WO2010126101A1 - プリン誘導体およびそれを用いた抗腫瘍剤 - Google Patents
プリン誘導体およびそれを用いた抗腫瘍剤 Download PDFInfo
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- WO2010126101A1 WO2010126101A1 PCT/JP2010/057614 JP2010057614W WO2010126101A1 WO 2010126101 A1 WO2010126101 A1 WO 2010126101A1 JP 2010057614 W JP2010057614 W JP 2010057614W WO 2010126101 A1 WO2010126101 A1 WO 2010126101A1
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- compound
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- purine
- methyl
- methoxybenzylsulfanyl
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- 0 NCc1ccc(CC*I)cc1 Chemical compound NCc1ccc(CC*I)cc1 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N C1NCCOC1 Chemical compound C1NCCOC1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- NFKIZZKKEXHBNB-UHFFFAOYSA-N COc1ccc(CSc2nc(N)cc(Cl)n2)cc1 Chemical compound COc1ccc(CSc2nc(N)cc(Cl)n2)cc1 NFKIZZKKEXHBNB-UHFFFAOYSA-N 0.000 description 1
- HWRNHGUKJHLSIT-UHFFFAOYSA-N COc1ccc(CSc2nc(N)cc(N3CCOCC3)n2)cc1 Chemical compound COc1ccc(CSc2nc(N)cc(N3CCOCC3)n2)cc1 HWRNHGUKJHLSIT-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
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- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
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- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
Definitions
- the present invention relates to a purine derivative and a composition thereof, and also relates to a method for treating a tumor and an antitumor agent using the purine derivative.
- 6-Mercaptopurine which is currently used as an anticancer agent, was discovered in 1948 by Hitchings et al. During the study of antimetabolites, and in 1952 Elion et al. Synthesized from Hypoxanthine. In 1953, Clarke, Law et al. Experimentally confirmed its anti-tumor activity, and for the first time in 1953 Burchenal et al. Clinically applied and excellent effects not only for acute childhood leukemia but also for adult acute leukemia. Was recognized. Therefore, it is also the first substance called anti-leukemic drug among many known leukemia chemotherapeutic agents. In addition, it is known to be used and effective at the early or late stages of chronic leukemia.
- 6-Mercaptopurine is a therapeutic agent for nucleic acid anti-metabolic leukemia which is effective when administered orally, and is used for amelioration of subjective and objective symptoms of acute leukemia and chronic myelogenous leukemia.
- QOL quality of life
- this drug is also used as antimetabolite immunosuppressant, and it is used in cases where predonin ineffective and predonin withdrawal and weight loss are difficult. You need to be aware of the side effects, as it takes three to four months for the effects to appear. Furthermore, as a side effect, it is easy to cause an infection due to bone marrow suppression and to cause kidney damage. In addition, it becomes resistant to all kinds of bacteria, including colds. In addition, various complications may occur.
- the present invention aims to provide novel purine derivatives and compositions, methods of treating tumors using purine derivatives, and antitumor agents.
- a purine derivative or a pharmaceutically acceptable salt, solvate or hydrate thereof is provided.
- the above purine derivative has the following general formula (I): It is a compound represented by
- Ar represents a phenyl group, pyridyl group, thiazolyl group, benzofuranyl group, dihydrobenzofuranyl group, naphthalenyl group, imidazolyl group or pyrazolyl group.
- the above-mentioned phenyl group, pyridyl group, thiazolyl group, benzofuranyl group, dihydrobenzofuranyl group, naphthalenyl group, imidazolyl group or pyrazolyl group is halogen, formyl group, cyano group, nitro group, amino group, hydroxyl group, carboxyl group.
- Y represents a (C1-C6) alkylene group.
- the (C1-C6) alkylene group may contain a carbonyl group in the carbon chain.
- the (C1-C6) alkylene group may be substituted one or two times by Ar.
- R 1 represents a (C1-C6) alkyl group, a (C2-C6) alkenyl group, an amino group, a (C1-C6) alkylcarbonylamino group, a heterocyclic group or a phenyl group.
- the above amino group or (C1-C6) alkylcarbonylamino group is a (C1-C6) alkyl group, a (C1-C6) alkoxy group, a (C1-C6) alkoxy (C1-C6) alkyl group, (C3-C6).
- C6) may be substituted by 1 or 2 by a cycloalkyl group or a (C2-C6) alkenyl group.
- the above-mentioned heterocyclic group is a nitroso group, a formyl group, a hydroxyl group, a (C1-C6) alkyl group, a (C1-C6) alkyl carbonyl group, a (C1-C6) alkoxy group, a (C1-C6) alkoxy carbonyl group Or may be substituted one or two by a hydroxy (C 1 -C 6) alkylamino group.
- the above phenyl group may be substituted one or two by halogen, formyl group, cyano group, nitro group, amino group, hydroxyl group, (C3-C6) or carboxyl group.
- R 2 represents H, a (C 1 -C 6) alkyl group, a (C 2 -C 6) alkenyl group, a (C 2 -C 6) alkynyl group or a (C 3 -C 6) cycloalkyl group.
- the above (C1-C6) alkyl group, (C2-C6) alkenyl group, (C2-C6) alkynyl group or (C3-C6) cycloalkyl group is substituted one or two times by halogen, nitro group or amino group. It may be done.
- R 3 represents a (C 1 -C 6) alkyl group, a (C 2 -C 6) alkenyl group, a (C 2 -C 6) alkynyl group, a (C 3 -C 6) cycloalkyl group, a (C 3 -C 6) cyclo group Represents an alkyl (C1-C6) alkyl group, an amino (C1-C6) alkyl group, a 3- to 5-membered cyclic ether- (C1-C6) alkyl group or a (C1-C6) alkylcarbonylamino (C1-C6) alkyl group .
- An amino (C1-C6) alkyl group, a 3- to 5-membered cyclic ether- (C1-C6) alkyl group or a (C1-C6) alkylcarbonylamino (C1-C6) alkyl group is substituted by a halogen or a hydroxyl group May be
- the above-mentioned purine derivative, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and a pharmaceutically acceptable adjuvant, diluent or carrier thereof there is provided a composition comprising
- a pharmaceutical composition for treating a tumor which comprises the above-mentioned purine derivative or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- an antitumor agent comprising the above-mentioned purine derivative, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- treatment of a tumor comprising administering to a patient (in need) a purine derivative as described above, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- a method is provided.
- the Purine Derivative as described above or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for use in the treatment of a tumor.
- a purine derivative as described above or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, in the manufacture of a medicament for treating a tumor.
- halogen or halo mean fluorine, chlorine, bromine or iodine.
- hydroxyl means an -OH group.
- cyano means a -CN group.
- amino means an -NH 2 group or a divalent or trivalent group in which hydrogen is substituted on another atom.
- nitro means an -NO 2 group.
- nitroso refers to the -NO group.
- alkyl alkenyl, alkynyl or cycloalkyl
- alkyl alkenyl, alkynyl or cycloalkyl
- alkylene alkenylene, alkynylene or cycloalkylene
- (Cx-Cy) alkyl has x to y carbon atoms Means each group having When any divalent or higher group is substituted at a position capable of forming a single ring or a multiple ring, the divalent or higher group may form a ring structure unless otherwise specified.
- (C 1 -C 6) alkyl or “(C 1 -C 6) alkylene” mean a branched or linear saturated hydrocarbon group having 1 to 6 carbon atoms, for example, (C 1 -C 6) alkyl C3) alkyl, (C1-C4) alkyl, (C1-C6) alkyl, (C2-C6) alkyl, (C3-C6) alkyl and the like.
- Representative (C1-C6) alkyls include, for example, methyl, ethyl, propyl (eg, propan-1-yl, propan-2-yl [or iso-propyl]), butyl (eg, 2-methylpropane- 2-yl [or tert-butyl], butan-1-yl, butan-2-yl), pentyl (eg, pentan-1-yl, pentan-2-yl, pentan-3-yl), 2-methylbutane- 1-yl, 3-methylbutan-1-yl, hexyl (eg, hexane-1-yl) and the like.
- propyl eg, propan-1-yl, propan-2-yl [or iso-propyl]
- butyl eg, 2-methylpropane- 2-yl [or tert-butyl], butan-1-yl, butan-2-yl
- pentyl eg, pentan
- (C 2 -C 6) alkenyl or “(C 2 -C 6) alkenylene” refer to linear or branched non-linear having 2 to 6 carbon atoms and at least one carbon-carbon double bond.
- An aromatic hydrocarbon group is meant, including, for example, (C2-C3) alkenyl, (C2-C4) alkenyl, (C2-C6) alkenyl, (C3-C6) alkenyl, (C4-C6) alkenyl and the like .
- Representative (C2-C6) alkenyl groups include, for example, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl -1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, and 5- Hexenyl and the like.
- (C 2 -C 6) alkynyl or “(C 2 -C 6) alkynylene” are linear or branched non-aromatic having 2 to 6 carbon atoms and at least one carbon-carbon triple bond
- hydrocarbon group means a hydrocarbon group having a group character, and includes, for example, (C2-C3) alkynyl, (C2-C4) alkynyl, (C2-C6) alkynyl, (C3-C6) alkynyl, (C4-C6) alkynyl and the like.
- Representative (C2-C6) alkynyl groups include, for example, ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-budienyl, 2-budienyl, 3-budienyl, 2-methyl-1-propynyl, 1 -Pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl and the like.
- (C3-C6) cycloalkyl means a saturated monocyclic carbocycle having from 3 to 6 carbon atoms.
- Representative (C3-C6) cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- alkoxy or "alkyloxy” refer to the group --O--R where R is alkyl as described above. Also, when the term “R oxy” is used, it means a -OR group which is a monovalent or divalent group.
- (C1-C6) alkoxy means a (C1-C6) alkyl-O- group, for example (C1-C3) alkoxy, (C1-C4) alkoxy, (C1-C6) alkoxy, ( C2-C6) alkoxy, (C3-C6) alkoxy and the like.
- Representative (C 1 -C 6) alkoxy includes, for example, methoxy, ethoxy, prop-oxy (eg, 1-prop-oxy, 2-prop-oxy), butoxy (eg, 1-butoxy, 2-butoxy, 2 And -methyl-2-prop-oxy), penta-oxy (1-penta-oxy, 2-penta-oxy), hexa-oxy (1-hexa-oxy, 3-hexa-oxy) and the like.
- alkylthio means a group -SR where R is alkyl as described above. Also, when the term “R thio” is used, it refers to a monovalent or divalent group -S-R group.
- the ring, bicyclic or polycyclic, saturated or unsaturated non-aromatic group or aromatic group (heteroaryl) is meant.
- Heterocyclic groups include, for example, non-aromatic cyclic amino groups.
- the heterocyclic group in the present invention is preferably a 5- to 7-membered ring, more preferably a 5- or 6-membered ring.
- heterocyclic groups include, for example, morpholino, oxazinyl, dihydrooxazinyl, piperazinyl, thiomorpholino, piperidino, pyrrolidinyl, homomorpholino, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, pyridinyl, pyrimidinyl, pyridazinyl, Pyrazinyl, oxazolyl, isoxazolyl, thienyl or furyl and the like can be mentioned.
- non-aromatic cyclic amino means a mono-, bi- or polycyclic non-aromatic group containing a nitrogen atom in the ring.
- Representative non-aromatic cyclic aminos include, for example, morpholino, dihydrooxazinyl, piperazinyl, thiomorpholino, piperidino, pyrrolidinyl, homomorpholino and the like.
- three- to five-membered cyclic ether means a three-, four- to five-membered saturated or non-aromatic unsaturated carbocycle containing an oxygen atom in the ring, ie an ether linkage.
- a representative three-membered cyclic ether group is an oxiranyl group.
- aryl means mono-, bi- or polycyclic carbocyclic aromatic rings. Representative aryls include phenyl, naphthalenyl and the like.
- Representative heteroaryls include pyridyl, thiazolyl, benzofuranyl, dihydrobenzofuranyl, imidazolyl, pyrazolyl and the like.
- saturated or unsaturated is whether the group in question is a saturated group free of double bonds or triple bonds, or an unsaturated group containing at least one double bond or triple bond It means that it is either.
- substitutions are 1, 2, 3, 4 or 5, but preferably 1, 2 or 3, more preferably 1 or 2, even more preferably 1 number of substitutions.
- substituents may be the same or different.
- an alkylene group which may contain a carbonyl group includes an alkylene group, an alkylene carbonyl group, a carbonyl alkylene group, an alkylene carbonyl alkylene group and a carbonyl alkylene carbonyl group.
- Ar is optionally substituted by halogen, formyl group, cyano group, nitro group, amino group, hydroxyl group or carboxyl group; or alternatively, halogen, cyano group, amino group, hydroxyl group or carboxyl group, (C1-C6 ) Alkyl group, (C2-C6) alkenyl group, (C1-C6) alkyl carbonyl group, (C1-C6) alkyl amino group, (C1-C6) alkyl carbonyl amino carbonyl group, (C3-C6) cycloalkyl amino group , (C1-C7) alkoxycarbonylamino group, di [(C1-C6) alkyl] amino group, (C1-C6) alkylcarbonylamino group, (C3-C6) cycloalkylcarbonylamino group, di [(C1-C6) ) Alkyl] aminocarbonylamino group
- Ar may be substituted with halogen, formyl group, cyano group, nitro group, amino group, hydroxyl group or carboxyl group; or alternatively, halogen, cyano group, amino group, hydroxyl group or carboxyl group, (C1-C6 ) Alkyl group, (C2-C6) alkenyl group, (C1-C6) alkyl carbonyl group, (C1-C6) alkyl amino group, (C3-C6) cycloalkyl amino group, (C1-C6) alkoxy carbonyl amino group, Di [(C1-C6) alkyl] amino group, (C1-C6) alkylcarbonylamino group, (C3-C6) cycloalkylcarbonylamino group, di [(C1-C6) alkyl] aminocarbonylamino group, di [(di) [C1-C6) alkyl] aminothiocarbonylamino group, heteroarylcarbonyl Mino
- (C1-C6) alkyl group Ar may be substituted with halogen, formyl group, cyano group, nitro group, amino group, hydroxyl group, carboxyl group; or, alternatively, halogen.
- the divalent or higher group when any divalent or higher group is substituted at a position capable of forming a single ring or a multiple ring, the divalent or higher group may form a ring structure unless otherwise specified.
- a (C 1 -C 6) alkylenedioxy group forms a ring structure to be substituted, a structure as shown below can be formed.
- Ar is a halogen, a cyano group, a nitro group, an amino group, a hydroxyl group, a (C1-C6) alkyl group, a (C2-C6) alkenyl group, a (C1-C6) alkyl carbonyl Amino group, heteroarylcarbonylamino group, phenylcarbonylamino group, di [(C1-C6) alkyl] aminosulfonylamino group, (C1-C6) alkoxy group, phenyl (C1-C6) alkoxy group or amino (C1-C6) )
- the compound according to any one of the above aspects which is a phenyl group, a naphthalenyl group or a pyrazolyl group which may be independently substituted 1, 2 or 3 with an alkylcarbonylamino group, or a pharmaceutically acceptable thereof Salts, solvates, hydrates or prodrugs.
- a further preferred embodiment of the present invention is a compound according to any one of the above embodiments, wherein Y is a (C1-C6) alkylene group, or a pharmaceutically acceptable salt, solvate, hydrate thereof Or a prodrug.
- R 1 is a (C2-C6) alkenyl group; An amino group or a (C1-C6) alkylcarbonylamino group which may be two-substituted; or a nitroso group, a (C1-C6) alkyl group, a (C1-C6) alkyl carbonyl group or a (C1-C6) alkoxy group
- an amino group or (C1-C6) alkyl in which R 1 may be substituted one or two times with a (C1-C6) alkyl group or a (C1-C6) alkoxy group Any of the above, which is a carbonylamino group; or a heterocyclic group which may be substituted one or two times by a nitroso group, a (C1-C6) alkyl group or a (C1-C6) alkyl carbonyl group;
- still another aspect of the present invention is an amino group wherein R 1 is a (C 2 -C 6) alkenyl group; or, alternatively, one or two substituents may be substituted by a (C 1 -C 6) alkyl group or (C 1 -C6) an alkylcarbonylamino group; or 1 or 2 optionally substituted by a nitroso group, a (C1-C6) alkyl group, a (C1-C6) alkylcarbonyl group or a (C1-C6) alkoxycarbonyl group A non-aromatic cyclic amino group; a compound of any of the above aspects, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- a compound, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof any of the above embodiments.
- the heterocyclic group is morpholino group, oxazinyl group, dihydrooxazinyl group, piperazinyl group, thiomorpholino group, piperidino group, pyridinyl group, homomorpholino group, pyrrolinyl group, pyrrolyl group, imidazolyl
- the pharmaceutical preparation thereof according to any of the above aspects, which is a group, pyrazolyl group, triazolyl group, triazinyl group, pyridinyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, oxazolyl group, isoxazolyl group, thienyl group or furyl group
- Pharmaceutically acceptable salts, solvates, hydrates or prodrugs Pharmaceutically acceptable salts, solvates, hydrates or prodrugs.
- the heterocyclic group is morpholino group, oxazinyl group, dihydrooxazinyl group, piperazinyl group, pyrrolinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, oxazolyl group, isoxazolyl group
- the present invention is a compound according to any of the above embodiments, wherein the heterocyclic group is morpholino group, dihydrooxazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isoxazolyl group or thienyl group. Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- Still another embodiment of the present invention is a compound according to any one of the above-mentioned embodiments, wherein the heterocyclic group or the nonaromatic cyclic amino group is a morpholino group or a piperazinyl group, or a pharmaceutically acceptable thereof Salts, solvates, hydrates or prodrugs.
- R 2 is H, (C1-C6) alkyl group, (C2-C6) alkenyl group or (C3-C6) cycloalkyl group Or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- a further preferred embodiment of the present invention is a compound according to any one of the above-mentioned embodiments, wherein R 2 is H, (C1-C6) alkyl group or (C2-C6) alkenyl group, or a pharmaceutically acceptable thereof Salts, solvates, hydrates or prodrugs.
- Another preferred embodiment of the present invention is that (C1-C6) alkyl group, (C2-C6) alkenyl group or acetylamino (C1-C6) alkyl group in which R 3 may be substituted by halogen or hydroxyl group
- (C1-C6) alkyl group, (C2-C6) alkenyl group or acetylamino (C1-C6) alkyl group in which R 3 may be substituted by halogen or hydroxyl group A compound of any of the above aspects, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- a further preferred embodiment of the present invention is a compound according to any one of the above-mentioned embodiments, wherein R 3 is a (C 1 -C 6) alkyl group which may be substituted by a halogen or a hydroxyl group, or a pharmaceutical thereof Are acceptable salts, solvates, hydrates or prodrugs.
- purine derivative of the above aspect examples include, for example, the following compounds, but the purine derivative of the present invention is not limited to these compounds.
- the above-mentioned purine derivative has an asymmetric carbon atom in the structure, it includes both of an isomer derived from the asymmetric carbon atom and a mixture thereof (racemic mixture).
- Methods for preparing, separating and isolating desired stereoisomers from racemic mixtures or non-racemic mixtures are known to those skilled in the art, for example preparation of diastereoisomeric salts or complexes which can be separated by crystallization ; Eg preparation of diastereoisomers which can be separated by crystallization, gas-liquid or liquid chromatography; selective reaction of one optical isomer with an optical isomer specific reagent, eg enzymatic oxidation or reduction and it Subsequent separation of optical isomers; or separation by gas-liquid or liquid chromatography or the like in a chiral environment (eg, in the presence of a chiral support such as linked chiral ligand-bonded silica, or chiral solvent).
