TWI226240B - Piperazine compound - Google Patents
Piperazine compound Download PDFInfo
- Publication number
- TWI226240B TWI226240B TW091114338A TW91114338A TWI226240B TW I226240 B TWI226240 B TW I226240B TW 091114338 A TW091114338 A TW 091114338A TW 91114338 A TW91114338 A TW 91114338A TW I226240 B TWI226240 B TW I226240B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- trimethoxyphenyl
- production example
- synthesis
- yield
- Prior art date
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- -1 Piperazine compound Chemical class 0.000 title claims abstract description 92
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 123
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 230000008595 infiltration Effects 0.000 claims abstract description 15
- 238000001764 infiltration Methods 0.000 claims abstract description 15
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 9
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 9
- 230000021164 cell adhesion Effects 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 206010061218 Inflammation Diseases 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 230000004054 inflammatory process Effects 0.000 claims abstract description 6
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 4
- 230000007815 allergy Effects 0.000 claims abstract description 4
- 208000026935 allergic disease Diseases 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 27
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 19
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
- 241001674048 Phthiraptera Species 0.000 claims 1
- 210000003754 fetus Anatomy 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 208000006673 asthma Diseases 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 abstract description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract description 2
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 116
- 238000004519 manufacturing process Methods 0.000 description 110
- 230000015572 biosynthetic process Effects 0.000 description 76
- 238000003786 synthesis reaction Methods 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 55
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 51
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 51
- 101150041968 CDC13 gene Proteins 0.000 description 42
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- OKWNDHFPWXJEHM-UHFFFAOYSA-N 2-(3,4,5-trimethoxyphenyl)pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=CC=CC=2)=C1 OKWNDHFPWXJEHM-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 229950001902 dimevamide Drugs 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 210000000265 leukocyte Anatomy 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 125000001680 trimethoxyphenyl group Chemical group 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 229940063675 spermine Drugs 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000007429 general method Methods 0.000 description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- SBGHNDCBGPREJJ-UHFFFAOYSA-N 4-(chloromethyl)-2-(3,4,5-trimethoxyphenyl)pyridine Chemical compound COC1=C(OC)C(OC)=CC(C=2N=CC=C(CCl)C=2)=C1 SBGHNDCBGPREJJ-UHFFFAOYSA-N 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QRCJVAADFAROKA-UHFFFAOYSA-N amino 2-aminoacetate Chemical compound NCC(=O)ON QRCJVAADFAROKA-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
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- 239000012458 free base Substances 0.000 description 6
- 229950005223 levamfetamine Drugs 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- CRUILBNAQILVHZ-UHFFFAOYSA-N 1,2,3-trimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1OC CRUILBNAQILVHZ-UHFFFAOYSA-N 0.000 description 5
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 210000003556 vascular endothelial cell Anatomy 0.000 description 5
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- 229920002472 Starch Polymers 0.000 description 4
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
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- TWBYTHNVQFSRJE-UHFFFAOYSA-N methyl 2-[(2-nitrophenyl)sulfonyl-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]acetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1S(=O)(=O)N(CC(=O)OC)CC(C=1)=CC=NC=1C1=CC(OC)=C(OC)C(OC)=C1 TWBYTHNVQFSRJE-UHFFFAOYSA-N 0.000 description 1
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- SMBBZHGTZJNSRQ-UHFFFAOYSA-N n'-(6,6-dichlorohexyl)methanediimine Chemical compound ClC(Cl)CCCCCN=C=N SMBBZHGTZJNSRQ-UHFFFAOYSA-N 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
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- 229940100662 nasal drops Drugs 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
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- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
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- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
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- 238000005096 rolling process Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000003971 tillage Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
