SI9300331A - Azabicyclo and azabicycloalkyldien hydroxylamines - Google Patents

Abstract

Pharmacologically active azacyclic and azabicyclic alkyliden hydroxylamines as cholinergic agents, useful in the treatment of neurological and mental diseases of formula (I), wherein A, n, R1 and R2 have the meanings specified in the description, a process for their preparation and pharmaceutical compositions containing them, are disclosed.

Description

Azacyclic and azabicyclic alkylidene hydroxylamines

The present invention relates to a class of pharmacologically active azacyclic and azabicyclic alkylidene hydroxylamines, to a process for their preparation and to pharmaceutical compositions containing them. The new compounds stimulate cortical cholinergic neurotransmission and are therefore useful in the treatment of neurological and mental illnesses whose clinical manifestations result from impaired cholinergic transmission.

Cognitive impairment is characterized by symptoms of forgetfulness, confusion, memory loss and emotional disorders. They can occur as a result of the process of normal aging or in pathological conditions from organic brain disease. The etiology and pathogenesis of these mental illnesses are still unknown. Several neurotransmitter systems (acetylcholine, norepinephrine, dopamine, serotonin, GABA, etc.) are damaged, which are involved in the transmission of messages via synapses from one cell to another in areas of the brain that are related to cognitive function, but the obvious role is central cholinergic system overwhelmingly convincing [Coyle, JJ et al., Science, 219, 1184 (1983); Briley M. et al., Pharmacopsych. 23, 75 (1990)], Diseases attributed to cholinergic deficiency include pre-adolescent and age-related dementia (also known as Alzheimer's disease), Huntington's chorea, tardive dyskinesia, hyperkinesis, mania, and Tourette syndrome. Many of the symptoms of these disorders are associated with the observed decrease in acetylcholine synthesis and the deterioration or loss of cholinergic neurons in specific areas of the brain, such as the cerebral cortex and hippocampus [Davies et al., The Lancet 2,1403 (1976); Perry et al., J. Neurol. Sci. 32, 247 (1977)].

In treating the diseases described above, according to this cholinergic hypothesis, different strategies have been sought to restore acetylcholine levels or mimic the function of the natural transmitter itself [Kuman V. et al., Int. J. Ciin. Pharmacol. 29, 23 (1991)]. They suggested acetylcholinesterase inhibitors, such as physostigmine or tacrine, which increase the available amount of acetylcholine in the synaptic gap by blocking the inactivating enzyme [Drachnan D.A. et al., Arch. Neurol. 37, 674 (1980); Summers W.K. et al., New Engl. J. Med. 315, 1241 (1986)]. Compounds that promote the synthesis or release of acetylcholine from the bubbles in which it is found have also been tested [Etienne P. Treatment of Alzheimer's disease with lecithin in Alzheimer's disease, Reisberg B. Editor, Free Press New York, 1983; Davis H. P. et al., Exp. Aging Res. 9, 211 (1983)]. However, the most direct way to improve the central nervous system functions associated with the cholinergic pathway is to directly stimulate the cholinergic muscarinic receptors themselves. The loss or damage of these receptors may occur in the presence of these diseases, but there is increasing evidence that patients suffering from dementia show different loss of muscarinic receptor sites. The marked decline of presynaptic cholinergic terminals in the cerebral cortex and hippocampus is not accompanied by a significant change or loss of the postsynaptic muscarinic receptor [Quirion R., J. of Neuroch. 1914 (1988); Caulfield M.P. et al., The Lancet, 1277 (1982)].

The use of drugs that activate central muscarinic sites has so far been limited or unrewarding due to adverse circumstances. Most known muscarinic agonists have quaternary ammonium groups (eg carbachol), and therefore it is not expected that they will be able to cross the brain blood barrier after peripheral administration. Arecolin, aceclidin, and RS86, which have a tertiary amine group, can penetrate the brain. However, side effects (miosis, tearing, motility disorders, and cardiac effects) have been observed to result from the activation of peripheral muscarinic receptors; in addition, the first two compounds have a very limited duration of action due to the presence of an easily hydrolyzable ester group [Davidson M. et al., Current Research in Alzheimer Therapy, Giacobini E. and Becker R. Editors; Taylor-Francis, New York 333 (1988)].

Recent discovery of at least five structurally distinct muscarinic receptor subtypes [Bonner JJ et al., Science 237, 527 (1987); Bonner JJ et al., Neurochem. 1, 403 (1988)] and classification into three subtypes (M _p M ₂ and M ₃ ) according to functional tests (Birdsall NN et al. Nomenclature for muscarinic receptor subtypes in Subtypes of Muscarinic Receptors IV; Levine RR Editor, Trends Pharmac (Sci. VII), however, have again aroused interest in the cholinomimetic approach.

Accordingly, the aim of the latest research in the field of holinomimetičnem subtype selective activation of the M ₁ muscarinic receptors which is embedded in the postsynaptic cholinergic neurons, which, as we have already said, are still present in damaged brain areas. The inability to activate the M ₂ and M ₃ subtypes is highly desirable, as they are responsible for the undesirable effects resulting from peripheral cholinergic stimulation. This aspect is particularly important considering that a large number of drugs that penetrate the central nervous system are nevertheless present in the periphery. In addition, the lack of agonist effect on M ₂ subtypes may usefully be accompanied by a weak antagonistic effect on the same receptor subtypes. Acetylcholine release is hypothesized to negatively regulate the endogenous agonist-mediated feedback mechanism that acts as a presynaptic muscarinic receptor of the subtype Thus, the increased amount of acetylcholine released will enhance the beneficial effect resulting from direct stimulation of the M _r receptor

We have now found, and this is the object of the present invention, a new class of compounds which have a good affinity for muscarinic receptors and which are capable of stimulating theistic receptors. An additional advantageous feature of the compounds included in the present invention is their ability to differentially activate the M _p M ₂ and M ₃ muscarinic receptor subtypes by different intrinsic efficacy. As a result, some of the compounds made available here have selective stimulating activity at the Μ _χ receptor sites compared to M ₂ and M ₃ . For other specific compounds, the selective stimulating effect of the subtype Μ _{χ is} even enhanced by the antagonistic effect on the subtype

These new compounds may be useful in treating or preventing disorders that are associated with central cholinergic deficiency. Their use may be particularly beneficial in the treatment of cognitive impairment, such as age-related memory impairment, various forms of dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesis, and Tourette syndrome. In addition, as centrally acting muscarinic agents, the compounds included in the present invention can also be used as analgesics in the treatment of pain.

According to the present invention, compounds of the general formula (I) with ^R 'are made available

A (CH 2) _n “0 - N = (|) in which

A represents a residue of 4- to 8-membered azacycloalkane or 7- to 9-membered azabicycloalkane, which is optionally N-substituted with C ₁₃ alkyl;

n is 0 or 1;

R ₁ and R ₂ independently represent hydrogen; a linear or branched C _w alkyl, which is optionally substituted by alkoxy groups, alkylmercapto, CN or by halogen; _C2 ^ alkenyl; C ₂₆ alkynyl; halogen; aryl optionally substituted by halogen, C ₁₃ alkyl, C ₁₃ alkoxy; C ₆₁₂ aralkyl; heteroaryl; or together with the carbon atom to which they are attached, form a 4- to 7-membered ring; wherein the chain - (CH ₂ ) _n -ON = CR ₁ R _{2 is} attached to carbon atoms other than the nitrogen atom of azacycloalkane or azabicycloalkane.

Non-limiting examples of the azacycloalkane residue A are the 1-azacyclobut-3-yl, 1-azacyclopent-3-yl, 1-azacyclohex-3-yl, 1-azacyclohex-4-yl and 1-azacyclopent3-yl group, as the case may be. N-substituted with C ₁₃ alkyl.

Non-limiting examples of the azabicycloalkane residue A are 1-azabicyclo [2.2.1] -hept-3yl, 1-azabicyclo [2.2.2] -oct-3-yl, 1-azabicyclo [3.2.1] -oct-3-yl, 1-azabicyclo [3.2.1] -oct-6-yl, 1-azabicyclo [3.3.1] -non-3-yl, and

An 8-azabicyclo [3.2.1] oct-3-yl group optionally N-substituted with C ₁₃ alkyl.

If, in the compounds of formula (I), R ₇ and R 2 represent a straight or branched C ₁₆ alkyl group, it may be e.g. methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, 2-methylpentyl and the like. If R _x and R ₂ are alkyl groups containing optionally substituted methoxyethyl, methylthioethyl, ethylthioethyl or cyanoethyl. The term halogen means fluoro, chloro, bromo and iodo. Preferred halogens are fluoro, chloro and bromo, especially fluoro and chloro. If R _x and R ₂ represent a C _{2 6} alkenyl group, it may be e.g. allyl or 3-methylbuten-2-yl. If R ₁ and R ₂ represent a C _2-6 alkynyl group, e.g. propargyl. If R 1 and R ₂ represent an aryl group, e.g. phenyl optionally substituted by one or more substituents selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro or bromo. If R _x and R ₂ represent a C ₆₁₂ aralkyl group, e.g. benzyl. If R, and R ₂ is heteroaryl, it may, for example. 5- to 6-membered ring containing 1-3 heteroatoms, such as furan, pyridine, pyridazine or oxadiazole. If R < ₂ & gt _; and R < ₂ > together with the carbon atom to which they are attached are a 4- to 7-membered ring, it may be cyclobutane or cyclopentane. Compounds of the present invention having one or more asymmetric carbon atoms may exist as optically active enantiomers of a particular configuration or may exist as a separate diastereoisomer or diastereoisomeric mixture and also as a fully racemic mixture. In addition, some of the compounds of the present invention may exist as endo and exo isomers. The term endo refers here to one having a hydroxylamine side chain on the opposite side as a methylene bridge - (CH ₂ ) _n> In addition, an additional isomer may be present in accordance with the particular characteristics of the oxime group forming part of the compounds of the present invention. geometric type. Compounds having the E or Z configuration are derived from the isomeric oxime group. Compounds having this isomerism can be obtained in a single form or as a mixture; in certain cases one isomer can be converted to another. It is to be understood that the invention encompasses all such isomers of both optical and geometric types and mixtures thereof.

