The present invention relates to a method for using azacyclic or azabicyclic compounds for treating anxiety in a human.

Extensive research has been conducted for a number of years directed toward the development of compounds capable of treating anxiety m humans that are safer to the user and which exhibit fewer side-effects. For example, several clinically established anxiolytic agents such as the barbituates, meprobamate and the benzodiazepines have numerous side effects such as potential for abuse and addiction or potentiation of the effects of ethanol. The mechanism of action of these compounds is believed to involve the GABA/benzodiazepme receptor complex m humans.

Buspirone is another compound which has been studied for the treatment of anxiety. The literature states that Buspirone interacts with reasonable potency only at the 5-HT _1A and dopamine receptors. Alfred Goodman, et al . , Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8:482 (1990); Tompkins et al . Research Communications m Psychology, Psychiatry, and Behavior, 5:4, p. 338 (1980) .

The art haε reported that compounds which act as agonists of the cholinergic muscarmic receptor can actually produce anxiety. See, Risch et al . Psvchopharmacol . Bull . , 19: 696-698 (1983), Nurnberger et al . Psychiatry Res. , 9:191- 200 (1983) , and Nurnberger et al . Psvchopharmacol. Bull., 17:80-82 (1982).

Surprisingly, we have discovered that a group of compounds having muscarmic cholinergic activity can be useful for treating anxiety. The present invention relates to a method of treating anxiety. More specifically, the invention provides a method of treating anxiety humans usmg a specified tetrahydropyπdme or azabicyclic oxadiazole or thiadiazole compound. The activity of these compounds is believed to be based on agonist action at the m- 1 muscarmic cholinergic receptor.

The present invention provides a method for treating anxiety humans comprising administering to a human in need thereof, an antianxiety dose of a compound of Formula I

wherein

W is oxygen or sulphur; P is hydrogen, ammo, halogen, NHR ⁶ , NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -S0 R ⁴ , C ₃ -ιo-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C _{3 10} -cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) wherein R ⁴ is Cι- ₁₅ -alkyl, C2-l5-alkenyl, C2-l5-alkynyl, each of which is optionally substituted with one or more halogen(s) , -CF ₃ , -CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci- ₄ -alkyl, Cι- ₄ -alkoxy, -OCF3, -CF _3/ -CONH ₂ or -CSNH ₂ ; or

R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Cι- ₄ -alkyl, C ₁ -. ₄ - alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ or -CSNH ₂ ; or

R is -OR ⁵ Y, -SR ⁵ Y, OR ⁵ -Z-Y, -SR ⁵ ZY, -0-R ⁵ -Z-R ⁴ or -S-R ⁵ -Z-R ⁴ wherein Z is oxygen or sulphur, R ⁵ is Cι_i ₅ -alkyl, C2-15- alkenyl, C ₂ -l ₅ -alkynyl, and Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic ring systems:

het-5 het-6 het-7 or G can optionally be substituted C ₃ -C ₈ cycloalkyl or optionally substituted Ci-g-alkyl wherein the substitution is -NR ⁶ R ⁷ ;

R6 and R ⁷ independently are hydrogen, Cι- ₆ -alkyl; or

R ⁶ and R ⁷ together with the nitrogen atom optionally form a

4- to 6-member ring;

R ¹ and R ² independently are hydrogen, Cι_i ₅ -alkyl, C2-5- alkenyl, C2-5~alkynyl, Cι_ιo-alkoxy, Cι-5-alkyl substituted with -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH ₂ , carboxy, or phenyl;

R ³ is hydrogen, Cι- ₅ -alkyl, C ₂ - ₅ -alkenyl or C ₂ - ₅ -alkynyl;

R ⁶ ' is hydrogen, Cι- ₆ -alkyl; n is 0, 1 or 2;

m i s 0 , 1 or 2 ; p i s 0 , 1 or 2 ; q i s 1 or 2 ; r i s 0 , 1 or 2 ; is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

The use of a compound of Formula I or the quaternized form thereof:

wherein

W is oxygen or sulphur; R is selected from the group consisting of hydrogen, amino, halogen, NHR ⁶ , NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -S0 ₂ R ⁴ , C ₃ -icr cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C ₃ -ιo-cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) ; R ⁴ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-l5-alkenyl, and C2-1 ₅ alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s) , -CF ₃ , -CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, -CN, C ₁ - ₄ - alkyl, Ci- ₄ -alkoxy, -OCF3, -CF ₃ , -CONH ₂ and -CSNH ₂ ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, Cι- ₄ -alkyl, Cι- ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ and -CSNH ₂ ; or R is selected from the group consisting of -OR ⁵ Y, -SR ⁵ Y, OR ⁵ -Z-Y, -SR ⁵ ZY, -0-R ⁵ -Z-R ⁴ and -S-R ⁵ -Z-R ⁴ - ^' Z is oxygen or sulphur;

R ⁵ is selected from the group consisting of C ₁ - ₁₅ alkyl, C2- ₁ 5-alkenyl , and C2-i5-alkynyl;

Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic ring systems:

het-5 het-6 het-7 or G can optionally be substituted C ₃ -C ₈ cycloalkyl or substituted Cι- ₆ -alkyl wherein the substitution is -NR ⁶ R ⁷ ; R^ and R ⁷ independently are selected from the group consisting of hydrogen and Cι- ₆ -alkyl; or R ⁶ and P ^"7 together with the nitrogen atom optionally form a 4- to 6-member ring;

R ¹ and R ² independently are selected from the group consisting of hydrogen, Cι- ₁₅ -alkyl, C2-5-alkenyl, C2-5- alkynyl, Cι- ₁₀ -alkoxy, and Cι-5-alkyl substituted with a subsituent independently selected from the group consisting of -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2, carboxy, and phenyl;

R ³ is selected from the group consisting of hydrogen, Ci ₅ - alkyl, C ₂ - ₅ ~alkenyl and C ₂ - ₅ ~alkynyl;

R ^fc is selected from the group consisting of hydrogen and

Cι- ₆ -alkyl; m is 0, 1 or 2;

p is 0, 1 or 2;

is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof; for the manufacture of a medicament for the treatment of anxiety.

