U.S. patent application number 10/923621 was filed with the patent office on 2005-02-03 for carbinols for the treatment of neuropathic dysfunction.
This patent application is currently assigned to Endo Pharmaceuticals, Inc., a Delaware corporation. Invention is credited to Carliss, Richard, Lee, David A.H..
Application Number | 20050026956 10/923621 |
Document ID | / |
Family ID | 23287359 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050026956 |
Kind Code |
A1 |
Carliss, Richard ; et
al. |
February 3, 2005 |
Carbinols for the treatment of neuropathic dysfunction
Abstract
Compositions and methods are provided for treating neuropathic
pain or neuropathic dysfunction that include the administration of
an effective amount of a defined carbinol or a pharmaceutically
acceptable salt or prodrug thereof.
Inventors: |
Carliss, Richard; (West
Chester, PA) ; Lee, David A.H.; (Chadds Ford,
PA) |
Correspondence
Address: |
IP DEPARTMENT OF PIPER RUDNICK LLP
ONE LIBERTY PLACE, SUITE 4900
1650 MARKET ST
PHILADELPHIA
PA
19103
US
|
Assignee: |
Endo Pharmaceuticals, Inc., a
Delaware corporation
Chadds Ford
PA
|
Family ID: |
23287359 |
Appl. No.: |
10/923621 |
Filed: |
August 20, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10923621 |
Aug 20, 2004 |
|
|
|
10272375 |
Oct 16, 2002 |
|
|
|
6825217 |
|
|
|
|
60329869 |
Oct 16, 2001 |
|
|
|
Current U.S.
Class: |
514/326 |
Current CPC
Class: |
C07D 409/04 20130101;
A61P 19/02 20180101; A61P 5/00 20180101; A61K 31/451 20130101; C07D
405/04 20130101; A61P 31/22 20180101; A61P 25/28 20180101; A61P
43/00 20180101; A61P 9/00 20180101; A61P 25/00 20180101; C07D
207/08 20130101; C07D 223/04 20130101; A61K 31/4535 20130101; A61P
25/04 20180101; A61P 31/18 20180101; A61P 37/06 20180101; C07D
401/04 20130101; A61P 25/02 20180101; A61P 21/00 20180101; A61P
3/00 20180101; A61K 31/40 20130101; A61P 3/10 20180101; A61P 39/02
20180101; A61P 29/00 20180101; A61P 7/00 20180101; A61P 31/12
20180101; A61K 31/55 20130101; A61P 35/00 20180101; A61P 29/02
20180101; C07D 211/22 20130101; A61P 17/02 20180101 |
Class at
Publication: |
514/326 |
International
Class: |
A61K 031/453 |
Claims
1-34. (cancelled)
35. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 29or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional
neuropathic pain, wherein: m is 1, 2 or 3; R.sup.1 is CH.sub.3,
C.sub.2H.sub.5, n-C.sub.3H.sub.7 or allyl; R.sup.2 and R.sup.3
independently are H or alkyl of 1-4 carbon atoms; or R1 and R.sup.2
taken together is a branched or unbranched alkylene bridge wherein
the bridge is of 3 or 4 carbon atoms; or R.sup.2 and R.sup.3 taken
together is a branched or unbranched alkylene bridge wherein the
bridge is of 3 to 6 carbon atoms; R.sup.4 is: (a) phenyl or
30wherein X is independently one or two substituents, selected from
F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino,
alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing
groups being of 1 to 12 carbon atoms; (b) 2-, 3-, or 4-biphenyl or
2-, 3-, or 4-biphenyl where either or both aromatic groups are
substituted with 1 or 2 substituents, the same or different,
selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy,
alkylthio, perfluoroalkoxy, arylthio, perfluoroalkyl-thio and
dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon
atoms and said aryl groups being of 6-12 carbon atoms; (c) 1- or
2-naphthyl optionally having one or two X substituents as defined
in (a) above; (e) 2-, 3-, or 4-pyridyl, or 2- or 3-pyrrolyl
optionally substituted with one to three alkyl groups of 1-4 carbon
atoms; (f) 2- or 3-thienyl optionally substituted with one
substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
(g) 2- or 3-benzothienyl or benzofuryl optionally substituted on
the aromatic ring with Cl, Br, or CF.sub.3; R.sup.5 is alkyl of 1-4
carbon atoms, or is taken together with R.sup.6 to form a branched
or unbranched alkylene bridge of 3-11 carbon atoms; R.sup.6 is H,
alkyl of 1-4 carbon atoms, or is taken together with R.sup.5 to
form a branched or unbranched alkylene bridge of 3-11 carbon atoms;
and R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4 carbon
atoms, or --CH.sub.2phenyl; or a pharmaceutically salt or N-oxide
thereof, provided that when (i) R.sup.1, R.sup.5 and R.sup.6 are
methyl, and R.sup.2 and R.sup.3 are H, then R.sup.4 is not
3,4-F.sub.2C.sub.6H.sub.3, 3,4-C.sub.l2C.sub.6H.sub.3,
p-t-butylphenyl, 2,3-(MeO).sub.2C.sub.6H.sub.3,
2,5-(MeO).sub.2C.sub.6H.sub.3, or 3-pyridyl; (ii) R.sup.2, R.sup.5
and R are methyl or R.sup.5 and R.sup.6 are taken together as
--(CH.sub.2).sub.6-- and --(CH.sub.2).sub.7--, then R.sup.4 is not
3-(MeO)C.sub.6H.sub.4.
36. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 31or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional pain,
wherein: when m is 2; R.sup.1 is CH.sub.3, C.sub.2H.sub.5,
n-C.sub.3H.sub.7 or allyl; R.sup.2 and R3 independently are H or
alkyl of 1-4 carbon atoms; or R1 and R2 taken together is a
branched or unbranched alkylene bridge wherein the bridge is of 3
or 4 carbon atoms; or R.sup.2 and R.sup.3 taken together is a
branched or unbranched alkylene bridge wherein the bridge is of 3
to 6 carbon atoms; R.sup.4 is: (a) 32(b) 1-naphthyl optionally
substituted with one or two substituents, the same or different,
selected from F, Cl, Br; perfluoroalkyl, alkylthio, alkoxy,
phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the
alkyl-containing groups being 1-12 carbon atoms, (c) 3-pyrrolyl
optionally substituted with one to three alkyl groups of 1-4 carbon
atoms, (d) 2-, or 3-thienyl optionally substituted with Cl, Br, or
alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted
with alkyl it is other than the 5-position, or (e) 2-, or
3-benzothienyl or benzofuryl optionally substituted on the aromatic
ring with Cl, Br or CF.sub.3; R.sup.5 independently is alkyl of 1-4
carbon atoms or when taken together with R.sup.6 is a branched or
unbranched alkylene bridge of 3-11 carbon atoms; R.sup.6
independently is alkyl of 1-4 carbon atoms, or when taken together
with R.sup.5 is a branched or unbranched alkylene bridge of 3-11
carbon atoms; R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or
--CH.sub.2 phenyl.
37. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 33or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional or
neuropathic pain, wherein: m is 1 or 3; R.sup.1 independently is
CH.sub.3, C.sub.2H.sub.5, n-C.sub.3H.sub.7, or allyl; R.sup.2 and
R.sup.3 independently are H or alkyl of 1-4 carbon atoms; or
R.sup.1 and R.sup.2 taken together is a branched or unbranched
alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or
R.sup.2 and R.sup.3 taken together is a branched or unbranched
alkylene bridge where the bridge is of 3 to 6 carbon atoms; R.sup.4
is: (a) phenyl or 34where X is one or two substituents the same or
different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or
dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the
alkyl-containing groups being of 1 to 12 carbon atoms; (b) 2-, 3-,
or 4-biphenyl where either or both aromatic groups are substituted
with 1 or 2 substituents, the same or different selected from F,
Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio,
perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said
alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl
groups being of 6-12 carbon atoms; (c) 1- or 2-naphthyl optionally
having one or two X substituents as defined in (a) above; (d) 2-,
3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with
one to three alkyl groups of 1-4 carbon atoms; (e) 2- or 3-thienyl
optionally substituted with one substituent selected from Cl, Br,
or alkyl of 1-4 carbon atoms; or (f) 2- or 3-benzothienyl or
benzofuryl optionally substituted on the aromatic ring with Cl, Br,
or CF.sub.3; R.sup.5 independently is alkyl of 1-4 carbon atoms, or
when taken together with R.sup.6 is a branched or unbranched
alkylene bridge of 3-11 carbon atoms; R.sup.6 independently is H,
alkyl of 1-4 carbon atoms, or when taken together with R.sup.5 is a
branched or unbranched alkylene bridge of 3-11 carbon atoms;
R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or
--CH.sub.2phenyl; or a pharmaceutically suitable salt or N-oxide
thereof.
38. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 35or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional
neuropathic pain, wherein: m is 2; R.sup.6 is H; R.sup.1
independently is CH.sub.3, C.sub.2H.sub.5, n-C.sub.3H.sub.7, or
allyl; R.sup.2 and R.sup.3 independently are H or alkyl of 1-4
carbon atoms; or R1 and R.sup.2 taken together is a branched or
unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon
atoms; or R.sup.2 and R.sup.3 taken together is a branched or
unbranched alkylene bridge where the bridge is of 3 to 6 carbon
atoms; R.sup.4 is: (a) phenyl or 36where X is one or two
substituents the same or different selected from F, Cl, Br,
perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or
phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12
carbon atoms; (b) 2-, 3-, or 4-biphenyl where either or both
aromatic groups are substituted with 1 or 2 substituents, the same
or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy,
aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio
and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12
carbon atoms and said aryl groups being of 6-12 carbon atoms; (c)
1- or 2-naphthyl optionally having one or two X substituents as
defined in (a) above; (e) 2-, 3-, or 4-pyridyl, or 2-, or
3-pyrrolyl optionally substituted with one to three alkyl groups of
1-4 carbon atoms; (f) 2- or 3-thienyl optionally substituted with
one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;
or (g) 2- or 3-benzothienyl or benzofuryl optionally substituted on
the aromatic ring with Cl, Br, or CF3; R.sup.5 independently is
alkyl of 1-4 carbon atoms; R.sup.7 is H, alkyl of 1-4 carbon atoms,
alkanoyl, or --CH.sub.2phenyl; or a pharmaceutically suitable salt
or N-oxide thereof.
39. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 37or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional or
neuropathic pain, wherein: m is 2; R.sup.6 is H; R.sup.1 is methyl;
R.sup.2 and R.sup.3 independently are H or alkyl of 1-4 carbon
atoms; or R.sup.2 and R.sup.3 taken together is a branched or
unbranched alkylene bridge where the bridge is of 3 to 6 carbon
atoms; R.sup.4 is: (a) 38where X is one or two substituents the
same or different selected from F, Cl, Br, perfluoroalkyl, alkyl,
alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in
the alkyl-containing groups being of 1 to 12 carbon atoms; (b) 2-,
3-, or 4-biphenyl where either or both aromatic groups are
substituted with 1 or 2 substituents, the same or different
selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy,
alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and
dialkylamine, amino, said alkyl and alkoxy groups being of 1-12
carbon atoms and said aryl groups being of 6-12 carbon atoms; (c)
1- or 2-naphthyl optionally having one or two X substituents as
defined in (a) above; (d) 2-, 3-, or 4-pyridyl, or 2-, or
3-pyrrolyl optionally substituted with one to three alkyl groups of
1-4 carbon atoms; (e) 2- or 3-thienyl optionally substituted with
one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;
or (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on
the aromatic ring with Cl, Br, or CF.sub.3; R.sup.5 independently
is alkyl of 1-4 carbon atoms; R.sup.7 is H, alkyl of 1-4 carbon
atoms, alkanoyl, or --CH.sub.2 phenyl; or a pharmaceutically
suitable salt or N-oxide thereof.
40. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 39or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional or
neuropathic pain, wherein: m is 2; R.sup.1 is CH.sub.3; R.sup.2 and
R.sup.3 are H; R.sup.4 is 2- or 3-thienyl, 40 where X is Cl, Br, F,
CF.sub.3; R.sup.5 is CH.sub.3; R.sup.6 is H or CH.sub.3; and
R.sup.7 is H.
41. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 41or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional or
neuropathic pain, wherein: m is 1 or 3; R.sup.1 is CH.sub.3;
R.sup.2, R.sup.3 and R.sup.7 are H; R.sup.4 is 42 where X is Cl,
Br, F or CF.sub.3; R.sup.5 is CH.sub.3; and R is H or CH.sub.3.
42. The method of claim 35, wherein the compound is selected from
the group consisting of: (a) 4-(3'-Thienyl)-.alpha.,.alpha.,
1-trimethyl-4-piperidinemethanol; (b) 4-(3'-Chlorophenyl)-.alpha.,
1-dimethylpiperidinemethanol; (c)
4-(3'-Chlorophenyl)-.alpha.,.alpha.,
1-trimethyl-4-piperidinemethanol; (d) 4-(3'-Bromophenyl)-.alpha.,
1-dimethylpiperidinemethanol; (e)
4-(3'-Bromophenyl)-.alpha.,.alpha.,
1-trimethyl-4-piperidinemethanol; (f) 4-(2-Thienyl)-.alpha.,
1-dimethylpiperidinemethanol; (g) 4-(3-Thienyl)-.alpha.,
1-dimethylpiperidinemethanol; (h) 4-(3'-Chlorophenyl)-.alpha.,
1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1-methanol; (i)
3-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-3-pyrrolidinemethanol;
(j)
4(4'-Trifluoromethylphenyl)-.alpha.-1-dimethylpiperidinemethanol;
or a pharmaceutically suitable salt thereof.
43. A method for the treatment of neuropathic pain in a patient,
comprising administering an effective amount of a compound of the
formula: 43or a pharmaceutically acceptable salt or prodrug
thereof, in combination or alternation with one or more other
agents that are useful for the treatment of conventional or
neuropathic pain, wherein: X.sup.1 and X.sup.2 are independently O
or NR.sup.2; and R.sup.1 is H, alkyl, lower alkyl alkenyl, alkynyl,
acyl, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6, --C(O)OR.sup.5,
--C(O)SR.sup.5, --C(S)R.sup.5, --C(S)NR.sup.5R.sup.6,
--C(S)OR.sup.5, --C(S)SR.sup.5, --C(NR.sup.7)R.sup.5,
--C(NR.sup.7)NR.sup.5R.sup.6, --C(NR.sup.7)OR.sup.5,
--C(NR.sup.7)SR.sup.5 or phosphate; and R.sup.2, R.sup.5, R.sup.6
and R.sup.7 are independently H or alkyl.
44-67. (Cancelled)
68. The method according to claim 43, wherein the lower alkyl is
C.sub.1-C.sub.6 optionally substituted, branched or
straight-chained alkyl.
69. The method of claim 35, wherein the compound is in the form of
a dosage unit.
70. The method of claim 69, wherein the patient is a human.
71. The method of claim 69, wherein the dosage is 50-1000 mg.
72. The method of claim 69, wherein the dosage unit is an immediate
release tablet, controlled release tablet, capsule, oral solution,
oral suspension, pill, gel, or cream.
73. The method of claim 35, wherein the compound is suitable for
oral delivery.
74. The method of claim 35, wherein the compound is suitable for
parental delivery.
75. The method of claim 35, wherein the compound is suitable for
intravenous delivery or intranasal delivery.
76. The method of claim 35, wherein the compound is suitable for
transdermal delivery.
77. The method of claim 35, wherein the compound is suitable for
rectal suppository delivery or transmucosal delivery.
78. The method of claim 35, wherein the neuropathic pain is caused
by a disorder selected from carpal tunnel syndrome, cervical or
lumbar radiculopathy, complex regional pain syndrome, spinal cord
injury, or stump pain.
79. The method of claim 35, wherein the neuropathic pain is caused
by a disorder selected from metabolic or toxic diseases.
80. The method of claim 35, wherein the neuropathic pain is caused
by endocrinologic disorders.
81. The method as in claim 80, wherein the endocrinologic disorder
is selected from diabetes mellitus, diabetic neuropathy,
amyloidosis, or amyloid polyneuropathy.
82. The method as in claim 35, wherein the neuropathic pain is
caused by a malignant tumor, Eosinophilia-myalgia syndrome,
monoclonal gammopathy, mulitiple sclerosis, stroke, postherpetic
neuralgia, neuropathy with monoclonal protein, vasculitic
neuropathy, neuropathy associated with Guillain-Barr syndrome,
neuropathy associated with Fabry's disease, entrapment due to
anatomic abnormality, trigeminal, CNS neuralgia, malignancy,
inflammatory condition, autoimmune disorder, idiopathic distal
small-fiber neuropathy, toxin, drug, dietary or absorption
abnormality, immuno-globulinemia, hereditary abnormality,
mastectomy, or amputation.
83. The method of claim 35, wherein the neuropathic pain is caused
by a viral infection.
84. The method of claim 83, wherein the viral infection is HIV
infection or herpes.
