US3551437A - Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof - Google Patents

Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof Download PDF

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Publication number
US3551437A
US3551437A US875527A US87552769A US3551437A US 3551437 A US3551437 A US 3551437A US 875527 A US875527 A US 875527A US 87552769 A US87552769 A US 87552769A US 3551437 A US3551437 A US 3551437A
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oxadiazol
oxadiazole
derivatives
certain
methyl
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US875527A
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Victor John Bauer
William Joseph Fanshawe
Sidney Robert Safir
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority to NL6813336A priority Critical patent/NL6813336A/en
Priority to FR166957A priority patent/FR1598975A/en
Priority to DE19681795369 priority patent/DE1795369A1/en
Priority to FR166958A priority patent/FR8478M/en
Priority to CH1413168A priority patent/CH521371A/en
Priority to BE721158D priority patent/BE721158A/xx
Priority to US875525A priority patent/US3551436A/en
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US875526A priority patent/US3555036A/en
Priority to US875527A priority patent/US3551437A/en
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Publication of US3551437A publication Critical patent/US3551437A/en
Priority to US127023A priority patent/US3703577A/en
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B63—SHIPS OR OTHER WATERBORNE VESSELS; RELATED EQUIPMENT
    • B63H—MARINE PROPULSION OR STEERING
    • B63H1/00—Propulsive elements directly acting on water
    • B63H1/02—Propulsive elements directly acting on water of rotary type
    • B63H1/04—Propulsive elements directly acting on water of rotary type with rotation axis substantially at right angles to propulsive direction
    • B63H1/06—Propulsive elements directly acting on water of rotary type with rotation axis substantially at right angles to propulsive direction with adjustable vanes or blades
    • B63H1/08—Propulsive elements directly acting on water of rotary type with rotation axis substantially at right angles to propulsive direction with adjustable vanes or blades with cyclic adjustment

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  • This invention relates to new quaternary lower alkoxy- (lower)alkyl-1,2,4-oxadiazolylpyridinium salts which may be illustrated by the following formula:
  • R is lower alkyl
  • R is lower alkoxy(lower)alkyl
  • X is a pharmaceutically acceptable anion
  • Z is a trivalent radical selected from the group consisting of and The dotted line represents one double bond, the position of which is dependent upon the definition of Z. When Z is the double bond is between the N and carbon containing R, and when Z has the other meaning, the double bond is in the other position.
  • the terms lower alkyl and lower alkoxy include those radicals having 1 to 4 carbon atoms.
  • the compounds are crysaalline solids, soluble in water.
  • the compounds of the present invention may be prepared by reaction of a 1,2,4-oxadiazolylpyridine with a lower alkoxy(lower)alkyl halide at a temperature of to 200 C. with or without a solvent, such as a lower alkyl alcohol, for a time of one minute to twenty-four hours in an open vessel or a sealed bomb.
  • quaternary compounds of the present inven tion are, for example: 1-(2-ethoxyethyl)-4-(5-methyl-1,2, 4-oxadiazol 3 yl)pyridinium chloride, 1-(2-methoxyethyl) -4- (S-methyl-1,2,4-oxadiazol-3 -yl) pyridinium chloride, 1-(2-propoxyethyl) 4 (S-methyl-1,2,4-oxadiazol- 3-yl)pyridinium bromide, 1-(2-ethoxymethyl) 4 (5- methyl-1,2,4-oxadiazol 3 yl)pyridinium iodide, 1-(2- propoxypropyl) 4 (S-methyl-1,2,4-oxadiazol-3-yl)- pyridinium chloride.
  • the quaternary compounds of the present invention show hypoglycemic activity which indicates they are use ful as medicaments in the lowering of blood sugar levels.
  • the compounds of this invention are administered by gavage as saline solutions to CF1 mice (Carworth Farms, 18-25 grams (4-6 animals). Control animals receive an equivalent volume of saline. Food is withheld from animals after dosing. Blood glucose is determined on 0.05 ml. samples of blood by the method of Hotfman [1. Biol. Chem, 120, 51 (1937)] as adapted to the Technicon AutoAnalyzer and is expressed as percent change from predose values. The data are shown in the table hereinafter. These results show that the compounds of the present invention are useful in lowering the blood glucose concentrations of warm-blooded animals.
  • hypoglycemic agents can be incorporated in various pharmaceutical forms such as tablets, capsules, pills and so forth, for immediate or sustained release, by combining with suitable carriers. They may be in the form of dosage units for a single therapeutic dose or in small units for multiple dosages or in larger units for division into single doses. Obviously, in addition to the therapeutic hypoglycemic compounds, there may be present excipients, binders, fillers and other therapeutically inert ingredients necessary in the formulation of the desired pharmaceutical preparation.
  • EXAM PLE 1 Preparation of 4-(S-methyl-1,2,4-oxadiazol-3-yl)pyridine 'A mixture of 27 g. of isonicotinamidoxime and 50 ml. of acetic anhydride is warmed on a steam bath for 2 hours, and then heated under reflux for 3 hours. The solvent is distilled and the dark liquid residue is diluted with water. The crystals which form are collected, washed with water, and recrystallized from ethanol to provide colorless crystals, melting point 92-93 C.
  • EXAMPLE 2 Preparation of l-(2-ethoxyethyl)-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridinium chloride A mixture of 5.0 g. of 4-(S-methyl-1,2,4-oxadiazol-3- yl)pyridine and 15 ml. of 2-chloroethyl ethyl ether is heated in a bomb at C. for 20 hours. The excess 2-chloroethyl ether is evaporated and the black residue is recrystallized from isopropyl alcohol-ether to give offwhite crystals, melting point l87188 C.
  • EXAMPLE 4 Preparation of l-(3-propoxypropyl)-4-(5-ethyl-1,2,4-oxa diaZol-3-yl)pyridinium chloride A mixture of 5.0 g. of 4-(5-ethyl-l,2,4-oxadiazol-3-yl) pyridine and 15 ml. of 3-chloropropyl propyl ether is heated in a bomb at 130 C. for 20 hours. The excess 3- chloropropyl ether is evaporated and the residue is recrystallized to give the product of the example.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Combustion & Propulsion (AREA)
  • Mechanical Engineering (AREA)
  • Ocean & Marine Engineering (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

