U.S. patent application number 12/459224 was filed with the patent office on 2010-02-04 for process for the preparation of benzoimidazol-2-yl pyrimidine derivatives.
Invention is credited to Diego Broggini, Sergio Cesco-Cancian, Jeffrey S. Grimm, Susanne Lochner, Neelakandha S. Mani, Christopher M. Mapes, David C. Palmer, Daniel J. Pippel, Tong Xiao.
Application Number | 20100029942 12/459224 |
Document ID | / |
Family ID | 41426846 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100029942 |
Kind Code |
A1 |
Cesco-Cancian; Sergio ; et
al. |
February 4, 2010 |
Process for the preparation of benzoimidazol-2-yl pyrimidine
derivatives
Abstract
The present invention is directed to benzoimidazol-2-yl
pyrimidine derivatives useful as histamine H.sub.4 receptor
modulators and processes for the preparation of such compounds.
Inventors: |
Cesco-Cancian; Sergio;
(Bethlehem, PA) ; Grimm; Jeffrey S.; (Somerville,
NJ) ; Mani; Neelakandha S.; (San Diego, CA) ;
Mapes; Christopher M.; (La Mesa, CA) ; Palmer; David
C.; (Doylestown, PA) ; Pippel; Daniel J.; (Del
Mar, CA) ; Xiao; Tong; (Edison, NJ) ;
Broggini; Diego; (Zurich, CH) ; Lochner; Susanne;
(Singen, DE) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
41426846 |
Appl. No.: |
12/459224 |
Filed: |
June 29, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61076759 |
Jun 30, 2008 |
|
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|
Current U.S.
Class: |
544/331 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
21/04 20180101; A61P 1/04 20180101; A61P 19/02 20180101; A61P 17/00
20180101; A61P 19/08 20180101; A61P 11/02 20180101; A61P 25/00
20180101; A61P 37/08 20180101; C07D 403/04 20130101; A61P 37/06
20180101; A61P 17/04 20180101; A61P 27/02 20180101; A61P 11/00
20180101; A61P 37/00 20180101; A61P 29/00 20180101; A61P 11/06
20180101; A61P 9/10 20180101; A61P 7/06 20180101; A61P 17/06
20180101; A61P 15/00 20180101 |
Class at
Publication: |
544/331 |
International
Class: |
C07D 401/14 20060101
C07D401/14 |
Claims
1. A process for the preparation of a compound of formula (I)
##STR00033## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
independently selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, phenyl,
--CF.sub.3, --OCF.sub.3, --CN, halo, --NO.sub.2, --OC.sub.1-4alkyl,
--SC.sub.1-4alkyl, --S(O)C.sub.1-4alkyl, --SO.sub.2C.sub.1-4alkyl,
--C(O)C.sub.1-4alkyl, --C(O)phenyl, --C(O)NR.sup.aR.sup.b,
--CO.sub.2C.sub.1-4alkyl, --CO.sub.2H, --C(O)NR.sup.aR.sup.b, and
--NR.sup.aR.sup.b; wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H,
C.sub.1-4alkyl, and C.sub.3-7cycloalkyl; X.sup.1 is C--R.sup.c;
wherein R.sup.c is selected from the group consisting of H, methyl,
hydroxymethyl, dimethylaminomethyl, ethyl, propyl, isopropyl,
--CF.sub.3, cyclopropyl, and cyclobutyl; X.sup.2 is N; n is 1 or 2;
Z is selected from the group consisting of N, CH, and
C(C.sub.1-4alkyl); R.sup.6 is selected from the group consisting of
H, C.sub.1-6alkyl, and a monocyclic cycloalkyl; R.sup.8 is selected
from the group consisting of H and C.sub.1-4alkyl; R.sup.9,
R.sup.10 and R.sup.11 are each independently selected from the
group consisting of H and C.sub.1-4alkyl; or pharmaceutically
acceptable salt, or pharmaceutically acceptable prodrug, or
pharmaceutically active metabolite thereof; comprising ##STR00034##
reacting a compound of formula (V) with a reducing agent system; in
a solvent; at a temperature in the range of from about 0.degree. C.
to about 25.degree. C., to yield compound of formula (VI); and
##STR00035## reacting compound of formula (VI) with a compound of
formula (VII) in the presence of an oxidizing agent system, in a
solvent, at a temperature in the range of from about 25.degree. C.
to about 100.degree. C.
2. A process for the preparation of a compound of formula (I-A)
##STR00036## or pharmaceutically acceptable salt, or
pharmaceutically acceptable prodrug, or pharmaceutically active
metabolite thereof; comprising ##STR00037## reacting a compound of
formula (V-S) with a reducing agent system; in a solvent; at a
temperature in the range of from about 0.degree. C. to about
25.degree. C., to yield compound of formula (VI-S); ##STR00038##
reacting compound of formula (VI-S) with a compound of formula
(VII-A) in the presence of an oxidizing agent system, in a solvent,
at a temperature in the range of from about 25.degree. C. to about
100.degree. C., to yield compound of formula (I-A).
3. A process as in claim 2 wherein the reducing agent system is
selected from the group consisting of Diabl-H, and RANEY.RTM.
nickel and a source of hydrogen.
4. A process as in claim 2, wherein the reducing agent system is
DIBAL-H; wherein the DIBAL-His present in an amount in the range of
from about 1.0 to about 5.0 molar equivalents; and wherein the
solvent in said reacting a compound of formula (V-S) is selected
from the group consisting of anhydrous toluene and anhydrous
THF.
5. A process as in claim 4, wherein DIBAL-His present in an amount
of about 2.5 molar equivalents.
6. A process as in claim 2, wherein the reducing agent system is
RANEY.RTM. nickel and a source of hydrogen; wherein the source of
hydrogen is formic acid; and wherein the solvent in said reacting a
compound of formula (V-S) is water.
7. A process as in claim 6, wherein the RANEY.RTM. nickel is
present in an amount in of about 200% by weight and wherein the
formic acid is present in an excess amount.
8. A process as in claim 2, wherein compound of formula (V-S) is
reacted with the reducing agent system at a temperature of about 5
to about 25.degree. C.
9. A process as in claim 2, wherein compound of formula (VII-A) is
present as its corresponding free base.
10. A process as in claim 2, wherein the compound of formula
(VII-A) is present in an amount in the range of from about 1.0 to
about 1.25 molar equivalents.
11. A process as in claim 10, wherein the compound of formula
(VII-A) is present in an amount in the range of from about 1.0 to
about 1.1 molar equivalents.
12. A process as in claim 2, wherein the oxidizing agent system is
selected from the group consisting of Na.sub.2S.sub.2O.sub.5/air
and Na.sub.2SO.sub.3/air.
13. A process as in claim 2, wherein the oxidizing agent or
oxidizing agent system is present in an amount in the range of from
about 0.90 to about 1.5 molar equivalents.
14. A process as in claim 13, wherein the oxidizing agent system is
present in an amount of about 1.0 molar equivalents.
15. A process as in claim 2, wherein the compound of formula (VI-S)
is reacted with compound of formula (VII-A) in water.
16. A process as in claim 2, wherein the compound of formula (VI-S)
is reacted with compound of formula (VII-A) at a temperature in the
range of from about 55.degree. C. to about 65.degree. C.
17. A process for the preparation of a compound of formula (I-B)
##STR00039## or pharmaceutically acceptable salt, or
pharmaceutically acceptable prodrug, or pharmaceutically active
metabolite thereof; comprising ##STR00040## reacting a compound of
formula (V-S) with a reducing agent system; in a solvent; at a
temperature in the range of from about 0.degree. C. to about
25.degree. C.; to yield compound of formula (VI-S); and
##STR00041## reacting the compound of formula (VI-S) with a
compound of formula (VII-B) in the presence of an oxidizing agent
system, in a solvent at a temperature in the range of from about
25.degree. C. to about 100.degree. C., to yield compound of formula
(I-B).
18. A process as in claim 17, wherein the reducing agent system is
selected from the group consisting of DIBAL-H, and RANEY.RTM.
nickel and a source of hydrogen.
19. A process as in claim 17, wherein the reducing agent system is
DIBAL-H; wherein the DIBAL-His present in an amount in the range of
from about 1.0 to about 5.0 molar equivalents; and wherein the
solvent in said reacting a compound of formula (V-S) is selected
from the group consisting of anhydrous THF and anhydrous
toluene.
20. A process as in claim 19, wherein the DIBAL-His present in an
amount of about 2.5 molar equivalents.
21. A process as in claim 17, wherein the reducing agent system is
RANEY.RTM. nickel and a source of hydrogen; wherein the source of
hydrogen is formic acid; and wherein the solvent in said reacting a
compound of formula (V-S) is water.
22. A process as in claim 21, wherein the RANEY.RTM. nickel is
present in an amount of about 20% by weight and wherein the formic
acid is present in an excess amount.
23. A process as in claim 17, wherein the compound of formula (V-S)
is reacted with the reducing agent system at a temperature of from
about 5.degree. C. to about 25.degree. C.
24. A process as in claim 17, wherein the compound of formula
(VII-B) is present as its corresponding free base.
25. A process as in claim 17, wherein the compound of formula
(VII-B) is present in an amount in the range of from about 1.0 to
about 1.25 molar equivalents.
26. A process as in claim 25, wherein the compound of formula
(VII-B) is present in an amount in the range of from about 1.0 to
about 1.1 molar equivalents.
27. A process as in claim 17, wherein the oxidizing agent system is
selected from the group consisting of Na.sub.2S.sub.2O.sub.5/air
and Na.sub.2SO.sub.3/air.
28. A process as in claim 17, wherein the oxidizing agent system is
present in an amount in the range of from about 0.90 to about 1.5
molar equivalents.
29. A process as in claim 28, wherein the oxidizing agent system is
present in an amount of about 1.0 molar equivalents.
30. A process as in claim 17, wherein the compound of formula
(VI-S) is reacted with the compound of formula (VII-B) in
water.
31. A process as in claim 17, wherein the compound of formula
(VI-S) is reacted with the compound of formula (VII-B) at a
temperature in the range of from about 55.degree. C. to about
65.degree. C.
32. A crystalline hemi-tartrate of compound of formula (I-A)
##STR00042##
33. A crystalline hemi-tartrate of compound of formula (I-A)
##STR00043## whose powder X-ray diffraction spectrum comprises the
following powder X-ray diffraction peaks: TABLE-US-00005 Pos.
[.degree.2.theta.] d-spacing [.ANG.] 6.49 13.62 8.58 10.30 9.17
9.64 10.35 8.55 10.75 8.23 16.72 5.30 17.46 5.08 18.89 4.70 23.60
3.77
34. A process for the preparation of a hemi-tartrate of compound of
formula (I-A) ##STR00044## comprising: dissolving the compound of
formula (I-A) in an organic solvent forming a solution; heating
said solution to a first temperature in the range of from about
35.degree. C. to about reflux; adding L-tartaric acid to form a
tartrate solution; and heating said tartrate solution to a second
temperature in the range of from about 50.degree. C. to about
reflux to form a heated mixture.
35. A process as in claim 34, wherein said heating said first
temperature is about 50.degree. C.
36. A process as in claim 34, wherein the L-tartaric acid is added
in an amount of about 0.5 molar equivalents.
37. A process as in claim 34, wherein said second temperature is a
temperature of about 70.degree. C. to about 75.degree. C.
38. A process as in claim 34, further comprising cooling said
heated mixture to a temperature in the range of from about
0.degree. C. to about -5.degree. C.
39. A process for the recrystallization of a hemi-tartrate of
compound of formula (I-A) ##STR00045## comprising: dissolving the
hemi-tartrate of compound of formula (I-A) in a mixture of water
and an organic solvent, or in a mixture of organic solvents; and
removing a sufficient amount of water to yield a mixture with
boiling point of between about 78.degree. C. and about 80.degree.
C.
40. A process as in claim 39, wherein the hemi-tartrate of compound
of formula (I-A) is dissolved in one of the following mixtures: a
mixture of water and denatured ethanol, and a mixture of methanol
and denatured ethanol.
41. A process as in claim 40, wherein the hemi-tartrate of compound
of formula (I-A) is dissolved in a mixture of water and denatured
ethanol; and wherein the water in the mixture is present in an
amount of from about 1% to about 1.5% by weight.
42. A process as in claim 41, wherein said water is present in an
amount of about 1.4% by weight.
43. A process as in claim 39, wherein said dissolving is made in a
mixture of water and an organic solvent, and further comprising
heating said hemi-tartrate of the compound of formula (I-A) in said
mixture of water and an organic solvent to azeotropically remove
the water.
Description
[0001] This application claims the benefit of U.S. Provisional
Application 61/076,759, filed on Jun. 30, 2008, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to benzoimidazol-2-yl
pyrimidine derivatives useful as histamine H.sub.4 receptor
modulators and processes for the preparation of such compounds.
SUMMARY OF THE INVENTION
[0003] The present invention is directed to a process for the
preparation of compounds of formula (I)
##STR00001##
[0004] wherein
[0005] each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
independently selected from the group consisting of H,
C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, phenyl,
--CF.sub.3, --OCF.sub.3, --CN, halo, --NO.sub.2, --OC.sub.1-4alkyl,
--SC.sub.1-4alkyl, --S(O)C.sub.1-4alkyl, --SO.sub.2C.sub.1-4alkyl,
--C(O)C.sub.1-4alkyl, --C(O)phenyl, --C(O)NR.sup.aR.sup.b,
--CO.sub.2C.sub.1-4alkyl, --CO.sub.2H, --C(O)NR.sup.aR.sup.b, and
--NR.sup.aR.sup.b; wherein R.sup.a and R.sup.b are each
independently selected from the group consisting of H,
C.sub.1-4alkyl, and C.sub.3-7cycloalkyl;
[0006] X.sup.1 is C--R.sup.C; wherein R.sup.c is selected from the
group consisting of H, methyl, hydroxymethyl, dimethylaminomethyl,
ethyl, propyl, isopropyl, --CF.sub.3, cyclopropyl, and cyclobutyl;
and X.sup.2 is N;
[0007] n is 1 or 2;
[0008] Z is selected from the group consisting of N, CH, and
C(C.sub.1-4alkyl);
[0009] R.sup.6 is selected from the group consisting of H,
C.sub.1-6alkyl, and a monocyclic cycloalkyl;
[0010] R.sup.8 is selected from the group consisting of H and
C.sub.1-4alkyl;
[0011] R.sup.9, R.sup.10 and R.sup.11 are each independently
selected from the group consisting of H and C.sub.1-4alkyl;
[0012] and pharmaceutically acceptable salts, pharmaceutically
acceptable prodrugs, and pharmaceutically active metabolites
thereof; comprising
##STR00002##
[0013] reacting a compound of formula (V) with a reducing agent
system; in a solvent; at a temperature in the range of from about
0.degree. C. to about 25.degree. C.; to yield compound of formula
(VI); and
##STR00003##
[0014] reacting compound of formula (VI) with a compound of formula
(VII); in the presence of a suitably selected oxidizing agent or
oxidizing agent system, in water or in an organic solvent, at a
temperature in the range of from about 25.degree. C. to about
100.degree. C.
