U.S. patent application number 15/091776 was filed with the patent office on 2017-02-16 for pyridinoylpiperidines as 5-ht1f agonists.
The applicant listed for this patent is Eli Lilly and Company. Invention is credited to Michael Philip Cohen, Daniel Timothy Kohlman, Sidney Xi Liang, Frantz Victor, Yao-Chang Xu, Bai-Ping Ying, DeAnna Piatt Zacherl, Deyi Zhang.
Application Number | 20170044136 15/091776 |
Document ID | / |
Family ID | 28791923 |
Filed Date | 2017-02-16 |
United States Patent
Application |
20170044136 |
Kind Code |
A1 |
Cohen; Michael Philip ; et
al. |
February 16, 2017 |
Pyridinoylpiperidines As 5-HT1F Agonists
Abstract
The present invention relates to compounds of formula I:
##STR00001## or pharmaceutically acceptable acid addition salts
thereof, where; R.sup.1 is C.sub.1-C.sub.6 alkyl, substituted
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, substituted
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl-C.sub.1-C.sub.3 alkyl, substituted C.sub.3-C.sub.7
cycloalkyl-C.sub.1-C.sub.3 alkyl, phenyl, substituted phenyl,
heterocycle, or substituted heterocycle; R.sup.2 is hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 cycloalkyl-C.sub.1-C.sub.3
alkyl, or a group of formula II ##STR00002## R.sup.3 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sup.4 is hydrogen, halo, or
C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen or C.sub.1-C.sub.3
alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.6 alkyl; and n is an
integer from 1 to 6 inclusively. The compounds of the present
invention are useful for activating 5-HT.sub.1F receptors,
inhibiting neuronal protein extravasation, and for the treatment or
prevention of migraine in a mammal. The present invention also
relates to a process for the synthesis of intermediates in the
synthesis of compounds of Formula I.
Inventors: |
Cohen; Michael Philip;
(Indianapolis, IN) ; Kohlman; Daniel Timothy;
(Camby, IN) ; Liang; Sidney Xi; (Bethany, CT)
; Victor; Frantz; (Indianapolis, IN) ; Xu;
Yao-Chang; (Fishers, IN) ; Ying; Bai-Ping;
(Sunnyvale, CA) ; Zacherl; DeAnna Piatt;
(Noblesville, IN) ; Zhang; Deyi; (Carmel,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Eli Lilly and Company |
Indianapolis |
IN |
US |
|
|
Family ID: |
28791923 |
Appl. No.: |
15/091776 |
Filed: |
April 6, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14296911 |
Jun 5, 2014 |
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15091776 |
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13363895 |
Feb 1, 2012 |
8748459 |
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14296911 |
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12221919 |
Aug 7, 2008 |
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13363895 |
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10509770 |
Sep 28, 2004 |
7423050 |
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PCT/US2003/008455 |
Mar 27, 2003 |
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12221919 |
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60369088 |
Mar 29, 2002 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/06 20180101;
A61P 25/18 20180101; A61P 43/00 20180101; C07D 417/14 20130101;
C07D 401/14 20130101; C07D 401/06 20130101; A61P 25/28 20180101;
C07D 405/14 20130101; A61P 25/24 20180101; A61P 25/22 20180101;
A61P 25/20 20180101; A61P 15/00 20180101; C07D 409/14 20130101;
A61P 17/14 20180101; A61P 25/00 20180101; A61P 25/32 20180101; A61P
9/08 20180101; A61P 25/34 20180101; A61P 15/10 20180101 |
International
Class: |
C07D 401/06 20060101
C07D401/06; C07D 417/14 20060101 C07D417/14; C07D 401/14 20060101
C07D401/14; C07D 409/14 20060101 C07D409/14; C07D 405/14 20060101
C07D405/14 |
Claims
1. A compound of formula I: ##STR00102## or a pharmaceutically
acceptable acid addition salt thereof, where; R.sup.1 is
C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.7 cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl,
C.sub.3-C.sub.7 cycloalkyl-C.sub.1-C.sub.3 alkyl, substituted
C.sub.3-C.sub.7 cycloalkyl-C.sub.1-C.sub.3 alkyl, phenyl,
substituted phenyl, heterocycle, or substituted heterocycle;
R.sup.2 is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6
cycloalkyl-C.sub.1-C.sub.3 alkyl, or a group of formula II
##STR00103## R.sup.3 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.4
is hydrogen, halo, or C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl; and n is an integer from 1 to 6 inclusively.
2. The compound claim 1, wherein R.sup.5 is hydrogen and R.sup.4 is
hydrogen or halogen.
3. The compound of claim 2, wherein R.sup.4 is hydrogen.
4. The Compound of claim 1, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl.
5. The compound of claim 1, wherein R.sup.1 is phenyl, substituted
phenyl, heterocycle, or substituted heterocycle.
6. The compound of claim 1, wherein R.sup.1 is phenyl, substituted
phenyl, heterocycle or substituted heterocycle, wherein the
heterocycle moiety is selected from the group consisting of
furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl,
N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl,
N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl,
quinolinyl, benzofuranyl, benzothiophenyl, and indolyl, and wherein
substituted is taken to mean the ring moiety is substituted with
one to three halo substituents; or substituted with one to two
substituents independently selected from the group consisting of
halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and
C.sub.1-C.sub.4 alkylthio, wherein each alkyl, alkoxy and alkylthio
substituent can be further substituted independently with
C.sub.1-C.sub.2 alkoxy or with one to five halo groups each
independently selected from fluoro and chloro; or substituted with
one substituent selected from the group consisting of phenyloxy,
benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the
phenyloxy, benzyloxy, phenylthio, benzylthio, or pyrimidinyloxy
moiety can be further substituted with one to two substituents
selected from the group consisting of halo, C.sub.1-C.sub.2 alkyl,
and C.sub.1-C.sub.2 alkoxy; or substituted with one substituent
selected from the group consisting of C.sub.1-C.sub.4 acyl and
C.sub.1-C.sub.4 alkoxycarbonyl, and further substituted with zero
to one substituent selected from the group consisting of halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkylthio.
7. The compound of claim 1, wherein R.sup.1 is phenyl, substituted
phenyl, heterocycle or substituted heterocycle, wherein the
heterocycle moiety is selected from the group consisting of
pyridinyl, indolyl, benzofuranyl, furanyl, thiophenyl,
benzodioxolyl, and thiazolidinyl, and wherein substituted is taken
to mean the ring moiety is substituted with one to three halo
substituents; or substituted with one to two substituents
independently selected from the group consisting of halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can
be further substituted independently with C.sub.1-C.sub.2 alkoxy or
with one to five halo groups each independently selected from
fluoro and chloro; or substituted with one substituent selected
from the group consisting of phenyloxy, benzyloxy, phenylthio,
benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy,
phenylthio, benzylthio, or pyrimidinyloxy moiety can be further
substituted with one to two substituents selected from the group
consisting of halo, C.sub.1-C.sub.2 alkyl, and C.sub.1-C.sub.2
alkoxy; or substituted with one substituent selected from the group
consisting of C.sub.1-C.sub.4 acyl and C.sub.1-C.sub.4
alkoxycarbonyl, and further substituted with zero to one
substituent selected from the group consisting of halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkylthio.
8. A method for activating 5-HT.sub.1F receptors in a mammal
comprising administering to a mammal in need of such activation an
effective amount of a compound of formula I: ##STR00104## or a
pharmaceutically acceptable acid addition salt thereof, where;
R.sup.1 is C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.7 cycloalkyl, substituted C.sub.3-C.sub.7
cycloalkyl, C.sub.3-C.sub.7 cycloalkyl-C.sub.1-C.sub.3 alkyl,
substituted C.sub.3-C.sub.7 cycloalkyl-C.sub.1-C.sub.3 alkyl,
phenyl, substituted phenyl heterocycle, or substituted heterocycle;
R.sup.2 is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6
cycloalkyl-C.sub.1-C.sub.3 alkyl, or a group of formula II
##STR00105## R.sup.3 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sup.4
is hydrogen, halo, or C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.6
alkyl; and n is an integer from 1 to 6 inclusively.
9. The method according to claim 8, wherein the mammal is a
human.
10. A method for the treatment or prevention of migraine in a
mammal comprising administering to a mammal in need of such
treatment or prevention an effective amount of a compound of
formula I: ##STR00106## or a pharmaceutically acceptable acid
addition salt thereof, where; R.sup.1 is C.sub.1-C.sub.6 alkyl,
substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl,
substituted C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl-C.sub.1-C.sub.3 alkyl, substituted C.sub.3-C.sub.7
cycloalkyl-C.sub.1-C.sub.3 alkyl, phenyl, -substituted phenyl,
heterocycle, or substituted heterocycle; R.sup.2 is hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6 cycloalkyl-C.sub.1-C.sub.3
alkyl, or a group of formula II ##STR00107## R.sup.3 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sup.4 is hydrogen, halo, or
C.sub.1-C.sub.3 alkyl; R.sup.5 is hydrogen or C.sub.1-C.sub.3
alkyl; R.sup.6 is hydrogen or C.sub.1-C.sub.6 alkyl; and n is an
integer front 1 to 6 inclusively.
11. The method according to claim 10, wherein the mammal is a
human.
12. The compound of claim 5, wherein R.sup.5 is hydrogen and
R.sup.4 is hydrogen or halogen.
13. The compound of claim 12, wherein R.sup.4 is hydrogen.
14. The compound of claim 5, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl.
15. The compound of claim 6, wherein R.sup.5 is hydrogen and
R.sup.4 is hydrogen or halogen.
16. The compound of claim 15, wherein R.sup.4 is hydrogen.
17. The compound of claim 6, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl.
18. The compound of claim 7, wherein R.sup.5 is hydrogen and
R.sup.4 is hydrogen or halogen.
19. The compound of claim 18, wherein R.sup.4 is hydrogen.
20. The compound of claim 7, wherein R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl.
Description
RELATED APPLICATIONS
[0001] This application is a continuation and claims the benefit of
priority under 35 U.S.C. 120 to U.S. application Ser. No.
13/363,895, filed Feb. 1, 2012, which is a continuation of U.S.
application Ser. No. 12/221,919, filed Aug. 7, 2008, which is a
continuation of U.S. application Ser. No. 10/509,770, filed Sep.
28, 2004, now U.S. Pat. No. 7,423,050, which is a U.S. national
stage application, filed under 35 U.S.C. 371, of International
Application PCT/US03/08455, filed Mar. 27, 2003, which claims
priority to U.S. provisional Application No. 60/369,088, filed Mar.
29, 2002, the disclosures of each of which are incorporated by
reference herein in their entireties.
BACKGROUND OF THE INVENTION
[0002] Until recently, theories regarding the pathophysiology of
migraine have been dominated since 1938 by the work of Graham and
Wolff. Arch. Neurol. Psychiatry, 39:737-63, 1938. They proposed
that the cause of migraine headache was vasodilatation of
extracranial vessels. This view was supported by knowledge that
ergot alkaloids and sumatriptan, a hydrophilic 5-HT.sub.1 agonist
which does not cross the blood-brain barrier, induce contraction of
cephalic vascular smooth muscle and are effective in the treatment
of migraine. Humphrey, et al., Ann. NY Acad. Sci., 600:587-600,
1990. Recent work by Moskowitz has shown, however, that the
occurrence of migraine headaches is independent of changes in
vessel diameter. Cephalalgia, 12:5-7, 1992.
[0003] Moskowitz has proposed that currently unknown triggers for
pain stimulate trigeminal ganglia that innervate vasculature within
the cephalic tissue, giving rise to release of vasoactive
neuropeptides from axons on the vasculature. These released
neuropeptides then activate a series of events, a consequence of
which is pain. This neurogenic inflammation is blocked by
sumatriptan and ergot alkaloids by mechanisms involving 5-HT
receptors, believed to be closely related to the 5-HT.sub.1D
subtype, located on the trigeminovascular fibers. Neurology,
43(suppl. 3):S16-S20 1993. Sumatriptan, in fact, has high affinity
for the 5-HT.sub.1B and 5-HT.sub.1D receptors, Ki=10.3 nM and 5.1
nM, respectively, which activity may be indicative of
vasoconstrictive activity. Sumatriptan and similar compounds
previously advanced for the treatment of migraine had tended to be
selected on the basis of this vasoconstrictive activity under the
premises of the prior art models for migraine.
[0004] Serotonin (5-HT) exhibits diverse physiological activity
mediated by at least seven receptor classes, the most heterogeneous
of which appears to be 5-HT.sub.1. A human gene which expresses one
of these 5-HT.sub.1 receptor subtypes, named 5-HT.sub.1F, was
isolated by Kao and coworkers. Proc. Natl. Acad. Sci. USA,
90:408-412, 1993. This 5-HT.sub.1F receptor exhibits a
pharmacological profile distinct from any serotonergic receptor yet
described. It was found that sumatriptan, in addition to the above
mentioned strong affinities for the 5-HT.sub.1B and 5-HT.sub.1D
receptors, also has affinity for this receptor subtype, with a
K.sub.i of about 23 nM. This suggests a possible role of the
5-HT.sub.1F receptor in migraine.
[0005] Various 5-HT.sub.1F receptor agonists have subsequently been
developed which have shown relative selectivity for the 5-HT.sub.1F
receptor subclass and it has been shown that such selectivity
generally reduces the vasoconstrictive activity characteristic of
other compounds advanced as potential agents for the treatment of
migraine and associated disorders.
[0006] Included among these 5-HT.sub.1F receptor agonists are
compounds disclosed in the following: [0007] X-09763 U.S. Pat. Nos.
5,708,187 and 5,814,653, describing a family of
6-substituted-3-amino(alkyl)-tetrahydrocarbazoles and
7-substituted-4-amino(alkyl)cyclohepta[7,6b]Indoles; [0008] X-9801
U.S. Pat. No. 5,521,196, U.S. Pat. No. 5,721,252, X-9850 U.S. Pat.
No. 5,521,197, and X-10054A WO 96/29075, describing various
families of 5-substituted piperidin-3-yl-indoles and 5-substituted
1,2,3,6 tetrahydropyridin-3-yl-indoles; [0009] X-10224 WO 97/13512
describing a family of 5-substituted 3-aminoethylindoles; [0010]
X-10252 WO 98/46570 describing a family of 5-substituted indoles,
pyrrolo[3,2-b]pyridines, benzofurans, and benzothiophenes, having
the 3-position substituted with octahydroindolizinyl,
octahydro-2H-quinolizinyl, decahydropyrido[1,2-a]azepinyl,
1,2,3,5,8,8a-hexahydroindolizinyl,
1,3,4,6,9,9a-hexahydro-2H-quinolizinyl, or
1,4,6,7,8,9,10,10a-octahydropyrido[1,2-a]azepinyl; [0011] X-10612
WO 98/20875 and X-11700 WO 99/25348 describing two families of
5-substituted piperidin-3-yl-azaindoles and 5-substituted
1,2,3,6-tetrahydropyridin-3-yl-azaindoles; [0012] X-10810 WO
00/00487 describing a family of 5-substituted (piperidin-3-yl or
1,2,3,6-tetrahydropyridin-3-yl)indoles, azaindoles, benzofurans,
and benzothiophenes; [0013] X-10830 WO 98/08502 describing a family
of 8-substituted-1,2,3,4-tetrahydro-2-dibenzofuranamines and
9-substituted-2-aminocyclohepta[b]benzofurans; [0014] X-10833 WO
98/55115 describing a family of
3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides and
4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides; [0015] X-11000
WO 98/15545 describing a select family of 3,5-disubstituted indoles
and benzofurans; [0016] X-11044 WO 00/00490 describing a family of
5-allyl-substituted (piperidin-3-yl or
1,2,3,6-tetrahydropyridin-3-yl)indoles, azaindoles, benzofurans,
and benzothiophenes; [0017] X-11704 WO 00/47559 describing a family
of 4-(3-substituted-benzoyl)piperidines; [0018] X-11818 WO 00/50426
describing a family of 3,5-disubstituted azabenzofurans; and [0019]
X-12288 WO 00/34266 describing a family of 3-heteroaryl-5-[2-(aryl
or heteroaryl)-2-oxoethyl]indoles.
[0020] Continued research has now surprisingly yielded a new and
unexpected class of novel selective 5-HT.sub.1F agonists having
distinct chemical and receptor binding properties, which inhibit
peptide extravasation, while avoiding significant vasoconstrictive
activity, and are therefore useful for the treatment of migraine
and other 5-HT.sub.1F receptor associated disorders. Furthermore,
the compounds of the present invention may provide improved
solubility, which facilitates suitability in preferred
formulations, such as sublingual, buccal, and/or nasal
formulations.
SUMMARY OF THE INVENTION
[0021] The present invention relates to pyridinoylpiperidine
compounds of the general formula I:
##STR00003##
and pharmaceutically acceptable acid addition salts thereof,
where;
[0022] R.sup.1 is C.sub.1-C.sub.6 alkyl, substituted
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, substituted
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl-C.sub.1-C.sub.3 alkyl, substituted C.sub.3-C.sub.7
cycloalkyl-C.sub.1-C.sub.3 alkyl, phenyl, substituted phenyl,
heterocycle, or substituted heterocycle;
[0023] R.sup.2 is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6
cycloalkyl-C.sub.1-C.sub.3 alkyl, or a group of formula II
##STR00004##
[0024] R.sup.3 is hydrogen or C.sub.1-C.sub.3 alkyl;
[0025] R.sup.4 is hydrogen, halo, or C.sub.1-C.sub.3 alkyl;
[0026] R.sup.5 is hydrogen or C.sub.1-C.sub.3 alkyl;
[0027] R.sup.6 is hydrogen or C.sub.1-C.sub.6 alkyl; and
[0028] n is an integer from 1 to 6 inclusively.
[0029] In one preferred embodiment, the present invention relates
to pyridinoylpiperidine compounds of the general formula I:
##STR00005##
and pharmaceutically acceptable acid addition salts thereof,
wherein;
[0030] R.sup.1 is phenyl, substituted phenyl, heterocycle or
substituted heterocycle;
[0031] R.sup.2 is hydrogen or C.sub.1-C.sub.2 alkyl;
[0032] R.sup.3 is hydrogen or methyl; and
[0033] R.sup.4 and R.sup.5 are both hydrogen.
[0034] Other preferred compounds are those of formula I wherein
R.sup.3 is hydrogen.
[0035] This invention also relates to pharmaceutical formulations
comprising a compound of formula I, or a pharmaceutically
acceptable acid addition salt thereof, and a pharmaceutical
carrier, diluent, or excipient. In preferred embodiments of this
aspect of the present invention, there are provided pharmaceutical
formulations containing a compound of formula I, or a
pharmaceutically acceptable salt thereof, adapted for the
activation of 5-HT.sub.1F receptors, for the inhibition of neuronal
protein extravasation, for the treatment or prevention of migraine,
and/or the treatment or prevention of anxiety in mammals,
particularly humans.
