CN103435545B - Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof - Google Patents
Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof Download PDFInfo
- Publication number
- CN103435545B CN103435545B CN201310354975.XA CN201310354975A CN103435545B CN 103435545 B CN103435545 B CN 103435545B CN 201310354975 A CN201310354975 A CN 201310354975A CN 103435545 B CN103435545 B CN 103435545B
- Authority
- CN
- China
- Prior art keywords
- tetrahydroisoquinoline
- methyl
- indenes
- chloro
- quaternary ammonium
- 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
- -1 Tetrahydroisoquinoline quaternary ammonium salt Chemical class 0.000 title claims abstract description 23
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000036592 analgesia Effects 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 230000000202 analgesic effect Effects 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 7
- 229910052740 iodine Inorganic materials 0.000 claims 7
- 239000011630 iodine Substances 0.000 claims 7
- 150000003839 salts Chemical class 0.000 claims 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000012360 testing method Methods 0.000 abstract description 7
- 208000019901 Anxiety disease Diseases 0.000 abstract description 6
- 230000036506 anxiety Effects 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 6
- 208000002193 Pain Diseases 0.000 abstract description 5
- 239000002632 kappa opiate receptor agonist Substances 0.000 abstract description 4
- 229940126470 kappa opioid receptor agonist Drugs 0.000 abstract description 4
- 230000036407 pain Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract description 3
- 150000003233 pyrroles Chemical class 0.000 description 36
- 238000000034 method Methods 0.000 description 18
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 229940127240 opiate Drugs 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 230000031709 bromination Effects 0.000 description 10
- 238000005893 bromination reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 150000002469 indenes Chemical class 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- FWFXEZIPHMCTQH-UHFFFAOYSA-N N1CCOCC1.C1CCCN2CCCCC12 Chemical compound N1CCOCC1.C1CCCN2CCCCC12 FWFXEZIPHMCTQH-UHFFFAOYSA-N 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000027455 binding Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 231100001274 therapeutic index Toxicity 0.000 description 5
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 239000002287 radioligand Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 3
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- WJBMRZAHTUFBGE-UHFFFAOYSA-N 2-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC(CCN)=C1 WJBMRZAHTUFBGE-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 206010068676 Pneumoretroperitoneum Diseases 0.000 description 2
- 208000005727 Retropneumoperitoneum Diseases 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000001353 anxiety effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 239000003401 opiate antagonist Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 1
- CKLFJWXRWIQYOC-UHFFFAOYSA-N 2-(4-fluorophenyl)ethanamine Chemical compound NCCC1=CC=C(F)C=C1 CKLFJWXRWIQYOC-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- XKLMLKSXPIITAL-UHFFFAOYSA-N 2-chloro-3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1Cl XKLMLKSXPIITAL-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- OIJXLIIMXHRJJH-ZXJLXYCOSA-N [3h]diprenorphine Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@]22C[C@@H]([C@]3(OC)CC2)C(C)(C)O)C([3H])C1[3H])CC1CC1 OIJXLIIMXHRJJH-ZXJLXYCOSA-N 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000006400 anxiety behaviour Effects 0.000 description 1
- 125000006278 bromobenzyl group Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002756 mu opiate receptor agonist Substances 0.000 description 1
- 229940126487 mu opioid receptor agonist Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004760 visceral afferent Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to medicinal chemistry art, be specifically related to tetrahydroisoquinoliderivatives quaternary ammonium salt derivative, composition containing this tetrahydroisoquinoline quaternary ammonium salt derivative, and described derivative or composition are as the purposes of κ-opioid receptor agonist at ease pain.Pharmacodynamics test proves, compound of the present invention has analgesic activity, and the central not having such medicine common is calm and anxiety side effect.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to tetrahydroisoquinoliderivatives quaternary ammonium salt derivative, composition containing this tetrahydroisoquinoline quaternary ammonium salt derivative, and described derivative or composition are as the purposes of κ-opioid receptor agonist at ease pain.
Background technology
After κ-opioid receptor agonist is combined with κ-opiate receptor, except can producing potent analgesic activity, because κ-opium opiate receptor does not participate in analgesia and the reward effect of morphine, the precipitated morphine withdrawal of animal and human can be alleviated, and can also the respiration inhibition effect of antagonism μ-opioid receptor agonist, from the 1980s, become the focus of analgesia area research.
The result of contriver's early-stage Study describes tetrahydroisoquinoliderivatives derivatives in CN1887872, has good κ-opiate receptor affinity and μ/κ-opiate receptor selectivity.The chemistry that particularly embodiment 3 describes is called 1-(Pyrrolidine-1-methyl)-2-(6-chloro-2,3-dihydro-indenes-3-ketone-1-carbonyl)-1,2,3, the compound of 4-tetrahydroisoquinoline (is also called indenes quinoline promise woods, structural formula is as follows), be the κ-opioid receptor agonist of a kind of high reactivity and highly selective.Through radioligand-binding study display, this compound is Ki (M) κ=2.99 × 10 to κ-opiate receptor avidity
-11, μ/κ-opiate receptor selectivity reaches μ Ki/ κ Ki=22341, in mouse analgesic test, demonstrates stronger analgesic activities (ED
50=3.1ug/kg (s.c)), but mouse runner test and mouse elevated plus-maze experiment find, and indenes quinolizidine morpholine shows calmness and the anxiety side effect of obvious central.
