U.S. patent application number 10/404076 was filed with the patent office on 2003-10-02 for methods for treatment of disorders of cardiac contractility.
This patent application is currently assigned to John Hopkins University. Invention is credited to Marban, Eduardo.
Application Number | 20030186998 10/404076 |
Document ID | / |
Family ID | 22059278 |
Filed Date | 2003-10-02 |
United States Patent
Application |
20030186998 |
Kind Code |
A1 |
Marban, Eduardo |
October 2, 2003 |
Methods for treatment of disorders of cardiac contractility
Abstract
The present invention relates to methods for modulating calcium
sensitivity of cardiac muscle. In preferred aspects, the invention
provides methods for enhancing myocardial contractility and cardiac
performance, and methods for treatment of heart failure and other
disorders associated with cardiac contractility by administration
of one or more xanthine oxidase inhibitor compounds.
Inventors: |
Marban, Eduardo;
(Lutherville, MD) |
Correspondence
Address: |
Peter F. Corless
DIKE, BRONSTEIN, ROBERTS & CUSHMAN, LLP
130 Water Street
Boston
MA
02109
US
|
Assignee: |
John Hopkins University
|
Family ID: |
22059278 |
Appl. No.: |
10/404076 |
Filed: |
April 1, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10404076 |
Apr 1, 2003 |
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09680876 |
Oct 6, 2000 |
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6569862 |
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09680876 |
Oct 6, 2000 |
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09186755 |
Nov 5, 1998 |
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6191136 |
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60064942 |
Nov 7, 1997 |
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Current U.S.
Class: |
514/262.1 ;
514/263.3 |
Current CPC
Class: |
A61K 31/4439 20130101;
A61K 31/216 20130101; A61K 31/549 20130101; A61K 31/53 20130101;
A61K 31/519 20130101; A61K 31/00 20130101; A61K 31/437
20130101 |
Class at
Publication: |
514/262.1 ;
514/263.3 |
International
Class: |
A61K 031/522; A61K
031/519 |
Claims
What is claimed is:
1. A method for treating heart failure in a mammal suffering from
or susceptible to heart failure, comprising administering to the
mammal a therapeutically effective amount of a compound that
provides increased cardiac contractile force as measured in a
standard in vitro calcium-sensitizing assay.
2. A method for enhancing efficiency of cardiac contraction in a
mammal, comprising administering to a mammal in need of such
treatment an effective amount of a xanthine oxidase inhibitor
compound.
3. The method of claim 2 wherein the mammal has been identified and
selected for treatment to increase myocardial contractility with
reduced energy requirements, and the compound is then administered
to the identified and selected mammal.
4. The method of any one of claims 1-3 wherein the compound is
administered to the mammal within about 6 hours after the mammal
has suffered heart failure.
5. The method of any one of claims 1-3 wherein the compound is
administered to the mammal within about 18 hours after the mammal
has suffered heart failure.
6. The method of any one of claims 1-3 wherein the compound is
administered to the mammal for at least about 1 week after the
mammal has suffered heart failure.
7. The method of any one of claims 1-3 wherein the compound is
administered to the mammal for at least about 4 weeks after the
mammal has suffered heart failure.
8. The method of any one of claims 1-7 wherein the mammal is
suffering from or susceptible to congestive heart failure.
9. The method of any one of claims 1-7 wherein the mammal is
suffering from or susceptible to cardiogenic shock.
10. A method for treatment of a disorder of cardiac contractility
in a mammal suffering from or susceptible to the disorder,
comprising administering to the mammal a therapeutically effective
amount of a xanthine oxidase inhibitor compound.
11. A method of increasing calcium sensitivity of cardiac muscle,
comprising administering to mammalian cardiac muscle an effective
amount of a xanthine oxidase inhibitor compound.
12. A method of claim 1 wherein the administered compound is a
xanthine oxidase inhibitor.
13. A method of any one of claims 1 through 11 wherein the compound
is allopurinol.
14. A method of any one of claims 1 through 11 wherein the compound
is oxypurinol.
15. A method of any one of claims 1 through 11 wherein the compound
is of any one of Formulae I through XXIII as those formulae are set
forth above.
16. A method of any one of claims 1 through 11 or 15 wherein the
compound induces at least about a 10 percent increase in cardiac
contractile force in a standard in vitro calcium-sensitizing
assay.
17. A method of any one of claims 1 through 11 or 15 wherein the
compound induces at least about a 20 percent increase in cardiac
contractile force in a standard in vitro calcium-sensitizing
assay.
18. A method of any one of claims 1 through 11 or 15 through 17
wherein the compound induces at least about a 3 percent decrease in
intracellular calcium concentration as measured in a standard in
vitro calcium-sensitizing assay.
19. A method of any one of claims 1 through 11 or 15 through 17
wherein the compound induces at least about a 5 percent decrease in
intracellular calcium concentration as measured in a standard in
vitro calcium-sensitizing assay.
20. The method of any one of claims 1 through 19 wherein the
compound is administered to a primate.
21. The method of any one of claims 1 through 19 wherein the
compound is administered to a human.
22. The method of any one of claims 1 through 21 wherein a mammal
that is suffering from heart failure is selected for treatment for
heart failure, and the compound is then administered to the
selected mammal.
23. The method of claim 11 wherein a mammal suffering from a
disorder of cardiac contractility is selected for treatment for the
disorder, and the compound is then administered to the selected
mammal.
24. A method for treating heart failure in a mammal suffering from
or susceptible to heart failure, comprising administering to the
mammal a therapeutically effective amount of a compound that
inhibits xanthine oxidase.
25. The method of claim 21 wherein the compound is administered to
the mammal within about 6 hours after the mammal has suffered heart
failure.
26. The method of claim 21 wherein the compound is administered to
the mammal within about 18 hours after the mammal has suffered
heart failure.
27. The method of claim 21 wherein the compound is administered to
the mammal for at least about 1 week after the mammal has suffered
heart failure.
28. The method of claim 21 wherein the compound is administered to
the mammal for at least about 4 weeks after the mammal has suffered
heart failure.
29. The method of any one of claims 21-28 wherein the mammal is
suffering from or susceptible to congestive heart failure.
30. The method of any one of claims 21-28 wherein the mammal is
suffering from or susceptible to cardiogenic shock.
31. A method for treatment method for a disorder of cardiac
contractility in a mammal suffering from or susceptible to the
disorder, comprising administering to the mammal a therapeutically
effective amount of a compound that inhibits xanthine oxidase.
32. A method of increasing calcium sensitivity of cardiac muscle,
comprising administering to mammalian cardiac muscle an effective
amount of a compound that inhibits xanthine oxidase.
33. A method of any one of claims 21 through 32 wherein the
compound is allopurinol.
34. A method of any one of claims 21 through 32 wherein the
compound is oxypurinol.
35. A method of any one of claims 21 through 32 wherein the
compound exhibits an IC.sub.50 of at least about 1 mM in a standard
in vitro xanthine oxidase assay.
36. A method of any one of claims 21 through 32 or 35 wherein the
compound is of any one of Formulae I through XXIII as those
formulae are set forth above.
37. A method of any one of claims 21 through 32 or 36 wherein the
compound induces at least about a 10 percent increase in cardiac
contractile force in a standard in vitro calcium-sensitizing
assay.
38. A method of any one of claims 21 through 32 or 36 wherein the
compound induces at least about a 20 percent increase in cardiac
contractile force in a standard in vitro calcium-sensitizing
assay.
39. A method of any one of claims 21 through 32 or 36 through 38
wherein the compound induces at least about a 3 percent decrease in
intracellular calcium concentration as measured in a standard in
vitro calcium-sensitizing assay.
40. A method of any one of claims 21 through 32 or 36 through 38
wherein the compound induces at least about a 5 percent decrease in
intracellular calcium concentration as measured in a standard in
vitro calcium-sensitizing assay.
41. The method of any one of claims 21 through 40 wherein the
compound is administered to a primate.
42. The method of any one of claims 21 through 40 wherein the
compound is administered to a human.
43. The method of any one of claims 21 through 42 wherein a mammal
that is suffering from heart failure is selected for treatment for
heart failure, and the compound is then administered to the
selected mammal.
44. The method of claim 31 wherein a mammal suffering from a
disorder of cardiac contractility is selected for treatment for the
disorder, and the compound is then administered to the selected
mammal.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 60/064,942, filed Nov. 7, 1997, which is
incorporated herein by reference in its entiretv.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to methods for modulating
calcium sensitivity of cardiac muscle. In preferred aspects, the
invention provides methods for enhancing myocardial contractility
and cardiac performance, and methods for treatment of heart failure
and other disorders associated with cardiac contractility bv
administration of one or more compounds that can increase cardiac
contractility such as a xanthine oxidase inhibitor compound. The
invention also provides methods for increasing cardiac contraction
efficiency through administration of a xanthine oxidase
inhibitor.
[0004] 2. Background
[0005] Heart failure afflicts more than two million Americans, and
congestive heart failure is recognized as the most common cause of
hospitalization and mortality in Western society.
[0006] Congestive heart failure is a syndrome characterized by left
ventricular dysfunction, reduced exercise tolerance, impaired
quality of life and dramatically shortened life expectancy.
Decreased contractility of the left ventricle leads to reduced
cardiac output with consequent systemic arterial and venous
vasoconstriction.
[0007] Captopril, enalapril and other inhibitors of
angiotensin-converting enzyme (ACE) have been used to treat
congestive heart failure. See Merck Index, 1759 and 3521 (11.sup.th
ed. 1989); Kramer, B. L. et al. Circulation 1983, 67(4):755-763.
However, such ACE inhibitors have generally provided only moderate
or poor results. For example, captopril therapy generally provides
only small increases in exercise time and functional capacity.
Captopril also has provided only small reductions in mortality
rates.
[0008] It thus would be desirable to have new therapies for
treatment of heart failure.
SUMMARY OF THE INVENTION
[0009] The present invention includes methods for modulating,
particularly increasing, calcium sensitivity of cardiac muscle.
That is, the invention provides new methods for increasing
contractile force of cardiac myofilaments, while decreasing
intracellular calcium concentrations.
[0010] It has been surprisingly found that administration of a
compound that can increase cardiac contractility, particularly a
xanthine oxidase inhibitor compound, can sensitize cardiac muscle
to intracellular calcium, and thus enable treatment of disorders
associated with cardiac contractility. See, for instance, the
results of the examples which follow.
[0011] Additionally, it has been unexpectedly found that xanthine
oxidase inhibitor compounds can improve efficiency of cardiac
contraction. In particular, it has been found that a xanthine
oxidase inhibitor compound can induce a positive inotropic effect
without increasing energy expenditure, thereby increasing
mechanical efficiency. See the examples which follow.
[0012] Still further, it has been found that significantly elevated
levels of xanthine oxidase activity may exist in subjects suffering
from heart failure, relative to control subjects not suffering from
heart failure. See, for instance, Example 6 below and FIG. 10 of
the drawings, which details a four-fold increase in xanthine
oxidase activity in subjects with heart failure, relative to
controls. Those results indicate that xanthine oxidase inhibitors
can act preferentially in heart failure patients, i.e. that
xanthine oxidase inhibitors can boost contractility and efficiency
more in failing than normal hearts.
[0013] More specifically, methods of the invention include
treatment of disorders associated with cardiac contractility,
particularly heart failure including congestive heart failure and
cardiogenic shock. In one aspect, the treatment methods of the
invention in general comprise administration of a therapeutically
effective amount of one or more compounds that can increase cardiac
contractility to a patient in need of treatment, such as a mammal,
particularly a primate such as a human. Preferred compounds for
administration include those that inhibit xanthine oxidase (a
xanthine oxidase inhibitor).
[0014] The invention also includes methods for improving efficiency
of cardiac contraction to a patient in need of such treatment.
These methods in general comprise administration of an effective
amount of a xanthine oxidase inhibitor compound to the patient,
particularly an effective amount of allopurinol or oxypurinol.
