CN115925699B - Fused ring compound with analgesic activity and preparation method and application thereof - Google Patents

Fused ring compound with analgesic activity and preparation method and application thereof Download PDF

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CN115925699B
CN115925699B CN202211366859.5A CN202211366859A CN115925699B CN 115925699 B CN115925699 B CN 115925699B CN 202211366859 A CN202211366859 A CN 202211366859A CN 115925699 B CN115925699 B CN 115925699B
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CN115925699A (en
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张爱琴
杨谋伟
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Nanjing Zhihe Medical Technology Co ltd
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Abstract

The application provides a condensed-cyclic compound with analgesic activity as shown in formula I, a preparation method and application thereof, the compound has remarkable analgesic activity, can be developed into a medicament for treating various diseases such as pain symptoms, alzheimer disease and the like, and is simultaneously suitable for openingIs available in various dosage forms.

Description

Fused ring compound with analgesic activity and preparation method and application thereof
Technical Field
The application relates to the technical field of medicines, in particular to a condensed-cyclic compound and a composition taking the condensed-cyclic compound as an active ingredient, and application of the condensed-cyclic compound and the composition in preparing medicines for treating pain.
Background
Pain is a self-protective response caused by or underlying tissue injury, accompanied by physiological conditions such as emotional anxiety, tension, etc., and is a common symptom or concomitant symptom of clinical multiple diseases. Pain is classified into acute pain and chronic pain, and the acute pain is mainly caused by the causes of surgery, serious physical trauma and the like; chronic pain is often caused by nociceptive pain, inflammation, neuropathic pain, migraine and the like.
Analgesic drugs (Analgesis) are a class of drugs which act on the central nervous system, can effectively relieve or eliminate pain without affecting other sensations, and have important significance in emergency treatment. The analgesic drugs currently reported to be marketed are mainly composed of opioid alkaloids (Opioids) and nonsteroidal anti-inflammatory drugs (Nonsteroidal Anti-inflammatory Drugs, NSAIDs), but opioid receptor drugs still dominate. Opioid receptors include classical receptors μ, δ, κ and non-classical Nociceptin (NOP) receptors. Mu receptor agonists have the strongest analgesic effect, but generally increase craving and even cause respiratory depression; delta receptor agonists are less addictive, but the analgesic effect is far less than mu receptor agonists; the kappa receptor agonist has an analgesic effect between the two, but is easy to cause side effects such as illusion, mydriasis, dysphoria and the like. Currently mainstream opioid receptor agonists are mainly morphine, oxycodone, fentanyl, sufentanil, remifentanil, methadone, and the like. It is alarming that abuse of opioids also now has led researchers to expand new research directions, but mostly in the early clinical stages. Antipyretic analgesics are a class of agents that can relieve fever and pain locally, and exert antipyretic and analgesic effects by inhibiting the synthesis and release of Prostaglandins (PGs) in the hypothalamus, usually with anti-inflammatory effects. The medicine has better effect on dull pain such as local pain, neuralgia, arthralgia, menstrual pain and the like, but has poorer effect on other types of pain. The current clinical common use is: aspirin, ibuprofen, futazidime Lin Heji, etc., but the use of such drugs is considered in a number of situations.
Analgesic drugs currently have significant side effects. Therefore, development of superior analgesic is still urgent.
Disclosure of Invention
The invention provides a novel fused ring compound and a composition thereof, which have strong stability, obvious analgesic activity and are suitable for being developed into various dosage forms.
The compound provided by the other aspect of the invention can overcome the defects of the prior art, has higher efficacy in organisms, and has long duration of analgesic effect without obvious side effects.
The present invention provides a compound having formula I:
or a solvate, pharmaceutically acceptable salt, enantiomer, diastereomer, or racemic mixture thereof;
in formula I:
y is selected from CH or N;
R 1 、R 2 、R 3 each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, benzyl, picolyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Carbocyclyl, C 2 - 8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, carbocyclyl, heterocyclyl and aryl groupsHeteroaryl may be further optionally substituted with one or more of the following groups a;
L is selected from
R 4 Selected from the group consisting of
T is selected from O or S;
m is selected from 1, 2, or 3;
R 5 、R 6 each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R 5 、R 6 Are connected into a ring;
R 7 selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
R 8 、R 9 each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R 8 、R 9 Are connected into a ring;
R a 、R b each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R a 、R b Are connected into a ring;
R c 、R d each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R c 、R d Are connected into a ring;
X 1 selected from O, or N;
X 1 when O is, R 11 Absence of;
R 10 selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
R 11 selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3 - 8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
X 2 、X 3 each independently selected from O, NH, or S;
R 12 、R 13 each independently selected from hydrogen, na, K, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl, or R 12 、R 13 Are connected into a ring; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one OR more of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto methyl, mercapto ethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, - (c=o) OR 16 、-(C＝S)NHR 16 Substitution;
R 14 selected from the group consisting ofHydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 An alkylamino group;
R 15 selected from the group consisting of
Z is selected from CH or N;
R 16 selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 An alkylamino group,
R 17 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
R 18 selected from C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
the group A is: hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto methyl, mercapto ethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
The compound provided by the invention has the structure shown in the following formula II:
definition of substituents in formula II formula I is defined.
The compound provided by the invention has the structure shown in the following formula III:
the definition of the substituent in the formula III is defined as in the formula I.
The compound provided by the invention has the structure shown in the following formula IV:
the definition of the substituent in the formula IV is defined as in the formula I.
The compound provided by the invention has the structure shown in the following formula V:
The definition of the substituent in the formula V is defined as in the formula I.
In some embodiments, in formulas (I) - (V) above, Y is selected from CH, or N;
in some embodiments, in formulas (I) - (V) above, R 1 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; wherein the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
preferably, R 1 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, cyano, trifluoromethyl, C 1-8 Alkyl, C 1 - 8 An alkoxy group; more preferably, R 1 Is hydrogen.
In some embodiments, in formulas (I) - (V) above, R 2 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto methyl, mercapto ethyl, amino, nitroCyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; wherein the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
preferably, R 2 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6 - 18 Aryl, C 3-12 Heteroaryl;
more preferably, R 2 Selected from F, cl, hydroxy, hydroxyethyl, methoxy, cyano, trifluoromethyl, methanesulfonyl.
In some embodiments, in formulas (I) - (V) above, R 3 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; wherein the above alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
Preferably, R 3 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, benzyl, picolyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6 - 18 Aryl, C 3-12 Heteroaryl;
more preferably, R 3 Selected from hydrogen, or methyl.
