ES2352927A1 - Deuterated 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin -4(1h)-one compounds and method for the preparation thereof - Google Patents
Deuterated 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin -4(1h)-one compounds and method for the preparation thereof Download PDFInfo
- Publication number
- ES2352927A1 ES2352927A1 ES201001573A ES201001573A ES2352927A1 ES 2352927 A1 ES2352927 A1 ES 2352927A1 ES 201001573 A ES201001573 A ES 201001573A ES 201001573 A ES201001573 A ES 201001573A ES 2352927 A1 ES2352927 A1 ES 2352927A1
- Authority
- ES
- Spain
- Prior art keywords
- metal
- group
- deuterated
- methyl
- formula
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 6
- VWCOFDJYABIUAC-FIBGUPNXSA-N 6-methyl-2-sulfanylidene-5-(trideuteriomethyl)-1h-pyridin-4-one Chemical class [2H]C([2H])([2H])C1=C(C)NC(=S)CC1=O VWCOFDJYABIUAC-FIBGUPNXSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 3
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 3
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims abstract description 3
- 229910052751 metal Inorganic materials 0.000 claims description 26
- 239000002184 metal Substances 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000001514 detection method Methods 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- -1 deuterated methyl halide Chemical class 0.000 claims description 7
- 229910052987 metal hydride Inorganic materials 0.000 claims description 7
- 150000004681 metal hydrides Chemical class 0.000 claims description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000004703 alkoxides Chemical class 0.000 claims description 6
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 6
- 150000004692 metal hydroxides Chemical class 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001247 metal acetylides Chemical class 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical group CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 claims description 2
- OSPXPPWEAKYOOC-UHFFFAOYSA-N [ethoxy(methoxy)amino]oxy-phenylmethanol Chemical compound CCON(OC)OC(O)C1=CC=CC=C1 OSPXPPWEAKYOOC-UHFFFAOYSA-N 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical class 0.000 abstract 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 2
- VWCOFDJYABIUAC-UHFFFAOYSA-N 5,6-dimethyl-2-sulfanylidene-1h-pyridin-4-one Chemical compound CC1=C(C)C(=O)CC(=S)N1 VWCOFDJYABIUAC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003200 antithyroid agent Substances 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical class C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- BYTCDABWEGFPLT-UHFFFAOYSA-L potassium;sodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[K+] BYTCDABWEGFPLT-UHFFFAOYSA-L 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/56—One oxygen atom and one sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
Compuestos deuterados de 5-trideuterometil-6-metil-2-tioxo-2,3-dihidropiridin-4(1H)-ona y procedimiento de preparación de los mismos.Deuterated compounds of 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one and procedure for their preparation.
La invención se enmarca en el campo de la síntesis de derivados deuterados de compuestos químicos. Concretamente, en la síntesis de derivados deuterados de compuestos tireostáticos.The invention falls within the field of synthesis of deuterated derivatives of chemical compounds. Specifically, in the synthesis of deuterated derivatives of compounds thyrostatics.
Como es bien conocido en el estado de la técnica, los compuestos tireostáticos son fármacos activos por vía oral que se pueden emplear en el engorde fraudulento del ganado previamente a su sacrificio. Las principales consecuencias del abuso de estos compuestos no son sólo la obtención de carne de menor calidad, sino el riesgo potencial que constituyen para la salud humana. Por estas razones, el uso de estos compuestos se encuentra prohibido en el marco de la Unión Europea desde 1981 (directiva 81/602/EC).As is well known in the state of the technique, thyrostatic compounds are active drugs via the oral that can be used in the fraudulent fattening of cattle prior to their sacrifice. The main consequences of abuse of these compounds are not just obtaining meat from less quality, but the potential risk they pose to health human. For these reasons, the use of these compounds is found banned within the framework of the European Union since 1981 (directive 81/602 / EC).
La detección de estos compuestos en muestras de diversa procedencia (orina, leche, carne, sangre, muestras de tiroides) resulta problemática debido a la existencia de formas tautoméricas de los mismos, además de por presentar una elevada polaridad, lo que dificulta enormemente su detección empleando cromatografía líquida de alta resolución de fase reversa (RP-HPLC).Detection of these compounds in samples of diverse origin (urine, milk, meat, blood, samples of thyroid) is problematic due to the existence of forms tautomeric of the same, in addition to presenting a high polarity, which makes its detection extremely difficult using reverse phase high performance liquid chromatography (RP-HPLC).
