-72-
We Claim:
1. A composition for treating pain comprising an
analgesic dose of a compound selected from the group
consisting of:
<IMG>
wherein R1 is hydrogen, C1-C6 alkyl or
phenyl-C1-C4 alkyl, in which the phenyl group may be substituted with
halogen, C1-C6 alkyl, or C1-C4 alkoxy;
R2 is C1-C6alkyl, C3-C6 alkenyl, C3-C6 alkynyl, branched or
unbranched with 1-6 carbon atoms inclusive, which group may
be optionally substituted with fluoro, hydroxy or phenyl
optionally substituted with fluoro, trifluoromethyl, lower
alkyl, hydroxy, or lower alkoxy;
R3 and R4 are independently hydrogen, C1-C6 alkyl, C3-C6
cycloalkyl, phenyl optionally substituted with halogen
trifluroromethyl, C1-C4 alkyl, hydroxy, or C1-C4 alkoxy, or
phenyl-C1-C4 alkyl, in which the phenyl group may be
substituted with halogen, C1-C4 alkyl or C1-C4 alkoxy;
<IMG>
in which R5 represents the radical
<IMG>
-73-
in which R6 at any position on the benzene ring represents
linear, branched or cyclic C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or the radical
<IMG>
in which R7 and R8 which may be identical or different
represent hydrogen, linear C1-C8 alkyl, C2-C8 alkenyl or
C2-C9 alkynyl or form together with the nitrogen atom to which
they are attached a carbonaceous hetercyclic radical
optionally containing another heteroatom, or the radical OR9,
R9 representing hydrogen, linear, branched or cyclic C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl or aryl containing up
to 14 carbon atoms, or the radical SR10 or S(O)R11, R10 and
R11 represent linear, branched or cyclic C1-C8 alkyl, C2-C8
alkenyl or C2-C8 alkynyl, or R5 represents naphthyl optionally
substituted with R6', R6' being defined above for R6;
<IMG>
in which R12 represents the radical
<IMG>
in which R13 at any position on the benzene ring represents
linear, branched or cyclic C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or the radical
<IMG>
-74-
in which R14 and R15 which may be identical or different
represent hydrogen, linear C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or form together with the nitrogen atom to which
they are attached a carbonaceous hetercyclic radical
optionally containing another heteroatom, or the radical or
NO2, or OR12', R12' representing hydrogen, linear, branched or
cyclic C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl or aryl
containing up to 14 carbon atoms, or the radical SR16 or
S(O)R17, R16 and R17 represent linear, branched or cyclic
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or R12 represents
naphthyl optionally substituted with R13', R13' being defined
above for R13;
<IMG>
wherein, one of R18, R19, and R20 represents nitrogen and the
remainder represent carbon atoms; substituted on one of the
ring carbon atoms with a R24 substituent represented by a
non-aromatic azacyclic or azabicyclic ring system and
independently substituted on each of the other ring carbon
atoms with R23, R21, or R22 substituent of low lipophilicity
or a hydrocarbon having a maximum of 20 carbon atoms;
<IMG>
wherein one of R28, R29 or R30 is an oxygen atom and
the other two are nitrogen atoms, and the dotted circle
represents aromaticity (two double bonds) thus forming a
-75-
1,3,4-oxadiazole or 1,2,4-oxadiazole nucleus; R31 represents a
non-aromatic '927azacycle or '927azabicyclic ring system; and
R32 represents a substituent which is convertable in vivo to
an amino group;
<IMG>
wherein R34 represents a non-aromatic; non-fused
1-azabicyclic ring system; and
R35, R36, and R37 independently represent hydrogen, F, Cl, Br,
-CF3, -OR38, -NR38R39, -NHOR38, -NHNH2, -CN, COR40, or a
substituted or unsubstituted, saturated or unsaturated
hydrocarbon group, provided that at least one of R35, R36, and
R37 is other than hydrogen or a hydrocarbon group, or R35 and
R36 or R37 taken together form a C1-6alkylenedioxy ring,
wherein R38 is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, R39 is
hydrogen, C1-6 alkyl,or -COCH3, and R40 represents OH, -OR38,
NHR39, or -NR38R39
<IMG>
wherein R43 is
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from two to six carbon atoms,
alkenyl of from two to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkynyl of from two to six carbon atoms,
-76-
alkynyl of from two to six carbon atoms,
substituted with hydroxy or alkoxy of from one to four carbon
atoms, cycloalkyl of from three to six carbon atoms,
<IMG>
wherein n is zero or an integer of one to eight and R47 and
R48 are independently hydrogen, fluorine, chlorine, bromine,
hydroxy, alkyl of from one to three carbon atoms, or alkoxy
of from one to three carbon atoms, or alkoxy of from one to
four carbon atoms, or
<IMG>
wherein
R47 and R48 are as defined above;
X is oxygen or sulfur;
R44 is
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms
alkenyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
-77-
cycloalkyl of from three to six carbon atoms, or
<IMG>
wherein n, R47 and R48 are as defined above R45 and R46 are
each independently hydrogen,
alkyl of from one to twenty carbon atoms,
alkyl of from one to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkenyl of from three to twenty carbon atoms,
alkenyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to twenty carbon atoms,
alkynyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to eight carbon atoms,
phenyl,
phenyl substituted with alkyl of from one to four
carbon atoms, alkyl of from one to four carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, chlorine,
bromine, hydroxy, nitro or trifluoromethyl of R45 and R46 are