Preferably, a patient will be identified and selected for such
treatment, e.g. a patient that is suffering heart failure,
including congestive heart failure, where an increase in myocardial
contractility with reduced energy requirements is an intended
desired therapy.
[0015] The methods of the invention include both acute and chronic
therapies.
[0016] For example, a xanthine oxidase inhibitor can be immediately
administered to a patient (e.g. i.p. or i.v.) that has suffered or
is suffering from congestive heart failure or cardiogenic shock.
Such immediate administration preferably would entail
administration of a xanthine oxidase inhibitor within about 1, 2,
4, 8, 12 or 24 hours, or from more than one day to about 2 or three
weeks, after a subject has suffered from heart failure such as
congestive heart failure or cardiogenic shock.
[0017] Relatively long-term administration of a therapeutic agent
also will be beneficial after a patient has suffered from chronic
heart failure to provide increased exercise tolerance and
functional capacity. For example, a xanthine oxidase inhibitor can
be administered regularly to a patient for at least 2, 4, 6, 8, 12,
16, 18, 20 or 24 weeks, or longer such 6 months, 1 years, 2 years
three years or more, after having suffered heart failure to promote
enhanced functional capacity. An oral dosage formulation would be
preferred for such long-term administration.
[0018] A wide variety of compounds, including xanthine oxidase
inhibitors, can be employed in the methods of the invention. For
example, suitable xanthine oxidase inhibitor compounds have been
previously reported including the compounds disclosed in U.S. Pat.
Nos. 5,674,887; 5,272,151; 5,212,201; 4,495,195; 4,346,094;
4,281,005; 4,241,064; 4,179,512; 4,058,614; 4,024,253; 4,021,556;
3,920,652; 3,907,799; 3,892,858; 3,892,738; 3,890,313; 3,624,205;
3,474,098; and 2,868,803.
[0019] Specifically preferred therapeutic compounds for use in the
methods of the invention include allopurinol
(4-hydroxy-pyrazolo[3,4-dlpyrimidine- ) and oxypurinol
(4,6-dihydroxypyrazolo[3,4-dlpyrimidine), and pharmaceutically
acceptable salts of those compounds.
[0020] Other aspects of the invention are disclosed below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 shows graphically the results of Example 1 which
follows, specifically the effects of allopurinol on the contractile
force (lower panel) and calcium ion concentration of cardiac muscle
relative to a control that was not exposed to allupurinol.
[0022] FIG. 2 shows graphically the results of Example 2,
specifically the effects on the steady state contractile force of
cardiac muscle upon exposure to allopurinol (open circles in plot)
and a control of no drug (closed circles in plot).
[0023] FIG. 3 shows graphically the results of Example 3 which
follows, specifically effects on the steady state contractile force
of cardiac muscle upon exposure to oxypurinol (open circles in
plot) and a control of no drug (closed circles in plot).
[0024] FIG. 4 shows graphically the results of Example 3 which
follows, specifically the effects on the steady state contractile
force of cardiac muscle upon exposure to allopurinol (open circles
in plot), oxypurinol (open circles in plot) and a control of no
drug (closed circles in plot).
[0025] FIGS. 5-8 show graphically the results of Example 4. In
FIGS. 5-7, squares in plot represent control dogs and circles in
plots represent heart failure dogs.
[0026] FIG. 5 shows graphically the results of Example 4 which
follows, specifically the effect of allopurinol on relation between
stroke work and end-diastolic dimension (preload recruitable stroke
work).
[0027] FIGS. 6A-6B show graphically the results of Example 4 which
follows, specifically the effect of allopurinol on myocardial
contractility in conscious dogs.
[0028] FIGS. 7A-7B show graphically the results of Example 4 which
follows, specifically the effect of allopurinol on O.sub.2
consumption and mechanical efficiency anesthetized control and
heart failure dogs.
[0029] FIG. 8 show graphically the results of Example 4 which
follows, specifically representative tracings of left circumflex
blood velocity before and 10 minutes after 200 mg allopurinol i.v.
administration over 30 minutes in a heart failure dog.
[0030] FIG. 9 shows graphically the results of Example 5 which
follows, specifically the comparison of energetic effects of
allopurinol to those of dobutamine.
[0031] FIG. 10 shows graphically the results of Example 6 which
follows, specifically the comparison of xanthine oxidase activity
in normal and heart failure dogs.
DETAILED DESCRIPTION OF THE INVENTION
[0032] As stated above, and demonstrated in the examples which
follow, it has now been found that administration of a compound
that can increase cardiac contractility, particularly a xanthine
oxidase inhibitor compound, to a subject can sensitize cardiac
muscle to intracellular calcium ions ([Ca.sup.2+]). Calcium is the
intracellular chemical signal that initiates contraction by binding
to cardiac myofilaments. Thus, xanthine oxidase inhibitors which
increase calcium sensitivity of cardiac myofilaments can boost
contractility without imparting a primary effect on calcium cycling
properties of heart cells.
[0033] It is believed the methods of the invention are further
unique in that cardiac myofilaments are sensitized to calcium
without altering cyclic AMP levels by phosphodiesterase
inhibition.
[0034] It is also believed that preferred methods of the invention
can sensitize myofilaments to Ca.sup.2+ to cause cardiac myocytes
to generate more force for a given amount of cytoplasmic free
Ca.sup.2+. In this regard, it should be appreciated that myocyte
Ca.sup.2+ cycling can be slowed and blunted during heart
failure.
[0035] Moreover, as discussed above, it has been found that
preferred xanthine oxidase inhibitor compounds can improve
efficiency of cardiac contraction. See the results set forth in the
examples which follow.
[0036] The methods of the invention in general comprise
administration of a therapeutically effective amount of one or more
compounds that can increase cardiac contractility, particularly a
xanthine oxidase inhibitor compounds. Allopurinol and oxypurinol
are particularly preferred agents.
[0037] Typical subjects for treatment include persons susceptible
to, suffering from or that have suffered a disorder associated with
cardiac contractility. In particular, suitable subjects for
treatment in accordance with the invention include persons that are
susceptible to, suffering from or that have suffered heart failure,
particularly congestive heart failure or acute cardiogenic shock.
The efficacy of any particular therapeutic agent the treatment
methods of the invention can be readily determined. For example,
suitable compounds can be identified through the in vitro
calcium-sensitizing assay as disclosed in Example 1 which follows,
and which includes the following steps a) through c): a) mounting
dissected rat cardiac specimens in a tissue bath in which fura-2
has been microinjected into the tissue to enable measurement of
intracellular calcium concentration ([Ca.sup.2+].sub.i], b) adding
a candidate therapeutic compound to the tissue bath, c) measuring
contractile force and/or (Ca.sup.2+].sub.i] of the cardiac specimen
both before and after addition of the candidate compound.
References herein to a standard in vitro calcium-sensitizing assay
refers to that protocol of steps a) through c).
[0038] Preferred compounds for use in the therapeutic methods of
the invention induce at least about a 3% or 5% increase in cardiac
contractile force relative to contractile force measured in absence
of the tested compound in such a standard in vitro
calcium-sensitizing assay, more preferably at least about a 10% or
15% increase in cardiac contractile force relative to a control,
and still more preferably induce at least about 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90% or 100% increase in cardiac contractile force
relative to absence of the tested compound in such a standard in
vitro calcium-sensitizing assay.
[0039] Even more preferred compounds for use in the present
therapeutic methods induce such increases in contractile force, and
further induce a decreased intracellular calcium concentration
([Ca.sup.2+].sub.i). Preferably, such compounds induce at least
about a 3% or 5% decrease in intracellular calcium concentration
relative to intracellular calcium concentration measured in absence
of the compound in such a standard in vitro calcium-sensitizing
assay, more preferably at least about a 10 or 15% decrease in
intracellular calcium concentration, and still more preferably
induce at least about 20%, 25%, 30%, 40% or 50% decrease in
intracellular calcium concentration relative to intracellular
calcium concentration measured in absence of the therapeutic
compound in such a standard in vitro calcium-sensitizing assay.
Such decrease in intracellular calcium concentration would be
expected to be an energy saving effect.
[0040] Even more preferred compounds for use in the methods of the
invention are those that improve efficiency of cardiac contraction.
Preferably such compounds can induce at least about a 5% or 10%
increase in preload-recruitable stroke work (PRSW) in heart failure
dogs relative to control dogs (no therapeutic compound
administered) with PRSW values measured at 30 minutes after test
compound administration, more preferably at least about a 15%, 20%,
30%, 40%, 50%, or even about 55%, 60% or 70% increase in PRSW in
heart failure dogs relative to control dogs with PRSW values
measured at 30 minutes after test compound administration, and with
PRSW values determined in a standard in vivo dog pacing induced
heart failure model as such model is described in Example 5 which
follows and includes the following steps a) through c): a) inducing
heart failure in dogs by chronic rapid ventricular pacing, b)
infusing a xanthine oxidase inhibitor, such as allopurinol or
oxypurinol, into the right atrium of the test dogs at a rate of 3.3
mL/min. at a properly determined dosage, c) recording the
pressure-dimension relationships and the arterial pressure
response. References herein to a "standard in vivo dog pacing
induced heart failure model" designate a protocol as described in
Example 5 below and including those steps a) through c).
[0041] As discussed above, xanthine oxidase inhibitors are
particularly preferred for use in the treatment methods of the
invention. The ability of a particular candidate compound to
inhibit xanthine oxidase can be assessed by known protocols, such
as the following. This following described protocol is referred to
herein as "a standard in vitro xanthine oxidase assay": Xanthine
oxidase can be obtained from known sources such as from rat liver
according to method disclosed in Della Corte, E. et al., Biochem J
1970, 117:97, and aged for at least 24 hours prior to use.
Solutions of 3 ml of 0.1M aqueous tris hydrochloride buffer (pH 8.
1) containing 10.sup.-5 M xanthine are treated with 200 .mu.l of
xanthine oxidase dissolved in 0.1 M aqueous tris hydrochloride
buffer (pH 8.1) and incubated at 30.degree. C. in the presence and
absence of a candidate compound, and where the formation of uric
acid from xanthine is monitored by measunng light absorption at 293
nm. The IC.sub.50 (concentration of candidate compound to provide
50% inhibition of xanthine oxidase-catalyzed oxidation of xanthine
to uric acid) then can be determined. Xanthine oxidase inhibitors
generally suitable for purposes of the invention will exhibit a
detectable inhibition of the xanthine oxidase-catalyzed oxidation
of xanthine to uric acid in the above assay, and preferably will
exhibit an IC.sub.50 of at least about 1 mM, more preferably an
IC.sub.50 about 100 mM in that assay.
[0042] As mentioned above, in one aspect, the methods of the
invention in general comprise administration of a therapeutically
effective amount of one or more compounds that can increase cardiac
contractility, such as xanthine oxidase inhibitor compounds.
Compounds that exhibit in vitro activity may then be further
evaluated. The in vivo efficacy of any particular therapeutic agent
in the treatment methods of the invention can be readily
determined. For example, suitable compounds can be identified
through the in vivo induced heart failure model as disclosed in
Example 5 which follows, and which includes the following steps a)
through c) as also discussed above: a) inducing heart failure in a
dog by chronic rapid ventricular pacing, b) infusing a xanthine
oxidase inhibitor, such as allopurinol or oxypurinol, into the
right atrium at a rate of 3.3 mL/min. at a properly determined
dosage, c) recording the pressure-dimension relationships and the
arterial pressure response. Cardiac oxygen consumption also may be
measured as disclosed in Example 5.
[0043] In addition to the above discussed xanthine oxidase
inhibitors, suitable inhibitor compounds for use in the methods of
the invention are disclosed below. It should be appreciated however
that the present invention is not limited by the particular
xanthine oxidase inhibitor, and the invention is applicable to any
such xanthine oxidase inhibitor compound now known or subsequently
discovered or developed.
