SI8811778A - Process for preparing novel benzimidazoline-2-oxo-1-carboxylic acid derivatives - Google Patents

Abstract

The process for preparing new derivatives is described benzimidazoline-2-oxo-1-carboxylic acids in general formula O.C-T-A l R in which R represents a hydrogen atom, C 1-6 alkyl, C 1-6 alkenyl or C 1-6 alkynyl, Y is oxygen or N-R 5 in which R 3 is hydrogen, C1-6alkyl or optionally with one or more C 1-4 alkoxy substituted gasoline, A is the group selected of in which p is 0.1; R is 0.1, 2, 3; R4 is a hydrogen atom or C1-6 alkyl; R 5 is a hydrogen atom or C 1-6 alkyl; C3-cycloalkyl, C3-e cycloalkyl-C1-4alkyl, C1-4alkyl substituted with phenyl, or R 5 is a group of formula -CR 6 = N-R 7, v which R 6 is a hydrogen atom, a C 1-4 alkyl or amino group and R 7 is a hydrogen atom or C 1-6 alkyl wherein it is reactive derivative of the formula (Vlil) I X in which A is defined as above and denotes X outgoing a group reacted with a compound of formula (IX) Ζ-Υ-Α in which Z represents a hydrogen, lithium, sodium or atom potassium and Y and A are defined as above in aprotic solvent in the presence of an acid acceptor at a temperature of 0 degrees Celsius. New benzimidazoline-2-oxo-1-carboxyl derivatives acids are useful in pharmaceuticals industry as 5-HT receptor antagonists, primarily in the treatment of nausea and vomiting that cause them chemotherapy and radiation.

Description

Process for the preparation of new benzimidazoline-2-oxo-1-carboxylic acid derivatives

FIELD OF THE INVENTION

The invention is within the scope of the pharmaceutical industry and relates to a process for the preparation of novel benzimidazoline 2-oxo-1-carboxylic acid derivatives. The novel compounds are 5-HT receptor antagonists and are useful as anti-vomiting agents and as gastric motility enhancers. Serotonin (5-HT) is known to play an important role in both the central nervous system (CNS) and the peripheral nervous system (PNS). Compounds that act as receptor antagonists

5-HT can be used to help prevent or treat migraines, intermittent headaches and trigeminal neuralgia. They can also be used to treat certain CNS disorders, such as anxiety and psychosis. Because 5-HT antagonists may play a useful role in gastrointestinal motility, the continued use of these compounds is in gastric emptying, digestive disorders, flatulence, esophageal reflux, peptic ulcer, constipation and irritable bowel syndrome.

A technical problem

There is an ongoing need to prepare novel 5-HT receptor antagonists in a technologically advantageous manner, which, by their pharmacological properties, will outperform the known 5-HT receptor antagonists.

The state of the art

J.R. Fozard-Trends reports in Pharmacological Sciences 8 44, 1987 about some 5-HT receptor antagonists useful in the treatment of chemotherapy-induced nausea and vomiting. The compounds prepared according to the process of the invention are, however, novel and have not yet been described either by themselves or by the processes for their preparation.

Description of solution to a technical problem with implementation examples

We have now synthesized, and this is the object of the present invention, a new class of structurally distinct compounds exhibiting specific blocking activity of 5-HT receptors that may be useful in the treatment of nausea and vomiting caused by chemotherapy and radiation, and / or discharge congestion of the stomach. They can also be beneficial in treating kinetosis, arrhythmia, migraines, intermittent headaches, trigeminal neuralgia, anxiety and psychosis. They can also be used for gastrointestinal disorders such as indigestion, flatulence, esophageal reflux, peptic ulcer, constipation, irritable bowel syndrome and hypokinesia.

The compounds of the present invention have the general formula (I)

wherein R represents a hydrogen atom, C1-6alkyl, C1-6alkenyl or C1-6alkylnyl; R ₁ and R 8 may or may not be simultaneously hydrogen, halogen, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 acyl, carboxyl, C 1-6 alkoxycarbonyl, hydroxy, nitro, amino, optionally N-mono or di-substituted, C 1-6 gacylamino, C 1-4 alkoxycarbonylamino, carbamoyl, which is optionally N-mono or di-substituted, cyano, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino sulfonyl, optionally N -mono or di-substituted with C1-6 alkyl, with C1-6 alkyl N-mono- or di-substituted aminosulfonylamino, aminosulfonylamino; Y is oxygen or N-Rg in which R4 is hydrogen, C1-6alkyl or optionally with one or more C1-6alkoxy substituted benzyl; A is a group selected from

(d)

- -; * <

in which p is O, 1; R is O, 1, 2, 3; R1 is a hydrogen atom or C1-4 alkyl; Rg is a hydrogen atom, C ^ alkyl, C ^ gdkloalkil C ₃ _gCikloalkil-C ₁ _ || alkyl. C 1-6 alkyl substituted by phenyl, or R g is a group of formula - C '=' N-N 'in which R g is a hydrogen atom, C 1-6 alkyl or amino group and R is? a hydrogen atom

I or C 1-6 alkylJ

For pharmaceutical use, compounds of the general formula (I) are used per se or in the form of tautomers or physiologically acceptable acid addition salts. The term acid addition salts includes salts with inorganic or organic acids. The physiologically acceptable acids used to form salts include e.g. maleic, citric, tartaric, fumaric, methanesulfonic, hydrochloric, hydrobromic, hydrochloric, nitric, sulfuric, phosphoric, acetic, benzoic and ascorbic acids.

Physiologically tolerable salts also include quaternary derivatives of compounds of formula (I) obtained by the metabolism of the above compounds with compounds of formula Rg - Q in which Rg is C1-6alkyl, phenyl-C1-6alkyl or C1-6cycloalkylC1-6alkyl and Q is leaving group such as halogen, p-toluenesulfonate and mesylate. Preferred R8 groups are methyl, ethyl, n-propyl, i-propyl, cyclopropylmethyl. Physiologically acceptable salts also include internal salts of compounds of formula (I), such as N-oxides. The compounds of formula (I) and their physiologically acceptable salts may also exist as physiologically acceptable solvates such as hydrates, which represents a further

-J5 χ. feature of the present invention.

It is understood that the carbonyl group in position 2 of general formula (I) may exist in its monolayer form if R is hydrogen, and that there are also tautomers of amidino derivatives of formula (I) in which Re is a group of formula - C = N - R 'and ⁵ I ^{7 R} 6 are Rg and R? defined as above. The present invention therefore includes within its scope these tautomeric forms both in terms of compounds and in processes of manufacture.

