtains compound (G) after the saponification, and then with
Reaction obtains general formula (H) compound:
Wherein said X, R
3-R
5Definition and claim 1 in identical, R
6Be selected from C
1-6Alkyloyl or C
6-10Aroyl;
When (e) needing, (c) or the compound that (d) obtains be converted into its pharmaceutical salts.
6. preparation method as claimed in claim 5, wherein, described saponifying agent is selected from mineral alkali or C
1-4Sodium alkoxide or ammoniacal liquor; Described saponification reaction solvent is selected from C
1-4Fatty Alcohol(C12-C14 and C12-C18), water or its combination.
7. preparation method as claimed in claim 6, wherein said mineral alkali is selected from sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, described C
1-4Sodium alkoxide is selected from sodium methylate or sodium ethylate; Described C
1-4Fatty Alcohol(C12-C14 and C12-C18) is selected from methyl alcohol, ethanol, propyl alcohol or Virahol.
8. preparation method as claimed in claim 5, step (a) and 1,2 wherein, the condensing agent phosphorus oxychloride or the tribromo oxygen phosphorus of the reaction of 4-triazole; Acid binding agent is pyridine, triethylamine; Solvent is single halogen or polyhalid alkane, second cyanogen; In the step (c) with HXR
3The solvent of reaction is selected from ether, benzene, tetrahydrofuran (THF), single halogen or polyhalid alkane, dioxane, second cyanogen or its combination; In the step (d) with NH
3The solvent of reaction is selected from ether, benzene, tetrahydrofuran (THF), single halogen or polyhalid alkane, dioxane, second cyanogen; With N, the solvent of the disubstituted dimethylacetal reaction of N-is selected from C in the step (d)
1-4Fatty Alcohol(C12-C14 and C12-C18), C
1-4Single halogen or polyhalid alkane, C
1-4Aliphatic ether, acetonitrile, dioxane.
9. preparation method as claimed in claim 8, with N, the solvent of the disubstituted dimethylacetal reaction of N-is methyl alcohol, ethanol, ether in the step (d).
10. antineoplastic pharmaceutical compositions, it comprises arbitrary described compound or pharmaceutically acceptable salt thereof as claim 1-4, and pharmaceutically acceptable carrier.
11. as the application of the arbitrary described compound or pharmaceutically acceptable salt thereof of claim 1-4 in the preparation antitumor drug.
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| US4071680A (en) * | 1976-12-20 | 1978-01-31 | Hoffmann-La Roche Inc. | 5'-Deoxy-5-fluoropyrimidine nucleosides |
| JP7103149B2 (en) * | 2018-10-15 | 2022-07-20 | コニカミノルタ株式会社 | Information processing device, common processing execution method and common processing execution program |
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| US4071680A (en) * | 1976-12-20 | 1978-01-31 | Hoffmann-La Roche Inc. | 5'-Deoxy-5-fluoropyrimidine nucleosides |
| JP7103149B2 (en) * | 2018-10-15 | 2022-07-20 | コニカミノルタ株式会社 | Information processing device, common processing execution method and common processing execution program |
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