CN107922340A - 1,2,3,4 tetrahydro isoquinoline derivatives, its preparation method and application - Google Patents

1,2,3,4 tetrahydro isoquinoline derivatives, its preparation method and application Download PDF

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CN107922340A
CN107922340A CN201680050320.5A CN201680050320A CN107922340A CN 107922340 A CN107922340 A CN 107922340A CN 201680050320 A CN201680050320 A CN 201680050320A CN 107922340 A CN107922340 A CN 107922340A
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heterocyclic ring
heteroaryl
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circle heterocyclic
alkyl
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CN107922340B (en
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孙广俊
马建斌
谭松良
高鹏
李成海
包如迪
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Lianyungang Hongchuang Pharmaceutical Co ltd
Shanghai Hansoh Biomedical Co Ltd
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Shanghai Hansoh Biomedical Co Ltd
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    • 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

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Abstract

Provide a kind of 1,2,3,4 tetrahydro isoquinoline derivatives, its preparation method and application with formula (I) structure.Formula (I) compound can be used for the exploitation of primary neuropathy, secondary neuropathy, peripheral nerve disease, neuropathy, painful diabetic neuropathy (PDN) or related neurological disease medicament as caused by mechanical nerve injury or biochemical nerve damage, have broad application prospects.

Description

1,2,3,4- tetrahydro isoquinoline derivative, preparation method and application Technical field
The invention belongs to course of drug development, and in particular to 1,2,3,4- tetrahydro isoquinoline derivative, preparation method and application.
Background technique
Neuropathic pain is that a kind of chronic pain disorders as caused by nervous system primary lesion or dysfunction, a variety of different damages, such as wound, neurotrosis or infection disease can all cause neuropathic pain.The most common neuropathic pain type includes diabetic neuralgia (DNP), post-herpetic neuralgia (PHN and the relevant neuropathic pain of AIDS.With secondary (injury pain) on the contrary, neuropathic pain may occur after a couple of days or even several months after wound generation, usually from chronic ache, it is characterized in that hyperalgia, sense organ is sensitive to stimulation oversaturation, allodynia and spontaneous burning pain.The therapeutic agent of neuropathic pain mainly includes anticonvulsive drug, antidepressants, narcotic analgeiscs and local anesthetic at present.The anticonvulsant drug Lyrica (Pregabalin) of standard care drug such as Pfizer.These drugs can effectively treat nociceptive pain, but very limited to the treatment of neuropathic pain, and be accompanied by serious side effect, including cognitive change, sedation, nauseous and generation drug resistance and dependence.Accordingly, it is desirable to provide one kind can effectively treat and prevent neuropathic pain and the lesser drug of side effect.The pathomechanism of nerve pain is also not very clear, is studied and is thought that the sensitization reciprocation of nociceptor and cornu dorsale medullae spinalis may be exactly the basis that neuropathic pain generates.
Renin-angiotensin system (RAS) is not only present in circulation, and is present in many histoorgans such as angiocarpy, kidney, in brain, and play a role by autocrine and paracrine.RAS generates biological effect by Angiotensin II (AngII) in conjunction with angiotensin receptor.Explicitly mainly there is blood angiotonin II receptor I receptor (AT1) at present, blood angiotonin II receptor I I receptor (AT2).AT1 is distributed widely in almost all of histoorgan.AT2 is distributed mainly on embryonic tissue, immature brain, the less distribution of normal tissue of growing up, but after tissue damage, expression is increased.Neuropathic pain animal model and patient the study found that its internal AngII, AngII receptor AT2 expression increase, moreover, AT2 it is frequent with pain signal molecule (such as substance P, TRPV1) co-express.The study found that can be to the analgesic activity of anti-morphine ab after the activation of Mice brain tissues angiotensin-ii-receptor；It can cause hyperalgia after the activation of caudal ventrolateral medulla angiotensin-ii-receptor, giving Angiotensin Ⅱ receptor antagonist can reduce this hyperalgia.EMA401, it is researched and developed by Australian biomedical company Spinifex company, it is a kind of 2 antagonist of highly selective angiotensin-ii receptor, it is first disclosed as US5246943, being currently in the clinical II phase tests, it is existing research shows that the drug have preferable analgesic activity, especially to include the neuropathic pain treatments significant effect such as diabetic neuralgia (DNP), post-herpetic neuralgia (PHN).
Summary of the invention
Inventor has found a kind of 1,2,3,4- tetrahydro isoquinoline derivative, preparation method and application with formula (I) structure in the course of the research.The series compound has the activity in terms for the treatment of, preventing or ameliorating neuropathy or neuropathic pain, the exploitation that can be applied to primary neuropathy, secondary neuropathy, peripheral nerve disease, neuropathy, painful diabetic neuropathy (PDN) or related neurological disease medicament caused by mechanical nerve injury or biochemical nerve damage, has broad application prospects.
