US3914426A - Piperidinesulfonylurea derivatives for lowering blood sugar levels - Google Patents

Piperidinesulfonylurea derivatives for lowering blood sugar levels Download PDF

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US3914426A
US3914426A US464331A US46433174A US3914426A US 3914426 A US3914426 A US 3914426A US 464331 A US464331 A US 464331A US 46433174 A US46433174 A US 46433174A US 3914426 A US3914426 A US 3914426A
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hept
urea
ethyl
methyl
endo
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George R Evanega
Donald E Kuhla
Reinhard Sarges
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Pfizer Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1836—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid
    • C07C273/1845—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid comprising the -N-C(O)-Hal moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • This invention relates to a new and useful sulfamylurea derivatives, which are effective in reducing blood sugar levels to a remarkably high degree. More particularly, it is concerned with certain novel 4- substituted-l-piperidinesulfonylureas and their base salts with pharmacologically acceptable cations, which are useful in therapy as oral hypoglycemic agents for the treatment of diabetes.
  • novel 1- piperidinesulfonylureas i.e., sullfamylureas
  • sullfamylureas derived from a nitrogen-containing monocarboxylic acid
  • novel sulfamylurea compounds of this invention are all selected from the group consisting of 1- piperidinesulfonylureas of the formula:
  • R is a member selected from the group consisting of 2-methoxy-3-pyridyl, 2-ethoxy- 3-pyridyl, 4-chloro-2-pyridyl and 8-quinolinyl
  • R is a member selected from the group consisting of bicyclo[2.2. l ]hept-5-en-2-yl-endo-methyl, bicyclo[ 2.2. l hept-Z-yl-endo-methyl, 7-oxybicyclo 2.2.1 ]hept-2- ylmethyl.
  • I-adamantyl and cycloalkyl having from 5 to 8 carbon atoms.
  • RCONHCH CH is reacted with an organic isocyanate reagent of the formula R'NCO wherein R corresponds to the previously defined l-substituent on the urea moiety of the desired final product.
  • R corresponds to the previously defined l-substituent on the urea moiety of the desired final product.
  • R corresponds to the previously defined l-substituent on the urea moiety of the desired final product.
  • R is defined as previously indicated.
  • This particular reaction is normally conducted in a basic solvent medium, most desirably employing an aprotic organic solvent such as tetrahydrofuran, dimethylsulfoxide or dimethylformamide and preferably using a light excess in moles of a base, like triethylamine or sodium hydride (in mineral oil), which may then be admixed with the solvent.
  • R'NCO isocyanate reagents
  • R'NCO isocyanate reagents
  • any temperature below that of reflux may be used in order to effect the reaction, it is normally found most convenient in practice to employ elevated temperatures so as to shorten the required reaction time, which may range anywhere from several minutes up to about 24 hours depending, of course, upon the particularly l-piperidinesulfonylurea actually being prepared.
  • the product Upon completion of the reaction, the product is easily recovered from the spent reaction mixture in a conventional manner, e.g., by pouring same into an excess of ice-water containing a slight excess of acid, such as hydrochloric acid, whereby the desired l-piperidinesulfonylurea readily precipitates means as suction filtration and the like.
  • a slight excess of acid such as hydrochloric acid
  • Another method for preparing the subject compounds of this invention involves reacting a lpiperidinesulfamide in the form of an alkali metal or alkaline-earth metal salt (either employed as such or else formed in situ) with an appropriate 1,1,3- trisubstituted urea of the formula (R") NCONHR', wherein R" is an aryl group such as phenyl, pchlorophenyl, p-bromophenyl, pnitrophenyl, pacetylaminophenyl, p-tolyl, p-anisyl, a-naphthyl, ,B-naphthyl, and the like.
  • This reaction is preferably carried out in the presence of a neutral polar organic solvent medium.
  • Typical organic solvents for use in this connection include the N,N-dialkyl lower alkanoamides like dimethylformamide, dimethylacetamide, diethylformamide and diethylacetamide, as well as lower dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and di-n-propyl sulfoxide, etc. It is desirable that the aforesaid solvent for this reaction be present in sufficient amount to dissolve each of the previously mentioned starting materials. In general, the reaction is conducted at a temperature that is in the range of from about 20C. up to about l50C. for a period of about 1% to about ten hours.
  • the relative amounts of reagents employed are such that the molar ratio of lpiperidinesulfamide to the l l -diaryl-3- (monosubstituted)urea is most desirably in the pre' ferred range of from about 1:1 to about l:2, respectively.
  • Recovery of the desired product from the reaction mixture is then achieved by first diluting the reaction solution with water and then adjusting if necessary the pH of the resulting solution to a value of at least about 8.0, followed by subsequent extraction of the basic aqueous solution with any water-immiscible organic solvent in order to remove the diarylamine byproduct of formula (R) NH as well as minor amounts of unreacted or excess starting material that might possibly be present at this stage.
  • Isolation of the desired 1- piperidinesulfonylurea from the basic aqueous layer then follows in due course, viz., by adding a sufficient amount of a dilute aqueous acid solution to cause precipitation of the desired sulfamylurea to occur.
  • the two major type starting materials required for this reaction viz., the l-piperidinesulfamides and the l,1-diaryl-3-(monosubstituted)ureas, are both readily prepared by those skilled in the art in accordance with the conventional methods of organic chemistry.
  • the l-piperidinesulfamides which are novel compounds and are also used as starting materials in the previously described isocyanate method, are suitably obtained by using classical methods of synthesis starting from the known 4-(2-aminoethyl)pyridine and proceeding in accordance with standard organic procedure as hereinafter described in the experimental section of this specification in some detail (see Preparations A-D and Examples I-lV).
  • the l,l-diaryl-3- monosubstituted)-ureas are all readily prepared from common organic reagents by employing standard procedures well known in the art, e.g., the desired l,l,3-trisubstituted urea may be prepared from the corresponding disubstituted carbamyl chloride [(R") NCOCl] and the appropriate amine (R'NH in accordance with the general procedure of J. F. L. Reudler, as described in Recueil des Travaux Chimiques des Pays-Bus, Vol. 33, p. 64 (l9l4).
  • the chemical bases which are used as reagents in this invention to prepare the aforementioned pharmaceutically acceptable base salts are those which form nontoxic salts with the many herein described acidic lpiperidinesulfonylureas, such as l-(bicyclo [2.2.1]hept--en-2-yl-endo-methyl)-3 4-[2-(2- methoxynicotinamido )eeth'yl]- l -piperidinesulfonyl urea, for example.
  • These particular non-toxic base salts are of such nature that their cations are said to be essentially non-toxic in character over the wide -methoxynicotinamido)ethyl of dosage administered.
  • Examples of such cations include those of sodium, potassium, calcium and magnesium, etc.
  • These salts can easily be prepared by simply treating the aforementioned 1- piperidinesulfonylureas with an aqueous solution of the desired pharmacologically acceptable base, i.e., those oxides, hydroxides or carbonates, which contain pharmacologically acceptable cations, and then evaporating the resulting solution to dryness while preferably being placed under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the said acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution in the same manner as before. In either case, stoichiometric amounts'of reagents must be employed in order to ensure completeness of reaction and maximum production of yields with respect to the desired final product.
  • the l-piperidinesulfonylurea compounds of this invention are all readily adapted to therapeutic use as oral hypoglycemic agents, in view of their ability to lower the blood sugar levels of diabetic and non-diabetic subjects to a statistically significant degree.
  • all the herein described compounds of this invention can be administered orally, for the present purposes at hand, without causing any significant untoward pharmacological side reactions to occur in the subject to whom they are so administered.
  • these compounds are ordinarily administered at dosage levels ranging from about 0.1 mg. to about 2.5 mg. per kg. of body weight per day, although variations will necessarily occur depending upon the condition and individual response of the subject being treated and the particular type of oral formulation chosen.
  • novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspension,
  • Such carrier include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • Such oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • tablets contain ing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules; preferred materials in this connection would also include the high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • the activity of the compounds of the present invention is determined by their ability to lower blood sugar levels in the normal fasted rat when tested therein for such purposes according to the procedure described by W. S. Hoffman, as reported in the Journal of Biological Chemistry, Vol. 120, p. 51 (1937).
  • the latter method measures directly the amount of glucose in the blood at any giiven time and from this, the maximum percent decrease in blood sugar can be readily calculated and reported as hypoglycemic activity per se.
  • the present 1- piperidinesulfonylurea compounds are shown to markedly reduce the blood sugar levels of non-anesthetized rats when administered to them at dose levels as low as 1 .0 mg./kg.
  • a l5-gal. autoclave was charged with 1.8 kg. (7.13 moles) of 4-(2-phthalimidoethyl)pyridine, 10.62 gal. of anhydrous methanol saturated with dry hydrogen chloride gas and 72.2 g. of platinum oxide catalyst.
  • the autoclave and its contents were then placed under 200 p.s.i. pressure of hydrogen, while at 50C. and held at that point until 95% of the theoretical hydrogen uptake was complete (this required approximately 4.33 hours).
  • the reaction mixture was cooled to 24C., vented and then purged with nitrogen. After removal of the catalyst by means of filtration, the resulting filtrate was concentrated in vacuo to a final volume of ca.
  • Preparation B A stirred suspension consisting of 57 g. (0.362 mole) of 2-chloronicotinic acid [6. M. Badger et al., Australian Journal of Chemistry, Vol. 18, p. 1267 (1965)] in 800 ml. of methanol was treated portion-wise with 43 g. (0.797 mole) of sodium methoxide. The resulting turbid solution was then heated in an autoclave at 110C. for a period of 11 hours. The reaction mixture obtained in this manner was then evaporated to near dryness (while under reduced pressure) and the residue was subsequently dissolved in 2000 ml. of water, filtered and the resulting filtrate thereafter acidified with 1000 ml. of glacial acetic acid.