- the above-mentioned purine derivative may be in the form of solution in a pharmaceutically acceptable solvent such as, for example, water, ethanol and the like.
- a pharmaceutically acceptable solvent such as, for example, water, ethanol and the like.
- the dissolved form is considered equivalent to the undissolved form for the purposes of the present invention.
- purine derivatives may take the form of hydrates, solvates or pharmaceutically acceptable salts (acid addition salts or base addition salts).
- “Pharmaceutically acceptable salt” means a salt that is pharmaceutically acceptable and capable of exerting the desired pharmacological activity of the parent compound. It is understood that pharmaceutically acceptable salts are within the range of non-toxic or toxic to human body. Further information on suitable pharmaceutically acceptable salts may be found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985, SMBerge et al., "Pharmaceutical Salts", which is incorporated herein by reference. J. Pharm. Sci., 1977; 66: 1-19 etc. as known in the art.
- Examples of pharmaceutically acceptable acid addition salts include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and acetic acid, trifluoroacetic acid, propionic acid, hexanone acid, cyclopentadiene, etc.
- Pentanpropionic acid glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3- (4-hydroxybenzoyl) benzoic acid Acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, Camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid And salts formed by addition of 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl
- Examples of pharmaceutically acceptable base addition salts include, for example, acidic protons present in the parent compound such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. It contains salts replaced by metal ions. Also included are salts derived from organic bases, such as, for example, primary, secondary and tertiary amines, substituted amines and cyclic amines.
- organic bases are, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine Ethylene diamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resin and the like.
- Representative organic bases include, for example, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
- solvates include, for example, dimethyl sulfoxide solvate, dimethylformamide solvate, or alcohol solvate such as ethanol solvate, methanol solvate or n-propyl alcohol solvate, etc.
- alcohol solvate such as ethanol solvate, methanol solvate or n-propyl alcohol solvate, etc.
- Organic solvates and the like are included.
- the above-mentioned purine derivatives or their pharmaceutically acceptable salts, solvates or hydrates and the like may also be in the form of prodrugs.
- Prodrugs mean compounds that are converted in vivo to yield the parent compound, for example, by hydrolysis in blood. Common examples include, but are not limited to, the ester and amide forms of compounds having a carboxyl group, as well as the amide forms of compounds having an amino group.
- Examples of pharmaceutically acceptable esters include, but are not limited to, alkyl esters where the alkyl group is linear or branched (eg, having 1 to 6 carbons) .
- Acceptable esters also include, for example, cycloalkyl esters, arylalkyl esters such as benzyl and the like.
- Examples of pharmaceutically acceptable amides include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (eg, having 1 to 6 carbons) included. These amides and esters can be prepared according to methods known in the art.
- prodrugs can also be prepared by methods known in the art. In general, these methods modify appropriate functional groups of the compound. These modified functional groups reform the original functional group by predetermined manipulation or conversion in vivo. Details on pro-drugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. As is described in Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, it is known in the art.
- the embodiments of the above purine derivative, or a pharmaceutically acceptable salt, solvate or hydrate thereof and the like also include the N-oxide derivative and the protected derivative of the above purine derivative.
- the purine derivative contains a nitrogen atom that can be oxidized, the nitrogen atom can be converted to an N-oxide by methods known in the art.
- the above purine derivatives comprise, for example, groups comprising hydroxy, carboxy or nitrogen atoms, these groups may be protected by appropriate protecting groups. Representative examples of suitable protecting groups are described in T. W. Greene, protective groups in Organic Synthesis, John Wiley & Sons, Inc. 1991, the disclosure of which is incorporated herein by reference. Protected derivatives of the above purine derivatives can also be prepared by methods known in the art.
- purine derivative etc. in the present specification is used as a generic term including all of the above various forms which can be taken by the purine derivative Be
- compositions, a pharmaceutical composition, a preparation, a medicament or a drug comprising the above-mentioned purine derivative etc.
- the above composition, pharmaceutical composition, preparation, medicament or medicament may contain, in addition to the above purine derivative etc., a pharmaceutically acceptable adjuvant, diluent and / or carrier.
- the above composition, pharmaceutical composition, preparation, medicament or drug may further contain other medicine or drug.
- an embodiment of the above composition, pharmaceutical composition, preparation, medicament or drug is any of the above purine derivatives or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof And a pharmaceutically acceptable adjuvant, diluent or carrier.
- compositions, the pharmaceutical composition, the preparation, the medicament or the drug described above are the purine derivatives of any of the above, or a pharmaceutically acceptable salt, solvate, hydrate or It is a pharmaceutical composition for the treatment of a tumor, including a prodrug.
- compositions, the pharmaceutical composition, the preparation, the medicament or the drug described above are the purine derivatives of any of the above, or a pharmaceutically acceptable salt, solvate, hydrate or It is an antitumor agent that contains a prodrug.
- compositions, pharmaceutical composition, preparation, medicament or drug can be administered orally or parenterally, and as a dosage form for oral administration, for example, tablets, fine granules, coated tablets, powders, granules, Capsules (eg, hard gelatin capsules, soft gelatin capsules), microcapsules, syrups and the like can be used.
- a dosage form for parenteral administration for example, an injection (including a lyophilizing agent for injection used by dissolving at the time of use), a suppository, and the like can be used.
- a suppository and the like can be used as a liposomal agent.
- syrups for oral administration and injections for parenteral administration can also be used as (including a lyophilizing agent for injection which is used after dissolving in use).
- compositions, pharmaceutical composition, preparation, medicament or medicament may be, for example, solution, suspension, emulsion, microemulsion, multiphase emulsion, foam, salve, paste, plaster, ointment, coated tablet, rinse, Rectal capsules, drops, gels, sprays, powders, aerosols, inhalants, eye drops, eye ointments, eye rinses, eye rinses, vaginal pessaries, vaginal rings, vaginal ointments, infusions, or implants etc. Good.
- Adjuvants, diluents and / or carriers can be used in the preparation of the compositions, pharmaceutical compositions, formulations, medicaments or medicaments described above.
- auxiliaries for example, coloring agents, sweeteners, flavoring agents, binders, wetting agents, adsorbents, lubricants, disintegrants, softeners, suspending agents, emulsifiers, preservatives, antioxidants, Surfactants, stabilizers, pH adjusters, dispersants, isotonic agents, and / or absorption enhancers can be used, and as the diluent, for example, distilled water or saline can be used. it can.
- the diluent for example, distilled water or saline can be used. it can.
- the above dosage forms may further be provided with a functional coating such as an enteric coating, depending on the situation to be used.
- a functional coating such as an enteric coating
- solid dosage forms they can be prepared, for example, using coatings such as enteric coatings and shells.
- Such dosage forms can also be made to release the compound to certain parts of the intestinal tract in a delayed manner.
- suitable embedding compositions are, for example, polymeric substances and waxes. It may also be in micro-encapsulated form with an excipient.
- excipients for example, crystalline cellulose, saccharides (glucose, sucrose, lactose, D-mannitol, D-sorbitol etc.), starches (corn starch, potato starch, wheat starch, rice starch etc.)
- carboxycellulose for example, crystalline cellulose, saccharides (glucose, sucrose, lactose, D-mannitol, D-sorbitol etc.), starches (corn starch, potato starch, wheat starch, rice starch etc.)
- Magnesium silicate sodium hydrogen phosphate, calcium hydrogen phosphate, sodium citrate, talc and the like.
- disintegrants examples include sodium carbonate, calcium carbonate, gum arabic, starches (corn starch, potato starch, wheat starch, tapioca starch, rice starch etc.), agar, alginic acid, silicate complex, tragacanth, crystals Cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, carmellose sodium, carboxymethyl starch sodium and the like can be mentioned.
- binder for example, cellulose derivatives, starch, alginates, gelatin, polyvinyl pyrrolidone, sucrose, acacia gum and the like can be mentioned.
- wetting agent examples include glycerol, cetyl alcohol, and glycerol monostearate, magnesium stearate, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate and the like.
- a quaternary ammonium compound etc. are mentioned, for example.
- Examples of the above-mentioned adsorbent include kaolin and bentonite.
- lubricant examples include carnauba wax, hydrogenated oil, magnesium stearate, calcium stearate, sodium hydrogen phosphate, calcium hydrogen phosphate, white beeswax and the like.
- preservative examples include paraben, chlorobutanol, phenol, sorbic acid and the like.
- Examples of the above-mentioned isotonic agent include sugar, sodium chloride and the like.
- suspending agent examples include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth and the like.
- aluminum monostearate and gelatin can be used as agents for delaying absorption of injectable drugs.
- Liquid dosage forms for oral administration of the compositions, pharmaceutical compositions, formulations, medicaments or agents described above include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
- Such administration forms generally include, for example, the above-mentioned purine derivatives and the like, for example, distilled water, physiological saline, aqueous dextrose, glycerol, ethanol etc .; for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Solubilisers and emulsifiers such as alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; eg cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol Or carriers such as polyethylene glycols, and oils such as fatty acid
- compositions, formulations, medicaments or medicaments are physiologically acceptable aqueous or non-aqueous sterile solutions, dispersions, suspensions or emulsions, sterile injectable It can be prepared using sterile powders to be reconstituted into solutions and / or dispersions.
- suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include, for example, distilled water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol etc.), suitable mixtures thereof, vegetable oils (eg Olive oil and the like, and injectable organic esters such as ethyl oleate.
- Dosage forms suitable for rectal administration of the above-mentioned compositions, pharmaceutical compositions, formulations, medicaments or medicaments can be prepared as suppositories, using, for example, suitable carriers (excipients).
- the excipient is preferably a non-irritating excipient, such as cocoa butter, polyethylene glycol, or solid at normal temperature but liquid at body temperature and dissolves in an appropriate body cavity where it is active Suppository wax etc. which can release an ingredient are mentioned.
- Dosage forms for topical application of a compound of this invention include ointments, powders, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
- Ophthalmic preparations, ophthalmic ointments, powders and solutions are considered to fall within the scope of this invention.
- any dosage form suitable for the desired delivery route may be used orally or parenterally (eg, transdermal, intradermal, intrabronchial, intranasal Delivered via routes such as intraarterial, intravenous, intramuscular, subcutaneous, intravaginal, transvaginal, transrectal, sublingual, intracranial, epidural, intratracheal, intratracheal or other localized areas) be able to.
- parenterally eg, transdermal, intradermal, intrabronchial, intranasal Delivered via routes such as intraarterial, intravenous, intramuscular, subcutaneous, intravaginal, transvaginal, transrectal, sublingual, intracranial, epidural, intratracheal, intratracheal or other localized areas
- One preferred route of administration including when used prophylactically, is oral administration, in which the dosage etc. can be adjusted according to the severity of the target pathological condition and the quality of life of the user can be enhanced.
- tumors include, for example, lung tumor, prostate tumor, breast tumor, colon tumor, stomach tumor, pancreas tumor, liver tumor (for example, hepatocellular carcinoma, cholangiocarcinoma and the like), esophageal tumor, brain tumor (for example, glia) Blastoma), ovarian tumor, uterine tumor (eg uterine fibroid, endometrial cancer, cervical cancer etc), vaginal cancer, malignant melanoma, renal tumor, head and neck tumor, skin tumor, urological tumor (eg urinary tract tumor) , Bladder tumor, ureteral tumor, pelvic tumor, etc), osteosarcoma, biliary tumor, vulvar tumor, testicular tumor, penile tumor, rectum tumor, mediastinal tumor, urothelial tumor, chorio
- one aspect of the present invention is a pharmaceutical composition or an anti-tumor composition for treating a tumor, which comprises the above-mentioned purine derivative, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.
- a tumor agent and preferred target tumors include lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, liver cancer, esophageal cancer, brain cancer, ovarian cancer, uterine cancer, malignant melanoma, kidney cancer, head and neck cancer , Skin cancer, bladder cancer, osteosarcoma, biliary tract cancer, vulvar cancer, testicular tumor, penile cancer, rectal cancer, mediastinal tumor, urothelial cancer, choriocarcinoma, soft tissue sarcoma, thyroid cancer, parathyroid cancer, adrenal cancer, Malignant pheochromocytomas, germ cell tumors, malignant lymphomas, leukemias and multiple myelomas can be mentioned.
- target tumors of the pharmaceutical composition or anti-tumor agent of the present invention include lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, pancreatic cancer, liver cancer, esophageal cancer, brain cancer, ovarian cancer, uterine cancer, kidney cancer, Head and neck cancer, skin cancer, bladder cancer, vulvar cancer, testicular cancer, testicular cancer, rectal cancer, choriocarcinoma, germ cell tumor, malignant lymphoma, leukemia and multiple myeloma can be mentioned, and even more preferable target tumors include lung cancer , Prostate cancer, breast cancer, gastric cancer, esophagus cancer, brain cancer, ovarian cancer, uterine cancer, head and neck cancer, vulvar cancer, testicular cancer, choriocarcinoma, germ cell tumor, malignant lymphoma, leukemia and multiple myeloma
- Appropriate dosing regimens can be determined based on known technical knowledge, the information provided herein and experience with the individual subject to be treated. In general, it is preferable to administer the above-mentioned purine derivative etc. at a concentration that can produce effective results without causing dangerous or harmful side effects.
- therapeutically effective amount is meant an amount of a Purine Derivative of the invention which ameliorates the symptoms of the disease when administered to a subject.
- the therapeutically effective amount of the above-mentioned purine derivative etc. is the activity, metabolic stability, action time, excretion rate, delivery mode (administration mode) and administration time of each compound, age, weight, general health condition to be treated It may vary depending on a variety of factors, including gender, daily diet, drug combination at the time of administration (drug interactions), the severity of the condition being treated, and the like.
- Therapeutically effective amounts can be routinely determined by one of ordinary skill in the art, in light of information known in the art and the present disclosure. Several divided doses may be administered per day (eg, 2 to 4 divided doses per day), or a single dose may be administered. Also, administration may be daily, weekly or monthly.
- the above-mentioned purine derivative etc. can be administered to a patient, for example, at a dose ranging from 0.1 to 2000 mg per day.
- the dose of the active ingredient varies depending on the patient's condition, age, body weight, etc. For example, for adults weighing 60 kg, a daily dose of 10 to 2000 mg once Alternatively, they may be divided into two or three or more divided doses.
- For injection into blood vessels it varies depending on the patient's condition, age, body weight, etc. For example, for adults weighing 60 kg, a daily dose of 10 to 1000 mg once or 2 to 3 times Alternatively, it can be divided and administered.
- a body cavity such as the thoracic cavity, intraperitoneal cavity, or intrathecal cavity, or at a local site such as intravesical bladder
- a local site such as intravesical bladder
- the administration can be divided into two or three or more times.
- eye drops, inhalation into the lungs or nasal cavity, injection into the inflamed joint cavity may differ depending on the patient's condition, but 0.1 to 100 mg as a daily dose for adults may be divided into one or two or three times It can be administered.
- purine derivatives etc. within the above dose range may be used.
- the purine derivative or the like within the dose range described above and other pharmaceutically active agents within the approved dose range are used. If the combined preparation is not suitable, purine derivatives etc may be used sequentially with other pharmaceutically active agents within the approved dose range.
- (Treatment) subject or “patient” includes mammals and other organisms, in particular humans. Thus, the method can be applied to both human therapy and veterinary applications.
- the "(treatment) subject” or “patient” is a human.
- treat or “treatment” of a disease, disorder or syndrome includes treatment of a disease state (tumor) characterized by abnormal cell proliferation, and (i) a human being is Preventing the development of a disease state in a human when it is susceptible to a disease state but has not yet been diagnosed as having the disease; (ii) inhibiting the disease state (or the progression of the disease); And (iii) at least one of alleviating the disease state (regressing the disease state). Preferably it is said (ii) or (iii), More preferably, it is said (iii).
- the details of the treatment can be confirmed by ordinary experiments, examinations and the like by experts in the relevant technical field.
- the preparation of the 2-mercaptopurine derivative (VIII) represented by the above scheme 1 is carried out in seven steps from the commercially available product (I).
- a solvent such as N, N-dimethylformamide (DMF) is used for 2-mercaptopyrimidine, and an equivalent to an excess of p-methoxy in the presence of an equivalent to an excess of amine.
- Benzyl chloride can be added and reacted at 0 ° C. to 150 ° C. for 1 to 24 hours, preferably at 100 ° C. for 2 hours to obtain methoxybenzylsulfanyl pyrimidine derivative (II).
- the hydrogen chloride capturing agent used in this reaction includes, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine or pyridine.
- the solvent includes, for example, acetone, toluene, hexane, xylene, dioxane , Tetrahydrofuran or dichloroethane, DMF and the like. This reaction may be carried out using a base as the above-mentioned solvent.
- the amine has a low boiling point, it is preferable to carry out in a sealed tube under heating.
- the monochloropyrimidine derivative (i) is reacted at 0 ° C. to 100 ° C. for 1 to 24 hours with an equivalent to an excess of primary amine with respect to dichloropyrimidine derivative (III) IV) can be obtained.
- the amine has a low boiling point, it is preferable to carry out in a sealed tube under heating.
- the reaction may be carried out using a solvent or in the presence of a hydrogen chloride scavenger other than the amine to be reacted. Examples of the solvent include acetone, toluene, hexane, xylene, dioxane, tetrahydrofuran or dichloroethane, DMF and the like.
- the reaction with monochloropyrimidine derivative (IV) is carried out at 0 ° C. to 100 ° C. for 1 to 72 hours, preferably at 80 ° C. for 24 hours, with an equivalent to an excess of amine.
- the diaminopyrimidine derivative (V) can be obtained.
- the amine has a low boiling point, it is preferable to carry out in a sealed tube under heating.
- the reaction may be carried out using a solvent or in the presence of a hydrogen chloride scavenger other than the amine to be reacted. Examples of the solvent include acetone, toluene, hexane, xylene, dioxane, tetrahydrofuran or dichloroethane, DMF and the like.
- the diaminopyrimidine derivative (V) is dissolved in acetic acid, and the 5-position is nitrosated with sodium nitrite and subsequently converted to an amino group by catalytic reduction without isolation and purification. be able to.
- the desired 5-nitrosopyrimidine derivative can be obtained by reacting the nitrosation reaction at 0 ° C. to 40 ° C. for 1 to 24 hours, preferably at room temperature for 5 hours.
- a suitable solvent such as water may be used.
- the desired 5-aminopyrimidine derivative (VI) can be obtained by reacting at 0 ° C. to 60 ° C.
- various metal catalysts eg, Pd catalyst, Pt catalyst, Ru catalyst, etc.
- Pd catalyst e.g., Pd catalyst, Pt catalyst, Ru catalyst, etc.
- the equivalent amount preferably the catalyst amount
- the solvent include ethyl acetate, ethanol, methanol, acetone, toluene, hexane, xylene, dioxane, tetrahydrofuran, dichloroethane, DMF and the like, with preference given to ethyl acetate.
- construction of a purine skeleton can be performed by condensation reaction of 5-aminopyrimidine derivative (VI) with an aldehyde.
- the desired product (VII) can be obtained by reacting with an equal amount to an excess of aldehyde at 0 ° C. to 100 ° C. for 1 to 24 hours, preferably at room temperature for 3 hours.
- the solvent include ethanol, methanol, ethyl acetate, acetone, toluene, hexane, xylene, dioxane, tetrahydrofuran, dichloroethane, DMF and the like, with preference given to methanol.
- the aldehyde has a low boiling point and heating is required, it is preferable to carry out heating in a sealed tube.
- the intermediate (VII) is deprotected by heating in a trifluoroacetic acid-anisole system to deprotect the p-methoxybenzyl group to release the mercapto group, and then various
- the compound can be converted to the desired product (VIII) by reacting a substituted arylalkyl halide, a substituted benzyl halide or the like.