[0015] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I-A)
##STR00004##
[0016] (also known as
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine) or a pharmaceutically
acceptable salt, or a pharmaceutically acceptable prodrug, or a
pharmaceutically active metabolite thereof; comprising
##STR00005##
[0017] reacting a compound of formula (V-S) with a reducing agent
system; in a solvent; at a temperature in the range of from about
0.degree. C. to about 25.degree. C., to yield compound of formula
(VI-S); and
##STR00006##
[0018] reacting compound of formula (VI-S) with a compound of
formula (VII-A); in the presence of a suitably selected oxidizing
agent or oxidizing agent system, in water or in an organic solvent,
at a temperature in the range of from about 25.degree. C. to about
100.degree. C., to yield compound of formula (I-A).
[0019] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-B)
##STR00007##
[0020] (also known as
[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3--
(1-methyl-piperidin-4-yl)-propyl]-amine) or a pharmaceutically
acceptable salt, or a pharmaceutically acceptable prodrug, or a
pharmaceutically active metabolite thereof; comprising
##STR00008##
[0021] reacting a compound of formula (V-S) with a reducing agent
system; in a solvent; at a temperature in the range of from about
0.degree. C. to about 25.degree. C., to yield compound of formula
(VI-S); and
##STR00009##
[0022] reacting compound of formula (VI-S) with a compound of
formula (VII-B); in the presence of a suitably selected oxidizing
agent or oxidizing agent system, in water or in an organic solvent,
at a temperature in the range of from about 25.degree. C. to about
100.degree. C., to yield compound of formula (I-B).
[0023] The present invention is directed to a product prepared
according to any of the processes described herein. The present
invention is further directed to a crystalline hemi-tartrate of
compound of formula (I-A). The present invention is further
directed to a process for the preparation of a hemi-tartrate of
compound of formula (I-A). The present invention is further
directed to a process for the recrystallization of the
hemi-tartrate of compound of formula (I-A).
[0024] In a further general aspect, the invention relates to
pharmaceutical compositions each comprising: (a) an effective
amount of at least one agent selected from compounds of Formula
(I), prepared according to the process as described herein; and
pharmaceutically acceptable salts, pharmaceutically acceptable
prodrugs, and pharmaceutically active metabolites thereof; and (b)
a pharmaceutically acceptable excipient.
[0025] In another general aspect, the invention is directed to a
method of treating a subject suffering from or diagnosed with a
disease, disorder, or medical condition mediated by histamine
H.sub.4 receptor activity, comprising administering to the subject
in need of such treatment an effective amount of at least one
compound of Formula (I), or a pharmaceutically acceptable salt,
pharmaceutically acceptable prodrug, or pharmaceutically active
metabolite of such compound, wherein compound of formula (I),
pharmaceutically acceptable salt, prodrug or metabolite thereof is
prepared according to the process as described herein. In certain
embodiments of the inventive method, the disease, disorder, or
medical condition is inflammation. Inflammation herein refers to
the response that develops as a consequence of histamine release,
which in turn is caused by at least one stimulus. Examples of such
stimuli are immunological stimuli and non-immunological
stimuli.
[0026] In another general aspect, the invention is directed to a
method for modulating histamine H.sub.4 receptor activity,
comprising exposing histamine H.sub.4 receptor to an effective
amount of at least one of a compound of Formula (I) and a
pharmaceutically acceptable salt, prodrug or metabolite thereof;
wherein compound of formula (I), pharmaceutically acceptable salt,
prodrug or metabolite thereof is prepared according to the process
as described herein.
[0027] Additional embodiments, features, and advantages of the
invention will be apparent from the following detailed description
and through practice of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0028] FIG. 1 illustrates a powder X-ray diffraction (XRD) pattern
for a crystalline hemi-tartrate of compound of formula (I-A).
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention is directed to a process for the
preparation of compound of formula (I)
##STR00010##
[0030] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X.sup.1,
X.sup.2, R.sup.6, R.sup.8, Z, n, R.sup.9, R.sup.10 and R.sup.11 are
as herein defined. Embodiments of compounds of the present
invention are useful as histamine H.sub.4 receptor modulators.
[0031] In an embodiment of the present invention, compound of
formula (I) is selected from the group consisting of a compound of
formula (I-A)
##STR00011##
[0032] and pharmaceutically acceptable salts thereof; and a
compound of formula (I-B)
##STR00012##
[0033] and pharmaceutically acceptable salts thereof.
[0034] In some embodiments of compounds of Formula (I), each of
R.sup.1-4 is independently H, methyl, tert-butyl, methoxy,
--CF.sub.3, --CN, fluoro, chloro, methoxycarbonyl, or benzoyl. In
some embodiments, X.sup.2 is N. In other embodiments, X.sup.1 is N.
In some embodiments, R.sup.c is H, methyl, ethyl, CF.sub.3,
cyclopropyl, or cyclobutyl. In further embodiments, R.sup.c is H or
methyl. In some embodiments, n is 1. In some embodiments, Z is N or
CH. In further embodiments, Z is CH. In some embodiments, R.sup.6
is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.
In further embodiments, R.sup.6 is H or methyl. In some
embodiments, R.sup.8 is H. In some embodiments, R.sup.9 and
R.sup.10 are each independently H or methyl. In further
embodiments, R.sup.9 and R.sup.10 are both H. In some embodiments,
R.sup.11 is H or methyl. In further embodiments, R.sup.11 is
methyl.
[0035] In an embodiment, the present invention is directed to a
process for the preparation of compounds of formula (I)
##STR00013##
[0036] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X.sup.1,
X.sup.2, R.sup.6, R.sup.8, R.sup.9, R.sup.10, R.sup.11 and n are as
herein defined; and pharmaceutically acceptable salts,
pharmaceutically acceptable prodrugs, and pharmaceutically active
metabolites thereof; comprising
##STR00014##
[0037] reacting a compound of formula (VI) with a compound of
formula (VII); in the presence of a suitably selected oxidizing
agent or oxidizing agent system, in water or in an organic solvent,
at a temperature in the range of from about 25.degree. C. to about
100.degree. C.; to yield the compound of formula (I).
[0038] In another embodiment, the present invention is directed to
a process for the preparation of a compound of formula (I-A)
##STR00015##
[0039] (also known as
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine) or a pharmaceutically
acceptable salt, or a pharmaceutically acceptable prodrug, or a
pharmaceutically active metabolite thereof; comprising
##STR00016##
[0040] reacting a compound of formula (VI-S) with a compound of
formula (VII-A); in the presence of a suitably selected oxidizing
agent or oxidizing agent system, in water or in an organic solvent,
at a temperature in the range of from about 25.degree. C. to about
100.degree. C., to yield compound of formula (I-A).
[0041] In yet another embodiment, the present invention is directed
to a process for the preparation of a compound of formula (I-B)
##STR00017##
[0042] (also known as
[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3--
(1-methyl-piperidin-4-yl)-propyl]-amine) or a pharmaceutically
acceptable salt, or a pharmaceutically acceptable prodrug, or a
pharmaceutically active metabolite thereof; comprising
##STR00018##
[0043] reacting a compound of formula (VI-S) with a compound of
formula (VII-B); in the presence of a suitably selected oxidizing
agent or oxidizing agent system, in water or in an organic solvent,
at a temperature in the range of from about 25.degree. C. to about
100.degree. C., to yield compound of formula (I-B).
[0044] The invention may be more fully appreciated by reference to
the following description, including the following glossary of
terms and the concluding examples. For the sake of brevity, the
disclosures of the publications, including patents, cited in this
specification are herein incorporated by reference.
[0045] As used herein, the terms "including", "containing" and
"comprising" are used herein in their open, non-limiting sense.
[0046] The terms "halogen" and "halo" represents chlorine,
fluorine, bromine, or iodine. The term "halo" represents chloro,
fluoro, bromo, or iodo.
[0047] The term "alkyl" refers to a straight- or branched-chain
alkyl group having from 1 to 12 carbon atoms in the chain. Examples
of alkyl groups include methyl (Me, which also may be structurally
depicted by the symbol "/"), ethyl (Et), n-propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl,
tert-pentyl, hexyl, isohexyl, and groups that in light of the
ordinary skill in the art and the teachings provided herein would
be considered equivalent to any one of the foregoing examples.
[0048] The term "alkenyl" refers to a straight- or branched-chain
alkenyl group having from 2 to 12 carbon atoms in the chain. (The
double bond of the alkenyl group is formed by two sp.sup.2
hybridized carbon atoms.) Illustrative alkenyl groups include
prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl,
hex-2-enyl, and groups that in light of the ordinary skill in the
art and the teachings provided herein would be considered
equivalent to any one of the foregoing examples.
[0049] The term "cycloalkyl" refers to a saturated or partially
saturated, monocyclic, fused polycyclic, or spiro polycyclic
carbocycle having from 3 to 12 ring atoms per carbocycle.
Illustrative examples of cycloalkyl groups include the following
entities, in the form of properly bonded moieties:
##STR00019##
[0050] When a particular group is "substituted" (e.g., alkyl,
cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group
may have one or more substituents, for example, from one to five
substituents, or from one to three substituents, or one to two
substituents, independently selected from the list of
substituents.
[0051] With reference to substituents, the term "independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0052] Any formula given herein is intended to represent compounds
having structures depicted by the structural formula as well as
certain variations or forms. In particular, compounds of any
formula given herein may have asymmetric centers and therefore
exist in different enantiomeric forms. All optical isomers and
stereoisomers of the compounds of the general formula, and mixtures
thereof, are considered within the scope of the formula. Thus, any
formula given herein is intended to represent a racemate, one or
more enantiomeric forms, one or more diastereomeric forms, one or
more atropisomeric forms, and mixtures thereof.
[0053] Furthermore, certain structures may exist as geometric
isomers (i.e., cis and trans isomers), as tautomers, or as
atropisomers. Additionally, any formula given herein is intended to
represent hydrates, solvates, and polymorphs of such compounds, and
mixtures thereof.
[0054] Reference to a chemical entity herein stands for a reference
to any one of: (a) the actually recited form of such chemical
entity, and (b) any of the forms of such chemical entity in the
medium in which the compound is being considered when named. For
example, reference herein to a compound such as R--COOH,
encompasses reference to any one of, for example, R--COOH(s),
R--COOH.sub.(sol), and R--COO.sup.-.sub.(sol). In this example,
R--COOH(s) refers to the solid compound, as it could be for example
in a tablet or some other solid pharmaceutical composition or
preparation; R--COOH.sub.(sol) refers to the undissociated form of
the compound in a solvent; and R--COO.sup.-.sub.(sol) refers to the
dissociated form of the compound in a solvent, such as the
dissociated form of the compound in an aqueous environment, whether
such dissociated form derives from R--COOH, from a salt thereof, or
from any other entity that yields R--COO.sup.- upon dissociation in
the medium being considered. In another example, an expression such
as "exposing an entity to compound of formula R--COOH"refers to the
exposure of such entity to the form, or forms, of the compound
R--COOH that exists, or exist, in the medium in which such exposure
takes place. In this regard, if such entity is for example in an
aqueous environment, it is understood that the compound R--COOH is
in such same medium, and therefore the entity is being exposed to
species such as R--COOH.sub.(aq) and/or R--COO.sup.-.sub.(aq),
where the subscript "(aq)" stands for "aqueous" according to its
conventional meaning in chemistry and biochemistry. A carboxylic
acid functional group has been chosen in these nomenclature
examples; this choice is not intended, however, as a limitation but
it is merely an illustration. It is understood that analogous
examples can be provided in terms of other functional groups,
including but not limited to hydroxyl, basic nitrogen members, such
as those in amines, and any other group that interacts or
transforms according to known manners in the medium that contains
the compound. Such interactions and transformations include, but
are not limited to, dissociation, association, tautomerism,
solvolysis, including hydrolysis, solvation, including hydration,
protonation, and deprotonation. In another example, a zwitterionic
compound is encompassed herein by referring to a compound that is
known to form a zwitterions, even if it is not explicitly named in
its zwitterionic form. Terms such as zwitterion, zwitterions, and
their synonyms zwitterionic compound(s) are standard IUPAC-endorsed
names that are well known and part of standard sets of defined
scientific names. In this regard, the name zwitterion is assigned
the name identification CHEBI:27369 by the Chemical Entities of
Biological Interest (ChEBI) dictionary of molecular entities. (See,
for example its on line version at
http://www.ebi.ac.uk/chebi/init.do). As generally well known, a
zwitterion or zwitterionic compound is a neutral compound that has
formal unit charges of opposite sign. Sometimes these compounds are
referred to by the term "inner salts". Other sources refer to these
compounds as "dipolar ions", although the latter term is regarded
by still other sources as a misnomer. As a specific example,
aminoethanoic acid (the amino acid glycine) has the formula
H.sub.2NCH.sub.2COOH, and it exists in some media (in this case in
neutral media) in the form of the zwitterion
.sup.+H.sub.3NCH.sub.2COO.sup.-. Zwitterions, zwitterionic
compounds, inner salts and dipolar ions in the known and well
established meanings of these terms are within the scope of this
invention, as would in any case be so appreciated by those of
ordinary skill in the art. Because there is no need to name each
and every embodiment that would be recognized by those of ordinary
skill in the art, no structures of the zwitterionic compounds that
are associated with the compounds of this invention are given
explicitly herein. They are, however, part of the embodiments of
this invention when compounds referred to herein can form
zwitterions. No further examples in this regard are provided herein
because these interactions and transformations in a given medium
are known by any one of ordinary skill in the art.
