U.S. patent application number 10/464582 was filed with the patent office on 2004-01-01 for phenylalkynes.
Invention is credited to Apodaca, Richard, Deng, Xiaohu, Jablonowski, Jill A., Mani, Neelakandha, Pandit, Chennagiri R., Xiao, Wei.
Application Number | 20040002604 10/464582 |
Document ID | / |
Family ID | 27616564 |
Filed Date | 2004-01-01 |
United States Patent
Application |
20040002604 |
Kind Code |
A1 |
Apodaca, Richard ; et
al. |
January 1, 2004 |
Phenylalkynes
Abstract
Substituted phenylalkynes of formula (I), compositions
containing them, and methods of making and using them to treat
histamine-mediated conditions.
Inventors: |
Apodaca, Richard; (San
Diego, CA) ; Deng, Xiaohu; (San Diego, CA) ;
Jablonowski, Jill A.; (San Diego, CA) ; Mani,
Neelakandha; (San Diego, CA) ; Pandit, Chennagiri
R.; (San Diego, CA) ; Xiao, Wei; (San Diego,
CA) |
Correspondence
Address: |
AUDLEY A. CIAMPORCERO JR.
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27616564 |
Appl. No.: |
10/464582 |
Filed: |
June 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10464582 |
Jun 17, 2003 |
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10307870 |
Dec 2, 2002 |
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60339523 |
Dec 10, 2001 |
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Current U.S.
Class: |
544/60 ; 544/111;
544/120; 544/126; 544/359; 544/360 |
Current CPC
Class: |
A61K 31/444 20130101;
A61P 11/00 20180101; C07D 239/42 20130101; C07D 401/04 20130101;
C07D 295/073 20130101; C07D 401/14 20130101; C07D 471/10 20130101;
C07D 491/10 20130101; A61K 31/5377 20130101; A61K 31/4709 20130101;
C07D 211/14 20130101; C07D 401/12 20130101; C07D 203/12 20130101;
C07D 211/44 20130101; C07D 211/60 20130101; A61K 31/4453 20130101;
C07D 211/78 20130101; C07D 273/01 20130101; C07D 295/096 20130101;
C07D 273/00 20130101; A61P 25/00 20180101; C07D 209/14 20130101;
C07D 211/62 20130101; C07D 491/113 20130101; C07D 295/135 20130101;
C07D 211/46 20130101; C07D 213/38 20130101; C07D 417/10 20130101;
C07D 401/10 20130101; A61K 31/5355 20130101; C07D 209/16 20130101;
C07D 211/22 20130101; C07D 277/04 20130101; C07D 295/03 20130101;
C07D 295/02 20130101; C07D 295/205 20130101; C07D 413/10 20130101;
A61K 31/541 20130101; C07D 215/06 20130101; C07D 295/112
20130101 |
Class at
Publication: |
544/60 ; 544/120;
544/111; 544/126; 544/359; 544/360 |
International
Class: |
C07D 413/02; C07D
43/02 |
Claims
What is claimed is:
1. A method of making a compound of formula (I) 99wherein n is an
integer from 0 to 1; R.sup.1 and R.sup.2 are independently selected
from C.sub.1-3 alkyl, allyl, and C.sub.3-8 cycloalkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 4-7 membered heterocyclyl optionally including up to
two additional heteroatoms independently selected from O, S, and N;
one of R.sup.3, R.sup.4, and R.sup.5 is G, one of the remaining two
is hydrogen, and the other is selected from hydrogen, fluoro, and
chloro; G is L.sup.2Q; L.sup.2 is methylene; Q is NR.sup.8R.sup.9
wherein R.sup.8 is independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.1-6
alkylene, and (phenyl) C.sub.1-6 alkylene; and R.sup.9 is
independently selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; or Q is a saturated 3-13 membered N-linked
heterocyclyl, wherein, in addition to the N-linking nitrogen, the
3-13 membered heterocyclyl may optionally contain between 1 and 3
additional heteroatoms independently selected from O, S, and N;
wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,
cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be
independently and optionally substituted with between 1 and 3
substituents independently selected from methoxy, halo, amino,
nitro, hydroxyl, and C.sub.1-3 alkyl; and wherein 1-3 substituents
of Q can be further independently selected (in addition to the
preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C.sub.1-6 alkyl, 5-9-membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9
membered heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3
alkylene, phenyl, C.sub.1-2-hydroxyalkylene, C.sub.2-6 alkoxy,
(C.sub.3-6 cycloalkyl)-O--, phenyl, (phenyl)C.sub.1-3 alkylene, and
(phenyl)C.sub.1-3 alkylene-O-- and where said substituent groups of
Q may optionally have between 1 and 3 substituents independently
selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a
pharmaceutically acceptable salt, ester, or amide thereof,
comprising at least one of the following steps: reacting a compound
of formula (VI) with a compound of formula (V) 100performing a
nucleophilic substitution of X.sub.1 in compound of formula (VIII)
with an organic base R.sup.1R.sup.2NH, wherein X.sup.2 is a
suitable leaving group in a coupling reaction with an alkyne, and
X.sup.1 is a suitable leaving group in a nucleophilic substitution
with an amine.
2. A method according to claim 1, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, methylpiperidinyl, dimethylamino,
pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or
dipropylamino.
3. A method according to claim 2, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino.
4. A method according to claim 3, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl.
5. A method according to claim 1, wherein one of R.sup.4 and
R.sup.5 is G.
6. A method according to claim 5, wherein R.sup.4 is G.
7. A method according to claim 5, wherein R.sup.5 is G.
8. A method according to claim 1, wherein n is 1.
9. A method according to claim 1, wherein Q is a saturated N-linked
nitrogen-containing heterocyclyl.
10. A method according to claim 9, wherein Q is selected from
substituted or unsubstituted piperidinyl, substituted or
unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl.
11. A method according to claim 10, wherein substituted Q is
selected from N-(C.sub.1-6 alkyl) piperazinyl,
N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and
1,4-dioxa-8-aza-spiro[4.5]decyl.
12. A method according to claim 9, wherein Q is a monovalent
radical of an amine selected from aziridine,
1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
piperidine-3-carboxylic acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']bi- pyridinyl,
4-(3-trifluoromethyl-phenyl)-piperazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-yl-1,3-dihydro-benz- oimidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin--
2-yl-amine, phenylamine, pyridin-2-ylamine.
13. A method according to claim 11, wherein Q is selected from
N-morpholinyl and N-piperidinyl, optionally substituted with
between 1 and 3 substituents selected from hydroxyl, carboxamide,
C.sub.1-6 alkyl, 5-9 membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9
membered heterocyclyl)C.sub.1-3 alkylene,
C.sub.1-2-hydroxyalkylene, O(5-9 membered heterocyclyl), 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 halo, nitro, cyano, and C.sub.1-3 alkyl.
14. A method according to claim 11, wherein Q is substituted with a
substituent comprising a C.sub.1-6 heterocyclyl group selected
from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,
(imidazolyl)C.sub.1-6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and
pyrrolyl.
15. A method according to claim 14, wherein Q is a substituted or
unsubstituted N-morpholinyl.
16. A method according to claim 1, wherein n is 1; R.sup.1 and
R.sup.2 are independently selected from C.sub.2 alkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 5-6 membered heterocyclyl optionally including an
additional heteroatom independently selected from O, S, and N; one
of R.sup.3, R.sup.4, and R.sup.5 is G and the two remaining are H;
G is L.sup.2Q; L.sup.2 is methylene; Q is NR.sup.8R.sup.9 wherein
R.sup.8 is independently selected from hydrogen, C.sub.1-2 alkyl,
C.sub.3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.2 alkylene,
and (phenyl) C.sub.2 alkylene; and R.sup.9 is independently
selected from C.sub.1-2 alkyl, C.sub.3 alkenyl, 6-9 membered
carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered
heterocyclyl)C.sub.2 alkylene, and (phenyl) C.sub.2 alkylene; or Q
is a saturated 3-13 membered N-linked heterocyclyl, wherein, in
addition to the N-linking nitrogen, the 3-13 membered heterocyclyl
may optionally contain between 1 and 3 additional heteroatoms
selected from O, S, and N; wherein each of the above alkyl,
alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups
may each be independently and optionally substituted with between 1
and 3 substituents selected from methoxy, halo, amino, nitro,
hydroxyl, and C.sub.1-3 alkyl; and wherein substituents of Q can be
further selected from tert-butyloxycarbonyl, carboxamide,
5-9-membered heterocyclyl, NH(6-membered heterocyclyl),
O(6-membered heterocyclyl), phenyl, C.sub.2-hydroxyalkylene,
hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and
alkyl substituent groups of Q may be optionally substituted with
trifluoromethyl.
17. A method according to claim 1, wherein (a) NR.sup.1R.sup.2
taken together form piperidinyl, pyrrolidinyl, or diethylamino, and
(b) Q is selected from substituted or unsubstituted piperidinyl,
piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and
morpholinyl.
18. A method according to claim 1, wherein said organic base
R.sup.1R.sup.2NH is piperidine and said nucleophilic substitution
is performed at room temperature.
19. A method according to claim 1, wherein said nucleophilic
substitution is performed at room temperature with 10 equivalents
of piperidine in the presence of ethanol.
20. A method according to claim 1, wherein said nucleophilic
substitution is performed at room temperature with 10 equivalents
of piperidine in the presence of ethanol and X.sup.1 is mesylate,
to yield a mixture of a substituted base and an elimination
product.
21. A method according to claim 20, further comprising exposing
said mixture to HCl to yield a saline solution, selectively
precipitating and crystallizing form said saline solution a
phenylalkyne dihydrochloride salt.
22. A method according to claim 21, wherein said phenylalkyne
dihydrochloride salt is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]morphol- ine
dihydrochloride.
23. A method according to claim 1, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
selected from morpholinyl and piperidinyl.
24. A method according to claim 1, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
morpholinyl or substituted morpholinyl.
25. A method according to claim 1, wherein n=1, R.sup.3 is H,
R.sup.5 is H, R.sup.4 is L.sup.2Q, with Q being morpholinyl,
L.sup.2 as defined in claim 1, and NR.sup.1R.sup.2 taken together
form piperidinyl.
26. A method according to claim 1, wherein said organic base
R.sup.1R.sup.2NH is piperidine.
27. A method according to claim 1, wherein said nucleophilic
substitution is performed in the presence of ethanol at room
temperature.
28. A method according to claim 1, wherein said nucleophilic
substitution is performed in the presence of ethanol at room
temperature and said organic base R.sup.1R.sup.2NH is
piperidine.
29. A method according to claim 28, wherein the amount of said
piperidine is 10 equivalents.
30. A method according to claim 1, wherein n=1, R.sup.3 is H,
R.sup.5 is H, R.sup.4 is L.sup.2Q, with Q being morpholinyl,
L.sup.2 as defined in claim 1, said organic base R.sup.1R.sup.2NH
is piperidine, and said nucleophilic substitution is performed in
the presence of ethanol at room temperature.
31. A method according to claim 1, wherein said nucleophilic
substitution yields a mixture of a substitution product and an
elimination product and is performed in an alcoholic medium at a
temperature such that said substitution product is obtained in at
least 80%.
32. A method according to claim 1, wherein said nucleophilic
substitution yields a mixture of a substitution product and an
elimination product and is performed in the presence of ethanol at
room temperature, and said organic base R.sup.1R.sup.2NH is
piperidine, further comprising treating said mixture with an acid
to obtain a saline solution, and selectively precipitating and
crystallizing said saline solution to obtain a salt.
33. A method according to claim 32, wherein said acid is HCl.
34. A method according to claim 32, wherein diethyl ether and
ethanol are used in said crystallization.
35. A method according to claim 34, wherein n=1, R.sup.3 is H,
R.sup.5 is H, R.sup.4 is L.sup.2Q, with Q being morpholinyl,
L.sup.2 as defined in claim 1, and NR.sup.1R.sup.2 taken together
form piperidinyl, said substitution product is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpho- line and said
salt is the dihydrochloride salt of said substitution product.
36. A method according to claim 28, further comprising converting
an alcohol of formula (VII) to said compound of formula (VIII).
37. A method according to claim 36, further comprising the
reductive amination of a compound of formula (VIIa) with an amine
R.sup.8R.sup.9NH, wherein one of R.sup.3', R.sup.4', and R.sup.5'
is C(O)H and the other two are selected from H, chloro and bromo,
to give a compound of formula (VII), wherein one of R.sup.3,
R.sup.4, and R.sup.5 is NR.sup.8R.sup.9 and the other two are
selected from H, chloro and bromo, 101
38. A method according to claim 37, wherein said amine is
morpholine.
39. A method according to claim 37, further comprising the coupling
in the presence of a palladium-containing catalyst and a copper
salt of a compound of formula (II) with a disubstituted benzene,
wherein one of said benzene substitutents is C(O)H and the other of
said benzene substitutents is selected from chloro and bromo, to
yield a compound of formula (VIIa).
40. A method of making a compound of formula (I) 102wherein n is an
integer from 0 to 1; R.sup.1 and R.sup.2 are independently selected
from C.sub.1-3 alkyl, allyl, and C.sub.3-8 cycloalkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 4-7 membered heterocyclyl optionally including up to
two additional heteroatoms independently selected from O, S, and N;
one of R.sup.3 and R.sup.5 is G, one of the remaining and R.sup.4
is H, and the other is selected from hydrogen, fluoro, and chloro;
G is L.sup.2Q; L.sup.2 is methylene; Q is NR.sup.8R.sup.9 wherein
R.sup.8 is independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.1-6
alkylene, and (phenyl) C.sub.1-6 alkylene; and R.sup.9 is
independently selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; or Q is a saturated 3-13 membered N-linked
heterocyclyl, wherein, in addition to the N-linking nitrogen, the
3-13 membered heterocyclyl may optionally contain between 1 and 3
additional heteroatoms independently selected from O, S, and N;
wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,
cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be
independently and optionally substituted with between 1 and 3
substituents independently selected from methoxy, halo, amino,
nitro, hydroxyl, and C.sub.1-3 alkyl; and wherein 1-3 substituents
of Q can be further independently selected (in addition to the
preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C.sub.1-6 alkyl, 5-9-membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9
membered heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3
alkylene, phenyl, C.sub.1-2-hydroxyalkylene, C.sub.2-6 alkoxy,
(C.sub.3-6 cycloalkyl)-O--, phenyl, (phenyl)C.sub.1-3 alkylene, and
(phenyl)C.sub.1-3 alkylene-O-- and where said substituent groups of
Q may optionally have between 1 and 3 substituents independently
selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a
pharmaceutically acceptable salt, ester, or amide thereof,
comprising reacting at least one of the compounds of formulae
(XXIIIw) and (XXIIIow) with a compound of formula (V) 103wherein W
is C(O)H or G, and X.sup.2 is a suitable leaving group in a
coupling reaction with an alkyne.
41. A method according to claim 40, wherein said W is C(O)H,
further comprising performing a reductive amination of said W with
an organic base R.sup.9R.sup.3NH.
42. A method according to claim 40, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, methylpiperidinyl, dimethylamino,
pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or
dipropylamino.
43. A method according to claim 42, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino.
44. A method according to claim 43, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl.
45. A method according to claim 40, wherein R.sup.5 is G.
46. A method according to claim 40, wherein R.sup.3 is G.
47. A method according to claim 40, wherein n is 1.
48. A method according to claim 40, wherein Q is a saturated
N-linked nitrogen-containing heterocyclyl.
49. A method according to claim 40, wherein Q is selected from
substituted or unsubstituted piperidinyl, substituted or
unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl.
50. A method according to claim 49, wherein substituted Q is
selected from N-(C.sub.1-6 alkyl) piperazinyl,
N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and
1,4-dioxa-8-aza-spiro[4.5]decyl.
51. A method according to claim 48, wherein Q is a monovalent
radical of an amine selected from aziridine,
1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
piperidine-3-carboxylic acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']bi- pyridinyl,
4-(3-trifluoromethyl-phenyl)-piperazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-y-1,3-dihydro-benzo- imidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-
-yl-amine, phenylamine, pyridin-2-ylamine.
52. A method according to claim 40, wherein Q is selected from
N-morpholinyl and N-piperidinyl, optionally substituted with
between 1 and 3 substituents selected from hydroxyl, carboxamide,
C.sub.1-6 alkyl, 5-9 membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9
membered heterocyclyl)C.sub.1 3 alkylene,
C.sub.1-2-hydroxyalkylene, O(5-9 membered heterocyclyl), 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 halo, nitro, cyano, and C.sub.1-3 alkyl.
53. A method according to claim 40, wherein Q is substituted with a
substituent comprising a C.sub.1-6 heterocyclyl group selected
from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,
(imidazolyl)C,-.sub.6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and
pyrrolyl.
54. A method according to claim 40, wherein Q is a substituted or
unsubstituted N-morpholinyl.
55. A method according to claim 40, wherein n is 1; R.sup.1 and
R.sup.2 are independently selected from C.sub.2 alkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 5-6 membered heterocyclyl optionally including an
additional heteroatom independently selected from O, S, and N; one
of R.sup.3 and R.sup.5 is G, and the remaining and R.sup.4 are H; G
is L.sup.2Q; L.sup.2 is methylene; Q is NR.sup.8R.sup.9 wherein
R.sup.8 is independently selected from hydrogen, C.sub.1-2 alkyl,
C.sub.3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.2 alkylene,
and (phenyl) C.sub.2 alkylene; and R.sup.9 is independently
selected from C.sub.1-2 alkyl, C.sub.3 alkenyl, 6-9 membered
carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered
heterocyclyl)C.sub.2 alkylene, and (phenyl) C.sub.2 alkylene; or Q
is a saturated 3-13 membered N-linked heterocyclyl, wherein, in
addition to the N-linking nitrogen, the 3-13 membered heterocyclyl
may optionally contain between 1 and 3 additional heteroatoms
selected from O, S, and N; wherein each of the above alkyl,
alkylene, alkenyl, alkenylene, heterocyclyl, and carbocyclyl groups
may each be independently and optionally substituted with between 1
and 3 substituents selected from methoxy, halo, amino, nitro,
hydroxyl, and C.sub.1-3 alkyl; and wherein substituents of Q can be
further selected from tert-butyloxycarbonyl, carboxamide,
5-9-membered heterocyclyl, NH(6-membered heterocyclyl),
O(6-membered heterocyclyl), phenyl, C.sub.2-hydroxyalkylene,
hydroxy, benzyl and, where each of above heterocyclyl, phenyl, and
alkyl substituent groups of Q may be optionally substituted with
trifluoromethyl.
56. A method according to claim 40, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino, and Q is
selected from substituted or unsubstituted piperidinyl,
piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and
morpholinyl.
57. A method according to claim 40, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
selected from morpholinyl and piperidinyl.
58. A method according to claim 40, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
morpholinyl or substituted morpholinyl.
59. A method according to claim 40, wherein n is 1, R.sup.4 is H,
one of R.sup.3 and R.sup.5 is H, the other one of R.sup.3 and
R.sup.5 is L.sup.2Q, with Q being morpholinyl, and L.sup.2 as
defined in claim 40, and NR.sup.1R.sup.2 taken together form
piperidinyl.
60. A method of making a compound of formula (I) 104wherein n is an
integer from 0 to 1; R.sup.1 and R.sup.2 are independently selected
from C.sub.1-3 alkyl, allyl, and C.sub.3-8 cycloalkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 4-7 membered heterocyclyl optionally including up to
two additional heteroatoms independently selected from O, S, and N;
one of R.sup.3, R.sup.4, and R.sup.5 is G, one of the remaining two
is hydrogen, and the other is selected from hydrogen, fluoro, and
chloro; G is L.sup.2Q; L.sup.2 is methylene; Q is NR.sup.8R.sup.9
wherein R.sup.8 is independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.1-6
alkylene, and (phenyl) C.sub.1-6 alkylene; and R.sup.9 is
independently selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; or Q is a saturated 3-13 membered N-linked
heterocyclyl, wherein, in addition to the N-linking nitrogen, the
3-13 membered heterocyclyl may optionally contain between 1 and 3
additional heteroatoms independently selected from O, S, and N;
wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,
cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be
independently and optionally substituted with between 1 and 3
substituents independently selected from methoxy, halo, amino,
nitro, hydroxyl, and C.sub.1-3 alkyl; and wherein 1-3 substituents
of Q can be further independently selected (in addition to the
preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C.sub.1-6 alkyl, 5-9-membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9
membered heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3
alkylene, phenyl, C.sub.1-2-hydroxyalkylene, C.sub.2-6 alkoxy,
(C.sub.3-6 cycloalkyl)-O--, phenyl, (phenyl)C.sub.1-3 alkylene, and
(phenyl)C.sub.1-3 alkylene-O-- and where said substituent groups of
Q may optionally have between 1 and 3 substituents independently
selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a
pharmaceutically acceptable salt, ester, or amide thereof,
comprising reacting a compound of formula (VII) 105with an organic
base R.sup.1R.sup.2NH in the presence of a trialkylphosphonium
halide and a base.
61. A method according to claim 60, wherein said
trialkylphosphonium halide is (cyanomethyl)trimethylphosphonium
iodide, and said base is DIPEA.
62. A method according to claim 60, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, methylpiperidinyl, dimethylamino,
pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or
dipropylamino.
63. A method according to claim 60, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino.
64. A method according to claim 60, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl.
65. A method according to claim 60, wherein one of R.sup.4 and
R.sup.5 is G.
66. A method according to claim 65, wherein R.sup.4 is G.
67. A method according to claim 66, wherein R.sup.5 is G.
68. A method according to claim 60, wherein n is 1.
69. A method according to claim 60, wherein Q is a saturated
N-linked nitrogen-containing heterocyclyl.
70. A method according to claim 60, wherein Q is selected from
substituted or unsubstituted piperidinyl, substituted or
unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl.
71. A method according to claim 60, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino, and Q is
selected from substituted or unsubstituted piperidinyl,
piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and
morpholinyl.
72. A method according to claim 60, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
selected from morpholinyl and piperidinyl.
73. A method according to claim 60, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
morpholinyl or substituted morpholinyl.
74. A method according to claim 60, wherein n=1, R.sup.3 is H,
R.sup.5 is H, R.sup.4 is L.sup.2Q, with Q being rmorpholinyl,
L.sup.2 as defined in claim 60, and NR.sup.1R.sup.2 taken together
form piperidinyl.
75. A method of making a compound of formula (I) 106wherein n is an
integer from 0 to 1; R.sup.1 and R.sup.2 are independently selected
from C.sub.1-3 alkyl, allyl, and C.sub.3-8 cycloalkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 4-7 membered heterocyclyl optionally including up to
two additional heteroatoms independently selected from O, S, and N;
R.sup.4 is G, one of the remaining R.sup.3 and R.sup.5 is hydrogen,
and the other is selected from hydrogen, fluoro, and chloro; G is
L.sup.2Q; L.sup.2 is methylene; Q is NR.sup.8R.sup.9 wherein
R.sup.8 is independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.1-6
alkylene, and (phenyl) C.sub.1-6 alkylene; and R.sup.9 is
independently selected from C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; or Q is a saturated 3-13 membered N-linked
heterocyclyl, wherein, in addition to the N-linking nitrogen, the
3-13 membered heterocyclyl may optionally contain between 1 and 3
additional heteroatoms independently selected from O, S, and N;
wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,
cycloalkyl, carbocyclyl, and aryl groups of formula (I) may each be
independently and optionally substituted with between 1 and 3
substituents independently selected from methoxy, halo, amino,
nitro, hydroxyl, and C.sub.1-3 alkyl; and wherein 1-3 substituents
of Q can be further independently selected (in addition to the
preceding paragraph) from tert-butyloxycarbonyl, carboxamide,
C.sub.1-6 alkyl, 5-9-membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9
membered heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3
alkylene, phenyl, C.sub.1-2-hydroxyalkylene, C.sub.2-6 alkoxy,
(C.sub.3-6 cycloalkyl)-O--, phenyl, (phenyl)C.sub.1-3 alkylene, and
(phenyl)C.sub.1-3 alkylene-O-- and where said substituent groups of
Q may optionally have between 1 and 3 substituents independently
selected from trifluoromethyl, halo, nitro, cyano, and hydroxy; a
pharmaceutically acceptable salt, ester, or amide thereof,
comprising: reacting a compound of formula (XXIIImw) with a
compound of formula (V). 107wherein W is C(O)H or G, and X.sup.2 is
a suitable leaving group in a coupling reaction with an alkyne.