[0044] More specifically, suitable compounds to use in the
treatment methods of the invention include compounds of the
following Formulae I and II: 1
[0045] and pharmacologically acceptable salts thereof wherein R,
R.sup.1 and R.sup.4 are similar or dissimilar groups selected from
hydrogen and lower alkyl having from 1 to about 5 carbon atoms, X
is selected from halogen, particularly chloro or bromo,
trifluoromethyl, and lower alkyl having advantageously from 1 to 3
carbon atoms and R.sup.2 is a diazine attached through one of its
carbon atoms to the benzothiadiazine nucleus and optionally mono-
or di-substituted with similar or dissimilar groups selected from
C.sub.1-3 alkyl, halo, preferably chloro and bromo, lower alkoxy
and hydroxy. The diazine substituent is derived from a pyrazine,
pyridazine or pyrimidine and attachment to the benzothiadiazine
nucleus can be through any of the available carbons of the diazine
nucleus. Compounds of the above Formula I and II can be suitably
synthesized prepared through any of the known procedures for making
benzothiadiazine compounds (for compounds of Formula I) or
3,4-dihydrobenzothiadiazine compounds (for compounds of Formula
II). See also U.S. Pat. No. 3,890,313.
[0046] Additional suitable compounds for use in the methods of the
invention include those of the following Formula III: 2
[0047] and pharmacologically acceptable salts thereof wherein X
represents halo (preferably chloro), C .sub.13-alkyl (particularly
methyl) and trifluoromethyl; R represents hydrogen, a straight or
branched chain lower alkyl having from 1 to 6 carbon atoms and
phenyl-lower alkyl having from 1 to 3 carbon atoms (preferably
benzyl); R.sup.1 represents hydrogen, lower alkyl having from 1 to
5 carbon atoms or substituted lower alkyl wherein the substituent
is mono or dihalo (preferably chloro), and phenyl, the group
--CO.sub.2 lower alkyl having from 1 to 5 carbon atoms, an azine
optionally substituted with one or more lower alkyl having 1 to 3
carbon atoms or a diazine optionally substituted with one or more
lower alkyl having from 1 to 3 carbon atoms, or the group
--CONR.sup.2 R.sup.3 wherein R.sup.2 and R.sup.3 can be similar or
dissimilar and selected from hydrogen, lower alkyl having 1 to 5
carbon atoms or hydroxy substituted lower alkyl having 1 to 5
carbon atoms. Compounds of Formula III can be suitably prepared by
known methods. See, in particular, the procedures disclosed in U.S.
Pat. No. 3,892,738.
[0048] Additional compound that will be useful in the methods of
the invention include compounds of the following Formula IV: 3
[0049] and pharmaceutically acceptable salts thereof wherein X
represents halo (preferably chloro), C.sub.1-3-alkyl (particularly
methyl) and trifluoromethyl; R represents a straight or branched
chain lower alkyl having from 1 to 6 carbon atoms and phenyl-lower
alkyl having from 1 to 3 carbon atoms (preferably benzyl); R.sup.1
represents (1) hydrogen, (2) lower alkyl having from 1 to 5 carbon
atoms or substituted lower alkyl wherein the substituent is mono,
di- or trihalo (preferably chloro), and phenyl, (3) the group
--CO.sub.2R.sup.2 wherein R-2- is hydrogen or lower alkyl having
from 1 to 5 carbon atoms, (4) the group --CONH.sub.2 or (5) an
azine optionally substituted with one or more lower alkyl having 1
to 3 carbon atoms or a diazine optionally substituted with one or
more lower alkyl having from 1 to 3 carbon atoms. Compounds of
Formula IV can be suitably prepared by known methods for making
benzothiadiazine compounds. See, in particular, the procedures
disclosed in U.S. Pat. No. 3,892,858.
[0050] Additional useful compounds for use in the methods of the
invention include imidazo [1 ,2,a] and pyrazolo[1,5, a]pyrimidine
compounds, particularly those of the following Formula V: 4
[0051] Y.sub.1 and Y.sub.2 are carbon or nitrogen; R.sub.1 is H or
an alkali metal or ammonium; R.sub.2 is H, CH.sub.3, a halogen,
phenylazo or NO.sub.2;
[0052] R.sub.3 is OR.sub.1, H, or a halogen; and R.sub.4 is H,
NO.sub.2 or a halogen. When Y.sub.1 is carbon, Y.sub.2 is nitrogen,
thereby forming the pyrazolo compounds, and when Y.sub.1 is
nitrogen, Y.sub.2 is carbon, thus providing the imidazo compounds.
Such imidazo [1,2,a] and pyrazolo[1,5,a]pyrimidine compounds can be
synthesized by known procedures. See, in particular, the procedures
disclosed in U.S. Pat. No. 3,907,799.
[0053] Additional suitable pyrazolo[1,5a]pyrimidine compounds for
use in the methods of the invention include compounds of the
following Formula VI: 5
[0054] R is an aromatic or substituted aromatic nucleus, as for
example, phenyl, naphthyl, tolyl, halogenated phenyls, heterocyclic
nucleus, etc., R.sub.1 is H, an alki metal or ammonium, and R.sub.2
is H or OR.sub.1. Examples of suitable R substituents include
phenyl, 1-naphthyl, substituted phenyls of the formula VIa 6
[0055] where R.sub.3 is CH.sub.3, a halogen, or 7
[0056] m-tolyl, heterocyclic nucleus as for example 8
[0057] R.sub.1 is preferably H thus yielding 5,7-dihydroxy
pyrazolo[1,5a] pyrimidines where R.sub.2 is OR.sub.1, although
physiologically acceptable salts as for example, alkali metal or
ammonium, may also be used. Again, such pyrazolo[1,5,a]pyrimidine
compounds can be synthesized by known procedures, e.g. as disclosed
in U.S. Pat. No. 3,920,652.
[0058] Additional compounds useful in the methods of the invention
include those of the following Formula VII: 9
[0059] wherein
[0060] R.sup.1 is 10
[0061] in which Y is lower alkyl or phenyl;
[0062] R.sup.2 is substituted either at the 4'-position or at the
5'-position and is hydrogen, fluoro, bromo, chloro, hydroxy, lower
alkyl or 11
[0063] in which Y is lower alkyl or phenyl;
[0064] R.sup.3 is chloro, bromo or lower alkyl;
[0065] R.sup.4 is hydroxy, amine, lower alkoxy or 12
[0066] in which Y is lower alkyl or phenyl;
[0067] R.sup.5 is hydrogen, fluoro, bromo, chloro, carboxyl, lower
alkyl or 13
[0068] in which Z is lower alkyl; and the nontoxic,
pharmaceutically acceptable metal salts of said compound in which
R.sup.5 is carboxyl. Compounds of Formula VII may be suitably
prepared as described in U.S. Pat. No. 4,024,253.
[0069] Additional suitable compounds for use in the methods of the
invention include substituted imidazole compounds of the following
Formula VIII: 14
[0070] wherein
[0071] R.sub.1 is hydrogen or alkyl containing 1 to 3 carbon
atoms;
[0072] R.sub.2 is halogen; and
[0073] R.sub.3 is halogen or --CF.sub.3;
[0074] or a pharmaceutically acceptable salt thereof. Preferred
compounds of Formula VII include those where R.sub.1 is hydrogen,
R.sub.2 is chlorine or bromine and R.sub.3 is chlorine, bromine or
CF.sub.3. Compounds of Formula VIII may be suitably prepared as
described in U.S. Pat. No. 4,058,614.
[0075] Further suitable compounds for use in the methods of the
invention include 2,4(5)disubstituted imidazoles, including
compounds of the following Formulae IX and X: 15
[0076] and pharmaceutically acceptable salts thereof wherein:
[0077] R.sub.1 is selected from the group consisting of monohalo
(e.g. Cl, Br, I or F)-phenyl, dihalo(e.g. Cl or Br)-phenyl and
pyridyl (e.g. 3-pyridyl, 4-pyridyl), halo is Cl, Br,I or F
[0078] R.sub.2 is selected from the group consisting of
C.sub.1-C.sub.5 alkyl--S--, C.sub.1-C.sub.5 alkyl--SO--,
C.sub.1-C.sub.5 alkyl--SO.sub.2-- and R.sub.3R.sub.4N--SO.sub.2--,
and
[0079] R.sub.3 and R.sub.4 are independently selected from H,
C.sub.1-C.sub.5 alkyl and hydroxy substituted C.sub.2-C.sub.5
alkyl. The alkyl moiety in the R.sub.2 groups defined above
includes branched or straight chain alkyl groups such as
CH.sub.3--, t-butyl, n-pentyl and the like. The hydroxy substituted
C.sub.2-C.sub.5 alkyl groups are also branched and straight chain
alkyls having 1-2 hydroxy groups - the monohydroxy straight chain
alkyls are preferred e.g. --CH.sub.2--CHOH--CH.sub.3 and
--(CH.sub.2).sub.5--OH. Compounds of Formulae IX and X may be
suitably prepared as described in U.S. Pat. No. 4,179,512. That
patent also disclose preferred compounds of the above formulae,
identified as compounds of formulae II and III in U.S. Pat. No.
4,179,512.
[0080] Additional suitable compounds for use in the methods of the
invention include 1-substituted-9H-pyrido[3,4-b]indole compounds,
including compounds of the following Formula XI: 16
[0081] wherein
[0082] one of R.sup.1 and R.sup.2 is hydrogen and the other is
hydrogen, hydroxy or --OR.sup.4 wherein R.sup.4 is alkanoyl of 2 to
7 carbon atoms, tosyl or mesyl and
[0083] R.sup.3 is hydroxymethyl, formyl, carboxy or carbalkoxy
wherein alkoxy contains 1 to 6 carbon atoms. In that formula X, the
term "alkanoyl of 2 to 7 carbon atoms" refers to a group of the
formula (C.sub.xH.sub.2x+1)CO wherein x has a value of 1 to 6, e.g.
acetyl, propionyl, butyryl and the like. Alkoxy of 1 to 6 carbon
atoms refers to the group (C.sub.xH.sub.2x+1)--O-- wherein x is
again 1 to 6. Compounds of Formula XI may be suitably prepared as
described in U.S. Pat. No. 4,241,064.
[0084] Further compounds suitable for use in the methods of the
invention include compounds of the following Formulae XII through
XV: 17
[0085] wherein in Formula XII, R is 3-pyridyl or 4-pyridyl and
R.sub.1 is C.sub.1-C.sub.5 alkyl, branched or unbranched, e.g.
t-butyl, n-pentyl, isopropyl, and pharmaceutically acceptable salts
thereof; 18
[0086] wherein in Formula XIII, R is 3-pyridyl or 4-pyridyl,
R.sub.2 is bromo or chloro, and R.sub.3 is hydrogen, bromo or
chloro, and pharmaceutically acceptable salts thereof; and 19
[0087] wherein in each of Formula XIV and XV, R is 3-pyridyl or
4-pyridyl, and pharmaceutically acceptable salts thereof. Compounds
of those Formula XI through XIV can be suitably prepared as
disclosed in U.S. Pat. No. 4,281,005.
[0088] Additional suitable compounds include 3-aryl-5-isothiazoles,
including compounds of the following Formula XVI: 20
[0089] wherein
[0090] Ar is pyridyl, thienyl, phenyl or 21
[0091] wherein R.sup.1, R.sup.2 and R.sup.3 are individually H,
CF.sub.3, halogen, alkyl or O-alkyl or R.sup.1 and R.sup.2 or
R.sup.2 and R.sup.3 when taken together are methylenedioxy;
[0092] X is NH.sub.2, H, halogen, OH or NH-alkyl;
[0093] R is OH, OM, O-alkyl, NH.sub.2, NH-alkyl or
N(alkyl).sub.2;
[0094] wherein halogen is Cl, F, I, or Br; and M is a nontoxic
cation, preferably an alkali metal cation such as K or Na. an
alkaline earth metal cation such as Mg or Ca, another nontoxic
metal cation such as Al or Zn or a nontoxic metalloid cation such
as NH.sub.4.sup.+, piperazinium, 2-hydroxyethylammonium and the
like. In that Formula XVI, alkyl is preferably lower alkyl such as
(C.sub.1-C.sub.3) alkyl including methyl, ethyl, n-propyl or
isopropyl. Compounds of Formula VXI may be suitably prepared as
described in U.S. Pat. No. 4,346,094.
