KR20230141062A - Polyheterocyclic derivatives containing pyrimidine and use thereof - Google Patents
Polyheterocyclic derivatives containing pyrimidine and use thereof Download PDFInfo
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- KR20230141062A KR20230141062A KR1020220040133A KR20220040133A KR20230141062A KR 20230141062 A KR20230141062 A KR 20230141062A KR 1020220040133 A KR1020220040133 A KR 1020220040133A KR 20220040133 A KR20220040133 A KR 20220040133A KR 20230141062 A KR20230141062 A KR 20230141062A
- Authority
- KR
- South Korea
- Prior art keywords
- cancer
- alkyl
- halo
- benzyl
- methoxybenzyl
- Prior art date
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- -1 hydroxy, amino, carboxy Chemical group 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 201000005787 hematologic cancer Diseases 0.000 claims description 3
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010005949 Bone cancer Diseases 0.000 claims description 2
- 208000018084 Bone neoplasm Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000000821 Parathyroid Neoplasms Diseases 0.000 claims description 2
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- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 2
- 201000009036 biliary tract cancer Diseases 0.000 claims description 2
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
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- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 2
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
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- 208000014018 liver neoplasm Diseases 0.000 claims description 2
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- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000029559 malignant endocrine neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 claims description 2
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- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000002314 small intestine cancer Diseases 0.000 claims description 2
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
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- 150000003230 pyrimidines Chemical class 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010568 chiral column chromatography Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- OFRQIORIBGXHBF-UHFFFAOYSA-N cladospolide D Natural products CC1CCCCCC(O)C(=O)C=CC(=O)O1 OFRQIORIBGXHBF-UHFFFAOYSA-N 0.000 description 1
- OFRQIORIBGXHBF-BQYQJAHWSA-N cladospolide d Chemical compound CC1CCCCCC(O)C(=O)\C=C\C(=O)O1 OFRQIORIBGXHBF-BQYQJAHWSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
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- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
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- ZRJBXPCQRSLIKK-BDPAYSQHSA-N fluvirucin A1 Chemical compound C1C[C@H](C)CCC[C@H](CC)CCCNC(=O)[C@H](C)[C@H]1O[C@H]1[C@H](O)[C@H](N)[C@H](O)[C@H](C)O1 ZRJBXPCQRSLIKK-BDPAYSQHSA-N 0.000 description 1
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- 230000002068 genetic effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- PXJMQYXPSSIUGS-UHFFFAOYSA-N phomoidride C Natural products C1C2(CC(O)=O)C(=O)OC3(O)C2=CC(CCCCCC=CC)C(CC(O)C(=O)CCC=CC)C3C2=C1C(=O)OC2=O PXJMQYXPSSIUGS-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TYSZETYVESRFNT-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C TYSZETYVESRFNT-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/16—Peri-condensed systems
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
본 발명은 암질환을 치료하는 의약품의 제조에 유용한 신규한 폴리헤테로사이클 유도체에 관한 것으로서, 보다 상세하게는 우수한 종양 성장 억제 효과를 갖는 피리미딘을 포함하는 폴리헤테로사이클 유도체, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체, 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물에 관한 것이다.The present invention relates to novel polyheterocycle derivatives useful for the production of drugs for treating cancer diseases, and more specifically, polyheterocycle derivatives containing pyrimidines with excellent tumor growth inhibition effects, or pharmaceutically acceptable derivatives thereof. It relates to possible salts or isomers and pharmaceutical compositions for preventing or treating cancer containing them as active ingredients.
Description
본 발명은 암질환을 치료하는 의약품의 제조에 유용한 신규한 폴리헤테로사이클 유도체에 관한 것으로서, 보다 상세하게는 우수한 종양 성장 억제 효과를 갖는 피리미딘을 포함하는 폴리헤테로사이클 유도체, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체, 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약제학적 조성물에 관한 것이다.The present invention relates to novel polyheterocycle derivatives useful for the production of drugs for treating cancer diseases, and more specifically, polyheterocycle derivatives containing pyrimidines with excellent tumor growth inhibition effects, or pharmaceutically acceptable derivatives thereof. It relates to possible salts or isomers and pharmaceutical compositions for preventing or treating cancer containing them as active ingredients.
피리미딘은 우리 몸의 유전 정보를 보존하고 발현하는 DNA와 RNA의 중심 골격일뿐만 아니라 항암, 항바이러스, 항말라리아 등 다양한 생리 활성을 띠는 천연 물질 및 약물 물질들에서 빈번하게 발견되는 중요한 약물작용발생단(pharmacophore) 중 하나이다.Pyrimidine is not only the central framework of DNA and RNA that preserves and expresses our body's genetic information, but is also an important drug agent frequently found in natural substances and drug substances with various biological activities such as anticancer, antiviral, and antimalarial. It is one of the pharmacophores.
기존에 알려진 피리미딘 유도체들은 주로 flat한 형태의 monocycle 또는 bicycle에 한정되어 있었고, 실제로 알프라졸람(alprazolam, 정신안정제), 로라타딘 (loratadine, 항히스타민제), 레보플록사신(levofloxacin, 항생제) 등은 공통적으로 폴리헤테로사이클 구조를 가지며, apicularen A(항암제), brazilone(항응혈제), pterocayanin C(항바이러스제) 등은 공통적으로 중고리 구조를 가지는 약물 물질들이다. 또한, 좀 더 복잡한 구조인 다리걸친 고리(bridged cycle), 거대 고리 (macrocycle) 관련하여 실제로 아즈말린(항부정맥제), 롱기폴렌(항균제), phomoidride A(항암제) 등은 공통적으로 다리걸친 구조를 가지며, fluvirucin A1 (항바이러스제), pladienolide B (항암제), cladospolide D (항생제) 등은 공통적으로 거대고리 구조를 가지는 약물 물질들이다. 이로 미루어 볼 때 폴리헤테로사이클, 중고리 다리걸친 고리, 거대 고리 물질의 약효성은 이미 검증된 바 있으며, 본 발명에서 제안하는 구조들 역시 폴리헤테로사이클, 중고리, 다리걸친 고리, 거대 고리를 포함하는 물질들이므로 새로운 치료제의 개발 후보군으로서 활용될 수 있을 것으로 기대할 수 있다.Previously known pyrimidine derivatives were mainly limited to flat monocycles or bicycles, and in fact, alprazolam (a tranquilizer), loratadine (an antihistamine), and levofloxacin (an antibiotic) were commonly used. It has a polyheterocycle structure, and apicularen A (anticancer drug), brazilone (anticoagulant), and pterocyanin C (antiviral drug) are drugs that commonly have a mesocyclic structure. In addition, in relation to the more complex structures such as bridged cycle and macrocycle, ajmaline (antiarrhythmic drug), longipolene (antibacterial drug), phomoidride A (anticancer drug), etc. actually have a bridged structure in common. , fluvirucin A1 (antiviral drug), pladienolide B (anticancer drug), and cladospolide D (antibiotic) are drugs that have a common macrocyclic structure. In view of this, the medicinal efficacy of polyheterocycles, mesocyclic bridges, and macrocyclic substances has already been verified, and the structures proposed in the present invention also include polyheterocycles, mesocycles, bridged rings, and macrocycles. Since these are substances, it can be expected that they can be used as candidates for the development of new treatments.
본 발명은 우수한 종양 성장 억제 효과를 갖는 피리미딘을 포함하는 폴리헤테로사이클 유도체, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체를 제공하는 것을 기술적 과제로 한다.The technical object of the present invention is to provide a polyheterocycle derivative containing pyrimidine, or a pharmaceutically acceptable salt or isomer thereof, which has an excellent tumor growth inhibitory effect.
또한, 본 발명은 상기 피리미딘을 포함하는 폴리헤테로사이클 유도체, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체를 활성성분으로, 약제학적으로 허용되는 담체와 함께 포함하는 약제학적 조성물을 제공하는 것을 다른 기술적 과제로 한다.In addition, the present invention provides a pharmaceutical composition comprising a polyheterocycle derivative containing the pyrimidine, or a pharmaceutically acceptable salt or isomer thereof as an active ingredient, together with a pharmaceutically acceptable carrier. Make it an assignment.
본 발명의 일 측면에 따르면, 하기 화학식 1의 화합물, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체가 제공된다:According to one aspect of the present invention, there is provided a compound of formula 1 below, or a pharmaceutically acceptable salt or isomer thereof:
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
R1은 수소, 알킬, 할로알킬, 알킬카르보닐, 할로알킬카르보닐, 아릴, 아르알킬, 헤테로사이클릴, 헤테로사이클릴-알킬을 나타내고;R 1 represents hydrogen, alkyl, haloalkyl, alkylcarbonyl, haloalkylcarbonyl, aryl, aralkyl, heterocyclyl, heterocyclyl-alkyl;
R2는 수소, 하이드록시, 아미노, 카르복시(-COOH), 알킬, 알킬아미노, 할로알킬, 알콕시, 할로알콕시, 알킬티오(alkylthio), 할로알킬티오, 설포닉(-SO3H), 알킬에스터 또는 알킬아마이드를 나타내며;R 2 is hydrogen, hydroxy, amino, carboxy (-COOH), alkyl, alkylamino, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, sulfonic (-SO 3 H), alkyl ester or represents an alkylamide;
R3는 수소, 알킬, 알킬카르보닐, 아릴카르보닐, 알킬아미노카르보닐 또는 아릴아미노카르보닐을 나타내고;R 3 represents hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl or arylaminocarbonyl;
R4는 존재하지 않거나, 또는 수소, 알킬, 시아노(-CN) 또는 시아노알킬을 나타내며;R 4 is absent or represents hydrogen, alkyl, cyano(-CN) or cyanoalkyl;
R5는 하이드록시, 할로, 알킬, 할로알킬, 알콕시, 할로알콕시, 아르알킬, 아르알콕시 또는 아르알킬옥시카르보닐을 나타내고;R 5 represents hydroxy, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aralkyl, aralkoxy or aralkyloxycarbonyl;
m은 1 또는 2이며;m is 1 or 2;
n은 0, 1 또는 2이고;n is 0, 1 or 2;
o는 1 또는 2이며;o is 1 or 2;
여기에서 상기 아릴 및 헤테로사이클은 하이드록시, 할로, 알킬, 알콕시, 할로알킬, 알콕시카르보닐 및 아릴로부터 선택되는 하나 이상의 치환기로 치환될 수 있으며;wherein the aryl and heterocycle may be substituted with one or more substituents selected from hydroxy, halo, alkyl, alkoxy, haloalkyl, alkoxycarbonyl and aryl;
상기 헤테로사이클은 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 포함한다.The heterocycle contains one or more heteroatoms selected from N, O and S.
이하에서 본 발명에 대하여 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에서의 하기 용어들은 달리 지시되지 않으면 하기에 기재된 의미를 가진다. 정의되지 않은 임의의 용어는 당해 분야에서 이해되는 의미를 가진다.The following terms in the present invention have the meanings set forth below unless otherwise indicated. Any undefined terms have meanings understood in the art.
본 발명에서 용어 “할로” 또는 “할로겐”은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 할로알킬 또는 할로알콕시) 불소(F), 염소(Cl), 브롬(Br) 또는 요오드(I)를 의미한다.In the present invention, the term “halo” or “halogen” when used alone or in combination with additional terms (e.g., haloalkyl or haloalkoxy), fluorine (F), chlorine (Cl), It means bromine (Br) or iodine (I).
본 발명에서 용어 “하이드록시”기는 -OH를 의미한다.In the present invention, the term “hydroxy” group means -OH.
본 발명에서 용어 “아미노”기는, 단독으로 또는 조합되어, 질소 원자를 통하여 결합된 일차, 이차 또는 삼차 아미노기를 의미하는 것일 수 있다.In the present invention, the term “amino” group, alone or in combination, may refer to a primary, secondary or tertiary amino group bonded through a nitrogen atom.
