U.S. patent application number 14/881080 was filed with the patent office on 2016-03-31 for treatment of osteoarthritis pain.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Jorge D. Brioni, Marlon D. Cowart, Gin C. Hsieh, James P. Sullivan.
Application Number | 20160089378 14/881080 |
Document ID | / |
Family ID | 42992667 |
Filed Date | 2016-03-31 |
United States Patent
Application |
20160089378 |
Kind Code |
A1 |
Cowart; Marlon D. ; et
al. |
March 31, 2016 |
TREATMENT OF OSTEOARTHRITIS PAIN
Abstract
This invention discloses a method of treatment of osteoarthritis
pain by administration of a histamine H.sub.3 receptor antagonist,
described herein, a salt thereof, or a composition comprising such
compound or salt.
Inventors: |
Cowart; Marlon D.; (Round
Lake Beach, IL) ; Hsieh; Gin C.; (Long Grove, IL)
; Brioni; Jorge D.; (Vernon Hills, IL) ; Sullivan;
James P.; (Deerfield, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
42992667 |
Appl. No.: |
14/881080 |
Filed: |
October 12, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12767608 |
Apr 26, 2010 |
9186353 |
|
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14881080 |
|
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61173161 |
Apr 27, 2009 |
|
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61173132 |
Apr 27, 2009 |
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Current U.S.
Class: |
514/217.01 ;
514/218; 514/252.03; 514/254.1; 514/300; 514/303; 514/321;
514/422 |
Current CPC
Class: |
A61K 31/428 20130101;
A61K 31/395 20130101; A61K 31/517 20130101; A61P 29/00 20180101;
A61K 31/445 20130101; A61K 31/497 20130101; A61K 31/55 20130101;
A61K 31/41 20130101; A61K 31/4025 20130101; A61K 31/4375 20130101;
A61K 31/454 20130101; A61K 31/501 20130101; A61K 31/4545 20130101;
A61K 31/496 20130101; A61K 31/425 20130101; A61K 31/551 20130101;
A61K 31/40 20130101 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/454 20060101 A61K031/454; A61K 31/496 20060101
A61K031/496; A61K 31/55 20060101 A61K031/55; A61K 31/4545 20060101
A61K031/4545; A61K 31/501 20060101 A61K031/501; A61K 31/4025
20060101 A61K031/4025 |
Claims
1. A method of treatment of osteoarthritis pain comprising
administration of a histamine H.sub.3 receptor antagonist, a salt
thereof, or a composition comprising such histamine H.sub.3
receptor antagonist or salt, to a mammal in need of treatment
thereof.
2. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of formula: ##STR00014## or a
pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; one
of R.sub.A-1 and R.sub.A-2 is hydrogen, acyl, acyloxy, alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,
alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl,
amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,
alkylthio, --NR.sub.A-AR.sub.A-B, (NR.sub.A-AR.sub.A-B)carbonyl,
--SO.sub.2N(R.sub.A-14a)(R.sub.A-14b),
N(R.sub.A-.sub.14a)SO.sub.2(R.sub.A-14b), a group of the formula
-L.sub.A-2-R.sub.A-6, or a group of the formula
-L.sub.A-3a-R.sub.A-6a-L.sub.A-3b-R.sub.A-6b; the other of R.sub.1
and R.sub.2 is selected from hydrogen, cyano, halogen, alkyl,
cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy,
alkylthio, --SO.sub.2N(R.sub.A-14a)(R.sub.A-14b), and
--N(R.sub.A-14a)SO.sub.2(R.sub.A-14b); R.sub.A-3a and R.sub.A-3b
are each independently selected from hydrogen, cyano, halogen,
alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy,
alkylthio, --SO.sub.2N(R.sub.A-14a)(R.sub.A-14b), and
--N(R.sub.A-14a)SO.sub.2(R.sub.A-14b); R.sub.A-4 and R.sub.A-5 are
each independently selected from alkyl, fluoroalkyl, hydroxyalkyl,
alkoxyalkyl, and cycloalkyl; or R.sub.A-4 and R.sub.A-5 taken
together with the nitrogen atom to which each is attached form a
non-aromatic ring; R.sub.A-6 is selected from aryl, heterocycle,
and heterocyclealkyl; R.sub.A 6a is selected from aryl and
heterocycle; RA-6b is selected from aryl and heterocycle; L is a
bond or alkylene; L.sub.2 is selected from a bond, --O--, alkylene,
--C(.dbd.O)--, --S--, --SO.sub.2N(R.sub.A-14a)--,
--N(R.sub.A-14a)SO.sub.2--, --C(O)N(R.sub.A-14a)--,
--N(R.sub.A-14a)C(O)--, --N(R.sub.A-15)--; L.sub.3a and L.sub.3b
are each independently selected from a bond, --O--, alkylene,
--C(.dbd.O)--, --S--, --SO.sub.2N(R.sub.A-14a)--,
--N(R.sub.A-14a)SO.sub.2--, --C(O)N(R.sub.A-14a)--,
--N(R.sub.A-14a)C(O)--, and --N(R.sub.A 15)--; R.sub.A-10 is
selected from hydrogen, cyano, fluoro, hydroxy, and alkyl;
R.sub.A-14a and R.sub.A-14b are each independently selected at each
occurrence from hydrogen, alkyl, and cycloalkyl; R.sub.A-15 is
selected from hydrogen, alkyl, acyl, alkoxycarbonyl and
(R.sub.A-14a)(R.sub.A-14b)NC(O)--; and R.sub.A-A and R.sub.A-B are
independently selected from hydrogen, alkyl, acyl, haloalkyl,
alkoxycarbonyl, cycloalkyl, and formyl.
3. The method of claim 2, wherein the histamine H.sub.3 receptor
antagonist is
(S)-3-hydroxy-1-[2-(3-piperidin-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrro-
lidin-2-one;
trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3-
(2H)-one; or
cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2-
H)-one.
4. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of formula: ##STR00015## or a
pharmaceutically acceptable salt thereof, wherein one of R.sub.B-1
and R.sub.B-2 is a group of the formula
-L.sub.B-2-R.sub.B-6a-L.sub.B-3-R.sub.B-6b; the other of R.sub.B-1
and R.sub.B-2 is selected from hydrogen, alkyl, alkoxy, halogen,
cyano, and thioalkoxy; R.sub.B-3, R.sub.B-3a, and R.sub.B-3b are
each independently selected from the group consisting of hydrogen,
alkyl, trifluoroalkyl, trifluoroalkoxy, alkoxy, halogen, cyano, and
thioalkoxy; R.sub.B-4 and R.sub.B-5 are each independently selected
from alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl,
or R.sub.B-4 and R.sub.B-5 taken together with the nitrogen atom to
which each is attached form a non-aromatic ring of the formula:
##STR00016## R.sub.B-7, R.sub.B-8, R.sub.B-9, and R.sub.B-10 at
each occurrence are each independently selected from hydrogen,
hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; R.sub.B-11,
R.sub.B-12, R.sub.B-13, and R.sub.B-14 are each independently
selected from hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl;
R.sub.B-6a is selected from a 5- to 6-membered heteroaryl ring,
cyanophenyl, an 8- to 12-membered bicyclic heteroaryl ring, and a
4- to 12-membered heterocyclic ring; R.sub.B-6b is selected from
hydrogen, a 5- to 6-membered heteroaryl ring, an aryl ring, an 8-
to 12-membered bicyclic heteroaryl ring, and a 4- to 12-membered
heterocyclic ring; Q is selected from O and S; L.sub.B is
--[C(R.sub.B-16)(R.sub.B-17)].sub.k; L.sub.B-2 is selected from a
bond, alkylene, --O--, --C(.dbd.O)--, --S--, --NH--,
--N(R.sub.B-16)C(.dbd.O)--, --C(.dbd.O)N(R.sub.B-16), and
--N(alkyl)-; L.sub.B-3 is selected from a bond, alkylene, --O--,
--C(.dbd.O)--, --S--, --N(R.sub.B-16)C(.dbd.O)--,
--C(.dbd.O)N(R.sub.B-16), and --N(R.sub.B-15)--; R.sub.B-15 is
selected from hydrogen, alkyl, acyl, alkoxycarbonyl, amido, and
formyl; R.sub.B-16 and R.sub.B-17 at each occurrence are
independently selected from hydrogen and alkyl; R.sub.B-x and
R.sub.B-y at each occurrence are independently selected from
hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and
dialkylamino; k is 1, 2, or 3; and m2 is an integer from 1 to
5.
5. (canceled)
6. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of formula: ##STR00017## or a
pharmaceutically acceptable salt, wherein A is selected from the
group consisting of carbonyl and a covalent bond; D is selected
from the group consisting of O and S; Lc is selected from the group
consisting of lower alkylene, fluoroalkylene, and hydroxyalkylene;
Pc and Qc taken together form a covalent bond or are both hydrogen;
R.sub.C-1 and R.sub.C-2 are each independently selected from the
group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl,
alkenyl, and alkynyl; or R.sub.C-1 and R.sub.C-2 taken together
with the nitrogen atom to which they are attached, together form a
heterocycle; R.sub.C-3 is selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy, alkylsulfmyl, alkylsulfonyl, alkylthio, aryl,
carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen,
haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl,
mercapto, nitro, --NR.sub.C-ARC--.sub.B,
(NR.sub.C-.sub.AR.sub.C--B)alkyl, (NR.sub.C-AR.sub.C--B)carbonyl,
and (NR.sub.c-AR.sub.c-B)sulfonyl; R.sub.C-4, R.sub.C-5, R.sub.C-6
and R.sub.C-7 are each independently selected from the group
consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl,
alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl,
cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle,
hydroxy, hydroxyalkyl, mercapto, nitro, --NR.sub.C-AR.sub.C--B,
(NR.sub.C-AR.sub.C--B)alkyl, (NR.sub.C-AR.sub.C--B)carbonyl,
(NR.sub.C-AR.sub.C--B)sulfonyl, -L.sub.C-2R.sub.C-20, and
--R.sub.C21L.sub.C-3R.sub.C-22; L.sub.C-2 is selected from the
group consisting of alkylene, alkenylene, O, S, S(O), S(O).sub.2,
C(.dbd.O), C.dbd.(NOR.sub.C-21), and N(R.sub.C-A); L.sub.C-3is
selected from the group consisting of a covalent bond, alkylene,
alkenylene, O, S, C(.dbd.O), N(.dbd.OR.sub.C-21), and N(R.sub.C-A);
R.sub.C-20 is selected from the group consisting of aryl,
heterocycle, and cycloalkyl; R.sub.C-21is selected from the group
consisting of hydrogen and alkyl; R.sub.C-22 is selected from the
group consisting of aryl, heterocycle, and cycloalkyl; R.sub.C-A
and R.sub.C--B are each independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl and formyl; provided
that at least one of R.sub.C-4, R.sub.C-5, R.sub.C-6, or
R.sub.C-7is aryl, heterocycle, cycloalkyl, -L.sub.C-2R.sub.C-20 or
--R.sub.C-20L.sub.C-3R.sub.C-22.
7. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of the formula: ##STR00018## wherein
X.sub.D is CH or N, or a pharmaceutically acceptable salt
thereof.
8. The method of claim 7, wherein the histamine H.sub.3 receptor
antagonist is
(6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-n-
icotinamide) or GSK-189254.
9. The method of claim 7, wherein the histamine H3 receptor
antagonist is
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpy-
razine-2-carboxamide) or GSK-207040.
10. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound having structure: ##STR00019## (E) or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridi-
nyl}-2-pyrrolidinone, or a pharmaceutically acceptable salt
thereof.
11. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound structure: ##STR00020## (F) or GSK-334429
or
(4-isopropyl-1,4-diazepan-1-yl)(1-(6-(trifluoromethyl)pyridin-3-yl)piperi-
din-4-yl)methanone, or a pharmaceutically acceptable salt,
thereof.
12. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of formula: ##STR00021## wherein Ar is a
divalent group formed by eliminating two hydrogen atoms from
benzene, pyrimidine, pyridine, thiazole, oxazole, pyrazole,
thiadiazole or thiophene (this divalent group may be further
substituted by a halogen atom, lower alkoxy (this lower alkoxy
group may be further substituted by halogen), hydroxy or lower
alkyl); X.sub.1 is a nitrogen atom, sulfur atom or oxygen atom;
R.sub.G-1 is a 5- or 6-membered heteroaryl group having 1 to 4
heteroatoms selected from among nitrogen, sulfur and oxygen,
heteroarylalkyl group (heteroaryl in this group has the same
meaning as the above), straight chain or branched lower alkyl (this
lower alkyl group may be further substituted by hydroxy, halogen,
alkoxy, allyloxy or aralkyloxy), phenyl, aralkyl, alkoxy, alkylthio
or lower alkylamino; Ring A is a 5- or 6-membered heteroaryl ring
having 1 or 2 nitrogen atoms or sulfur atoms in the ring, or a
benzene ring; R.sub.2 and R3 may be the same or different, and each
represents hydrogen, amino, alkylamino, dialkylamino, nitro, cyano,
hydroxy, lower alkylsulfonyl, halogen, lower alkyl (this lower
alkyl group may be further substituted by halogen), lower
cycloalkyl (this lower cycloalkyl group may be further substituted
by halogen), lower alkoxy (this lower alkoxy group may be further
substituted by halogen or hydroxy), lower cycloalkoxy (this lower
cycloalkoxy group may be further substituted by halogen), aryloxy,
aralkyloxy, heteroaryloxy, heteroarylalkyloxy, aryl, heteroaryl,
arylcarbamoyl, heteroarylcarbamoyl, arylalkylcarbamoyl,
heteroarylalkylcarbamoyl, mono-lower alkylcarbamoyl, di-lower
alkylcarbamoyl, lower alkylcarboxamide, arylcarboxamide,
heteroarylcarboxamide, arylalkylcarboxamide,
heteroarylalkylcarboxamide, alkanoyl, arylcarbonyl,
arylalkylcarbonyl, alkylsulfonylamino, arylsulfonylamino,
alkylaminosulfonyl, arylaminosulfonyl, aralkyl, alkanoylamino or
alkanoylalkylamino; Y is CH or a nitrogen atom; --X.sub.2 is a
group represented by --(CH.sub.2).sub..PI.--NRG-4RG-5, n is an
integer of 2 to 4, where RG-4 and R.sub.G-.sub.5 taken together
with a nitrogen atom together form a 5- to 8-membered monocyclic
ring (this monocyclic ring may be substituted by a halogen atom, an
oxo group, or a lower alkyl group of 1-3 carbon atoms which itself
may be substituted by halogen, or where --X.sub.2 is a group
represented by ##STR00022## where m is an integer from 0 to 4, and
R.sub.G-.sub.6 is a lower alkyl or cycloalkyl group), or a
pharmaceutically acceptable salt thereof.
13. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is
2-methyl-3-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5-(trifluoromethyl)quin-
azolin-4(3H)-one or
3-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-2-methyl-5-(trifluoromethyl)q-
uinazolin-4(3H)-one.
14. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of structure: ##STR00023## (H) or
6-(2-(1-isopropylpiperidin-4-yloxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl-
)nicotinamide, or a pharmaceutically acceptable salt thereof.
15. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of structure: ##STR00024## (I) or
N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobutanec-
arboxamide, and stereoisomeric forms
(1r,3r)-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cycl-
obutanecarboxamide and
trans-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclob-
utanecarboxamide or a pharmaceutically acceptable salt thereof.
16. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of formula: ##STR00025## or a
pharmaceutically acceptable salt thereof, wherein R.sub.1 is
C.sub.1-10alkyl, C.sub.3-8 alkenyl, C.sub.3-8 cycloalkyl,
(C.sub.3-8 cycloalkyl)C.sub.1-6 alkyl, (C.sub.3-8
cycloalkyl)C.sub.3-8 alkenyl, or (C.sub.1-8 alkylcarbonyl)C.sub.1-8
alkyl; n is 1 or 2; X.sub.J is O or S; one of R.sub.2, R.sub.3 and
R.sub.4 is G and the other two independently are hydrogen, fluoro,
chloro, bromo, nitro, trifluoromethyl, methyl, or C.sub.1-3 alkoxy;
G is LQ; L is unbranched --(CH.sub.2).sub.m,-- wherein m is an
integer from 1 to 7; Q is NR.sub.8R.sub.9 wherein R.sub.8 is
independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-6
alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl,
phenyl, (6-9 membered heterocyclyl)C.sub.1-6 alkylene, and
(phenyl)C.sub.1-6 alkylene; and R.sub.9 is independently selected
from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 6-9 membered carbocyclyl,
3-12 membered heterocyclyl, phenyl, (6-9-membered
heteroyclyl)C.sub.1-6 alkylene, and (phenyl) C.sub.1-.sub.6
alkylene; or Q is a saturated 3-12 membered N-linked heterocyclyl,
wherein, in addition to the N-linking nitrogen, the 3-12 membered
heterocyclyl may optionally contain between 1 and 3 additional
heteroatoms independently selected from O, S, and NH; wherein Q is
optionally substituted with 1-3 substituents independently selected
from the group consisting of hydroxy, halo, carboxamide, C.sub.1-6
alkyl, 5-9 membered or 6-9 membered heterocyclyl, --N(C.sub.1-6
alkyl)(5-9 membered or 6-9 membered heterocyclyl), --NH(5-9
membered or 6-9 membered heterocyclyl), -0(5-9 or 6-9 membered
heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C.sub.1-3
alkylene, C.sub.1-6 alkoxy, (C.sub.3-6 cycloalkyl)-O--, phenyl,
(phenyl)C.sub.1-3 alkylene, and (phenyl)C.sub.1-3 alkylene-O--,
where each of above heterocyclyl, phenyl, and alkyl groups may be
optionally substituted with from 1 to 3 substituents independently
selected from trifluoromethyl, methoxy, halo, nitro, cyano,
hydroxy, and C.sub.1-3 alkyl; provided however that when R.sub.1 is
methyl, G is not piperidin-1-ylmethyl; and wherein each of the
above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl,
carbocyclyl, and aryl groups may each be independently and
optionally substituted with between 1 and 3 substituents
independently selected from trifluoromethyl, methoxy, halo, amino,
nitro, hydroxy, and C.sub.1-3 alkyl.
17. The method of claim 16, wherein the histamine H.sub.3 receptor
antagonist is
((4-isopropylpiperazin-1-yl)(4-(piperidin-1-ylmethyl)phenyl)methanone),
or
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methy-
lpyrazine-2-carboxamide).
18. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of structure: ##STR00026## or
(1-((2-amino-6-methylpyridin-4-yl)methyl)-4-fluoropiperidin-4-yl)(4-(2-(p-
yridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)methanone,
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is a compound of structure: ##STR00027## or
1-(1-methylethyl)-4-{[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]carbonyl}pipe-
razine, or a pharmaceutically acceptable salt thereof.
20. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is BF2649
(1-{3-[3-(4-chloro-phenyl)-propoxy]-propyl}-piperidine),
6-{4-[3-(r-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2h-pyridazin-3-one,
GSK- 239512, PF-3654746, MK-0249, JNJ- 17216498, CEP-26401,
SCH-497079, ATH-90879, SAR-110894, APD916, S-38093, MK-3134, or
JNJ-3100174.
21. The method of claim 1, wherein the histamine H.sub.3 receptor
antagonist is administered in a therapeutically effective amount
with an effective amount of ibuprofen, celecoxib, or rofecoxib.
22. (canceled)
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. patent application
Ser. No. 61/173,132, filed Apr. 27, 2009, and U.S. patent
application Ser. No. 61/173,161, filed Apr. 27, 2009, which are
hereby incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
BACKGROUND OF THE INVENTION
[0003] 1. Technical Field of the Invention
[0004] The invention relates a method of treatment of
osteoarthritis pain. The method more particularly relates to the
treatment of osteoarthritis pain by administration of a histamine
H.sub.3 receptor antagonist, a salt thereof, or a composition
comprising such compound or salt.
[0005] 2. Description of Related Technology
[0006] Pain of various different types afflicts virtually all
humans and animals at one time or another. A substantial number of
medical disorders and conditions produce some sort of pain as a
prominent concern requiring treatment. Pain is the one of the most
common significant medical issues reported in the clinic and it
affects the broadest group of patients. Distinct types and
manifestations of pain are reported. Different pain types can be
related to the origin of the pain, the underlying pathology, or
different pharmacological agents that demonstrate efficacy (or lack
thereof) in treating the pain.
[0007] The pain can be caused by different reasons. For example,
the prominent causes of inflammatory pain are burns and chemical
irritation. Post-surgical pain can arise after incisions of the
skin and internal organs, among other conditions. Nerve damage can
lead to neuropathic pain and neuropathy arising from sciatic nerve
irritation, chronic diabetes, and chemotherapy. Osteoarthritis pain
typically arises from a cause having physical origin, for example,
such as the erosion of joint cartilage with a resulting mechanical
irritation of the bones and joint.
[0008] Various types of pain are treated with distinct, different
therapeutic agents. For example, acute inflammatory pain is
typically treated with non-steroidal anti-inflammatory (NSAID)
agents and cyclooxygenase inhibitors, for example aspirin or
celecoxib. Post-surgical pain is typically treated with opiate
receptor agonists, for example codeine. Neuropathic pain can be
treated with anti-depressant agents and neurotransmitter reuptake
inhibitors, for example duloxetine. Osteoarthritis pain is commonly
treated with acetominophen.
[0009] A distinct type of pain where patients are not completely
treatable by any of the currently available drugs or by agents is
neuropathic pain. The drug duloxetine can usefully provide partial
relief of this type of pain. Neuropathic pain can develop in
response to previous injury or ongoing tissue injury, nerve injury,
or diabetes. Neuropathic pain is distinct from other types of pain,
for example inflammatory pain, in that it persists long after signs
of the original injury or damage have disappeared. Neuropathic pain
also is associated with allodynia, hyperalgesia, or causalgia
(Dworkin Clinical Journal of Pain (2002) vol. 18(6) pp. 343-9). The
topic and physiology of neuropathic pain has been reviewed in the
scientific literature (Smith, et al. Drug Development Research
(2001) vol. 54(3), pp. 140-153; Collins and Chessell Expert Opinion
on Emerging Drugs (2005) vol. 10(1), pp. 95-108; Vinik and
Mehrabyan Medical Clinics of North America (2004), vol. 88(4), pp.
947-999; Dray, Urban, and Dickenson Trends in Pharmacological
Sciences (1994) vol. 15(6) pp. 190-7; Dworkin Clinical Journal of
Pain (2002) vol. 18(6) pp. 343-9.) Some histamine H.sub.3 receptor
antagonists have been reported to have efficacy in animal models of
neuropathic pain (Medhurst, et al. Biochemical Pharmacology (2007)
73, pp. 1182-1194; Medhurst, et al. Pain (2008) 138, pp.
61-69).
[0010] A very wide variety of compounds with H.sub.3 receptor
antagonist activity has been reported (Berlin and Boyce, Expert
Opinion in Therapeutic Patents (2007) 17(6) pp. 675-687;
Esbenshade, Browman, Bitner, Strakhova, Cowart, and Brioni, Br. J.
Pharmacol. (2008), 154, pp. 1166-1181.) Different H.sub.3
antagonists have been found active in models of specific human
diseases, including for example, Alzheimer's disease, age-related
cognitive and memory impairment, attention-deficit hyperactivity
disorder, cognitive disfunction related to schizophrenia, allergic
rhinitis, and sleep disorders.
[0011] In contrast to neuropathic pain, pain from osteoarthritis is
thought to arise first from some structural pathology, and then
from damage or destruction of the cartilage and alteration of the
joint surface. Consequent mechanical irritation of nerves in bones
and joints leads to pathological sensitization of peripheral and
central nerves (Dray and Read, Arthritis Research and Therapy
(2007) 9, p. 212). The pain of osteoarthritis in the clinic is
independent of ongoing inflammation (Fernihough, et al. Pain (2004)
112, pp. 83-93; Joshi and Honore, Expert Opinion in Drug Discovery
(2006), 1(4), pp. 323-334). As yet, there is no pharmacological
therapy that reverses the damage to the joint in osteoarthritis. As
such, therapeutic agents of diverse pharmacological mechanisms are
used to treat the pain symptoms of osteoarthritis. These agents are
associated with either incomplete relief of pain or mechanism- and
agent-based side effects that compromise the quality of the
treatment (Rubin, Journal of the American Osteopathic Association
(2005) 105, S23-S28; Dray and Read, Arthritis Research and Therapy
(2007) 9, p. 212). As such, it would be particularly beneficial to
identify new methods for treating osteoarthritis. It would be
particularly beneficial if such methods are based on previously
unexplored mechanisms for pain treatment that may offer improved
pain relief or are less associated with side effects. However, no
H.sub.3 antagonist has yet been reported to demonstrate effect in
osteoarthritis pain.