Además, el estudio mediante espectrometría de masas de estos compuestos de bajo peso molecular no es satisfactorio en términos de sensibilidad (relación señal/ruido de fondo), ya que frecuentemente las señales debidas a estas moléculas aparecen solapadas con el ruido de fondo.In addition, the study by spectrometry of masses of these low molecular weight compounds is not satisfactory in terms of sensitivity (signal / background noise ratio), since frequently signals due to these molecules appear overlapped with background noise.
Sin embargo, las técnicas de cromatografía líquida de alta resolución (HPLC) y de cromatografía de gases (GC) acopladas a espectrometría de masas son las más utilizadas en la detección de este tipo de compuestos. Una reciente directiva de la Unión Europea (96/23/CE), indica que el uso de derivados deuterados de los compuestos tireostáticos a analizar constituye un método analítico de alta precisión para la detección de estos compuestos [E.C. Council directive 96/23/CE, Off. J. Eur. Commun. 2002 L221/8].However, high performance liquid chromatography (HPLC) and gas chromatography (GC) techniques coupled to mass spectrometry are the most widely used in the detection of this type of compounds. A recent European Union directive (96/23 / CE) indicates that the use of deuterated derivatives of the thyrostatic compounds to be analyzed constitutes a high precision analytical method for the detection of these compounds [EC Council directive 96/23 / CE , Off. J. Eur. Commun . 2002 L221 / 8].
Continúa existiendo, por tanto, la necesidad de proporcionar nuevos derivados deuterados de los compuestos tireostáticos para la detección fiable y precisa de los mismos mediante técnicas cromatográficas de alta resolución combinadas con espectrometría de masas.There continues to be, therefore, the need to provide new deuterated derivatives of the compounds thyrostatic for accurate and reliable detection using high-resolution chromatographic techniques combined with mass spectrometry.
Uno de estos compuestos tireostáticos es el 5,6-dimetil-2-tioxo-2,3-dihidropiridin-4(1H)-ona. Sin embargo, no se conoce en el estado de la técnica ningún derivado deuterado del mismo.One of these thyrostatic compounds is 5,6-dimethyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one. However, no derivative is known in the state of the art. deuterated of it.
El objeto de la invención es el diseño y la preparación química de un isotopómero trideuterado del compuesto 5,6-dimetil-2-tioxo-2,3-dihidropiridin-4(1H)-ona, concretamente el compuesto deuterado de fórmula (I).The object of the invention is the design and chemical preparation of a trideuterated isotopomer of the compound 5,6-dimethyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one, specifically the deuterated compound of formula (I).
En el que:In which:
R_{1} y R_{2} representan de forma independiente un átomo de hidrógeno o un grupo alquilo C_{1}-C_{4} sustituido conR1 and R2 represent in the form independently a hydrogen atom or an alkyl group C 1 -C 4 substituted with
- un grupo -OR_{4}, siendo R_{4} un átomo de hidrógeno o un grupo alquilo C_{1}-C_{3} opcionalmente sustituido con fenilo;a group -OR4, where R4 is a hydrogen atom or an alkyl group C 1 -C 3 optionally substituted with phenyl;
- un grupo -NR_{5}R_{6}, siendo R_{5} y R_{6} de forma independiente un átomo de hidrógeno, o un grupo alquilo C_{1}-C_{3}, tosilo o mesilo;a group -NR5 R6, where R5 and R6 are independently a hydrogen atom, or an alkyl group C 1 -C 3, tosyl or mesyl;
- un grupo -SR_{7}, siendo R_{7} un átomo de hidrógeno o un grupo alquilo C_{1}-C_{3};a group -SR 7, where R 7 is a hydrogen atom or an alkyl group C 1 -C 3;
- un grupo -OCOR_{8}, siendo R_{8} un grupo alquilo C_{1}-C_{3} o fenilo; oa group -OCOR 8, where R 8 is an alkyl group C 1 -C 3 or phenyl; or
- un átomo de halógeno; yan atom of halogen; and
D representa deuterio.D represents deuterium.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Otro objeto de la invención es el propio compuesto deuterado (I).Another object of the invention is the deuterated compound (I).
