US3812147A - Acylxylidide local anaesthetics - Google Patents
Acylxylidide local anaesthetics Download PDFInfo
- Publication number
- US3812147A US3812147A US00164022A US16402271A US3812147A US 3812147 A US3812147 A US 3812147A US 00164022 A US00164022 A US 00164022A US 16402271 A US16402271 A US 16402271A US 3812147 A US3812147 A US 3812147A
- Authority
- US
- United States
- Prior art keywords
- ether
- mole
- amide
- butyroxylidide
- filtered
- 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.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/38—Acyl halides
- C07C53/46—Acyl halides containing halogen outside the carbonyl halide group
- C07C53/50—Acyl halides containing halogen outside the carbonyl halide group of acids containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
Definitions
- the present invention relates to 2-alkyl-2-alkylamino- 2',6-acetoxylidide local anaesthetic compounds.
- acylxylidide local anaesthetic compounds which are commercially available are N-n-butylpipecolyl- 2,6- xylidide or bupivacaine sold under the trademark Marcaine having the structural formula O C H:
- the principal object of the present invention to provide compounds which generally have the combined properties of long lasting local anaesthetic effect or high local anaesthetic activity, a satisfactory low level of tissue irritation and a satisfactory low acute toxicity.
- the compounds of the present invention are the 2- alkyl-2-alkylamino-2',6' acetoxylidide local anaesthetic compounds having the structural formula wherein R is ethyl, propyl or butyl; R and R may be the same or diiferent alkyl radicals and are methyl, ethyl,
- Representative compounds include the following: 2- diethylamino-Z,6'-n-butyroxylidide, which can be alternatively named 2-ethyl-2-diethylamino-2',6'-acetoxylidide,
- R R and R are as stated above and X is a bromine or a chlorine atom. More detailed and other procedures of preparation are given in the representative examples hereinafter.
- racemic compounds may be resolved into their dand l-optical isomers by treatment with land d-tartaric acid.
- the compounds of the invention are useful as local anaesthetics in the conventional manner and employing conventional dosages thereof.
- These bases may be conventionally used in the form of solutions of their pharmaceutically acceptable salts, e.g., the hydrochlorides, tartrates and citrates.
- EXAMPLE 1 This example illustrates the preparation of Z-diethylamino-2', -n-butyroxylidide or or. (diethylamino) nbutyro-2,6-xylidide.
- a product sufiiciently pure for the following reaction was obtained by omitting the vacuum distillation and allowing a stream of dry argon (or nitrogen) to pass through the u-bromo-n-butyryl chloride at 80100 C. for 1.5-2 hours after the main bulk of thionyl chloride had been distilled 01f.
- EXAMPLE 2 This example illustrates the preparation of Z-(N-ethyln-propylamino) 2',6' butyroxylidide or a-(N-ethyl-n propylamino)-n-butyro-2,6-xylidide.
- the uncrystallized product contains some of the bromo compound but was sufliciently pure for the following step.
- the solid fraction I and the acid solution II were corn-t bined and based out with 7 M NaOH and the freed base was extracted into ether. After drying over anhydrous sodium sulfate the ether extract was filtered and evaporated yielding 93 g. of a partly solidifying marooncolored residue.
- the ether extracts yielded 79.2 g. of a base that contained mainly the desired compound and which was sufficiently pure for the next step.
- the hydrochloride hydrate was prepared from the base with ethereal hydrogen chloride and addition of water. Recrystallized from ethanol/ether it melted at 199-1995 C. Calculated for the base (C H N O): C, 72.5; H, 9.74; N, 11.3. Found: C, 72.5; H, 9.81; N, 11.2.
- the bases were liberated from the two tartrates with sodium hydroxide in water.
- the bases from (I) and (II) had specific rotation of +34.1 and -32.8, respectively.
- the rotation of their hydrochlorides were +6.2 and -6.2, respectively, after recrystallization from abs. ethanol-ether.
- Their melting points were identical, 184- 185 C.
- racemic compounds of Examples 1 and 4-8 can be resolved into the dand l-optical isomers thereof by a procedure similar to the one of Example 3.
- EXAMPLE 4 This example illustrates the preparation of Z-diethylamino-2',6-n-valeroxylidide.
- 2-diethylamino-Z,6'-n-valeroxylidide A mixture of 2-bromo-2,6'-n-valeroxylidide (0.176 mole), diethylamine (0.528 mole), and benzene (125 ml.) was placed in a pressure vessel and heated to C. for 35 hours. After cooling, the dark brown content was filtered and the solid (23.2 g. of diethylammonium bromide) washed carefully with benzene.