United States Patent 01 free ABSTRACT OF THE DISCLOSURE Quaternary lower alkoxy(lower) alkyl-1,2,4-oxadiazolylpyridinium salts are described along with methods of preparing the same. These compounds show hypoglycemic activity evidenced by their ability to lower blood sugar levels.
The present application is a continuation-in-part of our application Ser. No. 676,706 filed Oct. 20, 1967, now abandoned.
PRIOR ART Applicants are aware of British Pat. 875,887 directed to pyridinium salts. However the present invention is directed to subject matter and utility not disclosed therein.
SUMMARY OF THE INVENTION This invention relates to new quaternary lower alkoxy- (lower)alkyl-1,2,4-oxadiazolylpyridinium salts which may be illustrated by the following formula:
wherein R is lower alkyl, R is lower alkoxy(lower)alkyl, X is a pharmaceutically acceptable anion and Z is a trivalent radical selected from the group consisting of and The dotted line represents one double bond, the position of which is dependent upon the definition of Z. When Z is the double bond is between the N and carbon containing R, and when Z has the other meaning, the double bond is in the other position. The terms lower alkyl and lower alkoxy include those radicals having 1 to 4 carbon atoms.
In general, the compounds are crysaalline solids, soluble in water.
The compounds of the present invention may be prepared by reaction of a 1,2,4-oxadiazolylpyridine with a lower alkoxy(lower)alkyl halide at a temperature of to 200 C. with or without a solvent, such as a lower alkyl alcohol, for a time of one minute to twenty-four hours in an open vessel or a sealed bomb.
The reaction is illustrated schematically below:
3,551,437 Patented Dec. 29, 1970 wherein R, R Z and X are as hereinbefore defined.
Among the quaternary compounds of the present inven tion are, for example: 1-(2-ethoxyethyl)-4-(5-methyl-1,2, 4-oxadiazol 3 yl)pyridinium chloride, 1-(2-methoxyethyl) -4- (S-methyl-1,2,4-oxadiazol-3 -yl) pyridinium chloride, 1-(2-propoxyethyl) 4 (S-methyl-1,2,4-oxadiazol- 3-yl)pyridinium bromide, 1-(2-ethoxymethyl) 4 (5- methyl-1,2,4-oxadiazol 3 yl)pyridinium iodide, 1-(2- propoxypropyl) 4 (S-methyl-1,2,4-oxadiazol-3-yl)- pyridinium chloride.
The quaternary compounds of the present invention show hypoglycemic activity which indicates they are use ful as medicaments in the lowering of blood sugar levels. When the quaternary compounds are administered orally to normal mice, a reduction of blood sugar levels is observed. The compounds of this invention are administered by gavage as saline solutions to CF1 mice (Carworth Farms, 18-25 grams (4-6 animals). Control animals receive an equivalent volume of saline. Food is withheld from animals after dosing. Blood glucose is determined on 0.05 ml. samples of blood by the method of Hotfman [1. Biol. Chem, 120, 51 (1937)] as adapted to the Technicon AutoAnalyzer and is expressed as percent change from predose values. The data are shown in the table hereinafter. These results show that the compounds of the present invention are useful in lowering the blood glucose concentrations of warm-blooded animals.
TABLE Decrease in blood glucose in normal mice after oral administration of 1,2,4-0xadiazolylpyridinium salts Compound--l (2 ethoxyethyl)-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridinium chloride:
Dose, mmoles/kg. 3.0 Hours after dosing 3 Percent decrease in blood glucose 27:4
