CN107922340B - 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof - Google Patents
1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof Download PDFInfo
- Publication number
- CN107922340B CN107922340B CN201680050320.5A CN201680050320A CN107922340B CN 107922340 B CN107922340 B CN 107922340B CN 201680050320 A CN201680050320 A CN 201680050320A CN 107922340 B CN107922340 B CN 107922340B
- Authority
- CN
- China
- Prior art keywords
- membered
- neuropathy
- radical
- pharmaceutically acceptable
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided are 1,2,3, 4-tetrahydroisoquinoline derivatives having a structure of formula (I), a preparation method and applications thereof. The compound of the formula (I) can be used for developing medicaments for primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve injury or biochemical nerve injury, Painful Diabetic Neuropathy (PDN) or related neuropathy, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of drug development, and particularly relates to a 1,2,3, 4-tetrahydroisoquinoline derivative, and a preparation method and application thereof.
Background
The most common types of neuropathic pain include Diabetic Neuralgia (DNP), postherpetic neuralgia (PHN and AIDS-related neuropathic pain), often chronic pain, characterized by hyperalgesia, sensory hypersensitivity to stimuli, allodynia and idiopathic causalgia, as opposed to secondary (damaging pain), the current treatments for neuropathic pain include mainly anticonvulsants, antidepressants, narcotic analgesics and local anesthetics, standard treatments such as anticonvulsants L yrinca (Pregabalin), by Perey company, these drugs are effective in the treatment of nociceptive pain, but have very limited treatment of neuropathic pain, with severe side effects, including cognitive changes, sedatives, as well as resistance and dependence on drugs, thus providing a potent and pathological mechanism for neuropathic pain, and the underlying pathological mechanisms of nociception are not well understood.
The renin-angiotensin system (RAS) is present not only in the circulation but also in many tissue organs such as the cardiovascular, renal, brain and acts by autocrine and paracrine. RAS produces biological effects by binding angiotensin ii (angii) to angiotensin receptors. The angiotensin II receptor type I receptor (AT1) and the angiotensin II receptor type II receptor (AT2) are the major receptors that have been identified. AT1 is widely distributed in almost all tissues and organs. AT2 is mainly distributed in embryonic tissue, immature brain tissue, and adult normal tissue, but its expression is increased after tissue damage. In animal models and patient studies of neuropathic pain, it was found that the expression of AngII, the AngII receptor AT2 is increased in vivo, and that AT2 is frequently co-expressed with pain signaling molecules (e.g., substance P, TRPV 1). Researches show that after the angiotensin II receptor of the brain tissue of a mouse is activated, the analgesic effect on anti-morphine can be achieved; activation of angiotensin II receptors in the ventral region of the caudal end of the medulla oblongata can cause hyperalgesia, which can be alleviated by administration of angiotensin II receptor antagonists. EMA401, researched and developed by Spinifex corporation of Australian biomedicine, is a high-selectivity angiotensin II receptor 2 antagonist, is disclosed in US5246943 for the first time, is in a clinical phase II experiment at present, and the existing research shows that the medicine has a good analgesic effect and particularly has a remarkable treatment effect on neuropathic pain such as Diabetic Neuralgia (DNP), postherpetic neuralgia (PHN) and the like.
Disclosure of Invention
The inventor discovers a 1,2,3, 4-tetrahydroisoquinoline derivative with a structure shown in a formula (I) and a preparation method and application thereof in the research process. The series of compounds have activity in treating, preventing or relieving neuropathy or neuropathic pain, can be applied to development of primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve injury or biochemical nerve injury, Painful Diabetic Neuropathy (PDN) or related neuropathic disease medicines, and have wide application prospect.