There are some researches show at present, κ-opiate receptor does not exist only in central nervous system, and is present in the different tissues organ of periphery, as internal organ and visceral afferent volley nerve etc., is called periphery property κ-opiate receptor.Selectivity exciting periphery κ-opiate receptor, not only can alleviate or diminish inflammation, internal organ and neuropathic chronic pain, and can avoid or alleviate the side effects such as the calm and anxiety of central, the therapeutic quality of raising pain.If by introducing hydrophilic radical, increase molecular polarity, reduce logP value, effectively stop compound to enter central nervous system, avoid excitomotor center κ-opiate receptor to produce maincenter side effect, believe the analgesic of the periphery κ-opiate receptor excitement that can obtain there is wide application prospect.
Summary of the invention
The invention discloses the tetrahydroisoquinoline quaternary ammonium salt derivative shown in general formula I that the calm and anxiety side effect of a class central obviously reduces:
Wherein, R
1, R
2represent hydrogen, halogen, hydroxyl, C independently of one another
1-6alkoxyl group or C
1-6alkyl;
R
3represent C
1-C
6alkyl, allyl group or benzyl;
X represents halogen;
M, n represent 1,2,3 or 4 independently.
R
2preferably represent hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, oxyethyl group, methyl, ethyl or propyl group independently of one another.
R
3preferably represent methyl, ethyl, propyl group, Cvclopropvlmethvl, allyl group or benzyl.
X preferably represents iodine, bromine or chlorine.
Preferred compound is as follows:
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes--1-formyl radical) fluoro-1,2,3, the 4-tetrahydroisoquinoline-1-base of-7-)-methyl) pyrroles;
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-6-methoxyl group-1,2,3,4-tetrahydroisoquinoline-1-base)-methyl) pyrroles;
Iodate 1-methyl isophthalic acid-((2-(6-methoxyl group-7-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-base)-methyl) pyrroles;
Bromination 1-benzyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Bromination 1-allyl group-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Bromination 1-(4-luorobenzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Bromination 1-(4-methoxy-benzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Iodate 1-ethyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Iodate 1-normal-butyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles;
Bromination 1-Cvclopropvlmethvl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles.
General formula of the present invention (I) compound can be prepared with the following method:
Wherein R
1, R
2, R
3, X, m, n definition the same.
The compound of formula II is obtained according to the method for patent CN1887872; With formula II compound for raw material, in organic solvent with alkylating agent R
3x reacts, obtained formula I.Wherein, organic solvent is selected from the mixed solvent of one or more compositions in acetone, acetonitrile, methylene dichloride, 1,2-ethylene dichloride, DMF, N,N-dimethylacetamide, methyl-sulphoxide, preferred acetone, acetonitrile.R
3x be selected from methyl iodide, iodoethane, butyl iodide, bromomethyl cyclopropane, cylite, to methoxyl group cylite, to chlorine cylite, 2,4-dichloro cylites, to fluorine bromobenzyl, preferred butyl iodide, bromomethyl cyclopropane.
The tetrahydroisoquinoline quaternary ammonium salt derivative of general formula of the present invention (I) can be mixed with into the various preparations in pharmaceutics with pharmaceutically acceptable carrier, comprise tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspensoid, injection etc.The tetrahydroisoquinoline quaternary ammonium salt derivative of general formula (I) also can add other anodynes such as morphine, fentanyl etc. and be prepared into compound pain medicine.
Compound Doses used in clinical practise of the present invention is 0.01mg ~ 1000mg/ days, also can depart from this scope according to the difference of the weight of the state of an illness or formulation.
Pharmacodynamics test proves, tetrahydroisoquinoline quaternary ammonium salt derivative of the present invention not only analgesic activity is strong, and the calm side effect almost not having such medicine common.
Embodiment
Embodiment 1
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-1)
With reference to the method for Chinese patent CN1887872, with phenylethylamine and 3-chlorobenzaldehyde for raw material, prepare 1-(Pyrrolidine-1-methyl)-2-(the chloro-3-oxo-2 of 6-; 3-dihydro-1H-indenes-1-formyl radical)-1; 2,3,4-tetrahydroisoquinoline.
1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2 is added in 50ml eggplant-shape bottle; 3,4-tetrahydroisoquinoline (0.2g, 0.49mmol); acetone 10ml; methyl iodide (0.31ml, 49mmol), stirring at normal temperature 2h; a large amount of solid is separated out; filter to obtain white solid I-1, yield 77.4%, m.p.170 ~ 172 DEG C.