- the desired product can be obtained by reacting an excess of trifluoroacetic acid and a catalytic amount of anisole at 0 ° C. to 150 ° C. for 1 to 72 hours, preferably at 80 ° C. for 24 hours.
- the acid in addition to trifluoroacetic acid, various organic acids and mineral acids (for example, hydrochloric acid, hydrobromic acid and the like) can be used.
- the hydrogen donor one other than anisole may be used.
- the reaction is carried out with an equivalent to an excess of substituted benzyl halide, optionally in a solvent, in the presence of a hydrogen chloride scavenger.
- the hydrogen chloride capturing agent used in this reaction includes, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine or pyridine.
- the solvent includes, for example, acetone, toluene, hexane, xylene, dioxane , Tetrahydrofuran or dichloroethane, DMF and the like. The same conditions can be applied to the schemes 2 and 3 above.
- Acetic acid was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and then washed sequentially with 2N aqueous NaOH and water, dried over MgSO 4 and the solvent was evaporated under reduced pressure.
- the residue was dissolved in ethyl acetate (100 ml), added with 1.0 g of Pd / C and subjected to catalytic hydrogenation for 4 hours at normal pressure.
- the Pd / C was filtered using celite and the filtrate was evaporated under reduced pressure.
- Table 1 shows the compounds (compounds 1 to 174) described in the above examples and their structures.
- the compound numbers in the table correspond to the compounds (compounds 1 to 174) described in the above examples.
- test results confirming the effects of the compounds (compounds 1 to 174) described in the above examples will be described.
- the test compound numbers in each test correspond to the compounds (compounds 1 to 174) described in the above examples.
- Pharmacology test 1 in vitro antitumor activity test 1) Antitumor activity against various tumor cells (Test method) i) Adherent cancer cells: WiDr cells passaged at 37 ° C., 5% carbon dioxide in a culture medium obtained by adding 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin to MEM medium (Human colon cancer cells) were treated with trypsin / EDTA to make single floating cells, and suspended in MEM medium (supplemented with 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin) at 3 ⁇ 10 4 single cells / ml. The solution was prepared.
- test substance is dissolved in DMSO and then diluted with RPMI 1640 medium (containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin) to give a concentration of 2.0 ⁇ 10 ⁇ 9 to 2.0 ⁇ 10 ⁇ . It was prepared to 4 M. 0.1 ml of this cell suspension is placed in a 96-well microplate per well, and cultured for 24 hours to attach the cells to the microplate, then 0.1 ml of the sample solution is added, and it is in 5% carbon dioxide gas The cells were cultured at 37 ° C. for 72 hours.
- RPMI 1640 medium containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin
- the adjustment conditions of the cell used other than the WiDr cell and the single cell suspension of each cell are as follows.
- A549 cells human lung cancer cells: 2 ⁇ 10 4 cells / ml PC-3 cells (human prostate cancer cells): 2 ⁇ 10 4 cells / ml B16F10 cells (mouse melanoma [malignant melanoma] cells): 1 ⁇ 10 4 cells / ml
- P388 cells blood tumor
- P388 cells mouse leukemia cells
- RPMI 1640 medium 10% fetal bovine serum, 25 mM HEPES, 0.1 mg / ml kanamycin and 5 ⁇ M 2-hydroxyethyl disulfide added
- floating P388 cells were made into 4 ⁇ 10 4 single cell suspensions / ml with the same RPMI 1640 medium.
- test substance is dissolved in DMSO and then diluted with RPMI 1640 medium (containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin) to give a concentration of 2.0 ⁇ 10 ⁇ 9 to 2.0 ⁇ 10 ⁇ . It was prepared to 4 M. 0.1 ml of this cell suspension was added to a 96-well microplate per well, followed by addition of 0.1 ml of the sample solution, and the cells were cultured in 5% carbon dioxide at 37 ° C. for 72 hours. Thereafter, the growth inhibition degree at various sample concentrations was determined by XTT colorimetric assay, and 50% growth inhibition concentration (GI 50 value [ ⁇ M]) was calculated.
- RPMI 1640 medium containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin
- Compound A 6-mercaptopurine
- Compound B a compound described in the literature "Chemistry & Biology, Vol. 11, 135-146, January, 2004”:
- Compound C Compound described in patent (WO 99/28321):
- MCF-7 cells human breast cancer cells passaged at 37 ° C., 5% carbon dioxide gas in a culture medium obtained by adding 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin to MEM medium
- the suspension was treated with trypsin / EDTA to make single suspension cells, and 4 ⁇ 10 4 single cell suspensions were prepared in 1 ml of MEM medium (containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin).
- test substance (compound 2 and compound 7) is dissolved in DMSO and then diluted with MEM medium (containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin) to give a concentration of 6.4 ⁇ 10 ⁇ It was prepared to be 8 to 2.0 ⁇ 10 -5 M.
- MEM medium containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin
- MEM medium containing 10% fetal bovine serum, 25 mM HEPES and 0.1 mg / ml kanamycin
- Example 8 Pharmacology test 2 in vivo antitumor activity test 1) Effects of Compound 2 and Compound 7 on human lung cancer A549 implanted in nude mice (Test method) A tumor piece (3 mm ⁇ 3 mm ⁇ 3 mm) of human lung cancer A549 was transplanted subcutaneously into the chest of a 6-week-old female BALB / c-nu / nu mouse, and sample administration was started when the tumor volume reached about 100 mm 3 or more (Day 0). Compound 2 and Compound 7 were suspended in 1% hydroxypropyl cellulose (HPC [L]) solution using an agate mortar.
- HPC [L] hydroxypropyl cellulose
- 400 mg / kg of Compound 2 was orally administered on consecutive days from day 0 to day 13 (12 times in total excluding day 3 and day 10). 400 mg / kg of Compound 7 was administered intraperitoneally on consecutive days from day 0 to day 13 (12 times in total excluding day 4 and day 11).
- the tumor volume is measured to calculate the tumor volume (1/2 x major axis x minor axis x minor axis), and the tumor volume at 14 days after the start of sample administration (day 14) is divided by the tumor volume at the start of administration to calculate relative tumor growth The rate was calculated.
- the percentage ratio of the relative tumor growth rate of the control group to the relative tumor growth rate of the compound 2 and compound 7 administration groups was defined as T / C (%). (result) Compound 2 and Compound 7 significantly suppressed tumor growth, and their T / C was 73.1% and 55.4%, respectively.
- the tumor volume is measured to calculate the tumor volume (1/2 x major axis x minor axis x minor axis), and the tumor volume at 14 days after the start of sample administration (day 14) is divided by the tumor volume at the start of administration to calculate relative tumor growth
- the rate was calculated.
- the percentage ratio of the relative tumor growth rate of the control group to the relative tumor growth rate of the compound 2 administration group was defined as T / C (%).
- the tumor volume is measured to calculate the tumor volume (1/2 x major axis x minor axis x minor axis), and the tumor volume at 14 days after the start of sample administration (day 14) is divided by the tumor volume at the start of administration to calculate relative tumor growth
- the rate was calculated.
- the percentage ratio of the relative tumor growth rate of the control group to the relative tumor growth rate of the compound 2 administration group was defined as T / C (%).
- the purine derivative of the present invention exerts a high effect as an antitumor agent / anticancer agent.
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Abstract
Description
本明細書中においては、次の用語は以下に示す意味を有する。
「ヒドロキシル」という用語は、-OH基を意味する。
「シアノ」という用語は、-CN基を意味する。
「カルボキシル」という用語は、-(C=O)OH基を意味する。
「アミノ」という用語は、-NH2基、あるいは水素が他の原子に置換する二価または三価の基を意味する。
「ニトロ」という用語は、-NO2基を意味する。
「ニトロソ」という用語は、-NO基を意味する。
「ホルミル」という用語は、-(C=O)H基を意味する。
「スルホニル」という用語は、二価の基である-S(=O)2-基を意味する。
「カルボニル」という用語は、二価の基である-(C=O)-基を意味する。
「チオカルボニル」という用語は、二価の基である-(C=S)-基を意味する。
「(Cx-Cy)アルキル」、「(Cx-Cy)アルケニル」、「(Cx-Cy)アルキニル」または「(Cx-Cy)シクロアルキル」という用語の接頭辞は、xからy個の炭素原子を有するそれぞれの基を意味する。
また、任意の二価以上の基について、単環あるいは複環を形成可能な位置で置換する場合、特に限定されない限り、その二価以上の基は環構造を形成してもよい。
「(C1-C6)アルコキシ」という用語は、(C1-C6)アルキル-O-基を意味し、例えば、(C1-C3)アルコキシ、(C1-C4)アルコキシ、(C1-C6)アルコキシ、(C2-C6)アルコキシ、(C3-C6)アルコキシなどを含む。代表的な(C1-C6)アルコキシとしては、例えば、メトキシ、エトキシ、プロパ-オキシ(例えば、1-プロパ-オキシ、2-プロパ-オキシ)、ブトキシ(例えば、1-ブトキシ、2-ブトキシ、2-メチル-2-プロパ-オキシ)、ペンタ-オキシ(1-ペンタ-オキシ、2-ペンタ-オキシ)、ヘキサ-オキシ(1-ヘキサ-オキシ、3-ヘキサ-オキシ)などが挙げられる。
上記の用語の一部は、組み合わせて用いられ得るが、その場合、最初に記された基が、後に記された基上の置換基となり、置換点(付加点)は、その基全体の最後に記された部分上にある。
本発明者らは、抗腫瘍剤の探索を進めた結果、以下にその実施形態を示す強力な抗腫瘍活性を持つプリン誘導体を見出すに至った。
以下に本発明の実施の形態について説明する。
Arは、ハロゲン、ホルミル基、シアノ基、ニトロ基、アミノ基、ヒドロキシル基またはカルボキシル基;あるいは、ハロゲン、シアノ基、アミノ基、ヒドロキシル基またはカルボキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C1-C6)アルキルカルボニル基、(C1-C6)アルキルアミノ基、(C1-C6)アルキルカルボニルアミノカルボニル基、(C3-C6)シクロアルキルアミノ基、(C1-C7)アルコキシカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノ基、(C1-C6)アルキルカルボニルアミノ基、(C3-C6)シクロアルキルカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノチオカルボニルアミノ基、ヘテロアリールカルボニルアミノ基、フェニルオキシカルボニルアミノ基、フェニルカルボニルアミノ基、(C1-C6)アルキルスルホニルアミノ基、ジ[(C1-C6)アルキル]アミノスルホニルアミノ基、(C1-C6)アルコキシ基、(C1-C6)アルキルチオ基、(C1-C6)アルキレンジオキシ基、(C1-C6)アルコキシカルボニル基、アミノ(C1-C6)アルキルカルボニルアミノ基、フェニル(C2-C6)アルケニルカルボニルアミノ基、(C1-C6)アルコキシ(C1-C6)アルキルカルボニルアミノ基、(C1-C6)アルコキシカルボニルアミノ(C1-C6)アルキルカルボニルアミノ基、フェニル基またはフェニル(C1-C6)アルコキシ基;により、独立して1、2または3個置換されていてもよい、フェニル基、ピリジル基、チアゾリル基、ベンゾフラニル基、ジヒドロベンゾフラニル基、ナフタレニル基、イミダゾリル基またはピラゾリル基を表し;
Yは、炭素鎖中にカルボニル基を含んでいてもよく、かつ/またはArにより1または2個置換されていてもよい、(C1-C6)アルキレン基を表し;
R1は、(C1-C6)アルキル基または(C2-C6)アルケニル基;あるいは、(C1-C6)アルキル基、(C1-C6)アルコキシ基、(C1-C6)アルコキシ(C1-C6)アルキル基、(C3-C6)シクロアルキル基または(C2-C6)アルケニル基、により1または2個置換されていてもよい、アミノ基または(C1-C6)アルキルカルボニルアミノ基;あるいは、ニトロソ基、ホルミル基、ヒドロキシル基、(C1-C6)アルキル基、(C1-C6)アルキルカルボニル基、(C1-C6)アルコキシ基、(C1-C6)アルコキシカルボニル基またはヒドロキシ(C1-C6)アルキルアミノ基、により1または2個置換されていてもよい、複素環基;あるいはハロゲン、ホルミル基、シアノ基、ニトロ基、アミノ基、ヒドロキシル基、(C3-C6)またはカルボキシル基で置換されているフェニル基;を表し;
R2は、H;あるいは、ハロゲン、ニトロ基またはアミノ基、により1または2個置換されていても良い、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基または(C3-C6)シクロアルキル基;を表し;
R3は、ハロゲンまたはヒドロキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基、(C3-C6)シクロアルキル基、(C3-C6)シクロアルキル(C1-C6)アルキル基、アミノ(C1-C6)アルキル基、三~五員環状エーテル-(C1-C6)アルキル基または(C1-C6)アルキルカルボニルアミノ(C1-C6)アルキル基を表す]
で表される化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグである。
Arが、ハロゲン、ホルミル基、シアノ基、ニトロ基、アミノ基、ヒドロキシル基またはカルボキシル基;あるいは、ハロゲン、シアノ基、アミノ基、ヒドロキシル基またはカルボキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C1-C6)アルキルカルボニル基、(C1-C6)アルキルアミノ基、(C3-C6)シクロアルキルアミノ基、(C1-C6)アルコキシカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノ基、(C1-C6)アルキルカルボニルアミノ基、(C3-C6)シクロアルキルカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノチオカルボニルアミノ基、ヘテロアリールカルボニルアミノ基、フェニルオキシカルボニルアミノ基、フェニルカルボニルアミノ基、(C1-C6)アルキルスルホニルアミノ基、ジ[(C1-C6)アルキル]アミノスルホニルアミノ基、(C1-C6)アルコキシ基、(C1-C6)アルキルチオ基、(C1-C6)アルキレンジオキシ基、(C1-C6)アルコキシカルボニル基、アミノ(C1-C6)アルキルカルボニルアミノ基、フェニル(C2-C6)アルケニルカルボニルアミノ基、(C1-C6)アルコキシ(C1-C6)アルキルカルボニルアミノ基、(C1-C6)アルコキシカルボニルアミノ(C1-C6)アルキルカルボニルアミノ基、フェニル基またはフェニル(C1-C6)アルコキシ基;により、独立して1、2または3個置換されていてもよい、フェニル基、ピリジル基、チアゾリル基、ベンゾフラニル基、ジヒドロベンゾフラニル基、ナフタレニル基、イミダゾリル基またはピラゾリル基を表し;
Yが、炭素鎖中にカルボニル基を含んでいてもよい(C1-C6)アルキレン基を表し;
R1が、(C1-C6)アルキル基または(C2-C6)アルケニル基;あるいは、(C1-C6)アルキル基または(C2-C6)アルケニル基、により1または2個置換されていてもよい、アミノ基または(C1-C6)アルキルカルボニルアミノ基;あるいは、ニトロソ基、ホルミル基、(C1-C6)アルキル基、(C1-C6)アルキルカルボニル基、(C1-C6)アルコキシカルボニル基またはヒドロキシ(C1-C6)アルキルアミノ基、により1または2個置換されていてもよい、非芳香族性環状アミノ基;を表し;
R2が、H;あるいは、ハロゲン、ニトロ基またはアミノ基、により1または2個置換されていても良い、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基または(C3-C6)シクロアルキル基;を表し;
R3が、ハロゲンまたはヒドロキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基、(C3-C6)シクロアルキル基、アミノ(C1-C6)アルキル基または(C1-C6)アルキルカルボニルアミノ(C1-C6)アルキル基を表す、上記の何れかの態様の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグである。
ラセミ体混合物または非ラセミ体混合物から、所望の立体異性体を調製・分離・単離する方法は、当業者には公知であり、例えば結晶化により分離され得るジアステレオ異性体塩または錯体の調製;例えば結晶化、ガス-液体または液体クロマトグラフィーにより分離され得るジアステレオ異性体の調製;光学異性体特異的試薬を用いた一方の光学異性体の選択的反応、例えば酵素的酸化または還元とそれに続く光学異性体の分離;またはキラル環境(例えば結合キラルリガンド結合シリカのようなキラル支持体、またはキラル溶媒の存在下)におけるガス-液体または液体クロマトグラフィーなどにより分離することができる。
塩が含まれる。
これらの反応では、必要に応じて溶媒中、塩化水素補足剤の存在下で、反応させる。この反応で用いる塩化水素補足剤としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、トリエチルアミンまたはピリジンなどが挙げられ、溶媒としては、例えば、アセトン、トルエン、ヘキサン、キシレン、ジオキサン、テトラヒドロフランまたはジクロロエタン、DMFなどが挙げられる。本反応は、上記の溶媒として塩基を用いて行ってもよい。また、アミンが低沸点の場合には加熱下封管中で行うことが好ましい。
ことが好ましい。
上記スキーム2、3に関しても、同様の条件で実施することができる。
8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物1)の合成
(1-1) 4,6-ジヒドロキシ-2-(4-メトキシベンジルスルファニル)ピリミジンの合成
1H-NMR (CDCl3+CD3OD) δ: 3.80(3H, s), 4.39(2H, s), 5.32(1H, s), 6.85(2H, d, J=8.9Hz), 7.31(2H, d, J=8.9Hz).
1H-NMR (CDCl3) δ: 3.79(3H, s), 4.33(2H, s), 6.83(2H, d, J=8.7Hz), 7.01(1H, s), 7.37(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 2.93(3H, d, J=5.2Hz), 3.79(3H, s), 4.30(2H, s), 6.04(1H, s), 6.83(2H, d, J=8.8Hz), 7.33(2H, d, J=8.8Hz).
1H-NMR (CDCl3) δ: 2.86(3H, d, J=5.2Hz), 3.52-3.56(4H, m), 3.73-3.77(4H, m), 3.78(3H, s), 4.29(2H, s), 4.66-4.69(1H, m), 5.12(1H, s), 6.81(2H, d, J=8.6Hz), 7.31(2H, d, J=8.6Hz).
融点:79.5-84℃. MS m/z: 361(M+).
1H-NMR (CDCl3) δ: 2.82(2H, brs), 3.02(3H, d, J=5.1Hz), 3.11-3.16(4H, m), 3.78(3H, s) 3.79-3.83(4H, m), 4.33(2H, s), 4.52-4.55(1H, m), 6.81(2H, d, J=8.6Hz), 7.35(2H, d, J=8.6Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.80(2H, q, J=7.4Hz), 3.65(3H, s), 3.78(3H, s), 3.80(4H, m), 4.25(4H, brs), 4.38(2H, s), 6.80(2H, d, J=8.6Hz), 7.36(2H, d, J=8.6Hz).
2-(3-アミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物2)の合成
(2-1) 8-エチル-9-メチル-6-モルホリノ-2-(3-ニトロ-4-メトキシベンジルスルファニル)-9H-プリンの合成
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.80(2H, q, J=7.4Hz), 3.67(3H, s), 3.78(4H, m), 3.92(3H, s), 4.23(4H, brs), 4.34(2H, s), 6.99(1H, m), 7.62(1H, m), 8.05(1H, m).
融点:139℃
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.80(2H, q, J=7.4Hz), 3.62(3H, s), 3.79(4H, m), 3.82(3H, s), 4.24(4H, brs), 4.32(2H, s), 6.66-6.80(3H, m).
