JP5997762B2 - 心血管疾患の治療における3−カルボキシ−n−エチル−n,n−ジメチルプロパン−1−アミニウム塩の使用 - Google Patents
心血管疾患の治療における3−カルボキシ−n−エチル−n,n−ジメチルプロパン−1−アミニウム塩の使用 Download PDFInfo
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- JP5997762B2 JP5997762B2 JP2014506893A JP2014506893A JP5997762B2 JP 5997762 B2 JP5997762 B2 JP 5997762B2 JP 2014506893 A JP2014506893 A JP 2014506893A JP 2014506893 A JP2014506893 A JP 2014506893A JP 5997762 B2 JP5997762 B2 JP 5997762B2
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- ethyl
- carboxy
- dimethylpropane
- aminium
- dimethyl
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- ISMYCKWHOZKHNJ-UHFFFAOYSA-N 4-[ethyl(dimethyl)azaniumyl]butanoate Chemical class CC[N+](C)(C)CCCC([O-])=O ISMYCKWHOZKHNJ-UHFFFAOYSA-N 0.000 title claims description 34
- 208000024172 Cardiovascular disease Diseases 0.000 title description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- MGZVXKHMPJQTMB-UHFFFAOYSA-M (4-ethoxy-4-oxobutyl)-ethyl-dimethylazanium;bromide Chemical compound [Br-].CCOC(=O)CCC[N+](C)(C)CC MGZVXKHMPJQTMB-UHFFFAOYSA-M 0.000 claims description 15
- DQSCWIHGBKJVRY-UHFFFAOYSA-N 3-carboxypropyl-ethyl-dimethylazanium;dihydrogen phosphate Chemical compound OP(O)([O-])=O.CC[N+](C)(C)CCCC(O)=O DQSCWIHGBKJVRY-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 claims description 8
- PPDPFXLNXLDRNM-WLHGVMLRSA-N (e)-but-2-enedioate;3-carboxypropyl-ethyl-dimethylazanium;hydron Chemical compound OC(=O)\C=C\C([O-])=O.CC[N+](C)(C)CCCC(O)=O PPDPFXLNXLDRNM-WLHGVMLRSA-N 0.000 claims description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- -1 3-carboxy-N-ethyl-N, N-dimethylpropane-1-aminium dihydrogen phosphate 3-Carboxy-N-ethyl-N, N-dimethylpropane-1-aminium salt Chemical compound 0.000 claims description 6
- 239000003456 ion exchange resin Substances 0.000 claims description 6
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- DRMIOPJGPNKEQL-UHFFFAOYSA-N 3-carboxypropyl-ethyl-dimethylazanium;2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical compound CC[N+](C)(C)CCCC(O)=O.[O-]C(=O)C1=CC(=O)NC(=O)N1 DRMIOPJGPNKEQL-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims 3
- 239000001530 fumaric acid Substances 0.000 claims 1
- 229960005010 orotic acid Drugs 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- JHPNVNIEXXLNTR-UHFFFAOYSA-N 4-(trimethylammonio)butanoate Chemical compound C[N+](C)(C)CCCC([O-])=O JHPNVNIEXXLNTR-UHFFFAOYSA-N 0.000 description 28
- 208000010125 myocardial infarction Diseases 0.000 description 18
- 206010061216 Infarction Diseases 0.000 description 16
- 230000007574 infarction Effects 0.000 description 15
- JFWLFLLRLZSBRA-UHFFFAOYSA-N 3-[(trimethylazaniumyl)amino]propanoate;dihydrate Chemical compound O.O.C[N+](C)(C)NCCC([O-])=O JFWLFLLRLZSBRA-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 9
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 6
- 230000003293 cardioprotective effect Effects 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- RGELZKZTNZWGFO-UHFFFAOYSA-N 3-carboxypropyl-ethyl-dimethylazanium;4-hydroxy-4-oxobutanoate Chemical compound OC(=O)CCC([O-])=O.CC[N+](C)(C)CCCC(O)=O RGELZKZTNZWGFO-UHFFFAOYSA-N 0.000 description 5
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 5
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- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 3
