CN110669017B - Polysubstituted triazole formate derivative and application thereof - Google Patents

Polysubstituted triazole formate derivative and application thereof Download PDF

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CN110669017B
CN110669017B CN201910965229.1A CN201910965229A CN110669017B CN 110669017 B CN110669017 B CN 110669017B CN 201910965229 A CN201910965229 A CN 201910965229A CN 110669017 B CN110669017 B CN 110669017B
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CN110669017A (en
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马海军
王昌华
解振彪
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Chengdu Mabeisan Pharmaceutical Technology Co ltd
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Priority to PCT/CN2020/120218 priority patent/WO2021068943A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a compound shown in a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof, which is a polysubstituted triazole formate derivative with a novel structure, and belongs to the field of pharmaceutical chemistry. The invention also discloses the application of the polysubstituted triazole formate derivative in preparing medicaments with sedative, hypnotic and/or anesthetic effects and in preparing medicaments capable of controlling epileptic persistance, the compound has a better inhibiting effect on a central nervous system, and a new choice is provided for clinically screening and/or preparing medicaments with sedative, hypnotic and/or anesthetic effects and for controlling epileptic persistance.

Description

Polysubstituted triazole formate derivative and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a polysubstituted triazole formate derivative with a novel structure, and application of the polysubstituted triazole formate derivative in preparation of a medicament with sedative, hypnotic and/or general anesthesia effects and preparation of a medicament capable of controlling status epilepticus.
Background
The imidazole derivative etomidate, the chemical name of which is R- (+) -1- (1-phenethyl) -1-hydro-imidazole-5-ethyl formate, is a hypnotic intravenous general anesthetic, has a large safety range, and is one of the common drugs for anesthesia induction. The clinical application of the imidazole derivative has been 30 years old (Br J Anaesth.1976;48 (3): 213-6.PubMed:1259887;Arch Int Pharmacodyn Ther.1975;214 (1): 92-132.PubMed:1156027;Acad Emerg Med.2006;13 (4): 378-83.PubMed: 16531603). Etomidate is a non-barbital intravenous sedative, has the action intensity of 4 times of barbital sodium and 12 times of thiobarbital sodium respectively, is quick in general anesthesia induction, quick in recovery after administration, and free from sleepiness, dizziness and other adverse reactions after patient recovery, so that the etomidate is widely applied. The structural formula is shown in the following figure, and the molecular formula is C14H16N2O2 and the molecular weight is 244.29. The imidazole derivative is insoluble in water and unstable in neutral solution.
The first to begin with etomidate in the last 70 th century in the yansen pharmacy. As the most major developer, janssen PA et al reported in one of the study reports published in 1965 that recorded the major process of etomidate synthesis and described the passage of how etomidate was screened from 42 similar compounds. Among the 11 compounds with defined anesthetic action etomidate showed the best safety in rats (i.e. highest therapeutic index TI). In addition, researchers have found that etomidate is stereoselective in sedative hypnotic effect, with the drug in the R configuration being ten times more potent than the drug in the S configuration (J Med chem.1965;8:220-3.PubMed:14332665; anesthesiology.1998;88 (3): 708-17.PubMed: 9523815). The imidazole derivative has outstanding advantages, such as larger treatment window and smaller inhibition to circulatory system in the existing general anesthetic, and is especially suitable for the elderly, coronary heart disease and hypertension patients and critical patients. Standard drugs, once anesthesia-induced, are also used as drugs for total intravenous anesthesia.
However, since the eighties of the last century, some drawbacks of etomidate (such as slightly poorer awakening quality than the other general anesthetic drug propofol), especially adverse effects on adrenocortical function, have been increasingly observed with long-term clinical use. It has been reported that etomidate inhibits the synthesis of adrenocortical hormone, thereby reducing survival in critically ill patients (Lancet.1983; 1 (8339): 1434.PubMed:6134189;Crit Care.2007;11 (3): 145.PubMed: 1761749; anesthesiology.2011;114 (3): 695-707.PubMed: 21263301). Even some studies have shown that use of etomidate in anesthesia induction increases mortality in hospitalized patients (Crit Care med.2012;40 (11): 2945-53.PubMed:22971586;Anesth Analg.2013;117 (6): 1329-37.Pubmed: 24257383); many researchers speculate that this high mortality occurs in association with etomidate inhibition of adrenocortical hormone synthesis (Cochrane Database Syst Rev.2015;1: CD010225.PubMed: 25568981). Meanwhile, the other general intravenous anesthetic propofol commonly used in clinic at present has the disadvantage of obviously reducing blood pressure in the anesthesia induction process (Crit Care.2015; 19:45.PubMed:25887642) except for small treatment window, and cardiovascular adverse events are often increased. Therefore, a new compound is designed, so that the compound can not only keep the excellent characteristics of etomidate circulation stability, but also has excellent reviving quality without inhibiting synthesis of adrenocortical hormone, and has very important clinical significance and wide application prospect.
The literature suggests that etomidate can be bound to 11 beta-hydroxylase through the imidazole ring in the structure, thereby inhibiting adrenocortical function, primarily manifested by a significant reduction in the synthesis of corticosterone and cortisol in vivo. (N Engl J Med.1984;310 (22): 1415-21.PubMed:6325910;J Clin Endocrinol Metab.1984;59 (6): 1143-7.PMID:6092411; anesthesiology.2010;112 (3): 637-44.PMID: 20179500). Atucha et al (Bioorg Med Chem Lett.2009;19 (15): 4284-7.PubMed: 19497738) found that the esteric side chain of etomidate can affect not only GABA receptors (the primary site of the anesthetic effect of etomidate) but also the synthesis of adrenocortical hormone. Whereas etomidate, the major product of etomidate metabolism, was found to have little 11-beta hydroxylase inhibiting effect compared to etomidate (Anesthesiology 2016;125 (5): 943-951.PubMed: 27541316). Thus, if the inhibition of adrenocortical function by the compound itself is reduced or eliminated by modification of the etomidate structure and the metabolite of the compound is also not affecting adrenocortical function, the inhibition of adrenocortical function by the drug can be reduced or eliminated. Subsequent studies based on etomidate structure have focused on how to reduce or eliminate the inhibition of adrenocortical function in addition to retaining the advantages of etomidate in clinical use.
For example, WO 2009/146024A1 discloses an etomidate analogue with improved pharmacokinetic and pharmacodynamic properties and its use as an anaesthetic and discloses that the compound may be MOC- (R) -etomidate.
WO 2011/005969A2 discloses an etomidate analogue with improved pharmacokinetic and pharmacodynamic properties and its use as an anaesthetic and discloses that the compound may be MOC-carboetomidate.
CN201380014062 discloses that an analogue of medetomidine and etomidate can be obtained with improved pharmacokinetic and pharmacodynamic properties, and that the compound may be cyclopropyl MOC-medetomidate.
Although scientists follow-up studies based on etomidate structure have focused on how to reduce or eliminate the inhibition of adrenocortical function in addition to retaining the advantages of etomidate in clinical use. And etomidate analogs such as Dimethylmethoxycarbonyl metomidate (DMMM) and Cyclopropyl methoxycarbonyl metomidate (CPMM) have been discovered sequentially, compounds that retain the unique advantages of etomidate (e.g., high potency, safety) while eliminating its inhibitory effect on adrenocortical function have not yet been sought.
Therefore, the novel compound is designed and synthesized, so that the excellent characteristics of etomidate circulation stability can be maintained, the adrenocortical hormone can be not inhibited, the awakening quality after continuous infusion can be improved, and the novel compound has very important clinical significance and wide application prospect.
At the same time, there is a need for safer clinical use of such derivatives for the preparation of drugs with sedative, hypnotic and/or general anesthetic actions and for the control of status epilepticus.
Disclosure of Invention
In order to solve the problems, the invention provides a polysubstituted triazole formate derivative with a novel structure.
The invention also provides the application of the polysubstituted triazole formate derivative in preparing medicaments with sedative, hypnotic and/or anesthetic effects and in preparing medicaments capable of controlling status epilepticus.
The present invention provides a compound of formula i, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof:
R 1 each independently selected from deuterium, halogen, -CN, -NO 2 、-OR 32 、-C(O)R 31 、-CO 2 R 31 、-CON(R 32 ) 2 、-N(R 32 ) 2 、-OC(O)R 31 、-SO 2 R 31 Substituted or unsubstituted 3-to 8-membered heterocyclic group, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl;
wherein R is 31 Each independently selected from deuterium, R 32 Substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl; r is R 32 Each independently selected from hydrogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 3-8 Cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof;
r is as described above 1 、R 31 、R 32 Wherein the substituents are selected from deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 3-8 A membered cycloalkyl or halo or deuterated thereof, a 3-to 8-membered heterocyclyl or halo or deuterated thereof, an aryl or halo or deuterated thereof, a heteroaryl or halo or deuterated thereof;
n is an integer of 0 to 5;
R 2 selected from hydrogen, deuterium, halogen, C 1-8 Alkyl or halo or deuterated, C 1-8 Alkoxy or halo or deutero, C 2-8 Alkenyl or halo or deuterated, C 2-8 Alkynyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof;
R 4a and R is 4b Wherein one is R 4 The other is
Wherein R is 4 Selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-8 Alkyl, N (R) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituent is deuterium, halogen and C 1-8 Alkyl or halo or deuterated, C 1-8 Alkoxy or halo or deutero, C 3-8 Cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof, -N (R) 3 ) 2 ，R 3 Is H or C 1-8 An alkyl group;
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen or C 1-8 An alkyl group;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-8 An alkylene group; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 1-8 Alkyl or halo or deuterated, C 2-8 Alkenyl or halo or deuterated, C 2-8 Alkynyl or halo or deuterated, C 1-8 Alkoxy or halo or deutero, C 3-8 Cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof;
L 1 and L 2 May be attached to an atom in the A ring which is either co-located or ectopic;
m is an integer of 0 to 4;
the ring A is none, or the ring A is selected from 3-8 membered saturated carbocycle, 3-8 membered unsaturated carbocycle, 3-8 membered saturated heterocycle or 3-8 membered unsaturated heterocycle;
R 5 selected from hydrogen, deuterium, halogen, allenyl, and,Substituted or unsubstituted C 1-8 Alkyl, -OR 33 、-SR 33 、-OC(O)R 34 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -N (R) 33 ) 2 、-C(O)R 34 、-C(S)R 34 、-S(O)R 34 、-CON(R 33 ) 2 、-SO 2 R 34 Substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, cyano, isocyano, isothiocyano, nitro, -L 33 -R 36 Or=r 39 ；
L 33 Selected from C 1-4 An alkylene group;
R 36 selected from cyano, nitro, -OC (O) R 34 、-C(O)R 34 、-S(O)R 34 、-C(O)N(R 33 ) 2 ；
R 33 Selected from hydrogen, methylsulfonyl, -L 31 -COO-L 32 Substituted or unsubstituted: c (C) 1-8 Alkyl, C 3-8 A membered cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R 34 selected from R 33 Deuterium, substituted or unsubstituted: c (C) 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, or-S-C 1-8 An alkyl group;
L 31 selected from substituted or unsubstituted C 1-8 An alkylene group; l (L) 32 Selected from substituted or unsubstituted C 1-8 An alkyl group;
r is as described above 5 、R 33 、R 34 Wherein the substituents are selected from deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 3-8 Cycloalkyl or halo or deuterated thereof, heterocyclyl of 3 to 8 members or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof, -S-C 1-4 Alkyl, disubstituted cyclic keto, =r 39 、C 2-8 Alkenyl or C 2-8 Alkynyl;
R 39 selected from O, S, NR 40 Or C (R) 41 ) 2 ，R 40 Selected from hydrogen, halogen, C 1-4 Alkyl or halo or deuterated thereof; r is R 41 Selected from R 40 Or deuterium.
Further, the method comprises the steps of,
R 1 each independently selected from deuterium, halogen, -CN, -NO 2 、-OR 32 、-C(O)R 31 、-CO 2 R 31 、-CON(R 32 ) 2 、-N(R 32 ) 2 、-OC(O)R 31 、C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl;
wherein R is 31 Each independently selected from deuterium, R 32 、C 2-3 Alkenyl, C 2-3 Alkynyl; r is R 32 Each independently selected from hydrogen, C 1-3 An alkyl group;
or n is an integer of 0 to 2;
or, R 2 Selected from hydrogen, deuterium, halogen, C 1-3 Alkyl or halo or deuterated thereof.
