TW201618764A - 用於組織自修復及再生之經取代芳族化合物及醫藥組合物 - Google Patents
用於組織自修復及再生之經取代芳族化合物及醫藥組合物 Download PDFInfo
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- TW201618764A TW201618764A TW104137375A TW104137375A TW201618764A TW 201618764 A TW201618764 A TW 201618764A TW 104137375 A TW104137375 A TW 104137375A TW 104137375 A TW104137375 A TW 104137375A TW 201618764 A TW201618764 A TW 201618764A
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- acceptable salt
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
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Abstract
本文描述式I化合物,或其醫藥學上可接受之鹽,或其組合,以及其用途。此類用途包括促進器官之組織自修復或組織再生;刺激產生組織生長;調節(例如增加)組織修復標記物之含量;治療器官、組織或細胞中之物理損傷;促進傷口癒合;以及抗老化应用。亦描述相應組合物、方法、套組及用途。
Description
本發明係關於醫學領域。本發明之特定態樣係關於用於損傷器官之組織自修復及/或組織再生、用於刺激產生組織生長及/或用於調節組織自修復標記物及/或組織再生標記物(諸如金屬蛋白酶及生長因子)之表現的化合物、醫藥組合物及其用途。
組織再生涉及已知標記物,諸如金屬蛋白酶及包括但不限於以下之生長因子:HGF(肝細胞生長因子)、LOX(離胺醯氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3、ILK(整合素連接激酶)。
HGF在組織修復及再生中之作用充分描述於以下科學綜述中:The discovery of Hepatocyte Growth factor(HGF)and its significance for cell biology,life sciences and clinical medicine,Nakamura及Mizuno,Proc.Jpn.Acad.Ser B86(2010)。此綜述文章描述HGF在肝臟、腎臟、心臟及肺中之組織再生中的作用。另外,HGF為皮膚、胃、腸道、肌肉及軟骨損傷之後自修復所需的,且亦參與器官發育(包括有絲分裂發生、運動發生及形態發生之器官發生)。HGF亦因其對再生酶(金屬蛋白酶)之調節並且因抑制凋亡而與損傷組織之再生有關。此外,新近報導表明HGF具有抗炎作用且減緩細胞衰老。因此,HGF基因治療或增加HGF表現及分泌之化合物可為心血管疾病中之抗老化治療(Nakagami,Morishita,2009)。HGF亦已知加速傷口癒合(Li等人,BioMed Research International,第2013卷(2013),文章ID 470418。
再生酶(包括金屬蛋白酶)在損傷器官之修復及再生中亦非
常重要。
近期出版物(由Radtke等人在2014年整形外科會議(Plastic surgery meeting 2014)上所呈現之標題為Single treatment With Alpha-1 antitrypsin Enhances Nerve Regeneration After Peripheral Nerve Injury的摘要)已證實AAT改良周圍神經再生。AAT应用至急性轴突切断术模型中与类似对照动物相比引起显著改良之轴突再生及髓鞘再生。此外,在急性周围神经病変后直接注射AAT之后观测到组织改良而且观测到功能改良。其结果表明递送至损伤周围神经中之AAT参与神经修复。
皮膚老化為一種對皮膚之進行性變化負有責任之複雜現象。皮膚老化起因於兩種過程:(1)固有過程,其對應於隨時間老化;及(2)非固有過程,其主要起因於暴露環境應力之有害作用。遺傳、UV曝露、氣候因素(惡劣/風/冷/暖)、污染(化學、自由基、污染物、氮氧化物、金屬)、酒精消耗或吸煙為皮膚老化中所涉及之因素。
暴露於刺激劑損害角質層之障壁功能且降低其保護皮膚不受環境應力(例如紫外線照射、感染劑等)影響之能力。重複及長期暴露於環境刺激劑使得皮膚蛋白質變性、脂質薄層瓦解、保護性細胞間脂質移除、天然潤濕因子損失及細胞間內聚力減小。此等損傷亦對負責角質細胞剝離之酶的功能損失負有責任。在暴露於污染、冷、太陽、風、低濕度或化學試劑之情況下,此等問題加重。刺激劑為若暴露充足時間且以充足濃度暴露,則能夠產生細胞損傷之任何試劑。損傷之嚴重性取決於暴露於此等刺激因素之類型及強度。亦存在使人易於因外部因素而造成皮膚損傷之內在因素。此等因素包括具有活性皮膚病,諸如濕疹、遺傳性乾燥皮膚病狀、先前皮膚病史、敏感性皮膚及/或年長。
需要新穎化合物及藥劑來刺激損傷器官中之組織自修復及組織再生。
本發明之一般態樣係關於如本文所定義之根據式I之化合物及其醫藥學上可接受之鹽的醫藥用途。
本發明之特定態樣係關於化合物及組合物用於損傷器官之
組織自修復及/或組織再生及/或用於調節諸如金屬蛋白酶及包括但不限於以下之生長因子之組織自修復標記物及/或組織再生標記物之表現的用途:HGF、LOX(離胺醯氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3及ILK(整合素連接激酶)。
一種用於有需要之個體中之器官的組織自修復或組織再生的方法,其包括向有需要之個體投與由式I表示之化合物或其醫藥學上可接受之鹽的步驟:
根據另一態樣,本發明係關於一種用於有需要之個體中之器官的組織自修復或組織再生之方法,其包括向該個體投與如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽。在一實施例中,本發明係關於一種用於有需要之個體中之器官的組織自修復之方法,其包括向該個體投與如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽。在一實施例中,本發明係關於一種用於有需要之個體中之器官的組織重建之方法,其包括向該個體投與如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽。在一實施例中,本發明係關於一種用於有需要之個體中之器官的組織再生之方法,其包括向該個體投與如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽。
根據另一態樣,本發明係關於一種用於用如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽刺激產生組織生長的方法。
根據另一態樣,本發明係關於一種用於用如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽刺激組織自修復標記物及/或組織再生標記物之表現的方法。更特定而言,該等標記物包括但不限於金屬蛋白酶、生長因子、肝細胞生長因子(HGF)、LOX(離胺醯氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3及ILK(整合素連接激酶)。
根據另一態樣,本發明係關於一種用於增加器官中之HGF含量的方法,其包括向該器官投與如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽的步驟。該器官包括但不限於腎臟、心臟、肝臟、肺、
皮膚、胃、腸道、肌肉及軟骨。
根據另一態樣,本發明係關於一種用於增加器官中之AAT含量的方法,其包括向該器官投與如本文所定義之由式I表示之化合物或其醫藥學上可接受之鹽的步驟。
由以下描述、申請專利範圍及本文之概述本發明之其他態樣對熟習此項技術者而言將顯而易知。
圖1為化合物I關於增加肝細胞生長因子(HGF,一種參與組織自修復及再生之生長因子)之mRNA表現之作用的例證。
圖2為化合物I關於調節在損傷纖維母細胞(NHDF)中表現之參與組織自修復及再生的再生標記物之作用的例證。
圖3為化合物I關於調節在損傷上皮細胞(HK-2)中表現之參與組織自修復及再生的再生標記物之作用的例證。
圖4證實化合物I可增加參與神經產生之Serpin A1(AAT)的mRNA表現。
圖5為關於在存在化合物I之情況下所觀測到之器官功能(GFR)增加且指示損傷腎臟之組織再生的圖示。
本發明揭示式I化合物、其醫藥學上可接受之鹽、包含該等物質之組合物及其用途。本發明之各個實施例包括:
根據一個態樣,本發明係關於由式I表示之化合物或其醫藥學上可接受之鹽的醫藥用途:
其中
A為C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;或為C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3;或為C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為4;R1為H、F或OH;或為H或OH;R2為H、F、OH、C5烷基、C6烷基、C5烯基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3或4;或為C5烷基、C5烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為3;或為C6烷基、C6烯基、C(O)-(CH2)n-CH3或CH(OH)-(CH2)n-CH3,其中n為4 R3為H、F、OH或CH2Ph;或為H、F或OH;或為H或OH;R4為H、F或OH;或為H或OH;Q為1)(CH2)mC(O)OH,其中m為1或2,2)CH(CH3)C(O)OH,3)C(CH3)2C(O)OH,4)CH(F)-C(O)OH,5)CF2-C(O)OH,或6)C(O)-C(O)OH。
根據一特定實施例,A為C5烷基或C6烷基。較佳地,C5烷基為直鏈C5烷基。
根據一特定實施例,R1為H或OH。
根據一特定實施例,R2為H、F、OH、C5烷基或C6烷基。
根據一特定實施例,R3為H或OH。
根據一特定實施例,R4為H或OH。
根據一特定實施例,Q為:1)(CH2)mC(O)OH,其中m為1或2,2)CH(F)-C(O)OH,3)CF2-C(O)OH,或4)C(O)-C(O)OH。
根據一特定實施例,Q為(CH2)mC(O)OH,其中m為1或2。
根據另一實施例,化合物具有式I,其中A為C5烷基或C6烷基;R1為H、F或OH;R2為H、F、OH、C5烷基或C6烷基;R3為H、OH或CH2Ph;R4為H、F或OH;且Q為(CH2)mC(O)OH,其中m為1或2。
根據另一實施例;化合物具有式I;其中A為C5烷基;R1為H;R2為H或C5烷基;R3為H;R4為H;且Q為(CH2)mC(O)OH,其中m為1。
如本文所用,術語「烷基」旨在包括具有呈線性排列之指定數目之碳原子的直鏈飽和脂族烴基,及具有呈非線性排列之指定數目之碳原子的分枝鏈飽和脂族烴基,或具有呈環狀排列之指定數目之碳原子的環狀鏈飽和脂族烴基。
如本文所用,術語「烯基」旨在意謂不飽和直鏈烴基,其中具有指定數目之碳原子且其中至少兩個碳原子藉由雙鍵彼此鍵結,且具有E或Z區域選擇性及其組合。
式I化合物之實例包括但不限於列於下文之表1中的化合物I至XXXIII及其酸形式。
鹽
如本文所用,術語「醫藥學上可接受之鹽」旨在意謂鹼加成鹽。醫藥學上可接受之鹽之實例亦描述於例如Berge等人,「Pharmaceutical Salts」,J.Pharm.Sci.66,1-19(1977)中。醫藥學上可接受之鹽可藉由習知化學方法自含有酸性部分之母體試劑合成。一般而言,此類鹽係藉由使此等試劑之游離酸形式與化學計量之量的適當的鹼在水中或在有機溶劑中或在
兩者之混合物中反應來製備。鹽可在最終分離或純化試劑期間或藉由分開地使呈游離酸形式之純化的本發明化合物與所需相應鹼反應且分離由此形成之鹽而原位製備。
式I化合物之醫藥學上可接受之鹽可選自由以下各項之鹼加成鹽組成之群:鈉、鉀、鈣、鎂、鋰、銨、錳、鋅、鐵或銅。在較佳實施例中,根據本發明之化合物的醫藥學上可接受之鹽可為鈉、鉀、鈣、鎂或鋰鹽。更佳地,醫藥學上可接受之鹽為鈉鹽。
本文所揭示之式I化合物可呈任何形式,包括任何酸、鹽或其他離子及非離子形式。舉例而言,若在本文中化合物顯示為酸,則亦包括化合物之鹽形式。同樣地,若化合物顯示為鹽,則亦包括酸形式。
前藥
在某些實施例中,本文所揭示之式I化合物(其中該等化合物以游離羧酸形式存在)亦可包括其所有醫藥學上可接受之鹽、諸如四唑之等排等效物及前藥形式。後者之實例包括在乙醇或胺(包括胺基酸)與由式I定義之游離酸反應後獲得之醫藥學上可接受之酯或醯胺。
對掌性
本文所揭示之式I化合物、其醫藥學上可接受之鹽或其前藥可含有一或多個不對稱中心、對掌性軸及對掌性平面,且因此可產生對映異構體、非對映異構體及其他立體異構形式,且可用諸如(R)-或(S)-之絕對立體化學來定義。本發明旨在包括所有此類可能的異構體以及其外消旋及光學純形式。光學活性(+)及(-)、(R)-及(S)-異構體可使用對掌性合成纖維或對掌性試劑來製備,或使用諸如逆相HPLC之習知技術進行解析。可製備外消旋混合物且其後分離成個別光學異構體,或者此等光學異構體可藉由對掌性合成來製備。對映異構體可藉由熟習此項技術者已知之方法進行解析,例如藉由形成非對映異構鹽,然後可將該等非對映異構鹽藉由結晶、氣-液或液相色譜、一種對映異構體與對映異構體特異性試劑之選擇性反應來加以分離。熟習此項技術者亦將瞭解,在所需對映異構體藉由分離技術轉化成另一化學實體之情況下,然後需要額外的步驟來形成所需對映異構形式。或者,特定對映異構體可藉由使用光學活性試劑、受質、催化劑或
溶劑進行不對稱合成或藉由通過不對稱轉換將一種對映異構體轉化成另一種對映異構體來進行合成。
本文所揭示之式I化合物或其醫藥學上可接受之鹽中的某些可以兩性離子形式存在,且本發明包括使用此等化合物之兩性離子形式及其混合物。
水合物
此外,本文所揭示之式I化合物或其醫藥學上可接受之鹽亦可以水合物及無水形式存在。本文包括使用本文所描述之式I化合物或其醫藥學上可接受之鹽中任一者之水合物,其可以單水合物形式或以多水合物形式存在。
一般而言,所有本文所揭示之所有式I化合物或其醫藥學上可接受之鹽均可藉由任何習知方法使用可容易獲得及/或習知可製備之起始物質、試劑及習知合成程序來製備。特別受關注的是Hundertmark,T.;Littke,A.F.;Buchwald,S.L.;Fu,G.C.Org.Lett.12,1729-1731(2000)之工作。
下文之例示部分提供用於合成化合物I-XXXIII之一般方案及特定但非限制性實例。
本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)適用於:損傷器官、組織或細胞之組織自修復及/或組織再生、刺激在活體外細胞培養物中產生新的細胞及/或調節組織自修復標記物及/或組織再生標記物(諸如金屬蛋白酶及生長因子)之表現。根據一實施例,本文所揭示之式I化合物或其醫藥學上可接受之鹽適用於抗老化治療。在一實施例中,該治療較佳包括投與本文所揭示之式I化合物或其醫藥學上可接受之鹽或其組合或包含治療有效量之一或多種本文所揭示之式I化合物或其醫藥學上可接受之鹽的醫藥組合物。本文所用之表述「組織自修復」及「組織再生」亦可指抗老化治療中所涉及之過程。已發現根據本文所揭示之式I的代表性化合物刺激已知與抗老化、組織再生及組織自修復相關之標記物的表現,且刺激產生新的細胞。
在一實施例中,損傷器官、組織或細胞不為因炎性相關疾病而損傷之器官、組織或細胞。在一實施例中,損傷器官、組織或細胞不為因癌症而損傷之器官、組織或細胞。
在一實施例中,器官、組織或細胞損傷係起因於物理損傷(亦即在急性暴露於對器官、組織或細胞產生一些形式之損害/損傷的外部試劑或應力之後),例如因物理外傷/傷損(例如割、咬、衝撞、撕、刺入、穿孔、灼傷(熱或化學)、冷凍、輻射、電擊、身體用力過度)或手術而損傷之器官、組織或細胞。如本文所用之物理損傷排除由以下原因引起之器官、組織或細胞損害(亦即主要原因為以下各項之器官、組織或細胞損害):原發疾病,例如炎性或自體免疫疾病,諸如炎性腸道疾病、腎小球性腎炎、血管炎、銀屑病性關節炎、全身性紅斑狼瘡(SLE)、特發性血小板減少性紫癜(ITP)、銀屑病、克羅恩氏病(Crohn's disease)、炎性腸道疾病、強直性脊柱炎、休格倫氏症候群(Sjogren's syndrome)、斯蒂爾氏病(Still's disease)(巨噬細胞活化症候群)、葡萄膜炎、硬皮病、肌炎、賴特爾氏症候群(Reiter’s syndrome)及韋格納氏症候群(Wegener’s syndrome)。然而,本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)可用於促進組織自修復及/或該組織再生以治療由初始物理損傷之引起繼發性組織損害/損傷,例如由在初始物理損傷之後可產生之炎症引起的繼發性組織損害/損傷。
因此,在另一態樣中,本發明提供一種用於治療器官、組織或細胞中之物理損傷(例如用於促進損傷器官、組織或細胞之自修復及/或組織再生)的方法,該方法包括使器官、組織或細胞與有效量之本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)接觸。
在另一態樣中,本發明提供本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)之用途,其係用於治療器官、組織或細胞中之物理損傷(例如用於促進損傷器官、組織或細胞之自修復及/或組織再生)。在另一態樣中,本發明提供本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物),其係用於治療器官、組織或細胞中之物理損傷(例如用於促進損傷器官、組織或細胞之自修復及/或組織再生)。
在一實施例中,(物理)損傷器官、組織或細胞不為腎臟或腎
臟組織。在另一實施例中,(物理)損傷器官、組織或細胞不為骨骼或骨骼組織。在一實施例中,(物理)損傷器官、組織或細胞為皮膚、肌肉、肌腱、韌帶、肝臟、心臟、胰腺、消化道/胃腸道(例如口腔、食管、胃、腸道)之器官/組織、膽囊、肝臟、呼吸道(例如肺)之器官、脊髓、脾臟、乳房、眼組織、血管、牙周組織、黏膜(例如口腔黏膜、鼻黏膜)及/或軟骨。
在一實施例中,本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)係緊急使用/投與,亦即在損傷之後不久使用/投與。在一實施例中,本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)係為在損傷器官、組織或細胞中發生纖維化之前(例如在發生纖維化疾病之前)促進組織自修復及/或組織再生而使用/投與。