  • the acidified filtrate was then concentrated in vacuo to a volume of ca. 800 ml., cooled in an ice bath for a period of approximately 1 hour and the resulting crystalline crop (i.e., precipitate) thereafter collected by means of suction filtration. After air drying to constant weight, there were obtained 33.3 g. (60%) of final product melting at l43l46C. Crystallization of the latter material from 150 ml. of acetonitrile then gave 27.6 g. (50%) of pure 2-methoxynicotinic acid, m.p. 144l46C. [literature m.p. 144-146C., according to Chemical Abstracts, Vol. 68, p. 12876g (1968)].
  • Preparation C The procedure described in Preparation B is repeated except that sodium ethoxide is the reagent of choice employed instead of sodium methoxide.
  • 2-chloronicotinic acid is converted to 2- ethoxynicotinic acid in a most facile manner.
  • Treatment of the latter material with an excess of thionyl chloride then yields 2-ethoxynicotinoyl chloride.
  • Preparation F A 3-liter round-bottomed flask was charged with 212 g. (4.0 moles) of acrylonitrile, 272 g. (4.0 moles) of furan and 50 mg. of hyroquinone all dissolved in a total of 1 liter of dry benzene. Stirring was then commenced, while a solution consisting of 55 ml. (0.5 mole) of titanium tetrachloride dissolved in 500 ml. of benzene was added at such a rate that the temperature did not exceedd 35C. The resulting mixture was then stirred at room temperature (-25C.) for a period of 5 days in order to complete the reaction, followed by treatment with 500 ml. of 0.5N hydrochloric acid.
  • Preparation G A methanolic solution of the exo-nitrile compound prepared as described in Preparation F was treated in exactly the same manner as that previously described for the corresponding endo-isomer, with respect to Raney nickel and sodium borohydride reduction. In this way, pure exo-7-oxabicyclo[2.2.llhept-2-yl-nitrile was converted to exo-7-oxabicyclo[2.2.l]hept-2- ylmethylamine in substantially high yield. The latter material was used as such in the next reaction step without any further purification being necessary.
  • Example I A solution consisting of 286.5 g (1.67 moles) of 2- methoxynicotinoyl chloride dissolved in 2.0 liters of chloroform and a solution of 530 g. (5.0 moles) of sodium carbonate in 2225 ml. of water were added simultaneously at the rate of 25 ml./minute to 407 g. (1.67 moles) of 4-(2-aminoethyl)-l-piperidinesulfonamide hydrochloride dissolved in 2.75 liters of water, which also contained 177 g. (1.67 moles) of sodium carbonate. Vigorous agitation was maintained throughout the addition step, after which the reaction mixture was then further stirred at room temperature (-25C.) for 1.5 hours.
  • Example 11 i The procedure described in Example 1 is repeated iusing 2-ethoxynicotinyl chloride in place of 2- methoxynicotinoyl chloride on the same molar basis as before. In this particular case, the corresponding final product thus obtained is 4- 2-( 2- ethoxynicotinamido)ethyl]-1-piperidinesulfonamide.
  • Example 111 To a mixture of 1.95 g. (0.008 mole) of 4-(2- aminoethyl)- l -piperidinesulfonamide hydrochloride and 2.22 ml. (0.016 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there were added 1.41 g. (0.008 mole) of 4-chloropicolinoyl chloride dissolved in 15 ml. of tetrahydrofuran. The initial addition step was slightly exothermic (-40C.) and after completion of same, the resulting reaction mixture was stirred at ambient temperatures for a period of approximately 16 hours. At this point, the thoroughly stirred mixture was poured into 50 ml.
  • Example lV In a ml. three-necked, round bottom flask equipped with mechanical stirrer, reflux condenser and heating mantle, there were placed 3.0 g. (0.0173 mole) of quinoline-8-carboxylic acid, 8.1 g. (0.0327 mole) of N-ethoxycarbonyl-Z-ethoxycarbonyl-2-ethoxy-1 ,3- dihydroquinoline (EEDQ), 3.82 g. (0.01635 mole) of 4-(2-aminoethyl)-l-piperidinesulfonamide hydrochloride and 1.66 g. (0.01635 mole) of triethylamine all in a total of 50 ml.
  • EEDQ N-ethoxycarbonyl-Z-ethoxycarbonyl-2-ethoxy-1 ,3- dihydroquinoline
  • EEDQ N-ethoxycarbonyl-Z-ethoxycarbonyl-2-ethoxy-1 ,3
  • Example V To a solution consisting of 407 g. (1.19 mole) of 4- [2-(Z-methoxynicotinamido)ethyl]-1- piperidinesulfonamide and 380 g. (1.19 moles) of 1,1- diphenyl-3-(bicyclo[2.2.1 ]hept-5-en-2-yl-endomethyl)urea dissolved in 3.0 liters of dry N,N- dimethylforamide, there were added 51 g. (1.19 moles) of 56% sodium hydride (in mineral oil) in one full portion. The resulting reaction mixture was then heated to 65C., at which point it became slightly exothermic and the temperature rose to 70C.
  • Example VI A mixture of 983 mg. (0.002 mole) of 1- (bicyclo[2.2. l ]hept-5-en-2-yl-endo-methyl)-3- ⁇ 4-[ 2- (2-methoxynicotinamido )ethyl]- l piperidinesulfonyllurea in 50 ml. of tetrahydrofuran containing 50 mg. of 5% palladium-on-carbon catalyst was hydrogenated at 48 psi. pressure for a period of 30 minutes. Upon completion of this step, the catalyst was removed by means of suction filtration and the resulting filtrate thereafter evaporated to near dryness while under reduced pressure to afford a white solid material as the crude residual product.
  • Example VII The procedure described in Example V was repeated except that 900 mg. (0.0026 mole) of 4-[2'(4- ch1oropicolinamido)ethyl]- 1 -piperidinesulfonamide and 930 mg. (0.0029 mole) of 1,1-diphenyl-3- (bicyclo)[2.2. l ]hept-S-en-2-yl-endo-methyl)urea were reacted in 5.0 m1. of dry N,N-dimethylformamide in the presence of 130 mg. (0.0029 mole) of 56% sodium hydride in mineral oil. The reaction mixture was heated at 60C. for a period of 30 minutes, at which point thinlayer chromatography(TLC) analysis showed the conversion to be substantially complete.
  • TLC thinlayer chromatography
  • Example VIII The procedure described in Example V was repeated except that 1.0 g. (0.00276 mole) of 4-[2-(8- quinolinecarboxamido ethyl 1 -piperidinesulfonamide and 879 mg. (0.00276 mole) of 1,1-diphenyl-3- (bicycl0[2.2.1]hept-5-en-2-yl-endo-methyl)urea were reacted in 10 ml. of N,N-dimethylformamide in the presence of 118 mg. (0.00276 mole) of 56% sodium hydride (in mineral oil). In this manner, there was obtained a 210 mg.
  • Example X The procedure described in Example V was repeated except that 500 mg. (0.00145 mole) of 4-[2-(2- methoxynicotinamido )ethyl l -piperidinesulfonamide and 316 mg. (0.00175 mole) of l-adamantyl isocyanate [H. Stetter et al., Chemische Berichte, V01. 95, p. 2302 (1962)] were reacted in 5.0 ml. of dry N,N-dimethylformamide in the presence of 75 mg. (0.00175 mole) of 56% sodium hydride (in mineral oil). In this manner, there was obtained a 250 mg.
  • Example XI The procedure described in Example V was repeated except that 1.0 g. (0.00276 mole) of 4-[2-(8- quinolinecarboxamido )ethyl 1 -piperidinesulfonamide and 345 mg. (0.00276 mole) of cyclohexyl isocyanate were reacted in m1. of dry N,N-dimethylformamide in the presence of 118 mg. (0.00276 mole) of 56% sodium hydride (in mineral oil). In this manner, there was obtained 820 mg.
  • Example XII The procedure described in Example V was repeated except that 190 mg. (0.00055 mole) of 4-[2-(2- methoxynicotinamido )ethyl]- l -piperidinesulfonamide and 225 mg. (0.0007 mole) of 1,1-diphenyl-3-(7- oxabicyclo[2.2. l ]hept-2-yl-endo-methyl)urea were reacted in 5.0 ml. of N,N-dimethylformamide in the presence of 34 mg. (0.0007 mole) of 49% sodium hydride (in mineral oil). The reaction mixture was then allowed to stand at room temperature (-25C.) overnight (a period of approximately 16 hours) prior to work-up.
  • Example XIII The procedure described in the preceding Example was repeated again except that 1,1-diphenyl-3-(7- oxabicyclo[2.2.l]hept-Z-yl-exo-methyl)urea was the reagent employed instead of the corresponding endoisomer.
  • the corresponding final product obtained was l-(7-oxabicyclo[2.2. l ]hept-2-ylexo-methyl)-3- ⁇ 4-[2-( Z-methoxynicotinamido)ethyl]- l-piperidinesulfonyl ⁇ urea, m.p. 105l 10C.
