http://rdf.ncbi.nlm.nih.gov/pubchem/patent/KR-20110115601-A
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_60da379fb33c192ef77f86a60c5ac029 http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_32f9a8e7588f433211b1445cf231d492 |
| classificationCPCAdditional | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/Y02A50-30 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K2300-00 |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K45-06 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-18 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-22 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P35-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-14 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07H19-16 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07H19-173 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07H19-20 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-712 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-708 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7105 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7028 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-706 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7068 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7076 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7042 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7052 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-675 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-7064 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D473-16 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D473-18 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07H19-00 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61P35-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-7076 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07H19-16 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D473-18 |
| filingDate | 2010-02-09-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_992cd0ff63bf0806c5b1fd42218dd5df http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_7ded3723c77042aa0ddfa4b777d6324d http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_2d6c453253168d571e484742e394330f http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_4c924efcf010e6de97173c9ecf24b876 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_b791e7fa2f20cc8e75a8f10722958ff6 |
| publicationDate | 2011-10-21-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | KR-20110115601-A |
| titleOfInvention | Purine nucleoside monophosphate prodrugs for the treatment of cancer and viral infections |
| abstract | The present invention relates to cancer or HIV-1, HIV-2, HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever in the host. Or to compounds, methods and compositions for the treatment and prevention of HBV infection. The method is cancer or HIV-1, HIV-2, HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever, or Therapeutically or prophylactically-effectively administering one or more compounds described for the treatment or prevention of HBV infection, or administering an amount sufficient to reduce biological activity. The pharmaceutical composition is cancer or HIV-1, HIV-2, HCV, Norovirus, Saporovirus, HSV-1, HSV-2, Dengue virus, Yellow fever Or combinations with one or more compounds, pharmaceutically acceptable carriers or excipients described herein, for the treatment or prevention of HBV infection. The formulas may further comprise at least one therapeutic agent. In addition, the present invention includes processes for preparing such compounds. Like the hepatitis C virus replicon, norovirus replicons require viral helicase, protease, and polymerase, which have the function for