HRP950049A2 - Process for the preparation of new benzimidazoline-2oxo-1-carboxylic acid derivatives - Google Patents

Description

The technical field to which the invention belongs

The invention belongs to the pharmaceutical industry and relates to a process for the preparation of new derivatives of benzimidazoline-2-oxo-1-carboxylic acid. The new compounds are 5-HT receptor antagonists and are used as antiemetics and as agents to reduce gastric upset. 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 5-HT receptor antagonists can be successfully used to prevent or treat migraine, intermittent headaches and trigeminal neuralgia. We can use them in the treatment of corresponding CNS disorders, such as anxiety and psychosis. Since 5-HT antagonists have a useful role in gastrointestinal disorders, the next use of these compounds is in the case of gastric emptying, indigestion, flatulence, exophagal reflux, peptic ulcer, hard stools and sensitive bowel syndrome.

Technical problem

There is a constant need to prepare new 5-HT receptor antagonists in a technologically convenient way, which would surpass the known 5-HT receptor antagonists with their pharmacological properties.

State of the art

J.R. Fozard-Trends reports in Pharmacological Sciences 8 44, 1987 about some 5-HT receptor antagonists that have been used in the treatment of nausea and vomiting caused by chemotherapy. The compounds prepared according to the process according to the invention are new and so far neither they nor the processes for their preparation have been described.

Description of the solution to the technical problem with implementation examples

We have now synthesized, and are the subject of the present invention, a new class of structurally diverse compounds that exhibit specific 5-HT receptor blocking activity that can be used in the treatment of nausea and vomiting caused by chemotherapy and radiation and/or gastric emptying obstruction. They can also be beneficial in the treatment of motion sickness, arrhythmia, migraine, intermittent headaches, trigeminal neuralgia, anxiety and psychosis. In addition, we can use them for gastrointestinal disturbances, such as indigestion, flatulence, esophageal reflux, peptic ulcer, hard stool, irritable bowel syndrome, and hypokinesia.

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

[image]

in which R represents a hydrogen atom, C1-6 alkyl, C1-6 alkenyl or C1-6 alkynyl; R1 and R2 can be, but not simultaneously, a hydrogen atom, halogen, trifluoromethyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 acyl, carboxyl, C1-6 alkoxycarbonyl, hydroxy, nitro, amino, which is in a given example N-mono or di-substituted, C1-6 acylamino, C1-6 alkoxycarbonylamino, carbamoyl, which in a given example is N-mono or di-substituted, cyano, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl , which in the given example is N-mono or di-substituted with C1-4 alkyl, with C1-4 alkyl N-mono or di-substituted aminosulfonylamino, aminosulfonylamino; Y is oxygen or N-R3, wherein R3 is hydrogen, C1-6alkyl or in a given example with one or more C1-6 alkoxy substituted benzyl; A group is chosen between

[image]

where p is 0, 1; R is 0, 1, 2, 3; R4 is a hydrogen atom or C1-4 alkyl; R5 is a hydrogen atom, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-4 alkyl, C1-4 alkyl, substituted with phenyl, or R5 is a group of the formula

[image]

where R 6 is a hydrogen atom, C 1-4 alkyl or an amino group and R 7 is a hydrogen atom or C 1-6 alkyl.

For pharmaceutical use, we use compounds with the general formula (I) as such or in the form of tautomers or physiologically acceptable acid addition salts. The term "acid addition salt" includes salts with inorganic or organic acids. Physiologically acceptable acids that we use to form salts include, for example, maleic, citric, tartaric, formic, methanesulfonic, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, benzoic or ascorbic acid.

Physiologically acceptable salts also include quaternary derivatives of compounds of formula (I) obtained by reaction of compounds with compounds of formula R8-Q, where R8 is C1-6alkyl, phenyl-C1-6alkyl or C3-7cycloalkyl-C1-4alkyl and Q is a leaving group, such as halogen , p-toluenesulfonate and mesylate. Favorable R8 groups are methyl, ethyl, n-propyl, i-propyl, cyclopropylmethyl. Physiologically acceptable salts also include internal salts of compounds of formula (I), as N-oxides. The compounds of formula (I) and their physiologically acceptable salts may also exist as physiologically acceptable solvates, such as hydrates, which represent further features of the present invention.

It is understood that the carbonyl group can remain in position 2 of the general formula (I) in its enol form if R is hydrogen, and that tautomers of amidino derivatives of the formula (I) also remain, where R5 is a group of the formula

[image]

where R6 and R7 are the same as previously defined. The present invention therefore includes in its scope these tautomeric forms as compounds and as methods for their preparation.

Some compounds of formula (I) in accordance with the present invention contain chiral or prochiral centers and can exist in different stereoisomeric forms that include enantiomers of type (+) and (-) or their mixtures. The present invention includes in its scope the isomers created in this way as well as their mixtures.

