TWI738162B - Condensed tricyclic deuterated derivatives and their compositions and uses - Google Patents
Condensed tricyclic deuterated derivatives and their compositions and uses Download PDFInfo
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- TWI738162B TWI738162B TW108148256A TW108148256A TWI738162B TW I738162 B TWI738162 B TW I738162B TW 108148256 A TW108148256 A TW 108148256A TW 108148256 A TW108148256 A TW 108148256A TW I738162 B TWI738162 B TW I738162B
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- 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
- A61P25/06—Antimigraine agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本發明涉及一種稠合三環氘代衍生物及其組合物和應用，具體關於通式(I)所示稠合三環氘代衍生物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥及含有該衍生物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥的藥物組合物，以及其作為治療及/或預防疼痛的藥物中的用途。
Description
本發明涉及一種稠合三環氘代衍生物及其組合物和應用，具體關於通式(I)所示稠合三環氘代衍生物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥及含有該衍生物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥的藥物組合物，以及其作為治療及/或預防疼痛的藥物中的用途。The present invention relates to a condensed tricyclic deuterated derivative and its composition and application, in particular to the condensed tricyclic deuterated derivative represented by the general formula (I) or its stereoisomers, solvates, metabolites, pharmaceuticals Acceptable salts, co-crystals or prodrugs and pharmaceutical compositions containing the derivatives or their stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, and their use as treatment And/or use in medicines to prevent pain.
電壓門控鈣離子通道由α1亞單位和輔助蛋白α2δ、β、γ亞基共同構成。α2δ蛋白可以調節鈣離子通道的密度及鈣離子通道電壓依賴性動力學 (Felix et al (1997) J. Neuroscience 17: 6884- 6891; Klugbauer et al (1999) J. Neuroscience 19: 684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496)。已經證實，對電壓依賴性鈣離子通道亞基α2δ表現出高親合力結合的化合物可有效治療疼痛，例如普瑞巴林和加巴噴丁。在哺乳動物中，α2δ蛋白有4個亞型，每個亞型均由不同的基因編碼。α2δ亞型1和亞型2與普瑞巴林表現出高親和力，而α2δ亞型3和亞型4無顯著的藥物結合力。Voltage-gated calcium channels are composed of α1 subunits and auxiliary protein α2δ, β, and γ subunits. α2δ protein can regulate the density of calcium ion channels and the voltage-dependent dynamics of calcium ion channels (Felix et al (1997) J. Neuroscience 17: 6884-6891; Klugbauer et al (1999) J. Neuroscience 19: 684-691; Hobom et al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496). It has been confirmed that compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit α2δ are effective in treating pain, such as pregabalin and gabapentin. In mammals, there are 4 subtypes of α2δ protein, and each subtype is encoded by a different gene. α2δ subtype 1 and subtype 2 show high affinity with pregabalin, while α2δ subtype 3 and subtype 4 have no significant drug binding ability.
然而，對於加巴噴丁，其較大程度改善糖尿病周圍神經病變患者病痛的比例約為60％(Acta Neurol. Scand. 101:359-371, 2000)，對於普瑞巴林，雖然其耐受性優於加巴噴丁，但其安全性更低，且有濫用或者使患者產生依賴的可能(Am J Health Syst Pharm. 2007; 64(14): 1475-1482)。However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy that it greatly improves the pain of diabetic peripheral neuropathy is about 60% (Acta Neurol. Scand. 101:359-371, 2000). For pregabalin, although its tolerance is better than gabapentin , But its safety is lower, and there is the possibility of abuse or dependence on patients (Am J Health Syst Pharm. 2007; 64(14): 1475-1482).
鑒於加巴噴丁和普瑞巴林的局限性，需要開發新的具有更好藥效的化合物。In view of the limitations of gabapentin and pregabalin, it is necessary to develop new compounds with better efficacy.
PCT/CN2017/101364專利申請公開了一種稠合三環γ-氨基酸衍生物及其製備方法和在醫藥上的應用，其中化合物A具有良好的生物活性，然不應認為此專利中對於化合物A及其他部份的具體描述屬於本發明的一部分，
本發明的目的是提供一種稠合三環氘代衍生物，或者其所有的立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其藥物組合物以及其在鎮痛領域的用途。The purpose of the present invention is to provide a fused tricyclic deuterated derivative, or all its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, its pharmaceutical composition and its Use in the field of pain relief.
本發明涉及一種通式（I）所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其中
R1 、R2 、R3 、R4 、R5 、R6 、R7 、R8 、R9 、R10 、R11 、R12 、R13 、R14 、R15 、R16 、R17 、R18 、R19 各自獨立的選自H或D，條件是不同時為H。R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently selected from H or D, provided that they are not H at the same time.
本發明的一些具體實施例，一種通式（I）所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其中R10 、R11 各自獨立的選自D。In some specific embodiments of the present invention, a compound of general formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein R 10 , R 11 Each independently selected from D.
本發明的一些具體實施例，一種通式（I）所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其中R13 、R14 各自獨立的選自D。In some specific embodiments of the present invention, a compound of general formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein R 13 , R 14 Each independently selected from D.
本發明的一些具體實施例，一種通式（I）所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其中R10 、R11 、R13 、R14 各自獨立的選自D。In some specific embodiments of the present invention, a compound of general formula (I) or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein R 10 , R 11 , R 13 , and R 14 are each independently selected from D.
本發明涉及一種通式（I）所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其中所述的鹽選自苯磺酸鹽、對甲苯磺酸鹽、甲磺酸鹽、馬來酸鹽、富馬酸鹽、氫鹵酸鹽、硫酸鹽、磷酸鹽、L-酒石酸鹽、檸檬酸鹽、L-蘋果酸鹽、馬尿酸鹽、D-葡萄糖醛酸鹽、乙醇酸鹽、黏酸鹽、琥珀酸鹽、乳酸鹽、乳清酸鹽、帕莫酸鹽、丙二酸鹽、龍膽酸鹽、草酸鹽、戊二酸鹽或糖精鹽，較佳為苯磺酸鹽、對甲苯磺酸鹽、甲磺酸鹽、馬來酸鹽、富馬酸鹽、氫溴酸鹽或鹽酸鹽。The present invention relates to a compound of general formula (I) or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, wherein the salt is selected from besylate , P-toluenesulfonate, methanesulfonate, maleate, fumarate, hydrohalide, sulfate, phosphate, L-tartrate, citrate, L-malate, hippuric acid Salt, D-glucuronate, glycolate, mucate, succinate, lactate, orotate, pamoate, malonate, gentisate, oxalate, glutarate The acid salt or saccharinate is preferably benzenesulfonate, p-toluenesulfonate, methanesulfonate, maleate, fumarate, hydrobromide or hydrochloride.
本發明涉及一種通式（I）所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，其中所述的鹽的H可以被1個或多個D取代。The present invention relates to a compound of general formula (I) or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, wherein the H of the salt can be divided by one Or multiple D substitutions.
本發明涉及一種通式（II）或通式（III）所述化合物及其立體異構物或藥學上可接受的鹽，其中
B1 、B2 、B3 、B4 、B5 、B6 、B7 、B8 、B9 、B10 、B11 、B12 各自獨立的選自H或D，條件是不同時為H。B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , B 9 , B 10 , B 11 , B 12 are each independently selected from H or D, provided that they are not H at the same time .
