AU715645B2

AU715645B2 - Method for treating pain

Info

Publication number: AU715645B2
Application number: AU11476/97A
Authority: AU
Inventors: Charles H. Mitch; Harlan E Shannon
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1995-12-07
Filing date: 1996-12-05
Publication date: 2000-02-10
Anticipated expiration: 2016-12-05
Also published as: WO1997020556A1; NO982582L; NO982582D0; PL327144A1; HUP0000110A3; CZ174598A3; EA199800535A1; KR19990071977A; JP2000501711A; CA2239732A1; NZ324594A; CN1208348A; EP0866702A1; HUP0000110A2; EP0866702A4; IL124786A0; AU1147697A

Description

Method for Treating Pain The present invention relates to a method for using azacyclic, azabicyclic, or tetrahydropyridine compounds for treating pain.

This invention relates to a therapeutic combination of compounds to provide analgesic activity.

More active analgesic combinations effects are in 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 1 composition is the subject of the present invention.

The present invention provides a method for treating pain comprising administering to a patient in need thereof, an analgesic composition comprising a compound of Formula

I

NX\

GN

A or A' wherein X is oxygen or sulphur; A is hydrogen, amino, halogen, -CHO, -NO 2

-OR

4

-SR

4

-SOR

4

-SO

2

R

4 C3_7-cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C 3 7 -cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R is straight or branched Cis.

1 -alkyl, straight or branched C2- 1 5 -alkenyl, straight 20 or branched C2-1s-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, C 1 -4-alkoxy, -OCF 3

-CONH

2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, CI_ 4 -alkyl, Cl-4-alkoxy, -OCF 3

-CONH

2 or -CSNH 2 or A is -ORsY, -SR 5

Y,

ss -OR'ZY, -SR ZY, -O-R 4

-Z-R

5 or -S-R 4

-Z-R

5 wherein Z is oxygen or sulphur, R 5 is straight or branched Cl.s5-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 [R:\LIBVV]02067.doc:SSD R (C or R 2 -Cq 9 Cn,\ ~iXflII N N '3

R

wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R' and R 2 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 straight or branched Clj-o-alkoxy, straight or branch Cl-s-alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3 is H, straight or branched Ci.

5 s-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 0@ Go** 0 0 0 06 @0 0@ 0* so so 0080 0* 80 0

S

wherein A' is hydrogen, halogen, amino, -NHCO-R2' C3- 7 -cycloalkyl,

C

4 1 0 -(cycloalkylalkyl), -Z 2 '-C3- 7 -cycloalkyl optionally substituted with CIl-6-alkyl, -Z2'-C 4 -1 o-(cycloalkylalkyl), -Z2'-C4-1 o-(cycloalkenylalkyl), -Z2'-C 4 2' 2' 3'2' 15 (metylenecycloalkyl-alkyl), -NH-R2', -NR2'R -NH-OR phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, X, R2', -Z2'R -SOR 2

-SO

2 R2, -z 2'-R2'- Z -Z2'-R 2 '-Z3-R -Z-R 2'CO-R3 -Z2'-R2'-C0 2 -R Z-2'_R2'-O2C-R 3 -Z2' -R 2'-CONH-R -Z2'-R2'-NHCOR 3

-Z

2 -Z2'-R 2 wherein Z 2 Z3 and Z independently are oxygen or sulphur, and R 2

R

3 and R 4 independently are straight or branched CI 15 is-alkyl, straight or branched C2-15s-alkenyl, straight or branched

C

2 -15-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR2'R 3 C,.--alkyl 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 C 1 -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 straight or branched

(IT

V cL [R:\LJBVV]02067.doc:SSD 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 fused with a phenyl group; and

R

5 and R 6 may be present at any position, including the point of attachment of the S thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C ,--alkyl, straight or branched C2-5-alkenyl, straight or branched C2-5-alkynyl, straight or branched CIlo-alkoxy, straight or branched CIs.-alkyl substituted with -OH, halogen,

-NH

2 or carboxy; R' is hydrogen, straight or branched C.-s-alkyl, straight or branched or straight or branched C2-5-alkynyl; or Io a pharmaceutically acceptable salt thereof; and a nonsteroidal anti-inflammatory drug in a weight ratio of Formula I to nonsteroidal anti-inflammatory drug of from about 1 to about 1000.

Preferred NSAIDS include, but are in no way limited to salicylates such as aspirin, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. Especially preferred NSAIDS include aspirin, ibuprofen, and naproxen. Alternative preferred

NSAIDS

include ibuprofen and naproxen. Alternative particularly preferred NSAIDS include ibuprofen.

*The invention further provides a composition for treating pain comprising a 20 compound of Formula I; or a pharmaceutically acceptable salt or solvate thereof; and a nonsteroidal anti-inflammatory drug in a weight ratio of Compound to a nonsteroidal antiinflammatory drug of from about 1 to about 1000.

The present invention provides a method for treating pain comprising administering to a patient in need thereof, an analgesic composition comprising a 25 compound of Formula I; 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.

A composition for treating pain comprising an analgesic dose of a compound of Formula I

GN

3o A or A' wherein j [R:\LIBVV]02067.doc:SSD 2/ X is oxygen or sulphur; A is hydrogen, amino, halogen, -CHO, -NO 2

-OR

4

-SR

4

-SOR

4 -SO2R 4

C

3 ;-7-cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C 4 -8-(cycloalkylalkyl) wherein R 4 is straight or branched Ci i 5 -alkyl, straight or branched C2- 1 5 -alkenyl, straight or branched C 2 1 5 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci.4-alkyl, CI- 4 -alkoxy, -OCF 3 -CONH2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci- 4 -alkyl, Cl-4-alkoxy, -OCF 3

-CONH

2 or -CSNH 2 or A is -OR 5 Y, -SR Y, to -OR'ZY, -SR 5 ZY, -O-R 4

-Z-R

5 or -S-R 4

-Z-R

5 wherein Z is oxygen or sulphur, R 5 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 carbon or nitrogen atom(s) with straight or branched

C

1 -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 Rl R Rz or .R2-Cq Cp 2..

N N o wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R' and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight 20 or branched Cl_ 5 -alkyl, straight or branched C2-5-alkenyl, straight or branched

C

2 -5-alkynyl, straight or branched Cl-lo-alkoxy, straight or branch C 1 alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3 is H, straight or branched straight or branched C 2 -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 6' R6

N

[R:\LIBVV]02067.doc:SSD wherein A' is hydrogen, halogen, amino, -NHCO-R 2 C3-7-cycloalkyl, C4- 1 -(cycloalkylalkyl), -Z2'-C 3 -7-cycloalkyl optionally substituted with Ci-6-alkyl, -Z2'-C 4 0-(cycloalkylalkyl),

-Z

2 -C4-1I-(cycloalkenylalkyl),

-Z

2

'-C

4 o 1 0 -(methylenecycloalkyl-alkyl),

-NH-R

2 -NR2'R 3

-NH-OR

2 phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, X, R 2 -Z2'R 2

-SOR

2 -S02R 2 -Z -Z 2 3

-R

3

'-Z

4

-Z

2

'-R

2

CO-R

3

Z

2 '_R2'-C0 2

-R

3

Z

2

'-R

2 2

C-R

3 -R '-CONH-R 3

-Z

2 '-R2'-NHCOR 3

-Z

2 '-R2'-Z 3 wherein Z 2

Z

3 and Z 4 independently are oxygen or sulphur, and R 2

R

3 and R 4 independently are straight or branched Cl.

1 5 -alkyl, straight or branched C2- 1 5 -alkenyl, straight or branched to C2- 1 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR 'R 3

C

1 -6-alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, C 1 4 -alkyl or 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 straight or branched

C

1 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 R 5 and R 6 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, 0 20 straight or branched C1-5-alkyl, straight or branched C 2 -5-alkenyl, straight or branched

C

2 -5-alkynyl, straight or branched Ci-lo-alkoxy, straight or branched C 1 5 -alkyl substituted with -OH, halogen, -NH 2 or carboxy; R 1 is hydrogen, straight or branched •o straight or branched C2-5-alkenyl or straight or branched C 2 -5-alkynyl; or a pharmaceutically acceptable salt or solvate thereof; and acetaminophen in a weight ratio o 25 of Compound to 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 final preferred ratio may be from about 1 to about 3.

'0 The invention further provides a composition for treating pain comprising a Compound of Formula I 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.

.[R:\LIBVV02067.doc:SSD The present invention provides a composition for treating pain comprising a Compound of Formula 1 or a pharmaceutically acceptable salt thereof; and a central alpha-adrenergic active compound in a weight ratio of Compound to central alphaadrenergic 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 A particularly preferred central alpha-adrenergic active compound is Clonidine or a pharmaceutically acceptable salt thereof The chemical name for clonidine is to 2-(2,6-dichlorophenylamino)-2-imidazoline.

The invention further provides a method for treating pain comprising administering an effective amount of a compound of Formula I 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 method for treating pain comprising administering to a patient in need thereof, an analgesic composition comprising a Compound of Formula I 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 Preferred opioid compounds are morphine, codeine, meperidine, methadone, 25 propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine.

S

Especially preferred opioid compounds are selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fcntanyl, and alphaprodine.

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.

'[R:\LIBVV]02067.doc:SSD The invention further provides a composition for treating pain comprising a Compound of Formula I 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.

The term "NSAIDS", as used herein, represents a nonsteroidal anti-inflammatory drug which can be identified as such by the skilled artisan. For example, the Merck Manual, 16 th Edition, Merck Research Laboratories (1990) pp 1308 1309 provide well known examples of NSAIDS. The term is intended to include, but is not limited to salicylates such as aspirin, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. Especially preferred NSAIDS include aspirin, ibuprofen, and naproxen. Alternative preferred NSAIDS are indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. Particularly preferred NSAIDS include aspirin and ibuprofen. The salicylates may include acetylsalicylic acid, sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylic 0*

S

(the next page is page 11) Ci-j

W:

r" rR:\Ll BVV]02067.do:SSD EDITORIAL NOTE NO. 11476/97 This specification does not contain pages numbered 8 WO 97/20556 PCT/US96/19390 -11acid, and sodium salicylate. An especially preferred NSAID is ibuprofen.

The term "acetaminophen", as used herein, shall have the art accepted meaning and refers to N-(4- Hydroxyphenyl)acetamide and 4'-hydroxyacetanilide. The compound is claimed in U.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 central alpha-adrenergic receptor activity. The most preferred central alpha-adrenergic active compound is clonidine or a pharmaceutically acceptable salt thereof having the chemical name: 2-(2,6-dichlorophenylamino)-2imidazoline.

Clonidine is known to be useful for treating hypertension, see Physicians' Desk Reference, 45th Ed.

(1991) p. 673.

The term "opioid", as used herein, represents opioid analgesics and antagonists including natural opioid 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, 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, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine.

Especially preferred opioid compounds are selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, WO 97/20556 PCT/US96/19390 -12nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl, and alphaprodine.

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 in combination with non-steroidal antiinflammatory agents (NSAIDS). More specifically, the invention provides a method of treating pain in humans using a specified azacyclic, azabicyclic or tetrahydropyridine compounds (collectively referred to herein as "selected muscarinic compounds") in 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 in no way limited by the mechanism of action.

There are many NSAIDS known in 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 in combination with acetaminophen.

More specifically, the invention provides a method of treating pain in humans using a specified Selected Muscarinic Compounds in 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, the invention provides a method of 13 treating pain in 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, 5 th edition, Macmillan Publishing Co., 1975, pp 325-358.

In the composition of this invention a compound of Formula I 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 I0 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.

In the composition of this invention a Compound of Formula I and acetaminophen are combined in a weight ratio of Formula I to acetaminophen of from about 1 to about 1000.

A preferred composition is a weight ratio of Formula I to acetaminophen of from about I to about 100. An especially preferred ratio is from about 1 to about 30. A further 4 preferred ratio may be from about 1 to about 10. A final preferred ratio may be from about I to about 3.

The compounds of Formula I 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 dosage.

The amount of acetaminophen present in the composition is adjusted as described above in ratio to the Formula I dosage. For example, dosages per day of the Formula I 25 compounds will normally fall 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 the range of about 0.005 to about 100 mg/kg of body weight and the NSAIDS in the composition would be from 3 to 1000 times this amount.

o In the composition of this invention a Compound selected from the group consisting of Formula I 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.

R\LIBVV]02067.docSSD 'y |:\LIVVJ02067.doc:SSD 14 A preferred composition is a weight ratio of Compound to opioid compound of lfrom about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A liurther 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 is as low as possible. The amount of opioid compound present in the composition is adjusted as described above in ratio to the Compound dosage. For example, dosages per day of the Formula I compounds will normally fall within the range of about 0.005 to about 100 mg/kg of body weight and the opioid 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 of the Compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of Compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not 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 compounds may also be administered by a variety of other routes such as the transdermal, parenterally, subcutaneous, intranasal, intramuscular and ooooo 2o intravenous routes. Such formulations may be designed to provide delayed or controlled oe oo release using formulation techniques which are known in the art.

Transdermal formulations containing the composition claimed herein most preferably deliver the active substances in an effective amount for from about three days .to about seven days. However, for chronic pain such as arthritis or cancer pain, a 2-5 transdermal delivery of from about three days to up to about two weeks is desirable.

Alternatively, it may be preferred to deliver the claimed compositions 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 mental condition once it has been established or alleviation of the characteristic symptoms of such condition.

H IR:\L1BVV]02067.doc:SSD The compounds of Formula 1 employed in the invention are not believed to act via the GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present Formula I 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 invention is not limited by any mode of operation.

The compounds of Formula I are described in 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 reference. The Sauerberg Patents teach the artisan how to 0o make the compounds of Formula I used herein for the claimed analgesic composition.

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

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g.

rectal, transdermal, depot, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.

a The dosage administered will, of course, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of the o• 25 symptoms, kind of concurrent treatment, frequency of treatment, and the 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 I compound and from about 0.6 to about 200 mg/kg of NSAIDS.

Compositions suitable for internal administration contain from about one half 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% to about 95% by weight based on the total weight of the composition.

[R:\LIBVV]02067.doc:SSD 16 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 I compound and from about 0.6 to about 200 mg/kg of acetaminophen.

5 Typical compositions include a compound of Formula I or a pharmaceutically acceptable 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 in the form of a capsule, sachet, paper, or other container. In making the compositions, conventional techniques for the 0t 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, 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 is active compound can be adsorbed on a granular solid container for example in a sachet.

Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

Typical compositions include a compound of Formula I or a pharmaceutically o: 25 acceptable acid addition salt thereof and acetaminophen, 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 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 above.

;0 A preferred composition is a weight ratio of Compound to central alphaadrenergic 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 A final preferred ratio may be from about 1 to about 3.

B, .0i l q' [R:\LIBVV]02067.doc:SSD 17 The compounds of Formula I are effective over a wide dosage range; however, it is desirable to administer a dosage that is as low as possible. The amount of central alpha-adrenergic active compound present in the composition is adjusted as described above in ratio to the Formula I dosage. For example, dosages per day of the Formula I compounds will normally fall within the range of about 0.005 to about 100 mg/kg of body weight and the central alpha-adrenergic active compound in the composition would be from 3 to 1000 times this amount.

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 I I compound and from about 0.6 to about 200 mg/kg of central alpha-adrenergic active compound.

Typical compositions include a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof; and one or more central alpha-adrenergic active compounds, 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 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.

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 deleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in •polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder 25 or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

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

3o The compositions of this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferredly, the animal is a vertebrate. Most preferredly, a compound of this invention -[R:\LIBVV]02067.doc:SSD 18 shall be administered to a mammal. It is especially preferred that the animal is a domestic mnammal or a human. The most preferred mammal is a human. For 9* 9 9 9 9 9999 9 9 9 .999 9 *999 9999 9*9999 9 9*9999 9 999 99 99 9999 99 *9 9. 9 9) 9.

9 999999 9 9 999999 9 (the next page is page [R:\L-IBVV]02O67.doc:SSD EDITORIAL NOTE NO. 11476/97 This specification does not contain a page numbered 19.

WO 97/20556 PCT/US96/19390 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 herein.

Nociceptive pain model: Acetic acid-induced writhing: A standard procedure for detecting and comparing the analgesic activity of different 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 intraperitoneally with acetic acid solution, 10 ml/kg) 5 min 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 min after receiving the acetic acid. Inhibition of writhing behavior is demonstrative of analgesic activity.

See, Haubrich, Ward, Baizman, Bell, M.R., Bradford, Ferrari, Miller, Perrone, M., Pierson, Saelens, J.K. and Luttinger, D.: Pharmacology of pravadoline: a new analgesic agent. The Journal of Pharmacology and Experimental Therapeutics 255 (1990) 511-522.

NeuroPathic pain model: Sciatic nerve ligation model: Rats are anesthetized and 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 by placing the rats in a chamber with a clear 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 hindpaw is demonstrative of analgesic WO 97/20556 PCT/US96/19390 -21activity. 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 grams of force required to bend them. Rats with sciatic nerve ligation respond to lower grams of mechanical stimulation by reflexive withdrawal of the foot than unoperated rats. This response to stimuli which are normally innocuous is termed allodynia. Increases in the grams of mechanical force required to produce foot withdrawal is demonstrative of antiallodynic activity.

See, Bennett, G.J. and Xie, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33 (1988) 87-107.

See also, Lee, 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 is a loss of spontaneous movement the rats are injected subcutaneously in the dorsal surface of the hindpaw with 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 min, the animal displays recovery from anesthesia with spontaneous activity and normal motor function. Pain behavior is quantified by periodically counting the incidents of spontaneous flinching/shaking of the injected paw. The flinches are counted for 1-min periods at 1- to 5- to 6and 5min intervals during the interval from 10 to 60 min.

Inhibition of the pain behavior is demonstrative of an analgesic activity.

See, Malmberg, A.B. and Yaksh, Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. The Journal of Pharmacology and Experimental Therapeutics 263 (1992) 136-146.

WO 97/20556 PCT/US96/19390 -22- Inflammatory pain model: Brewer's yeast-induced hyperalgesia (Randall-Selitto Test): To assess nociceptive threshold in rats, ascending pressure is applied gradually to the paw with a motor driven 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 injection of 0.1 ml of 1% suspension of brewer's yeast in 0.9% saline. The composition of this invention is administered at varying times 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.

Utility Test Methods The unexpectedly enhanced analgesic activity of the composition of the invention is evidenced by tests intially conducted on mice. Male mice are fasted for 16-22 hours 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 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 a pharmacological dispersant and containing 100% polysorbate 80, and 1% by weight Methocel MC powder, and containing 100% methylcellulose, in distilled water. The mixture may be sonicated for about 10 to about 15 seconds using an 23 ultrasound system. All dosing suspensions are prepared by dilution of the stock suspension with Methocel/Tween 80. All suspensions are used within two hours of preparation.

Mouse Writhing Test An accepted standard for detecting and comparing the analgesic activity of different classes of analgesic compounds for which there is a good correlation with human analgesic activity is the prevention of phenyl-p-benzoquinone induced writhing in mice.

Blumberg et al. Proc. Soc. Exp. Biol. Med., 118, 763-766 (1965)1.

Mice, treated with various doses of compound of Formula I, composition or vehicle to are injected intraperitoneally with a standard challenge dose of phenyl-p-benzoquinone minutes prior to a designated observation period. The phenyl-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 "writhe" is indicated by whole body stretching or contracting of the abdomen during an observation period beginning about five minutes after phenyl-p-benzoquinone dose.

All ED50 values and their 95% confidence limits 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 Loewe, Pharm. Rev. 9, 237-242 20 (1957)).

The solid line connecting the ED50 dosages of Formula I (alone) and classical analgesic as claimed herein (alone) represent the "ED50 addition line" which indicates I: the expected location of the ED50's for Formula I and classical analgesic combinations if simple additivity were to describe their combined effects. The 95% confidence range for 25 the ED50 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 the expected location of the ED50's of the Formula I and classical analgesic component of each fixed dosage ratio would be contained within or overlap the .0 region of the ED50 addition line. Combination of ED50's located significantly below the addition line would represent unexpectedly enhanced analgesic activity and combination ED50's located above the line would represent unexpected diminished analgesic effect.

[R:\LIBVV]02067.doc:SSD 24 One method to establish the significance of such unexpected enhanced or dimninished activity is to calculate the best fitting polynomial regression line to the observed ED5O's using standard mathematical techniques.

Such experiments demonstrate that compositions comprised of a compound of Formula I and one or more classical analgesics provides a statistically significant synergistic analgesic effect.