taken together with the nitrogen atom to which they are
attached to form a ring denoted by
<IMG>
-78-
wherein R49 is hydrogen, alkyl of from one to ten carbon
atoms, alkyl of from one to ten carbon atoms substituted with
hydroxy or alkoxy of from one to four carbon atoms, alkenyl
of from two to ten carbon atoms, alkenyl of from two to ten
carbon atoms substituted with hydroxy or alkoxy of from one
to four carbon atoms, alkynyl of from two to ten carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms and n is as defined above,
<IMG>
wherein X is defined above or
<IMG>
wherein R50 is hydrogen or alkyl of from one to six carbon
atoms,
<IMG>
wherein R51 is selected from the group consisting of
-79-
<IMG>
<IMG>
<IMG>
<IMG> <IMG> <IMG>
<IMG>
<IMG><IMG> <IMG>
<IMG> <IMG> <IMG>
<IMG> <IMG> <IMG>
<IMG>
and
<IMG>
R52 is hydrogen, alkyl of from one to ten carbon atoms,
alkynyl of from two to ten carbon atoms or aryl; n' is zero
or an integer of one or two; X' is carbon or nitrogen; and
~~~ represents a single or double bond with the proviso that
when, ~~~ represents a double bond X' is nitrogen and when
represents a single bond X' is CH2;
- 80 -
<IMG>
wherein R53 is selected from the group consisting
<IMG> , and <IMG> ,
R54, R55, R56, and R57 are each independenty hydrogen, alkyl
of from one to ten carbon atoms, alkynyl of from two to ten
carbon atoms, phenyl or phenyl substituted by one to four
substituents selected from C1-C10 alkyl, alkoxy, C1-C10
halogen or trifluoromethyl; n' is an interger of one or two;
<IMG>
wherein X is oxygen, sulfur, or -N-R62, wherein R62 is
hydrogen or alkyl of from one to ten carbon atoms; R58 is
selected from the group consisting of
-81-
<IMG> <IMG><IMG>
<IMG> <IMG><IMG>
<IMG> <IMG> <IMG>
<IMG> <IMG> <IMG>
<IMG> <IMG> <IMG>
<IMG> <IMG> <IMG>
<IMG>
and
<IMG>
R59, R60, and R61 are each independently hydrogen, alkyl of
from one to ten carbon atoms, alkynyl of from two to ten
carbon atoms or aryl; --- represents a single or double bond
with the proviso that when --- represents a double bond R57
and R60 are absent;
-82-
<IMG>
wherein R63, R64, and R65 are each independently hydrogen,
alkyl of from one to ten carbon atoms, alkynyl of from two to
ten carbon atoms, phenyl or phenyl substituted by one to four
substituents selected from the group consisting of alkyl,
alkoxy, thioalkoxy, halogen, and trifluoromethyl; R66 is
hydrogen, hydroxy or alkoxy of from one to ten carbon atoms;
and R67 is selected from the group consisting of
<IMG> <IMG> <IMG> <IMG>
<IMG> <IMG> <IMG> <IMG>
<IMG> and <IMG> ;or
-83-
<IMG>
wherein
R69 is hydrogen and R67 is hydrogen,
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms,
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
R68 and R69 are taken together with the nitrogen atom to which
they are attached to form a ring denoted by
<IMG>
wherein n' is zero or an integer from one to eight and R73 is
hydrogen, alkyl of from one to ten carbon atoms, alkyl of
from one to ten carbon atoms substituted with hydroxy or
alkoxy of from one to four carbon atoms, alkenyl of from two
to ten carbon atoms, alkenyl of from two to ten carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkynyl of from two to ten carbon atoms or alkynyl of
from two to ten carbon atoms substituted with hydroxy or
alkoxy of from one to four carbon atoms;
R70 is hydrogen,
-84-
alkyl of from one to six carbon atoms,
alkyl of form one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
R70 when taken together with R68 forms a ring denoted by
<IMG>
wherein n is an integer from one to three and R68 are as
defined above;
R71 and R72 are each independently hydrogen,
alkyl of from one to twenty carbon atoms,
alkyl of from one to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkenyl of from three to twenty carbon atoms,
alkenyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to twenty carbon atoms,
alkynyl of from three to twenty carbon atoms
substituted with dydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to eight carbon atoms,
phenyl,
-85-
phenyl substituted with alkyl of from one to four
carbon atoms, alkyl of from one to four carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, chlorine,
bromine, hydroxy, nitro or trifluoromethyl of R3 and R4 are
taken together with the nitrogen atom to which they are
attached to form a ring denoted by
<IMG>
wherein n' and R73 are ad defined above,
<IMG>
wherein X is defined above or
<IMG>
wherein R74 is hydrogen or alkyl of from one to six carbon
atoms,
<IMG>
in which Z is a heterocyclic group
-86-
<IMG>
in which Q represents a 3-membered divalent residue
completing a 5-membered aromatic ring and comprises one or
two heteroatoms selected from oxygen, nitrogen and sulphur,
or three nitrogen atoms, any amino nitrogen being substituted
by a C1-2 alkyl, cyclopropyl or propargyl group, and any ring
carbon atom being optionally substituted by a group R1; or a
group
<IMG>
in which A1, A2 and A3 complete a 5-membered aromatic ring and
A1 is oxygen or sulphur, one of A2 and A3 is CR2 and the other
is nitrogen or CR3, or A2 is oxygen or sulphur, one of A1 and
A3 is CR2 and the other is CR3; and R1, R2 and R3 are
independently selected from hydrogen, halogen, CN, OR4, SR4,
N(R4)2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, NO2, COR4,
COR5, cyclopropyl, C2-5 straight chain alkenyl, C2-5 straight
chain alkynyl or C1-5 straight chain alkyl optionally
terminally substituted with OR4, N(R4)2, SR4, CO2R4, CON(R4)2
or one, two or three halogen atoms, in which each R4 is
independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or
NHR4; or in which Z is a group -C(R7)=NR6 in which R6 is a
group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4
alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group
NHR10 or NR11R12 where R10, R11 and R12 are independently
C1-2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the
-87-
proviso that when R6 is a group OCOR9 or NHR10, R7 is C1-4
alkyl
<IMG>
in which one of X and Y represents hydrogen and the other
represents Z, and Z' is a group
<IMG>
in which Q' represents a 3-membered divalent residue
completing a 5-membered aromatic ring and comprises two or
three nitrogen atoms, any amino nitrogen being substituted by
a C1-2 alkyl, cyclopropyl or propargyl group, r represents
the integer of 2 or 3, s represents an integer of 1 or 2 and
t represents 0, with the proviso that when Y is hydrogen s is
1;
<IMG>
wherein R75 represents
-88-
<IMG> or
<IMG>
in which
each of p and q independently represents an integer
of 2 to 4, r represents an integer of 2 to 4, s represents 1
or 2 and t represents 0 or 1;
R76 is a group OR78, where R78 is C1-4 alkenyl, C2-4
alkynyl, a group OCOR79 where R79 is hydrogen or R78, or a
group NHR80 or NR81, R82, where R80, R81 and R82 are
independently C1-2 alkyl; and R77 is hydrogen or C1-4alkyl,
subject to the proviso that when R76 is a group OCOR79 or a
group NHR80, R77 is alkyl;
(3R,4R)-3-(3-cyclopropyl-1,2,4-oxadiazol-5-y1)-1-
azabicyclo[2.2.1heptane; or
a pharmaceutically acceptable salt or solvate thereof;
and one or more Synergistic Analgesics in a weight ratio of
Compound to Synergistic Analgesic of from about 1 to about
1000 .
2. A composition as claimed by Claim 1 wherein
the Compound is selected from the group consisting of Formula
IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
3. A composition as claimed by Claim 1 wherein the
Synergistic Analgesic is a nonsteroidal anti-inflammatory
drug.
-89-
4. A composition as claimed by Claim 3 wherein the
nonsteroidal anti-inflammatory drug is selected from the
group consisting of indomethacin, ibuprofen, naproxen,
fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen,
piroxicam, flurbiprofen, and diclofenac.
5. A composition as claimed by Claim 3 wherein the
nonsteroidal anti-inflammatory drug is ibuprofen.
6. A composition as claimed by Claim 3 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
7. A composition as claimed by Claim 1 wherein the
Synergistic Analgesic is an opioid.
8. A composition as claimed by Claim 7 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
9. A composition as claimed by Claim 8 wherein the
Compound is selected from the group consisting of
1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
1-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-y1)acetonitrile,
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
1-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
a pharmaceutically acceptable salt thereof.
10. A composition as claimed by Claim 8 wherein
the opioid is 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.
-90-
11. A composition as claimed by Claim 8 wherein
the opioid is selected from the group consisting of
hydromorphone, hydrocodone, meperidone, buprenorphine,
butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone,
levorphanol, fentanyl, and alphaprodine.
12. A composition as claimed by Claim 8 wherein
the opioid is selected from the group consisting of
propoxyphene, methadone, hydrocodone, hydromorphine, and
codeine.
13. A composition as claimed by Claim 1 wherein
the Compound is selected from the group consisting of Formula
I, II, and III; or a pharmaceutically acceptable salt or
solvate thereof.
14. A composition as claimed by Claim 1 wherein
the Compound is selected from the group consisting of Formula
XIV and XV; or a pharmaceutically acceptable salt or solvate
thereof.
15. A composition as claimed by Claim 14 wherein
the Compound is selected from the group consisting of
1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
1-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
l-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile,
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
1-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
a pharmaceutically acceptable salt thereof.
16. A composition as claimed by Claim 1 wherein
the Synergistic Analgesic is acetaminophen.
17. A composition as claimed by Claim 15 wherein
the Compound is selected from the group consisting of Formula
IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
18. A composition as claimed by Claim 17 wherein
the Compound is selected from the group consisting of
-91-
1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
1-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile,
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
1-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
a pharmaceutically acceptable salt thereof.
19. A composition as claimed by Claim 1 wherein
the Synergistic Analgesic is an alpha-adrenergic compound.
20. A composition as claimed by Claim 19 wherein
the Compound is selected from the group consisting of Formula
IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
21. A composition as claimed by Claim 20 wherein
the Compound is selected from the group consisting of
1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
1-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile,
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
1-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
a pharmaceutically acceptable salt thereof.
