CN103420980A - Dabigatran derivatives - Google Patents
Dabigatran derivatives Download PDFInfo
- Publication number
- CN103420980A CN103420980A CN2012101586001A CN201210158600A CN103420980A CN 103420980 A CN103420980 A CN 103420980A CN 2012101586001 A CN2012101586001 A CN 2012101586001A CN 201210158600 A CN201210158600 A CN 201210158600A CN 103420980 A CN103420980 A CN 103420980A
- Authority
- CN
- China
- Prior art keywords
- och
- dabigatran
- methyl
- carbonyl
- amino
- 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.)
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- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical class N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 230000003287 optical effect Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 230000010100 anticoagulation Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 3
- 229910052799 carbon Inorganic materials 0.000 abstract 3
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 230000014508 negative regulation of coagulation Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 29
- 239000001301 oxygen Substances 0.000 description 24
- 229910052760 oxygen Inorganic materials 0.000 description 24
- 229960003850 dabigatran Drugs 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 16
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 229940000635 beta-alanine Drugs 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- -1 amino hexyl Chemical group 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 229960000288 dabigatran etexilate Drugs 0.000 description 5
- IDWUSJOEYZAKSW-UHFFFAOYSA-N 3-(pyridin-1-ium-2-ylamino)propanoate Chemical compound OC(=O)CCNC1=CC=CC=N1 IDWUSJOEYZAKSW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 229940122388 Thrombin inhibitor Drugs 0.000 description 4
- 231100000956 nontoxicity Toxicity 0.000 description 4
- 239000003868 thrombin inhibitor Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- UITNIDFEANEWPC-UHFFFAOYSA-N ethyl 3-(pyridin-2-ylamino)propanoate Chemical compound CCOC(=O)CCNC1=CC=CC=N1 UITNIDFEANEWPC-UHFFFAOYSA-N 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 2
- ZOAMZFNAPHWBEN-UHFFFAOYSA-N 2-$l^{1}-oxidanylpropane Chemical compound CC(C)[O] ZOAMZFNAPHWBEN-UHFFFAOYSA-N 0.000 description 2
- FTINTRPSAYYLMB-UHFFFAOYSA-N 2-amino-4-methyl-3-nitrobenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(N)=C1[N+]([O-])=O FTINTRPSAYYLMB-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MLRVZFYXUZQSRU-UHFFFAOYSA-N 1-chlorohexane Chemical compound CCCCCCCl MLRVZFYXUZQSRU-UHFFFAOYSA-N 0.000 description 1
- IJDRTYIIAPJELW-UHFFFAOYSA-N 2-chloroethyl cyclohexyl carbonate Chemical compound ClCCOC(=O)OC1CCCCC1 IJDRTYIIAPJELW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- ILUWVORABZTBIU-UHFFFAOYSA-N chloromethyl 2-methylpropanoate Chemical compound CC(C)C(=O)OCCl ILUWVORABZTBIU-UHFFFAOYSA-N 0.000 description 1
- GDUQVLASZBFABN-UHFFFAOYSA-N chloromethyl 3-methylbutanoate Chemical compound CC(C)CC(=O)OCCl GDUQVLASZBFABN-UHFFFAOYSA-N 0.000 description 1
- SMJYMSAPPGLBAR-UHFFFAOYSA-N chloromethyl acetate Chemical compound CC(=O)OCCl SMJYMSAPPGLBAR-UHFFFAOYSA-N 0.000 description 1
- DKXDLGITOKUSLC-UHFFFAOYSA-N chloromethyl cyclohexyl carbonate Chemical compound ClCOC(=O)OC1CCCCC1 DKXDLGITOKUSLC-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- HOFHLRCDGWSLHX-UHFFFAOYSA-N clamoxyquine Chemical compound C1=CC=NC2=C(O)C(CNCCCN(CC)CC)=CC(Cl)=C21 HOFHLRCDGWSLHX-UHFFFAOYSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention aims to provide dabigatran derivatives, which are presented by the formula I with anticoagulant activity, optical isomers, and medicinal salts thereof. R1 represents H or alkyl group with a carbon number between 1 and 3, R2 represents R3 or -OR3, and R3 represents an alkyl group with a carbon number between 1 and 8 or a naphthenic group with a carbon number between 3 and 8.