Further, the method comprises the steps of,
the compound is shown as a formula II-1 or a formula II-2:
R 4 selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 Alkyl, N (R) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 3-6 Cycloalkyl or halo or deuterated thereof, 3-to 6-membered heterocyclyl or halo or deuterated thereof, -N (R) 3 ) 2 ，R 3 Is H or C 1-4 An alkyl group;
x is selected from O or S;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-4 An alkylene group; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 3-5 Cycloalkyl or halo or deuterated thereof, 3-to 5-membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof;
L 1 and L 2 May be attached to an atom in the A ring which is either co-located or ectopic;
m is an integer of 0 to 4;
the ring A is none, or the ring A is selected from 3-6 membered saturated carbocycle, 3-6 membered unsaturated carbocycle, 3-6 membered saturated heterocycle or 3-6 membered unsaturated heterocycle;
R 5 selected from hydrogen, deuterium, halogen, allenyl, and,Substituted or not takenSubstituted C 1-8 Alkyl, -OR 33 、-SR 33 、-OC(O)R 34 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -N (R) 33 ) 2 、-C(O)R 34 、-C(S)R 34 、-S(O)R 34 、-CON(R 33 ) 2 、-SO 2 R 34 Substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, cyano, isocyano, isothiocyano, nitro, -L 33 -R 36 Or=r 39 ；
L 33 Selected from C 1-4 An alkylene group;
R 36 selected from cyano, nitro, -OC (O) R 34 、-C(O)R 34 、-S(O)R 34 、-C(O)N(R 33 ) 2 ；
R 34 Selected from deuterium or R 33 ，R 33 Selected from hydrogen, methylsulfonyl, substituted or unsubstituted: c (C) 1-8 Alkyl, C 3-8 A membered cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R 34 selected from R 33 Deuterium, substituted or unsubstituted: c (C) 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl;
r is as described above 5 、R 33 、R 34 Wherein the substituents are selected from deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 3-8 Cycloalkyl or halo or deuterated thereof, heterocyclyl of 3 to 8 members or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof, -S-C 1-4 Alkyl, disubstituted cyclic keto, =r 39 、C 2-6 Alkenyl or C 2-6 Alkynyl;
R 39 selected from O, S, NR 40 Or C (R) 41 ) 2 ，R 40 Selected from hydrogen, halogen, C 1-4 Alkyl or halo or deuterated thereof; r is R 41 Selected from R 40 Or deuterium.
Further, the method comprises the steps of,
R 4 selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 Alkyl, N (R) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 3-6 Cycloalkyl or halo or deuterated thereof, 3-to 6-membered heterocyclyl or halo or deuterated thereof, -N (R) 3 ) 2 ，R 3 Is H or C 1-4 An alkyl group;
or, L 1 And L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-4 An alkylene group; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 3-5 Cycloalkyl or halo or deuterated thereof, 3-to 5-membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof;
m is an integer of 0 to 4;
or, the ring A is absent, or, the ring A is selected from 3-6 membered saturated carbocycle, 3-6 membered unsaturated carbocycle, 3-6 membered saturated heterocycle or 3-6 membered unsaturated heterocycle;
or, R 5 Selected from hydrogen, deuterium, halogen, allenyl, and,Substituted or unsubstituted C 1-6 Alkyl, -OR 33 、-SR 33 、-OC(O)R 34 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -N (R) 33 ) 2 、-C(O)R 34 、-C(S)R 34 、-S(O)R 34 、-CON(R 33 ) 2 、-SO 2 R 34 Substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, cyano, isocyano, isothiocyano, =r 39 ；
R 33 Selected from hydrogen, methylsulfonyl,Substituted or unsubstituted following groups: c (C) 1-4 Alkyl, C 3-8 A membered cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
R 34 selected from R 33 Deuterium, substituted or unsubstituted: c (C) 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl;
r is as described above 5 、R 33 、R 34 Wherein the substituents are selected from deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -S-C 1-4 Alkyl, disubstituted cyclic keto, =r 39 、C 2-4 Alkenyl or C 2-4 Alkynyl;
R 39 selected from O, S, NR 40 Or C (R) 41 ) 2 ，R 40 Selected from hydrogen, halogen, C 1-4 Alkyl or halo or deuterated thereof; r is R 41 Selected from R 40 Or deuterium.
Further, the method comprises the steps of,
R 4 selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-2 Alkyl, N (R) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The substituent is deuterium, halogen and C 1-2 Alkyl or halo or deuterated, C 1-2 Alkoxy or halo or deuterate, -N (R) 3 ) 2 ，R 3 Is H or C 1-4 An alkyl group;
or, L 1 And L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-3 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 2-3 Alkenyl or halo or deuterated, C 2-3 Alkynyl or halo or deuterated, C 1-3 Alkoxy or halo or deuterated thereof;
m is an integer of 0 to 3;
or, the ring A is none, or, the ring A is selected from 3-6 membered saturated carbocycle, 3-6 membered unsaturated carbocycle or 3-6 membered saturated heterocycle;
or, R 5 Selected from hydrogen, deuterium, halogen, allenyl, and,Substituted or unsubstituted C 1-4 Alkyl, -OR 33 、-SR 33 、-OC(O)R 34 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -N (R) 33 ) 2 、-C(O)R 34 、-C(S)R 34 、-S(O)R 34 、-CON(R 33 ) 2 、-SO 2 R 34 Substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, cyano, isocyano, isothiocyano, =r 39 ；
R 33 Selected from hydrogen, methylsulfonyl, substituted or unsubstituted: c (C) 1-3 Alkyl, C 3-6 A membered cycloalkyl, 3-6 membered heterocyclyl, aryl, heteroaryl;
R 34 selected from R 33 Deuterium, substituted or unsubstituted C 1-3 An alkoxy group;
r is as described above 5 、R 33 、R 34 Wherein the substituents are selected from deuterium, halogen, cyano, C 1-2 Alkyl, C 1-2 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, aryl, heteroaryl, -S-C 1-2 Alkyl, disubstituted cyclic keto, =r 39 、C 2-4 Alkenyl or C 2-4 Alkynyl;
R 39 selected from O, S, NR 40 Or C (R) 41 ) 2 ，R 40 Selected from hydrogen, halogen, C 1-3 Alkyl or halo or deuterated thereof; r is R 41 Selected from R 40 Or deuterium.
Further, the method comprises the steps of,
R 4 selected from hydrogen, deuterium, halogen, halogenated or non-halogenated methyl, -N (R) 3 ) 2 ，R 3 Is H or C 1-2 An alkyl group;
or, L 1 And L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-2 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl;
m is an integer of 0 to 2;
or, the ring A is none, or, the ring A is selected from 3-6 membered saturated carbocycle, 3-6 membered unsaturated carbocycle or 3-6 membered saturated heterocycle;
or, R 5 Selected from hydrogen, deuterium, halogen, allenyl, and,Substituted or unsubstituted C 1-3 Alkyl, -OR 33 、-SR 33 、-OC(O)R 34 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -N (R) 33 ) 2 、-C(O)R 34 、-C(S)R 34 、-S(O)R 34 、-CON(R 33 ) 2 、-SO 2 R 34 Substituted or unsubstituted C 2-3 Alkenyl, substituted or unsubstituted C 2-3 Alkynyl, cyano, isocyano, isothiocyano, =r 39 ；
R 33 Selected from hydrogen, methylsulfonyl, acetyl, C 1-3 An alkyl group;
R 34 selected from R 33 Deuterium, C 1-3 An alkoxy group;
r is as described above 5 Wherein the substituents are selected from deuterium, halogen, cyano, C 1-2 Alkyl, 3-5 membered heterocyclyl, -S-CH 3 Disubstituted cyclic keto, =r 39 、C 2-4 Alkenyl or C 2-4 Alkynyl;
R 39 selected from O, S, NR 40 Or C (R) 41 ) 2 ，R 40 Selected from hydrogen, halogen, C 1-3 An alkyl group; r is R 41 Selected from R 40 Or deuterium.
Further, the method comprises the steps of,
the compound is shown as a formula II-1 or a formula II-2:
wherein:
the A ring is a 3-6 membered saturated carbocycle;
x is selected from O or S; m is an integer of 0 to 2;
R 4 selected from hydrogen, deuterium, halogen, methyl, halogenated or non-halogenated, N (R) 3 ) 2 ，R 3 Is H or C 1-2 An alkyl group; preferably, R 4 Selected from hydrogen, deuterium, F, cl, br, I, CF 3 、-N(CH 3 ) 2 ；
L 1 And L 2 Each independently selected from methylene groups which are unsubstituted, substituted or unsubstituted with 1 to 2 substituents; the substituent is deuterium, C 1-4 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl;
L 1 and L 2 May be attached to an atom in the A ring which is either co-located or ectopic;
R 5 selected from hydrogen, deuterium, C 1-2 Alkyl, allenyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, -OR 33 、-SR 33 、-C(O)R 34 Halogen, =r 39 ；
R 33 Selected from C 1-3 An alkyl group;
R 34 selected from R 33 Deuterium, C 1-3 An alkoxy group;
R 5 wherein the substituents are selected from =r 39 、C 2-4 Alkenyl or C 2-4 Alkynyl;
R 39 selected from O, S, CH 2 ；
Or, wherein:
the A ring is 3-6 membered saturated heterocycle; preferably, ring A isM is O or S;
x is selected from O or S; m is an integer of 0 to 2;
R 4 selected from hydrogen, deuterium, halogen, methyl, halogenated or non-halogenated, N (R) 3 ) 2 ，R 3 Is H or C 1-2 An alkyl group; preferably, R 4 Selected from hydrogen, deuterium, F, cl, br, I, CF 3 、-N(CH 3 ) 2 ；
L 1 And L 2 Each independently selected from methylene groups which are unsubstituted, substituted or unsubstituted with 1 to 2 substituents; the substituent is deuterium, C 1-4 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl;
R 5 selected from hydrogen, deuterium, C 1-2 Alkyl, allenyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, -OR 33 、-SR 33 、-C(O)R 34 Halogen, =r 39 ；
R 33 Selected from C 1-3 An alkyl group;
R 34 selected from R 33 Deuterium, C 1-3 An alkoxy group;
R 5 wherein the substituents are selected from =r 39 、C 2-4 Alkenyl or C 2-4 Alkynyl;
R 39 selected from O, S, CH 2 ；
Or, wherein:
the A ring is 5-6 membered unsaturated carbocycle; preferably, ring A is
X is selected from O or S; m is an integer of 0 to 1;
R 4 selected from hydrogen, deuterium, halogen, methyl, halogenated or non-halogenated, N (R) 3 ) 2 ，R 3 Is H or C 1-2 An alkyl group; preferably, R 4 Selected from hydrogen, deuterium, F, cl, br, I, CF 3 、-N(CH 3 ) 2 ；
L 1 And L 2 Each independently selected from methylene groups which are unsubstituted, substituted or unsubstituted with 1 to 2 substituents; the substituent is deuterium, C 1-4 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl;
R 5 selected from-C (O) R 34 ，R 34 Selected from deuterium, R 33 、C 1-2 Alkoxy, R 33 Selected from hydrogen, C 1-2 An alkyl group;
or, wherein:
ring a is absent;
x is selected from O or S; m is an integer of 0 to 1;
R 4 selected from hydrogen, deuterium, halogen, halogenated or non-halogenated methyl, -N (R) 3 ) 2 ，R 3 Is H or C 1-2 An alkyl group; preferably, R 4 Selected from hydrogen, deuterium, F, cl, br, I, CF 3 、-N(CH 3 ) 2 ；
L 1 And L 2 Each independently selected from methylene groups which are unsubstituted, substituted or unsubstituted with 1 to 2 substituents; the substituent is deuterium, C 1-4 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl;
R 5 selected from hydrogen, deuterium, C 1-4 Alkyl, 1-3 halogen substituted C 1-4 Alkyl, allenyl, and,Substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, -OR 33 、-SR 33 、-C(O)R 34 ；
R 33 Selected from C 1-3 An alkyl group;
R 34 selected from deuterium, R 33 、C 1-3 An alkoxy group;
R 5 wherein the substituents are selected from the group consisting of disubstituted cyclopentanone groups, =r 39 、C 2-4 Alkenyl or C 2-4 Alkynyl, R 39 Selected from O, S, CH 2 。
Further, the method comprises the steps of,
the compound is as follows:
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the invention also provides a medicine, which is a preparation prepared from the compound, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative, or a composition thereof, and pharmaceutically acceptable auxiliary materials.
The invention also provides the application of the compound, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative, or a composition thereof in preparing medicines with sedative, hypnotic and/or anesthetic effects and/or for controlling epileptic persistance states.
The invention relates to a drug with sedation, which is a drug for effectively helping sleep and effectively improving sleep. Can avoid serious harm of insomnia to human body, treat insomnia and improve sleep quality.
The invention relates to a drug with hypnotic effect, which is a drug capable of inducing drowsiness and promoting sleep. I.e. has an inhibitory effect on the central nervous system, a small dose causes sedation, and an excess leads to general anesthesia.
The term "drug with anesthesia" as used herein refers to a reversible inhibition of central and/or peripheral nervous system functions, which is characterized by a loss of sensation, particularly pain, resulting from the drug.
Preferably, the anesthesia is general anesthesia.
The general anesthesia is abbreviated as general anesthesia, and refers to temporary inhibition of central nervous system after anesthetic enters the body, and clinical manifestations of the general anesthesia are loss of mind, loss of general pain, forgetfulness, reflex inhibition and skeletal muscle relaxation.
The use of a compound as defined above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of a medicament capable of controlling status epilepticus.
The invention relates to a status epilepticus, which means that consciousness between epileptic continuous seizures is not completely recovered and frequently recurred, or the seizure is not stopped by itself after more than 30 minutes. If the epileptic seizure is not treated in time, irreversible brain damage can be caused by hyperthermia, circulatory failure or neuronal excitotoxic damage, and the disability rate and the death rate are high, so that the epileptic status is a common emergency in the department of medicine.
The invention provides a medicine which is a preparation prepared from the compound, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative thereof, and pharmaceutically acceptable auxiliary materials.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that one or more hydrogen atoms in a molecule are replaced by other atoms or molecules other than hydrogen, including 1 or more substitutions on a co-or off-site atom in the molecule.
The structures of the compounds in the invention all refer to structures which can exist stably.
"deuterium" refers to an isotope of hydrogen (H), also known as deuterium, with the elemental symbol typically D or 2H.