- the filtrate was extracted with 4 N hydrochloric acid (3 X 50 ml.), the acid extract washed with ether (3X 50 ml.), and based out with 7 N sodium hydroxide under cooling and stirring and in the presence of ether (100 ml.). After two further extractions with ether (2X 50 ml.) the combined ether extracts were dried (Na SO and the ether evaporated leaving 16.5 g. of residue.
- the hydrochloride was prepared from the residue by dissolving it in ether and adding ethereal hydrogen chloride. The hydrochloride was recrystallized from abs. ethanolzether (3:5) twice M.P. 205-206 C.
- EXAMPLE 5 This example illustrates the preparation of 2-pyrrolidino-2,6'-n-butyroxylidide.
- 2-pyrrolidino-2',6'-n-butyroxylidide A mixture of 2- bromo-2',6'-butyroxylidide (0.0463 mole), pyrrolidine (0.13 g. mole) and benzene (100 ml.) was refluxed for 21 hrs. The solvent and excess pyrrolidine were evaporated in vacuo leaving a partly solidifying residue that was dissolved in 1 N hydrochloric acid ml.). The acid solution was washed with ether (2X 50 ml.) whereafter it was made alkaline with 7 N sodium hydroxide and extracted with ether (3 X 50 ml.). The ether extract was dried (Na SO and the solvent evaporated in vacuo.
- the hydrocloride was prepared by dissolving the residue in ether and adding a. sufficient amount of gaseous hydrogen chloride; yield 0.0414 mole. After two recrystallizations from 95% ethanol:ethyl acetate (1:1) the colorless crystals melted at 238-240 C. Calculated for C H N OC1: C, 64.7; H, 8.49; CI, 11.9. Found: C, 64.9; H, 8.59; Cl, 12.1. LR.
- EXAMPLE 6 This example illustrates the preparation of Z-(N-ethyln-butylamino) 2,6' n butyroxylidide.
- 2-n-butylamino 2,6 butyroxylidide A mixture of 2-iodo-2', butyroxylidide (0.0315 mole), n-butylamine (0.0945 mole) and anhydrous benzene (100 ml.) was refluxed for hrs. After cooling, the benzene and excess n-butylamine were evaporated in vacuum. The residue was taken up in 1 N hydrochloric acid, washed with ether (3X 25 ml.)., filtered, made alkaline to a pH of 9 with 7 N sodium hydroxide and extracted with ether (4X 25 ml.).
- amide NH 2960 (s) and 2890 (ms) (CH and CH 2615-2595 (m, broad); 2505 (m, NH 1680 (s, amide I); 1594 (w, Ph); 1530 (s, amide II); 1470 (s); 1228 (m, amide III); 781 (m, 3 adjacent Ph hydrogens out of plane).
- EXAMPLE 7 This example illustrates the preparation of Z-dimethylamino-2',6'-caproylxylidide.
- 2-bromo 2',6 caproylxylidide A mixture of 2,6- xylidine (0.125 mole) and glacial acetic acid (115 ml.) was cooled to 10 C. in a 1 liter bottle and-2-bromocaproyl bromide (0.136 mole) was added and mixed rapidly. As fast as possible this was followed by a cool (50 C.) solution of sodium acetate trihydrate (45 g.) in water (190 ml.). The mixture was shaken for 45 min. and filtered.
- 2-dimethylamino 2,6' caproylxylidide A mixture of 2-bromo-2,6-caproylxylidide (0.119 mole), dimethylamine (0.356 mole) and benzene (177 ml.) were heated in a pressure vessel for 22 hrs. at 100 C. After cooling the reaction mixture was filtered. The weight of the obtained dimethylammonium bromide indicated that 97% of the bromo compound had reacted. The filtrate was extracted with 4 N hydrochloric acid (1 X 50+2 25 ml.), the acid solution based out to pH 11 with 7 N sodium hydroxide and extracted with ether (3X 50 ml.). The combined ether extracts were dried (Na SO and evaporated in vacuo.
- 2-pyrrolidino-2,6'-n-valeroxylidide A mixture of 2- iodo 2,6' n valeroxylidide (0.0754 mole), pyrrolidine (0.226 mole) and benzene (65 ml.) was heated in a pres sure vessel for 24 hrs. at C. After cooling, the benzene and excess pyrrolidine were evaporated in vacua. The residue was stirred with water ml.) for 30 min. and filtered. To the filtrate 7 N sodium hydroxide was added (pH 11) with stirring and after 30 min. the solid base was filtered, washed carefully and repeatedly with water and dried in vacuo.