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 3
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- 238000002474 experimental method Methods 0.000 description 3
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 3
- 230000001338 necrotic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 0 C*c1c(*=C)cccc1 Chemical compound C*c1c(*=C)cccc1 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 description 2
- 229960002937 meldonium Drugs 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
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- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- PERYPNLSKBMHJJ-TYYBGVCCSA-N (e)-but-2-enedioic acid;propan-1-amine Chemical compound CCCN.OC(=O)\C=C\C(O)=O PERYPNLSKBMHJJ-TYYBGVCCSA-N 0.000 description 1
- YILYLUWROZODCU-WLHGVMLRSA-N 1-carboxypropyl-ethyl-dimethylazanium (E)-4-hydroxy-4-oxobut-2-enoate Chemical compound OC(=O)\C=C\C([O-])=O.CCC(C(O)=O)[N+](C)(C)CC YILYLUWROZODCU-WLHGVMLRSA-N 0.000 description 1
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- YXUZGLGRBBHYFZ-UHFFFAOYSA-N 2,4-dioxo-1h-pyrimidine-6-carboxylic acid;hydrate Chemical compound O.OC(=O)C1=CC(=O)NC(=O)N1 YXUZGLGRBBHYFZ-UHFFFAOYSA-N 0.000 description 1
- OXOWTLDONRGYOT-UHFFFAOYSA-N 4-(dimethylamino)butanoic acid Chemical compound CN(C)CCCC(O)=O OXOWTLDONRGYOT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229940122224 Gamma butyrobetaine hydroxylase inhibitor Drugs 0.000 description 1
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- 206010019280 Heart failures Diseases 0.000 description 1
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 1
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
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- 125000000656 azaniumyl group Chemical group [H][N+]([H])([H])[*] 0.000 description 1
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- 238000004364 calculation method Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
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- 210000000748 cardiovascular system Anatomy 0.000 description 1
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- 230000037213 diet Effects 0.000 description 1
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- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
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- 229930195729 fatty acid Natural products 0.000 description 1
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- 150000004665 fatty acids Chemical class 0.000 description 1
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- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical group C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
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- 230000005923 long-lasting effect Effects 0.000 description 1
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- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical class CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
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- 208000026451 salivation Diseases 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-M succinate(1-) Chemical compound OC(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