The substituent "-C (O) R" in the present invention 32 "has the structural formula:
substituent "-CO" in the present invention 2 R 32 "has the structural formula:
substituent "-CON (R) in the present invention 32 ) 2 "has the structural formula:
substituent "-N (R) in the present invention 32 ) 2 "has the structural formula:
substituent "-OC (O) R in the present invention 32 "has the structural formula:
substituent "-SO" in the present invention 2 R 32 "has the structural formula:
the substituent "-C (S) R" in the present invention 34 "has the structural formula:
in the present invention, the substituent "-S (O) R 34 "has the structural formula:
the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by prefixes, for example, prefixes (C a ～C b ) Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～C 8 Alkyl refers to alkyl groups containing 1 to 8 carbon atoms. C (C) 1 ～C 8 Alkyl refers to a straight or branched hydrocarbon chain containing one to eight carbon atoms.
"alkyl" is a hydrocarbon radical containing few hydrogen atoms in the alkane molecule, e.g. methyl-CH 3 ethyl-CH 3 CH 2 Etc.
"alkylene" refers to a hydrocarbon group of alkane molecules with a reduced number of two hydrogen atoms, e.g. methylene-CH 2 -, ethylene-CH 2 CH 2 -and the like. "C 1-8 Alkylene "refers to a straight or branched hydrocarbon chain containing one to eight carbon atoms.
"substituted or unsubstituted C 1-8 Alkyl "means C 1-8 The alkyl group may be substituted or unsubstituted.
The A ring of the compound isWhen (I)>Representing ring A and L respectively 1 And L 2 Is a ligation site of (2). Similarly, the A ring of the compounds of the invention is +.>When (I)>Representing ring A and L respectively 1 And L 2 Is a ligation site of (2).
In the present invention, "ring A is none" means L 1 And L 2 Directly connected through chemical bond.
The "3-to 6-membered saturated carbocycle" in the "A-ring is a 3-to 6-membered saturated carbocycle" in the present invention means a carbocycle composed of 3 to 6 carbon atoms, wherein there is no double bond in the carbocycle.
The "3-to 6-membered unsaturated carbocycle" in the "A-ring is a 3-to 6-membered unsaturated carbocycle" in the present invention means a carbocycle composed of 3 to 6 carbon atoms, wherein the carbocycle contains a double bond.
The "3-6 membered saturated heterocyclic ring" in the present invention means a saturated heterocyclic ring having no double bond, wherein the heterocyclic ring carries at least one nitrogen atom selected from O, S or substitution, and the remaining ring atoms are carbon.
The "3-to 6-membered unsaturated carbocycle" in the "A-ring is a 3-to 6-membered unsaturated heterocycle" in the present invention means a saturated heterocycle having a double bond, wherein at least one nitrogen atom selected from O, S or substitution is carried in the heterocycle, and the remaining ring atoms are carbon.
"alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group may be straight or branched. Having a definition of the number of carbon atoms before alkynyl (e.g. C 2-8 Alkynyl), for example, the term "C 2-8 Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms.
"alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. The alkenyl group may be straight or branched. Having a limit on the number of carbon atoms before the alkenyl group (e.g. C 2-8 Alkenyl), for example, the term“C 2-8 Alkenyl "refers to straight or branched alkenyl groups having 2 to 8 carbon atoms.
Halogen is fluorine, chlorine, bromine or iodine.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be a single ring or multiple rings. For example, "C 3-8 Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms.
"3-8 membered heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and may carry at least one cycloalkyl group selected from O, S or a substituted nitrogen atom, the remaining ring atoms being carbon.
“C 1-4 Alkyl or halo or deuterated "means C 1-4 Alkyl, C substituted by halogen or deuterium 1-4 An alkyl group. Other terms are similarly defined with respect to "or halo or deuterated thereof".
Among all the compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.
"pharmaceutically acceptable carrier" means: one or more compatible solids or liquidsBulk filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention with pharmaceutically acceptable inorganic and organic acids, suitable for contact with the tissues of a subject (e.g., a human) without undue adverse side effects. Among the preferred mineral acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
The term "pharmaceutically acceptable solvate" refers to a solvate of a compound of the invention with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.
As used herein, the term "pharmaceutically acceptable stereoisomer" refers to a chiral carbon atom referred to in the compounds of the invention that can be in the R configuration, or in the S configuration, or a combination thereof.
The compounds of the invention or compositions and methods of use thereof:
the compounds of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, as well as pharmaceutical compositions containing the compounds of the present invention as the primary active ingredient, are useful in the administration of sedation, hypnosis and/or general anesthesia. The compounds of the present invention are also useful in the control of status epilepticus and the like.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
Modes of use of the compounds or pharmaceutical compositions of the present invention include (but are not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administration.
Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When used in pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically safe and effective dosage.
When a pharmaceutical composition is used, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is pharmaceutically effective, and for a human of 60 kg body weight, the daily dosage is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The room temperature is 25+/-5 ℃.
The "overnight" according to the invention is 12.+ -. 1 hour.
The "1N HCl" of the invention is 1mol/L HCl.
The invention provides a compound shown in a formula I, which is a polysubstituted triazole formate derivative with a novel structure, has a good inhibition effect on a central nervous system, can be used for preparing medicines with sedative, hypnotic and/or anesthetic effects, can be used for preparing medicines capable of controlling epileptic persistance, and provides a new choice for clinically screening and/or preparing medicines with sedative, hypnotic and/or anesthetic effects, epileptic persistance control and the like.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1: effects of the compounds of the invention on adrenal cortex function; * The representation was statistically significant compared to the 0.9% NaCl group.
Fig. 2: the effect of the compounds of the invention on Mean Arterial Pressure (MAP) (measured value); remarks: (1) All test animals showed no loss of eversion and specular reflection within 1min after the end of dosing; (2) 0min on the abscissa in the graph represents the end of administration; (3) The time for recovery of the eversion of each compound or drug is PRO:645s (10.75 min); ETO:440s (7.33 min); compound 1:120.6s (2.01 min); compound 6:133s (2.22 min); compound 8:139s (2.32 min); compound 10:80s (1.34 min); compound 18:186s (3.10 min); compound 21:251s (4.19 min); compound 36:214s (3.57 min); compound 51:132s (2.20 min); compound 80:203s (3.39 min); compound 99:127s (2.12 min); compound 108:100s (1.63 min); compound 127:116s (1.93 min).
Fig. 3: the effect (rate of change) of the compounds of the invention on Mean Arterial Pressure (MAP); remarks: (1) All test animals showed no loss of eversion and specular reflection within 1min after the end of dosing; (2) 0min on the abscissa in the graph represents the end of administration; (3) The time for recovery of the eversion of each compound or drug is PRO:645s (10.75 min); ETO:440s (7.33 min); compound 1:120.6s (2.01 min); compound 6:133s (2.22 min); compound 8:139s (2.32 min); compound 10:80s (1.34 min); compound 18:186s (3.10 min); compound 21:251s (4.19 min); compound 36:214s (3.57 min); compound 51:132s (2.20 min); compound 80:203s (3.39 min); compound 99:127s (2.12 min); compound 108:100s (1.63 min); compound 127:116s (1.93 min).
Fig. 4: the effect (measured value) of the compounds of the invention on Heart Rate (HR); remarks: (1) All test animals showed no loss of eversion and specular reflection within 1min after the end of dosing; (2) 0min on the abscissa in the graph represents the end of administration; (3) The time for recovery of the eversion of each compound or drug is PRO:645s (10.75 min); ETO:440s (7.33 min); compound 1:120.6s (2.01 min); compound 6:133s (2.22 min); compound 8:139s (2.32 min); compound 10:80s (1.34 min); compound 18:186s (3.10 min); compound 21:251s (4.19 min); compound 36:214s (3.57 min); compound 51:132s (2.20 min); compound 80:203s (3.39 min); compound 99:127s (2.12 min); compound 108:100s (1.63 min); compound 127:116s (1.93 min).
Fig. 5: the effect of the compounds of the invention on Heart Rate (HR) (rate of change); remarks: (1) All test animals showed no loss of eversion and specular reflection within 1min after the end of dosing; (2) 0min on the abscissa in the graph represents the end of administration; (3) The time for recovery of the eversion of each compound or drug is PRO:645s (10.75 min); ETO:440s (7.33 min); compound 1:120.6s (2.01 min); compound 6:133s (2.22 min); compound 8:139s (2.32 min); compound 10:80s (1.34 min); compound 18:186s (3.10 min); compound 21:251s (4.19 min); compound 36:214s (3.57 min); compound 51:132s (2.20 min); compound 80:203s (3.39 min); compound 99:127s (2.12 min); compound 108:100s (1.63 min); compound 127:116s (1.93 min).
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III) nuclear magnetic resonance apparatus, in which the solvent was deuterated dimethyl sulfoxide (d) 6 -DMSO) or deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
LCMS was measured (Agilent LCMS 1260-6110) (ESI), column: waters X-Bridge C18 (50mm X4.6mm X3.5 μm). Column temperature is 40 ℃; the flow rate is 2.0mL/min; mobile phase from 95% [ water+0.05% TFA over 3 minutes]And 5% [ CH ] 3 CN+0.05％TFA]Gradient to 0% [ water+0.05% TFA]And 100% [ CH ] 3 CN+0.05％TFA]Under these conditions for 1 minute and then a gradient of 95% over 0.05 minute [ water+0.05% TFA]And 5% [ CH ] 3 CN+0.05％TFA]This condition was maintained for an additional 0.7 minutes.
1) Medicinal materials and reagents
The thin layer chromatography silica gel plate is HSGF254 silica gel plate of Ministry of Chemicals, ministry of tobacco, and has a thickness of 1mm.
Thin Layer Chromatography (TLC) was developed using a smoke table Jiang You silica gel, a product of the company limited, with a specification of 0.2±0.03mm.
The column layer is generally carried by silica gel of 100-200 mesh or 200-300 mesh of solar desiccant Co., ltd., shandong Wisea.
2) Main instrument
JA2003N electronic balance (Shanghai bleb instruments, inc.);
98-2 magnetic stirrer (Shanghai Sele instruments Co., ltd.);
contact voltage regulator (Zhejiang day positive electric machine Co., ltd.);
temperature controller (Shanghai position, electric appliance Co., ltd.);
ZF-2 three-purpose ultraviolet instrument (Shanghai Anting electronic instruments works);
r-201 rotary evaporator (Shanghai Shen Shun Biotechnology Co., ltd.);
W201D thermostatic water bath (Shanghai Shen Shun Biotechnology Co., ltd.);
SHB-III circulating water vacuum pump (Zhengzhou Hui Cheng Co., ltd.);
SHB-B95 mobile water pump (Zhengzhou Hui Cheng Kong trade Co., ltd.);
a cryo-cooling circulation pump (incorporated by reference, inc.);
rotary vane vacuum pump (Yogham vacuum equipment Co., ltd.) in the ocean.
General operation a:
r-1- (1-phenethyl) -1H-pyrazole-5-carboxylic acid or the corresponding pyrazole 3-, 4-or 34-substituted carboxylic acid (1 eq), DCC (1.5 eq) and DMAP (1.5 eq) were dissolved in dichloromethane at room temperature, stirred for 5 minutes at room temperature, then alcohol or thiol (1.5 eq) was slowly added to the reaction system using a syringe, and stirred overnight at room temperature. The reaction of the system is monitored to be complete by TLC, the solvent is removed by decompression concentration, methyl tertiary butyl ether is added and stirred, suction filtration is carried out, a filter cake is washed by methyl tertiary butyl ether, the filtrate is decompressed and concentrated to obtain a crude product, and the crude product is purified by preparative TLC or silica gel column chromatography to obtain a pure product.
Example 1 preparation of Compounds 1 and 2 of the invention
1. Preparation of (R) - (1-Azidoethyl) benzene (1-2)
1-1 (20 g,164 mmol) and PPh were incubated in an ice-water bath at 0deg.C 3 (85.9 g,328 mmol) was dissolved in THF (300 mL), then a solution of DEAD (57.1 g,328 mmol) in THF (50 mL) was added dropwise at a rate of 10mmol/min to the system, DPPA (54.1 g, 197mmol) was added dropwise to the system at a rate of 6mmol/min, and after the addition was completed, the mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction by TLC, saturated brine (150 mL) was added to the reaction system, extracted with n-hexane (3×50 mL), separated into three layers, the uppermost layer was collected, the uppermost organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/100 to 1/50), TLC (ethyl acetate/petroleum ether (v/v) =1/10) was monitored, and rf=0.5 to 0.6 fraction was collected to give the objective compound 1-2 (20 g, yield 83%).
2. Preparation of target Compounds 1 and 2
1-2 (4.8 g,32.6 mmol) and ethyl propiolate (6.4 g,65.2 mmol) were dissolved in toluene (100 mL) at room temperature, and then stirred under reflux for 2 hours. After completion of the reaction by TLC, saturated brine (30 mL) was added to the reaction system, extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/10 to 1/1), TLC (ethyl acetate/petroleum ether (v/v) =1/5) was monitored, and rf=0.5 to 0.6 fractions were collected to give the objective compound 1 (1.3 g, yield 16%) and the objective compound 2 (4.0 g, yield 50%).
Compound 1: ESI [ M+H ]] + ＝246.3
1 H NMR(400MHz,CDCl 3 )δ8.17(s,1H),7.42–7.29(m,5H),6.58(q,J＝7.1Hz,1H),4.45–4.26(m,2H),2.08(d,J＝7.1Hz,3H),1.37(t,J＝7.1Hz,3H).