本發明涉及一種通式（IV）或通式（V）所述化合物及其立體異構物或藥學上可接受的鹽，其中
A選自-NO2 或-NB15 B16 ；A is selected from -NO 2 or -NB 15 B 16 ;
B15 、B16 各自獨立的選自H、D或氨基保護基；B 15 and B 16 are each independently selected from H, D or amino protecting groups;
B19 選自H、D或羧基保護基；B 19 is selected from H, D or carboxyl protecting group;
B1 、B2 、B3 、B4 、B5 、B6 、B7 、B8 、B9 、B10 、B11 、B12 、B13 、B14 、B17 、B18 各自獨立的選自H或D，B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , B 9 , B 10 , B 11 , B 12 , B 13 , B 14 , B 17 , B 18 are each independent Selected from H or D,
B1 、B2 、B3 、B4 、B5 、B6 、B7 、B8 、B9 、B10 、B11 、B12 、B13 、B14 、B15 、B16 、B17 、B18 、B19 條件是不同時為H。B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , B 9 , B 10 , B 11 , B 12 , B 13 , B 14 , B 15 , B 16 , B 17 , B 18 and B 19 are not H at the same time.
本發明的一些具體實施例，一種通式（IV）或通式（V）所述化合物及其立體異構物或藥學上可接受的鹽，其中In some specific embodiments of the present invention, a compound of general formula (IV) or general formula (V) and its stereoisomers or pharmaceutically acceptable salts thereof, wherein
氨基保護基選自Boc、乙醯基、苄氧羰基、苯甲醯基、苄基、對甲氧基苄基、鄰苯二甲醯基；The amino protecting group is selected from Boc, acetoxy, benzyloxycarbonyl, benzyl, benzyl, p-methoxybenzyl, phthalyl;
羧基保護基選自tBu、苄基、甲基、乙基、正丙基、異丙基、對甲氧基苄基。The carboxy protecting group is selected from tBu, benzyl, methyl, ethyl, n-propyl, isopropyl, p-methoxybenzyl.
本發明涉及一種藥物組合物，所述藥物組合物包含本發明所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥，和一種或者多種藥學上可接受的載體及/或賦形劑。The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, and one or more A pharmaceutically acceptable carrier and/or excipient.
本發明涉及本發明所述的藥物組合物或者本發明所述的化合物或其立體異構物、溶劑化物、代謝產物、藥學上可接受的鹽、共晶或者前藥在製備用於治療及/或預防疼痛的藥物中的用途。The present invention relates to the preparation of the pharmaceutical composition of the present invention or the compound of the present invention or its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs for treatment and/ Or use in medicines to prevent pain.
本發明的一些具體實施例，本發明所述的在製備用於治療及/或預防疼痛的藥物中的用途，所述的疼痛包括：皰疹後神經痛、三叉神經痛、偏頭痛、與骨關節炎或關節風濕病相關的疼痛、下背疼痛、坐骨神經痛、牙痛、由燒傷引起的疼痛、由糖尿病性神經病引起的疼痛、由化療誘導的神經病變引起的疼痛、與HIV 相關的神經痛、與AIDS 相關的神經痛、與癌症相關的神經痛或非神經痛、急性或慢性緊張性頭痛、手術後疼痛、或纖維肌痛。In some specific embodiments of the present invention, the use of the present invention in the preparation of a medicament for the treatment and/or prevention of pain, the pain includes: postherpetic neuralgia, trigeminal neuralgia, migraine, and bone Arthritis or joint rheumatism related pain, lower back pain, sciatica, toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related neuralgia or non-neuralgia, acute or chronic tension headache, postoperative pain, or fibromyalgia.
除非有相反的陳述，在說明書和申請專利範圍中使用的術語具有下述含義。Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.
本發明所述基團和化合物中所涉及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況，及本發明所述基團和化合物中所涉及的碳、氫、氧、硫或氮任選進一步被一個或多個它們對應的同位素所替代，其中碳的同位素包括12 C、13 C和14 C，氫的同位素包括氕 (H)、氘 (D，又叫重氫)、氚 (T，又叫超重氫)，氧的同位素包括16 O、17 O和18 O，硫的同位素包括32 S、33 S、34 S和36 S，氮的同位素包括14 N和15 N，氟的同位素包括17 F和19 F，氯的同位素包括35 Cl和37 Cl，溴的同位素包括79 Br和81 Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, and I involved in the groups and compounds of the present invention include their isotopes, and the carbon involved in the groups and compounds of the present invention , Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, Also called heavy hydrogen), tritium (T, also called super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
「氨基保護基」是指用於氨基保護的基團，該基團適用於保護氨基，使氨基不進行化學反應，但是在分子的其它部分完成所需化學反應之後該基團容易除去。非限制性實施例包括但不限於甲醯基、乙醯基、苯基醯基、甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧羰基、丙氧基羰基、第三丁氧基羰基、苄基氧基羰基、苯氧基羰基、9-芴基甲基氧基羰基、金剛烷基氧基羰基、苄基氧基羰基、苄基羰基、苄基、苯甲基、三苯甲基、鄰苯二甲醯基。"Amino protecting group" refers to a group used to protect an amino group. This group is suitable for protecting an amino group so that the amino group does not undergo a chemical reaction, but the group can be easily removed after the other parts of the molecule complete the required chemical reaction. Non-limiting examples include, but are not limited to, formyl, acetyl, phenylyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, propoxycarbonyl, and Tributoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 9-fluorenylmethyloxycarbonyl, adamantyloxycarbonyl, benzyloxycarbonyl, benzylcarbonyl, benzyl, benzyl , Trityl, Phthalic acid base.
「羧基保護基」是指用於羧基保護的基團，該基團適用於保護羧基，使羧基不進行化學反應，但是在分子的其它部分完成所需化學反應之後該基團容易除去。非限制性實施例包括但不限於指甲基、乙基、正丙基、異丙基、正丁基、第二丁基、新丁基、第三丁基、正戊基、異戊基、新戊基、正己基、三氯乙基、苄基、對硝基苄基、鄰硝基苄基、對甲氧基苄基、對第三丁基苄基、乙醯氧基甲基、丙醯氧基甲基、丁醯氧基甲基、異丁醯氧基甲基、戊氧基甲基、新戊醯氧基甲基、乙醯氧基乙基、乙醯氧基丙基、乙醯氧基丁基、丙醯氧基乙基、丙醯氧基丙基、丁醯氧基乙基、異丁醯氧基乙基、新戊醯氧基乙基、己醯氧基乙基、異丁醯氧基甲基、乙基丁醯氧基甲基、二甲基丁醯氧基甲基、戊醯氧基乙基、甲氧基羰氧基甲基、乙氧基羰氧基甲基、丙氧基羰氧基乙基、異丙氧基羰氧基乙基、第三丁氧基羰氧基甲基、甲氧基羰氧基乙基、乙氧基羰氧基乙基、異丙氧基羰氧基乙基、第三丁基二甲基甲矽烷基、三甲基甲矽烷基、甲氧基甲基、乙氧基甲基、丙氧基甲基、異丙氧基甲基、(2-甲基硫代)-乙基、3-甲基-2-丁烯基、5-茚滿基和3-2-苯並[C]呋喃酮亞基。"Carboxy protecting group" refers to a group used to protect a carboxyl group. This group is suitable for protecting the carboxyl group so that the carboxyl group does not undergo a chemical reaction, but the group can be easily removed after the other parts of the molecule complete the required chemical reaction. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, neobutyl, tertiary butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, trichloroethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl, p-tert-butylbenzyl, acetoxymethyl, propyl Acetyloxymethyl, butyroxymethyl, isobutyroxymethyl, pentoxymethyl, neopentyloxymethyl, acetoxyethyl, acetoxypropyl, ethyl Acetyloxybutyl, propionyloxyethyl, propionyloxypropyl, butyroxyethyl, isobutyroxyethyl, neopentyloxyethyl, hexyloxyethyl, Isobutyroxymethyl, ethylbutyroxymethyl, dimethylbutyroxymethyl, pentyloxyethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl Group, propoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, tertiary butoxycarbonyloxymethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, Isopropoxycarbonyloxyethyl, tert-butyldimethylsilyl, trimethylsilyl, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxy Methyl, (2-methylthio)-ethyl, 3-methyl-2-butenyl, 5-indanyl and 3-2-benzo[C]furanone subunits.
