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  • C07F13/005—Compounds without a metal-carbon linkage

Definitions

• the present invention relates to new rhenium compounds, preferably non-radioactive rhenium compounds for medical use, corresponding pharmaceutical compositions as well as medical uses thereof.
• carbon monoxide is a signaling molecule in the inducible defensive system against stressful stimuli; it has a fundamental role in the circulatory system by improving vasorelaxation and cardiac blood supply; it suppresses arteriosclerotic lesions associated with chronic graft rejection; like NO it influences neurotransmission in the hypothalamic-pituitary-adrenal axis and there is evidence that carbon monoxide influences the circadian rhythm of mammals by interacting with NPAS2, the so-called human "clock" protein. Due to the relevance of carbon monoxide for mammalian physiology, the interest in its medicinal use is growing.
• CO-releasing molecules represent an alternative approach to the administration of carbon monoxide.
• Motterlini and Mann e.g. Motterlini et al., Circ. Res., 2002 90, E17-24; Motterlini et al., Intensive Care Med. 2008, 34, 649-658;
• CORM- 3 releases one mol carbon monoxide within ten minutes after being dissolved in water and significantly reduces blood pressure in vivo and relaxes pre-contracted aortic rings in vitro. Its cardioprotective effects have been documented.
• Today metal carbonyls have been recognized as a potential new class of pharmaceuticals (for a review on CO-RMs see Johnson et al., Metal Carbonyls in Medicine, Angew. Chem. Int. Ed., 2003, 42, 3722-3729).
• WO 02/092075 A2 pharmaceutical compositions comprising metal carbonyl compounds teaches, wherein the metal is selected from Fe, Mn, Ru, Rh, Ni, Mo or Co, for stimulating guanylate cyclase activity, neurotransmission or vasodilatation, for treating hypertension, radiation damage, endotoxic shock, inflammation, inflammation- related diseases, hyperoxia-indu injury, apoptosis, cancer, transplant rejection, arteriosclerosis, post-ischemic organ damage, myocardial infarction, angina, haemorrhagic shock, sepsis, penile erectile dysfunction and adult respiratory distress symptom.
• Rhenium is an extremely rare group 7 transition metal that is mainly used for super- alloy and catalyst production.
• Radioactive isotopes 188 Re and 186 Re are presently used for treatment of liver cancer. They both have similar penetration depths in tissue (5 mm for 186 Re and 11 mm for 188 Re), but 186 Re has the advantage of longer lifetime (90 hours vs. 17 hours for the 188 isotope).
• rhenium has a chemistry similar to technetium. Results on work done to label rhenium onto target compounds can often be transferred to technetium. This transfer aspect has proven useful for radiopharmacy, where it is difficult to work with technetium, especially with the medically used 99m isotope. So far medical applications of rhenium have been limited to the cytotoxic use of its radioactive isotopes.
• cardiovascular diseases preferably cardiac hypoxia, cardiac infarction, cardiac hypertrophy, arteriosclerosis and hypertension
• ischemia-reperfusion injury inflammatory diseases, preferably asthma or angina
• traumatic injury preferably of the brain, kidney or liver
• transplant rejection preferably allograft and xenograft rejection, platelet aggregation and/or monocyte activation
• neuron degeneration of the nervous system radiation damage, cancer, penile erectile dysfunction, adult respiratory distress syndrome, and disorders of the circadian rhythm of mammals, preferably jet lag.
• a further object is to provide (i) new diagnostic and/or medical uses for rhenium compounds, in particular non-radioactive rhenium compounds as well as (ii) pharmaceutical and diagnostic compositions comprising said compounds.
• Re is Re(l) or Re(ll), preferably Re(ll);
• n is selected from 3- to 3+, preferably 2-, 1-, 0, 1 + and 2+, more preferably 1 -, 0, 1 +;
• L1 , L2, L3 and L4 denote in each case independently of one another pharmaceutically acceptable monodentate ligands.
• the rhenium metal in the compounds of the present invention is not radioactive. It was surprisingly found that compounds of formula (I) featuring monodentate ligands to Re 1 or Re" do not only demonstrate aerobic stability in solid or dissolved form as previously reported by the inventors (Zobi et al., Inorg. Chem. 2009, 48, 8965-8970), they actually release carbon monoxide under physiological conditions in a controllable manner, the rate of release depending on the nature of the monodentate ligands and the pH.