76. A method according to claim 75, wherein said W is C(O)H,
further comprising performing a reductive amination of said W with
an organic base R.sup.9R.sup.8NH.
77. A method according to claim 75, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, methylpiperidinyl, dimethylamino,
pyrrolidinyl, diethylamino, methylethylamino, ethylpropylamino, or
dipropylamino.
78. A method according to claim 75, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino.
79. A method according to claim 75, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl.
80. A method according to claim 75, wherein n is 1.
81. A method according to claim 75, wherein Q is a saturated
N-linked nitrogen-containing heterocyclyl.
82. A method according to claim 75, wherein Q is selected from
substituted or unsubstituted piperidinyl, substituted or
unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl.
83. A method according to claim 75, wherein substituted 0 is
selected from N-(C.sub.1-6 alkyl) piperazinyl,
N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and
1,4-dioxa-8-aza-spiro[4.5]decyl.
84. A method according to claim 75, wherein Q is a monovalent
radical of an amine selected from aziridine,
1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
piperidine-3-carboxylic, acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']b- ipyridinyl,
4-(3-trifluoromethyl-phenyl)-piperazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-yl-1,3-dihydro-benz- oimidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin--
2-yl-amine, phenylamine, pyridin-2-ylamine.
85. A method according to claim 75, wherein Q is selected from
N-morpholinyl and N-piperidinyl, optionally substituted with
between 1 and 3 substituents selected from hydroxyl, carboxamide,
C.sub.1-6 alkyl, 5-9 membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9
membered heterocyclyl)C.sub.1 3 alkylene,
C.sub.1-2-hydroxyalkylene, O(5-9 membered heterocyclyl), 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 halo, nitro, cyano, and C.sub.1-3 alkyl.
86. A method according to claim 75, wherein Q is substituted with a
substituent comprising a C.sub.1-6 heterocyclyl group selected
from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,
(imidazolyl)C.sub.1-6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and
pyrrolyl.
87. A method according to claim 75, wherein Q is a substituted or
unsubstituted N-morpholinyl.
88. A method according to claim 75; wherein n is 1; R.sup.1 and
R.sup.2 are independently selected from C.sub.2 alkyl, or taken
together with the nitrogen to which they are attached, they form a
non-aromatic 5-6 membered heterocyclyl optionally including an
additional heteroatom independently selected from O, S, and N;
R.sup.3 and R.sup.5 are H; G is L.sup.2Q; L.sup.2 is methylene; Q
is NR.sup.8R.sup.9 wherein R.sup.8 is independently selected from
hydrogen, C.sub.1-2 alkyl, C.sub.3 alkenyl, 6-9 membered
carbocyclyl, 3-12 membered heterocyclyl, phenyl, (5-9-membered
heterocyclyl)C.sub.2 alkylene, and (phenyl) C.sub.2 alkylene; and
R.sup.9 is independently selected from C.sub.1-2 alkyl, C.sub.3
alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl,
phenyl, (5-9-membered heterocyclyl)C.sub.2 alkylene, and (phenyl)
C.sub.2 alkylene; or Q is a saturated 3-13 membered N-linked
heterocyclyl, wherein, in addition to the N-linking nitrogen, the
3-13 membered heterocyclyl may optionally contain between 1 and 3
additional heteroatoms selected from O, S, and N; wherein each of
the above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl, and
carbocyclyl groups may each be independently and optionally
substituted with between 1 and 3 substituents selected from
methoxy, halo, amino, nitro, hydroxyl, and C.sub.1-3 alkyl; and
wherein substituents of Q can be further selected from
tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl,
NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl,
C.sub.2-hydroxyalkylene, hydroxy, benzyl and, where each of above
heterocyclyl, phenyl, and alkyl substituent groups of Q may be
optionally substituted with trifluoromethyl.
89. A method according to claim 75, wherein NR.sup.1R.sup.2 taken
together form piperidinyl, pyrrolidinyl, or diethylamino, and Q is
selected from substituted or unsubstituted piperidinyl,
piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and
morpholinyl.
90. A method according to claim 75, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
selected from morpholinyl and piperidinyl.
91. A method according to claim 90, wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
morpholinyl or substituted morpholinyl.
92. A method according to claim 75, wherein n is 1, R.sup.5 is H,
R.sup.3 is H, and R.sup.4 is L.sup.2Q, with Q being morpholinyl,
and L.sup.2 as defined in claim 75, and NR.sup.1R.sup.2 taken
together form piperidinyl.
93. A method according to claim 75, wherein n is 1, R.sup.3 is H,
R.sup.5 is H, W is C(O)H, and X.sup.2 is choloro or bromo, and
compound of formula (V) is 1-but-3-ynyl-piperidine, to form a
phenylalkyne.
94. A method according to claim 93, wherein said reacting is
performed in the presence of pyrrolidine and at a temperature of
about 50.degree. C. to form a phenylalkayne.
95. A method according to claim 94, wherein said reacting is
performed in the presence of a palladium-containing catalyst and a
copper salt.
96. A method according to claim 93, wherein X.sup.2 is bromo, and
said reacting is performed under conditions such that the yield of
said phenylalkyne is at least 80%.
97. A method according to claim 93, further comprising a reductive
amination with R.sup.8R.sup.9NH of said phenylalkyne to yield a
base.
98. A method according to claim 97, wherein said R.sup.8R.sup.9NH
is morpholine and said base is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-mo- rpholine.
99. A method according to claim 97, further comprising forming a
saline solution with HCl.
100. A method according to claim 99, further comprising obtaining a
dihydrochloride salt of said base by crystallization.
101. A method according to claim 100, wherein said base is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine.
102. A method according to claim 40, wherein n is 1, R.sup.4 is H,
R.sup.3 is H, R.sup.5 is C(O)H, NR.sup.1R.sup.2 taken together form
a piperidinyl, wherein said reacting is performed at room
temperature.
103. A method according to claim 40, wherein n is 1, R.sup.4 is H,
R.sup.3 is H, R.sup.5 is C(O)H, NR.sup.1R.sup.2 taken together form
a piperidinyl, wherein said reacting is performed at room
temperature in the presence of a plaadadium-containing catalyst and
a copper salt, and said reacting yields a phenylalkyne.
104. A method according to claim 40, wherein n is 1, R.sup.4 is H,
R.sup.3 is H, R.sup.5 is C(O)H, NR.sup.1R.sup.2 taken together form
a piperidinyl, X.sup.2 is bromo, wherein said reacting is performed
at room temperature in the presence of a palladium-containing
catalyst and a copper salt, and said reacting yields a
phenylalkyne.
105. A method according to claim 40, wherein n is 1, R.sup.4 is H,
R.sup.3 is H, R.sup.5 is C(O)H, NR.sup.1R.sup.2taken together form
a piperidinyl, wherein said reacting is performed at room
temperature in the presence of a plaadadium-containing catalyst and
a copper salt, and said reacting yields a phenylalkyne, further
comprising a reductive amination with R.sup.8R.sup.9NH of said
phenylalkyne to yield a base.
106. A method according to claim 105, wherein said R.sup.8R.sup.9NH
is morpholine and said base is
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-mo- rpholine
107. A method according to claim 105, further comprising forming a
saline solution with HCl.
108. A method according to claim 107, further comprising obtaining
a dihydrochloride salt of said base by crystallization.
109. A method according to claim 108, wherein said base is
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine.
Description
[0001] This application is a continuation-in-part application of
U.S. Ser. No. 10/307,870, filed on Dec. 2, 2002, which claims
priority to provisional application 60/339,523, filed on Dec. 10,
2001, all of which are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to phenylalkynes, their
synthesis and their use, for example, for the treatment of
disorders and conditions mediated by the histamine receptor.
BACKGROUND OF THE INVENTION
[0003] Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter
substance. Histamine exerts a physiological effect via multiple
distinct G-protein coupled receptors. It plays a role in immediate
hypersensitivity reactions and is released from mast cells
following antigen IgE antibody interaction. The actions of released
histamine on the vasculature and smooth muscle system account for
the symptoms of the allergic response. These actions occur at the
H.sub.1 receptor (Ash, A. S. F. and Schild, H. O., Br. J. Pharmac.
Chemother. 1966, 27:427-439) and are blocked by the classical
antihistamines (e.g. diphenhydramine). Histamine is also an
important regulator of gastric acid secretion through its action on
parietal cells. These effects of histamine are mediated via the
H.sub.2 receptor (Black, J. W. et al., Nature 1972, 236:385-390)
and are blocked by H.sub.2 receptor antagonists (e.g. cimetidine).
The third histamine receptor --H.sub.3-- was first described as a
presynaptic autoreceptor in the central nervous system (CNS)
(Arrang, J. -M. et al., Nature 1983, 302:832-837) controlling the
synthesis and release of histamine. Recent evidence has emerged
showing that the H.sub.3 receptors are also located presynaptically
as heteroreceptors on serotonergic, noradrenergic, dopaminergic,
cholinergic, and GABAergic (gamma-aminobutyric acid containing)
neurons. These H.sub.3 receptors have also recently been identified
in peripheral tissues such as vascular smooth muscle. Consequently
there are many potential therapeutic applications for histamine
H.sub.3 agonists, antagonists, and inverse agonists. (See: "The
Histamine H.sub.3 Receptor-A Target for New Drugs", Leurs, R., and
Timmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature
2000, 408:860-864.) A fourth histamine receptor --H.sub.4-- was
recently described by Oda, T. et al. (J. Biol. Chem. 2000,
275(47):36781-36786).
[0004] The potential use of histamine H.sub.3 agonists in
sleep/wake and arousal/vigilance disorders is suggested based on
animal studies (Lin, J. -S. et al., Brain Res. 1990, 523:325-330;
Monti, J. M. et al., Eur. J. Pharmacol. 1991, 205:283-287). Their
use in the treatment of migraine has also been suggested (McLeod,
R. L. et al., Soc. Neurosci. Abstr. 1996, 22:2010) based on their
ability to inhibit neurogenic inflammation. Other applications
could be a protective role in myocardial ischemia and hypertension
where blockade of norepinephrine release is beneficial (Imamura, M.
et al., J. Pharmacol. Exp. Ther. 1994, 271(3):1259-1266). It has
been suggested that histamine H.sub.3 agonists may be beneficial in
asthma due to their ability to reduce non-adrenergic
non-cholinergic (NANC) neurotransmission in airways and to reduce
microvascular leakage (Ichinose, M. and Barnes, P. J., Eur. J.
Pharmacol. 1989, 174:49-55).
[0005] Several indications for histamine H.sub.3 antagonists and
inverse agonists have similarly been proposed based on animal
pharmacology experiments with known histamine H.sub.3 antagonists
(e.g. thioperamide). These include dementia, Alzheimer's disease
(Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21:1977), epilepsy
(Yokoyama, H. et al., Eur. J. Pharmacol. 1993, 234:129-133),
narcolepsy, eating disorders (Machidori, H. et al., Brain Res.
1992, 590:180-186), motion sickness, vertigo, attention deficit
hyperactivity disorders (ADHD), learning and memory (Barnes, J. C.
et al., Soc. Neurosci. Abstr. 1993, 19:1813), and schizophrenia
(Schlicker, E. and Marr, I., Naunyn-Schmiedeberg's Arch. Pharmacol.
1996, 353:290-294). (Also see: Stark, H. et al., Drugs Future 1996,
21 (5):507-520; and Leurs, R. et al., Prog. Drug Res. 1995,
45:107-165 and references cited therein.) Histamine H.sub.3
antagonists, alone or in combination with a histamine H.sub.1
antagonist, are reported to be useful for the treatment of upper
airway allergic response (U.S. Pat. Nos. 5,217,986; 5,352,707 and
5,869,479). Recently, a histamine H.sub.3 antagonist (GT-2331) was
identified and is being developed by Gliatech Inc. (Gliatech Inc.
Press Release Nov. 5, 1998; Bioworld Today, Mar. 2, 1999) for the
treatment of CNS disorders.
[0006] As noted, the prior art related to histamine H.sub.3 ligands
has been comprehensively reviewed ("The Histamine H.sub.3
Receptor-A Target for New Drugs", Leurs, R., and Timmerman, H.,
(Eds.), Elsevier, 1998). Within this reference the medicinal
chemistry of histamine H.sub.3 agonists and antagonists was
reviewed (see: Krause, M. et al., and Phillips, J. G. and Ali, S.
M., respectively). The importance of an imidazole moiety containing
only a single substitution in the 4 position was noted together
with the deleterious effects of additional substitution on
activity. Particularly, methylation of the imidazole ring at any of
the remaining unsubstituted positions was reported to strongly
decrease activity. Additional publications support the hypothesis
that an imidazole function is essential for high affinity histamine
H.sub.3 receptor ligands (see: Ali, S. M. et al., J. Med. Chem.
1999, 42:903-909, and Stark, H. et al., and references cited
therein). However many imidazole-containing compounds are
substrates for histamine methyl transferase, the major histamine
metabolizing enzyme in humans, which leads to shortened half-lives
and lower bioavailability (see: Rouleau, A. et al., J. Pharmacol.
Exp. Ther. 1997, 281(3):1085-1094). In addition,
imidazole-containing drugs, via their interaction with the
cytochrome P450 monooxygenase system, can result in unfavorable
biotransformations due to enzyme induction or enzyme inhibition
(see: Kapetanovic, I. M. and Kupferberg, H. J., Drug Metab. Dispos.
1984, 12(5):560-564; Sheets, J. J. and Mason, J. I., Drug Metab.
Dispos. 1984, 12(5):603-606; Back, D. J. and Tjia, J. F., Br. J.
Pharmacol. 1985, 85:121-126; Lavrijsen, K. et al., Biochem.
Pharmacol. 1986, 35(11):1867-1878; Albengres, E. et al., Drug
Safety 1998, 18(2):83-97). The poor blood-brain barrier penetration
of earlier histamine H.sub.3 receptor ligands may also be
associated with the imidazole fragment (Ganellin, C. R. et al.,
Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.) 1998,
331:395-404).
[0007] More recently, several publications have described histamine
H.sub.3 ligands that do not contain an imidazole moiety, for
example: Ganellin, C. R. et al.; Walczynski, K. et al., Arch.
Pharm. Pharm. Med. Chem. (Weinheim, Ger.) 1999, 332:389-398;
Walczynski, K. et al., Farmaco 1999, 54:684-694; Linney, I. D. et
al., J. Med. Chem. 2000, 43:2362-2370, Tozer, M. J. and Kalindjian,
S. B., Exp. Opin. Ther. Patents 2000, 10:1045-1055; U.S. Pat. No.
5,352,707; PCT Application WO 99/42458; PCT Application WO
02/076925; and EP Application 0978512, Feb. 9, 2000.
[0008] The compounds of the present invention do not contain the
imidazole moiety, and its inherent liabilities, and yet maintain
potency at the human H.sub.3 receptor as determined by receptor
binding to the human histamine H.sub.3 receptor (see: Lovenberg, T.
W. et al., Mol. Pharmacol. 1999, 55:1101-1107). Screening using the
human receptor is particularly important for the identification of
new therapies for the treatment of human disease. Conventional
binding assays, for example, are determined using rat synaptosomes
(Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992,
263(1):304-310), rat cortical membranes (West, R. E. et al., Mol.
Pharmacol. 1990, 38:610-613), and guinea pig brain (Korte, A. et
al., Biochem. Biophys. Res. Commun. 1990, 168(3):979-986). Only
limited studies have been performed previously using human tissue
but these allude to significant differences in the pharmacology of
rodent and primate receptors (West, R. E. et al., Eur. J.
Pharmacol. 1999, 377:233-239).
[0009] We now describe a series of phenylalkynes with the ability
to modulate the activity of the histamine receptor, specifically
the H.sub.3 receptor, without the inherent problems associated with
the presence of an imidazolyl moiety.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to pharmaceutically active
phenylalkynes, methods of making them, and methods of using them.
The invention features a compound of formula (I) 1
[0011] wherein n is an integer from 0 to 1;
[0012] R.sup.1 and R.sup.2 are independently selected from
C.sub.1-3 alkyl, allyl, and C.sub.3-8 cycloalkyl, or taken together
with the nitrogen to which they are attached, they form a
non-aromatic 4-7 membered heterocyclyl optionally including up to
two additional heteroatoms independently selected from O, S, and
N;
[0013] one of R.sup.3, R.sup.4, and R.sup.5 is G, one of the
remaining two is hydrogen, and the other is selected from hydrogen,
fluoro, and chloro;
[0014] G is L.sup.2Q;
[0015] L.sup.2is methylene;
[0016] Q is NR.sup.8R.sup.9 wherein R.sup.8 is independently
selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or
5-8-membered heterocyclyl), phenyl, (5-9-membered
heterocyclyl)C.sub.1-6 alkylene, and (phenyl) C.sub.1-6 alkylene;
and R.sup.9 is independently selected from C.sub.1-6 alkyl,
C.sub.3-6 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl), phenyl,
(5-9-membered heterocyclyl)C.sub.1-6 alkylene, and (phenyl)
C.sub.1-6 alkylene; or
[0017] Q is a saturated 3-13 membered N-linked heterocyclyl,
wherein, in addition to the N-linking nitrogen, the 3-13 membered
heterocyclyl may optionally contain between 1 and 3 additional
heteroatoms independently selected from O, S, and N;
[0018] wherein each of the above alkyl, alkylene, alkenyl,
heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups of Formula
(I) may each be independently and optionally substituted with
between 1 and 3 substituents independently selected from methoxy,
halo, amino, nitro, hydroxyl, and C.sub.1-3 alkyl;
[0019] and wherein 1-3 substituents of Q can be further
independently selected (in addition to the preceding paragraph)
from tert-butyloxycarbonyl, carboxamide, C.sub.1-6 alkyl,
5-9-membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9 membered
heterocyclyl), NH(5-9 membered heterocyclyl), O(5-9 membered
heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3 alkylene,
phenyl, C.sub.1-2-hydroxyalkylene, C.sub.2-6 alkoxy, (C.sub.3-6
cycloalkyl)-O--, phenyl, (phenyl)C.sub.1-3 alkylene, and
(phenyl)C.sub.1-3 alkylene-O-- and where said substituent groups of
Q may optionally have between 1 and 3 substituents independently
selected from trifluoromethyl, halo, nitro, cyano, and hydroxy;
[0020] or a pharmaceutically acceptable salt, ester, or amide
thereof.
[0021] The present invention also features methods of making a
compound of formula (I), a pharmaceutically acceptable salt, ester,
or amide thereof, comprising at least one of the following steps:
Reacting a compound of formula (VI) with a compound of formula (V),
2
[0022] performing a nucleophilic substitution of X.sub.1 in
compound of formula (VIII) with an organic base R.sup.1R.sup.2NH,
wherein X.sup.2 is a suitable leaving group in a coupling reaction
with an alkyne, and X.sup.1 is a suitable leaving group in a
nucleophilic substitution with an amine.
[0023] The present invention also features methods of making a
compound of formula (I), a pharmaceutically acceptable salt, ester,
or amide thereof, wherein more specifically one of R.sup.3 and
R.sup.5 is G, one of the remaining and R.sup.4 is H, and the other
is selected from hydrogen, fluoro, and chloro, comprising: reacting
at least one of the compounds of formulae (XXIIIw) and (XXIIIow)
with a compound of formula (V); 3
[0024] wherein W is C(O)H (denoting 4
[0025] or G, and X.sup.2 is a suitable leaving group in a coupling
reaction with an alkyne.
[0026] The present invention also features methods of making a
compound of formula (I), a pharmaceutically acceptable salt, ester,
or amide thereof, wherein more specifically R.sup.4 is G, one of
the remaining R.sup.3 and R.sup.5 is hydrogen, and the other is
selected from hydrogen, fluoro, and chloro G is a m-substituent
with respect to the alkyne chain substituent, comprising: reacting
a compound of formula (XXIIImw) with a compound of formula (V).
5
[0027] wherein W is C(O)H or G, and X.sup.2 is a suitable leaving
group in a coupling reaction with an alkyne.
[0028] The present invention also features methods of making a
compound of formula (I), a pharmaceutically acceptable salt, ester,
or amide thereof, comprising reacting a compound of formula (VII)
with an organic base R.sup.1R.sup.2NH in the presence of a
trialkylphosphonium halide and a base. 6
[0029] The invention also features a pharmaceutical composition
comprising a compound of the invention and a pharmaceutically
acceptable carrier; and methods of preparing or formulating such
compositions. A composition of the invention may further include
more than one compound of the invention, or a combination therapy
(combination formulation or combination of differently formulated
active agents).
[0030] The invention also provides methods of treating certain
conditions and diseases, each of which methods includes
administering a therapeutically effective (or jointly effective)
amount of a compound or composition of the invention to a subject
in need of such treatment. The disclosed compounds are useful in
methods for treating or preventing neurologic disorders including
sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet
lag), attention deficit hyperactivity disorders (ADHD), learning
and memory disorders, cognitive dysfunction, migraine, neurogenic
inflammation, dementia, mild cognitive impairment (pre-dementia),
Alzheimer's disease, epilepsy, narcolepsy, eating disorders,
obesity, motion sickness, vertigo, schizophrenia, substance abuse,
bipolar disorders, manic disorders and depression, as well as other
histamine H.sub.3 receptor mediated disorders such as upper airway
allergic response, asthma, itch, nasal congestion and allergic
rhinitis in a subject in need thereof. For example, the invention
features methods for preventing, inhibiting the progression of, or
treating upper airway allergic response, asthma, itch, nasal
congestion and allergic rhinitis.
[0031] In yet another embodiment, the disclosed compounds may be
used in a combination therapy method including administering a
jointly effective dose of an H.sub.3 antagonist and administering a
jointly effective dose of a histamine H.sub.1 antagonist, such as
loratidine (CLARITIN.TM.), desloratidine (CLARINEX.TM.),
fexofenadine (ALLEGRA.TM.) and cetirizine (ZYRTEC.TM.), for the
treatment of allergic rhinitis, nasal congestion, and allergic
congestion.
[0032] In yet another embodiment, the disclosed compounds may be
used in a combination therapy method, including administering a
jointly effective dose of an H.sub.3 antagonist and administering a
jointly effective dose of a neurotransmitter re-uptake blocker,
such as a selective serotonin re-uptake inhibitor (SSRI) or a
non-selective serotonin, dopamine or norepinephrine re-uptake
inhibitor, including fluoxetine (PROZAC.TM.), sertraline
(ZOLOFT.TM.), paroxetine (PAXIL.TM.) and amitryptyline, for the
treatment of depression, mood disorders or schizophrenia.
[0033] Additional features and advantages of the invention will
become apparent from the detailed description and examples below,
and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention provides phenylalkyne compounds useful
for the treatment of disorders and conditions modulated by a
histamine receptor.
[0035] A. Terms
[0036] Certain terms are defined below and by their usage
throughout this disclosure.
[0037] As used herein, "halo" or "halogen" shall mean monovalent
radicals of chlorine, bromine, fluorine and iodine.
