CZ309329B6 - Monopyridinium salts for reactivating organophosphate-inhibited acetylcholinesterase - Google Patents
Monopyridinium salts for reactivating organophosphate-inhibited acetylcholinesterase Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
Description
Monopyridiniové soli pro reaktivaci organofosfáty inhibované acetylcholinesterasyMonopyridinium salts for reactivation of organophosphate-inhibited acetylcholinesterase
Oblast technikyField of technology
Vynález se týká reaktivátorů enzymatické aktivity acetylcholinesterasy (AChE) inhibované organofosforovými sloučeninami na bázi derivátů monopyridiniových solí a jejich léčebného použití.The invention relates to reactivators of the enzymatic activity of acetylcholinesterase (AChE) inhibited by organophosphorus compounds based on derivatives of monopyridinium salts and their therapeutic use.
Dosavadní stav technikyCurrent state of the art
Organofosforové sloučeniny (OF) jsou známy od 30. let 20. století jako insekticidy (př. paraoxon, chlorpyrifos ad.) nebo bojové chemické látky (př. sarin, VX, tabun, ad.) ze skupiny nervověparalytických látek. OF jsou známými ireverzibilními inhibitory acetylcholinesterasy (AChE). Touto inhibicí blokují katalytickou aktivitu AChE, která nemůže rozkládat neuromediátor acetylcholin, a ten se následně hromadí v synapsích. Díky hromadění acetylcholinu dochází k řadě příznaků, které jsou označovány jako muskarinové, nikotinové a centrální a mohou vyústit v cholinergní krizi až smrt organismu (Marrs TC. Pharmacol Ther. 1993; 58: 51-66).Organophosphorus compounds (OF) have been known since the 1930s as insecticides (e.g. paraoxon, chlorpyrifos, etc.) or chemical warfare agents (e.g. sarin, VX, tabun, etc.) from the group of nerve agents. OFs are known irreversible acetylcholinesterase (AChE) inhibitors. With this inhibition, they block the catalytic activity of AChE, which cannot break down the neurotransmitter acetylcholine, and it subsequently accumulates in synapses. Due to the accumulation of acetylcholine, a number of symptoms occur, which are referred to as muscarinic, nicotinic and central, and can result in cholinergic crisis or death of the organism (Marrs TC. Pharmacol Ther. 1993; 58: 51-66).
Při intoxikaci OF jsou využívána kauzální antidota v podobě reaktivátorů AChE (př. pralidoxim, methoxim, trimedoxim, obidoxim, asoxim), které pomocí oximové funkční skupiny štěpí vazbu mezi OF a AChE, a tak reaktivují katalytickou funkci AChE. Tato aktivita je závislá na nukleofilitě oximové skupiny přítomné v molekule reaktivátorů a tvorbě oximátového aniontu (Bajgar J. Adv Clin Chem. 2004; 38: 151-216).In OF intoxication, causal antidotes are used in the form of AChE reactivators (e.g. pralidoxime, methoxime, trimedoxime, obidoxime, asoxime), which use the oxime functional group to cleave the bond between OF and AChE, thus reactivating the catalytic function of AChE. This activity is dependent on the nucleophilicity of the oxime group present in the reactivators molecule and the formation of the oximate anion (Bajgar J. Adv Clin Chem. 2004; 38: 151-216).
Žádný z dosud využívaných reaktivátorů nemá spektrum účinku dostatečně široké pro reaktivaci většiny OF (Winter T, et al. Toxicol Lett. 2016; 244: 136-142), z nichž jsou nejvíce zkoumány sarin (pro velkou těkavost), VX (pro dlouhou perzistenci v prostředí) a paraoxon (j ako modelový a silně toxický OF insekticid). Nové reaktivátory AChE tudíž mohou vést ke zlepšené reaktivaci AChE a zároveň širšímu spektru účinku vůči různým OF (Zorbaz T, et al. J Med Chem. 2018; 61(23): 10753-10766).None of the reactivators used so far has a spectrum of action broad enough to reactivate most OF (Winter T, et al. Toxicol Lett. 2016; 244: 136-142), of which the most studied are sarin (for high volatility), VX (for long persistence in the environment) and paraoxon (as a model and highly toxic OF insecticide). New AChE reactivators can therefore lead to improved AChE reactivation and at the same time a wider spectrum of action against various OFs (Zorbaz T, et al. J Med Chem. 2018; 61(23): 10753-10766).