Compound 2: ESI [ M+H ]] + ＝246.3
1 H NMR(400MHz,CDCl 3 )δ7.97(s,1H),7.46–7.36(m,3H),7.35–7.29(m,2H),5.91(q,J＝7.1Hz,1H),4.42(q,J＝7.1Hz,2H),2.03(d,J＝7.1Hz,3H),1.41(t,J＝7.1Hz,3H).
EXAMPLE 2 preparation of Compounds 3 to 32 of the present invention
1. Preparation of Compound A
LiOH.H was then added at room temperature 2 O (220 mg,5.24 mmol) was added in one portion to MeOH/THF/H of Compound 1 (643 mg,2.62 mmol) 2 The solution of O (3 mL, 1/1/1) was stirred overnight at room temperature. After completion of the reaction by TLC, the reaction solution was concentrated, water (10 mL) was added thereto, pH was adjusted to 4-5 with 1N hydrochloric acid, and then extracted with methylene chloride (3X 15 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to give Compound A as a white solid (545 mg, yield 96%). ESI [ M+H ]] + ＝218.2
1 H NMR(400MHz,CDCl 3 )δ8.25(s,1H),7.38–7.30(m,5H),6.58–6.52(m,1H),2.10(d,J＝7.0Hz,3H).
2. Preparation of target Compounds 3 to 32
Preparation of compounds 3 to 32 were synthesized according to the general procedure a using compound a (100 mg,0.46 mmol) and the corresponding alcohol (0.69 mmol) as starting materials, the crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/5) and the fraction of rf=0.4 to 0.6 was collected to give the title compound as a colourless oil.
Compound 3:21mg, ESI [ M+H ]] + ＝312.3
1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.39–7.29(m,5H),6.48(q,J＝7.0Hz,1H),5.64(t,J＝6.6Hz,1H),5.04–4.75(m,6H),2.09(d,J＝7.1Hz,3H).
Compound 4:82mg, ESI [ M+H ]] + ＝342.1
1 H NMR(400MHz,CDCl 3 )δ8.18(s,1H),7.38–7.29(m,5H),6.46(q,J＝7.0Hz,1H),3.57(s,3H),2.82–2.55(m,4H),2.05–1.88(m,2H),2.07(d,J＝7.1Hz,3H).
Compound 5:77mg, ESI [ M+H ]] + ＝296.1
1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.39–7.28(m,5H),6.47(q,J＝7.0Hz,1H),5.87–5.60(m,3H),5.59–5.23(m,1H),2.07(d,J＝7.1Hz,3H),1.66(t,J＝6.0Hz,3H).
Compound 6:105mg, ESI [ M+H ]] + ＝272.2
1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.41–7.29(m,5H),6.56(q,J＝7.1Hz,1H),5.17(p,J＝7.5Hz,1H),2.51–2.34(m,2H),2.25–2.11(m,2H),2.08(d,J＝7.1Hz,3H),1.94–1.82(m,1H),1.77–1.63(m,1H).
Compound 7:96mg, ESI [ M+H ]] + ＝272.2
1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.39–7.29(m,5H),6.58(q,J＝7.0Hz,1H),4.21–4.04(m,2H),2.09(d,J＝7.1Hz,3H),1.26–1.14(m,1H),0.69–0.58(m,2H),0.42–0.28(m,2H).
Compound 8:46mg, ESI [ M+H ]] + ＝302.2
1 H NMR(400MHz,CDCl 3 )δ8.17(s,1H),7.40–7.30(m,5H),6.54(q,J＝7.0Hz,1H),4.89–4.80(m,1H),3.70–3.61(m,1H),3.28(s,3H),2.95–2.78(m,2H),2.18–2.10(m,2H),2.08(d,J＝7.1Hz,3H).
Compound 9:33mg, ESI [ M+H ] ] + ＝298.0
1 H NMR(400MHz,CDCl 3 )δ7.97(s,1H),7.46–7.36(m,3H),7.35–7.29(m,2H),5.91(q,J＝7.1Hz,1H),4.85–4.73(m,2H),4.35–4.18(m,2H),2.89–2.71(m,2H),2.74–2.29(m,3H),2.03(d,J＝7.1Hz,3H).
Compound 10:85mg, ESI [ M+H ]] + ＝258.3
1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.40–7.29(m,5H),6.57(q,J＝7.3Hz,1H),6.05–5.90(m,1H),5.44–5.28(m,2H),4.87–4.71(m,2H),2.09(d,J＝7.1Hz,3H).
Compound 11:20mg, ESI [ M+H ]] + ＝338.2
1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.41–7.29(m,5H),6.55(q,J＝7.1Hz,1H),5.60(s,1H),4.93(d,J＝3.8Hz,2H),2.35–2.18(m,2H),2.17–2.03(m,5H),1.62–1.49(m,4H),1.46–1.33(m,2H).
Compound 12:39mg, ESI [ M+H ]] + ＝274.3
1 H NMR(400MHz,CDCl 3 )δ8.08(s,1H),7.40–7.30(m,5H),6.59(q,J＝6.7Hz,1H),2.08(d,J＝7.0Hz,3H),1.55(s,9H).
Compound 13:94mg, ESI [ M+H ]] + ＝286.3
1 H NMR(400MHz,CDCl 3 )δ8.17(s,1H),7.42–7.28(m,5H),6.58(q,J＝7.5Hz,1H),5.89–5.74(m,1H),5.41–5.17(m,3H),2.13–2.03(m,3H),1.77–1.67(m,2H),1.00–0.87(m,3H).
Compound 14:55mg, ESI [ M+H ]] + ＝288.3
1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.41–7.29(m,5H),6.48(q,J＝7.1Hz,1H),4.81(dd,J＝27.0,7.3Hz,2H),4.57(t,J＝6.6Hz,2H),2.09(d,J＝7.1Hz,3H),1.77(s,3H).
Compound 15:15mg, ESI [ M+H ]] + ＝340.3
1 H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.37–7.30(m,5H),6.50(q,J＝7.2Hz,1H),2.45–2.38(m,2H),2.36–2.28(m,2H),2.12(d,J＝7.0Hz,3H),2.06(s,3H),1.83–1.76(m,2H),1.75–1.68(m,2H).
Compound 16:15mg, ESI [ M+H ]] + ＝288.2
1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H),7.38–7.29(m,5H),6.42(q,J＝7.2Hz,1H),4.29–4.21(m,1H),2.59–2.44(m,2H),2.25–2.07(m,4H),2.06(d,J＝7.1Hz,3H).
Compound 17:86mg, ESI [ M+H ]] + ＝260.2
1 H NMR(400MHz,CDCl 3 )δ8.14(s,1H),7.43–7.29(m,5H),6.58(q,J＝7.1Hz,1H),5.29–5.13(m,1H),2.08(d,J＝7.1Hz,3H),1.35(d,J＝6.2Hz,3H),1.32(d,J＝6.3Hz,3H).
Compound 18:98mg, ESI [ M+H ]] + ＝258.3
1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),7.42–7.28(m,5H),6.55(q,J＝7.1Hz,1H),4.36–4.25(m,1H),2.08(d,J＝7.1Hz,3H),0.92–0.70(m,4H).
Compound 19:102mg, ESI [ M+H ]] + ＝300.2
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.43–7.28(m,5H),6.54(q,J＝7.1Hz,1H),6.24–6.13(m,1H),5.37–5.14(m,2H),4.97–4.61(m,4H),2.08(d,J＝7.1Hz,3H).
Compound 20:56mg, ESI [ M+H ]] + ＝338.3
1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.41–7.25(m,5H),6.56(q,J＝7.1Hz,1H),2.17–2.02(m,5H),2.01–1.90(m,2H),1.87(s,3H),1.69–1.25(m,6H).
Compound 21:49mg, ESI [ M+H ]] + ＝314.2
1 H NMR(400MHz,CDCl 3 )δ8.13(s,1H),7.44–7.28(m,5H),6.52(q,J＝7.1Hz,1H),5.97–5.61(m,2H),5.03–4.71(m,3H),4.71(d,J＝8.0Hz,1H),2.08(d,J＝7.1Hz,3H),1.73–1.60(m,3H).
Compound 22:34mg, ESI [ M+H ]] + ＝318.2
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.43–7.28(m,5H),6.53(q,J＝7.1Hz,1H),4.41–4.33(m,4H),3.33(s,2H),2.08(d,J＝7.1Hz,3H),1.31(s,3H).
Compound 23:75mg, ESI [ M+H ]] + ＝302.2
1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.42–7.29(m,5H),6.53(q,J＝7.1Hz,1H),4.52–4.32(m,6H),2.08(d,J＝7.1Hz,3H),1.31(s,3H).
Compound 24:29mg, ESI [ M+H ]] + ＝302.2
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.43–7.28(m,5H),6.55(q,J＝7.1Hz,1H),2.08(d,J＝7.1Hz,3H),2.03(s,3H),1.49(s,3H),1.45(s,3H).
Compound 25:54mg, ESI [ M+H ]] + ＝318.2
1 H NMR(400MHz,CDCl 3 )δ8.13(s,1H),7.45–7.29(m,5H),6.53(q,J＝7.1Hz,1H),2.12(s,3H),2.05(d,J＝7.1Hz,3H),1.55(s,3H),1.44(s,3H).
Compound 26:45mg, ESI [ M+H ]] + ＝330.3
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.43–7.29(m,5H),6.52(q,J＝7.1Hz,1H),4.76(t,J＝7.4Hz,1H),3.74(t,J＝7.0Hz,1H),3.64–3.58(m,1H),2.89–2.72(m,2H),2.21–2.07(m,2H),2.10(d,J＝7.1Hz,3H),1.15(d,J＝8.0Hz,6H).
Compound 27:34mg, ESI [ M+H ]] + ＝360.3
1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.41–7.27(m,5H),6.54(q,J＝7.1Hz,1H),5.07–4.95(m,1H),3.49–3.36(m,4H),2.81–2.66(m,2H),2.32–2.22(m,2H),2.08(d,J＝7.1Hz,3H),1.20(q,J＝7.0Hz,6H).
Compound 28:17mg, ESI [ M+H ]] + ＝426.3
1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),7.42–7.28(m,5H),6.55(q,J＝7.1Hz,1H),6.14–5.81(m,1H),3.85–3.62(m,1H),3.59–3.13(m,3H),2.55–2.39(m,1H),2.18–1.92(m,7H),1.91–1.83(m,3H),1.82–1.41(m,2H),1.28–1.14(m,4H),1.08–0.88(m,2H).
Compound 29:38mg, ESI [ M+H ]] + ＝328.3
1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),7.44–7.29(m,5H),6.55(q,J＝7.1Hz,1H),4.63–4.49(m,1H),4.32–4.16(m,1H),2.80–2.61(m,1H),2.50–2.01(m,7H),1.98–1.91(m,1H),1.77–1.31(m,3H).
Compound 30:78mg, ESI [ M+H ]] + ＝356.3
1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.43–7.29(m,5H),6.55(q,J＝7.1Hz,1H),3.50(s,3H),2.48–2.23(m,4H),2.08(d,J＝7.1Hz,3H),1.81–1.63(m,4H).
Compound 31:46mg, ESI [ M+H ]] + ＝326.2
1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),7.42–7.28(m,5H),6.55(q,J＝7.1Hz,1H),2.67–2.64(m,2H),2.46–2.44(m,2H),2.08(d,J＝7.1Hz,3H),1.88-1.71(m,4H),1.81–1.72(m,2H).
Compound 32:47mg, ESI [ M+H ]] + ＝318.2
1 H NMR(400MHz,CDCl 3 )δ8.10(s,1H),7.42–7.28(m,5H),6.55(q,J＝7.1Hz,1H),4.23–4.20(m,2H),3.09–3.07(m,2H),2.94–2.91(m,2H),2.08(d,J＝7.1Hz,3H),1.33(s,3H).
EXAMPLE 3 preparation of Compounds 33 and 34 of the invention
1-2 (5.1 g,34.7 mmol) and 33-1 (8.1 g,69.8 mmol) were dissolved in toluene (50 mL) at room temperature and stirred at reflux for 14 hours. After the completion of the reaction by TLC, the crude product was obtained by concentrating under reduced pressure, and purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/10 to 1/1), and the rf=0.5 to 0.6 fraction was collected by TLC (ethyl acetate/petroleum ether (v/v) =1/5), to obtain the objective compound 33 (890 mg, yield 10%) and the objective compound 34 (1.2 g, yield 13%).
Compound 33: ESI [ M+H ]] + ＝264.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.21(m,5H),6.57–6.53(m,1H),4.45–4.26(m,2H),2.02(d,J＝7.1Hz,3H),1.37(t,J＝7.1Hz,3H).
Compound 34: ESI [ M+H ]] + ＝264.3
1 H NMR(400MHz,CDCl 3 )δ7.41–7.23(m,5H),6.54–6.51(m,1H),4.41–4.21(m,2H),2.03(d,J＝7.1Hz,3H),1.33(t,J＝7.1Hz,3H).
EXAMPLE 4 preparation of Compounds 35 to 64 of the present invention
LiOH.H was then added at room temperature 2 O (223 mg,5.32 mmol) was added in one portion to Compound 33 (700 mg,2.66 mmol) MeOH/THF/H 2 The solution of O (3 mL, 1/1/1) was stirred overnight at room temperature. After completion of the reaction by TLC, the reaction solution was concentrated, water (10 mL) was added thereto, pH was adjusted to 4-5 with 1N hydrochloric acid, and then extracted with methylene chloride (3X 15 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to give Compound B as a white solid (586 mg, yield 94%). ESI [ M+H ]] + ＝236.1
1 H NMR(400MHz,CDCl 3 )δ7.41–7.14(m,5H),6.55–6.49(m,1H),2.03(d,J＝7.1Hz,3H).
2. Preparation of target Compounds 35 to 64
Preparation of compounds 35 to 64 were synthesized according to general procedure a using compound B (100 mg,0.43 mmol) and the corresponding alcohol (0.64 mmol) as starting materials, the crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/5) and the fraction of rf=0.4 to 0.6 was collected to give the title compound as a colourless oil.
