JP2004307440A - 2-amino-1,3-propanediol derivatives and their addition salts - Google Patents
2-amino-1,3-propanediol derivatives and their addition salts Download PDFInfo
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- JP2004307440A JP2004307440A JP2003106727A JP2003106727A JP2004307440A JP 2004307440 A JP2004307440 A JP 2004307440A JP 2003106727 A JP2003106727 A JP 2003106727A JP 2003106727 A JP2003106727 A JP 2003106727A JP 2004307440 A JP2004307440 A JP 2004307440A
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- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical class OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 150000003839 salts Chemical class 0.000 title claims description 15
- BYNCLFJFGOOQTD-UHFFFAOYSA-N 2-amino-2-[3-[4-(1,3-benzothiazol-2-ylamino)phenyl]propyl]propane-1,3-diol Chemical compound C1=CC(CCCC(CO)(CO)N)=CC=C1NC1=NC2=CC=CC=C2S1 BYNCLFJFGOOQTD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 156
- -1 2-amino-2- [3- [4- (quinolin-2-ylamino) phenyl] propyl] -1,3-propanediol Chemical compound 0.000 claims description 58
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 239000003018 immunosuppressive agent Substances 0.000 claims description 24
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 230000001861 immunosuppressant effect Effects 0.000 claims description 16
- 229910052727 yttrium Inorganic materials 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 7
- 238000002054 transplantation Methods 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000355 1,3-benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 238000010322 bone marrow transplantation Methods 0.000 claims description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims 4
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims 1
- 230000003449 preventive effect Effects 0.000 claims 1
- 229940043274 prophylactic drug Drugs 0.000 claims 1
- 229940126585 therapeutic drug Drugs 0.000 claims 1
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 6
- 206010062016 Immunosuppression Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 105
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000007810 chemical reaction solvent Substances 0.000 description 41
- 230000015572 biosynthetic process Effects 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
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- 239000002904 solvent Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000010898 silica gel chromatography Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 0 CC(C)(C)OC(NC(*)(CO)[In](C)C)=O Chemical compound CC(C)(C)OC(NC(*)(CO)[In](C)C)=O 0.000 description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 17
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 14
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 12
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo(3.3.1)nonane Chemical compound C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
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- 238000001816 cooling Methods 0.000 description 10
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- 229940098779 methanesulfonic acid Drugs 0.000 description 8
- 150000007522 mineralic acids Chemical class 0.000 description 8
- 150000007524 organic acids Chemical class 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 239000011698 potassium fluoride Substances 0.000 description 7
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 239000011591 potassium Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
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- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
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- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 5
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- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 5
- 229910000105 potassium hydride Inorganic materials 0.000 description 5
- LOTKRQAVGJMPNV-UHFFFAOYSA-N 1-fluoro-2,4-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C([N+]([O-])=O)=C1 LOTKRQAVGJMPNV-UHFFFAOYSA-N 0.000 description 4
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
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- 125000006850 spacer group Chemical group 0.000 description 3
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- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
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- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
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- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
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- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
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- 239000011521 glass Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、免疫抑制剤として有用な２‐アミノ−１，３‐プロパンジオール誘導体とその付加塩並びにその水和物に関する。
【０００２】
【従来の技術】
【特許文献１】ＷＯ９４／０８９４３号パンフレット
【特許文献２】特開平９−２５７９６０２号公報
【特許文献３】ＷＯ０２／０６２６８号パンフレット
【特許文献４】特開平２００２−５３５７５号公報
【特許文献５】特開平２００２−１６７３８２号公報
【特許文献６】特開平２００２−３１６９８５号公報
【０００３】
免疫抑制剤は関節リウマチ、腎炎、変形性関節炎、全身性エリテマトーデス等の自己免疫疾患や炎症性腸疾患などの慢性炎症性疾患、喘息、皮膚炎などのアレルギー疾患の治療薬として多方面に利用されている。特に、医療技術の進歩に伴い、組織や臓器等の移植手術が数多く実施されるようになってきた近年の医療現場においては、移植後の拒絶反応をいかにうまくコントロールすることができるかが移植の成否を握っており、この領域においても免疫抑制剤は大変重要な役割を果たしている。
【０００４】
臓器移植においては、アザチオプリンやミコフェノール酸モフェチルに代表される代謝拮抗剤、シクロスポリンＡやタクロリムスに代表されるカルシニューリン阻害剤、プレドニゾロンに代表される副腎皮質ホルモン剤が用いられている。しかしながら、これらの薬剤は効果が不十分であったり、また腎障害などの重篤な副作用を回避するために薬物の血中濃度モニタリングが必須とされているものもあり、その効果や副作用の点で必ずしも満足のできるものではない。
【０００５】
さらに、免疫抑制剤の副作用を軽減し十分な免疫抑制作用を得るために、作用機序の異なる複数の薬剤を使用する多剤併用療法が一般的であり、前述した免疫抑制剤とは異なる作用機序を持つ新しいタイプの薬剤の開発も望まれている。
【０００６】
本発明者らはこのような課題を解決するために、２‐アミノ‐１，３‐プロパンジオール誘導体に着目し、新しいタイプの免疫抑制剤の探索を行った。
【０００７】
免疫抑制剤として２‐アミノ‐１，３‐プロパンジオール誘導体が
【特許文献１】、
【特許文献２】に開示されているが、本発明の特徴であるアミノ基、アミド基及びメチレン鎖などのスペーサーを用い二つの芳香環を連結させた２‐アミノ‐１，３‐プロパンジオール誘導体が優れた免疫抑制効果を示すことは知られていなかった。また、
【特許文献３】、
【特許文献４】、
【特許文献５】、
【特許文献６】に複素環を連結させた２−アミノ−エタノール誘導体が免疫抑制作用を示すことが開示されているが、本出願化合物とは構造を異にするものである。
【０００８】
【発明が解決しようとする課題】
本発明が解決しようとする課題は、優れた免疫抑制作用を有し、かつ副作用の少ない２‐アミノ‐１，３‐プロパンジオール誘導体を提供することにある。
【０００９】
【課題を解決するための手段】
本発明者らは、代謝拮抗剤やカルシニューリン阻害剤とは作用機序を異にする免疫抑制剤について鋭意研究を重ねた結果、これまでに知られている免疫抑制剤とは構造を異にした新規な２‐アミノ‐１，３‐プロパンジオール誘導体、特にアミノ基、アミド基及びメチレン鎖などのスペーサーを用い二つの芳香環を連結させた２‐アミノ‐１，３‐プロパンジオール誘導体が強力な免疫抑制作用を有することを見出し、本発明を完成した。
【００１０】
すなわち本発明は、一般式（１）
【００１１】
【化７】
［式中、Ａｒは置換基を有しても良いフェニル基、置換基を有しても良いベンゾチアゾール基、置換基を有しても良いチアゾール基、ベンゾオキサゾール基、ナフチル基、置換基を有しても良いベンズイミダゾール基、置換基を有しても良いピリミジル基、キノリニル基、イソキノリニル基、置換基を有しても良いチエノピリミジル基又はチアゾロピリジニル基を示し、
Ｘは、ＮＲ１（Ｒ１は水素原子あるいは炭素数１〜４の低級アルキル基を示す）、ＣＨ２ＮＨ、ＮＨＣＨ２、ＣＯＮＨ、ＮＨＣＯ、−（ＣＨ２）ｍ−（ｍは０または１を示す）又はＣＯを示し、
Ｙは炭素原子又は酸素原子を示し、
ｎは０〜３の整数を示す。］で表されることを特徴とする２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とする免疫抑制剤である。
【００１３】
更に詳しくは、一般式（１ａ）
【００１４】
【化８】
［式中、Ｒ２は水素原子、炭素数１〜４の低級アルキル基、トリフルオロメチル基、炭素数１〜７の低級アルコキシ基、ヒドロキシ基、炭素数１〜７の低級アルコキシメチル基又は置換基を有しても良いベンジルオキシ基を示し、Ｙ及びｎは前記定義に同じ］で表されることを特徴とする２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物、及び一般式（１ｂ）
【００１６】
【化９】
［式中、Ｙ及びｎは前記定義に同じ］
で表されることを特徴とする請求項１に記載の２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とする免疫抑制剤である。
【００１８】
本発明における上記一般式（１）、一般式（１ａ）及び一般式（１ｂ）は新規化合物である。
【００１９】
本発明の好ましい化合物として、
１） ２−アミノ‐２‐［３‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール、
２） ２−アミノ‐２‐［３‐［４‐（キノリン−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール、
３） ２−アミノ−２−［３−［４−（３，５−ビストリフルオロメチルフェニルアミノ）フェニル］プロピル］−１，３−プロパンジオール、
４） ２−アミノ−２−（３−［４−［４−（４−クロロフェニル）チアゾール−２−イルアミノ］フェニル］プロピル）−１，３−プロパンジオール、
５） ２−アミノ‐２‐［３‐［４‐（５−ヘプチルオキシメチルベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール
又は
６） ２−アミノ‐２‐［２‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］エチル］‐１，３‐プロパンジオールである請求項１記載の２−アミノ−１、３−プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物を挙げることができる。
【００２０】
【発明の実施の形態】
以下、本発明を詳細に説明する。
【００２１】
本発明における一般式（１）で表される化合物の薬理学的に許容される塩には、塩酸塩、臭化水素酸塩、酢酸塩、トリフルオロ酢酸塩、メタンスルホン酸塩、クエン酸塩、酒石酸塩のような酸付加塩が挙げられる。
【００２２】
また、本発明の一般式（１）において、「置換基を有しても良いフェニル基」、「置換基を有しても良いベンゾチアゾール基」、「置換基を有しても良いチアゾール基」、「置換基を有しても良いピリミジル基」、「置換基を有しても良いチエノピリミジル基」、「置換基を有しても良いベンズイミダゾール基」とは、芳香環上の任意の位置にフッ素原子、塩素原子、臭素原子、ヨウ素原子などのハロゲン原子、トリフルオロメチル基、炭素数１〜４の低級アルキル基、炭素数１〜７の低級アルコキシ基、炭素数１〜７の低級アルコキシメチル基、水酸基、置換基を有しても良いベンジル基、ジメチルアミノ基を有するものが挙げられる。「炭素数１〜４の低級アルキル基」とは、例えばメチル、エチル、プロピル、イソプロピル、ブチル、ｔ−ブチルなどの直鎖もしくは分岐した炭素数１〜４の炭化水素が挙げられる。「炭素数１〜７の低級アルコキシ基」、「炭素数１〜７の低級アルコキシメチル基」などの「低級アルキル基」とは、例えばメチル、エチル、プロピル、イソプロピル、ブチル、ｔ−ブチル、ペンチル、ヘキシル、ヘプチルなどの直鎖もしくは分岐した炭素数１〜７の炭化水素が挙げられる。「置換基を有しても良いベンジル基」とは、ベンゼン環上の任意の位置にフッ素原子、塩素原子、臭素原子、ヨウ素原子などのハロゲン原子、トリフルオロメチル基を有するものが挙げられる。
【００２３】
本発明によれば、上記一般式（１）で表される化合物は例えば以下に示すような経路により製造することができる。
【００２４】
【化１０】
合成経路１で一般式（３）
【００２６】
【化１１】
［式中、Ｒ３は炭素数１〜４の低級アルキル基を、Ｂｏｃはｔ−ブトキシカルボニル基を示し、Ａｒ、Ｘ、Ｙおよびｎは前述の通り］で表される化合物は、一般式（２）
【００２８】
【化１２】
［式中、Ｚは塩素原子、臭素原子又はヨウ素原子を示し、Ａｒ、Ｘ、Ｙ及びｎは前述の通り］で表される化合物と一般式（５）
【００３０】
【化１３】
［式中、Ｒ３及びＢｏｃは前述の通り］で表される化合物を塩基存在下作用させることによって製造することができる（工程Ａ）。
【００３２】
反応はメタノール、エタノール、１，４−ジオキサン、ジメチルスルホキシド（ＤＭＳＯ）、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、テトラヒドロフラン（ＴＨＦ）などを反応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシドなどの無機塩基の存在下、反応温度としては０℃〜加熱還流下にて、好適には８０℃〜１００℃にて行うことができる。
【００３３】
合成経路１で一般式（４）
【００３４】
【化１４】
［式中、Ａｒ、Ｘ、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（３）で表される化合物を還元することによって製造することができる（工程Ｂ）。
【００３６】
反応は、ボラン（ＢＨ３）や９−ボラビシクロ［３．３．１］ノナン（９−ＢＢＮ）のようなアルキルボラン誘導体、ジイソプロピルアルミニウムヒドリド（ｉＢｕ２ＡｌＨ）、水素化ホウ素ナトリウム（ＮａＢＨ４）、水素化アルミニウムリチウム（ＬｉＡｌＨ４）等の金属水素錯化合物、好ましくは水素化ホウ素リチウム（ＬｉＢＨ４）を用い、反応溶媒としてはＴＨＦやエタノール、メタノールなどを用い、反応温度は−７８℃〜加熱還流下、好適には常温下にて行うことができる。
【００３７】
合成経路１で一般式（１）
【００３８】
【化１５】
［式中、Ａｒ、Ｘ、Ｙ及びｎは前述の通り］で表される化合物は、一般式（４）で表される化合物を酸分解することによって製造することができる（工程Ｃ）。
【００４０】
反応は、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸などの無機酸又は有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチルなどの有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【００４１】
一般式（１）の化合物のうちＸがＮＨである化合物、すなわち一般式（６）
【００４２】
【化１６】
［式中、Ａｒ、Ｙ及びｎは前述の通り］で表される化合物は下記の合成経路２−１あるいは２−２によっても製造することができる。
【００４４】
【化１７】
合成経路２−１で一般式（８）
【００４６】
【化１８】
［式中、Ｃｂｚはベンジルオキシカルボニル基を示し、Ｒ３、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（７）
【００４８】
【化１９】