- A is Z-diethylamino-2',6'-n-butyroxylidide.
- B is 2-(N-ethyl-n-propylamino)-2',6'-n-butyroxylidide.
- C is the d-optical isomer of the racemic compound B.
- D is the l-optical isomer of the racemic compound B.
- E is 2-diethylamino-2,6'-n-valeroxylidide.
- F is 2-pyrrolidino-2',6'-n-butyroxylidide.
- Tables I through V contain comparative data on the duration of several of these local anaesthetic compounds
- Table VI contains comparative data on the degree of tissue irritation of several of these local anaesthetic compounds
- Tables VII and VIII contain comparative data on the acute toxicity of several of these local anaesthetic compounds.
- Noam-Solutions did not contain epinephrine.
- Irritation indices reported in Table VI are determined Norm-All solutions contained 12100,!00 epinephrine. the followmg manner:
- a 2-alkyl-2-alkylamino-2',6'-acetoxylidide local .anaesthetic compound having the structural formula wherein R is ethyl, propyl or butyl; R and R are each separately seelcted from the group consisting of methyl, ethyl, propyl and butyl; R together with 'R is tetramethylene; the total sum of carbon atoms in R R and R is at least six; and the pharmaceutically acceptable salts thereof.
- the local anaesthetic compound defined by claim 1 which is Z-diethylamino-Z,6'-n-butyroxylidide.
- the local anaesthetic compound defined by claim 1 which is 2-(N-ethyl-n-propylamino)-2,6'-n-butyroxylidide.
- the local anaesthetic compound defined by claim 1 which is 2-pyrrolidin0-2',6-n-butyroxylidide.
- the local anaesthetic compound defined by claim 1 which is 2-(N-ethyl-n-butylamino)-2',6'-n-butyroxylidide.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Priority Applications (27)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US00164022A US3812147A (en) | 1970-12-22 | 1971-07-19 | Acylxylidide local anaesthetics |
SE7115656A SE393374B (sv) | 1970-12-22 | 1971-12-07 | Forfarande for framstellning av 2-alkyl-2-dialkylamino-2, '6'-acetoxylidider med lokalestetisk effekt |
BE776656A BE776656A (fr) | 1970-12-22 | 1971-12-14 | Anesthetiques locaux a l'acylxylidide |
SU1726195A SU419023A3 (ru) | 1970-12-22 | 1971-12-15 | Способ получения ацильных ксилидидов |
HUAA690A HU163373B (pl) | 1970-12-22 | 1971-12-16 | |
DE2162744A DE2162744C3 (de) | 1970-12-22 | 1971-12-17 | N,N-Disubstituierte α -Aminocarbonsäure-(2',6'-xylidide) und diese Verbindungen enthaltende lokalanästhetische Mittel |
DK619771AA DK139814B (da) | 1970-12-22 | 1971-12-17 | Analogifremgangsmåde til fremstilling af lokalanæstetisk aktive 2-alkyl-2-(dialkylamino- eller pyrrolidino)-2',6'-acetoxylidider i optisk aktiv eller racemisk form eller farmaceutisk acceptable salte deraf. |
NO4669/71A NO135934C (pl) | 1970-12-22 | 1971-12-17 | |
IT54845/71A IT1066334B (it) | 1970-12-22 | 1971-12-18 | Composizione an estetica locale della 2-alchil-2-alchil ammino 2',6' acetossilidide e relativo procedimento di produzione |
AT1089671A AT319205B (de) | 1970-12-22 | 1971-12-20 | Verfahren zur Herstellung von neuen razemischen oder optisch aktiven 2-Alkyl-2-dialkylaminoacet-2',6'-xylididen und ihren Salzen |
IE1609/71A IE35909B1 (en) | 1970-12-22 | 1971-12-20 | Acylxylidide local anaesthetics |
AU37099/71A AU468489B2 (en) | 1970-12-22 | 1971-12-20 | Acyl xylidide local anaesthetics |
FR7145983A FR2118985B1 (pl) | 1970-12-22 | 1971-12-21 | |
DD159785A DD99779A5 (pl) | 1970-12-22 | 1971-12-21 | |
AR239721A AR193840A1 (es) | 1970-12-22 | 1971-12-21 | Un procedimiento para la preparacion de compuestos de 2-alquil-2-alquilamino-2',6'-acetoxilidida |
ES398210A ES398210A1 (es) | 1970-12-22 | 1971-12-21 | Un procedimiento para preparar compuestos de acil-xilidida. |