One aspect of the present invention provides a kind of 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts having such as following formula (I) structure,
Wherein:
R1、R2、R3It is independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11,
Alternatively, R1With R2、R1With R3、R2With R3C is formed together with the carbon atom being connected directly3-8Naphthenic base or 3-8 circle heterocyclic ring base, the hetero atom are selected from O, S, N,
Halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
R4Selected from hydrogen, deuterium, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, alkali metal, alkaline-earth metal or ammonium are optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
R5、R6、R9、R10It is independently selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
R7、R8It is independently selected from hydrogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl or 5-10 unit's heteroaryl are optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced, optionally further by one or more be selected from halogen, hydroxyl, sulfydryl, cyano, nitro, acetamido, azido, sulfonyl, mesyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C1-8Alkoxy carbonyl group, C1-8Alkyl-carbonyl, C1-8Alkyl carbonyl epoxide, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, amino, C1-8Alkyl monosubstituted amino or C1-8Replaced the substituent group of alkyl disubstituted amino；
R12Selected from hydrogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, C1-8Alkyl acyl, C1-8Alkyl amino or C1-8Alkylamidoalkyl is optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, acetamido, azido, sulfonyl, mesyl, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C1-8Alkoxy carbonyl group, C1-8Alkyl-carbonyl, C1-8Alkyl carbonyl epoxide, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, amino, C1-8Alkyl monosubstituted amino or C1-8Replaced the substituent group of alkyl disubstituted amino；
R11、R13、R14Selected from from hydrogen, deuterium, C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl, hydroxyl replace C1-8Alkyl, phenyl or p-methylphenyl；
R is 0,1,2.
As further preferred scheme, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (I) structure, the stereoisomer refer to 1-, 3-, 4- or 2,Position includes spatial configuration, may respectively be R- configuration or S- configuration, and structure correspondence is expressed asOrIt is preferred that " 3R- " or " 3S- " stereoisomer.
As further preferred scheme, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (I) structure, R5、R6、R9、R10It is independently selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-4Alkyl, halogen replace C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl group, C3-6Naphthenic base, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base oxygroup, 3-6 circle heterocyclic ring base sulfenyl, C5-8Aryl, C5-8Aryloxy, C5-8Artyl sulfo, 5-8 unit's heteroaryl, 5-8 unit's heteroaryl oxygroup, 5-8 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11；Halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
R1、R2、R3、R4、R7、R8、R11、R12、R13、R14, r such as formula (I) compound defined.
As further preferred scheme, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (I) structure, R5、R6、R9、R10Be independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, Methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
R4Selected from hydrogen, deuterium, C1-8Alkyl, halogen replace C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, alkali metal, alkaline-earth metal or ammonium；
R1、R2、R3、R7、R8、R11、R12、R13、R14, r such as such as formula (I) compound defines.
As further preferred scheme, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (I) structure, R5、R6、R9、R10It is independently selected from hydrogen, deuterium, fluorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxyl group, ethyoxyl, isopropoxy, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, 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、R14, r such as formula (I) compound defined.
As scheme still more preferably, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (I) structure, selected from such as following formula (II) compound:
Wherein, R4Selected 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, C1-8Alkyl, C2-8Alkenyl, halogen replace C1-8Alkyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11；
M is selected from 0,1,2,3,4 or 5；
R2、R3、R7、R8、R11、R12、R13、R14, r such as formula (I) compound defined.
As scheme still more preferably, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (II) structure, R2With R3C is formed together with the carbon atom being connected directly3-8Naphthenic base is optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring Base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
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, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
R7、R8、R11、R12、R13、R14, r such as formula (I) compound defined；M is as defined above.
As scheme still more preferably, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (II) structure, R2With R3C is formed together with the carbon atom being connected directly3-8Naphthenic base, fluorine is further optionally selected from by one or more, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, replaced the substituent group of acetylamino or dimethyl-aminocarbonyl；
R4Selected from hydrogen, sodium, potassium, calcium or ammonium；
R15Selected from hydrogen, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
R7、R8、R11、R12、R13、R14, r such as formula (I) compound defined；M is as defined above.
As most preferred scheme, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (II) structure are selected from following compound:
As scheme still more preferably, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (II) structure, R2、R3It is independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11,
Halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
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, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
R7、R8、R11、R12、R13、R14, r such as formula (I) compound defined；M is as defined above.
As scheme still more preferably, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (II) structure, R2、R3It is independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-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, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
R7、R8、R11、R12、R13、R14, r such as formula (I) compound defined；M is as defined above.
As most preferred scheme, 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts of formula (II) structure are selected from following compound:
Another aspect of the present invention provides the preparation method of formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, includes the following steps:
X is selected from hydroxyl or halogen, preferably hydroxyl or chlorine；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14, r such as formula (I) compound defined.