V roce 1955 popsal Wilson et al. pralidoxim jako monopyridiniovou sloučeninu s karbaldoximovou skupinou schopnou reaktivovat alkylfosfylovanou AChE (Wilson IB, Ginsburg S. Biochim Biophys Acta 1955; 18: 168-170).In 1955, Wilson et al. pralidoxime as a monopyridinium compound with a carbaldoxime group capable of reactivating alkyl-phosphorylated AChE (Wilson IB, Ginsburg S. Biochim Biophys Acta 1955; 18: 168-170).
pralidoximpralidoxime
Pralidoxim se stal nejvíce využívaným monopyridiniovým léčivem (antidotem) ze skupiny reaktivátorů AChE pro vojenské nebo civilní použití. Jeho reaktivace OF ale není širokospektrá, a navíc je reaktivace relativně nízká při nižších koncentracích pralidoximu (Kuca K et al. Bratisl Lek Listy. 2010; 111(9): 502-4).Pralidoxime has become the most widely used monopyridinium drug (antidote) from the group of AChE reactivators for military or civilian use. However, its OF reactivation is not broad-spectrum, and in addition, reactivation is relatively low at lower concentrations of pralidoxime (Kuca K et al. Bratisl Lek Listy. 2010; 111(9): 502-4).
Ginsburg et al. v roce 1957 (Ginsburg S, Wilson IB. J Am Chem Soc 1957; 79: 481-483) připravili skupinu monopyridiniových solí s jednou oximovou skupinou a dalším substituentem (methyl, hydroxy nebo methoxy). Aldoximový substituent byl v poloze ortho k dusíkovému atomu, ostatní substituenty v poloze meta, v případě methylu také v ortho poloze. Tato práce se zabývala syntézou a charakterizací připravených sloučenin, nezabývala se jejich biologickou aktivitou.Ginsburg et al. in 1957 (Ginsburg S, Wilson IB. J Am Chem Soc 1957; 79: 481-483) prepared a group of monopyridinium salts with one oxime group and another substituent (methyl, hydroxy or methoxy). The aldoxime substituent was in the ortho position to the nitrogen atom, the other substituents in the meta position, and in the case of methyl also in the ortho position. This work dealt with the synthesis and characterization of the prepared compounds, it did not deal with their biological activity.
R; CH3, OH, OCH3 R; CH 3 , OH, OCH 3
Markovac et al. (Markovac A, Stevens CL, Ash AB, Hackley BE. J Org Chem 1970; 35: 841-843) publikovala skupinu monopyridiniových solí s oximovou skupinou v poloze 2 a dalšími substituenty v polohách 4-6. Testování reaktivační aktivity nebylo v této práci publikováno.Markovac et al. (Markovac A, Stevens CL, Ash AB, Hackley BE. J Org Chem 1970; 35: 841-843) published a group of monopyridinium salts with an oxime group in the 2-position and additional substituents in the 4-6 positions. Testing for reactivation activity was not published in this work.
R: CH3í CH3CH2, Cl, COOCH3, CONH2, CH=NOH. N(CH3)2 R: CH 3 i CH 3 CH 2 , Cl, COOCH 3 , CONH 2 , CH=NOH. N(CH 3 ) 2
Arena et al. v roce 1975 (Arena F, Manna F, Pizza C, Stein ML, Grifantini M. J Med Chem. 1975; 18: 1147-1150) popsala skupinu 4-styrylpyridiniových solí s oximovou skupinou v poloze 2. Připravené sloučeniny byly testovány na diisopropylfluorofosfátem inhibované AChE s reaktivačními výsledky horšími než pralidoxim, zhoršenou rozpustností a vyšší inhibiční aktivitou na samotném enzymu než pralidoxim.Arena et al. in 1975 (Arena F, Manna F, Pizza C, Stein ML, Grifantini M. J Med Chem. 1975; 18: 1147-1150) described a group of 4-styrylpyridinium salts with an oxime group in position 2. The prepared compounds were tested for diisopropylfluorophosphate inhibited AChE with worse reactivation results than pralidoxime, impaired solubility and higher inhibitory activity on the enzyme itself than pralidoxime.
R: benzyl: H, 2-Ci, 3-Ci. 4-Ct 2-Br, 3-Br, 2-OCH3i 3-OCH3, 4-OCH3 1 -nafty!, N-henzyl-2-imídazalyL 4-imidazoly*R: benzyl: H, 2-Ci, 3-Ci. 4-Ct 2-Br, 3-Br, 2-OCH 3i 3-OCH 3 , 4-OCH 3 1 -naphtha!, N-henzyl-2-imidazalL 4-imidazoles*
Markovac et al. v roce 1975 (Markovac A, Ash AB, Stevens CL. J Het Chem. 1977; 14: 19-26) připravila skupinu 4- nebo 5-substituovaných pyridiniových solí s oximovou skupinou v poloze 2, kdy testování reaktivační aktivity nebylo publikováno.Markovac et al. in 1975 (Markovac A, Ash AB, Stevens CL. J Het Chem. 1977; 14: 19-26) prepared a group of 4- or 5-substituted pyridinium salts with an oxime group in the 2-position, when testing for reactivation activity was not published.
