WO1999032489A1 - Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions - Google Patents

Abstract

A new group of compounds having muscarinic activity is disclosed. 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

MUSCARINICAGENTSANDUSETHEREOFTO TREAT GLAUCOMA,MYOPIAAND VARIOUS OTHERCONDITIONS

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 hum.an 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 imp-airment 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 Iras 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 hum.an 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 mech.anism 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 atropme 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 th.an pilocarpine therapy.

The present invention is b-ased 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 structural 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 piper-azine derivatives as tachykinin receptor antagonists for treating pain;

(3) PCT International Publication Number WO 97/16187 discloses 1,3-dihydro- l-[l-(l-hetero^lpiper^in-4-yl)cyclohex-4-yl]-2H-benzimid^ol-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- y l]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 musc-arinic -antagonists in the treatment of myopia; and

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

Surnm-ary 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) h-as 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 and n .are independently 0 or 1 ; o .and p are independently 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, N(SO)₂C(R)_3ι

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 C=O, S(=O), S(=O)_2ιC=S or C=NR; and J is O, CR, C(R)₂, NR or NRC(=O); R¹, R² and R³ are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH₂, aryl, ∑trylalkyl, SR or N(R)₂; .and A is selected from the group consisting of

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 (C, to C₁₅) 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: o and p are 1; R¹, R² and

R³ are H or C,.₆ alkyl; and X is S(O)_q, 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 or N(SO)₂C(R)₃. Among these preferred compounds the most preferred compounds .are those wherein m, n, o and p are 1 ; R is H, C,^ alkyl, alkynyl, alkenyl or cycloalkyl; and X is CHOR, C=NOR, NC(=0)OR, NC(=O)R, CHC(=O)OR or CHC(=O)N(R)₂.

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 Schemes 1-3 below:

Scheme 1

Compound (3) is prepared by combining (1), (2) and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of 20° C to 40° C at a pH in the range of 2 to 7.

The starting materials (1) and (2) 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 (3) 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.

Scheme 2:

Compounds of formula (9) c-an be prepared by a number of routes, including the following:

Scheme 2

The nitrogen of compound (4) can be alkylated using the appropriate halide (alkyl halide, or alkynylalkyl halide for example) or sulfonate (alkyl methanesulfonate, alkeneylalkyl toluenesulfonate, for example) in the presence of a base such as sodium hydride, or potassium carbonate, in an solvent such as dimethylformamide, or acetonitrile at a temperature of -20° C to 120° C. When the substitutent on nitrogen is hydrogen (R = H), then it is necessary to use a protecting group. For example, compound (4) is reacted with triethyl orthoformate at a temperature of 110° C to 160° C to form the diethyl acetal protected compound. Compound (5) was converted to compound (6) by bis alkylation with 2-bromoethoxy-tert-butyldimethyl silane in the presence of a base such as sodium hydride at a temperature of -20° C to 60° C in a solvent such as dimethylformamide or tetr.ahydrofur.an. The tert-butyldimethyl silyl (TBDMSi) protecting group can then be removed by treating the bis-alkylated compound (6) with a reagent such as tert-butyl ammonium fluoride in a solvent such as tetrahydrofur.an. The result.ant diol (7) is converted in to the bts-meth.anesulfonate by adding methanesulfonic anhydride in a solvent such as tetrahydrofuran containing triethylamine. The bis- meth.anesulfonate can be reacted directly with the primary amine (8) in a solvent such as dimethylformamide at a temperature of 10° C to 100° C to provide compound (9).

The starting materials (4) and (8) 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 ait. Compounds of the formula (9) 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.

Compounds of the formula 14 and 15 can be prepared by a number of routes including the route illustrated in Scheme 3 below:

Scheme 3 :

Scheme 3

15 14

Compound (12) is prep-ared by combining compounds (10), (11) .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 ketal protecting group of compound (12) is removed by warming the compound in .an acidic (hydrochloric acid, sulfuric acid, or trifluoroacetic acid ) aqueous solution at a temperature r-anging from 20° C to 100° C for 1 to 12 hours ("h"). An organic co-solvent such as methanol or tetrahydrofuran may be added to aid in the solubilization of the reaction components. The resulting ketone (13) is converted to the 1,3,8- triazaspiro[4,5]decane-2,4-dione (14) by treating the compound with a mixture of sodium cyanide .and .ammonium carbonate in an ethanol/water solvent mixture, at a temperature of 20° C to 100° C. Reaction of (14) with the appropriate alcohol in a solvent such as tetrahydrofuran in the presence of diisopropyl azodicarboxylate or diethyl azodicarboxylate and triphenylphosine or trimethyl phosphine at a temperature of -30° C to 40° C provides the N- substituted derivative (15).

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 r.ange 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 ex.ample, 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 r-ange 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 ophth-almic 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, thimeros , 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 ait. 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 a t. 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 ex-ample, 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 5 and 6 is intended to represent a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Example 1

Preparation of 8-( 1 -ethyloxycarbonylpiperidinyl)- 1 -phenyl- 1 ,3 ,8-triazaspiro[4,5]decan-4-one monohydrochloride:

To a mixture of l-carbethoxy-4-piperidone (1.11 g, 6.48 mmol) -and 1 -phenyl- 1,3,8- triazaspiro[4,5]decan-4-one (1 g, 4.32 mmol) in 100 mL of CH₂C1₂ was added 0.26 mL of acetic acid followed by sodium triacetoxyborohydride (1.47 g, 6.93 mmol). The reaction mixture was stirred at room temperature for 12 h and then poured into 200 mL of CHC1₃ and 200 mL of a saturated solution of bicarbonate. The layers were separated. The aqueous layer was extracted with CHC1₃ (2 x 100 mL) and the combined organic layers dried (MgSO₄) and concentrated under reduced pressure. The oily residue was dissolved in ethanol .and tr.ansformed to the hydrochloride salt by adding a 1 M solution of HC1 in ether. Recrystallization of the crude product from 20 mL ethyl acetate-methanol (1 : 1) gave 0.2 g of the title compound as a white solid (decomposition > 280 °C). MS (ES) m/e 387 (M+H). 'HNMR (DMSO, d6) d 1.24 (t, 3H), 1.67 (m, 2H), 1.92 (d, 2H), 2.19 (d, 2H), 2.88 (m, 2H), 3.08 (m, 2H), 3.37 (m, 3H), 3.75 (m, 2H) 4.12 (q, 2H), 418 (m, 2H), 4.80 (s, 2H), 6.82 (t, 1H), 7.15-7.40 (m, 4H), 9.09 (s, 1H), 11.01 (bs, 1H). Analysis for C₂₁H₃₀N₄O₃. 1HC1 . 0.9 H₂O. Calculated: C: 57.67; H: 7.51; N: 12.81. Found: C: 57.74; H: 7.36; N: 12.81.

Example 2

Preparation of: l-(l-ethoxycarbonylpiperidine-4-yl)-spiropyrolidine[4,3]indol-2'-one hydro- chloride.

Step 1 :

Preparation of 2,3-dihydro-2-oxo-l-indolecarbaldehyde diethyl acetal.

2-Indolone (10 g, 75.04 mmol) was dissolved in triethyl orthoformate (25 mL, 0.15 mol) and heated at 160°C overnight. The volatiles were removed in vacuo .and the oily residue was purified by flash chromatography (SiO2, ethyl acetate -hexane (2:8)) to give 10 g (56% ) of the title compound as an oil. MS(ES): 258 (M+Na) 'HNMR (DMSO, d6) d 1.07 (t, 6H), 3.46 (m, 2H), 3.60 (m, 4H), 6.11 (s, 1H), 6.97 (dd, 1H), 7.16 (dd, 1H), 7.22 (m, 2H).

Step 2: Preparation of 3-dihydro-3-di-(ethan-2-ol)-2-oxo-l-indolecarbaldehyde diethyl acetal.