［式中、Ｚは塩素原子、臭素原子及びヨウ素原子を示し、Ｙ、Ｃｂｚ及びｎは前述の通り］で表される化合物と一般式（５）で表される化合物を塩基存在下作用させることによって製造することができる（工程Ｄ）。
【００５０】
反応はメタノール、エタノール、１，４−ジオキサン、ＤＭＳＯ、ＤＭＦ、ＴＨＦなどを反応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシドなどの無機塩基の存在下、反応温度としては０℃〜加熱還流下にて、好適には８０℃〜１００℃にて行うことができる。
【００５１】
合成経路２−１で一般式（９）
【００５２】
【化２０】
［式中、Ｙ、Ｃｂｚ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、上記一般式（８）で表される化合物を還元することによって製造することができる（工程Ｅ）。
【００５４】
反応は、ＢＨ３や９−ＢＢＮのようなアルキルボラン誘導体、ｉＢｕ２ＡｌＨ、ＮａＢＨ４、ＬｉＡｌＨ４等の金属水素錯化合物、好ましくはＬｉＢＨ４を用い、反応溶媒としてはＴＨＦやエタノール、メタノールなどを用い、反応温度は−７８℃〜加熱還流下、好適には常温下にて行うことができる。
【００５５】
合成経路２−１で一般式（１０）
【００５６】
【化２１】
［式中、Ｒ４、Ｒ５は同一または異なって炭素数１〜４の低級アルキル基を示し、Ｙ、Ｂｏｃ、Ｃｂｚ、及びｎは前述の通り］で表される化合物は、一般式（９）で表される化合物に一般式（１８）
【００５８】
【化２２】
［式中、Ｒ６は塩素原子又はトリフルオロメタンスルホニルオキシ基を示し、Ｒ４、Ｒ５は前述の通り］で表される化合物を作用させることによって製造することができる（工程Ｆ）。
【００６０】
反応は、トリエチルアミン、ピリジン、２，６−ルチジン、イミダゾールのような有機塩基の存在下、反応溶媒としてはＤＭＦ、ＴＨＦ、塩化メチレン、クロロホルム、アセトニトリルを用い、反応温度は０℃〜１００℃にて行うことができる。
【００６１】
合成経路２−１で一般式（１１）
【００６２】
【化２３】
［式中、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（１０）を接触還元することによって製造することができる（工程Ｇ）。
【００６４】
反応は、パラジウム炭素、ラネーニッケル、酸化白金等の金属触媒存在下、反応溶媒としては、メタノール、エタノール、ＤＭＦ等を用い、反応温度は０℃〜８０℃にて水素ガス気流下行うことができる。
【００６５】
合成経路２−１で一般式（１２）
【００６６】
【化２４】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（１１）で表される化合物に一般式（１９）
Ａｒ−Ｚ （１９）
［式中、Ａｒ、Ｚは前述の通り］で表される化合物、あるいは一般式（２０）
Ａｒ−Ｂ（ＯＨ）２ （２０）
を作用させることによって製造することができる（工程Ｈ）。
【００６８】
一般式（１１）で表される化合物と一般式（１９）で表される化合物との反応は、ピリジニウムパラトルエンスルホン酸等の酸触媒存在下、無溶媒あるいはＤＭＦ、Ｎ，Ｎ−ジメチルイミダゾリジノンを反応溶媒として用い、反応温度は常温〜１６０℃にて行うことができる。
【００６９】
また、一般式（２０）で表される化合物との反応は、無水酢酸銅（ＩＩ）を用い、トリエチルアミン、ピリジン等の有機塩基存在下、塩化メチレン、クロロホルム等を反応溶媒に用い、反応温度は０℃〜常温にて行うことができる。
【００７０】
合成経路２−１で一般式（６）
【００７１】
【化２５】
［式中、Ａｒ、Ｙ及びｎは前述の通り］で表される化合物は、一般式（１２）で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｉ）。
【００７３】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜常温下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【００７４】
合成経路２−２で一般式（１４）
【００７５】
【化２６】
［式中、Ｒ３、Ｙ、Ｂｏｃおよびｎは前述の通り］で表される化合物は、一般式（１３）
【００７７】
【化２７】
［式中、Ｙ、Ｚ及びｎは前述の通り］で表される化合物と一般式（２１）
【００７９】
【化２８】
［式中、Ａｃはアセチル基を示し、Ｒ３は前述の通り］で表される化合物を塩基存在下作用させることによって製造することができる（工程Ｊ）。
【００８１】
反応はメタノール、エタノール、１，４−ジオキサン、ＤＭＳＯ、ＤＭＦ、ＴＨＦなどを反応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシドなどの無機塩基の存在下、反応温度としては０℃〜加熱還流下にて、好適には８０℃〜１００℃にて行うことができる。
【００８２】
反応経路２−２で一般式（１５）
【００８３】
【化２９】
［式中、Ｒ３、Ｙ、Ａｃ及びｎは前述の通り］で表される化合物は、一般式（１４）を還元することによって製造することができる（工程Ｋ）。
【００８５】
反応は、パラジウム炭素、ラネーニッケル、酸化白金等の金属触媒存在下、反応溶媒としては、メタノール、エタノール、ＤＭＦ等を用い、反応温度は０℃〜８０℃にて水素ガス気流下行うことができる。
【００８６】
反応経路２−２で一般式（１６）
【００８７】
【化３０】
［式中、Ａｒ、Ｒ３、Ｙ、Ａｃ及びｎは前述の通り］で表される化合物は、一般式（１５）で表される化合物に一般式（１９）で表される化合物、あるいは一般式（２０）で表される化合物を作用させることによって製造することができる（工程Ｌ）。
【００８９】
一般式（１５）で表される化合物と一般式（１９）で表される化合物との反応は、ピリジニウムパラトルエンスルホン酸等の酸触媒存在下、無溶媒あるいはＤＭＦ、Ｎ，Ｎ−ジメチルイミダゾリジノンを反応溶媒として用い、反応温度は常温〜１６０℃にて行うことができる。
【００９０】
また、一般式（２０）で表される化合物との反応は、無水酢酸銅（ＩＩ）を用い、トリエチルアミン、ピリジン等の有機塩基存在下、塩化メチレン、クロロホルム等を反応溶媒に用い、反応温度は０℃〜常温にて行うことができる。
【００９１】
合成経路２−２で一般式（１７）
【００９２】
【化３１】
［式中、Ａｒ、Ｙ、Ａｃ及びｎは前述の通り］で表される化合物は、一般式（１６）で表される化合物を還元することによって製造することができる（工程Ｍ）。
【００９４】
反応は、ＢＨ３や９−ＢＢＮのようなアルキルボラン誘導体、ｉＢｕ２ＡｌＨ、ＮａＢＨ４、ＬｉＡｌＨ４等の金属水素錯化合物、好ましくはＬｉＢＨ４を用い、反応溶媒としてはＴＨＦやエタノール、メタノールなどを用い、反応温度は−７８℃〜加熱還流下、好適には常温下にて行うことができる。
【００９５】
合成経路２−２で一般式（６）
【００９６】
【化３２】
［式中、Ａｒ、Ｙ及びｎは前述の通り］で表される化合物は、一般式（１７）で表される化合物をアルカリ加水分解することによって製造することができる（工程Ｎ）。
【００９８】
反応は、溶媒として水、メタノール、エタノール、ＴＨＦ、ＤＭＦを用い、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸カリウム等のアルカリ存在下で、反応温度としては０℃〜１００℃で行うことができる。
【００９９】
一般式（１）の化合物のうちＡｒが４−置換チアゾールでＸがＮＨである化合物、すなわち一般式（２２）
【０１００】
【化３３】
［式中、Ｒ７は炭素数１〜４の低級アルキル基又は置換されていても良いフェニル基を示し、Ｙ及びｎは前述の通り］で表される化合物は、下記の合成経路３−１によっても製造することができる。
【０１０２】
【化３４】
合成経路３−１で一般式（２３）
【０１０４】
【化３５】
［式中、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、前述一般式（１１）で表される化合物に、ベンゾイルイソチオシアネートを作用させることによって製造することができる（工程Ｏ）。
【０１０６】
反応は、アセトン、塩化メチレン、クロロホルム、ベンゼン等を反応溶媒に用い、反応温度としては０℃〜常温下にて行うことができる。
【０１０７】
合成経路３−１で一般式（２４）
【０１０８】
【化３６】
［式中、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（２３）で表される化合物を塩基で分解することによって製造することができる（工程Ｐ）。
【０１１０】
反応は、アンモニア、水酸化ナトリウム、水酸化カリウム等の水、メタノール、エタノール、ＴＨＦ等の溶液中で、反応温度としては０℃〜加熱還流下にて行うことができる。
【０１１１】
合成経路３−１で一般式（２５）
【０１１２】
【化３７】
［式中、Ｒ４、Ｒ５、Ｒ７、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（２４）で表される化合物に一般式（２６）
【０１１４】
【化３８】
［式中、Ｒ７及びＺは前述の通り］で表される化合物を作用させることにより製造することができる（工程Ｑ）。
【０１１６】
反応は、無水硫酸マグネシウム、無水硫酸ナトリウム等の脱水剤存在下、反応溶媒としてはアセトン、ＴＨＦ等を用い、反応温度としては常温〜加熱還流下にて行うことができる。
【０１１７】
合成経路３−１で一般式（２２）
【０１１８】
【化３９】
［式中、Ｒ７、Ｙ及びｎは前述の通り］で表される化合物は、一般式（２５）で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｒ）。
【０１２０】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜常温下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下にて行うことができる。
【０１２１】
一般式（１）の化合物のうちＡｒがイソキノリンでＸがＮＨである化合物、すなわち一般式（２７）
【０１２２】
【化４０】
［式中、Ｙ及びｎは前述の通り］で表される化合物は下記の合成経路３−２によっても製造することができる。
【０１２４】
【化４１】
合成経路３−２で一般式（２８）
【０１２６】
【化４２】
［式中、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（１１）で表される化合物に下記に示す化合物（２９）を反応させることによって製造することができる（工程Ｓ）。
【０１２８】
【化４３】
化合物（２９）との反応は、触媒量のトリフルオロ酢酸存在下、反応溶媒としてメタノール、エタノール等を用い、反応温度は常温〜加熱還流下にて行うことができる。
【０１３０】
合成経路３−２で一般式（２７）
【０１３１】
【化４４】
［式中、Ｒ７、Ｙ及びｎは前述の通り］で表される化合物は、一般式（２８）で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｔ）。
【０１３３】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜常温下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【０１３４】
一般式（１）でＸがＣＨ２ＮＨあるいはＣＯＮＨである化合物、すなわち一般式（３０）
【０１３５】
【化４５】
［式中、ｋは０又は１を示し、Ａｒ、Ｙ及びｎは前述の通り］で表される化合物は、下記に示す合成経路４によっても製造できる。
【０１３７】
【化４６】
合成経路４で一般式（３１）
【０１３９】
【化４７】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ、ｋ及びｎは前述の通り］で表される化合物は、前述一般式（１１）で表される化合物に一般式（３２）
【０１４１】
ＡｒＣＨＯ （３２）
［式中、Ａｒは前述の通り］で表される化合物、あるいは一般式（３３）
【０１４２】
ＡｒＣＯＣｌ （３３）
［式中、Ａｒは前述の通り］で表される化合物、あるいは一般式（３４）
【０１４３】
ＡｒＣＯＯＨ （３４）
［式中、Ａｒは前述の通り］で表される化合物を作用させることにより製造することができる（工程Ｕ）。
【０１４４】
一般式（１１）で表される化合物と一般式（３２）で表される化合物との反応は、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウムを用い、反応溶媒としてはＴＨＦやエタノール、メタノールなどを用い、反応温度は０℃〜加熱還流下にて行うことができる。
【０１４５】
一般式（３３）で表される化合物との反応は、トリエチルアミン、ピリジン等の塩基存在下、反応溶媒としては塩化メチレン、ＤＭＦ、ＴＨＦ等を用い、反応温度としては０℃〜常温下にて行うことができる。
【０１４６】
一般式（３４）で表される化合物との反応は、ジシクロヘキシルカルボジイミド（ＤＣＣ）、Ｎ−エチル−Ｎ’‐３‐ジメチルアミノプロピルカルボジイミド（ＥＤＣ、ＷＳＣ）等の脱水縮合剤を用い、反応溶媒として塩化メチレン、ＤＭＦ、ＴＨＦ等を用い、反応温度としては０℃〜常温下にて行うことができる。
【０１４７】
合成経路４で一般式（３０）
【０１４８】
【化４８】
［式中、Ａｒ、Ｙ、ｋ及びｎは、前述の通り］で表される化合物は、一般式（３１） で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｖ）。
【０１５０】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜常温下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【０１５１】
一般式（１）でＸがＮＨＣＯである化合物、すなわち一般式（３５）
【０１５２】
【化４９】
［式中、Ａｒ、Ｙ及びｎは前述の通り］で表される化合物は、下記に示す合成経路５によって合成することができる。
【０１５４】
【化５０】
合成経路５で一般式（３７）
【０１５６】
【化５１】
［式中、Ｒ３、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（３６）
【０１５８】
【化５２】
［式中、Ｙ、Ｚ及びｎは前述の通り］で表される化合物と一般式（５）で表される化合物を塩基存在下作用させることによって製造することができる（工程Ｗ）。
反応はメタノール、エタノール、１，４−ジオキサン、ＤＭＳＯ、ＤＭＦ、ＴＨＦなどを反応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシドなどの無機塩基の存在下、反応温度としては０℃〜加熱還流下にて、好適には８０℃〜１００℃にて行うことができる。
【０１６０】
合成経路５で一般式（３８）
【０１６１】
【化５３】
［式中、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（３７）で表される化合物を還元することによって製造することができる（工程Ｘ）。
【０１６３】
反応は、ＢＨ３や９−ＢＢＮのようなアルキルボラン誘導体、ｉＢｕ２ＡｌＨ、ＮａＢＨ４、ＬｉＡｌＨ４等の金属水素錯化合物、好ましくはＬｉＢＨ４を用い、反応溶媒としてはＴＨＦやエタノール、メタノールなどを用い、反応温度は−７８℃〜加熱還流下、好適には常温下にて行うことができる。
【０１６４】
合成経路５で一般式（３９）
【０１６５】
【化５４】
［式中、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（３８）で表される化合物に一般式（１８）で表される化合物を作用させることによって製造することができる（工程Ｙ）。
【０１６７】
反応は、トリエチルアミン、ピリジン、２，６−ルチジン、イミダゾールのような有機塩基の存在下、反応溶媒としてはＤＭＦ、ＴＨＦ、塩化メチレン、クロロホルム、アセトニトリルを用い、反応温度は０℃〜１００℃にて行うことができる。
【０１６８】
合成経路５で一般式（４０）
【０１６９】
【化５５】
［式中、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（３９）で表される化合物をメタル化後、炭酸ガスを作用させることによって製造することができる（工程Ｚ）。
【０１７１】
反応は、反応溶媒としてＴＨＦ、ジエチルエーテル等を用い、反応温度として−７８℃〜常温下にてノルマルブチルリチウム等のアルキルリチウムや金属マグネシウムを用いメタル化後、炭酸ガスを作用させることにより製造することができる。
【０１７２】
合成経路５で一般式（４１）
【０１７３】
【化５６】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（４０）で表される化合物に一般式（４２）
Ａｒ−ＮＨ２ （４２）
［式中、Ａｒは前述の通り］で表される化合物を作用させることによって製造することができる（工程Ａ’）。
【０１７５】
反応は、 ＤＣＣ、 ＥＤＣ等の脱水縮合剤を用い、反応溶媒として塩化メチレン、ＤＭＦ、ＴＨＦ等を用い、場合によってはＤＭＡＰを加え、反応温度としては０℃〜常温下にて行うことができる。
【０１７６】
合成経路５で一般式（３５）
【０１７７】
【化５７】
［式中、Ａｒ、Ｙ及びｎは前述の通り］で表される化合物は、一般式（４１）で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｂ’）。
【０１７９】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜常温下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【０１８０】
一般式（１）で、ＸがＣＯまたはＣＨ２である化合物、すなわち一般式（４３）
【０１８１】
【化５８】
［式中、Ａｒ、Ｙ、ｋ及びｎは前述の通り］で表される化合物は、下記に示す合成経路６によっても製造することができる。
【０１８３】
【化５９】
合成経路６で一般式（４４）
【０１８５】
【化６０】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（３９）で表される化合物をメタル化後、一般式（４６）
【０１８７】
【化６１】
［式中、Ａｒは前述の通り］で表される化合物を作用させることによって製造することができる（工程Ｃ’）。
【０１８９】
反応は、反応溶媒としてＴＨＦ、ジエチルエーテル等を用い、反応温度として−７８℃〜常温下にてノルマルブチルリチウム等のアルキルリチウムや金属マグネシウム等を用いメタル化後、一般式（４６）で表される化合物を作用させることにより製造することができる。
【０１９０】
合成経路６で一般式（４５）
【０１９１】
【化６２】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｙ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（４４）で表される化合物を還元することによって製造できる（工程Ｄ’）。
【０１９３】
反応は、パラジウム炭素、ラネーニッケル、酸化白金等の金属触媒存在下、塩酸、酢酸等の酸を加え、反応溶媒としては、メタノール、エタノール等を用い、反応温度は０℃〜８０℃にて水素ガス気流下行うことができる。
【０１９４】
合成経路６で一般式（４３）
【０１９５】
【化６３】
［式中、Ａｒ、Ｙ、ｋ及びｎは前述の通り］で表される化合物は、一般式（４４）及び（４５）で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｅ’）。
【０１９７】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン、水等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜加熱還流下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【０１９８】
一般式（１）で、ＹがＣＨ２で、ｎが２である化合物、すなわち一般式（４７）
【０１９９】
【化６４】
［式中、Ａｒ、Ｙ、ｋ及びｎは前述の通り］で表される化合物は、下記に示す合成経路７によっても製造することができる。
【０２０１】
【化６５】
合成経路７で一般式（４９）
【０２０３】
【化６６】
［式中、Ｒ３及びＢｏｃは前述の通り］で表される化合物は、一般式（４８）
【０２０５】
【化６７】
［式中、Ｚは前述の通り］で表される化合物と一般式（５）で表される化合物を塩基存在下作用させることによって製造することができる（工程Ｆ’）。
【０２０７】
反応はメタノール、エタノール、１，４−ジオキサン、ＤＭＳＯ、ＤＭＦ、ＴＨＦなどを反応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキシドなどの無機塩基の存在下、反応温度としては０℃〜加熱還流下にて、好適には８０℃〜１００℃にて行うことができる。
【０２０８】
合成経路７で一般式（５０）
【０２０９】
【化６８】
［式中、Ｙ、Ｃｂｚ、Ｂｏｃ及びｎは前述の通り］で表される化合物は、一般式（４９）で表される化合物を還元することによって製造することができる（工程Ｇ’）。
【０２１１】
反応は、ＢＨ３や９−ＢＢＮのようなアルキルボラン誘導体、ｉＢｕ２ＡｌＨ、ＮａＢＨ４、ＬｉＡｌＨ４等の金属水素錯化合物、好ましくはＬｉＢＨ４を用い、反応溶媒としてはＴＨＦやエタノール、メタノールなどを用い、反応温度は−７８℃〜加熱還流下、好適には常温下にて行うことができる
合成経路７で一般式（５１）
【０２１２】
【化６９】
［式中、Ｒ４、Ｒ５及びＢｏｃは前述の通り］で表される化合物は、一般式（５０）で表される化合物に一般式（１８）で表される化合物を作用させることによって製造することができる（工程Ｈ’）。
【０２１４】
反応は、トリエチルアミン、ピリジン、２，６−ルチジン、イミダゾールのような有機塩基の存在下、反応溶媒としてはＤＭＦ、ＴＨＦ、塩化メチレン、クロロホルム、アセトニトリルを用い、反応温度は０℃〜１００℃にて行うことができる。
【０２１５】
合成経路７で一般式（５２）
【０２１６】
【化７０】