The invention provides 1,2,3, 4-tetrahydroisoquinoline derivatives with the structure shown in the formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof,
wherein:
R1、R2、R3each independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11，
Or, R1And R2、R1And R3、R2And R3Together with the directly attached carbon atom form C3-8Cycloalkyl or 3-8 membered heterocyclyl, said heteroatom selected from O, S, N,
optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo-substituted C1-8Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
R4selected from hydrogen, deuterium, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-to 10-membered heteroaryl, alkali metal, alkaline earth metal or ammonium, optionally further substituted by one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo-substituted C1-8Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
R5、R6、R9、R10each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Optionally further substituted with one or more substituents selected from halogen, hydroxy,Mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
R7、R8each independently selected from hydrogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl or 5-to 10-membered heteroaryl, optionally further substituted by one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Optionally further substituted with one or more substituents selected from halogen, hydroxy, mercapto, cyano, nitro, acetamido, azido, sulfonyl, methanesulfonyl, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C1-8Alkoxy radical, C1-8Alkoxycarbonyl, C1-8Alkylcarbonyl group, C1-8Alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, C1-8Alkyl monosubstituted amino or C1-8Substituted by a substituent of alkyl disubstituted amino;
R12selected from hydrogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C1-8Alkoxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, C1-8Alkyl acyl radical, C1-8Alkylamino or C1-8Alkylamido, optionally further substituted with one or more substituents selected from halogen, hydroxy, mercapto, cyano, nitro, acetamido, azido, sulfonyl, methylsulfonyl, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C1-8Alkoxy radical, C1-8Alkoxycarbonyl, C1-8Alkylcarbonyl group, C1-8Alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, amino, C1-8Alkyl monosubstituted amino or C1-8Substituted by a substituent of alkyl disubstituted amino;
R11、R13、R14selected from hydrogen, deuterium, C1-8Alkyl radical, C3-8Cycloalkyl, halo-substituted C1-8Alkyl, hydroxy substituted C1-8Alkyl, phenyl or p-methylphenyl;
r is 0, 1, 2.
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives of the structure of formula (I), its stereoisomers or its pharmaceutically acceptable salts thereof, wherein the stereoisomers refer to the 1-, 3-, 4-or 2' -position containing the stereoconfiguration, which can be respectively R-configuration or S-configuration, and the structural correspondence is represented by
Or
The "3R-" or "3S-" stereoisomer is preferred.
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, R5、R6、R9、R10Each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, azido, C1-4Alkyl, halo-substituted C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C5-8Aryl radical, C5-8Aryloxy radical, C5-8Arylthio, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11(ii) a Optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclic groupOxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
R1、R2、R3、R4、R7、R8、R11、R12、R13、R14and r is as defined for the compound of formula (I).
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, R5、R6、R9、R10Each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, mercapto, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino, or dimethylaminocarbonyl;
R4selected from hydrogen, deuterium, C1-8Alkyl, halo-substituted C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, alkali metal, alkaline earth metal or ammonium;
R1、R2、R3、R7、R8、R11、R12、R13、R14r is asThe compounds of formula (I) are defined.
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, R5、R6、R9、R10Each independently selected from hydrogen, deuterium, fluorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino or dimethylamino;
R4selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, phenyl, alkali metal, alkaline earth metal or ammonium;
R1、R2、R3、R7、R8、R11、R12、R13、R14and r is as defined for the compound of formula (I).
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivative of the structure of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the compounds of formula (II) below:
wherein R is4Selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, phenyl, alkali metal, alkaline earth metal or ammonium;
R15selected from hydrogen, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C1-8Alkyl radical, C2-8Alkenyl, halogen-substituted C1-8Alkyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11；
m is selected from 0, 1,2,3,4 or 5;
R2、R3、R7、R8、R11、R12、R13、R14and r is as defined for the compound of formula (I).
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (II), stereoisomers thereof or pharmaceutically acceptable salts thereof, R2And R3Together with the directly attached carbon atom form C3-8Cycloalkyl, optionally further substituted by one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo-substituted C1-8Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
R4selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, sodium, potassium, calcium or ammonium;
R15selected from hydrogen, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridineA group selected from the group consisting of phenyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino, and dimethylaminocarbonyl;
R7、R8、R11、R12、R13、R14r is as defined for compounds of formula (I); m is as defined above.
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (II), stereoisomers thereof or pharmaceutically acceptable salts thereof, R2And R3Together with the directly attached carbon atom form C3-8Cycloalkyl optionally further substituted with one or more substituents selected from fluoro, chloro, hydroxy, mercapto, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino, or dimethylaminocarbonyl;
R4selected from hydrogen, sodium, potassium, calcium or ammonium;
R15selected from hydrogen, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino or dimethylaminocarbonyl;
R7、R8、R11、R12、R13、R14r is as defined for compounds of formula (I);m is as defined above.
As a most preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivative of the structure of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds:
as a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (II), stereoisomers thereof or pharmaceutically acceptable salts thereof, R2、R3Each independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11，
Optionally further substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo-substituted C1-8Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
R4selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, sodium, potassium, calcium or ammonium;
R15selected from hydrogen, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino or dimethylaminocarbonyl;
R7、R8、R11、R12、R13、R14r is as defined for compounds of formula (I); m is as defined above.