It is understood that we can separate the mixture of optical isomers, if present, according to classical methods for separation, which are based on their different physicochemical properties, for example with fractional crystallization of their acid addition salts with a favorable optically active acid or with chromatographic separation with an exemplary solvent mixture.

In the present invention, expression A of formula (a) means 8-azabicyclo[3.2.1]octane or 9-azabicyclo[3.3.1]nonane attached in position 3 or 7-azabicyclo[2.2.1]heptane attached in position 2, in position 4 linked piperidine; the same one with formula (b) means 1-azabicyclo[2.2.2]octane attached in position 3 or 4; the same one with formula (c) means 1-azabicyclo[3.3.1]nonane attached in position 4 and the same one with formula (d) means 2-azabicyclo[2.2.2]octane attached in position 5.

The term halogen means fluorine, chlorine, bromine, or iodine. It is understood that in the compounds of formula (I) the azabicyclic parts of group A can be endo or exo substituted. Compounds of formula (I) that contain pure endo or exo parts can be prepared by starting from suitable precursors or by separating the endo or exo isomers from the mixture that we have synthesized non-stereospecifically with usual methods, such as chromatography.

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

[image]

where R 1 , R 2 , Y and A are as defined above, with a reactive carbonyl derivative of formula (III)

[image]

where X and X1 are releasing groups, which are the same or different from each other, such as halogen, halogenated alkoxy, alkoxy, heterocycle. Favorable groups are chlorine, trichloromethoxy, methoxy, ethoxy or imidazolyl. 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 from 0° to 100°C, preferably at 5° or at the boiling point of the chosen solvent. In some examples, the presence of an acid acceptor, such as triethylamine, is advantageous.

Compounds of the general formula (II), which we use as starting materials in the above procedure, can be prepared by reducing the compound of the formula (IV)

[image]

where R 1 , R 2 , Y and A are listed above, with hydrogen or with a hydrogen donor such as ammonium formate, cyclohexene, cyclohexadiene, hydrazine. The reduction is preferably carried out with hydrogen in the presence of an exemplary catalyst, preferably 5% or 10% Pd/C or Raney nickel in the presence of an exemplary solvent, such as methanol, ethanol, toluene, water or their mixture. The same reduction can usually be carried out with iron in an acidic medium or in the presence of FeCl3, with Zn in acetic or hydrochloric acid, with SnCl2 in hydrochloric acid or with other reducing agents such as titanium trichloride, iron (II) sulfate, hydrogen sulfide or its salts, sodium hydrosulphite.

Compounds of the general formula (IV) can be prepared by rearranging the compound of the general formula (V)

[image]

where R1 and R2 are as defined above, with a reactive intermediate of general formula (VI)

[image]

where X, Y and A are listed earlier. The reaction is carried out in an aprotic solvent, such as tetrahydrofuran, acetonitrile, chloroform, toluene, chlorobenzene or without a solvent, in the given example in the presence of an acid acceptor, preferably in pyridine at temperatures from 20° to 100°C, preferably at 20° or at 80°C .

Compounds of the general formula (I) in which R1 and R2 are both hydrogen atoms and R, Y and A are listed earlier can usually be obtained by rearranging the compound of formula (VII)

[image]

where 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 temperatures from 0° to 100°C, preferably at room temperature.

Compound (VIII) 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 the general formula (I) in which R1 and R2 are both hydrogen atoms, R, Y and A are listed earlier can also be prepared by rearranging the reactive compound of the general formula (VIII)

[image]

where R and X are as defined above, with a compound of formula (IX)

Z – Y – A (IX)

where Z is a hydrogen atom, the metal is preferably Li, Na or K, Y and A are listed above.

The reaction is carried out in an aprotic solvent, such as tetrahydrofuran, chloroform, acetonitrile, o-dichlorobenzene and in the given example in the presence of an acid acceptor, such as pyridine or triethylamine, preferably pyridine, at a temperature of 0° to 200°C, preferably at 20° or at 160° C.

It is understandable that the compounds of the general formula (I) containing the group R, R1, R2, R3 and R5, which can be translated to other groups R, R1, R2, R3 and R5, are useful as new intermediates. Some of these transformations can be carried out in intermediates for compounds of the general formula (I).

Some examples of such conversions, which of course do not cover all possibilities, are:

1) The nitro group can be converted into an amino group by reduction.

2) The amino group can be converted into a C1-6 acylamino group by acylation with an exemplary carboxylic acid derivative.

3) The amino group can be converted with C1-6 alkyl into an N-mono or di-substituted group by alkylation.

4) The amino group can be converted into a C1-6 alkoxycarbonylamino group by reaction with an exemplary reactive C1-6 alkyl monoester carbonic acid derivative.

5) The carboxyl group can be converted into a C1-6 alkoxycarbonyl group or into a carbonyl group, which in the given example is N-mono or di-substituted with C1-4 alkyl, by reaction with an exemplary reactive carboxylic acid derivative with exemplary alcohols or amines.

