AZACYCLICANDAZABICYCLIC HYDROXYLAMINESAS MUSCARINIC RECEPTOR AGONISTS

The present invention relates to a class of phar¬ macologically active azacyclic and azabicyclic alkyli¬ den hydroxylamines, to the process for their produc¬ tion, to the pharmaceutical compositions containing them. The new compounds stimulate cortical cholinergic neurotransmission and therefore they are useful in the treatment of neurological and mental diseases whose clinical manifestations are due to impaired cholinergic transmission. Cognitive disorders are characterized by symptoms of forgetfulness, confusion, memory loss and affective disturbance. They may arise as a consequence of the normal aging process or, under pathological conditions, from an organic brain disease. The etiology and the pathogenesis of those mental diseases are still unk¬ nown. Several neurotransmitter systems (acetylcholine, noradrenaline, dopamine, serotonin, GABA, etc.), which are involved in the communication across the synapses from one cell to the other in brain areas associated with the cognitive functions, become impaired, but the evidence of the central role of the cholinergic system is overwhelming [Coyle, J.J. et al., Science, 219, 1184 (1983); Briley M. et al., Pharmacopsych. 2J3, 75 (1990)]. Diseases ascribed to a cholinergic deficiency include presenile and senile dementia (also known as Alzheimer\'s disease) Huntington\'s chorea, tardive dyskinesia, hyperkinesia, mania and Tourette syndrome. Many of the symptoms of these disorders are associated with the observed decrease of acetylcholine synthesis

and the impairment or the loss of cholinergic neurons just in specific brain areas such as cerebral cortex and hippocampus [Davies et al. , The Lancet 2_, 1403 (1976); Perry et al., J. Neurol. Sci. 3_2, 247 (1977)]. According to this "cholinergic hypothesis", diffe¬ rent strategies have been attempted to restore acetyl¬ choline levels or to mimic the action of the natural transmitter itself in the treatment of the above de¬ scribed diseases [Kuman V. et al.. Int. J. Clin. Phar- macol. 29_, 23 (1991)]. Acetylcholinesterase inhibitors such as physostigmine or tacrine, which increase the available amount of acetylcholine in the synaptic cleft by blocking the inactivating enzyme, have been proposed [Drachnan D.A. et al.. Arch. Neurol. 3_7_, 674 (1980); Summers .K. et al., New Engl. J. Med. 315, 1241 (1986)]. Also compounds which promote acetylcholine synthesis or its release from the containing vesicles have 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 straightforward way of improving CNS functions linked to a cholinergic pathway, appears to be the direct sti¬ mulation of the cholinergic muscarinic receptors the - selves. These receptors may became lost or damaged in the presence of those diseases, but there is an increa¬ sing evidence that in patients suffering from dementia there is a differential loss of muscarinic receptor si¬ tes: the pronounced decrease of presynaptic cholinergic terminals in cerebral cortex and hippocampus is not ac¬ companied by significant changes or losses of the post-

synaptic muscarinic receptor [Quirion R. , J. of Neu- roch. 1914 (1988); Caulfield M.P. et al. , The Lancet, 1277 (1982)].

The use of drugs activating the central muscarinic sites has been so far limited or disappointing, owing to unfavourable circumstances. Most of the known musca¬ rinic agonists possess quaternary ammonium groups (for instance carbachol) and therefore are expected not to cross the blood brain barrier following peripheral ad- ministration. Arecoline, aceclidine and RS86, posses¬ sing a tertiary amine group, can penetrate the brain. However, the onset of side effects (miosis, lacrima- tion, motility disturbances and cardiac effects) coming from the activation of peripheral muscarinic receptors, has been observed; moreover the former two compounds have a very limited duration of action owing to the presence of an easily hydrolyzable ester group [Davidson M. et al. , Current Research in Alzheimer The¬ rapy, Giacobini E. and Becker R. Editors; Taylor-Fran- cis, New York 333 (1988)].

The recent discovery of at least five structurally distinct subtypes of muscarinic receptors [Bonner J.J. et al. , Science 237, 527 (1987); Bonner J.J. et al., Neurochem. _1, 403 (1988] and the classification into three subtypes (M. , M_ and M, ) according to functional tests (Birdsall N.N. et al. "Nomenclature for muscari¬ nic receptor subtypes" in Subtypes of Muscarinic Recep¬ tors IV; Levine R.R. Editor, Trends Pharmac. Sci. VII), has renewed the interest for the cholinomimetic appro- ach.

Accordingly, the target of recent research in the

cholinomimetic field is the selective activation of the M.. muscarinic receptor subtype which is postsynapti- cally placed in the cholinergic neurones and, as said before, is still present in the damaged cerebral areas. The inability to activate M_ and M~ subtypes is highly sought as these latter are responsible for unwanted effects resulting from peripheral cholinergic stimulation. This aspect is particularly relevant con¬ sidering that a large amount of a drug penetrating into the CNS, is however present in the periphery. Moreover, the lack of agonistic activity at M_ subtypes could be favourably accompanied by a weak antagonistic effect at the same receptor subtypes. It has been suggested that the release of acetylcholine is negatively regulated by a feed-back mechanism, mediated by the endogenous ago¬ nist acting at a presynaptic muscarinic receptor of M_ subtype. Thus the beneficial effect coming from direct stimulation of M, receptors will be boosted by a incre¬ ased amount of the acetylcholine released. It has now been found, and this is the object of the present invention, a new class of compounds which possess good affinity for the muscarinic receptors and are able to stimulate the same receptors. An additional favourable feature of the these compounds, included in the present invention, is their capacity to activate differentially the M. , M„ and M ₃ muscarinic receptor subtypes owing to a different intrinsic efficacy. As a consequence, certain of the compounds, here provided, possess a selective stimulant action at the M, receptor sites relative to the M_ and M_, . In other particular compounds the selective stimulant effect at the M. sub-

type is even increased by an antagonistic effect at the M_ subtype.

These new compounds can be useful in the treatment or in the prevention of disorders related to a central cholinergic deficit. In particular their use may be be¬ neficial in the treatment of cognitive disorders, age associated memory impairment, in different forms of de¬ mentia, in Alzheimer\'s disease, in Huntington\'s chorea, in tardive dyskinesia, in hyperkinesia, in Tourrette syndrome. Moreover, as centrally acting muscarinic agents, the compounds included in the present invention can be also of use as analgesics in the treatment of pain.

According to the present invention, we provide compounds of general formula (I)

wherein: A represents the residue of a 4-8 membered azacyclo- alkane, or of a 7-9 membered azabicycloalkane, op¬ tionally N- substituted by a C, . alkyl; n represents 0 or 1; R, and R~ represent independently hydrogen; linear or branched ^c _τ _ _fi alkyl optionally substituted by alkoxy groups, alkylmercapto, CN or by halogen; C ₂ _ ₆ alkenyl; C__, alkynyl; halogen; aryl optio¬ nally substituted by halogen, C. ., alkyl, C, _, alkoxy; C^ i _? aralkyl; heteroaryl; or together with the carbon atom to which they are linked, re¬ present a 4-7 membered ring; the chain -(CH„) -0-

N=CR,R ₂ being linked to carbon atoms not close to the nitrogen atom of azacycloalkane or azabicyclo- alkane.

Non-limitative examples of azacycloalkane reside A are l-azacyclobut-3-yl, l-azacyclopent-3-yl, 1-azacy- clohex-3-yl, l-azacyclohex-4-yl and l-azacyclopent-3-yl groups, optionally N-substituted by C _1-3 alkyl.

Non-limitative examples of azabicycloalkane resi¬ due A are l-azabicyclo[2.2.l]-hept-3-yl, 1-azabicy- clo[2.2.2]-oct-3-yl, l-azabicyclo[3.2.l]-oct-3-yl, 1- azabicyclo[3.2.l]-oct-6-yl, l-azabicyclo[3.3.1]-non-3- yl, and 8-azabicyclo[3.2.l]-oct-3-yl groups optionally N-substituted by C, ₃ alkyl.

When in the compounds of formula (I) R, and R ₂ re- present a linear or branched C, _g alkyl group, it may, for example, be methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, 2-methylpentyl and the like. When R, and R- represent an alkyl groups optionally contai¬ ning a substituent, they may be, methoxyethyl, methyl- thioethyl, ethylthioethyl or cyanoethyl. The term halo¬ gen means fluorine, chlorine, bromine and iodine. Pre¬ ferred halogens are fluorine, chlorine and bromine, particularly fluorine and chlorine. When R, and R ₂ re¬ present C ₂ _ _fi alkenyl group, it may, for example, be al- lyl or 3-methyl-buten-2-yl. When R, and R ₂ represent ^~ ₂ _ _c alkynyl group, it may, for example, be propargyl. When R, and R ₂ represent an aryl group, it may, for example, be phenyl, optionally substituted by one or more substituents selected from methyl, ethyl, methoxy, ethoxy, fluorine, chlorine or bromine. When R, and R_ represent a C _fi _ ₁₂ aralkyl group, it may, for example,

be benzyl. When R, and R_ are heteroaryl, it may, for example, be a 5-6 membered ring containing 1-3 heteroa- toms, such as furan, pyridine, piridazine, oxadiazole. When R, and R~ together with the carbon atom to which they are linked represent a 4 to 7 membered ring, it may, for example, be cyclobutane or cyclopentane.