[0055] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, chlorine, and iodine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18O,
.sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.1F, .sup.38Cl,
.sup.125I, respectively. Such isotopically labelled compounds are
useful in metabolic studies (for example with .sup.14C), reaction
kinetic studies (with, for example .sup.2H or .sup.3H), detection
or imaging techniques [such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT)] including
drug or substrate tissue distribution assays, or in radioactive
treatment of patients. In particular, an .sup.18F or .sup.11C
labeled compound may be particularly preferred for PET or SPECT
studies. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements. Isotopically
labeled compounds of this invention and prodrugs thereof can
generally be prepared by carrying out the procedures disclosed in
the schemes or in the examples and preparations described below by
substituting a readily available isotopically labeled reagent for a
non-isotopically labeled reagent.
[0056] When referring to any formula given herein, the selection of
a particular moiety from a list of possible species for a specified
variable is not intended to define the same choice of the species
for the variable appearing elsewhere. In other words, where a
variable appears more than once, the choice of the species from a
specified list is independent of the choice of the species for the
same variable elsewhere in the formula, unless stated
otherwise.
[0057] By way of a first example on substituent terminology, if
substituent S.sup.1.sub.example is one of S.sub.1 and S.sub.2, and
substituent S.sup.2.sub.example is one of S.sub.3 and S.sub.4, then
these assignments refer to embodiments of this invention given
according to the choices S.sup.1.sub.example is S.sub.1 and
S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is S.sup.1 and
S.sup.2.sub.example is S.sub.4; S.sup.1.sub.example is S.sub.2 and
S.sup.2.sub.example is S.sub.4; and equivalents of each one of such
choices. The shorter terminology "S.sup.1.sub.example is one of
S.sub.1 and S.sub.2, and S.sup.2.sub.example is one of S.sub.3 and
S.sub.4" is accordingly used herein for the sake of brevity, but
not by way of limitation. The foregoing first example on
substituent terminology, which is stated in generic terms, is meant
to illustrate the various substituent assignments described herein.
The foregoing convention given herein for substituents extends,
when applicable, to members such as R.sup.1-11, X.sup.1, X.sup.2,
and n, and any other generic substituent symbol used herein.
[0058] Furthermore, when more than one assignment is given for any
member or substituent, embodiments of this invention comprise the
various groupings that can be made from the listed assignments,
taken independently, and equivalents thereof. By way of a second
example on substituent terminology, if it is herein described that
substituent S.sub.example is one of S.sub.1, S.sub.2, and S.sub.3,
this listing refers to embodiments of this invention for which
S.sub.example is S.sub.1; S.sub.example is S.sub.2; S.sub.example
is S.sub.3; S.sub.example is one of S.sub.1 and S.sub.2;
S.sub.example is one of S.sub.1 and S.sub.3; S.sub.example is one
of S.sub.2 and S.sub.3; S.sub.example is one of S.sub.1, S.sub.2
and S.sub.3; and S.sub.example is any equivalent of each one of
these choices. The shorter terminology "S.sub.example is one of
S.sub.1, S.sub.2, and S.sub.3" is accordingly used herein for the
sake of brevity, but not by way of limitation. The foregoing second
example on substituent terminology, which is stated in generic
terms, is meant to illustrate the various substituent assignments
described herein. The foregoing convention given herein for
substituents extends, when applicable, to members such as
R.sup.1-11, X.sup.1, X.sup.2, and n, and any other generic
substituent symbol used herein.
[0059] The nomenclature "C.sub.i-j" with j>i, when applied
herein to a class of substituents, is meant to refer to embodiments
of this invention for which each and every one of the number of
carbon members, from i to j including i and j, is independently
realized. By way of example, the term C.sub.1-3 refers
independently to embodiments that have one carbon member (C.sub.1),
embodiments that have two carbon members (C.sub.2), and embodiments
that have three carbon members (C.sub.3).
[0060] The term C.sub.n-malkyl refers to an aliphatic chain,
whether straight or branched, with a total number N of carbon
members in the chain that satisfies n.ltoreq.N.ltoreq.m, with
m>n.
[0061] Any disubstituent referred to herein is meant to encompass
the various attachment possibilities when more than one of such
possibilities are allowed. For example, reference to disubstituent
-A-B--, where A.noteq.B, refers herein to such disubstituent with A
attached to a first substituted member and B attached to a second
substituted member, and it also refers to such disubstituent with A
attached to the second substituted member and B attached to the
first substituted member.
[0062] According to the foregoing interpretive considerations on
assignments and nomenclature, it is understood that explicit
reference herein to a set implies, where chemically meaningful and
unless indicated otherwise, independent reference to embodiments of
such set, and reference to each and every one of the possible
embodiments of subsets of the set referred to explicitly.
[0063] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula
##STR00020##
[0064] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows
[0065] DDQ=2,3-Dichloro-5,6-dicyanobenzoquinone
[0066] Dibal-H, DIBAL-H=Diisobutylaluminum hydride
[0067] DMA=Dimethylacetamide
[0068] DME=1,2-Dimethoxyethane
[0069] DMF=N,N-Dimethylformamide
[0070] EtOH=Ethanol
[0071] HPLC=High Pressure Liquid Chromatography
[0072] IPA=Isopropyl alcohol
[0073] 2-Me-THF=2-Methyl-tetrahydrofuran
[0074] MTBE=Methyl-t-butyl ether
[0075] NMM=N-Methylmorpholine
[0076] NMP=1-Methyl-2-pyrrolidinone
[0077] OXONE.RTM.=Potassium monopersulphate triple salt
[0078] RANEY.RTM. Nickel=Aluminum-nickel alloy
[0079] Red-AI=Sodium bis(2-methoxyethoxy)aluminum hydride
[0080] TEA=Triethylamine
[0081] TEMPO.RTM.=[2,2,6,6-tetramethyl-1-piperidinyloxy free
radical]
[0082] THF=Tetrahydrofuran
[0083] XRD=X-Ray Diffraction
[0084] As used herein, unless otherwise noted, the term "isolated
form" shall mean that the compound is present in a form which is
separate from any solid mixture with another compound(s), solvent
system or biological environment. In an embodiment of the present
invention, compound of formula (I) is prepared as an isolated form.
In another embodiment of the present invention, compound of formula
(I-A) is prepared as an isolated form. In another embodiment of the
present invention, compound of formula (I-B) is prepared as an
isolated form.
[0085] As used herein, unless otherwise noted, the term
"substantially pure" shall mean that the mole percent of impurities
in the isolated compound is less than about 5 mole percent, for
example, at less than about 2 mole percent. In an embodiment, the
mole percent of impurities is less than about 0.5 mole percent, for
example, less than about 0.1 mole percent. In an embodiment of the
present invention, compound of formula (I) is prepared as a
substantially pure compound. In another embodiment of the present
invention, compound of formula (I-A) is prepared a substantially
pure compound. In another embodiment of the present invention,
compound of formula (I-B) is prepared a substantially pure
compound.
[0086] As used herein, unless otherwise noted, the term
"substantially free of a corresponding salt(s)" when used to
described compound of formula (I) shall mean that mole percent of
the corresponding salt form(s) in the isolated base of formula (I)
is less than about 5 mole percent, for example, less than about 2
mole percent. In an embodiment, the mole percent of the
corresponding salt form(s) is less than about 0.5 mole percent, for
example, less than about 0.1 mole percent. In an embodiment of the
present invention, compound of formula (I) is prepared in a form
which is substantially free of corresponding salt. In another
embodiment of the present invention, compound of formula (I-A) is
prepared in a form which is substantially free of corresponding
salt. In another embodiment of the present invention, compound of
formula (I-B) is prepared in a form which is substantially free of
corresponding salt.
[0087] The invention includes also pharmaceutically acceptable
salts of the compounds represented by Formula (I), for example
those described above and of the specific compounds exemplified
herein.
[0088] A "pharmaceutically acceptable salt" is intended to mean a
salt of a free acid or base of a compound represented by Formula
(I) that is non-toxic, biologically tolerable, or otherwise
biologically suitable for administration to the subject. See,
generally, S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm.
Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts,
Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH
and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable
salts are those that are pharmacologically effective and suitable
for contact with the tissues of patients without undue toxicity,
irritation, or allergic response. A compound of Formula (I) may
possess a sufficiently acidic group, a sufficiently basic group, or
both types of functional groups, and accordingly react with a
number of inorganic or organic bases, and inorganic and organic
acids, to form a pharmaceutically acceptable salt. Examples of
pharmaceutically acceptable salts include sulfates, pyrosulfates,
bisulfates, sulfites, bisulfites, phosphates,
monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,
pyrophosphates, chlorides, bromides, iodides, acetates,
propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycolates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0089] If compound of Formula (I) contains a basic nitrogen, the
desired pharmaceutically acceptable salt may be prepared by any
suitable method available in the art, for example, treatment of the
free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric
acid, phosphoric acid, and the like, or with an organic acid, such
as acetic acid, phenylacetic acid, propionic acid, stearic acid,
lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid,
isethionic acid, succinic acid, valeric acid, fumaric acid, malonic
acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,
oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such
as mandelic acid, citric acid, or tartaric acid, an amino acid,
such as aspartic acid or glutamic acid, an aromatic acid, such as
benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic
acid, a sulfonic acid, such as laurylsulfonic acid,
p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid,
any compatible mixture of acids such as those given as examples
herein, and any other acid and mixture thereof that are regarded as
equivalents or acceptable substitutes in light of the ordinary
level of skill in this technology.
[0090] If compound of Formula (I) is an acid, such as a carboxylic
acid or sulfonic acid, the desired pharmaceutically acceptable salt
may be prepared by any suitable method, for example, treatment of
the free acid with an inorganic or organic base, such as an amine
(primary, secondary or tertiary), an alkali metal hydroxide,
alkaline earth metal hydroxide, any compatible mixture of bases
such as those given as examples herein, and any other base and
mixture thereof that are regarded as equivalents or acceptable
substitutes in light of the ordinary level of skill in this
technology. Illustrative examples of suitable salts include organic
salts derived from amino acids, such as glycine and arginine,
ammonia, carbonates, bicarbonates, primary, secondary, and tertiary
amines, and cyclic amines, such as pyrrolidines, piperidine,
morpholine, and piperazine, and inorganic salts derived from
sodium, calcium, potassium, magnesium, manganese, iron, copper,
zinc, aluminum, and lithium.
[0091] The invention also relates to treatment methods employing
pharmaceutically acceptable prodrugs of compounds of Formula (I).
The term "prodrug" means a precursor of a designated compound that,
following administration to a subject, yields the compound in vivo
via a chemical or physiological process such as solvolysis or
enzymatic cleavage, or under physiological conditions (e.g., a
prodrug on being brought to physiological pH is converted to
compound of Formula (I)). A "pharmaceutically acceptable prodrug"
is a prodrug that is not toxic, biologically intolerable, or
otherwise biologically unsuitable for administration to the
subject. Illustrative procedures for the selection and preparation
of suitable prodrug derivatives are described, for example, in
"Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[0092] Examples of prodrugs include compounds having an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or
four) amino acid residues, covalently joined through an amide or
ester bond to a free amino, hydroxy, or carboxylic acid group of a
compound of Formula (I). Examples of amino acid residues include
the twenty naturally occurring amino acids, commonly designated by
three letter symbols, as well as 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine,
ornithine and methionine sulfone.
[0093] Additional types of prodrugs may be produced, for instance,
by derivatizing free carboxyl groups of structures of Formula (I)
as amides or alkyl esters. Examples of amides include those derived
from ammonia, primary C.sub.1-6alkyl amines and secondary
di(C.sub.1-6alkyl) amines. Secondary amines include 5- or
6-membered heterocycloalkyl or heteroaryl ring moieties. Examples
of amides include those that are derived from ammonia,
C.sub.1-3alkyl primary amines, and di(C.sub.1-2alkyl)amines.
Examples of esters of the invention include C.sub.1-7alkyl,
C.sub.5-7cycloalkyl, phenyl, and phenyl(C.sub.1-6alkyl) esters.
Preferred esters include methyl esters. Prodrugs may also be
prepared by derivatizing free hydroxy groups using groups including
hemisuccinates, phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, following procedures such as those
outlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate
derivatives of hydroxy and amino groups may also yield prodrugs.
Carbonate derivatives, sulfonate esters, and sulfate esters of
hydroxy groups may also provide prodrugs. Derivatization of hydroxy
groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the
acyl group may be an alkyl ester, optionally substituted with one
or more ether, amine, or carboxylic acid functionalities, or where
the acyl group is an amino acid ester as described above, is also
useful to yield prodrugs. Prodrugs of this type may be prepared as
described in J. Med. Chem. 1996, 39, 10. Free amines can also be
derivatized as amides, sulfonamides or phosphonamides. All of these
prodrug moieties may incorporate groups including ether, amine, and
carboxylic acid functionalities.
[0094] Pharmaceutically active metabolites may also be used in the
methods of the invention. A "pharmaceutically active metabolite"
means a pharmacologically active product of metabolism in the body
of a compound of Formula (I) or salt thereof. Prodrugs and active
metabolites of a compound may be determined using routine
techniques known or available in the art. See, e.g., Bertolini, et
al., J. Med. Chem. 1997, 40, 2011-2016; Shan, et al., J. Pharm.
Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34,
220-230; Bodor, Adv. Drug Res. 1984, 13, 224-331; Bundgaard, Design
of Prodrugs (Elsevier Press, 1985); and Larsen, Design and
Application of Prodrugs, Drug Design and Development
(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers,
1991).