As a further preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (II), stereoisomers thereof or pharmaceutically acceptable salts thereof, R2、R3Each independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido and C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, halo-substituted C1-8Alkyl radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11；
R4Selected from hydrogen, sodium, potassium, calcium or ammonium;
R15selected from hydrogen, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, ethynyl, cyclopropyl, pyridyl, tetrahydrofuranyl, morpholinyl, phenyl, methoxy, ethoxy, isopropoxy, benzyloxy, sulfonyl, methanesulfonyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetyl, acetoxy, amino, dimethylamino, acetylamino or dimethylaminocarbonyl;
R7、R8、R11、R12、R13、R14r is as defined for compounds of formula (I); m is as defined above.
As a most preferred embodiment, the 1,2,3, 4-tetrahydroisoquinoline derivative of the structure of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds:
in another aspect, the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
x is selected from hydroxy or halogen, preferably hydroxy or chloro;
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14and r is as defined for the compound of formula (I).
As a further preferred embodiment, the acid-binding agent is an organic base or an inorganic base, the organic base is selected from trimethylamine, triethylamine, pyridine, piperidine, morpholine or a mixture thereof, and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium acetate or a mixture thereof; the condensing agent is selected from DIC, DCC, HOBT, EDC & HCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI or their mixture.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides the use of a compound of formula (I) as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment, prevention, or amelioration of a neuropathy or neuropathic pain in a subject.
As a further preferred embodiment, the neuropathy is primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical nerve injury or biochemical nerve injury, Painful Diabetic Neuropathy (PDN), or related neurological disease.
Detailed Description
Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
“C1-8Alkyl "refers to straight and branched alkyl groups comprising 1 to 8 carbon atoms, alkyl refers to a saturated aliphatic hydrocarbon group, C0-8Means containing no carbon atoms or C1-8Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptylpentyl2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof and the like.
Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, "C3-8Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms," 5-10 membered cycloalkyl "refers to cycloalkyl groups comprising 5 to 10 carbon atoms, for example:
non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups that share a single carbon atom (called a spiro atom) between single rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spirocycloalkyl groups, non-limiting examples of which include:
"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, non-limiting examples of fused ring alkyl groups including:
"bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following, independently selectedFrom halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11
"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)r(wherein r is an integer 0, 1, 2) but does not include the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-8 membered heterocyclyl" refers to a cyclic group containing 3 to 8 ring atoms.
Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Spirocycloalkyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group, or a multiple spiroheterocyclyl group according to the number of spiro atoms shared between rings. Non-limiting examples of spirocycloalkyl groups include:
"fused heterocyclyl" refers to polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O)r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, non-limiting examples of fused heterocyclic groups include:
"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O)r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, non-limiting examples of which include:
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and a "C" group5-10Aryl "means an all-carbon aryl group having 5 to 10 carbons, and" 5-to 10-membered aryl "means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen, and S (O)r(wherein r is an integer of 0, 1, 2), 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"alkenyl" means a group consisting of at leastAlkyl consisting of two carbon atoms and at least one carbon-carbon double bond, C2-8Alkenyl means a straight or branched chain alkenyl group containing 2 to 8 carbons. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.
The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, C2-8Alkynyl refers to straight or branched chain alkynyl groups containing 2-8 carbons. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like.
Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. C1-8Alkoxy means an alkyloxy group having 1 to 8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C5-10Aryl radical, C5-10Aryloxy, -C0-8-S(O)rR11、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-N(R13)-C(O)R12or-N (R)13)-C(O)OR11Substituted with the substituent(s);
"halogen-substituted C1-8Alkyl "refers to a 1-8 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl, such as difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
"halogen-substituted C1-8Alkoxy "a 1-8 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
The term "condensing agent" refers to an agent capable of causing a condensation reaction. Condensation is the reaction of two or more organic molecules interacting and covalently bonded to form a macromolecule, while losing water or other relatively simple small inorganic or organic molecules. The small molecule substance is usually water, hydrogen chloride, methanol or acetic acid. The corresponding Chinese names of the various condensing agents are shown in Table 1.
TABLE 1 corresponding Chinese names for short for various condensing agents
| For short | Name of Chinese |
| DIC | N, N-diisopropylcarbodiimide |
| DCC | N, N-dicyclohexylcarbodiimide |
| HOBT | 1-hydroxybenzotriazoles |
| EDC·HCl | 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride |
| PyBOP | Benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphates |
| PyBroP | Tripyrrolidinobosphonium hexafluorophosphates |
| HATU | 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate |
| HCTU | 6-chlorobenzotriazole-1, 1, 3, 3-tetramethylurea hexafluorophosphate |
| DEPBT | 3- (diethoxyphosphoryloxy) -1, 2, 3-benzotriazin-4-one |
| EEDQ | 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline |
| CDI | Carbonyl diimidazoles |
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefinic).
