TWI461413B - 用於製備〔４－（２－氯－４－甲氧基－５－甲基苯基）－５－甲基－噻唑－２－基〕－〔２－環丙基－１－（３－氟－４－甲基苯基）－乙基〕－胺之新穎方法 - Google Patents
用於製備〔４－（２－氯－４－甲氧基－５－甲基苯基）－５－甲基－噻唑－２－基〕－〔２－環丙基－１－（３－氟－４－甲基苯基）－乙基〕－胺之新穎方法 Download PDFInfo
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- TWI461413B TWI461413B TW099113599A TW99113599A TWI461413B TW I461413 B TWI461413 B TW I461413B TW 099113599 A TW099113599 A TW 099113599A TW 99113599 A TW99113599 A TW 99113599A TW I461413 B TWI461413 B TW I461413B
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- methylphenyl
- iii
- amine
- methoxy
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- 238000002360 preparation method Methods 0.000 title claims description 23
- 238000000034 method Methods 0.000 title claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 36
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 32
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- -1 3-fluoro-4-methylphenyl Chemical group 0.000 claims description 4
- SOHMWVXOAKNVTH-UHFFFAOYSA-N [1-(2-chloro-4-methoxy-5-methylphenyl)-1-oxopropan-2-yl] thiocyanate Chemical compound COC1=CC(Cl)=C(C(=O)C(C)SC#N)C=C1C SOHMWVXOAKNVTH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- NQCCWXKFKYSSBV-UHFFFAOYSA-N 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethanamine Chemical compound C1=C(F)C(C)=CC=C1C(N)CC1CC1 NQCCWXKFKYSSBV-UHFFFAOYSA-N 0.000 claims description 3
- 229910002056 binary alloy Inorganic materials 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- GCPRCXZISRDEDG-UHFFFAOYSA-N 2-bromo-1-(2-chloro-4-methoxy-5-methylphenyl)propan-1-one Chemical compound COC1=CC(Cl)=C(C(=O)C(C)Br)C=C1C GCPRCXZISRDEDG-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000003445 Hantzsch reaction Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- ZQEZIYWSFFWVDJ-UHFFFAOYSA-N n-thiophen-2-ylhydroxylamine Chemical compound ONC1=CC=CS1 ZQEZIYWSFFWVDJ-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/02—Thiocyanates
- C07C331/04—Thiocyanates having sulfur atoms of thiocyanate groups bound to acyclic carbon atoms
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- C07—ORGANIC CHEMISTRY
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- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/04—Five-membered rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F216/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical
- C08F216/12—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical by an ether radical
- C08F216/14—Monomers containing only one unsaturated aliphatic radical
- C08F216/1466—Monomers containing sulfur
- C08F216/1483—Monomers containing sulfur and nitrogen
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- Thiazole And Isothizaole Compounds (AREA)
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Description
本發明之標的為用於製備式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-環丙基-1-(3-氟-4-甲基苯基)-乙基]-胺 之新穎方法
及該製備方法之新穎中間物。
式(I)化合物為用以製備式(VI)之[4-(2-氯-4-甲氧基-5-甲基苯基)-N-丙炔基-5-甲基-噻唑-2-基]-[2-環丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的關鍵中間物
-其為具有潛在抗抑鬱及/或抗焦慮作用之已知CRF1(皮質激素(corticrotropin)釋放因子1)受體拮抗劑。式(I)之噻唑胺目前係利用Hantzsch合成以數個步驟製備(WO2001005776 Sanofi-Aventis)。到現在為止所使用之製備步驟(WO2001005776 Sanofi-Aventis)係從通式(II)之化合物開始
-其中X表示鹵素原子。然而，此化合物容易分解、其為刺激性的、其品質難以再現、其分離和處理困難。
我們的目的是要發現一種用於製備式(I)化合物的起始材料，其特徵為容易處理、可良好結晶、且可以高產率方便地製備。令我們驚訝地，我們發現：式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
為符合我們所有需求的起始材料。應用式(III)化合物的進一步利益為在特定條件下，也就是在相轉移觸媒存在下，其可在水性介質中從先前使用之通式(II)化合物容易地製備。此根據我們的發明之新穎方法是環保的，因為只有形成水性流出物，所使用之有機溶劑的量很小且該溶劑可再使用，所以該方法可以工業規模實施且其以高產率產生純產物。
酮衍生物(III)在水性條件下之製備是令人驚訝的，因為硫氰酸酯基團對水敏感，所以其容易轉化成異硫氰酸酯，或其會進行水解。因此，現有技術，其係在離子液體中(Tetrahedron Letters 46(2005)1489-1491)或在醇介質中(J. Indian Chem. Soc.,81(2004)786-788)製備，但是無論如何都沒有水。
本發明之標的為一種製備式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-環丙基-1-(3-氟-4-甲基苯基)-乙基]-胺之新穎方法
其中
a .)
