US3338916A - Benzimidazolone derviatives - Google Patents

Benzimidazolone derviatives Download PDF

Info

Publication number
US3338916A
US3338916A US429160A US42916065A US3338916A US 3338916 A US3338916 A US 3338916A US 429160 A US429160 A US 429160A US 42916065 A US42916065 A US 42916065A US 3338916 A US3338916 A US 3338916A
Authority
US
United States
Prior art keywords
formula
benzimidazolone
base
carbon atoms
phenyl
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
Application number
US429160A
Other languages
English (en)
Inventor
Hunziker Fritz
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.)
Wander AG
Original Assignee
Wander AG
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 Wander AG filed Critical Wander AG
Application granted granted Critical
Publication of US3338916A publication Critical patent/US3338916A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms

Definitions

  • R denotes a straight or branched alkylene residue with 2 to 4 carbon atoms
  • R denotes a hydrogen atom, or together with R an alkylene residue with 2 to 4 carbon atoms
  • R denotes a straight or branched alkylene residue with 2 to 4 carbon atoms
  • R denotes, besides, an alkyl residue with 1 to 3 carbon atoms, or together with R an alkylene residue with 4 to 6 carbon atoms;
  • R denotes, besides, hydrogen or an alkyl residue with l to 3 carbon atoms;
  • R is in 5- or 6-position and denotes hydrogen, a halogen atom, or an alkyl residue containing 1 to 3 carbon atoms; and
  • R denotes hydrogen, a halogen atom, or an alkyl residue with 1 to 3 carbon atoms.
  • the said compounds are pharmacologically active substances whose pharmacological properties suggest that they may be useful especially as antidepressant and anticonvulsants. Whereas these two modes of action are found in similar measure in some representatives of the drug group, so in others one or other of the two modes of actionis prominent.
  • the antidepressant action predominates in the products substituted in S-position and especially in 6-position, and the anticonvulsant action is especially prominent in the compounds substituted in the l-phenyl residue, preferably in p-position'Halogen atoms, and particularly chlorine, are preferred as substituents R and R
  • the basic side-chain in 3-position is preferably a y-dimethylaminopropyl, -diethylaminopropyl, or -pyrrolidin-1'-ylpropyl residue.
  • Examples of compounds with special anticonvulsant activity are l-p-chlorophenyl-3-vdiethylaminopropyl-benzimidazolone, 1-p-chlorophenyl-3- 'y-pyrrolidin-1'-yl-propyl benzimidazolone and their acid addition salts, and of those having special antidepressant activity are l-phenyl-3-'y-dimethylaminopropyl-G-chlorobenzimidazolone and its acid addition salts.
  • the new compounds of this invention can be administered in the form of pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration.
  • the pharmaceutical preparations may be, for instance, in the form of tablets, dragees, or solutions for injection, one dosage unit containing from 40 to 100 mg. of active substance, depending on its nature, on the Patented Aug. 29, 1967 route of administration and on the physicians prescription, the effective daily dose amounting from to 1000 mg. of active substance.
  • R, R R and R have the meaning indicated earlier, preferably at increased temperature and if necessary after prior or during simultaneous exposure to the action of a condensing agent.
  • Suitable esters are those of inorganic and organic acids such as hydrohalic, sulphuric, sulphonic, or carbonic acid. If carbonic acid esters are used the condensing agent can in general be dispensed with, but it is usually necessary in case of the other esters just mentioned.
  • Suitable condensing agents are especially alkaline metals, their hydrides and amides, as well as other compounds of alkaline metals, for example sodium alcoholate, sodium amide, sodium hydride, phenylsodium, alkyl lithium, or potassium-t-butoxide.
  • the benzimidazolones of Formula II used in this reaction are obtained, for example, by reacting appropriately substituted phenylenediamines of the formula:
  • R5 (IV) wherein R and R have the meaning mentioned earlier, with a reactive carbonic acid derivative such as phosgene.
  • R in Formula I denotes hydrogen
  • esters of alcohols of Formula .V are in turn obtained, for example, by reacting compounds of Formula II with apreferably mixed-diester of an alkyleneglycol containing 2 to 4 carbon atoms, e.g. with an alkylene chlorobromide, if necessary after prior or during simultaneous exposure to the action of a condensing agent.
  • compounds of Formula II with an alkylene oxide or alkylene halohydrin containing 2 to 4 carbon atoms or with an alkylene-halohydrin tetrahydropyranyl ether of the formula:
  • Halogen-R-O- and thenin the latter case, after splitting off the protective groupfor-rn the desired ester, for example, by reacting with a thionylhalide or a hydrohalic acid.
  • Products of Formula I, wherein R is hydrogen, are also formed by introducing residues R and R into primary amines having the formula:
  • R, R and R have the meaning indicated earlier, for example by reacting the latter with esters, especially hydrohalic acid esters, of alcohols of the formula HO-'R or HO-R R OH, or by reacting the primary amines with corresponding aldehydes in accordance with the method of reductive alky-lation, using hydrogen in the presence of a catalyst or using a reducing agent such as formic acid.
  • the starting materials of Formula VII are in turn obtained, for example, by reacting esters of the alcohols of Formula V with ammonia or by reduction of suitable nitriles.