[0095] Additional suitable compounds useful in the methods of the
invention include substituted pyrazole compounds, particularly
those of the following Formulae XVII, XVIII and XIX: 22
[0096] wherein Ar is pyridyl, thienyl or 23
[0097] wherein
[0098] R.sup.1, R.sup.2and R.sup.3 are individually H, C.sub.1-3
haloalkyl, F, Br, Cl, I, C.sub.1-3 alkyloxy, R.sup.1 and R.sup.2 or
R.sup.2 and R.sup.3 taken together represent methylmedioxy,
provided at least one of R.sup.1, R.sup.2 and R.sup.3 is H, one of
R.sup.1, R.sup.2 and R.sup.3 is other than H and only one of
R.sup.1, R.sup.2 and R.sup.3 can be I;
[0099] R is OH, OM, NH.sub.2, N-alkyl, N(alkyl).sub.2, O-alkyl or
N-alkenyl-N(alkyl).sub.2;
[0100] X is NH.sub.2, OH, H, F, Cl, Br, I or C.sub.1-3 alkyl; alkyl
is C.sub.1-5 alkyl; alkenyl is (CH.sub.2).sub.2 or
(CH.sub.2).sub.3; and M is a nontoxic cation. It should be
appreciated that compounds of the above Formula XVIII and XIX can
exist as a corresponding tautomeric pair, i.e. as a
3-aryl-pyrazole-5-carboxylic acid and a 5-arylpyrazole-3-carbox-
ylic acid. Also, when one or more of R.sup.1, R.sup.2 or R.sup.3
substituents of Formulae XVII, XVIII and XIX are C.sub.1-3
haloalkyl derivatives, preferably such group will be fully
halogenated such as in a trifluoromethyl or pentachloroethyl group.
Such a fully halogenated alkyl radical is more stable than
partially-halogenated haloalkyl radicals and maintain their
structural integrity during most synthetic procedures. A preferred
group of compounds of Formula XVII, XVIII and XIX are those where
Ar is substituted phenyl, in particular 3 or
4-trifluoromethylphenyl, 3 or 4-chlorophenyl, 3 or 4-bromophenyl or
3 or 4-methoxyphenyl. Compounds where Ar is 3-trifluoromethylphenyl
are especially preferred. Also preferred are those compounds of
Formulae XVII, XVIII and XIX in which X is H, OH or NH.sub.2, and
particularly preferred compounds include those where X is H. Still
further preferred are those compounds of Formulae XVII, XVIII and
XIX that are free acids (R.dbd.OH) or pharmaceutically-acceptable
salts thereof (M is a non-toxic cation). The term "C.sub.1-5 alkyl"
as used in reference to Formulae XVII, XVIII and XIX includes such
radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 3-pentyl,
3-methyl-1-butyl, 3-methyl-2-butyl and the like. The term
"C.sub.1-3 alkyl" as used in reference to Formulae XVII, XVIII and
XIX includes methyl, ethyl, n-propyl and isopropyl.
[0101] The term "C.sub.1-3 haloalkyl" as used in reference to
Formulae XVII, XVIII and XIX designates halogenated derivations of
the C.sub.1-3 alkyl radicals listed above and includes such
radicals as trifluoromethyl, trichloromethyl, difluoromethyl,
chlorodifluoromethyl, bromomethyl, .alpha.,.alpha.-difluoroethyl,
pentafluoroethyl, heptafluoro-n-propyl, pentachloroethyl,
iodomethyl, etc. Preferred pharrnaceutically-acceptable salts of
compounds of Formula XVII, XVIII and XIX include those formed with
a non-toxic cation, preferably an alkali metal cation such as K or
Na, an alkaline earth metal cation such as Mg or Ca, another
non-toxic metal cation such as Al or Zn or a non-toxic metalloid
cation such as NH.sub.4.sup.+, piperazinium or
2-hydroxyethylammonium. Compounds of Formulae XVII, XVIII and XIX
may be suitably prepared by methods disclosed in U.S. Pat. No.
4,495,195.
[0102] Further compounds suitable for use in the methods of the
invention include those of the following Formula XX: 24
[0103] wherein R is 4'--OH or 5'--OH, or a pharmaceutically
acceptable salt thereof. Methods for obtaining compounds of Formula
XX are disclosed in U.S. Pat. No. 5,212,201.
[0104] Additional suitable compounds for use in the methods of the
invention include aminoacyl and oligopeptidyl derivatives of
allopurinol of the following Formula XXI: 25
[0105] and pharmaceutically acceptable salts thereof with
pharmacologically-acceptable cations, and in which above formula n
is an integer between 2 and 6, preferably 5, Y is H or CO--A, in
which A is a racemic or chiral amino acid, dipeptide, tripeptide,
tetrapeptide, or pentapeptide chose, respectively, from the groups
consisting of:
[0106] a) arginine, aspartic acid, lysine, leucine;
[0107] b) glycylaspartate, glycylglycine, aspartylarginine,
leucylarginine, alanylglycine;
[0108] c) arginyllysylaspartate, aspartyllysylarginine,
lysylprolylarginine, prolylprolylarginine,
lysylhistidylglycinamide, prolylphenylalanylarginine,
phenylalanylprolylarginine;
[0109] d) arginyllysylaspartylvaline, valylaspartyllysylarginine,
threonylvalylleucylhistidine;
[0110] e) arginyllysylaspartylvalyltyrosine. For the purposes of
Formula XXI, "amino acid, dipeptide, tripeptide, tetrapeptide, or
pentapeptide" are taken to mean an amino acid, dipeptidyl,
tripeptidyl, tetrapeptidyl, or pentapeptidyl moiety bonded to a CO
group by an amino nitrogen. By "pharmacologically-acceptable
cations" is meant cations such as sodium, potassium, magnesium,
ammonium, and whichever other cations experts in the field may
elect to designate a pharmacologically acceptable. Compounds of
Formula XXI can be readily prepared by known methods such as
disclosed in U.S. Pat. No. 5,272,151.
[0111] Additional suitable compounds for use in the methods of the
invention include pyrazolotriazine compounds, particularly those of
the following Formula XXII: 26
[0112] wherein
[0113] R.sup.1 is hydroxy or a lower alkanoyloxy,
[0114] R.sup.2 is hydrogen atom, hydroxy, or mercapto,
[0115] R.sup.3 is (1) an unsaturated heterocyclic group containing
nitrogen or sulfur atom as the hetero atom, which may optionally
have one or two substituents selected from a halogen atom, nitro,
and phenylthio, (2) naphthyl, (3) a phenyl which may optionally
have one to three substituents selected from the group consisting
of (i) a lower alkyl, (ii) phenyl, (iii) a lower alkoxycarbonyl,
(iv) cyano, (v) nitro, (vi) a lower alkoxy, (vii) a phenyl-lower
alkoxy, (viii) a phenylthio-lower alkyl, (ix) phenoxy, (x) a group
of the formula: 27
[0116] wherein R is a lower alkyl, a halogen-substituted lower
alkyl, a phenyl which may optionally have one to three substituents
selected from a halogen atom, a lower alkyl and a lower alkoxy, or
pyridyl, and I is an integer of 0, 1 or 2, (xi) a halogen atom,
(xii) a phenyl-lower alkyl, (xiii) carboxy, (xiv) a lower alkanoyl,
(xv) a benzoyl which may optionally have one to three substituents
selected from a halogen atom, a phenoyl-lower alkoxy and hydroxy on
the phenyl ring, (xvi) amino, (xvii) hydroxy, (xviii) a lower
alkanoyloxy, (xix) a group of the formula: 28
[0117] wherein R.sup.4 and R.sup.5 are the same or different and
are each hydrogen atom, a cycloalkyl, a lower alkyl which may
optionally have a substituent selected from hydroxy, furyl,
thienyl, tetrahydrofuranyl and phenyl, a phenyl which may
optionally have one to three substituents selected from a lower
alkyl, a hydroxy-substituted lower alkyl, a lower alkanoyl, cyano,
carboxy, a lower alkoxycarbonyl, hydroxy, a lower alkoxy, and a
halogen atom, or a heterocyclic group selected from pyridyl,
pyrimidinyl, thiazolyl, isoxazolyl, and pyrazolyl, said
heterocyclic group being optionally substituted by a lower alkyl,
amino, or a lower alkanoylamino, or R.sup.4 and R.sup.5 may join
together with the adjacent nitrogen atom to form a saturated 5- or
6-membered heterocyclic group which may optionally be intervened
with oxygen atom, or (xx) a group of the formula: 29
[0118] wherein A is a lower alkylene.
[0119] In the above Formula XXII, the identified groups include
specifically the following groups. The "lower alkyl" includes alkyl
groups having 1 to about 6 carbon atoms, for example, methyl,
ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc. The
"halogen atom" includes, for example, fluorine, chlorine, bromine,
and iodine. The "lower alkoxy" includes alkoxy groups having 1 to
about 6 carbon atoms, for example, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc. The "lower
alkoxy", "lower alkanoyloxy" and "lower alkanoylamino" include as
the lower alkanoyl moiety alkanoyl groups having 1 to about 6
carbon atoms, for example, forrnyl, acetyl, propionyl, butyryl,
isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc. The
"unsaturated heterocyclic group containing nitrogen or sulfur atom
as the hetero atom" includes monocyclic or condensed heterocyclic
groups containing nitrogen or sulfur atom, for example, pyrrolyl,
pyridyl, thienyl, thiopyranyl, indolyl, benzothienyl,
2,3-dihydrobenzothienyl, thiochromanyl, dibenzothienyl, etc. The
heterocyclic group may optionally have one or two substituents
selected from a halogen atom, nitro and phenylthio. Suitable
examples of the heterocyclic group are, for example, 2-pyrrolyl,
3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl.