본 발명에서 용어 “카르복시”기는 -COOH를 의미한다.In the present invention, the term “carboxy” group refers to -COOH.
본 발명에서 용어 “카르보닐(carbonyl)”기는 -C(=O)-를 의미한다.In the present invention, the term “carbonyl” refers to -C(=O)-.
본 발명에서 용어 “설포닉(sulfonic)”기는 -SO3H를 의미한다.In the present invention, the term “sulfonic” group refers to -SO 3 H.
본 발명에서 용어 “시아노(cyano)”기는 -CN을 의미한다.In the present invention, the term “cyano” group refers to -CN.
본 발명에서 용어 “에스터(ester)”는 R-C(=O)-OR'를 의미한다.In the present invention, the term “ester” means R-C(=O)-OR'.
본 발명에서 용어 “아마이드(amide)”는 R-C(=O)N-R'R”을 의미한다.In the present invention, the term “amide” means R-C(=O)N-R'R”.
본 발명에서 용어 “알킬”은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우(예를 들면, 할로알킬) 직쇄형 또는 측쇄형의, 예를 들면 1개 내지 7개의 탄소 원자 또는 1개 내지 5개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다. 전형적인 알킬 그룹의 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 세크-부틸, 터트-부틸, n-펜틸, 이소펜틸, 네오펜틸, 터트-펜틸, 1-메틸부틸, 2-메틸부틸, 1-에틸프로필 및 1,2-디메틸프로필 등을 포함하나 이에 제한되는 것은 아니다.In the present invention, the term “alkyl” when used alone or in combination with additional terms (e.g., haloalkyl) refers to a straight or branched chain, for example, 1 to 7 carbon atoms. or a radical of a group of saturated aliphatic hydrocarbons having 1 to 5 carbon atoms. Typical examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and 1-methylbutyl. , 2-methylbutyl, 1-ethylpropyl and 1,2-dimethylpropyl, etc., but are not limited thereto.
본 발명에서 용어 “알콕시”는 알킬옥시(-O-알킬기), 예를 들면 1개 내지 7개의 탄소 원자 또는 1개 내지 5개의 탄소 원자를 갖는 알킬옥시를 의미한다.In the present invention, the term “alkoxy” means alkyloxy (-O-alkyl group), for example, alkyloxy having 1 to 7 carbon atoms or 1 to 5 carbon atoms.
본 발명에서 용어 “알킬티오”는 -S-알킬기를 의미한다.In the present invention, the term “alkylthio” refers to an -S-alkyl group.
본 발명에서 용어 “아릴”은 예를 들면 6개 내지 10개의 탄소원자를 갖는 방향족 탄화수소를 의미하며, 구체적인 예로는 페닐, 나프틸을 포함하나 이에 제한되는 것은 아니다.In the present invention, the term “aryl” refers to an aromatic hydrocarbon having, for example, 6 to 10 carbon atoms, and specific examples include, but are not limited to, phenyl and naphthyl.
본 발명에서 용어 “헤테로사이클”은 N, O 및 S 중에서 선택된 하나 이상의 헤테로 원자를 환원자로서 포함하는 고리형의, 예를 들면 3 내지 10원 또는 4 내지 8원의 포화 또는 불포화된 지방족 탄화수소를 의미한다.In the present invention, the term “heterocycle” refers to a cyclic, for example, 3- to 10-membered or 4- to 8-membered saturated or unsaturated aliphatic hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing agent. it means.
본 발명의 일 구체예에 따르면, 상기 화학식 1에서According to one embodiment of the present invention, in Formula 1
R1은 수소, C1-C7 알킬, 할로-C1-C7 알킬, C1-C7 알킬카르보닐, 할로-C1-C7 알킬카르보닐, C6-C10 아릴, C6-C10 아릴-C1-C7 알킬, 3 내지 10원 헤테로사이클릴, 3 내지 10원 헤테로사이클릴-C1-C7 알킬을 나타내고;R 1 is hydrogen, C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, halo-C 1 -C 7 alkylcarbonyl, C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, 3 to 10 membered heterocyclyl, 3 to 10 membered heterocyclyl-C 1 -C 7 alkyl;
R2는 수소, 하이드록시, 아미노, 카르복시, C1-C7 알킬, C1-C7 알킬아미노, 할로-C1-C7 알킬, C1-C7 알콕시, 할로-C1-C7 알콕시, C1-C7 알킬티오, 할로-C1-C7 알킬티오, 설포닉, C1-C7 알킬에스터 또는 C1-C7 알킬아마이드를 나타내며;R 2 is hydrogen, hydroxy, amino, carboxy, C 1 -C 7 alkyl, C 1 -C 7 alkylamino, halo-C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 represents alkoxy, C 1 -C 7 alkylthio, halo-C 1 -C 7 alkylthio, sulfonic, C 1 -C 7 alkyl ester or C 1 -C 7 alkylamide;
R3는 수소, C1-C7 알킬, C1-C7 알킬카르보닐, C6-C10 아릴카르보닐, C1-C7 알킬아미노카르보닐 또는 C6-C10 아릴아미노카르보닐을 나타내고;R 3 is hydrogen, C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, C 6 -C 10 arylcarbonyl, C 1 -C 7 alkylaminocarbonyl, or C 6 -C 10 arylaminocarbonyl. represents;
R4는 존재하지 않거나, 또는 수소, C1-C7 알킬, 시아노 또는 시아노-C1-C7 알킬을 나타내며;R 4 is absent or represents hydrogen, C 1 -C 7 alkyl, cyano or cyano-C 1 -C 7 alkyl;
R5는 하이드록시, 할로, C1-C7 알킬, 할로-C1-C7 알킬, C1-C7 알콕시, 할로-C1-C7 알콕시, C6-C10 아릴-C1-C7 알킬, C6-C10 아릴-C1-C7 알콕시 또는 C6-C10 아릴-C1-C7 알킬옥시카르보닐을 나타내고;R 5 is hydroxy, halo, C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkoxy, C 6 -C 10 aryl-C 1 - represents C 7 alkyl, C 6 -C 10 aryl-C 1 -C 7 alkoxy or C 6 -C 10 aryl-C 1 -C 7 alkyloxycarbonyl;
m은 1 또는 2이며;m is 1 or 2;
n은 0, 1 또는 2이고;n is 0, 1 or 2;
o는 1 또는 2이며;o is 1 or 2;
여기에서 상기 아릴 및 헤테로사이클은 하이드록시, 할로, C1-C7 알킬, C1-C7알콕시, 할로-C1-C7 알킬, C1-C7 알콕시카르보닐 및 C6-C10 아릴로부터 선택되는 1개 내지 5개의 치환기로 치환될 수 있으며;wherein the aryl and heterocycle are hydroxy, halo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkyl, C 1 -C 7 alkoxycarbonyl and C 6 -C 10 may be substituted with 1 to 5 substituents selected from aryl;
상기 헤테로사이클은 N, O 및 S로부터 선택되는 1개 내지 5개의 헤테로원자를 포함한다.The heterocycle contains 1 to 5 heteroatoms selected from N, O and S.
본 발명의 일 구체예에 따르면, 상기 화학식 1의 화합물이 하기 화학식 2의 화합물일 수 있다:According to one embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 2 below:
[화학식 2][Formula 2]
상기 화학식 2에서, R1, R2, R3, R5, m, n 및 o는 화학식 1에서 정의된 것과 같다.In Formula 2, R 1 , R 2 , R 3 , R 5 , m, n and o are as defined in Formula 1.
본 발명의 일 구체예에 따르면, 상기 화학식 1의 화합물이 하기 화학식 3의 화합물일 수 있다:According to one embodiment of the present invention, the compound of Formula 1 may be a compound of Formula 3 below:
[화학식 3][Formula 3]
상기 화학식 3에서, R1, R2, R3, R4, R5, m 및 n은 화학식 1에서 정의된 것과 같다.In Formula 3, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined in Formula 1.
상기 화학식 2의 다리걸친 고리 화합물의 경우 피리미딘과 중고리가 접합된 이중 고리 물질을 시작 물질로 하여 고리화 반응을 통해 만들어질 수 있다. 상기 화학식 3의 거대고리 화합물의 경우 화학식 2의 다리걸친 고리 화합물을 시작 물질로 하여 금 촉매가 매개하는 선택적인 C-C 결합의 절단 및 새로운 친핵체의 도입을 통해 형성될 수 있며, 도입된 친핵체는 추가적인 기능화가 가능하다는 유용성을 가질 수 있다.In the case of the bridged ring compound of Formula 2, it can be produced through a cyclization reaction using a double ring material in which a pyrimidine and a middle ring are bonded as a starting material. In the case of the macrocyclic compound of Formula 3, it can be formed through selective cleavage of the C-C bond mediated by a gold catalyst and introduction of a new nucleophile using the bridged ring compound of Formula 2 as a starting material, and the introduced nucleophile can be further functionalized. It can be useful because it is possible.
본 발명에 따른 화학식 1의 화합물의 대표적인 예로는 하기 화합물들이 포함될 수 있으나 이에 제한되는 것은 아니다:Representative examples of compounds of Formula 1 according to the present invention may include, but are not limited to, the following compounds:
1) 12-벤질-15-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노에타노)피리미도[4,5-b][1,5]다이아제신;1) 12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4,5- b][1,5]diazesin;
2) 12-벤질-16-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노프로파노)피리미도[4,5-b][1,5]다이아제신;2) 12-benzyl-16-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminopropano)pyrimido[4,5- b][1,5]diazesin;
3) 2-(10-벤질-2-(4-메톡시벤질)-2,5,10-트리아자-1(4,6)-피리미디나사이클로데카판-5-일)아세토나이트릴;3) 2-(10-benzyl-2-(4-methoxybenzyl)-2,5,10-triaza-1(4,6)-pyrimidinacyclodecapan-5-yl)acetonitrile;
4) 2-(11-벤질-2-(4-메톡시벤질)-2,6,11-트리아자-1(4,6)-피리미디나사이클로운데카판-6-일)아세토나이트릴;4) 2-(11-benzyl-2-(4-methoxybenzyl)-2,6,11-triaza-1(4,6)-pyrimidinacycloundecapan-6-yl)acetonitrile ;
5) 2-(12-벤질-2-(4-메톡시벤질)-2,6,12-트리아자-1(4,6)-피리미디나사이클로도데카판-6-일)아세토나이트릴;5) 2-(12-benzyl-2-(4-methoxybenzyl)-2,6,12-triaza-1(4,6)-pyrimidinacyclododecapan-6-yl)acetonitrile ;
6) 2-(11-벤질-2-(4-메톡시벤질)-2,5,11-트리아자-1(4,6)-피리미디나사이클로운데카판-5-일)아세토나이트릴; 및6) 2-(11-benzyl-2-(4-methoxybenzyl)-2,5,11-triaza-1(4,6)-pyrimidinacycloundecapan-5-yl)acetonitrile ; and
7) 28-벤질-29-[(4-메톡시페닐)메틸]-25,26,27,28,29-펜타자트리사이클로펜타데카-10(25),22,24(26)-트리엔.7) 28-benzyl-29-[(4-methoxyphenyl)methyl]-25,26,27,28,29-pentazatricyclopentadeca-10(25),22,24(26)-triene .
상기 기술한 화합물들의 명명은 캠브리지 소프트(CambridgeSoft) 의 CS ChemDraw Ultra (version: 19.0.1.28) 소프트웨어에서 제공하는 명명법에 준하여 기재하였다.The names of the compounds described above were written according to the nomenclature provided by CambridgeSoft's CS ChemDraw Ultra (version: 19.0.1.28) software.