1H-NMR(300MHz,DMSO-d
6),δ(ppm):1.98～2.08(4H,m,2×CH
2),2.74～2.80(1H,d,J=15.9Hz,1/2CH
2),2.93～3.15(4H,m,2×1/2CH
2,CH
2),3.11(3H,s,NCH
3),3.48～3.79(4H,m,2×CH
2),3.92～4.06,4.13～4.32(2H,m,2×1/2CH
2),4.63～4.86(1H,dd,J=4.2Hz,14.1Hz,1/2CH
2),5.05～5.06(1H,d,J=5.7Hz,CH),6.11～6.08(1H,d,J=9.9Hz,CH),7.24～7.40(3H,m,ArH),7.41～7.44(1H,m,ArH),7.58～7.66(3H,m,ArH).MS(ESI(+)70V,m/z):423.3([M+H]
+,base peak).
Embodiment 2
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes--1-formyl radical) fluoro-1,2,3, the 4-tetrahydroisoquinoline-1-base of-7-)-methyl) pyrroles (I-2)
With reference to the method for Chinese patent CN1887872; with 4-fluorophenethylamine and 3-chlorobenzaldehyde for raw material, prepare 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-7-fluoro-1; 2; 3,4-tetrahydroisoquinoline, then with iodomethane reaction; the method being similar to embodiment 1 obtains I-2; for white solid, yield 81.2%, m.p.190 ~ 192 DEG C.
1H-NMR(300MHz,DMSO-d
6),δ(ppm):1.98～2.08(4H,m,2×CH
2),2.73～2.80(1H,d,J=18.6Hz,1/2CH
2),2.93～3.10(4H,m,1/2CH
2,CH
2,1/2CH
2),3.10(3H,s,NCH
3),3.48～3.82(4H,m,2×CH
2),3.92～4.06,4.13～4.32(2H,m,2×1/2CH
2),4.63～4.86(1H,m,1/2CH
2),5.04～5.06(1H,d,J=6.1Hz,CH),6.11～6.08(1H,d,J=10.1Hz,CH),7.12～7.18(1H,m,ArH),7.31～7.38(2H,m,ArH),7.58～7.72(3H,m,ArH).
HRMS(ESI):m/z[M+H]
+Calcd for C
25H
27ClFN
2O
2:441.1740;Found:441.1746.
Embodiment 3
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-6-methoxyl group-1,2,3,4-tetrahydroisoquinoline-1-base)-methyl) pyrroles (I-3)
With reference to the method for Chinese patent CN1887872; with 3-methoxyphenethylamine and 3-chlorobenzaldehyde for raw material, prepare 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-6-methoxyl group-1; 2; 3,4-tetrahydroisoquinoline, then with iodomethane reaction; the method being similar to embodiment 1 obtains I-3; for white solid, yield 84.7%, m.p.266 ~ 268 DEG C.
1H-NMR(500MHz,DMSO-d
6),δ(ppm):1.94～2.08(4H,m,2×CH
2),2.72～2.78(1H,d,J=18.4Hz,1/2CH
2),2.85～3.06(4H,m,1/2CH
2,CH
2,1/2CH
2),3.09(3H,s,NCH
3),
3.40～3.70(3H,m,CH
2,1/2CH
2),3.75～3.85(1H,m,1/2CH
2),3.75(3H,s,OCH
3),3.92～3.99,4.09～4.17(2H,m,2×1/2CH
2),4.59～4.62(1H,d,J=10.6Hz,1/2CH
2),5.04～5.05(1H,d,J=5.9Hz,CH),5.99～6.02(1H,d,J=10.0Hz,CH),6.83～6.87(2H,m,ArH),7.31～7.34(1H,d,J=8.4Hz,ArH),7.58～7.60(1H,d,J=8.1Hz,ArH),7.65(1H,s,ArH),7.69～7.72(1H,d,J=8.1Hz,ArH).
HRMS(ESI):m/z[M+H]
+C
26H
30ClN
2O
3:453.1945;Found:453.1949.
Embodiment 4
Iodate 1-methyl isophthalic acid-((2-(6-methoxyl group-7-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-4)
With reference to the method for Chinese patent CN1887872; with phenylethylamine and the chloro-m-methoxybenzaldehyde of 2-for raw material, prepare 1-(Pyrrolidine-1-methyl)-2-(6-methoxyl group-7-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1; 2; 3,4-tetrahydroisoquinoline, then with iodomethane reaction; the method being similar to embodiment 1 obtains I-4; for white solid, yield 75.9%, m.p.205 ~ 207 DEG C.
1H-NMR(500MHz,DMSO-d
6),δ(ppm):2.04～2.08(4H,m,2×CH
2),2.52～2.57(1H,m,1/2CH
2),2.90～2.95(2H,m,CH
2),3.15(3H,s,NCH
3),3.16～3.20(2H,m,2×1/2CH
2),3.48～3.87(5H,m,2×CH
2,1/2CH
2),3.84(3H,s,OCH
3),4.07～4.15(1H,m,1/2CH
2),4.25～4.28(1H,m,1/2CH
2),4.72～4.73(1H,d,J=4.8Hz,CH),6.06～6.09(1H,d,J=9.2Hz,CH),7.16～7.21(1H,m,ArH),7.26～7.30(3H,m,ArH),7.40～7.44(1H,m,ArH),7.67(1H,s,ArH).
