US2594419A - Di-salicylate of 7-chloro-4-(4'-diethylamino-1'-methylbutylamino) quinoline - Google Patents

Di-salicylate of 7-chloro-4-(4'-diethylamino-1'-methylbutylamino) quinoline Download PDF

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Publication number
US2594419A
US2594419A US118998A US11899849A US2594419A US 2594419 A US2594419 A US 2594419A US 118998 A US118998 A US 118998A US 11899849 A US11899849 A US 11899849A US 2594419 A US2594419 A US 2594419A
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Prior art keywords
quinoline
chloro
diethylamino
methylbutylamino
salicylate
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US118998A
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Charles F Geschickter
Martin I Rubin
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GESCHICKTER FUND FOR MEDICAL RESEARCH Inc
GESCHICKTER FUND MED RES
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GESCHICKTER FUND MED RES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms

Definitions

  • the present invention relates to a new therapeutic agent. More particularly the present invention relates to a new antihistamine especially effective on allergic diseases affecting the respiratory tract.
  • antihistamines in current use have not proven to be entirely effective in the control of many cases of asthma and non-seasonal rhinitis. Where effective, they afford symptomatic rather than permanent relief or cure. The same is true or" the desensitizing injections of protein substances which have the added disadvantage of requiring elaborate intradermal testing to determine the nature of the sensitizing agent or allergen.
  • the particular antihistamines which. are the subject of the present invention are aminoquinolines and in particular the di-salicylates of 7 chloro i substituted quinolines.
  • the particular salieylates involved are the di-salicylates of compounds represented by the following formula:
  • It represents a polymethylene chain of from 2 to 6 carbon atoms preferably substituted by a hydroxy radical or a methyl radical and R1 and R2 are alkyl radicals of from 2 to 6 carbon atoms.
  • Especially desirable compounds were the disalicylates of 7-chloro-4 (4-diethylamino-l'- methylbutylamino) quinoline and 'l-chloro-4- (3 -diethylamino-2 -hydroxypropy1amino) quinoline.
  • the above compounds were administered to a number of patients and they were found to have a low toxicity and that plasma concentrations as high as 0.3 mg. per liter could be maintained on a daily dose of 0.4 gr.
  • the compounds showed a high retention in the tissue and body fluids with a high concentration in the respiratory tissue. They were found to have good results in various types of allergy.
  • the di-salicylate salts were prepared by reacting the known compounds 7-chloro-4-( i'-diethylamino-l'-methylbutylamino) quinoline and 7-chloro-4-(3-diethylamino-2 hydroxypropylamino) quinoline for a short period of time with a solution of salicylic acid in absolute ethyl ether.
  • a solution of salicylic acid in absolute ethyl ether Preferably an amount of salicylic acid was used equivalent to in excess of 2 mols of salicylic acid to one mol of the aforesaid compounds.
  • the solution was decanted and the precipitate ground and extracted with successive portions of hot petroleum ether (YO-90 0.).
  • the residual solids showed on analysis the correct values for the di-salicylate salts.
  • the compounds formed were in part quaternary salt combinations with the aforesaid amino quino lines.
  • the compounds thus produced were suitably formed into
  • Example I 3 grs. of '7-chloro-4-(4'diethylamino-1-methylbutylamino) quinoline were added to a solution of 7.5 grs. of salicylic acid in 50 cc. of absolute ethyl ether. After thorough mixing the resultant precipitate was separated by decantation of the supernatant solution. The residue was ground and then extracted with three 50 cc. portions of hot (90 C.) petroleum ether. The residual solid, after removal of the petroleum ether, showed on analysis the correct values for the disalicylate salt of 7-chloro-4-(4'-diethylamino-l methylbutylamino) quinoline.
  • Example II 3 grs. of 7-chloro-4-(3-diethylamino-2-hydroxypropylamino) quinoline were added to a solution of 7.5 grs. of salicylic acid in 56 cc. of absolute ethyl ether. After thorough mixing the resultant precipitate was separated by decantation of the supernatant solution. The residue was ground and then extracted with three 50 cc. portions of hot (70-90" C.) petroleum ether. The residual solid, after removal of the petroleum ether, showed on analysis the correct values for the di-salicylate salt of 7-chloroi-(3-diethylamino-2'-hydroxypropylamino) quinoline.
  • Wiselogle Survey of Antimalarial Drugs, A new compound consisting of the di-salicylate 1941-1945 (J. W. Edwards; Ann Arbor, Mich. of 7-ch1oro-4-(4'-diethy1amino-1'-methy1buty1a- 1946), vol. II, part 2, pp. 1145 and 1157; vol. I,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Patented Apr. 29, 1952 Ni'iED STATES PATENT orrics DI-SALICYLATE OF 7-CHLORO 4 -(4'- DI- E THYLAMINO 1'-METHYLBUTYLAMINO QUINQLENE No Drawing. Application September 30, 1949, Serial No. 118,998
1 Claim. 1!
The present invention relates to a new therapeutic agent. More particularly the present invention relates to a new antihistamine especially effective on allergic diseases affecting the respiratory tract.
