FI114472B - New aza:bi:cyclo and aza:cyclo oxime and amine cholinergic agents - e.g. 1-aza:bi:cyclo-(2,2,1)heptan-3-one, O-ethyl:oxime hydrochloride, for treating symptoms of cognitive decline - Google Patents

Abstract

Azabicyclo and azacyclo oxime and amine compounds of formula (I)-(IV) are new. n = 1 or 2; p = 0-4. R1, R2 = H or 1-4C alkyl. R3 = H, 1-6C alkyl, OH, 1-4C alkoxy, 2-5C acyloxy, -(CH2)q-NR8R9 or 3-6C cycloalkyl. R = H, -Y-Z, 3-6C cycloalkyl, 2- or 3-thienyl, 2- or 3-furanyl or 2- or 3-pyrroyl; all the aromatic gps. being opt. substd. by 1-2 Cl, Br, F, CF3, NO2, NH2, mono or di 1-4C alkyl-amino or 1-4C alkoxy gps.), NR4R5, CONR4R5, COR6, CN, CO2R7 or XR10. R4, R5 and R8, R9 = independently H or 1-4C alkyl. R6 = 1-6C alkyl. R7 = H, 1-6C alkyl or benzyl. R10 = 1-6C hydrocarbon which may contain 1 or 2 double or triple bonds. X = O or S. q = 0-4. Y = a bond or 1-20C hydrocarbon with 0-4 double and/or triple bonds; Z = H. The following compounds are excluded: (a) (I) where n = 2 and R = H or Y-Z where Y = a bond and Z = -CO-NR4R5 or COR6, and (b) (III) or (IV) when R = H.

Description

1 4472

The present invention relates to a process for the preparation of a plurality of oximes which are muscarinic agents, which render them useful as pharmaceutical agents. The present invention relates to a process for the preparation of azabicyclo and azacyclo In particular, the compounds of the invention are azabicyclic and azacyclic oximes.

Disorders of consciousness are usually characterized by symptoms such as forgetfulness, confusion, memory loss, lack of attention, and / or, in some cases, mental disorders. The onset of these symptoms may be due to aging in general and / or organic brain disease, cerebrovascular disease, head injury or developmental disorder or genetic disorder.

The general decline in consciousness associated with aging is well accepted. The same phenomenon has been observed and documented: in many lower mammals, including those commonly used in pharmacological testing programs for testing and evaluating the utility of certain drugs in higher animals, including humans.

Although consciousness disorders are often associated with general aging - '!!! primary, degenerative dementias are the mental deterioration of the elderly *; its most common causes. It has been estimated that: at least 10% of those over the age of 60 are likely to suffer from severe mental retardation. A much larger group * I t j feel that their consciousness is impaired to the extent that it is an obstacle to their activities.

1 1 4472 2

Many symptoms of impaired consciousness, particularly impaired memory, are associated with decreased acetylcholine synthesis and impairment of choline-responsive neurons. Patients with primary degenerative dementia, for example, may have as much as 90% reduction in choline acetyltransferase enzyme (CAT) concentration in the hippocampus and cerebral cortex. (See Davies et al., The Lancet, 1976 (Vol. 2): 1403;

Perry et al., J. Neurol. Sci., 34: 247-265 (1977) and White et al., The Lancet, 1977 (Vol. 1): 668-679.

Because CAT catalyzes the synthesis of acetylcholine from its precursors, which are choline and acetyl coenzyme A, the disappearance of CAT is reflected in the loss of cholinergic or acetylcholine-releasing nerve endings in the cerebellum and cortex. There is ample evidence that cholinergic terminals in the hippocampus are critically important for memory formation.

The cholinergic hypothesis suggests that drugs that restore acetylcholine levels or that mimic the action of acetylcholine (i.e., choline mimics) are effective in correcting this deficiency in neu- / rotransmission chemistry and can be used to treat memory impairment due to cerebral insufficiency. Several biochemical, pharmacological, and electrophysiological evidence support the hypothesis that deficiencies in the cholinergic system are behind dysfunctions of geriatric consciousness. (See C. Peterson and GEGibson, Neurobiol.Aging, 4: 25-30 (1983).) Elderly and reduced conscious primates show improved memory when treated with, for example, acetylcholinesterase inhibitors such as physostigin. - mine. These agents increase the amount of synaptic acetylcholine available by inhibiting its hydrolysis.

3, 114472

Aminopyridines, such as 3,4-diaminopyridine, ameliorate age-related deficits in consciousness by increasing the release of acetylcholine from the presynaptic nerve endings and thereby increasing synaptic acetylcholine. (See H.P. Davis et al., Exp.Aging Res., 9: 211-214 (1983).)

For some time now, it has been known that the natural alkaloid, muscarinic, has the ability to act relatively selectively on autonomic influencing cells, producing qualitatively the same effects as acetylcholine. The two closely related alkaloids, pilocarpine and arecoline (methyl ester of 1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxylic acid) share the same bases of action as muscarinic and acetylcholine and are thus classified as having "muscarinic" activity. . Although these naturally occurring alkaloids have great value as pharmacological tools, current clinical use is largely limited to the use of pilocarpine as a miotic agent.

Recently, arecoline has been shown to be effective in ameliorating some of the symptoms of impaired consciousness in patients. clinically diagnosed as presenil. primary degenerative dementia.

Significant improvement was observed in the double-blind study in the image recognition test after i · i '. · - patients were treated with arecoline. (See Christie et al., Brit.J.Psychiatry, 138: 46-50 (1981).); * U.S. Patent No. 3,004,979 includes certain 3-carboxylic acid derivatives of 1- (lower alkyl) -1,2,5,6-tetrahydropyridines. - or 4-ketoximes, in which, the oxygen is unsubstituted and useful as parasympathomimetic agents acting on the non-stained li *; ' muscle.

U.S. Patent No. 4,710,508 describes O-substituted 1- (1,2,3,6-tetrahydro-1-methyl-3-pyridyl) ketone oximes and O-, 4,114,472 substituted 1- (1,2,3, e-tetrahydro) -pyridinyl jketone oximes useful as analgesic agents or agents for the treatment of symptoms of cerebral dysfunction characterized by reduced central production of acetylcholine.

Dissertation Abstracts Int. B 1984, 45 (7), 2120; CA 102; 113440m describes oxime O-ethers having anticholinergic properties having the following formula wherein R is F, Cl, Br, NO 2, OCH 3, CF 3 or CH 3. Of particular interest are pages 128-136, 166, 167, 198-203.

FR patent 2,086,292 describes 3-quinuclidinone oxime carbamates having insecticidal and acaricidal activity and the following formula 0

Il xRi V: Κ; γτγ "\": 1: .. [(chj) J K2 '; wherein R 3 is alkyl, alkenyl, alkylidene, halogen, · ;;; cyano, haloalkyl, haloalkenyl, alkoxy, etc .; R 1 and R 2: are hydrogen, lower alkyl, acyl which may be substituted, lower alkenyl or a group R-O-CH 2 - where R is methyl, ethyl, isopropyl, propyl-1,2-dienyl, allyl- l, 1-methyl-2-propenyl, phenyl or benzyl.

The present invention relates to a process for the preparation of the following compounds of general formulas M 'III and IV and their pharmaceutically acceptable salts.

/ s 114472 .NOR nor kr> I (C «2) p 'r3

I I

r2 r2

III IV

wherein n is 1 or 2; p is 0 or 1-4, R 2 is hydrogen or straight or branched lower alkyl of 1-4 carbon atoms,

R 3 is hydrogen, R is a group -Y-Z wherein Y

is a bond or a straight or branched hydrocarbon chain containing from 1 to 20 carbon atoms, optionally having from 1 to 4 double and / or triple bonds, and Z is hydrogen, a cycloalkyl group containing from 3 to 6 carbon atoms, an aromatic group which is phenyl; 2- or 3-thienyl, 2- or 3-furanyl, 2- • or 3-pyrrolyl, in which the aromatic group is substituted with one or two substituents selected from the group consisting of chlorine, bromine, fluorine, trifluoromethyl, nitro, amino, amino substituted with one or two straight or branched lower alkyl groups containing from 1 to 4 carbon atoms or straight or branched alkoxy containing from 1 to 4 carbon atoms; -NR 4 R 5 where R 4 and R 5 are the same or different and::: hydrogen or straight or branched alkyl of 1 to 4 carbon atoms, 114472

O

o

II

-CNR 4 R 5 where R 4 and R 8 are as defined above, O-CR 8 where R 8 is a straight or branched alkyl group having 1 to 6 carbon atoms; -CN, -CO 2 R 7 / wherein Ry is hydrogen, straight or branched, lower alkyl or benzyl of 1 to 6 carbon atoms, -XR 10 where X is oxygen or sulfur and R 10 is a straight or branched hydrocarbon chain of 1 to 6 carbon atoms optionally containing one or two double or triple bonds, provided that the following compounds are excluded: compounds of formulas III and IV wherein R is hydrogen.

_! Pharmaceutical compositions containing compounds of formulas III or IV may be used as analgesic agents and for the treatment of loss of consciousness.

;;; The various substituents of the compounds represented by the general formulas III and IV are further described below. Illustrative examples of straight or branched lower alkyl of 1 to 4 carbon atoms or 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl.

Illustrative examples of lower alkoxy groups containing 1 to 4 carbon atoms are methoxy, ethoxy and n-propoxy.

7, 114472

Illustrative examples of saturated, straight or branched hydrocarbon chains having 1 to 8 carbon atoms include n-octyl, n-heptyl and all of the above illustrative examples of straight or branched lower alkyl groups having 1 to 6 carbon atoms.

Illustrative examples of straight or branched, unsaturated hydrocarbon chains having 1-3 unsaturated sites which are double or triple bonds include ethenyl, 2,4-pentadienyl, 1,4-pentadienyl, 2,4-pentadienyl, , 4-pentadynyl, (E&Z) -2-penten-4-yl, 2-pentyn-4-enyl, 2-propenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 2-ethyl-3 -butenyl, 4-hexenyl, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 1-ethyl-2-propynyl, 1-methyl-3-butynyl, 3-butynyl or 4-pentynyl. Illustrative examples of cycloalkyl groups having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl and cyclohexyl.

Pharmaceutically acceptable acid addition salts of compounds of formulas III and IV include, for example; Hydrogen chloride, sulfur, phosphorus, vinegar, benzo, citrus: malonic, salicyl, apple, fumaric, oxalic, me ··· ripple, wine, milk , glucone, ascorbine, maleic, aspartin, benzenesulfone, methane and ethane sulf *; protection of phonic, hydroxymethane and hydroxyethanesulfonic acid; lat. (See, e.g., "Pharmaceutical Salts", J.Pharm.

: Sci. , 66 (1): 1-19 (1977). Preferred compounds of this invention are compounds of formula III.

π 4472 8

In the compounds of formulas III and IV, the group = NOR is attached to either the 2-, 3- or 4-position of the ring (formula III) or the 3- and 4-position of the ring (formula IV).

The compounds of the invention may be formulated into pharmaceutical compositions useful as analgesics, comprising an analgesically effective amount of a compound as defined above, together with a pharmaceutically acceptable carrier. In a method of alleviating pain in a mammal, a mammal in need of such treatment is administered an analgesically effective amount of a compound as defined above in association with a pharmaceutically acceptable carrier.

15

The pharmaceutical compositions for the treatment of senile dysfunctional symptoms comprise a cholinergically effective amount of a compound as defined above together with a pharmaceutically acceptable carrier. In the method of treating senile patients with senile dysfunctioning symptoms characterized by reduced production or release of cerebral acetylcholine, such treatment requires. ; a cholinergically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.

t »* · ;;; The compounds of the present invention may have v 'in either of the two Z and E isomeric forms. This invention relates to both forms of the compounds and to mixtures of the Z and E forms. Formulas IX and X illustratively illustrate compounds of Formula I which; are compounds close to the compounds of formulas III and IV and shown in the Reference Examples, Z and 35 E forms. In addition, in compounds having a double bond in the carbon chain, both Z and E forms of olefins: are within the scope of this invention.

114472 9

OR

fly or fly (CH2) n j (CH2) n

'NT

Z shape E shape

IX X

Compounds of Formulas I, III and IV are prepared by reacting a ketone of Formulas XI, XII and XIII with an amine of Formula NH 2 R 2 .HCl, in Formulas R and R 3 having the same meaning as above in Formulas I, II, III and IV.

R .- ^ ty0 MeOH

3 | (CH3> n1 + nh, or HCl - formula I

v. s room lamp.

OF

XI

R 3 -T ^ (CH 2) n + nh 2OR -HCl 1 Me ° -H- ^ Formula 11 v S room. temp.

. . 'R2

! XII

: 1

^ i \ MeOH

:: <ch2) p 2Lr3 + Nh2or -hci - formula 111 | ^ N ^ room temp.

; * i •: r2

* »I

XIII

In each of the above reactions, solvent is typically used in methanol and the reaction is carried out at room temperature.

»» I t * 1 o 114472

Salts are prepared by contacting the free base form of the compounds with a sufficient amount of the desired acid to produce the salt in a conventional manner. The free base forms can be obtained again by treating the salt form with a base if desired. For example, dilute aqueous solutions of bases such as sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate can be used for this purpose.

The free base forms of the compounds differ somewhat from their corresponding salt forms in physical properties such as melting point and solubility in polar solvents, but otherwise the salts are equivalent to their corresponding free acid or base forms for the purposes of this invention.

The starting materials represented by the formulas XI, XII and XIII are known in the art or may be prepared by methods well known in the art. See, for example, J. Saunders et al., J. Chem. Soc., Chem.Comm., 1988, 1618, and R. J. Smith and L.J. Street, Tet.Lett. 1989, 30, 5795. The amines represented by the formula NH2OR are also commercially available or can be prepared by methods known in the art.

'* · Example 1 (Reference Example) 1-Azabicyclo [2.2.2] hept-3-one oxime hydrochloride-1-azabicyclo [2.2.1] hept-3-one was prepared according to the procedure described in J. Chem. Soc. Chem.Comm. 1988, I 1618.

114472 11 L-Azabicyclo [2.2.1] hept-3-one (2g, 18 mmol) and hydroxylamine hydrochloride (1.25 g, 18 mmol) were dissolved in 10 mL of MeOH and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The crystalline residue was recrystallized from ethanol to give 2.04 g (70%) of the title compound, m.p. 211 "C. for C 6 H 11 ClN 2 O 3: Calc'd: C, 44.31; H, 6.82; N, 17.23 Found: C, 44.25; H, 6.64; N, 17.18

Mass spectrum: m / e 126.1 (M + for free base) 1 HNMR: δ (CDCl 3) 0.87 (1H, m), 1.31-1.46 (1H, m), 2.39-2.57 (5H , m), 3.01-3.21 (2H, m), 10.15 (1H, S), 10.58-10.82 (1H, broad s) 13CNMR: δ (CDCl3) 25.2, 40 , 50.5, 54.5, 58.5, 153.5.

Example 2 (Reference Example) 1-Azabicyclo [2.2.11] hept-3-one-0-ethyl-oxime hydrochloride 1-Azabicyclo [2.2.1] hept-3-one (2 g, 18 mmol) was dissolved in 25 L of methanol. Ethoximine hydrochloride was added; / dia (1.76 g, 18 mmol) and the reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was concentrated in vacuo to give a yellow solid. The residue v was dissolved in water, basified with saturated aqueous potassium carbonate and extracted with dichloromethane (3 x 150 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. A clear, yellow liquid was obtained. The liquid was dissolved in diethyl ether and filtered through Celite. The filtrate was treated with ethereal hydrogen chloride to give 2.5 g (75%) of the title product, m.p. 158-160 ° C.

144472 12 C 8 H 15 ClN 2 O: calcd: C 50.39; H, 7.93; N, 14.69 Found: C, 49.96; H, 7.76; N, 14.56

Mass spectrum: m / e 154.1 (M + for free base) 1 HNMR: δ (CDCl 3) 1.20-1.28 (3H, t), 1.97-2.05 (1H, m), 2.40-2 , 53 (1H, m), 3.29-3.42 (2H, m), 3.52-3.62 (2H, m), 3.83-3.95 (2H, m), 4.06 -4.14 (2H, q), 4.20-4.27 (1H, m) 13CNMR: δ (CDCl3) 14.4, 26.1, 40, 51.7, 55.8, 59.6, 70.3, 153.1.

Example 3 (Reference Example) 1-Azabicyclo [2.2.1] hept-3-one-O-methyloxime hydrochloride 11-azabicyclo [2.2.1] hept-3-one (1.9 g, 17.1 mmol) was dissolved in 10 mL: methanol. Methoxyamine hydrochloride (1.4 g, 17.1 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give a white solid.

The residue was recrystallized from a mixture of ethanol and diisopropyl / ether to give 2.27 (75%) of the title compound; product as a mixture of syn- and anti-isomers, m.p. 210-211 ° C.

C 7 H 13 ClN 2 O: calcd: C, 47.59; H, 7.42; N, 15.86 Found: C, 47.46; H, 7.54; N, 15.84

Mass spectrum: m / e 140.1 (M + for free base) 1 HNMR: δ (CDCl 3) 1.99 (1H, m), 2.36-2.52 (1H, m), 3.37-3.65 (4H , m), 3.86, 3.88 (3H, 2s) (3H, s), 3.89-4.00 (2H, m), j 4.21-4.29 (1H, m)

t! I

13 114472 13CNMR: δ (CDCl 3) 25, 26, 37.2, 40, 51.5, 51.7, 55.7, 56.5, 59.0, 59.6, 62.3, 153, 153, 5

The above procedure was used to synthesize the products listed in Table 1. Examples 4-36 are reference examples.

14 114472 _Table 1__

Hydroksyyllamiini. Product Example HCl_Number NH 2 OCH 2 CH 2 CH 1 -azabicyclo [2.2.1] heptan-4-one-0- (2-propynyl) oxime hydrochloride, m.p. 203 ° C (dec.) NH 2 OCH 2 Ph 1-azabicyclo [2.2.1] heptan-3-one O- (phenylmethyl) oxime hydrochloride, m.p. 173-174 ° C NH 2 OCH 2 CH 2 CH 3 1-Azabicyclo [2.2.1] heptan-6 3-one O-propyloxime hydrochloride, m.p. 165-166 ° C NH 2 OCH (CH 3) 2 1-azabicyclo [2.2.1] heptan-7 3-one O- (1-methylethyl) oxime hydrochloride,

mp 188-189 ° C

NH 2 OCH 2 CH = CH 2 1-Azabicyclo [2.2.1] heptan-8 3-one O- (2-propenyl) oxime oxalate, m.p. 125-127 ° C NH2OCH2CH2NH2 1-Azabicyclo [2.2.1] heptane 9

3-one-O- (2-aminoethyl) oxime. a hydrochloride, m.p. 232-234 ° C

NH2OCH2 · * · * 1-Azabicyclo [2.2.1] heptan-10 * 3-one O- (cyclopropylmethyl) oxime hydrochloride, m.p. 165-167 eC-NH2OCH2CH2OCH3 1-Azabicyclo [2.2.1] heptane-11; : 3-one-O- (2-methoxyethyl) oxime

hydrochloride, m.p. 176-178 ° C

; * NH 2 OPh 1-Azabicyclo [2.2.1] heptan-12 3-one-0-phenyloxime

* - hydrochloride, m.p. 130-131 ° C

1: NH 2 OCH 2 -1-azabicyclo [2.2.1] heptan-13 S 3-one O- (2-thienylmethyl) -: oxime hydrochloride,

; mp 188-191 eC

I. t | 15 1 1 4472 _Table l_

Hydroksyyliamilni. Product Example HCl f-number NH 2 OCH 2 -? 0.01-Azabicyclo [2.2.1] heptan-14 3-one-O- (2-furylmethyl) oxime oxalate,

ΓΓλ sul.p. 116-117 ° C

NH 2 OCH 2 -1-azabicyclo [2.2.1] heptan-3-one-O- (3-furylmethyl) oxime hydrochloride, m.p. 120-122 ° C NH 2 OCH (CH 3) CH = CH 2 1-azabicyclo [2.2.1] heptane

3-one O-(1-methyl-2-propenyl) oxime oxalate, m.p. 120-122 ° C

NH2OCH2CH2CH = CH2 1-azabicyclo [2.2.1] heptane-17

Oxalate of 3-one-O- (3-butenyl) oxime, m.p. 96-98 eC

NH 2 OC (CH 3) 3 1-Azabicyclo [2.2.1] heptan-18 3-one O- (tert-butyl) oxime hydrochloride, m.p. 231-232 ° C NH 2 OCH 2 -C-C-CH 3 1-azabicyclo [2.2.1] heptan-19: 3-one O-(2-butynyl) oxime

.: oxalate, m.p. 68-70 ° C

'NH2OCH2CH2-C = CH1-azabicyclo [2.2.1] heptane-20; v. 3-one-O- (3-Butynyl) oxime

oxalate, m.p. 177-178 ° C

«NH 2 OCH (CH 3) C = CH 1 -azabicyclo [2.2.1] heptan-21 3-one O-(1-methyl-2-propynyl) oxime oxalate,

· ;;; mp Mp 108-111 ° C

: ···: NH 2 OCH 2 CH = CH-C = CH 1 -azabicyclo [2.2.1] heptan-22 3-one O- (E-2-penten-4-ynyl) oxime hydrochloride,

, \ sul.p. 130-134 ° C

t 1 16 114472 _Table 1___

Hydroxylamine. Product Example number HCl NH2OCH2CH = CH-C = CH1-azabicyclo [2.2.1] heptan-23 3-one-O- (z-2-penten-4-ynyl) -oxime hydrochloride, NH2OCH2C = C-CH = CH2 -azabicyclo [2.2.1] heptan-24 3-one-O- (2-pentyn-4-enyl) -oxime hydrochloride NH 2 OCH 2 C 5 C -C 3 CH 1 -azabicyclo [2.2.1] heptan-3-one-O- (2 , 4-Pentadynyl) -oxime hydrochloride NH 2 OCH (CSCH) 2 1-Azabicyclo [2.2.1] heptan-26 3-one-O- (1-ethynylpropynyl) -oxime hydrochloride H2NOCH2ChN [[(1-Azabicyclo [2.2.1]) hept-3- 27

ylidene) amino] oxy] acetonitrile hydrochloride, m.p. 202-203 eC

H2NOCH2CH = CH-1-azabicyclo [2.2.1] heptane-28CH = CH2 3-one-O- (2,4-pentadienyl) -

oxime hydrochloride, m.p. 150-154 ° C

r] h2NOCH2CH = CH-1-azabicyclo [2.2. 1 Heptan 29 CH = CHCH 3 3-one-O- (2,4-Hexadienyl) -: · 'oxime hydrochloride,

... T sul.p. 179-180 ° C

v: H2NOCH2CH = CHCH3 1-Azabicyclo [2.2.1] heptane

3-one-O- (Z-2-butenyl)) oxime ··· oxalate, m.p. 135-140 ° C

H2NOCH2CH = CHCH3 1-Azabicyclo [2.2.1] heptan-31,3-one-O- (E-2-butenyl) oxime

hydrochloride, m.p. 154-156 ° C

17 114472 _Table 1_

Hydroksyyliamiinl. Product Example number HCl H2N0CH2CSCCH2C = CH1-azabicyclo [2.2.1] heptane-32

3-one-O- (2,5-Hexadynyl) -oxime oxalate, m.p. 144-146 ° C

H2NOCH2CH = CH-C2CH1-Azabicyclo [2.2.1] heptane- 33

3-one-O- (2-penten-4-ynyl) -oxime oxalate, m.p. 130-134 ° C

H2NOCH2CsC-CH2OCH3 1-Azabicyclo [2.2.1] heptane- 34

3-One-O- (4-Methoxy-2-butynyl) -oxime hydrochloride, m.p. 193-195 ° C

H2NOCH2CO2CH3 [[(1-Azabicyclo [2.2.1] heptane- 35

3-Ylidene) Aminooxy Acetic acid methyl ester hydrochloride, m.p. 174-175 ° C

H2NOCH2C2CCH2CH3 1-Azabicyclo [2.2.1] heptane- 36

3-one-O- (2-pentynyl) oxime hydrochloride, m.p. 147-149 ° C

; · ·, Example 37 (Reference example): ;; 1-Azabicyclo [2.2.2] octan-3-one-O-methyloxime

A mixture of ketoamine.HCl (5.56 g, 0.03 mol), 3-quinuclidinone (2.51 g, 0.03 mol) and potassium carbonate (11.0 g, 0.08 mol) was added. mole) in methanol (250 mL) was allowed to reflux for 2 hours. The methanol was removed under reduced pressure, after which the solution was suspended in water and extracted with ethyl ether (3 x 125 mL), dried over MgSO 4, filtered and concentrated to give a mixture of syn and anti-isomers. The oxalate salt was composed of an oil, m.p. 125-128 ° C.

144472 NMR: δ (CDCl3) 9.01 (broad s, 2H), 4.03 (S, 1H), 3.89 (S, 1H), 3.80, 3.79 (two s, 3H) 3 , 27-3.12 (br m, 5H), 2.10-1.79 (br m, 4H) 13CNMR: δ 164.7, 155.1, 154.6, 61.4, 59.4, 50 , 7, 50.1, 45.6, 45.5, 26.7, 22.5, 22.1, 21.4, 21.2 IR (cm -1) 2361, 1748, 1693, 1652, 1463, 1403, 1320, 1221, 1103, 1048, 861, 832, 785, 721, 670

Mass Spectrum: 154, 137, 123, 108, 97, 82, 67, 55 C 8 H 14 N 2 O * 1 25 C 2 H 2 O 4 * calculated: C 47.28; H, 6.23; N, 10.50 Found: C, 47.57; H, 6.32; N, 10.27

Example 38 (Reference Example) (E) -1a (Z) -1-Azabicyclo [2.2.2] octan-3-one-O- (2-propyl) oxime 3-quinuclidinone (1.5 g, 12 mmol) and 2 propynylhydroxylamine hydrochloride (1.29 g, 12 mmol) was dissolved in 20 mL of methanol and stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo to give a dark brown semi-solid. Raw, semi-solid! basified with aqueous ICO2 and extracted with Ί ;; chloroform. The chloroform extract was evaporated to give the crude "·" chaoxime as a mixture of E and Z isomers. Chromatographic separation of these isomers (silica gel; dichloromethane-acetone-methanol (150: 10: 5)) afforded 1.0 g of the isomer A (m.p. 81-83 ° C) and 0.42 g of the isomer B, respectively. mp 100-101 ° C).

'* Isomer A: i: C 10 H 14 N 2 O: calcd: C 67.39; H, 7.92; N, 15.72; Found: C, 67.26; H, 7.94; N 15.59 19 1 1 4472

Mass spectrum: m / e 178 1 HNMR: δ (CDCl 3) 1.7-1.85 (4H, m), 2.40-2.55 (1H, m), 2.58-2.65 (1H, m) , 2.75-3.05 (4H, m), 3.63 (2H, S), 4.62 (2H, s) 13CNMR: δ (CDCl3) 26.3, 28.6, 47.2, 52 , 3, 60.9 74.2, 81.0, 166.0.

Isomer B: C10H14N2O: Calc'd: C, 67.39; H, 7.92; N, 15.72 Found: C, 66.95; H, 8.02; N, 15.59

Mass spectrum: m / e 178 1HNMR: δ (CDCl3) 1.6-1.8 (4H, m), 2.45-2.50 (1H, m), 2.78-3.0 (4H, m) , 3.35-3.44 (1H, m), 3.45 (2H, S), 4.6 (2H, S) 13CNMR: δ (CDCl3) 23.5, 24.8, 47.2, 53 , 6, 60.8, 70.1, 81.0, 165.0.

Example 39 4-piperidinone-O-methyloxime hydrochloride · 4-piperidinone hydrochloride monohydrate (5 g, 32.5 mmol), methoxyamine hydrochloride (4.18 g, 50 mmol) and; potassium carbonate (13.82 g, 100 mmol) was added to 100 mL of ethanol and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate evaporated to give a white solid. The solid raw material was dissolved in water, made basic with solid potassium chloride. : Bonate and extracted with dichloromethane (3 x 100 mL).

The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to give a clear, colorless liquid. It was converted to its hydrochloride salt by treatment with ethereal hydrogen chloride to give the product 233 g, m.p.

140-141 ° C.

20.14472 C 6 H 12 N 2 O * HCl: Calcd: C 43.77; H, 7.96; N, 17.02 Found: C, 43.78; H, 7.96; N 17.08 1 HNMR: δ (CDCl 3) 2.68-2.73 (t, 2H), 2.92-2.97 (t, 2H), 3.27-3.34 (m, 4H), 3 , 84 (s, 3H), 9.93 (broad s, 1H) 13CNMR: δ (CDCl3) 21.76, 28.05, 42.92, 44.29, 61.61, 150.07

Mass Spectrum: m / e 128.08 (M + of free base).

Example 40 1-Methyl-1-piperidinone-O-methyloxymethyl-hydrochloride-1-methyl-4-piperidone (5 g, 44.2 mmol) and methoxyamine hydrochloride (3.59 g, 44.2 mmol) were added to 25 mL methanol and stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo to give a solid residue. The residue was dissolved in water, basified with solid potassium carbonate and extracted with dichloromethane; purple (3 x 100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a clear yellow liquid which was purified on silica gel eluting with dichloromethane: methanol 95: 5; oxide, 2.55 g of the desired product were obtained. Processing ;; ethereal hydrochloride gave the hydrochloride salt, 2.99g, m.p. 145-147 ° C.

C 7 H 14 N 2 O.HCl: Calcd: C, 47.06; H, 8.46; N, 15.68 Found: C, 46.94; H, 8.41; N 15.60 1 H NMR: δ (CDCl 3) 2.53-2.58 (m, 1H), 2.69-3.20 (m, 4H), 2.87-T * 2.89 (d, 3H) , 3.36-3.49 (m, 1H), 3.55-3.76 (m, 2H), 3.84 (s, 13H), 12.90 (broad s, 1H) 21.14472 13CNMR: δ (CDCl3) 21.97, 28.25, 43.46, 53.09, 54.36, 61.64, 149.17

Mass Spectrum: m / e 142.17 (M + for free base).

Example 41 (Reference Example) Z- (±) -1-Azabicyclo [2.2.11] heptan-3-one-2-propenyloxamine Oxalate and E- (±) -1-Azabicyclo [2.2.1] heptan-3-one O-z-Propenyloxlime Oxalate 1-Azabicyclo [2.2.1] heptan-3-one (2 g, 18 mmol) and O-allyl hydroxylamine hydrochloride hydrate (1.97 g, 18 mmol) were dissolved in 25 mL of methanol and stirred at room temperature 18 hours. The reaction mixture was evaporated in vacuo to give a viscous oil. The crude oil was dissolved in 50 mL of water, basified with a saturated solution of potassium carbonate and extracted with ether (3 x 100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a clear yellow liquid which was purified on silica gel, eluting with a 10: 1 mixture of dichloromethane and methanol. Isomer A, which was less polar,. isolated and converted to the oxalate salt, 1.365 g, m.p. 130-132 ° C.

Calcd .: C, 51.55; H, 6.29; N, 10.93 Found: C, 51.52; H, 6.37; N, 10.88 1HNMR: δ (DMSO) 12.0 (broad s, 2H), 5.86-6.02 (m, 1H), 5.17 (1H, 5.31 (m, 2H), 4). , 5-4.52 (d, 2H), 3.85-4.06 (q, 2H), 3.16-3.42 (m, 5H), 2.14-2.27 (m, 1H) , 1.70-1.75 (m, 1H)

Mass Spectrum: m / e 166.1 (M + for free base).

. : Isomer B, which was more polar, was converted to oxalate to give 0.829 g, m.p. 102-104 ° C.

22 114472 C 9 H 14 N 2 ° * C 2 H 2 ° 4: calcd: C, 51.55; H, 6.29; N, 10.93 Found: C, 51.02; H, 6.22; N, 10.63 1 HNMR: δ (DMSO) 11.2 (broad s, 2H), 5.88-6.04 (m, 1H), 5.17- 5.33 (m, 2H), 4.50-. 4.55 (d, 2H), 3.73-4.00 (m, 3H), 3.11-3.42 (m, 4H), 2.08-2.21 (m, 1H), 1, 62-1.66 (m, 1H)

Mass Spectrum: m / e 166.1 (M + for free base).

The above procedure was used to synthesize the following E and Z isomers (Examples 42-65 are reference examples): «« <»» »1 U472 23 £

Example: Amine.HCl Product Number_42 H2NOCH2C = CH Z- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-0-2-propynyloxime hydrochloride, m.p. 199-200 ° C

s 43 H2NOCH2 - ^ = 555 / Z- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one O- (3-thienylmethyl) oxime oxalate, m.p. 142-144 ° C

S

44 H2NOCH2-1E- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one O- (3-thienylmethyl) oxime oxalate, m.p. 142-143 ° C

45 H2NOZ- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-O- (2-methyl-2-propenyl) oxime oxa ·. tile, m.p. 131-133 ° C

/ 46 Η2Ν0 ′ ^ Νγ / E- (±) - 1-Azabicyclo [2.2.1] -; heptan-3-one-O- (2-methyl-2-; propenyl) oxime oxime

tile, m.p. 124-126 ° C

47 H2NO- <Y ^> Z- (±) -1-Azabicyclo [2.2.1] - ,,; 'Heptan-3-one-O-cyclobutyloxime hydrochloride,

; mp Mp 209-210 ° C

* ·: * ’48 H2N0 - <^> E- (±) -1-Azabicyclo [2.2.1] -. ·! heptan-3-one-O-cyclobutyl; oxime hydrochloride,

mp 207-208 ° C

24 114472

Example: Amine.HCl Product Number_49 H2NO (CH2) 3CHCH Z- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-0-4-pentynyl oxime oxalate, m.p. 119-121 ° C

50 H2NO (CH2) 3C = H E- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-0-4-pentynyl oxime oxalate, m.p. 110-113 ° C

51 H2NO (CH2) 2C = C-CH3 Z- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-0-3-pentynyl oxime oxalate, m.p. 161-162 ° C

52 H2NO (CH2) 2C = C-CH3 E- (±) -1-Azabicyclo [2.2.1] heptan-3-one-0-3-pentynyl oxime oxalate,

; ; ; mp 149-150 ° C

,: ·! 53 H2NOCH2CsCCH2C = CCH3 Z- (±) -1-Azabicyclo [2.2.1] -. i'm! heptan-3-one-O- (2,5-heptadinyl) oxime oxalate,

· ;;; mp 65-70 ° C

* I (54 H2NOCH2 <^ CCH2C ^ CCH3 E- (±) -1-Azabicyclo [2.2.1] heptan-3-one-O- (2,5-heptadinyl) oxime oxalate,

X: mp Mp 108-110 ° C

55 H2NOCH2C1CCH2CH = CH2 Z- (±) -1-Azabicyclo [2.2.1] li-heptan-3-one-O- (2-hexyn-5-enyl) oxime oxalate, m.p. 94-96 ° C / 25 1 U472

Ex. Amine.HCl Product number_56 H2NOCH2C = C-Ph Z- (±) -1-azabicyclo [2.2.1] heptan-3-one-O- (3-phenyl)

2-propynyl) oxime oxalate, m.p. 162-164 ° C

57 H2NOCH2C = C-Ph E- (±) -1-Azabicyclo [2.2.1] heptan-3-one-0- (3-phenyl)

2-propynyl) oxime oxalate, m.p. 83-85 ° C

58 H2NOCH2C = C-Z- (±) -1-Azabicyclo [2.2.1] -C (CH3) = CH2 heptan-3-one-0- (4-methyl-

2-pentyn-4-enyl) oxime oxalate, m.p. Mp 118-119 ° C

59 H2NOCH2C = CC (CH3) = CH2 E- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-O- (4-methyl-pentyn-4-enyl) oxime oxalate, m.p. 78-83 ° C

60 H2NOCH2C ^ C (CH2) 2CH3 Z- (±) -1-azabicyclo [2.2.1] - .1; heptan-3-one-O- (2-hexenyl) oxime oxalate,

mp 109-110 ° C

61 H2NOCH2C = C (CH2) 2CH3 E - (+) - 1-Azabicyclo [2.2.1] heptan-3-one O- (2-hexenyl) oxime oxalate,

;. mp 105-107 ° C

62 H2NOCH2C = C (CH2) 3CH3 Z- (±) -1-Azabicyclo [2.2.1] heptan-3-one-O- (2-heptynyl) oxime oxalate,

mp 109-110 ° C

26 1 14472

Eg Amine.HCl Item number____ 63 H2NOCH2C = C (CH2) 3CH3 E- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one-O- (2-heptynyl) oxime oxalate, m.p. 100-104 ° C

64 H2NOCH2CH2SCH2CHCH Z- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one O- (2- (2-propynylthio) ethyl) oxime oxalate, m.p. 101-103 ° C

65 H2NOCH2CH2SCH2C ^ CH E- (±) -1-Azabicyclo [2.2.1] -

heptan-3-one O- (2- (2-propynylthio) ethyl) oxime oxalate, m.p. 121-122 ° C

Example 66 N-Methyl-8-azabicyclo [3.2.1] Tocta-3-one-methyloxime Hydrochloride A solution of methoxyamine hydrochloride (4.18 g, 0.05 mol) in methanol was added to a stirred solution of V and of N-methyl-8-azabicyclo [3.2.1] octa-3-one (commercially available) (6.96 g, 0.05 mol) in methanol was cooled in an ice bath.

; The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 16 hours, after which; · The solvent was removed. The resulting solid residue was partitioned between 'CH2Cl2 and concentrated aqueous K2CO3 solution; . The organic layer was dried (K 2 CO 3) and concentrated to give an oil. The oil was dissolved in ether and treated with ethereal HCl. The white solid formed was filtered off and recrystallized from a mixture of isopropanol / isopropyl ether to give 4.88 g (45%) of oxime hydrochloride as a white solid which upon melting turns brown at 197 ° C to 200 ° C and decomposes with decomposition at 217 ° C. C-220 ° C; * HNMR (D 2 O) δ 4,710 (S, 4H), 4,013- 3,939 (bd, 1H), 3,765 (S, 3H), 3,259-3,194 (bd, 1H), 2,745 (S, 3H), 2,476-2,232 (m , 3H), 1.909-1.722 (m, 1H) 13CNMR (D 2 O) δ 154.411, 66.306, 65.520, 64.257, 41.756, 38.930, 33.925, 27.461, 26.657 MS: m / e (relative intensity) 182 (0.15), 170 (8), 169 (71), 168 (64), 167 (9), 153 (2), 138 (13), 137 (97), 136 (4), 122 (7), 109 (7), 108 (11), 98 (3), 97 (16), 96 (16), 96 (71), 95 (12), 94 (26), 93 (3), 88 (4), 87 (72), 85 (2), 92 (100), 81 (24), 80 (7)

Analysis calculated for C 9 H 16 N 2 O.HCl: C, 52.80; H, 8.37; N, 13.69 Found: C, 52.87; H, 8.31; N, 13.45

Example 67 N-Methyl-8-azabicyclo [3.2.1] octan-3-one methyloxime hydrochloride

(1 I

·; ·; The preparation of this compound is described in the reaction scheme at the end of the specification and is shown below.

»I

»»> I I |

• I

28 1U472 (a) Preparation of ethyl 1,3,4,5-cycloheptatriene-1-carboxylate (2)

Ethyldiazoacetate (43.4 g, 0.38 mol) was added slowly (syringe pump) over 7 hours to a mixture of benzene (594.32 g, 7.61 mol) and tetrakis (perfluorobenzoate) dirodium (II) (0, 84 g, 0.16 mol). After stirring at room temperature for 16 hours, the solvent was removed and the oily residue was distilled in vacuo to give 50.44 g (81%) of ethyl 1,3,5-cycloheptatriene-1-carboxylate, b.p. 90-96 ° C 2.4-3.0 mmHg, 1 H NMR (CDCl 3) δ 6.6 (m, 2H), 6.2 (m, 2H), 5.3 (m, 2H), 4.2 ( q, 2H, OCH 2 CH 3), 2.5 (t, 1H), 1.3 (t, 3H, CH 2 CH 3).

(b) Preparation of N-methyl-ethyl-8-azabicyclo [3.2.11] oct-2-ene-2-carboxylate (3)

A mixture of ethyl 1,3,5-cycloheptatriene-1-carboxylate (12.72 g, 0.077 mol), methylamine (23.13 g, 0.74 mol) and NaOH (3.1 g) (0.078 mol) in MeOH v: (60 ml) was kept in an autoclave at 125 ° C for 26 hours. The reaction mixture was filtered and the filtrate was concentrated to give an oil. The oil was dissolved in MeOH (400 mL) and saturated with HCl gas; concentrated sulfuric acid (8 mL) was added and the mixture was refluxed for 12 hours. The MeOH was evaporated to give an oily residue, which was partitioned between aqueous concentrated Na 2 CO 3 and ET 2 O. The ether layer was evaporated to a brown oil.

* · 'IR (neat, neat): 1720 (COOCH3)

> I

: '·; 1 HNMR (CDCl 3) δ 6.8 (bt, 1H), 3.7 (S, 3H,? CH 3), 2.35 (S, 3H,? NCH 3), 3.4-2.4 (m, 3H). , 2.3-1.4 (m, 6H).

/ 29 114472 (c) Preparation of N-methyl-2-acetyl-8-azabicyclo [3.2.1] oct-2-ene (4)

To a mixture of ethyl trop-2-ene-2-carboxylate (3.43 g, 0.019 mol) and Me 3 SiCl (10.32 g, 0.095 mol) in THF (70 mL) cooled to -100 ° C, MeLirt (1.4 M, 17.07 mL, 0.0239 mol) was added dropwise. After warming to room temperature, the reaction mixture was stirred for 16 hours. The excess Me 3 SiCl and THF was evaporated and the resulting residue was stirred with EtOH (6 mL) followed by water (6 mL).

The mixture was then acidified (6 N HCl) and extracted with ether. The aqueous layer was made basic (solid K 2 CO 3) and extracted with chloroform, dried (K 2 CO 3) and concentrated to give 3.14 g (81%) of 2-acetyltrop-2-ene as an oil.

IR (neat): 1670 (COCH 3) 1 HNMR (CDCl 3) δ 6.7 (bt, 1H), 2.3 (S, NCH 3), 2.2 (s, C (= O) CH 3).

: (d) N-methyl-2-acetyl-8-azabicyclo [3.2.11] octane, compound (5), was obtained by catalytic reduction of compound (4) (H2 / RaNi) and modification of N-methyl-8-azabicyclo [ 3.2.1] to octane-2-octanone, compound (7), using methods known in the art, see J.Qrq.Chem. 55, 5025 (1990). In compound (6), TBDMSO means tert-butyldi-methylsilyloxy. Ketones, i.e. compound (7) is converted to methyl oxime as generally described above; at 66.

»I

In the same manner as N-methyl-2-acetyl-9-azabicyclo [4.2.1] nonane, which can be prepared from 2-acetyl-9- * 1-azabicyclo [4.2.1] non-2-ene, is commercially ·; ' ; available, replacing N-methyl-2-acetyl-8-azabicyclo [3.2.1] octane, which is compound (5), yields N-methyl-8-azabicyclo [4.2.1] nonan- 2-one oxime. Compounds prepared according to the present invention act centrally as muscarinic agents and are thus useful as analgesic agents for treating pain in mammals, including man, as sleeping pills and for treating senile dementia, Alzheimer's disease, Huntington's dementia, tardive dyskinesia, conditions characterized by reduced cerebral acetylcholine production or release.

The biological activity of the compounds of this invention was evaluated using numerous assays. The activity of the compounds as key muscarinic binding site antagonists and counteractors was measured. In the RQNB screening assay, fully described by Mark Watson et al., J.Pharmacol. and Ext.Ther., 237 (2), - 411 (1986), rat cortical tissue was treated with radiolabeled quinuclidinyl benzylate, a known muscarinic binding site antagonist. The concentrations of test compound required to inhibit binding of this muscarinic counteractor by 50% were then measured.

Similarly, in the RCMD screening assay, fully described by T.W. Vickeroy et al., 29 (3), -747 (1984), rat cerebral tissue was treated with radiolabeled cis-methyl.

* »I

'Dioxidane, which is known to act as a muscarinic binding site. The concentrations of test compounds required to inhibit the binding of this muscarinic agent were then determined; 50%. These values are expressed as IC50 concentrations. Table 2 and show that the close reference compounds have significant muscarinic activity.

/ 31 1 1 4472

Table 2

I im. nro IC ^ q nM ICgQ

_RCDM_RQNB_ 3 18.2 24558 2 12.5 3112 4 3.5 2967 5 133 5947 6 120 3846 7 46 2030 8 53 4775 27 116 8820 28 (Isomer A) 12.9 434 28 (Isomer B) 256_9650_

In therapeutic use as agents for treating pain or treating brain dysfunction, the compounds are used in a pharmaceutical method for administration to a patient at dosages in the range of 0.07 mg to 700 mg per day. For a normal elderly person weighing approximately 70 kg this means a dose of 0.01 mg / kg to 100 mg / kg / day.

.: However, the specific doses used may vary depending on the requirements of the patient, the stability of the condition being treated! and the activity of the compound used. Optimian-; Whereas the determination of hoists in a given situation is within the skill of the art ;;; in his job.

* ·

For the preparation of pharmaceutical compositions from the compounds, the inert, pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, disintegrating granules, capsules, starch capsules and suppositories.

The solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it may also be an encapsulating agent.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides and cocoa butter, is first thawed and the active ingredient is dispersed therein, for example, by mixing. The molten homogeneous mixture is then poured into molds of appropriate size and allowed to cool and solidify.

The powders and tablets preferably contain from about 5% to about 70% by weight of active ingredient. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose. : loose, low melting wax, cocoa butter and the like.

; The term "preparation" includes the active ingredient and the carrier. a capsule formulation of a combination of encapsulating agent used as a capsule; ; wherein the active agent (with or without other carriers) is surrounded by a carrier which is then in contact with the active agent. The same applies to starch capsules.

Tablets, powders, starch capsules and capsules' can be used in solid dosage forms suitable for oral administration.

; Liquid preparations include solutions suitable for oral or parenteral administration, or suspensions and emulsions suitable for oral administration. Sterile aqueous solutions of the active component or sterile solutions of the active component in solvents containing water, ethanol or propylene glycol may be mentioned as examples of liquid preparations suitable for parenteral administration.

Sterile solutions may be prepared by dissolving the active component in a desired solvent system and subsequently passing the solution through a membrane filter to sterilize the solution, or alternatively, the sterile compound may be pre-dissolved in a sterilized solvent under sterile conditions.

Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavors, colorants, stabilizers, and thickening agents as desired. aqueous suspensions for oral use can be prepared by dispersing the finely divided active component in water in association with known suspending agents in the preparation of viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other pharmaceutical preparations.

; Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.

The unit dosage form may be a packaged preparation, the package containing various quantities of the preparation, for example, coated tablets, capsules and powders in vials; or in ampoules. The unit dosage form can also be a capsule, starch capsule or tablet itself, or it can be the appropriate number of any of these packaged forms.

34 1U472

Chart 0

ON2CHCO2Et 1. H2NCH3 / NaOH / MeOH

Rh 2 (C 6 F 5 CO 2) 4 125 ° C / 26h 81% 2. MeOH / HCl 1 2. 49%

O O

^^ x ^ nOCH3 1. MeLi / Me3SiCl / -100 ° C room temperature ^^^ \

N 2. H + 81% N

'1 1 1

Oh TBDMSO

H2 NaH / THF

TBDMS

1 5. 1 £ Γ: ^ -v. ° / ^^ N "0CH3;. O3 r h2noch3-hci f y *. ' : £ N MeOH * «K ~ y

, ··. N N

·, ·. 1 7 * 1 * * * /

Claims (3)

35 1 ^ 4472 A process for the preparation of an aza-bicyclo or azacyclooxime of formula III or IV, or a Z or E form thereof, or a pharmaceutically acceptable salt thereof, for use as a cholinergic agent NOR> * NO R 3 - <2 ^ CH 2 '(CH 2). ) R 1 R 2 k 2 R 2 III IV wherein n is 1 or 2; p is 0 or 1-4; R 2 is hydrogen or straight or branched lower alkyl of 1 to 4 carbon atoms; [R3 is hydrogen, R is a group -Y-Z wherein Y is a bond or a straight or branched; \; nut, a hydrocarbon chain containing from 1 to 20 carbon atoms, optionally containing from 1 to 4 double and / or triple bonds, and; Z is hydrogen, a cycloalkyl group containing 3-6 carbon atoms, an aromatic group which is phenyl, 2- or 3-thienyl, 2-, ···. or 3-furanyl, 2- or 3-pyrrolyl, where the aromatic group is unsubstituted or substituted by one or two. a substituent selected from the group consisting of chlorine, bromine, fluorine, trifluoromethyl, nitro, amino, amino which is substituted; substituted with one or two straight or branched lower alkyl groups of 1-4, ·, · carbon atoms or straight alkoxy, 1-4 carbon atoms or -NR 4 R 5 where R 4 and R 5 are the same or different and are hydrogen or straight or branched alkyl having 1 to 4 carbon atoms, O-CNR 4 R 5 where R 4 and R 5 are as defined above, O 2 -CR 8 where R 8 is a straight or branched alkyl group having 1 to 6 carbon atoms, CN, -CO 2 R 7 / wherein R 7 is hydrogen, straight or branched, lower alkyl or benzyl of 1 to 6 carbon atoms, or -XR 10 wherein X is oxygen or sulfur and R 10 is a straight or branched hydrocarbon chain of 1 to 6 carbon atoms, optionally containing one or two double or triple bonds, provided that the following Compounds are not included: Compounds of Formulas III and IV wherein R is hydrogen, characterized in that Formula III or IV, respectively; To obtain the compound of formula (I): a ketone selected from the compounds of the following formulas:; (i :: R3-rj '2) o or (c ^ i, T_Rj SN / 1 R2 Rj *' · '·· is reacted with the amine hydrochloride of the formula NH 2 OR.HCl, wherein n, p, R 3, R 2 and R have the same meaning as above in methanol at room temperature. ll4472 Process according to claim 1, characterized in that N-methyl-8-azabicyclo [3.2.1] octa-3-one methyloxime hydrochloride or N-methyl-8-azabicyclo [3.2.1 ] octa-2-one-methyloxime hydrochloride. 3. A process according to claim 1, characterized in that 4-piperidinone-0-methyloxime hydrochloride or 1-methyl-4-piperidinone-0-methyloxime hydrochloride is prepared. 114472