85. The method as in claim 82, wherein said autoimmune disorder is
selected from the group consisting of demyelinating inflammatory
disorders, rheumatoid arthritis, systemic lupus erythematosus, or
Sjogren's syndrome.
86. The method as in claim 82, wherein toxin or drug is selected
from the group consisting of arsenic, lead, mercury, thallium,
alcohol, vincrisitne, cisplatinum, or dideoxynucleo-side.
87. The method of claim 35, wherein the compound inhibits uptake of
serotonin, norepinephrine, or dopamine.
88. The method of claim 35, wherein the compound inhibits ectopic
activity.
89. The method of claim 35, wherein the compound inhibits ectopic
discharge in the peripheral nervous system pathways.
90. The method of claim 35, wherein the compound inhibits ectopic
discharge in the dorsal-root-ganglion cells of damaged afferent
axons.
91. The method of claim 35, wherein the treatment is a maintenance
treatment to prevent the reoccurrence of neuropathic pain.
92. The method of claim 35, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenytoin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
93. The method of claim 36, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenyloin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
94. The method of claim 37, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenyloin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
95. The method of claim 38, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenyloin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
96. The method of claim 39, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenyloin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
97. The method of claim 40, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenyloin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
98. The method of claim 41, wherein the other agents are at least
one selected from the group consisting of gabapentin, lamotrigine,
baclofen, topiramate, pregabalin, phenyloin, carbamazepine,
valproic acid, venlafaxine, paroxetine, amitriptyline HCl,
nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine
HCl, mexiletine HCl, tocainide, lidocaine, clomipramine,
clonazepam, dexamethasone, morphine, methadone HCl, fentanyl,
oxycodone, tramadol HCl and capsaicin.
Description
[0001] This application claims priority to U.S. Ser. No.
60/329,869, filed on Oct. 16, 2001.
FIELD OF THE INVENTION
[0002] This invention describes the use of
4-aryl-4-piperidinecarbinols in the treatment of neuropathic
dysfunction and neuropathic pain.
BACKGROUND OF THE INVENTION
[0003] Many people, including over three million in the United
States alone, experience neuropathic dysfunction. Neuropathic pain
associated with neuropathic dysfunction is defined as pain
associated with damage or dysfunction of peripheral or central
nervous system.
[0004] Neuropathic pain is considered a malfunction in the response
to a pathologic process occurring along and within the nervous
system nociceptive pathways and is a much more complex phenomenon
than simple pain. Pain has been defined as "an unpleasant sensory
and emotional experience associated with tissue damage or described
in terms of such damage."
[0005] The most common types of conventional pain are associated
with a response to a pathophysiologic process occurring within the
tissues, such as inflammation, due to an ongoing injury or damage.
The pain signal generates from intact primary afferent nerves that
signal noxious events, or nociceptors. Nociceptors can be
sensitized by release of algogenic agents (eg, protons,
prostaglandins, bradykinin, serotonin, adenosine, cytokines,
etc).
[0006] In contrast, neuropathic pain is associated with signals
generated ectopically and often in the absence of ongoing noxious
events by pathologic processes in the peripheral or central nervous
system. This dysfunction is associated with common symptoms such as
allodynia (pain evoked by normally nonpainful touch), hyperalgesia
(abnormally intensive and long-lasting pain from a painful
stimuli), intermittent abnormal sensations, and spontaneous,
burning, shooting, stabbing, paroxysmal or
electrical-sensations.
[0007] Neuropathic pain has been associated with sensory changes
such as paresthesias (abnormal, intermittent but nonpainful
sensations, perceived spontaneously or evoked by a stimulus) or
dysesthesias (abnormal painful sensations that are spontaneous or
evoked). Allodynia, hyperalgesia and hyperpathia are positive
sensory phenomena as opposed to the negative sensory phenomena
defined by anesthesia and hypoesthesia. Allodynia, which may be
mechanical or thermal, is the painful response to an ordinarily
non-noxious stimulus, such as one's clothing, the mere movement of
air, touch, or the nonpainful application of a cold or warm
stimulus. Hyperalgesias are exaggerated pain responses to a mildly
noxious mechanical or thermal stimulus. Hyperpathia may be
characterized as a delayed and explosive pain response to a
noxious, or at times, non-noxious stimulus.
[0008] Neuropathic pain may result from peripheral or central
nervous system pathologic events (eg, trauma, ischemia, infections)
or from ongoing metabolic or toxic diseases, infections or
endocrinologic disorders (eg, diabetes, mellitus, diabetic
neurophathy, amyloidosis, amyloid polyneuropathy (primary and
familial), neuropathies with monoclonal proteins, vasculitic
neuropathy, HIV infection, herpes zoster--shingles and postherpetic
neuralgia, etc), neuropathy associated with Guillain-Barr syndrome,
neuropathy associated with Fabry's disease, entrapment due to
anatomic abnormalities, trigeminal and other CNS neuralgias,
malignancies, inflammatory conditions or autoimmune disorders
(including demyelinating inflammatory disorders, rheumatoid
arthritis, systemic lupus erythematosus, Sjogren's syndrome), and
cryptogenic causes (idiopathic distal small-fiber neuropathy).
Other causes of neuropathic pain include exposure to toxins or
drugs (such as aresnic, thallium, alcohol, vincristine, cisplatinum
and dideoxynucleosides), dietary or absorption abnormalities,
immuno-globulinemias, hereditary abnormalities and amputations
(including mastectomy). Neuropathic pain may also result from
compression of nerve fibers, such as radiculopathies and carpal
tunnel syndrome.
[0009] During neuropathic pain, ectopic activity causes a
spontaneous discharge in the peripheral nervous system (PNS)
pathways, or depending on the location and type of nerve injury,
ectopic discharge also may originate in the dorsal-root-ganglion
(DRG) cells of damaged afferent axons. Within the same DRG, cell
bodies of uninjured axons may exhibit ectopic activity too. Within
the central nervous system (CNS), hyperexcitability of the
signaling neurons may arise, and other mechanisms that facilitate
or distort afferent input are likely. Central mechanisms underlying
chronic neuropathic pain are poorly understood. Neuroanatomic,
neurophysiologic, and neurochemical changes all occur as a response
to PNS or CNS injury. Central sensitization at a dorsal horn level,
which is mediated in part via the N-methyl-D-aspartate (NMDA)
receptor, is the best characterized change involved in the
generation of this dysfunction.
[0010] Table 4 below sets out common causes of neuropathic
dysfunction. Se generally:
www.uspharmacist.com/NewLook/DisplayArticle.cfm?item_num=536).
1 Common Etiologies of Neuropathic pain Alcohol Diabetes mellitus
type 1 and 2 Eosinophilia-myalgia syndrome Guillain-Barre syndrome
Heavy metals Arsenic Lead Mercury Thallium HIV/AIDS Malignant
tumor-related Medications amiodarone aurothioglucose cisplatinum
dapsone d4T (stavudine) ddC (zalcitabine) ddI (didanosine)
disulfiram FK 506 hydralazine isoniazid metronidazole
nitrofurantoin paclitaxel phenytoin vincristine Monoclonal
gammopathies Multiple sclerosis Post-stroke central pain
Postherpetic neuralgia Traumatic/Compression Carpal tunnel syndrome
Radiculopathy(sciatica, etc) Cervical or lumbar radiculopathy
Complex regional pain syndrome Spinal cord injury Stump pain
Trigeminal neuralgia Vasculitis Vitamin B.sub.6 megadosing Vitamin
deficiencies (B.sub.12, B.sub.1, B.sub.6 and E)
[0011] The treatment of neuropathic pain continues to be a
difficult and often unsuccessful medical challenge. For years
neuropathic pain has confounded scientists. Drugs for the treatment
of standard pain are typically ineffective against neuropathic
pain, the drugs for the treatment of neuropathic pain often have no
effect on normal pain sensation. Traditional pain treatments,
including powerful medications of last resort such as morphine and
other opioid analgesics, useful in the treatment of severe pain,
rarely alleviate neuropathic pain. The development of tolerance,
psychic and physical dependence and potentially serious opioid side
effects also limit the usefulness of opioids in treating
dysfunction. Anti-inflammatory analgesics, including the Cox-2
inhibitors, lack the efficacy of opioid analgesics and produce
other serious side effects including gastrointestinal bleeding and
gastric erosion that limits their usefulness in treating
neuropathic pain.
[0012] Starting in 1988, researchers began to identify animal
models that mimic the clinical signs of neuropathic pain. For
example, a rat with nerve injuries has been found to exhibit a
super-sensitive reaction to a hair tapped on its hindpaw. The rat
will quickly jerk away. Some humans with neuropathic pain
experience a similarly severe reaction. For them, the tickle of a
hair can translate into a long lasting, burning sensation. The
animal models of the ailment are helping scientists understand the
underlying mechanism of neuropathic pain.
[0013] Drugs that have been investigated for the use to treat
neuropathic pain include sodium channel antagonists, calcium
channel supressors, N-methyl-D-aspartate (NMDA) receptor blockers,
anticonvulsant medications, and oral tricyclic antidepressants.
[0014] Neurons have many calcium channels, including the
high-conductance channel found in the NMDA receptor. Some
participate in triggering the release of neurotransmitter from
presynaptic vesicles. In chronic constriction injury (CCI) rats,
calcium channels are known to affect the spontaneous discharge of
injured nociceptive afferents (FIG. 2). However, the drug also
exerts its well-known effects on calcium channels in cardiovascular
muscle, and the dosages that relieve pain are at or above those
causing unacceptable heart-rate and blood-pressure changes.
[0015] However, among the many varieties of calcium channels, at
least one, the N-type, a voltage-gated channel, occurs only on
neurons, not on cardiovascular muscle. In the Philippines, and
subsequently at the University of Utah, B. M. Olivera and
colleagues studied the venom of poisonous marine snails of the
genus Conus. Among hundreds of snail species throughout the Indian
and Pacific Oceans, a few survive by hunting fish. Waving a long
proboscis, they evidently create the impression of a worm. When a
fish investigates, the snail employs the proboscis to sting the
fish in the gills. In this way, it introduces a poison directly
into the fish's cardiopulmonary circulation. The fish drops dead on
the spot. Fractionating this powerful venom, the researchers found
it to be a collection of small peptides, each consisting of 13 to
29 amino acids.
[0016] Among these substances (classified as omega-conopeptides),
the researchers found one that affects the N-type calcium channel.
A synthetic replica of a compound from the fish-paralyzing snail
venom is one agent that offers relief in these animal models and
now also appears to benefit humans. New human studies indicate that
low doses of the agent cause minimal side effects and offer relief
for patients with neuropathic pain. Under the name SNX-111, it has
been synthesized by a biotechnology firm. When applied to the site
of sciatic-nerve injury in CCI rats, the treatment reduced heat
hyperalgesia and mechanical allodynia for at least three hours, but
had no effect on mechanical hyperalgesia. Application to normal
nerve had no effect on the animals' responses to any sensory
stimuli, thermal or mechanical. Hence, the relief did not represent
any anesthetic-like nerve block. Since the boluses were too small
for any significant quantities to have diffused to the spinal cord,
presynaptic blockade of neurotransmitter release within the dorsal
horn was not a tenable explanation, either. Most probably, the SNX
compound had reduced spontaneous discharge in primary afferent
fibers at and near the site of nerve damage. However, patients
cannot take the drug orally, because the stomach digests these
agents before they are able to reach the calcium entryways.
Instead, physicians administer the agent directly into the spinal
cord during a hospital visit. SNX-111 is administered by an
implanted pump and catheter that delivers it directly to the lumbar
spinal cord.
[0017] Other promising agents that can be consumed in pill form
incapacitate areas on cells called N-methyl-D-aspartate (NMDA)
receptors. Animal models have helped researchers uncover evidence
that these receptors share a special relationship with neuropathic
pain. It appears that continuous activation of NMDA receptors
reorganizes pain-sensing circuits and leads to the super-sensitive
quality of neuropathic pain. In a range of animal models studied in
numerous laboratories, several different NMDA receptor blockers
have significantly reduced neuropathic pain. Limited data amassed
from human volunteers suggest a similar effect. Among the drugs is
dextrorphan, known pharmacologically as the primary metabolite of
the over-the-counter cough suppressant dextromethorphan. When
dextrorphan was tested in CCI rats, an intraperitoneal dosage of 25
mg/kg was beneficial against heat hyperalgesia, where it normalized
the latency of the withdrawal reflex on the nerve-injured side, but
had no effect against mechanical allodynia and caused no changes on
the animals' control side.
[0018] However, unlike a neurotransmitter receptor that binds
acetylcholine or serotonin, the NMDA receptor has binding sites not
only for neurotransmitter (glutamate) but also for many other
ligands, which modifies the receptor's responsiveness. Indeed,
glutamate has no effect unless other conditions are met. The first
of these conditions involves a glycine binding site. If the site is
unoccupied, the receptor remains inactive. Throughout the CNS,
however, the extracellular concentration of glycine seems
perennially sufficient to saturate the site. A further hurdle
involves magnesium ions. The receptor incorporates a
high-conductance ion channel, which in turn can bind Mg.sup.2+. The
binding is voltage-sensitive. If the cell membrane is at its
resting bioelectric potential, the ion stays in place, preventing
other ions from passing. If, however, the cell has been excited by
other inputs, so that the membrane is partially depolarized, the
Mg.sup.2+ is released and ionic currents can flow. The partial
depolarization can be accomplished by the cell's excitatory inputs,
which, for a dorsal-horn neuron, may include glutamate (received at
non-NMDA receptors), acetylcholine, and, among peptide
neurotransmitters, substance P and calcitonin gene-related peptide.
Inhibitory influences are a similarly long list, including GABA
(from local inhibitory neurons), norepinephrine and serotonin (from
the brain), and, among neuropeptides, dynorphin and enkephalin;
Presumably, exogenous Mg.sup.2+ keeps NMDA receptors unresponsive
to glutamate. Only with glycine present and the membrane partially
depolarized, the binding of glutamate to the NMDA receptor can have
an effect. The opened ion channel conducts not only Na.sup.+, which
enters the cell, and K.sup.+, which leaves, but also Ca.sup.2+,
which enters.
[0019] Because the receptors are important components of a variety
of circuits in the brain and spinal cord that carry out different
mental functions, blocking their activity also has side effects,
such as clouded thinking. The NMDA receptor occurs at a high
density in the cerebral cortex and hippocampus. In consequence,
drugs that block the receptor can have psychological effects. One
strategy has been to identify a relatively ineffective blocker,
such that normal mental activity involving NMDA receptors may
represent low-frequency discharge at the brain's NMDA synapses and
hence may not be affected by a weak receptor blockade. In contrast,
neuropathic pain may represent high-frequency discharge, which
might be blunted even by a blocker with low affinity for the
receptor. Another strategy has been to identify usable differences
among NMDA receptor subtypes. So far, at least five have been
identified, among which one appears to show a high concentration
only in the spinal cord. A drug specific for this spinal subtype
might avoid side effects arising from engagement of the brain's
NMDA receptors.
[0020] In certain respects, epilepsy resembles neuropathic pain.
Injured sensory fibers may discharge spontaneously, though with a
clocklike regularity unlike the irregular pattern of an
epileptiform burst in cortical neurons. In both cases, the
discharge is probably due in part to abnormal distribution or
activation of voltage-gated sodium channels at the neuronal
cell-surface membrane. Therefore, the standard anticonvulsant
carbamazepine has been used against neuropathic pain, in
particular, tic douloureux, which is one of the rarest of
neuropathic syndromes. Against neuropathic pain, as against
epilepsy, the drug is thought to have dual modes of action:
blockade of sodium channels (in the manner of lidocaine) along with
potentiation of GABAergic neurotransmission (in the manner of a
barbiturate). Cells utilizing GABA as their inhibitory
neurotransmitter are known to affect the dorsal-horn neurons that
receive primary sensory afferents and emit ascending fibers. In
both neuropathic pain and epilepsy, use of the drug has been
impeded by the need to monitor liver function.
[0021] New generations of anticonvulsant medications, in particular
felbamate, were found to be effective against abnormalities
involved in neuropathic pain, at least as modeled in CCI rats.
Felbamate is implicated in a voltage-gated sodium-channel blockade,
a slight potentiation of GABAergic neurotransmission, and NMDA
receptor blockade (owing to its capacity to bind not only glutamate
but also NMDA). Nociceptive C fibers are known to use glutamate to
signal dorsal-horn neurons, which express NMDA receptors (along
with other known types of glutamate receptor). At intraperitoneal
doses of up to 600 mg/kg (the drug's antiepileptic range in rats),
the high doses completely abolished abnormal sensations in the four
measurable ways: heat hyperalgesia, mechanical hyperalgesia,
mechanical allodynia and hindpaw guarding. Heat hyperalgesia was
tested by noxious heat to the hindpaw. Mechanical hyperalgesia was
tested by the tip of a safety pin, pushed slowly until it dimpled
the hindpaw skin. Mechanical allodynia was tested by von Frey
hairs. All effects lasted two to 12 hours. In the control hindpaw,
all responses were unaffected, indicating that the drug acted
specifically against neuropathic pain, rather than being broadly
analgesic. With only limited solubility in intrathecal media,
felbamate could not be tested directly for a spinal site of action.
