US3729463A - P-aminoalkylbenzenesulfonamide derivatives - Google Patents

P-aminoalkylbenzenesulfonamide derivatives Download PDF

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US3729463A
US3729463A US00068796A US3729463DA US3729463A US 3729463 A US3729463 A US 3729463A US 00068796 A US00068796 A US 00068796A US 3729463D A US3729463D A US 3729463DA US 3729463 A US3729463 A US 3729463A
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imino
phenylsulfonyl
imidazolidine
acid
dihydrochloride
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US00068796A
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H Dietrich
C Lehmann
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/46—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids

Definitions

  • the present invention relates to derivatives of l-[paminoalkyl benzenesulfonyl]-2-imidazolidines, to pharmaceutical compositions containing these compounds and to the use thereof.
  • the present invention relates to compounds of formula R is alkyl having at most six carbon atoms, allyl, cycloalkyl or cycloalkenyl having from five to nine carbon atoms, or phenylalkyl having at most nine carbon atoms;
  • R is hydrogen, methyl or ethyl
  • R is alkyl having at most seven carbon atoms, alkenyl having from three to five carbon atoms, cycloalkyl having at most eight carbon atoms, phenyl or tolyl;
  • n is the integer 2 or 3;
  • hypoglycemic action can be demonstrated in the standard tests on experimental animals.
  • alkyl can be, eg the methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, 1- methylbutyl, l-ethylpropyl, 1,2-dimethylpropyl, or the hexyl group; as cycloalkyl, R can be, eg..
  • R can be, e.g. the Z-cyclopenten-l-yl, 2-cyclohexen-1-yl, 3-cyclohexen-l-yl, 2-methyl-2-cyclohexen-l-yl or the 3-cycl0heptenl-yl group
  • phenylalkyl R can be, e.g. the benzyl, phenethyl or the a-methylphenethyl group.
  • the substiuent R can be, as alkyl, anyone of the alkyl groups listed under R having at most seven carbon atoms; as alkenyl, R can be the allyl, l-methylallyl, Z-methylallyl, butenyl or pentenyl group; as cycloalkyl, R can be the cyclopropyl,
  • cyclopropylmethyl cyclobutyl, cyclobutylmethyl, cyclopentyl, 'cyclopentylmethyl, cyclohexyl, methylcyclohexyl, 4-methylcyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cycloheptylmethyl or the cycl-ooctyl group.
  • Compounds of Formula I are produced by reacting a dithiocarboxylic acid ester, especially a benzyl ester, of formula wherein R has the meaning given under Formula I, and R represents a hydrocarbon radical having at most seven carbon atoms, with a compound of formula bl H (III) wherein m, R and R have the meaning given under Formula I;
  • reaction product with an inorganic or organic acid into an addition salt.
  • the reaction of the dithio esters of Formula II with an amine of Formula III is performed, e.g. in an inert organic solvent.
  • Suitable inert organic solvents are, e.g. hydrocarbons such as benzene, toluene or xylene; chlorinated hydrocarbons such as methylene chloride; ethereal liquids such as diethyl ether, dioxane or tetrahydrofuran; and lower ketones such as acetone or methyl ethyl ketone.
  • the reaction can, however, also be carried out without any solvent being present.
  • the required reaction temperatures are between 0 and 150, preferably, however, at ca. r
  • the dithiocarboxylic acid esters required as starting materials are, in some cases, described in the literature [Marvel et al.: J. Am. Chem. Soc. 77 (1955), 5997 599 9]; others are produced analogously by reacting the corresponding cyanides with the corresponding merca'ptans in the presence of hydrogen chlorideto give iminothiocarboxylic acid ester.
  • the obtained iminothiocarboxylic' acid esters react with hydrogen sulfide to give the corresponding dithiocarboxylic acid esters.
  • the" described reactions can be depicted as follows:
  • the hitherto unknown starting materials of the Formula III are obtained, e.g. by reacting substituted p-(aminoalkyl)benzenesulfonamides of Formula 1V.
  • the compounds of Formula I obtained by the process according to the invention are optionally subsequently converted into their salts with inorganic as well as organic acids. These salts are produced, e.g. by reaction of the compounds of Formula I with the equivalent amount of an acid in a suitable aqueous-organic or organic solvent such as, e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.
  • a suitable aqueous-organic or organic solvent such as, e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.
  • Suitable addition salts are, e.g. salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, fl-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid, as well as salts with hypoglycemic sulfonyl ureas such as, e.g.
  • the compounds of the invention are administered preferably orally, in amounts depending on the species, the age, weight and the particular condi-.
  • the daily dosage varies between about 0.1 and 100 mg./kg. of body weight for warm-blooded animals.
  • the compounds of the invention are administered in dosage units. Suitable dosage units such as drages and tablets, preferably contain 30-300 mg. of an active substance according to the invention, i.e. 20 to 80% of a compound of Formula I.
  • the active substance e.g. with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder, cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or drage cores.
  • the latter are coated, e.g. with concentrated sugar solutions which may also contain, e.g. gum arabic, talcum and/ or titanium dioxide; or they are coated with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents.
  • Dyestuffs can be added to these coatings, e.g. for identification of the various dosage amounts.
  • Further dosage units suitable for oral administration are hard gelatine capsules as well as soft closed capsules made from gelatine and a softener, such as glycerin.
  • the hard capsules contain the active substance preferable as a granulate, e.g. in admixture with filters such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulfite (Na S O or ascorbic acid.
  • the active substance is preferably dissolved or suspended in suitable liquids such as polyethylene glycols, whereby likewise stabilizers can be added.
  • a granulate is produced from 1000 g. of 1-[p-(2- thioacetamidoethyl)-phenylsulfonyl] 2 imino-3-cyclopentyl-imidazolidine, 345.0 g. of lactose, and the aquecits s u o of at gof g atine are: dry g, h gran:
  • ulate is mixed with 10.0 g. of colloidal silicon dioxide, 40.0 g. of talcum, 40.0 g. of potato starch and 5.0 g. of magnesium stearate; the mixture is then pressed into 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 533.0 g. of crystallised saccharose, 20.0 g. of shellac, 75.0 g. of gum arabic, 250 g. of talcum, 20 g. of colloidal silicon dioxide and 1.5 g. of dyestufi; and then dried. The obtained drages each weigh 240 mg. and each contain 100 mg. of active substance.
  • EXAMPLE 1 (a) An amount of 41.5 g. of 1-[p-(2-aminoethyl)- phenylsulfonyl] -2-imino-3-isobutylimidazolidine dihydrochloride monohydrate is dissolved in 200 ml. of water; to this solution are then added 300 m1. of 2-n sodium hydroxide solution. The liberated base is taken up in methylene chloride. The methylene chloride solution, dried over sodium sulphate, is concentrated by evaporation to dryness; to the oily base remaining as residue are then added at 30 40, in a nitrogen atmosphere, 18.2 g. of dithioacetic acid benzyl ester.
  • the reaction mixture well mixed by being shaken, is heated for /2 hour on the water bath (temperature ca. 80), whereby the colouration of the dithioester gradually disappears, and the obtained product crystallises.
  • the thereby forming benzyl mercaptan is removed by the crystals being washed with four portions of petroleum ether each of 100 ml.
  • the 1-[p-(2 thioacetamidoethyl)-phenylsulfonyl]-2-imino-3- isobutyl imidazolidine is recrystallised from acetone, and melts at 180-182.
  • the applied starting products are produced as follows:
  • N-(2-chloroethy1)-N-ethylcyanamide l-[p- (Z-aminoethyl)-phenylsulfonyl] 2 imino-3-ethylimidazolidine dihydrochloride, M.P. 242-244;
  • N-(2-chloroethyl)-N-allylcyanamide l-[p- (2 aminoethyl)-phenylsulfonyl]-2-imino-3-allylimidazolidine dihydrochloride, M.P. 232233;
  • N-(2-chloroethyl)-N-tert.butylcyanamide 1-[p-(2-aminoethyl) phenylsulfonyl1-2-imino 3 tert. butylimidazolidine dihydrochloride monohydrate, M.P. 232234;
  • N-(2-bromoethyl)-N-cyclohexylcyanamide 1-[p-(Z-aminoethyl)-phenylsulfonyl] 2 imino-3-cyclohexylimidazolidine dihydrochloride, M.P. 247250;
  • EXAMPLE 2 (a) An amount of 42.3 g. of 1-[p-(2-aminoethyl)- phenylsulfonyl] 2 imino-3-cyclohexyl-imidazolidine dihydrochloride is dissolved in 200 ml. of water; to this solution are then added 300 ml. of 2-n sodium hydroxide solution. The liberated base is taken up in methylene chloride. The methylene chloride solution, dried over sodium sulphate, is concentrated by evaporation to dryness; to the oily base remaining as residue are then added at 3040, in a nitrogen atmosphere, 21.0 g. of dithiobutyric acid benzyl ester.
  • the reaction mixture well mixed by being shaken, is heated for half an hour on a waterbath (temperature ca. 80), whereby the colouration of the dithio ester disappears, and the obtained product crystallises.
  • the thereby formed benzylmercaptan is removed by the crystals being washed with four portions of petroleum ether each of 100 ml.
  • the 1-[p-(2-thiobutyramidoethyl)-phenylsulfonyl]-2-irnino 3 cyclohexyl-imidazolidine is recrystallised from ethyl acetate, and melts at 134-135.