Asimismo, otro objeto de la invención es proporcionar una composición farmacéutica que comprende dicho compuesto deuterado.Likewise, another object of the invention is providing a pharmaceutical composition comprising said deuterated compound.
Finalmente, otro objeto de la invención es proporcionar el uso de dicho compuesto deuterado para fabricar medicamentos destinados al tratamiento del hipertiroidismo o para usar como patrón en la detección del fármaco tireostático correspondiente.Finally, another object of the invention is provide the use of said deuterated compound to manufacture medicines intended to treat hyperthyroidism or to use as a standard in the detection of thyrostatic drug correspondent.
La presente invención proporciona un compuesto deuterado de fórmula (I).The present invention provides a compound deuterate of formula (I).
En una realización particular del compuesto
deuterado de la invención, R_{1} y R_{2} representan de forma
independiente hidrógeno, o bien un grupo metilo o etilo que está
opcionalmente sustituido con un grupo hidroxi (-OH), metoxi
(-OMe), etoxi (-OEt), benciloxi (-OBn), amina (-NH_{2}),
metilamina (-NHMe), etilamina(-NHEt), tosilamina (-NHTs), mesilamina
(-NHMs), tiol (-SH), tiometoxi (-SMe), tioetoxi (-SEt), acetoxi
(-OCOCH_{3}) o benzoiloxi (-OBz); o con un átomo de flúor, cloro,
bromo o yodo.In a particular embodiment of the deuterated compound of the invention, R1 and R2 independently represent hydrogen, or a methyl or ethyl group that is optionally substituted with a hydroxy group (-OH), methoxy
(-OMe), ethoxy (-OEt), benzyloxy (-OBn), amine (-NH2), methylamine (-NHMe), ethylamine (-NHEt), tosylamine (-NHTs), mesylamine (-NHMs), thiol (-SH), thiomethoxy (-SMe), thioethoxy (-SEt), acetoxy (-OCOCH3) or benzoyloxy (-OBz); or with a fluorine, chlorine, bromine or iodine atom.
En una realización preferida, R_{1} y R_{2} representan de forma independiente hidrógeno o metilo. En una realización aún más preferida, R_{1}, R_{2} y R_{3} representan hidrógeno.In a preferred embodiment, R 1 and R 2 independently represent hydrogen or methyl. In a Even more preferred embodiment, R 1, R 2 and R 3 represent hydrogen.
Así, el compuesto deuterado de fórmula (I) preferido de la invención es el 5-trideuterometil-6-metil-2-tioxo-2,3-dihidropiridin-4(1H)-ona.Thus, the deuterated compound of formula (I) preferred of the invention is the 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one.
Con carácter general, el procedimiento para la preparación de los compuestos de fórmula general (I) comprende las etapas siguientes:In general, the procedure for the Preparation of the compounds of general formula (I) comprises the next stages:
- (a)(to)
- hacer reaccionar un compuesto de fórmula (1)react a compound of Formula 1)
- con un haluro de metilo deuterado en presencia de una base a baja temperatura.with a halide of deuterated methyl in the presence of a base at low temperature.
- (b)(b)
- hacer reaccionar el metil derivado deuterado obtenido en la etapa (a) con el compuesto (2) en presencia de una base fuerte a temperatura elevada;reacting the methyl derivative deuterate obtained in step (a) with compound (2) in the presence of a strong base at elevated temperature;
- en la que R_{1} y R_{2} tienen los significados dados previamente.in which R1 and R2 have the given meanings previously.
- (c)(c)
- tratar el producto de reacción de la etapa (b) con un ácido hasta pH ácido.treat the reaction product of the step (b) with an acid until acidic pH.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
En la primera etapa del procedimiento, la metilación del compuesto correspondiente se efectúa empleando una base y un reactivo de metilación deuterado adecuados.In the first stage of the procedure, the methylation of the corresponding compound is carried out using a base and a suitable deuterated methylating reagent.
Como reactivo de metilación deuterado se puede emplear cualquier haluro de metilo deuterado, preferentemente cloruro de metilo deuterado (CD_{3}Cl) o el bromuro de metilo deuterado (CD_{3}Br) y, más preferentemente, yoduro de metilo deuterado (CD_{3}I).As a deuterated methylation reagent it can be use any deuterated methyl halide, preferably deuterated methyl chloride (CD 3 Cl) or methyl bromide deuterated (CD3 Br) and, more preferably, methyl iodide deuterated (CD 3 I).