R: 4-CH-NOH, NO2 R: 4-CH-NOH, NO 2
5-CH2CH3, OH, N(CH3)2, COOCHS5-CH 2 CH 3 , OH, N(CH 3 ) 2 , COOCHS
V roce 2006 publikovala Racakova et al. (Racakova V, Hrabinova M, Jun D, Kuca K. Arh Hig Rada Toksikol 2006; 57: 387-390) skupinu 4- nebo 5-substituovaných monopyridiniových solí s oximovou skupinou v poloze 2. Připravené sloučeniny byly testovány na potkaní AChE inhibované cyklosarinem, kde neprokázaly reaktivační účinnost, a na AChE inhibované chlorpyrifosem, kde prokázaly srovnatelnou nebo nižší reaktivační účinnost v porovnání s pralidoximem.In 2006, Racakova et al. (Racakova V, Hrabinova M, Jun D, Kuca K. Arh Hig Rada Toksikol 2006; 57: 387-390) a group of 4- or 5-substituted monopyridinium salts with an oxime group in position 2. The prepared compounds were tested on cyclosarin-inhibited rat AChE , where they did not show reactivation efficiency, and on AChE inhibited by chlorpyrifos, where they showed comparable or lower reactivation efficiency compared to pralidoxime.
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R: 4-CONH2, COOCH2CH3 5-COOCH2CH3 R: 4-CONH 2 , COOCH 2 CH 3 5-COOCH 2 CH 3
Musilek et al. v roce 2008 (Musilek K, Kucera J, Jun D, Dohnal V, Opletalova V, Kuca K. Bioorg Med Chern 2008; 16: 8218-8223) popsal skupinu monopyridiniových solí s oximovou skupinou v poloze 2, 3 nebo 4 modifikovaných alkylací na dusíku s variabilními substituenty. Sloučeniny byly testovány na potkaní AChE inhibované tabunem, kde neprokázaly reaktivační účinnost, a na AChE inhibované paraoxonem, kde prokázaly srovnatelnou nebo nižší reaktivační účinnost v porovnání s pralidoximem.Musilek et al. in 2008 (Musilek K, Kucera J, Jun D, Dohnal V, Opletalova V, Kuca K. Bioorg Med Chern 2008; 16: 8218-8223) described a group of monopyridinium salts with an oxime group in position 2, 3 or 4 modified by alkylation at of nitrogen with variable substituents. The compounds were tested on tabun-inhibited rat AChE, where they showed no reactivation activity, and on paraoxon-inhibited AChE, where they showed comparable or lower reactivation activity compared to pralidoxime.
R: CH3, CH3(CH2)2, CH2=CHCH2, PhCH2, Ph(CH2)2, Ph(CH2)3 R: CH 3 , CH 3 (CH 2 ) 2 , CH 2 =CHCH 2 , PhCH 2 , Ph(CH 2 ) 2 , Ph(CH 2 ) 3
Okuno et al. v roce 2008 (Okuno S, Sakurada K, Ohta H, Ikegaya H, Kazui Y, Akutsu T, Takatori T, Iwadate K. Toxicol Appl Pharmacol 2008; 227: 8-15) připravil skupinu monopyridiniových solí s oximovou skupinou v poloze 2 nebo 4 modifikovaných alkylací na dusíku s variabilními substituenty. Sloučeniny prokázaly zvýšený průnik do centrální nervové soustavy v porovnání s pralidoximem, ale byly shledány relativně více toxické než pralidoxim a testování reaktivační aktivity nebylo publikováno.Okuno et al. in 2008 (Okuno S, Sakurada K, Ohta H, Ikegaya H, Kazui Y, Akutsu T, Takatori T, Iwadate K. Toxicol Appl Pharmacol 2008; 227: 8-15) prepared a group of monopyridinium salts with an oxime group at position 2 or 4 modified by alkylation on nitrogen with variable substituents. The compounds showed increased penetration into the central nervous system compared to pralidoxime, but were found to be relatively more toxic than pralidoxime and testing for reactivation activity was not reported.
RR
X R:CH3(CH2)7, CH3(CH2)8, CH3(CH2)11,4-tBut-PhCH2, Ph(CH2)2 XR: CH 3 (CH 2 ) 7 , CH 3 (CH 2 ) 8 , CH 3 (CH 2 ) 11 , 4-tBut-PhCH 2 , Ph(CH 2 ) 2
NOHFOOT
Jeong et al. v roce 2009 (Jeong HC, Kang NS, Park NJ, Yum EK, Jung YS. Bioorg Med Chem Lett 2009; 19: 1214-1217) popsala monopyridiniový deriváty s oximovou skupinou v poloze 4 substituované fluorem v poloze 2 nebo 3. Sloučeniny byly testovány na myší nebo lidské erytrocytámí AChE inhibované paraoxonem, kde prokázaly nižší reaktivační účinnost v porovnání s pralidoximem.Jeong et al. in 2009 (Jeong HC, Kang NS, Park NJ, Yum EK, Jung YS. Bioorg Med Chem Lett 2009; 19: 1214-1217) reported monopyridinium derivatives with an oxime group at position 4 substituted with fluorine at position 2 or 3. The compounds were tested on paraoxon-inhibited murine or human erythrocyte AChE, where they demonstrated lower reactivation efficiency compared to pralidoxime.