2-thiopyranyl, 3-thiopyranyl, 4-thiopyranyl, 5-chloro-2-thienyl,
5-bromo-2-thienyl, 4-bromo-2-thienyl, 2-bromo-3-thienyl,
2,5-dichloro-3-thienyl, 2,5-dibromo-3-thienyl,
4,5-dibromo-2-thienyl, 4,5-dibromo-3-thienyl, 2-chloro-5-pyridyl,
2,3-dibromo-5-pyridyl, 5-nitro-2-thienyl, 4-nitro-2-thienyl,
3-nitro-2-thienyl, 2-nitro-3-thienyl, 2-nitro-4-pyridyl,
6-nitro-2-pyridyl, 3-phenylthio-2-thienyl, 5-phenylthio-2-thienyl,
5-phenylthio-3-thienyl 4-phenylthio-2-pyridyl,
5-phenylthio-2-pyridyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl,
5-indolyl, 6-indolyl, 7-indolyl, 1-benzothiophen-2-yl,
1-benzothiophen-3-yl, 1-benzothiophen-4-yl 1-benzothiophen-5-yl,
1-benzothiophen-6-yl, 1-benzodihydro-1-benzothiophen-5-yl, 2
,3-dihydro- 1-benzothiophen-6-yl, 2,3-dihydro-1-benzothiophen-7-yl,
thiochroman-5-yl, thiochroman-6-yl, thiochroman-7-yl,
thiochrornan-8-yl, dibenzothiophen-1-yl, dibenzothiophen-2-yl,
dibenzothiophen-3-yl, dibenzothiophen-4-yl, etc. The term
"naphthyl" includes, for example, 1-naphthyl, 2-naphthyl, etc. The
term "lower alkoxycarbonyl" includes alkoxycarbonyl groups having 1
to about 6 carbon atoms in the alkoxy moiety, for example,
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,
pentyloxycarbonyl, hexyloxycarbonyl, etc. The term "phenyl-lower
alkoxy" includes phenylalkoxy groups having 1 to about 6 carbon
atoms in the alkoxy moiety, for example, benzyloxy, 1-phenylethoxy,
2-phenylethoy, 3-phenylpropoxy, 2-phenyl-1-methylethoxy,
4-phenylbutoxy, 2-phenyl-1,1-dimethylethoy, 5-phenyl-pentyloy,
6-phenylhexyyloxy, etc. The term "phenylthio-lower alkyl" includes
phenylthioalkyl groups having 1 to about 6 carbon atoms in the
alkyl moiety, for example, phenylthiomethyl, 1-phenylthioethyl,
2-phenylthioethyl, 3-phenylthiopropyl, 2-phenylthio-1-methylethyl,
4-phenylthiobutyl, 2-phenylthio-1,1-dimethylethyl,
5-phenylthiopentyl, 6-phenylthiohexyl, etc. The term
"halogen-substituted lower alkyl" includes halogen-substituted
alkyl groups having 1 to about 6 carbon atoms in the alkyl moiety,
for example, chloromethyl, bromo-methyl, 1-chloroethyl,
2-chloroethyl, 2-bromoethyl, 3-chloropropyl, 2-chloro-
1-methylethyl, 2-bromobutyl, 4-bromobutyl,
2-chloro-1,1-dimethylethyl, 5-chloropentyl, 6-bromohexyl, etc. The
term "phenyl which may optionally have one to three substituents
selected from a halogen atom, a lower alkyl and a lower alkoxy"
includes phenyl groups which may optionally have one to three
substituents selected from a halogen atom, an alkyl having 1 to
about 6 carbon atoms, for example, phenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,
4-bromophenyl, 4-fluorophenyl, 4-iodophenyl, 2,4-dibromophenyl,
2,6-dibromophenyl, 2,4,6-tribromophenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 4-ethylphenyl,
3-propylphenyl, 4-(t-butyl)phenyl, 4-pentylphenyl, 4-heylphenyl,
2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-methyl-4-ethylphenyl,
2,4,6-trimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2-ethoxyphenyl, 4-ethoxylphenyl, 3-propoxyphenyl,
4-(t-butoxy)phenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl,
2,6-dimethoxyphenyl, 2-methoxy-4-ethoxyphenyl,
2,4,6-trimethoxyphenyl, 2-chloro-4-methylphenyl,
2,6-dibromo-4-methylphen- yl, 2-chloro-4-methoxyphenyl,
2,6-dichloro-4-methoxylphenyl, 2-bromo-4-methoxyphenyl,
2,6-dibromo-4-methoxyphenyl, 2,6-dibromo-4-ethoxyphenyl, etc. The
term "phenyl-lower alkyl" includes phenylalkyl groups having 1 to 6
carbon atoms in the alkyl moiety, for example, benzyl,
1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,
2-phenyl-1-methylethyl, 4-phenylbutyl, 2-phenyl-1,1-dimethylethyl,
5-phenylpentyl, 6-phenylhexyl, etc. The term "benzoyl which may
optionally have one to three substituents selected from a halogen
atom, a phenoyl-lower alkoxy and hydroxy on the phenyl ring"
includes benzoyl groups which may optionally have one to three
substituents selected from a halogen atom, a phenylalkoxy having 1
to about 6 carbon atoms in the alkoxy moiety and hydroxy, for
example, benzoyl, 3-bromo-benzoyl, 4-benzyloxybenzoyl,
4-hydroxybenzoyl, 3,5-dibromobenzoyl, 3-bromo-4-benzyloxybenzoyl,
3-chloro-4-hydroxybenzoyl, 3,5-dibromo-4-benzyloxy-benzoyl,
3,5-dibromo-4-(1-phenethyloxy)benzoyl,
3,5-dibromo-4-(2-pheethyloxy)benzoyl,
3,5-dibromo-4-(3-phenylpropoxy)benz- oyl,
3,5-dibromo-4-(4-phenyl-butoxy)benzoyl, 3
,5-dibromo-4-(5-phenylpenty- loxy)-benzoyl,
3,5-dibromo-4-(6-phenylhexyloxybenzoyl,
3,5-dichloro-4-benzyloxybenzoyl, 3,5-dichloro-4-hydroxybenzoyl,
3,4-dichloro-5-hydroxybenzoyl, etc. The "term cycloalkyl" includes
cycloalkyl groups having 3 to 8 carbon ring atoms, for example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, etc. The term "furyl" includes, for example, 2-furyl,
3-furyl, etc. The term "thienyl" includes, for example, 2-thienyl,
3-thienyl, etc. The term "tetrahydrofuranyl" includes, for example,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, etc. The
"hydroxy-substituted lower alkyl" includes hydroxy-substituted
alkyl groups having 1 to about 6 carbon atoms in the alkyl moiety,
for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroyethyl,
3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl,
etc. The term "lower alkyl which may optionally have a substituent
selected form hydroxy, furyl, thienyl, tetrahydrofuranyl and
phenyl" includes alkyl groups having 1 to 6 carbon atoms which may
optionally have a substituent selected from hydroxy, furyl,
thienyl, tetrahydrofuranyl and phenyl, for example, 2-furfuryl,
3-furylmethyl, 1-(2-furyl)ethyl, 2-(3-firyl)ethyl,
3-2-furyl)propyl, 4-(3-furyl)butyl, 3-(2-furyl)pentyl,
6-(.sup.9-furyl)hexyl, 2-thienylmethyl, 3-thienylmethyl,
1-(2-thienyl)ethyl, 2-(3-thienyl)ethyl, 3-(2-thienyl)propyl,
4-(3-thienyl)butyl, 5-(2-thienyl)pentyl, 6-(2-thienyl)hexyl,
2-tetrahydrofuranylmethyl, 3-tetrahydrofuranylmethyl,
1-(2-tetrahydrofuranyl)ethyl, 2-(3-tetrahydrofuranyl)ethyl,
3-(2-tetrahydrofuranyl)propyl, 4-(3-tetrahydrofuranyl)-butyl,
5-(2-tetrahydrofuranyl)pentyl, 6-(2-tetrahydrofuranyl)hexyl, etc.
The term "phenyl which may optionally have one to three
substituents selected from a lower alkyl, a hydroxy-substituted
lower alkyl, a lower alkanoyl, cyano, carboxy, a lower
alkoxycarbonyl, hydroxy, a lower alkoxy, and a halogen atom"
includes phenyl groups which may optionally have one to three
substituents selected from an alkyl having 1 to 6 carbon atoms, a
hydroxyalkyl having 1 to 6 carbon atoms, an alkanoyl having 1 to 6
carbon atoms, cyano, carboxy, an alkoxycarbonyl having 1 to 6
carbon atoms in the alkoxy moiety, hydroxy, an alkoxy having 1 to 6
carbon atoms, and a halogen, for example, phenyl, 2-methylphenyl,
3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl,
4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl,
4-isopropylphenyl, 3-propylphenyl, 4-butylphenyl,
2-(t-butyl)phenyl, 3-(t-butyl)phenyl, 4-(t-butyl)phenyl,
4-pentylphenyl, 4-hexylphenyl, 4-hydroxymethylphenyl,
2-(1-hydroxyethyl)-phenyl, 3-(1-hydroxyethyl)phenyl, 4-(l
-hydroxyethyl)-phenyl, 2-(2-hydroxyethyl)phenyl,
4-(2-hydroxyethyl)-pheny- l, 3-(3-hydroxypropyl)phenyl,
4-(4-hydroxybutyl)phenyl, 4-(5-hydroxypentyl)phenyl,
4-(6-hydroxyhexyl)phenyl, 2-acetylphenyl, 3-acetylphenyl,
4-acetylphenyl, 3-propionylphenyl, 4-butyrylphenyl,
3-valerylphenyl, 4-hexanoylphenyl, 2-cynaophenyl, 3-cyanophenyl,
4-cynaophenyl, 2-carbonxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl,
2-methoxycarbonyl-phenyl, 3-methoxycarbonylphenyl,
4-methoxycarbonylphenyl, 2-ethoxycarbonylphenyl,
4-propoxycarbonylphenyl, 4-(t-butoxycarbonyl)phenyl,
4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl,
2,4,6-trimethoxyphenyl, 3,4,5-trimethoxvphenyl, 4-ethoxyphenyl,
4-t-butoxyphenyl, 4-hexyloxyphenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2,4,-dichlorophenyl, 3,5-dichlorophenyl,
2,4,6-trichlorophenyl, 3,4,5-trichlorophenyl, 4-bromophenyl,
4-fluorophenyl, 4-iodophenyl, 2-hydroxy-4-carboxyphenyl,
3-hydroxy-4-carboxyphenyl, 4-hydroxy-3-carboxyphenyl,
2-hydroxy-4-methoxycarbonylphenyl,
3-hvdroxy-4-methoxycarbonylphenyl,
4-hydroxy-3-methoxycarbonylphenyl,
2-methoxy-4-methoxycarbonylphenyl,
3-methoxy-4-methoxycarbonylphenyl,
4-methoxy-3-methoxycarbonlyphenyl, etc. The heterocyclic group
selected from pyridyl, pyrimidinyl, thiazolyl, isoxazolyl, and
pyrazolyl, said heterocyclic group being optionally substituted by
a lower alkyl, amino, or a lower alkanoylamino+ includes
heterocyclic groups selected from pyridyl, pyrimidinyl, thiazolyl,
isoxazolyl, and pyrazolyl which may optionally substituted by an
alkyl having 1 to about 6 carbon atoms, amino, or an alkanoylamino
having 1 to about 6 carbon atoms in the alkanoyl moiety, for
example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidnyl, 2-thiazolyl, 4-isoxazolyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-methyl-4-pyridyll,
4-methyl-3-pyridyl, 3-amino-5-pyridyl, 4-amino-2-pyridyl,
2-acetylamino-4-pyridyl, 3-propanoylamino-5-pyridyl,
2-methyl-4-pyrimidinyl, 4-methyl-6-pyrimidinyl,
5-ethyl-2-pyrimidinyl, 2-amino-5-pyrimidinyl, 2-amino-4-pyrimidiny,
4-acetylamino-2-pyrimidinyl, 4-acetylamino-6-pyrimidinyl,
4-propanoylamino-2-pyrimidinyl, 2-methyl-4-thiazolyl,
2-ethyl-5-thiazolyl, 4-methyl-2-thiazolyl, 2-amino-4-thiazolyl,
4-amino-5-thiazolyl, 2-acetylamino-4-thiazolyl,
5-acetylamino-2-thiazolyl, 5-methyl-3-isoxazolyl,
4-methyl-3-isoxazolyl, 4-methyl-5-isoxazolyl, 5-ethyl-3-isoxazolyl,
5-propyl-4-isoxazolyl, 4-isopropyl-3-isoxazolyl,
5-butyl-3-isoxazolyl, 5-pentyl-4-isoxazolyl, 5-heyl-3-isoxazolyl,
3-amino-4-isoxazolyl, 4-amino-5-isoxazolyl,
3-acetylamino-4-isoxazolyl, 5-acetylamino-3-isoxazolyl,
1-methyl-3-pyrazolyl, 3-methyl-5-pyrazolyl, 4-ethyl-1-pyrazolyl,
5-amino-1-pyrazolyl, 4-amino- 1-pyrazolyl, 3-amino-1-pyrazolyl,
5-amino-3-pyrazolyl, 5-acetylamino-1-pyrazolyl,
4-acetylamino-1-pyrazolyl- , 3-acetylamino-1-pyrazolyl,
5-acetylamino-3-pyrazolyl, 5-porpanoylamino-1-pyrazolyl,
4-butyrylamino-1-pyrazolyl, 5-isobutyrylamino-1-pyrazolyl,
5-valerylamino-1-pyrazolyl, 5-hexanoylamino-1-pyrazolyl, etc. The
term "saturated 5- or 6-membered heterocyclic group which may
optionally be intervened with oxygen atom formed by joining of
R.sup.4 and R.sup.5 together with the adjacent nitrogen atom"
includes, for example, pyrrollidinyl, piperidinyl,
tetrahydro-1,2-oxazinyl, tetrahydro-1,3-oxazinyl, morpholino, etc.