Some of the compounds of formula (I) according to the present invention contain chiral or prokaryl centers, and thus may exist in various stereoisomeric forms comprising enantiomers of type (+) and (-) or mixtures thereof. The present invention includes in its scope both individual isomers and mixtures thereof.

It is understood that mixtures of optical isomers, if present, can be separated according to conventional separation methods based on their different physicochemical properties, e.g. by fractional crystallization of their acidic adiate salts with a suitable optically active acid or by chromatographic separation with a suitable solvent mixture.

In the present invention, expression A of formula (a) is 8-azabiocyclo / 3.2.1 / octane or in position 3 bound 9-azabicyclo / 3.3.1 / nonane or in position 2 bound 7-azabicyclo / 2.2.1 / heptane, in legi 4 bound piperidine; those of formula (b) means, in position 3 or 4, bound 1-azabicyclo / 2.2.2 / octane; those of formula (c) mean, in position 4, bound 1-azabicyclo / 3 '3.1 / nonane, and those of formula (d) means in position 5 bound 2-azabicyclo / 2.2.2 / octane.

The term halogen means fluorine, chlorine, bromine or iodine. It is understood that in the compounds of formula (I), the azabicyclic moieties of group A may be endo or exo substituted. Compounds of formula (I) containing pure endo or exo moieties can be prepared by starting from suitable precursors or by separating mixtures of endo or exo isomers that have been synthesized non-specific, by conventional methods, such as e.g. by chromatography.

Compounds of general formula (I), if R is H, can be prepared by reacting a compound of general formula (II)

H

in which R 1, R 2, Y and A are defined as a front, with a reactive carbonyl derivative of formula (III) i «| χ - C - X ¹ (III) in which X and X ^{1 are} leaving groups that are identical or different from each other, such as halogen, halogenated alkoxy, alkoxy, heterocycle. Preferred groups are chlorine, trichloromethoxy, methoxy, ethoxy or imldazolyl. The reaction can usually be carried out in aprotic solvents such as benzene, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, methylene chloride, chloroform, carbon tetrachloride or dimethylformamide, at a temperature of 0 ° to 100 ° C, preferably at 5 ° C or at a boiling point of choice. . In some cases, the presence of an acid acceptor such as triethylamine may be advantageous.

Compounds of general formula (II) used as starting materials in the above-mentioned process can be prepared by reducing a compound of formula (IV)

H ^R i ¹

N - CO - V - A. . I < ^{| v)} .

Κ. ΧΛ NO, in which Rp R ₂ , Y and A are defined as anterior, with hydrogen or a hydrogen donor, such as ammonium formate, cyclohexene, cyclohexadiene, hydrazine. The reduction is preferably carried out with hydrogen in the presence of a suitable catalyst, preferably of 5% or 10% Pd / C or Raney nickel in the presence of a suitable solvent, such as methanol, ethanol, toluene, water or a mixture thereof. The same reduction may be usually carried out with iron in acidic medium or in the presence of FeCl ^ "with Zn in acetic or hydrochloric acid, with SnCl ₂ in hydrochloric acid or with other reducing agents such as titanium trichloride, iron (II) sulphate, hydrogen sulphide or its salts, sodium hydrosulphite.

Compounds of general formula (IV) can be prepared by metabolizing a compound of general formula (V)

wherein R ₁ and R ₂ are as defined above, with a reactive intermediate of general formula (VI),

X - C - Y - A (VI), in which X, Y and A are defined as the front. The reaction is carried out in an aprotic solvent such as tetrahydrofuran, acetonitrile, chloroform, toluene, chlorobenzene, or solvent-free, and optionally in the presence of an acid acceptor, preferably in pyridine, at a temperature of 20 ° to 100 ° C, preferably at 20 ° or at 80 ° C.

Compounds of general formula (I) in which R. | and R ₂ are both hydrogen atoms and R, Y and A are defined as the front, which can usually be obtained by reacting a compound of formula (VII)

ΝΘ '

M®

(VII) in which M is a metal atom such as sodium, potassium or lithium, preferably sodium, with a compound of formula (VI). The reaction is preferably carried out in a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran, at a temperature of from 0 ° to 100 ° C, preferably at room temperature.

The compound (VII) is prepared in situ from the corresponding hydrogen compounds with sodium, potassium, sodium hydride, potassium hydride, potassium tert.butylate, butyllithium, lithium diisopropylamide, preferably sodium hydride.

Compounds of general formula (I) in which R 1 and R 2 are both hydrogen atoms, R, Y and A are defined as fore, can also be prepared by reacting a reactive compound of general formula (VIII)

--------- R

I

C = 0

I

X in which R and X are defined as the front, with the compound of formula (IX)

Z - Y - A (IX) in which Z is a hydrogen atom and a metal, preferably Li, Na or K, Y and A are defined as the front.

The reaction is carried out in an aprotic solvent such as tetrahydrofuran, chloroform, acetonitrile, o-dichlorobenzene and optionally in the presence of an acid acceptor such as pyridine or triethylamine, preferably pyridine, at a temperature of. . a · 1C

0 ° to 200 ° C, preferably at 20 ° or 16 ° C. .

It is understood that compounds of the general formula (I) containing the group R, Rp Rg, R ^ and R ^, which may give rise to other groups R, Rp Rg, R ^ and R ^, are useful as novel intermediates. Some of these conversions may also occur in intermediates for compounds of general formula (I).

Some examples of such conversions, which of course do not include all the options, are:

1) The nitro group can be converted to the amino group by reduction.

2) The amino group can be converted to the C 1- gacylamine group by acylation with a suitable carboxylic acid derivative.

3) The amino group can be converted to a C1-6 alkyl N-mono or di-substituted alkyl group.

4) The amino group can be converted to a C 1-4 alkoxycarbonylamino group by reaction with a suitable reactive C 1-6 alkyl monoester carbonic acid derivative.

5) The carboxyl group may be converted to a C 1-4 alkoxycarbonyl group or a carbamoyl group, which is optionally N-mono or di-substituted with C 1-6 alkyl, by reaction with a suitable reactive carboxylic acid derivative with suitable alcohols and amines.

6) The carbamoyl group can be converted to a cyano group by dehydration.

7) A C 1-6 alkylthio or C 1-6 alkylsulfinyl group may be converted to a C 1-6 alkylsulfinyl or C 1-6 alkylsulfonyl group by oxidation.

- ·· 8) The aromatic hydrogen group may be converted to a nitro group by nitration.

9) The hydrogen group can be converted to the halogen group by halogenation.