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

7) C1-6alkylthio or C1-6alkylsulfinyl group can be converted into C1-6alkylsulfinyl or C1-6 alkylsulfonyl group by oxidation.

8) An aromatic hydrogen group can be converted into a nitro group by nitration.

9) The hydrogen group can be converted into a halogen group by halogenation.

10) The secondary amide group, in the given example conjugated with other carboxamide parts, can be converted into a C1-6N-alkyl tertiary amide group by alkylation.

11) The secondary amino group can be converted into an amidino derivative by reaction with exemplary reactive compounds, such as ethyl formimidate, ethyl acetimidate or cyanamide.

12) A tertiary amino group can be converted into a quaternary ammonium derivative by reaction with a suitable alkylating agent, such as methyl bromide or methyl iodide.

13) The tertiary amide group, which in the given example is conjugated with other carboxamide parts, can be converted into a secondary amide group by removing the benzyl substituted in the given example with C1-6 alkoxy.

These conversions are essentially well known to any expert.

Compounds of the general formula (I), prepared by the process described above, can in the given example be converted with anoganic or organic acids into corresponding physiologically acceptable acid addition salts, e.g. with the usual methods, the compound is rearranged as a base for a solution of the corresponding acid in an exemplary solvent. Particularly preferred acids include, for example, hydrochloric, hydrobromic, sulfuric, acetic, citric and tartaric acids.

Due to their better activity as 5-HT receptor blocking agents, favorable groups of compounds according to the present invention are those that form groups of the general formula (I), where:

-A endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl, R1 and R2 are H, R is H or CH3 and Y is oxygen or the group NH.

-A 1-azabicyclo[2.2.2]oct-3-yl, R 1 and R 2 are H, R is H or CH 3 and Y is oxygen or the group NH.

-A endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl, R1 and R2 are H, R is H or CH3 and Y is oxygen or the group NH.

-A endo-1-azabicyclo[3.3.1]non-4-yl, R1 and R2 are H, R is H or CH3 and Y is oxygen or the group NH.

As we mentioned earlier, the new compounds of formula (I) according to the present invention have interesting pharmacological properties due to their ability to antagonize the physiological effects of 5-HT in warm-blooded animals. 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 obstruction. The following tests show that the compounds according to the present invention have good characteristics in this respect.

PHARMACOLOGY

Bazold-Jarisch reflex in anesthetized rats

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

We induced the Bazold-Jarisch effect with a rapid bolus intravenous injection of 5-HT (20 (g/kg).

We injected increased doses of antagonists 5 min before 5-HT, and we observed their effect on the initial unexpected slowing of the heart and the related drop in blood pressure, which is a consequence of reflex vagal stimulation. In other experiments, we stimulated the right vagus with platinum electrodes at 10 V, 10 Hz, 2 msec, to induce bradycardia (stimulator Grass 248). The ED50 value was calculated by linear regression analysis of the data, expressed as percentage inhibition.

The obtained effect of the two compounds that are the subject of the present invention is shown below:

TABLE

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Longitudinal muscular-myenteric plexus of guinea pig ileum

Male guinea pigs (Dunkin Hartley, 450 to 550 g) were killed with cervical dislocation, a 2 cm segment of the distal ileum, separated about 10 cm from the appendix, was suspended under a tension of 0.5 g in a 10 ml organ bath containing Tyrode's solution (mM : NaCl 137; KCl 2.68; CaCl2 1.82; NaHCO3 5.9; MgCl2 1; NaH2PO4 0.42; glucose 5.6), oxygenated with 95% O2 and 5% CO2 at 37°C. We recorded 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 supramaximal tension. When the contractions stabilized, we constructed cumulative concentration-response curves for the tested compounds by adding increasing concentrations at 5-minute intervals.

We determined the effect of the compounds on the EFS of the induced concentration as a percentage of the size of the contraction, measured before the addition of the compounds.

The compounds that are the subject of the present invention enhanced the contractions caused by electrical stimulation of the guinea pig ileum in the concentration range from 10-10 to 10-8 M, where they had no effect on muscle tone.

In accordance with further features of the present invention, pharmaceutical preparations are available which contain as an active ingredient at least one compound of formula (I) as previously defined, or its physiologically acceptable acid addition salt together with pharmaceutical carriers or excipients. For pharmaceutical administration, compounds of the general formula (I) and their physiologically acceptable acid addition salts can be prepared as usual pharmaceutical preparations either in solid or liquid form. We can offer preparations, for example, in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, capsules, tablets, coated tablets, ampoules, suppositories, and oral drops.

Active ingredients can be incorporated into excipients or carriers that are commonly used in pharmaceutical preparations, such as talc, gum arabic, lactose, gelatin, magnesium stearate, corn starch, aqueous or non-aqueous solvents, polyvinylpyrrolidone, mannitol, semi-synthetic glycerides of fatty acids, sorbitol, propylene glycol, citric acid, sodium citrate.