However, the U.S. Food and Drug Administration found that felbamate
had been found to cause liver failure and aplastic anemia,
sometimes fatally, in humans.
[0022] Anticonvulsants, gabapentin and lamotrigine, have been
widely used for several years. In CCI rats, gabapentin was tested
both intraperitoneally (at 10 to 75 mg/kg) and intrathecally (to
the lumbar spinal cord, at 37.5 to 150 mg/kg). At two and four
hours, the intraperitoneal injections suppressed heat hyperalgesia
and mechanical allodynia. In some instances, the suppression of
heat hyperalgesia was complete. Against mechanical hyperalgesia,
the drug lacked effect. At 24 hours, abnormal responses had
returned. For the intrathecal injections, the pattern was similar,
implying a spinal site of drug action. On the control side,
gabapentin, like felbamate, caused no significant change in any
responses. Chemically, gabapentin is a small, cyclic GABA analogue.
Curiously, it has no direct effect on GABA receptors. Indirect
effects have been proposed, for example, an upregulation of
intracellular GABA storage. Gabapentin binds with high affinity to
a subunit of a voltage-gated calcium channel distributed unevenly
throughout the nervous system. It remains uncertain precisely which
types of calcium channel have the subunit.
[0023] It is widely accepted that oral tricyclic antidepressants
(TCAs) are useful adjuncts in treating neuropathic pain. In
addition, tricyclic antidepressants may be better tolerated than
anticonvulsants. While tricyclic antidepressants are not recognized
as primary agents to treat neuropathic pain, TCAs have an effect of
serotonin (5-HT) release, the noradrenergic pathways and a sodium
channel blocking effect (S. Butler, Adv. Pain Res. Ther. 7:173-197,
1984), with evidence of efficacy existing for amitriptylin,
imipramine, desimipramine and clomipramine. This effect is
independent of their antidepressant effect and may be dose related.
In fact, there is a lack of evidence for efficacy of selective
serotonin reuptake inhibitors (SSRI) antidepressants for treating
neuropathic pain. Recent work has highlighted a potential effect of
topical doxepin, a TCA, in neuropathic pain. The topical
application of doxepin is associated with few side effects, and
particularly central side-effects.
[0024] Venlafaxine has been clinically evaluated for painful
diabetic neuropathy (See for example, Pernia, A.; Mico, J. A.;
Calderon, E.; Torres, L. M. "Venlafaxine for the treatment of
neuropathic pain" J Pain Symptom Manage, 2000, 19(6):408-10;
Kiayias, J. A.; Vlachou E. D.; Lakka-Papadodima, E. "Venlafaxine
HCl in the treatment of painful peripheral diabetic neuropathy"
Diabetes Care, 2000, 23(5):699; Ansari, A. "The efficacy of newer
antidepressants in the treatment of chronic pain: a review of
current literature" Harv Rev Psychiatry 2000; 7(5):257-77; and
Davis, J. L.; Smith, R. L. "Painful peripheral diabetic neuropathy
treated with venlafaxine HCl extended release capsules" Diabetes
Care 1999, 22(11):1909-10).
[0025] Despite the research on, neuropathic pain to date, very few
therapies have been identified that are not associated with
significant negative side effects. The research has been made more
difficult by the inability to extrapolate success in conventional
pain therapy to successful treatment of neuropathic dysfunction and
associated pain. Because of neuropathic pains' distinct
pathophysiology and response to pharmacotherapy, the FDA considers
"neuropathic pain", a unique and stand-alone indication, separate
from "chronic pain," "arthritis pain," "migraine pain," and "acute
pain." Certain 4-arylpiperidinecarbinols are known to have
antidepressant activity. These compounds and methods for preparing
them are disclosed in Ciganek, U.S. Pat. No. 4,485,109, issued Nov.
27, 1984 (E. I. DuPont de Nemours and Company).
[0026] 4-Aryl4-piperdine (or pyrrolidine or
hexahydroazepine)carbinols and heterocyclic analogs, including
4-(3-thienyl)-.alpha.,.alpha.,1-trimethyl- -4-piperidinemethanol,
are disclosed in U.S. Pat. Nos. 5,019,650 and 5,086,063 as
compounds useful in the treatment of depression and conventional
pain.
[0027] U.S. Pat. No. 3,108,111 to Stern et al., Nov. 22, 1963,
discloses piperidine compounds useful as cough suppressants and
analgesics.
[0028] U.S. Pat. No. 3,080,372 to Janssen, Mar. 5, 1963, discloses
pharmaceutically useful piperidines.
[0029] JP 5,9106-460-A discloses antifungal and analgesic nitrogen
containing heterocycles, including piperidines.
[0030] BE 775,611 discloses
1-(3,3-diphenyl-1-propyl)-4-arylpiperidines as analgesics,
spasmolytics and antitussive agents.
[0031] Several secondary piperidinecarbinols have been reported in
the literature. Representative of these are M. A. lorio et al.,
Tetrahedron, 4983 (1971); F. Bergel et al., J. Chem. Soc., 26,
(1944); A. D. MacDonald et al., Brit J. Pharmacol., 1,4 (1946); A.
L. Morrison et al., J. Chem. Soc., 1467, (1950); H. Kagi et al.,
Helv. Chim. Acta, 7,2489 (1949); U. Bondesson et al., Drug Metab.
Dispos., 9, 376 (1981); U. Bondesson et al., Acta Pharm. Suec., 11,
1 (1980).
[0032] Given that neuropathic disorders are chronic, extremely
disabling and refractory to currently available analgesics, it
would be of great benefit to provide new compositions and methods
for its treatment.
[0033] Therefore, it is one object of the present invention to
provide pharmaceutical compositions for the treatment of
neuropathic disorders and associated dysfunction and pain.
[0034] It is another embodiment of the present invention to provide
methods and uses of compounds and compositions for the treatment of
neuropathic pain.
SUMMARY OF THE INVENTION
[0035] It has been discovered that
4-(3-thienyl)-.alpha.,.alpha.,1,1-trime- thyl-4-piperidinemethanol
(the compound of formula III, also referred to herein as compound A
or EN 3215) or its pharmaceutically acceptable salt or prodrug is a
superior compound for the treatment of neuropathic pain, and thus
can be used to treat a patient suffering from any symptom arising
from this dysfunction. Unlike opioid analgesics, it does not show
significant activity at mu, kappa, delta or sigma receptor sites in
the brain. Studies in animals show that it lacks the addictive and
respiratory depressant properties of narcotic-related analgesics.
Unlike anti-inflammatory analgesics, it does not inhibit
prostaglandin synthesase activity or show anti-inflammatory effects
in vivo. Like the tricyclic antidepressants, it inhibits uptake of
serotonin, norepinephrine and/or dopamine in rat brain
preparations. Effective doses of the compound of the invention for
the treatment of neuropathic pain are not accompanied by
significant anticholinergic side effects, sedation or other signs
of motor impairment observed with tricyclic antidepressants.
[0036] In another embodiment, a compound of the formula (I) is
provided for the treatment of neuropathic pain: 1
[0037] or its pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0038] m is 1, 2 or 3;
[0039] R.sup.1 is CH.sub.3, C.sub.2H.sub.5, n-C.sub.3H.sub.7 or
allyl;
[0040] R.sup.2 and R.sup.3 independently are H or alkyl of 1-4
carbon atoms; or R.sup.1 and R.sup.2 taken together is a branched
or unbranched alkylene bridge wherein the bridge is of 3 or 4
carbon atoms; or R.sup.2 and R.sup.3 taken together is a branched
or unbranched alkylene bridge wherein the bridge is of 3 to 6
carbon atoms;
[0041] R.sup.4 is:
[0042] (a) phenyl or 2
[0043] wherein X is one or two substituents, the same or different,
selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or
dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the
alkyl-containing groups being of 1 to 12 carbon atoms;
[0044] (b) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where
either or both aromatic groups are substituted with 1 or 2
substituents, the same or different, selected from F, Cl, alkyl,
perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy,
arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and
alkoxy groups being of 1-12 carbon atoms and said aryl groups being
of 6-12 carbon atoms;
[0045] (c) 1- or 2-naphthyl optionally having one or two X
substituents as defined in (a) above;
[0046] (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally
substituted with one to three alkyl groups of 1-4 carbon atoms;
[0047] (e) 2- or 3-thienyl optionally substituted with one
substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;
or
[0048] (f) 2- or 3-benzothienyl or benzofuryl optionally
substituted on the aromatic ring with Cl, Br, or CF.sub.3;
[0049] R.sup.5 is alkyl of 1-4 carbon atoms, or is taken together
with R.sup.6 to form a branched or unbranched alkylene bridge of
3-11 carbon atoms;
[0050] R.sup.6 is H, alkyl of 1-4 carbon atoms, or is taken
together with R.sup.5 to form a branched or unbranched alkylene
bridge of 3-11 carbon atoms; and
[0051] R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 14
carbon atoms, or --CH.sub.2phenyl; or a pharmaceutically salt or
N-oxide thereof, provided that when
[0052] 1) R.sup.1, R.sup.5 and R.sup.6 are methyl, and R.sup.2 and
R.sup.3 are H, then R.sup.4 is not 3,4-F.sub.2C.sub.6H.sub.3,
3,4-C.sub.12C.sub.6H.sub.3, p-t-butylphenyl,
2,3-(MeO).sub.2C.sub.6H.sub.- 3, 2,5-(MeO).sub.2C.sub.6H.sub.3, or
3-pyridyl;
[0053] 2) R.sup.1, R.sup.5 and R.sup.6 are methyl or R.sup.5 and
R.sup.6 are taken together as --(CH.sub.2).sub.6-- and
--(CH.sub.2).sub.7--, then R.sup.4 is not
3-(MeO)C.sub.6H.sub.4.
[0054] Also provided is a novel class of carbinols useful for the
treatment of neuropathic pain, having the formula (II): 3
[0055] wherein
[0056] when m is 2 and R.sup.6 is other than H, R.sup.1, R.sup.2
and R.sup.3 are as defined above;
[0057] R.sup.4 is:
[0058] (a) 4
[0059] (b) 1-naphthyl optionally substituted with one or two
substituents, the same or different, selected from F, Cl, Br;
perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or
dialkylamino, said alkyl in the alkyl-containing groups being 1-12
carbon atoms.
[0060] (c) 3-pyrrolyl optionally substituted with one to three
alkyl groups of 1-4 carbon atoms,
[0061] (d) 2-, or 3-thienyl optionally substituted with Cl, Br, or
alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted
with alkyl it is other than the 5-position, or
[0062] (e) 2-, or 3-benzothienyl or benzofuryl optionally
substituted on the aromatic ring with Cl, Br or CF.sub.3;
[0063] R.sup.5 independently is alkyl of 1-4 carbon atoms or when
taken together with R.sup.6 is a branched or unbranched alkylene
bridge of 3-11 carbon atoms;
[0064] R.sup.6 independently is alkyl of 1-4 carbon atoms, or when
taken together with R.sup.5 is a branched or unbranched alkylene
bridge of 3-11 carbon atoms;
[0065] R.sup.7 is H, alkyl of 14 carbon atoms, alkanoyl, or
--CH.sub.2phenyl; and
[0066] when m is 1 or 3, or when R.sup.6 is H and m is 2; then
R.sup.1 independently is CH.sub.3, C.sub.2H.sub.5,
n-C.sub.3H.sub.7, or allyl;
[0067] R.sup.2 and R.sup.3 independently are H or alkyl of 1-4
carbon atoms; or R.sup.1 and R.sup.2 taken together is a branched
or unbranched alkylene bridge wherein the bridge is of 3 or 4
carbon atoms;
[0068] or R.sup.2 and R.sup.3 taken together is a branched or
unbranched alkylene bridge where the bridge is of 3 to 6 carbon
atoms;
[0069] R.sup.4 is:
[0070] (a) phenyl or 5
[0071] where X is one or two substituents the same or different
selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or
dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the
alkyl-containing groups being of 1 to 12 carbon atoms;
[0072] (b) 2-, 3-, or 4-biphenyl where either or both aromatic
groups are substituted with 1 or 2 substituents, the same or
different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy,
aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio
and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12
carbon atoms and said aryl groups being of 6-12 carbon atoms;
[0073] (c) 1- or 2-naphthyl optionally having one or two X
substituents as defined in (a) above;
[0074] (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally
substituted with one to three alkyl groups of 1-4 carbon atoms;
[0075] (e) 2- or 3-thienyl optionally substituted with one
substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;
or
[0076] (f) 2- or 3-benzothienyl or benzofuryl optionally
substituted on the aromatic ring with Cl, Br, or CF.sub.3;
[0077] R.sup.5 independently is alkyl of 1-4 carbon atoms, or when
taken together with R.sup.6 is a branched or unbranched alkylene
bridge of 3-11 carbon atoms;
[0078] R.sup.6 independently is H, alkyl of 1-4 carbon atoms, or
when taken together with R.sup.5 is a branched or unbranched
alkylene bridge of 3-11 carbon atoms;
[0079] R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or
--CH.sub.2.degree. phenyl; or
[0080] a pharmaceutically suitable salt or N-oxide thereof,
[0081] provided that when R.sup.6 is H, R.sup.1 is methyl and m is
2, then R.sup.4 is other than C.sub.6H.sub.5,
2-(MeO)C.sub.6H.sub.4, 2,3-(MeO).sub.2C.sub.6H.sub.3 and
pharmaceutically suitable salts or N-oxides thereof.
[0082] Preferred compounds are those of Formula (I) where when m is
2:
[0083] (a) R.sup.1 is CH.sub.3; or
[0084] (b) R.sup.2 and R.sup.3 are H; or
[0085] (c) R.sup.4 is 2- or 3-thienyl, or 6
[0086] where X is Cl, Br, F, CF.sub.3; or
[0087] (d) R.sup.5 is CH.sub.3; or
[0088] (e) R.sup.6 is H or CH.sub.3; or
[0089] (f) R.sup.7 is H.
[0090] Preferred compounds are those of Formula (I) where when m is
1 or 3;
[0091] (a) R.sup.1 is CH.sub.3; or
[0092] (b) R.sup.2, R.sup.3 and R.sup.7 are H; or
[0093] (c) R.sup.4 is 7
[0094] where X is Cl, Br, F or CF.sub.3; or
[0095] (d) R.sup.5 is CH.sub.3; or
[0096] (e) R.sup.6 is H or CH.sub.3.
[0097] Specifically preferred compounds are the following:
[0098] (a)
4-(3'-Thienyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethanol-
;
[0099] (b) 4-(3'-Chlorophenyl)-.alpha.,
1-dimethylpiperidinemethanol;
[0100] (c)
4-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemet-
hanol;
[0101] (d)
4-(3'-Bromophenyl)-.alpha.,1-dimethylpiperidinemethanol;
[0102] (e)
4-(3'-Bromophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemeth-
anol;
[0103] (f) 4-(2-Thienyl)-.alpha.,1-dimethylpiperidinemethanol;
[0104] (g) 4-(3-Thienyl)-.alpha.,1-dimethylpiperidinemethanol;
[0105] (h)
4-(3'-Chlorophenyl)-.alpha.,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-
-azepine-1-methanol;
[0106] (i)
3-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-3-pyrrolidineme-
thanol; and
[0107] (j)
4(4'-Trifluoromethylphenyl)-.alpha.-1-dimethylpiperidinemethano-
l
[0108] or a pharmaceutically suitable salt thereof.
[0109] Also provided is a compound having the formula (III): 8
[0110] or its pharmaceutically acceptable salt or prodrug thereof,
for the treatment or prophylaxis of neuropathic pain.
[0111] Alternatively, provided is a compound having the formula
(IV): 9
[0112] or its pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0113] X.sup.1 and X.sup.2 are independently O or NR.sup.2; and
[0114] R.sup.1 is H, alkyl, lower alkyl (such as a C.sub.1 to
C.sub.6 optionally substituted branched or straight-chained alkyl);
alkenyl, alkynyl, acyl, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--C(O)OR.sup.5, --C(O)SR.sup.5, --C(S)R.sup.5,
--C(S)NR.sup.5R.sup.6, --C(S)OR.sup.5, --C(S)SR.sup.5,
--C(NR.sup.7)R.sup.5, --C(NR.sup.7)NR.sup.5R.sup.6,
--C(NR.sup.7)OR.sup.5, --C(NR.sup.7)SR.sup.5 or phosphate; and
[0115] R.sup.2, R.sup.5, R.sup.6 and R.sup.7 are independently H,
alkyl or lower alkyl (such as a C.sub.1 to C.sub.4 optionally
substituted branched or straight-chained alkyl).