A preferred group of compounds according to the present invention is a group formed by compounds of the general formula (I) in which A is a residue of azabicycloalkane, n is 0, R ₁ is hydrogen, a lower C ₁₂ alkyl group or halogens and R ₂ is hydrogen or a lower C ₁₃ alkyl group optionally substituted by alkoxyl or halogen, alkynyl or halogen.

Particularly preferred compounds according to the present invention are the following:

R (-) - O- (1-azabicyclo [222] oct-3-yl) -N-ethylidene-hydroxylamine, hydrochloride (Compound 2) (±) -exo-O- (1-azabicyclo [321] oct-6 -yl) -N-ethylidenehydroxylamine, hydrochloride (Compound 22) (±) -exo-O- (1-azabicyclo [221] hept-3-yl) -N-ethylidenehydroxylamine, fumarate (Compound 20) (±) -exo- O- (1-Azabicyclo [321] oct-3-yl) -N-ethylidene-hydroxylamine, fumarate (Compound 24)

S (±) -O- (1-azabicyclo [222] oct-3-yl) -N- (2.2.2-trifluoroethylidene) -hydroxylamine, fumarate (Compound 7)

Compounds of general formula (I) can be prepared e.g. according to the following method, which is a further feature of the present invention.

Compounds of formula (I) are obtained by reacting azacyclo or azabicyclo O-substituted hydroxylamine of formula (II)

A- (CH,) _n -O-NH ₂ (II) with a carbonyl derivative of formula (III)

Λ

0 = C \

(III) in which A, n, R _x and R _{2 are} defined as the front. The metabolism can conveniently be carried out in a hydroxyl solvent selected from methanol, ethanol, isopropanol or in tetrahydrofuran or in toluene, preferably in methanol. The reaction temperature is generally kept between 0 ° C and the boiling point of the selected solvent, preferably at room temperature. The intermediates of formula (II) used as starting material can be used as free bases or, if desired, as derivatives of addition salts.

The intermediates of formula (II) from the process described above can be prepared by reducing O-substituted hydroxy-phthaloyl derivatives of general formula (IV)

in which A and n are defined as before.

The process is carried out with a suitable reducing agent such as hydrazine hydrate or ethanolamine, preferably hydrazine hydrate in an alcoholic solvent such as methanol, ethanol and isopropanol, preferably methanol. The metabolic temperature is maintained between 10 ° C and 80 ° C, preferably at room temperature.

Phthaloyl derivatives of general formula (IV) are conveniently obtained from a suitable azacyclic or azabicyclic hydroxyderivate of formula (V) and hydroxyphthalimide (VI) according to a method known as the Mitsunobu reaction [Mitsunobu O., Synthesis 1 (1981)]

A- (C ^H 2) _n -OH + (V)

where A and n are defined as the front.

The condensation-dehydration process is carried out in an anhydrous aprotic solvent such as diethyl ether or tetrahydrofuran, at or below room temperature in the presence of triphenyl phosphine as a dehydrating agent and using DEAD (diethylazodicarboxylate) as the activating agent.

The key intermediates of formula (III) and (V) (hydroxyl derivatives) used in the steps of the process described are commercially available or are prepared according to known methods of operation described in the literature.

Alternatively, compounds of general formula (I) can be prepared by reacting a compound of formula (VII) with an oxime of formula (VIII)

Z ^R '

A- (CH ₂ ) _n -X + HO-N = C \ -> (,) (VII) (VIII) where R _x and R ₂ , A, n are defined as the front and X is a suitable leaving group such as mesyl or sued or halogen, preferably chlorine.

The metabolism is carried out in a protic aprotic solvent such as methanol, ethanol or dimethylformamide, preferably methanol, in the presence of sodium or NaH to activate the oxime function. The temperature is maintained between 30 ° C and 100 ° C, preferably at 60 ° C. The oximes of formula (VIII) are obtained by reacting the carbonyl compound of formula (III) described previously with hydroxylamine hydrochloride in methanol at room temperature according to a known method of operation (Organic Functional Groups Preparation, Vol. III Sec Edition by Sadler and Karo, Academic Press S. Diego, 1989). Compounds of general formula (I) may, if desired, be converted to the corresponding salts of physiologically acceptable inorganic or organic acids by conventional methods, e.g. by treating the compounds as bases with a solution of the appropriate acid in a suitable solvent.

Examples of salts of physiologically acceptable acids are those formed with hydrochloric, fumaric, maleic, succinic, citric, tartaric, phosphoric, sulfuric, salicylic, lactic, gluconic, aspartic or methanesulfonic acids [see, e.g. Berg S.M. et al. Pharmaceutical Salts in J. Pharm. Sci. 66.1 (1977)].

Particularly preferred acids include e.g. hydrochloric, tartaric and fumaric acids. As previously mentioned, the novel compounds of formula (I) have interesting pharmacological properties because of their ability to stimulate different subtypes of the muscarinic receptors M _r and M ₃ with inherent efficacy specific to each subtype. Therefore, novel compounds are therapeutically useful in treating or preventing disorders that are associated with central cholinergic deficiency. In particular, their use may be advantageous in the treatment of cognitive impairment, age-related memory impairment, various forms of dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, hyperkinesis, Tourette syndrome. In addition, the compounds included in the present invention, as centrally acting muscarinic agents, may also be useful as analgesics in the treatment of pain.

The compounds of the present invention may be administered orally, parenterally or rectally at a daily dose of 0.01 to 100 mg / kg body weight, preferably about 0.5 to 10 mg / kg, and may be administered 1 to 4 times daily.

Pharmaceutical compositions which are a further feature of the present invention include tablets, pills, capsules, powders, granules, sterile parenteral solutions or suppositories.

In solid pharmaceutical preparations, a suitable pharmaceutical carrier, such as maize starch, lactose, sorbitol, magnesium stearate, etc., is used together with the active ingredient. Liquid forms into which novel compounds for oral administration or injection may be incorporated include aqueous solutions, flavored syrups and emulsions with oils or other carriers. Dispersing or suspending agents are also useful.

In order to prevent peripheral side effects, it may be advantageous to include in the pharmaceutical preparation a peripherally acting cholinergic antagonist such as N-methylscopolamine or glycopyrrolate or propantheline.

Pharmacology

The affinity of compounds (I) for M _p M ₂ and M ₃ muscarinic receptor subtypes was determined in vitro by receptor binding assays in three tissues containing M _p M ₂ and M ₃ receptor subtypes (rat cerebral cortex, heart, or submandibulam) ). The efficacy and intrinsic activity of the compounds of formula (I) in the M _r M ₂ and M ₃ receptor subtypes were tested in three functional models: the rat upper cervical ganglion (Μ _χ ), the budine aryl (M ₂ ) and the budrine ileum (M ₃ ).

Receptor binding studies

Tissue preparation. The tissue rats were removed, purified, homogenized (m / v: cerebral cortex, 1: 100; whole heart, 1: 200; submandibular salivary glands, 1: 200) with Ultra-Turrax at a maximum speed of 30 s, then using a Potter- Elvehjem homogenizer (30 bars) in Na ⁺ -Mg ²⁺ -HEPES buffer, pH 7.4 (nM: NaCl, 100; MgCl ₂ , 10; HEPES, 20) and filtered through two layers of gauze.

Attempts to bind. The binding curves for the various compounds were derived indirectly from competitive anti-radiolabeling experiments for muscarinic brain scotch receptors with 0.5 nM [ ³ H] pyrenzepine and 0.3 nM [ ³ H] NMS for muscarinic receptors of the heart and submandibular glands. One ml portion of the homogenisate was incubated for 45 min at 30 ° C in the presence of the labeled ligand and different concentrations of the unlabeled ligand. Incubation was completed by centrifugation (3 min at 12000 rpm) at room temperature with an Eppendorf microcentrifuge. The resulting pellet was washed twice with 1.5 ml of saline to remove free radioactivity and allowed the final pellet to dry. The ends of the pellet-containing tubes were cut off, 200 μΐ of tissue solvent (Lumasolve, Lumac) were added and allowed to stand overnight. Then, after addition of 4 ml of liquid scintillation solution (Lipoluma, Lumac), the radioactivity was measured in a counter. Analyzes were performed in triplicate and nonspecific binding was defined as radioactivity bound or trapped in the pellet if the incubation medium contained 1 μΜ racemic 3-quinuclidinyl benzylate (QNB) mixture. Non-specific binding was less than 30% or. 10%. Inhibition constants (Ki) were calculated after correction for occupancy with radioligand using the Cheng and Prusoff equation (see Cheng Y. et al., Biochem. Pharmacol. 22, 3099, 1973). The results are listed in Table 1.