본 발명에 따른 화학식 1의 화합물은 비대칭 탄소중심과 비대칭축 또는 비대칭평면을 가질수 있으므로 E 또는 Z 이성질체, R 또는 S 이성질체, 라세미체 등의 입체이성질체로 존재할 수 있으며, 이들 모든 이성질체 및 혼합물은 본 발명의 범위에 포함된다. 본 발명에 따른 화학식 1의 화합물이 라세미체일 수 있으며, 이 라세미체는 통상의 분리방법에 의하여, 예컨대 순상 또는 역상의 카이랄 컬럼크로마토그래피 장치를 이용하여 그에 해당하는 전개용매, 바람직하게는 순상에서 헥산, 에틸 아세테이트, 디클로로메탄, 메탄올을 혼합한 용매, 역상에서는 물과 아세토니트릴 등의 혼합액을 이용하는 방법에 의하여 각각의 이성질체로 분리될 수 있다.The compound of Formula 1 according to the present invention may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, so it may exist as stereoisomers such as E or Z isomers, R or S isomers, and racemates, and all of these isomers and mixtures are present in the present invention. included in the scope of the invention. The compound of Formula 1 according to the present invention may be a racemate, and this racemate may be separated by a conventional separation method, for example, using a normal phase or reverse phase chiral column chromatography apparatus, and a corresponding developing solvent, preferably It can be separated into each isomer by using a solvent mixture of hexane, ethyl acetate, dichloromethane, and methanol in the normal phase, and a mixture of water and acetonitrile in the reverse phase.
본 발명에 따른 화학식 1의 화합물은 또한 약제학적으로 허용되는 염을 형성할 수 있다. 이러한 약제학적으로 허용되는 염의 제조에 사용될 수 있는 대표적인 산에는 하기의 것들이 포함되나, 이에 한정되는 것은 아니다. 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들면, 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타르타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산 또는 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산 등과 같은 유기 카본산, 메탄설폰산, 벤젠설폰산, p-톨루엔설폰산 또는 나프탈설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함되며, 아울러 나트륨, 칼륨 등의 알칼리금속과의 염도 포함된다. 그밖에도 방향족 아미딘 유도체 또는 락탐 유도체가 속하는 기술분야에서 공지되어 사용되고 있는 다른 산 또는 염기와의 염을 포함할 수도 있다. 이들은 통상 알려진 공정에 의하여 제조된다.The compounds of formula 1 according to the present invention can also form pharmaceutically acceptable salts. Representative acids that can be used in the preparation of such pharmaceutically acceptable salts include, but are not limited to, the following. Acids that form non-toxic acid addition salts containing anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, It includes acid addition salts formed by organic carboxylic acids such as gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalsulfonic acid, as well as sodium and potassium. Salts with alkali metals such as these are also included. In addition, aromatic amidine derivatives or lactam derivatives may include salts with other acids or bases that are known and used in the technical field to which they belong. These are manufactured by commonly known processes.
상기 화학식 1의 구조를 갖는 본 발명의 화합물들은 하기 실시예에 기술하는 방법에 의거하여 제조할 수 있으나, 이에 한정되는 것은 아니다. Compounds of the present invention having the structure of Formula 1 can be prepared according to the method described in the Examples below, but are not limited thereto.
본 발명의 다른 측면에 따르면, 활성성분으로서 치료학적 유효량의 상기 화학식 1의 화합물, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체를, 약제학적으로 허용되는 담체와 함께 포함하는 약제학적 조성물이 제공된다.According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt or isomer thereof, as an active ingredient, together with a pharmaceutically acceptable carrier.
본 발명에 따른 화학식 1의 화합물은 암질환을 치료할 수 있는 활성을 가진다. 본 발명에 따른 화학식 1의 화합물은 암질환 치료제로, 특히 대장암, 피부암, 흑색종, 교모세포종, 골암, 간암, 위암, 췌장암, 결장암, 직장암, 혈액암, 방광암, 신장암, 담도암, 자궁경부암, 자궁암, 난소암, 유방암, 폐암, 비소세포성폐암, 식도암, 소장암, 내분비선암, 갑상선암 및 부갑상선암으로 이루어진 군에서 선택된 암질환의 치료에 유용하다. The compound of Formula 1 according to the present invention has the activity to treat cancer diseases. The compound of formula 1 according to the present invention is a treatment for cancer diseases, especially colon cancer, skin cancer, melanoma, glioblastoma, bone cancer, liver cancer, stomach cancer, pancreas cancer, colon cancer, rectal cancer, blood cancer, bladder cancer, kidney cancer, biliary tract cancer, and uterus. It is useful in the treatment of cancer diseases selected from the group consisting of cervical cancer, uterine cancer, ovarian cancer, breast cancer, lung cancer, non-small cell lung cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, and parathyroid cancer.
본 발명에 따른 약제학적 조성물은 약제학적으로 허용되는 담체, 수용체, 결합제, 안정화제 및/또는 희석제와 활성성분으로서 치료학적 유효량의 화학식 1의 화합물, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체를 혼합하여 제조될 수 있다. 또한, 본 발명에 따른 약제학적 조성물을 주사액의 형태로 제조할 경우, 약제학적으로 허용되는 완충액, 용해 보조제 및/또는 등장제를 본 발명의 화학식 1의 화합물, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체와 혼합할 수 있다.The pharmaceutical composition according to the present invention is a mixture of a pharmaceutically acceptable carrier, receptor, binder, stabilizer and/or diluent and a therapeutically effective amount of the compound of Formula 1, or a pharmaceutically acceptable salt or isomer thereof, as an active ingredient. It can be manufactured. In addition, when preparing the pharmaceutical composition according to the present invention in the form of an injection solution, a pharmaceutically acceptable buffer, solubilizing agent, and/or isotonic agent may be added to the compound of Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, or Can be mixed with isomers.
본 발명에 따른 약제학적 조성물은 당업자에게 이용가능하게 되거나 공지된 조제 기술 및 적합한 약제학적 부형제를 사용하여, 약제학적 약제의 하나 이상의 투여량 유닛을 포함하는 약제학적 조성물의 전달 형태를 제조할 수 있다. 본 발명의 방법에서 조성물은 적합한 전달 경로, 예를 들어, 경구 또는 비경구 투여, 장관외, 직장, 국소, 또는 흡입에 의해 투여될 수 있다. 상기 약학 제제는 정제, 캡슐, 향낭 (sachet), 당의정, 분말, 과립, 로젠지 (lozenge), 사용시조제 (reconstitution)용 분말, 액상 제재 또는 좌제의 형태일 수 있다. 예를 들어, 조성물은 정맥내 주입, 분무용, 구소투여 또는 경구 투여용으로 제형화된다.The pharmaceutical composition according to the invention can be prepared using suitable pharmaceutical excipients and preparation techniques available or known to those skilled in the art, in delivery forms of the pharmaceutical composition comprising one or more dosage units of the pharmaceutical agent. . The compositions in the methods of the present invention may be administered by any suitable route of delivery, for example, oral or parenteral administration, parenteral, rectal, topical, or inhalation. The pharmaceutical preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations or suppositories. For example, the composition is formulated for intravenous infusion, nebulization, oral administration, or oral administration.
경구용 제제를 제조하는 경우에는 통상의 약제학적 담체를 사용할 수 있다. 예를 들어, 현탁액, 시럽제, 엘릭시르 및 용액제와 같은 경구용 액체 제제의 경우 물, 글리콜, 오일, 알코올 등을 담체로 사용할 수 있고, 산제, 환제, 캅셀제 및 정제와 같은 고체 제제의 경우에는 전분, 설탕, 카올린, 윤활제, 결합제, 붕해제 등을 사용할 수 있다. 투여의 용이성으로 인하여 정제 및 캅셀제가 가장 편리한 복용형태이며, 정제 및 환제는 장피제로 제조하는 것이 바람직하다.When preparing oral preparations, conventional pharmaceutical carriers can be used. For example, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, water, glycol, oil, alcohol, etc. can be used as carriers, and in the case of solid preparations such as powders, pills, capsules and tablets, starch can be used as a carrier. , sugar, kaolin, lubricants, binders, disintegrants, etc. can be used. Due to ease of administration, tablets and capsules are the most convenient dosage forms, and tablets and pills are preferably manufactured as enteric tablets.
비경구 제제의 경우 담체로는 통상 멸균수를 사용하며, 용해보조제와 같은 다른 성분도 포함시킬 수 있다. 주사용 제제, 예를 들면, 멸균 주사용 수성 또는 유성 현탁액은 공지된 기술에 따라 적합한 분산제, 습윤제, 또는 현탁제를 사용하여 제조할 수 있다. 이를 위해 사용될 수 있는 용매에는 물, 링거액 및 등장성 NaCl 용액이 있으며, 멸균 고정오일도 통상적으로 용매 또는 현탁 매질로서 사용한다. 모노-, 디-글리세라이드를 포함하는 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있으며, 또한 올레산과 같은 지방산도 주사용 제제에 사용할 수 있다.In the case of parenteral preparations, sterilized water is usually used as a carrier, and other ingredients such as solubilizing agents may also be included. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be prepared according to known techniques using suitable dispersing, wetting, or suspending agents. Solvents that can be used for this purpose include water, Ringer's solution and isotonic NaCl solution, and sterile fixed oil is also commonly used as a solvent or suspending medium. Any non-irritating fixed oil, including mono- and di-glycerides, can be used for this purpose, and fatty acids such as oleic acid can also be used in injectable preparations.
경피 제제의 경우에는 담체로서 침투촉진제 및/또는 적당한 습윤제를 임의로 피부에 대한 자극성이 없는 적당한 첨가제와 함께 사용할 수 있다. 첨가제로는 피부를 통한 투여를 촉진시키고/시키거나 목적하는 조성물을 제조하는데 도움이 되는 것을 선택한다. 경피 제제는 경피용 패취, 점적제 또는 연고와 같은 다양한 방식으로 투여된다.In the case of transdermal preparations, a penetration enhancer and/or a suitable humectant may be used as a carrier, optionally along with suitable additives that are not irritating to the skin. The excipient is selected to facilitate administration through the skin and/or to help prepare the desired composition. Transdermal formulations are administered in a variety of ways, such as transdermal patches, drops, or ointments.
본 발명에 따른 약제학적 조성물이 투여량 및 투여 시간은 환자의 질환, 상태, 연령, 체중 및 투여 형태에 따라 달라질 수 있으며, 상기 조성물은 성인에 있어서, 매일 0.1~2,000 mg, 바람직하게는 1~200 mg을 1회에 또는 수회로 나누어서 투여할 수 있으나, 이에 제한되는 것은 아니다.The dosage and administration time of the pharmaceutical composition according to the present invention may vary depending on the patient's disease, condition, age, weight, and administration form, and the composition is administered in an amount of 0.1 to 2,000 mg per day for adults, preferably 1 to 2,000 mg per day. 200 mg can be administered at once or in several divided doses, but is not limited thereto.
본 발명에 따른 화학식 1의 화합물, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체는 종양 성장 억제 효과를 갖기에, 단독요법 및 종래의 면역 억제제들과의 병용 요법을 통하여 피부암 및 다양한 고형암, 혈액암 등의 암 질환을 효율적으로 치료할 수 있다.The compound of Formula 1 according to the present invention, or a pharmaceutically acceptable salt or isomer thereof, has a tumor growth inhibitory effect, and is used as monotherapy or in combination with conventional immunosuppressants to treat skin cancer, various solid cancers, blood cancer, etc. Cancer diseases can be treated efficiently.
이하, 본 발명을 하기 실시예 및 실험예에 의하여 더욱 구체적으로 설명한다. 그러나 이들 실시예 및 실험예는 본 발명의 예시일 뿐, 어떤 식으로든 본 발명의 범위가 이들에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, these examples and experimental examples are only illustrative of the present invention, and the scope of the present invention is not limited by them in any way.
이하의 실시예에서 사용된 약어의 정의는 다음의 표 1과 같다.The definitions of abbreviations used in the examples below are shown in Table 1 below.