使通式(II)之2-鹵-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
其中X表示鹵素，與鹼金屬-硫氰酸鹽在相轉移觸媒存在下反應，及
b.) 使如此獲得之式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
或其互變異構形式與式(IV)的2-環丙基-1-(3-氟-4-甲基苯基)-乙基-胺反應
為了製備式(I)化合物之適當光學活性異構物，我們必須開始從式(IV)之個別光學活性胺開始。
在根據本發明方法之一具體實例中，在步驟a.)中該反應係在由非質子溶劑和水組成之二元系中實施。
在根據本發明方法之一替代方法中，將通式(II)化合物-其中X有利地表示氯或溴基團，較佳溴基團，-溶解在非質子有機溶劑中且與鹼金屬-硫氰酸鹽-較佳硫氰酸鉀-之水溶液在相轉移觸媒-較佳TBAB(溴化四丁基銨)存在下反應。反應混合物係藉由在用水稀釋混合物之後分離有機相而進行處理。在所給定的情形中，在溶劑交換之後，式(III)化合物可以高產率充份結晶。
在一步驟b.)的變型中，將式(III)化合物加至式(IV)化合物中，以獲得具有有利雜質輪廓且於高產率之所要產物。為了達成最佳產率，持續至少一小時之另一段時間。在步驟b.)中有利地施用非極性非質子溶劑，較佳地甲基-環己烷或甲苯。步驟b.)較佳係在介於25℃和回流溫度之間的溫度範圍實施，最佳在回流溫度下實施。通式(II)化合物和式(IV)的胺，以及其製備係從專利申請案公開號WO2001005776得知的。
本發明之另一標的為新穎的式(III)化合物及其互變異構物，以及其製備。
關於化合物(III)之互變異構物，式(V)之5-(2-氯-4-甲氧基-5-甲基苯基)-4-甲基-[1.3]-亞氧硫雜環戊烷(oxathiol)-2-基胺
也為本發明之標的。
我們的方法進一步細節說明於下列實例中，但申請專利範圍不被限制於該等實例。
實例
實例1. 從在二氯甲烷(DCM)中之化合物(II)製備化合物(III)
291.5克 2-溴-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮(II)被溶解在291克 DCM中，5.3克 TBAB(溴化四丁基銨)觸媒加至其中。
167克 KSCN被溶解在83.6克 水中。將水溶液加至DCM溶液中。
將所得二元系加熱至40℃(回流)並攪拌3-4小時。
反應伴隨鹽沈澱。將水加至中混合物中直到鹽溶解。分離下層水相，蒸發上層有機相，同時將870毫升 甲醇(MeOH)加至其中。
在冷卻時化合物(III)從甲醇溶液結晶。濾出結晶，用MeOH洗滌數次。
產率：90-95%
熔點：75℃(MeOH)
IR-光譜：2158 cm-1
(CN),1664 cm-1
(C=O)1
H-光譜(DMSO-d6
,TMS)：7.73(1H,s),7.14(1H,s),5.28(1H,q,J=7,2Hz),3.89(3H,s),2.16(3H,s),1.60(3H,d,J=7.2Hz)
13
C-NMR-光譜：194.7,160.9,132.6,131.5,126.3,125.5,113.5,111.4,56.7,49.4,18.8,15.8
實例2. 從在甲基-環己烷(MCH)中之化合物(II)製備化合物(III)
製備步驟係如化合物1中所述，但使用MCH取代DCM作為溶劑。在冷卻時化產物從MCH結晶。
產率：60%
實例3. 在胺存在下從在非極性溶劑中之化合物(III)製備化合物(V)
26.4克 化合物(III)(如化合物1.或2.中所述製備)被懸浮在52毫升 MCH中。
將於化學計量之胺(較佳苯甲胺)加至混合物中。
將混合物攪拌0.5-1小時(胺的結構影響反應時間)。獲得稠沈澱物，將其濾出且用甲基-環己烷洗滌數次。
產率：85%。
實例4. 從在作為溶劑之三級胺中之化合物(III)製備化合物(V)
製備步驟係如化合物3中所述，其差異為將化合物(III)懸浮在取代MCH作為溶劑之三乙胺中，且沒有將其他胺加至混合物中。
產率：85%。
熔點：106℃(EtOH)
IR-光譜：3253 cm-1
(NH),1679 cm-1
(C=N)1
H-光譜(DMSO-d6
,TMS)：7.30(1H,s),7.14(1H,s),3.86(3H,s),2.14(3H,s),1.88(3H,s)
13
C-NMR-光譜：163.1(s),158.9(s),138.9(d),133.0(s),131.4(s),125.3(s),118.3(s),111.8(d),111.5(s),56.0(t),15.3(t),11.6(t)
實例5. 從在甲基-環己烷(MCH)中之化合物(III)製備化合物(I)
26.3克 經單離之產物(III)被溶解在52毫升 MCH中。
將反應混合物加熱至85-90℃且加至19.2克 胺(IV)在MCH中的85-90℃溶液(20%)中。添加期間為2-4小時。添加之後，將反應混合物在85-90℃下攪拌1小時。冷卻粗產物(I)之MCH溶液且濾出沈澱之結晶。用小量的MCH覆蓋結晶產物。
產率：80%。
實例6. 從在MCH和MeOH中之化合物(III)製備化合物(I)
該製備步驟係如化合物5中所述，但在溶劑交換之後從取代MCH的MeOH結晶產物(I)。
產率：90%
實例7. 從化合物(V)製備化合物(I)
該製備步驟係如實例5和6中所述，但使用相同量的化合物(V)取代化合物(III)。
產率：85%
Claims (13)
- 一種製備式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-環丙基-1-(3-氟-4-甲基苯基)-乙基]-胺之方法，
- 如申請專利範圍第1項之方法，其特徵為在步驟b.)中，將式(III)的酮加至式(IV)的胺中。
- 如申請專利範圍第2項之方法，其特徵為將式(III)的酮加至式(IV)的胺需要至少1小時。
- 如申請專利範圍第1-3項中任一項之方法，其特徵為在步驟a.)中，反應係在由非質子溶劑和水組成之二元系中實施。
- 如申請專利範圍第1-3項中任一項之方法，其特徵為步驟b.)係在非極性非質子溶劑中進行。
- 如申請專利範圍第5項之方法，其特徵為在步驟b.)中所使用之非極性非質子溶劑為甲基-環己烷或甲苯。
- 如申請專利範圍第1-3項中任一項之方法，其特徵為步驟b.)係在介於25℃和回流溫度之間的溫度下進行。
- 如申請專利範圍第7項之方法，其特徵為步驟b.)在回流溫度下進行。
- 如申請專利範圍第1-3項中任一項中所定義之方法，其特徵為在通式(II)中，X表示溴基團。
- 一種式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
- 根據申請專利範圍第10項之式(III)化合物，其中該式(III)化合物的互變異構物為式(V)的5-(2-氯-4-甲氧基-5-甲基苯基)-4-甲基-[1.3]-亞氧硫雜環戊烷(oxathiol)-2-基胺
- 一種製備式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲 基苯基)-丙-1-酮之方法，
- 一種製備式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-環丙基-1-(3-氟-4-甲基-苯基)-乙基]-胺之方法，
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0900267A HUP0900267A2 (en) | 2009-04-30 | 2009-04-30 | Process for preparing of thiazole amines and intermediates thereof |
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| TW201105640A TW201105640A (en) | 2011-02-16 |
| TWI461413B true TWI461413B (zh) | 2014-11-21 |
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| TW099113599A TWI461413B (zh) | 2009-04-30 | 2010-04-29 | 用於製備〔４－（２－氯－４－甲氧基－５－甲基苯基）－５－甲基－噻唑－２－基〕－〔２－環丙基－１－（３－氟－４－甲基苯基）－乙基〕－胺之新穎方法 |
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| US (1) | US8314249B2 (zh) |
| EP (1) | EP2424848B1 (zh) |
| JP (1) | JP5608221B2 (zh) |
| KR (1) | KR20120014005A (zh) |
| CN (1) | CN102414185B (zh) |
| AR (1) | AR076478A1 (zh) |
| AU (1) | AU2010243362B2 (zh) |
| BR (1) | BRPI1014627A2 (zh) |
| CA (1) | CA2760384A1 (zh) |
| HU (1) | HUP0900267A2 (zh) |
| IL (1) | IL216017A0 (zh) |
| IN (1) | IN2011KN04192A (zh) |
| MX (1) | MX2011011530A (zh) |
| MY (1) | MY152269A (zh) |
| RU (1) | RU2523793C2 (zh) |
| SG (1) | SG175829A1 (zh) |
| TW (1) | TWI461413B (zh) |
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| US8943551B2 (en) * | 2008-08-14 | 2015-01-27 | Microsoft Corporation | Cloud-based device information storage |
| HUP0900267A2 (en) | 2009-04-30 | 2011-03-28 | Sanofi Aventis | Process for preparing of thiazole amines and intermediates thereof |
| CA2936974A1 (en) | 2014-01-21 | 2015-07-30 | Neurocrine Biosciences, Inc. | Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia |
| US10207974B1 (en) | 2017-12-05 | 2019-02-19 | Chevron Phillips Chemical Company Lp | Synthesis of gamma dicarbonyl and pyrrole compounds |
| MX2021006552A (es) * | 2018-12-07 | 2021-07-07 | Neurocrine Biosciences Inc | Antagonista del receptor del factor de liberacion de corticotropina 1 (crf1), formulaciones farmaceuticas y formas solidas del mismo para el tratamiento de hiperplasia suprarrenal congenita. |