Quinn et al. v roce 2018 (patent US 9884052 B2) patentovali monopyridiniové sloučeniny s ortho polohou oximové skupiny, variabilní polohou methoxyskupiny (připraveny byly však konkrétně jen látky s ortho a para polohou methoxyskupiny) a dvěma dalšími substituenty. Připravené sloučeniny nebyly použity na přímou reaktivaci AChE, ale na reaktivaci zestárlé AChE po inhibici analogem sarinu tj. 7-methoxymethylfosfonyl-4-methylumbelliferonem. Reaktivace zestárléQuinn et al. in 2018 (US patent 9884052 B2) they patented monopyridinium compounds with an ortho position of the oxime group, a variable position of the methoxy group (however, only substances with an ortho and para position of the methoxy group were specifically prepared) and two other substituents. The prepared compounds were not used for direct reactivation of AChE, but for reactivation of aged AChE after inhibition by a sarin analogue, i.e. 7-methoxymethylphosphonyl-4-methylumbelliferone. Reactivation aged
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AChE u jedné testované sloučeniny dosahovala maxima po 8,7 % po 24 h a nebyla porovnána s jinou sloučeninou nebo standardem.AChE for one tested compound peaked at 8.7% after 24 h and was not compared to another compound or standard.
R1 ,bL ΘR 1 , bL Θ
H3COt; tta ^'r2 nohH 3 CO 2 ; tta ^' r2 foot
Podstata vynálezuThe essence of the invention
Předmětem tohoto vynálezu jsou reaktivátory aktivity AChE na bázi monopyridiniových solí. Předmětem tohoto vynálezu jsou sloučeniny spadající do obecného vzorce I,The subject of this invention are reactivators of AChE activity based on monopyridinium salts. The subject of this invention are compounds belonging to the general formula I,
a jejich farmaceuticky přijatelné adiční soli s kyselinami, kde Xje farmaceuticky přijatelný aniont; pro použití jako léčiva, zejména pro léčení intoxikací organofosforovými sloučeninami.and pharmaceutically acceptable acid addition salts thereof, wherein X is a pharmaceutically acceptable anion; for use as a medicine, in particular for the treatment of intoxication with organophosphorus compounds.
Látky obecného vzorce I jsou antidota reaktivující acetylcholinesterasu při expozici organofosforovým sloučeninám.Substances of general formula I are an antidote reactivating acetylcholinesterase upon exposure to organophosphorus compounds.
Sloučenina obecného vzorce I je vybrána z látek majících následující kombinaci R1, R2 a R3, přičemž X je farmaceuticky přijatelný aniont:A compound of general formula I is selected from substances having the following combination of R 1 , R 2 and R 3 , where X is a pharmaceutically acceptable anion:
Ve výhodném provedení je sloučenina obecného vzorce vybrána z následujících kombinací X, R1, R2 a R3:In a preferred embodiment, the compound of the general formula is selected from the following combinations of X, R 1 , R 2 and R 3 :
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V rámci předkládaného vynálezu bylo překvapivě zjištěno, že sloučeniny podle vynálezu jeví významněji vyšší reaktivační aktivitu vůči AChE inhibované organofosforovými sloučeninami než sloučeniny známé ze stavu techniky.Within the framework of the present invention, it was surprisingly found that the compounds according to the invention show a significantly higher reactivation activity towards AChE inhibited by organophosphorus compounds than the compounds known from the prior art.
Sloučeniny podle vynálezu jsou s výhodou vybrané ze skupiny sestávající z 3-fluor-2(hydroxyimino)methyl-1 -methylpyridinium-j odidu, 3 -chlor-2-(hydroxyimino)methyl-1 methylpyridinium-j odidu, 3 -brom-2-(hydroxyimino)methyl-1 -methylpyridinium-jodidu, 3 hydroxy-2-(hydroxyimino)methyl-1 -methylpyridinium-j odidu, 2-(hydroxyimino)methyl-3 methoxy-1 -methylpyridinium-j odidu, 2-(hydroxyimino)methyl-1 -methyl-3 (trifluormethyl)pyridinium -jodidu, a jejich farmaceuticky přijatelné adiční soli s kyselinami.The compounds according to the invention are preferably selected from the group consisting of 3-fluoro-2(hydroxyimino)methyl-1-methylpyridinium iodide, 3-chloro-2-(hydroxyimino)methyl-1-methylpyridinium iodide, 3-bromo-2 -(hydroxyimino)methyl-1-methylpyridinium iodide, 3-hydroxy-2-(hydroxyimino)methyl-1-methylpyridinium iodide, 2-(hydroxyimino)methyl-3-methoxy-1-methylpyridinium iodide, 2-(hydroxyimino) )methyl-1-methyl-3-(trifluoromethyl)pyridinium iodide, and their pharmaceutically acceptable acid addition salts.