In some embodiments, L is in formulas (I) - (II) aboveWherein, the liquid crystal display device comprises a liquid crystal display device,
r is as described above 5 、R 6 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R 5 、R 6 Are connected into a ring;
preferably, R 5 、R 6 Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R 5 And R is 6 Are all hydrogen;
r is as described above 7 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3 - 8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
preferably, R 7 Is C 1-8 An alkyl group;
more preferably, R 7 Selected from isopropyl, or tert-butyl;
in some embodiments, L is in the above formulas (I) and/or (III) Wherein, the liquid crystal display device comprises a liquid crystal display device,
r is as described above 8 、R 9 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R 8 、R 9 Are connected into a ring;
preferably, R 8 、R 9 Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R 8 And R is 9 Are all hydrogen;
above X 1 Selected from O, or N;
preferably X 1 Is O, in which case R 11 Absence of;
r is as described above 10 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3 - 8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
preferably, R 10 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl;
more preferably, R 10 Selected from methyl, or isopropyl;
r is as described above 11 Selected from C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3 - 8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a; in particular, at this time X 1 Is N;
in some embodiments, L is in the above formulas (I) and/or (IV)Wherein, the liquid crystal display device comprises a liquid crystal display device,
r is as described above a 、R b Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R a 、R b Are connected into a ring;
preferably, R a 、R b Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R a And R is b Are all hydrogen;
r is as described above c 、R d Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, or R a 、R b Are connected into a ring;
preferably, R c 、R d Each independently selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R a And R is b Are all hydrogen, or R a And R is b One of which is hydrogen and the other of which is methyl;
above X 1 、R 10 And R 11 As defined above;
in some embodiments, L is in formula (I) and/or (V) aboveWherein, the liquid crystal display device comprises a liquid crystal display device,
above X 2 、X 3 Each independently selected from O, NH, or S;
preferably X 2 、X 3 Each independently selected from O, or NH;
r is as described above 12 、R 13 Each independently selected from hydrogen, na, K, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl, or R 12 、R 13 Are connected into a ring; wherein the above alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl A group selected from the group consisting of methoxy, ethoxy, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridinyl, picolyl, - (c=o) OR 16 、-(C＝S)NHR 16 Substitution;
preferably, R 12 、R 13 Each independently selected from hydrogen, na, C 1-8 Alkyl, C 6-18 Aryl, or R 12 、R 13 Are connected into a ring; wherein the above alkyl, alkoxy, aryl, can be further optionally substituted with one OR more of hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, amino, nitro, cyano, trifluoromethyl, methoxy, ethoxy, carboxyl, acetyl, formaldehyde, methylsulfonyl, ethylsulfonyl, phenyl, benzyl, pyridyl, picolyl, - (c=o) OR 16 、-(C＝S)NHR 16 Substitution;
more preferably, R 12 、R 13 Each independently selected from hydrogen, na, C 1-8 Alkyl, C 6-18 Aryl, or R 12 、R 13 Are connected into a 5-6 membered ring; wherein the alkyl group may be further substituted by- (C=O) OR 16 Substitution; wherein, the liquid crystal display device comprises a liquid crystal display device,
r is as described above 16 Selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylamino or alkylamino groups
In some embodiments, in formulas (I) - (V) above, R 4 Is thatWherein, the liquid crystal display device comprises a liquid crystal display device,
t is selected from O or S;
m is selected from 1, 2, or 3;
preferably, m is selected from 1, or 2;
r is as described above 14 Selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 An alkylamino group;
preferably, R 14 Selected from hydrogen, or C 1-8 An alkyl group;
more preferably, R 14 Selected from hydrogen, methyl, or ethyl;
r is as described above 15 Is thatWherein, the liquid crystal display device comprises a liquid crystal display device,
z is selected from CH or N;
r is as described above 17 Selected from hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, cyano, trifluoromethyl, methoxy, ethoxy, isopropoxy, methylthio, acetyl, methylsulfonyl, ethylsulfonyl;
preferably, R 17 Selected from hydroxy, methylthio, isopropoxy, acetyl;
r is as described above 18 Selected from C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
preferably, R 18 Selected from C 5-6 Carbocyclyl, or C 2-5 A heterocyclic group; wherein the above carbocyclyl, heterocyclyl may be further optionally substituted with one or more of the following groups a;
the group A is: hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, mercapto methyl, mercapto ethyl, amino, nitro, cyano, trifluoromethyl, carboxyl, acetyl, formaldehyde, methanesulfonyl, ethanesulfonyl, phenyl, benzyl, pyridyl, picolyl, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino.
The compound provided by the invention has the following structure:
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in another aspect, in some embodiments, the invention provides pharmaceutical compositions comprising the above compounds, or solvates, pharmaceutically acceptable salts, enantiomers, diastereomers, racemic mixtures (as active ingredients), and inert carriers.
The composition, the form of which can be applied, comprises: injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, gum, powder, granule, gel, cream, ointment, patch, suppository, suspension, syrup.
The composition comprises an active ingredient which occupies a unit dose of 0.01 mg-1.0 g of the body weight of the individual in need of treatment.
In some embodiments, the present invention provides the use of the above pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of a related disease or disorder.
The related diseases or conditions include neuropathic pain, oral pain, facial pain, internal organ pain, headache, insomnia, cognitive decline, appetite dysfunction, mood dysfunction, sunset syndrome, and Alzheimer's disease.
A method of treating a disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of the compound or the composition.
The compounds disclosed herein have an inhibitory effect on the deposition of beta-amyloid.
Compared with TM, the compound disclosed by the invention has more remarkable analgesic effect.
The compound disclosed by the invention has stronger blood brain barrier penetration and larger in vivo exposure compared with TM, and particularly the compound RE-33 has the most excellent performance in the aspects.
In the present invention, each term has the following definition in order for each skilled person to understand the present invention more thoroughly.
"amino" herein refers to a functional group having 1 nitrogen atom and 0, 1, to 2 hydrogen atoms.
Halogen herein means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
"C1-8 alkyl" refers to a straight, side chain or cyclic hydrocarbon group having 1 to 8 carbon atoms. Such as methyl, ethyl, propyl, isopropyl, isobutyl, pentyl, methylpentanyl, 2-methylhexlkyl, isooctane, cyclopentyl, cyclohexyl, and the like.
"C1-8 alkoxy" refers to a straight, side chain or cyclic hydrocarbon group of 1 to 8 carbon atoms, interrupted by an-OH, or-O-group at any reasonable position. Such as methoxy, ethoxy, isopropoxy, isobutoxy, tert-butoxy, 2-methoxypropyl, (S) - (+) -1-methoxy-2-propyl, 1-propoxy-2-propyl, ethylene glycol monobutyl and the like.
"C1-8 alkylamino" means an amino group attached to the "C1-8 alkyl" at any reasonable position-NH-, -NH2 radical. Such as methylamino, ethylamino, diisopropylamino, N-methyl-N-propylamino, di-N-propylamino, N-ethylisopropylamino, 2- (isopropylamino) ethyl, and the like.