[0095] The compounds of Formula (I) and their pharmaceutically
acceptable salts, pharmaceutically acceptable prodrugs, and
pharmaceutically active metabolites (collectively, "agents") of the
present invention are useful as histamine H.sub.4 receptor
modulators in the methods of the invention. The agents may be used
in the inventive methods for the treatment or prevention of medical
conditions, diseases, or disorders mediated through modulation of
the histamine H.sub.4 receptor, such as those described herein.
Agents according to the invention may therefore be used as an
anti-inflammatory agents. Symptoms or disease states are intended
to be included within the scope of "medical conditions, disorders,
or diseases."
[0096] Accordingly, the invention relates to methods of using the
pharmaceutical agents described herein to treat subjects diagnosed
with or suffering from a disease, disorder, or condition mediated
through histamine H.sub.4 receptor activity, such as
inflammation.
[0097] In another embodiment, an agent of the present invention is
administered to treat inflammation. Inflammation may be associated
with various diseases, disorders, or conditions, such as
inflammatory disorders, allergic disorders, dermatological
disorders, autoimmune disease, lymphatic disorders, and
immunodeficiency disorders, including the more specific conditions
and diseases given below. Regarding the onset and evolution of
inflammation, inflammatory diseases or inflammation-mediated
diseases or conditions include, but are not limited to, acute
inflammation, allergic inflammation, and chronic inflammation.
[0098] Illustrative types of inflammation treatable with a
histamine H.sub.4 receptor-modulating agent according to the
invention include inflammation due to or associated with any one of
a plurality of conditions such as allergy, asthma, dry eye, chronic
obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid
arthritis, multiple sclerosis, inflammatory bowel diseases
(including colitis, Crohn's disease, and ulcerative colitis),
psoriasis, pruritis, itchy skin, atopic dermatitis, urticaria
(hives), ocular inflammation, conjunctivitis, nasal polyps,
allergic rhinitis, nasal itch, scleroderma, autoimmune thyroid
diseases, immune-mediated (also known as type 1) diabetes mellitus
and lupus, which are characterized by excessive or prolonged
inflammation at some stage of the disease. Other autoimmune
diseases that lead to inflammation include Myasthenia gravis,
autoimmune neuropathies, such as Guillain-Barre, autoimmune
uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune
thrombocytopenia, temporal arteritis, anti-phospholipid syndrome,
vasculitides, such as Wegener's granulomatosis, Behcet's disease,
dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary
biliary cirrhosis, autoimmune hepatitis, autoimmune oophoritis and
orchitis, autoimmune disease of the adrenal gland, polymyositis,
dermatomyositis, spondyloarthropathies, such as ankylosing
spondylitis, and Sjogren's syndrome.
[0099] Pruritis with a histamine H.sub.4 receptor-modulating agent
according to the invention includes that which is a symptom of
allergic cutaneous diseases (such as atopic dermatitis and hives)
and other metabolic disorders (such as chronic renal failure,
hepatic cholestasis, and diabetes mellitus).
[0100] In another embodiment, an agent of the present invention is
administered to treat allergy, asthma, autoimmune diseases, or
pruritis.
[0101] The term "treat" or "treating" as used herein is intended to
refer to administration of an agent or composition of the invention
to a subject for the purpose of effecting a therapeutic or
prophylactic benefit through modulation of histamine H.sub.4
receptor activity. Treating includes reversing, ameliorating,
alleviating, inhibiting the progress of, lessening the severity of,
or preventing a disease, disorder, or condition, or one or more
symptoms of such disease, disorder or condition mediated through
modulation of histamine H.sub.4 receptor activity. The term
"subject" refers to a mammalian patient in need of such treatment,
such as a human. "Modulators" include both inhibitors and
activators, where "inhibitors" refer to compounds that decrease,
prevent, inactivate, desensitize or down-regulate histamine H.sub.4
receptor expression or activity, and "activators" are compounds
that increase, activate, facilitate, sensitize, or up-regulate
histamine H.sub.4 receptor expression or activity.
[0102] In treatment methods according to the invention, an
effective amount of at least one pharmaceutical agent according to
the invention is administered to a subject suffering from or
diagnosed as having such a disease, disorder, or condition. An
"effective amount" means an amount or dose sufficient to generally
bring about the desired therapeutic or prophylactic benefit in
patients in need of such treatment for the designated disease,
disorder, or condition. Effective amounts or doses of the agents of
the present invention may be ascertained by routine methods such as
modeling, dose escalation studies or clinical trials, and by taking
into consideration routine factors, e.g., the mode or route of
administration or drug delivery, the pharmacokinetics of the agent,
the severity and course of the disease, disorder, or condition, the
subject's previous or ongoing therapy, the subject's health status
and response to drugs, and the judgment of the treating physician.
An example of a dose is in the range of from about 0.01 to about
200 mg of agent per kg of subject's body weight per day, or any
range therein; for example about 0.05 to 100 mg/kg/day, or any
range therein; or for example, about 1 to 35 mg/kg/day, or any
range therein; in single or divided dosage units (e.g., BID, TID,
QID). For a 70-kg human, an illustrative range for a suitable
dosage amount is from about 0.05 to about 7 g/day, or any range
therein; for example about 0.1 to about 2.5 g/day, or any range
therein; for example 0.2 to about 1.0 g/day, or any range
therein.
[0103] Once improvement of the patient's disease, disorder, or
condition has occurred, the dose may be adjusted for preventative
or maintenance treatment. For example, the dosage or the frequency
of administration, or both, may be reduced as a function of the
symptoms, to a level at which the desired therapeutic or
prophylactic effect is maintained. Of course, if symptoms have been
alleviated to an appropriate level, treatment may cease. Patients
may, however, require intermittent treatment on a long-term basis
upon any recurrence of symptoms.
[0104] In addition, the agents of the invention may be used in
combination with additional active compounds in the treatment of
the above conditions. The additional compounds may be
coadministered separately with an agent of Formula (I) or included
with such an agent as an additional active ingredient in a
pharmaceutical composition according to the invention. In an
illustrative embodiment, additional active compounds are those that
are known or discovered to be effective in the treatment of
conditions, disorders, or diseases mediated by histamine H.sub.4
receptor activity, such as another histamine H.sub.4 receptor
modulator or a compound active against another target associated
with the particular condition, disorder, or disease. The
combination may serve to increase efficacy (e.g., by including in
the combination a compound potentiating the potency or
effectiveness of an agent according to the invention), decrease one
or more side effects, or decrease the required dose of the agent
according to the invention.
[0105] When referring to modulating the target receptor, an
"effective amount" means an amount sufficient to affect the
activity of such receptor. Measuring the activity of the target
receptor may be performed by routine analytical methods. Target
receptor modulation is useful in a variety of settings, including
assays.
[0106] The agents of the invention are used, alone or in
combination with one or more other active ingredients, to formulate
pharmaceutical compositions of the invention. A pharmaceutical
composition of the invention comprises an effective amount of at
least one pharmaceutical agent in accordance with the invention. A
pharmaceutically acceptable excipient is part of some embodiments
of pharmaceutical compositions according to this invention.
[0107] A "pharmaceutically acceptable excipient" refers to a
substance that is not toxic, biologically intolerable, or otherwise
biologically unsuitable for administration to a subject, such as an
inert substance, added to a pharmacological composition or
otherwise used as a vehicle, carrier, or diluent to facilitate
administration of a pharmaceutical agent and that is compatible
therewith. Examples of excipients include calcium carbonate,
calcium phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils, and polyethylene glycols.
[0108] Delivery forms of the pharmaceutical compositions containing
one or more dosage units of the pharmaceutical agents may be
prepared using suitable pharmaceutical excipients and compounding
techniques known or that become available to those of ordinary
skill in the art. The compositions may be administered in the
inventive methods by a suitable route of delivery, e.g., oral,
parenteral, rectal, topical, or ocular routes, or by
inhalation.
[0109] The preparation may be in the form of tablets, capsules,
sachets, dragees, powders, granules, lozenges, powders for
reconstitution, liquid preparations, or suppositories. In an
example, the compositions are formulated for intravenous infusion,
topical administration, or oral administration.
[0110] For oral administration, the compounds of the invention can
be provided in the form of tablets or capsules, or as a solution,
emulsion, or suspension. To prepare the oral compositions, the
agents may be formulated to yield a dosage of, e.g., from about
0.01 to about 200 mg/kg daily, or any range therein; for example
from about 0.05 to about 100 mg/kg daily, or any range therein; or
for example from about 0.05 to about 50 mg/kg daily, or any range
therein; or for example from about 0.05 to about 25 mg/kg/day, or
any range therein; or for example, from about 0.1 to about 10
mg/kg/day, or any range therein.
[0111] Oral tablets may include the agent and any other active
ingredients mixed with compatible pharmaceutically acceptable
excipients such as diluents, disintegrating agents, binding agents,
lubricating agents, sweetening agents, flavoring agents, coloring
agents and preservative agents. Suitable inert fillers include
sodium and calcium carbonate, sodium and calcium phosphate,
lactose, starch, sugar, glucose, methyl cellulose, magnesium
stearate, mannitol, sorbitol, and the like. Examples of liquid oral
excipients include ethanol, glycerol, water, and the like. Starch,
polyvinyl-pyrrolidone (PVP), sodium starch glycolate,
microcrystalline cellulose, and alginic acid are examples of
disintegrating agents. Binding agents may include starch and
gelatin. The lubricating agent, if present, may be magnesium
stearate, stearic acid or talc. If desired, the tablets may be
coated with a material such as glyceryl monostearate or glyceryl
distearate to delay absorption in the gastrointestinal tract, or
may be coated with an enteric coating.
[0112] Capsules for oral administration include hard and soft
gelatin capsules. To prepare hard gelatin capsules, active
ingredient may be mixed with a solid, semi-solid, or liquid
diluent. Soft gelatin capsules may be prepared by mixing the active
ingredient with water, an oil such as peanut oil or olive oil,
liquid paraffin, a mixture of mono and di-glycerides of short chain
fatty acids, polyethylene glycol 400, or propylene glycol.
[0113] Liquids for oral administration may be in the form of
suspensions, solutions, emulsions or syrups or may be lyophilized
or presented as a dry product for reconstitution with water or
other suitable vehicle before use. Such liquid compositions may
optionally contain: pharmaceutically-acceptable excipients such as
suspending agents (for example, sorbitol, methyl cellulose, sodium
alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
aluminum stearate gel and the like); non-aqueous vehicles, e.g.,
oil (for example, almond oil or fractionated coconut oil),
propylene glycol, ethyl alcohol, or water; preservatives (for
example, methyl or propyl p-hydroxybenzoate or sorbic acid);
wetting agents such as lecithin; and, if desired, flavoring or
coloring agents.
[0114] The active agents of this invention may also be administered
by non-oral routes. For example, the compositions may be formulated
for rectal administration as a suppository. For parenteral use,
including intravenous, intramuscular, intraperitoneal, or
subcutaneous routes, the agents of the invention may be provided in
sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity or in parenterally acceptable oil.
Suitable aqueous vehicles include Ringer's solution and isotonic
sodium chloride. Such forms may be presented in unit-dose form such
as ampules or disposable injection devices, in multi-dose forms
such as vials from which the appropriate dose may be withdrawn, or
in a solid form or pre-concentrate that can be used to prepare an
injectable formulation. Illustrative infusion doses range from
about 1 to 1000 .mu.g/kg/minute of agent, admixed with a
pharmaceutical carrier over a period ranging from several minutes
to several days.
[0115] For topical administration, the agents may be mixed with a
pharmaceutical carrier at a concentration of about 0.1% to about
10% of drug to vehicle. Another mode of administering the agents of
the invention may utilize a patch formulation to affect transdermal
delivery.
[0116] Agents may alternatively be administered in methods of this
invention by inhalation, via the nasal or oral routes, e.g., in a
spray formulation also containing a suitable carrier.
[0117] Examples of agents useful in methods of the invention will
now be described by reference to illustrative synthetic schemes for
their general preparation below and the specific examples that
follow. Artisans will recognize that, to obtain the various
compounds herein, starting materials may be suitably selected so
that the ultimately desired substituents will be carried through
the reaction scheme with or without protection as appropriate to
yield the desired product. Alternatively, it may be necessary or
desirable to employ, in the place of the ultimately desired
substituent, a suitable group that may be carried through the
reaction scheme and replaced as appropriate with the desired
substituent. Unless otherwise specified, the variables are as
defined above in reference to Formula (I).
[0118] As more extensively provided in this written description,
terms such as "reacting" and "reacted" are used herein in reference
to a chemical entity that is any one of: (a) the actually recited
form of such chemical entity, and (b) any of the forms of such
chemical entity in the medium in which the compound is being
considered when named.
[0119] One of ordinary skill in the art will recognize that, where
not otherwise specified, the reaction step(s) is performed under
suitable conditions, according to known methods, to provide the
desired product. One of ordinary skill in the art will further
recognize that, in the specification and claims as presented
herein, wherein a reagent or reagent class/type (e.g., base,
solvent, etc.) is recited in more than one step of a process, the
individual reagents are independently selected for each reaction
step and may be the same of different from each other. For example
wherein two steps of a process recite an organic or inorganic base
as a reagent, the organic or inorganic base selected for the first
step may be the same or different than the organic or inorganic
base of the second step. Further, one of ordinary skill in the art
will recognize that wherein a reaction step of the present
invention may be carried out in a variety of solvents or solvent
systems, said reaction step may also be carried out in a mixture of
the suitable solvents or solvent systems.
[0120] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that, whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
equivalents and approximations due to the experimental and/or
measurement conditions for such given value. Whenever a yield is
given as a percentage, such yield refers to a mass of the entity
for which the yield is given with respect to the maximum amount of
the same entity that could be obtained under the particular
stoichiometric conditions. Concentrations that are given as
percentages refer to mass ratios, unless indicated differently.