TABLE 1

In vitro receptor binding assays (Ki χ 10 ^-6 M)

Compound The rat cerebral cortex The rat's heart Rat submandibular gland (M ₃ ) 2 5.0 7.4 19,4 4 1.0 4.4 4.3 6 0.43 3.2 1.9 7 1.7 5.2 11,8 8 0.50 2.4 3.3 11 3.3 7.4 11.9 13 2.0 6.6 11,8 15 0.51 6,7 18,2 17 0.90 4.4 5.9 20 9.0 2.2 31.0 22 3.0 2.2 6.2 24 2.2 2.2 8.8 25 3.1 3.1 21.3 26 0.51 0.50 2.5 28 1.0 1.5 5.0 42 0.29 2.1 1.3 46 6.0 14,8 17.6

Functional research

Upper cervical ganglion of rat

The upper cervical ganglia were excised in Sprague-Dawley male rats weighing 150-200 g, which were anesthetized with urethane (1.2 g / kg ip). Each ganglion was extracted from the envelope under a microscope and then immersed in a three-section bath. The ganglion body was placed in the central compartment, and the preganglionic (cervical sympathetic) and postganglionic (internal carotid) sections reached through the oiled slots into both outer chambers. The central section (volume of about 0.5 ml) was continuously perfused with a Krebs-Henseleit solution at 25 ° C (2 to 2.5 ml min ' ¹ ), which was previously equilibrated with 5% carbon dioxide in oxygen; the same solution in the outer divisions is stationary. The medium was an aqueous solution containing (mM): NaCl 124.1, KC1 4.8, NaHCO ₃ 24.8, CaCl ₂ 2.5, MgSO ₄ 1.2, KH ₂ PO ₄ 1.2, glucose 10. Changes in the ganglion potential induced by active substance perfusion were recorded using Ag / AgCl electrodes between chambers containing the ganglion body (grounded) and the postganglion moiety. The potentials were amplified and plotted on a potentiometric diagram binder. After a stabilization time of 30 min, we superfunded for 75 sec at 15 min intervals of 1 μΜ muscarinic until two consecutive equally strong depolarizing responses were observed (usually 3-4 applications). The last of these responses, measured in each experiment, was considered as the standard maximum response. After zeroing, one agonist was superfused for 75 seconds in increasing semilogarithmic units of molar concentration (e.g., 1, 3, 10 μΜ) until the maximum response was elicited. We typically ran these applications at intervals of 10 to 15 minutes, but we used longer intervals in case of slower zeroing. After obtaining the maximal response, we superfused 60 min of pyrenzepine at a concentration of 0.1 μΜ, and then re-determined the agonist-response concentration curve in the presence of pyrenzepine in the superfusion medium. The concentration of agonist giving 50% of its maximal response (EC ₅₀ ) was calculated by linear least squares regression analysis used in the first concentration-response curve. The relative maximum (RM) was obtained by comparing the maximal agonist response with the standard maximal response to 1 μar muscarin, taken as 1. To check the muscarinic character of the agonist response, we shifted from the shift of the concentration-response agonist curve to the right that it is caused by pyrenzepine after calculating the parallelism of the curves and calculating the dose ratio at the EC _S0 level. The affinity value for pyrenzepine (pAj) was calculated as described by Furchgott (Handbook of Experimental Phar13 macology, vol. 33; H. Blaschko & E. Muschall (Eds.), 283-335; Springer-Verlag, Berlin, 1972): = -log ([antagonist] / dose ratio-1).

The results are listed in Table II.

TABELAH

Functional in vitro studies

Upper rat cervical ganglion Compound ec ₅₀ GuM) RM * 2 14,4 1 7 0.4 1.1 20 0.8 1 22 2 1 24 1.1 0.8

* RM = relative maximum compared to the effect of 1 μΜ muscarin taken as 1.

The following examples illustrate some of the compounds of the present invention, but should not in any way be construed as limiting the scope of the invention itself.

Example 1

R (-) N - [(1-azabicyclo [222] -oct-3-yl) -oxy] -phthalimide

A mixture of S (+) 1-azabicyclo [222] -octane-3-ol (37.5 g) [Eur. J. Med. Chem. 14, 111 (1979)], triphenylphosphine (77.3 g), N-hydroxy-phthalimide (48.1 g) and molecular sieves (70 g) in dry THF (750 ml) were stirred for 2 hours at room temperature and then cooled with an ice bath. Diethyl azodicarboxylate (DEAD) (51.4 g) was added dropwise and the resulting solution was stirred overnight. Water (300 ml) was added and the molecular sieve was filtered off. THF was removed in vacuo and the residue acidified with 10% aqueous HCl was washed twice with ethyl acetate. The aqueous layer was basified with Κ ^ Ο ₃ and extracted extensively with ethyl acetate. The combined organic layers were dried and evaporated to dryness to give the desired product as a white solid (33.5 g).

Tal. > 280 ° C (ethanol as hydrochloride salt)

MS (CI) = 273 m / e [M + Η] [a] _D = -36.34 ° (c = 1% in IN HCl)

Following the method described above, the following compounds were prepared:

S (+) N - [(1-azabicyclo [222] -oct-3-yl) oxyl phthalimide from R (-) 1-azabicyclo [222] -octane3-ol [Eur. J. Med. Chem. 14,111 (1979)]

Tal. > 280 ° C (ethanol as hydrochloride salt)

MS (CI) = 273 m / e [M + Η] [a] _D = + 36.15 ° (c = 1% in IN HCl) (±) -endo-N - [(l-azabicyclo [221] hept -3-yl) oxy] -phthalimide from (±) -exo-1-azabicyclo [221] -heptan-3-ol [J. Org. Chem. 34.3674 (1969)]

Tal. > 220-225 ° C, dec. (as the hydrochloride salt).

MS (CI) = 259 m / e [M + Η] (±) -exo-N - [(1-azabicyclo [221] hept-3-yl) oxy] -phthalimide from (±) -endo-1-azabicyclo [221] -Heptan-3-ol [EP 427390]

Tal. 145-150 ° C

MS (CI) = 259 m / e [M + Η] (±) -endo-N - [(1-azabicyclo [321] oct-6-yl) oxy] -phthalimidiz (±) -exo-1-azabicyclo [ 321] -octane-6-ol [J. Org. Chem. 33.4376 (1968)]

Tal. > 250 ° C (as the hydrochloride salt).

MS (CI) = 273 m / e [M + Η] (±) -exo-N - [(1-azabicyclo [321] oct-6-yl) oxy] -phthalimidiz (±) -endo-1-azabicyclo [ 321] -octane-6-ol [J. Org. Chem. 33, 4376 (1968)]

Tal. Mp 148-152 ° C

MS (CI) = 273 m / e [M + Η] (±) -endo-N - [(1-azabicyclo [321] oct-3-yl) oxy] -phthalimidiz (±) -exo-N - [( 1-Azabicyclo [321] -octan-3-ol [J. Org. Chem. 33,4376 (1968), EP 257741]

Tal. 110-118 ° C, dec.

MS (CI) = 273 m / e [M + Η] (±) -exo-N - [(1-azabicyclo [321] oct-3-yl) oxy] -phthalimide from (±) -endo-1-azabicyclo [321] -Octane-3-ol [J. Org. Chem. 33.4376 (1968)]

Tal. 108 -ll ° C

MS (CI) = 273 m / e [M + Η] (±) -endo-N- [1-azabicyclo [331] non-3-yl) oxy] -phthalimide, from (±) -exo-1-azabicyclo [331] -nonan-3-ol [J. Amer. Chem. Soc. 89.1431 (1967), EP 257741]

Tal. 135-140 ° C

MS (CI) = 287 m / e [M + Η] (±) -exo-N- [1-azabicyclo [331] non-3-yl) oxy] -phthalimidiz (±) -endo-1-azabicyclo [331 ] -nonan-3-ol [J. Amer. Chem. Soc. 89.1431 (1967)

Tal. 160 ° C, dec.

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

R (-) - N- [1-azabicyclo [222] oct-3-yl) methoxy] -phthalimide from R (-) - 1-aza-3-hydroxymethyl-bicyclo [222] -octane [EP 458214]

Tal. 85-95 ° C (isopropyl ether)

MS (CI) = 287 m / e [M + Η] [a] _D = -27.49 ° (c = 1% in IN HCI)

S (+) - N- [1-azabicyclo [222] oct-3-yl) -methoxy] -phthalimide from S (+) - 1-aza-3-hydroxymethyl-bicyclo [222] -octane [EP 458214]

Tal. 90-95 ° C (isopropyl ether)

MS (CI) = 287 m / e [M + Η] [a] _D = + 25.93 ° (c = 1% in IN HCI)

N - [(1-ethyl-1-azacyclobut-3-yl) oxy] -phthalimide from 1-ethyl-1-azacyclobutan-3-ol [see example 2]

N - [(1-azacyclobut-3-yl) oxy] -phthalimide from 1-azacyclobutan-3-ol [Synth. Comm. 20, 407 (1990)]

N - [(1-methyl-1-azacyclohex-4-yl) oxy] -phthalimide

Melting point: 95 ° C

MS (CI) = 261 m / e [M + Η] (±) -N - [(1-methyl-1-azacyclohept-3-yloxy] -phthalimidis 1-methyl-1-azacycloheptan-3-ol (see example 3)

Tal. 70-72 ° C

MS (C.I.) = 275 m / e [M + Η] exo-N - [(8-methyl-8-azabicyclo [321] -oct-3-yl) -oxy] -phthalimide

Melting point: 255 ° C (dec.) (Isopropanol as hydrochloride salt)

MS (C.I.) = 287 m / e [M + Η] (±) N - [(1-methyl-1-azacyclopent-3-yl) -oxy] -phthalimide

M.p .: 87-91 ° C

MS (C.I.) = 247 m / e [M + Η]

Example 2 1-ethyl-1-azacyclobutan-3-ol

Example 3

a) N-methyl-N- (ethoxy carbonylmethyl) -5-aminopentanoic acid, ethyl ester

While stirring well, 5-bromo-pentanoic acid ethyl ester (30 g) was added portionwise to a suspension of sarcosine hydrochloride (22 g) and triethylamine (29 g) in toluene (220 ml). The reaction mixture was refluxed for 20 hours and then cooled to 5 ° C. A solution of 5% aqueous hydrochloric acid (200 ml) was added, the organic layer was separated and discarded. The aqueous solution was basified with 17% Na ₂ CO ₃ solution and the separating oil was taken up with diethyl ether. The organic solution was washed with water, dried and evaporated to dryness to give the crude title compound. This was purified by distillation to give 17.5 g of the product by boiling. 120-125 ° C (0.66 mbar).

b) 1-methyl-1-aza-2-ethoxycarbonyl-cycloheptan-3-one

A solution of the intermediate described above (8 g) in toluene (65 ml) was added dropwise to a solution of potassium tert-butylate (11 g) in anhydrous toluene (400 ml) during refluxing and stirring.