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (L C-MS). NMR chemical shifts () are given in parts per million (ppm). NMR is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer using deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
Determination of LC-MS L C-MS by Agilent 1200 Infinity Series Mass spectrometer HP L C was determined using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 ×.6mm column) and Waters 2695-.
The thin-layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, T L C adopts the specification of 0.15 mm-0.20 mm, the thin-layer chromatography separation and purification product adopts the specification of 0.4 mm-0.5 mm, and the column chromatography generally adopts the tobacco yellow sea silica gel 200-300 meshes as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, and the solvent is a dry solvent, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon of about 1L volume and a hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1L volume.
The solutions in the examples are aqueous solutions unless otherwise specified. The reaction temperature was room temperature. The room temperature is the most suitable reaction temperature and is 20-30 ℃.
The monitoring of the reaction progress in the examples uses thin layer chromatography (T L C) or liquid chromatography-mass spectrometry (L C-MS) as the developing solvent system, such as dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, acetone, the volume ratio of the solvent can be adjusted according to the polarity of the compound.
Preparation of intermediates
1. Intermediate 1: preparation of ethyl 3- (2- (benzyloxy) -3-methoxyphenyl) -2- ((diphenylmethylene) amino) propionate
To an acetonitrile solution (60m L) of 2- (benzyloxy) -1- (chloromethyl) -3-methoxybenzene (6.8g, 25.88mmol) at room temperature were added potassium iodide (5.59g, 33.65mmol), cesium carbonate (16.87g, 51.76mmol), ethyl 2- ((diphenylmethylene) amino) acetate (6.92g, 25.88mmol), followed by stirring overnight in an oil bath at 50 ℃ under nitrogen protection, after cooling, the organic solvent was removed by rotary evaporation under reduced pressure, ethyl acetate and an aqueous layer were added, the ethyl acetate phase was washed with saturated brine again, dried over sodium sulfate, and column chromatography was concentrated (eluent: petroleum ether/ethyl acetate ═ 10: 1) to give ethyl 3- (2- (benzyloxy) -3-methoxyphenyl) -2- ((diphenylmethylene) amino) propionate (8.9g, 70%).
MS m/z(ESI)：494.6[M+H]+.
2. Intermediate 2: preparation of ethyl 2-amino-3- (2- (benzyloxy) -3-methoxyphenyl) propionate
To a solution of ethyl 3- (2- (benzyloxy) -3-methoxyphenyl) -2- ((diphenylmethylene) amino) propionate (8.9g, 18.03mmol) in tetrahydrofuran (60M L) at room temperature was added HCl (3M, 30M L), stirring was continued for 2 hours at that temperature, then the organic solvent was removed under reduced pressure, about 100M L water was added, extraction was performed with ethyl acetate, the ethyl acetate phase was washed with saturated brine several times, dried over anhydrous sodium sulfate, and concentrated to give ethyl 2-amino-3- (2- (benzyloxy) -3-methoxyphenyl) propionate (5.2g, 88%).
MS m/z(ESI)：330.5[M+H]+。
3. Intermediate 3: preparation of ethyl 5- (benzyloxy) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid ester
To a solution of ethyl 2-amino-3- (2- (benzyloxy) -3-methoxyphenyl) propionate (5g, 15.18mmol) and paraformaldehyde (2.28g, 75.90mmol) in dichloromethane (50m L) was added trifluoroacetic acid (25m L), followed by stirring overnight at room temperature, removal of the organic solvent under reduced pressure, addition of about 100m L water, extraction with ethyl acetate, washing of the ethyl acetate phase with saturated brine multiple times, washing of the organic phase with saturated aqueous sodium bicarbonate solution and saturated brine in this order, drying over anhydrous sodium sulfate, concentration, and column chromatography (eluent: petroleum ether/ethyl acetate ═ 3: 1) to give ethyl 5- (benzyloxy) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid ester (3.2g, 62%).
MS m/z(ESI)：342.4[M+H]+。
Preparation of the Compounds of examples
Example 1: preparation of 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclohexane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
The first step is as follows: preparation of 1-phenylcyclohexane-1-carbonyl chloride
Oxalyl chloride (248mg, 1.96mmol), DMF (0.2m L) was added to a solution of 1-phenylcyclohexane-1-carboxylic acid (200mg, 0.98mmol) in dichloromethane (5m L) at room temperature, the reaction was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure to give crude 1-phenylcyclohexane-1-carbonyl chloride (230mg) which was used directly in the next reaction.
