METHOD FOR TREATING ANXIETY

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

Extensive research has been conducted for a number of years directed toward the development of compounds capable of treating anxiety in 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 benzodiazepmes 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-HTI _A and dopamine receptorε.

Alfred Goodman, et al . , Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8:482 (1990); Tompkms et al . Research Communications Psychology, Psychiatry, and Behavior. 5:4, p. 338 (1980) . The art has reported that compounds which act as agonists of the cholinergic muscarinic receptor can actually produce anxiety. See, Risch et al . Psychopharmacol . Bull.. 19: 696-698 (1983) , Nurnberger et al . Psychiatry Res.. 9:191- 200 (1983) , and Nurnberger et al . Psychopharmacol. Bull., 17:80-82 (1982) .

Surprisingly, we have discovered that a group of compounds having muscarinic 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 m humans using a specified tetrahydropyridine or azabicyclic oxadiazole or thiadiazole compound. The activity of these compounds is believed to be based on agonist action at the m- 1 muscarinic cholinergic receptor.

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

wherein is oxygen or sulfur;

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 , C ₃ _ιo- 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 C2-i5-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 independently selected from the group consisting of halogen, -CN, Cι_ - alkyl, Cι- ₄ -alkoxy, -OCF3, -CF ₃ , -CONH and -CSNH ₂ ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently 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 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 Cι_i ₅ -alkyl, C ₂ -i5-alkenyl, and C2-i5-alkynyl;

Y is a 5 or 6 membered heterocyclic group; G is selected from one of the following azacyclic or azabicyclic ring systems:

or G is optionally substituted C ₃ -C ₈ cycloalkyl wherem the cycloalkyl substituents are selected from R ¹ and R ² ; or optionally 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 Ci-e-alkyl; or P 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- ₁ 5-alkyl, C2-5-alkenyl, C2-5- alkynyl, Cι_ιo-alkoxy, and Ci-5-alkyl substituted with one or more independently selected from the group consisting of -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2 , carboxy, and phenyl;

R ⁶ ' is hydrogen, Cι_6-alkyl;

R ³ is selected from the group consisting of hydrogen, Ci-s¬ alkyl, C ₂ - ₅ -alkenyl and C ₂ - ₅ -alkynyl; n is 0, 1 or 2 , p is 0, 1 or 2 q is 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

wherein is oxygen or sulfur;

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 , C ₃ - ₁₀ - cycloalkyl, C ₄ _ι ₂ - (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-l ₅ ~alkenyl and C2-l5-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 independently selected from the group consisting of halogen, -CN, C ₁ -. ₄ - alkyl, C ₁ - 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 independently 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 selected from the group consistmg 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 Ci- ₁₅ -alkyl, C2-l5-alkenyl, and C2-i5-alkynyl;

Y is a 5 or 6 membered heterocyclic group; G is selected from one of the following azacyclic or azabicyclic ring systems:

het-1 het-2 het-3 het-4

het-5 het-6 het-7 or G is optionally substituted C ₃ -C ₈ cycloalkyl wherein the cycloalkyl substituents are selected from R ¹ and R ² ; or optionally substituted Cι_ ₆ -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 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 one or more independently selected from the group consisting of -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2, carboxy, and phenyl;

R ⁶ ' is hydrogen, Cι- ₆ -alkyl; R ³ is selected from the group consisting of hydrogen, C ₁ -- ₅ - alkyl, C ₂ - ₅ -alkenyl and C ₂ - ₅ -alkynyl; n is 0, 1 or 2,- rn 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

wherein W is oxygen or sulfur;

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 , C ₃ - ₁₀ - cycloalkyl, C ₄ _ι ₂ - (cycloalkylalkyl) , -Z-C ₃ -ιo-cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) ,- R ⁴ is selected from the group consisting of Cι_ις-alkyl, ^c 2-15 ^_ 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 is optionally substituted with one or more independently selected from the group consistmg of halogen, -CN, Cι_ - alkyl, Cj -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 independently 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 selected from the group consisting of -OR ⁵ Y, -SR ⁵ Y, OR ⁵ -Z-Y, -ΞR ⁵ ZY, -0-R ⁵ -Z-R ⁴ and -S-R ⁵ -Z-R ⁴ _'

Z is oxygen or sulphur, R ⁵ is Cι_i ₅ -alkyl, C2-i5-alkenyl, and C2-i5-alkynyl;

Y is a 5 or 6 membered heterocyclic group;

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

or G is optionally substituted C ₃ -C ₈ cycloalkyl wherein the cycloalkyl substituents are selected from R ¹ and R ² ; or optionally substituted Cι- ₆ -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 ring; R ¹ and R ² independently are selected from the group consisting of hydrogen, Cι_i5-alkyl, C2-5-alkenyl, C2-5- alkynyl, Cι_ιo-alkoxy, and Ci-5-alkyl substituted with one

or more independently selected from the group consisting of -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2, carboxy, and phenyl;

R ⁶ ' is hydrogen, C _ ₆ -alkyl;

R ³ is selected from the group consisting of hydrogen, C ₁ - ₅ - alkyl, C ₂ -s-alkenyl and C ₂ - ₅ -alkynyl ^■

is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

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

wherein

W is oxygen or sulphur;

R is hydrogen, ammo, halogen, NHR ⁶ , NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -S0 ₂ R ⁴ , C ₃ _ιo-cycloalkyl, C _ ₁₂ - (cycloalkylalkyl) , -Z-C ₃ -ιo-cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) wherem R ⁴ is Cι_i ₅ -alkyl, C2-i5-alkenyl, C2-i5-alkynyl, each of which is optionally substituted with one or more halogen(s) , -CF ₃ , -CN, Y, phenyl or phenoxy wherem phenyl or phenoxy is optionally substituted with halogen, -CN, Ci- ₄ -alkyl, Cι_ ₄ -alkoxy, -OCF ₃ , -CF ₃ , -C0NH 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, -OCF3, -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 Ci-iς-alkyl, C2-15- alkenyl, C2-15-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-l het-2 het-3 het-4

R- het-5 het-6 het-7

or G can optionally be substituted C ₃ -C ₈ cycloalkyl or optionally substituted Cι- ₆ -alkyl wherein the substitution is -NR ⁶ R ⁷ _' ^'

R ⁶ 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, Ci-is-alkyl, C2-5- alkenyl, C2-5-alkynyl, Cι_ιo-alkoxy, Ci-5-alkyl substituted with -OH, -COR ⁶ ', CH ₂ -0H, halogen, -NH2, carboxy, or phenyl;

R ³ is hydrogen, Cι-5-alkyl , C ₂ - ₅ -alkenyl or C ₂ - ₅ -alkynyl , • n is 0 , 1 or 2 ;

-li ^¬

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 wherem 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 compoundε of the present invention as well as the pure diastereomeric, pure enatiomeπc, and racemic forms of the compounds of this invention. The term "antianxiety dose", as used herein, represents an amount of compound necessary to prevent or treat a human susceptible to or suffering from anxiety followmg administration to such human. The active compounds are effective over a wide dosage range. For example, dosages per day will normally fall withm 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, single or divided doses, is preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, m the light of the relevant circumstances including 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 mtended to limit the scope of the invention m any way. While the present compounds are preferably administered

orally to humans suεceptible to or suffering from anxiety, the compounds may also be administered by a variety of other routes such aε 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 in the art .

As used herein the term "treating' includeε 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.

As used herein the term "anxiety" refers to an anxiety diεorder. Examples of anxiety disorders which may preferredly be treated using an effective amount of a named compound or pharmaceutically acceptable salt thereof include, but are not limited to: Panic Attack; Agoraphobia; Acute Stresε Disorder; Specific Phobia; Panic Disorder; Psychoactive Substance Anxiety Disorder; Organic Anxiety Disorder; Obsesεive-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; Obsessive- Compulsive Anxiety Disorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS. Examples of the anxiety disorders which are most preferredly treated usmg a named compound mclude Organic Anxiety Disorder; Obseεεive-Compulsive Disorder; Posttraumatic Stress Disorder; Generalized Anxiety Disorder; and Anxiety Disorder NOS. The named anxiety disorders have been characterized the DS -IV-R. Diagnostic and Statistical Manual of Mental Disorders, Revised, 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 catagoπes. 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 in the invention are not believed to act via the GABA/benzodiazepme, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present compounds as antianxiety agents is believed to be based upon modulation of muscarinic cholinergic receptorε. However, the mechanism by which the preεent 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 substituent, the - (CH ₂ ) _r -W-thιadιazole 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 ) _r -W-thιadιazole moiety.

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 rmg" means that R ⁶ and R ⁷ are each independently hydrogen, Ci-Cβ alkyl wherein the R ⁶ and R ⁷ groupε may optionally join to form a 4- to 6-member rmg including the nitrogen. For example, optionally joined groups mclude, but are not limited to:

As used herein the phrase "interacting with a muscarinic cholinergic receptor" shall mclude compounds which block muscarinic cholinergic receptors or modulate

such receptors. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a muscarinic cholinergic receptor.

As used herein, h ⁺ is alkoxide metal wherein the term "alkoxide metal" meanε 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" meanε Cl, Br,

F, and I. Especially preferred halogens include Cl, Br, and I.

As used herein the phrase "one or more selected from" shall more preferredly refer to from 1-3 substituents. The term shall further preferredly refer to from 1-2 substituents.

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-Cς alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso¬ 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 groupε include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, and the like.

The terms "halogen ( Cι-C _& ) alkyl' and "halogen(C - Cβ) alkenyl" refer to alkyl or alkenyl substituents having one or more independently selected halogen atoms attached at one or more available carbon atoms. Theεe terms mclude, but are not limited to, chloromethyl, 1-bromoethyl, 2-bromoethyl, 1, 1, 1-trιfluoroethyl, 1, 1, 2-trιfluoroethyl, 1,2,2- trifluoroethyl, 2, 2, 2-trιfluoroethyl, trifiuoromethyl, trifluoroethylenyl, 3-bromopropyl, 3-bromo-1-propenyl, 2- bromopropyl, 2-bromo-1-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 "C2-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 " (Ci-Cg alkyl) ammo" refers to a monoalkylammo group. Examples of such groups are methylamino, ethylamino, iso-propylammo, n-propylammo, ( n- propyl)ammo, (iso-propyl)ammo, n-propylammo, t-butylammo, 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(Cs-C _n ■ ) cycloalkyl" refers to a cycloalkyl group aε deεcribed supra wherein the cycloalkyl group may be εubεtituted with from one to four εubstituents independently selected from the group consisting of hydrogen, ι~C alkyl, N0 , halogen, halogen(Ci-Cδ) alkyl, halogen(C ₂ - C ₆ )alkenyl, C ₂ -C6 alkenyl, C0 ₂ R ² °. (Cι-C ₃ alkyl) ammo, -SR ²⁰ , and OR ²⁰ ; wherein R ²⁰ is selected from the group consiεting of Cι- ₁₅ -alkyl, C2-i5-alkenyl, C2-i5~alkynyl . The term "C ₃ -C ₈ cycloalkyl- (C ₁ -C ₃ )alkyl" represents an alkyl group substituted at a terminal carbon with a C ₃ -C ₈ cycloalkyl group. Typical cycloalkylalkyl groups mclude

cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.

The term "C ₅ -C8 cycloalkenyl" represents an olefinically unsaturated ring having five to eight carbon atoms. Such groups include, but are not limited to, cyclohexyl-1, 3-dienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexyl-1, -dienyl, cycloheptyl-1, 4-dienyl, 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-Cβ alkyl, N0 ₂ , halogen, halogen(C ₁ -C ₆ ) alkyl, halogen(C -Cg)alkenyl, C ₂ -C ₆ alkenyl, COR ²⁰ , C ₂ -Cι ₀ alkanoyl, C ₇ -C ₁₆ arylalkyl, CO ₂ R ²⁰ , (Ci-Cβ alkyl) amino, -SR ²⁰ , and

-OR ²⁰ ; wherein R ²⁰ is selected from the group consiεting of Ci- ₁₅ -alkyl, C2-i5-alkenyl, and C2-l5-alkynyl .

The term "C ₅ -C ₈ cycloalkenyl- (C ₁ -C )alkyl" represents a C ₁ -C ₃ alkyl group substituted at a terminal carbon with a C ₅ -C ₈ cycloalkenyl group.

As used herein, the phrase "5 or 6 membered heterocyclic group" meanε a group containing from one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with Ci-g-alkyl, -CF3 , phenyl, benzyl or thienyl, or a carbon atom in 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" includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans) ; 5-membered heterocycles having two heteroatomε m 1,2 or 1,3 positions (e.g. oxazoles, pyrazoleε, imidazoleε, thiazoles, purines); 5-membered heterocycles having three heteroatomε (e.g. triazoles, thiadiazoleε) ; 5-membered heterocycles having 3-heteroatoms; 6-membered heterocycles

with one heteroatom (e.g. pyridme, quinoline, lsoqu olme, phenanthr e, 5, 6-cycloheptenopyrιdme) ; 6- membered heterocycles with two heteroatoms (e.g. pyπdazineε, c nolmes, phthalazines, pyrazmes, pyrimidines, qu azolmes) ; 6-membered heterocycles with three heteroatomε (e.g. 1, 3 , 5-trιazme) ; and 6-member heterocycles with four heteroatoms. Particularly preferred are thiopheneε, pyridmeε, and furans.

As used herein the term "carboxy" refers to a substituent 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 uεed herein the term "aryl" meanε an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g., phenyl or naphthyl. Most preferably, aryl refers to Cβ-Cio aryl, wherein the aryl ring system, mcludmg any alkyl substitutions, compriseε from 6 to 10 carbon atomε; e.g., phenyl, 3 ,3-dιmethylphenyl, naphthyl, and the like. The aryl radical may be subεtituted by one or two C -Cξ straight or branched alkyl. The term

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

As used herein the term "phosphorous (III) compound" has the art accepted meaning of the term. For example, the term includes, but is no way limited to, triphenylphosphine, tri (p-toluyl) phoεphme, tributyl phosphine, tri (p-dimethylaminiophenyl) phosphine, triethyl phosphine, and trimethyl phosphine. The artisan can choose other appropriate phosphorouε (III) compounds usmg methods and literature references which are commonly available to the chemist artisan.

As used herein the term "diester of azodicarboxylate" has the art accepted meaning of the term. For example, the term includes, but is m no way limited to diethylazodicarboxylate, dimethylazodicarboxylate, dnsopropylazodicarboxylate, and di- tertbutylazodicarboxylate. The skilled chemist can

determme other appropriate dieεterε of azodicarboxylate using methods and literature readily available to the chemist artisan.

Examples of pharmaceutically acceptable 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, and mclude the pharmaceutically acceptable salts listed Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form εolvateε with εtandard low molecular weight εolvents usmg methods known to the εkilled artiεan.

The compoundε of this invention can be prepared using the chemical processes illustrated Scheme I. The starting materials for the illustrated procesε are commercially available or may be prepared using methods known to the εkilled artiεan.

Schβme I

As used in Scheme I, R, h ⁺ , and G are as defined supra . As used in Scheme I, the term "Hal" refers to Cl, Br, and R ⁹ S0 ₂ . Preferred oxidizing agents for the process of Scheme I include oxone and sodium periodate. Oxone is an especially preferred oxidizing agent for the procesε of Scheme I. Compounds of Formula 3, as illustrated in Scheme I wherein the OR group is replaced by an R ⁴ group, can be prepared using methods well known in the art. 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 II

Scheme II

ize

As used in Scheme II, Q may be N, O or S; R ²⁴ is selected from the group consisting of hydrogen, R ⁴ , R ⁵ , R ⁶ , and R ^{7 ;} R ²⁵ is εelected from the group conεiεting of SOR ⁴ and S0 ₂ R ⁴ ; all other meaningε are as defined supra .

Additional compounds of Formula I may be prepared using the procesε illustrated by Scheme III.

Scheme III

reduction

Aε uεed m Scheme III, Hal, W, r, and G are as defmed supra . As used in Scheme III, R ²² and R ²³ are independently selected from the group consistmg of hydrogen, R ⁶ and R ⁷ .

Certam intermediates of the present invention may be prepared using the procesε illustrated m Scheme IV.

Scheme IV

10

1 HCl

2 Nitrosatc Cu(Br,I)

11

As used Scheme IV, R ⁸ , Si, R ¹⁰ ,R ^1:L , R ¹² , R ¹³ ,

P ¹⁴ , R ^1R ', R ¹⁵ and R ¹⁶ are as defined supra . For example, R ⁸ N[ (R ¹⁰ R ^ι;L R ¹² Sι) (R ¹³ R ¹⁴ R ¹⁵ 'Sι) may be, but is not limited to lithium bis (trι-2-propylsιlyl) amide, sodium bis (trimethylsilyl)amide, potassium bis (trimethylsilyl)amide, lithium bιs(trι-2- propylεilyl) amide, εodium bis (ethyldimethylsilyl) amide, potassium bis (1-propylethylmethylsιlyl)amide, lithium bis (tri-phenylεilyl)amide, sodium bisftri- phenylmethylεilyl)amide, potaεsiu bis (2-butyl-2- propylmethylsilyl)amide, lithium (trι-2-propylsιlyl) (2- butyldiethylεilyl)amide, εodium

(trimethylsilyl) (triphenylsilyl)amide, potassium (dimethyl phenylsilyl) (ethyldimethylεilyl) amide, and the like Most

preferably, R ¹⁵ and R ¹⁶ are each hydrogen when the process of Scheme III is used for preparing a compound of 11 from a compound of 10. The intermediate 10 may be nitrosated using standard nitrosatmg procedures. A preferred nitrosatmg agent is isoamyl nitrite; however, other known nitrosatmg agentε are appropriate. Aε used in Scheme III, the term "Cu(Br,D " refers to copper (I) bromide, copper (II) bromide, or copper (I) iodide. The artisan will recognize that the copper (I) bromide, copper (II) bromide, or copper (I) iodide reagent shall determme the substitution on the product of the proceεε illustrated m Scheme III.

Certam compounds of this invention may more preferably be prepared by a proceεs using a hydroxyalkylamme (G-OH) wherem G has the meaning defmed supra , the presence of a phosphorus (III) compound and a diester of azodicarboxylate to give the 1, 2, 5-thιadιazoyloxyalkylamme as illustrated by Scheme V.

Scheme V

The G groups are as defmed supra. The R'IS selected from the group consisting of hydrogen, halogen, NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -S0 ₂ R ⁴ , C ₃ -io-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C3--ιo-cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) ;

R ⁴ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-I5~alkenyl, C2-I5~alkynyl, each of which is optionally substituted with one or more independently selected from the group consiεting of halogen(ε), -CF ₃ , -CN, Y, phenyl

and phenoxy wherein phenyl or phenoxy is optionally substituted with one or more independently selected from the group consisting of halogen, -CN, Cχ- ₄ -alkyl, C ₁ -- ₄ - alkoxy, -OCF ₃ , or -CF ₃ ; or R ¹ is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more independently selected from the group consistmg of halogen, -CN, C _ ₄ - alkyl, Cι- ₄ -alkoxy, -OCF ₃ , and -CF ₃ ; or

R' selected from the group consiεting of -OR ⁵ Y, -ΞR 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 consiεting of Cι- ₁₅ -alkyl, ^c ₂ -15 ^_ alkenyl, and C2-l5~alkynyl;

Y is a 5 or 6 membered heterocyclic group; R ¹ ' is selected from the group consisting of phenyl, C -. ₅ - alkyl, C2-5-alkenyl, C2-5-alkynyl and (NR ² ') ₃ ;

R ' and R ³ ' are independently selected from the group consisting of hydrogen, Cι- ₁₅ -alkyl, C2-5~alkenyl, C2-5- alkynyl, and C1-5-alkyl substituted with one or more selected from the group consisting of halogen and phenyl;

W is oxygen or sulphur;

R ⁶ , and R ⁷ independently are Ci-g-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 are independently selected from hydrogen, C ₁ - ₁₅ - alkyl, C2-5-alkenyl, C2-5-alkynyl, C - ₁₀ -alkoxy, and C1-5- alkyl substituted with one or more independently selected from the group consisting of -COR ⁶ ', halogen, and phenyl;

R ⁶ ' is hydrogen or C ₁ -C ₃ alkyl; R ³ is εelected from the group consisting of Cι- ₅ -alkyl, C ₂ _

₅ -alkenyl and C ₂ - ₅ -alkynyl;

r is 0, 1 or 2;

is a single or double bond.

Preferred R ^{1 '} groups include phenyl, Cι- ₁₅ -alkyl, and (NR ² ') ₃ . The procesε of Scheme IV iε particularly advantageous becauεe the proceεs provides a method for inverting the εtereochemiεtry at the carbon bearing the hydroxyl group in G.

Another new process illustrated by Scheme VI, involves the εequential reaction of 3 , 4-dihydroxy-l, 2 , 5- thiadiazole with G-OH wherein G iε defined as defined supra . in the presence of a phosphorouε (III) compounds and a diester of azodicarboxylate to give an unisolated hydroxy-1, 2 , 5- thiadiazole ether I ¹ ' followed by reaction of I' ¹ with R ⁴ OH where R ⁴ iε defined as supra , with phosphorous (III) compounds and a diester of azodicarboxylate to give the diethers of 3 , 4-dihydroxy-1, 2, 5-thiadiazole which are uεeful aε muεcarinic agoniεtε and antagonists. (See, Org . Prep . & Procedureε 1969, 1 , 255-258) The subεtituentε illustrated in Scheme VI are as defined supra .

Scheme VI

Alternatively, the order of addition of the alcohols may be reversed as shown above to give unisolated hydroxy-1, 2 , 5-thiadiazole ether II which is εubsequently converted to the same final muscarinic active compound.

The process illustrated by Scheme VII encompases the reaction of a phenol or hydroxyheteroaryl compound with compound III in the presence of a phosphorus (III) compound and a diester of azodicarboxylate to give compound IV.

Scheme VII

Aryl—OH

l )

In compound III, G(CH ₂ ) _r W is as defmed supra , and R ⁶ ' is selected from the group consisting of R ⁷ , -OR ⁷ , -SR ⁷ , -SOR ⁷ , -S0 ₂ R ⁷ , C3_ιo-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -z- C ₃ -ιo ^_ cycloalkyl and -Z-C ₄ - ₁₂ - (cycloalkylalkyl) ; R ⁷ is Cι- ₁₅ -alkyl, C2-i5~alkenyl, C2-l5-alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(ε), -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, Cι- ₄ -alkyl, Cι_ ₄ -alkoxy, -OCF ₃ , and -CF ₃ ; provided that at least one alkyl atom of R ⁶ ' is substituted with a hydroxyl group or R ⁶ 'ιs a substituent selected from the group consisting of -OR ⁸ Y, -SR ⁸ Y, OR ⁸ -Z-Y, -SR ⁸ ZY, -O-R ⁸ - Z-R ⁷ and -S-R ⁸ -Z-R ⁷ wherein each -OR ⁸ Y, -SR ⁸ Y, OR ⁸ -Z-Y, -SR ⁸ ZY, -0-R ⁸ -Z-R ⁷ and -S-R ⁸ -Z-R ⁷ is substituted with a alkylhydroxy1; Y is a 5 or 6 membered heterocyclic group; Z is oxygen or sulphur; R ⁸ is Cι- ₁₅ -alkyl, C2-i5-alkenyl, C2-i5-alkynyl; aryl and heteroaryl iε optionally εubstituted with one or more independently selected from the group consisting of halogen, -CN, Cι- ₄ -alkyl, Cι- ₄ -alkoxy, Cι- ₄ -alkylthιo, C ₁ -. ₄ - alkylsulfone, Cι- ₄ -alkylsulfoxide, -OCF ₃ , N0 ₂ , N(R ⁷ ) ₂ , and -CF ₃ ; heteroaryl group is a 5 or 6 membered heterocycle

contammg one to four N, 0, or S atoms or a combination thereof.

Another process of this invention, illustrated by Scheme VIII, is the synthesis of 3-hydroxy-4-alkylthιo-l, 2, 5- thiadiazoles by treating 3-halo-4-alkylthιo-l, 2 , 5- thiadiazoles with aqueous alkaline metal hydroxides the presence or absence of a dipolar aprotic solvent. In this scheme, Hal has the meanings defined supra , and M is an alkali metal, is 0 or Ξ.