在一實施例中,本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)適用於促進傷口癒合。
在另一實施例中,損傷器官、組織或細胞為神經系統(例如神經組織)之器官、組織或細胞,例如中樞神經系統或周圍神經系統之器官、組織或細胞。在一實施例中,本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)適用於在神經損傷(例如脊髓損傷、周圍神經損傷或與多發性硬化相關之神經損傷)之後的組織自修復及/或組織再生。
在一實施例中,本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)適用於在皮膚中例如在皮膚割傷、刺入、擦傷或灼傷之後的組織自修復及/或組織再生。
在一實施例中,損傷器官、組織或細胞為呼吸系統(例如肺)之器官、組織或細胞。
在一實施例中,損傷器官、組織或細胞為肝臟或肝臟組織。
在一實施例中,損傷器官、組織或細胞為膀胱或膀胱組織。
在一實施例中,損傷器官、組織或細胞為卵巢或卵巢組織。
在一實施例中,損傷器官、組織或細胞為前列腺或前列腺組織。
在一實施例中,損傷器官、組織或細胞為脾或脾組織。
在一實施例中,損傷器官、組織或細胞為肌肉,例如因肌肉
拉傷、肌肉撕裂及/或任何其他類型之物理肌肉損傷而損傷之肌肉。
在一實施例中,損傷器官、組織或細胞為血管(例如動脈)。
在一實施例中,損傷器官、組織或細胞為消化道/胃腸道(例如口腔、食管、胃、腸道)之器官/組織。
在特定實施例中,本文所描述之方法及用途並非用於骨骼重建及/或胰島再生。在一特定實施例中,組織不為骨骼。在一實施例中,組織不為胰腺組織。
本發明人已證實本文所揭示之代表性式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)使刺激個體中損傷器官之組織自修復及組織再生之標記物增加。在一實施例中,本文所描述之式I化合物發揮組織再生活性。
在另一態樣中,本發明係關於一種化妝品組合物,其包含本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)。在另一態樣中,本發明係關於一種皮膚護理組合物,其包含本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)。在另一態樣中,本發明係關於一種抗老化皮膚護理組合物,其包含本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)。
在另一態樣中,本發明係關於以上所提及之用於抗老化皮膚護理之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)。在另一實施例中,以上所提及之式I化合物或包含其之組合物係用於在與老化相關之皮膚損害之後刺激皮膚修復及/或再生。在另一實施例中,以上所提及之化合物或組合物係用於在皮膚損害或損傷之後刺激皮膚修復及/或再生。在一實施例中,皮膚損害或損傷係起因於曝露於UV照射,例如曝露於太陽(例如日灼)。
在一實施例中,本文所揭示之方法及用途進一步包括確定一個體具有損傷器官、組織或細胞,且需要用以上所提及之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)進行治療,以促進損傷器官、組織或細胞中之組織自修復及/或組織再生。該方法可包括確定在個體之樣品(諸如器官、組織或細胞樣品)中,一或多種包括但不限於以下之組織自修復及/
或組織再生標記物(諸如金屬蛋白酶及生長因子)之含量降低:HGF、LOX(離胺醯氧化酶)、MMP1、MMP2、MMP9、MMP13、PLAT(tPA)、PLAU(uPA)、Serpin A1(AAT)、Serpin E1(PAI-1)、TIMP3及ILK(整合素連接激酶),及使該器官、組織或細胞與有效量之本文所揭示之式I化合物或其醫藥學上可接受之鹽(或包含其之組合物)接觸。
術語「個體」包括需要如本文所揭示之治療的活有機體,例如其中器官為損傷的。術語「個體」包括諸如哺乳動物或鳥之動物。較佳地,個體為哺乳動物,包括但不限於人類、馬、狗及貓。在一些實施例中,哺乳動物不為小鼠。更佳地,個體為人類。
在一實施例中,本文所描述之式I化合物或其醫藥學上可接受之鹽包含於包含治療有效量之該等化合物或其醫藥學上可接受之鹽的醫藥組合物中。如上文所指示,醫藥組合物可適用於:損傷器官之組織自修復及/或組織再生,刺激在活體外細胞培養物中產生新的細胞及/或調節組織自修復標記物及/或組織再生標記物(諸如金屬蛋白酶及生長因子)之表現。
如本文所用,術語「治療有效量」意謂化合物在向個體投與以治療或預防特定病症、疾病或病狀,或發揮生物作用(例如用於刺激損傷器官之組織自修復及/或組織再生,刺激在活體外細胞培養物中產生新的細胞及/或調節(增加)組織自修復標記物及/或組織再生標記物之表現)時,足以實現該病症、疾病或病狀之此類治療或預防或發揮生物作用的量。劑量及治療有效量可例如視包括以下之多種因素而不同:所使用特定試劑之活性、個體之年齡、體重、總體健康、性別及膳食、投藥時間、投藥途徑、排泄速率及任何藥物組合(若可適用)、從業者需要化合物對個體具有之作用、化合物之性質(例如生物可用性、穩定性、效能、毒性等)及個體忍受之特定病症。此外,治療有效量可視以下而定:個體之血液參數(例如鈣含量、脂質型態、胰島素含量、血糖)、疾病狀態之嚴重性、器官功能或原發疾病或併發症。此類適當劑量可使用包括本文所描述之分析的任何可獲得之分析來確定。當向人類投與本文所揭示之式I化合物或其醫藥學上可接受之鹽中之一或多者時,醫師可例如首先開出相對低劑量,隨後增加劑量直至獲
得適當反應。所要投與之劑量將最終由健康照護專家。然而,一般而言,設想本文所揭示之式I化合物或其醫藥學上可接受之鹽的劑量可在於人類中約1至約50mg/kg每天範圍內。在所選實施例中,該範圍可在於人類中1至30mg/kg每天之間。在所選實施例中,該範圍可在於人類中1至20mg/kg每天之間。在所選實施例中,該範圍可在於人類中5至18mg/kg每天之間。在所選實施例中,該範圍可在於人類中1至18mg/kg每天之間。
如本文所用,術語「醫藥組合物」係指存在至少一種如本文所定義之根據式I之化合物或其醫藥學上可接受之鹽及至少一種醫藥學上可接受之載劑、稀釋劑、媒劑或賦形劑。如本文所用,術語「醫藥學上可接受之載劑」、「醫藥學上可接受之稀釋劑」或「醫藥學上可接受之賦形劑」旨在意謂但不限於任何助劑、載劑、賦形劑、助流劑、甜味劑、稀釋劑、防腐劑、染料/染色劑、增味劑、表面活性劑、潤濕劑、分散劑、懸浮劑、穩定劑、等張劑、溶劑、乳化劑或囊封試劑,諸如脂質體、環糊精、囊封聚合遞送系統或聚乙二醇基質,其可為在個體、較佳人類中使用可接受的。其較佳指由聯邦政府或州政府之管理機構批准或可批准或列於美國藥典或其他普遍認可用於動物且更特定而言用於人類之藥典中的化合物或組合物。醫藥學上可接受之媒劑可為含有例如水、乙醇、多元醇(例如甘油、丙二醇及液體聚乙二醇)、其適合之混合物及植物油的溶劑或分散介質。醫藥學上可接受之媒劑之其他實例包括但不限於:注射用水USP;水性媒劑,諸如但不限於氯化鈉注射液、林格氏注射液、葡萄糖注射液、右旋糖及氯化鈉注射液及乳酸鹽林格氏注射液;水可混溶媒劑,諸如但不限於乙醇、聚乙二醇及聚丙二醇;及非水性媒劑,諸如但不限於玉米油、棉籽油、花生油、芝麻油、油酸乙酯、肉豆蔻酸異丙酯及苯甲酸苯甲酯。對微生物之作用的預防可藉由添加抗細菌及抗真菌劑(例如對羥基苯甲酸酯、氯丁醇、苯酚、抗壞血酸、硫柳汞及其類似物)來達成。在許多情況下,在組合物中包括等張劑,例如糖、氯化鈉或多元醇,諸如甘露糖醇及山梨糖醇。可注射組合物之延長吸收可藉由在組合物中包括一種延遲吸收之試劑(例如單硬脂酸鋁或明膠)來產生。
本發明之組合物可包括一或多種如本文所定義之式I化合
物或其醫藥學上可接受之衍生物、鹽前藥、類似物、異構體或對映異構體。可製備活性化合物之調配物,從而提供呈適合用於腸道、黏膜(包括口腔、舌下、眼部、鼻內、肺部及直腸)、非經腸(包括肌肉內、真皮內、皮下及靜脈內)或局部(包括軟膏、乳膏、洗劑或滴劑)投與之形式的醫藥組合物。在適當的情況下,調配物可能宜以離散劑量單元形式存在,且可藉由醫藥調配技術中熟知之方法中之任一種來製備。所有方法均包括根據需要將活性醫藥成分與液體載劑或精細粉碎之固體載劑或兩者彙集在一起之步驟。在適當時,可修改以上所描述之調配物,從而提供活性醫藥成分之持續釋放。此項技術熟知之持續釋放調配物包括使用快速注射、連續輸注、生物相容聚合物或脂質體。
以上所提及之化合物或組合物可調配成表面可適用之化妝品組合物(例如局部調配物)。此類表面可適用組合物之非限制性實例包括皮膚護理乳膏、清潔霜、軟膏、皮膚護理洗劑、皮膚護理凝膠、皮膚護理泡沫、防曬護理組合物、遮光皮膚護理物、卸妝乳膏、卸妝洗劑、粉底霜、液體粉底、沐浴及淋浴製劑、除臭組合物、止汗組合物、剃須產品組合物、剃須後凝膠或洗劑、美容組合物、脫毛乳膏、肥皂組合物、洗手劑組合物、清潔棒、寶寶護理物、毛髮護理物、洗髮香波、捲髮洗劑、治療洗劑、髮乳、毛膠、著色組合物、重建組合物、永久性組合物或適合用於局部化妝品方案中之任何其他組合物。此類組合物可進一步包含一或多種藥妝可接受之媒劑。
如醫藥及藥妝調配物技術中熟知之乳膏為水包油或油包水之黏性液體或半固體乳液。乳膏基質為水可洗滌的,且含有油相、乳化劑及水相。油相(亦稱為「內部」相)通常包含礦脂及脂肪醇,諸如鯨蠟醇或硬脂醇。水相之體積通常(不過未必)超過油相,且通常含有濕潤劑。乳膏調配物中之乳化劑通常為非離子型、陰離子型、陽離子型或兩性表面活性劑。
洗劑為要施加至皮膚表面而不會有摩擦之製劑,且典型地為液體或半液體製劑,其中包括活性劑之固體粒子存在於水或乙醇基質中。洗劑通常為固體之懸浮液,且較佳出於本發明目的包含水包油型液體油性乳液。洗劑為用於治療大身體面積之較佳調配物,因為流動性更大之組合
物易於施加。洗劑中之不溶性物質通常需要為精細粉碎的。洗劑將典型地含有用於產生適合用於定位且保持活性劑與皮膚接觸之更佳分散體以及化合物的懸浮劑,例如甲基纖維素、羧甲基-纖維素鈉或其類似物。
溶液為藉由將將一或多種化學物質(溶質)溶解於液體中使得溶解物質之分子分散於溶劑分子之間而製備之均勻混合物。溶液可含有其他藥妝可接受之化學品以緩衝、穩定或保存溶質。用於製備溶液之溶劑的常見實例為乙醇、水、丙二醇或任何其他藥妝可接受之媒劑。
凝膠為半固體、懸浮液型系統。單相凝膠含有實質上均勻地分佈於載劑液體中之有機巨分子,該載劑液體典型地為水溶液,而且較佳含有乙醇及視情況存在之油。「有機巨分子」(亦即凝膠劑)為交聯丙烯酸聚合物,諸如「卡波姆(carbomer)」家族之聚合物,例如在商業上可以CarbopolTM獲得之羧基聚烯烴。其他實例為親水聚合物,諸如聚氧化乙烯、聚氧乙烯-聚氧丙烯共聚物及聚乙烯醇;纖維素聚合物,諸如羥丙基纖維素、羥乙基纖維素、羥丙基甲基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯及甲基纖維素;樹膠,諸如黃蓍膠及黃原膠;海藻酸鈉;及明膠。為製備均勻凝膠,可添加諸如乙醇或甘油之分散劑,或可藉由研磨、機械混合或攪拌分散凝膠劑,或其組合。
軟膏為典型地基於礦脂或其他石油衍生物之半固體製劑。如熟習此項技術者將瞭解,要使用之特定軟膏基質為將提供許多所需特徵(例如潤滑性或其類似物)之軟膏基質。在其他載劑或媒劑存在之情況下,軟膏基質應為惰性、穩定、無刺激且不致敏的。如Remington:The Science and Practice of Pharmacy,第19版(Easton,Pa.:Mack Publishing Co.,1995)第1399-1404頁所述,且軟膏基質可劃分為四種類別:油脂性基質;可乳化基質;乳劑基質;及水溶性基質。油性軟膏基質包括例如植物油、獲自動物之脂肪及獲自石油之半固體烴類。可乳化軟膏基質(亦稱為吸收性軟膏基質)幾乎不含水且包括例如羥基硬脂精硫酸酯、無水羊毛脂及親水性礦脂。乳劑軟膏基質為油包水(W/O)乳液或水包油(O/W)乳液,且包括例如十六烷醇、單硬脂酸甘油酯、羊毛脂及硬脂酸。較佳水溶性軟膏基質係自具有不同分子量之聚乙二醇製備;關於其他資訊,再次參見Remington:The Science
and Practice of Pharmacy。
糊劑為活性劑懸浮於適合之基質中的半固體劑型。視基質之性質而定,將糊劑劃分為脂肪糊劑或由單相水性凝膠製成之糊劑。脂肪糊劑中之基質通常為礦脂或親水性礦脂等。由單相水溶液凝膠製成之糊劑通常並有羧甲基纖維素或其類似物作為基質。
調配物亦可用脂質體、膠束及微球製備。脂質體為具有包含雙層脂質之脂質壁的微觀囊泡,且在本發明上下文中,囊封抗老化調配物之一或多種組分。本文之脂質體製劑包括陽離子(帶正電荷)、陰離子(帶負電荷)及中性製劑。陽離子脂質體可容易地獲得。舉例而言,N[1-2,3-二油烯基氧基)丙基]-N,N,N-三乙基銨(DOTMA)脂質體可以商標名LipofectinTM(GIBCO BRL,Grand Island,N.Y.)獲得。類似地,陰離子及中性脂質體同樣可容易地獲得,例如來自Avanti Polar Lipids(Birmingham,Ala.),或可使用可容易地獲得之材料容易地製備。此類材料包括磷脂醯膽鹼、膽固醇、磷脂醯乙醇胺、二油醯基磷脂醯膽鹼(DOPC)、二油醯基磷脂醯甘油(DOPG)及二油醯基磷脂醯乙醇胺(DOPE)等。此等材料亦可以適當比率與DOTMA混合。用於使用此等材料製備脂質體之方法為此項技術中熟知的。
膠束在此項技術中已知包含表面活性劑分子,該等表面活性劑分子經佈置使得其極性頭部基團形成外部球形殼體,同時疏水性烴鏈朝向球形之中心取向,從而形成核心。膠束形成於含有足夠高濃度之表面活性劑以使得膠束自然地產生之水溶液中。適合用於形成膠束之表面活性劑包括但不限於月桂酸鉀、辛烷磺酸鈉、癸烷磺酸鈉、十二烷磺酸鈉、月桂基硫酸鈉、多庫酯鈉(docusate sodium)、溴化癸基三甲基銨、溴化十二烷基三甲基銨、溴化十四烷基三甲基銨、氯化十四烷基三甲基銨、氯化十二烷基銨、聚氧乙烯(polyoxyl)-8十二烷基醚、聚氧乙烯-12十二烷基醚、壬苯醇醚(nonoxynol)10及壬苯醇醚30。
類似地,可將微球併入本發明調配物。像脂質體及膠束一樣,微球基本上囊封本發明調配物之一或多種組分。其通常不過未必由脂質、較佳帶電荷脂質(諸如磷脂)形成。脂質微球之製備為此項技術中熟知的且描述於相關文本及文獻中。
本文所揭示之式I化合物或其醫藥學上可接受之鹽可經包裝作為套組之部分,該套組視情況包括一容器(例如包裝一箱、一小瓶等)。套組可在商業上根據本文所描述之方法使用,且可包括在本文所揭示之方法中的使用說明。其他套組組分可包括酸、鹼、緩衝劑、無機鹽、溶劑、抗氧化劑、防腐劑或金屬螯合劑。其他套組組分係以純組合物形式或以並有一或多種其他套組組分之水性或有機溶液之形式存在。任何或所有套組組分均視情況進一步包含緩衝液。
本文所揭示之式I化合物或其醫藥學上可接受之鹽可能或可能不同時或藉由相同投藥途徑向患者投與。因此,本發明之方法涵蓋套組,在由醫學從業者使用時其可使得向患者投與適當量之兩種或更多種活性成分簡化。
本發明之典型套組包含至少一種如本文所定義之式I化合物或其醫藥學上可接受之鹽的單位劑型,及至少一種其他活性成分之單位劑型。可與本發明之化合物結合使用之其他活性成分之實例包括但不限於在上文指出可與如本文所定義之式I化合物或其醫藥學上可接受之鹽組合使用之藥物中之任一者。
本發明之套組可進一步包含可用於投與一或多種活性成分之醫藥學上可接受之媒劑。舉例而言,若活性成分係以必須複水以便非經腸投與之固體形式提供,則套組可包含密封容器或適合之媒劑,其中活性成分可溶解以形成不含粒子之適合用於非經腸投與之無菌溶液。醫藥學上可接受之媒劑的實例提供於上文中。
以下實例進一步說明對本發明之實踐,但不旨在對其進行限制。
實例1:用於製備某些代表性化合物之實驗程序
所有HPLC層析譜及質譜均記錄於HP 1100 LC-MS AgilentTM儀器上,使用分析型C18管柱(250×4.6mm,5微米),使用5min內15-99% CH3CN-H2O之梯度,以0.01% TFA作為溶離劑,且流速為2
mL/min。
化合物I:使用改良型薗頭反應程序(Sonogashira procedure)合成(3-戊基苯基)乙酸之鈉鹽
步驟1
在室溫下向3-溴苯基乙酸(5.02g、23.33mmol)於乙醇(100mL)中之溶液/懸浮液中添加濃硫酸(1mL)。然後將無色固體在80℃下攪拌隔夜。將溶液在減壓下濃縮。將殘餘物用乙酸乙酯(25mL)、水(25mL)稀釋,且將兩個層分離。將水層用乙酸乙酯(2×25mL)及鹽水(20mL)萃取。將合併之有機層用NaHCO3之飽和溶液(2×25mL)、鹽水(25mL)洗滌且經硫酸鈉乾燥。在溶液過濾之後,將其蒸發至乾燥。此舉得到淺黃色油狀物(5.4g,95%)。1H-NMR(400MHz,CDCl3):δ 1.26(t,J=4.7Hz,3H),3.57(s,2H),4.15(Q,J=7.0及14.3Hz,2H),7.17-7.26(m,2H),7.38-7.44(m,1H),7.44(d,J=1.56Hz,1H)。
步驟2
在密封管中將(3-溴苯基)乙酸乙酯(0.3g,1.24mmol)與水合氟化四丁銨(0.97g,3.72mmol)之混合物用PdCl2(PPh3)2(26mg,0.037mmol;3莫耳%)及1-戊炔(367μL,3.72mmol)處理。將管子在80℃下加熱2h。將混合物用水處理,且用二乙醚萃取。將有機萃取物經硫酸鈉乾燥,過濾且在真空中蒸發,得到粗產物。在BiotageTM 25M管柱(二氧化矽)上純化,用乙酸乙酯/己烷0:1至2:98溶離,得到呈淡黃色油狀之(3-(戊炔-1-基)苯基)乙酸乙酯(0.23g,79%)。
步驟3
在氮氣氛圍下向含[3-[戊炔-1-基]苯基]-乙酸乙酯(0.23g,0.98mmol)之乙醇(5mL)中添加碳載Pd(10%,25mg,10% w/w)。將混合物在氫氣氛圍下在室溫下劇烈攪拌隔夜。將溶液過濾且將鈀/碳用乙醇(20mL)洗滌。將濾液用矽膠濃縮。將粗產物藉由急驟層析使用10%己烷/乙酸乙酯之混合物加以純化。獲得透明油狀物(0.21g,90%)。
步驟4
在0℃下向酯(0.2g,0.9mmol)於四氫呋喃(5mL)、甲醇(1.5mL)及水(1.5mL)中之溶液中添加氫氧化鋰(0.09g,3.6mmol)。將反應混合物在室溫下攪拌隔夜。將不溶物質過濾且將濾液在減壓下濃縮。然後將殘餘物用2M HCl處理且用乙酸乙酯萃取。將有機相經硫酸鈉乾燥且在減壓下蒸發。使用乙酸乙酯/己烷(0:10至4:6)作為溶離劑,將粗物質在40L Biotage管柱(二氧化矽)上純化。此舉得到呈白色膠狀固體之純(3-戊基苯基)乙酸(0.19g,99%)。1H NMR(400MHz,CD3OD):δ 0.90(t,J=7.0Hz,3H),1.28-1.38(m,4H),1.61(qt,J=7.6Hz,15.0Hz,2H),2.58(t,J=7.6Hz,2H),3.56(s,2H),7.07(m,3H),7.20(m,1H);LRMS(ESI):m/z 207(MH+);HPLC:4min。