SUMMARY OF THE INVENTION
[0012] The invention relates a method of treatment of
osteoarthritis pain. The method more particularly relates to the
treatment of osteoarthritis pain by administration of a histamine
H.sub.3 receptor antagonist, a salt thereof, or a composition
comprising such sompound or salt.
[0013] Suitable histamine H.sub.3 antagonists are, for example,
compounds of formula:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein:
[0014] m is 0 or 1;
[0015] one of R.sub.A-1 and R.sub.A-2 is hydrogen, acyl, acyloxy,
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl,
alkynyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,
nitro, alkylthio, --NR.sub.A-AR.sub.A-B,
(NR.sub.A-AR.sub.A-B)carbonyl,
--SO.sub.2NR.sub.A-14a)(R.sub.A-14b),
N(R.sub.A-14a)SO.sup.2(R.sub.A-14b), group of the formula
-L.sub.A-2-R.sub.A-6, or a group of the formula
-L.sub.A-3a-R.sub.A-6a-L.sub.A-3b-R.sub.A-6b;
[0016] the other of R.sub.1 and R.sub.2 is selected from hydrogen,
cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy,
alkoxyalkyl, fluoroalkoxy, alkylthio,
--SO.sub.2N(R.sub.A-14a)(R.sub.A-14b), and
--N(R.sub.A-14a)SO.sub.2(R.sub.A-14b);
[0017] R.sub.A-3a and R.sub.A-3b are each independently selected
from hydrogen, cyano, halogen, alkyl, cycloalkyl, fluoroalkyl,
alkoxy, alkoxyalkyl, fluoroalkoxy, alkylthio,
--SO.sub.2N(R.sub.A-14a)(R.sub.A-14b), and
--N(R.sub.A-14a)SO.sub.2(R.sub.A-14b);
[0018] R.sub.A-4 and R.sub.A-5 are each independently selected from
alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl; or
R.sub.A-4 and R.sub.A-5 taken together with the nitrogen atom to
which each is attached form a non-aromatic ring;
[0019] R.sub.A-6 is selected from aryl, heterocycle, and
heterocyclealkyl;
[0020] R.sub.A-6a is selected from aryl and heterocycle;
[0021] R.sub.A-6b is selected from aryl and heterocycle;
[0022] L is a bond or alkylene;
[0023] L.sub.2 is selected from a bond, --O--, alkylene,
--C(.dbd.O)--, --S--, --SO.sub.2N(R.sub.A-14a)--,
--N(R.sub.A-14a)SO.sub.2--, --C(O)N(R.sub.A-14a)--,
--N(R.sub.A-14a)C(O)--, --N(R.sub.A-15)--;
[0024] L.sub.3a and L.sub.3b are each independently selected from a
bond, --O--, alkylene, --C(.dbd.O)--, --S--,
--SO.sub.2N(R.sub.A-14a)--, --NR.sub.A-14a)SO.sub.2---,
--C(O)N(R.sub.A-14a)--, --N(R.sub.A-14a)C(O)--, and
--N(R.sub.A-15)--;
[0025] R.sub.A-10 is selected from hydrogen, cyano, fluoro,
hydroxy, and alkyl;
[0026] R.sub.A-14a and R.sub.A-14b are each independently selected
at each occurrence from hydrogen, alkyl, and cycloalkyl;
[0027] R.sub.A-15 is selected from hydrogen, alkyl, acyl,
alkoxycarbonyl and (R.sub.A-14a)(R.sub.A-14b)NC(O)--; and
[0028] R.sub.A-A and R.sub.A-B are independently selected from
hydrogen, alkyl, acyl, haloalkyl, alkoxycarbonyl, cycloalkyl, and
formyl.
[0029] Such compounds, salts, and methods for preparing them are
described in US Patent Publication No. 2007/0066588, published Mar.
22, 2007, and the related U.S. Pat. No. 7,576,110, issued Aug. 18,
2009, both the contents of which are herein incorporated by
reference. Compounds generally and specifically useful in the
invention are described in US Patent Publication No. 2007/0066588,
published Mar. 22, 2007. Some specific compounds of interest, are
for example,
(S)-3-hydroxy-1-[2-(3-piperidin-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrro-
lidin-2-one,
trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3-
(2H)-one, and
cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2-
H)-one.
[0030] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein
[0031] one of R.sub.B-1 and R.sub.B-2 is a group of the formula
L.sub.B-2-R.sub.B-6a-L.sub.B-3-R.sub.B-6b;
[0032] the other of R.sub.B-1 and R.sub.B-2 is selected from
hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;
[0033] R.sub.B-3, R.sub.B-3a, and R.sub.B-3b are each independently
selected from the group consisting of hydrogen, alkyl,
trifluoroalkyl, trifluoroalkoxy, alkoxy, halogen, cyano, and
thioalkoxy
[0034] R.sub.B-4 and R.sub.B-5 are each independently selected from
alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl, or
R.sub.B-4 and R.sub.B-5 taken together with the nitrogen atom to
which each is attached form a non-aromatic ring of the formula:
##STR00003##
[0035] R.sub.B-7, R.sub.B-8, R.sub.B-9, and R.sub.B-10 at each
occurrence are each independently selected from hydrogen,
hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;
[0036] R.sub.B-11, R.sub.B-12, R.sub.B-13, and R.sub.B-14 are each
independently selected from hydrogen, hydroxyalkyl, alkyl, and
fluoroalkyl;
[0037] R.sub.B-6a is selected from a 5- to 6-membered heteroaryl
ring, cyanophenyl, an 8- to 12-membered bicyclic heteroaryl ring,
and a 4- to 12-membered heterocyclic ring;
[0038] R.sub.B-6b is selected from hydrogen, a 5- to 6-membered
heteroaryl ring, an aryl ring, an 8- to 12-membered bicyclic
heteroaryl ring, and a 4- to 12-membered heterocyclic ring;
[0039] Q is selected from O and S;
[0040] L.sub.B is --[C(R.sub.B-16)(R.sub.B-17)].sub.k;
[0041] L.sub.2 is selected from a bond, alkylene, --O--,
--C(.dbd.O)--, --S--, --NH--, --N(R.sub.B-16)C(.dbd.O)--,
--C(.dbd.O)N(R.sub.B-16), and --N(alkyl)-;
[0042] L.sub.3 is selected from a bond, alkylene, --O--,
--C(.dbd.O)--, --S--, --N(R.sub.B-16)C(.dbd.O)--,
--C(.dbd.O)N(R.sub.B-16), and --N(R.sub.B-15)--;
[0043] R.sub.B-15 is selected from hydrogen, alkyl, acyl,
alkoxycarbonyl, amido, and formyl;
[0044] R.sub.B-16 and R.sub.B-17 at each occurrence are
independently selected from hydrogen and alkyl;
[0045] R.sub.B-x and R.sub.B-y at each occurrence are independently
selected from hydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro,
and dialkylamino;
[0046] k is 1, 2, or 3; and
[0047] m2 is an integer from 1 to 5.
[0048] Such compounds, salts, and methods for preparing them are
described in US Patent Publication No. 2008/0242653, published Oct.
2, 2008, the contents of which are herein incorporated by
reference. Compounds generally and specifically, as well as the
salts thereof, useful in the invention are described in US Patent
Publication No. 2008/0242653, published Oct. 2, 2008. A preferred
compound of interest is
2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-
pyridazin-3(2H)-one.
[0049] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00004##
or a pharmaceutically acceptable salt, wherein
[0050] A is selected from the group consisting of carbonyl and a
covalent bond;
[0051] D is selected from the group consisting of O and S;
[0052] L is selected from the group consisting of lower alkylene,
fluoroalkylene, and hydroxyalkylene;
[0053] P.sub.C and Q.sub.c taken together form a covalent bond or
are both hydrogen;
[0054] R.sub.C-1 and R.sub.C-2 are each independently selected from
the group consisting of hydrogen, alkyl, aryl, arylalkyl,
cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl,
hydroxyalkyl, alkenyl, and alkynyl; or
[0055] R.sub.C-1 and R.sub.C-2 taken together with the nitrogen
atom to which they are attached, together form a heterocycle;
[0056] R.sub.C-3 is selected from the group consisting of hydrogen,
alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,
alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy,
carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy,
haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro,
--NR.sub.C-AR.sub.C--B, (NR.sub.C-AR.sub.C--B)alkyl,
(NR.sub.C-AR.sub.C--B)carbonyl, and
(NR.sub.C-AR.sub.C--B)sulfonyl;
[0057] R.sub.C-4, R.sub.C-5, R.sub.C-6 and R.sub.C-7 are each
independently selected from the group consisting of hydrogen,
alkoxy, alkoxycarbonyl, alkyl, alkyl carbonyl, alkylcarbonyloxy,
alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy,
carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen,
haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl,
mercapto, nitro, --NR.sub.C-AR.sub.C--B,
(NR.sub.C-AR.sub.C--B)alkyl, (NR.sub.C-AR.sub.C--B)carbonyl,
(NR.sub.C-AR.sub.C--B)sulfonyl, -L.sub.C-2R.sub.C-20, and
--R.sub.C-21L.sub.C-3R.sub.C-22;
[0058] L.sub.C-2 is selected from the group consisting of alkylene,
alkenylene, O, S, S(O), S(O).sub.2, C(.dbd.O),
C.dbd.(NOR.sub.C-21), and N(R.sub.C-A);
[0059] L.sub.3 is selected from the group consisting of a covalent
bond, alkylene, alkenylene, O, S, C(.dbd.O), N(.dbd.OR.sub.C-21),
and N(R.sub.C-A);
[0060] R.sub.C-20 is selected from the group consisting of aryl,
heterocycle, and cycloalkyl;
[0061] R.sub.C-21 is selected from the group consisting of hydrogen
and alkyl;
[0062] R.sub.C-22 is selected from the group consisting of aryl,
heterocycle, and cycloalkyl;
[0063] R.sub.C-A and R.sub.C--B are each independently selected
from the group consisting of hydrogen, alkyl, alkylcarbonyl and
formyl;
[0064] provided that at least one of R.sub.C-4, R.sub.C-5,
R.sub.C-6, or R.sub.C-7 is aryl, heterocycle, cycloalkyl,
-L.sub.C-2R.sub.C-20 or R.sub.C-20L.sub.C-3R.sub.C-22.
[0065] Such compounds, salts, and method for preparing them are
described in U.S. Pat. No. 6,969,730, issued Nov. 29, 2005, the
contents of which are herein incorporated by reference. Compounds
generally and specifically, as well as the salts thereof, useful in
the invention are described in U.S. Pat. No. 6,969,730, issued Nov.
29, 2005. A specific compound of interest, is
(4-(2-(2-[2(R)-methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-5-yl)benzonitril-
e) (ABT-239).
[0066] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00005##
wherein X.sub.D is CH or N, or a pharmaceutically acceptable salt
thereof. Such compounds, salts, and methods for preparing them are
described in WO2004/056369, published Jul. 8, 2004, the contents of
which are herein incorporated by reference. Compounds generally and
specifically, as well as the salts thereof, useful in the invention
are described in US20070299056, published Dec. 27, 2007, the
contents of which are herein incorporated by reference. Specific
compounds of interest are, for example,
6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-ni-
cotinamide or GSK-189254 and
5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpyr-
azine-2-carboxamide or GSK-207040.
[0067] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of structure:
##STR00006##
or
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyr-
idinyl}-2-pyrrolidinone, and pharmaceutically acceptable salts
thereof. Such compound, salts, and method of preparing them are
described in WO2008/104590, published Sep. 4, 2008, WO2004/056369,
published Jul. 8, 2004, and US 20070299056, published Dec. 27,
2007, the contents of which are all herein incorporated by
reference.
[0068] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of structure:
##STR00007##
(4-isopropyl-1,4-diazepan-1-yl)(1-(6-(trifluoromethyl)pyridin-3-yl)piperi-
din-4-yl)methanone, or GSK-334429, and pharmaceutically acceptable
salts thereof. Such compounds, salts, and method of preparing them
are described in WO2004/101546, published Nov. 25, 2004, the
contents of which are herein incorporated by reference.