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Description
− 英国特許第1238868号明細書(1971年7月14日)において、4−トリメチルアンモニオブタノアートのような、ポリマーに使用されるベタインが開示された。しかしながら、これらのベタインの薬理学的特性は示されなかった。
− 米国特許第5973026号明細書(XEROX CORP)(1999年10月26日)において、インク組成物への使用のための、4−トリメチルアンモニオブタノアートおよび3−[ジエチル(メチル)アンモニオ]プロピオナートが開示された。
− LLOYD ANDREWら、A comparison of glycine,sarcosine,N,N−dimethylglycine,glycinebetaine and N−modified betaines as liposome cryoprotectants.Journal of pharmacy and pharmacology.1992年、第44巻、第6号、第507〜511ページにおいて、リポソーム用の抗凍結剤として使用される2−[エチル(ジメチル)アンモニオ]アセタートが開示された。
− DAVID B.,THOMASら、Synthesis,Characterization,and Aqueous Solution Behavior of Electrolyte− and pH−Responsive Carboxybetaine−Containing Cyclocopolymers.Macromolecules.2003年、第36巻、第26号、第9710〜9715ページにおいて、4−[ジアリル(メチル)アンモニオ]ブタノアート、ならびにN,N−ジアリル−N−メチルアミニウムおよびエチル4−ブロモブタノアートから開始されるその合成が開示されている。遊離酸は、Amberliteイオン交換樹脂を用いる第二段階においてエステルから得られる。生成物は、ポリマーを合成するための中間体として使用される。
− Prelog V.1930年、第2巻、第712〜722ページにおいて、4−ジメチルアンモニオブタノアートおよびヨウ化メチルから開始される4−トリメチルアンモニオブタノアートの合成が開示された。
− 4−トリメチルアンモニオブタノアート、ならびにトリメチルアミンおよびエチル4−ブロモブタノアートから開始されるその合成が、特開第2009−096766号公報(甲南学園)(2009年5月7日)において記載された。遊離酸は、Amberliteイオン交換樹脂を用いる第二段階においてエステルから得られる。
− 国際公開第2008/055843号(KALVINSH IVARS;CHERNOBROVIJS ALEKSANDRS;VARACHEVA LARISA;PUGOVICHS OSVALDS)(2008年5月15日)において、4−トリメチルアンモニオブタノアート、および対応するエステルから開始されKOH溶液を使用する合成が記載された。
− 加国特許出願第2508094号明細書(VIVIER CANADA INC)(2006年11月20日)において、コラーゲン合成を促進するための薬剤として用いるための、4−トリメチルアンモニオブタノアートなどのベタインが開示された。
− 米国特許第5965615号明細書(大鵬薬品工業株式会社、VALSTS ZINATNISKA IESTADE BEZP)(1999年10月12日)において、心筋代謝障害の治療用の薬剤として4−トリメチルアンモニオブタノアートが開示され、同じ化合物が米国特許出願公開第2007/191381号明細書(CONCERT PHARMACEUTICALS INC)(2007年8月16日)において、心筋梗塞の治療用に開示された。
a)N,N−ジメチルエチルアミンを、適切な溶媒中のエチル4−ブロモブタノアート(1)に加えて、4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミド(2)を得る段階、
b)4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミド(2)を、イオン交換樹脂カラムに通して、4−[エチル(ジメチル)アンモニオ]ブタノアート(3)を得る段階、
c)2−(アセチルオキシ)安息香酸(4a)または(E)−ブテン二酸(4b)またはコハク酸(4c)または2,6−ジオキソ−1,2,3,6−テトラヒドロピリミジン−4−カルボン酸一水和物(4d)またはリン酸(4e)から選ばれる酸を、適切な溶媒中の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)に加えて、3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム塩(4)を得る段階。
工程A
アセトニトリル(70ml)中のエチル4−ブロモブタノアート(1)(20.0g、102.5mmol)の溶液に、N,N−ジメチルエチルアミン(15ml、139mmol)を加え、3日間、室温で撹拌した。反応混合物を蒸発させ、残留物をアセトン(50ml)で粉砕し、濾過し、エーテルで洗浄し、そして乾燥させて、26.051g(94.8%)の4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミドを得た。LCMS(ESI+,m/z):[M−Br-]+188、純度98.9%。
1H NMR(CDCl3,HMDSO)δ:1.26(t,J=7.2Hz,3H);1.44(t,J=7.4Hz,3H);2.00〜2.11(m,2H);2.52(t,J=6.6Hz,2H);3.40(s,6H);3.64〜3.73(m,2H);3.69(q,J=7.4Hz,2H);4.14(q,J=7.2Hz,2H)。
アセトン(70ml)中のエチル4−ブロモブタノアート(1)(19.5g、100mmol)の溶液に、N,N−ジメチルエチルアミン(15ml、139mmol)を加え、3日間、室温で撹拌した。反応混合物を濾過した。固形材料をアセトン、エーテルで洗浄し、そして乾燥させて、24.19g(90.2%)の表題化合物2を得た。濾液を蒸発させた。残留物(2.147g)をエーテルで粉砕し、乾燥させて、追加バッチ(0.962g、3.6%)の、主部分と同じ質の生成物2を得た。エーテル洗浄液の蒸発により、0.956g(4.9mmol、4.9%)の出発材料1を回収することができた。4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミド:LCMS(ESI+,m/z):[M−Br-]+188、純度98.4%。
水(10ml)中の4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミド(2)(12.00g、44.7mmol)の溶液を、エタノールでゆっくりと溶出する(約10滴/分)Amberlite(登録商標)IRA−410(OH)イオン交換樹脂カラム(250ml)に通した(TLCコントロール)。溶出液を蒸発させ、残留物(12g)を水(50ml)の中に溶解させた。この溶液にDOWEX(登録商標)50WX8イオン交換樹脂(5g)を加え、0.5時間、室温で撹拌した。反応混合物をセライト(1cm)を通して濾過し、溶出液を蒸発させた。残留物を、イソプロパノール、アセトニトリル、およびアセトンで共沸乾燥させた。得られた固形物をアセトン(10ml)で粉砕し、混合物を2時間、0℃に保った。沈殿物を濾過し、P2O5上で真空乾燥して、4.65g(65%)の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)を得た。