22. A method for treating pain comprising
administering an analgesic dose of a composition comprising a
compound a Compound selected from the group consisting of:
-92-
<IMG>
wherein R1 is hydrogen, C1-C6 alkyl or phenyl-C1-C4
alkyl, in which the phenyl group may be substituted with
halogen, C1-C4 alkyl or C1-C4 alkoxy;
R2 is C1-C6alkyl, C3-C6 alkenyl, C3-C6 alkynyl, branched or
unbranched with 1-6 carbon atoms inclusive, which group may
be optionally substituted with fluoro, hydroxy or phenyl
optionally substituted with fluoro, trifluoromethyl, lower
alkyl, hydroxy, or lower alkoxy;
R3 and R4 are independently hydrogen, C1-C6 alkyl, C3-C6
cycloalkyl, phenyl optionally substituted with halogen
trifluroromethyl, C1-C4 alkyl, hydroxy, or C1-C4 alkoxy, or
phenyl-C1-C4 alkyl, in which the phenyl group may be
substituted with halogen, C1-C4 alkyl or C1-C4 alkoxy;
<IMG> ;
in which R5 represents the radical
<IMG>
in which R6 at any position on the benzene ring represents
linear, branched or cyclic C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or the radical
-93-
<IMG>
in which R7 and R8 which may be identical or different
represent hydrogen, linear C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or form together with the nitrogen atom to which
they are attached a carbonaceous hetercyclic radical
optionally containing another heteroatom, or the radical OR9,
R9 representing hydrogen, linear, branched or cyclic C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl or aryl containing up
to 14 carbon atoms, or the radical SR10 or S(O)R11, R10 and
R11 represent linear, branched or cyclic C1-C8 alkyl, C2-C8
alkenyl or C2-C8 alkynyl, or R5 represents naphthyl optionally
substituted with R6', R6' being defined above for R6;
<IMG>
in which R12 represents the radical
<IMG>
in which R13 at any position on the benzene ring represents
linear, branched or cyclic C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or the radical
<IMG>
in which R14 and R15 which may be identical or different
represent hydrogen, linear C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or form together with the nitrogen atom to which
-94-
they are attached a carbonaceous hetercyclic radical
optionally containing another heteroatom, or the radical or
NO2, or OR12', R12' representing hydrogen, linear, branched or
cyclic C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl or aryl
containing up to 14 carbon atoms, or the radical SR16 or
S(O)R17, R16 and R17 represent linear, branched or cyclic
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or R12 represents
naphthyl optionally substituted with R13' R13' being defined
above for R13;
<IMG>
wherein, one of R18, R19, and R20 represents nitrogen and the
remaider represent carbon atoms; substituted on one of the
ring carbon atoms with a R24 substituent represented by a
non-aromatic azacyclic or azabicyclic ring system and
independently substituted on each of the other ring carbon
atoms with R23, R21, or R22 substituent of low lipophilicity
or a hydrocarbon having a maximum of 20 carbon atoms;
<IMG>
wherein one of R28, R29 or R30 is an oxygen atom and
the other two are nitrogen atoms, and the dotted circle
represents aromaticity (two double bonds) thus forming a
1,3,4-oxadiazole or 1,2,4-oxadiazole nucleus; R31 represents a
non-aromatic '927azacycle or '927azabicyclic ring system; and
-95-
R32 represents a substituent which is convertable in vivo to
an amino group;
<IMG>
wherein R34 represents a non-aromatic; non-fused
1-azabicyclic ring system; and
R35, R36, and R37 independently represent hydrogen, F, C1, Br,
-CF3, -OR38, -NR38R39, -NHOR38 -NHNH2, -CN, COR40, or a
substituted or unsubstituted, saturated or unsaturated
hydrocarbon group, provided that at least one of R35, R36, and
R37 is other than hydrogen or a hydrocarbon group, or R35 and
R36 or R37 taken together form a C1-6alkylenedioxy ring,
wherein R38 is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, R39 is
hydrogen, C1-6 alkyl,or -COCH3, and R40 represents OH, -OR38,
NHR39, or -NR38R39
<IMG>
wherein R43 is
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from two to six carbon atoms,
alkenyl of from two to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkynyl of from two to six carbon atoms,
alkynyl of from two to six carbon atoms,
substituted with hydroxy or alkoxy of from one to four carbon
atoms, cycloalkyl of from three to six carbon atoms,
-96-
<IMG>
wherein n is zero or an integer of one to eight and R47 and
R48 are independently hydrogen, fluorine, chlorine, bromine,
hydroxy, alkyl of from one to three carbon atoms, or alkoxy
of from one to three carbon atoms, or alkoxy of from one to
four carbon atoms, or
<IMG>
wherein
R47 and R48 are as defined above;
X is oxygen or sulfur;
R44 is
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
-97-
<IMG>
wherein n, R47 and R48 are as defined above R45 and R46 are
each independently hydrogen,
alkyl of from one to twenty carbon atoms,
alkyl of from one to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkenyl of from three to twenty carbon atoms,
alkenyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to twenty carbon atoms,
alkynyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to eight carbon atoms,
phenyl,
phenyl substituted with alkyl of from one to four
carbon atoms, alkyl of from one to four carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, chlorine,
bromine, hydroxy, nitro or trifluoromethyl of R45 and R46 are
taken together with the nitrogen atom to which they are
attached to form a ring denoted by
<IMG>
wherein R49 is hydrogen, alkyl of from one to ten carbon
atoms, alkyl of from one to ten carbon atoms substituted with
-98-
hydroxy or alkoxy of from one to four carbon atoms, alkenyl
of from two to ten carbon atoms, alkenyl of from two to ten
carbon atoms substituted with hydroxy or alkoxy of from one
to four carbon atoms, alkynyl of from two to ten carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms and n is as defined above.