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- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1226240 A7 ___ B7 五發明説明(1 ~) 技術範_ 本發明係關於具有細胞接著抑制作用及細胞浸潤抑制作 用’而在做為抗氣喘劑、抗過敏劑、抗風濕症、抗動脈硬 化劑及抗炎症劑等上有用之六氫吡畊化合物或其之鹽以及 含有彼等之醫藥。 背景技術 在各種炎症性疾病中,觀察到白血球對於炎症部位之浸 潤。例如:氣喘患者中嗜酸性球對於支氣管之浸潤 (Ohkawara Y. et al. Am. J. Respir. Cell Mol. Biol. 12, 4-12(1995)),動脈硬化症中巨噬細胞及τ細胞對於血管之浸 >F| (Sakai A. et Arterioscler Thromb. Vase. Biol. 17, 310-316 (1997)) ’ 異位性皮膚炎患者(wakita H· et al J. Cutan. Pathol. 21,33-3 9(1994))及接觸性皮膚炎患者(Satoh T et al,Eur· J. Immunol· 27,85_9i (1997))中τ細胞及嗜酸性球對於皮膚之 浸潤’以及慢性關節風濕症患者中各種白血球對於關節滑 膜之浸潤(Tak PP· et al·,Clin. Immunol. Immunopathol. 77, 236-242 (1995))等 。 此等白血球之浸潤,係由炎症局部處所產生之細胞激素 (cytokine)、化學增活素(chem〇kin)、脂肪及補體等引起 (Albelda SM et al·,FASEB J· 8, 504-512 (1994))。活性化血 流中之白血球以及被相同活性化之血管内皮細胞藉由所謂 滾動(rolling)及拘束(tethering)之相互作用,與血管内皮細 胞接著。之後,移居血管内皮以及浸潤至炎症部位 (Springer TA et al.,Annu. Rev. Physiol· 57, 827-872 (1995)) -5- 本紙張尺度適用中國國家橾準(CNS) A4規格(210 X 297公釐) 1226240 A7 _______B7 五、發明説明(2 ) 。在孩過程中 < 白血球與血管内皮細胞接著方面,被細胞 激素等刺激而在細胞表面表現之免疫球蛋白家族GCAM4 及VCAM-1等),選擇素家族(£_選擇素等),整合蛋白等 (LFA-1及VLA-4等)以及CD44等各種細胞接著分子扮演著 重要角色(臨床免疫,30, Suppl. 18 (1998)),曾有人指出病 態與細胞接著分子之表現亢進具關聯性。 因此,能夠抑制經由細胞接著分子接著之藥劑被認為在 做為支氣管性氣喘、皮膚炎、鼻炎及結膜炎等過敏疾病, 慢性關節風濕症、腎炎、炎症性腸疾病、糖尿病及動脈硬 化症等自體免疫疾病以及慢性炎症性疾病等之預防藥及治 療藥上有效。事實上,對抗LFA-1、Mac_l及VLA·4等白血 球侧之細胞接著分子之抗體,或者對抗成為其之配位子之 血管内皮細胞侧之ICAM-1、VCAM-1、P-選擇素、E-選擇 素等之抗體,在各種動物病態模型中可以抑制白血球對於 炎症部位之浸潤。舉例言之,曾報告對抗VC AM-1及為其 之受體之VLA-4之中和抗體在糖尿病自然發病之n〇D小氣 模型中’可以延遲其之發病(Michie SA. et al Curr· Top· Microbiol· Immunol. 231,65-83 (1998))。又,對抗 VLA-4或 ICAM-1及其之對應受體LFA-1之抗體在土撥鼠或小鼠過敏 性結膜炎模型中可以抑制嗜酸性球之浸潤(Ebihara et al.,
Current Eye Res· 19, 20-25 (1999),Whitcup SM et al. Clin. Immunol. 93,107-1 13 (1999)),對抗 VCAM-1 之單株抗體在 小鼠DSS謗導性大腸炎模型中可以抑制白血球浸潤以及延 遲大腸炎之發病(Soriano A et al·,Lab. Invest. 80,1541-1551 -6 - 本紙張尺度適用中國國家棣準(CNS) A4規格(210X297公釐) 1226240 A7 B7 五、發明説明(3 ) (2000))。再者,抗VLA-4抗體及抗CD44抗體在小鼠膠原謗 導性關節炎模型中,可以抑制其之發病(2^丨(11^八.以&1· Autoimmunity 21,245-252(1995))。又’在缺損此爭細胞接 著分子之小鼠中,與炎症模型之試驗同樣地,可以觀察到 會抑制白血球對於炎症組織之浸潤(以11(^11〇11117.以&1· Clin. Exp. Immunol. 1 19, 57-63 (2000) ^ Wolyniec WW.et al. Am· J. Respir. Cell Mol. Biol· 18, 777-785 (1998),Bullard DC.et al· J. Immunol· 157,3 153-3 158 (1996))。 但是,在使用抗體類之開發方面,由於抗體為胜肽性高 分子,所以被認為不僅經口投與困難,而且可能有因抗原 性而產生過敏反應等副作用之問題點。 相對於此,曾報告以經口投與為目的之各種低分子細胞 接著抑制作用化合物。雖然已有苯并噻吩衍生物 (Boschelli DH. et al·,J. Med. Chem. 38, 4597-4614 (1995)), 莕衍生物(特開平10-147568號公報),羥芊酸衍生物(特開 平10-182550號公報),木脂素類特開平10-67656號公報), 2-取代苯并噻唑衍生物(特開2000-086641號公報),縮合吡 畊化合物(特開2000-3 19277號公報)以及2,6-二烷基-4-矽烷 基-酚(特開2000-509070號公報)等,但目前未必能充分達 成目的。在特開平9-143075號公報及特開平11-92282號公 報記載之環狀二胺化合物未顯示充分的細胞接著抑制作 用,而期望進一步提高活性。 因此,本發明之目的為提供一種具有細胞接著及細胞浸 潤抑制作用,並進而具有優異抗氣喘作用、抗過敏作用、 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 、發明說明(4 抗風邊作用、抗動脈硬化作 發明之揭# 利及抗火症作用之物質。 鑒於上述實情,為了得到抑制 質, ^ 、 1剌、、田脃接耆及細胞浸潤之物 仃冰入研咒《結果發現通式⑴表示之化合物具有 優:的細胞接著及細胞浸潤抑制作用,在做為抗過敏劑, 抗乳喘劑 '抗風濕劑、抗動脈硬化劑及抗炎症 用’而完成本發明。 亦即、’本發明提供一種通式⑴表示之六氫吡呼化合 物,其之酸附加鹽或彼等之水合物 OMe
OMe OMe [式中,X表示 _CH2-、-C(0)_4-CH(CH3)- ; R1表示氫原 子或燒基;以及R2表示氫原子、燒基、經燒基、芳燒基、 雜芳燒基、羧烷基、胺甲醯烷基、胺烷基或胍烷基]。 又,本發明提供一種含有上述之六氫吡畊化合物、其之 酸加成鹽或彼等之水合物以做為有效成分之醫藥。 再者,本發明提供一種含有上述之六氫吡畊化合物、其 之酸加成鹽或彼等之水合物以及醫藥上容許之載體之醫藥 組合物。 再者,本發明提供一種上述之六氫?比喷化合物、其之酸 -8 - 本紙張尺度適财S ®家標準(CNS) A4規格(210X 297公爱)
1226240 A7 —-~__— B7______ 五、發明説明(5 ) 加成鹽或彼等之水合物在醫藥製造上之用途。 更進一步而言,本發明提供一種細胞接著及/或細胞浸 潤引起之疾病之處置方法,其之特徵為將上述環狀二胺化 合物、其之酸加成鹽或彼等之水合物之有效量投給有需要 之患者。 實施發明之最佳形態 在通式(1)中,R1及R2表示之烷基以Cl-C6烷基為較佳, 具體而言,-例如為甲基、乙基、正丙基、異丙基、正丁 基、異丁基、第二丁基、第三丁基、戊基及己基等,尤其 是以甲基、乙基、正丙基、異丙基、異丁基及第二丁基等 為較佳。 R表示之羥烷基以羥基_Cl-C6烷基為較佳,具體而言為 羥甲基、2-羥基乙基、2-羥基_1_甲基乙基、2-羥基_ι,ι_二 甲基乙基、3-羥基丙基、3-羥基-2·甲基丙基、4-羥-基丁 基、5_羥基戊基及6-羥基己基等,尤其以羥甲基、羥基 乙基、2-羥基_1_甲基乙基、2-羥基q,卜二甲基乙基及弘羥 基丙基為特佳。芳烷基,以C6_ClG芳基_Ci_c6烷基為較 佳’具體而言,為芊基及苯乙基等苯基-Ci-C6烷基。雜芳 基烷基,以含有1或2個氮原子以做為雜原子之5或6員雜芳 基-(να燒基為較佳。更佳者為吡啶基_C「C6烷基、喊淀 基-q-C6烷基、咪唑基-Cl-C6烷基及吡咯基_Ci_C6烷基等。 做為羧烷基者,以羧基-Ci-C6烷基為較佳,具體而言,例 如為羧甲基及羧乙基等。做為胺甲醯烷基者,以胺甲醯 基Ci_C(5:l:7〇基為較佳,具體而言,例如為胺甲酿基甲基及 -9- 1226240 A7 B7 五、發明説明(6 ) 胺甲醯基乙基等。做為胺烷基者,以胺基-CrQ烷基為較 佳,具體而言,例如為胺甲基、胺乙基及胺丙基等。做為 脈燒基者,以脈基-Ci-C6垸基為較佳,具體而言,例如為 胍甲基、胍乙基及胍丙基等。 做為本發明化合物(1)之酸加成鹽,若為藥學上容許之 鹽將無特殊限制,例如為鹽酸鹽、氫溴酸鹽、氫破酸鹽、 硫酸鹽及磷酸鹽等礦酸之酸加成鹽;以及苄酸鹽、甲磺酸 鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽、草酸鹽、順丁 烯二酸鹽、反丁烯二酸鹽、酒石酸鹽、檸檬酸鹽及乙酸鹽 等有機酸之酸加成鹽。 又,本發明化合物(1)可以溶媒合物(以水合物為代表)之 形態存在,該溶媒合物亦被包含在本發明之中。 本發明化合物(1)之中X為-CH(CH3)-及-(:112者,可以依 照下述反應式所示之方法製造。
本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 A7 B7 五、發明説明(7 HN" OMe
OMe
X NH L (7) [式中X奏示-CH(CH3)或-CH2-;以及R1及R2與上述者 同]。 亦即,將氯體(2)及3,4,5_三甲氧苯棚酸(3)於肆(三苯膦) 把(0)等金屬觸媒及碳酸鋼等驗存在下,在甲苯、苯、四 氫呋喃(THF)、二呤烷及乙腈等溶媒中,在至回流溫度 (較佳90°C)下反應10分鐘至數日(較佳反應5小時),得到二 合體(4)。將其在THF中,於-2〇t:至室溫(較佳〇t)與氫化 鋰鋁反應數秒鐘至數小時(較佳丨小時),而得到醇體(^。 將化合物(5)在氯仿、二氯甲燒、乙酸乙酿、乙趟、㈣及 二呤烷等溶媒中,與硫醯氯在_2(rc至回留溫度(較佳於 溫成拌!小時至數日(較佳5小時),得到氯體⑹匕八 物(6)及二胺體⑺在二甲基甲醯胺(DMf)、二 口 (DMS0)及乙腈等溶媒中,於碳酸鉀存在下,^ 基亞砜 t (較佳8〇t)撥拌i小時至數日(較佳 至溫至100 化合物(U)。 時)’仵到本發明 又,本發明化合物(1)之中父為4(0)•者, 述之反應式所示之方法製造。 猎由例如下 -11 - 本纸張尺度適财规格(21GX297公愛) 1226240 A7 B7
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(9 ) [式中,X為-C(0)-;以及…及民2如同上述]。 亦即,將甘胺酸甲酯(8)按照既知之方法,與硝基笨磺 醯氯反應,得到2-硝基苯磺醯體(9)。將化合物⑼在與上 述者同樣(條件下,與上述之氯體(6)反應,得到化合物 (1〇)。繼而藉由將化合物(10)以既知之方法處理,得到化 合物(11)。將化合物(11)在與上述者同樣之條件下,用氫 化鋰鋁還原,得到醇體(12)。將化合物(12)在二氯甲烷、 乙腈及DMF等溶媒中,於咪唑、三乙胺、4_甲基嗎福啉、 4-(二甲胺基)吡啶等鹼存在下,與第三丁基二甲基氯矽烷 (TBDMS-C1)於0°C至回流溫度(較佳5〇〇c )反應丨小時至數曰 (較佳一夜),而得到TBDMMf(13)。藉由將化合物(13)與 9-芴基甲氧羰基-胺基酸(Fmoc_胺基酸)(14)在氯仿、二氯甲 烷、乙腈、THF、DMF及DMSO等溶媒中,於二環己基碳 化二亞胺、1-乙基-3-(3-二甲胺丙基)碳化二亞胺·鹽酸鹽 (水溶性碳化二亞胺)及〇-(1Η-苯并三唑小基>n,n,n,,n、 甲基脲鑌六氟亞磷酸鹽(HBTU)等脫水縮合劑存在下,於〇 。(:至回流溫度(較佳於室溫)反應1分鐘至數日(較佳1〇分 鐘),得到化合物(15)。藉由將化合物(15)按照既知之方法 與六氫咐症反應,得到胺基體(16)。將化合物(16)與上述 2-硝基苯磺醯氯在與上述者相同之條件下反應,得到2_確 基苯磺醯體(17)。將化合物(17)用既知之方法處理,得到 酵體(18)。將化合物(18)溶於THF及二哼烷等溶媒中,然後 與二+騰及偶氣一-,一乙SS (DEAD)於0。〇至回流溫产(較 佳於室溫)反應1小時至數日(較佳一夜),得到化合物 -13- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 A7 B7 五、發明説明(1Q ) (19)。將化合物(19)以既知之方法進行2-硝基苯磺醯化, 得到化合物(20),將化合物(20)與上述之氯體(6)在與上述 者相同之條件下反應,得到本發明化合物(lb)。 又,本發明化合物(1)之中X為-CH2-者,可藉由例如下 述之反應式所示之方法製造。
[式中,X為-CH2-;以及R1及R2如同上述]。 亦即,將N-芊基甘胺酸乙酯(21)與Fmoc-胺基酸(N-(9-芴 基甲氧羰基)胺基酸(22)按照既知之方法反應,得到二胜肽 衍生物(23)。化合物(23),按照既知之方法同時進行Fmoc 化及環化,得到二酮基六氫吡畊衍生物(24)。化合物 (24),藉由使用氫化鋰鋁等之既知還原方法處理,可以得 到六氫说畊衍生物(25)。化合物(25),藉由使用飽-碳之既 -14- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(11 ) 知接觸還原方法進行脫芊基化,得到化合物(26)。將化合 物(26)與上述之氯體(6)在與上述者相同之條件下反應,得 到本發明化合物(1 c)。 本發明化合物(1)雖可藉由上述方法得到,但如有需要 時,可用再結晶法及管柱層析法等通常之精製手段精製。 又需要時,可以藉由一般方法做成上述所期望之鹽或溶媒 合物。又,本發明化合物(1)具有不對稱碳之場合,本發 明亦包含任何立體異構物。 如此得到之本發明化合物(1),其之鹽或溶媒合物顯示 後述實施例所示之優異細胞接著抑制作用,在做為包含人 類之動物之氣喘、過敏、風濕症、動脈硬化症及炎症等之 治療或預防用醫藥上有用。 本發明之醫藥,為以上述化合物(1)、其之鹽或其之溶 媒合物作為有效成分者,其之投與形態無特殊限定,可視 治療目的適當地選擇,例如為口服劑、注射劑、栓劑、軟 膏劑、吸入劑、點眼劑、點鼻劑及貼附劑之任一者,此等 之投與形態,可以藉由添加藥學上容許之載體,以及以本 技藝人士公知慣用之製劑方法製造。 調製口服用固形製劑之場合,可以在本發明化合物(1) 中加入賦形劑,並於需要時添加黏合劑、崩散劑、潤滑 劑、著色劑、矯味劑及矯臭劑等後,藉由一般方法製造錠 劑、加衣錠劑、顆粒劑、散劑及膠囊劑等。作為此等添加 劑者,可為該領域一般使用者,舉例言之,做為賦形劑者 例如為乳糖、白糖、氣化鈉、葡萄糖、;殿粉、碳酸鈣、白 -15- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)
