WO1999032443A1

WO1999032443A1 - Muscarinic agents and use thereof to treat glaucoma, myopia, and various other conditions

Info

Publication number: WO1999032443A1
Application number: PCT/US1998/027586
Authority: WO
Inventors: Bryon S. Severns; Mark R. Hellberg; Abdelmoula Namil; 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: AU2206499A

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

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 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 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- 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;

(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 and n are independently 0 or 1 ; o and p are independently 1 or 2;

X is C(R)₂, O, S(0)_q, NR, C(=O), CHOR, C=NOR, NC(=0)OR, NC(=0)N(R)₂,

NC(=O)R, CHC(=0)OR, CHC(=0)N(R)₂, CHC(=0)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 C=0, S(=O), S(=0)_2,C=S or C=NR; and

J is O, CR, C(R)₂, NR or NRC(=0); R¹, R² and R³ are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH₂, aryl, arylalkyl, SR and N(R)₂; and

A is selected from the group consisting of (R)₂NC(=O)O, (R)₃COC(=0)NR, (R)₃CS(=O)₂NR, (R)₂NC(=0)NR, (R)₃C(=O)O and RC(O)NR.

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, 1 -methyl-2-propenyl and 4-pentenyl.

The term "alkynyl" includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms (C, to C,₅) 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, 1 -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 and p are 1 ; R is H, lower alkyl, alkynyl or alkenyl; and X is S(O)_q, C(=O)CHOR, C=NOR, NC(=O)OR, NC(=0)N(R)₂, NC(=O)R, CHC(=0)OR, CHC(=O)N(R)₂, CHC(=O)R or NS(O)₂C(R)₃ Among these preferred compounds, the most preferred compounds are those wherein A is

m, n, o and p are 1; R is H, lower alkyl, alkoxyl, alkynyl or alkenyl: R', R² and R³ are H or lower alkyl; and X is CHOR. C=NOR, NC(=0)OR, NC(=0)N(R)₂, NC(=O)R, CHC(=0)OR, CHC(=0)N(R)₂ or NS(O)₂C(R)₃

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

3

Compound (3) is prepared by combining compounds (1.), (2) 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 compounds of the present invention where A is an ester or a carbamate where the oxygen atom is connected directly to the ring may be prepared by the means of the method illustrated in scheme 2 below:

Scheme 2

Compound (5) is prepared by combining compounds (2), (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 ketal protecting group of compound (5) is removed by warming the compound in an acidic (hydrochloric acid, sulfuric acid, or trifluoroacetic acid ) aqueous solution at a temperature ranging 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 6 may be reduced to the alcohol 7 using a reducing agent such as sodium borohydride in a solvent such as ethanol or isopropyl alcohol at a temperature ranging from -10° C to 70° C for 1 to 12 h. The ester 8 may be formed by reacting the alcohol 7 with the appropriate carboxylic acid in the presence of a coupling reagent such as dicyclohexyldiimide or l-(3-dimethylaminopropyl)3-ethyl carbodiimde HCl and 4-dimethylamino pyridine or 1-hydroxybenzotriazole hydrate in an organic solvent, such as acetonitrile, dimethylformamide or tetrahydrofuran and at a temperature ranging from -10° C to 70° C. Alternately, the ester 8 may be formed by reacting the alcohol 7 with the appropriate carboxylic acid chloride in an inert solvent such as tetrahydrofuran or methylene chloride in the presence of pyridine or a tertiary amine such as triethylamine at a temperature ranging from -20° C to 50° C. The carbamate compounds 9 can be formed by reacting the alcohol 7 with the appropriate isocyanate in an inert solvent such as methylene chloride, acetonitrile or tetrahydrofuran at a temperature ranging from -20° C to 40° C.

The compounds of the present invention where A is a sulfonamide, urea, amide or a carbamate where the nitrogen is connected directly to the ring may be prepared by the methods illustrated in scheme 3 below:

Scheme 3

Compound (10) is prepared by combining compound (6), the appropriate amine 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 amide H. may be formed by reacting the amine 1O with the appropriate carboxylic acid in the presence of a coupling reagent such as dicyclohexyldiimide or l-(3-dimethylaminopropyl)3-ethyl carbodiimde HCl and 4-dimethylamino pyridine or 1-hydroxybenzotriazole hydrate in an organic solvent, such as acetonitrile, dimethylformamide or tetrahydrofuran and at a temperature ranging from -10° C to 70° C. Alternately, the amide π_ may be formed by reacting the alcohol 10 with the appropriate carboxylic acid chloride in an inert solvent such as tetrahydrofuran or methylene chloride in the presence of pyridine or a tertiary amine such as triethylamine. The sulfonamide compounds 12 may be prepared by reacting the appropriate sulfonyl chloride with the amine 1O in an inert solvent such as tetrahydrofuran in the presence of pyridine or a tertiary amine base such as triethylamine at a temperature ranging from -20° C to 50° C. The carbamate compounds 13 may be prepared by reacting the amine 10 with appropriate chloroformate derivative in an inert solvent such as tetrahydrofuran or methylene chloride in the presence of pyridine or a tertiary amine base such as triethylamine at a temperature ranging from -20° C to 50° C. The urea compounds 14 can be prepared by reacting the amine 10 with the appropriate isocyanate in an inert solvent such as methylene chloride, chloroform of tetrahydrofuran in the presence of pyridine or a tertiary amine base such as triethylamine at a temperature ranging

The starting materials (1), (2), 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 formulas (3), (8), (9), (IT), (12), (13), and (14), 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 1 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 5 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- l o 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.

15

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 20 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: 25 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.

30

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 preparing the ophthalmic compositions of the present invention are further illustrated by the following examples. The term "Compound" in Examples 2 and 3 is intended to represent a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Example 1 Preparation of N-benzyl-0-[l-[l-(ethoxycarbonyl)piperidin-4-yl]piperidin-4-yl]carbamate hydrochloride:

Step 1

Preparation of l-[(ethoxycarbonyl)piperidin-4-yl]piperidin-4-ol. A solution of 4-hydroxypiperidine (12.00 g, 119 mmol), 4-hydroxy-l-(ethoxy- carbonyl)piperidine (30.47 g, 178 mmol) and acetic acid (7.22 ml, 126 mmol) was stirred for 15 minutes. Sodium triacetoxyborohydride (40.35 g, 190 mmol) was added and the reaction mixture was stirred at room temperature for two days. The volitiles were evaporated and the resulting residue was taken up in water (200 ml) and washed with ether (100 ml X 3). The aqueous layer was basified with potassium carbonate (to pHIO) and extracted with dichloromethane (100 ml X 3). The combined organic layers were dried over magnesium sulfate and evaporated to provide an orange oil, 10.69 g. This residue was purified by chromatography using silica gel and ethyl acetate — > methanol/dichloromethane (1:9) to give the title compound as an orange oil, 5.10 g (17%), MS (electrospray, M + H⁺ = 257 m/e). Step 2

Preparation of N-benzy l-O- [ 1 - [ 1 -(ethoxycarbonyl)piperidin-4-y l]piperidin-4-y l]carbamate hydrochloride.

A solution of of l-[(ethoxycarbonyl)piperidin-4-yl]piperidin-4-ol (0.20 g, 0.78 mmol) in THF (5 ml) and triethylamine (0.22 ml, 1.56 mmol) was treated with benzyl isocyanate (0.22 ml, 1.76 mmol) and heated to 70 °C overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (100 ml) and the resulting mixture was extracted with dichloromethane (50 ml X 2). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting residue was treated with ethanolic hydrochloric acid and evaporated to a yellow oil. This residue was purified by chromatography using silica gel, eluting with ethyl acetate --> methanol/dichloromethane (1:9) to give the title compound as a yellow solid, 0.13 g (40%), mp 90-3 °C, MS (electrospray, M + H⁺ = 390 m/e).

Example 2

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 3

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(0)_q, NR. C(=0), CHOR, C=NOR, NC(=0)OR, NC(=0)N(R)₂,

NC(=0)R, CHC(=0)OR, CHC(=0)N(R)₂, CHC(=0)R, NS(0)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=0, S(=0), S(=0)₂ C=S or C=NR; and J is O, CR, C(R)₂, NR or NRC(=0);

R', R² and R³ are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH₂, aryl, arylalkyl, SR and N(R)₂; and

A is selected from the group consisting of (R)₂NC(=0)0, (R)₃COC(=0)NR, (R)₃CS(=0)₂NR, (R)₂NC(=0)NR, (R)₃C(=O)0 and RC(0)NR; 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.