[0116] In one embodiment of the present invention, a compound of
formula (I)-(IV), optionally in a pharmaceutically acceptable
carrier, are used for the treatment or prophylaxis of neuropathic
disorders and associated dysfunction and neuropathic pain.
[0117] In another embodiment of the invention, compositions
comprising compounds of the formula (I)-(IV), optionally in a
pharmaceutically acceptable carrier, in combination with one or
more other agents are useful for the treatment of neuropathic
pain.
[0118] In another embodiment of the invention, a method is provided
for the treatment or prophylaxis of neuropathic disorder,
dysfunction or pain comprising administering to a host, preferably
a human, an effective amount of a compound of formula (I)-(IV).
[0119] In yet another embodiment of the invention, a method is
provided for the treatment or prophylaxis of neuropathic disorder,
dysfunction or pain comprising administering to a host, preferably
a human, an effective amount of a compound of formula (I)-(IV) in
combination or alternation with one or more other active
agents.
[0120] In yet another embodiment, a use of compounds of the formula
(I)-(IV), optionally in a pharmaceutically acceptable carrier, and
optionally in combination or alternation with one or more other
agents for the treatment or prophylaxis of neuropathic disorder,
dysfunction or pain is provided.
[0121] In yet another embodiment, a use of compounds of the formula
(I)-(IV), optionally in a pharmaceutically acceptable carrier,
optionally in combination or alternation with one or more other
agents in the manufacture of a medicament for the treatment or
prophylaxis of neuropathic pain is provided.
BRIEF DESCRIPTION OF THE FIGURES
[0122] FIG. 1 is an illustration of the anatomic and biochemical
rewiring seen in the CNS after nerve injury, indicating that
neuropathic pain represents the activity of a sensory processing
system at least partly new. In the normal circuitry (top), sensory
axons with cell bodies in dorsal root ganglia convey sensation to
the spinal cord's dorsal horn, which in turn emits signals via
ascending sensory pathways. A representative large-diameter touch
fiber has its own ascending branch, while a thinner pain fiber is
shown making local spinal connections. After nerve injury, the pain
fiber appears to use an altered set of peptides. Meanwhile,
substance P begins to appear in touch fibers, which now arborize in
dorsal-horn laminae, where their ramifications would not normally
occur. See Table below:
2 Site Biochemical Change Anatomic Change 1. Sensory periphery De
novo expression of functional receptors (e.g., opioid, alpha-
adrenergic) at nociceptive terminals 2. Primary afferent Decreased
synthesis (e.g., of Sprouting of sympathetic neuron with small-
substance P, calcitonin gene-related fibers from normal targets
diameter, presumably peptide) (blood vessels) to primary
nociceptive, fiber Increased synthesis (e.g., of neuro- afferent
cell bodies peptide Y, vasoactive intestinal polypeptide,
somatostatin, galanin) 3. Primary afferent Increased synthesis
(e.g., of Sprouting of presynaptic neuron with large- substance P,
neuropeptide Y) ramifications into diameter touch fiber superficial
dorsal horn, where normally only nociceptors terminate 4.
Dorsal-horn neuron Increased synthesis (e.g., of opioid peptides)
Time-varying changes in opioid receptor classes (micro, delta,
kappa) 5. Brainstem neuron Responsiveness to substance P (dorsal
column nuclei) released from touch fibers
[0123] This rewiring helps explain why drugs useful against normal
pain are largely ineffective against neuropathic pain, whereas
drugs against neuropathic pain are not analgesic (see
www.hosppract.com/issues/1998/10/- bennett.htm).
[0124] FIG. 2 is an illustration of the receptor implicated in the
treatment of neuropathic pain.
[0125] FIG. 3 is a non-limiting example of the synthesis of
compounds of the present invention.
[0126] FIG. 4 is a non-limiting example of a preferred embodiment
for the synthesis of a compound of the present invention,
4-(3-thienyl)-.alpha.,.-
alpha.,1-trimethyl-4-piperidinemethanol.
[0127] FIG. 5 is an illustration of the efficacy of the compound of
the present invention, and in particular of
4-(3-thienyl)-.alpha.,.alpha.,1-t- rimethyl-4-piperidinemethanol,
in the treatment of neuropathic pain using the formalin model with
respect to venlafaxine and a saline control. FIGS. 5A and 5C are
line graphs showing the measured flinches per minute over sixty
minutes of observation of animals dosed with EN3512 or venlafaxine,
respectively. EN3512 and venlafaxine were given at 200 mg/100 mg/50
mg per kg orally and saline was administered as a control. FIGS. 5B
and 5D are bar graphs depicting the cumulative measured flinches
during the two main phases of the formalin test: phase I--an acute
nociceptive component; and phase II--a chronic nociceptive
component characterized by hyperalgesia.
[0128] FIG. 6 is an illustration of the efficacy of the compound of
the present invention, and in particular of
4-(3-thienyl)-.alpha.,.alpha.,1-t- rimethyl-4-piperidinemethanol,
in the treatment of neuropathic pain using the Chung model with
respect to venlafaxine and a saline control. FIGS. 6A and 6C are
line graphs showing the increased tactile threshold of the animals
at different doses of compound A (200 mg/kg; 100 mg/kg, 50 mg/kg,
and saline PO control) and venlafaxine (200 mg/kg; 100 mg/kg; 50
mg/kg; and saline PO control), respectively, over a 24 hour period.
FIGS. 6B and 6D are bar graphs depicting the percent maximum effect
of drug relative to rats that did not undergo the surgical
procedure.
DETAILED DESCRIPTION OF THE INVENTION
[0129] It has been discovered that the compound of formulas I-IV,
and in particular,
4-(3-thienyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethano- l
(the compound of formula III, also referred to herein as compound A
or EN3215) or its pharmaceutically acceptable salt or prodrug is a
superior compound for the treatment of neuropathic dysfunction and
associated pain, and thus can be used to treat a patient suffering
from any symptom arising from this dysfunction.
[0130] Unlike opioid analgesics, EN3215 does not show significant
activity at mu, kappa, delta or sigma receptor sites in the brain.
Studies in animals show that it lacks the addictive and respiratory
depressant properties of narcotic-related analgesics. Unlike
anti-inflammatory analgesics, it does not inhibit prostaglandin
synthesase activity or show anti-inflammatory effects in vivo. Like
the tricyclic antidepressants, it inhibits uptake of serotonin,
norepinephrine and/or dopamine in rat brain preparations. However,
effective doses of the compound of the invention for the treatment
of neuropathic pain are not accompanied by anticholinergic side
effects, sedation or other signs of motor impairment observed with
tricyclic antidepressants.
[0131] In one embodiment, compounds of the present invention,
optionally in a pharmaceutically acceptable carrier, are used for
the treatment or prophylaxis of neuropathic dysfunction or
pain.
[0132] In another embodiment of the invention, compositions
comprising compounds of the present invention, optionally in a
pharmaceutically acceptable carrier, in combination with one or
more other agents are useful for the treatment of neuropathic
dysfunction or pain.
[0133] In another embodiment of the invention, a method is provided
for the treatment or prophylaxis of neuropathic dysfunction or pain
comprising administering to a host, preferably a human, an
effective amount of a compounds of the present invention.
[0134] In yet another embodiment of the invention, a method is
provided for the treatment or prophylaxis of neuropathic
dysfunction or pain comprising administering to a host, preferably
a human, an effective amount of a compounds of the present
invention in combination or alternation with one or more other
agents are useful for the treatment of neuropathic pain.
[0135] In yet another embodiment, use of the compound of the
present invention, optionally in a pharmaceutically acceptable
carrier, and optionally in combination or alternation with one or
more other agents for the treatment or prophylaxis of neuropathic
dysfunction or pain is provided.
[0136] In yet another embodiment, use of the compound of the
present invention, optionally in a pharmaceutically acceptable
carrier, and optionally in combination or alternation with one or
more other agents in the manufacture of a medicament for the
treatment or prophylaxis of neuropathic dysfunction or pain is
provided.
[0137] I. Active Compounds of the Invention
[0138] The invention includes a compound of the formula: 10
[0139] or its pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0140] m is 1, 2 or 3;
[0141] R.sup.1 is CH.sub.3, C.sub.2H.sub.5, n-C.sub.3H.sub.7 or
allyl;
[0142] R.sup.2 and R.sup.3 independently are H or alkyl of 1-4
carbon atoms; or R.sup.1 and R.sup.2 taken together is a branched
or unbranched alkylene bridge wherein the bridge is of 3 or 4
carbon atoms; or R.sup.2 and R.sup.3 taken together is a branched
or unbranched alkylene bridge wherein the bridge is of 3 to 6
carbon atoms;
[0143] R.sup.4 is:
[0144] (g) phenyl or 11
[0145] wherein X is one or two substituents, the same or different,
selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or
dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the
alkyl-containing groups being of 1 to 12 carbon atoms;
[0146] (h) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where
either or both aromatic groups are substituted with 1 or 2
substituents, the same or different, selected from F, Cl, alkyl,
perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy,
arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and
alkoxy groups being of 1-12 carbon atoms and said aryl groups being
of 6-12 carbon atoms;
[0147] (i) 1- or 2-naphthyl optionally having one or two X
substituents as defined in (a) above;
[0148] (1) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally
substituted with one to three alkyl groups of 1-4 carbon atoms;
[0149] (k) 2- or 3-thienyl optionally substituted with one
substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;
or
[0150] (l) 2- or 3-benzothienyl or benzofuryl optionally
substituted on the aromatic ring with Cl, Br, or CF.sub.3;
[0151] R.sup.5 is alkyl of 1-4 carbon atoms, or is taken together
with R.sup.6 to form a branched or unbranched alkylene bridge of
3-11 carbon atoms;
[0152] R.sup.6 is H, alkyl of 1-4 carbon atoms, or is taken
together with R.sup.5 to form a branched or unbranched alkylene
bridge of 3-11 carbon atoms; and
[0153] R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4
carbon atoms, or --CH.sub.2phenyl; or a pharmaceutically salt or
N-oxide thereof, provided that when
[0154] 3) R.sup.1, R.sup.5 and R.sup.6 are methyl, and R.sup.2 and
R.sup.3 are H, then R.sup.4 is not 3,4-F.sub.2C.sub.6H.sub.3,
3,4-Cl.sub.2C.sub.6H.sub.3, p-t-butylphenyl,
2,3-(MeO).sub.2C.sub.6H.sub.- 3, 2,5-(MeO).sub.2C.sub.6H.sub.3, or
3-pyridyl;
[0155] 4) R.sup.1, R.sup.5 and R.sup.6 are methyl or R.sup.5 and
R.sup.6 are taken together as --(CH.sub.2).sub.6-- and
--(CH.sub.2).sub.7--, then R.sup.4 is not
3-(MeO)C.sub.6H.sub.4.
[0156] Also provided is a novel class of carbinols useful for the
treatment of neuropathic pain, having the formula (II): 12
[0157] wherein
[0158] when m is 2 and R.sup.6 is other than H, R.sup.1, R.sup.2
and R.sup.3 are as defined above;
[0159] R.sup.4 is:
[0160] (f) 13
[0161] (g) 1-naphthyl optionally substituted with one or two
substituents, the same or different, selected from F, Cl, Br;
perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or
dialkylamino, said alkyl in the alkyl-containing groups being 1-12
carbon atoms.
[0162] (h) 3-pyrrolyl optionally substituted with one to three
alkyl groups of 1-4 carbon atoms,
[0163] (i) 2-, or 3-thienyl optionally substituted with Cl, Br, or
alkyl of 14 carbon atoms, provided when 2-thienyl is substituted
with alkyl it is other than the 5-position, or
[0164] (j) 2-, or 3-benzothienyl or benzofuryl optionally
substituted on the aromatic ring with Cl, Br or CF.sub.3;
[0165] R.sup.5 independently is alkyl of 1-4 carbon atoms or when
taken together with R.sup.6 is a branched or unbranched alkylene
bridge of 3-11 carbon atoms;
[0166] R.sup.6 independently is alkyl of 1-4 carbon atoms, or when
taken together with R.sup.5 is a branched or unbranched alkylene
bridge of 3-11 carbon atoms;
[0167] R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or
--CH.sub.2phenyl; and
[0168] when m is 1 or 3, or when R.sup.6 is H and m is 2; then
R.sup.1 independently is CH.sub.3, C.sub.2H.sub.5,
n-C.sub.3H.sub.7, or allyl;
[0169] R.sup.2 and R.sup.3 independently are H or alkyl of 1-4
carbon atoms; or R.sup.1 and R.sup.2 taken together is a branched
or unbranched alkylene bridge wherein the bridge is of 3 or 4
carbon atoms; or R.sup.2 and R.sup.3 taken together is a branched
or unbranched alkylene bridge where the bridge is of 3 to 6 carbon
atoms;
[0170] R.sup.4 is:
[0171] (g) phenyl or 14
[0172] where X is one or two substituents the same or different
selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or
dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the
alkyl-containing groups being of 1 to 12 carbon atoms;
[0173] (h) 2-, 3-, or 4-biphenyl where either or both aromatic
groups are substituted with 1 or 2 substituents, the same or
different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy,
aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio
and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12
carbon atoms and said aryl groups being of 6-12 carbon atoms;
[0174] (i) 1- or 2-naphthyl optionally having one or two X
substituents as defined in (a) above;
[0175] (1) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally
substituted with one to three alkyl groups of 1-4 carbon atoms;
[0176] (k) 2- or 3-thienyl optionally substituted with one
substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms;
or
[0177] (1) 2- or 3-benzothienyl or benzofuryl optionally
substituted on the aromatic ring with Cl, Br, or CF.sub.3;
[0178] R.sup.5 independently is alkyl of 1-4 carbon atoms, or when
taken together with R.sup.6 is a branched or unbranched alkylene
bridge of 3-11 carbon atoms;
[0179] R.sup.6 independently is H, alkyl of 1-4 carbon atoms, or
when taken together with R.sup.5 is a branched or unbranched
alkylene bridge of 3-11 carbon atoms;
[0180] R.sup.7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or
--CH.sub.2phenyl; or
[0181] a pharmaceutically suitable salt or N-oxide thereof,
[0182] provided that when R.sup.6 is H, R.sup.1 is methyl and m is
2, then R.sup.4 is other than C.sub.6H.sub.5,
2-(MeO)C.sub.6H.sub.4, 2,3-(MeO).sub.2C.sub.6H.sub.3 and
pharmaceutically suitable salts or N-oxides thereof.
[0183] Preferred compounds are those of Formula (I) where when m is
2:
[0184] (g) R.sup.1 is CH.sub.3; or
[0185] (h) R.sup.2 and R.sup.3 are H; or
[0186] (i) R.sup.4 is 2- or 3-thienyl, or 15
[0187] where X is Cl, Br, F, CF.sub.3; or
[0188] (j) R.sup.5 is CH.sub.3; or
[0189] (k) R.sup.6 is H or CH.sub.3; or
[0190] (l) R.sup.7 is H.
[0191] Preferred compounds are those of Formula (I) where when m is
1 or 3;
[0192] (f) R.sup.1 is CH.sub.3; or
[0193] (g) R.sup.2, R.sup.3 and R.sup.7 are H; or
[0194] (h) R.sup.4 is 16
[0195] where X is Cl, Br, F or CF.sub.3; or
[0196] (i) R.sup.5 is CH.sub.3; or
[0197] (j) R.sup.6 is H or CH.sub.3.
[0198] Specifically preferred compounds are the following:
[0199] (a)
4-(3'-Thienyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethanol-
;
[0200] (b) 4-(3'-Chlorophenyl)-.alpha.,
1-dimethylpiperidinemethanol;
[0201] (c)
4-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemet-
hanol;
[0202] (d)
4-(3'-Bromophenyl)-.alpha.,1-dimethylpiperidinemethanol;
[0203] (e)
4-(3'-Bromophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemeth-
anol;
[0204] (f) 4-(2-Thienyl)-.alpha.,1-dimethylpiperidinemethanol;
[0205] (g) 4-(3-Thienyl)-.alpha.,1-dimethylpiperidinemethanol;
[0206] (h) 4-(3'-Chlorophenyl)-.alpha.,
1-dimethyl-2,3,4,5,6,7-hexahydro-1- H-azepine-1-methanol;
[0207] (i)
3-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-3-pyrrolidineme-
thanol; and
[0208] (j)
4(4'-Trifluoromethylphenyl)-.alpha.,1-dimethylpiperidinemethano-
l
[0209] or a pharmaceutically suitable salt thereof.
[0210] Also provided is a compound having the formula (III): 17
[0211] or its pharmaceutically acceptable salt or prodrug thereof,
for the treatment or prophylaxis of neuropathic pain.