二纖=:秒酸等。做為黏合劑者’例如為水、 基纖維素、幾丙基纖维:萄糖液、激粉液、明膠液、叛甲 基鑣維去 基纖、、隹素、禮丙基澱粉、甲基纖維素、乙 ^ '、蟲膠、磷酸鈣及聚乙缔吡咯啶酮等,做Λ…今 甽者,例如為乾燥 、> 仏為朋欢 為、碳酸舞、十其以U、瓊脂粉末、碳酸氫 作為潤滑為丨去 納、硬脂酸單甘油醋及乳糖等, 乙二醇菩〔、’例如為精製滑石粉、硬脂酸鹽、硼砂及聚 酒:酸等。’—做為橋味劑者’例如為白糖、撥皮、檸檬酸及 姝::口服用欲劑之場合’可在本發明化合物⑴中添加 緩衝劑、线化劑及矯臭劑等,並藉由—般方法 ^内服瑕劑、糖漿劑及_等。在該場合,做為矯味劑 外如為香草素等,做為缓衝劑者,例如為檸權酸納 :’做為安定化劑者,例如為西黃耆膠'阿拉伯膠及明膠 爭。 調製注射劑之場合,可在本發明化合物⑴中添加阳調 郎劑、緩衝劑、安定化劑、等張化劑及局部麻醉劑等,以 ,藉由-般方法製造皮下、肌肉及靜脈内注射劑。做為該 場合之pH值調節劑及緩衝劑者,例如為擰檬酸鈉、乙酸 納及磷酸鈉等。做為安定化劑者,例如為亞硫酸鈉、 EDTA、硫代羥乙酸及硫代乳酸等。做為局部麻醉劑者, 例如為鹽酸普魯卡因(procaine HC1)及鹽酸利多卡因 (lidocame HC1)等。做為等張劑者例如為氯化鈉及葡萄糖 等。 -16 -本紙银尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 五、發明説明(13 調製栓劑之場合, 知之製劑用裁體,例如聚乙本 防酸甘油酿等,再者可可^及三脂 丁ween(登錄商標)等後,藉由一般方法製、告面洽性劑如 調製軟膏劑之場合,如 坆 入基劑、安定化,、、^ J π 發明化合物(1)中加 文疋化剑、濕潤劑及保存劑等, 法混合及製劑化。做為基劑者,例如 :由-般方 士林'晒密蠟、十八碳醇及 ::去白色凡 為對幾基爷酸甲醋、對禮基爷酸為:存Μ5,例如 等。 丁敗G g日及對踁基芊酸丙酯 及外’可以藉由—般方法做成吸入劑、點眼劑 形 〜 ,、仁通$對於成人而言,本發明化 否物⑴之每日劑量以卜侧mg,單次或分成數次經口投 與或非經口投與為較佳。 實施例 下文雖列舉實施例說明本發明,但本發明並不限於此。 製造例1 2 (3’4,5-二甲氧苯基)異菸鹼酸乙酯之合成: ,C02Et N、 17- 祕狀跳用中國國家標準(CN^· Μ規格(摩297公爱〉 1226240 A7 ___B7 五、發明説明(14 ) 將3,4,5·三甲氧苯基硼酸(20.64 g)及2-氯異菸鹼酸乙酯 (19.06 g)懸浮於甲苯(200 mi)及THF (100 ml)之混合溶媒 中,然後加入2M碳酸鈉(20〇1111)及肆(三苯膦)鈀(〇)(5 93 §) 。將混合物在氬氣蒙氣及90。(:下攪拌一夜,加入乙酸乙醋 並將有機層分離。將有機層用飽和食鹽水洗淨,用無水硫 酸鎂乾燥後減壓濃縮。將殘餘物用矽膠管柱層析(己燒·· 乙酸乙酯=5 : 1)精製,得到標題化合物。 產量·· 27.70 g (85%) 'H-NMR (400 MHz, CDC13) δ: 1.45 (t? 3H, J = 7.0 Hz), 3.92 (s,3H),3·99 (s,6H),4.46 (q,2H,J = 7.0 Hz),7.30 (s,2H), 7.76 (dd,1H,J = 5.1 Hz,1.6 Hz),8.24 (dd,1H,J = 1·6 Hz, 0.8 Hz),8.81 (dd,1H,J = 5.1 Hz,0.8 Hz)。 製造例2 經甲基-2_(3,4,5_三甲氧苯基)吡啶之合成:
將2_(3,4,5-三甲氧苯基)異菸鹼酸乙酯(27·70 g)溶於THF (200 ml)中,在〇°C及氬氣蒙氣下,加入氫化鋰鋁(3.3 1 mg) ,然後在0°C攪拌1小時。在反應液中加入少量水,繼而加 入硫酸鈉,將反應液經矽藻土過濾後,將濾液減壓濃縮, 將得到之結晶從乙酸乙酯-己烷中再結晶,得到標題化合 物0 -18- 本紙張瓦度適用中國國家標準(CNS) A4規格(210 X 297公釐)
裝 訂
線 A7 B7 1226240 五、發明説明(15 ) 產量:18.15 g (76%) iH-NMR (400 MHz,CDC13) δ: 3.90 (s,3H),3.95 (s,6H),4.79 (s,2H),7·19 (d,1H,J = 5·1 Hz),7.21 (s,2H),7.66 (s,1H), 8.60 (d, 1H, J = 5.1 Hz) 製造例3 4-氯甲基-2-(3,4,5-三甲氧苯基)吡啶之合成:
將4-羥甲基_2-(3,4,5-三甲氧苯基)吡啶(18·15 g)溶於氯仿 (300 ml)中,在加入硫醯氯(19.2 ml),然後在〇。〇攪拌 30分鐘,及在室溫攪拌4小時。反應結束後,將反應溶液 用水及飽和食鹽水洗淨,用無水硫酸鈉乾燥。減壓濃縮 後’將得到之結晶從氯仿-己统中再結晶,得到標題化合 物。 產量:17.87 g (92%) lH-NMR (400 MHz, CDC13) δ: 3.91 (s? 3H), 3.97 (s, 6H)? 4.61 (s,2H),7.24 (s,2H),7.26 (d,1H,J = 5.1 Hz),7.68 (s,1H), 8.67 (d, 1H, J = 5.1 Hz) 實施例1 順式-N,N’-貳[[2_(3,4,弘三甲氧苯基)吡淀I基]甲基]-2,卜二 甲基六氫吡畊· 4鹽酸鹽之合成:
線
1226240 A7 B7
五、發明説明
將‘氯甲基-2-(3,4,5-三甲氧苯基),比啶(123 mg)及順式_ 2,6-二甲基六氫毗畊(23 mg)溶於DMF (5 ml)中,然後加入 碳酸鉀(5 8 mg)。將該混合物在80°C攪捽4小時,並將反應 溶液減壓濃縮。在殘餘物中加入水並用氯仿萃取,將有機 層用飽和食鹽水洗淨,用無水硫酸鎂乾燥後減壓濃縮。將 殘餘物用矽膠管拄層析(氯仿:甲醇=40 : 〇精製,得到標 題化合物之游離鹼。將其溶於乙酸乙酯後,加入4M氯化 氫之乙酸乙酯溶液,以形成鹽酸鹽。 產量:101 mg (68%) h-NMR (以游離鹼測定,400 MHz,CDC13) δ: 0.97 (d,6H,J =6.1 Hz),1·99 (t,2H,J = ll.l Hz),2.75 (d,4H,J = 9.8 Hz), 3.53 (s,2H),3.81 (s, 2H),3.90 (s,6H),3.97 (s,6H),3.98 (s, 6H),7.22-7.24 (m,5H),7.32 (d,1H,J = 4.3 Hz),7.64 (s,1H), 7.67 (s,1H),8.57 (d,1H,J = 5.1 Hz),8.61 (d,1H,J = 5·1 Hz) m/z (E/I) : 628 [M+] 實施例2 反式-N,N’-貳[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-2,5-二 甲基六氫吡畊· 4鹽酸鹽之合成: ___ -20- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7 1226240 五、發明説明(17
將4-氯甲基-2_(3,4,5-三甲氧苯基)吡啶(I23 mg)及反式-2,5 -二甲基六氫吡畊(23 mg)以與實施例1同樣之方式反 應,得到為鹽酸鹽之目的物。 產量:117 mg (93%) iH-NMR (以游離鹼測定,400 MHz,CDC13) δ: 1.07 (d,6H,J =6.1 Hz),2.02 (t,2H,J = 1〇·5 Hz),2.46-2.49 (m,2H),2·67 (dd,2H,J = 11.2 Hz,2.6 Hz),3.16 (d,2H,J = 14·4 Hz),3·91 (s,6H),3.97 (s,12H),4.10 (d,2H,J = 14.3 Hz),7·24 (s,4H), 7.26 (d,2H,J = 5·3 Hz),7.63 (s,2H),8.60 (d,2H,J = 5.1 Hz) m/z (E/I) ·· 628 [M+] 實施例3 N,N*-貳[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]·2-羥甲基六 氫吡畊· 2順丁烯二酸鹽之合成:
線
將4-氯甲基-2-(3,4,5-三甲氧苯基)吡啶(1.44 g)及2-羥甲 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(18 ) 基六氫吡畊(463 mg)以與實施例1同樣之方式反應,得到為 順丁婦二酸鹽之目的物。 產量:116 mg (19%) W-NMR (以順丁烯二酸鹽測定,400 MHz,DMSO-d6) δ: 2·37-2.79 (m,7Η),3.57-3.62 (m,4Η),3.78 (s,6Η),3.89 (s, 12H),4.05-4.11 (m,2H),6.64 (s,4H),7.23 (d,1H,J = 5.1 Hz),7.26 (d,1H,J = 4.6 Hz),7.34 (s,2H),7.34 (s,2H),7.76 (s,1H),7.78—(s,1H),8.52 (d,1H,J = 6.3 Hz),8.53 (d,1H,J =5.4 Hz) m/z (E/I) : 630 [M+] 製造例4 N-(2-硝基苯磺醯基)甘胺酸甲酯之合成:
將甘胺酸甲酯鹽酸鹽(15.0 g)溶於二氯甲烷中,在〇。〇加 入三乙胺(26.48 g)。然後慢慢滴入2_硝基苯磺醯氯(23 57 g) 之二氯甲烷(50 ml)溶液。在室溫下攪拌2小時後,將反應 溶液減壓濃縮,在殘餘物中加入乙酸乙酯並用2M_鹽酸、 水及飽和食鹽水洗淨及用無水硫酸鈉乾燥後,減壓濃縮。 將得到之結晶從乙酸乙酯-正己烷中再結晶,得到無色之 標題化合物。 產量:26.20 g (90%) W-NMR (400 MHz, CDC13) δ:3·61 (s,3H),4·02 (d,2H,J = -22 - 本紙張尺度適用巾國國家標準(CNS) A4規格(21〇 x 297公董)
線 1226240 A7
5.9 Hz), 6.07 (br. s, 1H), 7.73-7.77 (m, 2H), 7.92-7.95 (m, 1H), 8.07-8.11 (m, 1H) 製造例5 N-(2-硝基苯磺醯基甲氧苯基M啶_4_基]甲 基]甘胺酸甲酯之合成:
將N-(2-確基苯續酿基)甘胺酸甲酯(5 6〇 g)溶於乙赌(綱 πα)中,加入碳酸鉀(3.10g)及碘化鉀(2 29幻,然後加入4 氯甲基-2-(3,4,5-三甲氧苯基V比啶(6 〇〇 g)並在s〇t下攪拌丄 小時。將反應液減壓濃縮,在殘餘物中加入乙酸乙酯,並 用飽和碳酸氫鈉,水及飽和食鹽水洗淨及用無水硫酸鈉乾 燥後,減壓濃縮。將殘餘物用矽膠管柱層析(氯仿:甲醇 =5 0 : 1)精製,得到標題化合物。 產量:11.35 g (理論量) lH-NMR (400 MHz, CDC13) δ: 3.63 (s? 3H), 3.90 (s, 3H)? 3.97 (s,6H),4.13 (s,2H),4.75 (s,2H),7.13 (d,1H,J = 3.5 Hz) 7.20 (s,2H),7·60 (s,1H),7.65-7.73 (m,3H),8.07 (dd,1H j =8.8 Hz, 1.6 Hz), 8.61 (d, 1H, J = 5.1 Hz) 製造例6 N-[[2-(3,4,5-三甲氧苯基)吡啶-4_基]甲基]甘胺酸甲酯之合 成: -23-
1226240 A7 B7 五、發明説明(2〇
Me丨 Me
將N-(2-硝基苯磺醯基)-N-[[2-(3,4,5-三甲氧苯基)吡啶_4_ 基]甲基]甘胺酸甲酯(11.35 g)溶於乙腈(3〇 ml)中,並加入 碳酸鉀(3.3 9 g)。然後加入硫代酚ο」? g),並在室溫下攪 捽一夜。在滿合物中加入乙酸乙酯,並用飽和碳酸氫鈉水 落液’水及飽和食鹽水洗淨’用無水硫酸鈉乾燥。減壓濃 縮後,將殘餘物用矽膠管柱層析(氯仿:甲醇=2〇 : 1)# 製,得到標題化合物。 產量:6.54 g (92%) iH-NMR (400 MHz,CDC13) δ:3·46 (s,2H),3.74 (s,3H), 3.90 (s? 5H)5 3.97 (s? 6H)? 7.24 (s, 2H)? 7.25 (d? 1H? J = 4.1 Hz), 7.67 (s,1H),8.65 (d,1H,J = 4.9 Hz) 製造例7 N-(2-^乙基)-N-[[2-(3,4,5-三甲氧苯基)u比咬_4_基]甲基]胺 之合成:
Me〇
MeO 將N-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]甘胺酸甲酯 (6·54 g)溶於THF (80 ml)中,在0°C及氬氣蒙氣下加入少量 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7