Preferred compounds of Formula I for use in the analgesic compositions are selected from the following: 3 -CHLORO-3 -CHLORO- 1,2,5-THIADIAZOL-4-YL)- 1iuAZABICYCLO [2.2.2]JOCTANE; CHLORO- 1 ,2,5 -THIADIAZOL-4-YL)-3 -HYDROXY- I AZABIC YCLO [2.2.21]OCTANE; 3-METHOXY-3 -METHOXY-l 1,2,5 -THIADIAZOL-4-YL)-1I AZABICYCLO OCTANE; 1 5 3 -METHOXY-1I,2,5-THIADIAZOL-4-YL)-t1-AZABICYCLO OCT-2-ENE; 0 400 *0000 a *500: *g t.

oe0060 o 96 [R:\LIBVV]02067.doe:SSD WO 97/20556 WO 9720556PCTIUS96/19390 3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO [2.2 .21 OCT- 2- ENE; 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- AZABICYCLO[2 .2.2]OCTANE; 3(3CHLR-1,2,5THIADIAZOL4YL)--AZABICYCLO[22.2]OCTANE; 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-l-AZABICYCLO[2.2.2]OCTANE; 3- (3-PROPOXY-1, 2, 5-THIADIAZOL-4-YL) -1- 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- [2.2.21OCTANE; 3-(3-ETHOXY-1,2,5-THIADIAZOL-4-YL)-l-AZABICYCLO[2.2.2]OCTANE; 3- (3-HEXYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[2.2.2]OCTANE; 3- (3-PHENYLPROPYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-l- AZABICYCLO OCTANE; 3- (4-CYANOBENZYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO [2.2.2]OCTANE; EXO-6- (3-CHLORO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; WO 97/20556 WO 9720556PCTIUS96/19390 -26- ENDO-6- 3 -CHIORO-1,2,5-THIADIAZOL-4-YL)-1.- AZABICYCLO [3 .2.11 OCTANE; ENDO-6- (3-HEXYLTIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3 1] OCTANE; ENDO-6-(3-(5-HEXENYLTHIO)-1,2,5-THIAIAZOL.4-YL)...

AZABICYCLO[3 1]OCTANE; ENDO-6- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO [3 OCTANE; ENDO-6- (3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)...

AZABICYCLO[3 1]OCTANE; ENDO-6-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4YL)-l- AZABICYCLO[3 1]OCTANE; ENDO-6- 3 -PHENYLPROPYLTHIO)-1,2,5-THIADIAZOL-4YL)-..

AZABICYCLO [3 OCTANE; Particularly preferred compounds of Formula I include: 3- (3-H-EXYLTHIO-l,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[2.2.2]OCTANE; 3- (3-PHENYLPROPYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO

OCTANE;

3 3 -CHLORO-1,2,5-THIADIAZOL4YL)-l-AZABICYCLO(2.22)OCTANE 3- (3-PROPOXY-l,2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO(2 .2 .2)OCTANE WO 97/20556 WO 9720556PCTIUS96/1 9390 -27- 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-Yr,)-l- AZABICYCLO(2 .2 .2)OCTANE 3-(3-PENTYLTHO-1,2,5-THIDIAZOL-4YL)-l AZABICYCLO(2 .2.2)OCTANE ENDO (3-ETHYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- (3 1) OCTANE ENDO (3-BUTYLTIo-1,2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- (3 .2.1)OCTANE 3 -BTTYLTHIO-1,2,5-THIADIAZOL-4-YL)-lAZABICYCLO.

(3.2.1)OCTANE 3- (BUTOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYcLO

OCTANE

E-XO-3- (3-PROPYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- 2.1) HEPT.ANE EXO-3- (3-BtTYLTHIO-1,2,5-THIADIAZOL-4-YL) -1- AZABICYCLO

-HEPTANE

ENDO-3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-l AZABICYCLO

-HEPTANE

3- (3-ETHYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO(2.2 .2)OCTANE 3- (3-PROPYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO

OCTANE

4-CHLORO-3- (3-PROPYLOxY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- (3.3.1)NON-2-E 3- (3 -ISOPENTYLOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO WO 97/20556 WO 9720556PCT/US96/19390 -28-

OCTANE

ENDO 3- (3-PROPYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1-AZA'BICYCLO- (3 .2.1)OCTANE

EXO(+-)

3 -(3-PROPYLTHIO-.1,2,5-THIADIAZOL-4-.YL)-l-AZABICYCLO- (3 .2.1)OCTANE (3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-l-AZABICYCLO(222)-

OCTANE

3 -(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-l-AZABICYCLO(2.2.2)-

OCTANE

3 3 -CHLORO-1, 2,5-THIADIAZOL-4-YL) -1-AZAIBICYCLO(22.2)

OCTANE

)-6-(3-CILORO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO- (3 .2.1)OCTANE 3 3 -ETHOXY-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO(2.2.2)OCTANE 3- (3-PROPOXY-1, 2 ,5-THIADIAZOL-4-YL) -1-AZABICYCLO

OCTANE

3- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-yL) -1- AZABICYCLO(2.2.2)OCTANE 3 -(3-PENTYLTHIO-1,2,5-THIAIAZL-4.YL)-l AZABICYCLO

OCTANE

ENDO(+-)-6-(3-ETHYLTHIO-1,2,5-THIDIAZOL-4-YL) -1-AZABICYCLO- (3 2. 1) OCTANE ENDO(+-) (3-BUTYLTHIo-1,2, 5-TH-IADIAZOL-4-YL) -l-AZABICYCLO- (3 1) OCTANE (3-BUrYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- (3 .2 .1)OCTANE WO 97/20556 WO 9720556PCT/US96/1 9390 -29- 3-(3-(BUTOXY--1,2,5-THIADIAZOL--4-YL)-1-AZABICYCLO(2.2.2)OCTANE EXO-3- (3-PROPYLTHIO-1, 2, 5-THIADTAZOL-4-YL) -1- AZABICYCLO(2.2.1)-

HEPTANE

3- (3-ETHYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE EXO-3- (3-BTJTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO -HEPTANE 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)-l- AZABICYCLO (2.2.2 )OCTANE 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 3- (3-ISOPENTYLOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- (2.2 .2 )OCTANE ENDO(--) 3- (3-PROPYLTHIO-1,2, 5-THIADIAZOL-4-YCL) -1l-AZABICYCLO- (3.2.1)OCTANE BIS-1,4-(3-(1-METHYL-1,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5- THIADIAZOL-4 -YL) BtTANEDITHIOL EXO(+-)3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1-AZABICYCLO-

OCTANE

)-BUTYLTHIO- 1,2,5 -THIADIAZOL-4-YL)- I -AZABICYCLO-(2.2.2)OCTANE -BUTYLTHIO- 1,2,5-THIADIAZOL-4-YL)-l1-AZABICYCLO-(2.2.2

.)OCTANE;

and a pharmaceutically acceptable salt or solvate thereof.

More preferred compounds include the following: 3 )-BUTYLTfHIO-1I,2,5-THIADIAZOL-4-YL)- 1 -AZABICYCLO(2.2 .2)OCTANE 3 -PENTYLTHIO- 1,2,5 -THIADIAZOL-4-YL)-l1-AZABICYCLO(2 .2 .2)OCTANE ENDO(±)-6-(3--ETHYLTHIO-1 ,2,5-THJADJAZOL-4-YL)-1-AZABICYCLo- (3.2.1 )OCTANE ENDO(±)-6-(3-BUTYLTHIO- 1,2,5-THIADIAZOL-4-YL)-l1-AZABICYCLO- 1)OCTANE UTYLTHIO- 1,2,5-THIADIAZOL-4-YL,)- 1-AZABICYCLO- (3.2.1 ])OCTANE 3-(-)-PROP YLTHIO- 1 ,2,5 -THIADIAZOL-4-YL,)- 1 -AZABICYCLO(2.2.2)OCTANE; or a pharmaceutically acceptable salt or solvate thereof.

The most especially preferred compound of Formula I is 3-(3-BIJTYLTHIO-1,2,5- THIADIAZOL-4- YL)- 1 -AZABICYCLO [2 .2 .2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof.

Further preferred compounds of Formula I for the analgesic composition are selected from the following: 3 METHOXY- 1,2,5-THIADIAZOL-4-YL)- 1,2,5,6..TETRAHYDRO- 1

METHYLPYRIDINE

r R:LIVV006.dc.S WO 97/20556 PCTIUS96/19390 -31- 3 3 -ETHOXY-1,2,5-THIADIAZOL..4YL)125,6-TETRAHYDRO-1-

METHYLPYRIDINE

3-3POOY125TIDAO--L-,,,-ERHDO1

METHYLPYRIDINE

3 3 -BUTOXY-,2,-THAIADIZOL4YL)1,2,,6TETTRHYRO-1

METHYLPYRIDINE

3- (3-ISOPROXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-

METHYLPYRIDINE

3- (3-CYCLOPROPYLMETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -PENTOXY-1,2,-THIDIAZOL4.YL)1256TETRA.HYDRO-1 METHYL PYRIDINE 3 3 -ISOBUTOXY-1,2,-TIIAZOL4YL).1256TETRAHYDRO-1

METHYLPYRIDINE

3 3 3 -BUTENOXY)1,2,-THIAIA~Z 4YL)125,6TETRAHYDRO- 1 -METHYL PYRIDINE 3- (BUT-2-ywoxy) 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYLPYRI]DINE 3 3 3 -METHLBUTOXY)-1,2,5THIIAZL4YL)Jj 2 5,6 TE-TRAHYDRO- 1-METHYLPYRIDINE 3 3 -HXYLOXY-1,2,THIDIAZOL4YL)125,6TETRAHYDRO-1

METHYLPYRIDINE

-3(RP2YOY1,,-HAIZL4Y)1256 TETRAHYDRO- 1-METHYLPYRIDINE WO 97/20556 PCT/US96/1 9390 -32- 3- (3-BENZYLOXY-1,2, 5-THIADIAZOL-4-YL) 6 -TETRARJyDRO-.1-

METHYLPYRIDINE

3- (3 -CHLORO-1, 2, 5-TIADIAZOL-4-YL) 6 -TETRAHYDRO.1-

METHYLPYRIDINE

3- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL)

E-TETRAHYDROPYRIDINE

3- (3 -BITOXY-1, 2, 5-THIADIAZOL-4-YL) 6

-TETRAHYDROPYRIDINE

3 3 -ETHOXY-1,2,5THIAIAZOL4YL)12,56-TETRAHYDRO-1-

ETHYLPYRIDINE

3-3CLR-,,-HAIZL--L-,,,-ERHDO1

ETHYLPYRIDINE

3- (3-METHOXYETHOXY-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYLPYRIDINE 3-3HPYOY125TIDAO--L-,,,-ERHDO1 METHYLPYR

IDINE

3 3 3 -PENTYNYLOXY)-1, sT IAZ 4YL) 2 5,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -PENTENYLOXY)-1,2,-THIDIAZOL4.YL)1 2 sE6 TETRAHYDRO- 1-METHYL

PYRIDINE

3 -(3-(2-PROPENLOXY)1,2,-THIDIAZOL4YL) 1 25 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-OCTYLOXY-1, 2, 5-THIADIAZOL-4-YL) 5, 6-TETRAHYDRO-1-

METHYLPYRIDINE

3 3 3 -HEXYNYLOXY)-1,2,THIIAZOL-4L) 2 s 6 TETRAHYDRO- 1-METHYL

PYRIDINE

WO 97/20556 WO 9720556PCT/US96/19390 -33- 3 -(3-(3-BUTE-NYL-2-OXY)-1,2,5--THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYL-PYRIDINE 3- (4-H-EXNYLOXY(-1, 2, 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE TRANS-3-(3-(3-HEXENYLOXY)-1,2,5-THIAjjIAZOL-4-YL)-,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE CIS-3-(3-(2-PENTENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE CIS-3- (2-HEXENYLOXY) 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 CIS-3-(3-(3-lEXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,4,5- TETRAHYDRO- 1-METHYLPYRIDINE TRANS-3- (2-HEXENYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYL PYRIDINE 3- 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (4-METHyLPIpERID)INO-1,2, 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -MORPHOLINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6.TETAHYDRO-1

METHYLPYRIDINE

3- (3-DIMETHYLAMINO-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYL PYRIDINE 3- (3-HEXYLAMINO-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-

METHYLPYRIDINE

WO 97/20556 WO 9720556PCT/US96/1 9390 -34- 3- 3 -HE-XYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETR.1uYDRO-1

DEUTEROMETHYLPYRIDINE

1,2,5,6-TETRAHYDRO-3- (3-HEXYLOXY-1,2,5-THIADIAZOL-4- YL) PYRIDINE 3- (2-METHOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-ETHOXY-1-PROPOXY) 5-THIADIAZOL-4-YL) TETRAHYDRO- 1-METHYLPYRIDINE 3 2 -ETHOXYETHOXY)-1,2,-TDIAZO4YL)12,56TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-BUTOXYETHOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 2 2 -BtTOXYETHOXY)-ETOXY)-1,2,5THIIAZOL4YL)- 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (2-ETHOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -BUTYLTHIO-1,2,5-THIAIAZOL4YL) 6-TETRAHYDRO-1-

METHYLPYRIDINE

3 3 -METHYLTHIO-1,2,5-THIDIAZQL.4-YL) -1,2,5,9-TETRAHYDRo-1-

METHYLPYRIDINE

3 3 -PENTYL-1,2,5-THIADIAZL4.YL)...12,56-TETRAHyDRO-1-

METHYLPYRIDINE

3 3 -PROPYLTHIO-1,2,5-THIDIAZOL4-YL)1,256TETRAHRO.1-

METHYLPYRIDINE

WO 97/20556 WO 9720556PCT/US96/19390 3-(3-HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHJYDR 0 -1 MET1{YIPYRIDINE 3-(3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO.1-

METHYLPYRIDINE

3- (3-ETHYLTHIo-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-

METHYLPYRIDINE

3-(3-OCTYLTHIO-1,2,5-THIAIAZOL-4-YL)-1,2,5,6-rETRAHJYDRO-1

METHYLPYRIDINE

3-(3-PROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHjYDRQ-1-

METHYLPYRIDINE

3-(3-HEPTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-

METHYLPYRIDINE

3-(3-(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1,2,,6-TETRAHiYDRo-1-

METHYLPYRIDINE

3 -(3-OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRA~HYDRO-1-

METHYPYRIDINE

3-(3-(2-METHYL)-BUTYL-1,2,5-THIDIAZOL-4-YL)-1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3 -(3-METHYLCYCLOPROPYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDR-1-METHYLPYRIDINE 3 -(3-CYCLOPENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(1-ETHYLTHIO-2-METHOXY)-1,2,5-THIAIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/1 9390 -36- 3- (3-CHLORO-1-PROPYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-METHOXYETHOXY) -ETHYLTHIo) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-CYANO-1-PROPYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -BENZYLTHIO125THIADIAZOL4YL)12,56TETRAHYD -1

METHYLPYRIDINE

3 3 2 -ETOXY-EHYTHIOY ,-TH1 HIIAZOL4YL)1 2 s 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- (4-PENTYNYLTETO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-ETHOXYMETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-yL) 1,2,5, 6 -TETRAHYDRO-1-METHYLPYRIDINE 3 3 -(-CYAO-1-PENTYLTHIO)-1,2,5THIDIAzoL4YL)1, 2 ,5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 3 -PHENYL-1-PROPYLTHIO)1,2,5THIIAZOL4YL)l, 2 5 6 TETRAHYDRO- 1-METHYIJPYRIDINE 3-3(-HNXEHYTI)125TIDIZL4 )1256- TETRAHYDRQ-1-METHYLPYRIDINE 3 3 4 -CYANOBUTYLTHIO)-1,2,THIIAZOL-4YL)l, 2 5,6 TETRAHYDRO- 1-METHYLPYRIDINE 3- 2 -ETHYLBTYxTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL

PYRIDINE

WO 97/20556 WO 9720556PCTIUS96/19390 -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 TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(7-OCTENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRARYDRO- 1-METHYLPYRIDINE 3- (3-CYCLOPROPYLMETHYLTHIO-1,2,5-THIADIAZOL4YL125, 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 -METHYL PYRIDINE 3- (4-PENTENYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 4 -ISOHEXYLOXY-1,2,5-THIADIAZOL-3-YL)-1,2,5,6TETJHYDRO.1-

METHYLPYRIDINE

1-METHYL-i, 2,5, 6-TETRAHYDRO-3- ((4-CYCLOPENTYLPRQPYL) OXY) 1,2, 5-THIADIAZOL-3-YL)

PYRIDINE

1-METHYL-1, 2,5, 6-TETRAHYDRO-3- (4-ISOHEPTYLXY-1, THIADIAZOL-3-YL)PYRIDINE 1-METHYL-i, 2,5, 6-TETRAHYDRO-3- (4 ((2-CYCLOHEXYLETHYL)OXY) 1,2, 5-THIADIAZOL-3-YL)

PYRIDINE

1, 2 ,5, 6 -TETRHYDRO-1-METHYL-3-(4-(1-METHYLHEXLOXY)..125- THIADIAZOL-3-L)

PYRIDINE

WO 97/20556 PCT/US96/1 9390 -38- 3 4 -(l-ETHYLPENTYLOxy)-1,2 THIDIAZOL3.YL)1 2 5,6 TETRAHyDRO- 1-METHYLPYRIDINE 3- (1-ETHYLBTOXY) 5-THIADIAZOL-3-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 1,,,-ERHDO1MTY--4(-EHLETLX)125 THIADIAZOL-3 YL) PYRIDINE 1-EHL3(-5HXNLX)1,,-HAIZL3Y)1256

TETRAHYDROPYRIDINE

1, 2 ,5,6-TETRAHYDRO1METHYL3(4-(-METHYLBITOXY)l 2 THIADIAZOL-3 -YL) PYRIDINE 1,,,-ERHDO1MTY--4(-EHLETLX)125 THIADIAZOL-3 -YL) PYRIDINE 1,2,5, 6 -TETRAHYDRO-1-METI{YL-3-(4- 2 2 2 -TRIFLUOROETHOXY) 1,2, S-THIADIAZOL-3-YL)PYRIDINE l-METHYL1,2,5,6TETHYDRO3(4(3ETHYLPNYLOXY) 1 2 THIADIAZOL-3 -YL) PYRIDINE 3 3 -(3-METYL-2-BUTENYLoxy)-1, 5THDIAZO 4 YL)1 2 5 6 TETRAHYDO -1 -METHYLPYRIDINEI 3 3 -ISOBUTOXY1,2,THIIAZOL4YL)125,6TETRAHYDRol1

METHYLPYRIDINE

lI 2 ,5,6-TETRHYDRo1METL3-(4-(2METHYLBTOXY)l1 2 THIADIAZOL-3 -YL) PYRIDINE 3-3(-Y~xpooy-,,-HAIZL4Y)1256 TETRAHyDRO- 1-METHYLPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -39- (+-)1,6-DIMETHYL-3-(3-HEXYLOXY-1,2,5--THIADIAZOL-4-YL)- 1,2,5, 6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETHYLTIIO)-1,2,5-THIADIAZOL-4-Y.)-1,2,5,6 TETRAHYDRO- 1-METHYLPYRIDINE BIS-1,4-(3-(1-METHYL-1,2,5,6-TETRAHYDROPYRIDIN-3-YL).12,5 THIADIAZOL-4-YL) BUTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUOXY)-1,2,5-THIDIAZOL-4-YL)-12,5 THIADIAZOL-4-YL) 6-TETRAHYDRO-1-METHYLPYRIDINE 3- 3-TRIFLUOROPROPYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3-PROPYLTHIn-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-

TETRAHYDROPYRIDINE

3-(3-BUTYLTHIn-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 (+-)l,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

3 -(3-3-MTHYL-2-BUTENYLOXY)-1,2,5-THIIAZOL-4-YL)-1,2,5,6- TETRAI{YDO -1 -METHYL PYRIDINE 3- (3-ISOBUTOXY-1,2,5-THIAJIAZOL-4-YL)-1,2,5,6-TTYDRO-1-

METHYLPYRIDINE

WO 97/20556 WO 9720556PCTIUS96/1 9390 1,2,5, 6-TETRAIIYDRO-1-METHYIJ3. (2-METHYLBUTOXY) -1,2,5- THIADTAZOL-3 -YL) PYRIDINE 3- (3-HYDROXYPROPOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRTDINE (+-)1,6-DIMETYL-3-(3HEXYLOXY-1,2,5-THIADIAZOL-4YL)- 1,2,5, 6-TETRAHYDROPYRIDINE 3 3 3 -PHENYL-ETHYLTHIO-1,2,5TIIIAZO-4-YL) 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE BI-,-3(-EHL1256TTAYRPRDN3Y)125 THIADIAZOL-4 -YL) BUTANEDITHIOL 3 3 4 ,4,4-TRIFLUOROBUTOXY)-1,2,5-THIIAZL4YL)12,5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 3 3 ,3-TRIFLUOROPROPYLTHO)-1,2,-THIADIAZOL-4YL..

1,2,5, 6-TETRAYDRO-1-METHYLPYRIDINE 3 3 -PROPYLTHIo-1,2THIDIAZOL4YL)125,6TETRAHYDRO-1

METHYLPYRIDINE

3 3 -PROPYLTHIO-1,2,5THIIAZOL4YL)1256-

TETRAHYDROPYRIDINE

3- (3-BTYLTHIO-1 5-THIADIAZOL-4-YL) -1,2,5,6-

TETRAHYDROPYRIDINE

3 3 -BUTYLTHIo-1,2,THIIAZO4YL)1,256TETHYDRO-1ll DIMETHYLPYRIDINIM

IODIDE

1, 6-DIMETHYL-3- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAJYDRPYRIDINE WO 97/20556 WO 9720556PCTIUS96/1 9390 -41- 1, 6-DIMETHYL-3- (3-BTJTOXY-1,2, 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAIHYDROPYRIDINE; or a pharmaceutically acceptable salt thereof.