[표 1][Table 1]
중간체: 12-벤질-6(2-((tert-부틸다이페닐실릴)옥시)에틸)-N-(4-메톡시벤질)- 5,6,7,8,9,10,11,12-옥타하이드로피리미도[4,5-b][1,5]다이아제신-4-아민(12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-5,6,7,8,9,10,11,12-octahydropyrimido[4,5-b][1,5]diazecin-4-amine)의 제조Intermediate: 12-benzyl-6(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-5,6,7,8,9,10,11,12- Octahydropyrimido[4,5-b][1,5]diazecin-4-amine (12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl) -Manufacture of 5,6,7,8,9,10,11,12-octahydropyrimido[4,5-b][1,5]diazecin-4-amine)
단계 1: 다이-tert-부틸 1,2-다이아제판-1,2-다이카르복실레이트(di-tert-butyl 1,2-diazepane-1,2-dicarboxylate)의 제조Step 1: Preparation of di-tert-butyl 1,2-diazepane-1,2-dicarboxylate
다이-tert-부틸 하이드라조다이카르복실레이트(di-tert-butyl hydrazodicarboxylate)(5.0 g, 21.5 mmol)를 톨루엔/50% aq. NaOH=2:1 용액 (0.1 M)에 녹인 후 테트라에틸암모늄 브로마이드(TEAB)(468.5 mg, 3.23 mmol, 0.15 equiv.) 과 1,5-다이브로모펜탄 (4.98 mL, 36.6 mmol, 1.7 equiv.)을 실온에서 적가하였다. 반응 온도를 100℃로 올린 후 교반하였다. TLC 모니터링으로 반응이 종료됨을 확인한 후 H2O와 포화 aq. NaCl 용액 및 에틸아세테이트(ethylacetate)를 이용하여 유기층을 분리하여 Na2SO4로 건조하고, 여과한 다음 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(column chromatography)로 정제하여 표제 화합물 (5.39 g, 17.9 mmol, 83%)을 얻었다.Di-tert-butyl hydrazodicarboxylate (5.0 g, 21.5 mmol) was dissolved in toluene/50% aq. After dissolving in NaOH=2:1 solution (0.1 M), tetraethylammonium bromide (TEAB) (468.5 mg, 3.23 mmol, 0.15 equiv.) and 1,5-dibromopentane (4.98 mL, 36.6 mmol, 1.7 equiv.) was added dropwise at room temperature. The reaction temperature was raised to 100°C and stirred. After confirming that the reaction was complete by TLC monitoring, H 2 O and saturated aq. The organic layer was separated using NaCl solution and ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (5.39 g, 17.9 mmol, 83%).
단계 2: 1,2-다이아제판 2TFA 염(1,2-diazepane 2TFA salt)의 제조Step 2: Preparation of 1,2-diazepane 2TFA salt (1,2-diazepane 2TFA salt)
상기 단계 1에서 수득한 화합물 (3.73 g, 12.4 mmol)을 다이클로로메탄(DCM)(0.1 M)에 녹인 후 트리플루오로아세트산(TFA)(12.4 mL)을 적가하고 반응 혼합물은 실온에서 교반하였다. TLC 모니터링으로 반응이 종료됨을 확인한 후 후 감압 건조하였다. 얻어진 잔사는 정제 과정 없이 바로 다음 반응에 사용하였다.The compound (3.73 g, 12.4 mmol) obtained in Step 1 was dissolved in dichloromethane (DCM) (0.1 M), trifluoroacetic acid (TFA) (12.4 mL) was added dropwise, and the reaction mixture was stirred at room temperature. After confirming that the reaction was complete through TLC monitoring, it was dried under reduced pressure. The obtained residue was immediately used in the next reaction without purification.
단계 3: N-(4-메톡시벤질)-8,9,10,11-테트라하이드로-5H,7H-피리미도[4',5':3,4]피라졸로[1,2-a][1,2]다이아제핀-4-아민(N-(4-methoxybenzyl)-8,9,10,11-tetrahydro-5H,7H-pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazepin-4-amine)의 제조Step 3: N-(4-methoxybenzyl)-8,9,10,11-tetrahydro-5H,7H-pyrimido[4',5':3,4]pyrazolo[1,2-a] [1,2] Diazepin-4-amine (N-(4-methoxybenzyl)-8,9,10,11-tetrahydro-5H,7H-pyrimido[4',5':3,4]pyrazolo[1, Preparation of 2-a][1,2]diazepin-4-amine)
4-클로로-6-(4-메톡시벤질아미노)피리미딘-5-카복스알데하이드(4-chloro-6-(4-methoxybenzylamino)pyrimidine-5-carboxaldehyde)(497.7 mg, 1.79 mmol)를 에탄올 (0.1 M)에 용해시키고, 상기 단계 2에서 수득한 화합물(705.0 mg, 2.15 mmol)과 트리에틸아민 (1.25 ml, 5 eq.)을 실온에서 적가하고 반응액 온도를 80℃로 가열한 후 교반하였다. TLC 모니터링으로 반응 중의 1,2-다이자제판의 사라짐을 확인한 후 반응액을 실온으로 낮추어 NaBH4 (203.1 mg, 3 eq.)을 반응 혼합물에 적가하고 교반하였다. TLC 모니터링으로 반응 종결을 확인한 후 H2O와 포화 aq. NaCl 용액 및 에틸아세테이트를 이용하여 유기층을 분리하여 Na2SO4로 건조하고, 여과한 다음 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 표제 화합물 (393.9 mg, 1.21 mmol, 68%)을 얻었다.4-chloro-6-(4-methoxybenzylamino)pyrimidine-5-carboxaldehyde (4-chloro-6-(4-methoxybenzylamino)pyrimidine-5-carboxaldehyde) (497.7 mg, 1.79 mmol) was dissolved in ethanol (497.7 mg, 1.79 mmol) 0.1 M), the compound obtained in step 2 (705.0 mg, 2.15 mmol) and triethylamine (1.25 ml, 5 eq.) were added dropwise at room temperature, the reaction solution was heated to 80°C and stirred. . After confirming the disappearance of 1,2-diazepan during the reaction through TLC monitoring, the reaction solution was lowered to room temperature, NaBH 4 (203.1 mg, 3 eq.) was added dropwise to the reaction mixture, and stirred. After confirming the completion of the reaction by TLC monitoring, it was added with H 2 O and saturated aq. The organic layer was separated using NaCl solution and ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (393.9 mg, 1.21 mmol, 68%).
1H NMR (500 MHz, CDCl3) δ8.21 (s, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 6.87 (m, J = 8.8 Hz, 2 H), 4.56 (d, J = 5.4 Hz, 2 H), 4.51 (brs, 1 H), 4.11 (s, 2 H), 3.79 (s, 3 H), 3.52 (t, J = 5.9 Hz, 2 H), 2.89 (t, J = 5.9 Hz, 2 H), 1.83 (quint, J = 4.9 Hz, 2 H), 1.742-1.737 (m, 4 H) 1 H NMR (500 MHz, CDCl 3 ) δ8.21 (s, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 6.87 (m, J = 8.8 Hz, 2 H), 4.56 (d, J = 5.4 Hz, 2 H), 4.51 (brs, 1 H), 4.11 (s, 2 H), 3.79 (s, 3 H), 3.52 (t, J = 5.9 Hz, 2 H), 2.89 (t, J = 5.9 Hz, 2 H), 1.83 (quint, J = 4.9 Hz, 2 H), 1.742-1.737 (m, 4 H)
HRMS (ESI) m/z calcd for C18H24N5O [M+H]+: 326.1976; Found: 326.1975.HRMS (ESI) m/z calcd for C18H24N5O [M+H]+: 326.1976; Found: 326.1975.
단계 4: 6-(2-((tert-부틸다이페닐실릴)옥시)에틸)-4-((4-메톡시벤질)아미노)- 6,7,8,9,10,11-헥사하이드로-5H-피리미도[4',5':3,4]피라졸로[1,2-a][1,2]디아제핀-6-윰 아이오다이드(6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-((4-methoxybenzyl)amino)-6,7,8,9,10,11-hexahydro-5H-pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazepin-6-ium iodide)의 제조Step 4: 6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-((4-methoxybenzyl)amino)-6,7,8,9,10,11-hexahydro- 5H-pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazepine-6-ium iodide (6-(2-((tert-butyldiphenylsilyl) oxy)ethyl)-4-((4-methoxybenzyl)amino)-6,7,8,9,10,11-hexahydro-5H-pyrimido[4',5':3,4]pyrazolo[1,2- Preparation of a][1,2]diazepin-6-ium iodide)
상기 단계 3에서 수득한 N-(4-메톡시벤질)-8,9,10,11-테트라하이드로-5H,7H-피리미도[4',5':3,4]피라졸로[1,2-a][1,2]다이아제핀-4-아민(N-(4-methoxybenzyl)-8,9,10,11-tetrahydro-5H,7H-pyrimido[4',5':3,4]pyrazolo[1,2-a][1,2]diazepin-4-amine)(365 mg, 1.12 mmol)을 아세토나이트릴 (0.2 M)에 용해시키고, tert-부틸(2-아이오도에톡시)다이페닐실란(tert-butyl(2-iodoethoxy)diphenylsilane)(1.38 g, 3.37 mmol)을 실온에서 적가하고 반응액 온도를 80℃로 가열한 후 교반하였다. TLC 모니터링으로 반응 종결을 확인한 후 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 표제 화합물 (825.3 mg, 0.91 mmol, 81%)을 얻었다. N-(4-methoxybenzyl)-8,9,10,11-tetrahydro-5H,7H-pyrimido[4',5':3,4]pyrazolo[1,2] obtained in step 3 above. -a][1,2]diazepine-4-amine (N-(4-methoxybenzyl)-8,9,10,11-tetrahydro-5H,7H-pyrimido[4',5':3,4]pyrazolo [1,2-a][1,2]diazepin-4-amine) (365 mg, 1.12 mmol) was dissolved in acetonitrile (0.2 M), and tert-butyl(2-iodoethoxy)diphenyl Silane (tert-butyl(2-iodoethoxy)diphenylsilane) (1.38 g, 3.37 mmol) was added dropwise at room temperature, the reaction solution was heated to 80°C, and then stirred. After confirming the completion of the reaction by TLC monitoring, it was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (825.3 mg, 0.91 mmol, 81%).
1H NMR (400 MHz, MeOH-d4) δ 8.33 (s, 1 H), 7.58 (d, J = 6.8 Hz, 2 H), 7.35-7.44 (m, 8 H), 7.25 (d, J = 8.4 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 5.79 (d, J = 14.4 Hz, 1 H), 5.22 (d, J = 14.4 Hz, 1 H), 4.56 (ABq, ΔδAB = 0.05, JAB = 14.6 Hz, 2 H), 4.31-4.48 (m, 2 H), 4.22 (d, J = 16.8 Hz, 1 H), 3-98-4.06 (m, 3 H), 3.85 (dd, J = 13.4 Hz, 3.0 Hz, 1 H), 3.76 (d, J = 11.2 Hz, 1 H), 3.72 (s, 3 H), 2.07 (t, J = 5.6 Hz, 1 H), 1.73-1.85 (m, 3 H), 1.59 (t, J = 9.2 Hz, 2 H), 0.92 (s, 9 H) 1 H NMR (400 MHz, MeOH-d4) δ 8.33 (s, 1 H), 7.58 (d, J = 6.8 Hz, 2 H), 7.35-7.44 (m, 8 H), 7.25 (d, J = 8.4 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 5.79 (d, J = 14.4 Hz, 1 H), 5.22 (d, J = 14.4 Hz, 1 H), 4.56 (ABq, ΔδAB = 0.05, JAB = 14.6 Hz, 2 H), 4.31-4.48 (m, 2 H), 4.22 (d, J = 16.8 Hz, 1 H), 3-98-4.06 (m, 3 H), 3.85 (dd , J = 13.4 Hz, 3.0 Hz, 1 H), 3.76 (d, J = 11.2 Hz, 1 H), 3.72 (s, 3 H), 2.07 (t, J = 5.6 Hz, 1 H), 1.73-1.85 (m, 3 H), 1.59 (t, J = 9.2 Hz, 2 H), 0.92 (s, 9 H)
HRMS (ESI) m/z calcd for C36H46N5O2Si+ [M]+: 608.3415; Found: 608.3415. HRMS (ESI) m/z calcd for C36H46N5O2Si+ [M]+: 608.3415; Found: 608.3415.