• monodentate ligands of the inventive compounds is meant to exclude those ligands that no longer allow for medical utility of the inventive compounds because the adverse effects of the particular ligand, i.e. toxicity, at the dose and the mode administered no longer render the compound medically useful.
• Mono- or also called unidentate ligands are those wherein only one atom binds to the central rhenium ion in the compounds of the invention.
• Re(ll) is preferred because its complexes features 17 electrons, hence, are electronically unsaturated and thus more reactive.
• ligands of the compounds of the invention require the presence of either at least one heteroatom, preferably N, O, S and/or P, or at least one carbon-carbon double or triple bond for binding the rhenium metal of the complex.
• the group of suitable ligands was experimentally verified to encompass water, carbon monoxide, halogens, heteroaromatic and alcoholic compounds, i.e. virtually any compound or atom capable of forming a monodentate rhenium I or II complex together with at least two carbon monoxides.
• the ligands can be independently selected from neutral, positively or negatively charged monodentate ligands.
• the compounds of the invention are those, wherein at least one, preferably two, more preferably three, most preferably all of L1 , L2, L3 and L4 are independently selected from the group consisting of neutral or negatively charged, preferably neutral monodentate ligands.
• suitable positively charged ligands are pyrazinium, pyrimi- dinium or ,4'-bipyrimidinium-type ligands, preferably pyrimidinium.
• suitable neutral ligands are imidazole, pyridine and pyrazine-type ligands, preferably imidazole.
• Non-limiting examples of suitable negatively charged ligands are cyanide, hydroxide and halogens, preferably hydroxide and halogens, more preferably bromide. Further examples are described throughout the description.
• the monodentate ligands for practicing the invention can be selected from an extremely broad repertoire of chemical compounds of highly diverse nature, e.g. size, charge, spatial and functional arrangement of atoms. Because the present invention is a breakthrough in medicinal rhenium chemistry, vastly expanding the previous very limited use as radioactive cytotoxin and Tc-model compound, there is little information on ligand constraints; and also those highly diverse compounds of the invention already tested do not indicate any constraints. Hence, the ligands for practicing the invention can only be defined functionally without unduly limiting the scope of the invention.
• the term "independently selected from the group consisting of is meant to indicate that the four ligands may be selected from the same or different members of the indicated group. It is preferred that at least two ligands are the same; more preferably three ligands are the same and most preferably all four ligands are the same.
• the compounds of the present invention are selected from those, wherein at least one, preferably two, more preferably three, most preferably all of L1 , L2, L3 and L4 are independently selected from the group consisting of:
• alkyl and cycloalkyl comprising at least one heteroatom, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxyl, oxo, halogen, trifluoromethyl, nitro, nitrile, isocyanide, alcohol, phosphine, phosphite, phosphonite, sulphide, sulfoxide and amino or guanidine, each amino or guanidine optionally mono-, di- or tri-substituted, preferably mono- or di-substituted by alkyl, acyl or alkoxycarbonyl, each member of the group optionally substituted by one to four
• each R" is independently selected from
• alkyl alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted, preferably mono- or di-substituted by alkyl, acyl or alkoxycarbonyl,
• any members of the group and/or R" are optionally halogenated where possible.
• Alkyl ligands comprising at least one heteroatom are preferably C 1-20 , more preferably d. 12 , most preferably Ci -6 .
• Cycloalkyl ligands comprising at least one heteroatom are preferably C 3-2 o, more preferably C 3 . 12 , more preferably C 3 . 6 and most preferably C 5 . 6 .
• Alkenyl, alkynyl and alkylidene ligands are preferably C 2 . 20 , more preferably C 2-12 , most preferably C 2-6 .
• Aryl, heteroaryl, arylalkyl and aryloxy ligands are preferably C 5 . 20 , more preferably C 5- 2l most preferably C 5-6 .
• Alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino and alkylsulfonyl are preferably C -20 , more preferably C 1- 2 , most preferably C-i.
• the at least two carbon monoxides have a cis configuration towards each other, i.e. a cis-[Re ,/ "(CO) 2 L 1- ] stereochemistry.
• at least two of the four ligands L 1-4 are of the same type, preferably are halogens, more preferably bromide and have a trans configuration. This leaves a cis configuration for the remaining two ligands resulting in a cis-trans-cis stereochemistry, i.e.