"C2-8 alkenyl" refers to a straight, branched or cyclic hydrocarbon group having 2 to 8 carbon atoms and containing at least one carbon-carbon double bond in the molecule. Such as allyl, butenyl, cis-2-pentenyl, trans-2-hexenyl, 3-dimethyl-1-butenyl, 2, 5-dimethyl-3-hexenyl, 2, 4-trimethyl-2-pentenyl, cis-2-pentenyl, trans-2-hexenyl, cyclohexenyl, 3-methyl-1-cyclohexenyl, and the like.
"C2-8 alkynyl" refers to a straight, branched or cyclic hydrocarbon group having 2 to 8 carbon atoms and containing at least one carbon-carbon triple bond in the molecule. Such as 2-propynyl, 3-dimethyl-1-butynyl, cyclopropylethynyl, 2-pentynyl, 4-methyl-2-hexynyl, methyl-n-propylethynyl, cyclopentylethynyl, cyclohexylethynyl, 3-cyclopentyl-1-propynyl, 4-octynyl, prop-1-ynylcyclopropynyl, 1-ethynyl-1-methylcyclohexylyl, and the like.
"C3-8 carbocyclyl" refers to a saturated or unsaturated alicyclic hydrocarbon group having 3 to 8 carbon atoms. The cyclic hydrocarbon group may be selected from a ring, or polycyclic condensed, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, dicyclopentanyl, methylcyclohexyl, ethylcyclohexyl, naphthylalkyl, 3-cyclopentyl-1-propyl, 1, 3-cyclohexanedienyl, 1-methyl-1-cyclohexenyl, and the like.
"C2-8 heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic group having heteroatoms in at least one ring of 2 to 8 carbon atoms, each ring of such polycyclic heterocycloalkyl groups may have different ways of attachment, such as fused, bridged, spiro, and the like. For example pyrrolidinyl, piperidinyl, morpholinyl, homopiperazinyl, 4-pyrrolidin-1-yl-piperidinyl, 3-methylpiperidinyl, N-ethylpiperidinyl, furanyl, thienyl, pyrazolyl, oxazolyl, tetrahydro-3-thiophenyl, 4-methyl-1-piperazinoethyl and the like.
"C6-18 aryl" refers to a group having at least one aromatic ring of 6 to 18 carbon atoms, each ring of the polycyclic aryl group may have different attachment means, such as condensed, bridged, etc., in addition to the covalent groups, and the condensed rings may be saturated or unsaturated. Such as phenyl, indanyl, indenyl, diphenylmethyl, alpha-tetrahydronaphthyl, and the like.
"C3-12 heteroaryl" refers to a 3-12 carbon monocyclic or polycyclic aromatic heterocyclic group containing at least one heteroatom, each ring of the polycyclic heteroaryl group may have different linkages such as fused, bridged, etc., for example, furyl, thienyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, pyrazinyl, quinolinyl, pyridazinyl, indenyl, indanyl, benzofuranyl, etc.
The double bond containing compounds of the present invention include all configurational isomers (e.g., cis and trans isomers).
"heteroatom" in the present invention includes nitrogen atom, oxygen atom, phosphorus atom, boron atom, sulfur atom, selenium atom and the like.
The compounds of the present invention have one or more asymmetric centers and the present invention thus relates to the use of all optical isomers and stereoisomers of these compounds and mixtures thereof. Also included are uses of compounds having tautomers and mixtures thereof.
The compounds of the present invention contain basic nitrogen atoms (heterocyclic or aliphatic amino groups, etc.) which are readily oxidized by oxidants such as atmospheric oxygen, hydrogen peroxide selected from the group consisting of N-oxides to form other compounds of the present invention. Thus, the converted N-oxide derivative is used as part of a compound selected from the group consisting of the compounds of the present invention.
The term "optionally" in the present invention refers to having 1 or more variables, then the selection of each instance of a substituent from among the available variable definitions is independent of the other selected definition variables. Thus, each substituent may be the same or different from the other substituents.
"treating" refers to achieving a significant reversal of symptoms of a disorder or causing the progression of a reversal of a disorder by administering a drug or pharmaceutical composition to an individual.
The "individual in need of treatment" in the present invention means a warm-blooded animal or a cold-blooded animal such as human, rat, mouse, rabbit, dog, pig, sheep, chicken, duck, goose, cat, cow, horse, etc.
The term "compound and its salt" as used herein refers to a complex of a compound with a corresponding acid, the nature of which depends on the nature of the compound, and the addition salt of the compound with the acid, e.g., an inorganic acid salt such as hydrochloride, sulfate, hydrobromide, etc. Organic acid salts such as maleate, fumarate, acetate, propionate, malate, tartrate, malonate, succinate, citrate, cinnamate, mandelate, methanesulfonate, p-toluenesulfonate, salicylate, and the like.
The term "compound and salt thereof" as used herein refers to addition salts of the compound with a base, and salts with inorganic bases such as sodium, potassium, ammonium, calcium, magnesium, and the like. Salts of organic amines such as diethylamine salt, ethylenediamine salt, meglumine salt, tromethamine salt, arginine salt, lysine salt, histidine salt, piperidine salt and the like.
The "inert carrier" as used herein refers to a substance that aids the individual in taking or absorbing the active substance in the pharmaceutical composition and does not cause significant adverse effects to the patient or individual, including dextrose, disintegrants, fillers, flavoring agents, lubricants, fatty acid esters, hydroxymethyl cellulose, stabilizers, emulsifiers, colorants, starches, sodium saccharin, cellulose, and the like.
The term "disease or disorder" as used herein refers to neuropathic pain, joint pain, postoperative pain, obstetric pain, herpetic pain, gout, joint degeneration pain, intervertebral disc-derived pain, trigeminal neuralgia, intractable headache, tumor pain, angina pectoris, idiopathic chest and abdominal pain, oral pain, facial pain, internal organ pain, etc.
The term "disease or disorder" as used herein includes insomnia, alzheimer's disease, sunset syndrome, parkinson's disease, hypomnesis, inattention, mental retardation, addiction, etc.
The term "composition" as used herein refers to any product comprising or obtained by direct or indirect means from a specific amount of a compound provided herein.
The compounds of the present invention may be used alone or in combination with one or more other agents to treat, prevent, or ameliorate the diseases or conditions described by the compounds of the present invention. The combination can be used with more remarkable curative effects.
The compound of the present invention occupies a unit dose of 0.01mg to 1.0g of the body weight of the individual in need of treatment, more preferably occupies a unit dose of 0.1mg to 0.5g of the body weight of the individual in need of treatment.
Drawings
FIG. 1 shows the results of an analgesic test of a compound of the present invention with TM.
FIG. 2 shows the β -amyloid deposition inhibiting activity of the compounds of the present invention.
Detailed Description
The invention is further described below in connection with examples, which are not intended to be limiting. The experimental solvents or reagents used in the examples described below are commercially available unless otherwise specified.