HRMS(ESI):m/z[M+H]
+C
26H
30ClN
2O
3:453.1939;Found:453.1944.
Embodiment 5
Iodate 1-methyl isophthalic acid-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-base)-methyl) pyrroles (I-5)
With reference to the method for Chinese patent CN1887872; with 3-methoxyphenethylamine and 3-chlorobenzaldehyde for raw material, prepare 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-6-hydroxyl-1; 2; 3,4-tetrahydroisoquinoline, then with iodomethane reaction; the method being similar to embodiment 1 obtains I-5; for white solid, yield 43.2%, m.p.258 ~ 260 DEG C.
1H-NMR(300MHz,DMSO-d
6),δ(ppm):1.91～2.08(4H,m,2×CH
2),2.72～2.78(1H,d,J=18.7Hz,1/2CH
2),2.88～3.15(4H,m,1/2CH
2,CH
2,1/2CH
2),3.09(3H,s,NCH
3),
3.48～3.78(4H,m,2×CH
2),3.93～4.06,4.13～4.26(2H,m,2×1/2CH
2),4.56～4.60(1H,d,J=10.4Hz,1/2CH
2),5.03～5.05(1H,d,J=5.5Hz,CH),5.93～5.96(1H,d,J=10.1Hz,CH),6.62～6.70(2H,m,ArH),7.20～7.23(1H,d,J=8.4Hz,ArH),7.58～7.72(3H,m,ArH).
MS(ESI(+)70V,m/z):419.3([M+H]
+,base peak)
Embodiment 6
Bromination 1-benzyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-6)
1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2 is added in 50ml eggplant-shape bottle; 3,4-tetrahydroisoquinoline (0.2g, 0.49mmol); acetonitrile 10ml, bromobenzyl (0.58ml, 49mmol); temperature rising reflux 2h; reaction solution directly adds silica gel, with methylene dichloride: methyl alcohol=40:1 column chromatography, obtains white solid 0.16g; yield 56.8%, m.p.172 ~ 174 DEG C.
1H-NMR(300MHz,DMSO-d
6),δ(ppm):1.72～2.08(4H,m,2×CH
2),2.73～2.80(1H,d,J=18.6Hz,1/2CH
2),2.90～3.30(4H,m,1/2CH
2,CH
2,1/2CH
2),3.58～3.69(4H,m,2×CH
2),4.09～4.16,4.23～4.32(2H,m,2×1/2CH
2),4.63～4.86(3H,dd,J=9.1Hz,9.1Hz,PhCH
2,1/2CH
2),5.11～5.13(1H,d,J=6.7Hz,CH),6.28～6.31(1H,d,J=9.8Hz,CH),7.12～7.27(4H,m,ArH),7.48～7.54(5H,m,ArH),7.69～7.72(2H,m,ArH).
MS(ESI(+)70V,m/z):499.3([M+H]
+,base peak)
Embodiment 7
Bromination 1-allyl group-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-7)
With 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline and allyl bromide 98 are raw material, and the method being similar to embodiment 6 obtains white solid I-7; yield 46.0%, m.p.178 ~ 180 DEG C.
1H-NMR(500MHz,DMSO-d
6),δ(ppm):1.88～2.08(4H,m,2×CH
2),2.57～2.64(1H,d,J=18.5Hz,1/2CH
2),2.94～3.16(4H,m,1/2CH
2,CH
2,1/2CH
2),3.57～3.72(4H,m,2×CH
2),3.98～4.23(4H,m,CH
2,2×1/2CH
2),4.60～4.62(1H,d,J=10.1Hz,1/2CH
2),5.06～5.07(1H,d,J=6.3Hz,CH),5.65～5.70(2H,m,CH=CH
2),6.06～6.08(1H,d,J=9.8Hz,CH),6.17～6.20(1H,m,CH=CH
2),7.24～7.30(4H,m,ArH),7.58～7.60(1H,d,J=8.1Hz,ArH),7.65(1H,sArH),7.70～7.72(1H,d,J=8.1Hz,ArH).
MS(ESI(+)70V,m/z):449.2([M+H]
+,base peak).
Embodiment 8
Bromination 1-(4-luorobenzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-8)
With 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline and 4-fluoro benzyl bromide are raw material, and the method being similar to embodiment 6 obtains white solid I-8; yield 57.2%, m.p.210 ~ 212 DEG C.
1H-NMR(500MHz,DMSO-d
6),δ(ppm):1.72～2.04(4H,m,2×CH
2),2.72～2.76(1H,d,J=18.4Hz,1/2CH
2),2.97～3.23(4H,m,1/2CH
2,CH
2,1/2CH
2),3.61～3.68(4H,m,2×CH
2),4.14～4.27,4.29～4.32(2H,m,2×1/2CH
2),4.61～4.64,4.83～4.85(3H,m,PhCH
2,1/2CH
2),5.11～5.12(1H,d,J=6.7Hz,CH),6.24～6.26(1H,d,J=9.3Hz,CH),7.23～7.32(6H,m,ArH),7.52(3H,s,ArH),7.67～7.70(2H,m,ArH).