［式中、Ｒ４、Ｒ５及びＢｏｃは前述の通り］で表される化合物は、一般式（５１）で表される化合物を接触還元することによって製造することができる（工程Ｉ’）。
【０２１８】
反応は、パラジウム炭素、ラネーニッケル、酸化白金等の金属触媒存在下、反応溶媒としては、メタノール、エタノール、ＤＭＦ等を用い、反応温度は０℃〜８０℃にて水素ガス気流下行うことができる。
【０２１９】
合成経路７で一般式（５３）
【０２２０】
【化７１】
［式中、Ｒ４、Ｒ５及びＢｏｃは前述の通り］で表される化合物は、一般式（５２）で表される化合物を酸化することによって製造することができる（工程Ｊ’）。
【０２２２】
反応は、酸化剤としてクロロクロム酸ピリジウム（ＰＣＣ）、活性二酸化マンガン、テトラプロピルアンモニウム過ルテニウム酸塩（ＴＰＡＰ）等を用い、あるいは触媒量のＴＰＡＰ等と４−メチルモルホリンＮ−オキシド等の再酸化剤を用い、反応溶媒として塩化メチレン、ＤＭＦ等を用い、反応温度は０℃〜常温にて行うことができる。
【０２２３】
反応経路７で一般式（５４）
【０２２４】
【化７２】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｘ及びＢｏｃは前述の通り］で表される化合物は、一般式（５３）で表される化合物に一般式（５６）
【０２２６】
【化７３】
［式中、Ａｒ、Ｘ及びＺは前述の通り］で表される化合物を作用させることによって製造することができる（工程Ｋ’）。
【０２２８】
反応は、水素化ナトリウム、ナトリウムアルコキシド、カリウムアルコキシド、アルキルリチウム等の塩基存在下、反応溶媒としてＴＨＦ、１，４−ジオキサン、ＤＭＦ、ＤＭＳＯ等を用い、反応温度として‐７８℃〜常温にて行うことができる。
【０２２９】
反応経路７で一般式（５５）
【０２３０】
【化７４】
［式中、Ａｒ、Ｒ４、Ｒ５、Ｘ及びＢｏｃは前述の通り］で表される化合物は、一般式（５４）で表される化合物を還元することによって製造することができる（工程Ｌ’）。
【０２３２】
反応は、パラジウム炭素、ラネーニッケル、酸化白金等の金属触媒存在下、反応溶媒としては、メタノール、エタノール、ＤＭＦ等を用い、反応温度は０℃〜８０℃にて水素ガス気流下行うことができる。
【０２３３】
反応経路７で一般式（４７）
【０２３４】
【化７５】
［式中、Ａｒ及びＸは前述の通り］で表される化合物は、一般式（５５）で表される化合物を脱シリル化後に酸分解することによって製造することができる（工程Ｍ’）。
【０２３６】
反応は、ＴＨＦ、ＤＭＦ、１，４−ジオキサン、水等を反応溶媒として用い、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフルオリド等を０℃〜加熱還流下に作用させた後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルオロ酢酸等の無機酸または有機酸中、あるいはメタノール、エタノール、ＴＨＦ、１，４−ジオキサン、酢酸エチル等の有機溶媒との混合溶液中に作用させ、反応温度は０℃〜常温下に行うことができる。
【０２３７】
【実施例】
次に本発明を具体例によって説明するが、これらの例によって本発明が限定されるものではない。
【０２３８】
＜参考例１＞
３−（４−ベンジルオキシカルボニルアミノフェニル）ジヒドロシンナミルヨージド
【０２３９】
【化７６】
３−（４−ベンジルオキシカルボニルアミノフェニル）ジヒドロけい皮酸エチル（１８ｇ）をＴＨＦに溶解し、氷冷撹拌下ＬｉＢＨ４（５．９９ｇ）及びエタノール（５０ｍＬ）を加え、同温にて３０分、更に常温にて８時間撹拌した。飽和塩化アンモニウム水溶液でクエンチ後、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて乾燥し、溶媒を減圧濃縮し、無色の粉末晶を得た。
【０２４１】
これをＴＨＦに溶解し、イミダゾール（７．４９ｇ）及びトリフェニルホスフィン（２７．５ｇ）を加えた。氷冷後、ヨウ素（２７．９ｇ）を加え、同温にて３０分撹拌した。１０％チオ硫酸ナトリウム水溶液にてクエンチ後、酢酸エチルにて抽出し、１０％チオ硫酸ナトリウム水溶液、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムにて乾燥後、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１〜５：１）にて精製し、目的物（１７．９ｇ）を無色粉末晶として得た。
＜参考例２〜１３＞
参考例１と同様な方法によって各種エステルから表１に記載の化合物を合成した。
【０２４２】
【表１】
＜実施例１＞
２‐［３‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐２‐ｔ‐ブトキシカルボニルアミノマロン酸ジエチル
【０２４４】
【化７７】
アルゴン気流下、２‐ｔ‐ブトキシカルボニルアミノマロン酸ジエチル（２．４６ｇ）のエタノール（２０ｍＬ）溶液に、常温にてナトリウム−ｔ‐ブトキシド（８５７ｍｇ）を加えた。６５℃にて３０分撹拌後、参考例３の化合物（１．７６ｇ）のＴＨＦ（２０ｍＬ）溶液を加えた。その後、４時間加熱還流し、放冷後溶媒を留去した。残留物に水を加え、酢酸エチルで抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）にて精製し、目的物（２．０７ｇ）を淡黄色アモルファス状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．２３（６Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．４３（９Ｈ，ｂｒ ｓ）， １．４５−１．５４（２Ｈ，ｍ）， ２．３４（２Ｈ， ｂｒ），２．６４（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ）， ５．９５（１Ｈ，ｂｒ ｓ）， ７．１３−７．１９（３Ｈ，ｍ）， ７．３４（１Ｈ，ｍ）， ７．３８（２Ｈ，ｄ，Ｊ＝８．３ Ｈｚ）， ７．６０−７．６３（２Ｈ，ｍ）．
【０２４６】
＜実施例２〜１３＞
参考例１、２、４〜１３の化合物を用い、実施例１と同様な方法によって表２に記載の化合物を合成した。
【０２４７】
【表２】
＜実施例１４＞
２‐［３‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐２‐ｔ‐ブトキシカルボニルアミノ‐１，３‐プロパンジオール
【０２４９】
【化７８】
水素化アルミニウムリチウム（４３６ｍｇ）をＴＨＦ（２０ｍＬ）に懸濁し、‐７８℃撹拌下、実施例１の化合物（２．０７ｇ）のＴＨＦ（２０ｍＬ）溶液を滴下した。反応温度を徐々に常温に戻し、更に５時間撹拌した。氷冷後、水でクエンチし、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１ｍＬ）を加え、析出した不溶物をセライトを用い濾去した。不溶物を酢酸エチルでよく洗浄した後、有機層を合せ、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、目的物（７２６ｍｇ）を淡黄色粉末晶として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．４４（９Ｈ，ｓ），１．５６−１．６２（４Ｈ，ｍ）， ２．６２（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），３．３９（２Ｈ，ｂｒｓ），３．５８（２Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），３．８３（２Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），４．９０（１Ｈ，ｂｒ ｓ），７．１６（１Ｈ，ｔ，Ｊ＝７．８Ｈｚ），７．１９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．３２−７．３７（１Ｈ，ｍ）， ７．４１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）， ７．６３（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）．
【０２５１】
＜実施例１５〜２６＞
実施例２〜１３の化合物を用い、実施例１４と同様な方法によって表３に記載の化合物を合成した。
【０２５２】
【表３】
＜実施例２７＞
５‐［３‐［４‐（ベンジルオキシカルボニルアミノ）フェニル］プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０２５４】
【化７９】
実施例２４の化合物（２０ｇ）及び２，６‐ルチジン（１５．３ｍＬ）のＤＭＦ（５００ｍＬ）溶液に、０℃にてジ−ｔ‐ブチルシリルビストリフルオロメタンスルホネート（１５．９ｍＬ）の塩化メチレン（１００ｍＬ）溶液をゆっくりと加えた。０℃にて２時間撹拌後、反応液を氷水中に注ぎ、酢酸エチルにて抽出した。有機層を希塩酸、水（２回）、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：１）で精製し、目的物（１４．５ｇ）を無色アモルファス状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４２（９Ｈ，ｓ）， １．５３（４Ｈ，ｂｒ ｓ），２．５４（２Ｈ，ｔ，Ｊ＝６．４Ｈｚ），３．８８（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ）， ４．２１（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ）， ４．９０（１Ｈ，ｂｒ ｓ），５．１９（２Ｈ，ｓ），６．５９（１Ｈ，ｂｒ ｓ）， ７．０７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２６−７．４２（７Ｈ，ｍ）．
【０２５６】
＜実施例２８、２９＞
５‐［３‐（４‐ブロモフェニル）プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン及び５‐（２‐ベンジルオキシエチル）‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０２５７】
【化８０】
実施例２５、２６の化合物を用い実施例２７と同様の方法によって、実施例２８の化合物を無色粉末晶（収率７７％）として、実施例２９の化合物を無色油状物（収率４９％、前工程から２ステップ収率）としてそれぞれ合成した。
【０２５９】
＜実施例３０＞
５‐［３‐（４‐アミノフェニル）プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０２６０】
【化８１】
実施例２７の化合物（１４．５ｇ）のエタノール（２００ｍＬ）溶液に１０％パラジウム炭（１．５ｇ）を加え、水素ガス気流下（常圧）、常温で５時間撹拌した。触媒をセライトを用い濾去し、濾液を減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル５：１〜３：１）で精製し、目的物（９．５５ｇ）を無色粉末晶として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４３（９Ｈ，ｓ）， １．４７−１．５６（４Ｈ，ｍ），２．４６（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），３．５６（２Ｈ，ｂｒ ｓ）， ３．８８（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２２（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．８９（１Ｈ，ｂｒ ｓ）， ６．６２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９３（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
【０２６２】
＜実施例３１＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐（２‐ヒドロキシエチル）‐１，３，２‐ジオキサシラン
【０２６３】
【化８２】
実施例２９の化合物を用い、実施例３０と同様の方法によって合成した（無色油状、収率ｑｕａｎｔ．）。
【０２６５】
＜実施例３２＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐［４‐（キノリン−２‐イルアミノ）フェニル］プロピル］‐１，３，２‐ジオキサシラン
【０２６６】
【化８３】
実施例３０の化合物（８０ｍｇ）、２‐クロロキノリン（３５ｍｇ）のＮ，Ｎ‐ジメチルイミダゾリジノン（２ｍＬ）溶液を１００℃で７．５時間撹拌した。放冷後重曹水でクエンチし、酢酸エチルで抽出した。有機層を水（５回）、飽和食塩水の順で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）で精製し、目的物（３１ｍｇ）を淡黄色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０５（９Ｈ，ｓ），１．０７（９Ｈ，ｓ），１．４４（９Ｈ，ｓ）， １．５９（４Ｈ，ｂｒ），２．５８（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ）， ３．９０（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２４（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ）， ４．９２（１Ｈ，ｂｒ），６．７８（１Ｈ，ｂｒ），６．９６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ）， ７．２８（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．４５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５８（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ）， ７．６３（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ）， ７．７６（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．９０（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ）．
【０２６８】
＜実施例３３〜４８＞
実施例３０の化合物と様々なヘテロ環のクロル体を用い、上記実施例３２と同様な方法によって表４に記載の化合物を合成した。
【０２６９】
【表４】
＜実施例４９＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐［４‐（３，５‐ジクロロフェニルアミノ）フェニル］プロピル］‐１，３，２‐ジオキサシラン
【０２７１】
【化８４】
実施例３０の化合物（３００ｍｇ）、３，５‐ジクロロフェニルホウ酸（２４６ｍｇ）及び無水酢酸銅（ＩＩ）（１１７ｍｇ）の塩化メチレン（３ｍＬ）溶液にトリエチルアミン（０．１８ｍＬ）を加え、常温で２０時間撹拌した。反応溶媒をそのままシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）で精製し、目的物（２４０ｍｇ）を黄色アモルファス状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０５（９Ｈ，ｓ），１．０７（９Ｈ，ｓ），１．４３（９Ｈ，ｓ）， １．５７（４Ｈ，ｂｒ ｓ），２．５５（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．９０（２Ｈ，ｄ，Ｊ＝１１．７Ｈｚ）， ４．２３（２Ｈ，ｄ，Ｊ＝１０．３Ｈｚ），４．９２（１Ｈ，ｂｒ ｓ），５．６８（１Ｈ，ｂｒ ｓ），６．７９−６．８１（３Ｈ，ｍ）， ７．０２（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．１１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
【０２７３】
＜実施例５０〜６８＞
実施例３０の化合物と様々なフェニルホウ酸誘導体を用い、実施例４９と同様な方法によって表５に記載の化合物を得た。
【０２７４】
【表５】
＜実施例６９＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐［４‐（イソキノリン‐３‐イルアミノ）フェニル］プロピル］‐１，３，２‐ジオキサシラン
【０２７６】
【化８５】
２‐アセトニトリルベンズアルデヒド（１４５ｍｇ）のエタノール（５ｍＬ）溶液に、実施例３０の化合物（４６５ｍｇ）及びトリフルオロ酢酸（２滴）を加え、２０時間加熱還流した。放冷後、溶媒を減圧留去し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１〜７：１）で精製し、目的物（６１５ｍｇ）を黄色粉末晶として得た。
ＦＡＢＭＳ［Ｍ＋Ｈ］＋；５９２
【０２７８】
＜実施例７０＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐［４‐（３，５‐ジクロロベンジルアミノ）フェニル］プロピル］‐１，３，２‐ジオキサシラン
【０２７９】
【化８６】
実施例３０の化合物（２００ｍｇ）及び３，５‐ジクロロベンズアルデヒド（７５．３ｍｇ）の塩化メチレン（１０ｍＬ）溶液に、トリアセトキシ水素化ホウ素ナトリウム（１４６ｍｇ）及び酢酸（２滴）を加え、常温で終夜撹拌した。反応液に飽和重曹水を加え、酢酸エチルにて抽出し、飽和重曹水、水、飽和食塩水の順に洗浄した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：１）で精製し、目的物（１９５ｍｇ）を淡黄色アモルファス状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４２（９Ｈ，ｓ）， １．４３−１．５６（４Ｈ，ｍ）， ２．４６（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．８８（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），
４．０４（１Ｈ，ｂｒ ｓ），４．２２（２Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），４．２８（２Ｈ，ｓ），４．８９（１Ｈ，ｂｒ ｓ）， ６．５１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），６．９６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２６（３Ｈ，ｓ）．
【０２８１】
＜実施例７１、７２＞
実施例３０の化合物と３，５‐ビストリフルオロメチルベンズアルデヒド及び２‐ホルミルベンゾチアゾールを用い、実施例７０と同様な方法によって表６に記載の化合物を合成した。
【０２８２】
【表６】
＜実施例７３＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐［４‐（３，５‐ジクロロベンゾイルアミノ）フェニル］プロピル］‐１，３，２‐ジオキサシラン
【０２８４】
【化８７】
３，５‐ジクロロ安息香酸（４９．３ｍｇ）及び１‐ヒドロキシベンゾトリアゾール・１水和物（３９．５ｍｇ）のＤＭＦ（２ｍＬ）溶液に、実施例３０の化合物（１００ｍｇ）及びＮ−エチル−Ｎ’‐３‐ジメチルアミノプロピルカルボジイミド塩酸塩（ＷＳＣ‐ＨＣｌ）（６１．９ｍｇ）を加え、常温で２時間撹拌した。反応液を氷水中に注ぎ、酢酸エチルにて抽出した。有機層を水（２回）、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物（１３５ｍｇ）を淡褐色粉末晶として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０５（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４３（９Ｈ，ｓ），１．５８（４Ｈ，ｂｒ ｓ），２．５７（２Ｈ，ｂｒ ｓ），３．８８（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２２（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９２（１Ｈ，ｂｒ ｓ），７．１６（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５３（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ）， ７．６８（１Ｈ，ｂｒ ｓ），７．７３（２Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
【０２８６】
＜実施例７４、７５＞
実施例３０の化合物とキノリン‐２‐カルボン酸及びベンゾチアゾール‐２‐カルボン酸を用い、実施例７３と同様の方法で表７に記載の化合物を合成した。
【０２８７】
【表７】
＜実施例７６＞
５‐［３‐［４‐（３‐ベンゾイルチオウレイド）フェニル］プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０２８９】
【化８８】