[0121] To provide a more concise description, some of the
quantitative expressions herein are recited as a range from about
amount X to about amount Y. It is understood that wherein a range
is recited, the range is not limited to the recited upper and lower
bounds, but rather includes the full range from about amount X
through about amount Y, or any range therein.
[0122] Examples of suitable solvents, bases, reaction temperatures,
and other reaction parameters and components are provided in the
detailed descriptions which follows herein. One of ordinary skill
in the art will recognize that the listing of said examples is not
intended, and should not be construed, as limiting in any way the
invention set forth in the claims which follow thereafter.
[0123] As used herein, unless otherwise noted, the term "aprotic
solvent" shall mean any solvent that does not yield a proton.
Suitable examples include, but are not limited to DMF, 1,4-dioxane,
THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE,
toluene and acetone.
[0124] As used herein, unless otherwise noted, the term "leaving
group" shall mean a charged or uncharged atom or group which
departs during a substitution or displacement reaction. Suitable
examples include, but are not limited to, Br, Cl, I, mesylate,
tosylate, cyano and triflate.
[0125] As used herein, unless otherwise noted, the term "nitrogen
protecting group" shall mean a group which may be attached to a
nitrogen atom to protect said nitrogen atom from participating in a
reaction and which may be readily removed following the reaction.
Illustrative suitable nitrogen protecting groups include, but are
not limited to, carbamates (which are groups that contain a moiety
--C(O)O--R, wherein R is for example methyl, ethyl, t-butyl,
benzyl, phenylethyl, CH.sub.2.dbd.CH--CH.sub.2-- and
2,2,2-trichloroethyl); amides (which are groups that contain a
moiety --C(O)--R', wherein R' is for example methyl, phenyl,
trifluoromethyl and t-butyl (pivalol)); N-sulfonyl derivatives
(which are groups that contain a moiety --SO.sub.2--R'', wherein
R'' is for example methyl, tolyl, phenyl, trifluoromethyl,
2,2,5,7,8-pentamethylchroman-6-yl- and
2,3,6-trimethyl-4-methoxybenzene). Other suitable nitrogen
protecting groups may be found in texts such as P. G. M. Wuts &
T. W. Greene Protective Groups in Organic Synthesis, John Wiley
& Sons, 2007, and Protective Groups in Organic Chemistry, ed.
J. F. W. McOmie, Plenum Press, 1973.
[0126] One of ordinary skill in the art will recognize that wherein
a reaction step of the present invention may be carried out in a
variety of solvents or solvent systems, said reaction step may also
be carried out in a mixture of the suitable solvents or solvent
systems.
[0127] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0128] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and P. G. M.
Wuts & T. W. Greene Protective Groups in Organic Synthesis,
John Wiley & Sons, 2007. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0129] The present invention is directed to a process for the
preparation of a compound of formula (I) as outlined in more detail
in Scheme 1, below.
##STR00021##
[0130] Referring to Scheme 1, a suitably substituted compound of
formula (V), a known compound or compound prepared by known
methods, is reacted with a suitably selected reducing agent system
such as DIBAL-H, RANEY.RTM. nickel in the presence of a source of
hydrogen such as H.sub.2(g), formic acid, and any other source of
hydrogen that behaves like H.sub.2(g) and formic acid under these
conditions, Red-AI, sodium borohydride, cupric hydride or lithium
triethylborohydride, to yield compound of formula (VI). In some
embodiments DIBAL-H or RANEY.RTM. nickel is used in the presence of
a source of hydrogen. When the reducing agent system is a single
agent, such as DIBAL-H, the reducing agent system is present in an
amount in the range of from about 1.0 to about 5.0 molar
equivalents (relative to the moles of compound of formula (V). In
some embodiments, in an amount in the range of from about 2.0 to
about 3.0 molar equivalents. In other embodiments, at about 2.5
molar equivalent. In an another example, the reducing agent system
is RANEY.RTM. nickel in the presence of a source of hydrogen and
RANEY.RTM. nickel is present in an amount in the range of from
about 1.0 to about 10.0 molar equivalents, for example at about
200% by weight. In another example, the source of hydrogen is
formic acid, and the formic acid is present in excess amount, for
example at about 40 molar equivalents.
[0131] Examples of suitable solvents include the following. Where
the reducing agent system is DIBAL-H, the reduction can be
performed in an organic solvent, such as THF, toluene, 2-Me-THF,
DME or MTBE. Such organic solvent may be an anhydrous organic
solvent, such as THF ortoluene. In another example, the reducing
agent system is RANEY.RTM. nickel and a source of hydrogen such as
formic acid, in water. The reaction temperature is in the range of
from about 0.degree. C. to about 25.degree. C. In some embodiments,
where the reducing agent system is DIBAL-H, the temperature is from
about 5.degree. C. to about 10.degree. C. In other embodiments,
where the reducing agent system is RANEY.RTM. nickel and a source
of hydrogen such as formic acid, the temperature is about room
temperature.
[0132] Compound of formula (VI) is reacted with a suitably
substituted compound of formula (VII) to yield compound of formula
(I), such compound of formula (VII) being present as a free base or
as its corresponding salt form, a known compound or compound
prepared by known methods. Compound of formula (VII) is present in
an amount in the range of from about 1.0 to about 1.25 molar
equivalents, for example in an amount in the range of from about
1.0 to about 1.1 molar equivalents, for example at about 1.01 molar
equivalents. This reaction is performed in the presence of a
suitably selected oxidizing agent or oxidizing agent system, such
as Na.sub.2SO.sub.3/air, Na.sub.2S.sub.2O.sub.5/air,
NaHSO.sub.3/air, DDQ, OXONE.RTM. or TEMPO.RTM. in combination with
sodium hypochlorite, for example Na.sub.2SO.sub.3/air or
Na.sub.2S.sub.2O.sub.5/air. The term "oxidizing agent system" is
herein used to generically refer to any such oxidizing agent or
oxidizing agent system. Such oxidizing agent or oxidizing agent
system is present in an amount in the range of from about 0.90 to
about 1.5 molar equivalents, for example in an amount in the range
of from about 0.95 to about 1.3 molar equivalents, for example in
an amount of about 1.3 molar equivalents, and still in another
example in an amount of about 1.0 molar equivalents. This
reaction's medium is water in some embodiments or an organic
solvent in other embodiments. Examples of such organic solvents
include DMF, NMP, DMA, acetonitrile and ethanol. Some reaction
media are DMF, and in other examples, they are water. This reaction
is performed at a temperature in the range of from about 25.degree.
C. to about 100.degree. C., for example at a temperature in the
range of from about 55.degree. C. to about 65.degree. C.
[0133] One of ordinary skill in the art will recognize that when
compound of formula (VI) is reacted with compound of formula (VII)
as its corresponding salt form in an organic solvent, then the
reaction is run in the presence of a suitably selected organic or
inorganic base such as such as NMM, TEA or K.sub.2CO.sub.3, for
example K.sub.2CO.sub.3. One of ordinary skill in the art will
further recognize that the base is present to neutralize the salt
form of compound of formula (VII) and thereby liberate the diamine
compound of formula (VII). One of ordinary skill in the art will
further recognize that compound of formula (VI) may alternatively
be reacted with compound of formula (VII) as its corresponding salt
form in water, in the presence of a suitably selected acid such as
HCl, H.sub.2SO.sub.4, and any other acid that behaves like any of
these acids in the present reaction conditions.
[0134] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I-A), as
outlined in more detail in Scheme 2, below.
##STR00022##
[0135] Referring to Scheme 2, a suitably substituted compound of
formula (V-S), a known compound or compound prepared by known
methods, is reacted with a suitably selected reducing agent system
to yield to yield compound of formula (VI-S). Examples of reducing
agent systems include DIBAL-H, RANEY.RTM. nickel in the presence of
a source of hydrogen such as H.sub.2(g), formic acid, and any other
hydrogen source that behaves under these conditions like hydrogen
gas and formic acid, Red-AI, sodium borohydride, cupric hydride or
lithium triethylborohydride. In some embodiments, the reducing
agent system is DIBAL-H or RANEY.RTM. nickel in the presence of a
source of hydrogen.
[0136] Where the reducing agent system is a single agent such as
DIBAL-H, the reducing agent system is present in an amount in the
range of from about 1.0 to about 5.0 molar equivalents (relative to
the moles of compound of formula (V-S). In other embodiments, in an
amount in the range of from about 2.0 to about 3.0 molar
equivalents. Still in other embodiments at about 2.5 molar
equivalent.
[0137] In other embodiments, the reducing agent system is
RANEY.RTM. nickel in the presence of a source of hydrogen and
RANEY.RTM. nickel is present in an amount in the range of from
about 1.0 to about 10.0 molar equivalents, for example at about
200% by weight. In other embodiments, the source of hydrogen is
formic acid, and the formic acid is present in excess amount, for
example at about 40 molar equivalents.
[0138] Examples of solvents for this reaction include the
following. The reducing agent system DIBAL-His used in an organic
solvent, such as THF, toluene, 2-Me-THF, DME and MTBE. In some
embodiments, the organic solvent is an anhydrous organic solvent,
for example in THF or toluene. The reducing agent system RANEY.RTM.
nickel and a source of hydrogen, such as formic acid, the solvent
is water. The temperature is in the range of from about 0.degree.
C. to about 25.degree. C. When the reducing agent system is
DIBAL-H, then the temperature is from about 5 to about 10.degree.
C. In another example, where the reducing agent system is
RANEY.RTM. nickel and a source of hydrogen, such as formic acid,
the reaction is performed at about room temperature.
[0139] Compound of formula (VI-S) is reacted with a suitably
substituted compound of formula (VII-A), to yield compound of
formula (I-A), wherein compound of formula (VII-A) may be present
as a free base or as its corresponding salt form, a known compound
or compound prepared by known methods. Compound of formula (VII-A)
is present in an amount in the range of from about 1.0 to about
1.25 molar equivalents. In some embodiments, it is present in an
amount in the range of from about 1.0 to about 1.1 molar
equivalents. In still other embodiments, at about 1.01 molar
equivalents. This reaction is performed in the presence of a
suitably selected oxidizing agent or oxidizing agent system, such
as Na.sub.2SO.sub.3/air, Na.sub.2S.sub.2O.sub.5/air,
NaHSO.sub.3/airDDQ, OXONE.RTM. or TEMPO.RTM. in combination with
sodium hypochlorite. In some embodiments, this oxidizing agent
system is Na.sub.2SO.sub.3/air or Na.sub.2S.sub.2O.sub.5/air. The
oxidizing agent or oxidizing agent system is present in an amount
in the range of from about 0.90 to about 1.5 molar equivalents. In
some embodiments, in an amount in the range of from about 0.95 to
about 1.3 molar equivalents. In other embodiments, in an amount of
about 1.3 molar equivalents, and still in other embodiments in an
amount of about 1.0 molar equivalents. The medium for this reaction
is water or an organic solvent such as DMF, NMP, DMA, acetonitrile
and ethanol. In some embodiments, the medium is DMF, and in other
examples, it is water. The reaction temperature is in the range of
from about 25.degree. C. to about 100.degree. C. In some
embodiments, the temperature is in the range of from about
55.degree. C. to about 65.degree. C.
[0140] One of ordinary skill in the art will recognize that when
compound of formula (VI-S) is reacted with compound of formula
(VII-A) as its corresponding salt form in an organic solvent, then
the reaction is run in the presence of a suitably selected organic
or inorganic base such as such as NMM, TEA or K.sub.2CO.sub.3, for
example K.sub.2CO.sub.3. One of ordinary skill in the art will
further recognize that the base is present to neutralize the salt
form of compound of formula (VII-A) and thereby liberate the
diamine compound of formula (VII-A). One of ordinary skill in the
art will further recognize that compound of formula (VI-A) may
alternatively be reacted with compound of formula (VII-A) as its
corresponding salt form in water, in the presence of a suitably
selected acid such as HCl, H.sub.2SO.sub.4, and any other acid that
behaves like hydrochloric and sulfuric acids in these
conditions.
[0141] In an embodiment, the present invention is directed to a
process for the preparation of a compound of formula (I-B), as
outlined in more detail in Scheme 3, below.
##STR00023##
[0142] With reference to Scheme 3, a suitably substituted compound
of formula (V-S), a known compound or compound prepared by known
methods, is reacted with a suitably selected reducing agent system
such as Dibal-H, RANEY.RTM. nickel in the presence of a source of
hydrogen such as H.sub.2(g), formic acid, and any other hydrogen
source that behaves under these conditions as hydrogen gas and
formic acid do, Red-AI, sodium borohydride, cupric hydride or
lithium triethylborohydride, to yield the compound of formula
(VI-S). In some embodiments, the reducing agent system is Dibal-H
or RANEY.RTM. nickel in the presence of a source of hydrogen.
[0143] In an embodiment, where the reducing agent system is a
single agent, such as DIBAL-H, the reducing agent system is present
in an amount in the range of from about 1.0 to about 5.0 molar
equivalents (relative to the moles of compound of formula (V-S). In
another embodiment, in an amount in the range of from about 2.0 to
about 3.0 molar equivalents, and still in other embodiments, in an
amount of about 2.5 molar equivalent.
[0144] Where the reducing agent system is RANEY.RTM. nickel in the
presence of a source of hydrogen, RANEY.RTM. nickel is present in
an amount in the range of from about 1.0 to about 10.0 molar
equivalents, for example at about 200% by weight. Where the source
of hydrogen is formic acid, it is present in an excess amount, for
example about 40 molar equivalents of formic acid.
[0145] Examples of solvents for this reaction are the following
where the reducing agent system is DIBAL-H, the solvent is an
organic solvent, such as THF, toluene, 2-Me-THF, DME and MTBE. Such
organic solvent may in some embodiments be an anhydrous organic
solvent, for example THF or toluene. Where the reducing agent
system is RANEY.RTM. nickel and the source of hydrogen is formic
acid, the solvent is typically water.
