US3712899A - P-aminoalkylbenzenesulfonamide derivatives - Google Patents

P-aminoalkylbenzenesulfonamide derivatives Download PDF

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Publication number
US3712899A
US3712899A US00068794A US3712899DA US3712899A US 3712899 A US3712899 A US 3712899A US 00068794 A US00068794 A US 00068794A US 3712899D A US3712899D A US 3712899DA US 3712899 A US3712899 A US 3712899A
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United States
Prior art keywords
imino
imidazolidine
ethyl
phenylsulphonyl
phenylsulfonyl
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US00068794A
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Inventor
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 l-[pcarboxamidoalkyl) phenylsulfonyl] 2 iminoimidazolidines, to pharmaceutical compositions containing these compounds and to the use thereof.
  • the present invention relates to compounds of formula H (1) wherein R is alkyl having at most six carbon atoms, cycloalkyl having from five to eight carbon atoms, phenylalkyl having at most nine carbon atoms or allyl;
  • R is hydrogen, methyl or ethyl
  • R is a five to six membered mononuclear heterocycle with one or two heteroatoms, which is unsubstituted or substituted by lower alkyl or phenyl, and of which a methylene group can be replaced by a carbonyl group;
  • n is the integer 2 or 3;
  • cycloalkyl group can be the cyclopentyl group, which can be optionally substituted by alkyl groups having 13 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; as the phenylalkyl group, R
  • 3,712,899 Patented Jan. 23, 1973 can be the benzyl, the phenethyl or the a-methylphenethyl group.
  • the substituent R embraces mononuclear heterocycles having 5-6 ring members, including 1-2 heteroatoms, whereby suitable hetero atoms are nitrogen, oxygen and sulfur. Accordingly, as a heterocycle having 5 ring members, R, can be, e.g. furan, tetrahydrofuran, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, thiazolidine and pyrrolidinone.
  • R can be, e.g. pyridine, pyrimidine, pyrazine or pyridazine.
  • heterocycles can be substituted by lower alkyl groups and/or by phenyl groups. Further, a methylene group being present in one of these rings can be substituted by a carbonyl group.
  • compounds of Formula I are produced by reacting a compound of formula wherein R R and m have the meaning given under Formula I, with a carboxylic acid of formula Rg-COOH (III) or with a reactive derivative of such a carboxylic acid, wherein R, has the meaning given under Formula I; and, optionally, converting the obtained reaction products into the salt of an inorganic or organic acid.
  • the reaction of a carboxylic acid of Formula HI with an amine of Formula II can be performed by firstly producing the corresponding carboxylic acid salt of the amine, and converting this, by subsequent heating, into the amide of Formula I.
  • an amine of Formula II is reacted with a carboxylic acid of Formula III in an inert solvent at temperatures of -5 to +5 C. in the presence of a water-splitting agent.
  • inert solvents it is possible to use, e.g.
  • hydrocarbons such as a benzene, toluene or xylene, ethers such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, and lower ketones suchas acetone or methyl ethyl ketone.
  • a suitable water-splitting agent is, in particular, N,N-dicyc1ohexylcarbodiimide.
  • carbonyldipyrazole it is also possible to use carbonyldipyrazole.
  • Suitable reactive derivatives of a carboxylic acid of Formula III are, e.g. halides, lower alkyl esters, especially methyl or ethyl ester, phenyl ester, amides, lower monoor dialkylamides, particularly N-methyl amides and N,N- dimethylamides, diphenylamides, also N-acylamides such as, e.g. acetylamides and benzoylamides.
  • reaction of reactive derivatives of a carboxylic acid of Formula III with amines of Formula II is performed, e.g. at room temperature, or by heating in an inert organic solvent. Suitable as such are, e.g. the above already mentioned solvents.
  • the reaction can be carried out without the addition of condensation agents; such agents, e.g. alkali metal alcoholates and alkali metal hydroxides, may, however, optionally be added.
  • a halide of a carboxylic acid of Formula IH is reacted according to the invention preferably in the presence of an acid-binding agent.
  • inorganic bases or salts can be used such as, e.g. an alkali hydroxide, -acetate, -hydrogen carbonate, -carbonate and -phosphate, such as sodium hydroxide, -acetate, -hydrogen carbonate, -carbonate and -phosphate, or the corresponding potassium compounds. It is also possible to use calcium oxide, -carbonate, as well as -phosphate, and magnesium carbonate. Also suitable, in place of inorganic bases or salts, are organic bases such as, e.g. pyridine, trimethylamine or triethylamine, diisopropylamine, or collidine. Added in excess, these may also be used as solvent.
  • organic bases such as, e.g. pyridine, trimethylamine or triethylamine, diisopropylamine, or collidine. Added in excess, these may also be used as solvent.
  • N-alkali metal derivatives of these compounds such as, e.g. sodium, potassium or lithium derivatives.
  • the starting compounds of Formula II are, for their part, new compounds and may be produced, e.g. by reacting a reactive derivative of a sulphonic acid of for- H (IV) wherein R represents an alkyl or aryl radical, e.g. a methyl or a phenyl group, and
  • n has the meaning given in Formula I, with a 2-amino-2- imidazoline derivatives of formula ILIHQ wherein R and R have the meaning given under Formula I,
  • Suitable reactive derivatives of a sulphonic acid of Formula IV are halides, especially chlorides and anhydrides of Formula wherein R and m have the meaning given under Formulas IV and I.
  • the anhydrides of Formula IVa can be obtained in a simple manner by the reaction of corresponding substituted sulphonic acid halides with salts of correspondingly substituted sulphonic acids.
