TW202330470A - Synthetic cannabinoid compounds, pharmaceutical compositions, and treatment methods - Google Patents

Synthetic cannabinoid compounds, pharmaceutical compositions, and treatment methods Download PDF

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TW202330470A
TW202330470A TW111145292A TW111145292A TW202330470A TW 202330470 A TW202330470 A TW 202330470A TW 111145292 A TW111145292 A TW 111145292A TW 111145292 A TW111145292 A TW 111145292A TW 202330470 A TW202330470 A TW 202330470A
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alkyl
group
independently selected
heteroaryl
aryl
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TW111145292A
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Chinese (zh)
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老強尼 Ｒ 威廉斯
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美商米拉洛克斯有限責任公司
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract

Cannabinoid derivatives may exhibit anti-inflammatory properties such as by inhibition of cannabinoid type 2 (CB 2) receptors. Pharmaceutical compositions comprising the cannabinoid derivatives may be used to treat various diseases and conditions in mammals, including pain, anxiety, a sleep disorder, addiction, epilepsy, depression, or Alzheimer's disease.

Description

合成大麻素化合物、醫藥組合物及治療方法Synthetic cannabinoid compounds, pharmaceutical compositions and methods of treatment

近年來已對大麻的治療作用進行了大量研究，包括其成分四氫大麻酚(tetrahydrocannabinol，THC)及大麻二酚(cannabidiol，CBD)。仍需要用於治療諸如以下病症的經改良化合物：抑鬱、焦慮、物質成癮、睡眠障礙、疼痛、癌症、自體免疫病症及與慢性發炎相關之其他病症。尤其需要研發可以合成方式製備且調配為固體經口劑型的化合物。In recent years, a lot of research has been done on the therapeutic effects of cannabis, including its constituents tetrahydrocannabinol (THC) and cannabidiol (CBD). There remains a need for improved compounds for the treatment of conditions such as depression, anxiety, substance addiction, sleep disorders, pain, cancer, autoimmune disorders and other conditions associated with chronic inflammation. In particular, there is a need to develop compounds that can be prepared synthetically and formulated into solid oral dosage forms.

根據一個態樣，合成大麻素衍生物具有式(I)之結構： 式(I) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 各 表示單鍵或雙鍵，其限制條件為在5員環內，一個 為雙鍵且其他四個 為單鍵； 或其醫藥學上可接受之鹽或酯。 According to one aspect, the synthetic cannabinoid derivative has the structure of formula (I): Formula (I) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent is selected from hydrogen and C 1-4 alkyl; each Indicates a single bond or a double bond, with the restriction that in a 5-membered ring, one is a double bond and the other four is a single bond; or a pharmaceutically acceptable salt or ester thereof.

根據另一態樣，一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(I)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。According to another aspect, a method of treating cancer, tumor, addiction, epilepsy, anxiety or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (I) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

在一些態樣中，合成大麻素衍生物具有式(IA)之結構： 式(IA) 其中R 1、R 2及R 3係如先前所定義。 In some aspects, the synthetic cannabinoid derivative has the structure of formula (IA): Formula (IA) wherein R 1 , R 2 and R 3 are as previously defined.

根據另一態樣，一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(IA)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。According to another aspect, a method of treating cancer, tumor, addiction, epilepsy, anxiety or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (IA) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

根據其他態樣，合成大麻素衍生物具有式(II)之結構： 式(II) 其中R 1、R 2、R 3及 係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to other aspects, the synthetic cannabinoid derivative has the structure of formula (II): Formula (II) wherein R 1 , R 2 , R 3 and is as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在另一態樣中，治療焦慮、成癮、抑鬱或阿茲海默氏症(Alzheimer's disease)之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(II)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。In another aspect, a method of treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of the formula ( II) Synthetic cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

根據其他態樣，合成大麻素衍生物具有式(IIA)之結構： 式(IIA) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to other aspects, the synthetic cannabinoid derivative has the structure of formula (IIA): Formula (IIA) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在另一態樣中，治療焦慮、成癮、抑鬱或阿茲海默氏症之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(IIA)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。In another aspect, a method of treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (IIA) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

在另一態樣中，醫藥組合物包含治療有效量的式(I)、(IA)、(II)或(IIA)之合成大麻素衍生物或其組合，及針對該等化合物之醫藥學上可接受之載劑。In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid derivative of formula (I), (IA), (II) or (IIA) or a combination thereof, and a pharmaceutically effective acceptable carrier.

根據另一態樣，合成大麻素衍生物具有式(III)之結構： 式(III) 其中R 1、R 2、R 3及 係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to another aspect, the synthetic cannabinoid derivative has the structure of formula (III): Formula (III) wherein R 1 , R 2 , R 3 and is as previously defined, or a pharmaceutically acceptable salt or ester thereof.

根據另一態樣，一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(III)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。According to another aspect, a method of treating cancer, tumor, addiction, epilepsy, anxiety or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (III) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

在一些態樣中，合成大麻素衍生物具有式(IIIA)之結構： 式(IIIA) 其中R 1、R 2及R 3係如先前所定義。 In some aspects, the synthetic cannabinoid derivative has the structure of Formula (IIIA): Formula (IIIA) wherein R 1 , R 2 and R 3 are as previously defined.

根據另一態樣，一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(IIIA)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。According to another aspect, a method of treating cancer, tumor, addiction, epilepsy, anxiety or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (IIIA) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

根據其他態樣，合成大麻素衍生物具有式(IV)之結構： 式(IV) 其中R 1、R 2、R 3及 係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to other aspects, the synthetic cannabinoid derivative has the structure of formula (IV): Formula (IV) wherein R 1 , R 2 , R 3 and is as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在另一態樣中，治療焦慮、成癮、抑鬱或阿茲海默氏症之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(IV)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。In another aspect, a method of treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (IV) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

在其他態樣中，合成大麻素衍生物具有式(IVA)之結構： 式(IVA) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯。 In other aspects, the synthetic cannabinoid derivative has the structure of formula (IVA): Formula (IVA) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在另一態樣中，治療焦慮、成癮、抑鬱或阿茲海默氏症之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(IVA)之合成大麻素衍生物及針對該化合物之醫藥學上可接受之載劑。In another aspect, a method of treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (IVA) Cannabinoid derivatives and pharmaceutically acceptable carriers for the compounds.

在另一態樣中，醫藥組合物包含治療有效量的式(III)、(IIIA)、(IV)或(IVA)之合成大麻素衍生物或其組合，及針對該化合物之醫藥學上可接受之載劑。In another aspect, a pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid derivative of formula (III), (IIIA), (IV) or (IVA) or a combination thereof, and a pharmaceutically acceptable Accepted carrier.

在另一態樣中，合成大麻素衍生物具有式(V)之結構： 式(V) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯。 In another aspect, the synthetic cannabinoid derivative has the structure of formula (V): Formula (V) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof.

根據另一態樣，一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(V)之合成大麻素衍生物或其醫藥學上可接受之鹽及針對該化合物之醫藥學上可接受之載劑。According to another aspect, a method of treating cancer, tumor, addiction, epilepsy, anxiety or depression comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (V) A cannabinoid derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the compound.

根據另一態樣，合成大麻素衍生物具有式(VI)之結構： 式(VI) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to another aspect, the synthetic cannabinoid derivative has the structure of formula (VI): Formula (VI) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在另一態樣中，治療焦慮、成癮、抑鬱或阿茲海默氏症之方法包含向有需要之個體投與醫藥組合物，該醫藥組合物包含治療有效量的式(VI)之合成大麻素衍生物或其醫藥學上可接受之鹽及針對該化合物之醫藥學上可接受之載劑。In another aspect, a method of treating anxiety, addiction, depression, or Alzheimer's disease comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a synthetic compound of formula (VI) A cannabinoid derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the compound.

在另一態樣中，醫藥組合物包含治療有效量的式(V)或式(VI)之合成大麻素衍生物或其醫藥學上可接受之鹽，及針對該化合物之醫藥學上可接受之載劑。In another aspect, the pharmaceutical composition comprises a therapeutically effective amount of a synthetic cannabinoid derivative of formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

在一些實施例中，本文所揭示之化合物可用於治療與單胺氧化酶(monoamine oxidase，MAO)活性相關之疾病及病狀的方法中。在一些實施例中，個體罹患抑鬱、疼痛或成癮。在一些實施例中，治療與單胺氧化酶(MAO)活性相關之疾病及病狀的方法包含向有需要之個體投與醫藥組合物，其中該醫藥組合物包含具有式(VI)之結構的化合物： 其中R1及R2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NRARB、-S-烷基、-SO-烷基、-SO2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中RA及RB各自獨立地選自氫及C1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C1-4烷基、-C(O)O-C1-4烷基、NRCRD、-S-烷基、-SO-烷基及-SO2-烷基；其中RC及RD各自獨立地選自氫及C1-4烷基；R3係選自由以下組成之群：H、烷基、醯基、-SO2-烷基、-SO2-芳基及-SO2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NRERF、-S-烷基、-SO-烷基、-SO2-烷基、芳基及雜芳基；且其中RE及RF各自獨立地選自氫及C1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NRGRH、-S-烷基、-SO-烷基及-SO2-烷基；其中RG及RH各自獨立地選自氫及C1-4烷基；或其醫藥學上可接受之鹽或酯，其限制條件為該化合物不為2,4,4-三甲基-7-戊基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。 In some embodiments, the compounds disclosed herein are useful in methods of treating diseases and conditions associated with monoamine oxidase (MAO) activity. In some embodiments, the individual suffers from depression, pain, or addiction. In some embodiments, methods of treating diseases and conditions associated with monoamine oxidase (MAO) activity comprise administering to a subject in need thereof a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound having the structure of Formula (VI): Wherein R1 and R2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein The alkyl, alkenyl, alkynyl or acyl group is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NRARB, -S -Alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein RA and RB are each independently selected from hydrogen and C1-4 Alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O- Alkyl, -COOH, -C(O)-C1-4alkyl, -C(O)O-C1-4alkyl, NRCRD, -S-alkyl, -SO-alkyl and -SO2-alkyl ; wherein RC and RD are each independently selected from hydrogen and C1-4 alkyl; R3 is selected from the group consisting of: H, alkyl, acyl, -SO2-alkyl, -SO2-aryl and -SO2- Heteroaryl; wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NRERF, -S-alkyl, -SO-alkyl, -SO2-alkyl, aryl and heteroaryl; and wherein RE and RF are each independently selected from hydrogen and C1-4 alkyl; wherein the aryl or Heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRGRH, -S-alkyl, -SO-alkyl and -SO2-alkyl; wherein RG and RH are each independently selected from hydrogen and C1-4 alkyl; or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 2,4,4- Trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]methen-9-ol.

在一些實施例中，用於治療MOA相關之疾病或病狀的醫藥組合物包含2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。In some embodiments, a pharmaceutical composition for treating a disease or condition associated with MOA comprises 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[ c] methene-9-ol.

在一些實施例中，本文所揭示之化合物包含： 或其醫藥學上可接受之鹽或酯。 In some embodiments, compounds disclosed herein comprise: or a pharmaceutically acceptable salt or ester thereof.

在一些實施例中，本發明係關於一種治療睡眠障礙之方法，其中該方法包含投與有效量的本文所揭示之化合物或醫藥組合物。在一些實施例中，治療睡眠障礙之方法包含向有需要之個體投與以下化合物中之一或多者： 或其醫藥學上可接受之鹽或酯。 In some embodiments, the present invention relates to a method of treating sleep disorders, wherein the method comprises administering an effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the method of treating sleep disorders comprises administering to an individual in need thereof one or more of the following compounds: or a pharmaceutically acceptable salt or ester thereof.

相關申請案之交互參考 本申請案主張根據35 U. S. C. §119的2022年9月2日申請之美國臨時申請案63/403544及2021年11月27日申請之美國臨時申請案63/283431的優先權，該申請案之內容特此以全文引用之方式併入。 Cross-references to related applications This application claims priority under 35 U.S.C. §119 to U.S. Provisional Application 63/403544, filed September 2, 2022, and U.S. Provisional Application 63/283431, filed November 27, 2021, the contents of which It is hereby incorporated by reference in its entirety.

由印度大麻( Cannabis sativa)植物產生之大麻素具有治療各種類別之疾病及其他人類病痛之潛能。多於100種不同大麻素已自大麻分離且各大麻素化合物展現各種作用。例如，THC因其精神作用(psychological effect)而熟知且CBD因其非精神作用(non-psychoactive effect)而得知。THC及相關衍生物通常經由發現於人類及其他哺乳動物中之大麻素受體發揮治療活性。CBD為THC之異構體。CBD及CBD衍生物亦通過與大麻素受體無關之路徑展現抗氧化及抗炎作用。大麻素1型(CB 1)受體主要發現於腦，包括基底神經節中及邊緣系統及海馬體及紋狀體以及小腦中。CB 1受體可見於人類前眼及視網膜中。研究指示大麻素2型(CB 2)受體負責抗炎及與大麻素相關之其他治療作用。 Cannabinoids produced by the Indian cannabis ( Cannabis sativa ) plant have the potential to treat various types of diseases and other human afflictions. More than 100 different cannabinoids have been isolated from cannabis and each cannabinoid compound exhibits various effects. For example, THC is known for its psychological effects and CBD for its non-psychoactive effects. THC and related derivatives generally exert their therapeutic activity through cannabinoid receptors found in humans and other mammals. CBD is an isomer of THC. CBD and CBD derivatives also exhibit antioxidant and anti-inflammatory effects through pathways independent of cannabinoid receptors. Cannabinoid type 1 (CB 1 ) receptors are primarily found in the brain, including the basal ganglia and limbic system and the hippocampus and striatum, as well as the cerebellum. CB 1 receptors are found in the human anterior eye and retina. Studies indicate that the cannabinoid type 2 (CB 2 ) receptor is responsible for the anti-inflammatory and other therapeutic effects associated with cannabinoids.

含有高含量大麻素之大麻(cannabis)植物，諸如THC例如通常稱為「毒品大麻(marijuana)」植物。具有低大麻素含量之大麻植物分類為「工業大麻(hemp)」植物。個別國家通常確定大麻素之含量以區分分類為毒品大麻植物或工業大麻植物的大麻植物。一般而言，分類為工業大麻植物之大麻植物以乾重計的THC含量為0.3%或更低。具有大於0.3%之THC、CBD及其他大麻素內含物含量的印度大麻植物通常視為毒品大麻植物。醫用毒品大麻通常含有5與20%之間的大麻素含量。其他印度大麻植物可產生25至30%之大麻素含量。Cannabis plants containing high levels of cannabinoids, such as THC for example are commonly referred to as "marijuana" plants. Cannabis plants with low cannabinoid content are classified as "hemp" plants. Individual countries usually determine the cannabinoid content to distinguish between cannabis plants classified as narcotic cannabis plants or industrial cannabis plants. Generally, hemp plants classified as industrial hemp plants have a THC content of 0.3% or less on a dry weight basis. Indian cannabis plants having THC, CBD and other cannabinoid content greater than 0.3% are generally considered drug cannabis plants. Medical drug marijuana usually contains between 5 and 20% cannabinoid content. Other Indian cannabis plants can yield 25 to 30 percent cannabinoid content.