Especially preferred compounds include the following: 3- (3-BUTYLTHIO- 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-

METHYLPYRIDINE

3-(3-METHYLTHIO-l,2,5-THIADIAZOL-4-YL) -l,2,5,6-TETRAHYIDRO-l-

METHYLPYRIDINE

3- (3 -PENTYL-l, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYL PYRIDINE 3-(3-PROPYLTHIO-1,2,5-THIDIAZOL-4-YL)-,2,5,6-TETRAHYDRO-1-

METHYLPYRIDINE

3-(3-HEXYLTHIO-1,2,5-THIAJJIAZOL-4-YL)-l,2,5,6-TETRAHYDRO-l-

METHYLPYRIDINE

3-(3-PENTYLTHIO-1,2,5-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-1,2,5-THIDIAZOL-4-YL)-,2,,6-ETRjHwDRO-1-

METHYLPYRIDINE

3- (3-METHOXY-l, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-l-

METHYLPYRIDINE

3 3 -ETHOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1-

METHYLPYRIDINE

WO 97/20556 WO 9720556PCT/US96/19390 -42- 3-(3-PROPOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETpAHYDRO-1

METHYLPYRIDINE

3- (3-BUTOXY-1, 2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETTRAHYDRO-1-

METHYLPYRIDINE

3-(3-ISOPROPOXY-1,2,5-THIAIAZOL-4-YL)-,2,5,6-TETRAHYDRO-1.

METHYLPYRIDINE

3-(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3-(3-PENTQXY-l,2,5-THIADIAZOL-4-YL) -1,2,5,6-TETRAHYDRO-1-

METHYLPYRIDINE

3- (3-ISQBtJTOXY-l,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-l-

METHYLPYRIDINE

3-(3-(3-BUTENOXY)-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRjHYDRO- 1 -ME-THYLPYRIDINE 3- (BUT-2-YNOXY) 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYL PYRIDINE 3-(3-(3-METHYLBUTOXY)-1,2,5-THIADIAZOL-4-YL)-l,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 -(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRjA{YDRO-1-

METHYLPYRIDINE

3- (PROP-2-YNOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAYDRO-1-METHYLPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof.

Compound which are particularly preferred include: 3 3 -HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-l,2,5,6-TETRJHYDRO-1- METHYLPYRIDINE; and WO 97/20556 PCT/US96/19390 -43- 3- (3-HEXYLTHIO-l,2,5-THIADIAZOL-4-YL) -l,2,5,6-TETRAHYD)RO-l- METHYLPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof.

Claims

1. A composition for treating pain comprising an analgesic dose of a Compound of formula 1 IN GN A or A' wherein X is oxygen or sulphur; A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR, -S0 2 R 4 C3. 7 -cycloalkyl, C4- 8 -(cycloalkylalkyl), -Z-C3- 7 -cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R 4 is straight or branched C.i-i-alkyl, straight or branched C2- 1 5 -alkenyl, straight to or branched C2- 15 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C 1 -4-alkyl, C 4 -alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, C 1 4 -alkyl, Cl-4-alkoxy, -OCF 3 -CONH 2 or A is -ORY, -SR'Y, -OR'ZY, -SRSZY, -O-R 4 or -S-R 4 -Z-R 5 wherein Z is oxygen or sulphur, R 5 is straight or branched C_ 1 i5-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 20 one of the following azabicyclic rings R R 2ol• Cn C R wherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R' and R 2 may be present at any position, including the point of S25 or branched Ci.-alkyl, straight or branched C2-5-alkenyl, straight or branched alkynyl, straight or branched Clo-alkoxy, straight or branched Ci-5-alkyl substituted with r13 -OH, OR 4 halogen, -NH2 or carboxy; R 3 is H, straight or branched Cl-alyl, straight or [R:\LIBVV]02067.doc:SSD 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 6' R N R wherein A' is hydrogen, halogen, amrnino, -NHCO-R 2 C3- 7 -cycloalkyl, C 4 1 -(cycloalkylalkyl), -Z2'-C 3 7 -cycloalkyl optionally substituted with Cl-6-alkyl, -Z -C4-10-(cycloalkylalkyl), -Z 2 -C 4 I1 o-(cycloalkenylalkyl), -C 4 -1 o-(methylenecycloalkyl-alkyl), -NH-R 2 -NR 2 'R -NIH-OR2', phenyl, phenoxy, benzoyl, bcnzyloxycarbonyl, tetrahydronaphthyl, indenyl, R2', -Z 2 'R 2 -SOR 2 o -SO 2 R -Z2'-R _Z -R 2'_Z -R -Z -R 4 -Z 2 '-R2'CO-R -Z 2 '-R 2 '-C0 2 -R, Z -R 2'-0 2 C-R -Z2'-R 2 '-CONH-R 3 -Z 2 '-R 2 -NHCOR 3 -Z 2 -Z 2 '-R 2 -Z wherein Z2', Z3', and Z 4 independently are oxygen or sulphur, and R R and R 4 independently are straight or branched C 1 1 5 -alkyl, straight or branched C 2 1 5 -alkenyl, straight or branched C2-15-alkynyl, each of which is optionally substituted with halogen(s), -OH, 2 2' 3' is -CN, -CF 3 -SH, -COOH, -NH-R2', -NR2'R Ci-6alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, C 1 4 -alkyl or 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 20 Straight or branched Cl-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 fused with a phenyl group; and R 5 and R 6 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C-s-alkyl, straight or branched 25 C2-5-alkenyl, straight or branched C 2 -5-alkynyl, straight or branched Cl- 1 lo-alkoxy, straight or branched C 1 5 -alkyl substituted with -OH, halogen, -NH 2 or carboxy; R is hydrogen, straight or branched C 1 s-alkyl, straight or branched C 2 5 -alkenyl or straight or branched C 2 -s-alkynyl; or [R:\LIBVV]02067.doc:SSD 46 a pharmaceutically acceptable salt or solvate thereof; and a nonsteroidal anti- inflammatory drug in a weight ratio of Compound to nonsteroidal anti-inflammatory drug (NSAIDS) of from about 1 to about 1000.

2. A composition as claimed by claim 1 wherein the Compound is of the formula SI GN A orA' wherein X is oxygen or sulphur; A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -S0 2 R 4 C 3 -7-cycloalkyl, C 4 -8-(cycloalkylalkyl), -Z-C 3 7 -cycloalkyl, and -Z-C 4 _8-(cycloalkylalkyl) wherein R 4 is straight or branched Cil 1 5 -alkyl, straight or branched C 2 1 5 -alkenyl, straight or branched C2- 1 5 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, CI- 4 -alkyl, C 1 4 -alkoxy, -OCF 3 i1 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, CI- 4 -alkyl, CI- 4 -alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is -OR Y, -SRSY, -OR'ZY, -SR 5 ZY, -O-R 4 -Z-R 5 or -S-R4-Z-R 5 wherein Z is oxygen or sulphur, R 5 is straight or branched Ci-s-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 20 heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched Ci_--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 S. EDITORIAL NOTE NO. 11476/97 This specification does not contain a page numbered 47. WO 97/20556 PCT/US96/19390 -48- R or R Cn\ Cm 1r R N N R wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R 1 and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1 5 alkyl, straight or branched C 2 -5 alkenyl, straight or branched C2-5-alkynyl, straight or branched C1-lo-alkoxy, straight or branched C1- 5 -alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3 is H, straight or branched C 1 I -alkyl, straight or branched C 2 -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 a nonsteroidal anti-inflammatory drug in a weight ratio of Formula I to nonsteroidal anti-inflammatory drug (NSAIDS) of from about 1 to about 1000.

3. A composition of Claim 2 wherein X is S, G is R CP R n\ Cm wherein n is 1, p is 1 or 2 and m is 1 or 2, R 1 and R 2 independently are hydrogen, methyl, hydroxy, halogen or amino; or a pharmaceutically acceptable salt or solvate thereof. WO 97/20556 WO 9720556PCT/IJS96/19390 -49-

4. A composition of Claim 2 wherein X is S, G is R~i N wherein n is 1, p is 1 or 2 and m is 1 or 2. A composition according to Claim 2 wherein the compound of Formula I1 is selected from the group consisting of the following: 3-CHLORO-3- (3-CHLORO-l,2,5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) -3-HYDROXY-1- AZABICYCLO[2 2]OCTANE; 3-METHiOXY--3-(3-METHOXY-l,2, 5-THiIADIAZOL-4-YL) -1- AZABICYCLO[2 .2.2]OCTANE; 3-(3-METHOXY-1,2,5-THIAJJIAZOL-4-YL)-1-AZABICYCLO[2.2.2]ocT-2- ENE; 3- (3-HEXYLOxY-l, 2, 5-THIADIAZOL-4-YL) -l-AZABICYCLO(2 .2 .2]OCT- 2- ENE; 3-HEXYLOXY-3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO- [2.2 2]OCTANE;.4 3- (3-HE-XYLOXY-1, 2, 5-THIADIAZOL-4-YL) -3-HYDROXY-l- AZABICYCLO OCTANE; 3-(3-CHLORO-l,2,5-THIADIAZOL-4-YL)-l-AZABICYCLO[2.2.2]OCTANE; 3- (3-ETHOXY-l, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO[(2.2.2 ]OCTANE; WO 97/20556 WO 9720556PCTIUS96/19390 3- (3-PROPOXY-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO 2]OCTANE; 3- 3 -PENTYLTHIO-1,2,5-THIDIAZOL.4-YL) -1-AZABICYCLO- [2.2 OCTANE; 3- (3-HEXYLTHIO-1, 2, 5-THiIADIAZOL-4-YL) -1- AZABICYCLO [2 .2.2]OCTANE; 3- (3-PHENYLPROPYLTHIO)

5-THIADIAZOL-4-YL) -1- AZABICYCLO 211OCTANE; 3- (3-HEXYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3-( 3 4 -CYANOBENZYLTHIO)125THIADIAZOL4Y)-. AZABICYcLO 211OCTANE; E-XO-6- (3-CHLORO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3 1]OCTANE; E-NDO-6- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; ENDO-6- (3-HEXYLTHIO-1, 2,5-THIADIAZOL-4-YL) -1-4 AZABICYCLO[3.2.1]OCTANE; ENDO-6- (5-HEXENYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3 lIOCTANE,; ENDO-6- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; WO 97/20556 PCT/US96/19390 -51- ENDO-6-(3-PENTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- AZABICYCLO[3.2.1]OCTANE; ENDO-6-(3-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1- 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.

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 thereof.

7. A composition of Claim 2 wherein the the non-steroidal antiinflammatory drug is selected from the group consisting of salicylates, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.

8. A composition of Claim 7 wherein the non- steroidal antiinflammatory drugs is selected from the group consisting of aspirin, ibuprofen, and naproxen.

9. A composition of Claim 2 wherein the weight ratio of a compound of Formula I to NSAIDS is from about to about 100. A composition of Claim 7 wherein the weight ratio is from about 1 to about

11. A composition of Claim 10 wherein the weight ratio is from about 1 to about 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 non-steroidal anti-inflammatory drug is selected from the group consisting of aspirin and ibuprofen.

14. A composition of claim 7 wherein the weight ratio of compound of Formula I to NSAIDS is from about 1 to about 100. A composition of claim 8 wherein the weight ratio of compound of Formula I to NSAIDS is from about 1 to about 100.

16. A method for treating pain comprising administering an analgesic dose of a t0 composition comprising a compound of Formula I N N G N A wherein X is oxygen or sulphur; A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -S0 2 R 4 C3-7-cycloalkyl, C 4 8 -(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C 4 -8-(cycloalkylalkyl) wherein R 4 is straight or branched Ci- 1 5 -alkyl, straight or branched C2-15-alkenyl, straight or branched C2- 1 5 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally S substituted with halogen, -CN, Cl- 4 -alkyl, C 1 4 -alkoxy, -OCF 3 o 20 -CONI1 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, C 1 4 -alkyl, Ci- 4 -alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is -OR'Y, -SRSY, -ORSZY, -SR'ZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z is oxygen [R:\LIBVV]02067doc:SSD a a a a a S.[R:\LIBVV]02067.doc:SSD WO 97/20556 PCT/US96/19390 -53- or sulphur, R 5 is straight or branched Cl-15-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 C1-6-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 R2 or R 2 N N R 3 3 wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R 1 and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1 5 alkyl, straight or branched C 2 5 alkenyl, straight or branched C2-5-alkynyl, straight or branched straight or branched C1-5-alkyl substituted with -OH, OR 4 halogen, -NH2 or carboxy; R 3 is H, straight or branched CI- 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 method of Claim 16 wherein the non- steroidal antiinflammatory drug is selected from the group consisting of salicylates, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. 54

18. A method of claim 17 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, and naproxen.

19. A method of claim 16 wherein the weight ratio of a compound of Formula I to NSAIDS of from about 1 to about 100. A method of claim 19 wherein the weight ratio is from about 1 to about

21. A method of claim 20 wherein the weight ratio is from about 1 to about

22. A method of claim 21 wherein the weight ratio is from about 1 to about 3.

23. A method of claim 22 wherein the compound of Formula I is 3-(3- BUTYLTIIIO-1,2,5-THIADIAZOL-4-YL)-I -AZAB1CYCLO [2.2.2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof.

24. A method of claim 22 wherein the composition is administered using a transdermal formulation. A composition of claim 1 wherein A is hydrogen, halogen, amino, -NHCO-R 2 C 3 -7-cycloalkyl, C4-10-(cycloalkylalkyl), -Z2'-C3- 7 -cycloalkyl optionally substituted with Ci-6-alkyl, -Z2'-C41o-(cycloalkylalkyl), -Z 2 '-C4-1 0 -(cycloalkenylalkyl), -Z'-C4- 1 0 -(methylenecycloalkyl-alkyl), -NH-R 2 -NR -NH-OR 2 phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, X, R -Z 2 'R 2 -SOR 2 -S0 2 R 2 -Z 2 '_R 2 '_Z 3 4 -Z2'_R2'CO-R 3 -Z2'-R2'-C0 2 -R 3 Z2'R2'-O 2 C-R 3 -Z'-R2'-CONH-R 3 -Z'-R2-NHCOR 3 -Z2-R2-X, -Z 2 '-R2'-Z 3 wherein Z 2 Z 3 and Z 4 independently are oxygen or sulphur, and R 2 R' and R 4 independently are straight or Sbranched C-a 1 5 -alkyl, straight or branched C2- 15 -alkenyl, straight or branched 9* C2- 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR2'R 3 CI-6-alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two 25 halogen, -CN, C 1 -4-alkyl or C 1 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 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 o30 fused with a phenyl group; and G is BVV]0206.doc:D l lIR:\LIBVV]02067.doc:SSD R N R wherein R 5 and R' may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C l 5 -alkyl, straight or branched C2-5-alkenyl, straight or branched C2-5-alkynyl, straight or branched Cl~lo-alkoxy, straight or branched Cij_-alkyl substituted with -OH, halogen, -NH 2 or carboxy; R' is hydrogen, straight or branched CI-j-alkyl, straight or branched C2.s-alkenyl or straight or branched or a pharmaceutically acceptable salt or solvate thereof; and one or more nonsteroidal anti-inflammatory drugs in a weight ratio of Formula I to nonsteroidal anti-inflammatory drug of from about 1 to about 1000.

26. A composition of claim 25 wherein X' is sulphur.

27. A composition of claim 25 wherein X is sulphur, R" is hydrogen or straight or branched C s-alkyl, R 5 and R 6 independently are selected from the group consisting of hydrogen, methyl, methoxy, hydroxy, halogen, and amino.

