DD297815A5 - IR PRISM SPECTROMETER - Google Patents

Abstract

Pharmacologically active benzanellated N-containing heterocyclic derivatives are described as muscarinic receptor blockers for the treatment of disorders of the gastrointestinal tract and respiratory tract of the following formula wherein R is H or C 1 -C 6 alkyl; R1 and R2 are H, halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkoxycarbonyl, carboxy, hydroxy, nitro, cyano, optionally mono- or disubstituted with C1-C4-alkyl Carbamoyl, optionally mono or di-substituted with C 1 -C 4 alkyl, C 1 -C 6 acylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 acyl; R3 is H, C1-C6 alkyl, aryl, aralkyl, or may be absent; A is CO, CS, SO or B; nitrogen means when R3 is absent and the BD bond is a single bond or carbon; D is CO, CH2CH2 , when the BD bond is a single bond, or D is CR when the DB bond is a double bond wherein R 4 is H, C 1 -C 6 alkyl, aryl, aralkyl, hydroxy, C 1 -C 4 alkoxy, and R 5 H means; X is oxygen, NR means or is absent; Y represents a basic group selected from wherein n is 2 or 3; p is independently 0 or 1; q is 0, 2 or 3; R6 and R7 may be the same or different and are H, C1-C4 alkyl, aralkyl or, when R7 is H or C1-C4 alkyl, {compounds; benzannulation; Heterocycles; Method; manufacture; Drug; Medicine; Pharmacy; muscarinic receptor; Disorders of the gastrointestinal tract; acute or chronic obstructive spasticity of the respiratory tract}

Description

The present invention relates to novel pharmacologically active benzanellated heterocyclic derivatives, to the methods of their preparation and to pharmaceutical compositions containing them. The new compounds are muscarinic receptor blockers and are useful for treating disorders of the gastrointestinal tract and respiratory tract. As is known, administration of muscarinic receptor blockers results in a number of pharmacological effects such as decreased gastrointestinal motility, cessation of acid secretion, bronchodilation, dry mouth, mydriasis, urinary retention, decreased sweating, tachycardia. In addition, antimuscarinic agents with tertiary amine structure can lead to central effects because of their passage through the blood-brain barrier. The lack of selectivity in these effects makes it difficult to prepare a therapy for a particular indication, which gave rise to a chemical modification of these agents. Significant improvement in this direction has been achieved with the discovery of pirenzepine, which can be bound with high affinity to muscarinic receptors (M ₁ -type P) in nervous tissue (brain, ganglia), in the enteral nervous system and in lung tissue; Recently, "irenzepine" has been used therapeutically as an antisecretory agent and as an anticoagulant (R. Hnmer et al., Nature, 1980, 283, 90; NJM Birdsall et al., Scand. J. Gastroentorol., 1980, 15, Suppl., 66, 1). In addition, its use for the treatment of bronchoconstriction has been claimed (Patent Application WO 8608278) The low affinity receptors for pirenzepine (M ₂ type) predominantly, but not exclusively, present in the nerve end organs are further subdivided according to the different ability of selected ones Antagonists for inhibiting the muscarinic reaction in tissue preparations such as guinea pig longitudinal and guinea pig left atrial (RB Barlow et al., British J. Pharmacol., 1986, 89, 837, R. Micheletti et al., J. Pharmacol. Exp. Ther., 1987, SB Burlow et al., British J. Pharmacol., 1976, 58, 6331.) The compound ΛΡ-DX-116 (11- [2- (2-diethylaminomethyl-piperidin-1-yl) -acetyl-5,11-dihydro -6H-pyridoI2,3-b] [1,4) benzodiazep in-6-on) may be considered a prototype of cardioselective compounds, while 4-DAMP (4-diphenylacetoxy-1-methyl-piperidine-methobromide) is the prototype of smooth muscle selective compounds. We have now presented as subject matter of the present invention a novel class of benzanellated N-containing heterocyclic derivatives which exhibit affinity and selectivity towards M _t receptors compared to M ₂ receptors and which, as measured by receptor binding studies, are far superior to pirenzepine.

In addition, these new compounds, unlike pirenzepine are capable of counteracting> jnktionellen Muscarinreaktion in selected smooth muscles active and selective, as shown by in vitro and in vivo experiments. The new compounds can therefore be used for the treatment of gastrointestinal disorders such as peptic ulcer, irritable bowel syndrome, spasticity, cardiospasm, pylorospasm without concomitant effect on the heart rate and without other atropine-like side effects.

The compounds which are the subject of the present invention can also be used for the treatment of obstructive acute and chronic respiratory tract disorders such as bronchoconstriction, chronic bronchitis, emphysema and asthma without atropine-like side effects, especially on the heart.

In addition, they can be used to treat spasms of the urinary and biliary tract and to treat urinary incontinence

 According to the present invention, we introduced compounds of general formula I,

(I)

R is H or C, -C _e alkyl;

R ¹ and R ² is H, halogen, C, _-C6 alkyl, C, -C _s alkoxy, C, -C ₆ alkylthio, C | -C 6 alkoxycarbonyl, carboxy, hydroxy, nitro, & Oy n, optionally Ct -Cj-alkyl mono- or disubstituted carbamoyl, optionally C _l -C ₄ -alkyl mono- or di-substituted amino, C ₁ -C ₆ -acylamino, C ₁ -C ₄ alkoxycarbonylamino, Ct-Cg-Al '-. / Lsulfinyl.Ci- Ce-alkylsulfonyl, C) -C _e -alkyl;

R ³ is H, C, -C _e alkyl, aryl, aralkyl or may be absent;

.0

CO, C = S, S-> O or S

>. means;

Nitrogen means when R ³ is missing and the BD bond is a single bond, or is carbon.

> 4

.R

CO ₁ CH ₂ -CH ₂ , C-

when the B-D bond is a single bond or D is C-R when the

DB bond is a double bond wherein R ^{4 is} H, C ₁ -C ₈ alkyl, aryl, aralkyl, hydroxy, C ₁ -C ₄ alkoxy and R ^{5 is} H; X is oxygen, NR means or is absent;

Y means a basic group chosen from

b)

(Mp ·

c)

wherein η is 2 or 3; ρ is independently 0 or 1; q is 0.2 or 3; R ⁶ and R ^{7 are} independently H, C ₁ -C ₄ alkyl, aralkyl or, when R ^{7 is} H or C ₁ -C ₄ alkyl, R ^e -C = NR where R ^{8 is} H, C C ₄ alkyl or

R ⁸

Amino is.

For pharmaceutical use, the compounds of general formula I can be used as such or in the form of their tautomers; In addition, the invention includes physiologically acceptable acid addition salts of the compounds of formula I and tautomers thereof. The term "acid addition salt" includes salts with both inorganic and organic acids.Physiologically acceptable organic acids useful for salt formation include η, Β, maleic acid, citric acid, tartaric acid, fumaric acid, methanesulfonic acid and benzenesulfonic acid, and suitable inorganic acids are hydrochloric acid , Hydrobromic acid, nitric acid and sulfuric acid.

Physiologically acceptable salts also include quaternary derivatives of compounds of the formula I which are obtained by reacting the above compounds with compounds of the formula R ⁹ -Q, where R ^{9 is} a branched or unbranched Ct-Cg-alkyl or Cj-C ₇ -CyClOalkyl- (CHj) _n , m is 1 or 2 and Q is a leaving group such as halogen, p-toluenesulfonate or methanesulfonate. Preferred groups R ⁹ are methyl, ethyl, isopropyl, 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. All of these forms are components of the invention

The invention further comprises the tautomers of the amidine derivatives of the formula I in which R ^e is a group of the formula -C = NR,

wherein R ⁸ and R are as defined above. The present invention encompasses these tautomeric forms in both the

Compounds as well as in the manufacturing process. Some of the compounds of the formula I according to the invention contain chiral or prochiral centers and can thus be used in

different stereoisomeric forms such as enantiomers of (+) - or (-) - type as well as their mixtures exist. The present invention includes both the individual isomers and their mixtures.

If mixtures of optical isomers are present, they can be separated by classical separation methods, which are based on the

different physical-chemical properties are based, for. B. by fractional crystallization of

Acid addition salts with a suitable optically active acid or by chromatographic separation with a

suitable solvent system. - ··

In the preferred embodiments of the present invention, the term "halogen" generally means fluoro, chloro, bromo

or iodine, and when Y in formula I is of the formula b), Y is a 3- or 4-linked 1-azabicyclo [2.2.2] octane. If Y the

Formula c), Y is piperidin-3-yl or piporidin-4-yl, 8-azabicyclo (3.2.1) oct-3-yl or 9-azabicyclo [3.3.1] non-3-yl. In the compounds of the formula I, the azabicyclo units of the group Y may be endo- or exo-substituted. links

of the formula I containing the pure endo or exo moiety can be represented by the corresponding precursors or by separation of mixtures of the endo or exo isomers which have not been stereospecifically prepared, according to conventional methods, e.g. B. Chromatography.

Preferred compounds according to the present invention include those wherein Y is endo-8-methyl-8-azabicyclo [3.2.1] octane

2-yl and endo-9-methyl-9-azabicyclo [3.2.1] oct-3-yl, B is nitrogen, R is hydrogen, R ³ is absent, the BD bond is one

Is single bond and R ¹ , R ² , D, X are as defined above. Such compounds basically have a good affinity

versus M 'receptor subtypes and ileum receptors.

The compounds of general formula I can be prepared by several alternative methods. As a further part of the invention, we provide a process for the preparation of compounds of the formula I as described above, in which a) a compound of the general formula II

wherein R, R ¹ , R ² , R ³ , A, B, D are as defined above, with a compound of formula I.