The preparations are then formulated into dosage units, where each dosage unit is adapted to provide the required dose of the active ingredient. Each dosage unit may suitably contain from 50 mg to 1000 mg, suitably from 100 mg to 500 mg of the above ingredient.

The following examples illustrate novel compounds in accordance with the present invention; these examples should not be considered in any way as limiting the scope of the invention itself.

Example 1

2,3-dihydro-2-oxo-1H-benzimidazole-1-carbonyl chloride

We prepared it by suspending 5 g of 2,3-dihydro-1H-benzimidazol-2-one in 200 ml of distilled tetrahydrofuran and obtaining 13.5 ml of trichloromethyl-chloroformate. The reaction mixture was refluxed for 3 h, until a clear solution was obtained. After cooling, the excreted solid was removed by filtration, and after concentrating the mother solutions to dryness, we obtained 6.5 g of the title compound. Tal. 188 to 190°C (decomposition).

Example 2

Endo-3-[(2,4-dimethoxyphenyl)methyl]amino-9-methyl-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 chloride were added to the solution cooled to 0°C with stirring. After refluxing for 4 hours, the reaction mixture was evaporated to dryness. The residue was taken up in water, made alkaline and extracted with methylene chloride. After evaporation of the solvent, we obtained 2 g of crude oil and after purification by light chromatography on silica gel (eluent: methylene chloride-methanol-32% ammonium hydroxide 97:3:0.3) 0.8 g of endo-3-chloro-9-methyl- 9-azabicyclo[3.3.1]-nonane.

Tal. 177 to 178°C.

b) A solution of endo-3-chloro-9-methyl-azabicyclo[3.3.1]nonane (0.5 g) and 2,4-dimethoxybenzylamine (0.62 g) in absolute ethanol (50 ml) was refluxed for 4 hours. After cooling, the crude product obtained with the evaporated solvent was purified by light chromatography on silica gel (eluent: methylene chloride-methanol-32% ammonium hydroxide 90:10:1). We obtained 0.35 g of oil. Using known methods, we obtained 0.24 g of the title compound as dihydrochloride.

Tal. 173 to 175°C.

Example 3

Endo-3-methylamino-9-methyl-9-azabicyclo[3.3.1]nonane

10 ml of a solution of 33% ethanolic methylamine was added to a solution of 9-methyl-9-azabicyclo[3.3.1]nonan-3-one (1.7 g) in ethanol (30 ml). We left the reaction mixture in a closed container for 4 days, then hydrated it at room temperature and atmospheric pressure in the presence of previously reduced PtO2 (0.2 g) and ammonium acetate (1.0 g). When hydrogen absorption was completed, the catalyst was removed by filtration. The reaction mixture was concentrated to dryness, taken up in water, made alkaline with sodium hydroxide and extracted with ethyl acetate. After drying over MgSO4, the organic phase gave a residue of 1.2 g of the title compound as a yellow oil, which we used as such in the following reaction.

Example 4

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

We obtained the product in accordance with R. F. Borne, J. Med. Chem. 16. 853-856 (1973). In that article, the compound was identified as "cis".

Example 5

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

We obtained the product in accordance with R. F. Borne, J. Med. Chem. 16. 853-856 (1973). In that article, the compound was identified as "trans".

Example 6

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

The product was obtained in accordance with J.R. Phister, J. Pharm. Sci. 74 208 (1985).

Example 7

(Compound 1)

2.3-dihydro-2-oxo-1H-benzimidazol-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 stopped and left for 10 minutes at that temperature. Then the residue was taken up in acidified water and washed with ethyl acetate. We made the aqueous phase very alkaline and re-extracted. We dried the last mentioned extracts and after evaporation of the solvent, the crude title compound remained, which we crystallized from acetonitrile. 0.4 g.

Melting point 190 to 192°C.

Analysis: C16H19N3O3

Found: % C 63.45 H 6.41 N 13.81

Calculated: % C 63.77 H 6.36 N 13.95

Analogously, we got:

(Endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl) 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester

(Compound 19)

Citrate (lyophilized). Melting point 96 to 100°C.

MS (C.I.): 316 m/e [M + H] +

Analysis: C17H221N3O3. C6H8O7

Found: % C 51.36 H 5.91 N 7.74

Calculated: % C 54.43 H 5.76 N 8.28

(Exo-9-methyl-9-azabicyclo[3.3.1]non-3-yl) 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 20)

Citrate. Melting point 77 to 80°C.

MS (C.I.): 316 m/e [M + H] +

Analysis: C17H21N3O3. C6H8O7

Found: % C 51.09 H 5.86 N 7.97

Calculated: % C 54.43 H 5.76 N 8.28

(1-azabicyclo[2.2.2]oct-4-yl) 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 21)

Hydrochloride. Tal. 254 to 256°C.

Analysis: C15H17O3. HCI

Found: % C 54.96 H 5.71 N 12.75

Calculated: % C 55.64 H 5.60 N 12.98

(Endo-7-methyl-7-azabicyclo[2.2.1]hept-2-yl) and 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 22)

Base. Tal. 175 to 178°C.