단계 5: 6-[2-[tert-부틸(다이페닐)실릴]옥시에틸]-N-[(4-메톡시페닐)메틸]-7,8,9,10,11,12-헥사하이드로-5H-피리미도[4,5-b][1,5]다이아제신-4-아민 (6-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-N-[(4-methoxyphenyl)methyl]-7,8,9,10,11,12-hexahydro-5H-pyrimido[4,5-b][1,5]diazecin-4-amine)의 제조Step 5: 6-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-N-[(4-methoxyphenyl)methyl]-7,8,9,10,11,12-hexahydro- 5H-pyrimido[4,5-b][1,5]diazesin-4-amine (6-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-N-[(4-methoxyphenyl)methyl] -Manufacture of 7,8,9,10,11,12-hexahydro-5H-pyrimido[4,5-b][1,5]diazecin-4-amine)
상기 단계 4에서 수득한 화합물 (139.0 mg, 0.19 mmol)을 에탄올 (0.05 M)에 녹인 후 NaOEt (19.4 mg, 0.29 mmol, 1.5 equiv.)과 NaBH4 (143.8 mg, 3.80 mmol, 20 equiv.)를 실온에서 적가하고 반응액 온도를 60℃로 올린 후 교반하였다. TLC 모니터링으로 반응이 종료됨을 확인한 후 감압증류하고 H2O와 NaHCO3l 용액으로 반을을 종결하였다. 에틸아세테이트를 이용하여 유기층을 분리하여 Na2SO4로 건조하고, 여과한 다음 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 표제 화합물 (79.9 mg, 0.13 mmol, 71%)을 얻었다.The compound (139.0 mg, 0.19 mmol) obtained in step 4 was dissolved in ethanol (0.05 M), then NaOEt (19.4 mg, 0.29 mmol, 1.5 equiv.) and NaBH 4 (143.8 mg, 3.80 mmol, 20 equiv.) were added. It was added dropwise at room temperature, the temperature of the reaction solution was raised to 60°C, and then stirred. After confirming that the reaction was complete through TLC monitoring, it was distilled under reduced pressure and the reaction was completed with 3 l of H 2 O and NaHCO solution. The organic layer was separated using ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (79.9 mg, 0.13 mmol, 71%).
1H NMR (400 MHz, CDCl3) δ 8.67 (brs, 1 H), 8.25 (s, 1 H), 7.66 (d, J = 6.4 Hz, 4 H), 7.32-7.41 (m, 6 H), 7.25 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 4.56 (d, J = 4.8 Hz, 2 H), 4.10 (t, J = 3.6 Hz, 1 H), 3.80 (s, 5 H), 3.31 (brs ,2 H), 2.67 (brs, 4 H), 2.33 (brs, 2 H), 1.60 (brs, 6 H), 1.04 (s, 9 H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (brs, 1 H), 8.25 (s, 1 H), 7.66 (d, J = 6.4 Hz, 4 H), 7.32-7.41 (m, 6 H), 7.25 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 4.56 (d, J = 4.8 Hz, 2 H), 4.10 (t, J = 3.6 Hz, 1 H) ), 3.80 (s, 5 H), 3.31 (brs, 2 H), 2.67 (brs, 4 H), 2.33 (brs, 2 H), 1.60 (brs, 6 H), 1.04 (s, 9 H)
HRMS (ESI) m/z calcd for C36H48N5O2Si [M+H]+: 610.3572; Found: 610.3572.HRMS (ESI) m/z calcd for C36H48N5O2Si [M+H]+: 610.3572; Found: 610.3572.
단계 6: 12-벤질-6(2-((tert-부틸다이페닐실릴)옥시)에틸)-N-(4-메톡시벤질)- 5,6,7,8,9,10,11,12-옥타하이드로피리미도[4,5-b][1,5]다이아제신-4-아민(12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-5,6,7,8,9,10,11,12-octahydropyrimido[4,5-b][1,5]diazecin-4-amine)의 제조Step 6: 12-Benzyl-6(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-5,6,7,8,9,10,11,12 -Octahydropyrimido[4,5-b][1,5]diazecin-4-amine (12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl )-5,6,7,8,9,10,11,12-octahydropyrimido[4,5-b][1,5]diazecin-4-amine) production
상기 단계 5에서 수득한 6-[2-[tert-부틸(다이페닐)실릴]옥시에틸]-N-[(4-메톡시페닐)메틸]-7,8,9,10,11,12-헥사하이드로-5H-피리미도[4,5-b][1,5]다이아제신-4-아민(6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-6,7,8,9,10,11-hexahydro-5H-pyrimido[4,5-b][1,5]diazecin-4-amine)(435.0 mg, 0.73 mmol)을 아세토나이트릴 (0.05 M)에 녹인 용매에 벤질브로마이드 (1.51eq)를 실온에서 적하한 후 교반하였다. TLC 모니터링으로 반응이 종료됨을 확인한 후 감압증류하고 H2O와 NaHCO3 용액으로 반을을 종결하였다. 에틸아세테이트를 이용하여 유기층을 분리하여 Na2SO4로 건조하고, 여과하여 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 표제 화합물 (49.0 mg, 33%)을 얻었다.6-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-N-[(4-methoxyphenyl)methyl]-7,8,9,10,11,12- obtained in step 5 above. Hexahydro-5H-pyrimido[4,5-b][1,5]diazesin-4-amine (6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)- 6,7,8,9,10,11-hexahydro-5H-pyrimido[4,5-b][1,5]diazecin-4-amine) (435.0 mg, 0.73 mmol) was mixed with acetonitrile (0.05 M). Benzyl bromide (1.51eq) was added dropwise to the dissolved solvent at room temperature and stirred. After confirming that the reaction was complete through TLC monitoring, it was distilled under reduced pressure and the reaction was completed with H 2 O and NaHCO 3 solutions. The organic layer was separated using ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (49.0 mg, 33%).
1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1 H), 7.63 (d, J = 6.4 Hz, 4 H), 7.30-7.43 (m, 11 H), 7.22 (t, J = 4.0 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H), 4.74 (s, 2 H), 4.51 (d, J = 5.6 Hz, 2 H), 3.71 (s, 3 H), 3.58-3.60 (m, 4 H), 3.46 (brs, 2 H), 2.67 (brs, 2 H), 2.61(t, J = 7.0 Hz, 2 H), 1.641 (quint, J = 6.4 Hz, 2 H), 1.48 (brs, 4 H), 1.03 (s, 9 H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (s, 1 H), 7.63 (d, J = 6.4 Hz, 4 H), 7.30-7.43 (m, 11 H), 7.22 (t, J = 4.0 Hz) , 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H), 4.74 (s, 2 H), 4.51 (d, J = 5.6 Hz, 2 H) ), 3.71 (s, 3 H), 3.58-3.60 (m, 4 H), 3.46 (brs, 2 H), 2.67 (brs, 2 H), 2.61(t, J = 7.0 Hz, 2 H), 1.641 (quint, J = 6.4 Hz, 2 H), 1.48 (brs, 4 H), 1.03 (s, 9 H)
HRMS (ESI) m/z calcd for C43H54N5O2Si [M+H]+: 700.4042; Found: 700.4041.HRMS (ESI) m/z calcd for C43H54N5O2Si [M+H]+: 700.4042; Found: 700.4041.
실시예 1: 12-벤질-15-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노에타노)피리미도[4,5-b][1,5]다이아제신(12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4,5-b][1,5]diazecine)의 제조Example 1: 12-Benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido [4, 5-b][1,5]Diazecin (12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4 Manufacturing of ,5-b][1,5]diazecine)
단계 1: 2-(12-벤질-4-((4-메톡시벤질)아미노) )-7,8,9,10,11,12-헥사하이드로피리미도[4,5-b][1,5]다이아제신-6(5H)-일)에탄-1-올(2-(12-benzyl-4-((4-methoxybenzyl)amino)-7,8,9,10,11,12-hexahydropyrimido[4,5-b][1,5]diazecin-6(5H)-yl)ethan-1-ol)의 제조Step 1: 2-(12-benzyl-4-((4-methoxybenzyl)amino))-7,8,9,10,11,12-hexahydropyrimido[4,5-b][1, 5] Diazin-6(5H)-yl)ethan-1-ol (2-(12-benzyl-4-((4-methoxybenzyl)amino)-7,8,9,10,11,12-hexahydropyrimido[ Preparation of 4,5-b][1,5]diazecin-6(5H)-yl)ethan-1-ol)
11-벤질-6-(2-((tert-부틸다이페닐실릴)옥시)에틸)-N-(4-메톡시벤질)- 6,7,8,9,10,11-헥사하이드로-5H-피리미도[4,5-b][1,5]다이아조닌-4-아민(11-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-6,7,8,9,10,11-hexahydro-5H-pyrimido[4,5-b][1,5]diazonin-4-amine)(102.9 mg, 0.15 mmol)을 HF : 피리미딘 : THF=5 : 5 : 90 용액 (0.1 M)에 녹인 후 혼합물을 실온에서 교반하였다. TLC 모니터링으로 반응이 종료됨을 확인한 후 에톡시메틸실란을 적가한 다음, 감압 건조하였다. 얻어진 잔사는 정제 과정 없이 바로 다음 반응에 사용하였다.11-Benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-6,7,8,9,10,11-hexahydro-5H- Pyrimido[4,5-b][1,5]diazonin-4-amine (11-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-6 ,7,8,9,10,11-hexahydro-5H-pyrimido[4,5-b][1,5]diazonin-4-amine) (102.9 mg, 0.15 mmol) HF: Pyrimidine: THF=5 : 5 : 90 After being dissolved in solution (0.1 M), the mixture was stirred at room temperature. After confirming that the reaction was complete through TLC monitoring, ethoxymethylsilane was added dropwise, and then dried under reduced pressure. The obtained residue was immediately used in the next reaction without purification.
LRMS (ESI) m/z calcd for C27H35N5O2 [M+H]+: 462.3; Found: 462.4.LRMS (ESI) m/z calcd for C27H35N5O2 [M+H]+: 462.3; Found: 462.4.
단계 2: 2-(12-2-(12-벤질-4-((4-메톡시벤질)아미노)-7,8,9,10,11,12-헥사하이드로피리미도[4,5-b][1,5]다이아제신-6(5H)-일)에틸 메탄설포네이트(2-(12-2-(12-benzyl-4-((4-methoxybenzyl)amino)-7,8,9,10,11,12-hexahydropyrimido[4,5-b][1,5]diazecin-6(5H)-yl)ethyl methanesulfonate)의 제조Step 2: 2-(12-2-(12-benzyl-4-((4-methoxybenzyl)amino)-7,8,9,10,11,12-hexahydropyrimido[4,5-b ][1,5] Diazin-6(5H)-yl)ethyl methanesulfonate (2-(12-2-(12-benzyl-4-((4-methoxybenzyl)amino)-7,8,9, Preparation of 10,11,12-hexahydropyrimido[4,5-b][1,5]diazecin-6(5H)-yl)ethyl methanesulfonate)
상기 단계1에서 수득한 화합물 (45.3 mg, 0.10 mmol)을 다이클로로메탄(DCM) (0.03 M)에 녹인 후 트라이에틸아민(TEA) (0.17 mL)과 메탄설포닐 클로라이드 (0.06 mL, 0.77 mmol)를 적가하고 반응 혼합물을 실온에서 교반하였다. TLC 모니터링으로 반응이 종료됨을 확인한 후 감압 건조하였다. 얻어진 잔사는 정제 과정 없이 바로 다음 반응에 사용하였다.The compound obtained in step 1 (45.3 mg, 0.10 mmol) was dissolved in dichloromethane (DCM) (0.03 M), then triethylamine (TEA) (0.17 mL) and methanesulfonyl chloride (0.06 mL, 0.77 mmol). was added dropwise and the reaction mixture was stirred at room temperature. After confirming that the reaction was complete through TLC monitoring, it was dried under reduced pressure. The obtained residue was immediately used in the next reaction without purification.