Q-C-X-Y (III)

wherein X and Y are as defined above and Q is a leaving group such as halogen, C ₁ -C ₄ alkoxy, Ci-C ₄ alkanoyloxy, C ₁ -C ₄ alkoxycarbonyloxy, preferably chlorine, methoxy, ethoxy is reacted. The compound of the formula II must previously be a reactive compound of the general formula IV

(IV)

wherein M is a metal atom such as lithium, sodium or potassium, with an activating agent such as butyllithium, lithium diisopropylamide (LDA), sodium hydride, sodium amide, potassium hydride, potassium tert-butylate, preferably butyllithium, LDA or sodium hydride at -70 ° C or at room temperature an aprotic solvent such as tetrahydrofuran or dimethylformamide are reacted to a reactive compound, after which the reaction in the same solvent at -70 to 60 ⁰ C, preferably between -5O ⁰ C and room temperature, depending on the chosen solvent occurs, b) If compounds of Formula I, wherein B is carbon and X is oxygen or NR, becomes a compound of formula V

(V)

wherein R, R ¹ , R ² , R ³ , A, D are as defined above and Q is hydroxy or one of the groups defined above, with a compound of formula Vl

H-X-Y (Vl)

where X and Y are as defined above. When Q is halogen, preferably chlorine, the reaction is carried out in an inert aprotic solvent such as tetrahydrofuran, methylene chloride, ethyl acetate, acetonitrile, acetone, benzene, optionally in the presence of an organic or inorganic acid acceptor such as triethylamine, pyridine, 1,8-diazabicyclo [5.4. 0] undec-7-ene (DBU), sodium or potassium carbonate. The reaction can be carried out between -10 ° C and the boiling point of the chosen solvent, preferably at room temperature. In some cases, compounds of formula VI, wherein X is oxygen, may be reacted as reactive derivatives, e.g. B. as salts with alkali metals, preferably lithium or sodium salts. When Q is C ₁ -C ₄ -alkoxy, preferably methoxy or ethoxy, the reaction is generally carried out in an inert solvent such as benzene, toluene, heptane, which are suitable for the azeotropic removal of the alcohol QOH formed, optionally in the presence of a catalyst such as metallic sodium. The reaction temperature is preferably at the boiling point of the selected solvent. When Q is hydroxy, the reaction is generally carried out in an inert aprotic solvent such as tetrahydrofuran, methylene chloride, dimethylformamide in the presence of a condensing agent such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole, optionally in the presence of a catalyst such as pyridine, 4-dimethylaminopyridine or ÜBU performed. Compounds of formula VI wherein X is oxygen can be used as reactive derivatives as defined above. The reaction can in principle be carried out between ⁰ ° C. and 80 ^° C., preferably at room temperature. When Q, C) -C ₄ alkanoyloxy or C 1 -C ₄ alkoxycarbonyloxy, preferably propionyloxy or propoxycarbonyloxy, the reaction can be carried out basically in the same way as when Q is halogen.

c) If compounds of the formula I are to be prepared in which B is nitrogen, R is hydrogen and R ³ is absent, a compound of the general formula VII

(VII)

where / in R ¹ , R ² , D, X and Y are as defined above, with compounds of general formula VIII

Q'-CO-Q ² (VIII)

wherein Q ¹ and Q ² , which may be different or the same, are leaving groups such as halogen, optionally halogenated C 1 -C ₄ alkoxy, imidazolyl, optionally substituted phenoxy, preferably chlorine, ethoxy, phenoxy, trichloromethoxy or imidazolyl. The reaction can, in principle, in an aprotic solvent such as tetrahydrofuran, methylene chloride, in Chlorofoi, acetone, acetonitrile, carried out optionally in the presence of an acid acceptor such as triethylamine, pyridine, sodium or potassium carbonate at 20 to 100 ⁹ C, preferably at room temperature. The same compounds can also be obtained by reacting an intermediate of general formula IX,

(IX)

which is formed in the above reaction and then isolated, wherein R ¹ , X, X, Y, R ² and Q 'are as defined above, in solvents such as ethanol, tetrahydrofuran, dimethylformamide, benzene, toluene in the presence of an organic or inorganic Base such as triethylamine, trimethylamine, DBU, sodium hydroxide, sodium hydride, potassium tert-butoxide, preferably triethylamine or sodium hydroxide, between room temperature and the boiling point of the solvent used, preferably between room temperature and 60 ⁰ C.

The compound of general formula VII used as starting material in the above process can be prepared by reducing a compound of general formula X.

wherein R ', D, X, Y and R ^{2 are} as defined above. The reduction is carried out basically in a solvent such as water, methanol, ethanol, tetrahydrofuran or mixtures thereof in a hydrogen atmosphere in the presence of a suitable catalyst such as palladium or carbon, platinum dioxide, Raney nickel, preferably palladium or platinum at a temperature between 20 and 60 ⁰ C. and a pressure between 1 and 20 atm, preferably at 20 ° C and atmospheric pressure. The compounds of formula X wherein R ', R ² , D, X and Y are as defined above can be prepared by reacting compounds of general formula XI

(XI)

with compounds of general formula XII

Q'-CO-X-Y (XII)

wherein Q ^{1 is} as defined above. The reaction is carried out in an inert or basic solvent such as methylene chloride, tetrahydrofuran, chloroform, pyridine or mixtures thereof at 0 to 8O ⁰ C, preferably between 20 ⁰ C and 50 ⁰ C. In an additional option, the compounds of formula X can be represented by Reaction of a compound of general formula XIII

(XIII)

wherein D is as defined above, with a compound of formula Vl. The reaction is carried out in an inert solvent such as tetrahydrofuran, methylene chloride, chloroform, ethyl acetate, acetonitrile, acetone or a mixture thereof, preferably methylene chloride, at a temperature between 0 and 60 ° C, preferably at 20 ° C.

Compounds of the general formula XIII can be used as such or in situ from the rearrangement of suitable carboxylic acid derivatives of the general formula XIV

-W

wherein D is as defined above and W is CONH ₂ , CONHNH ₂ or CONj. The reaction is carried out by conventional methods similar to the Hofmann · and the Curtis rearrangement.

Compounds of general formula I which contain one group R, R ¹ , R ² , R ⁴ , R ⁵ , R ^e and R ⁷ , from which another group R, R ¹ , R ² , R ⁴ , R ⁶ , R ^e , R ⁷ can be formed are also new useful intermediates. Some examples of such rearrangements that certainly do not exhaustively describe all possibilities are:

1. A halogen atom can be converted to a hydrogen atom by hydrogenolysis.

2. A carbamoyl group can be converted to a cyano group by dehydration.

3. A secondary amide group can be converted to a tertiary amide group by alkylation in the presence of an activator such as sodium hydride.

4. A methylene group can be converted by oxidation into a -CH-OH group.

5. An amino group can be converted to an amidine group by reaction with suitable reagents such as imidic acid ester, cyanamide, N-nitro-S-methylisothiourea, S-methylthiouronium sulfate.

6. A secondary amino group can be converted to a mono-tertiary amino group by alkylation.

7. A benzylamino derivative can be debenzylated by hydrogenation.

These conversions are well known. The compounds of general formula I, which are prepared by the method described above, can be converted, if desired, with organic or inorganic acids into the corresponding physiologically acceptable acid addition salts, for. By conventional methods such as by reacting the compounds as bases with a solution of the corresponding acid in a suitable solvent. Especially preferred acids are, for. Hydrochloric, hydrobromic, citric, tartaric, benzenesulfonic acid.

Especially preferred compounds according to the present invention are:

I ^ .S ^ -Tetrahydro-a-oxo-quinazoline-a-carboxylic acid endo-e-methyl-e-azabicycloia ^ .oiloct-a-ylester (Compound 16). N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1,3,1-tetrahydro-oxo-quinazoline-S-carbamide (Compound 23). 7-Chloro-1,2,3,4-Tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 25). 1,2,3,4-Tetrahydro-6-fluoro-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 26). 1,2,3,4-Tetrahydro-4-hydroxy-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 49). As already mentioned above, the novel compounds of the formula I according to the invention have interesting pharmacological properties due to their ability to act as antagonists of the physiological muscarinic action in warm-blooded animals. Therefore, the novel compounds are therapeutically useful for the prevention or treatment of disorders involving muscarinic receptors, specifically disorders due to excessive acid secretion, altered intestinal motility, and obstructive spasticity of respiratory tract without effect on heart rate. The following tests show that the compounds according to the invention have favorable properties in this respect.

pharmacology

Antimuscarinic enhancement and selectivity

Antimuscarinin activity and selectivity were assessed in vitro by receptor binding studies on two tissues possessing M ₁ and M ₂ muscarinic receptors (cerebral cortex, heart), functional studies on isolated guinea pig ileum and guinea pig left ventricle, and in vivo functional tests on bronchi and heart anesthetized guinea pigs.

Receptor binding studies in vitro

The MpMuscarin effect was determined by assaying the displacement of ³ H-pironzepine from cerebral cortex homogenate according to the following procedure:

The cerebral cortex donors were male CD-COOE'BS rats of 220 to 250g body weight. The homogenization process was carried out in a Potter-Evelhjem apparatus in Gegei.wart Na ⁺ / Mg ⁺⁺ HEPES buffer, pH 7.4 (10OmM NaCl, 1OmM MgCl ₂ , 2OmM HEPES) by filtration of the suspension through two layers of gauze. The binding curves for the investigated compounds are derived indirectly from comparative experiments against 0.5 riM ³ H-pirenzepine for labeling the muscarinic receptors of the cerebral cortex. 1 ml of the homogenate is incubated for 45 min at 30 ° in the presence of a marker ligand and various concentrations of the cold ligand, under which conditions the achievement of equilibrium was determined by appropriate association experiments. The incubation is completed by centrifuging (12000 rpm, 3 min) at room temperature with an Eppendorf microcentrifuge. That formed? Pellet is washed twice with 1.5 ml of brine to remove the free radioactivity and allowed to dry. The tips of the tubes containing the pellet were cut and 200 μΙ tissue solubilizer (Lumasolve, Lumac) was added and allowed to stand overnight. The radioactivity was then counted after addition of 4 ml liquid scintillation mixture (Dimilume / Toluene 1/10 vol., Packard).

The measurements were made three times or four times, and the non-specific binding is defined as the radioactivity bound or trapped in the pellet when the incubation medium contained 1 μM of atropine sulfate. The nonspecific binding was less than 30% on average. The co-values (dissociation constants) were obtained by nonlinear regression analysis based on the single-binding-point model with the TOPFIT pharmacokinetic program package (G.Heinzel "Pharmacokinetics During Drug Development: Data Analysis and Evaluation Techniques", ed. G. Bolzer and JM Van Rossum, page 207, G. Isher, New York, 1982) after correction for the radioligand occupancy shift after the equation K ₀ = IC ₆₀ ZI + »C / * K ₀ , where ♦ C and * K _D denote the concentration and dissociation constants of the particular radioligand used Muscarin M ₂ activity was determined by assaying for the replacement of ³ H-NMS from whole heart homogenate by a method identical to that described for muscarinic M activity.