La base empleada en la etapa (a) se selecciona entre un hidruro metálico, un hidróxido metálico, un alcóxido metálico, un amiduro metálico, una base orgánica nitrogenada, un acetiluro metálico, una hexametildisilazida metálica y un alquil metal. Preferentemente, se emplearán hidruros metálicos tales como el hidruro sódico o el hidruro potásico; hidróxidos metálicos tales como el hidróxido de litio, el hidróxido de sodio o el hidróxido de potasio; alcóxidos metálicos tales como el metóxido de litio, el metóxido de sodio, el metóxido de potasio, el etóxido de litio, el etóxido de sodio o el etóxido de potasio; amiduros metálicos tales como el amiduro de litio, el amiduro de sodio, el amiduro de potasio o el diisopropil amiduro de litio (LDA); bases orgánicas nitrogenadas tales como la 1,8-diazabiciclo[5.4.0]undec-7-eno (DBU); hexametildisilazidas metálicas tales como la hexametildisilazida de litio, la hexametildisilazida de sodio o la hexametildisilazida de potasio; o alquilmetales tales como el tert-butil litio o el butil litio.The base used in step (a) is selected between a metal hydride, a metal hydroxide, an alkoxide metal, a metal amide, a nitrogenous organic base, a metal acetylide, a metal hexamethyldisilazide and an alkyl metal. Preferably, metal hydrides such as sodium hydride or potassium hydride; metal hydroxides such such as lithium hydroxide, sodium hydroxide, or sodium hydroxide potassium; metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide or potassium ethoxide; metal amides such such as lithium amide, sodium amide, potassium amide or lithium diisopropyl amide (LDA); organic bases nitrogenous such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); Metal hexamethyldisilazides such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or alkyl metals such as tert-butyl lithium or butyl lithium.
En la realización preferida del procedimiento de la invención, la base empleada en la etapa (a) es un hidruro metálico seleccionado entre hidruro sódico (NaH) e hidruro potásico (KH).In the preferred embodiment of the the invention, the base used in step (a) is a hydride metal selected from sodium hydride (NaH) and potassium hydride (KH).
El disolvente empleado en esta etapa (a) será cualquier disolvente adecuado del estado de la técnica, tal como tetrahidrofurano (THF), dimetilformamifa (DFM), o dietiléter (Et_{2}O), por ejemplo, si bien se prefiere el tetrahidrofurano.The solvent used in this step (a) will be any suitable state of the art solvent, such as tetrahydrofuran (THF), dimethylformamifa (DFM), or diethyl ether (Et 2 O), for example, although the tetrahydrofuran.
Asimismo, esta reacción se efectúa a 0ºC y durante un tiempo de 10 minutos a 1 hora, preferiblemente de 0.5 horas.Also, this reaction is carried out at 0 ° C and for a time of 10 minutes to 1 hour, preferably 0.5 hours.
Tras la reacción de metilación de la etapa (a), el producto de reacción se trata con una base fuerte a elevada temperatura.After the methylation reaction of step (a), the reaction product is treated with a strong to high base temperature.
Así, en otra realización particular del procedimiento de la invención, la base fuerte empleada en la etapa (b) se selecciona entre un hidruro metálico, un hidróxido metálico, un alcóxido metálico, un amiduro metálico, una base orgánica nitrogenada, un acetiluro metálico, una hexametildisilazida metálica y un alquil metal.Thus, in another particular embodiment of the process of the invention, the strong base used in the step (b) is selected from a metal hydride, a metal hydroxide, a metal alkoxide, a metal amide, an organic base Nitrogen, a metal acetylide, a metal hexamethyldisilazide and a metal alkyl.