[0038] As used herein, the term "alkyl", whether used alone or as
part of a substituent group, shall include straight and branched
carbon chains. For example, alkyl radicals include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and
the like. Unless otherwise noted, "lower" when used with alkyl
means a carbon chain composition of 1-4 carbon atoms. "Alkylene"
refers to a bivalent hydrocarbyl group, such as methylene
(CH.sub.2), ethylene (--CH.sub.2--CH.sub.2--) or propylene
(--CH.sub.2CH.sub.2CH.sub.2--), and so on.
[0039] As used herein, unless otherwise noted, "alkenyl" shall mean
a straight or branched hydrocarbon group with at least two hydrogen
atoms replaced with a pi bond to form a carbon-carbon double bond,
such as propenyl, butenyl, pentenyl, and so on. Where the alkenyl
group is R.sup.8 or R.sup.9, the open radical (point of attachment
to the rest of the molecule) is on sp.sup.3 carbon, as illustrated
by allyl, and the double bond or bonds is therefore at least alpha
(if not beta, gamma, etc.) to the open radical.
[0040] As used herein, unless otherwise noted, "alkoxy" shall
denote an oxygen ether radical of the above described straight or
branched chain alkyl groups. For example, methoxy, ethoxy,
n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
[0041] As used herein, unless otherwise noted, "cycloalkyl" shall
denote a three- to eight-membered, saturated monocyclic carbocyclic
ring structure. Suitable examples include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0042] As used herein, unless otherwise noted, "cycloalkenyl" shall
denote a three- to eight-membered, partially unsaturated,
monocyclic, carbocyclic ring structure, wherein the ring structure
contains at least one double bond. Suitable examples include
cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl,
cyclohexa-1,3-dienyl and the like.
[0043] As used herein, unless otherwise noted, "aryl" shall refer
to carbocyclic aromatic groups such as phenyl, naphthyl, and the
like. Divalent radicals include phenylene (--C.sub.6H.sub.4--)
which is preferably phen-1,4-diyl, but may also be
phen-1,3-diyl.
[0044] As used herein, unless otherwise noted, "aralkyl" shall mean
any alkyl group substituted with an aryl group such as phenyl,
naphthyl and the like. Examples of aralkyls include benzyl,
phenethyl, and phenylpropyl.
[0045] As used herein, unless otherwise noted, "carbocyclyl" shall
mean any cyclic group consisting of 3-13 carbon atoms, and
preferably 6-9 carbon atoms, in the skeleton ring or rings, if the
carbocycle is a fused or spiro bicyclic or tricyclic group. A
carbocycle may be saturated, unsaturated, partially unsaturated, or
aromatic. Examples include cycloalkyl, cycloalkenyl, cycloalkynyl;
specific examples include phenyl, benzyl, indanyl, and biphenyl. A
carbocycle may have substituents that are not carbon or hydrogen,
such as hydroxy, halo, halomethyl, and so on as provided elsewhere
herein.
[0046] As used herein, unless otherwise noted, the terms
"heterocycle", "heterocyclyl" and "heterocyclo" shall denote any
three-, four-, five-, six-, seven-, or eight-membered monocyclic,
eight or nine or ten or eleven membered bicyclic or twelve or
thirteen or fourteen membered tricyclic ring structure containing
at least one heteroatom moiety selected from the group consisting
of N, O, SO, SO.sub.2, (C.dbd.O), and S, and preferably N, O, or S,
optionally containing one to four additional heteroatoms in each
ring. In some embodiments, the heterocyclyl contains between 1 and
3 or between 1 and 2 additional heteroatoms. Unless otherwise
specified, a heterocyclyl may be saturated, partially unsaturated,
aromatic or partially aromatic. The heterocyclyl group may be
attached at any heteroatom or carbon atom, which results in the
creation of a stable structure.
[0047] Exemplary monocyclic heterocyclic groups can include
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl,
hexahydroazepinyl, 4-piperidinyl, pyridyl, N-oxo-pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl,
thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl
sulfone, 1,3-dixolane and tetrahydro-1,1-dioxothienyl, dioxanyl,
isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl,
tetrazolyl, azetidinyl and the like.
[0048] For example, where Q is a saturated 3-13 membered N-linked
heterocyclyl, Q necessarily contains at least one nitrogen, and the
carbon atoms are sp.sup.3 hybridized.
[0049] In general, exemplary bicyclic heterocyclyls include
benzthiazolyl, benzoxazolyl, benzoxazinyl, benzothienyl,
quinuclidinyl, quinolinyl, quinolinyl-N-oxide,
tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,
cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl
(such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such
as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as
1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as
1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isoindolyl, tetrahydroindoazolyl (such as
4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,
naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,
quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,
thienothienyl, 7
[0050] and the like.
[0051] Exemplary tricyclic heterocyclic groups include acridinyl,
phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl,
phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the
like.
[0052] Preferred heterocyclyl groups include morpholinyl,
piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl,
pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl,
hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl,
thiadiazolyl, quinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl,
4,5,6,7-tetrahydroindadolyl, benzoxazinyl, benzoxazolyl,
benzthiazolyl, benzimidazolyl, tetrazolyl, oxadiazolyl, 8
[0053] As used herein, unless otherwise noted, the term
"heterocyclyl-alkyl" or "heterocyclyl-alkylene" shall denote any
alkyl group substituted with a heterocyclyl group, wherein the
heterocycly-alkyl group is bound through the alkyl portion to the
central part of the molecule. Suitable examples of
heterocyclyl-alkyl groups include, but are not limited to
piperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl,
piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl,
pyridylmethyl, pyrimidylethyl, and the like.
[0054] When a particular group is "substituted" (e.g., alkyl,
alkylene, cycloalkyl, aryl, heterocyclyl, heteroaryl), that group
may have one or more substituents, preferably from one to five
substituents, more preferably from one to three substituents, most
preferably from one to two substituents, independently selected
from the list of substituents.
[0055] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0056] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a "phenyl(alkyl)amido(alkyl)"
substituent refers to a group of the formula 9
[0057] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0058] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes prevention,
inhibition of onset, or alleviation of the symptoms of the disease
or disorder being treated.
[0059] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0060] Abbreviations used in the specification, particularly in the
Schemes and Examples, are as follows:
1 DBAD = Di-tert-butyl azodicarboxylate DCE 1,2-dichloroethane DCM
= Dichioromethane DEAD = Diethyl azodicarboxylate DIPEA
Disopropylethylamine DMAC (or = N,N-dimethylacetamide DMA) DMAP =
4-N,N-dimethylamino- pyridine DME = 1,2-dimethoxyethane DMF =
Dimethylformamide DMSO = Dimethylsulfoxide TEA = Triethylamine TFA
= Trifluoroacetic acid THF = Tetrahydrofuran
[0061] The next section describes the compounds provided by the
invention in more detail.
[0062] B. Compounds
[0063] The invention features compounds of formula (I) as
described, for example, in the above summary section and in the
claims. Preferred compounds include those wherein:
[0064] (a) NR.sup.1R.sup.2 taken together form piperidinyl,
methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino,
methylethylamino, ethylpropylamino, or dipropylamino;
[0065] (b) NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino;
[0066] (c) NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl;
[0067] (d) one of R.sup.4 and R.sup.5 is G;
[0068] (e) R.sup.4 is G;
[0069] (f) R.sup.5 is G;
[0070] (g) n is 1;
[0071] (h) Q is a saturated N-linked nitrogen-containing
heterocyclyl;
[0072] (i) Q is selected from substituted or unsubstituted
piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, and morpholinyl;
[0073] (j) substituted Q is selected from N--(C.sub.1-6 alkyl)
piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl,
and 1,4-dioxa-8-aza-spiro[4.5]decyl;
[0074] (k) Q is a monovalent radical of an amine selected from
aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-sp- iro[4.5]decan-4-one,
piperidine-3-carboxylic acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl,
4-(3-trifluoromethyl-phenyl)-pip- erazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-yl-1,3-dihydro-benz- oimidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin--
2-yl-amine, phenylamine, and pyridin-2-ylamine;
[0075] (l) Q is selected from N-morpholinyl and N-piperidinyl,
optionally substituted with between 1 and 3 substituents
independently selected from hydroxyl, 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), (5-9 membered or 6-9 membered
heterocyclyl)C.sub.1-3 alkylene, 5-9 membered or 6-9 membered
heterocyclyl-O--, 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 halogen, nitro, cyano, and C.sub.1-3
alkyl;
[0076] (m) Q is substituted with a substituent comprising a 5-9
membered or 6-9 membered heterocyclyl group selected from: pyridyl,
pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C.sub.1-6
alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,
2-oxobenzimidazolyl, (tetrazolyl)C.sub.1-6 alkylene, tetrazolyl,
(triazolyl)C.sub.1-6 alkylene, triazolyl, (pyrrolyl)C.sub.1-6
alkylene, and pyrrolyl;
[0077] (n) Q is a substituted or unsubstituted N-morpholinyl;
[0078] (o) R.sup.8 is hydrogen;
[0079] (p) R.sup.9 is selected from phenyl or 5-9 membered aromatic
heterocyclyl, wherein said phenyl or aromatic heterocyclyl is
optionally substituted with 1-3 substituents selected from halo,
nitro, cyano, and C.sub.1-3 alkyl;
[0080] (q) R.sup.9 is selected from substituted or unsubstituted
phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,
(imidazolyl)C.sub.1-6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and
pyrrolyl;
[0081] (r) R.sup.9 is substituted or unsubstituted phenyl;
[0082] (s) R.sup.9 is substituted or unsubstituted pyridyl;
[0083] (t) wherein n is 1; R.sup.1 and R.sup.2 are independently
selected from C.sub.2 alkyl, or taken together with the nitrogen to
which they are attached, they form a non-aromatic 5-6 membered
heterocyclyl optionally including an additional heteroatom
independently selected from O, S, and N; one of R.sup.3, R.sup.4,
and R.sup.5 is G and the two remaining are H; G is L.sup.2Q;
L.sup.2 is methylene; Q is NR.sup.8R.sup.9 wherein R.sup.8 is
independently selected from hydrogen, C.sub.1-2 alkyl, C.sub.3
alkenyl, 6-9 membered carbocycle, 3-12 membered heterocyclyl
(preferably 5-9 or 6-9), phenyl, (5-9-membered
heterocyclyl)C.sub.1-6 alkylene, and (phenyl) C.sub.1-6 alkylene;
and R.sup.9 is independently selected from C.sub.1-2 alkyl, C.sub.3
alkenyl, 5-9 membered carbocyclyl, 3-12 membered heterocyclyl (for
example, 5-9 membered or 6-9 membered heterocyclyl, and in some
cases preferably 6-membered), phenyl, (5-9-membered
heterocyclyl)C.sub.1-6 alkylene, and (phenyl) C.sub.1-6 alkylene;
or Q is a saturated 3-13 membered N-linked heterocyclyl (preferably
5-9 or 6-9), wherein, in addition to the N-linking nitrogen, the
3-13 membered heterocyclyl may optionally contain between 1 and 3
additional heteroatoms independently selected from O, S, and N;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene,
heterocyclyl, cycloalkyl, and aryl groups may each be independently
and optionally substituted with between 1 and 3 substituents
independently selected from methoxy, halo, amino, nitro, hydroxyl,
and C.sub.1-3 alkyl; and wherein substituents of Q can be further
independently selected from tert-butyloxycarbonyl, carboxamide,
6-9-membered heterocyclyl, NH(6-membered heterocyclyl),
O(6-membered heterocyclyl), phenyl, C.sub.2-hydroxyalkylene,
hydroxy, and benzyl, and,where each of above heterocyclyl, phenyl,
and alkyl substituent groups of Q may be optionally substituted
with trifluoromethyl; or a pharmaceutically acceptable salt, ester,
or amide thereof;
[0084] (u) (1) NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino, and (2) Q is selected from
substituted or unsubstituted piperidinyl, piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, and morpholinyl;
[0085] (v) (1) NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, (2) n is 1, and (3) Q is selected from morpholinyl
and piperidinyl;
[0086] (w) Q is morpholinyl or substituted morpholinyl;
[0087] (x) NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino,
[0088] n is 1, and
[0089] wherein Q is NR.sup.8R.sup.9 and R.sup.8 is H and R.sup.9 is
selected from phenyl or aromatic 5-9 membered heterocyclyl, wherein
said phenyl or heterocyclyl is optionally substituted with 1-3
substituents selected from halo, nitro, cyano, and C.sub.1-3 alkyl;
or
[0090] (y) or combinations of the above.
[0091] Examples of compounds of the invention include:
1-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine
dihydrochloride;
1-[4-(4-pyrrolidin-1-yl-but-1-ynyl)-benzyl]-piperidine;
diethyl-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-amine;
4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-thiomorpholine;
4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-morpholine;
1-methyl-4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperazine;
1-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine;
diethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
1-{4-[4-(4-benzyl-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-piperidine;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
2-{1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-2-yl}-ethanol;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-decahydro-quinoline;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-carboxylic
acid amide;
8-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,4-dioxa-8-aza-spiro[4-
.5]decane;
1-methyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
cyclohexyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
indan-1-yl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
1-phenyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-benzyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine-1-carboxylic
acid tert-butyl ester;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-isopropyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-phenyl-8-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,3,8-triaza-spiro[4.-
5]decan-4-one;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-3-car-
boxylic acid diethylamide;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,2,-
3,4,5,6-hexahydro-[2,3']bipyridinyl;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-be-
nzyl]-4-(3-trifluoromethyl-phenyl)-piperazine;
2-{4-[3-(4-piperidin-1-yl-b-
ut-1-ynyl)-benzyl]-piperazin-1-yl}-pyrimidine;
1-[3-(4-piperidin-1-yl-but--
1-ynyl)-benzyl]-piperidine-4-carboxylic acid amide;
methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-(2-pyridin-2-yl-ethyl)-am-
ine;
[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1-yn-
yl)-benzyl]-amine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholi- ne;
allyl-cyclopentyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
10-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,4,7-trioxa-10-aza-cyclodode-
cane;
1-[4-(3-thiazolidin-3-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
[2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-
-amine;
1-{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-1,3--
dihydro-benzoimidazol-2-one;
phenyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzy- l]-amine;
1-[4-(3-pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-azacyclotridecane;
dimethyl-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-amine;
dimethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
phenyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
1-[4-(3-aziridin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
2-{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yloxy}-pyrimidi-
ne;
{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-pyridin-2--
yl-amine;
4-[4-(3-morpholin-4-ylmethyl-phenyl)-but-3-ynyl]-morpholine;
4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-morpholine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholine;
4-[4-(3-thiomorpholin-4-ylmethyl-phenyl)-but-3-ynyl]-morpholine;
4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-thiomorpholine;
4-{4-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-but-3-ynyl}-morpholine;
4-{4-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-but-3-ynyl}-thiomorpholin-
e; 1-methyl-4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
1-[3-(4-morpholin-4-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
1-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
1-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-piperidine;
4-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-morpholine;
and
4-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-thiomorp-
holine.
[0092] Additional compounds include:
1-[4-(4-piperidin-1-ylmethyl-phenyl)-- but-3-ynyl]-piperidine;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperid- ine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine
dihydrochloride;
1-[4-(4-pyrrolidin-1-yl-but-1-ynyl)-benzyl]-piperidine;
1-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
diethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
2-{1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-2-yl}-ethanol;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-decahydro-quinoline;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-carboxylic
acid amide;
8-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,4-dioxa-8-aza-spiro[4-
.5]decane;
1-methyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
cyclohexyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
indan-1-yl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
1-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-isopropyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-phenyl-8-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,3,8-triaza-spiro[4.-
5]decan-4-one;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-car-
boxylic acid amide;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorphol- ine;
allyl-cyclopentyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
10-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,4,7-trioxa-10-aza-cyclodode-
cane;
1-[4-(3-thiazolidin-3-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
[2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-
-amine;
1-{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-1,3--
dihydro-benzoimidazol-2-one; and
1-[4-(3-pyrrolidin-1-ylmethyl-phenyl)-but- -3-ynyl]-piperidine.
[0093] More preferred compounds include:
4-[3-(4-piperidin-1-yl-but-1-ynyl- )-benzyl]-morpholine and
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpho- line; and
particularly the former.
[0094] Additional examples of compounds include:
1-[3-(4-piperidin-1-yl-bu- t-1-ynyl)-benzyl]-piperidine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-m- orpholine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine
dihydrochloride;
1-phenyl-8-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,3,-
8-triaza-spiro[4.5]decan-4-one;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-
-piperidine-3-carboxylic acid diethylamide;
1-[3-(4-piperidin-1-yl-but-1-y-
nyl)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-4-(3-trifluoromethyl-phenyl)-p-
iperazine;
2-{4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazin-1-yl}-p-
yrimidine;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-carboxy-
lic acid amide;
methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-(2-pyridin-
-2-yl-ethyl)-amine;
[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidi-
n-1-yl-but-1-ynyl)-benzyl]-amine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzy- l]-thiomorpholine;
allyl-cyclopentyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benz- yl]-amine;
10-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,4,7-trioxa-10-aza-
-cyclododecane;
1-[4-(3-thiazolidin-3-ylmethyl-phenyl)-but-3-ynyl]-piperid- ine;
[2-(1H-indol-3-yl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-ben-
zyl]-amine;
1-{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}--
1,3-dihydro-benzoimidazol-2-one;
phenyl-[3-(4-piperidin-1-yl-but-1-ynyl)-b- enzyl]-amine;
1-[4-(3-pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine- ; and
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-azacyclotridecane.
[0095] Further examples include:
dimethyl-[4-(4-piperidin-1-ylmethyl-pheny- l)-but-3-ynyl]-amine;
dimethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-am- ine;
phenyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine;
1-[4-(3-aziridin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine;
2-{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yloxy}-pyrimidi-
ne;
{1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-pyridin-2--
yl-amine;
4-[4-(3-morpholin-4-ylmethyl-phenyl)-but-3-ynyl]-morpholine;
4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-morpholine;
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholine;
4-[4-(3-thiomorpholin-4-ylmethyl-phenyl)-but-3-ynyl]-morpholine;
4-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-thiomorpholine;
4-{4-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-but-3-ynyl}-morpholine;
4-{4-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-but-3-ynyl}-thiomorpholin-
e; 1-methyl-4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine;
1-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
1-[3-(4-morpholin-4-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
1-[3-(4-thiomorpholin-4-yl-but-1-ynyl)-benzyl]-piperidin-4-ol;
1-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-piperidine;
4-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-morpholine;
and
4-{4-[3-(4-methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-thiomorp-
holine.
[0096] The invention also provides compounds that are useful as
synthetic intermediates of the compounds of the invention. Such
compounds, which themselves may or may not have pharmaceutical
activity, include those provided in the schemes and synthetic
examples.
[0097] The invention also contemplates compounds
isotopically-labelled to be detectable by positron emission
tomography (PET) or single-photon emission computed tomography
(SPECT) useful for studying H.sub.3-mediated disorders.
[0098] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. In addition, compounds of the invention may be modified
by using protecting groups; such compounds, precursors, or prodrugs
are also within the scope of the invention. This may be achieved by
means of conventional protecting groups, such as those described in
"Protective Groups in Organic Chemistry", ed. J. F. W. McOmie,
Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 3.sup.rd ed., John Wiley
& Sons, 1999. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
[0099] Hydroxyl Protecting Groups
[0100] Protection for the hydroxyl group includes methyl ethers,
substituted methyl ethers, substituted ethyl ethers, substitute
benzyl ethers, and silyl ethers.
[0101] Substituted Methyl Ethers
[0102] Examples of substituted methyl ethers include
methyoxymethyl, methylthiomethyl, t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,
p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,
t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,
2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,
tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,
4-methoxytetrahydrothiop- yranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and
2,3,3a,4,5,6,7,7a-octahydro--
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
[0103] Substituted Ethyl Ethers
[0104] Examples of substituted ethyl ethers include 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyeth- yl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
[0105] Substituted Benzyl Ethers
[0106] Examples of substituted benzyl ethers include
p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-
and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxy)phenyldiphenylmethyl,
4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4"-tris(levulinoyloxyphenyl)methyl,
4,4',4"-tris(benzoyloxyphenyl)me- thyl,
3-(Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
[0107] Silyl Ethers
[0108] Examples of silyl ethers include trimethylsilyl,
triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl, and
t-butylmethoxyphenylsilyl.
[0109] Esters
[0110] In addition to ethers, a hydroxyl group may be protected as
an ester. Examples of esters include formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate,
3-phenylpropionate, 4-oxopentanoate(levulinate),
4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate(mesitoate).
[0111] Carbonates
[0112] Examples of carbonates include methyl, 9-fluorenylmethyl,
ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl,
vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl
thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
[0113] Assisted Cleavage
[0114] Examples of assisted cleavage include 2-iodobenzoate,
4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl carbonate,
4-(methylthiomethoxy)butyrate, and
2-(methylthiomethoxymethyl)benzoate.
[0115] Miscellaneous Esters
[0116] Examples of miscellaneous esters include
2,6-dichloro-4-methylpheno- xyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),
o-(methoxycarbonyl)benzoate, p-P-benzoate, .alpha.-naphthoate,
nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate,
N-phenylcarbamate, borate, dimethylphosphinothioyl, and
2,4-dinitrophenylsulfenate
[0117] Sulfonates
[0118] Examples of sulfonates include sulfate,
methanesulfonate(mesylate), benzylsulfonate, and tosylate.
[0119] Protection for 1,2- and 1,3-Diols
[0120] Cyclic Acetals and Ketals
[0121] Examples of cyclic acetals and ketals include methylene,
ethylidene, 1-t-butylethylidene, 1-phenylethylidene,
(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide
(isopropylidene), cyclopentylidene, cyclohexylidene,
cycloheptylidene, benzylidene, p-methoxybenzylidene,
2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and
2-nitrobenzylidene.
[0122] Cyclic Ortho Esters
[0123] Examples of cyclic ortho esters include methoxymethylene,
ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,
1-ethoxyethylidine, 1,2-dimethoxyethylidene,
.alpha.-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene
derivative, .alpha.-(N,N-dimethylamino)be- nzylidene derivative,
and 2-oxacyclopentylidene.
[0124] Silyl Derivatives
[0125] Examples of silyl derivatives include di-t-butylsilylene
group, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene)
derivative.
[0126] Amino Protecting Groups
[0127] Protection for the amino group includes carbamates, amides,
and special --NH protective groups.
[0128] Examples of carbamates include methyl and ethyl carbamates,
substituted ethyl carbamates, assisted cleavage carbamates,
photolytic cleavage carbamates, urea-type derivatives, and
miscellaneous carbamates.
[0129] Carbamates
[0130] Examples of methyl and ethyl carbamates include methyl and
ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,
9-(2,7-dibromo)fluorenylme- thyl,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]me-
thyl, and 4-methoxyphenacyl.
[0131] Substituted Ethyl
[0132] Examples of substituted ethyl carbamates include
2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and
4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,
1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,
benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,
p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl and diphenylmethyl.
[0133] Assisted Cleavage
[0134] Examples of assisted cleavage include 2-methylthioethyl,
2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,
[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,
2,4-dimethylthiophenyl, 2-phosphonioethyl,
2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,
m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,
5-benzisoxazolylmethyl, and
2-(trifluoromethyl)-6-chromonylmethyl.
[0135] Photolytic Cleavage
[0136] Examples of photolytic cleavage include m-nitrophenyl,
3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,
and phenyl(o-nitrophenyl)methyl.
[0137] Urea-Type Derivatives
[0138] Examples of urea-type derivatives include
phenothiazinyl-(10)-carbo- nyl derivative,
N'-p-toluenesulfonylaminocarbonyl, and
N'-phenylaminothiocarbonyl.