Description
Technical field
The present invention relates to derivative and the non-toxicity pharmacy acceptable salt thereof of new dabigatran, and contain the pharmaceutical composition of these compounds as activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Background technology
Dabigatran (Dabigatran) is a kind of optionally high performance thrombin inhibitor.But due to the existence of strong basicity amidino groups, oral can not the absorption.For improving its bioavailability, respectively the free carboxy in the dabigatran molecule is become to ethyl ester, amidino groups becomes amino hexyl formate, obtains its bi precursor medicine dabigatran dibasic acid esters (Dabigatran Etexilate).After the dabigatran dibasic acid esters is oral, from gastrointestinal absorption, then be converted in vivo the dabigatran of activity form, the performance blood coagulation resisting function.The dabigatran dibasic acid esters, in listing in 2008, becomes first oral thrombin inhibitors, for deep vein thrombosis after preventing artificial joint replacement, forms and pulmonary embolism.But the oral administration biaavailability of dabigatran dibasic acid esters (6.5%) still remains further to be improved.
Summary of the invention
The present invention relates to ester derivative and non-toxicity pharmacy acceptable salt thereof by the dabigatran shown in structural formula I, and contain the pharmaceutical composition of these compounds as activeconstituents, and described compound and pharmaceutical composition are as the purposes of anaesthetic.
First aspect of the present invention provides dabigatran derivative and optical isomer and the pharmacologically acceptable salt thereof of formula I representative:
Wherein, R
1Represent H, or C
1-C
3Alkyl; R
2Represent R
3Or-OR
3R
3Represent C
1-C
8Alkyl or C
3-C
8Cycloalkyl.
Each substituting group of objectives compound is defined as follows respectively:
I
1: R
1For H, R
2For-CH
3
I
2: R
1For H, R
2For-CH
2CH
3
I
3: R
1For H, R
2For-CH
2CH
2CH
3
I
4: R
1For H, R
2For-CH (CH
3)
2
I
5: R
1For H, R
2For-C (CH
3)
3
I
6: R
1For H, R
2For-CH (CH
3) CH
2CH
3
I
7: R
1For H, R
2For-CH
2CH (CH
3) CH
3
I
8: R
1For H, R
2For-CH
2CH
2CH
2CH
3
I
9: R
1For H, R
2For
I
10: R
1For H, R
2For
I
11: R
1For H, R
2For
I
12: R
1For H, R
2For
I
13: R
1For CH
3, R
2For-CH
3
I
14: R
1For CH
3, R
2For-CH
2CH
3
I
15: R
1For CH
3, R
2For-CH
2CH
2CH
3
I
16: R
1For CH
3, R
2For-CH (CH
3)
2
I
17: R
1For CH
3, R
2For-C (CH
3)
3
I
18: R
1For CH
3, R
2For-CH (CH
3) CH
2CH
3
I
19: R
1For CH
3, R
2For-CH
2CH (CH
3) CH
3
I
20: R
1For CH
3, R
2For-CH
2CH
2CH
2CH
3
I
21: R
1For CH
3, R
2For
I
22: R
1For CH
3, R
2For
I
23: R
1For CH
3, R
2For
I
24: R
1For CH
3, R
2For
I
25: R
1For H, R
2For-OCH
3
I
26: R
1For H, R
2For-OCH
2CH
3
I
27: R
1For H, R
2For-OCH
2CH
2CH
3
I
28: R
1For H, R
2For-OCH (CH
3)
2
I
29: R
1For H, R
2For-OC (CH
3)
3
I
30: R
1For H, R
2For-OCH (CH
3) CH
2CH
3
I
31: R
1For H, R
2For-OCH
2CH (CH
3) CH
3
I
32: R
1For H, R
2For-OCH
2CH
2CH
2CH
3
I
33: R
1For H, R
2For
I
34: R
1For H, R
2For
I
35: R
1For H, R
2For
I
36: R
1For H, R
2For
I
37: R
1For CH
3, R
2For-OCH
3
I
38: R
1For CH
3, R
2For-OCH
2CH
3
I
39: R
1For CH
3, R
2For-OCH
2CH
2CH
3
I
40: R
1For CH
3, R
2For-OCH (CH
3)
2
I
41: R
1For CH
3, R
2For-OC (CH
3)
3
I
42: R
1For CH
3, R
2For-OCH (CH
3) CH
2CH
3
I
43: R
1For CH
3, R
2For-OCH
2CH (CH
3) CH
3
I
44: R
1For CH
3, R
2For-OCH
2CH
2CH
2CH
3
I
45: R
1For CH
3, R
2For
I
46: R
1For CH
3, R
2For
I
47: R
1For CH
3, R
2For
I
48: R
1For CH
3, R
2For
Second aspect of the present invention relates to pharmaceutical composition, and it comprises derivative and pharmacologically acceptable salt and one or more pharmaceutically acceptable carrier or the vehicle of the dabigatran of at least one formula I representative.