ベンゾイルチオイソシアネート（３２６ｍｇ）のアセトン（１０ｍＬ）溶液に氷冷撹拌下、実施例３０の化合物（９２９ｍｇ）のアセトン（５ｍＬ）溶液を１０分間かけてゆっくりと滴下した。０℃で１時間撹拌後、溶媒を留去した。残さを少量の酢酸エチルで溶解後、多量のヘキサンを加え目的物を析出させた。析出晶を濾取後乾燥し、目的物（１．１４ｇ）を無色粉末晶として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０５（９Ｈ，ｓ），１．０７（９Ｈ，ｓ），１．４４（９Ｈ，ｓ），１．５７（４Ｈ，ｂｒ ｓ），２．６０（２Ｈ，ｂｒ ｓ），３．９０（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２３（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９２（１Ｈ，ｂｒ ｓ），７．２０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５６（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．６１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）， ７．６６（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ），７．９０（２Ｈ，ｄ，Ｊ＝７．３Ｈｚ），９．０７（１Ｈ，ｂｒ ｓ），１２．５３（１Ｈ，ｂｒ ｓ）．
【０２９１】
＜実施例７７＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐（４‐チオウレイドフェニル）プロピル］‐１，３，２‐ジオキサシラン
【０２９２】
【化８９】
実施例７６の化合物（５００ｍｇ）のＴＨＦ（２ｍＬ）溶液に氷冷下、飽和アンモニアエタノール溶液（８ｍＬ）を加え、常温下、封管中で１６時間撹拌した。溶媒を減圧留去し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル２：１〜１：１）で精製し、目的物（４１０ｍｇ）を無色アモルファス状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４１（９Ｈ，ｓ），
１．５４（２Ｈ，ｂｒ ｓ），１．６２（２Ｈ，ｂｒ ｓ），２．５９（２Ｈ，ｂｒ ｓ），３．８９（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．１９（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９２（１Ｈ，ｂｒ ｓ），６．０４（２Ｈ，ｂｒ ｓ），７．１４（２Ｈ，ｄ，Ｊ＝８．３），７．２１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．８３（１Ｈ，ｂｒ ｓ）．
【０２９４】
＜実施例７８＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５‐［３‐［４‐（４‐メチルチアゾール−２‐イルアミノ）フェニル］プロピル］‐１，３，２‐ジオキサシラン
【０２９５】
【化９０】
無水硫酸マグネシウム（５００ｍｇ）のアセトン（１０ｍＬ）懸濁液にクロロアセトン（６２．３μＬ）を加えた。加熱還流下、実施例７７の化合物（４１０ｍｇ）のアセトン（５ｍＬ）溶液を滴下し、２時間加熱還流した。その後、クロロアセトン（６２．３μＬ）を加え、更に５時間加熱還流した。放冷後、不溶物を濾去し、濾液を減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１〜４：１）で精製し、目的物（１０７ｍｇ）を黄色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４３（９Ｈ，ｓ），１．５５（２Ｈ，ｂｒ ｓ），１．７０（２Ｈ，ｂｒ ｓ），２．２９（３Ｈ，ｓ），２．５５（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．８９（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ）， ４．２２（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９１（１Ｈ，ｂｒｓ），６．１６（１Ｈ，ｄ，Ｊ＝１．０Ｈｚ），７．１１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
【０２９７】
＜実施例７９、８０＞
実施例７７の化合物と４‐フルオロフェナシルブロミド及び４−クロロフェナシルブロミドを用い、実施例７８と同様な方法で表８に記載の化合物を合成した。
【０２９８】
【表８】
＜実施例８１＞
４−［３−（５−ｔ−ブトキシカルボニルアミノ‐２，２−ジ−ｔ−ブチル‐［１，３，２］ジオキサシリナン‐５−イル）プロピル］安息香酸
【０３００】
【化９１】
アルゴン気流下、実施例２８の化合物（５２９ｍｇ）のジエチルエーテル（５ｍＬ）溶液に、−７８℃下でｎ−ブチルリチウムのヘキサン溶液（１．６ｍｏｌ／Ｌ，１．２５ｍＬ）を滴下し、−７８℃で１５分更に０℃で３０分撹拌した。反応液を再び‐７８℃に冷却後、炭酸ガスをバブリングさせながら徐々に常温まで昇温させた。希塩酸で中和後、酢酸エチルにて抽出した。有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１〜１：１）で精製し、目的物（２００ｍｇ）を無色粉末晶として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４３（９Ｈ，ｓ），１．５８（４Ｈ，ｂｒ ｓ），２．６５（２Ｈ，ｂｒ ｓ），３．８８（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２２（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．９４（１Ｈ，ｂｒ ｓ），７．２４（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），８．０１（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ）．
【０３０２】
＜実施例８２＞
５‐［３‐［４‐（ベンゾチアゾール−２‐イルアミノカルボニル）フェニル］プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０３０３】
【化９２】
実施例８１の化合物（２００ｍｇ）及び１‐ヒドロキシベンゾトリアゾール・１水和物（６２．０ｍｇ）のＤＭＦ（３ｍＬ）溶液に、２−アミノベンゾチアゾール（９１．３ｍｇ）及びＮ−エチル−Ｎ’‐３‐ジメチルアミノプロピルカルボジイミド塩酸塩（ＷＳＣ‐ＨＣｌ）（１１７ｍｇ）を加え、常温で２時間撹拌した。反応液を氷水中に注ぎ、酢酸エチルにて抽出した。有機層を水（２回）、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル５：１）で精製し、目的物（１６０ｍｇ）を無色粉末晶として得た。
ＦＡＢＭＳ［Ｍ＋Ｈ］＋； ６２６．
【０３０５】
＜実施例８３＞
５‐［３‐［４‐（３，５−ビストリフルオロメチルベンゾイル）フェニル］プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０３０６】
【化９３】
アルゴン気流下、実施例２８の化合物（５３０ｍｇ）のジエチルエーテル（１０ｍＬ）溶液に、−７８℃撹拌下、ｎ−ブチルリチウム（１．３０ｍＬ：１．５２ｍｏｌ／Ｌヘキサン溶液）をゆっくりと加えた。０℃までゆっくりと昇温し、同温にて３０分撹拌した。再び−７８℃に冷却後、Ｎ−メトキシ−Ｎ−メチル−３，５−ビストリフルオロメチルベンズアミド（３００ｍｇ）のジエチルエーテル（３ｍＬ）溶液を加えた。ＴＨＦ（５ｍＬ）を加え、ゆっくりと０℃まで昇温し、同温にて１時間撹拌した。反応液を水に注ぎ、酢酸エチルにて抽出した。有機層を水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製し、目的物（２２０ｍｇ）を無色アモルファス状物として得た。
ＦＡＢＭＳ［Ｍ＋Ｈ］＋；６９０．
【０３０８】
＜実施例８４＞
５‐［３‐［４‐（３，５−ビストリフルオロメチルベンジル）フェニル］プロピル］‐５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−１，３，２‐ジオキサシラン
【０３０９】
【化９４】
実施例８３の化合物（２８０ｍｇ）のエタノール（１０ｍＬ）溶液に、１０％パラジウム炭素（６０ｍｇ）及び酢酸（数滴）を加え、水素ガス（常圧）気流下、常温にて５時間撹拌した。セライトを用い不溶物を濾去し、濾液に少量のトリエチルアミンを加え、減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）にて精製し、目的物（１６６ｍｇ）を無色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０５（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４２（９Ｈ，ｓ），１．５２−１．６０（４Ｈ，ｂｒ），２．５６（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），３．８９（２Ｈ，ｄ，Ｊ＝１１．０Ｈｚ），４．０３（２Ｈ，ｓ），４．２２（２Ｈ，ｄ，Ｊ＝１１．０Ｈｚ），４．９１（１Ｈ，ｂｒ ｓ），７．０７（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），
７．１１（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．６２（２Ｈ，ｓ），７．７２（１Ｈ，ｓ）．
【０３１１】
＜実施例８５＞
５‐ｔ‐ブトキシカルボニルアミノ−２，２‐ジ−ｔ‐ブチル−５−（２−オキソエチル）−１，３，２‐ジオキサシラン
【０３１２】
【化９５】
実施例３１の化合物（２００ｍｇ）及び４−メチルモルホリンＮ−オキシド（９２ｍｇ）の塩化メチレン（１ｍＬ）溶液に、モレキュラーシーブス４Ａ（２７０ｍｇ）及びテトラプロピルアンモニウム過ルテニウム酸塩（１０ｍｇ）を加え、常温にて２時間撹拌した。反応液をそのままシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、目的物（１４４ｍｇ）を無色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０６（９Ｈ，ｓ），１．０９（９Ｈ，ｓ），１．４３（９Ｈ，ｓ），２．７０（２Ｈ，ｂｒ）， ４．０５（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２９（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），５．１９（１Ｈ，ｂｒ ｓ），９．７５（１Ｈ，ｔ，Ｊ＝２．０Ｈｚ）．
【０３１４】
＜実施例８６＞
５−［３−（３’，５’−ビストリフルオロメチルビフェニル‐４−イル）アリル］−５−ｔ−ブトキシカルボニルアミノ‐２，２−ジ−ｔ−ブチル‐１，３，２‐ジオキサシラン
【０３１５】
【化９６】
（３，５−ビストリフルオロメチルビフェニル‐４−イルメチル）トリフェニルホスホニウムブロミド（２５０ｍｇ）のＴＨＦ（５ｍＬ）懸濁液に、氷冷撹拌下ナトリウム‐ｔ−ブトキシド（３５ｍｇ）を加えた。常温下で１時間撹拌後、氷冷撹拌下実施例８５の化合物（１４４ｍｇ）のＴＨＦ（２ｍＬ）溶液を加え、常温下で２時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を水、飽和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサンのみ〜ヘキサン：酢酸エチル＝２０：１）で精製し、目的物（１３９ｍｇ）を無色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ １．０４（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４４（９Ｈ，ｓ）， ２．６８（２Ｈ，ｄ，Ｊ＝５．８Ｈｚ），３．８９（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），４．２６（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），５．０２（１Ｈ，ｂｒｓ），５．７４−５．８１（１Ｈ，ｍ），６．５９（１Ｈ，ｄ，Ｊ＝１１．７Ｈｚ），７．３７（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）， ７．５９（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ）， ７．８５（１Ｈ，ｓ），８．０２（２Ｈ，ｓ）．
【０３１７】
＜実施例８７＞
５−［３−（３’，５’−ビストリフルオロメチルビフェニル‐４−イル）プロピル］−５−ｔ−ブトキシカルボニルアミノ‐２，２−ジ−ｔ−ブチル‐１，３，２‐ジオキサシラン
【０３１８】
【化９７】
実施例８６の化合物（１３９ｍｇ）のエタノール（１０ｍＬ）溶液に１０％パラジウム炭素を加え、水素ガス（常圧）気流下、常温にて２時間撹拌した。セライトを用い触媒を濾去し、溶媒を留去した。残さをシリカゲルカラムクロマトグラフィー（酢酸エチルのみ）で精製し、目的物（１４６ｍｇ）を無色油状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３） δ１．０５（９Ｈ，ｓ），１．０６（９Ｈ，ｓ），１．４３（９Ｈ，ｓ）， １．５０−１．６２（４Ｈ，ｂｒ），２．６５（２Ｈ， ｂｒ ｓ），３．９０（２Ｈ，ｄ，Ｊ＝１１．０Ｈｚ），４．２３（２Ｈ，ｄ，Ｊ＝１１．０Ｈｚ），４．９３（１Ｈ，ｂｒ ｓ），７．２８（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．５２（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．８３（１Ｈ，ｂｒ ｓ），７．９９（１Ｈ，ｂｒ ｓ）．
【０３２０】
＜実施例８８＞
２−アミノ‐２‐［３‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール・ニ塩酸塩
【０３２１】
【化９８】
実施例１４の化合物（１００ｍｇ）をエタノール（３ｍＬ）と酢酸エチル（１ｍＬ）の混合溶媒に溶解させ、氷冷撹拌下、３ｍｏｌ／Ｌ塩酸含有酢酸エチル（２ｍＬ）を加えた。常温で２０時間撹拌後、酢酸エチル（５０ｍＬ）で希釈した。析出晶を濾取後、乾燥し、目的物（６０．１ｍｇ）を無色粉末晶（吸湿性 大）として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６） δ １．５７（４Ｈ ｂｒ ｓ），２．５４（２Ｈ，ｂｒ ｓ）， ３．４４（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），３．４７（２Ｈ，ｄ，Ｊ＝１１．２Ｈｚ），７．１３−７．１７（１Ｈ，ｍ），７．２０（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．２９−７．３４（１Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ）， ７．６９（２Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．７３（３Ｈ，ｂｒ ｓ），７．７９（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），１０．５７（２Ｈ，ｂｒ ｓ）．
ＦＡＢＭＳ［Ｍ＋Ｈ］＋；３５８．
【０３２３】
＜実施例８９〜９７＞
実施例１５〜２３の化合物を用い、実施例８８と同様な方法で表９に記載の化合物を合成した。
【０３２４】
【表９】
＜実施例９８＞
２−アミノ‐２‐［３‐［４‐（キノリン−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール・ニ塩酸塩
【０３２６】
【化９９】
実施例３２の化合物（３０ｍｇ）のＴＨＦ（１ｍＬ）溶液に１Ｍテトラ−ｎ−ブチルアンモニウムフルオリドＴＨＦ溶液（１ｍＬ）を加え、常温で２時間撹拌した。反応液を水に注ぎ、酢酸エチルにて抽出した。有機層を水、飽和食塩水の順で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、淡黄色の油状物を得た。これをエタノール（２ｍＬ）、酢酸エチル（２ｍＬ）に溶解し、３ｍｏｌ／Ｌ塩酸含有酢酸エチル（２ｍＬ）を加え、常温で５時間撹拌した。溶媒を減圧留去し、目的物（８ｍｇ）を黄色アモルファス状物として得た。
１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６） δ １．４５（２Ｈ，ｂｒ ｍ），１．５９（２Ｈ， ｂｒ ｍ）， ２．５３（２Ｈ，ｂｒ），３．４３（４Ｈ，ｂｒ），４．９１
（１Ｈ，ｂｒ），７．０３（１Ｈ， ｄ， Ｊ＝８．８Ｈｚ），７．１５（２Ｈ，ｄ， Ｊ＝８．５Ｈｚ），７．２７（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．５６（１Ｈ，ｔ，Ｊ＝７．５Ｈｚ），７．６４（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．７０（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．８８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），９．３４（１Ｈ，ｓ）．
ＦＡＢＭＳ［Ｍ＋Ｈ］＋；３５２．
融点 １２８−１３０℃．
【０３２８】
＜実施例９９〜１４８＞
実施例３３〜７５、７８〜８０、８２〜８４及び８７を用い、実施例９８と同様な方法によって表１０、１１に記載の化合物を合成した。
【０３２９】
【表１０】
【表１１】
次に本発明化合物について、有用性を裏付ける成績を実験例によって示す。
【０３３２】
＜実験例１＞ マウス宿主対移植片拒絶反応に対する被験化合物の抑制作用
トランスプランテーション（Ｔｒａｎｓｐｌａｎｔａｔｉｏｎ）、第５５巻、第３号、第５７８−５９１頁，１９９３年．に記載の方法を参考にして行った。ＢＡＬＢ／ｃ系雄性マウス８〜１１週齢（日本クレア）から脾臓を採取した。脾臓は、リン酸緩衝生理食塩水（ＰＢＳ（−）、日水製薬）またはＲＰＭＩ−１６４０培地（ギブコ）中に取り出し、ステンレス・メッシュを通過させることにより、または、スライドグラス２枚ですり潰しセルストレーナー（７０ミクロン、ファルコン）を通過させることにより脾細胞浮遊液にした。この脾細胞浮遊液を遠心して上清を除去した後、塩化アンモニウム−トリス等張緩衝液を加えて赤血球を溶血させた。ＰＢＳ（−）またはＲＰＭＩ−１６４０培地で３回遠心洗浄した後、ＲＰＭＩ−１６４０培地に浮遊した。これに最終濃度が２５μｇ／ｍＬとなるようにマイトマイシンＣ（協和醗酵）を加え、３７℃、５％ＣＯ２下で３０分間培養した。ＰＢＳ（−）またはＲＰＭＩ−１６４０培地で３回遠心洗浄した後、ＲＰＭＩ−１６４０培地に２．５×１０８個／ｍＬとなるように浮遊し、これを刺激細胞浮遊液とした。刺激細胞浮遊液２０μＬ（５×１０６個／匹）を、２７Ｇ針およびマイクロシリンジ（ハミルトン）を用いてＣ３Ｈ／ＨｅＮ系雄性マウス８週齢（日本クレア）の右後肢足蹠部皮下に注射した。正常対照群には、ＲＰＭＩ−１６４０培地のみを注射した。４日後に、右膝下リンパ節を摘出し、メトラーＡＴ２０１型電子天秤（メトラー・トレド）を用いて重量を測定した。被験化合物は、刺激細胞注射日から３日後まで、１日１回、計４回、連日腹腔内投与した。対照群には、被験化合物の調製に用いたものと同じ組成の溶媒を投与した。表１２に示す。なお、抑制率は下記の計算式を用いて算出した。
【０３３３】
【数１】
【表１２】
＜実験例２＞ マウス遅延型過敏反応に対する被験化合物の抑制作用
メソッズ・イン・エンザイモロジー（Ｍｅｔｈｏｄｓ ｉｎ Ｅｎｚｙｍｏｌｏｇｙ）、第３００巻、第３４５−３６３頁、１９９９年．に記載の方法を参考にして行った。１％（ｖ／ｖ）となるように１−フルオロ−２，４−ジニトロベンゼン（ＤＮＦＢ、ナカライテスク）をアセトン：オリブ油（４：１）混合液に溶解した。１％ＤＮＦＢ溶液をＢＡＬＢ／ｃ系雄性マウス（日本クレア）８または９週齢の左右後肢足蹠部に１０μＬずつ塗布して抗原感作を行った。正常対照群には、アセトン：オリブ油（４：１）混合液のみを塗布した。この抗原感作を２日連続して行い、これを０日目および１日目とした。５日目に同抗原を耳にチャレンジして遅延型過敏反応を惹起した。まず、抗原チャレンジ前の左右耳厚をダイヤルシックネスゲージＧ（０．０１−１０ｍｍ、尾崎製作所）を用いて測定した。次に、被験化合物を腹腔内投与した。対照群には被験化合物の調製に用いたものと同じ組成の溶媒を投与した。３０分後、アセトン：オリブ油（４：１）混合液に溶解した０．２％（ｖ／ｖ）ＤＮＦＢ溶液を左右耳の表裏に１０μＬずつ塗布（２０ｍＬ／耳塗布）し、抗原チャレンジを行った。左耳には、溶媒のみをチャレンジした。２４時間後に左右の耳厚を測定し、耳厚増加量を求めた。左右耳の耳厚増加量の平均を各個体のデータとした。結果を表１３に示す。なお、抑制率は下記の計算式を用いて算出した。
【０３３６】
【数２】
【表１３】
以上のように、一般式（１）で表される本発明化合物は動物実験モデルにおいてその有効性が確認された。
【０３３９】
【発明の効果】
上述のように、本発明は、新規な２−アミノ−１，３−プロパンジオール誘導体、特にアミノ基、アミド基及びメチレン鎖などのスペーサーを用い二つの芳香環を連結させた２−アミノ−１，３−プロパンジオール誘導体が強力な免疫抑制作用を有することを見出したものである。このような免疫抑制作用を有する化合物は、臓器移植および骨髄移植における拒絶反応の予防または治療薬、自己免疫疾患の予防または治療薬、関節リウマチの予防または治療薬、乾癬またはアトピー性皮膚炎の予防または治療薬及び気管支喘息または花粉症の予防または治療薬として有用である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a 2-amino-1,3-propanediol derivative, an addition salt thereof and a hydrate thereof useful as an immunosuppressant.