步驟5
向酸(0.19g,0.82mmol)於乙醇(4mL)及水(1mL)中之攪拌溶液中添加碳酸氫鈉(0.07g,0.82mmol)。將反應混合物在室溫下攪拌隔夜。蒸發溶劑且將白色膠狀固體溶解於水中且將溶液凍幹。此舉得到呈白色固體之純的(3-戊基苯基)乙酸之鈉鹽(0.17g,92%)。mp 110-112℃;1H NMR(400MHz,CD3OD):δ 0.89(t,J=6.8Hz,3H),1.28-1.37(m,4H),1.60(qt,J=7.4Hz,15.0Hz,2H),2.56(t,J=7.6Hz,2H),3.43(s,2H),6.96(m,1H),7.12(m,3H);LRMS(ESI):m/z 207((MH+);HPLC:4min。
化合物II:3-(3-戊基苯基)丙酸之鈉鹽
以上化合物係以3-側氧基-3-溴苯基丙酸乙酯為起始物質如化合物I一般進行製備。在氫氣壓力下在乙醇中使用鈀/碳同時將酮基及雙鍵還原。白色固體;1H NMR(400MHz,CDCl3):δ 7.14-7.10(m,1H),7.04-7.00(m,2H),6.95-6.93(m,1H),2.88-2.84(m,2H),2.55(t,J=7.4Hz,2H),
2.44-2.40(m,2H),1.63-1.55(m,2H),1.35-1.28(m,4H),0.90(m,3H);13C NMR(101MHz,CD3OD):δ 179.3,141.2,140.8,126.7,126.4,124.0,123.8,38.6,34.2,31.2,29.9,29.8,20.9,11.7;LRMS(ESI):m/z 203(MH+-CO-NaOH);HPLC:4.5min。
化合物III:3-(3-丁基苯基)丙酸之鈉鹽
步驟1
在圓底燒瓶(250mL)中稱取異酞醛(1.0g,7.5mmol),繼之以二氯甲烷(100mL)。在室溫下在壓力平衡下經由分液漏斗添加含(三苯基-伸正膦基)乙酸甲酯(2.7g,8.2mmol)之二氯甲烷(25mL)。將反應物在室溫下攪拌隔夜。將混合物經小矽膠墊過濾,且用二氯甲烷(150mL)洗滌。然後將溶劑在減壓下蒸發且未進一步純化即將粗產物用於下一步驟。
步驟2
在氮氣下,將溴化丙基三苯基鏻(3.2g,8.2mmol)置放於圓底燒瓶中,且添加無水THF(5mL)。將燒瓶在冰/丙酮(-10℃)浴中冷卻,且緩慢添加正丁基鋰(2.5M己烷溶液,3.28mL,8.2mmol)。將攪拌30分鐘
之同時混合物變為深色的。在氮氣下將含來自先前步驟之粗反應混合物的無水THF(5mL)置放於冰/丙酮(-10℃)浴中。在-10℃下將鏻溶液緩慢添加至醛溶液中,且將反應混合物緩慢升溫至室溫且攪拌4h。添加飽和氯化銨溶液(10mL)且將有機層用乙酸乙酯萃取(3次)。將有機層經無水硫酸鈉乾燥、過濾且添加矽膠以獲得防潮包裝(drypack)。將化合物用SP1(乙酸乙酯/己烷)純化。此舉得到預期產物(8.8g,54%)。1H NMR(400MHz,CDCl3):δ 7.70-7.65(m,1H),7.45-7.24(m,4.5H),6.45-6.28(m,2.5H),5.70-5.67(m,0.5H),3.78(m,3H),2.34-2.20(m,2H),1.10-1.03(m,3H)。
步驟3
將溶解於乙酸乙酯(10mL)中之不飽和酯(140mg,0.65mmol)置放於圓底燒瓶(25mL)中。向此溶液中添加10%活性炭載鈀Pd/C(10mg)。將燒瓶用隔板加蓋,且在頂部置放氫氣囊。將燒瓶用氫氣吹掃三次,且將反應物在室溫下攪拌隔夜。然後將固體經CeliteTM過濾。添加矽膠且製備防潮包裝。藉由急驟層析使用0-20%乙酸乙酯/己烷純化,得到所需產物(124mg,87%)。LRMS(ESI):m/z 221(MH+);HPLC:5.0min。
步驟4
將依次酯(124mg,0.56mmol)與甲醇(4mL)及氫氧化鋰(118mg,2.8mmol)置放於圓瓶燒瓶中。添加水(1mL)且將反應物在攪拌下在50℃下加熱17h。將反應物轉移至分液漏斗中,用HCl(1M)酸化至pH值較低於4,且用乙酸乙酯萃取(3次)。將有機層經無水硫酸鈉乾燥,過濾且蒸發。將粗物質藉由HPLC/水純化。此舉得到白色固體(80mg,70%)。1H NMR(400MHz,CD3OD):δ 7.16-7.12(m,1H),7.01-6.96(m,3H),2.88-2.84(m,2H),2.57-2.53(m,4H),1.60-1.52(m,2H),1.37-1.28(m,2H),0.91(t,3H,J=7.3Hz);LRMS(ESI):m/z 205(M-H);HPLC:4.2min。
步驟5
依次將酸(80mg,0.39mmol)與NaHCO3(33mg,0.39mmol)及水(8mL)置放於燒瓶(20mL)中。向混合物中添加乙腈(3mL)且將反應物超音處理,加熱且攪拌直至幾乎所有固體呈溶液狀態。將溶液經耐綸過濾器過濾。藉由將小瓶浸沒於乾冰/丙酮浴中來將水固化,且凍幹隔夜。此舉
得到呈白色固體之所需產物。1H NMR(400MHz,CD3OD):δ 7.14-7.10(m,1H),7.04-6.93(m,3H),2.88-2.84(m,2H),2.57-2.54(m,2H),2.44-2.40(m,4H),1.61-1.53(m,2H),1.39-1.30(m,2H),0.93(t,3H,J=7.3Hz);13C NMR(101MHZ,CD3OD):δ 142.7,142.4,128.2,128.0,125.6,125.4,125.3,40.1,35.5,33.9,32.7,22.2,13.1;LRMS(ESI):m/z 251.0(m,MNa+),229.0(w,MH+),189.2(100%,醯陽離子[M-Na++2H+-H2O]);HPLC:4.1min。
化合物IV:E-(3-戊-1-烯基-苯基)乙酸之鈉鹽。
以上化合物係以E-(3-戊-1-烯基-苯基)乙酸甲酯為起始物質如化合物I一般進行製備。後者係藉由使3-溴苯基乙酸甲酯與反-1-戊烯基硼酸頻哪醇酯在鈴木條件(Suzuki condition)下反應來進行製備。白色固體;1H NMR(400MHz,CD3OD):δ=7.32(s,1H),7.11-7.18(m,3H),6.35(d,J=15.7Hz,1H),6.20-6.27(m,1H),3.44(s,2H),2.19(m,2H),1.45-1.54(m,2H),0.96(t,J=7.4,3H);13C NMR(101MHz,CD3OD):δ=179.26,138.25,137.92,130.32,130.04,128.06,127.59,126.60,123.52,45.21,35.06,22.52,12.89;LRMS(ESI):m/z 205(MH+);HPLC:4.1min。
化合物V:2-(3-(己-1-烯基]苯基)乙酸之鈉鹽。
以上化合物係如下製備:如化合物VII一般進行2-(3-溴苯基)乙酸甲酯與(E)-己-1-烯基硼酸頻哪醇酯之鈴木偶合(Suzuki coupling);隨後如化合物I一般進行酯水解及鈉鹽形成。白色固體:1H NMR(400MHz,CD3OD):δ 7.33(s,1H),7.12-7.19(m,3H),6.35(d,J=15.8Hz,1H),6.20(dt,J=15.8,6.8Hz,1H),3.46(s,2H),2.17-2.22(m,2H),1.33-1.49(m,4H),0.93(t,J=7.2Hz,3H);13C NMR(101MHz,CD3OD):δ 179.35,138.27,137.95,130.27,130.16,128.10,127.61,126.64,123.56,45.24,32.66,31.67,22.16,13.22;LRMS(ESI):m/z 263.1(100%,M+Na+);HPLC:4.4min。
化合物VI:2-(3-己基苯基)乙酸之鈉鹽
以上化合物係如下製備:如化合物VII一般進行2-(3-溴苯基)乙酸甲酯與(E)-己-1-烯基硼酸頻哪醇酯之鈴木偶合;隨後如化合物I一般進行加氫、酯水解及鈉鹽形成。白色固體;1H NMR(400MHz,D2O):δ 7.14(dd,J=7.8,7.6Hz,1H),7.01(s,1H),7.00(d,J=7.8Hz,1H),6.96(d,J=7.6
Hz,1H),3.34(s,2H),2.46(d,J=7.5Hz,2H),1.41-1.48(m,2H),1.10-1.18(m,6H),0.70(t,J=6.8Hz,3H);13C NMR(101MHz,D2O):δ 181.23,143.98,137.46,129.47,128.73,126.63,126.48,44.58,35.14,31.12,30.94,28.23,22.13,13.53;LRMS(ESI):m/z 265(100%,M+Na+);HPLC:4.6min。
化合物VII:3-羥基-5-戊基苯基乙酸之鈉鹽
步驟1
將[3,5-二羥苯基]乙酸甲酯(2.1g,11.5mmol)於丙酮(100mL)中之溶液用碳酸鉀(2.4g,17.4mmol)、碘化鉀(383mg,2.31mmol)及溴甲苯(1.5mL,12.7mmol)處理,且將混合物在室溫下攪拌隔夜。將反應物用水稀釋且用二氯甲烷萃取(3次)。將合併之有機萃取物經硫酸鈉乾燥且在真空中蒸發。將粗物質在BiotageTM 40M管柱(二氧化矽)上純化,用40%乙酸乙酯/己烷溶離,得到[3-苯甲基氧基-5-羥苯基]乙酸甲酯(1.0g,33%)。1H NMR(400MHz,CDCl3):δ 7.32-7.42(m,5H),6.48(d,J=1.4Hz,1H),6.38-6.39(m,
2H),4.99(s,2H),3.69(s,3H),3.53(s,2H)。
步驟2
將0℃下之二甲苯醚(1.04g,3.8mmol)於二氯甲烷(15mL)中之溶液用N-苯基-雙(三氟磺醯基)醯亞胺(1.40g,3.9mmol)處理,且然後緩慢添加三乙胺(0.6mL,4.1mmol)。將反應物在0℃下攪拌1h,且然後在室溫下攪拌1h。將反應混合物用水稀釋,且然後用二乙醚萃取(2次)。將合併之有機萃取物用1M氫氧化鈉水溶液、水(2次)及飽和氯化鈉水溶液洗滌,然後經硫酸鈉乾燥,過濾且在真空中蒸發,得到粗產物。在BiotageTM 40M管柱(二氧化矽)上純化,用25%乙酸乙酯/己烷溶離,得到[3-苯甲基氧基-5-三氟甲磺醯氧基苯基]乙酸甲酯(1.2g,79%)。1H NMR(400MHz,CDCl3):δ 7.36-7.46(m,5H),6.98(s,1H),6.97(s,1H),6.84(s,1H),5.06(s,2H),3.72(s,3H),3.63(s,2H)。
步驟3
將E-1-伸戊-1-基硼酸頻哪醇酯(0.8g,3.9mmol)於二甲氧基乙烷(5mL)中之溶液用三氟甲磺酸酯(1.2g,3.0mmol)於二甲氧基乙烷(5mL)中之溶液處理。將溶液用鈀零(0.7g,0.6mmol)及2M碳酸鈉水溶液(1.3mL,2.6mmol)處理。然後將混合物在90℃下加熱3天。將反應物冷卻至室溫且經CeliteTM過濾。將濾液在真空中蒸發,且將粗物質在BiotageTM 25M管柱(二氧化矽)上純化,用5%乙酸乙酯/己烷溶離,得到[3-苯甲基氧基-5-[戊-1-烯基]苯基]乙酸甲酯(0.4g,40%)。1H NMR(400MHz,CDCl3):δ 7.36-7.47(m,5H),6.90-6.92(m,2H),6.79(dd,J=2.0,2.0Hz,1H),6.35(d,J=15.9Hz,1H),6.24(dt,J=15.9,6.8Hz,1H),5.07(s,2H),3.70(s,3H),3.59(s,2H),2.20(td,J=7.4,6.8Hz,2H),1.51(dt,J=7.4Hz,2H),0.98(t,J=7.4Hz,3H)。
步驟4
將鏈烯(0.4g,1.2mmol)於乙醇(13mL)中之溶液用1%碳載鈀(40mg)處理。將混合物在室溫下在1大氣壓氫氣下攪拌隔夜。將反應物過濾,在真空中蒸發,且在BiotageTM 25S管柱(二氧化矽)上純化,用15%乙酸乙酯/己烷溶離,得到[3-羥基-5-戊基苯基]乙酸甲酯(0.3g,93%)。1H NMR(400MHz,CDCl3):δ 6.64(s,1H),6.58-6.60(m,2H),3.70(s,3H),3.55
(s,2H),2.51(t,J=7.7Hz,2H),1.55-1.59(m,2H),1.28-1.34(m,4H),0.88(t,J=7.0Hz,3H)。
步驟5
將酯(0.3g,1.3mmol)於乙醇(12mL)中之溶液用水(3mL)及氫氧化鋰(155mg,6.4mmol)處理,且將混合物在室溫下劇烈攪拌隔夜。將反應混合物用水(100mL)稀釋;用二氯甲烷洗滌;然後用1M鹽酸水溶液酸化至pH 1且用二氯甲烷萃取(3次)。將合併之有機萃取物經硫酸鈉乾燥(0.3g,95%)。此材料未進一步純化即使用。1H NMR(400MHz,CDCl3):δ 6.66(s,1H),6.58-6.59(m,2H),3.55(s,2H),2.52(t,J=7.7Hz,2H),1.55-1.59(m,2H)。
步驟6
將酸(0.27g,1.23mmol)於乙醇(6mL)及水(6mL)中之溶液用碳酸氫鈉(0.1g,1.2mmol)處理,且將反應物在室溫下攪拌幾個小時。將溶劑真空濃縮,且將溶液用水稀釋,過濾(0.2μm)且凍幹,得到呈白色固體之[3-羥基-5-戊基苯基]乙酸鈉(0.3g,95%)。mp 63-66℃;1H NMR(400MHz,CD3OD):δ 6.63(s,1H),6.58(s,1H),6.42(s,1H),3.36(s,2H),2.48(t,J=7.6Hz,2H),1.55-1.62(m,2H),1.26-1.38(m,4H),0.89(t,J=6.8Hz,3H);13C NMR(101MHz,CD3OD):δ 177.79,155.31,142.36,137.62,119.08,111.66,111.18,43.70,34.17,29.95,29.56,20.87,11.64;LRMS(ESI):m/z 445.2(2M-2Na++3H+),m/z 223(M-Na++2H+);HPLC:3.5min。
化合物VIII:2-(4-羥基-3-戊基苯基)乙酸之鈉鹽
以上化合物係如下製備:如實例VII一般進行2-(4-(苄氧基)-3-溴苯基)乙酸苯甲酯與(E)-戊-1-烯基硼酸頻哪醇酯之鈴木偶合;隨後加氫。白色固體;熔點192-195℃;1H NMR(400MHz,CD3OD):δ 7.01(d,J=2.3Hz,1H),6.93(dd,J=8.2,2.3Hz,1H),6.64(d,J=8.2Hz,1H),3.35(s,2H),2.53(t,J=7.7Hz,2H),1.54-1.61(m,2H),1.30-1.37(m,4H),0.90(t,J=7.2Hz,3H);13C NMR(101MHz,CD3OD):δ 180.25,153.20,130.54,128.80,128.76,127.10,114.49,44.45,31.84,30.10,29.73,22.52,13.31;LRMS(ESI):m/z 245.2(55%,MH+),177.4(100%,M-CO2Na);HPLC:1.9min。
化合物IX:2-(2-羥基-3-戊基苯基)乙酸之鈉鹽
步驟1
將2-(2-羥苯基)乙酸(3.00g,19.7mmol)於甲醇(40mL)中之溶液用硫酸(0.95mL,17.8mmol)處理且將反應物在室溫下攪拌18小時。將反應混合物用乙酸乙酯(250mL)稀釋,且將溶液用水(2×150mL)且用飽和氯化鈉水溶液(150mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。自熱己烷中再結晶,得到2-(2-羥苯基)乙酸甲酯(2.83g,87%)。1H NMR(400MHz,CDCl3):δ 7.20(ddd,J=7.7,7.4,1.8Hz,1H),7.09-7.11(m,1H),6.94(dd,J=8.0,1.2Hz,1H),6.88(ddd,J=7.4,7.4,1.2Hz,1H),3.75(s,3H),3.69(s,2H)。
步驟2
將2-(2-羥苯基)乙酸甲酯(1.00g,6.0mmol)、三苯基膦(2.37g,9.0mmol)及戊-1-烯-3-醇(0.78g,9.0mmol)於四氫呋喃(30mL)中之溶液在氮氣下冷卻至0℃,且歷時10分鐘逐滴添加氮雜二甲酸二異丙酯(1.86mL;9.0mL)。然後將反應物加熱至60℃持續21.5小時。將溶劑在真空中蒸發且將殘餘物用5%乙酸乙酯/己烷萃取。將萃取物過濾且在真空中蒸發,得到粗產物。在BiotageTM SP1系統(120g二氧化矽管柱)上純化,用0-3%乙酸乙酯/己烷溶離,得到2-(2-(戊-1-烯-3-基氧基)苯基)乙酸甲酯(0.39g,28%)。1H NMR(400MHz,CDCl3):δ 7.21-7.26(m,1H),7.20(d,J=7.6Hz,1H),6.91(ddd,J=7.4,7.4,1.0Hz,1H),6.87(d,J=8.0Hz,1H),5.84(ddd,J=
17.4,10.7,6.0Hz,1H),5.26(d,J=17.4Hz,1H),5.22(d,J=10.7Hz,1H),4.63(dt,J=6.0,6.0Hz,2H),3.70(s,3H),3.68(s,2H),1.71-1.87(m,2H),1.02(t,J=7.5Hz,3H);13C NMR(101MHz,CDCl3):δ 172.58,156.28,137.75,131.19,128.50,123.87,120.52,116.66,113.18,79.76,52.00,36.61,28.71,9.62。
步驟3
將2-(2-(戊-1-烯-3-基氧基)苯基)乙酸甲酯(0.24g,1.0mmol)於N-甲基-2-吡咯啶酮(1.0mL)中之溶液在Biotage引發器中在180℃下用微波輻射照射30分鐘,然後持續15分鐘。將溶液用乙酸乙酯(25mL)稀釋,然後用水(4×25mL)且用飽和氯化鈉水溶液(25mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM SP1系統(40g二氧化矽管柱)上純化,用0-7%乙酸乙酯/己烷溶離,得到(E)-2-(2-羥基-3-(戊-2-烯基)苯基)乙酸甲酯(0.89g,37%)。1H NMR(400MHz,CDCl3):δ 7.09(s,1H),7.08(dd,J=7.4,1.6Hz,1H),7.01(dd,J=7.6,1.6Hz,1H),6.85(dd,J=7.6,7.4Hz,1H),5.59-5.70(m,2H),3.75(s,3H),3.69(s,2H),3.41(d,J=4.7Hz,2H),2.04-2.11(m,2H),1.01(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ 174.31,153.53,134.44,129.86,129.32,128.62,127.13,121.08,120.82,52.79,37.59,34.17,25.77,13.97。