Compounds according to the present invention, which possess one or more asymmetric carbon atoms can exist as the optical active enantiomers with a defined configuration, or they can exist as a particular dia- stereoisomer or a diastereoisomeric mixture and also as a full racemic mixture. In addition some of the com¬ pounds of the present invention can exist as endo and exo isomers; the term endo is here referred to that possessing the hydroxylamine side chain on the opposite side of the methylene bridge -(CH ₂ ) . Moreover, accor¬ ding to the peculiar features of the oxime group, which is part of the compounds of the present invention, an additional isomerism of geometric type can be present. Compounds possessing E or Z configuration originate from the oxime group isomerism. Compounds possessing this type of isomerism can be obtained in a single form or as a mixture; in particular cases one isomer may be converted to the other. It is to be understood that the invention covers all such isomers both of optical and geometric type and mixture thereof.

A preferred group of compounds, according to the present invention, is the one formed by the compounds of general formula (I) wherein A is the residue of an azabicycloalkane, n is o, R, is hydrogen, lower C, ~ alkyl group or halogens and R_ is hydrogen or lower

C,_, alkyl group optionally substituted by alkoxyl or halogen, ₂ _ _g alkynyl or halogen.

Particularly preferred compounds, according to the present invention, are the following: R(-)-0-(1-Azabicyclo[2.2.2]oct-3-yl)-N-ethylidenhydro- xylamine, hydrochloride (Compound 2)

(±)-Exo-O-(1-Azabicyclo[3.2.1]oct-6-yl)-N-ethylidenhy- droxylamine, hydrochloride (Compound 22)

(±)-Exo-O-(1-Azabicyclo[2.2.1]hept-3-yl)-N-ethylidenhy- droxylamine, fumarate (Compound 20)

(±)-Exo-O-(1-azabicyclo[3.2.1]oct-3-yl)-N-ethylidenhy- droxylamine fumarate

(Compound 24)

S(+)-0-(1-azabicyclo[2.2.2]oct-3-yl)-N-(2.2.2-trifluo- roethyliden)-hydroxylamine, fumarate

(Compound 7)

The compounds of general formula (I) may, for example, be prepared by the following process which constitute a further feature of the present invention. Compounds of formula (I) are obtained by reacting azacyclo or azabicyclo O-substituted hydroxylamine of formula (II) with a carbonyl derivative of formula ( III )

in which A, n, R, and R ₂ are as hereinbefore defined.

The reaction can be conveniently carried out in an hy- droxylic solvent selected from methanol, ethanol, iso- propanol, or in tetrahydrofuran or in toluene prefera-

bly in methanol. The reaction temperature is generally kept between 0°C and the boiling point of the solvent of choice, preferably at room temperature. The interme¬ diates of formula (II) used as starting material may be used as free bases or, if desired, as salt addition de¬ rivatives.

The intermediates of formula (II) of the previou¬ sly described process, can be prepared, in turn, by re¬ ducing O-substituted hydroxy-phthaloyl derivatives of general formula (IV)

wherein A and n are as hereinbefore defined.

The process is carried out by means of a suitable reducing agent such as hydrazine hydrate or ethanola- ine , preferably hydrazine hydrate in an alcoholic sol¬ vent such as methanol , ethanol and isopropanol , prefe- rably methanol . The temperature of the reaction process is kept between 10 °C and 80 °C preferably at room tempe¬ rature .

The phthaloyl derivatives of general formula ( IV) are conveniently obtained from the suitable azacyclic or azabicyclic hydroxy derivative of formula (V) and hydroxyphthalimide ( VI ) , according to a procedure known as the Mitsunobu reaction [Mitsunobu 0. , Synthe¬ sis 1 ( 1981) ]

(V) (VI ) wherein A and n are as hereinbefore defined.

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

The key intermediates of formula (III) and (V) (hydroxyl derivatives) used in the steps of the descri- bed process are commercially available or obtained ac¬ cording to already known proceedings described in the literature.

According to a different option, the compounds of general formula (I) can be prepared by reacting a com- pound of formula (VII) with an oxime of formula (VIII)

(VII) (VIII) wherein R, , R ₂ , A and n are as hereinbefore defined, and X is a suitable leaving groups such as mesyl or tosyl or halogen, preferably chlorine.

The reaction is carried out in a protic or 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 kept

between 30°C and 100°C preferably at 60°C. Oximes of formula (VIII) are obtained by reacting carbonyl com¬ pound of formula (III) previously described with hy- droxylamine hydrochloride in methanol at room tempera- ture, according to a well known procedure (Organic Fun¬ ctional Groups Preparation, Vol. Ill Sec. Edition by Sadler and Karo, Academic Press S. Diego, 1989).

The compounds of general formula (I) may be, if desired, converted into the corresponding salts of phy- siologically acceptable inorganic or organic acid by conventional methods, for example by reacting the com¬ pounds as bases with a solution of the corresponding acid in a suitable solvent.

Examples of salts of physiologically acceptable acids are those formed with hydrochloric, fumaric, ma- leic, succinic, citric, tartaric, phosphoric, sulphu¬ ric, salicylic, lactic, gluconic, aspartic or methane- sulphonic acid [see for example Berg S.M. et al. "Pharmaceutical "Salts" in J. Pharm. Sci. 6, 1 (1977)].

Particularly preferred acids include for example hydrochloric, tartaric and fumaric acid.

As already mentioned hereinbefore, the new com¬ pounds of formula (I) have interesting pharmacological properties owing to their capacity to stimulate the different muscarinic receptor subtypes M.,, M ₂ and M ₃ with an intrinsic efficacy which is peculiar to each subtype. Therefore the new compounds are therapeuti¬ cally useful in the treatment or in the prevention of disorders related to a central cholinergic deficit. In particular their use may be beneficial in the treatment

of cognitive disorders, age associated memory impair¬ ment, in different forms of dementia, in Alzheimer\'s disease, in Huntington\'s chorea, in tardive dyskinesia, in hyperkinesia, in Tourette syndrome. Moreover, as centrally acting muscarinic agents, the compounds in¬ cluded in the present invention can be also of use as analgesics in the treatment of pain.

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

The pharmaceutical formulations which constitute a further feature of the present invention comprise ta- blets, pills, capsules, powders, granules, sterile pa¬ renteral solutions or suppositories.

In the solid pharmaceutical compositions together with the active principle is used a suitable pharmaceu- tic carrier such as corn starch, lactose, sorbitol, ma- gnesium stearate, etc. The liquid forms in which the novel compounds may be incorporated for orally admini¬ stration or injection, include aqueous solutions, fla¬ voured syrup and emulsions with oils or other vehicles. Also dispersing or suspending agents are of use. It may be advantageous, in order to prevent pe¬ ripheral side effects, to include in the pharmaceutical composition a peripherally acting cholinergic antago¬ nist such as N-methylscopolamine, or glycopyrrolate or propantheline. Pharmacology

The affinity of the compounds (I) for the M. , M„

and M- muscarinic receptor subtypes was assessed "in vitro" by receptor binding studies in three tissues en¬ dowed with M. , M ₂ and M ₃ receptor subtypes (rat cere¬ bral cortex, heart and submandibular glands, respecti- vely) . The potency and the intrinsic activity of the compounds of formula (I) at M.,, M ₂ and M., receptor sub¬ types was checked in three functional models: the rat superior cervical ganglion (M.), the guinea pig atrium (M ₂ ) and the guinea pig ileum ( ₃ ). Receptor binding studies

Tissue Preparation. Rat tissues were removed, cle¬ aned, homogenized (w/v: cerebral cortex, 1:100; whole heart, 1:200; submandibular salivary glands, 1:200) with an Ultra- urrax at maximal speed for 30 s, fol- lowed by use of a Potter-Elvehjem homogenizer (30 strokes), in Na ⁺ -Mg ²⁺ -HEPES buffer, pH 7.4 (nM: NaCl, 100; MgCl ₂ , 10; HEPES, 20), and filtered through two layers of cheesecloth. Binding Experiments. Binding curves for the different compounds were derived indirectly from competition ex-

3 periments against 0.5 nM [ H]pirenzepine labelling the cerebral cortex muscarinic receptors, and 0.3 nM

3 [ H]NMS for the muscarinic receptors of the heart and submandibular glands. A 1 ml portion of homogenate was incubated for 45 min at 30°C in the presence of the marked ligand and different concentrations of the cold ligand. The incubation was terminated by centrifugation (12000 rpm for 3 min) at room temperature with an Ep- pendorf microcentrifuge. The resultant pellet was wa- shed twice with 1.5 ml of saline to remove the free ra¬ dioactivity and the final pellet was allowed to drain.