As further preferred scheme, the acid binding agent is organic base or inorganic base, the organic base is selected from or mixtures thereof trimethylamine, triethylamine, pyridine, piperidines, morpholine, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, or mixtures thereof sodium acetate；The condensing agent is selected from or mixtures thereof DIC, DCC, HOBT, EDCHCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI.
Another aspect of the present invention provides pharmaceutical composition comprising aforementioned formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts for the treatment of effective dose and pharmaceutical carrier.
Another aspect of the present invention provides aforementioned formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts or foregoing pharmaceutical composition and is preparing the application in neuropathy or neuropathic pain drug for treating, preventing or ameliorating object.
As further preferred scheme, the neuropathy is primary neuropathy, secondary neuropathy, peripheral nerve disease, neuropathy, painful diabetic neuropathy (PDN) or related neurological disease caused by mechanical nerve injury or biochemical nerve damage.
Specific embodiment
It is described in detail: unless stated to the contrary, following that there are following meanings with term in the specification and in the claims.
“C1-8Alkyl " refers to that straight chained alkyl and containg branched alkyl radical including 1 to 8 carbon atom, alkyl refer to the aliphatic hydrocarbon group of saturation, C0-8Refer to not carbon atoms or C1-8Alkyl, for example, it is methyl, ethyl, n-propyl, different Propyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1, 1- dimethyl propyl, 1, 2- dimethyl propyl, 2, 2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1, 1, 2- thmethylpropyl, 1, 1- dimethylbutyl, 1, 2- dimethylbutyl, 2, 2- dimethylbutyl, 1, 3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2, 3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2, 3- dimethyl amyl group, 2, 4- dimethyl amyl group, 2, 2- dimethyl amyl group, 3, 3- dimethyl amyl group, 2- ethyl Amyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl or its various branched isomer etc..
Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be substituted on any workable tie point, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, " C3-8Naphthenic base " refers to the naphthenic base including 3 to 8 carbon atoms, and " 5-10 member naphthenic base " refers to the naphthenic base including 5 to 10 carbon atoms, such as:
The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..
Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring." spiro cycloalkyl group " refers to the polycyclic moiety that a carbon atom (claiming spiro-atom) is shared between monocycle, these can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl group bases or more spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring, the non-limiting embodiment of spiro cycloalkyl group includes:
" cycloalkyl " refers to the full carbon polycyclic moiety of each ring in system and shared a pair of of the carbon atom adjoined of other rings in system, wherein one or more rings can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl can be divided into according to a group cyclic number, the non-limiting embodiment of cycloalkyl includes:
" bridge ring alkyl " refers to that any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, these can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, the non-limiting embodiment of bridge ring alkyl includes:
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to link together with precursor structure is naphthenic base, non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..
Naphthenic base can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11
" heterocycle " refers to that the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), but do not include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon." 5-10 circle heterocyclic ring base " refers to the ring group comprising 5 to 10 annular atoms, and " 3-8 circle heterocyclic ring base " refers to the ring group comprising 3 to 8 annular atoms.
The non-limiting embodiment of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc..
Multiring heterocyclic includes the heterocycle of loop coil, condensed ring and bridged ring." spiro heterocyclic radical " refers to that the polycyclic heterocyclic group that an atom (claiming spiro-atom) is shared between monocycle, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom are carbon.These can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, double spiro heterocyclic radicals or more spiro heterocyclic radicals according to the number for sharing spiro-atom between ring and ring.The non-limiting embodiment of spiro cycloalkyl group includes:
" condensed hetero ring base " refers to the polycyclic heterocyclic group of each ring in system and shared a pair of of the atom adjoined of other rings in system, one or more rings can contain one or more double bonds, but none ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom are carbon.Bicyclic, tricyclic, Fourth Ring or polycyclic fused heterocycloalkyl can be divided into according to a group cyclic number, the non-limiting embodiment of condensed hetero ring base includes:
" bridge heterocycle " refers to that any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, these can contain one or more double bonds, but none ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom are carbon.Bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to a group cyclic number, the non-limiting embodiment of bridge ring alkyl includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring to link together with precursor structure is heterocycle, non-limiting embodiment includes:
Heterocycle can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
" aryl " refers to full carbon monocycle or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, has polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of the pi-electron system of conjugation, " C5-10Aryl " refers to the full carbon aryl containing 5-10 carbon, and " 5-10 member aryl " refers to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthalene.The aryl rings can be condensed on heteroaryl, heterocycle or cycloalkyl ring, wherein with parent knot The ring that structure links together is aryl rings, and non-limiting embodiment includes:
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
" heteroaryl " refers to comprising 1 to 4 heteroatomic heteroaromatic system, and the hetero atom includes nitrogen, oxygen and S (O)rThe hetero atom of (wherein r is integer 0,1,2), 5-7 unit's heteroaryl refers to the heteroaromatic system containing 5-7 annular atom, 5-10 unit's heteroaryl refers to heteroaromatic system containing 5-10 annular atom, such as furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring, wherein the ring to link together with precursor structure is heteroaryl ring, non-limiting embodiment includes:
Heteroaryl can be optionally substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
" alkenyl " refers to the alkane as defined above being made of at least two carbon atoms and at least one carbon-to-carbon double bond Base, C2-8Alkenyl refers to the straight chain containing 2-8 carbon or containing branched-chain alkenyl.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyl etc..
Alkenyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
" alkynyl " refers to the alkyl as defined above of at least two carbon atoms and at least one carbon-carbon triple bond composition, C2-8Alkynyl group refers to the straight chain containing 2-8 carbon or containing branch alkynyl.Such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- butynyl etc..
Alkynyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
" alkoxy " refers to-O- (alkyl), and wherein alkyl is as defined above.C1-8Alkoxy refers to the alkyl oxy containing 1-8 carbon, and non-limiting embodiment includes methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
Alkoxy can be optionally it is substituted or unsubstituted, when substituted, substituent group, preferably one or more following groups, independently selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, 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 (R13)-C(O)OR11Substituent group replaced；
" the C that halogen replaces1-8Alkyl " refers to the optional 1-8 carbon alkyl group, such as difluoromethyl, dichloromethyl, two bromomethyls, trifluoromethyl, trichloromethyl, trisbromomethyl that are replaced by fluorine, chlorine, bromine, iodine atom etc. of the hydrogen on alkyl.
" the C that halogen replaces1-8The 1-8 carbon alkoxy base replaced by fluorine, chlorine, bromine, iodine atom of hydrogen optionally on alkoxy " alkyl.Such as difluoro-methoxy, dichloro methoxyl group, dibromo methoxyl group, trifluoromethoxy, trichloromethoxy, tribromo methoxyl group etc..
" halogen " refers to fluorine, chlorine, bromine or iodine.
Term " condensing agent " refers to the reagent that can cause condensation reaction.Condensation reaction, which refers to, synthesizes a macromolecular with covalently bonded after the interaction of two or more organic molecules, at the same lose water or other it is fairly simple inorganic or The reaction of small organic molecule.Small-molecule substance therein is usually water, hydrogen chloride, methanol or acetic acid etc..The corresponding Chinese of the abbreviation of various condensing agents is as shown in table 1 in the present invention.
The corresponding Chinese of abbreviation of the various condensing agents of table 1
Referred to as Chinese
DIC N, N- diisopropylcarbodiimide
DCC N, N- dicyclohexylcarbodiimide
HOBT I-hydroxybenzotriazole
EDC·HCl 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride
PyBOP Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl
PyBroP Tripyrrole alkane base phosphonium bromide hexafluorophosphate
HATU 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
HCTU 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester
DEPBT 3- (diethoxy phosphoryl oxy) -1,2,3- phentriazine -4- ketone
EEDQ 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline
CDI Carbonyl dimidazoles
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes the event or environment occurs or not spot occasion.For example, mean " optionally by alkyl-substituted heterocyclic group " alkyl can with but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to that one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom are replaced by the substituent group of respective number independently of one another.Self-evident, substituent group is only in their possible chemistry position, and those skilled in the art can determine in the case where not paying and excessively making great efforts and (pass through experiment or theory) possible or impossible substitution.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated bond (such as olefinic).
" pharmaceutical composition " indicates mixture and other components such as physiology/pharmaceutical carrier and excipient containing one or more compounds described herein or its physiologically/pharmaceutical salt or pro-drug and other chemical constituents.The purpose of pharmaceutical composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
Below with reference to embodiment, the present invention is described in further detail and completely, but the limitation present invention, the present invention are also not intended to be limited to the content of embodiment by no means.
The compound of the present invention structure is by nuclear magnetic resonance (NMR) or/and LC-MS chromatography (LC-MS) come what is determined.Nmr chemical displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).The measurement of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is deuterated methanol (CD3) and deuterated chloroform (CDCl OD3) in be designated as tetramethylsilane (TMS).
The measurement of LC-MS chromatography LC-MS 1200 Infinity Series mass spectrograph of Agilent.HPLC's Measurement uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire 150 × 4.6mm of C18 chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini 150 × 4.6mm of C18 chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, and the specification that TLC is used is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Starting material in the embodiment of the present invention is known and can be commercially available, or can use or synthesize according to methods known in the art.