Embodiment one: preparation of intermediate E
Step 1: synthesis of intermediate B:
(2S) -2-methyl-2-piperidinecarboxylic acid (14.3 g,0.1mol,1.0 eq) was dissolved in acetonitrile (200 mL), and triethylamine (30.4 g,0.3mol,3.0 eq) was added. The reaction system was cooled to 0-5℃and Boc anhydride (21.8 g,0.1mol,1.0 eq) was carefully added dropwise. After the addition, the system was left to react at room temperature for 15 hours. Acetonitrile was removed under reduced pressure and the residue was then slowly added to water (250 mL). Ethyl acetate (2 x 250 ml) extraction, concentration of the organic phase, column chromatography separation gave 11.9g of intermediate B, yield: 49% [ M+H ]] + ＝244.10。
Step 2: synthesis of intermediate D:
intermediate B (24.3 g,0.1mol,1.0 eq) was dissolved in ethyl acetate (500 mL), HOBt (13.5 g,0.1mol,1.0 eq) and EDCI (19.1 g,0.1mol,1.0 eq) were added, and after stirring for 1 hour, C (12.7 g,0.1mol,1.0 eq) was added. The reaction was stirred at room temperature for 6 hours, washed with water (2 x 300 ml), concentrated under reduced pressure, and isolated by column chromatography to yield 15.5g of intermediate D, yield: 44% [ M+H ] ] + ＝353.19。
Step 3: synthesis of intermediate E:
intermediate D (3.5 g,10mmol,1.0 eq) was dissolved in acetic acid (60 mL), heated to 100deg.C and reacted for 3 hours. Acetic acid was removed by concentration, the residue was dissolved in DCM (60 mL), trifluoroacetic acid (10 mL) was then added and stirring was continued for 3 hours, water washing (2 x 300 mL), concentration under reduced pressure, column chromatography to give 0.7g of intermediate E, yield: 30% [ M+H ]] + ＝235.11。
Embodiment two: preparation of Compound RE-01
Step 1: synthesis of intermediate G:
intermediate F (21.7G, 0.1mol,1.0 eq) was dissolved in tetrahydrofuran (THF, 300 mL), sodium hydroxide (12.0G, 0.3mol,3.0 eq) was slowly added under nitrogen protection and reacted with 2-bromopropane (12.3G, 0.1mol,1.0 eq), heated to 60℃for 3 hours, washed with water (2X 200 mL), the organic phase was adjusted to acidic (pH 2-3) with hydrochloric acid (2.0M), concentrated under reduced pressure, and isolated by column chromatography to give 9.1G of intermediate G, yield: 35% [ M+H ]] + ＝259.16。
Step 2: synthesis of intermediate H:
in a three-necked flask under nitrogen, intermediate G (25.9G, 0.1mol,1.0 eq), 1, 4-dioxane (500 mL) and water (50 mL) were added slowly cyclopentylboronic acid (11.4G, 0.1mol,1.0 eq), dichloro [1,1' -bis (diphenylphosphine) ferrocene]Palladium (7.3 g,0.01mol,0.1 eq) and cesium carbonate (32.6 g,0.1mol,1.0 eq) are heated to reflux for 16 hours, cooled, hydrochloric acid (2.0M) is adjusted to pH 3-4, concentrated, water (300 mL) is added, ethyl acetate is extracted (2 x 300 mL), the organic phase is concentrated, column chromatography is separated to 13.6g intermediate H, yield: 55% [ M+H ] ] + ＝249.14。
Step 3: synthesis of intermediate I:
in a three-necked flask under nitrogen protection, add intermediate H (2.5 g,0.01mol,1.0 eq) to dichloromethane (100 mL), add HOBt (1.4 g,0.01mol,1.0 eq) and EDCI (1.9 g,0.01mol,1.0 eq), stir for 1 hour, add intermediate E (2.4 g,0.01mol,1.0 eq), stir for 6 hours at room temperature, wash (2X 50 mL), concentrate under reduced pressure, isolate 1.6g intermediate I by column chromatography, yield: 35% [ M+H ]] + ＝465.09。
Step 4: synthesis of Compound RE-01:
in a three-necked flask under nitrogen, intermediate I (4.6 g,0.01mol,1.0 eq) was added and dissolved in THFTo (100 mL) was added sodium hydrogen (0.48 g,0.02mol,2.0 eq) and chloromethyl isobutyrate (1.4 g,0.01mol,1.0 eq), and the mixture was stirred at room temperature for 16 hours, filtered, concentrated under reduced pressure, and separated by column chromatography to give 1.4g of compound RE-01, yield: 25% [ M+H ]] + ＝565.13。 1 H NMR(CDCl 3 )δ8.45-8.43(m,1H),7.55-7.54(m,2H),7.41-7.39(m,1H),7.10(d,J＝6.5Hz,1H),6.51(s,2H),4.74-4.72(m,1H),3.62-3.60(m,1H),3.52-3.50(m,1H),2.83-2.82(m,1H),2.53-2.51(m,1H),2.06-2.05(m,1H),1.90-1.88(m,2H),1.76-1.74(m,3H),1.66-1.63(m,5H),1.59-1.57(m,2H),1.51-1.50(m,1H),1.48(d,J＝12.3Hz,3H),1.31-1.29(m,6H),1.14-1.12(m,6H)。
Embodiment III: preparation of Compound RE-22 and Compound RE-23
Synthesis of Compound RE-22:
in a three-necked flask under the protection of nitrogen, intermediate I (4.6 g,0.01mol,1.0 eq) was added and dissolved in THF (100 mL), sodium hydrogen (1.4 g,0.02mol,2.0 eq) and diisopropyl chlorophosphate (2.0 g,0.01mol,1.0 eq) were added, stirred at room temperature for 16 hours, filtered, hydrochloric acid (20 mL) and water (20 mL) were added and the reaction was continued for 16 hours, concentrated, and 0.7g of compound RE-22 was obtained by liquid phase separation, yield: 12% [ M+H ] ] + ＝575.20。 1 H NMR(CDCl 3 )δ8.44-8.43(m,1H),7.52-7.50(m,2H),7.40-7.39(m,1H),7.07(d,J＝6.3Hz,1H),6.53(s,2H),4.72-4.70(m,1H),3.59-3.57(m,1H),3.51-3.49(m,1H),2.80-2.78(m,1H),2.04-2.03(m,1H),1.87-1.85(m,2H),1.73-1.71(m,3H),1.63-1.60(m,5H),1.55-1.53(m,2H),1.49-1.47(m,1H),1.44(d,J＝12.1Hz,3H),1.28-1.26(m,6H)。
Synthesis of Compound RE-23:
in a three-necked flask under the protection of nitrogen, compound RE-22 (5.7 g,0.01mol,1.0 eq) was added, dissolved in anhydrous THF (100 mL), thionyl chloride (2.4 g,0.02mol,2.0 eq) was added, the reaction was continued with stirring for 1 hour, methanol (10 mL) and triethylamine (3.0 g,0.03mol,3.0 eq) were added, the reaction was continued for 6 hours, and the mixture was filtered and concentrated under reduced pressure to prepareLiquid phase separation gave 0.6g of compound RE-23, yield: 10% [ M+H ]] + ＝603.10。 1 H NMR(CDCl 3 )δ8.43-8.42(m,1H),7.51-7.50(m,2H),7.38-7.37(m,1H),7.05(d,J＝6.2Hz,1H),6.55(s,2H),4.71-4.70(m,1H),3.79-3.77(m,6H),3.58-3.57(m,1H),3.50-3.48(m,1H),2.78-2.76(m,1H),2.03-2.02(m,1H),1.84-1.82(m,2H),1.72-1.69(m,3H),1.65-1.63(m,5H),1.54-1.52(m,2H),1.43-1.42(m,1H),1.41(d,J＝12.4Hz,3H),1.29-1.27(m,6H)。
Embodiment four: preparation of Compound RE-24
In a three-necked flask under nitrogen protection, compound RE-22 (5.7 g,0.01mol,1.0 eq) was added, dissolved in acetone (100 mL) and water (10 mL), sodium hydroxide (4.0 g,0.1mol,10.0 eq) was added, stirred at room temperature for 16 hours, filtered, concentrated, and the resulting residue was recrystallized from acetone/water to give 1.3g of compound RE-24, yield: 21% [ M+Na ]] + ＝641.11。 1 H NMR(CDCl 3 )δ8.42-8.40(m,1H),7.50-7.48(m,2H),7.39-7.38(m,1H),7.02(d,J＝6.5Hz,1H),6.51(s,2H),4.71-4.70(m,1H),3.56-3.55(m,1H),3.51-3.48(m,1H),2.81-2.80(m,1H),2.02-2.01(m,1H),1.86-1.85(m,2H),1.72-1.70(m,3H),1.61-1.57(m,5H),1.53-1.51(m,2H),1.46-1.44(m,1H),1.41(d,J＝12.3Hz,3H),1.25-1.23(m,6H)。
Fifth embodiment: preparation of Compound RE-25
In a three-necked flask under the protection of nitrogen, compound RE-22 (5.7 g,0.01mol,1.0 eq) was added, dissolved in anhydrous THF (100 mL), thionyl chloride (2.4 g,0.02mol,2.0 eq) was added, the reaction was continued with stirring for 1 hour, phenol (1.0 g,0.01mol,1.0 eq) and triethylamine (4.0 g,0.04mol,4.0 eq) were added, the reaction was continued for 6 hours, L-alanine isopropyl ester (1.7 g,0.01mol,1.0 eq) was added, the reaction was continued for 6 hours, filtration and concentration under reduced pressure were carried out to prepare a liquid phase separation Yield 0.8g of compound RE-25: 11% [ M+H ]] + ＝764.19。 1 H NMR(CDCl 3 )δ8.47-8.46(m,1H),7.58-7.56(m,2H),7.45-7.42(m,3H),7.25-7.23(m,3H),7.15(d,J＝6.3Hz,1H),6.56(s,2H),4.89-4.87(m,1H),4.77-4.76(m,1H),3.65-3.64(m,2H),3.53-3.52(m,2H),2.86-2.85(m,1H),2.09-2.07(m,1H),1.96-1.94(m,2H),1.79-1.76(m,3H),1.68-1.65(m,5H),1.63-1.61(m,2H),1.55-1.54(m,1H),1.49(d,J＝12.1Hz,3H),1.35-1.33(m,6H),1.30(d,J＝12.2Hz,3H),1.23-1.21(m,6H)。
Example six: preparation of Compound RE-28
In a three-necked flask under the protection of nitrogen, compound RE-22 (5.7 g,0.01mol,1.0 eq) was added and dissolved in anhydrous THF (100 mL), thionyl chloride (2.4 g,0.02mol,2.0 eq) was added, stirring was continued for reaction for 1 hour, ethylene glycol (0.6 g,0.01mol,1.0 eq) and triethylamine (4.0 g,0.04mol,4.0 eq) were added, reaction was continued for 6 hours, filtration and concentration under reduced pressure were performed to prepare 0.6g compound RE-28 by liquid phase separation, yield: 10% [ M+H ]] + ＝601.12。 1 H NMR(CDCl 3 )δ8.47-8.46(m,1H),7.57-7.55(m,2H),7.44-7.43(m,1H),7.13(d,J＝6.2Hz,1H),6.41(s,2H),4.76-4.75(m,1H),4.49-4.47(m,4H),3.64-3.63(m,1H),3.55-3.53(m,1H),2.86-2.84(m,1H),2.09-2.07(m,1H),1.95-1.93(m,2H),1.77-1.74(m,3H),1.68-1.64(m,5H),1.60-1.58(m,2H),1.55-1.53(m,1H),1.47(d,J＝12.4Hz,3H),1.32-1.30(m,6H)。
Embodiment seven: synthesis of Compound TM
Step 1: preparation of Compound IM01
SM01 (7.5 g,45.28 mmol) was dissolved in a mixed solvent of acetonitrile (45 mL) and water (75 mL), triethylamine (13.75 g,135.85 mmol) was added, the system was exothermic, the reaction system was cooled to 10℃and a solution of Boc anhydride (14.83 g,67.93 mmol) in acetonitrile (15 mL) was added, and after completion of the dropwise addition, the mixture was stirred at room temperature for 70h, and the reaction was completed by TLC.
Most of acetonitrile was concentrated out, then the concentrated residue was poured into a 2N aqueous sodium hydroxide solution (40 mL), extracted three times with ethyl acetate, the aqueous phase was adjusted to pH 1 to 2 with a 2N aqueous hydrochloric acid solution, a large amount of solids were precipitated, 16g of off-white solid was obtained by filtration, and the solid was dried in air drying at 50 ℃ for 3 hours to obtain the off-white solid, namely, compound IM01 (8.88 g), yield 84.78%. [ M+H ] ] + ＝230.15。
Step 2: preparation of Compound IM02
IM01 (8.88 g,38.73 mmol) was dissolved in dichloromethane (60 mL), benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (HBTU, 14.69g,38.73 mmol) and N, N-diisopropylethylamine (DIPEA, 13.02g,100.7 mmol) were added, stirred for 0.5h, then a DCM solution (40 mL) with SM02 (10.00 g,63.85 mmol) was added, and the reaction was allowed to react overnight at room temperature and was detected by TLC.
The solvent was removed by concentration under reduced pressure, the reaction was poured into water, extracted with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a brown oil which was column chromatographed to give compound IM02 (7.5 g) as a white solid in 52.74% yield. [ M+H ]] + ＝368.18。
Step 3: preparation of Compound IM03
IM02 (7.00 g,19.03 mmol) was dissolved in acetic acid and heated to 100deg.C for 1h, after which the reaction was completed by TLC.
