US3183260A - Sulfonylurea hypoglycemic agents - Google Patents

Sulfonylurea hypoglycemic agents Download PDF

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US3183260A
US3183260A US244582A US24458262A US3183260A US 3183260 A US3183260 A US 3183260A US 244582 A US244582 A US 244582A US 24458262 A US24458262 A US 24458262A US 3183260 A US3183260 A US 3183260A
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urea
mole
alkyl
hypoglycemic agents
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US244582A
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Loev Bernard
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Smith Kline and French Laboratories Ltd
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Smith Kline and French Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues

Definitions

  • Z is either nitro or cyano and R is lower alkyl, cycloalkyl, phenyl, phenyl(lower)alkyl, phenoxy(lower) alkyl, (lower)alkoxyl(lower)alkyl, l-azacyclohexane or l-azacycloheptane.
  • compositions of these compounds may be administered as capsules, tablets, powders, or the like. Although the dosage must of course be tailored to the particular individual and specific condition, from about mg./kg. of body weight to about 50 rug/kg. of body weight generally is a highly satisfactory range.
  • the compounds of the instant invention are p-cyanophenylethyl or p-nitrophenylcthylsulfonylureas.
  • the remainder of the molecule as represented by R is not critical and may be a relatively inert group such as alkyl (e.g., butyl), cycloalkyl (e.g., cyclopentyl), phenylalkyl (e.g., phenethyl), phenyl, alkoxyalkyl (e.g., ethoxyethyl) or the like.
  • hypoglycemic activity vof these compounds is of considerable surprise and totally unpredictable. It is known for example that compounds of Formula II below possess hypoglycemic activity when n is 0, Y being a variable such as hydrogen, amino, trifluoromethyl, or the Two exceptions to the above are those compounds wherein Y is nitro or cyano in which case the compounds are inactive.
  • n 1
  • inactive compounds regardless of the substituents at Y.
  • n 2
  • sulfonylurea of Formula II it must be 0 and Y a group other than cyano or nitro. Quite to the contrary I have discovered that when Y is cyano or nitro and n is 2, the resultant compounds are extremely active hypoglycemic agents.
  • the process involved for the preparation of the com pounds of this invention involves the treatment of either the p-nitro or p-cyanophenylethylsulfonamide with an appropriate isocyanate.
  • the reaction is preferably executed under alkaline conditions employing an inert water miscible organic solvent, e.g., acetone.
  • the product is readily isolated by standard techniques such as acidification, evaporation of the solvent and recrystallization.
  • EXAMPLE 1 1 -butyl-3-[,8- (p-nitrophenyl) -ethylsulfonyl] -urea
  • a solution of 25 g. (0.109 mole) of B-(p-nitrophenyl)-ethylsulfonamide in 109 m1. (0.109 mole) of 1 N sodium hydroxide and 109 ml. of acetone is added dropwise, with stirring and cooling, a solution of 10.8 g. (0.109 mole) of n-butylisocyanate in an equal volume of acetone.
  • the solution is allowed to stand at ice bath temperature for one hour and then at room temperature for two hours.
  • the acetone is then removed at 50 C. by aspirator and the resulting aqueous solution acidified with dilute hydrochloric acid to give an oil which soon crystallizes. Recrystallization from ethyl alcohol yields the product which melts at 153-155 C.
  • EXAMPLE 2 1-butyl-3- [fl- (p-cyanophenyl) -ethylsulf0nyl] -urea
  • fi-(p-Cyanophenyl)-sulf0namide To a solution of 10.8 g. (0.0539 mole) of fi-(p-aminophenyl)-ethylsulfonamide in 200 ml. of water and 22.4 ml. (0.27 mole) of concentrated hydrochloric acid is added dropwise at 0 C. a concentrated solution of 3.72 g. (0.0539 mole) of sodium nitrite in water. The resultant suspension is stirred at 0 C.
  • Z is a member selected from the group cons1st1ng of pp. 815 822 (1962) ⁇ mm and cyano and Loev et al.: Journal of Medicinal Chemistry, vol. 6, R 18 a member selected from the group consisting of (lower)alkyl, cyclo(lower)alkyl, phenyl, phenyl 20 p 5 2 5 5 d Pb ch i t l 5 N (lower)alkyl, phenoxy(lower)alkyl, (lower)alkoxy 2 p g 2 l i g ems 1 e lk 1, 1- 1 h d g g: r)a y azacyco exane an lazacyclohep Ruschig et al.: Arzn. Fol-sch, vol. 8, No. 7a, pages 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