步驟4
將(E)-2-(2-羥基-3-(戊-2-烯基)苯基)乙酸甲酯(0.14g,0.6mmol)如化合物I,步驟3一般進行氫化,但使用甲醇作為溶劑,得到2-(2-羥基-3-戊基苯基)乙酸甲酯(0.11g,76%)。1H NMR(400MHz,CDCl3):δ 7.57(s,1H),7.11(dd,J=7.4,1.6Hz,1H),6.96(dd,J=7.4,1.6Hz,1H),6.84(dd,J=7.4,7.4Hz,1H),3.76(s,3H),3.70(s,2H),2.68(t,J=7.8Hz,2H),1.61-1.67(m,2H),1.36-1.43(m,4H),0.93(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ 175.01,153.48,131.75,129.98,128.75,120.74,120.60,53.01,38.30,32.10,30.50,29.91,22.87,14.34。
步驟5
將2-(2-羥基-3-戊基苯基)乙酸甲酯(0.11g,0.5mmol)如化合
物I,步驟4一般進行水解,使用乙腈/水(4:1)作為溶劑,得到2-(2-羥基-3-戊基苯基)乙酸(0.57g,57%)。1H NMR(400MHz,CDCl3):δ 8.70(br s,1H),7.09(dd,J=7.6,1.6Hz,1H),6.98(dd,J=7.4,1.6Hz,1H),6.84(dd,J=7.6,7.4Hz,1H),3.68(s,2H),2.62(t,J=7.8Hz,2H),1.57-1.65(m,2H),1.31-1.40(m,4H),0.91(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ 179.89,152.79,130.92,130.04,128.98,121.08,120.24,37.74,32.02,30.34,29.78,22.80,14.30。
步驟6
將2-(2-羥基-3-戊基苯基)乙酸(22mg,0.098mmol)如化合物I,步驟5一般轉化為鈉鹽,得到2-(2-羥基-3-戊基苯基)乙酸鈉(24mg,98%)。1H NMR(400MHz,CD3OD):δ 6.91(dd,J=7.5,1.6Hz,1H),6.87(dd,J=7.5,1.6Hz,1H),6.66(dd,J=7.5,7.5Hz,1H),3.49(s,2H),2.59(t,J=7.7Hz,2H),1.55-1.62(m,2H),1.28-1.38(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 180.26,154.27,130.75,128.21,127.90,124.24,119.23,42.91,31.83,30.21,29.82,22.51,13.29;LRMS(ESI負):m/z 220.8(100%,M-Na+);UPLC(系統A):5.0min。UPLC系統A:移動相A=10mM甲酸銨水溶液;移動相B=乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物X:2-(3-氟-5-戊基苯基)乙酸之鈉鹽
步驟1
將3-溴-5-氟苯甲酸(2.74g,12.5mmol)於四氫呋喃(6mL)中之溶液在0℃下在氮氣下用硼烷-四氫呋喃複合物(1M,15mL,15mmol)以小份進行處理歷時12min,且然後將反應物在0℃下攪拌70分鐘,且在室溫下攪拌22h。藉由添加甲醇(10mL)中止反應,且將甲醇混合物在室溫下攪拌3h,且然後在真空中蒸發,同時自甲醇中然後自乙酸乙酯共蒸發,得到粗產物。將物質溶解於乙酸乙酯(200mL)中,且將溶液用0.5M氫氧化鈉水溶液(200mL)且用飽和氯化鈉水溶液(100mL)洗滌;然後經硫酸鈉乾燥;過濾且在真空中蒸發,得到3-溴-5-氟苯甲醇(1.79g,67%)。1H NMR(400MHz,CDCl3):δ 7.29(s,1H),7.15(ddd,J HF=8.2Hz,J HH=2.2,1.8Hz,1H),7.00-7.02及7.02-7.04(dm,J HF=9.2Hz,J HH=未解析,1H),4.66(s,2H),2.04(br s,1H);19F NMR(377MHz,CDCl3):δ -111.05(dd,J HF=9.3,8.0Hz,1F);13C NMR(101MHz,CDCl3):δ 162.87(d,J CF=250.6Hz),145.42(d,J CF=6.9Hz),125.45(d,J CF=3.1Hz),122.69(d,J CF=9.2Hz),118.01(d,J CF=24.6Hz),112.51(d,J CF=21.5Hz),63.60(d,J CF=2.3Hz)。
步驟2
將3-溴-5-氟苯甲醇(1.79g,8.39mmol)及三苯基膦(3.65g,10.10mmol)於二氯甲烷(45mL)中之溶液用四溴化碳(3.34g,10.10mmol)以小份進行處理歷時10min,且然後將反應物在室溫下攪拌隔夜。將溶劑在真空中蒸發,且將殘餘物用二乙醚(50mL)處理。將所得白色漿料在室溫下攪拌,且然後經CeliteTM過濾。將殘餘物用二乙醚(2×50mL)洗滌,且將合併之濾液及洗滌液在真空中蒸發得到粗產物。在二氧化矽墊上純化,用2%乙酸乙酯/己烷溶離,得到3-溴-5-氟苯甲基溴化物(2.21g,98%)。1H NMR(400MHz,CDCl3):δ 7.33(s,1H),7.18(ddd,J HF=8.2Hz,J HH=2.0,2.0Hz,1H),7.05(ddd,J HF=9.0Hz,J HH=1.8,1.6Hz,1H),4.38(s,2H);19F NMR(377MHz,CDCl3):δ -110.19至-110.14(m,1F);13C NMR(101MHz,CDCl3):δ 162.67(d,J CF=252.1Hz),141.61(d,J CF=8.5Hz),128.17(d,J CF=3.1Hz),122.94(d,J CF=10.0Hz),119.39(d,J CF=24.6Hz),115.34(d,J CF=22.3Hz),31.31(d,J CF=2.3Hz)。
步驟3
將氰化鈉(0.38g,7.73mmol)於水(0.35mL)中之懸浮液用3-溴-5-氟苯甲基溴化物(1.38g,5.15mmol)於二甲基甲醯胺(2.6mL)中之溶液處理,且將反應物在密封管中在75℃下加熱3h。將反應物冷卻至室溫且分配於乙酸乙酯(50mL)與2.5% w/v碳酸氫鈉水溶液(100mL)之間。將水相用另一部分乙酸乙酯(50mL)萃取;且將合併之萃取物用水(2×50mL)且用飽和氯化鈉水溶液(50mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM 40iM管柱(二氧化矽)上純化,用10%乙酸乙酯/己烷溶離,得到2-[3-溴-5-氟苯基]乙腈(0.64g,58%)。1H NMR(400MHz,CDCl3):δ 7.26-7.28(m,1H),7.17-7.19 & 7.19-7.21(dm,J HF=8.0Hz,J HH=未解析,1H),6.98-7.00 & 7.00-7.02(dm,J HF=8.8Hz,J HH=未解析,1H),3.73(s,2H);19F NMR(377MHz,CDCl3):δ -109.46(dd,J HF=8.0,8.0Hz,1F);13C NMR(101MHz,CDCl3):δ 162.90(d,J CF=252.1Hz),133.95(d,J CF=8.5Hz),127.24(d,J CF=3.8Hz),123.53(d,J CF=10.0Hz),119.22(d,J CF=23.8Hz),117.00,114.50(d,J CF=23.1Hz),23.30(d,J CF=1.5Hz)。
步驟4
將芳基溴(0.55g,2.58mmol)及(E)-1-伸戊-1-基硼酸頻哪醇酯(0.61g,3.13mmol)於二甲氧基乙烷(13mL)中之溶液用碳酸鈉(0.55g,5.17mmol)於水(3mL)中之溶液處理。將溶液用氮氣脫氧,且用肆(三苯基膦)鈀(0.15g,0.13mmol;5莫耳%)處理。然後將混合物在密封管中在90℃下加熱17h。將反應物冷卻至室溫且分配於乙酸乙酯(50mL)與1M鹽酸水溶液(50mL)之間。將有機相用飽和氯化鈉水溶液(30mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM 40iM管柱(二氧化矽)上純化,用(3%)乙酸乙酯/己烷溶離,得到(E)-2-[3-氟-5-[戊-1-烯基]苯基]乙腈(0.43g,82%)。1H NMR(400MHz,CDCl3):δ 7.04(s,1H),6.97(ddd,J HF=9.8Hz,J HH=2.0,1.5Hz,1H),6.82-6.85(m,1H),6.31(d,J=15.8Hz,1H),6.25(ddd,J=15.8,5.9,0Hz,1H),3.68(s,2H),2.18(td,J=7.2,5.4Hz,2H),1.49(qt,J=7.4,7.4Hz,2H),0.95(t,J=7.4Hz,3H);19F NMR(377MHz,CDCl3):δ -112.93(dd,J HF=10.6,9.3Hz,1F);13C NMR(101MHz,CDCl3):δ 163.43(d,J CF=246.0Hz),141.44(d,J CF=8.5Hz),133.99,132.37(d,J CF=8.5Hz),
128.42(d,J CF=2.3Hz),121.60(d,J CF=3.1Hz),117.66,113.40(d,J CF=23.1Hz),112.21(d,J CF=22.3Hz),35.22,23.49(d,J CF=2.3Hz),22.51,13.94。
步驟5
將苯基乙腈衍生物(0.43g,2.10mmol)於甲醇(42mL)中之溶液用氫氧化鈉水溶液(5M;21mL,105mmol)處理,且將混合物在密封管中在75℃下加熱4.5h。將反應混合物冷卻至室溫,且用6M鹽酸水溶液(21mL)中止反應;在室溫下攪拌10min;然後用乙酸乙酯(2×75mL)萃取。將有機萃取物用飽和氯化鈉水溶液(75mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM 40iM管柱(二氧化矽)上純化,用70%乙酸乙酯/己烷溶離,得到所需產物之甲酯(0.09g,18%),及約95%純(E)-2-[3-氟-5-[戊-1-烯基]苯基]乙酸(0.22g,48%)。1H NMR(400MHz,CDCl3):δ 11.17(br s,1H),7.02(s,1H),6.98(ddd,J HF=9.8Hz,J HH=2.0,1.8Hz,1H),6.85(ddd,J HF=9.0Hz,J HH=1.8,1.6Hz,1H),6.33(d,J=15.8Hz,1H),6.25(dt,J=15.8,6.4Hz,1H),3.62(s,2H),2.17-2.22(m,2H),1.51(qt,J=7.4,7.4Hz,2H),0.96(t,J=7.4Hz,3H);19F NMR(377MHz,CDCl3):δ -114.10(dd,J HF=9.3,9.3Hz,1F)。
步驟6
將部分純化之酸(0.28g,1.26mmol)於丙酮(5mL)中之溶液用碳酸鉀(0.26g,1.90mmol)、碘化鉀(0.04g,0.25mmol)及溴甲苯(0.18mL,1.5mmol)進行處理,且將反應物在室溫下攪拌18h。將反應混合物分配於乙酸乙酯(25mL)與1M鹽酸水溶液(25mL)之間。然後將有機相用飽和氯化鈉水溶液(25mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM 40iM管柱(二氧化矽)上純化,用5%乙酸乙酯/己烷溶離,得到(E)-2-[3-氟-5-[戊-1-烯基]苯基]乙酸苯甲酯(0.3g,75%)。1H NMR(400MHz,CDCl3):δ 7.32-7.40(m,5H),7.03(s,1H),6.97(ddd,J HF=10.0Hz,J HH=2.3,1.5Hz,1H),6.86(ddd,J HF=9.0Hz,J HH=2.0,1.7Hz,1H),6.33(d,J=15.8Hz,1H),6.23(dt,J=15.8,6.5Hz,1H),5.16(s,2H),3.64(s,2H),2.17-2.23(m,2H),1.52(qt,J=7.4,7.4Hz,2H),0.97(t,J=7.4Hz,3H);19F NMR(377MHz,CDCl3):δ -114.34(dd,J HF=9.3,9.3Hz,1F);13C NMR(101MHz,CDCl3):δ
171.08,163.32(d,J CF=244.4Hz),140.65(d,J CF=7.7Hz),136.17(d,J CF=8.5Hz),135.93,133.05,128.95(d,J CF=3.1Hz),128.84,128.52(d,J CF=9.2Hz),128.48,123.09(d,J CF=2.3Hz),114.78(d,J CF=22.3Hz),111.46(d,J CF=22.3Hz),67.04,41.26(d,J CF=1.5Hz),35.27,22.63,14.00。
步驟7
將苯甲酯(0.16g,0.50mmol)於乙酸乙酯(2mL)中之溶液用碳載鈀(1% w/w Pd;15mg)處理。將混合物用氫氣脫氣,且在1大氣壓之氫氣下在室溫下攪拌隔夜。將反應物過濾,且在真空中蒸發,得到2-[3-氟-5-戊基苯基]-乙酸(0.11g,97%)。1H NMR(400MHz,CDCl3):δ 11.47(br s,1H),6.89(s,1H),6.81-6.86(m,2H),3.62(s,2H),2.60(t,J=7.8Hz,2H),1.58-1.66(m,2H),1.28-1.41(m,4H),0.92(t,J=6.8Hz,3H);19F NMR(377MHz,CDCl3):δ -114.34(dd,J HF=9.3,9.3Hz,1F);13C NMR(101MHz,CDCl3):δ 178.15,163.08(d,J CF=246.0Hz),145.02(d,J CF=7.7Hz),135.04(d,J CF=8.5Hz),125.49(d,J CF=2.3Hz),114.49(d,J CF=20.8Hz),113.83(d,J CF=22.3Hz),41.01(d,J CF=1.5Hz),35.87(d,J CF=1.5Hz),31.67,31.03,22.74,14.24。
步驟8
將酸(0.11g,0.49mmol)於乙醇(3mL)中之溶液用碳酸氫鈉(0.041g,0.49mmol)於水(0.75mL)中之溶液處理,且將反應物在室溫下攪拌17h。在真空中蒸發乙醇,且將殘餘水性漿用水(10mL)稀釋,過濾(0.2μm)且凍幹,得到呈白色固體之2-[3-氟-5-戊基苯基]乙酸鈉(0.12g,99%)。mp 120-123℃;1H NMR(400MHz,CD3OD):δ 6.94(s,1H),6.87(ddd,J HF=9.8Hz,J HH=2.0,2.0Hz,1H),6.70(ddd,J HF=10.0Hz,J HH=2.0,2.0Hz,1H),3.45(s,2H),2.56(t,J=7.7Hz,2H),1.58-1.63(m,2H),1.26-1.39(m,4H),0.90(t,J=7.0Hz,3H);19F NMR(377MHz,CD3OD):δ -117.54(dd,J HF=10.0,10.0Hz,1F);13C NMR(101MHz,CD3OD):δ 178.66,163.04(d,J CF=242.9Hz),145.07(d,J CF=7.7Hz),140.42(d,J CF=8.5Hz),125.03(d,J CF=2.3Hz),112.99(d,J CF=22.3Hz),112.30(d,J CF=20.8Hz),44.96,35.53(d,J CF=1.5Hz),31.46,31.00,22.45,13.30;HPLC:1.2min。
化合物XI:2-(2-氟-3-戊基苯基)乙酸之鈉鹽
以上化合物係以3-溴-2-氟苯甲酸為起始物質如化合物X一般進行製備。白色固體;1H NMR(400MHz,CD3OD):δ 7.13(ddd,J HF=7.0Hz,J HH=7.4,1.9Hz,2H),7.03(ddd,J HF=7.0Hz,J HH=7.4,1.9Hz,1H),6.97(dd,J HH=7.4,7.4Hz,1H),3.51(d,J HF=1.4Hz,2H),2.61(t,J=7.6Hz,2H),1.56-1.63(m,2H),1.28-1.40(m,4H),0.90(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD):δ 178.21,159.70(d,J CF=242.9Hz),129.07(d,J CF=4.6Hz),128.88,128.43(d,J CF=5.4Hz),125.02(d,J CF=17.7Hz),123.31(d,J CF=4.6Hz),37.89(d,J CF=3.8Hz),31.55,29.98,28.91(d,J CF=3.1Hz),22.41,13.26;19F NMR(377MHz,CD3OD):δ -126.09 to -126.05(m,1F);LRMS(ESI):m/z 220.0(M-CO2Na+乙腈),179.4(M-CO2Na);HPLC:1.2min。
化合物XII:2-(4-氟-3-戊基苯基)乙酸之鈉鹽
以上化合物係自2-(3-溴-4-氟苯基)乙酸甲酯如下進行製備:如化合物VII一般進行鈴木偶合;隨後如化合物I一般進行加氫、酯水解及鹽形成。起始酯係藉由使2-(3-溴-4-氟苯基)乙酸與甲醇在硫酸存在下進行反應來製備。白色固體;1H NMR(400MHz,CD3OD):δ 7.16(dd,J HF=7.4Hz,J HH=2.3Hz,2H),7.08(ddd,J HF=5.0Hz,J HH=8.3,2.3Hz,1H),6.88(dd,J HF=10.1Hz,J HH=8.3Hz,1H),3.40(s,2H),2.59(t,J=7.7Hz,2H),1.55-1.63(m,2H),1.28-1.40(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 179.12,159.88(d,J CF=240.6Hz),133.88(d,J CF=3.8Hz),131.26(d,J CF=4.6Hz),128.78(d,J CF=16.1Hz),127.96(d,J CF=8.5Hz),114.26(d,J CF=23.1Hz),44.38,31.51,30.00,28.76(d,J CF=1.5Hz),22.36,13.18;19F NMR(377MHz,CD3OD):δ -126.45 to -126.40(m,1F);LRMS(ESI):m/z 225.2(M-Na++2H+);HPLC:1.9min。