The 3rd aspect of the present invention relates to derivative and the non-toxicity pharmacy acceptable salt thereof of the dabigatran shown in formula I, and the derivative that comprises the dabigatran shown in formula I and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents the purposes as anticoagulation.
The compound of formula I representative can form pharmaceutical salts with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts with organic acid, such as acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc.Selecting and preparing suitable salt is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, such as hydrate, alcohol adduct etc.; Selecting and preparing suitable solvate is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.
Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they are conducive to active compound is processed into to the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can be manufactured according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows while having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared for administered parenterally or transdermal administration or mucosal.Perhaps adopt the mode administration of suppository or implants.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system (MS) to obtain more favourable effect.
It may be noted that in addition, the compounds of this invention using dosage and using method depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.
Embodiment
The following examples can conduct further description the present invention, yet these embodiment should be as the restriction to scope of the present invention.
At first, reference literature (Hauel NH, Nar H, Priepke H, et al.Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors.J.Med.Chem.2002; 45:1757-1766) the synthetic dabigatran dibasic acid esters (Dabigatran Etexilate) of method:
The 3-nitro-4-methyl amino-phenylformic acid of take is starting raw material, with sulfur oxychloride, reacts, and becomes acyl chlorides (intermediate 2); Intermediate 2 reacts with N-(pyridine-2-yl)-Beta-alanine ethyl ester, obtains intermediate 4; By the nitro of intermediate 4, under palladium-charcoal effect, catalytic hydrogenation obtains intermediate 5; (4-cyano group-phenyl amino) acetic acid first reacts with carbonyl dimidazoles, then reacts with intermediate 5, obtains intermediate 7; By intermediate 7 and hcl reaction, then, with the volatile salt alkalization, the ethyl ester derivative 8,8 that obtains dabigatran reacts with the own ester of chloroformic acid, obtains dabigatran dibasic acid esters (Dabigatran Etexilate).
The dabigatran dibasic acid esters is hydrolyzed with LiOH, obtains carboxylic acid derivative 9,9 and react with chloro thing 10, obtain target compound:
Wherein, R
1Represent H, or C
1-C
3Alkyl; R
2Represent R
3Or-OR
3R
3Represent C
1-C
8Alkyl or C
3-C
8Cycloalkyl.
Reference example 1N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-preparation of N-(pyridine-2-yl)-Beta-alanine ethyl ester (dabigatran dibasic acid esters)
40 grams (0.2mol) 3-nitro-4-methyl amino-phenylformic acid is added in the 400mL sulfur oxychloride, add the 0.2mL dimethyl formamide, back flow reaction 0.5h, vacuum concentration, obtain 3-nitro-4-methyl amino-Benzoyl chloride (intermediate 2), be dissolved in the 300mL tetrahydrofuran (THF).
37 grams (0.2mol) N-(pyridine-2-yl)-Beta-alanine ethyl ester and 60mL triethylamine are dissolved in the 500mL tetrahydrofuran (THF), at room temperature drip the tetrahydrofuran solution of intermediate 2.After adding, room temperature reaction spends the night, vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of ethanol (99: 1) obtains 41 gram intermediates 4.