  • starting materials of Formula II are obtained by reacting substituted p-(aminoalkyl)- benzenesulphonamides, (produced analogously to the method of E. Miller, J. Amer. Chem. Soc. 62, 2101 (1940)) of formula wherein in has the meaning given under Formula I, with substituted N-(Z-bromoalkyl)-cyanamides in alkaline medium.
  • the preparation of the starting compounds of Formula HI is carried out using the generally known preparation methods for the corresponding carboxylic acid derivatives.
  • the new active substances of Formula I, or the pharmaceutically acceptable salts thereof, can be administered orally, rectally or parenterally.
  • physiologically harmless inorganic or organic acids such as, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic 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
  • 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 or tablets preferably contain 10-200 mg. of an active substance according to the invention, whereby the content of active substance is 20- 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.
  • the tablets and drage cores are coated, e.g. with concentrated sugar solutions which can 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 may be added to these coatings, e.g. for identification of the various dosage amounts.
  • 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 stabilisers 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 stabilisers may be added.
  • a granulate is produced from 1000 g. of 1-[p-(2- nicotinamidoethyl) phenylsulphonyl] 2-imino-3-cyclohexylimidazolidine, 345.0 g. of lactose and the aqueous solution of 6.0 g. of gelatine. After drying, the granulate 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.
  • Example 1 An amount of 39.7 g. of 1-[p-(Z-aminoethyl)-phenylsulfonyl]-2-imino-3-tert.-butyl-imidazo1idine dihydrochloride monohydrate, M.P. 232234, is dissolved in 200 ml. of water; and the base liberated with ml. of 2-n sodium hydroxide solution. It is extracted with methylene chloride. To the methylene chloride solution, dried with sodium sulfate, are added 15 g. of triethylamine. To this solution are thereupon added dropwise at room temperature, within 20 minutes, 15 g. of furan-Z-carboxylic acid chloride in 100 ml.
  • the dihydrochlorides (used as starting materials) of 1 [p (2 aminoethyl) phenylsulphonyl]-2-iminoimidazolidines varying substituted in the 3-position can be obtained, e.g. in a simple manner by reaction of p-(2- acylamidoethyl)-benzenesulphochloride with correspondingly substituted 2amino-imidazolines of Formula V, and subsequent hydrolytic cleavage of the acyl radical of the p-acylamindoethyl group with aqueous hydrochloric acid, as is described in the following for 1-[p-(2-aminoethyl)- phenylsulphonyl] 2 imino-3-cyclohexyl-imidazolidine dihydrochloride.
  • the applied sulphochlor-ide can be produced as follows: To 35.0 g. of chlorosulphonic acid are added portionwise, with stirring, 16.3 g. of N-phenethylacetamide. The obtained mixture is stirred for 3 hours at 60, and then poured on to ice, whereby p-(Z-acetamidoethyl)-benzenesulphochloride precipitates in crystalline form. It is filtered 01f under suction, washed with water, dried in vacuco, and further processed as crude product.
  • Example 2 42.3 g. of 1-[p-(2-aminoethyl)-phenylsulfonyl]-2- irnino-3-cyclohexyl-imidazolidine dihydrochloride, M.P. 247-25 0 are dissolved in 200 ml, of Zn sodium hydroxide the free base is extracted with methylene chloride, the extract is dried over sodium sulfate and the methylene chloride is distilled off in vacuo. The residue is then taken up with 300 ml. of dioxane and after addition of 16.0 g. of nicotinic acid methyl ester and 0.5 g. of sodium methylate the whole is refluxed for 4 hours. The solvent is distilled oil?
  • Example 3 42.3 g. of 1-[p-(Z-aminoethyl)-phenylsulphonyl]-2- imino-3-cyclohexyl-imidazolidine dihydrochloride, M.P. 247-25 0 are dissolved in 200 ml. of water. After addition of ml. of 2-n sodium hydroxide the free base is taken up with methylenechloride and the methylenechloride solution is dried over sodium sulphate. Then 12.3 g. of nicotinic acid and 60 g. of N,N'-dicyclohexy1 carbodiimide are added. The whole is kept for 1 hour at room temperature and evaporated to dryness in vacuo.
  • Example 4 Analogously to Example 1 are obtained:
  • nicotinic acid chloride 1-[p-(Z-nicotinamido-ethyl)- phenylsulphonyH-Z-imino 3 benzyl-imidazolidine, M.P. 173-175 From 44.5 g. l-[p-(Z-amino-ethyl)-phenylsulphonyl]- 2-imino 3 (2-phenethyl)-imidazolidine-dihydrochloride and 15.0 g.
  • furan-2-carboxylic acid chloride 1[p-(2-(2- furancarboxamido)-ethyl)-phenylsulphonyl] 2 imino 3-(Z-phenethyl)-imidazolidine, M.P. 182-183";
  • furan-Z-carboxylic acid chloride I-[p-(Z-(Z-furancarboxamido)-ethyl)-phenylsulphonyl] 2 imino 3 methylimidazolidine, M.P. 210.5-211.5;
  • R is alkyl of at most six carbon atoms, cycloalkyl or alkyl substituted cycloalkyl of, in all, from five to eight carbon atoms, phenylalkyl of at most three carbon atoms in the alkyl chain, or allyl;
  • R is hydrogen, methyl or ethyl
  • R is a five to six membered mononuclear heterocycle with one or two heteroatoms, which is unsubstituted or substituted by lower alkyl or phenyl and of which a methylene group can be replaced by a carbonyl group furan, thiophene or pyridine, which is unsubstituted or substituted by lower alkyl;
  • n is the integer 2 or 3;
  • a compound according to claim 1 which is 1-[p-(2- (3-furancarboxamido)-ethyl)-phenylsulfonyl] 2 imino- 3-cyclohexyl-imidazolidine.
  • a compound according to claim 1 which is 1-[p-(2- (2 thiophenecarboxamido) ethyl) phenylsulfony1]-2- imino-3-cyclopentyl-imidazolidine.
  • a compound according to claim 1 which is 1-[p-(2- (2 thiophenecarboxamido) ethyl) phenylsulfonyl]- 2-imino-3-cyclohexyl-imidazolidine.
  • a compound according to claim 1 which is 1-[p-(2- nicotinamidoethyl)-phenylsulfonyl] 2 imino 3 cyclohexyl-imidazolidine.
  • R is furan, which is unsubstituted or substituted by lower alkyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US00068794A 1969-09-04 1970-09-01 P-aminoalkylbenzenesulfonamide derivatives Expired - Lifetime US3712899A (en)