10) The secondary amide group, optionally conjugated to other carboxamide moieties, can be converted into a C 1-6 N-alkyl tertiary amide group by alkylation.

11) The secondary amino group can be converted to the amidine derivative by reaction with suitable reactive compounds such as e.g. ethyl formimidate, ethyl acetimidate or cyanamide.

12) The tertiary amino group may be converted to a quaternary ammonium derivative by reaction with a suitable alkylating agent such as methyl bromide or methyl iodide.

13) The tertiary amide group conjugated to other carboxamide moieties can optionally be converted to a secondary amide moiety by removing, optionally, C 1-4 alkoxy substituted benzyl.

These conversions are well known to any industry expert.

Compounds of general formula (I) prepared according to the procedure described above may optionally be converted by inorganic or organic acids to the corresponding physiologically acceptable acid addition salts, e.g. by conventional methods, such as by metabolizing compounds as bases with a solution of the appropriate acid in a suitable solvent. Particularly preferred acids include e.g. hydrochloric, hydrobromic, sulfuric, acetic, citric acid and tartaric acid.

The preferred groups of compounds of the present invention, due to their better activity than the 5-HT receptor blocker agents, are those formed by compounds of the general formula (I), in which:

- A endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl, R and R ₂ are H, R is H or CH and Y is oxygen or the group NH.

- A is 1-azabicyclo / 2.2.2 / oct-3-yl, R ₁ and R ₂ are H, R is H or CH 2 and Ϊ is oxygen or an NH group.

- A endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-yl> R 1 and R ₂ are H, R is H or CH 2 and Y is oxygen or an NH group.

- A is endo-1-azabicyclo / 3.3.1 / non-4-yl, R ₁ and R ₂ are H, R is H or CHg and Y is oxygen or NH group.

As mentioned earlier, the novel compounds of formula (I) according to the present invention have interesting pharmacological properties because of their ability to antagonize the physiological effects of 5-HT in warm-blooded creatures. Therefore, new compounds are commercially available for the prevention and treatment of disorders involving 5-HT receptors, such as chemotherapy or radiation-induced nausea and vomiting and gastric emptying. The following tests show that the compounds according to the present invention have favorable characteristics in this respect.

PHARMACOLOGY

Bezold-Jarisch reflex in anesthetized rats

Rats (250 to 275 g) were anesthetized with urethane (1.25 g / kg i.p.). Blood pressure was recorded in the left femoral artery with a pressure transducer (Statham) and heart rate was recorded by delivering a blood pressure signal to the cardiotachometer.

The Bezold-Jarisch effect was elicited by rapid bolus intravenous injection of 5-HT (20 ^ ug / kg).

Increasing doses of antagonists were injected 5 min before 5-HT to determine their effect on the initial sudden slowing of the heart and the associated drop in blood pressure resulting from reflex vagal stimulation. In other experiments, we stimulated the right vagus with platinum electrodes of 10 V, 10 Hz, 2 msec to induce bradycardia (Grass 248 stimulator). Values were calculated by analyzing linear regression of data expressed as percent inhibition.

The resulting efficacy of the two compounds of the present invention is shown below:

TABLE

-Mtfr - * · Compound Bradycardia ED -1 ⁵⁰ Qxg / kg, iv, ipotension ξθ _] 50 Qig / kg, i.v.) 26 0.3 0.4 27 0.35 0.51 28 1.0 1.5 31 0.49 1.97 41 0.07 0.13 44 0,0003 0,0004 45 b ⁷ 1.0 47 b ⁷ 2.2 60 3.2 5.2

Longitudinal musculoskeletal plexus of the guinea pig ileum

Male guinea pigs (Dunkin Hartley, 450 to 550 g) were killed by cervical dislocation. A 2 cm segment of the distal ileum, removed about 10 cm from the appendix, was suspended under a strain of 0.5 g in a 10 ml organ bath containing Tyrod's solution (mM: NaCl 137; KC1 2.68; CaCl ₂ 1.82; NaHCOg 5.9; MgCl ₂ 1; NaH ₂ PO ₄ 0.42; glucose 5.6) oxygenated with 95% 0 ₂ and 5% CO ₂ at 37 ° C. We registered the responses with an isotonic transducer on a polygraph (Basile).

Electrical field stimulation (EFS) was performed with bipolar platinum electrodes with pulses of 0.5 ms at a frequency of 0.1 Hz, with a supramaximal voltage. When the contractions stabilized, cumulative concentration-response curves were constructed for the compounds tested by adding at 5 min increments of increasing concentration.

The effect of compounds on EFS-induced contractions was determined as a percentage of the contraction size measured before the addition of the compounds.

The compounds of the present invention enhance the contractions induced by electrical stimulation of the guinea pig ileum in a concentration range of 10 ” ¹ θ to -8

10- M, with no effect on muscle tone.

According to a further feature of the present invention, pharmaceutical compositions containing at least one compound of formula (I) as defined above, or a physiologically tolerable acid addition salt thereof, together with pharmaceutical carriers or excipients, are available as the active ingredient. For pharmaceutical administration, the compounds of general formula (I) and their physiologically acceptable acid addition salts can be incorporated into conventional pharmaceutical preparations, either in solid or liquid form. Preparations can be offered e.g. in a form suitable for oral, rectal or parenteral administration. Preferred forms include e.g. capsules, tablets, coated tablets, ampoules, suppositories and oral drops.

The active ingredients can be incorporated into excipients or carriers commonly used in pharmaceutical preparations such as e.g. talc, gum arabicum, lactose, gelatin, magnesium stearate, maize starch, aqueous or non-aqueous vehicles polyvinylpyrrolidone, mannitol, semi-synthetic fatty acid glycerides, sorbitol, propylene glycol, citric acid, sodium citrate.

The formulations are conveniently formulated into dosage units, each dosage unit being adapted to give a single dose of the active ingredient. Each dosage unit may suitably contain from 50 mg to 1000 mg and preferably from 100 mg to 500 mg of the above ingredient.

The following examples illustrate novel compounds of the present invention; these cases should in no way be construed as limiting the scope of the invention itself.

-.17>

EXAMPLES '

2,3 "dlhydro-2-oxo-1H-benzimldazole-1-carbonyl chloride

It was prepared by suspending 5 g of 2,3-dihydro-1H-benzimidazol-2-one in 200 ml of distilled tetrahydrofuran and adding 13.5 ml of trichloromethylchloroformate. The reaction mixture was refluxed for 3 h until a clear solution was obtained. After cooling, the recovered solid was removed by filtration and 6.5 g of the title compound were obtained after concentration of the mother liquors to dryness.

Tal. 188 DEG-190 DEG C. (dec.).