化合物XIII:(RS)-2-氟-2-(3-戊基苯基)乙酸之鈉鹽
以上化合物係自2-氟-2-(3-戊基苯基)乙酸乙酯如化合物I一般進行製備。酯係藉由使2-(3-戊基苯基)乙酸乙酯與二異丙基醯胺鋰及N-氟苯磺醯亞胺在-78℃下在四氫呋喃中進行反應來製備。白色固體;1H NMR(400MHz,CD3OD):δ 7.34(s,1H),7.30(dd,J=7.6,1.4Hz,1H),7.24(dd,J=7.6,7.6Hz,1H),7.13(dd,J=7.4,1.0Hz,1H),5.53(d,J HF=51.3Hz,1H),
2.60(t,J=7.7Hz,2H),1.59-1.65(m,2H),1.27-1.39(m,4H),0.76(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD):δ 173.73(d,J CF=23.9Hz),141.34,136.37(d,J CF=20.0Hz),126.79(d,J CF=2.3Hz),126.40,125.41(d,J CF=5.4Hz),122.84(d,J CF=5.4Hz),90.34(d,J CF=183.4Hz),34.13,29.91,29.65,20.85,11.64;19F NMR(377MHz,CD3OD):δ -168.83(d,J HF=51.7Hz,1F);LRMS(ESI負):m/z 223.0(100%,M-Na+);HPLC:4.1min。
化合物XIV:2-[3,5-二戊基苯基]乙酸鈉
步驟1
在0℃下在氮氣下,將2-[3,5-二羥苯基]乙酸甲酯(1.00g,5.49mmol)及N-苯基-雙(三氟甲基磺醯基)醯亞胺(4.31g,12.1mmol)於二氯甲烷(20mL)中之懸浮液用三乙胺(1.68mL,12.1mmol)處理。形成透明溶液。然後將反應物在氮氣下在0℃下攪拌2h,且在室溫下攪拌21h。將反應物用乙酸乙酯(100mL)稀釋,且將溶液用0.5M氫氧化鈉水溶液(2×100mL)且用飽和氯化鈉水溶液(75mL)洗滌,然後經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM 40iM管柱(二氧化矽)上純化,用乙酸乙酯/己烷0:1至1:9溶離,得到呈淡色油狀物之2-[3,5-雙(三氟甲基磺醯氧基)苯基]乙酸甲酯(2.23g,91%)。1H NMR(400MHz,CDCl3):δ 7.32(d,J=2.2Hz,2H),7.18(dd,J=2.2,2.2Hz,1H),3.72(s,5H);19F NMR(377MHz,CDCl3):δ -73.20(s,3F);13C NMR(101MHz,CDCl3):δ 170.05,149.48,139.01,122.95,118.87(q,JCF=320.5Hz),114.42,52.62,40.29。
步驟2
將雙(三氟甲磺酸)芳基酯(2.23g,4.99mmol)及(E)-1-伸戊-1-基硼酸頻哪醇酯(2.45g,12.5mmol)於1,2-二甲氧基乙烷(25mL)中之溶液用碳酸鈉(1.59g,15.0mmol)於水(8mL)中之溶液處理。將溶液用氮氣脫氧,且然後用肆(三苯基膦)鈀(0.58g,0.50mmol)處理。將混合物在密封管中在90℃下加熱17h。將反應物冷卻至室溫且分配於乙酸乙酯(200mL)與1M鹽酸水溶液(150mL)之間。將有機相用5%碳酸氫鈉水溶液(150mL)且用飽和氯化鈉水溶液(150mL)洗滌;然後經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM 40iL管柱(二氧化矽)上純化,用乙酸乙酯/己烷0:1至3:97溶離,得到呈與過量(E)-1-伸戊-1-基硼酸頻哪醇酯之不可分離10:4混合物形式之2-[3,5-二[(E)-1-戊-1-烯基]苯基]乙酸甲酯(1.12g,61%)。1H NMR(400MHz,CDCl3):δ 7.21(s,1H),7.10(d,J=1.3Hz,2H),6.34(d,J=15.8Hz,1H),6.22(dd,J=15.8,6.7Hz,1H),3.65(s,3H),3.55(s,2H),2.18(tdd,J=6.8,6.8,1.0Hz,2H),1.49(qt,J=7.4,7.2Hz,2H),0.96(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ 172.04,138.59,134.47,131.34,129.97,125.57,122.75,52.07,41.32,35.39,22.77,13.97。
步驟3
將不飽和化合物(1.12g,78.5% w/w,3.07mmol)於乙酸乙酯(1mL)及甲醇(1mL)中之溶液用碳載鈀(10% w/w Pd;0.12g)處理。將混合物用氫氣脫氣,且在1大氣壓氫氣下在室溫下攪拌22h。將反應物過濾,且在真空中蒸發,得到呈與苯基硼酸頻哪醇酯之不可分離10:4混合物形式之2-[3,5-二戊基苯基]乙酸甲酯(0.86g,76%)。1H NMR(400MHz,CDCl3):δ 6.93(s,3H),3.70(s,3H),3.59(s,2H),2.58(t,J=7.9Hz,2H),1.58-1.66(m,2H),1.32-1.38(m,4H),0.91(t,J=6.8Hz,3H)。
步驟4
將甲酯(0.86g,79% w/w,2.34mmol)於乙腈(24mL)中之溶液用氫氧化鋰(0.28g,11.7mmol)於水(6mL)中之溶液處理,且將反應物在室溫下攪拌22h。將反应用1M鹽酸水溶液(55mL)中止,且然後用乙酸乙酯(100mL)萃取。將有機萃取物用飽和氯化鈉水溶液(50mL)洗滌;然後經
硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在SiliaSep二氧化矽管柱上純化,用乙酸乙酯/己烷0:1至1:4溶離,得到呈無色油狀之2-[3,5-二戊基]苯基]乙酸(0.55g,84%)。1H NMR(400MHz,CDCl3):δ 6.99(s,3H),3.65(s,2H),2.63(t,J=7.8Hz,2H),1.64-71(m,2H),1.36-1.44(m,4H),0.97(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ 178.96,143.55,133.21,127.93,127.06,41.47,36.13,31.94,31.47,22.86,14.34。
步驟5
將酸(0.48g,1.75mmol)於乙醇(12mL)中之溶液用碳酸氫鈉(0.15g,1.75mmol)於水(3mL)中之溶液處理,且將反應物在室溫下攪拌3d。在真空中蒸發乙醇,且將殘餘水性漿用水(50mL)稀釋,過濾(PES,0.2μm)且凍幹,得到呈白色固體之2-[3,5-二戊基苯基]乙酸鈉(0.52g,定量)。mp 225-230℃;1H NMR(400MHz,CD3OD+D2O):δ 6.92(s,2H),6.76(s,1H),3.41(s,2H),2.50(t,J=7.5Hz,2H),1.52-1.59(m,2H),1.23-1.33(m,4H),0.85(t,J=6.9Hz,3H);13C NMR(101MHz,CD3OD+D2O):δ 179.99,142.66,137.63,126.66,126.16,45.11,35.61,31.36,31.19,22.41,13.47;LRMS(ESI):m/z 277.5(w,[M-Na++2H+]),231.1(100%,因損失羧基而產生之卓鎓離子);HPLC:3.0min。
化合物XV:2-(3,5-二己基苯基)乙酸之鈉鹽
以上化合物係自(E)-己-1-烯基硼酸頻哪醇酯如化合物XIV一般進行製備。白色固體;1H NMR(400MHz,CD3OD):δ 6.96(s,2H),6.79(s,1H),3.43(s,2H),2.54(d,J=7.7Hz,4H),1.55-1.63(m,4H),1.28-1.36(m,12H),0.89(t,J=6.8Hz,6H);13C NMR(101MHz,CD3OD):δ 179.68,142.38,137.82,126.55,126.07,45.30,35.87,31.83,31.67,29.02,22.61,13.42;LRMS(ESI):m/z 322.0(100%,M-Na++H++NH4+)及259.0(35%,M-CO2Na);UPLC(系統A):8.9min。UPLC系統A:移動相A=10mM碳酸氫銨水溶液;移動相B=乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XVI:2-(2-羥基-3,5-二戊基苯基)乙酸之鈉鹽
步驟1
將2,4-二溴-6-(溴甲基)苯酚(3.5g,10.0mmol)於乙腈(17mL)中之溶液用氰化鈉(2.5g,50.0mmol)之溶液處理,且將反應物在100℃下在回流下加熱1h。將反應混合物冷卻至室溫且傾入水(100mL)中。用1M鹽酸水溶液將pH值自10調節至8,且將混合物用乙酸乙酯(3×250mL)萃取。將合併之萃取物用1M鹽酸水溶液(250mL)且用飽和氯化鈉水溶液(250mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。用丙酮萃取;過濾;且在真空中蒸發,得到2-(3,5-二溴-2-羥苯基)乙腈(2.6g,90%)。1H NMR(400MHz,d6-丙酮):δ 8.75(br s,1H),7.69(d,J=2.3Hz,1H),7.54(d,J=2.3Hz,1H),3.92(s,2H);13C NMR(101MHz,d6-丙酮):δ 151.31,134.51,131.92,122.80,117.43,111.89,111.53,18.70。
步驟2
將2-(3,5-二溴-2-羥苯基)乙腈(2.6g,9.0mmol)用硫酸(2.5mL)、乙酸(2.5mL)及水(2.5mL)之混合物處理,且將反應物在125℃下在回流下加熱2h。將反應混合物冷卻至室溫且傾入冰(50mL)與水(50mL)之混合物中,且然後攪拌直至冰已溶解為止。將混合物用乙酸乙酯(250mL)萃取;且然後將萃取物用水(100mL)且用飽和氯化鈉水溶液(100mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗2-(3,5-二溴-2-羥苯基)乙酸(3.1
g)。此物質未進一步純化或表徵即直接用於下一步驟。
步驟3
將粗2-(3,5-二溴-2-羥苯基)乙酸(3.1g,9.0mmol)於甲醇(17mL)中之溶液用硫酸(0.43mL,8.1mmol)處理,且將反應物在周圍溫度下攪拌16h。在真空中蒸發甲醇,且將殘餘物溶解於乙酸乙酯(270mL)中。將溶液用水(2×200mL)且用飽和氯化鈉水溶液(130mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM SP1系統(120g二氧化矽管柱)上純化,用0-20%乙酸乙酯/己烷溶離,得到2-(3,5-二溴-2-羥苯基)乙酸甲酯(1.4g,49%)。1H NMR(400MHz,CDCl3):δ 7.52(d,J=2.2Hz,1H),7.23(d,J=2.2Hz,1H),6.42(br s,1H),3.72(s,3H),3.65(s,2H);13C NMR(101MHz,CDCl3):δ 172.06,150.60,133.74,133.50,123.94,112.62,111.77,52.78,36.61。
步驟4
將2-(3,5-二溴-2-羥苯基)乙酸甲酯(0.5g,1.54mmol)於丙酮(5mL)中之溶液用碳酸鉀(0.26g,1.86mmol)、碘化鉀(0.05g,0.32mmol)及溴甲苯(0.20mL,1.7mmol)處理,且將反應物在室溫下攪拌1h。在真空中蒸發丙酮,且將殘餘物分配於乙酸乙酯(50mL)與1M鹽酸水溶液(50mL)之間。將有機相用飽和氯化鈉水溶液(50mL)洗滌;經硫酸鈉乾燥;過濾且在真空中蒸發,得到粗產物。在BiotageTM SP1系統(40g二氧化矽管柱)上純化,用0-10%乙酸乙酯/己烷溶離,得到2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.6g,95%)。1H NMR(400MHz,CDCl3):δ 7.67(d,J=2.4Hz,1H),7.48-7.51(m,2H),7.37(d,J=2.4Hz,1H),7.34-7.43(m,3H),4.99(s,2H),3.66(s,3H),3.60(s,2H);13C NMR(101MHz,CDCl3):δ 171.26,153.79,136.56,135.38,133.57,132.04,128.82,128.64,128.52,118.69,117.56,75.53,52.50,35.86。
步驟5
如化合物I,步驟2一般使2-(2-(苄氧基)-3,5-二溴苯基)乙酸甲酯(0.3g,0.73mmol)與(E)-戊-1-烯基硼酸頻哪醇酯(0.4g,1.79mmol)偶合,得到2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.21mg,72%)。
1H NMR(400MHz,CDCl3):δ 7.50(d,J=7.2Hz,2H),7.44(dd,J=7.2,7.2Hz,2H),7.43(d,J=2.1Hz,1H),7.38(dd,J=7.2,7.2Hz,1H),7.18(d,J=2.1Hz,1H),6.72(d,J=15.8Hz,1H),6.39(d,J=15.8Hz,1H),6.32(dt,J=15.8,7.0Hz,1H),6.22(dt,J=15.8,6.8Hz,1H),4.87(s,2H),3.69(s,3H),3.67(s,2H),2.20-2.29(m,4H),1.50-1.60(m,4H),1.01(t,J=7.3Hz,3H),1.00(t,J=7.4Hz,3H);13C NMR(101MHz,CDCl3):δ 172.49,153.59,137.58,134.35,132.91,131.91,130.84,129.53,128.78,128.32,128.30,128.24,127.26,125.21,123.89,75.89,52.21,35.94,35.74,35.42,22.87,22.77,14.07,14.06。
步驟6
如化合物I,步驟3一般將2-(2-(苄氧基)-3,5-二((E)-戊-1-烯基)苯基)乙酸甲酯(0.2g,0.53mmol)氫化,得到2-(2-羥基-3,5-二戊基苯基)乙酸甲酯(0.12g,73%)。1H NMR(400MHz,CDCl3):δ 7.37(s,1H),6.92(d,J=2.1Hz,2H),6.77(d,J=2.1Hz,1H),3.76(s,3H),3.67(s,2H),2.65(t,J=7.8Hz,2H),2.51(t,J=7.8Hz,2H),1.58-1.66(m,4H),1.31-1.41(m,8H),0.93(t,J=7.0Hz,3H),0.92(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ 175.01,151.27,135.14,131.48,129.92,128.52,120.30,52.95,38.35,35.34,32.15,31.86,31.74,30.61,30.03,22.87,22.83,14.34,14.31。
步驟7
陣化合物I,步驟4一般將2-(2-羥基-3,5-二戊基苯基)乙酸甲酯(0.2g,0.53mmol)水解,得到混合有內酯化物質之粗產物。將一小部分在BiotageTM SP1系統(120g二氧化矽管柱)上純化,用0-100%乙酸乙酯/己烷溶離,得到2-(2-羥基-3,5-二戊基苯基)乙酸(13.5mg)。1H NMR(400MHz,CDCl3):δ 10.5(br s,1H),6.89(d,J=2.2Hz,1H),6.78(d,J=2.2Hz,1H),6.32(br s,1H),3.66(s,2H),2.58(t,J=7.9Hz,2H),2.48(t,J=7.8Hz,2H),1.52-1.63(m,4H),1.26-1.37(m,8H),0.90(t,J=7.0Hz,3H),0.88(t,J=6.8Hz,3H)。
步驟8
如化合物I,步驟5一般將2-(2-羥基-3,5-二戊基苯基)乙酸(13.5mg,0.046mmol)轉化為鈉鹽,得到2-(2-羥基-3,5-二戊基苯基)乙酸鈉
(11mg,77%)。1H NMR(400MHz,CD3OD):δ 6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.6Hz,2H),1.50-1.61(m,4H),1.25-1.37(m,8H),0.90(t,J=6.8Hz,3H),0.88(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 180.33,151.94,133.47,130.37,128.21,127.81,123.99,42.90,34.97,31.81,31.60,31.40,30.25,29.88,22.51,22.45,13.29,13.24;LRMS(ESI負):m/z 291.2(100%,M-Na+);UPLC(系統B):7.7min。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XVII:2-(3,5-二己基-2-羥苯基)乙酸之鈉鹽
以上化合物係使用(E)-己-1-烯基硼酸頻哪醇酯如化合物XVI一般進行製備。1H NMR(400MHz,CD3OD):δ 6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.80Hz,3H);LRMS(ESI負):m/z 319(100%,M-Na+);UPLC(系統B):8.7min。ULC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XVIII:2-(4-羥基-3,5-二戊基苯基)乙酸之鈉鹽
以上化合物係自2-(3,5-二溴-4-羥苯基)乙酸如化合物XVI一般進行製備。1H NMR(400MHz,CD3OD):δ 6.87(s,2H),3.33(s,2H),2.55(t,J=7.7Hz,4H),1.53-1.61(m,4H),1.31-1.37(m,8H),0.90(t,J=7.0Hz,6H);LRMS(ESI負):m/z 291.1(100%,M-Na+);UPLC(系統B):6.8min。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XIX:2-(3,5-二己基-4-羥苯基)乙酸之鈉鹽