実測値:C51.36、H11.40、N7.34。
3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム 2−(アセチルオキシ)ベンゾアートを、水混合液の形状で調製した。つまり、約90%の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)(2.20g、12.44mmol)および2−(アセチルオキシ)−安息香酸(2.266g、12.57mmol)を容量フラスコの中に置き、100mlになるまで水で希釈した。混合物の内容物は、加熱によって溶解し、そして温度を下げることによって沈殿する。1H−NMRによると、沈殿した固形材料は、ほぼ純粋な2−(アセチルオキシ)−安息香酸から成る。
無水エタノール(10ml)中の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)(2.0g、12.56mmol)の溶液に、エタノール(50ml)中の(E)−ブテン二酸(1.46g、12.56mmol)の熱溶液(60℃)を加えた。反応混合物を、2時間、室温に置き、沈殿した結晶を濾過し、そしてP2O5上で乾燥させて、2.98g(85%)の3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム(2E)−3−カルボキシアクリラートを得た。M.p.122〜123℃。
実測値:C51.52、H7.35、N4.61。
3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム 3−カルボキシプロパノアートを、水溶液の形状で調製した。つまり、約90%の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)(2.20g、12.44mmol)およびコハク酸(1.49g、12.62mmol)を容量フラスコの中に置き、溶解させ、100mlになるまで水で希釈した。
イソプロパノール(100ml)中の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)(2.0g、12.56mmol)の溶液に、2,6−ジオキソ−1,2,3,6−テトラヒドロピリミジン−4−カルボン酸一水和物(2.187g、12.56mmol)を加え、そして反応混合物を、すべてのカルボン酸が溶解するまで加熱還流した。反応混合物を室温まで冷却させ、沈殿した結晶を濾過し、イソプロパノール(5ml)およびジエチルエーテル(20ml)で洗浄し、そしてP2O5上で乾燥させて、3.238g(97.4%)の3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム2,6−ジオキソ−1,2,3,6−テトラヒドロピリミジン−4−カルボキシラートを得た。M.p.150.7℃。
実測値:C49.59、H6.69、N13.26。
水(10ml)中の4−[エチル(ジメチル)アンモニオ]ブタノアート(3)(6.4g、40mmol)の溶液に、アセトン(10ml)中の85%H3PO4(4.73g、40mmol)の水溶液を加え、得られた溶液を、10分間、室温で撹拌した。反応混合物を、45℃でロータリーエバポレーターによって蒸発させ、アセトンで数回共沸乾燥させた。得られた白い結晶物質をP2O5上で乾燥させて、9.82g(95%)の3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウムジヒドロゲンホスファートを得た。M.p.110〜135℃。
実測値:C36.20、H7.72、N5.11。
実測値:C37.52、H7.85、N5.39。
体重200〜250gの、50頭のオスの10週齢のウィスターラットを、飼料(R3規定食、LactaminAB、スウェーデン)および水を自由摂取にして、標準条件下(21〜23℃、12時間の明/暗サイクル)で飼育した。
単離ラット心臓の実験を、基本的に、先に記載されたように行った(Liepinshら,J.Cardiovasc.Pharmacol.2006;48(6):314〜9)。最後の投薬の24時間後、心臓を摘出し、37℃で、酸素を含んだクレブス−ヘンゼライト緩衝液を用いて、一定の圧力で大動脈を介して逆行性かん流した。心拍数、左心室拡張終期圧、および最大左心室圧を連続的に記録した。冠血流を、超音波探傷器(HSE)およびADInstruments製のPowerLab8/30システムを使って測定した。心臓を、血行動態機能を安定させるために20分間かん流し、それからプラスチックチューブに通した糸を締め付けることによって、60分間、閉塞させた。冠血流の約40%の減少によって、閉塞の成功が確認された。糸を解放することによって再かん流を行った。150分間の再かん流期間の終わりに、リスク領域に0.1%のメチレンブルーで印を付けた。次いで心臓を、心尖から心底まで、2mm厚の5枚の薄片に横方向に切片化し、そして、10分間、リン酸緩衝液(pH7.4、37℃)中の1%のトリフェニルテトラゾリウムクロリドの中で培養して、生存組織を赤色に、また壊死組織を白色に染色した。Image−Pro Plus 6.3ソフトウェアを使用して、SONY A900の写真のコンピュータによる面積測定分析を行って、左心室の%で表されるリスク領域および壊死領域を決定した。次に、得られた値を用いて、以下の式に従ってリスク領域の%としての梗塞サイズ(IS)を計算した。
梗塞サイズ=壊死領域/リスク領域×100%。
調査対象物質の抗梗塞効果を、単離ラット心筋梗塞モデルにおいて調べた。左冠状動脈の閉塞の間に、全ての実験群における冠血流が40%減少した(11ml/分から7ml/分)。さらに、最大左心室圧の50%の低下が観察された。閉塞期間の間の心拍数には著しい変化はなかった。再かん流の段階において、冠血流、最大左心室圧、±dp/dtの値は、対照レベルの約80%まで回復した。対照群と治療群との間に著しい差はなかった。
★対照群と比べてp<0.05、#ガンマ−ブチロベタイン群と比べてp<0.05、$メルドニウム二水和物群と比べてp<0.05。
Claims (6)
- a.N,N−ジメチルエチルアミンを、適切な溶媒中のエチル4−ブロモブタノアートに加えて、4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミドを得る段階、
b.4−エトキシ−N−エチル−N,N−ジメチル−4−オキソ−1−ブタンアミニウムブロミドを、イオン交換樹脂カラムに通して、4−[エチル(ジメチル)アンモニオ]ブタノアートを得る段階、
c.適切な溶媒中に、フマル酸、オロチン酸、およびリン酸から成る群から選ばれる酸を加えて、対応する3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム塩を得る段階
を含む、3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム塩を調製するための方法。 - 段階a)において、適切な溶媒がアセトニトリルあるいはアセトンである、請求項4に記載の方法。
