US3341413A - Compositions containing pyrazolylpyridinium salts and method of administration - Google Patents

Description

United States Patent s 341 413 COMPOSITIONS coNiAmING PYRAZOLYLPYRI- DINIUM SALTS AND METHOD OF ADMINIS- TRATION Edward Charles Tocus, West Nyack, N. and Victor N.J., assiguors to American Cy- Maine No Drawing. Filed June 15, 1965,

20 Claims. (Cl. 167-65) This invention relates to new compositions of matter. More particularly, it relates to compositions containing as an active ingredient a pyrazolylpyridinium salt and method of administering the same.

The active components of the new compositions may be illustrated by the following formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl and cyclopropyl; R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of lower alkyl, lower alkenyl, cinnamyl, cyclopropyl-methyl and lower alkoxy (lower) alkyl; R is selected from the group consisting of hydrogen and lower alkyl and X is a pharmaceutically acceptable anion such as, for example, chloride, bromide or iodide. Illustrations of compounds of the present compositions and their activity are shown in table hereinafter.

The above-described compounds which are active components of the compositions of this invention may be prepared by a three-stage sequence. Thus, an ester of a pyridine-4-canboxylic acid is reacted with a methyl ketone to provide a 1-(4-pyridyl)-1,3-alkyldione; or ethyl formate is reacted with a pyridyl ketone in the presence of a base such as, for example, sodium methoxide to provide a 1-- (4-pyridyl)-1,3-a1kyldione salt. The resulting dione or salt is reacted with hydrazine hydrate or hydrazine dihydrochloride to give a 4-[3 (5)-pyrazolyl]pyridine. These latter compounds are quaternized to the active components of this invention generically described as 4- [3(5)-pyrozolyl]-pyridiniurn salts, with a lower alkyl, lower alkenyl, cinnamyl, cyclopropylmethyl, or lower alkwherein R, R R R and X are as hereinbefore defined and A is a lower alkyl group. The preparation of the active ingredients of the compositions of this invention will be described in greater detail in conjunction with the examples hereinafter.

The active components of the compositions of this invention have been hound, in standard laboratory measurements using chicks and alloxan-diabetic mice, to tbe orally active hypoglycemic agents. The procedure used to measure blood sugar-lowering properties of the active ingredients of the compositions of this invention are as follows:

(A) Not less than two Hall Cross cockerels, 18-20 days of age, weighing 120-200 grams are fasted 18 hours before oral administration of each test compound. For administration the test compound is suspended in 0.5% aqueous carboxymethylcellulose solution such that one milliliter of suspension per 100 grams of chick contains the intended dose. Two hours after drug administration, blood samples are obtained from the wing veins and analyzed for blood glucose concentrations by means of a Technicon Auto Analyzer using the method of W. S. Hoffman, J. Biol. Chem. 120, 51 (1937). Appropriate standards and controlsare tested at the same time for comparison. An average reduction of blood glucose concentration greater than 12% is considered hypoglycemic.

(B) Alloxan monohydrate causes selective destruction of the insulin producing ,8-cells of the pancreas with consequent diabetes in experimental animals Manor Farms male mice weighing 23-27 grams are given intravenously mg/kg. of aqueous alloxan monohydrate via the tail vein five days before oral administration of the test compound. The test compound is suspended in 0.5% aqueous carboxymethyl-cellulose solution such that 0.2 milliliter of suspension per 25 grams of mouse contains the intended dose. Groups of not less than 5 mice for each dose are bled from the tail immediately prior to, and 2 to 4 hours after, oral administration of the test compound. Blood is analyzed for glucose concentrations as described for chicks. Appropriate controls and standards are tested at the same time for comparison.

Results obtained from the administration of active components of the compositions of this invention compared to standard commercial anti-diabetic agents are shown in the table.

In general, the active ingredients of the compositions of this invention are given at doses from 1 to 250 mg. per kilogram body weight of warm blooded animal. The following table summarizes results obtained when the active components of the present compositions are tested as described above.

3 The amount of active ingredient to be given will depend upon the age, condition, Weight and other factors present in the warm-blooded animal. In the instance of a warm-blooded animal of, for example, 75 kg. the dose boxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin and the like. Sterile suspensions or solutions are required where parenteral use is desired. Isotonic preparations containing suitable preservatives are also highly may vary from 0.075 g. to 18.75 g. 5 desirable for injection use.