The tips of the tubes containing the pellet were cut off and 200 μl of tissue solubilizer (Lumasolve, Lumac) was added and left to stand overnight. Radioactivity was then counted after addition of 4 ml of liquid scin- tillation solution (Lipoluma, Lumac). Assays were car¬ ried out in triplicate and the nonspecific binding was defined as the radioactivity bound or entrapped in the pellet when the incubation medium contained 1 μM 3-qui- nuclidinyl benzylate racemic mixture (QNB) . Nonspecific binding averaged less than 30% and 10%, respectively. The inhibition constants (Ki) were calculated after correction for the radioligand occupancy shift with the equation of Cheng and Prusoff (see Cheng Y. et al., Biochem. Pharmacol. 22 _^ , 3099, 1973). The results are reported in Table I.

TABLE I

"In vitro" Receptor Binding Studies (Ki x 10 -6 M)

Functional studies

Rat superior cervical ganglion

Superior cervical ganglia were excised from male Sprague-Dawley rats, weighing 150-200 g, which had been anaesthetized with urethan (1.2 g/kg i.p.). Each gan¬ glion was desheathed under a microscope and then sub¬ merged in a three compartments bath. The ganglion body was situated in the central compartment and the pregan- glionic (cervical sympathetic) and postganglionic (internal carotid) trunks protruded through greased slots into two outer chambers. The central compartment (volume approx. 0.5 ml) was continually perfused (2-2.5 ml min ^" ) with Krebs-Henseleit solution at 25°C, pre- equilibrated with 5% carbon dioxide in oxygen; the same solution in the outer compartments was static. The me¬ dium was an aqueous solution containing (mM) : NaCl 124.1, KC1 4.8, NaHC0 ₃ 24.8, CaCl ₂ 2.5, MgS0 ₄ 1.2, KH ₂ P0 ₄ 1.2, glucose 10.

Ganglionic potential changes, induced by drug per- fusion, were recorded using Ag/AgCl electrodes between the chambers containing the ganglion body (earthed) and the postganglionic trunk. The potentials were amplified and plotted on a potentiometric chart recorder. After a 30\' stabilization period, 1 μM muscarine was superfused for 75 sec periods at 15 min intervals, until two con¬ secutive equally sized depolarizing responses were ob¬ served (usually 3-4 applications) . The last of these responses, measured in every experiment, was considered as standard maximum response. Following the return to a stable base-line, one agonist was superfused for 75 sec periods in increasing semi-logarithmic molar concentra-

tion units (e.g. 1, 3, 10 μM) until the maximum re¬ sponse was evoked. These applications were usually made at 10-15 min intervals, but longer intervals were used in case of a slower return to the base-line. After ob- taining the maximum response, pirenzepine was superfu¬ sed at 0.1 μM for 60 min, followed by re-determination of the agonist concentration-response curve in the pre¬ sence of pirenzepine in the superfusion medium. The concentration of agonist producing 50%, of its maximal response (EC-,.) was calculated by the least squares li¬ near regression analysis applied to the first concen¬ tration-response curve. The relative maximum (RM) was obtained by comparing the agonist maximum response to the standard maximum response to 1 μM muscarine taken as 1. To verify the muscarinic nature of the response to the agonist, the dose-ratio was calculated at the EC ₅₀ level from the rightward displacement by pirenze¬ pine of the concentration-response curve to the ago¬ nist, after checking for parallelism of the curves. The affinity value for pirenzepine (pA ₂ ) was calculated as described by Furchgott (Handbook of Experimental Phar¬ macology, vol. 33, H. Blaschko & E. Muschall (Eds.), 283-335, Springer-Verlag, Berlin, 1972): pA ₂ = -log ( [antagonist] /dose-ratio-1) . The results are reported in Table II.

TABLE II

"In vitro" functional studies

RM = Relative maximum, in comparison with the ef¬ fect of 1 μM muscarine taken as 1

The following examples illustrate some of the com¬ pounds according to the present invention, but they are not considered in any way limitative of the scope of the invention itself: Example 1 R (-)N-[(l-azabicyclo[2.2.2]-oct-3-yl)-oxy]-phthalimide

A mixture of S(+) 1 azabicyclo[2.2.2]-octan-3-ol

(37.5 g) [Eur. J. Med. Chem. 14_, 111 (1979)], triphenylphosphine (77.3 g), N-hydroxy-phthalimide

(48.1 g) and Molecular Sieve (70 g) in dry THF (750 ml) was stirred for 2 hours at room temperature and then cooled with ice-bath. Diethylazodicarboxylate (DEAD) (51.4 g) was added dropwise and the resulting solution was stirred overnight. Water was added (300 ml) and the Molecular Sieve filtered off; the THF was removed in vacuo and the residue, acidified with 10% aqueous HC1 solution, was washed 2-times with ethyl acetate. The

aqueous layer was basified with K ₂ C0 ₃ and extracted exhaustively with ethyl acetate. The combined organic layers were dried and evaporated to dryness to obtain the desired product as a white solid (33.5 g). M.p. > 280°C (ethanol, as hydrochloride salt)

MS (C.I.) = 273 m/e [M + H] Søtl _D = - 36.34° (c = 1% in IN HCl)

According to the above described procedure the following compounds have been prepared: s( + )N-[ (l-azabicyclo[2.2.2]-oct-3-yl)-oxy]-phtha- limide, starting from R(-) l-azabicyclo[2.2.2]-octan-3- ol [Eur. J. Med. Chem. 14_, 111 (1979)]

M.p. > 280°C (ethanol, as hydrochloride salt)

MS (C.I.) = 273 m/e [M + H] [rtl _D = +36.15° (c = 1% in IN HCl)

(±)-endo-N-[ (1-azabicyclo[2.2.1]-hept-3-yl)-oxy]-phtha- limide, starting from (±)-exo-l-azabicyclo[2.2.1]-hep- tan-3-ol [J. Org. Chem. 3_4, 3674 (1969)] M.p. = 220-225°C dec. (as hydrochloride salt). MS (C.I.) = 259 m/e [M+H]

(±)-exo-N-[ (l-azabicyclo[2.2.l]-hept-3-yl)-oxy]-phtha- limide, starting from (±)-endo-l-azabicyclo[2.2 ,l]-hep- tan-3-ol [EP 427390] M.p. 145-150°C MS (C.I.) = 259 m/e [M + H]

( ± ) -endo-N- [ l-azabicyclo[ 3.2.1] -oct-6-yl ) -oxy ] -phthali- mide, starting from (±)-exo-l-azabicyclo[3.2.l]-octan- 6-ol [J. Org. Chem. 3_3, 4376 (1968)] M.p. > 250°C (as hydrochloride salt) MS (C.I.) = 273 m/e [M + H]

(±)-exo-N-[ 1-azabicyclo[3.2.1]-oct-6-yl)-oxy]-phthali-

mide, starting from (±)-endo-l-azabicyclo[3.2.l]-octan-

6-ol [J. Org. Chem. 3_3, 4376 (1968)]

M.p. 148-152°C

MS (C.I.) = 273 m/e [M + H] (±)-endo-N-[1-azabicyclo[3.2.1]-oct-3-yl )-oxy]-phthali- mide , starting from (±)-exo-N-[ (l-azabicyclo[3.2.l]-oc- tan-3-ol [J. Org. Chem. 3_3, 4376 (1968), EP 257741]

M.p. = 110-118°C dec.

MS (C.I.) = 273 m/e [M + H] (±)-exo-N-[1-azabicyclo[3.2.1]-oct-3-yl)-oxy]-phthali- mide , starting from (±)-endo-l-azabicyclo[3.2.l]-octan-

3-ol [J. Org. Chem. 3_3, 4376 (1968)]

M.p. = 108-111°C

MS (C.I.) = 273 m/e [M +H] (±)-endo-N-[1-azabicyclo[3.3.1]non-3-yl)-oxy]-phthali- mide , starting from (±)-exo-l-azabicyclo[3.3.l]nonan-3- ol [J. Amer. Chem. Soc. 8_9, 1431 (1967), EP 257741]

M.p. = 135-140°C

MS (C.I.) = 287 m/e [M + H] (±)-exo-N-[1-azabicyclo[3.3.1]non-3-yl)-oxy]-phthali- mide , starting from (±)-endo-l-azabicyclo[3.3.l]nonan-

3-ol [J. Amer. Chem. Soc. 8 , 1431 (1967)

M.p. = 160°C dec.