Compound 35:36mg, ESI [ M+H ]] + ＝330.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),5.63(t,J＝6.4Hz,1H),5.03–4.75(m,6H),2.02(d,J＝7.1Hz,3H).
Compound 36:52mg, ESI [ M+H ]] + ＝360.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.28(m,5H),6.55–6.52(m,1H),3.58(s,3H),2.82–2.55(m,4H),2.05–1.88(m,5H).
Compound 37:48mg, ESI [ M+H ]] + ＝314.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.51(m,1H),5.87–5.69(m,3H),5.61–5.54(m,1H),2.04(d,J＝7.1Hz,3H),1.65(t,J＝5.9Hz,3H).
Compound 38:66mg, ESI [ M+H ]] + ＝290.3
1 H NMR(400MHz,CDCl 3 )δ7.41–7.27(m,5H),6.57–6.53(m,1H),5.20–5.01(m,1H),2.51–2.34(m,2H),2.24–2.08(m,2H),2.02(d,J＝7.1Hz,3H),1.93–1.62(m,2H),1.77–1.63(m,1H).
Compound 39:67mg, ESI [ M+H ]] + ＝290.3
1 H NMR(400MHz,CDCl 3 )δ7.43–7.28(m,5H),6.58–6.53(m,1H),4.21–4.04(m,2H),2.01(d,J＝7.1Hz,3H),1.26–1.14(m,1H),0.68–0.28(m,4H).
Compound 40:88mg, ESI [ M+H ]] + ＝320.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.27(m,5H),6.56–6.52(m,1H),4.88–4.80(m,1H),3.70–3.60(m,1H),3.29(s,3H),2.94–2.78(m,2H),2.17–2.10(m,2H),2.03(d,J＝7.1Hz,3H).
Compound 41:38mg, ESI [ M+H ]] + ＝316.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.26(m,5H),6.57–6.53(m,1H),4.85–4.74(m,2H),4.35–4.17(m,2H),2.85–2.75(m,2H),2.74–2.59(m,1H),2.53–2.39(m,2H),2.01(d,J＝7.1Hz,3H).
Compound 42:45mg, ESI [ M+H ] ] + ＝276.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),6.05–5.90(m,1H),5.44–5.28(m,2H),4.87–4.71(m,2H),2.04(d,J＝7.1Hz,3H).
Compound 43:25mg, ESI [ M+H ]] + ＝356.3
1 H NMR(400MHz,CDCl 3 )δ7.44–7.29(m,5H),6.56–6.52(m,1H),5.61(s,1H),4.91(d,J＝3.8Hz,2H),2.35–2.18(m,2H),2.17–2.02(m,5H),1.62–1.33(m,6H).
Compound 44:47mg, ESI [ M+H ]] + ＝292.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.28(m,5H),6.55–6.51(m,1H),2.02(d,J＝7.1Hz,3H),1.55(s,9H).
Compound 45:39mg, ESI [ M+H ]] + ＝304.3
1 H NMR(400MHz,CDCl 3 )δ7.41–7.28(m,5H),6.55–6.53(m,1H),5.88–5.73(m,1H),5.40–5.17(m,3H),2.01(d,J＝7.1Hz,3H),1.77–1.67(m,2H),1.03–0.81(m,3H).
Compound 46:67mg, ESI [ M+H ]] + ＝306.2
1 H NMR(400MHz,CDCl 3 )δ7.43–7.28(m,5H),6.57–6.53(m,1H),4.87–4.70(m,2H),4.60–4.41(m,2H),2.02(d,J＝7.1Hz,3H),1.77(s,3H).
Compound 47:74mg, ESI [ M+H ]] + ＝358.2
1 H NMR(400MHz,CDCl 3 )δ7.44–7.29(m,5H),6.58–6.54(m,1H),2.45–2.38(m,2H),2.36–2.28(m,2H),2.06(s,3H),2.01(d,J＝7.1Hz,3H),1.83–1.63(m,4H).
Compound 48:46mg, ESI [ M+H ]] + ＝306.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.27(m,5H),6.56–6.53(m,1H),4.28–4.21(m,1H),2.56–2.44(m,2H),2.25–2.08(m,4H),2.01(d,J＝7.0Hz,3H).
Compound 49:75mg, ESI [ M+H ]] + ＝278.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),5.29–5.13(m,1H),2.02(d,J＝7.1Hz,3H),1.36(d,J＝6.3Hz,3H),1.33(d,J＝6.3Hz,3H).
Compound 50:42mg, ESI [ M+H ]] + ＝276.2
1 H NMR(400MHz,CDCl 3 )δ7.43–7.26(m,5H),6.58–6.54(m,1H),4.36–4.25(m,1H),2.02(d,J＝7.1Hz,3H),0.92–0.70(m,4H).
Compound 51:28mg, ESI [ M+H ]] + ＝318.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),6.24–6.13(m,1H),5.22–5.14(m,2H),4.79–4.63(m,4H),2.03(d,J＝7.1Hz,3H).
Compound 52:92mg, ESI [ M+H ]] + ＝356.3
1 H NMR(400MHz,CDCl 3 )δ7.40–7.28(m,5H),6.56–6.53(m,1H),2.16–2.02(m,5H),2.01–1.90(m,2H),1.86(s,3H),1.69–1.25(m,6H).
Compound 53:46mg, ESI [ M+H ]] + ＝332.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),5.95–5.64(m,2H),5.02–4.72(m,4H),2.02(d,J＝7.1Hz,3H),1.73–1.60(m,3H).
Compound 54:47mg, ESI [ M+H ]] + ＝336.2
1 H NMR(400MHz,CDCl 3 )δ7.43–7.25(m,5H),6.55–6.51(m,1H),4.41–4.30(m,4H),3.33(s,2H),2.02(d,J＝7.1Hz,3H),1.31(s,3H).
Compound 55:56mg, ESI [ M+H ]] + ＝320.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),4.52–4.31(m,6H),2.02(d,J＝7.1Hz,3H),1.36(s,3H),
Compound 56:24mg, ESI [ M+H ]] + ＝320.3
1 H NMR(400MHz,CDCl 3 )δ7.41–7.28(m,5H),6.58–6.53(m,1H),2.04(d,J＝7.1Hz,3H),1.98(s,3H),1.54(s,3H),1.47(s,3H).
Compound 57:16mg, ESI [ M+H ]] + ＝336.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.27(m,5H),6.57–6.52(m,1H),2.15(s,3H),2.01(d,J＝7.0Hz,3H),1.57(s,3H),1.48(s,3H).
Compound 58:60mg, ESI [ M+H ]] + ＝348.3
1 H NMR(400MHz,CDCl 3 )δ7.43–7.29(m,5H),6.56–6.52(m,1H),4.85–4.69(m,1H),3.82–3.521(m,2H),2.90–2.76(m,2H),2.22–2.08(m,2H),2.10(d,J＝7.1Hz,3H),1.18(d,J＝6.1Hz,6H).
Compound 59:31mg, ESI [ M+H ]] + ＝378.3
1 H NMR(400MHz,CDCl 3 )δ7.42–7.26(m,5H),6.57–6.51(m,1H),5.08–4.95(m,1H),3.48–3.34(m,4H),2.81–2.62(m,2H),2.32–2.22(m,2H),2.01(d,J＝7.1Hz,3H),1.20(q,J＝7.0Hz,6H).
Compound 60:35mg, ESI [ M+H ]] + ＝444.3
1 H NMR(400MHz,CDCl 3 )δ7.43–7.27(m,5H),6.59–6.54(m,1H),6.15–5.80(m,1H),3.87–3.13(m,4H),2.58–2.35(m,1H),2.18–0.88(m,18H).
Compound 61:42mg, ESI [ M+H ]] + ＝346.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.57–6.53(m,1H),4.65–4.11(m,2H),2.82–2.64(m,1H),2.50–1.90(m,8H),1.78–1.31(m,3H).
Compound 62:86mg, ESI [ M+H ]] + ＝374.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.27(m,5H),6.57–6.53(m,1H),3.55(s,3H),2.49–2.19(m,4H),2.01(d,J＝7.1Hz,3H),1.82–1.61(m,4H).
Compound 63:88mg, ESI [ M+H ]] + ＝344.3
1 H NMR(400MHz,CDCl 3 )δ8.11(s,1H),7.43–7.29(m,5H),6.58–6.53(m,1H),2.67–2.61(m,2H),2.46–2.40(m,2H),2.01(d,J＝7.1Hz,3H),1.89-1.85(m,2H),1.81–1.70(m,2H).
Compound 64:88mg, ESI [ M+H ]] + ＝336.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,5H),6.58–6.53(m,1H),4.23–4.20(m,2H),3.09–3.05(m,2H),2.99–2.85(m,2H),2.01(d,J＝7.1Hz,3H),1.33(s,3H).
EXAMPLE 5 preparation of Compounds 65 and 66 of the present invention
1. Preparation of Ethyl 3-chloropropiolate (65-1)
Ethyl propiolate (9.0 g,91.7 mmol) and t-butyl hypochlorite (10 g,92.1 mmol) were dissolved in t-butanol (100 mL) at room temperature, t-BuOK (2.0 g,17.8 mmol) was added to the reaction system twice in 5 min and stirred overnight at room temperature after the addition. After the reaction is monitored to be complete by TLC, the filtrate is filtered by suction, and the crude product 65-1 is obtained after concentration and is directly used for the next reaction without purification.
2. Preparation of target Compound 65 and Compound 66
The crude products 65-1 and 1-2 (3.2 g,21.7 mmol) obtained in the previous step were dissolved in toluene (100 mL) at room temperature, and then stirred under reflux for 14 hours. After completion of the reaction by TLC, saturated brine (30 mL) was added to the reaction system, extracted with ethyl acetate (3×30 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/10 to 1/1), TLC (ethyl acetate/petroleum ether (v/v) =1/5) was monitored, rf=0.5 to 0.6 fraction was collected to give the objective compound 65 (620 mg, yield 10%) and the objective compound 66 (3.2 g, yield 53%).
Compound 65: ESI [ M+H ]] + ＝280.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.52(q,J＝7.1Hz,1H),4.43–4.33(m,2H),2.07(d,J＝7.1Hz,3H),1.38(t,J＝7.1Hz,3H).
Compound 66: ESI [ M+H ]] + ＝280.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),5.76(q,J＝7.1Hz,1H),4.45(q,J＝7.1Hz,2H),2.11(d,J＝7.1Hz,3H),1.43(t,J＝7.1Hz,3H).
EXAMPLE 6 preparation of Compounds 67 to 98 of the present invention
LiOH.H was then added at room temperature 2 O (156 mg,3.72 mmol) was added in one portion to MeOH/THF/H of compound 65 (520 mg,1.86 mmol) 2 The solution of O (3 mL, 1/1/1) was stirred overnight at room temperature. After completion of the reaction by TLC, the reaction solution was concentrated, water (10 mL) was added to the system, pH was adjusted to 4-5 with 1N hydrochloric acid, and then extracted with methylene chloride (3X 15 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to give Compound C as a white solid (445 mg, yield 95%). ESI [ M+Na ] ] + ＝274.1,[M+H-105] + ＝148.1 1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.52(q,J＝7.1Hz,1H),2.08(d,J＝7.0Hz,3H).
2. Preparation of target Compounds 67-98
Preparation of compounds 67-98 were synthesized according to general procedure a using compound C (80 mg,0.32 mmol) and the corresponding alcohol (0.48 mmol) as starting materials, the crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/5) and the fractions rf=0.4-0.6 were collected to give the title compound as a colourless oil.
Compound 67:47mg, ESI [ M+H ]] + ＝346.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.51(q,J＝7.1Hz,1H),5.64(t,J＝6.6Hz,1H),5.04–4.75(m,6H),2.09(d,J＝7.1Hz,3H).
Compound 68:82mg, ESI [ M+H ]] + ＝376.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.52(q,J＝7.1Hz,1H),3.56(s,3H),2.82–2.55(m,4H),2.07(d,J＝7.1Hz,3H),2.05–1.88(m,2H).
Compound 69:28mg, ESI [ M+H ]] + ＝330.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.28(m,5H),6.53(q,J＝7.1Hz,1H),5.86–5.68(m,3H),5.61–5.54(m,1H),2.08(d,J＝7.1Hz,3H),1.66(t,J＝5.9Hz,3H).
Compound 70:28mg, ESI [ M+H ]] + ＝306.2
1 H NMR(400MHz,CDCl 3 )δ7.37–7.26(m,5H),6.50(q,J＝7.1Hz,1H),5.23–5.14(m,1H),2.51–2.37(m,2H),2.26–2.13(m,2H),2.06(d,J＝7.1Hz,3H),1.95–1.85(m,1H),1.77–1.66(m,1H).
Compound 71:80mg, ESI [ M+H ]] + ＝306.1
1 H NMR(400MHz,CDCl 3 )δ7.36–7.25(m,5H),6.52(q,J＝7.1Hz,1H),4.20–4.03(m,2H),2.08(d,J＝7.1Hz,3H),1.27–1.14(m,1H),0.69–0.25(m,4H).
Compound 72:54mg, ESI [ M+H ]] + ＝336.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.30(m,5H),6.52(q,J＝7.1Hz,1H),4.88–4.80(m,1H),3.71–3.61(m,1H),3.27(s,3H),2.96–2.78(m,2H),2.18–2.10(m,2H),2.07(d,J＝7.1Hz,3H).
Compound 73:29mg, ESI [ M+H ]] + ＝332.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.53(q,J＝7.1Hz,1H),4.85–4.73(m,2H),4.35–4.18(m,2H),2.89–2.75(m,2H),2.74–2.59(m,1H),2.53–2.39(m,2H),2.07(d,J＝7.1Hz,3H).
Compound 74:22mg, ESI [ M+H ]] + ＝292.2
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),6.50(q,J＝7.1Hz,1H),6.03–5.91(m,1H),5.48–5.30(m,2H),4.88–4.75(m,2H),2.07(d,J＝7.1Hz,3H).
Compound 75:66mg, ESI [ M+H ]] + ＝372.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.27(m,5H),6.52(q,J＝7.1Hz,1H),5.63(s,1H),4.99–4.86(m,2H),2.36–2.18(m,2H),2.15–2.03(m,5H),1.61–1.431(m,6H).
Compound 76:23mg, ESI [ M+H ]] + ＝308.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.26(m,5H),6.53(q,J＝7.1Hz,1H),2.07(d,J＝7.1Hz,3H),1.56(s,9H).
Compound 77:33mg, ESI [ M+H ]] + ＝320.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.28(m,5H),6.52(q,J＝7.1Hz,1H),5.89–5.75(m,1H),5.42–5.17(m,3H),2.14–2.03(m,3H),1.78–1.67(m,2H),1.01–0.87(m,3H).
Compound 78:46mg, ESI [ M+H ]] + ＝322.1
1 H NMR(400MHz,CDCl 3 )δ7.36–7.26(m,5H),6.50(q,J＝7.1Hz,1H),4.82–4.80(m,2H),4.59–4.56(m,2H),2.08(d,J＝7.1Hz,3H),1.77(s,3H).
Compound 79:89mg, ESI [ M+H ]] + ＝374.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.52(q,J＝7.1Hz,1H),2.46–2.21(m,4H),2.07(d,J＝7.0Hz,3H),2.05(s,3H),1.84–1.61(m,4H).
Compound 80:35mg, ESI [ M+H ]] + ＝322.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.38(q,J＝7.2Hz,1H),4.27–4.20(m,1H),2.59–2.44(m,2H),2.23–2.06(m,4H),2.04(d,J＝7.1Hz,3H).
Compound 81:27mg, ESI [ M+H ]] + ＝294.3
1 H NMR(400MHz,CDCl 3 )δ7.37–7.30(m,5H),6.50(q,J＝7.2Hz,1H),5.27–5.17(m,1H),2.07(d,J＝7.1Hz,3H),1.36(d,J＝6.2Hz,3H),1.32(d,J＝6.3Hz,3H).
Compound 82:55mg, ESI [ M+H ]] + ＝292.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.52(q,J＝7.1Hz,1H),4.36–4.25(m,1H),2.08(d,J＝7.1Hz,3H),0.94–0.58(m,4H).
Compound 83:24mg, ESI [ M+H ]] + ＝294.2
1 H NMR(400MHz,CDCl 3 )δ7.38–7.30(m,5H),6.53(q,J＝7.1Hz,1H),4.34–4.23(m,2H),2.07(d,J＝7.1Hz,3H),1.82–1.72(m,2H),1.02(t,J＝7.4Hz,3H).
Compound 84:39mg, ESI [ M+H ]] + ＝296.1
1 H NMR(400MHz,CDCl 3 )δ7.36–7.30(m,5H),6.40(q,J＝7.1Hz,1H),3.06(q,J＝7.4Hz,2H),2.05(d,J＝7.1Hz,3H),1.31(t,J＝7.4Hz,3H).
Compound 85:54mg, ESI [ M+H ]] + ＝334.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.52(q,J＝7.1Hz,1H),6.25–6.13(m,1H),5.22–5.14(m,2H),4.79–4.63(m,4H),2.07(d,J＝7.1Hz,3H).
Compound 86:67mg, ESI [ M+H ]] + ＝372.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.52(q,J＝7.1Hz,1H),2.17–1.90(m,7H),1.88(s,3H),1.69–1.21(m,6H).
Compound 87:77mg, ESI [ M+H ]] + ＝348.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.28(m,5H),6.53(q,J＝7.1Hz,1H),5.96–5.64(m,2H),5.05–4.77(m,3H),4.74(d,J＝8.0Hz,1H),2.08(d,J＝7.1Hz,3H),1.73–1.60(m,3H).
Compound 88:42mg, ESI [ M+H ]] + ＝352.1
1 H NMR(400MHz,CDCl 3 )δ7.36–7.29(m,5H),6.51(q,J＝7.1Hz,1H),4.41–4.33(m,4H),3.33(s,2H),2.06(d,J＝7.1Hz,3H),1.32(s,3H).
Compound 89:68mg, ESI [ M+H ]] + ＝336.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.52(q,J＝7.1Hz,1H),4.52–4.32(m,6H),2.08(d,J＝7.1Hz,3H),1.32(s,3H).
Compound 90:24mg, ESI [ M+H ]] + ＝336.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.27(m,5H),6.50(q,J＝7.1Hz,1H),2.04(d,J＝7.1Hz,3H).2.00(s,3H),1.49(s,3H),1.45(s,3H).
Compound 91:16mg, ESI [ M+H ] ] + ＝352.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.28(m,5H),6.52(q,J＝7.1Hz,1H),2.12(s,3H),2.07(d,J＝7.1Hz,3H),1.56(s,3H),1.47(s,3H).
Compound 92:35mg, ESI [ M+H ]] + ＝364.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.27(m,5H),6.53(q,J＝7.1Hz,1H),4.76(t,J＝7.4Hz,1H),3.75(t,J＝7.0Hz,1H),3.64–3.58(m,1H),2.88–2.72(m,2H),2.21–2.07(m,2H),2.08(d,J＝7.1Hz,3H),1.15(d,J＝8.0Hz,6H).
Compound 93:28mg, ESI [ M+H ]] + ＝394.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.28(m,5H),6.55(q,J＝7.1Hz,1H),5.07–4.95(m,1H),3.48–3.36(m,4H),2.83–2.66(m,2H),2.33–2.22(m,2H),2.07(d,J＝7.1Hz,3H),1.20(q,J＝7.0Hz,6H).
Compound 94:26mg, ESI [ M+H ]] + ＝460.2
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.51(q,J＝7.1Hz,1H),6.15–5.81(m,1H),3.86–3.62(m,1H),3.58–3.13(m,3H),2.55–2.39(m,1H),2.19–1.92(m,7H),1.90–1.83(m,3H),1.82–1.42(m,2H),1.28–1.14(m,4H),1.09–0.88(m,2H).
Compound 95:29mg, ESI [ M+H ]] + ＝362.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.54(q,J＝7.1Hz,1H),4.64–4.49(m,1H),4.33–4.16(m,1H),2.80–2.64(m,1H),2.51–2.26(m,2H),2.24–2.03(m,5H),1.99–1.91(m,1H),1.76–1.25(m,3H).
Compound 96:88mg, ESI [ M+H ]] + ＝390.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.28(m,5H),6.52(q,J＝7.1Hz,1H),3.51(s,3H),2.48–2.21(m,4H),2.07(d,J＝7.1Hz,3H),1.82–1.63(m,4H).
Compound 97:48mg, ESI [ M+H ]] + ＝360.1
1 H NMR(400MHz,CDCl 3 )δ8.18(t,J＝2.0Hz,1H),7.39–7.29(m,5H),6.52(q,J＝7.1Hz,1H),2.68–2.64(m,2H),2.47–2.44(m,2H),2.06(d,J＝7.1Hz,3H),1.89-1.85(m,2H),1.81–1.72(m,2H).
Compound 98:28mg, ESI [ M+H ]] + ＝352.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.52(q,J＝7.1Hz,1H),4.23–4.20(m,2H),3.09–3.07(m,2H),2.96–2.90(m,2H),2.07(d,J＝7.1Hz,3H),1.35(s,3H).
EXAMPLE 7 preparation of Compounds 99 and 100 of the invention
Ethyl propiolate (12.0 g,122 mmol), NBS (26.2 g,147 mmo) and AgNO were added at room temperature 3 (10.4 g,61 mmol) was dissolved in acetone (400 mL) and stirred overnight at room temperature. After TLC monitoring the reaction to completion, suction filtration and concentration of the filtrate gave a crude product 99-1, which was used directly for the next reaction without purification.
2. Preparation of target Compound 99 and Compound 100
The crude products 99-1 and 1-2 (7.1 g,48.2 mmol) from the previous step were dissolved in toluene (100 mL) at room temperature and then stirred at reflux for 14 hours. After completion of the reaction by TLC, saturated brine (30 mL) was added to the reaction system, extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/10 to 1/1), TLC (ethyl acetate/petroleum ether (v/v) =1/5) was monitored, and rf=0.5 to 0.6 fractions were collected to give the objective compound 99 (2.3 g, yield 15%) and the objective compound 100 (6.0 g, yield 38%).
Compound 99: ESI [ M+H ]] + ＝324.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),6.53(q,J＝7.1Hz,1H),4.45–4.31(m,2H),2.07(d,J＝7.1Hz,3H),1.39(t,J＝7.1Hz,3H).
Compound 100: ESI [ M+H ]] + ＝324.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),5.80(q,J＝7.1Hz,1H),4.45(q,J＝7.1Hz,2H),2.12(d,J＝7.1Hz,3H),1.44(t,J＝7.1Hz,3H).
EXAMPLE 8 preparation of Compounds 101 to 126 of the invention
1. Preparation of Compound D
LiOH.H was then added at room temperature 2 O (337 mg,8.0 mmol) was added in one portion to MeOH/THF/H of Compound 100 (1.3 g,4.0 mmol) 2 O (15 mL, 1/1/1) solution,stirred at room temperature for 5 hours. After completion of the reaction by TLC, the reaction solution was concentrated, water (10 mL) was added to the system, pH was adjusted to 4-5 with 1N hydrochloric acid, and then extracted with methylene chloride (3X 15 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to give a white solid D (445 mg, yield 95%). ESI [ M+H-105 ]] + ＝191.0
1 H NMR(400MHz,CD 3 OD)δ7.48–7.13(m,5H),6.76–6.65(m,1H),2.00(d,J＝5.5Hz,3H).
2. Preparation of target Compounds 101-126
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Preparation of Compounds 101-126 Using Compound D (100 mg,0.34 mmol) and the corresponding alcohol (0.51 mmol) as starting materials, synthesized according to general procedure A, the crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/5) and fractions of Rf=0.4-0.6 were collected to give the title compound as a colourless oil.
Compound 101:16.8mg, ESI [ M+H ]] + ＝390.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.24(m,5H),6.44(q,J＝7.1Hz,1H),5.60(t,J＝6.6Hz,1H),5.09–4.76(m,6H),2.07(d,J＝7.1Hz,3H).
Compound 102:80mg, ESI [ M+H ]] + ＝420.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.28(m,5H),6.41(q,J＝7.1Hz,1H),3.57(s,3H),2.82–2.55(m,4H),2.12(d,J＝7.1Hz,3H),2.05–1.88(m,2H).
Compound 103:66mg, ESI [ M+H ]] + ＝374.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),6.42(q,J＝7.1Hz,1H),5.88–5.69(m,3H),5.60–5.54(m,1H),2.11(d,J＝7.1Hz,3H),1.65(t,J＝5.9Hz,3H).
Compound 104:62mg, ESI [ M+H ]] + ＝246.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.51(q,J＝7.1Hz,1H),5.24–5.14(m,1H),2.54–2.37(m,2H),2.27–2.14(m,2H),2.06(d,J＝7.1Hz,3H),1.96–1.85(m,1H),1.78–1.66(m,1H).
Compound 105:55mg, ESI [ M+H ]] + ＝350.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.53(q,J＝7.1Hz,1H),4.23–4.10(m,2H),2.07(d,J＝7.1Hz,3H),1.27–1.17(m,1H),0.69–0.59(m,2H),0.41–0.32(m,2H).
Compound 106:56mg, ESI [ M+H ]] + ＝380.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.28(m,5H),6.51(q,J＝7.1Hz,1H),4.89–4.80(m,1H),3.71–3.61(m,1H),3.28(s,3H),2.96–2.78(m,2H),2.18–2.02(m,5H).
Compound 107:33mg, ESI [ M+H ] ] + ＝376.2
1 H NMR(400MHz,CDCl 3 )δ7.41–7.29(m,5H),6.49(q,J＝7.1Hz,1H),4.86–4.73(m,2H),4.36–4.18(m,2H),2.89–2.76(m,2H),2.74–2.59(m,1H),2.54–2.39(m,2H),2.06(d,J＝7.1Hz,3H).
Compound 108:63mg, ESI [ M+H ]] + ＝336.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.52(q,J＝7.1Hz,1H),6.04–5.91(m,1H),5.50–5.30(m,2H),4.89–4.74(m,2H),2.07(d,J＝7.1Hz,3H).