[0002]
[Prior art]
[Patent Document 1] WO94 / 08943 pamphlet
[Patent Document 2] Japanese Patent Application Laid-Open No. 9-257602
[Patent Document 3] Pamphlet of WO02 / 06268
[Patent Document 4] JP-A-2002-53575
[Patent Document 5] JP-A-2002-167382
[Patent Document 6] JP-A-2002-316985
[0003]
Immunosuppressants are widely used as therapeutic agents for autoimmune diseases such as rheumatoid arthritis, nephritis, osteoarthritis, systemic lupus erythematosus, chronic inflammatory diseases such as inflammatory bowel disease, and allergic diseases such as asthma and dermatitis. ing. In particular, in recent medical practice where transplantation of tissues and organs has been performed with the advancement of medical technology, how well rejection after transplantation can be controlled depends on how well transplantation can be controlled. We know the success and the immunosuppressants also play a very important role in this area.
[0004]
In organ transplantation, antimetabolites represented by azathioprine and mycophenolate mofetil, calcineurin inhibitors represented by cyclosporin A and tacrolimus, and corticosteroids represented by prednisolone are used. However, some of these drugs are inadequately effective, and some require monitoring of blood levels of the drug in order to avoid serious side effects such as renal impairment. Is not always satisfactory.
[0005]
Furthermore, in order to reduce the side effects of immunosuppressive drugs and obtain sufficient immunosuppressive action, multidrug combination therapy using multiple drugs with different mechanisms of action is common, and the effect differs from that of the aforementioned immunosuppressants. The development of new types of drugs with a mechanism is also desired.
[0006]
The present inventors have focused on 2-amino-1,3-propanediol derivatives and searched for a new type of immunosuppressant in order to solve such problems.
[0007]
2-amino-1,3-propanediol derivatives as immunosuppressants
[Patent Document 1],
Patent Document 2 discloses a 2-amino-1,3-propanediol derivative in which two aromatic rings are linked using a spacer such as an amino group, an amide group and a methylene chain, which is a feature of the present invention. Was not known to show an excellent immunosuppressive effect. Also,
[Patent Document 3],
[Patent Document 4],
[Patent Document 5],
Patent Document 6 discloses that a 2-amino-ethanol derivative linked to a heterocyclic ring exhibits an immunosuppressive action, but has a different structure from the compound of the present application.
[0008]
[Problems to be solved by the invention]
The problem to be solved by the present invention is to provide a 2-amino-1,3-propanediol derivative which has an excellent immunosuppressive action and has few side effects.
[0009]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on immunosuppressive agents having a different mechanism of action from antimetabolites and calcineurin inhibitors, and as a result, they differed in structure from previously known immunosuppressants. New 2-amino-1,3-propanediol derivatives, especially 2-amino-1,3-propanediol derivatives in which two aromatic rings are linked using spacers such as amino groups, amide groups and methylene chains, are powerful The present inventors have found that they have an immunosuppressive effect, and have completed the present invention.
[0010]
That is, the present invention relates to the general formula (1)
[0011]
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[In the formula, Ar represents a phenyl group which may have a substituent, a benzothiazole group which may have a substituent, a thiazole group which may have a substituent, a benzoxazole group, a naphthyl group, a substituent. A benzimidazole group which may have, a pyrimidyl group which may have a substituent, a quinolinyl group, an isoquinolinyl group, which represents a thienopyrimidyl group or a thiazolopyridinyl group which may have a substituent,
X represents NR1 (R1 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), CH 2 NH, NHCH 2 , CONH, NHCO,-(CH 2 ) m -(M represents 0 or 1) or CO,
Y represents a carbon atom or an oxygen atom,
n shows the integer of 0-3. An immunosuppressant comprising at least one of a 2-amino-1,3-propanediol derivative, a pharmacologically acceptable salt, and a hydrate thereof as an active ingredient. .
[0013]
More specifically, the general formula (1a)
[0014]
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[In the formula, R2 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a trifluoromethyl group, a lower alkoxy group having 1 to 7 carbon atoms, a hydroxy group, a lower alkoxymethyl group having 1 to 7 carbon atoms or a substituent. Wherein Y and n are as defined above, and a pharmaceutically acceptable salt thereof. And hydrates thereof, and general formula (1b)
[0016]
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[Wherein, Y and n are the same as defined above]
The at least one of the 2-amino-1,3-propanediol derivative, the pharmacologically acceptable salt, and the hydrate thereof according to claim 1, which is represented by the following formula: It is an immunosuppressant.
[0018]
The general formulas (1), (1a) and (1b) in the present invention are novel compounds.
[0019]
As preferred compounds of the present invention,
1) 2-amino-2- [3- [4- (benzothiazol-2-ylamino) phenyl] propyl] -1,3-propanediol,
2) 2-amino-2- [3- [4- (quinolin-2-ylamino) phenyl] propyl] -1,3-propanediol,
3) 2-amino-2- [3- [4- (3,5-bistrifluoromethylphenylamino) phenyl] propyl] -1,3-propanediol,
4) 2-amino-2- (3- [4- [4- (4-chlorophenyl) thiazol-2-ylamino] phenyl] propyl) -1,3-propanediol,
5) 2-amino-2- [3- [4- (5-heptyloxymethylbenzothiazol-2-ylamino) phenyl] propyl] -1,3-propanediol
Or
6) 2-amino-1,3-propanediol according to claim 1, which is 2-amino-2- [2- [4- (benzothiazol-2-ylamino) phenyl] ethyl] -1,3-propanediol. Derivatives and pharmacologically acceptable salts and hydrates thereof can be mentioned.
[0020]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
[0021]
Pharmaceutically acceptable salts of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, citrate And acid addition salts such as tartrate.
[0022]
In the general formula (1) of the present invention, “a phenyl group which may have a substituent”, “a benzothiazole group which may have a substituent”, “a thiazole group which may have a substituent” ``, '' A pyrimidyl group which may have a substituent, '' `` a thienopyrimidyl group which may have a substituent, '' and `` a benzimidazole group which may have a substituent '' are any on the aromatic ring. Halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom, trifluoromethyl group, lower alkyl group having 1 to 4 carbon atoms, lower alkoxy group having 1 to 7 carbon atoms, lower having 1 to 7 carbon atoms Examples include those having an alkoxymethyl group, a hydroxyl group, a benzyl group which may have a substituent, and a dimethylamino group. The “lower alkyl group having 1 to 4 carbon atoms” includes, for example, straight-chain or branched hydrocarbons having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and t-butyl. "Lower alkyl group" such as "lower alkoxy group having 1 to 7 carbon atoms" and "lower alkoxymethyl group having 1 to 7 carbon atoms" means, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl , Hexyl, heptyl and the like, and linear or branched hydrocarbons having 1 to 7 carbon atoms. The “benzyl group optionally having substituent (s)” includes those having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a trifluoromethyl group at an arbitrary position on a benzene ring.
[0023]
According to the present invention, the compound represented by the general formula (1) can be produced, for example, by the following route.
[0024]
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Formula (3) in synthesis route 1
[0026]
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[Wherein, R 3 represents a lower alkyl group having 1 to 4 carbon atoms, Boc represents a t-butoxycarbonyl group, and Ar, X, Y and n are as described above]. )
[0028]
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[Wherein, Z represents a chlorine atom, a bromine atom or an iodine atom, and Ar, X, Y and n are as described above] and a compound represented by the general formula (5)
[0030]
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[Wherein R3 and Boc are as defined above] and can be produced by acting in the presence of a base (Step A).
[0032]
The reaction uses methanol, ethanol, 1,4-dioxane, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or the like as a reaction solvent, and uses sodium hydride, potassium hydride, sodium alkoxide, The reaction can be carried out in the presence of an inorganic base such as potassium alkoxide, at a reaction temperature of 0 ° C to under reflux with heating, preferably at 80 ° C to 100 ° C.
[0033]
In the synthesis route 1, the general formula (4)
[0034]
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[Wherein Ar, X, Y, Boc and n are as described above], can be produced by reducing the compound represented by the general formula (3) (Step B).
[0036]
The reaction is borane (BH 3 ) Or 9-borabicyclo [3.3.1] nonane (9-BBN), diisopropylaluminum hydride (iBu) 2 AlH), sodium borohydride (NaBH) 4 ), Lithium aluminum hydride (LiAlH) 4 ), Preferably lithium borohydride (LiBH 4 ), Using THF, ethanol, methanol, or the like as a reaction solvent, at a reaction temperature of -78 ° C to heating under reflux, preferably at room temperature.
[0037]
General formula (1) in synthesis route 1
[0038]
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[Wherein Ar, X, Y and n are as described above], can be produced by acid-decomposing the compound represented by the general formula (4) (Step C).
[0040]
The reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or by mixing with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. The reaction is carried out in a solution, and the reaction can be carried out at a temperature of 0 ° C. to normal temperature.
[0041]
A compound of the general formula (1) wherein X is NH, that is, a compound of the general formula (6)
[0042]
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[Wherein Ar, Y and n are as described above] can also be produced by the following synthetic route 2-1 or 2-2.
[0044]
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Formula (8) in synthesis route 2-1
[0046]
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[Wherein Cbz represents a benzyloxycarbonyl group, and R3, Y, Boc and n are as described above], and the compound represented by the general formula (7)
[0048]
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Wherein Z represents a chlorine atom, a bromine atom and an iodine atom, and Y, Cbz and n are as described above, and a compound represented by the general formula (5) is allowed to act in the presence of a base. (Step D).
[0050]
The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, or potassium alkoxide, at a reaction temperature of 0. It can be carried out at a temperature of from 80 ° C to 100 ° C under heating to reflux.
[0051]
Formula (9) in synthesis route 2-1
[0052]
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[Wherein, Y, Cbz, Boc and n are as described above] can be produced by reducing the compound represented by the above general formula (8) (Step E).
[0054]
The reaction is BH 3 Alkylborane derivatives such as and 9-BBN, iBu 2 AlH, NaBH 4 , LiAlH 4 Metal-hydrogen complex compound, preferably LiBH 4 The reaction can be carried out at a reaction temperature of −78 ° C. to reflux under heating, preferably at room temperature, using THF, ethanol, methanol or the like as a reaction solvent.
[0055]
Formula (10) in synthesis route 2-1
[0056]
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[Wherein R4 and R5 are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms, and Y, Boc, Cbz, and n are as described above]. The compound represented by the general formula (9) The compound represented by the general formula (18)
[0058]
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[In the formula, R6 represents a chlorine atom or a trifluoromethanesulfonyloxy group, and R4 and R5 are as described above] to produce a compound (Step F).
[0060]
The reaction is carried out in the presence of an organic base such as triethylamine, pyridine, 2,6-lutidine, and imidazole, using DMF, THF, methylene chloride, chloroform, and acetonitrile as the reaction solvent at a reaction temperature of 0 ° C to 100 ° C. It can be carried out.
[0061]
Formula (11) in synthesis route 2-1
[0062]
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[Wherein R 4, R 5, Y, Boc and n are as described above], can be produced by catalytic reduction of the general formula (10) (Step G).
[0064]
The reaction can be performed in the presence of a metal catalyst such as palladium carbon, Raney nickel, and platinum oxide, using methanol, ethanol, DMF, or the like as a reaction solvent, at a reaction temperature of 0 ° C. to 80 ° C. in a stream of hydrogen gas.
[0065]
Formula (12) in synthesis route 2-1
[0066]
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[Wherein Ar, R4, R5, Y, Boc and n are as described above], the compound represented by the general formula (11) is replaced by the compound represented by the general formula (19)
Ar-Z (19)
[Wherein Ar and Z are as described above], or a compound represented by the general formula (20):
Ar-B (OH) 2 (20)
(Step H).
[0068]
The reaction between the compound represented by the general formula (11) and the compound represented by the general formula (19) is carried out without solvent or in the presence of DMF, N, N-dimethylimidazolyl in the presence of an acid catalyst such as pyridinium paratoluenesulfonic acid. Nonone can be used as a reaction solvent, and the reaction can be performed at a normal temperature to 160 ° C.
[0069]
The reaction with the compound represented by the general formula (20) is performed using anhydrous copper (II) acetate, methylene chloride, chloroform or the like as a reaction solvent in the presence of an organic base such as triethylamine or pyridine. It can be performed at 0 ° C. to normal temperature.
[0070]
Formula (6) in synthesis route 2-1
[0071]
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[Wherein Ar, Y and n are as described above] can be produced by subjecting the compound represented by the general formula (12) to desilylation followed by acid decomposition (step I). .
[0073]
In the reaction, THF, DMF, 1,4-dioxane or the like is used as a reaction solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride or the like is allowed to act at 0 ° C. to normal temperature, and then acetic acid, hydrochloric acid, odor, etc. The reaction is carried out in an inorganic or organic acid such as hydrocyanic acid, methanesulfonic acid or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. Can be performed at 0 ° C. to normal temperature.
[0074]
In the synthesis route 2-2, the general formula (14)
[0075]
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[Wherein R 3, Y, Boc and n are as described above], represented by the general formula (13)
[0077]
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Wherein Y, Z and n are as described above, and a compound represented by the general formula (21):
[0079]
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[Wherein Ac represents an acetyl group, R3 is as described above], and the compound can be produced by acting in the presence of a base (Step J).
[0081]
The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, or potassium alkoxide, at a reaction temperature of 0. The reaction can be carried out at a temperature of from 0 ° C to 100 ° C under heating to reflux.
[0082]
In the reaction route 2-2, the general formula (15)
[0083]
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[Wherein R3, Y, Ac and n are as described above] can be produced by reducing the general formula (14) (Step K).
[0085]
The reaction can be carried out in the presence of a metal catalyst such as palladium carbon, Raney nickel, platinum oxide or the like, using methanol, ethanol, DMF or the like as a reaction solvent at a reaction temperature of 0 ° C to 80 ° C under a stream of hydrogen gas.
[0086]
In the reaction route 2-2, the general formula (16)
[0087]
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[Wherein Ar, R3, Y, Ac and n are as described above], the compound represented by the general formula (15) is a compound represented by the general formula (19), or the compound represented by the general formula (19). It can be produced by allowing the compound represented by (20) to act (Step L).
[0089]
The reaction between the compound represented by the general formula (15) and the compound represented by the general formula (19) is carried out in the presence of an acid catalyst such as pyridinium p-toluenesulfonic acid in the absence of a solvent or DMF, N, N-dimethylimidazolide. Nonone can be used as a reaction solvent, and the reaction can be carried out at a normal temperature to 160 ° C.