MS (C.I.) = 287 m/e [M + H] R(-)-N-[ (1-azabicyclo[2.2.2]oct-3-yl)-methoxy]-phthali- mide , starting from R(-)-l-aza-3-hydroxy-methyl-bicy- clo[2.2.2] octane [EP 458214]

M.p. 85-95°C (isopropyl ether)

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

[0(] _D = - 27 .49 ° (c = 1% in IN HCl )

S ( + ) -N- [ ( 1-azabicyclo [ 2 .2 . 2 ]oct-3-yl ) -methoxy ] -phthali-

mide, starting from S(+)-l-aza-3-hydroxy-methyl-bicy- clo[2.2.2]-octane [EP 458214]

M.p. 90-95°C (Isopropyl ether)

MS (C.I.) = 287 m/e [M + H] [θfl _D = + 25.93° (c = 1% in IN HCl)

N-[ (l-ethyl-l-azacyclobut-3-yl)-oxy]-phthalimide, star¬ ting from l-ethyl-l-azacyclobutan-3-ol [see example 2]

N-[ (l-azacyclobut-3-yl)-oxy]-phthalimide, starting from l-azacyclobutan-3-ol [Synth. Comm. 2Q_, 407 (1990)] N-[ (l-methyl-l-azacyclohex-4-yl)-oxy]-phthalimide

M.p. 95°C

MS (C.I.) = 261 m/e [M + H]

(±)-N-[ (l-Methyl-l-azacyclohept-3-yl)-oxy]-phthalimide, starting from l-methyl-l-azacycloheptan-3-ol [see exam- pie 3]

M.p. = 70-72°C

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

Exo-N-[ (8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-oxy]- phthalimide M.p. 255°C (dec.) (Isopropanol, as hydrochloride salt)

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

(±)N-[ (l-methyl-l-azacyclopent-3-yl)-oxy]-phthalimide

M.p. 87-91°C

MS (C.I.) = 247 m/e [M + H] Example 2 l-Ethyl-l-azacyclobutan-3-ol

Example 3 a) N-methyl-N-(ethoxy carbonylmethyl)-5-aminopenta- noic acid, ethyl ester 5-bromopentanoic acid ethyl ester (30 g) was added portionwise to a well stirred suspension of sarcosine

hydrochloride (22 g) and triethylamine (29 g) in to¬ luene (220 ml). The reaction mixture was refluxed 20 hours, then cooled at 5°C. A solution of 5% aqueous hy¬ drochloric acid (200 ml) was added, the organic layer separated and discharged. The aqueous solution was made alkaline with 17% Na ₂ C0 ₃ solution and the oil which se¬ parated 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 pu- rified by distillation, g 17.5, b.p. 120°-125°C (0.5 mm Hg) . b) l-Methyl-l-aza-2-ethoxycarbonyl-cycloeptan-3-one

A solution of the previously described interme¬ diate (8 g) in toluene (65 ml) was dropped into a re- fluxing solution of potassium tert-butylate (11 g) in anhydrous toluene (400 ml) under stirring.

The reaction mixture was refluxed for additionally 10 minutes and cooled at room temperature. A 5% hydro¬ chloric acid solution was continuously introduced (50 ml) and the resulting organic solution was separated and discharged. The aqueous layer was made alkaline with a 17% sodium carbonate solution and the oily pro¬ duct which separated was extracted into ethyl acetate. From this solution after evaporation to dryness (5.78 g) of the crude intermediate was obtained sufficiently pure to be used in the next step. I.R. (nujol) = car¬ bonyl absorption bands 1710 and 1740 cm- . c) l-Methyl-l-azacycloheptan-3-one

A solution of the ethoxy carbonyl intermediate (5.68 g) in concentrated aqueous hydrochloric acid (56 ml) was refluxed for seven hours, then cooled at room

temperature. 15% Aqueous sodium hydroxide solution was added until a pH 9 was obtained. The separated oil was extracted into ethyl acetate, and from the dried and evaporated solution the decarboxylated keto derivative was obtained as a yellow oil (2.8 g) .

The H-NMR and M.S. were consistent with the pro¬ posed structure; d) l-Methyl-l-azacycloheptan-3-ol

Li Al H. (1.04 g) was added portionwise to a coo- led solution (5°C) of the above intermediate (3.5 g) in anhydrous tetrahydrofuran. The reaction mixture was further stirred for 1 hour, then a solution of tetrahy¬ drofuran (30 ml) containing water (0.5 ml) was dropped in. The separated salts were filtered and from the evaporated organic solution the title compound was ob¬ tained as a yellowish oil (3.5 g) . The H-NMR and M.S. were consistent with the proposed structure. Example 4 R(-)-0-(l-azabicyclo[2.2.2]oct-3-yl)-hydroxylamine di- hydrochloride

In absolute ethanol (300 ml) were dissolved R(-)- N-[ (l-azabicyclo[2.2.2]-oct-3-yl)-oxy]-phthalimide (31.5 g) and hydrazine hydrate 85% (13.3 ml). The mix- ture was stirred overnight at room temperature, the so¬ lid was filtered and the filtrate evaporated to dry¬ ness. The residue was dissolved in water and, after cooling with ice-bath, acidified with 10% HCl solution; 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.

M.p. 195-200°C

MS (C.I.) = 143 m/e [M + H]

[ ^β t] _D = - 39.53° (c = 1% in IN HCl) Following the above described procedure and star¬ ting from suitable intermediates the following com¬ pounds have been prepared:

S(+)_o-(1-azabicyclo[2.2.2]-oct-3-yl)-hydroxylamine di- hydrochloride M.p. 200-205°C (dec.)

MS (C.I.) = 143 m/e [M + H]

[C(] _D = + 40° (c = 1% in IN HCl)

(±)-Endo-0-(1-azabicyclo[2.2.1]-hept-3-yl)-hydroxylami¬ ne dihydrochloride M.p. = 210-215°C dec.

MS (C.I.) = 129 m/e [M + H]

(±)-Exo-0-(l-azabicyclo[2.2.1]-hept-3-yl)-hydroxylamine dihydrochloride

M.p. 165-170°C MS (C.I.) = 129 m/e [M + H]

(±)-Endo-0-(l-azabicyclo[3.2.1]-oct-6-yl)-hydroxylamine dihydrochloride

M.p. = 210-215°C dec.

MS (C.I.) = 142 m/e [M + H] (±)-Exo-0-(l-azabicyclo[3.2.1]-oct-6-yl)-hydroxylamine

Thick oil

MS (C.I.) = 143 m/e [M + H]

(±)-Endo-0-(l-azabicyclo[3.2.1]-oct-3-yl)-hydroxylamine dihydrochloride M.p. = 205-210°C dec.

MS (C.I.) =143 m/e [M + H]

(±)-Exo-O-(l-azabicyclo[3.2.1]-oct-3-yl)-hydroxylamine dihydrochloride

M.p. = 183-185°C dec.

MS (C.I.) = 143 m/e [M + H] (±)-Endo-0-(1-azabicyclo[3.3.1]-non-3-yl)-hydroxylamine dihydrochloride

M.p. = 185-189°C dec.

MS (C.I.) = 157 m/e [M + H]

(±)-Exo-O-(l-azabicyclo[3.3.1]-non-3-yl)-hydroxylamine dihydrochloride

M.p. = 200-205°C dec.

MS (C.I.) = 157 m/e [M +H] (-)-0-[ (1-azabicyclo[2.2.2]-oct-3-yl)-methyl]-hydroxy- lamine dihydrochloride M.p. 110-120°C (dec.)

MS (C.I.) = 157 m/e [M + H]

[β(] _D = - 21.59° (c = 1% in IN HCl)

S(+)-0-[ (1-azabicycl [2.2.2]-oct-3-yl)-methyl]-hydroxy- lamine dihydrochloride Hygroscopic solid

MS (C.I.) = 157 m/e [M + H]

[β <] _D = + 21.22° (c = 1% in IN HCl)

0-(l-ethyl-l-azacyclobut-3-yl)-hydroxylamine dihydro¬ chloride 0-(l-azacyclobut-3-yl)-hydroxylamine dihydrochloride

0-(l-methyl-l-azacyclohex-4-yl)-hydroxylamine dihydro¬ chloride

M.p. 195°C (dec.)

MS ( C . I . ) = 131 m/e [M + H ] ( ± ) -0- ( l-methyl-l-azacyclohept-3-yl ) -hydroxylamine dihydrochloride

Thick oil

MS (C.I.) = 145 m/e [M + H]

(±)-0-(l-methyl-l-azacyclohex-3-yl)-hydroxylamine dihy¬ drochloride M.p. = 205-210°C dec.