The second step is that: preparation of ethyl 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclohexane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid ester
To a solution of 1-phenylcyclohexane-1-carbonyl chloride (100mg, 0.45mmol) in dichloromethane (5m L) was added ethyl 5- (benzyloxy) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylate (183mg, 0.538mmol), triethylamine (137mg, 1.35mmol) at room temperature, and the reaction was stirred at room temperature for two hours, about 10m L water was added, and the organic phase was extracted with dichloromethane, followed by saturated aqueous sodium bicarbonate solution, saturated aqueous salt, dried over anhydrous sodium sulfate, concentrated, and column-chromatographed (eluent: petroleum ether/ethyl acetate 1: 1) to give the title compound ethyl 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclohexane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylate (95mg, 40%).
MS m/z(ESI)：528.6[M+H]+。
The third step: preparation of 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclohexane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
In a tetrahydrofuran solution of ethyl 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclohexane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid ester (70mg, 0.133mmol)Methanol (2M L) and water (3M L) were added to a solution of pyran (6M L), followed by addition of lithium hydroxide (55.2mg, 1.33mmol), reaction at room temperature for 2 hours, removal of the organic solvent under reduced pressure, addition of about 100M L water, washing of the aqueous phase with a small amount of ethyl acetate, collection of the aqueous phase, adjustment of the pH to 2 with dilute hydrochloric acid, extraction of the aqueous phase with ethyl acetate, collection of the ethyl acetate phase, washing with saturated brine, drying of the organic phase with anhydrous sodium sulfate, and concentration to give the title compound 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclohexane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid (51mg, 77%). MSm/z (ESI) 500.2[ M + H ], (ESI)]+；
1H NMR(400MHz，CDCl3)7.41-7.17(m，11H)，6.63-6.43(m，1H)，5.94(d，J＝6.3Hz，1H)，4.94(dd，J＝33.7，10.4Hz，2H)，4.63(s，1H)，4.18(d，J＝14.7Hz，1H)，3.80(s，3H)，3.23-2.76(m，2H)，2.44-2.21(m，2H)，1.83-1.56(m，8H)。
Example 2: preparation of 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclopropane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
Preparation of 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclopropane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid reference was made to example 1. MS m/z (ESI): 458.2[ M + H]+；
1H NMR(400MHz，CDCl3)7.41-7.28(m，6H)，7.23-7.13(m，4H)，6.88-6.69(m，1H)，6.68-6.44(m，1H)，5.11-4.82(m，3H)，4.66-4.13(m，2H)，3.84(s，3H)，3.40-2.75(m，2H)，1.54-1.19(m，4H)。
Example 3: preparation of 5- (benzyloxy) -6-methoxy-2- (1-phenylcyclopentane-1-carbonyl) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
5- (benzyloxy) -6-methoxy-2- (1-phenylcyclopentane-1-carbonyl) -1,2,3, 4-four hydrogen isoquinoline-3-carboxylic acid preparation method refers to example 1. MS m/z (ESI): 486.3[ M + H]+；
1H NMR(400MHz，CDCl3)7.42-7.32(m，6H)，7.23-7.18(m，4H)，6.60(t，J＝14.1Hz，1H)，6.08(d，J＝8.2Hz，1H)，4.95(dt，J＝22.6，11.3Hz，2H)，4.64(m，2H)，4.17(d，J＝15.0Hz，1H)，3.82(s，3H)，2.99(m，2H)，2.51-2.33(m，2H)，2.17-1.96(m，2H)，1.79-1.70(m，4H)。
Example 4: preparation of 5- (benzyloxy) -2- (2, 2-diphenylpropionyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
Preparation of 5- (benzyloxy) -2- (2, 2-diphenylpropionyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid was carried out in accordance with example 1. MS m/z (ESI): 522.3[ M + H]+；
1H NMR(400MHz，CDCl3)7.53-7.43(m，2H)，7.43-7.26(m，12H)，7.24-7.12(m，1H)，6.55(d，J＝8.4Hz，1H)，6.01(d，J＝8.3Hz，1H)，4.98(dd，J＝25.7，11.2Hz，1H)，4.89(d，J＝11.0Hz，1H)，4.78-4.65(m，1H)，4.04-3.89(m，1H)，3.81(s，3H)，3.75(d，J＝15.0Hz，1H)，3.08(dt，J＝23.0，11.5Hz，1H)，2.98-2.82(m，1H)，1.97-1.86(m，3H)。
Example 5: preparation of 2- (2, 2-diphenylpropionyl) -6-methoxy-5- ((4-methoxy-3-methylbenzyl) oxo) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