以上化合物係自2-(3,5-二溴-4-羥苯基)乙酸及(E)-己-1-烯基硼酸頻哪醇酯如化合物XVI一般進行製備。1H NMR(400MHz,CD3OD):δ 6.72(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),3.46(s,2H),2.56(t,J=7.6Hz,2H),2.44(t,J=7.5Hz,2H),1.50-1.60(m,4H),1.27-1.37(m,12H),0.89(t,J=6.6Hz,3H),0.88(t,J=6.8Hz,3H);LRMS(ESI負):m/z 319.1(100%,M-
Na+);UPLC(系統B):7.6min。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XX:2-(4-氟-3,5-二己基苯基)乙酸之鈉鹽
以上化合物係以3,5-二溴-4-氟苯甲基溴化物及(E)-己-1-烯基硼酸頻哪醇酯為起始物質如化合物XVI一般進行製備。3,5-二溴-4-氟苯甲基溴化物係藉由在80℃下於乙腈中用N-溴丁二醯亞胺及偶氮二異丁腈將3,5-二溴-4-氟代甲苯溴化來進行製備。1H NMR(400MHz,CD3OD):δ 6.98(d,JHF=7.0Hz,2H),3.38(s,2H),2.57(t,J=7.7Hz,4H),1.54-1.61(m,4H),1.28-1.37(m,12H),0.89(t,J=6.7Hz,6H);19F NMR(377MHz,CD3OD):δ -132.17(d,JHF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ 179.44,158.11(d,JCF=239.8Hz),133.26(d,JCF=3.8Hz),128.73(d,JCF=5.4Hz),128.56(d,JCF=16.9Hz),44.52,31.69,30.35(d,JCF=1.5Hz),28.98,28.97(d,JCF=3.1Hz),22.51,13.29;LRMS(ESI負):m/z 321.0(100%,M-Na+);UPLC(系統B):9.2min。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XXI:2-(4-氟-3,5-二戊基苯基)乙酸之鈉鹽
以上化合物係以3,5-二溴-4-氟苯甲基溴化物為起始物質如化合物XVI一般進行製備。1H NMR(400MHz,CD3OD):δ 6.98(d,JHF=6.8Hz,2H),3.37(s,2H),2.57(t,J=7.6Hz,4H),1.54-1.62(m,4H),1.28-1.37(m,8H),0.90(t,J=7.0Hz,6H);19F NMR(377MHz,CD3OD):δ -132.34(d,JHF=6.6Hz,1F);13C NMR(101MHz,CD3OD):δ 179.41,158.10(d,JCF=239.8Hz),133.26(d,JCF=3.8Hz),128.72(d,JCF=4.6Hz),128.56(d,JCF=16.9Hz),44.51,31.54,30.07,28.92(d,JCF=3.1Hz),22.38,13.22;LRMS(ESI負):m/z 293.0(100%,M-Na+);UPLC(系統B):8.4min。UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3管柱;梯度=10分鐘內5-100% B/A。
化合物XXII:2-(2-苯甲基-3,5-二戊基苯基)乙酸之鈉鹽
標題化合物係自2-(2-苯甲基-3,5-二((E)-戊-1-烯基)苯基)乙
酸甲酯如化合物XIV一般進行製備。自按比例增加之化合物XIV中分離後者作為副產物(1.1%產率)。1H NMR(400MHz,CD3OD):δ 7.17(dd,J=7.3,7.3Hz,2H),7.09(dd,J=7.3,7.3Hz,1H),6.97-6.99(m,3H),6.86(d,J=1.8Hz,1H),4.13(s,2H),3.40(s,2H),2.55(t,J=7.7Hz,2H),2.49(t,J=7.8Hz,2H),1.59-1.67(m,2H),1.31-1.45(m,6H),1.21-1.26(m,4H),0.91(t,J=7.0Hz,3H),0.82(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 179.48,141.46,141.24,140.47,137.46,133.70,128.36,128.05,127.86,127.75,125.42,43.25,35.54,33.90,33.61,31.86,31.65,31.25,30.96,22.49,22.40,13.31,13.23;LRMS(ESI負):m/z 365.0(20%,M-Na+),321.1(100%,M-CO2Na);UPLC(系統B):9min。(UPLC系統B:移動相A=0.1%甲酸水溶液;移動相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=10分鐘內5-100% B/A。)
化合物XXIII:2-[3,5-二[(E)-戊-1-烯基]苯基]乙酸鈉
標題化合物係使用與化合物XIV相同之程序進行製備,但省略加氫步驟。mp 226-30℃;1H NMR(400MHz,CD3OD):δ 7.18(d,J=1.2Hz,2H),7.11(d,J=1.2Hz,1H),6.34(d,J=15.9Hz,2H),2.23(dt,J=15.9,6.7Hz,2H),3.44(s,2H),2.14-2.19(m,4H),1.49(tq,J=7.4,7.4Hz,4H),0.95(t,J=7.3Hz,6H);13C NMR(101MHz,CD3OD):δ 179.41,138.34,138.06,130.30,130.16,125.26,121.60,45.24,35.10,22.55 & 12.98;LRMS(負模式):m/z 271(w,[M-Na+]),227.2(100%,[M-Na+-CO2]);UPLC:8min。(UPLC;條件溶劑A=0.1%甲酸/水;溶劑B=0.1%甲酸/乙腈;梯度:在0.7mL/min下在10m內5-100% B/A。)
化合物XXIV:3-[3,5-二戊基苯基]丙酸鈉
標題化合物係以3-[3,5-二溴苯基]丙酸為起始物質使用與化合物XIV相同之程序進行製備。mp 211-217℃;1H NMR(400MHz,CDCl3):δ 6.73(s,1H),6.68(s,2H),2.73-2.77(m,2H),2.42-2.46(m,2H),2.38(t,J=7.8Hz,4H),1.43-1.51(m,4H),1.19-1.28(m,8H),0.83(t,J=6.9Hz,6H);13C NMR(101MHz,CDCl3):δ 182.55,142.93,141.85,125.96,125.77,39.80,36.13,32.77,31.99,31.47,22.79 & 14.27;LRMS(負模式):m/z 289.4(100%,[M-Na+]);UPLC:9min。(UPLC:條件溶劑A=0.1%甲酸/水,溶劑B=0.1%
甲酸/乙腈,梯度:在0.7mL/min下在10min內5-100% B/A。
化合物XXV:2-甲基-2-(3-戊基苯基)丙酸之鈉鹽
標題化合物係自2-[3-溴苯基]乙酸甲酯如化合物XIV一般進行製備,同時具有用氫化鈉及碘甲烷將2-[3-戊基苯基]乙酸甲酯烷基化之額外步驟;且其中酯水解步驟之溫度升至50℃。米白色固體:1H NMR(400MHz,D2O):δ 7.11(dd,J=7.7,7.7Hz,1H),7.07(s,1H),7.02(d,J=7.6Hz,1H),6.95(d,J=7.4Hz,1H),2.44(t,J=7.7Hz,2H),1.43(tt,J=7.4,7.4Hz,2H),1.28(s,6H),1.09-1.17(m,4H),0.68(t,J=7.0Hz,3H);13C NMR(101MHz,D2O):δ 186.51,148.17,143.67,128.48,126.27,126.24,123.26,48.67,35.33,30.90,30.77,27.20,22.01,13.46;LRMS(ESI +ve):m/z 189.1(100%,MH+-CO2Na);HPLC:5min(5min內15-99%乙腈/水(於兩種溶劑中之三氟乙酸)。
化合物XXVI:(RS)-2-(3-戊基苯基)丙酸之鈉鹽
步驟1
將碘化銅(I)(17mg,0.09mmol)、2-吡啶甲酸(22mg,0.18mmol)及碳酸銫(1.7g,5.30mmol)之混合物在氬氣下用無水1,4-二噁烷(3ml)、丙二酸二乙酯(0.54ml,3.5mmol)及1-溴-3-碘苯(0.23ml,1.77mmol)處理。然後將反應物在氬氣下在70℃下加熱15h。將粗反應混合物蒸發至
矽膠上且在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(0-12%)溶離,得到2-[3-溴苯基]丙二酸二乙酯(0.34g,64%)。1H NMR(400MHz,CDCl3):δ 7.30-7.47(m,3H),7.20-7.26(m,1H),4.16-4.24(m,4H),3.36(s,1H),1.23-1.29(m,6H)。
步驟2
將氫化鈉(60% w/w;0.53g,13.3mmol)於無水THF(16ml)中之懸浮液在氬氣下冷卻至0℃,且用2-[3-溴苯基]丙二酸二乙酯(3.0g,9.52mmol)於無水THF(20ml)中之溶液處理。將反應混合物在0℃下攪拌30min,且然後用碘甲烷(0.8ml,13.3mmol)逐滴處理。然後將反應混合物升溫至室溫,且在室溫下在氬氣下攪拌隔夜。用飽和氯化銨水溶液(100ml)中止反應,且將混合物用乙酸乙酯(3×100ml)萃取。將合併之有機萃取物乾燥(硫酸鎂)且在真空中蒸發,得到粗化合物。在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(0-5%)溶離,得到2-[3-溴苯基]-2-甲基丙二酸二乙酯(2.6g,82%)。1H NMR(400MHz,CDCl3):δ 7.52(ddd,J=1.9,1.9,0.4Hz,1H),7.43(ddd,J=7.9,1.9,1.0Hz,1H),7.31(ddd,J=8.0,1.9,1.0Hz,1H),7.20(ddd,J=7.9,7.9,0.4Hz,1H),4.21-4.26(m,4H),1.84(s,3H),1.26(t,J=7.2Hz,6H)。
步驟3
使用在化合物X,步驟4中所描述之方法使2-[3-溴苯基]-2-甲基丙二酸二乙酯(2.6g,7.8mmol)與(E)-1-伸戊-1-基硼酸頻哪醇酯(2.1g,10.9mmol)偶合,得到(E)-2-甲基-2-[3-[戊-1-烯基]苯基]丙二酸二乙酯(1.7g,68%)。1H NMR(400MHz,CDCl3):δ 7.24-7.32(m,3H),7.21(ddd,J=7.1,1.9,1.9Hz,1H),6.37(d,J=15.9Hz,1H),6.20(dt,J=15.9,6.9Hz,1H),4.21-4.26(m,4H),2.15-2.21(m,2H),1.87(s,3H),1.49(tt,J=7.3,7.3Hz,2H),1.26(t,J=7.2Hz,6H),0.95(t,J=7.4Hz,3H)。
步驟4
使用在化合物I,步驟3中所描述之方法將(E)-2-甲基-2-[3-[戊-1-烯基]苯基]丙二酸二乙酯(1.4g,4.27mmol)氫化,得到2-甲基-2-[3-戊基苯基]丙二酸二乙酯(1.2g,91%)。1H NMR(400MHz,CDCl3):δ 7.24(dd,J=7.3,7.3Hz,1H),7.16(d,J=7.3Hz,1H),7.15(s,1H),7.10(d,J=
7.6Hz,1H),4.20-4.25(m,4H),2.59(t,J=7.9Hz,2H),1.85(s,3H),1.49(tt,J=7.6,7.6Hz,2H),1.28-1.34(m,4H),1.25(t,J=7.0Hz,6H),0.88(t,J=7.0Hz,3H)。
步驟5
將2-甲基-2-[3-戊基苯基]丙二酸二乙酯(1.1g,3.5mmol)於乙腈(9ml)、甲醇(3ml)及水(3ml)中之溶液用氫氧化鋰(1.3g,52.8mmol)處理,且將混合物在50℃下加熱48h。將反應混合物在真空中濃縮,用水(10ml)稀釋,且然後用二氯甲烷(15ml)洗滌。然後將水相之pH值用1M鹽酸水溶液調節至pH 4,且將混合物用二氯甲烷(3×25ml)萃取。將合併之有機萃取物乾燥(硫酸鎂)且在真空中蒸發,得到粗化合物。在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(0-20%)溶離,得到(RS)-2-[3-戊基苯基]丙酸(0.4g,52%)。1H NMR(400MHz,CD3OD):δ 7.20(dd,J=7.6,7.6Hz,1H),7.03-7.12(m,3H),3.66(q,J=7.1Hz,1H),2.58(t,J=7.8Hz,2H),1.60(tt,J=7.6,7.6Hz,2H),1.42(d,J=7.1Hz,3H),1.27-1.38(m,4H),0.90(t,J=7.1Hz,3H)。
步驟6
使用在化合物I,步驟5中所描述之方法將(RS)-2-[3-戊基苯基]丙酸(0.4g,1.8mmol)轉化為鈉鹽,得到(RS)-2-[3-戊基苯基]丙酸鈉(0.44g,定量)。1H NMR(400MHz,CD3OD):δ 7.19(s,1H),7.14-7.17(m,1H),7.13(dd,J=7.5,7.5Hz,1H),6.95(d,J=6.9Hz,1H),3.54(q,J=7.1Hz,1H),2.56(t,J=7.8Hz,2H),1.60(tt,J=7.5,7.5Hz,2H),1.39(d,J=7.2Hz,3H),1.29-1.35(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 182.18,144.23,142.49,127.76,127.55,125.82,124.73,49.17,35.85,31.54,31.33,22.43,18.95,13.22;HPLC:5min(5min內15-99%乙腈/水(於兩種溶劑中之三氟乙酸)。
化合物XXVII:2-(2-羥基-5-戊基苯基)乙酸之鈉鹽
以上化合物係使用2-[2-(苄氧基)-5-溴苯基]乙酸甲酯(以2個步驟自2-[5-溴-2-羥苯基]乙酸製備)以與化合物VII,步驟3-6相同之方式製備。白色固體:1H NMR(400MHz,CD3OD):δ 6.82-6.88(m,2H),6.69(d,J=
8.6Hz,1H),3.47(s,2H),2.47(t,J=7.7Hz,2H),1.51-1.59(m,2H),1.24-1.36(m,4H),0.89(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 180.04,154.04,134.05,130.25,127.36,124.15,116.57,42.50,34.90,31.59,31.42,22.44,13.23;LRMS(ESI -ve):m/z 221.1(100%,M-Na+),177.1(m,M-Na+-CO2);HPLC:2min(梯度使用在5min內70-99%乙腈/水及於兩種溶劑中之三氟乙酸)。
化合物XXVIII:2-側氧基-2-[3-戊基苯基]乙酸之鈉鹽
步驟1:
i)將2-[3-戊基苯基]乙酸甲酯(0.5g,2.0mmol)於乙腈(15ml)中之溶液在氮氣下用1,8-二氮雜雙環[5.4.0]十一-7-烯(0.22ml,1.5mmol)處理,且將反應物在室溫下攪拌15min。將反應物冷卻至0℃,且緩慢添加4-乙醯胺基苯磺醯基疊氮化物(0.6g,2.4mmol)。然後將反應物升溫至室溫,且在氮氣下攪拌22.5h。
ii)將2-重氮基-2-[3-戊基苯基]乙酸甲酯中間物之此溶液用甲苯(15ml)、丙酮(11ml)及水(15ml)稀釋,且然後用碳酸氫鈉(6.4g,75.7mmol)處理。緩慢添加過硫酸氫鉀(12.1g,19.7mmol),且然後將反應混合物在室溫下劇烈攪拌25min。將反應物用水(30ml)稀釋,且然後用乙酸乙酯(3×30ml)萃取。將合併之萃取物用飽和氯化鈉水溶液(30ml)洗滌,經硫酸鈉乾燥,且在真空中蒸發,得到粗產物。用二氯甲烷萃取且在SiliaSep SiO2
管柱上純化,用乙酸乙酯/己烷(0-2%)溶離,得到2-側氧基-2-[3-戊基苯基]乙酸甲酯(0.13g,30%)。1H NMR(400MHz,CDCl3):δ 7.79-7.82(m,2H),7.47(d,J=7.6Hz,1H),7.66(dd,J=7.6,7.6Hz,1H),3.97(s,3H),2.66(d,J=7.8Hz,2H),1.58-1.64(m,2H),1.27-1.35(m,4H),0.88(t,J=6.9Hz,3H);13C NMR(101MHz,CDCl3):δ 186.61,164.48,144.17,135.53,132.61,129.88,129.01,127.97,52.96,35.87,31.58,31.18,22.70,14.22。
步驟2
如化合物IX,步驟5中所描述將2-側氧基-2-[3-戊基苯基]乙酸甲酯(64mg,0.8mmol)水解,得到2-側氧基-2-[3-戊基苯基]乙酸(60mg,定量)。1H NMR(400MHz,CDCl3):δ 10.32(br s,1H),7.98(d,J=7.4Hz,1H),7.96(s,1H),7.43(d,J=7.5Hz,1H),7.36(dd,J=7.4,7.4Hz,1H),),2.60(d,J=7.7Hz,2H),1.52-1.59(m,2H),1.20-1.29(m,4H),0.81(t,J=6.8Hz,3H);13C NMR(101MHz,CDCl3):δ 185.51,164.18,144.28,136.10,132.04,130.81,129.12,128.85,35.90,31.59,31.19,22.71,14.23。
步驟3