Compound 109:51mg, ESI [ M+H ]] + ＝416.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.29(m,5H),6.48(q,J＝7.1Hz,1H),5.61(s,1H),4.92(d,J＝3.8Hz,2H),2.34–2.18(m,2H),2.17–2.02(m,5H),1.63–1.49(m,4H),1.46–1.33(m,2H).
Compound 110:66mg, ESI [ M+H ]] + ＝352.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.30(m,5H),6.52(q,J＝7.1Hz,1H),2.06(d,J＝7.1Hz,3H),1.56(s,9H).
Compound 111:56mg, ESI [ M+H ]] + ＝364.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.28(m,5H),6.51(q,J＝7.1Hz,1H),5.89–5.72(m,1H),5.41–5.16(m,3H),2.15–2.02(m,3H),1.77–1.68(m,2H),1.00–0.66(m,3H).
Compound 112:46mg, ESI [ M+H ]] + ＝366.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),6.49(q,J＝7.1Hz,1H),4.82–4.79(m,2H),4.59–4.56(m,2H),2.10(d,J＝7.1Hz,3H),1.77(s,3H).
Compound 113:79mg, ESI [ M+H ]] + ＝418.2
1 H NMR(400MHz,CDCl 3 )δ7.42–7.29(m,5H),6.50(q,J＝7.1Hz,1H),2.46–2.38(m,2H),2.35–2.27(m,2H),2.06(d,J＝7.0Hz,3H),2.07(s,3H),1.84–1.76(m,2H),1.75–1.68(m,2H).
Compound 114:35mg, ESI [ M+H ]] + ＝366.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.25(m,5H),6.35(q,J＝7.1Hz,1H),4.29–4.20(m,1H),2.59–2.42(m,2H),2.23–2.05(m,4H),2.04(d,J＝7.1Hz,3H).
Compound 115:57mg, ESI [ M+H ]] + ＝338.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.52(q,J＝7.2Hz,1H),5.25–5.19(m,1H),2.07(d,J＝7.1Hz,3H),1.37(d,J＝6.2Hz,3H),1.33(d,J＝6.3Hz,3H).
Compound 116:67mg, ESI [ M+H ]] + ＝336.0
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.51(q,J＝7.1Hz,1H),4.41–4.29(m,1H),2.07(d,J＝7.1Hz,3H),0.89–0.80(m,4H).
Compound 117:39mg, ESI [ M+H ]] + ＝310.1
1 H NMR(400MHz,CDCl 3 )δ7.41–7.29(m,5H),6.52(q,J＝7.1Hz,1H),3.92(s,3H),2.07(d,J＝7.1Hz,3H).
Compound 118:238mg, ESI [ M+H ]] + ＝324.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.53(q,J＝7.1Hz,1H),4.45–4.31(m,2H),2.07(d,J＝7.1Hz,3H),1.39(t,J＝7.1Hz,3H).
Compound 119:63mg, ESI [ M+H ]] + ＝338.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.30(m,5H),6.55(q,J＝7.2Hz,1H),4.35–4.22(m,2H),2.07(d,J＝7.1Hz,3H),1.84–1.72(m,2H),1.03(t,J＝7.4Hz,3H).
Compound 120:82mg, ESI [ M+H ]] + ＝340.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.37(q,J＝7.0Hz,1H),3.09–3.01(m,2H),2.05(d,J＝7.1Hz,3H),1.30(t,J＝7.4Hz,3H).
Compound 121:99mg, ESI [ M+H ]] + ＝394.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.47(q,J＝7.1Hz,1H),3.70(s,3H),2.08(d,J＝7.1Hz,3H),1.71–1.60(m,2H),1.35–1.21(m,2H).
Compound 122:194mg, ESI [ M+H ]] + ＝558.0
1 H NMR(400MHz,CDCl 3 )δ7.37–7.30(m,5H),6.56(q,J＝7.2Hz,0H),5.16(s,0H),2.10(d,J＝7.1Hz,1H).
Compound 123:32mg, ESI [ M+H ]] + ＝322.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.31(m,5H),6.51(q,J＝7.2Hz,1H),5.16(dd,J＝13.8,2.1Hz,1H),4.82(dd,J＝6.1,2.1Hz,1H),2.08(d,J＝7.1Hz,3H).
Compound 124:26mg, ESI [ M+H ]] + ＝320.1
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),6.52(q,J＝7.1Hz,1H),2.55(s,1H),2.12(d,J＝7.1Hz,3H).
Compound 125:48mg, ESI [ M+H ]] + ＝370.1
1 H NMR(400MHz,CDCl 3 )δ7.41–7.29(m,5H),6.48(q,J＝7.1Hz,1H),4.51–4.34(m,2H),2.80(t,J＝6.9Hz,2H),2.18(s,3H),2.10(d,J＝7.1Hz,3H).
Compound 126：37mg，ESI[M+H] + ＝386.1
1 H NMR(400MHz,CDCl 3 )δ7.41–7.29(m,5H),6.51(q,J＝7.1Hz,1H),3.38–2.95(m,2H),2.78–2.59(m,2H),2.18(s,3H),2.11(d,J＝7.1Hz,3H).
EXAMPLE 9 preparation of Compounds 127 and 128 of the invention
1. Preparation of Ethyl 3-bromoopionate (127-1)
Ethyl propiolate (12.0 g,122 mmol), NIS (33.1 g,147 mmo) and AgNO were added at room temperature 3 (10.4 g,61 mmol) was dissolved in acetone (400 mL) and stirred overnight at room temperature. After the reaction was completed by TLC, the filtrate was concentrated to give a crude product 127-1, which was used in the next reaction without purification.
2. Preparation of target Compound 127 and target Compound 128
The crude 127-1 and 1-2 (4.5 g,30.6 mmol) obtained in the previous step were dissolved in toluene (100 mL) at room temperature, and then stirred under reflux for 14 hours. After completion of the reaction by TLC, saturated brine (30 mL) was added to the reaction system, extracted with ethyl acetate (3×50 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) =1/10 to 1/1), TLC (ethyl acetate/petroleum ether (v/v) =1/5) was monitored, and rf=0.5 to 0.6 fractions were collected to give the objective compound 127 (4.5 g, yield 40%) and the objective compound 128 (4.9 g, yield 43%).
Compound 127: ES (ES)I[M+H] + ＝372.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.55(q,J＝7.1Hz,1H),4.46–4.30(m,2H),2.06(d,J＝7.1Hz,3H),1.41(t,J＝7.1Hz,3H).
Compound 128: ESI [ M+H ]] + ＝372.1
1 H NMR(400MHz,CDCl 3 )δ7.42–7.29(m,5H),5.83(q,J＝7.0Hz,1H),4.46(q,J＝7.1Hz,2H),2.13(d,J＝7.1Hz,3H),1.45(t,J＝7.1Hz,3H).
EXAMPLE 10 preparation of Compounds 129 to 144 of the present invention
1. Preparation of Compound E
LiOH.H was then added at room temperature 2 O (906 mg,21.6 mmol) was added in one portion to MeOH/THF/H of compound 127 (4.0 g,10.8 mmol) 2 The solution of O (30 mL, 1/1/1) was stirred at room temperature for 5 hours. After completion of the reaction by TLC, the reaction solution was concentrated, water (10 mL) was added to the system, pH was adjusted to 4-5 with 1N hydrochloric acid, and then dichloromethane (3X 10 mL) was used for extraction, and the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to give white solid E (3.0 g, yield 81%). ESI [ M+H ]] + ＝344.0,[M+H-105] + ＝240.1
1 H NMR(400MHz,CD 3 OD)δ7.39–7.22(m,5H),6.74–6.64(m,1H),1.99(d,J＝6.0Hz,3H).
2. Preparation of target Compounds 129 to 144
Preparation of compounds 129-144 were synthesized according to general procedure a using compound E (100 mg,0.34 mmol) and the corresponding alcohol (0.51 mmol) as starting materials, the crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/5) and the fraction of rf=0.4-0.6 was collected to give the title compound as a colourless oil.
Compound 129:37mg, ESI [ M+H ]] + ＝438.1
1 H NMR(400MHz,CDCl 3 )δ7.46–7.29(m,5H),6.46(q,J＝7.3Hz,1H),5.61(t,J＝6.9Hz,1H),5.10–4.69(m,6H),2.07(d,J＝7.6Hz,3H).
Compound 130:82mg, ESI [ M+H ]] + ＝468.1
1 H NMR(400MHz,CDCl 3 )δ7.46–7.29(m,5H),6.46(q,J＝7.1Hz,1H),3.57(s,3H),2.82–2.55(m,4H),2.07(d,J＝7.1Hz,3H),2.05–1.88(m,2H).
Compound 131:49mg, ESI [ M+H ]] + ＝422.0
1 H NMR(400MHz,CDCl 3 )δ7.39–7.30(m,5H),6.59–6.49(m,1H),5.87–5.69(m,3H),5.61–5.54(m,1H),2.07(d,J＝6.9Hz,3H),1.65(t,J＝5.9Hz,3H).
Compound 132:68mg, ESI [ M+H ]] + ＝398.0
1 H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,5H),6.53(q,J＝7.2Hz,1H),5.26–5.15(m,1H),2.53–2.37(m,2H),2.31–2.18(m,2H),2.05(d,J＝7.1Hz,3H),1.98–1.85(m,1H),1.80–1.65(m,1H).
Compound 133:72mg, ESI [ M+H ]] + ＝398.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.62–6.50(m,1H),4.25–4.09(m,2H),2.07(d,J＝6.2Hz,3H),1.28–1.19(m,1H),0.72–0.60(m,2H),0.44–0.33(m,2H).
Compound 134:33mg, ESI [ M+H ]] + ＝428.0
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.52(q,J＝7.1Hz,1H),4.92–4.82(m,1H),3.71–3.62(m,1H),3.29(s,3H),2.95–2.79(m,2H),2.26–2.15(m,2H),2.06(d,J＝7.1Hz,3H).
Compound 135:72mg, ESI [ M+H ] ] + ＝424.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.28(m,5H),6.53(q,J＝7.1Hz,1H),4.86–4.73(m,2H),4.36–4.18(m,2H),2.90–2.77(m,2H),2.74–2.56(m,1H),2.53–2.39(m,2H),2.07(d,J＝7.1Hz,3H).
Compound 136:66mg, ESI [ M+H ]] + ＝384.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),6.54(q,J＝7.0Hz,1H),6.06–5.94(m,1H),5.49–5.41(m,1H),5.38–5.31(m,1H),4.89–4.75(m,2H),2.06(d,J＝7.1Hz,3H).
Compound 137:21mg, ESI [ M+H ]] + ＝464.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.30(m,5H),6.53(q,J＝7.0Hz,1H),5.57(s,1H),4.96–4.90(m,2H),2.35–2.21(m,2H),2.16–2.10(m,2H),2.07(d,J＝7.1Hz,3H),1.56–1.49(m,2H),1.49–1.37(m,2H).
Compound 138:17mg, ESI [ M+H ]] + ＝400.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.53(q,J＝6.9Hz,1H),2.05(d,J＝7.1Hz,3H),1.57(s,9H).
Compound 139:80mg, ESI [ M+H ]] + ＝412.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.30(m,5H),6.61–6.52(m,1H),5.91–5.75(m,1H),5.45–5.17(m,3H),2.11–1.99(m,3H),1.88–1.70(m,2H),1.03–0.90(m,3H).
Compound 140:28mg, ESI [ M+H ]] + ＝414.1
1 H NMR(400MHz,CDCl 3 )δ7.38–7.23(m,5H),6.45(q,J＝7.1Hz,1H),4.93–4.79(m,2H),4.63–4.52(m,2H),2.07(d,J＝7.1Hz,3H),1.75(s,3H).
Compound 141:51mg, ESI [ M+H ]] + ＝466.1
1 H NMR(400MHz,CDCl 3 )δ7.37–7.22(m,5H),6.50(q,J＝7.1Hz,1H),2.55–2.15(m,4H),2.09(d,J＝7.1Hz,3H),2.00(s,3H),1.87–1.67(m,4H).
Compound 142:72mg，ESI[M+H] + ＝414.1
1 H NMR(400MHz,CDCl 3 )δ7.36–7.24(m,5H),6.29(q,J＝7.1Hz,1H),4.31–4.17(m,1H),2.59–2.42(m,2H),2.23–2.05(m,4H),2.04(d,J＝7.1Hz,3H).
compound 143:76mg, ESI [ M+H ]] + ＝386.0
1 H NMR(400MHz,CDCl 3 )δ7.37–7.29(m,5H),6.54(q,J＝7.2Hz,1H),5.29–5.18(m,1H),2.06(d,J＝7.1Hz,3H),1.39(d,J＝6.3Hz,3H),1.35(d,J＝6.3Hz,3H).
Compound 144:102mg, ESI [ M+H ]] + ＝384.1
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,5H),6.53(q,J＝7.1Hz,1H),4.42–4.34(m,1H),2.06(d,J＝7.1Hz,3H),0.94–0.78(m,4H).
EXAMPLE 11 preparation of Compounds 145 and 146 of the invention
1-2 (200 mg,1.36 mmol) and 127-1 (452 mg,2.72 mmol) were dissolved in toluene (2 mL) at room temperature, and then stirred under reflux for 14 hours. After completion of the reaction by TLC, the crude product was obtained by concentrating under reduced pressure, and the crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/5) and the fraction having rf=0.4 to 0.6 was collected to give the target compound 145 (230 mg, yield 54%) and the target compound 146 (192 mg, yield 45%) as a colorless oil.