The products of the present invention as hypoglycemic agents can be incorporated in various pharmaceutical forms such as tablets, capsules, pills and so forth, for immediate or sustained release, by combining with suitable carriers. They may be in the form of dosage units for a single therapeutic dose or in small units for multiple dosages or in larger units for division into single doses. Obviously, in addition to the therapeutic hypoglycemic compounds, there may be present excipients, binders, fillers and other therapeutically inert ingredients necessary in the formulation of the desired pharmaceutical preparation.
DETAILED DESCRIPTION The following examples describe in detail the preparation of representative quaternary lower alkoxy(lower) alkyl 1,2,4-oxadiazolylpyridinium salts of this invention.
EXAM PLE 1 Preparation of 4-(S-methyl-1,2,4-oxadiazol-3-yl)pyridine 'A mixture of 27 g. of isonicotinamidoxime and 50 ml. of acetic anhydride is warmed on a steam bath for 2 hours, and then heated under reflux for 3 hours. The solvent is distilled and the dark liquid residue is diluted with water. The crystals which form are collected, washed with water, and recrystallized from ethanol to provide colorless crystals, melting point 92-93 C.
EXAMPLE 2 Preparation of l-(2-ethoxyethyl)-4-(5-methyl-l,2,4-oxadiazol-3-yl)pyridinium chloride A mixture of 5.0 g. of 4-(S-methyl-1,2,4-oxadiazol-3- yl)pyridine and 15 ml. of 2-chloroethyl ethyl ether is heated in a bomb at C. for 20 hours. The excess 2-chloroethyl ether is evaporated and the black residue is recrystallized from isopropyl alcohol-ether to give offwhite crystals, melting point l87188 C.
EXAMPLE 3 Preparation of 4-(5-ethyl-l,2,4-oxadiazol-3-yl)pyridine A mixture of 27 g. of isonicotinamidoxime and 60 ml. of propionic anhydride is warmed on a steam bath for 2 hours and then heated at 145 C. for 4 hours. The solvent is distilled and the dark liquid residue is diluted with water. The crystals which form are collected, washed with water, and recrystallized from petroleum ether to provide colorless crystals, melting point 42-44" C.
EXAMPLE 4 Preparation of l-(3-propoxypropyl)-4-(5-ethyl-1,2,4-oxa diaZol-3-yl)pyridinium chloride A mixture of 5.0 g. of 4-(5-ethyl-l,2,4-oxadiazol-3-yl) pyridine and 15 ml. of 3-chloropropyl propyl ether is heated in a bomb at 130 C. for 20 hours. The excess 3- chloropropyl ether is evaporated and the residue is recrystallized to give the product of the example.
We claim:
1. A quaternary oxadiazolylpyridinium salt of the wherein R is lower alkyl, R is lower alkoxy(lower)alkyl, X is a pharmaceutically acceptable anion, Z is a trivalent radical selected from the group consisting of and References Cited FOREIGN PATENTS 875,887 8/l96l Great Britain 260296 ALAN L. ROTMAN, Primary Examiner US. Cl. X.R. 260999
US875527A 1967-09-22 1969-11-10 Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof Expired - Lifetime US3551437A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
NL6813336A NL6813336A (en) 1967-09-22 1968-09-18 Process for preparing pyridine derivatives.
FR166958A FR8478M (en) 1967-09-22 1968-09-20 New pyridine derivatives and their pyridinium salts, useful as muscle relaxants and antiepileptics.
CH1413168A CH521371A (en) 1967-09-22 1968-09-20 Process for the preparation of new cyclopropyl-1,2,4-oxadiazolylpyridines
BE721158D BE721158A (en) 1967-09-22 1968-09-20
FR166957A FR1598975A (en) 1967-09-22 1968-09-20 Process for the preparation of pyridinium salts.
DE19681795369 DE1795369A1 (en) 1967-09-22 1968-09-20 New pyridinium salts and processes for their preparation
US875525A US3551436A (en) 1967-09-22 1969-11-10 Certain 4-(thiazolyl) and 4-(oxazolyl) pyridinium salts
US875526A US3555036A (en) 1967-09-22 1969-11-10 Cyclopropyl-1,2,4-oxadiazolylpyridines
US875527A US3551437A (en) 1967-09-22 1969-11-10 Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof
US127023A US3703577A (en) 1967-09-22 1971-03-22 4-(thiazolyl) pyridinium salts and 4-(oxazolyl) pyridinium salts for lowering blood glucose levels