Scheme VIII

R ^R is hydrogen, R , C ₃ -ιo-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl), R ⁴ -Z-C ₃ _ o-cycloalkyl and R ⁴ -Z-C ₄ _ι - (cycloalkylalkyl) ;

R ⁴ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-15 ^_ alkenyl, and C2-I5~alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s) , -CF ₃ , Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, Cι_ ₄ -alkyl, Cι- ₄ -alkoxy, and -CF ₃ ; or

R ^R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, Cι- ₄ -alkyl, C _ ₄ -alkoxy, and

-CF ₃ ; or

R ^R is R -OR ⁵ Y, R ⁴ -SR ⁵ Y, R ⁴ -OR ⁵ -Z-Y, R -SR ⁵ ZY, R -0-R ⁵ -Z-R ⁴ or R -S-R ⁵ -Z-; Z is oxygen or sulphur;

R ⁵ is selected from the group consisting of Cι_ ₅ -alkyl,

C2-l5-alkenyl, and C2-i5-alkynyl;

Y lε a 5 or 6 membered heterocyclic group; and

R ⁶ , 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- ₁₅ -alkyl, C2-5- alkenyl, C2-5-alkynyl, Cι_ιo-alkoxy, Cι-5-alkyl substituted with -OH, -COR ^6' , CH -OH, halogen, -NH2, carboxy, or phenyl;

R ⁶ ' is hydrogen or C ₁ -C ₃ alkyl; Hal is selected from Cl, Br, F, I, and if W is O then Hal may be S0 ₂ R ⁴ ' ; R ⁴ ' is C ₁ -C ₃ alkyl or phenyl.

The compounds (11) are useful intermediates for the preparation of 1, 2 , 5-thiadiazole compounds. The artisan will recognize that the intermediates 11 are useful for preparing 1, 2 , 5-thιadιazole compounds as illustrated by the procesεes of Schemes I, II, and III.

When the G substituent contams a secondary nitrogen protected by a protecting group, the protecting group may be removed using εtandard methodε known to the skilled artisan. An especially preferred protecting group is carbamate. One particularly useful reference concerning protecting groups is Greene, Protecting Groups Organic Synthesis , (John Wiley & Sons, New York, 1981) .

The concentration of the reactants is not critical. The art worker can alter the concentration of the reactants to achieve the deεired rate of reaction and prodαct yield. The length of time for carrying out the processes described are not critical. As is alwayε the case in chemistry, the rate of the reaction depends on a variety of factors, such as the temperature and the exact compound which is to be prepared. The course of the reaction may be followed using methods such as thin layer chromatography (TLC) , high performance liquid chromatography (HPLC) , gas

chromatography (GC) and nuclear magnetic resonance spectroscopy (NMR) to detect the degree of completion of the reaction. The operator may obtain maximum yields using the procesε by extendmg the reaction time. Alternatively, the operator may wish to obtain maximum throughput by cutting off the reaction at the point at which it reaches an economical degree of completion.

When the product of a step the following procesε is an oil, it may be iεolated by εtandard methodε. Such methods include distillation, flash chromatography, HPLC and the like.

The pharmacological properties of the compounds of the mvention can be illustrated by determining their capability to inhibit the specific binding of ³ H- Oxotremorine-M ( ³ H-Oxo) . Birdsdall N.J.M., Hulme E.C., and Burgen A.S.V. (1980) . "The Character of Muεcarinic Receptors m Different Regions of the Rat Brain". Proc. Roy. Soc. London (Series B) 207,1.

³ H-Oxo labels muscarinic receptor in the CNS

(with a preference for agonist domains of the receptors) . Three different siteε are labeled by ³ H-Oxo. Theεe εiteε have affinity of 1.8, 20 and 3000 nM, reεpectively. 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 muscarinic 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) iε homogenized for 5-10 seconds in 10 mL 20 nM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is 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 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 25 μL of test solution and 25 μL of ³ H-Oxotremorme (1.0 nM, final concentration) mixed and incubated for 30 mm. at 25°C. Non-specific binding is determined m triplicate using arecolme (1 μg/mL, final concentration) as the test substance. After incubation samples are added 5 mL of ice- cold buffer and poured directly onto Whatman GF/C glasε fiber filters under suction and immediately washed 2 times with 5 mL of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation countmg. Specific binding is total binding minus non specific binding.

Test subεtanceε are dissolved m 10 mL water (if necessary heated on a steam-bath for lesε 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 teεt 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 subεtance concentration) x(C _x /C ₀ -C _x )nM where C ₀ is specific binding in control assays and C _x is the specific binding the test asεay. (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 (pirenzepme, [N-methyl- ³ H] ) binding to rat cerebral cortex membranes.

Pirenzepme binds selectively to subtype of muscarinic receptorε. Hiεtorically the type is named the

Mι-sιte, whereaε pirenzepme sensitive site would be more appropriate. Although selective for Mi-sites pirenzepme also interact with M ₂ -sιtes.

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 ε in 10 mL 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 2 x 10 mL of buffer and the combined suspension centrifuged for 15 min. 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 L 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 determined in triplicate using atrop e (1 ,μg/mL, final cone.) as the test subεtance . 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 determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.

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

The followmg Examples are studies to establish the uεefulneεs of the named compounds for treating anxiety.

Example 1

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

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 presentation only. In a second component, responding produces both food pellet presentation and is alεo punished by presentation of a brief electric shock. Each component of the multiple schedule is approximately 4 minutes duration, and the shock duration is approximately 0.3 seconds. The shock intensity is adjusted for each individual animal so that the rate of punished responding is approximately 15 to 30% of the rate the unpunished component of the multiple schedule. Seεεionε are conducted each weekday and are approximately 60 mm in duration. Vehicle or a doεe of compound are administered 30 mm to 6 hr before the start of the test session by the subcutaneous or oral route. Compound effectε for each doεe for each animal are calculated aε a percent of the vehicle control data for that animal. The data are expreεεed aε the mean +. the standard error of the mean.

Example 2

Monkey Taming Model Further, the antianxiety activity of the compounds is established by demonstrating that the compounds are effective in 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 waε 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 εuch as diazepam as a measure of antiaggressive potential, and to obtain an indication of the duration of action of the compound.

Male and female rhesus or cynomologous monkeys, selected for their aggreεεiveness toward a pole, are housed individually m 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) elapseε between treatmentε. Treatments are assigned in random fashion except that no monkey receives the same compound two times consecutively.

Aggreεεiveneεs and motor impairment are graded by response to a pole being introduced mto the cage as described Table 1. The individuals responsible for grading the responεes are unaware of the doεe 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 aε it was placed at opening m cage.

Monkey grabbed and/or bit pole only after the tip was extended into 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 m attempting to avoid it or rode on the pole (avoidance) .

0 No pushing, grabbing or ridmg of

Biting 2 Monkey bit aggressively and frequently.

1 Monkey bit weakly or infrequently 0 No bitmg observed.

Ataxia 2 Monkey exhibited a marked loss of coordination.

1 Slight loss of coordination

0 No effects on coordination observed.

Hypoactivity Marked: Monkey was observed in 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 waε active n decreasing Activity of global assessment of aggressive behavior Drug Dose Dose of drug was not active m 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 deεigned 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 teεt compound. The doεages are administered orally with food. Patients are observed at four visits to provide baseline meaεurementε . Visits 5-33 served as the treatment phase for the study.

During the visits, patients and their caregivers are queεtioned and observed for εignε of agitation, mood swings, vocal outbursts, suεpiciouεneεε, and fearfulneεε.

Each of these behaviors are indicative of the effect of the test compound on an anxiety disorder.

For example , one study provided the followmg results :

P l ac ebo 25 mg 50 mg 75 mg p - Va l u e

(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

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

Fearfulneεs 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) .

The compoundε of the mvention are effective over a wide dosage range. For example, m the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to about 70 mg per day. In choosing a regimen for patients suffering from anxiety it may frequently be neceεεary to begin with a dosage of from about 20 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 0.1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, form m which administered, the εubject to be treated and the body weight of the subject to be treated, and the preference and experience of the phyεician or prescribing caregiver in charge.

The route of administration may be any route, which effectively tranεportε the active compound to the appropriate or deεired site of action, such aε oral or parenteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.

Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, asεociated 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 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 m the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves aε a diluent, it may be solid, semi-solid, or liquid material which acts as a

vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid contamer for example in a sachet. Some examples of suitable carriers are water, salt solutionε, alcohols, polyethylene glycols, 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 εo aε to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

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

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutionε with the active compound diεsolved m polyhydroxylated castor oil.

Tablets, drageeε, 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 mclude lactose, corn starch, and/or potato starch. A syrup or elixir can be used m cases where a sweetened vehicle can be employed.

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

The compounds of this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animalε εuch aε wildlife. More preferredly, the animal lε a vertebrate. Most preferredly, a compound of this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administered as a feed additive.

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

EXAMPLE 1 3-Chloro-4- (1-butylthιo) -1.2 , 5-thιadιazole

Cyanogen (36 g, 0.69 mol) was bubbled into ether (250 mL) maintained at -10°C. To the solution was added dropwise diethylamine (3 mL) followed by dropwise addition of 1-butylthιol (47 mL, 0.64 mol) at such a rate that the temperature did not exceed -5°C. The reaction was maintained below 0°C for 5 h then stirred at ambient overnight. Ether was distilled from the reaction until the pot temperature reached 50°C. The reaction was cooled to ambient and then added dropwise to a solution of sulfur monochloride (55 mL, 0.688 mol) in DMF (50 mL) that was cooled to 5°C . Cooling was removed and reaction was stirred overnight. The reaction was cooled in an ice-water bath and excess sulfur monochloride destroyed by careful addition of H2O while maintaining the temperature below 40°C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous

fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H ₂ 0, aqueous aHC0 ₃ , brine, dried, and the solvent evaporated. The residue was distilled at 2 mm Hg to give a yellow liquid (24.6 g) , b.p. 105-110°C. (Compound 1) .

EXAMPLE 2

3-Chloro-4-butylsulfonyl-1, 2, 5-thιadιazole

A solution of Oxone™ (12 g, 0.0195 mol) in H ₂ 0

(60 mL) was vigorous stirred as 3-chloro-4-butylthιo-l, 2, 5- thiadiazole (2.1 g, 0.01 mol) in THF (30 mL) was added dropwise. After 24 h, the THF was evaporated and the residue extracted with ether (3X) . Extracts were washed with H ₂ O, dried, and solvent evaporated to give a clear liquid. Radial chromatography eluting with 30 % EtOAc/hexane gave a colorless liquid (2.3 g) . (Compound 2) .

EXAMPLE 3 3-Chloro-4-ethylthιo-l.2.5-thιadιazole

Cyanogen (36 g, 0.69 mol) was bubbled mto ether (250 mL) maintained at -10°C. To the solution was added dropwise diethylamine (3 mL) followed by dropwise addition of ethanethiol (47 mL, 0.64 mol) at such a rate that the temperature did not exceed -5°C. The reaction was maintained below 0°C for 5 h then εtirred at ambient temperature overnight. Ether waε distilled from the reaction until the pot temperature reached 50°C. The reaction was cooled to ambient and then added dropwiεe to a solution of sulfur monochloride (125 mL, 1.56 mol) DMF (150 mL) that was cooled to 5°C. Cooling was removed and the reaction waε stirred overnight. The reaction was cooled an EtOH-ice bath as the excess sulfur monochloride waε deεtroyed by dropwiεe addition of water while maintaining the temperature below 35°C. The liquid waε decanted from the semi-solid sulfur precipitant and the sulfur residue

triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H ₂ O, aqueous NaHCθ ₃ , brine, dried, and the solvent evaporated. The brown liquid residue was distilled at 3 mm Hg to give a yellow liquid (80.2 g) , b.p. 91-96°C. (Compound 3 ) .

EXAMPLE 4

3-Chloro-4-ethylsulfonyl-1, 2, 5-thιadιazole

A solution of Oxone (84 g, 0.137 mol) in H ₂ 0 (400 mL) was rapidly stirred as 3-chloro-4-ethylthιo-l,2, 5- thiadiazole (12.2 g, 0.067 mol) m THF (200 mL) was added. After stirring overnight, the THF was evaporated and the residue extracted with ether (3X) . The extracts were washed with H ₂ O, aqueous NaHCθ ₃ , and brine then the solvent dried and evaporated to give a clear liquid (13.6 g) . (Compound 4) .

EXAMPLE 5

(±) -3-Methoxy-4- (1-azabιcvclo[2.2.21 octyl-3-oxy) -

1,2, 5-thιadiazole

A solution of 1-azabιcyclo[2.2.2]octan-3-ol (1.36 g, 0.0104 mol) THF (20 mL) was treated dropwise with 1.6 M n-butyllithium m hexane (7.4 mL, 0.0118 mol) . To this solution was added 3-methoxy-4-methanesulfonyl- 1,2,5-thιadιazole (2.08 g, 0.0107 mol) in THF (40 mL) , the reaction heated to 40°C for 2 h, and then stirred at ambient temperature overnight. The solvent was evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueouε solution was made baεic and extracted with EtOAc. The extracts were washed with H ₂ O, dried, and the solvent evaporated. The residue was purified by radial chromatography (2.5 % EtOH-0.25 % NH ₄ OH- CHCI ₃ ) to give a clear oil. The HCl salt of the oil (0.85

g) crystallized from MeOH-EtOAc, m.p. 197-198°C. (Compound 5) .

EXAMPLE 6 (±) -3-Ethoxy-4- (l-azabιcvclor2.2.21octyl-3-oxy) -

1.2, 5-thιadιazole

A solution of 1-azabιcyclo [2.2.2]octan-3-ol (0.75 g, 0.0059 mol) in THF (50 mL) waε treated dropwise with 1.6 M n-butyllithium in hexane (3.7 mL, 0.0059 mol) . To this solution was added 3-ethoxy-4-methanesulfonyl- 1,2, 5-thιadιazole (1.0 g, 0.0048 mol) in THF (12 mL) and the reaction heated to 60°C for 5 h. The εolvent waε evaporated, the reεidue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted with ether. The extracts were washed with H ₂ 0, dried, and the solvent evaporated to give a clear oil. The HCl salt of the oil (0.47 g) crystallized from 2- propanol, m.p. 212-213°C. (Compound 6) .

EXAMPLE 7 (±) -3-Propyloxy-4- (1-azabιcvclof2.2.21 octyl-3-oxy) -

1,2, 5-thiadiazole

A solution of 1-azabιcyclo[2.2.2]octan-3-ol (1.1 g, 0.0087 mol) THF (75 mL) was treated dropwise with 1.6 M n-butyllithium hexane (5.0 mL, 0.008 mol) . To this solution was added 3-propyloxy-4-methanesulfonyl-l, 2, 5- thiadiazole (1.3 g, 0.0059 mol) in THF (15 mL) and the reaction heated to 60°C for 4 h. The solvent was evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted with EtOAc. The extracts were washed with H ₂ O, dried, and the solvent evaporated to give a clear oil. The HCl salt of the oil (0.59 g) crystallized from 2- propanol, m.p. 218-219°C. (Compound 7) .

-42- EXAMPLE 8

(±) -3-Butyloxy-4- (1-azabιcvclo \ 2 . 2 . 21octyl-3-oxy) -

1.2.5-thπadιazole

A εolution of 1-azabιcyclo[2.2.2] octan- -ol (2.2 g, 0.0168 mol) THF (25 mL) waε treated dropwise with 1.6 M n-butyllithium m hexane (10.8 mL, 0.0173 mol) . To this solution was added 3-butyloxy-4-methanesulfonyl-l, 2, 5- thiadiazole (1.98 g, 0.084 mol) in THF (25 mL) and the reaction heated to 52°C for 3.5 h. The solvent was evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted with EtOAc. The extracts were washed with H ₂ 0, dried, and the solvent evaporated to give a clear oil. The HCl salt of the oil (2.0 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 204-205°C. (Compound 8) .

EXAMPLE 9

(±) -3-Pentyloxy-4- (1 -azabicvclo [2.2.21octyl-3-oxy) - 1,2, 5-thιadιazole

A solution of 1-azabιcyclo[2.2.2]octan-3-ol (0.75 g, 0.0059 mol) in THF (50 mL) was treated dropwise with 1.6 M n-butyllithium in hexane (3.7 mL, 0.0059 mol) . To this solution was added 3-pentyloxy-4-methanesulfonyl-

1,2, 5-thιadιazole (1.0 g, 0.004 mol) in THF (10 mL) and the reaction heated to 60°C for 4 h. The solvent was evaporated, the reεidue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted with ether. The extracts were washed with H ₂ 0, dried, and the solvent evaporated to give a clear oil. The HCl salt of the oil (0.75 g) crystallized from EtOAc, m.p. 171-172°C. (Compound 9) .

EXAMPLE 10

(±) -3-Hexyloxy-4- (1-azabιcvclo[2.2.21 octyl-3-oxy) -

1.2, 5-thιadιazole

A solution of 1-azabιcyclo [2.2.2]octan-3-ol (2.2 g, 0.0168 mol) in THF (25 mL) was treated dropwise with 1.6 M n-butyllithium hexane (10.8 mL, 0.0173 mol) . To this solution was added 3-hexyloxy-4-methanesulfonyl-1, 2, 5- thiadiazole (2.2 g, 0.004 mol) in THF (25 mL) and the reaction heated to 52°C for 3.5 h. The solvent was evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted with ether. The extracts were washed with H ₂ 0, dried, and the solvent evaporated to give a clear oil. The HCl salt of the oil (1.76 g) crystallized from EtOAc, m.p. 165-166°C. (Compound 10) .

EXAMPLE 11

(±) -3- (4-Methylpentyloxy) -4- (1-azabιcvclo [2.2.21 - octyl-3-oxy) -1.2.5-thiadiazole

A εolution of 1-azabιcyclo [2.2.2 ] octan-3 -ol (0.75 g, 0.0059 mol) in THF (50 mL) waε treated dropwiεe with 1.6 M n-butyllithium in hexane (3.7 mL, 0.0059 mol) . To this solution was added 3- (4-methylpentyloxy) -4- methaneεulfonyl-1, 2, 5-thiadiazole (1.2 g, 0.0045 mol) in THF (10 mL) and the reaction heated to reflux for 6 h. The solvent waε evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueouε solution waε made baεic and extracted with ether. The extracts were washed with H ₂ 0, dried, and the solvent evaporated to give a clear oil. The HCl salt of the oil (1.1 g) crystallized from EtOAc, m.p. 179-180°C. (Compound 11) .

EXAMPLE 12

(±) -3-Chloro-4- (l-azabιcvclof2.2.21octyl-3-oxy) - 1,2, 5-thιadιazole

A solution of 1-azabιcyclo[2.2.2]octan-3-ol (1.1 g, 0.0084 mol) THF (25 mL) was treated dropwise with 1.6 M n-butyllithium in hexane (5.4 mL, 0.0086 mol) . This solution was added dropwise to a solution of 3-chloro-4- butylsulfonyl-1, 2, 5-thιadιazole (2.1 g, 0.0086 mol) THF (15 mL) at such a rate that the temperature did not exceed 32°C. After stirring for 3 days, the reaction was treated with H ₂ 0 (10 mL) , diluted with ether (100 mL) , and extracted with 1 N HCl (25 mL) . The aqueous solution waε washed with ether, made basic, and extracted with ether. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (2.5 % EtOH-0.25 % NH ₄ OH-CHCI ₃ ) to give a straw colored liquid (1.1 g) . The oxalate salt (0.39 g) crystallized from MeOH-EtOAc, m.p. 154-156°C. (Compound 12) .

Alternative synthesis of (±) -3 -Chloro-4- (1- azabicvclo[2.2.21octyl-3-oxy) -1.2.5-thiadiazole:

A solution of 1-azabιcyclo [2.2.2] octan-3-ol (1.2 g, 0.0092 mol) in THF (25 mL) was treated dropwise with 1.6 M n-butyllithium in hexane (5.9 mL, 0.0095 mol) . The εolution was cooled to -8°C and a solution of 3-chloro-4- ethylεulfonyl-l,2,5-thιadιazole (1.83 g, 0.0086 mol) in THF (15 mL) waε added dropwise. After 15 mm, cooling was removed and the reaction stirred overnight. The reaction was treated with H ₂ 0 (10 mL) , diluted with ether (100 mL) , and extracted with 1 N HCl (25 mL) . The aqueous solution was washed with ether, made basic, and extracted with ether. The extracts were dried and the εolvent evaporated to give crude (compound 12) (1.05 g) as a brownish liquid.

Alternative synthesis of (±) -3-Chloro-4- (1- azabicvclo [2.2.21octyl-3-oxy) -1.2, 5-thiadiazole:

A mixture of 1-azabιcyclo[2.2.2]octan-3-ol (12.7 g, 0.1 mol), triethylamine (0.3 mL), and CHCI ₃ (150 mL) was cooled to 5°C and cyanogen (7.25 g, 0.139 mol) bubbled mto the mixture. The reaction was stirred another hour then allowed to come to ambient temperature overnight. The solvent was evaporated, the residue dissolved DMF (20 mL), and the solution added dropwiεe to a solution of S ₂ C1 (47.3 g, 0.35 mol) in DMF (30 mL) that waε cooled in an ice-water bath. After addition, cooling was removed and reaction exothermed to 32°C. After 5 h, reaction cooled and excess S ₂ C1 ₂ destroyed by careful addition of H ₂ 0. The reaction was diluted with more H ₂ O (300 mL) and the aqueous solution decanted from the sulfur residue. The sulfur reεidue was triturated with H ₂ O and the combined aqueous solutions evaporated to a small volume (150 mL) . The solution was washed with ether and then made basic with 50 % NaOH while maintaining the temperature below 30 °C. The mixture was extracted with CHCI ₃ , the extracts dried, and the solvents thoroughly evaporated. The residue was suspended ether, dried, filtered and the solvent evaporated to give (compound 12) (18.1 g) as a yellow oil that slowly solidified.

EXAMPLE 13

(±) -3-Propylthιo-4- (1-azabicvclo \ 2 .2.21octyl-3-oxy) -

1,2, 5-thiadiazole

A solution of the crude compound 12 (1.67 g, 0.0068 mol) in DMF (25 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.8 g, 0.0075 mol) . After 40 mm, 1-bromopropane (1.25 g, 0.010 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and

extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid. The HCl salt (1.28 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 174-176°C. (Compound 13) .

EXAMPLE 14 (±) -3-Butylthιo-4- (l-azabιcvclo[2.2.21octyl-3-oxy) -

1.2.5-thιadιazole

A solution of the crude compound 12 (1.8 g,

0.0073 mol) in DMF (25 mL) waε treated portionwise with freεhly ground flaked Na ₂ S-9H ₂ 0 (1.94 g, 0.0081 mol) . After 1 h, 1-ιodobutane (2 g, 0.011 mol) was added and the reaction stirred overnight. The solvent waε evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous waε made baεic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-coloured liquid. The HCl salt (1.82 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 151-153°C. (Compound 14) .

EXAMPLE 15

(+) - -Pen ylthio- - (1-azabicvclor2.2.21octyl-3-oxy) -

1,2, 5-thιadιazole

A εolution of the crude compound 12 (1.67 g, 0.0068 mol) in DMF (25 mL) waε treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.8 g, 0.0075 mol) . After 1 h, 1-bromopentane (1.53 g, 0.010 mol) was added and the reaction εtirred overnight. The εolvent waε evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made baεic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-coloured liquid. The HCl salt (1.07 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 186-187°C. (Compound 15) .

ΞXAMPLE 16

(S) -3-Pentylthιo-4- (1-azabicvclo[2.2.21 octyl-3-oxy) -

1,2, 5-thιadιazole

A solution of (S) -1-azabιcyclo[2.2.2]octan-3-ol

(2.0 g, 0.0157 mol) in THF (40 mL) was cooled to 10°C as 1.6 M n-butyllithium hexane (10 mL, 0.016 mol) was added dropwise. The resulting mixture was treated with 3-chloro- ethylεulfonyl-1, 2, 5-thιadιazole (3.34 g, 0.0157 mol) in THF (25 mL) and stirred for 16 h. The reaction was treated with H ₂ 0 (10 mL) , ether (170 mL) and extracted with 1 N HCl (43 mL) . The aqueous fraction waε washed with ether, made basic, and extracted with ether. The extracts were dried and the solvent evaporated to give an oil (1.7 g) . The oil waε dissolved m DMF (25 mL) , treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.83 g, 0.0076 mol), and heated (40°C) . After 1.25 h, 1-bromopentane (1.58 g, 0.0105 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid that was purified by radial chromatography (5% EtOH- 0.5% NH ₄ OH-CHCI ₃ ) . The HCl salt (0.87 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 194-195°C, [α] _D = 25.41° (EtOH) . (Compound 16) .