[0090]
The reaction with the compound represented by the general formula (20) is performed using anhydrous copper (II) acetate, methylene chloride, chloroform or the like as a reaction solvent in the presence of an organic base such as triethylamine or pyridine. It can be performed at 0 ° C. to normal temperature.
[0091]
In the synthesis route 2-2, the general formula (17)
[0092]
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[Wherein Ar, Y, Ac and n are as described above] can be produced by reducing the compound represented by the general formula (16) (Step M).
[0094]
The reaction is BH 3 Alkylborane derivatives such as and 9-BBN, iBu 2 AlH, NaBH 4 , LiAlH 4 Metal-hydrogen complex compound, preferably LiBH 4 The reaction can be carried out at a reaction temperature of −78 ° C. to reflux under heating, preferably at room temperature, using THF, ethanol, methanol or the like as a reaction solvent.
[0095]
Formula (6) in synthesis route 2-2
[0096]
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[Wherein Ar, Y and n are as described above] can be produced by subjecting the compound represented by the general formula (17) to alkaline hydrolysis (step N).
[0098]
The reaction is carried out using water, methanol, ethanol, THF, DMF as a solvent in the presence of an alkali such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, and the like, at a reaction temperature of 0 ° C to 100 ° C. Can be.
[0099]
A compound of the general formula (1) wherein Ar is 4-substituted thiazole and X is NH, that is, a compound of the general formula (22)
[0100]
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[Wherein R 7 represents a lower alkyl group having 1 to 4 carbon atoms or an optionally substituted phenyl group, and Y and n are as described above], by the following synthesis route 3-1. Can also be manufactured.
[0102]
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Formula (23) in synthesis route 3-1
[0104]
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[Wherein R4, R5, Y, Boc and n are as described above], can be produced by reacting a compound represented by the aforementioned general formula (11) with benzoyl isothiocyanate. (Step O).
[0106]
The reaction can be carried out using acetone, methylene chloride, chloroform, benzene or the like as a reaction solvent at a reaction temperature of 0 ° C. to normal temperature.
[0107]
In the synthesis route 3-1, the general formula (24)
[0108]
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[Wherein R4, R5, Y, Boc and n are as described above], can be produced by decomposing the compound represented by the general formula (23) with a base (Step P) ).
[0110]
The reaction can be carried out in a solution of ammonia, sodium hydroxide, potassium hydroxide or the like, methanol, ethanol, THF or the like, at a reaction temperature of 0 ° C. to reflux under heating.
[0111]
In the synthesis route 3-1, the general formula (25)
[0112]
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[Wherein R4, R5, R7, Y, Boc and n are as described above], the compound represented by the general formula (24) is replaced by the compound represented by the general formula (26)
[0114]
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[Wherein R7 and Z are as defined above] to produce a compound (Step Q).
[0116]
The reaction can be carried out in the presence of a dehydrating agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate, using acetone, THF, or the like as a reaction solvent, and at a reaction temperature from room temperature to heating under reflux.
[0117]
Formula (22) in synthesis route 3-1
[0118]
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[Wherein R 7, Y and n are as described above] can be produced by subjecting the compound represented by the general formula (25) to acid decomposition after desilylation (step R). .
[0120]
In the reaction, THF, DMF, 1,4-dioxane or the like is used as a reaction solvent, potassium fluoride, cesium fluoride, tetrabutylammonium fluoride or the like is allowed to act at 0 ° C. to normal temperature, and then acetic acid, hydrochloric acid, odor, etc. The reaction is carried out in an inorganic or organic acid such as hydrocyanic acid, methanesulfonic acid or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. Can be performed at 0 ° C. to normal temperature.
[0121]
A compound of the general formula (1) wherein Ar is isoquinoline and X is NH, that is, a compound of the general formula (27)
[0122]
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[Wherein Y and n are as described above] can also be produced by the following synthetic route 3-2.
[0124]
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In the synthesis route 3-2, the general formula (28)
[0126]
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[Wherein R4, R5, Y, Boc and n are as described above], are produced by reacting a compound represented by the general formula (11) with a compound (29) shown below. (Step S).
[0128]
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The reaction with compound (29) can be carried out in the presence of a catalytic amount of trifluoroacetic acid, using methanol, ethanol, or the like as a reaction solvent, at a reaction temperature of room temperature to heating under reflux.
[0130]
In the synthesis route 3-2, the general formula (27)
[0131]
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[Wherein R7, Y and n are as described above] can be produced by subjecting the compound represented by the general formula (28) to acid decomposition after desilylation (step T). .
[0133]
In the reaction, THF, DMF, 1,4-dioxane or the like is used as a reaction solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride or the like is allowed to act at 0 ° C. to normal temperature, and then acetic acid, hydrochloric acid, odor, etc. The reaction is carried out in an inorganic or organic acid such as hydrocyanic acid, methanesulfonic acid or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. Can be performed at 0 ° C. to normal temperature.
[0134]
In the general formula (1), X is CH 2 A compound represented by NH or CONH, that is, a compound represented by the general formula (30):
[0135]
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[In the formula, k represents 0 or 1, and Ar, Y and n are as described above.] The compound represented by the following synthesis route 4 can also be produced.
[0137]
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In synthesis route 4, general formula (31)
[0139]
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[Wherein, Ar, R4, R5, Y, Boc, k and n are as described above], and the compound represented by the general formula (11) is a compound represented by the general formula (32)
[0141]
ArCHO (32)
[Wherein Ar is as defined above], or a compound represented by the general formula (33)
[0142]
ArCOCl (33)
Wherein Ar is as described above, or a compound represented by the general formula (34)
[0143]
ArCOOH (34)
[Wherein Ar is as defined above] to produce a compound (Step U).
[0144]
The reaction between the compound represented by the general formula (11) and the compound represented by the general formula (32) uses sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride as a reaction solvent. The reaction can be performed using THF, ethanol, methanol, or the like, at a reaction temperature of 0 ° C. to heating under reflux.
[0145]
The reaction with the compound represented by the general formula (33) is performed in the presence of a base such as triethylamine or pyridine, using methylene chloride, DMF, THF, or the like as a reaction solvent, and at a reaction temperature of 0 ° C. to normal temperature. be able to.
[0146]
The reaction with the compound represented by the general formula (34) is performed using a dehydration condensing agent such as dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-3-dimethylaminopropylcarbodiimide (EDC, WSC) as a reaction solvent. The reaction can be performed using methylene chloride, DMF, THF, or the like, at a reaction temperature of 0 ° C. to ordinary temperature.
[0147]
In synthesis route 4, general formula (30)
[0148]
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[Wherein Ar, Y, k and n are as described above], can be produced by subjecting the compound represented by the general formula (31) to acid decomposition after desilylation ( Step V).
[0150]
In the reaction, THF, DMF, 1,4-dioxane or the like is used as a reaction solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride or the like is allowed to act at 0 ° C. to normal temperature, and then acetic acid, hydrochloric acid, odor, etc. The reaction is carried out in an inorganic or organic acid such as hydrocyanic acid, methanesulfonic acid or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. Can be performed at 0 ° C. to normal temperature.
[0151]
A compound in which X is NHCO in the general formula (1), that is, the general formula (35)
[0152]
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[Wherein Ar, Y and n are as described above] can be synthesized by the following synthesis route 5.
[0154]
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In the synthesis route 5, the general formula (37)
[0156]
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[Wherein R 3, Y, Boc and n are as described above], represented by the general formula (36)
[0158]
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[Wherein Y, Z and n are as described above] and a compound represented by the general formula (5) in the presence of a base to produce a compound (Step W).
The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, or potassium alkoxide, at a reaction temperature of 0. The reaction can be carried out at a temperature of from 0 ° C to 100 ° C under heating to reflux.
[0160]
In synthesis route 5, general formula (38)
[0161]
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[Wherein Y, Boc and n are as described above] can be produced by reducing the compound represented by the general formula (37) (Step X).
[0163]
The reaction is BH 3 Alkylborane derivatives such as and 9-BBN, iBu 2 AlH, NaBH 4 , LiAlH 4 Metal-hydrogen complex compound, preferably LiBH 4 The reaction can be carried out at a reaction temperature of −78 ° C. to reflux under heating, preferably at room temperature, using THF, ethanol, methanol or the like as a reaction solvent.
[0164]
In the synthesis route 5, the general formula (39)
[0165]
Embedded image
[Wherein R4, R5, Y, Boc and n are as described above], the compound represented by the general formula (38) is allowed to act on the compound represented by the general formula (18). (Step Y).
[0167]
The reaction is carried out in the presence of an organic base such as triethylamine, pyridine, 2,6-lutidine, and imidazole, using DMF, THF, methylene chloride, chloroform, and acetonitrile as the reaction solvent at a reaction temperature of 0 ° C to 100 ° C. It can be carried out.
[0168]
In synthesis route 5, the general formula (40)
[0169]
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[Wherein R4, R5, Y, Boc and n are as described above], are produced by metallating a compound represented by the general formula (39) and then reacting with carbon dioxide gas. (Step Z).
[0171]
The reaction is carried out using THF, diethyl ether, or the like as a reaction solvent, metallizing using alkyl lithium such as normal butyl lithium or metal magnesium at a reaction temperature of -78 ° C. to room temperature, and then reacting with carbon dioxide gas. be able to.
[0172]
In synthesis route 5, the general formula (41)
[0173]
Embedded image
[Wherein Ar, R 4, R 5, Y, Boc and n are as described above], the compound represented by the general formula (40) is replaced by the compound represented by the general formula (40)
Ar-NH 2 (42)
[In the formula, Ar is as described above] to produce a compound (Step A ′).
[0175]
The reaction can be carried out using a dehydrating condensing agent such as DCC or EDC, using methylene chloride, DMF, THF or the like as a reaction solvent, optionally adding DMAP, and at a reaction temperature of 0 ° C. to room temperature.
[0176]
In synthesis route 5, general formula (35)
[0177]
Embedded image
[Wherein Ar, Y and n are as described above] can be produced by subjecting the compound represented by the general formula (41) to acid decomposition after desilylation (step B ′). ).
[0179]
In the reaction, THF, DMF, 1,4-dioxane or the like is used as a reaction solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride or the like is allowed to act at 0 ° C. to normal temperature, and then acetic acid, hydrochloric acid, odor, etc. The reaction is carried out in an inorganic or organic acid such as hydrocyanic acid, methanesulfonic acid or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. Can be performed at 0 ° C. to normal temperature.
[0180]
In the general formula (1), X is CO or CH 2 A compound represented by the general formula (43)
[0181]
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[Wherein Ar, Y, k and n are as described above], can also be produced by the following synthetic route 6.
[0183]
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In the synthesis route 6, the general formula (44)
[0185]
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[Wherein Ar, R4, R5, Y, Boc and n are as described above], the compound represented by the general formula (39) is metallized, and then the compound represented by the general formula (46)
[0187]
Embedded image
[Wherein Ar is as defined above] to produce a compound (Step C ′).
[0189]
The reaction is represented by the general formula (46) after metallization using an alkyl lithium such as normal butyl lithium or metal magnesium at a reaction temperature of −78 ° C. to room temperature using THF, diethyl ether or the like as a reaction solvent. The compound can be produced by allowing a compound to act.
[0190]
In the synthesis route 6, the general formula (45)
[0191]
Embedded image
[Wherein Ar, R4, R5, Y, Boc and n are as described above], can be produced by reducing the compound represented by the general formula (44) (Step D ′).
[0193]
In the reaction, an acid such as hydrochloric acid or acetic acid is added in the presence of a metal catalyst such as palladium carbon, Raney nickel, or platinum oxide, and methanol or ethanol is used as a reaction solvent. Can be performed under airflow.
[0194]
In the synthesis route 6, the general formula (43)
[0195]
Embedded image
[Wherein Ar, Y, k and n are as described above], are produced by subjecting compounds represented by the general formulas (44) and (45) to desilylation followed by acid decomposition. (Step E ′).
[0197]
In the reaction, THF, DMF, 1,4-dioxane, water and the like are used as reaction solvents, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride and the like are allowed to act under a temperature of 0 ° C. to heating under reflux, and then acetic acid, Act on inorganic or organic acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid and trifluoroacetic acid, or on mixed solutions with organic solvents such as methanol, ethanol, THF, 1,4-dioxane and ethyl acetate. The reaction can be performed at a reaction temperature of 0 ° C. to normal temperature.
[0198]
In the general formula (1), Y is CH 2 Wherein n is 2; that is, a compound of the general formula (47)
[0199]
Embedded image
[Wherein Ar, Y, k and n are as described above], can also be produced by the following synthetic route 7.
[0201]
Embedded image
In the synthesis route 7, the general formula (49)
[0203]
Embedded image
[Wherein R3 and Boc are as described above], represented by the general formula (48)
[0205]
Embedded image
[Wherein, Z is as defined above] and a compound represented by the general formula (5) in the presence of a base to produce the compound (Step F ').
[0207]
The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent, in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, or potassium alkoxide, at a reaction temperature of 0. The reaction can be carried out at a temperature of from 0 ° C to 100 ° C under heating to reflux.
[0208]
In the synthesis route 7, the general formula (50)
[0209]
Embedded image
[Wherein Y, Cbz, Boc and n are as described above], can be produced by reducing the compound represented by the general formula (49) (Step G ′).
[0211]
The reaction is BH 3 Alkylborane derivatives such as and 9-BBN, iBu 2 AlH, NaBH 4 , LiAlH 4 Metal-hydrogen complex compound, preferably LiBH 4 The reaction can be carried out at a reaction temperature of −78 ° C. to reflux under heating, preferably at room temperature, using THF, ethanol, methanol or the like as a reaction solvent.
In the synthesis route 7, the general formula (51)
[0212]
Embedded image
[Wherein R4, R5 and Boc are as described above], are produced by reacting a compound represented by the general formula (18) with a compound represented by the general formula (50). (Step H ′).
[0214]
The reaction is carried out in the presence of an organic base such as triethylamine, pyridine, 2,6-lutidine, and imidazole, using DMF, THF, methylene chloride, chloroform, and acetonitrile as the reaction solvent at a reaction temperature of 0 ° C to 100 ° C. It can be carried out.
[0215]
In the synthesis route 7, the general formula (52)
[0216]
Embedded image
[Wherein R 4, R 5 and Boc are as described above] can be produced by catalytic reduction of the compound represented by the general formula (51) (Step I ′).
[0218]
The reaction can be performed in the presence of a metal catalyst such as palladium carbon, Raney nickel, and platinum oxide, using methanol, ethanol, DMF, or the like as a reaction solvent, at a reaction temperature of 0 ° C. to 80 ° C. in a stream of hydrogen gas.
[0219]
In the synthesis route 7, the general formula (53)
[0220]
Embedded image
[Wherein R 4, R 5 and Boc are as described above] can be produced by oxidizing the compound represented by the general formula (52) (Step J ′).
[0222]
The reaction is carried out using pyridium chlorochromate (PCC), activated manganese dioxide, tetrapropylammonium perruthenate (TPAP) or the like as an oxidizing agent, or reoxidation of a catalytic amount of TPAP or the like with 4-methylmorpholine N-oxide. The reaction can be carried out at a temperature of 0 ° C. to room temperature using an agent, methylene chloride, DMF, or the like as a reaction solvent.
[0223]
In the reaction route 7, the general formula (54)
[0224]
Embedded image
[Wherein Ar, R4, R5, X and Boc are as described above], the compound represented by the general formula (53) is replaced by the compound represented by the general formula (56)
[0226]
Embedded image
[Wherein, Ar, X and Z are as defined above] to produce a compound (Step K ′).
[0228]
The reaction is carried out in the presence of a base such as sodium hydride, sodium alkoxide, potassium alkoxide, and alkyl lithium, using THF, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent, and at a reaction temperature of −78 ° C. to room temperature. be able to.
[0229]
In the reaction route 7, the general formula (55)
[0230]
Embedded image
[Wherein Ar, R4, R5, X and Boc are as described above], can be produced by reducing the compound represented by the general formula (54) (step L ′). .
[0232]
The reaction can be performed in the presence of a metal catalyst such as palladium carbon, Raney nickel, and platinum oxide, using methanol, ethanol, DMF, or the like as a reaction solvent, at a reaction temperature of 0 ° C. to 80 ° C. in a stream of hydrogen gas.
[0233]
In the reaction route 7, the general formula (47)
[0234]
Embedded image
[Wherein Ar and X are as described above] can be produced by subjecting the compound represented by the general formula (55) to acid decomposition after desilylation (Step M ′).
[0236]
In the reaction, THF, DMF, 1,4-dioxane, water and the like are used as reaction solvents, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride and the like are allowed to act under a temperature of 0 ° C. to heating under reflux, and then acetic acid, Act on inorganic or organic acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid and trifluoroacetic acid, or on mixed solutions with organic solvents such as methanol, ethanol, THF, 1,4-dioxane and ethyl acetate. The reaction can be performed at a reaction temperature of 0 ° C. to normal temperature.