The term "lower alkylene" includes alkylene groups having 1 to 6
carbon atoms, for example methylene, ethylene, trimethylene,
dimethylmethylene, tetramethylene, pentamethylene, hexamethylene,
etc. The "group of the formula: 30
[0120] (wherein A is as defined above)" includes, for example,
phenylmethylenedioxymethyl, phenylethylenedioxymethyl,
phenylpropylenedioxymethyl, etc. Compounds of formula XXII can be
suitably prepared by methods disclosed in U.S. Pat. No.
4,824,834.
[0121] Additional suitable triazine compounds for use in the
methods of the invention include compounds of the following Formula
XXIII: 31
[0122] wherein A is a grouping of the formula 32
[0123] in which R.sup.1 and R.sup.2 each individually is hydrogen,
halogen, trifluoromethyl, nitro, amino, cyano,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C3-C6-alkenyloxy,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkanoylamino, aryloxy,
aryl-(C.sub.1-C.sub.6-alkyl), aryl-(C.sub.1-C.sub.6-alkoxy),
aryl-(C.sub.1-C.sub.6-alkoxy)carbonylamino or
--O--CH.sub.2--R.sup.3, or R.sup.1 and R.sup.2 on adjacent carbon
atoms together are --CH.dbd.CH--CH.dbd.CH-- or
--CH.sub.2--CH.sub.2--O--, and R.sup.3 is
hydroxy-(C.sub.1-C.sub.4-alkyl) or vicinal
dihydroxy-(C.sub.2-C.sub.5-alkyl), and pharmaceutically acceptable
acid addition salts of those compounds of formula I in which at
least one of R.sup.1 and R.sup.2 is amino, or tautomers thereof. As
used in reference to Formula XXIII, the terms
"C.sub.1-C.sub.4-alkyl", "C.sub.2-C.sub.5-alkyl" and
"C.sub.1-C.sub.6-alkyl", mean straight-chain or branched-chain
alkyl groups which contain the number of carbon atoms specified,
such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl,
tert.butyl, n-pentyl, n-hexyl and the like. The term
"C.sub.1-C.sub.6-alkoxy" means a C.sub.1-C.sub.6-alkyl group as
defined above which is attached via an oxygen atom, examples of
C.sub.1-C.sub.6-alkoxy groups being methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, tert butoxy and the like. The term
"C.sub.3-C.sub.6-alkenyloxy" means a straight-chain or
branched-chain alkenyloxy group containing from 3 to 6 carbon atoms
such as allyloxy, butenyloxy and the like. The term
"C.sub.1-C.sub.6-alkylthio" means a C.sub.1-C.sub.6-alkyl group as
defined above which is attached via a sulfur atom, examples of
C.sub.1-C.sub.6-alkylthio groups being methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio and the like. The
C.sub.1-C.sub.6-alkanoyl residue of a C.sub.1-C.sub.6-alkanoyla-
mino group is derived from a straight-chain or branched-chain
alkanecarboxylic acid containing from 1 to 6 carbon atoms such as
formyl acetyl, propionyl, butyryl and the like. The aryl moiety of
an aryloxy, aryl-(C.sub.1-C.sub.6-alkyl),
aryl-(C.sub.1-C.sub.6-alkoxy) or
arvl-(C.sub.1-C.sub.6-alkoxy)carbonylamino group is an
unsubstituted phenyl group or a phenyl group carrying at least one
substituent selected from halogen, trifluoromethyl,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, nitro and cyano.
Phenoxy, 4-chlorophenoxy, 4-tolyloxy etc are examples of aryloxy
groups. Benzyl, 4-chlorobenzyl, 4-tolyl, 4-methoxybenzyl, phenethyl
etc are examples of aryl (C.sub.1-C.sub.6alkyl) groups. Benzyloxy,
4-chlorobenzyloxy, 4-tolyloxy, 4-methoxybenzyloxy etc are examples
of aryl-(C.sub.1-C.sub.6alkoxy) groups. Examples of groups of the
formula --O--CH.sub.2--R.sup.3 are 2-hydroxyethoxy,
3-hydroxypropoxy and the like when R.sub.3 are 2-hydroxyethoxy,
3-hydroxypropoxy and the like when R.sup.3 represents
hydroxy-(C.sub.1-C.sub.4-alkyl) and 2,3-dihydroxypropoxy,
3,4-dihydroxybutoxy and the like when R.sup.3 represents vicinal
dihydroxy-(C.sub.2-C.sub.5-alkyl). The term "halogen" means
fluorine, chlorine, bromine or iodine. The compounds of Formula
XXIII in which R.sup.1 and/or R.sup.2 represents amino form
pharmaceutically acceptable salts with acids. Examples of such
salts are mineral acid salts such as hydrohalides (e.g.
hydrochlorides, hydrobromides etc), sulphates, phosphates, nitrates
etc and organic acid salts such as acetates, maleates, fumarates,
tartrates, citrates, salicylates, methanesulphonates,
p-toluenesulphonates etc.
[0124] It will be appreciated that the compounds of Formula XXIII
can exist in tautomeric forms, and that such tautomers are within
the scope of Formula XXIII.
[0125] A preferred group of compound of Formula XXIII above
comprises those in which A represents a group of sub-formula (a) as
specified above. In such compounds R.sup.1 preferably represents
hydrogen, halogen, trifluoromethyl or cyano and R.sup.2 preferably
represents hydrogen C.sub.1-C.sub.6-alkoxy,
aryl-(C.sub.1-C.sub.6-alkoxy) or a group of the formula
--O--CH.sub.2--R.sup.3 in which R.sup.3 represents vicinal
dihydroxy-(C.sub.2-C.sub.5-alkyl), with the proviso that at least
one of R.sup.1 and R.sup.2 represents other than hydrogen.
Particularly preferred compounds in which A represents a group of
sub-formula (a) are
7-(3-trifluoromethyl-4-methoxyphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3-
H)-one;
7-(3-chloro-4-methoxyphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-
-one;
7-(3-fluoro-4-methoxyphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-o-
ne;
7-(3-trifluoromethylphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one;
7-(4-isopropoxyphenyl)isothiazolo[4,5]d]-1,2,3-triazin-4(3H)-one;
7-(4-benzyloxyphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one;
7-(3-cyano-4-methoxyphenyl)isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one;
and 7-[3-cyano-4-(2,3-dihydroxypropoxy)phenyl)isothiazolo[4,5-d]- I
,2,3-triazin-4(3H)-ene.
[0126] Another preferred group of compounds of Formula XXIII
comprises those in which A represents a group of sub-formula (c) as
specified above. In such compounds R preferably represents hydrogen
and R.sup.2 preferably represents C.sub.1-C.sub.6-alkoxy.
[0127] Compounds of Formula XXIII can be suitably prepared as
disclosed in U.S. Pat. No. 4,920,119.
[0128] Additional compounds suitable for use in the methods of the
invention are also disclosed in the following published patents and
patent applications: European 429,038, particularly the disclosed
phenylethenyl esters of phenyl-propenoic acid;
[0129] PCT Publication 9113623, particularly the disclosed
C.sub.5-monosubstituted barbiturates;
[0130] Czechoslovakia 264505, particularly the disclosed salts of
N-acetyl-p-aminosalicylic acid;
[0131] German 3912092, particularly the disclosed heterocyclic
compounds with more than one hetero atom, such as
amino-triazolopyridoquinazolinone- ;
[0132] Japanese 02245198, particularly the disclosed phenol
compounds such as sodium salicylate;
[0133] European 269859, particularly the disclosed
pyrazolotriazines;
[0134] European 274654, particularly the disclosed
heterocylotriazinones such as
7-phenylisothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one;
[0135] Netherlands 8602382, particularly the disclosed catechol
derivatives such as 4-(+)-methylthiocatechol);
[0136] German 3632841 particularly the disclosed catechol
derivatives;
[0137] German 3632824, particularly the disclosed bicyclic catechol
derivatives;
[0138] Japanese 59219229, particularly the disclosed indoles, such
as 1-formyl-4-hydroy-9H-pyridol[3,4-b]indole;
[0139] U.S. Pat. No. 4,336,257, particularly the disclosed
2-(4-pyridyl)-5-chlorobenzimidazole, 1H-imidazo[4,5-b]pyridines,
and imidazo[4,5-c]pyridines;
[0140] European 28660, particularly the disclosed
pyrazolobenzotriazine derivatives;
[0141] Japanese 55055185, particularly the disclosed compounds
derived from extraction of picrasma quassioides;
[0142] German 2941449, particularly the disclosed pyridolindoles
isolated according to the above patent;
[0143] U.S. Pat. No. 4,110,456, particularly the disclosed
imidazoles, including sulfamoylimidazoles;
[0144] U.S. Pat. No. 4,032,522, particularly the disclosed
trifluoromethylimidazoles;
[0145] U.S. Pat. No. 3,988,324, particularly the disclosed
heterocyclobenzothiadiazinesulfonamides;
[0146] Japanese 51054576, particularly the disclosed hydroxy or
acyloxyalkylaminobenzothiadiazines;
[0147] U.S. Pat. No. 3,960,854, particularly the disclosed
7-mercapto (or thio) benzothiadiazine-1,1-dioides;
[0148] U.S. Pat. No. 3,969,518, particularly the disclosed
3-haloalkyl benzothiadiazine-1,1-dioxides;
[0149] U.S. Pat. No. 3,951,966, particularly the disclosed
heterocycle-substituted benzothiodiazines;
[0150] Japanese 51006992, particularly the disclosed
dihydrothiazoloadenines;
[0151] Japanese 51006993, particularly the disclosed
imidazoadenines and pyrimidnoadenines;
[0152] French 2262977, particularly the disclosed
formylaminoallylidenehyd- razines, substituted with aryl
groups;
[0153] French 2262976, particularly the disclosed fonnamidrazones,
substituted with aryl groups;
[0154] Gernan 2410650, particularly the disclosed formamidrazones,
isonicotinyl pyrimidinones and the like;
[0155] German 2410579, particularly the disclosed orotic acid
hydrazide, and the corresponding nicotinic and isonicotinic acid
derivative;
[0156] Gerrnan 2509130, particularly the disclosed
acryloylformamidrazones- , pyrimidinones and the like;
[0157] German 2410653, particularly the disclosed
acylpyrazolocarboxamides- ;
[0158] German 2508934, particularly the disclosed
fornylcarbamoylpyrazoles substituted with heterocyclic and
carbocyclic aryl groups;
[0159] German 2410611, particularly the disclosed nicotinic acid
hydrazide, azapentadienylidene;
[0160] German 2509094, particularly the disclosed
aminoazapentadienylidene hydrazine;
[0161] German 2509049, particularly the disclosed
morpholinoacryloylgormam- idrazones substituted with various aryl
groups;
[0162] German 2509175, particularly the disclosed substituted
2-hydrazonomethyl-3-hydroxy-4-aza-2,4-pentadienenitriles;
[0163] German 2410614, particularly the disclosed heterocyclic
N-acyl-N'-(3-amino-2-cyanoacryloy)formamidrazones;
[0164] Japanese 50004039, particularly the disclosed
salicylanilides;
[0165] British 1403974, particularly the disclosed
dioxo-6,6-azopurine;
[0166] Japanese 49072298, particularly the disclosed 9-substituted
palmatine derivatives;
[0167] German 2457127, particularly the disclosed haloimidazoles
substituted with pyridyl and the like;
[0168] Japanese 49127943, particularly the disclosed
4-(2-hydroxybenzamido)salicylic acids;
[0169] German 2418467, particularly the disclosed
hydroxybenzanilides;
[0170] Japanese 49048664, particularly the disclosed hydroxyalkyl
imidazoles;
[0171] U.S. Pat. No. 3,816,625, particularly the
disclosed-7-alkylsulfonyl- -substituted
benzothiadiazine-dioxides;
[0172] U.S. Pat No. 3,816,626, particularly the disclosed
3-pyridyl-1,2,4-benzothiadiazine-1,1-dioxides;
[0173] U.S. Pat. No. 3,816,631, particularly the disclosed
6-sulfamoyl-7-substituted-(3H)quinazolinones;
[0174] German 2356690, particularly the disclosed
pyrazolo[3,4-d]pyrimidin- e N-oxides;
[0175] German 2344767, particularly the disclosed
2-cyanopyrimidine-4(1H)o- nes;
[0176] German 2351126, particularly the disclosed
6-sulfamoyl-4(3H)quinazo- linones;
[0177] German 2343702, particularly the disclosed
4-mercapto-1H-pyrazolo[3- ,4d]pyrimidine;
[0178] German 2344733, particularly the disclosed
3-chloro-2-(hydrazonomet- hyl)-4-aza-2,4-pentadienenitriles;
[0179] German 2344738, particularly the disclosed
2-hydrazonomethyl-3-hydr- oxy-4-aza-2,4-pentadienenitriles;
[0180] German 2224379, particularly the disclosed
7-.beta.D-ribofuranosyl--
4,6-dihydroxypyrazolo[3,4-d]pyrimidine;
[0181] German 2318784, particularly the disclosed
N-(2,4-dihydroxybenzoyl)- -4aminosalicyclic acids;
[0182] Japanese 48067491, particularly the disclosed
formyluracils;
[0183] German 2313573, 7-mercapto-1,2,4benzothiadiazine
1,1-dioxide;
[0184] German 2313636, particularly the disclosed benzothiadiazines
substituted with heterocyclic groups;
[0185] German 1966640, particularly the disclosed
4-hydroxypyrazolo[3,4-d]- pyrimidines;
[0186] French 214377, particularly the disclosed
3-(2-chlorobenzoylamino)b- enzoic acid derivatives;
[0187] German 2255247, particularly the disclosed
5-(5-indanyloxy)tetrazol- es;
[0188] German 2236987, particularly the disclosed
pyrazolo[1,5-a]pyrimidin- es;
[0189] French 2109005, particularly the disclosed
4-(2-quinoxalinyl)phenox- yacetic acid derivatives;
[0190] French 2081360, particularly the disclosed 2,5-disubstituted
imidazoles;
[0191] German 2147794, particularly the disclosed 1,2,4-triazoles
substituted with heterocyclic and other aryl groups;
[0192] German 1927136, particularly the disclosed
1-D-ribosylallopurinol;
[0193] French 4777, particularly the disclosed
4-mercaptopyrazolo[3,4-d]py- rimidine; and
[0194] French 1480652, particularly the disclosed
4-oxo-5-alkylpyrazolo[3,- 4-pyrimidines.
