US2671805A - Basically substituted o-arylamino-benzamides - Google Patents
Basically substituted o-arylamino-benzamides Download PDFInfo
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- US2671805A US2671805A US296941A US29694152A US2671805A US 2671805 A US2671805 A US 2671805A US 296941 A US296941 A US 296941A US 29694152 A US29694152 A US 29694152A US 2671805 A US2671805 A US 2671805A
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- 229940054066 benzamide antipsychotics Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- -1 alkylene radical Chemical class 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000005840 aryl radicals Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 125000005023 xylyl group Chemical group 0.000 description 2
- AVMHMVJVHYGDOO-NSCUHMNNSA-N (e)-1-bromobut-2-ene Chemical compound C\C=C\CBr AVMHMVJVHYGDOO-NSCUHMNNSA-N 0.000 description 1
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 1
- DOXCWSBETLOACP-UHFFFAOYSA-N 2-anilinobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1NC1=CC=CC=C1 DOXCWSBETLOACP-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- 241001480079 Corymbia calophylla Species 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- 235000006552 Liquidambar styraciflua Nutrition 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical group C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- ANNNGOUEZBONHD-UHFFFAOYSA-N ethyl phenylmethanesulfonate Chemical compound CCOS(=O)(=O)CC1=CC=CC=C1 ANNNGOUEZBONHD-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003457 ganglion blocking agent Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- CZXGXYBOQYQXQD-UHFFFAOYSA-N methyl benzenesulfonate Chemical compound COS(=O)(=O)C1=CC=CC=C1 CZXGXYBOQYQXQD-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
Definitions
- Ar is an aryl radical
- Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms
- NRR is either a lower dialkylamino radical or a nitrogen containing heterocyclic radical attached through a nitrogen in the heterocycle to the radical Alk.
- Ar is a lower aryl radical and, preferably, a monocyclic aromatic hydrocarbon radical such as phenyl, tolyl, xylyl, ethylphenyl, or cumyl.
- the radical Alk is a straight-chained or branch-chained hydrocarbon radical such as ethylene, propylene, butylene, amylene, or a polymethylene radical such as trimethylene or octamethylene.
- the radicals .R and R are lower alkyl radicals of the straightchained or branch-chained type such as methyl, ethyl, propyl, butyl, amyl, and hexyl.
- the radicals R and R can also be combined to form a lower alkylene radical containing 4 to 7 carbon atoms, 4 to of which are in nuclear position as in the case of pyrrolidino, piperidino, 2,5-dimethylpyrrolidino, and 2,6-1upetidino radicals. They may also be combined as an ethyleneoxyethylene radical, ethylenethiaethylene radical, or ethyleneaminoethylene radical as in the cases of the morpholino, thiamorphalino and piperazino radicals.
- the bases described herein form salts which are non-toxic in therapeutic dosage with a variety of inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic gluconic, benzoic, cinnamic, or related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids.
- esters are methyl chloride, bromide, and iodide; the ethyl halides, propyl halides, butyl halides, isobutyl halides, benzyl halides, phenethyl halides, naphthylmethyl halides, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, ethylene bromohydrin, the propylene halohydrins, 'allyl chloride, methallyl bromide, and crotyl bromide.
- EXAMPLE '1 N- (fl-diethylaminoethyl) -o-anilinobenzamide A mixture of 426 parts of N-phenylanthranilic acid, 1100 parts of anhydrous ethyl ether, and 272 parts of thionylchloride is heated in a water bath at 40 C. for one hour. The ether is then removed under vacuum at room temperature and the crude a'cid chloride residue is used in the reactions with the dialkylaminoalkylamines.
- This salt has the structural formula 3 EXAMPLE 2 [i- (o-anz'linobenzamidoethyl) triethylammomum bromide A mixture of 110 parts of N-(B-diethylaminoethyl) -o-anilinobenzamide, 76 parts of ethyl bromide, and 1600 parts of butanone is sealed in a pressure bottle and heated in the steam bath for 3 hours. Observing the usual precautions, the pressure bottle is cooled and opened. A heavy syrup is separated from the reaction mixture by dilution with anhydrous ethyl ether. The syrup is washed by ether decantation, taken up in acetone, and crystallized by cooling in the refrigerator.
- the salt has the structural formula EXAMPLE 3 N y-dimethylaminopropyl) -o -ahilinobenzamide
- a solution of 20 parts of 'y-dimethylaminopropylamine in 100 parts of acetone is added slowly with stirring. After heating at reflux temperature for an hour the acetone is distilled off under vacuum and the residue is dissolved in water.