[0069] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00008##
wherein Ar is a divalent group formed by eliminating two hydrogen
atoms from benzene, pyrimidine, pyridine, thiazole, oxazole,
pyrazole, thiadiazole or thiophene (this divalent group may be
further substituted by a halogen atom, lower alkoxy (this lower
alkoxy group may be further substituted by halogen), hydroxy or
lower alkyl); X.sub.1 is a nitrogen atom, sulfur atom or oxygen
atom; R.sub.G-1 is a 5- or 6-membered heteroaryl group having 1 to
4 heteroatoms selected from among nitrogen, sulfur and oxygen,
heteroarylalkyl group (heteroaryl in this group has the same
meaning as the above), straight chain or branched lower alkyl (this
lower alkyl group may be further substituted by hydroxy, halogen,
alkoxy, allyloxy or aralkyloxy), phenyl, aralkyl, alkoxy, alkylthio
or lower alkylamino; Ring A is a 5- or 6-membered heteroaryl ring
having 1 or 2 nitrogen atoms or sulfur atoms in the ring, or a
benzene ring; R.sub.2 and R.sub.3 may be the same or different, and
each represents hydrogen, amino, alkylamino, dialkylamino, nitro,
cyano, hydroxy, lower alkylsulfonyl, halogen, lower alkyl (this
lower alkyl group may be further substituted by halogen), lower
cycloalkyl (this lower cycloalkyl group may be further substituted
by halogen), lower alkoxy (this lower alkoxy group may be further
substituted by halogen or hydroxy), lower cycloalkoxy (this lower
cycloalkoxy group may be further substituted by halogen), aryloxy,
aralkyloxy, heteroaryloxy, heteroarylalkyloxy, aryl, heteroaryl,
arylcarbamoyl, heteroarylcarbamoyl, arylalkylcarbamoyl,
heteroarylalkylcarbamoyl, mono-lower alkylcarbamoyl, di-lower
alkylcarbamoyl, lower alkylcarboxamide, aryl carboxamide,
heteroarylcarboxamide, arylalkylcarboxamide,
heteroarylalkylcarboxamide, alkanoyl, arylcarbonyl,
arylalkylcarbonyl, alkylsulfonylamino, arylsulfonylamino,
alkylaminosulfonyl, arylaminosulfonyl, aralkyl, alkanoylamino or
alkanoylalkylamino; Y is CH or a nitrogen atom; --X.sub.2 is a
group represented by --(CH.sub.2).sub.n--NR.sub.G-4R.sub.G-5, n is
an integer of 2 to 4, where R.sub.G-4 and R.sub.G-5 taken together
with a nitrogen atom together form a 5- to 8-membered monocyclic
ring (this monocyclic ring may be substituted by a halogen atom, an
oxo group, or a lower alkyl group of 1-3 carbon atoms which itself
may be substituted by halogen, or where --X.sub.2 is a group
represented by
##STR00009##
where m is an integer from 0 to 4, and R.sub.G-6 is a lower alkyl
or cycloalkyl group), or a pharmaceutically acceptable salt
thereof. Such compounds, salts, and methods of preparing them are
described in US Patent Publication No. 2005/0182045, published on
Aug. 18, 2005, the contents of which are herein incorporated by
reference. Compounds generally and specifically, and salts thereof,
useful in the invention are further described therein. Specific
compounds of interest are,
2-methyl-3-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5-(trifluoromethyl)quin-
azolin-4(3H)-one and
3-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-2-methyl-5-(trifluoromethyl)q-
uinazolin-4(3H)-one.
[0070] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00010##
or
6-[2-(1-isopropylpiperidin-4-yloxy)-7,8-dihydro-5H-[1,6]naphthyridin-6-
-yl]nicotinamide and pharmaceutically acceptable salts thereof.
Compounds, salts, and methods for their preparation are described
in WO2007/052124, published May 10, 2007, the contents of which are
herein incorporated by reference.
[0071] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00011##
or
N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobuta-
necarboxamide, and stereoisomeric forms of the compound.
Stereoisomeric forms are
(1r,30-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)ph-
enyl)cyclobutanecarboxamide and
trans-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclob-
utanecarboxamide. Such compounds and stereoisomeric forms are
described in patent application US Patent Publication No.
2008/0176925, published Jul. 24, 2008, the contents of which are
herein incorporated by reference.
[0072] Other suitable histamine H.sub.3 antagonists are, for
example, compounds of formula:
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein
[0073] R.sub.1 is C.sub.1-10alkyl, C.sub.3-8 alkenyl, C.sub.3-8
cycloalkyl, (C.sub.3-8 cycloalkyl)C.sub.1-6 alkyl, (C.sub.3-8
cycloalkyl)C.sub.3-8 alkenyl, or (C.sub.1-8 alkylcarbonyl)C.sub.1-8
alkyl;
[0074] n is 1 or 2;
[0075] X.sub.J is O or S;
[0076] one of R.sub.2, R.sub.3 and R.sub.4 is G and the other two
independently are hydrogen, fluoro, chloro, bromo, nitro,
trifluoromethyl, methyl, or C.sub.1-3 alkoxy;
[0077] G is L.sub.jQ.sub.J;
[0078] L.sub.J is unbranched --(CH.sub.2).sub.m3,-- wherein m3 is
an integer from 1 to 7;
[0079] Q.sub.J is NR.sub.8R.sub.9 wherein R.sub.8 is independently
selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 3-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9
membered heterocyclyl)C.sub.1-6 alkylene, and (phenyl)C.sub.1-6
alkylene; and
[0080] R.sub.9 is independently selected from C.sub.1-6 alkyl,
C.sub.3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (6-9-membered heteroyclyl)C.sub.1-6 alkylene,
and (phenyl)C.sub.1-6 alkylene; or
[0081] Q.sub.J is a saturated 3-12 membered N-linked heterocyclyl,
wherein, in addition to the N-linking nitrogen, the 3-12 membered
heterocyclyl may optionally contain between 1 and 3 additional
heteroatoms independently selected from O, S, and NH; wherein Q is
optionally substituted with 1-3 substituents independently selected
from the group consisting of hydroxy, halo, carboxamide, C.sub.1-6
alkyl, 5-9 membered or 6-9 membered heterocyclyl, --N(C.sub.1-6
alkyl)(5-9 membered or 6-9 membered heterocyclyl), --NH(5-9
membered or 6-9 membered heterocyclyl), --O(5-9 or 6-9 membered
heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C.sub.1-3
alkylene, C.sub.1-6 alkoxy, (C.sub.3-6 cycloalkyl)-O--, phenyl,
(phenyl)C.sub.1-3 alkylene, and (phenyl)C.sub.1-3 alkylene-O--,
where each of above heterocyclyl, phenyl, and alkyl groups may be
optionally substituted with from 1 to 3 substituents independently
selected from trifluoromethyl, methoxy, halo, nitro, cyano,
hydroxy, and C.sub.1-3 alkyl; provided however that when R.sub.1 is
methyl, G is not piperidin-1-ylmethyl; and wherein each of the
above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl,
carbocyclyl, and aryl groups may each be independently and
optionally substituted with between 1 and 3 substituents
independently selected from trifluoromethyl, methoxy, halo, amino,
nitro, hydroxy, and C.sub.1-3 alkyl. Such compounds, salts, and
methods for preparing such compounds and salts are described in
WO2004/037801, published May 6, 2004, the contents of which are
herein incorporated by reference. Specific compounds of interest
are
((4-isopropylpiperazin-1-yl)(4-(piperidin-1-ylmethyl)phenyl)methanone),
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpy-
razine-2-carboxamide), as described in US2007/066821, published
Mar. 22, 2007, the contents of which are herein incorporated by
reference.
[0082] Other suitable histamine H.sub.3 receptor antagonists
are:
##STR00013##
or
(1-((2-amino-6-methylpyridin-4-yl)methyl)-4-fluoropiperidin-4-yl)(4-(2-
-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)methanone,
or a pharmaceutically acceptable salt thereof. Such compounds,
salts, and methods of preparing them are as described in patent
application US Patent Publication No. 2007/0066644, published Mar.
22, 2007, the contents of which are herein incorporated by
reference.
[0083] Another suitable histamine H.sub.3 receptor antagonist is
3-[4-[(1-cyclobutyl-4-piperidinyl)-oxy]phenyl]-2-methyl-5-trifluoromethyl-
-4(3H)-quinazolinone, and salts thereof, which are described in
WO2006/132424, published Dec. 14, 2006, the contents of which are
herein incorporated by reference.
[0084] Another suitable histamine H.sub.3 receptor antagonist is
2-methyl-3-[4-[3-(1-pyrrolidinyl)propoxy]phenyl]-5-trifluoromethyl-4(3H)--
quinazolinone and salts thereof, which are described in
WO2006/085692; published Aug. 17, 2006, and the related US Patent
Publication No. 2008/0139589, published Jun. 12, 2008, as well as
and WO2007/004735, published Aug. 17, 2006, and the related US
Patent Publication No. 2009/0131664, published May 21, 2009, the
contents of which are all incorporated by reference.
[0085] Other H.sub.3 antagonist compounds are known, and are
suitable for the treatment of osteoarthritis pain, including BF2649
(1-{3-[3-(4-chloro-phenyl)-propoxy]-propyl}-piperidine),
6-{4-[3-(r-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2h-pyridazin-3-one,
GSK-239512, PF-3654746, MK-0249, JNJ-17216498, CEP-26401,
SCH-497079, ATH-90879, SAR-110894, APD916, S-38093, MK-3134, and
JNJ-3100174. Another aspect of the invention relates to
pharmaceutical compositions comprising the aforementioned
compounds. Such compositions can be administered in accordance with
a method of the invention, typically as part of a therapeutic
regimen for treatment of the pain of osteoarthritis.
[0086] Another suitable histamine H.sub.3 receptor antagonist is
1-(1-methylethyl)-4-{[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]carbonyl}pipe-
razine, or a pharmaceutically acceptable salt thereof, such the
hydrochloride salt. This compound and salts arc described in
WO2009/030716, published Mar. 12, 2009, the contents of which are
herein incorporated by reference.
[0087] Yet other H.sub.3 antagonist compounds are known, and are
suitable for the treatment of osteoarthritis pain, specifically
those described in U.S. Pat. No. 7,153,889, issued Dec. 26, 2006;
U.S. Pat. No. 7,205,316, issued Apr. 17, 2007; U.S. Pat. No.
7,098,222, issued Aug. 29, 2006; U.S. Pat. No. 7,358,263, issued
Apr. 15, 2008; U.S. Pat. No. 7,094,790, issued Aug. 22, 2006; U.S.
Pat. No. 7,345,034, issued Mar. 18, 2008; WO2006/132914, published
Dec. 14, 2006; US Patent Publication No. 2008/0027041, published
Jan. 31, 2008; WO2004/101546, published Nov. 24, 2005; EP1595881,
published Nov. 16, 2005; and US Patent Publication No.
2008/0096955, published Apr. 24, 2008, the contents of which are
all incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
Histamine H.sub.3 Receptor Antagonists and Compositions Thereof
[0088] Histamine H.sub.3 receptor antagonists of various structural
classes have been identified. Histamine H.sub.3 receptor
antagonists have been identified as useful for treating various
indications. However, the invention relates to the use of histamine
H.sub.3 antagonists for treating a particular indication,
osteoarthritis pain. Many histamine H.sub.3 receptor antagonists
are reported in the literature.
[0089] Suitable histamine H.sub.3 receptor antagonists are as
described in the Summary of the Invention. Where the terms for
describing the compound formulae are not explicitly defined,
suitable definitions are described below in the Definition of
Terms.