[0195] As discussed above, suitable therapeutic compounds for use
in the methods of the invention can be synthesized by known
procedures, including by procedures described in the above-cited
documents. Some therapeutic compounds also are commercially
available, such as allopurinol and oxypurinol.
[0196] As also discussed above, typical subjects for administration
in accordance with the invention are mammals, such as primates,
especially humans. For veterinary applications, a wide variety of
subjects will be suitable, e.g. livestock such as cattle, sheep and
the like; and domesticated animals, particularly pets such as dogs
and cats.
[0197] Allopurinol has several theoretical advantages over
currently available Ca.sup.2+ sensitizers. Current Ca.sup.2+
sensitizers shift the range of Ca.sup.2+ activation so that force
is activated at lower levels of Ca.sup.2+ with a consequent risk
for diastolic dysfunction. Additionally, most of the currently
available Ca.sup.2+ have phosphodiesterase inhibitor activity. The
advantages of in vivo use of XO inhibitors, specifically
allopurinol are first, allopurinol has no adverse effect on
diastolic function. Second. allopurinol acted only in dogs with
heart failure and therefor did not adversely affect healthy dogs.
Third, it is well established that allopurinol exhibits no
phosphodiesterase inhibition thereby decreasing the occurrence of
side-effects associated with such inhibition. As shown in examples
5-, allopurinol can act as a novel inotropic agent which
simultaneously decreases oxygen consumption and markedly increase
myocardial mechanical efficiency in the canine heart in vivo.
[0198] In the therapeutic methods of the invention, a subject such
as a mammal is suitably selected that is need of treatment, e.g. a
subject that is suffering from heart failure including congestive
heart failure and cardiogenic shock, and then administering to such
selected subject a therapeutic compound in accordance with the
invention.
[0199] Compounds of the invention are suitably administered to a
subject in a protonated and water-soluble form, e.g., as a
pharmaceutically acceptable salt of an organic or inorganic acid,
e.g., hydrochloride, sulfate, hemi-sulfate, phosphate, nitrate,
acetate, oxalate, citrate, maleate, mesylate, etc. Also, where an
acidic group is present on a therapeutic compound, a
pharmaceutically acceptable salt of an organic or inorganic base
can be employed such as an ammonium salt, or salt of an organic
amine, or a salt of an alkali metal or alkaline earth metal such as
a potassium, calcium or sodium salt. Specifically suitable
pharmaceutically acceptable salts also have been disclosed
above.
[0200] In the methods of the invention, a therapeutic compound such
as a xanthine oxidase inhibitor compound may be administered to a
subject by a variety of routes including parenteral (including
intravenous, subcutaneous, intramuscular and intradermal), topical
(including buccal, sublingual), oral, nasal and the like.
[0201] Therapeutic compounds for use in the methods of the
invention can be employed, either alone or in combination with one
or more other therapeutic agents, as a pharmaceutical composition
in mixture with conventional excipient, i.e., pharmaceutically
acceptable organic or inorganic carrier substances suitable for a
desired route of administration which do not deleteriously react
with the active compounds and are not deleterious to the recipient
thereof. Suitable pharmaceutically acceptable carriers include but
are not limited to water, salt solutions, alcohol, vegetable oils,
polyethylene glycols, gelatin, lactose, amylose, magnesium
stearate, talc, silicic acid. viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, petroethral fatty acid
esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings, flavorings and/or aromatic
substances and the like which do not deleteriously react with the
active compounds.
[0202] For parenteral application, particularly suitable are
solutions, preferably oily or aqueous solutions as well as
suspensions, emulsions, or implants, including suppositories.
Ampules are convenient unit dosages.
[0203] For enteral application, particularly suitable are tablets,
dragees or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc. Tablets,
capsules and syrups or other fluids are generally preferred for
oral administration.
[0204] A single or combination of more than one distinct
therapeutic compound may be administered in a particular therapy.
In this regard, a particular therapy can be optimized by selection
of an optimal therapeutic compound, particularly optimal xanthine
oxidase inhibitor compound, or optimal "cocktail" of multiple
xanthine oxidase inhibitor compounds. Such optimal compound(s) can
be readily identified by those skilled in the art, such as by the
in vitro and in vivo assays of the examples which follow.
[0205] Also, as mentioned above, other pharmaceutical agents may be
administered in coordination with administration of a therapeutic
compound of the invention, particularly a xanthine oxidase
inhibitor. For example, an ACE-inhibitor such as captopril or
enalapril may be administered with a xanthine oxidase inhibitor,
e.g. separately or substantially simultaneously such as by
formulating the two agents as a unitary pharmaceutical composition
for administration to a patient.
[0206] It will be appreciated that the actual preferred amounts of
active compounds used in a given therapy will vary according to the
specific compound being utilized, the particular compositions
formulated, the mode of application, the particular site of
administration, etc. Optimal administration rates for a given
protocol of administration can be readily ascertained by those
skilled in the art using conventional dosage determination tests
conducted with regard to the foregoing guidelines. At least some
therapeutic compounds such as allopurinol have been previously used
clinically and thus safety of such compounds is established. Also,
doses employed in such prior clinical applications will be provide
further guidelines for preferred dosage amounts for methods of the
present invention.
[0207] All documents mentioned herein are incorporated herein by
reference.
[0208] The following non-limiting examples are illustrative of the
invention.
Example 1
[0209] Thin specimens of rat cardiac muscle were dissected, mounted
in a tissue bath for the measurement of contractile force, and
microinjected with fura-2 to enable measurement of intracellular
calcium concentration ([Ca.sup.2+ ]i). Procedures of this assay are
disclosed in Gao, W. D. et al., Circulation Research 1995,
76(6):1036-1048. FIG. 1 of the drawings shows the effects of
exposure to allopurinol. As shown in FIG. 1, allopurinol increases
contractile force, while decreasing calcium ion concentration. This
is the hallmark of a calcium-sensitizing effect.
Example 2
[0210] A particularly rigorous method of assessing calcium
sensitivity is by steady-state analysis by procedures disclosed in
Gao, W. D. et al., supra. FIG. 2 of the drawings shows a plot of
steady-state force versus steady-state [Ca.sup.2+].sub.i in control
muscles (exposed to no drug; filled circles) and in muscles exposed
to allopurinol (open circles). Allopurinol shifted the contractile
activation curve to lower [Ca.sup.2+].sub.i and increased maximal
force. That response represents defining characteristics of a
calcium-sensitizing agent.
Example 3
[0211] FIG. 3 of the drawings shows that oxypurinol-treated muscles
(open circles) generate more force at any given [Ca.sup.2+].sub.i
than control muscles (filled circles). FIG. 4 compares the effects
of allopurinol (open circles) and oxypurinol (triangles); the two
agents have essentially indistinguishable effects on calcium
sensitivity.
[0212] General Comments for Examples 4-6
[0213] In Examples 4-6 below, the following materials and methods
were employed.
[0214] 1. Surgical preparation for chronic dog protocol. Male
mongrel dogs (20-30 kg) were anesthetized with 1-2% halothane after
induction with sodium pentothal. The chest was opened via a lateral
thoracotomy, and indwelling catheters (Tygon; Norton Plastics and
Synthetic Division) were secured in the right atrium (for drug
infusion) and in the descending aorta (for pressure measurement).
An indwelling high fidelity micromanometer (P22, Konigsberg
Instruments) was placed in the left ventricle (LV) through an
apical stab. Endocardial sonomicrometer crystals were inserted for
the measurement of anterior-posterior short axis dimension, and a
pneumatic occluder was placed around the inferior vena cava (IVC)
to allow preload reduction in order to assess LV pressure-dimension
relations. Pacing leads were attached to the left atrium for acute
pacing during experimentation, and epicardial leads for chronic
pacing were attached to the right ventricular free wall and
connected to a programmable pacemaker (Spectrax, Medtronics) within
a subcutaneous pocket. The chest was closed in layers, catheters
and leads were externalized to the mid-scapulae, and protected by
an external jacket. Analgesia (morphine, 10 mg s.c.) was given in
the immediate postoperative period as necessary. Antibiotics were
administered for the first 72 hours after surgery. The dogs were
allowed to recover fully for 7-10 postoperative days before
experimentation. The surgical and experimental protocol was
approved by Johns Hopkins School of Medicine Animal Care and Use
Committee.
[0215] 2. Drugs Preparation. 200 mg allopurinol (Sigma) was
dissolved in 100 ml normal saline after slight heating and
alkalization with NaOH. Control experiments demonstrated that the
vehicle itself had no effect on cardiac or systemic hemodynamics
and did not change arterial acid base balance.
[0216] 3. Heart failure was induced by chronic rapid ventricular
pacing at a rate of210 bpm for 3 weeks, followed by 240 bpm for one
week. This brought the dogs into heart failure with an average left
ventricular end-diastolic pressure (LVEDP) of 23.5.A-inverted.5.2
mm Hg. Acute pacing (140 bpm) was used to keep heart rate constant
during the experiments.
[0217] 4. Methods of Hemodynamic and Energetic Data Analysis
[0218] a. The analysis of pressure-dimension relationships and the
arterial pressure response allowed the evaluation of variables
related to myocardial systolic and diastolic performance. Averaged
data from 10-20 consecutive beats were used to derive steady-state
parameters, and data measured during transient unloading of the
heart by occlusion of the inferior vena cava (IVC) was used to
assess pressure-dimension or pressure-volume relations. Preload was
indexed as the left ventricular end diastolic anterior -posterior
short axis dimension (LVEDD) or the LV end-diastolic volume from
the conductance catheter. Afterload was evaluated as effective
arterial elastance (Ea, ratio of LV systolic pressure to stroke
dimension (Kass, D. A. 1997, Myocardial Mechanics. In Heart
Failure. P. Poole-Wilson et al., eds. Churchill Livingstone, N.Y.