「藥學上可接受的鹽」或者「其藥學上可接受的鹽」是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性，且所述的游離酸通過與無毒的無機鹼或者有機鹼，所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or organic Base, the free base is a salt obtained by reacting with a non-toxic inorganic acid or organic acid.
「藥物組合物」是指一種或多種本發明所述化合物、其藥學上可接受的鹽或前藥和其它化學組分形成的混合物，其中，「其它化學組分」是指藥學上可接受的載體、賦形劑及/或一種或多種其它治療劑。"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, where "other chemical components" refer to pharmaceutically acceptable Carriers, excipients and/or one or more other therapeutic agents.
「載體」是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.
「賦形劑」是指加入到藥物組合物中以促進化合物給藥的惰性物質。非限制性實施例包括碳酸鈣、磷酸鈣、糖、澱粉、纖維素衍生物 (包括微晶纖維素)、明膠、植物油、聚乙二醇類、稀釋劑、成粒劑、潤滑劑、黏合劑和崩解劑。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate the administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders And disintegrants.
「前藥」是指可經體內代謝轉化為具有生物活性的本發明化合物。本發明的前藥通過修飾本發明化合物中的氨基或者羧基來製備，該修飾可以通過例行的操作或者在體內被除去，而得到母體化合物。當本發明的前藥被施予哺乳動物個體時，前藥被割裂形成游離的氨基或者羧基。"Prodrug" refers to a compound of the present invention that can be converted into a biological activity by metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by routine operation or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is split to form free amino or carboxyl groups.
「共晶」是指活性藥物成分(API)和共晶形成物(CCF)在氫鍵或其他非共價鍵的作用下結合而成的晶體，其中API和CCF的純態在室溫下均為固體，並且各組分間存在固定的化學計量比。共晶是一種多組分晶體，既包含兩種中性固體之間形成的二元共晶，也包含中性固體與鹽或溶劑化物形成的多元共晶。"Co-crystal" refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both at room temperature. It is a solid, and there is a fixed stoichiometric ratio between the components. A eutectic is a multi-component crystal, which includes both a binary eutectic formed between two neutral solids and a multi-element eutectic formed between a neutral solid and a salt or solvate.
「動物」是指包括哺乳動物，例如人、陪伴動物、動物園動物和家畜，較佳為人、馬或者犬。"Animal" refers to mammals, such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
「立體異構物」是指由分子中原子在空間上排列方式不同所產生的異構物，包括順反異構物、對映異構物和構象異構物。"Stereoisomers" refer to isomers produced by the different arrangements of atoms in the molecule in space, including cis-trans isomers, enantiomers, and conformational isomers.
「任選」或「任選地」或「選擇性的」或「選擇性地」是指隨後所述的事件或狀況可以但未必發生，該描述包括其中發生該事件或狀況的情況及其中未發生的情況。例如，「選擇性地被烷基取代的雜環基」是指該烷基可以但未必存在，該描述包括其中雜環基被烷基取代的情況，及其中雜環基未被烷基取代的情況。"Optional" or "optionally" or "selective" or "optionally" means that the event or condition described later can but does not necessarily occur, and the description includes the circumstances in which the event or condition occurs and its failures. What happened. For example, "heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may but does not necessarily exist. The description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. Condition.
IC50 (被測量的抑制劑的半抑制濃度)：通過測試受試化合物50%抑制加巴噴丁(gabapentin)與鈣離子通道結合所需的濃度。IC 50 (inhibitor measured half inhibitory concentration): Inhibition of gabapentin (gabapentin) and the calcium channel binding test required by the test compound concentration of 50%.
以下通過具體實施例詳細說明本發明的實施過程和產生的有益效果，旨在幫助閱讀者更好地理解本發明的實質和特點，不作為對本案可實施範圍的限定。The following specific examples illustrate the implementation process and beneficial effects of the present invention in detail, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.
化合物的結構是通過核磁共振 (NMR) 或 (和) 質譜 (MS) 來確定的。 NMR 位移 (δ) 以10-6 (ppm) 的單位顯示。NMR的測定是用 (BrukerAvance III 400和BrukerAvance 300) 核磁儀，測定溶劑為氘代二甲基亞碸 (DMSO-d6 )，氘代氯仿 (CDCl3 )，氘代甲醇 (CD3 OD)或氘代乙腈(CD3 CN)，內標為四甲基矽烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is displayed in units of 10 -6 (ppm). NMR is measured by (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) or Deuterated acetonitrile (CD 3 CN), the internal standard is tetramethylsilane (TMS).
MS的測定用Agilent 6120B(ESI) 和Agilent 6120B(APCI)。Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS measurement.
HPLC的測定使用安捷倫1260DAD高壓液相層析儀 (Zorbax SB-C18 100×4.6 mm)。HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm).
薄層層析矽膠板使用煙臺黃海HSGF254 或青島GF254 矽膠板，薄層層析法 (TLC) 使用的矽膠板採用的規格是0.15 mm~0.20 mm，薄層層析分離純化產品採用的規格是0.4 mm~0.5 mm。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15 mm~0.20 mm, and the specification used for thin layer chromatography separation and purification products is 0.4 mm~0.5 mm.
管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
本發明的己知的起始原料可以採用或按照本領域已知的方法來合成，或可購買於泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、百靈威科技等公司。The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology Waiting for the company.
本發明矽膠管柱層析所示比例為體積比。The ratio shown in the silica gel column chromatography of the present invention is the volume ratio.
tBu：第三丁基。tBu: tertiary butyl group.
BOC：第三丁氧基羰基。BOC: The third butoxycarbonyl group.
中間體1 通過以下兩步反應製備Intermediate 1 is prepared by the following two-step reaction
(±) 2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-3-基)乙酸乙酯
第一步：first step:
(±) 2-(1R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷]-3-亞基)乙酸乙酯
反應瓶中加入氫化鈉 (7.73 mol) 和四氫呋喃 (3000 mL)，降溫至0℃，滴加三乙基膦醯乙酸酯(1600 g, 7.13 mol)，0℃下反應20分鐘後滴加1A (1000 g，5.95 mol, 溶於200 mL四氫呋喃，購買於上海喀露藍科技有限公司，(1R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-3-酮, (1R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-one)，室溫反應1小時。向反應液中加入氯化銨水溶液 (2000 mL)，水相用乙酸乙酯萃取(3000 mL × 3)，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，管柱層析分離（PE:EA = 10:1），得到無色油狀物1B （1150 g, 81%）。Add sodium hydride (7.73 mol) and tetrahydrofuran (3000 mL) into the reaction flask, reduce the temperature to 0°C, add triethylphosphine acetate (1600 g, 7.13 mol) dropwise, react at 0°C for 20 minutes and then add 1A dropwise (1000 g, 5.95 mol, dissolved in 200 mL tetrahydrofuran, purchased from Shanghai Kalulan Technology Co., Ltd., (1R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3] Dioxolane]-3-one, (1R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-one), react at room temperature for 1 hour. Aqueous ammonium chloride solution (2000 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (3000 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by column chromatography (PE:EA = 10:1) to obtain 1B (1150 g, 81%) as a colorless oil.
第二步：The second step:
(±) 2-(1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷]-3-基)乙酸乙酯
向反應瓶中加入原料1B (250 g, 1.05 mol)，加入溶劑甲醇（3 L），加入10%鈀碳（50g），氫氣換氣三次，35℃下反應4小時，將反應液抽濾，甲醇洗滌（50 mL x 3），合併濾液，減壓濃縮，得粗產品中間體 1 ， 不純化直接用於下一步反應。 Add raw material 1B (250 g, 1.05 mol) to the reaction flask, add solvent methanol (3 L), add 10% palladium on carbon (50g), add hydrogen gas three times, react at 35°C for 4 hours, and filter the reaction liquid. Wash with methanol (50 mL x 3), combine the filtrate, and concentrate under reduced pressure to obtain the crude product Intermediate 1 , which is directly used in the next reaction without purification.