[0090] Particularly preferred compounds for the method include, but
are not limited to,
(S)-3-Hydroxy-1-[2-(3-piperidin-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrro-
lidin-2-one, Trans-2-[2-(3-piperidin-1-yl
cyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one,
Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2-
H)-one,
(4-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-5-yl)benz-
onitrile),
(6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)--
N-methyl-nicotinamide),
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpy-
razine-2-carboxamide),
1-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridi-
nyl}-2-pyrrolidinone,
(4-isopropyl-1,4-diazepan-1-yl)(1-(6-(trifluoromethyl)pyridin-3-yl)piperi-
din-4-yl)methanone,
2-methyl-3-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5-(trifluoromethyl)quin-
azolin-4(3H)-one,
3-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-2-methyl-5-(trifluoromethyl)q-
uinazolin-4(3H)-one,
6-(2-(1-isopropylpiperidin-4-yloxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl-
)nicotinamide,
N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobutanec-
arboxamide,
(1r,3r)-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cycl-
obutanecarboxamide,
trans-N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclob-
utanecarboxamide,
((4-isopropylpiperazin-1-yl)(4-(piperidin-1-ylmethyl)phenyl)methanone),
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpy-
razine-2-carboxamide),
(1-((2-amino-6-methylpyridin-4-yl)methyl)-4-fluoropiperidin-4-yl)(4-(2-(p-
yridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)methanone,
and (1-{3-[3-(4-Chloro-phenyl)-propoxy]-propyl}-piperidine),
6-{4-[3-(r-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2h-pyridazin-3-one,
1-(1-methylethyl)-4-{[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]carbonyl}pipe-
razine.
[0091] More particularly preferred compounds include, but are not
limited to,
Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-
-3(2H)-one,
Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3-
(2H)-one,
(S)-3-Hydroxy-1-[2-(3-piperidin-1-yl-cyclobutyl)-benzothiazol-6--
yl]-pyrrolidin-2-one,
(4-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-5-yl)benzonitril-
e),
(6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methy-
l-nicotinamide),
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpy-
razine-2-carboxamide),
(4-isopropyl-1,4-diazepan-1-yl)(1-(6-(trifluoromethyl)pyridin-3-yl)piperi-
din-4-yl)methanone
Definition of Terms
[0092] Unless otherwise defined, terms as used in the specification
refer to the following definitions, as detailed below.
[0093] The term "acyl" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through a
carbonyl group, as defined herein. Representative examples of acyl
include, but are not limited to, acetyl, 1-oxopropyl,
2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
[0094] The term "acyloxy" as used herein means an acyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of acyloxy include, but are
not limited to, acetyloxy, propionyloxy, and isobutyryloxy.
[0095] The term "alkenyl" as used herein means a straight or
branched chain hydrocarbon containing from 2 to 10 carbons, and
preferably 2, 3, 4, 5, or 6 carbons, and containing at least one
carbon-carbon double bond formed by the removal of two hydrogens.
Representative examples of alkenyl include, but are not limited to,
ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,
5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
[0096] The term "alkoxy" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy.
[0097] The term "alkoxyalkoxy" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through another alkoxy group, as defined herein. Representative
examples of alkoxyalkoxy include, but are not limited to,
tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and
methoxymethoxy.
[0098] The term "alkoxyalkyl" as used herein means an alkoxy group,
as defined herein, appended to the parent molecular moiety through
an alkyl group, as defined herein. Representative examples of
alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
[0099] The term "alkoxycarbonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
[0100] The term "alkoxyimino" as used herein means an alkoxy group,
as defined herein, appended to the parent molecular moiety through
an imino group, as defined herein. Representative examples of
alkoxyimino include, but are not limited to, ethoxy(imino)methyl
and methoxy(imino)methyl.
[0101] The term "alkoxysulfonyl" as used herein means an alkoxy
group, as defined herein, is appended to the parent molecular
moiety through a sulfonyl group, as defined herein. Representative
examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl, and propoxysulfonyl.
[0102] The term "alkyl" as used herein means a straight or branched
chain hydrocarbon containing from 1 to 10 carbon atoms, and
preferably 1, 2, 3, 4, 5, or 6 carbons. Representative examples of
alkyl include, but are not limited to, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tut-butyl, n-pentyl,
isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,
2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
[0103] The term "alkylamino" as used herein means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a NH group. Representative examples of alkylamino include, but are
not limited to, methylamino, ethylamino, isopropylamino, and
butylamino.
[0104] The term "alkylcarbonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to,
methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl,
and the like.
[0105] The term "alkylene" means a divalent group derived from a
straight or branched chain hydrocarbon of from 1 to 10 carbon
atoms. Representative examples of alkylene include, but are not
limited to, --CH.sub.2--, --CH(CH.sub.3)--, --C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0106] The term "alkylsulfonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl.
[0107] The term "alkynyl" as used herein means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms, and preferably 2, 3, 4, or 5 carbons, and containing at
least one carbon-carbon triple bond. Representative examples of
alkynyl include, but are not limited to, acetylenyl, 1-propynyl,
2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
[0108] The term "amido" as used herein means an amino, alkylamino,
or dialkylamino group appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of amido include, but are not limited to, aminocarbonyl,
methyl aminocarbonyl, dimethyl aminocarbonyl, and
ethylmethylaminocarbonyl.
[0109] The term "amino" as used herein means a --NH.sub.2
group.
[0110] The term "aryl" as used herein means a monocyclic
hydrocarbon aromatic ring system. Representative examples of aryl
include, but are not limited to, phenyl.
[0111] The aryl groups of this invention are substituted with 0, 1,
2, 3, 4, or 5 substituents independently selected from acyl,
acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkylcarbonyl,
formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
mercapto, nitro, thioalkoxy, NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)sulfonyl.
[0112] The term "arylalkyl" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl, 2-phenylethyl
and 3-phenylpropyl.
[0113] The term "carbonyl" as used herein means a --C(.dbd.O)--
group.
[0114] The term "carboxy" as used herein means a --CO.sub.2H group,
which may be protected as an ester group --CO.sub.2-alkyl.
[0115] The term "cyano" as used herein means a --CN group.
[0116] The term "cyanophenyl" as used herein means a --CN group
appended to the parent molecular moiety through a phenyl group,
including, but not limited to, 4-cyanophenyl, 3-cyanophenyl, and
2-cyanophenyl.
[0117] The term "cycloalkyl" as used herein means a saturated
cyclic hydrocarbon group containing from 3 to 8 carbons. Examples
of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl.
[0118] The cycloalkyl groups of the invention are substituted with
0, 1, 2, 3, or 4 substituents selected from acyl, acyloxy, alkenyl,
alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,
alkyl, alkynyl, amido, carboxy, cyano, ethylenedioxy, formyl,
haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
methylenedioxy, oxo, thioalkoxy, and --NR.sub.AR.sub.B.
[0119] The term "cycloalkylcarbonyl" as used herein means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of cycloalkylcarbonyl include, but are not
limited to, cyclopropylcarbonyl, cyclopentylcarbonyl,
cyclohexylcarbonyl, and cycloheptylcarbonyl.
[0120] The term "dialkylamino" as used herein means two independent
alkyl groups, as defined herein, appended to the parent molecular
moiety through a nitrogen atom. Representative examples of
dialkylamino include, but are not limited to, dimethylamino,
diethylamino, ethylmethylamino, and butylmethylamino.
[0121] The term "fluoro" as used herein means --F.
[0122] The term "fluoroalkoxy" as used herein means at least one
fluoroalkyl group, as defined herein, appended to the parent
molecular moiety through an oxygen group, as defined herein.
Representative examples of fluoroalkyl include, but are not limited
to, trifluoromethoxy (CF.sub.3O), and difluoromethoxy
(CHF.sub.2O).
[0123] The term "fluoroalkyl" as used herein means at least one
fluoro group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of fluoroalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,
and 2,2,2-trifluoroethyl.
[0124] The term "formyl" as used herein means a 13 C(O)H group.
[0125] The term "halo" or "halogen" as used herein means Cl, Br, I,
or F.
[0126] The term "haloalkoxy" as used herein means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein. Representative examples
of haloalkoxy include, but are not limited to, 2-fluoroethoxy,
trifluoromethoxy, and pentafluoroethoxy.
[0127] The term "haloalkyl" as used herein means at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and
2-chloro-3-fluoropentyl.
[0128] The term "heteroaryl", as used herein, refers to an aromatic
ring containing one or more heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a tautomer thereof. Such rings can
be monocyclic or bicyclic as further described herein. Heteroaryl
rings are connected to the parent molecular moiety, or to L.sub.2
or L.sub.3, wherein L.sub.2 and L.sub.3 are defined in formula (I),
through a carbon or nitrogen atom.
[0129] The terms "monocyclic heteroaryl" or "5- or 6-membered
heteroaryl ring", as used herein, refer to 5- or 6-membered
aromatic rings containing 1, 2, 3, or 4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a tautomer thereof.
Examples of such rings include, but are not limited to, a ring
wherein one carbon is replaced with an O or S atom; one, two, or
three N atoms arranged in a suitable manner to provide an aromatic
ring; or a ring wherein two carbon atoms in the ring are replaced
with one O or S atom and one N atom. Such rings can include, but
are not limited to, a six-membered aromatic ring wherein one to
four of the ring carbon atoms are replaced by nitrogen atoms,
five-membered rings containing a sulfur, oxygen, or nitrogen in the
ring; five membered rings containing one to four nitrogen atoms;
and five membered rings containing an oxygen or sulfur and one to
three nitrogen atoms. Representative examples of 5- to 6-membered
heteroaryl rings include, but are not limited to, furyl,
imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl,
thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl,
[1,2,3]triazolyl, and [1,2,4]triazolyl.
[0130] The term "bicyclic heteroaryl" or "8- to 12-membered
bicyclic heteroaryl ring", as used herein, refers to an 8-, 9-,
10-, 11-, or 12-membered bicyclic aromatic ring containing at least
3 double bonds, and wherein the atoms of the ring include one or
more heteroatoms independently selected from oxygen, sulfur, and
nitrogen. Representative examples of bicyclic heteroaryl rings
include indolyl, benzothienyl, benzofuranyl, indazolyl,
benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl,
benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, pteridinyl, purinyl, naphthyridinyl,
cinnolinyl, thieno[2,3-d]imidazole, thieno[3,2-b]pyridinyl, and
pyrrolopyrimidinyl.
[0131] Heteroaryl groups of the invention, whether monocyclic or
bicyclic, may be substituted with hydrogen, or optionally
substituted with one or more substituents independently selected
from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylsulfonyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy,
formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,
mercapto, nitro, alkylthio, --NR.sub.AR.sub.B, and
(NR.sub.AR.sub.B)carbonyl. Monocyclic heteroaryl or 5- or
6-membered heteroaryl rings are substituted with 0, 1, 2, 3, 4, or
5 substituents. Bicyclic heteroaryl or 8- to 12-membered bicyclic
heteroaryl rings are substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or
9 substituents. Heteroaryl groups of the present invention may be
present as tautomers.
[0132] The terms "heterocyclic ring" and "heterocycle", as used
herein, refer to a 4- to 12-membered monocyclic or bicyclic ring
containing one, two, three, four, or five heteroatoms independently
selected from the group consisting of nitrogen, oxygen, and sulfur
and also containing either at least one carbon atom attached to
four other atoms or one carbon atom substituted with an oxo group
and attached to two other atoms. Four- and five-membered rings may
have zero or one double bond. Six-membered rings may have zero,
one, or two double bonds. Seven- and eight-membered rings may have
zero, one, two, or three double bonds. The non-aromatic heterocycle
groups of the invention can be attached through a carbon atom or a
nitrogen atom. The non-aromatic heterocycle groups may be present
in tautomeric form. Representative examples of nitrogen-containing
heterocycles include, but are not limited to, azepanyl, azetidinyl,
aziridinyl, azocanyl, dihydropyridazinyl, dihydropyridinyl,
dihydropyrimidinyl, morpholinyl, piperazinyl, piperidinyl,
pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, and
thiomorpholinyl. Representative examples of non-nitrogen containing
non-aromatic heterocycles include, but are not limited to,
dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl,
tetrahydropyranyl, and [1,3]dioxolanyl.
[0133] The heterocycles of the invention are substituted with
hydrogen, or optionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8,
or 9 substituents independently selected from acyl, acyloxy,
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, amido,
arylalkyl, arylalkoxycarbonyl, carboxy, cyano, formyl, haloalkoxy,
haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo,
thioalkoxy, --NR.sub.AR.sub.B, and (NR.sub.AR.sub.B)sulfonyl.