TABLE Chicks Alloxanized Mice Avg. Percent Avg. mg. Avg. Percent Decrease Decrease From Percent Blood in Control Blood Oral Dose, Control Blood Oral Dose, GlucoseiSE. Glucse:l:S.E.

mg./kg. Glucose After mg./kg. 0 Hour 2 Hours Control 2 Hours 4 Hours 1-methyl-4[5(3)-rnethyl-3(5)-pyrazolyl]pyridinlum lodido...-.- 250 73 100 4375:38 38$ 8 69 5 1-ethyl-4[5(3)-methyl-3(5)-pyrazolyl]pyridlnium iodide 200 55 100 520:1:18 29:1: 3 34:1: 6 1-n-butyl-4[5(3)-methy1-3(5)-pyrazolyl]pyridinium bromide. 100 18 100 515:l:42 62d: 3 81d: 6 l-methyl-4[5(3)-ethyl-3(5)-pyrazolyl]pyridinium iodide... 250 54 100 4893:33 551: 9 78:1: 6 1-methyl-4l3(5)-pyrazolyl]-pyridiniurn iodide 250 26 100 501i18 14:1: 8 50:1:14 1-n-propyl-4[5(3)-methyl-3(5)-pyrazolyl]-pyrldinium bromide.. 250 37 100 450:1:22 56$ 7 40:1: 8 1-methyl4[5(3l-isobutyl-3(5)-pyrazolyl]pyridi11ium iodide...-. 250 100 444:3?) 19$ 3 1:1: 6 1-mothyl-4I5(3)-ethyl-3(5)-pyrazolyl]pyridinium chloride 200 38 100 455:t:l8 52:1: 9 78:1: 6 1-isopropyl-4 [5 (3) -meth yl-3 (5)-pyrazolyl]pyridinium chloride..- 250 9 100 438i41 15:1: 28 26:1:39 1-is0propyl-4[5(3)-methyl3(5)-pyraz0lyl]pyridi11ium br0mide 250 12 100 444:1:27 12d: 4 14:i:14 1-isobutyl-4-[5(3)-methyl-3(5)-pyrazolyl]pryidin1um bromide..- 250 43 100 455:1:36 41:1:10 55i13 1-met-hyl-4[5(3)-methyl-3(5)-pyrazolyl]pyridinium chloride... 250 70 100 460:1:18 8 74:1: 6 1-methy1-4I3(5)-pyraz0lyl]pyridinium chloride 200 22 100 478:1:32 22:l:11 73:|:11 1-n-butyl-4[5(3)-methyl-3(5)-pyrazolyl]pyridiuium chloride. 200 37 100 436:1:44 59:|:15 77:1:12 1-allyl-4[5(3)-n1ethyl-3(5)-pyrazolyl]pyridinium chloride 100 54 100 4463:32 31:1: 9 34d: 9 1-methyl-4[6(3)-cyclopropyl-3(5)-pyrazolyl]pyridinium chloride 100 43 100 455:1:34 12:1: 8 38*19 l-rnethyl-4l4-methyl-3(5)-pyrazolyl]-pyradi um iodide 250 62 100 525:1:39 8:}: 3 14:1: 4 1-methallyl-4[5(3)-mcthyl-3(5)-pyrazolyl] yridinium chloride 270 88 100 5S7 24 49:|:1O 58:l11 1,3-dimethyl-4[5(3)-methyl-3(5)-pyrazolyfipyridinium chloride. 100 70 100 615:l:i2 59:1: 5 78:|: 8 1-einnamyl-4[5(3)-rnethyl-3(5)-pyrazolyl]pyrid1nium chloride. 250 32 100 4635 22 195; 8 465:15 1-(3methyl-2-buten-l-yl)-4[5(3)-methyl-3(5)-pyrazolyl]pyrid1nium chloride 250 29 100 479156 60:10 93: 2 -(2-buten-l-yl)-4[5(3)-methyl-3(5)-pyra diniurn chloride 250 66 100 assist 50:1: 7 83:1: 4 1-(2-methoxyethyl)4[5(3)-methyl-3-(5)pyra ium chloride 250 21 100 5135:44 14:1: 6 11:1: 6 i-cyclopropylmethyl-4[5(3)-methy1-3(5)-pyrazo1y bromide 200 35 100 455:4:34 50:1:10 59:1: 6 0.5%Aqueous Carboxymethylcellulose Solution T01 406:1:45 11:l: 3 0i 3 Standard 50 34 100 4mm 0:]: 3 --1l:l: 3 B-PhenethylblguanideHyd!0cl1lor1deStandard.-... 50 53 100 452:e29 21:1: 5 17 3 The active components of this invention can be used in Th term unit dosage form as used in the specification the fO m f c mp Preferably for Oral adminlstraand/ or claims refers to physically discrete units suitable ti-on in unit dosage form such as tablets, pills, capsules, as unitary dosage for warm-blooded animal subjects, each powders, granules or oral solutions or suspensions and the unit containing a predetermined quantity of active matelike. They may also be used as sterile parenteral solutions rial calculated to produce the desired therapeutic effect or suspensions. For preparing solid compositions such as in association with the required pharmaceutical diluent, tablets, the principal active ingredient is mixed with cOncarrier or vehicle. The specifications for the novel unit ventional tableting ingredients such as corn starch, lactose, dosage forms of this invention are dictated by and are sucrose, sorbitol, talc, stearic acid, magnesium stcarate, directly dependent on (a) the unique characteristics of dicalcium phosphate, gums, and fractionally similar matbthe active material and the amount of blood sugar-lowerrials as pharmaceutical diluents or carriers. The table-ts or ing eifect to be achieved, and (b) the limitations inherent pills of the novel compositions can be laminated or otherin the art of compounding such an active material for wise compounded to provide a dosage form affording the therapeutic use in warm-blooded animals as disclosed in advantage of prolonged or delayed action or predeterdetail in this specification, these being features of the mined successive action of the enclosed medication. For present invention. Examples of suitable oral unit dosage example, the tablet or pill can comprise an inner dosage forms in accord with this invention are tablets, capsules, and an outer dosage component, the latter being in the pills, powder packets, granules, wafers, cachets, teaspoonform of an envelope over the former. The two components 55 fuls, dropperfuls, ampules, vials, segregated multiples of can be separated by an enteric layer which serves to resist any of the foregoing, and other forms as herein described. disintegration in the stomach and permits the inner com- The present invention will be described in greater deponent to pass intact into the duodenum or to be delayed tail in the examples which follow which describe the prepin release. A variety of materials can be used for such aration of 4-[3(5)-pyrazolyl]pyridinium salts and formuenteric layers or coatings, such materials including a numlations containing the active components. ber of polymeric acids or mixtures of polymeric acids with EXAMPLE 1 such materials as shellac, shellac and cetyl alcohol, cellulose acetate and the like. A particularly advantageous Preparation of1-(4-pyridyl)-1,3-pentanedi0ne i 0a '11 0 rise t rene m lei acid 0 ol mer i zilfer wi t h kiio vz i'i ma t ri ai s contri uti n to She? eri teric A mlxture 137 (1 mole) of methyl lsomcotmate p ip of the coating g 200 ml. of methyl ethyl ketone, l 1. of ether, and 59.4 g.

