US 200601 15542A1
(19) United States
(12) Patent Application Publication (10) Pub. No.: US 2006/0115542 A1
(43) Pub. Date:
MOTTERLINI et al.
(54)
THERAPEUTIC DELIVERY OF CARBON
MONOXIDE
(30)
Foreign Application Priority Data
May 15, 2001
She?ield (GB)
(51)
Correspondence Address:
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
(GB) ....................................... .. 01118728
Publication Classi?cation
(76) Inventors: Roberto Angelo MOTTERLINI,
Middlesex (GB); Brian Ernest Mann,
Jun. 1, 2006
(52)
Int. Cl.
A61K 33/26
C01G 1/04
C07F 15/04
C07F 15/00
C07F 15/02
(2006.01)
(2006.01)
(2006.01)
(2006.01)
(2006.01)
US. Cl. ....................... .. 424/646; 423/418; 556/136;
ARLINGTON, VA 22203 (US)
(21) Appl. No.:
(22)
Filed:
556/140
11/275,780
(57)
Jan. 27, 2006
Metal carbonyls are used to deliver CO having biological
activity, for example vasodilatation and inhibition of trans
Related US. Application Data
plant rejection. The metal of the carbonyl is typically of
ABSTRACT
groups 7 to 10, eg Fe and Ru. The carbonyl preferably has
(62)
Division of application No. 10/ 143,824, ?led on May
14, 2002.
one or more ligands other than CO, such as amino acids, to
modulate the CO release property and solubility.
Patent Application Publication
Jun. 1, 2006 Sheet 1 0f 17
US 2006/0115542 A1
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Patent Application Publication
Jun. 1, 2006 Sheet 16 0f 17
US 2006/0115542 A1
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Jun. 1, 2006 Sheet 17 0f 17
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Jun. 1, 2006
US 2006/0115542 A1
THERAPEUTIC DELIVERY OF CARBON
MONOXIDE
[0001]
This is a divisional of Ser. No. 10/143,824, ?led
May 14, 2002 (allowed) Which claims bene?t of GB
0111872.8, ?led 15 May 2001, the entire contents of each of
Which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to pharmaceutical
compositions and compounds for the therapeutic delivery of
carbon monoxide to humans and other mammals. Another
use of the compositions and compounds is in organ perfu
s1on.
BACKGROUND OF THE INVENTION
[0003] Carbon monoxide (CO) is, by common de?nition,
[0006] Experimental studies on the physiological effects
of nitric oxide (NO) have been facilitated by the develop
ment of a Wide variety of organic compounds that sponta
neously release NO and can be easily acquired to reproduce
a physiological or pathophysiological function of NO. There
is noW abundant literature on the different types of NO
donors and NO-releasing agents that, depending on their
stability and half-life, can be used in disparate in vitro and
in vivo models to simulate the biological activity of this
important signaling molecule (25, 26). In clinical practice,
compounds that deliver NO into the circulation such as
sodium nitroprusside and glyceryl trinitrate are used to
loWer blood pressure and treat certain cardiovascular dis
eases (27). Drugs containing a functional NO group that can
selectively target an organ or tissue are currently being
developed or are under clinical trials for the treatment of
speci?c pathophysiological states (28, 29). HoWever, to date
no compounds capable of delivering CO therapeutically
a colorless, odorless, tasteless, non-corrosive gas of about
have been identi?ed.
the same density as that of air and is the most commonly
encountered and pervasive poison in our environment. It is
[0007] Us. Pat. No. 5,882,674 proposes administration of
CO via transderrnal delivery systems containing metal car
bonyl complexes such as iron pentacarbonyl and iron
enneacarbonyl. HoWever, since this document provides no
generally produced by the incomplete combustion of fossil
fuels such as natural gas, propane, coal, gasoline and Wood.
In the atmosphere, the average global levels are estimated to
be 0.19 parts per million (p.p.m.), 90% ofWhich comes from
natural sources including ocean micro-organism production,
and 10% of Which is generated by human activity. Thus,
experimental data, and no description of speci?c devices, it
is not clear hoW this proposal can be made to Work. In
particular it is not stated Whether the iron carbonyl complex
is capable of producing a myriad of debilitating and harmful
is intended to be absorbed from the patch, to release CO
Within the body, or Whether the complex breaks doWn Within
the patch to release CO Which then enters the bloodstream
after absorption through the skin. If, and to the extent that,
this document is considered to make available pharmaceu
residual effects to the organism (1). The most immediate of
these effects, and perhaps the most notorious one, is binding
to hemoglobin in the blood stream, Which rapidly decreases
the oxygen transport capability of the cardiovascular system.
devices, compositions and methods are excluded from the
scope of the present invention.
inhalation of even small quantities of CO is inevitable for
living organisms.