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US66970567A 1967-09-22 1967-09-22
US67670667A 1967-10-20 1967-10-20
US69038267A 1967-12-14 1967-12-14
US875525A US3551436A (en) 1967-09-22 1969-11-10 Certain 4-(thiazolyl) and 4-(oxazolyl) pyridinium salts
US875526A US3555036A (en) 1967-09-22 1969-11-10 Cyclopropyl-1,2,4-oxadiazolylpyridines
US875527A US3551437A (en) 1967-09-22 1969-11-10 Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof
US127023A US3703577A (en) 1967-09-22 1971-03-22 4-(thiazolyl) pyridinium salts and 4-(oxazolyl) pyridinium salts for lowering blood glucose levels

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US875526A Expired - Lifetime US3555036A (en) 1967-09-22 1969-11-10 Cyclopropyl-1,2,4-oxadiazolylpyridines
US875527A Expired - Lifetime US3551437A (en) 1967-09-22 1969-11-10 Certain 4-(1,2,4-oxadiazole-3 or 5-yl) pyridinium salts and derivatives thereof
US875525A Expired - Lifetime US3551436A (en) 1967-09-22 1969-11-10 Certain 4-(thiazolyl) and 4-(oxazolyl) pyridinium salts
US127023A Expired - Lifetime US3703577A (en) 1967-09-22 1971-03-22 4-(thiazolyl) pyridinium salts and 4-(oxazolyl) pyridinium salts for lowering blood glucose levels

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US875526A Expired - Lifetime US3555036A (en) 1967-09-22 1969-11-10 Cyclopropyl-1,2,4-oxadiazolylpyridines

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US875525A Expired - Lifetime US3551436A (en) 1967-09-22 1969-11-10 Certain 4-(thiazolyl) and 4-(oxazolyl) pyridinium salts
US127023A Expired - Lifetime US3703577A (en) 1967-09-22 1971-03-22 4-(thiazolyl) pyridinium salts and 4-(oxazolyl) pyridinium salts for lowering blood glucose levels

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BE (1) BE721158A (en)
CH (1) CH521371A (en)
DE (1) DE1795369A1 (en)
FR (2) FR8478M (en)
NL (1) NL6813336A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571402A (en) * 1982-06-22 1986-02-18 Schering Corporation Anti-bronchoconstriction 2-(4'-pyridinyl)-thiazole derivatives, composition, and method of use therefor
US20080108799A1 (en) * 2004-09-02 2008-05-08 Andre Weiss Use Of Thiazolyl-Pyridinium Based Dyes In Optical Layers For Optical Data Recording

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985754A (en) * 1975-05-08 1976-10-12 American Cyanamid Company Para-fluorobenzoylpropyl-N-heterocyclic substituted quaternary salts
US4528291A (en) * 1982-06-22 1985-07-09 Schering Corporation 2-(4'-Pyridinyl)-thiazole compounds and their use in increasing cardiac contractility
US4488647A (en) * 1983-07-18 1984-12-18 Paramount Packaging Corporation Flexible package with easy opening peel seal

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4571402A (en) * 1982-06-22 1986-02-18 Schering Corporation Anti-bronchoconstriction 2-(4'-pyridinyl)-thiazole derivatives, composition, and method of use therefor
US20080108799A1 (en) * 2004-09-02 2008-05-08 Andre Weiss Use Of Thiazolyl-Pyridinium Based Dyes In Optical Layers For Optical Data Recording
US7655767B2 (en) 2004-09-02 2010-02-02 Clariant Finance (Bvi) Limited Use of thiazolyl-pyridinium based dyes in optical layers for optical data recording

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US3551436A (en) 1970-12-29
FR1598975A (en) 1970-07-15
US3555036A (en) 1971-01-12
FR8478M (en) 1972-06-09
BE721158A (en) 1969-03-20
NL6813336A (en) 1969-03-25
US3703577A (en) 1972-11-21
CH521371A (en) 1972-04-15
DE1795369A1 (en) 1972-01-05

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