- 3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム(2E)−3−カルボキシアクリラート、3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム2,6−ジオキソ−1,2,3,6−テトラヒドロピリミジン−4−カルボキシラート、および二水素リン酸3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウムから成る群から選ばれる、薬剤として使用するための、3−カルボキシ−N−エチル−N,N−ジメチルプロパン−1−アミニウム塩。
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JO3117B1 (ar) * | 2012-12-20 | 2017-09-20 | Grindeks Jsc | استعمال 3- كربوكسي- ن-إيثيل- ن، ن- ثاني ميثيل بروبان-1– أمينيوم أو ملح منه مقبول صيدلانياً في معالجة تصلب الشرايين |
JO3333B1 (ar) * | 2013-09-26 | 2019-03-13 | Grindeks Jsc | استعمال 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium أو ملح مقبول دوائيا منه للوقاية من السكري وعلاجه |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1103259A (en) * | 1913-04-23 | 1914-07-14 | John J Buckley | Fly-paper holder. |
GB1238868A (ja) | 1967-08-08 | 1971-07-14 | ||
SU997646A1 (ru) | 1978-11-27 | 1983-02-23 | Ордена Трудового Красного Знамени Институт Органического Синтеза Ан Латвсср | Кормова добавка |
IT1210935B (it) | 1981-09-17 | 1989-09-29 | Inst Orch Sinteza Akademi Nauk | Composizione farmaceutica per il trattamento di malattie cardiovascolari. |
SU1680693A1 (ru) * | 1987-03-25 | 1991-09-30 | Институт Органического Синтеза Ан Латвсср | Этил-3-(2,2-диметил-2-этилгидразиний)пропионат иодистый, про вл ющий антиаритмическую активность |
JP3119430B2 (ja) * | 1995-07-25 | 2000-12-18 | 大鵬薬品工業株式会社 | 水酸基ラジカル消去剤 |
LV11727B (en) * | 1995-08-21 | 1997-08-20 | Kalvins Ivars | Pharmaceutical composition |
LV11728B (en) | 1995-08-21 | 1997-08-20 | Kalvins Ivars | Pharmaceutical composition |
US5973026A (en) | 1998-02-02 | 1999-10-26 | Xerox Corporation | Ink jet inks |
DE19956772A1 (de) * | 1999-11-25 | 2001-06-07 | Basf Ag | Verwendung von y-Butyrobetain Salzen zur Herstellung von Zubereitungen für die menschliche und tierische Ernährung |
ES2302011T3 (es) * | 2003-08-04 | 2008-07-01 | "JOINT STOCK COMPANY GRINDEKS" | Sales de meldonio, metodo para su preparacion y composicion farmaceutica basado en las mismas. |
CA2508094A1 (en) | 2005-05-20 | 2006-11-20 | Vivier Canada Inc. | Composition for accelerating collagen synthesis |
US7863274B2 (en) | 2005-07-29 | 2011-01-04 | Concert Pharmaceuticals Inc. | Deuterium enriched analogues of tadalafil as PDE5 inhibitors |
LV13705B (en) | 2006-11-06 | 2008-07-20 | Ivars Kalvins | Process for producing high purity intermolecular salt of 3-carboxy-n,n,n-trimethyl-propane-1-amine hydroxide |
JP4761265B2 (ja) | 2007-10-17 | 2011-08-31 | 学校法人甲南学園 | 核酸合成を促進する化合物を含む組成物およびその利用、並びに当該化合物の製造方法 |
TWI391131B (zh) * | 2007-12-05 | 2013-04-01 | Grindeks Jsc | 3-(2,2,2-三甲基肼)丙酸鹽的新用途 |
EP2070529B1 (en) * | 2007-12-12 | 2011-10-12 | Grindeks, a joint stock company | Medical use of 3-(2,2,2-trimethylhydrazinium) propionate orotate |
EP2445861B1 (en) * | 2009-06-25 | 2014-03-26 | Tetra, Sia | Novel acetylsalicylic acid salts |
WO2010149654A1 (en) * | 2009-06-25 | 2010-12-29 | Grindeks, A Joint Stock Company | Pharmaceutical composition of gamma-butyrobetaine or a pharmaceutically acceptable salt and meldonium or a pharmaceutically acceptable salt |
LV14345B (lv) * | 2009-10-22 | 2011-07-20 | Grindeks, A/S | 4-[Etil(dimetil)amonija]butanoāts un tā izmantošana kardiovaskulāro slimību ārstēšanai |
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