Analysis: C15H17N3O3

Found: % C 62.56 H 5.96 N 14.69

Calculated: % C 62.71 H 5.96 N 14.63

(Exo-2-methyl-2-azabicyclo2.2.2-oct-5-yl) and 2.3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 23)

Hydrochloride. Tal. 208 to 211°C.

Analysis: C16H19N3O3. HCI

Found: % C 56.88 H 6.12 N 12.25

Calculated: % C 56.89 H 5.97 N 12.43

(Endo-2-methyl-2-azabicyclo[2.2.2]oct-5-yl) 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester

(Compound 24)

Citrate. Tal. 73 to 75°C.

Analysis: C16H19N3O3. C6H8O7

Found: % C 52.96 H 5.64 N 8.39

Calculated: % C 53.55 H 5.52 N 8.52

Example 8

(Endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-methyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 25)

80% sodium hydride (0.04 g) was added in portions to the solution of (endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) ester 2,3-dihydro-2-oxo-1H- of benzimidazole-1-carboxylic acid (0.4 g) in dry DMF (10 ml). After the hydrogen evolution stopped, methyl iodide (0.082 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue was taken up in methylene chloride and washed with water. The organic phase was dried over MgSO4 and concentrated to dryness. Technique. by light chromatography (eluent: methylene chloride/methanol/32% NH4OH 90:10:1) on silica gel we obtained the pure title compound. We converted the oil base into a hydrochloride salt. 0.21 Mr. Tal. > 250°C.

MS (C.I.) 316 m/e [M + H] +

Analysis: C7H21N3O3. HCI

Found: % C 57.91 H 6.34 N 11.91

Calculated: % C 58.04 H 6.30 N 11.94

Analogously, we obtained the following compounds:

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2.3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 45)

Hydrochloride. Tal. 242 to 244°C.

Analysis: C18H24N4O2. HCI

Found: % C 58.35 H 7.06 N 15.01

Calculated: % C 59.25 H 6.91 N 15.36

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)i-2,3-dihydro-3-propyl-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 46)

Hydrochloride. Tal. 116 to 119°C.

Analysis: C19H26N4O2. HCI

Found: % C 59.54 H 7.23 N 14.44

Calculated: % C 60.23 H 7.18 N 14.79

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-[1-(methyl)-ethyl]-2-oxo-1H-benzimidazol-1

-carboxamide

(Compound 47)

Hydrochloride. Tal. 117 to 120°C.

Analysis: Cl9H26N4O2. HCI

Found: % C 58.97 H 7.34 N 14.23

Calculated: % C 60.23 H 7.18 N 14.79

(Endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)ester 3-[1-(methyl)-propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1

-carboxylic acids

(Compound 48)

Hydrochloride. Melting point (90°C (lyophilized).

Analysis: C20H27N3O3. HCI

Found: % C 60.03 H 7.03 N 10.41

Calculated: % C 60.98 H 7.16 N 10.67

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-[2-(methyl)propyl]-2-oxo-1H-benzimidazol-1 -carboxamide

(Compound 49)

Hydrochloride. Tal. 169 to 170°C.

Analysis: C20H28N4O2. HCI

Found: % C 60.83 H 7.37 N 14.36

Calculated: % C 61.14 H 7.44 N 14.26

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2.3-dihydro-3-hexyl-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 50)

Hydrochloride. Tal. 214 to 215°C.

Analysis: C22H32N4O2. HCl

Found: % C 62.64 H 8.00 N 13.23

Calculated: % C 62.77 H 7.90 N 13.31

N-(endo-9-methyl-9-azabicyclo[3.2.1.]non-3-yl)-2.3-dihydro-3-ethyl-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 51)

Hydrochloride. Tal. 259 to 260°C.

Analysis: Cl9H26N4O2. HCI

Found: % C 60.26 H 7.20 N 14.78

Calculated: % C 60.23 H 7.18 N 14.79

(Endo-9-methyl-9-azabicyclo[3.2.1]non-3-yl) 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 52)

Hydrochloride. Tal. 239 to 240°C.

Analysis: C19H25N3O3. HCI

Found: % C 59.99 H 6.97 N 11.04

Calculated: % C 60.07 H 6.90 N 11.06

(Endo-9-methyl-9-azabicyclo[3.2.1] non-3-yl) 3-methyl-2.3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 53)

Hydrochloride. Tal. 229 to 230°C.

Analysis: C18H23N3O3. HCl

Found: % C 58.33 H 6.98 N 11.03

Calculated: % C 59.09 H 6.61 N 11.49

(Endo-9-methyl-9-azabicyclo[3.2.1]non-3-yl) 3-butyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 54)

Hydrochloride. Tal. 167 to 168°C.