使用在化合物I,步驟5中所描述之方法將2-側氧基-2-[3-戊基苯基]乙酸(57mg,0.3mmol)轉化為鈉鹽,得到2-側氧基-2-[3-戊基苯基]乙酸鈉(51mg,95%)。1H NMR(400MHz,CD3OD):δ 7.79-7.81(m,2H),7.45(ddd,J=7.6,1.5,1.5Hz,1H),7.41(ddd,J=7.8,7.8,1.0Hz,1H),2.67(t,J=7.6Hz,2H),1.64(tt,J=7.5,7.5Hz,2H),1.28-1.39(m,4H),0.90(t,J=7.1Hz,3H);13C NMR(101MHz,CD3OD):δ 196.19,172.77,143.54,133.89,133.76,129.34,128.47,127.03,35.45,31.32,31.06,22.38,13.20;LRMS(ESI -ve):m/z 219.1(100%,M-Na+);HPLC:3.3min(梯度使用5min內15-99%乙腈/水及於兩種溶劑中之三氟乙酸)。
化合物XXIX:(E)-2-[2-氟-5-[戊-1-烯基]苯基]乙酸之鈉鹽
以上化合物係自2-[2-氟-5-溴苯基]乙酸甲酯如化合物XIV一般進行製備,且省略加氫步驟。白色固體;1H NMR(400MHz,CD3OD):δ 7.32(dd,JHF=7.4Hz,JHH=2.1Hz,1H),7.15-7.18(m,1H),6.92(dd,JHF=9.4Hz,JHH=8.8Hz,1H),6.33(d,J=15.8Hz,1H),6.16(dd,J=15.8,7.0
Hz,1H),2.16(td,J=7.1,7.1Hz,2H),1.48(tt,J=7.3,7.3Hz,2H),0.95(t,J=7.3Hz,3H);19F NMR(377MHz,CD3OD):δ -122.74 to -122.26(m,1F),13C NMR(101MHz,CD3OD):δ 177.91,160.51(d,JCF=243.6Hz),134.08(d,JCF=3.8Hz),129.87(d,JCF=1.5Hz),129.23,128.94(d,JCF=4.6Hz),125.09-125.26(m,2C),114.63(d,JCF=22.3Hz),37.75(d,JCF=1.5Hz),35.00,22.50,12.87;LRMS(ESI -ve):m/z 176.9(100%,M-Na+-CO2);HPLC:6min(UPLC梯度:移動相A=0.1%甲酸/水;移動相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=10分鐘內5-100% B/A。)
化合物XXX:2-[2-苯甲基-5-戊基苯基]乙酸之鈉鹽
步驟1
將化合物XXVII(2.4g,10.0mmol)以與化合物IX,步驟1相同之方式酯化,得到2-[2-羥基-5-戊基苯基]乙酸甲酯(2.3g,96%)。1H NMR(400MHz,CDCl3):δ 7.24(br s,1H),6.98(dd,J=8.2,2.3Hz,1H),6.90(d,J=2.3Hz,1H),6.83(d,J=8.2Hz,1H),3.73(s,3H),3.65(s,2H),2.50(t,J=7.9Hz,2H),1.52-1.60(m,2H),1.25-1.36(m,4H),0.86-0.90(m,3H)。
步驟2
如化合物VII,步驟2中所描述將2-[2-羥基-5-戊基苯基]乙酸甲酯(2.3g,9.6mmol)轉化為三氟甲烷磺酸酯衍生物,得到2-[5-戊基-2-(三氟甲基磺醯氧基)苯基]乙酸甲酯(3.4g,97%)。1H NMR(400MHz,CDCl3):δ 7.20(d,J=8.6Hz,1H),7.18(d,J=2.4Hz,1H),7.16(dd,J=8.6,2.4Hz,1H),
3.72(s,3H),3.71(s,2H),2.60(t,J=7.8Hz,2H),1.56-1.64(m,2H),1.27-1.37(m,4H),0.89(t,J=6.9Hz,3H);19F NMR(377MHz,CDCl3):δ -73.92(s,3F);13C NMR(101MHz,CDCl3):δ 170.59,146.25,143.76,132.42,129.30,126.95,121.31,118.76(q,JCF=319.8Hz),52.38,35.70,35.40,31.62,31.08,22.66,14.10。
步驟3
將氮氣沖洗之壓力容器連續地裝入磷酸三鉀(5.4g,25.3mmol);乙酸鈀(II)(74mg,0.33mmol);2-二環己基膦基-2’,6’-二甲氧基-1,1’-聯苯(0.14g,0.33mmol);2-[5-戊基-2-(三氟甲基磺醯氧基)苯基]乙酸甲酯(3.1g,8.3mmol)於無水四氫呋喃(20ml)中之溶液及9-苯甲基-9-硼雙環[3.3.1]壬烷於四氫呋喃(34ml,17mmol)中之0.5M溶液。然後將容器密封,且將反應物在60℃下加熱。在17h之後,將反應混合物冷卻至室溫且分配於乙酸乙酯(300ml)與0.5M氫氧化鈉水溶液(250ml)之間。將有機相用飽和氯化鈉水溶液(200ml)洗滌,經硫酸鈉乾燥,過濾且在真空中蒸發,得到粗化合物。在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(0-2%)溶離,得到2-[2-苯甲基-5-戊基苯基]乙酸甲酯(2.5g,96%)。1H NMR(400MHz,CDCl3):δ 7.29(dd,J=7.4,7.0Hz,2H),7.21(dd,J=7.4,7.0Hz,1H),7.13-7.15(m,2H),7.08-7.09(m,3H),4.04(s,2H),3.63(s,3H),3.60(s,2H),2.61(t,J=7.8Hz,2H),1.61-1.68(m,2H),1.34-1.39(m,4H),0.93(t,J=7.1Hz,3H);13C NMR(101MHz,CDCl3):δ 172.29,141.66,140.65,136.61,132.84,131.21,130.87,129.03,128.67,127.83,126.28,52.19,39.01,39.00,35.73,31.89,31.40,22.84,14.35。
步驟4
如化合物IX,步驟5中所描述將2-[2-苯甲基-5-戊基苯基]乙酸甲酯(2.9g,9.3mmol)係水解,得到2-[2-苯甲基-5-戊基苯基]乙酸(2.48g,90%)。1H NMR(400MHz,CDCl3):δ 7.26(dd,J=7.3,7.3Hz,2H),7.16(dd,J=7.5,7.5Hz,1H),7.10-7.13(m,2H),7.05-7.07(m,3H),4.01(s,2H),3.58(s,2H),2.58(t,J=7.8Hz,2H),1.57-1.65(m,2H),1.30-1.37(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CDCl3):δ 178.67,141.80,140.51,136.84,
132.20,131.37,130.95,129.08,128.75,128.13,136.39,39.07,38.98,35.74,31.93,31.41,22.87,14.38。
步驟5
使用在化合物I,步驟5中所描述之方法將2-[2-苯甲基-5-戊基苯基]乙酸(2.5g,8.4mmol)轉化為鈉鹽,得到2-[2-苯甲基-5-戊基苯基]乙酸鈉(2.5g,93%)。1H NMR(400MHz,CD3OD):δ 7.22(dd,J=8.4,7.4Hz,2H),7.09-7.15(m,3H),6.92-6.93(m,3H),4.03(s,2H),3.47(s,2H),2.55(t,J=7.8Hz,2H),1.57-1.65(m,2H),1.28-1.38(m,4H),0.90(t,J=7.0Hz,3H);13C NMR(101MHz,CD3OD):δ 179.25,141.25,140.60,136.90,136.48,130.45,129.78,128.83,128.13,126.13,125.64,42.70,38.49,35.49,31.64,31.32,22.51,13.35;LRMS(ESI -ve):m/z 295.2(40%,M-Na+),251.2(100%,M-Na+-CO2);HPLC:5.0min(梯度使用5min內70-99% MeCN/水及於兩種溶劑中之三氟乙酸)。
化合物XXXI:2-(3,5-二((E)-己-1-烯基)苯基)乙酸之鈉鹽
以與化合物II相同之方式製備標題化合物,但省略加氫步驟。米白色固體:1H NMR(400MHz,CD3OD):δ 7.17(d,J=1.1Hz,2H),7.10(s,1H),6.33(d,J=15.8Hz,2H),6.22(dt,J=15.8,6.7Hz,2H),3.44(s,2H),2.16-2.21(m,4H),1.34-1.46(m,8H),0.93(t,J=7.3Hz,6H);13C NMR(101MHz,CD3OD):δ 179.44,138.34,138.07,130.37,130.13,125.27,121.60,45.26,32.70,31.67,22.19,13.27;LRMS(ESI負模式):m/z 299.2(m,M-Na+)及255.2(100%,M-Na+-CO2);UPLC:8.7min.(UPLC條件:溶劑A=0.1%甲酸/水;移動相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=10分鐘內5-100% B/A)
化合物XXXII:2-(2-氟-3,5-二戊基苯基)乙酸之鈉鹽
步驟1:
使用關於化合物I所描述之方法使2-胺基-3,5-二溴苯甲酸甲酯(10.0g,32.4mmol)與(E)-1-伸戊-1-基硼酸頻哪醇酯(15.2g,77.7)偶合,得到2-胺基-3,5-二[(E)-戊-1-烯基]苯甲酸甲酯(6.00g,64%)。1H NMR(400MHz,CDCl3):δ 7.76(d,J=2.2Hz,1H),7.37(d,J=2.2Hz,1H),6.35(d,J=15.4Hz,1H),6.26(d,J=15.8Hz,1H),6.08(dt,J=15.6,7.0Hz,1H),6.06(dt,J=15.8,7.0Hz,1H),5.5-6.5(br s,2H),3.87(s.3H),2.19-2.25(m,2H),2.13-2.18(m,2H),1.43-1.56(m,8H),0.97(t,J=7.3Hz,3H),0.94(t,J=7.3Hz,3H)。
步驟2:
如關於化合物I所描述將2-胺基-3,5-[(E)-戊-1-烯基]苯甲酸甲酯(5.7g,19.9mmol)氫化,得到2-胺基-3,5-二戊基苯甲酸甲酯(5.50g,95%)。1H NMR(400MHz,CDCl3):δ 7.50(d,J=2.2Hz,1H),6.95(d,J=2.2
Hz,1H),5.5-6.1(br s,2H),3.79(s.3H),2.40(t,J=7.2Hz,4H),1.45-1.58(m,4H),1.20-1.32(m,8H),0.84(t,J=7.2Hz,3H),0.82(t,J=7.1Hz,3H)。
步驟3:
將2-胺基-3,5-二戊基苯甲酸甲酯(4.5g,15.4mmol)用四氟硼酸水溶液(5.5M,3.7ml,20mmol)及鹽酸水溶液(8.5M,3.3ml,28mmol)處理。將混合物冷卻至0℃,且然後歷時2分鐘用亞硝酸鈉(2.1M,8.8ml,18.5mmol)之水溶液逐滴處理。在0℃下60分鐘之後,將反應混合物用二甲苯(30ml)萃取。將二甲苯萃取物經硫酸鈉乾燥,且然後歷時55分鐘自60℃加熱至120℃。過濾且在真空中蒸發二甲苯,得到粗化合物,將其在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(0-5%)溶離,得到2-氟-3,5-二戊基苯甲酸甲酯(3.1g,69%)。1H NMR(400MHz,CDCl3):δ 7.50(dd,JHF=6.5Hz,JHH=2.4Hz,1H),7.15(dd,JHF=6.5Hz,JHH=2.4Hz,1H),3.91(s.3H),2.62(td,JHH=7.7Hz,JHF=1.2Hz,2H),2.56(t,J=7.7Hz,2H),1.55-1.63(m,4H),1.26-1.37(m,8H),0.89(t,J=7.0Hz,6H);19F NMR(377MHz,CDCl3):δ -121.31(dd,JHF=6.6,6.6Hz,1F)。
步驟4:
將2-氟-3,5-二戊基苯甲酸甲酯(3.1g,10.6mmol)於無水四氫呋喃(60ml)中之溶液冷卻至-78℃,且用氫化鋁鋰(0.5g,13.8mmol)緩慢處理。將反應混合物在-78℃下攪拌25分鐘,然後在0℃下攪拌30分鐘。藉由添加乙酸乙酯中止反應。將混合物用酒石酸鉀鈉水溶液(1M,100ml)且用飽和氯化鈉水溶液(100ml)洗滌;且然後經硫酸鈉乾燥,過濾且在真空中蒸發,得到粗化合物。在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(3-20%)溶離,得到2-氟-3,5-二戊基苯甲醇(1.8g,65%)。1H NMR(400MHz,CDCl3):δ 7.02(dd,JHF=6.8Hz,JHH=2.3Hz,1H),6.92(dd,JHF=7.1Hz,JHH=2.4Hz,1H),4.71(s.2H),2.59(td,JHH=7.6Hz,JHF=1.2Hz,2H),2.54(t,J=7.8Hz,2H),1.73(s,1H),1.54-1.62(m,4H),1.25-1.36(m,8H),0.894(t,J=7.0Hz,3H),0.890(t,J=7.1Hz,3H);19F NMR(377MHz,CDCl3):δ -131.25(dd,JHF=6.7,6.6Hz,1F);13C NMR(101MHz,CDCl3):δ 157.41(d,JCF=242.9Hz),138.48(d,JCF=4.3Hz),130.07(d,JCF=5.4Hz),129.33(d,JCF=
16.2Hz),127.33(d,JCF=15.6Hz),126.67(d,JCF=4.6Hz),59.84(d,JCF=5.4Hz),35.50,31.86,31.77,31.62,30.21,29.21(d,JCF=2.4Hz),22.80,22.74,14.28(2C)。
步驟5:
將2-氟-3,5-二戊基苯甲醇(1.4g,5.3mmol)於無水二氯甲烷(35ml)中之溶液冷卻至0℃,且歷時10分鐘用甲磺醯氯(0.5ml,5.8mmol)逐滴處理。將反應物在0℃下攪拌20分鐘,且然後藉由添加冰冷水(35ml)中止反應。將有機相用鹽酸水溶液(1M,35ml)、飽和碳酸氫鈉水溶液(35ml)及飽和氯化鈉水溶液(35ml)洗滌;且然後經硫酸鈉乾燥,過濾且在真空中蒸發,得到粗甲烷磺酸2-氟-3,5-二戊基苯甲酯(1.7g,93%)。此物質未純化即用於下一步驟。1H NMR(400MHz,CDCl3):δ 7.02-7.05(m,2H),5.26(d,JHF=1.0Hz,2H),2.98(s.3H),2.52-2.63(m,2H),2.54(t,J=7.8Hz,2H),1.54-1.62(m,4H),1.27-1.37(m,8H),0.892(t,J=7.0Hz,3H),0.888(t,J=7.0Hz,3H)。
步驟6:
用6M鹽酸水溶液將氰化鈉(0.4g,7.4mmol)於水(5ml)中之溶液的pH值調節至pH 10。然後添加甲烷磺酸2-氟-3,5-二戊基苯甲酯(1.7g,4.9mmol)於乙腈(25ml)中之溶液,且將反應物在60℃下加熱2h。將反應混合物在真空中濃縮至15ml,且用乙酸乙酯(100ml)萃取。將有機萃取物用酒水(100ml)且用飽和氯化鈉水溶液(100ml)洗滌;且然後經硫酸鈉乾燥,過濾且在真空中蒸發,得到粗化合物。在SiliaSep SiO2管柱上純化,用乙酸乙酯/己烷(1-10%)溶離,得到2-[2-氟-3,5-二戊基苯基]乙腈(0.7g,55%)。1H NMR(400MHz,CDCl3):δ 7.04(dd,JHF=6.9Hz,JHH=2.2Hz,1H),6.96(dd,JHF=7.1Hz,JHH=2.2Hz,1H),3.72(s.2H),2.59(td,JHH=7.7Hz,JHF=0.9Hz,2H),2.55(t,J=7.8Hz,2H),1.54-1.62(m,4H),1.27-1.37(m,8H),0.90(t,J=7.0Hz,6H);19F NMR(377MHz,CDCl3):δ -131.25(ddd,JHF=7.0,7.0,0.8Hz,1F);13C NMR(101MHz,CDCl3):δ 157.02(d,JCF=244.5Hz),139.16(d,JCF=4.7Hz),130.84(d,JCF=4.6Hz),129.93(d,JCF=16.1Hz),126.97(d,JCF=3.1Hz),117.52,116.79(d,JCF=
16.2Hz),35.38,31.74,31.66,31.54,30.06,29.16(d,JCF=2.4Hz),22.74,22.68,17.90(d,JCF=6.1Hz),14.26,14.23。
步驟7:
將2-[2-氟-3,5-二戊基苯基]乙腈(0.7g,2.7mmol)、乙酸(4ml)及水(4ml)之混合物用濃硫酸(4ml)逐滴處理;且然後將混合物在125℃下加熱3.5h。將反應物冷卻至室溫且然後藉由添加冰(40ml)中止反應。將混合物用乙酸乙酯(40ml)萃取,且然後將有機萃取物用飽和氯化鈉水溶液(40ml)洗滌;經硫酸鈉乾燥,過濾且在真空中蒸發,得到2-[2-氟-3,5-二戊基苯基]乙酸(537mg,67%)。1H NMR(400MHz,CDCl3):δ 6.84(dd,JHF=7.0Hz,JHH=2.3Hz,1H),6.80(dd,JHF=6.8Hz,JHH=2.2Hz,1H),3.59(d,JHF=1.2Hz,2H),2.52(t,J=7.5Hz,2H),2.45(t,J=7.8Hz,2H),1.46-1.55(m,4H),1.20-1.30(m,8H),0.80-0.84(m,6H)。
步驟8:
如關於化合物I所描述將2-[2-氟-3,5-二戊基苯基]乙酸(537mg,1.8mmol)轉化為鈉鹽,得到呈淡棕色黏性固體之2-[2-氟-3,5-二戊基苯基]乙酸鈉(465mg,81%):1H NMR(400MHz,CD3OD):δ 6.94(dd,JHF=6.9Hz,JHH=2.2Hz,1H),6.83(dd,JHF=7.0Hz,JHH=2.3Hz,1H),3.48(d,JHF=1.1Hz,2H),2.58(t,J=7.6Hz,2H),2.51(t,J=7.6Hz,2H),1.54-1.62(m,4H),1.28-1.38(m,8H),0.90(t,J=7.0Hz,3H),0.89(t,J=7.0Hz,3H);19F NMR(377MHz,CD3OD):δ -130.71(dd,JHF=6.6,6.6Hz,1F);13C NMR(101MHz,CD3OD):δ 178.31,157.95(d,JCF=240.6Hz),137.64(d,JCF=3.8Hz),128.72(d,JCF=4.6Hz),128.42(d,JCF=17.7Hz),128.21(d,JCF=5.4Hz),124.50(d,JCF=17.7Hz),37.94(d,JCF=3.1Hz),35.05,31.52,31.45,31.37,30.00,28.96(d,JCF=2.3Hz),22.43,22.38,13.23,13.21;LRMS(ESI負模式):m/z 293(w,M-Na+)及249.1(100%,M-Na+-CO2);UPLC:8.4min(UPLC條件:移動相A=0.1%甲酸/水;移動相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=10分鐘內5-100% B/A。