Předmětem tohoto vynálezu jsou dále sloučeniny 3-fluor-2-(hydroxyimino)methyl-lmethylpyridinium X, 3-chlor-2-(hydroxyimino)methyl-l-methylpyridinium X, 3-brom-2(hydroxyimino)methyl-1 -methylpyridinium X, 2-(hydroxyimino)methyl-1 -methyl-3 (trifluormethyl)pyridinium X, kde X je farmaceuticky přijatelný aniont.The subject of this invention is also the compounds 3-fluoro-2-(hydroxyimino)methyl-1-methylpyridinium X, 3-chloro-2-(hydroxyimino)methyl-1-methylpyridinium X, 3-bromo-2(hydroxyimino)methyl-1-methylpyridinium X , 2-(hydroxyimino)methyl-1-methyl-3(trifluoromethyl)pyridinium X, where X is a pharmaceutically acceptable anion.
Ve výhodném provedení jsou předmětem vynálezu sloučeniny, kde jsou X, R1, R2 a R3 vybrány z následujících kombinací:In a preferred embodiment, the subject of the invention are compounds where X, R 1 , R 2 and R 3 are selected from the following combinations:
Předmětem vynálezu je rovněž farmaceutický přípravek obsahující alespoň jeden monopyridiniový derivát uvedený výše, a alespoň jeden farmaceuticky přijatelný nosič. Vhodné nosiče jsou obzvláště plnidla jako sacharidy, škroby, dále karboxymethylový škrob, zesíťovaný polyvinylpyrrolidin, alginová kyselina a její soli, rozpouštědla, pojivá.The subject of the invention is also a pharmaceutical preparation containing at least one monopyridinium derivative mentioned above and at least one pharmaceutically acceptable carrier. Suitable carriers are especially fillers such as carbohydrates, starches, carboxymethyl starch, cross-linked polyvinylpyrrolidine, alginic acid and its salts, solvents, binders.
Farmaceuticky přijatelný aniont může být s výhodou vybrán ze skupiny zahrnující chlorid, bromid, jodid, acetát, adipát, askorbát, aspartát, benzensulfonát, benzoát, citrát, ethansulfonát, formiát, fosfát, fůmarát, glukonát, glukuronát, glutamát, glutarát, glykolát, laktát, laurát, maleát, malonát, malát, mesylát, nitrát, oleát, oxalát, palmitát, pamoát, pyroglutamát, salicylát, sebakát, stearát, sukcinát, sulfát, tartarát, thiokyanát, tosylát, trifluoracetát, trifluormethansulfonát.The pharmaceutically acceptable anion may preferably be selected from the group consisting of chloride, bromide, iodide, acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, citrate, ethanesulfonate, formate, phosphate, fumarate, gluconate, glucuronate, glutamate, glutarate, glycolate, lactate , laurate, maleate, malonate, malate, mesylate, nitrate, oleate, oxalate, palmitate, pamoate, pyroglutamate, salicylate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, trifluoroacetate, trifluoromethanesulfonate.
Objasnění výkresůClarification of drawings
Obr. 1: Relativní aktivity AChE inhibované sarinem a reaktivované v přítomnosti monopyridiniových solí při koncentraci 100 nebo 10 μΜ.Giant. 1: Relative activities of AChE inhibited by sarin and reactivated in the presence of monopyridinium salts at a concentration of 100 or 10 μΜ.
Obr. 2: Relativní aktivity AChE inhibované paraoxonem a reaktivované v přítomnosti monopyridiniových solí při koncentraci 100 nebo 10 pM.Giant. 2: Relative activities of AChE inhibited by paraoxon and reactivated in the presence of monopyridinium salts at a concentration of 100 or 10 pM.
-5CZ 309329 B6-5CZ 309329 B6
Příklady uskutečnění vynálezuExamples of implementation of the invention
Vynález je popsán v následujících příkladech, které nijak neomezují jeho rozsah. Výchozí suroviny pro sloučeninu obecného vzorce I jsou dostupné z komerčních zdrojů.The invention is described in the following examples, which do not limit its scope in any way. The starting materials for the compound of general formula I are available from commercial sources.