[0139] Miscellaneous Carbamates
[0140] Examples of miscellaneous carbamates include t-amyl,
S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,
o-(N,N-dimethylcarboxamido)benzyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,
2-iodoethyl, isobornyl, isobutyl, isonicotinyl,
p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,
1-methyl-1-(3,5-dimetho- xyphenyl)ethyl,
1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl- , and
2,4,6-trimethylbenzyl.
[0141] Examples of amides include:
[0142] Amides
[0143] N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,
N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,
N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, N-benzoyl, N-p-phenylbenzoyl.
[0144] Assisted Cleavage
[0145] N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,
N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl,
N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,
N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,
N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine
derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and
4,5-diphenyl-3-oxazolin-2-one.
[0146] Cyclic Imide Derivatives
[0147] N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,
5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and
1-substituted 3,5-dinitro-4-pyridonyl.
[0148] Special --NH Protective Groups
[0149] Examples of special NH protective groups include:
[0150] N-Alkyl and N-Aryl Amines
[0151] N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,
N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),
quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl,
N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl,
N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,
N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and
N-2-picolylamine N'-oxide.
[0152] Imine Derivatives
[0153] N-1,1-dimethylthiomethylene, N-benzylidene,
N-p-methoxybenzylidene, N-diphenylmethylene,
N-[(2-pyridyl)mesityl]methylene, and N-(N',
N'-dimethylaminomethylene).
[0154] Protection for the Carbonyl Group
[0155] Acyclic Acetals and Ketals
[0156] Examples of acyclic acetals and ketals include dimethyl,
bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and
diacetyl.
[0157] Cyclic Acetals and Ketals
[0158] Examples of cyclic acetals and ketals include 1,3-dioxanes,
5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,
5-(2-pyridyl)-1,3-dioxa- ne, 1,3-dioxolanes,
4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxola- ne,
4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane,
4,5-dimethoxymethyl-1,3-dioxolane, O,O'-phenylenedioxy and
1,5-dihydro-3H-2,4-benzodioxepin.
[0159] Acyclic Dithio Acetals and Ketals
[0160] Examples of acyclic dithio acetals and ketals include
S,S'-dimethyl, S,S'-diethyl, S,S'-dipropyl, S,S'-dibutyl,
S,S'-dipentyl, S,S'-diphenyl, S,S'-dibenzyl and S,S'-diacetyl.
[0161] Cyclic Dithio Acetals and Ketals
[0162] Examples of cyclic dithio acetals and ketals include
1,3-dithiane, 1,3-dithiolane and
1,5-dihydro-3H-2,4-benzodithiepin.
[0163] Acyclic Monothio Acetals and Ketals
[0164] Examples of acyclic monothio acetals and ketals include
O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or --S-phenyl and
O-methyl-S-2-(methylthio)ethyl.
[0165] Cyclic Monothio Acetals and Ketals
[0166] Examples of cyclic monothio acetals and ketals include
1,3-oxathiolanes.
[0167] Miscellaneous Derivatives
[0168] O-Substituted Cyanohydrins
[0169] Examples of O-substituted cyanohydrins include O-acetyl,
O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
[0170] Substituted Hydrazones
[0171] Examples of substituted hydrazones include N,N-dimethyl and
2,4-dinitrophenyl.
[0172] Oxime Derivatives
[0173] Examples of oxime derivatives include O-methyl, O-benzyl and
O-phenylthiomethyl.
[0174] Imines
[0175] Substituted Methylene Derivatives, Cyclic Derivatives
[0176] Examples of substituted methylene and cyclic derivatives
include oxazolidines, 1-methyl-2-(1'-hydroxyalkyl)imidazoles,
N,N'-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,
diethylamine adducts, and methylaluminum
bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)com- plex.
[0177] Monoprotection of Dicarbonyl Compounds
[0178] Selective Protection of .alpha.- and .beta.-Diketones
[0179] Examples of selective protection of .alpha.- and
.beta.-diketones include enamines, enol acetates, enol ethers,
methyl, ethyl, i-butyl, piperidinyl, morpholinyl,
4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and
trimethylsilyl.
[0180] Cyclic Ketals, Monothio and Dithio Ketals
[0181] Examples of cyclic ketals, monothio and dithio ketals
include bismethylenedioxy derivatives and
tetramethylbismethylenedioxy derivatives.
[0182] Protection for the Carboxyl Group
[0183] Esters
[0184] Substituted Methyl Esters
[0185] Examples of substituted methyl esters include
9-fluorenylmethyl, methoxymethyl, methylthiomethyl,
tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl,
p-bromophenacyl, .alpha.-methylphenacyl, p-methoxyphenacyl,
carboxamidomethyl, and N-phthalimidomethyl.
[0186] 2-Substituted Ethyl Esters
[0187] Examples of 2-substituted ethyl esters include
2,2,2-trichloroethyl, 2-haloethyl, .omega.-chloroalkyl,
2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl,
2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl,
[0188] 2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl,
1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl,
3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl,
.alpha.-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and
benzyl.
[0189] Substituted Benzyl Esters
[0190] Examples of substituted benzyl esters include
triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl,
9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl,
1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl,
2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl,
4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
[0191] Silyl Esters
[0192] Examples of silyl esters include trimethylsilyl,
triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl,
phenyldimethylsilyl and di-t-butylmethylsilyl.
[0193] Activated Esters
[0194] Examples of activated esters include thiols.
[0195] Miscellaneous Derivatives
[0196] Examples of miscellaneous derivatives include oxazoles,
2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,
5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and
pentaaminocobalt(III) complex.
[0197] Stannyl Esters
[0198] Examples of stannyl esters include triethylstannyl and
tri-n-butylstannyl.
[0199] Amides and Hydrazides
[0200] Amides
[0201] Examples of amides include N,N-dimethyl, pyrrolidinyl,
piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides,
N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and
p-P-benzenesulfonamides.
[0202] Hydrazides
[0203] Examples of hydrazides include N-phenyl and
N,N'-diisopropyl.
[0204] The compounds of the invention can be prepared according to
the methods described in the next section.
[0205] C. Synthesis
[0206] The compounds of the invention can be prepared according to
traditional synthetic organic methods and matrix or combinatorial
chemistry methods, as shown in Schemes 1-5 below and in Examples
1-76. A person of ordinary skill will be aware of variations and
adaptations of the schemes and examples provided to achieve the
compounds of the invention.
[0207] One skilled in the art will recognize that synthesis of the
compounds of the present invention may be effected by purchasing
intermediate or protected intermediate compounds described in any
of the Schemes disclosed herein. Throughout the schemes when the
reacting functionality is located at R.sup.3, one skilled in the
art will recognize that the choice of R.sup.3 is illustrative only
and that the reacting functionality could also be located at
R.sup.4 and R.sup.5 also.
[0208] One skilled in the art will further recognize that during
any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned.
This may be achieved by means of conventional protecting groups,
such as those described in "Protective Groups in Organic
Chemistry", ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, "Protective Groups in Organic
Synthesis", John Wiley & Sons, 1991. The protecting groups may
be removed at a convenient subsequent stage using methods known
from the art.
[0209] Throughout the schemes when the reacting functionality is
located at R.sup.5, one skilled in the art will recognize that the
choice of R.sup.5 is illustrative only and that the reacting
functionality could also be located at R.sup.3 and/or R.sup.4.
[0210] Compounds of formula (V) may be prepared according to the
processes outlined in Scheme 1. 10
[0211] A compound of formula (V) is prepared as outlined in Scheme
1 from a compound of formula (II). A compound of formula (II) is
reacted with a reagent capable of converting a hydroxyl function
into a leaving group X.sup.1 under hydroxyl activation
conditions.
[0212] Leaving group X.sup.1 is a suitable leaving group in a
nucleophilic substitution reaction with an amine, such as amine
R.sup.1R.sup.2NH. In a preferred embodiment, leaving group X.sup.1
is a sulfonate ester, obtained by reacting a compound of formula
(III) with an alkyl or arylsulfonyl chloride in a non-acoholic
solvent in the presence of an organic or inorganic base at
temperature from -78.degree. C. to 50.degree. C. Examples of such
solvent are benzene, DCM, DCE, THF, DMF, acetonitrile,
hexamethylphosphoramide (HMPA), hexane, pentane, and mixtures
thereof. Examples of organic bases are pyridine, TEA, and mixtures
thereof. Examples of inorganic bases are, KOH, NaOH,
Na.sub.2CO.sub.3, K.sub.2CO.sub.3 or mixtures thereof.
[0213] In a particularly preferred embodiment, a compound of
formula (II) is reacted with p-toluenesulfonyl chloride or
methanesulfonyl chloride in DCM in the presence of TEA at a
temperature between 0.degree. C. and room temperature.
[0214] A compound of formula (V) is obtained from a compound of
formula (III) by reacting a compound of formula (IV) with a
compound of formula (III) under nucleophilic displacement
conditions, either neat or in a solvent in the presence or absence
of a base at a temperature from 0.degree. C. to 100.degree. C.
Examples of such solvent are methanol, ethanol, propanol,
n-butanol, DMF, DMSO, DME, and compatible mixtures thereof.
Examples of such base, when present, are sodium carbonate,
potassium carbonate, cesium carbonate, triethylamine,
tetramethylguanidine, and compatible mixtures thereof.
[0215] The use of a high polarity solvent may increase the rate and
reduce by-product formation in these reactions. Such high polarity
solvent is provided in some embodiments as a mixture of a first
solvent with a cosolvent that increases the dielectric constant of
the mixture with respect to the dielectric constant of such first
solvent. For example, one of ordinary skill in the art will
recognize in light of this disclosure that the use of water as such
cosolvent may increase the rate and reduce by-product formation in
these reactions. In a preferred embodiment the solvent is water,
ethanol, or a mixture of water and ethanol and/or propanol, the
base is sodium or potassium carbonate or absent, and the
temperature is room temperature to 80.degree. C.
[0216] In a particularly preferred embodiment, the solvent is
ethanol, no exogenous base is used, and the temperature is
0.degree. C. to room temperature.
[0217] A compound of formula (V) may also be obtained from a
compound of formula (II) by reaction of a compound of formula (IV)
in the presence of a trialkylphosphonium halide, such as
(cyanomethyl)trimethylphosphonium iodide and a base such as DIPEA
in a solvent such as propionitrile at 90.degree. C.
[0218] Compounds of formula (I) may be prepared according to the
processes outlined in Scheme 2. 11
[0219] A compound of formula (I) is prepared from a compound of
formula (VI) as shown in Scheme 2.
[0220] Group X.sup.2, such as group X.sup.2 in compound (VI),
denotes a suitable leaving group for a coupling reaction with an
alkyne, wherein "alkyne" in this definition refers to a chain,
whether substituted or unsubstituted, that has a triple
carbon-carbon bond. Examples of such leaving group include halo,
such as iodo, bromo, and chloro, and sulfonate, such as
trifluoromethanesulfonate. A compound of formula (VI) is reacted
with a compound of formula (II) under Sonogashira conditions in the
presence of a palladium-containing catalyst, such as palladium on
carbon, Pd(PPh.sub.3).sub.2Cl.sub.2, Pd.sub.2(dba).sub.3,
Pd.sub.2(dba).sub.3.CHCl.sub.3, Pd(P.sup.tBu.sub.3).sub.2,
Pd.sub.2(dba).sub.3.CHCl.sub.3/Pd(P.sup.tBu.sub.3).sub.2,
Pd(OAc).sub.2, Pd(PhCN).sub.2Cl.sub.2, and PdCl.sub.2, and a base,
such as triethylamine, DIEA, di-isopropylamine, sodium carbonate,
potassium carbonate, cesium carbonate, and mixtures thereof in a
solvent such as THF, DME, dioxane, DCE, DCM, toluene, acetonitrile,
and mixtures thereof at a temperature from 0.degree. C. to
100.degree. C.
[0221] A copper compound is used as a catalyst in this reaction,
such as Cu(I) compound. Such Cu(I) catalyst is preferably
incorporated in the reaction medium as substoichiometric quantities
of a copper salt, such as CuI or CuBrMe.sub.2S. The use of
phosphine ligands, such as PPh.sub.3 or P(.sup.tBu).sub.3, is part
fo the methodology of some embodiments of the present
invention.
[0222] As in other process steps in the context of embodiments of
this invention, the use of a high polarity solvent may increase the
rate and reduce by-product formation in these reactions. Such high
polarity solvent is provided in some embodiments as a mixture of a
first solvent with a cosolvent that increases the dielectric
constant of the mixture with respect to the dielectric constant of
such first solvent. For example, one of ordinary skill in the art
will recognize in light of this disclosure that the use of water as
such cosolvent may increase the rate and reduce by-product
formation in these reactions.
[0223] In a preferred embodiment, the palladium source is
Pd.sub.2(dba).sub.3.CHCl.sub.3/Pd(P.sup.tBu.sub.3).sub.2,
Pd(PPh.sub.3).sub.2Cl.sub.2, or palladium on carbon, the base is
triethylamine or potassium carbonate, the solvent is THF, or a
mixture of DME and water, and the temperature is between room
temperature and 80.degree. C. In a particularly preferred
embodiment, the palladium source is Pd(PPh.sub.3).sub.2Cl.sub.2,
the base is triethylamine, the solvent is THF, a catalytic quantity
of CuI or CuBrMe.sub.2S is used, and the reaction temperature is
room temperature to reflux temperature.
[0224] A compound of formula (I) is obtained from a compound of
formula (VII) in analogy with Scheme 1, steps A and B, or by
analogy with Scheme 1 step C. A compound of formula (I) may also be
obtained directly from a compound of formula (VI) by reaction with
a compound of formula (V) under Sonogashira conditions.
[0225] Compounds of formula (XII) may be prepared according to the
processes outlined in Scheme 3. 12
[0226] A compound of formula (XII) is prepared as outlined in
Scheme 3 from a compound of formula (IX). One skilled in the art
will be capable of selecting a suitable protecting group P.sup.1
for the compound of formula (IX). A compound of formula (IX) is
reacted with a compound of formula (X) under reductive amination
conditions in the presence of a reducing agent such as
NaBH(OAc).sub.3 in a solvent such as DCE, THF, and mixtures thereof
at a temperature from 0.degree. C. to 80.degree. C. Amine (X)
reacts in this reductive amination with aldehyde (IX) to form an
iminium ion. According to this disclosure, one skilled in the art
will recognize that the addition of an acid, such as acetic acid,
may accelerate this reaction and decrease byproduct formation. The
iminium ion thus formed is subsequently reduced by NaBH(OAc).sub.3
to the desired product. In a particularly preferred embodiment, a
compound of formula (IX) is reacted with a compound of formula (X)
in the presence of NaBH(OAc).sub.3 and acetic acid in DCE at room
temperature.
[0227] A compound of formula (XII) is obtained from a compound of
formula (XI) by removal of the protecting P.sup.1 under conditions
familiar to one skilled in the art. Selection and removal of
protecting group P.sup.1 is within the ordinary skill in the art in
light of, for example, reference material cited herein (for
example, works by Greene, et al., and McOmie), and description of
protecing groups provided herein.
[0228] Compounds of formula (XVI) may be prepared according to the
processes outlined in Scheme 4. 13
[0229] A compound of formula (XVI) is prepared as outlined in
Scheme 4 from a compound of formula (XIII). As noted above, one
skilled in the art will be capable of selecting a suitable
protecting group P.sup.2 for the compound of formula (XIII).
[0230] A compound of formula (XIII) is reacted with a compound of
formula (XIV), where X.sup.3 is a leaving group such a halogen or
an activated ester, in the presence of a base, such as sodium
hydride, potassium hydride, sodium hydroxide, potassium hydroxide,
DBU, triethylamine, and butyllithium in a solvent such as DMF, THF,
toluene, DMAC, acetonitrile, and mixtures thereof, at a temperature
from room temperature to 140.degree. C.
[0231] Alternatively, a compound of formula (XIII) is reacted with
a compound of formula (XIV), where X.sup.3 is hydroxyl and R.sup.22
is an aromatic group, under Mitsunobu conditions. A compound of
formula (XVI) is obtained from a compound of formula (XV) by
removal of the protecting P.sup.2 under conditions familiar to one
skilled in the art.
[0232] Compounds of formula (XXVI) may be prepared according to the
processes outlined in Scheme 5. 14
[0233] A compound of formula (XXVI) is prepared from a compound of
formula (XXIII) as outlined in Scheme 5. The group X.sup.2 in the
compound of formula (XXIII) denotes a leaving group, as defined in
Scheme 2.
[0234] A compound of formula (XXVIII) is obtained by reacting a
compound of formula (XXIII) with a compound of formula (II) under
Sonogashira conditions, as outlined in Scheme 2, step A. A compound
of formula (XXIX) is obtained by reacting a compound of formula
(XXVIII) with a compound of formula (XXIV) under reductive
amination conditions as outlined in Scheme 3, step A. One skilled
in the art will recognize that a substituted or unsubstituted
nonaromatic heterocycle containing secondary amine functionality,
for example piperidine derivatives, such as compounds (XII) and
(XVI), may be used in place of the compound of formula (XXIV).
[0235] A compound of formula (XXVI) is obtained by reacting a
compound of formula (XXIX) under the conditions described in Scheme
1, step C, or Scheme 1, steps A and B. Alternatively, compound of
formula (XXVI) is obtained by reacting a compound of formula (XXV)
with a compound of formula (V) under Sonogashira conditions, as
described in Scheme 2, step A. Compound of formula (XXV) is
obtained by reacting a compound of formula (XXIII) under reductive
amination conditions, as described in Scheme 3, step A.
Alternatively, compound of formula (XXVI) is obtained by reacting a
compound of formula (XXVII) with a compound of formula (XXIV) under
reductive amination conditions, as described in Scheme 3, step A.
Compound of formula (XXVII) is obtained by reacting a compound of
formula (XXIII) with a compound of formula (V) under Sonogashira
conditions, as described in Scheme 2, step A.
[0236] Substituent X.sup.2 and the aldehyde group are shown in a
p-arrangement with respect to each other in compound (XXIII). Other
schemes similar to Scheme 5 with substituent X.sup.2 and the
aldehyde group in arrangements o- and m- with respect to each other
are not shown explicitly in the form of additional schemes. It is
understood in light of the description provided herein that
embodiments of this invention include schemes in which compound
(XXIII) is analogous to that shown in Scheme 5 with substituent
X.sup.2 and the aldehyde group in o-arrangement with respect to
each other. Similarly, it is also understood that embodiments of
this invention include schemes in which compound (XXIII) is
analogous to that shown in Scheme 5 with substituent X.sup.2 and
the aldehyde group in m-arrangement with respect to each other.
Specific examples with such m-arrangement are provided herein
because of the different reactivity under m-substitution conditions
as compared with those under o- and p-substitution conditions.
[0237] Examples of additional embodiments of compound (XXIII) with
various types of subsitutional arrangements are illustrated by
suitably substituted formulae (XXIIIw), (XXIIIow), and (XXIIImw):
15
[0238] In addition to the methods of making the compounds of this
invention that are described herein as implemented in light of the
present disclosure and the ordinary skill in the art, embodiments
of methods of making compounds according to this invention include
the following.
[0239] Some embodiments include methods of making compounds of
formula (I), a pharmaceutically acceptable salt, ester, or amide
thereof, comprising at least one of the steps: reacting a compound
of formula (VI) with a compound of formula (V) 16
[0240] performing a nucleophilic substitution of X.sub.1 in
compound of formula (VIII) with an organic base R.sup.1R.sup.2NH,
wherein X.sup.2 is a suitable leaving group in a coupling reaction
with an alkyne, and X.sup.1 is a suitable leaving group in a
nucleophilic substitution with an amine. More specifically,
additional embodiments include those methods wherein
NR.sup.1R.sup.2 taken together form piperidinyl, methylpiperidinyl,
dimethylamino, pyrrolidinyl, diethylamino, methylethylamino,
ethylpropylamino, or dipropylamino, more specifically, wherein
NR.sup.1R.sup.2 taken together form piperidinyl, pyrrolidinyl, or
diethylamino, and still more specifically, wherein NR.sup.1R.sup.2
taken together form piperidinyl or pyrrolidinyl. Additional
embodiments include methods wherein one of R.sup.4 and R.sup.5 is
G, more specifically, wherein R.sup.4 is G, or wherein R.sup.5 is
G. Additional embodiments include methods wherein n is 1.
Additional embodiments include methods wherein Q is a saturated
N-linked nitrogen-containing heterocyclyl, more specifically,
wherein Q is selected from substituted or unsubstituted
piperidinyl, substituted or unsubstituted piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, and morpholinyl; or wherein
substituted Q is selected from N--(C.sub.1-6 alkyl) piperazinyl,
N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl, and
1,4-dioxa-8-aza-spiro[4.5]decyl; or wherein Q is a monovalent
radical of an amine selected from aziridine,
1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-sp- iro[4.5]decan-4-one,
piperidine-3-carboxylic acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl,
4-(3-trifluoromethyl-phenyl)-pip- erazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-yl-1,3-dihydro-benz- oimidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin--
2-yl-amine, phenylamine, pyridin-2-ylamine; or wherein Q is
selected from N-morpholinyl and N-piperidinyl, optionally
substituted with between 1 and 3 substituents selected from
hydroxyl, carboxamide, C.sub.1-6 alkyl, 5-9 membered heterocyclyl,
N(C.sub.1-6 alkyl)(5-9 membered heterocyclyl), NH(5-9 membered
heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3 alkylene,
C.sub.1-2-hydroxyalkylene, O(5-9 membered heterocyclyl), 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 halo, nitro, cyano, and C.sub.1-3 alkyl; or wherein Q is
substituted with a substituent comprising a C.sub.1-6 heterocyclyl
group selected from: pyridyl, pyrimidyl, furyl, thiofuryl,
imidazolyl, (imidazolyl)C.sub.1-6 alkylene, oxazolyl, thiazolyl,
2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,
(tetrazolyl)C.sub.1-6 alkylene, tetrazolyl, (triazolyl)C.sub.1-6
alkylene, triazolyl, (pyrrolyl)C.sub.1-6 alkylene, and pyrrolyl, or
more specifically wherein Q is a substituted or unsubstituted
N-morpholinyl. Further embodiments include methods wherein
[0241] n is 1;
[0242] R.sup.1 and R.sup.2 are independently selected from C.sub.2
alkyl, or taken together with the nitrogen to which they are
attached, they form a non-aromatic 5-6 membered heterocyclyl
optionally including an additional heteroatom independently
selected from O, S, and N;
[0243] one of R.sup.3, R.sup.4, and R.sup.5 is G and the two
remaining are H;
[0244] G is L.sup.2Q;
[0245] L.sup.2 is methylene;
[0246] Q is NR.sup.8R.sup.9 wherein R.sup.8 is independently
selected from hydrogen, C.sub.1-2 alkyl, C.sub.3 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.2 alkylene, and (phenyl) C.sub.2
alkylene; and R.sup.9 is independently selected from C.sub.1-2
alkyl, C.sub.3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.2 alkylene,
and (phenyl) C.sub.2 alkylene; or
[0247] Q is a saturated 3-13 membered N-linked heterocyclyl,
wherein, in addition to the N-linking nitrogen, the 3-13 membered
heterocyclyl may optionally contain between 1 and 3 additional
heteroatoms selected from O, S, and N;
[0248] wherein each of the above alkyl, alkylene, alkenyl,
alkenylene, heterocyclyl, and carbocyclyl groups may each be
independently and optionally substituted with between 1 and 3
substituents selected from methoxy, halo, amino, nitro, hydroxyl,
and C.sub.1-3 alkyl;
[0249] and wherein substituents of Q can be further selected from
tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl,
NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl,
C.sub.2-hydroxyalkylene, hydroxy, benzyl and, where each of above
heterocyclyl, phenyl, and alkyl substituent groups of Q may be
optionally substituted with trifluoromethyl.
[0250] Still other embodiments include methods wherein
NR.sup.1R.sup.2 taken together form piperidinyl, pyrrolidinyl, or
diethylamino, and Q is selected from substituted or unsubstituted
piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl; or wherein said organic base
R.sup.1R.sup.2NH is piperidine and said nucleophilic substitution
is performed at room temperature; or wherein said nucleophilic
substitution is performed at room temperature with 10 equivalents
of piperidine in the presence of ethanol; or wherein said
nucleophilic substitution is performed at room temperature with 10
equivalents of piperidine in the presence of ethanol and X.sup.1 is
mesylate, to yield a mixture of a substituted base and an
elimination product; with or without further comprising exposing
said mixture to HCl to yield a saline solution, selectively
precipitating and crystallizing form said saline solution a
phenylalkyne dihydrochloride salt; and a more particular embodiment
being wherein said phenylalkyne dihydrochloride salt is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]morpholine
dihydrochloride. Further embodiments include methods wherein any
one of the following is satisfied:
[0251] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, n is 1, and Q is selected from morpholinyl and
piperidinyl;
[0252] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, n is 1, and Q is morpholinyl or substituted
morpholinyl;
[0253] n=1, R.sup.3 is H, R.sup.5 is H, R.sup.4 is L.sup.2Q, with Q
being morpholinyl, L.sup.2 as defined above, and NR.sup.1R.sup.2
taken together form piperidinyl;
[0254] said organic base R.sup.1R.sup.2NH is piperidine;
[0255] said nucleophilic substitution is performed in the presence
of ethanol at room temperature;
[0256] said nucleophilic substitution is performed in the presence
of ethanol at room temperature and said organic base
R.sup.1R.sup.2NH is piperidine, including when the amount of said
piperidine is 10 equivalents;
[0257] n=1, R.sup.3is H, R.sup.5is H, R.sup.4is L.sup.2Q, with Q
being morpholinyl, L.sup.2 as defined above, said organic base
R.sup.1R.sup.2NH is piperidine, and said nucleophilic substitution
is performed in the presence of ethanol at room temperature;
[0258] said nucleophilic substitution yields a mixture of a
substitution product and an elimination product and is performed in
an alcoholic medium at a temperature such that said substitution
product is obtained in at least 80%;
[0259] said nucleophilic substitution yields a mixture of a
substitution product and an elimination product and is performed in
the presence of ethanol at room temperature, and said organic base
R.sup.1R.sup.2NH is piperidine, further comprising treating said
mixture with an acid to obtain a saline solution, and selectively
precipitating and crystallizing said saline solution to obtain a
salt, including any one of said acid being HCl, and diethyl ether
and ethanol being used in said crystallization, in which latter
case, a still more specific embodiment is characterized in that
n=1, R.sup.3is H, R.sup.5is H, R.sup.4 is L.sup.2Q, with Q being
morpholinyl, L.sup.2 as defined above, and NR.sup.1R.sup.2 taken
together form piperidinyl, said substitution product is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine and said salt
is the dihydrochloride salt of said substitution product. Other
embodiments of methods wherein said nucleophilic substitution is
performed in the presence of ethanol at room temperature and said
organic base is R.sup.1R.sup.2NH is piperidine, further comprise
converting an alcohol of formula (VII) to said compound of formula
(VIII), which more specifically can further comprise the reductive
amination of a compound of formula (VIIa) with an amine
R.sup.8R.sup.9NH, wherein one of R.sup.3', R.sup.4', and R.sup.5'
is C(O)H and the other two are selected from H, chloro and bromo,
to give a compound of formula (VII), wherein one of R.sup.3,
R.sup.4, and R.sup.5 is NR.sup.8R.sup.9 and the other two are
selected from H, chloro and bromo, 17
[0260] and even more specifically methods wherein any one of the
following is satisfied: said amine is morpholine; and further
comprising the coupling in the presence of a palladium-containing
catalyst and a copper salt of a compound of formula (II) with a
disubstituted benzene, wherein one of said benzene substitutents is
C(O)H and the other of said benzene substitutents is selected from
chloro and bromo, to yield a compound of formula (VIIa).
[0261] Some embodiments include methods of making compounds of
formula (I), a pharmaceutically acceptable salt, ester, or amide
thereof, wherein more specifically one of R.sup.3 and R.sup.5 is G,
one of the remaining and R.sup.4 is H, and the other is selected
from hydrogen, fluoro, and chloro, these embodiments comprising
reacting at least one of the compounds of formulae (XXIIIw) and
(XXIIIow) with a compound of formula (V) 18
[0262] wherein W is C(O)H or G, and X.sup.2 is a suitable leaving
group in a coupling reaction with an alkyne. More specifically,
additional embodiments include methods wherein any one of the
following is additionally satisfied:
[0263] said W is C(O)H, further comprising performing a reductive
amination of said W with an organic base R.sup.9R.sup.8NH;
NR.sup.1R.sup.2 taken together form piperidinyl, methylpiperidinyl,
dimethylamino, pyrrolidinyl, diethylamino, methylethylamino,
ethylpropylamino, or dipropylamino, including the more specific
conditions wherein NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino, or wherein NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl;
[0264] R.sup.5 is G;
[0265] R.sup.3 is G;
[0266] n is 1;
[0267] Q is a saturated N-linked nitrogen-containing
heterocyclyl;
[0268] Q is selected from substituted or unsubstituted piperidinyl,
substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl, including more specific
characteristics such as any of wherein substituted Q is selected
from N-(C.sub.1-6 alkyl) piperazinyl, N-phenyl-piperazinyl,
1,3,8-triaza-spiro[4.5]decyl, and 1,4-dioxa-8-aza-spiro[4.5]decyl,
and wherein Q is a monovalent radical of an amine selected from
aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one,
piperidine-3-carboxylic acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']bi- pyridinyl,
4-(3-trifluoromethyl-phenyl)-piperazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-yl-1,3-dihydro-benz- oimidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin--
2-yl-amine, phenylamine, pyridin-2-ylamine; Q is selected from
N-morpholinyl and N-piperidinyl, optionally substituted with
between 1 and 3 substituents selected from hydroxyl, carboxamide,
C.sub.1-6 alkyl, 5-9 membered heterocyclyl, N(C.sub.1-6 alkyl)(5-9
membered heterocyclyl), NH(5-9 membered heterocyclyl), (5-9
membered heterocyclyl)C.sub.1-3 alkylene,
C.sub.1-2-hydroxyalkylene, O(5-9 membered heterocyclyl), C.sub.1-3
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 halo, nitro, cyano, and C.sub.1-3 alkyl;
[0269] Q is substituted with a substituent comprising a C.sub.1-6
heterocyclyl group selected from: pyridyl, pyrimidyl, furyl,
thiofuryl, imidazolyl, (imidazolyl)C.sub.1-6 alkylene, oxazolyl,
thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,
2-oxobenzimidazolyl, (tetrazolyl)C.sub.1-6 alkylene, tetrazolyl,
(triazolyl)C.sub.1-6 alkylene, triazolyl, (pyrrolyl)C.sub.1-6
alkylene, and pyrrolyl;
[0270] Q is a substituted or unsubstituted N-morpholinyl;
[0271] NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino, and Q is selected from substituted
or unsubstituted piperidinyl, piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, and morpholinyl;
[0272] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, n is 1, and Q is selected from morpholinyl and
piperidinyl;
[0273] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, n is 1, and Q is morpholinyl or substituted
morpholinyl;
[0274] n is 1, R.sup.4 is H, one of R.sup.3 and R.sup.5 is H, the
other one of R.sup.3 and R.sup.5 is L.sup.2Q, with Q being
morpholinyl, and L.sup.2 as defined above, and NR.sup.1R.sup.2
taken together form piperidinyl;
[0275] n is 1, R.sup.4 is H, R.sup.3 is H, R.sup.5is C(O)H,
NR.sup.1R.sup.2 taken together form a piperidinyl, wherein said
reacting is performed at room temperature;
[0276] n is 1, R.sup.4 is H, R.sup.3 is H, R.sup.5is C(O)H,
NR.sup.1R.sup.2 taken together form a piperidinyl, wherein said
reacting is performed at room temperature in the presence of a
plaadadium-containing catalyst and a copper salt, and said reacting
yields a phenylalkyne;
[0277] n is 1, R.sup.4 is H, R.sup.3 is H, R.sup.5is C(O)H,
NR.sup.1R.sup.2 taken together form a piperidinyl, X.sup.2 is
bromo, wherein said reacting is performed at room temperature in
the presence of a palladium-containing catalyst and a copper salt,
and said reacting yields a phenylalkyne; and
[0278] n is 1, R.sup.4 is H, R.sup.3 is H, R.sup.5is C(O)H,
NR.sup.1R.sup.2 taken together form a piperidinyl, wherein said
reacting is performed at room temperature in the presence of a
plaadadium-containing catalyst and a copper salt, and said reacting
yields a phenylalkyne, further comprising a reductive amination
with R.sup.8R.sup.9NH of said phenylalkyne to yield a base, with
still more specific embodiments satisfying at least one of
[0279] said R.sup.8R.sup.9NH is morpholine and said base is
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine; and
[0280] further comprising forming a saline solution with HCl, with
even more specific embodiments further comprsing obtaining a
dihydrochloride salt of said base by crystallization, and still
more specific embodiments satisfying that said base is
4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-m- orpholine.
[0281] Still additional embodiments include methods wherein n is
1;
[0282] R.sup.1 and R.sup.2 are independently selected from C.sub.2
alkyl, or taken together with the nitrogen to which they are
attached, they form a non-aromatic 5-6 membered heterocyclyl
optionally including an additional heteroatom independently
selected from O, S, and N;
[0283] one of R.sup.3 and R.sup.5 is G, and the remaining and
R.sup.4 are H;
[0284] G is L.sup.2Q;
[0285] L.sup.2 is methylene;
[0286] Q is NR.sup.8R.sup.9 wherein R.sup.8 is independently
selected from hydrogen, C.sub.1-2 alkyl, C.sub.3 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.2 alkylene, and (phenyl) C.sub.2
alkylene; and R.sup.9 is independently selected from C.sub.1-2
alkyl, C.sub.3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.2 alkylene,
and (phenyl) C.sub.2 alkylene; or
[0287] Q is a saturated 3-13 membered N-linked heterocyclyl,
wherein, in addition to the N-linking nitrogen, the 3-13 membered
heterocyclyl may optionally contain between 1 and 3 additional
heteroatoms selected from O, S, and N;
[0288] wherein each of the above alkyl, alkylene, alkenyl,
alkenylene, heterocyclyl, and carbocyclyl groups may each be
independently and optionally substituted with between 1 and 3
substituents selected from methoxy, halo, amino, nitro, hydroxyl,
and C.sub.1-3 alkyl;
[0289] and wherein substituents of Q can be further selected from
tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl,
NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl,
C.sub.2-hydroxyalkylene, hydroxy, benzyl and, where each of above
heterocyclyl, phenyl, and alkyl substituent groups of Q may be
optionally substituted with trifluoromethyl.
[0290] Some embodiments include methods of making compounds of
formula (I), a pharmaceutically acceptable salt, ester, or amide
thereof, comprising reacting a compound of formula (VII) 19
[0291] with an organic base R.sup.1R.sup.2NH in the presence of a
trialkylphosphonium halide and a base. More specifically,
additional embodiments include methods wherein any one of the
following is satisfied:
[0292] said trialkylphosphonium halide is
(cyanomethyl)trimethylphosphoniu- m iodide, and said base is
DIPEA;
[0293] NR.sup.1R.sup.2 taken together form piperidinyl,
methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino,
methylethylamino, ethylpropylamino, or dipropylamino;
[0294] NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino;
[0295] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl;
[0296] one of R.sup.4 and R.sup.5 is G;
[0297] R.sup.4 is G;
[0298] R.sup.5 is G;
[0299] n is 1;
[0300] Q is a saturated N-linked nitrogen-containing
heterocyclyl;
[0301] Q is selected from substituted or unsubstituted piperidinyl,
substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl;
[0302] NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino, and Q is selected from substituted
or unsubstituted piperidinyl, piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, and morpholinyl;
[0303] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, n is 1, and Q is selected from morpholinyl and
piperidinyl;
[0304] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl, n is 1, and Q is morpholinyl or substituted
morpholinyl; and
[0305] n=1, R.sup.3 is H, R.sup.5 is H, R.sup.4 is L.sup.2Q, with Q
being morpholinyl, L.sup.2 as defined above, and NR.sup.1R.sup.2
taken together form piperidinyl.
[0306] Some embodiments include methods of making compounds of
formula (I), a pharmaceutically acceptable salt, ester, or amide
thereof, wherein more specifically R.sup.4 is G, one of the
remaining R.sup.3 and R.sup.5 is hydrogen, and the other is
selected from hydrogen, fluoro, and chloro, these embodiments
comprising reacting a compound of formula (XXIIImw) with a compound
of formula (V). 20
[0307] wherein W is C(O)H or G, and X.sup.2 is a suitable leaving
group in a coupling reaction with an alkyne. More specifically,
additional embodiments include methods wherein any one of the
following is satisfied:
[0308] said W is C(O)H, further comprising performing a reductive
amination of said W with an organic base R.sup.9R.sup.8NH;
[0309] NR.sup.1R.sup.2 taken together form piperidinyl,
methylpiperidinyl, dimethylamino, pyrrolidinyl, diethylamino,
methylethylamino, ethylpropylamino, or dipropyl amino;
[0310] NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino;
[0311] NR.sup.1R.sup.2 taken together form piperidinyl or
pyrrolidinyl;
[0312] n is 1;
[0313] Q is a saturated N-linked nitrogen-containing
heterocyclyl;
[0314] Q is selected from substituted or unsubstituted piperidinyl,
substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,
thiomorpholinyl, and morpholinyl;
[0315] substituted Q is selected from N--(C.sub.1-6 alkyl)
piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro[4.5]decyl,
and 1,4-dioxa-8-aza-spiro[4.5]decyl;
[0316] Q is a monovalent radical of an amine selected from
aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,
1-phenyl-1,3,8-triaza-sp- iro[4.5]decan-4-one,
piperidine-3-carboxylic acid diethylamide,
1,2,3,4,5,6-hexahydro-[2,3']bipyridinyl,
4-(3-trifluoromethyl-phenyl)-pip- erazine,
2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide,
methyl-(2-pyridin-2-yl-ethyl)-amine,
[2-(3,4-dimethoxy-phenyl)-ethyl]-met- hyl-amine, thiomorpholinyl,
allyl-cyclopentyl-amine, [2-(1H-indol-3-yl)-ethyl]-methyl-amine,
1-piperidin-4-yl-1,3-dihydro-benz- oimidazol-2-one,
2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin--
2-yl-amine, phenylamine, pyridin-2-ylamine;
[0317] Q is selected from N-morpholinyl and N-piperidinyl,
optionally substituted with between 1 and 3 substituents selected
from hydroxyl, carboxamide, C.sub.1-6 alkyl, 5-9 membered
heterocyclyl, N(C.sub.1-6 alkyl)(5-9 membered heterocyclyl), NH(5-9
membered heterocyclyl), (5-9 membered heterocyclyl)C.sub.1-3
alkylene, C.sub.1-2-hydroxyalkylene, O(5-9 membered heterocyclyl),
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 halo, nitro, cyano, and C.sub.1-3 alkyl;
[0318] Q is substituted with a substituent comprising a C.sub.1-6
heterocyclyl group selected from: pyridyl, pyrimidyl, furyl,
thiofuryl, imidazolyl, (imidazolyl)C.sub.1-6 alkylene, oxazolyl,
thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,
2-oxobenzimidazolyl, (tetrazolyl)C.sub.1-6 alkylene, tetrazolyl,
(triazolyl)C.sub.1-6 alkylene, triazolyl, (pyrrolyl)C.sub.1-6
alkylene, and pyrrolyl;
[0319] Q is a substituted or unsubstituted N-morpholinyl;
[0320] NR.sup.1R.sup.2 taken together form piperidinyl,
pyrrolidinyl, or diethylamino, and Q is selected from substituted
or unsubstituted piperidinyl, piperazinyl, pyrrolinyl,
pyrrolidinyl, thiomorpholinyl, and morpholinyl; and
[0321] n is 1, R.sup.5 is H, R.sup.3 is H, and R.sup.4 is L.sup.2Q,
with 0 being morpholinyl, and L.sup.2 as defined above, and
NR.sup.1R.sup.2 taken together form piperidinyl.
[0322] Further embodiments include methods that satisfy:
[0323] n is 1;
[0324] R.sup.1 and R.sup.2 are independently selected from C.sub.2
alkyl, or taken together with the nitrogen to which they are
attached, they form a non-aromatic 5-6 membered heterocyclyl
optionally including an additional heteroatom independently
selected from O, S, and N;
[0325] R.sup.3 and R.sup.5 are H;
[0326] G is L.sup.2Q;
[0327] L.sup.2 is methylene;
[0328] Q is NR.sup.8R.sup.9 wherein R.sup.8 is independently
selected from hydrogen, C.sub.1-2 alkyl, C.sub.3 alkenyl, 6-9
membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,
(5-9-membered heterocyclyl)C.sub.2 alkylene, and (phenyl) C.sub.2
alkylene; and R.sup.9 is independently selected from C.sub.1-2
alkyl, C.sub.3 alkenyl, 6-9 membered carbocyclyl, 3-12 membered
heterocyclyl, phenyl, (5-9-membered heterocyclyl)C.sub.2 alkylene,
and (phenyl) C.sub.2 alkylene; or
[0329] Q is a saturated 3-13 membered N-linked heterocyclyl,
wherein, in addition to the N-linking nitrogen, the 3-13 membered
heterocyclyl may optionally contain between 1 and 3 additional
heteroatoms selected from O, S, and N;
[0330] wherein each of the above alkyl, alkylene, alkenyl,
alkenylene, heterocyclyl, and carbocyclyl groups may each be
independently and optionally substituted with between 1 and 3
substituents selected from methoxy, halo, amino, nitro, hydroxyl,
and C.sub.1-3 alkyl;
[0331] and wherein substituents of Q can be further selected from
tert-butyloxycarbonyl, carboxamide, 5-9-membered heterocyclyl,
NH(6-membered heterocyclyl), O(6-membered heterocyclyl), phenyl,
C.sub.2-hydroxyalkylene, hydroxy, benzyl and, where each of above
heterocyclyl, phenyl, and alkyl substituent groups of Q may be
optionally substituted with trifluoromethyl.
[0332] Still additional embodiments satisfy NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
selected from morpholinyl and piperidinyl, of which some
embodiments more specifically satisfy NR.sup.1R.sup.2 taken
together form piperidinyl or pyrrolidinyl, n is 1, and Q is
morpholinyl or substituted morpholinyl. Still additional
embodiments satisfy n is 1, R.sup.3 is H, R.sup.5 is H, W is C(O)H,
and X.sup.2 is choloro or bromo, and compound of formula (V) is
1-but-3-ynyl-piperidine, to form a phenylalkyne, of which some
embodiments more specifically satisfy at least one of:
[0333] said reacting is performed in the presence of pyrrolidine
and at a temperature of about 50.degree. C. to form a
phenylalkayne, with still some embodiments further satisfying
wherein said reacting is performed in the presence of a
palladium-containing catalyst and a copper salt;
[0334] X.sup.2 is bromo, and said reacting is performed under
conditions such that the yield of said phenylalkyne is at least
80%;
[0335] further comprising a reductive amination with
R.sup.8R.sup.9NH of said phenylalkyne to yield a base, with some
more specific embodiments additionally satisfying at least one
of:
[0336] wherein said R.sup.8R.sup.9NH is morpholine and said base is
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine, and
[0337] further comprising forming a saline solution with HCl, of
which embodiments some also further comprise obtaining a
dihydrochloride salt of said base by crystallization, and some even
more specifically satisfy said base being
4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine.
[0338] Disclosed herein are linear synthetic paths such as those
illustrated by embodiments of steps B, C, and D in Scheme 2, and by
embodiments of steps B and E in Scheme 2. Additional illustrations
of linear processes are provided by embodiments of steps C, D, and
E in Scheme 5, and the combination of steps C and D in Scheme 5 and
steps C and D in Scheme 2.
[0339] Disclosed herein are convergent synthetic paths such as
those illustrated by embodiments of step A in Scheme 2. Additional
illustrations of convergent processes are provided by embodiments
of steps A and B in Scheme 5, and also by embodiments of steps F
and G in Scheme 5.
[0340] Embodiments of processes according to this invention are
particularly suited for the scale-up synthesis of compounds
described herein and compounds related thereto that can be obtained
on the basis of the teachings provided herein and the ordinary
skill in the art. These related compounds include pharmaceutically
acceptable salts, esters, and amides of compounds according to the
present invention.
[0341] Conventional methodologies for nucleophilic substitutions
yield unpractical low yields of the substitution product of
interest, with yields of such product of about 50%, the remaining
by-product being mainly a corresponding elimination product. An
example of a substitution product of interest is the title compound
in Example 16. An example of an elimination by-product is the
following compound: 21
[0342] This elimination byproduct can be generated according to
conventional methodology with a yield of as much as 50%. The
following references provide background material on related
conventional methodologies: Abdel-Magid, A. F., et al., J. Org.
Chem. 1996, 61:3849-3862; Furst, A., Helvetica Chemica Acta 1947,
30:1454; and Kawai, S. H., et al., J. Org. Chem. 1994,
59:2620-2622. In contrast, methods according to the present
invention permit the reduction in the formation of such elimination
byproduct, so that its yield does not exceed 20%, and it was in
some embodiments as low as 15%.
[0343] Relevant conventional methodologies that use
palladium-containing catalysts and/or copper salts typically employ
palladium-containing catalyst in amounts that range from about 1%
to about 5% (both percentages given in terms of molar ratios). The
following reference provides background material on related
conventional methodologies: Sonogashera, K., et al., Tetrahedron
Letters 1975, 50:4467-4470. In contrast, methods according to the
present invention permit the reduction in the amount of palladium
catalyst, so that its effective use was in some embodiments as low
as 0.1% (also molar). This reduction in the amount of catalyst
leads to a reduction in the production cost, an important
consideration in scale-up processes. Furthermore, the less catalyst
is used, the less likely it is that catalyst contamination will
significantly propagate along the synthetic process. Purification
along the process and/or purification of the final product is/are
necessary when this contamination is significant.
[0344] Relevant conventional methodologies rely on chromatographic
purification of the final product. In contrast, the methods
according to the present invention, whether implemented in the form
of linear or convergent embodiments, permit the purification of the
final product by selective precipitation and/or crystallization.
These techniques led to the obtention of final products with purity
ranging from 95% to 99%, and they are much more suitable for
scale-up synthetic processes than chromatographic purification. In
light of the ordinary knowledge in crystallography, and in the
absence of the disclosure provided herein, the crystallographic
behavior of embodiments of compounds of the present invention is
deemed unpredictable. As described herein, it has been found in the
context of the present invention, that compounds of the present
invention can be crystallized and that this technique can be
implemented in their synthesis and purification.
[0345] Embodiments of convergent processes according to the present
invention remove the production of elimination byproduct. High
yields of final product were obtained in just a reduced number of
synthetic steps. Embodiments of the present invention are
illustrated by convergent methods that have at most three linear
steps. Such reduction in the number of synthetic steps leads to an
increase in efficiency.
[0346] Conventional methodologies that rely on Sonogashira coupling
reaction procedures involving acetylenic amines generally give
modest yields that are about 50%. Acetylenic compound dimerization
leads to byproducts that contribute to such low yield in
conventional practice. The following references provide background
material on related conventional methodologies: Kano, H., et al.,
J. Med. Chem. 1967, 10(3):411-418; Vaillancourt, V. A., et al., WO
0202558 A1; Guzikowski, A. P., et al., J. Med. Chem. 2000,
43:984-994; Wright, J. L., et al., J. Med. Chem. 2000,
43:3408-3419. In contrast, methods according to the present
invention increased such reactions yields to at least 80%, with
actual yields ranging from about 86% (m-, or meta, substitution, in
contrast with conventional yields of 25%-30% for the same
substitution) to about 92% (o-, or orto, and p-, or para,
substitution). The use of a strong base, such as pyrrolidine and
temperature conditions, such as those described herein, facilitated
high yields in the context of the present methods. Preferred
temperature conditions include about room temperature (RT) when
there is o- or p-substitution, and about 50.degree. C. when there
is m-substitution.
[0347] D. Formulation, Administration, and Therapy
[0348] The disclosed compounds, alone or in combination (with, for
example, a histamine H.sub.1 receptor antagonist), are useful for
treating or preventing neurologic disorders including sleep/wake
and arousal/vigilance disorders (e.g. insomnia and jet lag),
attention deficit hyperactivity disorders (ADHD), learning and
memory disorders, cognitive dysfunction, migraine, neurogenic
inflammation, dementia, mild cognitive impairment (pre-dementia),
Alzheimer's disease, epilepsy, narcolepsy, eating disorders,
obesity, motion sickness, vertigo, schizophrenia, substance abuse,
bipolar disorders, manic disorders and depression, as well as other
histamine H.sub.3 receptor mediated disorders such as upper airway
allergic response, asthma, itch, nasal congestion and allergic
rhinitis in a subject in need thereof.
[0349] 1. Formulation and Administration
[0350] The compounds or compositions of the invention may be
formulated and administered to a subject by any conventional route
of administration, including, but not limited to, intravenous,
oral, subcutaneous, intramuscular, intradermal and parenteral
administration. The quantity of the compound which is effective for
treating each condition may vary, and can be determined by one of
ordinary skill in the art.
[0351] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and salts formed with suitable organic ligands, e.g.,
quaternary ammonium salts.
[0352] Thus, representative pharmaceutically acceptable salts
include the following:
[0353] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0354] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
In addition to salts, the invention provides the esters, amides,
and other protected or derivatized forms of the described
compounds.
[0355] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0356] The present invention also provides pharmaceutical
compositions comprising one or more compounds of this invention in
association with a pharmaceutically acceptable carrier and
optionally additional pharmaceutical agents such as H.sub.1
antagonists or SSRIs. Preferably these compositions are in unit
dosage forms such as pills, tablets, caplets, capsules (each
including immediate release, timed release and sustained release
formulations), powders, granules, sterile parenteral solutions or
suspensions (including syrups and emulsions), metered aerosol or
liquid sprays, drops, ampoules, autoinjector devices or
suppositories; for oral parenteral, intranasal, sublingual or
rectal administration, or for administration by inhalation or
insufflation. Alternatively, the composition may be presented in a
form suitable for once-weekly or once-monthly administration; for
example, an insoluble salt of the active compound, such as the
decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. For preparing solid compositions such as
tablets, the principal active ingredient is mixed with a
pharmaceutical carrier, e.g. conventional tableting ingredients
such as corn starch, lactose, sucrose, sorbitol, talc, stearic
acid, magnesium stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a homogeneous mixture of a compound of the
present invention, or a pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous,
it is meant that the active ingredient is dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective dosage forms such as tablets,
pills and capsules. This solid preformulation composition is then
subdivided into unit dosage forms of the type described above
containing from 5 to about 1000 mg of the active ingredient of the
present invention. Examples include 5 mg, 7 mg, 10 mg, 15 mg, 20
mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg, and so on. The
tablets or pills of the disclosed compositions can be coated or
otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be septed by an enteric layer which serves to resist
disintegration in the stomach and permits the inner component to
pass intact into the duodenum or to be delayed in release. A
variety of material can be used for such enteric layers or
coatings, such materials including a number of polymeric acids with
such materials as shellac, cetyl alcohol and cellulose acetate.
[0357] The liquid forms in which the compounds and compositions of
the present invention may be incorporated for administration orally
or by injection include, aqueous solutions, suitably flavoured
syrups, aqueous or oil suspensions, and flavoured emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Suitable dispersing or suspending agents for aqueous suspensions,
include synthetic and natural gums such as tragacanth, acacia,
alginate, dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0358] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0359] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0360] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders, lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0361] The compound of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phophatidylcholines.
[0362] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamidephenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residue. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyepsilon caprolactone, polyhydroxy
butyric acid, polyoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels.
[0363] Compounds of this invention may be administered in any of
the foregoing compositions and according to dosage regimens
established in the art whenever treatment of ADHD is required.
[0364] The daily dosage of the products may be varied over a wide
range from 1 to 1,000 mg per adult human per day. For oral
administration, the compositions 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 ordinarily supplied at a dosage level of from
about 0.01 mg/kg to about 20 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.
[0365] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode 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, will result in the need to adjust
dosages.
[0366] 2. Combination Therapy
[0367] The disclosed compounds are useful in combination with other
therapeutic agents, including H.sub.1 receptor antagonists, H.sub.2
receptor antagonists, and neurotransmitter modulators such as SSRIs
and non-selective serotonin re-uptake inhibitors (NSSRIs).
[0368] Methods are known in the art for determining effective doses
for therapeutic and prophylactic purposes for the disclosed
pharmaceutical compositions or the disclosed drug combinations,
whether or not formulated in the same composition. For therapeutic
purposes, the term "jointly effective amount" as used herein, means
that amount of each active compound or pharmaceutical agent, alone
or in combination, that elicits the biological or medicinal
response in a tissue system, animal or human that is being sought
by a researcher, veterinarian, medical doctor or other clinician,
which includes alleviation of the symptoms of the disease or
disorder being treated. For prophylactic purposes (i.e., inhibiting
the onset or progression of a disorder), the term "jointly
effective amount" refers to that amount of each active compound or
pharmaceutical agent, alone or in combination, that inhibits in a
subject the onset or progression of a disorder as being sought by a
researcher, veterinarian, medical doctor or other clinician, the
delaying of which disorder is mediated, at least in part, by the
modulation of one or more histamine receptors. Thus, the present
invention provides combinations of two or more drugs wherein, for
example, (a) each drug is administered in an independently
therapeutically or prophylactically effective amount; (b) at least
one drug in the combination is administered in an amount that is
sub-therapeutic or sub-prophylactic if administered alone, but is
therapeutic or prophylactic when administered in combination with
the second or additional drugs according to the invention; or (c)
both drugs are administered in an amount that is sub-therapeutic or
sub-prophylactic if administered alone, but are therapeutic or
prophylactic when administered together. Combinations of three or
more drugs are analogously possible. Methods of combination therapy
include co-administration of a single formulation containing all
active agents; essentially contemporaneous administration of more
than one formulation; and administration of two or more active
agents separately formulated.
[0369] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that, whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
approximations due to the experimental and/or measurement
conditions for such given value. Whenever a yield is given as a
percentage, such yield refers to a mass of the entity for which the
yield is given with respect to the mamaximum amount of the same
entity that could be obtained under the particular stoichiometric
conditions.
[0370] E. Examples
EXAMPLE 1
[0371] 22
[0372] 1-(4-Bromo-benzyl)-piperidine
[0373] A solution of 4-bromobenzaldehyde (5 g), piperidine (2.9
mL), and acetic acid (1.5 mL) in DCE (65 mL) was treated with
sodium triacetoxyborohydride (6.9 g). After 27 h, the resulting
mixture was treated with saturated aqueous sodium bicarbonate (50
mL), and extracted with DCM (2.times.50 mL). The combined organic
phases were dried (magnesium sulfate) and evaporated. Kugelrohr
distillation of the residue (160.degree. C., 5 mm Hg) gave the
title compound as a pale yellow oil (5.9 g).
EXAMPLE 2
[0374] 23
[0375] 1-But-3-ynyl-piperidine
[0376] A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0
g) and piperidine (40 mL) in ethanol (70 mL) was treated with a
solution of potassium carbonate (27.8 g) in water (70 mL). The
mixture was heated to 80.degree. C. for 2 h, cooled to RT, and
extracted with DCM (3.times.100 mL). The combined organic phases
were dried (magnesium sulfate), and evaporated. Distillation of the
residue (110.degree. C., 30 mm Hg) gave the title compound as a
colorless oil (17.3 g).
EXAMPLE 3
[0377] 24
[0378] 4-But-3-ynyl-morpholine
[0379] May be prepared analogously to Example 2 using
morpholine.
EXAMPLE 4
[0380] 25
[0381] 4-But-3-ynyl-thiomorpholine
[0382] May be prepared analogously to Example 2 using
thiomorpholine.
EXAMPLE 5
[0383] 26
[0384] 3-(4-Hydroxy-but-1-ynyl)-benzaldehyde
[0385] This is an example of a coupling reaction to form compounds
such as the title compound by coupling compounds such as bromo
benzaldehyde and 3-butyn-1-ol. A 1-L, 3-necked round-bottom flask
was equipped with a magnetic stirring bar, a condenser with a
nitrogen inlet, and two stoppers. The vessel was charged with
3-bromobenzaldehyde (18.5 g, 0.1 mol), 3-butyn-1-ol (10.5 g, 0.15
mol), triethylamine (100 mL), and THF (100 mL). To this mixture was
then added PdCl.sub.2 (PPh.sub.3).sub.2 (1.4 g, 2 mmol) and
CuBrMe.sub.2S (0.405 g, 4 mmol). In other examples, the title
compound was also obtained by using CuI together with a
palladium-containing entity. The reaction mixture was heated to
reflux using a heating mantle. After 4 h when TLC (thin layer
chromatography) showed complete consumption of the bromide, the
mixture was allowed to cool to room temperature, transferred to a
1-L round-bottom flask and concentrated under reduced pressure. The
residue was dissolved in 250 mL of ethyl acetate. The solution was
washed with water and brine, dried over MgSO.sub.4, and filtered.
After filtration, the solvents were removed from the filtrate by
evaporation under reduced pressure to obtain the title compound as
pale yellow oil (16.8 g, yield 97%). Purity of the compound so
obtained was determined by HPLC to be greater than 95%. TLC
(R.sub.f=0.32, SiO.sub.2, ethyl acetate/hexanes, 1:1). MS (electro
spray, positive mode), M.sup.+174. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 2.72 (t, 2 H, J=6.3), 3.84 (t, 2 H, J=6.2),
7.47 (t, 1 H, J=7.7), 7.66 (dt, 1 H, J=7.7, 1.4), 7.81 (dt, 1 H,
J=7.7, 1.4), 7.91 (t, 1 H, J=1.4), 9.98 (s, 1 H). It was found in
the context of this invention, as illustrated by the embodiment
given in this example, that the amount of palladium catalyst can be
reduced down to catalyst amounts in the order of 0.1% (mol/mol). In
contrast, conventional methodologies rely on Pd catalyst amounts in
the range 1%-5%, with the percentages referred to the same units.
This reduction in the amount of palladium catalyst leads to a
significant cost reduction. Furthermore, this reduction in the
amount of palladium catalyst leads to a reduction in the palladium
contamination of the final product.
EXAMPLE 6
[0386] 27
[0387] 4-(3-Morpholin-4-ylmethyl-phenyl)-but-3-yn-1-ol
[0388] This is an example of a reductive amination to form
compounds such as the title compound by reacting compounds such as
an aldehyde and morpholine. A 1-L, 3-necked round-bottom flask was
equipped with a mechanical stirrer, a rubber septum with a nitrogen
inlet and a stopper. The flask was charged with the product of
Example 5 (14.6 g, 0.0838 mol) and dichloromethane (250 mL).
Morpholine (8.85 mL, 0.1 mol) was added, and then to this
well-stirred reaction mixture was added sodium
triacetoxyborohydride (32 g, 0.15 mol) in 4 equal portions. After
the addition, the reaction mixture was stirred at room temperature
overnight. Aqueous NaOH (10% w/v, 75 mL) was added, and the
reaction mixture was transferred to a 1-L separatory funnel, to
which water (100 mL) was then added. After separation of the
layers, the aqueous phase was extracted once with dichloromethane
(100 mL). The combined organic extracts were washed with brine (30
mL), dried over MgSO.sub.4, and filtered. After filtration, the
solvents were removed from the filtrate by evaporation under
reduced pressure to yield the product as yellow oil (19 g with a
90% yield). Purity at this stage did not exceed 90% as determined
by HPLC. The crude product was purified by filtration through a pad
of silica gel (ethyl acetate/hexanes; 7:3) to obtain the title
compound as a pale yellow oil (13.7 g). Purity of the product so
obtained was greater than 98% as determined by HPLC (a degree of
purity that is often referred to as "pure"). TLC (R.sub.f=0.22,
SiO.sub.2, ethyl acetate/hexanes, 3:1). MS (electro spray, positive
mode), (M.sup.++H) 246. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
2.43 (bt, 2 H, J=4.4), 2.70 (t, 2 H, J=6.2), 3.46 (s, 2 H), 3.71
(t, 4 H, J=4.6), 3.82 (t, 2 H, J=6.2), 7.24-7.39 (m, 4 H).
EXAMPLE 7
[0389] 28
[0390] Methanesulfonic acid
4-(3-morpholin-4-ylmethyl-phenyl)-but-3-ynyl ester
[0391] This is an example of the conversion of compounds such as
that illustrated in Example 6 to their methanesulfonate esters, as
illustrated by the title compound. A 500-mL 1-necked round-bottom
flask was equipped with a magnetic stirring bar and rubber septum
with a nitrogen inlet. The vessel was charged with the product of
Example 6 (13.6 g, 0.055 mol), dichloromethane (100 mL) and
triethylamine (8.43 mL, 0.060 mol). The reaction mixture was cooled
to 0.degree. C. in an ice bath, and a solution of methanesulfonyl
chloride (6.93 g) in dichloromethane (10 mL) was added in drops
over 30 min. The cooling was removed and the reaction mixture was
allowed to warm up to room temperature. After 1 h when TLC
indicated complete conversion, 50 mL ice water was added, and the
reaction mixture was transferred to a 500-mL separatory funnel. The
organic extract was separated and washed with aqueous NaHCO.sub.3,
brine, and dried over MgSO.sub.4. After filtration, the solvents
were evaporated under reduced pressure (rotary evaporator,
30.degree. C.) to obtain the title compound as pale yellow gum
(17.5 g; yield 98%). Purity of the product so obtained was greater
than 95% as determined by HPLC. TLC (R.sub.f=0.27, SiO.sub.2, ethyl
acetate/hexanes, 3:1), MS (electro spray, positive mode),
M.sup.+323. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 2.3 (bt, 2
H, J=4.4), 2.62 (t, 2 H, J=6.2), 3.38 (s, 2 H), 3.63 (t, 4 H,
J=4.6), 3.75 (t, 2 H, J=6.2), 7.12-7.32 (m, 4 H).
EXAMPLE 8
[0392] 29
[0393] Toluene-4-sulfonic acid 4-(4-formyl-phenyl)-but-3-ynyl
ester
[0394] A mixture of 4-bromobenzaldehyde (25.0 g), potassium
carbonate (46.6 g), copper(I) iodide (1.0 g), triphenylphosphine
(2.8 g), 10% palladium on carbon (288 mg) in water (250 mL) and DME
(250 mL) was stirred at room temperature for 30 min, and
3-butyn-1-ol (25 mL) was added. The resulting mixture was heated at
90.degree. C. for 16 h, cooled to room temperature, and filtered
through a pad of Celite. The pad was washed with DCM (3.times.50
mL), and the filtrate was diluted with water (100 mL). The aqueous
phase was extracted with ethyl acetate (2.times.400 mL), and the
combined organic phases were washed with water (100 mL) and brine
(100 mL), dried (magnesium sulfate), and concentrated under reduced
pressure. The residue was azeotroped with toluene (2.times.100 mL)
to give a brown solid (2.1 g). To a solution of this solid and
triethylamine (7.1 mL) in DCM (100 mL) was added p-toluene sulfonyl
chloride at 0.degree. C. The resulting mixture was warmed to room
temperature over a period of 2.5 h, diluted with water (10 mL), and
extracted with DCM (2.times.300 mL). The combined organic phases
were washed with water (2.times.40 mL) and brine (40 mL), and then
dried (magnesium sulfate) and concentrated under reduced pressure.
Chromatography of the residue (10-20% ethylacetate/hexane) gave the
title compound as a yellow oil (6.7 g).
EXAMPLE 9
[0395] 30
[0396] 3-(4-Piperidin-1-yl-but-1-ynyl)-benzaldehyde
[0397] A mixture of 3-bromobenzaldehyde (0.58 mL), potassium
carbonate (1.73 g), copper(I) iodide (38 mg), triphenylphosphine
(105 mg), 10% palladium on carbon (220 mg) in water (10 mL) and DME
(5 mL) was stirred at room temperature for 20 min, and treated with
a solution of the product of Example 2 (1.7 g) in DME (5 mL). The
resulting mixture was heated at 80.degree. C. for 16 h, cooled to
room temperature, and filtered through a pad of Celite. The pad was
washed with DCM (5.times.20 mL), and the filtrate was diluted with
water (30 mL). The aqueous phase was extracted with DCM (2.times.30
mL), and the combined organic phases were dried (magnesium sulfate)
and concentrated under reduced pressure. Chromatography of the
residue (0-3% 2 M methanolic ammonia/DCM) gave the title compound
as a pale yellow oil (734 mg).
EXAMPLE 10
[0398] 31
[0399] 3-(4-Morpholin-4-yl-but-1-ynyl)-benzaldehyde
[0400] May be prepared analogously to Example 9 using the product
of Example 3.
EXAMPLE 11
[0401] 32
[0402] 3-(4-Thiomorpholin-4-yl-but-1-ynyl)-benzaldehyde
[0403] May be prepared analogously to Example 9 using the product
of Example 4.
EXAMPLE 12
[0404] 33
[0405] 4-(4-Piperidin-1-yl-but-1-ynyl)-benzaldehyde
[0406] Method A: To a solution of the product of Example 8 (8.0 g)
in 1-butanol (20 mL) was added piperidine (2.4 mL) followed by
sodium carbonate (1.3 g) and potassium iodide (81 mg). The
resulting mixture was heated at 80.degree. C. for 16 h, cooled to
room temperature, diluted with water (200 mL) and extracted with
DCM (2.times.400 mL). The combined organic phases were washed with
water (100 mL) and brine (100 mL), dried (magnesium sulfate), and
concentrated under reduced pressure. Chromatography of the residue
(6-8% 2 M methanolic ammonia/DCM) gave the title compound as a
brown oil (4.6 g of a 1:1 mixture of the title compound and
1-[4-(4-Dibutoxymethyl-phenyl)-but-3-ynyl]-piperidine).
[0407] Method B: To a mixture of Pd(PPh.sub.3).sub.2Cl.sub.2 (0.57
g, 0.81 mmol, 0.01 equiv) and CuI (0.31 g, 1.6 mmol, 0.02 equiv),
THF (180 mL) and Et.sub.3N (90 mL, 0.64 mol, 8.0 equiv) were added
under N.sub.2. A stream of N.sub.2 was bubbled through the solution
for 15 min, and then 1-but-3-ynyl-piperidine (11.7 g, 85 mmol, 1.05
equiv) was added. The reaction mixture was stirred at room
temperature for 16 h. A white precipitate (Et.sub.3N.HBr) was
collected by filtration and washed with EtOAc. The filtrate was
concentrated under reduced pressure, and the resulting residue was
re-dissolved in EtOAc. The EtOAc solution was washed with 1 M NaOH
(aq) twice, dried over MgSO.sub.4, and then poured directly onto a
short pad of silica gel (neutralized with 5% Et.sub.3N in hexanes),
which was then washed with EtOAc. The filtrate was concentrated
under reduced pressure to afford the product as a dark brown oil
(18.1 g, 75 mmol, 92%), which was used without further purification
(purity >95% by HPLC). MS (electrospray): mass calculated for
C.sub.16H.sub.19ON, 241.1; m/z found, 242.2 [M+H].sup.+.
EXAMPLE 12a
[0408] 34
[0409] 3-(4-Piperidin-1-yl-but-1-ynyl)-benzaldehyde
[0410] To the mixture of Pd(PPh.sub.3)Cl.sub.2 (24 mg, 0.034 mmol,
0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and
3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10
mL) were added under N.sub.2. The use of pyrrolidine is preferred
in the context of this synthesis. A stream of N.sub.2 was bubbled
into to the solution for 5 min, and then 1-but-3-ynyl-piperidine
(0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was
stirred at 50.degree. C. for 40 h. This temperature is preferred in
the context of this synthesis. On TLC and HPLC, the reaction was
complete. The white precipitate (Et.sub.3N.HBr) was filtered and
washed with EtOAc. The solvent was evaporated and the residue was
re-dissolved in EtOAc. The organic layer was washed with aqueous
NaOH (1N) twice, and dried over MgSO.sub.4. After filtration, the
EtOAc solution was poured directly onto a short pad of silica gel
(neutralized with 5% Et.sub.3N in hexanes) and washed with EtOAc.
The solvent was evaporated to afford the product as a brown oil
(0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H.sup.+242.
This product does not need further purification in its use for
subsequent steps in the context of this invention. A yield of 86%
is in marked contrast with conventional methodologies, which
produce the title compound with typical yields that do not exceed
30%.
EXAMPLE 13
[0411] 35
[0412] Toluene-4-sulfonic acid
4-(4-piperidin-1-ylmethyl-phenyl)-but-3-yny- l ester
[0413] A solution of the product of Example 8 (2.0 g), piperidine
(0.91 mL), and acetic acid (0.42 mL) in DCM (100 mL) was treated
with sodium triacetoxyborohydride (1.95 g) at room temperature.
After 16 h, the resulting mixture was treated with 10% aqueous
sodium hydroxide (30 mL). The aqueous phase was extracted with DCM
(2.times.300 mL). The combined organic phases were dried (magnesium
sulfate) and concentrated under reduced pressure. The residue was
diluted in DCM (100 mL) and passed through a pad of silica gel. The
pad was washed with DCM (3.times.200 mL). The combined filtrate was
concentrated under reduced pressure, giving the title compound as a
brown oil (2.3 g).
EXAMPLE 14
[0414] 36
[0415]
1-[4-(4-Piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine
[0416] K.sub.i=1.6 nM
[0417] A mixture of the product of Example 1 (254 mg), potassium
carbonate (346 mg), copper(I) iodide (7.6 mg), triphenylphosphine
(21 mg), 10% palladium on carbon (43 mg) in water (2 mL) and DME (1
mL) was stirred at room temperature for 30 min, and treated with a
solution of the product of Example 2 (343 mg) in DME (1 mL). The
resulting mixture was heated at 80.degree. C. for 16 h, cooled to
room temperature, and filtered through a pad of Celite. The pad was
washed with DCM (3.times.3 mL), and the filtrate was diluted with
water (3 mL). The aqueous phase was extracted with DCM (2.times.3
mL), and the combined organic phases were dried (magnesium sulfate)
and concentrated under reduced pressure. Chromatography of the
residue (2.5%-5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (88 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.33 (d, J=7.4 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 3.44
(s, 2H), 2.68-2.56 (m, 4H), 2.50-2.43 (m, 4H), 2.39-2.30 (m, 4H),
1.64-1.52 (m, 8H), 1.48-1.38 (m, 4H).
EXAMPLE 15
[0418] 37
[0419] 1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine
[0420] K.sub.i=0.8 nM
[0421] A solution of the product of Example 9 (193 mg) and
piperidine (0.09 mL) in DCE (2 mL) was treated with sodium
triacetoxyborohydride (254 mg). After 16 h, the resulting mixture
was treated with 10% aqueous potassium hydroxide (2 mL), and
extracted with DCM (2.times.3 mL). The combined organic phases were
dried (magnesium sulfate) and concentrated under reduced pressure.
Chromatography of the residue (0-8% 2 M methanolic ammonia/DCM)
gave the title compound as a pale yellow oil (65 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.35 (br s, 1 H), 7.28-7.21 (m, 3H), 3.42
(s, 2H), 2.67-2.57 (m, 4H), 2.50-2.43 (m, 4H), 2.39-2.31 (m, 4H),
1.63-1.53 (m, 8H), 1.48-1.38 (m, 4H).
EXAMPLE 16
[0422] 38
[0423] 4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine
[0424] K.sub.i=0.8 nM
[0425] Method A: A solution of the product of Example 9 (193 mg)
and morpholine (0.08 mL) in DCE (2 mL) was treated with sodium
triacetoxyborohydride (254 mg). After 16 h, the resulting mixture
was treated with 10% aqueous potassium hydroxide (2 mL), and
extracted with DCM (2.times.3 mL). The combined organic phases were
dried (magnesium sulfate) and concentrated under reduced pressure.
Chromatography of the residue (0-8% 2 M methanolic ammonia/DCM)
gave the title compound as a pale yellow oil (188 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.36 (br s, 1 H), 7.30-7.22 (m, 3H), 3.70
(t, J=4.6 Hz, 4H), 3.45 (s, 2H), 2.68-2.57 (m, 4H), 2.51-2.40 (m,
8H), 1.64-1.57 (m, 4H), 1.48-1.41 (m, 2H).
[0426] Method B: A 500-mL, 3-necked round-bottom flask was equipped
with a magnetic stirring bar, an addition funnel, a thermometer,
and a rubber septum with a nitrogen inlet. The vessel was charged
with piperidine (54 mL, 46 g, 0.54 mol) and anhydrous ethanol (25
mL). The solution was cooled to 0.degree. C. in an ice bath, and a
solution of the product of Example 7 (17.5 g, 0.054 mol) in
anhydrous ethanol (30 mL) was added. The ice bath was removed, and
the reaction mixture was allowed to warm to room temperature. Room
temperature is a preferred temperature condition. The amount of 10
mol equivalent piperidine in ethanol given here is a preferred
amount. After 14 h when the reaction was judged complete by HPLC,
the reaction mixture was transferred to a 500 mL round-bottom flask
and concentrated under reduced pressure to dryness under reduced
pressure. The residue was dissolved in CH.sub.2Cl.sub.2 (300 mL),
washed with 5% aq. NaOH (75 mL), dried over MgSO.sub.4, and
filtered. After filtration, the filtrate was concentrated by
solvent evaporation under reduced pressure to give an oil (20 g),
which was determined by HPLC and .sup.1H NMR to contain an 85:15
mixture of the title compound and
4-(3-pent-4-en-1-ynyl-benzyl)-morpholine (this latter compound
being the elimination compound in this reaction). This mixture does
not need further purification in its use for subsequent steps in
the context of this invention. TLC: title compound, (R.sub.f=0.58,
SiO.sub.2, dichloromethane/0.02M NH.sub.3 in MeOH, 9:1);
4-(3-pent-4-en-1-ynyl-benzy- l)-morpholine, (R.sub.f=0.38,
SiO.sub.2, ethyl acetate/hexanes, 3/1). MS (electro spray, positive
mode), (M.sup.++H) 313. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
1.45 (bm, 2 H), 1.62 (m, 4 H), 2.41-2.48 (m, 8 H), 2.62 (m, 4 H),
3.44 (s, 2 H), 3.71 (t, 4 H, J=4.6), 7.22-7.36 (m, 4 H).
[0427] Method C.
4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine: To the
solution of 3-(4-Piperidin-1-yl-but-1-ynyl)-benzaldehyde (0.3 g,
1.24 mmol, 1 equiv.) in 20 mL dichloroethane, morpholine (0.13 g,
1.5 mmol, 1.2 equiv.) was added. To the well-stirred reaction
mixture, NaHB(OAc).sub.3 (0.4 g, 1.8 mmol, 1.5 equiv.) was added at
0.degree. C. under N.sub.2. After addition, the cold bath was
removed and the reaction mixture was stirred at room temperature
for 1.5 h., when the reaction was judged complete by HPLC. Aqueous
NaOH (1 N, 10 mL) was added slowly to quench the unreacted
reagents. The organic layer was washed with NaOH aqueous solution
(1 mol/L), dried over MgSO.sub.4. After filtration, the solvent was
evaporated under reduced pressure. The oily residue thus obtained
was re-dissolved in EtOAc, and passed through a pad of silica gel
(neutralized with 5% Et.sub.3N in hexanes) and washed with EtOAc.
Evaporation of the solvent afforded the product as a light yellow
oil (0.36 g, 1.16 mmol, 93%). Purity >95% on HPLC. MS M+H.sup.+
313.
EXAMPLE 17
[0428] 39
[0429] 4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine
dihydrochloride
[0430] Example of selective precipitation of compounds such as the
title compound. A 3-L, 3-necked round-bottom flask was charged with
the product of Example 16, Method B (77.0 g, 0.25 mol). To this was
added absolute EtOH (385 mL). The reaction mixture was stirred and
cooled to .about.0.degree. C. in an ice bath. HCl in dioxane (4 N,
126.5 mL) was added drop-wise over 0.5 h. The ice bath was removed,
and the reaction mixture was stirred at room temperature for 2 h.
The viscous reaction mixture was transferred to a 500 mL addition
funnel and then added in a slow, steady stream to a-3-L, 3-necked
round-bottom flask containing ether (500 mL), as the flask contents
were stirred. The addition funnel was rinsed with absolute EtOH
(115 mL), which was subsequently added to the ether solution. Ether
(500 mL) was added via an addition funnel in a slow, steady stream.
This resulted in the formation of a pale tan precipitate. The
suspension was stirred at room temperature for 12 h. More ether
(500 mL) was added, and the suspension was cooled to 0.degree. C.
and held at that temperature while stirred for 3 h. The product was
collected by suction filtration using a medium porosity glass frit
(filtration was slow). The filter cake was broken and washed with
absolute EtOH/Et.sub.2O (1:3, 2.times.75 mL). The product was dried
under house vacuum and, subsequently, in a vacuum oven at
35.degree. C. for 24 h. The dihydrochloride salt was obtained as an
off-white powder (80.7 g). HPLC and .sup.1H-NMR indicated the
product to be >95% pure. At most, only trace amounts of the
elimination product were present. A 2-L, 3-necked round-bottom
flask equipped with an addition funnel, a reflux condenser and a
mechanical stirrer was charged with the crude dihydrochloride salt
(80.0 g). Absolute EtOH (160 mL) was added, and the resulting
suspension was warmed to .about.50.degree. C. Ether (320 mL) was
added in a slow stream via the addition funnel. Heating was
discontinued, and the suspension slowly cooled to room temperature
with stirring over .about.4 h. The flask was cooled in an ice bath,
stirred, and maintained at 0-5.degree. C. for .about.3 h. The
precipitate was collected by suction filtration using a medium
porosity glass frit (filtration was slow). The filter cake was
broken and washed with cold EtOH/Et.sub.2O (1:2, 2.times.75 mL).
The product was dried in vacuo at 35.degree. C. The title compound
was obtained as an off white powder in an amount of 76.2 g, with a
yield of 95%. MP 239.degree. C. (decomp.). MS (electro spray,
positive mode), (M.sup.++H) 313. .sup.1H NMR (400 MHz, MeOH): 1.56
(bm, 1 H), 1.82-1.85 (m, 3 H), 1.96-1.99 (m, 2 H), 2.99-3.07 (m, 4
H), 3.17-3.24 (m, 2 H), 3.30-3.41 (m, 6 H), 3.62 (bd, J=12.7 Hz, 2
H), 3.79 (bt, J=12.6 Hz, 2 H), 4.01 (bd, J=12.5 Hz, 2 H), 4.37 (s,
2 H), 7.46-7.69 (m, 1 H), 7.53-7.56 (m, 2 H), 7.25 (m, 1 H). Anal.
Calcd. for C.sub.20H.sub.30N.sub.2OCl.sub.2: C, 62.33%; H, 7.85%;
N, 7.27%; found: C, 62.13%; H, 7.52%; N, 7.23%. In contrast with
conventional methodologies, the title compound was obtained with a
high yield. Furthermore, and also in contrast with conventional
methodologies, the title compound was obtained without the need of
chromatographic purification.
EXAMPLE 18
[0431] 40
[0432] 1-[4-(4-Pyrrolidin-1-yl-but-1-ynyl)-benzyl]-piperidine
[0433] K.sub.i=2.0 nM
[0434] A mixture of the product of Example 13 (199 mg), pyrrolidine
(0.084 mL), and potassium carbonate (69 mg) in 1:1 ethanol/water (6
mL) was heated at 80.degree. C. for 16 h. The resulting mixture was
cooled to room temperature, diluted with water (10 mL), and
extracted with DCM (2.times.100 mL). The combined organic phases
were washed with water (20 mL) and brine (20 mL), dried (magnesium
sulfate), and concentrated under reduced pressure. Chromatography
of the residue (0-5% 2 M methanolic ammonia/DCM) gave the title
compound as a pale yellow oil (60 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.33 (d, J=8.1 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 3.44
(s, 2H), 2.78-2.73 (m, 2H), 2.64-2.57 (m, 6H), 2.35 (br s, 4H),
1.82-1.78 (m, 4H), 1.59-1.53 (m, 4H), 1.45-1.40 (m, 2H).
EXAMPLE 19
[0435] 41
[0436]
Diethyl-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-amine
[0437] K.sub.i=2.4 nM
[0438] A mixture of the product of Example 13 (199 mg),
diethylamine (0.104 mL).and potassium carbonate (69 mg) in 1:1
ethanol/water (6 mL) was heated at 80.degree. C. for 16 h. The
resulting mixture was cooled to room temperature, diluted with
water (10 mL), and extracted with DCM (2.times.100 mL). The
combined organic phases were washed with water (20 mL) and brine
(20 mL), dried (magnesium sulfate), and concentrated under reduced
pressure. Chromatography of the residue (0-5% 2 M methanolic
ammonia/DCM) gave the title compound as a pale yellow oil (21 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.33 (d, J=8.0 Hz, 2H), 7.23 (d,
J=8.0 Hz, 2H), 3.44 (s, 2H), 2.81-2.73 (m, 2H), 2.64-2.51 (m, 6H),
2.35 (bs, 4H), 1.82-1.78 (m, 3H), 1.59-1.53 (m, 4H), 1.44-1.39 (m,
2H), 1.07 (t, J=7.2 Hz, 3H).
EXAMPLE 20
[0439] 42
[0440]
4-[4-(4-Piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-thiomorpholine
[0441] K.sub.i=6.0 nM
[0442] A mixture of the product of Example 13 (199 mg),
thiomorpholine (0.062 mL) and potassium carbonate (69 mg) in 1:1
ethanol/water (6 mL) was heated at 80.degree. C. for 16 h. The
resulting mixture was cooled to room temperature, diluted with
water (10 mL) and extracted with DCM (2.times.100 mL). The combined
organic phases were washed with water (20 mL) and brine (20 mL),
dried (magnesium sulfate), and concentrated under reduced pressure.
Chromatography of the residue (0-5% 2 M methanolic ammonia/DCM)
gave the title compound as a pale yellow oil (27 mg). .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.32 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.1 Hz,
2H), 3.44 (s, 2H), 2.83-2.80 (m, 4H), 2.74-2.68 (m, 6H), 2.59-2.55
(m, 2H), 2.35 (br s, 4H), 1.59-1.53 (m, 4H), 1.44-1.39 (m, 2H).
EXAMPLE 21
[0443] 43
[0444]
4-[4-(4-Piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-morpholine
[0445] K.sub.i=15 nM
[0446] A mixture of the product of Example 13 (199 mg), morpholine
(0.052 mL) and potassium carbonate (69 mg) in 1:1 ethanol/water (6
mL) was heated at 80.degree. C. for 16 h. The resulting mixture was
cooled to room temperature, diluted with water (10 mL) and
extracted with DCM (2.times.100 mL). The combined organic phases
were washed with water (20 mL) and brine (20 mL), dried (magnesium
sulfate), and concentrated under reduced pressure. Chromatography
of the residue (0-5% 2 M methanolic ammonia/DCM) gave the title
compound as a pale yellow oil (40 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.32 (d, J=8.1 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.73
(t, J=4.6 Hz, 4H), 3.44 (s, 2H), 2.72-2.58 (m, 4H), 2.54 (t, J=4.5
Hz, 4H), 2.35 (br s, 4H), 1.59-1.53 (m, 4H), 1.44-1.40 (m, 2H).
EXAMPLE 22
[0447] 44
[0448]
1-Methyl-4-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperazin-
e
[0449] K.sub.i=21 nM
[0450] A mixture of the product of Example 13 (199
mg),1-methylpiperazine (0.067 mL) and potassium carbonate (69 mg)
in 1:1 ethanol/water (6 mL) was heated at 80.degree. C. for 16 h.
The reaction mixture was cooled to room temperature. Water (10 mL)
was added, and the mixture was extracted with DCM (2.times.100 mL).
The combined organic phases were washed with water (20 mL) and
brine (20 mL), dried (magnesium sulfate), and concentrated under
reduced pressure. Chromatography of the residue (0-5% 2 M
methanolic ammonia/DCM) gave the title compound as a white solid
(13 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.32 (d, J=8.1 Hz, 2H),
7.23 (d, J=8.1 Hz, 2H), 3.44 (s, 2H), 2.71-2.46 (m, 12H), 2.35 (br
s, 4H), 2.30 (s, 3H), 1.59-1.53 (m, 4H), 1.45-1.38 (m, 2H).
EXAMPLE 23
[0451] 45
[0452]
1-[4-(4-Pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine
[0453] K.sub.i=1.4 nM
[0454] A solution of the product of Example 12 (241 mg),
pyrrolidine (0.125 mL) and acetic acid (0.067 mL) in DCM (2 mL) was
treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(73 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (d, J=8.0 Hz, 2H),
7.24 (d, J=8.0 Hz, 2H), 3.58 (s, 2H), 2.68-2.57 (m, 4H), 2.50-2.45
(m, 8H), 1.79-1.76 (m, 4H), 1.63-1.57 (m, 4H), 1.47-1.41 (m,
2H).
EXAMPLE 24
[0455] 46
[0456] 4-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine
[0457] K.sub.i=5.5 nM
[0458] A solution of the product of Example 12 (241 mg), morpholine
(0.131 mL) and acetic acid (0.067 mL) in DCM (2 mL) was treated
with sodium triacetoxyborohydride (318 mg) at room temperature.
After 16 h, the resulting mixture was treated with 10% aqueous
sodium hydroxide (10 mL). The aqueous phase was extracted with DCM
(2.times.100 mL). The combined organic phases were washed with
brine (50 mL), dried (magnesium sulfate), and concentrated under
reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a yellow oil (53
mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (d, J=8.2 Hz, 2H),
7.24 (d, J=8.2 Hz, 2H), 3.70 (t, J=4.6 Hz, 4H), 3.47 (s, 2H),
2.68-2.57 (m, 4H), 2.50-2.41 (m, 8H), 1.63-1.57 (m, 4H), 1.48-1.42
(m, 2H).
EXAMPLE 25
[0459] 47
[0460] Diethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0461] K.sub.i=1.1 nM
[0462] A solution of the product of Example 12 (241 mg),
diethylamine (0.155 mL) and acetic acid (0.067 mL) in DCM (2 mL)
was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(61 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.33 (d, J=8.1 Hz, 2H),
7.24 (d, J=8.0 Hz, 2H), 3.53 (s, 2H), 2.68-2.57 (m, 4H), 2.52-2.45
(m, 8H), 1.63-1.57 (m, 4H), 1.47-1.41 (m, 2H), 1.02 (t, J=7.1 Hz,
6H).
EXAMPLE 26
[0463] 48
[0464]
1-{4-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-piperid-
ine K.sub.i=2.9 nM
[0465] A solution of the product of Example 12 (241 mg),
4-benzylpiperidine (0.264 mL) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a white solid
(80 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.32 (d, J=8.0 Hz, 2H),
7.28-7.15 (m, 5H), 7.12 (d, J=7.1 Hz, 2H), 3.43 (s, 2H), 2.83-2.80
(d, J=11.5 Hz, 2H), 2.68-2.56 (m, 4H), 2.52 (d, 7.0 Hz, 2H), 2.46
(br s, 4H), 1.87 (t, J 9.9 Hz, 2H), 1.62-1.57 (m, 6H), 1.53-1.41
(m, 3H), 1.34-1.24 (m, 2H)
EXAMPLE 27
[0466] 49
[0467]
1-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol
[0468] K.sub.i=1.7 nM
[0469] A solution of the product of Example 12 (241 mg),
4-hydroxypiperidine (152 mg) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.1 00 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(60 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (d, J=8.0 Hz, 2H),
7.22 (d, J=8.0 Hz, 2H), 3.72-3.65 (m, 1H), 3.47 (s, 2H), 2.75-2.57
(m, 6H), 2.47 (brs, 4H), 2.13 (t, J=9.6 Hz, 2H), 1.90-1.84 (m, 2H),
1.63-1.53 (m, 5H), 1.47-1.41 (m, 3H).
EXAMPLE 28
[0470] 50
[0471]
2-{1-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-2-yl}-ethan-
ol
[0472] K.sub.i=0.4 nM
[0473] A solution of the product of Example 12 (241 mg),
2-piperidineethanol (194 mg) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(9 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (d, J=8.1 Hz, 2H),
7.22 (d, J=8.0 Hz, 2H), 4.15 (d, J=13.1 Hz, 1H), 3.95-3.90 (m, 1H),
3.77-3.71 (m, 1H), 3.43 (d, J=13.0 Hz, 1H), 2.96-2.90 (m, 1H),
2.74-2.57 (m, 7H), 2.47 (br s, 5H), 2.20-2.12 (m,1H), 1.97-1.25 (m,
11H)
EXAMPLE 29
[0474] 51
[0475]
1-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-decahydro-quinoline
[0476] K.sub.i=0.8 nM
[0477] A solution of the product of Example 12 (241 mg),
decahydroquinoline (0.224 mL) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(29 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.32 (d, J=8.0 Hz, 2H),
7.21 (d, J=8.0 Hz, 2H), 4.03 (d, J=13.7 Hz, 1H), 3.19 (d, J=13.7
Hz, 1H), 2.77 (d, J=11.1 Hz, 1H), 2.68-2.57 (m, 5H), 2.47 (br s,
5H), 2.23-2.18 (m, 1H), 1.95-0.83 (m, 18H).
EXAMPLE 30
[0478] 52
[0479]
1-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-carboxylic
acid amide
[0480] K.sub.i=1.6 nM
[0481] A solution of the product of Example 12 (241 mg),
isonipecotamide (192 mg) and acetic acid (0.067 mL) in DCM (2 mL)
was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a white solid
(87 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.33 (d, J=8.0 Hz, 2H),
7.23 (d, J=8.0 Hz, 2H), 3.94 (s, 2H), 3.49 (s, 2H), 2.67-2.57 (m,
4H), 2.51-2.45 (m, 8H), 1.77-1.71 (m, 5H), 1.63-1.57 (m, 4H),
1.47-1.42 (m, 2H).
EXAMPLE 31
[0482] 53
[0483]
8-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-1,4-dioxa-8-aza-spiro[4.-
5]decane
[0484] K.sub.i=1.8 nM
[0485] A solution of the product of Example 12 (241 mg),
1,4-dioxa-8-azaspiro[4.5]decane (0.192 mL) and acetic acid (0.067
mL) in DCM (2 mL ) was treated with sodium triacetoxyborohydride
(318 mg) at room temperature. After 16 h, the resulting mixture was
treated with 10% aqueous sodium hydroxide (10 mL). The aqueous
phase was extracted with DCM (2.times.100 mL). The combined organic
phases were washed with brine (50 mL), dried (magnesium sulfate),
and concentrated under reduced pressure. Chromatography of the
residue (0.5-5.5% 2 M methanolic ammonia/DCM) gave the title
compound as a colorless oil (108 mg). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.33 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 5.45
(br s, 1H), 5.31 (br s, 1H), 3.46 (s, 2H), 2.92-2.87 (m, 2H),
2.68-2.57 (m, 4H), 2.47 (brs, 4H), 2.19-2.11 (m, 1H), 2.02-1.95 (m,
2H), 1.87-1.83 (m, 2H), 1.79-1.57 (m, 7H), 1.47-1.41 (m, 2H).
EXAMPLE 32
[0486] 54
[0487]
1-Methyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine
[0488] K.sub.i=0.7 nM
[0489] A solution of the product of Example 12 (241 mg),
1-methylpiperazine (0.166 mL) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(65 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.33 (d, J=8.2 Hz, 2H),
7.23 (d, J=8.2 Hz, 2H), 3.47 (s, 2H), 2.68-2.57 (m, 4H), 2.47 (br
s, 12H), 2.28 (s, 3H), 1.62-1.57 (m, 4H), 1.47-1.41 (m, 2H).
EXAMPLE 33
[0490] 55
[0491]
Cyclohexyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0492] K.sub.i=0.5 nM
[0493] A solution of the product of Example 12 (241 mg),
cyclohexylamine (0.172 mL), and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(95 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (d, J=8.0 Hz, 2H),
7.23 (d, J=8.0 Hz, 2H), 3.79 (s, 2H), 2.68-2.57 (m, 4H), 2.49-2.40
(m, 5H), 1.92-1.86 (m, 2H), 1.76-1.69 (m, 2H), 1.62-1.54 (m, 4H),
1.47-1.41 (m, 2H), 1.29-1.05 (m, 6H).
EXAMPLE 34
[0494] 56
[0495]
Indan-1-yl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0496] K.sub.i=1.3 nM
[0497] A solution of the product of Example 12 (241 mg),
1-aminoindian (0.192 mL) and acetic acid (0.067 mL) in DCM (2 mL)
was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(118 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.37-7.28 (m, 8H),
4.27 (t, 6.6 Hz, 1H), 3.88 (d, 5.6 Hz, 2H), 3.05-2.97 (m,1H),
2.85-2.77 (m,1H), 2.68-2.57 (m, 4H), 2.49-2.57 (m, 5H), 1.90-1.82
(m, 1H), 1.63-1.57 (m, 4H), 1.47-1.41 (m, 2H).
EXAMPLE 35
[0498] 57
[0499]
1-Phenyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine
[0500] K.sub.i=7.0 nM
[0501] A solution of the product of Example 12 (241 mg),
1-phenylpiperazine (0.229 mL) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After 16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(38 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.17 (d, J=8.0 Hz, 2H),
7.09-7.05 (m, 4H), 6.74 (d, J=8.2 Hz, 2H), 6.67 (t, J=7.4 Hz, 1H),
3.36 (s, 2H), 3.01 (t, 4.9 Hz, 4H), 2.50-2.39 (m, 8H), 2.29 (br s,
4H), 1.45-1.37 (m, 4H), 1.30-1.23 (m, 2H).
EXAMPLE 36
[0502] 58
[0503]
1-Benzyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine
[0504] K.sub.i=9.0 nM
[0505] A solution of the product of Example 12 (241 mg),
1-benzylpiperazine (0.261 mL) and acetic acid (0.067 mL) in DCM (2
mL) was treated with sodium triacetoxyborohydride (318 mg) at room
temperature. After.16 h, the resulting mixture was treated with 10%
aqueous sodium hydroxide (10 mL). The aqueous phase was extracted
with DCM (2.times.100 mL). The combined organic phases were washed
with brine (50 mL), dried (magnesium sulfate), and concentrated
under reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(136 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.38-7.21 (m, 9H),
3.51 (s, 2H), 3.48 (s, 2H), 2.68-2.56 (m, 4H), 2.46 (br s, 10H),
1.62-1.56 (m, 6H), 1.47-1.42 (m, 2H).
EXAMPLE 37
[0506] 59
[0507]
4-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine-1-carboxylic
acid tert-butyl ester
[0508] K.sub.i=15 nM
[0509] A solution of the product of Example 12 (241 mg), tert-butyl
1-piperazinecarboxylate (559 mg) and acetic acid (0.067 mL) in DCM
(2 mL) was treated with sodium triacetoxyborohydride (318 mg) at
room temperature. After 16 h, the resulting mixture was treated
with 10% aqueous sodium hydroxide (10 mL). The aqueous phase was
extracted with DCM (2.times.100 mL). The combined organic phases
were washed with brine (50 mL), dried (magnesium sulfate), and
concentrated under reduced pressure. Chromatography of the residue
(0.5-5.5% 2 M methanolic ammonia/DCM) gave the title compound as a
white solid (218 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (d,
J=8.1 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 3.48 (s, 2H), 3.43-3.40 (m,
4H), 2.68-2.57 (m, 4H), 2.47 (br s, 4H), 2.36 (br s, 4H), 1.64-1.57
(m, 6H), 1.45 (s, 9H).
EXAMPLE 38
[0510] 60
[0511] 1-[4-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine
[0512] K.sub.i=1.3 nM
[0513] A solution of the product of Example 37 (184 mg) in
1,4-dioxane (7 mL) was treated with 4 N HCl in 1,4-dioxane at room
temperature for 16 h. The solvent was evaporated, and the resulting
mixture was treated with 10% aqueous sodium hydroxide (10 mL). The
aqueous phase was extracted with 10% methanol in DCM (2.times.100
mL). The combined organic phases were washed with brine (50 mL),
dried (magnesium sulfate), and concentrated under reduced pressure.
Chromatography of the residue (1-6% 2 M methanolic ammonia/DCM)
gave the title compound as a white solid (97 mg). .sup.1H NMR (400
MHz, CDCl.sub.3): 7.34 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H),
3.47 (s, 2H), 2.91 (t, J=4.8 Hz, 4H), 2.69-2.58 (m, 4H), 2.48-2.43
(m, 8H), 1.64-1.58 (m, 4H), 1.47-1.41 (m, 2H).
EXAMPLE 39
[0514] 61
[0515]
1-lsopropyl-4-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine
[0516] K.sub.i=1.3 nM
[0517] A solution of the product of Example 38 (74 mg), acetone (5
mL) and acetic acid (0.014 mL) in DCM (3 mL) was treated with
sodium triacetoxyborohydride (67 mg) at room temperature. After 16
h, the resulting mixture was treated with 10% aqueous sodium
hydroxide (10 mL). The aqueous phase was extracted with DCM
(2.times.100 mL). The combined organic phases were washed with
brine (50 mL), dried (magnesium sulfate), and concentrated under
reduced pressure. Chromatography of the residue (0.5-5.5% 2 M
methanolic ammonia/DCM) gave the title compound as a colorless oil
(65 mg). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.33 (d, J=8.0 Hz, 2H),
7.23 (d, J=8.1 Hz, 2H), 3.48 (s, 2H), 2.68-2.47 (m, 16H), 1.66 (br
s, 1H), 1.63-1.57 (m, 4H), 1.48-1.41 (m, 2H), 1.04 (d, J=6.5 Hz,
2H).
EXAMPLE 40
[0518] 62
[0519]
1-Phenyl-8-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-1,3,8-triaza-sp-
iro[4.5]decan-4-one
[0520] K.sub.i=2.0 nM
[0521] Prepared analogously to Example 15 using
1-phenyl-1,3,8-triaza-spir- o[4.5]decan-4-one. .sup.1H NMR (400
MHz, CDCl.sub.3): 7.41(s, 1H), 7.32-7.21(m, 5H), 6.94-6.85(m, 2H),
4.73(s, 2H), 3.54(s, 2H), 2.84-2.58(m, 1OH), 2.47(bs, 4H), 1.65(d,
23.2 Hz, 2H), 1.62-1.58(m, 4H), 1.47-1.43(m, 2H).
EXAMPLE 41
[0522] 63
[0523]
1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-3-carboxylic
acid diethylamide
[0524] K.sub.i=3.0 nM
[0525] Prepared analogously to Example 15 using
piperidine-3-carboxylic acid diethylamide. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.36(s, 1H), 7.28-7.21(m, 3H), 3.46(s, 2H),
3.38-3.25(m, 4H), 2.87-2.81 (m, 2H), 2.75-2.57(m, 5H), 2.46-2.42(m,
4H), 2.19(t, J=11.1 Hz, 1H), 1.99-1.94(m, 1H), 1.77-1.42(m, 10H),
3.94(t, J=7.1 Hz, 3H), 1.07(t, J=7.1 Hz, 3H).
EXAMPLE 42
[0526] 64
[0527]
1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-1,2,3,4,5,6-hexahydro-[2-
,3']bipyridinyl
[0528] K.sub.i=11 nM
[0529] Prepared analogously to Example 15 using
1,2,3,4,5,6-hexahydro-[2,3- ']bipyridinyl. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.64 (d, J=2.6 Hz, 1H), 8.50-8.48 (m, 1H), 7.80 (d,
J=7.9 Hz, 1H), 7.81-7.12(m, 5H), 3.64(d, J=13.5 Hz, 1H),
3.17-3.13(m, 1H), 2.94(d, J=11.4 Hz, 1H), 2.79(d, J=13.6 Hz, 1H),
2.60-2.58(m, 4H), 2.47(bs, 4H), 1.96-1.90(m, 1H), 1.82-1.75(m, 2H),
1.66-1.39(m, 10H).
EXAMPLE 43
[0530] 65
[0531]
1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-4-(3-trifluoromethyl-phe-
nyl)-piperazine
[0532] K.sub.i=91 nM
[0533] Prepared analogously to Example 15 using
1-(3-trifluoromethyl-pheny- l)-piperazine. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.39(s, 1H), 7.35-7.22(m, 4H), 7.10-7.03(m, 3H),
3.52(s, 2H), 3.24(t, J=5.0 Hz, 4H), 2.69-2.58(m, 8H), 2.47(bs, 4H),
1.63-1.58(m, 4H), 1.47-1,.42(m, 2H).
EXAMPLE 44
[0534] 66
[0535]
2-{4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperazin-1-yl}-pyrim-
idine
[0536] K.sub.i=9.0 nM
[0537] Prepared analogously to Example 15 using
2-piperazin-1-yl-pyrimidin- e. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.29(d, J=4.7 Hz, 2H), 7.39(s, 1H), 7.31-7.22(m, 3H), 6.46(t, J=4.8
Hz, 1H), 3.82(t, J=5.1 Hz, 4H), 3.50(s, 2H), 2.68-2.58(m, 4H),
2.50-2.47(m, 8H), 1.72-1.57(m, 4H), 1.47-1.41 (m, 2H).
EXAMPLE 45
[0538] 67
[0539]
1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidine-4-carboxylic
acid amide
[0540] K.sub.i=2.0 nM
[0541] Prepared analogously to Example 15 using
piperidine-4-carboxylic acid amide. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.29(s, 1H), 7.40(s, 1H), 7.31-7.23(m, 3H), 4.38-4.31
(m,1H), 3.52(S, 2H), 3.02(d, 2H), 2.70-2.55(m, 4H), 2.48-2.42(m,
8H), 2.19-2.13(m, 2H), 1.81-1.78(m, 2H)1.63-1.60(m, 2H),
1.46-1.45(m, 2H).
EXAMPLE 46
[0542] 68
[0543]
Methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-(2-pyridin-2-yl-eth-
yl)-amine
[0544] K.sub.i=4.0 nM
[0545] Prepared analogously to Example 15 using
methyl-(2-pyridin-2-yl-eth- yl)-amine. 1H NMR (400 MHz,
CDCl.sub.3): 8.53-8.51 (m,1H), 7.61-7.56(m, 1H), 7.30-7.09(m, 6H),
3.51 (s, 2H), 3.02-2.98(m, 2H), 2.82-2.78(m, 2H), 2.68-2.57(m, 4H),
2.47(bs, 4H), 2.26(s, 3H), 1.63-1.57(m, 4H), 1.47-1.42(m, 2H).
EXAMPLE 47
[0546] 69
[0547]
[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1--
ynyl)-benzyl]-amine
[0548] K.sub.i=3.0 nM
[0549] Prepared analogously to Example 15 using
[2-(3,4-dimethoxy-phenyl)-- ethyl]-methyl-amine. .sup.1H NMR (400
MHz, CDCl.sub.3): 7.36(s, 1H), 7.29-7.20(m, 3H), 6.80-6.71 (m, 3H),
3.86(s, 6H), 3.51 (s, 2H), 2.78-2.75(m, 2H), 2.68-2.57(m, 6H),
2.46(bs, 4H), 2.26(s, 3H), 1.63-1 .59(m, 4H), 1.47-1.44(m, 2H).
EXAMPLE 48
[0550] 70
[0551]
4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholine
[0552] K.sub.i=1.0 nM
[0553] Prepared analogously to Example 15 using thiomorpholine.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.34(s, 1H), 7.29-7.20(m, 3H),
3.46(s, 2H), 2.69-2.57(m, 12H), 2.47(s, 4H), 1.63-1.57(m, 4H),
1.47-1.42(m, 2H).
EXAMPLE 49
[0554] 71
[0555]
Allyl-cyclopentyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0556] K.sub.i=2.0 nM
[0557] Prepared analogously to Example 15 using
allyl-cyclopentyl-amine. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.37(s,
1H), 7.26-7.18(m, 3H), 5.94-5.84(m, 1H), 5.16-5.09(m, 2H), 3.57(s,
2H), 3.13-3.07(m, 3H), 2.69-2.57(m, 4H), 2.47(bs, 4H), 1.81-1.75(m,
2H), 1.67-1.43(m, 12H).
EXAMPLE 50
[0558] 72
[0559]
10-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-1,4,7-trioxa-10-aza-cyc-
lododecane
[0560] K.sub.i=2.0 nM
[0561] Prepared analogously to Example 15 using
1,4,7-trioxa-10-aza-cyclod- odecane. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.38(s, 1H), 7.30-7.19(m, 3H), 3.72-2.69(m, 8H),
3.64-3.62(m, 6H), 2.74(t, J=4.9Hz, 4H), 2.68-2.58(m, 4H), 2.47(bs,
4H), 1.63-1.57(m, 4H), 1.47-1.43(m, 2H).
EXAMPLE 51
[0562] 73
[0563]
1-[4-(3-Thiazolidin-3-ylmethyl-phenyl)-but-3-ynyl]-piperidine
[0564] K.sub.i=1.0 nM
[0565] Prepared analogously to Example 15 using thiazolidine.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.41 (s, 1H), 7.32-7.23(m, 3H),
4.05(s, 2H), 3.51 (s, 2H), 3.09(t, J=6.3 Hz, 2H), 2.95(t, J=6.4 Hz,
2H), 2.68-2.58(m, 4H), 2.47(bs, 4H), 1.63-1.58(m, 4H), 1.47-1.43(m,
2H).
EXAMPLE 52
[0566] 74
[0567]
[2-(1H-Indol-3-yl)-ethyl]-methyl-[3-(4-piperidin-1-yl-but-1-ynyl)-b-
enzyl]-amine
[0568] K.sub.i=2.0 nM
[0569] Prepared analogously to Example 15 using
[2-(1H-indol-3-yl)-ethyl]-- methyl-amine. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.11 (s, 1H), 7.55(d, 1H), 7.36-7.01 (m, 8H), 3.54(s,
2H), 3.00-2.96(m, 2H), 2.75-2.58(m, 6H), 2.48(bs, 4H), 2.32(s, 3H),
1.63-1.59(m, 4H), 1.47-1.43(m, 2H).
EXAMPLE 53
[0570] 75
[0571]
1-{1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-1,3-d-
ihydro-benzoimidazol-2-one
[0572] K.sub.i=1.0 nM
[0573] Prepared analogously to Example 15 using
1-piperidin-4-yl-1,3-dihyd- ro-benzoimidazol-2-one. .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.35(s, 1H), 7.29-7.21(m, 3H), 5.41 (d, 30.1
Hz, 2H), 3.45(s, 2H), 2.90(d, J=11.7 Hz, 2H), 2.68-2.57(m, 4H),
2.68-2.57(m, 4H), 2.47(bs, 4H), 2.19-2.11(m, 1H), 2.02-1.96(m, 2H),
1.88-1.63(m, 4H), 1.62-1.57(m, 4H), 1.47-1.42(m, 2H).
EXAMPLE 54
[0574] 76
[0575] Phenyl-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0576] K.sub.i=110 nM
[0577] Prepared analogously to Example 15 using aniline. .sup.1H
NMR (400 MHz, CDCl.sub.3): 7.41(s, 1H), 7.40-7.24(m, 3H),
7.19-7.15(m, 2H), 6.72(t, J=7.3 Hz, 1H), 6.63-6.61 (m, 2H), 4.29(d,
J=5.2 Hz, 2H), 4.03(bs, 1H), 2.68-2.57(m, 4H), 2.46(bs, 4H),
2.18(s, 1H), 1.62-1.57(m, 4H), 1.47-1.44(m, 2H).
EXAMPLE 55
[0578] 77
[0579]
1-[4-(3-Pyrrolidin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine
[0580] K.sub.i=1.0 nM
[0581] Prepared analogously to Example 15 using pyrrolidine.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.37(s,1H), 7.28-7.22(m, 3H),
3.56(s, 2H), 2.68-2.57(m, 4H), 2.51-2.46(m, 8H), 1.79-1.76(m, 4H),
1.70-1.57(m, 4H), 1.47-1.43(m, 2H).
EXAMPLE 56
[0582] 78
[0583]
1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-azacyclotridecane
[0584] K.sub.i=13 nM
[0585] Prepared analogously to Example 15 using azacyclotridecane.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.37(s,1H), 7.28-7.19(m, 3H),
3.43(s, 2H), 2.50(bs, 4H), 2.36-2.33(m, 8H), 1.65-1.38(m, 26H).
EXAMPLE 57
[0586] 79
[0587]
Dimethyl-[4-(4-piperidin-1-ylmethyl-phenyl)-but-3-ynyl]-amine
[0588] May be prepared analogously to Example 19 using
dimethylamine hydrochloride.
EXAMPLE 58
[0589] 80
[0590] Dimethyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0591] May be prepared analogously to Example 23 using
dimethylamine hydrochloride.
EXAMPLE 59
[0592] 81
[0593] Phenyl-[4-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-amine
[0594] May be prepared analogously to Example 23 using aniline.
EXAMPLE 60
[0595] 82
[0596]
1-[4-(3-Aziridin-1-ylmethyl-phenyl)-but-3-ynyl]-piperidine
[0597] May be prepared analogously to Example 15 using aziridine
hydrochloride.
EXAMPLE 61
[0598] 83
[0599]
2-{1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yloxy}-py-
rimidine
[0600] May be prepared analogously to Example 15 using
2-(piperidin-4-yloxy)-pyrimidine.
EXAMPLE 62
[0601] 84
[0602]
{1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-yl}-pyridin-
-2-yl-amine
[0603] May be prepared analogously to Example 15 using
piperidin-4-yl-pyridin-2-yl-amine.
EXAMPLE 63
[0604] 85
[0605]
4-[4-(3-Morpholin-4-ylmethyl-phenyl)-but-3-ynyl]-morpholine
[0606] May be prepared analogously to Example 15 using the product
of Example 10 and morpholine.
EXAMPLE 64
[0607] 86
[0608]
4-[3-(4-Thiomorpholin-4-yl-but-1-ynyl)-benzyl]-morpholine
[0609] May be prepared analogously to Example 15 using the product
of Example 11 and morpholine.
EXAMPLE 65
[0610] 87
[0611]
4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-thiomorpholine
[0612] May be prepared analogously to Example 15 using
thiomorpholine.
EXAMPLE 66
[0613] 88
[0614]
4-[4-(3-Thiomorpholin-4-ylmethyl-phenyl)-but-3-ynyl]-morpholine
[0615] May be prepared analogously to Example 15 using the product
of Example 10 and thiomorpholine.
EXAMPLE 67
[0616] 89
[0617]
4-[3-(4-Thiomorpholin-4-yl-but-1-ynyl)-benzyl]-thiomorpholine
[0618] May be prepared analogously to Example 15 using the product
of Example 11 and thiomorpholine.
EXAMPLE 68
[0619] 90
[0620]
4-{4-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-but-3-ynyl}-morphol-
ine
[0621] May be prepared analogously to Example 15 using the product
of Example 10 and 1-methylpiperazine.
EXAMPLE 69
[0622] 91
[0623]
4-{4-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-but-3-ynyl}-thiomor-
pholine
[0624] May be prepared analogously to Example 15 using the product
of Example 11 and 1-methylpiperazine.
EXAMPLE 70
[0625] 92
[0626]
1-Methyl-4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-piperazine
[0627] May be prepared analogously to Example 15 using
1-methylpiperazine.
EXAMPLE 71
[0628] 93
[0629]
1-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-piperidin-4-ol
[0630] May be prepared analogously to Example 15 using
piperidin-4-ol.
EXAMPLE 72
[0631] 94
[0632]
1-[3-(4-Morpholin-4-yl-but-1-ynyl)-benzyl]-piperidin-4-ol
[0633] May be prepared analogously to Example 15 using the product
of Example 10 and piperidin-4-ol.
EXAMPLE 73
[0634] 95
[0635]
1-[3-(4-Thiomorpholin-4-yl-but-1-ynyl)-benzyl]-piperidin-4-ol
[0636] May be prepared analogously to Example 15 using the product
of Example 11 and piperidin-4-ol.
EXAMPLE 74
[0637] 96
[0638]
1-{4-[3-(4-Methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-piperi-
dine
[0639] May be prepared analogously to Example 15 using
4-methoxypiperidine.
EXAMPLE 75
[0640] 97
[0641]
4-{4-[3-(4-Methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-morpho-
line
[0642] May be prepared analogously to Example 15 using the product
of Example 10 and 4-methoxypiperidine.
EXAMPLE 76
[0643] 98
[0644]
4-{4-[3-(4-Methoxy-piperidin-1-ylmethyl)-phenyl]-but-3-ynyl}-thiomo-
rpholine
[0645] May be prepared analogously to Example 15 using the product
of Example 11 and 4-methoxypiperidine.
EXAMPLE 77
[0646] Biological Methods
[0647] In Vitro
[0648] Transfection of Cells With Human Histamine Receptor
[0649] A 10 cm tissue culture dish with a confluent monolayer of
SK-N-MC cells was split two days prior to transfection. Using
sterile technique the media were removed and the cells were
detached from the dish by the addition of trypsin. One fifth of the
cells were then placed onto a new 10 cm dish. Cells were grown in a
37.degree. C. incubator with 5% CO.sub.2 in Minimal Essential Media
Eagle with 10% Fetal Bovine Serum. After two days cells were
approximately 80% confluent. These were removed from the dish with
trypsin and pelleted in a clinical centrifuge. The pellet was then
re-suspended in 400 .mu.L complete media and transferred to an
electroporation cuvette with a 0.4 cm gap between the electrodes.
One microgram of supercoiled H.sub.3 receptor cDNA was added to the
cells and mixed. The voltage for the electroporation was set at
0.25 kV, the capacitance was set at 960 .mu.F. After
electroporation the cells were diluted into 10 mL complete media
and plated onto four 10 cm dishes. Because of the variability in
the efficiency of electroporation, four different concentrations of
cells were plated. The ratios used were; 1:20, 1:10, 1:5, with the
remainder of the cells being added to the fourth dish. The cells
were allowed to recover for 24 hours before adding the selection
media (complete media with 600 .mu.g/mL G418). After 10 days dishes
were analyzed for surviving colonies of cells. Dishes with well
isolated colonies were used. Cells from individual colonies were
isolated and tested. SK-N-MC cells were used because they give
efficient coupling for inhibition of adenylate cyclase. The clones
that gave the most robust inhibition of adenylate cyclase in
response to histamine were used for further study.
[0650] [.sup.3H]-N-Methylhistamine Binding
[0651] Cell pellets from histamine H.sub.3 receptor-expressing
SK-N-MC cells were homogenized in 20 mM TrisHCl/0.5 mM EDTA.
Supernatants from a 800 g spin were collected, recentrifuged at
30,000 g for 30 min. Pellets were re-homogenized in 50 mM Tris/5 mM
EDTA (pH 7.4). Membranes were incubated with 0.8 nM
[.sup.3H]-N-methylhistamine plus/minus test compounds for 45 min at
25.degree. C. and harvested by rapid filtration over GF/C glass
fiber filters (pretreated with 0.3% polyethylenimine) followed by
four washes with ice cold buffer. Filters were dried, added to 4 mL
scintillation cocktail and then counted on a liquid scintillation
counter. Non-specific binding was defined with 10 .mu.M histamine.
The pK.sub.i values were calculated based on a K.sub.d of 800 pM
and a ligand concentration ([L]) of 800 pM according to the
formula:
K.sub.i=(IC.sub.50)/(1+([L]/(K.sub.d))
[0652] In Vivo
[0653] Elucidation of oral absorption and blood-brain barrier
penetration profiles of H.sub.3 receptor antagonists in the rat
[0654] A rat in vivo system was used to determine the blood-brain
barrier penetration profiles and kinetics of various H.sub.3
receptor antagonists after single bolus oral administration.
[0655] Female Sprague Dawley Rats (.about.300 gram body weight)
were housed in accordance with institutional standards and allowed
to acclimate for at least 7 days prior to the study. Each H.sub.3
antagonist was formulated in 0.5% hydroxypropylmethyl cellulose at
a concentration of 1 mg/mL for oral dosing. The test compound was
administered to each of eight animals as a single oral dose of 10
mL/kg (10 mg/kg). Remaining dosing solution was retained for
analysis. Two animals from each original group of eight were
euthanized via CO.sub.2 asphyxiation at t=1, 6, 24, and 48 h. After
each animal was euthanized, 0.1 mL of its blood was sampled via
cardiac puncture, and its brain was removed via dissection of the
cranial bones and placed in a pre-weighed 50 mL conical tube on dry
ice.
[0656] The blood was added to 0.3 mL of 6% trichloroacetic acid,
and the acidified sample was vortexed and then centrifuged (5 min
at 14,000 rpm in a microcentrifuge). The clear supernatant was
retained for analysis. The frozen brain was weighed, homogenized in
6% trichloroacetic acid (3 mUg wet weight of tissue), and then
centrifuged. The clear supernatant was retained for analysis. The
supernatants from the blood and brain samples were analyzed by
liquid chromatography with mass spectral detection utilizing
selective reaction monitoring (LC-MS/MS). The LC method used a
Phenomonex Polar RP column (2.times.50 mm) and a linear solvent
gradient of water and acetonitrile (both 1% in acetic acid).
[0657] Graphs of H.sub.3 receptor antagonist concentration versus
time for blood and brain were generated from the LC-MS/MS results.
The mean residency time (MRT) of the H.sub.3 receptor antagonist,
in blood or in the brain, was calculated from the ratio of the area
under the first moment curve (AUMC) to the area under the
concentration time curve (AUC): AUMC/AUC. The Blood Brain Barrier
index was calculated from the log of
AUC.sub.brain/AUC.sub.blood.
[0658] F. Other Embodiments
[0659] The features and advantages of the invention will be
apparent to one of ordinary skill in view of the discussion,
examples, embodiments, and claims relating to the invention. The
invention also contemplates variations and adaptations, based on
the disclosure herein concerning the key features and advantages of
the invention, and within the abilities of one of ordinary
skill.
* * * * *