Más en particular, dicha base fuerte puede ser un hidruro metálico tal como el hidruro sódico o el hidruro potásico; un hidróxido metálico tal como el hidróxido de litio, el hidróxido de sodio o el hidróxido de potasio; un alcóxido metálico tal como el metóxido de litio, el metóxido de sodio, el metóxido de potasio, el etóxido de litio, el etóxido de sodio o el etóxido de potasio; un amiduro metálico tal como el amiduro de litio, el amiduro de sodio, el amiduro de potasio o el diisopropil amiduro de litio (LDA); una base orgánica nitrogenada tales como la 1,8-diazabiciclo[5.4.0]undec-7-eno (DBU); una hexametildisilazida metálica tal como la hexametildisilazida de litio, la hexametildisilazida de sodio o la hexametildisilazida de potasio; o un alquilmetal tal como el tert-butil litio o el butil litio. Preferiblemente, la base fuerte a usar en la reacción de la etapa (b) es un alquilmetal tal como el tert-butil litio (t-BuLi), el butil litio (BuLi) o el fenil litio (PhLi); o bien un amiduro metálico tal como el diisopropil amiduro de litio (LDA).More particularly, such a strong base can be a metal hydride such as sodium hydride or hydride potassium; a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; a metal alkoxide such as lithium methoxide, sodium methoxide, potassium, lithium ethoxide, sodium ethoxide, or potassium; a metal amide such as lithium amide, sodium amide, potassium amide, or diisopropyl amide lithium (LDA); a nitrogenous organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); a metallic hexamethyldisilazide such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or an alkyl metal such as tert-butyl lithium or butyl lithium. Preferably, The strong base to use in the reaction of step (b) is a metal alkyl such as tert-butyl lithium (t-BuLi), butyl lithium (BuLi) or phenyl lithium (PhLi); or a metal amide such as diisopropyl amide lithium (LDA).
Así, en la realización preferida del procedimiento de la invención, la base fuerte empleada en la etapa (b) es etóxido de sodio.Thus, in the preferred embodiment of the process of the invention, the strong base used in the step (b) is sodium ethoxide.
En otra realización particular del procedimiento de la invención, la reacción con la base fuerte de la etapa (b) se efectúa a reflujo.In another particular embodiment of the procedure of the invention, the reaction with the strong base of step (b) is performed at reflux.
En otra realización particular del procedimiento de la invención, la reacción con la base fuerte de la etapa (b) se efectúa durante un tiempo de entre 30 minutos a 24 horas, preferiblemente durante un tiempo de entre 1 y 24 horas y, más preferiblemente, durante un tiempo de 20 horas.In another particular embodiment of the procedure of the invention, the reaction with the strong base of step (b) is carried out for a period of between 30 minutes to 24 hours, preferably for a time between 1 and 24 hours and, more preferably, for a time of 20 hours.
Finalmente, el producto metildeuterado y tratado con la base fuerte a alta temperatura se hace reaccionar con un ácido hasta pH ácido.Finally, the methyldeuterated and treated product with the strong base at high temperature is reacted with a acid to acidic pH.
Como reactivo ácido se empleará, de forma preferente, a modo de ejemplo, ácido sulfúrico (H_{2}SO_{4}), ácido nítrico (HNO_{3}) o ácido fosfórico (H_{3}PO_{4}) y, de forma más preferente ácido clorhídrico (HCl).The acid reagent will be used, so preferred, for example, sulfuric acid (H 2 SO 4), nitric acid (HNO 3) or phosphoric acid (H 3 PO 4) and, of more preferably hydrochloric acid (HCl).
En otra realización particular del procedimiento de la invención, la reacción con el ácido fuerte de la etapa (c) se efectúa a una temperatura de entre 5ºC y 30ºC, preferentemente a una temperatura de entre 10 a 25ºC y, más preferentemente, a una temperatura de 18ºC.In another particular embodiment of the procedure of the invention, the reaction with the strong acid of step (c) is carried out at a temperature between 5ºC and 30ºC, preferably at a temperature between 10 to 25 ° C and, more preferably, at a temperature 18 ° C.
En otra realización particular del procedimiento de la invención, la reacción con el ácido fuerte de la etapa (c) se efectúa durante un tiempo de entre 1 a 30 minutos, preferiblemente durante un tiempo de entre 1 y 15 minutos y, más preferiblemente, durante un tiempo de 5 minutos.In another particular embodiment of the procedure of the invention, the reaction with the strong acid of step (c) is carried out for a time between 1 to 30 minutes, preferably for a time between 1 and 15 minutes and, more preferably, for a time of 5 minutes.