MS(ESI(+)70V,m/z):517.2([M+H]
+,base peak).
Embodiment 9
Bromination 1-(4-methoxy-benzyl)-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-9)
With 1-(Pyrrolidine-1-methyl)-2-(the chloro-3-oxo-2 of 6-; 3-dihydro-1H-indenes-1-formyl radical)-1; 2; 3; 4-tetrahydroisoquinoline and 4-methoxy-benzyl bromine are raw material; the method being similar to embodiment 6 obtains white solid I-9, yield 67.4%, m.p.220 ~ 222 DEG C.
1H-NMR(500MHz,DMSO-d
6),δ(ppm):1.74～2.08(4H,m,2×CH
2),2.73～2.80(1H,d,J=18.4Hz,1/2CH
2),2.90～3.28(4H,m,1/2CH
2,CH
2,1/2CH
2),3.57～3.69(4H,m,2×CH
2),3.81(3H,s,OCH
3),4.09～4.13,4.17～4.26(2H,m,2×1/2CH
2),4.63～4.83
(3H,dd,J=8.2Hz,8.2Hz,PhCH
2,1/2CH
2),5.08～5.09(1H,d,J=6.1Hz,CH),6.27～6.29(1H,d,J=9.8Hz,CH),7.02～7.04(2H,m,ArH),7.15～7.42(4H,m,ArH),7.36～7.38(1H,d,J=8.4Hz,CH),7.53～7.55(1H,d,J=8.1Hz,CH),7.67～7.77(3H,m,ArH).
MS(ESI(+)70V,m/z):529.2([M+H]
+,base peak).
Embodiment 10
Iodate 1-ethyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-10)
With 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline and iodoethane are raw material, and the method being similar to embodiment 6 obtains white solid I-10; yield 57.2%, m.p.240 ~ 242 DEG C.
1H-NMR(500MHz,DMSO-d
6),δ(ppm):1.29～1.32(3H,t,J=7.0Hz,CH
3),1.98～2.04(4H,m,2×CH
2),2.71～2.75(1H,d,J=21.2Hz,1/2CH
2),2.94～3.12(4H,m,1/2CH
2,CH
2,1/2CH
2),3.57～3.89(4H,m,2×CH
2),3.62～3.65(2H,m,CH
2),4.09～4.13,4.02～4.11(2H,m,2×1/2CH
2),4.56～4.59(1H,d,J=10.6Hz,1/2CH
2),5.02～5.03(1H,d,J=6.1Hz,CH),5.97～5.99(1H,d,J=9.8Hz,CH),7.28～7.34(4H,m,ArH),7.59～7.60(1H,d,J=8.6Hz,ArH),7.66(1H,s,ArH),7.70～7.72(1H,d,J=8.2Hz,ArH).
HRMS(ESI):m/z[M+H]
+Calcd for C
26H
30ClN
2O
2:437.1990;Found:437.1966.
Embodiment 11
Iodate 1-normal-butyl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-11)
With 1-(Pyrrolidine-1-methyl)-2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2; 3,4-tetrahydroisoquinoline and butyl iodide are raw material, and the method being similar to embodiment 6 obtains white solid I-11; yield 40.7%, m.p.180 ~ 182 DEG C.
1H-NMR(300MHz,DMSO-d
6),δ(ppm):0.89～0.94(3H,t,J=7.1Hz,CH
3),1.26～1.30(2H,m,CH
2),1.65～1.75(2H,m,CH
2),2.01～2.08(4H,m,2×CH
2),2.72～2.75(1H,m,1/2CH
2),2.94～3.12(4H,m,1/2CH
2,CH
2,1/2CH
2),3.57～3.89(4H,m,2×CH
2),3.62～3.65(2H,m,CH
2),4.09～4.11(2H,m,2×1/2CH
2),4.56～4.59(1H,d,J=9.1Hz,1/2CH
2),5.02～5.03(1H,m,CH),5.77～5.79(1H,d,J=9.8Hz,CH),7.3(3H,s,ArH),7.59～7.60(1H,d,J=8.2Hz,ArH),7.67(1H,s,ArH),7.70～7.73(1H,d,J=8.2Hz,ArH).
MS(ESI(+)70V,m/z):465.3([M+H]
+,base peak).
Embodiment 12
Bromination 1-Cvclopropvlmethvl-1-((2-(6-chloro-3-oxo-2,3-dihydro-1H-indenes-1-formyl radical)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) pyrroles (I-12)
With 1-(Pyrrolidine-1-methyl)-2-(the chloro-3-oxo-2 of 6-; 3-dihydro-1H-indenes-1-formyl radical)-1; 2; 3; 4-tetrahydroisoquinoline and cyclopropylmethyl bromide are raw material; the method being similar to embodiment 6 obtains white solid I-12, yield 47.9%, m.p.106 ~ 108 DEG C.