<IMG>
wherein X is defined above or
<IMG>
wherein R50 is hydrogen or alkyl of from one to six carbon
atoms,
<IMG>
wherein R51 is selected from the group consisting of
- 99 -
<IMG><IMG><IMG>
<IMG><IMG> <IMG>
<IMG><IMG><IMG> <IMG>
<IMG><IMG> <IMG>
<IMG><IMG> <IMG>
<IMG> <IMG>
and
<IMG>
R52 is hydrogen, alkyl of from one to ten carbon atoms,
alkynyl of from two to ten carbon atoms or aryl; n' is zero
or an integer of one or two; X' is carbon or nitrogen; and
~~~ represents a single or double bond with the proviso that
when,~~~ represents a double bond X' is nitrogen and when
represents a single bond X' is CH2;
-100-
<IMG>
wherein R53 is selected from the group consisting
<IMG>, and
<IMG> ,
R54, R55, R56, and R57 are each independenty hydrogen, alkyl
of from one to ten carbon atoms, alkynyl of from two to ten
carbon atoms, phenyl or phenyl substituted by one to four
substituents selected from C1-C10 alkyl, alkoxy, C1-C10
halogen or trifluoromethyl; n' is an interger of one or two;
<IMG>
wherein X is oxygen, sulfur, or -N-R62, wherein R62 is
hydrogen or alkyl of from one to ten carbon atoms; R58 is
selected from the group consisting of
-101-
<IMG> ,<IMG>, <IMG> ,
<IMG>, <IMG>, <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> ,<IMG> ' <IMG> ,
<IMG> , <IMG> ,<IMG>,
<IMG>, <IMG> , <IMG>,
<IMG>, <IMG> and
<IMG>;
R59, R60, and R61 are each independently hydrogen, alkyl of
from one to ten carbon atoms, alkynyl of from two to ten
carbon atoms or aryl; --- represents a single or double bond
with the proviso that when --- represents a double bond R57
and R60 are absent;
-102-
<IMG>
wherein R63, R64, and R65 are each independently hydrogen,
alkyl of from one to ten carbon atoms, alkynyl of from two to
ten carbon atoms, phenyl or phenyl substituted by one to four
substituents selected from the group consisting of alkyl,
alkoxy, thioalkoxy, halogen, and trifluoromethyl; R66 is
hydrogen, hydroxy or alkoxy of from one to ten carbon atoms;
and R67 is selected from the group consisting of
<IMG>, <IMG>, <IMG> , <IMG> ,
<IMG>, <IMG>, <IMG> , <IMG> ,
<IMG> , and <IMG> ; or
,
-103-
<IMG>
wherein
R69 is hydrogen and R67 is hydrogen,
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms,
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
R68 and R69 are taken together with the nitrogen atom to which
they are attached to form a ring denoted by
<IMG>
wherein n' is zero or an integer from one to eight and R73 is
hydrogen, alkyl of from one to ten carbon atoms, alkyl of
from one to ten carbon atoms substituted with hydroxy or
alkoxy of from one to four carbon atoms, alkenyl of from two
to ten carbon atoms, alkenyl of from two to ten carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkynyl of from two to ten carbon atoms or alkynyl of
from two to ten carbon atoms substituted with hydroxy or
alkoxy of from one to four carbon atoms;
R70 is hydrogen,
-104-
alkyl of from one to six carbon atoms,
alkyl of form one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
R70 when taken together with R68 forms a ring denoted by
<IMG>
wherein n is an integer from one of three and R68 are as
defined above;
R71 and R72 are each independently hydrogen,
alkyl of from one to twenty carbon atoms,
alkyl of from one to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkenyl of from three to twenty carbon atoms,
alkenyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to twenty carbon atoms,
alkynyl of from three to twenty carbon atoms
substituted with dydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to eight carbon atoms,
phenyl,
-105-
phenyl substituted with alkyl of from one to four
carbon atoms, alkyl of from one to four carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, chlorine,
bromine, hydroxy, nitro or trifluoromethyl of R3 and R4 are
taken together with the nitrogen atom to which they are
attached to form a ring denoted by
<IMG>
wherein n' and R73 are as defined above,
<IMG>
wherein X is defined above or
<IMG>
wherein R74 is hydrogen or alkyl of from one to six carbon
atoms,
<IMG>
in which Z is a heterocyclic group
-106-
<IMG>
in which Q represents a 3-membered divalent residue
completing a 5-membered aromatic ring and comprises one or
two heteroatoms selected from oxygen, nitrogen and sulphur,
or three nitrogen atoms, any amino nitrogen being substituted
by a C1-2 alkyl, cyclopropyl or propargyl group, and any ring
carbon atom being optionally substituted by a group R1; or a
group
<IMG>
in which A1, A2 and A3 complete a 5-membered aromatic ring and
A1 is oxygen or sulphur, one of A2 and A3 is CR2 and the other
is nitrogen or CR3, or A2 is oxygen or sulphur, one of A1 and
A3 is CR2 and the other is CR3; and R1, R2 and R3 are
independent-y selected from hydrogen, halogen, CN, OR4, SR4,
N(R4)2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, N02, COR4,
COR5, cyclopropyl, C2-5 straight chain alkenyl, C2-5 straight
chain alkynyl or C1-5 straight chain alkyl optionally
terminally substituted with OR4, N(R4)2, SR4, CO2R4, CON(R4)2
or one, two or three halogen atoms, in which each R4 is
independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or
NHR4; or in which z is a group -C(R7)=NR6 in which R6 is a
group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4
alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group
NHR10 or NR11R12 where R10, R11 and R12 are independently
C1-2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the
-107-
proviso that when R6 is a group OCOR9 or NHR10, R7 is C1-4
alkyl;
<IMG>
in which one of X and Y represents hydrogen and the other
represents Z, and Z' is a group
<IMG>
in which Q' represents a 3-membered divalent residue
completing a 5-membered aromatic ring and comprises two or
three nitrogen atoms, any amino nitrogen being substituted by
a C1-2 alkyl, cyclopropyl or propargyl group, r represents
the integer of 2 or 3, s represents an integer of 1 or 2 and
t represents 0, with the proviso that when Y is hydrogen s is
1;
<IMG>
wherein R75 represents
-108 -
<IMG>
or
<IMG>
in which
each of p and q independently represents an integer
of 2 to 4, r represents an integer of 2 to 4, s represents 1
or 2 and t represents 0 or 1;
R76 is a group OR78, where R78 is C1-4 alkenyl, C2-4
alkynyl, a group OCOR79 where R79 is hydrogen or R78, or a
group NHR80 or NR81, R82, where R80, R81 and R82 are
independently C1-2 alkyl; and R77 is hydrogen or C1-4alkyl,
subject to the proviso that when R76 is a group OCOR79 or a
group NHR80, R77 is alkyl;
(3R,4R)-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-
azabicyclo[2.2.1heptane; or
a pharmaceutically acceptable salt or solvate thereof;
and one or more Synergistic Analgesics in a weight ratio of
Compound to Synergistic Analgesic of from about 1 to about
1000.