28. A composition according to claim 25 wherein the compound of Formula I is selected from the group consisting of the following: 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- 20 METHYLPYRIDINE *9* 9 9 99 (the next page is page 57) [R:\LIBVV]02067.doc:SSD EDITORIAL NOTE NO. 11476/97 This specification does not contain a page numbered 56. WO 97/20556 WO 9720556PCTIUS96/19390 -57- 3- (3-PROPOxY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -BUTOXY-1, 2 ,5-THIADIAZOL-4-YL)1,2,5,6-TETTRAJHYDRO-1 METHYLPYRIDINE 3 3 -ISOPROPOXY-1,2,-TIAIAZOL-4YL)1,2,,6-TETR{THYRO-1 METHYLPYRIDINE 3 -(3-CYCLOPROPYLMETHOXY-1,2,5-THIADIAZOL.4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -PENTOXY-1,2,5-THIAIAZOL-4-YL)-1,2,5,6TETAHYDRO-1- METHYLPYRIDINE 3-3IOUOY125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3 3 3 -BUTENOXY)-1,2,5-THIADIAZOL-4-L)-1,256TETRAHYDRO. 1 -METHYLPYRIDINE 3-3(3T2YOY-,,-HAIAO--L-,,,-ERHD0 1 -METHYL PYRIDINE 3 -(3-(3-METHYLtTOXY)-1,2,5-THIADIAZOL4YLy125,6 TETRAHYDRO- 1-METHYL PYRIDINE METHYLPYRIDINE 3 3 -(PROP-2-YNOXY)-1,2,5-THIADIAZOL..4-YL).125,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -BENZYLOXY-1,2,5-THIDIAZOL4YL)1,2,5,6TETR{YDRO-1 METHYLPYRIDINE WO 97/20556 PCTIUS96/19390 -58- 3 3 -CHLORO-1,2,5-THIADIAZOL4YL).1,2,5,6TETRAHDRO-1- METHYLPYRIDINE 3- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) 6 -TETRAHYDROPYRIDINE, 3- (3-BUTOXY-1, 2, 5-THIADIAZOL-4-YL) 6 -TETRAHYDROPYRIDINE 3- (3-ETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- ETHYLPYRIDINE 3 3 -CHLORO-1,2,-THIAZOL-zoL)4-y26TETRHYRO-1 ETHYL PYRIDINE 3- (3-METHOXYETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHjYDRO- 1-METHYLPYRIDINE 3 3 -HEPTYLOXY-,-,2,sATIAZOL-zLy 26TETAYDRO-1 METHYLPYRIDINE 3 3 3 -PENTYNYLOXY)-1,2,5-THIIAZOL4YL)1256- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -PENTENYLOXY)-1,2,5-TIDIAZOL4YL)12,56- TETRXHYDRO- 1-ME-THYLPYRIDINE 3 3 2 -PROPENYLOXY)-1,2,5-THIDIAZOL4.YL)1,256. TETRAHYDRO-MTPYRIDINE 3- (3-OCTYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 3 -HEXYNYLOXY)-1,2,5-THIDIAZOL4.YL)125 6 TETRAHYDRQ- 1-METHYL PYRIDINE 3 3 3 BUTENYL2OXY)1,2,5THIDIAZOL4YL)125 TETRAHYDRO -1 -METHYL -PYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -59- 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 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 3-(3-(5-HEXENYLOXY)--1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO-1 -METHYLPYRIDINE CIS-3-(3-(3-H-EXENYLOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,4,5- TETRAHYDRO- 1-METHYLPYRIDINE TRANS-3- (2-HEXENYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE 3- 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-(4-METHYLPIPERIDINO-1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-MORPHOLINO-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -DIMETHYLAMINO-1,2,5-THIAJJIAZOL-4-YL)-1,2,5,6-TETRAHYDRO- 1 -METHYLPYRIDINE 3 3 -HEXYLAINO-1,2,5-THIAJIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3 -(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETR.HYDRO-1- DEtYTEROMETHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 1,2, 5, 6-TETRAHYDRO-3 -HEXYLOXY-1, 2, 5-THIADIAZOL-4- YL) PYRIDINE 3-(3-(2-(2-METHOXYETHOXY)-ETHOXY)-1,2,5-THIDIAZOL.4-YL) 1,2,5, 6-TETRAIHYDRO-1-METHYLPYRIDINE 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-TETRJIYDRO- 1 -METHYLPYRIDINE 3- (2-BtJTOXYETHOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-BUTOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAJHYDRO-1-METHYLPYRTDTNE 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) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -METHYLTHIO-1,2,5-THIAIAZOL-4-YL)-1,2,5,6-TETRAYDRO.1- METHYLPYRIDINE 3- (3-PENTYL-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 -(3-PROPYLTHIO-1,2,5-THIAJIAZOL-4-YL)-1,2,5,6-TETRAHjYDRO-1- METHYLPYRIDINE 3-3HXLHO125TIDAOL4Y)1256TTRHDO1 METHYLPYRIDINE WO 97/20556 PTU9/99 PCTIUS96/19390 -61- 3-(3-PENTYLTHIO-1,2,5-TIIIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3- (3-ETHYLTHIO-1, 2, 5-TI-IADIAZOL-4-YL) 6-TETRAIIYDRO-1- METHYLPYRIDINE 3- (3-OCTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METH-YLPYRIDINE 3-(3-PROPYL-1,2,5-THIADTAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-HEPTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-(5-HEXENYL)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-OCTYL-1,2,5-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-METHYLPYRIDINEI 3- (3-CYCLOPENTYLTHIO-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- TETRAHYDRO -1 -METHYLPYRIDINE 3- (3-CHLORO-1-PROPYLTHIO) -1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -62- 3- (2-METHOXYETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (3-CYANO-1-PROPYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3- 3 -BENZYLTHIO-1,2,5THIADZO4-L)4- 256TETAYDRO-1 METHYLPYRIDINE 3 3 2 -ETHXY--ETHYLTHIO)1,2,5THIAAZOL4YL).1, 2 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -PENTYLTHIO)-1,2,5-THIDIAZL-4-YL)125, 6 TETRA2HYDRO- 1-METHYLPYRIDINE 3- (2-ETHOXYMETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -(5-CYANO-1-PENTYLTHO)-1,2,-THIDIAZOL4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 3 -PHENYL-1-PROPYLTHIO)1,2,5THIADIAZOL4..YL)12,56 TETRAHYDRO -1 -METHYL PYRIDINE 3 3 2 -PHENOXYETHYLTHIO)-1,2,5-THIAIAZOL4-YL).1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -CYAOBUTYLTHIO)-125TIIAZOL4.YL)1256 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 2 -ETHYLBUTYLTHIO)-1,2,-THIADIAZOL.4..YL)125,6 TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-CYCLOHE-XYLMETHYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6- TETRAHYDRO-1-METI{YLPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -63- 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) 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- (4-PENTENYLTHIO) -1,2,5-THTADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(4-ISOHEXYLOXY-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 1-METHYL-i, 2,5, 6-TETRAHYDRO-3- ((4-CYCLOPENTYLPROPYL)OXY) 1,2, 5-THIADIAZOL-3-YL) PYRIDINE 1-METHYL-1,2,5,6-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 1,2,5,6-TETRA1IYDRa-1-METHYL-3-(4-(l-METHYLHjEXLOXY)-1,2,5- THIADIAZOL-3 -YL) PYRIDINE 3 -(4-(1-ETHYLPENTYLOXY)-1,2,5-THIDIAZOL3-YL)-1,2,5,6- TETRAHYDRO-1-METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/'19390 -64- 3 4 -(l-ETHYLBUTOXY)1,2,5TIIAZOL3YL)1 2 ,5 6 TETRAHYDRO- 1-METHYLPYRIDINE 1,,,-ERHDO1MTY--4(-EHLETLX)125 THIADIAZOL-3-) YL) PYRIDINE 1-METHYLJ-3-(4-(5-HEXENYLOXY) -l,2,5-THIADIAZOL-3YLy.,2 5 6 TETRAHYDROPYRIDINE 1, 2 ,5, 6 -TETRHYDRO-1-METHYL3(4(2METHYLBTOXY)l1 2 THIADIAZOL-3 -YL) PYRIDINE 1, 2 ,5,-TETRAIYDRO-1-METHYL3(4-(2-METHYLPENTYLOXY)l 2 THIADIAZOL-3 -YL) PYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3-(4- 2 ,2,2-TRIFLUOROETHOXY) 1,2,5 -THIADIAZOL-3-YL) PYRIDINE 1-METHYL-i, 2,5, 6-TETRAHYDRO-3- (3-METHYLPENTYLOXY) -1,2,5- THIADIAZOL-3-YL) PYRIDINE 3 3 3 -METHYL-2-BUTENYLOXY)1,2,5THIIAZOL4YL) 2 5 6 TETRAHYDo-1 -METHYLPYRIDINE 3 3 -ISOBUTOXY1,2,5THIDIAZOL4-YL).125,6TETRA{YDRO-1 METHYLPYRIDINE 1, 2 ,5,6-TETRAHYDRO-1METHYL3(4(2ETHYLBUTOXY)..l 2 THIADIAZOL-3 -YL) PYRIDINE 3 3 -(3-HYDROXYPROXYoxy),-,THDIAZOL--L4T). 2 TETRAHYDRO- 1 -ETHYLPYRIDINE 1, 6-DIMETHYL-3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 3- (3-PHENYL-ETHYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYIJPYRIDINE BIS-l, 4 3 -(l-METHYL1,2,5,6TETAHYDROPYRD-3YL)l, 2 THIADIAZOL-4-YL) BUTANEDITHIOL 3 3 4 4 4 TRIFLUOROBJTOXY)-1,2,5-THADIAZOL-4-~YL)l 2 THIADIAZOL-4-yL) 6 -TETRAHYDRO-1-METHYLPYRIDINE 3 3 3 3 3 -TRIFLUOROPROPYLTIO)1,2,5THIADIAZOL-4-YL)- 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -PROPYLTHIO-1,2,5-THIADIAZOL4YL)125,6 TETRAHYDROPYRIDINE 3 3 -BUTYLTHIO-1,2,5THIDIAZL4..YLy125, TETRAHYDROPYRIDINE 3- (3-BUTYLTHIO-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRo-1, 1- DIMETI-YLPYRIDINIUM IODIDE 1, 6-DIMETHYL-3- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE (+-),-DIMETYL-3(3BUTO 125THIDIAZOL.4YL)125,6 TETRAHYDROPYRIDINE 3 3 -(3-METHYL-2-BUTENYLOXY)1,2,THIIAZOL-4YL)12,56 TETRAHYDO -1 -METHYL PYRIDINE 3- (3-ISOBUTOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 1 2 5 6 -TETRAHYDRO-1-METHYL-3-.(4(2..MTHYLBUTOXY)12,5 THIADIAZOL-3-YL) PYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -66- (3-HYDROXYPROPOXY) -l,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAIHYDRO-I1-METHYLPYRIDINE 1, 6-DIMETHYL-3- (3-HEXYLOXY-1,2, 5-THIADIAZOL.-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,56. TETRAHYDRO- 1-METHYLPYRIDINE BIS-1,4-(3-(l-METHYL-1,2,5,6-TETRYDROPYRIDI-3YL)12,5 THIADIAZOL-4 -YL) BUTANEDITHIOL 3- 4-TRIFLUOROBUTJOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO-l1-METHYLPYRIDINE (3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRjHYDR-1- METHYLPYRIDINE 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIAIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3- (3 -BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1, 1- DIMETHYLPYRIDINIUM IODIDE 6-DIMETHYL-3- (3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)- 1,2,5, 6-TETRAHYDROPYRIDINE; and 1, 6-DIiAETHYL-3- (3-BUTOXY-1, 2, 5-THIADIAZOL-4-YL) l, 2 ,5,6-TETRAHYDROPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof. 67

29. A composition of claim 25 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of salicylates, indomethacin, ibuprofern, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.

30. A composition of claim 29 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of aspirin, ibuprofen, and naproxen.

31. A composition of claim 25 wherein the weight ratio of a compound of Formula I to NSAIDS is from about 1 about 100.

32. A composition of claim 30 wherein the non-steroidal anti-inflammatory drug t1 is ibuprofen.

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 method for treating pain comprising administering an analgesic dose of a composition comprising a compound of the Formula I N1X GN\ A wherein X is oxygen or sulphur; A' is hydrogen, halogen, amino, -NHCO-R 2 C3- 7 -cycloalkyl, C 4 .o1-(cycloalkylalkyl), -Z2'-C3-7-cycloalkyl optionally substituted with Ci-6-alkyl, -Z2'-C 4 o-(cycloalkylalkyl), 20 -Z2'-C 4 1 o-(cycloalkenylalkyl), -Z2'-C 4 -10-(methylenecycloalkyl-alkyl), -NH-R 2 -NR2'R 3 -NH-OR 2 phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R 2 -Z2'R 2 -SOR 2 -SO 2 R 2 -Z2'-R2'-Z 3 -Z2'-R2'-Z 3 -R3'-Z4'-R 4 -Z2'-R2'CO-R 3 -Z2-R2'-CO2-R', Z2'-R2'-0 2 C-R 3 -Z 2 -R 2 '-CONH-R 3 -Z2'-R2'-NHCOR3', Z2'-R2'-X, wherein Z 2 Z 3 and Z 4 independently are oxygen or sulphur, and R 2 R 3 and R 4 independently are straight or branched Cl-ls-alkyl, straight or branched C 2 1 5 -alkenyl, straight or branched C2- 1 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR2'R 3 Ci-6-alkyl 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 C 1 -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 [R:\LIBVV]02067.doc:SSD #,1 S 5*555 S SSS S* S 68 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 fused with a phenyl group; and G is N R wherein R and R" may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C l_-alkyl, straight or branched C2-5-alkenyl, straight or branched C 2 -5-alkynyl, straight or branched Ci-_o-alkoxy, straight or branched Ci-5-alkyl substituted with -OH, halogen, -NH 2 or carboxy; R" is hydrogen, straight or branched Ci-s-alkyl, straight or branched n C2-5-alkenyl or straight or branched C2-5-alkynyl; 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. A method of claim 34 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of salicylates, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.

36. A method of claim 34 wherein the non-sterodial anti-inflammatory drug is selected from the group consisting of ibuprofen, and naproxen.

37. A method of claim 35 wherein the composition is administered using a 20 transdermal formulation.

38. A composition for treating pain comprising an analgesic dose of a Compound j of Formula I X SN' S.G A or A' wherein 25 X is oxygen or sulphur; [R\LIBVV02067docSSD .[R:\LIBVV]02067.doc:SSD 69 A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR4, -SOR 4 -S0 2 R 4 C 3 7-cycloalkyl, C 4 -8-(cycloalkylalkyl), -Z-C 3 7 -cycloalkyl, and -Z-C 4 -8-(cycloalkylalkyl) wherein R 4 is straight or branched CI.is-alkyl, straight or branched C2- 15 -alkenyl, straight or branched C2-15-alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C-1 4 -alkyl, Ci-4-alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci-4-alkyl, Cl-4-alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is -OR 5 Y, -SR Y, -OR ZY, -SR ZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z is oxygen or sulphur, R 5 is to straight or branched C 1 1 5 -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 C1. ,-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. R' R 2 n R 2 C or R 2 Cq CIn.\ r N N N R wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R 1 and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Cl_5-alkyl, straight or branched C2- 5 -alkenyl, straight or branched 20 C2-5-alkynyl, straight or branched Ci-lo-alkoxy, straight or branched C1-5-alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3 is H, straight or branched straight or branched C2-5-alkenyl or straight or branched C 2 -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; **4 or R N 6'' S. [R:\LIBVV]02067.doc:SSD wherein A is hydrogen, halogen, amino, -NHCO-R C3-7-cycloalkyl, C4- 1 -(cycloalkylalkyl), -Z 2 '-C 3 7 -cyeloalkyl optionally substituted with C 1 6 -alkyl, -Z 2 -C 44 o-(cycloalkylalkyl), -Z 2 '-C4p-o-(cycloalkenylalkyl), C 4 o-(methylenecycloalkyl-alkyl), -NH-R 2 -NR -NH-OR phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R -Z 2 'R 2 -SOR', -S0 2 R, -Z 2 2 Y, -Z 2 '-R 2 '_Z 3 3 4-1 Z 2 -R 2 CO-R 3 -Z 2 -R 2 -C0 2 Z 2 R 2 ,-O 2 C-R 3, _Z2 2-C ONH-R", -Z 2 2 -NHCOR 3,-Z 2 2 -Z 2 -R 2 -_Z 3 wherein Z 2 1, and Z 4 independently are oxygen or sulphur, and R 2 R 3 and R 4'independently are straight or branched C 1 15 -alkyl, straight or branched C2.is-alkenyl, straight or branched each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR TR 3 C;- 6 -alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, C 1 4 -alkyl or [R:\L[BVV]02067.doc:SSD 71 C-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 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 fused with a phenyl group; and R' and R 6 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C, 5 alkyl, straight or branched C2-5-alkenyl, straight or branched C 2 -5-alkynyl, straight or branched Cl-lo-alkoxy, straight or branched Cl 1 5 -alkyl substituted with -OH, halogen, io -NH2 or carboxy; R'is hydrogen, straight or branched Ci-.-alkyl, straight or branched C2- 5 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 38 wherein A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -SO2R 4 C 3 7 cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3- 7 -cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R 4 is straight or branched CI.i5-alkyl, straight or branched C2-15-alkenyl, straight or branched C2_i-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, C(i 4 -alkyl, Cl 4 -alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, C1- 4 -alkyl, Cl.4-alkoxy, -OCF 3 -CONH 2 or A is -OR 5 Y, -SR Y, -OR 5 ZY, -SRZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z is oxygen or sulphur, R 5 is straight or branched CI.s-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 5 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 RI R R2 C N N 13 NR 2 Cn 3 lwherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the s0 azabicyclic ring; R' and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Cls- 5 alkyl, straight or branched C2-5-alkenyl, straight or branched C25-alkynyl, straight or I\DAYLIB\iibvv\1658.docdoc 72 branched Cl-io-alkoxy, straight or branched C 1 .s-alkyl substituted with -OH, OR 4 halogen, NH 2 or carboxy; R 3 is H, straight or branched Cl. 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. A composition of Claim 39 wherein X is S, G is R2 R C N wherein n is 1, p is 1 or 2 and m is 1 or 2, R' and R 2 independently are hydrogen, methyl, hydroxy. halogen or amino; or a pharmaceutically acceptable salt or solvate thereof. 0* 00* 0* 0 I.\DAYLIB\libvv\1658 docdoc WO 97/20556 WO 9720556PCT/US96/19390 -73-

41. A composition of Claim 39 wherein X is s, G is Ri 2 Cm wherein n is 1, p is 1 or 2 and m is 1 or 2.

42. A composition according to Claim 39 wherein the compound of Formula I is selected from the group consisting of the following: 3-CHLORO-3- (3-CHLORO-l, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO [2.2.21 OCTANE; 3- (3-CHLORO-l, 2, 5-THIADIAZOL-4-YL) -3-HYDROXY-1- AZABICYCLO[2.2.2]OCTANE; 3-METHOXY-3- (3-METHOXY-l,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[2 .2.2]OCTANE; 3-(3-METHOXY-1,2,5-THIADIAZOL-4-YL) -l-AZABICYCLO[2.2.2IIOCT-2- ENE; 3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO[2 .2 .2]OCT- 2- ENE; 3-HEXYLOXY-3- (3-HEXYLOXY-l, 2, 5-THIADIAZOL-4-YI -1-AZABICYCLO- t2.2.21OCTANE; 3- (3-HEXYLOXY-1,2, 5-THIADIAZOL-4-YL) -3-HYDROXY-1- AZABICYCLO[2.2.2]OCTANE; 3-(3-CHLORO-1,2,5-THIADIAZOL-4-YL)-l-AZABICYCLO[2.2.2]OCTANE; 3- (3-ETHOXY-1, 2, 5-THIADIAZOL-4-YL) -1-AZABICYCLO OCTANE; WO 97/20556 WO 9720556PCT/US96/19390 -74- 3- (3-PROPOXY-1, 2, 5-TIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3 3 -BUTOXY.-l,2,5-THIADIAZOL-4-YL)l-1.AZABICYCLO[222]OCTANE; 3- (3-PENTYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1-AZABICyCLO- [2 .2 .2]OCTANE; 3 3 ETHOXY-,2,5THIADIAZOL-4.-YL)-1-AZABICYCLO[222]OCTANE; 3 -(3-HEXYLTHIO-1,2,5-THTADIAZOL-4-YL)-1- AZABICYCLO 2]OCTANE; 3 3 3 -PHENYLPROPYLTHIO-1,25THIDIAZOL4YL)1l AZABICYCLO OCTANE; 3- (3-HEXYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3- (4-CYANOBENZYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO 2]OCTANE; EXO-E- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3.2.1]OCTANE; ENDO-6- (3-CHLORO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; ENDO-6-(3-HEXYLTHIO-1,2,5THIDIAZOL4YL)1l AZABICYCLO[3 1]OCTANE; ENDO-6-(3- 5 -HEXENYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1. AZABICYCLO[3 lIOCTANE; ENDO-6- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3 lIOCTANE; ENDO-6-(- -PENTfYLTHIO- 1,2,5-THIADIAZOL-4-YL)- 1- AZABICYCLO[3.2.1IJOCTANE; ENDO-6-(-3-ETHYLTHIO-1 ,2,5-THIADIAZOL-4-YL)-l AZABICYCLO[3 .2.1 IJOCTANE; and 5ENDO-6-(3 -PHEN YLPROPYLTHIO)- 1,2,5 -THIADIAZOL-4-YL)- 1- AZABICYCLO[3.2.l ]OCTANE; or a pharmaceutically acceptable salt or solvate thereof.

43. A composition of claim 42 wherein the Compound of Formula I is B UTYLTH1O- 1,2,5 -THIADIAZOL-4-YL)- 1 -AZABICYCLO OCTANE; or a pharmaceutically acceptable salt or solvate thereof.

44. A composition of claim 43 wherein the weight ratio is from about 1 to about A composition of claim 38 wherein A is hydrogen, halogen, amino, -NHCO-R 2" C 3 7 -cycloalkyl, C 41 -(cycloalkyl alkyl), -Z2 -C 3 7 -cycloalkyl optionally substituted with C 1 6 -alkyl, _Z 2 '-C 4 1 0o(cycloalkylalkyl) _Z2' -C4-1 o-(cycloalkenylalk-yl), 2 2' 2' 3' 2' -Z -C4,c0-(mcthylenecycloalkyl-alkyl), -NH-R -NR R -NH-OR phenyl, phenoxy, benzoy], benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R -Z2'R 2 -SOR 2, -S0 2 R", -Z-'R2-Z 3 -R 3 -z _R2-Z3 4 Z2 -R 2CO-R -Z2 -R"-C0 2 Z2 -R2 -0 2 C-R,3 -Z 2 '-R 2 -CONH-R, 3- Z 2 '-R 2 '-NHCOR 3 _Z 2 -R 2 _Z 2 2 -Z 3 wherein Z2' Z 3 and Z 4 independently are oxygen or sulphur, and R 2 R 3 and R 4 independently are straight or 20 braniched C.I-s-alkyl, straight or branched C 2 -1 5 -alkenyl, straight or branched C 2 .js-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH-, -NH-R 2 -NR TR", Ci- 6 -alkyl ester, one or two phenyl, phenoxy, benzoyl. or beuzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, CI- 4 -alkyl or C 1 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 C 1 6-alkyl, phenyl, benzyl or pyridine, or a carbon atom in the heterocyclic group together withi an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group; and G is '>'[R:\L-IBVV]02067.doc:SSD R 5 N R wherein R and R 6 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C _s-alkyl, straight or branched C2-5-alkenyl, straight or branched C2.s-alkynyl, straight or S branched Cc-io-alkoxy, straight or branched Cl-s-alkyl substituted with -OH, halogen, -NH2 or carboxy; R' is hydrogen, straight or branched Ci-s-alkyl, straight or branched C2-_-alkenyl or straight or branched or a pharmaceutically acceptable salt or solvate thereof.

46. A composition of claim 45 wherein X is sulphur. t1 47. A composition of claim 45 wherein X is sulphur, R' is hydrogen or straight or branched Ci- 5 -alkyl, R and R 6 independently are selected from the group consisting of hydrogen, methyl, methoxy, hydroxy, halogen, and amino.