1H-NMR(300MHz,DMSO-d
6),δ(ppm):0.35～0.38(2H,m,CH
2),0.71～0.73(2H,m,CH
2),1.21～1.25(1H,m,CH),1.87～2.08(4H,m,2×CH
2),2.69～2.76(1H,d,J=18.5Hz,1/2CH
2),2.90～3.16(5H,m,1/2CH
2,2×CH
2),3.42～3.57(3H,m,CH
2,1/2CH
2),3.76～3.81(2H,m,2×1/2CH
2),4.01～4.08,4.18～4.27(2H,m,2×1/2CH
2),4.59～4.63(1H,d,J=11.3Hz,1/2CH
2),5.04～5.06(1H,d,J=5.6Hz,CH),6.03～6.06(1H,d,J=9.7Hz,CH),7.29～7.35(4H,m,ArH),7.59～7.73(3H,m,ArH).
HRMS(ESI):m/z[M+H]
+C
28H
32ClN
2O
2:463.2147;Found:463.2156.
Embodiment 13
Pharmacodynamics test
One, opiate receptor affinity research (radioligand-binding study)
Experimental technique:
Experiment point total binding pipe and non-specific binding pipe, separately establish several groups of sample hoses to add different concns competition part.Total binding pipe add the expression being equivalent to 20 μ g membrane receptor protein and [
3h] diprenorphine (0.5nM) (1.44Pbq.mol
-1wide spectrum opiate antagonist, Amersham company), corresponding non-specific binding pipe separately adds Narlan (the wide spectrum opiate antagonist of 1 μM, Sigma company), sample hose adds different concns compound to be screened, is adjusted to final volume 100 μ l with 50mM Tris (Amresco company)-HCl (pH7.4).Hatch 30min at 30 DEG C, then put termination reaction in frozen water.Through GF/ (Whatman) glass fiber filter paper negative pressure leaching on Millipore sample divider.Three times are rinsed with ice-cold 50mM Tris-HCl (pH7.4), each 4ml, after filter paper is dried, be placed in 0.5ml Eppendorff to manage, add 0.5ml lipophilic scintillation solution (Shanghai reagent one factory), Beckman LS6500 full-service fluid scintillation counter measures radioactive intensity, calculates inhibiting rate, each concentration is three multiple pipes, independent experiment 3-4 time each time.Method of calculation:
According to inhibiting rate, with Prism4.0 computed in software IC
50value.
K
i=IC
50/ (1+ [L]/K
d), ([L] is the concentration of added tagged ligand, K
dbalance dissociation parameters for radioligand).
The results are shown in Table 1
Table 1 part of compounds and competitive radioligand binding tests and binding affinity (the κ K to κ-acceptor
i)
Above data show, indenes quinolizidine morpholine quaternary ammonium salt derivative of the present invention still has stronger avidity to κ-opiate receptor.
Two, sedative effect research
Experiment establishes following several groups:
Physiological saline group: 10/group, only, 15min pneumoretroperitoneum injects 0.6% Glacial acetic acid 0.2ml to subcutaneous injection physiological saline 0.2ml/, observes writhing number of times in 15min;
Embodiment group: establish 3 various dose groups, 10/group, subcutaneous injection is by reagent 1ug/kg respectively for each group, and 5ug/kg, 10ug/kg, 15min pneumoretroperitoneum injects 0.6% Glacial acetic acid 0.2ml, observes writhing number of times in 15min, calculates analgesia ED
50value.
Utilize rotary wheel device, new mouse is placed on runner respectively, record the time that it falls down from runner, first screen before formal experiment, if the mouse fallen down in 60s, reject.Random 10 points one group of qualified mouse, give various dose indenes quinoline promise woods and by after reagent, record the time of falling down from runner, repeat to average for twice, calculate calm ED
50the same.The calm side effect of maincenter by reagent is evaluated by therapeutic index.Therapeutic index=calm ED
50/ analgesia ED
50.Therapeutic index is higher, and calm side effect is less.
The results are shown in Table 2
The analgesia of table 2 part of compounds and calm ED
50value and therapeutic index
Table 2 data show, the therapeutic index of indenes quinolizidine morpholine quaternary ammonium salt derivative of the present invention is obviously greater than indenes quinolizidine morpholine, illustrate that their calm side effect is weaker than indenes quinolizidine morpholine, and analgesia, sedative effect can separate.