[0134] Additional examples of heterocycles include, but are not
limited to, azetidin-2-one, azepan-2-one, isoindolin-1,3-dione,
(Z)-1H-benzo[e][1,4]diazepin-5(4H)-one, pyridazin-3(2H)-one,
pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-2,4(1H,3H)-dione,
pyrrolidin-2-one, benzo[d]thiazol-2(3H)-one, pyridin-4(1H)-one,
imidazolidin-2-one, 1H-imidazol-2(3H)-one, piperidin-2-one,
tetrahydropyrimidin-2(1H)-one, 1H-benzo[d]imidazol-2(3H)-one,
[1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl,
[1,3,4]thiadiazinonyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl,
[1,3,4]oxadiazinonyl, and
1,5-dihydro-benzo[b][1,4]diazepin-2-on-yl.
[0135] The term "hydroxy" as used herein means an --OH group.
[0136] The term "hydroxyalkyl" as used herein means at least one
hydroxy group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl,
3-hydroxypropyl, 2,3-dihydroxypentyl, and
2-ethyl-4-hydroxyheptyl.
[0137] The term "hydroxy-protecting group" means a substituent
which protects hydroxyl groups against undesirable reactions during
synthetic procedures. Examples of hydroxy-protecting groups
include, but are not limited to, methoxymethyl, benzyloxymethyl,
2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl,
triphenylmethyl, 2,2,2-trichloroethyl, t-butyl, trimethylsilyl,
t-butyldimethylsilyl, t-butyldiphenylsilyl, methylene acetal,
acetonide benzylidene acetal, cyclic ortho esters,
methoxymethylene, cyclic carbonates, and cyclic boronates.
Hydroxy-protecting groups are appended onto hydroxy groups by
reaction of the compound that contains the hydroxy group with a
base, such as triethylamine, and a reagent selected from an alkyl
halide, alkyl trifilate, trialkylsilyl halide, trialkylsilyl
triflate, aryldialkylsilyltriflate, or an alkylchloroformate,
CH.sub.2I.sub.2, or a dihaloboronate ester, for example with
methyliodide, benzyl iodide, triethylsilyltriflate, acetyl
chloride, benzylchloride, or dimethylcarbonate. A protecting group
also may be appended onto a hydroxy group by reaction of the
compound that contains the hydroxy group with acid and an alkyl
acetal.
[0138] The term "imino" as defined herein means a --C(.dbd.NH)--
group.
[0139] The term "mercapto" as used herein means a --SH group.
[0140] The term "--NR.sub.AR.sub.B" as used herein means two
groups, R.sub.A and R.sub.B, which are appended to the parent
molecular moiety through a nitrogen atom. R.sub.A and R.sub.B are
independently selected from hydrogen, alkyl, acyl, and formyl.
Representative examples of --NR.sub.AR.sub.B include, but arc not
limited to, amino, dimethylamino, methylamino, acetylamino, and
acetylmethylamino.
[0141] The term "(NR.sub.AR.sub.B)alkyl" as used herein means an
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)alkyl include, but are
not limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl,
2-(amino)ethyl, 2-(ethylmethylamino)ethyl, and the like.
[0142] The term "(NR.sub.AR.sub.B)carbonyl" as used herein means an
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0143] Representative examples of (NR.sub.AR.sub.B)carbonyl
include, but are not limited to, aminocarbonyl,
(methylamino)carbonyl, (dimethylamino)carbonyl,
(ethylmethylamino)carbonyl, and the like.
[0144] The term "(NR.sub.AR.sub.B)sulfonyl" as used herein means a
--NR.sub.AR.sub.B group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of (NR.sub.AR.sub.B)sulfonyl include, but
are not limited to, aminosulfonyl, (methylamino)sulfonyl,
(dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
[0145] The term "nitro" as used herein means a --NO.sub.2
group.
[0146] The term "nitrogen protecting group" as used herein means
those groups intended to protect a nitrogen atom against
undesirable reactions during synthetic procedures. Nitrogen
protecting groups comprise carbamates, amides, N-benzyl
derivatives, and imine derivatives.
[0147] Preferred nitrogen protecting groups are acetyl, benzoyl,
benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl,
tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and
triphenylmethyl (trityl). Nitrogen-protecting groups are appended
onto primary or secondary amino groups by reacting the compound
that contains the amine group with base, such as triethylamine, and
a reagent selected from an alkyl halide, an alkyl trifilate, a
dialkyl anhydride, for example as represented by
(alkyl-O).sub.2C.dbd.O, a diaryl anhydride, for example as
represented by (aryl-O).sub.2C.dbd.O, an acyl halide, an
alkylchloroformate, or an alkylsulfonylhalide, an
arylsulfonylhalide, or halo-CON(alkyl).sub.2, for example acetyl
chloride, benzoylchloride, benzylbromide,
benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,
pivaloylchloride, (tert-butyl-O--C.dbd.O).sub.2O, trifluoroacetic
anhydride, and triphenylmethylchloride.
[0148] The term "oxo" as used herein means (.dbd.O).
[0149] The term "sulfonyl" as used herein means a --S(O).sub.2--
group.
[0150] The term "thioalkoxy" as used herein means an alkyl group,
as defined herein, appended to the parent molecular moiety through
a sulfur atom. Representative examples of thioalkoxy include, but
are no limited to, methylthio, ethylthio, and propylthio.
[0151] The compounds of the invention can be used in the form of
pharmaceutically acceptable salts derived from inorganic or organic
acids. The term "pharmaceutically acceptable salts", as used
herein, refer to acid addition salts, carboxylate salts, amino acid
addition salts, and zwitterion salts of compounds of formulae (A),
(B), (C), (D), (E), (F), (G), (H), (I), (J), or (K) which are,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of humans and lower animals without undue
toxicity, irritation, allergic response, and the like, are
commensurate with a reasonable benefit/risk ratio, and are
effective for their intended use.
[0152] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well-known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base function with a suitable acid. Representative
acids suitable for formation of addition salts by combination with
the compounds of the invention include, but are not limited to,
ascorbic acid, (D)-tartaric acid, (L)-tartaric acid, maleic acid,
phosphoric acid, citric acid, hydrochloric acid, sulfuric acid and
trifluoroacetic acid. Other acids include acetic, adipic, aspartic,
glutamic, benzoic, benzenesulfonic, 4-methylbenzenesulfonic,
camphorsulfonic, proprionic, hydrobromic, glucuronic,
methanesulfonic, ethanesulfonic, naphthylene sulfonic, lactic,
fumaric, oxalic, and succinic acid.
[0153] The aforementioned histamine H.sub.3 antagonist antagonists
may exist as stereoisomers wherein, asymmetric or chiral centers
are present. These stereoisomers are "R" or "S" depending on the
configuration of substituents around the chiral carbon atom. The
terms "R" and "S" used herein are configurations as defined in
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The
invention contemplates various stereoisomers and mixtures thereof
and these are specifically included within the scope of this
invention. Stereoisomers include enantiomers and diastereomers, and
mixtures of enantiomers or diastereomers. Individual stereoisomers
of compounds of the invention may be prepared synthetically from
commercially available starting materials which contain asymmetric
or chiral centers or by preparation of racemic mixtures followed by
resolution well known to those of ordinary skill in the art. These
methods of resolution are exemplified by (1) attachment of a
mixture of enantiomers to a chiral auxiliary, separation of the
resulting mixture of diastereomers by recrystallization or
chromatography and optional liberation of the optically pure
product from the auxiliary as described in Furniss, Hannaford,
Smith, and Tatchell, "Vogel's Textbook of Practical Organic
Chemistry", 5th edition (1989), Longman Scientific & Technical,
Essex CM20 2JE, England, or (2) direct separation of the mixture of
optical enantiomers on chiral chromatographic columns or (3)
fractional recrystallization methods.
[0154] Histamine H.sub.3 receptor antagonists may exist as cis or
trans isomers, wherein substituents on a ring may attached in such
a manner that they are on the same side of the ring (cis) relative
to each other, or on opposite sides of the ring relative to each
other (trans). Such methods are well known to those of ordinary
skill in the art, and may include separation of isomers by
recrystallization or chromatography. It should be understood that
the compounds of the invention may possess tautomeric forms, as
well as geometric isomers, and that these also constitute an aspect
of the invention.
[0155] Compositions comprising a therapeutically effective amount
of a compound of formulae (A), (B), (C), (D), (E), (F), (G), (H),
(I), (J), or (K) in combination with a pharmaceutically acceptable
carrier also are suitable for the method. The compositions comprise
the histamine H.sub.3 receptor antagonist formulated together with
one or more non-toxic pharmaceutically acceptable carriers. The
pharmaceutical compositions can be formulated for oral
administration in solid or liquid form, for parenteral intravenous,
subcutaneous, intramuscular, intraperitoneal, intra-arterial, or
intradermal injection, for or for vaginal, nasal, topical, or
rectal administration.
[0156] The term "pharmaceutically acceptable carrier", as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol, and phosphate buffer solutions,
as well as other non-toxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
Administering the Histamine H.sub.3 Receptor Antagonist
[0157] Histamine H.sub.3 receptor antagonists are compounds which
block activation of the histamine H.sub.3 receptor. The histamine
H.sub.3 receptor antagonist compounds and compositions of the
invention can be used for treating and preventing osteoarthritis
pain in a mammal. The compound, including salts thereof, or a
composition can be administered for treatment of osteoarthritis
pain. The histamine-3 receptor antagonist can be administered,
either alone or in combination with another active agent, for
example, as part of a therapeutic regimen.
[0158] For example, the invention provides for a method of treating
osteoarthritis to a mammal requiring treatment, comprising
administering to the mammal an effective amount of ibuprofen,
celecoxib, or rofecoxib and an effective amount of a histamine
H.sub.3 receptor antagonist, or a pharmaceutically acceptable salt
thereof
[0159] The pharmaceutical compositions can be formulated for oral
administration in solid or liquid form, for parenteral intravenous,
subcutaneous, intramuscular, intraperitoneal, intra-arterial, or
intradermal injection, for or for vaginal, nasal, topical, or
rectal administration.
[0160] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof. Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0161] These compositions may also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of microorganisms may
be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form may be brought about by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0162] In some cases, in order to prolong the effect of a drug, it
is often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0163] Suspensions, in addition to the active compounds, may
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0164] If desired, and for more effective distribution, the
compounds of the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
[0165] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0166] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0167] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0168] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0169] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
[0170] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples
of materials which can be useful for delaying release of the active
agent can include polymeric substances and waxes.
[0171] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0172] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0173] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0174] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, ear drops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
[0175] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0176] Powders and sprays can contain, in addition to the compounds
of this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
[0177] Compounds of the invention may also be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0178] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y., (1976), p 33 et seq.
[0179] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants, which can be required. Opthalmic
formulations, eye ointments, powders and solutions are contemplated
as being within the scope of this invention. Aqueous liquid
compositions comprising compounds of the invention also are
contemplated.
[0180] The pharmaceutical compositions of this invention can be
administered to humans and other mammals by oral administration or
by injection, including by intravenous, subcutaneous,
intramuscular, intraperitoneal, intra-arterial, and intradermal
injection. The pharmaceutical compositions of this invention can be
administered to humans and other mammals topically (as by powders,
lotions, ointments or drops applied to the skin), bucally, or
inhaled, as an oral or nasal spray. The pharmaceutical compositions
of this invention can be administered to humans and other mammals
intrarectally, intravaginally. The term is "parenterally," as used
herein, refers to modes of administration, which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular.
[0181] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0182] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
invention can be employed in pure form or, where such forms exist,
in pharmaceutically acceptable salt form. Alternatively, the
compound can be administered as a pharmaceutical composition
containing the compound of interest in combination with one or more
pharmaceutically acceptable carriers. The phrase "therapeutically
effective amount" of the compound of the invention means a
sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the
compounds and compositions of the invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well known in the
medical arts. For example, it is well within the skill of the art
to start doses of the compound at levels lower than required to
achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved.
[0183] For treatment or prevention of disease, the total daily dose
of the compounds of formula (A) administered to a human or lower
animal may range from about 0.0003 to about 30 mg/kg of body
weight. For purposes of oral administration, more preferable doses
can be in the range of from about 0.0003 to about 1 mg/kg body
weight. If desired, the effective daily dose can be divided into
multiple doses for purposes of administration; consequently, single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose.
[0184] For treatment or prevention of disease, the total daily dose
of the compounds of formula (B) administered to a human or lower
animal may range from about 0.001 to about 30 mg/kg of body weight.