1.1 moles of sodium methoxi a The liquid forms in which the novel composition of the de 13 he ted mule? resent invention ma be incor orated for administration Wlth Snmng on a Steam bath for 3 hours The mlxture 15 3 de a ueous solitions suftaibl flavored emulsions cooled, acidified with 100 ml. of acetic acid, and diluted h ctto e ame coco With 500 ml. of Water. The ether layer is separated, and W1 e 1 e sue 0 ns 01 7 S s 01 the aqueous phase extracted with ether. The combined nut oil, peanut oil and the like, as Well as elixirs and similar vehicles well known in the pharmaceutical compounding arts. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as, tragacanth, acacia, alginate, dextran, sodium carether solution is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to 137 g. of red liquid The liquid gives a deep red color with ferric chloride test solution.

EXAMPLE 2 Preparation of 5-methyl-l-(4-pyridyl) -1,3-hexanedione The above compound is obtained as a red liquid from the reaction between methyl isobutyl ketone and methyl isonicotinate under the conditions described in Example 1.

. EXAMPLE 3 Preparation of 1-cycl0pr0pyl-3- (4-pyridyl) -1,3- propanedione This compound is obtained as a red liquid from the reaction between methyl cyclopropyl ketone and methyl isonicotinate under the conditions described in Example 1.

EXAMPLE 4 Preparation of 1-(3-methyl-4-pyridyl)-1,3-butanedione The above compound is obtained as a red liquid from the reaction of acetone and methyl 3-methylisonicotinate under the conditions described in Example 1.