In the case where no specified otherwise, all reactions of the invention under the stirring of continuous magnetic, carry out under drying nitrogen or argon atmospher, and solvent is dry solvent.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects the argon gas or nitrogen balloon of an about 1L volume.Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
In the case where no specified otherwise, the solution in embodiment refers to aqueous solution.The temperature of reaction is room temperature.Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
The monitoring of reaction process in embodiment, which reacts used solvent system using thin-layered chromatography (TLC) or LC-MS chromatography (LC-MS), to be had: methylene chloride and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, the volume ratio of acetone, solvent can be adjusted according to the polarity difference of compound.The system of the eluant, eluent of column chromatography includes: A: methylene chloride and methanol system, B: n-hexane and ethyl acetate system, C: methylene chloride and ethyl acetate system, D: ethyl acetate and methanol, the volume ratio of solvent is different according to the polarity of compound and is adjusted, and a small amount of ammonium hydroxide and acetic acid etc. can also be added and be adjusted.
The preparation of intermediate
1, intermediate 1: the preparation of ethyl 3- (2- (benzyloxy) -3- anisyl) -2- ((diphenyl methylene) amino) propionic ester
At room temperature; toward 2- (benzyloxy) -1- (chloromethyl) -3- methoxybenzene (6.8g; in acetonitrile solution (60mL) 25.88mmol), it is added potassium iodide (5.59g, 33.65mmol); cesium carbonate (16.87g; 51.76mmol), ethyl 2- ((diphenyl methylene) amino) acetic acid esters (6.92g, 25.88mmol); then under nitrogen protection, it is stirred overnight in 50 DEG C of oil baths.After cooling, vacuum rotary steam removes organic solvent, ethyl acetate and water stratification is added, ethyl acetate phase uses saturated common salt water washing again, it is dry with anhydrous sodium sulfate, evaporating column chromatographs (eluant, eluent: petrol ether/ethyl acetate=10:1), obtains ethyl 3- (2- (benzyloxy) -3- anisyl) -2- ((diphenyl methylene) amino) propionic ester (8.9g, 70%).
MS m/z(ESI):494.6[M+H]+.
2, intermediate 2: the preparation of ethyl 2- amino -3- (2- (benzyloxy) -3- anisyl) propionic ester
At room temperature, toward ethyl 3- (2- (benzyloxy) -3- anisyl) -2- ((diphenyl methylene) amino) propionic ester (8.9g, in tetrahydrofuran solution (60mL) 18.03mmol), HCl (3M is added, 30mL), continue to stir 2 hours at such a temperature, organic solvent is then removed under reduced pressure.About 100mL water is added, is extracted with ethyl acetate.Ethyl acetate phase is multiple with saturated common salt water washing, and anhydrous sodium sulfate is dry, is concentrated to get ethyl 2- amino -3- (2- (benzyloxy) -3- anisyl) propionic ester (5.2g, 88%).
MS m/z(ESI):330.5[M+H]+。
3, intermediate 3: the preparation of ethyl 5- (benzyloxy) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylate
Toward ethyl 2- amino -3- (2- (benzyloxy) -3- anisyl) propionic ester (5g, 15.18mmol), paraformaldehyde (2.28g, trifluoracetic acid (25mL) is added in dichloromethane solution (50mL) 75.90mmol), is then stirred overnight at room temperature.Organic solvent is removed under reduced pressure, about 100mL water is added, is extracted with ethyl acetate.Ethyl acetate phase is multiple with saturated common salt water washing, organic phase successively uses saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate is dry, concentration, column chromatograph (eluant, eluent: petrol ether/ethyl acetate=3:1), obtain ethyl 5- (benzyloxy) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylates (3.2g, 62%).
MS m/z(ESI):342.4[M+H]+。
The preparation of embodiment compound
The preparation of embodiment 1:5- (benzyloxy) -6- methoxyl group -2- (1- cyclohexylbenzene -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
Step 1: the preparation of 1- cyclohexylbenzene -1- carbonyl acyl chlorides
At room temperature, in 1- cyclohexylbenzene -1- carboxylic acid (200mg, oxalyl chloride (248mg is added in methylene chloride (5mL) solution 0.98mmol), 1.96mmol), DMF (0.2mL), reaction are stirred at room temperature 2 hours, and solvent is removed under reduced pressure, crude product 1- cyclohexylbenzene -1- carbonyl acyl chlorides (230mg) is obtained, is directly used in and reacts in next step.
Step 2: the preparation of ethyl 5- (benzyloxy) -6- methoxyl group -2- (1- cyclohexylbenzene -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylate
At room temperature, in 1- cyclohexylbenzene -1- carbonyl acyl chlorides (100mg, in methylene chloride (5mL) solution 0.45mmol), addition ethyl 5- (benzyloxy) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylate (183mg, 0.538mmol), triethylamine (137mg, 1.35mmol).Two hours are stirred at room temperature in reaction.About 10mL water is added, is extracted with dichloromethane.Organic phase successively uses saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate is dry, concentration, column chromatographs (eluant, eluent: petrol ether/ethyl acetate=1:1), obtain title compound ethyl 5- (benzyloxy) -6- methoxyl group -2- (1- cyclohexylbenzene -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylate (95mg, 40%).