Preparation of 2- (2, 2-diphenylpropionyl) -6-methoxy-5- ((4-methoxy-3-methylbenzyl) oxo) -1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid was carried out by referring to example 1. MS m/z (ESI): 566.2[ M + H]+；
1HNMR(400MHz，CD3OD)：7.36-7.17(m，12H)，6.96-6.85(m，3H)，4.13-4.10(m，3H)，3.98-3.95(m，1H)，3.77(s，3H)，3.70(s，3H)，3.66-3.59(m，1H)，2.80(m，2H)，2.12(s，3H)，2.02(s，3H)。
Example 6: preparation of 5- ((2, 3-dihydrobenzofuran-5-yl) methoxy) -2- (2, 2-diphenylpropionyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid
Preparation of 5- ((2, 3-dihydrobenzofuran-5-yl) methoxy) -2- (2, 2-diphenylpropionyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid was carried out by referring to example 1. MS m/z (ESI): 564.2[ M + H]+；
1H NMR(400MHz，MeOD)：7.46-7.29(m，11H)，7.19(d，J＝8.4Hz，1H)，7.06-7.00(m，2H)，6.77(d，J＝8.0Hz，1H)，4.58(t，J＝8.4Hz，2H)，4.22(m，3H)，4.05(m，1H)，3.79(s，3H)，3.70(m，1H)，3.23(t，J＝8.8Hz，2H)，2.89(m，2H)，2.11(s，3H)。
Biological activity assay
Test reagent and instrument
1. Storage liquid (500m L)
1)50mM Tris 25M L1M Tris (Sigma T2663) was diluted to 500M L in distilled water for use;
2)100mM NaCl 10M L of 5M NaCl (from Sigma) in distilled water was diluted to 500M L for use;
3)5mM MgCl22.5M L of 1M (from Fluka) distilled water was diluted to 500M L for use.
2. Working solution (50m L)
1) The stock solution 50m L above was taken and 0.1% BSA and 1 tablet of EDTA-free protease inhibitor (ex Roche) were added.
2)384 well Opti-Plate assay plates were purchased from Perkin Elmer, Inc. (Perkin Elmer, PE).
3) Iodine-labeled ligand: sar1-Ile8-AngII, [ solution ]125I]From PE (50uCi) dissolved in 1m L sterile water to 50uCi/mL stock solution, 2200Ci/mmol, working solution concentration of 0.1nM, and freezing at-20 deg.C for use.
3. Testing instrument
1) SPA scintillation beads, purchased from Perkin Elmer, Inc. (Perkin Elmer, PE), were dissolved in 20m L working solution to 25mg/m L stock solution, with a final working solution concentration of 250ug beads/well/25u L.
2)384 well Opti-Plate (from PE).
3) Automatic liquid separator: multidrop (thermo Fisher).
4) Detection analyzer, View L ux 1430 ultra HTS Microplate Imager (Perkin Elmer), II, test step
The present invention employs a proximity scintillation assay (SPA) technique to detect compound versus AT2Inhibiting activity of, iodine-labeled AT2Ligand: sar1-Ile8-AngII, [ solution ]125I]SPA beads and 384-well assay plates were purchased from PE (50uCi)) assay analyzer View L ux 1430 ultra HTS Microplate Imager (Perkin Elmer) the assay procedure was as follows:
1. the compounds, including positive control compounds, were plated in 384-well plates (Optiplates)
2. Mixing the working solution and the microbeads into a centrifuge tube, incubating and mixing for 1 hour at room temperature in a dark place, and uniformly mixing by a shaking table;
3. add the pre-mixed microbeads from step 2 to the lab plate (25u L/well) with an automatic dispenser Multidrop;
4. rapidly sealing the test plate with a cover film, and mixing and incubating for 1 hour at room temperature in a dark place (shaking table mixing);
5. 25u L developer (tracer) was added to each well with an automatic dispenser (Multidrop);
6. rapidly sealing the experimental plate with a cover film, mixing and incubating overnight at room temperature in a dark place, and uniformly mixing by a shaking table;
7. centrifuging the experimental plate in the next morning to precipitate the microbeads to the bottom of the plate;
8. placing the experimental plate into View L ux, detecting, reading and analyzing, and calculating IC50。
Thirdly, test results:
compounds of the examples of the inventionAnd the biochemical activity of a positive control compound (EMA-400, prepared according to example 20 of US 5246943) were determined by the above assay, and the IC was determined50The values are given in the following table.
Other exemplary Compounds of the invention, hAT2IC50The values are similar to the effects of the above examples, showing similar inhibitory activity and regularity.
And (4) conclusion: compounds of the examples of the invention part of the compound pairs hAT relative to the positive control compound2Shows strong inhibitory activity and improves the inhibitory effect by more than one time.