2-(4-メトキシベンジルスルファニル)-8,9-ジメチル-6-モルホリノ-9H-プリン(化合物3)
1H-NMR (CDCl3) δ: 2.49(3H, s), 3.65(3H, s), 3.78(3H, s), 3.78(4H, m), 4.22(4H, m), 4.38(2H, s), 6.82(2H, d, J=8.7Hz), 7.36(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.04(3H, t, J=7.3Hz), 1.80(2H, m), 2.74(2H, m), 3.65(3H, s), 3.80(4H, m), 3.81(3H, s), 4.24(4H, m), 4.38(2H, s), 6.82(2H, d, J=8.7Hz), 7.34 (2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.38(3H, t, J=7.4Hz), 2.78(2H, q, J=7.4Hz), 3.64(3H, s), 3.77(4H, m), 3.89(3H, s), 4.22(4H, m), 4.44(2H, s), 7.50(2H, d, J=8.2Hz), 7.96(2H, d, J=8.2Hz).
1H-NMR (CDCl3) δ: 0.93(3H, t, J=5.6Hz), 1.25(3H, t, J=7.4Hz), 1.78(2H, m), 2.77(2H, q, J=7.4Hz), 3.77(3H, s), 3.78(4H, m), 4.04(2H, m), 4.25(4H, m), 4.36(2H, s), 6.80(2H, d, J=8.4Hz), 7.35(2H, d, J=8.4Hz).
1H-NMR (CDCl3) δ: 1.38(3H, t, J=7.6Hz), 2.81(2H, q, J=7.6Hz), 3.68(3H, s), 3.89(3H, s), 3.90(2H, m), 4.27-4.50(6H, m), 4.38(2H, s), 6.82(2H, d, J=8.6Hz), 7.36(2H, d, J=8.6Hz).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.4Hz), 2.31(3H, s), 2.79(2H, q, J=7.4Hz), 3.65(3H, s), 3.70(4H, m), 4.25(4H, m), 4.39(2H, s), 7.09(2H, d, J=8.1Hz), 7.32(2H, d, J=8.1Hz).
1H-NMR (CDCl3) δ: 3.75(3H, s), 3.78(3H, s), 3.78(4H, m), 4.25(4H, m), 4.38(2H, s), 6.80(2H, d, J=8.7Hz), 7.34(2H, d, J=8.7Hz), 7.69(1H, s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.79(2H, q, J=7.4Hz), 3.65(3H, s), 3.78(4H, m), 4.25(4H, m), 4.41(2H, s), 5.18(1H, d, J=10.9Hz), 5.70(1H, d, J=17.6Hz), 6.66(1H, dd, J=10.9, 17.6Hz), 7.33(2H, d, J=8.2Hz), 7.40(2H, d, J=8.2Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.22(3H, s), 2.80(2H, q, J=7.6Hz), 3.63(3H, s), 3.78(4H, m), 4.25(4H, m), 4.36(2H, s), 7.03-7.14(3H, m).
1H-NMR (CDCl3) δ: 1.21(3H, t, J=7.6Hz), 1.36(3H, t, J=7.6Hz), 2.59(2H, q, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 3.65(3H, s), 3.78(4H, m), 4.25(4H, m), 4.40(2H, s), 7.10(2H, d, J=8.2Hz), 7.35(2H, d, J=8.2Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.80(2H, q, J=7.4Hz), 3.68(3H, s), 3.78(4H, m), 3.85(3H, s), 4.25(4H, m), 4.43(2H, s), 5.54(1H, brs), 6.73(1H, m), 6.91(1H, m), 7.03(1H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.79(2H, q, J=7.6Hz), 3.66(3H, s), 3.78(4H, m), 3.86(3H, s), 4.25(4H, m), 4.43(2H, s), 6.86(1H, m), 7.13(1H, m), 7.23(1H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=6.7Hz), 2.80(2H, q, J=6.7Hz), 3.60(3H, s), 3.78(3H, s), 3.78(4H, m), 4.25(4H, m), 4.38(2H, s), 4.48(2H, s), 6.40-6.50(1H, m), 6.80(1H, m), 7.20-7.50(6H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.86(2H, q, J=7.6Hz), 3.67(3H, s), 3.77(4H, m), 3.87(3H, s), 4.25(4H, m), 4.32(2H, s), 6.80(1H, m), 7.31(1H, m), 7.50(1H, m).
1H-NMR (CDCl3) δ: 1.36(6H, m), 2.80(2H, q, J=7.6Hz), 3.65(3H, s), 3.77(4H, m), 4.00(2H, q, J=4.1Hz), 4.25(4H, m), 4.37(2H, s), 6.78(2H, d, J=8.7Hz), 7.30(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 3.75(3H, s), 3.78(4H, m), 3.82(3H, s), 4.25(4H, m), 4.33(2H, s), 6.67-6.92(3H, m), 7.58(1H, s).
1H-NMR (CDCl3) δ: 3.50(6H, brs), 3.71(3H, s), 3.81(3H, s), 4.23(2H, s), 6.67-6.83(3H, m), 7.56(1H, s).
1H-NMR (CDCl3) δ: 1.38(3H, t, J=7.6Hz), 2.82(2H, q, J=7.6Hz), 3.68(3H, s), 3.86(3H, s), 3.89-3.93(4H, m), 4.25-4.33(2H, m), 4.35(2H, s), 4.36-4.49(2H, m), 6.87(1H, d, J=8.4Hz), 6.96-7.25(2H, m).
1H-NMR (CDCl3) δ: 3.74(6H, brs), 3.74(3H, s), 3.78(3H, s), 4.2(2H, s), 6.84(2H, d, J=8.4Hz), 7.37(2H, d, J=8.4Hz), 7.57(1H, s).
1H-NMR (CDCl3) δ: 1.38(3H, t, J=7.4Hz), 1.48(3H, t, J=6.6Hz), 2.79(2H, q, J=7.4Hz), 3.15-3.40(1H, m), 3.59-3.64(2H, m), 3.67(3H, s), 3.78(3H, s), 4.10-4.13(1H, m), 4.22-4.27(1H, m), 4.39(2H, s), 4.72-4.80(2H, m), 6.82(2H, d, J=8.5Hz), 7.36(2H, d, J=8.5Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 3.48(6H, brs), 3.64(3H, s), 3.82(3H, s), 4.36(2H, s), 6.68(1H, d, J=8.1Hz), 6.77-6.83(2H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.80(2H, q, J=7.5Hz), 3.48(6H, brs), 3.64(3H, s), 3.77(3H, s), 4.41(2H, s), 6.83(2H, d, J=8.7Hz), 7.36(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.25(6H, t, J=6.6Hz), 3.72(3H, s), 3.78(3H, s), 3.95(4H, brs), 4.41(2H, s), 6.82(2H, d, J=8.7Hz), 7.37(2H, d, J=8.7Hz), 7.57(1H, s).
1H-NMR (CDCl3) δ: 3.18(3H, d, J=4.1Hz), 3.75(3H, s), 3.78(3H, s), 4.43(2H, s), 5.62(1H, brs), 6.82(2H, d, J=8.7Hz), 7.38(2H, d, J=8.7Hz), 7.52(1H, s).
2-(3-アセチルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物27)の合成
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.4Hz), 2.18(3H, s), 2.79(2H, q, J=7.4Hz), 3.67(3H, s), 3.70-3.81(4H, m), 3.84(3H, s), 4.10-4.24(4H, m), 4.38(2H, s), 6.77(1H, d, J=8.7Hz), 7.15(1H, dd, J=2.1, 8.7Hz), 7.27(1H, brs), 8.47(1H, brs).
2-[3-(2-アミノアセチルアミノ)-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン塩酸塩(化合物28)の合成
2-(3-アミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(170mg、0.41mmol)をジクロロメタン(10ml)に溶かし、N,N-ジシクロヘキシルカルボジイミド(85mg、0.41mmol)とN-BOCグリシン(72mg、0.41mmol)を加え室温で4時間攪拌した。酢酸エチル(10ml)を加えて不溶物を濾過し、濾液を減圧留去した。シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=3:1)で精製し、2-[3-(2-tert-ブトキシカルボニルアミノアセチルアミノ)-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリンを146mg(収率62%)得た(化合物62)。
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.6Hz), 1.48(9H, s), 2.78(2H, q, J=7.6Hz), 3.66(3H, s), 3.77-3.81(4H, m), 3.83(3H, s), 3.92(2H, d, J=5.7Hz), 4.24(4H, brs), 4.38(2H, s), 5.20(1H, brs), 6.89(1H, d, J=8.4Hz), 7.16(1H, dd, J=2.0, 8.4Hz), 8.29(1H, brs), 8.46(1H, d, J=2.0Hz).
2-[3-(2-tert-ブトキシカルボニルアミノアセチルアミノ)-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物62)(140mg、0.24mmol)をテトラヒドロフラン(15ml)に溶かし、4N-塩酸ジオキサン溶液(2ml)を加え8時間攪拌した。溶媒を減圧留去した後、残渣をエーテルで洗浄し、化合物28を103mg(収率83%)得た。
1H-NMR (DMSO-d6) δ: 1.25(3H, t, J=7.6Hz), 2.81(2H, q, J=7.6Hz), 3.63(3H, s), 3.65-3.71(4H, m), 3.80(3H, s), 3.83(2H, d, J=5.7Hz), 4.12(4H, brs), 4.31(2H, s), 6.99(1H, d, J=8.6Hz), 7.14-7.18(1H, m), 8.06-8.10(1H, m), 8.18(1H, brs).
9-(2-アセチルアミノエチル)-8-エチル-2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物29)
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 1.87(3H, s), 2.78(2H, q, J=7.6Hz), 3.57(2H, m), 3.78(3H, s), 3.82(4H, m), 4.23(2H, m), 4.25(4H, brs), 4.35(2H, s), 6.58(1H, brs), 6.84(2H, d, J=8.7Hz), 7.36(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.34(3H, t, J=7.4Hz), 2.85(2H, q, J=7.4Hz), 3.77(3H, s), 3.78(4H, m), 4.26(4H, brs), 4.34(2H, s), 4.36(2H, m), 4.69(2H, dt, J=4.8, 47.3Hz), 6.81(2H, d, J=8.4Hz), 7.33(2H, d, J=8.4Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.80(2H, q, J=7.5Hz), 3.65(3H, s), 3.78(4H, m), 4.10(4H, brs), 4.43(2H, s), 5.32(2H, d, J=48.0Hz), 7.30(2H, d, J=7.4Hz), 7.48(2H, d, J=7.4Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.46(3H, s), 2.80(2H, q, J=7.6Hz), 3.51(3H, s), 3.78(4H, m), 4.23(4H, brs), 4.38(2H, brs), 7.18(2H, d, J=8.1Hz), 7.36(2H, d, J=8.1Hz).
1H-NMR (CDCl3) δ: 1.40(3H, t, J=7.6Hz), 2.82(2H, q, J=7.6Hz), 3.68(3H, s), 3.78(3H, s), 3.79(4H, m), 4.24(4H, brs), 4.38(2H, s), 6.59(2H, m), 7.38(1H, m).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.6Hz), 2.14(3H, s), 2.80(2H, q, J=7.6Hz), 3.52-3.56(2H, m), 3.66(3H, s), 3.68-3.72(2H, m), 3.78(3H, s), 4.22-4.28(4H, m), 4.38(2H, s), 6.82(2H, d, J=8.7Hz), 7.35(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.6Hz), 2.78(2H, q, J=7.6Hz), 2.91(6H, s), 3.66(3H, s), 3.79(4H, m), 4.25(4H, brs), 4.37(2H, s), 6.65(2H, d, J=8.9Hz), 7.31(2H, d, J=8.9Hz).
1H-NMR (CDCl3) δ: 1.33(3H, t, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 3.66(3H, s), 3.79(4H, m), 4.25(4H, brs), 4.35(2H, s), 5.91(2H, s), 6.69-6.96(3H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.17(3H, s), 2.81(2H, q, J=7.6Hz), 3.66(3H, s), 3.80(3H, s), 3.82(4H, m), 4.25(4H, brs), 4.35(2H, s), 6.70-6.80(2H, m), 7.21(1H, m).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.6Hz), 1.74(3H, d, J=7.1Hz), 2.77(2H, q, J=7.6Hz), 3.64(3H, s), 3.78(3H, s), 3.78(4H, m), 4.23(4H, brs), 5.00(1H, q, J=7.1Hz), 6.82(2H, d, J=8.9Hz), 7.40(2H, d, J=8.9Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.79(2H, q, J=7.6Hz), 3.66(3H, s), 3.76(3H, s), 3.77-3.81(4H, m), 3.82(3H, s), 4.24(4H, brs), 4.38(2H, s), 6.76(1H, d, J=8.2Hz), 7.10(1H, dd, J=2.1, 8.2Hz), 7.26(1H, d, J=2.1Hz), 8.19(1H, brs).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.6Hz), 2.12(3H, s), 2.79(2H, q, J=7.6Hz), 3.64(3H, s), 3.78(4H, t, J=4.8Hz), 4.22-4.26(4H, m), 4.33(2H, s), 6.75-6.77(2H, m), 6.95(1H, d, J=8.1Hz).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.5Hz), 2.38(3H, s), 2.81(2H, q, J=7.5Hz), 3.68(3H, s), 3.80(4H, m), 4.29(4H, brs), 4.38(2H, s), 7.35-7.55(5H, m).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.6Hz), 2.79(2H, q, J=7.6Hz), 3.67(3H, s), 3.78(4H, t, J=4.9Hz), 3.98(3H, s), 4.25(4H, brs), 4.85(2H, s), 6.73(1H, d, J=7.9Hz), 7.60(3H, m), 8.15(1H, d, J=3.9Hz), 8.28(1H, s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.79(2H, q, J=7.6Hz), 3.67(3H, s), 3.77(4H, t, J=4.9Hz), 3.90(3H, s), 4.31(4H, brs), 4.56(2H, s), 7.11(2H, m), 7.55(1H, dd, J=1.7, 8.5Hz), 7.66(2H, d, J=8.5Hz), 8.81(1H, s).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 2.97-3.03(2H, m), 3.31-3.37(2H, m), 3.66(3H, s), 3.79(3H, s), 3.79-3.83(4H, m), 4.27(4H, brs), 6.85(2H, d, J=8.6Hz), 7.18(2H, d, J=8.6Hz).
1H-NMR (CDCl3) δ: 3.19(3H, brs), 3.76(3H, s), 3.82(3H, s), 4.38(2H, s), 5.66(1H, brs), 6.69(1H, d, J=7.8Hz), 6.79-6.84(2H, m), 7.57(1H, s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.64(3H, s), 3.78(4H, m), 4.23(4H, brs), 4.35(2H, s), 7.29-7.40(4H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.79(2H, q, J=7.6Hz), 3.48-3.54(4H, m), 3.62(3H, s), 3.77(4H, t, J=4.9Hz), 4.22(4H, brs), 7.10-7.13(2H, m), 7.96-8.01(2H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.40(3H, s), 2.79(2H, q, J=7.5Hz), 3.49-3.51(4H, m), 3.62(3H, s), 3.75-3.77(4H, m), 4.22(4H, brs), 7.24(2H, d, J=8.2Hz), 7.86(2H, d, J=8.2Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 3.64(3H, s), 3.78(4H, t, J=4.8Hz), 4.21-4.25(4H, m), 4.34(2H, s), 7.20(2H, d, J=8.4Hz), 7.59(2H, d, J=8.4Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.00-2.11(2H, m), 2.72(2H, t, J=7.5Hz), 2.78(2H, q, J=7.5Hz), 3.15(2H, t, J=7.2Hz), 3.61(3H, s), 3.78(3H, s), 3.79-3.81(4H, m), 4.22(4H, brs), 6.82(2H, d, J=8.7Hz), 7.11(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 3.67(3H, s), 3.78(4H, m), 3.90(3H, s), 4.24(4H, brs), 4.32(2H, s), 6.87(1H, s), 7.60(1H, m), 7.69(1H, m).
1H-NMR (CDCl3) δ: 1.31(9H, s), 1.35(3H, t, J=7.6 Hz), 2.79(2H, q, J=7.6Hz), 3.66(3H, s), 3.77-3.81(4H, m), 3.86(3H, s), 4.24(4H, brs), 4.38(2H, s), 6.78(1H, d, J=8.4Hz), 7.15(1H, dd, J=2.1, 8.4Hz), 8.09(1H, s), 8.56(1H, d, J=2.1Hz).
MS m/z: 498 (M+).
1H-NMR (CDCl3) δ: 1.24(3H, t, J=7.5Hz), 1.35(3H, t, J=7.5Hz), 2.40(2H, q, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.66(3H, s), 3.77-3.80(4H, m), 3.84(3H, s), 4.24(4H, brs), 4.38(2H, s), 6.77(1H, d, J=8.4Hz), 7.14(1H, dd, J=1.9, 8.4Hz), 7.72(1H, s), 8.52(1H, d, J=1.9Hz).
MS m/z: 470 (M+).
1H-NMR (CDCl3) δ: 0.80-0.85(2H, m), 1.04-1.06(2H, m), 1.35(3H, t, J=7.4Hz), 1.54-1.56(1H, m), 2.78(2H, q, J=7.4Hz), 3.65(3H, s), 3.76-3.79(4H, m), 3.86(3H, s), 4.23(4H, brs), 4.36(2H, s), 6.78(1H, d, J=8.3Hz), 7.13(1H, dd, J=2.1, 8.3Hz), 7.90(1H, brs), 8.48(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 1.34(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.67(3H, s), 3.78-3.81(4H, m), 3.89(3H, s), 4.24(4H, brs), 4.41(2H, s), 6.53(1H, dd, J=1.7, 3.6Hz), 6.82(1H, d, J=8.4Hz), 7.17-7.24(2H, m), 7.51(1H, dd, J=1.4, 1.7Hz), 8.62(1H, d, J=1.4Hz), 8.72(1H, s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.80(2H, q, J=7.5Hz), 3.04(6H, brs), 3.65(3H, s), 3.78-3.85(4H, m), 3.82(3H, s), 4.26(4H, brs), 4.37(2H, s), 6.76(1H, d, J=8.2Hz), 6.94(1H, d, J=2.1Hz), 7.06(1H, dd, J=2.1, 8.2Hz), 7.52(1H, s).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.5Hz), 2.70(6H, s), 2.80(2H, q, J=7.5Hz), 3.69(3H, s), 3.78-3.82(4H, m), 3.86(3H, s), 4.25(4H, brs), 4.36(2H, s), 6.79(1H, d, J=8.5Hz), 6.82(1H, s), 7.13(1H, dd, J= 2.1, 8.5Hz), 7.65(1H, d, J=2.1Hz).
MS m/z: 521 (M+).
1H-NMR (CDCl3) δ: 1.33(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.31(6H, s), 3.66(3H, s), 3.78-3.82(4H, m), 3.83(3H, s), 4.25(4H, brs), 4.41(2H, s), 6.79(1H, d, J=8.4Hz), 7.16(1H, dd, J=2.1, 8.4Hz),7.34 (1H, s), 8.13(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.68(3H, s), 3.78-3.81(4H, m), 3.89(3H, s), 4.26(4H, brs), 4.43(2H, s), 6.83(1H, d, J=8.4Hz), 7.12-7.22(3H, m), 7.85-7.92(2H, m), 8.44(1H, s), 8.64(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.17(3H, s), 2.79(2H, q, J=7.6Hz), 3.48(6H, brs), 3.65(3H, s), 3.84(3H, s), 4.42(2H, s), 6.78(1H, d, J=8.4Hz), 7.16(1H, dd, J=2.1, 8.4Hz), 7.70(1H, brs), 8.46(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 2.03(3H, s), 3.59(3H, s), 3.78(3H, s), 3.86(3H, s), 4.42(2H, s), 6.84(2H, d, J=8.7Hz), 7.38(2H, d, J=8.7Hz), 7.88(1H, s).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.50(3H, s), 3.66(3H, s), 3.77-3.81(4H, m), 3.86(3H, s), 4.01(2H, s), 4.25(4H, brs), 4.39(2H, s), 6.80(1H, d, J=8.5Hz), 7.18(1H, dd, J=2.1, 8.5Hz), 8.51(1H, d, J=2.1Hz), 8.81(1H, s).
