JP4603531B2 - スフィンゴシン−1−ホスフェートレセプターモジュレーターとしての、アミノプロパノール誘導体 - Google Patents
スフィンゴシン−1−ホスフェートレセプターモジュレーターとしての、アミノプロパノール誘導体 Download PDFInfo
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- JP4603531B2 JP4603531B2 JP2006505327A JP2006505327A JP4603531B2 JP 4603531 B2 JP4603531 B2 JP 4603531B2 JP 2006505327 A JP2006505327 A JP 2006505327A JP 2006505327 A JP2006505327 A JP 2006505327A JP 4603531 B2 JP4603531 B2 JP 4603531B2
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- phenyl
- alkyl
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- methyl
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- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical class CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 title description 2
- 229940127530 Sphingosine 1-Phosphate Receptor Modulators Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical group 0.000 claims description 18
- -1 benzo [1, 3] dioxol-5-yl Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
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- 230000001154 acute effect Effects 0.000 claims description 5
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
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- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 claims description 2
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- 238000000034 method Methods 0.000 abstract description 25
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
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- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 8
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- NIDWUZTTXGJFNN-UHFFFAOYSA-N 3-bromopropoxybenzene Chemical compound BrCCCOC1=CC=CC=C1 NIDWUZTTXGJFNN-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- SZSIZNDEMBPRTJ-XMMPIXPASA-N tert-butyl n-[(2r)-4-[4-[2-(4-chlorophenoxy)ethoxy]phenyl]-1-hydroxy-2-methylbutan-2-yl]carbamate Chemical compound C1=CC(CC[C@](C)(CO)NC(=O)OC(C)(C)C)=CC=C1OCCOC1=CC=C(Cl)C=C1 SZSIZNDEMBPRTJ-XMMPIXPASA-N 0.000 description 3
- 150000003536 tetrazoles Chemical class 0.000 description 3
- QOLYRQVBLFCNRZ-UHFFFAOYSA-N 2-amino-2-[2-[4-(3-phenoxypropoxy)phenyl]ethyl]propane-1,3-diol;hydrochloride Chemical compound Cl.C1=CC(CCC(CO)(CO)N)=CC=C1OCCCOC1=CC=CC=C1 QOLYRQVBLFCNRZ-UHFFFAOYSA-N 0.000 description 2
- FQJZZLDWFVZLPH-UHFFFAOYSA-N 2-amino-2-ethoxy-4-[4-(2-phenoxyethoxy)phenyl]butan-1-ol;hydrochloride Chemical compound Cl.C1=CC(CCC(N)(CO)OCC)=CC=C1OCCOC1=CC=CC=C1 FQJZZLDWFVZLPH-UHFFFAOYSA-N 0.000 description 2