A pharmaceutical formulation adapted for the treatment of anxiety containing a compound of Formula I or the quaternized form thereof:

wherein

W is oxygen or sulphur;

R is selected from the group consisting of hydrogen, ammo, halogen, NHR ⁶ , NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -S0 ₂ R ⁴ , C3- ₁₀ - cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C ₃ -ιo-cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) ; R ⁴ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-15-alkenyl, and C ₂ - ₁ 5- alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s) , -CF ₃ , -CN, Y, phenyl and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, -CN, C ₁ - ₄ - alkyl, Cι- ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ and -CSNH ₂ ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, Cι- ₄ -alkyl, Cι- ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ and -CΞNH2; or R is selected from the group consisting of -OR ⁵ Y, -SR ⁵ Y, OR ⁵ -Z-Y, -SR ⁵ ZY, -0-R ⁵ -Z-R ⁴ and -S-R ⁵ -Z-R ⁴ _' - Z is oxygen or sulphur;

R ⁵ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-i5-alkenyl , and C2-i5-alkynyl;

Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic ring systems:

het-5 het-6 het-7 or G can optionally be substituted C ₃ -C ₈ cycloalkyl or substituted Ci-g-alkyl wherein the substitution is -NR ⁶ R ⁷ ; R ⁶ and R ⁷ independently are selected from the group consisting of hydrogen and Cι_ ₆ -alkyl; or R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member rmg;

R ¹ and R ² independently are selected from the group consisting of hydrogen, Cι_i ₅ -alkyl, C2-5-alkenyl, C ₂ -5- alkynyl, Cι_ι ₀ -alkoxy, and Ci-5-alkyl substituted with a subsituent independently selected from the group consistmg of -OH, -COR ⁶ ', CH ₂ -OH, halogen, - H2 , carboxy, and phenyl;

R ³ is selected from the group consisting of hydrogen, C ₁ -. ₅ - alkyl, C ₂ - ₅ -alkenyl and C2- ₅ -alkynyl;

R ^fc is selected from the group consisting of hydrogen and

Cι- ₆ -alkyl; m is 0, 1 or 2;

p is 0, 1 or 2; q is 1 or 2; r is 0, 1 or 2; is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

The invention claimed herein further provides a method for treating anxiety wherein the anxiety is selected from the group consisting of Panic Attack; Agoraphobia; Acute Stress Disorder; Specific Phobia; Panic Disorder; Psychoactive Substance Anxiety Disorder; Organic Anxiety Disorder; Obsessive-Compulsive Anxiety Disorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.

It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enatiomeric, and racemic forms of the compounds of Formula I.

Aε used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.

The term "antianxiety dose", as used herein, representε an amount of compound necessary to prevent or treat a human susceptible to or suffering from anxiety following administration to such human. The active compoundε are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.005 to about 500 mg/kg of body weight. In the treatment of adult humans, the range of about 0.05 to about 100 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of the compound actually

adm istered will be determined by a physician, in the light of the relevant circumstances mcludmg the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention any way. While the present compounds are preferably administered orally to humans susceptible to or suffering from anxiety, the compounds may also be administered by a variety of other routes such as the transdermal, parenterally, subcutaneous, intranasal, intramuscular and intravenous routes. Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known m the art.

As used herein the term "anxiety" refers to an anxiety disorder. Exampleε of anxiety disorders which may preferredly be treated using an effective amount of a named compound or pharmaceutically acceptable salt thereof mclude, but are not limited to: Panic Attack; Agoraphobia; Acute Stress Disorder; Specific Phobia; Panic Disorder; Psychoactive Substance Anxiety Disorder; Organic Anxiety Disorder; Obsessive-Compulsive Anxiety Disorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.

Examples of anxiety disorders which may more preferredly be treated using an effective amount of a named compound or a pharmaceutically acceptable salt thereof include Panic Attack; Panic Disorder; Psychoactive Substance Anxiety Disorder; Organic Anxiety Disorder; Obseεsive-

Compulεive Anxiety Disorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.

Examples of the anxiety disorders which are most preferredly treated using a named compound include Organic Anxiety Disorder; Obsessive-Compulsive Disorder;

Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS.

The named anxiety disorders have been characterized the DSM-IV-R. Diagnostic and Statistical Manual of Mental Diεorders. Reviεed, 4th Ed. (1994) . The DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic catagories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress.

The compounds employed m the invention are not believed to act via the GABA/benzodiazepme, 5HT1A, or Dl receptor syεtems humans. Rather, the activity of the present compounds as antianxiety agents is believed to be based upon modulation of muscarmic cholinergic receptors. However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra . , and the present invention is not limited by any mode of operation.