48. A composition according to claim 45 wherein the compound of Formula I is selected from the group consisting of the following: f 'ivo O S o WO 97/20556 WO 9720556PCT/US96,1 9390 -76- 3- (3-METHiOXY-1, 2, 5-THiIADIAZOL-4-YL) 6-TETRAHYDRO..>. METHYLPYRIDINE 3- (3 -ETHOXY-1, 2, 5-THiIADIAZOL-4-YL) 6-TETRAHYDRO1- METHYLPYRIDINE 3- (3-PROPOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3-3BTX-,,-HAIZL--L1256TTRHDO1 METHYLPYRIDINE 3-3IORPX -,,-HAIZO L -,,,-ERHDO1 METHYLPYRIDINE 3- 3 -CYCLOPROPYLMETHOXY12,5-THIADIAZOL-4-yL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -PENTOXY-1,2,5-THIAIAZOL-4YL) -l,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE METHYLPYRIDINE 3 3 3 -BUTEOXY)1,2,-THIADIAZOL4YL)12,5,6TETRAHDRO- 1-METHYLPYRIDINE 3- (3-METHYLB3UTOXY) 5-TH-IADIAZL4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDIE WO 97/20556 WO 9720556PCTIUS96/1 9390 -77- 3-(3-(PRQP-2-YNOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAIIYDRO -1 -METHYLPYRIDINE 3- (3-BENZYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1. METHYLPYRIDINE 3 3 -CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAjHYDRO 1 METHYLPYRIDINE 3- (3-CHLORO-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDROPYRTDINE 3- (3-BU'TOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDROPYRIDINE 3- (3 -ETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- ETHYLPYRIDINE 3 3 -CHLORO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETPJAHYDRO-1-. ETHYLPYRIDINE 3- (3-METHOXYETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYLPYRIDINE 3 3 -HEPTYLOXY-1,2,5-THIAIAZOL-4-YL)1,2,5,6TETAHYDR-1- METHYLPYRIDINE 3 3 -(3-PENTYNYLOXY)-1,2,5-THIAIAZOL-4-YL).1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3-(3-(4-PENTENYLOXY)-1,2,5- HIDIAZ 4YL),5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3 3 2 -PROPENYLOXY)-1,2,5-THIDIAZOL4..YL)12,56- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -OCTYLOXY-1,2,5-THIIAZOL-YL)1,256TETAHDRO-1- METHYLPYRIDINE WO 97/20556 PCT/US96/19390 -78- 3- (3-HEXYNYLOXy) 5-THIADIAZOL-4-YL) 5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(3-BUTENYL2OXY)1,2,-THIDIAZOL4YL)1 2 5 6 TETRAHYDRO -1-METHYL -PYRIDINE 3 3 4 -HEXENYLOXY1,2,5THIIAZOL4YL)l 2 ,5,6 TETRAHYDRO- 1-METHYLPYRIDINE TRANS- 3 3 (3HENLXEY)oxy1,2THDIA 4 YL) 2 5 6 TETRAHYDRO- 1-METHYL PYRIDINE CIS- 3 3 2 -PENTENYLOX)1,2,THIADIAZO-4YL) 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 3 2 -HEXENYL x)1,2,5THIIAZOL-4YL)l, 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- (5-HEXENYLOXY) -l, 2 ,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE CI--3(-EEYOY-,,-HAIZL4Y)1245 TETRAHYDRO- 1-METHYLPYRIDINE TRAS- 3 3 (2HEXYLOXY)125THIDIAZOL 4 YL)1 2 ,5,6 TETRAHYDRo-1 -METHYLPYRIDINE 3- 5-THIADIAZOL-4-YL) 6 -TETRAHYDRO-1-METHYLPYRIDINE 3 3 4 -METHYLPIPERIDINO..1,2,5THAIADIZOL.4YL) 2 ,5,6 TETRAHYDRO-1 -METHYLPYRIDINE 3 3 -MORPHOLINo1,2,-THIDIAZOL4.YL).1,2,56TETRAHYDRO-1 METHYLPYRIDINE 3- (3 -DIMETHYLAMINO-1, 2, 5-THIADIAZOL-4-YL) 6-TETEAHYDRO- 1 -METHYL PYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -79- 3- (3-HEXYLAMINO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3-(3-HEXYLOXY-1,2,5-THIAIAZOL-4-YL)-1,2,5,6.TETRAHYDRo-.1- DEtITEROMETHYLPYRIDINE 1,2,5, 6-TETRAHYDRO-3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4- YL) PYRIDINE 3- (2-METHOXYETHOXY) -ETHOXY) -1,2,5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 (3-ETHOXY-1-PROPXY) 2,5-THIADIAZOL-4-YL) 2,5,6, TETRAHYDRO -1 -METHYLPYRIDINE 3-(2-ETHOXYETHQXY) -1,2,5-THIADIAZQL-4-YL) -1,2,5,6-TETRAHYDRO- 1 -METHYL PYRIDINE 3 -(3-(2-BUTOXYETHOXY)-1,2,5-THIADJIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-BUTOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 112,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (2-ETHOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -BUTYLTHIO-1,2, -THAIZOLAZQL41256 ETAYDRO-l METHYLPYRIDINE 3- (3-METHYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -PENTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRJHYDRO-1- METHYLPYRIDINE. WO 97/20556 WO 9720556PCTIUS96/19390 3-(3-PROPYLTHIO-1,2,5-THTADIAZOL-4-YL)-1,2,5, 6-TETRAHiYDRO-1- METH-YLPYRIDINE 3-3HXLHO125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3-3PNYTI-,,-HAIZO--L-,,,-ERHDO1 METHYLPYRIDINE 3-(3EHLH 125THAIZL4Y)12,,-ERHDO1 METHYLPYRIDINE 3 3 OCTYLTHIo-1, ,s-THAIZOL-zoL41256TETRAYDRo-1 METHYLPYRIDINE 3 3 -PROPYL-1,2,5-THIADIAZOL-4-YL).1,2,5, 6-TETRAHYDRO-1- METHYLPYRIDINE 3- C 3 -HEPTYL-1,2,5-THIADIZO-L--126TETRAHYDRo-1 METHYLPYRIDINE 3 3 -(5-HEXENL)-1,2,5-THIDIAZL-4-YL)1,2,5,6TETRAHYDRO-1 METHYLPYRIDINE 3 3 -OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6TETAHYDRO-1 METHYPYRIDINE 3 3 2 -MTHYL-BUTYL-1,2,5-THIDIAZOL-4YL)-1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3 3 -METHYLCYCLOPROPYL-1,2, -THAIIA 4YL)1256- TETRAHYDRO- 1-METHYL PYRIDINE 3 3 -CYCLOPENTYLTHIO-1,2,5-TIDIAZOL-4YL)1,2,5,6. TETRAHYDRO- 1-METHYLPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -81- 3 -(3-(1-ETHYLTHIO-2-METHOXY)-1,2,5-THIADIAZOL-4-YL)1,2S 6 TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(3-CHLORO-1-PROPYLTHIO)-1,2,5-THIADIAZcL-4-YL)1,2 5 6 TETRAIHYDRO- 1-METHYLPYRIDINE 3- (2-METHOXYETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -(3-CYAO-1-PROPYLTHIO)-1,2,5-THIDIAZOL-4YL)12,56- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3BNYTI-,,-HAIZL--L-,,,-ERHDO1 METHYLPYRIDINE 3 3 2 -ETHOXY-1-ETHYLTHIO)-1,2,s-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (4-PENTYNYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE 3- (2-ETHOXYMETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -(5-CYANO-1-PENTYLTHIO)-1,2,5-THIAIAZL-4-YL).,2,5,6. TETRAHYDRO -1 -METHYLPYRIDINE 3 3 3 -PHENYL-1-PROPYLTHO)-1,2,-THIIAZOL4YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- 2 -PHENOXYETHYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDROMTPYRIDINE 3- (4-CYANOBUTYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYIJPYRIDINE WO 97/20556 WO 9720556PCT/US96/I 9390 -82- 3 3 -(2-ETHYLBUTYLTHIO)-1,2,5-TIAIIAZ4-YL)125, TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-CYCLOHEXYLMETHYLTHIO-1, 2, 5-THIADTAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(8-HYDROXYOCTYLTHIO-1,2,5-THIDIAZOL-4-YL)1l, 2 ,5, 6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(7-OCTENYLTHO)-1,2,5-THIDIAZOL4YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-CYCLOPROPYLMETHYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -CYCLOPROPYM2ETHYLTHIO)-1,2,5-THIAIAZOL.4-YL).1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(3-BUTENYLTHO-1,2,-THIDIAZOL4-YL)-1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3 3 4 -PENTENYLTHIO)-1,2,5-TIADIAZOL4YL)1256 TETRAHYDRO- 1-METHYLPYRIDINE 3 4 -ISOHEXYLOXY-1,2,5-THIDIAZL3YL)12,5,6TETRAHYDRO-1- METHYLPYRIDINEI 1-METHYL-i, 2,5, 6-TETRAHYDRO-3- ((4-CYCLOPENTYLPROPYL) OXY) 1,2, 5-THIADIAZOL-3-YL) PYRIDINE 1-METHYL-1,2,5, 6-TETRAHYDRO-3 -(4-ISOHEPTYLOXY-1,2,5- THIADIAZQL-3 -YL) PYRIDINE 1-METHYL-1,2,5, 6-TETRAHYDRO-3- (4 ((2-CYCLOHEXYLETHYL)OXY) 1,2,5 -THIADIAZOL-3 -YL) PYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -83- 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)-l1,2,5, 6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(4-(1-ETHYLBUTOXY)-1,2,5-THIAIAZOL-3-YL)-1,2,5,6. TETRAHYDRO- 1-METHYL PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(-METHYLPENTYLOXY)-12,5 THIADIAZOL-3 YL) PYRIDINE 1-METHYL-3-(4-(5-HEXENYLQXY)-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- THIADIAZOL-3 -YL) PYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYLr.-3-(4-(2-METHYLPETYLOXY)-1,2,5- THIADIAZOL-3-YL) PYRIDINE 1, 2 ,5,6-TETRAIIYDRO-1-METHYL-3-(4-(2,2,2-TRIFLUOROETHOXY)- 1,2, 5-THIADIAZOL-3-YL) PYRIDINE l-METHYL-1,2,5,6-TETRAHYDRO-3-(4-(3-METHYLPEN'rYLOXY)-1,2,5- THIADIAZOL-3 -YL) PYRIDINE 3 3 -(3-METHYL-2-BUTENYILOXY)-1,2,5-THIAJJIAZOL-4-YL)-l,2,5,6- TETRAHYDO-1-METHYLPYRIDINE 3 3 -ISOBUTOXY-1,2,5-THIAIAZOL-4-YL)-1,2,5,6-TETRjHYDRO-1- MIETHYLPYRIDINE l,2,5,6-TETRAYDRO-1-METHYL-3-(4-(2-ETHYLBUTyOXYyl2,.. THIADIAZOL-3-YL) PYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -84- 3 3 3 -HYDROXYPROPOXY)-1,2,5THIDIAZOL4-YL)-1,2,5 6 TETRAHYDRO -1 -METHYLPYRIDINE 1, 6-DIMETHYL-3- (3-HEXYLOXY-1,2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE 3 3 -(3-PHENL-ETHYLTHIO)-1,2,-THIIAZOL4yL)1,2,5 6 TETRAHYDRO- 1-METHYLPYRIDINE BIS-l, 4 -(3-(l-METHYL-1,2,5,6-TETAHYDROPYRIDIN3TY.l 2 THIADIAZOL- 4-YL) BUTANEDITHIOL 3- 4-TRIFLtJQROBUTOXY) 5-THIADIAZOL-4-YL) -1,2,5- THIADIAZOL-4-YL) -1,2,51 6-TETRAHYDRO-1-METHYLPYRIDINE 3- 3-TRIFLUQROPROPYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 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- TETRAHYDROPYRIDINE .3,(-UYTI-,,-HAIZO--L-,,,-ERHDO11 DIMETHYLPYRIDINIJM IODIDE 1, 6-DIMETHYL-3- (3-BUTYLTHIO-1,2, 5-THIADIAZOL-4-YL) 1,2, 5,6 -TETRAHYDROPYRIDINE (+-)1,6-DIMETHYL--3-(BTXY 125THIADIAZOL4L)125,6 TETRAHYDROPYRIDINE 3 3 3 -METHYL-2-BTENYLOXY)-,2,-THIADIAZOL-4YL)-1,25... TETRAHYDO-1-METHYL PYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 3- (3-ISOBUTOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAIHYDRO-1- METHYLPYRIDINE 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1,2,5 THIADIAZOL-3-YL) PYRIDINE 3- (3-HYDROXYPROPOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE (+-)1,6-DIMETHYL-3-(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL) 1,2, 5,6 -TETRAIIYDROPYRIDINE 3-(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 3-(3-(4,4,4-TRTFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METI-YLPYRIDINE 3- 3-TRIFLuOROPROPYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHJYDRO-1- METHYLPYRIDINE 3- (3-PROPYLTHIO-1, 2, 5-THIADIAZOL-4-YL) TETRAHYDROPYRIDINE 3-(3-BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3- (3-BUTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1, 1- DIMETHYLPYRIDINIJM IODIDE 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)-1,2,5,6- TETRAHYDROPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof.

49. A composition of claim 45 wherein the weight ratio of a compound of Formula I to acetaminophen is from about 1 to about 100. A method for treating pain comprising administering an analgesic dose of a composition comprising a Compound of Formula I or a pharmaceutically acceptable salt or solvate thereof; and acetaminophen in a weight ratio of Compound to acetaminophen 0o of from about 1 to about 1000.

51. A method of claim 50 wherein A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -S0 2 R 4 C 3 -7-cycloalkyl, C4- 8 -(cycloalkylalkyl), -Z-C 3 7 -cycloalkyl, and -Z-C 4 -8-(cycloalkylalkyl) wherein R 4 is straight or branched C 1 i 1 5 -alkyl, straight or branched C 2 -1 5 -alkenyl, straight or branched C2-15-alkynyl, each of 1i which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Ci- 4 -alkyl, CI-4-alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci-4-alkyl, Ci- 4 -alkoxy, -OCF 3 -CONH 2 or A is -OR Y, -SRSY, -ORsZY, -SRSZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z is oxygen or sulphur, R 5 is straight or branched Ci-.s-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 i SR' R II Cn R 2 or R 2 C Cp or R-Cq Swherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R' and R 2 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 C 2 -5-alkenyl, straight or branched [R:\IIBVV]02067,doc:SSD 86a C 2 -5-alkynyl, straight or branched CI 0 lo-alkoxy, straight or branched Ci.5-alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3 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, I 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.

52. A method of claim 51 wherein the weight ratio of a compound of Formula I to acetaminophen is from about 1 to about 100.

53. A method of claim 51 wherein the composition is administered using a transdermal formulation.

54. A method 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. A method of claim 50 wherein A' is hydrogen, halogen, amino, -NHCO-R 2 C3. 7 -cycloalkyl, C4-10-(cycloalkylalkyl), -Z2'-C37-cycloalkyl optionally substituted with C i--alkyl, -Z2'-C4 -(cycloalkylalkyl), -Z2'-C4 o-(cycloalkenylalkyl), -C4-1-(methylenecycloalkyl-alkyl), -NH-R 2 -NR 2 R 3 -NH-OR 2 phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R 2 -ZR 2 -SOR 2 -S0 2 R 2 -Z 2 -R-Z -Z 2 '-R 2 '-Z 3 -R -Z 4 '-R 4 -Z 2 '-R 2 'CO-R 3 -Z2'R2'_CO 2 -R 3 Z 2 '-R 2 '-0 2 C-R 3 -Z2'-R2'-CONH-R 3 -Z2'-R2'-NHCOR 3 -Z 2 -Z 2 '-R2'-Z 3 wherein S 20 Z 2 Z 3 and Z 4 independently are oxygen or sulphur, and R 2 R 3 and R 4 independently are straight or branched C 15 ls-alkyl, straight or branched C2-15-alkenyl, straight or branched C2- 1 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR2R 3 C .6alkyl ester, one or two phenyl, phenoxy, bbenzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, Cl- 4 -alkyl or 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 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 30 heterocyclic group is optionally fused with a phenyl group; and G is [R:\I,IBVV]02067.doc:SD 86b wherein R- and R 6 may be present at any position, including the point of attachmeto the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1 >5-alkyl, straight or branched C 2 5 -alkenyl, straight or branched C2- 5 -alkynyl, straight or branched CI-jo-alkoxy, straight or branched CI-5-alkyl substituted with -OH, halogen, or cai-boxy; R' is hydrogen, straight or branched C 1 5 -alkyl, straight or branched 5--alkenyl or straight or branched or a pharmaceutically acceptable salt or solvate thereof. rR\* 9V ]26.dc S WO 97/20556 WO 9720556PCT/US96/19390 -87-

56. A method of Claim 55 wherein the compound is selected from the group consisting of 3- (3-METHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3-( 3 -ETHOXY-1,2,5-THIADIAZOL-4-L)-1,2,5,6TETRAHYDROl.- METHYLPYRIDINE 3 3 -PROPOXY-l,2,5-THIAIAZOL-4-YL)-1,2,5,6TETAHYDRO-1 METHYLPYRIDINE 3 3 -BUTOXY-l,2,5-THIADIAZOL-4-YL)l,2,5,6-TETTRAYDRO.1- METHYLPYRIDINE 3-3IORPX-,,-HAIZO--L-,,,-ERHDO1 METHYLPYRIDINE 3- (3-CYCLQPRQPYLMETHOXY-1,2, 5-THIADIAZQL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYL PYRIDINE 3- (3-PENTOXY-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -ISOBUTOXY-1,2,5-THIDIAZOL4-YL)-125TE TRAHDRO.. 1- METHYLPYRIDINE 3 3 3 -BtTENOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO. 1 -METHYLPYRIDINE 3- (BUT-2-YNOXY) 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYL PYRIDINE 3- (3-METHYLBUTOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAIYDRO-1-METHYLPYRIDINE WO 97/20556 PCT/US96/1 9390 -88- 3-3HXLX-,,-HAIZL--L-,,,-ERHDO1 METHYLPYRIDINE 3- (PROP-2-YNOXY) 5-THIADIAZOL-4-YL) TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-BENZYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO.1- METHYLPYRIDINE 3- 3 -CHLORO-1,2,5-THIADIAZOL4YL) -l, 2 ,5,6-TETRAH{YDRO-1- METHYLPYRIDINE 3- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) 6 -TETRAHYDROPYRIDINE 3- (3-BUTOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDROPYRIDINE 3- (3-ETHOXY-1, 2, 5-THIADIAZOL-4-yL) 6-TETRAiHYDRO-1- ETHYLPYRIDINE 3 3 -CHLORO-1,2,5-THIADIO 4YL)1256-TETRAHYDRO-1 ETHYLPYRIDINE 3- (3-METHOXYETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAF{YDRO- 1 -METHYL PYRIDINE 3-3HPYOY125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3- (3-PENrYNYLOXY) 5-TIHIADIAZOL-4-YL) -172',5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(4-PENTENYIOXY)-1,2,-THIDIAZOL4-YL).. 2 5,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(2-PROPENYLOXY)-1,2,-THDIAZOL-4YL)1 2 TETRAHYDRO- 1-METHYLPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -89- 3 3 -OCTYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TTRAYDRQ.. 1 METHYLPYRIDINE 3- (3-HEXYWYLOXY) 5-THIADIAZOL-4-YL) 2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(3-BTENL-2-OXY)-1,2,5-THIIAZOL4YL)1,2,5,6 TETRAHYDRO- 1-METHYL-PYRIDINE 3-(3-(4-HEXENYLOXY(-1,2,5-THIDIAZOL-4-YL)-1,2,5, 6 TETRAHYDRO- 1-METHYLPYRIDINE TRANS-3-(3-(3-HEXENYLOXY)1,2,5H HIDIAZ 4YL)12,5 6 TETRAHYDRO- 1-METHYL PYRIDINE CIS-3-(3-(2-PENTENYLOXY)-1,2,5-THIADIA4YL)1256 TETRAHYDRO-1 -METHYLPYRIDINE CIS-3- (2-HEXENYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE 3 -(3-(5-HEXENYLOXY)-1,2,5-THIDIAZOL-4YL)1,25,6 TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 -(3-(3-HEXENYLOXY)-1,2,5THIIAZOL4YL)1,2,45 TETRAHYDRO- 1-METHYLPYRIDINE TRN--3(-iXNLX)12,-HAIZL4Y)1256 TETRAHYDRO-1-METHYLPYRIDINE 3- 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (4-METHYLPIPERIDINO-1, 2, 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- 3 -MOR HOLINo-1,2,-TADIAZo-4-YL)12s6TETRAIYDRo-1 METHYLPYRIDINE WO 97/20556 PCTIUS96/19390 3- 3 -DIMETHYLAMINO-1,2,5-THTIDIAZOL4YL) 6-TETRAHYDRO- 1 -METHYLPYRIDINE 3 3 -HEXYLAMINo1, THIIAZOL-4YL)12,5, 6 TETRAHYDO1 METHYLPYRIDINE 3 3 -HEXYLOXY-12THIDIAZOL4YL)125, 6 TETRAHYDO1 DEUTEROMETHYLPYRIDINE 1,2,5, 6-TETRAHYDRO-3- (3-HEXYLOXy-1, 2, 5-THIADIAZOL-4- YL) PYRIDINE 3- (2-METHOXYETHOXY) -ETHOXY) S-THIADIAZOL-4-YL) 112,5, 6-TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-ETHOXY-1-PROPOXY) 5-THIADIAZOL-4-YL) TETRAHYDRO- 1-METHYLPYRIDINE 3 2 ETHOXYETHOXY) -l, 2 ,5-THIADIAZOL-4-YL) -l, 2 ,5,6-TETRAHYDRO- 1 -METH-YLPYRIDINE 3 3 -(2-BUTOXYETHOXY)1,2,THIDIAZOL4.YL)1 2 5,6 TETRAHYDRO- l-METHYLPYRIDINE 3- (2-BUTOXYETHQXY) -ETHOXY) S-TI{IADIAZOL-4YL) 1,2,5, 6 -TETRAHYDRO1-METHYLJPYRIDINE 3 (3 (2 2 -ETHOXYETHOXY) -ETEOXY) 1,2, 5-THIADIAZOL-4 -YL) 1,2,5, 6 TETRAlYDRO-1-METH{YLPYRIDINE 3 3 BUTYLTHIO1,25THIADIAZOL..4YL)1,256-TETRAHYDRO-1 METHYLPYRIDINE 3-3MTYTI-,,-HAIZO--L-,,,-ERHDO1 METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -91- 3- (3-PENTYL-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3- (3-PROPYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3-3HXLHO125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3 3 -PENTYLTHIO-1,2,5-THIAIAZOL-4-YL)1,2,5,6TETAYDRO-1- METHYLPYRIDINE 3- (3-ETHYLTHIO-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3-3OTLHO125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3- (3-PROPYL-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3- (3-HEPTYL-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -(5-HEXENL)-1,2,5-THIDIAZOL-4-YL)1,2,5,6TETAHYDRO-1 METHYLPYRIDINE 3 3 -OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6TETRAHYDRO-1 METHYPYRIDINE 3- (2-METHYL) -BUTYL-1,2, 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYL PYRIDINE 3- (3-METHYLCYCLOPROPYL-1, 2, 5-THIADIAZOL-4-YL) 6- TETRAHYDRO-1-METHYLPYRIDINE WO 97/20556 PCT/UJS96/19390 -92- 3- (3-CYCLOPENTYLrHIo-1, 2, 5-TH-IADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3 3 -(l-ETHYLTHIO-2-METHO 125THIDIAZOL4YL)... 2 SE TETRAHYDRO- 1-METHYLPYRIDINE 3 3 3 -CHLORO-1-PLHOPYLTH2o2THIIAZOL4YL)l 2 ,5 6 TETRAHYDRO-1 -METHYLPYRIDINE 3-(3-(2-METHOXYETHOXY) -ETHYLTHIO)-1,2,5-THIDIAZOL4-YL) 1,2,5, G-TETRAHYDRO-1-METHYLPYRIDINE 3 3 3 -CYNo-1-PROPYLTHIO),,-,2,sTI)IAzo-4-YL)1 2 s5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- (3-BENZYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 2 -ETHOXY--ETHYLTHIO)-1,2,THIIAZOL-4YL)1 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -PEN rYLTHIO)-1,2,5THIIAZOL-4YL)1256 TETRAHYDRO- 1-METHYLPYRIDINE 3 2 (-ToYE~x).TLHo12s.TID~o~L 1,2,5, E-TETRAHYDRO-1-METHYLPYRIDINE 3- (5-CYANo-1-PETYrLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 3- 3 -PHENYL-1-PROPYLTHIO) -l,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(2-PHENOXYETHYLTHIO)-,-THTIIAZ4-YL)1 2 S 6 TETRAHYDRO-.1.METHYLPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -93- 3-(3-(4-CYANOBUTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(2-ETHYLBTrYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE 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- 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) 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-1,2,5-THIADIAZOL-3-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 1-METHYL-1,2,5, 6-TETRAHYDRO-3- ((4-CYCLOPENTYLPROPYL)OXY) 1,2, 5-THIADIAZOL-3-YL) PYRIDINE 1-METHYL-1,2,5,6-TETRAHYDRO-3-(4-ISOHEPTYLOXY-1,2,5- THIADIAZOL-3-YL) PYRIDINE WO 97/20556 WO 9720556PCTIUS96I1 9390 -94- 1-METHYL-i, 2,5, 6-TETRAHYDRO-3-(4 ((2-CYCLOHEXYLETHYL)QXY) 1,2, 5-THIADIAzOL-3-YL) PYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (1-METHYIJHEXLOXY) -1,2,5- THIADIAZOL-3-YL) PYRIDINE 3-(4-(1-ETHYLPENTYLOXY)-1,2,5-THIDIAZOL-3YL)1,2S 6 TETRAHjYDRO -1 -METHYLPYRIDINE 3 -(4-(l-ETHYLBUTOXY)-1,2,5-THIDIAZOL3-YL)-1,25 6 TETRAHYDRO -1 -METHYLPYRIDINE 1, 2 ,5,6-TETRHYDRO-1-METHYL-3-(4-(-METHYLPEYLOXY)12,5 THIADIAZOL-3 YL) PYRIDINE 1-METHYL-3-(4-(5-HEXENYLOXY)-1, ,5THI IIAZ3YL)125 TETRAHYDROPYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (2-METHYLBUTOXY) -1,2,5- THIADIAZOL-3-YL) PYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (2-METHYLPENTYLOXY) -1,2,5- THIADIAZOL-3 -YL) PYRIDINE 1, 2 ,5,6-TETRAHYDRO-1-METHYL-3-(4- (2,2,2-TRIFLTJOROETHOXY)- 1,2, 5-THIADIAZOL-3-YL) PYRIDINE l-METHYL-,2,5,6-TETRAHYDRO-3(4(3METHYLPENTYLOXY)12, THIADIAZOL-3 -YL) PYRIDINE 3 3 3 -METHYL-2-BUENYLOXY)-1,2,5THIIAZOL4YL)12,5,6 TETRAHYDO -1 -METHYLPYRIDINE 3 3 -ISOBUTOXY-1,2,-THIDIAZOL4YL)-1,2,6TETRAHYDRO1- METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96119390 1,2,5,6-TETRAHYDRO-1-METHYL-3-(4-(2-METHYLBUTOXY)-1,2,5- THIADIAZOL-3 -YL) PYRIDINE 3- (3-HYDROXYPROPOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO -1-METHYL PYRIDINE 1, 6-DIMETHYL-3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETHYLTHIO)-1,2,5-THIAIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE BIS-1,4- (1-METHYL-1,2, 5, 6-TETRAIHYDROPYRIDIN-3-YL) -1,2,5- THIADIAZOL-4-YL) BtTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5- THIADIAZOL-4-YL) 6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-(3,3,3-TRIFLUOROPROPYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2,5, 6-TETRAHiYDRO-1-METHYLPYRIDINE 3-(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3-(3-BUTYLTHIn-1,2,5-TIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE 3 3 -BUTYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRJ{YDRO-1,1- DIMETHYLPYRIDINIUM IODIDE 1, 6-DIMETHYL-3- (3-BUTYLTHIO-1, 2,5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE (+-)1,6-DIMETHYL-3-(3-BTOXY-1,2,5-THIDIAZOL-4-YL).1,2,5,6- TETRAHYDROPYRIDINE WO 97/20556 PCT/US96/19390 -96- 3- (3-METHYL-2-BJTENJYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDO -1 -METHYL PYRIDINE 3-3IOUOY125TIDAO--L-,,,-ER~DO1 METH-YLPYRIDINE 1,2,5, 6 -TETRAHYDRO-1METHYL3-(4- (2-METHYLBJTOXY) -1,2,5- THIADIAZOL-3 -YL) PYRIDINE 3 3 3 -HYDROXYPROPOXY)1,2,-TIIAZOL 4 YL)l, 2 5,6 TETRAHYDRO -1 -METHYLPYRIDINE 1, 6-DIMETHYL-3- (3-FEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) 1,2,5, 6 -TETRAHYDROPYRIDINE 3 3 3 -PHENYL-ETHYLTHT12,5.THIADIAZO-L) 1 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE BIS-1, 4- (1-METHyL-1,2,5, G-TETRAHYDROPYRIDIN-3-YL) -1,2,5- THIADIAZOL-4-YL) BUTANEDITHIOL 3-3(,,-RFURBTX)1,,-HAIZL4Y)1256 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 3 -TRIFLUOROPROPYLTHIO) -1, 2 ,5-THIADIAZOL-4-YL)- 1,2,5, 6 -TETRAHYDRO-1-METHYLPYRIDINE 3- (3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL) 2,5, 6-TETRAHYDRO-1- METHYLPYRIDINE 3- (3 -PROPYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6- TETRAHYDROPYRIDINE 3 3 -BUTYLTHIO1,25THIADIAZOL.4.YL)l, 2 S 6 TETRAHYDROPYRIDINE 97 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; and (-)1,6-DIMETHYL-3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROPYRIDINE; or a pharmaceutically acceptable salt thereof.