United States Patent 3,183,260 SULFONYLUREA HYPOGLYCEMIC AGENTS Bernard Loev, Broomall, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Dec. 14, 1962, Ser. No. 244,582 5 Claims. (Cl. 260-465) The invention described herein is concerned with novel organic compounds as well as with the processes employed in their preparation. These compounds are represent by the structural formula:
in which Z is either nitro or cyano and R is lower alkyl, cycloalkyl, phenyl, phenyl(lower)alkyl, phenoxy(lower) alkyl, (lower)alkoxyl(lower)alkyl, l-azacyclohexane or l-azacycloheptane.
The above compounds are hypoglycemic agents and are accordingly employed in the treatment of diabetes and other conditions where a high blood sugar level is undesirable. Being orally active, compositions of these compounds may be administered as capsules, tablets, powders, or the like. Although the dosage must of course be tailored to the particular individual and specific condition, from about mg./kg. of body weight to about 50 rug/kg. of body weight generally is a highly satisfactory range.
It will be noted that the compounds of the instant invention are p-cyanophenylethyl or p-nitrophenylcthylsulfonylureas. The remainder of the molecule as represented by R is not critical and may be a relatively inert group such as alkyl (e.g., butyl), cycloalkyl (e.g., cyclopentyl), phenylalkyl (e.g., phenethyl), phenyl, alkoxyalkyl (e.g., ethoxyethyl) or the like.
The hypoglycemic activity vof these compounds is of considerable surprise and totally unpredictable. It is known for example that compounds of Formula II below possess hypoglycemic activity when n is 0, Y being a variable such as hydrogen, amino, trifluoromethyl, or the Two exceptions to the above are those compounds wherein Y is nitro or cyano in which case the compounds are inactive.
Furthermore an increase of n to 1 results in inactive compounds, regardless of the substituents at Y. A similar lack of activity is also noted with the next homologous series wherein n is 2. It would thus appear that for a sulfonylurea of Formula II to be an active hypoglycemic agent, It must be 0 and Y a group other than cyano or nitro. Quite to the contrary I have discovered that when Y is cyano or nitro and n is 2, the resultant compounds are extremely active hypoglycemic agents.
The process involved for the preparation of the com pounds of this invention involves the treatment of either the p-nitro or p-cyanophenylethylsulfonamide with an appropriate isocyanate. The reaction is preferably executed under alkaline conditions employing an inert water miscible organic solvent, e.g., acetone. The product is readily isolated by standard techniques such as acidification, evaporation of the solvent and recrystallization.
The following examples will serve to further typify the compounds and processes of this invention but should not be construed as a limitation thereof.
"ice
EXAMPLE 1 1 -butyl-3-[,8- (p-nitrophenyl) -ethylsulfonyl] -urea To a solution of 25 g. (0.109 mole) of B-(p-nitrophenyl)-ethylsulfonamide in 109 m1. (0.109 mole) of 1 N sodium hydroxide and 109 ml. of acetone is added dropwise, with stirring and cooling, a solution of 10.8 g. (0.109 mole) of n-butylisocyanate in an equal volume of acetone. When addition is complete, the solution is allowed to stand at ice bath temperature for one hour and then at room temperature for two hours. The acetone is then removed at 50 C. by aspirator and the resulting aqueous solution acidified with dilute hydrochloric acid to give an oil which soon crystallizes. Recrystallization from ethyl alcohol yields the product which melts at 153-155 C.
Calc.: C47.40; H5.81. Found: C-47.74; H 5.80.
EXAMPLE 2 1-butyl-3- [fl- (p-cyanophenyl) -ethylsulf0nyl] -urea A. fi-(p-Cyanophenyl)-sulf0namide.To a solution of 10.8 g. (0.0539 mole) of fi-(p-aminophenyl)-ethylsulfonamide in 200 ml. of water and 22.4 ml. (0.27 mole) of concentrated hydrochloric acid is added dropwise at 0 C. a concentrated solution of 3.72 g. (0.0539 mole) of sodium nitrite in water. The resultant suspension is stirred at 0 C. for an additional 5 minutes and then added dropwise with stirring at 5 to 0 C. to a previously chilled solution of 4.83 g. (0.0539 mole) of cuprous cyanide, 10.5 g. (0.162 mole) of potassium cyanide and 27.2 g. (0.324 mole) of sodium bicarbonate in 200 ml. of water. The mixture is stirred at ice bath temperatures for an additional 1.5 hours and then filtered. The residue is dried and recrystallized from ethyl acetate and hexane to yield B-(p-cyanophenyl)-sulfonamide, M.P.=108 C.
B. l-butyl-j [,B-(p-cyanophenyl)-ethylsulfonyl] -urea. To a solution of 2.5 g. (0.0119 mole) of ,B-(p-cyanophenyl) ethylsulfonamide in 11.9 ml. (0.0119 mole) of 1 N sodium hydroxide and 11.9 ml. of acetone is added dropwise with stirring and cooling, 2. solution of 1.18 g.
EXAMPLE 3 The following isocyanates are substituted in equivalent amounts for butyl isocyanate in the procedure of Example 1.
Found: C
Ethylisocyanate n-Propylisocyanate Isobutylisocyanate Cyclopentylisocyanate Phenylisocyanate There are thus respectively prepared upon completion of the steps therein recited the following compounds:
1-ethyl-3- 8-(p-nitrophenyl) -ethylsulfonyl] -urea 1-n-propy1-3 B- (p-nitrophenyl -ethylsulfonyl] -urea l-isobutyl-3 ,8- (p-nitrophenyl) -ethylsulfonyl] -urea 1-cyclopentyl-3 l3- (p-nitrophenyl -ethylsulfonyl] -urea 1-phenyl-3 18- (p-nitrophenyl) -ethylsulfonyl] -urea A a Similarly by employing the corresponding equivalent 4. l-butyl-S-[B-(p-nitrophenyl)-ethylsulfo11y1]-urea. amounts of the above isocyanates in the procedure of 5, 1-butyl-3-[fi-(p-cyanophenyl)-ethyl ulf l]-ure Example 2, Part B, there are prepared the following compounds: References Cited by the Examiner 1-ethyl-3-[,8-(p-cyanophenyl)-ethylsulfonyl]-urea UNITED STATES PATENTS 5 -P P fi-( Y Y 2,979,437 4/61 McLamore et al 260-553 1-1sobuty1-3-[fl-(p-cyanophenyl)-ethylsulfony1]-urea 3,013,072 12/61 McLamore et aL 260 533 y p y -[B-(py p y y y 3 063 903 11/62 Wright et a1 167 65 1-phenyl-3-[;8(p-cyanophenyl)-ethylsulfony1]-urea 10 What is claimed is: FOREIGN PATENTS 1. A compound of the formula: 610,230 12/60 Canada.
1,195,278 5/59 France. Z-CHzCH2SOzNHCONI-IR 15 OTHER REFERENCES wherln Wright et al.: J. Med. Pharm. Chem., vol. 5, No. 4,
Z is a member selected from the group cons1st1ng of pp. 815 822 (1962) {mm and cyano and Loev et al.: Journal of Medicinal Chemistry, vol. 6, R 18 a member selected from the group consisting of (lower)alkyl, cyclo(lower)alkyl, phenyl, phenyl 20 p 5 2 5 5 d Pb ch i t l 5 N (lower)alkyl, phenoxy(lower)alkyl, (lower)alkoxy 2 p g 2 l i g ems 1 e lk 1, 1- 1 h d g g: r)a y azacyco exane an lazacyclohep Ruschig et al.: Arzn. Fol-sch, vol. 8, No. 7a, pages 2. A compound of the formula: 448-454 (1958)- O2NCH,CH2SO2NHCONHJOWGI. alkyl 25 IRVING MARCUS, Primary Examiner.
NICHOLAS S. RIZZO, WALTER A. MODANCE,
3. A compound of the formula:
N C -C H20 H28 OzNHC O NH-lower alkyl 30 Examiners.

Claims (2)

1. A COMPOUND OF THE FORMULA:
3. A COMPOUND OF THE FORMULA:
US244582A 1962-12-14 1962-12-14 Sulfonylurea hypoglycemic agents Expired - Lifetime US3183260A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3932658A (en) * 1969-02-25 1976-01-13 Hoechst Aktiengesellschaft Composition and method for lower blood sugar containing N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea
US4066639A (en) * 1965-05-06 1978-01-03 Hoechst Aktiengesellschaft Benzene-sulfonyl semicarbazides and process for preparing them

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1195278A (en) * 1956-12-06 1959-11-16 Hoechst Ag Sulfonyl ureas and their preparation
CA610230A (en) * 1960-12-06 Korger Gerhard Sulfonyl-ureas and process of preparing them
US2979437A (en) * 1958-09-02 1961-04-11 Pfizer & Co C Substituted styryl, and thienylethenyl, pyridylethenyl sulfonylureas and method of treating diabetes
US3013072A (en) * 1958-09-02 1961-12-12 Pfizer & Co C Novel process for the production of sulfonylureas
US3063903A (en) * 1961-03-29 1962-11-13 Upjohn Co Novel n-arylsulfonyl n'-(cyclicamino) ureas and oral antidiabetic compositions containing said novel compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA610230A (en) * 1960-12-06 Korger Gerhard Sulfonyl-ureas and process of preparing them
FR1195278A (en) * 1956-12-06 1959-11-16 Hoechst Ag Sulfonyl ureas and their preparation
US2979437A (en) * 1958-09-02 1961-04-11 Pfizer & Co C Substituted styryl, and thienylethenyl, pyridylethenyl sulfonylureas and method of treating diabetes
US3013072A (en) * 1958-09-02 1961-12-12 Pfizer & Co C Novel process for the production of sulfonylureas
US3063903A (en) * 1961-03-29 1962-11-13 Upjohn Co Novel n-arylsulfonyl n'-(cyclicamino) ureas and oral antidiabetic compositions containing said novel compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4066639A (en) * 1965-05-06 1978-01-03 Hoechst Aktiengesellschaft Benzene-sulfonyl semicarbazides and process for preparing them
US3932658A (en) * 1969-02-25 1976-01-13 Hoechst Aktiengesellschaft Composition and method for lower blood sugar containing N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea

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