產生各種大麻素之印度大麻植物的生物合成路徑開始於前驅型大麻萜酚酸(cannabigerolic acid)。酶，即THCA合成酶及CBDA合成酶分別催化大麻萜酚酸至四氫大麻酚酸(THCA)及大麻二酚酸(CBDA)以及其他大麻素之生物合成。已知各種其他大麻素係經由此路徑產生。THC、CBD及其他大麻素衍生物係藉由非酶素性去羧反應(non-enzymatic decarboxylation)自THCA及CBDA人工產生。Aizpurua-Olaizola等人,「Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes」, J. Natural Prods.2016 79 (2), 324-331。各類大麻素經由此通用路徑生物合成以包括四氫大麻酚(THC)、四氫大麻酚酸(THCA)、大麻二酚(CBD)、大麻二酚酸(CBDA)、大麻酚(cannabinol，CBN)、大麻萜酚(cannabigerol，CBG)、大麻環萜酚(cannabichromene，CBC)、大麻環酚(cannabicyclol，CBL)、次大麻酚(cannabivarin，CBV)、四氫次大麻酚(tetrahydrocannabivarin，THCV)、次大麻二酚(cannabidivarin，CBDV)、次大麻色酚(cannabichromevarin，CBCV)、次大麻萜酚(cannabigerovarin，CBGV)、大麻萜酚單甲醚(cannabigerol monomethyl ether，CBGM)、大麻艾爾松(cannabielsoin，CBE)及大麻二吡喃環烷(cannabicitran，CBT)。 I. 合成大麻素衍生物 The biosynthetic pathway of the Indian hemp plant that produces the various cannabinoids begins with the precursor cannabigerolic acid. The enzymes, THCA synthase and CBDA synthase, catalyze the biosynthesis of cannabigerolic acid to tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), respectively, and other cannabinoids. Various other cannabinoids are known to be produced via this pathway. THC, CBD and other cannabinoid derivatives are artificially produced from THCA and CBDA by non-enzymatic decarboxylation. Aizpurua-Olaizola et al., "Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes", J. Natural Prods. 2016 79 (2), 324-331. Various cannabinoids are biosynthesized via this common pathway to include tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN ), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), Cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielsoin , CBE) and cannabicitran (CBT). I. Synthetic cannabinoid derivatives

根據一些態樣，合成大麻素衍生物具有式(I)之結構： 式(I) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 各 表示單鍵或雙鍵，其限制條件為在5員環內，一個 為雙鍵且其他四個 為單鍵； 或其醫藥學上可接受之鹽或酯。 According to some aspects, the synthetic cannabinoid derivative has the structure of formula (I): Formula (I) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent is selected from hydrogen and C 1-4 alkyl; each Indicates a single bond or a double bond, with the restriction that in a 5-membered ring, one is a double bond and the other four is a single bond; or a pharmaceutically acceptable salt or ester thereof.

在一些態樣中，合成大麻素衍生物具有式(IA)之結構： 式(IA) 其中R 1、R 2及R 3係如先前所定義。 In some aspects, the synthetic cannabinoid derivative has the structure of Formula (IA): Formula (IA) wherein R 1 , R 2 and R 3 are as previously defined.

在其他實例中，合成大麻素衍生物具有式(II)之結構： 式(II) 其中R 1、R 2、R 3及 係如先前所定義，或其醫藥學上可接受之鹽或酯。 In other examples, synthetic cannabinoid derivatives have the structure of formula (II): Formula (II) wherein R 1 , R 2 , R 3 and is as previously defined, or a pharmaceutically acceptable salt or ester thereof.

根據其他態樣，合成大麻素衍生物具有式(IIA)之結構： 式(IIA) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to other aspects, the synthetic cannabinoid derivative has the structure of formula (IIA): Formula (IIA) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在一些態樣中，合成大麻素衍生物具有式(III)之結構： 式(III) 其中R 1、R 2、R 3及 係如先前所定義，或其醫藥學上可接受之鹽或酯。 In some aspects, the synthetic cannabinoid derivative has the structure of formula (III): Formula (III) wherein R 1 , R 2 , R 3 and is as previously defined, or a pharmaceutically acceptable salt or ester thereof.

在一些態樣中，合成大麻素衍生物具有式(IIIA)之結構： 式(IIIA) 其中R 1、R 2及R 3係如先前所定義。 In some aspects, the synthetic cannabinoid derivative has the structure of Formula (IIIA): Formula (IIIA) wherein R 1 , R 2 and R 3 are as previously defined.

在其他實例中，合成大麻素衍生物具有式(IV)之結構： 式(IV) 其中R 1、R 2、R 3及 係如先前所定義，或其醫藥學上可接受之鹽或酯。 In other examples, synthetic cannabinoid derivatives have the structure of Formula (IV): Formula (IV) wherein R 1 , R 2 , R 3 and is as previously defined, or a pharmaceutically acceptable salt or ester thereof.

根據其他態樣，合成大麻素衍生物具有式(IVA)之結構： 式(IVA) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯。 According to other aspects, the synthetic cannabinoid derivative has the structure of formula (IVA): Formula (IVA) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof.

根據一些態樣，合成大麻素衍生物具有式(V)之結構： 式(V) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 或其醫藥學上可接受之鹽或酯，其限制條件為該化合物不為2-(3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇。 According to some aspects, the synthetic cannabinoid derivative has the structure of formula (V): Formula (V) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent selected from hydrogen and C 1-4 alkyl; or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 2-(3-methyl-5-(prop-1-ene-2 -yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol.

根據其他態樣，合成大麻素衍生物具有式(VI)之結構： 式(VI) 其中R 1、R 2及R 3係如先前所定義，或其醫藥學上可接受之鹽或酯，其限制條件為該化合物不為2,4,4-三甲基-7-戊基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。 According to other aspects, the synthetic cannabinoid derivative has the structure of formula (VI): Formula (VI) wherein R 1 , R 2 and R 3 are as previously defined, or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 2,4,4-trimethyl-7 -Pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]alken-9-ol.

根據其他態樣，合成大麻素衍生物具有以下結構： 或其醫藥學上可接受之鹽或酯。 According to other aspects, the synthetic cannabinoid derivative has the following structure: or a pharmaceutically acceptable salt or ester thereof.

如本文所用，無論單獨或作為取代基一部分的術語「烷基」係指飽和C 1-C n碳鏈，其中碳鏈可為直鏈或分支鏈；其中n可為2、3、4、5、6、7、8、9或10。適合的實例包括但不限於甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、正戊基及正己基。 As used herein, the term "alkyl", whether alone or as part of a substituent, refers to a saturated C 1 -C n carbon chain, wherein the carbon chain may be straight or branched; wherein n may be 2, 3, 4, 5 , 6, 7, 8, 9 or 10. Suitable examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, and n-hexyl.

如本文所用，無論單獨或作為取代基一部分的術語「烯基」係指C 2-C n碳鏈，其中碳鏈可為直鏈或分支鏈，其中碳鏈含有至少一個碳-碳雙鍵，且其中n可為3、4、5、6、7、8、9或10。 As used herein, the term "alkenyl", whether alone or as part of a substituent, refers to a C2 - Cn carbon chain, wherein the carbon chain may be straight or branched, wherein the carbon chain contains at least one carbon-carbon double bond, And wherein n can be 3, 4, 5, 6, 7, 8, 9 or 10.

如本文所用，無論單獨或作為取代基一部分的術語「炔基」係指C 2-C n，其中碳鏈可為直鏈或分支鏈，其中碳鏈含有至少一個碳-碳參鍵，且其中n可為3、4、5、6、7、8、9或10。 As used herein, the term "alkynyl", whether by itself or as part of a substituent, refers to C 2 -C n , wherein the carbon chain may be straight or branched, wherein the carbon chain contains at least one carbon-carbon double bond, and wherein n can be 3, 4, 5, 6, 7, 8, 9 or 10.

如本文所用，無論單獨或作為取代基一部分的術語「芳基」係指未經取代之包含6至14個碳原子的羧酸芳環。適合的實例包括但不限於苯基及萘基。As used herein, the term "aryl", whether alone or as part of a substituent, refers to an unsubstituted carboxylic acid aromatic ring containing 6 to 14 carbon atoms. Suitable examples include, but are not limited to, phenyl and naphthyl.

如本文所用，術語「受保護之羥基」係指經適當選擇之氧保護基取代的羥基。更具體地說，「受保護之羥基」係指式-OPG 1之取代基，其中PG 1為經適當選擇之氧保護基。在用於製備本發明化合物之任何方法期間，可能必需及/或需要保護任何所關注之分子上之敏感性或反應性基團。此可藉助於習知保護基達成，諸如Protective Groups in Organic Chemistry, J. F. W. McOmie編, Plenum Press, 1973；及T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991中所描述之彼等保護基。保護基可在適宜後續階段使用此項技術中已知之方法來移除。 As used herein, the term "protected hydroxy" refers to a hydroxy group substituted with an appropriately selected oxygen protecting group. More specifically, "protected hydroxy" refers to a substituent of formula -OPG 1 , where PG 1 is a suitably selected oxygen protecting group. During any of the methods used to prepare the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any molecule concerned. This can be achieved by means of conventional protecting groups such as those described in Protective Groups in Organic Chemistry, JFW McOmie ed., Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 and other protective groups. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

如本文所用，術語「氧保護基」係指可連接至氧原子以保護該氧原子免於參與反應且可在反應之後容易地移除的基團。適合的氧保護基包括但不限於乙醯基、苯甲醯基、三級丁基-二甲基矽烷基、三甲基矽烷基(TMS)、MOM及THP。其他適合的氧保護基可發現於諸如T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991之文本中。As used herein, the term "oxygen protecting group" refers to a group that can be attached to an oxygen atom to protect the oxygen atom from participating in a reaction and can be easily removed after the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, tert-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, and THP. Other suitable oxygen protecting groups can be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

如本文所用，術語「氮保護基」係指可連接至氮原子以保護該氮原子免於參與反應且可在反應之後容易地移除的基團。適合的氮保護基包括但不限於式-C(O)-OR之胺基甲酸酯基，其中R可為甲基、乙基、三級丁基、苯甲基、苯乙基、CH 2=CH-CH 2-及類似基團；式-C(O)-R'之醯胺基，其中R'可為甲基、苯基、三氟甲基及類似基團；式-SO 2-R''之N-磺醯基衍生物基團，其中R''可為甲苯基、苯基、三氟甲基、2,2,5,7,8-五甲基𠳭烷(pentamethylchroman)-6-基-、2,3,6-三甲基-4-甲氧基苯及類似基團。其他適合的氮保護基可發現於諸如T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991之文本中。 As used herein, the term "nitrogen protecting group" refers to a group that can be attached to a nitrogen atom to protect the nitrogen atom from participating in a reaction and can be easily removed after the reaction. Suitable nitrogen protecting groups include, but are not limited to, carbamate groups of the formula -C(O)-OR, where R can be methyl, ethyl, tert-butyl, benzyl, phenethyl, CH =CH-CH 2 - and similar groups; amido groups of formula -C(O)-R', wherein R' can be methyl, phenyl, trifluoromethyl and similar groups; formula -SO 2 - The N-sulfonyl derivative group of R'', wherein R'' can be tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethyl 𠳭 alkane (pentamethylchroman)- 6-yl-, 2,3,6-trimethyl-4-methoxybenzene and similar groups. Other suitable nitrogen protecting groups can be found in texts such as TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

如本文所用，術語「醯基」係指式-CO-C n之基團，其中C n表示直鏈或分支鏈烷基鏈，其中n可為1、2、3、4、5、6、7、8、9或10。 As used herein, the term "acyl" refers to a group of formula -CO- Cn , wherein Cn represents a straight or branched alkyl chain, wherein n can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

如本文所用，術語「雜芳基」係指任何五員或六員單環芳環結構，其含有至少一個選自由O、N及S組成之群的雜原子且視情況含有一至三個獨立地選自由O、N及S組成之群的額外雜原子；或九員或十員雙環芳環結構，其含有至少一個選自由O、N及S組成之群的雜原子且視情況含有一至四個獨立地選自由O、N及S組成之群的額外雜原子。雜芳基可在環之任何雜原子或碳原子處連接以使得所得物為穩定結構。適合之雜芳基的實例包括但不限於吡咯基、呋喃基、噻吩基、㗁唑基、咪唑基、吡唑基、異㗁唑基、異噻唑基、三唑基、噻二唑基、吡啶基、嗒𠯤基、嘧啶基、吡𠯤基、哌喃基、呋呫基、吲哚𠯤基、吲哚基、異吲哚啉基、吲唑基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噻唑基、嘌呤基、喹𠯤基、喹啉基、異喹啉基、異噻唑基、㖕啉基、呔𠯤基、喹唑啉基、喹㗁啉基、㖠啶基及喋啶基。As used herein, the term "heteroaryl" refers to any five- or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S and optionally containing one to three independently Additional heteroatoms selected from the group consisting of O, N and S; or nine or ten membered bicyclic aromatic ring structures containing at least one heteroatom selected from the group consisting of O, N and S and optionally one to four additional heteroatoms independently selected from the group consisting of O, N and S. Heteroaryl groups may be attached at any heteroatom or carbon atom of the ring such that the resulting structure is a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridine Base, pyridyl, pyrimidyl, pyryl, pyranyl, furyl, indolyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, Benzimidazolyl, benzothiazolyl, purinyl, quinolyl, quinolinyl, isoquinolyl, isothiazolyl, phenolyl, thiazolyl, quinazolinyl, quinazolyl, phenidine base and pteridyl.

如本文所用，術語「環烷基」係指含有四至六個碳原子的任何單環，或含有八至十個碳原子的雙環。環烷基可在環之任何碳原子處連接以使得所得物為穩定結構。適合之環烷基的實例包括但不限於環丙基、環丁基、環戊基及環己基。As used herein, the term "cycloalkyl" refers to any monocyclic ring containing four to six carbon atoms, or a bicyclic ring containing eight to ten carbon atoms. Cycloalkyl groups may be attached at any carbon atom of the ring such that the resulting structure is a stable structure. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

如本文所用，術語「雜環」係指任何四員至六員單環結構，其含有至少一個選自由O、N及S組成之群的雜原子且視情況含有一至三個獨立地選自由O、N及S組成之群的額外雜原子；或八員至十員雙環結構，其含有至少一個選自由O、N及S組成之群的雜原子且視情況含有一至四個獨立地選自由O、N及S組成之群的額外雜原子。雜環基可在環之任何雜原子或碳原子處連接以使得所得物為穩定結構。適合之雜環基的實例包括但不限於氮雜環丁烷(azetidine)、氮唉(azete)、氧雜環丁烷(oxetane)、氧唉(oxete)、硫雜環丁烷(thietane)、硫唉(thiete)、二氮雜環丁烷、二氮唉、二氧雜環丁烷、二氧唉、二硫雜環丁烷、二硫唉、吡咯啶、吡咯、四氫呋喃、呋喃、硫雜環戊烷(thiolane)、噻吩、哌啶、㗁烷、噻烷、吡啶、哌喃及噻哌喃。As used herein, the term "heterocycle" refers to any four- to six-membered monocyclic ring structure containing at least one heteroatom selected from the group consisting of O, N, and S and optionally containing one to three heteroatoms independently selected from O , an additional heteroatom from the group consisting of N and S; or an eight- to ten-membered bicyclic structure containing at least one heteroatom selected from the group consisting of O, N and S and optionally containing one to four heteroatoms independently selected from O , N and S additional heteroatoms of the group. A heterocyclyl group may be attached at any heteroatom or carbon atom of the ring such that the resulting structure is a stable structure. Examples of suitable heterocyclyl groups include, but are not limited to, azetidine, azete, oxetane, oxete, thietane, Sulfur (thiete), diazetidine, diazetidine, dioxetane, dioxetane, dithietane, dithioazine, pyrrolidine, pyrrole, tetrahydrofuran, furan, thia Cyclopentane (thiolane), thiophene, piperidine, oxane, thiane, pyridine, pyran and thiopyran.