  • Example XIV The following l-piperidinesulfonylureas are prepared by employing the procedures described in the previous examples, starting from the corresponding sulfamide and the appropriate organic isocyanate or l,l-diphenyl-3-substituted urea in each instance:
  • Example XVI The sodium salt of l-(bicyclo[2.2.l]hept-5-en-2-yl endo-methyl)-3- ⁇ 4-[2-( 4-chloropicolinamido )ethyl]- l-piperidinesulfonyl ⁇ urea is prepared by dissolving said compound in anhydrous methanol and then adding said solution to another methanolic solution which contains an equivalent amount in moles of sodium methoxide. Upon subsequent evaporation of the solvent therefrom via freeze-drying, there is obtained the desired alkali metal salt in the form of an amorphous solid powder which is freely soluble in water.
  • potassium and lithium salts are also similarly prepared, as are the alkali metal salts of all the other acidic 1-piperidinesulfonylureas of this invention which are reported in the previous examples.
  • Example XVII Example XVIII
  • a dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
  • Example XIX A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
  • Example XX The l-piperidinesulfonylurea final products of Examples V-XIII were tested for hypoglycemic activity in What is claimed is:
  • a method for lowering blood sugar in the treatment of a diabetic animal which comprises orally administering to said animal an effective blood sugar lowering amount of a compound selected from the group consisting of l-piperidinesulfonylurea of the formula and a base salt thereof with a pharmacologically acceptable cation, wherein R is a member selected from the group consisting of 2-methoxy-3-pyridyl, 2-ethoxy- 3-pyridyl, and 4-chloro-2-pyridyl, and R is a member selected from the group consisting of bicyclo- [2.2.1]hept-5-en-2-yl-endo-methyl, bicyclo[2.2.11- hept-2-yl-endo-methyl, 7-oxabicycIo-[ 2.2. 1 ]hept-Z- ylmethyl, l-adamethyl and cycloalkyl having from 5 to 8 carbon atoms.
  • composition for oral administration comprising a pharmaceutically acceptable carrier and a blood sugar lowering amount of a compound selected from the group consisting of l-piperidinesulfonylurea of the formula:
  • R is a member selected from the group consisting of 2-methoxy-3-pyridyl, 2-ethoxy- 3-pyridyl and 4-chloro-2-pyridyl
  • R is a member selected from the group consisting of bicyclo[2.2.l1hept-5-en-2-yl-endo-methyl, bicyclo[2.2. 1 ]-hept-2-ylendo-methyl, 7-oxabicyc10[2.2. l ]hept-2-ylmethyl, ladamantyl and cycloalkyl having from 5 to 8 carbon atoms.
  • composition of claim 9 wherein the composition is l-('bicyclo[2.2.l ]-hept-5-en-2-yl-endo-methyl)- 3- 4-[ 2-( Z-methoxynicotinamido )ethyl]- l piperidinesulfonyl urea.
  • composition of claim 9 wherein the compound is l-(bicyclo[2.2.l ]hept-2-yl-endo-methyl-3-4- [2-(2-methoxynicotinamido)ethyl]-1- piperidinesulfonyl urea.
  • composition of claim 9 wherein the compound is 1-( 7-oxabicyclo[2.2. l ]hept-2-yl-endomethyl )-3 -4-[ 2-( Z-methoxynicotinamido )ethyl l piperidinesulfonyl urea.
  • composition of claim 9 wherein the compound is l-(7-oxabicyclo-[2.2. 1 ]hept-2-yl-exomethyl )-3-4-[2-( Z-methoxynicotinamido)ethyl]- 1 piperidinesulfonyl urea.

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Abstract

The 1-piperidinesulfonylureas of this invention are useful in therapy as oral hypoglycemic agents. Typical members include those compounds derived from 2-methoxy-nicotinic acid, of which 1-(bicyclo(2.2.1)hept-5-en-2-yl-endo-methyl)-3-(4-(2 -(2methoxynicotinamido)ethyl)-1-piperidinesulfonyl)-urea is a most preferred embodiment.

Description

United States Patent Evanega et al.
Oct. 21, 1975 PIPERIDINESULFONYLUREA DERIVATIVES FOR LOWERING BLOOD SUGAR LEVELS Inventors: George R. Evanega, Ledyard;
Donald E. Kuhla, Gales Ferry;' Reinhard Sarges, Mystic, all of Conn.
Assignee: Pfizer Inc., New York, NY.
Filed: Apr. 26, 1974 Appl. No.: 464,331
Related US. Application Data Division of Ser. No. 305,594, Nov. 10, 1972, Pat. No. 3,829,434.
US. Cl. 424/266; 424/258 lnt. Cl. A6lK 27/00 Field of Search 424/266 References Cited UNITED STATES PATENTS 3,697,527 10/1972 Hoehn et al. 424/266 Primary Exuminer-Frederick El Waddell Attorney, Agent, or Fir'mConnolly and Hutz [57] ABSTRACT 13 Claims, N0 Drawings PIPERIDINESULFONYLUREA DERIVATIVES FOR LOWERING BLOOD SUGAR LEVELS CROSS REFERENCE TO RELATED APPLICATION This application is a division of application Ser. No. 305,594, filed on Nov. 10, 1972, now U.S. Pat. No. 3,829,434.
BACKGROUND OF THE INVENTION This invention relates to a new and useful sulfamylurea derivatives, which are effective in reducing blood sugar levels to a remarkably high degree. More particularly, it is concerned with certain novel 4- substituted-l-piperidinesulfonylureas and their base salts with pharmacologically acceptable cations, which are useful in therapy as oral hypoglycemic agents for the treatment of diabetes.
In the past, various attempts have been made by numerous investigators in the field of organic medicinal chemistry to obtain new and better oral hypoglycemic kagents. For the most part, these efforts have principally involved the synthesis and testing of various new and heretofore unavailable organic compounds, particularly in the are of the sulfonylureas. However, in the search for still newer and more improved oral hypoglycemic agents, far less is known about the activity of various heterocyclic sulfonylureas like 4-substituted-1- piperidinesulfonylureas and their derivatives. For instance, J. M. McManus et al. in the Journal of Medicinal Chemistry, Vol. 8, p. 766 (1965) report on several cyclicsulfamylureas that are active, but none of these compounds possess any outstanding clinical advantages over that of either chlorpropamide or tolbutamide when used in t his connection.
SUMMARY OF THE INVENTION In accordance with the present invention, it has now been rather suprisingly found that certain novel 1- piperidinesulfonylureas (i.e., sullfamylureas) derived from a nitrogen-containing monocarboxylic acid are extremely useful when employed as oral hypoglycemic agents for the treatment of diabetic subjects. The novel sulfamylurea compounds of this invention are all selected from the group consisting of 1- piperidinesulfonylureas of the formula:
and the base salts thereof with pharmacologically acceptable cations, wherein R is a member selected from the group consisting of 2-methoxy-3-pyridyl, 2-ethoxy- 3-pyridyl, 4-chloro-2-pyridyl and 8-quinolinyl, and R is a member selected from the group consisting of bicyclo[2.2. l ]hept-5-en-2-yl-endo-methyl, bicyclo[ 2.2. l hept-Z-yl-endo-methyl, 7-oxybicyclo 2.2.1 ]hept-2- ylmethyl. I-adamantyl and cycloalkyl having from 5 to 8 carbon atoms. These compounds are all useful in lowering blood sugar levels when administered by the oral route of administration.
Of special interest in this connection are such typical and preferred member compounds of the invention as 2 [2-( 2-methoxynicotinamido )ethyl] lpiperidinesulfonyl} urea, l-(bicyclo[2.2.l]hept-Z-ylendo-methyl-3-{4-[2-(2-methoxynicotinamido)ethylll-piperidinesulfonyl} urea, l-(7- oxabicyclo[2.2. l ]hept-Z-yl-endo-methyl)-3- {4-[2-( 2- methoxynicotinamido)ethyl]- 1- piperidinesulfonyl} urea, l-(7-oxabicyclo-[2.2. l ]hept- 2-yl-exo-methyl)-3-{4-[2(2-methoxynicotinamido)ethyl]-l-piperidinesulfonyl} urea, l- (bicyclo[ 2.2. l ]hept-S-en-2-yI-endo-methyl-3-{4-[2- (4-chloropicolinamido)ethyl]- l -piperidinesulfonyl} urea, l-(bicyclo[2.2. l ]hept-5-en-2-yl-endo-methyl)-3- {4-[2-( 8-quinolinecarboxamido)ethyl ]piperidinesulfonyl} urea and l-cyclohexyI-3-{ 4-[2-(8- quinolinecarboxamido)ethyl]- I -piperidinesulfonyl} urea, and their corresponding sodium salts. These particular compounds are all highly potent as regards their hypoglycemic activity.
DETAILED DESCRIPTION OF THE INVENTION In accordance with the process employed for preparing the novel compounds of this invention, an appropriately substituted sulfamide compound of the formula:
RCONHCH CH is reacted with an organic isocyanate reagent of the formula R'NCO wherein R corresponds to the previously defined l-substituent on the urea moiety of the desired final product. In this way, the corresponding 1- piperidinesulfonylurea compound is formed where R is defined as previously indicated. This particular reaction is normally conducted in a basic solvent medium, most desirably employing an aprotic organic solvent such as tetrahydrofuran, dimethylsulfoxide or dimethylformamide and preferably using a light excess in moles of a base, like triethylamine or sodium hydride (in mineral oil), which may then be admixed with the solvent. Many of the aforesaid isocyanate reagents (R'NCO) are either known compounds or else that can easily be prepared, using methods well-known to those skilled in the art, starting from readily available materials. In practice, it is usually preferable to employ at least about a molar equivalent of the isocyanate reagent in the aforesaid reaction of the present invention, with best results often being achieved by using a slight excess of same. Although any temperature below that of reflux may be used in order to effect the reaction, it is normally found most convenient in practice to employ elevated temperatures so as to shorten the required reaction time, which may range anywhere from several minutes up to about 24 hours depending, of course, upon the particularly l-piperidinesulfonylurea actually being prepared. Upon completion of the reaction, the product is easily recovered from the spent reaction mixture in a conventional manner, e.g., by pouring same into an excess of ice-water containing a slight excess of acid, such as hydrochloric acid, whereby the desired l-piperidinesulfonylurea readily precipitates means as suction filtration and the like.