Functional investigations in vitro

Meerschwelnchen ileum. A 2 xm section of terminal ileum was prepared according to Edinburgh Staff 1974 "Pharmacological Experiments on Isolated Preparations" 2nd ed., Edinburgh: Churchill Livingstone, suspended in Tyrode's solution and contracted with increasing concentrations of bethanechol (concentration range 0 , 3-1 ΟμΜ, EC ₅₀ 1.5 μΜ) The reactions were recorded isotonic The K _b values were calculated according to Arunlakshana and Shild (British Journal of Pharmacology, 14, 48-54, 1959).

Guinea pig left atrium. Tissues were spotted into Ewens solution (NaCl, 131.6 mM, KCl, 5.6 mM, CaCl ₂ , 2.16 mM VI, NaHCO ₃ , 24.9 mM, NaH ₂ PO ₄ , 1.03 mM, glucose, 11 mM, sucrose 13 mM ) at 32 ⁰ C and with square wave pulses via platinum electrodes stimulated (2 msec, 3 Hz, 100% above threshold voltage, delivered by a Grass S48 stimulator). The inotropic activity was recorded isometrically (Statham transducer, Battaglia Rangoni ESOSOO recorder). Increasing concentrations of bethanecol (1-30 μΜ) were used to induce a negative inotropic effect. The Kb values were estimated as described above.

The test results are contained in the following table: Compound receptor binding function

Investigations Kd (nM) Investigations Kb (nM)

Mi (cerebral cortex) M ₂ (heart) ilium heart

16 1 23 1 26 3 25 7 49 2

133 1.5 122 60 0.6 22 400 4.5 250 1470 16.0 2 200 250 1.0 75

In vivar Aktlvitfit on muscarinic receptors in the bronchi and in the heart anesthetized guinea pig Guinea pigs of both sexes (550-60g) were anesthetized with urethane (1.4g, i.p.). A jugular vein became the Inject the medication with a cannula.

2001. E./kg of heparin were i. v. injected. A cannula was inserted into the trachea and the animals using a

Overpressure pump with a speed of 80 strokes / min with oxygen-enriched room air artificially ventilated. On Branch of the trachea cannula was connected to a water manometer of 10cm height. The tidal volume became like that

set that the maximum intratracheal pressure during ventilation exactly a pressure of 10cm water column

errfichte.

Apart from some modifications, the effects of the drugs on bronchial tone were similar to those of Konzett and Rössler (1940) method described. The volume of the respiratory gas mixture produced by bronchoconstriction

(Overflow) passed through the water manometer was measured with a Fleisch-Roh'-pneumotachometer (Model 0000) connected to an SP 2040 D Differential Pressure Transducer (HSE). The recording took place on an IFD

Recording device. Before the experiment, the trachea was briefly clamped to the highest possible for calibration To obtain degree of bronchoconstriction. A cannula was placed in the left common carotid artery and arterial blood pressure was measured with a Bell and Howell

4-3271 pressure transducer connected to an IFD recorder. The heart rate was measured with a heart rate monitor triggered by the arterial pulse wave.

The drugs to be tested were injected via the jugular vein and 5 minutes later the bronchial resistance (in%) and

the drop in heart rate (in beats / min) was measured against acetylcholine (50μς ^ ς i ν and i.a.). Dose-response curves were constructed by plotting the percentage inhibition of bronchoconstriction and bradycardia against the

Logarithm of dosages (mol / kg) of the drug to be tested. The results are given as mean values and

are included in the following table.

In vivo studies (- log ED ₆₀ ) compound bronchi heart

16 8.1 6.0

As a further component of the present invention, pharmaceutical preparations are presented which contain as active ingredient at least one compound of the formula I as defined above or a physiologically tolerable acid addition salt thereof together with one or more pharmaceutical carriers, diluents or vehicles. For pharmaceutical use, the compounds of formula I and their physiologically acceptable acid addition salts

be incorporated into conventional pharmaceutical preparations in solid or liquid form. The preparations may, for. In a form suitable for oral, rectal or perenteral administration. Suitable forms are for. B.

Capsules, tablets, coated tablets, ampoules, suppositories and oral drops.

The active ingredient may be incorporated in vehicles or carriers commonly used in pharmaceutical preparations, such as. Talc, gum arabic, lactose, gelatin, magnesium stearate, corn starch, aqueous or nonaqueous vehicles, polyvinylpyrrolidone, semi-synthetic glycerides of fatty acids, sorbitol, propylene glycol, citric acid, sodium citrate.

The formulations are advantageously formulated in dosage units, each unit of dosage being intended to deliver a single dose of the active ingredient. Each dosage unit may conveniently contain between 0.01 mg and 100 mg, preferably between 0.05 mg and 50 mg.

The following examples illustrate some of the novel compounds of the invention; these examples are by no means limitative of the scope of the invention itself.

example 1

2 (4-chloro-2-nitro-benzyl) malonate

3.5 ml of diethyl malonate are added dropwise in a suspension of 0.69q 8Ü% sodium hydride in oil in 10 ml of tetrahydrofuran at room temperature with stirring. Then 1 h is continued and then added a solution of 2.9 g of 4-chloro-2-nitrobenzyl bromide in 10 ml of tetrahydrofuran. The reaction mixture is stirred for a further hour and then added water and ethyl acetate. The organic phase is separated and dried over MgSO ₄ . After evaporation of the solvent, an oil remains, which is distilled to yield 1.5 g of the title compound. Bp 157-16O ⁰ C (0.5 mm Hg). The following intermediates are prepared analogously from the corresponding compounds: 2- (2-nitrobenzyl) -2-phenyl-malonic acid diethyl ester, bp. 180-182 ° C. (0.1 mm Hg). 2-methyl-2-! 2-nitro-benzyl) malonate; bp. 145-146 ⁰ C (0.2 mm Hg).

Example 2

7-chloro-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate

A mixture of 1.8 g of diethyl 2- (4-chloro-2-nitrobenzyl) malonate, 0.9 g of iron powder and 20 ml of acetic acid is stirred at 8O ⁰ C for 3 h. After cooling, the solvent is evaporated in vacuo and the residue taken up in ethyl acetate and Walser. The organic phase is separated and dried over MgSO ₄ . After evaporation of the solvent, 0.95 g of the pure title compound is obtained. F. 182-184 ° C.

Similarly, the following intermediates are shown:

3-Methyl-2-oxo-1 ^, S ^ -tetrahydroquinoline-S-carboxylic acid ethyl ester. F. 110-111 ⁰ C.

2-oxo-3-phenyl-1,2,3,4-tötrahydrochinolin-3-carboxylate. F. 157-158 ⁰ C.

Example 3

2-oxo-4-phenyl-1,2,3,4-tetrahydrochlnolin-3-carbons8ureethylester

80 g of concentrated sulfuric acid are added dropwise to a suspension of 15 g of 2-oxo-4-phenyl-1,2,3,4-tetrahydroquinoline-3-carbonitrile in 70 ml of ethanol and the mixture is refluxed for 1 h. After cooling, the reaction mixture is poured onto ice and the aqueous phase extracted with ethyl acetate. After the usual treatment, 20 g of crude product are obtained.

After purification by flash chromatography (silica gel, eluent methylene chloride / ethyl acetate 85/15), 8.3 g of the title compound are obtained. F. 178-180 ⁰ C.

Example 4

7-chloro-2-oxo-1,2,3,4-tetrahydrochinolln-3-carboxylic acid

1.35 g of ethyl 7-chloro-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate are dissolved in 15 ml of ethanol at room temperature with stirring in a solution of 0.76 g of potassium hydroxide. Soon, a solid separates out, which is filtered off after 2 h. The solid is dissolved in cold water and then hydrochloric acid added until a white precipitate is precipitated. The title compound is filtered off and gives after drying 1.0 g. F. 158-16G ⁰ C

Similarly, the following compounds are shown:

2-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxylic acid. F. 169-170 ⁰ C.

3-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carbonsäure.F.164-165 ° C.

3-ethyl-2-oxo-1 ^, S ^ -tetrahydrc-quinoline-S-carboxylic acid. F. 169-17O ⁰ C.

4-phenyl-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylic acid.

Example 5

A hot solution of 20 g (il-S-methyl ^ -oxo-1,2,3-tetrahydroquinoline-S-carboxylic acid and 12,43 ml L (-) - 1-phenyl-ethylamine in 41% ethanol is allowed to cool to room temperature and left for 48 h The precipitated white precipitate (9 g) is filtered off, mp 173-174 ° C., 3 g of this solid are dissolved in water, cooled to ⁰ ° C. and acidified by filtration to give 0.75 g of the title compound which is free from the other isomer was, as by TLC on Ciiiralplate® (Macherey-Nagel), eluent water / methanol / acetonitrile 50/50/10 detected in comparison with the racemic compound. F. 139-141 ⁰ C.

[a) § ⁶ +37.19 ⁰ C (c 2.0, EtOH).

Example 6

(-L-S-methyl ^ -oxo -. ^ S ^ -tetrahydrochinolin-S-carboxylic acid

Analogously to Example 5, from 26 g of racemic acid, 16.2 g of D (+) - 1-phenyl-ethylamine and 4.51 of ethanol, 9.5 g of a white solid are obtained. F. 175-176 ⁰ C. From 3 g of this compound are obtained 1.4 g of pure title compound. F. 139-141 ⁰ C.

[a) ⁶ g -38.98 ⁰ C (c 2.0, EtOH).

Example 7

phthalimld N- (5-fluoro-2-nltro-benzyl)

A solution of 6.2 g of 5-fluoro-2-nitro-benzyl bromide in 20 ml of dimethylformamide is added dropwise to a stirred suspension of 4.9 g of N-potassium phthalimide in 40 ml of the same solvent. The mixture is heated with stirring for 2 h at 90 ⁰ C, then cooled and diluted with water. By filtration, 7.2 g of the title compound are obtained. F. 198-200 ° C.

Similarly, the following compounds can be represented:

phthalimide N- (5-cyano-2-nitro-benzyl).

N- (5-carbamoyl-2-nitro-benzyl) phthalimid.F.265-267 ⁰ C.

N- (2-methyl-6-nitro-benzyl) phthalimide as a mixture with N- (2-methyl-3-nitro-benzyl) Phtha ^l imide. F. 100-124 ⁰ C.

N- (2-hydroxy-6-nitro-benzy !! phthalimide. F. 243-246 ⁰ C.

N- (4-Flüor-2-nitro-benzyl) phthalimide. F. 176-178 ⁰ C.