  • the reaction mixture is well mixed by shaking, and heated for one hour on a waterbath (temperature ca. 80), whereby the colouration of the dithio ester disappears, and the product crystallises.
  • the obtained benzylmercaptan is removed by washing of the crystals with four portions of petroleum ether each of 100 ml.
  • the 1-[p-(2-thioisobutyramido-ethyl)phenylsulfonyl] 2-imino-3-(4-methylcyclohexyl)-imidazolidine is recrystallised from acetone, and melts at -177.
  • dithioisobutyric acid benzyl ester l-[p- (2 thioisobutyramido-ethyl)phenylsulfonyl]2-imino-3- sec.butyl-imidazolidine, M.P. 154-155;
  • EXAMPLE 4 (a) An amount of 42.3 g. of l-[p-(Z-aminoethyD- phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is dissolved in 200 ml. of water, and to the base are added 300 ml. of 2-n sodium hydroxide solution. The liberated base is taken up in methylene chloride. The methylene chloride solution, after being dried over sodium sulfate is concentrated by evaporation to dryness; and to the oily base, remaining as residue, are added at 30- 40, in a nitrogen atmosphere, 22.4 g. of dithiovaleric acid benzyl ester.
  • the reaction mixture is heated for half an hour on a water-bath (temperature ca. 80 whereby the colouration of the dithio ester disappears, and the product crystallises.
  • the benzylmercaptan thereby obtained is removed by washing of the crystals with four portions, each of 100 ml. of petroleum ether.
  • the 1- [p- (thiovaleraminoethyl phenylsulfonyl] 2-imino- 3-cyclohexyl-imidazolidine is recrystallised from acetone, and melts at l51152.
  • EXAMPLE 5 (a) An amount of 42.3 g. of 1-[p-(2-aminoethy1)- phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidinedihydrochloride is dissolved in 200 ml. of Water; to this solution are then added 300 ml. of 2-n sodium hydroxide solution. The thereby liberated base is taken up in methylene chloride; and the methylene chloride solution, dried over sodium sulphate, is concentrated by evaporation to dryness. To the oily base, remaining as residue, are added at 30-40, in a nitrogen atmosphere, 24.4 g. of dithiobenzoic acid benzyl ester.
  • the reaction mixture is well mixed by shaking, and then heated for half an hour on a water-bath (temperature ca. whereby the colouration of the dithio ether disappears, and the product crystallises.
  • the formed benzylmercapban is removed by washing of the crystals with four portions, each of ml., of petroleum ether.
  • the 1-[p-(2-thiobenzamidoethyl) phenylsulfonyl] 2 imino-3 cyclohexyl-imidazolidine is recrystallised from acetone, and melts at 194 /zCH COCH The following are obtained in an analogous manner:
  • EXAMPLE 6 (a) An amount of 41 g. of 1-[p-2-aminoethyl)-pheny1- sulfonyl] 2 imino 3 cyclopentyl-imidazolidine dihydrochloride is dissolved in 200 ml. of water, and to the solution are then added 300 ml. of 2-n sodium hydroxide solution. The thereby liberated base is taken up in methylene chloride, and the methylene chloride solution, dried over sodium sulfate is concentrated by evaporation to dryness. To the oily base, remaining as residue, are added at 3040, in a nitrogen atmosphere, 25.0 g. of dithiocyclohexanecarboxylic acid benzyl ester.
  • the reaction mixture is well mixed by shaking, and then heated for /2 hour on the water-bath (temperature ca. 80), whereby the colouration due to the dithio ester gradually disappears, and the product crystallises.
  • the formed benzylmercaptan is removed by washing of the crystals with four portions, each of 100 ml., of petroleum ether.
  • the 1 [p-(2-thiocyclohexanecarboxamidoethyl)-phenylsru1fonyl]-2-imino-3-cyclopentylimidazolidine is recrystallised in acetone, and melts at 193 194.
  • EXAMPLE 7 Analogously to Example 6 are obtained the following: From 43.7 g. of 1-[p-(Z-amino-ethyl)-phenylsulfonyl]- Z-imino 3 cyclopentyl 4 ethyl-imidazolidine-dihydrochloride and 21.0 g. dithioisobutyric acid-benzylester, 1- [p-(2 thioisobutyramidoethyl)-phenylsulfony11-2-imino- 3-cyclopentyl-4-ethyl imidazolidine, M.P. 105107;
  • R is alkyl of at most six carbon atoms, allyl, cycloalkyl, methyl substituted cycloalkyl, cycloalkenyl or methyl substituted cycloalkenyl of, in all, from five to nine carbon atoms, or phenylalkyl of at most three carbon atoms in the alkyl chain;
  • R is hydrogen, methyl or ethyl
  • R is alkyl of at most seven carbon atoms, cycloalkyl or cycloalkylrnethyl of, in all, at most eight carbon atoms;
  • n is the integer 2 or 3;
  • a compound according to claim 1 which is 1-[p- (Z-thioacetamidoethyl)-phenylsulfony1] 2 imin0-3-isobutyl-imidazolidine.
  • a compound according to claim 1 which is I-[p- (2 thiocyclohexanecarboxamidoethyl) phenylsulfonyl] Z-imino-3-cyclopentylimidazolidine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hinges (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
US00068796A 1969-09-04 1970-09-01 P-aminoalkylbenzenesulfonamide derivatives Expired - Lifetime US3729463A (en)