[0212] Alternatively, provided is a compound having the formula
(IV): 18
[0213] or its pharmaceutically acceptable salt or prodrug thereof,
wherein:
[0214] X.sup.1 and X.sup.2 are independently O or NR.sup.2; and
[0215] R.sup.1 is H, alkyl, lower alkyl (such as a C.sub.1 to
C.sub.6 optionally substituted branched or straight-chained alkyl);
alkenyl, alkynyl, acyl, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6,
--C(O)OR.sup.5, --C(O)SR.sup.5, --C(S)R.sup.5,
--C(S)NR.sup.5R.sup.6, --C(S)OR.sup.5, --C(S)SR.sup.5,
--C(NR.sup.7)R.sup.5, --C(NR.sup.7)NR.sup.5R.sup.6,
--C(NR.sup.7)OR.sup.5, --C(NR.sup.7)SR.sup.5 or phosphate; and
[0216] R.sup.2, R.sup.5, R.sup.6 and R.sup.7 are independently H,
alkyl or lower alkyl (such as a C.sub.1 to C.sub.4 optionally
substituted branched or straight-chained alkyl).
[0217] II. Definitions
[0218] The term "alkyl," as used herein, unless otherwise
specified, refers to a saturated straight, branched, or cyclic,
primary, secondary, or tertiary hydrocarbon, including but not
limited to those of C.sub.1 to C.sub.16, and specifically includes
methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,
t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl,
isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl,
2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be
optionally substituted with one or more moieties selected from the
group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl,
acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino,
dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thiol,
imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl,
sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl,
phosphoryl, phosphine, thioester, thioether, acid halide,
anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphate,
phosphonate, or any other viable functional group that does not
inhibit the pharmacological activity of this compound, either
unprotected, or protected as necessary, as known to those skilled
in the art, for example, as taught in Greene, et al., Protective
Groups in Organic Synthesis, John Wiley and Sons, Second Edition,
1991, hereby incorporated by reference.
[0219] The term lower alkyl, as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.6 saturated straight,
branched, or if appropriate, a cyclic (for example, cyclopropyl)
alkyl group, including both substituted and unsubstituted forms.
Some non-limiting examples include methyl, (cyclopropyl)methyl,
(cyclobutyl)methyl, (cyclopentyl)methyl, ethyl,
1-cyclopropyl-ethyl, 2-cyclopropylethyl, 1-cyclobutylethyl,
2-cyclobutylethyl, propyl, isopropyl, 1-(cyclo-propyl)propyl,
2-(cyclopropyl)propyl, 3-(cyclopropyl)propyl, cyclopropyl,
methylcyclopropyl, 2,2-dimethylcyclopropyl,
1,2-dimethylcyclopropyl, ethylcyclopropyl, propylcyclopropyl,
1-ethyl-1-methylcyclopropyl, 1-ethyl-2-methylcyclopropyl,
1,1,2-trimethylcyclopropyl, 1,2,3-trimethylcyclopropyl, butyl,
isobutyl, t-butyl, sec-butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,
cyclobutyl, methylcyclobutyl, 1,1-dimethylcyclobutyl,
1,2-dimethylcyclobutyl, 1,3-dimethylcyclobutyl, ethylcyclobutyl,
pentyl, isopentyl, neopentyl, 2-methylpentyl, 3-methylpentyl,
cyclopentyl, methylcyclopentyl, spiropentyl, methylspiropentyl,
hexyl, isohexyl and cyclohexyl.
[0220] The term alkylene refers to a saturated hydrocarbyldiyl
radical of straight or branched configuration, including but not
limited to those that have from one to ten carbon atoms. Included
within the scope of this term are methylene, 1,2-ethane-diyl,
1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl,
1,3-butane-diyl, 1,4-butane-diyl and the like.
[0221] The term "protected" as used herein and unless otherwise
defined refers to a group that is added to an oxygen, nitrogen, or
phosphorus atom to prevent its further reaction or for other
purposes. A wide variety of oxygen and nitrogen protecting groups
are known to those skilled in the art of organic synthesis.
[0222] The term acyl refers to a carboxylic acid ester in which the
non-carbonyl moiety of the ester group is selected from straight,
branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including
methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as
phenoxymethyl, aryl including phenyl optionally substituted with
halogen, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkoxy,
sulfonate esters such as alkyl or aralkyl sulphonyl including
methanesulfonyl, the mono, di or triphosphate ester, trityl or
monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g.
dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the
esters optimally comprise a phenyl group. The term "lower acyl"
refers to an acyl group in which the non-carbonyl moiety is lower
alkyl.
[0223] The term "neuropathic dysfunction" refers to any malfunction
in the response to a pathologic process occurring along and within
the nervous system nociceptive pathways. As nonlimiting examples,
neuropathic pain refers to the dysfunction associated with the
following conditions (see
www.postgradmed.com/issues/1999/11.sub.--99/neuropathic.htm).
3 Type or distribution of Condition dysfunction Diabetes Peripheral
neuropathy Mononeuropathy Radiculopathy HIV infection or AIDS
Peripheral neuropathy Mononeuropathy Radiculopathy Myelopathy
Multiple sclerosis Myelopathy Trigeminal neuralgia Scattered nerve
pain Cancer chemotherapy Peripheral neuropathy Spine surgery
Radiculopathy Alcoholism with neuropathy Peripheral neuropathy
Mononeuropathy Herpes zoster Radiculopathy (dermatome) Amputation
Neuroma Phantom limb
[0224] The term host refers to animals, in particular, mammals,
primates and humans. In most animal applications of the present
invention, the host is a human patient. Veterinary applications, in
certain indications, however, are included by the present
invention.
[0225] The term "pharmaceutically acceptable salt or prodrug" is
used throughout the specification to describe any pharmaceutically
acceptable form (such as an ester, phosphate ester, salt of an
ester or a related group) of an active compound which, upon
administration to a patient, provides the active compound.
Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic or organic bases and acids.
Suitable salts include those derived from alkali metals such as
potassium and sodium, alkaline earth metals such as calcium and
magnesium, among numerous other acids well known in the
pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a
compound that is metabolized, for example hydrolyzed or oxidized,
in the host to form the compound of the present invention. Typical
examples of prodrugs include compounds that have biologically
labile protecting groups on a functional moiety of the active
compound. Prodrugs include, but are not limited to, compounds that
can be oxidized, reduced, aminated, deaminated, hydroxylated,
dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,
acylated, deacylated, phosphorylated, or dephosphorylated to
produce the active compound. The compounds of this invention are
effective for the treatment or prophylaxis of neuropathic pain, or
are metabolized to a compound that exhibits such activity.
[0226] III. Combination and Alternation Therapies
[0227] Therapy for the treatment of neuropathic pain can be
augmented with or with without increasing dosage, via combination
and/or alternation therapy with another active agent that treats
the same or a different indication. In general, in combination
therapy, effective dosages of two or more agents are administered
together, whereas during alternation therapy, an effective dosage
of each agent is administered serially. The dosage will depend on
absorption, inactivation and excretion rates of the drug as well as
other factors known to those of skill in the art. It is to be noted
that dosage values will also vary with the severity of the
condition to be alleviated. It is to be further understood that for
any particular subject, specific dosage regimens and schedules
should be adjusted over time according to the individual need and
the professional judgment of the person administering or
supervising the administration of the compositions.
[0228] Nonlimiting examples of agents that can be used in
combination or alternation with the compounds of the present
invention include the following.
4 Drug Class Gabapentin (Neurontin .RTM.) Antiepileptic Lamotrigine
Antiepileptic Baclofen Antiepileptic Topiramate Antiepileptic
Pregabalin Antiepileptic Phenytoin (Dilatin .RTM.) Antiepileptic
Carbamazepine (Tegratol .RTM.) Antiepileptic Valproic acid
(Depakote) Antiepileptic Venlafaxine Antidepressant Paroxetine
Antidepressant Amitriptyline HCl (Elavil) Tricyclic antidepressant
Nortriptyline HCl (Aventyl Tricyclic antidepressant HCl Pulvules,
Pamelor) Dothiepin (Dolsulepine, Tricyclic antidepressant
Prothiaden) Imipramine Tricyclic antidepressant Maprotiline
Tricyclic antidepressant Desipramine HCl (Norpramin) Tricyclic
antidepressant Mexiletine HCl (Mexitil .RTM.) Antiarrhythmic
Tocainide (Tonocard .RTM.) Antiarrhythmic Lidocaine HCl (Lidoderm
.RTM.) Antiarrhythmic Clomipramine Benzodiazepine Clonazepam
(Klonopin) Benzodiazepine Dexamethasone (Decadron) Corticosteroid
Morphine Opioid Methadone HCl (Dolophine Opioid HCl, Methadose)
Fentanyl Opioid Oxycodone Opioid Tramadol HCl (Ultram) Mixed weak
opioid and serotonin reuptake blocker Zostrix .RTM. and Zostrix-HP
.RTM. Capsaicinoid
[0229] IV. Pharmaceutical Compositions
[0230] A host, including a human, exhibiting symptoms of a
neuropathic disorder or neuropathic pain, can be treated by
administering to the patient an effective amount of the active
compound or a pharmaceutically acceptable prodrug or salt thereof
optionally in the presence of a pharmaceutically acceptable carrier
or diluent. The active materials can be administered by any
appropriate route, for example, orally, parenterally,
intravenously, intradermally, subcutaneously, or topically, in
liquid or solid form. Nonlimiting examples include oral dosage
forms, in both immediate release and extended-release or controlled
release formulations, transdermal drug delivery as either a patch,
gel, or cream, injection for intravenous, intraarterial,
subcutaneous, epidural, intrathecal, or peripheral nerve, rectal
suppository, and intranasal or inhalation therapy. The drug can be
in the form of IR or ER liquid, oral solution or suspension,
immediate release or controlled release tablets, pills or
capsules.
[0231] A preferred dose of the compound for a neuropathic disorder
will be in the range from about 1 to 50 mg/kg, preferably 1 to 20
mg/kg, of body weight per day, more generally 0.1 to about 100 mg
per kilogram body weight of the recipient per day. The effective
dosage range of the pharmaceutically acceptable salts and prodrugs
can be calculated based on the weight of the parent compound to be
delivered. If the salt or prodrug exhibits activity in itself, the
effective dosage can be estimated as above using the weight of the
salt or prodrug, or by other means known to those skilled in the
art.
[0232] The compound is conveniently administered in any suitable
dosage form, including, but not limited to one containing 7 to 3000
mg, preferably 70 to 1400 mg of active ingredient per unit dosage
form. An oral dosage of 50-1000 mg is usually convenient.
[0233] The concentration of active compound in the drug composition
will depend on absorption, inactivation and excretion rates of the
drug as well as other factors known to those of skill in the art.
It is to be noted that dosage values will also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
composition. The active ingredient may be administered at once, or
may be divided into a number of smaller doses to be administered at
varying intervals of time.
[0234] A preferred mode of administration of the active compound is
oral. Oral compositions will generally include an inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches or capsules.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition. Oral dosage
forms include IR and ER liquids.
[0235] The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a
disintegrating agent such as alginic acid, Primogel or corn starch;
a lubricant such as magnesium stearate or Sterotes; a glidant such
as colloidal silicon dioxide; a sweetening agent such as sucrose or
saccharin; or a flavoring agent such as peppermint, methyl
salicylate, or orange flavoring. When the dosage unit form is a
capsule, it can contain, in addition to material of the above type,
a liquid carrier such as a fatty oil. In addition, dosage unit
forms can contain various other materials which modify the physical
form of the dosage unit, for example, coatings of sugar, shellac,
or other enteric agents.
[0236] The compound can be administered as a component of an
elixir, solution, suspension, syrup, wafer, chewing gum or the
like. A syrup may contain, in addition to the active compounds,
sucrose as a sweetening agent and certain preservatives, dyes and
colorings and flavors. Oral dosage forms include IR and ER
liquids.
[0237] The compound or a pharmaceutically acceptable prodrug or
salts thereof can also be mixed with other active materials that do
not impair the desired action, or with materials that supplement
the desired action, such as antibiotics, antifungals,
anti-inflammatories, antivirals, antiepileptics, antidepressants,
including tricyclic antidepressants, antiarrhythmics,
benzodiazepines, corticosteroids, opioids, serotonin reuptake
blockers/inhibitors, and/or capsaicinoids. Solutions or suspensions
used for parenteral, intradermal, subcutaneous, or topical
application can include the following components: a sterile diluent
such as water for injection, saline solution, fixed oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic
acid; buffers such as acetates, citrates or phosphates and agents
for the adjustment of tonicity such as sodium chloride or dextrose.
The parental preparation can be enclosed in ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0238] If administered intravenously, preferred carriers are
physiological saline or phosphate buffered saline (PBS).
[0239] In a preferred embodiment, the active compounds are prepared
with carriers that will protect the compound against rapid
elimination from the body, such as a controlled release
formulation, including implants and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters and polylactic acid. Methods for
preparation of such formulations will be apparent to those skilled
in the art. The materials can also be obtained commercially from
Alza Corporation.
[0240] Liposomal suspensions (including liposomes targeted to
particular cells, for example with monoclonal antibodies) are also
preferred as pharmaceutically acceptable carriers. These may be
prepared according to methods known to those skilled in the art,
for example, as described in U.S. Pat. No. 4,522,811 (which is
incorporated herein by reference in its entirety). For example,
liposome formulations may be prepared by dissolving appropriate
lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl
phosphatidyl choline, arachadoyl phosphatidyl choline, and
cholesterol) in an inorganic solvent that is then evaporated,
leaving behind a thin film of dried lipid on the surface of the
container. An aqueous solution of the active compound or its
monophosphate, diphosphate, and/or triphosphate derivatives is then
introduced into the container. The container is then swirled by
hand to free lipid material from the sides of the container and to
disperse lipid aggregates, thereby forming the liposomal
suspension.
[0241] The dosage administered will, of course, vary depending upon
known factors, such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the age,
health and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired. Usually, a daily dosage of
active ingredient can be about 0.001 to 50 milligrams per kilogram
of body weight. Ordinarily, a total of 0.01 to 20, preferably 0.1
to 10, milligrams per day per kilogram of body weight, given in
divided doses 2 to 4 times a day or in sustained release form, is
effective to obtain the desired therapeutic results.
[0242] Dosage forms (compositions) suitable for internal
administration can contain about 0.25 to about 400 milligrams of
active ingredient per unit. In such pharmaceutical compositions the
active ingredient will ordinarily be present in a mount of about
0.01-90% by weight, based on the total weight of the
composition.
[0243] The active compound can also be administered parenterally in
sterile liquid dosage forms or rectally in the form of
suppositories, or as a transdermal, transmucosal or intranasal
formulation.
[0244] Gelatin capsules can contain the active ingredient and
suitable carriers, such as lactose, sucrose, mannitol, starch,
cellulose derivatives, magnesium stearate and steric acid. Similar
diluents can be used to make compressed tablets. Both tablets and
capsules can be manufactured as sustained release of medication
over a period of hours. Compressed tablets can be sugar coated or
film coated to mask any unpleasant taste and protect the tablet
from the atmosphere, or they can be enteric coated for selective
disintegration in the gastrointestinal tract.
[0245] Liquid dosage forms for oral administration can contain
coloring and flavoring to increase patient acceptance.
[0246] In general, water, a suitable oil, saline, aqueous dextrose
(glucose) and related sugar solutions and glycols, such as
propylene glycol or the polyethylene glycols, are suitable carriers
for parenteral solutions. Solutions for parenteral administration
contain preferably a water-soluble salt of the active ingredient,
suitable stabilizing agents, such as sodium bisulfite, sodium
sulfite and ascorbic acid, either alone or combined, are suitable
stabilizing agents. Also used are citric acid and its salts and
sodium EDTA (ethylenediaminetetraacetic acid). In addition,
parenteral solutions can contain preservatives, such as
benzalkonium chloride, methyl- or propylparaben and
chlorobutanol.
[0247] Suppositories can contain the active ingredient in a
suitable oleaginous or water-soluble base. The oleaginous class
includes cocoa butter and other fats with similar properties; the
water-soluble class includes the polyethylene glycols.
[0248] Suitable pharmaceutical carriers are described by E. W.
Martin in Remington's Pharmaceutical Sciences, a standard reference
text in this field.
[0249] Some non-limiting examples of useful pharmaceutical dosage
forms for administration of the compounds of this invention are
listed below.
[0250] Capsules (Hard)
[0251] Hard capsules can be prepared by filling standard two-piece
hard gelatin capsules with the following mixture using conventional
encapsulating equipment:
[0252] Active ingredient: 1 mg
[0253] Lactose: 125 mg
[0254] Talc: 12 mg
[0255] Magnesium stearate: 3 mg
[0256] Capsules (Soft)
[0257] A mixture of active ingredient in soybean oil can be
prepared and injected by means of a positive displacement pump in
gelatin to form soft gelatin capsules containing 5 mg of the active
ingredient. The capsules can be washed in petroleum ether and
dried.