實施例1
第一步：first step:
中間體2
: (±)-2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-3-基)乙酸
將中間體1 （104 g, 0.433mol）加到反應瓶中，加入800 mL四氫呋喃和水的混合溶劑（V/V = 1:1），攪拌溶解，加入LiOH . H2 O（36 g, 0.86 mol），加完室溫反應過夜。0℃下，TLC監測，反應完全後往反應體系內加入與LiOH等當量的HCl溶液150 mL（6 N），攪拌30 min，使pH約 為7，加入乙酸乙酯800 mL，萃取分液，水相以EA萃取（600 × 2），飽和食鹽水洗滌（400 mL），無水硫酸鈉乾燥，濃縮，得粗產物中間體2 (±)-2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-3-基)乙酸（90 g，產率：98%）。Add Intermediate 1 (104 g, 0.433mol) to the reaction flask, add 800 mL of a mixed solvent of tetrahydrofuran and water (V/V = 1:1), stir to dissolve, add LiOH . H 2 O (36 g, 0.86) mol), and react overnight at room temperature after adding. At 0℃, monitored by TLC. After the reaction is complete, add 150 mL of HCl solution (6 N) equivalent to LiOH into the reaction system, stir for 30 min, to make the pH about 7, add 800 mL of ethyl acetate, extract and separate. The aqueous phase was extracted with EA (600 × 2), washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product Intermediate 2 (±)-2-((1R,3R,5R)-spiro[ Bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolane]-3-yl)acetic acid (90 g, yield: 98%).
1 H NMR (400 MHz, CDCl3 ) δ 9.97 (s, 1H), 4.00 – 3.71 (m, 4H), 2.93 – 2.80 (m, 1H), 2.60 – 2.51 (m, 1H), 2.51 – 2.24 (m, 4H), 2.23 – 2.13 (m, 1H), 2.06 – 1.98 (m, 1H), 1.98 – 1.86 (m, 1H), 1.56 (ddd, , 1H), 1.16 (ddd, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.97 (s, 1H), 4.00 – 3.71 (m, 4H), 2.93 – 2.80 (m, 1H), 2.60 – 2.51 (m, 1H), 2.51 – 2.24 (m , 4H), 2.23 – 2.13 (m, 1H), 2.06 – 1.98 (m, 1H), 1.98 – 1.86 (m, 1H), 1.56 (ddd,, 1H), 1.16 (ddd, 1H).
第二步：The second step:
中間體3
: (±)-1,1-二氘-2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷]-3-基)乙醇
將中間體2 (±)-2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊環]-3-基)乙酸 (18 g, 0.085 mol)，N-甲基嗎啉(8.92 g, 0.088 mol)溶於四氫呋喃 (1500 mL) 中，降溫到0℃，再將氯甲酸乙酯(8.44mL, 0.088 mol)的四氫呋喃 (200 mL)滴加到反應液中，加畢0℃到室溫反應1小時。將反應過濾，濾餅用四氫呋喃(100 mL × 2）洗滌，濾液加入反應瓶中攪拌並冷卻到0℃，滴加入氘代硼氫化鈉（7.83 g, 0.186 mol)的氘水(15 mL)溶液，保持內溫不超過10℃，加畢於0℃到室溫反應2-3小時。TLC監測反應畢，將反應液降溫到0℃滴加入6 N的鹽酸溶液 (70 mL)攪拌到體系不再冒氣泡為止，分液，水相用乙酸乙酯 (200 mL × 2)萃取，合併有機相，用飽和食鹽水（100 mL × 1），5%的氫氧化鈉溶液（100 mL × 1）（此處應洗到pH值大於10保證中間體2 被洗淨），飽和食鹽水（100 mL × 2）依次洗滌，有機相加入無水硫酸鈉乾燥，攪拌20分鐘，過濾固體並用四氫呋喃 (100 mL × 2)洗滌。將合併的有機相濃縮得到中間體3 (±)-1,1-二氘-2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷]-3-基)乙醇 (15.6g，產率：92.0%)。Intermediate 2 (±)-2-((1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolane]-3-yl) Acetic acid (18 g, 0.085 mol), N-methylmorpholine (8.92 g, 0.088 mol) were dissolved in tetrahydrofuran (1500 mL), cooled to 0℃, and then ethyl chloroformate (8.44 mL, 0.088 mol) Tetrahydrofuran (200 mL) was added dropwise to the reaction solution, and after the addition, the reaction was carried out at 0°C to room temperature for 1 hour. The reaction was filtered, the filter cake was washed with tetrahydrofuran (100 mL × 2), the filtrate was added to the reaction flask, stirred and cooled to 0°C, and a solution of sodium deuterated borohydride (7.83 g, 0.186 mol) in deuterium water (15 mL) was added dropwise , Keep the internal temperature not more than 10 ℃, after adding, react at 0 ℃ to room temperature for 2-3 hours. After TLC monitoring the reaction, the reaction solution was cooled to 0℃ and 6 N hydrochloric acid solution (70 mL) was added dropwise. Stir until the system no longer bubbling. The liquid was separated. The aqueous phase was extracted with ethyl acetate (200 mL × 2) and combined For the organic phase, use saturated brine (100 mL × 1), 5% sodium hydroxide solution (100 mL × 1) (here should be washed until the pH value is greater than 10 to ensure that Intermediate 2 is washed), saturated brine ( 100 mL × 2) Wash sequentially, add anhydrous sodium sulfate to dry the organic phase, stir for 20 minutes, filter the solid and wash with tetrahydrofuran (100 mL × 2). The combined organic phase was concentrated to obtain intermediate 3 (±)-1,1-dideuterium-2-((1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1 ,3]Dioxolane]-3-yl)ethanol (15.6 g, yield: 92.0%).
1 H NMR (400 MHz, CDCl3 ) δ 3.95 – 3.72 (m, 4H), 2.93 – 2.75 (m, 1H), 2.54 (m, 1H), 2.41 – 2.30 (m, 1H), 2.18 – 2.05 (m, 1H), 2.04 – 1.94 (m, 2H), 1.90 (s, 1H), 1.87 – 1.80 (m, 1H), 1.69 (d, 2H), 1.57 – 1.43 (m, 1H), 1.15 – 1.02 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.95 – 3.72 (m, 4H), 2.93 – 2.75 (m, 1H), 2.54 (m, 1H), 2.41 – 2.30 (m, 1H), 2.18 – 2.05 (m , 1H), 2.04 – 1.94 (m, 2H), 1.90 (s, 1H), 1.87 – 1.80 (m, 1H), 1.69 (d, 2H), 1.57 – 1.43 (m, 1H), 1.15 – 1.02 (m , 1H).
第三步：third step:
中間體4
: (±)-(1R,3R,5R)-3-(2-二氘碘乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷:
將碘（26 g, 0.101 mol）加到反應瓶中，加入二氯甲烷（500 mL），降溫至0℃，加入咪唑（8.75 g, 0.13 mol）和三苯基膦（26.0 g, 0.099 mol），滴加中間體3 (±)-1,1-二氘-2-((1R,3R,5R)-螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷]-3-基)乙醇3 （15.6 g, 0.078 mol）（溶於100 mL DCM），加完室溫下反應2 h。抽濾，DCM洗滌（100 ml × 2），合併濾液，加水（200ml)，邊攪拌邊加入飽和硫代硫酸鈉溶液直至碘的顏色消失，分液，濃縮掉DCM，剩餘部分用甲基第三醚打漿（10 L × 2），濃縮，得粗產物，管柱層析分離，PE : EA = 15:1。得淡黃色油狀物中間體4 (±)-(1R,3R,5R)-3-(2-二氘碘乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷 （21.4 g, 89%）。Add iodine (26 g, 0.101 mol) to the reaction flask, add dichloromethane (500 mL), cool to 0°C, add imidazole (8.75 g, 0.13 mol) and triphenylphosphine (26.0 g, 0.099 mol) , Add dropwise intermediate 3 (±)-1,1-dideuterium-2-((1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]二Oxopentane]-3-yl)ethanol 3 (15.6 g, 0.078 mol) (dissolved in 100 mL DCM), after adding, react at room temperature for 2 h. Filter with suction, wash with DCM (100 ml × 2), combine the filtrate, add water (200ml), add saturated sodium thiosulfate solution while stirring until the color of iodine disappears, separate the layers, concentrate the DCM, and use the third methyl group for the remaining part Ether beating (10 L × 2), concentrated to obtain the crude product, column chromatography separation, PE: EA = 15:1. A pale yellow oily intermediate 4 (±)-(1R,3R,5R)-3-(2-dideuteroiodoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1 ,3] Dioxolane (21.4 g, 89%).