LRMS (ESI) m/z calcd for C28H37N5O4S [M+H]+: 540.3; Found: 540.3.LRMS (ESI) m/z calcd for C28H37N5O4S [M+H]+: 540.3; Found: 540.3.
단계 3: 12-벤질-15-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노에타노)피리미도[4,5-b][1,5]다이아제신Step 3: 12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4,5 -b][1,5]Diasesin (( 12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4,5-b][1,5]diazecine)의 제조12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4,5-b][1,5]diazecine) manufacture of
상기 단계 2에서 수득한 화합물 (47.15 mg, 0.10 mmol)을 디메틸포름아마이드(DMF)(0.01 M)에 녹인 후 소듐하이드라이드(NaH)(57.24 mg, 2.4 mmol)를 적가한 후, Ar 조건에서 반응 혼합물을 실온에서 교반하였다. TLC 모니터링으로 반응 종료됨을 확인한 후 H2O, 포화 aq. NaCl 용액 및 에틸아세테이트를 이용하여 유기층을 분리하여 Na2SO4로 건조하고, 여과하여 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 표제 화합물 (11.4 mg, 0.03 mmol, 34%)을 얻었다.The compound (47.15 mg, 0.10 mmol) obtained in step 2 was dissolved in dimethylformamide (DMF) (0.01 M), then sodium hydride (NaH) (57.24 mg, 2.4 mmol) was added dropwise, and then reacted under Ar conditions. The mixture was stirred at room temperature. After confirming the completion of the reaction by TLC monitoring, H 2 O, saturated aq. The organic layer was separated using NaCl solution and ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (11.4 mg, 0.03 mmol, 34%).
1H NMR (400 MHz, CDCl3) δ8.19 (s, 1 H), 7.20-7.32 (m, 7 H), 6.78 (d, J = 8.4 Hz, 2 H), 5.07 (d, J = 15.2 Hz, 1 H), 4.73 (s, 2 H), 4.23 (d, J = 14.4 Hz, 1 H), 4.13-4.20 (m, 1 H), 3.99 (d, J = 12.8 Hz, 1 H), 3.81 (s, 3 H), 3.25-3.32 (m, 2 H), 3.00 (dd, J = 13.6, 10.8 Hz, 1 H), 2.71-2.78 (m, 2 H), 2.67 (d, J = 13.2 Hz, 1 H), 2.37 (dt, J = 12.4 Hz, 4.1 Hz, 1 H), 2.28 (t, J = 11.0 Hz, 1 H), 2.02-2.07 (m, 1 H), 1.81-1.82 (m, 2 H), 1.55-1.61 (m, 2 H), 1.39-1.44 (m, 1 H) 1 H NMR (400 MHz, CDCl 3 ) δ8.19 (s, 1 H), 7.20-7.32 (m, 7 H), 6.78 (d, J = 8.4 Hz, 2 H), 5.07 (d, J = 15.2 Hz, 1 H), 4.73 (s, 2 H), 4.23 (d, J = 14.4 Hz, 1 H), 4.13-4.20 (m, 1 H), 3.99 (d, J = 12.8 Hz, 1 H), 3.81 (s, 3 H), 3.25-3.32 (m, 2 H), 3.00 (dd, J = 13.6, 10.8 Hz, 1 H), 2.71-2.78 (m, 2 H), 2.67 (d, J = 13.2 Hz, 1 H), 2.37 (dt, J = 12.4 Hz, 4.1 Hz, 1 H), 2.28 (t, J = 11.0 Hz, 1 H), 2.02-2.07 (m, 1 H), 1.81-1.82 (m , 2 H), 1.55-1.61 (m, 2 H), 1.39-1.44 (m, 1 H)
HRMS (ESI) m/z calcd for C27H34N5O [M+H]+: 444.2758; Found: 444.2758.HRMS (ESI) m/z calcd for C27H34N5O [M+H]+: 444.2758; Found: 444.2758.
실시예 2: 12-벤질-16-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노프로파노)피리미도[4,5-b][1,5]다이아제신(12-benzyl-16-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminopropano)pyrimido[4,5-b][1,5]diazecine)의 제조Example 2: 12-Benzyl-16-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminopropano)pyrimido [4, 5-b][1,5]Diazecin (12-benzyl-16-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminopropano)pyrimido[4 Manufacturing of ,5-b][1,5]diazecine)
12-벤질-6-(2-((tert-부틸다이페닐실릴)옥시)에틸)-N-(4-메톡시벤질)- 5,6,7,8,9,10,11,12-옥타하이드로피리미도[4,5-b][1,5]다이아제신-4-아민(12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-5,6,7,8,9,10,11,12-octahydropyrimido[4,5-b][1,5]diazecin-4-amine)으로부터 실시예 1과 동일한 방법을 실시하여 표제 화합물 (25.29 mg, 22%)을 얻었다.12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)-5,6,7,8,9,10,11,12-octa Hydropyrimido[4,5-b][1,5]diazecin-4-amine (12-benzyl-6-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-(4-methoxybenzyl)- The title compound (25.29 mg) was obtained from 5,6,7,8,9,10,11,12-octahydropyrimido[4,5-b][1,5]diazecin-4-amine) by the same method as in Example 1. , 22%) was obtained.
1H NMR (400 MHz, CDCl3) δ8.42 (s, 1 H), 7.21-7.29 (m, 7 H), 6.86 (d, J = 8.8 Hz, 2 H), 4.90 (d, J =14.4 Hz, 1 H), 4.49-4.58 (m, 2 H), 4.20-4.33 (m, 3 H), 3.80 (s, 3 H), 3.62-3.70 (m, 1 H), 3.51 (td, J = 12.5 Hz, 3.5 Hz, 1 H), 3.04-3.09 (m, 1 H), 2.86-2.93 (m, 1 H), 2.65 (brs, 2 H), 2.39-2.49 (m, 1 H), 2.19-2.26 (m, 1 H), 2.02-2.04 (m, 1 H), 1.94 (brs, 2 H), 1.80-1.86 (m, 2 H), 1.64-1.72 (m, 1 H), 1.50 (brs, 1 H), 1.39-1.43 (m, 1 H) 1 H NMR (400 MHz, CDCl 3 ) δ8.42 (s, 1 H), 7.21-7.29 (m, 7 H), 6.86 (d, J = 8.8 Hz, 2 H), 4.90 (d, J = 14.4 Hz, 1 H), 4.49-4.58 (m, 2 H), 4.20-4.33 (m, 3 H), 3.80 (s, 3 H), 3.62-3.70 (m, 1 H), 3.51 (td, J = 12.5 Hz, 3.5 Hz, 1 H), 3.04-3.09 (m, 1 H), 2.86-2.93 (m, 1 H), 2.65 (brs, 2 H), 2.39-2.49 (m, 1 H), 2.19- 2.26 (m, 1 H), 2.02-2.04 (m, 1 H), 1.94 (brs, 2 H), 1.80-1.86 (m, 2 H), 1.64-1.72 (m, 1 H), 1.50 (brs, 1 H), 1.39-1.43 (m, 1 H)
HRMS (ESI) m/z calcd for C28H36N5O [M+H]+: 458.2915; Found: 458.2914.HRMS (ESI) m/z calcd for C28H36N5O [M+H]+: 458.2915; Found: 458.2914.
실시예 3: 2-(10-벤질-2-(4-메톡시벤질)-2,5,10-트리아자-1(4,6)-피리미디나사이클로데카판-5-일)아세토나이트릴(2-(10-benzyl-2-(4-methoxybenzyl)-2,5,10-triaza-1(4,6)-pyrimidinacyclodecaphane-5-yl)acetonitrile)의 제조Example 3: 2-(10-benzyl-2-(4-methoxybenzyl)-2,5,10-triaza-1(4,6)-pyrimidinacyclodecapan-5-yl)acetonite Preparation of reel (2-(10-benzyl-2-(4-methoxybenzyl)-2,5,10-triaza-1(4,6)-pyrimidinacyclodecaphane-5-yl)acetonitrile)
11-벤질-14-(4-메톡시벤질)-5,7,8,9,10,11-헥사하이드로-4,6-(에피미노에타노)피리미도[4,5-b][1,5]다이아조닌(11-benzyl-14-(4-methoxybenzyl)-5,7,8,9,10,11-hexahydro-4,6-(epiminoethano)pyrimido[4,5-b][1,5]diazonine)(3.2 mg, 7.45 μmol)을 디클로로메탄(DCM)(0.05M)에 녹인 용액에 AuCl (0.86 mg, 3.72 μmol)와 트라이메틸실릴시아나이드 (21.44 μL, 0.17 mmol)를 실온에서 적가하였다. 반응액 온도를 80℃로 올린 후 교반하였다. TLC 모니터링으로 반응 종료됨을 확인한 후 반응액을 감압하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 표제 화합물 (3.2 mg, 66%)을 얻었다.11-Benzyl-14-(4-methoxybenzyl)-5,7,8,9,10,11-hexahydro-4,6-(epiminoethano)pyrimido[4,5-b][1 ,5]Diazonin (11-benzyl-14-(4-methoxybenzyl)-5,7,8,9,10,11-hexahydro-4,6-(epiminoethano)pyrimido[4,5-b][1, AuCl (0.86 mg, 3.72 μmol) and trimethylsilyl cyanide (21.44 μL, 0.17 mmol) were added dropwise to a solution of 5] diazonine (3.2 mg, 7.45 μmol) in dichloromethane (DCM) (0.05M) at room temperature. did. The temperature of the reaction solution was raised to 80°C and stirred. After confirming the completion of the reaction through TLC monitoring, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound (3.2 mg, 66%).
1H NMR (400 MHz, CDCl3) δ8.30 (s, 1 H), 7.23-7.32 (m, 5 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.87 (s, 1 H), 4.86 (d, J = 8.4 Hz, 4 H), 3.80 (s, 3 H), 3.41 (brs, 2 H), 3.39 (s, 2 H), 3.27 (brs, 2 H), 2.74 (brs, 2 H), 2.60 (t, J = 4.4 Hz, 2 H), 1.48 (brs, 4 H) 1 H NMR (400 MHz, CDCl 3 ) δ8.30 (s, 1 H), 7.23-7.32 (m, 5 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.87 (s, 1 H), 4.86 (d, J = 8.4 Hz, 4 H), 3.80 (s, 3 H), 3.41 (brs, 2 H), 3.39 (s, 2 H) , 3.27 (brs, 2 H), 2.74 (brs, 2 H), 2.60 (t, J = 4.4 Hz, 2 H), 1.48 (brs, 4 H)
HRMS (ESI) m/z calcd for C27H33N6O [M+H]+: 457.2711; Found: 457.2710.HRMS (ESI) m/z calcd for C27H33N6O [M+H]+: 457.2711; Found: 457.2710.