As used herein with reference to the G subεtituent, the - (CH ₂ ) _r -W-pyrazme moiety can be attached at any carbon atom of the azacyclic or azabicyclic rmg. Further, R ¹ and R ² of the G εubεtituent may be present at any position, including the point of attachment of the - (CH ) _r -W-oxadιazole or - (CH ) _r -W-pyrazme moiety.

Examples of pharmaceutically acceptable salts mclude 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, and mclude the pharmaceutically acceptable salts listed m Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

As used herein with reference to the G substituent, the - (CH ₂ ) _r -W-oxadιazole or - (CH ₂ ) _x -W-pyrazme moiety can be attached at any carbon atom of the azacyclic or azabicyclic rmg. Further, R ¹ and R ² of the G substituent may be present at any position, including the point of attachment of the - (CH ₂ ) _-W-oxadiazole or -(CH ₂ ) _r - W-pyrazine moiety.

Examples of pharmaceutically acceptable salts include inorganic and organic acid addition εalts εuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and mclude the pharmaceutically acceptable salts listed m Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

As used herein with reference to the G substituent, the numbering shall be as follows:

het-5

As used herein the term α shall refer to a position on the G substituent which is one position away from the N atom of the G substituent. For example, the following illustration (IE), both positions 2 and 6 are considered α. The term γ shall refer to the position on the G substituent which is opposite the N atom. For

example, in the illustration (IE) , position 4 is considered γ. Likewise, β shall refer to the 3 and 5 position in the illustration.

As used herein with reference to the G substituent, the phrase "R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring" means that R ⁶ and R ⁷ are each independently hydrogen,Ci-C _δ alkyl; the R ⁶ and R ⁷ groups may optionally join to form a 4- to 6- member ring including the nitrogen. For example, optionally joined groups include, but not limited to:

As used herein the phrase "interacting with a muscarinic cholinergic receptor" shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. Likewise, the term "interacting with a nicotinic cholinergic receptor" shall include compounds which block or modulate the receptor. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a cholinergic receptor.

As used herein, h ⁺ is alkoxide metal wherein the term "alkoxide metal" means a metal suitable for alkoxide formation. Such alkoxide metals include, but are not limited to, Li ⁺ , K ⁺ , Na ⁺ , Cs ⁺ , and Ca ⁺⁺ . Especially preferred alkoxide metals include Li ⁺ , K ⁺ , and Na ⁺ .

As used herein, the term "halogen" means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I.

The terms "Cι-C _n - alkyl" wherein n' can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical Ci-Cβ alkyl groups mclude methyl, ethyl, n- propyl, iso-propyl, butyl, so-butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The terms "C ₂ -C _n' alkenyl" wherein n' can be from 3 through 10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl (-CH ₂ -CH=CH ₂ ) , 1, 3-butadienyl, (-CH=CHCH=CH ₂ ) , 1-butenyl (-CH--.CHCH ₂ CH ₃ ) , hexenyl, pentenyl, and the like. The term "C ₂ -C ₅ alkynyl" refers to an unsaturated branched or linear group having from 2 to 5 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, and the like. Tne terms "halogen(Cχ-C ₆ ) alkyl" and "halogen(C ₂ -

Cg) alkenyl" refer to alkyl or alkenyl substituents having one or more independently selected halogen atoms attached at one or more available carbon atoms. These terms mclude, but are not limited to, chloromethyl, 1-bromoethyl, 2-bromoethyl, 1, 1, 1-trιfluoroethyl, 1, 1,2-tri luoroethyl, 1,2,2- tπfluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, trifluoroethylenyl, 3-bromopropyl, 3-bromo-l-propenyl, 2 bromopropyl, 2-bromo-l-propenyl, 3-chlorobutyl, 3-chloro-2- butenyl, 2 , 3-dιchlorobutyl, 1-chloroethylenyl, 2- chloroethylenyl, 5-fluoro-3-pentenyl, 3-chloro-2-bromo-5- hexenyl, 3-chloro-2-bromobutyl, trichloromethyl, 1,1- dichloroethyl, 1, 2-dιchloroethyl, 2 , 2-dιchloroethyl, 1,4- dichlorobutyl, 3-bromopentyl, 1, 3-dιchlorobutyl, 1,1- dichloropropyl, and the like. The term "C ₂ -C ₁₀ alkanoyl" represents a group of the formula C(0) (Cι-Cg) alkyl. Typical C ₂ -C ₁₀ alkanoyl groups mclude acetyl, propanoyl, butanoyl, and the like.

The term " (Cχ-C6 alkyl) ammo" refers to a monoalkylamino group. Examples of such groups are methylammo, ethylamino, so-propylammo, n-propylammo, { n- propyl) am o, ( so-propyl) am o, n-propylammo, t-butylamino, and the like.

The term "C ₃ -C _n cycloalkyl" wherein n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "substituted (C ₅ -C _n' ) cycloalkyl" refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituentε independently selected from the group consisting of hydrogen, Ci-Cβ alkyl, N0 ₂ , halogen, halogen(Ci-Ce) alkyl, halogen(C ₂ - C _δ ) alkenyl, C ₂ -C ₆ alkenyl, C0 ₂ R ² °, (Cι-C ₆ alkyl) ammo, -SR ²⁰ , and OR ²⁰ ; wherein R ²⁰ is selected from the group consisting of ^c _l - ₁₅ ^_a lkyl, C ₂ - _l5 ^alkenyl, and C ₂ - ₁₅ -alkynyl .