1 H NMR (400 MHz, CDCl3 ) δ 3.94 – 3.67 (m, 4H), 2.83 (dd, 1H), 2.59 – 2.48 (m, 1H), 2.38 (m , 1H), 2.19 – 2.06 (m, 1H), 2.03 – 1.90 (m, 2H), 1.90 – 1.78 (m, 1H), 1.69 (d, 2H), 1.56 – 1.43 (m, 1H), 1.18 – 1.03 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.94 – 3.67 (m, 4H), 2.83 (dd, 1H), 2.59 – 2.48 (m, 1H), 2.38 (m, 1H), 2.19 – 2.06 (m, 1H ), 2.03 – 1.90 (m, 2H), 1.90 – 1.78 (m, 1H), 1.69 (d, 2H), 1.56 – 1.43 (m, 1H), 1.18 – 1.03 (m, 1H).
第四步：the fourth step:
中間體5
: (±)-(1R,3R,5R)-3-(2-二氘碘乙基)雙環[3.2.0]庚烷-6-酮
將中間體4 (±)-(1R,3R,5R)-3-(2-二氘碘乙基)螺[雙環[3.2.0]庚烷-6,2'-[1,3]二氧戊烷（21.4 g, 0.069 mol）加到反應瓶中，加入四氫呋喃（300 mL），攪拌溶解，加入水（100 mL），0℃下滴加TFA（150 mL），加完40℃下反應4 h。0℃下往反應體系內加入與TFA等當量的氫氧化鈉（溶於約500 mL水中）再滴加飽和碳酸氫鈉溶液至pH為7-8，再加入500 mL EA，攪拌5 min，分液，有機相以飽和食鹽水洗滌（2 L），合併水相，以EA萃取（400 mL × 2），飽和食鹽水洗滌（100 mL），無水硫酸鈉乾燥，濃縮，得粗產物中間體5 (±)-(1R,3R,5R)-3-(2-二氘碘乙基)雙環[3.2.0]庚烷-6-酮 （12.5 g, 68%），直接用於下一步。Intermediate 4 (±)-(1R,3R,5R)-3-(2-dideuteroiodoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]diox Pentane (21.4 g, 0.069 mol) was added to the reaction flask, tetrahydrofuran (300 mL) was added, stirred to dissolve, water (100 mL) was added, and TFA (150 mL) was added dropwise at 0°C. After the addition, reaction 4 at 40°C h. Add sodium hydroxide equivalent to TFA (dissolved in about 500 mL of water) into the reaction system at 0°C, then add saturated sodium bicarbonate solution to pH 7-8, then add 500 mL of EA, stir for 5 min, divide Wash the organic phase with saturated brine (2 L), combine the aqueous phases, extract with EA (400 mL × 2), wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, and concentrate to obtain the crude intermediate 5 (±)-(1R,3R,5R)-3-(2-dideuteroiodoethyl)bicyclo[3.2.0]heptane-6-one (12.5 g, 68%), used directly in the next step.
第五步：the fifth step:
中間體6
: (±)- (1R,3S,6R,8R)-三環[4.2.1.03,8
]壬烷-2-酮-4,4-d2
將中間體5 （19.5 g, 0.073 mol）加到反應瓶中，加入溶劑DMF（150 mL），室溫下加入氫氧化鉀（20.5 g, 0.367 mol），邊加邊攪拌，加完室溫放置過夜. 將固體氫氧化鉀過濾，濾液加入到200 mL冰水中，以石油醚萃取（150 mL x 3），合併有機相，無水硫酸鈉乾燥，25℃減壓濃縮，管柱層析分離得產物中間體6 （6.0 g, 60%）。Add Intermediate 5 (19.5 g, 0.073 mol) to the reaction flask, add the solvent DMF (150 mL), add potassium hydroxide (20.5 g, 0.367 mol) at room temperature, stir while adding, and leave at room temperature after adding Overnight. Filter the solid potassium hydroxide, add the filtrate to 200 mL ice water, extract with petroleum ether (150 mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure at 25°C, and separate the product by column chromatography Intermediate 6 (6.0 g, 60%).
1 H NMR (400 MHz, CDCl3 ) NMR (400 MHz, CDCl4 H), 2.83 (dd, 1H), 2.59 – 2.48 (m, 1H), 2.38 (m , 1H), 2.19 – 2.06 (m, 1H), 2.03 – 1.90 (m, 2H), 1.90 – 1.78 (m, 1H), 1.69 (d, 2H), 1.5 (m, 1H), 1.18 (d, 1H). 1 H NMR (400 MHz, CDCl 3 ) NMR (400 MHz, CDCl 4 H), 2.83 (dd, 1H), 2.59 – 2.48 (m, 1H), 2.38 (m, 1H), 2.19 – 2.06 (m, 1H ), 2.03 – 1.90 (m, 2H), 1.90 – 1.78 (m, 1H), 1.69 (d, 2H), 1.5 (m, 1H), 1.18 (d, 1H).
第六步：The sixth step:
中間體7
: (±) 2-((1R,3S,6R,8R)-三環[4.2.1.03,8
]壬烷-2-亞基-4,4-d2
)乙酸第三丁酯
反應瓶中加入第三丁醇鉀 (10.6 g，94.1 mmol) 和四氫呋喃 (240 mL)，降溫至0℃，滴加二乙基磷醯乙酸第三丁酯 (21.1 g，64.1 mmol)，0℃下反應20分鐘後滴加中間體6 (10.0 g，72.4 mmol) 的四氫呋喃 (50 mL) 溶液，室溫反應2小時。向反應液中加入水 (100 mL) 和乙酸乙酯 (100 mL)，攪拌分液，水相用乙酸乙酯 (100 mL × 2) 萃取，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，管柱層析分離（PE:EA = 100:1），得到無色液體中間體7 （10.0 g, 58%）。Add potassium tert-butoxide (10.6 g, 94.1 mmol) and tetrahydrofuran (240 mL) into the reaction flask, cool to 0°C, and add tert-butyl diethyl phosphoacetate (21.1 g, 64.1 mmol) dropwise, at 0°C After reacting for 20 minutes, a solution of Intermediate 6 (10.0 g, 72.4 mmol) in tetrahydrofuran (50 mL) was added dropwise, and reacted at room temperature for 2 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, stirred and separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography separation (PE:EA = 100:1), a colorless liquid intermediate 7 (10.0 g, 58%) was obtained.
第七步：The seventh step:
中間體8
: (±) 2-((1R,2R,3S,6R,8R)-2-(硝基甲基)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸第三丁酯
將中間體7 (10.0 g, 42.3 mmol)，硝基甲烷 (6.46 g, 106 mmol) 和1,8-二氮雜雙環[5.4.0]十一碳-7-烯 (7.73 g, 50.8 mmol), 50 mL DMSO，依次加入反應瓶中，升溫至90℃反應10小時。向反應液中加入飽和食鹽水 (150 mL)，水相用乙酸乙酯 (100 mL x 2) 萃取，合併有機相，加入水 (100 mL x 2) 洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用矽膠柱層析分離純化 (石油醚/乙酸乙酯 (v/v) = 100:1)，得到無色油狀液體中間體8 （9.8 g，78%）。Intermediate 7 (10.0 g, 42.3 mmol), nitromethane (6.46 g, 106 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.73 g, 50.8 mmol) , 50 mL DMSO were added to the reaction flask in turn, and the temperature was raised to 90°C for 10 hours. Saturated brine (150 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL x 2), the organic phases were combined, washed with water (100 mL x 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced After pressure concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 100:1) to obtain a colorless oily liquid intermediate 8 (9.8 g, 78%).