The reaction mixture was stirred for another 10 minutes and cooled to room temperature. A solution of 5% hydrochloric acid (50 ml) was continuously introduced and the resulting organic solution separated and discarded. The aqueous layer was basified with 17% sodium carbonate solution and the oily product which was separated was extracted into ethyl acetate. From this solution, after evaporation to dryness, (5.78 g) of a crude intermediate was obtained which was sufficiently pure to be used in the next step. IR (nujol) = carbonyl absorption strips 1710 and 1740 cm ^-1 .

c) 1-methyl-1-azacycloheptan-3-one

A solution of ethoxycarbonyl intermediate (5.68 g) in concentrated aqueous hydrochloric acid (56 ml) was refluxed for 7 hours and then cooled to room temperature. A 15% aqueous solution of sodium hydroxide was added until pH 9. The extracted oil was extracted into ethyl acetate and a decarboxylated keto derivative (2.8 g) was obtained as a yellow oil.

¹ H-NMR and MS were consistent with the proposed structure;

d) 1-methyl-1-azacycloheptan-3-ol

LiAlH ₄ (1.04 g) was added in portions to the cooled solution (5 ° C) of the above intermediate (3.5 g) in anhydrous tetrahydrofuran. The reaction mixture was stirred for 1 hour and then a solution of tetrahydrofuran (30 ml) containing water (0.5 ml) was added dropwise.

The separated salts were filtered and the title compound (3.5 g) was obtained as a yellowish oil from the evaporated organic solution. ^{The 1} H-NMR and MS were consistent with the proposed structure.

Example 4

R (-) - O- (1-Azabicyclo [222] oct-3-yl) hydroxylamine dihydrochloride

In absolute ethanol (300 ml) dissolved R (-) - N - [(1-azabicyclo [222] -oct-3-yl) oxy-phthalimide (31.5 g) and 85% hydrazine hydrate (13, 3 ml). The mixture was stirred overnight at room temperature, the solid was filtered and the filtrate was evaporated to dryness. The residue was dissolved in water and acidified with 10% HCl after cooling with an ice bath; after stirring for 4 hours, the solid was filtered off. The solution was evaporated to dryness and the title compound was obtained by crystallization from ethanol as a white solid.

Tal. Mp 195-200 ° C

MS (CI) = 143 m / e [M + Η] [a] _D = -39.53 ° (c = 1% in IN HCl)

Following the procedure described above and from suitable intermediates, the following compounds were prepared:

S (+) - O- (1-azabicyclo [222] oct-3-yl) hydroxylamine dihydrochloride

Tal. 200-205 ° C (dec.)

MS (CI) = 143 m / e [M + Η] [a] _D = + 40 ° (c = 1% in IN HCI) (±) -endo-0- (1-azabicyclo [221] -hept-3 -yl) -hydroxylamine dihydrochloride

Tal. 210-215 ° C (dec.)

MS (C.I.) = 129 m / e [M + Η] (±) -exo-O- (1-azabicyclo [221] -hept-3-yl) -hydroxylamine dihydrochloride

Tal. Mp 165-170 ° C

MS (C.I.) = 129 m / e [M + Η] (±) -endo-O- (1-azabicyclo [321] -oct-6-yl) -hydroxylamine dihydrochloride

Tal. 210-215 ° C (dec.)

MS (C.I.) = 142 m / e [M + Η] (±) -exo-O- (1-azabicyclo [321] -oct-6-yl) -hydroxylamine

Thick oil

MS (C.I.) = 143 m / e [M + Η] (±) -endo-O- (1-azabicyclo [321] -oct-3-yl) -hydroxylamine dihydrochloride

Tal. 205-210 ° C (dec.)

MS (C.I.) = 143 m / e [M + Η] (±) -exo-O- (1-azabicyclo [321] -oct-3-yl) -hydroxylamine dihydrochloride

Tal. 183-185 ° C (dec.)

MS (C.I.) = 143 m / e [M + Η] (±) -endo-O- (1-azabicyclo [331] -non-3-yl) -hydroxylamine dihydrochloride

Tal. 185-189 ° C (dec.)

MS (C.I.) = 157 m / e [M + Η] (±) -exo-O- (1-azabicyclo [331] -non-3-yl) -hydroxylamine dihydrochloride

Tal. 200-205 ° C (dec.)

MS (C.I.) = 157 m / e [M + Η]

R (-) - O - [(1-Azabicyclo [222] -oct-3-yl) -methyl] -hydroxylamine dihydrochloride Mp. 110-120 ° C (dec.)

MS (CI) = 157 m / e [M + Η] [a] _D = - 21.59 (c = 1% in IN HCl)

S (+) - O - [(1-azabicyclo [222] -oct-3-yl) -methyl] -hydroxylamine dihydrochloride Hygroscopic solid MS (CI) = 157 m / e [M + Η] [a] _D = + 21.22 (c = 1% in IN HCl)

O- (ethyl-1-azacyclobut-3-yl) -hydroxylamine dihydrochloride

O-1-Azacyclobut-3-yl) -hydroxylamine dihydrochloride

O- (1-methyl-1-azacyclohex-4-yl) -hydroxylamine dihydrochloride M.p .: 195 (dec.)

MS (C.I.) = 131 m / e [M + H] (±) -O- (1-methyl-1-azacyclohept-3-yl) -hydroxylamine dihydrochloride Dense oil

MS (C.I.) = 145 m / e [M + Η] (±) -O- (1-methyl-1-azacyclohex-3-yl) -hydroxylamine dihydrochloride Mp. = 205-210 ° C (dec.)

MS (C.I.) = 131 m / e [M + Η]

Exo-O- (8-methyl-8-azabicyclo [321] -oct-3-yl) -hydroxylamine dihydrochloride m.p. 185 ° C (dec.)

MS (C.I.) = 157 m / e [M + Η] (±) -O- (1-methyl-1-azacyclopent-3-yl) -hydroxylamine dihydrochloride

Tal. = 162-6 ° C

MS (C.I.) = 117 m / e [M + Η]

Example 5

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 1)

A suspension of S (+) - O- (1-azabicyclo [222] -oct-3-yl) -hydroxylamine dihydrochloride (0.6 g), methanol (10 ml) and sodium (64 mg) was stirred at room temperature until the sodium did not disappear. Acetaldehyde (0.16 ml) was added dropwise to the cooled solution. The reaction mixture was stirred overnight at 0-5 ° C. The methanol was evaporated, the residue was dissolved in water and washed with ethyl acetate. The aqueous phase was basified with Na ₂ CO ₃ and extracted into CHC1 ₃ . The organic layers were combined, dried and evaporated to dryness. The residue was dissolved in ethyl acetate to give the title compound as the hydrochloride salt by the addition of anhydrous HCl solution in diethyl ether. The solid was filtered and dried in vacuo.

The pure title compound was obtained as a white solid (0.31 g).

Tal. Mp 165-170 ° C

MS (CI) = 169 m / e [M + Η] [a] _D = + 37.80 (c = 1% in IN HCl)

Ή-NMR (CDCl ₃ ): 1.7-2.3 (4H, m); 1.85 (3H, d); 2.52 (1H, m); 3.1-3.7 (6H, m); 4.51 (1H, m); 6.84 and 7.46 (1H, 2q); 12.27 (1H, b)

Analysis: C ₉ H _1? C1N ₂ O

C H N Cl Found :% 52.54 8.40 13,65 17.24 Calculated:% 52.81 8.37 13,69 17,32

Following the method described above, the following compounds were prepared

R (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 2)

Tal. 158-161 ° C (dec.)

MS (CI) = 169 m / e [M + Η] [a] _D = + 40.128 (c = 1% in IN HCl)

Ή-NMR (CDCl ₃ ): 1.7-2.3 (4H, m); 1.85 (3H, d); 2.51 (1H, m); 3.1-3.7 (6H, m); 4.54 (1H, m); 6.84 and 7.46 (1H, 2q); 12.20 (1H, b)

Analysis: C ₉ H ₁₇ C1N ₂ O

C H N Cl Found :% 52.31 8.42 13,57 17,27 Calculated:% 52.81 8.37 13,69 17,32

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -N-propylidene-hydroxylamine hydrochloride (Compound 3)

Tal. 147 ° C

MS (CI) = 183 m / e [M + Η] [a] _D = + 40.9 (c = 1% in IN HCI)

Ή-NMR (CDCl ₃ ): 1.08 (3H, t); 1.7-2.6 (7H, m); 3.1-3.5 (6H, m); 4.53 (1H, m); 6.72 and 7.45 (1H, 2t); 12.18 (1H, b)

Analysis: C ₁₀ H ₁₉ ClN ₂ O

C H N Cl Found :% 54.39 8.81 12.70 16,12 Calculated:% 54.91 8.76 12,81 16,21

R (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N-propylidene-hydroxylamine hydrochloride (Compound 4)

Tal. 150 ° C

MS (CI) = 183 m / e [M + Η] [a] _D = - 42.33 (c = 1% in IN HCI)

Ή-NMR (CDCl ₃ ): 1.08 (3H, t); 1.7-2.6 (7H, m); 3.1-3.7 (6H, m); 4.53 (1H, m); 6.72 and 7.45 (1H, 2t); 12.31 (1H, b)

Analysis: C ₁₀ H ₁₉ ClN ₂ O

C H N Cl Found :% 54.40 8.76 12.77 16.15 Calculated:% 54.91 8.76 12,81 16,21

S-O- (1-Azabicyclo [222] -oct-3-yl) -N-isobutylidene-hydroxylamine hydrochloride (Compound 5)

Tal. 160-162 ° C, dec.

MS (CI) = 197 m / e [M + Η] [a] _D = + 35.1 (c = 1% in Et ΟΗ]

Ή-NMR (DMSO + CDCl ₃ ): 10.86 (b, 1H); 7.41 (d, 1H); 4.48 (m, 1H); 2.9 - 3.7 (6H); 2.3-2.6 (2H); 1.89 (m, 4H); 1.05 (d, 6H).