[0146] The reaction temperature is in the range of from about
0.degree. C. to about 25.degree. C. In some embodiments, where the
reducing agent system is DIBAL-H, the temperature is from about
5.degree. C. to about 10.degree. C. In other embodiments, where the
reducing agent system is RANEY.RTM. nickel with a source of
hydrogen such as formic acid, the temperature is about room
temperature.
[0147] Compound of formula (VI-S) is reacted with a suitably
substituted compound of formula (VII-B), wherein compound of
formula (VII-B) may be present as a free base or as its
corresponding salt form, a known compound or compound prepared by
known methods, to yield the compound of formula (I-B). Compound of
formula (VII-B) is present in an amount in the range of from about
1.0 to about 1.25 molar equivalents. In some embodiments, in an
amount in the range of from about 1.0 to about 1.1 molar
equivalents. In other embodiments, in an amount of about 1.01 molar
equivalents. This reaction takes place in the presence of a
suitably selected oxidizing agent or oxidizing agent system, such
as Na.sub.2SO.sub.3/air, Na.sub.2S.sub.2O.sub.5/air,
NaHSO.sub.3/air, DDQ, OXONE.RTM. or TEMPO.RTM. in combination with
sodium hypochlorite. In some embodiments, Na.sub.2SO.sub.3/air or
Na.sub.2S.sub.2O.sub.5/air is used. The oxidizing agent or
oxidizing agent system is present in an amount in the range of from
about 0.90 to about 1.5 molar equivalents. In some embodiments, in
an amount in the range of from about 0.95 to about 1.3 molar
equivalents. In other embodiments, in an amount of about 1.3 molar
equivalents, and still in other embodiments, in an amount of about
1.0 molar equivalents. This reaction takes place in water or in an
organic solvent such as DMF, NMP, DMA, acetonitrile or ethanol. In
some embodiments, the reaction medium is provided by DMF. The
reaction temperature is in the range of from about 25.degree. C. to
about 100.degree. C. In other embodiments the reaction temperature
is in the range of from about 55 to about 65.degree. C.
[0148] One of ordinary skill in the art will recognize that when
compound of formula (VI-S) is reacted with a salt form of compound
of formula (VII-B) in an organic solvent, then the reaction is run
in the presence of a suitably selected organic or inorganic base
such as such as NMM, TEA and K.sub.2CO.sub.3. In some embodiments,
K.sub.2CO.sub.3 is used as such base. One of ordinary skill in the
art will further recognize that the base is present to neutralize
the salt form of compound of formula (VII-B) and thereby liberate
the diamine compound of formula (VII-B). One of ordinary skill in
the art will further recognize that compound of formula (VI-B) may
alternatively be reacted with compound of formula (VII-B) as its
corresponding salt form in water, in the presence of a suitably
selected acid such as HCl, H.sub.2SO.sub.4, and other acids that
behave like hydrochloric and sulfuric acids in these
conditions.
[0149] Powder X-ray diffraction patterns listed herein were
measured using an XPERT-PRO diffractometer system. The sample was
backloaded into a conventional x-ray holder and tested at
25.degree. C. The sample was scanned from 4.01.RTM.2.theta. to
40.98.RTM.2.theta. with a step size of 0.017002.theta. and a time
per step of 17.44 seconds. Instrument voltage and current settings
were 45 kV and 40 mA.
[0150] The present invention is further directed to a crystalline
hemi-tartrate of compound of formula (I-A). The crystalline
hemi-tartrate of compound of formula (I-A) may be characterized,
for example, by its powder XRD pattern, an example of which is
shown in FIG. 1 herein.
[0151] In an embodiment, the crystalline hemi-tartrate of compound
of formula (I-A) may be characterized by its powder X-ray
diffraction pattern comprising the peaks as listed in Table 1,
below.
TABLE-US-00001 TABLE 1 XRD Peaks Pos. [.degree.2.theta.] FWHM
[.degree.2.theta.] d-spacing [.ANG.] Rel. Int. [%] 6.49 0.15 13.62
100 8.58 0.17 10.30 48 9.17 0.20 9.64 5 10.35 0.13 8.55 10 10.75
0.20 8.23 23 12.92 0.20 6.85 4 15.37 0.40 5.77 1 16.72 0.40 5.30 6
17.46 0.20 5.08 6 18.89 0.17 4.70 9 20.72 0.54 4.29 2 22.14 0.40
4.02 4 23.60 0.22 3.77 24 25.92 0.80 3.44 2 28.09 0.54 3.18 1 29.88
0.27 2.99 1 35.53 0.80 2.53 0.2
[0152] In an embodiment of the present invention, the crystalline
hemi-tartrate of compound of formula (I-A) is characterized by its
powder XRD pattern which comprises peaks having a relative
intensity greater than or equal to about 5%, as listed in Table 2
below.
TABLE-US-00002 TABLE 2 XRD Peaks Pos. [.degree.2.theta.] FWHM
[.degree.2.theta.] d-spacing [.ANG.] Rel. Int. [%] 6.49 0.15 13.62
100 8.58 0.17 10.30 48 9.17 0.20 9.64 5 10.35 0.13 8.55 10 10.75
0.20 8.23 23 16.72 0.40 5.30 6 17.46 0.20 5.08 6 18.89 0.17 4.70 9
23.60 0.22 3.77 24
[0153] In an embodiment of the present invention, the crystalline
hemi-tartrate of compound of formula (I-A) is characterized by its
powder XRD pattern which comprises peaks having a relative
intensity greater than or equal to about 10%, as listed in Table 3
below.
TABLE-US-00003 TABLE 3 XRD Peaks Pos. [.degree.2.theta.] FWHM
[.degree.2.theta.] d-spacing [.ANG.] Rel. Int. [%] 6.49 0.15 13.62
100 8.58 0.17 10.30 48 10.35 0.13 8.55 10 10.75 0.20 8.23 23 23.60
0.22 3.77 24
[0154] In an embodiment of the present invention, the crystalline
hemi-tartrate of compound of formula (I-A) is characterized by its
powder XRD pattern which comprises peaks having a relative
intensity greater than or equal to about 20%, as listed in Table 4,
below.
TABLE-US-00004 TABLE 4 XRD Peaks Pos. [.degree.2.theta.] FWHM
[.degree.2.theta.] d-spacing [.ANG.] Rel. Int. [%] 6.49 0.15 13.62
100 8.58 0.17 10.30 48 10.75 0.20 8.23 23 23.60 0.22 3.77 24
[0155] The present invention is further directed to a process for
the preparation of a hemi-tartrate of compound of formula (I-A).
The hemi-tartrate of compound of formula (I-A) may be prepared
according to the following process.
[0156] Compound of formula (I-A) is dissolved in an organic solvent
such as denatured ethanol, methanol or IPA. In some embodiments,
denatured ethanol is used. In other embodiments, a mixture of
denatured ethanol and isopropanol is used.
[0157] Water is optionally removed from the compound of formula
(I-A) solution. In some embodiments, water is removed
azeotropically. For example, by adding a suitably selected organic
solvent, such as cyclohexane, to the compound of formula (I-A)
solution, and subjecting the resulting mixture to azeotropic
distillation.
[0158] With or without water removal from it, the solution of
compound of formula (I-A), is heated to a temperature in the range
of from about 35.degree. C. to about reflux, for example to a
temperature of about 50.degree. C., and L-tartaric acid is added to
the heated mixture. L-tartaric acid is added in an amount in the
range of from about 0.25 to about 1.0 molar equivalents. In some
embodiments, in an amount of about 0.5 molar equivalents.
[0159] The mixture with the added L-tartaric acid is heated to a
temperature in the range of from about 50.degree. C. to about
reflux. In some embodiments, to a temperature of about 50.degree.
C. In other embodiments, to a temperature from about 70.degree. C.
to about 75.degree. C. The resulting mixture is optionally
filtered. With or without filtration, a tartrate solution is
obtained.
[0160] Embodiments of this invention optionally include one or two
of the following additional steps to obtain solid
compound-of-formula-(I-A) hemi-tartrate.
[0161] Cooling the tartrate solution. In some embodiments, this
cooling is effectuated to a temperature below room temperature. In
other embodiments, the cooling is effectuated to a temperature of
from about 0.degree. C. to about -5.degree. C. A precipitate of the
hemi-tartrate of compound of formula (I-A) is obtained. In
addition, this precipitate can be further isolated. Such isolation
is achieved by washing the precipitate with cold organic solvent,
and further optionally drying the precipitate according to known
methods, for example under vacuum and/or under elevated
temperature.
[0162] The present invention is further directed to a process for
the recrystallization of the hemi-tartrate of compound of formula
(I-A). In some embodiments, the recrystallization is done as
follows.
[0163] Dissolving hemi-tartrate of compound of formula (I-A) in a
mixture of water and an organic solvent, such as denatured ethanol,
and optionally filtering the resultant mixture. Illustrative
examples of such water/organic solvent mixture are given by an
about 1% (vol/vol) water:denatured ethanol mixture; a mixture of
water and denatured ethanol, wherein the water is present in from
about 1.0% to about 1.5% by weight; and a mixture of water and
denatured ethanol, wherein the water is present in about 1.4% by
weight. Removing water from the so-prepared mixture to yield a
mixture with boiling point of between about 70.degree. C. and about
80.degree. C. In some embodiments, such boiling point is between
about 70.degree. C. and about 75.degree. C. In other embodiments,
such boiling point is between about 78.degree. C. and about
80.degree. C. This water removal is accomplished in some
embodiments by azeotropic distillation. The resulting mixture is
subsequently optionally filtered.
[0164] Embodiments of this invention optionally include one or two
of the following additional steps to obtain recrystallized
compound-of-formula-(I-A) hemi-tartrate. Cooling the mixture to
yield a precipitate of the crystalline hemi-tartrate of compound of
formula (I-A). For example, cooling to a temperature of about
0.degree. C. Subsequently isolating of the precipitate. For example
by filtration, which is optionally washed with cold organic
solvent. The washed precipitate is optionally dried according to
known methods, for example under vacuum and/or under elevated
temperature.
[0165] In another aspect, the present invention is directed to a
process for the recrystallization of the hemi-tartrate of compound
of formula (I-A) as follows.
[0166] Dissolving hemi-tartrate of compound of formula (I-A) in a
mixture of organic solvents, such as a mixture of methanol and
denatured ethanol. Optionally heating such mixture to a temperature
greater than about room temperature. Examples of such temperature
include about reflux temperature, and a temperature in the range of
from about 50.degree. C. to about 60.degree. C. Subsequently,
optionally filtering the resultant mixture.
[0167] The so-prepared mixture is subsequently cooled to yield a
precipitate of the crystalline hemi-tartrate of compound of formula
(I-A). In some embodiments, it is cooled to about 0.degree. C. In
some embodiments, such cooling is effectuated in a step-wise
manner. The so-formed precipitate is subsequently isolated. In some
embodiments, the isolation is effectuated by filtration, and the
isolated precipitate is optionally washed with cold organic
solvent. The precipitate is optionally dried according to known
methods, for example under vacuum and/or under elevated
temperature.
[0168] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
[0169] In the Examples which follow, some synthesis products are
listed as having been isolated as a residue. It will be understood
by one of ordinary skill in the art that the term "residue" does
not limit the physical state in which the product was isolated and
may include, for example, a solid, an oil, a foam, a gum or a
syrup.
[0170] Example 1, STEPS A-D describe recipes/procedures for the
synthesis of the title compounds. Several batches of said compounds
were prepared according to the recipes/procedures as described
below. The physical properties (e.g., MS.sup.+, .sup.1H NMR, etc.)
listed at the end of the synthesis descriptions below are a listing
of the physical properties measured for a representative sample of
the prepared compound.
Example 1
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-met-
hyl-piperidin-4-yl)-propyl]-amine
##STR00024##
[0171] Step A
[0172] A 100 L glass-lined reactor was charged with
2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzonitrile
(5.41 kg, 19.8 mol) and toluene (47.13 kg). The resultant
suspension was stirred and cooled to about 0 to -5.degree. C. Next,
1.0M diisobutylaluminum hydride (DIBAL-H) in toluene (40.55 kg,
47.33 mol) was added, via nitrogen pressure, while maintaining the
internal reaction temperature at <2.degree. C. After completing
the addition, the resultant reaction solution was warmed to about
5-10.degree. C. and the reaction monitored for completion by HPLC.
Cold ethyl acetate (4.89 kg) was then added over 30 min and the
resultant mixture stirred for 15-20 minutes. The resultant mixture
(containing
2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzaldehyde)
was transferred to a 100 L glass receiver and rinsed with toluene
(1.00 kg).
Step B
[0173] A cold solution of water/sulfuric acid (27.05 kg/2.26 kg) to
each, a 100 L Hastelloy reactor and a 100 L glass lined reactor.
The resultant aqueous acid solutions were stirred and cooled to
about 2-5.degree. C. Maintaining the temperature <30.degree. C.
at all times, 50% (by volume) of the mixture prepared in STEP A
above was added to each aqueous sulfuric acid solution. The
resultant suspension was checked for pH (target pH of 4-5) and
stirred at about 20-25.degree. C. for about 1.5-2 h. The
suspensions were then cooled to about 10-15.degree. C. and the pH
of the suspensions adjusted to pH.about.11-12, by adding 6N sodium
hydroxide (16.12 kg, 81.42 mol), over 20 min. The resultant
mixtures were then stirred to an additional 15-20 minutes, the
agitation was then stopped and the phases allowed to separate.
[0174] The organic phases were removed from the top of each reactor
via vacuum and combined. Then the aqueous phase and middle oil
phases were drained via the bottom valve of each reactor and
discarded. The combined organic phase was concentrated at
.about.40.degree. C. to yield a solid. This solid was transferred
to drying trays and dried (60 Torr, 30-35.degree. C.) overnight to
yield solid
2-Methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzaldehyde.