After concentrating to remove most of the acetic acid, adding DCM for dilution, adding in aqueous sodium bicarbonate (ice water), separating, extracting the aqueous phase with DCM three times, combining the organic phases, concentrating to obtain a beige foamy solid, namely the compound IM03 (6.0 g), with a yield of 90.10%. [ M+H ]] + ＝350.15。
Step 4: preparation of Compound IM04
IM03 (6.0 g,17.16 mmol) was dissolved in dioxane (50 mL), trifluoroacetic acid (TFA, 9.78g,85.82 mmol) was added under ice-bath, stirred overnight, and TLC was checked for completion.
The reaction solution was concentrated to dryness to give a brown oil, crude compound IM04 (6.5 g), which was fed next in 100% without further treatment.
Step 5: preparation of Compound IM05
SM03 (8.08 g,29.06 mmol) was dissolved in N, N-dimethylformamide (DMF, 70 mL) and the solution was yellowish brown, 1H-1,2, 3-triazole (4.01 g,58.12 mmol) and cesium carbonate (18.94 g,58.12 mmol) were added, the temperature was raised to 40℃with a small amount of gas evolved, cuprous iodide (0.277 g,1.45 mmol) was added, the solution was gradually changed to green, the temperature was not obvious, the temperature was raised to 70℃and stirred for 1H, and the TLC detection was completed.
The reaction solution was cooled to room temperature, poured into water, extracted once with Ethyl Acetate (EA), the aqueous phase was kept, the aqueous phase was made acidic with citric acid, extracted twice with EA, the organic phase was dried over anhydrous sodium sulfate, and concentrated to give a tan oil, compound IM05 (13.0 g), yield was 100%. [ M+H ]] + ＝220.06。
Step 6: preparation of Compound TM
IM04 (3.0 g,10.48 mmol) was dissolved in dichloromethane (30 mL), IM05 (2.30 g,10.48 mmol), DIPEA (6.77 g,52.40 mmol), HBTU (3.98 g,10.48 mmol) were added sequentially in an ice bath, the reaction was started (as the reaction proceeded, the solution color gradually became reddish brown), the reaction stirred overnight, and the TLC detection was complete.
Three times with water and dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude product (8.26 g), which was subjected to column chromatography to give compound TM (1.05 g) in 22.20% yield. [ M+H ]] + ＝451.6。 1 HNMR(DMSO,400MHz):12.24(brs,1H),8.03(s,2H),7.79(d,J＝8.8Hz,1H),7.41-7.249(m,3H),7.17(d,J＝8.8,1H),3.90(s,3H),3.61(m,1H),2.67(s,3H),2.3(m,1H),2.05-1.95(m,4H),1.89(s,3H)。
Example eight: preparation of Compound RE-31
Compound TM (400 mg,0.887 mmol) was dissolved in DMF under ice bath, 60% sodium hydride (70.96 mg,1.774 mmol) was added and stirred for 30 minutes, chloromethyl isobutyrate (242.29 mg,1.774 mmol) was added, the reaction was allowed to warm to room temperature for half an hour, and the reaction was completed by TLC.
After quenching with water, extraction with EA and water for 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and the product was isolated by chromatography (PE: ea=2:1) and concentrated to give a powdery solid, compound RE-31 (105 mg), yield 21.47%. [ M+H ]] + ＝551.14。 1 HNMR(DMSO,400MHz):8.07(s,2H),7.82(d,J＝8.8Hz,1H),7.40(m,1H),7.33(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.04(s,1H),6.47(m,2H),3.89(s,3H),3.60(m,2H),2.56(s,3H),2.33-2.08(m,5H),1.95(s,3H),1.07(d,6H)。
Example nine: preparation of Compound RE-32
TM (500 mg,1.109 mmol) in ice bath was dissolved in DMF (5 mL), 60% sodium hydride (88.72 mg,2.218 mmol) was added and after stirring for 30 min, methyl chloride pivalate (334.03 mg,2.218 mmol) was added and the reaction was completed by TLC for half an hour.
Post-treatment: after quenching with water, extraction with EA and water for 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and the product was isolated by chromatography (PE: ea=2:1) and concentrated to give compound RE-32 (100 mg) in 15.95% yield. [ M+H ] ] + ＝565.18。 1 HNMR(DMSO,400MHz):8.08(s,2H),7.83(d,J＝8.4Hz,1H),7.34(m,2H),7.20(d,J＝8.0Hz,1H),7.02(s,1H),6.44(m,2H),3.90(s,3H),3.58(m,2H),2.51(s,3H),2.33-2.09(m,4H),1.96(s,3H),1.09(s,9H)。
Example ten: preparation of Compound RE-33
Compound TM (1.1 g,2.44 mmol) was dissolved in DMF (5.5 mL), 60% sodium hydride (0.195 g,4.88 mmol) was added and stirred for 30 minutes, followed by chloromethyl methyl carbonate (0.608 g,4.88 mmol)l), reacting for half an hour, heating to room temperature, continuing to react for 5 hours, detecting that the material is mostly reacted by TLC, quenching by water, extracting 3 times by EA and water, merging organic phases, drying by anhydrous sodium sulfate, sequentially separating by chromatography, and preparing a liquid phase for separation to obtain a product compound RE-33 (15 mg), wherein the yield is 1.14%. [ M+H ]] + ＝539.17。
1 HNMR(DMSO,400MHz):8.07(s,2H),7.79(d,J＝8.8Hz,1H),7.47(d,J＝8.4Hz,1H),7.34(d,J＝8.8Hz,1H),7.20(d,J＝8.4Hz,1H),7.09(s,1H),6.46(m,2H),4.06(s,3H),3.96(s,3H),3.77-3.62(m,2H),2.67(s,3H),2.3-2.0(m,4H),1.91(s,3H)。
Example eleven: preparation of Compound RE-37
In a three-necked flask under nitrogen protection, compound TM (2.25 g,5.00 mmol) was added and dissolved in THF (35 mL), 60% sodium hydride (0.4 g,10.0 mmol) and diisopropyl chlorophosphate (1.0 g,5.0 mmol) were added and stirred at room temperature for 20 hours, filtered, hydrochloric acid (10 mL) and water (10 mL) were added and the reaction was continued for 20 hours, and concentrated to prepare compound RE-37 (0.43 g) by liquid phase separation, yield: 15.4% [ M+H ]] + ＝561.01。
Embodiment twelve: preparation of Compound RE-38
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In a three-necked flask under the protection of nitrogen, compound RE-37 (1.12 g,2.0 mmol) was added and dissolved in anhydrous THF (20 mL), thionyl chloride (0.470 g,4.0 mmol) was added, stirring reaction was continued for 1 hour, methanol (3 mL) and triethylamine (0.607 g,6.0 mmol) were added and reaction was continued for 6 hours, filtering and concentration under reduced pressure, and then the compound RE-38 (0.13 g) was obtained by liquid phase separation in yield: 11.0% [ M+H ] ] + ＝589.19。
Embodiment thirteen: preparation of Compound RE-39
In a three-necked flask under the protection of nitrogen, compound RE-37 (1.12 g,2.0 mmol) was added, dissolved in acetone (20 mL) and water (2 mL), sodium hydroxide (0.8 g,20 mmol) was added, stirred at room temperature for 18 hours, filtered, concentrated, and the obtained residue was recrystallized from acetone/water to obtain compound RE-39 (0.22 g), yield: 18.2% [ M+H ]] + ＝605.17。
The following example compounds were prepared by reasonable upper protecting group deprotection using a similar synthetic procedure:
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fourteen examples: determination of the Effect of acetic acid torsion method on pain in mice
Respectively preparing aqueous solutions of compounds TM, RE-01, RE-09, RE-19, RE-22, RE-23, RE-25, RE-26, RE-29, RE-31, RE-32, RE-33, RE-35, RE-37, RE-38, RE-40, RE-41, RE-45 and RE-47 for later use. The concentrations of the above compounds were 0.26mg/mL, 0.33mg/mL, 0.32mg/mL, 0.33mg/mL, 0.35mg/mL, 0.44mg/mL, 0.46mg/mL, 0.35mg/mL, 0.32mg/mL, 0.33mg/mL, 0.31mg/mL, 0.33mg/mL, 0.32mg/mL, 0.34mg/mL, 0.43mg/mL, 0.46mg/mL, 0.32mg/mL and 0.36mg/mL, respectively (the molar concentrations of the respective compounds were the same).