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Application Number Priority Date Filing Date Title
CH1339769A CH523254A (de) 1969-09-04 1969-09-04 Verfahren zur Herstellung von neuen Derivaten des p-Aminoalkyl-benzolsulfonamids

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US (1) US3729463A (fr)
AT (1) AT294821B (fr)
BE (1) BE755682A (fr)
BG (2) BG17541A3 (fr)
CA (1) CA920137A (fr)
CH (1) CH523254A (fr)
DE (1) DE2043801C3 (fr)
DK (1) DK131566C (fr)
ES (1) ES383341A1 (fr)
FI (1) FI52463C (fr)
FR (1) FR2070668B1 (fr)
GB (1) GB1305650A (fr)
IE (1) IE34502B1 (fr)
IL (1) IL35222A (fr)
NL (1) NL164556C (fr)
NO (1) NO128996B (fr)
PL (1) PL73406B1 (fr)
SE (1) SE367410B (fr)
SU (1) SU382285A3 (fr)
YU (1) YU34125B (fr)
ZA (1) ZA706038B (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1568606C3 (de) * 1966-10-15 1975-10-23 Hoechst Ag, 6000 Frankfurt Benzolsulfonylharnstoffe, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate
CH505829A (de) * 1968-03-14 1971-04-15 Ciba Geigy Ag Verfahren zur Herstellung von neuen Derivaten des p-Aminoalkylbenzolsulfonamids

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ES383341A1 (es) 1973-01-01
AT294821B (de) 1971-12-10
NL164556B (nl) 1980-08-15
YU220270A (en) 1978-06-30
BG17542A3 (fr) 1973-11-10
NL7012724A (fr) 1971-03-08
FI52463B (fr) 1977-05-31
CH523254A (de) 1972-05-31
NO128996B (fr) 1974-02-11
SU382285A3 (fr) 1973-05-22
DE2043801B2 (de) 1979-03-01
FR2070668A1 (fr) 1971-09-17
ZA706038B (en) 1971-04-28
DK131566B (da) 1975-08-04
DE2043801A1 (de) 1971-03-11
IL35222A (en) 1973-11-28
NL164556C (nl) 1981-01-15
IE34502B1 (en) 1975-05-28
FR2070668B1 (fr) 1973-08-10
BG17541A3 (fr) 1973-11-10
YU34125B (en) 1978-12-31
IL35222A0 (en) 1970-11-30
DK131566C (da) 1976-01-05
FI52463C (fi) 1977-09-12
PL73406B1 (fr) 1974-08-30
CA920137A (en) 1973-01-30
IE34502L (en) 1971-03-04
BE755682A (fr) 1971-03-03
DE2043801C3 (de) 1979-10-25
SE367410B (fr) 1974-05-27
GB1305650A (fr) 1973-02-07

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