  • R5 (VIII) wherein R, R R R R R and R have the meaning indicated earlier, preferably in the presence of an inert solvent, with a reactive derivative of carbonic acid, e.g. phosgene, diethylcarbonate, urea and the like, if required after prior or during simultaneous exposure to the action of a condensing agent.
  • a reactive derivative of carbonic acid e.g. phosgene, diethylcarbonate, urea and the like
  • Suitable solvents and condensing 7 derivative of Formula IV if necessary after, prior or during simultaneous exposure to the action of a condensing agent for the above-mentioned kind, if required with intermediate acylation of at least the primary amino group.
  • compounds of Formula I wherein R and/or R denote halogen, are obtained by replacing other substituents having the same position by the desired halogen atom, for example by diazotizing and subsequent Sandmeyers reaction of corresponding amino compounds, which in turn may be prepared by reduction of corresponding nitro compounds.
  • the basic-substituted benzimidazolones of Formula I synthesized according to one of the processes described earlier can be obtained and used, not only as free bases but also in the form of their addition salts with suit-able acids, such as hydrohalic acids, sulphuric, nitric, phosphoric, acetic, oxalic, mal-onic, succinic, malic, maleic, or toluene-sulphonic acid.
  • suit-able acids such as hydrohalic acids, sulphuric, nitric, phosphoric, acetic, oxalic, mal-onic, succinic, malic, maleic, or toluene-sulphonic acid.
  • EXAMPLE 1 7.5 g. of 1-phenyl-benzimidazolone (1-phenyl-2-oxobenzimidazoline) in 50 ml. of absolute dioxan are boiled with 1.68 gm. of pulverized sodium amide for 1 hour under reflux. After adding 5.4 gm. of fl-dimethylaminoethylchloride in 30 ml. of benzene the whole is heated at boiling temperature for another 16 hours. After evaporating the reaction mixture to dryness in vacuo the residue is distributed between benzene and water. The basic fractions are removed from the lipoid phase by exhaustive extraction with dilute acetic acid.
  • EXAMPLE 2 6.1 gm. of 1 phenyl 6'-chloro benzimidazolone are boiled with pot-assium-t-butoxide (from 1.0 gm. of potassium) in 40 ml. of t-butanol for 10 minutes under reflux. After evaporating the reaction mixture to dryness in vacuo the potassium compound is mixed with 40 ml. of dimethylformamide and heated with 4.8 gm. of freshly distilled 1-methyl-3-chloromethyl-piperidine for 18 hours at 50 C.
  • pot-assium-t-butoxide from 1.0 gm. of potassium
  • Example 2 On proceeding as described in Example 1 3.4 gm. of a crystalline neutral substance are obtained consisting mostly of 1 phenyl 6 chloro-benzmidazolone (starting material). As the base there are obtained 2.7 gm. of 1- phenyl 3 (1-methylpiperidyl-3)methyl-6-chloro-benzimidazolone in the form of colourless needles of melting point 112114 C. (from ether/petroleum ether), which, taking into consideration 2.8 gm. of pure starting material recovered, corresponds to a yield of 58% of the theoretical.
  • EXAMPLE 4 6.3 gm. of 1-phenyl-3- -aminopropyl-6-chloro-benzimdried. Recrystallizing of the residue from' methanol/ acetone/ether with use of charcoal yields 6.1 gm. of 1- phenyl 3 'y dimethylaminopropyl 6 l chloro benzimidazolone hydrochloride of melting point ISO-182 C.
  • EXAMPLE 5 12.3 gm. of N -phenyl-N -(B-dimethylamino)ethyl-ophenylenediamine are heated with 4.0 gm. of urea for hours at 200 C., while passing gaseous nitrogen over the reaction mixture. From the basic fractions, separated as described in Example 1, 8.4 gm. of 1-phenyl-3-[3-dimethylaminoethyl-benzimidazolone are obtained which is identical with the product of Example 1.
  • EXAMPLE 6 8.7 gm. of l-p-aminophenyl-3-' pyrrolidin-1'-yl-propylben zimidazolone are dissolved in 100 ml. of 1-n hydro- 6 chloric acid and diazotized at 0 C. with a solution of 1.9 gm. of sodium nitrite in 10 ml. of water. The diazonium solution is added within 10 minutes to an aqueous solution of cuprous chloride (prepared from 5.3 gm. of copper sulphate and 5.3 gm. of sodium chloride in 25 ml.
  • cuprous chloride prepared from 5.3 gm. of copper sulphate and 5.3 gm. of sodium chloride in 25 ml.
  • These 107 mg. tablets can be administered orally in a dosage of 3 to 15 tablets per day in the treatment of patients suffering from states of mental depression.
  • R denotes alkylene with from 2 to 4 carbon atoms
  • R is a member of the group consisting of hydrogen and, taken together with R alkylene with from 2 to 4 carbon atoms
  • R is a member of the group consisting of alkyl with from 1 to 3 carbon atoms, together with R alkylene with from 2 to 4 carbon atoms, and, together with R alkylene with from 4 to 6 carbon atoms
  • R is a member of the group consisting of hydrogen, alkyl with from 1 t0 3 carbon atoms, and, together with R alkylene with from 4 to 6 carbon atoms
  • R is in 5- or 6-position and denotes a member of the group consisting of hydrogen, halogen, and alkyl with from 1 to 3 carbon atoms
  • R is a member of the group consisting of hydrogen, halogen, and alkyl having from 1 to 3 carbon atoms
  • B pharmaceutically acceptable acid addition salts of A.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Detergent Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US429160A 1964-02-05 1965-01-29 Benzimidazolone derviatives Expired - Lifetime US3338916A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH133364A CH437315A (de) 1964-02-05 1964-02-05 Verfahren zur Herstellung von Benzimidazolonderivaten
CH501764 1964-04-17
CH1000264 1964-07-30