- JVIUOMCSCXPLGW-UHFFFAOYSA-N 4-[2-[4-(hydroxymethyl)-2-methyl-5h-1,3-oxazol-4-yl]ethyl]phenol Chemical compound C1OC(C)=NC1(CO)CCC1=CC=C(O)C=C1 JVIUOMCSCXPLGW-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- 201000004624 Dermatitis Diseases 0.000 description 2
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- IOQKOZLSJLTGEX-UHFFFAOYSA-N [2-methyl-4-[2-[4-(2-phenoxyethoxy)phenyl]ethyl]-5h-1,3-oxazol-4-yl]methanol Chemical compound C1OC(C)=NC1(CO)CCC(C=C1)=CC=C1OCCOC1=CC=CC=C1 IOQKOZLSJLTGEX-UHFFFAOYSA-N 0.000 description 2
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
Classifications
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
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- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
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Description
R1はC1−6アルキル;ヒドロキシ、C1−2アルコキシまたは1から6フッ素原子で置換されているC1−6アルキル;C2−6アルケニル;またはC2−6アルキニルであり;
X、Yの各々は、独立して、O、CH2、またはC=Oであり;
R2はフェニル;ナフチル;C3−6シクロアルキル;ヘテロアリール;ヘテロ環式残基;フェニル−C1−2アルキル;C3−6シクロアルキル−C1−2アルキル;ヘテロアリールC1−2アルキル;ヘテロ環式C1−2アルキル残基であり;
ここで、各々は、ヒドロキシ、ハロゲン、C1−4アルキル、1から5フッ素原子で置換されているC1−4アルキル、C3−6シクロアルキル、C1−4アルコキシ、1から5フッ素原子で置換されているC1−4アルコキシ、C3−6シクロアルコキシ、C3−6シクロアルキルC1−2アルキル、シアノ、フェニル、およびヒドロキシ、ハロゲン、C1−4アルキル、1から5フッ素原子で置換されているC1−4アルキル、C1−4アルコキシ、1から5フッ素原子で置換されているC1−4アルコキシ、またはシアノで置換されているフェニルからなる群から選択される1から5置換基で環置換されていてよく;
R3はZ−X2であり、ここで、ZはCH2、CHFまたはCF2であり、X2はOHまたは式(a)
の残基であり;そして
R4およびR5の各々は、独立して、H;所望により1、2または3ハロゲン原子で置換されているC1−4アルキル;またはアシルであり;
R6およびR7の各々は、独立して、H;ヒドロキシ;ハロゲン;C1−4アルキル;C1−6シクロアルキル;C1−4アルコキシ;C1−6シクロアルコキシ;C3−6シクロアルキルC1−2アルキル;またはシアノであり;そして
nは2または3である。〕
の化合物を提供する。
1. XがOである;
2. YがOまたはSである;
3. R1がCH3またはCH2−OHである;
4. R2がフェニル;ハロゲン、C1−2アルキルまたはC1−2アルコキシから選択される1個または2個の置換基で置換されたフェニル;シアノフェニル;ナフチル;または2−ベンゾ[1,3]ジオキソール−5−イルである;
5. R3がCH2−OHまたはCH2−OPO3H2である;
6. R4およびR5の各々が水素である;
7. R6が水素、メトキシ、メチルまたはクロロである;そして
8. R7が水素、メトキシ、メチルまたはクロロである。
a)R3がZ−X2であり、X2がOHである式Iの化合物の製造のために、式II
の化合物に存在する保護基を除去するか、または
b)R3がZ−X2であり、X2が式(a)の残基である式Iの化合物の製造のために、式III
の残基である〕
の化合物に存在する保護基を除去し、
そして、必要であれば、遊離形で得た式Iの化合物を所望の塩形に変換するか、または逆を行う
ことを含む、方法も含む。
の化合物を変換し、所望の残基−(CH2)n−Y−R2を、例えばアルキル化により挿入することを含む。式IVの化合物のアルキル化は当分野で既知の方法にしたがい、例えば求核置換により、例えばアルキル化剤R2−Y−(CH2)n−X3(式中、X3はメシレート、トシレート、トリフレート、ノシレート、クロライド、ブロミドまたはアイオダイドである)との反応により、行い得る。アルキル化は、光延プロトコールにしたがい、R2−Y−(CH2)n−OH(例えばHughes, Organic Preparations and Procedures International 28, 127-64, 1996またはD.L. Hughes, Org. React. 42, 335, 1992に記載の通り)を、溶液中または固相支持合成において、例えば式IVの化合物を樹脂に結合させて、行い得る。あるいは、トリフェニルホスフィンまたは、樹脂、例えばポリスチレンに結合した、例えば、ジエチルアゾカルボキシレートを使用できる。
tert−ブチル[(R)−1−ヒドロキシ−4−(4−ヒドロキシ−フェニル)−2−メチル−ブト−2−イル]−カルバメート(100mg、0.34mmol)および1−(2−ブロモエトキシ)−4−クロロベンゼン(120mg、0.51mmol、1.5当量)の無水DMF(2.5ml)溶液に、水を含まない炭酸セシウム(166mg、0.51mmol、1.5当量)を添加する。得られた懸濁液を一晩湿度から保護しながら、60℃で攪拌する。RTに冷却後、固体を濾取し、DMF(2×1ml)で濯ぐ。合わせた濾液を高真空で蒸発させて、濃オレンジ色シロップを得る。フラッシュクロマトグラフィー(FlashMaster II、MTBE/ヘキサン、0%MTBE→40%MTBEで勾配45分以内、次いで40%MTBE 15分)による精製により、無色結晶を得る:HPLC:tR=5.45分、ESI+ MS:m/z=450/452。