87-108; Kelly, R. P., C. T. Ting, and T. M. Yang. 1992, Circulation
86:513-521). This parameter is not preload-dependent and has been
validated to reflect total afterload, which incorporates systemic
vascular resistance, aortic impedance, and the reflected wave
properties of the vasculature. Contractility was indexed by +dP/dt
and the load-independent parameter, preload-recruitable stroke work
(PRSW; slope of stoke work/end-diastolic dimension relation) (Kass,
D. A., 1986, Circulation 73:586-595). Diastolic performance was
measured by peak -dP/dt, time to peak filling rate (ttpf), and the
time constant of relaxation (tau). Tau was calculated using the
method of Weiss and colleagues (Ingwall, J. S. 1993, Circulation
87:VII-58-VII-62.).
[0219] b. Oxygen consumption per unit time (MVO.sub.2) in the left
circumflex artery territory was calculated from the difference in
oxygen saturation in simultaneously sampled coronary sinus and
aortic blood, multiplied by left circumflex coronary blood flow.
This, in turn, was calculated from flow velocity multiplied by left
circumflex diameter. Left circumflex diameter was analyzed from a
film projector (CAP 35B, Angiogram Projection System) using
quantitative angiography (Cath View v1.36, Image Comm Systems).
[0220] c. The external useful work of the LV was indexed as stroke
work (SW=area of pressure-volume loops). Both stroke SW and
MVO.sub.2 were converted to Joules per beat (Suga, H. et al. 1983,
Circ. Res. 53:306-318). Cardiac mechanical efficiency was
calculated as SW/MVO.sub.2. Hemodynamic pressure-dimension data
were digitized at 200 Hz and stored for subsequent analysis on a
personal computer using customized software.
[0221] d. All results are reported as mean .A-inverted. SEM.
Baseline hemodynamic variables before and after the 4-week pacing
protocol were compared using Student's t-test or Kruskal-Wallis
test, as appropriate. Concentration-effect relationships were
analyzed with a two-way ANOVA using a term for individual
experiment. To analyze shifts in slope or position of the PRSW
relation (stroke work vs. end-diastolic dimension) we compared
SW-dimension data by multiple linear regression with an interaction
term for drug effect. For comparisons between normal and heart
failure dogs we used a two-tailed Student's t-test. All statistical
analyses were performed using SYSTAT of SAS software. Differences
were considered significant at P-values<0.05.
Example 4
[0222] In Vivo Evaluation In Canine Heart Muscle
[0223] To test the effects of allopurinol on cardiac performance in
the conscious state, data were collected with the dog standing
quietly in a sling. Allopurinol (200 mg) was infused into the right
atrium at a rate of 3.3 mL/min. The dose of allopurinol was
extrapolated from the plasma levels achieved in humans (3-9 mg/L)
after a standard dose (300 mg p.o.) of allopurinol (P. A. Insel
Analagestic-antipyretic and anti-inflammatory agents, The
Pharmacological Basis of Therapeutics (McGraw Hill, NY 1998)). In
our 25 kg dogs, using the plasma half-life of 1.5 h and a
distribution volume of 1.6 L/kg, a comparable plasma level (4.5
mg/L) was estimated to be attained by 200 mg allopurinol i.v.
Pressure-dimension relationships and the arterial pressure response
were recorded in the steady state and during IVC occlusion at
baseline, every 10 min during infusion, and 10 and 20 min after
cessation of the infusion. The ECG was continuously monitored.
[0224] Experiments to analyze the response to allopurinol in
cardiac energetics were performed under isoflurane anesthesia
(1.5-2.5%), after induction with sodium pentothal (25 mg/kg), in
normal and heart failure dogs using acute instrumentation.
Isoflurane was chosen as the anesthetic because of its relatively
mild and stable effect on the cardiovascular system (R M. Jones,
British Journal of Anaesthesia, 56 Suppl 1:57S-69S (1984); E. I.
Eger, British Journal of Anaesthesia, 56 Suppl 1:71S-99S (1984)). A
doppler flow velocimeter (0.014 Cardiometrics) and a 6 Fr.
angiography catheter (AL-I or JL 3.5, Cordis Laboratories Inc) were
inserted through an 8 Fr sheath (Cordis) in the right femoral
artery and advanced to the left circumflex coronary artery. These
catheters permitted measurement of coronary flow and injection of
contrast for the measurement of coronary diameter. A catheter (A2
multipurpose, 6 Fr.) was advanced from the left external jugular
vein via a 7 Fr. sheath (Cordis) into the great cardiac vein for
withdrawal of mixed coronary venous blood. To measure cardiac
oxygen consumption, blood samples from the coronary sinus and the
femoral artery were obtained simultaneously. At each time point,
blood flow velocity in the left circumflex artery was measured and
coronary angiography was performed.
[0225] In 4 of 11 experiments, preexisting indwelling
sonomicrometer crystals, Konigsberg micromanometers, and IVC
occluders (see above) were used for dimension and pressure
measurements, and for acute preload reduction. In the other 7
experiments, a combined micromanometer-conducta- nce catheter
(Millar) was advanced to the LV and positioned for continuous
measurement of LV pressure and volume via a 7 Fr. sheath (Cordis)
in the femoral artery. A Swan-Ganz catheter (Arrow, 7 Fr.) was
advanced via a 9F sheath in the femoral vein to the pulmonary
artery for measurement of cardiac output and for hypertonic saline
wash-in (Baan, J., E. van der Velde, A. D. van Dijk and et al.
1992, In Cardiovascular system dynamics: Models and measurements.
Anonymous Plenum Press, New York, 569; Kass, D. A. et al. 1986.
Circulation 73:586-595) to calibrate the volume signal. This
catheter was then replaced with a balloon occlusion catheter
(Cordis) positioned in the IVC for acute preload reduction for
pressure-volume analysis.
[0226] Results are shown in FIGS. 5-8 of the drawings. FIG. 5 shows
the effect of allopurinol on the relation between stroke work and
end-diastolic dimension. 200 mg allopurinol was infused in 100 mL
NS over 30 minutes in the right atrium of dogs chronically
instrumented to measure LV pressure and dimension at baseline and
after pacing-induced heart failure. Depicted are PRSW relationships
obtained by a transient occlusion of the inferior vena cava at
baseline and after allopurinol. Note the lack of inotropic effect
in controls and positive inotropy in heart failure dogs. The agent
did not affect the slope of the PRSW relation I the control state
but increased the slope after heart failure indicating a positive
inotropic effect.
[0227] FIG. 6 shows the time course of the allopurinol-induced
changes in LV contractility in conscious dogs before and after
pacing-induced heart failure. In control dogs (n=10), allopurinol
increased (dP/dt)max (FIG. 7A) from a base line value of
3101.+-.162 to 3373.+-.225 mm Hg/s (+8.3.+-.3.2%, p=0.01) at the
peak response, which occurred 10 min after the end of the infusion.
The positive inotropic effects of allopurinol persisted, and in
some cases continued to rise, for some time after the infusion,
with values not completely returning to baseline during a 20 min
observation period. However, PRSW (FIG. 6B) was not significantly
changed.
[0228] FIG. 7 shows the effects of allopurinol on O.sub.2
consumption and mechanical efficiency in anesthetized control and
heart failure dogs. A combined manometer-conductance catheter was
positioned in the left ventricle for continuous measurement of
volume and pressures in the ventricle for continuous measurement of
volume and pressures in the ventricle and aorta. Volume was
calibrated with measurement of cardiac output and hypertonic saline
wash-in. In addition, dogs were acutely instrumented a doppler flow
velocimeter probe and an angiography catheter in the left
circumflex coronary artery to measure coronary flow velocity and
coronary diameter. A catheter was placed in the great cardiac vein
for withdrawal of mixed coronary venous blood simultaneously with
arterial blood samples to calculation of cardiac oxygen extraction.
Depicted are effects of allopurinol on O.sub.2 consumption (panel
a) and mechanical efficiency (SW/O.sub.2 consumption; panel b) in
the circumflex territory of normal (n=5) and failing (n=6) dog
hearts.
[0229] FIG. 8 depicts an original tracing of left circumflex blood
flow velocity during allopurinol infusion. Panel a shows blood flow
velocity before and 10 min after 200 mg allopurinol iv over 30
minutes in a heart failure dog. Panel b shows compiled data for
blood flow and arterio-venous oxygen difference (panel c) from 5
control and 6 heart failure dogs. Note blood flow decrease, while
coronary oxygen extraction is unchanged, in response to allopurinol
in heart failure. The decrease in oxygen consumption was manifested
primarily as a decrease in left circumflex blood flow (-40.+-.6% 10
min post-infusion , p=0.0015), whereas myocardial arterio-venous
oxygen difference was not changed. These results indicate that
allopurinol decreases oxygen utilization and increases mechanical
efficiency in the failing canine left ventricle.
Example 5
[0230] Comparison of Energetic Effects of Allopurinol to those of
Dobutamine
[0231] In 5 of the 6 dogs undergoing assessment of energetics after
heart failure, dobutamine 10 .mu.g/Kg/min was also infused. This
was performed to compare the energetic consequences (oxygen cost
for increasing myocardial contractility) between allopurinol and a
.beta.-adrengergic agonist. This study was performed on a separate
day. In contrast to allopurinol, as shown in FIG. 9, dobutamine
caused a significant decrease in mechanical efficiency. Following
infusion of dobutamine, oxygen consumption increased by
145.+-.53.0% (p=0.007) and SW/MVO.sub.2 decreased -29.3.+-.6.8%
(p=0.05).
Example 6
[0232] Method of Evaluating Xanthine Oxidase Activity In Myocardium
Obtained From Control And Heart Failure Dogs
[0233] Myocardial tissue samples were obtained from additional
animals, dogs, (n 13) immediately after sacrifice using intravenous
KCI. The analysis was also performed in 2 dogs that received
allopurinol on the same day. $amples were immediately frozen in
liquid nitrogen and stored a -80.degree. C. for analysis of
xanthine oxidase (XO) activity. The analysis was performed using a
modification of the procedure of Xia and Zweier (Xia, Y. and J. L.
Zweier. 1995, J, Biol. Chem. 270:18797-18803). Frozen tissue
samples were ground and homogenized in a potassium phosphate
buffer, pH 7.8, containing 1 mM phenylmethylsulfonylfluoride (PMSF)
and 10 mM dithiothreitol (DTT), which prevented the in vitro
conversion of xanthine dehydrogenase to xanthine oxidase. After
repeated centrifugation (600 g.times.20 min at 4.degree. C., and
105,000 g.times.60 min at 4.degree. C.), the lipid layer was
removed, and the supernatants passed through a Sephadex G-25 column
(Pharmacia Biotech Inc.) equilibrated with the phosphate buffer.
The processed effluent was then assayed spectrophotometrically
(Beckman DU640 spectrophotometer) at 295 nm for the production of
uric acid in the presence of 0.15 mM xanthine. The reaction mixture
contained 0.1 mL of effluent, in 50 mM phosphate buffer containing
PMSF and DTT, and 0.15 mM xanthine in a 1 mL cuvette at room
temperature. Analyses were performed in pairs in the absence and
presence of allopurinol to block XO.
[0234] The activity of xanthine oxidase in failing hearts was
compared to normal controls. Results from experiments are shown in
FIG. 10. These results indicate that XO activity was significantly
increased in failing hearts compared to normal controls. This
increase of XO activity during heart failure may be responsible for
the increased effects of allopurinol on left ventricular
performance and mechanical efficiency observed during heart
failure.
[0235] This invention. has been described in detail with reference
to preferred embodiments thereof. However, it will be appreciated
that those skilled in the art, upon consideration of this
disclosure, may make modifications and improvements within the
spirit and scope of the invention.
* * * * *