Example 8

5-fluoro-2-nitro-benzylamln

1.67 ml of 85% hydrazine hydrate are added to a suspension of 7.1 g of N- (5-fluoro-2-nitro-benzyl) phthalimide in 90 ml of ethanol. The reaction mixture is boiled for 3 hours under reflux, then cooled to 4O ⁰ C. Then hydrochloric acid is added and stirring is continued for 1 h at this temperature. Then the solvent is removed in vacuo. The residue is taken up in water and the settled solid discarded. The mother liquors are treated with 10% sodium hydroxide solution and extracted with diethyl ether. After evaporation of the solvent 3.5 g of the title compound as

get reddish oil.

IR (nujol) ν (cm ^-1 ): 3400.3300, 1620, 1580, 1515.

Analogously, the following compounds can be obtained:

ö-cyano ^ -nitro-benzylamino.

S-carbamoyl ^ -nitro-benzylamine. F. 143-145 ⁰ C.

2-hydroxy-6-nitro-benzylamine hydrochloride. F.254-255 ° C.

2-Methyl-6-nitro-benzylamine in a mixture with 2-methyl-3-nitrobenzylamine, oil.

4-fluoro-2-nitro-benzylamine, oil.

Example 9

N- (2-nitrobenzyl) carbamic acid-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester 13.9 g of 2-nitrobenzylamine and 10.17 g of triethylamine are dissolved in 60 ml of methylene chloride and the formed solution in a suspension of 21.93 g of chloroformic acid-endo-8-methyl-8-azabicyclo [3.2.1loct-3-yl ester hydrochloride in 200 ml of the same solvent was added dropwise with stirring at room temperature. The yellow solution is stirred for 30 minutes, then evaporated to dryness. The residue is taken up in dilute hydrochloric acid, washed with a little ethyl acetate, treated with dilute sodium hydroxide solution and extracted with ethyl acetate. After evaporation of the solvent and recrystallization from ethanol, 26.1 ei of the title compound are obtained. F. 143-145X.

Similarly, the following compounds can be obtained from the corresponding starting materials: N- (5-methyl-2-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester. oil. IR (nujol) ν (cm ^-1 ): 3320, 1710, 1610, 1590, 1520.

N- (5-methoxy-2-nitro ^ enzyl) carbamic acid endo-S-methyl-8-azabicycloI3.2.1] oct-3-yl ester. F.216-218 ° C. N-JS-Chloro ^ -nitro-benzylJcarbamidsäure-endo-e-methyl-e-azabicyclolS ^ .iloct-S-yl ester hydrochloride. F.208-210 ° C. N- (2-nitro-benzyl) -1-methyl-piperidine-4-carboxamide. F. 126-128 ⁰ C

 N- (2-nitro-benzyl) -1-methyl-piperidin-4-acetamide. F.93-95 ° C

N- (2-nitro-benzyl) carbamic acid 1-azabicyclo [2.2.2] oct-3-yl ester. F.112-114 ° C. N- (2-Nitro-benzyl) -carbamic acid endo-8-benzyl-8-azabicyclo [3.2.1) oct-3-yl ester. F., ° 9-91 ° C. N- (2-Nitro-benzyl) -carbamic acid endo-8-ethyl-8-azabicyclo [3.2.1] oct-3-yl ester. F.130-132 ° C. N- (2-Nitrc-benzyl) carbamic acid-endo-9-methyl-o-azabicyclo [3.3.1) non-3-yl ester. Oil. IR (nujol) ν (cm ^-1 ): 3320, 1720-1690, 1610, 1580, 1520.

N- (4-chloro-2-nitro-benzyl) -carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester hydrochloride. F.204 ~ 206 ° C. N-ie-fluoro ^ -nitro-benzyDcarbamidsäure-endo-e-methyl-a-azabicyclc-O ^ .Uoct-S-yl ester. F.115-117 ° C. N- [2- (2-nitrophenyl) ethyl] carbamic acid-endo-8-methyl-8-azabicyclo ^f 3.2.1] oct-3-yl ester hydrochloride. F. 198-201 ⁰ C. N- (2-nitrobenzyl) carbamic acid 1-methylpyrrolidin-3-yl ester

Oil. IR (nujol) ν (cm ^-1 ): 3320, 1710-1690, 1610, 1580, 1520.

N- (5-cyano-2-nitro-benzyl) -carbamic acid-endo-8-methyl-8-azabicyclo (3.2.1loct-3-yl ester, N- (5-carbamoyl-2-nitro-benzyl) -carbamic acid endo 8-methyl-8-azabicycloI3.2.1) oct "3-yl ester, F.185-186 ° C, N- (4-fluoro-2-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2 .1) oct-3-yl ester, F.120-122 ° C, N '- (2-methyl-6-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3 -yl ester hydrochloride in admixture with N- (2-methyl-S-nitrobenzyldicarbamic acid-endo-S-methyl-e-azabicyclo) -siloct-S-yl ester hydrochloride, F.233-235 ^e C. N- ( 2-hydroxy-6-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1 joct-C ester F, 68-7O ⁰ C. N- (4,6-dichloro-2-nitro -benzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1loct-3-ylbJ he ^t. N-ie-chloro ^ -nitro-benzyDcarbamidsäure-endo-e-methyl-e-azabicyclolS ^ .iloct-S N-2- (2-amino-phenyl) ethyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1loct-3-yl ester, 1.134-136 ⁰ C. N- (2-nitrobenzyl) carbamic acid endo-8-cycloprop ylmethyl-8-azabicyclo [3.2.1) oct-3-yl ester. F.93-94 ° C. N- (2-nitro-benzyl) carbamidsäiire-endo-8-isopropyl-8-azabicyclo [3.2.1] oct-3-yl ester. F. 110-1'2 ⁰ C.

Example 10 N- (2-Nltro-benzyl) -N '- (endo-8-inethyl-azabicyclo [3,2.1] oct-3-yl) harn8toff

A solution of 1.0 g of (2-nitrophenyl) acetyl chloride in 3 ml of acetone is added dropwise to a solution of 0.39 g of sodium azide in 5 ml of water with stirring at room temperature. After 3OmIn settles a solid, which is obtained after dilution with water and filtration. This solid is dissolved in 20 ml of chloroform. The solution is dried over MgSO ₄ , filtered and refluxed for 30 min. To this solution are added at 5 ° C 0.55 g of 3a-amino-8-methyl-8-azabicyclo [3.2.1! Octane. After 1 h, the resulting solution is evaporated to dryness and the pure title compound (0.4 g) is obtained after flash chromatography on silica gel (eluent: Mothylon chloride / methanol / 32% ammonium hydroxide 80/20/2). F.191-193 ° C.

Similarly, from 2-nitro-benzyl isocyanate: N- (2-nitro-benzyl) -N '- (endo-8-methyl-8-azabicyclo | 3.2.1) oct-3-yl) urea. F.217-220 ° C.

Example 11 N- (2-Amlno-benzyl) carbamldsSure-endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yl ester

A solution of 26 g of N- (2-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester in 250 ml of ethanol is added at room temperature and atmospheric pressure in the presence of 10% Pd / C (1.3g) hydrogenation, whereby 20.65 g of the title compound are obtained after the usual work-up. F. 130-132 ⁰ C.

Similarly, with the appropriate catalyst, the following compounds are obtained: N- (2-amino-5-methylbenzyl) carbamic acid 8-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester. F. 128-131 ⁰ C. N- (2-amino-5-methoxy-benzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1 LOCT-3-yl ester. F. 115-118 ° C. N- (2-Amino-benzyl) -1-methyl-piperidine-4-carboxamide. F. 128-13O ⁰ C.

N- (2-Amino-benzyl) -1-methyl-piperidin-4-yl-acetamide. Oil. IR (Nujol) ν (cm ^-1 ): 1660.1 "330.1 550. N- (2-Amino-benzyl) carbamic acid 1-azabicyclo [2.2.2] oct-3-yl ester. F.125-128 ° C. N- (2-aminobenzyl) carbamic acid endo-8-benzyl azabicyclo [3.2.1] oct-3-yl ester. F. 129-132 ⁰ C. N- (2-Amino-benzyl) -carbamic acid endo-8-ethyl-8-azabicyclo [3.2.1 LOCT-3-yl ester. Oil. N- (2-Amino-benzyl) -carbamic acid-endo-9-methyl-9-azabicyclo [3.3.1] oct-3-yl ester. F.105-106 ° C. N- | 2- (2-Amino-phenyl) ethyl] carbamic acid endo-8-methyl-8-azabicyclol3.2.1] oct-3-ylestar. F.145-147 ° C. N-te-Amino-benzyDcarbamidsäure-i-methyl-pyrrolidin-S-yl ester. F. 129-131 "C.

N- (2-Amino-5-carbamoyl-benzyl) carbamic acid-endo-8-methyl-8-azabicyclo (3.2.1) oct-3-yl ester, mp74-75 ° C, N- (2-amino-) 6-methyl-benzyl) -carbamic acid-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester in admixture with N- (3-amino-2-methyl-benzyl) -carbamic acid-endo-8-methyl -8-azabicyclo [3.2.1) oct-3-yl ester. F. 72-74 "C. N- (2-Amino-6-hydroxybenzyl) carbamic acid endo-e-methyl-e-azabicycloO.sub.iloct-S-yl ester, m.p. 186-187 ⁰ C. N- (m.p. 2-amino-benzyl) -N '- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) urea F. 176-178 ⁰ C. N- (2-amino-benzyl). -N '- (endo-8-methyl-8-azabicyclo [3.2.ijoct-3-yl) urea hydrochloride. F.239-240 ° C. N- (3-Amino-benzyl) carbamic acid endo-8- cyclopropylmethyl-8-azabicycloI3.2.1) oct-3-yl ester. F. 131-132 ⁰ C. N- (2-amino-benzyl) -carbamic acid endo-8-isopropyl-8-azabicyclo [3.2.1] oct-3 ethyl ester.