실시예 4: 2-(11-벤질-2-(4-메톡시벤질)-2,6,11-트리아자-1(4,6)-피리미디나사이클로운데카판-6-일)아세토나이트릴(2-(11-benzyl-2-(4-methoxybenzyl)-2,6,11-triaza-1(4,6)-pyrimidinacycloundecaphane-6-yl)acetonitrile)의 제조Example 4: 2-(11-Benzyl-2-(4-methoxybenzyl)-2,6,11-triaza-1(4,6)-pyrimidinacycloundecapan-6-yl)aceto Preparation of nitrile (2-(11-benzyl-2-(4-methoxybenzyl)-2,6,11-triaza-1(4,6)-pyrimidinacycloundecaphane-6-yl)acetonitrile)
11-벤질-15-(4-메톡시벤질)-5,7,8,9,10,11-헥사하이드로-4,6-(에피미노프로파노)피리미도[4,5-b][1,5]다이아조닌(11-benzyl-15-(4-methoxybenzyl)-5,7,8,9,10,11-hexahydro-4,6-(epiminopropano)pyrimido[4,5-b][1,5]diazonine)(10.8 mg, 24.3 μmol)으로부터 실시예 3과 동일한 방법을 실시하여 표제 화합물 (6.6 mg, 58%)을 얻었다. 11-Benzyl-15-(4-methoxybenzyl)-5,7,8,9,10,11-hexahydro-4,6-(epiminopropano)pyrimido[4,5-b][1 ,5]Diazonin (11-benzyl-15-(4-methoxybenzyl)-5,7,8,9,10,11-hexahydro-4,6-(epiminopropano)pyrimido[4,5-b][1, The title compound (6.6 mg, 58%) was obtained from 5] diazonine (10.8 mg, 24.3 μmol) by the same method as in Example 3.
1H NMR (400 MHz, CDCl3) δ8.29 (s, 1 H), 7.24-7.32 (m, 5 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.09 (s, 1 H), 4.87 (brs, 2 H), 4.83 (s, 2 H), 3.79 (s, 3 H), 3.55 (s, 2 H), 3.29 (brs, 2 H), 3.19 (t, J = 8.6 Hz, 2 H), 2.66 (brs, 2 H), 2.44 (brs, 2 H), 1.66 (brs, 4 H), 1.40 (brs, 2 H) 1 H NMR (400 MHz, CDCl 3 ) δ8.29 (s, 1 H), 7.24-7.32 (m, 5 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.09 (s, 1 H), 4.87 (brs, 2 H), 4.83 (s, 2 H), 3.79 (s, 3 H), 3.55 (s, 2 H), 3.29 (brs, 2 H), 3.19 (t, J = 8.6 Hz, 2 H), 2.66 (brs, 2 H), 2.44 (brs, 2 H), 1.66 (brs, 4 H), 1.40 (brs, 2 H)
HRMS (ESI) m/z calcd for C28H35N6O [M+H]+: 471.2867; Found: 471.2867.HRMS (ESI) m/z calcd for C28H35N6O [M+H]+: 471.2867; Found: 471.2867.
실시예 5: 2-(12-벤질-2-(4-메톡시벤질)-2,6,12-트리아자-1(4,6)-피리미디나사이클로도데카판-6-일)아세토나이트릴(2-(12-benzyl-2-(4-methoxybenzyl)-2,6,12-triaza-1(4,6)-pyrimidinacyclododecaphane-6-yl)acetonitrile)의 제조Example 5: 2-(12-benzyl-2-(4-methoxybenzyl)-2,6,12-triaza-1(4,6)-pyrimidinacyclododecapan-6-yl)aceto Preparation of nitrile (2-(12-benzyl-2-(4-methoxybenzyl)-2,6,12-triaza-1(4,6)-pyrimidinacyclododecaphane-6-yl)acetonitrile)
실시예 1에서 수득한 화합물 (10.7 mg, 24.1 μmol)로부터 실시예 3과 동일한 방법을 실시하여 표제 화합물 (6.7 mg, 59%)을 얻었다. The title compound (6.7 mg, 59%) was obtained from the compound (10.7 mg, 24.1 μmol) obtained in Example 1 by performing the same method as Example 3.
1H NMR (400 MHz, CDCl3) δ8.32 (s, 1 H), 7.24-7.32 (m, 5 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.64 (s, 1 H), 4.92 (s, 2 H), 4.85 (s, 2 H), 3.80 (s, 3 H), 3.39 (s, 2 H), 3.38 (t, J = 5.6 Hz, 2 H), 3.21 (t, J = 7.4 Hz, 2 H), 2.62-2.65 (m, 4 H), 1.47-1.49 (m, 4 H), 1.38 (q, J = 6.4 Hz, 2 H) 1 H NMR (400 MHz, CDCl 3 ) δ8.32 (s, 1 H), 7.24-7.32 (m, 5 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.64 (s, 1 H), 4.92 (s, 2 H), 4.85 (s, 2 H), 3.80 (s, 3 H), 3.39 (s, 2 H), 3.38 (t, J = 5.6 Hz, 2 H), 3.21 (t, J = 7.4 Hz, 2 H), 2.62-2.65 (m, 4 H), 1.47-1.49 (m, 4 H), 1.38 (q, J = 6.4 Hz) , 2H)
HRMS (ESI) m/z calcd for C28H35N6O [M+H]+: 471.2867; Found: 471.2867.HRMS (ESI) m/z calcd for C28H35N6O [M+H]+: 471.2867; Found: 471.2867.
실시예 6: 2-(11-벤질-2-(4-메톡시벤질)-2,5,11-트리아자-1(4,6)-피리미디나사이클로운데카판-5-일)아세토나이트릴(2-(11-benzyl-2-(4-methoxybenzyl)-2,5,11-triaza-1(4,6)-pyrimidinacycloundecaphane-5-yl)acetonitrile)의 제조Example 6: 2-(11-benzyl-2-(4-methoxybenzyl)-2,5,11-triaza-1(4,6)-pyrimidinacycloundecapan-5-yl)aceto Preparation of nitrile (2-(11-benzyl-2-(4-methoxybenzyl)-2,5,11-triaza-1(4,6)-pyrimidinacycloundecaphane-5-yl)acetonitrile)
실시예 2에서 수득한 화합물 (18.62 mg, 40.7 μmol)로부터 실시예 3과 동일한 방법을 실시하여 표제 화합물 (7.62 mg, 39%)을 얻었다.The title compound (7.62 mg, 39%) was obtained from the compound (18.62 mg, 40.7 μmol) obtained in Example 2 by the same method as Example 3.
1H NMR (400 MHz, CDCl3) δ8.27 (s, 1 H), 7.24-7.32 (m, 5 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.48 (s, 1 H), 4.92 (s, 2 H), 4.87 (brs, 2 H), 3.79 (s, 3 H), 3.50 (s, 2H), 3.35 (brs, 2 H), 3.19 (dd, J = 10.0 Hz, 6.8 Hz, 2 H), 2.56 (brs, 2 H), 2.50 (brs, 2 H), 1.66 brs, 2 H), 1.58 (brs, 4 H), 1.38 (brs, 2 H) 1 H NMR (400 MHz, CDCl 3 ) δ8.27 (s, 1 H), 7.24-7.32 (m, 5 H), 7.19 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.48 (s, 1 H), 4.92 (s, 2 H), 4.87 (brs, 2 H), 3.79 (s, 3 H), 3.50 (s, 2H), 3.35 (brs, 2 H), 3.19 (dd, J = 10.0 Hz, 6.8 Hz, 2 H), 2.56 (brs, 2 H), 2.50 (brs, 2 H), 1.66 brs, 2 H), 1.58 (brs, 4 H), 1.38 (brs, 2H)
HRMS (ESI) m/z calcd for C29H37N6O [M+H]+: 485.3024; Found: 485.3023.HRMS (ESI) m/z calcd for C29H37N6O [M+H]+: 485.3024; Found: 485.3023.
실시예 7: 28-벤질-29-[(4-메톡시페닐)메틸]-25,26,27,28,29-펜타자트리사이클로펜타데카-10(25),22,24(26)-트리엔(28-benzyl-29-[(4-methoxyphenyl)methyl]-25,26,27,28,29-pentazatricyclopentadeca-10(25),22,24(26)-triene)의 제조Example 7: 28-Benzyl-29-[(4-methoxyphenyl)methyl]-25,26,27,28,29-pentazatricyclopentadeca-10(25),22,24(26)- Preparation of triene (28-benzyl-29-[(4-methoxyphenyl)methyl]-25,26,27,28,29-pentazatricyclopentadeca-10(25),22,24(26)-triene)
22-[(4-메톡시페닐)메틸]-18,19,20,21,22-펜타자트리사이클로펜타데카-5(18),15,17(19)-트리엔(22-[(4-methoxyphenyl)methyl]-18,19,20,21,22-pentazatricyclopentadeca-5(18),15,17(19)-triene)(23.6 mg, 0.07 mmol)을 디메틸포름아마이드(DMF)(0.05 M)에 녹인 후 소듐하이드라이드(NaH)(7.25 mg, 0.18 mmol, 60% purity)와 벤질클로라이드 (20.9 μL, 0.18 mmol)를 적가한 후, Ar 조건에서 반응 혼합물을 실온에서 교반하였다. TLC 모니터링으로 반응 종료됨을 확인한 후 H2O, 포화 aq. NH4Cl 용액 및 에틸아세테이트를 이용하여 유기층을 분리하여 Na2SO4로 건조하고, 여과한 다음 감압 하에서 농축하였다. 얻어진 잔사를 컬럼 크로마토그래피로 정제하여 목적 화합물 (12.2 mg, 0.03 mmol, 40%)을 얻었다.22-[(4-methoxyphenyl)methyl]-18,19,20,21,22-pentazatricyclopentadeca-5(18),15,17(19)-triene (22-[(4 -methoxyphenyl)methyl]-18,19,20,21,22-pentazatricyclopentadeca-5(18),15,17(19)-triene) (23.6 mg, 0.07 mmol) was mixed with dimethylformamide (DMF) (0.05 M). After dissolving in , sodium hydride (NaH) (7.25 mg, 0.18 mmol, 60% purity) and benzyl chloride (20.9 μL, 0.18 mmol) were added dropwise, and the reaction mixture was stirred at room temperature under Ar conditions. After confirming the completion of the reaction by TLC monitoring, H 2 O, saturated aq. The organic layer was separated using NH 4 Cl solution and ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the target compound (12.2 mg, 0.03 mmol, 40%).
1H NMR (500 MHz, CDCl3) δ8.22 (s, 1 H), 7.28-7.33 (m, 5 H), 7.23 (d, J = 8.5 Hz, 2 H) 6.86 (d, J = 9.0 Hz, 2 H), 5.05 (d, J = 15.5 Hz, 1 H), 4.93 (d, J = 15.5 Hz, 1 H), 4.76 (d, J = 15.0 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 4.43 (d, J = 15.0 Hz, 1 H), 4.20 (dd, J = 15.3 Hz, 1.8 Hz, 1 H, 3.85 (d, 11.0 Hz, 1 H), 3.79 (s, 3 H), 3.50-3.56 (m, 3 H), 2.75 (dd, J = 11.3 Hz, 8.3 Hz, 1 H), 2.39 (t, J = 10.5 Hz, 1 H), 2.08-2.15 (m, 1 H), 1.82-1.91 (m, 1 H), 1.29-1.34 (m, 1 H), 0.95-1.01 (m, 1 H) 1 H NMR (500 MHz, CDCl 3 ) δ8.22 (s, 1 H), 7.28-7.33 (m, 5 H), 7.23 (d, J = 8.5 Hz, 2 H) 6.86 (d, J = 9.0 Hz) , 2 H), 5.05 (d, J = 15.5 Hz, 1 H), 4.93 (d, J = 15.5 Hz, 1 H), 4.76 (d, J = 15.0 Hz, 1 H), 4.56 (d, J = 11.0 Hz, 1 H), 4.43 (d, J = 15.0 Hz, 1 H), 4.20 (dd, J = 15.3 Hz, 1.8 Hz, 1 H, 3.85 (d, 11.0 Hz, 1 H), 3.79 (s, 3 H), 3.50-3.56 (m, 3 H), 2.75 (dd, J = 11.3 Hz, 8.3 Hz, 1 H), 2.39 (t, J = 10.5 Hz, 1 H), 2.08-2.15 (m, 1) H), 1.82-1.91 (m, 1 H), 1.29-1.34 (m, 1 H), 0.95-1.01 (m, 1 H)
LRMS (ESI) m/z calcd for C25H29N5O [M+H]+: 416.2; Found: 416.3.LRMS (ESI) m/z calcd for C25H29N5O [M+H]+: 416.2; Found: 416.3.