60 female KM mice, 18-22g, were divided into 20 groups of 3. The administration group and the TM control group were each intraperitoneally injected with 0.4mL of the newly prepared compound solution, respectively, and the model group was intraperitoneally injected with an equal volume of water for injection.
After 30min of administration, 0.2mL of 0.6% glacial acetic acid solution was intraperitoneally injected into each mouse, and the number of times of twisting in 20min was recorded for each mouse, and the average value was calculated. The results are shown in FIG. 1.
The results show that the twisting times of each administration group and the TM control group are obviously less than those of the model control group; compared with the TM control group, the number of twists of each administration group is also obviously reduced, and the twists of the compounds RE-19, RE-33, RE-35, RE-37, RE-38 and RE-45 are most obviously reduced; in conclusion, the compounds disclosed by the invention have stronger analgesic activity.
Example fifteen: beta-amyloid deposition inhibitory Activity
Aging-accelerated mice (SAMP 8) were 63, males (8 months of age at study initiation) and were equally divided into 9 groups of 7. Normal tap water drinking by the non-intervention group; experimental groups 1-8 each received solutions of the compounds (RE-01, RE-23, RE-31, RE-32, RE-33, RE-37, RE-45, RE-47) dissolved in tap water at a dose of 0.1 mg/kg/day. Eight weeks after dosing, the rat brain was removed, fixed with metacarpin (methanol: chloroform: acetic acid=6:3:1) and paraffin was implanted. Then, 8 μm thick sections were prepared using a microtome.
The sections were immunostained with streptavidin-biotin using VECTASTATIN ABC kit. After one hour incubation in 10% normal goat serum, anti-beta-amyloid (aβ) antibodies were diluted 10-fold with PBS and incubated overnight at 4 ℃. The following day, PBS wash, incubation with biotinylated anti-rabbit secondary antibody for 1.5 hours, PBS wash, and incubation with peroxidase-labeled streptavidin for 1.5 hours were performed. The immune response was visualized with DAB and samples were prepared.
Immunoreactive aβ -like particles in the hippocampus were counted under a microscope. Aβ -like immunoreactive particles were observed as brown deposits in the hippocampus. Each individual was counted in a slice.
As shown in fig. 2, β -amyloid-like immunoreactivity in the hippocampus was observed in the non-interfered group of accelerated aging mice (SAMP 8). In the case of the administration dose of 0.1 mg/kg/day, the β -amyloid immunoreactivity was decreased in the experimental group 1-8 of the aging-accelerated mice (SAM 8). This suggests that the disclosed compounds are capable of inhibiting β -amyloid deposition due to the intervention of the disclosed compounds, which significantly reduces the number of β -amyloid-immunoreactive particles.
Example sixteen: the disclosed compound parallel artificial membrane permeation model (PAMPA) test compound was diluted to a solution of 25 μg/mL with a buffer having a pH of 7.4; dissolving pig brain lipid extract (PBL) in dodecane to prepare 20mg/mL solution as phospholipid membrane; dropping 4 mu L of PBL solution on a polyvinyl fluoride film of a 96-hole filter plate to form a phospholipid film simulating the brain environment; 300. Mu.L/well buffer was added above the phospholipid membrane as acceptor tube, and another 96-well plate was added with 150. Mu.L/well of 25. Mu.g/mL compound solution as donor tube, three wells per drug were in parallel; overlapping the two plates to enable the phospholipid membrane to be in contact with donor liquid to form a sandwich structure, and placing the sandwich structure in a constant temperature environment at 37 ℃ for 18 hours; the solution in the 96-well filter plate was removed and transferred to a blank 96-well plate, and OD was measured at 340 nm. Experiments were performed in parallel 3 times. The permeability Pe values were calculated according to the literature (Kiyohiko S., et al, optimized conditions of bio-mimetic artificial membrane permeation assay [ J ]. Int. J. Pharm.,2001,228,181-188). The results are shown in Table 1.
TABLE 1 results of Artificial Membrane permeation model (PAMPA) test
Numbering of compounds Pe value (10) -6 cm/s) Numbering of compounds Pe value (10) -6 cm/s)
RE-01 3.32 RE-35 10.45
RE-23 5.29 RE-37 1.98
RE-24 1.85 RE-38 11.59
RE-25 4.79 RE-40 3.56
RE-28 7.23 RE-41 3.26
RE-31 9.36 RE-45 11.59
RE-32 9.88 RE-47 4.57
RE-33 13.65 TM 0.85
The data show that the compounds disclosed by the invention have higher blood-brain barrier transmission capacity than the control compound TM, wherein the blood-brain barrier transmission capacity of the compounds RE-31, RE-32, RE-33, RE-35, RE-38 and RE-45 is 11-16 times that of the control compound TM. The compound disclosed by the invention can penetrate through the blood brain barrier to reach the brain more advantageously, so that the effect of treating brain diseases can be effectively exerted.
Example seventeenth: pharmacokinetic characterization in rats
Experimental animals: 12 male SD rats, 180g-220g, were subjected to an adaptive feeding for 3 days and then tested.
Preparing a test sample: and respectively weighing proper amounts of the test samples TM, RE-33, RE-37 and RE-38, respectively placing the test samples in reagent bottles, and adding proper amounts of 0.5% carboxymethyl cellulose solution to prepare test sample solutions with the concentrations of the TM, the RE-33, the RE-37 and the RE-38 of 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (the molar concentrations of the compounds are the same).