57. A composition for treating pain comprising a Compound of Formula I 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.

58. A composition of claim 57 wherein A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -S0 2 R 4 C3-7-cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C 4 -8-(cycloalkylalkyl) wherein R 4 is straight or branched Cil--alkyl, straight or branched C 2 15 -alkenyl, straight or branched C 2 -1 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C 1 4 -alkyl, C -4-alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Cl_ 4 -alkyl, C.-4-alkoxy, -OCF 3 -CONH2; or A is -OR 5 Y, -SR'Y, -OR'ZY, -SR 5 ZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z 20 is oxygen or sulphur, R 5 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-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 RI R R2_ Cn R P or R 2 Cq N N Cn N, m N 13 R wherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R' and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight o3 or branched Ci-_-alkyl, straight or branched C2-5-alkenyl, straight or branched [R:\LIBVV]02067.doc:SSD 97a Cx)-,-alkynyl, straight or branched CI-io-alkoxy, straight or branched CI-5-alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3is H, straight or branched C 1 5 -alkyl, straight or branched C 2 5 -alkenyl or straight or branched C2-5-alkynyl; n is 0, 1 or 2; m is 0, 1or 2 pis0, 1or 2; qislIor 2;and- -is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

59. A composition according to claim 58 wherein the compound of Formula I is selected from the group consisting of the following: 3 CHL ORO-3 -CHL ORO- 1 ,2,5 -THIADIAZOL.-4- YL). AZABICYCLO [2.2.2]OCTANE; I)3 -CHLORO- 1 ,2,5-THIADIAZOL-4-YL)-3 -HYDROXY- I1- AZABICYCLO[2.2.2]OCIAN3; 3 -METHOXY-' METHOXY ,2,5-THIADIAZOL-4YL)- I AZAB ICYCLO [2.2.21OCTANE; 3 )-METHOXY-1I,2,5-THIADIAZOL-4-YL> I -AZABICYCLO[2.2.2]OCT-2-ENE; 3 -HEXYLOXY-1I 2,5-THJADIAZOL-4-YL) 1-AZABICYCLO [2.2 .2]OCT-2-ENE; S. 5 S S 4 .5 6 S S See. S SOt S *OS* S S 4*4S S. S S. S S 5* C, 0* S S. O *g p 0 5*00~@ p S <0 [R:\IIBVV]02067.doc:SSD WO 97/20556 WO 9720556PCTIUS96/19390 -98- 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- AZABICYCLO[2.2.2]OCTANE; 3-( 3 -CHIORO-, 2 5-THIADIAZOL4YL)1-AZABICYCLO[22.2]ocTANE; 3- 3 -ETHOXY--, 2 5-THIADIAZOL4YL)1-AZABICYCLO[2221OCTANE; 3- 3 -PROPOXY-1,2,5-THIDIAZOL4YL) -1- AZABICYCLO [2.2 .2]1OCTANE; 3-( 3 -BUTOXY-l,2,5-THIADIAZOL-4-YL)..1.AZABICYCLo[22.2OCTANE; 3- (3-PENTYLTHIO-1, 2, 5-THIADIAZOJ-4-YL) -1-AZABICYCLO- [2.2 OCTANE; 3- 3 -ETHOXY-l,2,5-THIADIAZOL4YL).1..AZABICYCLO[2.22]OCTANE; 3- (3-HEXYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3- (3-PHENYLPROPYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO[2.2.2]OCTANE; 3- 3 -HEXYLTHIO-1,2,5-THIADIAZOL-4-YL)-l1 AZABICyCLO 2]OCTANE; 3 3 4 -CYANOBENZYLTHIO).1,25.THIDIAZOL4YL)1l AZABICYCLO OCTANE; Exo-6- 3 -CHLORO-1,2,5-THIADIAZOL4YL).1. AZABICYCLO [3 OCTANE; ENDO-6- (3-CHLORO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 99 ENDO-6-(3 )-HEXYLTHIO- 1,2,5-TIHIADIAZOL-4-YL)- 1- AZABICYCLO[3.2.1 ]OCTANE; ENDO-6-(3 -HEXENYLTH1O)- 1,2,5 -THIAD1AZOL-4-YL)- 1- AZABICYCLO[3 .2.1I ]OCTANE; 5ENDO-6-(- -BUTYLTHIO- 1,2,5-THIADIAZOL-4-YL)- 1- AZABICYCLO[3 .2.1 ]OCTANE; ENDO-6-(3 )-PENTYLTHIO- 1,2,5-TFHIADIAZOL-4-YL,)- I1- AZABICYCLO [3.2.1 ]OCTANE; 1!NDO-6-(3 -ETHYLTHIO- 1,2,5-THJADIAZOL-4-YL) 0 AZABICYCLO 1 ]OCTANE; and ENDO-6-(3-(3 -PHENYL PROPYLTHIO)- 1,2,5-THIADIAZOL-4-YL)- 1- AZABICYCLO[3 .2.1I ]OCTANE; or a pharmaceutically acceptable salt or solvate thereof. A composition of claim 59 wherein the Compound of Formula I is 3-(3- UTYLTHIO- 1,2,5 -THIADIAZOL-4-YL)- I -AZABICYCLO [2.2 OCTANE; or a pharmaceutically acceptable salt thereof.

61. A composition of claim 58 wherein the weight ratio of Compound to central aipha-adrenergic active compound is from about 1 to about

62. A composition of claim 61 wherein the aipha-adrenergic compound is 2-(2,6- dichlorophenylamino)-2-imidazoline.

63. A composition of claim 57 wherein A Iis hydrogen, halogen, amino, -NHCO-R", C 3 7 -cycloalkyl, C 4 1 -(cycloalkylalkyl), _Z 2 '-C 3 7 -cycloalkyl optionally substituted with C 1 6 -alkyl, _Z2' -C 4 1 0o(cycloalkylalkyl), _Z 21 C 41 Io-(cycloalkenylalkyl), 2_2' N 2 3 2' C4jo(-(methylenecycloalkyl-alkyl), -NH-R 2 -NH-OR phenyl, phenoxy, 25 benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, XY, R 2, _z 2R2, -SOR 2 -S0 2 R 2 -Z 2 2 '-Z 3 '-R 3 _Z 2 2 -_Z 3 -YZT-R 4 -Z 2 2 CO-R 3 _Z 2 -R 2 -C0 2 Z2 -R -0 2 C-R, 3z -Z'R -CONH-R, 3z _2-R 2'-NHCOR 3 -Z 2 '-R 2 -Z 2 -_R 2 '-Z 3 wherein z 2 Z 3 and Z 4 independently are oxygen or sulphur, and R 2 R 3 'and R4' independently are straight or branched C 1 15 -alkyl, straight or branched C 2 15 -alkenyl, straight or branched C 2 15 -alkynyl, each of which is optionally substituted with halogen(s), -OH, 2' 2' 3' -CN, -CF 3 -SH, -COGH, -NH-R -NR R C 1 6 alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, C 1 4 -alkyl or C 1 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, .000.* 0 I r [R:\IIBVV]02067.doc:SSD 100 which heterocyclic group is optionally substituted 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 fused with a phenyl group; and G is N R wherein R 5 and R 6 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched straight or branched C2- 5 -alkenyl, straight or branched C-1 5 -alkynyl, straight or branched CI-io-alkoxy, straight or branched C 1 -5-alkyl substituted with -OH, halogen, I -NH 2 or carboxy; R' is hydrogen, straight or branched Ci>_5-alkyl, straight or branched C2s-alkenyl or straight or branched or a pharmaceutically acceptable salt or solvate thereof.