실험예: 종양 세포 성장 억제 효과 확인Experimental example: Confirmation of tumor cell growth inhibition effect
HeLa 세포주 (자궁경부암 세포주)를 이용한 WST 평가계에서 실시예의 화합물의 세포 성장 억제 효과를 평가하였다. The cell growth inhibition effect of the compounds of the examples was evaluated in a WST evaluation system using the HeLa cell line (cervical cancer cell line).
HeLa 세포주 (인간 자궁경부암 세포주)를 96-well plate에 seeding하였다. 24시간이 지난 후, 검체를 10 μM 농도로 24시간 동안 처리하였다. 각각의 well로부터 배지를 흡인시키고, 10% FBS, 1% 항생제-항진균제를 포함하는 DMEM 100 μL를 즉시 채워주었다. 10 μL의 Ez-cytox WST assay reagent를 각각의 well에 처리하고, plate는 5% CO2 인큐베이터에서 37℃의 습한 조건으로 control well의 450 nm 흡광도가 1에 도달할 때까지 배양하였다. 바탕값은 10% FBS, 1% 항생제-항진균제를 포함하는 DMEM만 처리된 well로부터 얻었다. 모든 실험은 적어도 3번 독립적으로 시행하여 측정하였다.HeLa cell line (human cervical cancer cell line) was seeded in a 96-well plate. After 24 hours, the sample was treated at a concentration of 10 μM for 24 hours. The medium was aspirated from each well, and 100 μL of DMEM containing 10% FBS and 1% antibiotic-antifungal agent was immediately filled. 10 μL of Ez-cytox WST assay reagent was added to each well, and the plate was incubated in a 5% CO 2 incubator under humid conditions at 37°C until the 450 nm absorbance of the control well reached 1. The background value was obtained from wells treated with only DMEM containing 10% FBS and 1% antibiotic-antifungal agent. All experiments were performed and measured independently at least three times.
측정된 시험물질 투여군의 세포 성장 억제율은 control 군과 비교하여 계산하였다.The measured cell growth inhibition rate of the test substance administration group was calculated by comparing it with the control group.
Claims (6)
[화학식 1]
상기 화학식 1에서,
R1은 수소, 알킬, 할로알킬, 알킬카르보닐, 할로알킬카르보닐, 아릴, 아르알킬, 헤테로사이클릴, 헤테로사이클릴-알킬을 나타내고;
R2는 수소, 하이드록시, 아미노, 카르복시(-COOH), 알킬, 알킬아미노, 할로알킬, 알콕시, 할로알콕시, 알킬티오(alkylthio), 할로알킬티오, 설포닉(-SO3H), 알킬에스터 또는 알킬아마이드를 나타내며;
R3는 수소, 알킬, 알킬카르보닐, 아릴카르보닐, 알킬아미노카르보닐 또는 아릴아미노카르보닐을 나타내고;
R4는 존재하지 않거나, 또는 수소, 알킬, 시아노(-CN) 또는 시아노알킬을 나타내며;
R5는 하이드록시, 할로, 알킬, 할로알킬, 알콕시, 할로알콕시, 아르알킬, 아르알콕시 또는 아르알킬옥시카르보닐을 나타내고;
m은 1 또는 2이며;
n은 0, 1 또는 2이고;
o는 1 또는 2이며;
여기에서 상기 아릴 및 헤테로사이클은 하이드록시, 할로, 알킬, 알콕시, 할로알킬, 알콕시카르보닐 및 아릴로부터 선택되는 하나 이상의 치환기로 치환될 수 있으며;
상기 헤테로사이클은 N, O 및 S로부터 선택되는 하나 이상의 헤테로원자를 포함한다.A compound of formula 1 below, or a pharmaceutically acceptable salt or isomer thereof:
[Formula 1]
In Formula 1,
R 1 represents hydrogen, alkyl, haloalkyl, alkylcarbonyl, haloalkylcarbonyl, aryl, aralkyl, heterocyclyl, heterocyclyl-alkyl;
R 2 is hydrogen, hydroxy, amino, carboxy (-COOH), alkyl, alkylamino, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, sulfonic (-SO 3 H), alkyl ester or represents an alkylamide;
R 3 represents hydrogen, alkyl, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl or arylaminocarbonyl;
R 4 is absent or represents hydrogen, alkyl, cyano(-CN) or cyanoalkyl;
R 5 represents hydroxy, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, aralkyl, aralkoxy or aralkyloxycarbonyl;
m is 1 or 2;
n is 0, 1 or 2;
o is 1 or 2;
wherein the aryl and heterocycle may be substituted with one or more substituents selected from hydroxy, halo, alkyl, alkoxy, haloalkyl, alkoxycarbonyl and aryl;
The heterocycle contains one or more heteroatoms selected from N, O and S.
R1은 수소, C1-C7 알킬, 할로-C1-C7 알킬, C1-C7 알킬카르보닐, 할로-C1-C7 알킬카르보닐, C6-C10 아릴, C6-C10 아릴-C1-C7 알킬, 3 내지 10원 헤테로사이클릴, 3 내지 10원 헤테로사이클릴-C1-C7 알킬을 나타내고;
R2는 수소, 하이드록시, 아미노, 카르복시, C1-C7 알킬, C1-C7 알킬아미노, 할로-C1-C7 알킬, C1-C7 알콕시, 할로-C1-C7 알콕시, C1-C7 알킬티오, 할로-C1-C7 알킬티오, 설포닉, C1-C7 알킬에스터 또는 C1-C7 알킬아마이드를 나타내며;
R3는 수소, C1-C7 알킬, C1-C7 알킬카르보닐, C6-C10 아릴카르보닐, C1-C7 알킬아미노카르보닐 또는 C6-C10 아릴아미노카르보닐을 나타내고;
R4는 존재하지 않거나, 또는 수소, C1-C7 알킬, 시아노 또는 시아노-C1-C7 알킬을 나타내며;
R5는 하이드록시, 할로, C1-C7 알킬, 할로-C1-C7 알킬, C1-C7 알콕시, 할로-C1-C7 알콕시, C6-C10 아릴-C1-C7 알킬, C6-C10 아릴-C1-C7 알콕시 또는 C6-C10 아릴-C1-C7 알킬옥시카르보닐을 나타내고;
m은 1 또는 2이며;
n은 0, 1 또는 2이고;
o는 1 또는 2이며;
여기에서 상기 아릴 및 헤테로사이클은 하이드록시, 할로, C1-C7 알킬, C1-C7알콕시, 할로-C1-C7 알킬, C1-C7 알콕시카르보닐 및 C6-C10 아릴로부터 선택되는 1개 내지 5개의 치환기로 치환될 수 있으며;
상기 헤테로사이클은 N, O 및 S로부터 선택되는 1개 내지 5개의 헤테로원자를 포함하는 것을 특징으로 하는 화합물, 또는 이의 약제학적으로 허용가능한 염 또는 이성질체.According to paragraph 1,
R 1 is hydrogen, C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, halo-C 1 -C 7 alkylcarbonyl, C 6 -C 10 aryl, C 6 -C 10 aryl-C 1 -C 7 alkyl, 3 to 10 membered heterocyclyl, 3 to 10 membered heterocyclyl-C 1 -C 7 alkyl;
R 2 is hydrogen, hydroxy, amino, carboxy, C 1 -C 7 alkyl, C 1 -C 7 alkylamino, halo-C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 represents alkoxy, C 1 -C 7 alkylthio, halo-C 1 -C 7 alkylthio, sulfonic, C 1 -C 7 alkyl ester or C 1 -C 7 alkylamide;
R 3 is hydrogen, C 1 -C 7 alkyl, C 1 -C 7 alkylcarbonyl, C 6 -C 10 arylcarbonyl, C 1 -C 7 alkylaminocarbonyl, or C 6 -C 10 arylaminocarbonyl. represents;
R 4 is absent or represents hydrogen, C 1 -C 7 alkyl, cyano or cyano-C 1 -C 7 alkyl;
R 5 is hydroxy, halo, C 1 -C 7 alkyl, halo-C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkoxy, C 6 -C 10 aryl-C 1 - represents C 7 alkyl, C 6 -C 10 aryl-C 1 -C 7 alkoxy or C 6 -C 10 aryl-C 1 -C 7 alkyloxycarbonyl;
m is 1 or 2;
n is 0, 1 or 2;
o is 1 or 2;
wherein the aryl and heterocycle are hydroxy, halo, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo-C 1 -C 7 alkyl, C 1 -C 7 alkoxycarbonyl and C 6 -C 10 may be substituted with 1 to 5 substituents selected from aryl;
The heterocycle is a compound characterized in that it contains 1 to 5 heteroatoms selected from N, O and S, or a pharmaceutically acceptable salt or isomer thereof.
12-벤질-15-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노에타노)피리미도[4,5-b][1,5]다이아제신;
12-벤질-16-(4-메톡시벤질)-7,8,9,10,11,12-헥사하이드로-5H-4,6-(에피미노프로파노)피리미도[4,5-b][1,5]다이아제신;
2-(10-벤질-2-(4-메톡시벤질)-2,5,10-트리아자-1(4,6)-피리미디나사이클로데카판-5-일)아세토나이트릴;
2-(11-벤질-2-(4-메톡시벤질)-2,6,11-트리아자-1(4,6)-피리미디나사이클로운데카판-6-일)아세토나이트릴;
2-(12-벤질-2-(4-메톡시벤질)-2,6,12-트리아자-1(4,6)-피리미디나사이클로도데카판-6-일)아세토나이트릴;
2-(11-벤질-2-(4-메톡시벤질)-2,5,11-트리아자-1(4,6)-피리미디나사이클로운데카판-5-일)아세토나이트릴; 및
28-벤질-29-[(4-메톡시페닐)메틸]-25,26,27,28,29-펜타자트리사이클로펜타데카-10(25),22,24(26)-트리엔.The compound according to claim 1, wherein the compound of Formula 1 is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt or isomer thereof:
12-benzyl-15-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminoethano)pyrimido[4,5-b] [1,5]Diasesin;
12-benzyl-16-(4-methoxybenzyl)-7,8,9,10,11,12-hexahydro-5H-4,6-(epiminopropano)pyrimido[4,5-b] [1,5]Diasesin;
2-(10-benzyl-2-(4-methoxybenzyl)-2,5,10-triaza-1(4,6)-pyrimidinacyclodecapan-5-yl)acetonitrile;
2-(11-benzyl-2-(4-methoxybenzyl)-2,6,11-triaza-1(4,6)-pyrimidinacycloundecapan-6-yl)acetonitrile;
2-(12-benzyl-2-(4-methoxybenzyl)-2,6,12-triaza-1(4,6)-pyrimidinacyclododecapan-6-yl)acetonitrile;
2-(11-benzyl-2-(4-methoxybenzyl)-2,5,11-triaza-1(4,6)-pyrimidinacycloundecapan-5-yl)acetonitrile; and
28-benzyl-29-[(4-methoxyphenyl)methyl]-25,26,27,28,29-pentazatricyclopentadeca-10(25),22,24(26)-triene.
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Non-Patent Citations (7)
| Title |
|---|
| Acc. Chem. Res., 53, 703-718. (2020) |
| Chem. Sci., 10, 569-575 (2019) |
| Chem. Sci., 11, 2876-2881 (2020) |
| Chemistry Central Journal, 12, 38. (2018) |
| Nat. Chem. Biol., 8, 358-365. (2012) |
| RSC Adv., 10, 44247-44311 (2020) |
| RSC Adv., 4, 43241-43257 (2014) |
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