- the aqueous extract is Washed with ether, rendered alkaline by addition of potassium carbonate, and ether extracted. This ether extract is dried over anhydrous potassium carbonate, solvent stripped, and vacuum distilled to yield the N-(- -dimethyl-. aminopropyl)-o-anilinobenzamide as a viscous yellow oil boiling at about 223-230 C. and 0.3 mm. pressure.
- N- ('y-diethylaminopropyl) -o-anilinobenzamide 1 To the acid chloride residue prepared from 318 parts of N-phenylanthranilic acid is added, with stirring, a solution of 195 parts of 'y-diethylaminopropylamine in 1000 parts of acetone. The addition causes refluxing which is maintained for one hour by heating on the steam bath. The acetone is removed under vacuum and the residue is dissolved in water and ether washed. The aqueous phase is made alkaline with potassium carbonate and ether extracted. This ether extract is dried over anhydrous potassium carbonate, ether stripped and vacuum distilled.
- the N- ('y-diethylaminopropyl) -o-anilinobenzamide is a viscous yellow oil boiling at about 220-230 C. and 0.3 mm. pressure.
- the salt has the structural formula EXAMPLE 5 N-(e dimethylaminopropyl) o (mm xylyl) aminobenzamide
- the acid chloride residue prepared from '12 parts of N-(m,pxylyl)anthranilic acid is treated by dropwise addition with a solution of 31 parts of 5-dimethylaminopropylamine in 150 parts of After heating at reflux temperature for 90 minutes the solvent is removed under vacuum. The residue is dissolved in water and the resulting solution washed with ether, rendered alkaline by addition of potassium carbonate, and ether extracted.
- a compound of the structural formula 5 A compound of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.
- a compound of the structural formula 7 A compound of the structural formula 8.
- a compound of the structural formula 9. A salt of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms, and X is a nontoxic anion.
- Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Patented Mar. 9, 1954 UNITED STATES PATENT osFIcE 'BASICALLY SUBSTITUT-ED ;o-ARLAMINO- BENZAMIDES Carl Peter Krimmcl, Mundelin, IIL, assignor to G. D. Searle & '00., ChicagoQIlL, a corporation of Illinois No Drawing. Application July 2, 1952, Serial No. 296,941
and the non-toxic salts thereof, wherein Ar is an aryl radical, Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms, and NRR is either a lower dialkylamino radical or a nitrogen containing heterocyclic radical attached through a nitrogen in the heterocycle to the radical Alk.
In the above structural formula Ar is a lower aryl radical and, preferably, a monocyclic aromatic hydrocarbon radical such as phenyl, tolyl, xylyl, ethylphenyl, or cumyl. The radical Alk is a straight-chained or branch-chained hydrocarbon radical such as ethylene, propylene, butylene, amylene, or a polymethylene radical such as trimethylene or octamethylene. The radicals .R and R are lower alkyl radicals of the straightchained or branch-chained type such as methyl, ethyl, propyl, butyl, amyl, and hexyl. The radicals R and R can also be combined to form a lower alkylene radical containing 4 to 7 carbon atoms, 4 to of which are in nuclear position as in the case of pyrrolidino, piperidino, 2,5-dimethylpyrrolidino, and 2,6-1upetidino radicals. They may also be combined as an ethyleneoxyethylene radical, ethylenethiaethylene radical, or ethyleneaminoethylene radical as in the cases of the morpholino, thiamorphalino and piperazino radicals.
The bases described herein form salts which are non-toxic in therapeutic dosage with a variety of inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic gluconic, benzoic, cinnamic, or related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. Among such esters are methyl chloride, bromide, and iodide; the ethyl halides, propyl halides, butyl halides, isobutyl halides, benzyl halides, phenethyl halides, naphthylmethyl halides, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, ethylene bromohydrin, the propylene halohydrins, 'allyl chloride, methallyl bromide, and crotyl bromide.
11 Claims. (CIQZBO- -SBS) .'Ihe new group of amides described herein offers valuable intermediates in organic synthesis. These amides have shown valuable cardiovascular and specifically blood pressure reducing properties. Th acid addition salts are diuretics and the quaternary ammonium salts have been found to be potent ganglion blocking agents.
The examples below illustrate my invention in further detail. However, they are not'to be construed as limiting it in spirit or in scope. In these examples quantities of materials are given in parts by weight, temperatures in degrees Centigrade (C.), and pressures in millimeters (mm) of mercury.