The term "C ₃ -C ₈ cycloalkyl- (C ₁ -C3) alkyl" represents an alkyl group substituted at a terminal carbon with a C3-C8 cycloalkyl group. Typical cycloalkylalkyl groups mclude cyclohexylethyl, cyclohexylmethyl, -cyclopentyIpropyl, and the like.

The term "C ₅ -C ₈ cycloalkenyl" represents an olefinically unsaturated rmg having five to eight carbon atoms. Such groups mclude, but are not limited to, cyclohexyl-1, 3-dιenyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexyl-1, 4-dιenyl, cycloheptyl-1, 4-dιenyl , cyclooctyl-1, 3 , 5-trιenyl and the like.

The term "substituted (C ₅ -C ₈ ) cycloalkenyl" refers to a cycloalkenyl group as described supra , wherein the cycloalkenyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, Ci-Cε alkyl, O ₂ , halogen, halogen(Ci-Cβ) alkyl, halogen(C ₂ -C ₆ ) alkenyl, C ₂ -Cβ alkenyl, COR ²⁰ , C -Cιo alkanoyl, C ₇ -C ₁₆ arylalkyl, C0 ₂ R ² °, (Cι-C ₆ alkyl) ammo, -SR ²⁰ , and

-OR ²⁰ . Wherein R ²⁰ is selected from the group consisting of ^c _l - ₁₅ ~alkyl, C2-l5-alkenyl, C2-l5-alkynyl .

The term "C ₅ -C ₈ cycloalkenyl- (Ci C ₃ ) alkyl" repreεentε a C ₁ -C ₃ alkyl group εubstituted at a terminal carDon with a C ₅ -C ₈ cycloalkenyl group.

As used herein, the phrase "5 or 6 membered heterocyclic group" means a group containing from one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with Ci-ς-alkyl, -CF3, phenyl, benzyl or thienyl, or a carbon atom the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group. The phrase "5 or 6 membered heterocyclic group' mcludes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans) ; 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, puπnes); 5-membered heterocycleε having three heteroatomε (e.g. triazoles, thiad azoles) ; 5-membered heterocycles having 3-heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrme, 5, 6-cycloheptenopyπdme) ; 6- membered heterocycles with two heteroatoms (e.g. pyndazmes, cmnol es, phthalazmes, pyrazmes, pyrimidines, qu azolmes) ; 6-membered heterocycles with three heteroatoms (e.g. 1, 3 , 5-tπazme) ; and 6-member heterocycles with four heteroatoms. Particularly preferred are thiophenes, pyπdmes, and furans.

The term "heteroaryl" refers to a group which is a 5 or 6 membered heterocycle contammg one to four N, O, or S atoms or a combination thereof.

As uεed herein the term "carboxy" referε to a εubstituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group. As used herein the term "aryl" means an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g., phenyl or naphthyl. Most preferably,

aryl refers to C6-C ₁ 0 aryl, wherein the aryl rmg system, mcludmg any alkyl substitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl, 3, 3-dimethylphenyl, naphthyl, and the like. The aryl radical may be subεtituted by one or two C ₁ -C ₆ εtraight or branched alkyl. The term

"aryl (C ₁ -C ₃ )alkyl" referε to any aryl group which is attached to the parent moiety via the alkyl group.

As used herem the term "malfunctioning of the muscar ic cholinergic system" shall have the meaning accepted by the skilled artisan. Likewise, the term

"malfunctioning of the nicotmic cholinergic system" shall have the art recognized meaning. For example the term shall refer to, but is not m any way limited to, conditions such as glaucoma, psychosis, schizophrenia or schizophreniform conditions, depression, sleeping disorders, epilepsy, and gastrointestinal motility disorders. Other such conditions include Alzheimer's Disease and incontinence.

Compounds of this invention may be prepared by the process illustrated m Scheme II

Scheme II

The artisan will recognize that the starting materials for the process of Scheme II are commercially available or can be prepared using methods familiar to the skilled artisan.

Compounds of Formula I wherein R is an R ⁴ group, can be prepared using methods well known m the ar . See for example, U.S. Patent Number 5,043,345. Further, compounds of Formula I may be prepared using the process illustrated in the following Scheme III

Scheme III

ize

As used in Scheme III, Q may be N, 0 or S; P ²⁴ is selected from the group consisting of hydrogen, R ⁴ , R ⁵ , R ⁶ , and R ⁷ _' ' R ²⁵ iε selected from the group conεisting of SOP ⁴ and S0 ₂ R ⁴ ; all other meanings are as defmed supra .

Additional compounds of Formula I may be prepared using the proceεs illustrated by Scheme IV.

Scheme IV

reduction

8 As used in Scheme IV, Hal, W, r, and G are as defined supra . As used in Scheme IV, R ²² and R ²³ are

mdependently selected from the group consisting of hydrogen, R ⁶ and R ⁷ .

When the G subεtituent contains a secondary nitrogen protected by a protecting group, the protecting group may be removed using standard methods known to the skilled artisan. An especially preferred protecting group is carbamate. One particularly useful reference concerning protecting groups is Greene, Protecting Groups n Organic Svnthesiε, (John Wiley & Sons, New York, 1981) . The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of ³ H- Oxotremorme-M ( ³ H-Oxo) . Birdsdall N.J.M., Hulme E.C., and Burgen A.S.V. (1980) . "The Character of Muscarmic Receptors Different Regions of the Rat Bram". Proc. Roy. Soc. London (Series B) 207,1.