Analysis: C _n H ₂₁ ClN ₂ O

C H N Cl Found :% 55.18 8,35 11,91 15,12 Calculated:% 56.76 9.09 12.04 15,23

R - (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N-isobutylidene-hydroxylamine hydrochloride (Compound 6)

Tal. 165 ° C, dec.

MS (CI) = 197 m / e [M + Η] [a] _D = - 33.4 (c = 1% in Et ΟΗ]

Ή-NMR [DMSO]: 10.92 (b, 1H); 7.47 (d, 1H); 4.45 (m, 1H); 3.0-3.8 (6H); 2.50 (m, 1H); 2.29 (m, 1H); 1.6-2.2 (4H); 1.03 (d, 6H).

Analysis: C ₁₁ H ₂₁ C1N ₂ O

C H N Cl Found :% 55.21 9.07 11,71 15.17 Calc .:% 56.76 9.09 12.04 15,23

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -N- (2,2,2-trifluoroethylidene) -hydroxylamine fumarate (Compound 7)

Tal. 128-132 ° C, dec.

MS (CI) = 223 m / e [M + Η] [a] _D = + 31.3 (c = 1% in Et ΟΗ]

Ή-NMR [DMSO]: 8.25 (q, 1H); ~ 7.3 (b, 2H); 6.51 (s, 2H); 4.60 (m, 1H); 3.40 (m, 1H); 2.8 - 3.1 (5H); 2.23 (m, 1H); 1.05 -1.9 (4H).

Analysis: C ₁₃ H _1? N ₂ O ₅

Found:% Calc .:%

C H N

46.01 5.12 8.10

46.16 5.07 8.28

R - (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N- (2,2,2-trifluoroethylidene) -hydroxylamine fumarate (Compound 8)

Tal. 138-140 ° C, dec.

MS (CI) = 223 m / e [M + Η] [a] _D = - 31.5 (c = 1% in EtOH]

Ή-NMR [DMSO]: 88.8 (b, 2H); ~ 8.26 (q, 1H); 6.51 (s, 2H); 4.63 (m, 1H); 3.41 (m, 1H); 2.8 - 3.2 (5H); 2.25 (m, 1H); 1.05-2.0 (4H).

Analysis: C ₁₃ H ₁₇ F ₃ N ₂ O ₅

Found:% Calc .:%

C H N

46.22 5.11 8.19

46.16 5.07 8.28 (±) -0- (1-Azabicyclo [222] -oct-3-yl) -N- (benzylidene) -hydroxylamine hydrochloride (Compound 9)

Tal. 207-209 ° C

MS (C.I.) = 231 m / e [M + Η]

1 H-NMR [CDCl 3 12.42 (b, 1H); 8.12 (s, 1H); 7.2 - 7.6 (5H); 4.68 (m, 1H); 3.0-3.7 (6H); 2.62 (m, 1H); 1.6-2.4 (4H).

Analysis: C ₁₄ H ₁₉ C1N ₂ O

C H N Cl Found :% 62.81 7.27 10,43 13,23 Calc .:% 63.02 7.19 10.50 13,29

(±) -O - [(1-Azabicyclo [222] -oct-3-yl) -methyl] -N- (benzylidene) -hydroxylamine hydrochloride (Compound 10)

Tal. 200 ° C

MS (C.I.) = 245 m / e [M + Η]

1 H-NMR [CDCl 3 12.12 (b, 1H); 8.03 (s, 1H); 7.2-7.7 (5H); 4.20 (d, 2H); 1.8 - 3.7 (12H).

Analysis: C ₁₅ H ₂₁ C1N ₂ O

C H N Cl Found :% 63.98 7.61 9.88 12.58 Calculated:% 64.16 7.54 9.98 12,63

Example 6

R (-) - O- (1-Azabicyclo [222] oct-3-yl) -N-isopropylidene-hydroxylamine dihydrochloride (Compound 11)

Acetone (0.24) was added to a cooled (10 ° C) solution of R (-) - O- (1-azabicyclo [222] oct-3-yl) -hydroxylamine dihydrochloride (0.7 g) in methanol (15 ml). ml). The solution was stirred for 2 h at 10 ° C and then at room temperature for 36 h. The methanol was evaporated, the residue was dissolved in ethyl acetate and then evaporated to dryness. The residue was crystallized from ethyl acetate to give the title compound as a white solid (0.58 g). Tal. 130-132 ° C

MS (CI) = 183 m / e [M + Η] [α] _D =. 41.65 (c = 1% in IN HCl)

Ή-NMR (DMSO + CDCl ₃ ): 1.6-2.1 (4H, m); 1.84 (3H, s); 1.85 (3H, s); 2.35 (1H, m); 2.9 - 3.7 (6H, m); 4.47 (1H, m); 6.40 (1H + HDO, b); 10.82 (1H, b)

Analysis: C ₁₀ H ₂₀ Cl ₂ N ₂ O

C H N Cl Found :% 46.53 7.97 10.81 27.55 Calculated:% 47.07 7.90 10.98 27.79

Following the method described above and from suitable intermediates, the following compounds can be prepared

S (+) - O- (1-Azabicildo [222] -oct-3-yl) -N-isopropylidene-hydroxylamine dihydrochloride (Compound 12)

Tal. 135-140 ° C

MS (CI) = 183 m / e [M + Η] [a] _D = + 41.4 (c = 1% in IN HCl)

Ή-NMR [DMSO + CDCl ₃ ) 1.6-2.1 (4H, m); 1.84 (3H, s); 1.85 (3H, s); 2.35 (1H, m); 2.9 - 3.7 (6H, m); 4.47 (1H, m); 6.26 (1H + HDO, b); 10.73 (1H, b).

Analysis: C _{1 ()} H ₂₀ Cl ₂ N ₂ O

C H N Cl Found :% 47.11 7.95 11.17 27.49 Calc .:% 47.07 7.90 10.98 27.79

R (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N- (2,2-difluoroethylidene) -hydroxylamine fumarate (Compound 13)

Tal. 130-135 ° C, dec.

MS (CI) = 205 m / e [M + Η] [a] _D = + 41.4 (c = 1% in IN HCl)

Ή-NMR [DMSO] 9.20 (b, 2H); 7.91 (m, 1H; 6.53 (s, 2H); 6.56 (m, 1H); 4.59 (m, 1H); 3.47 (m, 1H); 2.9-3. 3 (5H); 2.27 (m, 1H); 1.5-2.0 (4H).

Analysis: C ₁₃ H _lg F ₂ N ₂ O ₅

Found:% Calc .:%

C H N

48.60 5.70 8.68

48.75 5.66 8.75

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -N- (2,2-difluoroethylidene) -hydroxylamine fumarate (Compound 14)

Tal. 110 ° C, dec.

MS (CI) = 205 m / e [M + Η]

Ή-NMR [CDCl ₃ ] 7.51 (m, 1H); 6.11 (m, 1H); 4.65 (m, 1H); 3.58 (m, 1H); 3.2 - 3.5 (5H); 2.56 (m, 1H); 1.7-2.3 (4H).

Analysis: C ₉ H ₁₅ C1F ₂ N ₂ O

C H N Cl Found :% 44,80 6.35 11,55 14,62 Calculated:% 44.91 6.28 11,64 14,73

R (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N- (2-fluoroethylidene) -hydroxylamine fumarate (Compound 15)

Tal. 118 ° C, dec.

MS (C.I.) = 187 m / e [M + Η]

Ή-NMR [DMSO] 7.75 and 7.26 (2m, 1H); 6.50 (s, 2H); ~ 6.4 (b, 2H); 5.30 and 4.99 (2m, 2H); 4.50 (m, 1H); 3.41 (m, 1H); 2.9-3.2 (5H); 2.25 (b, 1H); 1.5-2.0 (4H). Analysis: C ₁₃ H ₁₉ FN ₂ O ₅

Found:%

Calculated:%

C

51.83

51.65

H

6.25

6.34

N

9.31

9.27

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -N- (2-fluoroethylidene) -hydroxylaminfumarate (Compound 16)

Tal. 118 ° C, dec.

MS (C.I.) = 187 m / e [M + 1]

Ή-NMR [DMSO] 8.56 (b, 2H); 7.69 and 7.15 (2m, 1H); 6.54 (s, 2H); 5.25 and 4.95 (2m, 2H); 4.41 (m, 1H); 3.36 (m, 1H); 2.7-3.2 (5H); 2.23 (m, 1H); 1.4-2.1 (4H).

Analysis: C ₁₃ H ₁₉ FN ₂ O ₅ C H Found :% 51.40 6.40 Calc .:% 51.65 6.34

N

9.17

9.27

R (-) - O- (1-Azabicyclo [222] -oct-3-yl) -N-cyclobutylidene-hydroxylamine hydrochloride (Compound 17)

Tal. Mp 185-190 ° C

MS (CI) = 195 m / e [M + Η] [a] _D = - 36.35 (c = 1% in EtOH)

1 H-NMR [DMS + CDCl 3: 10.62 (b, 1H); 4.69 (m, 1H); 3.1-3.9 (6H); 0.7 - 2.7 (11H)

Analysis: C _n H ₁₉ ClN ₂ O

C H N Cl Found :% 57.11 8,32 12.17 15.01 Calculated:% 57.26 8.30 12.14 15.36

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -N-cyclobutylidene-hydroxylamine hydrochloride (Compound 18)

Tal. 190-195 ° C

MS (CI) = 195 m / e [M + Η] [α] _D =. 34.79 (c = 1% in EtOH)

Ή-NMR [DMSO + CDCl ₃ ] 10.79 (b, 1H); 4.44 (m, 1H); 2.7-3.7 (10H); 2.32 (m, 1H); 1.6 - 2.2 (6H)

Analysis: C _U H ₁₉ C1N ₂ O

C H N Cl Found :% 55.60 8,32 12.08 15,23 Calculated:% 57.26 8.30 12.14 15.36

(±) -endo-O- (1-Azabicyclo [221] -hept-3-yl) -N-ethylidene-hydroxylamine fumarate (Compound 19)

Tal. 160 ° C

MS (CI) = 155 m / e [M + Η]

Ή-NMR [DMSO]: 88.8 (broad, 2H); 6.99 (s, 2H); 7.51 and 6.94 (2q, 1H); 4.79 (m, 1H); 3.43 (m, 1H); 3.17 (m, 1H); 2.8 - 3.1 (4H); 2.60 (m, 1H); 1.6-2.0 (2H); 1.79 and 1.80 (2d, 3H).