23. A method as claimed by Claim 22 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
-109-
24. A method as claimed by Claim 22 wherein the
Synergistic Analgesic is a nonsteroidal anti-inflammatory
drug.
25. A method as claimed by Claim 24 wherein the
nonsteroidal anti-inflammatory drug is selected from the
group consisting of indomethacin, ibuprofen, naproxen,
fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen,
piroxicam, flurbiprofen, and diclofenac.
26. A method as claimed by claim 24 wherein the
nonsteroidal anti-inflammatory drug is ibuprofen.
27. A method as claimed by Claim 24 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
28. A method as claimed by Claim 22 wherein the
Synergistic Analgesic is an opioid.
29. A method as claimed by Claim 28 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
30. A method as claimed by Claim 29 wherein the
Compound is selected from the group consisting of
l-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
l-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
l-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
l-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile,
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
- 110 -
a pharmaceutically acceptable salt thereof.
31. A method as claimed by Claim 29 wherein the
opioid is 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.
32. A method as claimed by Claim 29 wherein the
opioid is selected from the group consisting of
hydromorphone, hydrocodone, meperidone, buprenorphine,
butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone,
levorphanol, fentanyl, and alphaprodine.
33. A method as claimed by Claim 29 wherein the
opioid is selected from the group consisting of propoxyphene,
methadone, hydrocodone, hydromorphine, and codeine.
34. A method as claimed by Claim 22 wherein the
Compound is selected from the group consisting of Formula I,
II, and III; or a pharmaceutically acceptable salt or solvate
thereof.
35. A method as claimed by Claim 22 wherein the
Compound is selected from the group consisting of Formula XIV
and XV; or a pharmaceutically acceptable salt or solvate
thereof.
36. A method as claimed by Claim 35 wherein the
Compound is selected from the group consisting of
1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
1-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile,
-111-
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
1-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
a pharmaceutically acceptable salt thereof.
37. A method as claimed by Claim 22 wherein the
Synergistic Analgesic is acetaminophen.
38. A method as claimed by Claim 37 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
39. A method as claimed by Claim 22 wherein the
Synergistic Analgesic is an alpha-adrenergic compound.
40. A method as claimed by Claim 39 wherein the
Compound is selected from the group consisting of Formula IV,
V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically
acceptable salt or solvate thereof.
41. A method as claimed by Claim 40 wherein the
Compound is selected from the group consisting of
1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone,
1-azabicyclo[2.2.1]hept-3-yl cyclopropyl ketone,
3-oxo-3-(1-azabicyclo[2.2.1]hept-3-yl)propionitrile,
1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide,
1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide,
1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide,
(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile,
oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and
1-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or
a pharmaceutically acceptable salt thereof.
42. The use of a First Compound selected from
the group consisting of
-112-
<IMG>
wherein R1 is hydrogen, C1-C6 alkyl or phenyl-C1-C4
alkyl, in which the phenyl group may be substituted with
halogen, C1-C4 alkyl or C1-C4 alkoxy;
R2 is C1-C6alkyl, C3-C6 alkenyl, C3-C6 alkynyl, branched or
unbranched with 1-6 carbon atoms inclusive, which group may
be optionally substituted with fluoro, hydroxy or phenyl
optionally substituted with fluoro, trifluoromethyl, lower
alkyl, hydroxy, or lower alkoxy;
R3 and R4 are independently hydrogen, C1-C6 alkyl, C3-C6
cycloalkyl, phenyl optionally substituted with halogen
trifluroromethyl, C1-C4 alkyl, hydroxy, or C1-C4 alkoxy, or
phenyl-C1-C4 alkyl, in which the phenyl group may be
substituted with halogen, C1-C4 alkyl or C1-C4 alkoxy;
<IMG> ;
in which R5 represents the radical
<IMG>
in which R6 at any position on the benzene ring represents
linear, branched or cyclic C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or the radical
-113-
<IMG>
in which R7 and R8 which may be identical or different
represent hydrogen, linear C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or form together with the nitrogen atom to which
they are attached a carbonaceous hetercyclic radical
optionally containing another heteroatom, or the radical OR9,
R9 representing hydrogen, linear, branched or cyclic C1-C8
alkyl, C2-C8 alkenyl or C2-C8 alkynyl or aryl containing up
to 14 carbon atoms, or the radical SR10 or S(O)R11, R10 and
R11 represent linear, branched or cyclic C1-C8 alkyl, C2-C8
alkenyl or C2-C8 alkynyl, or R5 represents naphthyl optionally
substituted with R6', R6' being defined above for R6;
<IMG>
in which R12 represents the radical
<IMG>
in which R13 at any position on the benzene ring represents
linear, branched or cyclic C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or the radical
<IMG>
in which R14 and R15 which may be identical or different
represent hydrogen, linear C1-C8 alkyl, C2-C8 alkenyl or
C2-C8 alkynyl or form together with the nitrogen atom to which
-114-
they are attached a carbonaceous hetercyclic radical