• the invention is directed to cis-trans-cis [Re l "(CO)2(LiU)(L 2 L 3 )], wherein U and L 4 are preferably halogens, more preferably Br.
• the invention is directed to cis-trans-cis [Re l M (CO)2(halogen)2(L2L3)] compounds, bromides being the preferred halogens.
• Preferred compounds of the invention are those, wherein the at least two carbon monoxide ligands are in a cis configuration towards each other and/or at least two of L1 , L2, L3 and L4 are halogen, preferably bromide and/or the at least two halogen are in a trans configuration towards each other.
• the compounds of the present invention are selected from those, wherein at least one, preferably two, more preferably three, most preferably four of L1 , L2, L3 and L4 are independently selected from the group consisting of
• Ci -12 alkyl and C 3- 2 cycloalkyl comprising at least one heteroatom, preferably C 1-6 alkyl and C 3-7 cycloalkyl, C 2- 12 alkenyl, preferably C 2- 6 alkenyl, C 2- 2 alkynyl, preferably C 2 -6 alkynyl, C 2- 12 alkylidene, preferably C 2 -6 alkylidene, C 1- 2 alkoxy, preferably Ci -6 alkoxy, C 1-12 alkylthio, preferably C -6 alkylthio, C 1-12 acyl, preferably C -6 acyl, C 2-12 alkoxycarbonyl, preferably C 2 .
• each R" is independently selected from
• any members of the group and/or R" are optionally halogenated where possible.
• the compounds of the present invention are selected from those, wherein at least one, preferably two, more preferably three, most preferably four of L1 , L2, L3 and L4 are independently selected from the group consisting of
• halides preferably Br, OH-, CNT, CI0 4 " , N0 3 " , N0 2 -, NCO ' , NCS-, N 3 " and (ii) water, carbon monoxide and nitrogen, and
• nitriles isocyanides, primary, secondary and tertiary amines, preferably primary and secondary amines, alcohols, phosphines, phosphates, phosphonites, sulfides, sulfoxides, each optionally substituted by one to four R" where possible;
• each R and/or R" is independently selected from alkyl, alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted by alkyl, acyl or alkoxycarbonyl, wherein any of the groups and/or R" are optionally halogenated where possible;
• each R and/or R" is independently selected from
• the compounds of the present invention are selected from those, wherein at least one, preferably two, more preferably three, most preferably four of L1 , L2, L3 and L4 are independently selected from the group of 5- or 6-membered heteroatomic (the heteroatoms is/are preferably at least one of N, O, S and/or P) carbon rings, preferably consisting of
• X is selected from N, O, S or P with the proviso that for ligands with two X, one X may be C, optionally substituted by one to four R" where possible;
• each R" is independently selected from
• the compounds of the present invention are selected from those, wherein at least one, preferably two, more preferably three, most preferably four of L1 , L2, L3 and L4 are independently selected from the group consisting of 5 to 6-membered heteroatomic (preferably N, O, S and/or P) carbon rings, preferably those described directly above, wherein 2 to 8, preferably 2 to 6, more preferably 2 to 4 of the 5 to 6-membered heteroatomic carbon rings are bound to a common linker, e.g.
• X is defined as above and n is preferably 1 to 7, more preferably 1 to 5; and "linker” denotes a functional group connecting the at least two 5 to 6-membered
• a linker selected from the group consisting of alkyl, alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl,
• Ci -12 preferably Ci -6 alkyl, Ci-i 2 , preferably C 1-6 alkenyl, C 1-12 , preferably C 1-6 alkynyl, C - 2 , preferably C -6 alkylidene, Ci.i 2 , preferably C 1-6 cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, C 1-12 , preferably Ci -6 alkoxy, Ci-i 2 , preferably C 1-6 alkylthio, Ci 12 , preferably C 1-6 acyl, Ci -12 , preferably C 1-6 alkoxycarbonyl, C 1- 2 , preferably d. 6 acyloxy, Ci-12, preferably Ci -6 acylamino, sulphonylamino, aminosulfonyl, Ci.i 2 , preferably C 1-6 alkylsulfonyl;
• each R" is independently selected from the group consisting of
• each R" is independently selected from the group consisting of Ci - 2 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 2- i 2 alkylidene, C 3- i 2 cycloalkyl, aryl,
• each R" is independently selected from the group consisting of C 1-6 alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, C 2 . 6 alkynyl, C 2- 6 alkylidene, C 3-7 cycloalkyl, aryl, arylalkyl, aryloxy, C 1-6 alkoxy, C 1-6 alkylthio, Ci -6 acyl, C 2-7 alkoxycarbonyl, C 1-6 acyloxy, C 1-6 acylamino, sulphonylamino, aminosulfonyl, C 1-6 alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted by C 1-5 alkyl, C 1-5 acyl or C 2-7 alkoxycarbonyl, wherein any of the linkers and/or R" are optionally mono-, di- or
• rhenium-coordinating atom preferably forms part of an aromatic system.