1H-NMR (CDCl3) δ: 1.28(3H, t, J=7.3Hz), 3.69(2H, brs), 3.76(3H, s), 3.78(3H, s), 4.42(2H, s), 5.62(1H, brs), 6.83(2H, d, J=8.7Hz), 7.38(2H, d, J=8.7Hz), 7.58(1H, s).
1H-NMR (CDCl3) δ: 1.20 (3H, t, J = 7.1Hz), 1.36 (3H, t, J = 7.5Hz), 2.80 (2H, q, J = 7.5Hz), 3.41 (3H, brs), 3.64 (3H, s), 3.78 (3H, s), 4.01 (2H, brs), 4.41 (2H, s), 6.82 (2H, d, J = 8.7Hz), 7.37 (2H, d, J = 8.7Hz).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.5Hz), 2.78(2H, q, J=7.5Hz), 3.67(3H, s), 3.77-3.81(4H, m), 3.87(3H, s), 4.25(4H, brs), 4.41(2H, s), 6.58(1H, d, J=15.5Hz), 6.80(1H, d, J=8.4Hz), 7.18(1H, dd, J=2.1, 8.4Hz), 7.36-7.40(3H, m), 7.53-7.56(2H, m), 7.70(1H, d, J=15.5Hz), 7.93(1H, s), 8.65(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.6Hz), 2.76(6H, s), 2.80(2H, q, J=7.6Hz), 3.66(3H, s), 3.79-3.82(4H, m), 3.86(3H, s), 4.26(4H, brs), 4.39(2H, s), 6.76(1H, d, J=8.7Hz), 7.03-7.06(2H, m).
1H-NMR (CDCl3) δ: 1.19 (3H, t, J = 7.1Hz), 1.36 (3H, t, J = 7.6Hz), 2.79 (2H, q, J = 7.6Hz), 3.41 (3H, brs), 3.63 (3H, s), 4.01 (2H, brs), 4.37 (2H, s), 7.21 (2H, d, J = 8.4Hz), 7.59 (2H, d, J = 8.4Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.80(2H, q, J=7.4Hz), 3.47(6H, brs), 3.65 (3H, s), 3.89(3H, s), 4.36(2H, s), 6.87(1H, d, J=8.6Hz), 7.62(1H, dd, J=2.2, 8.6Hz), 7.69(1H, d, J=2.2Hz).
1H-NMR (CDCl3) δ: 0.96(6H, d, J=6.8Hz), 1.35(3H, t, J=7.6Hz), 1.97(1H, m), 2.79(2H, q, J=7.6Hz), 3.66(3H, s), 3.77-3.81(4H, m), 3.83(3H, s), 3.93(2H, d, J=6.8Hz), 4.25(4H, brs), 4.38(2H, s), 6.76(1H, d, J=8.4Hz), 7.10(1H, d, J=8.4Hz), 7.18(1H, s), 8.21(1H, s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.5Hz), 2.79(2H, q, J=7.5Hz), 3.48(6H, brs), 3.63(3H, s), 3.84(3H, s), 4.37(2H, s), 6.81-7.12(1H, m), 7.19-7.20(1H, m), 7.23-7.24(1H,m).
1H-NMR (CDCl3) δ: 3.17(3H, brs), 3.77(3H, s), 3.89(3H, s), 4.36(2H, s), 5.64(1H, brs), 6.88(1H, d, J=8.7Hz), 7.59(1H, s), 7.64(1H, dd, J=2.1, 8.7Hz), 7.73(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 3.18(3H, brs), 3.76(3H, s), 3.85(3H, s), 4.39(2H, s), 5.10(1H, brs), 6.83-6.89(1H, m), 7.14-7.21(2H, m), 7.58(1H, s).
1H-NMR (CDCl3) δ: 1.22 (6H, t, J = 7.0Hz), 1.36 (3H, t, J = 7.5Hz), 2.79 (2H, q, J = 7.5Hz), 3.40 (2H, dd, J = 5.0, 10.0Hz), 3.63 (3H, s), 3.78 (3H, s), 3.94 (2H, brs), 4.41 (2H, s), 6.82 (2H, d, J = 8.7Hz), 7.36 (2H, d, J = 8.7Hz).
1H-NMR (CDCl3) δ: 1.24(3H, t, J=7.0Hz), 3.42(3H, brs), 3.74(3H, s), 3.80(3H, s), 4.05(2H, brs), 4.42(2H, s), 6.82(2H, d, J=8.7Hz), 7.37(2H, d, J=8.7Hz), 7.57(1H, s).
1H-NMR (CDCl3) δ: 2.64(3H, s), 3.79(3H, s), 3.83(3H, s), 4.43(2H, s), 6.84(2H, d. J=8.6Hz), 7.37(2H, d, J=8.6Hz), 7.81(1H, s), 8.51(1H, brs).
1H-NMR (CDCl3) δ: 0.86(3H, t, J=6.5Hz), 1.29-1.38(8H, m), 1.35(3H, t, J=7.5Hz), 1.61-1.72(2H, m), 2.79(2H, q, 7.5Hz), 3.66(3H, s), 3.77-3.81(4H, m), 3.83(3H, s), 4.14(2H, t, J=6.7Hz), 4.25(4H, brs), 4.38(2H, s), 6.76(1H, d, J=8.3Hz), 7.09(1H, d, J=8.3Hz), 7.17(1H, s), 8.22(1H, s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 2.80 (2H, q, J=7.6Hz), 3.66(3H, s), 3.78(4H, m), 3.86(3H, s), 4.25(4H, brs), 4.32(2H, s), 6.81(1H, m), 7.35 (1H, m), 7.68(1H, m).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.4Hz), 2.80 (2H, q, J=7.4Hz), 3.65(3H, s), 3.79(4H, m), 3.82(3H, s), 4.25(4H, brs), 4.37(2H, s), 5.25(1H, dd, J=1.5, 11.2Hz), 5.70(1H, dd, J=1.5, 17.7Hz), 6.80(1H, m), 7.00(1H, dd, J=11.2, 17.7Hz), 7.34(1H, m), 7.55(1H, m).
1H-NMR (CDCl3) δ: 3.73(3H, s), 3.77(4H, m), 3.91(3H,s), 4.25(4H, brs), 4.33(2H, s), 6.89(1H, m), 7.60(1H, s), 7.63(1H, m), 7.75(1H, m).
1H-NMR (CDCl3) δ: 1.35(3H, t, J=7.6Hz), 2.78(2H, q, J=7.6Hz), 2.99(3H, d, J=4.9Hz), 3.69(3H, s), 3.78(4H, m), 3.92(3H. s), 4.23(4H, brs), 4.39(2H,s), 6.90(1H, d, J=8.6Hz), 7.55(1H, dd, J=2.3, 8.6Hz), 7.75(1H, s), 8.32(1H, d, J=2.3Hz).
1H-NMR (CDCl3) δ: 1.23(3H, t, J=7.1Hz), 3.41(3H, brs), 3.74(3H, s), 3.86(3H, s), 4.04(2H, brs), 4.38(2H, s), 6.87(1H, t, J=8.4Hz), 7.15(1H, d, J=8.4Hz), 7.22(1H, m), 7.58(1H, s).
1H-NMR (CDCl3) δ: 3.76(3H, s), 3.81(4H, m), 3.86(3H, s), 4.25(4H, brs), 4.35(2H, s), 6.86(1H, m), 7.13(1H, m), 7.23(1H, m), 7.59(1H, s).
1H-NMR (CDCl3) δ: 1.24(3H, t, J=7.0Hz), 3.42(3H, brs), 3.71(3H, s), 3.73(2H, brs), 3.80(3H, s), 4.08(2H, brs), 4.36(2H, s), 6.68-6.70(1H, m), 6.77-6.83(2H, m), 7.57(1H, s).
1H-NMR (CDCl3) δ: 1.23(3H, t, J=6.9Hz), 3.39(3H, brs), 3.75(3H, s), 3.90(3H, s), 4.04(2H, brs), 4.36(2H, s), 6.89(1H, d, J=8.7Hz), 7.59(1H, s), 7.63(1H, dd, J=2.3, 8.7Hz), 7.69(1H, d, J=2.3Hz).
1H-NMR (CDCl3) δ: 3.50(6H, brs), 3.74(3H, s), 3.85(3H, s), 4.38(2H, s), 6.83-6.89(1H, m), 7.13-7.25(2H, m), 7.58(1H, s).
1H-NMR (CDCl3) δ: 3.49(6H, brs), 3.75(3H, s), 3.89(3H, s), 4.36(2H, s), 6.88(1H, d, J=8.5Hz), 7.55-7.64(2H, m), 7.70(1H, s).
1H-NMR (CDCl3) δ: 1.23(3H, t, J=7.0 Hz), 1.57(2H, s), 3.56-3.87(8H, m), 4.01-4.39(7H, m), 6.82(2H, d, J=6.8Hz), 7.37(2H, d, J=8.6Hz), 7.59(1H, s).
1H-NMR (CDCl3) δ: 1.27(3H, t, J=7.3Hz), 3.65(2H, brs), 3.76(3H, s), 3.89(3H, s), 4.35(2H, s), 5.88(1H, brs), 6.89(1H, d, J=8.7Hz), 7.59(1H, s), 7.63(1H, dd, J=2.2, 8.7Hz), 7.71(1H, d, J=2.2Hz).
1H-NMR (CDCl3) δ: 1.20(3H, t, J=7.5Hz), 1.36(3H, t, J=7.6Hz), 2.47(2H, q, J=7.5Hz), 2.79(2H, q, J=7.6Hz), 3.65(3H, s), 3.76-3.80(4H, m), 4.24(4H, brs), 4.34(2H, s), 6.78-6.82(2H, m), 6.97 (1H, d, J=7.6Hz).
1H-NMR (CDCl3) δ: 1.28(3H, t, J=7.3Hz), 3.68(2H, brs), 3.76(3H, s), 3.86(3H, s), 4.38(2H, s), 5.46(1H, brs), 6.87(1H, t, J=8.6Hz), 7.16-7.26 (2H, m), 7.58(1H, s).
1H-NMR (CDCl3) δ: 1.28(3H, t, J=7.2Hz), 3.69-3.71(4H, m), 3.74(3H, s), 3.82(3H, s), 4.36(2H, s), 5.80(1H, brs), 6.69(1H, d, J=8.1Hz), 6.78-6.84(2H, m), 7.56(1H, s).
1H-NMR (CDCl3) δ: 0.42(2H, dt, J=4.9, 5.9Hz), 0.64(2H, dt, J=4.9, 5.9Hz), 1.21-1.36(1H, m), 3.78(3H, s), 3.81(4H, t, J=4.6 Hz), 3.97(2H, d, J=7.3Hz), 4.27(4H, brs), 4.37(2H, s), 6.82(2H, d, J= 8.6Hz), 7.36(2H, d, J=8.6Hz), 7.72(1H, s).
1H-NMR (CDCl3) δ: 1.38(6H, t, J=7.4Hz), 2.85(2H, q, J=7.4Hz), 3.80(4H, m), 3.89(3H, s), 4.13(2H, q, J=7.4Hz), 4.24(4H, brs), 4.32(2H, s), 6.87(1H, m), 7.61(1H, m), 7.67(1H, m).
1H-NMR (CDCl3) δ: 2.49(1H, dd, J=2.4, 4.6Hz), 2.84(1H, t, J=4.1Hz), 3.29-3.37(1H, m), 3.78(3H, s), 3.80(4H, t, J=4.6Hz), 4.11(1H, d, J=5.9Hz), 4.15(1H, d, J=5.9Hz), 4.28(4H, brs), 4.37(2H, s), 6.82(2H, d, J=8.6Hz), 7.35(2H, d, J=8.6Hz), 7.68(1H, s).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.81(4H, t, J=4.9 Hz), 4.27(4H, brs), 4.37(2H,s), 4.75(2H, dd, J=1.4, 5.7 Hz), 5.17-5.31(2H, m), 5.90-6.10(1H, m),6.82(2H, d, J=8.6 Hz), 7.36(2H, d, J=8.6 Hz), 7.61(1H, s).
1H-NMR (CDCl3) δ: 1.37(6H, m), 2.80(2H, q, J=7.4Hz), 3.78(4H, m), 3.82(3H, s), 4.13(2H, q, J=7.3Hz), 4.25(4H, brs), 4.32(2H, s), 6.66-6.82(3H, m).
1H-NMR (CDCl3) δ: 2.49(1H, t, J=2.7Hz), 3.77(3H, s), 3.79(4H, t, J=4.6Hz), 4.25(4H, brs), 4.37(2H, s), 4.90(2H, d, J=2.7Hz), 6.82(2H, d, J= 8.6Hz), 7.35(2H, d, J=8.6Hz), 7.81(1H, s).
1H-NMR (CDCl3) δ: 1.39(3H, t, J=6.9Hz), 3.75(3H, s), 3.79(4H, m), 4.00(2H, q, J=6.9Hz), 4.26(4H, brs), 4.38(2H, s), 6.81(2H, d, J=8.6Hz), 7.34(2H, d, J=8.6Hz), 7.58(1H, s).
1H-NMR (CDCl3) δ: 1.32(3H, t, J=7.6Hz), 2.75(2H, q, J=7.3Hz), 3.58(3H, s), 3.67(4H, dd, J=4.6, 4.9Hz), 4.12(4H, brs), 6.23(1H, s), 7.17-7.30(6H, m), 7.46-7.49(4H, m).
1H-NMR (CDCl3) δ: 0.60-0.66(2H, m), 0.84-0.91(2H, m), 3.07(1H, brs), 3.67(3H, s), 3.78(3H, s), 4.46(2H, s), 5.77(1H, brs), 6.82(2H, d, J=8.6Hz), 7.40(2H, d, J=8.6Hz), 7.58(1H,s).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.3Hz), 2.51(3H, s), 3.78(3H, s), 3.78(4H, m), 4.12(2H, q, J=7.3Hz), 4.22, (4H, brs), 4.37(2H, s), 6.81(2H, d, J=8.7Hz), 7.35(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=7.6Hz), 1.39(3H, t, J=7.1Hz), 2.78(2H, q, J=7.6Hz), 3.65(3H, s), 3.79(4H, m), 4.02(2H, q, J=7.1Hz), 4.25(4H, brs), 4.32(2H, s), 6.65-6.82(3H, m).
1H-NMR (CDCl3) δ: 1.00(3H, m), 1.36(3H, t, J=7.3Hz), 1.80(2H, m), 2.75(2H, m), 3.77(3H, s), 3.78(4H, m), 4.12(2H, q, J=7.3Hz), 4.25(4H, brs), 4.37(2H, s), 6.80(2H, d, J=8.7Hz), 7.34(2H, d, J=8.7Hz).
1H-NMR (CDCl3) δ: 3.53(3H, s), 3.77(3H, s), 3.78(3H, s), 3.93(3H, s), 4.41(2H, s), 6.83(2H, d, J=8.6Hz), 7.37(2H, d, J=8.6Hz), 7.69(1H,s).
1H-NMR (CDCl3) δ: 1.37(6H, m), 1.39(3H, t, J=7.4Hz), 2.79(2H, q, J=7.4Hz), 3.79(4H, m), 4.12(4H, m), 4.25(4H, brs), 4.31(2H, s), 6.68-6.82(3H, m).
1H-NMR (CDCl3) δ: 1.41(3H, t, J=6.9Hz), 3.19(3H, brs), 3.75(3H, s), 4.02(2H, q, J=6.9Hz), 4.37(2H, s), 5.65(1H, brs), 6.67(1H, d, J=7.8Hz), 6.77-6.84(2H, m), 7.51(1H, s).
1H-NMR (CDCl3) δ: 3.34(3H, s), 3.40-3.60(5H, brs), 3.66(2H, m), 3.74(3H, s), 3.78(3H, s), 4.41(2H, s), 6.82(2H, d, J=8.7Hz), 7.37 (2H, d, J=8.7Hz), 7.57(1H, s).
1H-NMR (CDCl3) δ: 3.79(3H, s), 3.85(3H, s), 4.49(2H, s), 6.41(2H, t, J=2.3Hz), 6.84(2H, d, J=8.7Hz), 7.40(2H, d, J=8.7Hz), 7.86(1H,s), 8.28 (2H, t, J=2.3Hz).
1H-NMR (CDCl3) δ: 3.79(3H, s), 3.88(3H, s), 4.48(2H, s), 6.85(2H, d, J=8.6Hz), 7.23(1H, brs), 7.40(2H, d, J=8.6Hz),7.92(1H,s), 8.34(1H, brs), 9.10(1H, brs).
1H-NMR (CDCl3) δ: 1.22(3H, t, J=7.1Hz), 1.35(3H, t, J=7.6Hz), 2.80(2H, q, J=7.6Hz), 3.62 (2H, q, J=7.1Hz), 3.63 (3H, s), 3.77(3H, s), 3.80-3.90(2H, m), 4.10-4.20(2H, m), 4.25-4.35(2H, brs), 4.38(2H, s), 4.65-4.75(1H, m), 6.81(2H, d, J=8.7Hz), 7.36(2H, d, J=8.7H).
1H-NMR (CDCl3) δ: 3.77(3H, s), 3.95(3H, s), 4.38(3H, s), 4.50(2H, s), 6.83(2H, d, J=8.6Hz), 7.40(2H, d, J=8.6Hz), 7.94(1H, brs), 8.36(1H,s), 8.60(1H, brs), 10.52(1H, brs).
1H-NMR (CDCl3) δ: 1.03(3H, t, J=7.4Hz), 1.36(3H, t, J=7.6Hz), 1.80(2H, m), 2.80(2H, q, J=7.6Hz), 3.65(3H, s), 3.80(4H, m), 3.79(2H, t, J=4.6Hz), 4.24(4H, brs), 4.32(2H, s), 6.68-6.81(3H, m).
1H-NMR (CDCl3) δ: 1.41(3H, t, J=7.3Hz), 3.76(3H, s), 3.79(4H, m), 4.12(2H, q, J=7.3Hz), 4.26(4H, brs), 4.33(2H, s), 6.67(1H, d, J=8.1Hz), 6.75 (1H, dd, J=2.1, 8.1Hz), 6.82(1H, d, J=2.1Hz), 7.58(1H,s).
1H-NMR (CDCl3) δ: 1.38(6H, m), 2.80(2H, q, J=7.6Hz), 3.80(4H, m), 3.84(3H, s), 4.12(2H, q, J=7.3Hz), 4.25(4H, brs), 4.30(2H, s), 6.73(1H, d, J=8.4Hz), 7.40 (1H, dd, J=2.3, 8.4Hz), 7.89(1H, d, J=2.3Hz).
1H-NMR (CDCl3) δ: 1.13(3H, t, J=7.6Hz), 1.45 (3H, t, J=7.1Hz), 2.78 (2H, q, J=7.6Hz), 3.66(3H, s), 3.79(4H, m), 4.07(2H, q, J=7.1Hz), 4.25(4H, brs), 4.34(2H, s), 6.86(1H, m), 7.09(1H, m), 7.17(1H, m).
1H-NMR (CDCl3) δ: 1.39(9H, m), 2.79(2H, q, J=7.6Hz), 3.78(4H, m), 4.07(2H, q, J=6.9Hz), 4.13(2H, q, J=7.3Hz), 4.25(4H, brs), 4.33(2H, s), 6.86(1H, m), 7.20 (1H, m), 7.28 (1H, m).