Compound 145: ESI [ M+H ]] + ＝314.1
1 H NMR(400MHz,CDCl 3 )δ7.41–7.31(m,5H),6.52(q,J＝7.1Hz,1H),4.47–4.31(m,2H),2.11(d,J＝7.1Hz,3H),1.36(t,J＝7.2Hz,3H).
Compound 146: ESI [ M+Na ]] + ＝336.1
1 H NMR(400MHz,CDCl 3 )δ7.41–7.29(m,5H),5.90(q,J＝7.0Hz,1H),4.46(q,J＝7.1Hz,2H),2.13(d,J＝7.0Hz,3H),1.42(t,J＝7.1Hz,3H).
EXAMPLE 12 preparation of Compound 147 of the present invention
Compound 128 (200 mg,0.54 mmol), 18-crown-6 (29 mg,0.11 mmol) and AgF (69 mg,0.54 mmol) were dissolved in DMF (2 mL) at room temperature and then stirred at 160℃for 1 hour. After completion of the reaction by TLC, the crude product was obtained by concentrating under reduced pressure, purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/1) and the fraction rf=0.4 to 0.6 was collected to give 147 (20 mg, yield 13%) of the objective compound as a colorless oil. ESI [ M+H ] ] + ＝289.3
1 H NMR(400MHz,CDCl 3 )δ7.38–7.29(m,5H),5.79(q,J＝7.2Hz,1H),4.44(q,J＝7.1Hz,2H),2.66(s,6H),2.02(d,J＝7.2Hz,3H),1.45(t,J＝7.1Hz,3H).
The beneficial effects of the invention are illustrated by way of experimental examples:
experimental example 1 evaluation of general anesthesia action of the Compound of the invention Using disappearance of rat Innovative reflection as a criterion
Adult male SD rats with body weights ranging from 250 to 300 grams were selected for the trial. The compounds of the above examples and the control drug etomidate, CPMM, were dissolved in dimethyl sulfoxide (DMSO), and the blank group was given an equal volume of DMSO. Determination of the half-Effective Dose (ED) of the general anesthetic action of the Compounds of the invention Using the sequential method (Up-and-Down method) with loss of anti-normal reflection as a criterion 50 ). The rats were dosed intravenously at the time of the test, each rat at a dosing volume of 0.6ml and a dosing rate of 0.1 ml/sec. The disappearance of the rat eversion reflex (lor) was used as an indicator of the onset of the general anesthetic effect for 30 seconds. The results are shown in Table 1.
The results show that: the compounds of the invention can produce definite, transient general anesthetic action as do the control etomidate, CPMM. And the compounds of the invention exhibit the same or better potency as etomidate, CPMM.
TABLE 1 Compound of the invention uses disappearance of rat specular reflection as a determination indexED of (2) 50
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Remarks:
* The numbers in brackets represent 95% confidence limits (mg/kg);
A represents the measured ED 50 In the range of 0.04-0.50mg/kg (including 0.04mg/kg and 0.50 mg/kg);
b represents the measured ED 50 In the range of 0.50-1.00mg/kg (excluding 0.50mg/kg, including 1.00 mg/kg);
c represents the measured ED 50 In the range of 1.00-2.00mg/kg (excluding 1.00mg/kg, including 2.00 mg/kg);
d represents the measured ED 50 In the range of 2.00-10.00mg/kg (excluding 2.00mg/kg, including 10.00 mg/kg);
e represents the measured ED 50 In the range of 10.00-20.00mg/kg (excluding 10.00mg/kg, including 20.00 mg/kg).
Experimental example 2ED so that the rat eversion and the reflection disappear 50 Dose comparison of the pharmacological Effect of the Compounds of the invention
Adult male SD rats with body weights ranging from 250 to 300 grams were selected for the trial (n=8). The compounds of the above examples and the control drug etomidate, CPMM, were dissolved in dimethyl sulfoxide (DMSO), and the blank group was given an equal volume of DMSO. 2ED with disappearance of orthotopic reflection in rats 50 The dose was tested. The rats were dosed intravenously at the time of the test, each rat at a dosing volume of 0.6ml and a dosing rate of 0.1ml/s. The time at which the loss of the eversion reflex (lor) was taken as the time at which the anesthetic effect started to be produced. The results are shown in Table 2.
The results show that: the compound of the invention has the characteristics of quick response and quick recovery as compared with etomidate and CPMM. The duration of the pharmacological action can meet the time requirements of rapid induction of general anesthesia and the time requirements of diagnostic examination, short-term invasive examination or operation. In the experiment, the types and incidence of adverse reactions of the compounds of the invention are less than those of the control etomidate and CPMM.
TABLE 2 disappearance of 2ED with substantial rat eversion and specular reflection 50 Dose comparison of the pharmacological Effect of the Compounds of the invention
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Experimental example 3 in vitro cell assay to determine the effect of the compounds of the invention on adrenocortical function
Cell culture is performed by selecting H295R cell lines, incubating the cultured cells with the vehicle DMSO, etomidate, CPMM, etomidate metabolite etomidate, and a compound of the invention, and then determining the presence or absence of inhibition of adrenocortical function by the compound of the invention by measuring cortisol and corticosterone secreted by the cells in the supernatant of the cultured cells using HPLC-MS/MS method.
The results show that: the compounds of the invention meet the design requirements (see Table 3), and no inhibition of adrenocortical function is observed in the test.
TABLE 3 cell assay to test the effect of the compounds of the invention on adrenocortical function
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Experimental example 4 in vivo test to determine the Effect of the Compounds of the invention on adrenal cortex function
ED of the inventive Compounds with loss of rat Innovative reflection as an indicator of anesthesia was determined according to the sequential method (Up-and-Down method) 50 Administration of 2ED 50 Dose (n=8), changes in serum corticosterone in rats before and after administration were measured, and the effect of the compound of the present invention on the adrenal cortex function of rats was judged using serum corticosterone concentration (ng/ml) as a representative index.
The main test instrument equipment is as follows:
multifunctional ion meter (METTLER TOLEDO, model: sevenmulti), pipette (Eppendorf, specification: 1000ul,200ul,100ul,10 ul), 22G venous indwelling needle (BECTON DICKINSON Co., germany), 1ml microinjection needle (BD Co., germany), timer.
The drug administration process comprises the following steps: the test was uniformly started in the morning. 8:00 to 8:30 is the test preparation phase. The rats were placed in the holder, tail veins were exposed, a 22G indwelling needle was placed in the tail veins of the rats, and the rats were indwelled with heparin. ( Both administration and blood sampling pass through this channel. Heparin was leached out prior to blood collection, with about 0.4ml per blood collection. )
(1) Dexamethasone inhibition: once the indwelling needle is placed, dexamethasone (0.5 mg/kg) is administered intravenously.
(2) Two hours after dexamethasone administration, a first blood sampling is performed (S1);
(3) dexamethasone (0.2 mg/kg) +Compound (2 ED) was injected after blood sampling 50 Dosage), all the medicines or compounds are fixed to 0.6ml, and are administered at a constant speed of 0.1ml/s; exogenous ACTH (25 ug/kg) was injected 15 minutes later.
(4) Blood samples were collected again 30 minutes after ACTH administration (S2);
(5) after blood collection, the sample was allowed to stand at room temperature for 30-60 minutes, centrifuged at 3500rpm for 10 minutes, and the supernatant was collected and centrifuged again at 15000rpm for 5 minutes before being frozen in a-20℃refrigerator.
And (3) data acquisition: the concentration of rat serum corticosterone was measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) within 2-3 days after sampling.
The results show that: the compound of the invention hardly inhibits the synthesis of adrenocortical hormone as does control physiological saline (0.9% NaCl) and Propofol (PRO), while control Etomidate (ET) shows a remarkable inhibition of adrenocortical function (see figure 1).
Experimental example 5 determination of the effect of the compounds of the present invention on circulatory function in rats using a small animal implantable physiological signal telemetry system
Determination of the compounds of the invention according to the sequential method (Up-and-Down method) ED with loss of rat specular reflection as an indicator of anesthesia 50 Administration of 2ED 50 Dose (n=6), changes in heart rate and blood pressure of rats during and within 30 minutes after administration were observed using DSI (Data Science International, inc.) implanted physiological signal telemetry system, and the effect of the compounds of the present invention on circulatory function of rats was judged using Mean Arterial Pressure (MAP) and Heart Rate (HR) as representative indicators.
The main test instrument equipment is as follows:
DSI (Data Science International, inc.) implanted physiological signal telemetry systems for small animals include implants (model HD-S21, DSI corporation, usa), receiver boards (model RPC-1, DSI corporation, usa), signal converters (model DEM, DSI corporation, usa), perfusate gels (model, DSI corporation, usa), fibrin films (DSI corporation, usa), and the like.
Small animal breathing machine (model: HX-101E, manufacturer: chengdu Telechtin technology Co., ltd.); electronic balance (model: ME215S, manufacturer: sartorius, germany).
Firstly, establishing an animal model, placing a left ventricle catheter, an abdominal aorta catheter and placing an electrocardiosignal. Signals can be collected to begin the test at least one week after the post-operative stabilization.
The drug administration process comprises the following steps: placing the rat into a fixer to expose tail vein, placing 20G indwelling needle into tail vein of the rat, administering 0.2mL heparin, connecting with a pre-pumped extension tube, sticking adhesive tape to fix the extension tube on tail vein, taking the rat out of the fixer, placing into a rearing cage, and placing into a signal receiverAnd (3) upper part. After data acquisition begins, the rats are quietly adapted for 30 minutes and then calculated as 2ED 50 Dosing, dosing at a constant speed, observing and recording pharmacological effects, adverse reactions, behavior and the like of rats after dosing.
And (3) data acquisition: after the software is completed to set the parameters for data acquisition, the power supply of the implant is turned on, and the data acquisition can be started. The experimental data recording frequency was set to 15 seconds once for this experiment. Data acquisition was recorded for 30 minutes before and after rat dosing. And (5) ending data acquisition and stopping the test.
The results show that: the compounds of the present invention have little inhibitory effect on circulatory function as do the control etomidate, CPMM, whereas the control propofol shows a significant inhibition of circulatory function (see figures 2, 3, 4, 5).
Experimental example 6 pharmacological Effect of the Compound of the invention on sustained infusion into rats
Adult male SD rats with body weights ranging from 250 to 300 grams were selected for continuous infusion experiments. The compound of the invention and a control drug etomidate and CPMM are prepared into fat emulsion before the test, and are continuously infused through the tail vein of a rat at 2 times MIR (minimum infusion speed), so that the disappearance of the eversion and the positive reflection begin to be maintained for 1 hour, and the recovery time and the complete recovery time of experimental animals after the infusion is stopped are recorded. The results are shown in Table 4.
The results show that: the compound of the invention has recovery time which is equal to that of single intravenous injection 2ED after continuous infusion for 1 hour under 2 times MIR condition 50 There was no significant prolongation after the dose and the recovery time was significantly shorter than etomidate. The types and incidence of adverse reactions are also significantly better than etomidate and CPMM.
TABLE 4 pharmacological effects of continuous infusion of the compounds of the invention into rats
In summary, the invention discloses a polysubstituted triazole formate derivative with novel structure, which has better central nervous system inhibition effect, can generate sedative, hypnotic and/or general anesthesia effects and control status epilepticus, and provides a new choice for clinically screening and/or preparing drugs with sedative, hypnotic and/or general anesthesia effects and drugs for controlling status epilepticus.

Claims (4)

1. A compound, or a pharmaceutically acceptable salt thereof, which is:
as shown in a formula II-1 or a formula II-2;
ring a is absent;
x is selected from O or S;
R 4 selected from hydrogen, halogen, halomethyl;
L 1 and L 2 Each independently selected from methylene groups which are unsubstituted, substituted or unsubstituted with 1 to 2 substituents; the substituent is C 1-4 An alkyl group;
R 5 selected from C 1-4 Alkyl, C 2-4 Alkenyl groups;
m is 1;
or, as shown in formula II-1;
the A ring is a 3-6 membered saturated carbocycle;
x is selected from O or S;
R 4 selected from hydrogen, halogen;
L 1 and L 2 Each independently selected from methylene groups which are unsubstituted, substituted or unsubstituted with 1 substituent; the substituent is C 1-4 Alkyl, C 2-3 Alkenyl groups;
L 1 and L 2 May be attached to an atom in the A ring which is either co-located or ectopic;
R 5 selected from hydrogen, -OR 33 、-C(O)R 34 ；R 33 Selected from C 1-3 An alkyl group; r is R 34 Selected from C 1-3 An alkoxy group;
m is 1;
or, as shown in formula II-1;
ring A is
X is selected from O or S;
R 4 selected from hydrogen, halogen;
L 1 and L 2 Each independently selected from none;
R 5 selected from-C (O) R 34 ，R 34 Selected from C 1-2 Alkyl, C 1-2 An alkoxy group;
m is an integer of 1;
or, as shown in formula II-1;
the A ring is 3-6 membered saturated heterocycle; the 3-6 membered saturated heterocycle isM is O; x is selected from O;
R 4 selected from hydrogen, halogen;
L 1 and L 2 Each independently selected from none;
R 5 selected from C 1-2 Alkyl, allenyl, C 2-4 Alkenyl, =r 39 ；R 39 Selected from CH 2；
m is 1.
2. A compound, or a pharmaceutically acceptable salt thereof, which is:
3. a medicament, characterized in that: a formulation prepared from a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable excipients.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament having sedative, hypnotic, and/or anaesthetic effects, and/or useful for controlling status epilepticus.
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