MS m/z(ESI):528.6[M+H]+。
Step 3: the preparation of 5- (benzyloxy) -6- methoxyl group -2- (1- cyclohexylbenzene -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
In ethyl 5- (benzyloxy) -6- methoxyl group -2- (1- cyclohexylbenzene -1- carbonyl) -1, 2, 3, 4- tetrahydroisoquinoline -3- carboxylate (70mg, methanol (2mL) is separately added into tetrahydrofuran (6mL) solution 0.133mmol), water (3mL), it is subsequently added into lithium hydroxide (55.2mg, 1.33mmol), 2 hours are reacted at room temperature, organic solvent is removed under reduced pressure, about 100mL water is added, water phase is washed with a small amount of ethyl acetate, collect water phase dilute hydrochloric acid tune pH value to 2, water phase is extracted with ethyl acetate, collect ethyl acetate phase saturated common salt water washing, then with the dry organic phase of anhydrous sodium sulfate, concentration, obtain title compound 5- (benzyloxy) -6- methoxyl group -2- (1- phenyl hexamethylene Alkane -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid (51mg, 77%).MS m/z(ESI):500.2[M+H]+；
1H NMR(400MHz,CDCl3) δ 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).
The preparation of embodiment 2:5- (benzyloxy) -6- methoxyl group -2- (1- cyclo-propane -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
The preparation method of 5- (benzyloxy) -6- methoxyl group -2- (1- cyclo-propane -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid is referring to embodiment 1.MS m/z(ESI):458.2[M+H]+；
1H NMR(400MHz,CDCl3)δ7.41-7.28(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)。
The preparation of embodiment 3:5- (benzyloxy) -6- methoxyl group -2- (1- phenyl pentamethylene -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
The preparation method of 5- (benzyloxy) -6- methoxyl group -2- (1- phenyl pentamethylene -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid is referring to embodiment 1.MS m/z(ESI):486.3[M+H]+；
1H NMR(400MHz,CDCl3) δ 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).
The preparation of embodiment 4:5- (benzyloxy) -2- (2,2- diphenyl propionyl) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
The preparation method of 5- (benzyloxy) -2- (2,2- diphenyl propionyl) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid is referring to embodiment 1.MS m/z(ESI):522.3[M+H]+；
1H NMR(400MHz,CDCl3) δ 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).
The preparation of embodiment 5:2- (2,2- diphenyl propionyl) -6- methoxyl group -5- ((4- methoxyl group -3- methylbenzyl) oxo) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
The preparation method of 2- (2,2- diphenyl propionyl) -6- methoxyl group -5- ((4- methoxyl group -3- methylbenzyl) oxo) -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid is referring to embodiment 1.MS m/z(ESI):566.2[M+H]+；
1HNMR(400MHz,CD3OD):δ7.36-7.17(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)。
The preparation of embodiment 6:5- ((2,3- Dihydrobenzofuranes -5- base) methoxyl group) -2- (2,2- diphenyl propionyl) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid
The preparation method of 5- ((2,3- Dihydrobenzofuranes -5- base) methoxyl group) -2- (2,2- diphenyl propionyl) -6- methoxyl group -1,2,3,4- tetrahydroisoquinoline -3- carboxylic acid is referring to embodiment 1.MS m/z(ESI):564.2[M+H]+；
1H NMR (400MHz, MeOD): δ 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 test
One, test reagent and instrument
1. storing liquid (500mL)
1) 50mM Tris: 25mL1M Tris (Sigma T2663) is taken with distilled water to be diluted to 500mL spare；
2) 100mM NaCl: 10mLof 5M NaCl (purchased from Sigma (Sigma)) distilled water is taken to be diluted to 500mL spare；
3)5mM MgCl2: take 2.5mLof 1M (purchased from Fluka) distilled water to be diluted to 500mL spare.
2. working solution (50mL)
1) liquid 50mL stored above is taken, 0.1%BSA and the protease inhibitors 1 (being purchased from Roche Roche) without EDTA is added.
2) 384 hole Opti-Plate detection plates are purchased from Perkinelmer Inc. (Perkin Elmer, PE).
3) iodine labeling ligand: Sar1-Ile8-AngII, [125I]: it is purchased from PE (50uCi).1mL sterile water is added to be dissolved as 50uCi/mL storing liquid, 2200Ci/mmol.Working solution concentration is 0.1nM, and -20 degree freeze spare.