• the compounds of the present invention are selected from those, wherein at least one, preferably two, more preferably three, most preferably four of L1 , L2, L3 and L4 are independently selected from the group consisting of
• n is 1 to 6, preferably 1 to 3;
• linker denotes a functional group connecting the two nitrogen, two phosphor or two sulphur atoms
• a linker selected from the group consisting of alkyl, alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl,
• a linker selected from the group consisting of C- 2, preferably C 1-6 alkyl, C 1-12 , preferably C 1-6 alkenyl, preferably C -6 alkynyl, C - 2 , preferably alkylidene, Ci -12 , preferably C 1-6 cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, C -12 , preferably C -6 alkoxy, Ci.i 2 , preferably Ci -6 alkylthio, Ci.
• Ci -6 acyl C 1 -12, preferably C -6 alkoxycarbonyl, Ci -12 , preferably 6 acyloxy, Ci-i 2 , preferably C 1-6 acylamino, sulphonylamino, aminosulfonyl, C - 2 , preferably C 1-6 alkylsulfonyl;
• each R is independently selected from the group consisting of
• alkyl alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted, preferably mono- or disubstituted by Ci -6 alkyl, d -6 acyl or C 2-7 alkoxycarbonyl; preferably wherein each R is independently selected from the group consisting of C- 2 alkyl, C 2- 2 alkenyl, C 2- i 2 alkynyl, C 2-12 alkylidene, C 3- i 2 cycloalkyl, aryl,
• each R is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 2 . 6 alkynyl, C 2-6 alkylidene, C 3-7 cycloalkyl, aryl, arylalkyl, aryloxy, Ci -6 alkoxy, C 1-6 alkylthio, C 1-6 acyl, C 2 .
• the compounds of the present invention are selected from those, wherein at least one, preferably at least two, more preferably at least three and most preferably four of L1 , L2, L3 and L4 are independently selected from the group consisting of nucleotides, amino acids, vitamins, preferably vitamin B12, and oligomers of 1 to 10 moieties thereof, preferably
• each R" is independently selected from
• alkyl alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted, preferably mono- or disubstituted by C 1-6 alkyl, C 1-6 acyl or C 2- 7 alkoxycarbonyl; preferably wherein each R" is independently selected from d -12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 2-12 alkylidene, C 3- i 2 cycloalkyl, aryl, arylalkyl
• each R" is independently selected from C 1-6 alkyl, C 2-6
• alkenyl C 2 - 6 alkynyl, C 2-6 alkynyl, C 2-6 alkylidene, C 3-7 cycloalkyl, aryl, arylalkyl, aryloxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 acyl, C 2 .
• Ci -6 acyloxy C 1-6 acylamino, sulphonylamino, aminosulfonyl, C -6 alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri- substituted by C 1-5 alkyl, C 1-5 acyl or C 2-7 alkoxycarbonyl,
• the compounds of the present invention have formula [Re"Br 2 (CO)2(L)2], preferably cis-trans-cis [Re"Br 2 (CO) 2 (L) 2 ], wherein at least one, preferably both L are selected from the group consisting of halides, preferably Br " , carbon monoxide, N-methyl imidazole, benzimidazole, 4-methyl pyridine, imidazole, pyridine, pyridine, C 1-6 alkyl cyanide, preferably methyl cyanide and alcohol, preferably d. 6 alcohol, more preferably methanol or ethanol, optionally substituted by one to four R" where possible;
• each R" is independently selected from the group consisting of
• alkyl alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted, preferably mono- or disubstituted by Ci -6 alkyl, C -6 acyl or C 2- 7 alkoxycarbonyl; preferably wherein each R" is independently selected from the group consisting of Ci.