Analysis: C21H29N3O3. HCl

Found: % C 61.26 H 7.52 N 9.93

Calculated: % C 61.83 H 7.41 N 10.30

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-(2-propyl-1-yl)-2-oxo-1H-benzimidazol-1- carboxamide

(Compound 56)

Hydrochloride. Tal. 256 to 257°C.

Analysis: C19H22N4O2. HCl

Found: % C 60.86 H 6.36 N 14.97

Calculated: % C 60.88 H 6.18 N 14.95

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-1-carboxamide

(Compound 57)

Hydrochloride. Tal. 196 to 198°C.

Analysis: C21H28N4O2. HCI

Found: % C 61.53 H 7.32 N 13.81

Calculated: % 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: C20H26N4O2

Found: % C 67.57 H 7.42 N 15.77

Calculated: % C 67.77 H 7.39 N 15.81

(Endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) ester 3-[1-(methyl)ethyl]-2.3-dihydro-2-oxo-1H-benzimidazol-1

-carboxylic acids

(Compound 59)

Hydrochloride. Tal. 179 to 180°C.

Analysis: C19H25N3O3. HCl

Found: % C 59.30 H 6.95 N 10.94

Calculated: % C 60.07 H 6.90 N 11.06

(Endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-ethyl-2.3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

acid

(Compound 60)

Hydrochloride. Tal. 250°C (decomposition)

Analysis: C18H23N3O3. HCI

Found: % C 58.25 H 6.53 N 11.14

Calculated: % 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 trichloromethylchloroformate (2.43 ml) in dry o-dichlorobenzene (150 ml) was stirred overnight at 80°C. After cooling to 10°C, we obtained a reactive intermediate by filtration. This compound was added at room temperature with stirring to a solution of endo-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (1.41 g) in dry pyridine (20 ml) and upon completion of the addition, the reaction mixture was stirred 2 hours at 80°C. After evaporation of the solvent, we obtained 0.7 g of the pure title compound as the hydrochloride salt by usual processing.

Tal. > 250°C.

MS (C.I.): 316 m/e [M + H] +

Analysis: C17H21N3O3. HCI

Found: % C 57.85 H 6.36 N 11.83

Calculated: % C 58.04 H 6.30 N 11.94

Example 10

N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-2-oxo-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-azabicyclo[3.2 .1]octan-3-amine dissolved in tetrahydrofuran (5 ml). After the addition was complete, a solid separated out, and the reaction mixture was stirred for 30 minutes, concentrated to dryness and transferred to dilute HCl. The aqueous phase was evaporated with ethyl acetate, made alkaline with unsaturated sodium carbonate and extracted again. the last mentioned organic compounds were concentrated to dryness, to obtain 0.7 g of dry product. After crystallization from acetonitrile, we obtained 0.17 g of pure product.

Tal. 205 to 207°C.

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

IR (cm-1) : 1730, 1690

Analysis: C16H20N4O2

Found: % C 62.83 H 6.75 N 18.01

Calculated: % C 63.98 H 6.71 N 18.65

Using the same procedure, we prepared:

N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2.3-dihydro-2-oxo-1H-benzimidazole-1carboxamide

(Compound 27)

Hydrochloride. Tal. 269 to 270°C.

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

Analysis: C17H22N4O2. HCI

Found: % C 58.40 H 6.62 N 15.91

Calculated: % C 58.19 H 6.61 N 15.97

N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 28)

Tal. 196 to 198°C.

MS (C.I.) : 287 m/e [M + H] +

Analysis: C15H18N4O2

Found: % C 62.34 H 6.32 N 19.34

Calculated: % 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-benzimidazol-1-carboxamide

(Compound 31)

Tal. 175 to 176ºC.

MS (C.I.): 329 m/e [M + H] +

Analysis: C18H24N4O2

Found: % C 65.39 H 7.32 N 16.92

Calculated: % 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-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 32)

Tal. 194 to 197°C.

MS (C.I.): 275 m/e [M + H] +

Analysis: C14H18N4O2

Found: % C 61.18 H 6.80 N 20.34

Calculated: % C 61.30 H 6.61 N 20.42

N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-3-methyl-2.3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 31)

Tal. 175 to 176°C.

MS (C.I.): 329 m/e [M + H] +

Analysis: C18H24N4O2

Found: % C 65.39 H 7.32 N 16.92

Calculated: % 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-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 32)

Hydrochloride. Tal. 269 to 270°C.

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

Analysis: C17H22N4O2. HCl

Found: % C 58.14 H 6.49 N 16.01

Calculated: % C 58.19 H 6.61 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.

MS (C.I.): 329 m/e [M + H] +

Analysis: C18H24N4O2

Found: % C 65.72 H 7.53 N 16.85

Calculated: % C 65.83 H 7.37 N 17.06

N-(endo-9-methyl-9-azabicyclo[3.3.1.]non-3-yl)N-[(2.4-dimethoxyphenyl)methyl]-2.3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 34)

Tal. 100 to 104°C.

