US3708494A - Derivatives of p-aminoalkylphenylsulfonyl-2-imino-imidazolidines - Google Patents

Derivatives of p-aminoalkylphenylsulfonyl-2-imino-imidazolidines Download PDF

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Publication number
US3708494A
US3708494A US00068798A US3708494DA US3708494A US 3708494 A US3708494 A US 3708494A US 00068798 A US00068798 A US 00068798A US 3708494D A US3708494D A US 3708494DA US 3708494 A US3708494 A US 3708494A
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Prior art keywords
ethyl
imino
imidazolidine
phenylsulphonyl
acid
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Expired - Lifetime
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US00068798A
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English (en)
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H Dietrich
C Lehmann
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Novartis AG
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

Definitions

  • the present invention relates to derivatives of p-aminoalkylphenylsulfony1-2-iminoimidazolidines, to pharmaceutical compositions containing these compounds and to their use.
  • the present invention relates to compounds of formula wherein R is alkyl having from one to six carbon atoms, cycloalkyl or cycloalkenyl having from five to eight carbon atoms, or allyl;
  • R is hydrogen, methyl or ethyl
  • R is alkyl having from one to six carbon atoms, cycloalkyl having at most eight carbon atoms, allyl, phenyl or phenylalkyl having at most nine carbon atoms;
  • the therapeutic action can be demonstrated in standard tests on experimental animals.
  • R as alkyl can be e.g. the methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, l-methylbutyl, l-ethylpropyl, 1,2-dimethylpropyl, n-hexyl, methylpentyl, dimethylbutyl or ethylbutyl group.
  • R can be the cyclopentyl group which can be optionally substituted by alkyl groups having one to three carbon atoms, the cyclohexyl group which can be substituted by ethyl or methyl, and the cycloheptyl group optionally substituted by methyl, as well as the cyclooctyl group.
  • cycloalkenyl R, can be the 2-cyclopenten-1-yl, the 2-cyclohexen-l-yl, the 3-cyclohexen-1-yl, the Z-methyl- 2-cyclohexen-1-yl, the 3-cyclohepten-1-yl group, or a cyclooctenyl group.
  • the substituent R comprises the same alkyl and cycloalkyl groups which were mentioned for R as the phenylalkyl group, R can be the benzyl group, the phenylethyl group or the a-methylphenylethyl group.
  • reaction products obtained into the salt of an inorganic or organic acid are optionally converted into the reaction products obtained into the salt of an inorganic or organic acid.
  • chloroand bromoformates are particularly suitable in which R has the meaning given under Formula '1.
  • Suitable acyloxy compounds of Formula III are pyrocarboru'c acid esters of formula 0 O (i-O-(l-OR,
  • R has the meaning given under Formula I.
  • These substances can, for example, be obtained by reacting chloroformates with alkali-metal salts of monoesters of carbonic acid. Mixed pyrocarbonic acid esters may, however, also be used. In this case one of the R radicals represents a methyl or an ethyl group. W Thoma, H. Rinke [Liebigs Ann. Chem. 624, 30 (1959)].
  • the reaction is performed for example at temperatures between 20 and +20 C. in an inert organic solvent.
  • Suitable examples are: hydrocarbons such as benzene, toluene or xylene, ethers such as diethylether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, and lower ketones such as acetone or methyl ethyl ketone.
  • a chloroformate of Formula III is reacted according I to the invention preferably in the presence of an acidbinding agent.
  • inorganic bases or salts such as, for example, an alkali hydroxide, acetate, hydrogen carbonate, carbonate or phosphate such as sodium hydroxide, acetate, hydrogen carbonate and phosphate, or the corresponding potassium compounds may be used.
  • calcium oxide, carbonate, and phosphate, and magnesium carbonate may also be used.
  • organic bases such as, for example, pyridine, trimethylor triethylamine, diisopropylamine, or collidine are suitable. When these are used in excess they can also be used as solvent.
  • N-alkali metal derivatives of these compounds e.g. sodium, potassium or lithium derivatives may also be employed.
  • the starting materials of the general Formula II are new compounds and can be produced, e.g. by reacting a reactive derivative of a sulphonic acid of formula H (IV) wherein R represents a simple alkyl or aryl radical, for example a methyl or a phenyl group, and m has the meaning given in Formula I,
  • Suitable reactive derivatives of a sulphonic acid of Formula V are halides, especially chlorides and anhydrides of formula 2 (IVa) wherein m has the meaning given under Formula I.