For hAT1Exhibits an inhibitory activity of greater than 5000nM as well as the positive control compound.
In summary, the compounds of the examples of the invention are useful for hAT2And hAT1Has higher selectivity correspondingly and is more suitable for hAT2Pharmaceutical or clinical use for diseases.
Claims (6)
1. 1,2,3, 4-tetrahydroisoquinoline derivatives having the structure of formula (II) below, stereoisomers thereof or pharmaceutically acceptable salts thereof, having the structure:
wherein R is2And R3Together with the directly attached carbon atom form C5-6A cycloalkyl group;
R4selected from hydrogen, deuterium;
R7、R8each independently selected from hydrogen, C1-8Alkyl, optionally further substituted by one or more groups selected from C5-10Aryl or 5-10 membered heteroaryl;
R15selected from hydrogen
m is selected from 0 or 1.
2. The 1,2,3, 4-tetrahydroisoquinoline derivative, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1,
R4selected from hydrogen;
m is selected from 0.
3. The 1,2,3, 4-tetrahydroisoquinoline derivative, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, which is selected from the following compounds:
4. a pharmaceutical composition comprising a therapeutically effective amount of a 1,2,3, 4-tetrahydroisoquinoline derivative according to any one of claims 1-3, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. Use of a 1,2,3, 4-tetrahydroisoquinoline derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, for the manufacture of a medicament for the treatment, prevention, or amelioration of a neuropathy or neuropathic pain in a subject.
6. The use according to claim 5, wherein the neuropathy is primary neuropathy, secondary neuropathy, peripheral neuropathy, neuropathy caused by mechanical or biochemical nerve injury, Painful Diabetic Neuropathy (PDN), or related neurological disorder.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510541474.1A CN106478502B (en) | 2015-08-29 | 2015-08-29 | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof |
| CN2015105414741 | 2015-08-29 | ||
| PCT/CN2016/096167 WO2017036318A1 (en) | 2015-08-29 | 2016-08-22 | 1,2,3,4-tetrahydroisoquinoline derivative, preparation method therefor and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107922340A CN107922340A (en) | 2018-04-17 |
| CN107922340B true CN107922340B (en) | 2020-07-10 |
Family
ID=58186642
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510541474.1A Active CN106478502B (en) | 2015-08-29 | 2015-08-29 | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof |
| CN201680050320.5A Active CN107922340B (en) | 2015-08-29 | 2016-08-22 | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510541474.1A Active CN106478502B (en) | 2015-08-29 | 2015-08-29 | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN106478502B (en) |
| TW (1) | TW201713623A (en) |
| WO (1) | WO2017036318A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778194B (en) * | 2016-08-24 | 2022-04-05 | 浙江九洲药业股份有限公司 | Preparation and resolution method of phenylalanine ester compound |
| ES2878313T3 (en) * | 2017-06-09 | 2021-11-18 | Shandong Danhong Pharmaceutical Co Ltd | Carboxylic acid derivative as an AT2R receptor antagonist |
| TWI647229B (en) * | 2017-11-14 | 2019-01-11 | 國立暨南國際大學 | Method for synthesizing 3,4-hydroisoquinoline thiazolidine |
| CN111620816B (en) * | 2020-05-27 | 2023-06-02 | 上海赛默罗生物科技有限公司 | Propeller derivatives, preparation method, pharmaceutical composition and application thereof |
| CN113880825A (en) * | 2020-07-01 | 2022-01-04 | 浙江海正药业股份有限公司 | Salt of tetrahydroisoquinoline derivative, preparation method and medical application thereof |
| CN111777555B (en) * | 2020-09-04 | 2020-12-01 | 上海赛默罗生物科技有限公司 | Aliphatic cycloalkane derivative, preparation method thereof, pharmaceutical composition and application thereof |
| CN115925699B (en) * | 2022-02-25 | 2023-10-03 | 南京知和医药科技有限公司 | Fused ring compound with analgesic activity and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5246943A (en) * | 1992-05-19 | 1993-09-21 | Warner-Lambert Company | Substituted 1,2,3,4-tetahydroisoquinolines with angiotensin II receptor antagonist properties |
| CN101087619A (en) * | 2004-12-24 | 2007-12-12 | 昆士兰大学 | Method of treatment or prophylaxis |
| CN102821765A (en) * | 2010-01-19 | 2012-12-12 | 西芬克斯医药有限公司 | Methods and compositions for improved nerve conduction velocity |