MS (C.I.): 465 m/e [M + H] +

Analysis: C26H32N4O4

Found: % C 66.31 H 6.89 N 12.31

Calculated: % 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

(connection 35)

Tal. 221 to 224°C.

Analysis: C22H24N4O2

Found: % C 70.02 H 6.41 N 14.69

Calculated: % C 70.19 H 6.43 N 14.88

Example 11

N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)i-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 27)

Solvent N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-N-(2,4-dimethoxyphenyl)methyl]-2,3-dihydro-2-oxo-1H

-benzimidazole-1-carboxamide (1.0 g) and anisole (0.6 g) in trifluoroacetic acid (10 ml) were stirred at room temperature for 12 hours. The reaction mixture was then concentrated to dryness and the remaining oil was purified by light chromatography on silica gel; eluent: methylene chloride: methanol: 32% ammonium hydroxide 80:20:2. We obtained 0.12 g of the title compound.

Tal. 180 to 182°C.

Analysis: C17H22N4O2

Found: % C 64.83 H 7.02 N 17.75

Calculated: % C 64.95 H 7.05 N 17.82

Analogously, starting from the appropriate starting materials, we also obtained:

N-(endo-methyl-9-azabicyclo[3.3.1]non-3-yl)-methyl-2.3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 31)

Tal. 175 to 176°C.

Analysis: C18H24N4O2

Found: % C 65.12 H 7.38 N 16.94

Calculated: % C 65.83 H 7.36 N 17.06

Example 12

(Endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) 6-acetylamino-2.3-dihydro-2-oxo-1H-benzimidazol-1 ester

-carboxylic acids

(Compound 36)

a) Sodium hypophosphite (2.37 g) was added with stirring in portions to a suspension of hydrochloride (endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) ester 6-nitro-2,3-dihydro-2- of oxo-1H-benzimidazole-1-carboxylic acid (2.85 g) and 10% Pd/C (0.28 g) in 80 ml of water. When the addition was complete, the reaction mixture was heated to boiling for 30 minutes. After cooling, the mixture was filtered, made alkaline with saturated sodium carbonate and extracted with methyl chloride. After drying over MgSO4 and evaporation of the solvent, the organic compound gave 0.88 g of crude product. By adding alcoholic hydrochloric acid, 0.6 g of dichloride (endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) ester 6-amino-2,3-dihydro-2-oxo-1H-benzimidazol- 1-carboxylic acids. Tal. >260°C.

b) Pyridine (1.2 ml) and acetic anhydride (0.14 ml) were added to the solution of (endo-8-methyl-8-azabicyclo[3.2.1])oct-3-yl) ester 6-amino-2,3-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 remainder 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 way. Gain 0.3 g Tal. > 260°C.

MS (C.I.): 359 m/e [M + H] +

Analysis: C18H22N4O4. HCl

Found: % C 54.02 H 5.88 N 13.51

Calculated: % C 54.75 H 5.62 N 14.19

Example 13

2,3-dihydro-2-oxo-1H-benzimidazol-1 methobromide (endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) ester

-carboxylic acids

(Compound 37)

A solution of 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid (endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl) ester (0.5 g) in acetone (60 ml ) was added over 40 minutes to a mixture of acetone (20 ml) and methyl bromide 2 M solution in diethyl ester (20 ml), cooled to 5°C. We left the resulting mixture overnight at room temperature. The crude product precipitated as a solid and was collected by filtration. After crystallization from ethanol, we obtained 0.2 g of pure product. Tal. > 260°C.

Analysis: C17H22BrN3O3

Found: % C 51.02 H 5.65 N 10.33

Calculated: % C 51.48 H 5.60 N 10.60

Example 14

(Endo-8-azabicyclo[3.2.1]oct-3-yl) 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid ester

(Compound 37)

A suspension of 2,3-dihydro-2-oxo-1H-benzimidazol-1-carbonyl chloride (1.3 g) and endo-8-methyl-8-azabicyclo[3.2.1] octan-3-ol hydrochloride (1.0 g) in o -dichlorobenzene (5 ml) was heated with stirring for 1 hour at 180°C. The reaction mixture was then allowed to cool and the solvent was removed by filtration. The thus obtained crude product was washed with a little ethanol and crystallized from ethanol. We obtained 1.1 g of the desired product. Tal. >260°C.

MS (C.I.): 288 m/e [M + H] +

Analysis: C15H17N3O3. HCl

Found: % C 55.15 H 5.61 N 12.70

Calculated: % C 55.64 H 5.60 N 12.98

Example 15

N-(endo-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide

(Compound 39)

Suspension of N-(endo-8-phenylmethyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazol-1

-carboxamide (1.0 g) in 1:1 aqueous ethanol (50 ml) was hydrated at room temperature and a pressure of 9.8 bar in the presence of 10% Pd/C.

After the usual processing, we obtained 0.6 g of the title compound.

Hydrochloride. Tal. >250°C.