| US20220409592A1 (en) * | 2019-09-27 | 2022-12-29 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods of use |
| JP2023531164A (ja) | 2020-06-10 | 2023-07-21 | ニューロクライン バイオサイエンシーズ，インコーポレイテッド | 先天性副腎過形成を処置するためのｃｒｆ１受容体アンタゴニスト |
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| US6586456B1 (en) * | 1999-07-15 | 2003-07-01 | Sanofi-Synthelabo | Aminothiazole derivatives and their use as CRF receptor ligands |
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| US3222248A (en) * | 1961-12-12 | 1965-12-07 | Stauffer Chemical Co | Method of controlling microorganisms by means of organic thiocyanates |
| US3433803A (en) | 1966-12-01 | 1969-03-18 | Olin Mathieson | Substituted imino-1,3-oxathiols and their preparation |
| IL103586A (en) | 1991-10-30 | 1997-09-30 | Astra Ab | Process for the preparation of 4-methyl-5- (2-chloroethyl)-thiazole and analogues thereof |
| JPH1036360A (ja) | 1996-02-21 | 1998-02-10 | Kuraray Co Ltd | ２−クロロ−５−クロロメチル−１，３−チアゾールの製造方法 |
| HUP0900267A2 (en) | 2009-04-30 | 2011-03-28 | Sanofi Aventis | Process for preparing of thiazole amines and intermediates thereof |
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| US6586456B1 (en) * | 1999-07-15 | 2003-07-01 | Sanofi-Synthelabo | Aminothiazole derivatives and their use as CRF receptor ligands |
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Also Published As
| Publication number | Publication date |
|---|---|
| MX2011011530A (es) | 2011-11-18 |
| KR20120014005A (ko) | 2012-02-15 |
| EP2424848B1 (en) | 2013-03-13 |
| WO2010125414A1 (en) | 2010-11-04 |
| AU2010243362B2 (en) | 2015-07-30 |
| CN102414185B (zh) | 2014-02-26 |
| JP2012525368A (ja) | 2012-10-22 |
| AR076478A1 (es) | 2011-06-15 |
| HUP0900267A2 (en) | 2011-03-28 |
| CA2760384A1 (en) | 2010-11-04 |
| RU2011148584A (ru) | 2013-06-10 |
| US8314249B2 (en) | 2012-11-20 |
| BRPI1014627A2 (pt) | 2015-08-25 |
| TW201105640A (en) | 2011-02-16 |
| AU2010243362A1 (en) | 2011-11-17 |
| HU0900267D0 (en) | 2009-07-28 |
| SG175829A1 (en) | 2011-12-29 |
| IN2011KN04192A (zh) | 2015-10-02 |
| JP5608221B2 (ja) | 2014-10-15 |
| US20120083608A1 (en) | 2012-04-05 |
| IL216017A0 (en) | 2012-01-31 |
| RU2523793C2 (ru) | 2014-07-27 |
| WO2010125414A8 (en) | 2011-04-07 |
| UY32594A (es) | 2010-11-30 |
| CN102414185A (zh) | 2012-04-11 |
| EP2424848A1 (en) | 2012-03-07 |
| MY152269A (en) | 2014-09-15 |
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