tert−ブチル(R)−(3−{4−[2−(4−クロロ−フェノキシ)−エトキシ]−フェニル}−1−ヒドロキシメチル−1−メチル−プロピル)−カルバメート(40mg、0.089mmol、実施例1a)およびテトラゾール(19mg、0.27mmol、3当量、トルエンから再結晶)の乾燥THF(1mL)溶液に、ジ−tert−ブチルN,N−ジエチル−ホスホロアミデイト(36μL、0.13mmol、1.5当量)を添加した。反応混合物をアルゴン下、RTで2時間攪拌した。次いで、H2O2(30%、91μL、0.89mmol、10当量)を、0℃で、激しく攪拌しながら注入した。反応混合物をさらに30分攪拌し、その後、飽和チオ硫酸ナトリウム溶液(1ml)を添加した。有機層を分離し、水性相をエーテル(3×1mL)で抽出した。合わせた有機抽出物を塩水で洗浄し、MgSO4で乾燥させ、蒸発乾固した。粗物質をフラッシュクロマトグラフィー(FlashMaster II、MTBE/ヘキサン勾配0%MTBE→50%MTBE、45分以内、次いで、50%MTBE 15分)での精製により、無色結晶を得た:HPLC:tR=6.64分、ESI+ MS:m/z=642/644 (MH+)。
tert−ブチル[(R)−1−ヒドロキシ−4−(4−ヒドロキシ−フェニル)−2−メチル−ブト−2−イル]−カルバメート(100mg、0.34mmol)および(3−ブロモプロポキシ)−ベンゼン(109.6mg、0.51mmol、1.5当量)の無水DMF(2.5ml)溶液に、水を含まない炭酸セシウム(166mg、0.51mmol、1.5当量)を添加した。得られた懸濁液を一晩湿度から保護しながら、60℃で攪拌した。RTに冷却後、固体を濾取し、DMF(2×1ml)で濯いだ。合わせた濾液を高真空で蒸発させて、濃オレンジ色シロップを得た。フラッシュクロマトグラフィー(FlashMaster II、MTBE/ヘキサン、0%MTBE→40%MTBEで勾配45分以内、次いで40%MTBE 15分)による精製により、無色結晶を得た。ESI+ MS:m/z=430.4。
式Iの化合物は、下記のアッセイで決定される通り、個々のヒトS1Pレセプターに結合親和性を有する:
化合物のアゴニスト活性を、ヒトS1PレセプターEDG−1(S1P1)、EDG−3(S1P3)、EDG−5(S1P2)、EDG−6(S1P4)およびEDG−8(S1P5)に対して試験する。機能的レセプター活性化を、適当なヒトS1Pレセプターを安定に発現する、トランスフェクトしたCHOまたはRH7777細胞から調製した膜タンパク質への化合物誘発GTP[γ−35S]結合を定量することにより評価する。使用したアッセイ法は、SPA(シンチレーションプロキシミティアッセイ法)であった。簡単に言うと、DMSOに溶解した化合物を連続的に希釈し、SPA−ビーズ(Amersham-Pharmacia)固定化S1Pレセプター発現膜タンパク質(10−20μg/ウェル)に、50mM Hepes、100mM NaCl、10mM MgCl2、10μM GDP、0.1%無脂肪BSAおよび0.2nM GTP[γ−35S](1200Ci/mmol)の存在下で添加する。96ウェルマイクロタイタープレートで、RTで120分インキュベーション後、非結合GTP[γ−35S]を遠心分離工程により分離する。SPAビーズの膜結合GTP[γ−35S]により誘発された発光を、TOPcountプレートリーダー(Packard)で定量する。EC50を、標準曲線適合ソフトウェアを使用して計算する。本アッセイにおいて、式Iの化合物は、S1P1レセプターに<50nMの結合親和性を有する。
式Iの化合物または媒体を、ラットに胃管栄養法により経口で投与する。血液学的モニタリングのための尾血液を、−1日目に個々の基底値を得るために、そして投与後2、6、24、48および72時間後に得る。本アッセイにおいて、式Iの化合物は、0.03から3mg/kg投与したとき、末梢血リンパ球を枯渇させる。例えば、下記結果が得られる:50%を超える末梢血リンパ球の枯渇。
1.1 処置を必要とする対象における、例えば上記の、リンパ球が介在する障害または疾患を予防または処置する方法であり、該対象に有効量の式Iの化合物または薬学的に許容されるその塩を投与することを含む、方法;
1.2 処置を必要とする対象における、例えば上記の、急性もしくは慢性移植拒絶反応またはT細胞介在炎症性もしくは自己免疫性疾患を予防または処置する方法であり、該対象に有効量の式Iの化合物または薬学的に許容されるその塩を投与することを含む、方法;
2. 医薬として、例えば、上記1.1または1.2に記載の方法のいずれかにおいて使用するための、遊離形または薬学的に許容される塩形の式Iの化合物;
3. 遊離形または薬学的に許容される塩形の式Iの化合物を、薬学的に許容される希釈剤または担体と共に含む、例えば、上記1.1または1.2に記載のいずれかの方法において使用するための、医薬組成物;
4. 上記1.1または1.2に記載のいずれかの方法において使用するための医薬組成物の製造に使用するための、式Iの化合物またはその薬学的に許容される塩。
5. 治療的有効非毒性量の式Iの化合物および少なくとも1個の第二医薬物質、例えば、上記の、例えば免疫抑制剤、免疫調節剤、抗炎症剤または化学療法剤を、例えば、同時にまたは連続して併用投与することを含む、上記で定義の方法;
6. a)本明細書に記載の遊離形または薬学的に許容される塩形の式Iの化合物である第一剤、b)少なくとも1個の併用剤、例えば免疫抑制剤、免疫調節剤、抗炎症剤、化学療法剤または抗感染剤を含む、医薬的組み合わせ、例えばキット。該キットは、その投与のための説明書を含み得る。
Claims (5)
- 遊離形または塩形の、式I
R1はC1−6アルキル;ヒドロキシ、C1−2アルコキシまたは1個から6個のフッ素原子で置換されているC1−6アルキル;C2−6アルケニル;またはC2−6アルキニルであり;
Xは、Oであり;
Yは、OまたはSであり;
R2は、フェニル;ハロゲン、C 1−2 アルキルおよびC 1−2 アルコキシからなる群から選択される1個または2個の置換基で置換されたフェニル;シアノフェニル;ナフチル;またはベンゾ[1,3]ジオキソール−5−イルであり;
R 3は、Z−X2であり、ここで、ZはCH2、CHFまたはCF2であり、X2はOHまたは式(a)
の残基であり;そして
R4およびR5の各々は、独立して、Hであり;
R 6 は、水素、メトキシ、メチルまたはクロロであり;
R 7 は、水素、メトキシ、メチルまたはクロロであり;そして
nは、2または3である。〕
で示される化合物。 - R3が、CH2−OHまたはCH2−OPO3H2である、請求項1に記載の化合物。
- 医薬として使用するための、および、医薬の製造において使用するための、請求項1または2に記載の化合物。
- 有効成分として、請求項1または2に記載の化合物を含む、急性もしくは慢性移植拒絶反応またはT細胞介在炎症性もしくは自己免疫性疾患の処置用医薬。
- 請求項1または2に記載の化合物と少なくとも1個の併用剤を含む、急性もしくは慢性移植拒絶反応またはT細胞介在炎症性もしくは自己免疫性疾患の処置用医薬的組み合わせ剤。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0309944 | 2003-04-30 | ||
GB0329505A GB0329505D0 (en) | 2003-12-19 | 2003-12-19 | Organic compounds |
GB0329500A GB0329500D0 (en) | 2003-12-19 | 2003-12-19 | Organic compounds |
PCT/EP2004/004569 WO2004096752A1 (en) | 2003-04-30 | 2004-04-29 | Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator |
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JP2006524660A JP2006524660A (ja) | 2006-11-02 |
JP2006524660A5 JP2006524660A5 (ja) | 2010-09-16 |
JP4603531B2 true JP4603531B2 (ja) | 2010-12-22 |
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JP2006505327A Expired - Fee Related JP4603531B2 (ja) | 2003-04-30 | 2004-04-29 | スフィンゴシン−1−ホスフェートレセプターモジュレーターとしての、アミノプロパノール誘導体 |
Country Status (11)
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US (1) | US7625950B2 (ja) |
EP (1) | EP1622860B1 (ja) |
JP (1) | JP4603531B2 (ja) |
CN (1) | CN1777575B (ja) |
AT (1) | ATE547395T1 (ja) |
AU (1) | AU2004234066B2 (ja) |
BR (1) | BRPI0410025A (ja) |
CA (1) | CA2523582A1 (ja) |
ES (1) | ES2383298T3 (ja) |
MX (1) | MXPA05011596A (ja) |
WO (1) | WO2004096752A1 (ja) |
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CA2669102A1 (en) | 2006-11-21 | 2008-05-29 | University Of Virginia Patent Foundation | Tetralin analogs having sphingosine 1-phosphate agonist activity |
JP2010510250A (ja) | 2006-11-21 | 2010-04-02 | ユニバーシティ オブ バージニア パテント ファンデーション | スフィンゴシン=1−燐酸受容体アゴニスト活性を有するヒドリンダンアナログ |
JP2010510251A (ja) | 2006-11-21 | 2010-04-02 | ユニバーシティ オブ バージニア パテント ファンデーション | スフィンゴシン=1−燐酸受容体活性を有するベンゾシクロヘプチルアナログ |
US8524917B2 (en) | 2007-01-11 | 2013-09-03 | Allergan, Inc. | 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity |
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RU2010149311A (ru) | 2008-05-08 | 2012-06-20 | Аллерган, Инк. (Us) | ТЕРАПЕВТИЧЕСКИ ПОЛЕЗНЫЕ ЗАМЕЩЕННЫЕ 1,7-ДИФЕНИЛ-1,2,3,5,6,7-ГЕКСАГИДРОПИРИДО [3,2,1-ij]ХИНОЛИНОВЫЕ СОЕДИНЕНИЯ |