Step C
[0175] In a 100 L glass-lined reactor, sodium metabisulfite
(Na.sub.2S.sub.2O.sub.5) (1.96 kg, 9.79 mol) was dissolved in
purified water (54.63 kg), followed by the addition of
3,5-dimethyl-1,2-benzenediamine-2HCl (2.07 kg, 9.86 mol) and the
resultant mixture stirred at about 20-25.degree. C. to effect
solution. Next, concentrated hydrochloric acid (1.65 kg, 16.79 mol)
was added, followed by addition of
2-methyl-4-[3-(1-methyl-piperidin-4-yl)-propylamino]-benzaldehyde,
prepared as in STEP B above (2.74 kg, 9.79 mol) and the resultant
mixture stirred at about 23-27.degree. C. to effect solution. The
resultant mixture was heated to about 57-62.degree. C. and
monitored for completion by HPLC.
[0176] The reaction mixture was cooled to about 20-25.degree. C.
and then half of the volume (.about.30 L) was then added, via a
metering pump, to a stirring 50 L glass reactor system containing a
solution of potassium carbonate (3.9 kg, 28.2 mol) dissolved in
purified water (15 kg), resulting in the formation of a
precipitate. The precipitated product was stirred for .about.1 h
and then allowed to settle. The clear supernatant (.about.20 L) was
removed from the top of the 50 L reactor system and purified water
(.about.20 kg) was added. The resultant mixture was stirred for 10
min, filtered, washed with water (13 kg) and dried at 35-40.degree.
C. under vacuum to yield solid
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine.
[0177] MS: [M=H].sup.+=393
[0178] .sup.1H NMR (600 MHz, Methanol-d.sub.6) .delta. pp,
1.38-1.43 (m, 2H), 1.43-1.52 (m, 2H), 1.53-1.61 (br, 1H), 1.64-1.71
(m, 2H), 1.90-1.96 (br, m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.54
(s, 3H), 2.74 (s, 3H), 2.78-2.86 (br, m, 2H), 3.15-3.36 (m, 2H),
3.36-3.47 (m, 2H) 4.35 (s, 1H), 6.90 (s, 1H), 7.20 (s, 1H), 8.44
(br, s, 1H)
Step D: Preparation of Hemi-Tartrate of
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine
[0179] In a 100 L Hastelloy reactor,
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine, prepared as in STEP C above
(6.58 kg, 15.56 mol) was dissolved in denatured ethanol (31.00 kg,
95/5 ethanol/2-propanol) at about 48-52.degree. C. After stirring
for 15 minutes, the resultant hazy solution was cooled to about
25-30.degree. C. Magnesium sulfate (0.60 kg) was added and the
resultant mixture was stirred an additional 30 minutes. The
magnesium sulfate was filtered over CELITE.RTM. (0.30 kg) and the
resultant clear solution (KF=0.22%) was transferred to a clean
glass lined 100 L glass-lined reactor and heated to about
48-52.degree. C. A solution of L-tartaric acid (1.16 kg, 7.73 mol)
in denatured ethanol (10.0 kg) was charged to the reactor over 20
minutes. The resultant mixture was heated to about 70-75.degree. C.
and then aged for 1 h. The resultant yellow slurry was cooled to
about 0-5.degree. C. over a 2 h period and then aged for 20 min.
The product (as a precipitate) was filtered, washed with cold
denatured ethanol (5.20 kg), then dried at about 75-80.degree. C.
under vacuum to yield the
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine, as its corresponding
hemi-tartrate solid salt.
Step E: Recrystallization
[0180] In a 100 L Hastelloy reactor, the hemi-tartrate of
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine, prepared as in STEP D above
(5.19 kg, 11.10 mol) was dissolved in a mixture of denatured
ethanol (32.40 kg, 95/5 ethanol/2-propanol) and water (2.62 kg) at
about 75-78.degree. C. The resultant solution was cooled to about
50-55.degree. C. and polish filtered (to remove any foreign
particles) into a clean 100 L glass-lined reactor, followed by a
rinse with denatured ethanol (4.15 kg). Denatured ethanol (25.62
kg) was added and the resultant solution was stirred and heated to
about 78-80.degree. C. to atmospherically distill off 51 L of the
solvent. The resultant solution was cooled to about 55-60.degree.
C. and additional denatured ethanol (27.63 kg) was added, followed
by heating to about 78-80.degree. C. to atmospherically distill off
27 L of the solvent. The resultant solution was then cooled to
about 50-55.degree. C., seeded (2.0 g, 4.3 mmol), then further
cooled to about 18-22.degree. C. and then stirred for 1 h. The
resultant precipitate was filtered, washed with denatured ethanol
(5.00 kg) and dried at about 75-80.degree. C. under vacuum to yield
the solid hemi-tartrate of
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine.
[0181] m.p. 179.degree. C.
[0182] The .sup.1H NMR of a sample of the hemi-tartrate of
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine was as follows:
[0183] .sup.1H NMR (300 MHz, Methanol-d.sub.4) .delta. ppm
1.34-1.75 (m, o, 7H), 1.88-1.99 (br, m, 2H), 2.42 (s, 3H), 2.53 (s,
3H), 2.54 (s, 3H), 2.75 (s, 3H), 2.76-2.89 (o, m, 2H), 3.35-3.48
(m, 4H), 4.35 (s, 1H), 6.90 (s, 1H), 7.20 (s, 1H), 8.44 (br, s,
1H)
Example 2
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-met-
hyl-piperidin-4-yl)-propyl]-amine
##STR00025##
[0185] To a 4 mL vial were added
3,5-dimethyl-benzene-1,2-diamine.2HCl (69 mg, 0.33 mmol),
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbald-
ehyde (92 mg, 0.33 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone
(75 mg, 0.33 mmol), and DMF (2 mL). After addition of triethylamine
(0.09 mL, 0.66 mmol), the resultant mixture was stirred for 5 hours
at room temperature. The resultant mixture was then diluted with 1N
NaOH (7.5 mL) and dichloromethane (7.5 mL). The organic layer was
concentrated and purified by flash chromatography to yield the
title compound.
[0186] MS: [M=H].sup.+=393
[0187] .sup.1H NMR (600 MHz, Methanol-d.sub.6) 6 pp, 1.38-1.43 (m,
2H), 1.43-1.52 (m, 2H), 1.53-1.61 (br, 1H), 1.64-1.71 (m, 2H),
1.90-1.96 (br, m, 2H), 2.42 (s, 3H), 2.53 (s, 3H), 2.54 (s, 3H),
2.74 (s, 3H), 2.78-2.86 (br, m, 2H), 3.15-3.36 (m, 2H), 3.36-3.47
(m, 2H) 4.35 (s, 1H), 6.90 (s, 1H), 7.20 (s, 1H), 8.44 (br, s,
1H)
Example 3
4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbalde-
hyde
##STR00026##
[0189] To a 5-L jacketed reactor equipped with overhead mechanical
stirrer, nitrogen inlet, thermocouple probe, and J-Kem syringe pump
was added
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-c-
arbonitrile (160.0 g, 585 mmol) in THF (1.6 L). The resultant
mixture was cooled to 5.degree. C., and diisobutylaluminum hydride
(DIBAL-H) (1 M in toluene, 1.755 L, 1.755 mol) was added by syringe
pump over 2.33 hours, while maintaining an internal reaction
temperature of <8.degree. C. After completion of the addition,
the resultant mixture was warmed to 20.degree. C. over 40 min, then
maintained an additional 3 hours at room temperature. The reaction
was then quenched with aqueous H.sub.2SO.sub.4 (110 mL of sulfuric
acid in water, 2 L total volume). The quench was executed over 1
hour with a jacket temperature of 0.degree. C. and an internal
temperature of 20-30.degree. C. and was observed to be highly
exothermic. (A Rochelle's salt quench was also explored. This
approach was successful, but required long stirring times (after
the quench) to yield two clear layers. An HCl quench was also
employed and produced results similar to the sulfuric acid quench.)
The resultant mixture was then stirred for 45 minutes and the
aqueous layer and suspended solids were drained. The pH of the
aqueous layer was adjusted to pH.about.10.6 with 50% NaOH (336 mL).
Extraction of the aqueous layer (2.times.2 L dichloromethane) and
concentration of the combined aqueous layers yielded an oil, which
was used in the next step without further purification.
[0190] MS (electrospray): exact mass calculated for
C.sub.15H.sub.23N.sub.5, 276.20; m/z found, 277.1 [M+H].sup.+.
Example 4
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl-[3-(1-meth-
yl-piperidin-4-yl)-propyl]-amine
##STR00027##
[0192] To a 2 L Erlenmeyer flask were added
3,5-dimethyl-benzene-1,2-diamine .2HCl (54.85 g, 262.3 mmol) and
Na.sub.2S.sub.2O.sub.5 (64.82 g, 341.0 mmol), as well as
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbald-
ehyde (prepared as in Example 3 above) (72.5 g, 262.3 mmol) in DMF
(725 mL). After addition of triethylamine (73.1 mL, 524.6 mmol),
the resultant mixture was warmed on a hot plate with stirring to
90.degree. C. and held at this temperature for 2 hours. The
resultant mixture was then concentrated to near dryness and
partitioned between dichloromethane (0.7 L) and 1 N NaOH (1 L). The
resultant mixture was stirred for 1 hour and then filtered to
isolate the voluminous solid which had formed. The solids were
dried and then partitioned between chloroform (700 mL) and
saturated aqueous NaHCO.sub.3 (700 mL). The layers were separated,
the organic layer was dried over sodium sulfate and concentrated to
a residue. The residue was recrystallized in hot heptane/ethyl
acetate (1.8:1, 840 mL total volume) with initial hot filtration
(.about.1 g of oily residues removed) and final filter cake washing
with heptane/ethyl acetate (3:1, 250 mL total volume) to yield the
title compound as a crystalline solid.
[0193] .sup.1H-NMR: (400 MHz, CD.sub.3OD) .delta., 8.43 (s, 1H),
7.20 (s, 1H), 6.89 (s, 1H), 3.42 (t, J=7.0, 2H), 2.89-2.82 (m, 2H),
2.54 (s, 3H), 2.53 (s, 3H), 2.42 (s, 3H), 2.24 (s, 3H), 2.03-1.94
(m, 2H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H), 1.38-1.18 (m,
5H).
[0194] MS (electrospray): exact mass calculated for
C.sub.23H.sub.32N.sub.6, 392.27; m/z found, 393.2 [M+H].sup.+.
[0195] Elemental Analysis for C.sub.23H.sub.32N.sub.6.0.25H.sub.2O:
Calculated: C, 69.58; H, 8.25; N, 21.17; Measured: C, 69.45; H,
8.06; N, 21.30.
Example 5
Hemi-tartrate of
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine
[0196] To a 50-mL reactor equipped with an overhead mechanical
stirrer, liquid addition funnel, reflux condenser, internal
temperature probe and dynamic nitrogen inlet were added
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine (1.01 g, 2.58 mmol) and EtOH (15
mL, 200 proof). The resultant heterogeneous solution was heated to
50.degree. C., at which point the mixture was observed to become a
homogeneous solution. At 50.degree. C., a solution of L-tartaric
acid (0.193 g, 1.29 mmol) dissolved in EtOH (5.0 mL, 200 proof) was
added dropwise over 2.0 minutes. A slight precipitate was observed
at the site of addition; however, the precipitate was not
persistent. After completion of the addition, the resultant
homogeneous solution was aged at 50.degree. C. for 30 minutes. The
resultant solution was then cooled to about 20.degree. C. at which
time nucleation was observed after ageing for .about.30 min. The
resultant slurry was aged at about 20.degree. C. for 4.5 hours. The
solids were collected by suction filtration and dried in a vacuum
oven (under house vacuum) at 50.degree. C. for 2.5 days. After
complete solvent removal, the title compound was obtained as a
crystalline solid.
Example 6
Recrystallization of Hemi-tartrate of
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine
[0197] A representative sample of the hemi-tartrate of compound of
formula (I-A), prepared as described in Example 5 above, was
recrystallized as follows.
[0198] To a 500-mL, round bottom flask equipped with an overhead
mechanical stirrer, reflux condenser and internal temperature probe
were added the hemi-tartrate of
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine (8.03 g, 17.2 mmol) and EtOH
(160 mL, 200 proof). The resultant heterogeneous mixture was warmed
to reflux (77.3.degree. C.). At reflux, H.sub.2O was added dropwise
via syringe (1.6 mL) and a homogeneous solution was achieved. The
resultant solution was aged at reflux for 30 minutes then cooled to
about 21.3.degree. C. over a 90-minute period. Once this
temperature was reached, nucleation was observed after .about.30
min. The resultant slurry was aged at this temperature for an
additional 4 hours. The solids were collected by suction filtration
and dried at room temperature under house vacuum for 20 hours. The
cake was further dried at 50.degree. C. in a vacuum oven for 20
hours to yield the title compound as a crystalline solid.
Example 8
[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(-
1-methyl-piperidin-4-yl)-propyl]-amine
##STR00028##
[0200] To a 2 L Erlenmeyer flask were added
4-fluoro-3-methyl-benzene-1,2-diamine.HCl (46.32 g, 262.3 mmol),
Na.sub.2S.sub.2O.sub.5 (64.82 g, 341.0 mmol), and
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbald-
ehyde (72.5 g, 262.3 mmol) in DMF (725 mL). To the resultant
mixture was then added triethylamine (36.6 mL, 262.3 mmol), and the
reaction was warmed on a hot plate with stirring to 90.degree. C.
and held at this temperature for 2 hours. The resultant mixture was
then concentrated to near dryness and partitioned between
dichloromethane (1 L) and 1 N NaOH (1 L). After separation of the
layers, the aqueous layer was extracted a second time with
dichloromethane (1 L). The combined organic layers were then washed
with saturated aqueous NaHCO.sub.3 (1.6 L). The organics were then
extracted with a 1 M mono/dibasic phosphate buffer (pH 5.62, 1.23
L). The aqueous layer was then basified with 50% NaOH (80 mL) to pH
10.8. The resultant heterogeneous layer was then extracted with
dichloromethane (1.5 L and 500 mL), and the combined organics were
concentrated to yield the title compound.
[0201] The title compound was recrystallized from hot heptane/ethyl
acetate (2:1, 1.15 L total volume) with initial hot filtration and
final filter cake washing with heptane/ethyl acetate (3:1, 250 mL
total volume) to yield the title compound as a crystalline
solid.