Example 12 N- (2-Amlno-5-chloro-benzyl) carbamldsäure-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester

A solution of 2.0 g of N- (5-chloro-2-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester hydrochloride in 40 ml of water is added in the presence of 0 , 87g iron powder and a catalytic amount of FeCl _{3 3} 30min refluxed. The cooled reaction mixture is poured onto ice, treated with 10% sodium hydroxide, extracted with methylene chloride and dried over MgSO ₄ . After evaporation of the solvent, 1.43 g of the title compound are obtained. F. 156-158 ⁰ C. The following compounds are obtained similarly:

N- (2-Amino-4-chloro-benzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1) oct-3-yl ester. F.160-162 ° C. N- (2-Amino-5-fluoro-benzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester. F. 148-15O ⁰ C. N- (2-Amino-5-cyano-benzyl) -carbamic acid-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester. N- (2-amino-4-fluoro-benzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester. F. 145-146 ⁰ C. N- (2-amino-4,6-dichloro-benzyl) carbamic acid endo-8-methyl-8-azabicyclo | 3.2.1] oct-3-yl ester. N- (2-amino-6-chloro-benzyl) carbamic acid endo-8-rhethyl-8-azabicyclo [3.2.1] oct-3-yl ester. F. 165-167 "C.

Example 13

1,2,3,4-Tetrahydro-2-oxo-3-chloro-3-carbonic acid-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-ester (Compound 1)

To a solution of I ^ .S ^ -Tetrahydro ^ -oxo-quinoline-S-carboxylic acid in 6 ml of dry DMF 2.54 g of 1,1'-carbonyldiimidazole are added and the mixture stirred under nitrogen for 10 min at room temperature. To this solution is added a solution of 2.42 g of endo-e-methyl-e-azabicycloISH-octane-S-ol and 0.048 g of sodium hydride in the same solvent (6 ml). After a further 3 h stirring is neutralized with acetic acid. The solvent is evaporated in vacuo, the residue taken up in dilute hydrochloric acid and washed with ethyl acetate. The aqueous phase is then treated with saturated Na ₂ CO ₃ solution and the crude title compound is extracted with methylene chloride. From ethyl acetate, 3.7 g of the pure title compound are obtained as maleate. F. 195-197 ⁰ C

 analysis

C ₁₈ H ₂₂ N ₂ O ₃ -C ₄ H ₄ O ₄ Found .: C 60.28; H, 6.04; N 6.39%

Re: C 61.38; H 6.09; N 6.51%.

Similarly, the following compounds are obtained: N- (2-D, ethylamino-ethyl) -1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carbamide (Compound 2) M.121-122 ° C Analysis

CuH ₂₃ N ₂ O ₃ Found: C66.44; H8.16, N 14.47%

Ber .: C66.41; H8.01; N 14.52%.

! ^, S ^ -tetrahydro ^ -oxol-n-chloro-1-ylcarboxylic acid-1-methyl ester (Compound 3) F.154-156 "C Analysis

Ci ₆ H ₂₀ N ₂ O ₃ Found: C66.71; H7.08; Ν9, Γι%

Calc .: C, 66.64; H 6.99; N 9.72%.

LZ ^. 'I-Tetrahydro ^ -oxo-quinoline-a-carboxylic acid ^ -diethylamino-ethyl ester (Compound 4) F.92-93X Analysis

C ₁₈ H ₂₂ N ₂ O ₃ Found .: C66,25; H7.63; N9,61%

Ber .: C66.18; H7,64; N 9.63%.

7-Chloro-1,2,3,4-tetrahydro-2-oxo-ch: noline-3-carboxylic acid 1-azabicyclo [2.2.2] oct-3-yl ester (Compound 5) Hydrochloride. F.244-246 ° C

C ₁₇ H ₁₉ CIN ₂ O ₃ · HCl Found .: C54,71; H5.37; N7,45%

Re: C 55.08; H 6,42; N 7.54%.

1,2,3,4-Tetrahydro-2-oxo-chinnin-3-carboxylic acid endo-7-methyl-7-azabicyclo [2.2.1] hoptyl ester (Case 6)

Hydrochloride. F. 97-10O ⁰ C (freeze-dried) analysis

C ₁₇ H ₂₀ N ₂ O ₃ .HCl Found: C59.81; H6.29; N8,12%

Re: C 60.26; H 6,28; N 8.32%.

4-Phenyl-1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carboxylic acid-1-azabicyclo [2.2.2] oct-3-yloster (Compound 7) F.2U4-205 ° C

 analysis

C ₂₃ H ₂₄ N ₂ O ₃ Found: C, 73.01; H 6,28; N 7.45%

Ber .: C73.57; H6.18; N7,46%.

Example 14

(Compound 8)

1.5 g of 3-methyl-1 ^, S ^ -tetrahydro ^ -oxo-quinoline-S-carboxylic acid are dissolved in 15 ml of freshly distilled thionyl chloride and 1.5h to 4O ⁰ C erhiut. The halogenating agent is removed by means of benzene in vacuo. The acid chloride thus obtained is dissolved in 30 ml of acetonitrile and, while stirring at room temperature, in a solution of 1.13 g of endo-8-methyl-8-azabicyclo [3.2.1] octan-3-ol and 0.96 g of triethylamine in the same solvent ( 40ml). After stirring overnight, the reaction mixture is evaporated to dryness. The usual preparation provides 0.3 g of the title compound as the base, from which 0.35 g of tartrate are obtained, f. 101-102 "C (after freeze-drying). Analysis

C ₁₉ H ₂₄ N ₂ O ₃ Found: C, 57.03; H 6,34; N 5.75%

Ber .: C57.73; H6.32; N5,86%.

Similarly, the following compounds are obtained:

3-Methyl, 2,3,4-tetrahydro-oxo-3-chloro-3-carboxylate-1-azabicyclo [2.2.2] oct-3-yl ester (Compound 9)

Tartrate. F. = »70 ° C (freeze-dried) analysis

C ₁₈ H ₂₂ N ₂ O ₃ C ₄ H ₆ O ₈ Found .: C55.52; H6.17; N5,81%

Calc .: C, 56.88; H 6.07; N 6.03%.

S-methylmSi-tetrahydro-oxo-chloroline-S-carboxylic acid-i-methyl-p-lipyl-S-yl ester (Compound 10)

Tartrate. F.98-100 ° C (freeze-dried) analysis

C ₁₇ H ₂₂ N ₂ O ₃ -C ₄ H ₆ O ₆ Found: J54.93; H6,15; N6,03%

Re: C 55.74; H 6,24; N 6.19%.

(-l -) - 3 - ^ / lβthyl · 1 _> 2 _> 3,4 · tθtrahydro · 2 · oxo-chlnoline · 3-carboxylic acid · endo-8-mβthyl · 8-azablcyclo [3.2.1] oc → 3 ylθstθr (Compound 11) hydrochloride. F. 228-23O ⁰ C analysis

CjH ₂₄ N ₂ O ₃ -HCI Found: C62.36; H6,95; N7,51%

Calc .: C, 62.54; H, 6.91; N 7.68%. | aa ^s +21.29 ⁰ C Ic = 1.5, EtOH)

(H-3-Methyl-1,2,3,4-tetrahydro-2-oxo-chloroline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 12) Hydrochloride, F. 228-23O ⁰ C analysis

C ₁₉ H ₂₄ N ₂ O ₃ -HCI Found: C62.15; H6,97; N7,55%

Re: C62.54; H6.91; N7,68%. [α) έ ⁶ -22.76 ⁰ C (C = 1.5, EtOH)

1,2-Dlhydro-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-zablcyclo [3.2.1] oct-3-yl ester (Compound 13) Citrate.F.107-110 ° C analysis

Ci ₈ H ₂ ON ₂ O ₃ -C ₆ HgO ₇ Found: C56.83; H5,56; N5,38%

Re: C57.14; H5.59; N5,55%.

3-Ethyl-1,2,3,4-tetrahydro-2-oxo-quinoline-3-carbon ε-endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yl ester (Compound 14 )

Tartrate. F. 57-59 ⁰ C (freeze-dried) Analysis

C ₂₀ H ₂₆ N ₂ O ₃ -C ₄ HeO, Found: C, 57.39; H, 6.51; N 5.59%

Calc .: C, 58.52; H, 6.55; N 5.63%.

3-phenyl-1,2,3,4-tetrahydro-2-oxo-chlnolin-3-carbonsfiure-1-azablcyclo [.? 2.2] oct-3-yl ester (Compound 15) F. 223-224 ⁰ C. Analysis

C ₂₃ H ₂₄ N ₂ O ₃ Found: C, 73.18; H 6.45; N 7.41%

Ber .: C73.38; H 6,43; N 7.44%.

Example 15

1,2,3,4-Tetrahydro-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 16)

A solution of 30.4 ml of N- (2-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo (3.2.1loct-3-yl ester and 12.74 g of triethylamine in 0.5 l of methylene chloride is added dropwise within 2.5 h a cooled (3-6 ⁰ C) solution of 22,86g trichloromethyl chloroformate in the same solvent (240ml) was added. the resulting solution is stirred for another hour at room temperature. Then water is added and the organic phase discarded. the aqueous phase is extracted with treated 10% sodium hydroxide and extracted with methylene chloride. After drying and evaporation of the solvent a crude material which was recrystallized as hydrochloride from ethanol remains. 30,3g. F.> 260 ° C. Free base F. 175-177 ⁰ C. analysis

C ₁₇ H ₂₁ N ₃ O ₃ · HCl Found: C58.28; H6.36; N11,68%

Re: C 58.03; H 6,30; N 11.94%. MS (C.I.) 316m / e [M + Hr

Similarly, the following compounds are obtained:

I ^ .S ^ Tetrahydro-e-methyl ^ -oxo-quinazoline-S-carboxylic acid-endo-S-methyl-e-azabicycloctylsiloct-S-yl ester (Compound 17) Citrate.F.158-160 ° C analysis

C ₈ H ₂₃ N ₃ O ₃ C ₆ H ₈ O ₇ Found .: C54.72; H6,02; N7,90%

Re: C 55.27; H 5.99; N 8.05%.

1,2,3,4-Tetrahydro-6-methoxy-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azablcyclo [3,2,1] oct-3-yl ester (Compound 18) hydrochloride. F.> 260 ° C analysis

C ₁₈ H ₂₃ N ₃ O ₄ · HCl Found .: C56.19; H6,35; N10.90

Found: C, 56.61; H 6,33; N 11.00

6-Chloro-1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yl ester (Compound 19) hydrochloride. F.> 260 ^° C analysis

C ₁₇ H ₂₀ CIN ₃ O ₃ · HCl Found .: C52.88; H5.50; N10,68%

Calc .: C, 52.86; H 5.48; N 10.88%.