EXAMPLE '1 N- (fl-diethylaminoethyl) -o-anilinobenzamide A mixture of 426 parts of N-phenylanthranilic acid, 1100 parts of anhydrous ethyl ether, and 272 parts of thionylchloride is heated in a water bath at 40 C. for one hour. The ether is then removed under vacuum at room temperature and the crude a'cid chloride residue is used in the reactions with the dialkylaminoalkylamines.
To a solution of the above residue in 1600 parts of acetone, 232 parts of fi-diethyl'aminoethylamine are added by dropwise addition, with stirring. After the addition the reaction mixture is refluxed on the steam bath for an hour. The acetone is removed under vacuum and the residue is dissolved in water and ether extracted. The aqueous phase is made alkaline with potassium carbonate and ether extracted. The ether extract is dried over anhydrous potassium carbonate, ether stripped, and vacuum distilled. The N (B-di'ethylaminoethyl)-o-anilinobenzamid is a viscous, orange oil boiling at approximately 221-227 C. and 0.5 mm. pressure.
Toa solution "of 280 parts of the base in 11,000 parts of anhydrous ethyl ether, one equivalent of a 25% solution of hydrogen chloride in isopropanol is added. A brown gum separates which, after three recrystallizations from butanone, is converted to a tan-colored crystalline powder melting at 163-164" C. This salt has the structural formula 3 EXAMPLE 2 [i- (o-anz'linobenzamidoethyl) triethylammomum bromide A mixture of 110 parts of N-(B-diethylaminoethyl) -o-anilinobenzamide, 76 parts of ethyl bromide, and 1600 parts of butanone is sealed in a pressure bottle and heated in the steam bath for 3 hours. Observing the usual precautions, the pressure bottle is cooled and opened. A heavy syrup is separated from the reaction mixture by dilution with anhydrous ethyl ether. The syrup is washed by ether decantation, taken up in acetone, and crystallized by cooling in the refrigerator. Two recrystallizations from aceton and vacuum drying yield pale yellow crystals of the p-(o-anilinobenzamidoethyl)triethylammonium bromide which are too hygroscopic for the determination of a sharp melting point. The salt has the structural formula EXAMPLE 3 N y-dimethylaminopropyl) -o -ahilinobenzamide To the acid chloride residue prepared from 41 parts of N-phenylanthranilic acid, a solution of 20 parts of 'y-dimethylaminopropylamine in 100 parts of acetone is added slowly with stirring. After heating at reflux temperature for an hour the acetone is distilled off under vacuum and the residue is dissolved in water. The aqueous extract is Washed with ether, rendered alkaline by addition of potassium carbonate, and ether extracted. This ether extract is dried over anhydrous potassium carbonate, solvent stripped, and vacuum distilled to yield the N-(- -dimethyl-. aminopropyl)-o-anilinobenzamide as a viscous yellow oil boiling at about 223-230 C. and 0.3 mm. pressure.
To a solution of 9.5 parts of the base in 1400 parts of anhydrous ethyl ether is added one equivalent of a 25% solution of hydrogen chloride in isopropanol. The resultant granular pink precipitate is filtered, ether washed, and vacuum dried under an infrared lamp. Drying transforms the precipitate to a red gum. The latter is taken up to 40 parts of butanone from which it rapidly crystallizes. After one recrystallization from butanone a white, non-hygroscopic crystalline powder is obtained which melts at 133-135 C. This salt has the structural formula acetone.
4 EXAMPLE 4 N- ('y-diethylaminopropyl) -o-anilinobenzamide 1 To the acid chloride residue prepared from 318 parts of N-phenylanthranilic acid is added, with stirring, a solution of 195 parts of 'y-diethylaminopropylamine in 1000 parts of acetone. The addition causes refluxing which is maintained for one hour by heating on the steam bath. The acetone is removed under vacuum and the residue is dissolved in water and ether washed. The aqueous phase is made alkaline with potassium carbonate and ether extracted. This ether extract is dried over anhydrous potassium carbonate, ether stripped and vacuum distilled. The N- ('y-diethylaminopropyl) -o-anilinobenzamide is a viscous yellow oil boiling at about 220-230 C. and 0.3 mm. pressure.