33.4 grams (89.4mmol) intermediate 4 is dissolved in to 400mL ethanol, adds palladium-charcoal 1 gram of 10%, room temperature hydrogenation, remove by filter palladium-charcoal, by the filtrate vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (30: 1) obtains 21 gram intermediates 5.
12.8g (73mmol) (4-cyano group-phenyl amino) acetic acid and 11.8 grams (73mmol) carbonyl dimidazoles are added in the 300mL tetrahydrofuran (THF) to 50 ℃ of stirring reaction 30min.Then, add 21 gram intermediates 5, back flow reaction 24h in this solution.Vacuum concentration, be dissolved in residue in the 150mL glacial acetic acid, and reflux 1h, by 500mL water dilution for this solution, neutralizes with strong aqua.By ethyl acetate, extract, by the extracting solution vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (40: 1) obtains 18 gram N-{[2-(((4-cyano group-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 7).
18 gram intermediates 7 are dissolved in 800mL ethanol, are cooled to 0 ℃, logical anhydrous hydrogen chloride gas 2h, then stirring at room 5h.By the solvent evaporated in vacuo, then residue is dissolved in to 600mL ethanol, add 40 gram volatile salts, stirred overnight at room temperature.By the reaction solution vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (5: 1) obtains 13 gram N-{[2-(((4-amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 8).
1H?NMR?δ(ppm，DMSO-d
6)：1.14(t，3H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.42(m，1H)，8.55-9.28(bs，3H)。
12.0g (22.3mmol) intermediate 8 is dissolved in the solvent mixture of 500mL tetrahydrofuran (THF) and 100mL water, adds 10g salt of wormwood (72mmol), stirring at room 20min.Add the n-hexyl chloride manthanoate of 3.72g (22.3mmol), continue to stir 2h.Vacuum is steamed and is desolventized, and adds the 500ml saturated brine, uses dichloromethane extraction 3 times, 180ml/ time; United extraction liquid, use anhydrous sodium sulfate drying; Vacuum is steamed and is desolventized, and residue is separated with silica gel column chromatography, and use methylene dichloride: ethanol (95: 5) wash-out obtains target compound 9.1g, mp 128-130 ℃.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.16(t，3H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(m，4H)，4.25(t，2H)，4.62(d，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 1N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-preparation of N-(pyridine-2-yl)-Beta-alanine (9)
By 9g dabigatran etcxilate 250ml dissolve with methanol, stirring at room, add 80ml to contain the aqueous solution of 3.6g LiOH, stirs 60 minutes.Add 150ml water, the dilute hydrochloric acid neutralization with 1N, have solid to separate out.Filter, by solid drying, obtain target compound 97.4g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)，12.15(s，1H)。
Embodiment 2N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine acetyl-o-methyl ester (I
1) preparation
0.4g intermediate 9 use 8ml DMF are dissolved, logical drying nitrogen, stirring at room, add the 0.3ml triethylamine.Stir the lower 0.1ml of dropping chloromethyl acetate, gradually be warming up to 50 ℃ after adding, stirring reaction 5 hours.Remove solvent under reduced pressure, by residue 50ml acetic acid ethyl dissolution, washing; Organic layer is spent the night with anhydrous sodium sulfate drying.Filter, remove organic solvent under reduced pressure, residue is separated with silica gel column chromatography, with methylene dichloride: methyl alcohol (30: 1) mixed solvent wash-out, collect required component, evaporated under reduced pressure, obtain target compound I
10.25g.