3. test apparatus
1) SPA flashes microballon: being dissolved into 25mg/mL storing liquid with 20mL working solution purchased from Perkinelmer Inc. (Perkin Elmer, PE), working solution ultimate density is 250ugbeads/well/25uL.
2) 384 well Opti-Plate (being purchased from PE).
3) automatic liquid separation device: Multidrop (Thermo Fisher).
4) instrument: 1430 ultraHTS Microplate Imager (Perkin Elmer) of ViewLux is tested and analyzed.
Two, test procedure
The present invention is using scintillation proximity assay (SPA) technology come detection compound to AT2Inhibitory activity, iodine labeling AT2Ligand: Sar1-Ile8-AngII, [125I], SPA microballon and 384 hole detection plates are purchased from PE company (PE (50uCi)).Test and analyze instrument: 1430 ultraHTS Microplate Imager (Perkin Elmer) of ViewLux.Test procedure is as follows:
1. including that Quality Control positive compound is connected in 384 hole experimental plates (Optiplate) by compound
2. working solution, microballon are mixed into centrifuge tube, room temperature is protected from light incubation mixing 1 hour, and shaking table mixes；
3. the microballon of the premixing in step 2 is added in experimental plate (hole 25uL/) with automatic liquid separation device Multidrop；
4. being protected from light mixed at room temperature with the capping rapid sealing experiment plate of film and being incubated for 1 hour (shaking table mixing)；
5. the developer (tracer) of 25uL is added in every hole with automatic liquid separation device (Multidrop)；
6. being protected from light mixed at room temperature overnight incubation with the capping rapid sealing experiment plate of film, shaking table is mixed；
7. the next morning, centrefuge experiment plate, microballon is made to be deposited to board bottom；
8. experimental plate is put into ViewLux, detection, reading Analysis calculate IC50。
Three, test result:
The biochemical activity of compound of the embodiment of the present invention and positive reference compound (EMA-400 is prepared referring to US5246943 embodiment 20) is measured by above test, the IC measured50Value see the table below.
Other embodiments compound hAT of the present invention2IC50Value is similar with the effect of above-described embodiment, shows approximate inhibitory activity and rule.
Conclusion: compound of the embodiment of the present invention is relative to positive reference compound, and part of compounds is to hAT2Very strong inhibitory activity is shown, the inhibitory effect being more than doubled.
For hAT1Inhibitory activity, the inhibitory activity greater than 5000nM is shown as positive reference compound.
In conclusion compound of the embodiment of the present invention is for hAT2With hAT1Inhibitory effect accordingly also there is higher selectivity, be more suitable hAT2The pharmacy of disease or application clinically.

Claims (14)

  1. One kind having 1,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts such as following formula (I) structure,
    Wherein:
    R1、R2、R3It is independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11,
    Or R1With R2、R1With R3、R2With R3C is formed together with the carbon atom being connected directly3-8Naphthenic base or 3-8 circle heterocyclic ring base, the hetero atom are selected from O, S, N,
    Halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
    R4Selected from hydrogen, deuterium, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, alkali metal, alkaline-earth metal or ammonium are optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
    R5、R6、R9、R10It is independently selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 Circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
    R7、R8It is independently selected from hydrogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl or 5-10 unit's heteroaryl are optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced, optionally further by one or more be selected from halogen, hydroxyl, sulfydryl, cyano, nitro, acetamido, azido, sulfonyl, mesyl, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C1-8Alkoxy carbonyl group, C1-8Alkyl-carbonyl, C1-8Alkyl carbonyl epoxide, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, amino, C1-8Alkyl monosubstituted amino or C1-8Replaced the substituent group of alkyl disubstituted amino；
    R12Selected from hydrogen, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, C1-8Alkyl acyl, C1-8Alkyl amino or C1-8Alkylamidoalkyl is optionally further selected from halogen, hydroxyl, sulfydryl, cyano, nitro, acetamido, azido, sulfonyl, mesyl, C by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C1-8Alkoxy, C1-8Alkoxy carbonyl group, C1-8Alkyl-carbonyl, C1-8Alkyl carbonyl epoxide, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl, amino, C1-8Alkyl monosubstituted amino or C1-8Replaced the substituent group of alkyl disubstituted amino；
    R11、R13、R14Selected from hydrogen, deuterium, C1-8Alkyl, C3-8Naphthenic base, halogen replace C1-8Alkyl, hydroxyl replace C1-8Alkyl, phenyl or p-methylphenyl；
    R is 0,1,2.