To a solution of 60 parts of the base in 14,000 parts of anhydrous ethyl ether, an equivalent of a 25% solution of hydrogen chloride in isopropanol is added. The hydrochloride precipitates as a tacky deposit which becomes a crystalline powder on standing and scratching. Filtration and vacuum drying under an infrared lamp yield a cream colored, non-hygroscopic powder, melting at about 97-103" C. The salt has the structural formula EXAMPLE 5 N-(e dimethylaminopropyl) o (mm xylyl) aminobenzamide The acid chloride residue prepared from '12 parts of N-(m,pxylyl)anthranilic acid is treated by dropwise addition with a solution of 31 parts of 5-dimethylaminopropylamine in 150 parts of After heating at reflux temperature for 90 minutes the solvent is removed under vacuum. The residue is dissolved in water and the resulting solution washed with ether, rendered alkaline by addition of potassium carbonate, and ether extracted. This extract is dried EXAMPLE 6 N-(w-diethylaminopentyl) o anilznobenzamz'de A solution of phenylanthranilic acid chloride. prepared from parts of the acid in 500 parts of acetone, is treated with stirring by the gradual I claim: 1. A member of the class consisting of the compounds of the structural formula and the salts of the structural formula Air-NH wherein Ar is a monocyclic hydrocarbon radical containing 6 to 9 carbon atoms, Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least 2 carbon atoms and X is a non-toxic anion.
2. A compound of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.
3. A compound of the structural formula wherein Alk is a lower alkylene radical separatmg the two nitrogen atoms attached thereto by at least two carbon atoms.
4. A compound of the structural formula 5. A compound of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.
6. A compound of the structural formula 7. A compound of the structural formula 8. A compound of the structural formula 9. A salt of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms, and X is a nontoxic anion.
10. A salt of the structural formula C ONH-A1k-N (lower alkyl);
halogen wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.
11. A salt of the structural formula CARL PETER KRIMMEL.
References Cited in the file of this patent UNITED STATES PATENTS Name Date Eisleb Mar. 9, 1937 OTHER REFERENCES Bachman et al.: J. Am. Chem. Soc., vol. 68 (1946), page 2112.
Number
Claims (1)
1. A MEMBER OF THE CLASS CONSISTING OF THE COMPOUNDS OF THE STRUCTURAL FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US296941A US2671805A (en) | 1952-07-02 | 1952-07-02 | Basically substituted o-arylamino-benzamides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US296941A US2671805A (en) | 1952-07-02 | 1952-07-02 | Basically substituted o-arylamino-benzamides |
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| Publication Number | Publication Date |
|---|---|
| US2671805A true US2671805A (en) | 1954-03-09 |
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|---|---|---|---|
| US296941A Expired - Lifetime US2671805A (en) | 1952-07-02 | 1952-07-02 | Basically substituted o-arylamino-benzamides |
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| Country | Link |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2750387A (en) * | 1953-11-25 | 1956-06-12 | Searle & Co | Basically substituted derivatives of diarylaminobenzamides |
| US3217001A (en) * | 1963-08-19 | 1965-11-09 | American Home Prod | Derivatives of 1h-2, 1, 3-benzothiadiazin-4(3h)-one 2-oxide and intermediates therefor |
| US3409668A (en) * | 1964-11-07 | 1968-11-05 | Palazzo Giuseppe | Substituted anthranilamides and process for the preparation thereof |
| WO2008029199A1 (en) * | 2006-09-03 | 2008-03-13 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate |
| WO2008149181A1 (en) * | 2007-06-04 | 2008-12-11 | Techfields Inc | Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses |
| US20090238763A1 (en) * | 2006-07-09 | 2009-09-24 | Chongxi Yu | High penetration compositions and uses thereof |
| WO2012131656A3 (en) * | 2011-04-01 | 2012-11-22 | Société Splicos | Compounds for use as therapeutic agents affecting p53 expression and/or activity |
| US9233931B2 (en) | 2008-01-10 | 2016-01-12 | Centre Nationale De Recherche Scientifique | Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies |
| CN105669531A (en) * | 2007-06-04 | 2016-06-15 | 于崇曦 | Prodrug of non-steroidal anti-inflammatory drug having high skin and biological membrane penetration speed and novel medical application thereof |
| US11135153B2 (en) | 2006-07-09 | 2021-10-05 | Techfields Pharma Co., Ltd. | High penetration composition and uses thereof |