1H-NMR (CDCl3) δ: 1.22(3H, t, J=7.1Hz), 1.47(3H, t, J=7.4Hz), 3.74-3.80(2H, m), 3.82(3H, s), 3.85-3.91(2H, m), 4.05-4.19(2H, m), 4.11(2H, q, J=7.1Hz), 4.19(2H, q, J=7.4Hz), 4.32(2H, s), 4.65-4.75(1H, m), 6.68(1H, d. J=7.8Hz), 6.77-6.82(2H, m), 7.62(1H, s).
1H-NMR (CDCl3) δ: 1.22(3H, t, J=7.0Hz), 3.56-4.33 (18H, m), 4.73(1H, dd, J=5.1, 5.7Hz), 6.83-6.67(3H, m), 7.59(1H, s).
1H-NMR (CDCl3) δ: 3.77(3H, s), 3.87(3H, s), 4.49(2H, s), 6.54(1H, dd, J=1.0, 2.6Hz), 6.85(2H, d, J=8.7Hz), 7.42(2H, d, J=8.7Hz), 7.99(2H, m), 8.84(1H, d, J=2.6Hz).
1H-NMR (CDCl3) δ: 1.36(3H, t, J=6.9Hz), 1.40 (3H, t, J=7.1Hz), 2.51(3H, s), 3.78(4H, m), 4.02(2H, q, J=6.9Hz),4.14(2H, q, J=7.1Hz),4.23(4H, brs), 4.31(2H, s), 6.65-6.82(3H, m).
1H-NMR (CDCl3) δ: 1.38(6H, m), 2.80(2H, q, J=7.6Hz), 3.78(4H, m), 3.85(3H, s), 4.13(2H, q, J=7.1Hz), 4.25(4H, brs), 4.33(2H, s), 6.85-7.25(3H, m).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.90(3H, s), 4.48(2H, s), 6.84(2H, d, J=8.7Hz), 7.42(2H, d, J=8.7Hz), 8.02(1H, s), 8.28(1H, s), 9.50(1H, s).
1H-NMR (CDCl3) δ: 1.50(3H, t, J=7.4Hz), 3.19(3H, brs), 3.82(3H, s), 4.18(2H, q, J=7.4Hz), 4.36(2H, s), 5.59(1H, brs), 6.69(1H, d, J=8.1Hz), 6.79-6.84(2H, m), 7.61(1H, s).
1H-NMR (CDCl3) δ: 3.76(3H, s), 3.78(3H, s), 4.30(2H, brs), 4.41(2H, s), 5.17(1H, dd, J=2.8, 10.2Hz), 5.28(1H, dd, J=2.8, 17.1Hz), 5.83(1H, brs), 5.90-6.04(1H, m), 6.82(2H, d, J=8.6Hz), 7.37(2H, d, J=8.6Hz), 7.59(1H, s).
1H-NMR (CDCl3) δ: 3.74(3H, s), 3.78(3H, s), 4.05-5.13 (6H, m), 5.15(2H, dd, J=1.4, 1.6 Hz), 5.20(2H, d, J=4.9 Hz), 5.83-5.96(2H, m), 6.82(2H, d, J=8.6Hz), 7.36(2H, d, J=8.6 Hz), 7.58(1H, s).
1H-NMR (CDCl3) δ: 2.17(3H, s), 3.78(3H, s), 3.84(3H, s), 4.48(2H, s), 6.24(1H, dd, J=0.8, 2.6Hz), 6.84(2H, d, J=8.9Hz), 7.40(2H, d, J=8.9Hz), 7.86(1H, s), 8.02 (1H, d, J=0.8Hz), 8.16 (1H, d, J=2.6Hz).
1H-NMR (CDCl3) δ: 3.41(3H, s), 3.26-4.06(11H, m), 4.35(2H, s), 4.67-4.71(2H, m), 7.01(1H, d, J=8.6Hz), 7.60 (1H, s), 7.65(1H, dd, J=2.3, 8.6Hz), 8.05(1H, d, J=2.3Hz).
1H-NMR (CDCl3) δ: 3.76(3H, s), 3.78(3H, s), 4.44(2H, s), 4.53(2H, brs), 4.89(2H, brs), 5.96(2H, brd, J=3.2 Hz), 6.82(2H, d, J=8.6 Hz), 7.39(2H, d, J=8.6 Hz), 7.59(1H, s).
1H-NMR (CDCl3) δ: 3.60-3.75(2H, m), 3.76(3H, s), 3.92(3H, s), 4.10-4.20(2H, m), 4.30(2H, brs), 4.35(2H, s), 5.10(1H, t, J=3.5Hz), 7.01(1H, d, J=8.7Hz), 7.61 (1H, s), 7.64(1H, dd, J=2.3, 8.7Hz), 8.06(1H, d, J=2.3Hz).
1H-NMR (CDCl3) δ: 1.99(3H, dd, J=1.8, 6.8Hz), 3.71(3H, s), 3.78(3H, s), 3.80(4H, m), 4.27(4H, brs), 4.38(2H, s), 6.39(1H, dd, J=1.8, 13.7Hz), 6.81(2H, d, J=8.4Hz), 6.89(1H, dd, J=6.8, 13.7Hz), 7.36(2H, d, J=8.4Hz).
1H-NMR (CDCl3) δ: 1.21(3H, t, J=7.0Hz), 3.50-4.35(16H, m), 4.72(1H, t, J=3.5Hz), 6.87(1H, dd, J=8.1 8.6Hz), 7.13-7.17(1H, m), 7.22(1H, dd, J=2.2, 12.2Hz), 7.60(1H, s).
1H-NMR (CDCl3) δ: 1.21(3H, t, J=7.1Hz), 3.50-3.85(2H, m), 3.76(3H, s), 3.89(3H, s), 4.10(1H, m), 4.28(4H, brs), 4.33(2H, s), 4.74(1H, m), 6.89(1H, d, J=8.6Hz), 7.60(1H, s), 7.60-7.76(2H, m).
1H-NMR (CDCl3) δ: 1.21(3H, t, J=6.9Hz), 1.47(3H, t, J=7.2Hz), 3.53-3.59(1H, m), 3.65-3.70(1H, m), 3.85(3H, s), 4.10-4.13(2H, m), 4.16(2H, q, J=6.9Hz), 4.19(2H, q, J=7.2Hz), 4.32-4.34(2H, m), 4.36(2H, s), 4.70-4.73(1H, m), 6.86(1H, t, J=8.6Hz), 7.12-7.27(2H, m), 7.63(1H, s).
1H-NMR (CDCl3) δ: 1.47(3H, t, J=7.2Hz), 3.50(6H, brs), 3.81(3H, s), 4.16(2H, q, J=7.2Hz), 4.35(2H, s), 6.68(1H, d. J=8.0Hz), 6.77-6.90(2H, m), 7.61(1H, s).
1H-NMR (CDCl3) δ: 3.54(3H, s), 3.80(3H, s), 3.86(3H, s), 3.92(3H, s), 4.36 (2H, s), 6.87(1H, t, J=8.6Hz), 7.13-7.16(1H, m), 7.19-7.24(1H, m), 7.99(1H, s).
1H-NMR (CDCl3) δ: 1.21(3H, t, J=7.3Hz), 1.45(3H, t, J=7.0Hz), 1.48(3H, t, J=7.3Hz), 3.50-3.86(3H, m), 4.07-4.35(11H, m), 4.72(1H, t, J=3.8Hz), 6.98(1H, d, J=8.6Hz), 7.61(2H, d, J=8.6Hz), 7.98(1H, d, J=2.4Hz).
1H-NMR (CDCl3) δ: 3.88(3H, s), 3.93(3H, s), 4.45(2H, s), 6.40(2H, t, J=2.3Hz), 7.03(1H, d, J=8.6Hz), 7.69(1H, dd, J=2.3, 8.6Hz), 7.87(1H,s), 8.10(1H, d, J=2.4Hz), 8.24 (2H, t, J=2.3Hz).
1H-NMR (CDCl3) δ: 1.41(3H, t, J=6.9Hz), 3.49(6H, brs), 3.73(3H, s), 3.80(2H. Brs), 4.02(2H, q. J=6.9Hz), 4.36(2H, s), 6.67(1H, d. J=8.2Hz), 6.75-6.83(2H, m), 7.56(1H, s).
1H-NMR (CDCl3) δ: 3.82(3H, s), 3.87(3H, s), 4.49(2H, s), 6.40(2H, t, J=2.3Hz), 6.72(1H, d, J=8.4Hz), 6.85(1H, d, J=2.3Hz), 7.04(1H, dd, J=2.3, 8.4Hz), 7.85(1H,s), 8.29 (2H, t, J=2.3Hz).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.93(3H, s), 4.40(2H, s), 4.50(2H, brs), 4.88(2H, brs), 5.96(2H, d, J=2.7Hz), 7.01(1H, d, J=8.6Hz), 7.60(1H, s), 7.67(1H, dd, J=2.2, 8.6Hz), 8.07(1H, d, J=2.2Hz).
1H-NMR (CDCl3) δ: 3.52(3H, s), 3.76(3H, s), 3.92(3H, s), 3.93(3H, s), 4.37 (2H, s), 7.01(1H, t, J=8.7Hz), 7.66(1H, dd, J=2.3, 8.7Hz), 7.70(1H, s), 8.05(1H, d, J=2.3Hz).
1H-NMR (CDCl3) δ: 3.74(3H, s), 3.82(3H, s), 4.38(2H, s), 4.43-4.87(6H, m), 5.95(2H, d, J=2.7Hz), 6.69(1H, d, J=8.1Hz), 6.80(2H, m), 7.57(1H, s).
1H-NMR (CDCl3) δ: 3.56(3H, s), 3.77(3H, s), 3.82(3H, s), 3.93(3H, s), 4.36 (2H, s), 6.71(1H, t, J=8.4Hz), 6.81-6.86(2H, m), 7.67(1H, s).
1H-NMR (CDCl3) δ: 1.32(3H, t, J=7.3Hz), 2.70(2H, q, J=7.3Hz), 3.45(3H, s), 3.63(4H, t, J=4.7Hz), 3.96(3H, s), 4.12, (4H, brs), 4.67(2H, s), 7.12-7.20(2H, m), 7.80-7.86(2H, m), 8.08-8.11(2H, m), 8.59(2H, d, J=3.7Hz).
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(2,3,-ジヒドロ-[1,4]オキサジン-4-イル)-9-メチル-9H-プリン(化合物150)の合成
2-チオキサンチン(7.75g、46mmol)、トリエチルアミン(8.0ml、60mmol)、4-メトキシ-3-ニトロベンジルブロマイド(12.48g、51mmol)のDMF(100ml)溶液を100℃で3時間加熱攪拌した。反応液に水を加え、析出した結晶を濾取し水、エーテルで順次洗浄することにより6-ヒドロキシ-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9H-プリンを14.67g(収率95%)得た。
1H-NMR (DMSO-d6) δ: 3.89(3H, s), 4.45(2H, s), 7.32(1H, d, J=8.6Hz), 7.76(1H, dd, J=2.1, 8.6Hz), 7.99(1H, d, J=2.1Hz), 8.01(2H, brs), 12.5(1H, brs).
6-ヒドロキシ-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9H-プリン(14.67g、44mmol)をジオキサン(30ml)に懸濁させ、オキシ塩化リン(12.3ml、132mmol)、ジメチルアニリン(8.3ml、66mmol)を加え、100℃で2時間加熱攪拌した。反応液を氷水に注ぎ酢酸エチルで2回抽出した。酢酸エチル層を合わせ飽和食塩水で洗浄後、MgSO4で乾燥し溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=20:1)で分離精製し、6-クロロ-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9H-プリンを5.45g(収率35%)得た。
1H-NMR (DMSO-d6) δ: 3.89(3H, s), 4.46(2H, s), 7.31(1H, d, J=8.7Hz), 7.78(1H, dd, J=2.3, 8.7Hz), 8.01(1H, d, J=2.3Hz), 8.55(1H, s), 13.80(1H, brs).
6-クロロ-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9H-プリン(2.00g、6.3mmol)をN,N-ジメチルホルムアミド(20ml)に溶かし、氷冷下60%水素化ナトリウム(0.30g、7.6mmol)を加え5分間攪拌した後、ヨウ化メチル(1.08g、0.76mmol)を加え終夜攪拌した。反応液に水を加え、析出した結晶を濾取し水、エーテルで順次洗浄することにより6-クロロ-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリンを2.06g(収率89%)得た。
1H-NMR (CDCl3) δ: 3.89(3H, s), 3.95(3H, s), 4.39(2H, s), 7.03(1H, d, J=8.6Hz), 7.69(1H, dd, J=2.3, 8.6Hz), 7.94(1H, s), 8.10(1H, d, J=2.3Hz).
6-クロロ-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(850mg、2.32mmol)をテトラヒドロフラン(100ml)に溶かし、トリエチルアミン(1.57g、15.51mmol)と2-エトキシモルホリン塩酸塩(520mg、3.10mmol)を加え、7時間加熱還流した。溶媒を減圧留去した後、残渣に水を加え、酢酸エチルで2回抽出した後、有機層を飽和食塩水で洗浄し、MgSO4で乾燥した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:3)で精製し、6-(2-エトキシモルホリノ)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリンを738mg(収率69%)得た。
1H-NMR (CDCl3) δ: 1.22(3H, t, J=3.5Hz), 4.73(1H, t, J=3.8Hz), 3.26-4.35(16H, m), 7.01(1H, d, J=8.4Hz), 7.65(2H, dd, J=2.4, 8.4Hz), 8.05(1H, d, J=2.4Hz).
6-(2-エトキシモルホリノ)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(30mg、65.1μmol)に4N-HCl/ジオキサン(2ml)を氷冷下加え、2時間加熱還流した。溶媒を減圧留去し、残渣にジクロロメタンと水を加えた。飽和炭酸ナトリウム溶液を用いて中和し、ジクロロメタンで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去した後、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:4)に付し、6-(3,4-ジヒドロ-2H-[1,4]オキサジン-4-イル)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(15mg、56%)を得た。
1H-NMR (CDCl3) δ: 3.64-4.36 (11H, m), 4.37(2H, s), 6.15(1H, d, J=5.1 Hz), 7.01(1H, d, J=8.6 Hz), 7.05(2H, dd, J=2.4,8.6 Hz), 8.07(1H, d, J=2.4 Hz).
6-(3,4-ジヒドロ-2H-[1,4]オキサジン-4-イル)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(25mg、60.3μmol)、亜鉛末(90mg、1.38mmol)、塩化カルシウム(4mg、36.0μmol)、アセトニトリル(1ml)と水(0.3ml)の混合液を2時間加熱還流した。不溶物を濾別して濾液を減圧留去し、残渣にジクロロメタンと水を加えジクロロメタンで抽出した。有機層を硫酸マグネシウムで乾燥し、濾液を減圧留去した。残渣にクロロホルム及び酢酸エチルを加え溶解させ、ヘキサンを加えて析出した結晶濾取し、2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(3,4,-ジヒドロ-2H-[1,4]オキサジン-4-イル)-9-メチル-9H-プリン(12.7mg、55%)を得た。
1H-NMR (CDCl3) δ: 3.60-4.35 (14H, m), 6.15(1H, d, J=5.1Hz), 6.68-6.87 (4H, m), 7.64(1H, d, J=4.1Hz).
1H-NMR (CDCl3) δ: 3.64-4.22(10H, m), 4.41(2H, s), 6.15(1H, d, J=5.4Hz), 6.81-6.86 (3H, m), 7.37(2H, d, J=8.6Hz), 7.64(1H, s).
1H-NMR (CDCl3) δ: 1.39(3H, t, J=7.5Hz), 2.82(2H, q, J=7.5Hz), 3.69(3H, s), 3.78(3H, s), 4.20-4.50(2H, brs), 4.22(2H, brd, J=2.8Hz), 4.40(2H, s), 6.13(1H, d, J=5.1Hz), 6.83(2H, d, J=8.7H), 7.37(2H, d, J=8.7Hz), 7.90(1H, brs).
1H-NMR (CDCl3) δ: 1.47(3H, t, J=7.2Hz), 3.76(2H, brs), 3.82(3H, s), 4.13-4.23(4H, m), 4.34(2H, s), 6.14(1H, d, J=5.0Hz), 6.68(1H, d, J=8.1Hz), 6.77-6.82(2H, m), 7.67(1H, s), 7.89 (1H, brs).
1H-NMR (CDCl3) δ: 3.87-4.75 (12H, m), 6.33(1H, d, J=5.1Hz), 6.86-6.92(1H, m), 7.11-7.19(2H, m), 7.69(1H, brs), 8.09(1H, brs).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.89(3H, s), 4.20(2H, brs), 4.22(2H, m), 4.35(2H, s), 6.15(1H, d, J=4.9Hz), 6.89(1H, d, J=8.7Hz), 7.64(1H, dd, J=2.3, 8.7Hz), 7.65(1H, s), 7.70(1H, d, J=2.3Hz), 7.90(1H, brs).
1H-NMR (CDCl3) δ: 1.49(3H, t, J=7.3Hz), 3.86(3H, s), 4.15-4.24(4H, m), 4.22(2H, q, J=7.3Hz), 4.35(2H, s), 6.15(1H, d, J=5.1Hz), 6.87(1H, t, J=8.4Hz), 7.13-7.24(2H, m), 7.67(1H, s), 7.80 (1H, brs).
1H-NMR (CDCl3) δ: 1.46(3H, t, J=6.8Hz), 1.59(3H, t, J=7.0Hz), 4.12-4.43(10H, m), 6.28(1H, d, J=5.1Hz), 7.01(2H, d, J=8.6Hz), 7.61(1H, d, J=8.6Hz), 7.96(1H, d, J=2.4Hz), 8.11(1H, brs).
1H-NMR (CDCl3) δ: 1.41(3H, t, J=7.3Hz), 1.49(3H, t, J=7.3Hz), 3.61-4.30(10H, m), 4.34(2H, s), 6.15(1H, d, J=5.1Hz), 6.68(1H, d, J=8.1Hz), 6.77(1H, dd, J=2.2, 8.1Hz), 6.82(1H, d, J=2.2Hz), 7.67(1H, s), 7.88(1H, brs).
1H-NMR (CDCl3) δ: 1.38(3H, t, J=7.6Hz), 2.82(2H, q, J=7.6Hz), 3.67(3H, s), 3.86(3H, s), 4.15-4.33(4H, m), 4.36(2H, s), 6.13(1H, d, J=5.1Hz), 6.86(1H, t, J=8.6H), 7.13-7.24(2H, m), 7.77(1H, brs).
1H-NMR (CDCl3) δ: 1.37(3H, t, J=7.6Hz), 1.38(3H, t, J=7.3Hz), 2.81(2H, q, J=7.6Hz), 3.78(3H, s), 4.15(2H, q, J=7.3Hz), 4.20(2H, m), 4.30(2H, brs), 4.39(2H, s), 6.13(1H, d, J=5.1Hz), 6.82(2H, d, J=8.7Hz), 7.38(2H, d, J=8.7Hz), 7.88(1H, brs).
1H-NMR (CDCl3) δ: 1.44(3H, t, J=6.9Hz), 3.79(3H, s), 4.14(2H, q, J=6.9Hz), 4.20-4.23(2H, m), 4.36(2H, s), 4.75(2H, brs), 6.15(1H, d, J=5.0Hz), 6.98(1H, d, J=8.7Hz), 7.61(1H, dd, J=2.1, 8.7Hz), 7.64(1H, s), 7.88(1H, brs), 8.03(1H, d, J=2.1Hz).