Příklad 1: Příprava monopyridiniových solíExample 1: Preparation of monopyridinium salts
Jodmethan (7,20 mmol) byl přidán do roztoku pyridinaldoximu (1,44 mmol) v acetonu nebo v chloroformu (15 ml) při teplotě místnosti, a následně byla reakce refluxována 6 až 72 h. Reakční směs byla ochlazena na teplotu místnosti, precipitována, filtrována za sníženého tlaku a promyta acetonem nebo chloroformem. Surový produkt (monopyridiniová sůl) byl vysušen za sníženého tlaku.Iodomethane (7.20 mmol) was added to a solution of pyridinaldoxime (1.44 mmol) in acetone or chloroform (15 mL) at room temperature, and then the reaction was refluxed for 6 to 72 h. The reaction mixture was cooled to room temperature, precipitated , filtered under reduced pressure and washed with acetone or chloroform. The crude product (monopyridinium salt) was dried under reduced pressure.
Analogickým postupem byly připraveny následující deriváty, jejichž charakterizace je uvedena:The following derivatives were prepared by an analogous procedure, the characterization of which is given:
3-fluor-2-(hydroxyimino)methyl-l-methylpyridinium-jodid (K1222)3-Fluoro-2-(hydroxyimino)methyl-1-methylpyridinium iodide (K1222)
Výtěžek 51 %, t.t. 181 až 182 °C. Ή NMR (500 MHz, DMSO-í/6) δ 13,24 (s, 1H), 9,02 (d, = 6,1 Hz, 1H), 8,70 (t, J = 9,0 Hz, 1H), 8,55 (s, 1H), 8,21-8,17 (m, 1H), 4,40 (s, 3H). 13C NMR (126 MHz, DMSO-ď,) δ 158,94, 156,89, 144,14, 144,11, 138,72, 138,69, 137,45, 137,27, 133,08, 132,92, 127,76, 127,69, 47,53. HRMS (ESI) vypočteno pro C7H8FN2O+ [M+H]+ 155,06152, nalezeno 155,06125.Yield 51%, mp 181 to 182 °C. Ή NMR (500 MHz, DMSO-í/ 6 ) δ 13.24 (s, 1H), 9.02 (d, = 6.1 Hz, 1H), 8.70 (t, J = 9.0 Hz, 1H), 8.55 (s, 1H), 8.21-8.17 (m, 1H), 4.40 (s, 3H). 13 C NMR (126 MHz, DMSO-d,) δ 158.94, 156.89, 144.14, 144.11, 138.72, 138.69, 137.45, 137.27, 133.08, 132 .92, 127.76, 127.69, 47.53. HRMS (ESI) calcd for C 7 H 8 FN 2 O + [M+H] + 155.06152, found 155.06125.
3-chlor-2-(hydroxyimino)methyl-l-methylpyridinium-jodid (K1224)3-chloro-2-(hydroxyimino)methyl-1-methylpyridinium iodide (K1224)
Výtěžek 33 %, t.t. 192 až 194 °C. Ή NMR (500 MHz, DMSO-í/6) δ 13,11 (s. 1H), 9,14 (d, J = 6,1 Hz, 1H), 8,86 (d, J = 8,1 Hz, 1H), 8,42 (s, 1H), 8,18-8,15 (m, 1H), 4,36 (s, 3H). 13C NMR (126 MHz, DMSO-í/e) δ 146,80, 146,28, 144,82, 140,51, 134,18, 127,30, 48,43. HRMS (ESI) vypočteno pro C7H8C1N2O+ [M+H]+ 171,03197, nalezeno 171,03175.Yield 33%, mp 192 to 194 °C. Ή NMR (500 MHz, DMSO-í/ 6 ) δ 13.11 (s. 1H), 9.14 (d, J = 6.1 Hz, 1H), 8.86 (d, J = 8.1 Hz , 1H), 8.42 (s, 1H), 8.18-8.15 (m, 1H), 4.36 (s, 3H). 13 C NMR (126 MHz, DMSO-1/e) δ 146.80, 146.28, 144.82, 140.51, 134.18, 127.30, 48.43. HRMS (ESI) calcd for C 7 H 8 C 1 N 2 O + [M+H] + 171.03197, found 171.03175.
-brom-2-(hydroxyimino)methyl-1 -methylpyridinium-j odid (K1226)-bromo-2-(hydroxyimino)methyl-1-methylpyridinium iodide (K1226)
Výtěžek 45 %, t.t. 197 až 199 °C. Ή NMR (500 MHz, DMSO-í/6) δ 13,03 (s, 1H), 9,16 (d, J = 5,9 Hz, 1H), 8,98 (d, J = 8,4 Hz, 1H), 8,42 (s, 1H), 8,08-8,05 (m, 1H), 4,34 (s, 3H), 13C NMR (126 MHz, DMSO-í/e) δ 149,35, 147,17, 145,74, 142,01, 127,46, 123,75, 48,52. HRMS (ESI) vypočteno pro C7H8BrN2O+ [M+H]+ 214,98145, nalezeno 214,98114.Yield 45%, mp 197 to 199 °C. Ή NMR (500 MHz, DMSO-í/ 6 ) δ 13.03 (s, 1H), 9.16 (d, J = 5.9 Hz, 1H), 8.98 (d, J = 8.4 Hz , 1H), 8.42 (s, 1H), 8.08-8.05 (m, 1H), 4.34 (s, 3H), 13 C NMR (126 MHz, DMSO-í/e) δ 149 .35, 147.17, 145.74, 142.01, 127.46, 123.75, 48.52. HRMS (ESI) calcd for C 7 H 8 BrN 2 O + [M+H] + 214.98145, found 214.98114.