Three, anxiety Effect study
Experimental technique
Mouse gave by reagent after 15 minutes, be placed on the middle junction that Elevated plus-maze open arms closes arm, face open arms, the residence time that in 5 minutes, record enters open arms or closes arm accounts for the per-cent of total time as evaluation index, enters to close arm and rest on the time of closing arm to reflect anxiety behavior.Test-results is in table 3
The elevated plus-maze test of table 3 Compound I-2, I-7 and I-11
| Compound numbers | Open arms time/total time (%) | Close arm time/total time (%) |
| Contrast | 39 | 61 |
| Indenes quinolizidine morpholine (1 μ g/kg) | 34 | 66 |
| Indenes quinolizidine morpholine (2.5 μ g/kg) | 17 | 83 |
| Indenes quinolizidine morpholine (5 μ g/kg) | 3 | 97 |
| I-2(1.25mg/kg) | 38 | 62 |
| I-2(2.5mg/kg) | 23 | 77 |
| I-2(3.75mg/kg) | 16 | 84 |
| I-7(1.25mg/kg) | 36 | 64 |
| I-7(2.5mg/kg) | 22 | 78 |
| I-7(3.75mg/kg) | 13 | 87 |
| I-11(1.25mg/kg) | 34 | 66 |
| I-11(2.5mg/kg) | 25 | 75 |
| I-11(3.75mg/kg) | 15 | 85 |
Table 3 data show, I-2, I-7 and I-11 rest on the per-cent of the time of closing arm under low dosage (1.25mg/kg) and blank there is no difference, show that above-mentioned quaternary ammonium salt derivative is almost without causing anxiety effect under low dosage; Under 2.5mg/kg dosage, I-2, I-7 and I-11 only cause LA; Under high dosage (3.75mg/kg), I-2, I-7 and I-11 only cause moderate anxiety.And indenes quinolizidine morpholine can cause severe anxiety under high dosage (5 μ g/kg).
Claims (8)
1. the tetrahydroisoquinoline quaternary ammonium salt derivative of general formula (I):
Wherein, R
1, R
2represent hydrogen, halogen, hydroxyl, C independently of one another
1-6alkoxyl group or C
1-6alkyl;
R
3represent C
1-C
6alkyl, allyl group or benzyl;
X represents halogen;
M, n represent 1,2,3 or 4 independently.
2. the tetrahydroisoquinoline quaternary ammonium salt derivative of claim 1, wherein R
1, R
2represent hydrogen, fluorine, chlorine, bromine, hydroxyl, methoxyl group, oxyethyl group, methyl, ethyl or propyl group independently of one another.
3. the tetrahydroisoquinoline quaternary ammonium salt derivative of claim 1, wherein R
3represent methyl, ethyl, propyl group, allyl group or benzyl.
4. the tetrahydroisoquinoline quaternary ammonium salt derivative of claim 1, wherein X represents iodine, bromine or chlorine.
5. the tetrahydroisoquinoline quaternary ammonium salt derivative of claim 1, its formula of (I) compound is following arbitrary compound:
1-methyl isophthalic acid-(2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron salt compounded of iodine;
1-methyl isophthalic acid-((the fluoro-2-of 7-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron salt compounded of iodine;
1-methyl isophthalic acid-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-6-methoxyl group-1,2,3,4-tetrahydroisoquinoline-1-base)-methyl) Hygron salt compounded of iodine;
1-methyl isophthalic acid-((2-(chloro-2, the 3-dihydros of 6-methoxyl group-7--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron salt compounded of iodine;
1-methyl isophthalic acid-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-6-hydroxyl-1,2,3,4-tetrahydroisoquinoline-1-base)-methyl) Hygron salt compounded of iodine;
1-benzyl-1-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron bromine salt;
1-allyl group-1-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron bromine salt;
1-ethyl-1-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron salt compounded of iodine;
1-butyl-1-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron salt compounded of iodine.
6. the tetrahydroisoquinoline quaternary ammonium salt derivative of following arbitrary structure:
1-(4-luorobenzyl)-1-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron bromine salt;
1-(4-methoxy-benzyl)-1-((2-(chloro-2, the 3-dihydros of 6--indenes-3-ketone-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-1-bases)-methyl) Hygron bromine salt.
7. a pharmaceutical composition, the tetrahydroisoquinoline quaternary ammonium salt derivative wherein containing claim 1 or 6 and pharmaceutically acceptable carrier.