  • the starting materials of Formula III are prepared by the commonly known methods for chloroformates.
  • the new substances of Formula I, or the pharmaceutically acceptable acid addition salts thereof, can be administered orally or parenterally.
  • physiologically suitable inorganic or organic acids such as, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, succinic acid, tartaric acid and maleic acid, but also hypoglycemic sulfonyl ureas such as, e.g.
  • the compounds of the invention are administered in amounts depending on the species, the age, weight and the particular condition of the individual being treated, and the mode of administration.
  • the daily dosage varies between about 0.1 and 100 mg./kg. of body weight for warm-blooded animals.
  • Suitable dosage units, such as drages and tablets contain preferably -200 mg. of an active substance according to the invention, whereby the content of active substance is -80% by Weight.
  • the tablets and drages are produced by combining the active substance, e.g.
  • solid pulverulent carriers such as lactose, saccharose, sorbitol or 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 of suitable molecular weights.
  • Tablets and drage cores are coated, e.g. with concentrated sugar solutions which may also contain, e.g. gum arabic, talcum and/or titanium dioxide, or 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 dosages of active substance.
  • suitable dosage units 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 preferably as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilizers such as sodium metabisulphite (Na S O or ascorbic acid.
  • the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby likewise stabilizers can be added.
  • a granulate is produced from 1000 g. of 1-[p-(2- butoxycarbonylamino ethyl)-phenylsulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, 345.0 g. of lactose, and the aqueous solution of 6.0 g. of gelatine; the granulate is then mixed, after being dried, 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; and the mixture is pressed into 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 533.0 g.
  • EXAMPLE 1 From a solution of 37.0 g. of 1-[p-(2-amino-ethyl)- phenyl-sulphonyl] -2-imino-3-ethyl-imidazolidine dihydrochloride, M.P. 242-244", in 50 ml. of water, the base is set free by the addition of ml. of 2 N sodium hydroxide solution and extracted three times with 100 ml. each of methylene chloride. The extract which has been dried with sodium sulphate, is mixed with 11.0 g. of triethylamine and transferred to a dropping funnel which is mounted on a reaction vessel which is fitted with a stirrer and a cooling arrangement.
  • the reaction vessel has a second dropping funnel containing a solution of 13.7 g. of butyl chloroformate in 100 ml. of methylene chloride.
  • the two solutions are then allowed to run into the reaction vessel in such a manner that, per time unit, about equimolar amounts of the reactants flow into it while the temperature is constantly kept between 0 and 10.
  • the reaction solution is stirred for one hour at room temperature, washed with water, dried with sodium sulphate and the methylene chloride is removed by distillation.
  • the dihydrochlorides of 1-[p-(2-amino-ethyl)-phenylsulphonyl]-2-imino-imidazolidines of general Formula II with various substituents in the 3-position which are used in this and the following examples as starting materials may, for example, be obtained by reaction of the appropriately substituted Z-amino-imidazolines with p-(2- acylamido-ethyl) -benzene-sulpho-chlorides and subsequent hydrolytic cleavage of the acyl radical with aqueous hydrochloric acid, as is described below for p-[2-aminoethyl)-phenylsulphonyl]-2-imino-3-butylimidazolidine dihydrochloride:
  • EXAMPLE 2 Analogously to Example 1 there are obtained: from in each case 39.8 g. of 1-[p-(2-amino-ethyl)-pheny1sulphonyl]-2-imino-3-butyl imidazolidine dihydrochloride, M.P. 231-233",
  • EXAMPLE 3 Analogously to Example 1 there are obtained: from in each case 41.0 g. of 1-[p-(2-amino-ethyl)-phenylsulphonyl]-Z-imino 3 cyclopentyl-imidazolidine dihydrochloride, M.P. 270 (decomposition),
  • EXAMPLE 5 Analogously to Example 1 there are obtained from in each case 43.7 g. of 1-[p-(Z-amino-ethyl)-phenylsulphonyl]-2-imino 3 (4-methylcyclohexyl)-imidazolidine dihydrochloride, having a decomposition point of 260,
  • a compound according to claim 1 which is 1- [p-[2- ethoxycarbonylamino)-ethyl]-pheny1su1fonyl] 2-imino- 3-cyclohexyl-imidazolidine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US00068798A 1969-09-04 1970-09-01 Derivatives of p-aminoalkylphenylsulfonyl-2-imino-imidazolidines Expired - Lifetime US3708494A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH1340169A CH520683A (de) 1969-09-04 1969-09-04 Verfahren zur Hestellung von neuen Derivaten des p-Amino-alkyl-benzolsulfonamids