optionally containing another heteroatom, or the radical or
NO2, or OR12 , R12' representing hydrogen, linear, branched or
cyclic C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl or aryl
containing up to 14 carbon atoms, or the radical SR16 or
S(O)R17, R16 and R17 represent linear, branched or cyclic
C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, or R12 represents
naphthyl optionally substituted with R13', R13 being defined
above for R13;
<IMG>
wherein, one of R18, R19, and R20 represents nitrogen and the
remainder represent carbon atoms; substituted on one of the
ring carbon atoms with a R24 substituent represented by a
non-aromatic azacyclic or azabicyclic ring system and
independently substituted on each of the other ring carbon
atoms with R23, R21, or R22 substituent of low lipophilicity
or a hydrocarbon having a maximum of 20 carbon atoms;
<IMG>
wherein one of R28, R29 or R30 is an oxygen atom and
the other two are nitrogen atoms, and the dotted circle
represents aromaticity (two double bonds) thus forming a
1,3,4-oxadiazole or 1,2,4-oxadiazole nucleus; R31 represents a
non-aromatic '927azacycle or '927azabicyclic ring system; and
-115-
R32 represents a substituent which is convertable in vivo to
an amino group;
<IMG> ;
wherein R34 represents a non-aromatic; non-fused
1-azabicyclic ring system; and
R35, R36, and R37 independently represent hydrogen, F, C1, Br,
-CF3, -OR38, -NR38R39, -NHOR38, -NHNH2, -CN, COR40, or a
substituted or unsubstituted, saturated or unsaturated
hydrocarbon group, provided that at least one of R35, R36, and
R37 is other than hydrogen or a hydrocarbon group, or R35 and
R36 or R37 taken together form a C1-6alkylenedioxy ring,
wherein R38 is C1-6alkyl, C2-6alkenyl or C2-6alkynyl, R39 is
hydrogen, C1-6 alkyl,or -COCH3, and R40 represents OH, -OR38,
NHR39, or -NR38R39
<IMG>
wherein R43 is
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from two to six carbon atoms,
alkenyl of from two to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkynyl of from two to six carbon atoms,
alkynyl of from two to six carbon atoms,
substituted with hydroxy or alkoxy of from one to four carbon
atoms, cycloalkyl of from three to six carbon atoms,
-116-
<IMG>
wherein n is zero or an integer of one to eight and R47 and
R48 are independently hydrogen, fluorine, chlorine, bromine,
hydroxy, alkyl of from one to three carbon atoms, or alkoxy
of from one to three carbon atoms, or alkoxy of from one to
four carbon atoms, or
<IMG>
wherein
R47 and R48 are as defined above;
X is oxygen or sulfur;
R44 is
alkyl o~ from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms
alkenyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
-117 -
<IMG>
wherein n, R47 and R48 are as defined above R45 and R46 are
each independently hydrogen,
alkyl of from one to twenty carbon atoms,
alkyl of from one to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkenyl of from three to twenty carbon atoms,
alkenyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to twenty carbon atoms,
alkynyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to eight carbon atoms,
phenyl,
phenyl substituted with alkyl of from one to four
carbon atoms, alkyl of from one to four carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, chlorine,
bromine, hydroxy, nitro or trifluoromethyl of R45 and R46 are
taken together with the nitrogen atom to which they are
attached to form a ring denoted by
<IMG>
wherein R49 is hydrogen, alkyl of from one to ten carbon
atoms, alkyl of from one to ten carbon atoms substituted with
-118-
hydroxy or alkoxy of from one to four carbon atoms, alkenyl
of from two to ten carbon atoms, alkenyl of from two to ten
carbon atoms substituted with hydroxy or alkoxy of from one
to four carbon atoms, alkynyl of from two to ten carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms and n is as defined above,
<IMG>
wherein X is defined above or
<IMG>
wherein R50 is hydrogen or alkyl of from one to six carbon
atoms,
<IMG>
wherein R51 is selected from the group consisting of
-119 -
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , and
<IMG> ;
R52 is hydrogen, alkyl o from one to ten carbon atoms,
alkynyl of from two to ten carbon atoms or aryl; n' is zero
or an integer of one or two; X' is carbon or nitrogen; and
~ represents a single or double bond with the proviso that
when, ~ represents a double bond X' is nitrogen and when
~ represents a single bond X' is CH2;
-120-
<IMG>
wherein R53 is selected from the group consisting
<IMG> , and <IMG> ,
R54, R55, R56, and R57 are each independenty hydrogen, alkyl
of from one to ten carbon atoms, alkynyl of from two to ten
carbon atoms, phenyl or phenyl substituted by one to four
substituents selected from C1-C10 alkyl, alkoxy, C1-C10
halogen or trifluoromethyl; n' is an interger of one or two;
<IMG>
wherein X is oxygen, sulfur, or -N-R62, wherein R62 is
hydrogen or alkyl of from one to ten carbon atoms; R58 is
selected from the group consisting of
-121-
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> , <IMG> ,
<IMG> , <IMG> and
<IMG> ;
R59, R60, and R61 are each independently hydrogen, alkyl of
from one to ten carbon atoms, alkynyl of from two to ten
carbon atoms or aryl; --- represents a single or double bond
with the proviso that when --- represents a double bond R57
and R60 are absent;
-122-
<IMG>
wherein R63, R64, and R65 are each independently hydrogen,
alkyl of from one to ten carbon atoms, alkynyl of from two to
ten carbon atoms, phenyl or phenyl substituted by one to four
substituents selected from the group consisting of alkyl,
alkoxy, thioalkoxy, halogen, and trifluoromethyl; R66 is
hydrogen, hydroxy or alkoxy of from one to ten carbon atoms;