To a solution of 2,3-dihydro-2-oxo-l-indolecarbaldehyde diethyl acetal (5.62 g, 23.91 mmol) in DMF was added sodium hydride (2.1 g , 52 mmol). The reaction mixture was stirred at 0 °C for 20 min and then (2-bromoethoxy)-ter-butyldimethylsilane (11.44 g, 47.82 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. DMF was evaporated and then the oily residue was dissolved in EtOAc (200 mL) and washed with a saturated solution of bicarbonate. The EtOAc layer was dried and evaporated. The residue was dissolved in THF and then to this solution was added a 1M solution of tetra-butylammonium fluoride (80 mL). The solution was stirred for 3h and then diluted with EtOAc (100 mL). The organic layer was washed with a saturated solution of bicarbonate, dried (MgSO₄) and concentrated in vacuo to give the title compound as an oil which was purified by flash chromatography (SiO2, hexane-ethyl acetate (1 :1)). MS(ES): 346 (M+Na) 'HNMR (DMSO, d6) d 1.22 (t, 6H), 2.01 (m, 4H), 3.09 (m, 4H), 3.38 (m, 2H), 352 (m, 2H), 4.74 (m, IH), 6.17 (s, IH), 7.11-7.36 (m, 4H).

Step 3: Preparation of l-(l-ethoxycarbonylpiperidine-4-yl)-spiropyrolidine[4,3]indol-2'-one hydro- chloride.

To a solution of 2,3-dihydro-3-(diethan-2-ol)-2-oxo-l-indolecarbaldehyde diethyl acetal (1.9 g, 5.88 mmol) and TEA ( 2.38 g, 23.52 mmol) in THF at 0 °C was added meth.ane sulfonic anhydride (2.56 g, 14.69 mmol). The reaction mixture was stirred for 2h at 0 °C, allowed to warm to room temperature and stirred for an additional 2h. The volatiles were removed in vacuo and DMF (50 mL) was added. To this solution was added 1-ethoxycarbonyl -4- aminopiperidine (5.06 g, 29.37 mmol) the resulting mixture was heated at 100 °C for 30 min. The reaction mixture was allowed to cool to room temperature and was then allowed to stir overnight. The volatiles were removed in vacuo .and the residue was purified by flash chromatography (SiO₂, methylene chloride-methanol (9:1)) to give .an oil which was dissolved in ether and converted to the hydrochloride salt, mp: 110-112 °C. MS(ES): 358 (M+l) 'HNMR (DMSO, d6) d 1.17 (t, 3H), 1.64 (m, 2H), 1.89 (m, 2H), 2.03 (m, 2H), 2.35 (m, IH), 2.49 (m, IH), 2.61 (m, 2H), 3.32 (m, IH), 4.02 (m, 6H), 4.31 (m, 2H), 7.12-7.42 (m, 4H), 13.4 (s IH). Analysis C₂₀H₂₇N₃O₃.HC1C.0.8H₂O calculated: C58.80; H7.35; N10.29; found C58.91; H7.29; N10.27.

Ex-ample 3

Preparation of 8-[(l-ethoxycarbonyl)piperidin-4-yl]-l,3,8-tri.azaspiro[4,5]decane-2,4-dione.

Step l

Preparation of l-[l-(ethoxycarbonyl)piperidin-4-yl]piperidine-4-oxo ethylene glycol ketal.

A solution of piperidin-4-oxo ethylene glycol ketal (9.94 g, 69.4 mmol), l-ethoxycarbonyl-4- oxopiperidine (17.82 g, 104 mmol) and acetic acid (4.21 ml, 73.6 mmol) in dichloromethane (150) was stirred at room temperature for fifteen minutes. The solution was then treated with sodium triacetoxy borohydride (23.53 g, 111 mmol) (the solution was weakly acidic, pH 5) and allowed to stir at room temperature overnight. The volatiles were removed in vacuo and the resulting residue was dissolved in water (100 ml). The aqueous phase was washed with ether (50 ml X 6) and the aqueous layer was basified with potassium carbonate (to 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 a yellow oil, 19.25 g. This residue was purified by chromatography using silica gel and hexane/ethyl acetate (1:1 --> 4:6 - -> 2:8 — > 0:10) then eluted with methanol/dichloromethane (1:9) to provide 1-[1- (ethoxycarbonyl)piperidin-4-yl]piperidine-4-oxo ethylene glycol ketal as a colorless oil, 9.71 g (47%) MS (electrospray, M + H⁺ = 299 m/e).

Step 2

Preparation of 1 -[1 -(ethoxycarbonyl)piperidin-4-yl]-4-oxopiperidine.

l-[l-(ethoxycarbonyl)piperidin-4-yl]piperidine-4-oxo ethylene glycol ketal (7.59 g, 25.4 mmol) was dissolved in 2 N HC1 (50 ml) and refluxed for five hours. The reaction was quenched with potassium carbonate (to pH 10) and the mixture was extracted with dichloromethane (50 ml X 3). The organic layers were combined, dried over magnesium sulfate and evaporated to give l-[l-(ethoxycarbonyl)piperidin-4-yl]-4-oxopiperidine as a colorless oil 3.43 g (53%) which was verified by MS (electrospray, M + H⁺ = 255 m e).

Step 3:

Preparation of 8- [( 1 -ethoxycarbonyl)piperidin-4-y 1] -1,3 , 8-triazaspiro [4, 5] decane-2 ,4-dione .

A mixture of l-[l-(ethoxycarbonyl)piperidin-4-yl]-4-oxopiperidine (2.0 g, 7.87 mmol), sodium cyanide (0.58 g, 11.8 mmol) and ammonium carbonate (2.65 g, 27.5 mmol) in eth.anol/water (25 mL/25 mL) was stirred at ambient temperature for lh, heated at reflux temperature for 2h and stirred at ambient temperature overnight. The volatiles were evaporated, the residue mixed with a saturated aqueous solution of sodium bicarbonate (60 mL) and extracted with EtOAC (60 mL x 2) and methylene chloride (60 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give a white solid (1.75 g) Recrystallization from water (trace of MeOH) gave the title compound as a white solid (0.55 g, 22%): mp 220-223°C; MS (El) 325 (M+H); Η-NMR (DMSO-d6) δ 10.60 (s, NH, IH), 8.43 (s, NH, IH), 4.01 (m, 4H), 3.31 (m, 4 H), 2.73 (m, 4H), 2.31 (m, 3H), 1.73 (m, 4H), 1.49 (d, J = 4.0 Hz, 2H), 1.16 (q, J = 2.0 Hz, 2H), 1.06 (m, Me, 3H).

Ex-ample 4

Preparation of 3-thienylmethyl-8-[(l-ethoxycarbonyl)piperidin-4-yl]-l,3,8-triazaspiro[4,5]- decane-2,4-dione.

To a mixture of 8-[(l-ethoxyc^bonyl)piperidin-4-yl]-l,3,8-tri^aspiro[4,5]decane-2,4-dione (0.68 g, 2.10 mmol), 2-thiophenemethanol (0.26 g, 2.31 mmol) .and triphenylphosphine (0.826 g, 3.15 mmol) in anhydrous THF (30 mL) at -30°C was added diisopropyl azodicarboxylate (0.637 g, 3.15 mmol) with stirring under nitrogen. The reaction was allowed to proceed at ambient temperature overnight. The volatiles were removed in vacuo .and the residue mixed with a saturated aqueous solution of sodium bicarbonate (30 mL) and extracted with EtOAc (50 mL x 3). The organic combined extracts were dried over magnesium sulfate, filtered and evaporated to give an oil. Chromatography on silica (gradient, 6.5% to 10% methanol/methylene chloride) gave an oil. Crystallization from methylene chloride gave the title compound as a white solid (0.239 g, 24%): mp 214-216°; Η-NMR (DMSO-d6) δ 8.86 (s, NH, IH), 7.42 (d, IH), 7.04 (d, IH), 6.98 (d, IH), 4.60 (s, CH2, 2H), 4.01 (m, 4H), 3.31 (m, 3 H), 2.73 (m, 4H), 2.31 (m, 3H), 1.79 (m, 2H), 1.70 (m, 2H), 1.49 (d, J - 4.0 Hz, 2H), 1.16 (q, J = 2.0 Hz, 2H), 1.06 (m, Me, 3H).

Example 5

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 6

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 and n .are independently 0 or 1 ; o and p are independently 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, N(SO)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 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, R² .and R³ .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

.an

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 ophth mic ph-armaceutical 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.