1HNMRδ(ppm，DMSO-d
6)：0.89(t，3H)，1.31(m，6H)，1.60(m，2H)，2.23(s，3H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 3N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isobutyl acyl-oxygen methyl ester (I
4) preparation
With reference to the method for embodiment 2,0.4g intermediate 9 is reacted with the isopropylformic acid chloromethyl ester, with silica gel column chromatography, separate, obtain target compound I
40.28g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.14(d，6H)，1.31(m，6H)，1.60(m，2H)，2.53(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 4N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine pivaloyl oxygen methyl ester (I
5) preparation
With reference to the method for embodiment 2, intermediate 9 is reacted with chloromethyl pivalate, with silica gel column chromatography, separate, obtain target compound I
50.22g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.23(s，9H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 5N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isoamyl acyl-oxygen methyl ester (I
6) preparation
With reference to the method for embodiment 2, intermediate 9 is reacted with the isovaleric acid chloromethyl ester, with silica gel column chromatography, separate, obtain target compound I
60.21g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.02(t，3H)，1.21(d，3H)，1.25(m，2H)，1.31(m，6H)，1.60(m，2H)，2.59(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 6N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine cyclohexanecarbonyl oxygen methyl ester (I
12) preparation
With reference to the method for embodiment 2, intermediate 9 is reacted with the heptanaphthenic acid chloromethyl ester, with silica gel column chromatography, separate, obtain target compound I
120.20g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.31(m，6H)，1.32-1.41(m，6H)，1.60(m，2H)，1.66(m，2H)，1.91(m，2H)，2.25(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 7N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isobutyl acyl-oxygen ethyl ester (I
16) preparation
With reference to the method for embodiment 2,0.4g intermediate 9 is reacted with isopropylformic acid chloroethene ester, with silica gel column chromatography, separate, obtain target compound I
160.19g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.16(t，3H)，1.31(m，6H)，1.33(d，2H)，1.60(m，2H)，2.53(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.65(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 8N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine pivaloyl oxygen ethyl ester (I
17) preparation
With reference to the method for embodiment 2,0.4g intermediate 9 is reacted with trimethylacetic acid chloroethene ester, with silica gel column chromatography, separate, obtain target compound I
170.17g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.23(s，9H)，1.31(m，6H)，1.33(d，2H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.66(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 9N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isopropyl oxygen ketonic oxygen methyl ester (I
28) preparation
0.4g intermediate 9 use 8ml DMF are dissolved, logical drying nitrogen, stirring at room, add the 0.3ml triethylamine.Stir the lower 0.13ml of dropping chloromethyl sec.-propyl carbonic ether, gradually be warming up to 60 ℃ after adding, stirring reaction 5 hours.Remove solvent under reduced pressure, by residue 50ml acetic acid ethyl dissolution, washing; Organic layer is spent the night with anhydrous sodium sulfate drying.Filter, remove organic solvent under reduced pressure, residue is separated with silica gel column chromatography, with methylene dichloride: methyl alcohol (30: 1) mixed solvent wash-out, collect required component, evaporated under reduced pressure, obtain target compound I
280.29g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.19(d，6H)，1.31(m，6H)，1.60(m，2H)，2.23(s，3H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，4.79(m，1H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 10N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine hexamethylene oxygen ketonic oxygen methyl ester (I
36) preparation
With reference to the method for embodiment 9, by 0.4g intermediate 9 and chloromethyl cyclohexyl carbonate reaction, with silica gel column chromatography, separate, obtain target compound I
360.18g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.31(m，6H)，1.32-1.41(m，6H)，1.60(m，2H)，1.66(m，2H)，1.91(m，2H)，4.35(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.61(s，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 11N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine isopropyl oxygen ketonic oxygen ethyl ester (I
40) preparation
With reference to the method for embodiment 9, by 0.4g intermediate 9 and chloroethyl sec.-propyl carbonate reaction, with silica gel column chromatography, separate, obtain target compound I
400.20g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.19(d，6H)，1.31(m，6H)，1.33(d，2H)，1.60(m，2H)，2.23(s，3H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，4.79(m，1H)，5.66(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
Embodiment 12N-{[2-(((the own oxygen carbonyl-amidino groups of 4-N--phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine hexamethylene oxygen ketonic oxygen ethyl ester (I
48) preparation
With reference to the method for embodiment 9, by 0.4g intermediate 9 and chloroethyl cyclohexyl carbonate reaction, with silica gel column chromatography, separate, obtain target compound I
480.13g.