The test method comprises the following steps: rats were randomly divided into 4 groups, including TM, RE-33, RE-37 and RE-38, 3 each. Each animal was separately gastrically administered the newly formulated corresponding test solution. The administration doses were 4mg/kg in the TM group, 4.8mg/kg in the RE-33 group, 5.0mg/kg in the RE-37 group and 5.2mg/kg in the RE-38 group. The medicine is fasted for 16-17h before administration, 4h after administration, and the whole process is not forbidden. The eyeballs of the rats 0h before, 0.083h after, 0.17h, 0.33h, 0.5h, 1h, 2h, 4h, 8h and 24h after oral gavage administration are used for taking blood of about 300 mu L by vein.
Blood sample treatment and detection: placing rat venous blood into a centrifuge tube containing heparin sodium, placing the centrifuge tube on an ice bath, standing for 15 minutes, centrifuging (4000 rpm,10 minutes), taking a proper amount of plasma, and preserving at-80 ℃ to be tested. The results are shown in Table 2.
General clinical symptom observation: in the whole experimental process, general state observation is carried out on experimental animals, and the observation contents comprise: the rats have the conditions of feeding and water intake, weight change, hair color, behavior and mental state, abnormal secretion of eyes, ears, mouth and nose, and abnormal urination and urination. If the abnormality occurs, recording is immediately carried out, and the reason of the abnormality is analyzed.
TABLE 2 mean results of pharmacokinetic parameters in rats
Test article Dosage (mg/kg) Tmax(h) Cmax(ng/ml) AUClast(h*ng/ml)
TM 4.0 1 14.5 38.6
RE-33 4.8 1 20.5 58.1
RE-37 5.0 1 18.1 50.9
RE-38 5.2 1 17.6 50.1
The results show that compared with TM, the maximum blood concentration of the compound disclosed by the invention is more than 120%, the exposure is more than 130%, especially RE-33, the compound is most outstanding in the aspects of maximum blood concentration and in-vivo exposure, and the observation of general clinical symptoms is not abnormal, so that the compound disclosed by the invention has higher bioavailability.
Example eighteenth: rat brain tissue distribution experiment
Experimental animals: 12 male SD rats, 180g-220g, were subjected to an adaptive feeding for 3 days and then tested.
Preparing a test sample: and respectively weighing proper amounts of the test samples TM, RE-33, RE-37 and RE-38, respectively placing the test samples in reagent bottles, and adding proper amounts of 0.5% carboxymethyl cellulose solution to prepare test sample solutions with the concentrations of the TM, the RE-33, the RE-37 and the RE-38 of 2.0mg/mL, 2.4mg/mL, 2.5mg/mL and 2.6mg/mL (the molar concentrations of the compounds are the same).
The test method comprises the following steps: rats were randomly divided into 4 groups, including TM, RE-33, RE-37 and RE-38, 3 each. Each animal was separately gastrically administered the newly formulated corresponding test solution. The administration doses are 4mg/kg of TM group, 4.8mg/kg of RE-33 group, 5.0mg/kg of RE-37 group and 5.2mg/kg of RE-38 group; the medicine is fasted for 16-17h before administration, 4h after administration, and the whole process is not forbidden. Sampling and detecting: animals were sacrificed 3.0h after gavage administration for each group, brain tissue was isolated, homogenized, and analyzed for TM using LC-MS/MS. The results are shown in the following table. The results are shown in Table 3.
TABLE 3 rat brain tissue distribution results
Test article Dosage (mg/kg) Concentration of brain tissue for 3h (ng/g)
TM 4.0 1659
RE-33 4.8 4651
RE-37 5.0 3875
RE-38 5.2 3974
The results show that the concentration of TM in the brain tissue of the rat with the compound 3h disclosed by the application is obviously higher than that of a TM prototype, wherein the concentration of the brain tissue of RE-33 reaches more than 3 times of TM.
The features of the present application will be more fully understood from the foregoing detailed description of the application, and the modified forms of the application will fall within the scope of the appended claims.

Claims (8)

1. A compound having the formula I:
or a pharmaceutically acceptable salt thereof;
in formula I:
y is selected from CH or N;
R 1 is hydrogen;
R 2 selected from halogen, hydroxy, cyano, trifluoromethyl, hydroxy substituted C 1-8 Alkyl, methoxy, methanesulfonyl;
R 3 selected from hydrogen, halogen, C 1-8 An alkyl group;
l is selected from
R 4 Selected from the group consisting of
T is selected from O or S;
m is selected from 1, or 2;
R 5 、R 6 each independently selected from hydrogen, methyl;
R 7 selected from C 1-8 Alkyl, C 1-8 An alkoxy group;
R a 、R b each independently selected from hydrogen, methyl;
R c 、R d each independently selected from hydrogen, methyl;
X 1 selected from O;
X 1 when O is, R 11 Absence of;
R 10 selected from C 1-8 Alkyl, C 1-8 An alkoxy group;
X 2 、X 3 each independently selected from O,NH；
R 12 、R 13 Each independently selected from hydrogen, na, K, C 1-8 Alkyl, C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl, or R 12 、R 13 Are connected into a ring; the above alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one OR more of the following- (C=O) OR groups 16 Substitution;
R 14 selected from hydrogen, C 1-8 An alkyl group;
R 15 selected from the group consisting of
Z is selected from CH;
R 16 selected from C 1-8 Alkyl group,
R 17 Selected from hydroxy, methoxy, ethoxy, isopropoxy, methylthio, acetyl;
R 18 selected from C 3-8 Carbocyclyl, C 2-8 Heterocyclyl, C 6-18 Aryl, C 3-12 Heteroaryl; the above carbocyclyl, heterocyclyl, aryl, heteroaryl groups may be further optionally substituted with one or more of the following groups a;
The group A is: hydroxy, hydroxymethyl, hydroxyethyl, mercapto, mercaptomethyl, mercaptoethyl, C1-8 alkyl.
2. A compound according to claim 1 having the structure of formula ii:
the definition of substituents in formula II is as defined in formula I of claim 1.
3. A compound according to claim 1 having the structure of formula IV:
the definition of substituents in formula IV is as defined in formula I of claim 1.
4. A compound according to claim 1 having the structure of formula V:
the substituents in formula V are as defined in formula I of claim 1.
5. A compound according to any one of claims 1 to 4 having the structure:
6. a pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and an inert carrier.
7. The composition of claim 6, in a form of an applicable composition comprising: injection, powder, spray, inhalant, tablet, pill, capsule, lozenge, gum, powder, granule, gel, cream, ointment, patch, suppository, suspension, syrup.
8. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 6 to 7, in the manufacture of a medicament for the treatment and/or prophylaxis of a related disease or condition; wherein the disease or condition is selected from neuropathic pain, oral pain, facial pain, internal organ pain, headache.
CN202211366859.5A 2022-02-25 2022-11-02 Fused ring compound with analgesic activity and preparation method and application thereof Active CN115925699B (en)

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