For purposes of oral administration, more preferable doses can be
in the range of from about 0.001 to about 1 mg/kg body weight. If
desired, the effective daily dose can be divided into multiple
doses for purposes of administration; consequently, single dose
compositions may contain such amounts or submultiples thereof to
make up the daily dose.
[0185] For treatment or prevention of disease, the total daily dose
of the compounds of formula (C) administered to a human or lower
animal may range from about 0.003 to about 30 mg/kg of body weight.
For purposes of oral administration, more preferable doses can be
in the range of from about 0.1 to about 15 mg/kg body weight. If
desired, the effective daily dose can be divided into multiple
doses for purposes of administration; consequently, single dose
compositions may contain such amounts or submultiples thereof to
make up the daily dose.
[0186] Compositions having compounds of formula (D) may contain
from 0.1% to 99% by weight, preferably from 10 to 60%, by weight,
of the active material, depending on the method of administration.
The dose of the compound used in treatment will vary. However, as a
general guide suitable unit doses for compounds of formula (D) may
be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit
doses may be administered more than once a day, for example two or
three a day. Such therapy may extend for a number of weeks or
months.
[0187] Compositions having compound of structure (E) may be
prepared according to methods described in WO2008/104590, published
Sep. 4, 2008, the contents of which are herein incorporated by
reference.
[0188] Compositions having compounds of formula (F) may contain
from 0.1% to 99% by weight, preferably from 10 to 60%, by weight,
of the active material, depending on the method of administration.
The dose of the compound used in treatment will vary. However, as a
general guide suitable unit doses for compounds of formula (F) may
be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit
doses may be administered more than once a day, for example two or
three a day. Such therapy may extend for a number of weeks or
months.
[0189] Compositions having compound of structure (G) may be
prepared according to methods described in WO2005/018045, published
Aug. 18, 2005, the contents of which are herein incorporated by
reference.
[0190] Suitable methods for administering a compound of structure
(H) may be prepared according to methods described in
WO2007/052124, published May 10, 2007, the contents of which are
herein incorporated by reference.
[0191] Suitable methods for administering a compound of structure
(I) may be prepared according to methods described in US Patent
Publication No. 2008/0176925, published Jul. 24, 2008, the contents
of which are herein incorporated by reference.
[0192] The daily dosage of products having a compound of formula
(J) may be varied over a wide range from 1 to 1,000 mg per adult
human per day. For oral administration, the compositions having a
compound of formula (J) are preferably provided in the form of
tablets containing 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250, and
500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated. An effective
amount of the drug is oridinarily supplied at a dosage level of
from about 0.01 mg/kg to about 10 mg/kg of body weight per day.
Preferably, the range is from about 0.02 mg/kg to about 10 mg/kg of
body weight per day, and especially from about 0.05 mg/kg to about
10 mg/kg of body weight per day. The compounds may be administered
on a regimen of 1 to 4 times per day.
[0193] Suitable methods for administering a compound of structure
(K) may be prepared according to methods described in US Patent
Publication No. 2007/0066644, published Mar. 22, 2007, the contents
of which are herein incorporated by reference.
[0194] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mod of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet, and time of administration can result in the need to adjust
dosages.
Methods for Preparing Assayed Compounds
[0195] Suitable histamine H.sub.3 receptor antagonists for the
invention can be prepared in the aforementioned patent literature
references. The following example compounds illustrate the
preparation of some of the histamine H.sub.3 antagonists for use in
osteoarthritis pain therapy.
EXAMPLES
Example 1
Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H-
)-one
[0196] Preparation of the compound is described in US Patent
Publication No. 20070066588(A1). The title compound was prepared
according to the procedures described therein. Compound was an
off-white solid, mp 127-128.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.3). .delta. ppm 8.14 (t, J=2.61 Hz, 1H) 8.02 (d, J=8.59
Hz, 1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.66-7.70 (m, 1H) 7.23-7.30
(m, 1H) 7.08 (dd, J=9.36, 1.69 Hz, 1H) 3.52-3.65 (m, 1H) 2.75-2.86
(m, 1H) 2.62-2.73 (m, 2H) 2.25-2.41 (m, 6H) 1.55-1.66 (m, 4H)
1.41-1.52 (m, 2H). MS: (M+H).sup.+=367.
Example 2
Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(-
2H)-one
[0197] Preparation of this compound is described in US Patent
Publication No. 20070066588(A1). The title compound was prepared
according to the procedures described therein. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. ppm 8.15 (d, J=2.14 Hz, 1H) 8.05 (d,
J=8.85 Hz, 1H) 7.93 (dd, J=3.81, 1.68 Hz, 1H) 7.70 (dd, J=8.85,
2.14 Hz, 1H) 7.24-7.31 (m, 1H) 7.09 (dd, J=9.46, 1.83 Hz, 1H)
3.80-3.92 (m, 1H) 3.10-3.19 (m, 1H) 2.53-2.70 (m, 4H) 2.21-2.47 (m,
4H) 1.58-1.72 (m, 4H) 1.42-1.55 (m, 2H). MS: (M+H).sup.+=367.
Example 3
(S)-3-Hydroxy-1-[2-(3-piperidin-1-yl-cyclobutyl)-benzothiazol-6-yl]-pyrrol-
idin-2-one
[0198] To a microwave vial equipped with magnetic stir bar, 50 mg
(0.14 mmol) of
6-bromo-2-[trans-3-(1-piperidinyl)cyclobutyl]benzothiazole
(prepared as described in Cowart, et al. Benzothiazole
cyclobutylamine derivatives, US Patent Publication No.
2007/0066588(A1)) was added, followed by
(S)-3-hydroxypyrrolidin-2-one (50 mg, 0.50 mmol),
Pd.sub.2(dba).sub.3 (4.0 mg, 0.0044 mmol), xantphos (6.9 mg, 0.012
mmol) and Cs.sub.2CO.sub.3 (68 mg, 0.21 mmol). The reaction vial
was sealed with an aluminum cap, and purged with N.sub.2, then
dioxane (2 mL) was introduced via a syringe. The reaction mixture
was then heated in a microwave oven at 150.degree. C. for 60
minutes. The reaction mixture was cooled to room temperature,
filtered, and the solvent was removed under vacuum, after which the
residue was purified via chromatography on silica gel, eluting with
a gradient of 0-10% methanol in dichloromethane, to give the
desired product (21 mg, 40%). .sup.1H NMR (300 MHz,) .delta. 8.34
(d, J=2.2, 1H), 7.97 (d, J=8.9, 1H), 7.61 (dd, J=2.2, 8.9, 1H),
4.51 (dd, J=8.2, 9.7, 1H), 3.86 (m, 3H), 3.13 (m, 1H), 2.66 (m,
1H), 2.58 (m, 4H), 2.32 (m, 3H), 2.15 (ddd, J=9.5, 12.6, 19.1, 1H),
1.61 (m, 6H), 1.48 (m, 2H). MS (ESI) m/z=372.0 (M+H).sup.+
Example 4
(4-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-5-yl)benzonitrile-
)
[0199] Preparation of this compound is described in U.S. Pat. No.
6,969,730(B2). The title compound was prepared according to the
procedures described therein. .sup.1H NMR (300 MHz, CD.sub.3OD).
.delta. 7.88 (m, 1H), 7.71 (m, 4H), 7.50 (m, 2H), 6.82 (s, 1H),
3.72-3.9 (m, 2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, 1H),
2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, J=6 Hz, 3H); MS (DCI) m/z
331 (M+H).sup.+. The free base was converted to a pharmaceutically
acceptable salt, the phosphate salt as follows: 20 grams of free
base
4-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-5-yl)benzonitrile
was dissolved in 35 mL of 95:5 methanol/water at reflux, and 4.79 g
of phosphoric acid was added dropwise. On cooling a white powder
was deposited, which was collected by filtration and dried to give
15.1 grams of the monophosphate salt,
4-(2-(2-[2(R)-methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-5-yl)benzonitrile
phosphate, m.p. 203-204. Combustion analysis, calculated for
C.sub.22H.sub.22N.sub.2O:H.sub.3PO.sub.4 was C 61.68%, H 5.88%, N
6.54%; Found: C 61.30%, H 5.66%, N 6.39%.
Example 5
6-(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methyl-nic-
otinamide)
[0200] Preparation of this compound is described in US Patent
Publication No. 20070299056(A1). The title compound was prepared
according to the procedures described therein. .sup.1H NMR (300
MHz,) .delta. 8.56 (d, J=2.1, 1H), 8.47 (q, J=4.1, 1H), 8.19 (dd,
J=2.5, 8.6, 1H), 7.15 (d, J=8.1, 1H), 7.03 (d, J=8.5, 1H), 6.91 (d,
J=2.5, 1H), 6.86 (dd, J=2.5, 8.0, 1H), 2.83 (m, 4H), 2.78 (m, 4H),
2.37 (m, 4H), 1.99 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H). MS (ESI)
m/z=352.1 (M+H).sup.+.
Example 6
(5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-N-methylpyr-
azine-2-carboxamide)
[0201] Preparation of this compound is described in US Patent
Publication No. 20070299056(A1). The title compound was prepared
according to the procedures described therein. .sup.1H NMR (300
MHz, CDCL3) .delta. 8.90 (d, J=1.3, 1H), 8.26 (d, J=1.3, 1H), 7.61
(br s, 1H), 7.15 (d, J=8.8, 1H), 6.90 (m, 2H), 3.03 (d, J=5.1, 3H),
2.93 (m, 4H), 2.79 (dd, J=8.1, 16.2, 1H), 2.47 (m, 4H), 2.14-2.01
(m, 2H), 1.99-1.82 (m, 2H), 1.77-1.60 (m, 2H). MS (ESI) m/z=353.0
(M+H).sup.+. CHN: Found C: 68.09; H 6.73; N 15.74; Theory C 68.16;
H 6.86; N 15.90.
Example 7
(4-isopropyl-1,4-diazepan-1-yl)(1-(6-(trifluoromethyl)pyridin-3-yl)piperid-
in-4-yl)methanone
[0202] Preparation of this compound is described in
WO2004/101546(A1). The title compound was prepared according to the
procedures described therein. .sup.1H NMR (300 MHz, CHLOROFORM-D)
.delta. ppm 1.00 (dd, J=6.54, 4.56 Hz, 6H) 1.73-1.91 (m, 4H) 2.00
(dd, J=13.29, 1.78 Hz, 2H) 2.54-2.75 (m, 5H) 2.87-3.01 (m, 3H)
3.51-3.66 (m, 4H) 3.87 (d, J=12.69 Hz, 2H) 7.19 (dd, J=8.92, 2.97
Hz, 1H) 7.50 (d, J=9.12 Hz, 1H) 8.34 (d, J=2.78 Hz, 1H). MS
(DCI-NH.sub.3) m/z 399 (M+H).sup.+.
Example 8
2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]p-
yridazin-3(2H)-one
[0203] Preparation of this compound is described in
US2008/0242653(A1). The title compound was prepared according to
the procedures described therein, for example as described
below.
Example 8A
(E)-3-(4-bromophenyl)prop-2-en-1-ol
[0204] To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g,
96 mmol) in DCM (300 ml) under nitrogen and cooled to -78.degree.
C. was added dropwise DIBAL-H (240 ml, 1M in DCM, 240 mmol) in
about 20 minutes. The mixture was stirred at -78.degree. C. for 2
hours. Then, the dry ice bath was removed. The reaction was diluted
with DCM (500 mL), quenched with HCl (1N), and partitioned. The
combined organic phases were washed with H.sub.2O, dried and
concentrated under reduced pressure to provide the title compound.
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 1.43 (t, J=6 Hz, 1H),
4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz, 1H), 6.57 (d,
J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS
(DCI-NH.sub.3) m/z 214 (M+H).sup.+.
Example 8B
2-butyl-1,3,6,2-dioxazaborocane
[0205] To a solution of 2,2'-azanediyldiethanol (26.12 g, 246 mmol)
in DCM (250 ml) and ether (500 mL) was added n-butylboronic acid
(25.4 g, 242 mmol) and molecular sieves (3A, 4-6 mesh, 65 g). It
was stirred at ambient temperature for 2 hours. The mixture was
filtered, and the filtrate was concentrated under reduced pressure.