[0258] Tablets
[0259] Tablets can be prepared by conventional procedures so that
each unit will contain:
[0260] Active ingredient: 1 mg
[0261] Spray dried lactose: 150 mg
[0262] Microcrystalline cellulose: 35 mg
[0263] Magnesium stearate: 3 mg
[0264] Parenteral
[0265] Parenteral composition suitable for intramuscular
administration can be prepared so that each mL contains,
percentages being by weight:
[0266] Active ingredient: 1 mg
[0267] Sodium carboxymethyl cellulose: 0.75%
[0268] Polysorbate 80:0.04%
[0269] Benzyl alcohol: 0.9%
[0270] Sodium chloride: 0.9%
[0271] Water for injection Q.S.: 1 mL
[0272] Suspension
[0273] An aqueous suspension can be prepared for oral
administration so that each 5 mL contain, percentages being by
weight:
[0274] Active ingredient: 5 mg
[0275] Methylcellulose: 5%
[0276] Carboxymethyl cellulose: 5%
[0277] Syrup: 30%
[0278] Polysorbate 80:0.2%
[0279] Sodium saccharin: 2 mg
[0280] Cherry flavor: 0.1%
[0281] Sodium benzoate: 5 mg
[0282] Water Q.S.: 5 mL
[0283] V. Preparation of Active Compounds
[0284] The active compound can be prepared by the using ketones
R.sup.5C(O)R.sup.6 to give the tertiary carbinols as described in
U.S. Pat. No. 4,485,109, or by using aldehydes R.sup.5CHO to give
the secondary carbinols as described in U.S. Pat. Nos. 5,086,063
and 5,019,650.
[0285] The acetonitrile 1 (referring to FIG. 3 or 4) can be
purchased or made by any means known in the art. If a
piperidinethienylcarbinol is desired, the acetonitrile is difficult
to source, and some routes to synthesize the acetonitrile contains
highly toxic (lachrimotor) intermediates. Therefore, in a preferred
embodiment, the necessary acetonitrile 1 to obtain the
piperidinethienylcarbinol is synthesized from thiophene
carboxaldehyde. Thiophene carboxaldehyde can be reacted with an
isocyanide, preferably tosylmethyl isocyanide (TosMIC), in the
presence of a base, such as potassium t-butoxide, in a protic
solvent to obtain the desired acetonitrile 1.
[0286] Subsequently, the acetonitrile 1 is coupled with a
bis-(2-chloroethyl) alkylamine 2 (m=2) in the presence of a base by
methods described in the literature gives a
4-piperidinecarbonitrile 3 (m=2). The reaction can be carried out
with sodium or potassium hydroxide in aqueous phase in the presence
of a phase-transfer catalyst such as a quaternary ammonium or
phosphonium salt; alternatively, bases such as sodium or potassium
hydride, or sodium amide in an aprotic solvent, such as dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO), or tetrahydrofuran
(THF) can be used. Preferred temperatures are in the range of
25.degree. to 150.degree. C. In a preferred embodiment, the
coupling is achieved using potassium hydroxide in DMSO to minimize
formation of unwanted gaseous side products (as in the case of NMP,
resulting in massive heat evolution and hydrogen gas formation). In
addition, a mild work-up procedure is preferred to prevent
decomposition of the desired piperidinecarbonitrile 3.
[0287] The piperidinecarbonitrile 3 is then reacted with an
alkylmagnesium halide (such as alkylmagnesium chloride, a Grignard
reagent) in an aromatic hydrocarbon solvent, preferably at a
temperature in the range of 25'-150.degree. C., or with an
alkyllithium reagent in a mixture of ethyl ether and an aromatic or
aliphatic hydrocarbon solvent at a temperature in the range of
-50.degree. to 100.degree. C. In a preferred embodiment of the
present invention, the piperidinecarbonitrile 3 is reacted with a
alkylmagnesium bromide rather than alkylmagnesium chloride to
obtain a more complete conversion. Subsequent quenching with water
gives the imine 4 which can then be hydrolyzed with an aqueous
inorganic acid, such as hydrochloric or sulfuric acid, to give the
ketone 5. Imine 4 carrying an R.sup.4 group having substituents in
the ortho portion, usually need to be heated to 50'-100.degree. C.
to effect the hydrolysis; others hydrolyze at room temperature. The
conversion of 3 to 5 via 4 is also a well-known method in the
literature.
[0288] Reduction of a ketone 5 to a secondary alcohol (R.sup.6 is
hydrogen) is best effected by sodium borohydride in ethanol or
lithium borohydride in an ether solvent such as tetrahydrofuran at
a temperature in the range of -20.degree. to 50.degree. C. Other
hydride reducing agents, such as lithium aluminum hydride can also
be used.
[0289] Treatment of a ketone 5 with alkyllithium reagents or
alkylmagnesium halide reagents gives the tertiary carbinol 6
(R.sup.6 is alkyl). In a preferred embodiment, the ketone 5 is
treated with alkyllithium with the use of some polar additives to
promote further conversion of ketone 5 into the tertiary carbinol
6. Alternatively, the transformation can be carried out with alkyl
cerium species obtained from anhydrous cerium chloride and
alkyllithium reagents and described by T. Imamoto et al.,
Tetrahedron Lett., 25, 4233(1984). These reagents may give higher
yields and fewer side reactions. The reactions can be carried out
in ether solvents such as tetrahydrofuran, preferably at a
temperature in the range of -100.degree. to 50.degree. C. The
tertiary carbinol can also be prepared by reaction of the cerium
species with an ester derivative of ketone 5, which can be prepared
from a piperidinecarbonitrile 3 by methods described in the
literature, such as hydrolysis with sulfuric acid followed by
esterification.
[0290] Pyrrolidinecarbinols (m=1) and hexahydroazepinecarbinols
(m=3) are prepared analogously from the necessary bis-chloro
alkylamine to obtain the corresponding intermediate nitrile and
ester, which can be further derivatized to obtain the carbinol. The
esters are prepared by methods described in the literature.
[0291] Variation of R.sup.1: compounds of Formula (I) or (II) with
various groups R.sup.1 can be prepared starting from the
corresponding amines 2. Alternatively, a methyl group R.sup.1 can
be replaced by other groups as follows: 19
[0292] Nitriles 3, on heating with alkyl chloroformates in a
hydrocarbon solvent such as benzene or toluene at a temperature in
the range of 50.degree.-150.degree. C. give the urethanes 9. The
latter, on reaction with a Grignard reagent in a hydrocarbon
solvent such as benzene or toluene, give a ketones 10 where R.sup.1
is hydrogen. This ketone is converted into a ketones 5 with an
alkyl or allyl halide R.sup.1X (where X is halo, and preferably Cl,
Br or I) in a solvent such as dimethylformamide or tetrahydrofuran,
at a temperature in the range of 0.degree.-100.degree. C. in the
presence of a base such as sodium or potassium carbonate.
[0293] Alternatively, ketone of Formula 10 can also be obtained by
treating a ketone 5 (where R.sup.1 is methyl) with alkyl
chloroformates as described above to give a urethane of Formula 11.
This compound, on hydrolysis with an aqueous acid, such as
hydrochloric or sulfuric acid, at a temperature of
50.degree.-100.degree. C., gives a ketone of Formula 10. 20
[0294] For secondary carbinols (where R.sup.6 is hydrogen) having
groups R.sup.1 as CH.sub.2R.sup.9 the following methods can also be
used. 21
[0295] R.sup.9 is either methyl or ethyl, which on reduction of 12
gives compounds of Formula I where R.sup.1 is ethyl or n-propyl
respectively.
[0296] Ketones 10, on treatment with an acyl chloride R.sup.9COX
(where X is halo, and preferably chloro) or an anhydride
R.sup.9C(O)OC(O)R.sup.9 in the presence of a base, such as sodium
or potassium hydroxide in aqueous solution, or pyridine in an
aprotic solvent such as methylene chloride, at temperatures of
-30.degree. to 50.degree. C., give the amides 12 which on reduction
with borane or complex hydrides such as lithium aluminum hydride
give the secondary carbinols. This method is exemplified by Example
2.
[0297] Esters of compounds of formula (I) (R.sup.1 is alkanoyl) are
prepared by treatment of compounds of formula (I) (R.sup.1 is
hydrogen) with a suitable anhydride, or an acid chloride in the
presence of a base such as pyridine, preferably at temperatures of
.sup.0.degree.-150.degree- . C.
[0298] Ethers of compounds of formula (I) (R.sup.1 is alkyl) are
prepared by treatment of compounds of formula (I) (R.sup.1 is
hydrogen) with a base, such as sodium or potassium hydride, or
sodium amide, in an aprotic solvent such as tetrahydrofuran or
dimethylformamide, preferably at a temperature in the range of
0.degree.-100.degree. C., followed by addition of a alkylhalide
R.sup.1X (wherein X is a halogen, preferably Cl, Br or I),
preferably at temperatures of 0.degree.-100.degree. C. Any
quaternary ammonium salts of compounds of formula (I) formed are
then converted into the tertiary bases by treatment with potassium
methylmercaptide in an aprotic solvent such as dimethylformamide,
preferably at a temperature in the range of 50.degree.-150.degree.
C. Alternatively, such ethers can be prepared by reaction of
compounds of formula (I) (R.sup.1 is hydrogen) with diazoalkanes
R.sup.1N.sub.2 (wherein R.sup.1 is a methylene radical) in the
presence of a catalyst such as a rhodium complex.
[0299] Suitable salts formed with pharmaceutically acceptable
acids, such as hydrochloric, sulfuric, phosphoric and maleic acids,
can also be prepared. Such salts are usually preferable when the
free bases are oils. Such salts may also be more stable to storage,
and may be better absorbed orally, than the free bases. In a
preferred embodiment, the compound of the present invention is in
the form of its hydrochloride salt.
[0300] The present invention is described by way of illustration,
in the following examples. It will be understood by one of ordinary
skill in the art that these examples are in no way limiting and
that variations of detail can be made without departing from the
spirit and scope of the present invention.
EXAMPLES
[0301] All reagents were used as received unless stated otherwise.
Anhydrous solvents were purchased from Aldrich Chemical Company,
Inc. (Milwaukee). Melting points (mp) were determined on an
Electrothermal digit melting point apparatus and are uncorrected.
.sup.1H and .sup.13C NMR spectra were taken on a Varian Unity Plus
400 spectrometer at room temperature and reported in ppm downfield
from internal tetramethylsilane. Deuterium exchange, decoupling
experiments or 2D-COSY were performed in order to confirm proton
assignments. Signal multiplicities are represented by s (singlet),
d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet),
br (broad), bs (broad singlet), m (multiplet). All J-values are in
Hz. Mass spectra were recorded on a JEOL JMS-SX/SX102A/E mass
spectrometer. Analytic TLC was performed on Whatman LK6F silica gel
plates, and preparative TLC on Whatman PK5F silica gel plates.
Column chromatography was carried out on Silica Gel (Fisher,
S733-1) at atmospheric pressure.
Example 1
[0302] 4-(3'-Chlorophenyl)-.alpha.,1-dimethyl-4-piperidinemethanol
(m=2; R.sup.1,R.sup.5.dbd.Me;
R.sup.2,R.sup.3,R.sup.6,R.sup.7.dbd.H;
R.sup.4=3-ClC.sub.6H.sub.4)
[0303] Sodium borohydride (3.5 g, 92 mmoles) was added slowly to a
cooled mixture of 23.9 g (95 mmoles) of
1-[4-(3'-chlorophenyl)-1-methyl-4-piperi- dinyl]ethanone and 100 mL
of ethanol. Water was added after stirring at room temperature for
2 hours, and the mixture was extracted with methylene chloride to
give 24.1 g of crude product. A sample crystallized from ethyl
acetate had m.p. 125'-126.degree. C., .sup.1H NMR (CDCl.sub.3):
.delta. 7.2-7.4 (m,4H); 3.6 (quartet, J=7 Hz,1H); 2.8 (m,2H);
1.5-2.5 (m,10H) and 1.0 (d, J=7 Hz,3H).
[0304] The hydrochloride had m.p. 202.degree. C.-205.degree. C.
after crystallization from isopropyl alcohol.
[0305] Anal. Calcd. for C.sub.14H.sub.21Cl.sub.2NO: C, 57.93; H,
7.29; N, 4.83. Found: C, 57.92; H, 7.14; N, 5.11.
[0306] The starting material,
1-[4-(3'-chlorophenyl)-1-methyl-4-piperidiny- l]-ethanone was
obtained by either of the two following methods:
[0307] (a) To 400 mL of toluene was added 117 mL (0.35 mole) of 3M
methylmagnesium chloride in tetrahydrofuran. Using a Vigreux
column, 300 mL of solvent were then distilled off during 1 hour. To
the cooled residue was added 47 g (0.20 mole) of
4-(3'-chlorophenyl)-1-methylpiperid- ine-4-carbonitrile, and the
mixture was heated under reflux for 2 hours. Ten percent
hydrochloric acid (400 mL) was added to the mixture, keeping the
temperature below 25.degree. C. The layers were separated after
stirring at room temperature for 6 hours, and the toluene was
extracted with 50 mL of water. The combined water layers were made
strongly basic with conc. ammonium hydroxide solution. Extraction
with methylene chloride, removal of the solvent from the dried
extracts, and rapid short-path distillation of the residue
(160.degree. C. bath temperature, 0.1 mm) gave 44.2 g (88% yield)
of 1-[4-(3'-chlorophenyl)-1-methyl-4-pipe- ridinyl]-ethanone as an
oil that rapidly crystallizes. .sup.1H NMR (CDCl.sub.3): .delta.
7.2-7.4 (m,4H); 2.7 (m,2H); 2.5 (m,2H); 2.3 (s,3H); 2.0-2.3 (m,4H)
and 2.0 (s,3H). IR (neat) 1708 cm.sup.-1.
[0308] (b) To 12.37 g (52 mmoles) of
4-(3-chlorophenyl)-1-methylpiperidine- -4-carbonitrile dissolved in
75 mL of toluene was added 75 mL of 1.4M methyl lithium in ether
(105 mmoles), keeping the temperature below 0.degree. C. The
mixture was stirred at 0.degree. C. for 30 minutes and at
25.degree. C. for 3 hours. Ten percent hydrochloric acid (100 mL)
was added and the mixture was stirred at room temperature for 3
hours. The layers were separated, and the toluene/ether layer was
extracted with 20 mL of water. The combined aqueous phases were
made strongly basic with aqueous sodium hydroxide and the mixture
was extracted with methylene chloride. Removal of the solvent from
the dried solution gave 12.7 g of crude
1-[4-(3'-chlorophenyl)-1-methyl-4-piperidinyl]-ethanone, identical
by NMR and IR spectroscopy with the product prepared according to
procedure (a).
[0309] The starting material,
4-(3-chlorophenyl)-1-methylpiperidine-4-carb- onitrile was prepared
as follows by the procedure of T. Cammack and P. C. Reeves, J.
Heterocycl. Chem., 23, 73 (1986): a mixture of 100 g (0.52 mole) of
N,N-bis(chloroethyl)methylamine hydrochloride, 80 g (0.53 mole) of
3-chlorobenzyl cyanide, 13 g of hexadecyltributyl-phosphonium
bromide and 750 mL of 50% aqueous sodium hydroxide was stirred at
100.degree. C. internal temperature for 1 hour. Water (750 mL) was
added to the cooled mixture that was then extracted with 500 mL and
three 100-mL portions of toluene. Removal of the solvent from the
dried solution and rapid short-path distillation of the residue
(160.degree. C. bath temperature, 0.1 mm) gave 107.2 g (88% yield)
of 4-(3-chlorophenyl)-1-methylpiperidine- -4-carbonitrile as a
colorless oil which slowly crystallizes. .sup.1H NMR (CDCl.sub.3):
.delta. 7.5 (s,1H); 2.3 (m,3H); 3.0 (d,2H); 2.5 (m,2H); 2.4 (s,3H)
and 2.1 (m,4H). The hydrochloride had m.p. 235.degree.
C.-236.degree. C. after crystallization from isopropyl alcohol.
Example 1a
[0310]
4-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethano-
l (m=2; R.sup.1,R.sup.5; R.sup.6.dbd.Me;
R.sup.2,R.sup.3,R.sup.7.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4)
[0311] This compound was made by a modification of the general
method described by T. Imamoto, Y. Sagiura, and N. Takiyama,
Tetrahedron Lett., 25, 4233 (1984) for the addition of organocerium
reagents to ketones: cerium chloride heptahydrate (3.39 g, 9.1
mmoles) was dried at 140.degree. C./0.1 mm for 2 hours.