-hydroxy-2-(hydroxyimino)methyl-1 -methylpyridinium-j odid (K1228)-hydroxy-2-(hydroxyimino)methyl-1-methylpyridinium iodide (K1228)
Výtěžek 28 %, t.t. 214 až 216 °C. Ή NMR (500 MHz, DMSO-í/6) δ 12,81 (br s, 1H), 8,60 (d, J= 5,9 Hz, 1H), 8,49 (s, 1H), 8,01 (d, J = 8,5 Hz, 1H), 7,92-7,89 (m, 1H), 4,34 (s, 3H). 13C NMR (126 MHz, DMSO-í/e) δ 156,03, 140,81, 138,70, 133,83, 131,19, 127,27, 47,96. HRMS (ESI) vypočteno pro C7HgN2O2 +[M+H]+ 153,06585, nalezeno 153,06560.Yield 28%, mp 214 to 216 °C. Ή NMR (500 MHz, DMSO-í/ 6 ) δ 12.81 (br s, 1H), 8.60 (d, J= 5.9 Hz, 1H), 8.49 (s, 1H), 8, 01 (d, J = 8.5 Hz, 1H), 7.92-7.89 (m, 1H), 4.34 (s, 3H). 13 C NMR (126 MHz, DMSO-1/e) δ 156.03, 140.81, 138.70, 133.83, 131.19, 127.27, 47.96. HRMS (ESI) calcd for C 7 HgN 2 O 2 + [M+H] + 153.06585, found 153.06560.
2-(hydroxyimino)methyl-3 -methoxy-1 -methylpyridinium-j odid (K123 0)2-(Hydroxyimino)methyl-3-methoxy-1-methylpyridinium iodide (K123 0)
Výtěžek 46 %, t.t. 169 až 171 °C. Ή NMR (500 MHz, DMSO-í/6) δ 12,89 (s, 1H), 8,70 (d, J = 6,0 Hz, 1H), 8,39 (s, 1H), 8,36 (d, J = 8,8 Hz, 1H), 8,09 (dd, J = 8,9, 6,1 Hz, 1H), 4,35 (s, 3H), 4,05 (s, 3H). 13CNMR(126 MHz, DMSO-í/6) δ 156,66, 139,52, 139,08, 136,30, 127,51, 127,36, 57,90, 48,16. HRMS (ESI) vypočteno pro C8HnN2O2 + [M+H]+ 167,08150, nalezeno 167,08125.Yield 46%, mp 169 to 171 °C. Ή NMR (500 MHz, DMSO-í/ 6 ) δ 12.89 (s, 1H), 8.70 (d, J = 6.0 Hz, 1H), 8.39 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.09 (dd, J = 8.9, 6.1 Hz, 1H), 4.35 (s, 3H), 4.05 (s, 3H) . 13 CNMR (126 MHz, DMSO-1/ 6 ) δ 156.66, 139.52, 139.08, 136.30, 127.51, 127.36, 57.90, 48.16. HRMS (ESI) calcd for C 8 HnN 2 O 2 + [M+H] + 167.08150, found 167.08125.
2-(hydroxyimino)methyl-l-methyl-3-(trifluormethyl)pyridinium-jodid (K1232)2-(Hydroxyimino)methyl-1-methyl-3-(trifluoromethyl)pyridinium iodide (K1232)
Výtěžek 13 %, t.t. 176 až 178 °C. Ή NMR (500 MHz, DMSO-í/6) δ 13,17 (s, 1H), 9,40 (d, J = 6,1 Hz, 1H), 9,10 (d, J = 8,3 Hz, 1H), 8,58 (s, 1H), 8,41-8,38 (m, 1H), 4,36 (s, 3H). 13C NMRYield 13%, mp 176 to 178 °C. Ή NMR (500 MHz, DMSO-í/ 6 ) δ 13.17 (s, 1H), 9.40 (d, J = 6.1 Hz, 1H), 9.10 (d, J = 8.3 Hz , 1H), 8.58 (s, 1H), 8.41-8.38 (m, 1H), 4.36 (s, 3H). 13 C NMR
-6CZ 309329 B6 (126 MHz, DMSCM,) δ 150,79, 146,69, 143,78, 139,80, 128,32, 128,05, 127,75, 122,55, 120,36, 47,76. HRMS (ESI) vypočteno pro C8H8F3N2O+ [M+H]+ 205,05832, nalezeno 205,05788.-6CZ 309329 B6 (126 MHz, DMSCM,) δ 150.79, 146.69, 143.78, 139.80, 128.32, 128.05, 127.75, 122.55, 120.36, 47, 76. HRMS (ESI) calcd for C 8 H 8 F 3 N 2 O + [M+H] + 205.05832, found 205.05788.