如本文所定義，本文所描述之基團可為未經取代的或經取代的。另外，經取代之基團可經一或多個基團取代，諸如C 1-C 6烷基、C 1-4烷基、-O-C 1-4烷基、羥基、胺基、(C 1-4烷基)胺基、二(C 1-4烷基)胺基、-S-(C 1-4烷基)、-SO-(C 1-4烷基)、-SO 2-(C 1-4烷基)、鹵素、芳基、雜芳基及類似基團。 The groups described herein can be unsubstituted or substituted, as defined herein. In addition, a substituted group may be substituted with one or more groups, such as C 1 -C 6 alkyl, C 1-4 alkyl, -OC 1-4 alkyl, hydroxyl, amino, (C 1- 4 alkyl) amino, two (C 1-4 alkyl) amino, -S- (C 1-4 alkyl), -SO- (C 1-4 alkyl), -SO 2 -(C 1 -4 alkyl), halogen, aryl, heteroaryl and similar groups.

參考取代基，術語「獨立地」意謂當此類取代基可能多於一者時，此類取代基可彼此相同或不同。With reference to substituents, the term "independently" means that when more than one such substituent is possible, such substituents may be the same or different from each other.

本發明之化合物可含有至少一個羥基。此等至少一個羥基可與無機或有機酸形成酯。特別地，酸為醫藥學上可接受之酸。酯可形成對掌性碳。本發明係針對本發明化合物之所有立體化學形式，包括藉由形成一或多個酯基形成之彼等形式。 II. 根據本發明之合成大麻素衍生物的非限制性實例 The compounds of the present invention may contain at least one hydroxyl group. These at least one hydroxyl group can form esters with inorganic or organic acids. In particular, the acid is a pharmaceutically acceptable acid. Esters can form chiral carbons. The present invention is directed to all stereochemical forms of the compounds of the invention, including those formed by formation of one or more ester groups. II. Non-limiting examples of synthetic cannabinoid derivatives according to the invention

根據式I、IA、II及IIA之合成大麻素衍生物的非限制性實例係如下所示： Non-limiting examples of synthetic cannabinoid derivatives according to Formulas I, IA, II and IIA are shown below:

根據式III、IIIA、IV及IVA之合成大麻素衍生物的非限制性實例係如下所示： Non-limiting examples of synthetic cannabinoid derivatives according to Formulas III, IIIA, IV and IVA are shown below:

根據式V及VI之合成大麻素衍生物的非限制性實例係如下所示： 5-甲基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-丙基苯-1,3-二醇 5-丁基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 2,4-二羥基-3-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-6-戊基苯甲酸 2,4-二羥基-3-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-6-丙基苯甲酸 3-甲氧基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基酚 5-丁基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 (3R,4R)-3-(2,6-二羥基-4-戊苯基)-4-(丙-1-烯-2-基)環戊-1-烯-1-羧酸 2-((1R,5R)-3-(羥甲基)-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 (2S,3S,4S,5R)-3,4,5-三羥基-6-(3-羥基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯氧基)四氫-2H-哌喃-2-羧酸 6-((1S,2S)-2-(2,6-二羥基-4-甲基苯基)-4-甲基環戊-3-烯-1-基)-3-羥基庚-6-烯-2-酮 3-苯基-1-(2,4,6-三羥基-3-((1S,5S)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯基)丙-1-酮 2-((1S,5S)-5-異丙基-3-甲基環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 5-丁基-2-((1R,2S)-2-異丙基-4-甲基環戊基)苯-1,3-二醇 2-((1S,5S)-3-(羥甲基)-5-異丙基環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 2-((1R)-3-(羥甲基)-5-異丙基環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-(2-甲基辛-2-基)苯-1,3-二醇 (3R,4R)-3-(2,6-二羥基-4-(2-甲基辛-2-基)苯基)-4-(丙-1-烯-2-基)環戊-1-烯-1-羧酸 2-((1R,5R)-3-(羥甲基)-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-(2-甲基辛-2-基)苯-1,3-二醇 1,3-二甲氧基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-(2-甲基辛-2-基)苯 2-((1S,5S)-5-異丙基-3-甲基環戊-2-烯-1-基)-5-(2-甲基辛-2-基)苯-1,3-二醇 2-((1R,2S)-2-異丙基-4-甲基環戊基)-5-(2-甲基辛-2-基)苯-1,3-二醇 (S)-(3-(2,6-二甲氧基-4-(2-甲基辛-2-基)苯基)-4,4-二甲基環戊-1-烯-1-基)甲醇 (R)-(3-(2,6-二甲氧基-4-(2-甲基辛-2-基)苯基)-5,5-二甲基環戊-1-烯-1-基)甲醇 1-(3-(3,5-二羥基-4-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯甲基)氮雜環丁烷-1-基)乙-1-酮 5-(2-(1H-1,2,3-三唑-1-基)乙基)-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 2-(3,5-二羥基-4-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯基)-1-嗎啉基乙-1-酮 2-(3,5-二羥基-4-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯基)-1-嗎啉基乙-1-酮 5-(4-羥丁基)-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 4-(3,5-二羥基-4-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯基)丁酸 5-(2-乙氧基乙基)-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 4-氯-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 4,6-二氯-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 4-溴-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 4,6-二溴-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 4-碘-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 4,6-二碘-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 4-氟-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 二乙酸2-((1R,5R)-5-(1-氟乙烯基)-3-甲基環戊-2-烯-1-基)-5-戊基-1,3-伸苯酯 2-((1R,5R)-3-(氟甲基)-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 1,3-二甲氧基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯 2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基酚 (3S,4S)-3-(2,6-二乙醯氧基-4-戊苯基)-4-異丙基環戊-1-烯-1-羧酸 (3R,4R)-3-(2-(羧甲氧基)-6-羥基-4-戊苯基)-4-(丙-1-烯-2-基)環戊-1-烯-1-羧酸 3-(3-胺基丙氧基)-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基酚 2,2'-((2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基-1,3-伸苯基)雙(氧基))二乙腈 雙((二乙胺基)甲基) (2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基-1,3-伸苯基)雙(碳酸酯) 2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基-1,3-伸苯基雙(2-((三級丁基二甲基矽烷基)氧基)乙酸酯) 二乙酸2-((1R,5R)-3-甲基-5-(3-氧丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基-1,3-伸苯酯 二乙酸2-((1R,5R)-3-甲基-4-側氧基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基-1,3-伸苯酯 二乙酸2-((1R,5R)-4-乙醯氧基-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基-1,3-伸苯酯 二乙酸2-((1R,5R)-5-(3-乙醯氧基丙-1-烯-2-基)-3-甲基環戊-2-烯-1-基)-5-戊基-1,3-伸苯酯 3-羥基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基環己烷-2,5-二烯-1,4-二酮 2-(丁胺基)-5-羥基-6-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-3-戊基環己烷-2,5-二烯-1,4-二酮 2-(苯甲基胺基)-5-羥基-6-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-3-戊基環己烷-2,5-二烯-1,4-二酮 5-甲基-4-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯-1,3-二醇 4-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇 (Z)-2-(3,6-二甲基庚-2,5-二烯-1-基)-5-戊基苯-1,3-二醇 (3aR,9bR)-9-羥基-4,4-二甲基-7-(2-甲基辛-2-基)-1,3a,4,9b-四氫環戊并[c]𠳭烯-2-羧酸 2-(苯甲基胺基)-5-羥基-6-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-3-戊基環己烷-2,5-二烯-1,4-二酮 4-((3-甲基-1-側氧基-1-(((3aR,9bR)-2,4,4-三甲基-7-戊基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-基)氧基)丁-2-基)胺基)-4-氧丁酸 4-((1-((3-羥基-2-((1R,5R)-3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基環己烷-2,5-二烯-1-基)氧基)-3-甲基-1-氧丁-2-基)胺基)-4-氧丁酸 1-(3-(3,5-二羥基-4-((1R,5R)-5-(丙-1-烯-2-基)環戊-2-烯-1-基)苯甲基)氮雜環丁烷-1-基)乙-1-酮 。 III. 大麻素化合物之合成及純化 Non-limiting examples of synthetic cannabinoid derivatives according to Formulas V and VI are shown below: 5-methyl-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-di alcohol 2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylbenzene-1,3-di alcohol 5-Butyl-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-di alcohol 2,4-Dihydroxy-3-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-6-pentyl benzoic acid 2,4-Dihydroxy-3-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-6-propyl benzoic acid 3-methoxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenol 5-Butyl-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-di alcohol (3R,4R)-3-(2,6-Dihydroxy-4-pentylphenyl)-4-(prop-1-en-2-yl)cyclopent-1-ene-1-carboxylic acid 2-((1R,5R)-3-(Hydroxymethyl)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1, 3-diol (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-(3-hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-ene-2 -yl)cyclopent-2-en-1-yl)-5-pentylphenoxy)tetrahydro-2H-pyran-2-carboxylic acid 6-((1S,2S)-2-(2,6-dihydroxy-4-methylphenyl)-4-methylcyclopent-3-en-1-yl)-3-hydroxyhept-6- en-2-one 3-Phenyl-1-(2,4,6-trihydroxy-3-((1S,5S)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-ene -1-yl)phenyl)propan-1-one 2-((1S,5S)-5-isopropyl-3-methylcyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol 5-Butyl-2-((1R,2S)-2-isopropyl-4-methylcyclopentyl)benzene-1,3-diol 2-((1S,5S)-3-(Hydroxymethyl)-5-isopropylcyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol 2-((1R)-3-(Hydroxymethyl)-5-isopropylcyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol 2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-(2-methyloct-2- base) benzene-1,3-diol (3R,4R)-3-(2,6-Dihydroxy-4-(2-methyloct-2-yl)phenyl)-4-(prop-1-en-2-yl)cyclopent-1 -ene-1-carboxylic acid 2-((1R,5R)-3-(hydroxymethyl)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-(2-methyloctyl -2-yl)Benzene-1,3-diol 1,3-Dimethoxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5- (2-Methyloct-2-yl)benzene 2-((1S,5S)-5-isopropyl-3-methylcyclopent-2-en-1-yl)-5-(2-methyloct-2-yl)benzene-1,3- diol 2-((1R,2S)-2-isopropyl-4-methylcyclopentyl)-5-(2-methyloct-2-yl)benzene-1,3-diol (S)-(3-(2,6-Dimethoxy-4-(2-methyloct-2-yl)phenyl)-4,4-dimethylcyclopent-1-ene-1- Base) Methanol (R)-(3-(2,6-Dimethoxy-4-(2-methyloct-2-yl)phenyl)-5,5-dimethylcyclopent-1-ene-1- Base) Methanol 1-(3-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl ) benzyl) azetidin-1-yl) ethyl-1-one 5-(2-(1H-1,2,3-triazol-1-yl)ethyl)-2-((1R,5R)-3-methyl-5-(prop-1-ene-2- Base) cyclopent-2-en-1-yl) benzene-1,3-diol 2-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl )-1-morpholinoethan-1-one 2-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl )-1-morpholinoethan-1-one 5-(4-Hydroxybutyl)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene- 1,3-diol 4-(3,5-dihydroxy-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)phenyl ) butyric acid 5-(2-Ethoxyethyl)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl) Benzene-1,3-diol 4-Chloro-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1 ,3-diol 4,6-Dichloro-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl Benzene-1,3-diol 4-Bromo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1 ,3-diol 4,6-Dibromo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl Benzene-1,3-diol 4-iodo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1 ,3-diol 4,6-Diiodo-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl Benzene-1,3-diol 4-fluoro-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1 ,3-diol 2-((1R,5R)-5-(1-fluorovinyl)-3-methylcyclopent-2-en-1-yl)-5-pentyl-1,3-phenylene diacetate 2-((1R,5R)-3-(fluoromethyl)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1, 3-diol 1,3-Dimethoxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5- Amylbenzene 2-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylphenol (3S,4S)-3-(2,6-Diacetyloxy-4-pentylphenyl)-4-isopropylcyclopent-1-ene-1-carboxylic acid (3R,4R)-3-(2-(Carboxymethoxy)-6-hydroxy-4-pentylphenyl)-4-(prop-1-en-2-yl)cyclopent-1-en-1 -carboxylic acid 3-(3-aminopropoxy)-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl) -5-Amylphenol 2,2'-((2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl -1,3-Phenylylene)bis(oxyl))diacetonitrile Bis((diethylamino)methyl)(2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl) -5-Pentyl-1,3-phenylene)bis(carbonate) 2-((1R,5R)-3-Methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1,3-phenylene Bis(2-((tertiary butyldimethylsilyl)oxy)acetate) 2-((1R,5R)-3-methyl-5-(3-oxoprop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl-1 diacetate ,3-phenylene ester 2-((1R,5R)-3-methyl-4-oxo-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentyl diacetate 1,3-phenylene ester 2-((1R,5R)-4-acetyloxy-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5- diacetate Pentyl-1,3-phenylene ester 2-((1R,5R)-5-(3-Acetyloxyprop-1-en-2-yl)-3-methylcyclopent-2-en-1-yl)-5-pentyl diacetate 1,3-phenylene ester 3-Hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylcyclohexane -2,5-diene-1,4-dione 2-(butylamino)-5-hydroxy-6-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl) -3-Pentylcyclohexane-2,5-diene-1,4-dione 2-(Benzylamino)-5-hydroxy-6-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1- base)-3-pentylcyclohexane-2,5-diene-1,4-dione 5-methyl-4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzene-1,3-di alcohol 4-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-di alcohol (Z)-2-(3,6-Dimethylhept-2,5-dien-1-yl)-5-pentylbenzene-1,3-diol (3aR,9bR)-9-Hydroxy-4,4-dimethyl-7-(2-methyloct-2-yl)-1,3a,4,9b-tetrahydrocyclopenta[c]𠳭ene -2-carboxylic acid 2-(Benzylamino)-5-hydroxy-6-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1- base)-3-pentylcyclohexane-2,5-diene-1,4-dione 4-((3-methyl-1-oxo-1-(((3aR,9bR)-2,4,4-trimethyl-7-pentyl-3,3a,4,9b-tetrahydro Cyclopenta[c](en-9-yl)oxy)but-2-yl)amino)-4-oxobutanoic acid 4-((1-((3-Hydroxy-2-((1R,5R)-3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl) -5-pentylcyclohexane-2,5-dien-1-yl)oxy)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid 1-(3-(3,5-dihydroxy-4-((1R,5R)-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)benzyl) Azetidin-1-yl)ethan-1-one . III. Synthesis and purification of cannabinoid compounds

在一些實例中，本文所描述之大麻素化合物可以鹽形式形成，其可有助於改善化學純度、穩定性、溶解性及/或生物可用性。可能之鹽的非限制性實例描述於P. H. Stahl等人, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002中，其包括以下各者之鹽：1-羥基-2-萘甲酸、2,2-二氯乙酸、2-羥基乙磺酸、2-氧代戊二酸、4-乙醯胺基苯甲酸、4-胺基水楊酸、乙酸、己二酸、抗壞血酸(L)、天冬胺酸(L)、苯磺酸、苯甲酸、樟腦酸(+)、樟腦-10-磺酸(+)、羊蠟酸(癸酸)、羊油酸(己酸)、羊脂酸(辛酸)、碳酸、肉桂酸、檸檬酸、環己胺磺酸(cyclamic acid)、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡糖庚酸(D)、葡萄糖酸(D)、葡糖醛酸(D)、麩胺酸、戊二酸、甘油磷酸、乙醇酸、馬尿酸、氫溴酸、鹽酸、異丁酸、乳酸(DL)、乳糖酸、月桂酸、順丁烯二酸、蘋果酸(- L)、柰酸、杏仁酸(DL)、甲烷磺酸、萘-1,5-二磺酸、萘-2-磺酸、菸鹼酸、硝酸、油酸、草酸、棕櫚酸、雙羥萘酸(pamoic acid)、磷酸、丙酸、焦麩胺酸(- L)、水楊酸、癸二酸、硬脂酸、丁二酸、硫酸、酒石酸(+ L)、硫氰酸、甲苯磺酸(p)及十一碳烯酸。 In some examples, the cannabinoid compounds described herein can be formed in salt form, which can help to improve chemical purity, stability, solubility, and/or bioavailability. Non-limiting examples of possible salts are described in PH Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/Zürich: Wiley-VCH/VHCA, 2002, which include salts of 1-hydroxy -2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid Acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), caprylic acid (capric acid), caprylic acid ( caproic acid), caprylic acid (caprylic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, lauryl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid , formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate , Glycolic Acid, Hippuric Acid, Hydrobromic Acid, Hydrochloric Acid, Isobutyric Acid, Lactic Acid (DL), Lactobionic Acid, Lauric Acid, Maleic Acid, Malic Acid (- L), Nalinic Acid, Mandelic Acid (DL), Methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, coke Glutamic acid (- L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+ L), thiocyanic acid, toluenesulfonic acid (p) and undecylenic acid.