Tetrahydrofuran (20 mL) was added with ice cooling, and the mixture
was stirred under nitrogen for 2 hours. Methyl lithium (6.5 mL of a
1.4 M solution in ether, 9.1 mmoles) was added at -70.degree. C.,
and the mixture was stirred at -70.degree. C. for 30 minutes. A
solution of 0.72 g (2.7 mmoles) of
1-[4-(3'-chlorophenyl)-1-methyl-4-piperidinyl]-ethanone (Example 1)
in 2 mL of tetrahydrofuran was added at -70.degree. C., and the
mixture was allowed to come to room temperature. Methylene chloride
and aqueous ammonium hydroxide solution were added, keeping the
temperature below 0.degree. C. The mixture was filtered, and the
solids were washed repeatedly with methylene chloride. The layers
in the combined filtrate were separated and the methylene chloride
layer was dried. Removal of the solvent gave 0.76 g of the title
compound, identical by NMR and IR spectroscopy with the product
obtained by the procedure described in U.S. Pat. No. 4,485,109. The
hydrochloride had m.p. 276.degree. C. (dec.) after crystallization
from ethanol. Anal. Calcd. for C.sub.15H.sub.23Cl.sub.2NO: C,
59.21; H, 7.62; N, 4.60. Found: C, 59.08; H, 7.70; N, 4.37.
[0312]
4-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethano-
l was also prepared using the above procedure but starting with
ethyl 4-(3-chlorophenyl)-1-methylpiperidine-4-carboxylate. The
latter was prepared as follows by the procedure of J. Diamond, W.
F. Bruce, and F. T. Tyson, J. Org. Chem., 22, 399 (1957):
4-(3-chlorophenyl)-1-methylpiper- idine-4-carbonitrile (Example 1)
was added to 15 mL of 80% of sulfuric acid and the mixture was
stirred in an 125.degree. C. oil bath for 4 hours. Ethanol (60 mL)
was added with cooling, and the mixture was heated under reflux for
16 hours and then poured onto ice. The aqueous mixture was
extracted with methylene chloride and the extracts were washed with
aqueous sodium carbonate. Removal of the solvent from the dried
methylene chloride solution and short-path distillation of the
residue (180.degree. C. bath, I micron) gave 9.23 g (67%) of ethyl
4-(3-chlorophenyl)-1-methyl- piperidinecarboxylate. .sup.1H NMR
(CDCl.sub.3): .delta. 7.4 (s,1H); 7.3 (m,3H); 4.1 (quartet, J=7
Hz,2H); 2.8 (d,2H); 2.6 (d,2H); 2.3 (s,3H); 2.2 (t,2H); 2.0 (t,2H)
and 1.2 (t,J=7 Hz,3H).
Example 2
[0313]
4-(3'-Chlorophenyl)-1-ethyl-.alpha.-methyl-4-piperidinemethanol
(m=2; R.sup.1=Et; R.sup.4=3-ClC.sub.6H.sub.4; R.sup.5.dbd.Me;
R.sup.2,R.sup.3,R.sup.6,R.sup.7.dbd.H)
[0314] Ethyl chloroformate (6.5 g) was added to a solution of 5.0 g
of 1-[4-(3'-chlorophenyl)-1-methyl-4-piperidinyl]-ethanone (Example
1) in 25 mL of benzene. The mixture was heated under reflux for 3
hours, cooled, and filtered. The filtrate was washed with 10%
aqueous sodium carbonate, dried and concentrated to give 5.71 g of
ethyl 4-acetyl-4-(3'-chloropheny- l)-1-piperidine carboxylate (11;
R.sup.2,R.sup.3.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4).
[0315] A mixture of 4.69 g of the above product, 25 mL of conc.
hydrochloric acid, and 10 mL of water was heated under reflux for
18 hours. The cooled mixture was made basic with 15% aqueous sodium
hydroxide solution and extracted with methylene chloride to give
3.35 g of 1-[4-(3'-chlorophenyl).sub.4-piperidinyl]ethanone (10,
R.sup.1,R.sup.2,R.sup.3.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4). The
hydrochloride had m.p. 254.degree. C. (dec.). Anal. Calcd. for
C.sub.13H.sub.17Cl.sub.2NO; C, 56.94; H, 6.25; N, 5.11. Found: C,
56.89; H, 6.38; N, 5.51.
[0316] To a mixture of 1.0 g of the above free base, 10 mL of
methylene chloride and 20 mL of 15% aqueous sodium hydroxide was
added with cooling 1 mL of acetyl chloride and the mixture was
stirred at room temperature for 1 hour. The aqueous phase was
extracted with methylene chloride, and the combined organic phases
were dried and concentrated to give 1.15 g of
1,4-diacetyl-4-3'-chlorophenyl)-1-piperidine (12,
R.sup.2,R.sup.3.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4;
R.sup.5,R.sup.9.dbd.Me).
[0317] The above amide was dissolved in 10 mL of dry
tetrahydrofuran, and 1 mL of borane methyl sulfide complex was
added. The mixture was heated under reflux for 6 hours, cooled, and
treated with 5 mL of conc. hydrochloric acid. The solvents were
removed under vacuum, and the residue was heated with 20 mL of 10%
hydrochloric acid in an 100.degree. C. oil bath for 2 hours. The
cooled mixture was made basic with aqueous sodium hydroxide and
extracted with methylene chloride to give 0.90 g of the crude title
compound. It was purified by short-path distillation (to
200.degree. C. bath temperature, 1 micron) followed by
crystallization from ethyl acetate. M.p. 89.degree. C.-94.degree.
C.; .sup.1H NMR (CDCl.sub.3): .delta. 7.2-7.4 (m,4H); 3.7 (quartet,
J=7 Hz,1H); 2.8 (d,2H); 1.2-2.5 (m,9H); 1.0 (t,J=7 Hz,3H) and 0.9
(d,J=7 Hz,3H). Anal. Calcd. for C.sub.15H.sub.22ClNO: C, 67.27; H,
8.28; N, 5.23. Found: C, 67.18; H, 8.14; N, 5.21.
[0318] Table 1 is illustrative of the novel aryl
piperidinecarbinols that were prepared or could be prepared by the
methods listed hereinabove but is not meant to be limiting in
breadth.
5TABLE 2 22 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6
MP(.degree. C.) Me H H 3-ClC.sub.6H.sub.4 Me H 202-205* Me H H
3-ClC.sub.6H.sub.4 Me Me 278(dec)* Et H H 3-ClC.sub.6H.sub.4 Me H
89-94 Me H H C.sub.6H.sub.5 Me H 119-120 Me H H 2-FC.sub.6H.sub.4
Me H 181-184 (dec)** Me H H 3-FC.sub.6H.sub.4 Me H 127-128 Me H H
4-FC.sub.6H.sub.4 Me H 142-143 Me H H 3,4-F.sub.2C.sub.6H.sub.3 Me
H 135-136 Me H H 4-ClC.sub.6H.sub.4 Me H 171-172 Me H H
3,4-Cl.sub.2C.sub.6H.sub.3 Me H 175-177 Me H H 3-BrC.sub.6H.sub.4
Me H 179(dec)** Me H H 4-BrC.sub.6H.sub.4 Me H 186 Me H H
2-MeC.sub.6H.sub.4 Me H 102-106 Me H H 3-MeC.sub.6H.sub.4 Me H
97-99 Me H H 4-MeC.sub.6H.sub.4 Me H 161-163 (dec)** Me H H
3-CF.sub.3C.sub.6H.sub.4 Me H 111-112 Me H H
4-CF.sub.3C.sub.6H.sub.4 Me H 188-189 Me H H 4-MeOC.sub.6H.sub.4 Me
H 114-115 Me H H 3-Me.sub.2NC.sub.6H.sub.4 Me H Me H H
3-MeSC.sub.6H.sub.4 Me H Me H H 3,5-Cl.sub.2C.sub.6H.sub.3 Me H Me
H H 3-CF.sub.3C.sub.6H.sub.4 Me H Me H H
3-C.sub.6H.sub.5OC.sub.6H.sub.4 Me H Me H H
3-C.sub.6H.sub.13C.sub.6H.sub.4 Me H Me H H
2-C.sub.3H.sub.7SC.sub.6H.sub.4 Me H Me H H 2-naphthyl Me H 191-192
Me H H 2-thienyl Me H 104-105 Me H H 3-thienyl Me H 126-127 Me H H
2-benzothienyl Me H Me H H 3-benzothienyl Me H 184-188 (dec)** Me H
H 2-benzofuryl Me H Me H H 3-benzofuryl Me H Me H H 2-pyridyl Me H
Me H H 3-pyrrolyl Me H n-Pr H H 3-ClC.sub.6H.sub.7 Me H 108-110 Me
H H 3-ClC.sub.6H.sub.4 Et H 123.5-125 Me H H 3-ClC.sub.6H.sub.4
-n-Pr H 150-153** Me H H 3-ClC.sub.6H.sub.4 -n-Bu H 95-96 allyl Me
H 3-ClC.sub.6H.sub.4 Me H Me (CH.sub.2).sub.4 3-ClC.sub.6H.sub.4 Et
H Et H Me 3-ClC.sub.6H.sub.4 -n-Bu H Me H H 3-BrC.sub.6H.sub.4 Me
Me 285(dec)* allyl H H 3-ClC.sub.6H.sub.4 Me Me 131-132** Me H H
2-thienyl Me Me 133-134 Me H H 3-thienyl Me Me 157-158 Me H H
3-benzothienyl Me Me 134-135 Me H H 2-pyridyl Me Me 91-92 Me H H
2-benzothienyl Me Me Me H H 3-benzofuryl Me Me Me H H 3-(1'-methyl-
Me Me pyrrolyl) Me H H 1-naphthyl Me Me 131-132 Me H H
3-(5'-chloro- Me Me thienyl) Me n-Bu m-Pr 3-ClC.sub.6H.sub.4 Me H
(CH.sub.2).sub.3 H 3-ClC.sub.6H.sub.4 Me H Me (CH.sub.2).sub.6
3-ClC.sub.6H.sub.4 Me H Me H H 3-(n-C.sub.10H.sub.22)- Me H
C.sub.6H.sub.4 Me H H 3-C.sub.6H.sub.5-5- Me H ClC.sub.6H.sub.3 Me
H H 3-C.sub.6H.sub.5C.sub.6H.sub.3Cl-5 Me H Me H H
3-(3'-ClC.sub.6H.sub.4- Me H C.sub.6H.sub.4 Me H H 3-Cl-1-naphthyl
Me H Me H H 2-(3-CH.sub.3- Me H thienyl) Me H H 2-(5-Cl-benzo- Me H
thienyl) Me H H 2-(5-Cl-benzo- Me H furyl) Me H H 3-(5-Cl-benzo- Me
H furyl) Me H H 3-BrC.sub.6H.sub.4 (CH.sub.2).sub.3 Me H H
3-BrC.sub.6H.sub.4 (CH.sub.2).sub.6 *hydrochloride salt **fumarate
salt
Example 3
[0319] 4-(3'-Chlorophenyl)-.alpha.,1-dimethyl-4-piperidinemethanol
Acetate (m=2; R.sup.1,R.sup.5.dbd.Me; R.sup.4=3-ClC.sub.6H.sub.4;
R.sup.2,R.sup.3,R.sup.6.dbd.H; R.sup.7.dbd.CH.sub.3CO)
[0320] A mixture of 1.00 g of
4-(3'-chlorophenyl)-.alpha.,1-dimethyl-4-pip- eridinemethanol
(Example 1) and 5 mL of acetic anhydride was heated under reflux
for 90 minutes. Removal of the excess acetic anhydride and
short-path distillation of the residue (170.degree. C. bath
temperature, 1 micron) gave 1.05 g of the title compound as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 7.1-7.4 (m,4H); 4.9 (quartet, J=7
Hz,1H); 2.8 (m,2H); 2.2 (s,3H); 2.0 (s,3H); 1.9-2.4 (m,6H); and 0.9
(d,J=7 Hz,3H).
[0321] The salt with fumaric acid had m.p. 194.degree. C. (dec.)
after crystallization from isopropyl alcohol. Anal. Calcd. for
C.sub.20H.sub.26ClNO.sub.6; C, 58.23; H, 6.36. Found: C, 58.32; H,
6.41.
Example 4
[0322]
4-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-4-piperidinemethano-
l Acetate (m=2; R.sup.1,R.sup.5,R.sup.6.dbd.Me;
R.sup.2,R.sup.3.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4;
R.sup.7.dbd.CH.sub.3CO)
[0323] A mixture of 1.04 g of
4-(3'-Chlorophenyl)-.alpha.,.alpha.-1-trimet-
hyl-4-piperidinemethanol (Example 2) and 10 mL of acetic anhydride
was heated under reflux for 2 hours. Removal of the excess acetic
anhydride followed by short-path distillation of the residue
(170.degree. C. bath temperature, 1 micron) gave 1.07 g of the
title compound as an oil that slowly crystallized.
[0324] .sup.1H NMR (CDCl.sub.3): .delta. 7.3 (s,1H); 7.2 (m13H);
2.7 (d,2H); 2.2 (s,3H), 2.0 (s,3H); 1.8-2.5 (m,6H) and 1.4 (s,6H).
High-resolution mass spectrum m/e calcd. for
C.sub.17H.sub.24ClNO.sub.2; 309.1495; measured: 309.1486.
Example 5
[0325] 4-(3'-Chlorophenyl)-4-(1'-methoxymethyl)-1-methylpiperidine
(m=2; R.sup.1,R.sup.5,R.sup.7.dbd.Me;
R.sup.2,R.sup.3,R.sup.6.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4)
[0326] Potassium hydride oil suspension (3.80 g of 35%; 33 mmoles)
was washed with hexane, 15 mL of tetrahydro-furan was added, and
the suspension was treated with 4.25 g (16 mmoles) of
4-(3'-chlorophenyl)-.al- pha.,1-dimethyl-4-piperidinemethanol
(Example 1) dissolved in 15 mL of tetrahydrofuran. The mixture was
stirred at room temperature for 1 hour; methyl iodide (9.1 g, 64
mmoles) was added which caused the temperature to rise to
50.degree. C. Methanol (5 mL) was added after stirring for 2.75
hours, keeping the temperature below 25.degree. C. Water and
chloroform were added, and the mixture was filtered to remove 4.70
g of the methiodide of the title compound. This solid was combined
with the products obtained on removal of the solvent from the
chloroform layer, and heated with 7.0 g of potassium
methylmercaptide in 30 mL of dimethyl formamide in an 80.degree. C.
oil bath for 2.5 hours. The solvent was removed, water was added to
the residue and the mixture was extracted with methylene chloride.
Removal of the solvent from the dried extracts and short-path
distillation of the residue (130.degree. C. bath temperature, 1
micron) gave 3.94 g (88% yield) of the title compound as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 7.2-7.4 (m,4H); 3.3 (s,3H); 3.2
(quartet, J=7 Hz,1H); 2.7 (m,2H); 2.2 (s,3H); 1.8-2.4 (m,6H); and
0.9 (d,J=7 Hz,3H). High resolution mass spectrum: m/e calcd. for
C.sub.15H.sub.22ClNO: 267.1390; measured: 267.1393.
Example 6
[0327]
4-(3'-Chlorophenyl)-4-(1'-benzyloxymethyl)-1-methylpiperidine (m=2;
R.sup.1,R.sup.5.dbd.Me; R.sup.2,R.sup.3,R.sup.6.dbd.H;
R.sup.4=3-ClC.sub.6H.sub.4;
R.sup.7.dbd.CH.sub.6H.sub.5CH.sub.2)
[0328] Following the procedures above, but using benzyl bromide in
place of methyl iodide, the title compound was obtained as an oil,
distilling at a bath temperature of up to 210.degree. C. at 1
micron. .sup.1H NMR (CDCl.sub.3): .delta. 7.2-7.4 (m,9H); 3.4
(quartet, J=7 Hz,1H); 2.7 (m,2H); 2.4 (m,1H); 2.2 (s,3H); 2.0
(m,5H) and 0.9 (d,J=7 Hz,3H). High resolution mass spectrum: calcd.
for C.sub.21H.sub.26ClNO: m/e 343.1703; measured: 343.1693.
Example 7
[0329]
3-(3'-Chlorophenyl)-.alpha.,.alpha.,1-trimethyl-3-pyrrolidinemethan-
ol (m=1; R.sup.1,R.sup.5,R.sup.6.dbd.Me;
R.sup.2,R.sup.3,R.sup.7.dbd.H; R.sup.4=3-ClC.sub.6H.sub.4)
[0330] A solution of 2.83 g of ethyl
3-(3'-chlorophenyl)-1-methyl-3-pyrrol- idinecarboxylate in 5 mL of
tetrahydrofuran was added to 8 mL of 3M methylmagnesium chloride in
tetrahydrofuran and the mixture was heated under reflux for 4
hours. Ten percent hydrochloric acid was added and the mixture was
washed with ether. The aqueous phase was made basic with ammonium
hydroxide solution and extracted with methylene chloride. Removal
of the solvent from the dried extract gave 1.94 g of crude title
compound. It was purified by chromatography on silica (elution with
3:1 methylene chloride/methanol), followed by crystallization from
acetonitrile m.p. 98'-99.degree. C. .sup.1H NMR (CDCl.sub.3):
.delta. 7.0-7.3 (m,4H); 3.7 (d, J=7 Hz,1H); 3.2 (m,2H); 2.8 (m,1H);
2.4 (d, J=10 Hz,1H); 2.4 (s,3H) 2.2 (m,2H); 1.2 (s,3H) and 1.1
(s,3H). High resolution mass spectrum: m/e calcd. for
C.sub.14H.sub.20ClNO: 253.1233; measured: 253.1235.