[0237]
【Example】
Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
[0238]
<Reference Example 1>
3- (4-benzyloxycarbonylaminophenyl) dihydrocinnamyl iodide
[0239]
Embedded image
Ethyl 3- (4-benzyloxycarbonylaminophenyl) dihydrocinnamate (18 g) was dissolved in THF, and LiBH was stirred under ice cooling. 4 (5.99 g) and ethanol (50 mL) were added, and the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 8 hours. After quenching with a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain colorless powdery crystals.
[0241]
This was dissolved in THF, and imidazole (7.49 g) and triphenylphosphine (27.5 g) were added. After cooling with ice, iodine (27.9 g) was added, and the mixture was stirred at the same temperature for 30 minutes. After quenching with a 10% aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate, and washed sequentially with a 10% aqueous sodium thiosulfate solution, water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 5: 1) to obtain the desired product (17.9 g) as colorless powdery crystals.
<Reference Examples 2 to 13>
The compounds shown in Table 1 were synthesized from various esters in the same manner as in Reference Example 1.
[0242]
[Table 1]
<Example 1>
Diethyl 2- [3- [4- (benzothiazol-2-ylamino) phenyl] propyl] -2-t-butoxycarbonylaminomalonate
[0244]
Embedded image
Sodium-t-butoxide (857 mg) was added to a solution of diethyl 2-t-butoxycarbonylaminomalonate (2.46 g) in ethanol (20 mL) at room temperature under an argon stream. After stirring at 65 ° C. for 30 minutes, a solution of the compound of Reference Example 3 (1.76 g) in THF (20 mL) was added. Thereafter, the mixture was heated under reflux for 4 hours, allowed to cool, and the solvent was distilled off. Water was added to the residue, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (2.07 g) as a pale yellow amorphous substance.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.23 (6H, t, J = 7.3 Hz), 1.43 (9H, brs), 1.45-1.54 (2H, m), 2.34 (2H, br), 2 .64 (2H, t, J = 7.8 Hz), 5.95 (1H, brs), 7.13-7.19 (3H, m), 7.34 (1H, m), 7.38 ( 2H, d, J = 8.3 Hz), 7.60-7.63 (2H, m).
[0246]
<Examples 2 to 13>
Using the compounds of Reference Examples 1, 2, 4 to 13, the compounds shown in Table 2 were synthesized in the same manner as in Example 1.
[0247]
[Table 2]
<Example 14>
2- [3- [4- (benzothiazol-2-ylamino) phenyl] propyl] -2-t-butoxycarbonylamino-1,3-propanediol
[0249]
Embedded image
Lithium aluminum hydride (436 mg) was suspended in THF (20 mL), and a solution of the compound of Example 1 (2.07 g) in THF (20 mL) was added dropwise at −78 ° C. with stirring. The reaction temperature was gradually returned to room temperature, and the mixture was further stirred for 5 hours. After cooling with ice, the mixture was quenched with water, a 2 mol / L aqueous sodium hydroxide solution (1 mL) was added, and the precipitated insolubles were removed by filtration using Celite. After the insolubles were thoroughly washed with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (726 mg) as pale yellow powdery crystals.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.44 (9H, s), 1.56-1.62 (4H, m), 2.62 (2H, t, J = 6.3 Hz), 3.39 (2H, brs), 58 (2H, d, J = 11.7 Hz), 3.83 (2H, d, J = 11.7 Hz), 4.90 (1H, brs), 7.16 (1H, t, J = 7. 8 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.32-7.37 (1 H, m), 7.41 (2H, d, J = 8.3 Hz), 7.63 ( 2H, d, J = 7.8 Hz).
[0251]
<Examples 15 to 26>
Using the compounds of Examples 2 to 13, the compounds described in Table 3 were synthesized in the same manner as in Example 14.
[0252]
[Table 3]
<Example 27>
5- [3- [4- (benzyloxycarbonylamino) phenyl] propyl] -5-tert-butoxycarbonylamino-2,2-di-tert-butyl-1,3,2-dioxasilane
[0254]
Embedded image
In a solution of the compound of Example 24 (20 g) and 2,6-lutidine (15.3 mL) in DMF (500 mL) at 0 ° C., di-tert-butylsilylbistrifluoromethanesulfonate (15.9 mL) in methylene chloride ( 100 mL) solution was added slowly. After stirring at 0 ° C. for 2 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, water (twice) and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to obtain the desired product (14.5 g) as a colorless amorphous substance.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.42 (9H, s), 1.53 (4H, br s), 2.54 (2H, t, J = 6) .4 Hz), 3.88 (2H, d, J = 11.2 Hz), 4.21 (2H, d, J = 11.2 Hz), 4.90 (1H, brs), 5.19 (2H, s), 6.59 (1H, br s), 7.07 (2H, d, J = 8.8 Hz), 7.26-7.42 (7H, m).
[0256]
<Examples 28 and 29>
5- [3- (4-bromophenyl) propyl] -5-t-butoxycarbonylamino-2,2-di-t-butyl-1,3,2-dioxasilane and 5- (2-benzyloxyethyl)- 5-tert-butoxycarbonylamino-2,2-di-tert-butyl-1,3,2-dioxasilane
[0257]
Embedded image
By using the compounds of Examples 25 and 26 in the same manner as in Example 27, the compound of Example 28 was converted into colorless powdery crystals (yield 77%), and the compound of Example 29 was converted into a colorless oil (yield 49%). (2 steps yield from the previous process).
[0259]
<Example 30>
5- [3- (4-aminophenyl) propyl] -5-t-butoxycarbonylamino-2,2-di-t-butyl-1,3,2-dioxasilane
[0260]
Embedded image
To a solution of the compound of Example 27 (14.5 g) in ethanol (200 mL) was added 10% palladium on carbon (1.5 g), and the mixture was stirred at room temperature for 5 hours under a hydrogen gas stream (normal pressure). The catalyst was removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1 to 3: 1) to obtain the desired product (9.55 g) as colorless powdery crystals.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.43 (9H, s), 1.47-1.56 (4H, m), 2.46 (2H, t, J = 7.3 Hz), 3.56 (2H, brs), 3.88 (2H, d, J = 11.2 Hz), 4.22 (2H, d, J = 11.2 Hz), 4.89 (1H, brs), 6.62 (2H, d, J = 8.3 Hz), 6.93 (2H, d, J = 8.3 Hz).
[0262]
<Example 31>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- (2-hydroxyethyl) -1,3,2-dioxasilane
[0263]
Embedded image
The compound of Example 29 was synthesized in the same manner as in Example 30 (colorless oil, yield quant.).
[0265]
<Example 32>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- [4- (quinolin-2-ylamino) phenyl] propyl] -1,3,2-dioxasilane
[0266]
Embedded image
A solution of the compound of Example 30 (80 mg) and 2-chloroquinoline (35 mg) in N, N-dimethylimidazolidinone (2 mL) was stirred at 100 ° C. for 7.5 hours. After allowing to cool, the mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water (5 times) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (31 mg) as a pale yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.05 (9H, s), 1.07 (9H, s), 1.44 (9H, s), 1.59 (4H, br), 2.58 (2H, t, J = 6. 8 Hz), 3.90 (2H, d, J = 11.2 Hz), 4.24 (2H, d, J = 11.2 Hz), 4.92 (1H, br), 6.78 (1H, br) , 6.96 (1H, d, J = 8.8 Hz), 7.14 (2H, d, J = 8.5 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.45 ( 2H, d, J = 8.5 Hz), 7.58 (1H, t, J = 8.0 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.8 Hz).
[0268]
<Examples 33 to 48>
Using the compound of Example 30 and various chlorinated heterocycles, the compounds described in Table 4 were synthesized in the same manner as in Example 32.
[0269]
[Table 4]
<Example 49>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- [4- (3,5-dichlorophenylamino) phenyl] propyl] -1,3,2-dioxasilane
[0271]
Embedded image
Triethylamine (0.18 mL) was added to a methylene chloride (3 mL) solution of the compound of Example 30 (300 mg), 3,5-dichlorophenylboric acid (246 mg) and anhydrous copper (II) acetate (117 mg), and the mixture was added at room temperature for 20 hours. Stirred. The reaction solvent was directly purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired product (240 mg) as a yellow amorphous substance.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.05 (9H, s), 1.07 (9H, s), 1.43 (9H, s), 1.57 (4H, br s), 2.55 (2H, t, J = 6) .8 Hz), 3.90 (2H, d, J = 11.7 Hz), 4.23 (2H, d, J = 10.3 Hz), 4.92 (1H, brs), 5.68 (1H, br s), 6.79-6.81 (3H, m), 7.02 (2H, d, J = 8.3 Hz), 7.11 (2H, d, J = 8.3 Hz).
[0273]
<Examples 50 to 68>
Using the compound of Example 30 and various phenylboric acid derivatives, the compounds described in Table 5 were obtained in the same manner as in Example 49.
[0274]
[Table 5]
<Example 69>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- [4- (isoquinolin-3-ylamino) phenyl] propyl] -1,3,2-dioxasilane
[0276]
Embedded image
To a solution of 2-acetonitrile benzaldehyde (145 mg) in ethanol (5 mL) were added the compound of Example 30 (465 mg) and trifluoroacetic acid (2 drops), and the mixture was heated under reflux for 20 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 7: 1) to obtain the desired product (615 mg) as yellow powdery crystals.
FABMS [M + H] + 592
[0278]
<Example 70>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- [4- (3,5-dichlorobenzylamino) phenyl] propyl] -1,3,2-dioxasilane
[0279]
Embedded image
To a solution of the compound of Example 30 (200 mg) and 3,5-dichlorobenzaldehyde (75.3 mg) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (146 mg) and acetic acid (2 drops), and the mixture was stirred at room temperature overnight. Stirred. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate, and washed sequentially with saturated aqueous sodium bicarbonate, water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to obtain the desired product (195 mg) as a pale yellow amorphous substance.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.42 (9H, s), 1.43-1.56 (4H, m), 2.46 (2H, t, J = 6.8 Hz), 3.88 (2H, d, J = 11.2 Hz),
4.04 (1H, br s), 4.22 (2H, d, J = 11.7 Hz), 4.28 (2H, s), 4.89 (1H, br s), 6.51 (2H, br s) d, J = 8.3 Hz), 6.96 (2H, d, J = 8.3 Hz), 7.26 (3H, s).
[0281]
<Examples 71 and 72>
Using the compound of Example 30 and 3,5-bistrifluoromethylbenzaldehyde and 2-formylbenzothiazole, the compounds described in Table 6 were synthesized in the same manner as in Example 70.
[0282]
[Table 6]
<Example 73>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- [4- (3,5-dichlorobenzoylamino) phenyl] propyl] -1,3,2-dioxasilane
[0284]
Embedded image
A solution of 3,5-dichlorobenzoic acid (49.3 mg) and 1-hydroxybenzotriazole monohydrate (39.5 mg) in DMF (2 mL) was added to the compound of Example 30 (100 mg) and N-ethyl-N. '-3-Dimethylaminopropylcarbodiimide hydrochloride (WSC-HCl) (61.9 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water (twice) and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (135 mg) as pale brown powdery crystals.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.05 (9H, s), 1.06 (9H, s), 1.43 (9H, s), 1.58 (4H, br s), 2.57 (2H, br s), 3 .88 (2H, d, J = 11.2 Hz), 4.22 (2H, d, J = 11.2 Hz), 4.92 (1H, brs), 7.16 (2H, d, J = 8) .3 Hz), 7.51 (2H, d, J = 8.3 Hz), 7.53 (1H, t, J = 2.0 Hz), 7.68 (1H, brs), 7.73 (2H, d, J = 2.0 Hz).
[0286]
<Examples 74 and 75>
Using the compound of Example 30 and quinoline-2-carboxylic acid and benzothiazole-2-carboxylic acid, the compounds described in Table 7 were synthesized in the same manner as in Example 73.
[0287]
[Table 7]
<Example 76>
5- [3- [4- (3-benzoylthioureido) phenyl] propyl] -5-tert-butoxycarbonylamino-2,2-di-tert-butyl-1,3,2-dioxasilane
[0289]
Embedded image
A solution of the compound of Example 30 (929 mg) in acetone (5 mL) was slowly added dropwise to a solution of benzoylthioisocyanate (326 mg) in acetone (10 mL) under ice-cooling with stirring over 10 minutes. After stirring at 0 ° C. for 1 hour, the solvent was distilled off. After dissolving the residue with a small amount of ethyl acetate, a large amount of hexane was added to precipitate the desired product. The precipitated crystals were collected by filtration and dried to give the desired product (1.14 g) as colorless powder crystals.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.05 (9H, s), 1.07 (9H, s), 1.44 (9H, s), 1.57 (4H, br s), 2.60 (2H, br s), 3 .90 (2H, d, J = 11.2 Hz), 4.23 (2H, d, J = 11.2 Hz), 4.92 (1H, brs), 7.20 (2H, d, J = 8) .3 Hz), 7.56 (2H, t, J = 7.3 Hz), 7.61 (2H, d, J = 8.3 Hz), 7.66 (1H, t, J = 7.3 Hz), 7 .90 (2H, d, J = 7.3 Hz), 9.07 (1H, br s), 12.53 (1H, br s).
[0291]
<Example 77>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- (4-thioureidophenyl) propyl] -1,3,2-dioxasilane
[0292]
Embedded image
To a solution of the compound of Example 76 (500 mg) in THF (2 mL) was added a saturated ammonia ethanol solution (8 mL) under ice-cooling, and the mixture was stirred at room temperature in a sealed tube for 16 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1 to 1: 1) to obtain the desired product (410 mg) as a colorless amorphous substance.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.41 (9H, s),
1.54 (2H, br s), 1.62 (2H, br s), 2.59 (2H, br s), 3.89 (2H, d, J = 11.2 Hz), 4.19 (2H) , D, J = 11.2 Hz), 4.92 (1H, brs), 6.04 (2H, brs), 7.14 (2H, d, J = 8.3), 7.21 (2H) , D, J = 8.3 Hz), 7.83 (1H, brs).
[0294]
<Example 78>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- [3- [4- (4-methylthiazol-2-ylamino) phenyl] propyl] -1,3,2-dioxasilane
[0295]
Embedded image
Chloroacetone (62.3 μL) was added to a suspension of anhydrous magnesium sulfate (500 mg) in acetone (10 mL). Under reflux with heating, a solution of the compound of Example 77 (410 mg) in acetone (5 mL) was added dropwise, and the mixture was heated under reflux for 2 hours. Thereafter, chloroacetone (62.3 μL) was added, and the mixture was further heated under reflux for 5 hours. After allowing to cool, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 4: 1) to obtain the desired product (107 mg) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.43 (9H, s), 1.55 (2H, br s), 1.70 (2H, br s), 2 .29 (3H, s), 2.55 (2H, t, J = 6.8 Hz), 3.89 (2H, d, J = 11.2 Hz), 4.22 (2H, d, J = 11.1 Hz) 2 Hz), 4.91 (1H, brs), 6.16 (1H, d, J = 1.0 Hz), 7.11 (2H, d, J = 8.3 Hz), 7.21 (2H, d, J = 8.3 Hz).
[0297]
<Examples 79 and 80>
Using the compound of Example 77 and 4-fluorophenacyl bromide and 4-chlorophenacyl bromide, the compounds described in Table 8 were synthesized in the same manner as in Example 78.
[0298]
[Table 8]
<Example 81>
4- [3- (5-tert-butoxycarbonylamino-2,2-di-tert-butyl- [1,3,2] dioxasilinan-5-yl) propyl] benzoic acid
[0300]
Embedded image
A hexane solution of n-butyllithium (1.6 mol / L, 1.25 mL) was added dropwise at −78 ° C. to a diethyl ether (5 mL) solution of the compound of Example 28 (529 mg) under an argon stream, and −78 ° C. Stirred at 0 ° C for 15 minutes and further at 0 ° C for 30 minutes. After the reaction solution was cooled again to −78 ° C., the temperature was gradually raised to room temperature while bubbling carbon dioxide gas. After neutralization with dilute hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to obtain the desired product (200 mg) as colorless powdery crystals.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.43 (9H, s), 1.58 (4H, brs), 2.65 (2H, brs), 3 .88 (2H, d, J = 11.2 Hz), 4.22 (2H, d, J = 11.2 Hz), 4.94 (1H, brs), 7.24 (2H, d, J = 8) .3 Hz), 8.01 (2H, d, J = 8.3 Hz).
[0302]
<Example 82>
5- [3- [4- (benzothiazol-2-ylaminocarbonyl) phenyl] propyl] -5-tert-butoxycarbonylamino-2,2-di-tert-butyl-1,3,2-dioxasilane
[0303]
Embedded image
To a solution of the compound of Example 81 (200 mg) and 1-hydroxybenzotriazole monohydrate (62.0 mg) in DMF (3 mL) were added 2-aminobenzothiazole (91.3 mg) and N-ethyl-N′-. 3-Dimethylaminopropylcarbodiimide hydrochloride (WSC-HCl) (117 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water (twice) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to give the desired product (160 mg) as colorless powdery crystals.