本文所描述之化合物可使用已知技術以合成方式製備，其中對反應物進行適當改良以形成本文所示之結構，或藉由熟習此項技術者顯而易見之其他適合的途徑製備。藉助於非限制性實例，本文所描述之化合物可根據描述於Razdan, Total Synthesis of Cannabinoids, SISA Incorporated, Cambridge, Massachusetts中之以下路徑中的一或多者合成，以對熟習此項技術者將為顯而易見的方式對反應物進行適當改良，以得到本文所揭示之結構。替代地，描述於Dialer等人美國專利10,059,683 B2中的合成技術(其揭示內容以全文引用之方式併入本文中)可經適當調適以合成本文所描述之大麻素衍生物。 The compounds described herein may be prepared synthetically using known techniques, with appropriate modifications of the reactants to form the structures shown herein, or by other suitable routes apparent to those skilled in the art. By way of non-limiting example, the compounds described herein can be synthesized according to one or more of the following routes described in Razdan, Total Synthesis of Cannabinoids , SISA Incorporated, Cambridge, Massachusetts, so that those skilled in the art will Appropriate modifications of the reactants were made in obvious ways to obtain the structures disclosed herein. Alternatively, the synthetic techniques described in Dialer et al. US Patent No. 10,059,683 B2, the disclosure of which is incorporated herein by reference in its entirety, can be suitably adapted to synthesize the cannabinoid derivatives described herein.

本文之工作實例1提供用於合成2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇(化合物T-101)之說明性方法。Working Example 1 herein provides a method for the synthesis of 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]alken-9-ol (compound T- 101) of the descriptive method.

欲用於向人類或其他哺乳動物投與之化合物一般應具有極高的純度。就以合成方式製備之化合物而言，純度係指在任何純化步驟之後化合物之質量相對於總樣品質量的比。通常，純度含量為至少約95%，更通常至少約96%、約97%、約98%或更高。例如，純度含量可為約98.5%、99.0%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99.9%或更高。Compounds intended for administration to humans or other mammals should generally be of extremely high purity. For compounds prepared synthetically, purity refers to the ratio of the mass of the compound to the mass of the total sample after any purification steps. Typically, the purity content is at least about 95%, more typically at least about 96%, about 97%, about 98% or higher. For example, the purity content can be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or higher.

以多於一種光學異構體形式(鏡像異構體)存在的本文所描述之化合物可以外消旋混合物形式或藉由分離鏡像異構體中之一者提供，在後者情況下，如上文所描述之純度可指鏡像異構純度。 IV. 使用方法 Compounds described herein that exist in more than one optical isomeric form (enantiomers) may be provided as a racemic mixture or by isolating one of the enantiomers, in the latter case, as described above The purities described may refer to enantiomerically pure. IV. How to use

如上文所描述，大麻素及相關大麻素衍生物通常經由CB 2大麻素受體發揮治療及抗炎活性。雖然不希望受理論束縛，但本文所揭示之化合物亦可展現作為單胺氧化酶(MAO)活性之抑制劑的特性，該活性包括MAO-A及MAO-B活性中之任一者或兩者。此等特性可使得化合物能夠有效治療與MAO活性相關之適應症，諸如抑鬱、疼痛、睡眠障礙、物質成癮、戒菸及類似者。因此，在一些實施例中，本文所揭示之化合物可用於治療與單胺氧化酶(MAO)活性相關之疾病及病狀的方法中。在一些實施例中，個體罹患抑鬱、疼痛、睡眠障礙或成癮。在一些實施例中，治療與單胺氧化酶(MAO)活性相關之疾病及病狀的方法包含向有需要之個體投與醫藥組合物，其中該醫藥組合物包含具有式(VI)之結構的化合物： 其中R1及R2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NRARB、-S-烷基、-SO-烷基、-SO2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中RA及RB各自獨立地選自氫及C1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C1-4烷基、-C(O)O-C1-4烷基、NRCRD、-S-烷基、-SO-烷基及-SO2-烷基；其中RC及RD各自獨立地選自氫及C1-4烷基；R3係選自由以下組成之群：H、烷基、醯基、-SO2-烷基、-SO2-芳基及-SO2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NRERF、-S-烷基、-SO-烷基、-SO2-烷基、芳基及雜芳基；且其中RE及RF各自獨立地選自氫及C1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NRGRH、-S-烷基、-SO-烷基及-SO2-烷基；其中RG及RH各自獨立地選自氫及C1-4烷基；或其醫藥學上可接受之鹽或酯，其限制條件為該化合物不為2,4,4-三甲基-7-戊基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。 As described above, cannabinoids and related cannabinoid derivatives generally exert therapeutic and anti-inflammatory activities via the CB2 cannabinoid receptor. While not wishing to be bound by theory, the compounds disclosed herein may also exhibit properties as inhibitors of monoamine oxidase (MAO) activity, including either or both MAO-A and MAO-B activities. These properties may render the compounds effective in the treatment of indications associated with MAO activity, such as depression, pain, sleep disturbances, substance addiction, smoking cessation and the like. Accordingly, in some embodiments, the compounds disclosed herein are useful in methods of treating diseases and conditions associated with monoamine oxidase (MAO) activity. In some embodiments, the individual suffers from depression, pain, sleep disturbance, or addiction. In some embodiments, methods of treating diseases and conditions associated with monoamine oxidase (MAO) activity comprise administering to a subject in need thereof a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound having the structure of Formula (VI): Wherein R1 and R2 are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein The alkyl, alkenyl, alkynyl or acyl group is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NRARB, -S -Alkyl, -SO-alkyl, -SO2-alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein RA and RB are each independently selected from hydrogen and C1-4 Alkyl; wherein the aryl or heteroaryl, whether alone or as part of a substituent, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O- Alkyl, -COOH, -C(O)-C1-4alkyl, -C(O)O-C1-4alkyl, NRCRD, -S-alkyl, -SO-alkyl and -SO2-alkyl ; wherein RC and RD are each independently selected from hydrogen and C1-4 alkyl; R3 is selected from the group consisting of: H, alkyl, acyl, -SO2-alkyl, -SO2-aryl and -SO2- Heteroaryl; wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alkyl, NRERF, -S-alkyl, -SO-alkyl, -SO2-alkyl, aryl and heteroaryl; and wherein RE and RF are each independently selected from hydrogen and C1-4 alkyl; wherein the aryl or Heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, alkyl, -O-alkyl, NRGRH, -S-alkyl, -SO-alkyl and -SO2-alkyl; wherein RG and RH are each independently selected from hydrogen and C1-4 alkyl; or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 2,4,4- Trimethyl-7-pentyl-3,3a,4,9b-tetrahydrocyclopenta[c]methen-9-ol.

在一些實施例中，用於治療MOA相關之疾病或病狀的醫藥組合物包含2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。In some embodiments, a pharmaceutical composition for treating a disease or condition associated with MOA comprises 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[ c] methene-9-ol.

本文所揭示之化合物亦(或替代地)可由於化合物與發炎路徑之相互作用而展現抗炎特性，該等化合物包括例如介白素(諸如IL-1及IL-6)、TNF-α、環加氧酶(COX)及類似物。可使用一般熟習此項技術者熟知之分析來評估化合物抑制MAO-A及/或MAO-B活性的能力及/或其抑制COX及/或與發炎相關之其他路徑的能力。Compounds disclosed herein may also (or alternatively) exhibit anti-inflammatory properties due to the interaction of the compounds with inflammatory pathways, including, for example, interleukins (such as IL-1 and IL-6), TNF-α, cyclic Oxygenase (COX) and the like. The ability of a compound to inhibit MAO-A and/or MAO-B activity and/or its ability to inhibit COX and/or other pathways associated with inflammation can be assessed using assays well known to those of ordinary skill in the art.

在一些態樣中，向有需要之個體投與如本文所描述之大麻素衍生物以治療物質成癮，諸如酒精、菸草、類鴉片、處方藥物、可卡因、苯并二氮呯、安非他命(amphetamine)、迷幻藥(hallucinogen)、吸入劑、苯環己哌啶(phencyclidine)或其他藥物成癮。此類治療亦包括治療對苯并二氮呯、鴉片劑或酒精之依賴性的戒斷以及具有物質使用障礙之患者所經歷的症狀，諸如焦慮、情緒症狀、疼痛及諸如失眠之睡眠障礙。In some aspects, a cannabinoid derivative as described herein is administered to an individual in need thereof to treat addiction to substances such as alcohol, tobacco, opioids, prescription drugs, cocaine, benzodiazepines, amphetamine ), hallucinogen, inhalants, phencyclidine, or other drug addiction. Such treatment also includes treatment of withdrawal from dependence on benzodiazepines, opiates or alcohol and symptoms experienced by patients with substance use disorders, such as anxiety, mood symptoms, pain and sleep disturbances such as insomnia.

除與物質使用障礙相關之焦慮以外，大麻素衍生物可有效治療其他類型之焦慮症，諸如創傷後壓力症、一般焦慮症、恐慌症、社交焦慮症及強迫症。In addition to anxiety associated with substance use disorders, cannabinoid derivatives are effective in treating other types of anxiety disorders, such as post-traumatic stress disorder, general anxiety disorder, panic disorder, social anxiety disorder, and obsessive-compulsive disorder.

在其他態樣中，可向有需要之個體投與如本文所描述之大麻素衍生物以治療多發性硬化症、肌肉纖維疼痛、癲癇症或與癲癇症有關之神經精神病症，諸如神經退化、神經元損傷及精神疾病。大麻素衍生物可有效增強諸如苯妥英(phenytoin)及安定(diazepam)之其他活性劑的抗痙攣活性。In other aspects, a cannabinoid derivative as described herein may be administered to an individual in need thereof for the treatment of multiple sclerosis, fibromyalgia, epilepsy, or neuropsychiatric disorders associated with epilepsy, such as neurodegeneration, Neuronal damage and mental illness. Cannabinoid derivatives are effective in potentiating the anticonvulsant activity of other active agents such as phenytoin and diazepam.

在又其他態樣中，如本文所描述之大麻素衍生物可作為抗精神病藥用於治療患有精神分裂症之患者。大麻素衍生物亦可有效降低眼內壓，諸如在青光眼治療中。In yet other aspects, cannabinoid derivatives as described herein are useful as antipsychotics in the treatment of patients with schizophrenia. Cannabinoid derivatives are also effective in reducing intraocular pressure, such as in the treatment of glaucoma.

在又其他態樣中，可向有需要之個體投與如本文所描述之大麻素衍生物以治療癌症。大麻素衍生物可有效阻斷癌細胞在身體周圍擴散及完全侵入區域；用於遏制癌細胞之生長且/或促進癌細胞之死亡。In yet other aspects, a cannabinoid derivative as described herein may be administered to an individual in need thereof to treat cancer. Cannabinoid derivatives can effectively block the spread of cancer cells around the body and completely invade areas; used to curb the growth of cancer cells and/or promote the death of cancer cells.

如本文所描述之大麻素衍生物可適用於治療1型糖尿病，其係由免疫系統攻擊胰臟中之細胞時的發炎；以及痤瘡(其部分係由身體之發炎及過度作用(overworked)之皮脂腺引起)所引起。化合物之抗炎特性可減少導致痤瘡(包括尋常性痤瘡，最常見形式之痤瘡)之皮脂的產生。Cannabinoid derivatives as described herein may be useful in the treatment of type 1 diabetes, which is caused by inflammation when cells in the pancreas are attacked by the immune system; and acne, which is caused in part by inflammation of the body and overworked sebaceous glands caused by). The anti-inflammatory properties of the compounds can reduce the production of sebum that leads to acne, including acne vulgaris, the most common form of acne.

如本文所描述之大麻素衍生物可用於治療阿茲海默氏症，且尤其當在阿茲海默氏症之早期投與時用於預防個體出現社會認同缺陷(social recognition deficit)。可藉由如本文所描述之大麻素衍生物治療之病症的其他實例包括噁心、嘔吐、厭食及惡病質。化合物可例如在拒絕進食之AIDS患者或患有阿茲海默氏症之個體中產生食慾增強作用。Cannabinoid derivatives as described herein are useful for the treatment of Alzheimer's disease, and especially for preventing social recognition deficits in individuals when administered early in Alzheimer's disease. Other examples of conditions treatable by cannabinoid derivatives as described herein include nausea, vomiting, anorexia, and cachexia. Compounds may, for example, produce appetite-enhancing effects in AIDS patients who refuse to eat or in individuals with Alzheimer's disease.

如本文所描述之大麻素衍生物可適用於治療由多發性硬化症(MS)或脊髓損傷引起之痙攣、運動障礙，諸如妥瑞症(Tourette's syndrome)、肌肉緊張不足(dystonia)或遲發性運動不能。MS患者可在共濟失調(ataxia)及震顫減少之方面受益。Cannabinoid derivatives as described herein may be useful in the treatment of spasticity, movement disorders caused by multiple sclerosis (MS) or spinal cord injury, such as Tourette's syndrome, dystonia or tardive Can't exercise. MS patients may benefit from a reduction in ataxia and tremor.

大麻素衍生物之鎮痛特性可證明為有益的，例如利於治療由多發性硬化症、臂神經叢損傷及HIV感染所致之神經性疼痛、類風濕性關節炎之疼痛、癌症疼痛、頭痛、月經疼痛、慢性腸發炎及神經痛。The analgesic properties of cannabinoid derivatives may prove beneficial, for example, in the treatment of neuropathic pain caused by multiple sclerosis, brachial plexus injuries and HIV infection, pain in rheumatoid arthritis, cancer pain, headaches, menstruation Pain, chronic intestinal inflammation and neuralgia.

如本文所描述之大麻素衍生物可適用於治療哮喘。檢查THC或大麻之抗哮喘作用的實驗主要可追溯至20世紀70年代，且皆為急性研究。大麻香菸(2% THC)或經口THC (15 mg)之作用分別大致對應於用常見支氣管擴張劑藥物(沙丁胺醇(salbutamol)、異丙腎上腺素(isoprenaline))之治療劑量獲得的彼等作用。因為吸入大麻產品可刺激黏膜，所以經口投與或另一替代性遞送系統將為較佳的。極少患者在吸入THC之後出現支氣管收縮。Cannabinoid derivatives as described herein may be useful in the treatment of asthma. Experiments examining the anti-asthmatic effects of THC or cannabis mainly date back to the 1970s and were all acute studies. The effects of cannabis cigarettes (2% THC) or oral THC (15 mg), respectively, roughly corresponded to those obtained with therapeutic doses of common bronchodilator drugs (salbutamol, isoprenaline). Because inhaled cannabis products can irritate the mucous membranes, oral administration or another alternative delivery system would be preferred. Very few patients experience bronchoconstriction after inhaling THC.