[0036] In addition, the present invention relates to a method for
activating 5-HT.sub.1F receptors in mammals, particularly humans,
comprising administering to a mammal in need of such activation an
effective amount of a compound of formula I, or a pharmaceutically
acceptable acid addition salt thereof.
[0037] Moreover, the current invention relates to a method for
inhibiting neuronal protein extravasation in mammals, particularly
humans, comprising administering to a mammal in need of such
inhibition an effective amount of a compound of formula I, or a
pharmaceutically acceptable acid addition salt thereof.
[0038] Additionally, the present invention relates to a method for
treating or preventing migraine in mammals, particularly humans,
comprising administering to a mammal in need of such treatment or
prevention, an effective amount of a compound of formula I, or a
pharmaceutically acceptable acid addition salt thereof.
[0039] Additionally, the present invention relates to a method for
treating anxiety in mammals, particularly humans, comprising
administering to a mammal in need of such treatment or prevention,
an effective amount of a compound of formula I, or a
pharmaceutically acceptable acid addition salt thereof.
[0040] In another aspect, the present invention relates to a
compound of formula I, or a pharmaceutically acceptable acid
addition salt thereof, for use in the activation of 5-HT.sub.1F
receptors, in the inhibition of neuronal protein extravasation, in
the treatment or prevention of migraine, and/or in the treatment of
anxiety in mammals, particularly humans. That is to say, the
present invention relates to the use of a compound of formula I as
a medicament for the activation of 5-HT.sub.1F receptors, for the
inhibition of neuronal protein extravasation, for the treatment or
prevention of migraine, and/or for the treatment of anxiety in
mammals, particularly humans.
[0041] Additionally, the present invention relates to the use of
one or more compounds of formula I in the manufacture of a
medicament for the activation of 5-HT.sub.1F receptors, for the
inhibition of neuronal protein extravasation, for the treatment or
prevention of migraine, and/or for the treatment of anxiety in
mammals, particularly humans.
[0042] Furthermore, the present invention provides for methods for
the treatment of 5-HT.sub.1F mediated disorders comprising
administering to a mammal in need of such treatment, particularly a
human, an effective amount of a compound of formula I, or a
pharmaceutically acceptable acid addition salt thereof.
[0043] In another aspect of the present invention, there is
provided a process for the synthesis of compounds of formula I and
of novel intermediates in the synthesis. In one embodiment, the
present invention provides a process for preparing a
2-halo-6-(piperidin-4-carbonyl)pyridine compound of formula III
##STR00006##
[0044] where X is bromo or chloro;
[0045] R.sup.8 is an amino protecting group, C.sub.1-C.sub.3 alkyl,
C.sub.3-C.sub.6 cycloalkyl-C.sub.1-C.sub.3 alkyl, or a group of
formula II
##STR00007##
[0046] R.sup.6 is hydrogen or C.sub.1-C.sub.6 alkyl; and
[0047] n is an integer from 1 to 6 inclusively;
comprising
[0048] 1) reacting a 2,6-dihalopyridine selected from the group
consisting of 2,6-dibromopyridine and 2,6-dichloropyridine, with
n-butyl lithium to form 2-halo-6-lithium-pyridine; and then
[0049] 2) reacting the 2-halo-6-lithium-pyridine with a substituted
aminocarbonylpiperidine compound of formula IV
##STR00008##
wherein R.sup.9 and R.sup.10 are each methyl, or R.sup.9 and
R.sup.10, together with the nitrogen to which they are attached,
combine to form azetidinyl, pyrrolidinyl, or piperidinyl.
[0050] In a particular embodiment of this aspect of the present
invention, there is provided a process for preparing a
2-bromo-6-(piperidin-4-carbonyl)pyridine compound of formula
III
##STR00009##
wherein R.sup.7 is C1-C3 n-alkyl, or an amino protecting group;
comprising reacting 2,6-dibromopyridine with n-butyl lithium to
form 2-bromo-6-lithium pyridine, and then reacting the
2-bromo-6-lithium pyridine with a 4-(N,N'-dimethylamino)carbonyl
piperidine compound of formula IV
##STR00010##
in a methyl tert-butyl ether solvent.
DETAILED DESCRIPTION OF THE INVENTION
[0051] One embodiment of the present invention is a method for
increasing activation of 5-HT.sub.1F receptors, while avoiding
vasoconstrictive activity, for treating a variety of disorders that
have been linked to decreased neurotransmission of serotonin in
mammals. Included among these disorders are migraine, general pain,
trigeminal neuralgia, dental pain or temperomandibular joint
dysfunction pain, anxiety, general anxiety disorder, panic
disorder, depression, disorders of sleep, chronic fatigue syndrome,
premenstrual syndrome or late luteal phase syndrome, post-traumatic
syndrome, memory loss, dementia including dementia of aging, social
phobia, autism, attention deficit hyperactivity disorder,
disruptive behavior disorders, impulse control disorders,
borderline personality disorder, obsessive compulsive disorder,
premature ejaculation, erectile dysfunction, bulimia, anorexia
nervosa, alcoholism, tobacco abuse, mutism, and trichotillomania.
The compounds of this invention are also useful as a prophylactic
treatment for migraine. Any of these methods employ a compound of
formula I.
[0052] In those instances where the disorders which can be treated
by serotonin agonists are known by established and accepted
classifications, their classifications can be found in various
sources. For example, at present, the fourth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV.TM.)
(1994, American Psychiatric Association, Washington, D.C.),
provides a diagnostic tool for identifying many of the disorders
described herein. Also, the International Classification of
Diseases, Tenth Revision (ICD-10), provides classifications for
many of the disorders described herein. The skilled artisan will
recognize that there are alternative nomenclatures, nosologies, and
classification systems for disorders described herein, including
those as described in the DSM-IV and ICD-10, and that terminology
and classification systems evolve with medical scientific
progress.
[0053] The use of a compound of formula I for the activation of the
5-HT.sub.1F receptor, for the inhibition of neuronal peptide
extravasation, in general or due to stimulation of the trigeminal
ganglia specifically, and/or for the treatment of any of the
disorders described above, are all embodiments of the present
invention.
[0054] Likewise, the use of a compound of formula I, or a
combination of more than one compound of formula I, in the
manufacture of a medicament for the activation of the 5-HT.sub.1F
receptor, for the inhibition of neuronal peptide extravasation, in
general or due to stimulation of the trigeminal ganglia
specifically, and/or for the treatment of any of the disorders
described above, are also all embodiments of the present
invention.
The general chemical terms used throughout have their usual
meanings. For example, the term alkyl refers to a branched or
unbranched saturated hydrocarbon group. The term "n-alkyl" refers
to an unbranched alkyl group. The term "C.sub.x-C.sub.y alkyl"
refers to an alkyl group having between x and y carbon atoms,
inclusively, in the branched or unbranched hydrocarbon group. By
way of illustration, but without limitation, the term
"C.sub.1-C.sub.4 alkyl" refers to a straight chain or branched
hydrocarbon moiety having from 1 to 4 carbon atoms, including
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
and tert-butyl. The term "C.sub.1-C.sub.4 n-alkyl" refers to
straight chain hydrocarbon moieties having from 1 to 4 carbon atoms
including methyl, ethyl, n-propyl, and n-butyl. The term
"C.sub.3-C.sub.6 cycloalkyl" refers to cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl. The term "C.sub.3-C.sub.7 cycloalkyl"
also includes cycloheptyl. Cycloalkylalkyl refers to cycloalkyl
moieties linked through an alkyl linker chain, as for example, but
without limitation, cyclopropylmethyl, cyclopropylethyl,
cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl,
cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl,
cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl,
cyclohexylethyl, and cyclohexylpropyl. Each alkyl, cycloalkyl, and
cycloalkylalkyl group may be optionally substituted as specified
herein.
[0055] The terms "alkoxy", "phenyloxy", "benzoxy" and
"pyrimidinyloxy" refer to an alkyl group, phenyl group, benzyl
group, or pyrimidinyl group, respectively, each optionally
substituted, that is bonded through an oxygen atom.
[0056] The terms "alkylthio", "phenylthio", and "benzylthio" refer
to an alkyl group, phenyl group, or benzyl group, respectively,
each optionally substituted, that is bonded through a sulfur
atom.
[0057] The term "C.sub.1-C.sub.4 acyl" refers to a formyl group or
a C.sub.1-C.sub.3 alkyl group bonded through a carbonyl moiety. The
term "C.sub.1-C.sub.4 alkoxycarbonyl" refers to a C.sub.1-C.sub.4
alkoxy group bonded through a carbonyl moiety.
[0058] The term "halo" refers to fluoro, chloro, bromo, or iodo.
Preferred halo groups are fluoro, chloro, and bromo. More preferred
halo groups are fluoro and chloro.
[0059] The term "heterocycle" is taken to mean a saturated or
unsaturated 5- or 6-membered ring containing from 1 to 3
heteroatoms selected from nitrogen, oxygen and sulfur, said ring
optionally being benzofused. Exemplary heterocycles, for the
purposes of the present invention, include furanyl, thiophenyl
(thienyl), pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl,
oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl,
N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the
like. Benzofused heterocyclic rings include isoquinolinyl,
benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl,
benzofuranyl, benzothiophenyl, indolyl, and the like, all of which
may be optionally substituted, which also of course includes
optionally substituted on the benzo ring when the heterocycle is
benzofused.
[0060] Preferred heterocycles include pyridinyl, indolyl, furanyl,
benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, all of
which may be optionally substituted.
[0061] Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or
alkylthio, means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or
alkythio group, respectively, substituted one or more times
independently with a substituent selected from the group consisting
of halo, hydroxy, and C.sub.1-C.sub.3 alkoxy. By way of
illustration, but without limitation, examples include
trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl,
3-hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio,
3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like.
Preferred substitutions include substitution 1-5 times with halo,
each independently selected, or substituted 1-3 times with halo and
1-2 times independently with a group selected from hydroxy and
C.sub.1-C.sub.3 alkoxy, or substituted 1-3 times independently with
a group selected from hydroxy and C.sub.1-C.sub.3 alkoxy, provided
that no more than one hydroxy and/or alkoxy substituent may be
attached through the same carbon.
[0062] The terms "substituted phenyl" and "substituted heterocycle"
are taken to mean that the cyclic moiety in either case is
substituted with one or more halo substituents, preferably one to
five, each independently selected; or substituted with one or more
substituents, preferably one to two substituents, independently
selected from the group consisting of halo, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkylthio, wherein each
alkyl, alkoxy and alkylthio substituent can be further substituted
independently with C.sub.1-C.sub.2 alkoxy or with one to five halo
groups selected from fluoro and chloro; or substituted with one
substituent selected from the group consisting of phenyloxy,
benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the
phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy
moiety can be further substituted with one to two substituents
selected from the group consisting of halo, C.sub.1-C.sub.2 alkyl,
and C.sub.1-C.sub.2 alkoxy; or substituted with one substituent
selected from the group consisting of C.sub.1-C.sub.4 acyl and
C.sub.1-C.sub.4 alkoxycarbonyl, and further substituted with zero
to one substituent selected from the group consisting of halo,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkylthio. When a substituent is halo, preferred halo groups are
fluoro, chloro, and bromo.
[0063] Pd.sub.2(dba).sub.3 means
tris(dibenzylidineacetone)-dipalladium(0).
[0064] BINAP means 2,2'-bis(diphenylphosphino)-1,1'binaphthyl.
[0065] DMF means N,N-dimethylformamide.
[0066] HATU means
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate.
[0067] Collidine means trimethylpyridine.
[0068] HRMS means High Resolution Mass Spectrum.
[0069] CIMS means Chemical Ionization Mass Spectrum.
[0070] APCI MS means Atmospheric Pressure Chemical Ionization Mass
Spectrum.
[0071] The term "amino protecting group" as used in this
specification refers to a substituents commonly employed to block
or protect the amino functionality while reacting other functional
groups on the compound. Examples of such amino-protecting groups
include the formyl group, the trityl group, the phthalimido group,
the acetyl group, the trichloroacetyl group, the chloroacetyl,
bromoacetyl, and iodoacetyl groups, urethane-type blocking groups
such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), and
the like; and like amino protecting groups. The species of amino
protecting group employed is not critical so long as the
derivatized amino group is stable to the conditions of subsequent
reactions on other positions of the molecule and can be removed at
the appropriate point without disrupting the remainder of the
molecule. Further examples of groups referred to by the above terms
are described by T. W. Greene, "Protective Groups in Organic
Synthesis", John Wiley and Sons, New York, N.Y., 1991, Chapter 7
hereafter referred to as "Greene".
[0072] The term "pharmaceutical" or "pharmaceutically acceptable"
when used herein as an adjective, means substantially non-toxic and
substantially non-deleterious to the recipient.
[0073] By "pharmaceutical formulation" it is further meant that the
carrier, solvent, excipients and salt must be compatible with the
active ingredient of the formulation (e.g. a compound of formula
I). It is understood by those of ordinary skill in this art that
the terms "pharmaceutical formulation" and "pharmaceutical
composition" are generally interchangeable, and they are so used
for the purposes of this application.
[0074] The term "acid addition salt" refers to a salt of a compound
of formula I prepared by reaction of a compound of formula I with a
mineral or organic acid. For exemplification of pharmaceutically
acceptable acid addition salts see, e.g., Berge, S. M, Bighley, L.
D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, 1977. Since the
compounds of this invention are amines, they are basic in nature
and accordingly react with any of a number of inorganic and organic
acids to form pharmaceutically acceptable acid addition salts.
Since some of the free amines of the compounds of this invention
are typically oils at room temperature, it is preferable to convert
the free amines to their pharmaceutically acceptable acid addition
salts for ease of handling and administration, since the latter are
routinely solid at room temperature.
[0075] The pharmaceutically acceptable acid addition salts of the
invention are typically formed by reacting a compound of formula I
with an equimolar or excess amount of acid. Alternatively,
hemi-salts can be formed by reacting a compound of formula I with
the desired acid in a 2:1 ratio, compound to acid. The reactants
are generally combined in a mutual solvent such as diethylether,
tetrahydrofuran, methanol, ethanol, isopropanol, benzene, or the
like. The salts normally precipitate out of solution within about
one hour to about ten days and can be isolated by filtration or
other conventional methods.
[0076] Inorganic acids commonly employed to form such salts include
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, phosphoric acid, and the like. Organic acids commonly
employed to form such salts include p-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid,
carbonic acid, succinic acid, citric acid, benzoic acid, acetic
acid and the like. Examples of such pharmaceutically acceptable
salts thus are the sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,
propionate, decanoate, caprylate, acrylate, formate, isobutyrate,
caproate, heptanoate, propiolate, oxalate, malonate, succinate,
hemisuccinate, suberate, sebacate, fumarate, maleate,
butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,
methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
phthalate, sulfonate, xylenesulfonate, phenylacetate,
phenylpropionate, phenylbutyrate, citrate, lactate,
.beta.-hydroxybutyrate, glycollate, tartrate, methanesulfonate,
propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,
mandelate and the like. Preferred pharmaceutically acceptable salts
are those formed with hydrochloric acid and succinic acid.
[0077] The term "effective amount" means an amount of a compound of
formula I which is capable of activating 5-HT.sub.1F receptors
and/or inhibiting neuronal protein extravasation.
[0078] The term "suitable solvent" refers to any solvent, or
mixture of solvents, inert to the ongoing reaction that
sufficiently solubilizes the reactants to afford a medium within
which to effect the desired reaction.
[0079] All enantiomers, diastereomers, and mixtures thereof, are
included within the scope of the present invention. For example,
the compounds of formula I wherein R.sup.5 is other than hydrogen
contain two chiral centers, one at the 4-position of the piperidine
ring, and one where R.sup.5 attaches to the piperidine ring. By way
of illustration, but without limitation, the four stereoisomers of
N-[6-(1,2-dimethylpiperidine-4-carbonyl)-pyridin-2-yl]-isonicotinamide
are as follows, wherein the chiral centers are indicated with
asterisks, "*", and the R and S designations are as indicated.
##STR00011##
[0080] While all enantiomers, diastereomers, and mixtures thereof,
are useful as 5-HT.sub.1F agonists, single enantiomers and single
diastereomers are preferred. Furthermore, while all of the
compounds of this invention are useful as 5-HT.sub.1F agonists,
certain classes are preferred. The following paragraphs describe
such preferred classes. [0081] 1) R.sup.1 is phenyl, substituted
phenyl, heterocycle, or substituted heterocycle; [0082] 2) R.sup.1
is substituted phenyl; [0083] 3) R.sup.1 is mono- or di-substituted
phenyl wherein the substituents are independently selected from
halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
trifluoromethyl, trifluoromethoxy, trifluoroethoxy, phenyloxy, and
benzyloxy; [0084] 4) R.sup.1 is mono- or di-substituted phenyl
wherein the substituents are independently selected from halo,
C.sub.1-C.sub.2 alkoxy, trifluoromethyl, trifluoromethoxy, and
trifluoroethoxy; [0085] 5) R.sup.1 is di- or tri-halo substituted
phenyl; [0086] 6) R.sup.1 is heterocycle or substituted
heterocycle; [0087] 7) R.sup.1 is a substituted or unsubstituted
heterocycle selected from the group consisting of furanyl,
thiophenyl, pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl,
oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl,
N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl,
quinolinyl, benzofuranyl, benzothiophenyl, indolyl; [0088] 8)
R.sup.1 is a substituted or unsubstituted heterocycle selected from
the group consisting of pyridinyl, indolyl, benzofuranyl, furanyl,
thiophenyl, benzodioxolyl, and thiazolidinyl; [0089] 9) R.sup.1 is
a substituted or unsubstituted heterocycle selected from the group
consisting of pyridinyl, furanyl, thiophenyl; [0090] 10) R.sup.1 is
mono-, di-, or tri-halo-substituted heterocycle, each halo group
being independently selected; [0091] 11) R.sup.1 is mono- or
di-substituted heterocycle, wherein one of the substituents is
selected from the group consisting of C.sub.1-C.sub.2 alkoxy,
phenoxy, and phenylthio; [0092] 12) R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl; [0093] 13) R.sup.2 is hydrogen or methyl;
[0094] 14) R.sup.2 is C.sub.3-C.sub.6 cycloalkyl-C.sub.1-C.sub.3
alkyl; [0095] 15) R.sup.2 is pyrazolylalkyl or N-substituted
pyrazolylalkyl; [0096] 16) R.sup.2 is pyrazol-4-yl-ethyl; [0097]
17) R.sup.2 is 1-(C.sub.1-C.sub.3 alkyl)pyrazol-4-yl-ethyl; [0098]
18) R.sup.3 is hydrogen; [0099] 19) R.sup.3 is methyl; [0100] 20)
R.sup.3 is ethyl; [0101] 21) R.sup.4 is hydrogen; [0102] 22)
R.sup.4 is halo; [0103] 23) R.sup.4 is fluoro or chloro; [0104] 24)
R.sup.4 is C.sub.1-C.sub.3 alkyl; [0105] 25) R.sup.4 is methyl;
[0106] 26) R.sup.5 is hydrogen; [0107] 27) R.sup.5 is
C.sub.1-C.sub.3 alkyl; [0108] 28) R.sup.5 is methyl; [0109] 29)
R.sup.2 is hydrogen or methyl, and R.sup.3, R.sup.4 and R.sup.5 are
all hydrogen; [0110] 30) R.sup.2 is hydrogen or methyl, and R.sup.3
is methyl, and R.sup.4 and R.sup.5 are both hydrogen; [0111] 31)
R.sup.1 is mono- or di-substituted phenyl wherein the substituents
are independently selected from halo, C.sub.1-C.sub.2 alkoxy,
trifluoromethyl, trifluoromethoxy, and trifluoroethoxy, R.sup.2 is
hydrogen or methyl, and R.sup.3, R.sup.4 and R.sup.5 are hydrogen;
[0112] 32) R.sup.1 is a substituted or unsubstituted heterocycle
selected from the group consisting of pyridinyl, indolyl,
benzofuranyl, furanyl, thiophenyl, benzodioxolyl, and
thiazolidinyl, R.sup.2 is hydrogen or methyl, and R.sup.3, R.sup.4
and R.sup.5 are hydrogen; [0113] 33) R.sup.1 is substituted phenyl,
R.sup.2 is hydrogen or methyl, and R.sup.3, R.sup.4 and R.sup.5 are
all hydrogen; [0114] 34) R.sup.1 is substituted phenyl, R.sup.2 is
hydrogen or methyl, and R.sup.3 is methyl, and R.sup.4 and R.sup.5
are both hydrogen; [0115] 35) R.sup.1 is mono- or di-substituted
phenyl wherein the substituents are independently selected from
halo, C.sub.1-C.sub.2 alkoxy, trifluoromethyl, trifluoromethoxy,
and trifluoroethoxy, R.sup.2 is hydrogen or methyl, R.sup.3 is
methyl and R.sup.4 and R.sup.5 are hydrogen; [0116] 36) R.sup.1 is
di- or tri-halo substituted phenyl, R.sup.2 is hydrogen or methyl,
and R.sup.3, R.sup.4 and R.sup.5 are all hydrogen; [0117] 37)
R.sup.1 is di- or tri-halo substituted phenyl, R.sup.2 is hydrogen
or methyl, and R.sup.3 is methyl, and R.sup.4 and R.sup.5 are both
hydrogen; [0118] 38) R.sup.1 is a substituted or unsubstituted
heterocycle selected from the group consisting of pyridinyl,
indolyl, benzofuranyl, furanyl, thiophenyl, benzodioxolyl, and
thiazolidinyl, R.sup.2 is hydrogen or methyl, R.sup.3 is methyl,
and R.sup.4 and R.sup.5 are hydrogen; [0119] 39) any compound
exemplified; [0120] 40) the compound is an acid addition salt;
[0121] 41) the compound is a hydrochloride salt; [0122] 42) the
compound is the dihydrochloride salt. [0123] 43) the compound is
the hemisuccinate salt; [0124] 44) the compound is the succinate
salt; and [0125] 45) the compound is the disuccinate salt.