[0202] .sup.1H-NMR: (400 MHz, CD.sub.3OD) 6, 8.45 (s, 1H), 7.37
(dd, J=8.8, 4.4 Hz, 1H), 6.99 (dd, J=10.3, 8.8 1H), 3.42 (t, J=7.0,
2H), 2.89-2.82 (m, 2H), 2.54 (s, 3H), 2.49 (d, J=1.6 Hz, 3H), 2.24
(s, 3H), 2.03-1.94 (m, 2H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H),
1.38-1.18 (m, 5H).
[0203] MS (electrospray): exact mass calculated for
C.sub.22H.sub.29FN.sub.6, 396.2; m/z found, 397.2 [M+H].sup.+
[0204] Elemental Analysis for C.sub.22H.sub.29FN.sub.6: Calculated:
C, 66.64; H, 7.37; N, 21.19. Measured: C, 66.31; H, 7.61; N,
21.19.
Example 9
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-met-
hyl-piperidin-4-yl)-propyl]-amine
##STR00029##
[0205] Step A
[0206]
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-c-
arbonitrile (10.0 g, 36.6 mmol) was slurried in dry toluene (80.7
g) under a nitrogen atmosphere. At 3-10.degree. C.,
diisobutylaluminum hydride (DIBAL-H) (20% in toluene) (62.6 g, 88.0
mmol) was added over 80 min. The resulting mixture was kept at
10-20.degree. C. for 65 min, then ethyl acetate (9.0 g, 102.1 mmol)
was added over 15 min. After stirring for 30 min at room
temperature, the resulting yellow solution was added dropwise to a
solution of 37% aqueous hydrochloric acid (16.0 g, 162.4 mmol) in
water (70.0 g) over 60 min at about 20.degree. C. (exothermic
reaction, gas formation). The resulting biphasic mixture was
stirred at room temperature over night, then sodium hydroxide (30%
in water) (34.1 g, 255.8 mmol) was added over 20 min, resulting in
the formation of a third layer (orange oil). The mixture was
stirred at 35-40.degree. C. for 30 min, then the layers were
allowed to separate and the aqueous layer and the orange middle
layer were removed. The toluene layer was then extracted with a
mixture of 37% aqueous hydrochloric acid (3.60 g, 36.5 mmol) and
water (60.4 g) at room temperature. The aqueous layer (containing
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbald-
ehyde) was used in the next step without further purification or
product isolation.
Step B
[0207] In a clean reactor, sodium metabisulfite (4.87 g, 25.6 mmol)
and 3,5-dimethyl-benzene-1,2-diamine .1.5HCl (4.87 g, 25.6 mmol)
were slurried in water (64.9 g). 37% Aqueous hydrochloric acid
(3.61 g, 36.5 mmol) was added. To the resulting mixture was then
added the aqueous layer solution prepare din STEP A above, over 9
min at room temperature (slightly exothermic). The resulting
mixture was then heated to 55-65.degree. C. and maintained at this
temperature for 2-3 hours (open reactor, O.sub.2 from air). Upon
completion of the reaction (as determined by HPLC), the resulting
mixture was cooled to room temperature and filtered to remove any
insoluble salts that had precipitated.
Step C
[0208] Potassium carbonate (25.3 g, 183.0 mmol) was dissolved in
water (100.0 g) at room temperature, 2-methyltetrahydrofurane (9.0
g) was added, and then the filtrate as prepared in STEP B was added
dropwise over 60 min, resulting in precipitation of the desired
product. The resulting suspension was stirred overnight at room
temperature, the precipitate was isolated by filtration and washed
with water (60.5 g), to yield the title compound as a yellow
solid.
Example 10
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-met-
hyl-piperidin-4-yl)-propyl]-amine
##STR00030##
[0209] Step A
[0210]
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-c-
arbaldehyde (prepared from
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboni-
trile by reduction with Raney-Nickel) (20.0 g, 72.4 mmol) was
suspended in water (60.0 g) at room temperature. Hydrochloric acid
(37% in water) was added dropwise until the solid had completely
dissolved (10.0 g, 101.5 mmol).
Step B
[0211] A 1 L-reactor was then charged with sodium sulfite (9.15 g,
72.6 mmol) and 3,5-dimethyl-benzene-1,2-diamine .2HCl (15.2 g, 72.7
mmol). The solids were slurried in water (120.0 g) at room
temperature and hydrochloric acid (37% in water, 4.25 g, 43.1 mmol)
was added, followed by the addition of water (20.0 g). The
resulting mixture was stirred for approx. 5 min, then heated to
45-50.degree. C. The solution prepared in STEP A was added in 2
portions over 40 min, and the resulting mixture stirred (open
reactor, O.sub.2 from air) for 2 h 20 min at 55-62.degree. C. The
resulting mixture was then cooled to 45.degree. C. and sodium
hydroxide (30% in water) (11.5 g, 86.3 mmol) followed by
2-methyltetrahydrofurane (200.0 g) were added. After the pH was
adjusted with sodium hydroxide (30% in water) (27.3 g, 204.8 mmol),
the resulting biphasic mixture was stirred at 45-52.degree. C. for
25 min. The resulting phases were separated and the aqueous layer
was removed. To the organic layer was added water (100.0 g) and the
resulting mixture stirred at 45-52.degree. C. for 20 min. The
resulting phases were again allowed to separate and the aqueous
layer was removed. To the organic layer was added dropwise,
cyclohexane (122.0 g) over approx. 60 min at 50.degree. C. After
the addition was complete, the resulting mixture was slowly cooled
to room temperature, during which time crystallization set in
spontaneously. The resulting mixture was maintained at 0.degree. C.
for 2 h, the solid was isolated by filtration, washed with
cyclohexane (61.0 g) and dried in vacuo at 65.degree. C. to yield
the title compound as a light yellow solid.
Example 11
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-met-
hyl-piperidin-4-yl)-propyl]-amine
##STR00031##
[0212] Step A
[0213]
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-c-
arbaldehyde (prepared from
4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboni-
trile by reduction with Raney-Nickel) (22.5 g, 81.4 mmol) was
suspended in water (67.7 g) at room temperature. Hydrochloric acid
(37% in water) (9.67 g, 98.1 mmol) was added dropwise until the
solid had completely dissolved.
Step B
[0214] A 500 mL-reactor was charged with sodium sulfite (10.30 g,
81.8 mmol) and 3,5-dimethyl-benzene-1,2-diamine .2HCl (17.10 g,
81.7 mmol). The solids were slurried in water (135.6 g) at room
temperature and hydrochloric acid (37% in water) (6.40 g, 64.9
mmol) in water (21.6 g) was added. The mixture resulting was heated
to 45-50.degree. C. in 20 min. To the resulting mixture was then
added dropwise, over 30 mins the solution prepared in STEP A. The
resulting mixture was then heated to 60.degree. C. for 2.5 h (open
reactor, O.sub.2 from air). Upon completion of the reaction (as
monitoring by HPLC), the resulting mixture was filtered to remove
any insoluble salts that had precipitated.
Step C
[0215] In a clean 500 mL-reactor, potassium carbonate (56.27 g,
407.2 mmol) was dissolved in water (202.5 g), and then
2-methyltetrahydrofurane (20.3 g) was added at room temperature.
The filtrate prepared as in STEP B above was then added dropwise
over 2 h. The resulting yellowish suspension was stirred over night
at room temperature, and the resulting precipitate isolated by
filtration and washed with water.
[0216] The reactor was then charged with the wet
product/precipitate (49.26 g) and 2-methyltetrahydrofurane (200.0
g), and the resulting mixture heated to 50.degree. C. to dissolve
the solid. The resulting solution was washed twice with a mixture
sodium hydroxide (30% in water) (7.58 g, 60.6 mmol and 7.56, 60.8
mmol, respectively) in water (40.0 g, 40.5 g, respectively) at
45-55.degree. C. and once with water (40.1 g). After removal of the
aqueous layer, cyclohexane (135.0 g) was added dropwise over 50 min
at 50.degree. C., during which time, crystallization was observed
to set in spontaneously. The resulting mixture was then slowly
cooled, then maintained at 0.degree. C. for 1 h. The precipitate
was isolated by filtration, washed with cyclohexane (60.0 g) and
dried in vacuo at 65.degree. C. to yield the title compound as a
light yellow solid.
Example 12
Hemi-tartrate of
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine
[0217] A 2 L-reactor was charged with
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine (200.0 g, 486 mmol) in a
nitrogen atmosphere. Denatured ethanol (770.0 g) followed by
isopropanol (230 g) were added and the resulting mixture was heated
to 45.degree. C. to yield a clear, yellow solution. To this
solution was added a solution of L-(+) tartaric acid (36.5 g, 243
mmol) in denatured ethanol (294.0 g) at 40-50.degree. C. over 70
min. The resulting solution was maintained at 40-50.degree. C. for
75 min, over which time crystallization was observed to occur. The
resulting suspension was slowly cooled to 15.degree. C., maintained
at this temperature overnight, then cooled further to 0.degree. C.
After 3 h 15 min at 0.degree. C., the title compound as a
precipitate was isolated by filtration, washed with cold denatured
ethanol (400 g) and dried in vacuo at 45.degree. C. to yield the
title compound as a slightly yellow, crystalline solid.
Example 13
Hemi-tartrate of
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine
[0218]
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-
-(1-methyl-piperidin-4-yl)-propyl]-amine (4.6 g, 10.8 mmol) was
dissolved in denatured ethanol (24.3 g) at 40-50.degree. C.
Cyclohexane (15.6 g) was added and the resulting mixture was heated
to reflux at atmospheric pressure to distill off solvent. The
azeotropic distillation was continued until the reflux temperature
reached 75.degree. C. After distillation, denatured ethanol (12.5
g) was added and the resulting solution was stirred at
40-50.degree. C. A solution of L-(+) tartaric acid (0.80 g, 5.4
mmol) in denatured ethanol (6.7 g) was added over 45 min, and the
resulting mixture maintained at 40-50.degree. C. for 40 min, then
seeding crystals of the desired hemi-tartrate. The resulting thin
suspension was maintained at 40-50.degree. C. for 4 h, then slowly
cooled to room temperature and maintained at room temperature
overnight. The resulting mixture was then cooled to 0.degree. C.
for 30-60 min, the resulting precipitate isolated by filtration,
washed with denatured ethanol (10.0 g) in 2 portions and dried in
vacuo at 40-50.degree. C. to yield the title compound as a white
crystalline solid.
Example 14
Recrystallization of Hemi-tartrate of
[5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine
[0219] A 500 mL-reactor was charged with
[5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-me-
thyl-piperidin-4-yl)-propyl]-amine hemi-tartrate (24.0 g, 25.7
mmol) and methanol (63.0 g). The resulting mixture was warmed to
50.degree. C. for 15 min, until all the solids were observed to
dissolve. Denatured ethanol (105.0 g) was then added and the
resulting solution was filtered (at 50.degree. C.) to remove any
remaining particles. The filtrate was heated briefly to reflux,
then cooled to approx. 60.degree. C., before seeding with crystals
of the desired hemi-tartrate. The resulting mixture was subjected
to the following temperature profile for crystallization: 1 h at
60.degree. C., cooling to 40.degree. C. over 2 h, heating to
50.degree. C. over 1 h, cooling to 30.degree. C. over 2 h, heating
to 40.degree. C. over 1 h, cooling to 20.degree. C. over 2 h,
heating to 30.degree. C. over 1 h, cooling to 10.degree. C. over 2
h, heating to 20.degree. C. over 1 h, then cooling to 0.degree. C.
over 2 h. The resulting suspension was maintained at 0.degree. C.
for 7 h, then the resulting solid precipitate was isolated by
suction filtration, washed with denatured ethanol (3.times.30.0 g)
and dried in vacuo at 40.degree. C. to yield the title compound as
a white crystalline solid.
Example 15
4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbalde-
hyde
##STR00032##
[0221] The following procedure represents a recipe for the
preparation of the title compound. The title compound was prepared
several times following the recipe detailed below.
[0222] A vessel at room temperature was charged with formic acid
(800 mL) and
4-methyl-2-(3-(1-methylpiperidin-4-yl)propylamino)pyrimidine-5-carbon-
itrile (100 g) and the resulting mixture stirred to yield a clear
solution, then cooled to 10-15.degree. C. Water (200 mL) was added
and the resulting mixture cooled to -2 to 0.degree. C. To the
resulting mixture was then added RANEY.RTM. nickel (160 g)
maintaining the temperature at -2 to 0.degree. C. and then stirred
at this temperature for 2-3 hours. The resulting mixture was then
filtered to remove the RANEY.RTM. nickel and the filtercake washed
with water (100 mL), The filtrate was cooled to 0-5.degree. C. and
then slowly treated with 50% sodium carbonate solution in water
(3.0 L) to adjust the pH of the solution to pH.about.10. Toluene
(400 mL) was added and the resulting mixture stirred at room
temperature for about 30 minutes, then allowed to settle for about
1 hour. The resulting layers were separated and the aqueous layer
washed with toluene (400 mL.times.2). The combined toluene layer
and washed were distilled at 55-60.degree. C. to remove the
toluene, to yield the title compound as an oily residue.
[0223] To the residue was added hexane (100 mL), the resulting
mixture stirred for 30 minutes, then distilled under vacuum to
yield a residue. To this residue was added hexane (200 mL) and the
resulting mixture cooled to 10-15.degree. C., then stirred at this
temperature for 1 hour, resulting in the formation of a
precipitate. The resulting mixture was filtered and the filtercake
washed with hexane (50 mL) and then dried first under vacuum and
then in an air oven at 30-35.degree. C. to yield the title compound
as a white to light yellow solid.
Example 16
Oral Formulation
[0224] As a specific embodiment of an oral composition, 100 mg of
the compound prepared as in Example 1 is formulated with sufficient
finely divided lactose to provide a total amount of 580 to 590 mg
to fill a size 0 hard gel capsule.
[0225] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *
References