[0331] The starting material, ethyl
3-(3'-chlorophenyl)-1-methyl-3-pyrroli- dine carboxylate, was
prepared from 3-chlorobenzyl cyanide by the procedure of R. L.
Jacoby, K. A. Nieforth, and R. E. Willete, J. Med. Chem., 17,453
(1974). .sup.1H NMR (CDCl.sub.3): .delta. 7.1-7.4 (m,4H); 4.1
(quartet, J=7 Hz,2H); 3,6 (d, J=8 Hz,1H); 2.9 (m,2H); 2.7 (d, J=8
Hz, 1H); 2.0-2.5 (m+s,5H) and 1.2 (t,J=7 Hz,3H).
Example 8
[0332]
4-(3'-Chlorophenyl)-.alpha.,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-aze-
pine-4-m ethanol (m=3; R.sup.1,R.sup.5.dbd.Me;
R.sup.4=3-ClC.sub.6H.sub.4; R.sup.2,R.sup.3,R.sup.6,R.sup.7=H)
[0333] Sodium borohydride (0.22 g) was added with cooling to a
solution of 1.0 g of
1-[4-(3-chlorophenyl)-1-methyl-4-(2,3,4,5,6,7-hexahydro-1H-azepi-
nyl]ethanone in 2 mL of ethanol. The mixture was stirred at room
temperature for 18 hours. Water was added and the mixture was
extracted repeatedly with methylene chloride. Removal of the
solvent and crystallization of the residue from acetonitrile gave
0.54 g of the title compound, m.p. 123.degree.-124.degree. C.
.sup.1H NMR (CDCl.sub.3): .delta. 7.2-7.4 (m,4H); 3.6 (quartet, J=7
Hz,1H); 2.7 (m,2H); 2.4 (m,1H); 2.2 (s,3H); 1.6-2.0 (m,8H) and 1.0
(d, J=7 Hz,3H). High-resolution mass spectrum: m/e calcd. for
C.sub.15H.sub.22ClNO: 267.1390; measured: 267.1388.
[0334] The starting material,
1-[4-(3-chlorophenyl)-1-methyl-4-(2,3,4,5,6,-
7-hexahydro-1H-azepinyl]ethanone was prepared as described in
Example 1 by the addition of methylmagnesium chloride to
4-(3'-Chlorophenyl-.alpha.,1--
dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-4-carbonitrile. The
latter was prepared from 3-chlorobenzyl cyanide by the procedure of
J. Diamond, W. F. Bruce and F. T. Tyson, J. Org. Chem., 399
(1957).
6TABLE 3 23 R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7
m MP(.degree. C.) Me H H 3-ClC.sub.6H.sub.4 Me H Ac 2 194 (dec)**
Me H H 3-ClC.sub.6H.sub.4 Me Me Ac 2 (solid)* Me H H
3-ClC.sub.6H.sub.4 Me H Me 2 (oil)* Me H H 3-ClC.sub.6H.sub.4 Me H
CH.sub.2C.sub.6H.sub.5 2 (oil)* Me H H 3-ClC.sub.6H.sub.4 Me Me H 1
98-99 Me H H 3-ClC.sub.6H.sub.4 Me H H 3 123-124 Me H H
3-ClC.sub.6H.sub.4 Me Me H 3 Me H H 3-ClC.sub.6H.sub.4 Me H H 1 Me
H H 3-CF.sub.3C.sub.6H.sub.4 Me Me H 3 Me H H
3-CF.sub.3C.sub.6H.sub.4 Me Me H 1 Me H H 3-ClC.sub.6H.sub.4 Me Me
Me 1 Et Me H 3-thienyl Me Me H 3 n-Pr H Me 2-bromothienyl Me Et H 3
Me H H 3-BrC.sub.6H.sub.4 Me Me H 1 Me H H 3-BrC.sub.6H.sub.4 Me Me
H 3 Me H H 3-ClC.sub.6H.sub.4 Me H Ac 3 Me H H 2-thienyl Me H H 1
Me H H 2-thienyl Me Me H 3 Me H H 3-ClC.sub.6H.sub.4 Me H n-butyl 2
Me H H 3-ClC.sub.6H.sub.4 Me Me CO-n- 2 butyl *for NMR and HRMS
data, see experimental procedure **Fumarate salt
Example 9
[0335] Synthesis of the Acetonitrile (1)
[0336] The acetonitrile 1 of the present invention is synthesized
from thiophene carboxaldehyde. Thiophene carboxaldehyde can be
reacted with tosylmethyl isocyanide (TosMIC), in the presence of
potassium t-butoxide, in a solution of 1,2-dimethoxyethane (DME)
and ethanol to obtain the desired acetonitrile 1. 24
Example 10
[0337] Synthesis of the Piperidinecarbonitrile (3)
[0338] The acetonitrile 1 is coupled with a bis-(2-chloroethyl)
methylamine 2 in the presence of potassium hydroxide in DMSO at
18-20.degree. C. to obtain 3. 25
Example 11
[0339] Synthesis of the Ketone (5)
[0340] The piperidinecarbonitrile 3 is then reacted with a
methylmagnesium bromide in THF, at 80.degree. C. After the reaction
went to completion, the reaction mixture was quenching with water
to give the imine, which was then hydrolyzed with an aqueous
hydrochloric acid, to give the a ketone 5. 26
Example 12
[0341] Synthesis of the Tertiary Carbinol (6)
[0342] Ketone 5 was treated with 2 equivalents of methyllithium in
THF at -78.degree. C. Some polar additives were added to promote
further conversion of ketone 5 to obtain the tertiary carbinol 6.
27
Example 13
[0343] Formation of the Hydrochloride Salt
[0344] To the tertiary carbinol 6, methanol was added and cooled to
0.degree. C. A solution of HCl/Et.sub.2O was added to obtain the
hydrochloride salt. The precipitated hydrochloride salt was
filtered from the suspension to obtain the salt in isolated form.
28
[0345] VI. Biological Methods
[0346] In neuropathic pain, it is believed that C-fiber nociceptors
acquire two abnormal properties: spontaneous activity and
alpha-adrenergic sensitivity. These abnormalities in nociceptor
function are thought to contribute to neuropathic pain. Therefore,
the compounds of the present invention have a positive effect on
both, with significant inhibition of serotonin and norepinephrine,
synaptic uptake, implicating these compounds as useful agents for
the treatment of neuropathic pain.
[0347] The antinociceptive profile of an unknown agent can be
usefully assessed on the post tissue (formalin) and post nerve
injury (Chung) models. This recognizes that drugs which act on the
acute models will typically exert a full effect on the post tissue
injury model, but not vice versa and that the post nerve injury
model can have a drug activity profile distinct from the other two
paradigms (Yaksh 1999). In addition, the effect of these agents on
the three major classes of nociceptive processing acute post tissue
injury and post nerve injury can be assessed. The present studies
address the dose dependent potency of compounds of the present
invention on the formalin test and upon the Chung model tactile
allodynia. Compounds of the present invention were compared to
venlafaxine, which has been clinically evaluated for painful
diabetic neuropathy and has neurochemical and physiological
similarities to the present compounds.
[0348] Various animal models were studied using these models (see
Table below). The compounds of the present invention, and in
particular compound A showed activity for the treatment of
neuropathic pain.
7 Rat Mouse Dog Monkey PQW PQW Tooth pulp Tail dip Tail Flick* Tail
flick.sup..PHI. Randell-Selitto.sup..PHI. Tooth pulp *Inactive
.sup..PHI.Weakly active
Example 14
[0349] Serotonin and Norepinephrine Reuptake Assays
[0350] Compounds of the present invention are novel centrally
acting oral non-opioids by inhibiting serotonin and norepinephrine
synaptic uptake in a similar ratio to amitriptyline and
venlafaxine. Inhibition of serotonin and norepinephrine synaptic
uptake was found in a .about.2:1 Ratio (5HT:NE), with indirect
enhancement of brain enkephalin and endorphin activity and
secondary opioid effects. The duration of action is greater than
codeine or nalbuphine, with better efficacy for the treatment of
neuropathic pain than codeine, nalbuphine and ibuprofen.
[0351] Compound A and venlafaxine are potent and selective
inhibitors of rat synaptosomal 5-HT and NE Reuptake
8 5-HT uptake inhibition NE uptake inhibition 5-HT/NE inhibition
Compound IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) Compound A
120 223 1.85 Venlafaxine 210 640 3.05
Example 15
[0352] Formalin Model
[0353] Formalin induces inflammatory stimulation of peripheral
nerves that results in sensitization of CNS nociceptive
transmission pathways. There are two phases of formalin-induced
nociception: phase I-- an acute nociceptive component; and phase
II--a chronic nociceptive component characterized by
hyperalgesia.
[0354] On the morning of formalin testing, a small metal band (0.5
g) was loosely placed around the right hind paw. The rat was placed
in a cylindrical Plexiglas chamber for adaptation for a minimum of
30 minutes. Compound A, venlafaxine or a saline control was
administered into the dorsal surface of the right hindpaw of the
rat. The animal was then placed into the chamber of the automated
formalin apparatus where movement of the formalin-injected paw was
monitored and the number of paw flinches tallied by minute over the
next sixty minutes. Upon completion of the test the animal was
removed and euthanized.
[0355] In the formalin test, statistically significant effects were
seen for all administered doses of compound A during phases I, II
and IIA, while venlafaxine showed statistically significant effects
only during phases I and IIA. No statistical significance as
compared to the saline control was seen during Phase IIB for either
compound A or venlafaxine (See FIGS. 3 and 4).
Example 16
[0356] Chung Model
[0357] This model for neuropathic pain was performed on rats using
the surgical procedure described by Kim and Chung (1992) to induce
an allodynic state. Briefly, the left L-5 and L-6 spinal nerves
were isolated adjacent to the vertebral column and ligated with 6-0
silk suture distal to the dorsal root ganglion under isoflurane
anesthesia. This model allows for spinal cord structural
reorganization and growth of low threshold mechnoreceptor fibers
from the spinal cord with synaptic connections and rewiring of the
dorsal horn. This leads to spontaneous firing of invading
sympathetic nerves and upregulation of receptors and
voltage-dependent channels; i.e. mimics the development of
allodynia (nociceptive response to a previously neutral stimulus).
The rats were allowed a minimum of 7-days postoperative recovery
period before testing.
[0358] To assess tactile thresholds in the Chung model, rats were
placed in a clear plastic, wire mesh-bottomed cage, divided into
individual compartments. Animals were allowed to acclimate and then
baseline thresholds were assessed prior to drug treatment. To
assess the 50% mechanical threshold for paw withdrawal, vonFrey
hairs were applied to the plantar mid-hindpaw, avoiding the tori
(footpads). The eight vonFrey hairs used are designated by [log
(10*force required to bend hair,mg)] and range from 0.4-15.1 grams
(#'s 3.61-5.18). Each hair was pressed perpendicularly against the
paw with sufficient force to cause slight bending, and held for
approximately 6-8 seconds. A positive response was noted if the paw
was sharply withdrawn. Flinching immediately upon removal of the
hair was also considered a positive response. Absence of a response
("-") was cause to present the next consecutive stronger stimulus;
a positive response ("+") was cause to present the next weaker
stimulus. Stimuli were presented successively until either six data
points were collected, or the maximum or minimum stimulus was
reached. If a minimum stimulus was reached and positive responses
still occurred, the threshold was assigned an arbitrary minimum
value of 0.25 grams; if a maximum stimulus was presented and no
response occurred, a maximum threshold value of 15 grams was
assigned. If a change in response occurs, either "-" to "+" or "+"
to "-", causing a change in the direction of stimulus presentation
from descending to ascending or vice-versa, four additional data
points were collected subsequent to the change.
[0359] In the Chung model both compound A and venlafaxine showed
statistically significant effects on tactile allodynia at two hours
post injection in both of the doses 200 mg/kg and 100 mg/kg. This
suggests that compound A has significant antihyperpathetic effects
in models of nerve and tissue injury. It is shown that compound A
had a reliable dose dependent effect upon both the hyperalgesia
induced by the injection of formalin into the paw and the tactile
allodynia arising from nerve injury. Importantly, these effects
occurred at doses where the agent had no effect upon arousal or
motor function.
Example 17
[0360] Antiphenylquinone Writhing (PQW) Test
[0361] The anti-phenylquinone writhing (PQW) test modified from the
methods of Siegmund et al. (Proc. Soc. Exp. Biol. Med. 95: 729-731,
1957) and Blumberg et al. (Proc. Exp. Biol. Med. 118: 763-767,
1965) was used to assess the relief from the simulated symptoms of
neuropathic pain in mice. Male CF1 mice (Charles River Breeding
Laboratories, Wilmington, Mass.), fasted for 16-22 hours and
weighing 18-23 g, were injected with randomized and coded doses of
test compounds, then challenged with 1.25 mg/kg i.p.
phenyl-p-benzoquinone (phenylquinone) 5 minutes prior to the
specified observation time. The phenylquinone solution (0.1 mg/ml
in 5% aqueous ethanol) was prepared daily and stored in
foil-wrapped amber bottles to limit degradation. Mice were observed
10 minutes for the presence or absence of the characteristic
abdominal constriction and stretching response beginning 30 minutes
after injection of the test compound. Activity was calculated as
the percentage of mice failing to respond to the phenylquinone
challenge dose. Greater than 95% of the control (vehicle-treated)
mice exhibited a writhing response. Median effective doses (ED50's)
and 95% confidence limits were determined numerically by the
methods of Thompson (Bacteriological Rev. 11: 115-145, 1947), and
Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96: 99-113,
1949).
9 Randell-Selitto/Tail Flick/Tail Dip/Tooth Pulp COMPOUND A
TRAMADOL VENLAFAXINE ACTIVITY Mouse PQW: Mouse PQW: ED.sub.50 = 18
mg/kg ED.sub.50 = 7.8 mg/kg Rat PQW: Rat PQW: ED.sub.50 = 7.9 mg/kg
ED.sub.50 = 39.2 mg/kg Mouse Tail-Flick: Mouse Tail-Flick:
ED.sub.50 = 117 mg/kg ED.sub.50 = 31.2 Rat Tail-Flick: Rat
Tail-Flick: Inactive Inactive Rat Randall-Selitto: Rat Hot Plate:
Rat Hot Plate: ED.sub.50 = 32 mg/kg ED.sub.50 = 40 mg/kg
Inactive
Example 18
[0362] Toxicity Assay
[0363] In one embodiment of the invention, the therapeutic index
for a 70 kg human was approximately 175 mg/dose (2.5 mg/kg in dog)
to 2,100 mg/dose (30 mg/kg in rat).
10 In Vitro Bacterial Mutagenicity: Not mutagenic Modified Ames
Test Fourteen-day Oral Dose Range NOEL < 30 mg/kg
(exophthalamos) Finding Study in Rats MTD > 100, <300 mg/kg
(decreased BW) NOAEL = 100 mg/kg Five-day Oral Dose Escalation NOEL
< 2.5 mg/kg (mydriasis) in Beagle Dogs (modified dose- MTD <
20 mg/kg (decreased BW) range finding study)
Example 19
[0364] Safety Pharmacology
11 Safety Pharmacology with Compound A Multiple of effective
Species Route Effect dose (mg/kg) Other mouse po/iv mydriasis
1.times. LD = 900 mg/kg-po inhibition of GI 1.times. motility
cross-tolerance to 1-50.times. morphine dog po emesis/anorexia
1-10.times. BW loss respiratory 10.times. MTD.sup.1 = 20 mg/kg
acidosis iv-pentobarb hypotension/ 10.times. decreased cardiac
contractility anemia rat po respiratory 1-50.times. LD = 400
mg/kg-po acidosis LD = 270 mg/kg-sc exophthalmia anorexia 10, 100,
300 non-opioid physical dep Monkey iv/sc respiratory 16/32 MTD2 =
16-32 mg/kg depression Chronic dosing: 0.4 = retching at 7 LD =
1.6-32 mg/kg days 1.6 = death at 11 days 1.6 = death at 20 days
non-opioid physical dep
Example 20
[0365] Abuse Assay
[0366] Cynomologous monkeys are trained to self-administer drugs by
pressing on a lever a certain number of times. The number of times
an animal will press the lever before extinguishing in an attempt
to self-administer drug is calculated as their fixed ratio (FR).
For example, cynomologous monkeys that are trained to
self-administer codeine will press the lever 300 times (FR 300) and
or 10,000 times (FR 10,000) to obtain a dose of codeine.
Cynomologous monkeys were trained to self-administer the compounds
of the present invention. Response for compound A was achieved in
one out of four monkeys. Following involuntary injections of
compound A, two out of four monkeys responded with FR3 and
FR10.
[0367] This invention has been described with reference to its
preferred embodiments. Variations and modifications of the
invention, will be obvious to those skilled in the art from the
foregoing detailed description of the invention.
* * * * *
References