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US3708494A true US3708494A (en) 1973-01-02

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US (1) US3708494A (enrdf_load_stackoverflow)
AT (1) AT303753B (enrdf_load_stackoverflow)
BE (1) BE755686A (enrdf_load_stackoverflow)
BG (1) BG17764A3 (enrdf_load_stackoverflow)
CA (1) CA920602A (enrdf_load_stackoverflow)
CH (1) CH520683A (enrdf_load_stackoverflow)
DE (1) DE2043774C3 (enrdf_load_stackoverflow)
DK (1) DK123483B (enrdf_load_stackoverflow)
ES (1) ES383345A1 (enrdf_load_stackoverflow)
FR (1) FR2070672B1 (enrdf_load_stackoverflow)
GB (1) GB1269000A (enrdf_load_stackoverflow)
IE (1) IE34613B1 (enrdf_load_stackoverflow)
IL (1) IL35225A (enrdf_load_stackoverflow)
NL (1) NL7012727A (enrdf_load_stackoverflow)
PL (1) PL73278B1 (enrdf_load_stackoverflow)
SU (1) SU398038A3 (enrdf_load_stackoverflow)
ZA (1) ZA706039B (enrdf_load_stackoverflow)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1443908C3 (de) * 1964-11-21 1974-07-04 Farbwerke Hoechst Ag, Vormals Meister Lucius & Bruening, 6000 Frankfurt Benzolsulfonylharnstoffe, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel
CH505829A (de) * 1968-03-14 1971-04-15 Ciba Geigy Ag Verfahren zur Herstellung von neuen Derivaten des p-Aminoalkylbenzolsulfonamids

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Publication number Publication date
ES383345A1 (es) 1973-01-01
BE755686A (fr) 1971-03-03
FR2070672B1 (enrdf_load_stackoverflow) 1974-04-12
ZA706039B (en) 1971-04-28
PL73278B1 (enrdf_load_stackoverflow) 1974-08-30
BG17764A3 (bg) 1973-12-25
CH520683A (de) 1972-03-31
IL35225A (en) 1973-04-30
IE34613B1 (en) 1975-06-25
DE2043774C3 (de) 1979-10-25
DE2043774A1 (de) 1971-03-18
IL35225A0 (en) 1970-11-30
NL7012727A (enrdf_load_stackoverflow) 1971-03-08
GB1269000A (en) 1972-03-29
CA920602A (en) 1973-02-06
FR2070672A1 (enrdf_load_stackoverflow) 1971-09-17
SU398038A3 (enrdf_load_stackoverflow) 1973-09-17
AT303753B (de) 1972-12-11
IE34613L (en) 1971-03-04
DE2043774B2 (de) 1979-03-01
DK123483B (da) 1972-06-26

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