1H?NMR?δ(ppm，DMSO-d
6)：0.89(t，3H)，1.31(m，6H)，1.32-1.41(m，9H)，1.60(m，2H)，1.66(m，2H)，1.91(m，2H)，4.35(m，1H)，2.71(t，2H)，3.79(s，3H)，3.98(t，2H)，4.25(t，2H)，4.62(d，2H)，5.65(m，1H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(m，1H)，8.50-9.30(bs，2H)。
The evaluation of embodiment 13 anticoagulating actives
27.1 the mensuration of activated partial thromboplastin time (aPTT)
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate (Dabigatran Etexilate) and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/ml, dosage (amounting to into dabigatran calculates) gastric infusion by 5mg/kg, pass through heart puncturing extracting blood after half an hour, add 4% liquor sodii citratis to 0.4% final concentration anti-freezing, centrifugal 5 minutes of 12000r/min, get blood plasma 0.1ml, add aPTT reagent (Shanghai medical electric company limited product) 0.1ml, 37 ℃ of pre-temperature are after 3 minutes, the calcium chloride solution 0.1mL that adds 37 ℃ of pre-temperature, measure setting time with platelet aggregation thrombin analyser (Puli gives birth to the PLSC2000-4 type), be the aPTT value.The results are shown in Table 1.
The measurement result of table 1 activated partial thromboplastin time (aPTT)
27.2 the mensuration in bleeding time
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate (Dabigatran Etexilate) and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/ml, by dosage (amounting to into the dabigatran calculates) gastric infusion of 5mg/kg, after half an hour.Animal is fixed, make tail be dipped in 2min in the physiological saline of 37 ℃, then at distance tail end 2mm place, cut off the mouse tail, again immerse immediately in the physiological saline of 37 ℃, take and stop hemorrhagely continuing 30 seconds as the judgement terminal, measure the bleeding time.The results are shown in Table 2.
The measurement result in table 2 bleeding time
Claims (4)
1. the dabigatran derivative of formula I representative and optical isomer and pharmacologically acceptable salt thereof:
Wherein, R
1Represent H, or C
1-C
3Alkyl; R
2Represent R
3Or-OR
3R
3Represent C
1-C
8Alkyl or C
3-C
8Cycloalkyl.
2. according to the compound of claim 1, be selected from:
I
1: R
1For H, R
2For-CH
3
I
2: R
1For H, R
2For-CH
2CH
3
I
3: R
1For H, R
2For-CH
2CH
2CH
3
I
4: R
1For H, R
2For-CH (CH
3)
2
I
5: R
1For H, R
2For-C (CH
3)
3
I
6: R
1For H, R
2For-CH (CH
3) CH
2CH
3
I
7: R
1For H, R
2For-CH
2CH (CH
3) CH
3
I
8: R
1For H, R
2For-CH
2CH
2CH
2CH
3
I
9: R
1For H, R
2For
I
10: R
1For H, R
2For
I
11: R
1For H, R
2For
I
12: R
1For H, R
2For
I
13: R
1For CH
3, R
2For-CH
3
I
14: R
1For CH
3, R
2For-CH
2CH
3
I
15: R
1For CH
3, R
2For-CH
2CH
2CH
3
I
16: R
1For CH
3, R
2For-CH (CH
3)
2
I
17: R
1For CH
3, R
2For-C (CH
3)
3
I
18: R
1For CH
3, R
2For-CH (CH
3) CH
2CH
3
I
19: R
1For CH
3, R
2For-CH
2CH (CH
3) CH
3
I
20: R
1For CH
3, R
2For-CH
2CH
2CH
2CH
3
I
21: R
1For CH
3, R
2For
I
22: R
1For CH
3, R
2For
I
23: R
1For CH
3, R
2For
I
24: R
1For CH
3, R
2For
I
25: R
1For H, R
2For-OCH
3
I
26: R
1For H, R
2For-OCH
2CH
3
I
27: R
1For H, R
2For-OCH
2CH
2CH
3
I
28: R
1For H, R
2For-OCH (CH
3)
2
I
29: R
1For H, R
2For-OC (CH
3)
3
I
30: R
1For H, R
2For-OCH (CH
3) CH
2CH
3
I
31: R
1For H, R
2For-OCH
2CH (CH
3) CH
3
I
32: R
1For H, R
2For-OCH
2CH
2CH
2CH
3
I
33: R
1For H, R
2For
I
34: R
1For H, R
2For
I
35: R
1For H, R
2For
I
36: R
1For H, R
2For
I
37: R
1For CH
3, R
2For-OCH
3
I
38: R
1For CH
3, R
2For-OCH
2CH
3
I
39: R
1For CH
3, R
2For-OCH
2CH
2CH
3
I
40: R
1For CH
3, R
2For-OCH (CH
3)
2
I
41: R
1For CH
3, R
2For-OC (CH
3)
3
I
42: R
1For CH
3, R
2For-OCH (CH
3) CH
2CH
3
I
43: R
1For CH
3, R
2For-OCH
2CH (CH
3) CH
3
I
44: R
1For CH
3, R
2For-OCH
2CH
2CH
2CH
3
I
45: R
1For CH
3, R
2For
I
46: R
1For CH
3, R
2For
I
47: R
1For CH
3, R
2For
I
48: R
1For CH
3, R
2For
3. contain the pharmaceutical composition that the described compound of claim 1～2 and atoxic pharmacy acceptable salt thereof form as activeconstituents and suitable excipient.These pharmaceutical compositions can be solution, tablet, capsule or injection; These pharmaceutical compositions can pass through injection administration or oral administration.