8. the tetrahydroisoquinoline quaternary ammonium salt derivative any one of claim 1 to 6 is for the preparation of the purposes of analgesic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310354975.XA CN103435545B (en) | 2013-08-14 | 2013-08-14 | Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310354975.XA CN103435545B (en) | 2013-08-14 | 2013-08-14 | Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103435545A CN103435545A (en) | 2013-12-11 |
| CN103435545B true CN103435545B (en) | 2015-10-07 |
Family
ID=49689291
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310354975.XA Active CN103435545B (en) | 2013-08-14 | 2013-08-14 | Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103435545B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330469A2 (en) * | 1988-02-23 | 1989-08-30 | Glaxo Group Limited | Tetrahydroisoquinoline derivatives |
| US5254564A (en) * | 1989-07-18 | 1993-10-19 | Lo Zambeletti S.P.A. | Substituted isoquinoline compounds, pharmaceutical composition and method of use in treating pain in mammals |
| CN1096780A (en) * | 1991-12-23 | 1994-12-28 | 布茨公司 | The therapeutical agent that contains the novel tetrahydro isoquinoline compound |
| CN1141636A (en) * | 1994-02-21 | 1997-01-29 | 阿斯特拉公司 | Novel opioid peptides for treating pain, and use therefor |
| CN1887872A (en) * | 2006-07-12 | 2007-01-03 | 中国药科大学 | Tetrahydro isoquinoline derivative and its prepn process and medicine use |
-
2013
- 2013-08-14 CN CN201310354975.XA patent/CN103435545B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330469A2 (en) * | 1988-02-23 | 1989-08-30 | Glaxo Group Limited | Tetrahydroisoquinoline derivatives |
| US5254564A (en) * | 1989-07-18 | 1993-10-19 | Lo Zambeletti S.P.A. | Substituted isoquinoline compounds, pharmaceutical composition and method of use in treating pain in mammals |
| CN1096780A (en) * | 1991-12-23 | 1994-12-28 | 布茨公司 | The therapeutical agent that contains the novel tetrahydro isoquinoline compound |
| CN1141636A (en) * | 1994-02-21 | 1997-01-29 | 阿斯特拉公司 | Novel opioid peptides for treating pain, and use therefor |
| CN1887872A (en) * | 2006-07-12 | 2007-01-03 | 中国药科大学 | Tetrahydro isoquinoline derivative and its prepn process and medicine use |
Non-Patent Citations (1)
| Title |
|---|
| 郭婷等.外周选择性kappa阿片受体激动剂的最新研究进展.《药学进展》.2006,第30卷(第3期),第104-108页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103435545A (en) | 2013-12-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101519682B1 (en) | Quaternary opioid carboxamides | |
| Shinkai et al. | 4-Aminoquinolines: novel nociceptin antagonists with analgesic activity | |
| CN101686989B (en) | Substituted imidazoheterocycles | |
| ES2232168T3 (en) | PIRROLOQUINOLINAS FOR THE TREATMENT OF OBESITY. | |
| Ananthan et al. | Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido-and pyrimidomorphinans | |
| KR20030011275A (en) | Azacyclic compounds for use in the treatment of serotonin related diseases | |
| KR20180080245A (en) | Acrylic Acid Derivatives, Their Preparation and Their Use in Medicine | |
| JP5964809B2 (en) | Morphine derivatives containing carboxamide groups as opioid receptor ligands | |
| CN102695708A (en) | N1-pyrazolospiroketone acetyl-coA carboxylase inhibitors | |
| Bourgeois et al. | Synthesis and pharmacological evaluation of 5-pyrrolidinylquinoxalines as a novel class of peripherally restricted κ-opioid receptor agonists | |
| JP2010510328A (en) | (R) -N-stereoisomers of 7,8-saturated-4,5-epoxy-morphinanium analogs | |
| CA2731429C (en) | Large substituent, non-phenolic amine opioids | |
| JP6917379B2 (en) | 8-Amino-2-oxo-1,3-diaza-spiro- [4.5] -decane derivative | |
| KR20120078715A (en) | Sulfonamides as inhibitors of bcl-2 family proteins for the treatment of cancer | |
| CN107286113A (en) | A kind of isoquinolinone derivatives and its production and use | |
| Geiger et al. | Conformationally constrained κ receptor agonists: stereoselective synthesis and pharmacological evaluation of 6, 8-diazabicyclo [3.2. 2] nonane derivatives | |
| CN103435545B (en) | Tetrahydroisoquinoline quaternary ammonium salt derivative, its preparation method and analgesia purposes thereof | |
| CN103450079B (en) | Tetrahydroisoquinoline hydroxy derivatives, its preparation method and medicinal use thereof | |
| Gabet et al. | Identification of N-benzyltetrahydroisoquinolines as novel anti-neuroinflammatory agents | |
| Holl et al. | Relationships between the structure of 6-substituted 6, 8-diazabicyclo [3.2. 2] nonan-2-ones and their σ receptor affinity and cytotoxic activity | |
| CN102171191A (en) | Indazole derivative | |
| Gao et al. | Novel dual-target μ‑opioid and TRPV1 ligands as potential pharmacotherapeutics for pain management | |
| CN102040556B (en) | Optical isomers of indene quinazoline, preparation method and medicinal application thereof | |
| CN103159754A (en) | Amino propyl replacing tropane amine compound, medical composition thereof, preparation method and purpose thereof | |
| Wentland et al. | Redefining the structure–activity relationships of 2, 6-methano-3-benzazocines. Part 6: Opioid receptor binding properties of cyclic variants of 8-carboxamidocyclazocine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: Tong Xiang, Gulou District of Nanjing city of Jiangsu Province, No. 24 210009 Patentee after: CHINA PHARMACEUTICAL University Address before: 211200 Kechuang Center, 688 Tianshengqiao Avenue, Yongyang Town, Lishui County, Nanjing City, Jiangsu Province Patentee before: CHINA PHARMACEUTICAL University |