| US11541029B2 (en) | 2008-12-04 | 2023-01-03 | Techfields Pharma Co., Ltd. | High penetration compositions and their applications |
| US11813256B2 (en) | 2012-01-18 | 2023-11-14 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2073100A (en) * | 1934-07-26 | 1937-03-09 | Winthrop Chem Co Inc | Nu-aminoalkylamides of nu-alkyl-aminobenzoic acids and process of preparing them |
-
1952
- 1952-07-02 US US296941A patent/US2671805A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2073100A (en) * | 1934-07-26 | 1937-03-09 | Winthrop Chem Co Inc | Nu-aminoalkylamides of nu-alkyl-aminobenzoic acids and process of preparing them |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2750387A (en) * | 1953-11-25 | 1956-06-12 | Searle & Co | Basically substituted derivatives of diarylaminobenzamides |
| US3217001A (en) * | 1963-08-19 | 1965-11-09 | American Home Prod | Derivatives of 1h-2, 1, 3-benzothiadiazin-4(3h)-one 2-oxide and intermediates therefor |
| US3409668A (en) * | 1964-11-07 | 1968-11-05 | Palazzo Giuseppe | Substituted anthranilamides and process for the preparation thereof |
| US11135153B2 (en) | 2006-07-09 | 2021-10-05 | Techfields Pharma Co., Ltd. | High penetration composition and uses thereof |
| US20090238763A1 (en) * | 2006-07-09 | 2009-09-24 | Chongxi Yu | High penetration compositions and uses thereof |
| US9872846B2 (en) | 2006-07-09 | 2018-01-23 | Techfields Pharma Co., Ltd. | High penetration compositions and uses thereof |
| EP2623495A1 (en) * | 2006-09-03 | 2013-08-07 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate |
| WO2008029199A1 (en) * | 2006-09-03 | 2008-03-13 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate |
| CN105669531A (en) * | 2007-06-04 | 2016-06-15 | 于崇曦 | Prodrug of non-steroidal anti-inflammatory drug having high skin and biological membrane penetration speed and novel medical application thereof |
| AU2016228230C1 (en) * | 2007-06-04 | 2018-08-30 | Techfields Inc | Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses |
| AU2007354632B2 (en) * | 2007-06-04 | 2014-06-26 | Techfields Inc | Pro-drugs of NSAIAs with very high skin and membranes penetration rates and their new medicinal uses |
| WO2008149181A1 (en) * | 2007-06-04 | 2008-12-11 | Techfields Inc | Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses |
| CN105669531B (en) * | 2007-06-04 | 2019-05-07 | 于崇曦 | Prodrugs of non-steroidal anti-inflammatory drugs with fast skin and biofilm penetration rates and their new medicinal uses |
| US9371284B2 (en) | 2007-06-04 | 2016-06-21 | Techfields Pharma Co., Ltd. | Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses |
| US20100172960A1 (en) * | 2007-06-04 | 2010-07-08 | Chongxi Yu | Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses |
| US10233198B2 (en) | 2007-06-04 | 2019-03-19 | Techfields Pharma Co., Ltd. | Pro-drugs of NSAIAs with very high skin and membranes penetration rates and their new medicinal uses |
| AU2016228230B2 (en) * | 2007-06-04 | 2018-04-05 | Techfields Inc | Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses |
| RU2509076C2 (en) * | 2007-06-04 | 2014-03-10 | Текфилдз Инк | Prodrugs of nonsteroid anti-inflammatory agents (nsaia) with very high speed of penetration through skin and membranes, and new medical applications of above said prodrugs |
| US10130595B2 (en) | 2008-01-10 | 2018-11-20 | Centre Nationale De Recherche Scientifique | Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies |
| US10654813B2 (en) | 2008-01-10 | 2020-05-19 | Centre National De La Recherche Scientifique | Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies |
| US9233931B2 (en) | 2008-01-10 | 2016-01-12 | Centre Nationale De Recherche Scientifique | Chemical molecules that inhibit the slicing mechanism for treating diseases resulting from splicing anomalies |
| US11541029B2 (en) | 2008-12-04 | 2023-01-03 | Techfields Pharma Co., Ltd. | High penetration compositions and their applications |
| US9890112B2 (en) | 2011-04-01 | 2018-02-13 | Abivax | Compounds for use as therapeutic agents affecting p53 expression and/or activity |
| WO2012131656A3 (en) * | 2011-04-01 | 2012-11-22 | Société Splicos | Compounds for use as therapeutic agents affecting p53 expression and/or activity |
| US10538485B2 (en) | 2011-04-01 | 2020-01-21 | Abivax | Compounds for use as therapeutic agents affecting P53 expression and/or activity |
| US11813256B2 (en) | 2012-01-18 | 2023-11-14 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions |
| US11857545B2 (en) | 2012-01-18 | 2024-01-02 | Techfields Pharma Co., Ltd. | High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions |
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