• Ci_i 2 acyloxy Ci_i 2 acylamino, sulphonylamino, aminosulfonyl, CM 2 alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted, preferably mono- or disubstituted by Ci -6 alkyl, Ci -6 acyl or C 2- 7 alkoxycarbonyl;
• each R" is independently selected from the group consisting of Ci -6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 2-6 alkynyl, C 2-6 alkylidene, C 3-7 cycloalkyl, aryl, arylalkyl, aryloxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 acyl, C 2-7 alkoxycarbonyl, C 1-6 acyloxy, C 1-6 acylamino, sulphonylamino, aminosulfonyl, C 1-6 alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted by Ci -5 alkyl, C 1-5 acyl or C 2-7 alkoxycarbonyl,
• any members of the group and/or of the R" are optionally halogenated where possible.
• the compounds of the invention may comprise at least one, preferably two diagnostic and/or physiologically active ligands, preferably selected from the group consisting of targeting ligands, diagnostic ligands and physiologically, preferably medically active ligands.
• compounds of the invention can function as a "carrier” for "functional" ligands.
• the invention includes the use of any compounds described above containing one or more asymmetric carbon atoms which may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
• Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
• Some of the compounds of the invention can exist in more than one tautomeric form. The invention includes all such tautomers.
• heteroatom as used herein, for example in the context of the term heteroaryl shall be understood to mean atoms other than carbon and hydrogen such as and preferably O, N, S and P.
• alkyl, alkenyl, alkynyl, alkylidene, etc. shall be understood as encompassing linear and branched, substituted or non-substituted forms of carbon-containing chains where structurally possible.
• one or more carbon atoms can be optionally replaced by heteroatoms, preferably by O, S or N. If N is not substituted, it is NH.
• the heteroatoms may replace either terminal or internal carbon atoms within a linear or branched carbon chain.
• groups can be substituted as herein described by groups such as oxo to result in definitions such as but not limited to alkoxycarbonyl, aery I, amido and thioxo.
• Carbocycle shall be understood to mean a cyclic hydrocarbon containing from 3 to 20, preferably 3 to 12 carbon atoms, more preferably 5 or 6 carbon atoms. Carbocycles include hydrocarbon rings containing from 3 to 20, preferably 3 to 12 carbon atoms. These carbocycles may be either aromatic or non-aromatic, i.e. cycloalkyi systems or mixed cycloalkyl-aromatic systems. The non-aromatic ring systems may be mono- or polyunsaturated.
• Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydro- naphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl, and benzocycloheptenyl. Certain terms for cycloalkyi such as cyclobutanyl and cyclobutyl shall be used interchangeably.
• cycloalkyi shall be understood to mean aliphatic hydrocarbon-containing rings having from 3 to 20, preferably 3 to 12 carbon atoms. These non-aromatic ring systems may be mono- or polyunsaturated, i.e. the term encompasses cycloalkenyl and cycloalkynyl.
• the cycloalkyi may comprise heteroatoms, preferably O, S or N, and be substituted or non-substituted.
• cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, benzocyclobutanyl, benzocycloheptanyl und benzocycloheptenyl.
• heterocyclic refers to a stable non-aromatic, preferably 3 to 20-membered, more preferably 3 to 12-membered, most preferably 5 or 6-membered, monocyclic or multicyclic, preferably 8 to 12-membered bicyclic, heteroatom-containing cyclic compound, that may be either saturated or unsaturated.
• Each heterocycle consists of carbon atoms and one or more, preferably 1 to 4 heteroatoms chosen from nitrogen, oxygen, sulphur and phosphorus.
• the heterocyclic residue may be bound to the remaining structure of the complete molecule by any atom of the cycle, which results in a stable structure.
• heterocycles include, but are not limited to, pyrroli- dinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpho- linyl sulfone, dioxalanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, 1 -oxo-A4-thiomor- pholinyl, 13-oxa-1 1 -aza-tricyclo[7.3.1.0-2,7]tridecy-2,4,6-triene, tetrahydropyranyl, 2- oxo-2H-pyranyl, tetrahydrofuranyl, 1 ,3-dioxolanone, 1 ,3-dioxanone, 1 ,4-dioxanyl, 8- oxa-3-aza-bicyclo[3.2.1]octanyl, 2-oxa-5
• aryl as used herein shall be understood to mean an aromatic carbocycle or heteroaryl as defined herein.
• Each aryl or heteroaryl unless otherwise specified includes its partially or fully hydrogenated derivatives.