反應性抑鬱中之情緒的改善已在THC之若干臨床研究中觀測到。存在額外情況報導，其主張大麻素在諸如睡眠障礙、焦慮症、躁鬱症及輕鬱症之其他精神症狀及疾病中的益處。不同作者已表現出關於精神症候群及大麻之不同視點。雖然一些觀點強調由大麻引起之問題，但其他觀點提高治療可能性。視特定情況而定，大麻產品可極有可能為有益的或有害的。主治醫師及患者應對主題之關鍵檢查持開放態度，且對兩種可能性保持坦誠。Improvement of mood in reactive depression has been observed in several clinical studies of THC. There are additional reports arguing for the benefits of cannabinoids in other psychiatric symptoms and diseases such as sleep disorders, anxiety, bipolar and hypodepressive disorders. Different authors have shown different perspectives on psychosis and cannabis. While some perspectives emphasize problems caused by marijuana, others raise therapeutic possibilities. Depending on the particular situation, cannabis products can have a high potential to be beneficial or harmful. The attending physician and patient should keep an open mind about the critical examination of the subject and be honest about both possibilities.

在繼發於發炎過程之多種疼痛症候群(例如，潰瘍性結腸炎、關節炎)中，大麻產品不僅可充當鎮痛劑，且亦展現抗炎潛力。例如，採用大麻之一些患者報導其對類固醇及非類固醇抗炎藥物之需求降低。此外，大麻自療(self-medication)在過敏性病狀中存在一些積極作用之報導。大麻產品是否可對自體免疫疾病之致病過程具有相關影響亦係不明確的。In a variety of pain syndromes secondary to inflammatory processes (eg, ulcerative colitis, arthritis), cannabis products not only act as analgesics, but also exhibit anti-inflammatory potential. For example, some patients who use cannabis report a reduced need for steroids and non-steroidal anti-inflammatory drugs. In addition, there have been some reports of positive effects of cannabis self-medication in allergic conditions. It is also unclear whether cannabis products may have a relevant effect on the pathogenesis of autoimmune diseases.

存在許多關於無法容易地歸為以上類別之醫學病狀的陽性患者報導，諸如搔癢病、打嗝(hiccup)、注意力不足症候群(ADS)、高血壓、耳鳴、慢性疲勞症候群、不寧腿症候群及其他。不同作者已描述大麻及THC之數百種可能的適應症。例如，2.5至5 mg THC在患有由肝臟疾病所致之搔癢病的三名患者中有效。另一實例係成功治療手術後出現之慢性打嗝。無藥物係有效的，但抽大麻香菸完全消除了症狀。There are many positive patient reports of medical conditions that cannot be easily classified into the above categories, such as scrapie, hiccups, attention deficit syndrome (ADS), hypertension, tinnitus, chronic fatigue syndrome, restless legs syndrome and other. Various authors have described hundreds of possible indications for cannabis and THC. For example, 2.5 to 5 mg THC was effective in three patients with scrapie caused by liver disease. Another example is the successful treatment of chronic hiccups occurring after surgery. No drug was effective, but smoking marijuana cigarettes completely eliminated the symptoms.

大麻產品常常在具有多種症狀之疾病中顯示涵蓋在THC作用之範圍內的極佳作用，例如在具有發炎病因之疼痛病狀(例如，關節炎)中，或伴隨增加之肌肉張力(例如，月經絞痛、脊髓損傷)，或在分別伴隨疼痛、焦慮及抑鬱之具有噁心及厭食的疾病(例如，AIDS、癌症、C型肝炎)中。Cannabis products often show excellent effects encompassing the spectrum of THC action in diseases with multiple symptoms, such as in painful conditions with an inflammatory etiology (e.g., arthritis), or with increased muscle tone (e.g., menstrual colic, spinal cord injury), or in diseases with nausea and anorexia associated with pain, anxiety and depression respectively (eg, AIDS, cancer, hepatitis C).

COVID-19通過呼吸道飛沫傳播，且經由在肺組織以及口腔黏膜及鼻黏膜、腎臟、睾丸及胃腸道中表現的血管收縮素轉化酶II (ACE2)利用受體介導進入人體。調節此等閘道組織中之ACE2含量可降低疾病易感性。參見Wang等人, In Search of Preventative Strategies: Novel Anti-Inflammatory High-CBD Cannabis SativaExtracts Modulate ACE2 Expression in COVID-19 Gateway Tissues (2020年4月17日), doi: 10.20944/預印本202004.0315.v1。如本文所描述之大麻素衍生物可調節ACE2表現且可在諸如COVID-19之冠狀病毒的治療中具有效用。 COVID-19 is transmitted through respiratory droplets and enters the human body via receptor-mediated use of angiotensin-converting enzyme II (ACE2) expressed in lung tissue, oral and nasal mucosa, kidney, testis, and gastrointestinal tract. Modulating ACE2 levels in these gateway tissues reduces disease susceptibility. See Wang et al., In Search of Preventative Strategies: Novel Anti-Inflammatory High-CBD Cannabis Sativa Extracts Modulate ACE2 Expression in COVID-19 Gateway Tissues (April 17, 2020), doi: 10.20944/preprint 202004.0315.v1. Cannabinoid derivatives as described herein can modulate ACE2 expression and may have utility in the treatment of coronaviruses such as COVID-19.

在一些實施例中，本發明係關於一種治療睡眠障礙之方法，其中該方法包含投與有效量的以下各者： 或其醫藥學上可接受之鹽或酯。 V. 劑量及醫藥組合物 In some embodiments, the present invention relates to a method of treating sleep disorders, wherein the method comprises administering an effective amount of: or a pharmaceutically acceptable salt or ester thereof. V. Dosage and Pharmaceutical Compositions

適合劑量可視多種因素而在廣泛範圍內變化，該等因素包括疾病或病症之類型及/或嚴重程度、先前治療、個體之一般健康狀況、年齡及/或體重、治療頻率、自組合物釋放之速率及存在之其他疾病。此劑量可根據諸如個體之疾病狀態、年齡及體重的因素而變化。例如，可投與較高劑量以用於涉及處於晚期及/或危及生命之病狀的治療。亦可調整劑量方案以提供最佳治療反應。Suitable dosages may vary widely depending on many factors, including the type and/or severity of the disease or condition, previous therapy, the general health of the individual, age and/or weight, frequency of treatment, time of release from the composition, rate and other diseases present. The dosage may vary according to factors such as the disease state, age and weight of the individual. For example, higher doses may be administered for treatment involving advanced and/or life-threatening conditions. Dosage regimens may also be adjusted to provide the optimum therapeutic response.

醫藥組合物可與一或多種可接受之醫藥或食品級載劑或賦形劑一起調配。如本文所用，術語「可接受之醫藥或食品級載劑或賦形劑」意謂任何類型之無毒、惰性的固體、半固體或液體填充劑、稀釋劑、囊封材料或調配助劑。例如，根據調配者之判斷，糖，諸如乳糖、葡萄糖及蔗糖；澱粉，諸如玉米澱粉及馬鈴薯澱粉；纖維素及其衍生物，諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素；粉末狀黃蓍；麥芽；明膠；滑石；賦形劑，諸如可可脂及栓劑蠟；油，諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油；二醇，諸如丙二醇；酯，諸如油酸乙酯及月桂酸乙酯；瓊脂；緩衝劑，諸如氫氧化鎂及氫氧化鋁；褐藻酸；無熱原質水；等張生理鹽水；林格氏溶液(Ringer's solution)；乙醇及磷酸鹽緩衝溶液以及諸如月桂基硫酸鈉及硬脂酸鎂之相容潤滑劑，以及著色劑，釋放劑、包衣劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化劑亦可存在於組合物中。Pharmaceutical compositions can be formulated with one or more acceptable pharmaceutical or food grade carriers or excipients. As used herein, the term "pharmaceutically or food-grade acceptable carrier or excipient" means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. For example, sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate, at the discretion of the formulator; Powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol ; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution ; Ethanol and phosphate buffered saline solutions and compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants It can also be present in the composition.

醫藥組合物可藉由任何合適的技術製備且不受其產生之任何特定方法限制。例如，經純化之大麻素可與賦形劑及黏合劑組合，且隨後經粒化。粒化可與任何其餘成分經乾混(dry-blended)，且壓縮成固體形式，諸如錠劑。Pharmaceutical compositions may be prepared by any suitable technique and are not limited by any particular method of their production. For example, purified cannabinoids can be combined with excipients and binders, and then granulated. Granulations can be dry-blended with any remaining ingredients and compressed into a solid form, such as a lozenge.

醫藥組合物可藉由任何適合的途徑投與。例如，組合物可經口、非經腸、藉由吸入噴霧、局部、經直腸、經鼻、經頰、經陰道、經由植入式貯器投與，或以膳食補充劑或食物形式攝取。在一些實施例中，將組合物提供於吸入劑中，該吸入劑可經致動以投與吸入肺中之汽化介質。如本文所用，術語非經腸包括皮下、皮內、靜脈內、肌肉內及顱內注射或輸注技術。最通常，醫藥組合物易於經口投與及攝取。Pharmaceutical compositions can be administered by any suitable route. For example, compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, or ingested as a dietary supplement or food. In some embodiments, the composition is provided in an inhaler that is actuatable to administer a vaporized medium that is inhaled into the lungs. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular and intracranial injection or infusion techniques. Most generally, pharmaceutical compositions are easy to administer and ingest orally.

醫藥組合物可含有任何習知無毒的醫藥學上可接受之載劑、佐劑或媒劑。在一些情況下，調配物之pH可用可接受之醫藥或食品級酸、鹼或緩衝劑調整以增強調配之組合物或其遞送形式的穩定性。The pharmaceutical compositions may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically or food-acceptable acids, bases or buffers to enhance the stability of the formulated composition or its delivery form.

用於經口投與之液體劑型包括可接受之醫藥或食品級乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物以外，液體劑型可含有此項技術中常用之惰性稀釋劑，諸如水或其他溶劑；增溶劑及乳化劑，諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲亞碸(DMSO)二甲基甲醯胺、油(特別地，棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇及山梨糖醇酐之脂肪酸酯；及其混合物。除惰性稀釋劑以外，經口組合物亦可包括佐劑，諸如潤濕劑、乳化劑及懸浮劑、甜味劑、調味劑及芳香劑。Liquid dosage forms for oral administration include pharmaceutically or food-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzene Benzyl formate, propylene glycol, 1,3-butanediol, dimethylsulfoxide (DMSO) dimethylformamide, oils (especially, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan; and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

用於經口投與之固體劑型包括膠囊、錠劑、口含錠、丸劑、散劑及粒劑。在此類固體劑型中，將活性化合物與至少一種惰性、可接受之醫藥或食品級賦形劑或載劑(諸如檸檬酸鈉或磷酸二鈣)及/或以下各者混合：a)填充劑或增量劑，諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇及矽酸；b)黏合劑，諸如羧甲基纖維素、褐藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及阿拉伯膠；c)保濕劑，諸如甘油；d)崩解劑，諸如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、褐藻酸、某些矽酸鹽及碳酸鈉；e)溶液阻滯劑，諸如石蠟；f)吸收促進劑，諸如四級銨化合物；g)潤濕劑，諸如鯨蠟醇及甘油單硬脂酸酯；h)吸附劑，諸如高嶺土及膨潤土；i)潤滑劑，諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉及其混合物；及j)甜味劑、調味劑、芳香劑及其混合物。在膠囊、口含錠、錠劑及丸劑之情況下，劑型亦可包含緩衝劑。Solid dosage forms for oral administration include capsules, lozenges, lozenges, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, acceptable pharmaceutical or food grade excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or: a) a filler or bulking agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c ) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption enhancers g) wetting agents such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite; i) lubricants such as talc, calcium stearate, hard Magnesium fatty acid, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and j) sweetening, flavoring, perfuming agents and mixtures thereof. In the case of capsules, lozenges, lozenges and pills, the dosage form may also comprise buffering agents.

錠劑、膠囊、丸劑及粒劑之固體劑型可製備有包衣及殼，諸如腸溶包衣及醫藥調配技術中熟知之其他包衣。其可視情況含有乳濁劑，且亦可具有其僅在或優先在腸道之某一部分中或視情況以延遲或延長方式釋放活性成分的組合物。可使用之包埋組合物的實例包括聚合物質及蠟。延長釋放之錠劑調配物亦描述於美國專利第5,942,244號中。The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient(s) only or preferentially in a certain part of the intestinal tract or optionally in a delayed or prolonged manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Extended release tablet formulations are also described in US Patent No. 5,942,244.

組合物可含有單獨或與其他治療化合物一起之大麻素衍生物或化合物。治療化合物為在疾病之診斷、治癒、緩解、治療或預防中或在影響人或動物身體之結構或任何功能中提供藥理學活性或其他直接作用的化合物。本文所揭示之治療化合物可以醫藥學上可接受之鹽、溶劑合物或鹽之溶劑合物，例如鹽酸鹽的形式使用。另外，本文所揭示之治療化合物可以外消旋體形式或以個別鏡像異構體(包括R-或S-鏡像異構體)形式提供。因此，本文所揭示之治療化合物可包含治療化合物的僅R-鏡像異構體、僅S-鏡像異構體或R-鏡像異構體及S-鏡像異構體之組合。在一些態樣中，治療化合物可具有抗炎活性，諸如非類固醇抗炎藥物(NSAID)。NSAID為具有鎮痛、抗炎及解熱特性之一大組治療化合物。NSAID藉由阻斷環加氧酶減少發炎。NSAID包括但不限於乙醯氯芬酸(aceclofenac)、阿西美辛(acemetacin)、阿克他利(actarit)、阿氯芬酸(alcofenac)、阿明洛芬(alminoprofen)、胺芬酸(amfenac)、阿洛昔普林(aloxipirin)、胺基比林(aminophenazone)、安特非寧(antraphenine)、阿司匹靈(aspirin)、阿紮丙酮(azapropazone)、貝諾酯(benorilate)、苯惡洛芬(benoxaprofen)、苄達明(benzydamine)、布替布芬(butibufen)、塞內昔布(celecoxib)、氯西諾嗪(chlorthenoxacin)、膽鹼水楊酸酯、氯美辛(clometacin)、右酮洛芬(dexketoprofen)、雙氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依莫法宗(emorfazone)、依匹唑(epirizole)；依託度酸(etodolac)、依他昔布(etoricoxib)、苯氯布宗(feclobuzone)、聯苯乙酸(felbinac)、芬布芬(fenbufen)、芬氯酸(fenclofenac)、氟比洛芬(flurbiprofen)、格拉芬寧(glafenine)、水楊酸羥乙酯、布洛芬(ibuprofen)、吲哚美辛(indometacin)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、酮咯酸(ketorolac)、乳醯乙氧基苯胺(lactyl phenetidin)、洛索洛芬(loxoprofen)、羅美昔布(lumiracoxib)、甲芬那酸(mefenamic acid)、美洛昔康(meloxicam)、安乃近(metamizole)、甲嗪酸(metiazinic acid)、莫非布宗(mofebutazone)、莫苯唑酸(mofezolac)、萘丁美酮(nabumetone)、萘普生(naproxen)、尼芬那酮(nifenazone)、氟尼酸(niflumic acid)、奧沙美辛(oxametacin)、非那西汀(phenacetin)、哌布宗(pipebuzone)、普拉洛芬(pranoprofen)、丙非那宗(propyphenazone)、普羅喹宗(proquazone)、丙替嗪酸(protizinic acid)、羅非考昔(rofecoxib)、水楊醛胺(salicylamide)、雙水楊酸酯(salsalate)、舒林酸(sulindac)、舒洛芬(suprofen)、噻拉米特(tiaramide)、替諾立定(tinoridine)、托芬那酸(tolfenamic acid)、伐地考昔(valdecoxib)、及佐美酸(zomepirac)。The compositions may contain cannabinoid derivatives or compounds alone or together with other therapeutic compounds. A therapeutic compound is a compound that provides pharmacological activity or other direct action in the diagnosis, cure, mitigation, treatment or prevention of disease or in affecting the structure or any function of the human or animal body. The therapeutic compounds disclosed herein may be used in the form of pharmaceutically acceptable salts, solvates, or solvates of salts, eg, hydrochloride salts. Additionally, the therapeutic compounds disclosed herein may be provided as racemates or as individual mirror-image isomers, including R- or S-mirror-isomers. Accordingly, a therapeutic compound disclosed herein may comprise only the R-enantiomer, only the S-enantiomer, or a combination of the R-enantiomer and the S-enantiomer of the therapeutic compound. In some aspects, therapeutic compounds may have anti-inflammatory activity, such as non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are one of a large group of therapeutic compounds possessing analgesic, anti-inflammatory and antipyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase. NSAIDs include, but are not limited to, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac ( amfenac), aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, Benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin ), dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etacoxib ( etoricoxib), feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, salicylic acid Hydroxyethyl ester, ibuprofen, indomethacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin ), loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, metiazinic acid, Mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxameacin ( oxametacin), phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, Rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine ), tolfenamic acid, valdecoxib, and zomepirac.