氫化鋰鋁(717 mg)並攪拌4小時。加入少量永,卷 > §發泡終了 時,加入過剩之硫酸鈉。將反應液經矽藻土、馬 減壓濃縮,將殘餘物用矽膠管柱層析(氯仿· 精製,得到標題化合物。 ·’ 產量:5.03 g (84%) h-NMR (400 MHz,CDC13) δ: 2·14 (br,2H),2 83 ’ · (t,2H,J = 5-1 Hz), 3.71 (t, 2H, J = 5.1 Hz), 3.89 (s, 2H), 3.9〇 (s, 3H) 3.96 (s,6H),-7.19 (d,1H,J = 4·9 Hz),7.23 (s,2H) 7 64 , 1H),8.60 (d,1H,J = 5.1 Hz) (S’ 製造例8 N-[2-(第三丁基二甲基矽烷氧)乙基]_冰[[2_(3,4,5_三甲氧苯 基)吡啶-4-基]甲基]胺之合成:
^/v^OTBDMS Η 將仏(2-輕乙基三甲氧苯基)吡啶基]甲基] 胺(5.〇 g)溶於乙腈(100 ml)中,加入三乙胺(2 22幻及4_(二 甲胺V比啶(25〇 mg),然後加入第三丁基氯二甲基矽燒〇8 g) °將該混合物在5(TC下攪拌4小時。將反應溶液減壓濃 縮。在殘餘物中加入乙酸乙酯,用水及飽和食鹽水洗淨, 及用無水硫酸鈉乾燥後,減壓濃縮。將殘餘物用矽膠管柱 層析(氣仿:甲醇=30 : 1)精製,得到標題化合物。 產量:6.89 g (理論量) —-25- 本紙張尺度適用中國國家標準(CNS) Μ規格(㈣χ 297公董) ------- 1226240 A7 B7 H NMR (400 MHz,CDC13) δ: 0.07 (s,6H),0·90 (s,9H), 1.93 (br? 1H)? 2.76 (t? 2H, J = 5.1 Hz), 3.77 (t, 2H, J = 5.1 Hz),3.90 (s,5H),3.97 (s,6H),7.21 (d,1H,J = 4.7 Hz),7.24 (s,2H),7.66 (s,1H),8.60 (d,1H,J = 4.9 Hz) 製造例9 N-[2-(第二丁基二甲基矽烷氧)乙基>n_[[2-(3,4,5-三甲氧苯 基)吡哫-4_基]甲基]-Να -(9-芴基甲氧羰基)甘胺醯胺之合 成: — OMe
NHFmoc 將N-[2-(第三丁基二甲基矽烷氧)乙基]_n_[[2-(3,4,5•三甲 氧苯基Μ呢-4_基]甲基]胺(3.40 g),N-(9-苟基甲氧羰基)甘 胺酸(2.34 g),二異丙基乙胺(1 〇3 g)及4-(二甲胺基)吡啶 (961 mg)溶於乙腈(4〇 mi)中,加入HBTU (3.13 g),並於室 溫攪拌10分鐘。將反應液減壓濃縮,加入乙酸乙酯,用水 及飽和食鹽水洗淨,以及用無水硫酸鈉乾燥後,減壓漢 、‘ 將殘餘物用石夕膠管柱層析(正己燒··乙酸乙醋=1 : 1) 精製,得到標題化合物。 產量:5.15 g (92%) 〖H’MR (400 MHz,CDC13) δ: 0.04 (s,6H),0.87 (s,9H),3·43 〇,2Η,J = 5.1 Ηζ),3·75 (t,2Η,J = 5.1 Ηζ),3.90 (s,3Η), 本紙張尺'度適用中國國家標準(CNS) Α4規格(210 x 297公釐) 1226240 A7 B7 五、發明説明(23 ) 3.95 (s,6H),4.27 (d,1H,J = 4.5 Hz),4.34-4.39 (m,3H),4.75 (s,2H),5·83 (br,1H),7.09 (d,1H,J 二 4.1 Hz),7.19 (s,2H), 7.30 (t,2H,J 二 7.4 Hz),7.39 (t, 2H,J = 7.4 Hz),7.58 (s,1H), 7.61 (d,2H,J = 7.6 Hz),7.70 (d,2H,J = 7.6 Hz),8.61 (d,1H, J = 5.1 Hz) 製造例10 N-[2-(第三丁基二甲基矽烷氧)乙基]·ν_[[2-(3,4,5-三甲氧苯 基>比啶-4-基]甲基]•甘胺醯胺之合成:
將Ν-[2-(第三丁基二甲基矽烷氧)乙基]_Ν_[[2-(3,4,5-三甲 氧苯基V比嗓:-4·基]甲基]_Ν α —(9_芴基甲氧羰基)甘胺醯胺 (5· 15 g)溶於六氫吡啶之2〇〇/。乙腈溶液(4〇如)中,然後在室 溫下攪拌4小時。反應結束後加入乙酸乙酯,用水及飽和 食鹽水洗淨及用無水硫酸鈉乾燥後,減壓濃縮。將殘餘物 用矽膠管柱層析(氯仿:甲醇=20: υ精製,得到標題化合 物0 產量:2.76 g (78%) lH-NMR (400 MHz, CDC13) δ: 0.04 (s? 6m 〇 8〇 , 〜,υ.88 (s,9H),1 67 (bi*,2H),3.38 (t,2H,J = 5.2 Hz),3·7〇 (s 2H、”,
、s,2H),3·72 (t,2H J =5.2 Hz),3.90 (s,3H),3.96 (s,6H),4 73 , •/J (s,2H),7.08 (d, -27- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1226240 A7 ____B7 __ 五、發明説明(24 ) 1H,J = 4.1 Hz),7.20 (s,2H),7。50 (s,1H),8.60 (d,1H,J = 5.1 Hz) 製造例11 1^-[2-(第三丁基二甲基石夕燒氧)乙基]-^\[-[[2-(3,4,5-三甲氧苯 基)ρ比淀-4-基]甲基]-N α -(2-硝基苯續基)甘胺_胺之合 成:
將Ν_[2·(第三丁基二甲基矽烷氧)乙基]-Ν-[[2_(3,4,5-三甲 氧苯基)吡啶-4_基]甲基]甘胺醯胺(2.52 g)以與製造例4同樣 之方式處理,得到標題化合物。 產量:3.41 g (98%) h-NMR (400 MHz,CDC13) δ: 0·00 (s,6H),0.83 (s,9H),3.39 (t,2H,J = 4.8 Hz),3·47 (d,2H,J = 7.0 Hz),3.70 (t,2H,J = 4.8 Hz),3.89 (s,3H),3.95 (s,6H),4.60 (s,2H),6.50 (br. s, 1H),6.93 (d,1H,J = 4.9 Hz),7.18 (s,2H),7.44 (s,1H), 7.6 卜7·67 (m,2H),7.81 (dd,1H,J = 7.5 Hz,1.7 Hz),8.05 (dd, 1H,J = 7.7 Hz,2.0 Hz),8.54 (d,1H,J = 4.1 Hz) 製造例12
N-[2-羥乙基]-N-[[2-(3,4,5-三甲氧苯基)吡啶-4·基]甲基]-N ___ -28-____ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) Ϊ226240 A7 B7 五、發明説明(25 U -(2-硝基苯磺醯基)甘胺醯胺之合成:
將Ν-[2_(务三丁基二甲基矽烷氧)乙基]_Ν_[[2-(3,4,5-三甲 氧苯基)吡啶-4-基]甲基]-Να -(2-硝基苯磺醯基)甘胺醯胺 之(3.41 g)溶於THF (40 ml)中,在0°C下加入1.0Μ四丁基铵 氣化物之THF溶液(6.1 ml),並在室溫下攪:拌4小時。反應 結束後,將反應溶液減壓濃縮,加入乙酸乙酯,用水及飽 和食鹽水洗淨及用無水硫酸鋼乾燥後,減壓濃縮。將殘餘 物用矽膠管柱層析(氯仿:甲醇=10 : 1)精製,得到標題化 合物。 產量:2.22 g (78%) 【H-NMR (400 MHz,CDC13) δ: 3.38 (br,2H),3.55 (br,2H)
3.71 (br, 2H), 3.88 (s, 3H)? 3.93 (s, 6H)? 4.56 (s, 2H), 6.89 (d 1H,J = 4.9 Hz),7.19 (s,2H),7.46 (s,1H),7.50—7.63 (m,2H) 7.78 (d,1H,J = 7·4 Hz),8·04 (d,1H,J = 7.4 Hz),8·49 (d,iH J = 4.7 Hz) 製造例13 l-[[2_(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-4-(2-硝基苯碍釀 基)-2-酮基六氫吡畊之合成:
1226240 A7 B7 五、發明説明(26 OMe
將N_[2_羥乙基]-N-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲 基]-Ν α -(2-硝基苯磺醯基)甘胺醯胺之(2.22 g)溶於THF (80 ml)中,加入三苯膦(1.55 g),在室溫下慢慢加入DEAD (1·03 g),在—氬蒙氣及室溫下攪摔一夜。將反應液減壓濃 縮後,加入乙酸乙酯,用飽和碳酸氫鈉水溶液,水及飽和 食鹽水洗淨,用無水硫酸鈉乾燥後,減壓濃縮。將殘餘物 用秒膠管柱層析(乙酸乙酯)精製,得到標題化合物。 產量:2.01 g (94%) 'H-NMR (400 MHz, CDC13) δ: 3.42 (t? 2Η? J = 5.2 Hz), 3.67 (t,2H,J = 5·2 Hz),3.90 (s,3H),3·96 (s,6H),4.07 (s,2H), 4.67 (s,2H),7.05 (d,1H,J = 4.6 Hz),7.20 (s,2H),7.51 (s, 1H),7.63 (d,1H,J = 2.0 Hz), 7·69·7·76 (m,2H),8.03 (d,1H, J = 2.2 Hz)? 8.61 (d, 1H, J = 5.1 Hz) 製造例14 l-[[2-(3,4,5-三甲氧苯基)吡啶-4·基]甲基]-2-酮基六氫晚畊 之合成:
__-30- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(27 ) 將1-[[2-(3,4,5_三甲氧苯基比咬·4-基]甲基]_4-(2-硝基笨 磺醯基)-2-酮基六氫吡畊(1.83 g)以與製造例6同樣之方式 處理’得到標題化合物。 產量:118 mg (10%) iH-NMR (400 MHz,CDC13) δ: 1.82 (br,1H),3·09 (t,2H,J 二 5·4 Hz),3.29 (t,2H,J = 5.4 Hz),3.65 (s,2H),3.90 (s,6H), 3.96 (s,3H),4.67 (s,2H),7.12 (d,1H,J = 4·9 Hz),7·21 (s, 2H),7.55 (s,-1H),8.63 (d,1H,J = 5.1 Hz) 實施例4 2-酮基_N,N’-貳[[2_(3,4,5-三甲氧苯基)吡啶_4-基]甲基]六氫 吡畊· 2.5鹽酸鹽之合成:
將1-[[2_(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-2-酮基六氫 叶匕呼(62 mg)溶於乙腈(5 ml)中,加入碳酸卸(24 mg)、蛾化 鉀(29 mg)及4-氯甲基-2-(3,4,5-三甲氧苯基)吡啶(51 mg), 並在80°C下撥拌1小時。將反應液減壓濃縮,加入乙酸乙 酯,用飽和碳酸氫鈉水溶液、水及飽和食鹽水洗淨及用無 水硫酸鈉乾燥後,減壓濃縮。將油狀物用矽膠管柱層析 TLC (氣仿:甲醇=25 : 1)精製,得到為鹽酸鹽之標題化合 物。 -31 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(28 ) 產量:92 mg (87%) iH-NMR (以游離鹼測定,400 MHz,CDC13) δ: 2.73 (t,2H,J =5.1 Hz),3.32 (t,2H,J = 5.1 Hz), 3.34 (s,2H),3.65 (s,2H), 3.90 (s,6H),3.96 (s,12H),4.67 (s,2H),7.11 (d,1H,J = 4.9 Hz),7。22 (br,5H),7.55 (s,1H),7.61 (s,1H),8.63-8.64 (m, 2H) m/z (El) : 614 [M+] 製造例15 - N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)吡啶-2-基]甲基]-Να -(9-芴基甲氧羰基)-L-丙胺醯胺之 合成·
將N-[2-(第三丁基二甲基矽烷氧)乙基]_N_[[2_(3,4,5-三甲 氧苯基)吡啶·4·基]甲基]胺(756 mg)及N-(9_芴基甲氧羰基)· L-丙胺酸(544 mg)以與製造例9同樣之方式處理,得到標題 化合物。由於無法分離不純物,所以在未精製下用於下一 反應。 製造例16 N-[2-(弟二丁基一甲基秒坑氧)乙基]-N-[[2_(3,4,5_三甲氧笨 基)外b淀-4-基]甲基]-L-丙胺醯胺之合成: -32- 1226240 A7 B7 五、發明説明(29 )
n/^〇tbdms 將製造例15所得之混合物全量以與製造例10同樣之方式 處理,得到標題化合物。 產量:340 mg (2階段產率:39%) 製造例17 - N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)吡啶-4-基]甲基]-N α -(2-硝基苯磺醯基)-L-丙胺醯胺之 合成:
將N-[2-(第三丁基二甲基矽烷氧)乙基]-N_[[2-(3,4,5-三甲 氧苯基)吡啶-4-基]甲基]-L-丙胺醯胺(340 mg)以與製造例4 同樣之方式處理,得到標題化合物。 產量:303 mg (65%) 製造例18 N-(2-羥乙基)-N-[[2_(3,4,5-三甲氧苯基)吡啶·4·基]甲基]-N α-(2 -硝基苯續酿基)-L -丙胺驢胺之合成: 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(30 )