Another method for preparing the subject compounds of this invention involves reacting a lpiperidinesulfamide in the form of an alkali metal or alkaline-earth metal salt (either employed as such or else formed in situ) with an appropriate 1,1,3- trisubstituted urea of the formula (R") NCONHR', wherein R" is an aryl group such as phenyl, pchlorophenyl, p-bromophenyl, pnitrophenyl, pacetylaminophenyl, p-tolyl, p-anisyl, a-naphthyl, ,B-naphthyl, and the like. This reaction is preferably carried out in the presence of a neutral polar organic solvent medium. Typical organic solvents for use in this connection include the N,N-dialkyl lower alkanoamides like dimethylformamide, dimethylacetamide, diethylformamide and diethylacetamide, as well as lower dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and di-n-propyl sulfoxide, etc. It is desirable that the aforesaid solvent for this reaction be present in sufficient amount to dissolve each of the previously mentioned starting materials. In general, the reaction is conducted at a temperature that is in the range of from about 20C. up to about l50C. for a period of about 1% to about ten hours. The relative amounts of reagents employed are such that the molar ratio of lpiperidinesulfamide to the l l -diaryl-3- (monosubstituted)urea is most desirably in the pre' ferred range of from about 1:1 to about l:2, respectively. Recovery of the desired product from the reaction mixture is then achieved by first diluting the reaction solution with water and then adjusting if necessary the pH of the resulting solution to a value of at least about 8.0, followed by subsequent extraction of the basic aqueous solution with any water-immiscible organic solvent in order to remove the diarylamine byproduct of formula (R) NH as well as minor amounts of unreacted or excess starting material that might possibly be present at this stage. Isolation of the desired 1- piperidinesulfonylurea from the basic aqueous layer then follows in due course, viz., by adding a sufficient amount of a dilute aqueous acid solution to cause precipitation of the desired sulfamylurea to occur.
The two major type starting materials required for this reaction, viz., the l-piperidinesulfamides and the l,1-diaryl-3-(monosubstituted)ureas, are both readily prepared by those skilled in the art in accordance with the conventional methods of organic chemistry. For instance, the l-piperidinesulfamides, which are novel compounds and are also used as starting materials in the previously described isocyanate method, are suitably obtained by using classical methods of synthesis starting from the known 4-(2-aminoethyl)pyridine and proceeding in accordance with standard organic procedure as hereinafter described in the experimental section of this specification in some detail (see Preparations A-D and Examples I-lV). The l,l-diaryl-3- monosubstituted)-ureas, on the other hand, are all readily prepared from common organic reagents by employing standard procedures well known in the art, e.g., the desired l,l,3-trisubstituted urea may be prepared from the corresponding disubstituted carbamyl chloride [(R") NCOCl] and the appropriate amine (R'NH in accordance with the general procedure of J. F. L. Reudler, as described in Recueil des Travaux Chimiques des Pays-Bus, Vol. 33, p. 64 (l9l4).
The chemical bases which are used as reagents in this invention to prepare the aforementioned pharmaceutically acceptable base salts are those which form nontoxic salts with the many herein described acidic lpiperidinesulfonylureas, such as l-(bicyclo [2.2.1]hept--en-2-yl-endo-methyl)-3 4-[2-(2- methoxynicotinamido )eeth'yl]- l -piperidinesulfonyl urea, for example. These particular non-toxic base salts are of such nature that their cations are said to be essentially non-toxic in character over the wide -methoxynicotinamido)ethyl of dosage administered. Examples of such cations include those of sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by simply treating the aforementioned 1- piperidinesulfonylureas with an aqueous solution of the desired pharmacologically acceptable base, i.e., those oxides, hydroxides or carbonates, which contain pharmacologically acceptable cations, and then evaporating the resulting solution to dryness while preferably being placed under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the said acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution in the same manner as before. In either case, stoichiometric amounts'of reagents must be employed in order to ensure completeness of reaction and maximum production of yields with respect to the desired final product.
As previously indicated, the l-piperidinesulfonylurea compounds of this invention are all readily adapted to therapeutic use as oral hypoglycemic agents, in view of their ability to lower the blood sugar levels of diabetic and non-diabetic subjects to a statistically significant degree. For instance, l-(bicyclo[2.2.llhept-S-en-Z-ylendo-methyl )-3- {4-[ 2-( 2-methoxynicotinamido )ethyl]-l piperidinesulfonyhurea (as the sodium salt), a typical and preferred agent of the present invention, has been found to consistently lower blood sugar levels in the normal fasted rat (as well as in fed rats and dogs) to a statistically significant degree when given by the intraperitoneal route of administration at dose levels ranging from 1.0 gm./kg. to 15 mg./kg., respectively, without showing any substantial signs of toxic results. The other compounds of this invention also cause similar results. Furthermore, all the herein described compounds of this invention can be administered orally, for the present purposes at hand, without causing any significant untoward pharmacological side reactions to occur in the subject to whom they are so administered. In general, these compounds are ordinarily administered at dosage levels ranging from about 0.1 mg. to about 2.5 mg. per kg. of body weight per day, although variations will necessarily occur depending upon the condition and individual response of the subject being treated and the particular type of oral formulation chosen.
In connection with the use of the lpiperidinesulfonylurea compounds of this invention for the treatment of diabetic subjects, it is to be noted that they may be administered either alone or in combination with pharmaceutically acceptable carriers and that such administration can be carried out in both single and multiple dosages. More particularly, the novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspension,
-elixirs, syrups and the like. Such carrier include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
For purposes of oral administration, tablets contain ing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules; preferred materials in this connection would also include the high molecular weight polyethylene glycols. When aqueous suspensions and- /or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
The activity of the compounds of the present invention, as hypoglycemic agents, is determined by their ability to lower blood sugar levels in the normal fasted rat when tested therein for such purposes according to the procedure described by W. S. Hoffman, as reported in the Journal of Biological Chemistry, Vol. 120, p. 51 (1937). The latter method measures directly the amount of glucose in the blood at any giiven time and from this, the maximum percent decrease in blood sugar can be readily calculated and reported as hypoglycemic activity per se. In this way, the present 1- piperidinesulfonylurea compounds are shown to markedly reduce the blood sugar levels of non-anesthetized rats when administered to them at dose levels as low as 1 .0 mg./kg.
Preparation A To a rapidly-stirred solution consisting of 148.1 g. 1.0 mole) of phthalic anhydride dissolved in 1000 ml. of xylene and also containing 13 ml. of triethylamine, there was slowly added in a dropwise manner 122.1 g. (1.0 mole) of 4-(2-aminoethyl)-pyridine [L. E. Brady et al., Journal of Organic Chemistry, Vol. 26, p. 4758 (1961)] dissolved in 1000 ml. of xylene. The reaction was slightly exothermic in nature and a heavy orangeyellow gum was observed to precipitate from the stirred system toward the end of the addition step. Upon completion of the addition, the resulting reaction mixture was refluxed for a period of approxi mately 2 hours (using a Dean-Stark trap to remove the water therefrom) and there was thus obtained a completely homogeneous yellow liquid. The latter liquid was then decanted while still hot into a 2-liter Erlenmeyer flask and slowly allowed to crystallized on cooling to room temperature C.). In this manner, there were ultimately obtained 209 g. (83%) of crystalline 4-(2-phthalimidoethyl)pyridine in the form of a white solid material melting at 157C.
Anal. Calcd. for C I-1 N 0 C, 71.41; H, 4.80; N, 11.11. Found: C, 71.55; H, 4.91; N, 10.75.
A l5-gal. autoclave was charged with 1.8 kg. (7.13 moles) of 4-(2-phthalimidoethyl)pyridine, 10.62 gal. of anhydrous methanol saturated with dry hydrogen chloride gas and 72.2 g. of platinum oxide catalyst. The autoclave and its contents were then placed under 200 p.s.i. pressure of hydrogen, while at 50C. and held at that point until 95% of the theoretical hydrogen uptake was complete (this required approximately 4.33 hours). At the end of this time, the reaction mixture was cooled to 24C., vented and then purged with nitrogen. After removal of the catalyst by means of filtration, the resulting filtrate was concentrated in vacuo to a final volume of ca. 3.0 liters and the solid product, which had precipitated from the residual liquid during the course of the concentration step, and then recovered by means of collecting same on a filter funnel with the aid of suction filtration. Upon washing with isopropanol and air-drying to constant weight, there was obtained 1070 g. (51%) of crystalline 4-(2-phthalimidoethyl)piperidine hydrochloride in the form of a pure white solid (m.p. 235242C.). Recrystallization from ethanol-diethyl ether then raised the melting point to 240 242C. (analytical sample).
Anal. Calcd. for c.,-,H,,,N o .Hc1; C, 61.07; H, 6.49; N, 9.50. Found: C, 60.79; H, 6.37; N, 9.43.
A l2-liter three-necked, round-bottomed flask was charged with 1700 g. (5.69 mole) of 4(2-phthalimidoethyl)piperidine hydrochloride, 552 g. (5.69 mole) of sulfamide and 5.8 liters of pyridine. The resulting reaction mixture was then stirred under reflux conditions for a period of 24 hours and finally cooled to room temperature (-25C.). The cooled mixture was next poured into an ice-water mixture (36 liters) and stirred for an additional period of 30 minutes. At this point, the precipitated product was collected by means of suction filtration, washed with 5.0 liters of 0.1N hydrochloric acid, then with 15 liters of water and finally with 3.0 liters of cold ethanol. After air-drying to constant weight, there was obtained a 1326 g. (71%) yield of pure 4-( 2-phthalimidoethyl l piperidinesulfonamide, m.p. 197C. Recrystallization from ethanol then gave the analytical sample as a while solid material (m.p. 202-203C.).
A l-liter round-bottomed flask was charged with 28.4 g. (0.084 mole) of 4-( 2-phthalimidoethyl)-lpiperidinesulfonamide, 2.7 g. (0.084 mole) of anhydrous hydrazine and 250 ml. of methanol. The resulting white suspension was stirred and then refluxed for a period of 90 minutes, followed by removal of the most of the methanol via fractional distillation. At this point, the reaction mixture was observed to be a homogeneous yellow solution. Concentrated hydrochloric acid (350 ml.) was then added, and the resulting mixture was refluxed for an additional period of 3 hours before being cooled to room temperature. The insoluble byproduct, which appeared at this point as a precipitate, was then removed by means of suction filtration and the resulting filtrate was thereafter evaporated to near dryness while under reduced pressure to give a white solid material as the final residual product. The latter was subsequently triturated with hot acetone, filtered and air dried to constant weight to afford 18.5 g. (91% of pure 4-(2-aminoethyl)l-piperidinesulfonamide hydrochloride, m.p. 188-192C. Recrystallization from ethanol then gave the analytical sample (m.p. 195-l97C.).
Anal. Calcd. for C H,,N O S.HCl: C, 34.49; H, 7.44; N, 17.24. Found: C, 34.56; H, 7.45; N, 17.24.
Preparation B A stirred suspension consisting of 57 g. (0.362 mole) of 2-chloronicotinic acid [6. M. Badger et al., Australian Journal of Chemistry, Vol. 18, p. 1267 (1965)] in 800 ml. of methanol was treated portion-wise with 43 g. (0.797 mole) of sodium methoxide. The resulting turbid solution was then heated in an autoclave at 110C. for a period of 11 hours. The reaction mixture obtained in this manner was then evaporated to near dryness (while under reduced pressure) and the residue was subsequently dissolved in 2000 ml. of water, filtered and the resulting filtrate thereafter acidified with 1000 ml. of glacial acetic acid. The acidified filtrate was then concentrated in vacuo to a volume of ca. 800 ml., cooled in an ice bath for a period of approximately 1 hour and the resulting crystalline crop (i.e., precipitate) thereafter collected by means of suction filtration. After air drying to constant weight, there were obtained 33.3 g. (60%) of final product melting at l43l46C. Crystallization of the latter material from 150 ml. of acetonitrile then gave 27.6 g. (50%) of pure 2-methoxynicotinic acid, m.p. 144l46C. [literature m.p. 144-146C., according to Chemical Abstracts, Vol. 68, p. 12876g (1968)].
To a suspension of 256 g. (1.675 mole) of 2- methoxynicotinic acid in 5.0 liters of methylene chloride, there were aded 1000 ml. of thionyl chloride in one portion and the resulting reaction mixture was then heated on a steam bath to the reflux temperature. After a period of 2 hours at the reflux point, the clear solution was cooled and then concentrated in vacuo at room temperature to afford a residual oil. The excess thionyl chloride present was next removed by adding 500 ml. of benzene and subsequently evaporating the mixture to dryness while under reduced pressure. This particular purification step was then repeated twice and there was ultimately obtained 288 g. of pure 2- methoxynicotinoyl chloride as the residue, which solidified on standing and was used as such in the next reaction step. The yield of product was nearly quantitative.
Preparation C The procedure described in Preparation B is repeated except that sodium ethoxide is the reagent of choice employed instead of sodium methoxide. In this particular case, using the same molar proportions as before, 2-chloronicotinic acid is converted to 2- ethoxynicotinic acid in a most facile manner. Treatment of the latter material with an excess of thionyl chloride then yields 2-ethoxynicotinoyl chloride.
Preparation D A suspension of 1.26 g. (0.008 mole) of 4- chloropicolinic acid [I-l. Meyer et al., Chemische BeriChIe, Vol. 61, p. 2210 (2928)] in ml. of thionyl chloride was refluxed on a steam bath until the evolution of hydrogen chloride and sulfur dioxide gas both ceased. Excess thionyl chloride was then removed by means of evaporation under reduced pressure and there was ultimately obtained pure 4-chloropicolinoyl chloride as a white residual solid, which was used as such in the next reaction step without any further purification being necessary. The yield of product obtained in this manner was almost quantitative.
Preparation E A 500 ml. three-necked, round bottomed flask was charged with 14.6 g. (0.119 mole) of endo-Z- aminomethylbicyclo[2.2.l]hept-5-ene [P. Wilder et al., Journal of Organic Chemistry, Vol. 30, p. 3078 (1965)], 18.0 g. (0.178 mole) of triethylamine and ml. of tetrahydrofuran. The mixture was then rapidly cooled and stirred in an ice bath, while a solution consisting of 27.4 g. (0.119 mole) of N,N- diphenylcarbamoyl chloride dissolved in 100 ml. of tetrahydrofuran was slowly added thereto in a dropwise manner. After the addition was complete, the reaction mixture was stirred at room temperature (-25C.) for a period of 1 hour and the resulting solution was then concentrated in vacuo (to approximately one-third of its original volume to remove most of the tetrahydrofuran. On cooling, there was obtained a crystalline precipitate, which was subsequently collected by means of suction filtration and thereafter suspended in 250 ml. of 1N aqueous hydrochloric acid. Extraction of the latter aqueous solution with three 200-ml. portions of chloroform, followed by drying of the combined organic extracts then gave a clear organic solution upon filtration. After evaporating the clear filtrate to near dryness while under reduced pressure, there was ultimately obtained a heavy viscous oil, which subsequently crystallized on trituration with n-hexane. Recrystallization of this latter material from diethyl ether/n-hexane then gave pure 1,1-diphenyl- 3(bicyclo[2.2. 1 ]hept-5 -en-2-yl-endo-methyl)urea, m.p. l29l30C. The analytical sample was a crystalline white solid.
Anal. Calcd. for C l-1 N 02 C, 79.21; H, 6.96; N, 8.80. Found: C, 79.19; H, 7.05; N, 8.93.
Preparation F A 3-liter round-bottomed flask was charged with 212 g. (4.0 moles) of acrylonitrile, 272 g. (4.0 moles) of furan and 50 mg. of hyroquinone all dissolved in a total of 1 liter of dry benzene. Stirring was then commenced, while a solution consisting of 55 ml. (0.5 mole) of titanium tetrachloride dissolved in 500 ml. of benzene was added at such a rate that the temperature did not exceedd 35C. The resulting mixture was then stirred at room temperature (-25C.) for a period of 5 days in order to complete the reaction, followed by treatment with 500 ml. of 0.5N hydrochloric acid. After filtering the acidified mixture, the benzene layer was collected and subsequently saved, while the aqueous layer was extracted anew with a fresh portion of benzene. At this point, the organic layers were combined, washed with water and then dried over anhydrous magnesium sulfate. After removal of the drying agent by means of suction filtration and the organic solvent by means of evaporation under reduced pressure, there was obtained 156.3 g. (32%) of 7-oxabicyclo[2.2.ll-hept-S- en-2-ylnitrile in the form of a crude mixture of endoand exo-isomers.
The above crude mixture g.) was then hydrogenated in 1000 ml. of acetone at 50 p.s.i. pressure, using 2 g. of palladium-on-barium sulfate as catalyst. After removal of the catalyst by means of suction filtration and the solvent by means of evaporation under reduced pressure, there was obtained a residual liquid which on fractional distillation gave 55.5 g. (42%) of pure endo- 7-oxabicyclo[2.2.l]hept-2-ylnitrile (b.p. 45C/0.l mm. Hg) and 37.9 g. (29%) of pure exo-7- oxabicyclo[2.2.l]-hept-2-ylnitrile (b.p. 48C../0.02 mm.Hg) plus 14.7 g. (11%) of an endo/exo mixture.
Anal. Calcd. for C H NO: C, 68.27; H, 7.37; N, 11.37. Found: (endo): C, 67.96; H, 7.21; N, 11.37. (exo): C, 68.32; H, 7.42; N, 11.64.
To a well-stirred solution consisting of 54.3 g. (0.44 mole) of endo-7oxabicyclo[2.2.l]hept-2-ylnitrile dissolved in 500 ml. of methanol, there were added 24 ml. of a slurry of Raney nickel in methanol, followed by the dropwise addition of 33.2 g. (0.88 mole) of sodium borohyride dissolved in 1 10 ml. of 4N aqueous sodium hydroxide. The latter step was carried out with the aid of external cooling so as to keep the tempertaure of the reaction mixture within the 40-50C. range. After the addition was complete (and this required approximately 25 minutes), the mixture was further stirred at ambient temperatures (i.e., without cooling) for a period of 20 minutes, at which point no further gas evolution could be detected. The spent reaction mixture was then filtered to remove solid impurities, and the resulting filtrate thereafter concentrated in vacuo to afford a residue that was subsequently suspended in 500 ml. of 1N aqueous sodium hydroxide. After extracting the latter basic aqueous solution three times with chloroform, the chloroform extracts were combined, dried over anhydrous magnesium sulfate and thereafter evaporated to constant volume while under reduced pressure to give 55.5 g. (100%) of endo-7- oxabicyclo[2.2. 1 ]hept-2-ylmethylamine (b.p. 90C./ 10 mm. Hg.), which was used as such in the next reaction step without any further purification being necessary.
The procedure described in Preparation E was now repeated to prepare the 1,1-diphenyl-3- (monosubstituted)urea compound except that endo-7- oxabicyclo[2.2. 1 ]hept-2-ylmethylamine obtained as described above was the appropriate amine starting material employed in place of endo-2-aminomethylbicyclo[2.2.1]hept-5-ene, again using the same molar proportions as before. In this particular case, the corresponding final product thus obtained was 1,1-diphenyl- 3-(7-oxabicyclo[2.2. l ]hept-Z-yI-endo-methyl )-urea, m.p. 109-111C.
Anal. Calcd. for C ,,H N O C, 74.49; H, 6.89; N,
8.68. Found: C, 74.28; H, 6.93; N, 8.61.
Preparation G A methanolic solution of the exo-nitrile compound prepared as described in Preparation F was treated in exactly the same manner as that previously described for the corresponding endo-isomer, with respect to Raney nickel and sodium borohydride reduction. In this way, pure exo-7-oxabicyclo[2.2.llhept-2-yl-nitrile was converted to exo-7-oxabicyclo[2.2.l]hept-2- ylmethylamine in substantially high yield. The latter material was used as such in the next reaction step without any further purification being necessary.
The procedure described in Preparation E was repeated once again to prepare the desired 1,1-diphenyl- 3-(monosubstituted)-urea compound except that this time exo-7-oxabicyclo[ 2.2. 1 ]hept-2-ylmethylamine was the starting material employed in place of endo-2- aminomethylbicyclo[2.2.1]hept-S-ene, albeit on the same molar basis as before. In this particular case, the
corresponding final product thus obtained was 1,1- diphenyl-3-(7-oxabicyclo-[2.2.1]hept-Z-yl-exomethyl)urea, m.p. l28130C.
Anal. Calcd. for C H N O C, 74.49; H, 6.89; N, 8.68. Found: C, 74.70; H, 6.75; N, 8.87.
Example I A solution consisting of 286.5 g (1.67 moles) of 2- methoxynicotinoyl chloride dissolved in 2.0 liters of chloroform and a solution of 530 g. (5.0 moles) of sodium carbonate in 2225 ml. of water were added simultaneously at the rate of 25 ml./minute to 407 g. (1.67 moles) of 4-(2-aminoethyl)-l-piperidinesulfonamide hydrochloride dissolved in 2.75 liters of water, which also contained 177 g. (1.67 moles) of sodium carbonate. Vigorous agitation was maintained throughout the addition step, after which the reaction mixture was then further stirred at room temperature (-25C.) for 1.5 hours. At this point, the precipitated solids which formed were subsequently recovered by means of suction filtration and thereafter washed with two separate- 500 ml. portions of cold acetone. After air-drying to constant weight, the yield of crude material amounted to 630 g. of product melting at 165172C. Recrystallization from 12.5 liters of acetonitrile then gave 409 g. (71 of pure 4-[2-(2-(2-methoxynictinamido)ethyl]- l-piperidinesulfonamide, m.p. l821 83C.
Anal. Cald. for C I-1 N 05: C, 49.11; H, 6.48; N, 16.37. Found: C, 49.24; H, 6.46; N, 16.42.
Example 11 i The procedure described in Example 1 is repeated iusing 2-ethoxynicotinyl chloride in place of 2- methoxynicotinoyl chloride on the same molar basis as before. In this particular case, the corresponding final product thus obtained is 4- 2-( 2- ethoxynicotinamido)ethyl]-1-piperidinesulfonamide.
Example 111 To a mixture of 1.95 g. (0.008 mole) of 4-(2- aminoethyl)- l -piperidinesulfonamide hydrochloride and 2.22 ml. (0.016 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there were added 1.41 g. (0.008 mole) of 4-chloropicolinoyl chloride dissolved in 15 ml. of tetrahydrofuran. The initial addition step was slightly exothermic (-40C.) and after completion of same, the resulting reaction mixture was stirred at ambient temperatures for a period of approximately 16 hours. At this point, the thoroughly stirred mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting crystalline precipitate was then recovered by means of suction filtration and thereafter recrystallized twice from acetonitrile to afford 0.997 g. of pure product. In this way, there was ulimately obtained a 36% yield of 4-[2-( 4-chloropicolinamido )ethyl]-lpiperidinesulfonamide, m.p. 186 l 87C.
Anal. Calcd. for C, H ClN O S: C, 45.00; H, 5.52; N, 16.16. Found: C, 45.21; H, 5.38; N, 16.19.
Example lV In a ml. three-necked, round bottom flask equipped with mechanical stirrer, reflux condenser and heating mantle, there were placed 3.0 g. (0.0173 mole) of quinoline-8-carboxylic acid, 8.1 g. (0.0327 mole) of N-ethoxycarbonyl-Z-ethoxycarbonyl-2-ethoxy-1 ,3- dihydroquinoline (EEDQ), 3.82 g. (0.01635 mole) of 4-(2-aminoethyl)-l-piperidinesulfonamide hydrochloride and 1.66 g. (0.01635 mole) of triethylamine all in a total of 50 ml. of tetrahydrofuran. Stirring was commenced and the resulting mixture was heated under reflux for a period of approximately 16 hours. At the end of this time, the reaction mixture was cooled to room temperature (-25C.) and then diluted with 200 ml. of chloroform prior to extraction with two-100 ml. portions of 2N aqueous sodium hydroxide. The aqueous extracts so obtained were combined and then reextracted once with 75 ml. of chloroform prior to being adjusted to a pH value of ca. 7.0 via the slow addition of 2N aqueous hydrochloric acid solution thereto. The desired product precipitated at this point as a gummy white solid, which was collected and thereafter recrystallized from methanol to afford 3.8 g. (63%) of pure 4-[2-(8-quinolinecarboxamido)ethyl]-1- piperidinesulfonamide, m.p. 205.5206.5C.
Anal. Calcd. for C H N.,O S. /zl-l O: C, 54.96; H, 6.23; N,15.08. Found: C, 55.37; H, 6.38; N, 14.80.
Example V To a solution consisting of 407 g. (1.19 mole) of 4- [2-(Z-methoxynicotinamido)ethyl]-1- piperidinesulfonamide and 380 g. (1.19 moles) of 1,1- diphenyl-3-(bicyclo[2.2.1 ]hept-5-en-2-yl-endomethyl)urea dissolved in 3.0 liters of dry N,N- dimethylforamide, there were added 51 g. (1.19 moles) of 56% sodium hydride (in mineral oil) in one full portion. The resulting reaction mixture was then heated to 65C., at which point it became slightly exothermic and the temperature rose to 70C. After a period of stirring for minutes, a homogeneous solution was formed and the latter was subsequently poured into two volumes of diethyl ether, followed by extraction with one volume of water and acidification of the aqueous layer with 6N hydrochloric acid. After extracting the latter solution with one volume of ethyl acetate, the organic layer was decolorized with charcoal and then dried over anhydrous magnesium sulfate. Upon removal of the drying agent by means of suction filtration and the solvent by means of evaporation under reduced pressure, there was ultimately obtained a viscous oil, which was subsequently dissolved in 1 liter of acetonitrile. The latter solution was filtered while hot, allowed to cool to room temperature nad then slowly diluted with 2 liters of diethyl ether to give a pale yellow precipitate, which was subsequently collected by means of suction filtration. The crystalline material so obtained was then air-dried to constant weight to give 374 g. (64%) of pure l-(bicyclo[2.2. l ]hept-5-en-2-yl-endo-methyl)- 3-{4-[2-(2-methoxynicotinamido)ethyl]-1- piperidinesulfonyl}urea, m.p. 90-92C.
Anal. Calcd. for C H N O S: C, 56.19; H, 6.77; N, 14.25. Found: C, 56.27; H, 6.96; N, 13.84.
Example VI A mixture of 983 mg. (0.002 mole) of 1- (bicyclo[2.2. l ]hept-5-en-2-yl-endo-methyl)-3-{4-[ 2- (2-methoxynicotinamido )ethyl]- l piperidinesulfonyllurea in 50 ml. of tetrahydrofuran containing 50 mg. of 5% palladium-on-carbon catalyst was hydrogenated at 48 psi. pressure for a period of 30 minutes. Upon completion of this step, the catalyst was removed by means of suction filtration and the resulting filtrate thereafter evaporated to near dryness while under reduced pressure to afford a white solid material as the crude residual product. After recrystallizing the latter material from acetonitrile, there was obtained 550 mg. (56%) of pure 1- (bicycl0[2.2.1]hept-2-yl-endo-methyl)-3-{4-[2-(2- methoxynicotinamido)ethyl]-1- piperidinesulfonyl}urea, m.p. 105-108C.
Anal. Calcd. for C H N O S: C, 55.96; H, 7.15; N,l4.19. Found: C, 56.10; H, 7.07; N, 14.16.
Example VII The procedure described in Example V was repeated except that 900 mg. (0.0026 mole) of 4-[2'(4- ch1oropicolinamido)ethyl]- 1 -piperidinesulfonamide and 930 mg. (0.0029 mole) of 1,1-diphenyl-3- (bicyclo)[2.2. l ]hept-S-en-2-yl-endo-methyl)urea were reacted in 5.0 m1. of dry N,N-dimethylformamide in the presence of 130 mg. (0.0029 mole) of 56% sodium hydride in mineral oil. The reaction mixture was heated at 60C. for a period of 30 minutes, at which point thinlayer chromatography(TLC) analysis showed the conversion to be substantially complete. After pouring the mixture into 150 ml. of anhydrous diethyl ether, the sodium salt of the product precipitated as a white gum. The ehter was then decanted and the gum was subsequently dissolved in 20 ml. of water. Upon acidification with 5.0 ml. of 3N hydrochloric acid and extraction into chloroform, followed by decolorization with charcoal and drying over anhydrous magnesium sulfate, there was obtained a clear chloroform solution of the desired product. Evaporation of the latter solution to complete dryness while under reduced pressure then gave 1.11 g. (86.5%) of pure l-(bicyclo[2.2.l]hept-5- en-2-yl-endo-methyl)-3 4-[2-( 4- chloropicolinamido )ethyl 1 -piperidinesulfonyl urea as an amorphous solid material, m.p. 7580C.
Anal. Calcd. for C H ClN O S: C, 53.27; H, 6.10; N, 14.12. Found: C, 53.11; H, 6.05; N, 13.89.
Example VIII The procedure described in Example V was repeated except that 1.0 g. (0.00276 mole) of 4-[2-(8- quinolinecarboxamido ethyl 1 -piperidinesulfonamide and 879 mg. (0.00276 mole) of 1,1-diphenyl-3- (bicycl0[2.2.1]hept-5-en-2-yl-endo-methyl)urea were reacted in 10 ml. of N,N-dimethylformamide in the presence of 118 mg. (0.00276 mole) of 56% sodium hydride (in mineral oil). In this manner, there was obtained a 210 mg. (14.7%) yield of pure l-(bicyclo [2.2.1]hept-5-en-2-yl-endo-methyl)-3-{4-[2-(8- quinolinecarboxamido)ethyl] l piperidinesulfonyl}urea, m.p. C. (decomp.).
Anal. Calcd. for C H N O S.%H O: C, 59.98; H, 6.58; N,13.45. Found: C, 59.95; H, 6.43; N, 13.48.
Example 1X piperidinesulfonyl}urea, m.p. 173l75C. after recrystallization from ethanol.
Anal. Calcd. for C H N O S: C, 53.94; H, 7.11; N, 14.98. Found: C, 53.72; H, 7.00; N, 14.88.
Example X The procedure described in Example V was repeated except that 500 mg. (0.00145 mole) of 4-[2-(2- methoxynicotinamido )ethyl l -piperidinesulfonamide and 316 mg. (0.00175 mole) of l-adamantyl isocyanate [H. Stetter et al., Chemische Berichte, V01. 95, p. 2302 (1962)] were reacted in 5.0 ml. of dry N,N-dimethylformamide in the presence of 75 mg. (0.00175 mole) of 56% sodium hydride (in mineral oil). In this manner, there was obtained a 250 mg. (33%) yield of pure l-( l-adamantyl)-3- {4-[2-(2- methoxynicotinamido)ethyl]- l piperidinesulfonyllurea as a white solid material melting at 17ll73C.
Anal. Calcd. for C H N O S: C, 57.78; H, 7.18; N, 13.48. Found: C, 57.46; H, 7.09; N, 13.45.
Example XI The procedure described in Example V was repeated except that 1.0 g. (0.00276 mole) of 4-[2-(8- quinolinecarboxamido )ethyl 1 -piperidinesulfonamide and 345 mg. (0.00276 mole) of cyclohexyl isocyanate were reacted in m1. of dry N,N-dimethylformamide in the presence of 118 mg. (0.00276 mole) of 56% sodium hydride (in mineral oil). In this manner, there was obtained 820 mg. (61%) of pure l-cyclohexyl-3-{4-[2- (8-quino1inecarboxamido)ethyl]- l piperidinesulfony1}urea in the form of a white solid, m.p. 177l79C. (decomp) after recrystallization from acetonitrile.
Anal. Calcd. for C H N O S: C, 59.11; H, 6.28; N, 14.36. Found: C, 58.95; H, 6.78; N, 14.69.
Example XII The procedure described in Example V was repeated except that 190 mg. (0.00055 mole) of 4-[2-(2- methoxynicotinamido )ethyl]- l -piperidinesulfonamide and 225 mg. (0.0007 mole) of 1,1-diphenyl-3-(7- oxabicyclo[2.2. l ]hept-2-yl-endo-methyl)urea were reacted in 5.0 ml. of N,N-dimethylformamide in the presence of 34 mg. (0.0007 mole) of 49% sodium hydride (in mineral oil). The reaction mixture was then allowed to stand at room temperature (-25C.) overnight (a period of approximately 16 hours) prior to work-up. In this manner, there was obtained a 154 mg. (57%) yield of pure l-(7-oxabicyclo[2.2.1]hept-2-yl-endo-methyl)- 3- 4-[2-( 2-methoxynicotinamido)ethyl]- lpiperidinesulfonyl}urea, m.p. 109-1l0fC.
Anal. Calcd. for C H N O S: C, 53.31; H, 6.71; N, 14.13. Found: C, 53.09; H, 6.51; N, 13.88.
Example XIII The procedure described in the preceding Example was repeated again except that 1,1-diphenyl-3-(7- oxabicyclo[2.2.l]hept-Z-yl-exo-methyl)urea was the reagent employed instead of the corresponding endoisomer. In this particular case, the corresponding final product obtained was l-(7-oxabicyclo[2.2. l ]hept-2-ylexo-methyl)-3-{4-[2-( Z-methoxynicotinamido)ethyl]- l-piperidinesulfonyl}urea, m.p. 105l 10C.
Anal. Calcd. for C H N O S: C, 53.31; H, 6.71; N, 14.13. Found: C, 53.28; H, 6.65; N, 13.77.
Example XIV The following l-piperidinesulfonylureas are prepared by employing the procedures described in the previous examples, starting from the corresponding sulfamide and the appropriate organic isocyanate or l,l-diphenyl-3-substituted urea in each instance:
RCONHCH CH NSO NHCONHR' 2-methoxy-3-pyridyl cyclopentyl 2-methoxy-3 -pyridyl cycloheptyl 2-methoxy-3-pyridyl cyclooctyl bicyclo[2.2.l ]hept-S-en-2-yl-endo-methyl bicyclo[2.2.l ]hept-2 yl-endo-methyl 7-oxabicyclo[2.2.l ]hept-2-yl-endo methyl 7-oxabicyclol2.2. l ]hept-2-ylexo methyl 2-ethoxy-3-pyridyl 2-ethoxy-3-pyridyl 2-ethoxy-3pyridyl 2-ethoxy-3-pyridyl 2 ethoxy-3-pyridyl 1 -adamantyl 2-ethoxy-3pyridyl cyclopentyl 2-ethoxy-3-pyridyl cyclohexyl 2-ethoxy-3pyridyl cycloheptyl 2-ethoxy-3-pyridyl cyclooctyl 4-chloro-2-pyridyl 4-chloro-2-pyridyl 4-chloro-2-pyridyl bicyclo[2.2. l lhept-Z-yl-endo-methyl 7-oxabicyclo[2.2. l ]hept-2-yl-endo-methyl 7-oxabicyclo[ 2.2. l ]hept-2-yl-exo-methyl 4-chloro-2-pyridyl l-adamantyl 4-chloro-2-pyridyl cyclopentyl 4-chloro-2-pyridyl cyclohexyl 4-chloro-2-pyridyl cycloheptyl 4-chloro-2pyridyl cyclooctyl A solution consisting of 354 g. (0.72 mole) of l- (bicyc1o-[2.2. l ]hept-S-en-2-yl-endo-methyl)-3-{4-[2- (2-methoxynicotinamido)ethyl]-1- piperidinesulfonyl}urea dissolved in 2.0 liters of methanol was treated at 0C. with 38.9 g. (0.72 mole) of sodium methoxide divided into five separate portions. The reaction mixture was then concentrated in vacuo and the resulting residue thereafter recrystallized from 7.0 liters of acetonitrile to give a 353 g. yield of product, viz., the sodium salt of l-(bicyclo[2.2. 1 ]hept- 5-en-2-y1-endo-methyl)=3- {4-[ 2-( 2- methoxynicotinamido)ethyl]- lpiperidinesulfonyllurea, m.p. 208210C.
Anal. Calcd. for C H N O SNa: C, 53.79; H, 6.28; N, 13.64. Found: C, 53.54; H, 6.42; N, 13.40.
Example XVI The sodium salt of l-(bicyclo[2.2.l]hept-5-en-2-yl endo-methyl)-3- {4-[2-( 4-chloropicolinamido )ethyl]- l-piperidinesulfonyl}urea is prepared by dissolving said compound in anhydrous methanol and then adding said solution to another methanolic solution which contains an equivalent amount in moles of sodium methoxide. Upon subsequent evaporation of the solvent therefrom via freeze-drying, there is obtained the desired alkali metal salt in the form of an amorphous solid powder which is freely soluble in water.
In like manner, the potassium and lithium salts are also similarly prepared, as are the alkali metal salts of all the other acidic 1-piperidinesulfonylureas of this invention which are reported in the previous examples.