El disolvente empleado en esta etapa (c) será cualquier disolvente adecuado del estado de la técnica, tal como etanol absoluto (EtOH), tetrahidrofurano (THF) o dietiléter (Et_{2}O), por ejemplo, si bien se prefiere el etanol absoluto.The solvent used in this step (c) will be any suitable state of the art solvent, such as absolute ethanol (EtOH), tetrahydrofuran (THF), or diethyl ether (Et 2 O), for example, although ethanol is preferred absolute.
En otro aspecto de la invención se proporciona una composición farmacéutica, en adelante "composición farmacéutica de la invención (I)" que comprende el compuesto de la invención definido previamente y, al menos, un excipiente farmacéuticamente aceptable.In another aspect of the invention there is provided a pharmaceutical composition, hereinafter "composition Pharmaceutical of the invention (I) "which comprises the compound of the invention defined previously and at least one excipient pharmaceutically acceptable.
Los excipientes farmacéuticamente aceptables serán aquellos excipientes de la técnica que permitan la formulación adecuada de la composición farmacéutica de la invención. Dicha composición puede formularse para su administración oral, intravenosa, tópica, rectal, subdérmica, etc. Es decir, puede presentarse en forma de soluciones, comprimidos, cápsulas, implantes, etc. Asimismo, dicha formulación puede ser de liberación inmediata o de liberación controlada.Pharmaceutically acceptable excipients will be those excipients of the technique that allow the formulation suitable of the pharmaceutical composition of the invention. Bliss composition can be formulated for oral administration, intravenous, topical, rectal, subdermal, etc. That is, it can come in the form of solutions, tablets, capsules, implants, etc. Likewise, said formulation can be release immediate or controlled release.
Además, los compuestos de fórmula general (I) son especialmente ventajosos en el campo farmacéutico, como ingrediente activo, por lo pueden utilizarse para la fabricación de medicamentos para el tratamiento del hipertiroidismo.Furthermore, the compounds of general formula (I) are especially advantageous in the pharmaceutical field, as active ingredient, so they can be used for the manufacture of medicines for the treatment of hyperthyroidism.
Por otro lado, el los compuestos de fórmula general (I) se pueden usar como patrón en la detección de compuestos tireostáticos. En particular, como patrón para la detección de compuestos de fórmula (II).On the other hand, the compounds of formula general (I) can be used as a standard in the detection of compounds thyrostatics. In particular, as a standard for the detection of compounds of formula (II).
en la que R_{1} y R_{2} tienen los significados dados previamente,in which R1 and R2 have the meanings given previously,
mediante técnicas cromatográficas de alta resolución combinadas con espectrometría de masas como pueden ser la cromatografía liquida de alta resolución (HPLC) y la cromatografía de gases (GC).using chromatographic techniques of high resolution combined with mass spectrometry such as high performance liquid chromatography (HPLC) and chromatography gas (GC).
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
El siguiente ejemplo ilustra la invención y no debe ser considerado como limitativo del alcance de la misma.The following example illustrates the invention and does not it should be considered as limiting its scope.
A una disolución de 500 mg de acetoacetato de etilo comercial en tetrahidrofurano (THF) (25 ml) se le añadieron 169 mg de hidruro sódico (NaH) y 835 mg de yoduro de metilo deuterado comercial y la disolución se agitó a temperatura ambiente.To a solution of 500 mg of acetoacetate of commercial ethyl in tetrahydrofuran (THF) (25 ml) were added 169 mg of sodium hydride (NaH) and 835 mg of methyl iodide commercial deuterated and the solution was stirred at environment.
Al crudo de reacción se le añadió agua para eliminar el exceso de hidruro de sodio (NaH), se extrajo con dietiléter (Et_{2}O) y la fase orgánica se secó con Na_{2}SO_{4}, se filtró y evaporó el disolvente para dar un compuesto metildeuterado con un rendimiento del 100%.Water was added to the crude reaction to remove excess sodium hydride (NaH), it was extracted with diethyl ether (Et2O) and the organic phase was dried with Na 2 SO 4, the solvent was filtered and evaporated to give a methyldeuterated compound in 100% yield.