4. the described compound of claim 1～2 and atoxic pharmacy acceptable salt thereof, and contain the described compound of claim 1～6 and atoxic pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents the purposes as anticoagulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101586001A CN103420980A (en) | 2012-05-22 | 2012-05-22 | Dabigatran derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101586001A CN103420980A (en) | 2012-05-22 | 2012-05-22 | Dabigatran derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103420980A true CN103420980A (en) | 2013-12-04 |
Family
ID=49646404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101586001A Pending CN103420980A (en) | 2012-05-22 | 2012-05-22 | Dabigatran derivatives |
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| Country | Link |
|---|---|
| CN (1) | CN103420980A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130185A (en) * | 2014-07-01 | 2014-11-05 | 蚌埠丰原医药科技发展有限公司 | Method for preparing pradaxa intermediate |
| CN104356111A (en) * | 2014-10-14 | 2015-02-18 | 蚌埠丰原医药科技发展有限公司 | Method for preparing dabigatran etexilate hydrolysis impurities |
| CN104892501A (en) * | 2015-05-27 | 2015-09-09 | 上海应用技术学院 | Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate |
| WO2016019849A1 (en) * | 2014-08-06 | 2016-02-11 | 四川海思科制药有限公司 | Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof |
| TWI682928B (en) * | 2015-04-27 | 2020-01-21 | 大陸商四川海思科製藥有限公司 | Dabigatran alkyl ester derivative, its preparation method and use in pharmacy |
| CN111793058A (en) * | 2019-04-09 | 2020-10-20 | 鲁南制药集团股份有限公司 | Improved method for preparing dabigatran etexilate intermediate |
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| CN102050815A (en) * | 2009-11-06 | 2011-05-11 | 北京美倍他药物研究有限公司 | Dabigatran ester derivatives as prodrug |
| CN102391250A (en) * | 2011-08-29 | 2012-03-28 | 石药集团欧意药业有限公司 | Dabigatran compound and preparation method and medicinal composition thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130185A (en) * | 2014-07-01 | 2014-11-05 | 蚌埠丰原医药科技发展有限公司 | Method for preparing pradaxa intermediate |
| WO2016019849A1 (en) * | 2014-08-06 | 2016-02-11 | 四川海思科制药有限公司 | Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof |
| CN106536505A (en) * | 2014-08-06 | 2017-03-22 | 四川海思科制药有限公司 | Dabigatran carboalkoxy derivative, preparation method therefor, and pharmaceutical use thereof |
| CN104356111A (en) * | 2014-10-14 | 2015-02-18 | 蚌埠丰原医药科技发展有限公司 | Method for preparing dabigatran etexilate hydrolysis impurities |
| TWI682928B (en) * | 2015-04-27 | 2020-01-21 | 大陸商四川海思科製藥有限公司 | Dabigatran alkyl ester derivative, its preparation method and use in pharmacy |
| CN104892501A (en) * | 2015-05-27 | 2015-09-09 | 上海应用技术学院 | Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate |
| CN111793058A (en) * | 2019-04-09 | 2020-10-20 | 鲁南制药集团股份有限公司 | Improved method for preparing dabigatran etexilate intermediate |
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