CH1862971A CH573396A5 (en) | 1970-12-22 | 1971-12-21 | Acylxylidides - as local anaesthetics |
GB5937771A GB1369259A (en) | 1970-12-22 | 1971-12-21 | Acylxylidide local anaesthetics |
BR8466/71A BR7108466D0 (pt) | 1970-12-22 | 1971-12-21 | Anestesicos locais e acilxilididas e processo de sua preparacao |
PL1971152331A PL83097B1 (pl) | 1970-12-22 | 1971-12-21 | |
CA130,662A CA943966A (en) | 1970-12-22 | 1971-12-21 | Acyl xylidide local anaesthetics |
NLAANVRAGE7117644,A NL172149C (nl) | 1970-12-22 | 1971-12-22 | Werkwijze voor het bereiden van een farmaceutisch preparaat met locaal-anesthetische werking dat een dialkylamino-2',6'-butyroxylidide en/of een farmaceutisch aanvaardbaar zout daarvan bevat, alsmede de onder toepassing van deze werkwijze verkregen gevormde farmaceutische preparaten en werkwijze voor het bereiden van dialkylamino-2',6'-butyroxilididen en de farmaceutisch aanvaardbare zouten daarvan. |
FI3658/71A FI55027C (fi) | 1970-12-22 | 1971-12-22 | Foerfarande foer framstaellning av lokalanestetiskt verkande 2-alkyl-2-alkylamino-2',6'-acetoxylidider |
JP10453571A JPS5644063B1 (pl) | 1970-12-22 | 1971-12-22 | |
US447680A US3862321A (en) | 1971-07-19 | 1974-03-04 | Acyl xylidide local anaesthetics |
ES425626A ES425626A1 (es) | 1970-12-22 | 1974-04-24 | Un procedimiento para preparar compuestos de acil-xilidida. |
NL8204126A NL8204126A (nl) | 1970-12-22 | 1982-10-26 | Werkwijze voor het bereiden van een farmaceutisch preparaat met locaal-anesthetische werking dat een dialylamino-2',6'acetoxylidide en/of een farmaceutisch aanvaardbaar zout daarvan bevat, alsmede de onder toepassing van deze werkwijze verkregen gevormde farmaceutische preparaten en werkwijze voor het bereiden van dialkylamino-2',6'acetoxylididen en de farmaceutisch aanvaardbare zouten daarvan. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10077770A | 1970-12-22 | 1970-12-22 | |
US00164022A US3812147A (en) | 1970-12-22 | 1971-07-19 | Acylxylidide local anaesthetics |
Publications (1)
Publication Number | Publication Date |
---|---|
US3812147A true US3812147A (en) | 1974-05-21 |
Family
ID=26797539
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US00164022A Expired - Lifetime US3812147A (en) | 1970-12-22 | 1971-07-19 | Acylxylidide local anaesthetics |
Country Status (23)
Country | Link |
---|---|
US (1) | US3812147A (pl) |
JP (1) | JPS5644063B1 (pl) |
AR (1) | AR193840A1 (pl) |
AT (1) | AT319205B (pl) |
AU (1) | AU468489B2 (pl) |
BE (1) | BE776656A (pl) |
BR (1) | BR7108466D0 (pl) |
CA (1) | CA943966A (pl) |
DD (1) | DD99779A5 (pl) |
DE (1) | DE2162744C3 (pl) |
DK (1) | DK139814B (pl) |
ES (2) | ES398210A1 (pl) |
FI (1) | FI55027C (pl) |
FR (1) | FR2118985B1 (pl) |
GB (1) | GB1369259A (pl) |
HU (1) | HU163373B (pl) |
IE (1) | IE35909B1 (pl) |
IT (1) | IT1066334B (pl) |
NL (2) | NL172149C (pl) |
NO (1) | NO135934C (pl) |
PL (1) | PL83097B1 (pl) |
SE (1) | SE393374B (pl) |
SU (1) | SU419023A3 (pl) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3957996A (en) * | 1971-12-08 | 1976-05-18 | Astra Pharmaceutical Products, Inc. | Pharmaceutical local anesthetic compositions |
US3966934A (en) * | 1971-12-08 | 1976-06-29 | Astra Pharmaceutical Products, Inc. | Synergistic local anesthetic compositions |
US3975443A (en) * | 1972-06-06 | 1976-08-17 | Allen & Hanburys Limited | 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine |
US4125730A (en) * | 1975-08-22 | 1978-11-14 | Banyu Pharmaceutical Co., Ltd. | Preparation of -aminoalkanoic acid arylamides |
US4237068A (en) * | 1971-07-28 | 1980-12-02 | Astra Pharmaceutical Products, Inc. | Primary aminoacylanilides |