Example XVII Example XVIII A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
groups of six male albino rats (each weighing approximately 190-240 g.) of the Sprague-Dawley strain. No anesthetic was used in this study. The rats were fasted for approximately l824 hours prior to administration, a blood sample was then taken from the tail vein of each animal and the test compound was administered intraperitoneally (while in solution as the sodium salt in 0.9% saline) at does levels of 15, 5.0 and 1.0 mg./kg., respectively. Additional blood samples were then taken at l, 2 and 4 hour intervals after administration of the drug. The samples were immediately diluted 1:10 (by volume) with 1.0% heparin in 0.9% saline. Blood glucose was determined by adapting the method of W. S. Hoffman [Journal of Biological Chemistry, Vol. 120, p. 51 (1937)] to the Autoanalyzer instrument produced by Technicon Instruments Corporation of Chauncey, N.Y. On this basis, the maximum percent decrease in blood sugar was calculated and reported as such (i.e., as hypoglycemic activity) for the various compounds listed in the table below:
Hypoglycemic Activity (Max.% Fall) piperidinesulfonyl}urea 50 Sodium citrate Alginic acid 10 Polyvinylpyrrolidone l0 Magnesium stearate 5 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 75 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 5, 10, 25 and 50 mg. of the active ingredient, respectively, by merely using the appropirate amount of the l-piperidinesulfonylurea in each case.
Example XIX A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
l-piperidlnesulfonyl urea Calcium carbonate 20 Polyethylene glycol. average molecular weight,4000
Example XX The l-piperidinesulfonylurea final products of Examples V-XIII were tested for hypoglycemic activity in What is claimed is:
1. A method for lowering blood sugar in the treatment of a diabetic animal, which comprises orally administering to said animal an effective blood sugar lowering amount of a compound selected from the group consisting of l-piperidinesulfonylurea of the formula and a base salt thereof with a pharmacologically acceptable cation, wherein R is a member selected from the group consisting of 2-methoxy-3-pyridyl, 2-ethoxy- 3-pyridyl, and 4-chloro-2-pyridyl, and R is a member selected from the group consisting of bicyclo- [2.2.1]hept-5-en-2-yl-endo-methyl, bicyclo[2.2.11- hept-2-yl-endo-methyl, 7-oxabicycIo-[ 2.2. 1 ]hept-Z- ylmethyl, l-adamethyl and cycloalkyl having from 5 to 8 carbon atoms.
2. The method of claim 1 wherein the compound administered is l-(bicyclo[2.2.l]-hept-5-en-2-yl-endomethyl )-3- {4-[ 2-(2-methoxynicotinamido)ethyl]- 1 piperidinesulfonyl} urea.
3. The method of claim 1 wherein the compound administered is l-(bicyclo[2.2.l]hept-Z-yI-endo-methyl- 3- {4-[2-( Z-methoxynicotinamido )ethyl]- l piperidinesulfonyllurea.
4. The method of claim 1 wherein the compound administered is l-(7-oxabicyclo[2.2.l]hept-Z-yI-endo- 1 7 methyl )-3- {4-[ 2-( 2-methoxy-nicotinam'ido )ethyl]- l piperidinesulfonyl} urea.
5. The method of claim 1 wherein the compound administered is 1-(7-oxabicyclo-[2.2.l]hept-2-yl-exomethyl )-3- {4-[2-( 2-methoxynicotinamido )ethyl]- lpiperidinesulfonyl}urea.
6. The method of claim 1 wherein the compound administered is l-( l-adamantyl)-3- {4-[2-( 2- methoxynicotinamido )ethyl l piperidinesulfonyl}urea.
7. The method of claim 1 wherein the compound administered is l-cyclohexyl-3 {4-[ 2-( 2- methoxynicotinamido ethyl- 1 -piperidinesulfonyl} urea.
8. The method of claim 1 wherein the compound administered is l-(bicyclo[2.2.1]hept-5-en-2-yl-endomethyl )-3- {4-[ 2-(4-chloropicolinamido )ethyl 1 piperidinesulfonyl} urea.
9. A composition for oral administration comprising a pharmaceutically acceptable carrier and a blood sugar lowering amount of a compound selected from the group consisting of l-piperidinesulfonylurea of the formula:
and a base salt thereof with a pharmacologically acceptable cation, wherein R is a member selected from the group consisting of 2-methoxy-3-pyridyl, 2-ethoxy- 3-pyridyl and 4-chloro-2-pyridyl, and R is a member selected from the group consisting of bicyclo[2.2.l1hept-5-en-2-yl-endo-methyl, bicyclo[2.2. 1 ]-hept-2-ylendo-methyl, 7-oxabicyc10[2.2. l ]hept-2-ylmethyl, ladamantyl and cycloalkyl having from 5 to 8 carbon atoms.
10. The composition of claim 9 wherein the composition is l-('bicyclo[2.2.l ]-hept-5-en-2-yl-endo-methyl)- 3- 4-[ 2-( Z-methoxynicotinamido )ethyl]- l piperidinesulfonyl urea.
11. The composition of claim 9 wherein the compound is l-(bicyclo[2.2.l ]hept-2-yl-endo-methyl-3-4- [2-(2-methoxynicotinamido)ethyl]-1- piperidinesulfonyl urea.
12. The composition of claim 9 wherein the compound is 1-( 7-oxabicyclo[2.2. l ]hept-2-yl-endomethyl )-3 -4-[ 2-( Z-methoxynicotinamido )ethyl l piperidinesulfonyl urea.
13. The composition of claim 9 wherein the compound is l-(7-oxabicyclo-[2.2. 1 ]hept-2-yl-exomethyl )-3-4-[2-( Z-methoxynicotinamido)ethyl]- 1 piperidinesulfonyl urea.

Claims (13)

1. A METHOD FOR LOWERING BLOOD SUGAR IN THE TREATMENT OF A DIABETIC ANIMAL, WHICH COMPRISES ORALLY ADMINISTERING TO SAID ANIMAL AN EFFECTIVE BLOOD SUGAR LOWERING AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-PIPERIDINESULFONYLUREA OF THE FORMULA
2. The method of claim 1 wherein the compound administered is 1-(bicyclo(2.2.1)-hept-5-en-2-yl-endo-methyl)-3-(4-(2-(2 -methoxynicotinamido)ethyl)-1-piperidinesulfonyl)urea.
3. The method of claim 1 wherein the compound administered is 1-(bicyclo(2.2.1)hept-2-yl-endo-methyl-3-(4-(2-(2-methoxynicotinamido)ethyl)-1-piperidinesulfonyl)urea.
4. The method of claim 1 wherein the compound administered is 1-(7-oxabicyclo(2.2.1)hept-2-yl-endo-methyl)-3-(4-(2-(2-methoxy -nicotinamido)ethyl)-1-piperidinesulfonyl)urea.
5. The method of claim 1 wherein the compound administered is 1-(7-oxabicyclo-(2.2.1)hept-2-yl-exo-methyl)-3-(4-(2-(2 -methoxynicotinamido)ethyl)-1-piperidinesulfonyl)urea.
6. The method of claim 1 wherein the compound administered is 1-(1-adamantyl)-3-(4-(2-(2-methoxynicotinamido)ethyl)-1 -piperidinesulfonyl)urea.
7. The method of claim 1 wherein the compound administered is 1-cyclohexyl-3(4-(2-(2-methoxynicotinamido)ethyl-1-piperidinesulfonyl)urea.
8. The method of claim 1 wherein the compound administered is 1-(bicyclo(2.2.1)hept-5-en-2-yl-endo-methyl)-3-(4-(2-(4 -chloropicolinamido)ethyl)-1-piperidinesulfonyl)urea.
9. A composition for oral administration comprising a pharmaceutically acceptable carrier and a blood sugar lowering amount of a compound selected from the group consisting of 1-piperidinesulfonylurea of the formula:
10. The composition of claim 9 wherein the composition is 1-(bicyclo(2.2.1)-hept-5-en-2-yl-endo-methyl)-3-(4-(2-(2 -methoxynicotinamido)ethyl)-1-piperidinesulfonyl)urea.
11. The composition of claim 9 wherein the compound is 1-(bicyclo(2.2.1)hept-2-yl-endo-methyl-3-4-(2-(2-methoxynicotinamido)ethyl) -1-piperidinesulfonyl urea.
12. The composition of claim 9 wherein the compound is 1-(7-oxabicyclo(2.2.1)hept-2-yl-endo-methyl)-3-4-(2-(2 -methoxynicotinamido)ethyl)-1-piperidinesulfonyl urea.
13. The composition of claim 9 wherein the compound is 1-(7-oxabicyclo-(2.2.1)hept-2-yl-exo-methyl)-3-4-(2-(2 -methoxynicotinamido)ethyl)-1-piperidinesulfonyl urea.
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US5356906A (en) * 1989-10-27 1994-10-18 The Du Pont Merck Pharmaceutical Company (N-phthalimidoalkyl) piperidines useful as treatments for psychosis
US6964974B2 (en) * 2000-09-08 2005-11-15 Hoffmann-La Roche Inc. 2,3-oxidosqualene-lanosterol cyclase inhibitors
DE102004061017A1 (en) * 2004-12-18 2006-06-22 Sanofi-Aventis Deutschland Gmbh Piperidinesulfonylureas and thioureas, their preparation, their use and pharmaceutical compositions containing them

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US3697527A (en) * 1970-12-02 1972-10-10 Squibb & Sons Inc Doethyl phenyl sulfonylureas

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US3697527A (en) * 1970-12-02 1972-10-10 Squibb & Sons Inc Doethyl phenyl sulfonylureas

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5356906A (en) * 1989-10-27 1994-10-18 The Du Pont Merck Pharmaceutical Company (N-phthalimidoalkyl) piperidines useful as treatments for psychosis
US6964974B2 (en) * 2000-09-08 2005-11-15 Hoffmann-La Roche Inc. 2,3-oxidosqualene-lanosterol cyclase inhibitors
DE102004061017A1 (en) * 2004-12-18 2006-06-22 Sanofi-Aventis Deutschland Gmbh Piperidinesulfonylureas and thioureas, their preparation, their use and pharmaceutical compositions containing them

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