64. A composition of claim 63 wherein the Compound of Formula I is selected from the group consisting of (--METHOXY- 1,2,5 -TH1IADIAZOL-4-YL> 1,2,5 ,6-TETRAHYDRO- 1- METHYLPYRIDINE 3 -(3)-ETHOXY- 1,2,5-THIADIAZOL-4-YL) 1 ,2,5,6-TETRAHIYDRO. 1- METI YLPYRIDINE 3 (3)-PROPOXY- 1,2,5-THIADIAZOL-4-YL> 1,2,5 ,6-TETRAHYDRO- I- METHYLPYRIDINE 3-3-BUTOXY- 1 ,2,5 -THIADIAZOL-4-YL) I ,2,5 ,6-TETRAHYDRO- I1- METHYLPYRIDINE 3 -ISOPROPOXY- 1,2,5 -THIADIAZOL-4-YL> I ,2,5,6-TETRAHYDRO I METHYLP YRIDINE -(--CYCLOPROPYLMETHOXY1,2,5THIADJAZOI-4YL).l, 2 ,5 6 aaa: TLTRAHYDRO- 1-METE JYLPYRIDINE 3 -PENTOXY-1I,2,5-THIADJAZOL-4-YL).1,2,5 ,6-TETRAHYDRO- 1- METHYLPYRIDINE 3 -ISOBUTOXY- 1,2,5-THJADIAZOL-4YL> 1,2,5 ,6-TETRAHYDRO- 1- METHYLPYRIDINE [R:\LIBVV]02067.doc:SSD I 00a 3 -BUTENOXY)- 1,2,5-THIADJAZOL-4-YL) 1,2,5 ,6-TETRAHIYDRO- 1- METHYLP YRIDINE 3 -(BUT-2-YNOXY)- 1,2,5-THIADIAZOL-4-YL)- 1,2,5,6-TETRAHYDRO- 1- METHYLPYRIDINE 3 )-METHYLBUTOXY)-1I,2,5-THIADIAZOL-4-YL)- 1,2,5 ,6-TETRAHYDRO- 1- METHYLPYRIDINE [R:\LIBVV]02067.doc:SSD WO 97/20556 WO 9720556PCTIUS96/19390 -101- 3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDPo--1- METHYLPYRTDINE 3 3 -(PROP-2-YNOXY)-1,2,5-TIAIADIZOLL4YL)125, TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -BENZYLOXY-1,2,5-THIADIAZOL4YL)1,2,6TETAYDRO-l METHYLPYRIDINE 3 3 -CHLORO-1, 2 ,5-THIADIAZOL-4-YL)-1,2,5,6TETRAHYDRO-1- METHYLPYRIDINE 3- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAIHYDROPYRIDINE 3- (3-BUTOXY-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDROPYRIDINE 3- (3-ETHOXY-1, 2, 5-THIADIAZOL-4-YL) -1,2,51 6-TETRAHYDRO-1- ETHYLPYRIDINE 3 3 -CHLORO-l,2,5-THIADIAZOL-4-YL)-1,2,56TETRAHYDRO1 ETHYL PYRIDINE 3- (3-METHOXYETHOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYLPYRIDINE 3 3 -HEPTYLOXY-1,2,5 THAIZOZO-YL)1256TETRAHYDRO-1 METHYLPYRIDINE 3 3 -(3-PENTYNYLOXY)-1,2,5-THIIAZOL4YL)1,'25,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -PETENYLoxy)-1,2,-THIIAZOL4YL)12,5,6 TETRAI{YDRO- 1-METHYLPYRIDINE 3 3 2 -PROPENYLOXY)-1,2,5-THIIAZOL4YL)1,256- TETRAHYDRO- 1-METHYLPYRIDINE WO 97/20556 PCTIUS96/1 9390 -102- 3-3OTLX-,,-HAIZL--L-,,,-ERHDO1 METHYLPYRIDINE 3 3 3 -HXYLOXY)1,2,5THIADIAZOL4YL)1 2 5 6 TETRAHYDRO -1 -METHYLPYRIDINE 3- (3-BTJTENYL-2-OXY) -1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRo-1 -METHYL-PYRIDINE 3 3 4 -HEXENYLOXY(1,2,5THI IAZOL4YL)1 2 6 TETRAHYDRO- 1-METHYLPYRIDINE TRANS-3- (3-HEXENYLOXY) -1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 3 2 PENTELOXy-1,25THIADIAZOL-4YL) 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 3 2 HEXENYLOXY)-125THIDIAZOL4YL)1 2 5 6 TETRAIHYDRO- 1-METHYLPYRIDINE 3- (5-HEXENYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 3 3 HEXENOY)oxy2,THIIAZOL4YL)1 2 4 TETRAHYDRo-1 -METHYLPYRIDINE TRANS- 3 3 (2HEXENYLoxy)112,5THIDIAZOL 4 YL)1 2 ,5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- 5-THIADIAZQL-4-YL) 6 -TETRAHYDRO-1-METHYLPYRIDINE 3 3 4 -METHLPIPERIDINO1,2,5THIADIAZOL4YL)1 2 SG6 TETRAIHYDRO -1 -METHYLPYRIDINE 3- (3-MORPIHQLINO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRA-HYDRQ-1- METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -103- 3- (3-DIMETHYLAMINO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1-METHYL PYRIDINE 3 3 -HEXYLAMINO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6TETRAHYDRO-1- METHYLPYRIDINE 3 -(3-HEXYLOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETpRjjYDRO 1 DEUTEROMETHYLPYRIDINE 1,2,5,6-TETRAIYDRO-3- (3-HEXYLOXY-1,2,5-THIADIAZOL-4- YL) PYRIDINE 3- (2-METHOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 -ETHOXY-1 -PROPOXY) 2, 5-THIAIAZOL-4 -yL) 2, 5, 6, TETRAHYDRO- 1-METHYLPYRIDINE 3 2 -ETHOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)1,25TETETRAYDRO. 1 -METHjYLPYRIDINE 3 -(3-(2-BUTOXYETHOXY)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-BUTOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 (3 (2 (2 -ETHOXYETHOXY) -ETHOXY) 1, 2, 5 -THIADJiZOL-4 -YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 -(3-BUTYLTHIO-1,2,5-THIDIAZOL-4-YL)-1,2,56TETAHDRO-1 METHYLPYRIDINE 3 3 -METHYLTHIO-1,2,5-THIDIAZL4YL)-1,2,5,6-TETRAYDRO-1- METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -104- 3 3 -PENTYL-,2,-THIADIO zo-YL)1256TETRAHYDRO- METHYLPYRIDINE 3 3 -PROPYLTHIO-1,2,5-THIArAZOL-4.YL) -l, 2 ,5,6-.TETRAHYDRO-1- METHYLPYRIDINE 3-(3HXLH 125THAIZL4Y)12,,-ERHDO1 METHYLPYRIDINE 3 3 -PENTYLTHIo-1,2,TH HATAzoL4YL)1256TETRYDRO-1 METHYLPYRIDINE 3-3EHLHO125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3 3 -OCTYLTHIO-1,2,5-THIADIAZOL4YL) -1,2,5,6-TETRAH1YDRO-1- METHYLPYRIDINE 3- (3-PROPYL-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -HEPTYL-1,2,5-THIADIOz-YL)1256TETRAHYDRO-1 METHYLPYRIDINE 3 3 -(5-HEXENYL)-1,2,-THIIAZOL4YL)125,6TETRAHYDROl1 METHYLPYRIDINE 3- (3-OCTYL-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYPYRIDINE 3- (2-METHYL) -BTJTYL-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- TETRAHYDRO1-METHYLPYRIDINE WO 97/20556 WO 9720556PCT/US96/19390 -105- 3- (3 -CYCLOPENTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(l-ETHYLTHIO-2-METHOXY)-1,2,-THIADIAZOL-4-YL)-1256 TETRAHYDRO -1 -METHYL PYRIDINE 3- (3-CHLORO-1-PROPYLTHIO) -1,2,5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-METHOXYETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-YL) 1,2, 5,6 -TETRAHYDRO-l1-METHYLPYRIDINE 3 -(3-(3-CYANO-1-PROPYLTHIO)-1,2,5-THIADIAZQL-4-YL)-1,2,5,6- TETRAHYDRO -1 -METHYL PYRIDINE 3-(3-BENZYLTHIO-1,2,5-THIjjIAZOL-4-YL)-1,2,5,-TETRAHJYDRO..1- METHYLPYRIDINE 3 -(3-(2-ETHOXY-1-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRTDINE 3-(3-(4-PENTYNYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETR.AHYDRO- 1-METHYLPYRIDINE 3 3 2 2 -ETHOXYMETHOXY)-ETHYLTHIO)-1,2,5-THIADIAZOL-4-YL)- 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINEI 3 3 -(S-CYAO-1-PENTYLTHIO)-1,2,5-THIDIAZOL-4YL)-1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(3-PHENYL-1-PPOPYLTHIO)-1,2,5-THIuAIAZOL-4-YL)-1,2,5,6- TETRAHYDROMEHYPYRIDINE 3- (2-PHENOXYETHYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE WO 97/20556 PCT/US96/19390 -106- 3 3 -(4-CYAOBUTY TH125THIADIAZOL4YL)l 2 5 6 TETRAHYDRO -1 -METHYLPYRIDINE 3 3 2 -ETHYLBUTYLTHIO)125THIAJIAZOL4YL)-1 2 ,56 TETRAHYDRO- 1-METHYLPYRIDINE 3- (3 -CYCLOHEXYLMETHYLTHIO.1,2,5 -THIADIAZOL-4 -YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINSE 3 3 -(8-HYDROXYOCTYLTHI)1,2,5THIIAZOL 4 YL)1 2 SG6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 7 -OCTENYLTHIO)-1,2,THIIAZOL-4YL)1 2 5,6 TETRAIHYDRO- 1-METHYLPYRIDINE 3- 3 -CYCLOPROPYLMETHYLTHIO-1,2, 5-TH-IADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE 3 3 -CYCLOPROPYLMETHYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO-1 -METHYLPYRIDINE 3- (3-BUTENYLTHIO) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAIHYDRO- 1-METHYLPYRIDINE 3 3 -(4-PENTENYLTHIO125THIIAZOL4YL)1 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- 4 -ISOHEXYLOXY-,2THIIAZOL-3YL)12 6 TETRAHYl- METHYLPYRIDINE 1-METHYL-1,2, 5, 6-TETRAHYDRO-3- 4 -CYCLOPENTYLPROPYL)OXY) 1,2, S-THIADIAZOL.3-YL) PYRIDINE l-METHYL1,2,,6TETRAHRO-3(4-ISOHEPTYLOXY1 2 THIADIAZQL-3-YL) PYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -107- 1-METHYL-1,2, 5, 6-TETRAHYDRO-3- (4 ((2-CYCLOHEXYLETHYL)OXY) 1,2, 5-THiIADIAZQL-.3-yL) PYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (1-METHYLHEXLOXY) THIADIAZOL-3-YL) PYRIDINE 3- (1-ETHYLPENTYJOXY) 5-THIADIAZOL-3-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRTDINE 3 4 -(l-ETHYLBUTO 1,2,5THIIAZOL3YL)12,5 6 TETRAHYDRO- 1-METHYLPYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (1-METHYLPENTYLOXY) -1,2,5- THIADIAZOL-3 YL) PYRIDINE l-METHYL-3-(4-(5-HEXENYLOXY)12THIDIAZOL-3.YL)l, 2 5,6 TETRAIHYDROPYRIDINE 1,2,5, 6-TETRAHYDR0-1-METHYL-3- (2-METHYLBUTOXY) -1,2,5- THIADIAZOL-3 -YL) PYRIDINE 1,2,5, 6-TETRAHYDRO-1-METHYL-3- (2-METHYLPENTYLOXY) -1,2,5- THIADIAZOL-3 -YL) PYRIDINE 1, 2 ,5, 6 -TETRYDRO-1-METHYL-.3(4(2,2,2TRIFLUOROETHOXY)- 1,2, 5-THIADIAZOL-3-YL) PYRIDINE l-METHYL-1,2,5,6TE HYDR3(4(3ETHYLPNYLOXY)l1 2 THIADIAZOL-3 -YL) PYRIDINE 3- (3-METHYL-2-BUTENYLOXY) 5-THIADIAZOL-4-L) -1,2,5,6- TETRAHYDO -1 -METHYLPYRIDINE 3- 3 -ISOBUTOXY-1,2,5-THIAIAZOL4YL)..12,5,6-TETRAHYDRO-1 METHYLPYRIDINE WO 97/20556 WO 9720556PCTIUS96/19390 -108- 1, 2 ,5,6-TETRHYDRO-1-METYL3(4(2METHYLBUTOXY)l 2 THIADIAZOL-3 -YL) PYRIDINE 3- (3-HYDROXYPROPOXY) 5-THIADIAZCL-4-YL) -1,2,5,6- TETRAHYDRO -1 -METHYLPYRIDINE 6 -DIMETHYL-3-(3-HEXYLOXY1,2,.THIADIAZL.4.YL)- 1,2,5, 6-TETRAHYDROPYRIDINE 3 3 3 -PHENYL-ETHYLTHI),,2,5THIDIAZ 4YL) 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE BIS-1, 4 3 -(lMETHYL1,26TETAHYDROPYRIDIN3YL)± 2 THIADIAZOL-4-YL) BUTANEDITHIOL 3 3 4 4 ,4-TRFLUROBUTOXY)-1,2,5-THIIAZOL4YL)l 2 THIADIAZOL-4-YL) 6-TETRAHYDRO-1-METHYLPYRIDINE 3- 3 3 3 -TRIFLtJOROPROPYLTHIO)-1,2,5-THIADIAZOL.4-YL) 1,2,5, 6 -TETRAHYDRO-1-METHYLPYRIDINE 3 3 -PROPYLTHIO-1,2,5-THI IAZO4YL)125,6 TETRAHYDROPYRIDINE 3 3 -BUTYLTHI-1,2,5-THIIAZOL4YL)125 TETRAHYDROPYRIDINE 3 3 -BUTYLTHIo1, THIIAZO4YL)125,6TETRAHYDRO-1,l DIMETHYLPYRIDINIUM IODIDE (+-)l6-DIETHYL-3(3BUTYLTHIo125THIDIAZOL4-Y) 1,2,5, 6-TETRAHYDROPYRIDINE 6 -DIMETHYL--3-(BUTOXY-12s..TH IAZ-4YL)1 2 5,6 TETRAHYDROPYRIDINE WO 97/20556 PTU9/99 PCTfUS96/19390 -109- 3- (3-METHYL-2-BUTENYLOXY) 5-THIADIAZOL-4-YL) 2,5,6- TETRAHYDO- 1-METHYL PYRIDINE 3-(3-ISOBUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TFTRAHYDRO-1- METH-YLPYRIDINE 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- TETRAHYDRO- 1-METHYLPYRIDINE 1, 6-DIMETHYL-3- (3-HEXYLOXY-1,2, 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDROPYRIDINE 3-(3-(3-PHENYL-ETH{YLTHIo-1,2,5--THIADIAZOL-4-YL)-1,2,5,6- TETPAHYDRO-I1-METHYLPYR IDINE BIS-1,4-(3-(1-METHYL-1,2,5,6-TETRAHYDROPYRIDIN-3-YL)-1,2,5- THIADIAZQL-4-YL) BUTANEDITHIOL 3-(3-(4,4,4-TRIFLUOROBUTOXY)-1,2,5-THIADIAZL-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-1-METHYLPYRIDINE 3-(3-PROPYLTHIo-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1- METHYLPYRIDINE 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- TETRAHYDROPYRIDINE 110 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; and (+-)1,6-DIMETHYL-3-(3-BUTOXY-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAIYDROPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof. A method for treating pain comprising administering to a patient in need thereof, a composition comprising a Compound of Formula I or a pharmaceutically acceptable salt or solvate thereof; and a central alpha-adrenergic active compound in a to weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 1000.

66. A method of claim 65 wherein A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -S0 2 R 4 C 3 7 -cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3-7-cycloalkyl, and -Z-C 4 -8-(cycloalkylalkyl) wherein R 4 is straight or branched Cl-i5-alkyl, straight or branched C 2 15 -alkenyl, straight or branched C215-alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C 1 4 -alkyl, C 1 -4-alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci- 4 -alkyl, Ci- 4 -alkoxy, -OCF 3 -CONH2; or A is -OR 5 Y, -SRSY, -OR ZY, -SRsZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z o o is oxygen or sulphur, R' 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- 6 -alkyl, phenyl or benzyl, or which heterocyclic group is 25 optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings I R R o wherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R 1 and R 2 may be present at any position, including the point of 30 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 S[R:\LIBVV]02067.doc:SSD 111 C 2 5 -alkynyl, straight or branched ClIlo-alkoxy, straight or branched ClIs-alkyl substituted with -OH, OR 4 halogen, -NH 2 or carboxy; R 3 is H, straight or branched C 1 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 I or 2; and is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.

67. A method 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 method of claim 65 wherein A is hydrogen, halogen, amino, -NHCO-R 2 Ii C3- 7 -cycloalkyl, C4-1o-(cycloalkylalkyl), -Z2' -C3- 7 -cycloalkyl optionally substituted with CI. 6 -alkyl, -Z 2 -C 4 1 o-(cycloalkylalkyl), -Z 2 -C4- 1 I 0-(cycloalkenylalkyl), -Z2'_4 o-1-(methylenecycloalkyl-alkyl), -NR 2 -N phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R -Z2'R2', -SOR2 -SO2R2', 2 -R Z4'-R, TC4 -Z22'_R TC-R 3" _Z2 -CO2-R", Is Z 2 R 2 2 C-R'2 3 -Z 2 -R2'-CONH-R -Z 2 '-R 2 '-NHCOR -Z 2 -R 2 -Z 2 -R2'-Z 3 wherein and Z 4 independently are oxygen or sulphur, and R and R 4 independently are straight or branched C 1 15 s-alkyl, straight or branched C2-15j-alkenyl, straight or branched C2- 1 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 -SH, -COOH, -NH-R 2 -NR 2 Cl- 6 alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substitued with one or two halogen, -CN, C 14 -alkyl or C 14 -alkoxy, and X is a 5 or 6 membered heterocyclic group containing one to four N, O, or S atomr(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with S 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 fused with a phenyl group; and G is 6'' R N R l wherein R 5 and R" may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched [R:\LIBVV]02067.doc:SSD Illa C 1 alkyl, straight or branched C25-alkenyl, straight or branched C2-5-alkynyl, straight or branched Ci-lo-alkoxy, straight or branched C -s-alkyl substituted with -OH, halogen, -NH 2 or carboxy; R' is hydrogen, straight or branched C-5-alkyl, straight or branched C2- or straight or branched or a pharmaceutically acceptable salt or solvate thereof.

69. A composition for treating pain comprising an analgesic dose of a Compound of Formula I 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. 1i

70. A composition of claim 69 wherein A is hydrogen, amino, halogen, -CHO, -NO 2 -OR 4 -SR 4 -SOR 4 -S0 2 R 4 C3-7-cycloalkyl, C4-8-(cycloalkylalkyl), -Z-C3- 7 cycloalkyl, and -Z-C4-8-(cycloalkylalkyl) wherein R 4 is straight or branched Cli- 5 -alkyl, straight or branched C2-1s-alkenyl, straight or branched C 2 -1 5 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy wherein I phenyl or phenoxy is optionally substituted with halogen, -CN, CI4-alkyl, C1-4-alkoxy, -OCF 3 -CONH2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Ci- 4 -alkyl, C 1 4 -alkoxy, -OCF 3 -CONH 2 or A is -OR'Y, -SRsY, -ORZY, -SRsZY, -O-R 4 -Z-R 5 or -S-R 4 -Z-R 5 wherein Z is oxygen or sulphur, R' is straight or branched Ci-i 5 -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 Cli.-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 R R *R R 2_ Cn q R Cp or R2_ Cq N N R 2- wherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R' and R 2 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 C24 5 -alkenyl, straight or branched straight or branched Ci-lo-alkoxy, straight or branched Ci.5-alkyl substituted with -01I, OR 4 halogen, -NH 2 or carboxy; R 3 is H, straight or branched C 1 [R:\LIBVV]02067.doc:SSD 0^ y Ilib straight or branched C2- 5 -alkenyl or straight or branched C2-5-alkynyl; n is 0, 1 or 2; m is 0, 1or 2 pis0,lor 2 qis Ior 2;and is asingle or double bond; or a pharmaceutically acceptable salt or solvate thereof

71. A composition of claim 70 wherein the compound of Formula I is selected f-rm the group consisting of the following: 3-CHLORO-3-(3 -CHLORO- 1,2,5-THIADIAZOL4-Ly I AZABICYCLO [2.2.2]OCTANE; 3-(3-CJ-ILORO- 1,2,5-THIADIAZOL4YL-3-HYDROXY-1- AZABICYCLO [2.2.2]JOCTANE; 3 0 -METHOXY-3 -METHOXY- 1 ,2,5-THIADIAZOL-4YL.. I AZABICYCLG[2.22]OCTANE; 3 -METHOXY- 1,2,5 -THJADIAZOL-4-YL> 1 -AZABICYCLO[2.2 OCT-2-ENE; 3-(3-HEXYLOXY- 1,2,5-THIADJAZOL-4-YL)-1 AZABJCYCLO[2.2.2OCT2ENE; 3 -FEXYLOXY3(3 HEXYLOXY1,2,5THIADIAZOL4YL)- I -AZABICYCLO- [2.2.21OCTANE; 3 3 -HEXYLOXY 1,2,5TIADAZOL4YL)3 HYDROXY-I AZABICYCLOt[2.22] OCTANE; 3 -CHLORO- I ,2,5-THIADIAZOL-4-YL)- 1 -AZABICYCLO [2.2.2]OCTANE; 3 -ETHOXY- 1 ,2,5 -THIADIAZOL-4YL)- 1 AZABJCYCLO [2.2.21IOCTANE; 3 -PROPOXY- 1 ,2,5 -THIADIAZOL-4YL)- I -AZABICYCLO [2 OCTANE; 3 -BUTOXY- 1 ,2,5 -THIADIAZOL-4-YL)- 1 -AZABICYCLO [2.2.2]JOCTANE; [R\LBV. 67dc:S AN 00a WO 97/20556 PCT/US96/1 9390 -112- 3- (3-PENTYLTHIO-1,2,5-THIADiIAZOL-4-YL) -1-AZABICYCLO- 2. 2. 2] ORTANE; 3 3 -ETHOXY-1,2,5THIDIAZOL4-YL)lAZABICYCLO[2.22]OCTANE, 3- (3-HEXYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3- (3-PHENYLPROPYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; 3- (3-HEXYLTHIO-1, 2, 5-THIADIAZOL-4-L) -1- AZABICYCLO OCTANE; (4-CYANOBENZYLTHIO) -1,2,5-THIADIAZOL-4-YL) -1- AZABICYCLO 2]OCTANE; EXO-6-(3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3 lIOCTANE; ENDO-6-(3-CLORO-1,2,5-THIADIAZOL4YL)-l- AZABICYCLO [3 OCTANE; ENDo-6- (3-HEXYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO[3.2.1]OCTN; ENDO-6- (5-HEXENYLTHIO) 5-THIADIAZOL-4-YL) -1- AZABICYCLO OCTANE; ENDO-6-( 3 -BUTTHIo12THIDIAZOL4-YL)1 AZABICYCLO [3 OCTANE; ENDO-6- 3 -PENTYLTHIO-1,2,5-THIADIAZOL.4-YL) -1- AZABICYCLO[3 .2.1]OCTANE; ENDO-6- (3-ETHYLTHIo-1, 2, 5-THIADIAZOL-4-YL) -1- AZABICYCL, 3 OCTANE; and SUBSTITUTE SHEET (RULE 26) 113 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 method of claim 71 wherein the Compound is S3-(3-BUJTYLTHIO- 1,2,5-THIADIAZOL-4-YL)- I -AZABICYCLO [2.2.2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof.