1 H NMR (400 MHz, CDCl3 ) δ 4.85 (d, 2H), 2.85 (ddd , 1H), 2.61 – 2.53 (m, 1H), 2.51 (t, 2H), 2.33 (dd, 2H), 1.99 (dd, 1H), 1.82 – 1.70 (m, 1H), 1.62 (d, 1H), 1.54 – 1.43 (m, 11H), 1.33 – 1.21 (m, 1H). MS m/z (ESI): 320.3(M+23). 1 H NMR (400 MHz, CDCl 3 ) δ 4.85 (d, 2H), 2.85 (ddd, 1H), 2.61 – 2.53 (m, 1H), 2.51 (t, 2H), 2.33 (dd, 2H), 1.99 ( dd, 1H), 1.82 – 1.70 (m, 1H), 1.62 (d, 1H), 1.54 – 1.43 (m, 11H), 1.33 – 1.21 (m, 1H). MS m/z (ESI): 320.3(M +23).
手性拆分 ： Chiral split :
取中間體8 (2 g)用於拆分，製備條件：儀器：Thar 350 preparative SFC (SFC-9)，層析柱：ChiralPak AD (300×50 mm I.D., 10 µm)；流動相：A：CO2 B：甲醇；梯度：B 25%；流速：200 mL /min；柱溫：38℃。分離後得到兩個光學異構物：峰1 (保留時間：2.3分鐘，0.624 g)，峰2 (保留時間：3.1分鐘，0.636 g) 。Intermediate 8 (2 g) was used for resolution, preparation conditions: instrument: Thar 350 preparative SFC (SFC-9), chromatography column: ChiralPak AD (300×50 mm ID, 10 µm); mobile phase: A: CO 2 B: methanol; gradient: B 25%; flow rate: 200 mL/min; column temperature: 38°C. Two optical isomers were obtained after separation: peak 1 (retention time: 2.3 minutes, 0.624 g), and peak 2 (retention time: 3.1 minutes, 0.636 g).
第八步：The eighth step:
中間體9
: 2-((1S,2S,3R,6S,8S)-2-(氨基甲基)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸第三丁酯
向反應瓶中依次加入中間體8 (峰 2 ) (0.5 g, 2mmol)，甲醇 (10 mL)，六水合二氯化鎳（0.08 g，0.3 mmol），冷卻至0℃，加入硼氫化鈉（0.3 g, 7 mmol），室溫反應2小時。加入水（50 mL），用二氯甲烷（100 mL × 2）萃取，加入硫酸鈉乾燥，過濾，濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v)=40:1-10:1)，得到白色固體中間體9 （0.46 g, 100%）。MS m/z (ESI): 268.3 (M+1)。 Intermediate 8 ( peak 2 ) (0.5 g, 2mmol), methanol (10 mL), nickel dichloride hexahydrate (0.08 g, 0.3 mmol) were sequentially added to the reaction flask, cooled to 0°C, and sodium borohydride ( 0.3 g, 7 mmol), react at room temperature for 2 hours. Add water (50 mL), extract with dichloromethane (100 mL × 2), add sodium sulfate to dry, filter, and concentrate. The residue is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40 :1-10:1) to obtain Intermediate 9 (0.46 g, 100%) as a white solid. MS m/z (ESI): 268.3 (M+1).
第九步：Step 9:
中間體10
: 2-((1S,2S,3R,6S,8S)-2-(氨甲基)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸
向反應瓶中依次加入中間體9 （0.46 g），二氯甲烷 (4 mL)，三氟乙酸（2 mL），室溫反應2小時。濃縮至乾，加入二氯甲烷(30 mL)，加入三乙胺調至pH 為7-8，析出固體，濾出固體，用二氯甲烷(30 mL)沖洗濾餅，真空乾燥，得到白色固體中間體10 （0.23 g, 70%）。 Intermediate 9 (0.46 g), dichloromethane (4 mL), and trifluoroacetic acid (2 mL) were sequentially added to the reaction flask, and reacted at room temperature for 2 hours. Concentrate to dryness, add dichloromethane (30 mL), add triethylamine to adjust the pH to 7-8, precipitate a solid, filter the solid, rinse the filter cake with dichloromethane (30 mL), and dry in vacuo to obtain a white solid Intermediate 10 (0.23 g, 70%).
1 H NMR (400 MHz, MeOD) δ 3.10 (d, 2H), 2.83 (d, 1H), 2.59 – 2.36 (m, 3H), 2.30 (d, 1H), 2.06 (dd, 1H), 1.96 (dd, 1H), 1.67 (dt, 4H), 1.30 – 1.20 (m, 1H). MS m/z (ESI): 212.2(M+1)。 1 H NMR (400 MHz, MeOD) δ 3.10 (d, 2H), 2.83 (d, 1H), 2.59 – 2.36 (m, 3H), 2.30 (d, 1H), 2.06 (dd, 1H), 1.96 (dd , 1H), 1.67 (dt, 4H), 1.30 – 1.20 (m, 1H). MS m/z (ESI): 212.2(M+1).
第十步：The tenth step:
中間體11
: 2-((1S,2S,3R,6S,8S)-2-(((第三丁氧羰基)氨基)甲基)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸
向反應瓶中依次加入中間體10 （0.2 g, 0.95 mmol），四氫呋喃（10 mL），氫氧化鈉（0.087 g, 2.2 mmol）的水（5 mL）溶液，加入二碳酸二第三丁酯（0.23 g, 1.0 mmol）的四氫呋喃（5 mL）溶液，室溫反應2 h。補加氫氧化鈉（0.045 g），二碳酸二第三丁酯（0.12 g），繼續室溫反應1 h。加入水（50 mL），用石油醚：乙酸乙酯（5/1）（25 mL）洗滌三次，加磷酸二氫鈉飽和溶液，用乙酸乙酯(50 mL × 3)萃取，合併有機相，加入硫酸鈉乾燥，過濾，濃縮。加入環己烷（10 mL），加熱至回流溶解，冷卻至室溫，析出白色固體中間體11 (0.2 g,70%)。MS m/z (ESI): 334.2(M+23). Add Intermediate 10 (0.2 g, 0.95 mmol), tetrahydrofuran (10 mL), sodium hydroxide (0.087 g, 2.2 mmol) in water (5 mL) to the reaction flask, and add di-tert-butyl dicarbonate ( 0.23 g, 1.0 mmol) in tetrahydrofuran (5 mL) solution, react at room temperature for 2 h. Add sodium hydroxide (0.045 g) and di-tertiary butyl dicarbonate (0.12 g), and continue to react at room temperature for 1 h. Add water (50 mL), wash with petroleum ether: ethyl acetate (5/1) (25 mL) three times, add saturated sodium dihydrogen phosphate solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, Add sodium sulfate to dry, filter, and concentrate. Add cyclohexane (10 mL), heat to reflux to dissolve, cool to room temperature, and precipitate a white solid intermediate 11 (0.2 g, 70%). MS m/z (ESI): 334.2(M+23).
第十一步：The eleventh step:
產物12
: 2-((1S,2S,3R,6S,8S)-2-(氨甲基)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸苯磺酸鹽
向反應瓶中依次加入中間體11 （0.2 g, 0.64mmol），苯磺酸一水合物(0.2 g, 1.3 mmol)，加入水（10 mL），加熱至120℃反應2 h。冷卻至室溫，析出固體，用二氯甲烷（30 mL）打漿3次，過濾，得到白色固體產物12 （0.11 g, 46%）。Into the reaction flask were added Intermediate 11 (0.2 g, 0.64 mmol), benzenesulfonic acid monohydrate (0.2 g, 1.3 mmol), water (10 mL), and heated to 120°C for 2 h. After cooling to room temperature, a solid precipitated out, which was slurried 3 times with dichloromethane (30 mL) and filtered to obtain a white solid product 12 (0.11 g, 46%).
1 H NMR (400 MHz, MeOD) δ 7.97 – 7.73 (m, 2H), 7.42 (dd, 3H), 3.34 (s, 2H), 2.90 – 2.81 (m, 1H), 2.55 (d, 2H), 2.52 – 2.42 (m, 1H), 2.40 – 2.27 (m, 1H), 2.14 (dd, 1H), 2.02 (dd, 1H), 1.82 – 1.72 (m, 1H), 1.67 (s, 1H), 1.58 (s, 2H), 1.32 – 1.24 (m, 1H).MS m/z (ESI): 212.2(M+1)。 1 H NMR (400 MHz, MeOD) δ 7.97 – 7.73 (m, 2H), 7.42 (dd, 3H), 3.34 (s, 2H), 2.90 – 2.81 (m, 1H), 2.55 (d, 2H), 2.52 – 2.42 (m, 1H), 2.40 – 2.27 (m, 1H), 2.14 (dd, 1H), 2.02 (dd, 1H), 1.82 – 1.72 (m, 1H), 1.67 (s, 1H), 1.58 (s , 2H), 1.32 – 1.24 (m, 1H). MS m/z (ESI): 212.2(M+1).
實施例2
第一步：first step:
中間體13
: (±) 2-((1S,2S,3R,6S,8S)-2-(硝基甲基-d2
)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸第三丁酯
將中間體8 (峰2) (3.0 g, 10.1 mmol)，溶於THF (10 mL)中，加入氘水 (30 mL)和三乙胺 (1.0 g, 10.1 mmol)，升溫至80℃反應120小時。反應液用乙酸乙酯 (60 mL × 2）萃取，有機相合併，用飽和氯化銨水溶液 (60 mL)洗滌，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物經HPLC純化得到無色油狀液體中間體13 (1.57 g, 52%產率)。MS m/z (ESI): 322.2 (M+23).Intermediate 8 (peak 2) (3.0 g, 10.1 mmol) was dissolved in THF (10 mL), deuterium water (30 mL) and triethylamine (1.0 g, 10.1 mmol) were added, and the temperature was raised to 80°C to react 120 Hour. The reaction solution was extracted with ethyl acetate (60 mL × 2), the organic phases were combined, washed with saturated aqueous ammonium chloride (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to obtain a colorless oil Liquid Intermediate 13 (1.57 g, 52% yield). MS m/z (ESI): 322.2 (M+23).
第二步：The second step:
中間體14
: 2-((1S,2S,3R,6S,8S)-2-(氨基甲基-d2
)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸第三丁酯
向反應瓶中依次加入中間體-13 (1.57 g, 5.2 mmol)，甲醇 (10 mL)，六水合二氯化鎳（0.25 g, 1.1 mmol），冷卻至0℃，加入硼氫化鈉（0.8 g, 21.0 mmol），室溫反應2小時。加入水（50 mL），用二氯甲烷（100 mL × 2）萃取，加入硫酸鈉乾燥，過濾，濃縮，殘留物用矽膠柱層析分離純化(二氯甲烷/甲醇(v/v) = 40:1-10:1)，得到白色固體中間體14 -（1.20 g, 85%）。MS m/z (ESI): 270.3 (M+1)。 Add Intermediate-13 (1.57 g, 5.2 mmol), methanol (10 mL), nickel dichloride hexahydrate (0.25 g, 1.1 mmol) to the reaction flask in sequence, cool to 0°C, add sodium borohydride (0.8 g , 21.0 mmol), react at room temperature for 2 hours. Add water (50 mL), extract with dichloromethane (100 mL × 2), add sodium sulfate to dry, filter, and concentrate. The residue is separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 40 :1-10:1) to obtain a white solid intermediate 14- (1.20 g, 85%). MS m/z (ESI): 270.3 (M+1).
第三步：third step:
產物15
: 2-((1S,2S,3R,6S,8S)-2-(氨基甲基-d2
)三環[4.2.1.03,8
]壬烷-2-基-4,4-d2
)乙酸苯磺酸鹽
向反應瓶中依次加入中間體14 （1.2 g, 4.5 mmol），苯磺酸一水合物(1.0 g, 5.8 mmol),甲苯（5 mL），加熱至90℃反應2 h。加入水（10 mL），甲醇（8 mL），加熱至100℃，攪拌15 min，冷卻至室溫，析出固體，過濾，得到白色固體產物15 （1.1 g, 67%）。 Intermediate 14 (1.2 g, 4.5 mmol), benzenesulfonic acid monohydrate (1.0 g, 5.8 mmol), and toluene (5 mL) were sequentially added to the reaction flask and heated to 90°C for 2 h. Add water (10 mL) and methanol (8 mL), heat to 100°C, stir for 15 min, cool to room temperature, precipitate a solid, and filter to obtain a white solid product 15 (1.1 g, 67%).
1 H NMR (400 MHz, MeOD) δ 7.83 (dt , 2H), 7.58 – 7.25 (m, 3H), 2.86 (dd, 1H), 2.56 (t, 2H), 2.51 – 2.44 (m, 1H), 2.36 – 2.29 (m, 1H), 2.14 (dd, 1H), 2.02 (dd, 1H), 1.84 – 1.72 (m, 1H), 1.68 (d, 1H), 1.57 (d, 2H), 1.33 – 1.21 (m, 1H). MS m/z (ESI): 214.2(M+1)。 1 H NMR (400 MHz, MeOD) δ 7.83 (dt, 2H), 7.58 – 7.25 (m, 3H), 2.86 (dd, 1H), 2.56 (t, 2H), 2.51 – 2.44 (m, 1H), 2.36 – 2.29 (m, 1H), 2.14 (dd, 1H), 2.02 (dd, 1H), 1.84 – 1.72 (m, 1H), 1.68 (d, 1H), 1.57 (d, 2H), 1.33 – 1.21 (m , 1H). MS m/z (ESI): 214.2(M+1).
生物測試Biological test
1、化合物對鈣離子通道蛋白Cavα2δ的競爭結合能力測試1. Competitive binding ability test of the compound to calcium channel protein Cavα2δ
取大鼠大腦皮質組織於10倍體積 (w/v)冰冷的0.32 M蔗糖/5 mMTris-乙酸 (pH 7.4)，勻漿後，蔗糖密度梯度離心法製備突觸質膜，保存於Tris-乙酸 (pH 7.4)緩衝液，臨用前重新懸浮於10 mM HEPES (pH 7.4)緩衝液。測試化合物溶於1% DMSO，並稀釋成梯度濃度 (1 nM－1000 nM)，與20 nM [3H]加巴噴丁一起加入突觸質膜懸浮液 (约0.05－0.1 mg總蛋白質)，25℃孵育30分鐘。反應結束後反應體系經真空過濾至Whatman GFB 濾膜，濾膜以5 mL 100 mM冰冷的氯化鈉溶液洗3次，液閃基數測定濾膜的放射性。非特異結合以100 M加巴噴丁封閉。計算化合物（產物15 ）對放射標記加巴噴丁與突觸質膜的結合的抑制率，並計算化合物的IC50 （見表1）。Take the rat cerebral cortex tissue in 10 times the volume (w/v) of ice-cold 0.32 M sucrose/5 mMTris-acetic acid (pH 7.4), homogenize, prepare the synaptic plasma membrane by sucrose density gradient centrifugation, and store it in Tris-acetic acid (pH 7.4) buffer, resuspend in 10 mM HEPES (pH 7.4) buffer just before use. The test compound was dissolved in 1% DMSO and diluted to a gradient concentration (1 nM-1000 nM), and 20 nM [3H] gabapentin was added to the synaptic plasma membrane suspension (about 0.05-0.1 mg total protein), and incubated at 25°C for 30 minute. After the reaction, the reaction system was vacuum filtered to a Whatman GFB filter membrane, the filter membrane was washed 3 times with 5 mL of 100 mM ice-cold sodium chloride solution, and the radioactivity of the filter membrane was determined by the liquid scintillation base. Non-specific binding was blocked with 100 M gabapentin. Calculate the inhibitory rate of the compound (product 15 ) on the binding of radiolabeled gabapentin to the synaptic plasma membrane, and calculate the IC 50 of the compound (see Table 1).