Publications (1)

Publication Number Publication Date
US3338916A true US3338916A (en) 1967-08-29

Family

ID=27172901

Family Applications (1)

Application Number Title Priority Date Filing Date
US429160A Expired - Lifetime US3338916A (en) 1964-02-05 1965-01-29 Benzimidazolone derviatives

Country Status (14)

Country Link
US (1) US3338916A (en, 2012)
BE (1) BE659364A (en, 2012)
BR (1) BR6566831D0 (en, 2012)
CH (4) CH437317A (en, 2012)
DE (1) DE1620702A1 (en, 2012)
DK (4) DK109869C (en, 2012)
ES (1) ES308785A1 (en, 2012)
FI (1) FI44407B (en, 2012)
FR (1) FR3952M (en, 2012)
GB (1) GB1078251A (en, 2012)
IL (1) IL22841A (en, 2012)
NL (1) NL6501434A (en, 2012)
NO (1) NO116324B (en, 2012)
SE (4) SE343580B (en, 2012)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989707A (en) * 1974-06-21 1976-11-02 Janssen Pharmaceutica N.V. Benzimidazolinone derivatives
DE2609645A1 (de) * 1976-03-09 1977-09-15 Boehringer Sohn Ingelheim Aminoalkylheterocyclen
US4335132A (en) * 1980-12-29 1982-06-15 Sterling Drug, Inc. 5-(Py-Y)-1H-benzimidazol-2-ols and 5-(Py-Y-)-1H-benzimidazole-2-thiols
US5200422A (en) * 1990-09-24 1993-04-06 Neurosearch A/S Benzimidazole derivatives, their preparation and use
US7264587B2 (en) 1999-08-10 2007-09-04 Origin Medsystems, Inc. Endoscopic subxiphoid surgical procedures
US7526342B2 (en) 1999-08-10 2009-04-28 Maquet Cardiovascular Llc Apparatus for endoscopic cardiac mapping and lead placement

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3996238A (en) * 1972-02-08 1976-12-07 Ciba-Geigy Corporation 4- or 5-Nitroimidazoles and processes for their manufacture
GB9613423D0 (en) * 1996-06-26 1996-08-28 Lilly Industries Ltd Pharmaceutical compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3161654A (en) * 1962-01-05 1964-12-15 Merck & Co Inc alpha-(1-aroyl-3-indolyl) alkanoic acids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3161654A (en) * 1962-01-05 1964-12-15 Merck & Co Inc alpha-(1-aroyl-3-indolyl) alkanoic acids