Příklad 2: Testování sloučenin na reaktivaci lidské AChEExample 2: Testing compounds for reactivation of human AChE
Sloučeniny obecného vzorce I byly testovány na schopnost reaktivace enzymu lidské acetylcholinesterasy (AChE), která byla inhibována organofosforovými inhibitory. Pro inhibici AChE byly jednotlivě vybrány nervově paralytická látka sarin a organofosforový insekticid paraoxon.The compounds of general formula I were tested for their ability to reactivate the enzyme human acetylcholinesterase (AChE), which was inhibited by organophosphorus inhibitors. The nerve paralytic agent sarin and the organophosphorus insecticide paraoxon were selected individually for AChE inhibition.
Zdrojem lidského enzymu byly červené krvinky získané z krve zdravých dobrovolníků. Enzym byl inhibován 1 h zvoleným organofosfátem (sarin, paraoxon). Následně byl odstraněn přebytečný inhibitor za pomocí SPE kolony. Inhibovaný enzym byl inkubován 10 min s výslednou koncentrací reaktivátoru 100 μΜ při 37 °C. Reakce byla odstartována přidáním substrátu acetylcholinu. Aktivita AChE byla měřena spektrofotometricky při 436 nm modifikovanou metodou podle Ellmana. Všechna měření byla provedena v triplikátu. Získaná data byla použita ke kalkulaci reaktivační účinnosti dle rovnice:The source of the human enzyme was red blood cells obtained from the blood of healthy volunteers. The enzyme was inhibited for 1 h with a selected organophosphate (sarin, paraoxon). Subsequently, the excess inhibitor was removed using an SPE column. The inhibited enzyme was incubated for 10 min with a final reactivator concentration of 100 μΜ at 37 °C. The reaction was started by adding the substrate acetylcholine. AChE activity was measured spectrophotometrically at 436 nm using a modified Ellman method. All measurements were performed in triplicate. The obtained data were used to calculate the reactivation efficiency according to the equation:
R = | 1xlOO kde AAo vyjadřuje změny absorbance neinhibované AChE (rozpouštědlo bylo použito místo roztoku inhibitoru), AAi vyjadřuje změny absorbance inhibované AChE a AAr vyjadřuje změny absorbance reaktivované AChE.R = | 1xlOO where AAo represents absorbance changes of uninhibited AChE (solvent was used instead of inhibitor solution), AAi represents absorbance changes of inhibited AChE and AA r represents absorbance changes of reactivated AChE.
Aktivita AChE v případě inhibice šarmem a paraoxonem reaktivované v přítomnosti monopyridiniových solí byla porovnána se standardem pralidoximem. Výsledné relativní aktivity reaktivované AChE jsou uvedeny v Tabulce 1 a Obr. 1 a 2.AChE activity when inhibited by charm and paraoxon reactivated in the presence of monopyridinium salts was compared with the standard pralidoxime. The resulting relative activities of reactivated AChE are shown in Table 1 and Fig. 1 and 2.
Tabulka 1: Relativní aktivity AChE inhibované sarinem nebo paraoxonem a reaktivované v přítomnosti monopyridiniových solí při koncentraci 100 nebo 10 μΜ.Table 1: Relative activities of AChE inhibited by sarin or paraoxon and reactivated in the presence of monopyridinium salts at a concentration of 100 or 10 μΜ.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5180831A (en) * | 1990-08-10 | 1993-01-19 | Georgia Tech Research Corporation | Quaternary pyridinium compounds |
| US20140323473A1 (en) * | 2013-01-24 | 2014-10-30 | University Of Iowa Research Foundation | Compounds and methods to treat organophosphorus poisoning |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5180831A (en) * | 1990-08-10 | 1993-01-19 | Georgia Tech Research Corporation | Quaternary pyridinium compounds |
| US20140323473A1 (en) * | 2013-01-24 | 2014-10-30 | University Of Iowa Research Foundation | Compounds and methods to treat organophosphorus poisoning |
Non-Patent Citations (1)
| Title |
|---|
| JEONG, Hee Chun, et al. Fluorinated pyridinium oximes as potential reactivators for acetylcholinesterases inhibited by paraoxon organophosphorus agent. Bioorganic & medicinal chemistry, 2009, 17.17: 6213-6217, ISSN: 0968-0896 * |
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