the replication of the resulting replicon. The replicon can be used in high throughput assays, which is evidence that the compound identified as active inhibits the replication of the replicon, whether the norovirus helicase, protease, and / or polymerase inhibits the ability to function. Evaluate. The compound is a monophosphate or monophosphate form of various 6-substituted-2-amino purine nucleosides, or an analog of the monophosphate form, and when administered into the human body Transformed into triphosphorylated. We have surprisingly found that the preparation of the monophosphate prodrug form of the nucleoside protects the conversion of the 6-position substituent to the G analog. By preparing monophosphate prodrugs, we found a way to transfer nucleotide triphosphate to polymerase EH to reverse transcriptase, which was not possible before this invention, or at least not at pharmaceutically acceptable concentrations. The present invention enables a new and novel series of nucleotide triphosphates produced in the human body and requires its use as antiviral or anticancer agents. The compounds described in the present invention include monophosphates, phosphonates, and other analogs of β-D and β-L-6-substituted-2-amino purine nucleosides. In one embodiment of the invention, the active compound is of formula (I): Or in the pharmaceutically acceptable salts or prodrugs of formula (I): Iii) R 1 is an atom or group that is removed in vivo to form OH when administered as a parent nucleoside, for example halogen (F, Cl, Br, I), OR ', N (R ') 2 , SR', OCOR ', NHCOR', N (COR ') COR', SCOR 'and NHCOOR' Each R 'is independently H, lower alkyl (C 1 -C 6 ), lower haloalkyl (C 1 -C 6 ), lower alkoxy (C 1 -C 6 ), lower alkenyl (C 2 -C 6 ), Lower alkynyl (C 2 -C 6 ), lower cycloalkyl (C 3 -C 6 ) aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the group is It may be substituted with one or more substituents defined, for example hydroxyalkyl, aminoalkyl and alkoxy alkyl. Iii) W is independently N, CH, CF, CCN, CC≡CH, or CC (O) N (R ') 2 ; Iii) Sugar is ribose or modified ribose having a structure of Formula II; In Chemical Formula II, Y is O or S; Z is selected from the group consisting of CL 2 , CL 2 CL 2 , CL 2 OCL 2 , CL 2 SCL 2 , CL 2 O, OCL 2 and CL 2 NHCL 2 , where L is independently H, F, alkyl, al Selected from the group consisting of kenyl and alkynyl, wherein alkyl, alkenyl, alkynyl may each contain one or more heteroatoms as required; A is O, S, CH 2 , CHF, CF 2 , C = CH 2 , C = CHF, or C = CF 2 ; R 4 ' , R 5 , R 5' , R 6 , R 6 ' and R 7' are independently H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, NHNH 2 , N 3 , C Is selected from the group consisting of (O) OH, CN, C (O) NH 2 , C (S) NH 2, C (O) OR, R, OR, SR, SSR, NHR, and NR 2 ; In formula (I) having a sugar of formula (II), when A is O, the sugar is formula (II), R 4 ′ , R 5 , R 5 ′ , R 6 , R 7 ′ is H, and R 6 ′ is N 3 Cannot be; In formula (I) having a sugar of formula (II), when A is O or S, R 7 ' cannot be OH, SH, NH 2 , NHOH, NHNH 2 , OR, SR, SSR, NHR, and NR 2 ; R is independently lower alkyl (C 1 -C 6 alkyl), lower alkenyl, lower alkynyl, lower cycloalkyl (C3-C 6 cycloalkyl), aryl, alkylaryl, or arylalkyl, the group defined above It may be substituted with one or more substituents, for example hydroxyalkyl, aminoalkyl and alkoxy alkyl. R 2 And R 3 , when administered in vivo, theoretically provides the nucleoside monophosphate, monophosphonate, thiomonophosphonate, or thiomonophosphate There is strength. Representative R 2 And R 3 is independently selected from: (a) With respect to OR 8 , R 8 is H, C 1 -20 alkyl, C 3 -6 cycloalkyl, C 1 -6 haloalkyl, but it is not limited to, inde aryl, or heteroaryl C 1 -6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C 1 -6 alkoxy, (CH 2) 1-6 CO 2 R 9a, halogen, C 1 -6 haloalkyl, -N (R 9a) 2, C 1 -6 acylamino, - NHSO 2 C 1 -6 alkyl, -SO 2 N (R 9a) 2, -SO 2 C 1 -6 alkyl, COR 9b, nitro, cyano and phenyl which is substituted if necessary by one to three substituents independently selected from the group consisting of furnace that Or naphthyl; R 9a is independently H or C 1 -6 alkyl; R 9b is —OR 9a or —N (R 9a ) 2 ; (b) Against R 10a And R 10b is (Ⅰ) H, C 1 -10 alkyl, - (CH 2) r NR 9a 2, C 1 -6 alkyl, hydroxy, -CH 2 SH, - (CH 2) 2 S (O) p Me, - (CH 2 ) 3 NHC (= NH) NH 2 , (1 H -indol-3-yl) methyl, (1 H -imidazole-4 -Yl) methyl, - (CH 2) m COR 9b, aryl and -C 1 -3 are independently selected from the group been configured as alkyl, and the aryl group is a hydroxyl, C 1 -10 alkyl, C 1 -6 Optionally selected from the group consisting of alkoxy, halogen, nitro, and cyano; (Ⅱ) R 10a and R 10b is H and R 12 is (CH 2) forming a ring containing the N and C atom adjacent with 2- 4; (Iii) R 10a and R 10b together are (CH 2 ) n forming a ring; (Ⅳ) R 10a and R 10b both C 1 -6 Alkyl; or (Iii) R 10a is H and R 10b is H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 , CH 2 Ph , CH 2 -indol-3-yl, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C (O) NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C (O) NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 -CH 2 CH 2 CH 2 NHC (NH) NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH (OH) CH 3 , CH 2 ((4 '-OH) -Ph), CH 2 SH, or lower cycloalkyl; p is 0 to 2; r is 1 to 6; n is 4 to 5; m is 0 to 3; R 11 is H, C 1 -10 alkyl, or C 1 -10 alkyl which is substituted by lower alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow (fluoro), C 3-10 cycloalkyl, inde heteroaryl, substituted aryl, or substituted heteroaryl group, such as cycloalkyl-alkyl (alkyl cycloalkyl), cycloalkyl-heteroalkyl (cycloheteroalkyl), phenyl (phenyl) aryl, pyridinyl (pyridinyl), such as where and amino, flow, C 3 -10 cycloalkyl, or cycloalkyl, wherein the substituent is C 1 -5 alkyl, or a substituted C 1 -5 alkyl, alkoxy, di (lower alkyl) lower alkyl R 12 is H, C 1 -3 alkyl, or R 10a Or or, R 10b and R 12 are together (CH 2) 4 2- to form a ring containing the N and C atoms. (c) O with lipids (including phospholipids), N or O with peptides, O with cholesterol, or O with phytosterols; (d) R 2 and R 3 together May create a ring, in which W 2 is alkenyl selected from the group consisting of phenyl or heteroaryl between mono and if necessary C 1 -6 alkyl, CF 3, C 2 -6 Al, C 1 -6 alkoxy, OR 9c , CO 2 R 9a, COR 9a , halogen, C 1 -6 haloalkyl, -N (R 9a) 2, C 1-6 acylamino, CO 2 N (R 9a) 2, SR 9a, -NHSO 2 C 1 -6 alkyl, -SO 2 N (R 9a) 2, -SO 2 C 1 -6 alkyl, COR 9b, and from the group consisting of cyano and substituted independently with one to three substituents selected, wherein the monocyclic heteroaryl Aryl and substituted monocyclic heteroaryls have 1-2 heteroatoms independently selected from the group consisting of N, O and S, under the following conditions: a) when there are two hetero atoms and one is O, the other cannot be O or S, b) when there are two hetero atoms and one is S, the other cannot be O or S; R 9a is independently H or C 1 -6 alkyl; R 9b is —OR 9a or —N (R 9a ) 2 ; R 9c is H or C 1 -6 acyl; (e) Inde wherein, R 13 is H, C 1 -10 alkyl, C 1 -10 replaced as necessary by a lower alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow ( fluoro), C 3 -10 cycloalkyl, such as cycloalkyl-alkyl (alkyl cycloalkyl), cycloalkyl heteroalkyl, aryl such as phenyl, pyridinyl page interrogating aryl, substituted aryl, or substituted heteroaryl; Wherein the substituents are C 1 -5 alkyl, or lower alkyl substituted by a C 1 -5 alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow (fluoro), C 3 -10 Cycloalkyl, or cycloalkyl; f) R 2 and R 3 together Can form a ring, wherein R 14 is (i) H, C 1 -10 alkyl, - (CH 2) r NR 2 9a, C 1 -6 alkyl, hydroxy, -CH 2 SH, - (CH 2) 2 S (O) p Me,-(CH 2 ) 3 NHC (= NH) NH 2 , (1 H -indol-3-yl) methyl, (1 H -imidazol-4-yl) methyl,-(CH 2) m COR 9b, aryl and -C 1 - 3 alkyl, heteroaryl and heteroaryl -C 1 -3 are selected independently from the group been configured as alkyl, and the aryl and heteroaryl groups are as necessary hydroxyl, C 1 -10 alkyl, C 1 -6 alkoxy, halogen, and substituted by a group selected from nitro, and cyano group consisting of; ( ii ) R 14 is H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 , CH 2 Ph, CH 2 -indole -3-yl, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C (O) NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C (O) NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC (NH) NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH (OH) CH 3 , CH 2 ((4'-OH)- Ph), CH 2 SH, or lower cycloalkyl; p is 0 to 2; r is 1 to 6; m is from 0 to 3 Q 1 is NR 9a , O, or S; Q 2 is C 1 -10 alkyl, C 1 -6 alkyl, hydroxy, aryl and -C 1 -3 alkyl, heteroaryl and heteroaryl -C 1 -3 alkyl, and the aryl and heteroaryl groups are as necessary hydroxyl, which is substituted by C 1 -10 alkyl, a group selected from the group consisting of C 1 -6 alkoxy, and chloro-flow; R 11 is H, C 1 -10 alkyl, lower alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow (fluoro), C 3 -10 cycloalkyl, cycloalkylalkyl ( cycloalkyl alkyl), such as a cycloalkyl heteroalkyl, aryl such as phenyl, pyridinyl page interrogating aryl, substituted aryl or substituted heteroaryl is substituted if necessary by C 1 -10 alkyl and; Where the substituents are C 1 -5 alkyl, or lower alkyl substituted by a C 1 -5 alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow (fluoro), C 3 -10 cycloalkyl, or cycloalkyl; R 12 is H, or C 1 or -3 alkyl, or R 14b and R 12 are for forming a ring containing the N and C atom adjacent (CH 2) 2-, and 4; Iii) The other sugar (Sugar) is generally a modified ribose having the structure of formula (III): Here it is: A, R 2 , R 3 , Y, Z, R 4 ′ R 5 ′ , R 6 ′ , and R 7 ′ are as defined above; In formula (I) having a sugar of formula (III), when A is O or S, R 7 ′ is OH, SH, NH 2 , NHOH, NHNH 2 , OR, SR, SSR, NHR, and NR 2 Can't be R is independently lower alkyl (C 1 -C 6 alkyl), lower alkenyl, lower alkynyl, lower cycloalkyl (C 3 -C 6 cycloalkyl) aryl, alkylaryl, or arylalkyl Wherein the group may be substituted with one or more substituents as defined above, such as hydroxyalkyl, aminoalkyl, and alkoxyalkyl. V) other sugars are dioxolane or oxathiolane of formulas (IV), (V), (VI) and (iii). (Ⅳ) (Ⅴ) (Ⅵ) (iii) Here it is: V is S or Se, R 2 , R 3 , Y, and Z are as defined above. Xii) Another sugar is phosphonylmethoxyalkyl having formula (VII). Here it is: R 2 , R 3 and Y are as defined above; R 15 includes, but is not limited to, alkyl (including but not limited to C 1 -C 6 ), alkenyl (including but not limited to C 2 -C 6 ), and alkynyl (C 2 -C 6) ), Cycloalkyl (including but not limited to C 3 -C 8 ), aryl (including but not limited to C 6 -C 10 ), heteroaryl (including but not limited to C 6 -C 10) Unsubstituted), arylalkyl, and alkylaryl; Iii) other sugars generally have formula (VIII), or formula (VIII). Here it is: R 2 , R 3 , and Y are as defined above; Y 2 is O, S, Se NR; R is independently lower alkyl (C 1 -C 6 alkyl), lower alkenyl, lower alkynyl, lower cycloalkyl (C 3 -C 6 Cycloalkyl) aryl, alkylaryl, or arylalkyl, wherein the group may be substituted with one or more substituents as defined above, such as hydroxyalkyl, aminoalkyl and alkoxyalkyl; R 16 and R 17 are