  2. According to claim 11,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that the stereoisomer refers to that 1-, 3-, 4- or 2 '-positions include spatial configuration, may respectively be R- configuration or S- configuration；It is preferred that " 3R- " or " 3S- " stereoisomer,
  3. According to claim 11,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
    R5、R6、R9、R10It is independently selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-4Alkyl, halogen replace C1-4Alkyl, C2-4Alkenyl, C2-4Alkynyl group, C3-6Naphthenic base, 3-6 circle heterocyclic ring base, 3-6 circle heterocyclic ring base oxygroup, 3-6 circle heterocyclic ring base sulfenyl, C5-8Aryl, C5-8Aryloxy, C5-8Artyl sulfo, 5-8 unit's heteroaryl, 5-8 unit's heteroaryl oxygroup, 5-8 unit's heteroaryl sulfenyl ,-C0-4-S(O)rR11、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-N(R13)-C(O)R12Or-N (R13)-C(O)OR11；Halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced.
  4. According to claim 11,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
    R4Selected from hydrogen, deuterium, C1-8Alkyl, halogen replace C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, alkali metal, alkaline-earth metal or ammonium；
    R5、R6、R9、R10It is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, isopropyl oxygen Carbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl.
  5. According to claim 11,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
    R4Selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclohexyl, phenyl, alkali metal, alkaline-earth metal or ammonium；
    R5、R6、R9、R10It is independently selected from hydrogen, deuterium, fluorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxyl group, ethyoxyl, isopropoxy, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino or dimethylamino.
  6. According to claim 11,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that selected from such as following formula (II) compound:
    Wherein, R4Selected 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, C1-8Alkyl, C2-8Alkenyl, halogen replace C1-8Alkyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11；
    M is selected from 0,1,2,3,4 or 5.
  7. According to claim 61,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
    R2、R3It is independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11,
    Alternatively, R2With R3C is formed together with the carbon atom being connected directly3-8Naphthenic base,
    Halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-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 (R13)-C(O)OR11Substituent group replaced；
    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, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
    M is selected from 0,1,2,3,4 or 5.
  8. According to claim 61,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that
    R2、R3It is independently selected from deuterium, halogen, hydroxyl, sulfydryl, cyano, nitro, azido, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, halogen replace C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, 3-8 circle heterocyclic ring base oxygroup, 3-8 circle heterocyclic ring base sulfenyl, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8-S(O)rR10、-C0-8-O-R10、-C0-8-C(O)OR10、-C0-8-C(O)R11、-C0-8-O-C(O)R11、-C0-8-NR12R13、-C0-8-C(O)NR12R13、-N(R13)-C(O)R11Or-N (R13)-C(O)OR10,
    Alternatively, R2With R3C is formed together with the carbon atom being connected directly3-8Naphthenic base,
    Fluorine is further optionally selected from by one or more, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropylsulfonyl, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, replaced the substituent group of acetylamino or dimethyl-aminocarbonyl；
    R4Selected from hydrogen, sodium, potassium, calcium or ammonium；
    R15Selected from hydrogen, fluorine, chlorine, hydroxyl, sulfydryl, cyano, nitro, azido, methyl, ethyl, isopropyl, trifluoromethyl, vinyl, allyl, acetenyl, cyclopropyl, pyridyl group, tetrahydrofuran base, morpholinyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, benzyloxy, sulfonyl, mesyl, isopropyl sulphur Acyl group, p-toluenesulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group, acetoxyl group, amino, dimethylamino, acetylamino or dimethyl-aminocarbonyl；
    M is selected from 0,1,2,3,4 or 5.
  9. According to claim 61,2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts, which is characterized in that be selected from following compound:
  10. According to claim 1 to 91, the preparation method of 2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts includes the following steps:
    X is selected from hydroxyl or halogen, preferably hydroxyl or chlorine.
  11. Preparation method according to claim 10, it is characterized in that, the acid binding agent is organic base or inorganic base, the organic base is selected from or mixtures thereof trimethylamine, triethylamine, pyridine, piperidines, morpholine, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, lithium hydroxide, or mixtures thereof sodium acetate；The condensing agent is selected from or mixtures thereof DIC, DCC, HOBT, EDCHCl, PyBOP, PyBroP, HATU, HCTU, DEPBT, EEDQ, CDI.
  12. A kind of pharmaceutical composition comprising according to claim 1 to 9 the 1 for the treatment of effective dose, 2,3,4- tetrahydro isoquinoline derivatives, its stereoisomer or its pharmaceutically-acceptable salts and pharmaceutical Carrier.
  13. According to claim 1 to 91,2, pharmaceutical composition described in 3,4- tetrahydro isoquinoline derivative, its stereoisomer or its pharmaceutically-acceptable salts or claim 12 is preparing the application in neuropathy or neuropathic pain drug for treating, preventing or ameliorating object.
  14. Application according to claim 13, it is characterized in that, the neuropathy is primary neuropathy, secondary neuropathy, peripheral nerve disease, neuropathy, painful diabetic neuropathy (PDN) or related neurological disease caused by mechanical nerve injury or biochemical nerve damage.
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