將Ν-[2·(第三丁基二T基碎烷氧)乙基]-Ν_[Ι>(3,4,5-三甲 氧苯基)吡金-4-基]甲基]·Ν α -(2-硝基苯磺醯基)-L·丙胺酿 胺(669 mg)以與製造例12同樣之方式4理,得到標題化合 物。 產量:546 mg (98%) 製造例19 (3S)-l-[[2-(3,4,5-二甲氧表基)p 比淀-4-基]甲基]_3 -甲基_4_(2- 硝基苯橫醯基)-2-酮基六氫批β井之合成:
將Ν-(2·藉乙基三甲氧苯基)吡啶_2_基]甲 基]-Να-(2_硝基苯磺醯基•丙胺醯胺(546 mg)以與製造例 13同樣之方式處理,得到標題化合物。由於無法完全除去 副生成物,所以在未精製下,用於下一反應。 製造例20 (3 S)-l-[[2-(3,4,5_二甲氧苯基)咐啶·心基]甲基卜3 -甲基·2·酮 •34-
1226240 A7 B7 五、發明説明(31 基六氫吡畊之合成:
將製造例19之混合物全量以與製造例6同樣之方式處 理,得到標題化合物。 產量:174m:g(2階段產率為50%) 1H-NMR (400 MHz,CDC13) δ: 1.47 (d,3H,J = 6.8 Hz),1.78 (br,1H),3.02-3.09 (m,1H),3.15-3.22 (m,2H),3.39-3.45 (m, 1H),3.65 (q,1H,J = 6.8 Hz),3.90 (s,3H),3.96 (s,6H),4.60 (d,1H,J = 15.2 Hz),4.70 (d,1H,J = 15.2 Hz), 7.10 (dd,1H, J = 5.0 Hz,1.5 Hz),7.22 (s,2H),7.53 (s,1H),8.62 (d,1H,J =4.9 Hz) 實施例5 (3S)-3-甲基-2-酮基-N,N’-貳[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]六氫吡畊· 2·5鹽酸鹽^合成:
將(3S)-l-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-3-甲基-2-酮基六氫吡畊(80 mg)及4-氣甲基-2-(3,4,5-三甲氧苯基)吡 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(32 ) 啶(63 mg)以與實施例4同樣之方式反應,得到為鹽酸鹽之 標題化合物。 產量:124 mg (92%) iH-NMR (以游離驗測定,400 MHz,CDC13) δ: 1.56 (d,3H,J 二 6·6 Hz),2.53-2.59 (m,1H),2.95-2.99 (m,1H),3.21-3.33 (m, 2H),3.43 (q,1H,J = 6.8 Hz),3.52 (d,1H,J = 14.4 Hz),3.90 (s,6H),3.95 (s,6H),3.95 (s,7H), 4.58 (d,1H,J = 15.4 Hz), 4.75 (d,1H,-J = 15.2 Hz),7.10 (d,1H,J = 4.7 Hz),7.22 (s, 2H),7.23 (m,3H),7.54 (s,1H),7.62 (s,1H),8.61 (d,1H,J = 5.7 Hz),8.63 (d,1H,J = 5.9 Hz) m/z (El) : 628 [M+] 製造例21 N-[2-(第三丁基二甲基矽烷氧)乙基]-Ν_[[2·(3,4,5·三甲氧苯 基)毗啶_4-基]甲基]-Ν α -(9-芴基甲氧羰基)-L-纈草胺醯胺 之合成:
將Ν_[2·(第三丁基二甲基矽烷氧)乙基]·ν_[[2-(3,4,5-三甲 氧苯基)吡啶-4-基]甲基胺(679 mg)及Ν·(9_芴基甲氧羰基)· L-纈草胺酸(865 mg)以與製造例9同樣之方式處理,得到標 題化合物。 36 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(33 ) 產量:1.11 g (74%) 製造例22 N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)毗啶-4-基]甲基]-L-纈草胺醯胺之合成:
將Ν·[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲 氧苯基)吡啶-4-基]甲基]-Να-(9-芴基甲氧羰基)_L-纈草胺 醯胺(1.11 g)以與製造例10同樣之方式處理,得到標題化 合物。 產量:705 mg (90%) 製造例23 N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)毗啶-4-基]甲基]-N α -(2-硝基苯磺醯基)-L纈草胺醯胺之 合成:
線
將N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲 氡苯基)吡啶-2-基]甲基]-L-纈草胺醯胺(705 mg)以與製造例
本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1226240 A7 B7 五、發明説明(34 ) " '-— 4同樣之方式處理,得到標題化合物。 產量:877 mg (92%) 製造例24 N-(2_羥乙基)_N_[[2_(3,4,5·三甲氧苯基)吡啶基]甲基] a -(2-硝基苯續醯基)_L-顯草胺酿胺之合成:
將N-[2-(第三丁基二甲基矽烷氧)乙基卜N_[[2_(3,4,5_三甲 氧苯基 >比啶-4-基]甲基]-N α ·(2_硝基苯磺醯基)_L_顯草胺 龜胺(877 mg)以與製造例12同樣之方式處理,得到標題化 合物。 產量:698 mg (95%) 製造例25 (3S)-3-異丙基- l-[[2-(3,4,5-三甲氧苯基)β比咬-4-基]甲基]-4-(2-硝基苯磺醯基)-2-酮基六氫吡畊之合成:
將.(2-羥乙基)-N-[[2-(3,4,5-三甲氧苯基)吡啶基]甲 基]-Να-(2-硝基苯磺醯基)-L-纈草胺醯胺(546 mg)以與製造 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(35 ) 例13同樣之方式處理,得到標題化合物。由於無法完全除 去副生成物,所以將其在未精製下,用於下一反應。 製造例26 (3S)-3-異丙基- l-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-2-_基六氫0比啡之合成:
將製造例25之混合物之全量以與製造例6同樣之方式處 理,得到標題化合物。 產量:365 mg (2階段產率:79%) iH-NMR (400 MHz,CDC13) δ: 0.97 (d,3H,J = 6·8 Hz),1.05 (d,3H,J = 7.0Hz),1.63(br,lH),2.56-2.64 (m,lH),2.99-3.3 1 (m,3H),3.41-3.47 (m,2H),3.90 (s,3H),3.95 (s,6H), 4.48 (d,1H,J = 15.4 Hz),4.90 (d,1H,J = 15.4 Hz),7.10 (dd, 1H,J = 4.9 Hz,1.2 Hz),7.21 (s,2H),7.53 (s,1H),8.61 (d, 1H, J = 5.1 Hz) 實施例6 (3S)-3-異丙基-2-酮基-N,N’-貳[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]六氫吡畊·1·5鹽酸鹽之合成:
、 ^^ΌMe 〇Me 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1226240 A7 B7 五、發明説明(36 ) 將(3S)-3-異丙基-l-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲 基]-2-酮基六氫吡畊(80 mg)及4_氯甲基-2-(3,4,5-三甲氧苯 基)外b啶(5 9 mg)以與實施例4同樣之方式反應,得到鹽酸鹽 之標題化合物。 產量:98 mg (75%) W-NMR (以游離鹼測定,400 MHz,CDC13) δ: 1·13 (d,3H,J =6·8 Ηζ),1.22 (d,3Η,J = 6.8 Ηζ),2.23-2.27 (m,1Η),2.60-2·64 (m,1H); 3.03-3.35 (m,4H),3.65 (d,1H,J = 14.8 Hz), 3.90 (s,3H),3.91 (s,3H),3.95 (s,6H),3.96 (s,6H),3.96 (d, 1H,J = 14.8 Hz),4.48 (d,1H,J = 15.2 Hz),4.92 (d,1H,J = 15.2 Hz),7.12 (d,1H,J = 4.9 Hz),7.21-7.24 (m, 5H),7.56 (s, 1H),7·65 (s,1H),8.60 (d,1H,J = 4.9 Hz),8.63 (d,1H,J = 5.1 Hz) m/z (El) : 656 [M+] 製造例27 N_[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)毗啶-4-基]甲基]-Να-(9-芴基甲氧羰基)-D-纈草胺醯胺 之合成:
將Ν·[2_(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5_三甲 氡苯基)吡啶-4·基]甲基]胺(1.27 g)及N-(9-芴基甲氧羰基)一 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7
五、發明説明(37 D-纈草胺酸(1.00 g)以與製造例9同樣之方式處理,得到梗 題化合物。由於無法除去不純物,所以在未精製下,用、$ 下一反應。 ; 製造例28 N-[2-(第三丁基二甲基矽烷氧)乙基甲氧笨 基)吡啶-4-基]甲基]_D_纈草胺醯胺之合成:
將製造例27得到之粗製N-[2_(第三丁基二甲基矽垸氧)乙 基]-N-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基;]_Να-(9-苟基 甲氧羰基)-D-纈草胺醯胺以與製造例1〇同樣之方式處理, 得到標題化合物。 產量:1·00 g (2階段產率:64%) 製造例29 N-[2_(第三丁基二甲基矽烷氧)乙基]_Ν_[[2_(3,4,5·三甲氧苯 基)吡啶-4-基]甲基]-Ν α -(2-硝基苯磺醯基)-D-纈草胺醯胺 之合成: 裝 訂
線
將Ν·[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲 —_41 _ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7
五、發明説明(38 氧苯基V比啶-4-基]甲基]-D_纈草胺醯胺(1.00 §)以與製造例 4同樣之方式處理,得到標題化合物。 產量:1.36 g (94%) 製造例30 N-(2-羥乙基)-Ν-[[2·(3,4,5-三甲氧苯基>比啶{基]甲基]n α -(2-硝基苯續醯基)-D-纈草胺醯胺之合成:
^ °2 N〇2 將N-[2-(第三丁基二甲基矽烷氧)乙基]-N_[[2<3 & $ 一 氧苯基比咬-2-基]甲基]-N α -(2-硝基苯續醯基、n 办纈草胺 醯胺(1.36 g)以與製造例12同樣地處理,得到扭μ J知題化合 物。 產量:1.08 g (94%) 製造例3 1 (3R)-3-異丙基·1·[[2-(3,4,5·三甲氧苯基)吡啶基]甲基]_3_ 甲基-4-(2-硝基苯續醯基)-2-_基六氫υ比ρ井之合成:
將Ν·(2-羥乙基)-Ν-[[2·(3,4,5-三甲氧苯基)吡啶_4_基]甲 基]-Ν α -(2-硝基苯磺醯基)-D-纈草胺醯胺(258 mg)以與製 -42- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 _____ B7 五、發明説明(39 ) 造例13同樣之方式處理,得到標題化合物。由於無法完全 除去副生成物,所以將其在未精製下,用於下一反應。 製造例32 (3R)-3-異丙基- i-[[2-(3,4,5_三甲氧苯基)p比淀·4·基]甲基卜4_ (2-硝基苯續醯基)-2-_基六氫π比ρ井之合成:
將製造例3 1之混合物之全量以與製造例6 、 _ Ν樣之方式處 理,得到標題化合物。 產量:109 mg (2階段產率:63%) 'H-NMR (400 MHz, CDC13) δ: 1.01 (d, 3Η τ ^ ’ 、6.6 Hz), 1·08 (d,3H,J = 7.0 Hz),2.58-2.70 (m,1H),3.〇5 ° (m, 3H), 3.45-3.57 (m,2H),3.93 (s,3H),3.98 (s,6HW < Λ 4·51 (d,1H,J = 15.4 Hz), 4.92 (d, 1H, J = 15.4 Hz), 7.12 (d m 、,1H,J = 5·1 Hz), 7.24 (s, 2H), 7.56 (s, 1H), 8.64 (d, 1H,J = 4·9 ) 實施例7 (3R)-3-異丙基-2-酮基-N,N’-貳[[2-(3,4,5-三 ψ ^ , 氣笨基比淀- 4-基]甲基]六氫吡畊· 3鹽酸鹽之合成:
-43- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) '^— 1226240 A7 ___ B7 五、發明説明(4〇 ) 將(3R)-3·異丙基小[[2_(3,4,5-三甲氧苯基)吨啶_4_基]甲 基]-2-酮基六氫吡畊(109 mg)及4-氯甲基_2_(3,4,5·三甲氧苯 基)毗啶(104 mg)以與實施例4同樣之方式反應,得到為鹽 酸鹽之標題化合物。 產量:58 mg (50%) 4-NMR (以游離驗測定,400 MHz,CDC13) δ: 1.14 (d,3H,J =7.0 Hz), 1.23 (d, 3H, J - 6.8 Hz), 2.20-2.35 (m, 1H), 2.58- 2.70 (m,1H),3.03-3.45 (m,4H),3.67 (d,1H,J = 14.8 Hz), 3.90-3.91 (m,6H),3·96_3·97 (m,15H),7.13-7.15 (m,1H), 7.24 (s,5H),7.59 (s,1H),7.67 (s,1H),8.61 (d,1H,J = 5.1
Hz),8.64 (d,1H,J = 5.1 Hz) m/z (El) : 656 [M+] 製造例33 N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)毗啶基]甲基]-N α -(9_芴基甲氧羰基)-L-白胺醯胺之 合成··
將N-[2-(第三丁基二甲基矽烷氧)乙基]_N-[[2-(3,4,5_三甲 氧苯基)吡啶-4-基]甲基]胺(1.40 g)及N-(9-芴基甲氧羰基 L-白胺酸(1.16 g)以與製造例9同樣之方式處理,得到標題 44 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)~ 1226240 A7 B7 五、發明説明(41 ) 化合物。 產量:2.32 g (93%) 製造例3 4 N-[2-(第三丁基二甲基碎fe氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)外I:啶-4-基]甲基]-L-白胺醯胺之合成: OMe
將Ν·[2-(第三丁基二甲基矽烷氧)乙基]-N_[[2-(3,4,5_三甲 氧苯基)吡啶-4-基]甲基]-Να-(9-芴基甲氧羰基)-L_白胺醯 胺(2.32 g)以與製造例10同樣之方式處理,得到標題化合 物。 產量:1.57 g (96%) 製造例35 ]^-[2-(第三丁基二甲基碎坑氧)乙基]-;^-[[2-(3,4,5-三甲氧苯 基 >比赛;-4-基]甲基]-N α -(2_硝基苯續醯基)-L-白胺酿胺: 裝 訂
線
將N-[2_(第三丁基二甲基秒垸氧)乙基]_ν·[[2_(3,4,5-三甲 __ -45- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1226240 A7 B7 五、發明説明(42 ) 氧苯基)吡啶-4-基]甲基]-L-白胺醯胺(1.57 g)以與製造例4 同樣之方式處理,得到標題化合物。 產量:2.05 g (98%) 製造例36 N-(2_羥乙基)-N_[|>(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-Ν 硝基禾石灵酿基)-L-白胺酿胺之合成:
將N-[2-(第三丁基二甲基矽烷氧)乙基]_Ν·[[243,4,5-三甲 氧苯基)吡啶-4_基]甲基]-Να-(2-硝基苯磺醯基)-L-白胺醯 胺(2·05 g)以與製造例12同樣之方式處理,得到標題化合 物。 產量:1·61 g (93%) 製造例37 (3S)-l_[[2-(3,4,5_三甲氧苯基)吡啶-4-基]甲基]_3·(2-甲基丙 基)-4-(2-硝基苯橫酿基)-2-_基六氫ρ比哜之合成:
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(43 ) 將N-(2-#乙基)_N-[[2_(3,4,5-三甲氧苯基)说啶_4_基]甲 基]-N α -(2-硝基笨磺醯基)_L_白胺醯胺(i 57 g)以與製造例 13同樣之方式處理,得到標題化合物。由於無法完全除去 副生成物,所以將其在未精製下,用於下一反應。 製造例38 (3S)-l-[(2_(3,4,5_三甲氧苯基)β比咬基)甲基]_3_(2-甲基丙 基)-2-酮基六氫峨呼之合成:
將製造例37之混合物之全量以與製造例6同樣之方式處 理’得到標題化合物。 產量·· 689 mg (2階段產率:44%) ^-NMR (400 MHz, CDC13) δ: 0.95 (d, 3Η, J = 6.6 Hz), 〇·98 (d,3H,J = 6·6 Hz),1.60 (ddd,1H,J = 13.7 Hz,9.9 Hz,4 2
Hz),1.71 (br,1H),1.77-1.80 (m,1H),1.95 (ddd,1H,J 二 13.7
Hz,9.9 Hz,4.2 Hz),2.98_3.05 (m,1H),3.15-3.23 (m,2H), 3.35-3.42 (m,1H),3.55 (dd,1H,J = 10.1 Hz, 3.6 Hz),3.90 (s, 3H),3.96 (s,6H),4.63 (d,1H,J = 15·2 Hz),4.67 (d,1H,J = 15.2 Hz),7.09 (dd,1H,J = 5.1 Hz,1.6 Hz),7.21 (s,2H),7·53 (d,1H,J = 0.6 Hz),8.61 (dd,1H,J = 5.0 Hz,0.7 Hz) 實施例8
線
本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1226240 A7 B7 ___—— 五、發明説明(44 ) (3S)-3-(2-甲基丙基)-2-酮基-N,N,-貳[[2-(3,4,5-三甲氧苯基) 吡啶-4-基]甲基]六氫吡畊· 2.5鹽酸鹽之合成:
將(3S)-l_[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]_3_(2-甲 基丙基)-2-酮基六氫吡畊(100 mg)及4-氯甲基-2-(3,4,5-二 甲氧苯基)吡啶(71 mg)以與實施例4同樣之方式反應’得到 為鹽酸鹽之標題化合物。 產量:58 mg (50%) W-NMR (以游離鹼測定,400 MHz,CDC13) δ: 0·90 (d,3H,J = 6.2Hz),0.97(d,3H,J = 6.4Hz),1.78-1.81(m,lH),1.9〇- 2.00 (m,2H),2.63 (dt,1H,J = 13.3 Hz,4.9 Hz), 3.12-3.25 (m, 2H),3.30 (t,1H,J = 5.9 Hz),3.37-3.42 (m,1H),3.64 (d, 1H, j = 14.3 Hz),3.90 (s,6H),3.96 (m,13H),4.50 (d,1H,J = 5.0
Hz),4.86 (d,1H,J = 5.2 Hz),7.12 (d,1H,J = 3.7 Hz),7.21 (d,1H,J = 5.1 Hz),7.22 (s,2H),7.23 (s,2H),7·56 (s,1H), 7.65 (s,1H),8.61 (d,1H, J = 4.9 Hz),8.64 (d,1H,J = 4·7 Hz) m/z (El) : 670 [M+] 製造例39 N-[2-(第三丁基二甲基矽烷氧)乙基]-Ν-[[2_(3,4,5·三甲氧苯 基)毗啶-4·基]甲基]-Να -(9-芴基甲氧羰基)-L-苯丙胺醯胺 -48 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7
之合成
將N-[2-(第三丁基二甲基矽烷氧)乙基]_N_[[2_(3,4,5•三甲 氧苯基)吡啶-4-基]甲基]胺(973 mg)&N-(9_芴基甲氧羰基 L-苯丙胺酸(871 mg)以與製造例9同樣之方式處理,得到標 題化合物。 產量:1.35 g (75%) 製造例40 N-[2_(第三丁基二甲基矽烷氧)乙基气3,4,5_三甲氧苯 基)吡啶-4-基]甲基]-L-苯丙胺醯胺之合成:
將Ν_[2-(第三丁基二甲基矽烷氧)乙基]-Ν_[[2-(3,4,5_三甲 氧苯基 >比啶-4-基]甲基]·Ν α -(9-芴基甲氧羰基)-L-苯丙胺 酿胺(1.35 g)以與製造例1〇同樣之方式處理,得到標題化 合物。 產量:865 mg (89%) 本紙浪尺度適用中國國家襟準(CNS) A4規格(210X297公釐) 1226240 A7 B7 五、發明説明(46 ) 製造例41 N-[2-(第三丁基二甲基矽烷氧)乙基]_Ν-[[2-(3,4,5-三甲氧苯 基)毗啶-4-基]甲基]-Ν α -(2-硝基苯磺醯基)-L-苯丙胺醯胺 之合成:
將N_[2_(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲 氧苯基)吡啶·4-基]甲基]-L·苯丙胺醯胺(865 mg)以與製造例 4同樣之方式處理,得到標題化合物。 產量:1·〇7 g (94%) 製造例42 N-(2-羥乙基)-N-[[2-(3,4,5_三甲氧苯基)吡啶-4-基]甲基]-N j -(2_硝基苯續酿基)-L-苯丙胺酿胺之合成·
將Ν·[2·(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲 氧》苯基比政-4-基]甲基](2 -(2-梢基表^酿基)-L-木丙胺 胺(1.06 g)以與製造例12同樣之方式處理,得到標題化 -50- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(47 ) 合物。 產量:983 mg (理論量) 製造例43 (3S)-3-芊基-l-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]-4-(2-硝基苯磺醯基)-2-酮基六氫吡畊之合成:
將N-(2-羥乙基)-N-[〇(3,4,5-三甲氧苯基)吡啶-2_基]甲 基]-N (2 -(2-硝基苯績酿基)_L-苯丙胺酿胺(921 mg)以與製造 例1 3同樣之方式處理,得到標題化合物。由於無法完全除 去副生成物,所以在未將其精製下,用於下一反應。 製造例44 (3S)-3-芊基-1-[[2-(3,4,5_三甲氧苯基)吡啶_4_基]甲基]-2-酮 基六氫吡畊之合成:
浙製造例43之混合物之全量以與製造例6同樣之方式處 理,得到標題化合物。 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 A7 B7 五、發明説明(48 ) 產量:430 mg (2階段產率:69%) lH-NMR (400 MHz, CDC13) δ: 1.62 (br? 1Η), 2.90-2.96 (m, 2H),3.09-3.17 (m,2H),3.38 (dt,1H,J = 10.9 Hz,4.3 Hz), 3.52 (dd,1H,J = 13.6 Hz,3.4 Hz),3.74 (dd,1H,J = 9.8 Hz, 3.5 Hz),3.90 (s,3H),3.96 (s,6H),4,65 (d,1H,J = 15.2 Hz), 4·70 (d,1H,J = 15.2 Hz),7.05 (dd,1H,J 二 5.1 Hz,1.6 Hz), 7.22 (s,2H),7.25-7.34 (m,5H), 7.54 (s,1H),8.61 (d, 1H,J = 5.1 Hz) 實施例9 (3S)-3-芊基-2-酮基-Ν,Ν·-貳[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]六氫吡畊· 1.5鹽酸鹽之合成:
將(3S)-3_苄基_1-[[2-(3,4,5-三甲氧苯基)吡啶-4-基]甲基]_ 4-(2_硝基苯橫酸基)·2·酮基六氫咐^井(89 mg)及4_氯甲基-2-(3,4,5-三甲氧苯基)吡啶(59 mg)以與實施例4同樣之方式反 應,得到為鹽酸鹽之標題化合物。 產量:102 mg (72%) b-NMR (以游離驗測定,400 MHz,CDC13) δ: 2.52-2.58 (m 1H),3.01 (dt,1H,J = 12·9 Hz),4·5 Hz),3.11-3.13 (m,2H) 3.26 (dd,1H,J = 14.2 Hz,4.3 Hz),3.39 (dd, 1H,J = 14 2 Hz
____ -52- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 A7 _________ B7 五、發明説明(49 ) 5.8 Hz), 3.51 (d, 1H, J - 14.4 Hz), 3.58 (t, 1H, J = 4.8 Hz), 3.90 (s,3H),3·91 (s,3H),3.94 (s,l2H),4.13 (d,1H,J = 14.3 Hz),4.39 (d,1H,J = 15.2 Hz),4.87 (d,1H,J = 15.2 Hz),6.79 (d,1H,J = 4.1 Hz),7.00 (d,1H,J = 4.7 Hz),7.17-7.30 (m, 9H),7.48 (s,1H),7·50 (s,1H),8.53 (d,1H,J = 5.1 Hz), 8.55 (d,1H,J = 5.1 Hz) m/z (El) ·· 704 [M+] 製造例45 N-[2_(第三丁基二甲基矽烷氧)乙基]·ν·[[2-(3,4,5_三甲氧苯 基)喻淀-4-基]甲基]·Να-(9-芴基甲氧羰基)_Νω -三苯甲基_ L·精胺醯胺之合成: OMe
將Ν-[2·(第三丁基二甲.基矽烷氧)乙基]_n_[[2-(3,4,5三甲 氧苯基)u比咬_4_基]甲基]胺(725 mg)及N-(9-芴基甲氧羧基)_ -二本甲基-精胺故(1.〇〇 g)以與製造例9同樣之方式處 理,得到標題化合物。 產量:563 mg (33%) 製造例46 N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5·三甲氧苯 _ 53 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) '' -- !226240 A7 B7 五、發明説明(so ) 基)吡啶-4-基]甲基]-Νω-三苯甲基-L-精胺醯胺之合成··