S-II-methyl-p-pealyl-1-methyl-carbonyl-di-phenyl-tetrahydro-3-chloro-2-one (Compound 20) hydrochloride. F. 243-245 ⁰ C analysis

C ₁₆ H ₁₉ N ₃ O ₂ -HCI Found: C57.64; H6.51; N 13.57%

Ber .: C58,16; H6,51; N 13.56%.

3- [2- (1-methyl-piperidin-4-yl) acetyl] -1,2,3,4-tetrahydrochlnazolin-2-one (Compound 21) F. 159-161 ⁰ C. Analysis

C ₁₆ H ₂ IN ₃ O ₂ Found: C66.68; H7.39; N 14.64%

Ber .: C66.87; H7.39; N 14.62%.

1,2,3,4-tetrahydro-2-oxo-quinazo! Ln-3-carboxylic acid-1-azabicyclo [2.2.2] oct-3-yl ester (Compound 22) maleate. 15,15-118 ° C analysis

C ₁₆ H ₁₉ N ₃ O ₃ -C ₄ H ₄ O, Found: C57.01; H5.59; N 9.89%

Re: C 57.55; H, 5.55; N 10.07%.

N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carbamate (Compound 23) hydrochloride. F.> 260 ° C analysis

C ₁₇ H ₂₇ N ₄ O ₂ · HCl Found: C57.83; H6.64; N15,81%

Ber .: C58.19; H6.61; 15.97%.

1,2,3,4-Totahydro-2-oxo-quinazoline-3-carboxylic acid endo-9-methyl-9-azabicyclo [3.3.1] non-3-yl ester (Compound 24) hydrochloride, m.p. 220-222 ⁰ C analysis

C ₁₈ H ₂₃ N ₃ O ₃ -HCI Found .: C58,74; H6.65; N11,41%

Calc .: C59.09; H6.61; N 11.49%.

7-Chloro-1,2,3,4-tetrahydro-2-oxo-3-chloroazoline-3-carboxylic acid endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yl ester (Compound 25) hydrochloride. F.> 260 ° C analysis

C ₁₇ H ₂₀ CIN ₃ O ₃ -HCI Found: C51.55; H5.47; N1O, 66%

Re: C52.86; H 5.48; N 10.88%.

1,2,3,4-Tetrahydro-6-fluoro-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 26) hydrochloride. F.> 260 ° C analysis

C ₁₇ H ₂₀ FN ₃ O ₃ -HCI Found .: C54.96; H5.79; N11,24%

Re: C 55.21; H 5.72; N 11.36%.

1,2,3,4-Tetrahydro-4-methyl-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl-ester (Compound 27) hydrochloride. F.> 260 ° C analysis

C ₁₈ H ₂₃ N ₃ O ₃ -HCI Found .: C58.73; H6,65; N 11.38%

Calc .: C59.09; H6,61; N 11.49%.

I ^^ ATetrahydro ^ -oxo-quinazoline-S-carboxylic acid i-methylpyrrolldine-S-yl ester (Compound 28)

Hydrochloride (hygroscopic). F.90-91 ⁰ C analysis

C ₁₄ H ₁₇ N ₃ O ₃ -HCI Found .: C52.90; H6.18; N 13.24%

Re: C53.93; H5,82; N 13.48%.

6-cyano-1,2,3,4-tθ-tetrahydro-2-oxo-3-chloro-3-carbonyl-β-dox-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-styrene (Compound 29)

6-Carbamoyl-1,2,3,4-tetrahydro-2-oxo-quinazoline-3-carboxylic acid ondo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 30) mp 230 -232 ⁰ C analysis

C ₁₈ H ₂₂ N ₄ O ₄ Found .: C59.83; H6,23; N 15.51%

Ben: C60,32; Ηβ, 19; Ν 15.63%.

1,2,3,4-Tetrahydro-7-fluoro-2-oxo-quinazole-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (compound 31) hydrochloride. F.> 260 ° C analysis

C ₁₇ H ₂₀ FN ₃ O ₃ .HCl Found: C54.76; H5,79; N11,29%

Ben: C55.21; H5,72; N11,36%.

1,2,3,4-Tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-benzyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 32) hydrochloride. F. 257-258 ⁰ C analysis

C ₂₃ H ₂₆ N ₃ O ₃ -HCI Found: C64.62; H6.18; N9,71%

Calc .: C, 64.56; H 6,12; N 9.82%.

1,2,3,4-Tetrahydro-2-ovochlorazole-3-carboxylic acid endo-8-cyclopropylmethyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 33) mp 184-186 ° C analysis

C ₂₀ H ₂₅ N ₃ O ₃ Found: C67.46; H7.15; N 11.75%

Ber .: C67.58; H7.09; N 11.82%.

N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1,2,3,4-tetrahydro-2,4-dodecyloquinazole-3-carbamate (Compound 34)

Hydrochloride. F.184-185 ° C (dec.) Analysis

C ₁₇ H ₂₀ N ₄ O ₃ -HCI Found: C55.07; H5.82; N 15.18%

Re: C55.97; H5.80; N 15.36%.

5-Chloro-1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-ezabicyclo [3.2.1] oct-3-yl ester (Compound 35) hydrochloride. F.> 260 ° C analysis

C ₁₇ H ₂₀ CIN ₃ O ₃ -HCI Found: C, 52.67; H5.47; N1O, 83%

Re: C52.86; H5,48; N 10.88%.

1,2,3,4-Tetrahydro-5-methyl-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 36) hydrochloride. F.> 260 ° C analysis

C ₁₈ H ₂₃ N ₃ O ₃ -HCI Found .: C58.53; H6,67; N11,38%

Ber .: C59.09; H6,61; N 11.49%.

5,7-Dichloro-1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carboxylate endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 37)

1,2,3,4-Tetrahydro-5-hydroxy-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 38) Hydrochloride. F.> 260 ° C analysis

C ₁₇ H ₂₁ N ₃ O ₄ -HCI Found: C54.72; H5,97; N10,98%

Re: C 55.51; H 6.03; N 11.42%.

1,2,3,4-Tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-6-isopropyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 39) hydrochloride. F. 265-266 ⁰ C analysis

C ₁₉ H ₂₅ N ₃ O ₃ HCl Found: C59.90; H6.97; N 10.98%

Re: C60.07; H6,90; N 11.06%.

2,3,4,5-Tetrahydro-2-oxc-1H-1,3-benzodiazepine-3-carboxylic acid endo-8-methyl'-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 40) F.144-145 ° C analysis

Ci ₈ H ₂₃ N ₃ O ₃ Found: C 65.33; H7.09; N 12.67%

Ber .: C65.63; H 7.04; N 12.76%.

1,2,3,4-tetrahydro-2-oxo-quinazole-3-carboxylic acid endo-8-ethyl-8-azabicyclo [3.2.1] oct-3-yl ester (compound 41) hydrochloride. F.> 260 ° C analysis

Ci ₈ H ₂₃ N ₃ O ₃ -HCI Found: C58.88; H6,64; N 11.34%

Calc .: C 59.09; H, 6.61; N 11.49%.

Example 16

Tetrahydro-S-fi-methyl-plperldlrM-ylcarbonyl-2-chloronone (Compound 42)

Are 1.76 g 1,2,3,4-tetrahydroquinoline-2-one dissolved in 50 ml dry THF and the solution is cooled to -7O ⁰ C. 10.2 ml of a 2.5N solution of butyllithium in hexane are added dropwise with stirring at this temperature. Then, the reaction mixture is allowed to warm to -15 ⁰ C and left at this temperature for 20min. Thereafter, the reaction mixture is cooled again to -7O ⁰ C and added dropwise a solution of 2 g of 1-methyl-piperidin ^ -carboxylic acid ethyl ester in 5 ml of THF. The reaction mixture is allowed to warm to room temperature and stirred for a further 2 h. The reaction is quenched with water, acidified and washed with ethyl acetate. After treatment with sodium carbonate, the desired compound is extracted with ethyl acetate. The compound (0.34 g) is recrystallized from diisopropyl ether / isopropyl alcohol

 F. 159-161X analysis

C ₁₆ H ₂₀ N ₂ O ₂ Found .: C70.54; H7.40; N 10.26%

Re: C70.56; H7.40; N 10.28%. IR (nujol) ν (cm ^-1 ): 3200, 1705, 1670, 1595

Similarly, the following compound is prepared: I ^ .S ^ -tetrahydro-ad-methyl-plperldin-S-ylcerbonylJchinolin ^ -one (Compound 43) F. 170-172 ⁰ C. Analysis

Ci ₆ H ₂₀ N ₂ O ₂ Found: C 70.46; H 7,46; N 10.26%

Calc .: C70.56; H7.40; N 10.28%. IR (Nujol) (cm ^-1 ): 3200, 1710, 1670, 1595.

Similarly, from Lithlum diisopropylamide (LDA) and chloroamidic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester hydrochloride, the following compound is obtained:

2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-S-carboxylic acid endo-S-methyl-e-azablacylo clo [3.2.1] oct-3-yl ester (Compound 44) citrate .F.105-110 ° C analysis

Ci ₉ H ₂₄ N ₂ O ₃ .C ₆ H ₈ O ₇ Found: C57.14; H6.31; N5,19%

Re: C57.69; H6.20; N5,38%.

Similarly, with sodium hydride in DIViF, the following compounds are obtained: 1,2,3,4-tetrahydro-2,4-dioxo-3-chloroazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3 -y | jster (Compound 45) F. 181-183 ⁰ C Analysis

Ci ₇ H ₁₉ N ₃ O ₄ Found: C61.73; H5.89; N 12.56%

Ber .: C62.04; H5,81; N 12.76%. IR (nujol) ν (cm -3): 1780, 1725, 1680.

1,2,3,4-tetrahydro-2-oxo-chlnazolln-3-carboxylic acid-endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yl ester (Compound 16) F. 175-177 ⁰ C. analysis

C ₇ H ₂₁ N ₃ O ₃ Found: C64.51; H6,73; N 13.21%

Ber .: C64 / 74; H6,71; N 13.33%.

1,2,3,4-tetrahydro-2-oxo-chlnazolin-3-carboxylic acid-1-azablcyclo [2,2.2] oct-3-yl ester (Compound 22) F. 152-154 ⁰ C. Analysis

C ₆ H ₁₉ N ₃ O ₃ Found: C63.61; H6,34; N 13.91%

Re: C63.77; H 6,36; N 13.95%.