1H-NMR (CDCl3) δ: 1.41(3H, t, J=6.9Hz), 3.67(3H, s), 3.99(2H, brs), 4.02(2H, q, J=6.9Hz), 4.20-4.25(2H, m), 4.34(2H, s), 4.75(2H, brs), 6.15(1H, d, J=4.9Hz), 6.68(1H, d, J=8.2Hz), 6.77(1H, dd, J=2.1, 8.2Hz), 6.82(1H, d, J=2.1Hz), 7.62(1H, s), 7.87(1H, brs).
1H-NMR (CDCl3) δ: 1.39(3H, t, J=7.6Hz), 2.82(2H, q, J=7.6Hz), 3.68(3H, s), 3.89(3H, s), 4.13-4.22(4H, m), 4.34(2H, s), 6.14(1H, d, J=5.1Hz), 6.88(1H, d, J=8.6Hz), 7.62(1H, dd. J=2.1Hz, 8.6Hz), 7.69(1H, d, J=2.1Hz), 7.95(1H, brs).
1H-NMR (CDCl3) δ: 1.38(3H, t, J=7.6Hz), 2.81(2H, q, J=7.6Hz), 3.66(3H, s), 3.82(3H, s), 4.16-4.21(4H, m), 4.34(2H, s), 6.13(1H, d, J=5.1Hz), 6.68(1H, d, J=8.1Hz), 6.78(1H, dd. J=2.0Hz, 8.1Hz), 6.82(1H, d, J=2.0Hz), 7.91(1H, brs).
2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-6-(1-trans-プロペニル)-9H-プリン(化合物171)の合成
1H-NMR (CDCl3) δ: 2.05(3H, dd, J=1.8, 8.6Hz), 3.85(3H, s), 3.93(3H, s), 4.41(2H, s), 6.92(1H, m), 7.03(1H, d, J=8.6Hz), 7.58(1H, m), 7.69(1H, dd, J=2.5, 8.6Hz), 7.86(1H,s), 8.11(1H, d, J=2.5Hz).
1H-NMR (CDCl3) δ: 2.05(3H, dd, J=1.8, 6.9Hz), 3.78(3H, s), 3.81(3H, s), 4.47(2H, s), 6.83(2H, d, J=8.7Hz), 6.90(1H, m), 7.41(2H, d, J=8.7Hz), 7.50(1H, m), 7.85(1H, s).
1H-NMR (CDCl3) δ: 1.01(3H, t, J=7.4Hz), 1.87-1.91(2H, m), 3.09(2H, t, J=7.4Hz), 3.78(3H, s), 3.85(3H, s), 4.45(2H, s), 6.83(2H, d, J=8.7Hz), 7.42(2H, d, J=8.7Hz), 7.84(1H, s).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.83(3H, s), 4.47(2H, s), 5.93(1H, dd, J=2.0, 10.7Hz), 6.83(2H, d, J=8.7Hz), 7.01(1H, dd, J=2.0, 17.5Hz), 7.22(1H, dd, J=10.7, 17.5Hz), 7.48(2H, d, J=8.7Hz), 7.88(1H, s).
1H-NMR (CDCl3) δ: 3.79(3H, s), 3.91(3H, s), 4.54(2H, s), 6.85(2H, d, J=9.2Hz), 7.43(2H, d, J=9.2Hz), 8.02(1H, s), 8.37(2H, d, J=9.1Hz), 8.99(2H, d, J=9.1Hz).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.86(3H, s), 4.50(2H, s), 6.65(2H, dd, J=0.9, 1.8Hz), 6.84(2H, d, J=8.7Hz), 7.44(2H, d, J=8.7Hz), 7.75-7.78(2H, m), 7.94(1H,s).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.85(3H, s), 4.53(2H, s), 6.83(2H, d, J=8.4Hz), 7.41-7.44(3H, m), 7.91(1H, s) 8.26(1H, dd, J=1.2, 5.1Hz), 8.87(1H, dd, J=1.2, 3.1Hz).
1H-NMR (CDCl3) δ: 2.48(3H, s), 2.65(3H, s), 3.79(3H, s), 3.88(3H, s), 4.47(2H, s), 6.85(2H, d, J=8.4Hz), 7.39(2H, d, J=8.4Hz), 7.91(1H,s).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.87(3H, s), 4.51(2H, s), 6.85(2H, d, J=8.6Hz), 7.43(2H, d, J=8.6Hz), 7.88(1H,s), 8.70(2H,s).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.84(3H, s), 4.01(3H, s), 4.50(2H, s), 6.83(2H, d, J=8.6Hz), 7.42(2H, d, J=8.6Hz), 7.87(1H,s), 8.49(1H,s), 8.55(1H,s).
1H-NMR (CDCl3) δ: 2.05(3H, dd, J=1.8, 8.6Hz), 3.81(3H, s), 3.82(3H, s), 4.44(2H, s), 6.69(1H, m), 6.84(2H, m), 6.95(1H, ddt, J=1.8, 8.6, 17.5Hz), 7.60(1H, m), 7.84(1H,s).
1H-NMR (CDCl3) δ: 3.78(3H, s), 3.85(3H, s), 4.53(2H, s), 6.84(2H, d, J=8.7Hz), 7.24(1H, m), 7.43(2H, d, J=8.7Hz), 7.61(1H, d, J=4.9Hz), 7.92(1H,s), 8.62 (1H, d, J=3.7Hz).
〔薬理試験1:in vitro抗腫瘍活性試験〕
1)種々の腫瘍細胞に対する抗腫瘍活性
(試験方法)
i)接着性の癌細胞
MEM培地に10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシンを加えた培養液中で、37℃、5%炭酸ガスの条件下で継代維持したWiDr細胞(ヒト結腸癌細胞)をトリプシン/EDTA処理により、単浮遊細胞とし、MEM培地(10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシン添加)で、1ml当たり3×104個の単細胞浮遊液を調製した。被験物質はDMSOに溶解した後、RPMI1640培地(10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシン添加)にて希釈し、濃度を2.0×10-9~2.0×10-4Mに調製した。
96穴マイクロプレートに1ウェル当たり、この細胞懸濁液0.1mlを入れ、24時間培養して、細胞をマイクロプレートに接着させた後、試料溶液0.1mlを添加し、5%炭酸ガス中、37℃で72時間培養した。
その後、種々の試料濃度での増殖阻害度をXTT比色定量法で求め、50%増殖阻害濃度(GI50値[μM])を算出した。
また、WiDr細胞以外に使用した細胞と、各細胞の単細胞浮遊液の調整条件は下記の通りである。
A549細胞(ヒト肺癌細胞):2×104個/ml
PC-3細胞(ヒト前立腺癌細胞):2×104個/ml
B16F10細胞(マウスメラノーマ[悪性黒色腫]細胞):1×104個/ml
DBA/2マウスの腹腔内で継代したP388細胞(マウス白血病細胞)を腹水と共に採取し、RPMI1640培地(10%ウシ胎仔血清、25mM HEPES、0.1mg/mlカナマイシンおよび5μM 2-ヒドロキシエチルジスルフィド添加)で、5%炭酸ガス中、37℃で培養した。培養16時間後に、浮遊しているP388細胞を、同上のRPMI1640培地で、1mlあたり4×104個の単細胞浮遊液とした。被験物質はDMSOに溶解した後、RPMI1640培地(10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシン添加)にて希釈し、濃度を2.0×10-9~2.0×10-4Mに調製した。
96穴マイクロプレートに1ウェル当たり、この細胞懸濁液0.1mlを入れ、続いて、試料溶液0.1mlを添加し、5%炭酸ガス中、37℃で72時間培養した。
その後、種々の試料濃度での増殖阻害度をXTT比色定量法で求め、50%増殖阻害濃度(GI50値[μM])を算出した。
化合物B:文献「Chemistry & Biology, Vol.11, 135-146, January, 2004」記載化合物:
(試験方法)
MEM培地に10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシンを加えた培養液中で、37℃、5%炭酸ガスの条件下で継代維持したMCF-7細胞(ヒト乳癌細胞)をトリプシン/EDTA処理により、単浮遊細胞とし、MEM培地(10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシン添加)で、1ml当たり4×104個の単細胞浮遊液を調製した。被験物質(化合物2、および化合物7)はDMSOに溶解した後、MEM培地(10%ウシ胎仔血清、25mM HEPESおよび0.1mg/mlカナマイシン添加)にて希釈し、濃度を6.4×10-8~2.0×10-5Mに調製した。
96穴マイクロプレートに1ウェル当たり、この細胞懸濁液0.1mlを入れ、24時間培養して、細胞をマイクロプレートに接着させた後、試料溶液0.1mlを添加し、5%炭酸ガス中、37℃で72時間培養した。
その後、各ウェル内の細胞をトリプシン/EDTA処理により単浮遊細胞とし、セルカウンターを用いてその細胞数を計測することで、種々の試料濃度での増殖阻害率を求め、50%増殖阻害濃度(GI50値[μM])を算出した。
(結果)
化合物2および化合物7は濃度依存的にMCF-7細胞の増殖を阻害し、そのGI50値は化合物2で0.11μM、化合物7で0.13μMであった。
〔薬理試験2:in vivo抗腫瘍活性試験〕
1)化合物2および化合物7のヌードマウス移植ヒト肺癌A549に対する効果
(試験方法)
6週齢雌性BALB/c-nu/nuマウスの胸部皮下にヒト肺癌A549の腫瘍組織片(3mm×3mm×3mm)を移植し、腫瘍体積が約100mm3以上に達したところで検体投与を開始した(day0)。化合物2および化合物7はメノウ乳鉢を用いて1%ハイドロキシプロピルセルロース(HPC[L])溶液に懸濁した。化合物2の400mg/kgをday0からday13まで連日(day3およびday10を除く、計12回)経口投与した。化合物7の400mg/kgをday0からday13まで連日(day4およびday11を除く、計12回)腹腔内投与した。腫瘍径を計測して腫瘍体積(1/2×長径×短径×短径)を算出し、検体投与開始14日後(day14)の腫瘍体積を投与開始時の腫瘍体積で除して相対腫瘍増殖率を算出した。化合物2および化合物7投与群の相対腫瘍増殖率に対するコントロール群の相対腫瘍増殖率の百分比をT/C(%)とした。
(結果)
化合物2および化合物7は有意に腫瘍の増殖を抑制し、そのT/Cはそれぞれ73.1%および55.4%であった。
(試験方法)
6週齢雌性BALB/c-nu/nuマウスの胸部皮下にヒト前立腺癌PC-3の腫瘍組織片(3mm×3mm×3mm)を移植し、腫瘍体積が約100mm3以上に達したところで検体投与を開始した(day0)。化合物2はメノウ乳鉢を用いて1%HPC(L)溶液に懸濁した。化合物2の400mg/kgをday0からday13まで連日(day3およびday10を除く、計12回)経口投与した。腫瘍径を計測して腫瘍体積(1/2×長径×短径×短径)を算出し、検体投与開始14日後(day14)の腫瘍体積を投与開始時の腫瘍体積で除して相対腫瘍増殖率を算出した。化合物2投与群の相対腫瘍増殖率に対するコントロール群の相対腫瘍増殖率の百分比をT/C(%)とした。
(結果)
化合物2は有意に腫瘍の増殖を抑制し、そのT/Cは32.2%であった。
(試験方法)
6週齢雌性BALB/c-nu/nuマウスの胸部皮下にヒト結腸癌WiDrの腫瘍組織片(3mm×3mm×3mm)を移植し、腫瘍体積が約100mm3以上に達したところで検体投与を開始した(day0)。化合物2はメノウ乳鉢を用いて1%HPC(L)溶液に懸濁した。化合物2の400mg/kgを1日2回day0からday13まで連日(day3およびday10を除く、計12回)経口投与した。腫瘍径を計測して腫瘍体積(1/2×長径×短径×短径)を算出し、検体投与開始14日後(day14)の腫瘍体積を投与開始時の腫瘍体積で除して相対腫瘍増殖率を算出した。化合物2投与群の相対腫瘍増殖率に対するコントロール群の相対腫瘍増殖率の百分比をT/C(%)とした。
(結果)
化合物2は有意に腫瘍の増殖を抑制し、そのT/Cは62.1%であった。
Claims (17)
- 式(I):
Arは、ハロゲン、ホルミル基、シアノ基、ニトロ基、アミノ基、ヒドロキシル基またはカルボキシル基;あるいは、ハロゲン、シアノ基、アミノ基、ヒドロキシル基またはカルボキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C1-C6)アルキルカルボニル基、(C1-C6)アルキルアミノ基、(C1-C6)アルキルカルボニルアミノカルボニル基、(C3-C6)シクロアルキルアミノ基、(C1-C7)アルコキシカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノ基、(C1-C6)アルキルカルボニルアミノ基、(C3-C6)シクロアルキルカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノチオカルボニルアミノ基、ヘテロアリールカルボニルアミノ基、フェニルオキシカルボニルアミノ基、フェニルカルボニルアミノ基、(C1-C6)アルキルスルホニルアミノ基、ジ[(C1-C6)アルキル]アミノスルホニルアミノ基、(C1-C6)アルコキシ基、(C1-C6)アルキルチオ基、(C1-C6)アルキレンジオキシ基、(C1-C6)アルコキシカルボニル基、アミノ(C1-C6)アルキルカルボニルアミノ基、フェニル(C2-C6)アルケニルカルボニルアミノ基、(C1-C6)アルコキシ(C1-C6)アルキルカルボニルアミノ基、(C1-C6)アルコキシカルボニルアミノ(C1-C6)アルキルカルボニルアミノ基、フェニル基またはフェニル(C1-C6)アルコキシ基;により、独立して1、2または3個置換されていてもよい、フェニル基、ピリジル基、チアゾリル基、ベンゾフラニル基、ジヒドロベンゾフラニル基、ナフタレニル基、イミダゾリル基またはピラゾリル基を表し;
Yは、炭素鎖中にカルボニル基を含んでいてもよく、かつ/またはArにより1または2個置換されていてもよい、(C1-C6)アルキレン基を表し;
R1は、(C1-C6)アルキル基または(C2-C6)アルケニル基;あるいは、(C1-C6)アルキル基、(C1-C6)アルコキシ基、(C1-C6)アルコキシ(C1-C6)アルキル基、(C3-C6)シクロアルキル基または(C2-C6)アルケニル基、により1または2個置換されていてもよい、アミノ基または(C1-C6)アルキルカルボニルアミノ基;あるいは、ニトロソ基、ホルミル基、ヒドロキシル基、(C1-C6)アルキル基、(C1-C6)アルキルカルボニル基、(C1-C6)アルコキシ基、(C1-C6)アルコキシカルボニル基またはヒドロキシ(C1-C6)アルキルアミノ基、により1または2個置換されていてもよい、複素環基;あるいはハロゲン、ホルミル基、シアノ基、ニトロ基、アミノ基、ヒドロキシル基、(C3-C6)またはカルボキシル基で置換されているフェニル基;を表し;
R2は、H;あるいは、ハロゲン、ニトロ基またはアミノ基、により1または2個置換されていても良い、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基または(C3-C6)シクロアルキル基;を表し;
R3は、ハロゲンまたはヒドロキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基、(C3-C6)シクロアルキル基、(C3-C6)シクロアルキル(C1-C6)アルキル基、アミノ(C1-C6)アルキル基、三~五員環状エーテル-(C1-C6)アルキル基または(C1-C6)アルキルカルボニルアミノ(C1-C6)アルキル基を表す]
で表される化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。 - Arが、ハロゲン、ホルミル基、シアノ基、ニトロ基、アミノ基、ヒドロキシル基、カルボキシル基;あるいは、ハロゲンにより置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C1-C6)アルコキシカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノ基、(C1-C6)アルキルカルボニルアミノ基、(C3-C6)シクロアルキルカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノカルボニルアミノ基、ヘテロアリールカルボニルアミノ基、フェニルカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノスルホニルアミノ基、(C1-C6)アルコキシ基、アミノ(C1-C6)アルキルカルボニルアミノ基、フェニル(C1-C6)アルコキシ基、(C1-C6)アルキルチオ基、(C1-C6)アルキレンジオキシ基、(C1-C6)アルコキシカルボニル基またはフェニル基;により、独立して1、2または3個置換されていてもよい、フェニル基、ナフタレニル基またはピラゾリル基である、請求項1に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- Arが、ハロゲン、シアノ基、ニトロ基、アミノ基、ヒドロキシル基、(C1-C6)アルキル基、(C2-C6)アルケニル基、(C1-C6)アルキルカルボニルアミノ基、ヘテロアリールカルボニルアミノ基、フェニルカルボニルアミノ基、ジ[(C1-C6)アルキル]アミノスルホニルアミノ基、(C1-C6)アルコキシ基、フェニル(C1-C6)アルコキシ基またはアミノ(C1-C6)アルキルカルボニルアミノ基により、独立して1、2または3個置換されていてもよい、フェニル基、ナフタレニル基またはピラゾリル基である、請求項1に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- Yが、(C1-C6)アルキレン基である、請求項1ないし3の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- R1が、(C2-C6)アルケニル基;あるいは、(C1-C6)アルキル基、(C1-C6)アルコキシ基または(C3-C6)シクロアルキル基により1または2個置換されていてもよい、アミノ基または(C1-C6)アルキルカルボニルアミノ基;あるいは、ニトロソ基、(C1-C6)アルキル基、(C1-C6)アルキルカルボニル基または(C1-C6)アルコキシカルボニル基、により1または2個置換されていてもよい、複素環基;である請求項1ないし4の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- R1が、(C1-C6)アルキル基または(C1-C6)アルコキシ基により1または2個置換されていてもよい、アミノ基または(C1-C6)アルキルカルボニルアミノ基;あるいは、ニトロソ基、(C1-C6)アルキル基または(C1-C6)アルキルカルボニル基、により1または2個置換されていてもよい、複素環基;である請求項1ないし4の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- 前記複素環基が、モルホリノ基、オキサジニル基、ジヒドロオキサジニル基、ピペラジニル基、ピロリニル基、ピロリル基、イミダゾリル基、ピラゾリル基、トリアゾリル基、オキサゾリル基、イソオキサゾリル基、チエニル基またはフリル基である、請求項1ないし6の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- 前記複素環基が、モルホリノ基、ジヒドロオキサジニル基、ピロリル基、イミダゾリル基、ピラゾリル基、イソオキサゾリル基またはチエニル基である、請求項1ないし6の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- R2が、H、(C1-C6)アルキル基、(C2-C6)アルケニル基または(C3-C6)シクロアルキル基である、請求項1ないし8の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- R2が、H、(C1-C6)アルキル基または(C2-C6)アルケニル基である、請求項1ないし8の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- R3が、ハロゲンまたはヒドロキシル基により置換されていてもよい、(C1-C6)アルキル基、(C2-C6)アルケニル基またはアセチルアミノ(C1-C6)アルキル基である、請求項1ないし10の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- R3が、ハロゲンまたはヒドロキシル基により置換されていてもよい、(C1-C6)アルキル基である、請求項1ないし10の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。
- 前記化合物が、
8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物1);
2-(3-アミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物2);
2-(4-メトキシベンジルスルファニル)-8,9-ジメチル-6-モルホリノ-9H-プリン(化合物3);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-8-プロピル-9H-プリン(化合物4);
8-エチル-2-(4-メトキシカルボニルベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物5);
8-エチル-2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9-プロピル-9H-プリン(化合物6);
8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-6-(4-ニトロソピペラジン-1-イル)-9H-プリン(化合物7);
8-エチル-9-メチル-2-(4-メチルベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物8);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物9);
8-エチル-9-メチル-6-モルホリノ-2-(4-ビニルベンジルスルファニル)-9H-プリン(化合物10);
8-エチル-2-(3-フルオロ-4-メチルベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物11);
8-エチル-2-(4-エチルベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物12);
8-エチル-2-(3-ヒドロキシ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物13);
8-エチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物14);
2-(2-ベンジルオキシ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物15);
2-(3-クロロ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物16);
2-(4-エトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物17);
2-(3-アミノ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物18);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-ジメチルアミノ-9-メチル-9H-プリン(化合物19);
8-エチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-6-(4-ニトロソピペラジン-1-イル)-9H-プリン(化合物20);
6-ジメチルアミノ-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物21);
8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-6-[(3S)-3-メチル-4-ニトロソピペラジン-1-イル]-9H-プリン(化合物22);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-ジメチルアミノ-8-エチル-9-メチル-9H-プリン(化合物23);
6-ジメチルアミノ-8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物24);
6-ジエチルアミノ-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物25);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-メチルアミノ-9H-プリン(化合物26);
2-(3-アセチルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物27);
2-[3-(2-アミノアセチルアミノ)-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン塩酸塩(化合物28);
9-(2-アセチルアミノエチル)-8-エチル-2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物29);
8-エチル-9-(2-フルオロエチル)-2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物30);
8-エチル-2-(4-フルオロメチルベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物31);
8-エチル-9-メチル-2-(4-メチルスルファニルベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物32);
8-エチル-2-(2-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物33);
6-(4-アセチルピペラジン-1-イル)-8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物34);
2-(4-ジメチルアミノベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物35);
2-(ベンゾ[1,3]ジオキソール-5-イル-メチルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物36);
8-エチル-2-(4-メトキシ-3-メチルベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物37);
8-エチル-2-[1-(4-メトキシフェニル)エチルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物38);
8-エチル-2-(3-メトキシカルボニルアミノ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物39);
2-(3-アミノ-4-メチルベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物40);
2-(5-クロロ-3-メチル-1-フェニル-1H-ピラゾール-4-イルメチルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物41);
8-エチル-2-(6-メトキシナフタレン-2-イルメチルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物42);
8-エチル-2-(4-メトキシナフタレン-1-イルメチルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物43);
8-エチル-2-[2-(4-メトキシフェニル)エチルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物44);
2-(3-アミノ-4-メトキシベンジルスルファニル)-9-メチル-6-メチルアミノ-9H-プリン(化合物45);
2-(4-ブロモベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物46);
8-エチル-2-[2-(4-フルオロベンゾイル)エチルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物47);
8-エチル-2-[2-(4-メチルベンゾイル)エチルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物48);
8-エチル-2-(4-ヨードベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物49);
8-エチル-2-[3-(4-メトキシフェニル)プロピルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物50);
2-(3-シアノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物51);
8-エチル-2-(4-メトキシ-3-ピバロイルアミノベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物52);
8-エチル-2-(4-メトキシ-3-プロピオニルアミノベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物53);
2-(3-シクロプロパンカルボニルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物54);