表1
結論：本發明化合物具有較好的對鈣離子通道蛋白Cavα2δ的競爭結合能力。Conclusion: The compound of the present invention has good competitive binding ability to calcium channel protein Cavα2δ.
2、L5-L6脊神經結紮動物模型 (SNL)2. L5-L6 spinal nerve ligation animal model (SNL)
在動物手術環境下將6-7周齡的SD雄性大鼠 (購自維通利華) 使用5%異氟烷進行麻醉。將麻醉的動物俯臥位放置，在第5腰椎處切口，打開皮膚暴露出左側椎旁肌肉，並逐層撕裂暴露出L5和L6脊神經。使用4-0手術絲線結紮L5和L6背根神經節遠端。逐層縫合肌肉和皮膚，動物恢復一周。6-7 weeks old SD male rats (purchased from Vitonlivar) were anesthetized with 5% isoflurane in an animal surgery environment. Place the anesthetized animal in the prone position, make an incision at the 5th lumbar vertebrae, open the skin to expose the left paravertebral muscles, and tear layer by layer to expose the L5 and L6 spinal nerves. Use 4-0 surgical silk thread to ligate the distal end of L5 and L6 dorsal root ganglia. The muscles and skin were sutured layer by layer, and the animal recovered for a week.
待動物模型恢復後，採用Von Frey絲 (DanMic Global；USA) 測試動物的接觸性疼痛。並用「上下法」來衡量動物有50%縮腿反應的力度 (g；50% PWT)。首先，選取50% PWT力度為1-5 g的動物入組。給藥前測試動物的基線值，接著口服給予不同化合物 (產物12 和產物15 ， 使用5%羧甲基纖維素鈉配製)，在1.0 g-15 g的測試範圍內測試不同時間點動物的疼痛反應。After the animal model recovered, Von Frey silk (DanMic Global; USA) was used to test the animal's contact pain. And use the "up and down method" to measure the strength of the animal's 50% leg-shrinking response (g; 50% PWT). First, select animals with a 50% PWT strength of 1-5 g into the group. Test the animal's baseline value before administration, and then orally administer different compounds (product 12 and product 15 , formulated with 5% sodium carboxymethyl cellulose), and test the animal's pain at different time points within the test range of 1.0 g-15 g reaction.
結論：實驗結果顯示，本發明化合物能明顯抑制大鼠脊神經結紮引起的機械痛覺超敏。Conclusion: The experimental results show that the compound of the present invention can significantly inhibit mechanical hyperalgesia caused by spinal nerve ligation in rats.
3、藥代動力學評價3. Pharmacokinetic evaluation
雄性SD大鼠 (購自維通利華實驗動物有限公司) 180-240 g，禁食給水過夜，3隻大鼠口服灌胃10 mg/kg，3隻大鼠靜脈注射5 mg/kg。口服給藥組，化合物（產物12 和產物15 ）以0.5%甲基纖維素 (MC) 溶液配製成1.0 mg/mL的混懸液，在給藥前和在給藥後30分鐘以及1、2、4、6、8、12和24小時採血各200 μL；靜脈給藥組，化合物（產物12 和產物15 ）以生理鹽水配製成1.0 mg/mL的溶液，在給藥前和在給藥後5、15和30分鐘以及1、2、4、8、12和24小時採血，採集的樣品均肝素抗凝。血樣5500 轉/分鐘離心10分鐘，收集血漿，於-20℃保存。取各時間點大鼠血漿10 μL，加入含內標的乙腈溶液500 μL混合後，渦旋混合10分鐘，3700轉/分鐘離心18分鐘，取上清液50 μL與100 μL水混合，渦旋混合10分鐘，取混和液5 μL進行LC-MS/MS分析，測定原形藥物的血藥濃度。主要藥代動力學參數用WinNonlin 6.3軟體非房室模型分析。Male SD rats (purchased from Weitong Lihua Laboratory Animal Co., Ltd.) 180-240 g, fasted overnight with water, 3 rats orally gavage 10 mg/kg, 3 rats intravenously injected 5 mg/kg. In the oral administration group, the compounds (product 12 and product 15 ) were formulated into a 1.0 mg/mL suspension with a 0.5% methylcellulose (MC) solution, before and 30 minutes after the administration, and 1, 200 μL of blood was collected at 2, 4, 6, 8, 12, and 24 hours; in the intravenous administration group, the compound (product 12 and product 15 ) was formulated into a 1.0 mg/mL solution with physiological saline, and before and after the administration Blood was collected at 5, 15 and 30 minutes and at 1, 2, 4, 8, 12 and 24 hours after the administration. The collected samples were all anticoagulated with heparin. The blood sample was centrifuged at 5500 rpm for 10 minutes, and the plasma was collected and stored at -20°C. Take 10 μL of rat plasma at each time point, add 500 μL of acetonitrile solution containing internal standard to mix, vortex for 10 minutes, centrifuge at 3700 rpm for 18 minutes, take 50 μL of supernatant and mix with 100 μL of water, vortex to mix In 10 minutes, take 5 μL of the mixed solution for LC-MS/MS analysis to determine the plasma concentration of the original drug. The main pharmacokinetic parameters were analyzed by WinNonlin 6.3 software non-compartmental model.
結論：本發明化合物表現出良好的藥代動力學性質。Conclusion: The compound of the present invention shows good pharmacokinetic properties.
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| Application Number | Title | Priority Date | Filing Date |
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| TW108148256A TWI738162B (en) | 2019-01-30 | 2019-12-30 | Condensed tricyclic deuterated derivatives and their compositions and uses |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN113316564B (en) |
| TW (1) | TWI738162B (en) |
| WO (1) | WO2020155953A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| TW202535348A (en) * | 2024-01-08 | 2025-09-16 | 大陸商海思科醫藥集團股份有限公司 | Use of a fused tricyclic γ-amino acid derivative in treating central nervous system pathological pain |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018050046A1 (en) * | 2016-09-14 | 2018-03-22 | 四川海思科制药有限公司 | Fused tricyclic γ-amino acid derivative, preparation method therefor, and medical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2374595A (en) * | 2001-04-19 | 2002-10-23 | Warner Lambert Co | Fused bicyclic or tricyclic amino acids |
| CN106928080B (en) * | 2015-12-31 | 2020-12-25 | 四川海思科制药有限公司 | Fused ring gamma-amino acid derivative, preparation method and application thereof in medicine |
| WO2017114225A1 (en) * | 2015-12-31 | 2017-07-06 | 四川海思科制药有限公司 | Fused tricyclic γ-amino acid derivative and preparation method and pharmaceutical application thereof |
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2019
- 2019-12-25 CN CN201980064626.XA patent/CN113316564B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018050046A1 (en) * | 2016-09-14 | 2018-03-22 | 四川海思科制药有限公司 | Fused tricyclic γ-amino acid derivative, preparation method therefor, and medical use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113316564B (en) | 2023-06-09 |
| WO2020155953A1 (en) | 2020-08-06 |
| CN113316564A (en) | 2021-08-27 |
| TW202028172A (en) | 2020-08-01 |
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