NSAID可基於其化學結構或作用機制分類。NSAID之非限制性實例包括水楊酸鹽衍生物NSAID、對胺基酚衍生物NSAID、丙酸衍生物NSAID、乙酸衍生物NSAID、烯醇酸衍生物NSAID、芬那酸(fenamic acid)衍生物NSAID、非選擇性環加氧酶(COX)抑制劑、選擇性環加氧酶-1 (COX-1)抑制劑及選擇性環加氧酶-2 (COX-2)抑制劑。NSAID可為洛芬(profen)。適合之水楊酸酯衍生物NSAID的實例包括但不限於乙醯水楊酸(阿司匹靈)、二氟尼柳及雙水楊酸酯。適合之對胺基酚衍生物NSAID的實例包括但不限於撲熱息痛(paracetamol)及非那西汀(phenacetin)。適合之丙酸衍生物NSAID的實例包括但不限於阿明洛芬、苯惡洛芬、右酮洛芬、非諾洛芬(fenoprofen)、氟比洛芬、布洛芬、吲哚洛芬、酮洛芬、洛索洛芬、萘普生、奧沙普嗪(oxaprozin)、普拉洛芬及舒洛芬。適合之乙酸衍生物NSAID的實例包括但不限於乙醯氯芬酸、阿西美辛、阿克他利、阿氯芬酸、胺芬酸、氯美辛、雙氯芬酸、依託度酸、聯苯乙酸、芬氯酸、吲哚美辛、酮咯酸、甲嗪酸、莫苯唑酸、萘丁美酮、萘普生、奧沙美辛、舒林酸及佐美酸。適合之烯醇酸(昔康(oxicam))衍生物NSAID的實例包括但不限於屈噁昔康(droxicam)、伊索昔康(isoxicam)、氯諾昔康(lornoxicam)、美洛昔康(meloxicam)、吡羅昔康(piroxicam)及替諾昔康(tenoxicam)。適合之芬那酸衍生物NSAID的實例包括但不限於氟芬那酸(flufenamic acid)、甲芬那酸、甲氯芬那酸(meclofenamic acid)及托芬那酸。適合之選擇性COX-2抑制劑的實例包括但不限於塞內昔布、依他昔布、非羅昔布(firocoxib)、羅美昔布、美洛昔康、帕瑞昔布(parecoxib)、羅非考昔及伐地考昔。NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylate derivative NSAIDs, p-aminophenol derivative NSAIDs, propionic acid derivative NSAIDs, acetic acid derivative NSAIDs, enolic acid derivative NSAIDs, fenamic acid derivatives NSAIDs, nonselective cyclooxygenase (COX) inhibitors, selective cyclooxygenase-1 (COX-1) inhibitors, and selective cyclooxygenase-2 (COX-2) inhibitors. The NSAID can be profen. Examples of suitable salicylate derivative NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and disalicylate. Examples of suitable p-aminophenol derivative NSAIDs include, but are not limited to, paracetamol and phenacetin. Examples of suitable propionic acid derivative NSAIDs include, but are not limited to, alminoprofen, benzoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen. Examples of suitable acetic acid derivative NSAIDs include, but are not limited to, acetylclofenac, acemetacin, actarit, aclofenac, amfenac, clomethacin, diclofenac, etodolac, felbinac , fenchloric acid, indomethacin, ketorolac, methazinic acid, mobendazole, nabumetone, naproxen, oxameacin, sulindac, and zomeacin. Examples of suitable enolic acid (oxicam) derivative NSAIDs include, but are not limited to, droxicam, isoxicam, lornoxicam, meloxicam ( meloxicam), piroxicam, and tenoxicam. Examples of suitable fenamic acid derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etacoxib, firocoxib, lumiracoxib, meloxicam, parecoxib , rofecoxib and valdecoxib.

本文所揭示之治療化合物的治療有效量一般在約0.001毫克/公斤/天至約100毫克/公斤/天之範圍內。有效量可例如為至少0.001毫克/公斤/天、至少0.01毫克/公斤/天、至少0.1毫克/公斤/天、至少1.0毫克/公斤/天、至少5.0毫克/公斤/天、至少10毫克/公斤/天、至少15毫克/公斤/天、至少20毫克/公斤/天、至少25毫克/公斤/天、至少30毫克/公斤/天、至少35毫克/公斤/天、至少40毫克/公斤/天、至少45毫克/公斤/天或至少50毫克/公斤/天。在一些實例中，治療化合物之有效量可在約0.001毫克/公斤/天至約10毫克/公斤/天、約0.001毫克/公斤/天至約15毫克/公斤/天、約0.001毫克/公斤/天至約20毫克/公斤/天、約0.001毫克/公斤/天至約25毫克/公斤/天、約0.001毫克/公斤/天至約30毫克/公斤/天、約0.001毫克/公斤/天至約35毫克/公斤/天、約0.001毫克/公斤/天至約40毫克/公斤/天、約0.001毫克/公斤/天至約45毫克/公斤/天、約0.001毫克/公斤/天至約50毫克/公斤/天、約0.001毫克/公斤/天至約75毫克/公斤/天或約0.001毫克/公斤/天至約100毫克/公斤/天之範圍內。在其他實例中，本文所揭示之治療化合物的有效量可在例如約0.01毫克/公斤/天至約10毫克/公斤/天、約0.01毫克/公斤/天至約15毫克/公斤/天、約0.01毫克/公斤/天至約20毫克/公斤/天、約0.01毫克/公斤/天至約25毫克/公斤/天、約0.01毫克/公斤/天至約30毫克/公斤/天、約0.01毫克/公斤/天至約35毫克/公斤/天、約0.01毫克/公斤/天至約40毫克/公斤/天、約0.01毫克/公斤/天至約45毫克/公斤/天、約0.01毫克/公斤/天至約50毫克/公斤/天、約0.01毫克/公斤/天至約75毫克/公斤/天或約0.01毫克/公斤/天至約100毫克/公斤/天之範圍內。A therapeutically effective amount of a therapeutic compound disclosed herein will generally range from about 0.001 mg/kg/day to about 100 mg/kg/day. The effective amount can be, for example, at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg /day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day , at least 45 mg/kg/day or at least 50 mg/kg/day. In some instances, an effective amount of a therapeutic compound may range from about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, in the range of about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In other examples, an effective amount of a therapeutic compound disclosed herein can range, for example, from about 0.01 mg/kg/day to about 10 mg/kg/day, from about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg /kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day /day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day.

除醫藥組合物之外，本文所描述之化合物可調配為酏劑、飲料、咀嚼物、錠劑、口含錠、膠狀物或其類似者。根據另一態樣，醫藥組合物亦可調配為醫藥學上可接受之媒劑，諸如膠囊、錠劑、糖漿、口含錠、吸入劑、電子菸、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體(nanosome)、脂質體、非離子體(noisome)、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液或微胞。組合物亦可調配為例如膳食補充劑或營養藥劑。In addition to pharmaceutical compositions, the compounds described herein can be formulated as elixirs, drinks, chews, lozenges, lozenges, jellies, or the like. According to another aspect, the pharmaceutical composition can also be prepared as a pharmaceutically acceptable vehicle, such as capsules, lozenges, syrups, buccal tablets, inhalants, electronic cigarettes, chewable jelly, nasal spray, Transdermal patches, liquids, transmucosal vehicles, hydrogels, nanosomes, liposomes, noisomes, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, Nanosuspensions or micelles. Compositions can also be formulated, for example, as dietary supplements or nutraceuticals.

本發明之實施例之描述並不意欲為窮盡性的或將揭示內容限制於所揭示之確切形式。如熟習相關技術者將認識到，雖然本文出於說明性目的而描述本發明之特定實施例及實例，但在本發明之範疇內各種等效修改係可能的。例如，雖然方法步驟或功能係以給定次序呈現，但替代實施例可以不同次序執行功能，或可大體上同時執行功能。本文所提供之本發明教示內容可視需要應用於其他程序或方法。可組合本文所描述之各種實施例以提供其他實施例。必要時，可修改本發明之態樣以採用上文參考文獻及申請案之組合物、功能及概念，以提供本發明之其他實施例。此外，由於生物學功能等效性考慮因素，因此可對蛋白結構進行一些改變而不影響生物學或化學作用的種類或量。可鑒於實施方式來對本發明進行此等及其他變化。所有此類修改均意欲包括在隨附申請專利範圍之範疇內。The descriptions of embodiments of the present invention are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed. While specific embodiments of, and examples for, the invention are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. For example, although method steps or functions are presented in a given order, alternative embodiments may perform the functions in a different order, or may perform the functions substantially concurrently. The inventive teachings provided herein may be applied to other procedures or methods as desired. The various embodiments described herein can be combined to provide other embodiments. Aspects of this invention can be modified, as necessary, to employ the compositions, functions, and concepts of the above references and applications to provide other embodiments of this invention. Furthermore, due to considerations of biological functional equivalence, some changes in protein structure may be made without affecting the type or amount of biological or chemical effect. These and other changes can be made to the invention in light of the embodiments. All such modifications are intended to be included within the scope of the appended claims.

前述實施例中之任一者之特定要素可經組合或取代為其他實施例中之要素。此外，雖然與本發明之某些實施例相關之優點已在此等實施例之上下文中描述，但其他實施例亦可呈現此類優點，且並非所有實施例必定需要呈現屬於本發明範疇內的此類優點。Certain elements of any of the foregoing embodiments may be combined or substituted for elements of other embodiments. Furthermore, while advantages associated with certain embodiments of the invention have been described in the context of those embodiments, other embodiments may exhibit such advantages, and not all embodiments need necessarily exhibit advantages that fall within the scope of the invention. Such advantages.

雖然已根據特定實例描述本發明，但熟習此項技術者應瞭解存在屬於如隨附申請專利範圍中所闡述之本發明之精神及範疇內的上述系統及技術的眾多變化及排列。 VI. 工作實例 While the invention has been described in terms of specific examples, those skilled in the art will appreciate that there are numerous variations and permutations of the above-described systems and techniques that fall within the spirit and scope of the invention as set forth in the appended claims. VI. WORKING EXAMPLES

實例 1 - 合成 2,4,4- 三甲基 -7- 丙基 -3,3a,4,9b- 四氫環戊并 [c] 𠳭 烯 -9- 醇 ( 化合物 T-101) ： Example 1 - Synthesis of 2,4,4- trimethyl -7- propyl -3,3a,4,9b- tetrahydrocyclopenta [ c] alken -9- ol ( compound T-101) :

合成synthesis 4-4- 溴環戊bromide -2--2- 烯酮Enone (2)(2) ：:

在室溫下，在氬氣氛圍下歷經30分鐘之時段向環戊-2-烯-1-酮(100 g，1218 mmol)於無水氯仿(1.50 L)中之溶液中分批添加NBS (325 g，1827 mmol)。在完全添加之後，使反應混合物在80℃(油浴溫度)下回流48小時。將反應混合物冷卻至室溫，用水(2.0 L)稀釋且用CH 2Cl 2(2×1.0 L)萃取。合併之有機萃取物用冰冷水(1.0 L)、鹽水(1.0 L)洗滌，經Na 2SO 4乾燥，過濾且在減壓下濃縮，獲得呈黃色液體狀之4-溴環戊-2-烯-1-酮(150 g，76%)。 To a solution of cyclopent-2-en-1-one (100 g, 1218 mmol) in anhydrous chloroform (1.50 L) was added NBS (325 g, 1827 mmol). After complete addition, the reaction mixture was refluxed at 80°C (oil bath temperature) for 48 hours. The reaction mixture was cooled to room temperature, diluted with water (2.0 L) and extracted with CH2Cl2 (2 x 1.0 L). The combined organic extracts were washed with ice-cold water (1.0 L), brine (1.0 L ), dried over Na2SO4 , filtered and concentrated under reduced pressure to obtain 4-bromocyclopent-2-ene as a yellow liquid -1-one (150 g, 76%).

1H NMR顯示所需信號： 1H NMR (400 MHz, CDCl 3): δ7.67 (dd, J= 5.52, 2.56 Hz, 1H), 6.27 (dd, J= 5.52, 0.95 Hz, 1H), 5.23-5.06 (m, 1H), 3.05 (dd, J= 19.5, 6.28 Hz, 1H), 2.72 (dd, J= 19.5, 1.53 Hz, 1H)。 1 H NMR showed the desired signal: 1 H NMR (400 MHz, CDCl 3 ): δ 7.67 (dd, J = 5.52, 2.56 Hz, 1H), 6.27 (dd, J = 5.52, 0.95 Hz, 1H), 5.23- 5.06 (m, 1H), 3.05 (dd, J = 19.5, 6.28 Hz, 1H), 2.72 (dd, J = 19.5, 1.53 Hz, 1H).