將Ν-[2·(第三丁基二甲基矽烷氧)乙基]·Ν-[[2-(3,4,5-三甲 氡苯基)吡啶-4-基]甲基]-Να-(9-芴基甲氧羰基三苯甲 基-L_精胺醯胺(563 mg)以與製造例10同樣之方式處理,得 到標題化合物。 產量·· 396 mg (90%) 製造例47 N-[2-(第三丁基二甲基矽烷氧)乙基]-N-[[2-(3,4,5-三甲氧苯 基)毗啶-4-基]甲基]-Να -(2-硝基苯磺醯基)-Νω -三苯甲基-L-精胺醯胺之合成:
將Ν-[2-(第三丁基二甲基矽烷氧)乙基]-Ν-[[2-(3,4,5·三甲 氡苯基)吡啶-4-基]甲基]-Νω-三苯甲基-L-精胺醯胺(396 mg) 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(Μ ) 以與製造例4同樣之方式處理,得到標題化合物。 產量:465 mg (95%) 製造例48 N-(2-羥乙基4,5-三甲氧苯基)吡啶基]甲基]_n α-(2-硝基苯磺醯基三苯甲基-L-精胺醯胺之合成:
將Ν-[2-(第三丁基二甲基矽烷氧)乙基卜仏旧#/,%三甲 氧苯基)峨啶-4-基]甲基]-Να-(2-硝基苯磺醯基)_Νω-三苯 甲基-L_精胺酿胺(465 mg)以與製造例12同樣之方式處理, 得到標題化合物。 產量·· 410 mg (88%) 製造例49 (3 8)-1-[[2-(3,4,5-三甲氧苯基>比啶-4_基]甲基]_4_(2-確基苯 橫酿基)-2-酮基-3-[2-(三苯甲胺羰基)甲基]六氫吡啡之合 成: °
1226240 A7 B7
五、發明説明(52 ) --- 將N_(2_羥乙基)-Ν·[[2-(3,4,5-三甲氧笨基风啶冰基]甲 基]-Να·(2-硝基苯磺醯基)_Νω-三苯甲基吨-精胺醯胺(41〇 mg)以與製造例13同樣之方式處理,得到標題化合物。由 於無法芫全除去副生成物,所以在未將其精製下,用於下 一反應。 製造例5 0 (3S)-l-[[2-(3,4,5-三甲氧苯基)说啶-4-基]甲基]-2-酮基-3·Ι> (三苯甲胺羰基)甲基]六氫吡畊之合成··
PPSrNH 將製造例49之混合物之全量以與製造例6同樣之方式 處理,得到標題化合物。 產量:233 mg (2階段產率:75%) h-NMR (400 MHz,CDC13) δ: 2.74 (br,1H), 2.87-3.08 (m, 5H),3.35-3.39 (m,1H),3.73-3.76 (m,1H),3.89 (s, 3H),3·93 (s,6H),4.45 (dd,1H,J = 15.3 Hz,6.5 Hz),4.72 (dd,1H,J = 15.3 Hz,7.1 Hz),7.03 (d,1H,J = 3.5 Hz),7.18-7.28 (m,18H), 7.47 (s,1H),8.53 (d,1H,J = 4.9 Hz) 製造例5 1 (3 3)-2-酮基-3-[2-(三苯甲胺羰基)甲基]-队>^-貳[[2-(3,4,5-三 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(53 甲氧苯基)吡啶-4-基]甲基]六氫吡畊之合成:
將(3S)-1-[|>(3,4,5_三甲氧苯基)吡啶-4-基]甲基]嗣 基_3_[2-(三苯甲胺羰基)甲基]六氫吡畊(233 mg)及4_氯甲 基-2-(3,4,5-三甲氧苯基)吡啶(104 mg)以與實施例4同樣之 方式反應,得到標題化合物。 產量:292 mg (90%) iH-NMR (400 MHz,CDC13) δ: 2.91 -3.10 (m,3H),3.16 (d J = 13.2 Hz),3.29-3.44 (m,3H),3.51-3.59 (m,1H),3·86·3 % (m,19H), 4.40 (d,1H,J = 13·2 Hz),4.95 (d,1H,J = 15 4 只之) 6.98 (d,1H,J = 4.9 Hz),7.02 (d,1H,J = 4·9 Hz),7·ΐ6、7 % (m,19H),7.45 (s,1H),7.68 (s,1H),7.72 (s,1H),8.47 (d,1Ή J = 5.1 Hz),8.51 (d,1H,J = 4.9 Hz) 實施例10 (3S)-3-胺甲醯甲基_2-酮基_N,N’-貳[[2·(3,4,5_三甲氧笨基) 吡碇-4-基]甲基]六氫吡啡· 2鹽酸鹽之合成:
__-57- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1226240 A7 ___________ B7 五、發明説明(54 )"" - 將(3S)_2_嗣基_3_[2-(三苯甲胺羰基)甲基]_n,n,_貳 (3,4,5-三甲氧苯基)吡啶_4-基]甲基]六氫吡畊(292 mg)溶於 乙酸(2 ml)中,加入三氟乙酸(斗ml)並在8〇。〇下攪拌。減壓 濃縮後,加入氯仿,用飽和碳酸氫鈉水溶液、水及飽和食 鹽水洗淨,用無水硫酸鈉乾燥及減壓濃縮後,將殘餘物用 矽膠管住層析(氯仿··用氨飽和之甲醇=2〇 : υ精製,得到 為鹽酸鹽之標題化合物。 產量:108 mg (51%) 'H-NMR (400 MHz, CDC13) δ: 2.64 (t, 1Η? J = 10.5 Hz), 2.93. 3.00 (m,2H),3·08 (d,1H,J = 11.7 Hz),3.37-3.50 (m,4H), 3.80 (s,3H),3.82 (s,6H),3.83 (s,3H),3.86 (s,6H),4.02 (d, 1H,J = 15.6 Hz),4.09 (d,1H,J = 14.6 Hz),5.50 (d5 1H,卜 15.4 Hz),7.05 (s,2H),7·13 (s,2H),7.18 (d,1H,J = 4.9 Hz) 7.57-7.67 (m,3H),8.53 (d,1H,J = 5.1 Hz),8.82 (d,1H,卜 5.1 Hz) m/z (El) : 671 [M+] 製造例52 N-(9-芴基甲氧羰基)-L-纈草胺醯基(芊基)甘胺酸乙酷之 合成:
C02Et 〇 將N-(9-芴基甲氧羰基)-L-纈草胺酸(1.〇 g)溶於二氯甲燒 (10 ml)及DMTF (0.1 ml)之混合溶媒中,在ot下滴入草酿氣 -58-
1226240
(374 mg),並攪拌30分鐘。在〇t:下將該混合物滴入N_(苄 基)甘胺酸乙酯(587 mg)及三乙胺(477 mg)之二氯甲烷(1〇如) 溶液中。將混合物在室溫攪拌2小時,然後將反應液減壓 濃縮。在殘餘物中加入乙酸乙酯,用水及飽和食鹽水洗淨 及用無水硫酸鈉乾燥後,減壓濃縮。殘餘物用矽膠管柱層 析(正己烷:乙酸乙酯=3 : 1)精製,得到標題化合物。 產量:1.37 g (91%) 製造例53 環-[N-(苄基)甘胺醯基-L-纈草胺醯基]之合成:
將N-(9-芴基甲氧羰基)_L-纈草胺醯基-N_(苄基)甘胺酸乙 酯(1.23 g)溶於六氫吡啶之20%乙腈溶液(12 ml)中, ’ τ 並在室 溫下攪拌30分鐘。將反應液減壓濃縮,加 u敗Cj酷,將 有機層用水及飽和食鹽水洗淨,然後用無水硫酸舞乾燥 減壓濃縮後,將殘餘物用矽膠管柱層析(氯仿:甲1 1)精製,得到標題化合物。 產量:558 mg (95%) h-NMR (400 MHz, CDC13) δ·· 0.88 (d,3H,J =: u、 w 办),1.03 (d,3H,J = 7.2 Hz),2·42-2·49 (m,1H),3·77 (d 1H j 4.45 (br,1H),
Hz),3.86 (d,1H,卜 17.8 Hz),3·93 (t, 1H,J = 2 9 (d,1H,J = 14.3 Hz),4.76 (d,1H,J = 14.4 HZ),6.79 7.26-7.37 (m,5H) -59- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1226240 A7
製造例54 (3S)-1-苄基-3-異丙基-六氫吡畊之合成: 巳》V八 將環-[N-(芊基)甘胺醯基纈草胺醯基](558 mg)溶於 丁1^(2〇1111)中,在0^;下加入氫化鋰鋁(43〇1^),並在氬蒙 氣及1:溫下攪拌12小時。於(TC加入飽和氯化銨水溶液, 然後加入過剩之飽和碳酸氫鈉及用乙酸乙酯萃取。將有機 層用無水硫酸鈉乾燥。減壓濃縮後,將殘餘物用矽膠管柱 層析(氯仿:甲醇=30 : 1)精製,得到標題化合物。 產量:386 mg (78%) b-NMR (400 MHz,CDC13) δ:0·88 (d,3H,J = 6·8 Ηζ),〇·93 9d,3H,J = 6·8 Hz),1.51-1.59 (m,1H),1·78 (br, 2H),1·98 (dt 1H,J = 11.1 Hz,3·1 Hz),2·46-2·50 (m,1H),2·72 (d,1H,J = 1〇·9 Hz),2.85-2.89 (m,2H),2·98 (dt,1H,卜 11.9 Hz,2.7 Hz), 3·44 (d,1H,J = 13.1 Hz),3·56 (d,1H,J = 13.1 Hz), 7.23-7.3 1 (m,5H) 製造例55 (2S)-2-異丙基六氫峨p井之合成··
將(3S)_l•爷基-3-異丙基-六氫P比呼(358 mg)溶於乙酸(i〇 ________-60- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240
ml)中,在氬氣蒙氣下加入1〇%鈀-活性碳(4〇 mg),然後在 氫氣蒙氣及50 C下攪拌4小時。過濾反應液後,將濾液減 壓濃縮’將殘餘物用矽膠管柱層析(氯仿:氨飽和之甲醇 二20 : 1)精製,得到標題化合物。 產量 161 mg (77%) iH-NMR (400 MHz,CDC13) δ: 0.91 (d,3H,卜 6.8 Hz),0.93 (d, 3H? J = 6.6 Hz)? 1.48-1.57 (m? 1H)? 1.75 (br? 2H), 2.31- 2.45 (m,2H),2.67-2.83 (m,2H),2.90 (d,1H,J = 11·5 Hz), 2.99-3.02 (m,2H) 實施例11 (2S)-2·異丙基-N,N’-貳[[2-(3,4,5-三甲氧苯基)吡啶_4-基]甲 基]六氫吡畊· 3鹽酸鹽之合成: 〇Me
將(2S)_2-異丙基六氫吡畊(25 mg)及氯甲基_2-(3,4,5-三 甲氧苯基)吡咬(117 mg)以與實施例1同樣之方式反應,得 到為鹽酸鹽之標題化合物。 產量:129 mg (理論量) 巾一NMR (400 MHz, CDC13) δ: 0.95 (d,3H,J = 6.8 Ηζ),〇·98 (d,3H,J = 6·8 Hz),1.76-1.91 (m,1H),2.14-2.34 (m,4H), 2.62 (d,1H,J = 10.1 Hz),2.76-2.82 (m,2H),3.24 (d,1H,J = • 61 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐)
裝 訂
線 1226240 A7 B7 五、發明説明(58 14.4 Hz), 3.50 (d, 1H, J = 14.1 Hz), 3.62 (d5 1H, J = 14.1 Hz), 3.90 (s,6H),3.96 (s,6H),3.97 (S,6H),417 (d,1H,; = 14 4 HZ),7.2U.27 (m,6H),7.64 (s,1H),7·65 (s,1H),8 58 (d, 1H,J = 4.7 Hz),8.59 (d,1H,4.5 Hz) m/z (El) : 642 [M+] 製造例56 N-(9-芴基甲氧羰基)-L-白胺醯基(苄基)甘胺酸乙酯之合 成:
將N-(9-苟基甲氧羰基)-L-白胺酸(1 3 1幻及义(爷基)甘胺 酸乙酿(783 mg)以與製造例52同樣之方式反應,得到標題 化合物。 產量:1.65 g (84%) 製造例57 環-[N-(苄基)甘胺酿基-L-白胺醯基]之合成:
將N-(9-苟基甲氧羰基)-L-白胺酿基·N_(辛基)甘胺酸 ^9 g)以與製造例53同樣之方式處理,得到標題化: -62- 1226240 A7 B7 五、發明説明(59 ) 產量:775 mg (88%) iH-NMR (400 MHz,CDC13) δ: 0.95 (d,3H,J = 6.5 Hz),0.98 (d,3H,J = 6.5 Hz),1.62-1.67 (m,1H),1.75-1.85 (m,2H), 3·80 (d, 1H,J = 17.4 Hz),3.86 (d,1H,J = 17.2 Hz),4.04 (dt, 1H,J = 6.1 Hz,3.2 Hz),4.54 (d,1H,J = 14.3 Hz),4.65 (d, 1H,J = 14.4 Hz),6.80 (br,1H),7.24-7.37 (m,5H) 製造例58 (3S)-1-芊基-3-(2-甲基丙基)六氫吡畊之合成:
將環-[N·(苄基)甘胺醯基-L-白胺醯基](775 mg)以與製造 例54同樣之方式處理,得到標題化合物。 產量:700 mg (理論量) ^-NMR (400 MHz, CDC13) δ: 0.87 (d, 3Η? J - 6.4 Hz), 0.89 (d,3H,J = 6·6 Hz),1.08-1.26 (m,2H),1.61-1.71 (m,3H), 2.00(dt,lH,J=ll.lHz,3.6Hz),2.73-2.96 (m,5H),3.39-3.58 (m,2H),7.23-7.31 (m,5H) 製造例59 (2S)-2-(2_甲基丙基)六氫吡呼之合成:
本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 A7 -_-_ B7 五、發明説明(6〇 ) 將(3S)-1-苄基-3-(2-甲基丙基)六氫吡畊(7〇〇 mg)以與製 造例5 5同樣之方式處理,得到標題化合物。 產量:308 mg (72%) W-NMR (400 MHz,CDC13) δ: 〇·89 (d,3H,J = 6.6 Hz),0.91 (d,3H,J = 6.6 Hz),1.10-1.23 (m,2H),1.56 (br,2H),1.60-1.69 (m,1H),2·34 (dd,1H,J = U 8 Hz,9.9 Hz),2.64-2.98 (m,6H) 實施例12 (2S)-2-(2-甲基丙基)_N,N、貳[[2_(3,4,5-三甲氧苯基)吡啶-4-基]甲基]六氫吡畊· 3鹽酸鹽之合成:
將(2S)-2_(2_甲基丙基)六氫峨呼(28 mg)及氯甲基 (3,4,5·三甲氧苯基)吨淀(117 mg)以與實施例1同樣之方式 反應,得到鹽酸鹽之標題化合物。 產量:129 mg (99%) 'H-NMR (400 MHz, CDC13) δ: 0.86 (d, 3Η? J = 6.1 Hz), 〇·9〇 (d,3H,J = 6·1 Hz),1.50-1.56 (m,3H),2.25-2.78 (m,7H), 3.39 (d, 1H, J = 14.1 Hz), 3.51 (d, 1H, J = 14.1 Hz), 3.62 (d, 1H,J = 14.1 Hz),3.90 (s,6H),3.97 (br,13H),7.22-7.27 (m, 6H),7.65 (s,2H),8.59 (d,1H,J = 5.3 Hz),8·60 (d,1H,J = -64- ____ 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1226240 A7 B7
5.5 Hz) m/z (El) : 656 [M+] 製造例60 N-(9-苗基甲氧羰基)-L-異白胺醯基(芊基)甘胺酸乙酯之 合成:
FmocHN^^Y^00^1 〇 將N-(9-苗基甲氧羰基)-L-異白胺酸(1 36幻及^(苄基)甘
胺酸乙醋(770 mg)以與製造例52同樣之方式處理,得到標 題化合物。 T 產量:1.73 g (85%) 製造例61 環-[N-(芊基)甘胺酸基-L-異白胺酶基]之合成:
將N-(9-%基甲乳幾基)-L -異白胺酿基_N-(爷基)甘胺酸乙 酯(1.63 g)以與製造例53同樣之方式反應,得到標題化合 物。 產量:973 mg (包含不純物) iH-NMR (400 MHz,CDC13) δ: 0.90 (t,3H,J = 7.4 Ηζ),ι·00 (d,3H,J = 7.2 Hz),1·14_1·25 (m,1H),1.35.1.43 (m,1H) 2.09-2.15 (m,1H),3.77 (d,1H,J = 18.0 Hz),3.85 (d,1H J、 ___·65-__ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) " ---——- 1226240 A7 B7
立、發明説明(62 ) --- 17.8 Hz)? 3.95-3.97 (m? iH)> 4.51 (d, 1H, J = 14.3 Hz)? 4.69 (d, 1H, J - 14.4 Hz), 7.25-7.36 (m, 6H) 製造例62 (3S)_1-芊基-3-(卜甲基丙基)六氫吡畊之合成:
將環-[N-(芊基)甘胺醯基-L-異白胺醯基](973 mg,包本 不純物)以與製造例54同樣之方式處理,得到標題化I 物。 虞量:506 mg (2階段產率:71%) lH-NMR (400 MHz, CDC13) δ: 0.87 (d, 3H, J = 6.8 Hz), 0.87 (t9 3H, J = 7.4 Hz), 1.13-1.20 (m, 1H)? 1.30-1.41 (m, m), 1.46-1.70 (br,2H),1.78 (t,1H,J = 10·4 Hz), 1.97 (dd,1H,J < 11.1 Hz,3.3 Hz),2.57-2.62 (m,1H),2.68-2.76 (m,1H), 2.82_2·89 (m,2H),2.97 (dt,1H,J = 11·9 Hz,2·7 Hz),3.44 (d, lH,J = 13·1 Hz),3.56 (d,1H,J = 13.1 Hz),7·24-7·31 (5H,m) 製造例63 , (2S)-2_(1-甲基丙基)六氫p比啡之合成:
將(3S)-1-芊基-3-(1-甲基丙基)六氫吡畊(5〇6 mg)以與製 造例55同樣之方式處理,得到標題化合物。
1226240 A7 B7 五、發明説明(63 ) 產量:202 mg (65%) iH-NMR (400 MHz, CDC13) δ: 0.87 (d, 3H,J = 6.8 Ηζ),0·89 (t,3H,J = 7.4 Hz),1.12-1.23 (m,1H),1.29-1.32 (m,1H), 1.44-1.52 (m,1H),1.64 (br,2H),2.40-2.48 (m,2H),2.69 (dt, 1H,J = 11.3 Hz,2.9 Hz),2.80 (dt,1H,J = 11.3 Hz,2.7 Hz), 2.89 (d,1H,J = 11.5 Hz),2.94-3.01 (m,2H) 實施例13 (2S)_2_(1·甲基丙基)-N,N’-貳[[2_(3,4,5-三甲氧苯基)吡啶-4_ 基]甲基]六氫吡畊· 3鹽酸鹽之合成:
將(2S)-2-(l-甲基丙基)六氫吡畊(28 mg)及4-氯甲基2 (3,4,5·三甲氧苯基)吡啶(117 mg)以與實施例1同祥 俅 < 万式 反應,得到為鹽酸鹽之標題化合物。 產量:117 mg (90%) 4-NMR (400 MHz, CDC13) δ: 0.93 (t,3H,J 二 7.8 μ、 ηζ), 0.95 (d,3Η,J = 6.6 Ηζ),1.16-1.25 (m,1Η),1·35_1 41 γ (m,1Η) 1.90-2.05 (m,1H),2.11-2.32 (m,3H),2.45 (br,1H、〇 ^ ’ 厶65 (d, 1H,J = 10.3 Hz),2.74-2.79 (m,2H),3.17 (d,1H,J >
Hz) 90 (s5 3.52 (d,1H,J = 14.1 Hz),3.60 (d,1H,J = 14.1 H2),3
Hz), 6H),3.96 (s,6H),3.97 (s,6H),4.19 (d,1H,J = l4 2 -67-
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(64 ) 7.21-7.27 (m,6H),7.65 (s,2H),8.58 (d,1H,J = 3·1 Hz),8.60 (d,1H,J = 3.1 Hz) m/z (El) : 656 [M+] 試驗例1 (細胞接著抑制作用) 參考羅絲(Ross)等人 i*&(J.Biol.Chem.,267,8537-85 43 (1992))而進行。亦即,將來自人類臍帶靜脈之血管 内皮細胞(HUVEC)在48穴平皿中培養至匯集後,添加TNF α 。添加5小時後,添加用ΡΚΗ2 (大日本製藥公司製)螢光 標識之U937 (為來自人類單核球及組織球之細胞),每穴 添加1 X 106個細胞。於室溫靜置1小時後,洗出未接著之 U937,用1% Triton Χ-100溶解細胞,然後測定殘存之螢光 強度(激起波長485 nm,測定波長530 nm)。HUVEC係在 EGM-2 (三光純藥)中培養,U937係在含10%FCS之 RPMI1640中培養。對於HUVEC之藥物之添加係在TNFa添 加時進行;對於U937則是在細胞接著試驗之24小時之前進 行。抑制活性,用[100-(C-B)/(A-B) X 100 (%)]計算出,其 中A=(未添加藥物時,U937對於TNF α所刺激之HUVEC之 接著細胞數),B=(未添加藥物時,U937對於無刺激之 HUVEC之接著細胞數)以及C=(添加藥物時,U937對於 TNF α所刺激之HUVEC之接著細胞數)。將其之結果示於 表1中。同時評價做為對照化合物之特開平9-143075號公 報之試驗化合物1及特開平1 1-92382號公報之狄拉在普 (dilazep) 〇 -68- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1226240 A7 B7 五、發明説明(65 ) 表1 實施例 抑制率(%) 1 // M TNF α 刺激 10/zM TNFa 刺激 1 76 78 2 42 64 3 34 90 4 60 79 5 51 85 6 63 77 7 51 70 8 63 79 9 38 86 試驗化合物1 5 51 Dilazep 12 25
裝 下文顯示具體的製劑例。 製劑例1 (膠囊劑) (2S)-2-異丙基·2_酮基-Ν,Ν^貳[[2-(3,4,5-三甲氧苯基)吡啶· 訂
4-基]甲基]六氫吡畊· 1.5鹽酸鹽 30 mg 微結晶纖維素 3 0 mg 乳糖 30 mg 硬脂酸鎂 3 mg 全量 93 mg 將上述成分藉由一般方法混合後,充填至明膠膠囊中, 得到膠囊劑。 製劑例2 (錠劑) -69- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1226240 A7 B7 五、發明説明(66 苯基)吡淀-30 mg 44 mg 5.6 mg 0.4 mg 20 mg 100 mg (2S)_2-異丙基-2-酮基_N,N,-貳[[2_(3,4,5-三甲氧 4-基]甲基]六氫ττ比畊· ι·5鹽酸鹽 澱粉 澱粉(漿糊用澱粉) 硬脂酸鍰 羧甲基纖維素鈣 全量 將上述成分藉由一般方法混合後,得到錠劑 製劑例3 (注射劑) 將(2S)-2-異丙基-2-酮基·N,N,貳[[2_(3,4,5-三甲氧苯基) 吡啶-4-基]甲基]六氫吡畊· 15鹽酸鹽(1〇〇 mg)及氯化鈉 (900 mg)於约80 ml之注射用蒸館水中,繼而在得到之溶 液中加入注射用蒸餾水,以使總量成為1〇〇 ml。將其無菌 過濾及分注於10支遮光安瓿中後,密封,得到無菌之注射 劑。 產業上之利用可能性 本發明化合物(1)具有優異的細胞接著及細胞浸潤之抑 制作用,在過敏、氣喘、風濕症、動脈硬化症及炎症等之 預防或治療上有用。 -70-
Claims (1)
12262)4〇4338號專利申請案 中文申請專利範圍替換本(93年6月)
•一種通式(1)代表之六氫吡呼化合物、其之酸加成鹽或彼 等之水合物·· 〇Mc
R1 N ⑴
[式中,X表示-CH2-、·C(0)_4_CH(CH3) ;…表示氫原 子或基;以及r2表示氫原子、燒基、經基_ 2· CA垸基、«_Cl_C0燒基、胺甲醯基_Ci_c6燒基]。 種細胞接者及/或細胎泽、、卩EJ 2丨J 4 —、 尺、田腮A潤引起(疾病之治療用之醫藥 組合物’其含有如申g杳直-ill 1^· ^ 1 ·Τ2Γ 、 j專利範圍罘1項之六氫吡畊化合 物、其之酸加成鹽或彼菩士 k入 又仮寺义水合物以做為有效成分,其 中該疾病為從過敏、齑唑、力P ^ 虱而火症、風濕症及動脈硬化症 中選出之疾病。 3 -種細胞接著及/或細胞浸潤引起之疾病之治療用之醫藥 組合物、彳含有如申請專利範圍第1項之六氫t井化合 物、其之酸加成鹽或彼菩乏k人 、域寺《水合物、以及醫藥上容許之 載肖豆,/、中邊疾病為從過敏、^ , i 双風^而、炎症、風濕症及動 脈硬化症中選出之疾病。 O:\79\79328-930624.doc
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EP1400521A1 (en) | 2004-03-24 |
EP1400521B1 (en) | 2007-11-07 |
ES2295350T3 (es) | 2008-04-16 |
JP4220897B2 (ja) | 2009-02-04 |
CA2451562C (en) | 2010-02-09 |
WO2003002554A1 (fr) | 2003-01-09 |
ATE377596T1 (de) | 2007-11-15 |
CN1309720C (zh) | 2007-04-11 |
EP1400521A4 (en) | 2005-04-06 |
US6432957B1 (en) | 2002-08-13 |
KR100878416B1 (ko) | 2009-01-13 |
DE60223373D1 (de) | 2007-12-20 |
DE60223373T2 (de) | 2008-02-21 |
KR20040015739A (ko) | 2004-02-19 |
CN1520408A (zh) | 2004-08-11 |
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