EXAMPLE 2

Endo-3 / (2,4-dimethoxyphenyl) methyl / amino-9-niethyl-9-azabicyclo / -3-3.1/nonane

a) 2 g of exo-9-methyl-9-azabicyclo / 3.3.1 / nonan-3-ol were dissolved in methylene chloride (40 ml) and 3.8 ml of thionyl was added to the solution cooled to 0 ° C. of chloride. After refluxing for 4 hours, the reaction mixture was evaporated to dryness. The residue was taken up in water, basified and extracted with methylene chloride. After evaporation of the solvent, 2 g of crude oil was obtained and after purification by flash chromatography on silica gel (eluent: methylene chloride-methanol-32% ammonium hydroxide 97: 3: 0.3) 0.8 g of endo-3-chloro- 9-methyl-9azabicyclo / 3.3-1 / nonane.

Tal. 177 to 178 ° C.

b) A solution of endo-3-chloro-9-methyl-9-azabicyclo / 3.3-1 / nonane (0.5 g) and 2,4-dimethoxybenzylamine (0.62 g) in

- -: κ8 - „·. - absolute ethanol (50 ml) was refluxed for 4 h. After cooling, the crude product obtained by evaporation of the solvent was purified by flash chromatography on silica gel (eluent: methylene chloride-methanol-32% ammonium hydroxide 90: 10: 1). 0.35 g of oil was obtained. Using known methods, 0.24 g of the title compound as dihydrochloride was obtained.

Tal. 173 to 175 ° C.

EXAMPLE 3

Endo-3-methylamino-9-methyl-9-azabicyclo / 3.3.1 / nonane ml solution of 33% ethanol methylarainine was added to a solution of 9-methyl-9-azabicyclo / 3.3.1 / nonane-3one (1.7 g) in ethanol (30 ml). The reaction mixture was left in a closed vessel for -4 days, then hydrogenated at room temperature and at atmospheric pressure in the presence of previously reduced? T0 ₂ (0.2 g) and ammonium acetate (1.0 g). When the absorption of hydrogen was complete, the catalyst was removed by filtration. The reaction mixture was concentrated to dryness, taken up in water, basified with sodium hydroxy dom and extracted with ethyl acetate. After drying over KgSOj. gave the organic phase as a residue of 1.2 g of the title compound as a yellow oil, which was used as such for the next reaction.

EXAMPLE k

Exo-2-methyl-2-azabicyclo [2.2.2] octan-5-ol

The product was obtained according to R.F. Borne - J. Med. Chem. 16, 853-8.56 (1973). In this article, the compound was identified as cis.

EXAMPLE 5

Endo-2-methyl-2-azabicyclo [2.2.2] octan-5-ol

The product was obtained according to R.F. Borne - J. Med. Chem. 16, 853-856 (1973). In this article, the compound was identified as trans.

EXAMPLE 6

Endo-7-methyl-7-azabicyclo [2.2.1] heptan-2-ol

The product was obtained according to J.R. Phister - J. Pharm. Sci. 74. 208 (1985).

EXAMPLE 7 (Compound 1)

2,3-Dihydro-2-oxo-1H-benzimidazole-1-carbonyl chloride (2.15 g) was thoroughly mixed with endo-8-methyl-8-azabicyclo / 3.2.1 / octan-3-ol (1 , 55 g) and the mixture was melted and allowed to stand at this temperature for 10 minutes. Then the residue was taken up in acidified water and washed with ethyl acetate. We're in the water phase

Tal. 190 do

Analysis ^c 16 ^H 19 ^N 3 ° 3 strongly basified and extracted again. The last extracts were dried and after evaporation of the solvent, the crude title compound was left, which was crystallized from acetonitrile. 0,4 g.

192 ° C.

· «• Findings. % C 63.45 'H 6.41 N 13.81

Calc. % C 63.77 H 6.36 N 13.95

Analogically, we obtained:

2,3-Dihydro2-oxo-1H-benzimidazole-1-carboxylic acid endo-9-methyl-9-azabicyclo / 3.3.Ί / introduction-3-yl) ester (Compound 19)

Citrate (lyophilized). Tal. MS (C.I.): 316 m / e / M + H / + Analysis

Findings. % ^C 17 ^H 21 ^N 3 ° 3 ^C 6 ^H 8 ° 2 ""

Calc. % to 100 ° C.

C 51.36 H 5.91 N 7.74 CH 5.76 N 8.28 (Exo-9-niethyl-9-azabicyclo / 3 3-1 / non-3-yl) 2,3-dihydro2-oxo ester -1H-Berizimidazole-1-carboxylic acid (Compound 20)

Citrate. Tal. 77 to 80 ° C.

MS (CI): 316 m / e / M + H / ⁺

Analysis

Findings. %

C. — H—. N q0 - · C <-Ho0 «7 17 21 3 3 68 J _zra ._.

C 51.09 H 5.86 N 7.97 C 54/43 H 5.76 N 8.28 (1-Azabicyclo / 2.2.2 / oct-4-yl) ester 2,3-dihydro-2-oxo- 1H-Benzimidazole-1-carboxylic acid (Compound 21)

Hydrochloride. Tal. 254 to 256 ° C.

Analysis

Findings. % C 54.96 H 5.71 N 12.75

C _1c -H ₁₇ N '0 _o .HC1 ³ ' ^{5 and} Calc. % C 55.64 H 5.60 N 12.98 (Endo-7-methyl-7-azabicyclo / 2.2.1 / hept-2-yl) 2,3-dihydro2-oxo-1 H -benzimide201-1-carboxylic ester acids (Compound 22)

Base. Tal. 175 to 178 ° C. Analysis Findings. % C, 62.56 H, 5.96 N, 14.69 ^C 15 ^H 17 ^N 3 ° 3 Calc. % C, 62.71 H, 5.96 N, 14.63

2,3-Dichloro-2-oxo-1H-benzimidazole-1-carboxylic acid (Exo-2-methyl-2-azabicyclo / 2.2.2 / oct-5-yl) ester (Compound 23)

Hydrochloride. Tal. 208 to 211 ° C. Analysis c _i6 h ₁₉ n ₃ o ₃ .hci

Findings.

Calc.

C 56.88 C 56.89

H 6.12 H 5.97

N, 12.25; N, 12.43 (Endo-2-methyl-2-azabicyclo / 2.2.2 / oct-5-yl) 2,3-dihydro2-oxo-1H-benzimidazole-1-carboxylic acid ester (Compound 24)

Citrate. Tal. 73 to 75 ° C. Analysis

Findings.