MS (C.I.) = 131 m/e [M + H]

Exo-O-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-hydroxy¬ lamine dihydrochloride M.p. 185°C (dec.) MS (C.I.) = 157 m/e [M + H]

(±)-0-(l-methyl-l-azacyclopent-3-yl)-hydroxylamine di¬ hydrochloride M.p. 162-6°C MS (C.I.) = 117 m/e [M + H] Example 5

S(+)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-ethylidenhydro- xylamine hydrochloride (Compound 1)

A suspension of S(+)-0-(l-azabicyclo[2.2.2]-oct-3- yl)-hydroxylamine dihydrochloride (0.6 g), methanol (10 cc) and sodium (64 mg) was stirred at room temperature until sodium has disappeared. Acetaldehyde (0.16 ml) was added dropwise to the cooled solution. The reaction was stirred overnight at 0-5°C. The methanol was evapo- rated, the residue dissolved in water and washed with ethyl acetate. The aqueous phase was basified with Na ₂ C0_, and extracted into CHC1 ₃ . The organic layers were combined, dried and evaporated to dryness. The re¬ sidue was dissolved in ethyl acetate and the title com- pound was obtained as hydrochloride salt by adding an 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) . M.p. 165-170°C MS (C.I.) = 169 m/e [M + H]

[βϋ _D = + 38.70° (c = 1% in IN HCl)

^■ " ^" H-NMR (CDC1 ₃ ): 1.7÷2.3 (4H, m) ; 1.85 (3H, d) ; 2.52 (IH, m) ; 3.1-5-3.7 (6H, m) ; 4.51 (IH, m) ; 6.84 and 7.46 (IH, 2q) ; 12.27 (IH, b) Analysis: C _g H ₁₇ ClN ₂ 0

C H Found% 52.54 8.40 Calc.% 52.81 8.37 According to the above described procedure the following compounds have been prepared

R(-)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-ethylidenhydro- xylamine hydrochloride (Compound 2) M.p. 158-161°C MS (C.I.) = 169 m/e [M + H]

[Ofl _D = + 40.128° (c = 1% in IN HCl)

^■ " ^■ H-NMR (CDC1 ₃ ): 1.7÷2.3 (4H, m) ; 1.85 (3H, d) ; 2.51 (IH, m) ; 3.1÷3.7 (6H, m) ; 4.54 (IH, m) ; 6.84 and 7.46 (IH, 2q) ; 12.20 (IH, b) Analysis: C _Q H ₁₇ C1N ₂ 0

C H

Found% 52.31 8.42 Calc.% 52.81 8.37 S(+)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-propylidenhy- droxylamine hydrochloride (Compound 3)

M.p. 147°C

MS (C.I.) = 183 m/e [M + H] [ø(] _D = +40.9 (c = 1% in IN HCl)

^■ " ^■ H-NMR (CDC1 ₃ ): 1.08 (3H, t); 1.7÷2.6 (7H, m) ; 3.1÷3.5 (6H, m) ; 4.53 (IH, m) ; 6.72 and 7.45 (IH, 2t); 12.18 (IH, b) Analysis: C.-H. _Q CI^O

C H Found% 54.39 8.81 Calc.% 54.91 8.76

R(-)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-propylidenhy- droxylamine hydrochloride (Compound 4) M.p. 150°C MS (C.I.) = 183 m/e [M + H]

[P(] _D = -42.33 (c = 1% in IN HCl)

^■ " ^" H-NMR (CDC1 ₃ ): 1.08 (3H, t); 1.7*2.6 (7H, m) ; 3.1÷3.7 (6H, m) ; 4.53 (IH, m) ; 6.72 and 7.45 (IH, 2t) ; 12.31 (IH, b) Analysis: C ₁₍₎ H ₁₉ C1N ₂ 0

C H Found% 54.40 8.76 Calc.% 54.91 8.76 S-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-isobutylidenhydro- xylamine hydrochloride (Compound 5) M.p. = 160-162°C dec. MS (C.I. ) = 197 m/e [M + H]

[&fl _D = +35.1 (c = 1% in Et OH]

^• " ^■ H-NMR [DMSO + CDC1 ₃ ] 10.86 (b, IH) ; 7.41 (d, IH) ; 4.48

(m, IH); 2.9 ÷ 3.7 (6H) ; 2.3 ÷ 2.6 (2H); 1.89 (m, 4H) ;

1 . 05 ( d, 6H ) . Analysis : C. , H ₂ , C1N ₂ 0

C H

Found% 55.18 8.35 Calc.% 56.76 9.09

R(__)_o-(1-azabicyclo[2.2.2]-oct-3-yl)-N-isobutylidenhy- droxylamine hydrochloride (Compound 6) M.p. = 165°C dec. MS (C.I.) = 197 m/e [M + H]

[β{] = -33.4 (c = 1% in Et OH]

^■ " ^" H-NMR [DMSO] 10.92 (b, IH) ; 7.47 (d, IH) ; 4.45 (m, IH) ; 3.0 ÷ 3.8 (6H); 2.50 (m, IH) ; 2.29 (m, IH) ; 1.6 ÷ 2.2 (4H); 1.03 (d, 6H) . Analysis: C, .H^ClN _j O

C H

Found% 55.21 9.07 Calc.% 56.76 9.09 S(+)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2,2-trifluo- roethyliden)-hydroxylamine fumarate (Compound 7) M.p. = 128-132°C dec. MS (C.I.) = 223 m/e [M + H] [*] _D = +31.3 (c = 1% in Et OH] """H-NMR [DMSO] 8.25 (q, IH) ; - 7.3 (b, 2H) ; 6.51 (s, 2H); 4.60 (m, IH) ; 3.40 (m, IH) ; 2.8 ÷ 3.1 (5H); 2.23 (m, IH) ; 1.5 ÷ 1.9 (4H) .

Analysis: C,.,H, _F ₃ N ₂ 0 ₅

R(-)-0-(l-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2,2-trifluo- roethy1iden)-hydroxylamine fumarate

(Compound 8) M.p. = 138-140°C dec. MS (C.I.) = 223 m/e [M + H]

[Ct] = -31.5 (c = 1% in Et OH]

"" ^• H-NMR [DMSO] -. 8.8 (b, 2H) ; 8.26 (q, IH) ; 6.51 (s, 2H) ; 4.63 (m, IH) ; 3.41 (m, IH) ; 2.8 ÷ 3.2 (5H); 2.25 (m, IH) ; 1.5 ■_■ 2.0 (4H) . Analysis: ^c ι 3 ^H χ7 ^F 3 ^N °5

C H N Found% 46.22 5.11 8.19 Calc.% 46.16 5.07 8.28 (±)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-(benzyliden)-hy- droxylamine hydrochloride (Compound 9) M.p. 207-209°C MS (C.I.) = 231 m/e [M + H]

^■ " ^" H-NMR [CDC1 ₃ ] 12.42 (b, IH) ; 8.12 (s, IH) ; 7.2 ■_ ^■ 7.6 (5H); 4.68 (m, IH) ; 3.0 ÷ 3.7 (6H); 2.62 (m, IH) ; 1.6 ÷ 2.4 (4H). Analysis C ₁₄ H. _g ClN ₂ 0

C H

Found% 62.81 7.27 Calc.% 63.02 7.19

(±)-O-[(1-azabicyclo[2.2.2]-oct-3-yl)-methyl]-N-(benzy¬ liden)-hydroxylamine hydrochloride (Compound 10) M.p. 200°C MS (C.I.) = 245 m/e [M + H]

^• "-H-NMR [CDC1 ₃ ] 12.12 (b, IH); 8.03 (s, IH) ; 7.2 ÷ 7.7

(5H) ; 4.20 (d, 2H) ; 1.8 ÷ 3.7 (12H). Analysis: C, ₅ H ₂ -C1N ₂ 0

Found% Calc.% Example 6

R(-)-O-(1-azabicyclo[2.2.2]oct-3-yl)-N-isopropylidenhy- droxylamine dihydrochloride (Compound 11) Acetone (0.24 cc) was dropped into a cooled (10°C) solution of R(-)-0-(l-azabicyclo[2.2.2 ]-oct-3-yl)-hy¬ droxylamine dihydrochloride (0.7 g) in methanol (15 cc). The solution was stirred for 2 hours at 10°C and then stirring was maintained for 36 hours at room tem- perature. The methanol was evaporated, the residue dis¬ solved in ethyl acetate and then evaporated to dryness. The residue was crystallized from ethyl acetate to ob¬ tain the title compound as a white solid (0.58 g) . M.p. 130-132°C MS (C.I.) = 183 m/e [M + H]

[0M _D = - 41.65° (c = 1% in IN HCl)

^" " ^" H-NMR (DMSO + CDC1 ₃ ;): 1.6÷2.1 (4H, m) ; 1.84 (3H, s); 1.85 (3H, s); 2.35 (IH, m) ; 2.9÷3.7 (6H, m) ; 4.47 (IH, m) ; 6.40 (IH + HDO, b) ; 10.82 (IH, b) . Analysis: C ₁₀ H ₂₀ Cl ₂ N ₂ O

Following the above described procedure and star- ting from suitable intermediates the following com¬ pounds may be prepared

S(+)-o-(1-azabicyclo[2.2.2]-oct-3-yl)-N-isopropyliden- hydroxylamine dihydrochloride

(Compound 12) M.p. = 135-140°C MS (C.I.) = 183 m/e [M + H]

[tf] _D = + 41.4° (c = 1% in IN HCl)

^• ""H-NMR (DMSO + CDC1 ₃ ;): 1.6÷2.1 (4H, m) ; 1.84 (3H, s); 1.85 (3H, s); 2.35 (IH, m) ; 2.9÷3.7 (6H, m) ; 4.47 (IH, m) ; 6.26 (IH + HDO, b) ; 10.73 (IH, b) . Analysis: C ₁₍₎ H ₂₀ Cl ₂ N ₂ O

R(_)_0-(l-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2-difluoro- ethyliden)-hydroxylamine fumarate

(Compound 13) M.p. 130-135°C dec. MS (C.I.) = 205 m/e [M + H]

^■ " ^" H-NMR [DMSO] 9.20 (b, 2H) ; 7.91 (m, IH) ; 6.53 (s, 2H) ; 6.56 (m, IH) ; 4.59 (m, IH) ; 3.47 (m, IH) ; 2.9 ÷ 3.3 (5H); 2.27 (m, IH) ; 1.5 ÷ 2.0 (4H) . Analysis: ^c χ3 ^H τo ^F 2 ^N 2°5

S(+)-0-(1-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2-difluoro- ethyliden)-hydroxylamine_hydrochloride

(Compound 14) M.p. 110°C dec. MS (C.I.) = 205 m/e [M + H]

^■ " ^" H-NMR [CDC1 ₃ ] 7.51 (m, IH) ; 6.11 (m, IH); 4.65 ( ,

IH) ; 3.58 (m, IH) ; 3.2 ÷ 3.5 (5H); 2.56 (m, IH) ; 1.7 ÷

2.3 (4H).

Analysis: C _g H ₁₅ ClF ₂ N ₂ 0

C Found% 44.80 Calc.% 44.91

R(-)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-(2-fluoro- ethyliden)-hydroxylamine fumarate

(Compound 15) M.p. 118°C dec.

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

^■ " ^■ H-NMR [DMSO] 7.75 and 7.26 (2m, IH) ; 6.50 (s, 2H) ;

-6.4 (b, 2H); 5.30 and 4.99 (2m, 2H) ; 4.50 (m, IH) ;

3.41 (m, IH); 2.9 ÷ 3.2 (5H); 2.25 (b, IH) ; 1.5 ÷ 2.0 (4H).

S(+)-0-(l-azabicyclo[2.2.2]-oct-3-yl)-N-(2-fluoro- ethyliden)-hydroxylamine fumarate

(Compound 16) M.p. 118°C dec. MS (C.I.) = 187 m/e [M + H] -"-H-NMR [DMSO] 8.56 (b, 2H) ; 7.69 and 7.15 (2m, IH) ; 6.54 (s, 2H); 5.25 and 4.95 (2m, 2H) ; 4.41 (m, IH) ; 3.36 (m, IH); 2.7 ■_■ 3.2 (5H); 2.23 (m, IH) ; 1.4 -=• 2.1 (4H).

Analysis: ^c i3 ^H ιq ^FN 2 ⁰ 5

R(-)-0-(1-azabicyclo[2.2.2]-oct-3-yl)-N-cyclobutyliden- hydroxylamine hydrochloride

(Compound 17)

M.p. = 185-190°C

MS (C.I.) = 195 m/e [M + H]

EθC_3 _D = - 36.35 (c = 1% in EtOH) -" ^" H-NMR [DMS + CDC1 ₃ ]: 10.62 (b, IH) ; 4.69 (m, IH) ; 3.1

÷ 3.9 (6H) : 0.7 ÷ 2.7 (11H) Analysis: C,,H, _g ClN ₂ 0

S(+)-O-(1-azabicyclo[2.2.2]-oct-3-yl)-N-cyclobutyliden- hydroxylamine hydrochloride

(Compound 18)

M.p. = 190-195°C MS (C.I.) = 195 m/e [M + H] tθfl _D = - 34.79 (c = 1% in EtOH)

-" ^" H-NMR [DMSO + CDC1 ₃ ] 10.79 (b, I

÷ 3.7 (10H); 2.32 (m, IH) ; 1.6

Analysis: C.,,H _lg ClN ₂ 0

(±)-endo-O-(1-azabicyclo[2.2.1]-hept-3-yl)-N-ethyliden- hydroxylamine fumarate (Compound 19) M.p. = 160°C

MS (C.I.) = 155 m/e [M + H]

^" "-H-NMR [DMSO]: ~ 8.8 (broad, 2H) ; 6.99 (s, 2H) ; 7.51 and 6.94 (2q, IH) ; 4.79 (m, IH) ; 3.43 (m, IH) ; 3.17 (m, IH) ; 2.8 ÷ 3.1 (4H) ; 2.60 (m, IH) ; 1.6 ÷ 2.0 (2H) ;

1.79 and 1.80 (2d, 3H.) Analysis: ^c i ^H iR ^N 2°5

MS (C.I.) = 155 m/e [M + H] -" ^" H-NMR [DMSO + CDC1 ₃ ] 9.40 (b, 2H) ; 6.57 (s, 2H) ; 6.84 and 7.41 (2q, IH) ; 4.25 (m, IH) ; 2.4 ÷ 3.3 (7H); 1.81 (m, IH) ; 1.78 (d 3H) ; 1.24 (m, IH) . Analysis: ^c i2 ^H i8 ^N 2°5

(±)-Endo-O-(1-azabicyclo[3.2.1]-oct-6-yl)-N-ethyliden- hydroxylamine fumarate

(Compound 21) M.p. 135-140°C dec.

MS (C.I.) = 169 m/e [M + H]

-" ^" H-NMR [CDC1 ₃ ] 10.6 (b, 2H) ; 7.48 and 6.85 (2q, IH) ;

6.81 (s, 2H) ; 5.09 (m, IH) ; 4.04, (m, IH) ; 3.3 ÷ 3.6

(3H); 3.0 ÷ 3.3 (2H); 2.73 (b, IH) ; 2.21 (m, IH) ; 1.7 ÷ 2.1, (3H); 1.86 and 1.88 (2d, 3H) .

Analysis: C ₁₃ H _2Q N ₂ 0,-

(±)-Exo-O-(1-azabicyclo[3.2.1]-oct-6-yl)-N-ethyliden- hydroxylamine hydrochloride

(Compound 22) M.p. 170-173°C MS (C.I.) = 169 m/e [M + H]

-" ^" H-NMR [CDC1 ₃ ] 12.84 (b, IH) ; 8.03 (s, IH) ; 7.2 ÷ 7.7 (5H); 4.20 (d, 2H) ; 1.8 ÷ 3.7 (12H).

(±)-Endo-O-(l-azabicyclo[3.2.1]-oct-3-yl)-N-ethyliden- hydroxylamine fumarate

(Compound 23) M.p. = 125-127°C dec. MS (C.I.) = 169 m/e [M+H] ^" "-H-NMR [DMSO] 9.2 (b, 2H) ; 6.94 (q, IH) ; 6.47 (s, 2H) 4.31 (b, IH); 3.41 and 3.50 (d, m, 2H) ; 3.23 (m, 2H) 3.01 and 3.12 (m, d, 2H) ; 2.50 (m, IH) ; 1.9 ÷ 2.2 (4H) 1.81 (d, 3H) .

Analysis: ^c i3 ^H 2o ^N 2°5 C H N

Found% 54.43 7.11 9.75 Calc.% 54.92 7.09 9.85 (±)-Exo-O-(l-azabicyclo[3.2.1]-oct-3-yl)-N-ethyliden- hydroxylamine fumarate (Compound 24)

M.p. 119-121°C dec.

MS (C.I.) = 169 m/e [M + H]

-"-H-NMR [DMSO + CDC1 ₃ ] 9.46 (b, 2H) ; 7.39 and 6.82 (2q,

IH); 6.53 (s, 2H) ; 4.46 (m, IH) ; 2.5 ÷ 3.6 (7H); 1.4 ÷

2.3 (4H); 1.75 and 1.77 (2d, 3H) .

^A nalysis : ^c χ ₃ ^H 20 ^N 2°5

( ± ) -Endo-O- ( l-azabicyclo [3.3.1 ] -non-3-yl ) -N-ethyliden- hydroxylamine fumarate

( Compound 25 )

M.p. = hygroscopic solid

MS (C.I.) = 183 m/e [M+H]

-" ^" H-NMR [DMSO] 8.3 (b, 2H) ; 7.51 and 6.93 (2q, IH) ; 6.50 (s, 2H) ; 4.37 ( , IH) ; 3.60 (m, IH) ; 3.0÷3.3 (5H);

2.51 (m, IH); 2.23 (m, IH) ; 2.04 (b, IH) ; 1.4÷1.9 (4H) ;

1.81 and 1.82 (2d, 3H) .

Analysis: C- .H^^O _c -

C H N Found% 56.04 7.34 9.19 Calc.% 56.36 7.43 9.39

(±)-Exo-O-(l-azabicyclo[3.3.1]-non-3-yl)-N-ethyliden- hydroxylamine hydrochloride

(Compound 26) M.p. 155-160°C dec.

MS (C.I.) = 183 m/e [M + H]

-" ^" H-NMR [CDC1 ₃ ] 12.68 (b, IH) ; 7.41 and 6.80 (2q, IH) ;

4.98 (m IH); 3.60 (m, IH) ; 3.2 ÷ 3.5 (5H); 1.8÷2.5

(7H) ; 1.82 and 1.83, (2d, 3H) . Analysis: C ₁₀ H _lg ClN ₂ O

Exo-O-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-N-ethy- liden-hydroxylamine fumarate

(Compound 27) M.p. = 145°C dec. MS (C.I.) = 183 m/e [M+H]

^■ " ^" H-NMR [CDC1 ₃ ] 11.40 (b, 2H) ; 6.82 (s, 2H) ; 7.40 and 6.75 (2q, IH) ; 4.44 (m, IH) ; 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 χ4 ^H 22 ^N 2°5

C H N Found% 56.28 7.49 9.36 Calc.% 56.36 7.43 9.39

R(-)-O-[l-azabicyclo[2.2.2]-oct-3-yl]-methyl-N-methy-

1iden-hydroxylamine

(Compound 50)

S(+)-O-[l-azabicyclo[2.2.2]-oct-3-yl]-methyl-N-methy- liden-hydroxylamine

(Compound 51)

Example 7 R(-)-O-[ (l-azabicyclo[2.2.2]-oct-3-yl) ]-methyl-N-ethy- liden-hydroxylamine hydrochloride (Compound 28)

A mixture of R(-)-0-[ (l-azabicyclo[2.2.2]-oct-3- yl)-methyl]-hydroxylamine dihydrochloride (1.5 g) , methanol (25 cc) and sodium (300 mg) was stirred at room temperature until sodium has disappeared, then was

cooled with ice-bath and acetaldehyde (0.37 cc) was ad¬ ded dropwise. The solution was stirred at room tempera¬ ture for 2 hours and then the reaction mixture was eva¬ porated to dryness. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was then basified with Na ₂ C0 ₃ and extracted into CHC1 ₃ . The organic layers were combined, dried and evaporated to dryness. The crude residue was dissolved in ethyl ace¬ tate and the desired compound was obtained as hydro- chloride salt by adding an anhydrous HCl solution in diethyl-ether. The solid was filtered and dried in va- cuo. The pure title compound was obtained as a white solid (0.34 g) . M.p. 135-140°C MS (C.I.) = 183 m/e [M + H]

W] _D = - 39.46° (c = 1% in IN HCl)

"" ^" H-NMR (CDC1 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 (IH, 2q) , 12.05 (IH, b) Analysis: C ₁₀ H _ιg ClN ₂ O

C H

Found% 54.18 8.82 Calc.% 54.91 8.76 According to the above described procedure and starting from suitable intermediates, the following compounds have been prepared

S(+)-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-methyl]-N-ethy- liden-hydroxylamine hydrochloride (Compound 29) M.p. 145-150°C

MS (C.I.) = 183 m/e [M + H]

= + 41.63° (c = 1% in IN HCl)

-" ^" H-NMR (CDC1 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 (IH, 2q) , 12.08 (IH, b) Analysis: C, ₀ H, _g ClN ₂ O

C H

Found% 54.42 8.79

Calc.% 54.91 8.76

O- ( l-ethyl-l-azacyclobut-3-yl ) -N-ethyliden-hydroxylami- ne

(Compound 31)

(±)-O-(l-methyl-l-azacyclopent-3-yl)-N-ethylidenhydro- xylamine oxalate (Compound 33) M.p. = 105-109°C dec.

MS (C.I.) = 143 m/e [M+H]

-" ^" H-NMR [DMSO] 10.24 (b, 2H) ; 7.47 and 6.95 (2q, IH) ; 4.81 (m, IH) ; 3.2 ■_■ 3.6 (4H); 2.80 (s, 3H) ; 2.30 (m, IH) ; 2.07 (m, IH) ; 1.78 and 1.80 (2d, 3H) . Analysis: ^c q ^H i5 ^N 2 ⁰ 5

C H N

Found% 46.39 7.04 11.80 Calc.% 46.55 6.94 12.06 (±)-O-(l-methyl-l-azacyclohept-3-yl)-N-ethylidenhydro- xylamine maleate (Compound 35) M.p. 95-100°C dec. MS (C.I.) = 171 m/e [M + H]

^" " ^■ H-NMR [CDClg] 7.48 and 6.85 (2q, IH) ; 6.29 (s, 2H) ; 4.53 (b, IH); 3.1 ÷ 3.7 (b, 4H) ; 2.92 (ε, 3H) ; 1.6 ÷ 2.2 (6H) ; 1.87 (d, 3H) .

^A nalysis: ^c ₃ ^H ₂₂ ^N ₂ ° ₅

O-(l-methyl-l-azacyclohex-4-yl)-N-ethylidenhydroxylami- ne fumarate

(Compound 37)

M.p. 90-95°C dec.

MS (C.I.) = 157 m/e [M + H]

¹ H-NMR [DMSO + CDC1 ₃ ] 10.64 (b, 2H) ; 6.80 and 7.42 (2q,

IH); 6.57 (s, 2H) ; 4.12 (m, IH) ; 2.4 ÷ 3.1 (4H) ; 2.46

(s, 3H); 1.79 (d, 3H) ; 1.7 ÷ 2.2 (4H) .

( ± ) -O- ( l-methyl-l-azacyclohex-3-yl ) -N-ethylidenhydroxy- lamine hydrochloride

( Compound 39 ) M .p . 150-157 °C dec .

MS (C . I . ) = 157 m/e [M + H]

-" ^" H-NMR [CDC1 ₃ ] 12.7 and 11.7 (2b, IH) ; 7.80, 7.36 and 6.83 (3m, IH) ; 4.48 (m, IH) ; 3.58 (m, 2H) ; 2.84 (s, 3H); 2.6 -f 3.2 (2H) ; 1.5 ÷ 2.4 (4H) ; 1.82 and 1.83 (2d, 3H).

Analysis: C ₈ H ₁₇ C1N ₂ 0

C H Found% 49.56 8.99 Calc.% 49.87 8.89 R-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2,2-trichloro- ethyliden)-hydroxylamine hydrochloride

(Compound 40)

M.p. 225°C dec.

MS (C.I.) = 272 m/e [M + H]

[dU _D = - 30.0 (c= 1% in EtOH) ^" "-H-NMR [CDC1 ₃ ] 12.24 (b, IH) ; 7.90 (s, IH) ; 4.73 (m,

IH); 3.70 (m IH) ; 3.2 ÷ 3.6 (5H); 2.61 (b, IH) ; 1.8 ÷

2.3 (4H).

Analysis: C _g H, ₄ Cl ₄ N ₂ 0

C H Found% 34.80 4.65 Calc.% 35.09 4.58

S-O-[(l-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2,2-trichloro- ethyliden)-hydroxylamine hydrochloride

(Compound 41) M.p. 225°C dec.

MS (C.I.) = 272 m/e [M + H]

[0(] _D = + 31.3 (c= 1% in EtOH)

-" ^• H-NMR [CDC1 ₃ ] 12.55 (b, IH) ; 7.84 (s, IH) ; 4.70 (m,

IH) ; 3.62 (m, IH) ; 3.2 ÷ 3.5 (5H); 2.62 (b, IH) ; 1.7 ■_■ 2.3 (4H).

Analysis: C _g H, ₄ Cl ₄ N ₂ 0

C H

Found% 34.47 4.50 Calc.% 35.09 4.58 R-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2-dichloro- ethyliden)-hydroxylamine fumarate

(Compound 42)

M.p. 170-172°C dec.

MS (C.I.) = 238 m/e [M + H] [dU _D = - 30.73 (c= 1% in EtOH)

-" ^" H-NMR [DMSO + CDC1 ₃ ] 8.18 (b, 2H) ; 7.81 and 7.32,

(2d, IH); 7.16 and 6.79 (2d, IH) ; 6.56 (s, 2H) ; 4.49 (m, IH); 3.42 (m, IH) ; 2.8 ÷ 3.2 (5H); 2.26 (m, IH) ; 1.5 ÷ 2.0 (4H) . Analysis: C.3 ^H χR ^C1 2 ^N 2°5

S-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-(2,2-dichloro- ethyliden)-hydroxylamine fumarate (Compound 43)

M.p. 172-174°C dec.

MS (C.I.) = 238 m/e [M + H]

[0(] _D = - 31.61 (c= 1% in EtOH)

^• " ^" H-NMR [DMSO + CDC1 ₃ ] 9.75 (b, 2H) ; 7.81 and 7.34 (2d, IH) ; 7.16 and 6.80 (2d, IH) ; 6.56 (s, 2H) ; 4.47 (m,

IH); 3.44 (m, IH) ; 2.8 ÷ 3.2 (5H); 2.24 ( , IH) ; 1.5 ÷

2.0 (4H).

Analysis: ^c ι 3 ^H ηg ^C1 2 ^N 2°5

C H Found% 44.00 5.22 Calc.% 44.21 5.14

R-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-(1-fluoroethyli- den)-hydroxylamine fumarate

(Compound 46) M.p. 118-121°C dec.

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

[ _θ (] _D = - 29.7 (c= 1% in EtOH)

^• " ^" H-NMR [DMSO] 6.52 (s, 2H); 4.34 (m, IH) ; 3.42 (m, IH) ;

2.9 ÷ 3.2 (5H); 2.27 (m, IH) ; 2.19 and 2.04 (2d, 3H) ; 1.5 ÷ 2.0 (4H) .

Analysis: C..,H, _g F ₂ 0 ₅

S-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-(1-fluoroethyli- den)-hydroxylamine fumarate

(Compound 47) M.p. 140°C dec. MS (C.I.) = 187 m/e [M + H] [0(] _D = + 28.87 (c= 1% in EtOH) ^" " ^" H-NMR [DMSO] 8.2 (b, 2H) ; 6.53 (s, 2H) ; 4.35 (m, IH) ; 3.42 (m, IH); 2.9 ÷ 3.2 (5H); 2.18 and 2.04 (2d, 3H) ; 1.5 ÷ 2.0, (4H) ; 2.28 (m, IH) . Analysis: ^c ι3 ^H ιq ^FN 2°5

S-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-methylenhydroxy- 1amine hydrochloride

(Compound 48) M.p. 80-90°C dec. (hygroscopic solid)

MS (C.I.) = 155 m/e [M + H]

[θ(] _D = + 25.78 (c= 1% in MetOH)

^■ " ^" H-NMR [DMSO] 10.86 (b, IH) ; 7.16 (d, IH) ; 6.75 (d,

IH); 4.56 (m, IH) ; 3.0 ÷ 3.6 (6H); 1.5 ÷ 2.4 (5H). Analysis: CgH-gC^^O

R-O-[ (l-azabicyclo[2.2.2]-oct-3-yl)-N-methylen-hydroxy- lamine hydrochloride

(Compound 49)

M.p. 145-150°C dec. MS (C.I.) = 155 m/e [M + H] [θU _D = - 26.32 (c= 1% in MetOH)

^• " ^" H-NMR [DMSO] 7.16 (d, IH) ; 6.74 (d, IH) ; 4.56 (m, IH) ; 3.56 (m, IH) ; -3.6 (b, IH) ; 3.0 ÷ 3.3 (5H); 2.30 (m,

IH) ; 1.6 ÷ 2.0, (4H) . Analysis: C _g H,gCl ₂ N ₂ 0

C Found% 41.96 Calc.% 42.30 Example 8

Endo-O-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-N-ethy- liden-hydroxylamine hydrochloride (Compound 44) To a solution of sodium (0.237 g) in ethanol (10 cc) acetaldehyde oxime (1.97 cc) was added portionwise. The solution was stirred for 15 \' and then endo-8- methyl-3-chloro-8-azabicyclo[3.2.1]-octane (5.16 g) [J. Am. Chem. Soc. B0_, 4677 (1958)] was added. The solution was refluxed for 15 hours then cooled with ice-bath and the pH adjusted at 9 with an HCl so¬ lution in ethanol. The inorganic salts were filtered off and the solution 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:NH ₄ OH 30%). The crude product obtained was dissolved in ethyl ace¬ tate, an anhydrous solution of HCl in diethyl ether was added and the solution evaporated to dryness. The title compound was obtained as a solid (0.13 g) after cry- stallization from diethyl ether. M.p. 160°C

MS (C.I.) = 183 m/e [M + H]

^■ " ^" H-NMR (DMSO + CDC1 ₃ ) 1.81 (3H, d) , 2.0÷3.4 (8H, m) , 2.68 (3H, d), 3.82 (2H, b) , 4.26 (IH, m) , 6.86 and 7.44 (IH, 2q) , 11.36 (IH, b) Analysis: C, ₀ H, _g ClN ₂ 0

C H

Found% 53.55 8.83 Calc.% 54.91 8.76 According to the above described procedure the following compound was prepared

O-(l-methyl-l-azacyclohex-4-yl)-N-isopropylidenhydro- xylamine hydrochloride (Compound 45) M.p. 140°C MS (C.I.) = 171 m/e [M + H]

^■ " ^■ H-NMR (DMSO + CDC1 ₃ ) 1.8÷2.4 (10H, m) , 2.73 (3H, d) , 2.7÷3.6 (4H, m) , 4.26 (IH, m) , 10.92 (IH, b) Analysis: C _g H _ιg ClN ₂ 0

Found% Calc.% Example 9 a) (±)N-[ (l-azacyclohex-3-yl)-oxy]-phthalimide

A solution of N-[ (l-methyl-l-azacyclohex-3-yl)oxy] phthalimide (1.1 g) and 1.8 bis dimethylamino naphtha¬ lene (proton sponge) (0.9 g) in 1,2 dichloroethane (50 ml) was cooled at 5°C and 1-chloro-ethyldichloroformate (0.6 ml) was dropped. The reaction mixture was stirred overnight at room temperature, then was washed first with diluted aqueous Na ₂ C0 ₃ solution; then with diluted aqueous HCl solution. The organic layer was dried and

evaporated to dryness. The crude residue was dissolved in methanol (50 ml) and the resulting solution was re¬ fluxed 2 hours and then evaporated to dryness. The crude intermediate obtained (0.9 g, after crystalliza- tion from a mixture of ethyl acetate and diethyl ether, m.p. 233-236) was sufficiently pure to be used in the next step; b) (+)0-(l-azacyclohex-3-yl)-hydroxylamine dihydro¬ chloride The previously described intermediate (0.87 g) was dissolved into absolute ethanol (35 ml) and aqueous 85% hydrazine was dropped in under stirring. The reaction mixture was stirred further to 3 hours at room tempera¬ ture and filtered. The clear solution was made acidic with aqueous 10% HCl solution and then evaporated to dryness. The title compound was obtained as a white so¬ lid after crystallization from ethanol 0.45 g, m.p. 158-161°C. Example 10 0-(l-azacyclohex-4-yl)-N-ethyliden-hydroxylamine hydro¬ chloride (Compound 36)

A solution of 0-(l-methyl-l-azacyclohex-4-yl)-N- ethyliden hydroxylamine (0.4 g) and 1.8 bis dimethyla- mino naphthalene (proton sponge) (0.55 g) in 1,2 di- chloroethane was cooled at 5°C. 1-chloroethyl-chloro- formate (0.34 ml) was dropped into the stirred reaction mixture and the stirring was maintained overnight at room temperature. An aqueous Na ₂ Co ₃ solution was ad- ded, the organic layer was separated, washed with 5% aqueous hydrochloric solution and evaporated to dry-

ness. The residue was dissolved in methanol and the re¬ sulting solution was refluxed for 1 hour. From the so¬ lution after evaporation to dryness, the crude hydro¬ chloride of the title compound was obtained. 0.180 g after crystallization from ethyl acetate M.p. 130-140°C dec. MS (C.I.) = 143 m/e [M + H]

¹ H-NMR [DMSO + CDC1 ₃ ] 9.16 (b, 2H) ; 7.45 and 6.85 (2q, IH); 4.25 (m, IH) ; 3.07 (m, 4H) ; 1.97 (m, 4H) ; 1.80 (d, 3H).

Analysis: C ₇ H ₁₅ C1N ₂ 0

C H

Found% 46.81 8.56 Calc.% 47.06 8.46 According to the above described procedure and starting from suitable intermediates the following com¬ pounds may be prepared.

O-(l-azacyclobut-3-yl)-N-ethyliden-hydroxylanine (Compound 30) (±)O-(l-azacyclopent-3-yl)-N-ethyliden-hydroxylamine, oxalate (Compound 32) M.p. 150°C dec. MS (C.I.) = 129 m/e [M + H] -" ^" H-NMR [DMSO] 9.27 (b, 3H) ; 7.46 and 6.96 (2q, IH) ; 4.78 (m, IH); 3.1. ÷ 3.4 (4H); 2.08 (m, 2H) ; 1.77 and 1.80 (2d, 3H).

(±)O-(l-azacyclohept-3-yl)-N-ethyliden hydroxylamine, hydrochloride

(Compound 34)

M.p. 110°C dec.

MS (C.I.) = 157 m/e [M + H]

^" " ^" H-NMR [CDC1 ₃ ] 9.89 (b, IH) ; 9.36 (b, IH) ; 7.57 and

6.83 (2q, IH) ; 4.58 (m, IH) ; 3.2 ÷ 3.6 (4H); 1.6 ÷ 2.3

(6H); 1.86 and 1.91 (2d, 3H) .

Analysis: CgH, ₇ ClN ₂ 0

(±)-O-(l-azacyclohex-3-yl)-N-ethyliden-hydroxylamine hydrochloride (Compound 38)

M.p. 98-100°C dec.

MS (C.I.) = 143 m/e [M + H]

-" ^" H-NMR [CDC1 ₃ ] 9.84 (b, IH) ; 9.22 (b, IH) ; 7.60 and

6.84 (2q, IH) ; 4.45 (m, IH) ; 3.0 ÷ 3.4 (4H) ; 1.7 ÷ 2.2 (4H); 1.85 and 1.96 (2d, 3H) .

Analysis: C ₇ H ₁₅ C1N ₂ 0

Method of preparation: the active ingredient, lac-

tose and a portion of corn starch were mixed and granu¬ lated to a 10% corn starch paste. The resulting granu¬ lation is sieved, dried and blended with the remainder of the corn starch and magnesium stearate. The resul¬ ting granulation was then compressed into tablets con¬ taining 50 mg and 100 mg of the active ingredient per tablet.