US4891058A (en) * | 1988-07-18 | 1990-01-02 | Ici Americas Inc. | 1-alkyl-3-aryl imidazolidine-2,4-diones and herbicidal use |
US10729664B2 (en) | 2009-07-10 | 2020-08-04 | President And Fellows Of Harvard College | Permanently charged sodium and calcium channel blockers as anti-inflammatory agents |
US10780083B1 (en) | 2019-03-11 | 2020-09-22 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10786485B1 (en) | 2019-03-11 | 2020-09-29 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10842798B1 (en) | 2019-11-06 | 2020-11-24 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10927096B2 (en) | 2019-03-11 | 2021-02-23 | Nocion Therapeutics, Inc. | Ester substituted ion channel blockers and methods for use |
US10933055B1 (en) | 2019-11-06 | 2021-03-02 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10934263B2 (en) | 2019-03-11 | 2021-03-02 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10968179B2 (en) | 2019-03-11 | 2021-04-06 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11021443B2 (en) | 2015-08-03 | 2021-06-01 | President And Fellows Of Harvard College | Charged ion channel blockers and methods for use |
US11332446B2 (en) | 2020-03-11 | 2022-05-17 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57176939A (en) * | 1981-04-03 | 1982-10-30 | Goodrich Co B F | Improved synthesis of hindered amine stabilizer for high polymer materials |
SE8900685D0 (sv) * | 1989-02-28 | 1989-02-28 | Astra Ab | New compounds |
US5153226A (en) * | 1989-08-31 | 1992-10-06 | Warner-Lambert Company | Acat inhibitors for treating hypocholesterolemia |
KR20140097446A (ko) | 2006-11-20 | 2014-08-06 | 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 | 통증 및 소양증 치료용 방법, 조성물 및 키트 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1124837A (en) * | 1966-06-03 | 1968-08-21 | Wyeth John & Brother Ltd | Substituted anilides |
-
1971
- 1971-07-19 US US00164022A patent/US3812147A/en not_active Expired - Lifetime
- 1971-12-07 SE SE7115656A patent/SE393374B/xx unknown
- 1971-12-14 BE BE776656A patent/BE776656A/xx not_active IP Right Cessation
- 1971-12-15 SU SU1726195A patent/SU419023A3/ru active
- 1971-12-16 HU HUAA690A patent/HU163373B/hu unknown
- 1971-12-17 NO NO4669/71A patent/NO135934C/no unknown
- 1971-12-17 DK DK619771AA patent/DK139814B/da not_active IP Right Cessation
- 1971-12-17 DE DE2162744A patent/DE2162744C3/de not_active Expired
- 1971-12-18 IT IT54845/71A patent/IT1066334B/it active
- 1971-12-20 AT AT1089671A patent/AT319205B/de not_active IP Right Cessation
- 1971-12-20 AU AU37099/71A patent/AU468489B2/en not_active Expired
- 1971-12-20 IE IE1609/71A patent/IE35909B1/xx unknown
- 1971-12-21 BR BR8466/71A patent/BR7108466D0/pt unknown
- 1971-12-21 PL PL1971152331A patent/PL83097B1/pl unknown
- 1971-12-21 CA CA130,662A patent/CA943966A/en not_active Expired
- 1971-12-21 GB GB5937771A patent/GB1369259A/en not_active Expired
- 1971-12-21 AR AR239721A patent/AR193840A1/es active
- 1971-12-21 ES ES398210A patent/ES398210A1/es not_active Expired
- 1971-12-21 FR FR7145983A patent/FR2118985B1/fr not_active Expired
- 1971-12-21 DD DD159785A patent/DD99779A5/xx unknown
- 1971-12-22 FI FI3658/71A patent/FI55027C/fi active
- 1971-12-22 NL NLAANVRAGE7117644,A patent/NL172149C/xx not_active IP Right Cessation
- 1971-12-22 JP JP10453571A patent/JPS5644063B1/ja active Pending
-
1974
- 1974-04-24 ES ES425626A patent/ES425626A1/es not_active Expired
-
1982
- 1982-10-26 NL NL8204126A patent/NL8204126A/nl not_active Application Discontinuation
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4237068A (en) * | 1971-07-28 | 1980-12-02 | Astra Pharmaceutical Products, Inc. | Primary aminoacylanilides |
