MXPA97008337A - Maleate (r) - (z) -1-azabiciclo [2.2.1] heptan-3-ona, 0- [3- (3-metoxypenyl) -2-propinyl] -oxymy as an agent farmaceut - Google Patents

Abstract

The present invention relates to the salt [1: 1] of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one, O- [3- (3-methoxyphenyl) -2-propynyl ] oxime, a known muscarinic agonist, has unique properties relative to other salts of the compound, making it a desirable pharmacist.

Description

MALEATE (R) - (Z) - 1 - AZABICICLO [2.2.1] HEPTAN - 3 - ONE, O - [3 - (3-METOXYPENYL) -2-PROPINYL] OXIME AS A PHARMACEUTICAL AGENT. BACKGROUND OF THE INVENTION The present invention is a crystalline salt of (R) - (Z) -1-azabicyclo [2.2. ljheptan - 3 - one, or - [3 - (3-methoxyphenyl) -2-propynyl] oxime and maleic acid (ratio 1: 1) (the compound) which provides a pharmaceutical form with properties superior to free base or any other pharmaceutically acceptable salt forms of this compound.

The chemical structure of this salt is Compounds of Formula I below, and more specifically a subset of compounds of Formula II below, are covered in U.S. Patent No. 5,306,718 and U.S. Pat. No. 5,346,911, as Muscarinic Antagonists, above. useful for the treatment of pain and cognitive decline associated with cholinergic deficiency of the brain, such as Alzheimer's disease.

The compounds of Formula II wherein Ar is a phenyl group substituted by one or more methoxy groups possess some of the most interesting profiles of pharmacological activity in vitro (Jaen, et al., Life Sciences, 1995; 56: 845-852 ( Table I of the reference)). One of these particular compounds (1), which retains a (3-methoxyphenyl) propargyl side chain, was identified in this and other previous publications (Davis R., et al., Prog. Brain Res., 1993; 98: 439-445) for displaying a very favorable complete profile of pharmacological activity, as illustrated by its high affinity to muscarinic receptors of rat cerebral cortex, the ability to displace a radiolabeled ligand agonist (cis-metildioxolane) from muscarinic receptors. in concentrations 246 times lower than those required to displace an antagonist radioligand (quinuclidinyl benzilate) and its ability to selectively stimulate muscarinic receptors of the my subtype without significant stimulation of other muscarinic receptors not mi.

A compound with the chemical structure of 1 above can exist as any of four stereochemical isomers represented by the, lb, le and Id forward.

(R) - (Z) - stereoisomer (S) - (Z) - stereoisomer (R) - (E) - stereoisomer (S) - (E) - stereoisomer The isomers la and lb are enantiomers (ie, mirror images of each), the above is true for the isomers and Id. Since the asymmetric center of these molecules is on a bridgehead carbon, which can not be epimerizing under any normal situations, the resolution of these enantiomeric pairs (i.e., the separation of the lb or the dL separation) can be achieved by synthetic and resolution techniques described in U.S. Patent No. 5,346,911. And it is permanent. This means, for example, that it can not interconvert to its enantiomer lb and can not be interconverted to Id. On the other hand, it has the same absolute stereochemistry in the bridge-head carbon atom but not geometric isomers of each which in the oxime carbon-nitrogen double bond. The same relationship exists between the isomers lb and Id.

The agonist efficacy of oxime 1 muscarinic resides mainly in the la isomer (Jaén ibid and Table I below). Tables II and III of the reference indicate that the isomer la (designated R-8 in the Jaén reference) displays greater selectivity of the subtype of the receptor mi and greater power mi than the isomer lb (designated S-8). The small amount of activity displayed per lb could be due to the presence of small amounts of it in the lb samples. A comparison between the and a mixture of lc / ld, illustrated in Table I below, indicates that it is more potent and more efficient as a muscarinic agonist (as determined by the greater proportion of quinuclidinyl benzilate (QNB) with cis-methyldioxolane (CMD) with linkage for). As a result of these and others experiments, it was identified as an optimal compound (high efficiency agonist of muscarinica with high selectivity for subtypes of mi) receptors for development as a treatment for cognitive dysfunctions associated with cholinergic deficits, such as Alzheimer's disease.