8-エチル-2-[3-(2-フリルカルボニルアミノ)-4-メトキシベンジルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物55);
2-(3-ジメチルアミノカルボニルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物56);
2-(3-ジメチルスルファモイルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物57);
2-(3-ジメチルアミノチオカルボニルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物58);
8-エチル-2-[3-(4-フルオロベンゾイルアミノ)-4-メトキシベンジルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物59);
2-(3-アセチルアミノ-4-メトキシベンジルスルファニル)-6-ジメチルアミノ-8-エチル-9-メチル-9H-プリン(化合物60);
6-(N-アセチル-N-メチルアミノ)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物61);
2-[3-(2-tert-ブトキシカルボニルアミノアセチル)アミノ-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物62);
8-エチル-2-(3-メトキシアセチルアミノ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物63);
6-エチルアミノ-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物64);
8-エチル-6-(N-エチル-N-メチルアミノ)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物65);
[2-(3-trans-シンナモイルアミノ)-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物66);
2-(3-ジメチルアミノ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物67);
8-エチル-6-(N-エチル-N-メチルアミノ)-2-(4-ヨードベンジルスルファニル)-9-メチル-9H-プリン(化合物68);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-ジメチルアミノ-8-エチル-9-メチル-9H-プリン(化合物69);
2-[3-(iso-ブトキシカルボニルアミノ)-4-メトキシベンジルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物70);
6-ジメチルアミノ-8-エチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物71);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-メチルアミノ-9-メチル-9H-プリン(化合物72);
2-(3-フルオロ-4-メトキシベンジルスルファニル)-6-メチルアミノ-9-メチル-9H-プリン(化合物73);
6-ジエチルアミノ-8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物74);
6-(N-エチル-N-メチルアミノ)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物75);
6-アセチルアミノ-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物76);
8-エチル-2-(3-ヘプトキシカルボニルアミノ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物77);
2-(3-ブロモ-4-メトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物78);
8-エチル-2-(4-メトキシ-3-ビニルベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物79);
2-(3-シアノ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物80);
8-エチル-2-[3-(N-アセチルカルバモイル)-4-メトキシベンジルスルファニル]-9-メチル-6-モルホリノ-9H-プリン(化合物81);
6-(N-エチル-N-メチルアミノ)-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物82);
2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物83);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(N-エチル-N-メチルアミノ)-9-メチル-9H-プリン(化合物84);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-(N-エチル-N-メチルアミノ)-9-メチル-9H-プリン(化合物85);
6-ジメチルアミノ-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物86);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-ジメチルアミノ-9-メチル-9H-プリン(化合物87);
6-(2-エトキシモルホリノ)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物88);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-エチルアミノ-9-メチル-9H-プリン(化合物89);
2-(3-アミノ-4-エチルベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物90);
6-エチルアミノ-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物91);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-エチルアミノ-9-メチル-9H-プリン(化合物92);
9-(2-シクロプロピルメチル)-2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物93);
2-(3-シアノ-4-メトキシベンジルスルファニル)-8,9-ジエチル-6-モルホリノ-9H-プリン(化合物94);
2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9-オキシラニルメチル-9H-プリン(化合物95);
9-アリル-2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物96);
2-(3-アミノ-4-メトキシベンジルスルファニル)-8,9-ジエチル-6-モルホリノ-9H-プリン(化合物97);
2-(4-メトキシベンジルスルファニル)-6-モルホリノ-9-プロパルギル-9H-プリン(化合物98);
2-(4-エトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物99);
2-ベンズヒドリルスルファニル-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物100);
6-シクロプロピルアミノ-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物101);
9-エチル-2-(4-メトキシベンジルスルファニル)-8-メチル-6-モルホリノ-9H-プリン(化合物102);
2-(3-アミノ-4-エトキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物103);
2-(4-メトキシベンジルスルファニル)-9-エチル-6-モルホリノ-8-プロピル-9H-プリン(化合物104);
6-(N-メトキシ-N-メチルアミノ)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物105);
2-(3-アミノ-4-エトキシベンジルスルファニル)-8,9-ジエチル-6-モルホリノ-9H-プリン(化合物106);
2-(3-アミノ-4-エトキシベンジルスルファニル)-9-メチル-6-メチルアミノ-9H-プリン(化合物107);
2-(4-メトキシベンジルスルファニル)-6-[(2-メトキシエチル)-メチル-アミノ]-9-メチル-9H-プリン(化合物108);
9-メチル-2-(4-メトキシベンジルスルファニル)-6-(1-ピロリル)-9H-プリン(化合物109);
6-(イミダゾール-1-イル)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物110);
6-(2-エトキシモルホリノ)-8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物111);
3-[2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン-6-イル]-1-メチル-イミダゾリニウム ヨーダイド(化合物112);
2-(3-アミノ-4-プロポキシベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物113);
2-(3-アミノ-4-エトキシベンジルスルファニル)-9-メチル-6-モルホリノ-9H-プリン(化合物114);
8,9-ジエチル-2-(3-ヨード-4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物115);
2-(4-エトキシ-3-フルオロベンジルスルファニル)-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物116);
8,9-ジエチル-2-(4-エトキシ-3-フルオロベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物117);
6-(2-エトキシモルホリノ)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(化合物118);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(2-エトキシモルホリノ)-9-エチル-9H-プリン(化合物119);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(2-エトキシモルホリノ)-9-メチル-9H-プリン(化合物120);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(ピラゾール-1-イル)-9H-プリン(化合物121);
2-(3-アミノ-4-エトキシベンジルスルファニル)-9-エチル-8-メチル-6-モルホリノ-9H-プリン(化合物122);
8,9-ジエチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-6-モルホリノ-9H-プリン(化合物123);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(1,2,4-トリアゾール-1-イル)-9H-プリン(化合物124);
2-(3-アミノ-4-メトキシベンジルスルファニル)-9-エチル-6-メチルアミノ-9H-プリン(化合物125);
6-アリルアミノ-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物126);
6-(N,N-ジアリルアミノ)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物127);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(3-メチルピロール-1-イル)-9H-プリン(化合物128);
6-(2-メトキシモルホリノ)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(化合物129);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(3-ピロリン-1-イル)-9H-プリン(化合物130);
6-(2-ヒドロキシモルホリノ)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(化合物131);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-モルホリノ-8-(1-プロペニル)-9H-プリン(化合物132);
6-(2-エトキシモルホリノ)-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物133);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-(2-エトキシモルホリノ)-9-メチル-9H-プリン(化合物134);
6-(2-エトキシモルホリノ)-9-エチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9H-プリン(化合物135);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-ジメチルアミノ-9-エチル-9H-プリン(化合物136);
2-(3-フルオロ-4-メトキシベンジルスルファニル)-6-(N-メトキシ-N-メチルアミノ)-9-メチル-9H-プリン(化合物137);
6-(2-エトキシモルホリノ)-2-(4-エトキシ-3-ニトロベンジルスルファニル)-9-エチル-9H-プリン(化合物138);
2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-6-(1-ピロリル)-9H-プリン(化合物139);
2-(3-アミノ-4-エトキシベンジルスルファニル)-6-ジメチルアミノ-9-メチル-9H-プリン(化合物140);
2-(3-アミノ-4-メトキシベンジルスルファニル)-9-メチル-6-(1-ピロリル)-9H-プリン(化合物141);
2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-6-(3-ピロリン-1-イル)-9H-プリン(化合物142);
6-(N-メトキシ-N-メチルアミノ)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(化合物143);
2-(3-アミノ-4-メトキシベンジルスルファニル)-9-メチル-6-(3-ピロリン-1-イル)-9H-プリン(化合物144);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(N-メトキシ-N-メチルアミノ)-9-メチル-9H-プリン(化合物145);
2-[2-(6-メトキシナフタレン-2-イル)-2-オキソエチルスルファニル]-8-エチル-9-メチル-6-モルホリノ-9H-プリン(化合物146);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物147);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-8-エチル-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物148);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(化合物149);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-メチル-9H-プリン(化合物150);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-エチル-9H-プリン(化合物151);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物152);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-メチル-9H-プリン(化合物153);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-エチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9H-プリン(化合物154);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-エチル-2-(3-ニトロ-4-エトキシベンジルスルファニル)-9H-プリン(化合物155);
2-(3-アミノ-4-エトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-エチル-9H-プリン(化合物156);
6-(2,3-ジヒドロ[1,4]オキサジン-4-イル)-8-エチル-2-(3-フルオロ-4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物157);
8,9-ジエチル-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-2-(4-メトキシベンジルスルファニル)-9H-プリン(化合物158);
6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-2-(4-エトキシ-3-ニトロベンジルスルファニル)-9-メチル-9H-プリン(化合物159);
2-(3-アミノ-4-エトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-9-メチル-9H-プリン(化合物160);
2-(3-シアノ-4-メトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-8-エチル-9-メチル-9H-プリン(化合物161);
2-(3-アミノ-4-メトキシベンジルスルファニル)-6-(2,3-ジヒドロ-[1,4]オキサジン-4-イル)-8-エチル-9-メチル-9H-プリン(化合物162);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(1-trans-プロペニル)-9H-プリン(化合物163);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-プロピル-9H-プリン(化合物164);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-ビニル-9H-プリン(化合物165);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(4-ニトロフェニル)-9H-プリン(化合物166);
6-(2-フリル)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物167);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(3-チエニル)-9H-プリン(化合物168);
6-(3,5-ジメチルイソオキサゾール-4-イル)-2-(4-メトキシベンジルスルファニル)-9-メチル-9H-プリン(化合物169);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(ピラゾール-4-イル)-9H-プリン(化合物170);
2-(4-メトキシ-3-ニトロベンジルスルファニル)-9-メチル-6-(1-trans-プロペニル)-9H-プリン(化合物171);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(1-メチルピラゾール-4-イル)-9H-プリン(化合物172);または、
2-(3-アミノ-4-メトキシベンジルスルファニル)-9-メチル-6-(1-trans-プロペニル)-9H-プリン(化合物173);
2-(4-メトキシベンジルスルファニル)-9-メチル-6-(2-チエニル)-9H-プリン(化合物174);
である、請求項1に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグ。 - 請求項1ないし13の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグと、製薬学的に許容される補助剤、希釈剤もしくは担体とを含む組成物。
- 請求項1ないし13の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグを含む、腫瘍の治療のための医薬組成物。
- 請求項1ないし13の何れか一項に記載の化合物、あるいはその製薬学的に許容される塩、溶媒和物、水和物もしくはプロドラッグを含む抗腫瘍剤。
- 腫瘍が、肺癌、前立腺癌、乳癌、結腸癌、胃癌、膵臓癌、肝臓癌、食道癌、脳腫瘍、卵巣癌、子宮癌、悪性黒色腫、腎臓癌、頭頸部癌、皮膚癌、膀胱癌、骨肉腫、胆道癌、外陰癌、精巣腫瘍、陰茎癌、直腸癌、縦隔腫瘍、尿路上皮癌、絨毛癌、軟部肉腫、甲状腺癌、副甲状腺癌、副腎癌、悪性褐色細胞腫、胚細胞腫瘍、悪性リンパ腫、白血病、多発性骨髄腫である請求項16に記載の抗腫瘍剤。
Priority Applications (8)
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KR1020117028143A KR101725567B1 (ko) | 2009-04-28 | 2010-04-28 | 푸린 유도체 및 이를 사용하는 항종양제 |
US13/266,681 US9132130B2 (en) | 2009-04-28 | 2010-04-28 | Purine derivative and antitumor agent using same |
CN201080029347.9A CN102459269B (zh) | 2009-04-28 | 2010-04-28 | 嘌呤衍生物以及使用所述嘌呤衍生物的抗肿瘤剂 |
ES10769799.7T ES2538839T3 (es) | 2009-04-28 | 2010-04-28 | Derivado de purina y agente antitumoral que lo utiliza |
CA2760052A CA2760052C (en) | 2009-04-28 | 2010-04-28 | Purine derivative and antitumor agent using same |
JP2011511448A JP5685184B2 (ja) | 2009-04-28 | 2010-04-28 | プリン誘導体およびそれを用いた抗腫瘍剤 |
AU2010242394A AU2010242394B2 (en) | 2009-04-28 | 2010-04-28 | Purine derivative and antitumor agent using same |
EP20100769799 EP2426130B8 (en) | 2009-04-28 | 2010-04-28 | Purine derivative and antitumor agent using same |
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JP2009108781 | 2009-04-28 | ||
JP2009-108781 | 2009-04-28 |
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US (1) | US9132130B2 (ja) |
EP (1) | EP2426130B8 (ja) |
JP (1) | JP5685184B2 (ja) |
KR (1) | KR101725567B1 (ja) |
CN (1) | CN102459269B (ja) |
AU (1) | AU2010242394B2 (ja) |
CA (1) | CA2760052C (ja) |
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JPS5271492A (en) * | 1975-12-10 | 1977-06-14 | Kohjin Co Ltd | Synthesis of 9-substituted-2-substituted thioadenines |
WO1999028321A1 (fr) | 1997-11-28 | 1999-06-10 | Sumitomo Pharmaceuticals Company, Limited | Nouveaux composes heterocycliques |
JPH11180981A (ja) * | 1997-12-19 | 1999-07-06 | Sumitomo Pharmaceut Co Ltd | 複素環誘導体 |
WO2003051882A1 (en) * | 2001-12-18 | 2003-06-26 | Cv Therapeutics, Inc. | A2a adenosine receptor antagonists |
WO2007034185A1 (en) * | 2005-09-20 | 2007-03-29 | Vernalis (R & D) Ltd. | Purine compounds as hsp90 protein inhibitors for the treatment of cancer |
JP2008516938A (ja) * | 2004-10-15 | 2008-05-22 | アストラゼネカ アクチボラグ | 置換アデニンとその使用 |
CN101602765A (zh) * | 2009-05-13 | 2009-12-16 | 北京化工大学 | 6-烷氨基-2-烷硫基-9-含酯烷基嘌呤衍生物及其合成方法 |
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JPS5549592B2 (ja) * | 1972-06-16 | 1980-12-12 | ||
ES2222614T3 (es) * | 1997-11-12 | 2005-02-01 | Mitsubishi Chemical Corporation | Derivados de purina y medicina que los contiene como ingrediente activo. |
IL150061A0 (en) * | 1999-12-17 | 2002-12-01 | Ariad Pharma Inc | Purine derivatives |
US20010051612A1 (en) * | 2000-02-23 | 2001-12-13 | Gloria Cristalli | 2-Thioether A2A receptor agonists |
JP4768263B2 (ja) * | 2002-09-27 | 2011-09-07 | 大日本住友製薬株式会社 | 新規アデニン化合物及びその用途 |
CN101072787A (zh) * | 2004-10-15 | 2007-11-14 | 阿斯利康(瑞典)有限公司 | 取代的腺嘌呤及其用途 |
-
2010
- 2010-04-28 US US13/266,681 patent/US9132130B2/en not_active Expired - Fee Related
- 2010-04-28 WO PCT/JP2010/057614 patent/WO2010126101A1/ja active Application Filing
- 2010-04-28 EP EP20100769799 patent/EP2426130B8/en not_active Not-in-force
- 2010-04-28 TW TW099113462A patent/TWI394757B/zh not_active IP Right Cessation
- 2010-04-28 AU AU2010242394A patent/AU2010242394B2/en not_active Ceased
- 2010-04-28 ES ES10769799.7T patent/ES2538839T3/es active Active
- 2010-04-28 CN CN201080029347.9A patent/CN102459269B/zh not_active Expired - Fee Related
- 2010-04-28 CA CA2760052A patent/CA2760052C/en not_active Expired - Fee Related
- 2010-04-28 JP JP2011511448A patent/JP5685184B2/ja active Active
- 2010-04-28 KR KR1020117028143A patent/KR101725567B1/ko active IP Right Grant
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Also Published As
Publication number | Publication date |
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EP2426130B8 (en) | 2015-05-06 |
AU2010242394A1 (en) | 2011-12-22 |
KR20120003958A (ko) | 2012-01-11 |
JPWO2010126101A1 (ja) | 2012-11-01 |
US20120088765A1 (en) | 2012-04-12 |
CA2760052A1 (en) | 2010-11-04 |
CN102459269A (zh) | 2012-05-16 |
US9132130B2 (en) | 2015-09-15 |
EP2426130A4 (en) | 2012-10-03 |
JP5685184B2 (ja) | 2015-03-18 |
AU2010242394B2 (en) | 2014-05-15 |
CA2760052C (en) | 2017-06-13 |
TWI394757B (zh) | 2013-05-01 |
KR101725567B1 (ko) | 2017-04-10 |
CN102459269B (zh) | 2014-10-15 |
EP2426130A1 (en) | 2012-03-07 |
EP2426130B1 (en) | 2015-03-11 |
TW201043630A (en) | 2010-12-16 |
ES2538839T3 (es) | 2015-06-24 |
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