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MX354134B (es) | 2008-07-23 | 2018-02-14 | Arena Pharm Inc | Derivados de acido 1,2,3,4-tetrahidrociclopenta [b] indol-3-il) acetico sustituidos utiles en el tratamiento de enfermedades autoinmune e inflamatorias. |
CA2733671C (en) | 2008-08-27 | 2018-01-02 | Arena Pharmaceuticals, Inc. | Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders |
JP2013508385A (ja) * | 2009-10-23 | 2013-03-07 | アラーガン インコーポレイテッド | 治療上有用な、受容体修飾薬としてのクマリン化合物 |
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WO1996006068A1 (fr) * | 1994-08-22 | 1996-02-29 | Yoshitomi Pharmaceutical Industries, Ltd. | Compose benzenique et son utilisation medicale |
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JP2002316985A (ja) * | 2001-04-20 | 2002-10-31 | Sankyo Co Ltd | ベンゾチオフェン誘導体 |
ATE463478T1 (de) * | 2001-09-27 | 2010-04-15 | Kyorin Seiyaku Kk | Diaryletherderivat, dessen additionssalz und immunosuppressivum |
CA2461212C (en) * | 2001-09-27 | 2010-08-17 | Kyorin Pharmaceutical Co., Ltd. | Diaryl sulfide derivatives, salts thereof and immunosuppressive agents using the same |
EP1539674A1 (en) * | 2002-09-13 | 2005-06-15 | Novartis AG | Amino-propanol derivatives |
ES2383298T3 (es) * | 2003-04-30 | 2012-06-20 | Novartis Ag | Derivados del amino-propanol como moduladores del receptor esfingosina-1-fosfato |
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- 2004-04-29 JP JP2006505327A patent/JP4603531B2/ja not_active Expired - Fee Related
- 2004-04-29 BR BRPI0410025-5A patent/BRPI0410025A/pt not_active IP Right Cessation
- 2004-04-29 CN CN2004800110595A patent/CN1777575B/zh not_active Expired - Fee Related
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- 2004-04-29 CA CA002523582A patent/CA2523582A1/en not_active Abandoned
- 2004-04-29 AU AU2004234066A patent/AU2004234066B2/en not_active Ceased
- 2004-04-29 AT AT04730206T patent/ATE547395T1/de active
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Also Published As
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MXPA05011596A (es) | 2006-01-23 |
CA2523582A1 (en) | 2004-11-11 |
US20060211658A1 (en) | 2006-09-21 |
CN1777575A (zh) | 2006-05-24 |
CN1777575B (zh) | 2010-05-12 |
AU2004234066A1 (en) | 2004-11-11 |
ATE547395T1 (de) | 2012-03-15 |
ES2383298T3 (es) | 2012-06-20 |
US7625950B2 (en) | 2009-12-01 |
AU2004234066B2 (en) | 2008-02-21 |
EP1622860B1 (en) | 2012-02-29 |
BRPI0410025A (pt) | 2006-04-25 |
WO2004096752A1 (en) | 2004-11-11 |
EP1622860A1 (en) | 2006-02-08 |
JP2006524660A (ja) | 2006-11-02 |
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