Posteriormente, el compuesto obtenido se trató con etóxido de sodio y tiourea (SC(NH_{2})_{2}) en etanol (EtOH) absoluto y la mezcla se calentó a reflujo durante 18 h. Se añadió disolución de HCl al 10% hasta pH ácido, se eliminó el etanol (EtOH) a presión reducida. El precipitado aparecido se recogió y se lavó con hexano dando un rendimiento del 80%.Subsequently, the compound obtained was treated with sodium ethoxide and thiourea (SC (NH2) 2) in absolute ethanol (EtOH) and the mixture was heated under reflux for 18 h. 10% HCl solution was added until acidic pH, the ethanol (EtOH) under reduced pressure. The precipitate appeared collected and washed with hexane giving 80% yield.
Claims (16)
- un grupo -OR_{4}, siendo R_{4} un átomo de hidrógeno o un grupo alquilo C_{1}-C_{3} opcionalmente sustituido con fenilo;a group -OR4, where R4 is a hydrogen atom or an alkyl group C 1 -C 3 optionally substituted with phenyl;
- un grupo -NR_{5}R_{6}, siendo R_{5} y R_{6} de forma independiente un átomo de hidrógeno, o un grupo alquilo C_{1}-C_{3}, tosilo o mesilo;a group -NR5 R6, where R5 and R6 are independently a hydrogen atom, or an alkyl group C 1 -C 3, tosyl or mesyl;
- un grupo -SR_{7}, siendo R_{7} un átomo de hidrógeno o un grupo alquilo C_{1}-C_{3};a group -SR 7, where R 7 is a hydrogen atom or an alkyl group C 1 -C 3;
- un grupo -OCOR_{8}, siendo R_{8} un grupo alquilo C_{1}-C_{3} o fenilo; oa group -OCOR 8, where R 8 is an alkyl group C 1 -C 3 or phenyl; or
- un átomo de halógeno; yan atom of halogen; and
- D representa deuterio.D represents deuterium.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
- (a)(to)
- hacer reaccionar un compuesto de fórmula (1)react a compound of Formula 1)
- con un haluro de metilo deuterado en presencia de una base a baja temperatura.with a halide of deuterated methyl in the presence of a base at low temperature.
\global\parskip0.950000\baselineskipglobal \ parskip0.950000 \ baselineskip
- (b)(b)
- hacer reaccionar el metil derivado deuterado obtenido en la etapa (a) con el compuesto (2) en presencia de una base fuerte a temperatura elevada;reacting the methyl derivative deuterate obtained in step (a) with compound (2) in the presence of a strong base at elevated temperature;
- en la que R_{1} y R_{2} tienen los significados dados previamente.in which R1 and R2 have the given meanings previously.
- (c)(c)
- tratar el producto de reacción de la etapa (b) con un ácido hasta pH ácido.treat the reaction product of the step (b) with an acid until acidic pH.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES201001573A ES2352927B1 (en) | 2010-12-07 | 2010-12-07 | DEUTERATED COMPOUNDS OF 5-TRIDEUTEROMETIL-6-METHYL-2-THIOXO-2,3-DIHYDROPIRIDIN-4 (1H) -ONA AND PREPARATION PROCEDURE OF THE SAME. |
| PCT/ES2011/000360 WO2012076735A1 (en) | 2010-12-07 | 2011-12-07 | Deuterated 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin -4(1h)-one compounds and method for the preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES201001573A ES2352927B1 (en) | 2010-12-07 | 2010-12-07 | DEUTERATED COMPOUNDS OF 5-TRIDEUTEROMETIL-6-METHYL-2-THIOXO-2,3-DIHYDROPIRIDIN-4 (1H) -ONA AND PREPARATION PROCEDURE OF THE SAME. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2352927A1 true ES2352927A1 (en) | 2011-02-24 |
| ES2352927B1 ES2352927B1 (en) | 2012-01-12 |
Family
ID=43567846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES201001573A Active ES2352927B1 (en) | 2010-12-07 | 2010-12-07 | DEUTERATED COMPOUNDS OF 5-TRIDEUTEROMETIL-6-METHYL-2-THIOXO-2,3-DIHYDROPIRIDIN-4 (1H) -ONA AND PREPARATION PROCEDURE OF THE SAME. |
Country Status (2)
| Country | Link |
|---|---|
| ES (1) | ES2352927B1 (en) |
| WO (1) | WO2012076735A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2472343B1 (en) * | 2012-12-28 | 2015-08-10 | Universidad De Granada | 1,3 dihydro-6- (3 ') - trideuteroethyl-2-thioxo-pyrimidine - 4-one and derivatives, synthesis and uses of these deuterium-labeled thyrostatic |