74. A composition of claim 69 wherein A is hydrogen, halogen, amino, -NHCO-R 2, C3- 7 -cycloalkyl, C 4 -10o-(cycloalkylalkyl), -Z2' -C 3 7 -cycloalkyl optionally substituted with Ci- 6 -alkyl, -Z 2 '-C 4 1 o-(cycloalkylalkyl), -Z2'C4-1 o-(cycloalkenylalkyl), to -Z2' C4-1o-(methylenecycloalkyl-alkyl), -NH-R2', -NR2'R -NH-OR', phenyl, phenoxy, bcnzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R2', -Z 2 'R 2 -SOR 2 SO 2 R 2 -Z 2 -R 2 -Z -Z 2 -R-Z Z-R -Z 4 '-R 4 -Z 2 '-R 2 CO-R 3 -Z 2 -R 2 '-CO 2 -R, 2' 3' 2' 2' 3 3' 2'2'3''4 Z2'-R2'-O 2 C-R -Z2'-R2'-CONH-R -Z 2 '-R2'-NHCOR -Z 2 2 wherein Z, and Z 4 independently are oxygen or sulphur, and R2', R and R4' independently is are straight or branched CI-is-alkyl, straight or branched C2- 1 5 -alkenyl, straight or branched C2- 1 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, 2' 2' 3 -CN, -CF 3 -SH, -COOH, -NH-R2', -NR2'R 3 C 1 -6alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, C 14 -alkyl or 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 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 fused with a phenyl group; and G is =N R wherein R and R" may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1 5-alkyl, straight or branched C2-5-alkenyl, straight or branched C 2 -5-alkynyl, straight or branched CI-lo-alkoxy, straight or branched C 1 5 -alkyl substituted with -OH, halogen, [rR:\LIBVV]02067.doc:SSD 113a -NI- 2 or carboxy; R' is hydrogen, straight or branched C 1 5 -alkyl, straight or branched C 2 5 -alkenyl or straight or branched C 2 5 -alkynyl; or a pharmaceutically acceptable salt or solvate thereof. A composition of claim 74 wherein the Compound of Formula I is selected IFron- the group consisting of 3 -METHJOXY- 1,2,5 -THIADIAZOL-4-YL)- 1,2,5 ,6-TETRAHYDRO- 1- METHYLPYRIDINE 3 -ETHOXY- 1,2,5-THIADIAZOL-4-YL)- 1,2,5 ,6-TETRAHYDRO-1I- N4ETHYLPYRID1NE I) 3-3-PROPOXY- 1 ,2,5-THIADIAZOL-4-YL)- 1,2,5 ,6-TETRAHYDRO- I METI YLPYRIDINE -3 B TOXY- 1 ,2,5-THIADIAZOL-4-YL) I ,2,5 ,6-TETFRAHYDRO- 1 METH4YLPYRIDINE 3-3-ISOPROPOXY- 1 ,2,5-THIADIAZOL-4-YL)- 1,2,5 ,6-TIETRAHYDRO- I1- METHYLPRIDINE 3 -(3)-CYCLOPROPYLMETHOXY1,2,5-THJADIAZOL{.-YL-1 ,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3)-PENTOXY- 1 ,2,5-THIADIAZOL-4-YL)- 1 ,2,5,6-TETRAHYDRO- 1 N4ETHYLPYRIDINE [R:\LI BVV]02067.doe: SSD WO 97/20556 PCT/US96/'19390 -114- 3 3 -PENTOXY-1,2,-THIIAZOL4YL)1,2,,6-TETRAHYDRO-l METHYLPYRIDINE 3-3IOUOY125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3- (3-BUTENOXY) 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYLPYRIDINE 3-3(BT2YOY-,,-HAIAO--L-,,,-ERHDO 1 -METHYLPYRIDINE 3 3 3 -METHYLBUTOXY)1,2,5-THI IAZO4YL) 2 5 6 TETRAHYDRO1MEHYLPYRIDINE 3- (3-HEXYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRQ-1- METHYLPYRIDINE 3 3 -(PROP-2-YNOXY)1,2,-THIDIAZOL4YL)125, 6 TETRAHYDRO- 1-METHYLPYRIDINE 3- (3 -BENZYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -CHLaRO-1,2,5-THIADIAZOL4-YL).12,56TETRAHYDRol1 METHYL PYRIDINE 3- (3-CHLORO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDROPYRIDINE 3- (3-BuToxy-1, 2, 5-THIADIAZOL-4-YL) 6-TETRA.HYDROPYRIDINE 3-3EHX-,,-HAIZL--L-,,,-ERHDO1 ETHYLPYRIDINE 3-3CLR-,,-HAIZL--L-,,,-ERHDO1 ETHYLPYRIDINE SUBSTITUTE SHEET (RULE 26) WO 97/20556 PCTIUS96/19390 -115- 3- (3-METHOXYETHOXY-1, 2,5 -THIADIAZOL-4 -YL) 6-TETRAHYDRO- 1 -METHYL PYRIDINE 3- (3-HEPTYLOXY-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3- (3-PENTYNYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAI{YDRO- 1-METEYLPYRIDINE 3 3 4 -PENTENYLoxy)-1,2,5-THIADIAZOL.4-YL).... 2 5 6 TETRAHYDRO- 1-METHYL PYRIDINE 3 3 2 -PRPENYLOXY)-1,2,5THIAIAZ 4YL)125 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -OCTYLOXY-1,2THIADIAZOL4YL)125,6TETRAHYDROl1 METHYLPYRIDINE 3- (3-HEXYNYLOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO-1 -METHYLPYRIDINE 3 3 3 -BUTENYL-2-oxY-1,2THIADIAZOL-4YL)l 2 5 6 TETRAHYDRO- 1-METHYL -PYRIDINE 3 3 4 -HEXENYLOXY(1,2,5THIADIAZOL4.YL)1 2 S 6 TETRAHYDRO- 1-METHYL PYRIDINE TRANS-3- (3-HEXENYLOXY) 5-THIADIAZOL-4-yL) 5,6- TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 3 (2PENENYLOXY)125THIADIAZO-4YL)1 2 s 6 TETRAHYDRO- 1-METHYLPYRIDINE CIS- 3 3 2 HEXENYLOXY)125-THIADZO 4YL)1 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE SUBSTITUTE SHEET (RULE 26) WO 97/20556 PCTIUS96/1 9390 -116- 3- (5-HEXENYLOXY) 5-THIAIDIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE CI--3(-EEYOY-,,-HAIZL4Y)1245 TETRAHYDRO- 1-METHYLPYRIDINE TRN--3(-EEYOY-,,-HAIZL4Y)1256 TETRAHYDRO- 1-METHYL PYRIDINE 5-THIADIAZOL-4-YL) -1,2,51 6 -TETRAHYDRO-1-METHYLPYRIDINE 3 3 4 -METIYLPIPERIDIN-1,25THIADIAZOL4YL)l1 2 ,56 TETRAHYDROMEYPYRIDINE 3 3 -MORPHOLINo1,2,5THIIAZO4YL)1256TETRYDRo-1 METHYLPYRIDINE 3- (3-DIMETHYLAMINO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYL PYRIDINE 3-(-EYAIO125TIDAO--L-,,,-ERHDO1 METHYLPYRIDINE 3 3 -HEXYLOXY-1,5-THxAIAZ zoL4YL)1256TETRAYROl1 DEtJTEROMETHYLPYRIDINE 1,2,5, 6-TETRAHYDRO-3..(3-HF-XYLOXY-1, 2, 5-THIADIAzOL-4- YL) PYRIDINE 3 3 2 -(2-METHaXYETHOXY)ETHOXY)1,2,5THDIAZOL 4 -YL)- 1,2,5, G-TETRAHYDRO-1METHYLPYRIDINE 3 3 -(3-ETHOXY-1PROPOxy)-1,2sTHIIAZO-4YL) 2 56, TETRAHYDRO -1 -METHYL PYRIDINE 3- 2 -ETHOXYETHOXY) 5-THIADIAZOL-4-YL) 6-TETRAHYDRO- 1 -METHYLPYRIDINE SUBSTITUTE SHEET (RULE 26) WO 97/20556 WO 9720556PCTIUS96/19390 -117- 3- (2-BUTOXYETHOXY) 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3-(3-(2-(2-BUTOXYETHOXY)-ETHOXY)-1,2,5-HIAIAZOL-4-YL)- 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3- (2-ETHOXYETHOXY) -ETHOXY) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3-(3BTLH 125THAIZL4Y)12,,-ERHDO1 METHYL PYR IDINE 3- (3-METHYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 3 3 -PENTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRQ-1- METHYLPYRIDINE 3 -(3-PROPYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETJAjYDRO-1- METHYLPYRIDINE 3 -(3-HEXYLTHIO-1,2,5-THIAIAZOL-4-YL)-1,2,5,6-TETRAHjYDRQ-1- METHYLPYRIDINE 3 3 -PENTYLTHIO-1,2,5-THIAIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 METHYLPYRIDINE 3 3 -ETHYLTHIO-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-ETRJHYDRO-1- METHYLPYRIDINE 3- 3 -QCTYLTHIO-1,2,5-THTADIAZOL-4-YL)-1,2,5,6-TETRAHYDRQ-1- METHYLPYRIDINE 3 3 -PROPYL-1,2,5-THIDIAZOL-4-YL)-1,2,5,6TETRAHYDRO-.1- METHYLPYRIDINE SUBSTITUTE SHEET (RULE WO 97/20556 WO 9720556PCT/US96/1 9390 -118- 3 3 -HEPTYL-1,2,5-THIADIAZOL-4-YL)1,256TETRAHYDRO-1- METHYLPYRIDINE 3 3 -(5-HEXENL)-1,2,5-THIAIAZOL-4-YL..1,2,5,6TETRA~iYDRO.1 METHYLPYRIDINE 3 -(3-OCTYL-1,2,5-THIADIAZOL-4-YL)-1,2,5,6-TETRAHYDRO-1 METHYPYRIDINE 3 -(3-(2-METHYL)-BUTYL-1,2,5-THIAZOL-4YL)125,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -METHYLCYCLOPROPYL-1,2, -THAIIAZ4YL)1256- TETRAHYDRO- 1-METHYL PYRIDINE 3- 3 -CYCLOPENTYLTHIO-1,2,5-THIAIAZOL-4-YL).1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -(l-ETHYLTHIO-2-METHXY)-1,2,5-THIDIAZOL4-YL)-1,2,5,6- TETRAJEYDRO -1 -METHYLPYRIDINE 3 3 -(3-CHLORO-1-PROPYLTHI)-,2,5-THIAIAZOL-4-YL).1,2,,6- TETRAHYDRO- 1-METHYLPYRIDINE 3- (2-METHOXYETHOXY) -ETHYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, 6-TETRAHYDRO-1-METHYLPYRIDINE 3 3 3 -CYAO-1-PROPYLTHIO)25-THIIAZOL4YL)12,5,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 -BENZYLTHIO-1,2,5-TIIIIAZOL-4-YL)12,5,6TETAHYDRO-1 METHYLPYRIDINE 3 3 2 -ETHOXY-l-ETHYLTHIO)-1,2,5THIDIAZOL.4.YL)1256 TETRAHYDRQ-1-METHYLPYRIDINE SUBSTITUTE SHEET (RULE 26) WO 97/20556 PTU9/99 PCTIUS96/19390 -119- 3-(3-(4-PEN'rYNYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINB 3- (2-ETHOXYMETHOXY) -ETHYLTHIO) 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 3-(3-(3-PHENYL-1-PRQPYLTHIO)-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- TETRAHYDRO- 1-METHYL PYRIDINE 3- (4-CYANOBtJTYLTHIO) 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- TETRAHYDRO -1 -METHYLPYRIDINE 3- (3-CYCLOHEXYLMETHYLTHIO-1, 2, 5-THIADIAZOL-4-YL) -1,2,5,6- TETRAHYDRO- 1-METHYL PYRIDINE 3-(3-(8-HYDROXYOCTYLTHIO)-1,2,5-THIADIAZOL-4-YL)-1,2,5,6- TETRAHYDROMTPYRIDINE 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 SUBSTITUTE SHEET (RULE 26) WO 97/20556 PCT/US96/19390 -120- 3 3 -(3-IBUTENYLTHIO)-1,2,5-THIAIAZOL4..YL)l1, 2 ,5, 6 TETRAHYDRO- 1-METHYLPYRIDINE 3 3 4 -PENE YLTH)-,2,-1THIIAZOL4YL)1 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE 3-4IOEYOY125TIDAO--L-,,,-ERHDO1 METH-YLPYRIDINE 1--METHYL-1, 2,5, 6-TETRAHYDRO-3- ((4-CYCLOPENTYL.PROPYL) OXY) 1,2,5 -THIADIAZOL-3 -YL) PYRIDINE l-METHYL-l,2,5,6TETAYDRO..3(4ISOHEPTYLOXYl 2 THIADIAZOL-3 -YL) PYRIDINE 1-METHYL-i, 2,5, 6-TETRAHYDRO-3- (4 ((2-CYCLOHEXYLETHYL)OXY) 1,2, 5-THIADIAZOL-3-YL) PYRIDINE 1,,,-ERHDO1MTY--4(-EHLELX)125 THIADIAZOL-3-YL) PYRIDINE 3 4 -(l-ETHYLPENTYLOXY)-1, 5T IAZ 3YL) 2 5,6 TETRAHYDRO- 1-METHYLPYRIDINE 3 4 -(l-ETHYLBUTOXY)-1,2,5 THTDIA 3YL) 2 5 6 TETRAHYDRO- 1-METHYLPYRIDINE 1,2,5, E-TETRAHYDRO-1-METHYL-3 (1-METHYLPENTYLOXY) -1,2,5- THIADIAZOL-3 YL) PYRIDINE 1-METHYL-3- (5-HEXENYLOXY) 5-THIADIAZOL-3-YL) -1,2,5,6- TETRAHYDROPYRIDINE 1,2,5, G-TETRA{YDRO-1-MET{YJ.3-(4- (2-METHYLBUTOXY) -1,2,5- THIADIAZOL-3 -YL) PYRIDINE SUBSTITUTE SHEET (RULE 26) WO 97/20556 WO 9720556PCTIUS96/1 9390 -12 1- 1,2,5, 6-TETRAHYDRO-1-METHYL-3. (2-METHYLPENTYLOXY) -1,2,5- THIADIAZOL-3 -YL) PYRIDINE l, 2 ,5, 6 -TETRAYDRo-1METHYL3(4-(2,2,2TRIFLUOROETHOXY)- 1,2, 5-THIADIAZOL-3-YL) PYRIDINE l-METHYL-, 2 ,5,6TETRHYDRO-3.(4(3METHYLPENTYLOXY)l 2 THIADIAZOL-3 -YL) PYRIDINE 3 3 3 -METHYL-2-BUTENYLOXY)1,2,-THIDIAZOL4-.YL)1 2 5 6 TETRAHYDO -1 -METHYLPYRIDINE 3- (3-ISOBUTOXY-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE lI 2 ,SI 6 -TETRAHYDRO-1-METHYL-3-(4(2METHYLBUTOXY)12,5 THIADIAZOL-3 -YL) PYRIDINE 3 -HYDROXYPRPOXY)-1,2,5THIIAZOL4YL)12,56- TETRAHYDRO- 1-METHYLPYRIDINE 6 -DIMETHYL-3-(3-HEXYLOXY-1,2,5THIADIAZOL4YL) 1,2,5, 6-TETRAHYDROPYRIDINE 3 3 -(3-PHENYL-ETHYTHI)1,2,THIIAZOL-4L)1 2 ,5,6- TETRAHYDRO -1 -METHYL PYRIDINE BIS-, 4 3 (MEY yL2,6TETHYDROPYRIDIN3YL)12,5 THIADIAZOL-4 -YL) BUTANEDITHIOL 3- 4-TRIFLUOROBUTOXY) 5-THIADIAZOL-4-YL) -1,2,5- THIADIAZOL-4-YL) 6 -TETRAHYDRO-1-METHYLPYRIDINE 3- 3-TRIFLUOROPROPYLTHIO) 5-THIADIAZOL-4-YL) 1,2,5, G-TETRA1{YDRO-1-METHYrLPYRIDINE SUBSTITUTE SHEET (RULE 26) WO 97/20556 WO 9720556PCTIUS96/19390 -122- 3 3 -PROPYLTHIQ-1,2,5-THIADIAZOL.4YL).1,25, 6 TETRAHYDROPYRIDINE 3 3 -BUTYLTHIO-1,2,5-THIDIAZOL.4..YL).125,6 TETRAHYDROPYRIDINE 3- (3 -BtTYLTHIO-1, 2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1, 1- DIMETHYLPYRIDINIUM IODIDE 6 -DIMETHL-3-(3BYLTHIo-12THIDIAZOL4-YL)- 1,2,5, 6-TETRAH-YDROPYRIDINE (+-)lJG-DIMETH--3-UTOX 125THIDIAZOL4YL)1 2 5,6 TETRAHYDROPYRIDINE 3-3(-EHL2BTNLX)1,,-HAIZL4Y)1256 TETRAHYDO -1 -METHYL PYRIDINE 3- (3-ISOBUTOXY-1,2, 5-THIADIAZOL-4-YL) 6-TETRAHYDRO-1- METHYLPYRIDINE 1, 2 I,5,-TETRYDRO-1-METHYL3(4-(2-METHYLBTOXY)12,5 THIADIAZOL-3 -YL) PYRIDINE 3-( 3 3 -HYDROXYPROPOXY)-1,25.THIDIAZOL...YL)1256 TETRAHYDRO- 1-METHYL PYRIDINE 1, 6-DIMETHYL-3- 3 -HEXYLOXY-1,2,5-THIDIAZOL-4-YL) 1,2,5, 6-TETR.AIYDROPYRIDINE 3 3 3 -PHENYL-ETHYLTHIO125THIADIAZOL4YL) -1,2,5,6- TETRAHYDRO- 1-METHYLPYRIDINE BIS-1, 4- (1-METHYL-i, 2,5, 6-TETRAHYDRQPYRIDIN-3-YL) -1,2,5- THIADIAZOL-4-YL) BUTANEDITHIOL SUBSTITUTE SHEET (RULE 26) 3 (3-(,33-TRIFLUOROPROPYLTHIO)> 1 ,2,5-THJADAZLY>,256 TETRAHYDRO- 1-METH-YLPYRIDINE 3 -PROPYLTHIO- 1,2,5-THJADIAZOL4YL) 1 ,2,5,6-TETRAHYDRO. 1- N4ETHYLPYRIDINE 3 -(3-PIROPYLTHIO- 1,2,5-TFHIADIAZOL4YL>1 ,2,5,6-TETRAHYDROPYRJDINE 3 -B IJTYLTHIO- 1,2,5-THIADJAZOL4YL) 1,2,5 ,6-TETRAHYDROPYRIDINE 3-(3 -BUTYLTHIO- 1 ,2,5-THIADIAZOL4-L)- 1,2,5 ,6-TETRAHYDRO- 1, 1 DIMETHYLPYRIDINIUM IODIDE (-I-)1I,6-DIMETHYL3--(3 -BUTYLT'HIG- 1,2,5 -TfI IADIAZOL4-L)- 1,2,5,6- w0 TETRAHYDROPYRIDINE; and (H--)1I,6-DIMETHYL-3 -(3-BUTOXY- 1,2,5-THJADIAZOL4-L) 1,2,5,6- TETRAHYDROPYRIDINE; or a pharmaceutically acceptable salt or solvate thereof

76. A composition of claim 69 wherein the opioid compound is selected from the gYroup consisting of morphine, codeine, meperidine, methadone, propoxyphene, I levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine.

77. A composition of claim 69 wherein the opioid compound is selected from the goup consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorpheniol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl, and aiphaprodine. A composition of claim 69 wherein the opioid compound is selected from the group consisting of propoxyphene, methadone, morphine, hydrocodone, hydromorphine, and codeine.

79. A composition of claim 78 wherein the opioid compound is selected from in orphine and codeine. A method for treating pain comprising administering an analgesic dose of a composition comprising a Compound of Formula I 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. 8 1. A method of claim 80 wherein A is hydrogen, amino, halogen, -CHO, -OR -SR 4 -SOR 4 -S0 2 R 4 C-37-CYCloalkyl, C4x8-(cycloalkylalkyl), -Z 7 -cycloalkyl, and -C8-(cycloalkylalkyl) wherein R. is straight or branched C -15-alkyl, straight or branched C 2 1 -alkenyl, straight or branched C 2 5-alkynyl, each of w.>hich is optionally substituted with one or more halogens, -CF 3 -CN, phenyl or phenoxy I R :\L13 VV]02067 .doc: SS D 124 wherein phenyl or phenoxy is optionally substituted with halogen, -CN, CI-4-alkyl, Ci.4-alkoxy, -OCF 3 -CONH 2 or -CSNH 2 or A is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, C 1 4 -alkyl, CI-4-alkoxy, -OCF 3 -CONH 2 or A is -OR'Y, -SR Y, -OR'ZY, -SR 5 ZY, -O-R 4 -Z-R5 or -S-R 4 -Z-R5 wherein Z Sis oxygen or sulphur, R" is straight or branched 1_1s-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 S azabicyclic rings R R R Cn R or R Cq N N R- wherein the thiadizole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R 1 and R 2 Imay be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched Cl-s-alkyl, straight or branched C2-5-alkenyl, straight or branched C.--alkynyl, straight or branched CljIo-alkoxy, straight or branched Cvs-alkyl substituted with -011H, OR 4 halogen, -NH 2 or carboxy; R 3 is 1I, straight or branched C 1 s-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 pharmaceutically acceptable salt or solvate thereof.

82. A method of claim 81 wherein the Compound is -(3-BUTYLTHIO-I ,2,5-THIADIAZOL-4-YL)- 1-AZABICYCLO[2.2.2 IOCTANE; or a pharmaceutically acceptable salt or solvate thereof. S83. A method of claim 80 wherein A is hydrogen, halogen, amino, -NHCO-R 2 S 2 (-cycloalkyl, C4-10o-(cycloalkylalkyl), -Z2'-C3- 7 -cycloalkyl optionally substituted with CI I -alkyl, -Z 4-1 o-(cycloalkylalkyl), -Z2'-C 4 1 0o-(cycloalkenylalkyl), -Z -C4-1o-(methylenecycloalkyl-alkyl), -NH-R 2 -NR 2 'R 3 -NH-OR 2 phenyl, phenoxy, benzoyl, benzyloxycarbonyl, tetrahydronaphthyl, indenyl, R2, -Z2'R2', -SOR2 -SOR -Z2' -R2-Z -R 3 -Z 2 '-R 2 '-Z 3 -R 3 '_Z 4 '-R 4 -Z 2 '-R 2 'CO-R -Z 2 '-R2'-CO 2 -R3 \R V d V\tO D RAILI BVV]02067.doc:SS D 125 Z'-R 2 '-02C-R 3 -Z2'-R2'-CONH-R 3 -Z2'-R2'-NHCOR 3 -Z2'-R 2 -Z 2 wherein Z 2 Z 3 and Z 4 independently are oxygen or sulphur, and R 2 R 3 and R 4 independently are straight or branched Ci.i 5 -alkyl, straight or branched C2-s 5 -alkenyl, straight or branched C2- 15 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF3, -SH, -COOH, -NH-R 2 -NR2'R 3 C 6 alkyl 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 atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with I 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 fused with a phenyl group; and G is R 5 R6 N R wherein R and R 6 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C i--alkyl, straight or branched C2-5-alkenyl, straight or branched C2-5-alkynyl, straight or branched Ci-lo-alkoxy, straight or branched Cl-5-alkyl substituted with -OH, halogen, -NH- or carboxy; R' is hydrogen, straight or branched Ci.s-alkyl, straight or branched C 2 -alkenyl or straight or branched C 2 20 or a pharmaceutically acceptable salt or solvate thereof. S* 84. The use of a composition comprising a Compound of Formula I 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 for a a manufacture of a medicament for therapeutic application in the treatment of pain. 2 5

85. The use of a composition comprising a Compound of Formula I or a too**. pharmaceutically acceptable salt or solvate thereof; and one or more alpha-adrenergic compounds in a weight ratio of Compound to alpha-adrenergic compound of from about I to about 1000 for a manufacture of a medicament for therapeutic application in the treatment of pain. x [R:\LIBVV]02067.doc:SSD 126

86. The use of a composition comprising a Compound of Formula I or a pharmaceutically acceptable salt or solvate thereof; and one or more non-steroidal anti- inflammatory drug (NSAIDS) in a weight ratio of Compound to NSAIDS compound of from about 1 to about 1000 for a manufacture of a medicament for therapeutic application in the treatment of pain.

87. The use of a composition comprising a Compound of Formula 1 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 for a manufacture of a medicament for therapeutic application in the treatment of pain. Ic

88. A composition for treating pain, substantially as hereinbefore described with reference to any one of the Examples.

89. A medicament for therapeutic application in the treatment of pain whenever prepared by the use of any one of claims 84 to 87. A composition comprising a compound of Formula I 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 when used to treat pain.

91. A composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and acetaminophen in a weight ratio of Formula I to acetaminophen of from about 1 to about 1000 when used to treat pain.

92. A composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and a central alpha-adrenegic active compound in a weight ratio of Formula I to central alpha-adrenegic active compound of from about 1 to about 1000 when used to treat pain.

93. A composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and one or more opioid compounds in a weight ratio of For m u la I to one or more opioid compounds of from about 1 to about 1000 when used to S: treat pain. Dated 30 November, 1999 0'00 Eli Lilly and Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 7 [R:\LIBV V]02067.doc:SSD