³ H-Oxo labels muscarmic receptor in the CNS (with a preference for agonist domains of the receptors) . Three different sites are labeled by ³ H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.

The inhibitory effects of compounds on ³ H-oxo binding reflects the affinity for muscar ic acetylcholine receptors.

All preparations are performed at 0-4°C unless otherwise indicated. Fresh cortex (0.1-1 g) from male

Wistar rats (150-250 g) is homogenized for 5-10 s in 10 mL 20 nM Hepeε pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer lε rinsed with 10 mL of buffer and the combined suspension centrifuged for 15 mm. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2 x 10 mL of buffer and centrifuged for 10 mm. at 40,000 x g.

The final pellet is homogenized 20 mM Hepes pH: 7.4 (100 L per g of original tissue) and used for binding assay. Aliquots of 0.5 mL is added 25 μL of test solution and 25 μL of ³ H-Oxotremoπne (1.0 nM, final concentration) mixed and incubated for 30 mm. at 25°C. Non-specific bmding is determmed in triplicate using arecolme (1 μg/mL, final concentration) as the teεt εubεtance. After incubation εamples are added 5 mL of lce- cold buffer and poured directly onto Whatman GF/C glaεε fiber filters under suction and immediately washed 2 times with 5 mL of ice-cold buffer. The amount of radioactivity on the filters are determmed by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.

Test substanceε are diεεolved m 10 mL water (if neceεsary heated on a steam-bath for leεs than 5 mm. ) at a concentration of 2.2 mg/mL. 25-75% inhibition of specific binding must be obtained before calculation of IC ₅₀ . The test value will be given aε IC ₅₀ (the concentration (nM) of the teεt substance which inhibits the specific binding of ³ H-oxo by 50%) . IC ₅₀ = (applied test substance concentration) x(C _x /C ₀ -C _x )nM where C _Q is specific binding control assays and C _x is the specific binding the test assay. (The calculations assume normal mass-action kinetics) .

Furthermore the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit ³ HPRZ (pirenzepine, [N-methyl- ³ H] ) binding to rat cerebral cortex membranes.

Pirenzepine binds selectively to subtype of muscarinic receptors. Historically the type is named the Mχ-sιte, whereas pirenzepine sensitive site would be more

appropriate. Although selective for Mχ-sιtes pirenzepine also mteract with M ₂ -ειtes.

All preparations are performed at 0-4°C unless otherwise indicated. Fresh cortex (0.1-1 9) from male

Wistar rats (150-200 g) is homogenized for 5-10 s 10 mL 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer lε rinsed with 2 x 10 mL of buffer and the combined suspension centrifuged for 15 mm. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before m 3 x 10 mL of buffer and centrifuged for 10 mm. at 40,000 x g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 mL per g of original tissue) and used for binding assay. Aliquots of 0.5 mL is added 20 μL of test solution and 25 μL of ³ HPRZ (1.0 nM, final cone) , mixed and incubated for 60 mm. at 20°C. Non-specific binding is determmed in triplicate using atropme (1.0 μg/mL, final cone.) as the test substance. After incubation samples are added 5 mL of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 mL of ice-cold buffer. The amount of radioactivity on the filters are determmed by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.

Test substances are dissolved 10 mL water, at a concentration of 0.22 mg/mL. 25-75% inhibition of εpecific binding must be obtained before calculation of IC50.

The test value will be given as IC ₅₀ (the concentration (nM) of the test substance which inhibits the specific binding of ³ HPRZ by 50%) .

IC ₅₀ - (applied test substance concentration) x (C _x /C ₀ -C _x )nM where C _Q is specific binding in control assays and C _x is

the specific binding in the test assay. (The calculations assume normal mass-action kinetics) .

Test results obtained by testing some compoundε of the preεent invention will appear from the following table 1.

TABLE 1

Compound ³ H -Oxo-M ³ HPRZ

1 81 56

2 374 253

3 19.3 14.5

6 2.5 0.9

4 25 21

5 40 32

7 16 6.7

8 1040 >1000

9 36 30

10 354 223

11 56 53

12 25 13

13 74 42

14 26 21

15 14 13

16 39 23

17 17 4.5

18 21 5.4

19 121 108

20 245 246

21 26 123

22 140 52

Compound No. Oxo-M Pir

IC-50, nM IC-50, nM

23 4.9 2.7 24 2.2 0.54 25 180 680 26 >1000 1000 27 >1000 -1000 28 >10,000 5710 29 1.7 0.68 30 4.4 0.82 41 3.2 1.6 42 9.1 4.8 43 8.1 2.2 31 3.4 1.7 32 3.9 4.0 33 1.5 0.7 34 2.0 0.66 35 3.2 0.54 36 0.34 5.8 37 1.3 0.76 38 6.2 3.3 39 10 80 40 60 17

The following Examples are studies to establish the usefulnesε of the named compounds for treating anxiety.

Example 1

Punished Responding The antianxiety activity of the compounds employed in the method of the present invention is establiεhed by demonstrating that the compoundε increase punished responding. This procedure has been used to establish antianxiety activity in clinically established compounds.