^C 16 ^h 19 ^N 3 ° 3-W _? . "

Izrae. %

C 52.96 H 5.64 C 53.55 H 5.52

N, 8.39; N, 8.52

EXAMPLE 8 (Endo-8-methyl-8-azabicyclo / 3.2. V / oct-3-yl) ester

3-Methyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (Compound 25)% sodium hydride (0.04 g) was added in portions to the solution (endo-8-methyl-8- 2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid azabicyclo / 3.2.1 / oct-3yl) ester (0.4 g) in dry DMF (10 ml). After hydrogen evolution ceased, methyl iodide (0.082 mL) was added and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was taken up in methylene chloride and washed with water. The organic phase was dried - over MgSO 4 and concentrated to dryness. - Silica gel gave the pure title compound by flash chromatography (eluent: methylene chloride / methanol / 32% NH 4 OH 90: 10: 1). The oil base was converted to the hydrochloride salt. 0.21 g. Tal. > 250 ° C.

MS (CI): 3 Tfm / e / M + H / ⁺

Analysis

Findings. % C 57.91 H 6.34 N 11.91

C ₇ H _o .N, 0 _Q. HCI ' ^{d 3} * Calc. % C 5.8,04 H 6 ^ 30 .....- N11 _r 94. ....

Analogous compounds were obtained

N- (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3-dihydro-3ethyl-2-oxo-1H-benzimidazole-1-carboxamide (Compound 45)

Hydrochloride, m.p. 242-244 ° C.

Analysis

- · i ^C 18 ^H 24 ^N 4 ° 2 * ^HC1 Ugpt% l C 58.35 H 7.06 N 15.01 Calc .:% C 59.25 H 6.91 N 15.36

N- (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3 "dihydro-3-propyl-2-oxo-1H-benzimidazole-1-carboxamide (Compound 46)

Hydrochloride, m.p. 116 to 119 ° C

Analysis ^c 19 ^H 26 ^N 4 ° 2 · ^HCl C 59.54 H 7.23 N 14.44

Calcd.% C 60.23 H 7.18 N 14.79

- 24 N- (Endo-8-methyl-8-azabicyclo / 3.2.1 / οη ^ -ίΡ ^^ - άΙΚΙάΓΟ-βΖ 1- (methyl) -e ti1 / -2-oxo-1H-benzimidazole-1-carboxam ! d (Compound 47)

Hydrochloride, m.p. 117 to 120 ° C

Analysis ^C 19 ^H 26 ^N 4 ° 2 * ^HC1 Found% C 58.97 H 7.34 N 14.23 Calcd.% C 60.23 H 7.18 N 14.79 (Endo-8-methyl-8- 3- [1- (Methyl) propyl] -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid azabicyclo [3.2.1] oct-3-yl) ester (Compound 48)

Hydrochloride, m.p. ~ 90 ° C (lyophilized).

Analysis ^{C 2 O H} 27 ^N 3 ° 3 ' ^HC1 Found% C 60.03 H 7.03 N 10.41

Calcd.% C 60.98 H 7.16 N 10.67

N- (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3-dihydro3- / 2- (methyl) propyl / -2-oxo-1H-benzimidazole-1-carboxamide (Compound 49)

Hydrochloride, m.p. 169 to 170 ° C

Analysis ^C 20 ^H 28 ^N 4 ° 2 ' ^HCl

Found C 60.83 H 7.37 N 14.36 Calc. C 61.14 H 7.44 N 14.26

N- (endo-8-methyl-8-azabicyclo / 3.2,1 / oct-3-11) -2,3-dichloro-3-hexyl-2-oxo-1H-benzylindazole-1-carboxamide

(Compound 50)

Hydrochloride, m.p. 214 to 215 ° C

Analysis ^C 22 ^H 32 ^N 4 ° 2 ' ^{HC1 in} S ^ot · * ^{c 62} » ^{64 H 8} » °° ^N 13,23

Calcd.% C 62.77 H 7.90 N 13.31

N- (endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-H) -2,3-dihydro-

3-ethyl-2-oxo-1H-benzimidazole -1-carboxamide (Compound 51) Hydrochloride, m.p. 259 to 260 ° C Analysis ^C 19 ^H 26 ^N 4 ° 2 * ^HC1 Found% C, 60.26 H, 7.20 N 14,78 Calc.% c 60.23 H, 7.18 N 14,79

3-Ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (Endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-yl) ester (Compound 52)

Hydrochloride, m.p. 239 to 240 ° C

Analysis

% Found

C 59.99 H 6.97 N 11.04 C 60.07 H 6.90 N 11.06 ^C , 9 ^H 25 ^N 3 ° 3 · ^HC1

Calculate% (Endo-, 9-methyl-9-azabicyclo / 3.3.1 / non-3-yl) 3-methyl2,3-dihydro-2-oxo-1H-benzylindazole-1-carboxylic acid ester (Compound 53)

Hydrochloride, m.p. 229 to 230 ° C

Analysis ^C 18 ^H 23 ^N 3 ° 3 * ^{HC1 in} S ^ot · * ^c 58.33 H 6.68 N 11.03

Calcd.% C 59.09 H 6.61 N 11.49 3-Butyl-2,3-dihydro-2-oxo-endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-yl ester 1H-Benzimidazole-1-carboxylic acid (Compound 54)

Hydrochloride, m.p. 167 to 168 ° C Analysis ^C 21 ^H 29 ^N 3 ° 3 · ^{HC1 U} « ^ot · * ^C 61.26 H 7.52 N 9.93 Calc.% C 61.83 H 7.41 N 10.30

N- (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3-dihydro3- (2-propyl-1-yl) -2-ok30-1H-benzimidazol-1- carboxamide (Compound 56)

Hydrochloride, m.p. 256 to 257 ° C

Analysis ^C 19 ^H 22 ^N 4 ° 2 * ^HC1 C 60.86 H 6.36 N 14.97

Calcd.% C 60.88 H 6.18 N 14.95

- 27 N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,3-dihydro-3- [3- (methyl) -but-2-en-1-yl] - 2-Oxo-1H-benzimidazole-1carboxamide (Compound 57)

Hydrochloride, m.p. 196 to 198 ° C

Analysis ^C 21 ^H 28 ^N 4 ° 2 ' ^{HC1 U} « ^ot · * ^{C 61} ' ^{53 H 7 '32 N 13} ' ⁸¹ Calc.% C 62.29 H 7.22 N 13.84

N- (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3-dihydro-3-cyclopropylmethyl-2-oxo-1H-benzimidazole-1-carboxamide (Compound 58)

