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Publication numberUS3338916 A
Publication typeGrant
Publication dateAug 29, 1967
Filing dateJan 29, 1965
Priority dateFeb 5, 1964
Also published asDE1620702A1
Publication numberUS 3338916 A, US 3338916A, US-A-3338916, US3338916 A, US3338916A
InventorsHunziker Fritz
Original AssigneeA Wander S A Dr
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Benzimidazolone derviatives
US 3338916 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent O 4 Claims. (Cl. 260-3091) This invention is generally concerned with certain derivatives of benzimidazolone (2-oxo-benzimidazoline), and more specifically with new benzimidazolone derivatives having a basic substituent on one nitrogen, of the formula:

and with acid addition salts thereof. In Formula I, 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, 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.

Compounds of Formula I are obtained by introducing into benzimidazoles of the formula:

B (II) wherein R and R have the above-mentioned meaning, a basic residue of the formula R(R )--NR R wherein R, R R and R have the said meaning. The basic residue is introduced by treating the compound of Formula II, which is suitably dissolved in an inert solvent such as benzene, dioxan, dimethylformamide, dimethylsulphoxide or mixtures thereof, with the ester of an alcohol of the formula:

Ra wherein 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.

In so far as R in Formula I denotes hydrogen the desired benzi-midazolones are also obtained by reacting esters of alcohols having the formula:

wherein R, R and R have the meaning indicated earlier, e.g. hydrohalic, sulphuric, or sulphonic acid esters, with an amine of the formula H'NRzRg, wherein R and R have the above-mentioned meaning. 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. On the other hand one can also first treat 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:

(VII) wherein 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.

Compounds of Formula I are also obtained by reacting substituted o-phenylenediamine derivatives of the formula:

R5 (VIII) wherein 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. 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.

Lastly, 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.

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. The base precipitated from the combined extracts with concentrated ammonia solution is taken up in benzene. The benzene solution is washed several times with water, dried over sodium sulphate and evaporated to dryness. After clarification in benzene solution on alumina there are obtained from benzene/petroleum ether and acetone/petroleum ether 8.8 gm. (88% of the theory) of 1-pheny1-3-/8-dimethylaminoethyl-benzimidazolone of melting pont 116-117 C.

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.

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 3 7.3 gm. of l-phenyl-benzimidazolone in 40 ml. of absolute dioxan are boiled with potassium-t-butoxide (from 1.2 gm. of potassium) in 30 ml. t-butanol for 1 hour under reflux. Upon addition of 5.7 gm. of trirnethylene chlorobromide, refluxing is continued for another 7 hours. The reaction mixture is concentrated and the residue is distributed between ether and Water. A small amount of substance insoluble in either of both phases is separated by filtration. The ethereal solution is washed with Water and evaporated to dryness in vacuo, yielding 6.4 gm.

of a brown resin. The latter is boiled with 5.0 gm. of dimethylamine in 20 ml. of dioxan for 18 hours in a sealed tube. By Working up the reaction mixture in a usual manner, 4.9 gm. of 1-phenyl-3-'y-dirnethylaminopi'opyl-benzimidazolone of boiling point 163 C./ 0.03 mm. Hg are obtained.

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. of water by introducing gaseous sulphur dioxide) stirred at 80 0., this temperature being maintained for minutes after the evolution o'f -g'as had ceased. The reaction mixture is allowed to cool and then alkalized by addition of soda lye. The basic precipitate is dissolved in ether. The ethereal phase is washed with diluted soda lye and with water and worked up in a usual'manner. The residue is dissolved in petroleum ether, purified by contact with aluminium oxide, and crystallized-from cold petroleum ether. By this procedure 5.6 gm. of l-p-chlorophenyl-3- -pyrrolidin 1' yl propyl benzimidazolone of melting point 5456 C. are optained.

By means of the same procedure as in Examples 1 to 6 there are also obtained, for example, the products mentioned in the following table. In the table R, R R R R and R are the corresponding groups in Formula I, with the meaning stated earlier. In the column on the right are given in brackets the solvents or solvent mix tures from which crystallization was etfected: here ac means acetone, e ether, me methanol, pe petroleum ether and pn pentan.

TABLE I Example RN\ R4 R5 Melting point (M.P.) or Boiling point (B.P.)

7 '(CHz)3-N(CzH5)2 H H Hydrochloride: M.P. 153-155 O. (rue/e). s l -(CHz)zN(CHa)2 501 H Base: M.P.127128C.(e/pe). 9---; oHi)3N cH;)2 e01 H' Base: M. P.104105C. (e/pe).' 1o.- oH, ,-N(oH=), 6-01 11 Base: M.P.111-112C. (ac/pe).

11.- oH, 6-Cl- H Base: B.P. 210 C./0.05mm. Hg.