FABMS [M + H] + 626.
[0305]
<Example 83>
5- [3- [4- (3,5-bistrifluoromethylbenzoyl) phenyl] propyl] -5-tert-butoxycarbonylamino-2,2-di-tert-butyl-1,3,2-dioxasilane
[0306]
Embedded image
Under an argon stream, n-butyllithium (1.30 mL: 1.52 mol / L hexane solution) was slowly added to a solution of the compound of Example 28 (530 mg) in diethyl ether (10 mL) under stirring at -78 ° C. The temperature was slowly raised to 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. After cooling again to -78 ° C, a solution of N-methoxy-N-methyl-3,5-bistrifluoromethylbenzamide (300 mg) in diethyl ether (3 mL) was added. THF (5 mL) was added, the temperature was slowly raised to 0 ° C., and the mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (220 mg) as a colorless amorphous substance.
FABMS [M + H] + 690.
[0308]
<Example 84>
5- [3- [4- (3,5-bistrifluoromethylbenzyl) phenyl] propyl] -5-tert-butoxycarbonylamino-2,2-di-tert-butyl-1,3,2-dioxasilane
[0309]
Embedded image
To a solution of the compound of Example 83 (280 mg) in ethanol (10 mL) was added 10% palladium carbon (60 mg) and acetic acid (several drops), and the mixture was stirred at room temperature for 5 hours under a hydrogen gas (normal pressure) stream. Insolubles were removed by filtration using Celite, a small amount of triethylamine was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (166 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.05 (9H, s), 1.06 (9H, s), 1.42 (9H, s), 1.52-1.60 (4H, br), 2.56 (2H, t, J = 6.0 Hz), 3.89 (2H, d, J = 11.0 Hz), 4.03 (2H, s), 4.22 (2H, d, J = 11.0 Hz), 4.91 ( 1H, br s), 7.07 (2H, d, J = 8.0 Hz),
7.11 (2H, d, J = 8.0 Hz), 7.62 (2H, s), 7.72 (1H, s).
[0311]
<Example 85>
5-tert-butoxycarbonylamino-2,2-di-tert-butyl-5- (2-oxoethyl) -1,3,2-dioxasilane
[0312]
Embedded image
To a solution of the compound of Example 31 (200 mg) and 4-methylmorpholine N-oxide (92 mg) in methylene chloride (1 mL) was added molecular sieves 4A (270 mg) and tetrapropylammonium perruthenate (10 mg). And stirred for 2 hours. The reaction solution was directly purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (144 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.06 (9H, s), 1.09 (9H, s), 1.43 (9H, s), 2.70 (2H, br), 4.05 (2H, d, J = 11.1). 2Hz), 4.29 (2H, d, J = 11.2 Hz), 5.19 (1H, brs), 9.75 (1H, t, J = 2.0 Hz).
[0314]
<Example 86>
5- [3- (3 ', 5'-bistrifluoromethylbiphenyl-4-yl) allyl] -5-t-butoxycarbonylamino-2,2-di-t-butyl-1,3,2-dioxasilane
[0315]
Embedded image
To a suspension of (3,5-bistrifluoromethylbiphenyl-4-ylmethyl) triphenylphosphonium bromide (250 mg) in THF (5 mL) was added sodium-t-butoxide (35 mg) under ice-cooling and stirring. After stirring at room temperature for 1 hour, a THF (2 mL) solution of the compound of Example 85 (144 mg) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane only to hexane: ethyl acetate = 20: 1) to obtain the desired product (139 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.04 (9H, s), 1.06 (9H, s), 1.44 (9H, s), 2.68 (2H, d, J = 5.8 Hz), 3.89 (2H, s) d, J = 11.2 Hz), 4.26 (2H, d, J = 11.2 Hz), 5.02 (1H, brs), 5.74-5.81 (1H, m), 6.59 ( 1H, d, J = 11.7 Hz), 7.37 (2H, d, J = 7.8 Hz), 7.59 (2H, d, J = 7.8 Hz), 7.85 (1H, s), 8.02 (2H, s).
[0317]
<Example 87>
5- [3- (3 ', 5'-bistrifluoromethylbiphenyl-4-yl) propyl] -5-t-butoxycarbonylamino-2,2-di-t-butyl-1,3,2-dioxasilane
[0318]
Embedded image
10% palladium carbon was added to a solution of the compound of Example 86 (139 mg) in ethanol (10 mL), and the mixture was stirred at room temperature for 2 hours under a hydrogen gas (normal pressure) stream. The catalyst was removed by filtration using Celite, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate only) to obtain the desired product (146 mg) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) Δ 1.05 (9H, s), 1.06 (9H, s), 1.43 (9H, s), 1.50-1.62 (4H, br), 2.65 (2H, br s) , 3.90 (2H, d, J = 11.0 Hz), 4.23 (2H, d, J = 11.0 Hz), 4.93 (1H, brs), 7.28 (2H, d, J). = 8.0 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.83 (1H, br s), 7.99 (1H, br s).
[0320]
<Example 88>
2-amino-2- [3- [4- (benzothiazol-2-ylamino) phenyl] propyl] -1,3-propanediol dihydrochloride
[0321]
Embedded image
The compound of Example 14 (100 mg) was dissolved in a mixed solvent of ethanol (3 mL) and ethyl acetate (1 mL), and 3 mol / L hydrochloric acid-containing ethyl acetate (2 mL) was added under ice-cooling and stirring. After stirring at room temperature for 20 hours, the mixture was diluted with ethyl acetate (50 mL). The precipitated crystals were collected by filtration and dried to give the desired product (60.1 mg) as colorless powder crystals (large in hygroscopicity).
1 H-NMR (400 MHz, DMSO-d 6 ) Δ 1.57 (4H br s), 2.54 (2H, br s), 3.44 (2H, d, J = 11.2 Hz), 3.47 (2H, d, J = 11.2 Hz) , 7.13-7.17 (1H, m), 7.20 (2H, d, J = 8.3 Hz), 7.29-7.34 (1H, m), 7.57 (1H, d, J = 7.8 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.73 (3H, brs), 7.79 (1H, d, J = 7.8 Hz), 10.57 (2H, brs).
FABMS [M + H] + 358.
[0323]
<Examples 89 to 97>
Using the compounds of Examples 15 to 23, the compounds described in Table 9 were synthesized in the same manner as in Example 88.
[0324]
[Table 9]
<Example 98>
2-Amino-2- [3- [4- (quinolin-2-ylamino) phenyl] propyl] -1,3-propanediol dihydrochloride
[0326]
Embedded image
To a solution of the compound of Example 32 (30 mg) in THF (1 mL) was added a 1 M tetra-n-butylammonium fluoride THF solution (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a pale yellow oil. This was dissolved in ethanol (2 mL) and ethyl acetate (2 mL), and 3 mol / L hydrochloric acid-containing ethyl acetate (2 mL) was added, followed by stirring at room temperature for 5 hours. The solvent was distilled off under reduced pressure to obtain the desired product (8 mg) as a yellow amorphous substance.
1 H-NMR (400 MHz, DMSO-d 6 ) Δ 1.45 (2H, br m), 1.59 (2H, br m), 2.53 (2H, br), 3.43 (4H, br), 4.91
(1H, br), 7.03 (1H, d, J = 8.8 Hz), 7.15 (2H, d, J = 8.5 Hz), 7.27 (1H, t, J = 7.5 Hz) , 7.56 (1H, t, J = 7.5 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.70 (1H, d, J = 7.5 Hz), 7.88 ( 2H, d, J = 8.5 Hz), 8.02 (1H, d, J = 8.8 Hz), 9.34 (1H, s).
FABMS [M + H] + 352.
128-130 ° C.
[0328]
<Examples 99 to 148>
Using Examples 33 to 75, 78 to 80, 82 to 84, and 87, compounds described in Tables 10 and 11 were synthesized in the same manner as in Example 98.
[0329]
[Table 10]
[Table 11]
Next, results supporting the usefulness of the compound of the present invention will be shown by experimental examples.
[0332]
<Experimental example 1> Inhibitory effect of test compound on mouse host versus graft rejection
Transplantation, Vol. 55, No. 3, pp. 578-591, 1993. The procedure was carried out with reference to the method described in (1). Spleens were collected from BALB / c male mice 8-11 weeks of age (CLEA Japan). The spleen is taken out in phosphate buffered saline (PBS (-), Nissui Pharmaceutical) or RPMI-1640 medium (Gibco) and passed through a stainless steel mesh or crushed with two slide glasses and a cell strainer. (70 micron, Falcon) to give a spleen cell suspension. After removing the supernatant by centrifugation of the spleen cell suspension, ammonium chloride-tris isotonic buffer was added to lyse erythrocytes. After centrifugal washing three times with PBS (−) or RPMI-1640 medium, the cells were suspended in RPMI-1640 medium. To this was added mitomycin C (Kyowa Hakko) so that the final concentration was 25 μg / mL, and the mixture was added at 37 ° C. and 5% CO 2. 2 Incubated for 30 minutes under. After washing three times with PBS (−) or RPMI-1640 medium, 2.5 × 10 8 Cells / mL, and this was used as a stimulating cell suspension. 20 μL of the stimulated cell suspension (5 × 10 6 Were injected subcutaneously into the right hind footpad of 8-week-old C3H / HeN male mouse (CLEA Japan) using a 27G needle and a microsyringe (Hamilton). The normal control group was injected with RPMI-1640 medium only. Four days later, the lymph node below the right knee was excised and weighed using a METTLER AT201 electronic balance (METTLER TOLEDO). The test compound was intraperitoneally administered once a day for a total of four times a day from the day of stimulator cell injection to three days later. The control group received a solvent having the same composition as that used for preparing the test compound. It is shown in Table 12. The suppression rate was calculated using the following formula.
[0333]
(Equation 1)
[Table 12]
<Experimental example 2> Inhibitory effect of test compound on mouse delayed-type hypersensitivity reaction
Methods in Enzymology, 300, 345-363, 1999. The procedure was carried out with reference to the method described in (1). 1-Fluoro-2,4-dinitrobenzene (DNFB, Nacalai Tesque) was dissolved in a mixture of acetone and olive oil (4: 1) to a concentration of 1% (v / v). Antigen sensitization was performed by applying 10 μL of a 1% DNFB solution to the foot pads of the left and right hind limbs of 8 or 9 weeks old BALB / c male mice (CLEA Japan). The normal control group was applied only with a mixture of acetone and olive oil (4: 1). This antigen sensitization was performed for two consecutive days, which were designated as day 0 and day 1. On day 5, the same antigen was challenged in the ear to induce a delayed type hypersensitivity reaction. First, the left and right ear thicknesses before the antigen challenge were measured using a dial thickness gauge G (0.01-10 mm, Ozaki Seisakusho). Next, the test compound was administered intraperitoneally. The control group received a solvent having the same composition as that used for preparing the test compound. Thirty minutes later, a 0.2% (v / v) DNFB solution dissolved in a mixture of acetone and olive oil (4: 1) was applied to each of the right and left ears by 10 μL (20 mL / ear) on the front and back of the left and right ears to perform antigen challenge. Was. The left ear was challenged with solvent only. Twenty-four hours later, the thickness of the left and right ears was measured to determine the amount of increase in the ear thickness. The average of the increase in the ear thickness of the left and right ears was taken as data for each individual. Table 13 shows the results. The suppression rate was calculated using the following formula.
[0336]
(Equation 2)
[Table 13]
As described above, the effectiveness of the compound of the present invention represented by the general formula (1) was confirmed in an animal experimental model.
[0339]
【The invention's effect】
As described above, the present invention relates to novel 2-amino-1,3-propanediol derivatives, particularly 2-amino-1 in which two aromatic rings are linked using a spacer such as an amino group, an amide group and a methylene chain. , 3-propanediol derivatives have a strong immunosuppressive action. Compounds having such an immunosuppressive action include drugs for preventing or treating rejection in organ transplantation and bone marrow transplantation, drugs for preventing or treating autoimmune diseases, drugs for preventing or treating rheumatoid arthritis, preventing psoriasis or atopic dermatitis. Or, it is useful as a therapeutic agent and an agent for preventing or treating bronchial asthma or hay fever.
Claims (12)
Ｘは、ＮＲ１（Ｒ１は水素原子あるいは炭素数１〜４の低級アルキル基を示す）、ＣＨ２ＮＨ、ＮＨＣＨ２、ＣＯＮＨ、ＮＨＣＯ、−（ＣＨ２）ｍ−（ｍは０または１を示す）又はＣＯを示し、
Ｙは炭素原子又は酸素原子を示し、
ｎは０〜３の整数を示す。］
で表されることを特徴とする２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物。General formula (1)
X is, NR1 (R1 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), CH 2 NH, NHCH 2 , CONH, NHCO, - (CH 2) m - (m is 0 or 1) Or indicates CO,
Y represents a carbon atom or an oxygen atom,
n shows the integer of 0-3. ]
A 2-amino-1,3-propanediol derivative, a pharmacologically acceptable salt and a hydrate thereof, which are represented by the following formula:
で表される化合物であることを特徴とする請求項１に記載の２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物。The compound represented by the general formula (1) is represented by the general formula (1a)
The 2-amino-1,3-propanediol derivative, a pharmacologically acceptable salt and a hydrate thereof according to claim 1, which is a compound represented by the formula:
で表される化合物であることを特徴とする請求項１に記載の２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物。The compound represented by the general formula (1) is represented by the general formula (1b)
The 2-amino-1,3-propanediol derivative, a pharmacologically acceptable salt and a hydrate thereof according to claim 1, which is a compound represented by the formula:
１） ２−アミノ‐２‐［３‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール、
２） ２−アミノ‐２‐［３‐［４‐（キノリン−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール、
３） ２−アミノ−２−［３−［４−（３，５−ビストリフルオロメチルフェニルアミノ）フェニル］プロピル］−１，３−プロパンジオール、
４） ２−アミノ−２−（３−［４−［４−（４−クロロフェニル）チアゾール−２−イルアミノ］フェニル］プロピル）−１，３−プロパンジオール、
５） ２−アミノ‐２‐［３‐［４‐（５−ヘプチルオキシメチルベンゾチアゾール−２‐イルアミノ）フェニル］プロピル］‐１，３‐プロパンジオール
又は
６） ２−アミノ‐２‐［２‐［４‐（ベンゾチアゾール−２‐イルアミノ）フェニル］エチル］‐１，３‐プロパンジオールである請求項１記載の２−アミノ−１、３−プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物。A compound represented by the general formula (1): 1) 2-amino-2- [3- [4- (benzothiazol-2-ylamino) phenyl] propyl] -1,3-propanediol;
2) 2-amino-2- [3- [4- (quinolin-2-ylamino) phenyl] propyl] -1,3-propanediol,
3) 2-amino-2- [3- [4- (3,5-bistrifluoromethylphenylamino) phenyl] propyl] -1,3-propanediol,
4) 2-amino-2- (3- [4- [4- (4-chlorophenyl) thiazol-2-ylamino] phenyl] propyl) -1,3-propanediol,
5) 2-amino-2- [3- [4- (5-heptyloxymethylbenzothiazol-2-ylamino) phenyl] propyl] -1,3-propanediol or 6) 2-amino-2- [2- The 2-amino-1,3-propanediol derivative according to claim 1, which is [4- (benzothiazol-2-ylamino) phenyl] ethyl] -1,3-propanediol, and a pharmacologically acceptable salt, and Its hydrate.
Ｘは、ＮＲ１（Ｒ１は水素原子あるいは炭素数１〜４の低級アルキル基を示す）、ＣＨ２ＮＨ、ＮＨＣＨ２、ＣＯＮＨ、ＮＨＣＯ、−（ＣＨ２）ｍ−（ｍは０又は１を示す）又はＣＯを示し、
Ｙは炭素原子又は酸素原子を示し、
ｎは０〜３の整数を示す］で表されることを特徴とする２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とする免疫抑制剤。General formula (1)
X is, NR1 (R1 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms), CH 2 NH, NHCH 2 , CONH, NHCO, - (CH 2) m - (m is 0 or 1) Or indicates CO,
Y represents a carbon atom or an oxygen atom,
n represents an integer of 0 to 3], wherein at least one or more of a 2-amino-1,3-propanediol derivative, a pharmacologically acceptable salt, and a hydrate thereof are used. An immunosuppressant as an active ingredient.
で表される２−アミノ‐１，３‐プロパンジオール誘導体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とすることを特徴とする請求項５に記載の免疫抑制剤。The compound represented by the general formula (1) is represented by the general formula (1b)
6. The method according to claim 5, wherein the active ingredient is at least one of a 2-amino-1,3-propanediol derivative represented by the formula: and a pharmaceutically acceptable salt and a hydrate thereof. Immunosuppressants.
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