Example 17

1,2,3,4-tetrahydro-2-oxo-3-chloroazoline-3-carboxyl endo-8-methyl-8-a2a-bicyclo [3.2.1] oct-3-yl-ester-methobroniide (Compound 46)

A solution of 0.5 g of I ^ ATetrahydro ^ -oxo-quinazoline-S-carboxylic acid in 15 ml of acetone is added dropwise to a mixture of 15 ml of acetone and 15 ml of methyl bromide (2 M solution in diethyl ether) at 0 ° C. The Reaktionsgeiäß is then sealed and allowed to stand at room temperature for 20h. The crude material is obtained by evaporation of the solvent and recrystallized from ethanol. There are obtained 0.3 g of the title compound. F.> 260 ° C analysis

C ₁₈ H ₂₄ BrN ₃ O ₃ Found: C52.44; H5.87; N10,14; Br19,00%

Re: C52.69; H5,89; N10.24; Br19,47%.

Similarly, the following compounds are obtained:

1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carboxylic acid endo-8-isopropyl-8-azabicyclo [3.2.1] oct-3-yl ester methobromide (Compound 47) F. 259-261 ⁰ C analysis

C ₂₀ H ₂₈ BrN ₃ O ₃ Found: C, 54.22; H 6,46; N 9.43%

Calc .: C 54.79; H, 6.44; N 9.59%.

1,2,3,4-Tetrahydro · 2 · oxo · quinazole-3 · carboxylic acid · endo · 8 · cyclo · propylmethyl · 8 · azablcyclo [3.2.1] oct-3 · ylθstθr-mthobromide (Compound 48) F. 169 -172 ⁰ C analysis

C ₂₁ H ₂₈ BrN ₃ O ₃ Found: C, 55.23; H 6,28; N 9.19%

Calc .: C 56.00; H 6,27; N 9.33%.

1,2,3,4-Tetrahydro-2-oxo-quinazole-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-ester cyclopropylmethobromide (Compound 49, F.257-258 ⁰ C analysis

C ₂₁ H ₂₈ BrN ₃ O ₃ Found: C55.48; H6,28; N9,17%

Calc .: C 56.00; H 6,27; N 9.33%.

1,2,3,4-Tetrahydro-2-oxo-ch [nazole-3-carboxylic acid endo-8-ethyl-8-azabicyclo [3.2.1] oct-3-yl ester methobromide (Compound 50) F. 25O -252 ° C analysis

C ₁₉ H ₂₆ BrN ₃ O ₃ Found: C 53.19; H 6,22; N 9.63%

Calc .: C, 53.78; H 6,18; N 9.90%.

1,2,3,4-Tetrahydro-oxo-quinazol-In-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester ethobromide (Compound 51) mp> 260 ° C analysis

C ₁₉ H ₂₆ BrN ₃ O ₃ Found: C, 53.73; H 6,23; N 9.76%

Calc .: C, 53.78; H 6,18; N 9.90%.

1,2,3,4-tetrahydro-2-oxo-3-chloro-3-carboxylic acid ondo-8-benzyl-8-azabicyclo [3.2.1] oct-3-yl ester methobromide (Compound 52) F. 212- 214 ⁰ C analysis

C ₂₄ H ₂₈ BrN ₃ O ₃ Found: C59.01; H5.76; N8,58%

Re: C 59.26; H 5.80; N 8.64%.

Example 18

1,2,3,4-Tetrahydro-1-methyl-2-oxo-quinazole-3-carboxylic acid endo-3-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 53)

0.048 g of an 80% dispersion of sodium hydride in oil are added in portions at room temperature to a solution of 0.5 g of 1,2,3,4-tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8- azabicyclo (3.2.1) octyl-3-yl ester in dry DMF was added, and when the gas evolution ceased, 0.1 ml of methyl iodide was added and the reaction was stirred for 1 hour, after evaporation of the solvent left a residue, which was taken up in water and methylene chloride. from the organic phase the crude product is purified by flash chromatography (silica gel, eluent methylene chloride / methanol / 32% ammonium hydroxide 90/10/2) is cleaned. There are obtained 0.12 g of the title compound. F. 110-112 ⁰ C analysis

C ₁₈ H ₂₃ N ₃ O ₃ Found .: C65.02; H7.06; N 12.49%

Ber .: C65.63; H7.04; N 12.76%.

Example 19

1,2,3,4-Tetrahydro-4-hydroxy-2-oxo-3-chloro-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 54)

A solution of 3.45 g of I ^ .S ^ -Tetrahydro ^ -oxo-quinazoline-S-carboxylic acid endo-e-methyl-e-azabicyclola ^ .octo-S-ylester hydrochloride in 100 ml of water is added by addition of saturated Na ₂ CO ₃ solution brought to pH 7. While maintaining the pH 7 by the gradual addition of 0.1 N sulfuric acid, a solution of 3.1 g of potassium permanganate in 100 ml of water is slowly added to the bottom of the reaction vessel. After addition of 81 ml of the KMnO ₄ solution, the starting material was consumed after the thin layer chromatography.

The reaction mixture is filtered, treated with 10% sodium hydroxide solution and extracted with ethyl acetate. After drying the organic phase remains a residue which is recrystallized from ethyl acetate. There are obtained 1.55 g of the title compound

F. 178-18O ⁰ C analysis

Ci ₇ H ₂₁ N ₃ O ₄ Found: C61.47; H, 6.48; N 12.65%

Re: C61.62; H6.39; N 12.68%.

Similarly, the following compounds are obtained:

1,2,3,4-Tetrahydro-7-fluoro-4-hydroxy-2-oxo-3-chloro-3-carboxylic acid endo-8-azablcyclo [3.2.1] oct-3-yl ester (Compound 55) F. 169 -17O ⁰ C. analysis

C ₁₇ H ₂₀ FN ₃ O ₄ Found: C, 58.03; H 5.81; N 11.84%

Re: C58.45; H5,77; N 12.03%.

N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1,2,3,4-tetrahydro-4-hydroxy-2-oxo-3-chloro-3-carbamide (Compound 56 ) F. 150-152 ⁰ C analysis

C ₁₇ H ₂₂ N ₄ O ₃ Found: C61.45; H6,77; N 16.84%

Re: C61.80; H6,71; N 16.96%.

Example 20

1,2,3-tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-azabicyclo [3.2.1] oct-3-yl ester (compound 57)

A solution of 0.4 g of I ^. S ^ -Tetrahydro ^ -oxo-quinazoline-S-carboxylic acid endo-e-benzyl-ei ^ abicyclotS ^ .IJoct-S-ylesterhydrochlorid in 10 ml of ethanol at room temperature and atmospheric pressure in the presence of Hydrogenated 10% Pd / C (0.04g). The usual preparation yields 0.25 g of the title compound. Hydrochloride. F.> 260 ^° C analysis

C ₁₆ H ₁₉ N ₃ O ₃ -HCI Found: C55.81; H6.04; N 12.24%

Ber .: C56.89; H 5.97; N 12.44%.

Example 21

1,2,3,4-tetrahydro-2-oxo-chlazoline-3-carboxylic acid endo-8-carbamoimidol-8-azabicyclo [3.2.i; oct-3-yl ester (Compound 58)

A mixture of 0.6 g of 1,2,3,4-tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-azabicyclo [3.2.1] oct-3-yl ester hydrochloride, 0.15 g of cyanamide and 0 , 07g water is heated to 130-140 ⁰ C until the liquid M ₁ ; se solid. The cooled reaction mixture is taken up in hot ethanol and the insoluble residue is discarded. The mother liquors are evaporated to dryness and 0.21 g of the title compound are obtained by flash chromatography (eluent butane-1-ol / water / acetic acid 90/5/5).

Hydrochloride. F. 70-75 ⁰ C (freeze-dried). analysis

C ₁₇ H ₂₁ N ₆ O ₃ HCl Found: C53.61; H5,87; N18,33; CI9,21%

Re: C53.75; H5,84; N 18.44; CI9,33%.

Boispiel 22

I ^ SATetrahydro ^ -oxo-quinazoline, 3-carboxylic acid-endo-8-iminomethyl-8-azabicyclo [3.2.1] oct-3-yl-ester (Compound 59)

To a solution of 0.5 g of 1,2,3,4-tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-azabicyclo [3.2.1] oct-3-yl ester in a mixture of 5 ml of methylene chloride and 5 ml of ethanol 0.22 g of formimide acid ethyl ester hydrochloride are added. The reaction mixture is stirred for 2 h at room temperature. Then the solvents are removed. The pure title compound (0.13 g) is obtained by flash chromatography (eluent isopropyl alcohol / water / acetic acid 80/10/10). Hydrochloride. F. 70-73 ⁰ C (freeze-dried). analysis

C ₁₇ H ₂₀ N ₄ O _3. HCI Found: C55.13; H5,91; N 15.07; CI9,51%

Re: C55.97; H5,80; N 15.36; Cl 9.72%.

Example 23

17.3,4-Tetrahydro-2-thioxo-3-chloro-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester (Compound 60)

A solution of 2.0 g of N- (2-nitrobenzyl) carbaric acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester and 1.2 ml of triethylamine in 30 ml of methylene chloride is added dropwise at room temperature Stirring was added to a solution of 0, CmI thiophosgene in 10 ml of the same solvent. After 10 minutes, a solid settles. It is stirred for 1 h, then the solid is filtered off. The solid is suspended in 5 ml of 1,2-dichlorobenzene and heat the suspension to 160-170 ⁰ C 15min. After cooling, the solid is triturated with the same solvent and filtered off. After recrystallization from acetonitrile, 0.28 g of pure title compound is obtained as the hydrochloride

F. 224-.225 ⁰ C (dec.) Analysis

C ₁₇ H ₂₁ N ₃ O ₄ S-HCl Found .: C55,47; H6,05; N11.34; S8,64%

Calc .: C 55.50; H 6.03; N 11.42; S 8.72%.

Example 24

1,4-Dihydro-3-H-2,1,3-benzothladlazine-3-carboxylic acid-endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yl-ester-2,2-dioxld (Compound 62 )

0.23 ml of sulfuryl chloride in 5 ml of dry methylene chloride are added dropwise to a solution of 1.0 g of N- (2-nitrobenzyl) carbamic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester and 0.42 g Triethylamine in the same solvent (15 ml) added with stirring at room temperature. The reaction mixture turns dark and separates some rubbery material. After 30 minutes, stirring is stopped and the organic phase is evaporated to dryness. The residue is taken up in water and the pH of the solution brought to 8.5 by addition of saturated sodium bicarbonate solution. The crude title compound is extracted with ethyl acetate and purified by flash chromatography on silica gel (eluent methylene chloride / methanol / 32% NH ₄ OH 70/30/3). Evaporation of the eluant provides 0.1 g of pure title compound

F. 155-16O ⁰ C analysis

C ₁₆ H ₂₁ N ₃ O ₄ S Found: C54.27; H6.04; N 11.54%

Re: C54.68; H6.02; N 11.96%.

