NZ324594A

NZ324594A - A method and composition for treating pain using a composition comprising an azacyclic azabicyclic or tetrahydropyridine compound and an analgesic

Info

Publication number: NZ324594A
Application number: NZ324594A
Authority: NZ
Inventors: Charles Howard Mitch; Harlan Edgar Shannon
Original assignee: Lilly Co Eli
Priority date: 1995-12-07
Filing date: 1996-12-05
Publication date: 1999-09-29
Also published as: KR19990071977A; CZ174598A3; NO982582L; CA2239732A1; NO982582D0; EA199800535A1; IL124786A0; WO1997020556A1; EP0866702A4; HUP0000110A2; PL327144A1; HUP0000110A3; EP0866702A1; AU1147697A; AU715645B2; CN1208348A; JP2000501711A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 324594 New Zealand No 324594 International No. PCT/US96/19390 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 07 12 1995,07 12 1995,07 12 19095,07 12 19 95,07 12 1995,07 120 1995,07 12 1995, Complete Specification Filed 05 12 1996 Classification (6) A61K31/41, C07D285/10, C07D271/08, C07D417/04, C07D451/14 Publication date 29 September 1999 Journal No 1444 Title of Invention Method for treating pain Name, address and nationality of applicant(s) as in international application form ELI LILLY AND COMPANY, a corporation of the State of Indiana, USA of Lilly Corporate Center, City of Indianapolis, State of Indiana 46285, United States of America NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION METHOD FOR TREATING PAIN The present invention relates to a method for using azacyclic, azabicyclic, or tetrahydropyndme compounds for treating pain This invention relates to a therapeutic combination of compounds to provide analgesic activity. More active analgesic combinations effects are m constant demand because they offer the attractive possibility of relieving pain with reduced dosages, thereby diminishing the expected side effects and toxicity that would otherwise result from higher dosages. It would be particularly desirable to acquire a synergistic combination effect Such a composition is the subject of the present invention preparation of a medicament for treating pain in a patient in need thereof, of an analgesic composition comprising a compound of Formula I wherein X is oxygen or sulphur; R is hydrogen, amino, halogen, -CHO, -NO2, -OR4, -SR4, -SOR4, -SO2R4, C3_7-cycloalkyl, C4-8-(cycloallcylalkyl) , -Z-C3-7-cycloallcyl, and -Z-C4-8-(cycloalkylalkyl) wherein R4 is straight or branched Ci-is-alkyl, straight or branched C2-15-alkenyl, straight or branched C2-i5-alkynyl, each of which is optionally substituted with one or more halogens, -CF3, -CN, The present invention provides a use, m the I R - 2 JUL 1333 WO 97/20556 I»CT/US96/19390 phenyl or phenoxy wherein phenyl or phenoxy as optionally substituted with halogen, -CN, Ci_4-alkyl, Ci-4-alkoxy, -OCF3, -CONH2 or -CSNH2; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, -CONH2 or -CSNH2, or R is -OR5Y, -SRSY, -OR5ZY, -SR5ZY, -0-R4-Z- R5 or -S-R4-Z-R5 wherein Z is oxygen or sulphur, R5 is straight or branched Ci-is-alkynyl, and Y is a 5 or 6 membered heterocyclic group containing 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 straight or branched Ci-e-alkyl, phenyl or benzyl, or which heterocyclic group id optionally fused with a phenyl group, and G is selected from one o£ the following azabicyclic rings wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring, R1 and R2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Ci_5-alkyl, straight or branched C2-5 alkenyl, straight or branched C2-5~alkynyl, straight or branched Ci_io-alkoxy, straight or branched C1-5-alkyl substituted with -OH, OR4, halogen, -NH2 or carnoxy, R3 is H, straight or branched Ci_5-alkyl, straight or branched C2-5~alkenyl or straight or branched C2-s-alkynyl, n is 0, 1 or 2, m is 0, 1 or 2, p is 0, 1 or 2, q is 1 or 2, and is a single or double bond, or a pharmaceutical^ acceptable salt thereof, Printed from Mimosa 13 17 04 -3- and a nonsteroidal anti-inflammatory drug m a weight ratio of Formula I to nonsteroidal anti-inflammatory drug of from about 1 to about 1000. The present invention provides a use, in the manufacture of a medicament for treating pain in a patient in need thereof, of an analgesic composition comprising a compound of Formula II R1' wherein Z1' is oxygen or sulphur; R' is hydrogen, halogen, amino, -NHCO-R2', C3-7-cycloalkyl, C4-10-(cycloalkylalkyl) , -Z2 ' -C3_7-cycloalkyl optionally substituted with Ci-6-alkyl, -Z2' -C4-10-(cycloalkylalkyl) , -Z2'-C4-.10-(cycloalkenylalkyl) , -Z2'-C4_io_ (methylenecycloalkyl-alkyl), -NH-R2', -NR2'R3', -NH-OR2', phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, indenyl, X', R2', -Z2'R2', -SOR2', -SO2R2', -Z2,-R2,-Z3'-R3' , -Z2,-R2'-Z3,-R3'-Z4'-R4', -Z2'-R2'CO-R3 ', -Z2'-R2'-C02-R3,, Z2'-R2'-02C-R3', -Z2'-R2'-CONH-R3 ' , -Z2'-R2'-NHCOR3' , -Z2' -R2 '-X1, -Z2'-R2'-Z3'-X', wherein z2', Z3', and Z4' independently are oxygen or sulphur, and R2', R3' and R4' independently are straight or branched Ci-15-alkyl, straight or branched C2-i5~allcenyl, straight or branched C2-i5~alkynyl, each of which is optionally substituted with halogen(s), -OH, 1 | i - 2 JUL 1309 ! J , -CN, -CF3, -SH, -COOH, -NH-R2', -NR2'R3', Ci-6alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, Ci-4-alkyl or Ci-4-alkoxy, and X' is a 5 or 6 membered heterocyclic group containing one to four N, O or S atota(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched Ci-e-alkyl, phenyl, benzyl or pyridine, or a carbon atom m the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group; and R5' and R6' may be present at any position, including the point of- attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C1-5-alkyl, straight or branched C2-s~alkenyl, straight or branched C2-5-alkynyl, straight or branched Ci-io-alkoxy, straight or branched Ci-5-alkyl substituted with -OH, -OH, halogen, -NH2 or carboxy, R1' is hydrogen, straight or branched Ci_5-alkyl, straight or branched C2-5~alkenyl or straight or branched C2-s-alkynyl; or a pharmaceutical^ acceptable salt or solvate thereof; and one or more nonsteroidal ant1-inflammatory drug m a weight ratio of Formula IX to nonsteroidal antiinflammatory drug of from about 1 to about 1000 Preferred NSAXDS include, but are in no way limited to salicylates such as aspirin, mdomethacm, lbuprofen, naproxen, fenoprofen, tolmetin, sulmdac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. Especially preferred NSAIDS include aspirin, lbuprofen, and naproxen Alternative preferred NSAIDS include lbuprofen and naproxen Alternative particularly preferred NSAIDS include lbuprofen The invention further provides a composition for treating pain comprising an analgesic dose of a compound selected from the group consisting of formula I — r — (followed by page 4a) - 2 JUL 1339 -4a- 5P. A 5 9 4 G I R wherein X is oxygen or sulphur; R is hydrogen, amino, halogen, -CHO, -NO2, -OR4, -SR4, -SOR4, -SO2R4/ C3_7-cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R4 is straight or branched Ci-15-alkyl, straight or branched C2-15-alkenyl, straight or branched C2-is-alkynyl, each of which is optionally substituted with one or more halogens, -CF3, -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, -CONH2 or -CSNH2, or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, -CONH2 or -CSNH2, or R is -OR5Y, -SR5Y, -OR5ZY, -SRs2Y, -0-R4-Z- R5 or -S-R4-Z-R5 wherein Z is oxygen or sulphur, R5 is straight or branched Ci-15-alkynyl, and Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at caroon or nitrogen atom(s) with straight or branched Ci-s-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fuse with a phenyl group, and G is selected from one of the following azaoicyclic rings (followed by page 4b) - 2 JUL 1333 wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring, R1 and R2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Ci_5~ alkyl, straight or branched C2-5 alkenyl, straight or branched C2-5-alkynyl, straight or branched Ci_io-alkoxy, straight or branched C^-allcyl substituted with -OH, OR4, halogen, -NH2 or carboxy, R3 is H, straight or branched Ci-5-alky1, straight or branched C2-5~alkenyl or straight or branched C2-5~alkynyl, n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2, and is a single or double bond, or a pharmaceutical^ acceptable salt or solvate thereof; and Formula II wherein Z1' is oxygen or sulphur. (followed by page 4c) -2 JUL 1333 -Ac- TO /, Fj (J 4 t . ,, ^ J R' is hydrogen, halogen, amino, -NHCO-R2', C3_7-cycloalkyl, C4-10- (cycloalkylalkyl) , -Z2' -C3-.7-cycloalkyl optionally subscituted with Ci-6-alkyl, -Z2'-Ca-io-(cycloalkylalkyl) , -Z2' -C4-10- (cycloalkenylalkyl) , -zi2' -C4-10-(methylenecycloalkyl-alkyl), -NH-R2', -JTR2'R3', -NH-OR2' , phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, mdenyl, X', R2', -Z2'R2', -SOR2', -S02R2', -Z2'-R2'-Z3'-R3', ~Z2'-R2'-Z3'-R3'-z4,~ R4', -Z2'-R2'CO-R3', _z2'_r2'-co2-r3', z2'-r2'-O2C-r3' , -Z2'-r2'-conh-r3 ', -z2'-r2'-nhcor3' , -z2'-r2'-x', -z2'-r2'-z3'-x', wherein z2', z3', and z4' independently are oxygen or sulphur, and r2', r3' and r4' independently are straight or branched Ci-15-alkyl, straight or branched C2-is-alkenyl, straight or branched C^-is-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF3, -SH, -COOK, -nh-r2', -NR2'r3', Ci-galkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein eacn aromatic group is optionally substituted with one or two halogen, -CN, Ci-4-alkyl or C1-4-alkoxy, and X' is a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C1-5-alkyl, phenyl, benzyl or pyridine, or a caroon atom m the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused witn a phenyl group, and R-' and R5' may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C1-5-alkyl, straight or branched C2-5~alkenyl, straight or branched C2-s-alkynyl, straight or branched Ci-10-alkoxv, straight or branched Ci-5-alkyl substituted with -OH, -OH, nalogen, -NH2 or carboxy, R1' is hydrogen, straight or brancned Ci-5-alkyl. straight or branched C2-5~alkenyl or straight or branched C2_5-alkynyl; or a pharmaceutical^ acceptable salt or solvate thereof, and a nonsteroidal ant1-inflammatory drug in a weight ratio of Compound to nonsteroidal anti-mflammatory drug (NSAIDS) of from about 1 to about 1000 ' ^ ~' ~r ' ~ < I Li (followed by page J _ ?^ 7 0 -5- The present invention provides a use, m the preparation of a medicament for treating pain in a patient in need thereof, of an analgesic composition comprising a compound selected from the group consisting of Formula I and Formula II, or a pharmaceutically acceptable salt or solvate thereof; and acetaminophen m a weight ratio of Compound to acetaminophen of from about 1 to about 1000 A composition for treating pain comprising an analgesic dose of a compound selected from the group consisting of Formula I Nf"*\ /N A/ 1 R wherein X is oxygen or sulphur, r is hydrogen, ammo, halogen, -ch0, -no2, -or4, -sr4, -sor4, -SO2R4, C3_7-cycloalkyl, C4-8-(cycloalkylalkyl) , -Z-C3-7-cycloalkyl, and -Z-C4-8- (cycloalkylalkyl) wherein r4 is straight or branched ci-15-alkyl, straight or branched C2-15-alkenyl, straight or branched C2-i5-alkynyl, each of which is optionally substituted with one or more halogens, -cf3, -cn, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -cn, ci-4-alkyl, ci-4-alkoxy, -oc?3, -CONH2 or -csnh2» or r is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, 'cn, ci-4-alkyl, ci-4-alkoxy, -ocf3, -conh2 or -csnh2; or r is -0r5y, -sr5y, -0R5zy, -sr5zy, -0-r4-z- r5 or -s-r4-z-r5 wherein z is oxygen or sulphur, r5 is straight or branched ci-is-alkynyl, ana is a 5 or 6 membered heterocyclic group containing one to four . . r 7T:'-T . > ' (■" < -2 JUL 1339 j WO 97/20556 PCT/US96/19390 -6- N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched Ci-6-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group, and G is selected from one of the following azabicyclic rings wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring, R1 and R2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Ci_5~ alkyl, straight or branched C2-5 alkenyl, straight or branched C2-s-alkynyl, straight or branched Ci_io~alkoxy, straight or branched Ci-5-alkyl substituted with -OH, OR4, halogen, -NH2 or carboxy, R3 is H, straight or branched Ci_ 5-alkyl, straight or branched C2-s-alkenyl or straight or branched C2-5~alkynyl, n is 0, 1 or 2, m is 0, 1 or 2, p is 0, 1 or 2, q is 1 or 2, and is a single or double bond, and R' .3 Printed from Mimosa 13 17 04 WO 97/205.56 PCT/US96/I9390 -7- Formula II 5 wherein Z1' is oxygen or sulphur, R' is hydrogen, halogen, amino, -NHCO-R2' , C3_7-cycloalkyl, C4-10- ( cycloalkylalkyl) , -Z2' -C3-7-cycloalkyl optionally substituted with Ci-s-alkyl, -Z21 -C4-io~ (cycloalkylalkyl) , 10 -Z2'-C4_io_ (cycloalkenylalkyl) , -Z^-C^q-(methylenecycloalkyl-alkyl), -NH-R2', -NR2'R3', -NH-OR2', phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl. xndenyl, X', R2', -Z2'R2', -SOR2', -SO2R2', -Z2'-R2'-Z3'-R3', -Z2'-R2'-Z3'-R3'-Z4'-15 R4', -Z2'-R2'C0-R3', -Z2'-R2'-C02-R3', Z2'-R2'-O2C-R3 ', -Z2'-R2'-CONH-R3' , -Z2'-R2'-NHCOR3' , -Z21 -R2 ' -X1 , -Z2'-R2'-Z3'-X', wherein Z2 ' , Z3 ', and Z4' independently are oxygen or sulphur, and R2', R3' and R4' 20 independently are straight or branched Ci-is-alkyl, straight or branched C2-1.5-alk.enyl, straight or branched C2-i5-alkynyl, each o£ which is optionally substituted with halogen(s), -OH, -CN, -CF3, -SH, -COOH, -NH-R2', -NR2'R3', Ci-6alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein 25 each aromatic group is optionally substituted witn one or two halogen, -CN, C^-^-alkyl or Printed from Mimosa 13 17 04 Ci-4-alkoxy, and X' is a 5 or 6 membered heterocyclic group containing 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 1 uight or branched Ci_6~ 5 alkyl, phenyl, benzyl or pyridine, or a carbon atom m the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group, and r5' and R5' may be present at any position, including the 10 point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Ci_s~ alkyl, straight or branched C2-5-alkenyl, straight or branched C2-5~alkynyl, straight or branched Ci-io-alkojcy, straight or branched Ci-5-alkyl substituted with -OH, -OH, halogen, -NH2 15 or carboxy, R1' is hydrogen, straight or branched Ci-s-alkyl, straight or branched C2-s-alkenyl or straight or branched C2-5-alkynyl; or a pharmaceutically acceptable salt or solvate thereof, and acetaminophen in a weight ratio of Compound to 20 acetaminophen of from about 1 to about 1000. A preferred composition is a weight ratio of Compound to acetaminophen of from about 1 to about 100 An especially preferred ratio is from about 1 to about 30 A further preferred ratio may be from about 1 to about 10. A 25 final preferred ratio may be from about 1 to about 3. 30 The present invention provides a composition for treating pain comprising a Compound selected from the group 35 consisting of Formula I and Formula II, or a pharmaceutically acceptable salt thereof, - 2 JUL 1333 t n, r p n. / " ' J It 4 P m 1 l, * - 9- and a central alpha-adrenergic active compound in a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 1000. A preferred composition is a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 100 An especially preferred ratio is from about 1 to about 30 A further preferred ratio may be from about 1 to about 10 A particularly preferred central alpha-adrenergic active compound is Clonidme or a pharmaceutically acceptable salt thereof The chemical name for clonidme is 2-(2, 6-dichlorophenylammo) -2-imidazoline The invention further provides a use, in the preparation of a medicament for treating pain, of a compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof, and a central alpha-adrenergic active compound in a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 1000. The present invention provides a use, in the preparation of a medicament for treating pain in a patient m need thereof, of an analgesic composition comprising a compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and one or more opioid compounds in a weight ratio of Compound to an opioid active compound of from about 1 to about 1000 A preferred composition is a weight ratio of Compound to opioid compound of from about 1 to about 100 An especially preferred ratio is from about 1 to about 30. A further preferred ratio may be from about 1 to about 10. Preferred an opioid compounds are morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, r , I - 2 JUL 1333 WO 97/20556 PCT/US96/I9390 -10- naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine Especially preferred opioid compounds are selected from the group consisting of hydromorphone, 5 hydrocodone, mependone, buprenorphine, butorphenol, nalbuphine, pentazocine, ojcyxnorphme, oxycodone, levorphanol, fentanyl, and alphaprodme Particularly preferred opioid compounds are selected from the group consisting of propoxyphene, 10 methadone, morphine, hydrocodone, hydromorphine, and codeine The especially particularly preferred opioid compounds are selected from morphine and codeine The invention further provides a composition for treating pain comprising a Compound selected from the group 15 consisting of Formula I and Formula II, or a pharmaceutically acceptable salt or solvate thereof, and a one or more opioid compounds in a weight ratio of Compound to opioid compound of from about 1 to about 1000 20 The term "NSAIDS", as used herein, represents a nonsteroidal ant 1 -mflanuriatory drug which can be identified as such by the skilled artisan For example, the Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp 25 1308 - Z309 provide well known examples of NSAIDS The term is intended to include, but is not limited to salicylates such as aspirin, mdoniethacin, lbuprofen, naproxen, fenoprofen, tolmetm, sulmdac, meclofenamate, keoprofen, piroxicam. flurbiprofen, and diclofenac Especially 30 preferred NSAIDS include aspirin, lbuprofen. and naproxen. Alternative preferred NSAIDS are mdomethacin, lbuprofen, naproxen, fenoprofen, tolmetm, sulmdac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac Particularly preferred NSAIDS include aspirin and lbuprofen. 35 The salicylates may include acetylsalicylic acid, sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylic Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/1939(1 -13- acid. and sodium salicylate An especially preferred NSAID is lbupxofen The term "acetaminophen", as used herein, shall have the art accepted meaning and refers to N-(4-5 HydroxyphenyDacetamide and 4 1 -hydroxyacetanilide The compound is claimed in XJ S Patent No 2,998,450 and is Known to the skilled artisan The term "central alpha-adrenergic active compounds", as used herein, represents a compound having 10 central alpha-adrenergic receptor activity The most-preferred central alpha-adrenerqic active compound is clonidme or a pharmaceutically acceptable salt thereof having the chemical name 2-(2,6-dichlorophenylanuno)-2-imidazoline 15 Clonidme is known to be useful for treating hypertension see Physicians 1 Desk Reference, 45th Ed (1991) p 673 The term "opioid", as used herein, represents opioid analgesics and antagonists including natural opioid 20 analgesics, synthetic opioid analgesics, opioid antagonists and opioid agonist-antagonists Preferred an opioid compounds are selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, 25 brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine More preferred opioid compounds are selected from the group consisting of codeine, nabuphine, naloxone, and naltrexone Preferred an opioid compounds are morphine, 30 codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabupnine, and buprenorphine Especially preferred opioid compounds are 35 selected from the group consisting of hydromorphone, hydrocodone, mependone, buprenorphine, butorphenol. Printed from Mimosa 1317 04 -12- nalbuphine, pentazocine, oxymorphme, oxycodone, levorphanol, fentanyl, and alphaprodme. Particularly preferred opioid compounds are selected from the group consisting of propoxyphene, methadone, morphine, hydrocodone, hydromorphine, and codeine. The especially particularly preferred opioid compounds are selected from morphine and codeine. As used herein, the phrase "one or more" most preferredly refers to one, however, two, three, or more may be used. We have discovered that a group of compounds having muscarinic cholinergic activity can be particular useful for treating pain when used m combination with non-steroidal antiinflammatory agents (NSAIDS) More specifically, described is a method of treating pain in humans using a specified azacyclic, azabicyclic or tetrahydropyridme compounds (collectively referred to herein as "selected muscarinic compounds") m combination with a NSAIDS to provide a synergistic effect. The Selected Muscarinic Compounds are believed to be active based on activity at muscarinic cholinergic receptors; however, the present invention is m no way limited by the mechanism of action. There are many NSAIDS known m the literature and to the skilled artisan We have discovered that a group of compounds having muscarinic cholinergic activity can be particular useful for treating pain when used m combination with acetaminophen More specifically, described is a method of treating pain in humans using a specified Selected Muscarinic Compounds m combination with acetaminophen to provide a synergistic effect- Further, we have discovered that a group of compounds having muscarinic cholinergic activity can be particularly useful for treating pain when used in combination with central alpha-adrenergic active compounds. More specifically, described is a method of -13- treatmg pam m humans using Selected Muscarinic Compounds in combination with a central alpha-adrenergic active compound to provide a synergistic effect. Oral combinations of aspirin with codeine or other narcotic analgesics are known to provide additive analgesic effects in man The Pharmacological Basis of Therapeutics, 5th edition, Macmillan Publishing Co., 1975, pp 325-358. In the composition of this invention a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof and NSAIDS compound are combined in a weight ratio of Compound to NSAIDS of from about 1 to about 1000. A preferred composition is a weight ratio of Compound to NSAIDS of from about 1 to about 100. An especially preferred ratio is from about 1 to about 3 0 A further preferred ratio may be from about 1 to about 10 A final preferred ratio may be from about 1 to about 3. In the composition of this invention a Compound of Formula I or Formula II and acetaminophen are combined in a weight ratio of Formula I or Formula II to acetaminophen of from about 1 to about 1000 A preferred composition is a weight ratio of Formula I or Formula II to acetaminophen of from about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A further preferred ratio may be from about 1 to about 10. A final preferred ratio may be from about 1 to about 3. The compounds of Formula I and Formula II are effective over a wide dosage range; however, it is desirable to administer a dosage that is as low as possible The amount of NSAIDS present in the composition is adjusted as described above in ratio to the Formula I or Formula II dosage The amount of acetaminophen present m the composition is adjusted as described above in ratio to the Formula I or Formula II dosage For example, dosages per day of the Formula II compounds will normally fall WO 97/205S6 PCT/lIS96/l<»390 -14- within the range of about 0 005 to about 100 mg/kg of body weight and the acetaminophen in the composition would be from 3 to 1000 times this amount. For example, dosages per day of the Formula I compounds will normally fall within 5 the range of about 0 00S to about 100 mg/kg of body weight and the NSAIDS m the composition would be from 3 to 1000 times this amount, In the composition of this invention a Compound selected from the group consisting of Formula 1 and Formula 10 II, or a pharmaceutically acceptable salt thereof and one or more opioid compounds are combined in a weight ratio of Compound to opioid compound of from about 1 to about 1000 A preferred composition a weight ratio of Compound to opioid compound of from about 1 to about 100 An 15 especially preferred ratio is from about 1 to about- 30 A further preferred ratio may be from about 1 to about 10 A final preferred ratio may be from about 1 to about 3 The Compounds are effective over a wide dosage range, however, it is desirable to administer a dosage that 20 is as low as possible The amount of opioid compound present m the composition is adjusted as described above m ratio to the Compound dosage For example, dosages per day of the Formula I compounds will normally fall within the ranqe of about 0 005 to about 100 mg/kg of body weight and the opioid 25 compound in the composition would be from 3 to 1000 times this amount However, for each composition claimed herein, it will be understood that the amount ot the Compound actually administered will be determined by a physician, in the light 3 0 of the relevant circumstances including the condition to be treated, the choice of Compound to oe 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 3 5 intended to limit the scope of the invention in any way. While the present compounds are preferably administered orally to humans susceptible to or suffering from pain, the Printed from Mimosa 1317 04 WO 97/205% PCT/IIS96/19390 -15- compounds may also be administered by a variety of other routes such as the transdermal, parenrerally, subcutaneous, intranasal, intramuscular and intravenous routes Such formulations may be designed to provide delayed or controlled 5 release using formulation techniques which are known m the art Transdermal formulations containing the composition claimed herein most preferably deliver the active substances 10 in an effective amount foi from about three days to about seven days However, for chronic pain such as arthritis or cancer pain, a transdermal delivery of from about three days to up to about two weeks is desirable Alternatively, it may be prelrrred to deliver the claimed compositions 15 transdermally in an effective amount for from about one day to about three days As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or 20 mental condition once it has been established or alleviation of the characteristic symptoms of such condition The compounds of Formula I and Formula II employed in the invention are not believed to act via the GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans 25 Rather, the activity of the present Formula I and Formula II compounds as analgesic agents is believed to be based upon modulation of muscarinic cholinergic receptors However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra , and the present 3 0 invention is not limited by any mode of operation The compounds of Formula I and Formula II are described m Sauerberg et al in U S Patents 5,043,345, 5,041,455 and 5,260,314 (collectively herein "Sauerberg Patents"), each of which is herein incorporated by 35 reference The Sauerberg Patents teach the artisan how to make the compounds of Formula I and Formula II used herein for the claimed analgesic composition. Printed from Mimosa 13 17 04 WO 97/20556 PCT/IJS96/19390 -16- Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, 5 fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed m Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled 10 artisan The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan The route of administration may be any route, which effectively transports the active compound to the 15 appropriate or desired site of action, such as oral or parenteral e g rectal, transdermal, depot, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred The dosage administered will, of course, vary 20 depending on known factors such as the pharmacodynamic characteristics of the particular agent, and it smode and route of administration, age, health, and weight of the recipient, nature and extent of the symptoms, kind of concurrent treatment, frequency of treatment, and the 25 effect desired Usually, the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0 2 mg/kg to about 100 mg/kg of body weight Formula 1 or Formula IX compound and from about 0 6 to about 200 mg/kg of NSAIDS. 3 0 Compositions suitable for internal administration contain from about one half (0 5) milligrams to about 600 milligrams of active ingredient per unit In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of from about 0 5% 3 5 to about 95% by weight based on the total weight of the composition Printed from Mimosa 13 17 04 WO 97/20556 VCT/US96/19390 -17- For compositions containing acetaminophen, usually, the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0 2 mg/kg to about 100 mg/kg of body weight Formula II 5 compound and from about 0 6 to about 200 mg/kg of acetaminophen Typical compositions include a compound of Formula I or Formula II or a pharmaceutically acceptable 10 acid addition salt thereof and one or more NSAIDSs, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be m the form of a capsule, sachet, paper, or other container In IS 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 within a carrier which may be in the form of a ampoule, capsule, 20 sachet, paper, or other container When the carrier serves as 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 container for example in a sachet Some 25 examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycendes and diglycerides, pentaerythritol fatty acid esters, 3 0 hydroxymethylcellulose and polyvinylpyrrolidone The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents The formulations o£ the invention may be formulated so as to provide quick, 35 sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known m the art Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -18- Typical compositions include a compound of Formula I or Formula II or a pharmaceutically acccptable acid addition salt thereof and acetaminophen, associated with a pharmaceutically acceptable excipient which may be a 5 carrier, or a diluent or be diluted by a carrier, or enclosed within a carnei which can be in the form of a capsule, sachet, paper, or other container In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used, as described 10 above A preferred composition is a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 100 An especially preferred ratio is from about 1 to about 3 0 A further preferred ratio may be from 15 about 1 to about 10 A final preferred ratio may be from about 1 to about 3 The compounds of Formula I and Formula II are effective over a wide dosage range, however, it is desirable to administer a dosage that is as low as 20 possible The amount of central alpha-adrenergic active compound present in the composition is adjusted as described above m ratio to the Formula I or Formula II dosage For example, dosages per day of the Formula I compounds will normally fall within the range of about 25 0 005 to about 100 mg/kg of body weight and the central alpha-adrenergic active compound in the composition would be from J to 1000 times this amount. Usually, the daily dosage can be such that the active ingredient is administered at a daily dosage of from 30 about 0 2 mg/kg to about 100 mg/kg of body weight Formula I or Formula II compound and from about 0 6 to about 20 0 mg/kg of central alpha-adrenergic active compound Typical compositions include a compound of formula I or Formula II or a pharmaceutically acceptable 35 acid addition salt thereof, and one or more central alpha-adrenergic active compounds, associated with a pharmaceutically acceptable excipient which may be a Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -19- carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container in making the compositions, conventional techniques for the preparation 5 of pharmaceutical compositions may be used The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not 10 deleteriously react with the active compounds For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound 15 dissolved m polyhydroxylated castor oil Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application Preferable 20 carriers for tablets, dragees, or capsules include 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 Formula I or Formula II compounds 25 are dispensed in unit form comprising from about 0 1 to about 100 mg m a pharmaceutically acceptable carrier per unit dosage The compositions of this invention may be 30 suitable for administration to an animal Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife More preferredly, the animal is a vertebrate Most preferredly, a compound o£ this 35 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 Printed from Mimosa 13 17 04 WO 97/20SS6 PCT/US96/19390 -20- such purposes, a compound of this invention may be administered as a feed additive The following models and assays are useful for illustrating the effectiveness of the compositions claimed 5 herein Nociceptive pain model. Acetic acid-induced writhing: ^ standard procedure for detecting and comparing the analgesic activity of different 10 classes of analgesic drugs for which there is a good correlation with human analgesic activity is the prevention of acetic acid-induced writhing in mice Mice, are subcutaneously administered various doses of the claimed composition and are injected injected mtraperitoneally with 15 acetic acid (0 5% solution, 10 ml/kg) 5 nun prior to a designated observation period For scoring purposes a "writhe" is indicated by whole body stretching or contraction of the abdomen during the observation period beginning 5 mm after receiving the acetic acid inhibition of writhing 20 behavior is demonstrative of analgesic activity See, Haubrich, D R , Ward, S J , Baizman, E , Bell, M R , Bradford, J , Ferrari, R , Miller, M , Perrone, M . Pierson, A h , Saelens, J K and Luttinger, D Pharmacology of pravadolme a new analgesic agent The 25 Journal of Pharmacology and Experimental Therapeutics 255 (1990) 511-522. Neuropathic pain mgfls.1-;. Sciatic nerve ligation model. Rats are anesthetized and 30 a nerve ligation procedure performed The common sciatic nerve is exposed and 4 ligatures tied loosely around it with about 1 mm spacing One day to 10 weeks after surgery, the nociceptive testing is performed Responses to noxious heat are determined ay placing the rats m a chamber with a clear 35 glass floor and aiming at the plantar surface of the affected foot a radiant heat source from beneath the floor Increased latency to withdraw the hmdpaw is demonstrative of analgesic Printed from Mimosa 13 17 04 WO 97/205S6 rCT/HS96/1939n -21- activity Responses to normally innocuous mechanical stimuli is determined by placing the rats in a chamber with a screen floor and stimulating the plantar surface of the hind paw with graduated von Frey hairs which are calibrated by the 5 grams of force required to bend them. Rats with sciatic nerve ligation respond to lower grams of mechanical stimulation by reflexive withdrawal of the Coot than unoperated rats This response to stimuli which are normally innocuous is termed allodynia Increases m the grams of 10 mechanical force required to produce foot withdrawal is demonstrative of antiallodynic activity See, Bennett, G J and Xie, Y -K A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen m man Pain 33 (1988) 87-107 15 See also, Lee, Y -W , Chaplan, S R and Yaksh, T L : Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model Neuroci Lett 186 (1995) 111-114 Formalin, paw test: Rats are anesthetized and when there 20 is a loss of spontaneous movement the rats are injected subcutaneously m the dorsal surface of the hindpaw with 50 ul of 5% formalin solution using a 30 gauge needle Rats are then individually placed in an open Plexiglas chamber for observation, and within a maximum interval of 1 to 2 mm, the 25 animal displays recovery from anesthesia with spontaneous activity and normal motor function Pain behavior is quantified by periodically counting the incidents of spontaneous flinching/shakmg of the injected paw The flinches are counted for 1-min periods at 1- to 2-, 5- to 6-30 and 5min intervals during the interval from 10 to 60 mm. Inhibition of the pain behavior is demonstrative of an analgesic activity See, Malmberg, A B and Yaksh, T L Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on 35 the formalin test m the rat The Journal of Pharmacology and Experimental Therapeutics 263 (1992) 136-146 Printed from Mimosa 13 17 04 WO 97/20S56 PCT/US96/19390 -22- Inf lanunatorv pain model. Brewer's yeast-induced hyperalgesia (Randall-Selitto TeBt): To assess nociceptive threshold m rats, ascending pressure is applied gradually to the paw with a motor driven S weight of a Ugo Basile Analgesy Meter Rats respond to the pressure by either pulling free of the device, struggling or vocalizing Hyperalgesia is induced by a hind paw subplantar infection of 0 1 ml of 1% suspension of brewer's yeast in 0 9% saline The composition of this invention is 10 administered at varying tunes ( 0 - 4 hr) after injection of brewer's yeast and pressure threshold for the inflamed paw again determined at varying times Increases in the pressure which produces a behavioral response is demonstrative of analgesic activity 15 See, Haubrich, D R , Ward, S J , Baizman, E , Bell, M R , Bradford, J , Ferrari, R , Miller, M , Perrone, M , Pierson, A K , Saelens, J X and Luttinger, D Pharmacology of pravadoline a new analgesic agent The Journal of Pharmacology and Experimental Therapeutics 255 20 (1990) 511-522 Utility Test Methods The unexpectedly enhanced analgesic activity of t 'e composition of the invention is evidenced by tests 25 i/K lally conducted on mice Male mice are fasted for 16-22 hour:- and weighed Mice weighing from about 18-22 grams at the time of testing are used for the following studies All mice are dosed sequentially by the oral route with suspensions of a composition of this invention Doses are 30 coded using a code unknown to the observer A stock suspension of the test composition is prepared by mixing the active ingredients with about 40 mL of an aqueous vehicle containing about 2% Tween 80 (R), a pharmacological dispersant and containing 100% polysorbate 35 80, and 1% by weight Methocel (R) MC powder, and containing 100% methylcellulose, in distilled water The mixture may be sonicated for about 10 to about 15 seconds using an Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -23- ultrasound sytem All dosing suspensions are prepared by dilution of Che stock suspension with Methocel/Tween 80 All suspensions are used within two hours of preparation 5 Mouse writhing Test An accepted standard for detecting and comparing the analgesic activity o£ different classes of analgesic compounds for which there is a good correlation with human analgesic activity is the prevention of phenyl-p-10 benzoquinone induced writhing in mice [H Blumberg et al Proc Soc Exp biol Med . 118, 763-766 (1965)] Mice, treated with various doses of compound of Formula I or Formula II, composition or vehicle are injected intraperitoneally with a standard challenge dose 15 of phenyl-p-benzoqumone 5 minutes prior to a designated observation period The pheyl-p-benzoquinone is prepared as about 0 1 mg/ml solution in about 5% by volume of ethanol in water The writhing dose is 1.25 mg/kg injected at a volume of about 0 25ml/10g For scoring purposes a 20 "writhe" is indicated by whole body stretching or contracting of the abdomen during an observation period beginning about five minutes after the phenyl-p-benzoqumone dose All ED50 values and their 95% confidence limits 2 5 are determined using accepted numerical methods For example see W F Thompson, Bacteriological Rev , 11, 115-145 (1947) The interaction of the dosages on phenyl-p-benzoquinone induced writhing in mice is demonstrated by the Loewe isobologram (S Loewe, Pharm Rev 9, 237-242 30 (1957) The solid line connecting the ED50 dosages of Formula I or Formula II (alone) and classical analgesic as claimed herein (alone) represents the "ED50 addition line" which indicates the expected location of the ED50's for 35 Formula I or Formula II and classical analagesic combinations if simple additivity were to describe their combined effects The 95% confidence range for the ED50 Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -24- addition line is shown by the area between the broken lines above and below the ED50 addition line, According to Loewe's isobolic theory, if the analgesic effects are simply additive to one another, then 5 the expected location of the ED50's of the Formula I or Formula II and classical analgesic component of each fixed dosage ratio would be contained within or overlap the region of the ED50 addition line Combination ED50's located significantly below the CD50 addition line would 10 represent unexpectedly enhanced analgesic activity and combination EDBO's located above the line would represent unexpected diminished analgesic effect One method to establish the significance of such unexpected enhanced or diminished activity is to calculate 15 the best fitting polynomial regression line to the observed ED50's using standard mathematical techniques Such experiments demonstrate that compositions comprised of a compound of Formula I or Formula II and one or more classical analgesics provides a statistically 20 significant synergistic analgesic effect. Preferred compounds of Formula I for use in the analesic compositions are selected from the following 25 3-CHLORO-3-(3-CHL0R0-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2.2.2]OCTANE, 3 - (3 -CHLORO-1,2,5 -THIAMAZOL- 4-YL) - 3 -HYDROXY-1 -AZABICYCLO[2.2 2]OCTANE, 30 3-METHOXY-3 -(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2.2]OCTANE, 3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCT-2-35 ENE, Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -25- 3- (3-HEXYLOXY-l, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO [ 2 .2 ?]OCT- 2-ENE, 3-HEXYLOXY-3 -(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-5 [2 2 2]OCTANE, 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)- 3-HYDROXY-1-AZABICYCLO[2 2 2]OCTANE, 10 3-O-CHLORO-l,2,5-THIADIAZOL-4-YL)-l-A2ABICYCLO[2 2 2]OCTANE, 3-O-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 21OCTANE, 3-(3 - PROPOXY-1,2,5—THIADIAZOL-4 -YL) -1-15 AZABICYCLO[2 2.2]OCTANE, 3 -(3 -BUTOXY-1,2,5-THIADIAZOL-4- YL)-1-AZABICYCLO[2.2.2]OCTANE, 3 -(3 -PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-20 [2 2 2]OCTANE, 3 -(3-ETHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3-(3-HEXYLTHI0-1,2,5-THIADIAZOL-4-YL)-1-25 AZABICYCLO[2 2.2]OCTANE, 3-(3-(3-PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2.2]OCTANE, 30 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2 2.2]OCTANE, 3-(3-{4 -CYANOBENZYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2.2.2]OCTANE, 35 EXO-6-(3 -CKLORO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3.2.1]OCTANE, Printed from Mimosa 13 17 04 WO 97/205S6 FCT/US96/19390 -26- ENDO-6-(3-CHLORO-1,2,5-THIADIAZ0L-4-YL)-1-AZABICYCLO(3 2.1]OCTANE, 5 ENDO-6-(3-HEXYLTHI0-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-(5-HEXENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCL0[3 2.1]OCTANE, 10 ENDO-6-(3-BUTYLTHIO-l,2,5-THIADIAZOL-4-YL) -1-AZABICYCLO[3 2.1]OCTANE, FNDO-6-(3-PCNTYLTHIO-1.2,5-THIADIAZOL-4-YL)-1-15 AZABICYCLO[3 2.1]OCTANE, ENDO-6-(3-ETHYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3.2 1]OCTANE, 20 ENDO-6-(3-(3-PHENYLPROPYLTHIO)-1,2, 5-THIADIAZOL-4-YL)-1- AZABICYCLO[3 2 1]OCTANE, Particularly preferred compounds of Formula I include 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-25 AZABICYCLO[2 2.2]OCTANE, 3-(3-(3-PHENYLPROPYLTHIO) -1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE; 30 3-(3-CHLORO-1.2,5-THIADIA20L-4-YL)-1-AZABICYCLO(2.2.2)OCTANE (EXO(+-))-6-(3-CHLORO-1,2.5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3 2 1)OCTANE 35 3-(3-ETHOXY-1, 2, 5-THIADIA20L-4-YL)-1-AZABICYCLO(2 2 2)OCTANE 3-(3-PROPOXY-1.2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE Printed from Mimosa 13 17 04 WO 97/20556 PCT /U596/19390 -27- 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE 5 3 -{3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO(2 2 2)OCTANE ENDO(+-)- 6-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3 2 1)OCTANE 10 ENDO(+-)- 6-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3 2 1)OCTANE EXO(+-)-6-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-15 (3 2 1)OCTANE 3 -(3-(BUTOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE EXO-3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-20 (2 2.1)HEPTANE EXO-3 -(3-BUTYLTHIO-l,2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 1)-HEPTANE 25 ENDO-3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO(2.2 1)-HEPTANE 3 -(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2.2)OCTANE 30 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE 4-CHLORO-3-(3 -PROPYLOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-35 (3 3 UNON-2-ENE 3 -(3 -ISOPENTYLOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO (2 2.2)- Printed from Mimosa 13 17 04 WO 97/20556 PCT/tlS96/10V»0 -28- OCTANE ENDO(+ -)3 -(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3 .2 1)OCTANE 5 EXO(+-)3 -(3-PROPYLTHIO-l,2, 5-THIADIAZ0L-<1 - YL)-1-AZABICYCLO-(3 2 DOCTANE -)3-(3-BUTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2>-10 OCTANE ( + ) 3 -(3-BUTYLTHIO-1,2,5-TH1ADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)-OCTANE 15 3- (3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2.2)OCTANE (EXO( + -))-6-(3-CHLORO-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO-(3.2 1)OCTANE 20 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANS 3-(3-PROPOXY-l, 2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2.2)OCTANE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-25 AZABICYCLO(2 2 2)OCTANE 3 -(3-PENTYLTHIO-1,2,5-THIADIA20L-4-YL >-1-AZABICYCLO(2 2 2)OCTANE 3 0 ENDO(+-)-6-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO- (3 2 1)OCTANE ENDO(+-)-6-(3-BUTYLTHI0-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3.2.1)OCTANE 35 EXO(+-)-6-(3-BUTYLTHIO-l,2,5-TKIADIAZOL-4-YL)-1-AZABICYCLO-(3 2 1)OCTANE Printed from Mimosa 13 17 04 WO 97/205<;6 PCT/IJS96/19390 -29- 3-(3 - (BUTOXY-1, 2 , 5-THIADIAZOL-4-YL) -1-AZABICYCLO(2 ? ?) OCTANE EXO-3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-5 AZABICYCLO(2 2 1)- HEPT^NE 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE 10 EXO-3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 1)-HEPTANE ENDO-3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-15 AZABICYCLO(2 2 1)-HEPTANE 3-(3-ETHYLTHIO-1,2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE 20 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO(2 2 2)OCTANE 4-CHLORO-3 -(3-PROPYLOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3 3 1)NON-2-ENE 25 3 -(3-ISOPENTYLOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(2 2 2)OCTANE ENDO(+-)3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-30 (3 2 1)OCTANE BIS-1,4-(3-(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5-THIADIAZOL-4-YL)BUTANEDITHIOL 3 5 EXO(+-)3 -(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO- (3 2 1)OCTANE Printed from Mimosa 13 17 04 WO 97/20556 ITTAIS%/1031(1 -30- ( - ) 3 - (3-BUTYLTHIO-1 5-THIADIAZOL-4-YL) -1-AZABICYCLO-(2 2 ?)OCTANE (+)J-(3-BUTYLTHIO-1.2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO-5 (2 2 2 )OCTANE, AND a pharmaceutically acceptable salt or solvate thereof More preferred compounds include the following 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1 -10 AZABICYCLO(2 2 2)OCTANE 3-(3-PENTYLTHIO-1.2,5-THIADIAZOL-4-YL) -1-AZABICYCLO(2 2 2)OCTANE 15 ENDO(±)-6-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO- (3 2 1)OCTANE ENDO(+)-6- (3-BUTYLTHIO-1.2.5-THIADIAZOL-4 -YL)-1-AZABICYCLO-(3 2 1)OCTANE 20 EXO(+)-6-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(3 2 1)OCTANE 3 - (3 -PROPYLTHIO-1,2,5-THIADIAZOL-4-YL) -1 -25 AZABICYCLO(2 2.2)OCTANE, or a pharmaceutically acceptable salt or solvate thereof The most especially preferred compound of Formula I is 3- (3-BUTYLTHIO-1, 2,5-THIADIAZOL-4-YL)-1-30 AZABICYCLO[2 2 2]OCTANE, or a pharmaceutically acceptable salt or solvate thereof. Preferred compounds of Formula II for the 35 analgesic composition are selected from the following 3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97720556 PCT/IJS96/I9390 -31- 3-(3-ETH0XY-1,2.5-THIADIAZOL-4-YL)-1.?,5,G-TETRAHYDRO-1-METHYLPYRIDINE 5 3-(3-PROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,b, 6-TCTRAHYDRO-1- METHYLPYRIDINE 3-(3-BUTOXY-1,2, 5-THIADIAZOL-4-YL)1,2,5,6-TETTRAHYDRO-l-METHYLPYRIDINE. 10 3-(3-ISOPROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3- 13 -CYCLOPROPYLMETHOXY-1, 2 , 5-THIADIAZOL - 4 - YL) -1,2,5, 6-15 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PENTOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDR0-1-METHYLPYRIDINE 20 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3- (3 -(3-BUTENOXY)-1,2,5-THIADIAZOL-4 YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-<BUT-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-(3-MCTHYLBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-3 0 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1.2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3-(3 -(PROP-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1, 2, 5,6- TETRAHYDRO-1-METHYL PYRIDINE Printed from Mimosa 13 17 04 W0')7/205S6 rCTAISM/19390 -32- }-(J-BENZYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 3 -(3 -CHLORO-1,2,5-THIADIAZOL, - 4-YL)-l,2,5,6-TETRAHYDRO-1-5 METHYLPYRIDINE 3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TFTRAHYDROPYRIDINE 10 3-(3-ETHOXY-1,2, 5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-1-ETHYLPYRIDINE 3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-15 ETHYLPYRIDINE 3- (3-METHOXYETHOXY-l,2, 5-THIADIAZOL-4-YI.)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 20 3- (3-HEPTYLOXY-1,2, 5-THIADIAZOL-4-YL) -1, 5, 6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3 -(3 -PENTYNYLOXY)-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3 - (3 - (4 -PENTENYLOXY)-1.2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(2-PROPENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-30 TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-OCTYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3 -(3-(3-HEXYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYL PYRIDINE Printed from Mimosa 13 17 04 WO <)7/20S«;fi 1'CT/US96/I9390 -33- 3-(3-(3-BUTENYL-2-OXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METIIYL- PYRIDINE 3- (3 - (4-HEXENYLOXY (-1,2, 5-THIADIAZOL-4-'!iL) -1,2,5,6-5 TLTRAHYDRO-1-METHYLPYRIDINE TRANS-3-(3-(3-HEXENYLOXY)-1,?,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 CIS-3-(3-(2-PENTENYLOXY)-1.2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,4,5-20 TCTRAHYDRO-1-METHYLPYRIDINE TRANS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-METHYLPIPERIDINO-l,2,5-THIADIAZOL-4-YL >-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3-MORPHOLINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-DIMETHYLAMINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3 -(3-HEXYLAMINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/I9390 -34- 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-DEUTEROMETHYLPYRIDINE 5 1,2,5,6-TETRAHYDRO-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4- YL)PYRIDINE 3-(3-(2-(2-METHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-(3-ETHOXY-l-PROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6,-TETRAHYDRO-1-METHYLPYRIDINE 3-(2-ETHOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-15 1-METHYLPYRIDINE 3-(3-(2-BUTOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 20 3-(3-(2-(2-BUTOXYETHOXY)-ETHOXY)-l,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(2-(2-ETHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL>-1.2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 25 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-METHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-l-30 METHYLPYRIDINE 3 -(3-PENTYL-l,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-l-METHYLPYRIDINE 35 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/I9390 -35- 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1, 2,5, 6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-5 METHYLPYRIDINE 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-OCTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-TETRAHYDRO-l-METHYLPYRIDINE ?-(3-PROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 15 3-(3-HEPTYL-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-20 METHYLPYRIDINE 3 -(3-OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYPYRIDINE 25 3-(3-(2-METHYL)-BUTYL-1,2,5-THIADIAZOL-4-YL)-1,2 5.6- TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-METHYLCYCLOPROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3-CYCLOPENTYLTHIO-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 -(l-ETHYLTHIO-2-METHOXY)-1,2,5-THIADIAZOL-4-YL >-1,2,5,6 -3 5 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 l'CT/US96/19390 -36- 3- (3- (3-CHLORO-1-PROPYLTHIO) -1,2,5- THIADIAZOL)-4-YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 - 12-METHOXYETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-5 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-CYANO-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2, 5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 3 -{3 -BENZYLTHIO-1,2,5-THIADIAZOL-4-YL>-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-(2-ETHOXY-1-ETHYLTHIO)-1, 2 , 5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLP^ RIDINE 15 3-(3-(4-PENTYNYLTHIO)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-(2-(2-ETHOXYMETHOXY)-ETHYLTHIO)-1,2 , 5-THIADIAZOL-4-YL)-20 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3 - (5-CYANO-l- PENTYIiTHIO) -1,2, 5-THIADIAZOL-4 - YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3 -(3-PHENYL-l-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2, 5, 6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(2-PHENOXYETHYLTHIO)-l,2, 5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3 -(4-CYANOBUTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-{3 -{2-ETHYLBUTYLTHIO)-1,2,5-THIADIAZOL-4-YL >-1,2,5,6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCI/US96/19390 -37- 3-(3-CYCLOHEXYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(8-HYDROXYOCTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2.5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(7-OCTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-CYCLOPROPYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3(3-CYCLOPROPYLMETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINL 15 3-(3-(3-BUTENYITHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4 -PENTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3 -(4-ISOHEXYLOXY-1, 2 , 5-THIADI^ZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 1-METHYL-l,2,5,6-TETRAHYDRO-3 -{ (4-CYCLOPENTYLPROPYL)OXY)- 1,2,5-THIADIAZOL-3 - YL)PYRIDINE 1-METHYL-l,2,5,6-TETRAHYDRO-3 -(4-ISOHEPTYLOXY-l,2,5-THIADIAZOL-3-YL)PYRIDINE 30 1-METHYL-l,2,5,6-TETRAHYDRO-3 -(4( (2-CYCLOHEXYLETHYL)OXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3 -(4-(1-METHYLHEXLOXY)-1,2,5-35 THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 WO 97/20S56 I'Cr/LIS96/19390 -38- 3 - ( 4- (1 -ETHYLPENTYLOXY) -1, 2 , 5-THIADIAZOL-3-YL) -1. 2 , 5 , 6-TETRAHYDRO-1-METHYL PYRIDINE 3 -(4 -(1-ETHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)-1,2.5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 1,2,5.6-TETRAHYDRO-1-METHYL-3 -(4- (1-METHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-)YL)PYRIDINE 10 1-METHYL-3-(4-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6 TETRAHYDROPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4 -(2-METHYLBUTOXY>-1,2,5-THIADIAZ0L-3-YD PYRIDINE 15 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLPENTYLOXY)-1,2,5-THIADIAZ0L-3-YL)PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2,2,2-TRIFLUOROETHOXY)-20 1,2.5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3 - 14-(3-METHYLPENTYLOXY)-1.2,5-THIADIAZOL-3-YL)PYRIDINE 25 3-(3 -(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2, 5, 6 TETRAHYDO-1-METHYLPYRIDINE 3 -(3-ISOBUTOXY-1,2.5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-1-METHYLPYRIDINE 30 1,2.5, 6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 3-(3 -(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-35 TETRAHYDRO-l-METHYLPlt RIDINE Printed from Mimosa 13 17 04 wo <*ia (W6 l'Cn7US96/l9390 -39- ( + -)1,6-DIMETHYL-3 -(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3 -(3 -(3-PHENYL-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE BIS-1.4-(3-(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5-THIADIAZOL-4 -YL) BUTANEDITHIOL 10 3-(3-(4, 4, 4-TRIFLUOROBUTOXY) -1,2,5-THIADIAZOL-4-YL)-1,2,5- THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3, 3, 3-TRIFLUOROPROPYLTHIO) -1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 15 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDROPYRIDINE 3- (3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO- 1, 1-DIMETHYLPYRIDINIUM IODIDE 25 (+ -)1,6-DIMETHYL-3 -(3 -BUTYLTHIO-1,2,5-THIADIAZOL-4 -YL) - 1,2,5,6-TETRAHYDROPYRIDINE ( + -)1,6-DIMETHYL-3 -(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 30 3-(3-(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDO-1-METHYL PYRIDINE 3-(3-ISOBUTOXY-1,2, 5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- 35 METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/205S6 PCT/l IS96/19390 -40- 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-MCTHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 3-(3 -(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE (+-)1,6-DIMETHYL-3-(3-HEXYLOXY-l,2,5-THIADI1ZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 10 3 -(3 -(3-PHENYL-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE BIS-1,4-(3-(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5-THIADIAZOL-4-YL)BUTANEDITHIOL 15 3 -(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,b-THIADIAZOL-4-YL)-1,2,5,6-TETRAH'iDRO-1-METHYLPYRIDINE 3 -(3- (3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-20 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,G-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5, 6- TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDROPYRIDINE 30 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-l,1-DIMETHYLPYRIDINIUM IODIDE (+-)1,6-DIMETHYL-3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)- 3 5 1,2,5,6-TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -41- ( + -)1, 6-DIMETHYL-3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDROPYRIDINE, or a pharmaceutically acceptable salt thereof 5 Especially preferred compounds include the following 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 10 3-(3-METHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,G-TETRAHYDRO-1 METHYLPYRIDINE 3-(3-PENTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 METHYLPYRIDINE 3 - (3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1 -20 METHYLPYRIDINE 3-(3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 MFTHYLPYRIDINE 25 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3 - (3-OCTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3 - ETHOXY-1,2,5-THIADIAZOL-4-YL)-1 2,5,6-TETRAHYDRO-l- 35 METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20156 PCTAJS96/I9390 -42- 3 -(3 -PROPOXY-112,5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 -BUTOXY-1,2,5-THIADIAZOL-4-YL)l,2,5,6-TETTRAHYDRO-1 -METHYLPYRIDINE 3-(3-ISOPROPOXY-l,2.5-THIADIAZOL-4-YL)-I,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PENTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDIME 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-{3-(3-BUTENOXY)-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYL PYRIDINE 3-(3 -(BUT-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(3-METHYLBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-HEXYLOXY-l,2,5-THIAD1AZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(PROP-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE, or a pharmaceutically acceptable salt or solvate thereof Compound which are particularly preferred include 3-(3-HEXYLOXY-l,2,5-THJADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE , and Printed from Mimosa 1317 04 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 97720556 l'CT/llS96/tM90 -43- 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4 -YL) -1, 2 , 5,6-TETRAHYDRO-1-METHYLPYRIDINE. or a pharmaceutically acceptable salt or solvate thereof Printed from Mimosa 13 17 04 n \VO 97/205S6 l>cr/US96/l9390 t - -44-CXoLima 10 15 20 1 A composition for treating pain comprising an analgesic dose of a Compound selected from the group consisting of formula I wherein X is oxygen or sulphur, R is hydrogen, amino, halogen, -CHO, -NO2, -OR4, -SR4, -SOR"1, -so2r4. c3-7-cycloalkyl, c4-0-(cycloalkylalkyl), -Z-c3.7-cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R4 is straight or branched Ci-is-alkyl, straight <->r branched c2-15-alkenyl, straiqht or branched C2-i5-alkynyl, each of which is optionally substituted with one or more halogens, -era, -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci_4~alkoxy, -OCFj, -conh2 or -CSNH2, or r is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, C1-4-alkyl, Ci-4-alkoxy, -ocf3, -conh2 or -CSNH2, or R is -OR5Y, -SR5Y, -0R5ZY, -SRsZY, -o-r4-Z- r5 or -S-R4-Z-R5 wherein 2 is oxygen or sulphur, R5 is straight or branched Li-is-dlkynyl, and Y is a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched Ci-6-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group, and G is selected from one of the following azabicyclic rings I R Printed from Mimosa 13 17 04 WO •>7/20^56 l'CI/llS<)fi/l'>390 wherein the thiadiazole 01 oxadiazole ring can be attached at any carbon atom of the azabicyclic nnq, R1 and R2 may 5 be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently aze hydrogen, straight or branched Chalky!, straight or branched C2-b alkenyl, straight or branched Ca-s-alkynyl, straight or branched Ci_io~alkoxy, 10 straight or branched Cj-s-allcyl substituted with -OH, OR4, halogen, -NH2 or carboxy, R3 is H, straight oi branched Ci_ tj-alkyl, straight or branched C2-5-alkenyl or straight or branched C2-5-alkynyl, n is 0, 1 or 2, m is 0, 1 or 2, p is 0, 1 or 2, q is 1 or 2, and is a single or double bond, 15 or a pharmaceutically acceptable salt or solvate thereof, and formula II 2 0 wherein Z1' is oxygen or sulphur, Printed from Mimosa 13 17 04 WO 97/205Sfr l,CT/US96/l»3<)» -46- R' id hydrogen, halogen, amino, -NHCQ-R2', Cj-7-cycloalkyl, c4-1o~ (cycloalkylalkyl), -Z2' -c3-7-fycloolkyl optionally substituted with Ci-6-alkyl, -Z2' -C4.1 o' (cycloalkylalkyl), -Z2 1 "C4-10- (cycloalkenylalkyl) , 22' -C^io-5 (mothylenecycloalkyl-alkyl), -NH-R*!'. ~NR2*R3', -NH-OR2', phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, mdenyi, X', R2', -Z2'K2\ -SOR2', -S02R2', -Z2'-R2'-Z3 '-R3' , -Z2'-R2'-Z3'-R3'-Z4'-R4', -Z2 '-R2 'CO-R3 ' , 10 -Z2 ' -R2' -co2-R3' , Z2'-R2' -oic-r1' , -?,2'-r2,-conh-r3', -z2'-r2'- nhcor"3 ', -Z2 "-R-' -X', -Z2'-R2,-Z3,-X', wherein Z2', Z3' , and Z4' independently are oxygen or sulphur, and R2', Rv and R4' independently are straight: or branched c^^-alkyl, straight 15 or branched C^-is-alkenyl, straight or branched C2-i5~alkynyl, each of which is optionally substituted with halogen (s), -OH. -CN, -cf3, -SH, -COOH, -NH-R2', -WR2'R3\ Ci-6alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two 20 halogen, -CN, Ci-4-alkyl or Ci 4-dlkQxy, and X' is a 5 or 6 membered heterocyclic group containing 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 straight or branched Cj-g-25 alkyl, phenyl, benzyl or pyridine, or a carbon atom m the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group, and R5' and R6' may be present at any position, including the 30 point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Cj-5-alkyl, straight or branched c2-s-alkenyl, straight or branched Cs-s-alkynyl, straight or branched Ci-io~alkoyy, straight or branched Ci-5-alkyl substituted with -OH, -OH, halogen, -NH2 3 5 or carboyy, R1' is hydrogen, straight or branched Ci-5-alkyl, straight or branched C2-5~alkenyl or straight or branched Printed from Mimosa 1317 04 WO 97/20S56 i,ci/us«>6/i<mn -47- C2-5-alkynyl, or a pharmaceutical!/ acceptable salt or solvate thereof, and a nonsteroidal ant1-inflammatory drug in a weight ratio of Compound to nonsteroidal anti-inflammatory drug (NSAIDS) of from about 1 to about 1000 2 A composition a? claimed by Claim 1 wherein the Compound ir. of the formula I N X I R 10 wherein X is oxygen or sulphur, R is hydrogen, ammo, halogen, -CHO, -NO2, -OR4, -SR4, -SOR4, -so2r4, c3-7-cycloalkyl, C4-8-(cycloalkylalkyl), -Z-c3-7-cycloalkyl, and -Z-c4-8-(cycloalkylalkyl) wherein R4 is 15 straight or branched Ci-15-alkyl, straight or branched c2-15- alkenyl, straight or branched c2-is-alkynyl, each of which is optionally substituted with one or more halogens, -CF3, -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, 20 -conh2 or -csnh2, or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -ocf3, -conh2 or -CSNH2, or R is -OR5Y, -SRsY, -OR^ZY, -SR^ZY, -0-R4-Z- R^ or -S-R4-Z-R^ wherein "Z is oxygen or sulphur, R5 is straight or branched Ci.-15-alkynyl, and { is 25 a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched Ci-g-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused 30 with a phenyl group, and G is selected from one of the following azabicyclic rings Printed from Mimosa 13 17 04 wo waiTM I'Cl /UM6/I9390 -48- or FT R / N *3 R3 whex-ein Che thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring, R1 and may 5 be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Cx-5-alkyl, straight or branched C2-5 alkenyl, straight or branched c2-s~alkynyl, straight or branched Ci-10-alkoxy, 10 straight or branched Ci-5-alkyl substituted with -OH, OR4, halogen, -NH2 or carboxy, R3 is H, straight or branched Ci-5-alkyl, straight or branched C2-5-alkenyl or straight or branched c2-s-alkynyl, n is 0, 1 or 2, m is 0, 1 or 2, p is 0, 1 or 2, q is 1 or 2, and is a single or double bond, 15 or a pharmaceutically acceptable salt or solvate thereof, and a nonsteroidal ant 1-inflammatory drug m a weight ratio of Formula i to nonsteroidal anti-mflammatory drug (nsaids) of from about 1 to about 1000 20 3 A composition of Claim 2 wherein X is S, G is rx\ X 25 wherein n is 1, p is 1 or 2 and m is 1 or 2, R1 and R2 independently are hydrogen, methyl, hydroxy, halogen or ammo, or a pharmaceutically acceptable salt or solvate thereof Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -49- 4 A composition of Claim 2 wherein X is S, G is 'm wherein n is 1, p is 1 or 2 and m is 1 or 2 5 A composition according to Claim 2 wherein the compound of Formula 1 is selected from the group consisting of the following 10 3-CHLORO-3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2 2.2]OCTANE, 3 -(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-3-HYDROXY-1-AZABICYCLO[2 2 2]OCTANE, 15 3-METHOXY-3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3- (3-METHOXY-l,2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO!2 2 2]OCT-2- 3 -(3 -HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2.2]OCT-2-ENE, [2 2 2]OCTANE, 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)- 3-HYDROXY-1-AZABICYCLO[2 2 2]OCTANE; 30 3 -(3 -CHLORO-1,2,5-THIADIAZOL-4-YL)-l-AZ^BICYCLO[2.2 2]OCTANE, 3 -(3 -ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2.2 2]OCTANE, 20 ENE, 25 3-HEXYLOXY-3-(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO- Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/I930U -50- 3- (3-PROPOXY-l, 2,5-THIADIAZOL-4-YL) -1-AZABICYCLO[2.2 2]OCTANE, 3 - (3 -BUTOXY-1, 2 , 5-THIADIAZOL- '3 - YL) - 1-AZABICYCLO [ 2 2 2]OCTANE, 5 3 -(3 -PENTYLTHIO-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO-[2 2 2]OCTANE, 3-(3-ETHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 10 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3-(3-(3-PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-15 AZABICYCLO[2 2 2]OCTANE, 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO[2 2 2]OCTANE, 20 3 -(3-(4-CYANOBENZYLTHIO) -1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2 2 2]OCTANE, EXO-6-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, 25 ENDO-6-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-30 AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-(5-HEXENYLTHIO) -1,2,5-THIADIAZOL-4-YL)-1 -AZABICYCLO[3 2 1]OCTANE, 35 ENDO-6-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[3 2 1]OCTANE, Printed from Mimosa 13 17 04 WO 97/20556 l'CT/US96/lt)390 -51- ENDO-6-(3-PENTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-5 AZABICYCLO[3 2.1]OCTANE, ENDO-6-(3-(3 -PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, or a pharmaceutically acceptable salt or solvate thereof 10 6 A composition of Claim. 2 wherein compound is 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, or a pharmaceutically acceptable salt or solvate 15 thereof 7 A composition of Claim 2 wherein the the non-steroidal antiinflaminatoiy drug is selected from the group consisting of salicylates, mdomethacin, lbuprofen, 20 naproxen, fenoprofen, tolmetm, sulmdac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac 8 A composition of Claim 7 wherein the nonsteroidal antiinflammatory drugs is selected from the group 25 consisting of aspirin, lbuprofen, and naproxen 9 A composition of Claim 2 wherein the weight ratio of a compound of Formula I to NSAIDS is from about 1 to about 100 30 10 A composition of Claim 7 wherein the weight ratio is from about 1 to about 3 0 11 A composition of Claim 10 wherein the 3 5 weight ratio is from about 1 to about 10 Printed from Mimosa 13 17 04 -52- 12 A composition of Claim 11 wherein the weight ratio is from about 1 to about 3. 13. A composition of Claim 9 wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of aspirin and lbuprofen. 14 A composition of Claim 7 wherein the weight ratio of compound of Formula I to NSAIDS is from about 1 to about 100 15 A composition of Claim 8 wherein the weight ratio of compound of Formula I to NSAIDS is from about 1 to about 100 16 The use, in the manufacture of a medicament for treating pain, of a composition comprising a compound of Formula I wherein X is oxygen or sulphur; R is hydrogen, ammo, halogen, -CHO, -NO2, -OR4, -SR4, -SOR4, -SO2R41 C3_7~cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R4 is straight or branched Ci-15-alkyl, straight or branched C2-15-alkenyl, straight or branched C2-i5-alkynyl, each of which is optionally substituted with one or more halogens, -CF3, -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, -CONH2 or -CSNH2< or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci_4-alkyl, Ci-4-alkoxy, -OCF3, -CONH2 or -CSNH2; or R is -OR5Y, -SR5Y, -OR5ZY, -SR5ZY, -O-R4—Z— R5 or -S-R4-Z-R5 wherein Z is oxygen I R J - 2 JUL ra 7" A / » A / !• 3 9 4 -53- or sulphur, Rs as straight or branched Ci_i5-alkynyl, and Y is a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched Ci-g-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R1 and R2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Ci_s-alkyl, straight or branched C2-5 alkenyl, straight or branched C2-5~alkynyl, straight or branched Ci-10-alkoxy, straight or branched Ci-5-alkyl substituted with -OH, OR4, halogen, -NH2 or carboxy, R3 is H, straight or branched Ci-5-alkyl, straight or branched C2-5-alkenyl or straight or branched C2-5~alkynyl; n is 0, 1 or 2, m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2, and is a single or double bond, or a pharmaceutically acceptable salt or solvate thereof; and one or more NSAIDS in a weight ratio of Formula I to NSAIDS of from about 1 to about 1000 17. A use of Claim 16 wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of salicylates, mdomethacin, lbuprofen, naproxen, fenoprofen, tolmetm, sulmdac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac - 2 JUL 1339 T*) A R Q 4 _, -J L, 'v J <J f 54- 18. A use of Claim 17 wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of lbuprofen, and naproxen. 19. A use of Claim 16 wherein the weight ratio of a compound of Formula I to NSAIDS of from about 1 to about 100 20. A use of Claim 19 wherein the weight ratio is from about 1 to about 30. 21 A use of Claim 20 wherein the weight ratio is from about 1 to about 10. 22. A use of Claim 21 wherein the weight ratio is from about 1 to about 3 23. A use of Claim 22 wherein the compound of Formula I is 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2.2.2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof. 24 A use of Claim 22 wherein the medicament is formulated for transdermal administration 25 A composition of Claim 1 wherein the compound is a compound of the formula II \ - 1 JUL 1303 WO 97/20556 PCI /US96/I9390 -55- / N (II) N RJ' wherein 2l" is oxygen or sulphur, R' is hydrogen, halogen, amino, -NHCO-R2', c3_7-cycloalkyl, C4-10-(cycloalkylalkyl), -Z2' -c3-7~cycloalkyl optionally substituted with Ci_s-alkyl, -Z2' -c4-10- (cycloalkylalkyl) , -Z2'-C4_io- (cycloalkenylalkyl) , -Z2' -c4-10-(methylenecycloalkyl-alkyl), -NK-R2', -NR2'R3', -NH-OR2', phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, indenyl, X', R2', -Z2'R2', -SOR?\ -SO2R2', -Z2'-R2'-Z3 -R3'. -Z2'-R2'-Z3'-R3'-Z<1'- R4', -Z2'-R2'CO-R3', -Z2 -R2'-co2-R3, , Z2'-R2'-o2c-R3', -Z2'-R2'-CONH-R3', -Z2'-R2'-NHCOR3', -Z2'-R2'-X', -Z2'-R2'-Z3 ' -X', wherein Z2', Z3' , and Z4' independently are oxygen or sulphur, and R2'. R31 and R4' independently are straight or branched Ci_i5-alkyl, straight or branched c2-i5-alkenyl, straight or branched c2-is-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -cf3, -SK, -COOH, -NH-R2', -NR2'R3', Ci-6alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, Ci_4-alkyl or Ci-4-alkoxy, and X' is a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted Printed from Mimosa 13 17 04 WO 97/20556 l'CT/US06/19390 -56- at carbon or nitrogen atom(s) with straight or branched Ci_6-alkyl, phenyl, benzyl or pyridine, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally 5 fused with a phenyl group; and R5' and Rs' may bo present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogpn, straight or branched Ci-$-alkyl, straight or branched Ca-s-alkenyl, straight or branched 10 c2-5-alkynyl, straight or branched Ci-io-alkoxy, straight or branched Ci_5-alkyl substituted with -OH, -OH, halogen, -NH^ or carboxy, R1' is hydrogen, straight or branched Ci_5-alkyl, straight or branched c2-5-alkenyl or straight or branched c2-5~alkynyl, or 15 a pharmaceutically acceptable salt or solvate thereof, and one or more nonsteroidal anti-inflammatory drugs in a weight ratio of Formula II to nonsteroidal antiinflammatory drug of from about 1 to about 1000 20 26 A composition of Claim 25 wherein Z' is sulfur 27 A composition of Claim 25 wherein Z' is sulfur, R1' is hydrogen or straight or branched Ci_s-alkyl, 25 R5' and Rs' independently are selected from the group consisitng of hydrogen, methyl, methoxy, hydroxy, halogen, and ammo 28 A composition according to Claim 25 3 0 wherein the compound of Formula II is selected from the group consisting of the following 3-(3-METHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 35 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/101*6 rCT/US%/19390 -57- 3-{3-PROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 5 3-(3-BUT0XY-1.2, 5-THIADIAZOL-4-YL)1,2,5,6-TETTRAHYDRO-1- METHYLPYRIDINE 3-(3 -ISOPROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 10 3-(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PENTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-15 METHYLPYRIDINE 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 20 3-(3-(3-BUTENOXY)-1,2,5-THIADIAZOL-4-YL)-1.2,5,6-TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(BUT-2-YN0XY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 25 3-(3-(3-METHYLBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-3 0 METHYLPYRIDINE 3-(3-(PROP-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3-(3-BENZYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 I»CT/U«W6/I9390 -58- 3 ~(3-CHLORO-1.2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-CHLORO-1.2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 5 3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-1-ETHYLPYRIDINE 10 3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-ETHYLPYRIDINE 3 -(3-MSTHOXYETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,S-TETRAHYDRO-15 1-METHYLPYRIDINE 3-(3-HEPTYLOXY-1,2,5-THIADIASOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 20 3-(3-(3-PENTYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYL PYRIDINE 25 3 -(3 -(2-PROPENYLOXY >-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-OCTYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-30 METHYLPYRIDINE 3 -(3 -(3-HEXYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 35 3-(3 -(3-BUTENYL-2-OXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYL-PYRIDINE Printed from Mimosa 13 17 04 WO 07/20556 rci/us96/i«mo -59- 3-(3-(4-HEXENYLOXY(-1,2,5-THTADIAZOL-4-YL)-I, 2.5.6-TETRAHYDRO-1-METHYLPYRIDINE TRANS-3-(3 -(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-5 TETRAHYDRO-1 -METHYLPYRIDINE CIS-3 - (3- (2-PENTENYLOXY) -1,2, 5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 CIS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)- 1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 CIS-3-(3-(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,4,5-TETRAHYDRO-1-METHYLPYRIDINE TRAUS-3-(3- (2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL >-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(1,2,5-TIIIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-METHYLPIPERIDINO-l,2.5-THIADIAZOL-4-YL)-1,2,5,6-25 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-MORPHOLINO-l.2,5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 0 3-(3-DIMETHYLAMINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO- l-METHYLPYRIDINE 3-(3-HEXYLAMINO-1,2,5-THIADIAZOL-4-YL)-1.2.5.6-TETRAHYDRO-1-METHYLPYRIDINE 35 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5 » 6-TETRAHYDRO-1- DEUTEROMETHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/llSl)6/IU390 -60- 1,2,5,6-TETRAHYDRO-3-(3-HEXYLOXY-l, 2,5-THIADIAZOL-4-YL)PYRIDINE 3 - (3- (?- (2-METHOXYETHOXY) -ETHOXY) -1,2,5 - THIADIAZOL-<1 - YL) -1.2,5, 6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3 -(3 -ETHOXY-1-PROPOX^)-1,2.5-THIADIAZOL-4-YL)-l,2,5,6,-TETRAHYDRO-1-METHYLPYRIDINE 3 - (2 - ETHOXYETHOXY ) -1, 2 , 5-THIADIAZOL-4 - YL>) -I, 2, 5, 6 - TETRAHYDRO -1-METHYLPYRIDINE 3-(3 -(2-BUTOXYETHOXY)-!,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-MET HYLPYRIDINE 3-(3 -(2-(2-BUTOXYETHOXY)-ETHOXY)-1.2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(2-(2-ETHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-METHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3 -PENT YL-1,2,5 -THIADIAZOL-4-YL)-l,2,5, 6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO «J7/20,>56 rCT/US'WIWX) -61- 3 - (3 - PENTYLTHIO-l ,2,5 -THIADIAZOL- 4-YL >-1,2,5,6 - TETRAHYDRO 1 METHYLPYRIDINE 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-^ METHYLPYRIDINE 3 -(3-OCTYLTHIO-1,2,b-THIADIAZOL-4-YL)-1, 7 , 5, 6-TETRAHYDRO-l-METHYLPYRIDINE 10 3-(3-PROPYL-1.2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3 -(3-HEPTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1, 2, 5, 6-TETRAHYDRO-METHYLPYRIDINE 3-(3-OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-1 -2 0 METHYPYRIDINE 3- (3 -(2-METHYL)-BUTYL-1,2,5-THIADIAZOL-4-YL)-1.2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 2 5 3-(3-METHYLCYCLOPROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOPENTYLTHIO-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3- (3 - (l-ETHYLTHIO-2-METHOXY) -1,2, 5-THIADIAZOL-4 -YL) -1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-CHLORO-1-PROPYLTHIO)-1.2,5-THIADIAZOL-4-YL)-1,2,5,6 3 5 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 \YO ")7/20SSft I'C1/IJS')6/193W -62- 3- (3-(2-MCTHOXYETHOXY) -ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 (3 -(3-CYANO-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-BENSYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-TETRAHYDRO-1 METHYLPYRIDINE 3 -(3~(2-ETHOXY-1-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2, S,6-TLTRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-PENTYNYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3- (2-12-ETHOXYMETHOXY)-ETHYLTHIO)-1,2,5-THTADIAZOL-4-YL) 1,2,5.6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3 -(5-CYANO-l-PENTYLTHIO)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3 - PHENYL-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6 TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(2-PHENOXYETHYLTHIO)-1,2,5-THIADIAZOL-4-YL >-1,2,5,6-TETRA4YDR0-1-METHYLPYRIDINE 3 -(3 -(4-CYANOBUTYLTHIO)-1.2,5-THIADIAZOL-4 -YL >-1,2,5,6 -TETRAHYDRO-1-METHYLPYRIDINE 3- (3-(2-ETHYLBLTTYLTHIO) -1,2, 5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-{3-CYCLOHEXYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-l,2, 5,6- TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 NVO 'J7/2U516 I»C1/US«>WIWK» -63- 3-(3 -(8-HYDROXYOCTYLTHIO)-li2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINL 3- (1 - (7-OCTENYLTHIO) -1 , ? ,5-THIADIAZOL-4-YL)-1,2,5,6-5 TETRAHYDRO-I-METHYLPYRIDINE 3 - (J -CYCLOPROPYLMETHYLTIIIO-1,2 , 5-THIADIAZOL-4-YL) -1,2, 5,6-TETRAHYDRO-1-MFTHYLPYRIDINE 10 3(3-CYCLOPROPYLMETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1 -METHYI.PYRIDINfc1 3-(1 -(3-BUTENYLTHIO)-1,^,5-THIADIAZOL-1-YL)-1,2,5,6-TETRAIIYDRO-1 -METHYLPYRIDINE 15 3-(3 -(4-PENTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-MFTHYLPYRIDINE 3-(4-1SOHFXYLOXY-1,2,5-THIADIAZOL-3-YL)-1,2,5, 6-TETRAHYDRO-1- 2 0 METHYLPYRIDINE 1-METHYL-l,2.5,6-TETRAHYDRO-3 - ((4-CYCLOPENTYLPROPYL)OXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 25 1-METHYL-l ,2,5,6-TETRAHYDRO- 3- (4-ISOHEPT'iLOXY-1, 2 , 5- TIIIADI AZOL-1 - YL) PYRIDINE 1-METHYL-l.2,5,6-TETRAHYDRO-3-(4((2-CYCLOHEXYLETHYL)OXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 30 1,2,5,b-TETRAHYDRO-1-METHYL-3-(4 -(1-METHYLHEXLOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 3-(4-fl-ETHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6- 3 5 TETRAirYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/I9190 -64- 3-(4 (1 -ETHYLBUU'OXY) -1,2, 5-THIADIAZOL-3 - YL) l,?,5,f>-T ET RAHYDRO -1 -METHYLPYRIDINE 1,2,5.6 TETRAHYDRO-l-METHYL-3-(4- (1 -METHYLPENTYLOXY) -1,2,5-5 THIADIASOL-3-)YL)PYRIDINE 1-METHYL-3- (4 - (5-HEXENYLOXY) -1,2,5-THIADIAZOL- J-YL)-1,2 . 5 , f. l^TRAHYDROPYRIDINE 10 1,2.5,6-TETRAHYDRO-1-METHYL-3 -(4-(2-METHYLBUTOXY)-1,2,5- THIADIAZOL-3 -YL)PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-<4-i2-METHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 15 1,2,5,6-TETRAHYDRO-1-METHYL-3 -(4 -(2,2,2-TRIFLUOROETHOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-l,2,5,6-TETRAHYDRO-3 -(4-(3-METHYLPENTYLOXY)-1,2,5-20 THIADIAZOL-3-YL)PYRIDINE 3 -(3-(3-METHYL-2-BUTENYLOXY) -1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDO-1-METHYLPYRIDINE 25 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3 -(4 -(2-METHYLBUTOXY)-1.2,5-THIADIAZOL.-3 - YL) PYRIDINE 30 3-(3-(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE ( + -)1,6-DIMETHYL-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)- 3 5 1,2,5,6-TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/USOft/IWJO -65- 3-(3-(3-PHENYL-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)—1,2,5,6— TETRAHYDRO-1-METHYLPYRIDINE BIS-1,4-(3-(1-METHYL-l,2,5,b-TETRAHYDROPYRIDIN-3-YL)-1,2 , 5 -5 THIADIAZOL-4-YL)RUTANEDITHIOL 3- (3- (4, 4, 4-TRIFLUOROBUTOXY) -1,2, 5-THIADIAZOL-<l - YL) -1,2,5-THIADIAZQL-4-YL)-1,2,5,6-TETRAHYDRO-1-MCTHYLPYRIDINE 10 3-(3 -(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1, 2,5,6-TETRAHYDROPYRIDINE 15 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1,1-20 DIMETHYLPYRIDINIUM IODIDE (+-)1,6-DIMETHYL-3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 25 '+-)1,6-DIMETHYL-3-(3-BUTOXY-1,2.5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3-(3-(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDO-1-METHYL PYRIDINE 30 3 -(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1, 2,5- 35 THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 l'CI/USy6/l9390 -66- 3-(3-(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE ( + -)1,6-DIMETHYL-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-5 1,2,5,6-TETRAHYDROPYRIDINE 3 -(3 -(3-PHENYL-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 10 BIS-1,4-(3-(1-METHYL-l,2, 5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5- THIADIAZOL-4-YL)BUTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-20 METHYLPYRIDINE 3 -(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 25 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1,1-DIMETHYLPYRIDINIUH IODIDE 30 (+ -)1,6-DIMETHYL-3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE, and (+-)1,6-DIMETHYL-3 -(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)- 3 5 1,2,5,6-TETRAHYDROPYRIDINE, or a pharmaceutically acceptable salt, or solvate thereof Printed from Mimosa 13 17 04 y .*> •* 5 94 -67- 29. A composition of Claim 25 wherein the the non-steroidal antiinflammatory drug is selected from the group consisting of salicylates, mdomethacin, lbuprofen, naproxen, fenoprofen, tolmetm, sulmdac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. 30. A composition of Claim 29 wherein the nonsteroidal antiinflammatory drugs is selected from the group consisting of aspirin, lbuprofen, and naproxen. 31. A composition of Claim 25 wherein the weight ratio of a compound of Formula II to NSAIDS is from about 1 to about 100. 32. A composition of Claim 30 wherein the nonsteroidal antiinflammatory drug is lbuprofen. 33. A composition of Claim 2 wherein the weight ratio of compound of Formula I to NSAIDS is from about 1 to about 100. 34 A use, in the manufacture of a medicament for treating pain, of a composition comprising a compound of the Formula II R N (II) wherein - 2 JUL tro WO 97/20556 I'CI/US^/igjlO -68- Z1' is oxygen or sulphur, R' is hydrogen, halogen, amino, -NHCO-R2', c3.7-cycloa.Lkyl c4-10-(cycloalkylalkyl) , -Z2'-c3-7~cycloalkyl optionally substituted with Ci-g-alkyl, -Z2'-C4-io-(cycloalkylalkyl) , 5 -Z^'-C-i-io- (cycloalkenylalkyl), -z2' c4-10- (merhylenecycloalkyl-alkyl), -NH-R2', -NR2'R3', -NH-OR2'. phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, indenyl, X", R2', -Z2'R2', -SOR2', -SO2R2', -Z2'-R2'-?3'-R3', -Z2'-R?'-Z3'-R3'-Z4'- 10 R4', -Z2'-R2'CO-R3', -Z2'-R2'-C02-R3', Z2'-R2'-02C-R3', -Z2'-R2'-CONH-R3 , -Z2'-R2'-NHCOR3 ', -Z2'-R2'-X", -Z2'-R2'-Z3'-X' , wherein Z2', Z3' , and ZJ' independently are oxygen or sulphur, and R2', R3' and R4' 15 independently are straight or branched Ci-15-alkyl, straight or branched c2-is-alkenyl, straight or branched c2-15-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -Cr3, -SH, -COOH, -NH-R2', -NR2'R3', Ci-galkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein 20 each aromatic group is optionally substituted with one or two halogen, -CN, Ci_4-alkyl or Cj-4-alkoxy, and X' is a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted 25 at carbon or nitrogen atom(s) with straight or branched Ci-g-alkyl, phenyl, benzyl or pyridine, 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; and 30 R5' and R6' may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C1-5-alkyl, straight or branched c2-s-alkenyl, straight or branched c2-5~alkynyl, straight or branched Ci-10-alkoxy, straight or 35 branched Cj-s-alkyl substituted with -OH, -OH, halogen, -NH2 or carboxy, R1' is hydrogen, straight or branched Ci-s-alkyl, straight or branched C2-5~alkenyl or straight or branched Printed from Mimosa 13 17 04 yo - r '1 f V ■■■■ i '•I a -69- C2-5-alkynyl; or a pharmaceutically acceptable salt ox solvate thereof; and one or more NSAIDS in a weight ratio of Formula II to MSAIDS of from about 1 to about 1000. 35. A use of Claim 34 wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of salicylates, mdomethacin, lbuprofen, naproxen, fenoprofen, tolmetm, sulmdac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac 3 6 A use Claim 34 wherein the non steroidal antiinflammatory drug is selected from the group consisting of lbuprofen, and naproxen. 37 A use of Claim 35 wherein the medicament is formulated for transdermal administration 38 A composition for treating pain comprising an analgesic dose of a Compound selected from the group consisting of Formula I R wherein X is oxygen or sulphur, R is hydrogen, amino, halogen, -CHO, -NO2, -OR4, -SR4, -SOR4, -SO2R4, C3_7~cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C4-8- (cycloalkylalkyl) wherein R4 is straight or branched Ci-is-alkyl, straight or branched C2-15-alkenyl, straight or branched C2-i5-alkynyl, each of which is optionally substituted with one or more halogens, -CF3, -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, ~ 2 JUL \2Z2 WO 97/20556 I'CT/llS'Ni/IWO -70- -conh2 or -csnh2, or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci-4-alkoxy, -OCF3, -conh2 or -csnti2, or R is -0R5Y, -SR5Y, -OR5ZY, -SR5ZY, -0-R4-Z- R5 or -S-R4-Z-R5 wherein 2 is oxygen or sulphur, Rs is straight 01 branched Ci-15-alkynyl, and Y is a 5 or 6 membered heterocyclic group containing 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 straight or branched Ci-6-alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group, and G is selected from one of the following azabicyclic rings wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring, R1 and R2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C1-5-alkyl, straight or branched C2-5 alkenyl, straight or branched c2-5~alkynyl, straight or branched Ci_io~alkoxy, straight or branched Ci-5-alkyl substituted with -OH, OR4, halogen, -NH2 or carboxy; R3 is H, straight or branched Cj. 5-alkyl, straight or branched c2-5-alkenyl or straight or branched c2-s-alkynyl, n is 0, 1 or 2, m is 0, 1 or 2, p is 0, 1 or 2, q is 1 or 2, and is a single or double bond, and Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/1939(1 -71- Tormula II 5 wherein Z1' is oxygen or sulphur, R" is hydrogen, halogen, amino, -NHCO-R2', C3_7-cycloalkyl, C4-10" (cycloalkylalkyl), -Z2'-C3_7-cycloalkyl optionally substituted with Ci_g-alkyl, -Z2'-C4_io-(cycloalkylalkyl) , 10 -Z2 ' -C4-10-(cycloalkenylalkyl) , -Z2'-C4_io- (methylenecycloalkyl-alkyl), -NH-R2', -NR2'R3', -NH-OR2', phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphtyl, indenyl, X', R2', -Z2 R2', -SOR2', -S02R2'. -Z2'-R2'-Z3 -R3', -Z2'-R2'-23 -R3'-24 -15 R4', -Z2'-R2'CO-R3', -Z2 -R2'-CO2-R3,, 22'-R2'-02C-R3', -Z2'-R2' -CONH-R3', -Z2'-R2'-NHCOR3' , -22'-R2' -X' , -Z2'-R2'-Z3'-K', wherein Z2', Z3', and Z4' independently are oxygen or sulphur, and R2', R3' and R4' 20 independently are straight or branched Ci_is-alkyl, straight or branched C2-i5-alkenyl, straight or branched C2-i5-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN. -CF3, -SH, -COOH, -NH-R2', -NR2'R3', chalky! ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wnerein 25 each aromatic group is optionally substituted with one or two halogen, -CN, Ci_4-alkyl or Printed from Mimosa 1317 04 WO 07/20556 PCT/US96/19390 -72- Ci-4-alkoxy, and X' is a 5 or 6 membered heterocyclic group containing one to four N, O or S atorn(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C^s-alkyl, phenyl, benzyl or pyridine, 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, and R5' and R5' may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C1-5-alkyl, straight or branched c2-s-alkenyl, straight or branched Co-s-alkynyl, straight or branched Cj-io-alkoxy, straight or branched Ci-5-alkyl substituted with -oh, -oh, halogen, -nh2 or carboxy, R1' is hydrogen, straight or branched Ci-5-alkyl, straight or branched c2-s-alkenyl or straight or branched c2-5-alkynyl, or a pharmaceutically acceptable salt or solvate thereof, and acetaminophen in a weight ratio of Compound to acetaminophen of from about 1 to about 1000 39 A composition of Claim 3B wherein the compound is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof wherein n is 1, p is 1 or 2 and m is 1 or 2, R1 and R2 independently are hydrogen, methyl, hydroxy, halogen or amino; or a pharmaceutically acceptable salt or solvate thereof 4 0 A composition of Claim 39 wherein X is S, G is N Printed from Mimosa 13 17 04 \VO 97/20556 PCT/US96/I9390 -73- 41 A composition of claim 39 wherein X is S, G is 4 \ il 'nV I Cnv. \ "N wherein n is 1, p is 1 or 2 and m as 1 or 2 42 A composition according to Claim 39 wherein the compound of Formula 1 is selected from the group consisting of the following 10 3-CHL0R0-3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2.2 2]OCTANE, 3-(3-CHLORO-1,2,5-THIADIAZOL-4 -YL)-3-HYDROXY-1-15 AZABICYCLO[2 2.2]OCTANE, 3-METHOXY-3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2,2]OCTANE, 20 3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2}OCT-2- ENE, 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCT- 2-ENE, 25 3-HEXYLOXY-3-(3 -HEXYLOXY-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO-[2 2.2]OCTANE, 3 -(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-3-HYDROXY-1-30 AZABICYCLO[2.2 2]OCTANE, 3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, Printed from Mimosa 13 17 04 WO 97/20556 pcr/us%/iwyu -74- 3 -(3 -PROPOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3-(3-BUTOXY-1,?,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3 -(3-PENTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-(2 2 2]OCTANE. 3 -(3-ETHOXY-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO[2 2 2]OCTANE, 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2)OCTANE, 3 -{3 - (3-PHENYLPROPYLTHIO)-1.2,b-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2.2)OCTANE, 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2]OCTANE, 3 -(3 -(4 -CYANOBENZYLTHIO)-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO[2 2 2]OCTANE, EXO-6-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(3 .2 UOCTANE, ENDO-6-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-(5-HEXENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABlCYCLO[3 2 l]OCTANE, Printed from Mimosa 13 17 04 WO 97/20556 ITT AIS96/19190 -75- END0-6-(3-PENTYLTHIO-l.2,5-THIADIAZOL-4-YL)-1-A2ABICYCLO[3.2 1]OCTANE, 5 ENDO - 6 - ( 3 - ETHYLTHIO -1, 2 , 5 -THIADIAZOL- 4 - YL ) - 1 - AZABICYCLO[1 2 1]OCTANE, and FNDO-6-(3-(3-PHENYLPROPYLTHIO)-1,2, 5-THIADIAZOL-4-YL)-1-A2ABICYCL013 2.1]OCTANE, or a pharmaceutically acceptable 10 salt or solvate thereot. 43 A composition of Claim 42 wherein the Compound of Formula I is 3 -(3-BUTYLTHIO-1,2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, or 15 a pharmaceutically acceptable salt or solvate thereof 44. A composition of Claim 4 3 wherein the weight ratio is from about 1 to about 3 0 20 45. A composition of Claim 38 wherein the compound is of Formula II 46. A composition of Claim 45 wherein Z is 25 sulfur 47. A composition of Claim 45 wherein Z is sulfur, R1 is hydrogen or straight or branched Ci-5-alkyl, R5 and K6 independently are selected from the group 30 consisitng of hydrogen, methyl, methoxy, hydrory, halogen, and ammo 48. A composition according to Claim 45 wherein the compound of Formula II is selected from the 35 group consisting of the following Printed from Mimosa 13 17 04 WO I'CT/UVJ6/19390 -76- 3- (3 -METHOXY-1,2,5 -THIADIAZOL-4-YL) -3,2, 5, 6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-ETHOXY-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO"1-METHYLPYRIDINE 3-(3-PROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)1,2,5, 6-TFTTRAHYDR O-1-METHYLPYRIDINE 3-(3-ISOPROPOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2.5.6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PENTOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-(3-BUTENOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETPAHYDRO-1-METHYLPYRIDINE 3-(3-(BUT-2-YNQXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-METHYLBUTOXY) -1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1, 2, 5,6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO <>7/205S6 PCT/USV6/1WI) -77- 3- (3 - (PROP-2- YNOXY) -1, 2 , 5-THIADIAZOL-'!~YL)-1,2, 5, 6 TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-BENZYLOXY-1,2,5-THIADIAZOL-4 -YL) 1,2,5,6-TETRAHYDRO-1-5 MCTHYLPYRIDINE 3- (3-CHLORO-l, 2, 5-THXADIAZQL-4-YD-1, 2, 5. 6-TETRAHYDrO-I-METHYLPYRIDINE 10 3-(3-CHLORO-l,2,5-THlADlAZOL-4-YL)-1.2, 5, 6-TETRAHYDROPYRIDINF 3- (3-BUTOXY-l, 2, 5-THIADIAZOL-4-YD-1, 2, 5, 6-TETRAHYDROPYRIDINE 3-(3 -ethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-TETPAKYDRO-1-15 ethylpyridine 3 -(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1,?,5,6-TETRAHYDRO-1-ETHYLPYRIDINE 20 3-(3-METHOXYETHOXY-1, 2,5-THIADIAZOL-4-YL)-1,2.5.6-TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-HEPTYLOXY-1,2, 5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-(3-PENTYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1.2 . 5.6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 -(4 -PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-30 TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 -(2-PROPENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 -TETRAHYDRO-1-METHYLPYRIDINE 35 3 - (3-OCTYLOXY-l. 2 , 5 -THIADIAZOL-4-YL ) -1, 2, 5 , 6-TETRAHYDR.O-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 rcT/uswvmn -78- 3 - (3 - (3-HEXYNYLOXY) -1, 2 , 5 -THIADIAZOL-4-YL) -1, 2 , 5, G-TETRAIIYDRO-1 -METHYLPYRIDINE 3 (3-(3-BUTENYL-2-OXY)-1,2,5-THIADIAZOL-4-YL)-1,?,5,6-5 TETRAHYDRO-1-METHYL-PYRIDINE 3-(3-(4-HEXENYLOXY(-1,?,5-THIADIAZOL-4-YL)-1,2, 5,6-TFTRAHYDRO-1-METHYLPYRIDINE 10 TRANS-3-(3-(3-HEXEMYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(2-PENTENYLOXY)-!,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-1-METHYLPYRIDINE 15 CIS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,4,5-TETRAHYDRO-1-METHYLPYRIDINE 25 TRANS-3-(3 -(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3 -(4-METHYLPIFERIDINO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-MORPHOLINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 35 3-(3 -DIMETHYLAMINO-1.2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO- l-METHYLPYRIDINE Printed from Mimosa 13 17 04 wo"J7/JO<K6 I'CT/t>N1>6/l«»VM -74- 3 - O -HEXYLAMINO-1, ? , S -THIAM A7.0L-4 -YL) -1,2 , b , b -TLTKAHYDRO- 1 -METHYLPYRIDINE S 3- (3-HEXYLOXY-l, 2, 5-THIADIAZOL-4-YI^ -1,2,5,6 -TETRAHYDRO- 1- DCUTEROMhTHYLPYRIDINE 1,2.3, 6-TETRAHYDRO 3 - ( 3-HEXYLOXY-l, 2 , 5-THIADIA"QL-<l-YL)PYRTDTNF 10 3- (3- (2- (2-METMOXYETIIOXY)-ETHOXY) -1,2, 5-TIIIADIAZOL-4 YL) -1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINT 3-(3 -(3-ETHOXY-1-PROPOXY)-1,2,5-TH1ADIAZOL-4-YL)-1,2,5,6,-15 TETRAHYDRO-1-METHYLPYRIDINE 3-(2-ETHOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1, 2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 20 3-(3-(2-BUTOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(2-(2-BUTOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 25 3-(3-(2-(2-ETHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-3 0 METHYLPYRIDINE 3-(3-METHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 35 3-(3-PENTYL-1,2,5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 W0 97/ltM<ifr I't I/USWIWO -80- 3 - (3 -PKOPVLTHIO-1,2, 5-THIADIAZOL -4-YL) - L, 2 , b , G -TETRAHYDRO-1 • MPTHYIi PYRIDINE (3 -HEXYLTHIO-1,2, b-THIADIAZOL-4-YL) -1, ,b,6-TFTRAHYDRO-1 MrTHYI. PYRIDINE 3 13 -FrNTYLTHIO-1,2,5-THIADIAZOL-<1 -YL)-1,2,b,6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-FTHYLTIIIO-l, ?, 5-THIADIAZOL 4-YL) -15,6-TETRAHYDRO-1-MCTHYLPYRIDINE 3-(1-OCtYlTHIO-I.2,5-THIADIAZOL-4-YL)-1,2,b,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 - PROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TFTKAHYDRO-1 METHYLPYRIDINE 3 -(3-HEPTYL-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TLTRAHYDRO-1-METHYLPYRIDINE 3-I3-OCTYL-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYPYRIDINE 3-(3-(2-METHYL)-BUTYL-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-METHYLCYCLOPROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6~ TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOPENTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 \V0 97/20S5<5 l»C IAJSV6/19VJ0 -Hl- 3-(1-(1-ETHYLTHIO-2-METHOXY) -1, 2 ,5-THIADIAZOL-4 - YL)-1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 -{3 -CHLORO-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1.2.5,6 5 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(2-METHOXYETHOXY)-ETHYLTHIO)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 10 3-(3-(3-CYANO-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAIIYDRO-1 -METHYLPYRIDINE 3-<3-SENZYLTHIO-1, 2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 METHYLPYRIDINE 15 3 -(3 -(2-ETHOXY-1-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-PENTYNYLTHIO)-1.2.5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(2-(2-ETHOXYMETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL) 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 25 3-(3-(5-CYANO-l-PENTYLTHIO)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-PHENYL-l-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 30 3 -(3 -(2-PHENOXYETHYLTHIO)-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6 -TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-CYANOBUTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2, b,6- 3 5 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO Q7/20S56 PCTAJS96/IW00 -82- 3-(3-(2-ETHYLBUTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO- 1 -METHYLPYRIDINE 3- (3-CYCLOIIEXYLMETHYLTHIO-l, 2, 5-THIADIAZOL-4-YL) -1,2,5,6-5 TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(8-HYDROXYOCTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-(7-OCTENYLTHIO)-1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 3(3-CYCLOPROPYLMETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(3-BUTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(4-PENTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1, 2, 5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(4-ISOHEXYLOXY-l,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3 -((4-CYCLOPENTYLPROPYL)OXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 30 1-METHYL-l,2,5,6-TETRAHYDRO-3-(4-ISOHEPTYLOXY-1,2,5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-l,2,5,6-TETRAHYDRO-3-(4((2-CYCLOHEXYLETHYL)OXY)- 35 1,2,5-THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCn7US«>6/m«MI -83- 1,2,5, G-TETRAHYDRO-1-METHYL-3- (4 -(1-METHYLHEXLOXY)-1,2,5-THIADIAZOL-3 -YL)PYRIDINE 3-(4-(1-ETHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3-(4-(1-ETHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 1,2,5,6-tetrahydro-1-methyl-3-(4-(1-methylpentyloxy)-1,2,5- thiadiazol-3 -)yl)pyridine l-MFTHYL-3-(4-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6 TETRAHYDROPYRIDINE 15 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4 -(2-METHYLBUTOXY) -1,2,5-TJIIADIAZOL-3-YL) PYRIDINE 1,2,5,6-TETRAHYDRO-l-METHYL-3-(4-(2-METHYLPENTYLOXY)-1,2,5-70 THIADIAZOL-3-YL)PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2,2,2-TRIFLUOROETHOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 25 1-METHYL-1,2,5,6-TETRAHYDRO-3 -(4 -(3-METHYLPENTYLOXY) -1, 2 , 5 - THIADIAZOL-3-YL)PYRIDINE 3-(3 -(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDO-1-METHYLPYRIDINE 30 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1,2,5- 35 THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 WO 97/205S6 PCT/US96/1939(1 -84- 3-(3 -(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE (+-)1, 6-DIMETHYL-3-(3-HEXYLOXY-l,2,5-THTADIAZ0L-4-YL)-5 1,2 , 5, 6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 BIS-1,4-(3 -(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5- THIADIAZOL-4-YL)BUTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5-THIADIAZOL-4-YL) -1,2,5, 6-TETRAHYDRO-l-METHYLPYRIDINE 15 3-(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 25 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1,1- DIMETHYLPYRIDINIUM IODIDE (+-)1,6-DIMETHYL-3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 30 (+-)1,6-DIMETHYL-3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-35 TETRAHYDO-1-METHYL PYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US%/19390 -85- 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-MFTHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4 -(2-METHYLBUTOXY) -1, 2 , 5 -5 THI^DIAZOL-3-YL)PYRIDINE 3- (3-(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL) 1.2,b,6-TETRAHYDRO-1-METHYLPYRIDINE 10 (+-)1,6-DIMETHYL-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 BIS-1,4- (3- (1-METHYL-l ,2,5,6-TETFIAHYDROPYRIDIN-3-YL) -1,2,5-THIADIAZOL-4-YL)BUTANEDITHIOL 3-(3-(4 , 4, 4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 25 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1, 2,5, 6-TETRAHYDROPYRIDINE 30 3 -(3-BUTYLTHIO-1.2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1,1- 35 DIMETHYLPYRIDINIUM IODIDE Printed from Mimosa 13 17 04 7 9 / K A / 0 ' V *.> V ■"/ -86- (+ -)1,6-DIMETHYL-3 -(3 -BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE; and (+-)1,6-DIMETHYL-3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)- I,2,5,6-TETRAHYDROPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof 49 A composition of Claim 45 wherein the weight ratio of a compound of Formula II to acetaminophen of from about 1 to about 100. 50 A use, in the preparation of a medicament for treating pain, of a composition comprising a compound selected from the group consisting of Formula I and Formula II, or a pharmaceutically acceptable salt or solvate thereof; and acetaminophen in a weight ratio of Compound to acetaminophen of from about 1 to about 1000. 51. A use of Claim 59 wherein the compound is of Formula I. 52. A use of Claim 51 wherein the weight ratio of a compound of Formula I to acetaminophen of from about 1 to about 100 53. A use of Claim 51 wherein the medicament is formulated for transdermal administration. 54. A use of Claim 51 wherein the Formula I compound is 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2.2.2]OCTANE, or a pharmaceutically acceptable salt or solvate thereof. 55 A use of Claim 50 wherein the compound is of Formula II i - 2 JUL 1333 4 "i fJQ 4 , i / "'-i J vJ T -87- 0 L n 56. A use of Claim 55 wherein, the compound is selected from the group consisting of 3 -(3-METHOXY-1,2,5-THIADIAZOL-4 -YL)-1,2,5 , 6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PROPOXY-1,2, 5--THIADIAZOL-4-YL) -1, 2, 5 , 6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)1,2,5,6-TETTRAHYDRO-1-METHYLPYRIDINE 3 -(3-ISOPROPOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 - (3 -PENTOXY-1,2,5-THIADIAZOL-4 -YL>-1,2,5,6 -TETRAHYDRO-1-METHYLPYRIDINE 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(3-BUTENOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-(BUT-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO 1-METHYLPYRIDINE 3-(3-(3-METHYLBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE - 2 JUL 1X3 WO 97/20556 PCT/US9fi/l 9190 -88- 3-(3-HEXYLOXY-l,2,5-THIADIASOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(PROP-2-YNOXY)-1,2,S-THIADIAZOL-4-YL)-1,2.5.6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-BENZYLOXY-1,2,5-THIADIA70L-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-CHLORO-1,2,5-THI^DIA20L-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(I-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1~ ETHYLPYRIDINE 3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-ETHYLPYRIDINE 3 -(3-METHOXYETHOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 - (3-HEPTYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-PENTYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(4-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5 , 6-T ETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(2-PROPENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -89- 3 -(3-OCTYLOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TCTRAHYDR0-1-METHYLPYRIDINE 3 - (3- (3 -HEXYNYLOXY) -1, 2 , 5-THIADIAZOL-4-YL) -1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3 - (3- (3 -BUTENYL-2 -OXY) -1,2, 5-THIADIAZOL.-4 -YL) -1,2,5, 6-TETRAHYDRO-1-METHYL-PYRIDINE 10 3 -(3-(4-HEXENYLOXY(-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE TRANS-3 -(3-(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 CIS-3-13-(2-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 CIS-3-(3-(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4 -YL)-1,?,4 , 5 - TETRAHYDRO-1-METHYLPYRIDINE TRANS-3 -(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3 -(1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-METHYLPIPERIDINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 35 3 -(3-morpholino-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine Printed from Mimosa 13 17 04 WO 97/20556 rcT/us96/19310 -90- 3-(3-DIMETHYLAMINO-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO 1-METHYLPYRIDINE 5 3-(3-HEXYLAMINO-1,2,5-THIADIAZQL-4-YL) -1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-DEUTEROMETHYLPYRIDINE 10 1,2,5,6-TETRAHYDRO-3-(3-HEXY LOXY-1,2,5-THIADIAZOL-4-YL)PYRIDINE 3 -(3 -(2-(2-METHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4 -YL)-15 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(3-ETHOXY-l-PROPOXY)-1,2,5-THIADTAZOL-4-YL)-1,2,5,6,-TETRAHYDRO-1-METHYLPYRIDINE 20 3-(2-ETHOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO 1-METHYLPYRIDINE 3-(3-(2-BUTOXYETHOXY)-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6 -TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-(2-(2-BUTOXYETHOXY)-ETHOXY)-1,2 ,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3 -(2 -(2-ETHOXYETHOXY)-ETHOXY)-1,2, 5-THIADIAZOL-4 -YL)-30 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1.2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3-(3-METHYLTHIO-l,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 rCT/US96/19VJQ -91- 3 -(3-PENTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3- (J-PROPYLTHIO-1,2,5 -THIADIAZOL- 4 - YL) 1,2,5, 6-TETRAHYDRO-1 -5 METHYLPYRIDINE 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDRO-l-METHYLPYRIDINE 10 3-(3-PENTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1.2.5,6-TETRAHYDRO-1-KETHYLPYRIDINE 15 3 - (3 -OCTYLTHIO-1,2,5-THIADIAZOL-4 -YL(-1,2.5,6 -TETRAHYDRO-1 -METHYLPYRIDINE 3 -(3 -PROPYL-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1-20 METHYLPYRIDINE 3-(3-HEPTYL-1.2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1.2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-OCTYL-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYPYRIDINE 30 3-(3-(2-METHYL)-BUTYL-1, 2,5-THIADIAZ0L-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-METHYLCYCLOPROPYL-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-3 5 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/205S6 rCT/US9<>/1939t> -92- 3- (3 -CYCLOPENTYLTHTO-1 , 2 , 5-THIADIAZOL-4-YL)-1, 2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(1-ETHYLTHIO-2-METHOXY)-1,2,5-THIADIAZOL-4 -YL)-1, 2 , 5 , 6 5 TETRAHYDRO-1-METHYLPYRIDINE 3 -{3 -(3-CHLORO-l-PROPYLTHIO)-1,?,5-THIADIAZOL-4-Yb)-1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-(2-METHOXYETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2,5,G-TETRAHYDR0-1-METHYLPYRIDINE 3-(3 -(3-CYANO-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4 -YL)-1, 2, 5, b-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-BENZYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-TETRAHYDRO-1 METHYLPYRIDINE 3-(3-(2-ETHOXY-1-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1, 2, 5, 6-20 TETRAHYDRO-3-METHYLPYRIDINE 3-(3-(4-PENTYNYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1, 2, 5, 6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-(2 -(2 -ETHOXYMETHOXY)-ETHYLTHIO)-1,2,5"THIADIAZOL-4-YL) 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(5-CYANO-1-PENTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3-(3-PHENYL-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1, 2 , 5 , 6 TETRAHYDRO-1-METHYLPYRIDINE 3 -{3 -(2-PHENOXYETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/205S6 1'C r/US'Hi/lWHl -93- 3- (3 - (4-CYANOBUTYLTHIO) -1, ? , 5-THIADIAZOL - 4 - YL) -1,2,5,6 TETRAHYDRO-1-MCTHYLPYRIDINE 3 - (3 - (2-ETHYLBUTYLTHIO) -1, 2 , 5-THIAMAZOL-4-YL) -1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3- (3-CYCLOHEXYLMETHYLTHIO-l. 2, 5-THIADIAZOL-<1-YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 j-(3-(8-HYDROXYOCTYLTHIO)-1,2,5-THIADIAZOL-4-\h)-1,2,5,6- TETRAmDRO- 1-METHYLPYRIDINE 3-(3-(7-OCTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-1-METHYL PYRIDINE 15 3-(3-CYCLOPROPYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1, 2.5,6-TETRAHYDRO-1-METHYLPYRIDINE 3(3-CYCLOPROPYLMETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1.2.5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-BUTENYLTHIO)-1,2,5-THIADIAZOL-4-YL) -1.2.5.6-TETRAHYDRO-1-METHYLPYRIDINr 25 3-(3-(4-PENTENYLTHIO)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYL PYRIDINE 3- ( 4-ISOHEXYLOXY-l, 2, 5-THIADIA7.0L-3 -YL) -1 ,? ,5. 6-TETRAHYDRO-l-METHYLPYRIDINE 30 1-METHYL-l,2,5,6-TETRAHYDRO-3 -((4-CYCLOPENTYLPROPYL)OXY)-1.2.5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-l,2,5,6-TETRAHYDRO-3-(4-ISOHEPTYLOXY-1.2.5-35 THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 WO 97/20SS6 1C I7US96/I9190 -94- 1-METHYL-l.2,5,6-TETRAHYDRO 3-(4((2-CYCLOHEXYLETHYL)OXY)-1,2, 5-TIIIADIAZOL-3-YL) PYRIDINE 1, 2, 5, 6-TETRAHYDRO-l-METHYL-3 - ('I - (1-METHYLHEXLOXY)-1 .2.5 5 THIAD1AZOL-3-YL)PYRIDINE 3 -(4 -(1-ETHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-YL)-1.2.5.6-TETRAIIYDRO- 1 -METHYLPYRIDINE 10 3 -{4 -(l-CTHYLBUTOXY)-l,2,b-THIADIAZOL-3-YL)-1,2,5,6- TETRAHYDRO-1-MFTHYLPYRIDINE 1,2,5,6-TETRAHYDRO-l-METHYL-3-(4-(1-METHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-)YL)PYRIDINE 15 l-METHYL-3-{4-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2 . b.6-TETRAIIYDROPYRIDINE 1,2,5, 6 -TETRAHYDRO-l-METKYL-3 - ( 4 - (2-METHYLBUTOXY) -1,2.5-20 THIADIAZOL-3-YL)PYRIDINE 1.2,5. 6-TETRAHYDRO- 1-METHYL - 3 - (4 - ( 2 -METHYLPENTYLOXY) -1, 2 , 5 -THIADIAZOL-3-YL)PYRIDINE 25 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (4 - ( 2 , 2 , 2-TRIFLUOROETHOXY) - 1.2.5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3-(4-(3-METHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 30 3-(3-(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDO-1-METHYLPYRIDINE 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-3 5 METHYLPYRIDINE Printed from Mimosa 1317 04 WO <)7/205S6 rrr/usvh/iojw -95- 1,2,5,6-TETRAHYDRO-1-METHYL-3 - (4-(2-METHYLBUTOXY)-1,2.S-THIADIAZOL-3-YL)PYRIDINE 3 - (j - (3-hydroxypropoxy) -1,2, s-thiadiazol-4-yl) -1,2, 5. 6-5 tctrahydro 1-mcthylpyridine { + — ) 1, 6-DIMETHYL - 3- (3-HEXYLOXY-1,2, 5-THIADIAZOL-4-YL) -1,2,5, 6-TETRAHYDROPYRIDINE 10 3 - (1- (3 -phenyl-ethyiithio) -1, 2 , 5-thiadiazol-4-yl )-1, 2, 5, 6-tetrahydro-1-methylpyridine: BIS-1,4-(3-(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5-THIADIAZOL-4 -YL)BUTANEDITHIOL 15 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5-THIADIAZ0L-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(3,3,3-TRIFLUOROPROPYLTHTO)-1,2,5-THIADIAZOL-4-YL>-20 1,2,5.6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPY. RIDINE 25 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2, 5, 6- TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1,1-DIMETHYLPYRIDINIUM IODIDE 30 (+->1, 6-DIMETHYL-3- ( 3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDROPYRIDINE ( + -)1,6-DIMETHYL-3-(3-BUTOXY-l,2.5-THIADIAZOL-4-YL)-1,2,5,6-3 5 TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 WO '>7/20556 rri/ns«»<i/iW9o -l)6- 3- (3- (3-METHYL-2-BUTENYLOXY) -1,?,^-THIADIAZOL-4-YL) -1 , 2 , , 6 TETRAHYDO-1-METHYL PYRIDINE 1-(3-ISOBUTOXY-1,?, 5-THIADIAZOL 4-YI.)-1.2.5,6 TETRAHYDRO-1-METHYLPYRIDINE I . 2, b, 6-TETRAHYDRO-1-METHYL-1- (4- (2-METHYLRUTOXY )-1,J,5-THIADIAZOL-3-YL)PYRIDINE 3-(3-(3-HYDROXYPROPOXY)-1.2, 5-THIADIAZOL-4-YL)-1 ,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE (+-)1,6-DIMETHYL 3-(3-HEXYLOXY-1,2,b-THIADIAZOL 4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3- (3 - ( 3 - PHENYL-ETHYLTHIO-1,2,5 -THIADIAZOL - 4 - YL) -1, ~> , 5, 6-TETRAHYDRO-1-METHYLPYRIDINE BIS-1,4-(3 -(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL) -1, 2.5-THIADIAZOL-4 -YL)BUTANEDITHIOL 3- (3 -(4,4,4-TRIFLUOROBUTOXY!-1.2.5-THIADIAZOL-4-YL)-1,2,5,fe TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(3,3,3-TRIFLUOROPROPYLTHIO(-1,2.5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1.2,5, 6-TETRAHYDRO-1 METHYLPYRIDINE 3-13-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL) -1, 2, 5, 6-TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 VVO97/20Mh rcT/us'wiwo -97 )- (J-BUTYLTHIO-1 ,? , b-TllTADIAZOt,-4 - YL ) - 1, J , b , (>-TCTR AltYDUO-i , 1 -DIMbTHYLl'YKIDINIUK IODIDC ( »■ - > I , 6-DLMETHYI.-3 - (3-BUTYLTHIO-1, 2, 5-TH1MUAV.OL-4 YL) 1 , ? , 5, fi-TETRAHYDROPYf<rntNE j nnd ( + - ) 1, (i - DIMETHYL - 1 - ( 3 - BUTOXY-1, ? , S -THT AD I A7.0I.- 4 -YL)-1. ? , b. 6-TETRAHYDROPYRTniNr.; or n pharmaceut teal) y acceptable aalt thereof 57 A composition Lor treating pain comprising d compound selected fiom thu yioup consisting ot Formula T and ['oimula II, ot a pharmaceuticallv acceptable salt oi solvate thyrcof, and a central alphn-adronerqic active compound in a weight ratio ot Compound to central alpha-adrenergic active-compound o£ from about 1 to about 100Q 58 A composition of Claim 57 wherein the Compound id of Formula I. 59 A composition according to Claim 58 wherein the Compound of l-ormula I is selected from the group consisting of the following 3-CHLORO-3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2.2 21 OCTANE, 3 -(J -CHLORO-1,2,5-THIADIAZOL-4 -YL)- 3 -HYDROXY-1-AZABICYCLO[2 2 2]OCTANE, 3-METHOXY-3-(3-METHOXY-l,?,5-THIADIA70L-4-YL)-1-AZA3ICYCLO[2.2 2}OCTANE, 3-(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLOf2 2 2JOCT-2-ENE, 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2JOCT-2-ENE, Printed from Mimosa 13 17 04 WO <>7/20«i56 PCI/llS9fi/l 9190 -98 - 1 -HEXYLOXY-3 - (3-HEXYLOXY-l, 2 , 5-TIIIADIAZOL-4-YL) -1-A2ARICYCLO-[2 2 2]OCTANE; 3-(3-HEXYLOXY-1,2,5-THIADIAZOL-4 -YL)-3 -HYDROXY-1-5 AZABICYCLO[? 2 2]OCTANE, 3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 ?] OCTANE, 10 3-(3-PROPOXY-1,2,5-THIADIAZOL-4 -YL)-1-AZABICYCLO[2 2 2}OCTANE, 3-(3-BUTOXY-l,2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2 ]OCTANE, 15 3-(3-PENTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-[2 2 2]OCTANE. 3 -(3 -ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2]OCTANE, 20 3 -(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL) -1-AZABICYCLO{2 2 2]OCTANE, 3-(3-(3-PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-\L)-1-25 AZABICYCLO[2 2 2]OCTANE, 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2)OCTANE, 3 0 3-(3-(4-CYANOBENZYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2 2 2]OCTANE, EXO-6-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2.1]OCTANE, 35 ENDO-6-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, Printed from Mimosa 13 17 04 \VC> 97/2U5S6 rcT/iisqfi/i'n"}!) -99- ENDO-6- (3 -HEXYLTHIO-1, 2 , 5-THIADIAZQL-4-YL) -l-AZABICYCLO[3,2,1]OCTANE, 5 FNDO-6-(3-(5-HEXENYLTHIO)-1,2,S-THIADIAZOL-4-YL)-1- AZABICYCLO[3 2,1)OCTANE, ENDO-6-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL) -1 -AZABICYCLO[3 2 1)OCTANE, 10 ENDO-6- (3-PENTYLTHIO-l ,2, 5-THIADIAZOL - 4-YL.) -3-AZ ^BICYCLO[3,2,1)OCTANE, ENDO-6-(3-ETHYLTHIO-1.2,5-THIADIAZOL-4-YL)-1-15 AZABICYCLO[3 2 1]OCTANE, and ENDO-6-(3 -(3-PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZ*\BICYCLO[3 2 l]OCTANE, or a pharmaceutically acceptable salt or solvate thereof 20 60 A composition of Claim 59 wherein the Compound of Formula I is 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZ^BICYCLO(2 2 2]OCTANE, or a pharmaceutically acceptable salt thereof 25 61 A composition of Claim 58 wherin the weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 30 30 fe2 A composition of Claim 61 wherein the alpha-adrenergic compound is 2-(2 , 6-dichlorophenylammo)-2-imidazolme 63 A composition of Claim 57 wherein the 35 Compound is of Formula II Printed from Mimosa 13 17 04 WO 97/20556 PC r/llS9fi/l9390 -100- b4 A compoaition of Claim 63 wherein the Compound of Tormula II is selected from the group consisting of 1- (3-METHOXY-l, 2, 5-THIADIAZOL-4-YL) -1,2.5, f> -TETRAHYDRO 1-5 METHYLPYRIDINE 3 -(J -ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 10 3 -(3 -PROPOXY-1,2,5-THIADIAZOL 4-YL)-1,?,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-'3-BUTOXY-l.2.5-THIADIAZOL-4-YL)1,2,5,6-TFTTRAHYDRO-l-METHYLPYRIDINE 15 3- (3 -ISOPROPOXY- 1,2, 5-THIADIAZOL-4-YI.) -1, 2 , 5 , 6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL)-1,?,5, 6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PENTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 25 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3 -(3 -BUTENOXY)-1, 2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3 -(BUT-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 - (3 - (3 -METHYLBUTOXY) -1, 2 , 5 - Till ADIAZOL - 4-YL)-l,2,5,6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20S56 VCT/US9fc/lW0 -101- J-(3-HEXYLOXY-1,2,5-THIADIAZOL-4 -YL)-1,?,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-(PROP-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3 - (3 -BENZYLOXY-1,2, 5-THIADIAZOL-<1 - YL) -1,2 , 5 , 6 -TETRAHYDRO-1 -METHYLPYRIDINE 10 3-(3-CHLORO-l,2,5-THIADIASOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 15 3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-ETHYLPYRIDINE 20 3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- ETHYLPYRIDINE 3-(3-METHOXYETHOXY-l,2,5-THIADIAZOL-4-YL)-1,?,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-HEPTYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3 -(3 -PENTYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-30 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(4-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 35 3-(3-(2-PROPENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6- TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20 5<i6 I'C I7US96/19390 -10?- 3- (3 -OCTVLOXY-1, 2, 5-THIADIAZOL.-4-YL) -1,2 . 5 , 6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3 -(3-HEXYNYLOXY)-1,2,5-THIADIAZOL-4-YL1-1,2.5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(3 -BUTENYL-2 -OXYI-15-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYL-PYRIDINE 10 3-(3 -(4-HEXENYLOXY(-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAJIYDRO-1-METHYLPYRIDINE TRANS-3 - (3- (3-HEXENYLOXY) -1,2, 5-THIADIAZOL-4-YL) -1,2.5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 CIS-3-(3-(2-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL) -1, 2, b, 6-TETRAHYDRO-1-METHYLPYRIDINE 25 CIS-3-(3-(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2, 4, 5- TETRAHYDRO-1-METHYLPYRIDINE TRANS-3 -(3 -(2-HEXENYLOXY)-1.2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3 -(4 -METHYLPIPERIDINO-1,2,5-THIADIAZOL-4-YL1-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3 - (3-MORPHOLINO-1, 2 , 5-THIADIAZOL-4-YL) -1, 2, 5, 6-TETRAHYDRO-l-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/205^6 I'CWUS!! 6/19390 -103 - 3-(3-DIMETHYLAMINO-1,2,b-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO 1-METHYLPYRIDINE 5 3-(3-HCXYLAMINO-1,2.b-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3-HEXYLOXY-l,?,5-THIADIAZOL-4-YL)-3,2,5,6-TFTRAHYDRO-l-DEUTEROMETHYLPYRIDINE 10 1,2,5,6-TETRAHYDRO-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)PYRIDINE 3-(3 -(2-(2-METHOXYETHOXY)-ETHOXY)-1.2,5-THIADIAZOL-4-YL)-15 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(3-ETHOXY-1-PROPOXY)-1,2,5-THIADIAZOL-4-YL)-1.2,5,6,-TETRAHYDRO-1 METHYLPYRIDINE 20 3- (2-ETHOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO 1-METHYLPYRIDINE 3-(3-(2-BUTOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-(2-(2-BUTOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(2-(2-ETHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-3 0 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 5 3-(3-METHYLTHIO-1,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-l- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/205^6 l,CT/US96/|93t>0 -104- 3-(l-PENTYL-1,2,5-THIADIAZOL-; -YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-5 METHYLPYRIDINE 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO 1-MFTHYLPYRIDINE 10 3-(3-PENTYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-OCTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-{3 -PROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-20 METHYLPYRIDINE 3-(3-HEPTYL-l,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-l-METHYLPYRIDINE 25 3 - (3 -(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3 -(3-OCTYL-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1-METHYPYRIDINE 30 3- (3 -(2-METHYL)-BUTYL-1,2,5-THIADIAZOL-4-YL)-1, 2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-METHYLCYCLOPROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 NVO 97/205S6 I'CT/US96/I93<>(» -105- 3- (3 -CYCLOPENTYLTHlO-1,2,5-THIADIAZOL-4-YL)-1,2, 5,6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-(l-ETHYLTHIO-2-METHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6 5 TETRAHYDRO-1-METHYLPYRIDINE 3- O-(3-CHLORO-l-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6 TETRAHYDRO-1-METHYLPYRIDINE 10 3- (3-(2-METHOXYETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(3-CYANO-l-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TCTRAHYDRO-1-METHYLPYRIDINE 15 3- (3-BENZYLTHIO-1, 2, 5-THIADIAZOL-4-YD-1,2,5,6-TETRAHYDRO-l METHYLPYRIDINE 3- (3 -(2-ETHOXY-1-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1.?,5,6- 2 0 TETRAHYDRO-1-METHYLPYRIDINE 3- (3 -(4-PENTYNYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1.2.5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-12-{2-ETHOXYMETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL) 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(5-CYANO-l-PENTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3 -(3-PHENYL-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDRO-1 -METHYLPYRIDINE 3- (3-(2-PHENOXYETHYLTHlO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- 3 5 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/USW19390 -106- 3- (3 - (4-CYANOBUTYLTHIO) -1, 2 , 5-THIADIAZOL-4-YI.) -1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(2-ETHYLBUTYLTHIO)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOHEXYLMETHYLTHIO-l,2,5 THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(8-HYDROXYOCTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(7-OCTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1, 2, 5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3(3-CYCLOPROPYLMETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1, 2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(3-BUTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -{4-PENTENYLTHIO)-1,2,5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(4-ISOHEXYLOXY-l,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-METHYLPYRIDINE 1-METHYL-l,2,5,6-TETRAHYDRO-3- ( (4-CYCLOPENTYLPROPYL)OXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3-(4 -1S OHEPTYLOXY-1,2,5-THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 \VO QT/IO'Kfi PCI/US96/15)390 -107- 1-METHYL-1,2,5,6-TETRAHYDRO-3 -(4((2-CY'CLOHEXYLnTHYL)OXY)-1.2,b-THIADIAZOL-3-YL)PYRIDINE 1,2,5, 6-TETRAHYDRO-l -METHYL-3- (4 - (1 -METHYLTIEXLOXY) -1,2,5-5 THIADIAZOL-3-YL)PYRIDINE 3 -(4 -<1-ETHYLPCNTYLOXY)-1, 2,5-THIADIAZOL-3-YL)-1,2,5.6-TETRAHYDRO-1-METHYLPYRIDINE 10 3-(4-(1-ETHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPY RIDINE 1,2, 5, 6-TETRAHYDRO-l-METHYL-3-(4-(1-METHYLPENTYLOXY) -1,2,5-THIADIAZOL-3 -)YL)PYRIDINE 15 l-METHYL-3-(4-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6 TETRAHYDROPYRIDINE 1,2,5.6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1, 2,5-20 THIADIAZOL-3-YL)PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLPENTYLOXY)-1,2.5-THIADIAZOL-3-YL)PYRIDINE 25 1,2,5,6-TETRAHYDRO-l-METHYL-3-(4-(2,2,2-TRIFLUOROETHOXY)- 1,2,5-THIADIAZOL-3-YL)PYRIDINE 1-METHYL-l,2,5,6-TETRAHYDRO-3 -(4 -(3-METHYLPENTYLOXY)-1,2,5-THIADIAZ0L-3-YL)PYRIDINE 30 3-(3-(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2.5,6 TETRAHYDO-1-METHYLPYRIDINE 3 -(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-35 METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/205S6 PCT/IIS%/1!>39(> -108- 1,2, 5, 6-TETRAJIYDRO* l-METHYL-3- (4- (2 -METHYLBUTOXY) -1,2,5-THIADIAZOL-3-YL)PYRIDINE 3-(3-(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4 -YL)- 1,2, 5,6-5 TFTRAHYDRO-1-METHYLPYRIDINE (+-)1,6 -DIMETHYL- 3-(3 -HEXYLOXY-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDROPYRIDINE 10 3 -C 3 -(3-PHENYL-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE BIS-1,4-(3-{1-METHYL-1,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5-THIADIAZOL-4 -YL)BUTANEDITHIOL 15 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-20 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1, 2, 5, 6-TETRAHYDROPYRIDINE 25 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2, 5, 6- TETRAHYDROPYRIDINE 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-l.1 -DIMETHYLPYRIDINIUM IODIDE 30 ( + -) 1. 6-DIMETHYL-3-(3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL>-1,2,5.6-TETRAHYDROPYRIDINE (+ -)1,6-DIMETHYL-3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-1, 2 , 5,6-35 TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 WO 07/20556 l,CT/US9f./l<mO -109- 3- (3- (3 -METHYL- 2-BUTENYLOXY) -1,2,5 -THIADIAZOL-4-YL) -1,2, 5, 6 TETRAHYDO- 1-METHYL PYRIDINE 3- (3-ISOBUTOXY-1, 2, 5-THIADIAZOL-'!-YL) -1 , 2,b , 6-TETRAHYDRO-3 -5 MFTHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1,2,5-THIADIAZOL-3 -YL)PYRIDINE 10 3-(3-l3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TFTRAHYDRO-1-METHYLPYRIDINE (+ - ) 1, 6-DIMETHYL-3- (3-HEXYLOXY-1, 2 , 5-THIADIAZOL-<1 -YL) -1,2,5,6-TETRAHYDROPYRIDINE 15 3-(3-(3-PHENYL-ETHYLTHIO-i,2,5-THIADIAZOL-4-YL)-1.2. 5,6-TETRAHYDRO-1-METHYLPYRIDINE BIS-1,4 -(3 -(1-METHYL-1,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,?,5-20 THIADIAZOL-4-YL)BUTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,b-THIADIAZOL-4-YL)-1, 2 , 5 , 6 TETRAHYDRO-1-MLTHYLPYRIDINE 25 3-(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2.5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l METHYLPYRIDINE 30 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-3 5 TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 X 9 • r; C, ;• ' } -110- * ^ ' 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2 , 5,6-TETRAHYDRO-1,1-DIMETHYtiPYRIDINIUM IODIDE (-+•-) 1, 6-DIMETHYL-3- (3-BUTYLTHIO-1, 2 , 5-THIADIAZOL-4-YL) -1, 2,5,6-TETRAHYDROPYRIDINE; and (+-)1,6-DIMETHYL-3-(3-BUTOXY-l, 2, 5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDROPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof 65. A use, in the preparation of a medicament for treating pain in a patient m need thereof, of a composition comprising a compound selected from the group consisting of Formula I and Formula II, or a pharmaceutically acceptable salt or solvate thereof, and a central alpha-adrenergic active compound in a weight ratio of compound to central alpha-adrenergic active compound of from about 1 to about 1000 66. A use of Claim 65 wherein the Compound is of Formula I. 67. A use of Claim 66 wherein the Compound is 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2.2.2]OCTANE, or a pharmaceutically acceptable salt or solvate thereof 68 A use of Claim 65 wherein the Compound is of Formula II. 69. A composition for treating pain comprising an analgesic dose of a Compound selected from the group consisting of Formula I and Formula II, or a pharmaceutically acceptable salt or solvate thereof; and one or more opioid compounds in a weight ratio of Compound to opioid compound of from about 1 to about 1000 '! U _ WO «>7/2USS6 IT'lVIISWrno -111- 7 0 A composition oC claim 69 wherein the Compound is, of Formula I. 71 A compoaition of claim 70 wherein the 5 compound of Formula [ is selected from the group consistunq ot the followmq 3-CHI.ORO-J- (3-CHLORO-l, 2, 5-THIADIAZOL-4-YL) -1-A~ABICYCLO[2 2. 2] OCTANE. 10 3 -(3-CHLORO-1,2.5-THIADIAZOL-4-YL)-3-HYDROXY-1-AZABICYCLO(2 2 ?1OCTANE. 3-METHOXY-3 -(3-METHOXY-l,2,5-THIADIAZOL-4-YL)-1-15 AZABICYCLO[2 2 2]OCTANE, 3-(3 -METHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2,2.2]QCT-2-ENE, 20 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 ? 2]OCT- 2-ENF, 3-HEXYLOXY-l-(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL) 1-AZABICYCLO-[2.2 2]OCTANE, 25 3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-3-HYDROXY-1-AZABICYCLO[2 2 2]OCTANE, 3 -(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2 ]OCTANE, 30 3-(3-ETHOXY-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2 2 2)OCTANE, 3-(3-PROPOXY-l,2.5-THIADIAZOL-4-YL)-1-AZABICYCL0[2.2 2)OCTANE, 35 3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2 2 2)OCTANE, Printed from Mimosa 13 17 04 WO I'CT/llSWUM'Hl -112- 3- (3 -PENTYLTHIO-l, J, 5-THIADIAiSOl.-4-YL) -1-AZABICYCLO (?.? ?]OCTANE, 3- n-ETHOXY-1,2, 5-T1IIADIAZQI.-4-YL) -1-AZABICYCLO [2. ^.
2) OCTANE, 5 3- (3-HEXYLTHIO-1, 2,5-THIADIAZOL-4-YL) -1-AZAEICYCLO[2.2 2] OCTANE; 3-(3-(3-PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-10 AZABICYCLO[2 2 2]OCTANE, 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO [ 2 "> 2 J OCTANE; 15 3-(3-(4-CYANOBENZYLTHIOJ-l,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO f 2 2 2)OCTANE, EXO-6 -(3-CHLORO-1,2,5 -THIADIAZOL- 4 -YL)-1 -AZABICYCLOI 3 ? 1)OCTANE, 20 ENDO-6-<3 CHLORO-1,2, 5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-25 AZABICYCLO[3 2 1]OCTANE, ENDO-6-(3-(5-HEXENYLTHIO)-1.2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1]OCTANE; 30 ENDO-6-<3-BUTYLTHIO-1.2,5-THIADIAZOL-4-YL)-1- AZAB1CYCLO[3.2 1]OCTANE, ENDO-6-(3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[3 2 1J OCTANE, 35 ENDO-6-(3-ETHYLTHIO-l,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(3 2 1]OCTANE; and Printed from Mimosa 13 17 04 r\) -113- 'i h ENDO-6-(3-(3 -PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(3.2.1]OCTANE; or a pharmaceutically acceptable salt or solvate thereof. 73. A composition of Claim 70 wherein the Compound is 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO[2,2,2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof. 74. A composition of Claim 69 wherein the Compound is o£ Formula II. 75. A composition of Claim 74 wherein the Compound of Formula II is selected from the group consisting of 3-(3-METHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-ETHOXY-1,2,5-THIADIAZOL-4-YL1-1.2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-PR0P0XY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-BUTOXY-1,2,5-THIADIAZOL-4 -YL)1,2,5,6-TETTRAHYDRO-1 -METHYLPYRIDINE 3-(3-ISOPROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2 5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PENTOXY-1, 2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE - 2 jul :j;3 wo mow rci/iiswmw -114- 3 -(J ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDRO-1-MET1IYL PYRIDINE 3- (3- (3-BUTENOXY) -1,1, r«-THIADIAZOL-4 YL) -1 ,2, 5 , 6-T1 TRA1IYDR0-1-METHYLPYRIDINE 1- (1- (Bin -P-YNOXY) -1,2, 5-THIADIAZOL.-4-YL) -1, J, 5 , fi-TETKAHYDRO-1 -MT.THYLPYRTDINL 3- (3- (3-METHYLBUTOXY)-1, 2, b THIADTA7:0L-4-YL) -l,2,b,b-TETRAHYDRO-1 -METHYLPYRIDINE 3 - ( 3 - HtXYLOXY -1,2, r) -TH I ADIAZOL - 4 - YL) -1,2,5,6- TETRAHYDRO 1-METHYLPYRIDINE 3- (3- (PROP-P-YNOXY) -1, 2, b THIADTA7.0t.-4 -YL)-1,?,5 , 6 -TLTRAHYDRO-1-METHYLPYRIDINE 3-(3-BLN2YLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3- (3 -CHLORO- 1,2, 5-THIADIAZOL-4-YI.) -1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CHLORO-l5-THIAD1AZOL-4-YL)-1,2,5,fa-TETRAHYDROPYRIDINE 3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-1.2,5,6-TETRAHYDROFYRIDINE 3-(3-ETHOXY-1,2.5-THIADIAZOL-4-YL)-1,2.5,6-TETRAHYDRO-1-ETHYLPYRIDINE 3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-1,2.5.6-TETRAHYDRO-1-ETHYLPYRIDINE 3-(3-METHOXYETHOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/2U556 PCT/IIS96/I9390 -115- 3- (3-HEPTYLOXY-1, 2, 5-THIADIAZOL-4-YL.)-1,2, 5 , 6-TETRAHYDRO-l-METHYLPYRIDINE 5 3-(3-(3-PENTYNYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(4-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYL PYRIDINE 10 3-(3-(2-PROPENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-OCTYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-15 METHYLPYRIDINE 3-{3-(3-HEXYNYLOXY)-l,2.5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 20 3-(3-(3-BUTENYL-2-OXY) 1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYL-PYRIDINE 3-(3 -(4-HEXENYLOXY(-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 -METHYLPYRIDINE 25 TRANS-3 -(3 -(3-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(2-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-3 0 TETRAHYDRO-1-METHYLPYRIDINE CIS-3-(3-(2-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 35 3-(3-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1.2,5,6- TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20SS6 rCT/US96/l 939(1 -116- CIS-3- (3- ( 3-HEXENYLOXY) -1, 2 , 5-THIADIAZOL-4-YL) -1,2,4,5-TETRAHYDRO-1-METHYLPYRIDINE TRANS-3-(3 -(2-HEXENYLOXY)-1,2.5-THIADIAZOL-4-YL)-1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3-(1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3 -(4-METHYLPIPERIDINO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-10 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-MORPHOLINO-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-l-METHYLPYRIDINE 15 3-(3-DIMETHYLAMINO-1,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO- 1-METHYLPYRIDINE 3 -(3-HEXYLAMINO-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 20 3-(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-1, 2, 5, 6-TETRAHYDRO-1-DEUTEROMETHYLPYRIDINE 1,2,5,6-TETRAHYDRO-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-25 YL)PYRIDINE 3-(3-(2-(2-METHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3-(3-(3-ETHOXY-1-PROPOXY)-1,2,5-THIADIAZOL-4-YL) -1, 2,5,6,- TETRAHYDRO-1-METHYLPYRIDINE 3-(2-ETHOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 35 3 - (3- (2-BUTOXYETHOXY) -1.2 , 5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO -1 -METHYL PYRI DINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -117- 3- (3- (2- (2-BUTOXYETHOXY) -ETHOXY) -1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 5 3-(3-(2-(2-ETHOXYETHOXY)-ETHOXY)-1,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 10 3-(3-METHYLTHIO-1.2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l METHYLPYRIDINE 3-(3-PENTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-TETRAHYDRO-]-15 METHYLPYRIDINE 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l METHYLPYRIDINE 20 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 3-(3-PENTYLTHTO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l METHYLPYRIDINE 25 3-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-OCTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-3 0 METHYLPYRIDINE 3-(3-PROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 35 3-(3-HEPTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE Printed from Mimosa 13 17 04 WO *>7/20556 I'Cr/IJS<)6/lWJU -118- 3 -(3 -(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-METHYLPYRIDINE 3-(3-OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-5 METHYPYRIDINE 3-(3-(2-METHYL)-BUTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-METHYLCYCLOPROPYL-l,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYL PYRIDINE 3 -(3-CYCLOPENTYLTHIO-1,2,5-THIADIAZOL-4 YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 15 3 -(3 - (l-ETHYLTHIO-2-METHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2.5,6 TETRAHYDRO-1-METHYLPYRIDINE 3 -(3 - (3-CHLORO-1-PROPYLTHIO)-1,2,5-TH3ADIAZOL-4-YL)-1,2,5,6 20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(2-METHOXYETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 2 5 3-(3-(3-CYANO-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-BENZYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 METHYLPYRIDINE 30 3-{3-(2-ETHOXY-l-FTHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3 -(4-PENTYNYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/1939D -119- 3 - (3 - (2- {2-ETIIOXYMETHOXY) -ETHYLTHIO)-1, 2,5-THIADIAZOL-4-YL) 1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(5-CYANO-1-PENTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-5 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(3-PHENYL-1-PROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6 TETRAHYDRO-1-METHYLPYRIDINE 10 3-(3-(2-PHENOXYETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3- (3- (<3 -CYANOBUTYLTHIO) -1, 2 , 5-THIADIAZOL-4-YL) - 1, 2 , 5 , 6-TETRAHYDRO-1-METHYLPYRIDINE 15 3-(3-(2-ETHYLBUTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOHEXYLMETHYLTHIO-l.2,5-THIADIAZOL-4-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(3-(8-HYDROXYOCTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 3-(3-(7-OCTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE 3-(3-CYCLOPROPYLMETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 3(3-CYCLOPROPYLMETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYL PYRIDINE 3-(3-(3-BUTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCTIYUS 96/19390 -120- 3- (3- (4-pentenylithio) -1, 2 , 5-thiadiazol-4 - yl) -1,2,5,6-tetrahydro-1-methylpyridine 3- (4-ISOHEXYLOXY-1,2,5-THIADIAZOL-3-YL)-1,2, 5, 6-TETRAHYDRO-1-5 METHYLPYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3 - ((4-CYCLOPENTYLPROPYL)OXY)-1,2, 5-THIADIAZOL.-3-YL) PYRIDINE 10 1-METHYL-l,2,5,6-TETRAHYDRO-3- (4-ISOHEPTYLOXY-1,2,5- THIADIAZOL-3-YL)PYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3 - (4((2-CYCLOHEXYLETHYL)OXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 15 1,2,5,6-TETRAHYDRO-1-METHYL- 3 - (4 -(1-METHYLHEXLOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 3-<4-(1-ETHYLPENTYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-20 TETRAHYDRO-1-METHYLPYRIDINE 3-(4-(1-ETHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 2 5 1,2,5,6-TETRAHYDRO-l-METHYL-3 - (4-(1-METHYLPENTYLOXY)-1,2,5- THIADIAZOL-3 -)YL)PYRIDINE l-METHYL-3-(4-(5-HEXENYLOXY)-1,2,5-THIADIAZOL-3-YL)-1,2,5,6 -TETRAHYDROPYRIDINE 30 1,2,5,6-TETRAHYDRO-1-METHYL-3 - (4-(2-METHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 1,2,5,6-TETRAHYDRO-l-METHYL-3-(4-(2-METHYLPENTYLOXY)-1,2,5- 3 5 THIADIAZOL-3-YL)PYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCT/US96/19390 -121- 1,2,5, 6-TETRAHYDRO-1-METHYL-3- ('3- (2 , 2 , 2-TRIFLUOROETHOXY) -1,2,5-THIADIAZOL-3-YL)PYRIDINF 1-METHYL-1,2.5,6-TETRAHYDRO-3 -{4-(3-METHYLPENTYLOXY) -1. 2 . 5 -5 THIADIAZOL-3-YL)PYRIDINE 3-(3-(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDO-1-METHYLPYRIDINE 10 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l- METHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1,2,5-THIADIAZOL-3-YL)PYRIDINE 15 3-(3-(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAIIYDRO-1 -METHYLPYRIDINE {+-)1,6-DIMETHYL-3-(3-HEXYLOXY-l,2,5-THIADIAZOL-4-YL)-2 0 1,2,5,6-TETRAHYDROPYRIDINE 3-(3 -(3-PHENYL-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 2 5 BIS-1,4-(3-(1-METHYL-l,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5 - THIADIAZOL-4-YL)BUTANEDITHIOL 3-(3-(4, 4, 4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZ0L-4-YL)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 30 3-(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1, 2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- 3 5 TETRAHYDROPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 I-CT/US96/19390 -122- 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l,1-5 DIMETHYLPYRIDIMIUM IODIDE (+-)1,6-DIMETHYL-3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDROPYRIDINE 10 (+-)1,6-DIMETHYL-3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO PYRIDINE 3 -(3 -(3-METHYL-2-BUTENYLOXY)-1,2,5-THIADIAZOL-4 -YL)-1,2,5,6-TETRAHYDO-1-METHYL PYRIDINE 15 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 1,2,5,6-TETRAHYDRO-l-METHYL-3-(4-{2-METHYLBUTOXY)-1,2,5-?0 THIADIAZOL-3-YL)PYRIDINE 3 -(3-(3-HYDROXYPROPOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 25 ( n— )1,6-DIMETHYL-3- (3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETHYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-METHYLPYRIDINE 30 BIS-1,4-(3-(1-METHYL-1,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5-THIADIAZOL-4-YL)BUTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5.6-35 TETRAHYDRO-1-METHYLPYRIDINE Printed from Mimosa 13 17 04 WO 97/20556 PCI /US96/I9390 -123- 3- (3- (3,3, 3-TR1FLUOROPROPYLTHIO) -1,2, 5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-l-METHYLPYRIDINE 3-(3-PROPYLTHIO-l,2,5-THIADIAZOL-4-YL)-1,2,5, 6-TETRAHYDRO-1-5 METHYLPYRIDINE 3 - ( 3 - PROPYLTHIO-1,2,5 -THIADIAZOL- 4-YL)-l,2,'5,6-TETRAHYDROPYRIDINE 10 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3-(3-BUTYX.THIO-l,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1,1-DIMETHYLPYRIDINIUM IODIDE 15 ( +- ) 1, 6-DIMETHYL-3 - (3 -BUTYLTHIO-1, 2 , 5-THIADIAZ10L-4-YL) -1,2,5,6-TETRAHYDROPYRIDINE, and (+-)1,6-DIMETHYL-3-(3-BUTOXY-l,2,5-THIADIAZOL-4-YL)-20 1,2,5,6-TETRAHYDROPYRIDINE, or a pharmaceutically acceptable salt jr solvate thereof 7 6 A composition of Claim 69 wherein the opioid compound is selected from the group consisting of 25 morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine 30 77 A composition of Claim 69 wherein the opioid compound is selected from the group consisting of hydromorphone, hydrocodone, mependone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphme, oxycodone, levorphanol, fentanyl, and alphaprodme 35 78 A composition of Claim 69 wherein the opioid compound is selected from che group consisting of Printed from Mimosa 13 17 04 324594 -324- propoxyphene, methadone, morphine, hydrocodone, hydromorphme, and codeine. 79. A composition of Claim 78 wherein the opioid compound is selected from morphine and codeine. 80. A use, m the preparation of a medicament for treating pain, of a composition comprising a Compound selected from the group consisting of Formula I and Formula II, or a pharmaceutically acceptable salt or solvate thereof, and one or more opioid compounds m a weight ratio of Compound to opioid compound of from about 1 to about 1000. 81. A use of Claim 80 wherein the Compound is of Formula I. 82. A use of Claim 81 wherein the Compound is 3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[2 2.2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof 83. A use of Claim 80 wherein the Compound is of Formula II. - 2 JUL 13 -125- 84. A composition as defined in any one of claims 1, 38, 57 and 69 for treating pain or a pharmaceutically acceptable salt or solvate thereof substantially as herein described with reference to any example thereof 85. A use as defined m any one of claims 16, 34, 50, 65 and 80 substantially as herein described with reference to any example thereof ELI LILLY AND COMPANY By the authorised agents A J PARK & SON - 2 JUL 1303 </div>