TABLE I. Links of the Muscarinic Receptor Compound CMD Link (ICso (nm) Link QNB (ICS0 (nm) la 25 5300 (lc + ld) to 150 14800 a Racemic (E) -oxime was used in these assays.

Some oxime carbon-nitrogen double bonds are relatively stable, while others may undergo easy rearrangements, typically in the presence of acid catalysts. The specific substitution pattern around the half oxime typically determines the chemical stability of oxime (propensity to hydrolyze within its ketone and hydroxylamine components), its stereochemical integrity (the tendency of each geometric isomer to remain in the E or Z configuration) and the exact position of the thermodynamic equilibrium between both stereochemical forms (when the conditions Chemicals are such that a balance can be reached). As illustrated in Table II further, the Compound may undergo isomerization catalyzed in acid to produce its geometric isomer le. This equilibrization depends on the time - and the pH -. We have determined that the thermodynamic equilibrium ratio of the: le in solution is approximately 85:15.

TABLE p. Maximum proportions of Z area: E as a function of pH 24 hours after incubation at 37 ° C. pH Maximum area ratio (la: le) 0. 1N HC1 85:15 pH 1.97 88:12 pH 4.03 99.3: 0.7 > 4.03 100: 0 There are multiple reasons for not considering a 85:15 mixture of these two isomers as an optimal entity for the development of a pharmaceutical drug. The 85: 15 ratio of the isomers is not always produced in exactly the same starting amounts in departure, and the clinical efficacy of such mixtures would be more difficult than when dealing with a single compound, and the cost of developing a fixed mixture as a clinically useful drug it would also be significantly higher; and finally, the physical properties of a 85:15 combination of isomers are less optimal than those of the pure in terms of crystallinity, chemical and physical stability.

The development of the as a pharmaceutical drug required the identification of a saline or free base form with optimal physical and chemical properties. The most critical properties included: Ease and reproducibility of preparation, crystallinity, no hygroscopicity, aqueous solubility, stability to visible and ultraviolet light, low degradation ratio under accelerated temperature stability conditions and humidity, low isomerization ratio to its isomer under these conditions and safety for long-term administration in humans.

The free base and the pharmaceutically acceptable salts are covered by U.S. Patent No. 5,306,718 and the continuation in part 5,346,911. The listed salts are: hydrochloric, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methane and ethanesulfonic, hydroxymethane and hydroxyethanesulfonic .

There is no teaching or suggestion that the maieato is a superior salt form of the previous structure. Clearly the excellent properties of the salt of maieato were not known or appreciated until now.

These two patents are incorporated herein by reference. We have discovered that not all salts are equally useful, as judged by the list of properties described above. In particular, we have discovered the excellent unexpected properties of the salt of maleic acid (1: 1), which clearly distinguishes this salt.

SUMMARY OF THE INVENTION The large number of salts of the compound prepared and examined, quite unexpectedly, only the salt of the maieate [1: 1] fulfilled all the standards of the inventors as a pharmaceutically acceptable and desirable salt: ease of preparation without isomerization, consistent and reproducible stoichiometry, crystallinity, aqueous solubility, stability to the light, no gigroscopicity, no toxicity and physical and chemical stability in general. The present invention is, therefore, directed to the salt [1: 1] of the Compound with maleic acid, its preparation in a form such that crystals of large particles of this salt treat cognitive deficiencies and pain. The chemical name of this salt is (R) - (Z) -1 - azabicyclo [2.2. ljheptan-3-one, O - [3 - (3-methoxyphenyl) -2-propynyl] oxime, (Z) -butenedioic acid, [salt 1: 1]. Most glass particles are larger than 10 x 10 μm in size; at least half of the particles are larger than 10 x 10 μm.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the separation of the and by HPLC.

Figure 2 shows an electron micrograph of crystals of maieate from recrystallized from ethyl acetate.

Figure 3 shows an electron micrograph of crystals of maieate from that obtained by precipitation from diethyl ether.

Figure 4 shows a comparison of salts of oxalate and maieate of the biological activity.

DETAILED DESCRIPTION The salt selection process for the muscarinic agonist of the present invention revolved around key issues for pharmaceutical compounds.

The most critical properties included: easy and reproducible preparation, crystallinity, non-hygroscopicity, aqueous solubility, stability in visible and ultraviolet light, low degradation ratio under conditions of accelerated temperature and humidity stability, low isomerization ratio to its isomer. under these conditions and safety for prolonged administration to humans.

Many counter ions were evaluated for the salt-forming properties. See Table III below. The data presented in Table III answer the following questions: (1) Was a solid salt precipitated from ether when the free base was treated with each acid ?; (2) Following the collection of the salt either by filtration or evaporation of the ether, what solvents were used to catalyze the salt, and a crystalline salt of each solvent was obtained ?; (3) melting point information; and (4) total rating of each salt, based on considerations of ease of training and crystallinity.

TABLE ni. - Evaluation of acid addition salts of maieate (R) - (Z) - 1 - azabicyclo [2.2.1] heptan - 3 - one, O - [3 - (3 - methoxyphenyl) - 2 - propynyl] oxime Anion Acid Results : Solvent of Results Point of Qualification PPT a Dartir recrystallization Total Fusion of the one of Ether Salt Inorganic 1. Hydrobromide Si l. Et2O Precipitation Amorphous solid (very low hygroscopic) 2. Hydrochloride Si l. Et2O Precipitation Solid white 158 - 160 High 2. EtOAc Recrystallization White solid 159 - 160 Formation of E - isomer Monocarboxylic 3. Acetate No l. Et2O Evaporation Oil - Low 2. Pet Ether Crushing Oil 3. IPA / Pet Ether Crystallization Oil 4. Benzoate No l. Et2O High Oil Evaporation 2. Pentane Crushing White crystals 86 - 88 3. T - butylmethylether Crystallization White crystals 88 - 98 S. N - Butyrate "No I. Et2O Evaporation Oil - Low 2. Pentane Trituration Oil 6. Tert - Butyrate * No 1. Et2O Oil Evaporation - Low 2. Pentane Crushing Oil 7. L (+) - Lactate No (MeOH) 1. MeOH Evaporation Oil - Low 2. Pentane Crushing Oil 8. 1 - Naphthoate No 1. Et2O Evaporation Oil Low 2. Pentane Trituration Oil 9. 2 - Naphthoate No l. Et2O Low Gum Evaporation 2. Pentane Trituration Gum 3. Toluene Crystallization No PPT 4. Acetone Crystallization NoPPT 5. T - Butylmetileter Crystallization NoPPT 6. Cyclohexane Solid Crystallization = Naphthalic Acid 2 . Propionate No 1. Et2O Evaporation Oil - Low 2. Pentane Trituration Oil 11. Stearate No l. Et2O Solid Crystallization = 2 - stearic acid - Low 12. Undecanoato No l. Et2O Evaporation Oil - Low Polycarboxylic 13. Citrate Si l. Et2O White amorphous solid precipitation 53 - 54 Medium 14. Fumarate No (MeOH) 1. MeOH Evaporation Medium Gum (0.5 equi) 2. EtOAc Solid grinding 79 - 109 3. EtOAc: Pentane (l: 1) Crushing Solid 106 - 108 4. EtOAc Crystallization Gum 5. EtOAc / Pentane Crystallization No PPT 6. IPA Pentane Crystallization No PPT 7. EtOH Crystallization No PPT 8. IPA Crystallization No PPT 9. Cyclohexane / CHCl3 Crystallization . Fumarate Yes l. Et2O Amorphous Solid Precipitation Low (1 equi) 2. EtOH / Pentane Crystallization Oil 3. IPA / Pentane Recrystallization Oil 4. EtOH Recrystallization Oil 5. IPA Recrystallization Oil 6. EtOAc Recrystallization Oil 16. Maieato Si 1. Et2O Evaporation White crystals 115 - 116 High 2. EtOAc Recrystallization White crystals 118 - 119 3. IPA / EtOH Pentane Recrystallization White crystals 116.5 - 118 4. EtOH / Pentane Recrystallization White crystals 118.5 - 121 5. CHCVPentane Recrystallization White crystals 118 - 119.5 6. EtOH / Pentane Recrystallization White crystals 115 - 118 17. Maieato Si l. Et2O Precipitation White Gum _ Low 3. IPA EtOH / Pentane Recrystallization Oil 4. EtOH / Pentane Recrystallization Oil 18. Oxalate Yes l. Et2O Precipitation Solid white Variable Medium Inconsistent stoichiometry 110 - 113 for salt 1: 1 19. Succinate No (MeOH) l. MeOH Evaporation Oil Low 2. T - Crystallization Oil Butylmethylether / pentane Crystallization Oil 3. Et2O / Pentane 20. Tartrate No (MeOH) Evaporation Low Gum (L) - (+) l. MeOH Crushing Sticky gum (0.5 equi) 2. Pentane Crystallization Amorphous white 58 (glass) 3. MeOH / Ether Crystallization No PPT 4. T - butylmethylether Oily PPT crystallization . EtOAc Crystallization No PPT 6. EtOAc / Pentane Crystallization No PPT 7. EtOAc / Pentane 21. Tartrate No (MeOH) Evaporation Oil Low (L) - (+) 1. MeOH Crystallization No PPT (1 equi) 2. EtOH / Pet Ether 22. Tartrate No (MeOH) Evaporation Low Gum (D) - (-) 1. MeOH Crystallization No PPT (0.5 equi) 2. EtOH / Pet Ether 23. Tartrate No (MeOH) Evaporation Low Gum (D) - (-) 1. MeOH (1 equi) Sulfonic 24. Benzene No Evaporation Oil Low Sulfonate 1. Et2O Crushing Oil Sulfonate 2. Pentane Amino Acid 25. N No (EtOAc / Evaporation Oil Low acetylglycinate MeOH) 1. EtOAc / MeOH Trituration 2. Et2O and Pentane Other No (MeOH) Evaporation Oil Low 26. Saccharin l. MeOH Crushing Oil 2. Pentane Crushing Oil 3. Ether Crystallization No PPT 4. T - butylmethylether Oily PPT crystallization 5. Acetone / Pentane Of the more than 26 salts examined, only four salts gave crystal forms reasonably: the hydrochloride, the oxalate, the maieate and the benzoate.

Table IV below shows the moisture uptake of three of these fourth salts. The HCl salt took water more quickly and to the greatest extent; the maieato in the minor.

Generally, hygroscopicity is an important but not critical factor in the selection of salts. One can take precaution in manufacturing to deal with a wide variety of variables if necessary. On the other hand, other things being equal, a non-hygroscopic form is highly desirable.

For Compound 1, the fact that the hydrochloride salt is extremely hygroscopic is of great importance because the uptake of moisture lowers the micro environmental pH of the solid which leads to the formation of le, even in the solid state. Previous studies have shown that a-conversion occurs under low pH conditions. In addition, the hydrochloride form is difficult to recrystallize without converting it into le.

For pharmacists, higher melting points are more desirable than low melting points, since higher melting point compounds tend to be more stable, physically and chemically, during pharmaceutical processes. Both salts of maieate and hydrochloride provided these most desirable characteristics.

The oxalate salt, although less hygroscopic than the hydrochloride, can not be prepared with a consistent stoichiometry, thus limiting its potential for development. In addition, significant concerns exist about the toxicity of prolonged administration of oxalic acid to patients (The Merk Indez, 10th edition, Merck &Co., Inc., Rahway, New Jersey 1983: 6784; and Gosselin RE, et al., De. Clinical Toxicology of Commercial you produce William & Wilkins, Baltimore, 4th edition, 1976; Section 111: 260-263).

TABLE IV. Gigroscopicity of the salts of Compound la.

Benzoate Oxalate Maieate Hydrochloride Hygroscopicity (% by Not determined 6.38 ± 1.40 0.32 ± 0.02 27.77 + 0.40 weight t) at Melting Point (° C) 89 (DSC) 110 119 (DSC) 158 a Hygroscopicity at RT; 81% RH for 16 days using corrugated DSC pans.

Effect of Temperature. Relative humidity and light on crystalline salts of the Table V below summarizes the results of salt stability studies Crystals less hygroscopic. The salts of maieato and benzoato were studied in more detail. No temperature / humidity discrimination occurred with the condition accelerated, 30 ° C / 60% RH after two weeks; the maieato and the benzoate were both stable at 25 ° C / 60% RH and 30 ° C / 60RH.

TABLE V. Stability of the crystalline salts of the low Conditions of Accelerated Stability Maleate Benzoate Oxalate ° C / 60% RH: 2 weeks • • Not determined Xenon: 26 hours • E E Fluorescence: 5.5 months • Not determined Not determined Where: E = presence of 2% - 4% of le. The salts of maieato and benzoato are recrystallized from ethyl acetate and t-butyl methyl ether, respectively. Exposure to Xenon with the Atlas SunChex set for 0.4 ± 0.1 watts / m2. The exhibition fluorescent with 1000 - ± 100 - ft candelas.

• = No E. was detected Aqueous Solubility of the crystalline salts of the Compounds such as the muscarinic agonist, which were devised to prolonged oral administration usually displays better systemic bioability after of oral administration when they are easily soluble in water. Thus, the solubility in water is another key consideration in the identification of a viable salt of the. As illustrated in Table VI, the maieate is about 15 times more soluble in water than the benzoate of the.

TABLE VI. Aqueous Solubility of Maieate Salts and Benzoate Maieato Benzoate Solubility in water 89 6 (mg / ml, room temperature) As evidenced by all the above data, the maize salt of the It is the only crystalline salt that meets all the criteria established by the development optimum pharmacist. While maize salts are common in the field of Pharmaceuticals, out of more than 25 evaluated salts, is the only salt with the desired physical and chemical properties to allow pharmaceutical development to be in fact an unexpected discovery.

DETAILED DESCRIPTION OF THE DRAWINGS Figure 1. Selective Isomer Test For analytical purposes, the separation of the Compound was carried out with a 4.6 - x 250 - mm Zorbax SBCN 5 - μm column (PN 880975.905) in an HP system - 1090 with three solvent reserves. The conditions for the separation were: Mobile Phase: A = 80%: 50 mm TEA adjusted to pH 3 with H3PO4. B = 10%: CH3CN C = 10%: MeOH. Mobile Flow Rate: 1.5 ml / minute Temperature: room temperature Injection Volume: 100 μl Shipping speed: 83.3 μl / minute.

Figure 1 shows a typical separation of a malate sample from that which contains some maieate. The first maximum in 3.3 minutes is due to the maieate counter, while the maximums in l.3 and l3.0 are due to the and, respectively. These identifications were confirmed by NMR. The chromatogram shows a close equilibrium ratio of a at 85.5: 14.5.

Figures 2 and 3. Effect of the size of the particles Figures 2 and 3 show the order of difference in magnitude in the particle size of any recrystallized maieate salt of ethyl acetate of the compound (Figure 2) against the product precipitated from ether (Figure 3). For Figure 2, the range of particle sizes ranged from 150 x 10 μm to less than 10 x 10 μm; for the product precipitated from ether in Figure 3, all the particles were less than 10 x 10 μm. This product was formed when the free base of the compound in diethyl ether was mixed with maleic acid in diethyl ether. This type of in situ salt formation produced very fine particles due to rapid precipitation.

The product of precipitation from ether (Figure 3) was liquefied and reverted to its equilibrium ratio of Z - to E - oxime (85% Z - 15% E) after 2 weeks in the accelerated stability condition, 40 ° C / 75% RH. The recrystallized product from ethyl acetate (Figure 2) reported in Table II was more stable. This increased stability of the crystallized form from ethyl acetate was more likely due to the relatively small total surface area of the larger recrystallized particles (Figure 2) compared to the smaller precipitated particles (Figure 3).

Figure 4. Biological Activity Figure 4 shows a comparison of oxalate and maieate salts in their ability to improve the performance of hippocampal deficient mice in a mouse water maze test (see Jaen, et al, Life Sci. Ref Y references in the present for more details about this test).

This test measures the ability of a compound to decrease the amount of time it takes for the mouse to find a hidden platform in the water pool.

The graph represents two sets of experiments, each with its own control group. The data demonstrates that the oxalate salt of Compound A, which had previously been used to evaluate the effects of the mouse water maze test, can reduce the time required to find the platform in about 18 seconds (to 1 mg / kg). As the positive control, the acetylcholine esterase inhibitory tacrine (THA) produced an environment of around 27 seconds. In a separate test set, the maleate salt of the at 1 mg / kg resulted in latency improvement of about 24 seconds. These data show that no loss of biological activity is experienced with the maleate salt of the, in comparison with other salts that have been evaluated.

To assess the potential of the maleate salt of the compound to form polymorphs, crystallization was studied in five different solvent systems: isopropanol ethanol pentane, ethanol / pentane, ethanol, chloroform / pentane and dichloromethane / methane. The volume of solvent used, the percentage of production, the melting point before recrystallization and the melting point after recrystallization are given in Table VI. For each of the experiments in Table VI, 1.0 g of oxime maieate salt of the compound were dissolved under ambient conditions in the most polar solvent in the solvent system. The above was followed with the slow and incremental addition of pentane until small particles could be observed. The mixture was then sealed and stored in the refrigerator overnight, followed by cold filtration, pentane rinsing and high vacuum subjection. All products are pure by both elemental analysis and HPLC. X-ray diffraction studies of dust on these groups were carried out and based on the data, the maize salt of the crystallized compound in a variety of solvents showed the same defraction pattern and the same crystalline form. In general, the solvents that allow the slow crystallization of the salt of maieato led to material of larger particle size, which is more stable under accelerated stability conditions.

The maieato salt is, as discussed above, identified as significantly higher than all other salt forms considered.

TABLE VI. Recrystallizations at Ambient Temperature Solvent System Volume% dot point of (ml / g) melting production Before melting after Isopropanol - Ethanol 202 77.2 116 - 119 116.5 - 118 Pentano 125 85.8 116 - 118 118.5 - 121 Ethanol - Pentane 50 50.1 116 - 118 114 - 118 Ethanol 32.5 83.1 116 - 118 118 - 119.5 Chloroform - Pentane 13 64.5 116 - 118 118 - 120 Dichloromethane - Pentane The maieato preparation can be achieved in a variety of ways. By For example, the pure isomer can be obtained by column chromatography of the mixture approximately 1: 1 of the one obtained synthetically (United States 5,306,718, United States 5,346,911, and type et al., Bio. Org. Med. Chem. Letters 1995 (5): 631-636). The free base is typically obtained as an oil or oily solid. This free base can be stored refrigerated at - 4 ° C for up to several days without decomposition or notorious isomerization to produce it. The preparation of the maieate salt typically involves dissolving it in an organic solvent and adding about one mole equivalent of maleic acid in the same solvent. Organic solvents useful for this purpose are, for example, ether solvents, such as diethyl ether, THF and the like; ethyl acetate, isopropyl acetate and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like, hydrocarbon solvents such as hexane, benzene, toluene and the like and any other organic solvents that do not react with the. Preferred solvents include diethyl ether, ethyl acetate and ethanol. Depending on the choice of solvent, the salt will precipitate immediately from the organic solvent (as it is from diethyl ether), or it can be recovered by the sequential addition of a second solvent (as is the addition of diethyl ether or hexane to the solvent). a salt solution in ethanol) or by evaporating the solvent under reduced pressure. Since the small particle size leads to increased hygroscopicity, the maieate of the initial obtained can be recrystallized from an organic solvent or solvent mixtures, taking care to use solvents that do not require heating to induce solubilization of the salt. Examples of solvents useful for this purpose include ethyl acetate, isopropanol and diethyl ether, although other non-reactive solvents can be used, including water and mixtures of water with organic solvents miscible with water. The recrystallization temperatures are typically maintained at room temperature or less, to minimize the possibility of oxime isomerization. In some cases, such as when a non-protic solvent such as ethyl acetate is used, the recrystallization temperature may be higher than room temperature.

As an alternative, mixtures of various proportions of free base bases can be converted to the corresponding mixtures of maieate salts, by a procedure similar to those described above for the pure, and which can be recrystallized from organic or aqueous solvents. or mixtures of solvents to produce pure maieate. Preferred solvents for the recrystallization of / lc-maieate mixtures include, for example, isopropanol, ethanol, chloroform, dichloromethane, pentane, hexane, ethyl acetate and the like.

The physical properties of the maieate influence its chemical stability. The deliquescence seems to be an important initializing event. However, the particle size of the salt strongly influences the deliquescence, due to the larger surface area for exposure to moisture in smaller particles. In addition, contamination of the higher melting point of the maleate with the lower melting point mist facilitates deliquescence. Thus, the increased stability of the maieate of the solid can be achieved by minimizing the presence of isomeric as an impurity and by recrystallizing the maieate in such a way as to ensure the production of large particle crystals.

EXAMPLE 1 Preparation of [1: 1] maieate salt of [R - (Z)] -1-azabicyclo [2.2.1] heptan-3-one. O - [3 - (3-methoxyphenyl ') -2-propynyl] oxime Free base [R - (Z)] - 1-azabicyclo [2.2.1] heptan-3-one, O - [3 - (3 -methoxyphenyl) -2-propynyl] oxime (la) (6.8 g, 0.025 mol) in ether. Some insoluble white solid was separated by filtration and discarded. Maleic acid was dissolved (2,942 g, 0. 025 mol) in ether. The maleic acid solution was added dropwise into the ether solution of the free base while stirring vigorously. The resulting precipitate was separated by filtration, dried under vacuum at 40 ° C for 16 hours to give 8.93 g (yield of 92%) of maieate, melting point 116.5 - 118.0 ° C. [a] - 10.7 ° (c = 0.646, MeOH); Mass spectrum: m / z 272 (M + l), 271, 174, 145, 109, 99; IR KBr): 2926, 2237, 1697, 1618, 1606, 1576, 1487, 1360, 1294, 1208, 1173, 1055, 1030, 916, 870, 779 crn "1; 1H NMR (DMSO-d6): 67.31 (1H, t, J = 7.7 Hz), 7.00 (m, 3H), 6.04 (s, 2H), 4. 92 (s, 2H), 4.09 (dd, 2H, J = 2.4 Hz, J = 16.4 Mz), 3.76 (s, 3H), 3.52 (d, 1H), J = 0.001), 3. 36 (m, 6H), 2.24 (m, 1H), 1.75 (m, 1H); 13C NMR (DMSO-d6): d 26.0, 51.6, 55.7, 55.8, 59.5, 62.4, 85.9, 86.3, 115.9, 116. 8, 123.2, 124.4, 130.4, 136.0, 158.5, 159.6, 167.6; Elemental analysis (C ^ H ^ N ^ ^ C ^ 0 ») C, 62.17; H, 5.74; N, 7.25; Found: C, 61.97; H, 5.77; N, 7.15. HPLC analysis: 100% the, RT = 6.18 min (Column = Altech altima CN 4.5 x 150 cm, 5 μ; Mobile phase = 15% MeOH: AcCN (1: 1) and 85% of 50 mmol of Et3N in H2O; 1.5 ml / min).

EXAMPLE 2 Recrystallization from ethyl acetate The maieate salt of (0.6297 g, 1.6 mmol) was dissolved in 13 ml of boiling ethyl acetate. After cooling to room temperature, white crystals were separated. The above was left in the refrigerator for 14 hours. The resulting white crystals were separated by filtration, dried under high vacuum at 50 ° C to yield 0.528 g (84% recovery) of the recrystallized material, mp 118-119 ° C; HPLC, 99.8% la, 0.2% le (Column = Zorbax CN 4.5 x 250 cm, 5 μ, Mobile phase = 15% MeOH: AcCN (1: 1) and 85% 50 mmol of Et3N, 1.5 ml / min); [a] - 9.5 ° (c = 0.503, MeOH); m / z 212 (M + 1), 175, 145, 99, 82; IRKBr): 2926, 2237, 1697, 1618, 1606, 1576, 1487, 1360, 1294, 1208, 1173, 1055, 1030, 916, 870, 779 cm "1; 1H NMR (DMSO - d6): 57.31 (t, 1H, J = 7.7 Hz), 7.00 (m, 3H), 6.04 (s, 2H), 4.92 (s, 2H), 4.09 (dd, 2H, J = 2.4 Hz, J = 16.4 Mz), 3.76 (s, 3H), 3.52 (d, 1H, J = 0.01), 3.36 (m, 5H), 2.24 (m, 1H), 1.75 (m, 1H); 13C NMR (DMSO - d6): d 26.0, 51.6, 55.7, . 55.8, 59.5, 62.4, 85.9, 86.3, 115.9, 116.8, 123.2, 124.3, 130.4, 136.1, 158.6, 159.5, 167.6 elemental analysis (Ci6H 8N2O2 * CHO?) C, 62.17; H, 5.74; N, 7.25; Found : C, 61.98; H, 5.69; N, 7.14.

EXAMPLE 3 Recrystallisation from room temperature of maleate The maieate salt of (15.02 g) was dissolved in 800 ml of absolute ethanol with stirring under ambient conditions. Pentane (500 ml) was added in increments of 100 ml until visual detection of crystallization. The precipitation of a crystalline white solid was quickly ensured. The mixture was diluted with an additional 600 ml of absolute ethanol with vigorous stirring until homogeneous. Pentane (1.25 1) was added incrementally until visual detection of a few small crystals. The crystallization bottle was sealed and stored in the freezer overnight.

The white crystals were collected by vacuum filtration and dried in a high vacuum oven (ca.10 mm Hg; 40 ° C) for 2 hours to produce 11.96 g. (80% recovery) of the as a colorless crystalline solid; melting point 118 - 119 * 0 (dec) .HPLC: 99.93% the: 0.07% le (Column = Altech altima CN 4.5 x 150 cm, 5 u; Mobile phase = 15% MeOH: AcCN (1: 1) and 85% 50 mmol Et3N in H2O; 1.5 ml / min); 1H-NMR (400 MHz, DMSO-d6): 57.31 (t, 1H, J = 7.7 Hz), 7.04-7.00 (m, 2H), 6.99 (s, 1H), 6.06 (s, 2H), 4.93 (s) , 2H), 4.19 - 4.03 (m, 2H), 3.77 (s, 3H), 3.52 (d, 1H, J = 4.1 Hz), 3.45 - 3.29 (m, 4H), 2.27 - 2.20 (m, 1H), 1.78-1.72 (m, 1H) ppm; MS (Cl) M + l = 271; IR (KBr): 2926 (w), 2237 (w), 1697 (w), 1575 (s), 1360 (s), 1293 (m), 1207 (s), 1172 (m), 1054 (m), 1029 (m), 960 (w), 915 (m), 871 (m), 780 (m), 755 (w), 685 (w), 647 (w), 584 (w) cm'1. 13 C NMR (100 MHz; DMSO-de): 167.67, 159.60, 158.52, 136.19, 130.41, 124.37, 123.18, 116.82, 115.87, 86.33, 85.92, 62.40, 59.48, 55.79, 55.69, 51.58, 26.02 ppm; Elemental analysis (C16H? 8N2O2 * C H O4) C, 62.17; H, 5.74; N, 7.25; Found: C, 62.27; H, 5.86; N, 7.23.

Claims (6)

1. CLAIMS: 1. Maieate of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one, or - [3 - (3-methoxyphenyl) -2-propynyl] oxime as a pharmaceutical agent.
2. 2. A compound according to Claim 1 wherein most of the crystal particles are larger than 10 x 10 μm in size.
3. 3. A pharmaceutical composition useful for alleviating pain in a mammal comprising an effective analgesic amount of a compound according to Claim 1 together with a pharmaceutically acceptable carrier.
4. 4. A pharmaceutical composition useful for treating symptoms of cognitive impairment comprising a therapeutically effective amount of a compound according to Claim 1 together with a pharmaceutically acceptable carrier.
5. 5. A method for alleviating pain in a mammal comprising administering to said mammal a compound according to Claim 1.
6. 6. A method for treating symptoms of cognitive impairment in a mammal comprising administering to said mammal a compound according to Claim 1. EXTRACT OF THE INVENTION The maieate salt [1: 1] of (R) - (Z) -1-azabicyclo [2.2.1] heptan-3-one, O - [3 - (3-methoxyphenyl) -2-propynyl] oxime, a known muscarine agonist has unique properties relative to other salts of the compound, making it a desirable pharmacist.