and R67 is selected from the group consisting of
<IMG> , <IMG> , <IMG> , <IMG> ,
<IMG> <IMG> , <IMG> , <IMG> ,
<IMG> , and <IMG> ; or
,
-123-
<IMG>
wherein
R69 is hydrogen and R67 is hydrogen,
alkyl of from one to six carbon atoms,
alkyl of from one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms,
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
R68 and R69 are taken together with the nitrogen atom to which
they are attached to form a ring denoted by
<IMG>
wherein n' is zero or an integer from one to eight and R73 is
hydrogen, alkyl of from one to ten carbon atoms, alkyl of
from one to ten carbon atoms substituted with hydroxy or
alkoxy of from one to four carbon atoms, alkenyl of from two
to ten carbon atoms, alkenyl of from two to ten carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkynyl of from two to ten carbon atoms or alkynyl of
from two to ten carbon atoms substituted with hydroxy or
alkoxy of from one to four carbon atoms;
R70 is hydrogen,
-124-
alkyl of from one to six carbon atoms,
alkyl of form one to six carbon atoms substituted
with hydroxy or alkoxy of from one to four carbon atoms,
alkenyl of from three to six carbon atoms,
alkenyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to six carbon atoms,
alkynyl of from three to six carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to six carbon atoms, or
R70 when taken together with R68 forms a ring denoted by
<IMG>
wherein n is an integer from one to three and R68 are as
defined above;
R71 and R72 are each independently hydrogen,
alkyl of from one to twenty carbon atoms,
alkyl of from one to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkenyl of from three to twenty carbon atoms,
alkenyl of from three to twenty carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms,
alkynyl of from three to twenty carbon atoms,
alkynyl of from three to twenty carbon atoms
substituted with dydroxy or alkoxy of from one to four carbon
atoms,
cycloalkyl of from three to eight carbon atoms,
phenyl,
-125-
phenyl substituted with alkyl of from one to four
carbon atoms, alkyl of from one to four carbon atoms
substituted with hydroxy or alkoxy of from one to four carbon
atoms, alkoxy of from one to four carbon atoms, chlorine,
bromine, hydroxy, nitro or trifluoromethyl of R3 and R4 are
taken together with the nitrogen atom to which they are
attached to form a ring denoted by
<IMG>
wherein n' and R73 are ad defined above,
<IMG>
wherein X is defined above or
<IMG>
wherein R74 is hydrogen or alkyl of from one to six carbon
atoms,
<IMG>
in which z is a heterocyclic group
-126-
<IMG>
in which Q represents a 3-membered divalent residue
completing a 5-membered aromatic ring and comprises one or
two heteroatoms selected from oxygen, nitrogen and sulphur,
or three nitrogen atoms, any amino nitrogen being substituted
by a C1-2 alkyl, cyclopropyl or propargyl group, and any ring
carbon atom being optionally substituted by a group R1; or a
group
<IMG>
in which A1, A2 and A3 complete a 5-membered aromatic ring and
A1 is oxygen or sulphur, one of A2 and A3 is CR2 and the other
is nitrogen or CR3, or A2 is oxygen or sulphur, one of A1 and
A3 is CR2 and the other is CR3; and R1, R2 and R3 are
independently selected from hydrogen, halogen, CN, OR4, SR4,
N(R4)2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, NO2, COR4,
COR5, cyclopropyl, C2-5 straight chain alkenyl, C2-5 straight
chain alkynyl or C1-5 straight chain alkyl optionally
terminally substituted with OR4, N(R4)2, SR4, CO2R4, CON(R4)2
or one, two or three halogen atoms, in which each R4 is
independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or
NHR4; or in which Z is a group -C(R7)=NR6 in which R6 is a
group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4
alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group
NHR10 or NR11R12 where R10, R11 and R12 are independently
C1-2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the
-127-
proviso that when R6 is a group OCOR9 or NHR10, R7 is C1-4
alkyl
<IMG>
in which one of X and Y represents hydrogen and the other
represents Z, and Z' is a group
<IMG>
in which Q' represents a 3-membered divalent residue
completing a 5-membered aromatic ring and comprises two or
three nitrogen atoms, any amino nitrogen being substituted by
a C1-2 alkyl, cyclopropyl or propargyl group, r represents
the integer of 2 or 3, s represents an integer of 1 or 2 and
t represents 0, with the proviso that when Y is hydrogen s is
1;
<IMG>
wherein R75 represents
-128-
<IMG> or
<IMG>
in which
each of p and q independently represents an integer
of 2 to 4, r represents an integer of 2 to 4, s represents 1
or 2 and t represents 0 or 1;
R76 is a group OR78, where R78 is C1-4 alkenyl, C2-4
alkynyl, a group OCOR79 where R79 is hydrogen or R78, or a
group NHR80 or NR81, R82, where R80, R81 and R82 are
independently C1-2 alkyl; and R77 is hydrogen or C1-4alkyl,
subject to the proviso that when R76 is a group OCOR79 or a
group NHR80, R77 is alkyl;
(3R,4R)-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-
azabicyclo[2.2.1heptane; or
a pharmaceutically acceptable salt or solvate thereof; and
one or more Synergistic Analgesics in a weight ratio of
First Compound to Synergistic Analgesic of from about 1 to
about 1000 for a manufacture of a medicament for
therapeutic application in the treatment of pain.
43. A use as claimed by Claim 42 wherein the
Synergistic Analgesic is an opioid.
44. A use as claimed by Claim 42 wherein the
Synergistic Analgesic is acetaminophen.
-129-
45. A use as claimed by Claim 42 wherein the
Synergistic Analgesic is a nonsteroidal anti-inflammatory
drug.
46. A use as claimed by Claim 42 wherein the
Synergistic Analgesic is an alpha-adrenergic compound.