Analysis: C ₁₂ H _lg N ₂ O ₅

C H N Found :% 53.47 6.80 10,35 Calculated:% 53.32 6.71 10,37

(±) -Exo-O- (1-azabicyclo [221] -hept-3-yl) -N-ethylidene-hydroxylamine fumarate (Compound 20)

Tal. 175 ° C

MS (CI) = 155 m / e [M + Η]

Ή-NMR [DMSO + CDCl ₃ ] 9.40 (b, 2H); 6.57 (s, 2H); 6.84 and 7.41 (2q, 1H); 4.25 (m, 1H); 2.4-3.3 (7H); 1.81 (m, 1H); 1.78 (d, 3H); 1.24 (m, 1H).

Analysis: C ₁₂ H _lg N ₂ O ₅

C H N Found :% 52.98 6.71 10:18 Calculated:% 53.32 6.71 10,37

(±) -endo-O- (1-Azabicyclo [321] -oct-6-yl) -N-ethylidene-hydroxylamine fumarate (Compound 21)

Tal. 135-140 ° C, dec.

MS (CI) = 169 m / e [M + Η]

Ή-NMR [CDCl ₃ ] 10.6 (b, 2H); 7.48 and 6.85 (2q, 1H); 6.81 (s, 2H); 5.09 (m, 1H); 4.04 (m, 1H); 3.3-3.6 (3H); 3.0-3.3 (2H); 2.73 (b, 1H); 2.21 (m, 1H); 1.7-2.1 (3H); 1.86 and 1.88 (2d, 3H).

Analysis: Ο ₁₃ Η _2θ Ν ₂ Ο ₅

C H N Found :% 54.84 7.25 9.74 Calculated:% 54.92 7.09 9.85

(±) -exo-O- (1-azabicyclo [321] -oct-6-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 22)

Tal. 170-173 ° C

MS (C.I.) = 169 m / e [M + Η]

1 H-NMR [CDCl 3 12.84 (b, 1H); 8.03 (s, 1H); 7.2-7.7 (5H); 4.20 (d, 2H); 1.8 - 3.7 (12H).

Analysis: C ₉ H ₁₇ C1N ₂ O

C H N Cl Found :% 52.15 8.40 13,59 17,9 Calculated:% 52.80 8.37 13,69 17.2

(±) -endo-O- (1-azabicyclo [321] -oct-3-yl) -N-ethylidene-hydroxylamine fumarate (Compound 23)

Tal. 125-127 ° C, dec.

MS (C.I.) = 169 m / e [M + Η]

Ή-NMR [DMSO] 9.2 (b, 2H); 6.94 (q, 1H); 6.47 (s, 2H), 4.31 (b, 1H); 3.41 and 3.50 (d, m, 2H); 3.23 (m, 2H); 3.01 and 3.12 (m, d, 2H); 2.50 (m, 1H); 1.9-2.2 (4H); 1.81 (d, 3H).

Analysis: C ^ H ^ N ^

H N

7.11 9.75

7.09 9.85

C

Found: 54.43

Calc .:% 54.92 (±) -exo-O- (1-azabicyclo [321] -oct-3-yl) -N-ethylidene-hydroxylamine fumarate (Compound 24)

Tal. 119-121 ° C, dec.

MS (C.I.) = 169 m / e [M + Η]

1 H-NMR [DMSO + CDCl 3 9.46 (b, 2H); 7.39 and 6.82 (2q, 1H); 6.53 (s, 2H), 4.46 (m, 1H); 2.5-3.6 (7H); 1.4-2.3 (4H); 1.75 and 1.77 (2d, 3H).

Analysis: C ₁₃ H _2Q N ₂ O ₅ C H Found :% 53.60 6.93 Calculated:% 53.73 6.87

N

9,42

9.53 (±) -endo-O- (1-azabicyclo [331] -non-3-yl) -N-ethylidene-hydroxylamine fumarate (Compound 25)

Tal. - hygroscopic solid

MS (C.I.) = 183 m / e [M + Η]

Ή-NMR [DMSO] 8.3 (b, 2H); 7.51 and 6.93 (2q, 1H); 6.50 (s, 2H), 4.37 (m, 1H);

3.60 (m, 1H); 3.0-3.3 (5H); 2.51 (m, 1H); 2.23 (m, 1H); 2.04 (b, 1H); 1.4 -1.9 (4H) 1.81 and 1.82 (2d, 3H).

Analysis: C ₁₄ H ₂₂ N ₂ O ₅

Found:% Calc .:%

C H N

56.04 7.34 9.19

56.36 7.43 9.39 (±) -Exo-O- (1-azabicyclo [331] -non-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 26)

Tal. = 155-160 ° C, dec.

MS (CJ.) = 183 m / e [M + Η]

Ή-NMR [CDCl 3 12.68 (b, 1H); 7.41 and 6.80 (2q, 1H); 4.98 (m, 1H), 3.60 (m, 1H);

3.60 (m, 1H); 3.2 - 3.5 (5H); 1.8-2.5 (7H); 1.82 and 1.83 (2d, 3H).

Analysis: C _lff H ₁₉ ClN ₂ O

C H N Cl Found :% 54.00 8.61 12.57 16.10 Calculated:% 54.91 8.76 12,81 16,21

Exo-O- (8-methyl-8-azabicyclo [321] -oct-3-yl) -N-ethylidene-hydroxylamine fumarate (Compound 27)

Tal. = 145 ° C, dec.

MS (C.I.) = 183 m / e [M + Η]

Ή-NMR [CDCl ₃ ] 11.40 (b, 2H); 6.82 (s, 2H); 7.40 and 6.75 (2q, 1H); 4.44 (m, 1H), 3.98 (b, 2H); 2.78 (s, 3H); 2.1-2.4 (6H); 1.95 (d, 2H); 1.81 and 1.82 (2d, 3H). Analysis: C ₁₄ H ₂₂ N ₂ O ₅

Found :%

Calculated:%

C H N

56.28 7.49 9.36

56.36 7.43 9.39

R (-) - O- [1-Azabicyclo [222] -oct-3-yl) -methyl-N-methylidene-hydroxylamine (Compound 50)

S (+) - O- [1-Azabicyclo [222] -oct-3-yl) -methyl-N-methylidene-hydroxylamine (Compound 51)

Example 7

R (-) - O - [(1-Azabicyclo [222] -oct-3-yl) -methyl-N-ethylidene-hydroxylamine hydrochloride (Compound 28)

A mixture of R (-) - O - [(1-azabicyclo [222] -oct-3-yl) -methyl] -hydroxylamine dihydrochloride (1.5 g), methanol (25 ml) and sodium (300 mg) was stirred at at room temperature until the sodium disappeared, it was then cooled in an ice bath and acetaldehyde (0.37 ml) was added dropwise. The solution was stirred at room temperature for 2 h and then the reaction mixture was evaporated to dryness. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was basified with Na ₂ CO ₃ and extracted into CHC1 ₃ . The organic layers were combined, dried and evaporated to dryness. The crude residue was dissolved in ethyl acetate to give the desired compound as the hydrochloride salt by the addition of anhydrous HCl solution in diethyl ether. The solid was filtered and dried in vacuo. The pure title compound was obtained as a white solid (0.34 g).

Tal. = 135-140 ° C

MS (CI) = 183 m / e [M + Η] [a] _D = - 39.46 (c = 1% in IN HCl)

Ή-NMR [CDCl 3 1.7-2.8 (6H, m), 1.81 and 1.84 (3H, 2d), 2.9 - 3.7 (6H, m), 4.03 and 4, 13 (2H, 2d), 6.76 and 7.39 (1H, 2q), 12.05 (1H, b)

Analysis: C _{1 ()} H ₁₉ C1N ₂ O

C H N Cl Found :% 54.18 8.82 12,63 16.15 Calculated:% 54.91 8.76 12,81 16,24

Following the method described above and from suitable intermediates, the following compounds were prepared

S (+) - O- (1-Azabicyclo [222] -oct-3-yl) -methyl] -N-ethylidene-hydroxylamine hydrochloride (Compound 29)

Tal. 145-150 ° C

MS (CI) = 183 m / e [M + Η] [a] _D = + 41.63 (c = 1% in IN HCl)

Ή-NMR (CDCl ₃ ) 1.7-2.7 (6H, m); 1.80 and 1.84 (3H, 2d), 2.9-3.7 (6H, m), 4.04 and 4.12 (2H, 2d), 6.76 and 7.39 (1H, 2q) ), 12.08 (1H, b)

Analysis: C ₁₀ H ₁₉ ClN ₂ O

C H N Cl Found :% 54.42 8.79 12.66 16,18 Calculated:% 54.91 8.76 12,81 16,24

O- (1-ethyl-1-azacyclobut-3-yl) -N-ethylidene-hydroxylamine (Compound 31) (±) -O- (1-methyl-1-azacyclopent-3-yl) -N-ethylidene-hydroxylamine oxalate (Compound 33)

Tal. 105-109 ° C, dec.

MS (C.I.) = 143 m / e [M + Η]

Ή-NMR [DMSO] 10.24 (b, 2H); 7.47 and 6.95 (2q, 1H); 4.81 (m, 1H); 3.2-3.6 (4H), 2.80 (s, 3H); 2.30 (m, 1H); 2.07 (m, 1H); 1.78 and 1.80 (2d, 3H).