According to this procedure, the responding of rats or pigeons is maintained by a multiple schedule of food presentation. In one component of the schedule, responding produces food pellet preεentation only. In a εecond

component, responding produces both food pellet presentation and is also punished by presentation of a brief electric shock. Each component of the multiple schedule is approximately 4 mmutes duration, and the shock duration is approximately 0.3 seconds. The shock intensity is adjusted for each individual animal εo that the rate of punished responding is approximately 15 to 30% of the rate in the unpunished component of the multiple schedule. Sessions are conducted each weekday and are approximately 60 mm in duration. Vehicle or a dose of compound are administered 30 mm to 6 hr before the start of the test session by the subcutaneous or oral route. Compound effects for each dose for each animal are calculated as a percent of the vehicle control data for that animal . The data are expressed aε the mean +. the standard error of the mean.

Example 2

Monkey Taming Model Further, the antianxiety activity of the compoundε is established by demonstrating that the compounds are effective the monkey taming model. Plotnikoff Res. Comm. Chem. Path. & Pharmacol. , 5: 128-134 (1973) described the response of rhesus monkeys to pole prodding as a method of evaluating the antiaggressive activity of a test compound. In this method, the antiaggressive activity of a compound was considered to be indicative of its antianxiety activity. Hypoactivity and ataxia were considered to be indicative of a sedative component of the compound. The present study is designed to measure the pole prod response-inhibition induced by a compound of this invention in comparison with that of a standard antianxiety compound such aε diazepam aε a meaεure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.

Male and female rhesuε or cynomologouε monkeys, selected for their aggressiveness toward a pole, are housed individually a primate colony room. Compounds or appropriate vehicle are administered orally or subcutaneously

and the animals are observed by a trained observer at varying times after drug administration. A minimum of three days (usually a week or more) elapses between treatments. Treatments are assigned m random fashion except that no monkey receives the same compound two times consecutively.

Aggressiveneεs and motor impairment are graded by response to a pole being introduced into the cage aε described m Table 1. The individuals responεible for grading the reεponseε are unaware of the dose levels received by the monkeys.

Table 1

Grading of Monkey Response to Pole Introduction

Response Grade Description Attack 2 Monkey immediately grabbed and/or bit pole as it was placed at opening cage.

Monkey grabbed and/or bit pole only after the tip was extended mto the cage

12 inches or more.

0 No grabbing or biting observed.

Pole Push 2 Monkey grabbed the pole to attack it or push it away.

Monkey touched the pole only attempting to avoid it or rode on the pole (avoidance) .

0 No pushing, grabbing or riding of

Biting 2 Monkey bit aggressively and frequently.

1 Monkey bit weakly or infrequently 0 No biting observed.

Ataxia 2 Monkey exhibited a marked losε of coordination.

Slight loεs of coordination

No effects on coordination observed.

Hypoactivity Marked: Monkey was observed a prone position. May or may not have responded by rising and moving away when experimenter approached.

Slight: Monkey did not retreat as readily when experimenter approached

None.

Antiaggression + Dose of drug was active in decreasing Activity of global assessment of aggressive behavior Drug Dose Dose of drug was not active in

decreasing aggressive behavior

Example 3

Human Clinical Trials Finally, the antianxiety activity of the named compounds can be demonstrated by human clinical trials. The study was designed as a double-blind, parallel, placebo- controlled multicenter trial. The patients are randomized into four groups, placebo and 25, 50, and 75 mg tid of test compound. The dosages are administered orally with food. Patients are observed at four visits to provide baseline measurements. Visits 5-33 served as the treatment phase for the study .

During the visits, patients and their caregivers are questioned and observed for signs of agitation, mood swings, vocal outbursts, suspiciousness, and tearfulness. Each of these behaviors are indicative of the effect of the test compound on an anxiety disorder.

For example, one study provided the following resultε:

Placebo 25 mg 50 mg 75 mg p-Value

(N=87) (N=85) (N=83) (N=87) Behavioral

Event n (%) n (%) n (%) n (%)

Agitation 40 (46) 34 (40) 24 (29) 20 (23) .006

Mood swings 40 (46) 25 (29) 21 (25) 28 (32) .025 Vocal

Outbursts 33 (38) 29 (34) 24 (29) 11 (13) .001

Suspiciousness 32 (37) 23 (27) 26 (31) 7 (8) <.001

Fearfulness 25 (29) 28 (33) 19 (23) 13 (15) .038

Treatment groups are compared with respect to the number and percent of patients who ever had the symptom during the double-blind portion of the study (visits 5 through 33) , at a severity that was worse than during the baseline visits (1 through 4) .

Some examples of compounds contemplated for use in treating anxiety include, but are not limited to: (+/-)-3- butylthio-4- (azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-oxadiazole, (+/-) -3- (2-butyloxy) -4- [ (+/-) -3-azabicyclo[2.2.2]octyloxy) - 1,2, 5-oxadiazole, (+/-) -3-butyloxy-4- [endo- (+/-)-6-[l- azabicyclo [3.2.1]octyloxy) ] -1, 2, 5-oxadiazole, 3- (2,2,3,3,4,4,4-heptaflurorobutyloxy)-4-[ (+/-) -3- (1- azabicyclo [2.2.2]octyloxy) ] -1,2, 5-oxadiazole, 3-methoxy-4- (1- azabicyclo [2.2.2] octyl-3-oxy) -1, 2, 5-oxadiazole, 3-pentylthio- 4- (1-azabicyclo[2.2.2] ocy l-3-oxy) -1,2, 5-oxadiazole, tranε-3- butyloxy-4- (2-dimethylaminocyclopentyloxy) -1,2, 5-oxadiazole, 3-butylthio-4- (3-azetidinyloxy) -1,2, 5-oxadiazole, 3- (3-N- (2- thiazolidonyl)propylthio) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) - 1, 2, 5-oxadiazole, 3-chloro-4- (1-azabicyclo[3.2.1]octyl-6- oxy) -1,2, 5-oxadiazole, 3- (2-2-thio-5- trifluoromethylthienyl) ethylthio) - -azabicyclo[2.2.2]octyl-3- oxy) -1,2, 5-oxadiazole, 3-butylthio-4- [3-±-endo- (1- azabιcyclo[2.2.1]heptyloxy) ] -1,2, 5-oxadiazole, 3-hexyloxy-4- [6-±-endo- (2-azabicyclo[2.2.2]ocyloxy) ] -1, 2 , 5-oxadiazole, 3- (4,4, 4-trifluorobutylthio) -4- [2-±-exo- (7- azabicyclo [2.2.1]heptyloxy) ] -1,2, 5-oxadiazole, 3- (2- phenoxyethylthio) - A - [3-+-endo- (1-azabicyclo[3.2.1] octyloxy) ] - 1,2, 5-oxadiazole, 3- (5-hexenyloxy) -4- [7-±-endo- (2- azabicyclo [2.2.l]heptyloxy) ] -1, 2 , 5-oxadiazole, 3-butyl-4- [5- (1-azabicyclo[3.2.1]octyloxy) ] -1,2, 5-oxadιazole, and 3- cyclobutylmethyl-4- [2-±-endo- (8-azabιcyclo [3.2.1] octyloxy) ] - 1,2, 5-oxadiazole.

The route of adminiεtration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, depot, subcutaneouε, intravenous, intramuscular or intranasal, the oral route being preferred.

Typical compositions mclude a compound of formula I or a pharmaceutically acceptable acid addition

salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed withm a carrier which can be m the form of a capsule, sachet, paper, or other contamer. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed withm a carrier which may be the form of a ampoule, capsule, sachet, paper, or other contamer. When the carrier serveε as a diluent, it may be solid, semi-εolid, or liquid material which actε as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example m a sachet. Some examples of suitable carriers are water, salt solutionε, alcohols, polyethylene glycolε, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also mclude wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed releaεe of the active ingredient after administration to the patient by employing procedures well known the art.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substanceε and the like, which do not delete lously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensionε,

preferably aqueous solutions with the active compound dissolved polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used cases where a sweetened vehicle can be employed.

Generally, the compounds are dispensed unit form comprising from about 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.

Some prefered characteristics of compounds for the treatment of anxiety are:

C) G is selected from het-1 and het-5; D) G is unsaturated;

F) G lε an azabicycle having 7 rmg carbon atoms and a nitrogen atom;

I) R is εelected from halogen, -OR ⁵ Y, -SR ⁵ Y,

-OR ⁵ ZY, -SR ⁵ ZY, -OR ⁵ ZR ⁴ , -SR ⁵ ZR ⁴ , -OR ⁴ , and -SR ⁴ ;

P) a compound of Formula I Q) a compound of Formula I'

R) a compound of Formula I wherein W is oxygen or sulphur;

R is selected from the group consisting of hydrogen, amino, halogen, NHR ⁶ , NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -S0 ₂ R ⁴ , C ₃ - ₁₀ - cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C ₃ _ιo-cycloalkyl and -Z-C ₄ -. ₁₂ - (cycloalkylalkyl ) ; R ⁴ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-i5-alkenyl, and C2-15- alkynyl , each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s) , -CF ₃ , -CN, Y, phenyl and phenoxy wherein phenyl or phenoxy iε optionally substituted with one or more selected from the group consisting of halogen, -CN, C ₁ -. ₄ - alkyl, Cι- ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ and -CSNH ₂ ; or

R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more substituents independently selected from the group consiεting of halogen, -CN, Cι- ₄ -alkyl, Ci- ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ and -CSNH ₂ ; or

R is selected from the group consisting of -OR ⁵ Y, -SR ⁵ Y,

OR ⁵ -Z-Y, -SR ⁵ ZY, -0-R ⁵ -Z-R ⁴ and -S-R ⁵ -Z-R ⁴ - ^'

Z is oxygen or sulphur; R ⁵ is selected from the group consisting of C - ₁₅ -alkyl,

C ₂ -15 ^_ alkenyl , and C2-i5-alkynyl;

Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic rmg systems:

het - 5 het - 6 het -7 or G can optionally be substituted C ₃ -C ₈ cycloalkyl wherein the substitution is -NR ⁶ R ⁷ ;