Analysis: C15H18N4O2. HCl

Found: % C 55.64 H 5.96 N 17.21

Calculated: % C 55.81 H 5.93 N 17.36

Example 16

(Endo-8-cyclopropylmethyl-8-azabicyclo[3.2.1]oct-3-yl) 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester

(Compound 40)

Anhydrous sodium carbonate (1.0 g) and cyclopropyl-methyl bromide (0.3 g) were added to a solution of (endo-8-azabicyclo[3.2.1]oct-3-yl) ester of 2,3-dihydro-2-oxo-1H-benzimidazole -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. We concentrated the mother alkaline solutions to dryness. The residue was taken up in water, made alkaline with sodium carbonate and extracted with ethyl acetate. After drying over MgSO4, we obtained 0.4 g of crude product. We prepared its hydrochloride in the usual way. Yield 0.3 g.

Tal. > 270°C.

MS (C.I.): 342 m/e [M + H] +

Analysis: C19H23N3O3. HCl

Found: % C 59.71 H 6.42 N 11.06

Calculated: % C 60.37 H 6.40 N 11.27

Example 17

(Endo-8-iminomethyl-8-azabicyclo[3.2.1]oct-3-yl) 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester

(Compound 41)

Ethylformimidate hydrochloride (0.5 g) was added in portions to a solution of 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid (endo-8-azabicyclo[3.2.1]oct-3-yl) ester (0.1 g ) in ethanol (40 ml). The solution was stirred at room temperature for 1 hour, and the thus excreted solid matter was collected by filtration. Yield 0.4 g Hydrochloride.

Tal. 210 to 212°C.

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

Analysis: C16H18N4O3. HCl

Found: % C 53.96 H 5.51 N 15.62

Calculated: % C 54.78 H 5.46 N 15.97

Using an analogous procedure, we obtained:

N-(endo-8-iminomethyl-8-azabicyclo[3.2.1]non-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamide

(Compound 42)

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

MS (C.I.): 314 m/e [M + H] +

Analysis: C16H19N5O3. HCl

Found: % C 53.86 H 5.84 N 19.87

Calculated: % C 54.34 H 5.76 N 20.02

Example 18

(Endo-8-[1'-(methylimino)ethyl]-8-azabicyclo[3.2.1]oct-3-yl) ester 2,3-dihydro-2-oxo-1H-benzimidazol-1

-carboxylic acids

(Compound 43)

Phenyl N-methylacetimidate (0.52 g) was added to a solution of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid hydrochloride (endo-8-azabicyclo[3.2.1]oct-3-yl) ester (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 light chromatography; eluent: n-propanol-water-acetic acid 90:10:10. Yield 0.4 g Hydrochloride. Lyophilized. Tal. 68 to 72°C.

MS (C.I.): 343 m/e [M + H] +

Analysis: C18H22N4O3. HCl

Found: % C 56.83 H 6.09 N 14.91

Calculated: % C 57.07 H 6.12 N 14.79

Example 19

(Endo-8-amidino-8-azabicyclo[3.2.1]oct-3-yl) 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid ester

(Compound 44)

Cyanamide (0.26 g) was added with stirring to a suspension of hydrochloride (endo-8-azabicyclo[3.2.1]oct-3-yl) ester of 2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxylic acid in 0.5 ml water. The homogenized reaction mixture was heated to 130°C and, with stirring, maintained at that temperature for 2 hours. After cooling, the crude product was purified by light chromatography on silica gel; eluent: n-propanol-acetic acid-water 90:10:10. After lyophilization, we obtained 0.3 g of pure product.

Tal. 70 to 75°C.

MS (C.I.): 330 m/e [M + H] +

Analysis: C16Hţ9N5O3. HCI

Found: % C 51.73 H 5.45 N 19.17

Calculated: % C 52.53 H 5.51 N 19.14.

Claims (1)

1. Procedure for the preparation of new benzimidazoline-2-oxo-1-carboxylic acid derivatives of the general formula [image] in which R represents a hydrogen atom, C1-6alkyl, C1-6alkenyl or C1-6alkynyl; Y is oxygen or N-R 3 , wherein R 3 is hydrogen, C 1-6 alkyl or in a given example with one or more C 1-6 alkoxy substituted benzyl; A group is chosen between [image] where p is 0, 1; r is 0, 1, 2, 3; R 4 is a hydrogen atom or C 1-4 alkyl; R5 is a hydrogen atom, C1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkyl, substituted with phenyl, or R5 is a group of the formula [image] where R6 is a hydrogen atom, C1-4alkyl or an amino group and R7 is a hydrogen atom or C1-6alkyl, indicated by the fact that the reactive derivative of formula (VIII) [image] where R is listed earlier and X represents a leaving group, rearrange with the compound of formula (IX) Z-Y-A (IX), where Z is a hydrogen, lithium, sodium or potassium atom, and Y and A are listed above, in an aprotic solvent in the presence of an acid acceptor at temperatures from 0°C to 200°C.