Analysis: C ₉ H ₁₆ N ₂ O ₅

H N

7.04 11.80

6.94 12.06

C

Found:% 46.39

Calculated:% 46.55 (±) -O- (1-methyl-1-azacyclohept-3-yl) -N-ethylidene-hydroxylamine maleate (Compound 35)

Tal. 95-100 ° C, dec.

MS (C.I.) = 171 m / e [M + Η]

Ή-NMR [CDCl ₃ ] 7.48 and 6.85 (2q, 1H); 6.29 (s, 2H); 4.53 (b, 1H); 3.1 - 3.7 (b, 4H),

2.92 (s, 3H); 1.6-2.2 (6H); 1.87 (d, 3H). Analysis: C ^ H ^ N ^ C H Found :% 54.12 7.75 Calculated:% 54.53 7.74

N

9.59

9.78

O- (1-methyl-1-azacyclohex-4-yl) -N-ethylidene-hydroxylamine fumarate (Compound 37)

Tal. 90-95 ° C, dec.

MS (C.I.) = 157 m / e [M + Η]

Ή-NMR [DMSO + CDCl ₃ ] 10.64 (b, 2H); 6.80 and 7.42 (2q, 1H); 6.57 (s, 2H); 4.12 (m, 1H); 2.4-3.1 (4H), 2.46 (s, 3H); 1.79 (d, 3H); 1.7-2.2 (4H).

Analysis: C ^ N ^

C H N Found :% 52.67 7.59 10,22 Calc .:% 53.93 7.40 10,29

(±) -O- (1-methyl-1-azacyclohex-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 39)

Tal. 150-157 ° C, dec.

MS (C.I.) = 157 m / e [M + Η]

Ή-NMR [CDCl 3 12.7 and 11.7 (2b, 1H); 7.80, 7.36 and 6.83 (3m, 1H); 4.48 (m, 1H); 3.58 (m, 2H); 2.84 (s, 3H); 2.6-3.2 (2H); 1.5-2.4 (4H); 1.82 and 1.83 (2d, 3H). Analysis: C ₈ H _1? C1N ₂ O

C H N Cl Found :% 49.56 8.99 14,44 18,32 Calculated:% 49.87 8.89 14,54 18.40

R-O - [(1-Azabicyclo [222] -oct-3-yl) -N- (2,2,2-trichloro-ethylidene) -hydroxylamine hydrochloride (Compound 40)

Tal. 225 ° C, dec.

MS (CI) = 272 m / e [M + Η] [a] _D = - 30.0 (c = 1% in EtOH)

Ή-NMR [CDCl 3 12.24 (b, 1H); 7.90 (s, 1H); 4.73 (m, 1H); 3.70 (m, 1H); 3.2 - 3.6 (5H); 2.61 (b, 1H); 1.8-2.3 (4H). Analysis: C ₉ H ₁₄ C1 ₄ N ₂ O C H N Cl Found:% 34.80 4.65 8.99 46,18 Calc .:% 35.09 4,58 9.09 46.05

S-O - [(1-Azabicyclo [222] -oct-3-yl) -N- (2,2,2-trichloro-ethylidene) -hydroxylamine hydrochloride (Compound 41)

Tal. 225 ° C, dec.

MS (CI) = 272 m / e [M + Η] [a] _D = + 31.3 (c = 1% in EtOH)

1 H-NMR [CDCl 3 12.55 (b, 1H); 7.84 (s, 1H); 4.70 (m, 1H); 3.62 (m, 1H); 3.2 - 3.5 (5H); 2.62 (b, 1H); 1.7-2.3 (4H).

Analysis: C ₉ H ₁₄ C1 ₄ N ₂ O

C H N Cl Found :% 34.47 4,50 8.84 46.11 Calculated:% 35.09 4,58 9.09 46.05

R-O - [(1-Azabicyclo [222] -oct-3-yl) -N- (2,2-dichloro-ethylidene) -hydroxylamine fumarate (Compound 42)

Tal. 170-172 ° C, dec.

MS (CI) = 238 m / e [M + Η] [a] _D = - 30.73 (c = 1% in EtOH)

Ή-NMR [DMSO + CDCl ₃ ] 8.18 (b, 2H); 7.81 and 7.32 (2d, 1H); 7.16 and 6.79 (2d, 1H); 6.56 (s, 2H); 4.49 (m, 1H); 3.42 (m, 1H); 2.8 - 3.2 (5H); 2.26 (m, 1H); 1.5-2.0 (4H).

Analysis: C ₁₃ H _lg Cl ₂ N ₂ O ₅

C H N Cl Found :% 44.04 5.20 8.01 19,95 Calculated:% 44,21 5.14 7.93 20.08

S-O - [(1-Azabicyclo [222] -oct-3-yl) -N- (2,2-dichloro-ethylidene) -hydroxylamine fumarate (Compound 43)

Tal. 172-174 ° C, dec.

MS (CI) = 238 m / e [M + Η] [a] _D = - 31.61 (c = 1% in EtOH)

Ή-NMR [DMSO + CDCl ₃ ] 9.75 (b, 2H); 7.81 and 7.34 (2d, 1H); 7.16 and 6.80 (2d, 1H); 6.56 (s, 2H); 4.47 (m, 1H); 3.44 (m, 1H); 2.8 - 3.2 (5H); 2.24 (m, 1H); 1.5-2.0 (4H).

Analysis: C ₁₃ H _lg Cl ₂ N ₂ O ₅

C H N Cl Found :% 44.04 5,22 7.85 20.19 Calculated:% 44,21 5.14 7.93 20.08

R-O - [(1-Azabicyclo [222] -oct-3-yl) -N- (1-fluoro-ethylidene) -hydroxylamine fumarate (Compound 46)

Tal. 118-121 ° C, dec.

MS (CI) = 187 m / e [M + Η] [a] _D = - 29.7 (c - 1% in EtOH)

Ή-NMR [DMSO] 6.52 (s, 2H); 4.34 (m, 1H); 3.42 (m, 1H); 2.9-3.2 (5H); 2.27 (m, 1H); 2.19 and 2.04 (2d, 3H); 1.5-2.0 (4H).

Analysis: C ₁₃ H ₁₉ FN ₂ O ₅

Found:% Calc .:%

C

51.35

51.65

H

6.40

6.34

N

9:18

9.27

S-O - [(1-Azabicyclo [222] -oct-3-yl) -N- (1-fluoro-ethylidene) -hydroxylamine fumarate (Compound 47)

Tal. 140 ° C, dec.

MS (CI) = 187 m / e [M + Η] [a] _D = + 28.87 (c = 1% in EtOH)

1 H-NMR [DMSOj 8.2 (b, 2H); 6.53 (s, 2H); 4.35 (m, 1H); 3.42 (m, 1H); (5H); 2.18 and 2.04 (2d, 3H); 1.5-2.0 (4H); 2.28 (m, 1H).

2.9 - 3.2

Analysis: C ₁₃ H ₁₉ FN ₂ O ₅ C H Found :% 51.13 6.45 Calculated:% 51.65 6.34

N

9.12

9.27

S-0 - [(1-Azabicyclo [222] -oct-3-yl) -N-methylene-hydroxylamine hydrochloride (Compound 48)

Tal. 80-90 ° C, dec. (hygroscopic solid)

MS (CI) = 155 m / e [M + Η] [a] _D = + 25.78 (c = 1% in MetOH)

Ή-NMR [DMSO] 10.86 (b, 1H); 7.16 (d, 1H); 6.75 (d, 1H); 4.56 (m, 1H); 3.0-3.6 (6H); 1.5-2.4 (5H).

Analysis: C _g H ₁₆ Cl ₂ N ₂ O

C H N Cl Found :% 41.94 7.19 12,20 31,32 Calculated:% 42.30 7.10 12.33 31,22

R-O - [(1-Azabicyclo [222] -oct-3-yl) -N-methylene-hydroxylamine hydrochloride (Compound 49)

Tal. 145-150 ° C, dec.

MS (CI) = 155 m / e [M + Η] [a] _D = - 26.32 (c = 1% in MetOH)

Ή-NMR [DMSO] 7.16 (d, 1H); 6.74 (d, 1H); 4.56 (m, 1H); 3.56 (m, 1H); ~ 3.6 (b, 1H); 3.0-3.3 (5H); 2.30 (m, 1H); 1.6-2.0 (4H).

Analysis: CgH ^ Cl ^ O

C H N Cl Found :% 41,96 7.21 12.30 31.04 Calculated:% 42.30 7.10 12.33 31,22

Example 8

Endo-O- (8-methyl-8-azabicyclo [321] -oct-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 44)

Acetaldehyde oxime (1.97 ml) was added portionwise to a solution of sodium (0.237 g) in ethanol (10 ml). The solution was stirred for 15 min and then endo-8-methyl-3-chloro-azabicyclo [321] -octane (5.16 g) was added [J. Am. Chem. Soc. 80, 4677 (1958)]. The solution was refluxed for 15 hours, then cooled in an ice bath and the pH adjusted to pH 9 with ethanol solution. The inorganic salts were filtered off and the solution was evaporated to dryness. The crude residue was purified by flash column chromatography on silica gel (eluent: 95: 5: 0.5: CH ₂ Cl ₂ : CH ₃ OH: 30% Ni NH ₄ OH). The crude product obtained was dissolved in ethyl acetate, anhydrous HCl solution in diethyl ether was added and the solution was evaporated to dryness. Crystallization from diethyl ether gave the title compound as a solid (0.13 g).