The antihistamines in current use have not proven to be entirely effective in the control of many cases of asthma and non-seasonal rhinitis. Where effective, they afford symptomatic rather than permanent relief or cure. The same is true or" the desensitizing injections of protein substances which have the added disadvantage of requiring elaborate intradermal testing to determine the nature of the sensitizing agent or allergen.
In accordance with the present invention certain new antihistamine substances have been found which concentrate especially in the respiratory epithelium and which had a prolonged duration so that a serum level could be established and maintained.
The particular antihistamines which. are the subject of the present invention are aminoquinolines and in particular the di-salicylates of 7 chloro i substituted quinolines. The particular salieylates involved are the di-salicylates of compounds represented by the following formula:
wherein It represents a polymethylene chain of from 2 to 6 carbon atoms preferably substituted by a hydroxy radical or a methyl radical and R1 and R2 are alkyl radicals of from 2 to 6 carbon atoms.
Especially desirable compounds were the disalicylates of 7-chloro-4 (4-diethylamino-l'- methylbutylamino) quinoline and 'l-chloro-4- (3 -diethylamino-2 -hydroxypropy1amino) quinoline.
The above compounds were administered to a number of patients and they were found to have a low toxicity and that plasma concentrations as high as 0.3 mg. per liter could be maintained on a daily dose of 0.4 gr. The compounds showed a high retention in the tissue and body fluids with a high concentration in the respiratory tissue. They were found to have good results in various types of allergy.
Vii
The di-salicylate salts were prepared by reacting the known compounds 7-chloro-4-( i'-diethylamino-l'-methylbutylamino) quinoline and 7-chloro-4-(3-diethylamino-2 hydroxypropylamino) quinoline for a short period of time with a solution of salicylic acid in absolute ethyl ether. Preferably an amount of salicylic acid was used equivalent to in excess of 2 mols of salicylic acid to one mol of the aforesaid compounds. Thereafter the solution was decanted and the precipitate ground and extracted with successive portions of hot petroleum ether (YO-90 0.). The residual solids showed on analysis the correct values for the di-salicylate salts. Apparently the compounds formed were in part quaternary salt combinations with the aforesaid amino quino lines. The compounds thus produced were suitably formed into proper dosage capsules.
The following specific examples serve to illustrate the present invention but are not intended to limit the same.
Example I 3 grs. of '7-chloro-4-(4'diethylamino-1-methylbutylamino) quinoline were added to a solution of 7.5 grs. of salicylic acid in 50 cc. of absolute ethyl ether. After thorough mixing the resultant precipitate was separated by decantation of the supernatant solution. The residue was ground and then extracted with three 50 cc. portions of hot (90 C.) petroleum ether. The residual solid, after removal of the petroleum ether, showed on analysis the correct values for the disalicylate salt of 7-chloro-4-(4'-diethylamino-l methylbutylamino) quinoline.
Example II 3 grs. of 7-chloro-4-(3-diethylamino-2-hydroxypropylamino) quinoline were added to a solution of 7.5 grs. of salicylic acid in 56 cc. of absolute ethyl ether. After thorough mixing the resultant precipitate was separated by decantation of the supernatant solution. The residue was ground and then extracted with three 50 cc. portions of hot (70-90" C.) petroleum ether. The residual solid, after removal of the petroleum ether, showed on analysis the correct values for the di-salicylate salt of 7-chloroi-(3-diethylamino-2'-hydroxypropylamino) quinoline.
It will be obvious to those skilled in the art that various changes may be made without departing from the spirit of the invention and therefore the invention is not limited to What is described in the specification but only as indicated in the appended claim.
2,594,419 3 4 What is claimed is: Wiselogle: Survey of Antimalarial Drugs, A new compound consisting of the di-salicylate 1941-1945 (J. W. Edwards; Ann Arbor, Mich. of 7-ch1oro-4-(4'-diethy1amino-1'-methy1buty1a- 1946), vol. II, part 2, pp. 1145 and 1157; vol. I,
mino) quinoline. pp. 94-105.
CHARLES R GESC 6 Huttrer: Enzymologia, vol. XII, p. 321 (1948). MARTIN I. RUB Fischel: Proc. Soc. Exp. Biol. Med., v01. 66,
REFERENCES CITED 1'B Z 1 L' A (s Ed) 1 37 The following references are of record in the pp 2 22 1 gh 5500' C1 JO 1 file of this patent: 1o
US118998A 1949-09-30 1949-09-30 Di-salicylate of 7-chloro-4-(4'-diethylamino-1'-methylbutylamino) quinoline Expired - Lifetime US2594419A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3238572A (en) * 1963-12-11 1966-03-08 Leslie Welding Co Inc Window structure
US5596002A (en) * 1993-10-28 1997-01-21 Hoffmann-La Roche Inc. Method of treating chloroquine-resistant malaria with aminoquinoline derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3238572A (en) * 1963-12-11 1966-03-08 Leslie Welding Co Inc Window structure
US5596002A (en) * 1993-10-28 1997-01-21 Hoffmann-La Roche Inc. Method of treating chloroquine-resistant malaria with aminoquinoline derivatives
CN1130345C (en) * 1993-10-28 2003-12-10 霍夫曼-拉罗奇有限公司 Amino quinoline derivatives

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