EXAMPLE 5 Preparation of 1-(4-pyridyl) -],3-propanedione sodium salt A mixture of 74 g. (1 mole) of ethyl formate, 60.5 g. (0.5 mole) of methyl 4-pyridyl ketone, 54 g. (1 mole) of sodium methoxide, and 900ml. of benzene is heated under reflux on a steam bath with stirring for 18 hours. The mixture is cooled and filtered. The solid is washed with benzene and cold methanol, and dried, leaving 65 g. of a light brown solid, the sodium salt of the dione.

EXAMPLE 6 Preparation of Z-methyl-J-(4-pyridyl)-1,3-pr0panedione sodium salt The above compound is obtained as a brown solid from the reaction of ethyl formate and ethyl 4-pyridyl ketone under the conditions described in Example 5.

EXAMPLE 7 Preparation of 4- [5 (3 -ethy [-3 (5 -pyraz'lyl] pyridine To a stirred solution of 300 g. of 100% hydrazine hydrate is added during 15 minutes 137 g. (0.77 mole) of crude l-(4-pyridyl)-1,3-pentanedione. The temperature of the solution rises to 85 C. The mixture is stirred at room temperature for 1 hour, diluted with 450 ml. of water, and stored overnight at C. The solid which separates is collected and dried, and it is twice recrystallized from acetone. The product Weighs 31 g. and is white crystals, melting point 116-117 C.

EXAMPLE 8 Preparation of 4- [5 (3 -isobutyl-3 (5 -pyrazolyl] pyridine The compound, colorless crystals, melting point l56- 157 C., is prepared from hydrazine hydrate and 5- methyl-1-(4-pyridyl)-1,3-hexanedione under the conditions described in Example 7.

EXAMPLE 9 Preparation of 4- [5 (3 -cyclopropy l-3 (5 -pyrazolyl] pyridine The above compound, colorless crystals, melting point 126 -127 C. is prepared from hydrazine hydrate and 1- cyclopropyl-3-(4-pyridyl)-1,3 -propanedione under the conditions as described Example 7.

EXAMPLE 10 Preparation 0 j 3-methyl-4-[5 (3 -inethyl-3 (5 pyrazolyl] pyridine This compound, light brown crystals, melting point 136-138 C., is prepared from hydrazine hydrate and 6 1-(3-methyl-4-pyridyl)-1,3-butanedione in the manner described in Example 7.

EXAMPLE 11 Preparation of 4 [3 5 -pyrazolyl] pyridine To a stirred solution of 7.5 g. (0.07 mole) of hydrazine dihydrochloride in ml. of Water is added 5.0 g. (0.034 mole) of 1-(4-pyridyl)-1,3-propanedione sodium salt. After 2 hours, the solution is neutralized with sodium hydroxide, and the solid which separates is collected.

Three recrystallizations from acetone give a colorless solid, melting point 154-155 C.

EXAMPLE 12 Preparation of 4-[4-methyl-3 (5 -pyrazolyl] pyridine The above compound, a viscous orange liquid,

A 260 Inn RE 304 my EXAMPLE 14 Preparation of J-methyl-4-[5(3)-methyl-3(5)-pyrazolyl1- pyridiniam iodide The compound, off-White crystals, melting point 251- 252 C., is prepared from 4-[5(3)-methyl-3 (5)-pyrazolyl] pyridine and methyl iodide as described in Example EXAMPLE 15 Preparation of 1-ethyl-4-[5(3)-methyl-3-(5)-pyrazolyl] pyridinium iodide The above compound, colorless crystals, melting point -176 C., is prepared from 4-[5(3)-methyl-3(5)- pyrazolyl]pyridine and ethyl iodide following the procedure of Example 13, except that the reaction is carried out for 2 hours under reflux in ethanol.

EXAMPLE 16 Preparation of I-n-butyl-4-[5(3)-methyl-3(5)-pyrazolyl] pyridiniam bromide The compound, colorless crystals, melting point 211- 212 C., 'is prepared from 4-[5(3)-methyl-3 (5)-pyrazolyl] pyridine and n-butyl bromide as described in Example 13, except that the reaction is carried out for 18 hours under reflux in n-butyl alcohol.