EXAMPLE 17

(±) -3-Hexylthιo-4- (1-azabιcvclo \ 2 . 2 . 21octyl- -oxy) - 1,2, 5-thιadιazole

A solution of the crude compound 12 (1.8 g, 0.0073 mol) in DMF (25 mL) waε treated portionwiεe with freshly ground flaked Na ₂ S-9H ₂ 0 (1.94 g, 0.0081 mol) . After 1 h, 1-ιodohexane (2.3 g, 0.011 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture

extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid. The HCl salt (1.0 g) crystallized from CHCl -EtOAc-ether, m.p. 165 167°C. (Compound 17) .

EXAMPLE 18

(±) -3- (3 ,3-Dιmethylbutylthιo)-4- (1-azabicvclo \ 2 . 2 . 21 - octvl-3-oxv) -1.2. -thιadιazole

A solution of the crude (compound 12) (1.05 g, 0.0043 mol) in DMF (25 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.24 g, 0.0051 mol) . After 1 h, l-bromo-3 , 3-dimethylbutane (1.18 g, 0.007 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made baεic and extracted with ether. The extractε were dried and the εolvent evaporated to give a straw-colored liquid. The HCl salt (0.41 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 189-190°C. (Compound 18) .

EXAMPLE 19 (±) -3- (2- .2-Thιenylthιo)et.hylthio, -4- (1-azabιcvclo- r2.2.21octyl-3-oxy) -1.2.5-thiadiazole

A εolution of the crude (compound 12) (1.0 g, 0.0041 mol) in DMF (25 mL) waε treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.1 g, 0.0045 mol) . After

1 h, l-chloro-2- (2-thιenylthιo) ethane (1.1 g, 0.0062 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous waε made basic and extracted with ether. The extracts were dried, the solvent evaporated, and the residue purified by flash chromatography (10% EtOH-1% NH ₄ OH-CHCI ₃ ) to give a liquid.

The HCl salt (0.88 g) crystallized from ether, m.p. 179.5- 181°C. (Compound 19) .

EXAMPLE 20 (±)-3-(2,2,3,3 ,3-Pentafluoropropylthιo) -4- (1-azabιcvclo-

[2.2.21octyl-3-oxy) -1.2.5-thiadiazole

A solution of the crude (compound 12) (0.5 g, 0.002 mol) in DMF (15 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (0.53 g, 0.0022 mol) . After 1 h, 1-methanesulfonoxy-2,2, 3, 3 ,3-pentafluoropropane (0.003 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried, the solvent evaporated, and the residue purified by flash chromatography (5% EtOH-0.5% NH ₄ OH-CHCI3 ) to give a liquid. The HCl salt (0.016 g) crystallized from ether, m.p. 138-140°C (Compound 20) .

EXAMPLE 21

(±)-3- (3- (2-Thienyl)propylthio) -4- (1-azabιcvclo T2.2.21 - octyl-3-oxy) -1,2.5-thιadιazole

A solution of the crude (compound 12) (0.6 g,

0.0024 mol) DMF (15 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (0.6 g, 0.0027 mol) . After 1 h, l-chloro-3- (2-thιenyl)propane (0.6 g, 0.0036 mol) waε added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried, the solvent evaporated, and the residue purified by flash chromatography (10% EtOH-1% NH ₄ OH-CHCI ₃ ) to give a liquid. The HCl salt (0.16 g) crystallized from EtOH-EtOAc, m.p. 194-196°C. (Compound 21) .

EXAMPLE 22

(±) -3-Butylthιo-4- ( (1-azabicvclo T2.2.21octan-3-yl) - methoxy) -1.2.5-thiadiazole

A εolution of 3-hydroxymethyl-1-azabιcyclo [2.2.2]octane

(1.4 g, 0.01 mol) THF (30 mL) waε treated with 1.6 M n- butyllithium in hexane (6.5 mL, 0.0104 mol) . The mixture waε cooled to 10°C, and 3-chloro-4-ethylεulfonyl-l ,2, 5- thiad azole (2.21 g, 0.0104 mol) m THF (10 mL) waε added dropwise. Cooling was removed and the reaction stirred overnight. The reaction was treated with H ₂ 0, diluted with ether, and extracted with 1 N HCl (25 mL) . The acidic extracts were washed with ether, made baεic, and extracted with ether. The extractε were dried and the εolvent evaporated to give an orange liquid (1.82 g) . The liquid was dissolved m DMF (32 mL) and treated with freshly ground flaked a ₂ S-9H ₂ θ (2.5 g, 0.0104 mol) in portions. After 55 mm, the reaction was treated with 1-ιodobutane (2.6 g, 0.014 mol) and warmed to 44°C overnight. The solvent was evaporated, the reεidue acidified with 1 N HCl, and the mixture extracted with EtOAc-ether (1:1) . The aqueouε fraction waε made baεic and extracted with ether. The ether was dried, the solvent evaporated, and the reεidue purified by radial chromatography (5% EtOH-0.5% NH ₄ OH-CHCI ₃ ) to give a liquid. The HCl salt (0.84 g) crystallized from EtOAc-ether, m.p. 170-171°C. (Compound 22) .

EXAMPLE 23 (±) -exo-3-Pentylthιo-4- (1-azabicvclo[3.2.11octyl-6-oxy) - 1, 2, 5-thιadιazole and (±) -Endo-3-pentylthιo-4- (1- azabicvclo[3.2.11- octyl-6-oxy) -1.2.5-thιadιazole

A solution of the endo/exo mixture of 1- azabιcyclo[3.2.1]octan-6-ol (1.95 g, 0.0153 mol, ref.

Sternbach, L. H.; Kaiser, S. J. Amer. Chem. Soc. 1952, 2i _< 2215-2218.) in THF (25 mL) waε treated with 1.6 M n-

butyllithium m hexane (9.6 mL, 0.0153 mol) . When the mixture had cooled to ambient temperature, 3-chloro-4- ethylsulfonyl-1, 2, 5-thιadιazole (2.96 g, 0.014 mol) in THF (15 mL) was added dropwise and the reaction stirred overnight. The reaction was treated with H ₂ O, diluted with ether, and extracted with 1 N HCl (32 mL) . The acidic extract was made basic, extracted with ether, the extracts dried, and the solvent evaporated to give an orange liquid (1.25 g) . The liquid was dissolved in DMF (25 mL) and treated with freshly ground flaked Na ₂ S-9H 0 (1.82 g,

0.0076 mol) m portions. After 40 mm, 1-bromopentane (1.55 g, 0.0103 mol) was added and the reaction stirred overnight. The solvent was evaporated, the reεidue acidified, and the mixture extracted with ether. The aqueous fraction waε made basic, extracted with ether, the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography (2.5% EtOH-0.25% NH ₄ OH- CHCI ₃ ) to firεt elute the exo lεomer as a liquid. The HCl εalt (0.26 g) , cryεtallized from EtOAc, m.p. 159-160°C. (Compound 23) . Further elution provided the endo isomer as a liquid. The HCl salt (0.23 g) crystallized from EtOAc, m.p. 190-193°C. (Compound 24) .

EXAMPLE 24 (±) -endo-3-Butyloxy-4- (1-azabιcyclo [2.2.11heptyl-3-oxy) -

1,2.5-thιadιazole

A solution of a mixture of (±) -endo and (±) -exo- l-azabιcyclo[2.2.1]heptan3-ol (0.5 g, 0.0044 mol) (Ref. J Org. Chem. 1969, 3_4. 3674-3676) m THF (20 mL) was cooled m an ice-water bath and treated dropwise with 1.6 M n- butyllithium in hexane (2.8 mL, 0.0044 mol) . Cooling was removed, 3-butyloxy-4-methanesulfonyl-l,2 , 5-thιadιazole (1.4 g, 0.0059 mol) was added, and the reaction heated to reflux for 6 h. The solvent was evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted

with EtOAc. The extracts were washed with H 0, dried, and the solvent evaporated to give a clear oil. Radial chromatography (5% EtOH, 0.5% NH ₄ OH, CHCI ₃ ) eluted the title compound as the more polar of the two UV active εpots. The HCl salt of the title compound (0.5 g) crystallized from EtOAc with a quarter mole of H ₂ 0, m.p. 161.5-163°C. (Compound 25) .

EXAMPLE 25 (±) -Exo-3-butyloxy-4- (1-azabicvclo [2.2.11hePtyl-3-oxy) -

1,2, 5-thιadιazole

Rechromatography of the mixed fractions from the isolation of (compound 25) (5% EtOH, 0.5% NH ₄ OH, CHCI ₃ ) gave the less polar UV active material. The HCl salt (0.036 g) crystallized from EtOAc with a quarter mole of water, m.p. 156-157°C. (Compound 26) .

EXAMPLE 26 (±) -3-Butyloxy-4- (3-pyrrolld yloxy) -1,2, 5-thiadiazole

A suεpenεion of NaH (0.066 g, 0.0028 mol) in THF (25 mL) waε treated with l-£-butylcarbamoyl-3- hydroxypyrrolidme (Ref. Svn. Commun. 15, 587.) (0.5 g, 0.0027 mol) and the reaction warmed to 50°C for 30 mm. After cooling to ambient temperature, 3-butyloxy-4- methanesulfonyl-1, 2, 5-thiadiazole (0.55 g, 0.0027 mol) m THF (5 mL) was added and the reaction heated to reflux for 2.5 h. The solvent was evaporated, the residue treated with ice-water, and the mixture extracted with ether. The extractε were washed with brine, dried, and the solvent evaporated. The residue was dissolved m ether (50 mL) and treated with a slow stream of HCl for 5 mm. After stirring overnight, the reaction was extracted with cold water. The aqueous was washed with ether, made basic, and extracted with EtOAc. The extracts were washed with brine, dried, and the so]vent evaporated to give a clear oil. The HCl salt

(0.42 g) crystallized from EtOAc, m.p. 127-128°C. (Compound 27) .

EXAMPLE 27 (±) -3-Butyloxy-4- (l-methyl-3-Pyrrolιdιnyloxy) -1,2.5- thiadiazole

A solution of l-methyl-3-pyrrolιdιnol (0.6 g, 0.0059 mol) THF (20 mL) was treated with 1.6 M n- butyllithium m hexane (3.1 mL) , 0.005 mol) . To the solution was added 3-butyloxy-4-methanesulfonyl-l,2 , 5- thiadiazole (1.0 g, 0.0042 mol) and the reaction heated to reflux overnight. The εolvent was evaporated, the residue acidified with cold 1 N HCl, and the mixture extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, and the extracts washed with water. The extracts were dried and the solvent evaporated to give a liquid. The HCl salt (0.7 g) crystallized from EtOAc, m.p. 157-158°C. (Compound 28) .

EXAMPLE 28 (±) -3-Butylthιo-4- (1-methyl -3-piperιdyloxy) -1.2.5- thiadiazole

A solution of 3-hydroxy-l-methylpιperιdιne (1.12 g, 0.0095 mol) in THF (25 mL) was treated with 1.6 M n- butyllithium m hexane (5.9 mL, 0.0095 mol) . The mixture waε cooled to 8°C and treated dropwise with 3-chloro-4- ethylsulfonyl-1, 2, 5-thιadιazole (1.83 g, 0.0086 mol) in THF (20 mL) . The cooling was removed and the reaction stirred overnight. The mixture was treated with H ₂ 0, acidified with 1 N HCl and diluted with ether. The aqueous fraction was washed with ether, made basic, and extracted with ether. The extracts dried and solvent evaporated to give a brown liquid (1.95 g) . The liquid was dissolved in DMF (38 mL) and treated with freshly ground flaked Na ₂ S-9H 0 (2.98 g, 0.0124 mol) m portions. After 1 h, the mixture was treated

with 1-ιodobutane (3.1 g, 0.0169 mol) and stirred 64 h. The solvent was evaporated, the residue acidified with 1 N HCl, and the mixture extracted with ether. The aqueous solution was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give an orange liquid. Purification by radial chromatography (2.5% EtOH-0.25% NH ₄ OH-CHCI ₃ ) gave a liquid whose HCl salt (1.4 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 141-142°C. (Compound 29) .

EXAMPLE 29

3-Butylthιo-4- (1-methyl-4-piperidyloxy) -1.2, 5-thιadιazole

A solution of -hydroxy-1-methylpιperιdme (1.12 g, 0.0095 mol) THF (25 mL) was treated with 1.6 M n- butyllithium m hexane (5.9 mL, 0.0095 mol) . The mixture was cooled to 8°C and treated dropwise with 3-chloro-4- ethylsulfonyl-l,2,5-thιadιazole (1.83 g, 0.0086 mol) m THF (20 mL) . The cooling was removed and the reaction stirred overnight. The mixture was treated with H ₂ O, acidified with I HCl, and diluted with ether. The aqueous fraction was washed with ether, made basic, and extracted with ether. The extracts dried and solvent evaporated to give a brown liquid (1.52 g) . The liquid was dissolved in DMF (30 mL) and treated with freshly ground flaked Na ₂ S-9H ₂ θ (2.32 g, 0.0097 mol) m portions. After 50 mm, the mixture was treated with 1-ιodobutane (2.4 g, 0.013 mol) and stirred for 63 h. The solvent waε evaporated, the residue acidified with dilute HCl, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give 1.3 g liquid. The HCl salt (1.3 g) crystallized from EtOAc- ether, m.p. 140-142°C. (Compound 30) .

EXAMPLE 30

(S) -3-Butyloxy-4- (1 -methyl-2-pyrrolidinylmethoxy) -1,2.5- thiadiazole

A solution of (S) -l-methyl-2-pyrrolidinemethanol (0.86, 0.0075 mol) in THF (20 mL) was treated with 1.6 M n- butyllithium in hexane (4.7 mL, 0.0075 mol) . To the solution was added 3-butyloxy-4-methanesulfonyl-l, 2 , 5- thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6.5 h. The εolvent waε evaporated, the reεidue acidified with cold 1 N HCl, and the mixture extracted with ether. The aqueouε waε made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) cryεtallized from EtOAc, m.p. 115-116°C. (Compound 31) .

EXAMPLE 31

(S) -3-Butyloxy-4- (2-pyrrolidinylmethoxy) -1,2, 5-thiadiazole

A solution of (S) -l-butyloxycarbonyl-2- pyrrolidinemethanol (1.21, 0.006 mol) in THF (5 mL) waε added to a suspension of 60% NaH in oil (0.24 g, 0.006 mol) in THF (30 mL) . After 1 h, the mixture was heated to gentle reflux for 1 h. To the solution was added 3-butyloxy-4- methanesulfonyl-1,2, 5-thiadiazole (1 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue treated with cold H ₂ 0, and the mixture extracted with EtOAc. The extracts were dried and treated with a stream of dry HCl for 3 min. After another hour, the solvent was evaporated, the residue treated with cold H ₂ 0, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the εolvent evaporated to give a liquid. The HCl salt (0.72 g) cryεtallized from EtOAc, m.p. 99-100°C. (Compound 32) .

EXAMPLE 32

3-Butyloxy-4- (2- (dimethylamino) ethoxy) -1,2, 5-thιadιazole

A solution of 2-dιmethylammoethanol (0.67 g, 0.0075 mol) m THF (20 mL) was treated with 1.6 M n- butyllithium m hexane (4.7 mL, 0.0075 mol) . To the solution waε added 3-butyloxy-4-methaneεulfonyl-1, 2, 5- thiadiazole (1.2 g, 0.005 mol) and the reaction heated to reflux for 6 h. The solvent was evaporated, the reεidue acidified with cold 1 N HCl, and the mixture extracted with ether. The aqueouε waε made basic and extracted with EtOAc The extracts were washed with water, dried, and the solvent evaporated to give a clear oil. The HCl salt (0.94 g) recrystallized from EtOAc to give a white solid, m.p. 97- 98°C. (Compound 33) .

EXAMPLE 33

3-Butylthιo-4- (2- (diethylamino)ethoxy) -1,2, 5-thιadιazole

A solution of 2-dιethylammoethanol (1.11 g,

0.0095 mol) m THF (25 mL) was treated with 1.6 M n- butyllithium in hexane (5.9 mL, 0.0095 mol) . The mixture was cooled to 8°C and treated dropwise with 3-chloro-4- ethylsulfonyl-1, 2, 5thιadιazole (1.83 g, 0.0086 mol) THF (20 mL) . The cooling was removed and the reaction stirred overnight. The mixture was treated with H ₂ 0, acidified with

1 N HCl, and diluted with ether. The aqueous fraction was washed with ether, made basic, and extracted with ether. The extracts dried and solvent evaporated to give a brown liquid (1.6 g) . The liquid was dissolved DMF (30 mL) and treated with freshly ground flaked Na S-9H ₂ 0 (2.43 g, 0.010 mol) in portions. After 50 mm, the mixture was treated with 1-ιodobutane (2.52 g, 0.0137 mol) and stirred for 46 h. The solvent was evaporated, the residue acidified with dilute HCl, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with ether. The extractε were dried, the solvent evaporated, and the

residue purified by radial chromatography (5% EtOH-0.5% NH ₄ OH-CHCI ₃ ) to give a liquid. The HCl salt (1.15 g) crystallized from EtOAc-ether, m.p. 95-97°C. (Compound 34) .

EXAMPLE 34

3-Butyloxy-4- (2- (trimethylamino)ethoxy) -1.2 , 5-thiadiazole iodide

A solution of (compound 33) (from 0.5 g, 0.0018 mol of the HCl salt) EtOAc (30 mL) was treated with CH ₃ I (0.3 mL) and stirred overnight. The precipitant was collected, washed with EtOAc, and dried to give a white solid (0.64 g) , m.p. 137-138°C. (Compound 35) .

EXAMPLE 35

3-Butyloxy-4- (2- (dimethylamino) ethylthio) -1.2.5-thιadιazole

A suspension of 2-dιmethylammoethanthιol hydrochloride (0.57 g, 0.004 mol) m THF (25 mL) was treated with 1.6 M n-butyllithium m hexane (5 mL, 0.008 mol) . To the solution was added 3-butyloxy-4- methaneεulfonyl-1, 2, 5-thιadιazole (0.71 g, 0.003 mol) and the reaction heated to reflux for 2 h followed by stirring at ambient temperature overnight. The solvent waε evaporated, the residue acidified with cold 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were washed with water, dried, and the εolvent evaporated. The residue was purified by radial chromatography (5% EtOH-0.5% NH ₄ OH- CHCI ₃ ) to give a tan liquid. The HCl salt (0.22 g) recrystallized from EtOAc to give a white solid, m.p. 108- 109°C. (Compound 36) .

EXAMPLE 36

3-Chloro-4- (1-propylthio) -1.2.5-thiadiazole

Cyanogen (34 g, 0.65 mol) waε bubbled into ether (250 mL) maintained at -10°C. To the solution was added dropwise diethylamine (3 mL) followed by dropwise addition of 1-propanethιol (57 mL, 0.63 mol) m ether (25 mL) at such a rate that the temperature did not exceed -5°C. After 5 h, cooling was removed and the reaction stirred overnight. Ether was distilled from the reaction until the pot temperature reached 50°C. The reaction was cooled to ambient and added dropwise to a solution of sulfur monochloride (125 mL, 1.56 mol) in DMF (125 mL) that was cooled in an ice-water bath. Cooling was removed and the reaction allowed to exotherm to 35°C, recooled to below 30°C, then stirred overnight. The reaction was cooled m EtOH-ice and the excesε sulfur monochloride carefully destroyed by dropwise addition of H ₂ 0 (200 mL) such that the temperature did not exceed 30°C. The mixture was extracted with hexane, the extractε waεhed with brine, dried, and the solvent evaporated. The residue was distilled at 1.5 mm Hg to give a yellow liquid (98.6 g) , b.p. 84-94°C. (Compound 37) .

EXAMPLE 37

(R) -3-Pentylthιo-4- (1-azabιcvclo \ 2 . 2 .21octyl-3-oxy) -1.2.5- thiadiazole

A solution of (R) -1-azabιcyclo[2.2.2]octan-3-ol (3.0 g, 0.0236 mol) m THF (40 mL) was cooled to 10°C as 1.6 M n- butyllithium m hexane (15 mL, 0.024 mol) was added dropwise. The resulting mixture was treated with 3-chloro- 4-ethylεulfonyl-l,2,5-thιadιazole (5.01 g, 0.0236 mol) m THF (5 mL) and stirred for 22 h. The reaction waε treated with H ₂ 0 (10 mL) , ether (170 mL) and extracted with 1 N HCl (35 mL) . The aqueouε fraction was waεhed with ether, made basic, and extracted with ether. The extracts were dried

and the solvent evaporated to give an oil (2.35 g) . The oil waε dissolved in DMF (35 mL) , treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (2.53 g, 0.0105 mol) , and heated (40°C) . After 1.25 h, 1-bromopentane (2.18 g, 0.0145 mol) was added and the reaction stirred overnight at 38°C. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid that was purified by radial chromatography (5% EtOH- 0.5% NH ₄ OH-CHCI ₃ ) , The HCl salt (1.68 g) crystallized from CHCl ₃ -EtOAc, m.p. 195-196°C, [α] _D = -24.6° (EtOH) . (Compound 38) .

EXAMPLE 38

(±) -3- (4-Methylpentylthιo) -4- (1-azabicvclo \ 2.2.21octyl-3- oxy) -1.2.5-thiadiazole

A solution of the crude (compound 12) (1.65 g,

0.0067 mol) in DMF (25 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.83 g, 0.0076 mol) . After 1 h, l-bromo-4-methylpentane (1.73 g, 0.0105 mol) was added and the reaction stirred three days at 40°C. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid that was purified by radial chromatography (5% EtOH-0.5% NH ₄ OH- CHCI ₃ ) . The HCl salt (0.74 g) crystallized from CHCI ₃ - EtOAc-ether, m.p. 183-185°C. (Compound 39) .

EXAMPLE 39

(±)-3- (3-Phenylpropylthιo)-4- (1-azabicvclo \ 2 . 2.21octyl-3- oxy) -1.2.5-thιadιazole

A solution of the crude (compound 12) (0.9 g,

0.0037 mol) in DMF (25 mL) waε treated portionwiεe with freshly ground flaked Na ₂ S-9H ₂ 0 (0.97 g, 0.004 mol) . After 1 h, l-bromo-3-phenylpropane (1.11 g, 0.056 mol) was added and the reaction stirred 17 h at 50°C. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous waε made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid that was purified by radial chromatography (2.5% EtOH-0.25% NH ₄ OH- CHCI ₃ ) . The HCl salt (0.42 g) crystallized from CHCI ₃ - EtOAc-ether, m.p. 210-212°C. (Compound 40) .

EXAMPLE 40 (±) -3- (4-Cvanobenzylthιo)-4- (1-azabicvclo [2.2.21 octyl-3- oxy) -1.2.5-thιadιazole

A solution of the crude (compound 12) (1.15 g, 0.0047 mol) in DMF (25 mL) was treated portionwise w th freεhly ground flaked Na ₂ S-9H ₂ 0 (1.68 g, 0.007 mol). After 1 h, 4-cyanobenzyl bromide (1.85 g, 0.094 mol) was added and the reaction stirred 22 h. The solvent waε evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extractε were dried and the solvent evaporated to give a straw-colored liquid that waε purified by radial chromatography (5% EtOH-0.5% NH ₄ OH- CHCI ₃ ) . The HCl salt (0.12 g) crystallized from CHCI ₃ - EtOAc-ether, m.p. 211-213°C. (Compound 41).

EXAMPLE 41

(±) -3- (4-Fluorobenzylthιo) -4- (1 azabicvclo [2.2.21octyl-3- oxy) -1.2, 5-thic-ιdιazole

A solution of the crude (compound 12) (1.15 g,

0.0047 mol) m DMF (25 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.68 g, 0.007 mol) . After 1 h, 4-fluorobenzyl chloride (1.37 g, 0.094 mol) waε added and the reaction stirred 22 h. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid that was purified by radial chromatography (5% EtOH-0.5% NH ₄ OH- CHCI ₃ ) . The HCl salt (0.89 g) crystallized from MeOH-EtOAc- ether, m.p. 236-237°C. (Compound 42) .

EXAMPLE 42

(±) -3- .2-Phenylethylthιo. -4- (1 -azabicvclo \ 2 . 2 . 21octyl-3- oxy) -1,2, 5-thιadιazole

A solution of the crude (compound 12) (1.15 g,

0.0047 mol) in DMF (25 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.68 g, 0.007 mol) . After

1 h, the reaction was cooled to -30°C and treated with dropwise with l-bromo-2-phenylethane (1.75 g, 0.095 mol) m DMF (22 mL) . The cooling was removed after 1 h and the reaction stirred 22 h. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried and the solvent evaporated to give a straw-colored liquid that was purified by radial chromatography (5% EtOH-0.5% NH ₄ OH-

CHCI ₃ ) . The HCl salt (0.53 g) crystallized from MeOH-EtOAc- ether, m.p. 181-183°C. (Compound 43) .

EXAMPLE 43 (±) -3-(2-Phenyloxyethylthιo)-4- (1-azabιcvclo \ 2 . 2 . 21octyl-3- oxy)- 1, 2 , 5-thιadιazole

A solution of the crude (compound 12) (1.15 g, 0.0047 mol) in DMF (25 mL) waε treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.68 g, 0.007 mol) . After 1 h, the reaction was cooled to -50°C and treated with dropwise with l-bromo-2-phenyloxyethane (1.90 g, 0.0095 mol) m DMF (22 mL) . The cooling was removed after 1 h and the reaction stirred 22 h. Another εolution of bromo-2- phenyloxyethane (1.90 g, 0.0095 mol) in DMF (5 mL) was added m two portions with cooling to -30°C. After 2 h, the solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous waε made baεic and extracted with CHCI ₃ . The extracts were dried and the solvent evaporated to give a εtraw-colored liquid that waε purified by radial chromatography (5% EtOH- 0.5% NH ₄ OH-CHCI ₃ ) . The HCl salt (1.29 g) crystallized from MeOH-EtOAc-ether, m.p. 193-194°C. (Compound 44) .

EXAMPLE 44 endo-3-Butyloxy-4- (N-methyl-8-azabιcyclo[3.2.11 octyl-3- oxy) -1,2, 5-thιadιazole

A solution of tropme (1.36 g, 0.0094 mol) THF (25 mL) was treated dropwise with 1.6 M n-butyllithium m hexane (5.9 mL, 0.00095 mol) . To this solution was added 3-butyloxy-4-methaneεulfonyl-1, 2, 5-thιadιazole (2.04 g, 0.0086 mol) m THF (25 mL) and the reaction heated to 40°C for 19 h. The solution was treated with H ₂ 0 (40 mL) , 5 N HCl (5.5 mL) , and ether (150 mL) , the aqueous layer εeparated and made basic. The aqueous solution was extracted with ether, the extracts dried, and the solvent

evaporated to give a clear oil. The oil was purified by radial chromatography (5% EtOH-0.5% NH ₄ OH-CHCI ₃ ) and the HCl salt (1.49 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 168-169°C. (Compound 45) .

EXAMPLE 45 (±) -exo-3-Butyloxy-4- (6- (N-methyl-8-azabicvclo [3.2.11octan-

3-onoxy) ) -1.2 , 5-thiadiazole

A suspension of NaH (0.11 g, 0.00275 mol) in THF

(25 mL) was treated with (±) -exo-6-hydroxytropmone (1.36 g, 0.0094 mol) and the reaction heated to 50°C for 1 h. To this solution was added 3-butyloxy-4-methanesulfonyl-1,2, 5- thiadiazole (0.55 g, 0.0027 mol) and the reaction heated to reflux for 2 h. The solvent waε evaporated, the residue suεpended m ice-water, acidified, and the mixture extracted with ether. The aqueous layer was made basic, was extracted with ether, the extracts washed with brine, dried, and the solvent evaporated to give a clear oil. The oil was purified by radial chromatography (2.5% EtOH-0.25% NH ₄ OH-CHCI ₃ ) and the HCl salt (0.325 g) crystallized from

EtOAc, m.p. 178-179°C. (Compound 46) .

EXAMPLE 46 (±) -exo-3-Chloro-4- (1-azabicvclo [3.2.11octyl-6-oxy) -1,2, 5- thiadiazole and(±) -endo-3-Chloro-4- (1-azabιcvclo [3.2.1 1 octyl-6-oxy) -1,2, 5-thiadiazole

A solution of the endo/exo mixture of 1- azabicyclo[3.2.1]octan-6-ol (13 g, 0.102 mol, ref.

Sternbach, L. H. ; Kaiser, S. J. Amer. Chem. Soc. 1952, 7_4- 2215-2218) , triethylamine (0.3 mL) , and CHCI ₃ (100 mL) was cooled to 3°C and cyanogen (7.7 g, 0.148 mol) bubbled mto the solution. After 1 h, the cooling was removed, the reaction stirred another 3 h, and the solvent evaporated.

The residue was dissolved in DMF (30 mL) and added dropwise to a solution of S ₂ C1 ₂ (47.3 g, 0.35 mol) DMF (30 mL)

that was cooled in an ice-water bath. Cooling was removed, the reaction stirred overnight, and, after further cooling, the excess S C1 carefully destroyed with H ₂ O. The mixture waε diluted with H ₂ O (200 mL) , the aqueouε solution decanted, and the sulfur residue triturated with H ₂ 0. The combined aqueous solutions were evaporated to a small volume (150 mL) and extracted with hexane. The aqueous solution was cooled, made basic with 50% NaOH, and extracted with CHCI ₃ . The extracts were dried, the solvent thoroughly evaporated, the reεidue suspended ether and filtered. Evaporation of the solvent gave a brown liquid (12.76 g) , a 0.8 g sample of which was purified by radial chromatography (10% EtOH-1% NH ₄ OH-CHCI ₃ ) . The exo isomer eluted first and was converted to an HCl salt (0.1 g) that crystallized from acetone, m.p. 226°C, dec. (compound 47) . Further elution provided the endo isomer that crystallized as an HCl salt (0.2 g) from 2-propanol, m.p. 199.5-201°C. (Compound 48) .

EXAMPLE 47

(±) -endo-3- (4-Cvanobenzylthιo) -4- (1-azabιcvclo [3.2.11 octyl-

6-oxy) -1,2, 5-thiadiazole

A solution of the crude mixture of (compound 47) and (compound 48) (2.3 g, 0.0094 mol) in DMF (34 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H 0 (3.36 g, 0.014 mol) . After 2 h, the reaction was cooled to -30°C and treated with dropwise with 4-cyanobenzyl bromide (3.7 g, 0.0189 mol) in DMF (34 mL) . The cooling waε removed and after 1.5 h, the reaction was treated with 5 N NaOH (4 mL) . The solvents were evaporated, the residue dissolved m a mixture of CHCI ₃ and H2O, the CHCI ₃ extract separated, and washed with H 0. The organic extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (5% EtOH-0.5% NH OH-Et0Ac) to give the endo isomer. The HCl salt (0.31 g) crystallized from MeOH-EtOAc- ether, m.p. 250-251°C. (Compound 49) .

EXAMPLE 48

3-Butyloxy-4- (3-azetidmyloxy) -1,2.5-thiadiazole

A suεpenεion of NaH (0.24 g, 0.006 mol) THF

(30 mL) was treated with l-£-butylcarbamoyl-3- hydroxyazetidme (1.1 g, 0.006 mol) , the reaction stirred 1 h, followed by addition of 3-butyloxy-4-methanesulfonyl- 1,2, 5-thιadιazole (1.0 g, 0.0042 mol) m THF (5 mL) . The reaction was heated to reflux for 4 h, the solvent evaporated, the residue treated with ice-water, and the mixture extracted with EtOAc. The extracts were dried and treated with a slow stream of HCl for 3 mm. After 0.5 h, the εolvent waε evaporated, the residue treated with lce- water, and the solution extracted with ether. The aqueous phase was made baεic, extracted with EtOAc, the extractε waεhed with brine, dried, and the εolvent evaporated to give a clear oil. The HCl εalt (0.77 g) crystallized from 2-propanol, m.p. 167-168.5°C. (Compound 50) .

EXAMPLE 49 3-Butylthιo-4- (3-azetidmyloxy) -1,2, 5-thiadiazole

A suspenεion of NaH (0.24 g, 0.006 mol) THF (30 mL) waε treated with l- -butylcarbamoyl-3- hydroxyazetidme (1.6 g, 0.0092 mol) , and the reaction stirred 1 h. After cooling to 8°C, 3-chloro-4- ethylεulfonyl-l,2,5-thιadιazole (1.96 g, 0.0092 mol) in THF (5 mL) waε added, the reaction stirred 30 mm, cooling removed for 30 mm, and the reaction heated to 35°C for 45 mm. Heating was removed, the reaction εtirred overnight, and the εolvent evaporated. The residue waε εuspended in cold water, the mixture extracted with EtOAc, the extracts washed with brine, dried, and the εolvent evaporated to give a tan liquid, (2.98 g) . A DMF (30 mL) solution of the liquid was treated with freshly ground flaked Na ₂ S-9H 0 (3.3 g, 0.0138 mol) . After 1 h, 1-ιodobutane (2.1 mL) was

added, the reaction stirred 2 h, diluted with cold water, and extracted with ether. The ether was dried, the εolvent evaporated, the residue dissolved m EtOAc, and the solution treated with a stream of dry HCl for 5 min. After 1 h, the reaction was treated with icewater and the organic solvent evaporated. The aqueous solution was extracted with ether, made basic, and extracted with EtOAc. The EtOAc extracts were dried and the solvent evaporated to give a tan liquid that was purified by radial chromatography (10% EtOH-1% NH ₄ OH-CHCI3) • The HCl salt (0.41 g) crystallized from EtOAc, m.p. 138-139°C. (Compound 51) .

EXAMPLE 50

(±) -trans-3-Butyloxy-4- (2-dιmethylamιnocvclopentyloxy) - 1.2.5-thιadιazole

A suspension of NaH (0.25 g, 0.006 mol) THF (30 mL) was treated with (±)-trans- dimethylam ocyclopentanol (0.8 g, 0.006 mol) , the reaction heated to reflux 1 h, followed by addition of 3-butyloxy-4- methanesulfonyl-1, 2 , 5-thιadιazole (1.0 g, 0.0042 mol) , and the heatmg continued overnight. The solvent waε evaporated, the reεidue suspended cold water, and the mixture acidified. The solution was extracted with ether, made basic, and extracted with EtOAc. The EtOAc extracts were washed with brine, dried, the solvent evaporated, and the residue purified by radial chromatography (10% EtOH-1% NH ₄ OH-CHCI ₃ ) . The HCl salt (0.98 g) crystallized from

EtOAc, m.p. 148-149°C. (Compound 52) .

EXAMPLE 51

(±) -3-Butylthιo-4- (3-Pyrrolιdιnyloxy) -1.2, 5-thιadιazole

A suspension of NaH (0.22 g, 0.009 mol) THF (30 mL) was treated with (±) -l-^-butylcarbamoyl-3- hydroxypyrrolid e (1.73 g, 0.0092 mol), and the reaction heated to reflux for 35 mm. After cooling to 10°C, 3- chloro-4-ethylsulfonyl-l,2,5-thιadιazole (1.96 g, 0.0092 mol) in THF (5 mL) was added, cooling was removed, and the reaction heated to 35°C for 16 h. The reaction was diluted with H ₂ 0, ether added, and the ether extract separated. The ether extract was washed with H ₂ 0, dried, and the solvent evaporated to give a tan liquid, (3.05 g) . A DMF (42 mL) solution of the liquid was treated with freshly ground flaked Na ₂ S-9H ₂ 0 (3.3 g, 0.0138 mol) . After 1 h, 1- lodobutane (3.42 g, 0.0186 mol) was added, and the reaction εtirred at 40°C for 16 h. The εolvent was evaporated, the residue diluted with cold water, and the mixture extracted with ether. The ether was dried, the solvent evaporated, the residue dissolved ether, and the solution treated with a stream of dry HCl for 5 mm. After 66 h, the reaction waε treated with ice-water and the organic solvent evaporated. The aqueous solution was extracted with ether, made basic, and extracted with ether. The ether extracts were dried and the solvent evaporated to give a tan liquid that was purified by radial chromatography (5% EtOH-0.5% NH ₄ OH-CHCI ₃ ) . The HCl salt (0.67 g) crystallized from EtOAc, m.p. 99-100.5°C. (Compound 53) .

EXAMPLE 52 l-Chloro-2- (2-thιo-5-trιfluoromethylthienyl)ethane

A solution of 2-trιfluoromethylthiophene (1.2 g, 0.0105 mol, J. Fluorine Chem. 1990, » 445-459) THF (10 mL) waε cooled to -40°C as 1.6 M n-butyllithium m hexane (6.5 mL, 0.0103 mol) was added dropwiεe. After 2 h, the reaction waε cooled to -78°C and S (0.32 g, 0.01 mol)

was added and the reaction stirred 2 h. Cooling was removed and when temperature reached 0°C, the reaction was quenched with H ₂ 0 and dilute NaOH. The mixture was extracted with ether, the aqueous phase acidified, and the mixture extracted with ether. The final ether extractε were dried and the solvent evaporated to give 2 g of material. This was added to a mixture of KOH (0.6 g, 0.011 mol) , N(butyl) HS0 (0.3 g, 0.001 mol), and l-bromo-2- chloroethane (1.4 g, 0.01 mol) in THF (20 mL) and the reaction stirred at ambient overnight. The mixture waε poured mto H ₂ 0, extracted with CH ₂ C1 ₂ , the extracts dried, and the solvent evaporated. The residue was purified by flash chromatography (5% EtOAc-hexane) to give a liquid (0.42 g) . (Compound 54) .

EXAMPLE 53

(±) -3- (2- (2-Thιo-5-trιfluoromethylthιenyl) ethylthio) -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

A solution of the crude (compound 12) (0.37 g,

0.0015 mol) in DMF (8 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (0.41 g, 0.0017 mol) . After 1 h, l-chloro-2- (2-thιo-5-trιfluoromethylthienyl) ethane (0.42 g, 0.0017 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography (10% EtOH-1% NH ₄ OH-CHCI ₃ ) to give a liquid. The oxalate salt (0.107 g) crystallized from 2-propanol, m.p. 65-69°C. (Compound 55) .

EXAMPLE 54

2- (5- .2-Thιenyl) hion ene) thio.l

A εolution of 2- (2-thιenyl) thiophene (10 g,

0.0602 mol) m THF (50 mL) waε cooled to -40°C aε 1.6 M ri- butyllithium in hexane (37.2 mL, 0.0595 mol) waε added dropwise. After 2 h, the reaction was cooled to -78°C and S (1.8 g, 0.0575 mol) waε added and the reaction stirred 2 h. Cooling was removed and when temperature reached 0°C, the reaction waε quenched with H 0 and dilute NaOH. The mixture waε extracted with ether, the aqueouε phase acidified, and the mixture extracted with ether. The final ether extracts were dried and the solvent evaporated to give 9.9 g of material. (Compound 56) .

EXAMPLE 55

(±) -3-(2-(5- (2-Thιenyl)thιenyl)thιo)-4-(l -azabicvclo[2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

A mixture of 2- (5- (2-thιenyl) thiophene) thiol (1.2 g, 0.0061 mol), potassium -butoxιde (0.5 g, 0.0045 mol) , and a trace of 18-Crown-6 in THF (90 mL) was stirred for 1.5 h. To the εolution was added (compound 12) (1.0 g, 0.0041 mol) and the reaction heated to reflux overnight.

The reaction was poured mto H ₂ 0, extracted with ether, the extractε dried, and the εolvent evaporated. The reεidue waε purified by flaεh chromatography (5% EtOH-0.5% NH4OH-CHCI3) and the oxalate salt (0.41 g) crystallized from acetone, m.p. 215°C, dec. (Compound 57).

EXAMPLE 56 l-Chloro-2- (2- (5- (2-thιenyl)thienyl) thio) ethane

Crude 2- (5- (2-thienyl) thiophene) thiol (3 g,

0.0152 mol) was added to a mixture of KOH (0.93 g, 0.0166 mol), N(butyl) HS0 ₄ (0.51 g, 0.0015 mol) , and l-bromo-2-

chloroethane (2.2 g, 0.0152 mol) in THF (100 mL) and the reaction stirred at ambient overnight. The mixture was poured mto H ₂ 0, extracted with CH C1 , the extracts dried, and the solvent evaporated to give the desired product (3.5 g) . (Compound 58) .

EXAMPLE 57

■+.-.3-.2-.2-(5- (2-Thienyl) thienyl) thio) ethylthio) -4- (1- azabιcvclo[2.2.21octyl-3-oxy) -1.2.5-thiadiazole

A solution of the crude (compound 12) (0.5 g, 0.002 mol) in DMF (10 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (0.55 g, 0.0023 mol) . After 1 h, l-chloro-2- (2- (5- (2-thienyl) thienyl) thio)ethane (0.6 g, 0.0023 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried, the εolvent evaporated, and the residue purified by flash chromatography (5% EtOH-0.5% NH ₄ OH-CHCI ₃ ) to give a liquid. The oxalate salt (0.43 g) cryεtallized from acetone, m.p. 102-105°C. (Compound 59) .

EXAMPLE 58 (±) -3- (2-Thienyl) thio) -4- (1-azabicvclo \ 2 . 2 .21octyl-3-oxy) -

1.2, 5-thiadiazole

A mixture of 2-thiophenethιol (0.42 g, 0.0036 mol) and K ₂ C0 ₃ (0.59 g, 0.0043 mol) , in DMF (20 mL) waε heated at 60°C for 3 h. To the solution was added (compounα 12) (0.89 g, 0.0036 mol) and the reaction heated overnight. The reaction was poured into 1 N HCl (50 mL) , extracted with ether, the aqueous phase made basic, and the mixture extracted with EtOAc. The EtOAc extractε were dried, the solvent evaporated, and the residue purified by flash chromatography (5% EtOH-0.5% NH ₄ OH-CHCI ₃ ) . The oxalate salt

( 0 . 095 g ) crystall i zed f rom acetone , m . p . 133 - 136°C . ( Compound 60 ) .

EXAMPLE 59 (±) -3- (3-N- (2-Thiazolidonyl)propylthio) -4- (1-azabιcvclo- r .2.21 ctyl-3-oxy) 1.2.5-thiadiazole

A solution of the crude (compound 12) (0.5 g, 0.002 mol) in DMF (10 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (0.55 g, 0.0023 mol) . After 1 h, l-chloro-3-N- (2-thιazolιdone) propane (0.41 g, 0.0023 mol) was added and the reaction stirred overnight. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried, the εolvent evaporated, and the reεidue purified by radial chromatography (10% EtOH-1% NH ₄ OH-CHCI3 ) to give a liquid. The oxalate εalt (0.148 g) cryεtallized from acetone-ether, m.p. 70-~75°C. (Compound 61) .

EXAMPLE 60 (±) exo-Methyl-7-hvdroxy-2-azabicvclo[2.2.21oct-5-ene-2- carboxylate

A εolution of 2.1 g (8.4 mmol) methyl 7-acetoxy-

7-cyano-2-azabιcyclo[2.2.2] oct-5-ene-2-carboxylate (J. Org. Chem. 1989, 5 ., 2893) in 25 mL ethanol and 5 mL H ₂ 0 waε cooled in an ice bath. To thiε mixture waε added 2.4 g (42 mmol) KOH followed by 0.65 g (17 mmol) NaBH ₄ . After 15 min. the ice bath waε removed and the reaction was stirred for 16 h. The reaction was quenched by addition of 25 mL H ₂ O and then concentrated under vacuum. To the residue was added 25 mL H ₂ O and the mixture was extracted three times with 50 mL portionε of EtOAc. The combined extracts were dried over NaCl/Na ₂ Sθ ₄ and evaporated under vacuum. The reεidue was chromatographed (25% EtOAc/hexane) on silica gel to give 1.47 g of exo methyl 7-hydroxy-2-

azabicyclo [2.2.2]oct-5-ene-2-carboxylate and 135 mg of endo methyl 7-hydroxy-2-azabicyclo[2.2.2] oct-5-ene-2- carboxylate. (Compound 62) .

EXAMPLE 61

(±) exo-Methyl-6-hvdroxy-2-azabιcvclo[2.2.21 octane-2- carboxylate

A solution of 1.47 g (8 mmol) exo methyl 7- hydroxy-2-azabicyclo [2.2.2] oct-5-ene-2-carboxylate and 0.15 g 5% Pd/C 50 mL methanol was hydrogenated at 50 psi on a Parr shaker for 5 h at room temperature. Removal of the catalyst by filtration followed by evaporation under vacuum afforded 1.43 g. (Compound 63).

EXAMPLE 62

(±) 3-Butylthιo-4- (exo-2-methoxycarbonyl-2- azabicvclo [2.2.21oct-6-yloxy) -1,2, 5-thiadiazole

To a solution of 1.3 g (7.1 mmol) exo methyl 6- hydroxy-2-azabicyclo [2.2.2]octane-2-carboxylate and 0.80 g (7.1 mmol) potassium t-butoxide m 20 mL of THF was added 1.5 9 (7.1 mmol) 3-chloro-4-butylthιo-l, 2 , 5-thιadιazole After stirring the mixture at room temperature for 20 h, 50 mL of brine was added and the solution was extracted five times with 50 mL portions of EtOAc. The combined extracts were dried over NaCl/Na S0 ₄ and evaporated under vacuum.

Chromatography over silica gel (25% EtOAc/hexane) afforded 1.42 g. (Compound 64) .

EXAMPLE 63

(±) 3-Butylthιo-4- (exo-2-azabicvclo[2.2.21oct-6-yloxy) -

1.2.5-thιadιazole

Trimethylsilyliodide 0.70 mL (4.9 mmol) was added to a εolution of 3-butylthιo-4- (exo-2- methoxycarbonyl-2-azabicyclo [2.2.2] oct-6-yloxy) -1,2,5-

thiadiazole m 10 mL of CH ₂ C1 ₂ . After stirring for 5 h at room temperature, the solution was evaporated under vacuum. 10 mL of saturated NaHC0 ₃ was added and the solution waε extracted three times with 20 mL portions of EtOAc. The combined extracts were dried over NaCl/Na ₂ S0 ₄ and evaporated under vacuum. The residue was chromatographed over silica gel (10% EtOH, 1% NH4OH-CHCI ₃ ) and the resulting oil converted to its oxalate salt. Recrystallization from EtOH/EtOAc afforded 789 mg (mp. 148- 150°C) . (Compound 65) .

EXAMPLE 64

3-Amιno-4-butylthιo-l, 2 , 5-thiadiazole

A 1.04 g sample of 3-chloro-4-butylthιo-l, 2, 5- thiadiazole was dissolved m 20 mL of THF and added to a 50 mL reaction vesεel. The mixture was cooled to 0°C. A 10 mL sample of sodium bis (trimethylsilyl) amide THF (1.0 M) was added dropwise to the reaction vesεel. The mixture was stirred at 0°C . The reaction waε quenched uεing 50 mL water upon desired completion of reaction. The pH of the mixture waε adjuεted to 2.0 using HCl. The mixture waε εtirred for 15 mm. and then adηuεted to pH = 11 uεmg NaOH. The mixture was extracted usmg ether. The organic layers were combined, dried, and filtered. The filtrate was concentrated to dryness. The resulting product was purified using column chromatography. Yield: 1.07 g (65%) . The N,N- biε (trimethylsilyl) -3-ammo-4-butylthio-1,2, 5-thiadiazole waε εuεpended 3N HCl and heated to about 50°C. The mixture was stirred for 3 h. The pH was adjusted to 11 usmg NaOH. The mixture was extracted using t-butylmethyl ester. The organics were combined, dried, filtered and concentrated to dryness. Yield: 0.43 g (45%) . (Compound 66) . The procesε substantially as deεcribed waε repeated to yield 82% of the desired 3-ammo-4-butylthιo-l, 2, 5- thiadiazole.

EXAMPLE 65

3-Bromo-4-butylthιo-l, 2 , 5-thiadiazole

A 0.42 g sample of cupric bromide, 0.28 isoamyl nitrite and 6 mL acetonitrile were added to a 25 mL reaction vesεel. The mixture was warmed to 65°C. The acetonitrile mixture was added to a 4 mL acetonitrile solution containing 0.30 g 4-ammo-3-butylthιo-l, 2 , 5- thiadiazole. The mixture was stirred for 30 mm. at 65°. The mixture was cooled to room temperature and quenched with 50 mL of 1 N HCl. The organic layers were combined, dried, filtered and concentrated to drynesε. Yield: 0.38 g (94%) . The reεulting material waε purified using column chromatography to yield 0.30 g (73%) of material. (Compound 67) .

The process substantially as described above was completed using copper (I) iodide (0.61 9) to provide 3- ιodo-4-butylthιo-l,2, 5-thιadιazole. Yield: 0.23 g (48%) . (Compound 68) .

Example 66

(±)3-(2.2.3,3.4,4.4-heptafluorobutyloxy) -4- [-3- (1- azabicvclo[2.2.21 octyloxy) 1-1,2, 5-thiadiazole

A solution of potassium t-butoxide (1.6g, 0.0143 mol) in THF (12 mL) was treated with 2,2,3,3,4,4,4- heptafluorobutanol ( 2 mL, 0.016 mol) . After 5 mm, Compound 12 (0.75 g, 0.003 mol) was added, the reaction stirred 2 h followed by heating to reflux for 1.5 h. After stirring at ambient temperature overnight and heating to reflux for another 1.5 h, the solvent was evaporated, the residue suspended m H2O, and the mixture extracted with

EtOAc. The extracts were dried, the εolvent evaporated, and the reεidue purified by radial chromatography (20 % EtOH-2 % NH ₄ 0H-CHC1 ₃ ) to give an oil. The hydrochloride salt crystallized from EtOAc with a half mole of H2O as a

flocculent white solid (0.43 g) , m.p. 168.5-169.5 °C. (Compound 69) .

Example 67 (±)3- .l-Butylthio. -4- rendo--6- (1- azabicvclof3.2. lloctyloxy) 1-1,2, 5-thiadiazole

A solution of potassium t-butoxide (0.62 g, 0.0055 mol) in THF (12 L) was treated with endo-1- azabιcyclo[3.2.1]octan-6-ol (0.64 g, 0.005 mol) . After 5 mm, 3-chloro-4- (1-butylthιo) -1,2, 5-thιadιazole (1.2 g,

0.0057 mol) was added. After stirring overnight, the εolvent waε evaporated, the residue diluted with H2O, acidified, and extracted with ether. The aqueous phase was made basic and extracted with EtOAc, the extracts dried, washed with brine, dried, and the εolvent evaporated. The reεidue waε purified by radial chromatography (20 % EtOH-2 % NH ₄ OH-CHCl ₃ ) . The HCl εalt cryεtallized from EtOAc to give a white εolid (0.68 g), m.p. 201-202 °C dec.

(Compound 70) .

Example 68

(±) 3- (3-Phenylpropylthιo) -4- [endo--6- (1- azabicvclo [3.2.11octyloxy) 1-1,2, 5-thiadiazole

A εolution of Compound 48 (0.9 g, 0.0037 mol) m DMF (25 mL) was treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (0.97 g, 0.004 mol) . After 2 h, the reaction waε treated with dropwise with l-bromo-3-phenylpropane (1.11 g, 0.0059 mol) , the reaction stirred 3.25 h, followed by dropwise addition of additional l-bromo-3-phenylpropane

(1.11 g, 0.0059 mol) m DMF (5 mL) . After stirring overnight, the solventε were evaporated, the residue suspended in H2O, acidified, and the mixture extracted with ether. The aqueous phase was made baεic, extracted with CHCI3, the extractε dried, and the solvent evaporated. The residue purified by radial chromatography (MeOH:EtOAc:NH ₄ OH/15:30:l) to give an oil. The HCl salt

(0.41 g) crystallized from CHCI3-EtOAc-ether, m.p. 178-179

°C. (Compound 72)

Example 69 (±) 3- .3- (4-Fluorophenyl)propylthio1 -4- [-3- (1- azabicvclo[2.2.21octyloxy) 1-1,2, 5-thiadiazole

A solution of the crude Compound 12 (1.15 g, 0.0047 mol) m DMF (20 mL) waε treated portionwise with freshly ground flaked Na ₂ S-9H ₂ 0 (1.68 g, 0.007 mol) . After 1 h, 1 chloro-3- (4-fluorophenyDpropane (1.63 g, 0.0095 mol) in

DMF (2 mL) was added dropwise and the reaction stirred 2.5 days. The reaction was then treated with additional 1- chloro-3- (4-fluorophenyDpropane (0.815 g, 0.0047 mol) and warmed at 35 °C for 6 h. The solvent was evaporated, the residue was acidified with 1 N HCl, and the mixture extracted with ether. The aqueous was made basic and extracted with ether. The extracts were dried, the εolvent evaporated, and the residue purified by radial chromatography (MeOH:EtOAc:NH ₄ OH/15:30 : 1) . The HCl salt

(0.19 g) crystallized from CHCI3-EtOAc-ether, m.p. 189-191 °C. (Compound 73)

Example 70 (±) 3-f3- .4- (Trifluoromethyl)Phenyll ropylthio)-4- [-3- (1- azabicyclo[2.2.21octyloxy) 1-1.2.5-thiadiazole

A εolution of the Compound 12 (1.15 g, 0.0047 mol) in DMF

(20 mL) waε treated portionwise with freshly ground flaked Na ₂ S-9H 0 (1.68 g, 0.007 mol) . After 2 h, the reaction was cooled to -35 °C, treated dropwise with l-bromo-3- [4- (trifiuoromethyl)phenyl)propane (2.53 g, 0.0095 mo-.) in DMF (30 mL) , and the reaction stirred 2 h. Cooling was removed, reaction stirred 3.5 h, and again cooled to -35 °C. The reaction was then treated with additional 1-bromo- 3- [4- (trifluoromethyl) henyl) ropane (1.75 g, 0.0043 mol) in DMF (5 mL) , cooling removed, and reaction stirred over

night . Additional l-bromo-3- [4- (trifluoromethyl)phenyl)propane (0.75 g, 0.0028 mol) m DMF

(5 mL) was added and stirring continued for 1.5 h. The solvent was evaporated, the residue suspended H2O, and the mixture extracted with ether. The extractε were dried, the solvent evaporated, and the residue purified by radial chromatography (MeOH:EtOAc:NH ₄ OH/15:30 : 1) . The HCl salt

(0.32 g) crystallized from CHCl ₃ -EtOAc-ether, m.p. 182-184 °C. (Compound 74)

Example 71

3- (1-Butylammo) -4-[(+ ,-)-3- (1-azabicvclo [2.2.21 octyloxy) 1 -

1.2.5-thιadιazole

A mixture of Compound 12 (1.15 g, 0.0047 mol) and 1- butylamme (20 mL) was heated to reflux for 22 h. The solvent was evaporated, residue suspended H ₂ 0, the mixture acidified, and extracted with ether. The aqueous phase was made basic, extracted with EtOAc, extracts dried, and solvent evaporated. Purification by radial chromatography (MeOH:EtOAc:NH OH/15 :30 : 1) and conversion to a HCl salt gave a solid partial hydrate (0.046 g) , m.p. 193-195 °C. (Compound 75)

Example 72

Cyanogen butyloxyimide

A solution of 1-butanol (92 mL, 1 mol) and triethylamine (3 mL) was cooled to -8 °C and cyanogen (58 g, 1.12 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C. The reaction mixture was then distilled at 7 mm Hg to give a clear liquid (119.4 g) b.p. 43-49 °C. (Compound 76) .

Example 73

3-Chloro-4-butyloxy-l.2 , 5-thiadiazole

A solution of DMF (400 mL) and sulfur monochloride (230 mL) waε cooled to 5 °C and Compound 76 (119.4 g, 0.95 mol) was added dropwise such that the temperature did not exceed 10 °C . Cooling was removed and the reaction was stirred over night. The reaction was cooled m an ice-water bath and the excess sulfur monochloride destroyed by dropwise addition of H20 such that the temperature did not exceed 30 °C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H ₂ 0, aqueous NaHC0 ₃ , brine, dried, and the solvent evaporated. The yellow liquid residue was distilled at 14 mm Hg to give a clear liquid (153 g) , b.p. 120-125 °C. (Compound 77)

Example 74 3-Methylthιo-4-butyloxy-l,2 , 5-thιadιazole

A solution of Compound 77 (6 g, 0.031 mol) in DMF (75 mL) was rapidly stirred as ground flaked Na ₂ S-9 H ₂ 0 (8 g, 0.034 mol) was added. After 1 h, CH ₃ I (3 mL, 0.048 mol) was added and the reaction stirred 30 mm. Ice-water (150 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H 0 (2 X) , dried and the solvent evaporated to give a clear liquid (6.04 g) . (Compound 78)

Example 75

3-Methylεulfonyl-4-butyloxy-l , 2 , 5-thιadιazole

To a εolution of Oxone (18.4 g, 0.03 mol) m H 0 [100 mL) was added dropwise Compound 78 (3 g, 0.0147 mol)

m THF (45 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H ₂ 0 (2 X) , dried, and the εolvent evaporated. The residue was purified by radial chromatography eluting with 50 % EtOAc-hexane to give a clear colorless liquid (2.93 g) that solidified on standing, m.p. 39-40 °C. (Compound 79)

Example 76 3-Methylthio-4-hexyloxy-l,2 , 5-thiadiazole

A solution of 3-chloro-4-hexyloxy-l, 2, 5- thiadiazole (CA 60, 2796e, 1964) ( 1.1 g, 0.005 mol) in DMF (30 mL) was rapidly stirred aε ground flaked Na ₂ S-9 H ₂ 0 (1.5 g, 0.00625 mol) waε added. After εtirring overnight, CH ₃ I (2 mL ) waε added and the reaction stirred 30 min. Ice-water (150 mL) waε added to the reaction and the mixture extracted with ether (2 X) . The extractε were waεhed with H ₂ 0 (2 X), dried and the solvent evaporated to give a clear liquid (1.025 g) . (Compound 80)

Example 77

3-Methylsulfonyl-4-hexyloxy-l,2 , 5-thiadiazole

To a εolution of Oxone (18.4 g, 0.03 mol) in H ₂ 0

(100 mL) waε added dropwise Compound 80 (3.4 g, 0.0147 mol) in THF (50 mL) . After stirring for three days, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H ₂ 0 (2 X) , dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 50 % EtOAc- hexane to give a clear colorless liquid (3.58 g) . (Compound 81)

Example 78

Cyanogen propyloxyimide

A solution of 1-propanol (40 mL, 0.536 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (36 g, 0.69 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C. The reaction mixture was then distilled at 20 mm Hg to give a clear liquid ( 59 g) b.p. 63-64 °C. (Compound 82)

Example 79

3-Chloro-4-propyloxy-l, 2.5-thιadιazole

A solution of DMF (180 mL) and sulfur monochloride (120 mL, 1.5 mol) was cooled to 5 °C and Compound 82 (59 g, 0.527 mol) was added dropwise such that the temperature did not exceed 10 °C. Cooling was removed and the reaction was εtirred over night. The reaction was cooled an ice-water bath and the excess εulfur monochloride deεtroyed by dropwiεe addition of H2O such that the temperature did not exceed 30 °C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H 0, aqueous NaHC0 ₃ , brine, dried, and the solvent evaporated. The yellow liquid residue was distilled at 15 mm Hg to give a clear liquid (79.9 g), b.p. 103-106 °C. (Compound 83)

Example 80 3-Methylthιo-4-propyloxy-l, 2.5-thιadιazole

A solution of Compound 83 (11.1 g, 0.062 mol) DMF (150 mL) was rapidly stirred as ground flaked Na ₂ S-9

H ₂ 0 (16.4 g, 0.068 mol) was added. After 1 h, CH ₃ I (6 mL, 0.096 mol) was added and the reaction stirred 30 mm. Ice-

water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H ₂ 0 (2 X) , dried and the solvent evaporated to give a clear liquid (11.02 g) . (Compound 84)

Example 81 3-Methylsulfonyl-4-propyloxy-l .2 , 5-thιadιazole

To a solution of Oxone (20 g, 0.0325 mol) m H ₂ 0 (100 mL) waε added dropwise Compound 84 (3 g, 0.0158 mol) THF (50 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H ₂ 0 (2 X) , dried, and the solvent evaporated to give a colorlesε oil. The reεidue waε purified by radial chromatography eluting with 40 %

EtOAc-hexane to give a clear colorleεε liquid (3.09 g) that solidified on standing. Recrystallization from hexane gave a white εolid, m.p. 30-31 °C. (Compound 85)

Example 82

Cyanogen methoxyimide

A solution of methanol (25 mL, 0.618 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (38 g, 0.73 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C. The reaction mixture was then distilled at 45 mm Hg to give a clear liquid ( 51 g) b.p. 48-53 °C. (Compound 86)

Example 83

3-Chloro-4-methoxv-1.2.5-thιadιazole

A solution of DMF (180 mL) and sulfur monochloride (120 mL, 1.5 mol) was cooled to 5 °C and Compound 86 (51 g, 0.607 mol) was added dropwise such that the temperature did not exceed 15 °C. Cooling was removed and the reaction was stirred over night. The reaction waε cooled in an ice-

water bath and the exceεs sulfur monochloride destroyed by dropwiεe addition of H ₂ O εuch that the temperature did not exceed 30 °C . The εolution was further diluted with H ₂ 0 (350 mL) and steam distilled until almost all of the distillate was homogeneous. The distillate was extracted with hexane (3 X) and the combined extracts washed with H ₂ 0, aqueous aHCθ ₃ , brine, dried, and the solvent distilled off until the volume waε 200 mL. The hot mixture waε filtered and cooled to give white cryεtals (53 g) . (Compound 87)

Example 84 -Methylthιo-4-methoxy-l, 2.5-thιadιazole

A solution of Compound 87 (9.4 g, 0.0623 mol) in

DMF (150 mL) was rapidly stirred as ground flaked Na2S-9 H ₂ 0 (16.4 g, 0.068 mol) was added. After 1 h, CH3I (6 mL, 0.096 mol) was added and the reaction stirred 30 mm. Ice¬ water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H ₂ 0 (2 X), dried and the solvent carefully evaporated to give a clear liquid (4.4 g) . (Compound 88)

Example 85 3-Methylsulfonyl-4-methoxy-l, 2 , 5-thιadιazole

To a solution of Oxone (34 g, 0.0552 mol) m H ₂ 0 (170 mL) waε added dropwise Compound 88 (4.4 g, 0.027 mol) in THF (80 mL) . After stirring 5 h, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H ₂ 0 (2 X) , dried, and the solvent evaporated to give a floculant white solid. Recrystallization from ether gave a white solid (2.76 g) , m.p. 110.5-111.5 °C. (Compound 89)

Example 86

3-Chloro-4-pentyloxy-l.2 , 5-thiadiazole

A solution of 1-pentanol (60 mL, 0.55 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (36 g, 0.69 mol) was εlowly bubbled through the εolution while maintaining the temperature below 2 °C. The reaction was then stirred another hour at -5 °C then added dropwise to a solution of DMF (180 mL) and sulfur monochloride (120 mL, 1.5 mol) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10 °C. Cooling was removed and the reaction was stirred over night. The reaction was cooled m an ice-water bath and the excesε sulfur monochloride destroyed by dropwise addition of H20 such that the temperature did not exceed 30 °C. The liquid was decanted from the semi-εolid εulfur precipitant and the εulfur reεidue triturated with hexane. The aqueouε fraction waε extracted with hexane (3 X) and the combined extractε and tπturantε were waεhed with H ₂ 0, aqueous aHC0 ₃ , brine, dried, and the solvent evaporated. The yellow liquid reεidue waε diεtilled at 9 mm Hg to give a clear liquid (92.7 g) , b.p. 129-135 °C. (Compound 90)

Example 87

3-Methylthιo-4-pentyloxy-l, 2, 5-thιadιazole

A εolution of Compound 90 (12.8 g, 0.06 mol) DMF (150 mL) was rapidly stirred as ground flaked Na ₂ S-9 H2O (16.4 g, 0.068 mol) was added. After 1 h, CH ₃ I (6 mL, 0.096 mol) was added and the reaction stirred 30 mm. Ice¬ water (300 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H ₂ 0 (2 X) , dried and the solvent evaporated to give a clear liquid (12.6 g) . (Compound 91)

Example 88

3-Methylsulfonyl-4-pentlvoxy-l .2.5-thιadιazole

To a solution of Oxone (72 g, 0.117 mol) m H ₂ 0 (350 mL) waε added dropwise Compound 91 (12.4 g, 0.0569 mol) in THF (180 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H 0 (2 X) , dried, and the solvent evaporated to give a colorless oil. The residue was purified by flash chromatography eluting with 40 % EtOAc- hexane to give a clear colorlesε liquid (13 g) . (Compound 92)

Example 89 3-Chloro-4-ethoxy-1, 2.5-thiadiazole

A solution of ethanol (60 mL, 1.02 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (59 g, 1.13 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °c . The reaction was then added dropwise to a solution of DMF (275 mL) and sulfur monochloride (225 mL, 2.81 mol) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10 °C. Cooling waε removed and the reaction was εtirred over night. The reaction was cooled in an lce- water bath and the exceεε εulfur monochloride deεtroyed by dropwiεe addition of H ₂ O εuch that the temperature did not exceed 30 °C. Additional H ₂ 0 (400 mL) waε added and the reaction internally steam distilled until the distillate waε almost homogeneous. The distillate was extracted with hexane (3 X) and the combined extractε waεhed with H20, aqueouε NaHC0 ₃ , brine, dried, and the εolvent carefully evaporated. The liquid reεidue was distilled at 21 mm Hg to give a clear liquid (154.3 g) , b.p. 88-93 °C. (Compound 93)

Example 90

3-Methylthio-4-ethoxy-1.2 , 5-thiadiazole

A solution of Compound 93 (16.5 g, 0.1 mol) in DMF (250 mL) was rapidly stirred as ground flaked Na ₂ S-9

H ₂ 0 (27 g, 0.113 mol) was added. After 1 h, CH ₃ I (9.5 mL, 0.153 mol) was added and the reaction stirred 1 h. Ice¬ water (400 mL) was added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H ₂ O (2 X) , dried and the solvent evaporated to give a clear liquid (12.5 g) . (Compound 94)

Example 91

3-Methylsulfonyl-4-ethoxy-l,2, 5-thiadiazole

To a solution of Oxone (90 g, 0.146 mol) in H2O (435 mL) waε added dropwise 19 (12.5 g, 0.071 mol) in THF (220 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extractε were waεhed with H2O (2 X) , dried, and the εolvent evaporated to give a white εolid. Recryεtallization from ether gave a white solid (9.9 g), m.p. 94-95 °C. (Compound 95)

Example 92

3-Chloro-4- (4-methylpentyloxy) -1,2, 5-thiadiazole

A solution of 4-methylpentan-l-ol (25 mL, 0.245 mol) and triethylamine (1 mL) was cooled to -8 °C and cyanogen (14 g, 0.27 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C. The reaction was then stirred another hour at -5 °C then added dropwiεe to a εolution of DMF (75 mL) and sulfur monochloride (49 mL) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10

°C. Cooling was removed and the reaction was stirred over night. The reaction waε cooled in an ice-water bath and

the excess εulfur monochloride destroyed by dropwise addition of H20 such that the temperature did not exceed 35 °C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur reεidue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H2θ, aqueous NaHCθ3 , brine, dried, and the solvent evaporated. The yellow liquid reεidue was distilled at 4.5 mm Hg to give a clear liquid (40.45 g) , b.p. 120-124 °C. (Compound 96)

Example 93 3-Methylthio-4- (4-methylpentyloxy) -1,2, 5-thiadiazole

A solution of Compound 96 (22 g, 0.1 mol) in DMF (250 mL) waε rapidly εtirred aε ground flaked Na ₂ S-9 H ₂ O (27 g, 0..113 mol) waε added. After 1 h, CH I (9.5 mL, 0.153 mol) waε added and the reaction εtirred 30 mm. Ice¬ water (300 mL) waε added to the reaction and the mixture extracted with hexane (3 X) . The extracts were washed with H ₂ O (2 X), dried and the solvent evaporated to give a clear liquid (21.6 g) . (Compound 97)

Example 94

3-Methylsulfonyl-4- (4-methylpentyloxy) -1,2, 5-thιadιazole

To a solution of Oxone (119 g, 0.193 mol) in H ₂ 0 (600 mL) was added dropwise Compound 97 (21.6 g, 0.093 mol) m THF (300 mL) . After stirring overnight, the organics were evaporated and the residue extracted with ether (3 X) . The extracts were washed with H ₂ O (2 X) , dried, and the solvent evaporated to give a colorless oil. The residue was purified by HPLC (8 L gradient, hexane to 40 % EtOAc- hexane) to give a clear colorless liquid (19.7 g) . (Compound 98)

Example 95

3- (1-Butyloxy) -4- r ndo- (+, -) -6- (1- azabicvclo[3.2.11 octyloxy) 1

-1,2, 5-thiadiazole

A solution of potassium t-butoxide (0.62 g, 0.0055 mol) in THF (12 mL) was treated with endo- (+, -) -1- azabιcyclo[3.2.1]octan-6-ol (0.64 g, 0.005 mol) . After 5 mm, 3-chloro-4- (1-butyloxy) -1,2, 5-thιadιazole (1.5 g, 0.0072 mol) was added. After stirring overnight, the solvent was evaporated, the residue diluted with H ₂ 0, acidified, and extracted with ether. The aqueous phase was made basic and extracted with EtOAc, the extracts dried, washed with bnne, dried, and the solvent evaporated. The residue was purified by radial chromatography (20 % EtOH-2 % NH ₄ 0H-CHC1 ₃ ) . The HCl salt crystallized from EtOAc to give a white solid (0.21 g), m.p. 172-173 °C dec. (Compound 71)

Example 96 (±) -3- (2-Methylthioethyl) -4- (1-azabicvclo r2.2.21octyl-3- oxy) -1.2, 5-thiadiazole

A solution of 3- (2-methylthioethyl) -4-hydroxy- 1, 2, 5-thιadιazole (0.45 g) and triphenylphosphine (0.7 g) was cooled m ice-water as diethyldiazodicarboxylate (0.4 mL) was added dropwiεe. After addition, (±)-l- azabicyclo[2.2.2]octan-3-ol (0.33 g) waε added, cooling removed, and reaction εtirred for 1 hour. The εolvent waε evaporated, reεidue εuspended in water, the mixture acidified and washed with ether. The aqueous solution was made baεic and extracted with EtOAc. The extracts were dried, the solvent evaporated, the residue purified by radial chromotography elutmg with 10%-EtOH-l%-NH ₄ θH-CHCl ₃ , and the product converted to a HCl salt. Recrystallization from acetone gave 0.6 g white crystalε, m.p. 177-178 °C. (Compound 99) .

The followmg compounds were synthesized in substantially the same manner as Compound 99.

Example 97 (±) -3- (l-Azabιcvclo[2.2.21octyl-3-oxy) -1.2.5-thiadiazole

A sample of 3-Hydroxy-1, 2 , 5-thιadιazole (0.28 g) , triphenylphospme (0.7 g), diethyldiazodicarboxylate (0.4 mL), and (±) -1-azabιcyclo[2.2.2]octan-3-ol (0.33 g) gave the hydrochloride salt of (±)-3-(l- azabιcyclo[2.2.2]octyl-3-oxy) -1, 2, 5-thιadιazole, m.p. 240 °C dec. (0.36 g) . (Compound 100) .

Example 98 (±) -3-Hexyl-4- (l-azabιcvclor2.2.21octyl-3-oxy) -1.2.5- thiadiazole

A sample of 3-Hexyl-4-Hydroxy-1, 2, 5-thιadιazole (0.93 g) , triphenylphospme (1.31 g) , diethyldiazodi- carboxylate (0.8 mL) , and (±) -1-azabιcyclo[2.2.2]octan-3-ol (0.64 g) gave the hydrochloride εalt of (±) -3-hexyl-4- (1- azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-thιadιazole, m.p. 163- 164 °C dec. (1.11 g) . (Compound 101) .

Example 99

(±) -3-Butylsulfonyl-4- (1-azabicvclo[2.2.21 octyl-3-oxy) -

1.2.5-thιadιazole

A solution of potassium t-butoxide (1.2 g) m THF (50 mL) waε treated with (±) -1-azabιcyclo[2.2.2] octan-3-ol (1.3 g) . After 10 mm, the reaction was cooled m ice-water and Compound 1 (2.3 g) was added in one portion. Cooling was removed and after two hourε the εolution was heated to reflux for 4 hourε. The solvent was evaporated, residue suspended in water, the mixture acidified and extracted with ether. The aqueous fraction was made baεic and extracted with EtOAc. The extractε were washed with water

bπne, dried, and the εolvent evaporated to give Compound 14 (1.95 g) . The oil was dissolved m dilute 0.5 N HCl (17 mL) , cooled m ice-water, and a solution of Oxone (6 g) in water (25 mL) waε added over 5 mm. Cooling waε removed and after 4 hourε exceεε oxidizing agent waε destroyed with aHS0 ₃ . The reaction was cooled in ice-water, made basic with 5 N NaOH, and extracted with EtOAc. The extracts were washed with brine, dried, and the solvent evaporated to give (±) -3-butylsulfonyl-4- (1-azabicyclo[2.2.2]octyl-3- oxy) -1,2, 5-thιadιazole as a yellow oil (1.6 g) . The HCl salt crystallized from 2-propanol as a white solid, m.p. 180-181 °C. (Compound 102)

Example 100 (±) -3-Propylsulfonyl-4- (1-azabicvclo[2.2.21octyl-3-oxy) -

1.2.5-thιadιazole

Using εubstantially the same procedure aε for Compound 102, (±) -1-azabιcyclo [2.2.2]octan-3-ol (4 g) and Compound 37 (4.9 g) gave (±) -3-propylεulfonyl-4- (1- azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-thιadιazole (4.2 g) as a tan liquid that solidified on standing, m.p. 77-78 °C. (Compound 103 ) .

Example 101

(±) -3-(4.4.4-Trιfluorobutyloxy)-4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1.2.5-thiadiazole

A solution of , 4, 4-trifluorobutanol (0.75 g) in THF (20 mL) was cooled to 0 °C and potassium t-butoxide (0.65 g) was added. After 5 mm, a solution of Compound 102 (0.6 g) m THF (5 mL) was added and the reaction stirred one hour. The reaction was quenched with 5N HCl (1.5 mL) and the solvent evaporated. The residue was suspended in water and extracted with ether. The aqueous phase waε made baεic and extracted with EtOAc. The extractε were dried, the solvent evaporated, and the

residue purified by radial chromotography elut g with 20%- EtOH-l%-NH OH-CHCl ₃ to give a clear oil. The HCl salt was recryεtallized from EtOAc-ether to give a white solid, m.p. 122-124 °C (0.43 g) . (Compound 104) .

The followmg compounds were prepared in substantially the same manner:

Example 102 (+)-3-(2-butvnyloxy)-4-(l-azabιcvclo[2.2.21octyl-3- oxy) -1.2, 5-thιadιazole

Using substantially the same procedure used m the preparation Compound 104, 2-butynol (0.45 g) and Compound 102 (0.6 g) gave after chromatography, (±)-3-{2- butynyloxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.45 g) as an HCl salt that crystallized from 2-propanol, m.p. 200-201 °C. (Compound 105)

Example 103

(±) -3- (Cvclopropylmethoxy) -4- (1-azabicvclo[2.2.21octyl-3- oxy) -1,2, 5-thιadιazole

Using substantially the same procedure used in the preparation Compound 104, cyclopropylmethanol (0.5 mL) and Compound 102 (0.6 g) gave after chromatography, (±)-3- (CyclopropyImethoxy) -4- (1-azabicyclo[2.2.2] octyl-3-oxy) - 1, 2, 5-thιadιazole (0.49 g) as an HCl salt that crystallized from acetone, m.p. 217-218 °C. (Comound 106)

Example 104

(±) -3- (3-PhenylproPvnyloxy) -4- (1-azabicvclo \ 2 . 2.21octyl-3- oxy) -1.2, 5-thιadιazole

Using substantially the same procedure used m the preparation of Compound 104, 3-phenylpropynol (0.85 g) and Compound 102 (0.66 g) gave after chromatography (±)-3- (3-phenylpropynyloxy) -4- (1-azabicyclo[2.2.2] octyl-3-oxy) - 1, 2, 5-thιadιazole as an HCl salt (0.66 g) that cryεtallized from ether-CHCl ₃ , m.p. 184-186 °C. (Compound 107)

Example 105

(±) -3- (3-Butenyloxy) -4- (1-azabicvclo [2.2.21octyl-3-oxy) -

1,2, 5-thιadιazole

Uεmg εubstantially the same procedure used in the preparation Compound 104, 3-butenol (0.5 mL) and Compound 102 (0.6 g) gave after chromatography, (±)-3-(3- butenyloxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.47 g) as an HCl salt that crystallized from acetone, m.p. 198-199 °C. (Compound 108) .

Example 106

(±) -3- ( rans- 2-Butenyloxy) -4- (1-azabicvclo[2.2.21 octyl-3- oxy) -1,2, 5-thιadιazole

Using subεtantially the εame procedure used m the preparation Compound 104, tra.r-s-2-butenol (0.45 g) and Compound 102 (0.6 g) gave after chromatography, (±) -3- ( trans- 2-butenyloxy) -4- (1-azdbιcyclo[2.2.2] octyl-3-oxy) - 1, 2 , 5-thιadιazole (0.51 g) aε an HCl salt that crystallized from 2-propanol, m.p. 182.5-184 °C. (Compound 109) .

Example 107

(±) -3- ( ci s- 2-Butenyloxy) -4- (1-azabicvclo[2 ,2.21octyl-3- oxy) -1.2, 5-thiadiazole

Using substantially the same procedure used m the preparation Compound 104, c s-2-butenol (0.45 g) and Compound 102 (0.5 g) gave after chromatography, (±) -3- ( cis- 2-butenyloxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.34 g) as an HCl salt that crystallized from acetone, m.p. 178-179 °C. (Compound 110) .

Example 108 (±) -3- (2-Methoxyethoxy) -4- (1-azabιcvclo [2.2.21 octyl-3-oxy) -

1,2.5-thiadiazole

Using substantially the same procedure used m the preparation Compound 104, 2-methoxyethanol (0.45 g) and Compound 102 (0.5 g) gave after chromatography, (±) -3- (2- methoxyethoxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.32 g) as an HCl εalt that crystallized from acetone, m.p. 131-134 °C. (Compound 111) .

Example 109

(±) -3- (2-Phenoxyethoxy) -4- (1-azabicvclo[2.2.21octyl-3-oxy) -

1.2.5-thiadiazole

Using εubεtantially the εame procedure used in the preparation of Compound 104, 2-phenoxyethanol (0.55 g) and Compound 102 (0.4 g) gave (±) -3- (2-phenoxyethoxy) -4- (1- azabicyclo [2.2.2]octyl-3-oxy) -1, 2, 5-thιadiazole as an HCl salt (0.43 g) that cryεtallized from ether-CHCD, m.p. 213- 215 °C. (Compound 112) .

Example 110

(±) -3- (3-Butvnoxy) -4- (1-azabicvclo [2.2.21octyl-3-oxy) -

1,2, 5-thiadiazole

Uεing εubεtantially the same procedure used in the preparation of Compound 104, 3-butynol (0.27 g) and Compound 102 (0.4 g) gave after chromatography (±)-3-(3- butynoxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole as an HCl salt (0.19 g) that crystallized from ether-CHCl ₃ , m.p. 207-208 °C. (Compound 113) .

Example 111

(±) -3- (2-Cvclopropylethoxy) -4- (1-azabicvclo[2.2.21octyl-3- oxy) -1.2.5-thiadιazole

Using substantially the same procedure used m the preparation Compound 104, 2-cyclopropylethanol (0.52 g) and Compound 102 (0.5 g) gave after chromatography, (±)-3- (2-cyclopropylethoxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -

1,2, 5-thiadiazole (0.48 g) as an HCl salt that crystallized from acetone, m.p. 192-193 °C. (Compound 114) .

Example 112

(±) -3- (2- (Methylthio) ethoxy) -4- (1-azabιcvclo[2.2.21 octyl-3- oxy) -1.2.5-thiadiazole

Usmg substantially the same procedure used m the preparation Compound 104, 2- (methylthio) ethanol (0.52 mL) and Compound 102 (0.5 g) gave after chromatography, (±) ^■ 3- (2- (methylthio)ethoxy) -4- (1-azabicyclo[2.2.2]octyl-3- oxy) -1, 2, 5-thιadιazole (0.4 g) as an HCl salt that crystallized from acetone, m.p. 187-188 °C . (Compound 115)

Example 113

(±) -3- (3-Chloropropoxv) -4- (1-azabιcvclo[2.2.21octyl-3-oxy) - 1.2, 5-thιadιazole

Using substantially the same procedure used m the preparation Compound 104, 3-chloropropanol (0.5 mL) and Compound 102 (0.4 g) gave after chromatography, (±)-3-(3- chloropropoxy) -4- (1-azabicyclo [2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.25 g) as an HCl salt that crystallized from acetone-EtOAc, m.p. 167-168 °C. (Compound 116) .

Example 114 (±)-3- (4-Fluorobutyloxy) -4- (1-azab cvclo \ 2 . 2 . 21 octyl-3- oxy) -1.2, 5-thιadιazole

Using substantially the same procedure used m the preparation Compound 104, 4-fluorobutanol (0.6 g) and Compound 102 (0.4 g) gave after chromatography, (±) -3- (4- fluorobutyloxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.34 g) as an HCl salt that crystallized from acetone-EtOAc, m.p. 180.5-181.5 °C. (Compound 117) .

Example 115

(±) -3- (2- [4-Chlorophenoxyl ethoxy) -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1,2, 5-thιadιazole

Using substantially the same procedure used in the preparation of Compound 104, 2- (4-chlorophenoxy)ethanol (0.77 g) and Compound 102 (0.4 g) gave after chromatography (±) -3- (2- [4-chlorophenoxy]ethoxy) -4- (1- azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-thιadιazole as an HCl salt (0.44 g) that crystallized from ether-CHCl ₃ , m.p. 224- 226 °C. (Compound 118) .

Example 116

(±) -3- (3- [2-Methoxy-5-pyrιdyllpropyloxy) -4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1,2, 5-thiadiazole

Using substantially the same procedure used the preparation of Compound 104, 3 (2-methoxy-5- pyπdyl)propanol (0.75 g) and Compound 102 (0.4 g) gave after chromatography (±) -3- (3- [2-methoxy-5- pyridyl]propyloxy) -4- (1-azabicyclo [2.2.2]octyl-3-oxy) -

1, 2, 5-thιadιazole aε an HCl salt (0.48 g) that crystallized from ether-CHCl ₃ , m.p. 148-150 °C. (Compound 119) .

Example 117

(±) -3- ( rans-3-Chloro-2-propenyloxy) -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1,2, 5-thιadιazole

Using substantially the same procedure used in the preparation Compound 104 except that the reaction waε conducted at -15 °C, trans-3-chloro-2-propenol (0.5 g) and Compound 102 (0.4 g) gave after chromatography, (±) -3- ( trans-3 -chloro-2-propenyloxy) -4- (1-azabicyclo [2.2.2] octyl- 3-oxy) -1, 2 , 5-thiadιazole (0.33 g) as an HCl salt that crystallized from acetone, m.p. 176.5-177.5 °C. (Compound 120) .

Example 118

(±) -3- (2- [4-Fluorophenoxylethoxy) -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1,2.5-thiadiazole

Using subεtantially the same procedure used m the preparation of Compound 104, 2- (4-fluorophenoxy) ethanol (0.53 g) and Compound 102 (0.4 g) gave after chromatography (±) -3- (2- [4-fluorophenoxy] ethoxy) -4- (1- azabicyclo [2.2.2]octyl-3-oxy) -1, 2, 5-thiadiazole as an HCl salt (0.43 g) that crystallized from ether-CHCl ₃ , m.p. 187- 189 °C. (Compound 121) .

Example 119

(±) -3- (4-Pentenyloxy) -4- (1-azabιcvclor2.2.21octyl- -oxy) - 1,2,5-thιadiazole

Using substantially the same procedure uεed in the preparation Compound 104, 4-pentenol (0.6 mL) and Compound 102 (0.4 g) gave after chromatography, (±)-3-(4- pentenyloxy) -4- (1-azabicyclo [2.2.2] octyl-3-oxy) -1,2,5- thiadiazole (0.37 g) as an HCl salt that crystallized from EtOAc, m.p. 165-166 °C. (Compound 122) .

Example 120 (±) -3- (3-Fluoropropyloxy) -4- (1-azabicvclo[2.2.21octyl-3- oxy) -1.2.5-thiadiazole

Uεing substantially the same procedure used in the preparation Compound 104, 3-fluoropropanol (0.4 g) and Compound 102 (0.4 g) gave after chromatography, (±) -3- (3- fluoropropyloxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole (0.3 g) as an HCl salt that crystallized from acetone, m.p. 206-207 °C. (Compound 123) .

Example 121

(±) -3- (Cvclobutylmethoxy) -4- (1-azabιcvclo[2.2 ,21octyl-3- oxy) -1,2, 5-thιad azole

Using subεtantially the εame procedure used m the preparation Compound 104, cyclobutylmethanol (0.6 mL) and Compound 102 (0.4 g) gave after chromatography, (±)-3- (eyelobutyImethoxy) -4- (1-azabicyclo[2.2.2] octyl-3-oxy) - 1, 2 , 5-thιadιazole (0.33 g) as an HCl salt that crystallized from acetone, m.p. 212-213 °C. (Compound 124) .

Example 122

(±)-3- (3,3. .2.2-Pentafluoropropyloxy. -4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1.2, 5-thiadiazole

Using subεtantially the same procedure used in the preparation of Compound 104, 3,3,3,2,2- heptafluoropropanol (0.69 g) and Compound 102 (0.4 g) gave after chromatography (±) -3- (3 , 3 , 3, 2 ,2- heptafluoropropyloxy) -4- (1-azabιcyclo[2.2.2] octyl-3-oxy) -

1, 2, 5-thιadιazole as an HCl salt (0.44 g) that crystallized from ether-CHCl ₃ , m.p. 185-186 °C. (Compound 125) .

Example 123 (±) -3- (2- [Phenylthiolethoxy) -4- (1-azabicvclo[2.2.21octyl-3- oxy) -1.2.5-thιadιazole

Using substantially the same procedure used m the preparation of Compound 104, 2- (phenylthio) ethanol (0.71 g) and Compound 102 (0.4 g) gave after chromatography

(±) -3- (2- [phenylthio]ethoxy) -4- (1-azabicyclo [2.2.2]octyl-3- oxy) -1,2, 5-thιadιazole as an HCl εalt (0.37 g) that crystallized from ether-CHCl ₃ , m.p. 187-189 °C. (Compound 126) .

Example 124

(+) -3- (2- [1-Napthyloxyl ethoxy) -4- (l-azabicvclo[2.2.21octyl-

3-oxy) -1.2, 5-thiadiazole

Using substantially the same procedure used in the preparation of Compound 104, 2- (1-napthyloxy)ethanol (0.839 g) and Compound 102 (0.4 g) gave after chromatography (±) -3- (2- [1-napthyloxy] ethoxy) -4- (1- azabicyclo [2.2.2] octyl-3-oxy) -1, 2, 5-thiadiazole as an HCl εalt (0.51 g) that cryεtallized from ether-CHCl ₃ , m.p. 223-

225 °C. (Compound 127) .

Example 125

(±) —3- .2- f4-Bromophenoxy1 ethoxy) -4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1,2.5-thiadiazole

Using substantially the same procedure used in the preparation of Compound 104, 2- (4-bromophenoxy) ethanol (0.97 g) and Compound 102 (0.4 g) gave after chromatography (±) -3- (2- [ -bromophenoxy] ethoxy) -4- (1- azabicyclo[2.2.2]octyl-3-oxy) -1,2,5-thiadιazole as an HCl salt (0.53 g) that crystallized from ether-CHCD, m.p. 223- 224 °C. (Compound 128) .

Example 126

(±) -?- (2-Hvdroxyethoxy) -4- (l-azabicvclo[2.2.21 octyl-3-oxy) -

1,2, 5-thiadiazole

A solution of ethylene glycol (9 mL) and potassium t-butoxide (1.5 g) was treated with Compound 102 (0.8 g) . After stirring over night, the reaction was heated to 55 °C for 1 h. The reaction was then cooled, diluted with water, and extracted with EtOAc. The extracts were washed with brine, dried, and the solvent evaporated to give a clear liquid. The liquid was purified by radial chromatography eluting with 20%-EtOH-2%-NH OH-CHCl ₃ and

then crystallized from ether to give a white solid (0.45 g) , m.p. 119.5-120.5 °C. (Compound 129)

Example 127 3-Butylthιo-4-hvdroxy-l,2.5-thιadιazole

A solution of Compound 1 (20.9 g) , DMSO (20 mL) and 2N NaOH (205 mL) was headed to reflux overnight. The solution waε cooled to 15 °C and concentrated HCl was added until the pH was 1. The solid waε collected, washed with water, and dried to give a solid (17.68 g) . Recrystallization from heptane gave white crystals, m.p. 72-72.5 °C. (Compound 130) .

Example 128

(±) exo-3-Butylthιo-4- (l-azabicvclo [2.2. llheptyl-3-oxy) -

1,2.5-thιadιazole

A solution of triphenylphosphine (0.7 g) and Compound 130 (0.5 g) THF (20 mL) waε cooled in ice¬ water. Diethyl diazodicarboxylate (0.4 mL) was added dropwise followed by addition of (±) endo-3-hydroxy-1- azabicyclo[2.2.1]heptane (0.29 g) . Cooling was removed and after 1 h the solvent was evaporated. The residue was suεpended in cold water, acidified, and extracted with ether. The aqueouε fraction was made basic and extracted with EtOAc. The extractε were dried, the εolvent evaporated, and the reεidue purified by radial chromatography elutmg with 5%-EtOH-0.5% NH ₄ OH-CHCI ₃ to give a clear oil. The HCl salt crystallized from EtOAc as white crystals (0.44 g) , m.p. 147-148 °C. (Compound 131) .

Example 129

(±) -3- (2-[3-fl,2.5-Thιadιazoyloxy) 1 ethoxy) -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1.2.5-thiadiazole

A solution of triphenylphosphine (0.35 g) and 3- hydroxy-1, 2, 5-thιadιazole (0.14 g) m THF (15 mL) was cooled ice-water. Diethyl diazodicarboxylate (0.21 g) was added dropwise followed by (±) -3- (2-hydroxyethoxy) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-thiadiazole (0.35 g) . Cooling waε removed, reaction waε εtirred 1 h, and the solvent was evaporated. The residue was suspended in cold water, acidified, and extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were washed with brine, dried, the solvent evaporated, and the residue purified by radial chromatography elutmg with 10%-EtOH-l% NH ₄ OH-CHCI ₃ to give a clear oil. The HCl salt crystallized from acetone as a white powder (0.34 g) , m.p. 178-179 °C. (Compound 132) .

Example 130

(±) -exo-3-Butyloxy-4- (7-azabicvclo[2.2.11heptyl-3-oxy) -

1,2, 5-thιadιazole

A solution of exo-7-azabιcyclo [2.2.1]heptan-3-ol (0.4 g) (Ref . J. Org. Chem. 1994, 59 , 1771) m THF (25 mL) was cooled ice-water and treated dropwise with 1.6 M n- butyllithiu m hexane (3.5 mL) . Cooling was removed and, after 15 mm, compound 79 (0.65 g) was added. After another 45 mm, the reaction was heated to reflux over night. The solvent was evaporated, the residue suspended m water, the mixture acidified, and extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography elutmg with 5%-EtOH-0.5% NH ₄ OH-CHCI ₃ then 10%-EtOH-l% NH ₄ OH-CHCI ₃ to give a clear oil. The HCl εalt cryεtallized from EtOAc-

ether as floculant white cryεtalε (0.4 g) , m.p. 116-117 °C. (Compound 133 ) .

Example 131 (±) -3-Butyloxy-4- (3-piperιdmyloxy) -1,2, 5-thiadiazole

A εuspension of (±) -3-hydroxypiperidine hydrochloride (0.5 g) m THF (20 mL) was treated dropwise with 1.6 M n-butyllithium in hexane (4.6 mL) . After 1 h, compound 79 (0.6 g) was added and the reaction was heated to reflux for 6.5 h. The solvent waε evaporated, the reεidue εuεpended cold water, acidified, and extracted with ether. The aqueous fraction was made basic and extracted with CHCI ₃ . The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography elutmg with 10%-EtOH-l% NH ₄ OH-CHCI ₃ to give a clear oil. The HCl salt crystallized from EtOAc as a white solid (0.38 g) , m.p. 124-125 °C. (Compound 134) .

Example 132

3-Butyloxy-4- ( cis -IR- 2-am ocvclopentanoxy) -1.2,5- thiadiazole

A εuspension of c s-lR-2-ammocyclopentanol hydrochloride (0.35 g) m THF (25 mL) was cooled m ice¬ water as 1.6 M n-butyllithium in hexane (3.2 mL) was added. Cooling was removed and after 30 mm, compound 79 (0.3 g) waε added and the reaction waε heated to reflux for 1 h. Additional compound 79 (0.3 g) waε added and the reaction heated to reflux over night. The εolvent was evaporated, the residue suspended in ice-water, acidified, and extracted with ether. The aqueous fraction was made basic, extracted with CHCI ₃ , the extracts dried, the solvent evaporated, and the residue purified by raidal chromatography elutmg with 10%-EtOH-l% NH ₄ OH-CHCI ₃ to give

a straw colored oil. The HCl salt crystallized ether as a tan solid (0.19 g) , m.p. 105-106.5 °C. (Compound 135) .

Example 133 (±) - endo- 3-Hexyloxy-4- (1-azabicvclo[3.2.11octyl-6-oxy) -

1.2.5-thιadιazole

A solution of potassium tert-butoxide (0.65 g) in THF (15 mL) was treated with (±)-en o-l- azabicyclo [3.2. l]octan-6-ol (0.64 g) . After 10 mm, 3- chloro-4-hexyloxy-l, 2, 5-thιadιazole (1.4 g) was added and the reaction stirred for 3 days. The solvent was evaporated, the residue suspended in ice-water, the mixture acidified, and extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, the extracts dried and the εolvent evaporated. The residue was punfed by radial chromatography eluting with 20%-EtOH-2%-NH OH-CHCl ₃ to give a clear oil (0.5 g) . The HCl salt crystallized from EtOAc to give a white solid, m.p. 160-161 °C. (Compound 136) .

The resolved enantiomerε of endo-1-azabιcyclo[3.2.1]octan- 6-ol were obtained by the reduction of the reεolved ketoneε (reference the Novo patent) aε described reference.

Example 134

(5S. 6S) -er.do-3-Butylthιo-4- (l-azabicvclo[3.2.11octyl-6- oxy) -1.2.5-thιadιazole

A solution of potassium tert-butoxide (0.65 g) in THF (25 mL) was treated with <5S, 6S) -endo- 1 - azabicyclo [3.2.1] octan-6-ol (0.65 g) . After 5 mm, the reaction was cooled m ice-water and compound 1 (1.2 g) was added. Cooling was removed and the reaction was stirred over night. The solvent was evaporated, the residue suspended in ice-water, and the mixture acidified and

extracted with ether. The aqueous fraction was made baεic, extracted with EtOAc, the extracts dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 20%-EtOH-2% NH ₄ OH-CHCI ₃ to give an oil. The HCl salt crystallized from EtOAc as floculant white crystals (0.59 g) , m.p. 201 °C, [α] _D = 11.44 °

(EtOH) . (Compound 137) .

Example 135 (5R . 6R ) -endo-3-Butylthio-4- (l-azabicvclo [3.2.11octyl-6- oxy) -1.2, 5-thiadiazole

Using the procedure deεcribed for the preparation of Compound 137, (5R, SR) -endo-1- azabicyclo[3.2.1]octan-6-ol (0.65 g) , potassium tert- butoxide (0.65 g) and compound 1 (1.2 g) gave floculant white crystals of the HCl salt of 334559 (0.62 g) , m.p. 201-202 °C, [α] _D = -12.33 ° (EtOH) . (Compound 138)

Example 136

1-Azabicvclo [4.3.0Tnona-6 , 8-diene-5-one

A solution of Ethyl-4- (N-pyrrolo)butanoate (ref. Tetrahedron Letterε 1994, 35, 3905) (3.64 g) m CH ₂ C1 ₂ (400 mL) was treated dropwiεe with 1 M BBr ₃ in CH Cl ₂ (60 mL) .

After 30 mm, the reaction waε quenched with water (50 mL) and neutralized with aqueouε NaHC0 ₃ . The organics were separated, washed with aqueous NaHCθ ₃ , brine, dried, and the εolvent evaporated. The reεidue waε purified by hplc using a 10%-EtOAc-hexane to 30% EtOAc-hexane gradient to give an oil (5.2 g) . (Compound 139) .

Example 137

(±) -cis + trans-1-Azabicvclo[ .3.01nonan-5-ols

A mixture of Compound 139 (5.2 g) , 5% Rh/Al ₂ θ ₃ (1.3 g) , EtOH (95 mL) was treated with H ₂ at 60 psi for 2 h. Another aliquote of 5% Rh/Al ₂ θ ₃ (1.3 g) was added and hydrogenation was continued over night. The catalyεt waε removed and εolvent evaporated to give an oil (4.2 g) that had appropriate maεs εpectru for the alcohols, m/e = 141. (Compound 140) .

Example 138

(±) - trans-3-Butylthιo-4- (1-azabicvclo[4.3.01nonyl-5-oxy) -

1,2, 5-thιadιazole

A solution of Compound 140 (0.7 g) m THF (20 mL) was treated with potassium tert-butoxide (0.6 g) . After 5 mm, compound 1 (1.1 g) was added, the reaction εtirred 1 h, then heated to reflux 1 h. The solvent was evaporated, the residue suspended ice-water, and the mixture acidified. After extracting with ether, the aqueous fraction was made basic and extracted with EtOAc. The EtOAc extracts were dried, the solvent evaporated, and the residue purified by radial chromatography elutmg with 5%-EtOH-0.5% NH ₄ OH-CHCI ₃ to give an oil. The HCl salt crystallized from EtOAc as a white solid (0.21 g) , m.p. 162-163 °C. (Compound 141) .

Example 139 (±) - cis-3-Butylthio- - (1-azabicvclo[4.3.01nonyl-5-oxy) -

1,2, 5-thιadιazole

Further elution during the chromatographic purification of Compound 141 gave another clear oil. The HCl crystallized from EtOAc as a white solid (0.18 g) , m.p. 125-126 °C. (Compound 142) .

Example 140

(±) -trans-3-Butylthιo-4- (2-dιmethylammocvcIopentyloxy) -

1.2.5-thιadιazole

A solution of potaεsium tert-butoxide (0.7 g) m THF (20 mL) was treated with (±) -trans-2- dimethylammocyclopentanol (0.8 g) . After 10 mm, the reaction was cooled m ice-water and compound 1 (1.25 g) waε added. Cooling was removed and the reaction waε stirred over night. After heating to reflux for 2 h, the solvent was evaporated, the reεidue suεpended m ice-water, and the mixture acidified. The mixture was extracted with ether and the aqueous phase made basic. Extraction with EtOAc, drying of the extracts, evaporation of the solvent, and purification by radial chromatography eluting with 10%- EtOH-1% NH ₄ OH-CHCI ₃ gave a tan liquid. The HCl salt crystallized from EtOAc-ether to give a white solid (0.55 g) , m.p. 124-125 °C . (Compound 143) .

Example 141

3 -Butylthιo- 4 - ( 2 -dιmethylammoethoxy ) - 1 , 2 , 5 -thiadiazole

A solution of potasεium tert-butoxide (0.6 g) in THF (20 mL) waε treated with 2-dιmethylammoethanol (0.5 mL) . After 5 min, compound 1 (1.05 g) waε added and the reaction εtirred 2 h. The solvent was evaporated, reεidue εuspended in ice-water, and the mixture acidified. The mixture was extracted with ether then the aqueous fraction made basic. Extraction with EtOAc, drying of the extracts, evaporation of the solvent, and purification of the residue by radial chromatography elutmg with 5%-EtOH-0.5% NH ₄ OH- CHCI ₃ gave an oil. The HCl salt crystallized from EtOAc as a white solid (0.47 g) , m.p. 104-105 °C. (Compound 144) .

Example 142

(±) -trans-3-Butylthio-4- (N- er -butylcarboxy-4-hvdroxy pyrollιdm-3-oxy) -1.2.5-thιadιazole A mixture of NaOH (0.12 g) and DMF (15 mL) was treated with Compound 130 (0.95 g) and the reaction stirred 1 h. The solution was treated with 3 , 4-epoxy-N- er - butylcarboxypyrollidme (0.8 g) and the solution heated at 60 °C over night. The temperature of the reaction waε then increased to 110 °C for 7.5 h. The solvent was evaporated, the residue suεpended in ice-water, and the mixture extracted with EtOAc. The extractε were washed with water, brine, the extracts dried, and the solvent evaporated. The residue was purified by radial chromatography elutmg with 50% EtOAc-hexane to give an oil (0.44 g) . (Compound 145) .

Example 143 (±) -trans-3-Butylthio-4- (4-hvdroxy-pyrollιdm-3-oxy) -1.2.5- thiadiazole A solution of Compound 145 (0.44 g) in EtOAc (15 mL) waε cooled m ice-water aε a εtream of dry HCl was introduced for 2 mm. Cooling waε removed and after 5 mm the solvent was evaporated. The residue was dissolved m cold water, extracted with ether, and the aqueous phase made baεic. The aqueouε waε extracted with EtOAc, the extractε dried, the solvent evaporated, and the residue purified by radial chromatography elutmg with 20%-EtOH-2% NH ₄ OH-CHCI ₃ to give a white solid. The HCl εalt crystallized from acetone-ether as a white solid (0.23 g) , m.p. 106-108 °C. (Compound 146) .

Example 144 (±) -endo-3-Butyloxy-4- (1-azabicvclo[3.2.11octyl-6-oxy) -

1,2, 5-th adιazole A solution of potassium tert-butoxide (0.62 g) m THF (10 mL) waε treated with (±)-endo-l- azabicyclo[3.2.1]octan-6-ol (0.64 g) . After 5 mm, the reaction waε cooled ice-water, compound 77 (1.5 g) was

added, cooling was removed, and the reaction stirred over night. The solvent was evaporated, the residue suεpended in ice-water, the mixture acidified, and the mixture extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, the extracts dried, the solvent evaporated, and the residue purified by radial chromatography elutmg with 20%-EtOH-2% NH ₄ OH-CHCI ₃ . The HCl salt cryεtallized from EtOAc to give a white εolid (0.21 g) , m.p. 172-173 °C. (Compound 147) .

Example 145

(±) -3- (4-Phenylbutylthio) -4- (l-azabicvclo \ 2.2 ,21octyl-3- oxy) -1.2.5-thιadiazole

Using substantially the same procedure used in the preparation of compound 40, compound 12 (1.15 g) and 1- ιodo-4-phenylbutane (4.92 g) gave (±)-3-(4- phenylbutylthio) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2,5- thiadiazole as a HCl salt (0.59 g) crystallizing from ether-EtOAc-CHCl ₃ , m.p. 136-139 °C. (Compound 148) .

Example 146 (±) -3- (3-Phenyl-2-propenylthιo) -4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1.2.5-thiadiazole

Using substantially the same procedure used for the preparation of compound 44, compound 12 (1.15 g) and cinnamyl bromide (3.73 g) gave (±) -3- (3-phenyl-2- propenylthio) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5- thiadiazole as an HCl salt (0.095 g) crystallizing from ether-EtOAc-CHCl ₃ , m.p. 211-213 °C. (Compound 149) .

Example 147

(±) -3- (3- [4-Fluorophenyl1propan-3-onethιo) -4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1,2.5-thiadiazole

Using substantially the same procedure used m the preparation of compound 40, compound 12 (1.15 g) and 1- chloro-3- (4-fluorophenyl)propan-3-one (3.52 g) gave (±)-3- (3- [4-Fluorophenyl]propan-3-onethio) -4- (1- azabicyclo [2.2.2] octyl-3-oxy) -1, 2 , 5-thιadιazole as a HCl εalt (0.375 g) crystallizing from ether-EtOAc-CHCl ₃ , m.p.

203-204 °C. (Compound 150) .

Example 148

(±) -3- (3- [N-phenothiazmyllpropylthio) -4- (1- azabicvclo[2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

Using substantially the same procedure used m the preparation of compound 13, compound 12 (1.15 g) and 1- bromo-3- (N-phenothiazmyl)propane (1.25 g) gave (±)-3-(3- [N-phenothiazmyl]propylthio) -4- (1-azabicyclo[2.2.2] octyl- 3-oxy) -1, 2 , 5-thιadιazole as a HCl salt (0.35 g) crystallizing from EtOAc, m.p. 194-196 °C. (Compound 151) .

Example 149 (±) -3- (3- [4-Fluorophenyl1 -3- [ -fluorophenoxy1propylthio) -4- (1-azabicvclo[2.2.21 ctvl - -oxv) -1.2, 5-thiadiazole

Using substantially the same procedure used in the preparation of compound 13, compound 12 (1.15 g) and 1- chloro- -(4-fluorophenyl) -3- (4-fluorophenoxy)propane (2.6 g) gave (±) -3- (3- [4-fluorophenyl] -3- [4- fluorophenoxy]propylthio) -4- (1-azabicyclo [2.2.2]octyl-3- oxy) -1, 2, 5-thιadιazole as an oxalate salt (0.42 g) crystallizing from EtOAc-ether, m.p. 87-96 °C. (Compound 152) .

Example 150

(±) -3- (3-Phenyl-3- [4-trifluoromethylphenoxy1propylthio) -4- (1-azabicvclo [2.2.21 octyl-3-oxy) -1,2, 5-thiadiazole

Using subεtantially the same procedure used m the preparation of compound 13, compound 12 (1.15 g) and 1- chloro-3-phenyl-3- (4-trifluoromethylphenoxy)propane (2.0 g) gave (±) -3- (3-phenyl-3- [ - trifluoromethylphenoxy]propylthio) -4- (1- azabicyclo [2.2.2]octyl-3-oxy) -1,2, 5-thιadιazole as an oxalate salt (0.198 g) crystallizing from CHCD-ether, m.p. 74-83 °C. (Compound 153) .

Example 151

(±) -3- (4.4.4-trifluorobut.ylt-.hio. -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1.2, 5-thiadiazole

Using εubεtantially the same procedure used the preparation of compound 13, compound 12 (1.15 g) and bromo-4, 4, 4-trifluorobutane (1.81 g) gave (±) -3- (4, 4, 4- trifluorobutylthio) -4- (1-azabicyclo [2.2.2]octyl-3-oxy) - 1, 2, -thιadιazole as a HCl salt (1.43 g) crystallizing from CHCl ₃ -ether, m.p. 128-130 °C. (Compound 154) .

Example 152

(±)-3-(3-[3-pyrιdyllpropylthιo)-4-(l- azabicvclo [2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

Using substantially the same procedure used in the preparation of compound 13, compound 12 (1.15 g) and bromo-3- (3-pyrιdyl) propane (1.42 g) gave (±) -3- (3- [3- pyridyl]propylthio) -4- (1-azabicyclo[2.2.2]octyl-3-oxy) - 1, 2, 5-thιadιazole as a HCl salt (0.92 g) crystallizing from CHCl ₃ -ether-EtOAc, m.p. 202-204 °C. (Compound 155) .

Example 153

(±) - endo-3 - (2-Phenoxyethylthιo) -4- (1- azabιcvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Using substantially the same procedure uεed in the preparation of compound 72, compound 48 (1.15 g) and bromo-2-phenoxyethane (3.8 g) gave (±) -endo-3- (2- phenoxyethylthio) -4- (1-azabicyclo[3.2.1] octyl-6-oxy) -1,2,5- thiadiazole as a HCl salt (0.11 g) crystallizing from CHCD-ether-EtOAc, m.p. 144-146 °C. (Compound 156) .

Alternate procedure for the preparation of (±) -exo-methyl- 6-hvdroxy-2-azabicvclo[2.2.21octane-2-carboxylate

(±) -exo-methyl-2-azabicvclo[2.2.21oct-5-en-7-one-2- carboxylate

Postassium hydroxide (39.9g/712mmol) was added to a solution of methyl 7-acetoxy-7-cyano-2- azabιcyclo[2.2.2]oct-5-ene-2-carboxylate (J. Orσ. Chem. 1989, 5 , 2893) (35.6g/142mmol) , ethanol (450mL), and water (90mL) . Stirred at room temperature for 2 hours. Removed the ethanol by evaporation then extracted the aqueous residue with ethyl acetate. The organic extracts were dried over magnesium sulfate then evaporated. Purified by preprative HPLC over silica gel eluting with 10 to 100% ethyl acetate in hexaneε to yield (±) -exo-methyl 2- azabicyclo[2.2.2]oct-5-en-7-one-2-carboxylate (9.2g/50.8mmol) .

(±) -exo-Methyl-2-azabicvclo[2.2.21oct-6-one-2-carboxylate

A sample of (±) -exo-Methyl 2-azabιcyclo[2.2.2]oct-5-en- 7-one-2-carboxylate (9.2g/50.8mmol) was hydrogenated with 5% palladium on carbon (0.5g) in methanol (150mL) at 35 PSIG and room temperature for 1 hour. Filtered off the catalyst and

-Ill- evaporated the filtrate to yield (±) -exo-methyl-2- azabicyclo [2.2.2] oct-6-one-2-carboxylate (9g) .

(±) -exo-Methyl-6-hvdroxy-2-azabιcvclo[2.2.21octane-2- carboxylate

Sodium borohydride (1. g/36. lmmol) was added to a mixture of (±) -exo-methyl-2-azabιcyclo [2.2.2]oct-6-one-2- carboxylate (6g/32.8mmol) and cerium trichloride heptahydrate (13.4g/36.lmmol) in methanol (55mL) at O'C. Stirred at room temperature overnight. The reaction was evaporated, the residue was taken up in water then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate then evaporated. The residue was purified by flash chromatagraphy over silica gel elutmg with 25% ethyl acetate m hexaneε to yield (±) -exo- methyl-6-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate (3.6g/19.5mmol) .

(±) -endo-Methyl-6-hvdroxy-2-azabicvclo [2.2.21 octane-2- carboxylate

Separation of (±) -exo-methyl-6-hydroxy-2- azabicyclo [2.2.2]octane-2-carboxylate and (±) -endo-methy1- 6-hydroxy-2-azabιcyclo [2.2.2]octane-2-carboxylate, Compound 62, was achieved by hplc over silica gel elutmg with a 10% to 80% EtOAc-hexane gradient.

Example 154 (±) -exo-3-Propythιo-4- (2-methoxycarbonyl-2- azabιcvclo[2.2.21 octyl-6-oxy) -1,2, 5-thiadiazole

Sodium hydride (19.5mmol) was added to a solution of (±) -exo-methyl-6-hydroxy-2-azabicyclo[2.2.2]octane-2- carboxylate (3.6g/19.5mmol) in tetrahydrofuran (200mL) at room temperature. The reaction was stirred for 1 hour whereupon 3-chloro-4-propylthιo-l, 2 , 5-thιadιazole

(3.8g/19.5mmol) m tetrahydrofuran (50mL) was added to the reaction and εtirred for 16 hourε at room temperature. The reaction was poured mto water and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate then evaporated. The residue was purified by preprative HPLC over silica gel elutmg with 5 to 50% ethyl acetate m hexanes to yield [ exo] (±) -exo-3-Propythιo-4- (2 methoxycarbonyl-2-azabicyclo [2.2.2] octyl-6-oxy) -1,2,5- thiadiazole (2. lg/6. lmmol) . (Compound 157) .

Example 155

(±) -exo-3-Propvlsulfonvl-4- (2-methoxycarbonyl-2- azabιcvclof2.2.21octyl-6-oxy) -1.2, 5-thiadiazole

A εolution of Oxone® (7.6g/12.4mmol) water (30mL) was added to a εolution of (±) -exo-3-propythιo-4- (2- methoxycarbonyl-2-azabicyclo[2.2.2] octyl-6-oxy) -1,2,5- thiadiazole (2. lg/6. lmmol) , water (lOmL), and tetrahydrofuran (20mL) . Stirred at room temperature for 16 hours. The reaction was extracted with diethyl ether (3x50mL) . The organic extracts were washed with water, saturated aqueous sodium bicarbonate, water, dried over magnesium sulfate, then evaporated to yield (±) -exo-3-propylsulfonyl-4- (2- methoxycarbonyl-2-azabicyclo [2.2.2]octyl-6-oxy) -1,2,5- thiadiazole (2.4g) . (Compound 158) .

Example 156

(±) -exo-3- (4,4.4-Trιfluorobutyloxy) -4- (2-methoxycarbonyl-2 - azabicvclo[2.2.21octyl-6-oxy) -1.2, 5-thiadiazole

Sodium hydride (4. lmmol) was added to a solution of 4, 4, 4-trifluorobutanol in tetrahydrofuran (35mL) at room temperature. Stirred for 2 hours where upon (±)-exo-3- propylsulfonyl-4 (2-methoxycarbonyl-2-azabιcyclo[2.2.2] octyl- 6-oxy) -1, 2 , 5-thιadιazole (1. Og/2.7mmol) tetrahydrofuran (5mL) was added to the reaction. The reaction was refluxed for 16 hours. The reaction was poured mto brine then

extracted with ethyl acetate (3x75mL) . The organic extracts were dried over magnesium sulfate to yield (±) - exo-3 - (4 , 4, 4- tπfluorobutyloxy) -4- (2-methoxycarbonyl-2- azabicyclo [2.2.2]octyl-6-oxy) -1,2, 5-thiadiazole (1.0g/2.5mmol) . (Comound 159) .

Example 157

(±) -exo-3- (4,4, 4-Trιfluorobutyloxy) -4- (2- azabicvclo[2.2.21octyl-6-oxy) -1,2, 5-thiadiazole

Trimethylsilyl iodide (0.4mL/3. Ommol) was added to a solution of (±) -exo-3- (4 , 4, 4-trifluorobutyloxy) -4- (2- methoxycarbonyl-2-azabicyclo[2.2.2] octyl-6-oxy) -1,2,5- thiadiazole (1.Og/2.5mmol) and dichloromethane (30mL) . The reaction was refluxed for 16 hours then poured into methanol (25mL) , stirred at room temperature for 15 m utes, then evaporated. The residue was purified by radial chromatagraphy on silica gel eluting with 2% ehtanol / 10% triethylamine m ethyl acetate to yield (±) -exo-3- (4, 4, 4- trifluorobutyloxy) -4- (2-azabicyclo[2.2.2]octyl-6-oxy) -1,2,5- thiadiazole which was isolated as the oxalate salt to yield 251 mg (mp = 115-120'C) . (Compound 160) .

Example 158 (±) -exo-3- (Hexyloxy) -4- (2-azabicyclof2.2.21 octyl-6-oxy) -

1.2.5-thiadiazole

Substantially the same procedure used to prepare Compound 160 with substition of hexanol for 4,4,4- trifluorobutanol gave (±) -exo-3- (hexyloxy) -4- (2- azabicyclo [2.2.2] octyl-6-oxy) -1, 2, 5-thιadιazole oxalate (mp = 128-30'C) . (Compound 161) .

Example 159

(±) - endo-3 - (4,4, 4-Trifluorobutyloxy) -4- (2- azabicvclo[2.2.21octyl-6-oxy) -1,2, 5-thiadiazole

From (±) -endo-methyl-6-hydroxy-2- azabicyclo[2.2.2]octane-2-carboxylate was obtained (±) -endo- 3- (4, 4, 4-trifluorobutyloxy) -4- (2-azabicyclo[2.2.2]octyl-6- oxy) -1, 2, 5-thiadiazole Using substantially the same procedure used to synthesize Compound 160. The compound was isolated as the oxalate salt (mp = 151-153'C) . (Compound 162) .

Example 160

(±) -exo-3- (2- [Fluorophenoxyl ethylthio) -4- (2-methoxycarbonyl- 2-azabicvclo[2.2.21octyl-6-oxy) -1.2, 5-thiadiazole

Sodium sulfide nonahydrate (lg/4.lmmol) was added to (±) -exo-3-propylsulfonyl-4- (2-methoxycarbonyl-2- azabicyclo[2.2.2]octyl-6-oxy) -1,2, 5-thiadiazole (1.3g/3.5mmol) in dimethylformamide (25mL) at 100'C. Stirred for 2 hourε whereupon 2-bromoethyl 4-fluorophenyl ether (0.9g/4.2mmol) in dimethylformamide (5mL) was added to the reaction. Stirred for 1 hour at 100'C then 16 hours at room temperature. The reaction was poured into brine then extracted with ethyl acetate (3xl50mL) . The organic extractε were combined and dried over magnesium sulfate then evaporated. The residue was purified by radial chromatagraphy over silica gel eluting with 30% ethyl acetate in hexaneε to yield (±) -exo-3- (2- [fluorophenoxy]ethylthio) -4- (2-methoxycarbonyl-2-azabicyclo[2.2.2]octyl-6-oxy) -1,2,5- thiadiazole (0.9g/2. lmmol) . (Compound 163) .

Example 161

(±) -exo-3- (2- [Fluorophenoxyl ethylthio) -4- (2- azabicvclo[2.2.21 octyl-6-oxy) -1,2, 5-thiadiazole

Trimethylsilyl iodide (0.4 mL/2.5 mmol) was added to a solution of (±) -exo-3- (2- [ fluorophenoxy] ethylthio) -4- (2-

methoxycarbonyl-2-azabicyclo [2.2.2] octyl-6-oxy) -1,2,5- thiadiazole (0.9g/2. lmmol) and dichloromethane (50mL) . The reaction waε refluxed for 16 hourε then poured into methanol (25mL) , εtirred at room temperature for 15 mmutes, then evaporated. The residue was purified by radial chromatagraphy on silica gel elutmg with 2% ehtanol / 10% triethylamine m ethyl acetate to yield (±) -exo-3- (2- [fluorophenoxy] ethylthio) -4- (2-azabicyclo [2.2.2]octyl-6-oxy) - 1, 2, 5-thιadιazole which was isolated as the oxalate salt to yield 222 mg (mp = 145-149'C) . (Compound 164) .

Example 162

(±) - endo- 3-Propylthιo-4- (1-azabicvclo[3.2.11octyl-6-oxy) -

1,2.5-thιadιazole

A sample of (±) -endo-1-Azabicyclo[3.2.1] octan-6-ol (5.1 g, 40 mmoles) was added to a solution of potassium t-butoxide (5.4 g, 48 mmoles) m 120 ml THF and cooled in an ice bath. Compound 37 (8.0 g, 41 mmoles was added and the reaction stirred for 3 hr at room temperature. Ethyl acetate was added, the organic layer washed with water, dried over sodium sulfate and condensed to yield 10.0 g of crude product. HPLC purification elutmg with 5% ethanol/chloroform with 0.5% ammonium hydroxide yielded 8 g of (±) -endo-3-propylthιo-4- (1- azabicyclo [3.2.1] octyl-6-oxy) -1, 2, 5-thιadιazole aε an oil, 71%. (Compound 165) .

Example 163

(±) -endo-3-Propylsulfonyl-4- (1-azabicvclo[3.2.11octyl-6- oxy) -1,2, 5-thιadιazole

A solution of (±) -endo-3-propylthιo-4- (1- azabicyclo [3.2.1] octyl-6-oxy) -1, 2, 5-thιadιazole (5.7 g) m 1 N HCl (24 mL) was cooled m ice-water and Oxone (36.8 g) in H ₂ 0 (75 mL) was added dropwise over 5 mm. Cooling waε removed and after 5 h, excess oxidant was destroyed with NaHS0 ₃ . The reaction waε poured mto ice and the pH

adjusted to 12. The mixture was extracted with EtOAc, the extracts waεhed with water, the εolvent dried, and the εolvent evaporated to give analytically pure (±) -er-do-3- propylεulfonyl-4- (1-azabicyclo[3.2.1]octyl-6-oxy) -1,2,5- thiadiazole aε an oil (4.6 g) . (Compound 166) .

Example 164

(±) - endo- ^■ 3- (4, , 4, 4-Trιfluorobutoxv) - -4- (1- azablcvclo[3 .2 ,11octvl-6-oxv) -1,2 .5-thladiazole

A solution of 4, 4, 4-trifluorobutanol (0.32 g) in THF (15 mL) was cooled ice-water and treated with potasεium tert-butoxide (0.4 g) . A εolution of Compound 166 (0.4 g) m THF (10 mL) was added dropwise to the reaction and the mixture stirred 1 h. The reaction was diluted with cold water, the pH adjusted to 12, and the mixture extracted with EtOAc. The extracts were dried and the solvent evaporated. The residue was treated with dry HCl m ether and the resulting crystals collected, washed with ether, and dried to give a white solid (0.16 g) , m.p. 155- 156 °C. (Compound 167) .

The following compounds were obtained by substantially the same procedure substituting the appropriate alcohol for the 4, 4 , 4-trifluorobutanol.

Example 165

(±) -endo-3- (2-Butvnvloxv)-4- (1-azabicvclo[ .2.11octyl-6- oxv) -1 , 2 , 5-thιadιazole

Obtained from Compound 166 and 2-butynol as the HCl salt in 89% yield, m.p. 200-201. (Compound 168) .

Example 166

(±) -endo-3- ( rans-2-Butenyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2.5-thiadiazole

Obtained from Compound 166 and trans-2-butenol as the HCl salt in 54% yield, m.p. 160-161 °C. (Compound 169) .

Example 167

(±) -endo-3- (2-Methylthloethoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2- methylthioethanol as the HCl salt in 85% yield, m.p. 169- 170 °C. (Comound 170) .

Example 168

(±) -endo-3- (2- (4-Methyl-l.3-thiazol-5-yl) ethoxy) -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2- (4-methyl-l, 3- thiazol-5-yl) ethanol as the HCl salt m 73% yield, m.p. 171-172 °C. (Compound 171) .

Example 169

(±) -endo-3- (4-Methylthiobenzyloxy) -4- (1- azabicvclo[3.2.11 octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4- methylthiobenzyl alcohol as the HCl salt m 28% yield, m.p. 155-156 °C. (Compound 172) .

Example 170

(±) -endo-3- (2-Thιenylmethoxy) -4- (1-azabicvclo[3.2.11octyl-

6-oxy) -1.2, 5-thιa ιazole

Obtained from Compound 166 and 2- thiophenemethanol as the HCl salt in 29% yield, m.p. 134- 135 °C. (Compound 173) .

Example 171

(±) -endo-3- (2-Cvclohexenyloxy) -4- (l-azabicvclo [3.2.11octyl-

6-oxy) -1,2.5-thiadiazole

Obtained from Compound 166 and 2-cyclohexenol as the HCl salt in 55% yield, m.p. 179-180 °C. (Compound 174) .

Example 172

(±) -er.do-3- (3-Pentvnyloxy) -4- (1-azabicvclo[3.2.11octyl-6- oxy) -1,2, 5-thιadιazole

Obtained from Compound 166 and 3-pentynol as the HCl salt 40% yield, m.p. 118-119 °C. (Compound 175) .

Example 173

(±) -endo-3- (3-Hexynyloxy) -4- (1-azabicyclo[3.2.11octyl-6- oxy) -1.2, 5-thιadιazole

Obtained from Compound 166 and 3-hexynol as the HCl salt m 27% yield, m.p. 134-135 °C. (Compound 176) .

Example 174

(±) -endo-3- (3-Chloropropoxy) -4- (l-azabicvclo[3.2.11 octyl-6- oxy) -1.2, 5-thιadιazole

Obtained from Compound 166 and 3-chloropropanol as the HCl salt m 48% yield, m.p. 131-132 °C. (Compound 177) .

Example 175 (±)-endo-3- [2- (2-Napthalyl) ethoxy1 -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2- (2- napthalyl) ethanol as the HCl salt m 34% yield, m.p. 134- 139 °C. (Compound 178) .

Example 176

(±) -endo-3- (4-Methyl-3-pentenyloxy) -4- (1- azabicvclo [3.2.11 octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4-methyl-3- pentenol as the HCl salt in 98% yield, m.p. 113-114 °C. (Compound 180) .

Example 177

(±) -endo-3- (cis-2-Butenyloxy) -4- (1-azabicvclo[3.2.11octyl-

6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and cιs-2-butenol as the HCl salt in 37% yield, m.p. 151-152 °C. (Compound 181) .

Example 178

(±) -endo-3- (Cvclopropylmethoxy) -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and cyclopropylmethanol as the HCl salt in 50% yield, m.p. 165- 166 °C. (Compound 182) .

Example 179 (±) -endo-3- (2-Methoxyethoxy) -4- (l-azabicvclo [3.2.11 octyl-6- oxv) -1.2. -thιadιazole

Obtained from Compound 166 and 2-methoxyethanol as the HCl salt m 25% yield, m.p. 123-124 °C. (Compound 183) .

Example 180

(±) -endo-3 - (3-Butenvloxv) -4- fl-azabicvclo \ 3 .2 .11octvl-6- oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 3-butenol as the HCl salt in 20% yield, m.p. 168-169 °C. (Compound 184) .

Example 181 (±) -endo-3- (2-Cvclooropylethoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2- cyclopropylethanol as the HCl salt in 76% yield, m.p. 152- 153 °C. (Compound 185) .

Example 182

(±) -endo-3- (3-Butvnyloxy) -4- fl-azabicvclo[3.2.11 octyl-6- oxy) -1,2, 5-thιadιazole

Obtained from Compound 166 and 3-butynol as the HCl salt in 65% yield, m.p. 198-199 °C. (Compound 186) .

Example 183

(±) -endo-3- (4.4.4.3.3.2.2-HePtafluorobutoxy) -4- fl- azabicvclo [3.2.11 octyl-6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 4,4,4,3,3,2,2- heptafluorobutanol as the HCl salt m 23% yield, m.p. 192- 193 °C. (Compound 187) .

Example 184

(±) -endo-3- [2- (3-Trifluoromethylphenyl) ethoxy1 -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 2- (3- trifluoromethylphenyl) ethanol as the HCl salt 38% yield, m.p. 118-120 °C. (Compound 188) .

Example 185

(±) -endo-3- [2- (2-Thienyl) ethoxy1 -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 2- (2- thienyl) ethanol aε the HCl salt in 63% yield, m.p. 119-120 °C. (Compound 189) .

Example 186 (±) -endo-3- (3.3.3.2,2, Pentafluorooropoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2.5-thiadiazole

Obtained from Compound 166 and 3,3,3,2,2- pentafluoropropanol as the HCl salt 77% yield, m.p. 208- 209 °C. (Compound 190) .

Example 187

(±) -endo-3- (2-Phenoxyethoxy) -4- (1-azabicvclo [3.2.11 octyl-6 oxy) -1 , 2 , 5-thιadιazole

Obtained from Compound 166 and 2-phenoxyethanol as the HCl salt 80% yield, m.p. 165-166 °C. (Compound 191) .

Example 188 (±) -endo-3- (4-n-Butylbenzyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4-n-butylbenzyl alcohol as the HCl salt m 18% yield, m.p. 168-169 °C . (Compound 192) .

Example 189

(±) -endo-3- [3- (4-Methoxyphenyl)proooxyl -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 3- (4- methoxyphenyl)propanol as the HCl salt 54% yield, m.p. 161-162 °C. (Compound 193) .

Example 190

(±) -en do- 3- (4-Fluorobenzyloxy) -4- (1-azabicvclo [3.2.11octyl-

6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 4-fluorobenzyl alcohol as the HCl salt m 71% yield, m.p. 163-164 °C. (Compound 194) .

Example 191

(±) -endo-3- (2.4-Difluorobenzyloxy) -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2,4- difluorobenzyl alcohol aε the HCl salt m 17% yield, m.p. 168-169 °C. (Compound 195) .

Example 192 (±) -endo- - [4- (Trifluoromethoxy)benzyloxyl -4- (1- azabicvclo [3.2.11 octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4- trifluoromethoxybenzyl alcohol as the HCl salt m 8% yield, m.p. 185-186 °C. (Compound 196) .

Example 193

(±) -endo-3- (4-Fluorobutoxy) -4- (1-azabicvclo [3.2.11 octyl-6- oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4-fluorobutanol as the HCl salt m 56% yield, m.p. 142-143 °C. (Compound 197) .

Example 194

(±) -endo-3- (4-tert-Butylbenzyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 4-tert- butylbenzyl alcohol as the HCl εalt m 40% yield, m.p. 192- 194 °C. (Compound 198) .

Example 195

(±) -endo-3- (1-Cvclopropylethoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and (±)-l- cyclopropylethanol as the HCl salt m 39% yield, m.p. 171- 172 °C. (Compound 199) .

Example 196 (±) -endo-3- (2-Cvclohexylethoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2, 5-thiadiazole

Obtained from Compound 166 and 2- cyclohexylethanol as the HCl salt in 15% yield, m.p. 139- 141 °C. (Compound 200) .

Example 197

(±) -endo-3- (3-Methyl-2-butenyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2.5-thiadiazole

Obtained from Compound 166 and 3-methyl-2- butenol as the HCl salt in 60% yield, m.p. 149-150 °C. (Compound 201) .

Example 198

(±) -endo-3- (4-Cvclohexylbutoχy) -4- (1- azabicyclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4- cyclohexylbutanol m as the HCl salt 9% yield, m.p. 130-132 °C. (Compound 202) .

Example 199

(±) -endo-3- (3-Butvn-2-oxy) -4- (1-azabicvclo[3.2.11octyl-6- oxy) -1,2, 5-thιadιazole

Obtained from Compound 166 and (±) -3-butyn-2-ol in 58% yield as the HCl salt, m.p. 179-180 °C. (Compound 203) .

Example 200 (±) -endo-3- (3-Methyl-3-phenylbutoxy) -4- (.1 - azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 3-methyl-3- phenylbutanol as the HCl salt m 34% yield, m.p. 145-147 °C. (Compound 204) .

Example 201

(±) -endo-3- (3-Fluoropropoxy) -4- (1-azabicvclo[3.2.11 octyl-6- oxy) -1,2, 5-thιadιazole

Obtained from Compound 166 and 3-fluoropropanol as the HCl salt m 72% yield, m.p. 147-148 °C. (Compound

205) .

Example 202

(±) -endo-3- [3- (2-Thienyl)propoxyl -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 3- (2- thienyl)propanol in 75% yield, m.p. 140-142 °C. (Compound

206) .

Example 203

(±) -3- (2- [4-Fluorophenoxyl ethylthio) -4- (1- azabicvclo [2.2.21 octyl-3-oxy) -1,2, 5-thiadiazole

Uεing εubεtantially the εame procedure uεed for the preparation of compound 44, compound 12 (1.15 g) and 1- bromo- (4-fluorophenoxy) ethane (3.65 g) gave (±)-3-(2-[4- fluorophenoxy]ethylthio) -4- (1-azabicyclo[2.2.2]octyl-3- oxy) -1, 2, 5-thiadiazole as an HCl εalt (1.55 g) crystallizing from ether-EtOAc-CHCl ₃ , m.p. 160-161 °C. (Comound 207) .

Example 204

(±) -3- (2-Methylthioethyl) -4- (l-azabicvclo \ 2 . 2 .21octyl-3- oxy) -1,2, 5-thιadiazole

A solution of 3- (2-methylthioethyl) - -hydroxy- 1, 2, 5-thiadiazole (0.45 g) and triphenylphosphine (0.7 g) was cooled in ice-water as diethyldiazodicarboxylate (0.4 mL) was added dropwise. After addition, (±) -1- azabicyclo[2.2.2]octan-3-ol (0.33 g) was added, cooling removed, and reaction stirred for 1 hour. The solvent was evaporated, residue suεpended in water, the mixture acidified and washed with ether. The aqueous solution was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, the residue purified by radial chromotography eluting with 10%-EtOH-l%-NH ₄ θH-CHCl ₃ , and the product converted to a HCl salt. Recrystallization from acetone gave 0.6 g white cryεtalε, m.p. 177-178 °C. (Compound 208) .

The followmg compounds were synthesized in subεtantially the εame manner aε Compound 208.

Example 205

(±) -3- (l-azabicvclo[2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

A εample of 3-Hydroxy-l,2, 5-thiadiazole (0.28 g) , triphenylphoεpine (0.7 g), diethyldiazodicarboxylate (0.4 mL), and (±) -1-azabicyclo[2.2.2]octan-3-ol (0.33 g) gave the hydrochloride εalt of (±)-3-(l- azabicyclo [2.2.2]octyl-3-oxy) -1, 2 , 5-thιadiazole, m.p. 240 °C dec. (0.36 g) . (Compound 209) .

Example 206

(±) -3-Hexyl-4-(l-azabicvcl [2.2- 1 ctyl-3-oxy) -1.2.5- thiadiazole

A εample of 3-Hexyl-4-Hydroxy-1,2, 5-thiadiazole

(0.93 g) , triphenylphoεpine (1.31 g) , diethyldiazodicarboxylate (0.8 mL) , and (±)-l- azabicyclo [2.2.2] octan-3-ol (0.64 g) gave the hydrochloride salt of (±) -3-hexyl-4- (1-azabicyclo[2.2.2] octyl-3-oxy) -1,2, 5- thiadiazole, m.p. 163-164 °C dec. (1.11 g) . (Compound 210) .

Example 207

3-Butylth o-4-hvdroxy-l,2,5-thiadιazole

A solution of Compound 1 (20.9 g) , DMSO (20 mL) and 2N NaOH (205 mL) waε headed to reflux overnight. The solution was cooled to 15 °C and concentrated HCl was added until the pH waε 1. The solid was collected, washed with water, and dried to give a solid (17.68 g) . Recrystallization from heptane gave white crystals, m.p. 72-72.5 °C. (Compound 211).

Exa ple 208

(±) -3-(2-[3-(1.2.5-Thιadιazoyloxy)lethoxy)-4- (1- azabicvclo [2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

A solution of triphenylphosphine (0.35 g) and 3-hydroxy- 1, 2, 5-thιadιazole (0.14 g) m THF (15 mL) was cooled m ice-water. Diethyl diazodicarboxylate (0.21 g) was added dropwise followed by (±) -3- (2-hydroxyethoxy) -4- (1- azabicyclo [ 2 . 2 .2]octyl-3-oxy) -1,2 , 5-thιadιazole (0.35 g) . Cooling was removed, reaction was stirred 1 h, and the solvent was evaporated. The reεidue waε suspended in cold water, acidified, and extracted with ether. The aqueous fraction waε made basic and extracted with EtOAc. The extracts were washed with brine, dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 10%-EtOH-l% NH ₄ OH-CHCI ₃ to give a clear oil. The HCl salt crystallized from acetone as a white powder (0.34 g), m.p. 178-179 °C. (Compound 212) .

Example 209

(±)£xo-3-Butylthio-4- (1-azabicvclor2.2.11heotyl-3-oxy) -

1,2, 5-thιadιazole

A solution of triphenylphosphine (0 7 g) and 317260 (0.5 g) THF (20 mL) was cooled in ice-water. Diethyl diazodicarboxylate (0.4 mL) was added dropwise followed by addition of (±) endo- 3-hydroxy-1- azabicyclo[2.2.1]heptane (0.29 g) . Cooling was removed and after 1 h the solvent was evaporated. The residue was suεpended m cold water, acidified, and extracted with ether. The aqueouε fraction waε made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography elut g with 5%-EtOH-0.5% NH ₄ OH-CHCI ₃ to give a clear oil. The HCl salt crystallized from EtOAc aε white crystals (0.44 g) , m.p. 147-148 °C. (Compound 213) .

Example 210

(±) -endo- - f2- (4-Chlorophenyl)ethoxy1 -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2- (4-chlorophenyl) ethanol in 50% yield, HCl salt m.p. 136-138 °C. (Compound 214) .

Example 211

(±) -endo-3- [2- (4-Fluorophenyl) ethoxyl -4- (1- azabicvclo [ .2.11 octvl- -oxv) -1.2. -thiadiazole

Obtained from Compound 166 and 2- (4-fluorophenyl) ethanol in 61% yield, HCl salt m.p. 135-136 °C. (Compound 215) .

Example 212

(±) -endo-3- \ 2 - (3-Methyl henyl) ethoxyl -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2, 5-thiadiazole

Obtained from Compound 166 and 2- (3-methylphenyl) ethanol in 57% yield, HCl salt m.p. 114-115 °C. (Compound 216) .

Example 213

(±) -endo-3- (2-Phenylethoxy) -4- (l-azabicvclof3.2.11octyl-6 oxv) -1.2. -thιadιazole

Obtained from Compound 166 and 2-phenylethanol in 70% yield, HCl salt m.p. 135-136 °C. (Compound 217) .

Example 214 (±) -endo-3- \ 2 - (3-Thιenyl) ethoxyl -4- (1- azabicvclo[3.2.11 octyl-6-oxy) -1,2, 5-thιadιazole

Obtained from Compound 166 and 2- (3-thienyl)ethano 62% yield, HCl salt m.p. 142-144 °C. (Compound 218) .

Example 215 (±) -endo-3-Benzyloxy-4- (1-azabicvclo[3.2.11octyl-6-oxy) -

1.2.5-thiadiazole

Obtained from Compound 166 and benzyl alcohol in 71% yield, HCl salt m.p. 180-181 °C. (Compound 219) .

Example 216

(±) -endo-3- (4-Trιfluoromethylbenzyloxy) -4- (1- azabicvclo [3.2.11 octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 4-trifluoromethylbenzyl alcohol m 76% yield, maleate salt m.p. 174-175 °C. (Compound 220) .

Example 217

(5S, 6S) - endo-3 - (4-Fluorobenzyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2.5-thiadiazole

Obtained from ( 5S, SS) -Compound 166 and 4-fluorobenzyl alcohol 33% yield, HCl salt m.p. 181-182 °C. (Compound 221) .

Example 218

( 5R . SR) - endo-3 - (4-Fluorobenzyloxy) -4- tl- azabicvclo [3.2.11 octyl-6-oxy) -1,2.5-thiadiazole

Obtained from ( 5R, R) -Compound 166 and 4-fluorobenzyl alcohol m 68% yield, maleate salt m.p. 106-107 °C . (Compound 222) .

Example 219

( 5S. SS) - endo- 3 - (4-Trιfluoromethoxybenzyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from ( 5S, SS) -Compound 166 and 4- trifluoromethoxybenzyl alcohol 52% yield, HCl salt m.p. 138-140 °C. (Compound 223) .

Example 220

( 5R, SR) - endo- 3 - (4-Trifluoromethoxybenzyloxy) -4- (1- azabicvclo [3.2.11 octyl-6-oxy) -1.2, 5-thiadiazole

Obtained from ( 5R, SR) -Compound 166 and 4- tπfluoromethoxybenzyl alcohol in 71% yield, maleate salt m.p. 114-115 °C. (Compound 224).

Example 221

{ 5R . SR) -endo-3- (2-Cvclopropylethoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2.5-thiadiazole

Obtained from ( 5R , SR) -Compound 166 and 2-cyclopropylethanol m 84% yield, maleate salt m.p. 111-112 °C. (Compound 225) .

Example 222

( 5S . SS) -endo-3- (2-Cvclooropylethoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from ( 5S, 6S) -Compound 166 and 2-cyclopropylethano m 78% yield, maleate salt m.p. 109-110 °C. (Compound 226) .

Example 223 ( 5R . 6R) - endo-3 - (3-Methyl-2-butenyloxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from ( 5R, SR) -Compound 166 and 3-methyl-2-butenol in 81% yield, maleate salt m.p. 141-142 °C. (Compound 227) .

Example 224

(±) -endo-3- (2-Cvclopropylιdeneethoxy) -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 2-cyclopropylιdeneethanol m 67% yield, maleate salt m.p. 100-101 °C . (Compound 228) .

Example 225 (±) -endo-3- (3-Cvclopropylpropoxy) -4- (1- azabicvclo [3.2.11octyl-6-oxy) -1.2, 5-thiadiazole

Obtained from Compound 166 and 3-cyclopropylpropanol in 62% yield, maleate salt m.p. 114-115 °C. (Compound 229) .

Example 226

(±) -endo-3- (1-Cyclopropylethoxy) -4- (1- azabicvclo[3.2.11octyl-6-oxy) -1,2, 5-thiadiazole

Obtained from Compound 166 and 1-cyclopropylethanol m 78% yield, maleate salt m.p. 161-162 °C. (Compound 230) .

Example 227

(±) exo-3- (l-Azabicvclo[2.2.11hePtyl-3-oxy) -1.2.5- thiadiazole

Prepared in the same manner as Compound 131. (±)Exo-3-(l- azabicyclo [2.2. l]heptyl-3-oxy) -1,2, 5-thiadiazole was obtained from 3-hydroxy-l, 2, 5-thiadιazole (0.14 g) , triphenylphosphine (0.35 g) , diethyldiazodicarboxylate (0.21 mL) and (±) -endo-1-azabicyclo [2.2.1]heptane-3-ol (0.15 g) aε a hydrochloride εalt (0.096 g) , m.p. 223 °C, dec. (Compound 231) .

Example 228

(±) -3- (3- [3-Trifluoromethyl- -chlorophenyllpropoxy) -4- (1- azabicvclo [2.2.21octyl-3-oxy) -1,2, 5-thiadiazole

Using the same procedure uεed in the preparation of Compound 103, (3-trifluoromethyl-4-chlorophenyl)propanol and Compound 102 gave after chromatography (±) -3- (3- [3- trifluoromethyl-4-chlorophenyl]propoxy) -4- (1- azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-thiadiazole aε an HCl salt, m.p. 144-146 °C. (Compound 232) .

Example 229 (±) -3- (3-Phenylpropoxy) -4- (l-azabicvclo[2.2.21 octyl-3-oxy) -

1.2, 5-thiadiazole

Using the same procedure used in the preparation of Compound 103, 3-phenylpropanol and Compound 102 gave after chromatography (±) -3- (3-phenylpropoxy) -4- tl- azabicyclo [2.2.2]octyl-3-oxy) -1, 2, 5-thiadiazole as an HCl salt, m.p. 194-196 °C. (Compound 233).

Example 230

(R) -3- (2-Cvclopropylethoxy)-4- (l-azabicvclo f2.2.21octyl-3- oxy) -1.2, 5-thiadiazole

Uεing the same procedure uεed in the preparation Compound 114, 2-cyclopropylethanol and Compound 102 that had been prepared from (R ) -1-azabicyclo[2.2.2]octan-3-ol gave after chromatography, {R ) -3- (2-cyclopropylethoxy) -4- (1- azabicyclo[2.2.2]octyl-3-oxy) -1,2, 5-thiadiazole aε an HCl εalt that cryεtallized from acetone, m.p. 189-190 °C. (Compound 234) .

Example 231 3-Ethoxy-4-hvdroxy-1.2.5-thiadiazole

A mixture of Compound 93 (8.2 g) , 2 N NaOH (100 mL) , and

DMSO (10 mL) waε heated to reflux over night. The reaction was cooled and extracted with ether. The aqueouε fraction was acidified with cone. HCl and cooled 30 min in ice¬ water. The solid was collected from the resulting mixture by filtration and washed with a small amount of cold water to give white crystals (4.4 g) . Recrystallization from heptane gave white flakes, m.p. 104.5-105.5 °C. (Compound 235) .

Example 232

3-Propylthio-4-hvdroxy-l,2 , 5-thiadiazole

A mixture of 3-chloro-4-propylthio-l,2, 5-thiadiazole (Compound 37) (10 g) , 2 N NaOH (100 mL) , and DMSO (10 mL) was heated to reflux for 24 h. The solution was cooled and extracted with ether. The aqueous fraction was acidified with cone. HCl and cooled in ice-water for 3 h. The resulting solid was collected, washed with a small amount of cold water to give a white solid (8.15 g) . Recrystallization from heptane gave white cryεtalε, m.p. 84-85 °C. (Compound 236) .