合成synthesis 4-(4-( 丙C -1--1- 烯ene -2--2- 基base )) 環戊Cyclopentane -2--2- 烯ene -1--1- 酮ketone (3)(3) ：:

向LiCl (23.4 g，558 mmol)於無水THF (500 mL)中之攪拌溶液中添加CuCN (25.0 g，279 mmol)且在室溫下攪拌20分鐘。使反應混合物冷卻至-40℃且歷經60分鐘之時段逐滴添加異丙烯基溴化鎂(279.5 mL，0.5 M於THF中，139.7 mmol)，在-40℃下進一步攪拌20分鐘且隨後冷卻至-78℃。隨後歷經60分鐘之時段逐滴添加含4-溴環戊-2-烯-1-酮(15 g，93.1 mmol，1.0當量)之無水THF (100 mL)且在-78℃下攪拌反應混合物10分鐘。使反應混合物緩慢達到0℃且用飽和NH 4Cl溶液(500 mL)淬滅且在室溫下攪拌30分鐘。過濾反應混合物且用MTBE (2×1.0 L)萃取濾液。將合併之MTBE萃取物用鹽水(2×1.0 L)洗滌，經無水Na 2SO 4乾燥，過濾且在真空下濃縮，獲得粗產物。藉由矽膠層析(15至25% MTBE/己烷)純化產物。合併含有產物之份且在減壓下濃縮，獲得呈無色油狀物之4-(丙-1-烯-2-基)環戊-2-烯-1-酮(4.0 g，35%)。 注意 ：化合物 3在自然界中為揮發性的，旋轉蒸發浴溫度應＜ 20℃，真空度約為600毫巴。 1H NMR顯示所需信號以及痕量MTBE溶劑。 1H NMR (400 MHz, CDCl 3): δ7.60 (dd, J= 5.65, 2.49 Hz, 1H), 6.24 (dd, J= 5.54, 1.98 Hz, 1H), 4.90-4.71 (m, 2H), 3.64-3.40 (m, 1H), 2.60 (dd, J= 18.8, 6.75 Hz, 1H), 2.18 (dd, J= 18.8, 2.02 Hz, 1H), 1.71 (s, 3H)。 To a stirred solution of LiCl (23.4 g, 558 mmol) in anhydrous THF (500 mL) was added CuCN (25.0 g, 279 mmol) and stirred at room temperature for 20 min. The reaction mixture was cooled to -40°C and isopropenylmagnesium bromide (279.5 mL, 0.5 M in THF, 139.7 mmol) was added dropwise over a period of 60 minutes, stirred for a further 20 minutes at -40°C and then cooled to -78°C. 4-Bromocyclopent-2-en-1-one (15 g, 93.1 mmol, 1.0 equiv) in anhydrous THF (100 mL) was then added dropwise over a period of 60 min and the reaction mixture was stirred at -78 °C for 10 minute. The reaction mixture was slowly brought to 0 °C and quenched with saturated NH4Cl solution (500 mL) and stirred at room temperature for 30 min. The reaction mixture was filtered and the filtrate was extracted with MTBE (2 x 1.0 L). The combined MTBE extracts were washed with brine (2 x 1.0 L), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo to obtain the crude product. The product was purified by silica gel chromatography (15 to 25% MTBE/hexane). Fractions containing product were combined and concentrated under reduced pressure to afford 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (4.0 g, 35%) as a colorless oil. Note : Compound 3 is volatile in nature, the temperature of the rotary evaporation bath should be < 20 °C, and the vacuum degree should be about 600 mbar. 1 H NMR showed the desired signal along with traces of MTBE solvent. 1 H NMR (400 MHz, CDCl 3 ): δ 7.60 (dd, J = 5.65, 2.49 Hz, 1H), 6.24 (dd, J = 5.54, 1.98 Hz, 1H), 4.90-4.71 (m, 2H), 3.64 -3.40 (m, 1H), 2.60 (dd, J = 18.8, 6.75 Hz, 1H), 2.18 (dd, J = 18.8, 2.02 Hz, 1H), 1.71 (s, 3H).

合成synthesis 1-1- 甲基methyl -4-(-4-( 丙C -1--1- 烯ene -2--2- 基base )) 環戊Cyclopentane -2--2- 烯ene -1--1- 醇alcohol (4)(4) ：:

在-78℃下，在氬氣氛圍下歷經30分鐘之時段向4-(丙-1-烯-2-基)環戊-2-烯-1-酮(9.0 g，73 mmol)於無水THF (100 mL)之溶液中逐滴添加甲基鋰(1.6 M於二乙醚中，69.1 mL，73.72 mmol)之溶液，且在-78℃下攪拌反應混合物10分鐘。使反應混合物緩慢達到0℃，用NH 4Cl溶液(130 mL)淬滅且用MTBE (2×500 mL)萃取。合併之MTBE萃取物用水(500 mL)、鹽水(500 mL)洗滌且經Na 2SO 4乾燥，過濾且在減壓下濃縮，獲得呈淡黃色液體狀之1-甲基-4-(丙-1-烯-2-基)環戊-2-烯-1-醇(4.5 g，粗物質)，其直接用於下一步驟中。 To 4-(prop-1-en-2-yl)cyclopent-2-en-1-one (9.0 g, 73 mmol) in anhydrous THF at -78 °C over a period of 30 minutes under argon atmosphere To a solution of methyllithium (1.6 M in diethyl ether, 69.1 mL, 73.72 mmol) was added dropwise, and the reaction mixture was stirred at -78 °C for 10 min. The reaction mixture was slowly brought to 0 °C, quenched with NH4Cl solution (130 mL) and extracted with MTBE (2 x 500 mL). The combined MTBE extracts were washed with water (500 mL), brine (500 mL) and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain 1-methyl-4-(propane- 1-en-2-yl)cyclopent-2-en-1-ol (4.5 g, crude material), which was used directly in the next step.

注意 ：化合物 4在自然界中亦為揮發性的，旋轉蒸發浴溫度應＜ 20℃，真空度約為600毫巴。 Note : compound 4 is also volatile in nature, the temperature of the rotary evaporation bath should be < 20°C, and the vacuum degree should be about 600 mbar.

合成synthesis 2-(3-2-(3- 甲基methyl -5-(-5-( 丙C -1--1- 烯ene -2--2- 基base )) 環戊Cyclopentane -2--2- 烯ene -1--1- 基base )-5-)-5- 丙基苯Propylbenzene -1,3--1,3- 二醇diol (5)(5) ：:

在室溫下，歷經20分鐘之時段向Brockmann l活化鹼性氧化鋁(79 g，782 mmol)於無水CH 2Cl 2(300 mL)中之攪拌溶液中逐滴添加三氟化硼合二乙醚(boron trifluoride diethyl etherate) (13.4 mL，108.6 mmol)。將反應混合物緩慢加熱至40℃且再攪拌10分鐘，接著逐滴添加1-甲基-4-(丙-1-烯-2-基)環戊-2-烯-1-醇(6.0 g，138.1 mmol)、5-丙基苯-1,3-二醇(4.6 g，30 mmol)於無水CH 2Cl 2(100 mL)中之溶液。在40℃下攪拌反應混合物5分鐘。使反應混合物冷卻至室溫，且用飽和NaHCO 3(300 mL)稀釋且用CH 2Cl 2(300 mL×2)萃取。合併之有機萃取物用水(500 mL)、鹽水(500 mL)洗滌，經Na 2SO 4乾燥，過濾且在減壓下濃縮。粗殘餘物藉由矽膠層析(6至10% EtOAc/己烷)純化兩次。合併含有純產物之份且在減壓下濃縮，獲得呈棕色液體狀之2-(3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-丙基苯-1,3-二醇(3.0 g，粗物質)。 1H NMR顯示化合物 5及化合物 T-101之混合物。 To a stirred solution of Brockmann l activated basic alumina (79 g, 782 mmol) in anhydrous CH2Cl2 (300 mL) was added boron trifluoride diethyl ether dropwise over a period of 20 minutes at room temperature (boron trifluoride diethyl ether) (13.4 mL, 108.6 mmol). The reaction mixture was slowly heated to 40 °C and stirred for another 10 minutes, then 1-methyl-4-(prop-1-en-2-yl)cyclopent-2-en-1-ol (6.0 g, 138.1 mmol), 5 - propylbenzene-1,3-diol (4.6 g, 30 mmol) in anhydrous CH2Cl2 (100 mL). The reaction mixture was stirred at 40°C for 5 minutes. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO 3 (300 mL) and extracted with CH 2 Cl 2 (300 mL×2). The combined organic extracts were washed with water (500 mL), brine (500 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude residue was purified twice by silica gel chromatography (6 to 10% EtOAc/hexanes). Fractions containing pure product were combined and concentrated under reduced pressure to afford 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl as a brown liquid )-5-Propylbenzene-1,3-diol (3.0 g, crude material). 1 H NMR showed a mixture of compound 5 and compound T-101 .

合成synthesis 2,4,4-2,4,4- 三甲基Trimethyl -7--7- 丙基Propyl -3,3a,4,9b--3,3a,4,9b- 四氫環戊并Tetrahydrocyclopenta [c][c] 𠳭𠳭 烯ene -9--9- 醇alcohol (T-101)(T-101) ：:

向2-(3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-丙基苯-1,3-二醇(3.0 g，9.9 mmol)於無水CH 2Cl 2(500 mL)中之溶液中添加Fe(OTf) 3(0.99 g，1.98 mmol)且在室溫下攪拌72小時。使反應物冷卻至0℃，且用飽和NaHCO 3溶液(100 mL)淬滅且用CH 2Cl 2(2×100 mL)萃取。合併之CH 2Cl 2萃取物用水(100 mL)、鹽水(100 mL)洗滌，經無水Na 2SO 4乾燥，過濾且在真空下濃縮，獲得粗產物。產物藉由矽膠層析(3至6% EtOAc/己烷)純化兩次。合併含有純產物之份且在減壓下濃縮，獲得呈淡棕色液體狀之2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇(086 g，29%)。 To 2-(3-methyl-5-(prop-1-en-2-yl)cyclopent-2-en-1-yl)-5-propylbenzene-1,3-diol (3.0 g, 9.9 mmol) in anhydrous CH2Cl2 (500 mL) was added Fe( OTf ) 3 (0.99 g, 1.98 mmol) and stirred at room temperature for 72 hours. The reaction was cooled to 0 °C and quenched with saturated NaHCO 3 solution (100 mL) and extracted with CH 2 Cl 2 (2×100 mL). The combined CH 2 Cl 2 extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to obtain the crude product. The product was purified twice by silica gel chromatography (3 to 6% EtOAc/hexanes). Fractions containing pure product were combined and concentrated under reduced pressure to afford 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c ]Alken-9-ol (086 g, 29%).

1H NMR顯示所需信號： 1H NMR 1H NMR (400 MHz, DMSO- d 6 ): δ9.20 (s, 1H), 6.06 (s, 1H), 5.96 (s, 1H), 5.34 (s, 1H), 3.64 (d, J= 6.8 Hz, 1H), 2.66-2.60 (m, 1H), 2.40-2.33 (m, 3H), 2.02-1.95 (m, 1H), 1.70 (s, 3H), 1.53-1.44 (m, 2H), 0.90-0.84 (m, 9H). MS (MM) m/z273.1 [M + H] +。 1 H NMR showed desired signal: 1 H NMR 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.20 (s, 1H), 6.06 (s, 1H), 5.96 (s, 1H), 5.34 (s, 1H), 3.64 (d, J = 6.8 Hz, 1H), 2.66-2.60 (m, 1H), 2.40-2.33 (m, 3H), 2.02-1.95 (m, 1H), 1.70 (s, 3H), 1.53 -1.44 (m, 2H), 0.90-0.84 (m, 9H). MS (MM) m/z 273.1 [M + H] + .

實例example 2 -2 - 單胺氧化酶抑制monoamine oxidase inhibition

將遞增濃度之測試化合物添加至含有單胺氧化酶(MAO-B或MAO-A酶)之反應混合物中以產生反應曲線。反應混合物使用pH 7.4之100 mM磷酸鉀作為培育緩衝液。Increasing concentrations of test compounds were added to reaction mixtures containing monoamine oxidase (MAO-B or MAO-A enzyme) to generate response curves. The reaction mixture used 100 mM potassium phosphate pH 7.4 as incubation buffer.

使用4-羥基喹啉之螢光光譜定量法(spectrofluorimetric quantitation)確定MAO-B或MAO-A酶之活性。Activity of MAO-B or MAO-A enzymes was determined using spectrofluorometric quantitation of 4-hydroxyquinoline.

基本上按Biochem Pharmacol. 41(2): 155 - 162中所描述進行分析，且其由Eurofins Panlabs, Inc.進行。在存在之情況下，IC50值係藉由非線性最小平方回歸分析使用MathIQ™ (ID Business Solutions Ltd., UK)測定。在存在抑制常數(Ki)之情況下，計算Ki值：使用Cheng及Prusoff之方程式(Cheng, Y., Prusoff, W.H., Biochem. Pharmacol. 22:3099-3108, 1973)，使用所觀測之測試化合物的IC50、分析中採用之放射性配位體的濃度及配位體之KD歷史值(以實驗方式在Eurofins Panlabs, Inc.獲得)。在存在之情況下，使用MathIQ™計算定義競爭性結合曲線之斜率的希爾係數(Hill coefficient，nH)。希爾係數明顯不同於1.0，可表明結合置換不遵循使用單一結合位點之質量作用定律。The analysis was performed essentially as described in Biochem Pharmacol. 41(2): 155-162 and was performed by Eurofins Panlabs, Inc. Where present, IC50 values were determined by non-linear least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK). Calculation of Ki values in the presence of an inhibition constant (Ki): Using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W.H., Biochem. Pharmacol. 22:3099-3108, 1973), using the observed test compound IC50, the concentration of the radioactive ligand used in the analysis and the historical KD value of the ligand (obtained experimentally at Eurofins Panlabs, Inc.). Where present, the Hill coefficient (nH), which defines the slope of the competitive binding curve, was calculated using MathIQ™. Hill coefficients significantly different from 1.0 may indicate that binding displacement does not follow the law of mass action using a single binding site.

圖1顯示2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇(T-101)在x軸上所指示之遞增濃度的反應曲線且MAO-B之抑制百分比在y軸上顯示。如圖1中所示，MAO-B之T-101抑制的IC 50測定為20.1 µM。MAO-B之參考化合物R(-)-迪普寧抑制的IC 50測定為9.69 nM，如圖1中所示。 Figure 1 shows 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]alken-9-ol (T-101) on the x-axis Response curves for the indicated increasing concentrations and percent inhibition of MAO-B are shown on the y-axis. As shown in Figure 1, the IC50 for T-101 inhibition by MAO-B was determined to be 20.1 µM. The IC 50 for the inhibition of MAO-B by the reference compound R(-)-dipnin was determined to be 9.69 nM, as shown in FIG. 1 .

下表顯示其他實驗結果。表中所示之N.C.意謂「未計算的」。 表1：T-101及Delta 9-THC之實驗結果 目錄號分析名稱 批次* 物種 代表 濃度 抑制 % IC 50* K i n H R 化合物 ： Delta 9-THC ， PT 編號： 1267929                            140010單胺氧化酶MAO-A 491219 人類 2 30μM 19 N.C.                人類 2 10μM 12                   人類 2 3μM 9                   人類 2 1μM 5             140120單胺氧化酶MAO-B 491328 人類 2 30μM 44 N.C.                人類 2 10μM 36                   人類 2 3μM 26                   人類 2 1μM 12             化合物 ： T101 ， PT 編號： 1267930                            140010單胺氧化酶MAO-A 491219 人類 2 30μM 28 N.C.                人類 2 10μM 5                   人類 2 3μM -6                   人類 2 1μM -5             140120單胺氧化酶MAO-B 491220 人類 2 30μM 59 20.1 μM                人類 2 10μM 36                   人類 2 3μM 16                   hum 2 1μM 11             The table below shows other experimental results. NC shown in the table means "not calculated". Table 1: Experimental results of T-101 and Delta 9-THC Catalog Number Analysis Name batch * species represent concentration Inhibition % IC 50* Ki f R Compound : Delta 9-THC , PT No.: 1267929 140010 Monoamine oxidase MAO-A 491219 Humanity 2 30μM 19 NC Humanity 2 10μM 12 Humanity 2 3μM 9 Humanity 2 1μM 5 140120 Monoamine oxidase MAO-B 491328 Humanity 2 30μM 44 NC Humanity 2 10μM 36 Humanity 2 3μM 26 Humanity 2 1μM 12 Compound : T101 , PT Number: 1267930 140010 Monoamine oxidase MAO-A 491219 Humanity 2 30μM 28 NC Humanity 2 10μM 5 Humanity 2 3μM -6 Humanity 2 1μM -5 140120 Monoamine oxidase MAO-B 491220 Humanity 2 30μM 59 20.1 μM Humanity 2 10μM 36 Humanity 2 3μM 16 hum 2 1μM 11

氯吉靈(Clorgyline)及迪普寧用作參考化合物，如下表2中所示。 表2：參考化合物          歷史 同時 目錄號 分析名稱 參考化合物 IC 50* K i n H 批次* IC 50* 14D010 單胺氧化酶MAO-A 氯吉靈 0.93 nM       491219 0.79 nM 140120 單胺氧化酶MAO-B R(-)- 迪普寧 9.80 nM       491220 9 69 nM       R(-)- 迪普寧 9.80 nM       491328 13.6 nM Clorgyline and Dipnin were used as reference compounds, as shown in Table 2 below. Table 2: Reference compounds history at the same time catalog number analysis name reference compound IC 50* Ki f batch * IC 50* 14D010 Monoamine oxidase MAO-A Clogiline 0.93 nM 491219 0.79 nM 140120 Monoamine oxidase MAO-B R(-)- Deepning 9.80 nM 491220 9 69 nM R(-)- Deepning 9.80 nM 491328 13.6 nM

圖1如在x軸上所指示，顯示測試化合物2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇(T-101，圓形符號)及參考化合物R(-)-迪普寧(Deprenyl) (方形符號)之遞增濃度的反應曲線。MAO-B之抑制百分比示於y軸上。Figure 1 shows the test compound 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]alken-9-ol as indicated on the x-axis Response curves for increasing concentrations of (T-101, round symbols) and reference compound R(-)-Deprenyl (square symbols). The percent inhibition of MAO-B is shown on the y-axis.