[0004]
Depending on the extent and time of exposure, CO
Paradoxically, more than half a century ago it Was found that
CO is constantly formed in humans in small quantities (2),
and that under certain pathophysiological conditions this
endogenous production of CO may be considerably
increased (3-5). The discovery that hemoglobin, a heme
dependent protein, is required as substrate for the production
of CO in vivo (6, 7) and the identi?cation of the enZyme
heme oxygenase as the crucial pathWay for the generation of
this gaseous molecule in mammals (8) set the basis for the
early investigation of an unexpected and still unrecogniZed
role of CO in the vasculature (9). The succeeding cloning
(10) and characteriZation of constitutive (HO-2) and induc
ible (HO-1) isoforms of heme oxygenase (11-13) as Well as
studies on the kinetics and tissue distribution of these
tical devices, compositions and methods for the practical
and effective delivery of carbon monoxide in viva, such
[0008] Amongst literature relating to metal carbonyls,
WO98/48848 describes facial metal tricarbonyl compounds
and their use in the labelling of biologically active sub
strates. The metals, preferably radionuclides, are of Group 7,
the metals identi?ed being Mn, 99mTc, 186Re and 188Re. The
compounds fac-[M(CO)3(OH2)3]+ Where M is the metal are
proposed for labelling of biologically active substrates, as a
result of Which metal carbonyl compounds having a variety
of biologically active ligands are obtained. In the examples
radioactive Tc is used. The document describes preparation
of diagnostic and therapeutic compositions but no therapeu
tic composition is speci?cally disclosed, nor is any treatment
of any condition by therapy mentioned. There is no disclo
sure of use of the compounds for delivering carbon mon
enzymes (14) started to reveal a major importance of this
oxide to physiological targets. If, and to the extent that, this
pathWay in the physiological degradation of heme. That is,
the end products of heme degradation (CO, biliverdin and
bilirubin) might possess, after all, crucial biological activi
ties (15-17).
mode of therapeutic administration of the carbonyl com
pounds, that subject matter is excluded from the scope of the
[0005]
With regard to the cardiovascular system, the rec
ognition that CO possesses vasodilatory properties (18-20)
document is regarded as disclosing a therapeutic use or
present invention. Preferably the present invention excludes
use of the facial carbonyl compounds disclosed in this
document in any event.
is, perhaps, the most signi?cant evidence in favor of a
pharmacological function of CO. Although the molecular
[0009]
mechanisms and the chemical modi?cations that are
topical application or to treat acne or psoriasis by topical or
required to transduce the signals mediated by CO into a
speci?c biological effect need to be fully elucidated, con
vincing scienti?c reports have recently highlighted the sig
naling properties of endogenously generated CO (21-24).
WO 91/01128 and WO 91/01301 describe compo
sitions for treating skin to repair the effects of photoaging by
oral administration. The active compounds are polyene
esters and iron carbonyl complexes thereof. Speci?cally the
iron of iron tri-carbonyl is coordinated to the polyene chain.
No reason for including the iron carbonyl is mentioned.
Jun. 1, 2006
US 2006/0115542 A1
Insofar as therapeutic uses or compositions of carbonyl
compounds are disclosed in these tWo documents, such uses
and compositions are speci?cally excluded from the scope
of the present invention.
[0010] WO 98/29115 describes compositions and methods
for relaxing smooth muscle in a Warm-blooded animal by
administering certain transition metal nitrosyl compounds,
Treatments of hypertension, angina pectoris, congestive
heart failure and impotence are mentioned. Some of the
compounds contain, in addition to NO, CO as a ligand.
Speci?cally the CO-containing compound has the formula
L3M(NO)yX3_y Where L is a tWo-electron LeWis base or L3
is a six-electron LeWis base, M is a Group 6 or 8 transition
metal and When y is l, X is carbon monoxide. The essential
teaching of this document is concerned With the therapeutic
effect of nitrosyl complexes. There is no disclosure that the
CO ligand, When present, has any therapeutic effect by
delivery of CO to a physiological target. The CO-containing
metal nitrosyl complexes disclosed in it are excluded from
the novel metal carbonyls of the present invention and their
uses for treatments mentioned are also excluded from the
present invention. Preferably transition metal nitrosyl com
plexes containing CO are excluded from the scope of the
present invention in any event.