Tal. 103 to 106 ° C

Analysis ^C 20 ^H 26 ^N 4 ° 2 Found% C 67.57 H 7.42 N 15.77

Calcd.% C 67.77 H 7.39 N 15.81 3- (1- (methyl) ethyl) -2- (Endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) ester. 3-Dichloro-2-oxo-1H-benzimidazole-1-carboxylic acid (Compound 59)

Hydrochloride, m.p. 179 to 180 ° C

Analysis ^C 19 ^H 25 ^N 3 ° 3 ' ^HC1 Found% ^c 59.30 H 6.95 N 10.94

Calcd.% C 60.07 H 6.90 N 11.06 (3-ethyl-2,3-dihydro-2-oxo 3-ethyl-2,3-dihydro-8-azabicyclo / 3.2.1 / oct-3-yl) ester -1H-Benzimldazole-1-carboxylic acid (Compound 60)

Hydrochloride, m.p. 250 ° C (decomposition)

Analysis ^C 18 ^H 23 ^N 3 ° 3 * ^{HC1 Ueot} · * ^c 58.25 ^H 6.53 N 11.14

Calcd.% C 59.09 H 6.61 N 11.48

EXAMPLE 9 (Compound 25)

A suspension of 3-methyl-2,3-dihydro-1H-benzimidazol-2-one (1.5 g) and trichlororaethyl ethyl chloroformate (2.43 ml) in dry o-dichlorobenzene (150 ml) was stirred overnight at 80 ° C. After cooling to 10 ° C, the reactive intermediate was obtained by filtration. This compound was added at room temperature while stirring to a solution of endo-8-methyl-8-azabicyclo / 3-2.1 / octan3-ol (1.41 g) in dry pyridine (20 ml), and when the addition was complete, the reaction mixture was stirred for 2 h at 80 ° C. After evaporation of the solvent, 0.7 g of the pure title compound was obtained by conventional treatment as the hydrochloride salt.

Tal. > 250 ° C.

MS (C-1): 7T6 m / e / M + H / ⁺

Analysis

Findings. '

C ₁₇ H ₉₁ N-.O _o .HC1 ^{W 3 5} Calc. %

C 57.85 H 6.36 N 11.83 C 58.04 H 6.30 N 11.94

L * ...

EXAMPLE 10

N- (endo-3-roethyl-8-azabicyclo / 3.2.1 / oct-3-yl-2,3-dihydro-2oxo-1H-benzimidazole-1-carboxamide (Compound 26)

2,3-Dihydro-2-oxo-1H-benzimidazole-1-carbonyl chloride (1.5 g) was dissolved in tetrahydrofuran (40 ml) and a solution of endo-8-methyl-8- was added dropwise at room temperature. azabicyclo / 3-2.1 / octane-3-amine dissolved in tetrahydrofuran (5 ml). After the addition was complete, the solid was recovered and the reaction mixture was stirred for 30 minutes, concentrated to dryness and taken up in dilute HCl. The aqueous phase was washed with ethyl acetate, basified with saturated sodium carbonate and extracted again. The last organic layers were concentrated to dryness to give 0.7 g of crude product. Crystallization from acetonitrile gave 0.17 g of pure product.

Tal. 205 to 207 ° C.

301 m / e / M + H / ⁺

1730, 1690

Findings. % C 62.83 H 6.75 N 18.01 Calc. % C 63.98 H 6.71 N 18.65

Similarly, we have prepared:

N- (endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-yl) -2,3-dihydro-2oxo-1H-benzimidazole-1-carboxamide

MS (CI): IR (cm “ ¹ ): Analysis ^C 16 ^H 2 ^{O N} 4 ° 2 (Compound 27)

Hydrochloride. Tal. 269 to 270 ° C. MS (CI): 315 m / e / M + H./* Analysis ^C 17 ^H 22 ^N 4 ° 2 ' ^HCl

Findings. %

Calc. %

C 58.40 C 58.19

H 6.62 N 15.91 H 6.61 N 15.97

N- (1-Azabicyclo [2.2.2] oct-3-yl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (Compound 28)

Tal. 196 to 198 ° C.

<

MS (CI): 287 'm / e / M + H / ⁺

Analysis

Findings. % C 62.34 H 6.32 N 19.34

C15 ^ 18 ^ 4θ2 ^Ώ Calc. % C 62.92 H 6.34 N 19.57

N- (endo-1-azabicyclo / 3.3.1 / non-4-yl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (Compound 29)

Tal. 245 to 248 ° C.

MS (C.I.): 301 m / e / M + H / *

Analysis

Findings. % C 64.18 H 6.80 N 18.58

C.

Calc. % C 63.98 H 6.71 N 18.65

N- (1-methylpiperidin-4-yl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (Compound 30)

Tal. 194 to 197 ° C.

..... 3Τ - j- ·· * -Λ \

MS (C-I.): 275 m / e / M + H / *

Analysis

Findings. % C 61.18 H 6.80 N 20.34 ^ Ι4 ^ 1β ^ 4θ2

Calc. % C 61.30 H 6.61 N 20.42

N- (endo-9-methyl-9-azabicyclo / 3.3 · 1 / non-3-yl) -3-niethyl-2,3-dihydro-2-ox3Q-1H-benzimidazole-1-carboxamide (Compound 31)

Tal. 175 to 176 ° C.

MS (CI): 329 m / e / M + H / ⁺

Analysis

Findings. % C 65.39 H 7.32 N 16.92

C18 ^ 24 ^ 4θ2 ^cc Calc. % C 65.83 H 7.36 N 17.06

N- (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) -3-methyl-2,3,3-dihydro-2-oxo-1H-benzimidazole-1-carboxaraide (Compound 32)

Hydrochloride. Tal. 269 to 270 ° C. MS (CI): 315 m / e / M + H / ⁺ Analysis

Findings. % ^C 17 ^H 22 ^N 4 ° 2- ^HC1 - *

Calc. %

C 58.14 C 58.19

H 6.49 H 6.61

N, 16.01

N, 15.97

N-methyl-N- (endo-9-methyl-9-azabicyclo / 3.3 · 1 / non-3-yl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide (Compound 33)

Tal. 198 to 200 ° C.

---- *. 32. MS (CI): 329 m / e / M + H / * * Analysis ^C 18 ^H 24 ^N 4 ° 2

Findings. C 65.72 Calcd. % C 65.83

H, 7.53; H, 7.37

N, 16.85; N, 17.06

N- (endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-yl) -N - / (2,4-dimethoxyphenylmethyl) -2,3-dihydro-2-oxo-1H-benzimidazole -1-carboxatnide (Compound 34)

Tal. 100 to 104 ° C.