Example 25

endo-3- (1,2,3,4-tetrahydro-2-oxo-quinazolin-3-ylcarbonyloxy) -8-methyl-8-azabicyclo [3.2.1] octane-8-oxide (Compound 65)

A mixture of 2.7 g of 1,2,3,4-tetrahydro-2-oxo-quinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester and 2.5 g 35% hydrogen peroxide in 45 ml of 75% ethanol is stirred for 3 hours at room temperature and then allowed to stand for 2 days. Then, sodium sulfite is added until no more peroxides are present. Thereafter, water is added and the resulting milky solution washed with methylene chloride. The aqueous phase is evaporated to dryness and the title compound is purified by flash chromatography on silica gel (eluent methylene chloride / methanol / 32% NH ₄ OH 80/20/2) and recrystallized from acetone. There are obtained 60mg of pure title compound. F. 136-14O ⁰ C analysis

C ₁₇ H ₂₁ N ₃ O ₄ -SH ₂ O Found: C, 53.11; H 6,98; N 10.90%

Re: C52.98; H7.06; N 10.90%.

The following connections can also be displayed:

1,4-Dihydro-3H-2,1,3-benzothladiazine-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester 2-oxide (Compound 61)

6-Chloro-1,4-dihydro-3H-2,1,3-benzothladlazoline-3-carboxylic acid-endo-8-methyl-8-azablcyclo [3.2.1] oct-3-yloster-2-oxide (Compound 63 )

6-Chloro-1,4-dlhydro-3H-2,1,3-benzothladiazine-3-carboxylic acid endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl-ester-2,2-dodecyl ( Connection 64)

According to the invention, the following nonlimiting examples of pharmaceutical preparations are given.

Example 26 -Wirkstoff 10mg tablets - lactose 207 mg corn starch 30 mg - magnesium stearate 3 mg

Method of preparation: Active substance, lactose and maize starch are mixed and moistened homogeneously with water. After sieving the wet mass and drying in the oven, the mixture is sieved again and the magnesium stearate added. Then the mixture is compressed into tablets of 250 mg each. Each tablet contains 10mg of active ingredient.

Example 27 -Wirkstoff 10mg capsules lactose 188 mg magnesium stearate 2 mg

Method of preparation: The active ingredient is mixed with the excipients and the mixture is passed through a sieve and homogeneously mixed in a suitable device and the mixture is passed through a sieve and homogeneously mixed in a suitable device. The resulting mixture is filled into hard gelatin capsules (200mg per capsule); Each capsule contains 10mg of active substance.

Example 28 ampoules

Active ingredient 2 mg

Sodium chloride 9mg

Method of preparation: Active substance and sodium chloride are dissolved in the required amount of water for injection. The resulting solution is filtered and filled under sterile conditions in ampoules.

Example 29 suppositories

Active ingredient 25 mg

- Semisynthetic fatty acid glycerides 1175 mg

Method of preparation: The semisynthetic fatty acid glycerides are melted and the active ingredient added with homogeneous stirring. After cooling to a suitable temperature, the mass is poured in the form of suppositories of 1200mg each. Each suppository contains 25 mg of active ingredient.

Example 30 5 mg Oral drops 350 mg -Wirkstoff 200 mg sorbitol 1 mg -Propylenglycol 3mg -Citronensäure ad 1 ml -Natriumeitrat - Demineralised water

Method of preparation: Active substance, citric acid and sodium citrate were dissolved in a mixture of the necessary amount of water and propylene glycol. The sorbitol is added and the final solution filtered. The solution contains 1% of active ingredient and is delivered by means of a dropper.

Claims (19)

R ¹ and R ^{2 are} H, halogen, C ₁ -C ₈ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxycarbonyl, carboxy, hydroxy, nitro, cyano, if appropriate with C ₁ -C ₄ -alkyl mono- or disubstituted carbamoyl, optionally substituted by C ₁ -C ₄ -alkyl mono- or disubstituted amino, Cr-Ce-acylamino, Cv GrAlkoxycarbonylamino, Cr-Ce-alkylsulfonyl, Ci-Ce-alkylsulfinyl, C ₁ -C ₆ -alkyl; R ^{3 is} H, C ₁ -C ₆ alkyl, aryl, aralkyl, or may be absent; A is CO, C = S, S- * O or Sv; B represents nitrogen when R ³ is absent and the BD bond is a single bond, or Carbon is. D COjCH ₂ -CH ₂ , C _v c means when the BD bond is a single bond, or D CR is when the DB bond is a double bond wherein R ^{4 is} H, C ₁ -C ₆ alkyl, aryl, aralkyl, Hydroxy, C ₁ -C ₄ -alkoxy and R ^{6 is} H;
X is oxygen or NR is or is absent; Y means a basic group chosen from / R ⁶ b) C) wherein η is 2 or 3; ρ is independently O or 1; q is 0.2 or 3 isl, R ⁶ and R ^{7 are} independently H, C ₁ -C ₄ -alkyl or aralkyl or, when R ^{7 is} H or C ₁ -C ₄ -alkyl, R ⁶ -C = NR, wherein R ^{8 is} H, C ₁ -C ₄ alkyl or amino, and ie all optical isomers, tautomeric forms and mixtures thereof, as well as the acid addition salts, internal salts or quaternary derivatives thereof. 2. Compounds of the general formula I according to claim 1, characterized in that Y is endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl or endo-SJ-methyl-Q-azabicyclodione.Silnon- S-yl, B is nitrogen, R is hydrogen, R ³ is absent, the BD bond is a single bond and R ¹ , R ² , D, X are as defined in claim 1, tautomers thereof and / or acid addition salts of said compounds , 3. Physiologically acceptable acid addition salts of compounds of general formula I according to claim 1 Lind 2. 4. salts according to claim 3 with hydrochloric acid, hydrobromic acid, citric acid, tartaric acid or benzenesulfonic acid. 5. Compound according to formula I, selected from ! ^, S ^ ^ -tetrahydro-oxo-quinazoline-S-carboxylic acid endo-e-methyl-e-azabicycloO ^ .IJoct-S-yl ester N- (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -1,2,3,4-tetrahydro-2-oxo-quinazoline-3-carbamide T-chloro-1 ^. SAtetrahydro ^ -oxo-quinazolin-S-carboxylic acid-endo-e-methyl-e-azabicyclolS ^ .IJoct-3-yl ester I ^ .S ^ -tetrahydro-e-fluoro ^ -oxo-quinazolin-S-carboxylic acid-endo-S-methyl-S-azabicyclotS ^ .iloct-3-yl ester 1,2,3,4-tetrahydro-4-hydroxy-2-oxo-quinazolin-3-carboxylic acid-endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester and physiologically acceptable acid addition salts thereof. 6. A process for the preparation of compounds of the general formula I according to claim 1, characterized in that a compound of the general formula (ID wherein R, R ¹ , R ² , R ³ , A, B and D are as defined in claim 1 which has been previously activated to a reactive derivative of general formula IV Fri. (IV) wherein M is a metal atom selected from lithium, sodium or potassium, is reacted by means of an activating agent with a compound of formula III Q-C-X \ (111) wherein X and Y are as defined in claim 1 and Q is a leaving group in an aprotic solvent between -5O ⁰ C and room temperature. 7. The method according to claim 6, characterized in that the activating agent is granted from butyllithium, lithium diisopropylamide (LDA) or sodium hydride. 8. The method according to claim 6, characterized in that the leaving group of chlorine, methoxy and ethoxy is selected. 9. A process for the preparation of compounds of general formula I according to claim 1, characterized in that, when 3 is carbon and X is oxygen or N-R, a compound of formula V (V) wherein R, R ¹ , R ² , R ³ , A and D are as defined in claim 1 and Q is hydroxy or a group as defined in claim 8, is reacted with a compound of formula VI H-X-Y (Vl) wherein X and Y are as defined in claim 1. A process according to claim 9, characterized in that when Q is hydroxy the reaction is carried out in an inert aprotic solvent and in the presence of a suitable condensing agent and if desired in the presence of a catalyst. 11. The method according to claim 9, characterized in that when Q is chlorine, the reaction is carried out in an inert aprotic solvent, if desired in the presence of an organic or inorganic acid acceptor, at a temperature between -1O ⁰ C and the boiling point of the chosen solvent , A process according to claim 9, characterized in that when Q is methoxy or ethoxy, the reaction is carried out in an inert solvent capable of azeotropically removing the formed alcohol QOH, if desired in the presence of a catalyst. 13. The method according to claim 9, characterized in that the compound of formula VI, when X is oxygen, is reacted between 0 and 80 ⁰ C as a reactive derivative. 14. A process for preparing compounds of general formula I according to claim I, characterized in that when B is nitrogen, R is hydrogen and R ³ is absent, a compound of general formula VII (VII) wherein R ¹ , R ² , D, X and Y are as defined in claim 1, is reacted with a compound of general formula VIII QrX : -Q ₂ (VIII) wherein Q ¹ and Q ² , which may be the same or different, are leaving groups, in an aprotic solvent and if desired in the presence of an acid acceptor, between 20 and 100 ° C. 15. The method according to claim 14, characterized in that the leaving groups are selected from chlorine, ethoxy, Phenox \, trichloromethoxy or imidazolyl. 16. Pharmaceutical compositions containing as active ingredient at least one compound of general formula I as defined in claim 1, or a tautomer or a physiologically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier, diluent or vehicle. 17. Pharmaceutical compositions according to claim 16 for the treatment of patients with disorders of the gastrointestinal tract, in particular with gastric ulcers, irritable bowel syndrome, spastic constipation, cardiospasm, pylorospasm. 18. Pharmaceutical compositions according to claim 16 for the treatment of patients with acute or chronic obstructive spastic disorders of the respiratory tract, in particular bronchoconstriction, chronic bronchitis, emphysema, asthma. 19. Pharmaceutical compositions according to claim 16 for the treatment of patients with spastic disorders of the urinary and biliary tract and for the treatment of urinary incontinence.