defined as H, CH 3 , CH 2 OR 18 ; R 18 is H or lower acyl (C 1 -C 6 ). Iii) Other sugars are modified ribose, generally having the formula (XI). Here it is: R 2 , R 3 , and Y are as defined above; R 4 ' R 5 , R 5' , R 6 , and R 6 ' are as defined above; R 19 is H, F, Cl, Br, I, N 3 , C (O) OH, CN, C (O) NH 2 , C (S) NH 2 , C (O) OR, R. R is independently lower alkyl (C 1 -C 6 alkyl), lower alkenyl, lower alkynyl, lower cycloalkyl (C 3 -C 6 ) aryl, alkylaryl, or arylalkyl, wherein the group is It may be substituted with one or more substituents defined, for example hydroxyalkyl, aminoalkyl and alkoxyalkyl. In one embodiment of the invention, the active compound is H, F, Cl, Br, I, OH, SH, NH 2 , NHOH, NHNH 2 , C (O) OH, CN, C (O) NH 2 , C ( S) NH 2 , C (O) OR, R, OR, SR, SSR, NHR, and NR 2 ; and is a formula (I) having R 6 ' selected from the group consisting of. In another embodiment of the invention, the active compound is of formula (XII), (XIII), or (XIV): Or in the pharmaceutically acceptable salts or prodrugs of the above formulas: R 4 ' R 5 , R 5' , R 6 , Y, A, and R 7 ' are as defined above; R 20 is lower alkyl (C 1 -C 6 alkyl); M is O, S, or NR; R is lower alkyl (C 1 -C 6 alkyl), lower alkenyl, lower alkynyl, lower cycloalkyl (C 3 -C 6 Cycloalkyl) aryl, alkylaryl, or arylalkyl, wherein the group may be substituted with one or more substituents as defined above, such as hydroxyalkyl, aminoalkyl and alkoxyalkyl; Bases can be selected from: In another embodiment of the invention, the active compound is of formula (XV) or (XVI): ( XV ) ( XVI ) Or in the pharmaceutically acceptable salts or prodrugs of the above formulas: R 4 ' , R 5 , R 5' , R 6 , Y, A, R 7 ' , R 20 And bases are as defined above; R 21 is H, C 1 -10 alkyl, lower alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow (fluoro), C 3 -10 cycloalkyl, cycloalkylalkyl ( cycloalkyl alkyl), cycloalkyl heteroalkyl, phenyl, such as aryl, heteroaryl, such as pyridinyl, substituted aryl or substituted heteroaryl is substituted if necessary by C 1 -10 alkyl; Where the substituents are C 1 -5 alkyl, or lower alkyl substituted by a C 1 -5 alkyl, alkoxy, di (lower alkyl) amino (di (lower alkyl) -amino), a flow (fluoro), C 3 -10 cycloalkyl, or cycloalkyl; R 22 is H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CH (CH 3 ) CH 2 CH 3 , CH 2 Ph, CH 2 -indole-3- 1, -CH 2 CH 2 SCH 3 , CH 2 CO 2 H, CH 2 C (O) NH 2 , CH 2 CH 2 COOH, CH 2 CH 2 C (O) NH 2 , CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC (NH) NH 2 , CH 2 -imidazol-4-yl, CH 2 OH, CH (OH) CH 3 , CH 2 ((4'-OH) -Ph), CH 2 SH, or lower cycloalkyl; In another embodiment of the invention, the active compound is of formula (XVII) or (XVIII): Or in the pharmaceutically acceptable salts or prodrugs of the above formulas: R 4 ' R 5 , R 5' , R 6 , Y, M, R 7 ' , R 20 , R 21 , R 22 , and base are as defined above; The compounds described above may take the form of a mixture comprising a β-L- or β-D- configuration or a racemic mixture thereof. The compound is a mono-phosphate, for example after preparation of the 5'-OH analog. By modification to phosphonates, or other analogs. In addition, the compounds described herein are inhibitors of HIV-1, HIV-2, HCV, norovirus, saporovirus, HSV-1, HSV-2, dengue virus, yellow fever, cancer, and / or HBV. Therefore, the compounds may also be used to treat patients co-infected with HIV-1, HIV-2, HCV, norovirus, saporovirus, HSV-1, HSV-2, dengue virus, yellow fever, cancer, and / or HBV. Can be used. |
| isCitedBy | http://rdf.ncbi.nlm.nih.gov/pubchem/patent/KR-20160101708-A |
| priorityDate | 2009-02-06-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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Total number of triples: 1082.