MS (CI): 465m / e / M + H / ⁺

Analysis

Findings. % C 66.31 H 6.89 N 12.31 ^ 2ό ^ 32 ^ 4θ4 ⁰ Calc. % C 67.20 H 6.95 N 12.07

N- (endo-8-phenylmethyl-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3-dihydro

2-oxo-1H-benzimidazole-1-carboxamide (Compound 35)

Tal. 221 to 224 ° C

Analysis

Findings. % C 70.02 H 6.41 N 14.69 ^ 22 ^ 24 ^ 4θ2 * Calcd. % C 70.19 H 6.43 N 14.88

EXAMPLE 11

N- (endo-9-methyl-9-azabicyclo / 3.3.1 / non-3-yl) -2,3-dihydro-2oxo-1H-benzimidazole-1-carboxamide (Compound 27) '-, - 5 . ·, -. ^Λ '''·"' - · ·· '· ->? O - ·. - -er 'us9.

~ · 1

A solution of N- (endo-9-methyl-9-azabicyclo / 3.3.1 / non-3yl) -N - [(2,4-dimethoxypheoyl) methyl] -2,3-dihydro-2-oxo-1H-benzimidazole- Of 1-carboxaraid (1.0g) and anisole (0.6 g) in trifluoroacetic acid (10 ml) were stirred at room temperature for 12 h. The reaction mixture was then concentrated to dryness and the residual oil was purified by flash chromatography on silica gel: eluent: neretylene chloride-methanol-32% ammonium hydroxide 80: 20: 2. 0.12 g of the title compound are obtained. - ♦ * ci

Tal. 180 to 182 ° C.

H 7.02 N 17.75 H 7.05 N 17.82 precursor was also obtained:

N- (endo-9-methyl-9-azabicyclo / 33.1 / non-3-yl) -3-methyl-2,3,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide

Analysis ^C 17 ^H 22 ^N 4 ° 2 'Findings. % C 64.83

Calc. % C 64.95

Analogous and Derivative (Compound 31)

Tal. 175 to 176 ° C.

Analysis

Findings. % Calc. % ^C 18 ^H 24 ^N 4 ° 2

C 65.12 H 7.38 N 16.94 C 65.83 H 7.36 N 17.06

EXAMPLE 6 6-Acetyl amino-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (Endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) ester (Compound 36 )

3 »/) ••» • «.-, ·;«. »Ι. · <FVj: χι · λ ......

________ ·, ianr:

a) Sodium hypophosphite (2.37 g) was added, while stirring, to a suspension of the hydrochloride (endo-8-methyl-. 8-azabicyclo / 3.2.1 / oct-3-yl) ester of 6-nitro-2,3- dihydro-2-oxp1H-benzimidazole-1-carboxylic acid (2.85 g) and 10% Pd / C (0.28 g) in 80 ml of water. After the addition was complete, the reaction mixture was heated to boiling point for 30 minutes. After cooling, it was filtered, basified with saturated sodium carbonate and extracted with methylene chloride. Organic layer jel · * ¹

After drying over MgSO4 and evaporating the solvent, 0.88 g of crude product was obtained. The addition of alcohol hydrochloric acid gave 0.6 g of dichloride (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) ester of 6-aryano-2,3-dihydro-2-oxo by crystallization. 1H- · Benzimidazole-1-carboxylic acid. Tal. > 260 ° C.

b) Pyridine (1.2 ml) and acetic anhydride (0.14 ml) were added to a solution of (6-amino-2,3) endo-8-methyl-8-azabicyclo / 3.2.1 / oct3-yl ester. -Dihydro-2-oxo-1H-benzimidazole-1 carboxylic acid (0.48 g) in tetrahydrofuran (10 ml). The resulting mixture was stirred at room temperature for 30 minutes, concentrated to dryness and the residue taken up in water. We made it alkaline and the title product slowly crystallized from the mother liquors. Its hydrochloride was then obtained in the usual manner. Yield 0.3 g. Tal. > 260 ° C.

MS (CI): 359 m / e / M + H / ⁺

Analysis

Findings. % ^c , 8 ^h 22n _u o _v hci.

Calc. %

C 54.02 C 54.75

H, 5.88; H, 5.62

N 13.51 N 14.19 · * · '' · - - <! »·> !:. μ ·: 3Λ.-1 ·,

EXAMPLE, 13.?

Metobromide (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-ii) ester

2,3-Dichloro-2-oxo-1H-benzimidazole-1-carboxylic acid (Compound 37)

2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester (endo-8-methyl-8-azabicyclo / 3.2.1 / oct-3-yl) ester (0.5 g) in acetone (60 ml), a mixture of acetone (20 ml) and methyl bromide (2M solution in *, diethyl ether (20 ml) / cooled to 5 ° C was added over 40 minutes. The resulting mixture was left overnight at room temperature. The raw product is

he exposed the angle solid and gained we have it s filtration. After crystallization from ethanol get 0 , 2 g pure ' product. Tal. > 260 ° C. Analysis Findings. % c 51.02 H 5.65 N 10,33 C ₁₇ H ₂₂ BrNgO ₃ Calc. % C, 51.48 H 5.60 N 10.60

EXAMPLE 14 2,3-Dihydro-2-oxo- (Endo-8-azabicyclo / 3.2.1 / oct-3-yl) ester.

1H-benzimidazo-1-carboxylic acid (Compound 38)

Suspension of 2,3-dihydro-2-oxo-1H-benziraidazole-1 carbonyl chloride (1.3 g) and endo-8-azabicyclo / 3.2.1 / octane-3ol hydrochloride (1.0 g) in o-dichlorobenzene (5 ml) was heated at l80 ° C for 1 hour while stirring. The reaction mixture was then allowed to cool and the solvent was removed by filtration. The crude product thus obtained was washed with little ethanol and crystallized from ethanol. 1.1g of desired was obtained.

- 3H - '··. ·. · - '-Ί ?. .

'': -: · i -a, a of the product. Tal. > 260 ° C.

MS (C.I.): 288 ra / e / M + &lt; + &gt; / *

Analysis

Findings. % C 55.15 ^{15 17 3 3} Calc. % C 55.64

H 5.61 N 12.70 H 5.60 N 12.98

EXAMPLE 15 '

N- (endo-8-azabicyclo / 3.2.1 / oct-3-yl) -2,3-dihydro-2-oxo-1H • benzimidazole-1-carboxamide (Compound 39)

Suspension of N- (endo-8-phenylmethyl-8-azabicyclo / 3.2.1t oct-3-yl) -2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide r

(1.0 g) in 1: 1 aqueous ethanol (50 ml) was hydrogenated at room temperature and at a pressure of 9.8 bar in the presence of 10% Pd / C. 0.6 g of the title compound were obtained after normal processing. Hydrochloride. Tal. > 250 ° C.