EXAMPLE 17 Preparation of 1 -m ethyl-4- [3 (5 -pyraz0lyl] pyridinium zodzde The compound, colorless crystals, melting point 189- 190 C., is prepared from 4-[3 (5 )-pyrazolyl] pyridine and methyl iodide as described in Example 13, except that the reaction is carried out for 18 hours at room temperature in methanol.

g. of colorless crystals,

7 EXAMPLE 18 Preparation of 1-n-propyl-4- (3 -methyl-3 (5 pyrazolyl] pyridiniam bromide The above compound, colorless crystals, melting point 247248 C., is prepared using '4-[5(3)-methyl-3(5)- pyrazolyl]pyridine and n-propyl bromide in the procedure in Example 13, except that the reaction is carried out for 18 hours under reflux in ethanol.

EXAMPLE 19 Preparation of 1 -methyl-4-[5 (3 )-isobatyl-3 (5 )-pyrazolyl]pyridiniam iodide The compound, colorless crystals, melting point 206-- 207 C., is prepared from 4-[5(3)-isobutyl-3(5)-pyrazolyl]pyridine and methyl iodide as described in Example 13.

EXAMPLE 20* Preparation of 1-methyl-4-[5 (3) -ethyl-3 (5) -pyrazolyl] pyridinium chloride The compound, colorless crystals, melting point 250- 251 C., is prepared from the reaction of 4-[5(3)-ethyl- 3(5)-pyrazolyl]pyridine and methyl chloride as described in Example 13, except that the reaction is carried out for 18 hours in a bomb at 90 C. with excess methyl chloride as solvent.

EXAMPLE 21 Preparation of 1-isopropyl-4-[5 (3 )-methyl-3 (5 pyraxolyl]pyridinium chloride The compound, colorless crystals, melting point 242- 243 C., is prepared from 4-[5 (3)-methyl-3 (5 -pyrazolyl] pyridine and isopropyl chloride as described in Example 13, except that the reaction is carried out in a bomb for 18 hours at 80 C. with excess isopropyl chloride as solvent.

' EXAMPLE 22 Preparation of 1-isopropyl-4-[5 (3)-methyl-3 (5 )-pyrazolyl]pyridiniurn bromide The above compound, colorless crystals, melting point 217218 C., is prepared from 4-[5(3)-methyl-3(5)- pyrazolyl1pyridine and isopropyl bromide following the procedure of Example 13, except that the reaction is carried out 'for 42 hours in a bomb at 160 C. with excess isopropyl bromide as solvent.

EXAMPLE 23 Preparation of 1 -isobutyl-4-[5 (3 )-methyl-3 (5 -pyrazolyl] pyridinium bromide The compound, colorless crystals, melting point 235- 236 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl] pyridine and isobutyl bromide as described in Example 13, except that the reaction is carried out for 18 hours under reflux in n-butyl alcohol.

EXAMPLE 24 Preparation of 1-methyl-4-[5 (3 )-methyl-3 (5 )-pyrazolyl] pyridinium chloride The compound, colorless crystals, melting point 251 252 C., is prepared from 4-[5(3)-methyl-3 (5)pyrazolyl] pyridine and methyl chloride as described in Example 13, except that the reaction is carried out for 18 hours in a bomb at 90 C. with excess methyl chloride as solvent.

EXAMPLE 25 Preparation of 1-methyl-4- [3 (5) -pyrazolyl] pyridiniam chloride The compound, colorless crystals, melting point 232- 233 C., is prepared from 4-[3(5)-pyrazolyl]p-yridine and methyl chloride as described in Example 13, except that the reaction is carried out for 18 hours in a bomb at 90 C. with excess methyl chloride as solvent.

8 EXAMPLE 26 EXAMPLE 27 Preparation of 1-allyl-4-[5 (3)-methyl-3 (5 )-pyrazolyl] pyridinium chloride The compound, colorless crystals, melting point 243"- 244 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazo lyl]pyridine and allyl chloride as described in Example 13, except that the reaction is carried out for 18 hours under reflux in methanol.

EXAMPLE 28 Preparation 0) 1-methyl-4- [5 (3 -cyclopr0pyl-3 (5 pyrazolyl] pyridiniam chloride This compound, colorless crystals, melting point 259- 261 C., is prepared from 4-[5(3)-cyclopropyl-3(5)1 pyrazolyl]pyridine and methyl chloride as described in Example 13, except that the reaction is carried out for 18 hours in a bomb at C. with excess methyl chloride as solvent.