[0126] It will be understood that the above classes may be combined
to form additional preferred classes, as for example the
combination of preferred selections for two or more substituents.
Illustrative examples of combinations of preferred classes forming
additional preferred classes are: [0127] 46) the combination of any
one of preferred classes 1), 2), 8) or 9) with preferred classes
21), and 26); [0128] 47) the combination of any one of preferred
classes 1), 2), 8) or 9) with preferred classes 21), and 27);
[0129] 48) the combination of any one of preferred classes 1), 2),
8) or 9) with preferred classes 21), and 28); [0130] 49) the
combination of any one of preferred classes 1), 2), 8) or 9) with
preferred classes 23), and 26); [0131] 50) the combination of any
one of preferred classes 1), 2), 8) or 9) with preferred classes
23), and 28); [0132] 51) the combination of any one of preferred
classes 1), 2), 8) or 9) with preferred classes 25), and 26);
[0133] 52) the combination of any one of preferred classes 1), 2),
8) or 9) with preferred classes 25), and 28); [0134] 53) the
combination of any one of the preferred combinations 46)-52) with
preferred classes 12) and 18); [0135] 54) the combination of any
one of the preferred combinations 46)-52) with preferred classes
12) and 19); [0136] 55) the combination of any one of the preferred
combinations 46)-52) with preferred classes 13) and 18); [0137] 56)
the combination of any one of the preferred combinations 46)-52)
with preferred classes 13) and 19); [0138] 57) the combination of
any one of the preferred combinations 46)-52) with preferred
classes 14) and 18); [0139] 58) the combination of any one of the
preferred combinations 46)-52) with preferred classes 14) and 19);
[0140] 59) the combination of any one of the preferred combinations
46)-52) with preferred classes 15) and 18); and [0141] 60) the
combination of any one of the preferred combinations 46)-52) with
preferred classes 15) and 19).
[0142] In addition to those compounds presented in the examples,
the following compounds further illustrate the scope of the present
invention: [0143] 1)
4-Fluoro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide;
[0144] 2)
2,4-Difluoro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-
-benzamide [0145] 3)
N-[6(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide [0146]
4)
2-Chloro-4-fluoro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benz-
amide [0147] 5)
2-Chloro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0148] 6)
2,4,6-Trifluoro-N-[6-(piperidine-4-carbonyl)-pyridin-2-yl]-benz-
amide [0149] 7) 1H-5-Trifluoromethyl-indole-3-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0150] 8)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluoromethoxy-be-
nzamide [0151] 9) 3-Bromo-thiophene-2-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0152] 10)
4-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluorom-
ethyl-benzamide [0153] 11)
2,4,6-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benza-
mide [0154] 12)
2-Chloro-6-fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-ben-
zamide [0155] 13)
2,4,6-Trifluoro-N-methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2--
yl]-benzamide [0156] 14)
2,4,6-Trifluoro-N-methyl-N-[6-(piperidine-4-carbonyl)-pyridin-2-yl]-benza-
mide [0157] 15)
2,4,6-Trifluoro-N-methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2--
yl]-benzamide [0158] 16)
2,4,6-Trifluoro-N-ethyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-y-
l]-benzamide [0159] 17)
2-Chloro-4-fluoro-N-[6-(piperidin-4-carbonyl)-pyridin-2-yl]-benzamide
[0160] 18)
2-Chloro-4-fluoro-N-methyl-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-
-yl]-benzamide [0161] 19) 1H-5-Fluoro-indole-3-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0162] 20)
Cyclopropanecarboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0163] 21)
3-Methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-butanamide
[0164] 22) Thiophene-2-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0165] 23)
Furan-2-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0166] 24)
2-Chloro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0167] 25) Furan-3-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0168] 26)
3,4-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamid-
e [0169] 27)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-isonicotinamide
[0170] 28)
2-Methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0171] 29)
2-Bromo-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0172] 30) Thiophene-3-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0173] 31)
2-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-isonicotinam-
ide [0174] 32)
4-Chloro-2-methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-be-
nzamide [0175] 33)
2-Ethoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0176] 34)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-phenoxy-benzamide
[0177] 35)
5-Chloro-2-methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-be-
nzamide [0178] 36)
2-Methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-4-methylsul-
fanyl-benzamide [0179] 37) 2,3-Dihydro-benzofuran-7-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0180] 38)
2-Benzyloxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0181] 39)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-propoxy-benzamide
[0182] 40) 2,2-Difluoro-benzo[1,3]dioxole-4-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0183] 41)
4-Methoxy-2-(2-methoxy-ethoxy)-N-[6-(1-methyl-piperidine-4-carbonyl)-pyri-
din-2-yl]-benzamide [0184] 42)
5-Bromo-2-methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-ben-
zamide [0185] 43)
2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-N-[6-(1-methyl-piperidine-4-carbonyl)-
-pyridin-2-yl]-benzamide [0186] 44)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-butanamide
[0187] 45) Cyclohexanecarboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0188] 46)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-3-phenyl-propionamide
[0189] 47)
2,6-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamid-
e [0190] 48)
2-Ethoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-nicotinamide
[0191] 49)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-phenoxy-nicotinamid-
e [0192] 50) 3-Acetyl-thiazolidine-4-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0193] 51)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-phenylsulfanyl-nico-
tinamide [0194] 52)
5-Methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-(2,2,2-tr-
ifluoro-ethoxy)-benzamide [0195] 53)
2-Methoxy-6-methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-be-
nzamide [0196] 54)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-terephthalamic
acid methyl ester [0197] 55) Cyclobutanecarboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0198] 56)
2-(2-Chloro-1,1,2-trifluoro-ethoxy)-N-[6-(1-methyl-piperidine-4-carbonyl)-
-pyridin-2-yl]-benzamide [0199] 57)
2-Chloro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide
[0200] 58)
2,5-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamid-
e [0201] 59)
3,4-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamid-
e [0202] 60)
4-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluorom-
ethyl-benzamide [0203] 61)
2-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-6-trifluorom-
ethyl-benzamide [0204] 62)
2,3,4-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benza-
mide [0205] 63)
2,4,5-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benza-
mide [0206] 64) 3-Chloro-thiophene-2-carboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0207] 65)
2,6-Dichloro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamid-
e [0208] 66)
2-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-4-trifluorom-
ethyl-benzamide [0209] 67) Cyclopentanecarboxylic acid
[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide [0210] 69)
N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-nicotinamide
[0211] It is preferred that the mammal to be treated by the
administration of compounds of this invention is human.
[0212] The compounds of the present invention may be synthesized
through a condensation of a 6-lithio anion of 2-chloropyridine with
1-substituted- or N-protected piperidine-4-carboxylic acid
methoxy-methylamide, followed by conversion of the 2-halo group to
an amino group, and subsequent condensation with the appropriate
R.sup.1-acylhalide compound. (see Scheme 1.)
##STR00012##
[0213] Suitable reaction conditions for the steps of this scheme
are well known in the art and appropriate substitutions of solvents
and reagents are within the skill of the art. See for example, J.
C. S. Perkin T. (24), 3597-3600 (1997) for the initial
condensation.
[0214] Typically 2-chloropyridine is activated by reaction with a
mixture of n-butyl lithium and 2-dimethylamino-ethanol in a
suitable solvent, such as hexane, at -78.degree. C. The reaction is
generally complete within about an hour. Next
1-R.sup.7-substituted-piperidine-4-caboxylic acid
methoxy-methyl-amide in an organic solvent, such as hexane is added
and stirred to form the 2-chloropyridinoyl-piperidine intermediate.
The reaction is generally complete within about an hour. When the
desired final R.sup.2 substituent is hydrogen, the piperidinyl
nitrogen should first be protected with an amino protecting group,
the addition and later removal of which are accomplished by
standard procedures well known in the art.
[0215] Typically the first condensation reaction is quenched by the
addition of water and the mixture is extracted multiple times with
a suitable solvent, such as ethyl acetate. This
2-chloropyridinoyl-piperidine intermediate can then be dried, as
for example with anhydrous sodium sulfate, evaporated, and then
partially purified, as for example, by chromatography on a silica
gel column.
[0216] Next, the 2-chloropyridinoyl-piperidine intermediate is
reacted with benzophenone imine in the presence of
tris(dibenzylidineacetone)-dipalladium(0) Pd.sub.2(dba).sub.3) as a
catalyst, and 2,2'-bis(diphenylphosphino)-1,1'binaphthyl (BINAP)
and sodium t-butoxide in a suitable solvent, such as toluene, at
reflux, to substitute the halo group with the benzophenone imino
group. After work-up, this intermediate is typically reacted with
hydrochloric acid in a suitable solvent, such as tetrahydrofuran,
and then purified to give the corresponding
2-aminopyridinoyl-piperidine intermediate.
[0217] In the final stage of scheme I, the R.sup.1 moiety is added
by amide bond formation by reacting the
2-aminopyridinoyl-piperidine intermediate with the desired
R.sup.1-acylhalide. Typically, a mixture of the
2-aminopyridinoyl-piperidine intermediate, the desired
R.sup.1-acylhalide, a proton scavenger, such as triethylamine,
diisopropylethylamine, and the like, in an appropriate solvent,
such as dichloromethane, THF, MTBE and the like, is stirred at
about room temperature until the reaction is complete, as for
example, about 4 hrs. A strong base, such as sodium hydroxide, may
then be added to neutralize the reaction mixture, and the final
product purified by normal work-up procedures.
[0218] If the piperidinyl nitrogen is protected by an amino
protecting group, this group is removed after the condensation
reaction with the acylhalide. The piperidinyl nitrogen can then
remain as a secondary amine for compounds of the present invention
wherein R.sup.2 is hydrogen, or it may be further alkylated by
known procedures for compounds of the present invention wherein
R.sup.2 is C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.6
cycloalkyl-C.sub.1-C.sub.3 alkyl, or a group of formula II
##STR00013##
Although alternative alkylation methods are well known in the art,
one typical alkylation reaction proceeds by reductive alkylation of
the secondary amine with an appropriate aldehyde, an organic acid
such as glacial acetic acid or trifluoroacetic acid, and a reducing
agent such as sodium cyanoborohydride or sodium
triacetoxyborohydride, in an appropriate solvent, such as methanol
or dichloromethane, wherein the appropriate aldehyde is one that
will react to provide the desired R.sup.2 substituent. (Michael B.
Smith and Jerry March, March's Advanced Organic Chemistry:
Reactions, mechanisms and Structure, 5.sup.th ed., pgs 1185-1187
(sec. 16-12), John Wiley & Sons, Inc., New York, 2001.) By way
of illustration, for the synthesis of compounds having
R.sup.2=methyl, the desired aldehyde would be formaldehyde, whereas
for the synthesis of compounds having R.sup.2=3-cyclopentylpropyl,
the desired aldehyde would be 3-cyclopentylpropanal.
[0219] Compounds of the present invention wherein R.sup.3 is methyl
or ethyl can be synthesized by Scheme 2.
##STR00014##
[0220] The R.sup.3-aminocarbonyl-R.sup.1 reagents are easily
prepared by reacting the corresponding R.sup.1 acylhalide with the
desired amine (methylamine, ethylamine, propylamine, or
isopropylamine, as for example a 2 M solution thereof) in an
appropriate solvent, as for example methanol. Such a procedure is
trivial and well known in the art.
[0221] The 2-bromopyridinoyl-piperidine intermediate is synthesized
by first reacting 2,6-dibromopyridine in a suitable organic
solvent, such as dichloromethane, preferably under a nitrogen
atmosphere, with 1.1 equivalent of n-butyllithium in a suitable
solvent, such as hexanes, preferably at low temperatures, such as
-78.degree. C. An appropriate
1-R.sup.7-substituted-N-methoxy-N-methyl-piperidine-4-carboxamide
is then added to the reaction mixture. The reaction is subsequently
quenched with base, as for example, aqueous NaOH. The resulting
intermediate may then be purified by standard workup techniques,
such as extraction, solvent removal and subsequent
chromatography.
[0222] The 2-bromopyridinoyl-piperidine intermediate is reacted
under N.sub.2 in a mixture with the desired
methylaminocarbonyl-R.sup.1, ethylaminocarbonyl-R.sup.1, or
propylaminocarbonyl-R.sup.1, respectively,
tris(dibenzylidineacetone)-dipalladium(0) (Pd.sub.2(dba).sub.3),
2,2'-bis(diphenylphosphino)-1,1'binaphthyl (BINAP), and sodium
t-butoxide, in a suitable solvent, such as suitably anhydrous
toluene. The reaction is typically heated for several hours, as for
example at about 85.degree. C. for 16 hours. Additional
C.sub.1-C.sub.2 alkylaminocarbonyl-R.sup.1,
tris(dibenzylidineacetone)-dipalladium(0) (Pd.sub.2(dba).sub.3),
2,2'-bis(diphenylphosphino)-1,1'binaphthyl (BINAP), and sodium
t-butoxide can be added and the reaction continued for a similar
period of time to improve the reaction yield. The final product is
then purified by common methods.
[0223] Compounds of the present invention wherein R.sup.4 or
R.sup.5 are other than hydrogen can be synthesized by the above
schemes utilizing the corresponding substituted 2-halopyridine and
substituted piperidinyl starting reagents.
[0224] In a preferred embodiment, a novel condensation reaction is
used to synthesize the 2-bromopyridinoyl-piperidine intermediate to
provide highly selective mono-addition, as well as higher yields of
the desired intermediate product with fewer impurities. In another
preferred embodiment, a more favorable reaction is used to convert
the 2-bromopyridinoyl-piperidine intermediate to the
2-aminopyridinoyl-piperidine intermediate in preparation for the
final condensation reaction. (See Scheme 3.)
##STR00015##
[0225] The novel N,N-dimethylaminocarbonylpiperidine intermediate
is made in high yield from an R.sup.7-isonipicotic acid derivative
by reacting the acid with oxalyl chloride in the presence of a
catalytic amount of dimethylformamide (DMF) in a suitable solvent,
such as dichloromethane, tetrahydrofuran, dichloroethane,
diethylether, or the like, and concentrating to yield an
isonipecotyl chloride derivative. This is then resuspended in a
suitable solvent, such as tetrahydrofuran, dichloromethane,
dichloroethane, diethylether, or the like, and reacted with
dimethylamine in the presence of a proton scavenger, as for
example, a non-nucleophilic organic base, such as triethylamine,
diisopropylethylamine, or the like, and then purified to give the
N,N-dimethylaminocarbonylpiperidine intermediate.
[0226] The N,N-dimethylcarbonylpiperidine intermediates of the
present invention have the distinct advantages over the N-protected
piperidine-4-caboxylic acid methoxy-methylamide reagents (Weinreb
reagents) of the prior art, in that they are non-hygroscopic and
surprisingly provide significantly improved chemoselectivity and
yield in the subsequent condensation reaction as compared to the
condensation reaction using the corresponding Weinreb reagent. This
is particularly the case when, as in a preferred embodiment,
toluene or methyl-tert-butylether (MTBE) is used as the solvent. In
a yet more preferred embodiment, MTBE is used as the solvent.
[0227] Next, 2,6-dibromopyridine is activated by reaction with
n-butyllithium in cold MTBE or toluene, preferably MTBE, to produce
a bromolithiumpyridine intermediate. Subsequently, the
N,N-dimethylaminocarbonylpiperidine intermediate is added and the
mixture stirred, as for example for about an hour at between about
-100.degree. C. to about -60.degree. C., preferably about
-75.degree. C. In a preferred embodiment, the coupling reaction is
run with a ratio of the 2,6-dibromopyridine to the
N,N-dimethylaminocarbonylpiperidine intermediate of about a 1.0 to
about 2.0, more preferably with a ratio of between about 1.3 to
about 1.7, most preferably with a ratio of about 1.5. The reaction
is then quenched with saturated ammonium chloride at about
-20.degree. C. to about 10.degree. C., and then neutralized with
hydrochloric acid and additional water. The product can then be
isolated by typical work-up procedures, as for example, but without
limitation, by extraction of the aqueous phase with
dichloromethane, washing the organic fractions with acidified water
(as for example, pH 2), neutralizing the aqueous extract with
sodium hydroxide, followed by extraction with ethyl acetate, drying
the organic phase, as for example with magnesium sulfate, and
concentrating, as for example, by evaporation, rotoevaporation,
etc.
[0228] In another preferred embodiment, the
4-(N,N'-dimethylamino)carbonyl piperidine compound in Scheme 3 is
replaced with a substituted aminocarbonylpiperidine compound of
formula IV
##STR00016##
where R.sup.8, R.sup.9, and R.sup.10 are as defined above.
Preferred compounds of formula IV are those wherein R.sup.9 and
R.sup.10 are each methyl, or wherein R.sup.9 and R.sup.10, together
with the nitrogen to which they are attached, combine to form
pyrrolidinyl. Particularly preferred are those compounds wherein
R.sup.9 and R.sup.10, together with the nitrogen to which they are
attached, combine to form pyrrolidinyl.
[0229] Compounds where R.sup.9 and R.sup.10, together with the
nitrogen to which they are attached, combine to form azetidinyl,
pyrrolidinyl, or piperidinyl, can be synthesized by the same
methods as their N,N'-dimethyl analogs, by substituting azetidine,
pyrrolidine, or piperidine, respectively, for the dimethylamine
reagent described above.
[0230] The 4-(pyrrolidinylcarbonyl)piperidine reagents have the
added advantage over the 4-(N,N'-dimethylamino)carbonyl piperidine
reagents in that they tend to be even less hygroscopic and tend to
produce more stable crystals, improving the handling
characteristics of the reagents. As with the
4-(N,N'-dimethylamino)carbonyl piperidine reagents, the
4-(pyrrolidinylcarbonyl)piperidine reagents provide unexpected
significantly improved chemoselectivity and yield in the subsequent
condensation reaction over reactions run using the corresponding
Weinreb reagents.
[0231] By way of illustration, but without limitation,
1-methyl-4-(N,N'-dimethylamino)carbonyl piperidine is a low melting
point solid that crystallizes easily and has relatively low
hygroscopicity, particularly as compared to the corresponding
Weinreb reagent. However, when the crystalline form does absorb
water, it converts to an oil. In comparison,
1-methyl-4-(pyrrolidinylcarbonyl)piperidine is also a low melting
point solid that crystallizes easily, but is even less hygroscopic
than 1-methyl-4-(N,N'-dimethylamino)carbonyl piperidine and
produces more stable crystals, such that they retain their
crystalline form even if some water is absorbed.
1-methyl-4-(piperidin-1-yl)carbonylpiperidine generally remains an
oil.
[0232] In another embodiment of the present inventive process,
2,6-dichloropyridine can be used instead of 2,6-dibromopyridine in
scheme 3, above under similar reaction conditions, to provide the
corresponding 2-chloropyridinoylpiperidine intermediate.
[0233] In yet another preferred embodiment of the novel synthetic
process, MTBE or toluene is used as the solvent, resulting in
further improved chemoselectivity in the condensation reaction.
MTBE as solvent is most preferred.
[0234] In a further embodiment of the present inventive process,
the next step of the synthesis provides for the exchange of the
halo group for an amino group by reaction of a
2-bromo-6-(piperidinylcarbonyl)pyridine intermediate, as described
above, with ammonia and ethylene glycol, in the presence of
copper(I) oxide as a catalyst. In a preferred embodiment, this
reaction is run in an autoclave, with typical conditions being
about 80.degree. C. to about 110.degree. C., preferably about
100.degree. C., and from about 45 to about 60 psi (about 310 to
about 414 kPa), typically about 50 psi (about 345 kPa) Ammonia is
then removed from the organic fraction by evacuation. Aqueous
sodium hydroxide is then added and the mixture extracted with a
suitable organic solvent, as for example, methyl-tert-butylether or
dichloromethane, and then dried, as for example, with magnesium
sulfate.
[0235] In a preferred embodiment, the crude
2-amino-6-(1-R.sup.7-piperidine-4-ylcarbonyl)pyridine intermediate
is further purified by crystallization of the hydrochloric salt and
then neutralizing the salt with sodium hydroxide, organic solvent
extraction and solvent removal.
[0236] The final condensation reaction is as described in Scheme
1.
[0237] The following Preparations and Examples are illustrative and
should not be interpreted in any way so as to limit the scope of
the invention.
Preparations
##STR00017##
[0238] 1. 2-Chloro-6-(1-methylpiperidin-4-ylcarbonyl) pyridine
(GB2-B8P-055)
##STR00018##
[0240] Add 2-chloropyridine (1 g, 8.8 mmole) to a mixture of
n-butyl lithium (1.6 M in hexane) (22 mL, 35.2 mmole) and
2-dimethylamino-ethanol (1.56 g, 17.6 mmole) in hexane (20 mL at
-78.degree. C.) and stirred for 1 hour. Then add
1-methyl-piperidine-4-carboxylic acid methoxy-methyl-amide (3.2 g,
17.6 mmole) in hexane (5 mL) and stir the mixture for 1 hour.
Quench the reaction mixture with water and extract twice with ethyl
acetate, dry the organic layer with anhydrous sodium sulfate,
evaporate the solvent and purify the residual product by
chromatography on a silica gel column to give about 1 g of the
title product.
2. 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(GB2-B8P-056)
##STR00019##
[0242] Heat a mixture of
2-chloro-6-(1-methylpiperidin-4-ylcarbonyl) pyridine (800 mg, 3.35
mmole), benzophenone imine (729 mg, 4.02 mmole),
tris(dibenzylidineacetone)-dipalladium(0) (61 mg, 0.067 mmole),
racemic-2,2'-bis(diphenylphosphino)-1,1' binaphthyl (83 mmole,
0.134 mmole) and sodium t-butoxide (451 mg, 4.69 mmole) in toluene
(100 mL) at reflux for 2 hours. Evaporate the solvent and
re-dissolve the residue in ethyl acetate, wash with water, dry with
anhydrous sodium sulfate, evaporate and purify by chromatography on
a silica gel column to give about 1 g of a benzophenone-imine
intermediate. Add 1N HCl (12 mL) into a solution of the product in
THF (50 mL), and stir at room temperature for 2 hours. Then add 25
mL of 1N HCl and extract the mixture twice with (2:1) hexane:ethyl
acetate. Basify the aqueous phase, extract with dichloromethane,
dry with anhydrous sodium sulfate, evaporate the solvent and purify
the residual by chromatography on a silica gel column (ethyl
acetate:2M NH.sub.3 in methanol, 90:10) to give about 600 mg of the
title product.
EXAMPLES
1.
4-Fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide
dihydrochloride LY 520728 GB2-B8P-059
##STR00020##
[0244] Stir a mixture of
2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.150 g),
4-fluorobenzoyl chloride (0.218 g), triethylamine (0.192 mL) and
dichloromethane at room temperature for 4 hours. Add 1N aqueous
NaOH to basify the reaction mixture. Extract the mixture with
dichloromethane, dry the organic phase with anhydrous sodium
sulfate, evaporate the solvent, and purify the residue by HPLC to
provide the free base of the title compound. Re-dissolve the free
base in diethyl ether and add excess 1 M HCl. Evaporate the solvent
and dry the residue under vacuum to obtain 80 mg of the title
compound. M.p. 75-80.degree. C.; HRMS: 342.1605 (obs.) (Cal.
342.1618).
2.
2,4-Difluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benza-
mide dihydrochloride
##STR00021##
[0246] Use a method similar to the above example 1, with
2,4-difluorobenzoyl chloride to obtain the title compound. M.p.
108-110.degree. C.; mass spectrum (electric spray) m/z=360.
Mono-hydrochloride salt LY 522975 GB2-B8P-069-1 Di-hydrochloride
salt LY 545966 GB2-B8P-127-1 (free base M+1)
3.
2-Chloro-4-fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]--
benzamide
##STR00022##
[0248] Use a method similar to the above example 1, with
2-chloro-4-fluorobenzoyl chloride to obtain the title compound.
Free base (LY 526867, GB2-B8P-87) m.p. 53-55.degree. C.; HRMS:
376.1233 (obs.) (Cal. 376.1228). Di-HCl salt (LY 543057,
GB2-B8P-124) m.p. 243-245.degree. C.; HRMS: 376.1238 (obs.) (Cal.
376.1228).
4.
2-Chloro-6-fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]--
benzamide mono-hydrochloride salt LY622824 GB2-B8P-296
(PX104847)
##STR00023##
[0250] Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(0.18 g, 0.85 mmol), 2-chloro-6-fluoro-benzoyl chloride (0.318 g,
1.65 mmol), and 1,4-dioxane (10 mL). Stir and heat the mixture at
reflux. After 2 hr., cool the reaction mixture to ambient
temperature and concentrate. Load the mixture onto an SCX column
(10 g), wash with methanol, and elute with 2M ammonia/methanol.
Concentrate the eluent to obtain the free base of the title
compound (0.30 g, 94%) as an oil. Dissolve the oil in methanol (5
mL) and treat with ammonium chloride (0.045 g, 0.85 mmol).
Concentrate the mixture and dry under vacuum to obtain the title
compound. HRMS Obs. m/z 376.1237; Calc. m/z 376.1228; m.p.
155.degree. C. (dec).
5.
2-Bromo-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridine-2-yl]benzamide
hydrochloride salt (LY 574243, GJ2-H3K-177)
##STR00024##
[0252] Use a method similar to example 1, with 2-bromobenzoyl
chloride to obtain the free base of the title compound. Dissolve
the clean material (104.8 mg) in methanol and add 1 equivalent
(13.9 mg) of NH.sub.4Cl. Sonicate the reaction mixture at room
temperature for 15 min and then concentrate and dry the mixture to
provide the title compound as a white solid. Mass spectrum (ion
spray): m/z=402.1 (M+1); .sup.1H NMR .delta. (d6-DMSO, ppm) 11.15
(1H, s), 8.37 (1H, bs), 8.07 (1H, t, J=7.69, 8.05, 15.74 Hz), 7.74
(2H, m), 7.58 (3H, m), 3.70 (1H, bs), 2.87 (2H, m), 2.65 (3H, s),
2.12 (3H, m), 1.82 (3H, m)
6.
2-Chloro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide
LY 542968 MN4-B6K-251
##STR00025##
[0254] Mix 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(0.223 g) and 2-chlorobenzoyl chloride (0.175 g) in 1,4-dioxane (10
mL) and heat at reflux for 1 hour. Dilute with methanol (10 mL) and
load on a SCX column (10 g). Wash the column with methanol, elute
the product with 2 M NH.sub.3 in methanol, evaporate and purify the
product on a silica gel column (CH.sub.2Cl.sub.2 with 2 M NH.sub.3
in methanol) to obtain 0.305 g (84%) of the title compound: mass
spectrum (electric spray) m/z=358 (M+1) and 360 (M+2+1); .sup.1H
NMR (CDCl.sub.3): 8.60 (br s, 1H), 8.54 (d, 1H), 7.90 (dd, 1H),
7.81 (d, 1H), 7.76 (dd, 1H), 7.45 (m, 3H), 3.63 (m, 1H), 2.90 (m,
2H), 2.29 (s, 3H), 2.07 (m 2H), 1.85 (m, 4H). (file:
mn4-b6k-251)
[0255] Dissolve the free base in dichloromethane and add 1N HCl in
ether (0.85 mL), evaporate, and dry under vacuum to obtain the
monohydrochloride salt (0.354 g). (LY 572158, MN4-B6K-251)
7. N-[6-(1-Methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide
hydrochloride
##STR00026##
[0257] Use a method similar to the above example 1, with benzoyl
chloride to obtain the free base of the title compound. Re-dissolve
the free base in diethyl ether and add 1 M HCl in a 1:1 molar
ratio. Evaporate the solvent and dry the residue under vacuum to
obtain the title compound. hydrochloric acid salt LY 522976
GB2-B8P-069-2 HRMS: 324.1697 (obs.) (Cal. 324.1712). (There is no
other physical data available).
8.
2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-be-
nzamide mono-hydrochloride salt LY587815 GB2-B8P-261 (PX100246)
##STR00027##
[0259] Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84
mmol), and 1,4-Dioxane (10 mL), and stir while heating at reflux.
After 3 hr., cool the reaction mixture to ambient temperature and
concentrate. Load the concentrated mixture onto an SCX column (10
g), wash with methanol, and elute with 2M ammonia in methanol.
Concentrate the eluent to obtain the free base of the title
compound as an oil (0.365 g (>100%)). Dissolve the oil in
methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92
mmol). Concentrate the mixture and dry under vacuum to obtain the
title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p.
255.degree. C. (dec).
9.
2-Trifluoromethyl-4-fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyrid-
in-2-yl]-benzamide mono-hydrochloride salt LY586554 GB2-B8P-254
(PX097276)
##STR00028##
[0261] Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(0.19 g, 0.87 mmol), 2-trifluoromethyl-4-fluoro-benzoyl chloride
(0.395 g, 1.74 mmol), and 1,4-Dioxane (50 mL). Stir and heat the
mixture at reflux. After 3 hr., cool the reaction mixture to
ambient temperature and concentrate. Load the mixture onto an SCX
column (10 g), wash with methanol, and elute with 2M
ammonia/methanol. Concentrate the eluent to obtain the free base of
the title compound as an oil (0.241 g, 68%). Dissolve the oil in
methanol (5 mL) and treat with ammonium chloride (0.031 g, 0.59
mmol). Concentrate and dry under vacuum to obtain the title
compound. HRMS Obs. m/z 410.1490, Calc. 410.1491; m.p.
145-150.degree. C.
10.
2-Trifluoromethoxy-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl-
]-benzamide mono-hydrochloride salt LY572270 GH8-B8Q-284C
(PX097276)
##STR00029##
[0263] Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(0.18 g, 0.84 mmol), 2-trifluoromethoxybenzoyl chloride (0.23 g,
1.0 mmol) and 1,4-Dioxane (5 mL). Stir and heat the mixture at
reflux. After 3 hr., cool the reaction mixture to ambient
temperature. Load on an SCX column (10 g), wash with methanol, and
elute with 2M ammonia/methanol. Concentrate the eluent to obtain
the free base of the title compound (0.26 g, 76%). Dissolve the
free base in methanol (10 mL) and treat with ammonium chloride
(0.032 g). Concentrate and dry under vacuum to obtain the title
compound. HRMS Obs. m/z 408.1517, Calc. m/z 408.1535; m.p.
155-160.degree. C.
11.
3-Bromo-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-thiophene-
-2-carboxamide mono-hydrochloride salt LY586552 GB2-B8P-250
(PX099831)
##STR00030##
[0265] Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine
(0.104 g, 0.48 mmol), 3-Bromo-thiophene-2-carbonyl chloride (0.215
g, 0.95 mmol), and 1,4-Dioxane (10 mL). Stir and heat the mixture
at reflux. After 2 hr., cool the reaction mixture to ambient
temperature and concentrate. Load the mixture onto an SCX column
(10 g), wash with methanol, and elute with 2M ammonia/methanol.
Concentrate the eluent to obtain the free base of the title
compound as an oil (0.152 g, 78%). Dissolve the oil in
dichloromethane (10 mL), treat with 1M hydrogen chloride in ether,
concentrate and dry under vacuum to obtain the title compound. HRMS
Obs. m/z 408.0384, Calc. m/z 408.0381; m.p. 195-200.degree. C.
12.
1-H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-car-
boxamide dihydrochloride salt
##STR00031##
[0266] (i) Intermediate:
1-Benzylindol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-ca-
rboxamide
##STR00032##
[0268] Add oxalyl chloride (0.18 mL, 2.1 mmol) dropwise to a
solution of 1-benzylindol-3-carboxylic acid (0.48 g, 1.9 mmol) in
pyridine and CH.sub.3CN (5 mL each) cooled in an ice bath. Stir the
reaction mixture for 2.25 hr. and then add a suspension of
2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.56 g, 1.9
mmol) in CH.sub.3CN (5 mL) and pyridine (12 mL). Warm the reaction
mixture to room temperature overnight. Quench the reaction with
cold H.sub.2O (20 mL) and dilute with CHCl.sub.3. Adjust the pH to
11 with Na.sub.2CO.sub.3 and separate the layers. Extract the
aqueous layer with CHCl.sub.3 (2.times.30 mL). Combine the organic
fractions and dry with anhydrous MgSO.sub.4, filter and concentrate
the mixture in vacuo. Purify the product by chromatography on a
silica gel column, eluting with methanol/CH.sub.2Cl.sub.2 (5:95)
followed by methanol/CH.sub.2Cl.sub.2 (10:90) to afford the
sub-title compound (0.44 g, 51%). .sup.1H NMR (CD.sub.3OD)
.quadrature. .delta. .quadrature.8.45 (d, J=8 Hz, 1H), 8.32 (s,
1H), 8.26 (m, 1H), 7.95 (t, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.45
(m, 1H), 7.22-7.37 (m, 7H), 5.51 (s, 2H), 3.90 (m, 1H), 2.93-3.01
(m, 2H), 2.33 (s, 3H), 2.21-2.31 (m, 2H), 1.92-1.99 (m, 2H),
1.71-1.84 (m, 2H); CIMS (Methane) m/z 453
[C.sub.28H.sub.28N.sub.4O.sub.2+H].sup.+.
(ii)
1H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-car-
boxamide
##STR00033##
[0270] Add aluminum trichloride (106 mg, 0.795 mmol) to a
suspension of
1-benzylindol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-ca-
rboxamide (180 mg, 0.398 mmol) in benzene (6 mL) and heat the
mixture at reflux for 1.25 hr. Then add another 2 equivalents of
aluminum trichloride (108 mg) and continue heating at reflux for an
additional 5.5 hr. Cool the reaction mixture to room temperature.
Then pour the reaction into ice cold H.sub.2O (50 mL) and then
dilute with ethyl acetate. Adjusted the pH of the solution to 11
with saturated Na.sub.2CO.sub.3, separate the layers and extract
the aqueous layer with ethyl acetate (3.times.50 mL). Combined the
organic fractions, dry with Na.sub.2SO.sub.4, filter and
concentrate in vacuo. Purify the intermediate by flash
chromatography on a silica gel column, eluting with
CHCl.sub.3/methanol/NH.sub.4OH (93:7:1) to obtain the sub-title
compound (96 mg, 67%). .sup.1H NMR (CD.sub.3OD) .quadrature.
.delta. .quadrature.8.45 (d, J=8 Hz, 1H), 8.25 (s, 1H), 8.21 (m,
1H), 7.96 (t, J=8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.48 (m, 1H),
7.18-7.27 (m, 2H), 3.90 (m, 1H), 2.94-3.01 (m, 2H), 2.31 (s, 3H),
2.19-2.28 (m, 2H), 1.92-2.02 (m, 2H), 1.71-1.84 (m, 2H). CIMS
(Methane) m/z 363 [C.sub.21H.sub.22N.sub.4O.sub.2+H].sup.+.
(iii)
1-H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-c-
arboxamide dihydrochloride salt
##STR00034##
[0272] Add 2.0M HCl in diethylether (0.46 mL, 0.93 mmol) to a
suspension of
1H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carb-
oxamide (free base) (0.16 g, 0.44 mmol) in diethylether (10 mL).
After 2 hr. filter the reaction mixture and wash the solid with
diethylether to afford the title compound as a yellow solid.
R.sub.f 0.29 (93:7:1 CHCl.sub.3/methanol/NH.sub.4OH); m.p.
200-218.degree. C.; .sup.1H NMR (CD.sub.3OD, complex mixture of
rotamers) .quadrature..delta. .quadrature.8.38 and 8.49 (s, 1H),
8.46 (m, 1H), 8.08-8.10 and 8.18-8.29 (m, 2H), 7.61 and 7.72 (d,
J=8 Hz, 1H), 7.52 (m, 1H), 7.26-7.32 (m, 2H), 4.01 (m, 1H),
3.19-3.68 (m, 3H), 2.97 (m, 1H), 2.82 and 2.94 (s, 3H), 2.28-2.32
(m, 2H), 1.68-2.02 (m, 2H); CIMS (Methane) m/z 363
[C.sub.21H.sub.22N.sub.4O.sub.2+Hr; HPLC (Method A) 96.7%, t.sub.R
16.4 min.; anal. calculated for
C.sub.21H.sub.22N.sub.4O.sub.2.2.1HCl. 1.5H.sub.2O: C, 54.12; H,
5.86; N, 12.02; Cl, 15.98. Found: C, 54.13; H, 6.03; N, 12.37; Cl,
15.71.
13.
Cyclopropyl-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxam-
ide dihydrochloride salt
##STR00035##
[0274] Add cyclopropylcarbonyl chloride (0.08 mL, 0.83 mmol)
dropwise to a solution of
2-amino(6-pyridyl)-1-methyl(4-piperidyl)-ketone (221 mg, 0.76 mmol,
provided by Eli Lilly) and triethylamine (0.32 mL, 2.3 mmol) in
CH.sub.2Cl.sub.2 (5 mL) cooled in an ice bath. Warm the reaction
mixture to room temperature and stir for 3 hr. Extract the reaction
mixture with CH.sub.2Cl.sub.2 and H.sub.2O and adjust the pH of the
aqueous layer to 11 with Na.sub.2CO.sub.3. Separate the layers and
extract he aqueous layer with CH.sub.2Cl.sub.2 (2.times.50 mL).
Combine the organic fractions, dry (Na.sub.2SO.sub.4), filter and
concentrate in vacuo. Purify the concentrate by chromatography on a
silica gel column, eluting with a gradient of
CH.sub.2Cl.sub.2/methanol (95:5 to 90:10) to obtain the free base
of the title compound (180 mg, 83%). .sup.1H NMR (CDCl.sub.3,
complex mixture of rotamers) .quadrature. .delta. .quadrature.8.81
(bs, 1H), 8.39 (d, J=8 Hz, 1H), 7.82 (t, J=8 Hz, 1H), 7.71 (d, J=8
Hz, 1H), 3.50 (m, 1H), 3.13-3.21 (m, 2H), 2.51 (s, 3H), 2.37-2.48
(m, 4H), 1.95-2.04 (m, 2H), 1.55 and 1.82 (m, 1H), 0.75-0.81,
0.90-0.99 and 1.10-1.14 (m, 4H); APCI MS m/z 288
[C.sub.16H.sub.21N.sub.3O.sub.2+H].sup.+.
[0275] Add 2.0M HCl in diethyl ether (0.95 mL, 1.9 mmol) to a
solution of the free base (180 mg, 0.626 mmol) in diethyl ether (10
mL) and methanol (3 mL). After 2 hr. the reaction was filtered to
afford the title compound as a light yellow solid. R.sub.f 0.47
(93:7:1 CHCl.sub.3/methanol/NH.sub.4OH); m.p. 140-148.degree. C.;
.sup.1H NMR (CD.sub.3OD, complex mixture of rotamers) .delta.
.quadrature.8.24 and 8.50 (m, 1H), 8.05-8.08 (m, 1H), 7.52 and 7.64
(d, J=8.0 Hz, 1H), 3.98 and 4.16 (m, 1H), 3.62-3.66 (m, 1H),
3.20-3.28 and 3.44-3.56 (m, 2H), 2.91-3.04 (m, 1H), 2.80 and 2.93
(s, 3H), 2.13-2.29 (m, 2H), 1.57-1.79 and 1.92-2.06 (m, 3H),
1.01-1.21 (m, 4H); CIMS (Methane) m/z 288
[C.sub.16H.sub.21N.sub.3O.sub.2+Hr; HPLC (Method A)>99%, t.sub.R
14.9 min.; anal. calculated for
C.sub.16H.sub.21N.sub.3O.sub.2.2.3HCl.2.3H.sub.2O: C, 46.57; H,
6.81; N, 10.18; Cl, 19.76. Found: C, 46.43; H, 6.55; N, 10.00; Cl,
19.62.
14.
2-Methylprop-1-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]--
carboxamide dihydrochloride salt
##STR00036##
[0276] ALB 7533
[0277] (i) Free base: Add 3-methylbutanoyl chloride (0.11 mL, 0.90
mmol) dropwise to a solution of
2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (132 mg, 0.45
mmol) and triethylamine (0.19 mL, 1.4 mmol) in CH.sub.2Cl.sub.2 (5
mL) cooled in an ice bath. Warm the reaction mixture to room
temperature and stir for 3 hr. Dilute the reaction with
CH.sub.2Cl.sub.2 and wash with saturated NaHCO.sub.3 (50 mL).
Extract the aqueous layer with CH.sub.2Cl.sub.2 (2.times.25 mL).
Combine the organic fractions, dry (Na.sub.2SO.sub.4), filter and
concentrate in vacuo. Purify the product by chromatography on a
silica gel column, eluting with CH.sub.2Cl.sub.2/methanol (95:5) to
obtain the free base of the title compound (88 mg, 64%). .sup.1H
NMR (CDCl.sub.3) .delta. 8.44 (d, J=8.0 Hz, 1H), 7.81-7.86 (m, 1H),
7.73 (d, J=7.1 Hz, 1H), 3.50 (m, 1H), 3.00-3.18 (m, 2H), 2.18-2.46
(m, 7H), 1.92-2.01 (m, 2H), 1.52-1.71 (m, 3H), 1.05 (d, J=6.6 Hz,
6H); CIMS (Methane) m/z 304
[C.sub.17H.sub.25N.sub.3O.sub.2+H].sup.+.
[0278] (ii) Dihydrochloride salt: Add 2.0M HCl in diethyl ether
(0.36 mL, 0.73 mmol) to a solution of the free base (88 mg, 0.29
mmol) in diethyl ether (5 mL) and methanol (2 mL). After 2 hr.,
concentrate the reaction mixture in vacuo to obtain the title
compound as a brown solid. R.sub.f 0.58 (93:7:1
CHCl.sub.3/methanol/NH.sub.4OH); m.p. 93-95.degree. C.; .sup.1H NMR
(CD.sub.3OD, complex mixture of rotamers) .quadrature. .delta.
.quadrature.8.35 (m, 1H), 7.95 (m, 1H), 7.77 (m, 1H), 4.06 and 4.25
(m, 1H), 3.43-3.52 and 3.61-3.65 (m, 2H), 3.18-3.28 (m, 2H),
2.81-2.94 (m, 3H), 2.21-2.37 (m, 5H), 1.90-2.02 (m, 2H), 1.03-1.05
(m, 6H); CIMS (Methane) m/z 304
[C.sub.17H.sub.25N.sub.3O.sub.2+H].sup.+; HPLC 98.4%, Symmetry.RTM.
series C18 column, Waters Corporation, Milford, Mass.
(4.6.times.250 mm); anal. calculated for
C.sub.17H.sub.25N.sub.3O.sub.2.1.9HCl.1.2H.sub.2O: C, 51.79; H,
7.49; N, 10.66; Cl, 17.08. found: C, 51.78; H, 7.64; N, 10.35; Cl,
17.07.
15.
2,4,6-Trifluoro-N-methyl-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridi-
n-2-yl]-benzamide hydrochloride salt (H19-A01377-159, LY
2004686)
##STR00037##
[0280] Dissolve 2,6-dibromopyridine (3.6 g, 15.3 mmol) in anhydrous
dichloromethane (90 mL) under nitrogen atmosphere. Cool the
reaction mixture to -78.degree. C. Add a solution of n-butyl
lithium in hexane very slowly via a syringe (1.6 M, 10.5 mL, 16.9
mmol). After the addition is complete, stir the reaction at
-78.degree. C. for 1 hr. Add a solution of
4-(methoxy-methyl-aminocarbonyl)-piperidine-1-carboxylic acid
tert-butyl ester (2 g, 7.3 mmol) in anhydrous dichloromethane (10
mL) dropwise to the reaction mixture. Stir the reaction at
-78.degree. C. for 2 hrs., then allow it to slowly warm to room
temperature overnight. Quench the reaction with 0.1 N aqueous NaOH.
Dilute the solution with dichloromethane (100 mL), transfer into a
separation funnel and shake with 0.1 N NaOH (60 mL). Separate the
organic layer and dry it over anhydrous sodium sulfate. Evaporate
the solvent under reduced pressure. Further purify the residue by
chromatography on silica gel column (10%-30% ethyl acetate/hexane)
to obtain
2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (2.7
g, quantitative yield). Mass spectrum (ion spray): m/z 370
(M+1).
[0281] Heat a mixture of
2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (152
mg, 0.41 mmol), N-methyl-2,4,6-trifluorobenzamide (92.6 mg, 0.49
mmol), Pd.sub.2(dba).sub.3 (9.2 mg, 0.01 mmol), BINAP (12.4 mg,
0.02 mmol), sodium t-butoxide (55 mg, 0.57 mmol) in anhydrous
toluene (10 mL) at 85.degree. C. for 16 hrs. Cool the reaction to
room temperature and add another aliquot of
N-methyl-2,4,6-trifluorobenzamide, Pd.sub.2(dba).sub.3, BINAP and
sodium t-butoxide in the same amount. Re-heat the reaction at
85.degree. C. for 16 more hours. Extract the reaction mixture with
ethyl acetate and aqueous NaOH (0.1N). Collect and dry the organic
layers. Concentrate and purify the crude product by chromatography
(silica gel, 10%-30% ethyl acetate/hexane) to obtain
2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-
-pyridin-2-yl]-benzamide (86 mg, 44% yield).
[0282] Dissolve the
2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-
-pyridin-2-yl]-benzamide in 50% trifluoroacetic
acid/CH.sub.2Cl.sub.2 (24 mL) and stir for 45 min. Remove volatiles
under reduced pressure and extract with ethyl acetate and aqueous
NaOH (2M). Combine the organic layers and dry with sodium sulfate.
Concentrate and purify the residue by chromatography (silica gel/6%
of (2M NH.sub.3 in methanol)/CH.sub.2Cl.sub.2) to afford
2,4,6-trifluoro-N-methyl-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benz-
amide (77 mg, 85% yield).
[0283] Dissolve the
2,4,6-trifluoro-N-methyl-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benz-
amide (77 mg, 0.20 mmol) in methanol (10 mL), add 37% aqueous
formaldehyde (0.16 mL, 2.0 mmol), glacial acetic acid (0.34 mL, 6.0
mmol) and NaBH.sub.3CN (21.9 mg, 0.35 mmol). Stir the reaction
mixture at room temperature. Extract the mixture with ethyl acetate
and aqueous NaOH (2M) to obtain
2,4,6-trifluoro-N-methyl-N-[6-(a-hydroxy-(1-methylpiperidin-4-y-
lcarbonyl)-methyl)-pyridin-2-yl]-benzamide. Dissolve the
2,4,6-trifluoro-N-methyl-N-[6-(.alpha.-hydroxy-(1-methylpiperidin-4-ylcar-
bonyl)-methyl)-pyridin-2-yl]-benzamide in anhydrous
CH.sub.2Cl.sub.2 (12 mL) and treat under N.sub.2 with Dess-Martin
reagent (127 mg, 0.30 mmol) for 1 hr. Extract with ethyl acetate
and 2M aqueous NaOH. Collect and dry the organic layers.
Concentrate and purify the residue by chromatography (silica gel/6%
of (2M NH.sub.3 in methanol)/CH.sub.2Cl.sub.2) to afford the free
amine of the title compound (60.2 mg, 77% yield). Dissolve the free
base in methanol (10 mL) and treat with ammonium chloride (0.032
g). Concentrate and dry under vacuum to obtain the title compound.
LY 2004686 Mass spectrum (ion spray): m/z=392.0 (M+1); .sup.1H NMR
(methanol-d.sub.4): 7.85 (m, 2H), 7.50 (m, 1H), 6.80 (m, 2H), 3.75
(m, 1H), 3.52 (d, 2H), 3.47 (s, 3H), 3.20 (t, 2H), 2.94 (s, 3H),
2.03 (d, 2H), 1.83 (m, 2H).
16.
2,4,6-Trifluoro-N-ethyl-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-
-2-yl]-benzamide hydrochloride salt (H19-A01377-163, LY
2020146)H19-A01377-163 (LY 2020146)
##STR00038##
[0285] Dissolve 2,6-dibromopyridine (5.5 g, 23.2 mmol) in anhydrous
dichloromethane (140 mL) under a nitrogen atmosphere. Cool the
reaction mixture to -78.degree. C. Add a solution of n-butyl
lithium in hexane (1.6 M, 15.8 mL, 25.3 mmol) very slowly via a
syringe. After the addition is complete, stir the reaction at
-78.degree. C. for 1 hr. Add a solution of
1-methyl-N-methyl-N-methoxy-piperidine-4-carboxamide (2 g, 11 mmol)
in anhydrous dichloromethane (10 mL) dropwise to the reaction
mixture. Stir the reaction at -78.degree. C. for 2 hrs, and then
allow the mixture to slowly warm to room temperature overnight.
Quench the reaction with 0.1 N NaOH. Dilute the solution with
dichloromethane (100 mL), transfer into a separatory funnel and
shake with 2 N NaOH (50 mL). Separate the organic layer, dry it
over anhydrous sodium sulfate, and then evaporate the solvent under
reduced pressure. Further purify the residue by chromatography on
asilica gel column (6%, 2M NH.sub.3 in methanol/CH.sub.2Cl.sub.2)
to obtain 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine e
(2.3 g, 74% yield). Mass spectrum (ion spray): m/z 283 (M+1).
[0286] Combine 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridin
(189 mg, 0.67 mmol), N-ethyl-2,4,6-trifluorobenzamide (162 mg, 0.80
mmol), Pd.sub.2(dba).sub.3 (14.6 mg, 0.016 mmol), BINAP (19.9 mg,
0.032 mmol), sodium t-butoxide (90.2 mg, 0.94 mmol) and anhydrous
toluene (10 mL), and heat the mixture at 85.degree. C. for 16 hr.
under a nitrogen atmosphere. Cool the reaction to room temperature
and add additional N-ethyl-2,4,6-trifluorobenzamide,
Pd.sub.2(dba).sub.3, BINAP, sodium t-butoxide in the same amounts.
Re-heat the reaction at 85.degree. C. for 16 more hours. Extract
with ethyl acetate and aqueous NaOH (0.1N). Collect and dry the
organic layers. Concentrate and purify the residue by
chromatography (silica gel, 10%-30% ethyl acetate/hexanes) to
obtain the free base of the title compound of LY 2020146 (100 mg,
37% yield). Dissolve the free base in methanol (10 mL) and treat
with ammonium chloride (0.032 g). Concentrate and dry under vacuum
to obtain the title compound. LY 2020146 Mass spectrum (ion spray):
m/z=406.1 (M+1); .sup.1H NMR (methanol-d.sub.4): 7.94 (m, 2H), 7.54
(m, 1H), 6.88 (m, 2H), 4.12 (q, 2H), 3.86 (m, 1H), 3.77 (d, 2H),
3.18 (t, 2H), 2.94 (s, 3H), 2.15 (d, 2H), 1.92 (m, 2H).
17.
2,4,6-Trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide
LY 636773 MN4-A01246-118-1
##STR00039##
[0288] Add 1-chloroethyl chloroformate (0.8 g) into a solution of
2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benz-
amide (0.216 g) in dichloroethane (10 mL) and heat at reflux for 1
hr. Then add more 1-chloroethyl chloroformate (1 mL) and heat at
reflux overnight. Add methanol (10 mL) to the reaction mixture,
concentrate to a small volume, dilute with methanol again, load
onto an SCX column (10 g), wash with methanol, and elute with 2M
NH.sub.3-methanol, evaporate and purify on a silica gel column
(CH.sub.2Cl.sub.2 with 2 M NH.sub.3 in methanol) to obtain the
title compound (61 mg). Mass spectrum (electric spray) m/z=364
(M+1); .sup.1H NMR (CDCl.sub.3): 8.55 (d, J=8.1 Hz, 1H), 7.92 (dd,
J=8.0, 8.0 Hz 1H), 7.84(1H, J=8.0 Hz, 1H), 6.81 (m, 3H), 3.89 (m,
1H), 3.12 (br d, 2H), 2.81 (m, 2H), 1.85 (m, 2H), 1.74 (br, 2H),
1.61 (m, 2H). (file: mn4-a01246-118)
[0289] Add 0.17 mL of 1N HCl in ether into a solution of the free
base in methylene chloride-methanol, evaporate the solvent and dry
under vacuum to obtain the monohydrochloride salt. (LY 636774,
MN4-A01246-118-2)
18.
2,4,6-Trifluoro-N-[6-(1-ethylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-ben-
zamide LY 2030068 MN4-A01700-74-1 Bai-Ping Ying & Dan
Kohlman
##STR00040##
[0291] Mix
2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-ben-
zamide (26 mg), acetaldehyde (42 mg), sodium cyanoborohydride (10
mg) and trifluoroacetic acid (16.4 mg) in methanol (2 mL) in a
sealed tube and heat in an oil bath at 90.degree. C. overnight.
Dilute with methanol and load on a SCX column (10 g), wash with
methanol, elute the product with 2M NH.sub.3-methanol, evaporate,
purify on a silica gel column (4 g, solvent: dichloromethane-2M
NH.sub.3 in methanol, gradient) to obtain the title compound (8.4
mg). Mass spectrum (electrospray) m/z=392 (M+1); .sup.1H NMR
(CDCl.sub.3): 8.51 (d, 1H), 8.42 (br, 1H), 7.92 (t, 1H), 7.82 (dd,
1H), 6.84 (m, 2H), 3.63 (m, 1H), 3.02 (m, 2H), 2.44 (m, 2H), 2.04
(m, 2H), 1.87 (m, 4H), 1.60 (m, 5H), 1.11 (t, J=6.8 Hz, 3H). (file:
mn4-a01700-74)
[0292] Dissolve the free base (8.4 mg) in dichloromethane-methanol
and add 0.02 mL of 1N HCl in ether, evaporate and dry in vacuum to
give the hydrochloride salt. LY 2030069 MN4-A01700-74-2
19.
2,4,6-Trifluoro-N-[6-(1-propylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-be-
nzamide LY 2029650 MN4-A01700-72-1
##STR00041##
[0294] Mix
2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-ben-
zamide (50 mg), propionaldehyde (80 mg), sodium
triacetoxyborohydride (38 mg) and acetic acid (21 mg) with
dichloromethane (5 mL) and stir for 1.5 hrs. Dilute with methanol
and load on a SCX column (10 g), wash with methanol, elute the
product with 2M NH.sub.3-methanol. Purify the product on a silica
gel column (10 g, dichloromethane/2M NH.sub.3 in methanol,
gradient) to obtain the title compound as a free base (26 mg). Mass
spectrum (electrospray) m/z=406 (M+1); .sup.1H NMR (CDCl.sub.3):
8.52 (d, 1H), 8.38 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.82 (m,
2H), 3.61 (br, 1H), 3.00 (m, 2H), 2.34 (m, 2H), 2.11 (m, 2H), 1.87
(m, 3H), 1.60 (m, 5H), 0.90 (t, J=7.3 Hz, 3H). (file:
mn4-a01700-72)
[0295] Dissolve the free base (26 mg) in dichloromethane-methanol
and add 0.064 mL of 1N HCl in ether, evaporate and dry under vacuum
to obtain the hydrochloride salt. LY 2029652 MN4-A01700-72-2
20.
2,4,6-Trifluoro-N-[6-(1-cyclopropylmethyl-piperidin-4-ylcarbonyl)-pyri-
din-2-yl]-benzamide dihydrochloride salt LY2029823 GH8-A01546-104D
(PX114282)
##STR00042##
[0297] Combine
2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)pyridin-2-yl]benzamide
(0.05 g, 0.138 mmol), cyclopropylmethanal (0.10 g, 1.38 mmol) and
dichloromethane (5 mL), and stir at ambient temperature. After 15
minutes, add glacial acetic acid (0.02 mL, 0.35 mmol) followed by
sodium-triacetoxyborohydride (0.038 g, 0.18 mmol) with stirring.
After 3 hrs., dilute the reaction mixture with methanol (5 mL) and
load on an SCX column (10 g). Wash the column with methanol, elute
with 2M ammonia/methanol, and concentrate the eluent. Purify the
residue by flash chromatography, eluting with 10% ammonia/methanol
in dichloromethane, to obtain the free base of the title compound
(0.045 g, 77%). Dissolve the free base in dichloromethane (5 mL),
treat with 1M hydrogen chloride in diethylether (0.25 mL), and
concentrate the mixture to obtain the dihydrochloride salt.
M.p.=140.degree. C.; HRMS: Obs. m/z 418.1743; Calc. m/z 418.1742;
.sup.1H NMR (CDCl.sub.3): 11.51 (bs, 1H), 10.34 (bs, 1H), 8.38 (m,
1H), 8.11 (m, 1H), 7.78 (d, 1H), 7.42 (m, 2H), 3.79 (m, 1H), 3.64
(m, 2H), 2.98 (m, 4H), 2.17 (m, 2H), 1.99 (m, 2H), 1.13 (m, 1H),
0.65 (m, 2H), 0.39 (m, 2H).
Preparations
3. N-Methylisonipecotic acid
4. 415028
##STR00043##
[0299] Load isonipicotic acid (028608, 1 kg, 7.74 mol), water (10
L), formaldehyde (37% solution in water, 720 g, 8.87 mol, 1.15 eq.)
and wet Pd/C catalyst (10%; 55% paste, 100 g) into a stainless
steel hydrogenation reactor. Pressurize the reactor with H.sub.2 (3
bar) and stir the reaction mixture overnight at 200-300 rpm at
16-25.degree. C. Stop the reaction and filter off the catalyst.
Wash the filtrate with water (500 ml) and concentrate under vacuum.
Distill off the remaining water from the residue using ethanol
(2.times.1 L). Dry the solid overnight under vacuum at 50.degree.
C. to obtain the title product as an off-white solid (1087 g, 98.1%
yield).
4. N-Methylisonipecotyl chloride hydrochloride(Notebook 0793, p
068)
##STR00044##
[0301] Suspend N-methylisonipicotic acid (415028, 365 g, 2.55 mol)
in CH.sub.2Cl.sub.2 (3500 ml) and add a catalytic quantity of DMF
(2 ml). Add oxalyl chloride (435 g, 3.42 mol, 1.35 eq.) to the
reaction mixture maintaining the temperature at 20.degree. C. Heat
the suspension under reflux for 2 hrs. Cool the reaction mixture
and concentrate on a rotary evaporator. Resuspend the residue in
toluene (1000 ml), evaporate and dry under vacuum to yield the
title product (489 g, 96%) as an off-white solid residue, which is
used without further purification in the next reaction step.
5. N,N'-Dimethyl-N-methylisonipecotamide
##STR00045##
[0303] Resuspend N-methylisonipecotyl chloride hydrochloride (489
g, 2.54 mol) in anhydrous THF (5000 mL) and cool the suspension to
0-5.degree. C. Add a solution of dimethylamine in THF (2M, 2500 ml,
2 eq.) and triethylamine (775 g, 3 eq.) dropwise to the reaction
mixture maintaining the temperature below 7.degree. C. Stir the
suspension for 3 hrs. at this temperature and then allow the
reaction mixture to warm to 20.degree. C. overnight. Then cool the
reaction mixture to 5.degree. C. and 30% NaOH (600 mL) and add
CH.sub.2Cl.sub.2 (2 L). Separate the organic layer from the sticky
solid that is formed and redissolve the solid in water (2 L).
Extract the solution with CH.sub.2Cl.sub.2 (2 L). Combine the
organic fractions, concentrate to about 3500 mL, and wash twice
with water (500 mL). Dry the organic layer with Na.sub.2SO.sub.4,
filter, and concentrate to dryness. Dry the red oil under vacuum at
room temperature to produce the title product (378.7 g, 90% yield).
Treat with ether and evaporate to dryness to obtain the product as
a solid.
6. 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine (Notebook
0793, p 173)
##STR00046##
[0305] Cool methyl-ten-butyl ether (MTBE) (50 mL)
(T.sub.mass=-75.degree. C.) under a nitrogen atmosphere, and add
n-butyl litium (2.5M in n-hexane, 35 mL, 0.875 mol) to give a white
suspension. Add 2,6-Dibromopyridine (20.9 g, 0.088 mol) in MTBE
(210 mL) dropwise to the suspension at a rate that maintains the
T.sub.mass under -65.degree. C. (40 min). Stir the resulting yellow
heterogeneous solution at -70.degree. C. for 20 min. to produce a
green homogeneous solution. Then add
N',N-dimethyl-N-methylisonipecotamide (10 g, 0.0587 mol) in MTBE
(100 mL) dropwise at a rate that maintains the T.sub.mass under
-65.degree. C. (20 min). After the addition is completed, agitate
the mixture at -75.degree. C. for 1 hour. Quench the reaction
mixture with saturated ammonium chloride (30 mL) at 0-10.degree. C.
Neutralize the reaction mixture (pH=7) with 37% HCl (15 mL) and add
additional water (50 mL). Decant the aqueous phase and extract with
CH.sub.2Cl.sub.2 (3.times.500 mL). Combine the organic layers and
wash with acidic water (pH=2) (3.times.500 mL). Then basify the
aqueous phase with 30% NaOH (pH=12) and extract the mixture with
ethyl acetate (2.times.500 mL). Combine the organic layers, dry
with MgSO.sub.4, concentrate under reduced pressure, and then
vacuum dry at room temperature to provide the title product as an
oil (16 g, 96% yield). Mass spectrum (electrospray) m/z=283-285
(M+1); .sup.1H NMR: (400 MHz, CHLOROFORM-D) ppm 1.76 (m, 2H) 1.91
(m, 2H) 2.14 (m, 2H) 2.30 (s, 3H) 2.90 (d, J=11.85 Hz, 2H) 3.71 (m,
1H) 7.62 (d, J=7.54 Hz, 1H) 7.67 (t, J=7.54 Hz, 1H) 7.95 (d, J=7.54
Hz, 1H); .sup.13C-NMR: (100.61 MHz, Chloroform-D) ppm 28.08; 41.68;
46.36; 55.08; 121.26; 131.61; 139.25; 141.24; 153.59; 202.23.
7. 2-Amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (Notebook
0910, p 030)
##STR00047##
[0307] Load 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-piperidine
(20 g, 70.67 mmol, 1 eq) in 73.6 ml of 7M NH.sub.3/ethylene glycol
(530 mmol, 7.5 eq) into a 130 ml pressure autoclave, and add
Cu.sub.2O (101 mg, 0.706 mmol, 0.01 eq) as a catalyst. Seal the
autoclave and heat the reaction mixture to 85.degree. C. at about
50 psi (345 kPa) for 20 hrs. Cool the reaction mixture to room
temperature, transfer the organic layer to a 250 ml flask, and
place the flask under reduce pressure to remove ammonia. Add water
(70 mL) and of 30% NaOH (38 mL) and then extract the mixture with
methyl t-butyl ether (MTBE)(5.times.100 ml). Combine the organic
fractions and then dry with MgSO4, filter, and concentrate under
reduce pressure to obtain crude
2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (18.5 g).
Purification of 2-amino(6-pyridyl)-1-methyl(4-piperidyl)-ketone
(Notebook 0910, p 036)
[0308] Resuspend the crude
2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (14.5 g, 66.2
mmol) in ethanol (30 mL), add 2.5M HCl/ethanol (100 mL), stir the
mixture for 30 minutes, and then remove the solvent under reduce
pressure. Resuspend the resulting solid in 125 ml isopropanol and
heat under reflux for 30 minutes. Cool the reaction mixture to room
temperature, filtered-off the precipitate, rinse with 20 ml
isopropanol, and dry under vacuum at 50.degree. C. to obtain
2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine 2HCl (11 g,
63% yield corrected by HPLC % w/w).
Neutralization of 647714 2HCl (Notebook 0910, p 164)
[0309] Resuspend the
2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine 2HCl (129.5 g)
in ethyl acetate (100 mL) and add 10M NaOH (50 mL) and water (50
mL) to neutralize the suspension. Separate the organic layer and
extract the aqueous phase with ethyl acetate (2.times.150 mL).
Combine the organic layers, dry with MgSO.sub.4, filter, and
concentrate under reduce pressure to obtain the title product (21
g).
EXAMPLES
21.
2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-b-
enzamide (Notebook 0910, p 066)
##STR00048##
[0311] Add triethylamine (10.67 mL, 76.70 mmol, 2.4 eq) to a
solution of 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (7
g, 31.96 mmol, 1 eq) in anhydrous THF (100 mL) under a nitrogen
atmosphere. Add 2,4,6-triflubenzoylchloride (7.46 g, 5 mL, 38.35
mmol, 1.20 eq) dropwise at room temperature. After 2 hrs., add
additional 2,4,6-triflubenzoylchloride (0.75 mL, 0.15 eq) and
triethylamine (1.32 mL, 0.3 eq) to the reaction mixture and agitate
the mixture for an additional 3 hrs. Quench the reaction with
distilled water (10 mL) and 30% NaOH (15 mL). Stir the resulting
biphasic system for 1 hour and then separate the phases. Extract
the organic fraction by adding H.sub.2O (75 mL) and acetic acid (12
mL), followed by cyclohexane (70 mL). Wash the organic fraction
with H.sub.2O (50 mL) containing acetic acid (1 mL). Combine all
the aqueous fractions and washes and neutralize the mixture with
30% NaOH (15 mL). Extract with methyl-tert-butyl ether (MTBE)
(3.times.50 mL). Combine the organic fractions and dry with
MgSO.sub.4, filter, concentrate under reduce pressure, and vacuum
dry at room temperature, to obtain the title compound as a
light-brown solid (11.031 g, 91% yield). Mass spectrum
(Electrospray) m/z=378 (M+1); .sup.1H NMR (250 MHz, Chloroform-D)
ppm 1.54 (m, 2H) 2.02 (m, 2H) 2.13 (t, J=11.48 Hz, 2H) 2.29 (s, 3H)
2.80 (m, J=11.96 Hz, 1H) 3.56 (m, 1H) 4.26 (d, J=7.87 Hz, 1H) 6.17
(d, J=8.50 Hz, 1H) 6.75 (m, 2H) 7.45 (t, J=7.87 Hz, 1H) 7.53 (m,
1H) 7.95 (s, 1H); .sup.13C-NMR: (62.90 MHz, Chloroform-D) ppm
202.78; 162.6 (dm C-F-couplings); 162.0 (m C-F-couplings); 160.1 (m
C-F-couplings); 158.1; 150.0; 139.7; 119.3; 117.9; 110.2 (m
C-F-couplings); 100.9 (m C-F-couplings); 55.2; 46.5; 41.9; 28.1
22.
2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-b-
enzamide mono-hydrochloride salt (587815) (Notebook 0910, p
131)
##STR00049##
[0313] Dissolve
2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-benza-
mide-free base (5 g, 23.26 mmol) in isopropanol (50 mL) at room
temperature and add a solution of 3.3 M diethylether/HCl (8 mL).
Heat the reaction mixture under reflux for 30 minutes. Cool the
reaction mixture to room temperature and agitate for 2 hrs. Filter
the resulting white precipitate and rinse with isopropanol (5 mL).
Dry the residual solid under reduce pressure at 40.degree. C.
overnight to obtain the title compound (5.12 g, 93% yield). M.p.
223-224.degree. C. (sublimation); .sup.1H NMR (400 MHz, d6-DMSO) d
ppm 1.94 (m, 2H) 2.14 (m, J=11.15 Hz, 2H) 2.74 (s, 3H) 2.99 (m,
J=9.19 Hz, 2H) 3.49 (m, J=11.15 Hz, 2H) 3.77 (m, 1H) 7.41 (t,
J=8.71 Hz, 2H) 7.78 (d, J=7.43 Hz, 1H) 8.10 (t, J=7.92 Hz, 1H) 8.37
(d, J=6.85 Hz, 1H) 10.50 (s, 1H) 11.51 (s, 1H); .sup.13C-NMR:
(100.61 MHz, Chloroform-D) ppm 200.7; 130.6-158.0 (m,
C-F-couplings); 150.4; 150.1; 140.2; 118.5; 118.2; 111.9; 101.3 (t,
C-F couplings); 52.8; 42.6; 25.2
23.
2,4,6-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-be-
nzamide hemi-succinate salt 683974 (Notebook 0910, p 134)
##STR00050##
[0315] Add succinic acid (0.25 g, 2.148 mmol, 0.5 eq) to a solution
of
2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benz-
amide-free base (1.62 g, 4.297 mmol, 1 eq) in acetone (16.2 mL), at
room temperature. Warm the solution under reflux for 30 minutes.
Cool the solution to room temperature and filter off the resulting
white precipitate. Rinse the precipitate with acetone (0.2 mL) and
dry under vacuum at 50.degree. C. for 16 hours to provide the title
compound (1.5 g, 80% yield). M.p. 198.5.degree. C.; mass spectrum
(Electrospray) m/z=495.45 mass spec. presumed from data in
C.S.document, pg 19.
[0316] The following examples are prepared by combinatorial
chemistry techniques as follows:
Examples 24-54
##STR00051##
[0318] Combine R-acid (300 .mu.L of 0.5M solution in
dimethylformamide (DMF)), HATU (57 mg, 0.15 mmol), collidine (19
.mu.L, 0.15 mmol),
2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine and DMF (1.5
mL), and agitate for 48 hr. Dilute the reaction mixture with 10%
acetic acid in methanol (0.5 mL). Load the resulting reaction
mixture onto a 2 g SCX column Wash the column thoroughly with
methanol and then elute with 1 M ammonia in methanol. Concentrate
the eluent and further purify the product by high-throughput mass
guided chromatography. This procedure is repeated in parallel for
examples 24-54.
Examples 55-58
##STR00052##
[0320] Heat R-acid chloride (300 .mu.L of 0.5M solution in
pyridine) to 55.degree. C., add
2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (200 .mu.L of
0.5M solution in pyridine), and continue heating the reaction
mixture for 24 hr. Concentrate the reaction mixture and then dilute
with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL).
Load the resulting reaction mixture directly onto a 2 g SCX column
Thoroughly wash the column with methanol and then elute the column
with 1 M ammonia in methanol. Concentrate the eluent and then
further purify the product by high-throughput mass guided
chromatography. This procedure is repeated in parallel for examples
55-58.
Examples 59-71
##STR00053##
[0322] Heat 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine
(200 .mu.L of 0.5M solution in pyridine) to 55.degree. C. then add
R-acid chloride (0.10 mmol), heat for 2 hr. Concentrate the
reaction mixture and then dilute with 10% Acetic acid in methanol
(0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture
directly onto a 2 g SCX column Thoroughly wash the column with
methanol and then elute the column with 1 M ammonia in methanol.
Concentrate the eluent and then further purify the product by
high-throughput mass guided chromatography. This procedure is
repeated in parallel for examples 59-71.
[0323] Recombinant chemistry compounds are characterized by liquid
chromatography/mass spectroscopy on a Shimadzu QP8000.TM.. Examples
24-45 and 55-58 are run with a Metachem.TM. C18 column (monochrom 3
micron, 2.5.times.25 cm) using a 10-90% solvent B gradient in 4.5
min., where solvent A is 0.1% trifluoroacetic acid in water and
solvent B is 0.1% trifluoroacetic acid in acetonitrile. Examples
46-54 and 59-71 are run with a Metachem.TM. C18 column (monochrom 5
micron, 4.6.times.50 cm) using a 10-80% solvent B gradient in 9
min, where solvent A is 0.1% trifluoroacetic acid in water and
solvent B is 0.08% trifluoroacetic acid in acetonitrile.
TABLE-US-00001 24 N-[6-(1-Methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-thiophene-2- amide ##STR00054## LCMS Rf
2.871 min at 254 nm, 2.871 min at 190 nm, m/e 330 (M + 1). 25
N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2-
yl]-furan-2-amide ##STR00055## LCMS Rf 2.454 min at 254 nm, 2.454
min at 190 nm, m/e 314 (M + 1). 26 2-Chloro-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide
##STR00056## LCMS Rf 3.080 min at 254 nm, 3.080 min at 190 nm, m/e
358 (M + 1). 27 N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2-
yl]-furan-3-amide ##STR00057## LCMS Rf 2.448 min at 254 nm, 2.448
min at 190 nm, m/e 314 (M + 1). 28 3,4-Difluoro-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide
##STR00058## LCMS Rf 4.47 min at 254 nm, m/e 360 (M + 1). 29
N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2-
yl]-isonicotinamide ##STR00059## LCMS Rf 2.890 min at 254 nm, 2.890
min at 190 nm, m/e 325 (M + 1). 30 2-Methyl-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide
##STR00060## LCMS Rf 3.092 min at 254 nm, 3.092 min at 190 nm, m/e
338 (M + 1). 31 2-Bromo-N-[6-(1- methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00061## LCMS Rf 3.132 min
at 254 nm, 3.132 min at 190 nm, m/e 402 (M + 1). 32
2-trifluoromethoxy-N- [6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00062## LCMS Rf 2.771 min
at 254 nm, 2.771 min at 190 nm, m/e 330 (M + 1). 33
2-Fluoro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-isonicotinamide ##STR00063## LCMS Rf 2.669 min at 254 nm, 2.669
min at 190 nm, m/e 343 (M + 1). 34 4-Chloro-2-methoxy-
N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide
##STR00064## LCMS Rf 3.665 min at 254 nm, 3.664 min at 190 nm, m/e
387 (M + 1). 35 2-Ethoxy-N-[6-(1- methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00065## LCMS Rf 3.519 min
at 254 nm, 3.520 min at 190 nm, m/e 367 (M + 1). 36
2-Phenoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00066## LCMS Rf 3.841 min at 254 nm, 3.838 min
at 190 nm, m/e 415 (M + 1). 37 2-Methoxy-5-chloro- N-[6-(1-methyl-
piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00067## LCMS
Rf 3.661 min at 254 nm, 3.666 min at 190 nm, m/e 387 (M + 1). 38
2-Methoxy-4- methylsulfanyl-N-[6- (1-methylpiperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00068## LCMS Rf 3.683 min
at 254 nm, 3.692 min at 190 nm, m/e 399 (M + 1). 39 N-[6-(1-Methyl-
piperidin-4- ylcarbonyl)-pyridin-2- yl]-2,3- Dihydrobenzofuran-7-
amide ##STR00069## LCMS Rf 3.381 min at 254 nm, 3.381 min at 190
nm, m/e 365 (M + 1). 40 2-Benzyloxy-N-[6-(1- methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00070## LCMS Rf 4.086 min
at 254 nm, 4.089 min at 190 nm, m/e 429 (M + 1). 41
2-Propoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00071## LCMS Rf 3.811 min at 254 nm, 3.813 min
at 190 nm, m/e 381 (M + 1). 42 2,2-Difluoro-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-
benzo[1,3]dioxole-4- amide ##STR00072## LCMS Rf 3.531 min at 254
nm, 3.534 min at 190 nm, m/e 403 (M + 1). 43 2-(2-Methoxy-
ethoxy)-4-methoxy-N- [6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00073## LCMS Rf 3.552 min
at 254 nm, 3.556 min at 190 nm, m/e 427 (M + 1). 44
2-Methoxy-5-bromo- N-[6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00074## LCMS Rf 3.742 min
at 254 nm, 3.742 min at 190 nm, m/e 432 (M + 1). 45
2-(4,6-Dimethoxy- pyrimidin-2-yloxy)-N- [6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00075## LCMS Rf 3.428 min
at 254 nm, 3.425 min at 190 nm, m/e 477 (M + 1). 46
2-Ethoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-nicotinamide ##STR00076## LCMS Rf 1.56 min at 254 nm, m/e 368
(M + 1). 47 2-Phenoxy-N-[6-(1- methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-nicotinamide ##STR00077## LCMS Rf 1.61
min at 254 nm, m/e 416 (M + 1). 48 3-Acetyl-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-thiazolidine-4-
amide ##STR00078## LCMS Rf 1.23 min at 254 nm, m/e 376 (M + 1). 49
2-Phenylsulfanyl-N- [6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-nicotinamide ##STR00079## LCMS Rf 1.59
min at 254 nm, m/e 432 (M + 1). 50 2-(2,2,2- Trifluoroethoxy)-5-
methoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00080## LCMS Rf 1.69 min at 254 nm, m/e 451 (M +
1). 51 2-Methoxy-6-methyl- N-[6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00081## LCMS Rf 1.50 min
at 254 nm, m/e 367 (M + 1). 52 4-Methoxycarbonyl- N-[6-(1-methyl-
piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00082## LCMS
Rf 1.53 min at 254 nm, m/e 381 (M + 1). 53 N-[6-(1-Methyl-
piperidin-4- ylcarbonyl)-pyridin-2- yl]- Cyclobutylformamide
##STR00083## LCMS Rf 1.31 min at 254 nm, m/e 301 (M + 1). 54
2-(2-Chloro-1,1,2- trifluoroethoxy)-N-[6- (1-methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00084## LCMS Rf 1.64 min
at 254 nm, m/e 455 (M + 1). 55 N-[6-(1-Methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]-butanamide ##STR00085## LCMS Rf 2.23 min
at 254 nm, m/e 290 (M + 1). 56 N-[6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]- cyclohexylformamide ##STR00086## LCMS
Rf 4.23 min at 254 nm, m/e 330 (M + 1). 57 N-[6-(1-Methyl-
piperidin-4- ylcarbonyl)-pyridin-2- yl]-3-phenyl- propanamide
##STR00087## LCMS Rf 4.86 min at 254 nm, m/e 352 (M + 1). 58
2,6-Difluoro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00088## LCMS Rf 4.05 min 254 nm, m/e 360 (M +
1). 59 2-Chloro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00089## LCMS Rf 1.47 min at 254 nm, m/e 357 (M +
1). 60 2,5-Difluoro-N-[6-(1- methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00090## LCMS Rf 1.52 min
at 254 nm, m/e 359 (M + 1). 61 3,4-Difluoro-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide
##STR00091## LCMS Rf 1.54 min at 254 nm, m/e 359 (M + 1). 62
2-Trifluoromethyl-4- fluoro-N-[6-(1- methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00092## LCMS Rf 1.57 min
at 254 nm, m/e 409 (M + 1). 63 2-Fluoro-6- trifluoromethyl-N-[6-
(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide
##STR00093## LCMS Rf 1.60 min at 254 nm, m/e 409 (M + 1). 64
2,3,4-Trifluoro-N-[6- (1-methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00094## LCMS Rf 1.57 min at 254 nm, m/e 377 (M +
1). 65 2,4,5-Trifluoro-N-[6- (1-methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00095## LCMS Rf 1.56 min
at 254 nm, m/e 377 (M + 1). 67 3-Chloro-N-[6-(1-
methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-thiophene-2- amide
##STR00096## LCMS Rf 1.67 min at 254 nm, m/e 363 (M + 1). 68
2,6-Dichloro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-
yl]-benzamide ##STR00097## LCMS Rf 1.57 min at 254 nm, m/e 391 (M +
1). 69 2-Fluoro-4- trifluoromethyl-N-[6- (1-methyl-piperidin-4-
ylcarbonyl)-pyridin-2- yl]-benzamide ##STR00098## LCMS Rf 1.67 min
at 254 nm, m/e 409 (M + 1). 70 N-[6-(1-methyl- piperidin-4-
ylcarbonyl)-pyridin-2- yl]- Cyclopentylformamide ##STR00099## LCMS
Rf 3.06 min at 254 nm, m/e 315 (M + 1). 71 N-[6-(1-Methyl-
piperidin-4- ylcarbonyl)-pyridin-2- yl]-nicotinamide ##STR00100##
LCMS Rf 2.5 min at 254 nm, m/e 324 (M + 1).
Preparations
##STR00101##
[0324] 7. 1-Methyl-4-(pyrrolidin-1-yl-carbonyl)-piperidine
[0325] Add oxalyl chloride (5.08 mL, 0.058 mol) dropwise to a
suspension of 1-methyl-4-carboxypiperidine HCl (10 g, 0.056 mol) in
THF (100 mL) in the presence of a catalytic amount of DMF (0.1 mL)
at room temperature. Stir for 1 hr. and then heat the mixture at
reflux until gas emission stops (about 1 hr.). Cool the white
suspension to 5.degree. C. and add a solution of pyrrolidine (7.92
g, 0.111 mol) and triethylamine (16.9 g, 0.167 mol) dropwise over
30 min at a temperature between 5 and 13.degree. C. Stir the
suspension for 30 min. at 10.degree. C. and then warm to room
temperature. Quench the reaction mixture by adding 30% NaOH (20 mL,
0.2 mol) and water (10 mL). Decant the aqueous layer and extract
with THF (200 mL). Combine the organic layers, dry over
Na.sub.2CO.sub.3, and evaporate under vacuum at 40.degree. C.
Solubilize the resulting oil in cyclohexane (200 mL). Evaporate
under reduced pressure at 40.degree. C. to give a white solid (11
g). Heat the white solid (11 g) under reflux in cyclohexane (50 mL)
until completely dissolved. Cool the solution to room temperature
and stir at room temperature for 2 hr. Filter the suspension wash
the crystals with cyclohexane (10 mL). Dry the white crystals under
reduced pressure at 40.degree. C. to provide the title intermediate
(7.76 g, 75% yield).
8. 2-Bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine
[0326] Add a solution of n-butyllithium (1.9M in n-hexane, 4 ml,
7.6 mmol) to a solution of 2,6-dibromopyridine (1.81 g, 7.64 mmol)
in MTBE (20 mL) dropwise under nitrogen, over 20 min., maintaining
the temperature between -72 and -67.degree. C. Stir the yellow
heterogeneous solution at -70.degree. C. for 20 min. to provide a
green homogeneous solution. Add a solution of
1-methyl-4-(pyrrolidin-1-yl-carbonyl)piperidine (1 g, 5.09 mmol) in
10 mL MTBE dropwise over 20 min., maintaining the temperature below
-69.degree. C. Stir the yellow mixture at -75.degree. C. for 1 hr.
Quench the reaction mixture with a saturated solution of ammonium
chloride (5 mL) between 0 and 10.degree. C. Acidify the mixture to
pH 2 with fuming HCl (2 mL). Extract the organic layer. Wash the
aqueous phase with MTBE (50 mL), make the aqueous layer basic with
a solution of 30% NaOH, and extract with ethyl acetate (2.times.50
mL). Combine the organic layers, dry over MgSO.sub.4, and
concentrate under reduced pressure at 40.degree. C. to provide the
title intermediate as an oil (1.23 g, 85% yield).
[0327] The compounds of this invention are useful for increasing
activation of the 5-HT.sub.1F receptor. An increase in the
activation of the 5-HT.sub.1F is useful for treating a variety of
disorders which have been linked to decreased neurotransmission of
serotonin in mammals, e.g., migraine headaches. See U.S. Pat. No.
5,708,008 demonstrating the nexus between activation of the
5-HT.sub.1F receptor and migraine. To demonstrate the use of the
compounds of the present invention in the treatment of migraine,
their ability to bind to the 5-HT.sub.1F receptor subtype was
determined. The ability of the compounds of this invention to bind
to the 5-HT.sub.1F receptor subtype was measured essentially as
described in N. Adham, et al., Proceedings of the National 15
Academy of Sciences (USA), 90:408-412, 1993.
Membrane Preparation:
[0328] Membranes were prepared from transfected Ltk-cells
(transfected with the human 5-HT.sub.1F receptor sequence) which
were grown to 100% confluency. The cells were washed twice with
phosphate-buffered saline, scraped from the culture dishes into 5
mL of ice-cold phosphate-buffered saline, and centrifuged at
200.times.g for 5 minutes at 4.degree. C. The pellet was
resuspended in 2.5 mL of ice-cold Tris buffer (20 mM Tris HCl, pH
7.4 at 23.degree. C., 5 mM EDTA) and homogenized with a Wheaton
tissue grinder. The lysate was subsequently centrifuged at
200.times.g for 5 minutes at 4.degree. C. to pellet large fragments
which were discarded. The supernatant was collected and centrifuged
at 40,000.times.g for 20 minutes at 4.degree. C. The resulting
pellet was washed once in ice-cold Tris wash buffer and resuspended
in a final buffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH 7.4
at 23.degree. C. Membrane preparations were kept on ice and
utilized within two hours for the radioligand binding assays.
Protein concentrations were determined by the method of Bradford.
Anal. Biochem., 72:248-254, 1976.
Radioligand Binding:
[0329] [.sup.3H] 5-HT binding was performed using slight
modifications of the 5-HT.sub.1D assay conditions reported by
Herrick-Davis and Titeler (J. Neurochem., 50:1624-1631, 1988) with
the omission of masking ligands. Radioligand binding studies were
achieved at 37.degree. C. in a total volume of 250 .mu.L of buffer
(50 mM Tris, 10 mM MgCl.sub.2, 0.2 mM EDTA, 10 .mu.M pargyline,
0.1% ascorbate, pH 7.4 at 37.degree. C.) in 96 well microtiter
plates. Saturation studies were conducted using [.sup.3H] 5-HT at
12 different concentrations ranging from 0.5 nM to 100 nM.
Displacement studies were performed using 4.5-5.5 nM [.sup.3H]
5-HT. The binding profile of drugs in competition experiments was
accomplished using 6-12 concentrations of compound. Incubation
times were 30 minutes for both saturation and displacement studies
based upon initial investigations which determined equilibrium
binding conditions. Nonspecific binding was defined in the presence
of 10 .mu.M 5-HT. Binding was initiated by the addition of 50 .mu.L
membrane homogenates (10-20 .mu.g). The reaction was terminated by
rapid filtration through presoaked (0.5% poylethyleneimine) filters
using 48R Brandel Cell Harvester (Gaithersburg, Md.). Subsequently,
filters were washed for 5 seconds with ice cold buffer (50 mM Tris
HCl, pH=7.4 at 4.degree. C.), dried and placed into vials
containing 2.5 mL Readi-Safe (Beckman, Fullerton, Calif.) and
radioactivity was measured using a Beckman LS 5000TA liquid
scintillation counter. The efficiency of counting of [.sup.3H] 5-HT
averaged between 45-50%. Binding data was analyzed by
computer-assisted nonlinear regression analysis (Accufit and
Accucomp, Lunden Software, Chagrin Falls, Ohio). IC.sub.50 values
were converted to K.sub.i values using the Cheng-Prusoff equation.
Biochem. Pharmacol., 22:3099-3108 (1973). All experiments were
performed in triplicate. Representative compounds of the present
invention were found to have high affinity for the 5-HT.sub.1F
receptor as measured by the procedure described above, as for
example K.sub.i's of less than or equal to 300 nM. Preferred
compounds of the present invention have K.sub.i's of less than or
equal to 100 nM. A yet more preferred embodiment provides compounds
having a K.sub.i of less than or equal to 50 nM.
Selectivity for the 5-HT.sub.1F Receptor
[0330] Compounds of the prevent invention are relatively selective
for the 5-HT.sub.1F receptor, particularly in comparison to other
5-HT receptor subtypes, specifically other receptors in the
5-HT.sub.1 subclass, as for example, but without limitation, the
5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, and 5-HT.sub.1E receptor
subtypes. Affinity for these other receptor subtypes can readily be
determined by slight modification of the above described
radioligand receptor binding assays using cells transfected with
the desired receptor subtype in place of cells transfected with the
5-HT.sub.1F receptor subtype. The binding affinities of
representative compounds of the present invention were determined
by such assays and were found to be selective for the 5-HT.sub.1F
receptor; that is the affinities of the compounds for the
5-HT.sub.1F receptor were on the whole, higher than for other
receptor subtypes, particular for the 5-HT.sub.1B and 5-HT.sub.1D
receptor subtypes.
Measurement of cAMP Formation
[0331] As was reported by R. L. Weinshank, et al., WO93/14201, the
5-HT.sub.1F receptor is functionally coupled to a G-protein as
measured by the ability of serotonin and serotonergic drugs to
inhibit forskolin stimulated cAMP production in NIH3T3 cells
transfected with the 5-HT.sub.1F receptor. Adenylate cyclase
activity was determined using standard techniques. A maximal effect
is achieved by serotonin. An E.sub.max is determined by dividing
the inhibition of a test compound by the maximal effect and
determining a percent inhibition. N. Adham, et al., supra; R. L.
Weinshank, et al., Proceedings of the National Academy of Sciences
(USA), 89:3630-3634, 1992; and the references cited therein.
[0332] Human 5-HT.sub.1F receptor transfected NIH3T3 cells
(estimated B.sub.max from one point competition studies=488 fmol/mg
of protein) were incubated in DMEM, 5 mM theophylline, 10 mM HEPES
(4-[2-hydroxyethyl]-1-piperazineethanesulfonic acid) and 10 .mu.M
pargyline for 20 minutes at 37.degree. C., 5% CO.sub.2. Drug
dose-effect curves were then conducted by adding 6 different final
concentrations of drug, followed immediately by the addition of
forskolin (10 .mu.M). Subsequently, the cells were incubated for an
additional 10 minutes at 37.degree. C., 5% CO.sub.2. The medium was
aspirated and the reaction was stopped by the addition of 100 mM
HCl. To demonstrate competitive antagonism, a dose-response curve
for 5-HT was measured in parallel, using a fixed dose of
methiothepin (0.32 .mu.M). The plates were stored at 4.degree. C.
for 15 minutes and then centrifuged for 5 minutes at 500.times.g to
pellet cellular debris, and the supernatant was aliquoted and
stored at -20.degree. C. before assessment of cAMP formation by
radioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics,
Cambridge, Mass.). Radioactivity was quantified using a Packard
COBRA Auto Gamma counter, equipped with data reduction software.
Representative compounds of the present invention were tested and
found to be agonists of the 5-HT.sub.1F receptor in the cAMP assay
described above.
Protein Extravasation Assay
[0333] The following test was performed to determine the ability of
compounds of the present invention to inhibit protein
extravasation, which test is also a functional assay for the
neuronal mechanism of migraine.
[0334] Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from
Charles River Laboratories (225-325 g) were anesthetized with
sodium pentobarbital intraperitoneally (65 mg/kg or 45 mg/kg
respectively) and placed in a stereotaxic frame (David Kopf
Instruments) with the incisor bar set at -3.5 mm for rats or -4.0
mm for guinea pigs. Following a midline sagital scalp incision, two
pairs of bilateral holes were drilled through the skull (6 mm
posterially, 2.0 and 4.0 mm laterally in rats; 4 mm posteriorly and
3.2 and 5.2 mm laterally in guinea pigs, all coordinates referenced
to bregma). Pairs of stainless steel stimulating electrodes,
insulated except at the ends (Rhodes Medical Systems, Inc.), were
lowered through the holes in both hemispheres to a depth of 9 mm
(rats) or 10.5 mm (guinea pigs) from dura.
[0335] The femoral vein was exposed and a dose of the test compound
was injected intravenously (1 mL/kg). Approximately 7 minutes
later, a 50 mg/kg dose of Evans Blue, a fluorescent dye, was also
injected intravenously. The Evans Blue complexed with proteins in
the blood and functioned as a marker for protein extravasation.
Exactly 10 minutes post-injection of the test compound, the left
trigeminal ganglion was stimulated for 3 minutes at a current
intensity of 1.0 mA (5 Hz, 4 msec duration) with a Model 273
potentiostat/galvanostat (EG&G Princeton Applied Research).
[0336] Fifteen minutes following stimulation, the animals were
killed and exsanguinated with 20 mL of saline. The top of the skull
was removed to facilitate the collection of the dural membranes.
The membrane samples were removed from both hemispheres, rinsed
with water, and spread flat on microscopic slides. Once dried, the
tissues were coverslipped with a 70% glycerol/water solution.
[0337] A fluorescence microscope (Zeiss) equipped with a grating
monchromator and a spectrophotometer was used to quantify the
amount of Evans Blue dye in each sample. An excitation wavelength
of approximately 535 nm was utilized and the emission intensity at
600 nm was determined. The microscope was equipped with a motorized
stage and also interfaced with a personal computer. This
facilitated the computer-controlled movement of the stage with
fluorescence measurements at 25 points (500 .mu.m steps) on each
dural sample. The mean and standard deviation of the measurements
were determined by the computer.
[0338] The extravasation induced by the electrical stimulation of
the trigeminal ganglion was an ipsilateral effect (i.e. occurs only
on the side of the dura in which the trigeminal ganglion was
stimulated). This allows the other (unstimulated) half of the dura
to be used as a control. The ratio of the amount of extravasation
in the dura from the stimulated side compared to the unstimulated
side was calculated. Saline controls yielded a ratio of
approximately 2.0 in rats and 1.8 in guinea pigs. In contrast, a
compound which effectively prevented the extravasation in the dura
from the stimulated side would have a ratio of approximately 1.0. A
dose-response curve was generated and the dose that inhibited the
extravasation by 50% (ID.sub.50) was approximated. Representative
compounds of the present invention were assayed by the above
procedure and were found to significantly inhibit neuronal protein
extravasation. All compounds of the present invention tested had
ID.sub.50's of less than or equal to _ nM/Kg.
Rabbit Saphenous Vein Contraction
[0339] Representative compounds of the present invention were
tested in a rabbit saphenous vein contraction assay to measure
their ability to mediate vasoconstriction.
[0340] Male New Zealand White rabbits (3-6 lbs) (Hazleton,
Kalamazoo, Mich.) were sacrificed by a lethal dose of sodium
pentobarbital (325 mg) injected into the ear vein. Tissues were
dissected free of connective tissue, cannulated in situ with
polyethylene tubing (PESO, outside diameter=0.97 mm) and placed in
petri dishes containing modified Krebs solution (described infra).
The tips of two 30-gauge stainless steel hypodermic needles bent
into an L-shape were slipped into the polyetylene tubing. Vessels
were gently pushed from the cannula onto the needles. The needles
were then separated so that the lower one was attached with thread
to a stationary glass rod and the upper one was tied with thread to
the transducer.
[0341] Tissues were mounted in organ baths containing 10 mL of
modified Krebs solution of the following composition: 118.2 mMol
NaCl, 4.6 mMol KCl, 1.6 mMol CaCl.sub.2.H.sub.2O, 1.2 mMol
KH.sub.2PO.sub.4, 1.2 mMol MgSO.sub.4, 10.0 mMol dextrose and 24.8
mMol NaHCO.sub.3. Tissue bath solutions were maintained at
37.degree. C. and aerated with 95% O.sub.2 and 5% CO.sub.2. An
initial optimum resting force of 1 gm was applied to the saphenous
vein. Isometric contractions were recorded as changes in grams of
force on a Beckman Dynograph with Statham UC-3 transducers and
microscale accessory attachments. Tissues were allowed to
equilibrate 1 to 2 hours before exposure to drugs. Cumulative
agonist concentration-response curves were generated in tissues and
no tissue was used to generate more than two agonist
concentration-response curves. Results are expressed as a mean
EC.sub.50 and the maximal response expressed as a percentage of the
maximal tissue contraction response to 67 mM KCl administered
initially to each tissue.
[0342] This vasoconstriction assay measures two important
parameters, saphenous vein contraction (EC.sub.50) and maximal
contraction as a % maximal KCl response (%.sub.max KCl). The
saphenous vein contraction (EC.sub.50) is a measure of the dose
required to contract tissue to 50% of the maximal response that the
specific compound is capable of mediating. The maximal response
that the saphenous vein is capable of exhibiting is measured after
administration of a high concentration (67 mM) of KCl. The %
maximal KCl contraction is the ratio of the maximal response that
the specific compound is capable of mediating divided by the
maximal response that the tissue can produce upon stimulation with
KCl. For purposes of this application, a compound may be considered
to not have significant vasoconstrictive activity if it produces a
maximal contraction of less than or equal to 5% of the contraction
produced by the 67 mM KCl positive control at compound
concentrations of up to 100 .mu.M.
[0343] Representative compounds of the present invention were
tested with the above saphenous vein assay and found to not be
significantly vasoconstrictive. All compounds of the present
invention tested had an EC.sub.50 of less than or equal to _ mM and
a %.sub.max KCl of less than or equal to _ in this assay. This
contrasts greatly with prior art compounds for the treatment of
migraine targeting the neural vasoconstrictive model for migraine
treatment, which compounds were selected on the basis of strong
vasoconstrictive activity, as for example, sumatriptan, which has
an EC.sub.50 of 0.66 mM and a %.sub.max KCl of 64.20 in this
assay.
Specifidity Index
[0344] The specificity of compounds of the present invention for
5-HT.sub.1F mediated inhibition of neuronal protein extravasation
versus vasoconstrictive activity can be expressed with a
Specificity Index, which is the ratio of vasoconstriction to
efficacy in inhibiting neuronal protein extravasation:
Specificity Index = Corrected Vasoconstriction EC 50 ( M )
Extravasation ID 50 ( mMol / kg ) ##EQU00001##
[0345] The Corrected Vasoconstriction takes into consideration the
maximal contraction relative to KCl for each individual compound,
and is defined as the vasoconstriction EC.sub.50 value divided by
the %.sub.max KCl.
[0346] For example, sumatriptan has a corrected vasoconstriction
EC.sub.50 of 1.03.times.10.sup.-8 M (0.66 mM EC.sub.50/
64.20%.sub.max KCl) and an extravasation inhibition ID.sub.50 of
2.6.times.10-8 mMol/Kg, giving a Specificity Index of 0.40.
Compounds of the present invention have Specificity Indexes of
greater than or equal to 10. (10 picked for being a lower number in
dependent claim of X09150.)
[0347] Thus the procedure for determining the Specificity Index of
any given compound is as follows:
[0348] 1. Measure the affinity of the compound for the 5-HT.sub.1F
receptor using the radioligand binding method described above;
[0349] 2. Once affinity for the 5-HT.sub.1F receptor is
established, determine whether the compound is an agonist, partial
agonist or antagonist of the 5-HT.sub.1F receptor by its response
in the above described cAMP assay;
[0350] 3. If the compound is shown to be an agonist or partial
agonist with an E.sub.max of at least about 50%, measure efficacy
of the compound in inhibition of protein extravasation and
saphenous vein contraction using the above described assays;
and
[0351] 4. Calculate the Specificity Index as shown above.
[0352] While compounds with a Specificity Index greater than 1 are
useful for the methods and uses of the present invention, larger
values for the Specificity Index are preferred. A larger
Specificity Index indicates greater specificity for efficacy in
inhibition of neuronal protein extravasation over vasoconstriction.
Thus, preferred compounds have a Specificity Index of greater than
or equal to 10 (at least 10), preferably greater than or equal to
100 (at least 100). More preferred compounds have a Specificity
Index of greater than or equal to 1000 (at least 1000), and yet
more preferred compounds have Specificity Indexes greater than or
equal to 5000 (at least 5000).
Formulations
[0353] The type of formulation used for the administration of the
compounds employed in the methods of the present invention may be
dictated by the particular compounds selected, the type of
pharmacokinetic profile desired from the route of administration,
and the state of the patient.
[0354] Formulations amenable to oral, sublingual, nasal or
injectable administration are prepared in a manner well known in
the pharmaceutical art and comprise at least one active compound.
See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed.
1980).
[0355] In general, a formulation of the present invention includes
an active ingredient (a compound of formula I) and is usually mixed
with an excipient, diluted by an excipient or enclosed within such
a carrier which can be in the form of a capsule, sachet, paper or
other container. When the excipient serves as a diluent, it can be
a solid, semi-solid, or liquid material, which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the formulations
can be in the form of tablets, pills, powders, lozenges, sachets,
cachets, elixirs, suspensions, emulsions, solutions, syrups,
aerosols (as a solid or in a liquid medium), ointments containing
for example up to 10% by weight of the active compound, soft and
hard gelatin capsules, gels, suppositories, sterile injectable
solutions, and sterile packaged powders.
[0356] In preparing a formulation, it may be necessary to mill the
active compound to provide the appropriate particle size prior to
combining with the other ingredients. If the active compound is
substantially insoluble, it ordinarily is milled to a particle size
of less than 200 mesh. If the active compound is substantially
water soluble, the particle size is normally adjusted by milling to
provide a substantially uniform distribution in the formulation,
e.g., about 40 mesh. In one embodiment of the present invention,
the particle size range is between about 0.1 .mu.m to about 100
.mu.m.
[0357] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, syrup, and methyl cellulose. The formulations can
additionally include: lubricating agents such as talc, magnesium
stearate, and mineral oil; wetting agents; emulsifying and
suspending agents; preserving agents such as methyl- and
propylhydroxybenzoates; sweetening agents; and flavoring agents.
The compounds of the invention can be formulated so as to provide
quick, sustained or delayed release of the active ingredient after
administration to the patient by employing procedures known in the
art.
[0358] The following formulation examples are illustrative only and
are not intended to limit the scope of the present invention. The
term "active ingredient" refers to a compound of formula I.
Formulation Example 1
TABLE-US-00002 [0359] Hard Gelatin Capsules Ingredient Quantity
(mg/capsule) 2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 30.0
4-carbonyl)-pyridin-2-yl]-benzamide hydrochloric acid salt LY587815
Starch 305.0 Magnesium stearate 5.0
[0360] The above ingredients are mixed and filled into hard gelatin
capsules in 340 mg quantities.
Formulation Example 2
TABLE-US-00003 [0361] Tablet Ingredient Quantity (mg/tablet)
2-Chloro-6-fluoro-N-[6-(1-methyl-piperidine- 25.0
4-carbonyl)-pyridin-2-yl]-benzamide mono-hydrochloric acid salt
LY622824 Cellulose, microcrystalline 200.0 Colloidal silicon
dioxide 10.0 Stearic acid 5.0
[0362] The components are blended and compressed to form tablets,
each weighing 240 mg.
Formulation Example 3
TABLE-US-00004 [0363] Dry Powder Inhaler Ingredient Weight %
2,4,6-Trifluoro-N-methyl-N-[6-(piperidine- 5
4-carbonyl)-pyridin-2-yl]-benzamideLY2004686 Lactose 95
[0364] The active ingredient is mixed with the lactose and the
mixture is added to a dry powder inhaling appliance.
Formulation Example 4
TABLE-US-00005 [0365] Tablet Ingredient Quantity (mg/tablet)
2-Fluoro-N-[6-(1-methyl-piperidine-4- 30.0
carbonyl)-pyridin-2-yl]-isonicotinamide LY558431 Starch 45.0
Microcrystalline cellulose 35.0 Polyvinylpyrrolidone 4.0 (as 10%
solution in water) Sodium carboxymethyl starch 4.5 Magnesium
stearate 0.5 Talc 1.0 Total 120 mg
[0366] The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinylpyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50.degree. C.-60.degree. C. and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 120 mg.
Formulation Example 5
TABLE-US-00006 [0367] Capsules Ingredient Quantity (mg/capsule)
Furan-3-carboxylic acid[6-(1-methyl-piperidine- 40.0
4-carbonyl)-pyridin-2-yl]-amide LY558422 Starch 109.0 Magnesium
stearate 1.0 Total 150.0 mg
[0368] The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 20 mesh U.S. sieve, and
filled into hard gelatin capsules in 150 mg quantities.
Formulation Example 6
TABLE-US-00007 [0369] Suspensions Ingredient Amount
4-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)- 50.0 mg
pyridin-2-yl]-2-trifluoromethyl-benzamide mono-hydrochloric acid
salt LY586554 Xanthan gum 4.0 mg Sodium carboxymethyl cellulose
(11%) 50.0 mg Microcrystalline cellulose (89%) Sucrose 1.75 g
Sodium benzoate 10.0 mg Flavor and color q.v. Purified water to 5.0
ml
[0370] The active ingredient, sucrose and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed with a
previously made solution of the microcrystalline cellulose and
sodium carboxymethyl cellulose in water. The sodium benzoate,
flavor, and color are diluted with some of the water and added with
stirring. Sufficient water is then added to produce the required
volume.
Formulation Example 7
TABLE-US-00008 [0371] Capsules Ingredient Quantity (mg/capsule)
4-Chloro-2-methoxy-N-[6-(1-methyl-piperidine- 15.0
4-carbonyl)-pyridin-2-yl]-benzamide DZ13 Starch 407.0 Magnesium
stearate 3.0 Total 425.0 mg
[0372] The active ingredient, cellulose, starch, and magnesium
stearate are blended, passed through a No. 20 mesh U.S. sieve, and
filled into hard gelatin capsules in 425 mg quantities.
Formulation Example 8
TABLE-US-00009 [0373] Intravenous Formulation Ingredient Quantity
2-Ethoxy-N-[6-(1-methyl-piperidine- 250.0 mg
4-carbonyl)-pyridin-2-yl]-benzamide DZ14 Isotonic saline 1000
ml
Formulation Example 9
TABLE-US-00010 [0374] Sublingual or Buccal Tablets Ingredient
Quantity (mg/tablet) 2,4,6-Trifluoro-N-[6-(1-methyl-piperidine-
10.0 4-carbonyl)-pyridin-2-yl]-benzamide hemi-succinnic acid salt
LY683974 Glycerol 210.5 Water 143.0 Sodium citrate 4.5 Polyvinyl
alcohol 26.5 Polyvinylpyrrolidone 15.5 Total 410.0 mg
[0375] The glycerol, water, sodium citrate, polyvinyl alcohol, and
polyvinylpyrrolidone are admixed together by continuous stirring
and maintaining the temperature at about 90.degree. C. When the
polymers have gone into solution, the solution is cooled to about
50-55.degree. C. and the active ingredient is slowly admixed. The
homogenous mixture is poured into forms made of an inert material
to produce a drug-containing diffusion matrix having a thickness of
about 2-4 mm. This diffusion matrix is then cut to form individual
tablets having the appropriate size.
Formulation Example 9
TABLE-US-00011 [0376] Sublingual or Buccal Tablets Ingredient
Quantity (mg/tablet) 2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 5.0
(freebase equivalent) 4-carbonyl)-pyridin-2-yl]-benzamide
hemi-succinnic acid salt LY683974 Mannitol 20 Gelatine 2.0 Water
add to total volume of 100 .mu.L Total 27.0 mg
[0377] The compound was dissolved in water containing 20% mannitol
and 2% gelatine to provide a stock solution at a concentration of
50 mg/mL (free base equivalent). The solution was aliquoted into
forms holding 100 .mu.L solution each. The formulation was then
frozen at -20.degree. C. for 3 hours and freeze dried.
Formulation Example 8
TABLE-US-00012 [0378] Intravenous Formulation Quantity per
Ingredient 1.0 mL Formulation
2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 1.16 mg
4-carbonyl)-pyridin-2-yl]-benzamide hemi-succinnic acid salt DZ14
Mannitol parenteral 50.0 mg Water for injection: q.s. to 1.0 mL
[0379] The compound and mannitol are dissolved in water and then
water is added to obtain the desired final volume. The solution is
then sterile filtered and aseptically filled into suitable
vials.
[0380] While it is possible to administer a compound employed in
the methods of this invention directly without any formulation, the
compounds are usually administered in the form of pharmaceutical
formulations comprising a pharmaceutically acceptable excipient and
at least one active ingredient. These formulations can be
administered by a variety of routes including oral, buccal, rectal,
intranasal, transdermal, subcutaneous, intravenous, intramuscular,
and intranasal. Many of the compounds employed in the methods of
this invention are effective as both injectable and oral
compositions.
[0381] In order to administer transdermally, a transdermal delivery
device ("patch") is needed. Such transdermal patches may be used to
provide continuous or discontinuous infusion of a compound of the
present invention in controlled amounts. The construction and use
of transdermal patches for the delivery of pharmaceutical agents is
well known in the art. See, e.g., U.S. Pat. No. 5,023,252. Such
patches may be constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical agents.
[0382] Frequently, it will be desirable or necessary to introduce
the pharmaceutical composition to the brain, either directly or
indirectly. Direct techniques usually involve placement of a drug
delivery catheter into the host's ventricular system to bypass the
blood-brain barrier. One such implantable delivery system, used for
the transport of biological factors to specific anatomical regions
of the body, is described in U.S. Pat. No. 5,011,472, which is
herein incorporated by reference. The delivery of hydrophilic drugs
may be enhanced by intra-arterial infusion of hypertonic solutions
which can transiently open the blood-brain barrier.
[0383] In one preferred embodiment of the present invention, there
is provided a pharmaceutical formulation comprising at least one
active compound as described above in a formulation adapted for
buccal and/or sublingual, or nasal administration. This embodiment
provides administration of the active compound in a manner that
avoids gastric complications, such as first pass metabolism by the
gastric system and/or through the liver. This administration route
may also reduce adsorption times, providing more rapid onset of
therapeutic benefit. The compounds of the present invention may
provide particularly favorable solubility profiles to facilitate
sublingual/buccal formulations. Such formulations typically require
relatively high concentrations of active ingredients to deliver
sufficient amounts of active ingredients to the limited surface
area of the sublingual/buccal mucosa for the relatively short
durations the formulation is in contact with the surface area, to
allow the absorption of the active ingredient. Thus, the very high
activity of the compounds of the present invention combined with
their high solubilities, facilitate their suitability for
sublingual/buccal formulation.
[0384] A compound of formula I is preferably formulated in a unit
dosage form, each dosage containing from about 0.001 to about 100
mg, more usually about 1.0 to about 30 mg, of the active
ingredient. The term "unit dosage form" refers to physically
discrete units suitable as unitary dosages for human subjects and
other mammals, each unit containing a predetermined quantity of
active material calculated to produce the desired therapeutic
effect, in association with a suitable pharmaceutical excipient as
described above.
[0385] The compounds are generally effective over a wide dosage
range. For examples, dosages per day normally fall within the range
of about 0.0001 to about 30 mg/kg of body weight. In the treatment
of adult humans, the range of about 0.1 to about 15 mg/kg/day, in
single or divided dose, is especially preferred. However, it will
be understood that the amount of the compound actually administered
will be determined by a physician, in the light of the relevant
circumstances, including the condition to be treated, the chosen
route of administration, the actual compound or compounds
administered, the age, weight, and response of the individual
patient, and the severity of the patient's symptoms, and therefore
the above dosage ranges are not intended to limit the scope of the
invention in any way. In some instances dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, provided that such larger doses are first
divided into several smaller doses for administration throughout
the day.
* * * * *