R ⁶ and R ⁷ independently are selected from the group conεisting of hydrogen and Cχ- ₆ -alkyl; or R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R ¹ and R ² independently are selected from the group consisting of hydrogen, Cι_i ₅ ~alkyl, C2-5-alkenyl, C ₂ -5- alkynyl, Ci-io-alkoxy, and Cχ-5-alkyl substituted with a subsituent independently selected from the group consiεting of -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2 , carboxy, and phenyl; R ³ is selected from the group consiεting of hydrogen, C ₁ -. ₅ - alkyl, C ₂ - ₅ -alkenyl and C ₂ - ₅ -alkynyl; R ⁶ ' is εelected from the group consisting of hydrogen and Ci- ₆ -alkyl; n is 0, 1 or 2, m is 0, 1 or 2 , p is 0, 1 or 2, q is 1 or 2; r is 0, 1 or 2; is a single or double bond; provided that when W is O and G is a saturated azabicyclic group having from 7 to 11 ring carbon atoms and a nitrogen

atom wherem the nitrogen atom is separated from the W atom by 2 to 3 rmg carbon atoms; or a pharmaceutically acceptable εalt or solvate thereof; S) The G substituent is selected from the group consiεting of

T) The G substituent is

U) R is selected from the group consisting of -SR ⁴ ', SOR ⁴ ', -S0 ₂ R ⁴ ', substituted benzyloxycarbonyl wherein the substituents are one or more independently selected from the group consisting of -CN, -OCF ₃ , -CF ₃ , -CONH and -CSNH ₂ ; or C _{3 10} -cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C3-10- cycloalkyl and -Z-C4-12- (cycloalkylalkyl) .

V) R is εelected from the group consisting of R , C3_ιo-cycloalkyl, C ₄ -12- (cycloalkylalkyl) , -Z-C ₃ - ₁₀ - cycloalkyl and -Z-C ₄ - ₁ 2- (cycloalkylalkyl) ; and

R ⁴ is selected from the group consisting of substituted C ₅ - ₁₅ - alkyl, optionally substituted C2-i ₅ -alkenyl, and optionally substituted C2-I5~alkynyl, wherein such substituent is one or more independently selected from the group consisting of

halogen(s) , -CF ₃ , -CN, Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more subεtituents selected from the group consisting of halogen, -CN, Cι_ ₄ -alkyl, Cι- ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ and -CSNH ₂ .

W) G is selected from the group consisting of het-4, het-7, het-6 wherein n=2; het-3 wherein one of n and m is 0 or 2; and het-3 wherem the I or I ' group is attached at the bridgehead of het-3.

Especially preferred compounds of this invention have the characteristics of A-F,P; A-F,Q; characteristics of A, G, H, M, F; characteristics of G-0,Q; or the characteristics of G-J,M,P; or G-J,M,Q. The characteristics of R and S may be particularly preferred.

Further, especially preferred R groups mclude phenyl, benzyloxycarbonyl, -OR ⁵ Y, -SR ⁵ Y, OR ⁵ -Z-Y, -SR ⁵ ZY, -0-R ⁴ -Z-P ⁵ or -S-R ⁴ -Z-R ⁵ , -SOR ⁴ , C ₃ -i ₀ -cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C ₃ _ιo-cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) wherein Z is oxygen or sulphur, R ⁵ is Ci- ₅ -alkyl, C2-i5-alkenyl, C ₂ -l5-alkynyl, Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, R ₄ is Cj__i ₅ -alkyl, C2- 15-alkenyl, and C2-i ₅ -alkynyl .

Further, especially preferred G groups include the following heterocycles:

; wherein the point of attachment to the ~(CH ₂ ) _r -W- group is as indicated

Some particularly preferred G groups mclude

embodiment of this invent tion!" . It is another preferre that G is not an azabicycle, particularly when W is oxygen.

Additionally, another embodiment of this invention which can be preferred is that when W is 0 and G is alkyl, R is not halogen.

The mvention will now be described further detail with reference to the following examples. The examples are provided for illustrative purposes, and are not to be construed as limiting the scope of the invention any way.

EXAMPLE 1

(+/-) -3-Butyloxy-4- (1-azabicyclof2.2.2] octyl-3-oxy:

-1,2, 5-oxadiazole

A suspension of 3 , 4-dιphenylsulfonyl-1, 2 , 5- oxadiazole oxide (4.6 g, 0.126 mol, Ref. J.Chem. Soc. 1964, 904.) m

1-butanol (400 mL) waε heated to 55-60 "C as a solution of sodium 1-butyloxιde (0.3 g Na, 40 L 1-butanol) was added dropwise. After 1 h, the solvent was evaporated, residue was treated with H ₂ O, and the mixture extracted with ether (3X) . The extracts were washed with H ₂ O, dried, and the solvent evaporated to give a white solid (3.15 g) . The solid was heated to reflux overnight in P(OCH ₃ ) ₃ (30 mL) then poured mto ιce-H ₂ 0 containing HCl (6 mL, 5N) . The mixture was extracted with ether, the extracts washed with brme, dried, and the solvent evaporated to give a yellow liquid. Radial chromatography (15% EtOAc/hexane) gave a clear liquid (1.85 g) . The liquid was dissolved m THF (30 mL) and added dropwise to a mixture prepared from 1- azabιcyclo[2.2.2]octan-3-ol (1.85 g 0.014 mol), THF (20 mL) , and 1.6 M n-butyl lithium hexane (8.4 mL, 0.013 mol) . The reaction was then warmed to 52 "C for 5 h. The cooled reaction was acidified with dilute HCl and diluted wit ether, the aqueous fraction was washed with ether, made basic, and extracted with ether. The extracts were dried and evaporated to give a clear liquid. The HCl εalt (1.4 g) cryεtallized from CHCl ₃ -EtOAc-ether, m.p. 186-188'C. (Compound 1) .