Claims (38)

一種合成大麻素衍生物，其具有式(I)之結構： 式(I) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 各 表示單鍵或雙鍵，其限制條件為在5員環內，一個 為雙鍵且其他四個 為單鍵； 或其醫藥學上可接受之鹽或酯。 A synthetic cannabinoid derivative having a structure of formula (I): Formula (I) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent is selected from hydrogen and C 1-4 alkyl; each Indicates a single bond or a double bond, with the restriction that in a 5-membered ring, one is a double bond and the other four is a single bond; or a pharmaceutically acceptable salt or ester thereof. 一種醫藥組合物，其包含如請求項1之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable vehicle for the compound. 如請求項2之醫藥組合物，其中該醫藥學上可接受之媒劑係選自由以下組成之群：膠囊、錠劑、糖漿、口含錠、吸入劑、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體(nanosome)、脂質體、非離子體(noisome)、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液及微胞(micelle)。The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of capsules, lozenges, syrups, buccal tablets, inhalants, chewable jelly, and nasal sprays , transdermal patches, liquids, transmucosal vehicles, hydrogels, nanosomes, liposomes, noisomes, nanoparticles, nanospheres, microspheres, microparticles, microemulsions , nanosuspensions and micelles. 一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法，其包含向有需要之個體投與如請求項3之醫藥組合物。A method for treating cancer, tumor, addiction, epilepsy, anxiety or depression, comprising administering the pharmaceutical composition according to claim 3 to an individual in need. 一種合成大麻素衍生物，其具有式(II)之結構： 式(II) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 各 表示單鍵或雙鍵，其限制條件為在5員環內，一個 為雙鍵且其他四個 為單鍵； 或其醫藥學上可接受之鹽或酯。 A synthetic cannabinoid derivative having the structure of formula (II): Formula (II) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent is selected from hydrogen and C 1-4 alkyl; each Indicates a single bond or a double bond, with the restriction that in a 5-membered ring, one is a double bond and the other four is a single bond; or a pharmaceutically acceptable salt or ester thereof. 一種醫藥組合物，其包含至少一種如請求項5之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising at least one compound according to claim 5 and a pharmaceutically acceptable vehicle for the compound. 如請求項6之醫藥組合物，其中該醫藥學上可接受之媒劑係選自由以下組成之群：膠囊、錠劑、糖漿、口含錠、吸入劑、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體、脂質體、非離子體、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液及微胞。The pharmaceutical composition according to claim 6, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of capsules, lozenges, syrups, buccal tablets, inhalants, chewable jelly, and nasal sprays , transdermal patches, liquids, transmucosal vehicles, hydrogels, nanoparticles, liposomes, nonionics, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions and microcells. 一種治療焦慮、成癮或抑鬱之方法，其包含向有需要之個體投與如請求項7之醫藥組合物。A method for treating anxiety, addiction or depression, comprising administering the pharmaceutical composition according to claim 7 to an individual in need. 一種治療阿茲海默氏症(Alzheimer’s disease)之方法，其包含向有需要之個體投與如請求項7之醫藥組合物。A method for treating Alzheimer's disease, comprising administering the pharmaceutical composition according to claim 7 to an individual in need. 一種合成大麻素衍生物，其具有選自由以下組成之群的結構： 或其醫藥學上可接受之鹽。 A synthetic cannabinoid derivative having a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 一種醫藥組合物，其包含至少一種如請求項10之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising at least one compound according to claim 10 and a pharmaceutically acceptable vehicle for the compound. 一種合成大麻素衍生物，其具有式(III)之結構： 式(III) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 各 表示單鍵或雙鍵，其限制條件為在5員環內，一個 為雙鍵且其他四個 為單鍵； 或其醫藥學上可接受之鹽或酯。 A synthetic cannabinoid derivative having the structure of formula (III): Formula (III) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent is selected from hydrogen and C 1-4 alkyl; each Indicates a single bond or a double bond, with the restriction that in a 5-membered ring, one is a double bond and the other four is a single bond; or a pharmaceutically acceptable salt or ester thereof. 一種醫藥組合物，其包含如請求項12之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising the compound according to claim 12 and a pharmaceutically acceptable vehicle for the compound. 如請求項13之醫藥組合物，其中該醫藥學上可接受之媒劑係選自由以下組成之群：膠囊、錠劑、糖漿、口含錠、吸入劑、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體、脂質體、非離子體、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液及微胞。The pharmaceutical composition according to claim 13, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of capsules, lozenges, syrups, buccal tablets, inhalants, chewable jelly, and nasal sprays , transdermal patches, liquids, transmucosal vehicles, hydrogels, nanobodies, liposomes, nonionics, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions and microcells. 一種治療癌症、腫瘤、成癮、癲癇症、焦慮或抑鬱之方法，其包含向有需要之個體投與如請求項13或14之醫藥組合物。A method for treating cancer, tumor, addiction, epilepsy, anxiety or depression, comprising administering the pharmaceutical composition according to claim 13 or 14 to an individual in need. 一種合成大麻素衍生物，其具有式(IV)之結構： 式(IV) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 各 表示單鍵或雙鍵，其限制條件為在5員環內，一個 為雙鍵且其他四個 為單鍵； 或其醫藥學上可接受之鹽或酯。 A synthetic cannabinoid derivative having the structure of formula (IV): Formula (IV) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent is selected from hydrogen and C 1-4 alkyl; each Indicates a single bond or a double bond, with the restriction that in a 5-membered ring, one is a double bond and the other four is a single bond; or a pharmaceutically acceptable salt or ester thereof. 一種醫藥組合物，其包含至少一種如請求項16之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising at least one compound according to claim 16 and a pharmaceutically acceptable vehicle for the compound. 如請求項17之醫藥組合物，其中該醫藥學上可接受之媒劑係選自由以下組成之群：膠囊、錠劑、糖漿、口含錠、吸入劑、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體、脂質體、非離子體、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液及微胞。The pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of capsules, lozenges, syrups, lozenges, inhalants, chewable jelly, and nasal sprays , transdermal patches, liquids, transmucosal vehicles, hydrogels, nanoparticles, liposomes, nonionics, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions and microcells. 一種治療焦慮、成癮或抑鬱之方法，其包含向有需要之個體投與如請求項17或18之醫藥組合物。A method for treating anxiety, addiction or depression, comprising administering the pharmaceutical composition according to claim 17 or 18 to an individual in need. 一種治療阿茲海默氏症之方法，其包含向有需要之個體投與如請求項17或18之醫藥組合物。A method for treating Alzheimer's disease, comprising administering the pharmaceutical composition according to claim 17 or 18 to an individual in need. 一種合成大麻素衍生物，其具有選自由以下組成之群的結構： 或其醫藥學上可接受之鹽。 A synthetic cannabinoid derivative having a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 一種醫藥組合物，其包含至少一種如請求項21之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising at least one compound according to claim 21 and a pharmaceutically acceptable vehicle for the compound. 一種化合物，其具有式(V)之結構： 式(V) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 或其醫藥學上可接受之鹽或酯，其限制條件為該化合物不為2-(3-甲基-5-(丙-1-烯-2-基)環戊-2-烯-1-基)-5-戊基苯-1,3-二醇。 A kind of compound, it has the structure of formula (V): Formula (V) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent selected from hydrogen and C 1-4 alkyl; or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 2-(3-methyl-5-(prop-1-ene-2 -yl)cyclopent-2-en-1-yl)-5-pentylbenzene-1,3-diol. 一種醫藥組合物，其包含如請求項23之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising the compound according to claim 23 and a pharmaceutically acceptable vehicle for the compound. 如請求項24之醫藥組合物，其中該醫藥學上可接受之媒劑係選自由以下組成之群：膠囊、錠劑、糖漿、口含錠、吸入劑、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體、脂質體、非離子體、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液及微胞。The pharmaceutical composition according to claim 24, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of capsules, lozenges, syrups, lozenges, inhalants, chewable jelly, and nasal sprays , transdermal patches, liquids, transmucosal vehicles, hydrogels, nanobodies, liposomes, nonionics, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions and microcells. 一種治療癌症或腫瘤之方法，其包含向有需要之個體投與如請求項24或25之醫藥組合物。A method of treating cancer or tumor, comprising administering the pharmaceutical composition according to claim 24 or 25 to an individual in need. 一種治療成癮、癲癇症、焦慮或抑鬱之方法，該方法包含向有需要之個體投與如請求項24或25之醫藥組合物。A method of treating addiction, epilepsy, anxiety or depression, the method comprising administering the pharmaceutical composition according to claim 24 or 25 to an individual in need. 一種化合物，其具有式(VI)之結構： 式(VI) 其中R 1及R 2各自獨立地選自由以下組成之群：H、OH、受保護之羥基、烷基、烯基、炔基、醯基、芳基、雜芳基、環烷基及雜環；其中該烷基、烯基、炔基或醯基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR AR B、-S-烷基、-SO-烷基、-SO 2-烷基、烯基、炔基、芳基、雜芳基、環烷基及雜環；其中R A及R B各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、-COOH、-C(O)-C 1-4烷基、-C(O)O-C 1-4烷基、NR CR D、-S-烷基、-SO-烷基及-SO 2-烷基；其中R C及R D各自獨立地選自氫及C 1-4烷基； R 3係選自由以下組成之群：H、烷基、醯基、-SO 2-烷基、-SO 2-芳基及-SO 2-雜芳基；其中該烷基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR ER F、-S-烷基、-SO-烷基、-SO 2-烷基、芳基及雜芳基；且其中R E及R F各自獨立地選自氫及C 1-4烷基；其中無論單獨或作為取代基一部分的該芳基或雜芳基視情況經一或多個獨立地選自由以下組成之群的取代基取代：鹵素、-OH、烷基、-O-烷基、NR GR H、-S-烷基、-SO-烷基及-SO 2-烷基；其中R G及R H各自獨立地選自氫及C 1-4烷基； 或其醫藥學上可接受之鹽或酯，其限制條件為該化合物不為2,4,4-三甲基-7-戊基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。 A kind of compound, it has the structure of formula (VI): Formula (VI) wherein R and R are each independently selected from the group consisting of H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkane wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted by one or more substituents independently selected from the group consisting of: halogen, -OH, alkyl, -O-alk base, NR A R B , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocycle; wherein R A and R B are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: Halogen, -OH, Alkyl, -O-Alkyl, -COOH, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, NR C R D , - S-alkyl, -SO-alkyl and -SO 2 -alkyl; wherein R C and R D are each independently selected from hydrogen and C 1-4 alkyl; R 3 is selected from the group consisting of: H, Alkyl, acyl, -SO 2 -alkyl, -SO 2 -aryl and -SO 2 -heteroaryl; wherein the alkyl is optionally substituted by one or more substituents independently selected from the group consisting of Substitution: halogen, -OH, alkyl, -O-alkyl, NR E R F , -S-alkyl, -SO-alkyl, -SO 2 -alkyl, aryl, and heteroaryl; and wherein R E and R F are each independently selected from hydrogen and C 1-4 alkyl; wherein the aryl or heteroaryl, either alone or as part of a substituent, is optionally selected from one or more of the group consisting of Substituent Substitution: Halogen, -OH, Alkyl, -O-Alkyl, NR G R H , -S-Alkyl, -SO-Alkyl and -SO 2 -Alkyl; where R G and R H are independent selected from hydrogen and C 1-4 alkyl; or a pharmaceutically acceptable salt or ester thereof, provided that the compound is not 2,4,4-trimethyl-7-pentyl-3,3a ,4,9b-Tetrahydrocyclopenta[c]𠳭en-9-ol. 如請求項28之化合物，其中該化合物為2,4,4-三甲基-7-丙基-3,3a,4,9b-四氫環戊并[c]𠳭烯-9-醇。The compound according to claim 28, wherein the compound is 2,4,4-trimethyl-7-propyl-3,3a,4,9b-tetrahydrocyclopenta[c]alken-9-ol. 一種醫藥組合物，其包含如請求項28或29之化合物及針對此化合物之醫藥學上可接受之媒劑。A pharmaceutical composition comprising the compound according to claim 28 or 29 and a pharmaceutically acceptable vehicle for the compound. 如請求項30之醫藥組合物，其中該醫藥學上可接受之媒劑係選自由以下組成之群：膠囊、錠劑、糖漿、口含錠、吸入劑、可咀嚼膠狀物、鼻用噴霧、經皮貼片、液體、經黏膜媒劑、水凝膠、奈米體、脂質體、非離子體、奈米粒子、奈米球、微球體、微米粒子、微乳液、奈米懸浮液及微胞。The pharmaceutical composition according to claim 30, wherein the pharmaceutically acceptable vehicle is selected from the group consisting of capsules, lozenges, syrups, lozenges, inhalants, chewable jelly, and nasal sprays , transdermal patches, liquids, transmucosal vehicles, hydrogels, nanoparticles, liposomes, nonionics, nanoparticles, nanospheres, microspheres, microparticles, microemulsions, nanosuspensions and microcells. 一種治療焦慮、成癮或抑鬱之方法，其包含向有需要之個體投與如請求項30或31之醫藥組合物。A method for treating anxiety, addiction or depression, comprising administering the pharmaceutical composition according to claim 30 or 31 to an individual in need. 一種治療阿茲海默氏症之方法，其包含向有需要之個體投與如請求項30或31之醫藥組合物。A method for treating Alzheimer's disease, comprising administering the pharmaceutical composition according to claim 30 or 31 to an individual in need. 一種治療與單胺氧化酶(monoamine oxidase；MAO)活性相關之疾病及病狀的方法，其包含向有需要之個體投與如請求項30或31之醫藥組合物。A method for treating diseases and conditions associated with monoamine oxidase (monoamine oxidase; MAO) activity, comprising administering the pharmaceutical composition according to claim 30 or 31 to an individual in need. 如請求項34之方法，其中該個體罹患抑鬱、疼痛或成癮。The method of claim 34, wherein the individual suffers from depression, pain or addiction. 一種化合物，其係選自由以下組成之群： ， 及其醫藥學上可接受之鹽或酯。 A compound selected from the group consisting of: , and pharmaceutically acceptable salts or esters thereof. 一種醫藥組合物，其包含以下化合物中之一或多者： ， 或其醫藥學上可接受之鹽或酯。 A pharmaceutical composition comprising one or more of the following compounds: , or a pharmaceutically acceptable salt or ester thereof. 一種治療睡眠障礙之方法，其包含向有需要之個體投與如請求項36之化合物或如請求項37之醫藥組合物。A method for treating sleep disorders, comprising administering the compound according to claim 36 or the pharmaceutical composition according to claim 37 to an individual in need.
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