[0011] HU-B-2ll084 describes a composition, Which is
for oral administration, for the forti?cation of bones con
[0015] 1) CO derived by dissociation of the metal carbo
nyl is present in the composition in dissolved form;
[0016]
2) on contact With a solvent the metal carbonyl
releases CO;
[0017]
3) on contact With a tissue, organ or cell the metal
carbonyl releases CO;
[0018]
4) on irradiation the metal carbonyl releases CO.
[0019] Certain metal carbonyl compounds are capable of
releasing CO on contact With a suitable solvent. When the
pharmaceutical composition is to be administered in liquid
form, this solvent may form a component part of the
pharmaceutical composition. Thus in this aspect of the
invention, the pharmaceutical composition contains CO
derived from the metal carbonyl in dissolved form. The
conditions under Which the carbonyl compound is dissolved
in the solvent during preparation of the pharmaceutical may
be controlled such that the CO thus released is retained in
solution. This may be facilitated Where an equilibrium exists
betWeen the dissociated components and the undissociated
carbonyl.
[0020] The dissociated components of the parent carbonyl
may themselves be metal carbonyl complexes capable of
releasing further CO. For example, When [Ru(CO)3Cl2]2 is
dissolved in DMSO, CO is liberated into solution, and a
organic acid and optionally iron pentacarbonyl. The present
mixture of tri-carbonyl and di-carbonyl complexes is
formed, and these themselves may be capable of releasing
invention does not extend to the use of iron pentacarbonyl in
?lrther CO.
combination With calcium compounds as speci?ed in this
document in connection With the therapeutic uses and modes
of administration described there, and preferably does not
extend to the use of iron carbonyls and complexes including
iron and CO in combination With calcium phosphates and/or
calcium salts of organic acids in any event.
[0021] In a further aspect of the invention, the pharma
ceutical composition may not itself contain dissolved CO,
taining calcium phosphate, at least one calcium salt of an
but may be prepared such as to release CO on contact With
a suitable solvent or medium. For example, the composition
may contain a metal carbonyl compound capable of releas
ing CO on contact With water, eg on contact With an
[0012] WO 95/05814 (U.S. Pat. No. 6,284,752) and WO
aqueous physiological ?uid, such as blood or lymph. Alter
00/56743 both disclose a very Wide range of metal com
natively, the pharmaceutical composition may be intended to
plexes, for use in treatment of disease relating to the
be dissolved in Water prior to administration. Such pharma
ceutical compositions may be prepared in solution or in solid
form, such as in tablet form. If they are in solution form, they
Will typically be prepared in a solvent Which does not
overproduction of reactive oxygen species, particularly
overproduction of NO. The stated aim is to modulate NO
levels in the body by scavenging, or removing, NO in situ.
The ex-vivo test data are stated to shoW that vasconstriction
support dissociation of the metal carbonyl compound, such
is a direct result of the removal of endogenous nitric oxide.
Carbon monoxide is mentioned as a possible ligand, but no
that release of CO takes place only on contact With the
example of a complex containing carbon monoxide is given
and no effect is attributed to CO. Insofar as these documents
are considered to disclose practical use of a complex con
taining CO for the speci?ed purpose, such use does not form
part of the present invention.
SUMMARY OF THE INVENTION
[0013] As exempli?ed by the experimental data detailed
beloW, the present inventors have found that metal carbonyl
compounds can be used to deliver CO to a physiological
target so as to provide physiological effect.
[0014] Accordingly the present invention provides a phar
maceutical composition, for delivery of carbon monoxide to
a physiological target, comprising a metal carbonyl com
pound or pharmaceutically acceptable salt thereof and at
least one pharmaceutically acceptable carrier, Wherein the
metal carbonyl makes available CO suitable for physiologi
cal effect by at least one of the folloWing means:
appropriate solvent.
[0022] Alternatively or additionally, release of CO from
the complex can be stimulated by reaction With a ligand in
solution Which for example replaces one of the ligands of the
complex leading to loss of CO from the complex.
[0023] In another aspect of the invention the pharmaceu
tical composition may contain a metal carbonyl compound
Which releases CO on contact With a tissue, organ or cell. It
is shoWn beloW that certain metal carbonyl compounds do
not release CO to solution but are nevertheless capable of
releasing CO to physiological cellular materials or tissues,
such as vascular endothelium. For example, [Fe(SPh)2(2,2'
bipyridine)(CO)2] is shoWn beloW not to release CO to
myoglobin in solution, but is nevertheless capable of pro
moting dilatation of pre-contracted aortic rings. Without
Wishing to be limited by any particular theory, it is thought
that CO may be released from such compounds as a result
of an oxidation-reduction reaction, mediated by cellular
components such as cytochromes.