The resulting white solid was recrystallized with DCM/ether to
provide white crystals as the title product. NMR (300 MHz,
CDCl.sub.3): .delta. 0.47 (t, J=9 Hz, 2H), 0.88 (t, J=6 Hz, 3H),
1.20-1.37 (m, 4H), 2.82 (br, 2H), 3.24 (br, 2H), 3.95 (br, 4H),
4.27 (br, 1H). MS (DCI-NH.sub.3) m/z 172 (M+H).sup.+.
Example 8C
(4R,5R)-2-butyl-N4,N4,N5,N5-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxam-
ide
[0206] A solution of the product from Example 8B (31.3 g, 183 mmol)
and (2R,3R)-2,3-dihydroxy-N1,N1,N4,N4-tetramethylsuccinamide (31 g,
149 mmol) in DCM (600 mL) was treated with brine (120 mL) and
stirred at ambient temperature for 30 minutes. The organic layer
was separated, and the aqueous layer was extracted with additional
DCM. The organic layers were combined and washed with brine(700
mL), dried with MgSO.sub.4, and concentrated under reduced pressure
to provide the title product. NMR (300 MHz, CDCl.sub.3): .delta.
0.83-0.90 (m, 6H), 1.26-1.42 (m, 5H), 2.98 (s, 6H), 3.20 (s, 6H).
MS (DCI-NH.sub.3) m/z 205 (M+H).sup.+.
Example 8D
(1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol
[0207] A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under
nitrogen atmosphere was cooled to -10.degree. C., and diethylzinc
(235 mL, 1M in hexane, 235 mmol) was added over 5-10 minutes
followed by diiodomethane (37.9 mL, 469 mmol). The product from
Example 8C (33.0 g, 122 mmol) in 100 mL DCM was added in 5-10
minutes. The temperature was maintained from -5.degree. to
-10.degree. C. throughout the additions. The product from Example
8A, (E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150
mL) was added dropwise, and the reaction mixture was stirred at
ambient temperature for 16 hours. It was quenched with saturated
aqueous NH.sub.4Cl (300 mL), HCl (1N, 480 mL) and diluted with
ether (900 mL). The organic layer was separated. The aqueous layer
was extracted with additional ether. The organic layers were
combined and treated with NaOH (2N, 880 mL). To the solution,
H.sub.2O.sub.2 (30%, 136 mL) was added dropwise while the reaction
was cooled with an ice bath. The solution was stirred for 5-10
minutes. The organic layer was separated, washed with HCl (1N),
saturated aqueous Na.sub.2S.sub.2O.sub.3, saturated aqueous
NaHCO.sub.3, and brine, dried and concentrated. The residue was
chromatographed on silica gel eluting with 5-15% EtOAc/Hexane to
provide the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H),
3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H).
MS (DCI-NH.sub.3) m/z 228 (M+H).sup.+. (ee 94%).
Example 8E
(1S,2S)-2-(4-Bromophenyl)cyclopropanecarbaldehyde
[0208] To a solution of oxalyl chloride (17.50 mL, 2 M in DCM, 35.0
mmol) in DCM (150 mL) under nitrogen atmosphere and cooled to
-78.degree. C. was added dro wise DMSO (4.97 mL, 70.0 mmol),
followed with the dropwise addition of a solution of the product
from Example 8D, ((1S,2S)-2-(4-bromophenyl)cyclopropyl)methanol
(5.3 g, 23.34 mmol) in DCM (100 mL). The mixture was stirred 30
minutes at -78.degree. C. Then the mixture was treated with
triethylamine (13.01 mL, 93 mmol), and then the reaction
temperature was raised to ambient temperature. The mixture was
partitioned between DCM (400 mL) and H.sub.20 (400 mL). The organic
layer was separated, washed with water, dried and concentrated
under reduced pressure to provide the title product. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 1.48 (m, 1H), 1.65 (dt, J=9 Hz, J=6
Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98 (d, J=9 Hz, 2H), 7.45 (d,
J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS (DCI-NH.sub.3) m/z 226
(M+H).sup.+.
Example 8F
1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine
[0209] A solution of the product from Example 8E,
(1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde (5.7 g, 25.3
mmol) in DCM (20 ml) and MeOH (300 mL) was treated with
(S)-2-methylpyrrolidine tartrate (8.94 g, 38.0 mmol) at ambient
temperature, and the mixture was stirred for 5-10 minutes. Then,
the mixture was cooled to 0.degree. C., and a solution of
NaCNBH.sub.3 (2.51 g, 38.0 mmol) in MeOH (50 mL) was added
dropwise. After addition, the reaction mixture was raised to room
temperature and stirred overnight. The reaction mixture was treated
with NaOH (1N) till basic, extracted with DCM thrice (500
mL.times.3), dried and concentrated under reduced pressure. The
crude product was loaded onto a silica gel column and eluted with
1% to 3% methanol (containing 10% concentrated NH.sub.4OH) in
dichloromethane to provide the title product. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 0.87-0.92(m, 1H), 0.97-1.02 (m, 1H), 1.16 (d,
J=6 Hz, 2H), 1.22 (m, 1H), 1.39-1.49(m, 1H), 1.73-1.81(m, 3H), 2.0
(m, 2H), 2.36 (q, J=6 Hz, 1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6
Hz, 1H), 3.25 (m, 1H), 7.00 (d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H).
MS (DCI-NH.sub.3) m/z 294 (M+H).sup.+.
Example 8G
2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]p-
yridazin-3(2H)-one
[0210] A solution of the product from Example 8F,
1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine
(100 mg, 0.340 mmol), pyridazin-3(2H)-one (52.3 mg, 0.544 mmol),
N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and
copper(I) iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a
nitrogen atmosphere in a sealed vial was heated in an oil bath to
135.degree. C. for 16 hours. The reaction mixture was cooled and
diluted with DCM (10 mL), filtered through diatomaceous earth and
washed with DCM. The filtrate was washed sequentially with
H.sub.2O, 28-30% NH.sub.4OH (10 mL.times.2), and H.sub.2O, dried
with MgSO.sub.4 and concentrated under reduced pressure. The
residue was chromatographed on silica gel eluting with concentrated
concentrated NH.sub.4OH/MeOH/DCM (0.4/4/96) to provide the title
compound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 0.90-0.97 (m,
1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m, 1H),
1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05 (m, 3H), 2.26-2.42
(m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07
(d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d, J=6 Hz,
2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz,
1H). MS (DCI-NH.sub.3) m/z 310 (M+H).sup.+.
Example 8H
2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]p-
yridazin-3(2H)-one (2R,3R)-2,3-dihydroxysuccinate
[0211] A solution of the product from Example 8G (3.25 g, 10.5
mmol) in methanol (20 mL) was treated with L-tartaric acid (1.577
g, 10.5 mmol) and stirred at ambient temperature for 1 hour. The
mixture was concentrated under reduced pressure, and the resulting
solid was recrystallized from isopropyl alcohol/acetone to provide
the titled compound as the L-tartrate. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.12-1.19 (m, 1H), 1.23-1.30 (m, 1H), 1.43 (d,
J=6 Hz, 3H), 1.47-1.56 (m, 1H), 1.72-1.81 (m, 1H), 2.02-2.19 (m,
3H), 2.28-2.39 (m, 1H), 3.04-3.11 (m, 1H), 3.43-3.55 (m, 2H),
3.64-3.75 (m, 1H), 4.38 (s, 2H), 7.08 (dd, J=6 Hz, J=2 Hz, 1H),
7.28 (d, J=6 Hz, 2H), 7.44-7.50 (m, 3H), 8.03 (m, 1H). MS
(DCI-NH.sub.3) m/z 310 (M+H).sup.+. Anal. Calcd. for
C.sub.23H.sub.29N.sub.3O.sub.7: C, 60.12; 6.36; N, 9.14. Found:
60.07; 5.76; N, 8.82.
Determination of Efficacy in Blockade of Osteoarthritis Pain
[0212] Histamine H.sub.3 antagonists of the classes descrbed were
found to be effective in osteoarthritis pain. This model, the
MIA-OA model is well known to those skilled in the art. A general
review of various models of pain is found in Joshi and Honore,
Expert Opinion in Drug Discovery (2004) 1, pp. 323-334, and in the
book `Drug Discovery and Evaluation, 2.sup.nd edition` (H. Gerhard
Vogel, editor; Springer-Verlag, New York, 2002; pp. 702-706).
Activity in an Osteoarthritis Model
[0213] Pain behavior was assessed by measurement of hind limb grip
force (GF) in adult osteoarthritic rats. Male Sprague Dawley rats,
325-350 g, were injected in the unilateral knee join with a single
intra-articular injection of sodium monoiodoacetate (MIA). All rats
were tested at 20 days following MIA injection. A behavioral
measure of activity-induced pain was carried out. Measurements of
the peak hind limb grip force were conducted by recording the
maximum compressive force (CF.sub.max), in grams of force, exerted
on a hind limb strain gauge setup, in a commercially available grip
force measurement system (Columbus Instruments, Columbus,
Ohio).
[0214] During testing, each rat was gently restrained by grasping
it around its rib cage and then allowed to grasp the wire mesh
frame attached to the strain gauge. The experimenter then moved the
animal in a rostral-to-caudal direction until the grip was broken.
Each rat was sequentially tested twice at approximately 2-3 min
interval to obtain a raw mean grip force (CF.sub.max). This raw
mean grip force data was in turn converted to a maximum hindlimb
cumulative compressive force (CF.sub.max), as the grams of force/kg
of body weight, for each animal.
[0215] For evaluating the compound effects, the hind limb grip
force was conducted 20 days following the intra-articular injection
of MIA. A group of age-matched nave (not injected with MIA) animals
was added as a comparator to the drug-dosed groups. The vehicle
control response for each group of MIA-treated animals was defined
as the 0% response (0% effect), whereas the nave control group was
defined as the normal response and as 100% effect. The % effects
for each dose group was expressed as % return of reponse to
normalcy, compared to the naive group. That is, the %
effect=(Treatment CF.sub.max-Vehicle CF.sub.max)/Vehicle
CF.sub.max].times.100). Higher % effect numbers indicate increased
relief from the pain in the model, with 100% indicating a return to
the level of response seen in normal (non-osteoarthritic) animals.
All experiments evaluating drug effects in this model were
conducted in a randomized blinded fashion.
[0216] Animals, Compounds, and Dosing. Male Sprague Dawley rats
(250-300 g body weight) obtained from Charles River Laboratories
(Wilmington, Mass.) were used for all experiments, unless indicated
otherwise. The animals were housed in Association for Assessment
and Accreditation of Laboratory Animal Care (AAALAC) approved
facilities at Abbott Laboratories in a temperature-regulated
environment under a controlled 12-h light-dark cycle, with lights
on at 6:00 a.m. Food and water were available ad libitum at all
times except during testing. All testing was done following
procedures outlined in protocols approved by Abbott Laboratories'
Institutional Animal Care and Use Committee.
[0217] The following table illustrating the efficacy in OA pain is
provided, along with potency values:
TABLE-US-00001 Compound Name dose injected, (Example number) i.p.
(intraperitoneally) % Effect.sup.1 Example 1 1 mg/kg 51 .+-. 6%**
Example 1 3 mg/kg 79 .+-. 6%** Example 2 3 mg/kg 43 .+-. 13%*
Example 3 1 mg/kg 26 .+-. 2%** Example 3 3 mg/kg 53 .+-. 5%**
Example 4 1 mg/kg 40 .+-. 4%** Example 4 3 mg/kg 56 .+-. 6%**
Example 5 1 mg/kg 54 .+-. 5%** Example 5 3 mg/kg 74 .+-. 4%**
Example 6 1 mg/kg 65 .+-. 9%** Example 6 3 mg/kg 90 .+-. 17%**
Example 7 1 mg/kg 51 .+-. 8%** Example 7 3 mg/kg 66 .+-. 6%**
Example 8 1 mg/kg 47 .+-. 6%** Example 8 3 mg/kg 68 .+-. 4%**
Example 8 10 mg/kg 82 .+-. 5%** .sup.1Data represent mean .+-. SEM.
Statistical significance *p < 0.05, **p < 0.01 as compared to
vehicle-treated animals. Note that celecoxib (30 mg/kg) is active
as a positive control in this test, with a % Effect of 89% .+-.
5%**
[0218] Representative compounds are active in this model, with
preferred compounds of the invention active in the model at doses
of ranging about micromoles/kg of body weight.
[0219] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations, or methods, or any combination of such
changes and modifications of use of the invention, may be made
without departing from the spirit and scope thereof.
* * * * *