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989707A (en) * 1974-06-21 1976-11-02 Janssen Pharmaceutica N.V. Benzimidazolinone derivatives
DE2609645A1 (de) * 1976-03-09 1977-09-15 Boehringer Sohn Ingelheim Aminoalkylheterocyclen
US4215119A (en) * 1976-03-09 1980-07-29 Boehringer Ingelheim Gmbh Aminoalkyl-substituted benzimidazolidin-2-ones
US4335132A (en) * 1980-12-29 1982-06-15 Sterling Drug, Inc. 5-(Py-Y)-1H-benzimidazol-2-ols and 5-(Py-Y-)-1H-benzimidazole-2-thiols
US5200422A (en) * 1990-09-24 1993-04-06 Neurosearch A/S Benzimidazole derivatives, their preparation and use
US7264587B2 (en) 1999-08-10 2007-09-04 Origin Medsystems, Inc. Endoscopic subxiphoid surgical procedures
US7526342B2 (en) 1999-08-10 2009-04-28 Maquet Cardiovascular Llc Apparatus for endoscopic cardiac mapping and lead placement

Also Published As

Publication number Publication date
FR3952M (en, 2012) 1966-02-21
IL22841A (en) 1968-05-30
NO116324B (en, 2012) 1969-03-10
BE659364A (en, 2012)
SE343579B (en, 2012) 1972-03-13
CH437315A (de) 1967-06-15
FI44407B (en, 2012) 1971-08-02
NL6501434A (en, 2012) 1965-08-06
ES308785A1 (es) 1965-12-16
DK109988C (da) 1968-08-19
CH438335A (de) 1967-06-30
GB1078251A (en) 1967-08-09
DE1620702A1 (de) 1970-03-12
BR6566831D0 (pt) 1973-08-14
SE322223B (en, 2012) 1970-04-06
SE343580B (en, 2012) 1972-03-13
CH437318A (de) 1967-06-15
CH437317A (de) 1967-06-15
SE343581B (en, 2012) 1972-03-13
DK109869C (da) 1968-07-22
DK109804C (da) 1968-07-08
DK109805C (da) 1968-07-08

Similar Documents

Publication Publication Date Title
US5753629A (en) Distamycin A analogues as antitumour or antiviral agents
US3424762A (en) Certain 3-ureidopyrrolidines
US5137918A (en) N-(2'-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing them
US3740442A (en) 2-isopropylaminobenzophenones in treating inflammation
US3468887A (en) Process for the preparation of 2-phenylamino-1,3-diazacycloalkenes-2
US3338916A (en) Benzimidazolone derviatives
US3694456A (en) 1-disubstituted aminopyrazoles
US3305547A (en) Alkoxypiperidine derivatives and their salts
US3580949A (en) N,n'-bis-(aminoalkyl)-benzyl-amines
US3483185A (en) N-substituted 2,3,4,5-tetrahydro-1h-3-benzazepines
KOSASAYAMA et al. Cyclic guanidines. IV. Synthesis of hypoglycemic N-benzhydryl bicyclic guanidines
KR0152299B1 (ko) 시클로헵트이미다졸 유도체, 그의 제조방법 및 이 화합물을 함유하는 치료제
US3732243A (en) 2-(p-bromophenyl)-9-dimethyl-amino-propyl-9h-imidazo(1,2-a)benzimidazole
US4065451A (en) 1,3-Dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, substituted diamino acetate esters and their acid salts
US3526636A (en) Imidazoisoindoles
US3491097A (en) 3-(piperazinoalkyl)-pyrazoles
JPS6047255B2 (ja) ２−アミノ−５−スルフアモイル−安息香酸アミドの製法
US4208420A (en) New benzo [d] thiazole derivatives, process for their preparation and their therapeutic applications
US3654275A (en) Quinoxalinecarboxamide antiinflammatory agents
US3514486A (en) 3-isopropylnorbornanamine
JPH0372061B2 (en, 2012)
CA1100513A (en) Arylaminoimidazoline derivatives and the preparation thereof
US3174978A (en) Guanyl hydrazones of dialkylaminophenyl lower alkyl ketones
US3647877A (en) Aminopropionanilides
US2985653A (en) New piperazinyl-alkyl-phenthiazines and their preparation