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CH1339969A CH518944A (de) 1969-09-04 1969-09-04 Verfahren zur Herstellung von neuen Derivaten des p-Aminoalkyl-benzolsulfonamids

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US00290041A Expired - Lifetime US3787574A (en) 1969-09-04 1972-09-18 P-aminoalkylbenzenesulfonamide derivatives for treating diabetes mellitus

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AT (1) AT294823B (enrdf_load_stackoverflow)
BE (1) BE755684A (enrdf_load_stackoverflow)
BG (1) BG18604A3 (enrdf_load_stackoverflow)
CH (1) CH518944A (enrdf_load_stackoverflow)
DE (1) DE2043809C3 (enrdf_load_stackoverflow)
DK (1) DK123939B (enrdf_load_stackoverflow)
ES (1) ES383343A1 (enrdf_load_stackoverflow)
FI (1) FI52464C (enrdf_load_stackoverflow)
FR (1) FR2070670B1 (enrdf_load_stackoverflow)
GB (1) GB1306560A (enrdf_load_stackoverflow)
IE (1) IE34503B1 (enrdf_load_stackoverflow)
IL (1) IL35223A (enrdf_load_stackoverflow)
NL (1) NL165738C (enrdf_load_stackoverflow)
NO (1) NO129741B (enrdf_load_stackoverflow)
PL (1) PL73404B1 (enrdf_load_stackoverflow)
SE (1) SE367628B (enrdf_load_stackoverflow)
SU (1) SU373944A3 (enrdf_load_stackoverflow)
ZA (1) ZA706037B (enrdf_load_stackoverflow)

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PL73404B1 (enrdf_load_stackoverflow) 1974-08-30
GB1306560A (en) 1973-02-14
DK123939B (da) 1972-08-21
IE34503B1 (en) 1975-05-28
DE2043809C3 (de) 1979-11-15
FR2070670B1 (enrdf_load_stackoverflow) 1973-12-21
NL7012726A (enrdf_load_stackoverflow) 1971-03-08
US3787574A (en) 1974-01-22
FR2070670A1 (enrdf_load_stackoverflow) 1971-09-17
IL35223A0 (en) 1970-11-30
DE2043809A1 (de) 1971-04-01
SE367628B (enrdf_load_stackoverflow) 1974-06-04
ES383343A1 (es) 1973-01-01
SU373944A3 (enrdf_load_stackoverflow) 1973-03-12
FI52464B (enrdf_load_stackoverflow) 1977-05-31
NL165738C (nl) 1981-05-15
IL35223A (en) 1973-10-25
AT294823B (de) 1971-12-10
NO129741B (enrdf_load_stackoverflow) 1974-05-20
DE2043809B2 (de) 1979-03-22
BG18604A3 (bg) 1975-02-25
ZA706037B (en) 1971-04-28
BE755684A (fr) 1971-03-03
NL165738B (nl) 1980-12-15
FI52464C (fi) 1977-09-12
CH518944A (de) 1972-02-15
IE34503L (en) 1971-03-04

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