Tal. 160 ° C

MS (C.I.) = 183 m / e [M + Η]

NM-NMR [DMSO + CDCl ₃ ] 1.81 (3H, d), 2.0 - 3.4 (8H, m), 2.68 (3H, d), 3.82 (2H, b), 4 , 26 (1H, m), 6.86 and 7.44 (1H, 2q), 11.36 (1H, b)

Analysis: C ₁₀ H ₁₉ ClN ₂ O

C H N Cl Found :% 53.55 8.83 12,49 15.98 Calc .:% 54.91 8.76 12,81 16,21

Following the method described above, the following compound was prepared:

O- (1-methyl-1-azacyclohex-4-yl) -N-isopropylidene-hydroxylamine hydrochloride (Compound 45)

Tal. 140 ° C

MS (C.I.) = 171 m / e [M + Η]

Ή-NMR [DMSO + CDCl ₃ ] 1.8 - 2.4 (10H, m), 2.73 (3H, d), 2.7 - 3.6 (4H, m), 4.26 (1H, m), 10.92 (1H, b)

Analysis: C ₉ H ₁₉ C1N ₂ O

C H N Cl Found :% 51.54 9.30 13,25 16.88 Calc .:% 52.29 9.26 13,53 17.15

Example 9

a) (±) N - [(1-azacyclohex-3-yl) -oxy] -phthalimide

Solution of N - [(1-methyl-1-azacyclohex-3-yl) oxy] phthalimide (1.1 g) and 1,8-bisdimethylamino-naphthalene (proton sponge) (0.9 g) in 1,2-dichloroethane (50 ml) was cooled to 5 ° C and 1-chloro-ethyldichloroformate (0.6 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature and then washed first with dilute aqueous Na ₂ CO ₃ solution and then with dilute aqueous HCl. The organic layer was dried and evaporated to dryness. The crude residue was dissolved in methanol (50 ml) and the resulting solution was refluxed for 2 hours and then evaporated to dryness. The crude intermediate obtained (0.9 g, after crystallization from a mixture of ethyl acetate and diethyl ether, m.p. 233-236), was sufficiently pure to be used in the next step.

b) (±) O- (1-Azacyclohex-3-yl) -hydroxylamine dihydrochloride

The intermediate (0.87 g) described above was dissolved in absolute ethanol (35 ml) and aqueous 85% hydrazine was added dropwise while stirring. The reaction mixture was stirred for 3 hours at room temperature and filtered. The clear solution was acidified with aqueous 10% HCl solution and then evaporated to dryness. Crystallization from ethanol gave 0.45 g of the title compound as a white solid, m.p. Mp 158-161 ° C.

Example 10

O- (1-Azacyclohex-4-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 36)

A solution of O- (1-methyl-1-azacyclohex-4-yl) -N-ethylidene hydroxylamine (0.4 g) and 1,8bis-dimethylamino-naphthalene (proton sponge) (0.55 g) in 1,2- dichloroethane was cooled to 5 ° C. While stirring, 1-chloroethyl chloroformate (0.34 ml) was added dropwise to the reaction mixture and stirred at room temperature overnight. An aqueous solution of Na ₂ CO _{3 was added} , the organic layer was separated, washed with 5% aqueous hydrochloric acid and evaporated to dryness. The residue was dissolved in methanol and the resulting solution was refluxed for 1 hour. From the solution after purification to dryness, crude hydrochloride of the title compound was obtained. After crystallization from ethyl acetate 0.180 g.

Tal. 130-140 ° C, dec.

MS (C.I.) = 143 m / e [M + Η]

Ή-NMR [DMSO + CDCl ₃ ] 9.16 (b, 2H); 7.45 and 6.85 (2q, 1H); 4.25 (m, 1H); 3.07 (m, 4H); 1.97 (m, 4H); 1.80 (d, 3H).

Analysis: C ₇ H ₁₅ C1N ₂ O

C H N Cl Found :% 46.81 8.56 15,48 19.70 Calc .:% 47.06 8.46 15.60 19,84

Following the method described above and from suitable intermediates, the following compounds can be prepared:

O- (1-azacyclobut-3-yl) -N-ethylidene-hydroxylamine (Compound 30) (±) O- (1-azacyclopent-3-yl) -N-ethylidene-hydroxylamine, oxalate (Compound 32)

Tal. 150 ° C, dec.

MS (C.I.) = 129 m / e [M + Η]

Ή-NMR [DMSO] 9.27 (b, 3H); 7.46 and 6.96 (2q, 1H); 4.78 (m, 1H); 3.1-3.4 (4H); 2.08 (m, 2H); 1.77 and 1.80 (2d, 3H).

Analysis: C _g H ₁₄ N ₂ O ₅

C H N Found :% 42.98 6.31 12,62 Calculated:% 44.03 6.47 12,84

(±) O- (1-Azacyclohept-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 34)

Tal. 110 ° C, dec.

MS (C.I.) = 157 m / e [M + Η]

Ή-NMR [DMSO] 9.89 (b, 1H); 9.36 (b, 1H); 7.57 and 6.83 (2q, 1H); 4.58 (m, 1H); 3.2-3.6 (4H); 1.6-2.3 (6H); 1.86 and 1.91 (2d, 3H).

Analysis: C _g H ₁₇ ClN ₂ O

Found :%

C

50.10

H

8.99

N

14,27

Cl

18,25

Calc .:% 49.87 8.89 14.54 18.40 (±) O- (1-Azacyclohex-3-yl) -N-ethylidene-hydroxylamine hydrochloride (Compound 38)

Tal. 98-100 ° C, dec.

MS (C.I.) = 143 m / e [M + Η]

1 H-NMR [CDCl 3 9.84 (b, 1H); 9.22 (b, 1H); 7.60 and 6.84 (2q, 1H); 4.45 (m, 1H); 3.0-3.4 (4H); 1.7-2.2 (4H); 1.85 and 1.96 (2d, 3H).

Analysis: C _? H ₁₅ C1N ₂ O

C H N Cl Found :% 46.45 8.52 15.58 19,78 Calculated:% 47.06 8.46 15.60 19,84 Example 11 Pills - active substance 50 mg 100 mg - lactose 100 mg 200 mg - corn starch 4 mg 8 mg - Magnesium stearate 0.95 mg 1,80 mg

Preparation process: The active ingredient, lactose and part of cornstarch were mixed and granulated to 10% cornstarch paste. The resulting granulate is sieved, dried and mixed with the rest of the corn starch and magnesium stearate. The resulting granulate was then compressed into tablets containing 50 mg and 100 mg of active ingredient per tablet.

Claims (11)

PATENT APPLICATIONS 1. Compounds of general formula (I) A- (CH ₂ ) _n -ON = R ₂ in which A represents a residue of 4- to 8-membered azacycloalkane or 7- to 9-membered azabicycloalkane, which is optionally N-substituted with C _{x 3} alkyl; n is 0 or 1; and R4 are independently hydrogen; unbranched or branched alkyl optionally substituted by alkoxy groups, alkyl mercapto, CN or halogen; _C2 ^ alkenyl; _C2 ^ alkynyl; halogen; aryl optionally substituted by halogen, C _{x 3} alkyl, C ₁₃ alkoxy; C ₆₁₂ aralkyl; heteroaryl; or together with the carbon atom to which they are attached, form a 4- to 7-membered ring; wherein the chain - (CH ₂ ) _n -ON = CR ₁ R _{2 is} attached to carbon atoms other than the nitrogen atom of azacycloalkane or azabicycloalkane and their acid addition salts, their optical and geometric isomers and their diastereoisomers and mixtures thereof. Compounds according to claim 1, characterized in that the azacycloalkane residues A are 1-azacyclobut-3-yl, 1-azacyclopent-3-yl, 1-azacyclohex-3-yl, 1-azacyclohex-4yl and 1-azacyclopent- A 3-yl group optionally N-substituted with C ₁₃ alkyl. Compounds according to claim 1, characterized in that the azabicycloalkane residues A are 1-azabicyclo [2.2.1] -hept-3-yl, 1-azabicyclo [2.2.2] -oct-3-yl, 1-azabicyclo [ 3.2.1] -oct3-yl, 1-azabicyclo [3.2.1] -oct-6-yl, 1-azabicyclo [3.3.1] -non-3-yl, and 8-azabicyclo [3.2.1] -oct- 3-yl, optionally N-substituted by alkyl. Compounds of general formula (I) according to any one of the preceding claims, characterized in that A is an azabicycloalkane residue, n is 0, R 1 is hydrogen, lower C ₁₂ alkyl or halogen and is hydrogen or lower C ₁₃ alkyl containing optionally an alkoxy group or halogen, _C2 ^ alkynyl or halogen. A compound according to any one of the preceding claims, characterized in that it is selected from R (-) - (O) - (1-azabicyclo [222] oct-3-yl) -N-ethylidene-hydroxylamine hydrochloride, (±) -exo-O- (1-azabicyclo [321] oct-3-yl) ) -N-ethylidene-hydroxylamine hydrochloride, (±) -exo-O- (1-azabicyclo [321] oct-3-yl) -N-ethylidene-hydroxylamine fumarate, (±) -exo-O- (1-azabicyclo) [321] oct-3-yl) -N-ethylidene-hydroxylamine fumarate, S (+) -O- (1-azabicyclo [222] oct-3-yl) -N- (2.2.2-trifluoroethylidene-hydroxylamine fumarate). 6. Physiologically acceptable acid addition salts of the compounds of general formula (I) according to claims 1 to 5. Salts according to claim 6, characterized in that the physiologically acceptable acids are hydrochloric, tartaric or fumaric acid. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that azacyclo or azabicyclo O-substituted hydroxylamine of formula II A-tCH2-O-NH, (II) is reacted with a carbonyl derivative of formula III Λ o - ^c x (III) r ₂ where A, n, R ₃ and R ₂ are as defined in claim 1, in a hydroxyl solvent at a temperature from 0 ° C to the boiling point of the selected solvent. Process according to claim 8, characterized in that the hydroxyl solvent is selected from methanol, ethanol and isopropanol. Pharmaceutical preparations characterized in that they contain as an active ingredient an effective amount of a compound of formula (I) as defined in claim 1, or physiologically acceptable acid addition salts thereof, together with pharmacologically acceptable carriers, diluents or excipients. 11. Pharmaceutical preparations according to claim 10 for use in the treatment of patients suffering from neurological and mental disorders, in particular cognitive impairment, age-related memory impairment, various forms of dementia, Alzheimer's disease, Huntington's chorea, tardive dyskinesia, in hyperkinesis and Tourette syndrome.