US3917692A - Arylsulfonylcarbamoyl-1,3-dicarbonylalicyclic - Google Patents

Arylsulfonylcarbamoyl-1,3-dicarbonylalicyclic Download PDF

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Publication number
US3917692A
US3917692A US478497A US47849774A US3917692A US 3917692 A US3917692 A US 3917692A US 478497 A US478497 A US 478497A US 47849774 A US47849774 A US 47849774A US 3917692 A US3917692 A US 3917692A
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United States
Prior art keywords
cyclohexanedione
percent
compound
compounds
group defined
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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US478497A
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English (en)
Inventor
Frederick A Grunwald
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mead Johnson and Co LLC
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Mead Johnson and Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mead Johnson and Co LLC filed Critical Mead Johnson and Co LLC
Priority to US478497A priority Critical patent/US3917692A/en
Priority to AU81291/75A priority patent/AU8129175A/en
Priority to CA227,783A priority patent/CA1051924A/en
Priority to GB2445575A priority patent/GB1454737A/en
Priority to BE157097A priority patent/BE829953A/xx
Priority to NL7506830A priority patent/NL7506830A/xx
Priority to ZA00753689A priority patent/ZA753689B/xx
Priority to LU72697A priority patent/LU72697A1/xx
Priority to DK261775A priority patent/DK261775A/da
Priority to FR7518300A priority patent/FR2274288A1/fr
Priority to JP50069778A priority patent/JPS5829785B2/ja
Priority to SE7506707A priority patent/SE7506707L/xx
Priority to CH756575A priority patent/CH596158A5/xx
Priority to IE1312/75A priority patent/IE41477B1/en
Priority to DE19752526195 priority patent/DE2526195A1/de
Priority to YU1515/75A priority patent/YU40265B/xx
Priority to US05/604,971 priority patent/US3998879A/en
Application granted granted Critical
Publication of US3917692A publication Critical patent/US3917692A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/53—X and Y not being nitrogen atoms, e.g. N-sulfonylcarbamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • ABSTRACT A new class of arylsulfonylcarbamoyl-l,3- cyclohexanediones and arylsulfonylcarbamoyl-l,3- dicarbonylacyclic compounds are disclosed. These substances have hypoglycemic or hyperglycemic properties and are of value in controlling abnormal blood sugar levels.
  • the arylsulfonylcarbamoyl derivatives of 1,3-dicarbonylalicyclic and acyclic compounds are prepared by reacting an arylsulfonylisocyanate with a 1,3-dicarbonylalicyclic or acyclic reactant.
  • Typical embodiments are Z-(N-pchlorobenzenesulfonylc arbamoyl )-5 ,5 -dimethylcyclohexanel ,3-dione and 5-( l-ethylpropyl 2-( N-pchlorobenzenesulfonylcarbamoyl )-l ,3- cyclohexanedione.
  • This invention pertains to carbon compounds having drug and bio-affecting properties.
  • this invention relates to arylsulfonylcarbamoyl-l.3-dicarbonyl compounds effective in controlling blood sugar levels.
  • arylsulfonylcarbamoyl-l.3-dicarbonyl compounds effective in controlling blood sugar levels.
  • Both chronic hypoglycemic and hyperglycemic states are known but the most prevalent condition found with regard to abnormal levels of blood sugar is that caused by diabetes which produces increased blood glucose levels.
  • Various agents have been developed to lower blood sugar level for treatment of diabetes and among presently available antidiabetic agents there can be mentioned. by way of example.
  • This invention relates generally to sulfonylcarbamoyl derivatives of l.3-dicarbonylcompounds having blood sugar regulating properties. More particularly the invention pertains to arylsulfonylcarbamoyl-1.3- cyclohexanediones characterized by Formula I. arylsulfonylcarbamoyl-l.3-dicarbonylacyclic compounds of Formula II and pharmaceutically acceptable basic salts thereof.
  • R signifies a lower alkyl radical from 1 to carbon atoms inclusive or phenyl
  • R signifies hydrogen or a straight chain alkyl radical from 1 to 3 carbon atoms inclusive
  • R and R taken together form (CH R in Formulas I and II signifies hydrogen, halogen including chlorine, bromine. fluorine and iodine or lower alkyl from 1 to 4 carbon atoms inclusive.
  • R represents methyl, phenyl or benzyl.
  • lower alkyl comprehends both straight or branched chain hydrocarbon radicals such as methyl, ethyl. propyl. isopropyl. l-butyl. l-methylpropyl, 2- methylpropyl. tert.-butyl for those radicals containing 1 to 4 carbon atoms inclusive.
  • Lower alkyl radicals con- 2 taining 5 carbon atoms include pentyl and branched chain isomers thereof such as 3-methylbutyl. l-methylbutyl. l-ethylpropyl. 2.2-dimethylpropyl. and 1.1- dimethylpropyl.
  • pharmaceutically acceptable basic salts as used herein. reference is made to salts of the Formula I or II compounds with alkaline agents. Said pharmaceutically acceptable basic salts of the above compounds are provided by admixture of Formula I or II compounds with substantially one chemical equivalent of an alkaline agent, such as for example. alkali metal alkoxides. alkali metal hydroxides. alkaline earth metal hydroxides, alkali metal carbonates. alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates.
  • an alkaline agent such as for example. alkali metal alkoxides. alkali metal hydroxides. alkaline earth metal hydroxides, alkali metal carbonates. alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates.
  • a preferred method of a salt formation is to treat a compound of Formula I or II with substantially one chemical equivalent of sodium methoxide in methanol solution.
  • the desired sodium salt precipitates from methanolic solution upon the addition of anhydrous ether or the solvent is removed by distillation.
  • the arylsulfonylcarbamoyl-l.3-dicarbonyl compounds of the present invention characterized by For mulas l and II are prepared by a process which comprises reacting an alicyclic-l,3-dione or acyclic-1.3- dione selected from the group consisting of R O O 1 R l (H t H
  • reaction inert solvent refers to a solvent which functions as a diluent for the reaction and does not interact with the alicyclic or acyclic diketone or sulfonylisocyanate reactant.
  • Benzene is a preferred solvent for carrying out the process but other solvents such as toluene.
  • xylene, hexane, dioxane, tetrahydrofuran, 1,1-dichlorethane and the like are also satisfactory.
  • Cyclohexanedione intermediates of Formula III are known or they can be prepared by means of a Michael Condensation involving diethylmaloanate and the appropriate afi-unsaturated ketone according to the pro- 3 cedure of R. L. Frank and H. K. Hall. J. Am. Chem. Soc.. 72. 1645 (1950).
  • the process of the present invention for regulating blood sugar concentration in a mammal comprises administering to a mammal requiring blood sugar concentration regulation an effective amount of a compound characterized by Formula I or 11 ranging from 3 to 200 mg./kg. body weight of said mammal to exert a blood sugar regulating effect.
  • the compounds of the present invention are effective as hypoglycemic or hyperglycemic agents.
  • Oral administration of the compounds of the present invention is a particularly preferred form of administration but parenteral routes such as intramuscular. intravenous. intraperitoneal and subcutaneous administration may also be employed.
  • parenteral routes such as intramuscular. intravenous. intraperitoneal and subcutaneous administration may also be employed.
  • the compounds of the invention can be incorporated into pharmaceutical preparations such as tablets and capsules which contain the usual adjuvants and carriers such as talc. starch. lactose. magnesium stearate. and the like.
  • the compounds above provide a decrease in blood sugar for a period of more than eight hours after the animals were treated.
  • Compounds particularly preferred for long lasting hypoglycemic action are 5-isopropy1-(N-ptoluenesulfonylcarbamoyl)-1.3-cyclohexanedione and 2-( N-p-chlorobenzenesulfonylcarbamoyl )-5 .5-dimethylcyclohexane-1.3-dione whereafter 8 hours decreased blood sugar level values of 34 and 36 percent respectively were obtained.
  • Tolubutamide. by comparison. gave a 50 percent depression of the blood sugar level of rats one hour after dosing but 5 hours after dosing the blood sugar level had recovered to less than 20 percent below normal.
  • 5-( 1 -Ethy1propy1)-2-(N-pch1orobenzenesulfonylcarbamoyl)-1.3-cyclohexanedione is particularly preferred for its hyperglycemic activity.
  • Oral administration of 5-( l-ethylpropyl)-2-(N-p-chlorobenzenesulfonylcarbamoyl)-1.3-cyclohexanedione to rats at a 4 dose of mg./kg. provides a marked hyperglycemic effect with a 25 percent elevation of blood sugar at 6 hours increasing to 44 percent in 8 hours.
  • EXAMPLE 1 A mixture of 5,5-dimethyl-1,3-cyclohexanedione (7.0 g.. 0.05 mole) and p-toluenesulfonylisocyanate (9.86 g.. 0.05 mole) in ml. of benzene is stirred at 4060C. for a period of 6 hr. The mixture is then heated on a steam bath for 2 hr. and concentrated under reduced pressure providing a semi-solid residue which is taken up in a mixture of 45 ml. of acetone and 5 ml. of methanol. Addition of 10 ml. of water to the acetone-methanol solution provides a quantitative yield of product. m.p. 94108C.
  • EXAMPLE 7 Reaction of equimolar amounts of 5-isopropyl-l.3 cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords Z-(N-p-CHLOROBEN- ZENESULFONYLCARBAMOYL)-5-1SOPROPYL- 1.3-CYCLOHEXANED1ONE. m.p. 100.5-101.5C. (resolidified and melting at 183.5C. with dec. )(corr.
  • EXAMPLE 10 Reaction of equimolar amounts of 5-( 1-ethylpropyl)- 1.3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-( l-ETHYLPROPYLLZ-(N-p- TOLUENESULFONYLCARBAMOYL)-1.3- CYCLOHEXANEDIONE. m.p. 11 1.5-112.5C. corr.
  • EXAMPLE 1 1 Reaction of equimolar amounts of 5-( l-ethylpropyl 1.3-eyclohexanedione with p-chlorobenzenesul fonylisocyanate in benzene according to the procedure of Example 1 affords 5-( l-ETHYLPROPYL)-2-(N-p- CHLOROBENZENESULFONYLCARBAMOYL l.3-CYCLOHEXANEDIONE. m.p. 12l-122C. (corr.).
  • EXAMPLE 12 Reaction of equiimolar equimolar of l-phenyl-l.3- butanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords l-PHENYL-2-(N-p-TOLUENESULFONYLCAR- BAMOYL)-1.3-BUTANED1ONE. m.p. l13.5l16.5 C. (corr.).
  • EXAMPLE 14 Reaction of equimolar amounts of 5-propyl-l .3- cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-PROPYL -2-( N-p-TOLUENESULFONY L CARBAMOYL)-1.3-CYCLOHEXANED1ONE. m.p. l32.5133.5C. (corr.).
  • EXAMPLE 15 Reaction of equimolar amounts of 5-isopropyl-l.3- cyclohexanedionc with benzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-ISOPROPYL-2-( N-benzenesulfonylcarbamoyl)-1.3-CYCLOHEXANEDIONE. m.p. ll2.5l 14C. (corr.).
  • EXAMPLE 16 Reaction of equimolar amounts of 5-sec.-butyl-l .3- cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-sec.-BUTYL-2-(N-p-TOLUENESULFONYL- CARBAMOYLH.3-CYCLOHEXANED1ONE. m.p. 9293C. (corr.).
  • R is hydrogen or alkyl from 1 to 3 carbon atoms inclusive
  • CH R is hydrogen. halogen or lower alkyl of 1 to 4 carbon atoms inclusive; and basic salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US478497A 1974-06-12 1974-06-12 Arylsulfonylcarbamoyl-1,3-dicarbonylalicyclic Expired - Lifetime US3917692A (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
US478497A US3917692A (en) 1974-06-12 1974-06-12 Arylsulfonylcarbamoyl-1,3-dicarbonylalicyclic
AU81291/75A AU8129175A (en) 1974-06-12 1975-05-16 Sulfonylcarbamoyl derivatives
CA227,783A CA1051924A (en) 1974-06-12 1975-05-26 Arylsulfonylcarbamoyl-1,3-dicarbonylalicyclic and arylsulfonylcarbamoyl-1,3-dicarbony-lacyclic compounds
GB2445575A GB1454737A (en) 1974-06-12 1975-06-06 Sulphonylcarbamoyl derivatives
BE157097A BE829953A (fr) 1974-06-12 1975-06-06 Composes arylsulfonylcarbamoyl-1,3-dicarbonyles
ZA00753689A ZA753689B (en) 1974-06-12 1975-06-09 Sulfonylcarbamoyl derivatives
NL7506830A NL7506830A (nl) 1974-06-12 1975-06-09 Arylsulfonylcarbamoyl-1,3-dicarbonylverbindingen.
DK261775A DK261775A (da) 1974-06-12 1975-06-10 Sulfonylcarbamoylderivater og deres fremstilling
LU72697A LU72697A1 (ja) 1974-06-12 1975-06-10
JP50069778A JPS5829785B2 (ja) 1974-06-12 1975-06-11 スルホニルカルバモイルユウドウタイ
SE7506707A SE7506707L (sv) 1974-06-12 1975-06-11 Sulfonylkarbamoylderivat.
CH756575A CH596158A5 (ja) 1974-06-12 1975-06-11
IE1312/75A IE41477B1 (en) 1974-06-12 1975-06-11 Sulfonylcarbamoyl derivatives
FR7518300A FR2274288A1 (fr) 1974-06-12 1975-06-11 Nouveaux composes arylsulfonylcarbamoyl-1,3-dicarbonyliques, leur procede de preparation et medicament les contenant
DE19752526195 DE2526195A1 (de) 1974-06-12 1975-06-12 Sulfonylcarbamoylderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel
YU1515/75A YU40265B (en) 1974-06-12 1975-06-12 Process for obtaining arysulfonylcarbomoyl-1,3-dicarbonyl compounds
US05/604,971 US3998879A (en) 1974-06-12 1975-08-15 Arylsulfonylcarbamoyl-1,3-dicarbonylacyclic compounds

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Application Number Priority Date Filing Date Title
US478497A US3917692A (en) 1974-06-12 1974-06-12 Arylsulfonylcarbamoyl-1,3-dicarbonylalicyclic

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US (1) US3917692A (ja)
JP (1) JPS5829785B2 (ja)
AU (1) AU8129175A (ja)
BE (1) BE829953A (ja)
CA (1) CA1051924A (ja)
CH (1) CH596158A5 (ja)
DE (1) DE2526195A1 (ja)
DK (1) DK261775A (ja)
FR (1) FR2274288A1 (ja)
GB (1) GB1454737A (ja)
IE (1) IE41477B1 (ja)
LU (1) LU72697A1 (ja)
NL (1) NL7506830A (ja)
SE (1) SE7506707L (ja)
YU (1) YU40265B (ja)
ZA (1) ZA753689B (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4347380A (en) * 1979-04-20 1982-08-31 Stauffer Chemical Company N-Acylsulfonamide herbicidal antidotes
US5135941A (en) * 1989-12-18 1992-08-04 G. D. Searle & Co. LTB4 synthesis inhibitors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54156826A (en) * 1978-05-23 1979-12-11 Sumitomo Electric Ind Ltd Metod of making glass fiber for light transmission
AR037097A1 (es) 2001-10-05 2004-10-20 Novartis Ag Compuestos acilsulfonamidas, composiciones farmaceuticas y el uso de dichos compuestos para la preparacion de un medicamento
WO2004113091A1 (ja) * 2003-06-24 2004-12-29 Idemitsu Kosan Co., Ltd. 感熱記録体及びベンゼンスルホンアミド系誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3298917A (en) * 1964-09-15 1967-01-17 Merck & Co Inc Antidiabetic nu-acylaliphaticsulfonamides
US3578658A (en) * 1966-08-25 1971-05-11 Geigy Chem Corp N'-substituted n-arylsulfonyl ureas

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3298917A (en) * 1964-09-15 1967-01-17 Merck & Co Inc Antidiabetic nu-acylaliphaticsulfonamides
US3578658A (en) * 1966-08-25 1971-05-11 Geigy Chem Corp N'-substituted n-arylsulfonyl ureas

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4347380A (en) * 1979-04-20 1982-08-31 Stauffer Chemical Company N-Acylsulfonamide herbicidal antidotes
US5135941A (en) * 1989-12-18 1992-08-04 G. D. Searle & Co. LTB4 synthesis inhibitors

Also Published As

Publication number Publication date
CA1051924A (en) 1979-04-03
FR2274288A1 (fr) 1976-01-09
CH596158A5 (ja) 1978-02-28
JPS5829785B2 (ja) 1983-06-24
BE829953A (fr) 1975-12-08
YU40265B (en) 1985-12-31
IE41477B1 (en) 1980-01-16
ZA753689B (en) 1976-05-26
SE7506707L (sv) 1975-12-15
YU151575A (en) 1982-06-30
DK261775A (da) 1975-12-13
JPS5111734A (ja) 1976-01-30
IE41477L (en) 1975-12-12
LU72697A1 (ja) 1976-04-13
DE2526195A1 (de) 1976-01-02
AU8129175A (en) 1976-11-25
NL7506830A (nl) 1975-12-16
GB1454737A (en) 1976-11-03
FR2274288B1 (ja) 1978-11-10

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