I|q'. CH3

12 i-- --(CH )g-N(OH H p-Cl Eileen-M.P. 114-115 0. (e/pe).

oH, ,-N om H p-Cl Base: 'B.P. 176-177 0.10.01 mm. Hg. 1 Hydrochloride: M.P. 232-236 C. (me/e).

' 14 (CHg) N(CHa)2 5-OHa H Base: "M.P. -76" 0. (pm).

15. (CH1)3N c2115), G-Cl H 1 Hydrochloride: M.P. 184-185 O. (me/e).

1s -(CH)3'N s-cl H Base: M11 75-7e o. (ac/pe).

17 omn-Nj e01 H Base: Mlr.97-99o. (ac/pa).

" 1s" "L--. -(CHQ)QNH-CHH e01 H Base: M.P.88C. (e/pe).

19 (CHg) N(C H )g H p-Cl Base: M.P.52-54C.(pn).

2o oH, 3-N cm), 6-01 p-Cl Base: M.P.102-103O. (e/pe).

21 oH, 3-1 H p-Cl Base: M.P.102-1 03C.(ac/pe).

22 -(oH, H p-Cl Base: M.P.127129" 0. (ac/pe).

23 CH1 H p-Cl Hydrochloride: M.P. as from 217 C.

: N: (decomposition) (me/ac/e).

l CH3 24 (CHz)s-N(C:Ha)z H -oH, Base: M.P.61-52C.(pe).

TABLEContinued Ilia l Example -RN\ R R5 Melting point (M.P.) or Boiling point (13.1

(CHg)sN H p-CHs Base: M.P. 8587 C. (e/pe).

26 (CH2)3N(C2H5)3 H p-Br Hydrochloride: M.P. 198-199 0. (mole).

27 (CHz)3-N(C2H5)2 H p-F Base: M.P. 39.5-41" O. (pe).

28 (CH1);N(CH H p-F Hydrochloride: M.P. 200-202" 0. (mole).

29 -(CHr)3-N(O2Hs)z H o-Ol Base: BR 186' C./0.05 mm. Hg.

30 (CHz)3-N H o-Cl Hydrochloride: M.P. 174-178 C. (me/e).

31 (CH2)3-N(C2H5)3 H m-Cl Base: M.P. 48-52" C. (pe).

32 -(OH;);N H m-Cl Base: M.P. 75-77 C. (e/pe).

1 phenyl 3 'y dimethylaminopropyl 6 chlorobenzimidazolone hydrochloride 40 Lactose 6'0 Corn starch 5 Talcum 2 Magnesium stearate 0.1

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.

We claim:

1. A compound selected from the class consisting of A: benzimidazolone derivatives of the formula:

let

wherein 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; and R is a member of the group consisting of hydrogen, halogen, and alkyl having from 1 to 3 carbon atoms; and B: pharmaceutically acceptable acid addition salts of A.

2. 1 p chlorophenyl 3 7 diethylaminopropylbenzimidazolone.

3. 1 p chlorophenyl 3 'y pyrrolidin 1 yl propyl-benzimidazolone.

4. 1 phenyl 3 dimethylaminopropyl 6 chlorobenzimidazolone.

References Cited UNITED STATES PATENTS 3,161,654 12/1964 Janssen 260---332.3

OTHER REFERENCES 'Davoll et al.: Jour. Chem. Soc. 1960, pp. 314-18.

Oftedahl et al.: Chem. Abst., vol. 58, col. 10190C (1963).

JOHN D. RANDOLPH, Primary Examiner. N. TROUSOF, Assistant Examiner,

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3161654 *Jun 11, 1963Dec 15, 1964Merck & Co Incalpha-(1-aroyl-3-indolyl) alkanoic acids
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3989707 *Jun 21, 1974Nov 2, 1976Janssen Pharmaceutica N.V.Neuroleptic agents
US4215119 *Apr 3, 1979Jul 29, 1980Boehringer Ingelheim GmbhAminoalkyl-substituted benzimidazolidin-2-ones
US4335132 *Dec 29, 1980Jun 15, 1982Sterling Drug, Inc.Cardiotonic agents
US5200422 *Jul 17, 1991Apr 6, 1993Neurosearch A/SFor treating hypertension, asthma, ischemia and convulsions by opening potassium channels
US7264587Jan 17, 2003Sep 4, 2007Origin Medsystems, Inc.Endoscopic subxiphoid surgical procedures
US7526342Oct 29, 2003Apr 28, 2009Maquet Cardiovascular LlcApparatus for endoscopic cardiac mapping and lead placement
DE2609645A1 *Mar 9, 1976Sep 15, 1977Boehringer Sohn IngelheimAminoalkylheterocyclen
Classifications
U.S. Classification548/306.1, 564/369, 546/199, 546/248, 540/603, 549/416, 540/480, 548/306.4
International ClassificationC07D235/26
Cooperative ClassificationC07D235/26
European ClassificationC07D235/26