-
2010
- 2010-12-07 ES ES201001573A patent/ES2352927B1/en active Active
-
2011
- 2011-12-07 WO PCT/ES2011/000360 patent/WO2012076735A1/en active Application Filing
Non-Patent Citations (2)
| Title |
|---|
| S Abuín et al, Analytica Chimica Acta 2008, vol 617, páginas 184-191. "Analysis of thyreostatic drugs in thyroid samples by ultra-performance liquid chromatography tandem mass spectrometry detection", todo el documento * |
| S Abuín et al, Journal of Chromatography a 2008, vol 1207, páginas 17-23. "Analysis of thyreostatic drugs in thyroid samples by liquid chromatography tandem mass spectrometry: comparison of two sample treatment strategies" * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012076735A1 (en) | 2012-06-14 |
| ES2352927B1 (en) | 2012-01-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8710086B2 (en) | Substituted di-arylhydantoin and di-arylthiohydantoin compounds and methods of use thereof | |
| DK2538785T3 (en) | Methods for the synthesis of diarylthiohydantoin and diarylhydantoin compounds | |
| US9126962B2 (en) | Substituted phenylcarbamoyl alkylamino arene compounds and N,N′-BIS-arylurea compounds | |
| AU2014311148B2 (en) | Vancomycin derivative, and preparation method and application thereof | |
| US20100113547A1 (en) | Novel imidazolidine compounds as androgen receptor modulators | |
| PE20091723A1 (en) | DERIVATIVES OF L-GLUTAMIC ACID LABELED WITH [18 F] AND L-GLUTAMINE LABELED WITH [18F] | |
| EP3204364B1 (en) | A method for preparing gadobutrol | |
| JPS58126887A (en) | Novel 7-deazapurine derivative | |
| US20180273506A1 (en) | Preparation Method of Cobimetinib | |
| AU2013259779B2 (en) | N-ethyl-4-hydroxyl-1-methyl-5- (methyl(2,3,4,5,6-pentahydroxyhexyl) amino) -2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide | |
| AU2007337481B2 (en) | Process for production of precursor compound for radioactive halogen-labeled organic compound | |
| CA2941857A1 (en) | An intermediate iodonium ylide and its use in an iodine(iii)-mediated radiofluorination process | |
| CN106279047A (en) | A kind of preparation method of prostacyclin receptor agonist | |
| MX2022006990A (en) | Crystalline form of a 7h-benzo[7]annulene-2-carboxylic acid derivative. | |
| WO2015160307A1 (en) | Allenamide as an orthogonal handle for selective modification of cysteine in peptides and proteins | |
| RU2489422C1 (en) | Fluorine-substituted (3r,4r,5s)-5-guanidino-4-acylamino-3-(pentan-3-yloxy)cyclohexene-1-carboxylic acids, esters thereof and method of application | |
| Tong et al. | Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors | |
| ES2352927A1 (en) | Deuterated 5-trideuteromethyl-6-methyl-2-thioxo-2,3-dihydropyridin -4(1h)-one compounds and method for the preparation thereof | |
| ES2352926A1 (en) | Deuterated phenacyl and derivatives, method for the preparation thereof and uses thereof | |
| Wang et al. | A high-yield route to synthesize the P-glycoprotein radioligand [11C] N-desmethyl-loperamide and its parent radioligand [11C] loperamide | |
| ES2731274T3 (en) | Dipeptidyl ketoamide compounds and their use for the treatment and / or prevention of fat accumulation | |
| RU2695365C2 (en) | Radiopharmaceutical preparation kit | |
| CN104387288B (en) | As the compound of neuraminidase inhibitor and the application in medicine thereof | |
| ES2472343B1 (en) | 1,3 dihydro-6- (3 ') - trideuteroethyl-2-thioxo-pyrimidine - 4-one and derivatives, synthesis and uses of these deuterium-labeled thyrostatic | |
| ES2322015B2 (en) | TAPAZOL DEUTERADO AND DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND USES OF THE SAME. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG2A | Definitive protection |
Ref document number: 2352927 Country of ref document: ES Kind code of ref document: B1 Effective date: 20120112 |