化合物XXXIII:2-(3,5-二戊基苯基)-2-甲基丙酸之鈉鹽
以上化合物係以與化合物I相同之方式製備,同時具有用氫
化鈉及碘甲烷將2-[3,5-二戊基苯基]乙酸甲酯中間物烷基化之額外步驟;且其中酯水解步驟之溫度升至100℃。米白色固體:1H NMR(400MHz,CD3OD):δ 7.04(d,J=1.3Hz,2H),6.76(s,1H),2.54(t,J=7.7Hz,4H),1.55-1.63(m,4H),1.46(s,6H),1.27-1.38(m,8H),0.90(t,J=7.0Hz,6H);13C NMR(101MHz,CD3OD):δ 184.58,148.51,141.98,125.57,123.46,36.02,48.26,31.59,31.42,27.57,22.47,13.29;LRMS(ESI負模式):m/z 303.1(100%,M-Na+);UPLC:8.9min(UPLC條件:移動相A=0.1%甲酸/水;移動相B=0.1%甲酸/乙腈;固相=HSS T3;梯度=10分鐘內5-100% B/A)。
實例2:代表性式I化合物對在組織自修復、再生及抗老化中肝細胞生長因子(HGF)之表現的影響。
進行實驗以確定化合物對肝細胞生長因子在來自成人供體之活體外正常人類皮膚纖維母細胞(NHDF)(Clonetics #CC-2511)中之表現的影響。使NHDF在DMEM/F12+0.5% FBS中饑餓隔夜,且用rhTGF-β1(10ng/ml)及化合物I(500μM)處理24h或不處理。用miRNeasy®套組(QIAGEN®)分離RNA,包括管柱上脫氧核糖核酸酶消化步驟。使用RT2 First Strand套組(QIAGEN® #330401)進行cDNA合成(每次反應0.5μg RNA)。如RT2 Profiler PCR Array手冊中所描述在AB-7900HT實時循環器上進行實時PCR。使用△△Ct方法在RT2 Profiler PCR陣列資料分析網門戶網站上分析實時PCR資料。所有Ct值>35或未擴增者變成截止值為35。用於歸一化之看家基因為GAPDH及RPLP0。對照組為TGF-β1處理之細胞。
如圖1中所示,化合物I使與組織修復、再生及抗老化相關之生長因子HGF之表現增加。下表2表明TGF-β1使NHDF細胞(未處理)中之HGF表現降低,其在本文所揭示之代表性式I化合物(化合物#)之情況下得以校正或有所增加。
進行實驗以確定化合物對再生標記物之表現的影響。此實驗係使用在單次、多次或持續損傷之後參與組織再生之NHDF(正常人類皮膚纖維母細胞)及人上皮細胞(腎小管上皮細胞,HK-2)來進行。損傷係藉由使細胞與TGF-β1一起孵育來模擬。NHDF係如先前所描述進行使用,且使HK-2人上皮近端小管細胞(ATCC #CRL-2190)在DMEM/F12+0.2% FBS中饑餓隔夜且用rhTGF-β1(10ng/ml)及化合物I(500μM)處理24h或不處理。結果表明化合物I使再生標記物之表現水準在正常控制水平,從而指示損傷細胞之自修復機制。在NHDF中(圖2),LOX、MMP13、PLAU(uPA)、serpin E1、TIMP3及ILK全部以正常水平表現,另外在HK-2細胞中(圖3),LOX、MMP1、MMP2、MMP9、MMP13、TIMP3及PLAT(tPA)亦全部以接近於在健康細胞中觀測到之正常水準的水準表現。
實例3:化合物I對AAT之內源性產生及神經組織之再生的影響。
如以上所提及,AAT可誘導神經再生。通過關於NHDF之qPCR-panel分析(實例2中所描述之方法),化合物I已展示使在損傷細胞中
AAT mRNA表現增加的能力(圖4),表明化合物I可增加神經再生或其他損傷組織。化合物I代表本文所揭示之式I化合物。因此,本文所揭示之式I化合物可經由在損傷位點產生內源性AAT而增加神經再生。
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本文中包括標題供參考且用於幫助定位某些部分。此等標題不旨在限制其中所描述概念之範疇,且此等概念可在整個說明書通篇中之其他部分中具有適用性。因此,本發明不旨在限於本文所示之實施例,而是與符合本文所揭示之原理及新穎特徵的最寬範疇相一致。
除非上下文另外明確規定,否則單數形式「一」及「該」包括相應複數參考物。
除非另外指出,否則本說明書及申請專利範圍中所用之所有表示成分之量、反應條件濃度、性質等之數字應理解為在所有情況下由術語「約」修飾。最低限度地,各數值參數至少應根據具有所報導有效數位之數字且藉由应用一般舍入技術來理解。因此,除非指示為相反,否則本說明書及所附申請專利範圍中所闡述之數值參數為近似值,其可視設法獲得之性質而變化。儘管闡述實施例之廣泛範圍之數值範圍及參數為近似值,但特定實例中所闡述之數值為盡可能精確報導的。然而,任何數值固有地含有因實驗、測試量測、統計分析及此類因素而產生之某些誤差。
應瞭解,本文所描述之實例及實施例僅用於說明性目的,且將向熟習此項技術者建議對其作出之各種修改或變化,且其應包括在本發明及隨附申請專利範圍之範疇內。
Claims (53)
- 一種用於有需要之個體中之器官的組織自修復或組織再生的方法,其包括向該有需要之個體投與由式I表示之化合物或其醫藥學上可接受之鹽或其組合:
- 如申請專利範圍第1項之方法,其中A為C5烷基或C6烷基。
- 如申請專利範圍第1項或第2項中任一項之方法,其中R2為H、F、OH、C5烷基或C6烷基。
- 如申請專利範圍第1項至第3項中任一項之方法,其中R3為H、OH或CH2Ph。
- 如申請專利範圍第1項至第4項中任一項之方法,其中Q為 (CH2)mC(O)OH,其中m為1或2。
- 如申請專利範圍第1項之方法,其中A為C5烷基或C6烷基;R1為H、F或OH;R2為H、F、OH、C5烷基或C6烷基;R3為H、OH或CH2Ph;R4為H、F或OH;且Q為(CH2)mC(O)OH,其中m為1或2。
- 如申請專利範圍第1項之方法,其中A為C5烷基;R1為H;R2為H或C5烷基;R3為H;R4為H;且Q為(CH2)mC(O)OH,其中m為1。
- 如申請專利範圍第1項至第7項中任一項之方法,其中該化合物選自由由以下結構表示之化合物組成之群:
- 如申請專利範圍第1項之方法,其中該化合物由以下結構表示:
- 如申請專利範圍第1項之方法,其中該化合物由以下結構表示:
- 如申請專利範圍第1項至第10項中任一項之方法,其中該藥學上可接受的鹽為包含選自由以下組成之群的金屬相對離子的鹼加成鹽:鈉、鉀、鈣、鎂、鋰、銨、錳、鋅、鐵或銅。
- 如申請專利範圍第1項至第11項中任一項之方法,其中該藥學上可接受的鹽為鈉鹽。
- 如申請專利範圍第1項至第12項中任一項之方法,其中該器官為損傷器官,且其中該器官為心臟、肝臟、肺、皮膚、胃、腸道、肌肉或軟 骨。
- 一種用於刺激產生組織生長之方法,其包括向有需要之個體投與如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的步驟。
- 一種用於調節組織自修復標記物或組織再生標記物物在細胞培養物中或在個體之器官中之表現的方法,其包括向有需要之個體投與如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的步驟。
- 如申請專利範圍第15項之方法,其中該標記物為金屬蛋白酶或生長因子。
- 一種用於增加器官中之肝細胞生長因子(HGF)含量的方法,其包括使該器官與如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合接觸。
- 如申請專利範圍第17項之方法,其中該器官為腎臟、心臟、肝臟、肺、皮膚、胃、腸道、肌肉或軟骨。
- 一種用於增加器官中之Serpin A1(AAT)含量的方法,其包括使該器官與如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合接觸。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於有需要之個體中之器官的組織自修復或組織再生。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於製造用於有需要之個體中之器官的組織自修復或組織再生的藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於刺激產生組織生長。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於製造用於刺激產生組織生長之藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學 上可接受之鹽或其組合的用途,其係用於調節組織自修復標記物或組織再生標記物在細胞培養物中或在個體之器官中之表現。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於製造用於調節組織自修復標記物或組織再生標記物在細胞培養物中或在個體之器官中之表現的藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於增加個體之器官中之肝細胞生長因子(HGF)含量。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於製造用於增加個體之器官中之肝細胞生長因子(HGF)含量的藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於增加個體之器官中之Serpin A1(AAT)含量。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合的用途,其係用於製造用於增加個體之器官中之Serpin A1(AAT)含量的藥劑。
- 如申請專利範圍第24項或第25項之用途,其中該標記物為金屬蛋白酶或生長因子。
- 如申請專利範圍第20項至第30項中任一項之用途,其中該器官為損傷器官,且其中該器官為腎臟、心臟、肝臟、肺、皮膚、胃、腸道、肌肉或軟骨。
- 一種用於有需要之個體中的器官之組織自修復或組織再生的化合物,其中該化合物為如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合。
- 一種用於在有需要之個體中刺激產生組織生長之化合物,其中該化合物為如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合。
- 一種用於調節組織自修復標記物或組織再生標記物在細胞培養物中或 在個體器官中之表現的化合物,其中該化合物為如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合。
- 一種用於增加個體器官中之肝細胞生長因子(HGF)含量的化合物,其中該化合物為如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合。
- 一種用於增加個體器官中之Serpin A1(AAT)含量的化合物,其中該化合物為如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽或其組合。
- 如申請專利範圍第34項之供使用的化合物,其中該標記物為金屬蛋白酶或生長因子。
- 如申請專利範圍第32項至第37項中任一項之供使用的化合物,其中該器官為損傷器官,且其中該器官為腎臟、心臟、肝臟、肺、皮膚、胃、腸道、肌肉或軟骨。
- 一種用於治療器官、組織或細胞中之物理損傷的方法,該方法包括使該器官、組織或細胞與有效量之如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽接觸。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽的用途,其係用於治療器官、組織或細胞中之物理損傷。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽的用途,其係用於製備用於治療器官、組織或細胞中之物理損傷的藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽,其係用於治療器官、組織或細胞中之物理損傷。
- 一種用於促進傷口癒合之方法,該方法包括向該傷口或其極鄰近處投與有效量之如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽的用途,其係用於促進傷口癒合。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學 上可接受之鹽的用途,其係用於製備用於促進傷口癒合之藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽,其係用於促進傷口癒合。
- 一種用於治療諸如皮膚之組織的老化之方法,該方法包括向該組織投與有效量之如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽的用途,其係用於治療諸如皮膚之組織的老化。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽的用途,其係用於製備用於治療諸如皮膚之組織的老化的藥劑。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽,其係用於治療諸如皮膚之組織的老化。
- 如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽,其係用作抗老化劑。
- 一種抗老化組合物,其包含如申請專利範圍第1項至第12項中任一項所定義之化合物或其醫藥學上可接受之鹽。
- 如申請專利範圍第52項之抗老化組合物,其進一步包含一或多種藥妝可接受之媒劑。
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RU2289417C1 (ru) * | 2005-04-15 | 2006-12-20 | Равиль Шамилевич Мирхайдаров | Способ биологического омоложения кожи |
EP1953222A1 (en) * | 2007-01-24 | 2008-08-06 | Boehringer Ingelheim Pharma GmbH & Co. KG | Improvement of cell growth |
PT2427416E (pt) | 2009-05-04 | 2016-06-15 | Prometic Pharma Smt Ltd | Compostos aromáticos substituídos e seus usos farmacêuticos |
MX2011011756A (es) * | 2009-05-04 | 2012-01-25 | Prometic Biosciences Inc | Sales de acido 3-pentilfenilacetico y usos farmaceuticos. |
ES2351005B1 (es) * | 2009-07-10 | 2011-11-18 | Consejo Superior De Investigaciones Científicas (Csic) | Uso de anhidrasa carbónica ii para la elaboración de un medicamento. |
EP2632885B1 (en) | 2010-10-27 | 2018-01-03 | Prometic Pharma Smt Limited | Phenylketone carboxylate compounds and pharmaceutical uses thereof |
MY162420A (en) | 2010-10-27 | 2017-06-15 | Prometic Pharma Smt Ltd | Compounds and compositions for the treatment of cancer |
JP5388233B2 (ja) * | 2011-01-19 | 2014-01-15 | 富士ソフト株式会社 | 再生軟骨の軟骨特性を評価する方法 |
CA2844792A1 (en) * | 2011-08-10 | 2013-02-14 | Digna Biotech, S.L. | Use of cardiotrophin-1 for the treatment of kidney diseases |
TWI742541B (zh) * | 2013-03-15 | 2021-10-11 | 英商邊緣生物科技有限公司 | 用於治療肺纖維化、肝纖維化、皮膚纖維化及心臟纖維化之經取代之芳族化合物 |
TWI689490B (zh) | 2013-03-15 | 2020-04-01 | 英商邊緣生物科技有限公司 | 用於治療纖維化之經取代之芳族化合物及相關方法 |
SG11201702812PA (en) * | 2014-10-10 | 2017-05-30 | Prometic Pharma Smt Ltd | Substituted aromatic compounds and pharmaceutical compositions for the prevention and treatment of diabetes |
DK3203999T3 (da) * | 2014-10-10 | 2020-03-30 | Liminal Biosciences Ltd | Substituerede aromatiske forbindelser og farmaceutiske sammensætninger til forebyggelse og behandling af osteoporose |
MY187515A (en) * | 2014-11-12 | 2021-09-24 | Prometic Pharma Smt Ltd | Substituted aromatic compounds and pharmaceutical compositions for tissue self-repair and regeneration |
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