| CN103003244A (en) * | 2010-07-21 | 2013-03-27 | 西芬克斯医药有限公司 | Salt and solvates of a tetrahydroisoquinoline derivative |
| WO2015003223A1 (en) * | 2013-07-08 | 2015-01-15 | Spinifex Pharmaceuticals Pty Ltd | Heterocyclic compounds and methods of their use |
-
2015
- 2015-08-29 CN CN201510541474.1A patent/CN106478502B/en active Active
-
2016
- 2016-08-22 CN CN201680050320.5A patent/CN107922340B/en active Active
- 2016-08-22 WO PCT/CN2016/096167 patent/WO2017036318A1/en active Application Filing
- 2016-08-29 TW TW105127662A patent/TW201713623A/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5246943A (en) * | 1992-05-19 | 1993-09-21 | Warner-Lambert Company | Substituted 1,2,3,4-tetahydroisoquinolines with angiotensin II receptor antagonist properties |
| CN101087619A (en) * | 2004-12-24 | 2007-12-12 | 昆士兰大学 | Method of treatment or prophylaxis |
| CN102821765A (en) * | 2010-01-19 | 2012-12-12 | 西芬克斯医药有限公司 | Methods and compositions for improved nerve conduction velocity |
| CN103003244A (en) * | 2010-07-21 | 2013-03-27 | 西芬克斯医药有限公司 | Salt and solvates of a tetrahydroisoquinoline derivative |
| WO2015003223A1 (en) * | 2013-07-08 | 2015-01-15 | Spinifex Pharmaceuticals Pty Ltd | Heterocyclic compounds and methods of their use |
Non-Patent Citations (1)
| Title |
|---|
| "Synthesis of enantiopure angiotensin II type 2 receptor [AT2R] antagonist EMA401";WAKCHAURE, Prasad B.等;《Tetrahedron》;20150710;第71卷(第38期);第6881-6887页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201713623A (en) | 2017-04-16 |
| CN106478502B (en) | 2021-04-27 |
| CN107922340A (en) | 2018-04-17 |
| WO2017036318A1 (en) | 2017-03-09 |
| CN106478502A (en) | 2017-03-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107922340B (en) | 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof | |
| KR101991327B1 (en) | Opioid Receptor Ligands and Methods of Using and Making Same | |
| CN115175679A (en) | Methods of treating estrogen receptor-related disorders | |
| JP7120549B2 (en) | Activator of TREK (TWIK-associated K channel) channels | |
| ES2932441T3 (en) | Crystal forms and processes for the preparation of condensed azacyclos (cannabinoid receptor modulators) | |
| TW201726637A (en) | Hydroxyalkylamine- and hydroxycycloalkylamine-substituted diamine-arylsulfonamide compounds with selective activity in voltage-gated sodium channels | |
| BRPI0805826B1 (en) | spiro-substituted compounds, pharmaceutical composition and use | |
| KR20180094938A (en) | Combination of opioid receptor ligand and cytochrome P450 inhibitor | |
| CN108495618B (en) | New compound and application thereof | |
| CN113912663B (en) | Betulinic acid derivative, preparation method, pharmaceutical composition and application thereof | |
| ES2931537T3 (en) | Substituted pyrrolopyridines as activin receptor-like kinase inhibitors | |
| WO2020169042A1 (en) | 6-oxo-1,6-dihydropyridazine prodrug derivative, preparation method therefor, and application thereof in medicine | |
| US8492564B2 (en) | Salvinorin derivatives and uses thereof | |
| EP4103692A1 (en) | Novel tdzd analogs as agents that delay, prevent, or reverse age-associated diseases; and as anti-cancer and antileukemic agents | |
| CN107207476A (en) | Indoles and 7-azaindole derivatives and its for the purposes in neurodegenerative disorders | |
| US20170166531A1 (en) | 2-alkoxy-11-hydroxyaporphine derivatives and uses thereof | |
| ES2465005T3 (en) | Derived from benzothiophene oxide and its salts | |
| JP2023513922A (en) | Methods and Crystal Forms for the Preparation of 3-Aryloxy-3-5-Membered Heteroaryl-Propylamine Compounds | |
| CN107304199B (en) | New himbacine analogue and application thereof in medicine | |
| CN107304188A (en) | A kind of deuterated Kinase Selectivity inhibitor and its application | |
| CN107304200B (en) | New himbacine analogue and application thereof in medicine | |
| BR112021004094A2 (en) | crystalline forms of a phosphoinositide 3-kinase (pi3k) inhibitor | |
| JP2019089822A (en) | New crystal form of topiroxostat, and preparation method therefor | |
| WO2013147215A1 (en) | 4-alkanoylamino-3-pyrazolone derivative | |
| CN107235960A (en) | Amide derivatives, its preparation method and its in purposes pharmaceutically |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |