U.S. patent application number 12/551245 was filed with the patent office on 2010-02-11 for substituted pyrazolo[1,5-a] pyridine compounds and their methods of use.
This patent application is currently assigned to Avigen, Inc.. Invention is credited to Federico C.A. Gaeta, Matthew Gross, Kirk W. Johnson.
Application Number | 20100035920 12/551245 |
Document ID | / |
Family ID | 38626513 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100035920 |
Kind Code |
A1 |
Gaeta; Federico C.A. ; et
al. |
February 11, 2010 |
SUBSTITUTED PYRAZOLO[1,5-a] PYRIDINE COMPOUNDS AND THEIR METHODS OF
USE
Abstract
The present invention is directed to substituted
pyrazolo[1,5-a]pyridines and related methods for their synthesis
and use.
Inventors: |
Gaeta; Federico C.A.;
(Mountain View, CA) ; Gross; Matthew; (Vallejo,
CA) ; Johnson; Kirk W.; (Moraga, CA) |
Correspondence
Address: |
King & Spalding LLP
P.O. Box 889
Belmont
CA
94002-0889
US
|
Assignee: |
Avigen, Inc.
Alameda
CA
|
Family ID: |
38626513 |
Appl. No.: |
12/551245 |
Filed: |
August 31, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11810885 |
Jun 6, 2007 |
7585875 |
|
|
12551245 |
|
|
|
|
60811604 |
Jun 6, 2006 |
|
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Current U.S.
Class: |
514/300 ;
546/121 |
Current CPC
Class: |
A61P 25/02 20180101;
A61P 25/00 20180101; A61P 29/00 20180101; C07D 471/04 20130101;
A61P 25/36 20180101; Y10S 514/866 20130101; A61P 11/06 20180101;
A61P 25/04 20180101 |
Class at
Publication: |
514/300 ;
546/121 |
International
Class: |
A61K 31/437 20060101
A61K031/437; C07D 471/02 20060101 C07D471/02 |
Claims
1. A method for preparing a 2-substituted, 3-alkanoyl
pyrazolo[1,5-a]pyridine, said method comprising acylating a
2-substituted pyrazolo[1,5-a]pyridine under conditions effective to
provide a pyrazolo[1,5-a]pyridine compound comprising an acyl group
at the 3-ring position.
2. The method of claim 1, wherein said 2-substituted
pyrazolo[1,5-a]pyridine possesses a moiety at the 2-ring position
selected from alkyl, substituted alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy,
substituted aryloxy, alkanoyl, carbamoyloxy, thioalkyl, substituted
thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino,
halo, and carbamoylamino.
3. The method of claim 2, wherein said substituent at the 2-ring
position is selected from lower alkyl, substituted lower alkyl,
aryl, substituted aryl, alkoxy, halo, and alkanoyl.
4. The method of claim 3, wherein said substituent at the 2-ring
position is selected from methyl, ethyl, propyl, isopropyl,
tert-butyl, sec-butyl, phenyl, halophenyl, and methoxyphenyl.
5. The method of claim 1, wherein said acylating comprises a
Friedel Crafts acylation.
6. The method of claim 1, wherein said acylating comprises reacting
a 2-substituted pyrazolo[1,5-a]pyridine with an .alpha.-halo
alkanyol chloride in the presence of aluminum chloride to provide a
2-substituted, 3-(.alpha.-haloalkanoyl)pyrazolo[1,5-a]pyridine.
7. The method of claim 6, further comprising reacting the
2-substituted, 3-(.alpha.-haloalkanoyl)pyrazolo[1,5-a]pyridine with
a nucleophile to replace the .alpha.-halo group therewith.
8. A method for treating a mammalian subject experiencing
neuropathic pain by administering to the subject a therapeutically
effective amount of a substituted pyrazolo[1,5-a]pyridine compound
having the following structure: ##STR00255## where: R.sub.2 is
independently H or an organic radical selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy,
substituted aryloxy, carbamoyloxy, thioalkyl, substituted
thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino,
and carbamoylamino; R.sub.3 is independently H or an organic
radical selected from the group consisting of alkyl, substituted
alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, and substituted alkynyl; and R.sub.6 is independently H or
an organic radical selected from the group consisting of hydroxy,
sulfhydryl, alkoxy, aryloxy, thioalkyl, thioaryl, amino, halogen,
alkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, and carboxamido,
where at least one of R.sub.2, R.sub.3, and R.sub.6 is other than a
hydrogen, and in the event that R.sub.2 is isopropyl and R.sub.3 is
2-methylpropan-1-one, then R.sub.6 is an organic radical other than
hydrogen, whereby as a result of such administering, the subject
experiences relief of the neuropathic pain.
9. The method of claim 8, wherein said mammalian subject is
suffering from a condition selected from postherpetic neuralgia,
trigeminal neuralgia, diabetic neuropathy.
10. The method of claim 8, wherein said mammalian subject is
suffering from neuropathic pain associated with a condition
selected from the group consisting of migraine, herpes, HIV,
traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex
sympathetic dystrophy, complex regional pain syndrome, and
cancer-chemotherapeutic-induced neuropathic pain.
11. The method of claim 8, wherein the administering is over a
duration of time effective to result in attenuation or elimination
of the neuropathic pain.
12. The method of claim 8, wherein R.sub.6 of said substituted
pyrazolo[1,5-a]pyridine compound is H and R.sub.2 is isopropyl.
13. The method of claim 8, wherein said substituted
pyrazolo[1,5-a]pyridine compound possesses the structure:
##STR00256## where Z is O, N--OH, or N--O--C(O)NH.sub.2; W is lower
alkyl or amino; and V is lower alkyl or substituted phenyl.
14. The method of claim 8, wherein said substituted
pyrazolo[1,5-a]pyridine compound possesses the structure:
##STR00257## and R.sub.3 is selected from: ##STR00258##
15. The method of claim 8, wherein said substituted
pyrazolo[1,5-a]pyridine compound is selected from the group
consisting of compound 1013
(2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one),
1014
(1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime), 1019
(1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime), 1103 (2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine),
and 1137
(isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-y-
l]-amine.
16. The method of claim 8, wherein said substituted
pyrazolo[1,5-a]pyridine compound is administered in combination
with at least one other agent effective for treating pain.
17. A method for treating inflammation by administering to a
subject suffering from an inflammatory condition a therapeutically
effective amount of a substituted pyrazolo[1,5-a]pyridine compound
having the structure: ##STR00259## where: R.sub.2 is independently
H or an organic radical selected from the group consisting of
alkyl, substituted alkyl, aryl, substituted aryl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, hydroxy,
sulfhydryl, alkoxy, substituted alkoxy, aryloxy, substituted
aryloxy, carbamoyloxy, thioalkyl, substituted thioalkyl,
carbamoylthio, thioaryl, substituted thioaryl, amino, and
carbamoylamino; R.sub.3 is independently H or an organic radical
selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl; and R.sub.6 is independently H or an organic
radical selected from the group consisting of hydroxy, sulfhydryl,
alkoxy, aryloxy, thioalkyl, thioaryl, amino, halogen, alkyl,
alkenyl, alkynyl, aryl, cyano, carboxyl, and carboxamido, where at
least one of R.sub.2, R.sub.3, and R.sub.6 is other than a
hydrogen, and in the event that R.sub.2 is isopropyl and R.sub.3 is
2-methylpropan-1-one, then R.sub.6 is an organic radical other than
hydrogen.
18. A method of treating opioid dependence or opioid withdrawal
syndrome in a mammalian subject by administering a substituted
pyrazolo[1,5-a]pyridine compound having the following structure:
##STR00260## where: R.sub.2 is independently H or an organic
radical selected from the group consisting of alkyl, substituted
alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy,
substituted alkoxy, aryloxy, substituted aryloxy, carbamoyloxy,
thioalkyl, substituted thioalkyl, carbamoylthio, thioaryl,
substituted thioaryl, amino, and carbamoylamino; R.sub.3 is
independently H or an organic radical selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and
R.sub.6 is independently H or an organic radical selected from the
group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy,
thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl,
cyano, carboxyl, and carboxamido, where at least one of R.sub.2,
R.sub.3, and R.sub.6 is other than a hydrogen, and in the event
that R.sub.2 is isopropyl and R.sub.3 is 2-methylpropan-1-one, then
R.sub.6 is an organic radical other than hydrogen.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/810,885, filed Jun. 6, 2007, which claims the benefit
of priority to U.S. Provisional Application No. 60/811,604, filed
Jun. 6, 2006, the content of which is hereby expressly incorporated
herein by reference in its entirety.
FIELD
[0002] The present invention relates generally to substituted
pyrazolo[1,5-a]pyridine compounds and compositions thereof, as well
as methods for making and using such compounds, among others.
BACKGROUND
[0003] Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine)
is a small molecule drug that has been used for many years in Japan
and Korea for the treatment of bronchial asthma as well as for
treatment of cerebrovascular disorders such as post-stroke
dizziness. It is sold in these countries under the tradename,
Ketas.RTM.. Marketed indications for ibudilast in Japan include its
use as a vasodilator, for treating allergy, eye tissue
regeneration, ocular disease, and treatment of allergic ophthalmic
disease (Thompson Current Drug Reports). Its use in the treatment
of both chronic brain infarction (ClinicalTrials.gov) and multiple
sclerosis (News.Medical.Net; Pharmaceutical News, 2 Aug. 2005) is
currently being explored in separate, ongoing clinical trials.
[0004] The mechanisms of action of ibudilast have been widely
explored. Its role as a non-selective inhibitor of cyclic
nucleotide phosphodiesterase (PDE) has been described (Fujimoto,
T., et al., J. of Neuroimmunology, 95 (1999) 35-92). Additionally,
ibudilast has been reported to act as an LTD4 antagonist, an
anti-inflammatory, a PAF antagonist, and a vasodilatatory agent
(Thompson Current Drug Reports). Ibudilast is also thought to exert
a neuroprotective role in the central nervous system of mammals,
presumably via suppression of the activation of glial cells (Mizuno
et al. (2004) Neuropharmacology 46: 404-411). New uses for
ibudilast continue to be explored.
[0005] An analog of ibudilast, KC-764
(2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo(1,5-a)pyridine,
developed by Kyorin Pharmaceutical Co., has been reported to
possess antiplatelet and antithrombotic activity (Momo, K., et al.,
Arzneimittelforschung, 1992, January 42(1), 32-9). KC-764 possesses
a chemical structure that differs from ibudilast in the
substituents at the 2- and 3-ring positions. Interestingly, its
reported therapeutic use, primarily as an antiplatelet agent,
differs significantly from that of the parent compound,
ibudilast.
[0006] The applicants have surprisingly discovered that certain
compounds belonging to the substituted pyrazolo[1,5-a]pyridine
family are useful in the treatment of conditions such as
neuropathic pain. Additionally, such compounds are useful for
treating one or more of the following: inflammatory conditions,
opiate withdrawal and taxol-induced neuropathy, as well as for
antiviral therapy, among others. The shortcomings of current
therapeutic approaches in each of these areas are well-known. It is
believed that the compounds described herein provide one or more
advantages over currently existing therapies.
SUMMARY
[0007] The present invention is generally directed to substituted
pyrazolo[1,5-a]pyridine compounds. The compounds of the invention
are particularly useful in the treatment of conditions such as
neuropathic pain and migraine, among others.
[0008] In one aspect, provided herein are 2,3,6-substituted
pyrazolo[1,5-a]pyridine compounds having the following
structure:
##STR00001##
[0009] The compounds of the invention possess one or more
substituents as described in greater detail below at one or more of
ring positions 2, 3, and 6. That is to say, a compound of the
invention may possess a single substituent at position 2, a single
substituent at position 3, or a single substituent at position 6.
Alternatively, a compound of the invention may be
2,3-disubstituted, 2,6-disubstituted, or 3,6-disubstituted.
Further, a compound of the invention may be
2,3,6-trisubstituted.
[0010] In one particular embodiment, a compound in accordance with
structure I is di-substituted at ring positions 2 and 3.
[0011] Referring to structure I above, each of R.sub.2, R.sub.3 and
R.sub.6 generally corresponds to the following, where:
[0012] R.sub.2 is independently H or an organic radical selected
from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted
alkoxy, aryloxy, substituted aryloxy, carbamoyloxy, thioalkyl,
substituted thioalkyl, carbamoylthio, thioaryl, substituted
thioaryl, amino, and carbamoylamino;
[0013] R.sub.3 is independently H or an organic radical selected
from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl; and
[0014] R.sub.6 is independently H or an organic radical selected
from the group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy,
thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl,
cyano, carboxyl, and carboxamido. Illustrative carboxamido moieties
include both linear amido moieties as well as lactams,
morpholinamides, tetrahydroquinolineamides,
tetrahydroisoquinolineamides, coumarinamides, and the like.
[0015] Preferably, a substituted pyrazolo[1,5-a]pyridine compound
of the invention corresponding to structure I above is one where
when R.sub.2 is isopropyl and R.sub.3 is 2-methylpropan-1-one, then
R.sub.6 is not H (i.e., is an organic radical other than
hydrogen).
[0016] In one embodiment of the invention, R.sub.2 is lower alkyl,
substituted lower alkyl, amino, aryl, or substituted aryl.
[0017] In yet a further embodiment, R.sub.2 is phenyl or
substituted phenyl.
[0018] In a preferred embodiment, R.sub.2 is lower alkyl or
mono-substituted lower alkyl.
[0019] In a particular embodiment, R.sub.2 is isopropyl or
2-hydroxypropan-2-yl.
[0020] In yet another embodiment, R.sub.2 is phenyl or
mono-substituted phenyl.
[0021] In yet another embodiment, R.sub.2 is a phenyl ring
possessing either a single halogen or alkoxy substituent. Preferred
R.sub.2 substituents include 4-halo phenyl groups such
4-fluorophenyl, 4-chlorophenyl, and 4-iodophenyl, as well as
4-alkoxy phenyl substituents.
[0022] In another embodiment, R.sub.6 is H and R.sub.2 is
isopropyl.
[0023] In yet another embodiment, R.sub.3 possesses the
structure:
##STR00002##
where
##STR00003##
represents the pyrazolo[1,5-a]pyridine ring system, and the carbon
atom shown in structure II above is covalently attached to ring
carbon 3, and C can be saturated or unsaturated.
[0024] In the event that C in structure II is saturated, X and Y
are each independently selected from the group consisting of --H or
an organic radical selected from the group consisting of hydroxyl,
amino, alkoxy, cyano, halo, sulfhydryl, thioalkyl, lower alkyl, and
substituted lower alkyl.
[0025] In one embodiment of structure II, when C (referring to
structure II above) is unsaturated, X and Y, when taken together,
form a double bond attached to a functional group, Z, selected from
O, S, and N--R.sub.11, where R.sub.11 is selected from --OH,
--O--C(O)--NR.sub.12R.sub.13, --O--C(O)--R.sub.14, and
CR.sub.15R.sub.16, and R.sub.12, R.sub.13, R.sub.14 and R.sub.15
are each independently selected from --H, lower alkyl, and aryl.
Thus, when C is unsaturated, X and Y, when taken together with the
carbon atom, may form one or more of the following moieties:
.about.C.dbd.O, .about.C.dbd.S, .about.C.dbd.N--OH,
.about.C.dbd.N--O--C(O)--NR.sub.12R.sub.13,
.about.C.dbd.N--O--C(O)--R.sub.14, .about.C.dbd.CR.sub.15R.sub.16,
among others. In a preferred embodiment, R.sub.12 and R.sub.13 are
both hydrogen.
[0026] In reference to structure II above, R.sub.10 is
independently H or an organic radical selected from alkyl,
substituted alkyl, aryl, substituted aryl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, and ester. In a preferred
embodiment, R.sub.10 is lower alkyl or substituted lower alkyl.
Exemplary lower alkyl groups include isopropyl and
2-hydroxyisopropyl, among others. In yet another embodiment
R.sub.10 is an ester, e.g., a lower alkyl ester.
[0027] Alternatively, when C is unsaturated, X and Y, when taken
together, form a double bond to C that, when taken together with
R.sub.10, forms part of an aromatic heterocycle. For example, C,
together with X, Y, and R.sub.10 may form part of a pyridine ring,
a pyrazole ring, a pyrimidine ring, a pyridazine ring, an
imidazole, a 1H-imidazole-2-(3H)-thione, a thiazole, a
thiazole-2(5H)-imine, and the like, including substituted versions
thereof.
[0028] For example, in one embodiment, R.sub.3 corresponds to
structure II above, where C is unsaturated, and C, taken together
with X, Y, and R.sub.10, forms a 3-pyridin-4-yl substituent, while
R.sub.2 is isopropyl.
[0029] In yet another embodiment, R.sub.3 corresponds to structure
II above, where C is unsaturated, and C, taken together with X, Y,
and R.sub.10, forms a substituted pyrimidine ring having a
substituent at the 2-position of the pyrimidine ring, while R.sub.2
is isopropyl. In a particular embodiment thereof, the substituent
at the 2-position of the pyrimidine ring is an isopropylamino
group. Preferably, the pyrimidine ring is attached to the core
pyrazolo[1,5-a]pyridine ring at its 4 position.
[0030] In yet another embodiment, R.sub.3 corresponds to structure
II above, where C is unsaturated, and C, taken together with X, Y,
and R.sub.10, forms a 1H-imidazole-2-(3H)-thione, while R.sub.2 is
isopropyl.
[0031] In an alternative embodiment, R.sub.3 corresponds to
structure II above, where C is unsaturated, and C, taken together
with X, Y, and R.sub.10, forms a thiazole-2(5H)-imine, while
R.sub.2 is isopropyl.
[0032] In yet a further embodiment, a substituted
pyrazolo[1,5-a]pyridine compound of the invention possesses the
following generalized structure:
##STR00004##
[0033] where Z is O, N--OH, or N--O--C(O)NH.sub.2; W is lower alkyl
or amino; and V is lower alkyl or substituted phenyl. In one
embodiment, V is mono-substituted phenyl, where the substituents
can be ortho, meta or para. In a particular embodiment when V is
mono-substituted phenyl, the substituents are para to one
another.
[0034] In a particular embodiment of structure III, W is --CH.sub.3
or --NH.sub.2, and V is isopropyl or 4-fluorophenyl.
[0035] In one preferred embodiment of structure III, Z is O, W is
--NH.sub.2, and V is isopropyl.
[0036] In yet another preferred embodiment of structure III, Z is
N--O--C(O)NH.sub.2, W is methyl, and V is isopropyl.
[0037] In yet a further preferred embodiment of structure III, Z is
N--OH, W is methyl, and V is 4-fluorophenyl.
[0038] In yet another embodiment, R.sub.6 is --H or an organic
radical selected from the group consisting of hydroxy, lower
alkoxy, lower alkyl, and substituted lower alkyl. Exemplary
substituted lower alkyl groups include halomethyl, dihalomethyl,
and trihalomethyl, among others.
[0039] In yet another embodiment, provided is a compound having the
structure shown below,
##STR00005##
[0040] where R.sub.3 is selected from:
##STR00006##
[0041] Preferred substituted pyrazolo[1,5-a]pyridine compounds of
the invention include compounds corresponding to the following
designations used herein: 1001, 1002, 1003, 1004, 1005, 1006, 1007,
1008, 1009, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020,
1021, 1022, 1023, 1024, 1025, 1026, 1027, 1032, 1033, 1103, 1137,
1085, and 1087.
[0042] In a preferred embodiment, referring to structure I above,
R.sub.3 is selected from alkyl, substituted alkyl, alkanoyl (also
referred to as acyl), and substituted alkanoyl.
[0043] In yet another embodiment, R.sub.3 is selected from lower
alkyl, substituted lower alkyl, lower alkanoyl, and substituted
alkanoyl.
[0044] Particularly preferred R.sub.3 moieties include (i) lower
alkanoyls substituted with one or more polar substituents such as
hydroxy, alkoxy, amino, and cyano, and (ii) alkyl oximes. Exemplary
R.sub.3 moieties include 2-aminoethanone, 2-amino-propan-1-one,
2-methylpropan-1-one oxime, and 2-methylpropan-1-one-O-carbamoyl
oxime.
[0045] In a particularly preferred embodiment, R.sub.2 is
isopropyl, R.sub.3 is selected from 2-aminoethanone,
2-amino-propan-1-one, 2-methylpropan-1-one oxime, and
2-methylpropan-1-one-O-carbamoyl oxime, and R.sub.6 is H.
[0046] Illustrative compounds in accordance with the invention are
provided in Table 1, as well as in the accompanying examples. That
is to say, one particular embodiment of the invention include
compounds in accordance with structure I above, where each of
R.sub.2, R.sub.3 and R.sub.6 is selected from the structures
provided in Table 1.
[0047] In yet another embodiment, particular compounds of the
invention include those in which each of R.sub.2, R.sub.3, and
R.sub.6 possesses the individual structure provided in Table 1, for
each of the respective substituted pyrazolo[1,5-a]pyridine
compounds provided therein.
[0048] In yet another embodiment, a substituted
pyrazolo[1,5-a]pyridine compound is selected from compounds 1013
(2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one),
1014
(1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime), 1019
(1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime), 1103 (2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine),
1137
(isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-am-
ine, 1085
(4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-t-
hione), and 1087
(4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine).
[0049] The present invention also encompasses pharmaceutically
acceptable salt forms and prodrugs of the foregoing compounds.
[0050] The present invention further provides a pharmaceutical
composition comprising a 2,3,6-substituted pyrazolo[1,5-a]pyridine
compound as described above. Such compositions may optionally
include one or more pharmaceutically acceptable excipients.
[0051] In yet another aspect, provided herein is a method for
preparing a 2,3-substituted pyrazolo[1,5-a]pyridine compound. The
method comprises the step of acylating a 2-substituted
pyrazolo[1,5-a]pyridine under conditions effective to provide a
pyrazolo[1,5-a]pyridine compound comprising an acyl group at the
3-ring position ("2-substituted, 3-alkanoyl
pyrazolo[1,5-a]pyridine"). The reactant, a 2-substituted
pyrazolo[1,5-a]pyridine, typically possesses a moiety at the 2-ring
position selected from alkyl, substituted alkyl, aryl, substituted
aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy,
substituted aryloxy, alkanoyl, carbamoyloxy, thioalkyl, substituted
thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino,
halo, and carbamoylamino. Preferred 2-substituents include lower
alkyl, substituted lower alkyl, aryl, substituted aryl, alkoxy,
halo, and alkanoyl. Particularly preferred 2-substituents include
methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, phenyl,
halophenyl, and methoxyphenyl.
[0052] In the above method, the 2-substituted, 3-alkanoyl
pyrazolo[1,5-a]pyridine is optionally further transformed into one
or more desired 2,3-substituted pyrazolo[1,5-a]pyridine compounds.
For example, the resulting ketone functionality may be reduced to
an alcohol, or even an alkyl group, e.g., using the Clemmensen
reduction. Alternatively, the keto group may be converted to an
oxime or to an imine or hydrazone. In yet another approach, the
3-alkanoyl pyrazolo[1,5-a]pyridine may be prepared to contain a
leaving group, e.g., a halo group or other suitable functionality,
to allow yet further transformations. In a preferred approach, an
.alpha.-halo ketone is prepared from the acylation reaction.
[0053] In a particular embodiment of the method, the acylation
reaction is a Friedel Crafts acylation.
[0054] In yet another embodiment, the acylation reaction comprises
reacting a 2-substituted pyrazolo[1,5-a]pyridine with an
.alpha.-halo alkanyol chloride in the presence of aluminum chloride
to provide a 2-substituted,
3-(.alpha.-haloalkanoyl)pyrazolo[1,5-a]pyridine. In yet a further
embodiment, the 2-substituted,
3-(.alpha.-haloalkanoyl)pyrazolo[1,5-a]pyridine is then reacted
with a suitable nucleophilic reagent to replace the .alpha.-halo
group with a new functionality, e.g., an amino group, a nitrile
group, a hydroxyl group, or the like.
[0055] In yet another aspect, the compounds of the invention are
useful in the treatment of neuropathic pain, as evidenced by
results using standard neuropathic pain models. The compounds of
the invention have been found to be effective in significantly
attenuating mechanical allodynia. Thus, also provided herein is a
method for treating a mammalian subject experiencing neuropathic
pain by administering to the subject a therapeutically effective
amount of a substituted pyrazolo[1,5-a]pyridine compound as
described herein. As a result of such administering, the subject
experiences relief (i.e., attenuation or reduction, elimination, or
reversal) of the neuropathic pain.
[0056] Mammalian subjects for treatment include those suffering
from postherpetic neuralgia, trigeminal neuralgia, diabetic
neuropathy, and neuropathic pain associated with a condition
selected from the group consisting of migraine, herpes, HIV,
traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex
sympathetic dystrophy, complex regional pain syndrome, and
cancer-chemotherapeutic-induced neuropathic pain (e.g.,
taxol-induced neuropathy).
[0057] In a preferred embodiment of the treatment method, the
administering is over a duration of time effective to result in
attenuation or elimination of the neuropathic pain.
[0058] In a further embodiment of the method, a substituted
pyrazolo[1,5-a]pyridine compound as described above is administered
in combination with at least one other agent effective for treating
pain. Such agents include gabapentin, memantine, pregabalin,
morphine and related opiates, cannabinoids, tramadol, lamotrigine,
carbamazepine, duloxetine, milnacipran, and tricyclic
antidepressants, among others.
[0059] In yet another aspect, the compounds of the invention are
inhibitors of phosphodiesterases.
[0060] Further, in yet another aspect, the compounds of the
invention are particularly effective in inhibiting cytokine release
using a standard in-vitro peripheral blood mononuclear cell assay.
More particularly, the compounds of the invention are effective in
inhibiting the production of TNF-.alpha. and IL-1.beta.. Thus also
provided herein is a method for treating inflammation by
administering to a subject suffering from an inflammatory condition
a therapeutically effective amount of a substituted
pyrazolo[1,5-a]pyridine compound of the invention.
[0061] In yet another aspect, provided herein is a method for
treating opioid withdrawal or opioid dependence by administering to
a subject suffering from the same a therapeutically effective
amount of a substituted pyrazolo[1,5-a]pyridine compound of the
invention.
[0062] In yet another aspect, provided herein are methods for (i)
attenuating or abolishing the dopamine mediated "reward" associated
with addicts' cravings, as well as (ii) alleviating symptoms of
withdrawal syndromes after discontinuance of drug use or compulsive
behavior.
[0063] Specifically, provided herein is a method for suppressing
the release of dopamine in the nucleus accumbens of a subject
comprising administering to the subject an effective amount of a
pyrazolo[1,5-a]pyridine compound of the invention.
[0064] In certain embodiments, the subject has an addiction. In
certain embodiments, the addiction is a drug addiction, for
example, an opiate, cocaine, amphetamine, methamphetamine,
cannabinoid, alcohol, or nicotine addiction. In other embodiments,
the addiction is a behavioral addiction, for example, an eating,
drinking, smoking, shopping, gambling, sex, or computer use
addiction.
[0065] Each of the herein-described features of the invention is
meant to apply equally to each and every embodiment as described
herein, unless otherwise indicated.
[0066] Additional objects, advantages and novel features of the
invention will be set forth in the description that follows, and in
part, will become apparent to those skilled in the art upon reading
the following, or may be learned by practice of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0067] FIG. 1 is a plot demonstrating the results of an
illustrative compound of the invention in a rat chronic
constriction injury model for assessing efficacy in treatment of
neuropathic pain as described in detail in Example 72. The model
employed measures mechanical allodynia by response to von Frey
Fibers. The plot shows the 50% paw withdrawal threshold (in grams)
for rats administered vehicle or compound 1014 intraperitoneally at
two different doses at various time points post-administration;
and
[0068] FIG. 2 is a plot similarly demonstrating the results of an
illustrative compound of the invention in a rat chronic
constriction injury model for assessing efficacy in treatment of
neuropathic pain as described in detail in Example 72. The model
employed measures mechanical allodynia by response to von Frey
Fibers. The plot shows the 50% paw withdrawal threshold in grams
for rats administered the vehicle or compound 1013
intraperitoneally at three different doses (10 mg/kg; 20 mg/kg; and
40 mg/kg) at various time points post-administration.
DETAILED DESCRIPTION
[0069] The practice of the present invention will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, and pharmacology, within the skill of the art. Such
techniques are explained fully in the literature. See, e.g.; A. L.
Lehninger, Biochemistry (Worth Publishers, Inc., current addition);
Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc.,
current addition); J. March, Advanced Organic Chemistry (McGraw
Hill, current addition); Remington. The Science and Practice of
Pharmacy, A. Gennaro, Ed., 20.sup.th Ed.; Goodman & Gilman The
Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L.
Limbird, A. Gilman, 10.sup.th Ed.
[0070] All publications, patents and patent applications cited
herein, whether supra or infra, are hereby incorporated by
reference in their entirety.
Definitions
[0071] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
embodiments, as such may vary, as will be apparent from the
accompanying description, examples, and figures.
[0072] It must be noted that, as used in this specification and the
intended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a drug" includes a single drug as
well as two or more of the same or different drugs, reference to
"an optional excipient" refers to a single optional excipient as
well as two or more of the same or different optional excipients,
and the like.
[0073] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions described below. The following definitions are meant to
apply regardless of whether a term is used by itself or in
combination with another term. That is to say, the definition of
"alkyl" applies to "alkyl" as well as to the "alkyl" portions of
"alkoxy", "alkylamino", etc.
[0074] "Alkyl" refers to a hydrocarbon chain, typically ranging
from about 1 to 20 atoms in length. Such hydrocarbon chains are
preferably but not necessarily saturated and may be branched or
straight chain, although typically straight chain is preferred.
Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl,
butyl, pentyl, 1-methylbutyl, 1-ethylpropyl, 3-methylpentyl, and
the like. As used herein, "alky" includes cycloalkyl when three or
more carbon atoms are referenced.
[0075] "Lower" in reference to a particular functional group means
a group having from 1-6 carbon atoms.
[0076] For example, "lower alkyl" refers to an alkyl group
containing from 1 to 6 carbon atoms, and may be straight chain or
branched, as exemplified by methyl, ethyl, propyl, isopropyl,
1-ethylpropyl, 1,2-dimethylpropyl, n-butyl, i-butyl, sec-butyl,
t-butyl, and the like.
[0077] "Cycloalkyl" refers to a saturated or unsaturated cyclic
hydrocarbon chain, including bridged, fused, or spiro cyclic
compounds, preferably made up of 3 to about 12 carbon atoms, more
preferably 3 to about 8.
[0078] The term "alkylene" includes straight or branched alkylene
chains such as methylene, ethylene, trimethylene, tetramethylene,
pentamethylene, hexamethylene, and the like.
[0079] "Non-interfering substituents" are those groups that, when
present in a molecule, are typically non-reactive with other
functional groups contained within that molecule.
[0080] The term "substituted" as in, for example, "substituted
alkyl" or "substituted aryl" refers to a moiety (e.g., an alkyl or
aryl group) substituted with one or more non-interfering
substituents, such as, but not limited to: C.sub.3-C.sub.8
cycloalkyl (e.g., cyclopropyl, cyclobutyl, and the like), halogen,
(e.g., fluoro, chloro, bromo, and iodo), cyano, oxo, acyl, ester,
sulfhydryl, amino, thioalkyl, carbonyl, carboxyl, carboxamido,
alkoxy, lower alkyl, aryl, substituted aryl, phenyl, substituted
phenyl, cyclic amides (e.g., cyclopentamide, cyclohexamide, etc.,
morpholinamide, tetrahydroquinolineamide,
tetrahydroisoquinolineamide, coumarinamides, and the like). For
substitutions on a phenyl ring, the substituents may be in any
orientation (i.e., ortho, meta, or para).
[0081] "Alkoxy" refers to an --O--R group, wherein R is alkyl or
substituted alkyl, preferably C.sub.1-C.sub.20 alkyl (e.g.,
methoxy, ethoxy, propoxy, isopropoxy, etc.), preferably
C.sub.1-C.sub.7.
[0082] As used herein, "alkenyl" refers to a branched or unbranched
hydrocarbon group of 1 to 15 atoms in length, containing at least
one double bond, such as ethenyl, n-propenyl, isopropenyl,
n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, and the
like.
[0083] The term "alkynyl" as used herein refers to a branched or
unbranched hydrocarbon group of 2 to 15 atoms in length, containing
at least one triple bond, ethynyl, n-propynyl, isopropynyl,
n-butynyl, isobutynyl, octynyl, decynyl, and so forth.
[0084] "Aryl" means one or more aromatic rings, each of 5 or 6 core
carbon atoms. Aryl includes multiple aryl rings that may be fused,
as in naphthyl or unfused, as in biphenyl. Aryl rings may also be
fused or unfused with one or more cyclic hydrocarbon, heteroaryl,
or heterocyclic rings. As used herein, "aryl" includes heteroaryl.
Preferred aryl groups contain one or two aromatic rings.
[0085] "Heteroaryl" is an aryl group containing from one to four
heteroatoms, preferably N, O, or S, or a combination thereof.
Heteroaryl rings may also be fused with one or more cyclic
hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Exemplary
heteroaryl rings include pyridine, pyridazine, pyrrole, pyrazole,
triazole, imidazole, oxazole, isoxazole, thiazole, isothiazole,
tetrahyquinoline, tetrahyquinolineamide, tetrahydroisoquinoline,
tetrahydroisoquinolineamide, coumarin, courmarinamide, and the
like.
[0086] "Heterocycle" or "heterocyclic" means one or more rings of
5-12 atoms, preferably 5-7 atoms, with or without unsaturation or
aromatic character and having at least one ring atom which is not a
carbon. Preferred heteroatoms include sulfur, oxygen, and
nitrogen.
[0087] "Substituted heteroaryl" is heteroaryl having one or more
non-interfering groups as substituents.
[0088] "Substituted heterocycle" is a heterocycle having one or
more side chains formed from non-interfering substituents.
[0089] "Amino" as used herein, encompasses both mono-substituted
amino and di-substituted amino compounds. For example, amino refers
to the moiety, --NR.sub.aR.sub.b, where R.sub.a and R.sub.b are
each independently --H, alkyl, aryl, or alkylaryl.
[0090] Carbamoyl-derivatives, as referred to herein, e.g.,
carbamoyloxy, carbamoxythio, and carbamoylamino, encompass
carbamoyl moieties where the amino group comprised therein may be
unsubstituted, mono-substituted or di-substituted as set forth
under the definition for amino group above.
[0091] The term "reactive" or "activated" when used in conjunction
with a particular functional group, refers to a functional group
that reacts readily with an electrophile or a nucleophile,
typically present on another molecule, to undergo a transformation.
This is in contrast to those groups that require strong catalysts
or harsh reaction conditions in order to react (i.e., a
"nonreactive" or "inert" group).
[0092] The term "protected" or "protecting group" or "protective
group" refers to the presence of a moiety (i.e., the protecting
group) that prevents or blocks reaction of a particular chemically
reactive functional group in a molecule under certain reaction
conditions. The protecting group will vary depending upon the type
of chemically reactive group being protected as well as the
reaction conditions to be employed and the presence of additional
reactive or protecting groups in the molecule, if any. Protecting
groups known in the art can be found in Greene, T. W., et al.,
PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd ed., John Wiley &
Sons, Inc., New York, N.Y. (1999).
[0093] As used herein, the term "functional group" or any synonym
thereof is meant to encompass protected forms thereof.
[0094] "Pharmaceutically acceptable excipient or carrier" refers to
an excipient that may optionally be included in the compositions of
the invention and that causes no significant adverse toxicological
effects to the patient.
[0095] "Pharmaceutically acceptable salt" includes, but is not
limited to, non-toxic salts such as amino acid salts, salts
prepared with inorganic acids, such as chloride, sulfate,
phosphate, diphosphate, bromide, and nitrate salts, or salts
prepared from the corresponding inorganic acid form of any of the
preceding, e.g., hydrochloride, etc., or salts prepared with an
organic carboxylic or sulfonic acid, such as malate, maleate,
fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate,
lactate, methanesulfonate, benzoate, ascorbate,
para-toluenesulfonate, palmoate, salicylate and stearate, as well
as estolate, gluceptate and lactobionate salts. Similarly salts
containing pharmaceutically acceptable cations include, but are not
limited to, sodium, potassium, calcium, aluminum, lithium, and
ammonium (including substituted ammonium).
[0096] "Active molecule" or "active agent" as described herein
includes any agent, drug, compound, composition of matter or
mixture which provides some pharmacologic, often beneficial, effect
that can be demonstrated in-vivo or in vitro. This includes foods,
food supplements, nutrients, nutriceuticals, drugs, vaccines,
antibodies, vitamins, and other beneficial agents. As used herein,
the terms further include any physiologically or pharmacologically
active substance that produces a localized or systemic effect in a
patient.
[0097] "Substantially" or "essentially" means nearly totally or
completely, for instance, 95% or greater of some given
quantity.
[0098] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not.
[0099] By "pathological pain" is meant any pain resulting from a
pathology, such as from functional disturbances and/or pathological
changes, lesions, burns, injuries, and the like. One form of
pathological pain is "neuropathic pain" which is pain thought to
initially result from nerve damage but extended or exacerbated by
other mechanisms including glial cell activation. Examples of
pathological pain include, but are not limited to, thermal or
mechanical hyperalgesia, thermal or mechanical allodynia, diabetic
pain, pain arising from irritable bowel or other internal organ
disorders, endometriosis pain, phantom limb pain, complex regional
pain syndromes, fibromyalgia, low back pain, cancer pain, pain
arising from infection, inflammation or trauma to peripheral nerves
or the central nervous system, multiple sclerosis pain, entrapment
pain, and the like.
[0100] "Hyperalgesia" means an abnormally increased pain sense,
such as pain that results from an excessive sensitiveness or
sensitivity. Examples of hyperalgesia include but are not limited
to cold or heat hyperalgesia.
[0101] "Hypalgesia" (or "hypoalgesia") means the decreased pain
sense.
[0102] "Allodynia" means pain sensations that result from normally
non-noxious stimulus to the skin or body surface. Examples of
allodynia include, but are not limited to, cold or heat allodynia,
tactile or mechanical allodynia, and the like.
[0103] "Nociception" is defined herein as pain sense. "Nociceptor"
herein refers to a structure that mediates nociception. The
nociception may be the result of a physical stimulus, such as,
mechanical, electrical, thermal, or a chemical stimulus.
Nociceptors are present in virtually all tissues of the body.
[0104] "Analgesia" is defined herein as the relief of pain without
the loss of consciousness. An "analgesic" is an agent or drug
useful for relieving pain, again, without the loss of
consciousness.
[0105] The term "central nervous system" or "CNS" includes all
cells and tissue of the brain and spinal cord of a vertebrate.
Thus, the term includes, but is not limited to, neuronal cells,
glial cells, astrocytes, cerebrospinal fluid (CSF), interstitial
spaces and the like.
[0106] "Glial cells" refer to various cells of the CNS also known
as microglia, astrocytes, and oligodendrocytes.
[0107] The terms "subject", "individual" or "patient" are used
interchangeably herein and refer to a vertebrate, preferably a
mammal. Mammals include, but are not limited to, murines, rodents,
simians, humans, farm animals, sport animals and pets.
[0108] The terms "pharmacologically effective amount" or
"therapeutically effective amount" of a composition or agent, as
provided herein, refer to a nontoxic but sufficient amount of the
composition or agent to provide the desired response, such as a
reduction or reversal of neuropathic pain. The exact amount
required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the condition being treated, the particular drug or drugs employed,
mode of administration, and the like. An appropriate "effective"
amount in any individual case may be determined by one of ordinary
skill in the art using routine experimentation, based upon the
information provided herein.
[0109] The term "about", particularly in reference to a given
quantity, is meant to encompass deviations of plus or minus five
percent.
[0110] "Treatment" or "treating" neuropathic pain includes: (1)
preventing pain, i.e. causing pain not to develop or to occur with
less intensity in a subject that may be exposed to or predisposed
to pain but does not yet experience or display pain, (2) inhibiting
pain, i.e., arresting the development or reversing pain, or (3)
relieving pain, i.e., decreasing the amount of pain experienced by
the subject.
[0111] By "treating existing pain" is meant attenuating,
alleviating or reversing neuropathic pain in a subject that has
been experiencing pain for at least 24 hours, such as for 24-96
hours or more, such as 25 30 35 40 45 48 50 55 65 72 80 90 96 100,
etc. hours. The term also intends treating pain that has been
occurring long-term, such as for weeks, months or even years.
[0112] The term "addiction" is defined herein as compulsively using
a drug or performing a behavior repeatedly that increases
extracellular dopamine concentrations in the nucleus accumbens. An
addiction may be to a drug including, but not limited to,
psychostimulants, narcotic analgesics, alcohols and addictive
alkaloids such as nicotine, cannabinoids, or combinations thereof.
Exemplary psychostimulants include, but are not limited to,
amphetamine, dextroamphetamine, methamphetamine, phenmetrazine,
diethylpropion, methylphenidate, cocaine, phencyclidine,
methylenedioxymethamphetamine and pharmaceutically acceptable salts
thereof. Exemplary narcotic analgesics include, but are not limited
to, alfentanyl, alphaprodine, anileridine, bezitramide, codeine,
dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin,
hydrocodone, hydromorphone, isomethadone, levomethorphan,
levorphanol, metazocine, methadone, metopon, morphine, opium
extracts, opium fluid extracts, powdered opium, granulated opium,
raw opium, tincture of opium, oxycodone, oxymorphone, pethidine,
phenazocine, piminodine, racemethorphan, racemorphan, thebaine and
pharmaceutically acceptable salts thereof. Addictive drugs also
include central nervous system depressants, such as barbiturates,
chlordiazepoxide, and alcohols, such as ethanol, methanol, and
isopropyl alcohol. The term addiction also includes behavioral
addictions, for example, compulsive eating, drinking, smoking,
shopping, gambling, sex, and computer use.
[0113] A subject suffering from an addiction experiences
addiction-related behavior, cravings to use a substance in the case
of a drug addiction or overwhelming urges to repeat a behavior in
the case of a behavioral addiction, the inability to stop drug use
or compulsive behavior in spite of undesired consequences (e.g.,
negative impacts on health, personal relationships, and finances,
unemployment, or imprisonment), reward/incentive effects associated
with dopamine release, and dependency, or any combination
thereof.
[0114] Addiction-related behavior in reference to a drug addiction
includes behavior resulting from compulsive use of a drug
characterized by dependency on the substance. Symptomatic of the
behavior is (i) overwhelming involvement with the use of the drug,
(ii) the securing of its supply, and (iii) a high probability of
relapse after withdrawal.
Substituted Pyrazolo[1,5-a]pyridines
[0115] The present invention encompasses 2,3,6-substituted
pyrazolo[1,5-a]pyridine compounds. Based upon results in both
standard in-vitro and in-vivo assays, the compounds of the
invention have been found to be effective in treating neuropathic
pain, as well as in treating inflammation. Moreover, certain
compounds of the invention are inhibitors of phosphodiesterase.
These and other features of the invention will now be described in
the sections which follow.
[0116] The compounds of the invention can be described generally by
the following structure:
##STR00007##
These compounds are referred to generally as
pyrazolo[1,5-a]pyridine compounds, where the numbering of the
non-bridgehead ring atoms is shown in structure I. The compounds of
the invention typically possess a substituent at one or more of
ring positions 2, 3, and/or 6. That is to say, a compound of the
invention may possess a single substituent at position 2, a single
substituent at position 3, or a single substituent at position 6.
Such compounds are referred to as mono-substituted
pyrazolo[1,5-a]pyridines. Alternatively, a compound of the
invention may be 2,3-disubstituted, 2,6-disubstituted, or
3,6-disubstituted. Further, a compound of the invention may be
2,3,6-trisubstituted, where each of the substituents is
independently selected. Preferably, a compound in accordance with
the invention is one where when R.sub.2 is isopropyl and R.sub.3 is
2-methylpropan-1-one, then R.sub.6 is not H.
[0117] Generally, in reference to structure I above, R.sub.2 is
independently H or an organic radical selected from the group
consisting of alkyl, substituted alkyl, aryl, substituted aryl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy,
substituted aryloxy, carbamoyloxy, thioalkyl, substituted
thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino,
and carbamoylamino;
[0118] R.sub.3 is independently H or an organic radical selected
from the group consisting of alkyl, substituted alkyl, aryl,
substituted aryl, alkenyl, substituted alkenyl, alkynyl, and
substituted alkynyl; and
[0119] R.sub.6 is independently H or an organic radical selected
from the group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy,
thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl,
cyano, carboxyl, and carboxamido. Illustrative carboxamido moieties
include both linear amido moieties as well as lactams,
morpholinamides, tetrahydroquinolineamides,
tetrahydroisoquinolineamides, coumarinamides, and the like.
Preferably, R.sub.6 is H.
[0120] Preferred embodiments of R.sub.2 include lower alkyl,
substituted lower alkyl, aryl, and substituted aryl. Representative
lower alkyl groups include methyl, ethyl, propyl, isopropyl,
1-ethylpropyl, 1,2-dimethylpropyl, 1-ethyl-2-methylpropyl,
2-ethyl-1-methylpropyl, butyl, isobutyl, sec-butyl, tert-butyl,
1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, pentyl, isopentyl, neopentyl, tert-pentyl,
1-methylpentyl, 2-methylpentyl, 3-methylpentyl, hexyl, and
isohexyl. Preferred lower alkyl and substituted lower alkyl groups
include the foregoing, optionally substituted with one or more of
the following: hydroxyl, cyano, hydroxyimino, carbamoyloxy, and
halo. Particularly preferred R.sub.2 groups include lower alkyl,
substituted lower alkyl such as mono-substituted lower alkyl, e.g.,
isopropyl and 2-hydroxypropan-2-yl, amino, aryl, and substituted
aryl.
[0121] Representative aryl groups and substituted aryl groups
include phenyl, benzyl, diphenyl, napthyl, tetrahydronapthyl,
indanyl, indenyl and substituted forms thereof. Illustrative aryl
groups include phenyl, mono-substituted phenyl, di-substituted
phenyl, and tri-substituted phenyl. In a particular embodiment,
R.sub.2 is a phenyl ring possessing either a single halogen or
alkoxy substituent. Preferred R.sub.2 substituents include 4-halo
phenyl groups such 4-fluorophenyl, 4-chlorophenyl, and
4-iodophenyl, as well as 4-alkoxy phenyl substituents, where alkoxy
is preferably lower alkoxy.
[0122] In certain instances, R.sub.3 possesses the structure:
##STR00008##
where
##STR00009##
represents the pyrazolo[1,5-a]pyridine ring system, where the
carbon indicated is attached to ring carbon 3, and C can be
saturated or unsaturated.
[0123] In the event that C in structure II is saturated, X and Y
are each independently selected from the group consisting of --H or
an organic radical selected from the group consisting of hydroxyl,
amino, alkoxy, cyano, halo, sulfhydryl, thioalkyl, lower alkyl, and
substituted lower alkyl.
[0124] When C (referring to structure II above) is unsaturated, X
and Y, when taken together, form a double bond attached to a
functional group, Z, selected from O, S, and N--R.sub.11, where
R.sub.11 is selected from --OH, --O--C(O)--NR.sub.12R.sub.13,
--O--C(O)--R.sub.14, and CR.sub.15R.sub.16, and R.sub.12, R.sub.13,
R.sub.14 and R.sub.15 are each independently selected from --H,
lower alkyl, and aryl. Thus, when C is unsaturated, X and Y, when
taken together with the carbon atom, may form one or more of the
following moieties: .about.C.dbd.O, .about.C.dbd.S,
.about.C.dbd.N--OH, .about.C.dbd.N--O--C(O)--NR.sub.12R.sub.13,
.about.C.dbd.N--O--C(O)--R.sub.14, .about.C.dbd.CR.sub.15R.sub.16,
among others. In a preferred embodiment, R.sub.12 and R.sub.13 are
both hydrogen.
[0125] In reference to structure II above, R.sub.10 is
independently H or an organic radical selected from alkyl,
substituted alkyl, aryl, substituted aryl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, and ester. In a preferred
embodiment, R.sub.10 is lower alkyl or substituted lower alkyl.
Exemplary substituents such as these include isopropyl and
2-hydroxyisopropyl, among others. In yet another embodiment
R.sub.10 is an ester, e.g., a lower alkyl ester.
[0126] Alternatively, in reference to structure II, when C is
unsaturated, X and Y, when taken together, form a double bond to C
that, when taken together with R10, forms part of an aromatic
heterocycle, preferably a nitrogen-containing heterocycle. For
example, C, together with X, Y, and R.sub.10 may form part of a
pyridine ring, a pyrazole ring, a pyrimidine ring, a pyridazine
ring, and the like, including substituted versions thereof.
Preferred substituents are lower alkyl and halo.
[0127] In one representative example, R.sub.3 corresponds to
structure II above, where C is unsaturated, and C, taken together
with X, Y, and R.sub.10, forms a 3-pyridin-4-yl substituent, while
R.sub.2 is isopropyl.
[0128] In yet another illustrative example, R.sub.3 corresponds to
structure II above, where C is unsaturated, and C, taken together
with X, Y, and R.sub.10, forms a substituted pyrimidine ring having
a substituent at the 2-position of the pyrimidine ring, while
R.sub.2 is isopropyl. In a particular embodiment thereof the
substituent at the 2-position of the pyrimidine ring is an
isopropylamino group. Preferably, the pyrimidine ring is attached
to the core pyrazolo[1,5-a]pyridine ring at its 4 position.
[0129] A substituted pyrazolo[1,5-a]pyridine compound of the
invention may also possesses the following generalized
structure:
##STR00010##
[0130] where Z is O, N--OH, or N--O--C(O)NH.sub.2; W is lower alkyl
or amino; and V is lower alkyl or substituted phenyl. In one
embodiment, V is mono-substituted phenyl, where the substituents
can be ortho, meta or para. In a particular embodiment when V is
mono-substituted phenyl, the substituents are para. Further
representative structures in accordance with structure III include
those where: (i) W is --CH.sub.3 or --NH.sub.2, and V is isopropyl
or 4-fluorophenyl, (ii) Z is O, W is --NH.sub.2, and V is
isopropyl, (iii) Z is N--O--C(O)NH.sub.2 W is methyl, and V is
isopropyl, and (iv) Z is N--OH, W is methyl, and V is
4-fluorophenyl.
[0131] Returning now to the moiety, R.sub.6, R.sub.6 may, in one or
more embodiments, be --H or an organic radical selected from the
group consisting of hydroxy, lower alkoxy, lower alkyl, and
substituted lower alkyl. Exemplary substituted lower alkyl groups
include halomethyl, dihalomethyl, and trihalomethyl, among
others.
[0132] Yet another illustrative compound is one having the
structure shown below,
##STR00011##
[0133] where R.sub.3 is selected from:
##STR00012##
[0134] Yet another exemplary substituted pyrazolo[1,5-a]pyridine
compound possesses the following generalized structure:
##STR00013##
[0135] where Z is O, N--OH, or N--O--C(O)NH.sub.2.
[0136] Returning to structure I above, in reference to the moiety
R.sub.3 exemplary R.sub.3 groups include alkyl, substituted alkyl,
alkanoyl (also referred to as acyl), and substituted alkanoyl. For
instance, representative R.sub.3 moieties include lower alkyl,
substituted lower alkyl, lower alkanoyl, and substituted alkanoyl.
Particularly preferred R.sub.3 moieties include (i) lower alkanoyls
substituted with one or more polar substituents such as hydroxy,
alkoxy, amino, and cyano and (ii) alkyl oximes.
[0137] Illustrative R.sub.3 groups include 2-methylpropan-1-one,
2-hydroxy-2-methylpropan-1-one, 2-aminoethanone,
2-methylpropan-1-one oxime, 2-methylpropan-1-one-O-carbamoyl oxime,
4-chlorophenylmethanone, 4-methoxyphenylmethanone, propan-1-one,
2-methylpropan-1-ol, and 2-methylprop-1-enyl isobutyrate,
2-amino-propan-1-one, and 2-methylpropan-1-one-O-carbamoyl oxime,
among others.
[0138] In certain instances, R.sub.6 is --H or an organic radical
selected from the group consisting of hydroxy, lower alkoxy, lower
alkyl, and substituted lower alkyl. Exemplary substituted lower
alkyl groups include halomethyl, dihalomethyl, and trihalomethyl,
among others.
[0139] Preferably, at least one of R.sub.2, R.sub.3, and R.sub.6 is
a substituent other than hydrogen.
[0140] Preferred substituted pyrazolo[1,5-a]pyridine compounds of
the invention include compounds corresponding to the following
designations used herein: 1001, 1002, 1003, 1004, 1005, 1006, 1007,
1008, 1009, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020,
1021, 1022, 1023, 1024, 1025, 1026, 1027, 1032, 1033, 1085, 1087,
1103, and 1137. The structures corresponding to each of the
preceding compound designations is provided in the accompanying
examples, and in Table 1.
[0141] In a particularly preferred embodiment, R.sub.2 is
isopropyl, R.sub.3 is selected from 2-aminoethanone,
2-amino-propan-1-one, 2-methylpropan-1-one oxime, and
2-methylpropan-1-one-O-carbamoyl oxime, and R.sub.6 is H.
[0142] Particularly preferred substituted pyrazolo[1,5-a]pyridine
compounds include: 1013
(2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one),
1014
(1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime), 1019
(1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime), 1103 (2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine),
and 1137
(isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-y-
l]-amine.
[0143] Particular embodiments corresponding to each of R.sub.2,
R.sub.3 and R.sub.6 are provided in Table 1 and in the accompanying
examples.
[0144] As stated previously, a reference to any one or more of the
herein-described substituted pyrazolo[1,5-a]pyridines is meant to
encompass, where applicable, any and all enantiomers, mixtures of
enantiomers including racemic mixtures, prodrugs, pharmaceutically
acceptable salt forms, hydrates (e.g., monohydrates, dihydrates,
etc.), solvates, different physical forms (e.g., crystalline
solids, amorphous solids), and metabolites.
Method of Synthesizing Pyrazolo[1,5-a]pyridines
[0145] The 2,3,6-substituted pyrazolo[1,5-a]pyridine compounds of
the invention are prepared using conventional synthetic organic
chemistry techniques. Illustrative syntheses are provided in at
least Examples 1-71 and 75-78 herein.
[0146] One preferred method for preparing a 2,3-substituted
pyrazolo[1,5-a]pyridine compound of the invention comprises the
step of acylating a 2-substituted pyrazolo[1,5-a]pyridine under
conditions effective to provide a pyrazolo[1,5-a]pyridine compound
comprising an acyl group at the 3-ring position i.e., a
"2-substituted, 3-alkanoyl pyrazolo[1,5-a]pyridine". The reactant,
a 2-substituted pyrazolo[1,5-a]pyridine, typically possesses a
moiety at the 2-ring position selected from alkyl, substituted
alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl,
alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy,
substituted alkoxy, aryloxy, substituted aryloxy, alkanoyl,
carbamoyloxy, thioalkyl, substituted thioalkyl, carbamoylthio,
thioaryl, substituted thioaryl, amino, halo, and carbamoylamino.
Preferred 2-substituents include lower alkyl, substituted lower
alkyl, aryl, substituted aryl, alkoxy, halo, and alkanoyl.
Particularly preferred 2-substituents include methyl, ethyl,
propyl, isopropyl, tert-butyl, sec-butyl, phenyl, halophenyl, and
methoxyphenyl.
[0147] In the above-described method, the 2-substituted, 3-alkanoyl
pyrazolo[1,5-a]pyridine is optionally further transformed into one
or more desired 2,3-substituted pyrazolo[1,5-a]pyridine compounds.
For example, the resulting keto functionality may be reduced to an
alcohol, or even an alkyl group, e.g., using the Clemmensen
reduction. Alternatively, the keto group may be converted to an
oxime or to an imine or hydrazone. In yet another approach, the
3-alkanoyl pyrazolo[1,5-a]pyridine may be prepared to contain a
leaving group, e.g., a halo group or other suitable functionality,
to allow yet further transformations. In a preferred approach, the
acylation reaction results in formation of an .alpha.-halo
ketone.
[0148] In a particularly preferred embodiment of the method, the
acylation reaction is a Friedel Crafts acylation. Generally, such
reactions are carried out by reacting an arene such as a
pyrazolo[1,5-a]pyridine with an acyl chloride or anhydride in the
presence of a suitable Lewis acid catalyst such as AlCl.sub.3.
Other Lewis acid catalysts such as metal triflates can also be
used, e.g., lighter lanthanide III triflates--Sc, Y, In, La, Ce,
Pr, Dy, Er, Yb, Bi, and Th. The method is effective to provide
acylation at only one position of the pyrazolo[1,5-a]pyridine ring
system. For instance, for a 2-substituted pyrazolo[1,5-a]pyridine
(e.g., having an alkyl, substituted alkyl, aryl, substituted aryl,
alkoxy, ester, or halo substituent or the like at position 2),
Friedel Crafts acylation with an acid chloride or anhydride
typically results in introduction of an acyl group at the 3
ring-position, due to the presence of the bridgehead nitrogen in
the ring system.
[0149] In one preferred approach, the acylation reaction is carried
out by reacting a 2-substituted pyrazolo[1,5-a]pyridine with an
.alpha.-halo alkanoyl chloride in the presence of a Lewis acid
catalyst such as aluminum chloride to provide a 2-substituted,
3-(.alpha.-haloalkanoyl)pyrazolo[1,5-a]pyridine. The resulting
2-substituted, 3-(.alpha.-haloalkanoyl)pyrazolo[1,5-a]pyridine may
then optionally be further transformed into a desired product,
e.g., by reaction with a suitable nucleophilic reagent to replace
the .alpha.-halo group with a new functionality, e.g., an amino
group, a nitrile group, a hydroxyl group, or the like.
[0150] Alternatively, to prepare an oxime-carbamate substituted
pyrazolo[1,5-a]pyridine, the acylation reaction is carried out by
reacting a substituted pyrazolo[1,5-a]pyridine with an alkanoyl
chloride in the presence of a Lewis acid catalyst to provide the
corresponding acyl derivative. The acyl group is then transformed
into the corresponding oxime. Transformation of the oxime to the
corresponding oxime-carbamate may be effected by reacting the oxime
with a reagent such as imidazole-1-carboxamide, where one or both
amido nitrogens are optionally substituted with an alkyl,
substituted alkyl, aryl, or substituted aryl group. The
imidazole-1-carboxamide reagent is typically generated from the
precursor amine and carbonyldi-imidazole in the presence of a
catalytic amount of a weak base such as imidazole, triazole,
triethylamine, pyridine, and the like. The reaction is typically
carried out in an organic solvent such as tetrahydrofuran, dioxane
or a chlorinated hydrocarbon such as dichloromethane.
[0151] Additional illustrative synthetic approaches for preparing
substituted pyrazolo[1,5-a]pyridine compounds are provided in the
accompanying examples. In particular, provided are exemplary
approaches for introducing particular types of substituents at the
2, 3, and/or 6 position(s) of the core pyrazolo[1,5-a]pyridine ring
structure.
[0152] Reaction products are typically purified using any of a
number of conventional purification techniques for organic
compounds including recrystallization, distillation, column
chromatography, thin layer chromatography, high performance liquid
chromatography, and the like. Any of a number of chromatographic
columns and packing materials may be employed, depending upon the
particular components to be separated and the features of the
desired product. Chromatographic techniques include normal phase,
reverse phase, size exclusion, ion exclusion, and ion exchange
chromatography. For separations of enantiomers, chiral
chromatography or chiral HPLC may be employed using chiral columns
such as those available from Regis Technologies, Inc., and
Chromtech. See e.g., Gubitz, G., and Schmid, M. G., Eds. Methods in
Molecular Biology, Vol. 243, Chiral Separations Methods and
Protocols, Humana Press.
[0153] Products are typically identified using any of a number of
analytical techniques such as NMR spectroscopy, mass spectrometry,
IR, elemental analysis, etc.
Methods of Use
[0154] Based upon results using a standard animal model as
described herein, the inventors have discovered that the
administration of certain substituted pyrazolo[1,5-a]pyridines is
surprisingly effective in providing a measurable reduction in the
severity of neuropathic pain, and in particular, in providing a
measurable reduction in the severity of certain types of
neuropathic pain such as mechanical allodynia. Moreover, certain
compounds as provided herein are particularly effective in
inhibiting lipopolysaccharide-induced cytokine production, thus
providing an indication of their efficacy in treating inflammatory
conditions. In addition, certain compounds of the invention are
effective phosphodiesterase inhibitors. Thus, based upon the
pharmacological data provided herein (see Table 2), it is believed
that the compounds of the invention are particularly effective in
treating one or more of the following conditions.
[0155] The compounds of the invention are useful in treating
neuropathic pain associated with certain syndromes such as viral
neuralgias (e.g., herpes, AIDS), diabetic neuropathy, phantom limb
pain, stump/neuroma pain, post-ischemic pain (stroke),
fibromyalgia, reflex sympathetic dystrophy (RSD), complex regional
pain syndrome (CRPS), cancer pain, vertebral disk rupture, spinal
cord injury, and trigeminal neuralgia, cancer-chemotherapy-induced
neuropathic pain, and migraine, among others.
[0156] Additionally, the compounds of the invention may be useful
in treating opiate tolerance and withdrawal, and/or as antiviral
agents.
[0157] The compounds provided herein may also be useful in treating
depression.
[0158] Further, the compounds of the invention may be useful in
suppressing the release of dopamine in the nucleus accumbens of a
subject. Dopamine release in the nucleus accumbens is thought to
mediate the "reward" motivating drug use and compulsive behavior
associated with addictions.
[0159] Thus, the compounds of the invention may be used to
attenuate or abolish the dopamine mediated "reward" associated with
addictions, thus diminishing or eliminating cravings associated
with addictions and the accompanying addiction-related behavior and
withdrawal syndromes of a subject.
[0160] In certain embodiments, a therapeutically effective amount
of a pyrazolo[1,5-a]pyridine compound of the invention is
administered to a subject to treat a drug addiction. The subject
may be addicted to one or more drugs including, but not limited to,
psychostimulants, narcotic analgesics, alcohols and addictive
alkaloids, such as nicotine, cannabinoids, or combinations thereof.
Exemplary psychostimulants include, but are not limited to,
amphetamine, dextroamphetamine, methamphetamine, phenmetrazine,
diethylpropion, methylphenidate, cocaine, phencyclidine,
methylenedioxymethamphetamine and pharmaceutically acceptable salts
thereof. Exemplary narcotic analgesics include, but are not limited
to, alfentanyl, alphaprodine, anileridine, bezitramide, codeine,
dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin,
hydrocodone, hydromorphone, isomethadone, levomethorphan,
levorphanol, metazocine, methadone, metopon, morphine, opium
extracts, opium fluid extracts, powdered opium, granulated opium,
raw opium, tincture of opium, oxycodone, oxymorphone, pethidine,
phenazocine, piminodine, racemethorphan, racemorphan, thebaine and
pharmaceutically acceptable salts thereof. Addictive drugs also
include central nervous system depressants, including, but not
limited to, barbiturates, chlordiazepoxide, and alcohols, such as
ethanol, methanol, and isopropyl alcohol.
[0161] In yet other embodiments, a therapeutically effective amount
of a compound of the invention is administered to a subject to
treat a behavioral addiction. A behavioral addiction can include,
but is not limited to, compulsive eating, drinking, smoking,
shopping, gambling, sex, and computer use.
[0162] A subject suffering from an addiction experiences
addiction-related behavior, cravings to use a substance in the case
of a drug addiction or overwhelming urges to repeat a behavior in
the case of a behavioral addiction, the inability to stop drug use
or compulsive behavior in spite of undesired consequences (e.g.,
negative impacts on health, personal relationships, and finances,
unemployment, or imprisonment), reward/incentive effects associated
with dopamine release, and dependency, or any combination
thereof.
[0163] Addiction-related behavior in reference to a drug addiction
includes behavior resulting from compulsive use of a drug
characterized by dependency on the substance. Symptomatic of the
behavior is (i) overwhelming involvement with the use of the drug,
(ii) the securing of its supply, and (iii) a high probability of
relapse after withdrawal. The compounds provided herein may be
useful for treating addiction-related behavior as described
above.
[0164] Particularly preferred compounds in accordance with the
above-described uses include compounds 1013, 1014, 1019, 1103, and
1137.
[0165] In yet another aspect, certain compounds of the invention
are effective inhibitors of TNF-.alpha. and/or IL-1.beta.. Based
upon their ability to inhibit the production of
lipopolysaccharide-induced production of TNF-.alpha. and
IL-1.beta., the compounds of the invention may also be useful in
treating any of a number of inflammatory conditions. Representative
inflammatory disorders that may be treated by administering a
compound of the invention include rheumatoid arthritis, bronchitis,
tuberculosis, chronic cholecystitis, inflammatory bowel disease,
acute pancreatitis, sepsis, asthma, chronic obstructive pulmonary
disease, dermal inflammatory disorders such as psoriasis and atopic
dermatitis, systemic inflammatory response syndrome (SIRS), acute
respiratory distress syndrome (ARDS), cancer-associated
inflammation, reduction of tumor-associated angiogenesis,
osteoarthritis, diabetes, treatment of graft v. host disease and
associated tissue rejection, Crohn's disease, delayed-type
hypersensitivity, immune-mediated and inflammatory elements of CNS
disease; e.g., Alzheimer's, Parkinson's, multiple sclerosis,
etc.
[0166] In examining the pharmacological activity of the compounds
of the invention, it has been discovered that certain substituted
pyrazolo[1,5-a]pyridines are particularly effective in inhibiting
phosphodiesterase (PDE). See Example 73, which describes an
illustrative assay for assessing phosphodiesterase inhibition.
Phosphodiesterases regulate the intracellular levels of secondary
messengers, cAMP and cGMP, which affects cellular signaling.
Therapeutic indications for PDE inhibitors include hypertension,
congestive heart failure, thrombosis, glaucoma, asthma, autoimmune
disease and inflammation. Thus, any one or more of the foregoing
conditions may be treated by administering a
pyrazolo[1,5-a]pyridines compound of the invention. Particularly
preferred phosphodiesterase inhibitors as provided herein include
compounds 1004, 1006, 1008, 1012, 1019, 1022, 1024, 1025, and
1026.
[0167] Additionally, the compounds provided herein may be used for
treating opioid withdrawal syndrome in a mammalian subject. That is
to say, in another aspect, provided herein is a method of treating
an opioid withdrawal syndrome in a mammalian subject by
administering one or more of the substituted
pyrazolo[1,5-a]pyridines described herein. Exemplary opioids
include but are not limited to morphine and methadone.
[0168] Opioid-driven progressive glial activation causes glia to
release neuroexcitatory substances, including the proinflammatory
cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF), and
interleukin-6 (IL-6). These neuroexcitatory substances counteract
the pain-relieving actions of opioids, such as morphine, and drive
withdrawal symptomology, as demonstrated by experiments involving
co-administration or pro- or anti-inflammatory substances along
with morphine. Indeed, if morphine analgesia is established and
then allowed to dissipate, potent analgesia can be rapidly
reinstated by injecting IL-1 receptor antagonist, suggesting that
dissipation of analgesia is caused by the activities of
pain-enhancing proinflammatory cytokines rather than dissipation of
morphine's analgesic effects.
[0169] The activity of other opioids may also be opposed by
activation of glia. Studies show that glia and proinflammatory
cytokines compromise the analgesic effects of methadone, at least
in part, via non-classical opioid receptors (Hutchinson, M. R., et
al. (2005) Proc. Soc. Neurosci., in press). These results suggest
that glia and proinflammatory cytokines will be involved in
methadone withdrawal, and likely withdrawal from other opioids as
well. These data also expand the clinical implications of glial
activation, since cross-tolerance between opioids may be explained
by the activation of the glial pain facilitatory system, which
undermines all attempts to treat chronic pain with opioids.
[0170] In summary, opioids excite glia, which in turn release
neuroexcitatory substances (such as proinflammatory cytokines) that
oppose the effects of opioids and create withdrawal symptoms upon
cessation of opioid treatment. Compounds that suppress such glial
activation, such as those provided herein, may also then be
beneficial novel therapeutics for treatment of opioid
withdrawal.
[0171] In yet another aspect, provided herein is a method for
potentiation of opioid-induced analgesia in a subject by
administration of a phosphodiesterase 4 (PDE 4) inhibitor or glial
attenuator such as the substituted pyrazolo[1,5-a]pyridines
described herein. See, for example, Table 2. In particular,
provided is a method of treating or preventing acute or subchronic
pain by administration of an effective amount of a
phosphodiesterase 4 (PDE 4) inhibitor or glial attenuator, such as
the illustrative compounds provided herein, in combination with an
opioid analgesic. The substituted pyrazolo[1,5-a]pyridine compound
administered potentiates opioid-induced analgesia in the
subject.
[0172] In-Vivo and In-Vitro Models
[0173] Standard in-vitro and in-vivo models may be used to assess
the potential therapeutic uses of the compounds provided herein.
For example, any one or more of the following standard pain models
may be used to evaluate the ability of a compound such as those
described herein to treat neuropathic pain.
[0174] Carrageenan-induced Paw Hyperalgesia Model: The carrageenan
paw hyperalgesia test is a model of inflammatory pain. A
subcutaneous injection of carrageenan is made into the left
hindpaws of rats. The rats are treated with a selected agent
before, e.g., 30 minutes, the carrageenan injection or after, e.g.,
two hours after, the carrageenan injection. Paw pressure
sensitivity for each animal is tested with an analgesymeter three
hours after the carrageenan injection. See, Randall et al., Arch.
Int. Pharmacodyn. (1957) 111:409-419.
[0175] The effects of selected agents on carrageenan-induced paw
edema can also be examined. This test (see, Vinegar et al., J.
Phamacol. Exp. Ther. (1969) 166:96-103) allows an assessment of the
ability of a compound to reverse or prevent the formation of edema
evoked by paw carrageenan injection. The paw edema test is carried
out using a plethysmometer for paw measurements. After
administration of a selected agent, a carrageenan solution is
injected subcutaneously into the lateral foot pad on the plantar
surface of the left hind paw. At three hours post-carrageenan
treatment, the volume of the treated paw (left) and the un-treated
paw (right) is measured using a plethysmometer.
[0176] Von Frey Filament Test: The effect of compounds on
mechanical allodynia can be determined by the von Frey filament
test in rats with a tight ligation of the L-5 spinal nerve: a model
of painful peripheral neuropathy. The surgical procedure is
performed as described by Kim et al., Pain (1992) 50:355-363. A
calibrated series of von Frey filaments are used to assess
mechanical allodynia (Chaplan et al., J. Neurosci. Methods (1994)
53:55-63). Filaments of increasing stiffness are applied
perpendicular to the midplantar surface in the sciatic nerve
distribution of the left hindpaw. The filaments are slowly
depressed until bending occurred and are then held for 4-6 seconds.
The filament application order and number of trials were determined
by the up-down method of Dixon (Chaplan et al., supra). Flinching
and licking of the paw and paw withdrawal on the ligated side are
considered positive responses.
[0177] Chronic Constriction Injury: Heat and cold allodynia
responses as well as mechanical allodynia sensations can be
evaluated as described below in rats having a chronic constriction
injury (CCI). A unilateral mononeuropathy is produced in rats using
the chronic constriction injury model described in Bennett et al.,
Pain (1988) 33:87-107. CCI is produced in anesthetized rats as
follows. The lateral aspect of each rat's hind limb is shaved and
scrubbed with Nolvasan. Using aseptic techniques, an incision is
made on the lateral aspect of the hind limb at the mid-thigh level.
The biceps femoris is bluntly dissected to expose the sciatic
nerve. On the right hind limb of each rat, four loosely tied
ligatures (for example, Chromic gut 4.0; Ethicon, Johnson and
Johnson, Somerville, N.J.) are made around the sciatic nerve
approximately 1-2 mm apart. On the left side of each rat, an
identical dissection is performed except that the sciatic nerve is
not ligated (sham). The muscle is closed with a continuous suture
pattern with, e.g., 4-0 Vicryl (Johnson and Johnson, Somerville,
N.J.) and the overlying skin is closed with wound clips. The rats
are ear-tagged for identification purposes and returned to animal
housing.
[0178] This model is described in greater detail in Example 72.
Generally, compounds of the invention exhibiting a chronic
constriction injury threshold of 1.0 gram or greater are preferred
for use in treating neuropathic pain, while compounds exhibiting a
chronic constriction injury threshold of 1.5 grams or greater, or
even more preferably 2.0 grams or greater are particularly
preferred. Thus, compounds 1009, 1012, 1013, 1014, 1017, 1019,
1026, 1085, 1103, and 1137 are particularly advantageous for
treating allodynia. In summary, the aforementioned compounds are
particularly efficacious in treating neuropathic pain, as
demonstrated using a mechanical allodynia rat model.
[0179] Chung Model of Rat Neuropathic Pain: Heat and cold allodynia
responses as well as mechanical allodynia sensations can be
evaluated as described below in rats following spinal nerve injury
(e.g. ligation, transaction). Details are as initially described in
S H Kim and J M Chung, Pain (1992) 50:355-363.
[0180] Cancer-Chemotherapy-Induced Neuropathy: Chemotherapy induced
neuropathy using paclitaxel (taxol) is described in detail in
Polomano et al., Pain (1994) 3:293-304. Rats become allodynic
following a series of 4 intraperitoneal injections of taxol on
alternating days. Heat and cold hyperalgesia can be evaluated as
described below, as well as mechanical allodynia in response to von
Frey filaments.
[0181] The Hargreaves Test: The Hargreaves test (Hargreaves et al.,
Pain (1998) 32:77-88) is also a radiant heat model for pain. CCI
rats are tested for thermal hyperalgesia at least 10 days post-op.
The test apparatus consists of an elevated heated (80-82.degree.
F.) glass platform. Eight rats at a time, representing all testing
groups, are confined individually in inverted plastic cages on the
glass floor of the platform at least 15 minutes before testing. A
radiant heat source placed underneath the glass is aimed at the
plantar hind paw of each rat. The application of heat is continued
until the paw is withdrawn (withdrawal latency) or the time elapsed
is 20 seconds. This trial is also applied to the sham operated leg.
Two to four trials are conducted on each paw, alternately, with at
least 5 minutes interval between trials. The average of these
values represents the withdrawal latency.
[0182] Cold Allodynia Model: The test apparatus and methods of
behavioral testing is described in Gogas et al., Analgesia (1997)
3:111-118. The apparatus for testing cold allodynia in neuropathic
(CCI) rats consists of a Plexiglass chamber with a metal plate 6 cm
from the bottom of the chamber. The chamber is filled with ice and
water to a depth of 2.5 cm above the metal plate, with the
temperature of the bath maintained at 0-4.degree. C. throughout the
test. Each rat is placed into the chamber individually, a timer
started, and the animal's response latency was measured to the
nearest tenth of a second. A "response" is defined as a rapid
withdrawal of the right ligated hindpaw completely out of the water
when the animal is stationary and not pivoting. An exaggerated limp
while the animal is walking and turning is not scored as a
response. The animals' baseline scores for withdrawal of the
ligated leg from the water typically range from 7-13 seconds. The
maximum immersion time is 20 seconds with a 20-minute interval
between trials.
[0183] Additional information regarding models of neuropathic pain
is available in the following publications. Bennett G J, Xie Y K
(1988) "A peripheral mononeuropathy in rat that produces disorders
of pain sensation like those seen in man" Pain 33: 87-107; Chaplan
S R, Bach F W, Pogrel J W, Chung J M, Yaksh T L (1994)
"Quantitative assessment of tactile allodynia in the rat paw" J.
Neurosci. Meth. 53: 55-63; Fox A, Gentry C, Patel S, Kesingland A,
Bevan S (2003) "Comparative activity of the anti-convulsants
oxcarbazepine, carbamazepine, lamotrigin and gabapentin in a model
of neuropathic pain in the rat and guinea-pig" Pain 105: 355-362;
Milligan E D, Mehmert K K, Hinde J L, Harvey L O J, Martin D,
Tracey K J, Maier S F, Watkins L R (2000) "Thermal hyperalgesia and
mechanical allodynia produced by intrathecal administration of the
Human Immunodeficiency Virus-1 (HIV-1) envelope glycoprotein,
gp120" Brain Res. 861: 105-116; De Vry J, Kuhl E, Franken-Kunkel P,
Eckel G (2004) "Pharmacological characterization of the chronic
constriction injury model of neuropathic pain" Eur. J. Pharmacol.
491:137-148. Polomano R C, Mannes A J, Clark U S, Bennett G J
(2001) "A painful peripheral neuropathy in the rat produced by the
chemotherapeutic drug, paclitaxel" Pain 94:293-304.
[0184] Models for assessing anti-inflammatory activity include the
measurement of cytokine production, e.g., TNF-.alpha., IL-1.beta.,
in lipopolysaccharide-activated peripheral blood mononuclear cells
upon exposure to a test compound as described in Example 74.
Results are provided in Table 2. In this regard, i.e., for use as
an anti-inflammatory agent, preferred compounds are those having an
IC.sub.50 of less than or equal to about 50 .mu.M, preferably less
than about 40 .mu.M, and even more preferably, less than about 30
.mu.M. Thus, preferred compounds for use as anti-inflammatory
agents include 1001, 1004, 1006, 1007, 1008, 1009, 1013, 1014,
1018, and 1024. Since chronic inflammatory diseases are caused by
prolonged production of several proinflammatory cytokines such as
TNF-.alpha. and IL-1.beta., the ability of a compound to
effectively inhibit LPS-stimulated production of such cytokines
provides an indication of its efficacy in treating one or more
inflammatory conditions.
[0185] Additional assays for assessing anti-inflammatory activity
are described "Animal Models for Inflammation", ILAR Journal, 40
(4), 1999. Other suitable animal models that may be employed for
assessing anti-inflammatory activity include LPTA.RTM. Animal
Models available from Xenogen (Alameda, Calif.), which use
transgenic mice with a luciferase reporter driven by one of the
following promoters: Gadd45b, iNos, IL-2, COX-2, Ptgs2,
TNF-.alpha., etc.
Methods of Administration.
[0186] The compounds of the invention may be administered either
systemically or locally. Such routes of administration include but
are not limited to, oral, intra-arterial, intrathecal, intraspinal,
intramuscular, intraperitoneal, intravenous, intranasal,
subcutaneous, and inhalation routes.
[0187] More particularly, the compounds provided herein may be
administered for therapeutic use by any suitable route, including
without limitation, oral, rectal, nasal, topical (including
transdermal, aerosol, buccal and sublingual), vaginal, parenteral
(including subcutaneous, intramuscular, intravenous and
intradermal), intrathecal, and pulmonary. The preferred route will,
of course, vary with the condition and age of the recipient, the
particular condition being treated, and the specific combination of
drugs employed, if any.
[0188] One preferred mode of administration, e.g., for treating
neuropathic pain, is directly to neural tissue such as peripheral
nerves, the retina, dorsal root ganglia, neuromuscular junction, as
well as the CNS, e.g., to target spinal cord glial cells by
injection into, e.g., the ventricular region, as well as to the
striatum (e.g., the caudate nucleus or putamen of the striatum),
spinal cord and neuromuscular junction, with a needle, catheter or
related device, using neurosurgical techniques known in the art,
such as by stereotactic injection (see, e.g., Stein et al., J Virol
73:3424-3429, 1999; Davidson et al., PNAS 97:3428-3432, 2000;
Davidson et al., Nat. Genet. 3:219-223, 1993; and Alisky and
Davidson, Hum. Gene Ther. 11:2315-2329, 2000).
[0189] A particularly preferred method for targeting spinal cord
glia is by intrathecal delivery, rather than into the cord tissue
itself.
[0190] Another preferred method for administering a substituted
pyrazolo[1,5-a]pyridine-based composition of the invention, e.g.,
for treating neuropathic pain, is by delivery to dorsal root
ganglia (DRG) neurons, e.g., by injection into the epidural space
with subsequent diffusion to DRG. For example, such compositions
can be delivered via intrathecal cannulation under conditions
effective to diffuse the composition to the DRG. See, e.g., Chiang
et al., Acta Anaesthesiol. Sin. (2000) 38:31-36; Jain, K. K.,
Expert Opin. Investig. Drugs (2000) 9:2403-2410.
[0191] Yet another mode of administration to the CNS uses a
convection-enhanced delivery (CED) system. In this way, the
compounds of the invention can be delivered to many cells over
large areas of the CNS. Any convection-enhanced delivery device may
be appropriate for delivery of a substituted
pyrazolo[1,5-a]pyridine of the invention. In a preferred
embodiment, the device is an osmotic pump or an infusion pump. Both
osmotic and infusion pumps are commercially available from a
variety of suppliers, for example Alzet Corporation, Hamilton
Corporation, Alza, Inc., Palo Alto, Calif.). Typically, a
composition of the invention is delivered via CED devices as
follows. A catheter, cannula or other injection device is inserted
into CNS tissue in the chosen subject. Stereotactic maps and
positioning devices are available, for example from ASI
Instruments, Warren, Mich. Positioning may also be conducted by
using anatomical maps obtained by CT and/or MRI imaging to help
guide the injection device to the chosen target. For a detailed
description regarding CED delivery, see U.S. Pat. No. 6,309,634,
incorporated herein by reference in its entirety.
Dosages
[0192] Therapeutic amounts can be empirically determined and will
vary with the particular condition being treated, the subject, and
the efficacy and toxicity of each of the active agents contained in
the composition. The actual dose to be administered will vary
depending upon the age, weight, and general condition of the
subject as well as the severity of the condition being treated, the
judgment of the health care professional, and particular
substituted pyrazolo[1,5-a]pyridine being administered.
[0193] Therapeutically effective amounts can be determined by those
skilled in the art, and will be adjusted to the requirements of
each particular case. Generally, a therapeutically effective amount
of a substituted pyrazolo[1,5-a]pyridine of the invention will
range from a total daily dosage of about 0.1 and 1000 mg/day, more
preferably, in an amount between 1-200 mg/day, 30-200 mg/day, 1-100
mg/day, 30-100 mg/day, 30-300 mg/day, 1-60 mg/day, 1-40 mg/day, or
1-10 mg/day, administered as either a single dosage or as multiple
dosages. Preferred dosage amounts include dosages greater than or
equal to about 10 mg BID, or greater than or equal to about 10 mg
TID, or greater than or equal to about 10 mg QID. That is to say, a
preferred dosage amount is greater than about 20 mg/day or greater
than 30 mg/day. Dosage amounts may be selected from 30 mg/day, 40
mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day or
100 mg/day or more. Depending upon the dosage amount and precise
condition to be treated, administration can be one, two, or three
times daily for a time course of one day to several days, weeks,
months, and even years, and may even be for the life of the
patient. Illustrative dosing regimes will last a period of at least
about a week, from about 1-4 weeks, from 1-3 months, from 1-6
months, from 1-50 weeks, from 1-12 months, or longer.
[0194] Practically speaking, a unit dose of any given composition
of the invention can be administered in a variety of dosing
schedules, depending on the judgment of the clinician, needs of the
patient, and so forth. The specific dosing schedule will be known
by those of ordinary skill in the art or can be determined
experimentally using routine methods. Exemplary dosing schedules
include, without limitation, administration five times a day, four
times a day, three times a day, twice daily, once daily, every
other day, three times weekly, twice weekly, once weekly, twice
monthly, once monthly, and so forth.
Formulations
[0195] In addition to comprising a substituted
pyrazolo[1,5-a]pyridine of the invention, a therapeutic formulation
of the invention may optionally contain one or more additional
components as described below.
[0196] A composition of the invention may comprise, in addition to
a substituted pyrazolo[1,5-a]pyridine, one or more pharmaceutically
acceptable excipients or carriers. Exemplary excipients include,
without limitation, polyethylene glycol (PEG), hydrogenated castor
oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch),
inorganic salts, antimicrobial agents, antioxidants,
binders/fillers, surfactants, lubricants (e.g., calcium or
magnesium stearate), glidants such as talc, disintegrants,
diluents, buffers, acids, bases, film coats, combinations thereof,
and the like.
[0197] A composition of the invention may include one or more
carbohydrates such as a sugar, a derivatized sugar such as an
alditol, aldonic acid, an esterified sugar, and/or a sugar polymer.
Specific carbohydrate excipients include, for example:
monosaccharides, such as fructose, maltose, galactose, glucose,
D-mannose, sorbose, and the like; disaccharides, such as lactose,
sucrose, trehalose, cellobiose, and the like; polysaccharides, such
as raffinose, melezitose, maltodextrins, dextrans, starches, and
the like; and alditols, such as mannitol, xylitol, maltitol,
lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol,
myoinositol, and the like.
[0198] Also suitable for use in the compositions of the invention
are potato and corn-based starches such as sodium starch glycolate
and directly compressible modified starch.
[0199] Further representative excipients include inorganic salt or
buffers such as citric acid, sodium chloride, potassium chloride,
sodium sulfate, potassium nitrate, sodium phosphate monobasic,
sodium phosphate dibasic, and combinations thereof.
[0200] A substituted pyrazolo[1,5-a]pyridine-containing composition
of the invention may also include an antimicrobial agent, e.g., for
preventing or deterring microbial growth. Non-limiting examples of
antimicrobial agents suitable for the present invention include
benzalkonium chloride, benzethonium chloride, benzyl alcohol,
cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl
alcohol, phenylmercuric nitrate, thimersol, and combinations
thereof.
[0201] A composition of the invention may also contain one or more
antioxidants. Antioxidants are used to prevent oxidation, thereby
preventing the deterioration of the drug(s) or other components of
the preparation. Suitable antioxidants for use in the present
invention include, for example, ascorbyl palmitate, butylated
hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,
monothioglycerol, propyl gallate, sodium bisulfite, sodium
formaldehyde sulfoxylate, sodium metabisulfite, and combinations
thereof.
[0202] Additional excipients include surfactants such as
polysorbates, e.g., "Tween 20" and "Tween 80," and pluronics such
as F68 and F88 (both of which are available from BASF, Mount Olive,
N.J.), sorbitan esters, lipids (e.g., phospholipids such as
lecithin and other phosphatidylcholines, and
phosphatidylethanolamines), fatty acids and fatty esters, steroids
such as cholesterol, and chelating agents, such as EDTA, zinc and
other such suitable cations.
[0203] Further, a composition of the invention may optionally
include one or more acids or bases. Non-limiting examples of acids
that can be used include those acids selected from the group
consisting of hydrochloric acid, acetic acid, phosphoric acid,
citric acid, malic acid, lactic acid, formic acid, trichloroacetic
acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid,
fumaric acid, and combinations thereof. Examples of suitable bases
include, without limitation, bases selected from the group
consisting of sodium hydroxide, sodium acetate, ammonium hydroxide,
potassium hydroxide, ammonium acetate, potassium acetate, sodium
phosphate, potassium phosphate, sodium citrate, sodium formate,
sodium sulfate, potassium sulfate, potassium fumarate, and
combinations thereof.
[0204] The amount of any individual excipient in the composition
will vary depending on the role of the excipient, the dosage
requirements of the active agent components, and particular needs
of the composition. Typically, the optimal amount of any individual
excipient is determined through routine experimentation, i.e., by
preparing compositions containing varying amounts of the excipient
(ranging from low to high), examining the stability and other
parameters, and then determining the range at which optimal
performance is attained with no significant adverse effects.
[0205] Generally, however, the excipient will be present in the
composition in an amount of about 1% to about 99% by weight,
preferably from about 5% to about 98% by weight, more preferably
from about 15 to about 95% by weight of the excipient. In general,
the amount of excipient present in an ibudilast composition of the
invention is selected from the following: at least about 2%, 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,
75%, 80%, 85%, 90%, or even 95% by weight.
[0206] These foregoing pharmaceutical excipients along with other
excipients are described in "Remington: The Science & Practice
of Pharmacy", 19.sup.th ed., Williams & Williams, (1995), the
"Physician's Desk Reference", 52.sup.nd ed., Medical Economics,
Montvale, N.J. (1998), and Kibbe, A. H., Handbook of Pharmaceutical
Excipients, 3.sup.rd Edition, American Pharmaceutical Association,
Washington, D.C., 2000.
[0207] A formulation (or kit) in accordance with the invention may
contain, in addition to a substituted pyrazolo[1,5-a]pyridine of
the invention, one or more additional active agents, e.g., a drug
effective for treating neuropathic pain. Such actives include
gabapentin, memantine, pregabalin, morphine and related opiates,
cannabinoids, tramadol, lamotrigine, carbamazepine, duloxetine,
milnacipran, and tricyclic antidepressants.
[0208] Gabapentin, also known as Neurontin.RTM., is structurally
related to the neurotransmitter GABA. Although structurally related
to GABA, gabapentin does not interact with GABA receptors, is not
converted metabolically into GABA or a GABA agonist, and is not an
inhibitor of GABA uptake or degradation. Gabapentin has no activity
at GABAA or GABAB receptors of GABA uptake carriers of the brain,
but instead interacts with a high-affinity binding site in brain
membranes (an auxiliary subunit of voltage-sensitive Ca.sup.2+
channels). The exact mechanism of action is unknown, only that its
physiological site of action is the brain. The structure of
gabapentin allows it to pass freely through the blood-brain
barrier. In vitro, gabapentin has many pharmacological actions
including modulating the action of the GABA synthetic enzyme,
increasing non-synaptic GABA responses from neural tissue, and
reduction of the release of several mono-amine neurotransmitters.
Daily dosages of gabapentin typically range from about 600 to 2400
mg/day, more preferably from about 900 to 1800 mg/day, and are
administered in divided doses, for example, three times a day.
Conventional unit dosage forms are 300 or 400 mg capsules or 600 or
800 mg tablets.
[0209] The active agent, memantine, is a receptor antagonist.
Memantine is believed to function as a low to moderate affinity
uncompetitive (open-channel) NMDA receptor antagonist which binds
to the NMDA receptor-operated cation channels. Recommended daily
dosage amounts typically range from about 5 mg to 20 mg.
[0210] The opiate, morphine, clicits its effects by activating
opiate receptors that are widely distributed throughout the brain
and body. Once an opiate reaches the brain, it quickly activates
the opiate receptors found in many brain regions and produces an
effect that correlates with the area of the brain involved. There
are several types of opiate receptors, including the delta, mu, and
kappa receptors. Opiates and endorphins function to block pain
signals by binding to the mu receptor site.
[0211] The cannabinoids, e.g., tetrahydrocannabinol, bind to the
cannabinoid receptor referred to as CB.sub.1. CB.sub.1 receptors
are found in brain and peripheral tissues; CB receptors are present
in high quantities in the central nervous system, exceeding the
levels of almost all neurotransmitter receptors. An additional
cannabinoid receptor subtype termed `CB2` has also been identified.
See, e.g., Martin, B. R., et al., The Journal of Supportive
Oncology, Vol. 2, Number 4, July/August 2004.
[0212] Although its mechanism of action has not yet been fully
elucidated, the opioid, tramadol, is believed to work through
modulation of the GABAergic, noradrenergic and serotonergic
systems. Tramadol, and its metabolite, known as M1, have been found
to bind to .mu.-opioid receptors (thus exerting its effect on
GABAergic transmission), and to inhibit re-uptake of 5-HT and
noradrenaline. The second mechanism is believed to contribute since
the analgesic effects of tramadol are not fully antagonised by the
.mu.-opioid receptor antagonist naloxone. Typical daily dosages
range from about 50 to 100 milligrams every 4 to 6 hours, with a
total daily dosage not to exceed 400 milligrams.
[0213] Lamotrigine is a phenyltriazine that stabilizes neuronal
membranes by blocking voltage-sensitive sodium channels, which
inhibit glutamate and aspartate (excitatory amino acid
neurotransmitter) release. The daily dosage of lamotrigine
typically ranges from 25 milligrams per day to 500 mg per day.
Typical daily dosage amounts include 50 mg per day, 100 mg per day,
150 mg per day, 200 mg per day, 300 mg per day, and 500 mgs per
day, not exceed 700 mgs per day.
[0214] Carbamazepine acts by blocking voltage-sensitive sodium
channels. Typical adult dosage amounts range from 100-200
milligrams one or two times daily, to an increased dosage of
800-1200 milligrams daily generally administered in 2-3 divided
doses.
[0215] Duloxetine is a potent inhibitor of neuronal uptake of
serotonin and norephinephrine and a weak inhibitor of dopamine
re-uptake. Typical daily dosage amounts range from about 40 to 60
milligrams once daily, or 20 to 30 milligrams twice daily.
[0216] Milnacipran acts as a serotonin and norepinephrine reuptake
inhibitor. Daily dosage amounts typically range from about 50 to
100 milligrams once or twice daily.
[0217] The dosage amounts provided above are meant to be merely
guidelines; the precise amount of a secondary active agent to be
administered during combination therapy with a substituted
pyrazolo[1,5-a]pyridine of the invention will, of course, be
adjusted accordingly and will depend upon factors such as intended
patient population, the particular neuropathic pain symptom or
condition to be treated, potential synergies between the active
agents administered, and the like, and will readily be determined
by one skilled in the art based upon the guidance provided
herein.
[0218] Preferably, the compositions are formulated in order to
improve stability and extend the half-life of the active agent. For
example, the substituted pyrazolo[1,5-a]pyridine may be delivered
in a sustained-release formulation. Controlled or sustained-release
formulations are prepared by incorporating the active into a
carrier or vehicle such as liposomes, nonresorbable impermeable
polymers such as ethylenevinyl acetate copolymers and Hytrel.RTM.
copolymers, swellable polymers such as hydrogels, or resorbable
polymers such as collagen and certain polyacids or polyesters such
as those used to make resorbable sutures. Additionally, a
substituted pyrazolo[1,5-a]pyridine of the invention can be
encapsulated, adsorbed to, or associated with, particulate
carriers. Examples of particulate carriers include those derived
from polymethyl methacrylate polymers, as well as microparticles
derived from poly(lactides) and poly(lactide-co-glycolides), known
as PLG. See, e.g., Jeffery et al., Pharm. Res. (1993) 10:362-368;
and McGee et al., J. Microencap. (1996).
Delivery Forms
[0219] The compositions described herein encompass all types of
formulations, and in particular, those that are suited for systemic
or intrathecal administration. Oral dosage forms include tablets,
lozenges, capsules, syrups, oral suspensions, emulsions, granules,
and pellets. Alternative formulations include aerosols, transdermal
patches, gels, creams, ointments, suppositories, powders or
lyophilates that can be reconstituted, as well as liquids. Examples
of suitable diluents for reconstituting solid compositions, e.g.,
prior to injection, include bacteriostatic water for injection,
dextrose 5% in water, phosphate-buffered saline, Ringer's solution,
saline, sterile water, deionized water, and combinations thereof.
With respect to liquid pharmaceutical compositions, solutions and
suspensions are envisioned. Preferably, a composition of the
invention is one suited for oral administration.
[0220] In turning now to oral delivery formulations, tablets can be
made by compression or molding, optionally with one or more
accessory ingredients or additives. Compressed tablets are
prepared, for example, by compressing in a suitable tabletting
machine, the active ingredients in a free-flowing form such as a
powder or granules, optionally mixed with a binder (e.g., povidone,
gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent,
preservative, disintegrant (e.g., sodium starch glycolate,
cross-linked povidone, cross-linked sodium carboxymethyl cellulose)
and/or surface-active or dispersing agent.
[0221] Molded tablets are made, for example, by molding in a
suitable tabletting machine, a mixture of powdered compounds
moistened with an inert liquid diluent. The tablets may optionally
be coated or scored, and may be formulated so as to provide slow or
controlled release of the active ingredients, using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile. Tablets may optionally be provided with a
coating, such as a thin film, sugar coating, or an enteric coating
to provide release in parts of the gut other than the stomach.
Processes, equipment, and toll manufacturers for tablet and capsule
making are well-known in the art.
[0222] Formulations for topical administration in the mouth include
lozenges comprising the active ingredients, generally in a flavored
base such as sucrose and acacia or tragacanth and pastilles
comprising the active ingredients in an inert base such as gelatin
and glycerin or sucrose and acacia.
[0223] A pharmaceutical composition for topical administration may
also be formulated as an ointment, cream, suspension, lotion,
powder, solution, paste, gel, spray, aerosol or oil.
[0224] Alternatively, the formulation may be in the form of a patch
(e.g., a transdermal patch) or a dressing such as a bandage or
adhesive plaster impregnated with active ingredients and optionally
one or more excipients or diluents. Topical formulations may
additionally include a compound that enhances absorption or
penetration of the ingredients through the skin or other affected
areas, such as dimethylsulfoxidem bisabolol, oleic acid, isopropyl
myristate, and D-limonene, to name a few.
[0225] For emulsions, the oily phase is constituted from known
ingredients in a known manner. While this phase may comprise merely
an emulsifier (otherwise known as an emulgent), it desirably
comprises a mixture of at least one emulsifier with a fat and/or an
oil. Preferably, a hydrophilic emulsifier is included together with
a lipophilic emulsifier that acts as a stabilizer. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and/or fat make
up the so-called emulsifying ointment base which forms the oily
dispersed phase of cream formulations. Illustrative emulgents and
emulsion stabilizers include Tween 60, Span 80, cetostearyl
alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl
sulfate.
[0226] Formulations for rectal administration are typically in the
form of a suppository with a suitable base comprising, for example,
cocoa butter or a salicylate.
[0227] Formulations suitable for vaginal administration generally
take the form of a suppository, tampon, cream, gel, paste, foam or
spray.
[0228] Formulations suitable for nasal administration, wherein the
carrier is a solid, include a coarse powder having a particle size,
for example, in the range of about 20 to about 500 microns. Such a
formulation is typically administered by rapid inhalation through
the nasal passage, e.g., from a container of the powder held in
proximity to the nose. Alternatively, a formulation for nasal
delivery may be in the form of a liquid, e.g., a nasal spray or
nasal drops.
[0229] Aerosolizable formulations for inhalation may be in dry
powder form (e.g., suitable for administration by a dry powder
inhaler), or, alternatively, may be in liquid form, e.g., for use
in a nebulizer. Nebulizers for delivering an aerosolized solution
include the AERx.TM. (Aradigm), the Ultravent.RTM. (Mallinkrodt),
and the Acorn II.RTM. (Marquest Medical Products). A composition of
the invention may also be delivered using a pressurized, metered
dose inhaler (MDI), e.g., the Ventolin.RTM. metered dose inhaler,
containing a solution or suspension of a combination of drugs as
described herein in a pharmaceutically inert liquid propellant,
e.g., a chlorofluorocarbon or fluorocarbon.
[0230] Formulations suitable for parenteral administration include
aqueous and non-aqueous isotonic sterile solutions suitable for
injection, as well as aqueous and non-aqueous sterile
suspensions.
[0231] Parenteral formulations of the invention are optionally
contained in unit-dose or multi-dose sealed containers, for
example, ampoules and vials, and may be stored in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile
liquid carrier, for example, water for injections, immediately
prior to use. Extemporaneous injection solutions and suspensions
may be prepared from sterile powders, granules and tablets of the
types previously described.
[0232] A formulation of the invention may also be a sustained
release formulation, such that each of the drug components is
released or absorbed slowly over time, when compared to a
non-sustained release formulation. Sustained release formulations
may employ pro-drug forms of the active agent, delayed-release drug
delivery systems such as liposomes or polymer matrices, hydrogels,
or covalent attachment of a polymer such as polyethylene glycol to
the active agent.
[0233] In addition to the ingredients particularly mentioned above,
the formulations of the invention may optionally include other
agents conventional in the pharmaceutical arts and particular type
of formulation being employed, for example, for oral administration
forms, the composition for oral administration may also include
additional agents as sweeteners, thickeners or flavoring
agents.
[0234] The compositions of the present invention may also be
prepared in a form suitable for veterinary applications.
EXAMPLES
[0235] It is to be understood that while the invention has been
described in conjunction with certain preferred specific
embodiments thereof, the foregoing description as well as the
examples that follow are intended to illustrate and not limit the
scope of the invention. Other aspects, advantages and modifications
within the scope of the invention will be apparent to those skilled
in the art to which the invention pertains.
Materials and Methods
[0236] All chemical reagents, solvents, and the like referred to in
the appended examples are commercially available unless otherwise
indicated. All NMR data was generated by a 300 MHz NMR spectrometer
manufactured by Bruker or Varian.
Example 1
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone
##STR00014##
[0238] (a) Hydroxylamine-O-sulfonic acid (113 g, 1.0 mol) was
dissolved in water (500 ml) and 2-methylpyridine (279 g, 3 mol) was
added. The solution was stirred at 90.degree. C. for 45 minutes,
cooled in ice, and K.sub.2CO.sub.3 (138 g, 1 mol) was added in
portions to control foaming. After the addition was complete, the
beige suspension was evaporated to dryness on a rotary evaporator
at 40-50.degree. C., ethanol (450 ml) was added and the suspension
was filtered with suction. The precipitate was washed with 150 ml
of ethanol, the solution cooled in an ice/salt bath and HI (140 ml
of 57%) was added slowly in small portions. Crystals separated in
approximately 20 minutes, and were filtered and dried in vacuo to
afford 1-amino-2-methylpyridinium iodide, 87.2 g (51%). The mother
liquor was concentrated, cooled, and a second crop of crystals
collected and dried to yield an additional 68.8 g (40.4%) for a
combined yield of 156 g (91.4%) (K. T. Potts, et al., J. Org.
Chem., 33, 3766-3770 (1968)).
[0239] (b)
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one- .
The dry salt (113 g) from Example 1 (a) was suspended in isobutyric
anhydride (515 g) in a large round bottom flask equipped with a
mechanical stirrer and K.sub.2CO.sub.3 (85 g) was added with
stirring. The mixture was refluxed for 8 hours, cooled to room
temperature and water (10 ml) was added followed by addition of
K.sub.2CO.sub.3 (10 g) in portions. After the initial vigorous
reaction subsided, water (500 ml) and ethyl acetate (500 ml) were
added, followed by 280 g of K.sub.2CO.sub.3, added in portions with
continuous mechanical stirring to control foaming. The reaction
mixture was stirred for 1 hour at room temperature, 50 mL of 50%
NaOH was added, and the mixture extracted with ethyl acetate
(4.times.250 ml). Evaporation of the solution yielded a viscous
oil, which was distilled under high vacuum to provide 25.2 g
(32.9%) of 2-isopropylpyrazolo[1,5-a]pyridine (b.p. 45-75.degree.
C./0.25-0.5 mm Hg), and 60.4 g (51.3%) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
(b.p. 125-135.degree. C./0.1 mm Hg; m.p. 53-55.degree. C.) (T.
Irikura, et al., U.S. Pat. No. 3,850,941, Nov. 26, 1974). Compound
411.
[0240] (c) 2-isopropylpyrazolo[1,5-a]pyridine.
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
(28.1 g, 120 mmol) was added to 200 ml of 50% sulfuric acid with
stirring for 10-15 min., and then refluxed overnight. After
cooling, the solution was neutralized with about 134 g of NaOH
added portionwise, while maintaining the temperature at 0-5.degree.
C., to a final pH of 8-8.5. The mixture was extracted 3 times with
ethyl acetate. The organic phase was washed with brine and dried
over MgSO.sub.4. The ethyl acetate was evaporated under vacuum to
provide 16.07 g of 2-isopropylpyrazolo[1,5-a]pyridine (83.3%). (T.
Irikura, U.S. Pat. No. 4,097,483, Jun. 27, 1978).
[0241] (d) 2-isopropyl-3-(2-chloroacetyl)pyrazolo[1,5-a]pyridine.
2.0 ml of 2-isopropylpyrazolo[1,5-a]pyridine, 2.0 ml of
2-chloroacetyl chloride and 200 mg anhydrous AlCl.sub.3 were mixed
with stirring at room temperature for 4 days. After cooling, 50 ml
of ethyl acetate was added, followed by addition of cooled ammonia
solution to pH 8-8.5 at 0-5.degree. C. The mixture was extracted
with ethyl acetate twice. The organic phase was washed with brine
and dried over MgSO.sub.4. The ethyl acetate was evaporated under
reduced pressure to obtain 3 g of crude compound, which was
purified on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant to yield 1.44 g of
pure 2-isopropyl-3-(2-chloroacetyl)pyrazolo[1,5-a]pyridine (yield
48.6%).
[0242] (e)
2-isopropyl-3-(2-hexamethylenetetramine-acetyl)pyrazolo[1,5-a]p-
yridine hydrochloride. To a solution of 626 mg (2.64 mmol) of
2-isopropyl-3-(2-chloroacetyl)pyrazolo[1,5-a]pyridine in 2 ml of
chloroform was added 369 mg (2.1 mmol) of hexamethylenetetramine in
1 ml chloroform at room temperature with stirring, and then heated
to 60.degree. C. for 1 hour. After cooling, the solid was filtered
and washed with ethyl ether to yield 620 mg (78.4%) of
2-isopropyl-3-(2-hexamethylenetetramine-acetyl)pyrazolo[1,5-a]pyridine
hydrochloride.
[0243] (f)
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone. To 4.56
ml of ethanolic HCl solution (ethanol:conc.HCl:water 20:4.8:4) was
added 996 mg (2.64 mmol) of
2-isopropyl-3-(2-hexamethylenetetramine-acetyl)pyrazolo[1,5-a]pyridine
hydrochloride. The mixture was stirred at 40.degree. C. for 90
minutes. After the solvent was evaporated, the residue was washed
with ethyl ether. The remaining solid was dissolved in water and
purified on an open Cis column with 0.05% HCl-acetonitrile as
eluant to furnish 510 mg (79.3%.) of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone.
Compound 1009.
Example 2
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00015##
[0245] (a)
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridine-3-yl)ethanone. 2.0
ml of 2-isopropylpyrazolo[1,5-a]pyridine, 2.0 ml of
2-chloropropionyl chloride and 200 mg of anhydrous AlCl.sub.3 were
mixed with stirring at room temperature for 4 days. After cooling,
50 ml of ethyl acetate was added, followed by pre-cooled 4N KOH
solution to pH 8-8.5 at 0-5.degree. C. The mixture was extracted
with ethyl acetate twice. The organic phase was washed with brine
and dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure to obtain 2.6 g of crude compound, which was purified on
an aluminum oxide column with hexane-dichloromethane-ethyl acetate
as eluant to yield 1.16 g (37.2%.) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridine-3-yl)ethanone.
[0246] (b)
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one.
NH.sub.3 (gas) was bubbled through a solution of 1.16 g (4.6 mmol)
of 2-isopropyl-3-(2-chloropropyl)pyrazolo[1,5-a]pyridine in 100 ml
of 7N NH.sub.3-MeOH solution at 40.degree. C. for 50-60 hours in an
apparatus fitted with a dry-ice condenser. After evaporation of
solvent in vacuo, the residue was dissolved in 15 ml ethyl ether
and precipitated by the addition of 4N HCl-dioxane solution. The
precipitate was filtered and washed with ethyl ether. The residue
was dissolved in water and purified on an open C.sub.18 column with
0.05% HCl-acetonitrile as eluant to obtain 600 mg (49.2%) of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one.
Compound 1013.
Example 3
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime
##STR00016##
[0248] To a solution of 2.3 g (10 mmol) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in
32 ml of anhydrous EtOH was added hydroxylamine hydrochloride 1.5 g
(20 mmol), followed by dropwise addition of 2.4 g NaOH in 6 ml of
water. The mixture was stirred and refluxed over night. After
cooling, the solution was poured into a solution of 8.3 ml of 6N
HCl and 380 ml ice water with stirring for 30 minutes. The
precipitate was filtered and washed with ethyl ether-hexane to
furnish 1.2 g (74.5%) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime (as a mixture of cis- and trans-isomers), which was separated
on an aluminum oxide column with hexane-dichloromethane-ethyl
acetate as eluant to yield 0.3 g (cis-) and 0.325 g (trans-)
isomers of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime. Compound 1012.
Example 4
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime
##STR00017##
[0250] To a solution of 376 mg (1.53 mol) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime in 2 ml of anhydrous THF was added 540 .mu.l of
trimethylsilyl isocyanate (85%) dropwise at 0.degree. C. over 30
minutes. The reaction was stirred at room temperature overnight.
Solvent was removed in vacuo, and the residue obtained was purified
on an aluminum oxide column with hexane-dichloromethane-ethyl
acetate as eluant to yield 200 mg (45.3%.) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime. Compound 1014.
Example 5
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00018##
[0252] a) 4-methyl-1-phenylpent-1-yn-3-one. To a solution of 10.6 g
(100 mmol) of ethynylbenzene in 50 ml of anhydrous THF was added
dropwise 36 ml of n-butyl lithium (2.87M in hexane) at -50.degree.
C. under argon with stirring over a 10-15 minutes period, followed
by the addition of 13.6 g of anhydrous zinc chloride in 50 ml of
THF dropwise at -20.degree. C. to 0.degree. C. The reaction was
stirred at 0.degree. C. for 20 minutes, and 10.5 ml of isobutyryl
chloride was added dropwise. After stirring at room temperature for
2 hours, the mixture was quenched with 60 ml of saturated ammonium
chloride solution, followed by 10 ml of concentrated ammonium
hydroxide and 100 ml of ethyl ether at 0-5.degree. C. and extracted
3 times with ethyl acetate. The combined organic phases were washed
with saturated ammonium chloride solution again, dried over
MgSO.sub.4 and evaporated under vacuum to obtain 19.4 g of
4-methyl-1-phenylpent-1-yn-3-one as a crude oil.
[0253] (b)
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one. 5 g
(20 mmol) of 4-methyl-1-phenylpent-1-yn-3-one and 4.45 g of
1-aminopyridinium iodide were dissolved in 30 ml of dry
acetonitrile. To this solution was added dropwise 6.0 g of DBU in
10 ml of acetonitrile at 0.degree. C. under argon during 30
minutes. This mixture was allowed to stir at room temperature
overnight. The solvent was evaporated under reduced pressure and
ethyl acetate was added to the residue. An insoluble solid was
removed by filtration. The resulting ethyl acetate solution was
washed with 10% citric acid, saturated ammonium chloride solution
and dried over MgSO.sub.4. The ethyl acetate was evaporated to
furnish 5.2 g of crude product, which was purified on an aluminum
oxide column with hexane-dichloromethane-ethyl acetate as eluant to
yield 2.18 g (41.1%) of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one.
Compound 1015.
Example 6
Synthesis of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
oxime
##STR00019##
[0255] To a solution of 5.32 g (20 mmol) of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one in 32
ml of anhydrous EtOH was added 3 g of hydroxylamine hydrochloride,
followed by dropwise addition of a solution of 4.0 g NaOH in 12 ml
water. The mixture was stirred and refluxed over night. After
cooling, the solution was poured into a solution of 11 ml of 6N HCl
and 200 ml ice water with stirring for 30 minutes. The mixture was
extracted with ethyl acetate three times. The organic phase was
washed with brine and dried over MgSO.sub.4. The solvent was
removed under reduced pressure to obtain 4.6 g of crude compound,
which was purified on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant to furnish 1.58 g
(30.1%) of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime.
Compound 1016.
Example 7
Synthesis of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
O-carbamoyl oxime
##STR00020##
[0257] To a solution of 630 mg (2.24 mmol) of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime
in 2 ml of anhydrous THF was added 600 .mu.l of trimethylsilyl
isocyanate (85%) dropwise at 0.degree. C. over 30 minutes. The
mixture was stirred at room temperature overnight, followed by the
addition of 500 .mu.l pyridine and stirring for another 4 hours.
The solvent was removed in vacuo, and the residue obtained was
purified on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg
(66.3%) of
2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
O-carbamoyl oxime. Compound 1017.
Example 8
Synthesis of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
##STR00021##
[0259] Starting with 5.0 g (41.25 mmol) of 4-fluoroethynylbenzene
and 4.33 ml of isobutyryl chloride and 5.62 g ZnCl.sub.2, the
corresponding 1-(4-fluorophenyl)-4-methylpent-1-yn-3-one was
prepared using the same procedure as in Example 5(a) to obtain 8.3
g of crude oil intermediate. From 4 g (20 mmol) of
1-(4-fluorophenyl)-4-methylpent-1-yn-3-one, 4.45 g of
1-aminopyridinium iodide and 6.0 g DBU was obtained 2.18 g (44.8%)
of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
using the same procedure as in Example 5(b). Compound 1018.
Example 9
Synthesis of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime
##STR00022##
[0261] To a solution of 2.3 g (8.15 mmol) of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
in 32 ml of anhydrous EtOH was added 2.26 g of hydroxylamine
hydrochloride, followed by a solution of 1.63 g (8.15 mmol) NaOH in
5 ml water dropwise. The mixture was stirred and refluxed over
night. After cooling, the solution was poured into a solution of
4.8 ml 6N HCl in 100 ml ice water with stirring for 30 minutes. The
mixture was extracted with ethyl acetate three times. The combined
organic phases were washed with brine and dried over MgSO.sub.4.
After solvent evaporation under vacuum, 4.6 g of crude product was
obtained. Purification on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant afforded 1.65 g
(67%) of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime. Compound 1019.
Example 10
Synthesis of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime
##STR00023##
[0263] To a solution of 742 mg (2.5 mmol) of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl
isocyanate (85%) dropwise at 0.degree. C. over 30 minutes. The
mixture was stirred at room temperature over 48 hours, followed by
addition of 50 .mu.l pyridine. After stirring for another 4 hours,
the solvent was removed and the residue was purified on an aluminum
oxide column with hexane-dichloromethane-ethyl acetate as eluant to
yield 482 mg (56.7%) of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime. Compound 1020.
Example 11
Synthesis of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
##STR00024##
[0265] Starting with 5.0 g (36.7 mmol) of 4-methoxyethynylbenzene,
3.85 ml of isobutyryl chloride, and 5.0 g ZnCl.sub.2, the
corresponding 1-(4-methoxyphenyl)-4-methylpent-1-yn-3-one was
prepared using the same procedure as in Example 5(a) to obtain 7.87
g of crude oil intermediate. Starting with 7.5 g (37 mmol) of
1-(4-methoxyphenyl)-4-methylpent-1-yn-3-one, 8.22 g (37 mmol) of
1-aminopyridinium iodide and 11.6 g DBU, 4.84 g (45%) of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
was obtained as in Example 5(b). Compound 1021.
Example 12
Synthesis of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime
##STR00025##
[0267] To a solution of 4.4 (14.9 mmol) of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
in 32 ml of anhydrous EtOH was added 4.15 g of hydroxylamine
hydrochloride, followed by a solution of 13.73 g (14.9 mmol) of
NaOH in 10 ml water dropwise. The mixture was stirred and refluxed
over night. After cooling, the solution was poured into a solution
of 6 ml 6N HCl and 100 ml ice water with stirring for 30 minutes.
The mixture was extracted with ethyl acetate three times. The
organic phase was washed with brine and dried over MgSO.sub.4.
After evaporation of the solvent under vacuum, 5 g of crude product
was obtained. Purification on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant afforded 2.33 g
(50.5%) of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime. Compound 1022.
Example 13
Synthesis of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime
##STR00026##
[0269] To a solution of 775 mg (2.5 mmol) of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl
isocyanate (85%) dropwise at 0.degree. C. over 30 minutes. The
mixture was stirred at room temperature over 48 hours, followed by
addition of 500 .mu.l pyridine. After stirring for another 4 hours
the solvent was removed, and the residue was extracted with ethyl
acetate three times. The combined organic layers were washed with
10% citric acid twice and dried over MgSO.sub.4. After evaporation
of the solvent, 900 mg of crude product was obtained, which was
purified on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant to yield 263 mg
(29.8%) of
1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime. Compound 1023.
Example 14
Synthesis of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
##STR00027##
[0271] Starting with 4.9 g (35.8 mmol) of 4-chloroethynylbenzene,
3.76 ml of isobutyryl chloride and 4.88 g ZnCl.sub.2, the
corresponding 1-(4-chlorophenyl)-4-methylpent-1-yn-3-one was
prepared using the same procedure as in Example 5(a) to obtain 9.21
g of crude oil intermediate. Starting with 9.21 g (35.8 mmol) of
1-(4-chlorophenyl)-4-methylpent-1-yn-3-one, 9.90 g (44 mmol) of
1-aminopyridinium iodide and 11 g DBU, the desired product was
obtained -4.64 g (43%) of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
as in Example 5(b). Compound 1024.
Example 15
Synthesis of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime
##STR00028##
[0273] To a solution of 3.5 g (11.7 mmol) of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
in 65 ml of anhydrous EtOH was added 3.25 g of hydroxylamine
hydrochloride, followed by a solution of 2.92 g (11.7 mmol) NaOH in
8 ml water dropwise. The mixture was stirred and refluxed over
night. After cooling, the solution was evaporated and poured into a
solution of 6 ml 6N HCl and 100 ml ice water with stirring for 30
minutes. The mixture was extracted with ethyl acetate three times.
The organic phase was washed with brine and dried over MgSO.sub.4.
After evaporation of the solvent under vacuum, 5.11 g of crude
product was obtained. Purification on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant furnished 1.86 g
(50.7%) of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime. Compound 1025.
Example 16
Synthesis of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime
##STR00029##
[0275] a solution of 783 mg (2.5 mmol) of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl
isocyanate (85%) dropwise at 0.degree. C. over 30 minutes. The
mixture was stirred at room temperature over 48 hrs, followed by
addition of 500 .mu.l pyridine. After stirring for another 4 hours,
the solvent was removed and the residue was extracted by ethyl
acetate three times. The combined organic layers were washed with
1N HCl twice, brine and dried over MgSO.sub.4. After evaporation of
the solvent under vacuum, 935 mg of crude product was obtained.
Purification on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant furnished 621 mg
(69.6%) of
1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
O-carbamoyl oxime. Compound 1026.
Example 17
Synthesis of
(4-chlorophenyl)(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methanone
##STR00030##
[0277] 1.59 g of 2-isopropylpyrazolo[1,5-a]pyridine, 1.74 g of
4-chlorobenzoyl chloride and 200 mg anhydrous AlCl.sub.3 were mixed
with stirring at room temperature over night, then at
100-120.degree. C. for 4 hrs. After cooling, the mixture was
treated with 50 ml 20% dichloromethane in ethyl acetate and 15 ml
of 10% Na.sub.2CO.sub.3, followed by addition of 4N KOH to pH 8-8.5
at 0-5.degree. C. The mixture was extracted with ethyl acetate
twice. The combined organic phases were washed with brine and dried
over MgSO.sub.4. The ethyl acetate was evaporated under reduced
pressure to obtain 2.6 g of residue, which was purified on an
aluminum oxide column with hexane-dichloromethane as eluant to
yield 480 mg (16.3%) of
(4-chlorophenyl)(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methanone.
Compound 1007.
Example 18
Synthesis of
(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)(4-methoxyphenyl)methanone
##STR00031##
[0279] 3.2 ml of 2-isopropylpyrazolo[1,5-a]pyridine, 2.2 g of
4-methoxybenzoyl chloride and 200 mg anhydrous AlCl.sub.3 were
mixed with stirring at room temperature for 4 days. After cooling,
50 ml of ethyl ether was added to the mixture, followed by addition
of 4N KOH solution to pH 8-8.5 at 0-5.degree. C. The mixture was
extracted with ethyl acetate twice. The combined organic phases
were washed with brine and dried over MgSO.sub.4. The ethyl acetate
was evaporated under reduced pressure to obtain 6.4 g of crude
product, which was purified on an aluminum oxide column with
hexane-dichloromethane-ethyl acetate as eluant to yield 510 mg
(13.6%) of
(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)(4-methoxyphenyl)methanone.
Compound 1008.
Example 19
Synthesis of
1-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)-2-m-
ethylpropan-1-one
##STR00032##
[0281] (a)
1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone. To
a solution of 4-fluoroacetophenone (13.8 g, 100 mmol) and
2-chloro-5-trifluoromethylpyridine (20.0 g, 110 mmol) in 400 ml of
anhydrous THF was added NaH (5.56 g, 220 mmol) (washed with pentane
prior to use) in several portions. The reaction was stirred under
argon at room temperature for 3 days. The reaction was carefully
quenched with H.sub.2O (300 ml), followed by addition of diethyl
ether (200 ml). The organic layer was separated and extracted with
6N HCl (2.times.300 ml). The aqueous extracts were cooled to
0.degree. C. and 6N NaOH was added dropwise to adjust the pH of the
solution to pH 11-12. The mixture was then extracted with diethyl
ether (4.times.150 ml) and the combined organic layers were then
dried over MgSO.sub.4. Filtration and concentration furnished 22.4
g (79%) of the title compound as a tautomeric mixture.
[0282] (b)
1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone
oxime. To a solution of
1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone
(8.00 g, 28.2 mmol) in methanol (100 ml) at room temperature was
added 15% NaOH (29 ml, 109 mmol). The resulting solution was
stirred vigorously as solid hydroxylamine hydrochloride (9.8 g, 140
mmol) was added portionwise. The mixture was heated to reflux for 1
hour, treated with charcoal while hot, and then quickly filtered
through Celite before being allowed to cool. The filtrate was
concentrated to one-half of its original volume and then cooled to
0.degree. C. for 1 hour. The resultant solids were collected by
filtration, washed with water, and dried under vacuum at 50.degree.
C. overnight to provide 5.00 g (59%) of the title compound as a
dark yellow solid.
[0283] The oxime, compound 1032,
1-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)-2-m-
ethylpropan-1-one oxime, was prepared in a fashion similar to that
described in (b) above.
[0284] (c)
2-(3-(4-fluorophenyl)-2H-azirin-2-yl)-5-(trifluoromethyl)pyridi-
ne. To a solution of
1-(4-fluorophenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)ethanone
oxime (4.00 g, 13.4 mmol) in dichloromethane was added
triethylamine (7.5 ml, 53.6 mmol, dist. from CaH.sub.2). The
solution was cooled to 0.degree. C. under argon and trifluoroacetic
anhydride (2.2 ml, 16.2 mmol) was added dropwise. The reaction was
stirred for 30 minutes and then quenched with water (100 ml). The
organic layer was separated, dried over MgSO.sub.4, filtered and
concentrated to afford an oil. Purification by flash chromatography
(15% EtOAc-hexane) yielded 3.08 g (82%) of the title compound,
which crystallized on standing.
[0285] (d)
2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine. 2.82
g (10.0 mmol) of
2-(3-(4-fluorophenyl)-2H-azirin-2-yl)-5-(trifluoromethyl)pyridine
was dissolved in 1,2,4-trichlorobenzene (30 ml, >99%) and the
mixture was heated to 200.degree. C. for 10 hours. The reaction
mixture was cooled to room temperature and loaded onto a silica
column. The column was eluted with hexane to remove
1,2,4-trichlorobenzene, and then with 20% Et.sub.2O-hexane to elute
the product. Concentration provided 2.62 g (94%) of the title
compound.
[0286] (e)
1-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-
-3-yl)-2-methylprop-1-enyl isobutyrate. To 2.50 g (8.9 mmol) of
2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine in 43
ml of isobutyric anhydride was added conc. H.sub.2SO.sub.4 (5
drops). The mixture was stirred and heated at 142.degree. C.
overnight. The mixture was cooled to room temperature and poured
into water (120 ml) at 0.degree. C. The solution was then adjusted
to pH 10 with 2N NaOH. The aqueous layer was extracted with
Et.sub.2O (3.times.100 ml), dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by flash column
chromatography (3% EtOAc-hexane) to afford 2.54 g (68%) of the
title compound) as an orange solid. Compound 1033.
[0287] (f)
1-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-
-3-yl)-2-methylpropan-1-one. To product of (e) (0.45 g, 1.07 mmol)
was dissolved in THF (1 ml) and cooled to 0.degree. C. A 1.1M
solution of NaOMe in MeOH (1.3 ml, 1.4 mmol) was added dropwise and
the mixture warmed to room temperature over 3 hours. Saturated
NH.sub.4Cl solution was added to adjust the solution to pH 6-7 and
the mixture was extracted with Et.sub.2O (4.times.5 ml). The
combined organic layers were washed with water (3.times.2 ml),
brine, dried over MgSO.sub.4, filtered and concentrated to provide
the crude product as a solid. Recrystallization from hexane
provided 0.35 g (78%) of
1-(2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)-2-m-
ethylpropan-1-one; m.p. 129-130.degree. C. Compound 1027.
Example 20
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00033##
[0289] 3.70 g (23 mmol) of 2-isopropylpyrazolo[1,5-a]pyridine was
dissolved in 12.03 g (92.4 mmol) of propionic anhydride and 2 drops
of conc. H.sub.2SO.sub.4 were added. The reaction mixture was
heated to reflux until full consumption of starting material
(determined by .sup.1H NMR, 7 hours). The brown solution was cooled
to room temperature, and was poured on a mixture of ice (20 g) and
K.sub.2CO.sub.3 (20 g). K.sub.2CO.sub.3 was added until the pH of
the reaction mixture was 11 and then the reaction mixture was
stirred at room temperature for an additional hour. The aqueous
layer was extracted four times with ethyl acetate. The combined
organic layers were washed with brine, treated with charcoal, dried
over Na.sub.2SO.sub.4, and the solvent was evaporated under reduced
pressure. Flash column chromatography (hexanes-ethyl acetate, 9:1;
deactivated silica) of the residue afforded 760 mg (15.4%) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one as a yellow
oil, which crystallized when stored in the refrigerator; m.p.
41-43.degree. C. Compound 1001.
Example 21
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol
##STR00034##
[0291] 2.5 g (10.76 mmol) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one was
dissolved in MeOH (50 ml) (charcoal filtration) and cooled to
0.degree. C. NaBH.sub.4 (570 mg, 15.06 mmol) was added portion
wise. The reaction mixture was heated to reflux until complete
conversion of starting material (2-4 hours). The reaction mixture
was cooled to room temperature, and was quenched by the addition of
water (50 ml). The aqueous layer was extracted four times with
dichloromethane. The combined organic layers were washed with
brine, treated with charcoal, dried over Na.sub.2SO.sub.4, and the
solvent was evaporated under reduced pressure. Flash column
chromatography (hexanes-ethyl acetate, 5:2; 10% deactivated silica)
of the residue (yellow oil) afforded
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol as a
colorless oil (1.7 g, 68%), which crystallized upon trituration
with pentane; m.p. 69.degree. C. Compound 1002.
Example 22
Synthesis of
1-(2-isopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-2-methylpro-
pan-1-amine
##STR00035##
[0293] To a solution of 600 mg (4.6 mmol) of
N-benzyl-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-amin-
e in 10 ml of acetic acid was added 100 mg of PtO.sub.2 in
hydrogenation bottle. H.sub.2 was applied at 50 psi for 4 hours.
The reaction was worked up by filtration and dilution with 0.1N HCl
to provide 503 mg of crude product. Purification by C.sub.18
preparative HPLC furnished 400 mg of purified
1-(2-isopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-2-methylpro-
pan-1-amine after lyophilization. Compound 1011.
[0294] The products from Examples 22-58 were each characterized by
fast atom bombardment mass spectrometry (FAB MS) to provide the
corresponding M+1 ions. Products were also characterized by .sup.1H
NMR, and when warranted, their structures further confirmed by
.sup.13C NMR and correlated (multinuclear .sup.1H and .sup.13C) NMR
spectroscopy.
Example 23
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-morpholinopropan-1-one
hydrochloride
##STR00036##
[0296] To a solution of 500 mg (2 mmol)
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one in
4 ml of MeOH was added 227 mg (2.6 mmol) of morpholine and 150 mg
NaI. The mixture was stirred at RT for 3 days. The solvent was
removed and the residue dissolved in 5 ml of ether, followed by
titration with 4N HCl-dioxane to obtain a precipitate.
Recrystallization from isopropanol/ether produced 200 mg of pure
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-morpholinopropan-1-one
hydrochloride. Compound 1034.
Example 24
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)prop-
an-1-one hydrochloride
##STR00037##
[0298] A mixture of 500 mg (2 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one,
272 .mu.l (2.4 mmol) of N-methylpiperazine and 50 mg of NaI in 4 ml
of MeOH was stirred at RT for 4 days. The solvent was removed and
the crude residue was purified on an Al.sub.2O.sub.3 column. The
fractions containing purified product were titrated with 4N
HCl-dioxane to obtain a precipitate. Recrystallization from
isopropanol/ether produced 150 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(4-methylpiperazin-1-yl)prop-
an-1-one hydrochloride (shown in neutral form above). Compound
1035.
Example 25
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(piperidin-1-yl)propan-1-one
hydrochloride
##STR00038##
[0300] A mixture of 500 mg (2 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one,
478 ul (4.8 mmol) of piperidine and 50 mg of NaI in 4 ml of MeOH
was stirred at 50.degree. C. overnight. The residue obtained after
evaporation of the solvent was purified on an Al.sub.2O.sub.3
column. The fractions containing purified product were titrated
with 4N HCl-dioxane to obtain a precipitate. Recrystallization from
isopropanol/ether produced 175 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(piperidin-1-yl)propan-1-one
hydrochloride. Compound 1036.
Example 26
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(piperazin-1-yl)propan-1-one
hydrochloride
##STR00039##
[0302] A mixture of 980 mg (3.90 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one,
1.45 g (4 mmol) of N-Boc-piperazine and 100 mg of NaI in 10 ml of
MeOH was stirred at 50-70.degree. C. for 5 hours. The residue
obtained after evaporation of the solvent was purified on an
Al.sub.2O.sub.3 column. The fractions containing purified product
were titrated with 4N HCl-dioxane to obtain a precipitate.
Recrystallization from isopropanol/ether produced 150 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(piperazin-1-yl)propan-1-one
hydrochloride. Compound 1037.
Example 27
Synthesis of
(3-chloropyridin-2-yl)(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methanone
##STR00040##
[0304] Picolinic acid was reacted with thionyl chloride to yield
the corresponding acid chloride, which was used without
purification to acylate 2-isopropylpyrazolo[1,5-a]pyridine in the
presence of 300 mg of AlCl.sub.3 at RT for 4 days. 5 g of crude
product were obtained after workup, followed by purification on an
Al.sub.2O.sub.3 column to produce 373 mg of
(3-chloropyridin-2-yl)(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)m-
ethanone. The structure was assigned by NMR and LC-MS. Compound
1038.
Example 28
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-phenylethanone
##STR00041##
[0306] A mixture of 3.5 ml (21.8 mmol) of
2-isopropylpyrazolo[1,5-a]pyridine, 2 ml (10.5 mmol) of
2-chloro-phenylacetyl chloride and 300 mg of AlCl.sub.3 were
stirred at RT for 4 days. The resulting 1.5 g of crude chloride was
dissolved in 150 ml of MeOH, and reacted with NH3 (gas) in presence
of 20 mg of NaI at 400.degree. C. for 3 days to get 1.2 g of crude
product, followed by purification on an Al2O3 column to obtain 220
mg of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-phenylethanone.
Compound 1039.
Example 29
Synthesis of 1-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00042##
[0308] 4.35 g (47 mmol) of propionyl chloride was dropwise added to
4.5 g (23.5 mmol) of 2-methyl-1-aminopyridium bromide in 50 ml of
pyridine at 0.degree. C. over 20 minutes. The mixture was stirred
at RT for 1 hour and refluxed for another 2 hours. 3.39 g of crude
product obtained after workup was purified on an Al.sub.2O.sub.3
column and 1.27 g of
1-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one were obtained
after recrystallization from ether/hexane. Compound 1040.
Example 30
Synthesis of
2-(benzyl(methyl)amino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan--
1-one
##STR00043##
[0310] A mixture of 2.37 g (13.4 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one,
1.74 ml (13.4 mmol) of N-methyl benzylamine and 50 mg of NaI in 15
ml of MeOH was refluxed overnight. The mixture obtained after
evaporation of the solvent was purified on an Al.sub.2O.sub.3
column, and recrystallized from ether/hexane to obtain 1.5 g of
2-(benzyl(methyl)amino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan--
1-one. Compound 1041
Example 31
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(methylamino)propan-1-one
hydrochloride
##STR00044##
[0312] To 700 mg of
2-(benzyl(methyl)amino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan--
1-one in 2.5 ml H.sub.2O and 47.5 ml MeOH was added 30 mg of 10%
Pd--C. The mixture was hydrogenated at 50 psi for 5 hours. The
residue obtained after filtration and solvent evaporation was
dissolved in ether and treated with HCl/ether to obtain 640 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-(methylamino)propan-1-one
hydrochloride. Compound 1042.
Example 32
Synthesis of
N-(1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropyl)cyclopropana-
mine
##STR00045##
[0314] To a mixture of 2.3 g (10 mmol) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one and
4.8 ml (75 mmol) of cyclopropylamine in 25 ml of benzene were added
dropwise 735 .mu.l of TiCl4 in 5 ml of benzene at RT over 20
minutes under a nitrogen atmosphere. The mixture was stirred at RT
for 1 hour and refluxed for 2 hours. Filtration and evaporation of
the solvent furnished an intermediate imine, which was dissolved in
10 ml of MeOH and reacted with 378 mg of NaBH.sub.4 at RT
overnight. 4.3 g of crude material was obtained after workup.
Recrystallization from MeOH-acetone-ether yielded 770 mg of
N-(1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropyl)cy-
clopropanamine. Compound 1044.
Example 33
Synthesis of
N-(cyclopropylmethyl)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-
propan-1-amine hydrochloride
##STR00046##
[0316] To a mixture of 2.3 g (10 mmol) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one and
2.37 g (30 mmol) of aminomethylcyclopropane in 25 ml of benzene
were added 548 .mu.l of TiCl.sub.4 in 5 ml of benzene at RT over 20
minutes under a nitrogen atmosphere. The mixture was stirred at RT
for 1 hour and refluxed for 2 hours. Filtration and evaporation of
the solvent furnished an intermediate, which was purified by
chromatography on an Al.sub.2O.sub.3 column. 1.69 g of purified
intermediate imine was reduced by 338 mg of NaBH.sub.4 in 10 ml of
MeOH. The crude product was purified again on Al.sub.2O.sub.3
column to produce 1 g of an oil. Titration with 2N HCl-ether
furnished 616 mg of
N-(cyclopropylmethyl)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-
propan-1-amine hydrochloride. Compound 1048.
Example 34
Synthesis of
2-(cyclopropylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-o-
ne hydrochloride
##STR00047##
[0318] 621 mg (2.4 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was
reacted with 283 mg (4.8 mmol) cyclopropylamine in the presence of
20 mg of NaI in 6 ml of MeOH. The crude product obtained after
workup was acidified with 2N HCl-ether to furnish 405 mg of
2-(cyclopropylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-o-
ne hydrochloride. Compound 1045.
Example 35
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-amine
hydrochloride
##STR00048##
[0320] 3.5 g (15 mmol) of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one was
stirred at RT with 11.48 ml (7.times.15 mmol) of benzylamine and
1,097 .mu.l of TiCl.sub.4 in 40 ml of benzene, then refluxed for 2
hours. Filtration and evaporation of the solvent furnished an
intermediate, which was purified by chromatography on an
Al.sub.2O.sub.3 column to furnish 3.1 g of intermediate imine.
Reduction of the imine with 163 mg of NaBH.sub.4 in MeOH furnished
crude benzylamine, which was hydrogenated on 10% Pd--C. The crude
product was purified by C18-reverse-phase preparative HPLC.
Addition of dilute HCl to the fractions containing purified product
followed by lyophilization furnished 399 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-amine
hydrochloride. Compound 1051.
Example 36
Synthesis of
2-amino-1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one
hydrochloride
##STR00049##
[0322] To a mixture of 1.1 g (3.4 mmol) of
2-(5-(4-fluorophenyl)-3-oxopent-4-yn-2-yl)isoindoline-1,3-dione and
785 mg (3.4 mmol) of N-aminopyridinium iodide in 10 ml of
acetonitrile was added dropwise 1.04 g of DBU in 5 ml of
acetonitrile at 0.degree. C. for 20 minutes under a nitrogen
atmosphere. The reaction was stirred at RT overnight, and it was
worked up with ethyl acetate and ammonium chloride to produce
2-(1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl)iso-
indoline-1,3-dione as a crude solid. The phthalimide intermediate
was reacted with 5001 of hydrazine hydrate at RT in ethanol
overnight. After workup with ethyl acetate and ammonium chloride, 1
g of crude product was obtained. The crude product was purified by
C18-reverse-phase preparative HPLC. Addition of dilute HCl to the
fractions containing purified product followed by lyophilization
furnished 110 mg of
2-amino-1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one
hydrochloride. Compound 1052.
Example 37
Synthesis of
cyclopropyl(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methanone
##STR00050##
[0324] 2-isopropyl-pyrazolo[1,5-a]pyridine (2.00 g, 12.4 mmol) was
dissolved in cyclopropyl anhydride (8.00 g, 51.9 mmol).
Concentrated H.sub.2SO.sub.4 (3 drops) was added at room
temperature and the mixture was then heated to 140.degree. C. for
28 hours. The mixture was then cooled to 0.degree. C., diluted with
H.sub.2O (10 mL) and 50% NaOH (aq) was added to achieve a solution
pH of 11. This mixture was extracted with Et.sub.2O (3.times.10
mL). The combined organic layers were washed with H.sub.2O (15 mL),
brine (15 mL), dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude mixture was then immediately subjected to flash
chromatography (90% EtOAc/hexane) to afford 1.02 g (4.4 mmol, 36%)
of the title compound as a white powder. This material was then
recrystallized from n-heptane to afford 0.6115 g (2.7 mmol, 22%) of
SB-I1-61 was white needles. mp 72.degree. C. (n-heptane); IR (thin
film) .nu.=2969, 1635, 1506, 1439 .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.=8.42 (d, J=6.8 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.33-7.27
(m, 1H), 6.82 (ddd, J=6.8, 6.8, 1.2 Hz, 1H), 3.75 (sept, J=6.9 Hz,
1H), 2.47-2.39 (m, 1H), 1.40 (d, J=6.9 Hz, 6H), 1.27-1.17 (m, 2H),
0.99-0.93 (m, 2H); .sup.13C NMR (150 MHz, CDCl.sub.3)
.delta.=194.8, 163.1, 141.6, 128.9, 127.4, 118.9, 113.2, 110.7,
27.8, 22.4, 20.4, 10.2; MS (EI) m/z 229 (M+1, 18.2), 228 (M.sup.+,
100.0), 213 (46.4), 200 (13.1), 199 (23.4), 198 (14.1), 185 (23.2),
171 (23.2), 160 (13.5), 145 (11.8), 132 (10.2), 131 (13.8), 119
(11.6), 117 (18.0), 92 (10.2), 91 (10.9), 90 11.0), 84 (11.2), 78
(17.6), 69 (24.6) 51 (10.9); HRMS (EI) calcd for
C.sub.14H.sub.16N.sub.2O: 228.1263, found: 228.1261; Anal. Calcd
for C.sub.14H.sub.16N.sub.2O: C, 73.66%; H, 7.06%; Found: C,
73.93%; H, 7.25%. Compound 1046.
Example 38
Synthesis of
cyclopropyl(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)methanone
##STR00051##
[0326] 1-Aminopyridinium iodide (5.2 g, 0.024 mol) was suspended in
cyclopropyl anhydride (22.0 g, 0.143 mol) and K.sub.2CO.sub.3 (3.4
g, 0.025 mol) was added. The reaction mixture was slowly heated to
190.degree. C. and kept at the same temperature for 8 hours and
then stirred at rt for 12 hours. The suspension was diluted with
H.sub.2O (50 ml) and basified with 50% NaOH at 50.degree. C. The
aqueous layer was cooled to rt and extracted four times with EtOAc.
The combined organic layers were washed with brine, treated with
charcoal, dried over anhydrous MgSO.sub.4 and filtered. The solvent
was evaporated and the residue was purified by flash column
chromatography (EtOAc:hexanes, 10:1 to 5:1) to give the title
compound as colorless solid (2.4 g, 44%) after recrystallization
from n-heptane.
[0327] mp 102-104.degree. C. (n-heptane); IR (thin film) .nu.=3091,
3007, 1638, 1509, 1438, 1393, 1325, 1262, 1206, 1182 cm.sup.-1;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=8.39 (d, J=6.9 Hz, 1H),
8.23 (d, J=8.9 Hz, 1H), 7.33-7.41 (m, 1H), 6.90 (dt, J=6.9, 1.2 Hz,
1H), 2.75-2.87 (m, 1H), 2.51-2.63 (m, 1H), 1.26-1.34 (m, 2H),
1.16-1.23 (m, 2H) 1.07-1.15 (m, 2H) 0.97-1.06 (m, 2H); .sup.13C NMR
(75 MHz, CDCl.sub.3) .delta.=195.2, 158.6, 142.0, 128.5, 127.6,
119.2, 113.6, 112.4, 20.2, 10.2, 9.9, 8.6; MS (EI) m/z (%): 226
(54), 225 (11), 211 (33), 199 (14), 198 (26), 185 (59), 183 (12),
170 (26), 169 (43), 157 (27), 156 (14), 155 (20), 142 (13), 130
(16), 117 (18), 90 (12), 78 (27), 51 (13), 41 (33); HRMS (EI) calcd
for C.sub.14H.sub.14N.sub.2O: 226.1106, found: 226.1107; Anal.
Calcd for C.sub.14H.sub.14N.sub.2O: C, 74.31%; H, 6.24%; Found: C,
74.27%; H, 6.28%. Compound 1047.
Example 39
Synthesis of
1-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
##STR00052##
[0329] A mixture of 700 mg (4.7 mmol) of
2-methoxypyrazolo[1,5-a]pyridine, 550 mg of isobutyryl chloride and
300 mg of AlCl.sub.3 was stirred in 2 ml of DCE at RT for 5 hours.
The reaction was quenched with saturated NH.sub.4Cl and extracted
with ethyl acetate to yield 1 g of crude product. Purification on
an Al.sub.2O.sub.3 column furnished 323 mg of
1-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one.
Compound 1055.
Example 40
Synthesis of
2-amino-1-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00053##
[0331] A mixture of 500 mg (3.3 mmol) of
2-methoxypyrazolo[1,5-a]pyridine, 393 .mu.l of 2-chloro-propionyl
chloride and 300 mg of AlCl.sub.3 was stirred in 2 ml of DCE at RT
for 5 hours. The reaction was quenched with saturated NH.sub.4Cl
and extracted with ethyl acetate to yield 663 mg of crude
.alpha.-chloroketone. Crude .alpha.-chloroketone was reacted
without further purification with 1.03 g of NaN.sub.3 in 5 ml of
DMF overnight to provide 1 g of crude .alpha.-azidoketone.
Reduction of .alpha.-azidoketone was carried out with 1.17 g of
Ph.sub.3P in 10 ml of THF containing 60 .mu.l of H.sub.2O. The
product was purified on an Al.sub.2O.sub.3 column to yield 116 mg
of 2-amino-1-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)propan-1-one.
Compound 1057.
Example 41
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)butan-1-one
##STR00054##
[0333] Following the same procedure for the synthesis of compound
1057, 250 mg of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)butan-1-one was
obtained from 4 g (25 mmol) of 2-isopropylpyrazolo[1,5-a]pyridine,
3.5 g of 2-chloro-butyryl chloride and 600 mg of AlCl.sub.3.
Compound 1060.
Example 42
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-4-methylpentan-1-one
##STR00055##
[0335] Following the same procedure for the synthesis of compound
1057, 259 mg of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-4-methylpent-
an-1-one was obtained from 3.2 g (20 mmol) of
2-isopropylpyrazolo[1,5-a]pyridine, 3.37 g (20 mmol) of
2-chloro-valeryl chloride and 600 mg of AlCl.sub.3. Compound
1061.
Example 43
Synthesis of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00056##
[0337] To a mixture of 8.7 g (38 mmol) of
4-chloro-1-(4-fluorophenyl)pent-1-yn-3-one and 10 g (45 mmol) of
N-aminopyridinium iodide in 140 ml of acetonitrile was added
dropwise 11 g of DBU in 50 ml of acetonitrile at 0.degree. C. for
20 minutes under a nitrogen atmosphere. The reaction was then
stirred at RT overnight. After evaporation of the solvent, the
crude mixture was purified on an Al.sub.2O.sub.3 column, and the
desired product recrystallized from ethyl acetate-hexane to obtain
200 mg of
1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one.
Compound 1070.
Example 44
Synthesis of
1-(2-(dimethylamino)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
##STR00057##
[0339] A mixture of 560 mg (3.45 mmol) of
N,N-dimethylpyrazolo[1,5-a]pyridin-2-amine, 355 .mu.l (3.45 mmol)
of isobutyryl chloride and 100 mg of AlCl.sub.3 was stirred in 3 ml
of DCE at R overnight. The mixture was quenched with saturated
NH.sub.4Cl and extracted with EtOAc, and the crude product was
purified on an Al.sub.2O.sub.3 column to provide 208 mg of
1-(2-(dimethylamino)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one.
Compound 1072.
Example 45
Synthesis of
2-amino-1-(2-(dimethylamino)pyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00058##
[0341] A mixture of 620 mg (3.85 mmol) of
N,N-dimethylpyrazolo[1,5-a]pyridin-2-amine, 458.4 .mu.l of
2-chloro-propionyl chloride and 100 mg of AlCl.sub.3 was stirred in
6 ml of DCE at RT overnight. The mixture was quenched with
saturated NH.sub.4Cl and extracted with EtOAc to provide 756 mg of
crude .alpha.-chloroketone intermediate. Reaction of
.alpha.-chloroketone with 1.17 g of NaN.sub.3 in 5 ml of DMF,
followed by reduction with 1.17 g of Ph.sub.3P in 10 ml of THF
containing 72 .mu.l of H.sub.2O resulted in 1.3 g of crude product.
Purification on an Al.sub.2O.sub.3 column yielded 404 mg of
2-amino-1-(2-(dimethylamino)pyrazolo[1,5-a]pyridin-3-yl)propan-1-on-
e. Compound 1075.
Example 46
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)hexan-1-one
##STR00059##
[0343] A mixture of 4 g (25 mmol) of
2-isopropylpyrazolo[1,5-a]pyridine, 5.32 g (25 mmol) of
2-bromohexanoyl chloride and 600 mg of AlCl3 was stirred in 6 ml of
DCE at RT for 3 days. The mixture was quenched with saturated NH4Cl
and extracted with EtOAc to provide 4.85 g of .alpha.-bromoketone
intermediate. Reaction of .alpha.-bromoketone with 5.1 g of NaN3 in
25 ml of DMF, followed by reduction with Ph3P in 50 ml of THF
containing 594 .mu.l of H.sub.2O yielded 9 g of crude product.
Purification of the crude product on a silica gel column furnished
200 mg of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)hexan-1-one and
1.5 g of recovered 2-isopropylpyrazolo[1,5-a]pyridine starting
material. Compound 1077.
Example 47
Synthesis of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-3-methoxypropan-1-one
##STR00060##
[0345] A mixture of 4 g (25 mmol) of
2-isopropylpyrazolo[1,5-a]pyridine, 3.9 g (25 mmol) of
2-chloro-3-methoxy-propionyl chloride and 600 mg of AlCl.sub.3 in 6
ml of DCE was stirred at RT for 3 days. The mixture was quenched
with saturated NH.sub.4Cl and extracted with EtOAc to provide 6.3 g
of crude .alpha.-chloroketone intermediate. Reaction of
.alpha.-chloroketone with 5.1 g of NaN.sub.3 in 25 ml of DMF,
followed by reduction with 4.76 g of Ph.sub.3P in 50 ml of THF
containing 594 .mu.l of H.sub.2O furnished 9 g of crude product.
Purification of the desired product was carried out on a silica gel
column to furnish 560 mg of
2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-3-methoxypropan-1-one
along with 1.6 g of recovered 2-isopropylpyrazolo[1,5-a]pyridine
starting material. Compound 1082.
Example 48
Synthesis of
(Z)-2-(hydroxyimino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-o-
ne
##STR00061##
[0347] A mixture of 6.4 g (40 mmol) of
2-isopropylpyrazolo[1,5-a]pyridine, 3.7 g (40 mmol) of propionyl
chloride and 400 mg of AlCl3 was stirred at RT in 5 ml of CS2 for 3
days. The mixture was quenched with saturated NH4Cl and extracted
with EtOAc to provide 5.44 g of crude
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, which was
purified on a silica gel column to yield 700 mg of pure
intermediate along with 3.53 g of starting material. 700 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was reacted
with 600 .mu.l of 1M t-BuOK in t-BuOH at -20.degree. C. for 20
minutes, followed by the addition of 600 .mu.l of isoamylnitrite at
0.degree. C. and stirring at RT overnight. The mixture was quenched
with saturated NH4Cl and extracted with EtOAc to provide 1.2 g of
crude product, which was purified on a silica gel column to furnish
314 mg of
(Z)-2-(hydroxyimino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-o-
ne. Compound 1083.
Example 49
Synthesis of
4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-thione
##STR00062##
[0349] A mixture of 200 mg (0.63 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg
of thiourea and 100 .mu.l of HOAc were stirred in 1.5 ml of dioxane
at 60-700 C for 30 minutes. 197 mg of
4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-thione
was obtained after workup. Compound 1085.
Example 50
Synthesis of
4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine
##STR00063##
[0351] A mixture of 200 mg (0.63 mmol) of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg
of thiourea and 160 mg of sodium hydride were stirred in 2 ml of
dioxane containing 120 .mu.l of H.sub.2O at 60-70.degree. C. for 30
minutes. 100 mg of
4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine was
obtained after workup. Compound 1087.
Example 51
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl
acetate
##STR00064##
[0353] A solution of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
(1.0 g, 1 equivalent) and potassium acetate (0.6 g, 1.5
equivalents) in 5 mL of DMF was stirred at room temperature for 2
days. The solution was worked up with ethyl acetate and water to
give a crude oil. The oil was purified by silica gel flash column
chromatography to furnish
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl acetate
(0.95 g, 86% yield) as a paste. Compound 1067.
Example 52
Synthesis of
2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00065##
[0355] A solution of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl acetate
(0.33 g, 1 equivalent) and 1M NaOH (1.5 mL. 1.25 equivalents) in 3
mL of THF was stirred at room temperature for 24 hours. The
solution was worked up with ethyl acetate and saturated NaHCO3. The
crude solid obtained was recrystallized from ethyl acetate and
hexane to provide
2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
(0.27 g, 96% yield) as a white solid. Compound 1068.
Example 53
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methoxypropan-1-one
##STR00066##
[0357] A solution of
2-hydroxy-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
(0.6 g, 1 equivalent), silver oxide (5 g, 8 equivalents), and
methyl iodide (2.5 mL, 15 equivalents) in 2 mL of THF was stirred
in a sealed tube at room temperature for 26 hours. The mixture was
filtered to remove precipitated solids. The filtrate was worked up
with ethyl acetate and saturated NaHCO3. The crude oil obtained was
purified by silica gel flash column chromatography to give
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methoxypropan-1-one as
an oil. Compound 1069.
Example 54
Synthesis of 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde
##STR00067##
[0359] Upon stirring 3 mL of DMF at room temperature, neat
phosphorous oxychloride (0.8 mL 1.3 equivalents) was added
dropwise. The resulting mixture was stirred at room temperature for
10 minutes, followed by dropwise addition of neat
2-isopropylpyrazolo[1,5-a]pyridine (1 g, 1 equivalent). The
solution was stirred at room temperature for 19 hours and poured
into 100 mL of ice water. The pH of the aqueous solution was
adjusted to 8 using solid NaOH. The precipitate formed was
collected by filtration and dried under reduced pressure to furnish
2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.97 g, 82%
yield) as a white solid. Compound 1073.
Example 55
Synthesis of
(E)-2-((2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methylene)hydrazine-carbox-
amide
##STR00068##
[0361] A mixture of
2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g, 1
equivalent), semicarbazide hydrochloride (0.35 g, 1.2 equivalents),
and triethylamine (0.4 mL, 1.1 equivalent) in 5 mL of methanol was
reflux for 30 minutes. The solution was concentrated and the crude
solids produced were extracted with THF, and the mixture was
filtered through a 1 inch thick layer of sodium sulfate on top of a
thin pad of silica gel to remove the ammonium salt. The filtrate
was concentrated and the solid deposited was recrystallized from
THF and hexanes to give
(E)-2-((2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methylene)hydrazinecarboxa-
mide (0.46 g, 70% yield) as a yellow solid. Compound 1074.
Example 56
Synthesis of
S-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl
ethanethioate
##STR00069##
[0363] A solution of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
(0.9 g, 1 equivalent) and potassium thioacetate (0.61 g, 1.5
equivalents) in 4 mL of DMF was stirred at room temperature for 1
hour. The resulting solution was worked up with EtOAc and water.
The crude product was purified by silica gel flash column
chromatography to give
S-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl
ethanethioate (0.58 g, 55% yield) as a yellow solid. Compound
1081.
Example 57
Synthesis of 2-isopropylpyrazolo[1,5-a]pyridine-3-carboxylic
acid
##STR00070##
[0365] A mixture of
2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (1.5 g, 1
equivalent) and potassium permanganate (2.9 g, 2.1 equivalents) in
10 mL of THF was stirred at room temperature for 2 days. A solution
of potassium hydroxide (2.2 g, 5 equivalents) in 10 mL of water was
added and the resulting solution was stirred at room temperature
for 2 hours. The mixture was filtered to remove insoluble solids
and the filtrate was extracted to remove unreacted aldehyde. The
remaining aqueous solution was acidified with concentrated HCl and
the precipitates were collected by filtration and dried under
reduced pressure to give
2-isopropylpyrazolo[1,5-a]pyridine-3-carboxylic acid (0.98 g, 60%
yield) as a solid. Compound 1079.
Example 58
Synthesis of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone
##STR00071##
[0366] Solid aluminum chloride (0.82 g, 2 equivalents) was added to
a solution of acetyl chloride (0.24 mL, 1.1 equivalents) in 1 mL of
dichloromethane and the solution was stirred at room temperature
for 40 minutes. Neat 2-isopropylpyrazolo[1,5-a]pyridine (0.5 g, 1
equivalent) was added dropwise to this solution at room temperature
(exotherm was observed), and the resulting solution was stirred at
room temperature for 20 hours and worked up with EtOAc and
saturated NaHCO.sub.3. The crude product was purified by silica gel
flash column chromatography to give
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone (0.29 g, 46%
yield) as a solid. Compound 1080.
Example 59
Synthesis of
3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine
[0367] A general synthetic procedure for Suzuki reactions utilized
to synthesize compounds 1100-1104 and 1111-1112 is provided below.
The particular synthesis shown below is for compound 1100.
##STR00072##
[0368] Step 1.
1-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-2-methyl-propan-1-one
(30.0 g, 115 mmole), water (100 ml), and concentrated sulfuric acid
(100 ml) were combined and stirred at 130.degree. C. for 18 hours.
The mixture was cooled to room temperature and poured into a
solution of ice (400 g) and water (200 ml). The solution was
neutralized with sodium hydroxide solution and extracted with
chloroform. The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. The oil was purified by vacuum
distillation to give 14.9 g (81%) of
2-isopropyl-pyrazolo[1,5-a]pyridine. .sup.1H-NMR (250 MHz,
DMSO-d.sub.6) .delta. 8.37 (d, J=7.3 Hz, 1H), 7.41 (d, J=9.0 Hz,
1H), 7.00 (t, J=7.3 Hz, 1H), 6.66 (t, J=7.5 Hz, 1H), 6.28 (s, 1H),
3.16 (sept, J=7.0 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H).
[0369] Step 2. 2-Isopropyl-pyrazolo[1,5-a]pyridine (18.42 g, 115
mmol) and N-iodosuccinimide (28.45 g, 126 mmol) were dissolved in a
mixture of 1,2-dichloroethane (300 ml) and tetrahydrofuran (300
ml). The mixture was stirred at reflux for 18 hours. The mixture
was cooled and concentrated in vacuo. The crude material was
purified by silica gel flash chromatography (0 to 20% ethyl acetate
in hexanes) to give 30.9 g (94%) of
3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine. .sup.1H-NMR (250 MHz,
CDCl.sub.3) .delta. 8.36 (d, J=7.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H),
7.12 (t, J=7.9 Hz, 1H), 6.67 (t, J=7.6 Hz, 1H), 3.20 (sept, J=7.0
z, 1H), 1.37 (d, J=6.8 Hz, 6H).
[0370] Step 3. To a 20 ml microwave reaction vial was added
3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine (690 mg, 2.41 mmol),
3-aminophenylboronic acid monohydrate (411 mg, 2.65 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (197 mg, 0.24 mmol), acetonitrile (8 ml), and
1 M aqueous Na.sub.2CO.sub.3 solution (5 ml). The mixture was
placed in a microwave reactor for 2 hours at 140.degree. C. The
reaction mixture was concentrated in vacuo, and the crude material
partitioned between dichloromethane and water. The organic layer
was separated, dried over sodium sulfate, filtered, and
concentrated in vacuo. The crude material was purified by silica
gel flash chromatography (0 to 30% ethyl acetate in hexanes) to
give 205 mg (34%) of
3-(2-isopropyl-pyrazolo[1,55-a]pyridin-3-yl)-phenylamine.
.sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta. 8.40 (d, J=7.0 Hz, 1H),
7.44 (d, J=9.0 Hz, 1H), 7.25-7.18 (m, 1H), 7.03-6.97 (m, 1H), 6.81
(d, J=7.3 Hz, 1H), 6.71 (s, 1H), 6.67-6.62 (m, 2H), 3.65 (broad s,
2H), 3.35 (sept, J=6.9 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H). LC/MS 252.3
m/z (M+H.sup.+). Compound 1100.
Example 60
Synthesis of
4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine
##STR00073##
[0372] 4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine was
prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and
4-aminophenylboronic acid monohydrate following the method used in
Step 3 of the synthesis of
3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine as in
Example 59 above (134 mg, 18%). .sup.1H-NMR (250 MHz, DMSO-d.sub.6)
.delta. 8.58 (d, J=7.0 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.14-7.04
(m, 3H), 6.77 (t, J=7.0 Hz, 1H), 6.67 (d, J=8.5 Hz, 2H), 5.15 (s,
2H), 3.23 (sept, J=6.8 Hz, 1H), 1.26 (d, J=7.0 Hz, 6H). LC/MS 252.3
m/z (M+H.sup.+). Compound 1101.
Example 61
Synthesis of
2-Isopropyl-3-(4-morpholin-4-yl-phenyl)-pyrazolo[1,5-a]pyridine
##STR00074##
[0374]
2-Isopropyl-3-(4-morpholin-4-yl-phenyl)-pyrazolo[1,5-a]pyridine was
prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and
4-morpholinophenylboronic acid following the method used in Step 3
of the synthesis of
3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example
59) (157 mg, 16%). .sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta.8.61
(d, J=6.3 Hz 1H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (d, J 7.0 Hz, 2H),
7.15-7.06 (m, 3H), 6.81 (t, J=6.5 Hz, 1H), 3.79-3.75 (m, 4H), 3.25
(sept, J=6.3 Hz, 1H), 3.22-3.15 (m, 4H), 1.27 (d, J=6.8 Hz, 6H);
LC/MS 322.3 m/z (M+H.sup.+). Compound 1102.
Example 62
Synthesis of 2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine
##STR00075##
[0376] 2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine was
prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and
4-pyridineboronic acid following the method used in Step 3 of the
synthesis of
3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example
59) (1584 mg, 34%). .sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta.
8.87-8.82 (m, 3H), 8.09 (d, J=6.5 Hz, 2H), 7.95 (d, J=9.0 Hz, 1H),
7.52 (t, J=8.0 Hz, 1H), 7.11 (t, J=6.8 Hz, 1H), 3.48 (sept, J=6.8
Hz, 1H), 1.34 (d, J=6.8 Hz, 6H); LC/MS 238.3 m/z (M+H.sup.+).
Compound 1103.
Example 63
Synthesis of
2-Isopropyl-3-(1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine
##STR00076##
[0378] To two 20 ml microwave reaction vials were each added
3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine (486 mg, 1.69 mmol),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-pyrazolecarboxylate
(500 mg, 1.69 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complex with dichloromethane (139 mg, 0.17 mmol), acetonitrile (8
ml), and 1 M aqueous NaHCO.sub.3 solution (5 ml). The mixture was
placed in a microwave reactor for 2 hours at 140.degree. C. The
reaction mixture from the two vials were combined and concentrated
in vacuo, and the crude material was partitioned between
dichloromethane and water. The organic layer was separated, dried
over sodium sulfate, filtered, and concentrated in vacuo. The crude
material was purified by silica gel flash chromatography (0 to 50%
ethyl acetate in hexanes) to give the protected-analog. The
protected analog was dissolved in 20% trifluoroacetic acid in
dichloromethane (50 ml) and stirred at room temperature. The
reaction was monitored by HPLC for completion (2 hours). The
mixture was concentrated in vacuo, and the concentrated material
was dissolved in 4N hydrochloric acid in dioxane. Ether was added
to the acidic solution to precipitate out the desired material. The
material was filtered and dried in vacuo under high vacuum to give
235 mg (31%) of
2-isopropyl-3-(1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine as the
hydrochloric acid salt. .sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta.
8.70 (broad s, 1H), 8.64 (d, J=7.0 Hz, 2H), 8.07 (s, 1H), 7.61 (d,
J=9.0 Hz, 1H), 7.19 (dd, J=7.8, 6.8 Hz, 1H), 6.85 (t, J=6.8 Hz,
1H), 3.30 (sept, J=7.0 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H); LC/MS 227.1
m/z (M+H.sup.+). Compound 1104.
Example 64
Synthesis of 2-Isopropyl-3-pyridin-3-yl-pyrazolo[1,5-a]pyridine
##STR00077##
[0380] 2-Isopropyl-3-pyridin-3-yl-pyrazolo[1,5-a]pyridine was
prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and
3-pyridineboronic acid following the method used in Step 3 of the
synthesis of
3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example
59) (240 mg, 32%). .sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta. 8.69
(d, J=7.3 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J=4.0 Hz, 1H), 7.85 (d,
J=7.8 Hz, 2H), 7.56-7.47 (m, 1H), 7.20 (t, J=8.8 Hz, 1H), 6.89 (t,
J=6.8 Hz, 1H), 3.24 (sept, J=7.0 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H);
LC/MS 237.9 m/z (M+H.sup.+). Compound 1111.
Example 65
Synthesis of
2-Isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine
##STR00078##
[0382]
2-Isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine
was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and
1-Methylpyrazole-4-boronic acid pinacol ester following the method
used in Step 3 of the synthesis of
3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example
59) (138 mg, 13%). .sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta. 8.59
(d, J=6.8 Hz, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=9.0 Hz,
1H), 7.16 (t, J=7.6 Hz, 1H), 6.80 (t, J=6.8 Hz, 1H), 3.91 (s, 3H),
3.29 (sept, J=7.0 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H); LC/MS 241.1 m/z
(M+H.sup.+). Compound 1112.
Example 66
Synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne
[0383] A generalized procedure employed to synthesize compounds
1137, 1139, and 1134-1136 is provided below. The scheme below shows
the synthesis of compound 1137.
##STR00079##
[0384] Step 1. 2-Isopropyl-pyrazolo[1,5-a]pyridine (10.00 g, 66.7
mmol), acetic anhydride (100 ml), and concentrated sulfuric acid
(10 drops) were combined and stirred for 3 hours at reflux. The
reaction mixture was cooled to room temperature and poured into ice
water (300 ml). The mixture was quenched with 2 N sodium hydroxide
until the pH>10, and the quenched solution was extracted with
ethyl acetate. The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude material was
purified by silica gel flash chromatography (0 to 40% ethyl acetate
in hexanes) to give 11.8 g (87%) of
1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-ethanone. .sup.1H-NMR
(250 MHz, DMSO-d.sub.6) .delta. 8.47 (d, J=6.8 Hz, 1H), 8.12 (d,
J=9.0 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H), 3.76
(sept, J=6.9 Hz, 1H), 2.60 (s, 3H), 1.39 (d, J=6.8 Hz, 6H); LC/MS
203.3 m/z (M+H.sup.+).
[0385] Step 2. 1-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-ethanone
(7.56 g, 3.74 mmol) and N,N-dimethylformamide dimethyl acetal (80
ml) were combined and stirred at reflux for 24 hours. The reaction
mixture was concentrated in vacuo, and fresh N,N-dimethylformamide
dimethyl acetal (80 ml) was added to the concentrated reaction
mixture and stirred at reflux for 24 hours. The reaction mixture
was concentrated in vacuo once again, and a third portion of
N,N-dimethylformamide dimethyl acetal (80 ml) was added to the
concentrated reaction mixture and stirred at reflux for a third 24
hour period. The reaction mixture was concentrated in vacuo, and
the crude material was purified by silica gel flash chromatography
(0 to 40% acetone in dichloromethane) to give 4.30 g (44%) of a 2:1
mixture of
E-3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone
and
Z-3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propeno-
ne. .sup.1H-NMR (250 MHz, CDCl.sub.3) .delta. 8.37 (d, J=6.8 Hz,
1H), 7.99 (d, J=9.0 Hz, 1H), 7.69 (d, J=12.5 Hz, 1H), 7.17 (t,
J=7.0 Hz, 1H), 6.72 (t, J=6.0 Hz, 1H), 5.49 (d, J=12.5 Hz, 1H),
3.70 (sept, J=6.8 Hz, 1H), 2.95 (s, 6H), 1.37 (d, J=7.0 Hz, 6H);
LC/MS 258.4 m/z (M+H.sup.+) for
E-3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone.
.sup.1H-NMR (250 MHz, CDCl.sub.3) .delta. 8.39 (d, J=6.8 Hz, 1H),
8.00 (d, J=9.0 Hz, 1H), 7.71 (d, J=12.3 Hz, 1H), 7.17 (t, J=6.8 Hz,
1H), 6.73 (t, J=7.0 Hz, 1H), 5.50 (d, J=12.3 Hz, 1H), 3.72 (sept,
J=6.9 Hz, 1H), 2.97 (s, 6H), 1.39 (d, J=7.0 Hz, 6H); LC/MS 258.4
m/z (M+H.sup.+) for
Z-3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone.
[0386] Step 3. Isopropylamine (9.2 ml, 108.0 mmol),
2-methyl-2-thiopseudourea sulfate (15.00 g, 107.9 mmol), and
pyridine (30 ml) were combined and stirred at 30.degree. C. for 18
hours. The mixture was concentrated in vacuo to give
N-isopropyl-guanidine. LC/MS 102.1 m/z (M+H.sup.+).
[0387] Step 4.
3-Dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone
(2.90 g, 11.3 mmol) and N-isopropyl-guanidine (4.00 g, 39.5 mmol)
were dissolved in 2M sodium ethoxide in ethanol (150 ml), and the
mixture was stirred at reflux. The reaction mixture was monitored
by HPLC for completion (24 hours). The mixture was concentrated and
quenched with saturated sodium bicarbonate solution. The quenched
mixture was extracted with ethyl acetate. The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo. The
crude material was purified by silica gel flash chromatography (0
to 10% methanol in dichloromethane). A recrystallization in
methanol and hexanes gave
isopropyl-[4-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-am-
ine. The hydrochloride salt was obtained by dissolving the product
in 4N hydrogen chloride in dioxane (4 ml), followed by
precipitation with ether. The precipitated was dissolved in water,
cooled to -78.degree. C., and dried on a lyophilizer to obtain
isopropyl-[4-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-am-
ine as the hydrochloride salt 798 mg (24%). .sup.1H-NMR (250 MHz,
DMSO-d.sub.6) .delta. 8.87 (d, J=6.8 Hz, 1H), 8.36-8.22 (m, 2H),
7.66-7.55 (m, 1H), 7.20-7.07 (m, 2H), 4.18 (broad s, 1H), 3.72
(sept, J=6.9 Hz, 1H), 1.37 (d, J=7.0 Hz, 6H), 1.28 (d, J=6.5 Hz,
6H); LC/MS 296.3 m/z (M+H.sup.+). Compound 1137.
Example 67
Synthesis of
4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-ylamine
##STR00080##
[0389]
3-Dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propeno-
ne (591 mg, 2.30 mmol), guanidine hydrochloride (878 mg, 9.19
mmol), potassium carbonate (2.54 g, 18.38 mmol), and DMF (60 ml)
were combined and stirred for 48 hours at 120.degree. C. The
reaction mixture was concentrated in vacuo. The crude material was
purified by silica gel flash chromatography (2 to 10% methanol in
dichloromethane) to give (210 mg, 36%) of
4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-ylamine.
.sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta. 8.71 (d, J=7.3 Hz, 1H),
8.34 (d, J=9.0 Hz, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.36 (dd, J=7.9,
6.8 Hz, 1H), 6.96 (t, J=6.9 Hz, 1H), 6.79 (d, J=5.3 Hz, 1H), 6.55
(s, 2H), 3.71 (sept, J=6.9 Hz, 1H), 1.34 (d, J=7.0 Hz, 6H); LC/MS
254.3 m/z (M+H.sup.+). Compound 1139.
Example 68
Synthesis of
3-[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-ylamino]-propa-
n-1-ol
##STR00081##
[0391] Step 1. N-(3-Hydroxy-propyl)-guanidine was prepared from
3-amino-propan-1-ol and 2-methyl-2-thiopseudourea sulfate following
the method used in Step 3 of the synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne (Example 66). LC/MS118.2 m/z (M+H.sup.+).
[0392] Step 2.
3-[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-ylamino]-propa-
n-1-ol was prepared from
3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone
and N-(3-hydroxy-propyl)-guanidine following the method used in
Step 4 of the synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne (Example 66), except preparative-HPLC purification was used in
the place of recrystallization (166 mg, 18%). .sup.1H-NMR (250 MHz,
DMSO-d.sub.6) .delta. 8.85 (d, J=7.0 Hz, 1H), 8.44-8.22 (m, 3H),
7.59 (t, J=7.0 Hz, 1H), 7.18-7.05 (m, 2H), 4.07 (broad s, 1H), 3.79
(sept, J=6.9 Hz, 1H), 3.58-3.33 (m, 4H), 1.77 (pent, J=6.6 Hz, 2H),
1.37 (d, J=6.5 Hz, 6H); LC/MS 312.3 m/z (+H.sup.+). Compound
1134.
Example 69
Synthesis of
[4-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-[3-(4-methyl--
piperazin-1-yl)-propyl]-amine
##STR00082##
[0394] Step 1. N-[3-(4-Methyl-piperazin-1-yl)-propyl]-guanidine was
prepared from 3-(4-methyl-piperazin-1-yl)-propylamine and
2-methyl-2-thiopseudourea sulfate following the method used in Step
3 of the synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne (Example 66). LC/MS 200.2 m/z (M+H.sup.+).
[0395] Step 2.
[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-[3-(4-methyl-
-piperazin-1-yl)-propyl]-amine was prepared from
3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone
and N-[3-(4-methyl-piperazin-1-yl)-propyl]-guanidine following the
method used in Step 4 of the synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne (Example 66), except preparative-HPLC purification was used in
the place of recrystallization (162 mg, 19%). .sup.1H-NMR (250 MHz,
DMSO-d.sub.6) .delta. 8.72 (d, J=6.8 Hz, 1H), 8.28-8.20 (m, 2H),
7.37 (t, J=7.8 Hz, 1H), 7.16-7.10 (m, 1H), 6.99 (t, J=6.6 Hz, 1H),
6.80 (d, J=7.3 Hz, 1H), 3.78 (sept, J=7.3 Hz, 1H), 2.56-2.32 (m,
10H), 2.22 (s, 3H), 2.10-2.06 (m, 2H), 1.73 (pent, J=6.9 Hz, 2H),
1.35 (d, J=6.8 Hz, 6H); LC/MS 394.3 m/z (M+H.sup.1). Compound
1135.
Example 70
Synthesis of
Cyclopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-a-
mine
##STR00083##
[0397] Step 1. N-Cyclopropyl-guanidine was prepared from
cyclopropylamine and 2-methyl-2-thiopseudourea sulfate following
the method used in Step 3 of the synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne (Example 66). LC/MS100.2 m/z (M+H.sup.+).
[0398] Step 2.
Cyclopropyl-[4-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]--
amine was prepared from
3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone
and N-cyclopropyl-guanidine following the method used in Step 4 of
the synthesis of
Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-ami-
ne (Example 66), except preparative-HPLC purification was used in
the place of recrystallization (34 mg, 7%). .sup.1H-NMR (250 MHz,
DMSO-d.sub.6) .delta. 8.86 (d, J=6.8 Hz, 1H), 8.57 (d, J=8.3 Hz,
1H), 8.27 (d, J=6.5 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.19-7.10 (m,
2H), 4.62 (broad s, 1H), 3.86-3.78 (m, 1H), 2.80-2.72 (m, 1H), 1.38
(d, J=6.5 Hz, 6H), 0.90-0.84 (m, 2H), 0.70-0.64 (m, 2H); LC/MS
294.2 m/z (M+H.sup.+). Compound 1136.
Example 71
Synthesis of
2-Isopropyl-3-(1H-pyrazol-3-yl)-pyrazolo[1,5-a]pyridine
##STR00084##
[0400]
3-Dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propeno-
ne (860 mg, 3.34 mmol), hydrazine (1.0 ml, 31.85 mmol), and 2N
sodium ethoxide in ethanol (70 ml) were combined and stirred at
reflux for 18 hours. The mixture was cooled to room temperature and
concentrated in vacuo. The dried paste was partitioned between
saturated sodium bicarbonate solution and ethyl acetate. The
organic layer was separated, dried over sodium sulfate, filtered
and concentrated. The crude material was purified by silica gel
flash chromatography (0 to 15% methanol in dichloromethane). The
pure compound was dissolved in 1 N HCl dioxane (2 ml), and
precipitated out of solution with ether to give 230 mg (87%)
2-isopropyl-3-(1H-pyrazol-3-yl)-pyrazolo[1,5-a]pyridine as the
hydrochloride salt. .sup.1H-NMR (250 MHz, DMSO-d.sub.6) .delta.
8.66 (d, J=7.0 Hz, 1H), 7.95 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.26
(t, J=7.8 Hz, 1H), 6.89 (t, J=6.8 Hz, 1H), 6.60 (s, 1H), 6.55
(broad s, 1H), 3.54 (sept, J=6.5 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H);
LC/MS 227.1 m/z (M+H.sup.+). Compound 1141.
[0401] Table 1 provides a summary of exemplary compounds in
accordance with the invention, including structures for each of
R.sub.2, R.sub.3 and R.sub.6, corresponding name, and
cross-reference to relevant example describing synthesis or
literature reference.
TABLE-US-00001 TABLE 1 ##STR00085## R2 R3 R6 Ref. Code Name
Synthesis Method ##STR00086## ##STR00087## --H 411
1-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1- one
Example 1(b); T. Irikura, et al., U.S. Pat. No. 3,850,941, Nov. 26,
1974 ##STR00088## ##STR00089## --H 1001 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)propan-1-one Example 20; U.S. Pat. No. 4,097,483
##STR00090## ##STR00091## --H 1002 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- ol Example 21; U.S. Pat. No.
4,578,392 ##STR00092## ##STR00093## --H 1003
1-(2-(2-hydroxypropan-2- yl)pyrazolo[1,5-a]pyridin-3-yl)-2-
methylpropan-1-one K. Awano, et al., Chem. Pharm. Bull., 40, 631-38
(1992) ##STR00094## ##STR00095## --H 1004 2-hydroxy-1-(2-
ispropylpyrazolo[1,5-a]pyridin-3- yl)-2-methylpropan-1-one K.
Awano, et at., Chem. Pharm. Bull., 40, 631-38 (1992) ##STR00096##
##STR00097## OCH3 1005 1-(2-isopropyl-6-
methoxypyrazolo[1,5-a]pyridin-3- yl)-2-methylpropan-1-one K. Awano,
et al., Chem. Pharm. Bull., 40, 639-43 (1992) ##STR00098##
##STR00099## --OH 1006 1-(6-hydroxy-2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)-2-methylpropan-1-one K.
Awano, et al., Chem. Pharm. Bull., 40, 639-43 (1992) ##STR00100##
##STR00101## --H 1007 4-chlorophenyl)(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)methanone Example 17
##STR00102## ##STR00103## --H 1008 (2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)(4- methoxyphenyl)methanone Example 18 ##STR00104##
##STR00105## --H 1009 2-amino-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)ethanone Example 1(f)
##STR00106## ##STR00107## --H 1012 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one oxime Example 3 ##STR00108##
##STR00109## --H 1013 2-amino-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one Example 2
##STR00110## ##STR00111## --H 1014 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one O-carbamoyl oxime Example 4
##STR00112## ##STR00113## --H 1015 2-methyl-1-(2-
phenylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one Example 5; M.J.
Alberti, et al., U.S. patent application publication 2004/0053942
##STR00114## ##STR00115## --H 1016 2-methyl-1-(2-
phenylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one oxime Example 6
##STR00116## ##STR00117## --H 1017 2-methyl-1-(2-
phenylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one O-carbamoyl oxime
Example 7 ##STR00118## ##STR00119## --H 1018 1-(2-(4-
fluorophenyl)pyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1- one
Example 8; M.J. Alberti, et al., U.S. patent application
publication 2004/0053942 ##STR00120## ##STR00121## --H 1019
1-(2-(4- fluorophenyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one oxime Example 9 ##STR00122##
##STR00123## --H 1020 1-(2-(4- fluorophenyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one O-carbamoyl oxime Example 10
##STR00124## ##STR00125## --H 1021 1-(2-(4-
methoxyphenyl)pyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1- one
Example 11; M.J. Alberti, et al., U.S. patent application
publication 2004/0053942 ##STR00126## ##STR00127## --H 1022
1-(2-(4- methoxyphenyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one oxime Example 12 ##STR00128##
##STR00129## --H 1023 1-(2-(4- methoxyphenyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one O-carbamoyl oxime Example 13
##STR00130## ##STR00131## --H 1024 1-(2-(4-
chlorophenyl)pyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1- one
Example 14; M.J. Alberti, et al., U.S. patent application
publication 2004/0053942 ##STR00132## ##STR00133## --H 1025
1-(2-(4- chlorophenyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one oxime Example 15 ##STR00134##
##STR00135## --H 1026 1-(2-(4- chlorophenyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one O-carbamoyl oxime Example 16
##STR00136## ##STR00137## --CF3 1027 1-(2-(4-fluorophenyl)-6-
(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1-
one Example 19; M.J. Alberti, et al., U.S. patent application
publication 2004/0053942 ##STR00138## ##STR00139## --CF3 1032
1-(2-(4-fluorophenyl)-6- (trifluoromethyl)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one oxime Example 19(b).
##STR00140## ##STR00141## --CF3 1033 1-(2-(4-fluorophenyl)-6-
(trifluoromethyl)pyrazolo[1,5- a]pyridin-3-yl)-2-methylprop-1- enyl
isobutyrate Example 19(e); M.J. Alberti, et al., U.S. patent
application publication 2004/0053942 ##STR00142## ##STR00143## --H
1034 1-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-2-
morpholinopropan-1-one hydrochloride Example 23 ##STR00144##
##STR00145## --H 1035 1-(2-isopropylpyrazolo[1,5-
a]pyridin3-yl)-2-(4- methylpiperazin-1-yl)propan-1- one
hydrochloride Example 24 ##STR00146## ##STR00147## --H 1036
1-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-2-(piperidin-1-
yl)propan-1-one hydrochloride Example 25 ##STR00148## ##STR00149##
--H 1037 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-(piperazin-1- yl)propan-1-one hydrochloride
Example 26 ##STR00150## ##STR00151## --H 1038
(3-chloropyridin-2-yl)(2- isopropylpyrazolo[1,5-a]pyridin-3-
yl)methanone Example 27 ##STR00152## ##STR00153## --H 1039
2-amino-1-(2- isopropylpyrazolo[1,5-a]pyridin-3-
yl)-2-phenylethanone Example 28 ##STR00154## ##STR00155## --H 1040
1-(2-ethylpyrazolo[1,5-a]pyridin- 3-yl)propan-1-one Example 29
##STR00156## ##STR00157## --H 1041 2-(benzyl(methyl)amino)-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one Example 30
##STR00158## ##STR00159## --H 1042 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2- (methylamino)propan-1-one hydrochloride Example
31 ##STR00160## ##STR00161## --H 1044
N-(1-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-2-
methylpropyl)cyclopropanamine Example 32 ##STR00162## ##STR00163##
--H 1046 cyclopropyl(2- isopropylpyrazolo[1,5-
a]pyridin-3-yl)methanone Example 37 ##STR00164## ##STR00165## --H
1048 N-(cyclopropylmethyl)-1-(2- isopropylpyrazolo[1,5-a]pyridin-3-
yl)-2-methylpropan-1-amine hydrochloride Example 33 ##STR00166##
##STR00167## --H 1051 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- amine hydrochloride Example 35
##STR00168## ##STR00169## --H 1052 2-amino-1-(2-(4-
fluorophenyl)pyrazolo[1,5- a]pyridin-3-yl)propan-1-one
hydrochloride Example 36 ##STR00170## ##STR00171## --H 1055
1-(2-methoxypyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1- one
Example 39 ##STR00172## ##STR00173## --H 1057 2-amino-1-(2-
methoxypyrazolo[1,5-a]pyridin-3- yl)propan-1-one Example 40
##STR00174## ##STR00175## --H 1060 2-amino-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)butan-1-one Example 41
##STR00176## ##STR00177## --H 1061 2-amino-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)-4-methylpentan-1-one Example
42 ##STR00178## ##STR00179## --H 1067 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-1-oxopropan-2-yl acetate Example 51 ##STR00180##
##STR00181## --H 1068 2-hydroxy-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one Example 52
##STR00182## ##STR00183## --H 1069 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-methoxypropan- 1-one Example 53 ##STR00184##
##STR00185## --H 1070 1-(2-(4- fluorophenyl)pyrazolo[1,5-
a]pyridin-3-yl)propan-1-one Example 43 ##STR00186## ##STR00187##
--H 1072 1-(2- (dimethylamino)pyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1- one Example 44 ##STR00188##
##STR00189## --H 1073 2-isopropylpyrazolo[1,5-
a]pyridine-3-carbaldehyde Example 54 ##STR00190## ##STR00191## --H
1074 (E)-2-((2-isopropylpyrazolo[1,5- a]pyridin-3-
yl)methylene)hydrazine- carboxamide Example 55 ##STR00192##
##STR00193## --H 1075 2-amino-1-(2- (dimethylamino)pyrazolo[1,5-
a]pyridin-3-yl)propan-1-one Example 45 ##STR00194## ##STR00195##
--H 1077 2-amino-1-(2- isopropylpyrazolo[1,5-a]pyridin-3-
yl)hexan-1-one Example 46 ##STR00196## ##STR00197## --H 1079
2-isopropylpyrazolo[1,5- a]pyridine-3-carboxylic acid Example 57
##STR00198## ##STR00199## --H 1080 1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)ethanone Example 58 ##STR00200## ##STR00201## --H
1082 2-amino-1-(2- isopropylpyrazolo[1,5-a]pyridin-3-
yl)-3-methoxypropan-1-one Example 47 ##STR00202## ##STR00203## --H
1083 (Z)-2-(hydroxyimino)-1-(2- isopropylpyrazolo[1,5-a]pyridin-3-
yl)propan-1-one Example 48 ##STR00204## ##STR00205## --H 1085
4-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-1H-imidazole-
2(3H)-thione Example 49 ##STR00206## ##STR00207## --H 1087
4-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)thiazol-2(5H)-imine
Example 50 ##STR00208## ##STR00209## --H 1100
3-(2-Isopropyl-pyrazolo[1,5- a]pyridin-3-yl)-phenylamine Example 59
##STR00210## ##STR00211## --H 1101 4-(2-Isopropyl-pyrazolo[1,5-
a]pyridin-3-yl)-phenylamine Example 60 ##STR00212## ##STR00213##
--H 1102 2-Isopropyl-3-(4-morpholin-4-yl-
phenyl)-pyrazolo[1,5-a]pyridine Example 61 ##STR00214##
##STR00215## --H 1103 2-Isopropyl-3-pyridin-4-yl-
pyrazolo[1,5-a]pyridine Example 62 ##STR00216## ##STR00217## --H
1104 2-Isopropyl-3-(1H-pyrazol-4-yl)- pyrazolo[1,5-a]pyridine
Example 63 ##STR00218## ##STR00219## --H 1111
2-Isopropyl-3-pyridin-3-yl- pyrazolo[1,5-a]pyridine Example 64
##STR00220## ##STR00221## --H 1112 2-Isopropyl-3-(1-methyl-1H-
pyrazol-4-yl)-pyrazolo[1,5- a]pyridine Example 65 ##STR00222##
##STR00223## --H 1134 3-[4-(2-Isopropyl-pyrazolo[1,5-
a]pyridin-3-yl)-pyrimidin-2- ylamino]-propan-1-ol Example 68
##STR00224## ##STR00225## --H 1135 [4-(2-Isopropylpyrazolo[1,5-
a]pyridin-3-yl)-pyrimidin-2-yl]-[3-
(4-methyl-piperazin-1-yl)-propyl]- amine Example 69 ##STR00226##
##STR00227## --H 1137 Isopropyl-[4-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)-pyrimidin-2-yl]-amine
Example 66 ##STR00228## ##STR00229## --H 1139
4-(2-Isopropyl-pyrazolo[1,5- a]pyridin-3-yl)-pyrimidin-2- ylamine
Example 67 ##STR00230## ##STR00231## --H 1141
Isopropyl-3-(1H-pyrazol-3-yl)- pyrazolo[1,5-a]pyridine Example 71
##STR00232## ##STR00233## --H 1045 2-(cyclopropylamino)-1-(2-
isopropylpyrazolo[1,5-a]pyridin-3- yl)propan-1-one hydrochloride
Example 34
##STR00234## ##STR00235## --H 1047 cyclopropyl(2-
cyclopropylpyrazolo[1,5- a]pyridin-3-yl)methanone Example 38
##STR00236## ##STR00237## --H 1049 2-isopropyl-3-(2-methylprop-
1-enyl)pyrazolo[1,5-a]pyridine Example 79 ##STR00238## ##STR00239##
--H 1050 1-(2-cyclopropylpyrazolo[1,5- a]pyridin-3-yl)-2-
methylpropan-1-one Example 75 ##STR00240## ##STR00241## --H 1063
1-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-2-methyl-3-
(piperidin-1-yl)propan-1-one hydrochloride Example 78 ##STR00242##
##STR00243## --H 1065 3-amino-1-(2- isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2- methylpropan-1-one hydrochloride Example 77
##STR00244## ##STR00245## --H 1066 3-(benzylamino)-1-(2-
isopropylpyrazolo[1,5- a]pyridin-3-yl)-2- methylpropan-1-one
hydrochloride Example 76 ##STR00246## ##STR00247## --H 1071
2-(benzylamino)-1-(2- isopropylpyrazolo[1,5-
a]pyridin-3-yl)propan-1-one Example 80 ##STR00248## ##STR00249##
--H 1081 S-1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-1-oxopropan-2- yl ethanethioate Example 56
Example 72
Mechanical Allodynia Measured by Response to Von Frey Fibers for
Exemplary Substituted Pyrazolo[1,5-a]pyridine Compounds of the
Invention
[0402] To induce allodynia, male Sprague-Dawley rats underwent
chronic constriction injury (CCI) to the sciatic nerve as described
by Bennett and Xie, Pain 1988; 33(1):87-107. The plantar surface of
the hind paws was stimulated with von Frey filaments (Stoelting) to
induce a withdrawal response by blinded personnel. The bending
force of fiber required to induce a 50% withdrawal response was
calculated following CCI surgery (pre-dosing baseline). N=5-6
allodynic rats received a single intraperitoneal administration of
test compound or vehicle. Two hours post-dosing, 50% paw withdrawal
threshold was determined again by blinded testers using von Frey
filaments. The change in 50% withdrawal threshold relative to
pre-dosing baseline is reported in Table 2 for various substituted
pyrazolo[1,5-a]pyridine compounds of the invention.
[0403] Compounds exhibiting a chronic constriction injury threshold
of 1.0 gram or greater are preferred for use in treating
neuropathic pain, while compounds exhibiting a chronic constriction
injury threshold of 1.5 grams or greater, or even more preferably
2.0 grams or greater are particularly preferred. Thus, compounds
1009, 1012, 1013, 1014, 1019, 1026, 1085, 1103, and 1137 are
particularly advantageous for treating allodynia. In summary, the
aforementioned compounds are particularly efficacious in treating
neuropathic pain, as demonstrated using a mechanical allodynia rat
model.
[0404] A plot of 50% paw withdrawal threshold in grams for the
vehicle and compound 1014 administered intraperitoneally at two
different doses at various time points post-administration is
provided in FIG. 1. Similarly, FIG. 2 is a plot of 50% withdrawal
threshold in grams for the vehicle and compound 1013 administered
intraperitoneally at three different doses (10 mg/kg; 20 mg/kg; and
40 mg/kg) at various time points post-administration.
Example 73
Inhibition of PDE for Exemplary Substituted Pyrazolo[1,5-a]pyridine
Compounds of The Invention
[0405] In a 96-well plate, phosphodiesterase (PDE) enzyme (0.5-1
mU/well) derived from bovine brain (Sigma) was combined with 5 uM
cAMP substrate (Sigma). Test compounds (0-200 uM) or vehicle (0.5%
DMSO) were added to the enzyme/substrate and incubated for 1 hour.
Using a PDELight.RTM. kit (Cambrex), the amount of AMP produced in
the reaction from the hydrolysis of cAMP was quantified using
PDELight AMP Detection Reagent which converts the AMP directly to
ATP. The assay uses luciferase, which catalyses the formation of
light from the newly formed ATP and luciferin. The luminescence was
read on a Victor Light 1420 luminometer. IC.sub.50 calculations
were plotted using a nonlinear regression curve fit.
[0406] IC.sub.50 results are reported in Table 2 for various
substituted pyrazolo[1,5-a]pyridine compounds of the invention.
Compounds exhibiting an IC.sub.50 of less than about 50 .mu.M,
preferably less than about 20 .mu.M, more preferably less than
about 15 .mu.M, and even more preferably less than about 10 .mu.M
are preferred in terms of their ability to effectively inhibit
phosphodiesterase. Thus, in this regard, out of those compounds
evaluated, preferred compounds include 1004, 1006, 1008, 1012,
1019, 1022, 1024, 1025, and 1026.
Example 74
Lipopolysaccharide-Stimulation of Peripheral Blood Mononuclear
Cells (PBMCs) for Exemplary Substituted Pyrazolo[1,5-a]pyridine
Compounds of the Invention
[0407] IC.sub.50 values were determined for representative
compounds of the invention based upon their ability to inhibit
LPS-induced cytokine production in human peripheral blood
mononuclear cells. Human PBMCs (peripheral blood mononuclear cells)
were isolated over a Ficoll gradient from buffy coats obtained from
the local Red Cross. 10.sup.6 PBMC cells/well were seeded in
24-well tissue culture plates in RPMI 1640 medium supplemented with
10% human serum, hopes buffer and sodium pyruvate. The cells were
treated with 0.1% DMSO (vehicle) or test compounds (1, 10, and 100
uM) 30 minutes prior to activation with LPS (lipopolysaccharide)
(E. Coli) at 10 ng/mL. 6-10 hours post LPS stimulation the culture
supernatants were collected and levels of cytokines TNF-.alpha. and
IL-1.beta. were quantified by ELISA (R&D Systems) and/or
Luminex (Linco Diagnostics). IC.sub.50 calculations were plotted
using a nonlinear regression curve fit for exemplary substituted
pyrazolo[1,5-a]pyridine compounds of the invention; results are
provided in Table 2.
[0408] As demonstrated by the results in Table 2, certain compounds
of the invention are particularly useful for treating inflammatory
conditions, as indicated by their ability to suppress LPS-mediated
cytokine release in the above-described assay. In this regard,
i.e., for use as an anti-inflammatory agent, preferred compounds
are those having an IC.sub.50 of less than or equal to about 50
.mu.M, preferably less than about 40 .mu.M, and even more
preferably, less than about 30 .mu.M. Thus, preferred compounds for
use as anti-inflammatory agents include 1001, 1004, 1006, 1007,
1008, 1009, 1013, 1014, 1018, and 1024. Since chronic inflammatory
diseases are caused by prolonged production of several
proinflamnmatory cytokines such as TNF-.alpha. and IL-1.beta., the
ability of a compound to effectively inhibit LPS-stimulated
production of such cytokines provides an indication of its efficacy
in treating one or more inflammatory conditions.
TABLE-US-00002 TABLE 2 Summary of Assay Results for Substituted
Pyrazolo[1,5-.alpha.]pyridine Compounds Com- Mechanical PDE pound
Allodynia .DELTA.WT Inhibition, .mu.M TNF-.alpha., .mu.M
IL-1.beta., .mu.M Ref. (grams) (IC.sub.50) (IC.sub.50) (IC.sub.50)
Code (note a) (note b) (note c) (note c) 411 2.31-3.53 10.3 5 17.9
1001 0 58 13 >100 1002 0.79 >200 >100 >100 1003 0
>100 1004 0.48 12.6 28.8 >100 1005 0.17 59.5 76 1006 0 29.6
1.3 14.7 1007 0.92 >200 13 29.7 1008 0.84 5.8 50 >100 1009
1.15 >200 25 99 1012 1.56 40 >100 99 1013 10 mg/kg: 1.04
>200 13.6 >100 20 mg/kg: 1.33 40 mg/kg: 3.16 25 mg/kg PO:
1.39 1014 10 mg/kg: 2.18 100 1.3 1 20 mg/kg: 3.73 1015 0.51 80
>100 >100 1016 0 75 >100 >100 1017 0.91 >200 1018 0
>200 32.7 >100 1019 1.4 40 >100 >100 1020 >200 1021
0.45 >200 1022 0 23.9 1023 156 1024 0.43 18.2 1025 0.81 23.0
1026 1.14 27.7 1027 0 >200 1034 10 mg/kg: 1.71 43.3 20 mg/kg:
0.54 1035 0 198 1036 0 >200 1037 0 >200 1038 0.32 26.4 1039
0.05 8.2 1040 0.12 27.1 1041 0.22 21.5 1042 10 mg/kg: 0.37 31.9 20
mg/kg: 0.22 1044 0.08 >200 1045 0 61.1 1046 0 33.3 1047 0.68
15.4 1048 0 >200 1049 0 92.5 1050 0 1051 0.29 1052 10 mg/kg:
0.39 20 mg/kg: 0.31 1055 10 mg/kg: 2.80 20 mg/kg: 0 1057 0.06 1060
10 mg/kg: 1.87 20 mg/kg: 0.74 1061 0 1063 0 1065 0.91 1066 0.1 1067
0.46 1068 0.7 1069 0.13 1070 0 1071 0.57 1072 1.48 lethargy 1073 0
1074 3.64 lethargy 1075 0.67 1077 0.41 1080 1.14 1081 0.07 1082 0.5
1083 0 1085 1.93 1100 0 1101 0.02 1102 0 1103 1.54 1104 0.86 1111 0
1112 0 1134 0 1135 0 1137 3.26 1139 0.21 1141 1.04 (note a).
Mechanical allodynia measured by response to von Frey fibers at 2
hr post dosing (10 mg/kg, IP, or as indicated); reported as change
from pre-dosing withdrawal threshold; (note b). PDE obtained from
brain extract using cAMP as substrate; (note c). Inhibition of
LPS-stimulated cytokine release from PBMCs.
Example 75
Synthesis of
1-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
[0409] Step 1.
Cyclopropyl(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)methanone (1.0
g, 4.42 mmol) was heated in benzene (80 ml) to reflux in a
Dean-Stark apparatus, in the presence of TsOH monohydrate (0.8 g,
4.21 mmol, 0.95 eq.), for 10 minutes. Freshly distilled ethylene
glycol (2.0 g, 32.24 mmol, 7.3 eq.) was added and the biphasic
solution maintained at reflux for a further 12 hours. The reaction
was cooled to rt and extracted with a saturated NaHCO.sub.3
solution (25 ml.times.3). The organic phase was dried over
Na.sub.2SO.sub.4, filtered and concentrated in-vacuo. Purification
by column chromatography (4:1 hexane:ethyl acetate) provided
2-cyclopropylpyrazolo[1,5-a]pyridine as a faintly yellow oil (0.61
g, 3.85 mmol, 87%).
[0410] IR (film) .nu.=3435, 3081, 2088, 1635, 1523, 1435, 1331,
1254, 1221, 1021 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.=8.31 (d, J=6.9 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 6.96 (t,
J=7.8 Hz, 1H), 6.57 (t, J=7.0 Hz, 1H), 6.11 (s, 1H), 2.02-2.14 (m,
1H), 0.96-1.05 (m, 2H), 0.83-0.91 (m, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.=158.2, 140.9, 127.9, 123.0, 116.9, 110.4, 92.5,
9.3, 8.6 MS (EI) m/z (%): 159 (12), 158 (100), 157 (90), 156 (27),
155 (11), 132 (18), 131 (15), 130 (28), 118 (15), 80 (14), 79 (12),
78 (15), 69 (21), 64 (11), 57 (10), 44 (19), 41 (14).
##STR00250##
[0411] Step 2. 2-cyclopropylpyrazolo[1,5-a]pyridine (0.61 g, 3.85
mmol) was heated to 140.degree. C. in isobutyric anhydride (10.0
ml, 60.24 mmol) for 15 minutes. H.sub.2SO.sub.4 (conc., 5 drops)
was added to the reaction, and the temperature maintained for a
further 12 hours. The reaction was cooled to 50.degree. C., and
NaOH (50% aqueous) added until the pH of the solution was
.about.11. On cooling to rt, the aqueous mixture was extracted with
CHCl.sub.3 (4.times.25 ml). The organic phases were combined, dried
over Na.sub.2SO.sub.4, filtered and concentrated in-vacuo to
provide a 1:2 mixture of
1-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
and the enol ester
1-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylprop-1-enyl
isobutyrate. The crude mixture was treated with freshly prepared
MeOH/MeONa (1.0 M, 10 ml) at rt for 8 hours. The reaction was
quenched with NH.sub.4Cl (aqueous), extracted with CHCl.sub.3
(4.times.25 ml) and the organic phases combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated in-vacuo. The title
compound,
1-(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one,
was recovered as a yellow crystalline solid (0.35 g, 1.53 mmol,
39.7%). MP 108-109.degree. C.; IR (film) .nu.=3077, 2972, 2930,
2871, 1638, 1622, 1538, 1499, 1466, 1424, 1360, 1260, 1207, 1145,
1081 cm.sup.-1; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=8.35 (d,
J=6.8 Hz, 1H), 8.22 (d, J=8.9 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 6.88
(t, J=6.5 Hz, 1H), 3.59 (sept, J=6.8 Hz, 1H), 2.42-2.56 (m, 1H),
1.27 (d, J=6.8 Hz, 6H), 1.05-1.18 (m, 4H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.=199.7, 158.3, 142.3, 128.4, 127.6, 119.2,
113.4, 110.4, 38.0, 18.8, 9.5, 8.4; MS (EI) m/z (%): 228 (26), 200
(17), 186 (13), 185 (100), 157 (37), 117 (12), 78 (13), 41 (19);
HRMS (EI) calc'd for C.sub.14H.sub.16N.sub.2O: 228.1263, found:
228.1259; Anal. Calc'd for C.sub.10H.sub.12N.sub.2: C, 73.66%; H,
7.06%; Found: C, 73.13%; H, 6.95%. Compound 1050.
Example 76
Synthesis of
3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-
-1-one hydrochloride
[0412] To 2-isopropyl-pyrazolo[1,5-a]pyridine (6.80 g, 42.50 mmol)
in n-propionic anhydride (15 mL, 97%) at 140.degree. C. was added
concentrated H.sub.2SO.sub.4 (0.5 ml). The mixture was maintained
at 140.degree. C. overnight, cooled to room temperature basified
with NaOH (aqueous 50%) until pH>11. The aqueous layer was
extracted with chloroform (3.times.100 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude product
was purified by flash column chromatography (100% hexane, 9:1
hexane:ethyl acetate) to afford
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (4.81 g,
22.27 mmol, 53%) as a yellow oil.
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.500 g,
2.3 mmol), paraformaldehyde (0.069 g, 2.3 mmol), and benzylamine
hydrochloride (0.329 g, 2.3 mmol) were added to a 5-mL round bottom
flask. To this ethanolic hydrochloride (1 mL, 1.25% concentrated
HCl in ethanol) was added and the mixture was heated to reflux for
16 hours. The mixture was then cooled and diluted with Et.sub.2O (5
mL) and 1M NaOH (aq) (10 mL). The aqueous layer was then extracted
with Et.sub.2O (4.times.5 mL). The combined organic layers were
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated to afford a dark brown oil. This oil was subjected to
flash column chromatography (10% gradient of EtOAc/hexane ranging
from 0 to 90%) which afforded 0.073 g (9.5% yield) of
3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpro-
pan-1-one as a pale yellow oil.
[0413] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=8.47 (d, J=7.0 Hz,
1H), 8.03 (d, J=8.9 Hz, 1H), 7.37 (dt, J=8.9, 0.9 Hz, 1H),
7.30-7.25 (m, 4H), 7.23-7.18 (m, 1H), 6.89 (dt, J=7.0, 0.9 Hz, 1H),
3.78 (sept, J=6.9 Hz, 1H), 3.78 (s, 2H), 3.54-3.43 (m, 1H), 3.17
(dd, J=11.7, 7.5 Hz, 1H), 2.69 (dd, J=11.7, 5.7 Hz, 1H), 1.40 (d,
J=6.9 Hz, 3H), 1.39 (d, J=6.9 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta.=198.1, 164.4, 141.4,
140.4, 129.2, 128.3, 128.0, 127.7, 126.8, 118.9, 113.1, 109.3,
54.2, 52.3, 44.8, 27.7, 22.4, 22.1, 16.0; MS (EI) m/z 336 (M+1,
0.5), 335 (M.sup.+, 1.5), 217 (19.1), 216 (20.7), 188 (13.3), 187
(100.0), 106 (11.2), 91 (66.2); HRMS (EI) calcd for
C.sub.21H.sub.25N.sub.3O: 335.1998, found: 335.1995.
[0414] To MeOH (2 mL) cooled in an ice bath under argon was added
AcCl (0.047 mL) dropwise. This solution was stirred for 10 minutes
before adding dropwise to
3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-
-1-one (0.200 g) in dry Et.sub.2O (5 mL), which was also cooled in
an ice bath. The solvent was evaporated and the residue was treated
with hexane (1 ml). the solvent was evaporated and a yellow solid
was obtained. This solid was stirred in 10 mL of a solution
containing MeOH (1%) and Et.sub.2O (99%) for 8 hours. The solid was
filtered, washed with Et.sub.2O and dried under reduced pressure to
afford 172 mg of
3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-
-1-one hydrochloride as a pale yellow solid. mp=171-175.degree. C.
(Et.sub.2O, pentane), IR (KBr) .nu.=3428, 3034, 2965, 2784, 25589,
2425, 1642, 1538, 1507, 1481, 1440, 1360, 1264, 1210, 1188, 972;
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta.=9.60 (bs, 1H), 9.23
(bs, 1H), 8.86 (d, J=6.8 Hz, 1H), 8.09 (d, J=9.1 Hz, 1H), 7.56-7.68
(m, 3H), 7.37-7.47 (m, 3H), 7.15 (tr, J=6.8 Hz, 1H), 4.15-4.23 (m,
2H), 3.87-3.95 (m, 1H), 3.74 (sept, J=6.8 Hz, 1H), 3.34-3.42 (m,
1H), 2.94-3.01 (m, 1H), 1.33 (d, J=6.8 Hz, 3H), 1.28 (d, J=6.8 Hz,
3H), 1.22 (d, J=7.6 Hz, 3H); .sup.13C NMR (150 MHz, CDCl.sub.3)
.delta.=194.8, 164.4, 140.9, 132.3, 130.7, 130.6, 129.6, 129.4,
129.0, 118.7, 114.7, 107.4, 48.2, 41.3, 27.6, 22.9, 22.3, 17.1; MS
(FAB) m/z 337 (M+1, 25.5), 336 (M.sup.+, 100.0), 218 (16.7), 217
(99.6), 187 (28.1), 173 (17.8), 161 (13.1), 120 (31.9); HRMS (FAB)
calcd for C.sub.21H.sub.26N.sub.3O: 336.2076; found: 336.2066.
Compound 1066.
Example 77
Synthesis of
3-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
hydrochloride
##STR00251##
[0416]
3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-
propan-1-one (0.312 g, 0.93 mmol) was dissolved in MeOH (25 mL).
The flask was evacuated and flushed with argon (3 cycles). Pd on C
(0.312 g, 10 wt %) was added in small portions. The flask was then
evacuated and flushed with hydrogen (4 cycles). The heterogeneous
mixture was then vigorously stirred for 2 hours before evacuating
and flushing with argon (3 cycles). The mixture was then filtered
through Celite, washing with MeOH (50 mL), and concentrated. The
dark yellow oil was then subjected to flash column chromatography
(100% MeOH) while monitoring the fractions with HPLC and .sup.1H
NMR. The first major fractions contained 0.164 g (53% recovered
starting material); which was followed by 0.0379 g (16% yield) of
3-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
as a yellow oil.
[0417] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=8.46 (d, J=6.9 Hz,
1H), 8.04 (d, J=9.0 Hz, 1H), 7.37 (dt, J=9.0, 0.6 Hz, 1H), 6.88
(dt, J=6.9, 0.6 Hz, 1H), 3.77 (sept, J=6.9 Hz, 1H), 3.39-3.28 (m,
1H), 3.22-3.16 (m, 1H), 2.80-2.77 (m, 1H), 1.38 (d, J=6.9 Hz, 3H),
1.37 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H); MS (EI) m/z 246 (M
11, 2.9), 245 (M.sup.+, 17.7) 213 (14.0), 188 (14.0), 187 (100.0),
161 (16.1), 160 (27.9), 117 (10.6), 86 (46.7), 84 (72.6), 71
(10.7), 57 (23.5), 55 (10.2), 49 (15.1), 47 (18.8), 44 (11.1), 43
(24.9), 41 (16.7); HRMS (EI) calcd for C.sub.14H.sub.19N.sub.3O:
245.1528; found: 245.1533.
[0418] To MeOH (2 mL) cooled in an ice bath under argon was added
AcCl (0.12 mL) dropwise. This solution was stirred for 10 minutes
before adding dropwise to
3-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
(0.340 g) in dry Et.sub.2O (10 mL), which was also cooled in an ice
bath. Precipitate was formed immediately which was filtered,
washing with Et.sub.2O (4.times.15 mL) affording 0.390 g of an
yellow solid. This solid was stirred in 20 mL of a solution
containing MeOH (1%) and pentane (99%) for 8 hours. The solvent was
then aspirated to afford 313 mg of
3-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one
hydrochloride as a yellow solid.
[0419] mp 110-115.degree. C. (MeOH, pentane), .sup.1H NMR (600 MHz,
CDCl.sub.3) .delta.=8.87 (d, J=7.2 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H),
8.01 (br s, 3H), 7.66 (t, J=8.4 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H),
3.76-3.71 (m, 2H), 3.25-3.23 (m, 1H), 2.91-2.89 (m, 1H), 1.34 (d,
J=7.2 Hz, 3H), 1.30 (d, J=6.6 Hz, 3H), 1.21 (d, J=7.2 Hz, 3H);
.sup.13C NMR (150 MHz, CDCl.sub.3) .delta.=195.1, 164.4, 140.9,
130.6, 129.7, 118.7, 114.7, 107.6, 42.0, 40.7, 27.7, 22.9, 22.3,
16.5; IR (KBr) .nu.=3400, 3369, 2967, 2873, 1630 cm.sup.-1; MS
(FAB+) m/z 247 (M+1, 17.7), 246 (M.sup.+, 100.0), 217 (24.2), 187
(21.5), 161 (71.7), 147 (11.6), 136 (10.9), 91 (10.3), 73 (42.4),
43 (10.0), 30 (22.9); HRMS (FAB+) calcd for
C.sub.14H.sub.20N.sub.3O: 246.1606, found 246.1604. Compound
1065.
Example 78
Synthesis of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-3-(piperidin-1-yl)pro-
pan-1-one hydrochloride
##STR00252##
[0421] 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
(0.500 g, 2.3 mmol) (1.10 g, 5.1 mmol) was dissolved in dry DMF
(8.8 mL). To this solution was added piperidine hydrochloride
(0.985 g, 8.1 mmol) and paraformaldehyde (0.306 g, 10.2 mmol). The
vial was purged with argon, sealed and heated to 85.degree. C. for
16 hours, whereupon all of the starting material had been consumed.
The vial was cooled to room temperature and then diluted with
Et.sub.2O (10 mL) and H.sub.2O (5 mL). The layers were separated
and the pH of the aqueous layer was adjusted to pH 12 before
extracting with Et.sub.2O (5.times.5 mL). The combined organic
layers were then washed with H.sub.2O (5.times.5 mL), brine (10
mL), dried (Na.sub.2SO.sub.4), filtered and concentrated to afford
brown oil (1.88 g). This crude oil was subjected to flash column
chromatography (40% EtOAc/hexane and then 100% MeOH) to yield
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-3-(piperidin-1-yl)pro-
pan-1-one (1.34 g, 84% yield) as yellow oil.
[0422] IR (thin film) .nu.=2965, 2933, 1646, 1630, 1457, 1439;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=8.46 (d, J=6.9 Hz, 1H),
8.08 (d, J=9.0 Hz, 1H), 7.37 (dt, J=9.0, 1.2 Hz, 1H), 6.88 (dt,
J=6.9, 1.2 Hz, 1H), 3.75 (sept, J=6.9 Hz, 1H), 3.57-3.46 (m, 1H),
2.46-2.38 (m, 5H), 1.52-1.45 (m, 4H), 1.40-1.35 (m, 2H), 1.39 (d,
J=6.6 Hz, 3H), 1.38 (d, J=6.9 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta.=198.7, 164.0, 141.4,
129.1, 127.5, 118.9, 11.31, 109.5, 62.0, 54.9, 42.4, 27.7, 25.9,
24.2, 22.4, 22.2, 16.9; MS (EI) m/z 313 (M.sup.+, 2.1), 228 (17.9),
213 (14.0), 187 (30.3), 99 (12.3), 98 (100.0), 97 (17.2), 84
(12.9), 41 (13.2); HRMS (EI) calcd for C.sub.19H.sub.27N.sub.3O:
313.2154, found: 313.2164. To MeOH (1 mL) cooled in an ice bath
under argon was added AcCl (0.18 mL) dropwise.
[0423] This solution was stirred for 10 minutes before adding
dropwise to
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-3-(piperidin-1-yl)pro-
pan-1-one (0.661 g) in dry Et.sub.2O (10 mL), which was also cooled
in an ice bath. Precipitate was formed immediately which was
filtered, washing with Et.sub.2O (4.times.15 mL) affording 0.419 g
of an off-white solid. This solid was then stirred in 20 mL of a
solution containing MeOH (2%), pentane (60%) and EtOAc (38%) for 3
hours. The solvent was then aspirated to afford 323 mg of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methyl-3-(piperidin-1-yl)pro-
pan-1-one hydrochloride as a pure white solid.
[0424] mp=166-167.degree. C. (MeOH, pentane, EtOAc), IR (KBr)
.nu.=3435, 2973, 2953, 2936, 1635, 1503, 1475, 1441, 1185; .sup.1H
NMR (600 MHz, DMSO) .delta.=10.41 (s, 1H), 8.86 (d, J=6.0 Hz, 1H),
8.18 (d, J=9.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.16-7.14 (m, 1H),
4.03-3.95 (m, 1H), 3.79-3.74 (m, 1H), 3.70-3.66 (m, 1H), 3.44 (d,
J=12.0 Hz, 1H), 3.23 (d, J=12.0 Hz, 1H), 3.06 (dt, J=12.0, 3.6 Hz,
1H), 2.98-2.92 (m, 1H), 2.85-2.76 (m, 1H), 1.84-1.77 (m, 1H),
1.75-1.70 (m, 3H), 1.64-1.61 (m, 1H), 1.39-1.33 (m, 1H), 1.31 (d,
J=6.9 Hz, 3H), 1.28 (d, J=6.9 Hz, 3H), 1.22 (d, J=7.3 Hz, 3H);
.sup.13C NMR (150 MHz, DMSO) .delta.=194.0, 164.3, 140.4, 130.1,
129.3, 118.4, 114.3, 106.7, 57.1, 53.5, 52.1, 39.4, 27.2, 22.2,
22.2, 22.1, 21.7, 21.1, 17.6; MS (FAB+) m/z 315 (M+1, 7.7), 314
(M.sup.+, 33.3), 98(100.0); HRMS (FAB+) calcd for
C.sub.19H.sub.28N.sub.3O: 314.2232, found: 314.2169; Anal. Calcd
for C.sub.19H.sub.28N.sub.3OCl: C, 65.22%; H, 8.07%; Found: C,
65.37%; H, 8.09%. Compound 1063.
Example 79
Synthesis of
2-isopropyl-3-(2-methylprop-1-enyl)pyrazolo[1,5-a]pyridine
##STR00253##
[0426] To a solution of 9.2 g of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in
25 ml of MeOH was added 1.5 g of NaBH.sub.4. The solution was
stirred at RT overnight. 10.25 g of oily
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol was
obtained after workup. 1.05 g of
1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-ol in
10 ml of benzene was treated with 0.92 g of PCl.sub.5 and 1 ml of
pyridine with stirring for 3 hours at RT. The crude
2-isopropyl-3-(2-methylprop-1-enyl)pyrazolo[1,5-a]pyridine obtained
was purified on an Al.sub.2O.sub.3 column to furnish 255 mg of pure
compound. Compound 1049.
Example 80
Synthesis of
2-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
##STR00254##
[0428] To 2.51 g of
2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one and
2.25 ml of benzylamine in 20 ml of MeOH was added 10 mg of NaI and
the solution was refluxed for 4 hours, then stirred at RT
overnight. Crude
2-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one
was purified on an Al.sub.2O.sub.3 column to yield 2.51 g of pure
compound. Compound 1071.
[0429] Many modifications and other embodiments of the invention
will come to mind to one skilled in the art to which this invention
pertains having the benefit of the teachings presented in the
foregoing description. Therefore, it is to be understood that the
invention is not to be limited to the specific embodiments
disclosed herein, as such are presented by way of example. The
intent of the foregoing detailed description, although discussing
exemplary embodiments, is to be construed to cover all
modifications, alternatives, and equivalents of the embodiments as
may fall within the spirit and scope of the invention as defined by
the additional disclosure. Although specific terms are employed
herein, they are used in a generic and descriptive sense only and
not for purposes of limitation.
[0430] A number of publications and patents have been cited
hereinabove. Each of the cited publications and patents are hereby
incorporated by reference in their entireties.
* * * * *