US3957996A (en) * | 1971-12-08 | 1976-05-18 | Astra Pharmaceutical Products, Inc. | Pharmaceutical local anesthetic compositions |
US3966934A (en) * | 1971-12-08 | 1976-06-29 | Astra Pharmaceutical Products, Inc. | Synergistic local anesthetic compositions |
US3975443A (en) * | 1972-06-06 | 1976-08-17 | Allen & Hanburys Limited | 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine |
US4125730A (en) * | 1975-08-22 | 1978-11-14 | Banyu Pharmaceutical Co., Ltd. | Preparation of -aminoalkanoic acid arylamides |
US4891058A (en) * | 1988-07-18 | 1990-01-02 | Ici Americas Inc. | 1-alkyl-3-aryl imidazolidine-2,4-diones and herbicidal use |
US10729664B2 (en) | 2009-07-10 | 2020-08-04 | President And Fellows Of Harvard College | Permanently charged sodium and calcium channel blockers as anti-inflammatory agents |
US11021443B2 (en) | 2015-08-03 | 2021-06-01 | President And Fellows Of Harvard College | Charged ion channel blockers and methods for use |
US10968179B2 (en) | 2019-03-11 | 2021-04-06 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11603355B2 (en) | 2019-03-11 | 2023-03-14 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11643404B2 (en) | 2019-03-11 | 2023-05-09 | Nocion Therapeutics, Inc. | Ester substituted ion channel blockers and methods for use |
US10927096B2 (en) | 2019-03-11 | 2021-02-23 | Nocion Therapeutics, Inc. | Ester substituted ion channel blockers and methods for use |
US10780083B1 (en) | 2019-03-11 | 2020-09-22 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10934263B2 (en) | 2019-03-11 | 2021-03-02 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10828287B2 (en) | 2019-03-11 | 2020-11-10 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10786485B1 (en) | 2019-03-11 | 2020-09-29 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11512058B2 (en) | 2019-03-11 | 2022-11-29 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11377422B2 (en) | 2019-03-11 | 2022-07-05 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10933055B1 (en) | 2019-11-06 | 2021-03-02 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US10842798B1 (en) | 2019-11-06 | 2020-11-24 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11696912B2 (en) | 2019-11-06 | 2023-07-11 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
US11332446B2 (en) | 2020-03-11 | 2022-05-17 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
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Publication number | Publication date |
---|---|
IE35909L (en) | 1972-06-22 |
DE2162744A1 (de) | 1972-07-06 |
IT1066334B (it) | 1985-03-04 |
CA943966A (en) | 1974-03-19 |
NL172149C (nl) | 1983-07-18 |
HU163373B (pl) | 1973-08-28 |
AU3709971A (en) | 1973-06-28 |
BE776656A (fr) | 1972-06-14 |
AT319205B (de) | 1974-12-10 |
FI55027B (fi) | 1979-01-31 |
PL83097B1 (pl) | 1975-12-31 |
DE2162744B2 (de) | 1981-07-02 |
NO135934B (pl) | 1977-03-21 |
JPS5644063B1 (pl) | 1981-10-16 |
BR7108466D0 (pt) | 1973-06-14 |
DK139814C (pl) | 1979-10-01 |
DD99779A5 (pl) | 1973-08-20 |
ES425626A1 (es) | 1976-06-16 |
NL8204126A (nl) | 1983-02-01 |
AU468489B2 (en) | 1976-01-15 |
NL172149B (nl) | 1983-02-16 |
GB1369259A (en) | 1974-10-23 |
SU419023A3 (ru) | 1974-03-05 |
FR2118985A1 (pl) | 1972-08-04 |
IE35909B1 (en) | 1976-06-23 |
NL7117644A (pl) | 1972-06-26 |
DK139814B (da) | 1979-04-23 |
FR2118985B1 (pl) | 1975-12-26 |
SE393374B (sv) | 1977-05-09 |
AR193840A1 (es) | 1973-05-31 |
FI55027C (fi) | 1979-05-10 |
NO135934C (pl) | 1977-06-29 |
ES398210A1 (es) | 1975-03-16 |
DE2162744C3 (de) | 1982-04-15 |
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