EXAMPLE 29 Preparation of 1-methyl-4-[4-methyl-3 (5 )pyrazolyl] pyridinium iodide The compound, colorless crystals, melting point 213- 214 C., is prepared from 4-[4-methyl-3(5)-pyrazolyl] pyridine and methyl iodide following the procedure described in Example 13, except that the reaction is carried out for 2 hours under reflux in methanol.

EXAMPLE 30 Preparation of 1 ,3-dimethyl-4- [5 (3 -methyl-3 (5 pyrazolyll-pyridinium chloride The above compound, colorless crystals, melting point 263 265' C., is prepared from 3-methyl-4-[5(3)-methyl-3(5)-pyrazolyl]pyri-dine and methyl chloride as described in Example 13, except that the reaction is carried out for 20 hours in a bomb at 90 C. With excess methyl chloride as solvent.

EXAMPLE 31 Preparation 0 1-methylallyl-4- [5 (3 -methyl-3 (5) pyrazolyl] pyridinium chloride The compound, colorless crystals, melting point 229- 230 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl]pyridine and methallyl chloride following the procedure as described in Example 13, except that the reaction is carried out for 18 hours under reflux with excess methallyl chloride as solvent.

EXAMPLE 32 Preparation of 1-cinnamyl-4- [5 (3 -methyl-3 (5 pyrazolyl] piyridinium chloride This compound, colorless crystals, melting point 207- 208 C., is prepared by reacting 4-[5(3)-methyl-3(5)- pyrazolynpyridine and cinnamyl chloride and using the procedure as described in Example 13, except that the reaction is carried out :for 18 hours under reflux in ethanol.

EXAMPLE 33 Preparation of 1-(3-methyl-2-baten-1-yl)-4-[5(3)- methyl-3 (5) -pyrazolyl] pyridinium chlOrid e The compound, colorless crystals, melting point 19 C., is prepared from 4-[5(3)-rnethyl-3(5)-pyrazolyl]pyridine and 1-chloro-3-methyl-2-butene as described in Example 13, except that the reaction is carried out for 4 hours under reflux in n-propyl alcohol.

EXAMPLE 34 Preparation of J-(Z-batea-I-yl) -4-[5(3) methyl-3 pyrazolyl]pyridinium chloride The above compound, colorless crystals, melting point 162-163 C., is prepared by reacting 4-[5(3)-methyl- 3(5)-pyrazolyl]-pyridine and l-chloro-Z-butene using the procedure described in Example 13, except that the reaction is carried out for 18 hours under reflux in isopropyl alcohol.

1 EXAMPLE 35 Preparation of I-(Z-methoxyethyl) -4-[5 (3)-methyl-3 (5 pyrazolyflpyridiniam chloride The compound, colorless crystals, melting point 209- 210 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl]pyridine and l-chloro-Zanethoxyethane as described in Example 13, except that the reaction is carried out for 18 hours under reflux in n-p-ropyl alcohol.

EXAMPLE 36 Preparation of 1-cycl0pr0pylmethyl-4-[5 (3)-methyl-3 (5 pyrazolyflpyridiniwm bromide The above compound, colorless crystals, melting point 22022l C., is prepared from 4-[5(3)-methy1-3 (5)- pyrazolyl] pyridine and cyclopropylmethyl bromide as described in Example 13, except that the reaction is carried out for 18 hours at 90 C. in toluene.

EXAMPLE 37 Hard gelatin capsules Gm. 1 methy1-4- [5 (3 -ethyl-3 (5 -p-yrazolyl] pyridinium chloride 100 Cornstarch 75 Magnesium stearate, powder 25 Talc 25 The finely powdered ingredients are mixed thoroughly and then encapsulated in 1000 two-piece hard gelatin capsules each containing 100 mgs. of 1-methyl-4-[5(3)- ethyl-3 (5 -pyrazolyl] pyridinium chloride.

EXAMPLE 38 Soft gelatin capsules One piece soft gelatin capsules for oral use each containing 150 mgs. of 1-methyl-4-[5(3)-ethyl-3(5)-pyrazolyl]pyridinium iodide are prepared by first dispersing the compound in sufiicient corn oil to render the material capsulatable and then encapsulating in the usual manner.

pyrazolyl]pyridinium bromide are prepared from the following ingredients:

1- n butyl 4 [5(3) methyl 3(5) pyrazolylJ-pyridinium bromide 1000 Lactose 1500 Magnesium stearate 500 Talc 500 formula:

1 A N R2 R l 6 \llg/ I R: X

wherein R is selected from the group consisting of hydrogen, lower alkyl and cyclopropyl; R and R are selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of lower alkyl, lower alkenyl, cinnamyl, cyclopropylmethyl and lower alkoxy-(lower) alkyl; X is a pharmaceutically acceptable anion and a solid edible carrier.

2. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is l-methyl-4- [5 3 -ethyl-3 (5 -pyrazolyl] pyridinium chloride.

3. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1-methyl-4- [5 (3 -ethyl-3 5 -pyrazolyl] pyridinium iodide.

4. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1-methyl-4- [5 (3 methyl-3 (5 -pyrazolyl] pyridinium chloride.

5. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is l-n-butyl- 4- [5 (3 )-methyl-3 5 -pyrazolyl] pyridinium bromide.

6. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1-n-butyl-4- [5 (3 -methyl-3 (5 -pyrazolyl] pyridinium chloride.

7. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1-methyl-4- [3 (5 -pyrazolyl] pyridinium chloride.

8. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1,3-dimethyl- 4- [5 (3 -methyl-3 (5 -pyrazolyl] pyridinium chloride.

9. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1-(3- methyl-2-buten-1-yl)-4-[5(3)-methyl 3(5) pyrazolyl]- pyridinium chloride.

10. A therapeutic composition in accordance with claim 1 wherein the pyrazolylpyridinium salt is 1-(2- buten 1 yl) 4 [5(3) methyl 3(5) pyrazolyl] pyridinium chloride.

11. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic elfect is desired an amount sufficient to produce hypoglycemia of a pyrazolylpyridinium salt of the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl and cyclopropyl; R and R are selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of lower alkyl, lower alkenyl, cinnamyl, cyclopropylmethyl and lower alkoxy-(lower)alkyl; and X is a pharmaceutically acceptable anion.

12. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufficient amount of 1 1 methyl 4-[5(3)-ethyl-3 ()-pyrazolyl]pyridinium chloride.

13. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufiicient amount of 1 methyl 4 [5(3) ethyl 3(5) pyrazolyl] pyridinium iodide.

14. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a suflicient amount of 1 methyl 4 [5(3) methyl 3(5) pyrazolyl] pyridinium chloride.

15. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufiicient amount of 1- n butyl 4 [5(3) methyl 3(5) pyrazolyl] pyridinium bromide.

16. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufficient amount of 1 n butyl 4 [5(3) methyl 3(5) pyrazolyl] pyridinium chloride.

17. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufiicient amount of 1 methyl 4 [3(5) pyrazolyl1pyridinium chloride.

18. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic efiect is desired a sufficient amount of 1,3 dimethyl 4 [5(3) methyl 3(5) pyrazolyl] pyridinum chloride.

19. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufficient amount of 1- (3 methyl 2 buten 1 yl) 4 [5(3)- methyl-3 (5 -pyrazolyl] -pyridinium chloride.

20. The method of inducing hypoglycemia which comprises administering orally to a warm-blooded animal in whom a hypoglycemic effect is desired a sufficient amount of 1- (2 buten l yl) 4 [5(3) methyl 3(5)- pyrazolyl]pyridinium chloride.

References Cited UNITED STATES PATENTS 3,150,148 9/1964 Dulin 167--65 3,190,888 6/1965 Wolf 167-65 ALBERT T. MEYERS, Primary Examiner. JEROME D. GOLDBERG, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,341,413 September 12, 1967 Edward Charles Tocus et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Columns 3 and 4, in the TABLE, second column, line 18 thereof, for "270" read 250 same TABLE, third column, line 18 thereof, for "88" read 66 same TABLE, sixth column, line 12 thereof, for "35:8" read 36:8 column 7 line 30 for "pyraXo1-" in italics, read pyrazolin italics;

column 10, lines 16 to 21, for that portion of the formula reading I R2 read R3 Signed and sealed this 1st day of October 1968. (SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, Jr.

Attesting Officer

Claims (1)

11. THE METHOD OF INDUCING HYPOGLYCEMIA WHICH COMPRISES ADMINISTERING ORALLY TO A WARM-BLOODED ANIMAL IN WHOM A HYPOGLYCEMIC EFFECT IS DESIRED AN AMOUNT SUFFICIENT TO PRODUCE HYPOGLYCEMIA OF A PYRAZOLYLPYRIDINIUM SALT OF THE FORMULA: