WO1999032486A1

WO1999032486A1 - Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions

Info

Publication number: WO1999032486A1
Application number: PCT/US1998/027589
Authority: WO
Inventors: Bryon S. Severns; Mark R. Hellberg; Abdelmoula Namil; Hwang-Hsing Chen; Thomas R. Dean; Andrew Hoffman
Original assignee: Alcon Laboratories, Inc.
Priority date: 1997-12-23
Filing date: 1998-12-22
Publication date: 1999-07-01
Also published as: AU2307899A

Abstract

A new group of compounds (I) having muscarinic activity is disclosed, wherein m is 0 or 1; p is 1 or 2; X is C(R)2, O, S(O)q, NR, C(=O), CHOR, C=NOR, NC(=O)OR, NC(=O)N(R)2, NC(=O)R, CHC(=O)OR, CHC(=O)N(R)2, CHC(=O)R, NS(O)2C(R)3, (a) or (b); R?1 and R2¿ are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH, aryl, arylalkyl, SR or N(R)¿2?, and A is selected from the group consisting of: (c), (d) and (e) wherein ---- represents a double or single bond; n is 0 or 1; o is 1 or 2; R?3¿ is H, lower alkyl, halogen, lower alkoxyl, OH, HOCH¿2?, aryl, arylalkyl, SR or N(R)2; and B is selected from the group consisting of (f), (g), (h), (i), (j), (k) or CO2R. The use of the compounds and pharmaceutically acceptable salts thereof to treat glaucoma, myopia, psychosis and various other conditions involving muscarinic receptors is also disclosed.

Description

MUSCARINIC AGENTS AND USE THEREOF TO TREAT GLAUCOMA, MYOPIA AND VARIOUS OTHER CONDITIONS

Background of Invention:

The present invention relates to new compounds having muscarinic activity. The compounds are useful in treating glaucoma, myopia, various other medical conditions that directly or indirectly involve muscarinic receptors within the human body. The invention is also directed to the treatment of glaucoma by controlling the principal symptom of that disease, elevated intraocular pressure. More specifically, the invention relates to the use of particular muscarinic compounds to control intraocular pressure ("IOP") and thereby prevent or at least forestall progressive field of vision loss and other manifestations of glaucoma.

Glaucoma is a progressive disease which leads to optic nerve damage (i.e., glaucomatous optic neuropathy), and ultimately, partial or total loss of vision. The loss of visual field is secondary to the degeneration of optic nerve fibers which comprise the optic nerve. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. However, it is known that a major risk factor for glaucomatous optic neuropathy is abnormally high IOP.

The usual reason for elevated IOP is an impairment of the outflow of fluid (i.e., aqueous humor) from the eye. Although hypersecretion of aqueous humor is not considered to be a common factor for elevated IOP, the pressure may be reduced by inhibiting the production (i.e., inflow, secretion or formation) of aqueous humor by the ciliary processes of the eye. Beta adrenoceptor blockers and carbonic anhydrase inhibitors are examples of drug classes that lower intraocular pressure by inhibiting the inflow of aqueous humor. Other classes of drugs reduce IOP by increasing the outflow of aqueous humor from the eye. Examples of these drug classes include miotics, such as pilocarpine and carbachol, and adrenergics or sympathomimetics, such as epinephrine. While the use of the drug classes stated above is common practice in the medical therapy of glaucoma, it is not without side effects. Each class suffers from causing a particular set of side effects, locally and/or systemically, that is related to the pharmacological actions of that class. For example, beta blockers, by blocking beta adrenoceptors in the heart can cause bradycardia or slow heart rate, and by blocking beta adrenoceptors in the bronchi can cause bronchoconstriction. Systemic carbonic anhydrase inhibitors can cause malaise, headache, and other subjective symptoms which discourage their use by the patient. Muscarinic agents, such as pilocarpine, may be used to reduce IOP by increasing the outflow of aqueous humor, but the use of these agents frequently produces side effects such as miosis, impaired accommodation and/or browache.

Miosis is caused by the contractile effect of the muscarinic agents on the iris sphincter. Muscarinic agents also have a contractile effect on the ciliary muscle. This effect is believed to be responsible for impairment of accommodation, as well as the browache experienced by some patients.

Thus, the agents used in glaucoma therapy show multiple pharmacological effects, some beneficial and some not. Since glaucoma medication must be taken over the patient's lifetime, it is advantageous to minimize the above-discussed side effects, so as to promote patients' compliance with the prescribed drug therapy, while maintaining the beneficial effect on intraocular pressure.

It has been estimated that one of every four persons suffers from myopia. About half or more of these cases are the result of elongation of the eye along the visual axis. At birth, the human eye is two-thirds the adult size. Through-out life the eye grows under the control of a finely tuned regulatory process. Abnormal regulation of this mechanism can result in a lengthening of the eye, which results in the plane of focus being in front of the retina. This growth process is believed to be regulated by neural out-put from the retina. Although atropine, a muscarinic antagonist, has been used to retard the development of myopia, it use causes profound dilation of the pupil and impairs the ability to focus. The compounds of this invention have minimal effects on pupil dilation and therefore offer an advantage over atropine or other compounds having muscarinic activity that have been suggested as therapeutics for myopia. Studies of muscarinic receptors have shown that there are multiple subtypes of muscarinic receptors, and that these receptor subtypes may be localized in different tissues, or may otherwise mediate different pharmacological effects. While some non-selective muscarinic agents may interact with multiple receptors and cause multiple effects, other muscarinic agents may interact more selectively with one or a combination of muscarinic receptor subtypes such that the beneficial effects are increased while the detrimental side-effects are reduced. For example, PCT International Publication Number WO 97/16196 indicates that certain 1- [cycloalkylpiperidin-4-yl]-2H benzimidazolones are selective muscarinic agonists of the m2 subtype with low activity at the m3 subtype, and when utilized for glaucoma therapy have fewer side effects than pilocarpine therapy.

The present invention is based on the discovery of new muscarinic compounds and the use of these compounds to treat glaucoma, myopia and other medical conditions. The following publications may be referred to for further background information regarding medical uses of compounds having at least some structure similarities to the compounds of the present invention:

(1) PCT International Publication Number WO 97/24324 discloses 1-(1,2- disubstituted piperidinyl)-4-substituted piperidine derivatives as tachykinin receptor antagonists for treating pain;

(2) PCT International Publication Number WO 97/16440 discloses 1-(1,2- disubstituted piperidinyl)-4-substituted piperazine derivatives as tachykinin receptor antagonists for treating pain;

(3) PCT International Publication Number WO 97/16187 discloses 1,3-dihydro- l-[l-(l-heteroarylpiperazin-4-yl)cyclohex-4-yl]-2H-benzimidazol-ones as muscarinic antagonists for treating and/or preventing myopia;

(4) United States Patent No. 5,574,044 discloses l,3-dihydro-l-{ l-[piperidin-4- yl]piperidin-4-yl } -2H-benzimidazol-2-ones and 1 ,3 -dihydro- 1 - {4-amino- 1 -cyclohexyl } -2H- benzimidazol-2-ones as muscarinic antagonists for treating and/or preventing myopia; (5) United States Patent No. 5,691,323 discloses l,3-dihydro-l-{l-[piperidin-4- yl]piperidin-4-yl } -2H-benzimidazol-2-ones and 1 ,3 -dihydro- 1 - {4-amino- 1 -cyclohexyl } -2H- benzimidazol-2-ones as muscarinic antagonists for treating and/or preventing myopia;

(6) United States Patent No. 5,718,912 discloses the use of 1- [cycloalkylpioeridin-4-yl]-2H benzimidazolones to treat glaucoma;

(7) United States Patent No. 5,461,052 discloses the use of tricyclic compounds to prevent myopia;

(8) United States Patent No. 5,122,522 discloses the use of pirenzepine and other muscarinic antagonists in the treatment of myopia; and

(9) United States Patent No. 5,637,604 discloses the use of muscarinic antagonists in the treatment and control of ocular development.

Summary of the Invention:

The present invention is directed to a new group of compounds and to the use of these compounds to treat various conditions that directly or indirectly involve muscarinic receptors. The compounds may also be used to treat the symptoms of other types of conditions or injuries, based on the action of the compounds on muscarinic receptors. Examples of conditions that may be treated with the compounds of the present invention include glaucoma, myopia, dry eye and dry mouth (xerostoma). The compounds may also be utilized to treat conditions of the central nervous system, such as psychosis and Alzheimer's disease. The compounds have analgesic properties, and my therefore be used to treat various types of pain..

As indicated above, the compounds of the present invention are particularly useful in the treatment of glaucoma, based on the ability of the compounds to regulate intraocular pressure or

"IOP". Like pilocarpine, the compounds of the present invention are believed to control IOP via an action on muscarinic receptors. However, they are more potent than pilocarpine in lowering IOP, and, at a dose that causes an equal reduction in IOP, demonstrate a reduced level of miosis. The production of miosis (i.e., pupil constriction) has been a very troublesome side effect of pilocarpine therapy. The compounds of the present invention are also believed to be relatively free of the other major side effects associated with pilocarpine therapy, namely, impairment of accommodation and browache.

Detailed Description of the Invention:

The compounds of the present invention have the following formula:

wherein: m is 0 or 1 ; p is 1 or 2;

X is C(R)₂, O, S(O)_q, NR, C(=O), CHOR, C=NOR, NC(=O)OR, NC(=O)N(R)₂,

NC(=O)R, CHC(=O)OR, CHC(=O)N(R)₂, CHC(=O)R, NS(=O)₂C(R)₃,

wherein: q is 0, 1 or 2;

R is H, lower alkyl, alkoxyl, arylalkyl, alkynyl, alkenyl or cycloalkyl; D is CH or N;

E is CO, S(=O), S(=O)₂ C=S or C=NR; and J is O, CR, C(R)₂, NR or NRC(=O);

R¹ and R² are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH₂, aryl, arylalkyl, SR or N(R)₂; and A is selected from the group consisting of:

wherein: represents a double or single bond; n is 0 or 1 ; o is 1 or 2;

R³ is H, lower alkyl, halogen, lower alkoxyl, OH, HOCH₂, aryl, arylalkyl, SR or N(R)₂. and B is selected from the group consisting of:

wherein:

R in CO₂R does not equal H; and W is halogen, OR, R, N(R)₂ or SR, provided that when W is SR,

R does not equal H.

In the foregoing description of the compounds of formula (I), terms utilized to describe certain substituents (e.g., "alkyl") have the following meaning:

The term "alkyl" includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms (C, to C₁₅). The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxyl. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.

The term "cycloalkyl" includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.

The term "alkenyl" includes straight or branched chain hydrocarbon groups having 1 to

15 carbon atoms (C, to C₁₅) with at least one carbon-carbon double bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkenyl groups include, allyl, 1-butenyl, l-methyl-2-propenyl and 4-pentenyl.

The term "alkynyl" includes straight or branched chain hydrocarbon groups having 1 to

15 carbon atoms ( to C_I5) with at least one carbon-carbon triple bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkynyl groups include, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl and 2-pentynyl.

The term "alkoxyl" represents an alkyl group attached through an oxygen linkage.

The term "lower alkyl" represents alkyl groups containing 1 to 6 carbons (C, to C₆).

The term "lower alkoxyl" represents alkoxyl groups containing 1 to 6 carbons (C, to C₆).

The term "halogen" represents fluoro, chloro, bromo, or iodo.

The term "aryl" refers to carbon-based rings which are aromatic. Aromatic rings have alternating double and single bonds between an even number of atoms forming a system which is said to 'resonate'. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen. The preferred compounds of formula (I) are those wherein: m is 1 ; p is 1 ; X is CHOR, C=NOR, NC(=O)OR, NC(=O)N(R)₂, NC(=O)R, CHC(=O)OR, CHC(=O)N(R)₂ or CHC(=O)R; R is lower alkyl, alkynyl, alkenyl or cycloalkyl; R¹, R² and R³ are H or lower alkyl; and A is:

Among these preferred compounds, the most preferred compounds are those wherein m, n, o and p are 1 ; X is CHOR, C=NOR, NC(=O)OR, NC(=O)N(R)₂, NC(=O)R or CHC(=O)OR; and R is lower alkyl, alkynyl or alkenyl.

Pharmaceutically acceptable salts of the compounds of formula (I) may also be utilized in the present invention. Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.

The compounds of the present invention may be prepared by means of the methods illustrated in Scheme 1-3 below:

Scheme 1

Compounds (5-7) may be prepared by combining the respective amines (1-3) with the appropriate ketone (4) and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of 20° C to 40° C and a pH in the range of 2-7.

The starting materials (5-7) and (4) are either commercially available or can be obtained by conventional procedures. The use of certain protecting groups and deprotecting steps may be necessary, as will be appreciated by those skilled in the art. Compounds of the formula (5-7) may exist as mixtures of stereoisomers. The preparation of individual stereoisomers may be effected by the chromatographic separation of the stereoisomers or by the selective control of the reaction conditions.

The 1,3,4-thiadiazole derivatives, 12 and 13 may prepared by the route outlined in

Scheme 2 below: Scheme 2

12

Compound (9) may be prepared by combining the protected cyclic diamine (8), with the appropriate ketone (4) and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of 20° C to 40° C and a pH in the range of 2 to 7. The formamide protecting group may be removed by adding compound (9) to concentrated ammonium hydroxide and warming at reflux for 2 to 72 hours ("h") to provide the amine (10). Alternatively, the formamide protecting group can be removed by stirring in a mixture of water and dioxane containing hydrochloric acid at a temperature of 0° C to 80° C for 1 to 72 h. The 1,2,5-thiadiazole derivatives (lT)and (12) may be prepared by combining the appropriately substituted 3-chloro 1,2,5-thiadiazole derivative and the amine (10) in a solvent such as tefrahydrofuran, toluene or xylene and warming at a temperature of 40° C to 150° C for 1 h to 20 days. Compounds of the formula (13) can be prepared by reacting the appropriate amine (HNR₂) with the chloro derivative (12) in a solvent such as tefrahydrofuran, dioxane, xylene, or neat warming at a temperature of 40° C to 150° C for 1 h to 20 days.

The compounds of formula 15 and 16 may prepared by the route outlined in Scheme 3 below:

Scheme 3

16

Compounds of the formula (15) may be prepared by combining the protected amino ester (14) with the appropriate ketone (4) and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of 20° C to 40° C and a pH in the range of 2-7. The ester 15 can be converted to the heterocyclic derivatives represented by formula (16) by conventional procedures known to those experienced in the art. For example, the 1 ,2,4-oxadiazole derivative may be prepared by treating a solution of the ester (15) with a solution formed by reacting the appropriate amide oxime with a base such as sodium hydride in the presence of molecular sieves in a solvent such as tefrahydrofuran, dioxan or xylene at a temperature of 20° C to 100° C for 1 to 6 h. The 1,2,4-thiadiazole derivatives may be prepared by reacting the ester (15) with a strong base such as lithium diisopropylamine in an inert solvent such as tefrahydrofuran at a temperature of -20° C to 50° C, for 0.5 to 2 h, followed by the addition of 5-chlorothiadiazole. Ester hydrolysis and decarboxylation of the resulting product by sequential treatment with a base such as sodium hydroxide or lithium hydroxide followed by warming in an acidic solution (hydrochloric acid, trifiuoroacetic acid or sulfiiric acid) provides the 1, 2, 4- thiadiazole derivative.

The starting materials (8, 14) and (4) are either commercially available or can be obtained by conventional procedures. The use of certain protecting groups and deprotecting steps may be necessary, as will be appreciated by those skilled in the art. Compounds of the formula (11-13, 15, 16) may exist as mixtures of stereoisomers. The preparation of individual stereoisomers may be effected by the chromatographic separation of the stereoisomers or by the selective control of the reaction conditions.

The compounds of formula (I) are utilized to treat glaucoma, myopia and dry eye by topically applying a solution or other suitable ophthalmic composition containing the compound to the eye. The establishment of a specific dosage regimen for each individual patient is left to the discretion of clinicians. The amount of the compound applied to the eye with each dose may vary, depending on the severity of the condition being treated, the drug release characteristics of the compositions in which the compound is contained, and various other factors familiar to those skilled in the art. The amount of compound administered topically to the eye will generally be in the range of from about 0.3 to about 300 micrograms per dose, preferably from about 2 to about 100 micrograms per dose.

The compounds may be administered by topically applying one to two drops of a solution or comparable amount of a microemulsion, suspension, solid, or semi-solid dosage form to the affected eye(s) one to four times per day. The concentration of the compounds of formula (I) in such compositions will vary, depending on the type of composition utilized. For example, it may be possible to use a relatively lower concentration of the compound when compositions which provide for sustained release of the compounds or compositions which include a penetration enhancer are utilized. The concentrations generally will be in the range of from about 0.001 to about 1 percent by weight, based on the total weight of the composition ("wt.%"), preferably from about 0.01 to about 0.3 wt.%.

The compounds of formula (I) may be included in various types of ophthalmic compositions. Since the compounds are relatively stable and soluble in water, the compositions will generally be aqueous in nature. Aqueous solutions are generally preferred, based on ease of formulation, as well as patients' ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the compounds may also be readily incorporated into other types of aqueous compositions, such as viscous or semi- viscous gels or other types of solid or semi-solid compositions.

In addition to the compounds of formula (I) and the aqueous vehicles described above, the compositions of the present invention may also include one or more ancillary ingredients, such as preservatives, co-solvents and viscosity building agents.

Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium 1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001% to 1.0% by weight.

In order to enhance the aqueous solubility of the compounds of formula (I), a surfactant or other appropriate co-solvent may be included in the compositions. Such co-solvents include: polyethoxylated castor oils, such as those manufactured by BASF under the Cremophor® brand; Polysorbate 20, 60 and 80; nonionic surfactants, such as the following Pluronic® brand surfactants of BASF: Pluronic® F-68, F-84 and P-103; cyclodextrin; or other agents known to those skilled in the art. Such co-solvents are typically employed at a level of from 0.01% to 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirable to increase ocular absorption of the compound, to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the ophthalmic formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight.

An appropriate buffer system (e.g., sodium phosphate or sodium acetate or sodium borate) may be added to prevent pH drift under storage conditions.

The compounds of formula (I) may also be utilized to treat psychosis, Alzheimer's disease, dry mouth, pain and various other conditions. The compounds may be administered by any convenient method, for example, by oral, parenteral, buccal, rectal or transdermal administration. The compounds may be administered via conventional pharmaceutical compositions adapted for such administration. The compositions are generally provided in unit dose form (e.g., tablets), comprising 0.5 - 100 mg of one or more compounds of formula (I) in a pharmaceutically acceptable carrier, per each unit dose. The dosage of the compounds is 1 - 300 mg/day, preferably 10 - 100 mg/day, when administered to patients, e.g. humans, as a drug. The compounds may be administered one to four times a day.

The methods for synthesizing the compounds of formula (I) and the pharmaceutical compositions of the present invention are further illustrated by the following examples. The term " Compound" in Examples 4 and 5 is intended to represent a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Example 1 Preparation of 4-[3-ethyl-l,2,4-oxadiazol-5-yl]-l-(l,4-dioxaspiro[4,5]decan-8-yl)piperidine hydrochloride:

Step 1

Preparation of l-(l,4-dioxaspiro[4,5]decan-8-yl)-4-(ethoxycarbonyl)piperidine. A solution of ethyl isonipecotate (10.47 g, 66.6 mmol) and 1 ,4-cyclohexanedione mono ethylene ketal (15.6 g, 99.9 mmol) and acetic acid (4.04 ml, 70.6 mmol) was stirred at room temperature for ten minutes. This solution was treated with sodium triacetoxy borohydride (22.68 g, 107 mmol) with stirring overnight. The mixture was evaporated and the resulting residue was taken up in water (200 ml). The aqueous layer was washed with ether (100 mL X 3) and then basified with potassium carbonate (until pH 10). The aqueous layer was extracted with dichloromethane (100 mL X 3). The combined organic layers were dried over magnesium sulfate and evaporated to give the title compound as a yellow liquid, 20.07 g (100%), MS (electrospray, M + H⁺ = 298 m/e).

Step 2

4-[3-Ethyl- 1 ,2,4-oxadiazol-5-yl]- 1 -( 1 ,4-dioxaspiro[4,5]decan-8-yl)piperidine hydrochloride.

A solution of propionitrile (10.00 g, 180 mmol) in methanol (150 ml) was treated with a mixture of hydroxylamine hydrochloride (12.51 g, 180 mmol) and sodium bicarbonate (15.12 g, 180 mmol) and water (50 ml). The resulting mixture was warmed at reflux for one hour and then stirred at room temperature overnight. This mixture was evaporated and the resulting residue was treated with methanol (200 ml). The resulting suspension was filtered and the filtrate was evaporated to give an oily residue. This residue was taken up in methanol and heated to boiling and filtered hot. The resulting solution was concentrated under reduced pressure. The residue was heated under vacuum and purified by bulb-to-bulb distillation to give propionamide oxime as a colorless liquid, 4.40 g (28 %), of which the structure was verified by MS (electrospray, M + H⁺ = 89 m/e).

A solution of propionamide oxime (2.14 g, 24 mmol) in THF (50 ml) was treated with sodium hydride (60% in oil, 0.96 g, 24 mmol) and molecular sieves (0.5 g, 4 Angstrom) and heated to 70 °C for one hour. To the reaction was added a solution of l-(l,4-dioxaspiro[4,5]decan-8-yl)- 4-(ethoxycarbonyl)piperidine (6.02 g, 20 mmol) in THF (10 ml) and the mixture was refluxed overnight. The reaction was quenched with brine (20 ml) and the resulting mixture was extracted with dichloromethane (30 ml). The organic layer was dried over magnesium sulfate and evaporated to a crude brown oil, 3.78 g which contained the title compound as the main component according to MS (electrospray, M + H⁺ = 322 m/e). This residue was purified by chromatography using silica gel and methanol/dichloromethane (1:9) to afford the title compound as a yellow oil, 1.5 g, (20 %) MS (electrospray, M + H⁺ = 322 m/e). A small portion of this oil (90 mg) was treated with 1 M HCl (in ether) and evaporated to give the hydrochloride salt as a white solid, 100 mg, mp 252-5 °C Analyzed for C₁₇H₂₇N₃O₃.HCl s Calculated: C, 57.06%; H, 7.60%; N, 11.74%. Found: C, 56.89%; H, 7.92%; N, 11.55%.

Example 2 Preparation of 4-[3-ethyl- 1 ,2,4-oxadiazol-5-yl]- 1 -( 1 -oxocyclohexan-4-yl)piperidine: 0

The 4-[3-ethyl-l,2,4-oxadiazol-5-yl]-l-(l,4-dioxaspiro[4,5]decan-8-yl)piperidine (1.40 g, 3.9 mmol) was treated with aqueous 2 N HCl (30 ml) with stirring at room temperature for seven days. The reaction was quenched with potassium carbonate (basified to pH 10). The mixture was extracted with dichloromethane (50 ml X 3). The combined organic layers were dried s over magnesium sulfate and evaporated to give the title compound as a white solid, 1.01 g, (93%), mp 65-8 °C, MS (electrospray, M + H⁺ = 278 m/e). Η NMR (CDC1₃) d: 1.32 (t, J = 7.6 Hz, 3H), 1.95 (m, 9H), 2.4 (m, 6H), 2.7 (q, J = 7.6 Hz, 2H), 3.00 (m, 3H).

Example 3 0 Preparation of 4-(3-chloro-l,2,5-thiadiazine-4-yl)-l-[(l-ethoxycarbonyl)piperidin-4-yl]piper- azine hydrochloride:

Step l

Preparation of 4-[(l-ethoxycarbonyl)piperidin-4-yl]piperazin-l-formamide. 5

A solution of piperazin-1 -formamide (5.00 g, 43.8 mmol) and l-(ethoxycarbonyl)piperidin-4- one (9.91 ml, 65.7 mmol) and acetic acid (2.66 ml, 46.4 mmol) in dichloromethane (100 ml) was stirred for 15 minutes. The solution was treated with sodium triacetoxy borohydride (14.85 g, 70.1 mmol) with stirring at room temperature overnight. The reaction was quenched 0 with water (200 ml). The aqueous layer was washed with ether (100 ml X 4). Then the aqueous layer was basified with potassium carbonate (to pH 10) and extracted with dichloromethane (50 ml X 3). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a colorless oil, 11.82 g (100 %) MS (electrospray, M + H⁺ = 270 m/e).

Step 2 Preparation of 4-[(l-ethoxycarbonyl) piperidin-4-yl]piperazine.

A solution of 4- [(l-ethoxycarbonyl)piperidin-4-yl]piperazin-l -formamide (11.82 g, 43.9 mmol) in concentrated aqueous ammonium hydroxide (28% ammonia by weight, 100 ml) was refluxed for two days. The reaction was diluted with water (100 ml) and washed with ether (100 ml X 3). The aqueous layer was evaporated to give the title compound as a crude yellow paste, 10.52 g (100 %) MS (electrospray, M + H⁺ = 242 m/e).

Step 3

Preparation of 4-(3-chloro- 1 ,2,5-thiadiazine-4-yl)- 1 -[(1 -ethoxycarbonyl)piperidin-4-yl]piper- azine hydrochloride.

A solution of 4-[(l-ethoxycarbonyl) piperidin-4-yl]piperazine 5.00 g, 19 mmol), 3,4-dichloro- 1,2,5-thiadiazole (5.4 ml, 57 mmol) and diisopropylethyl amine (3.3 ml, 19 mmol) in THF (20 ml) was warmed at reflux for 17 days. The reaction mixture was quenched with aqueous saturated potassium carbonate (50 ml) and the mixture was extracted with dichloromethane (50 ml X 3). The organic layers were combined and concentrated under reduced pressure. The resulting residue was dissolved in 2 N HCl (25 ml) and the aqueous layer was washed with ether (50 ml X 2). The aqueous phase was basified with potassium carbonate (to pH 10) and was extracted with dichloromethane (50 ml X 3). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give a crude yellow oil. Purification of this residue by chromatography using silica gel and ethyl acetate gave a white solid, 1.21 g (18%), mp 63-6 °C, MS (electrospray, M + H⁺ = 360 m/e) Analyzed for C₁₄H₂₂N₅O₂: Calculated for C, 46.73%; H, 6.16%; N, 19.46%. Found: C, 47.00%; H, 6.14%; N, 19.35%. Example 4

The following formulation further illustrates the topical ophthalmic pharmaceutical compositions of the present invention.

Ingredient Amount (wt. %)

Compound 0.1

Benzalkonium chloride 0.01 Edetate sodium 0.05 Sodium chloride q.s.to render isosmotic Hydrochloric acid q.s. to adjust pH and/or

Sodium Hydroxide Purified water q.s. to 100% of volume

Example 5

The following formulation further illustrates the systemic pharmaceutical compositions of the present invention, particularly oral tablet compositions.

Ingredient Amount

Compound 5.0 mg Lactose 67.5 mg Avicel™ 31.5 mg Amberlite™ 1.0 mg Magnesium Stearate 0.25 g

Claims

What is claimed is:

1. A compound of the following formula:

wherein: m is O or l; p is 1 or 2;

X is C(R)₂, O, S(O)_q, NR, C(=O), CHOR, C=NOR, NC(=O)OR, NC(=O)N(R)₂,

NC(=O)R, CHC(=O)OR, CHC(=O)N(R)₂, CHC(=O)R, NS(=O)₂C(R)₃,

wherein: q is 0, 1 or 2;

R is H, lower alkyl, alkoxyl, arylalkyl, alkynyl, alkenyl or cycloalkyl; D is CH orN;

E is C=O, S(=O), S(=O)₂ C=S or C=NR; and J is O, CR, C(R)₂, NR or NRC(=O); R¹ and R² are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH₂, aryl, arylalkyl, SR or N(R)₂; and

A is selected from the group consisting of:

wherein: represents a double or single bond; n is 0 or 1 ; o is 1 or 2;

wherein:

R in CO₂R does not equal H; and W is halogen, OR, R, N(R)₂ or SR, provided that when W is SR, R does not equal H; or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for treating conditions involving muscarinic receptors, comprising a pharmacologically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier therefor.

3. A method of controlling intraocular pressure which comprises topically applying to the affected eye a topical ophthalmic pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable vehicle thereof.

4. A method of treating myopia which comprises topically applying to the affected eye a topical ophthalmic pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable vehicle thereof.

5. A method of treating dry eye which comprises topically applying to the affected eye a topical ophthalmic pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable vehicle thereof.

6. A method of treating psychosis which comprises administering to the patient a composition according to claim 2.