Analysis ^C 15 ^H 18 ^N 4 ° 2 ' ^HCl

Findings. 'Calc. %

C 55.64 C 55.81

H 5.96 N 17.21 H 5.93 N 17.36

EXAMPLE 16 (Endo-8-cyclopropylmethyl-8-azabicyclo / 3.2.1 / oct-3-yl) ester

2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (Compound 4o)

Anhydrous sodium carbonate (1.0 g) and cyclopropylmethyl bromide (0.3 g) were added to a solution of 2,3-dihydro-2-oxo 2,3-dihydro-2-oxo- (endo-8-azabicyclo / 3.2.1 / oct-3-yl) ester. 1H-benziroidazoltt · * «'*. , ·., ·; «. ·.» Η ·· · ·: ·.? .ujh

Of 1-carboxylic acid (0.5 g) in ethanol (20 ml). The resulting suspension was refluxed for 3 hours and, after cooling, the insoluble product was removed by filtration. The mother liquors were then concentrated to dryness. The residue was taken up in water, basified with sodium carbonate and extracted with ethyl acetate. After drying over MgSO 4, 0.4 g of crude product was obtained. 'We prepared his hydrochloride in the usual way. Yield 0.3 g. * · '

Tal. > 270 ° C.

MS (CI): 342'm / e / M + H / ⁺

Analysis ^C 19 ^H 23 ^N 3 ° 3 ' ^HC1

Findings. % Calc. %

C 59.71 C 60.37

H 6.42 N 11.06 H 6.40 N 11.27

EXAMPLE 17 2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (Endo-8-iminomethyl-8-azabicyclo / 3.2.1 / oct-3-yl) ester (Compound 41)

Ethylformimidate hydrochloride (0.5 g) was added portionwise to a solution of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid (endo-8-azabicyclo / 3.2.1 / oct-3-yl) ester (1.0 g) in ethanol (40 ml). The solution was stirred at room temperature for 1 hour to give the precipitated solid by filtration. Yield 0.4 'g ... Hydrochloride.

Tal. 210 to 212 ° C.

MS (C.I.): 315 m / e / M + H / *

Analysis

C ,, H _lQ N _h O.,. HCl

161843

Findings. % - C 53.96 H 5.51 N 15.62 Calcd. % C 54.78 H 5.46 N 15.97

Analogically, we obtained:

N- (endo-8-iminotoethyl-8-azabicyclo / 3.2.1 / non-3-11) -2,3-dihydro2-oxo-1H-benzytidazole-1-carboxamide (Compound 42)

Hydrochloride (lyophilized). Tal. 65 to 70 ° C.

MS (CI): 314 m / e / M + H / ⁺

Analysis

19 52

Findings. % C 53.86 H 5.84 N 19.87 Calcd. % C 54.34 H 5.76 N 20.02

EXAMPLE 18 2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxyl (Endo-8- (1 '- (methylimino) ethyl) -8-azabicyclo / 3.2.1 / oct-3-yl) ester acids (Compound 43)

Phenyl N-methylacetimidate (0.52 g) was added to a solution of the hydrochloride (endo-8-azabicyclo / 3.2.1 / oct-3-yl) ester of 2,3-dihydro-2-oxo-1H-benzimidazole-1- carboxylic acids (1.0 g) in ethanol (20 ml). The reaction mixture was stirred for 3 hours at 60 ° C. After evaporation of the solvent, the crude product was purified by flash chromatography; eluent: ... n-propanol-water-acetic acid 90:10:10. Yield 0.4 g. Hydrochloride. Freeze-dried. Tal. 68 to 72 ° C.

MS (CI): 343 m / e / M + H / ⁺ '39

- ΜΤί * .7 Λ

Analysis

C, _Q H _nn N „0 _n .HCl

22 4 3

Findings. % C 56.83 H 6.09 N 14.91 Calcd. % C 57.07 H 6.12 N 14.79

EXAMPLE 19 2,3-Dihydro2-oxo-1H-benzimidazole-1-carboxylic acid (Endo-8-amidino-8-azabicyclo / 3.2.1 / oct-3-yl) ester (Compound 44)

Cyanamide (0.26 g) was added while stirring to the suspension of the hydrochloride (endo-8-azabicyclo / 3.2.1 / oct-3-yl) ester

2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid in 0.5 ml of water. The homogenized reaction mixture was heated to 130 ° C and maintained at this temperature for 2 hours while stirring. After cooling, the crude product was purified by flash chromatography on silica gel: eluent: n-propanol-acetic acid-water 90 · 10 · 10. After lyophilization, 0.3 g of pure product was obtained.

Tal. 70 to 75 ° C.

MS (CI): 330 m / e / M + H / ⁺

Analysis

C ,, H, _n N _c O _n .HCl

19 5 ^υ 3

Findings. % C 51.73 H 5.45

N, 19.17

Calc. % C 52.53 H 5.51

N, 19.14

The following are non-limiting examples of pharmaceutical compositions according to the invention:

Claims (1)

PATENT APPLICATION Process for the preparation of novel benzimidazoline 2-oxo-1-carboxylic acid derivatives of the general formula O = CYA in which R represents a hydrogen atom, C1-6alkyl, C1-6alkenyl or C1-6alkynyl, Y is oxygen or NR ^ in which R4 is hydrogen, C1-6alkyl or optionally with one or more C1-6alkoxy substituted benzyl, A is a group selected from R. or R ^ is a group of the formula hydrogen, C ^ _ ₄ alkyl or amino, or C ^ _galkil, characterized by formula (VIII) R wherein p is O, 1; R is O, 1, 2, 3; R ₄ is a hydrogen atom or C _1-4 alkyl; R ₅ is a hydrogen atom, C ^ alkyl, C ^ gcikloalkil, C ₃ _ ₈ cycloalkyl-C ₁ _ _{l |} alkyl, C1-4alkyl substituted with phenyl, C = N - R ?, in which Rg is an atom 6 group and R _{7 is} a hydrogen atom to give the reactive derivative s (Vlil), c = o I X in which A is defined as above and denotes an X leaving group is reacted with a compound of formula (IX) Ζ-Υ-Α (IX) in which Z represents a hydrogen, lithium, sodium or potassium atom and Y and A are defined as above in an aprotic solvent in the presence of an acid acceptor at a temperature of 0 ⁰ to 200 ° C.