• quinolinyl may include decahydroquinolinyl and tetrahydroquinolinyl; naphthyl may include its hydro- genated derivatives such as tetrahydronaphthyl.
• Other partially or fully hydrogenated derivatives of the aryl and heteroaryl compounds described herein will be apparent to one of ordinary skill in the art.
• the term encompasses aralkyl and alkylaryl, both of which are preferred embodiments for practicing the compounds of the present invention.
• aryl encompasses phenyl, indanyl, indenyl, dihydro- naphthyl, tetrahydronaphthyl, naphthyl and decahydronaphthyl.
• heteroaryl shall be understood to mean an aromatic C 3 -C 2 o, preferably 5 to 8-membered monocyclic or preferably 8 to 12-membered bicyclic ring containing 1 to 4 heteroatoms such as N, O, P and S.
• heteroaryls comprise aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-/)]pyrimidinyl, purinyl, pyrrolo[2,3-£>]pyridinyl, pyrazole[3,4-i)]pyridinyl, tubercidinyl, oxazo
• nitrogen As used herein, the terms "nitrogen”, “sulphur” and phosphorus include any oxidized form of nitrogen, sulphur and phosphorus and the quaternized form of any basic nitrogen as long as the resulting compound is chemically stable.
• an -S- C -6 alkyl radical shall be understood to include -S(0)-C -6 alkyl and -S(0) 2 -C 1-6 alkyl.
• Pharmaceutically acceptable salts of the compounds of the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases, preferably non-oxidizing inorganic and organic acids and bases.
• suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.
• Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g. , magnesium), ammonium and N-(C 1-4 alkyl) + salts.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound according to the invention as described above and optionally one or more pharmaceutically acceptable carriers and/or adjuvants.
• compositions of the present invention typically comprise a pharmaceutically acceptable excipient, carrier, buffer, stabiliser, preservative and/or other materials well known to those skilled in the art. Such materials should be nontoxic and should not interfere unduly with the efficacy of the active ingredient.
• the precise nature of the carrier or other material may depend on the route of administration, e.g. oral, intravenous, subcutaneous, nasal, intramuscular, intraperitoneal or suppository routes.
• Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form.
• a tablet may include a solid carrier such as gelatin or an adjuvant or a slow-release polymer.
• Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil.
• Physiological saline solution dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
• Pharmaceutically acceptable amounts of other solvents may also be included, in particular where they are required for dissolving the particular metal carbonyl compound contained in the composition.
• the active ingredient will typically be in the form of a parenterally acceptable solution which is pyrogen-free and has suitable pH, isotonicity and stability.
• Those of skill in the pharmaceutical art are capable of preparing suitable solutions using, for example, isotonic vehicles such as physiological saline, Ringer's injection solution and Ringer ' s lactate solution for injection.
• Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required. Delivery systems for needle-free injection are also known, and compositions of the invention for use with such systems may be prepared accordingly.
• the present invention relates to a use of a compound of the invention as defined above for the preparation of a medicament for the treatment and/or protection of patients having or being prone to produce a disease or medical condition responsive to carbon monoxide treatment, preferably a disease or medical condition involving hypoxic, anoxic and/or inflamed mammalian tissue, preferably a tissue selected from the group consisting of heart, lung, liver, brain, gut, kidney, muscle, bone, skin and eye, preferably a disease or medical condition selected from the group consisting of cardiovascular diseases, preferably cardiac hypoxia, cardiac infarction, cardiac hypertrophy, arteriosclerosis and hypertension; ischemia- reperfusion injury, inflammatory diseases, preferably asthma or angina; traumatic injury, preferably of the brain, kidney or liver; transplant rejection, preferably allograft and xenograft rejection, platelet aggregation and/or monocyte activation; neuron degeneration of the nervous system, radiation damage, cancer, penile erectile dysfunction, adult
• the pharmaceutical composition/medicament is for administration prior to, after or concomitantly to a medical condition.
• a "patient” means any mammal that may benefit from a treatment with the compounds of the invention.
• a “patient” is selected from the group consisting of laboratory animals (e.g. mouse or rat), domestic animals (including e.g. guinea pig, rabbit, pig, sheep, goat, camel, cow, horse, donkey, cat, or dog), or primates including human beings. It is particularly preferred that the "patient” is a human being.
• treat means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
• administering includes in vivo administration, as well as
• Administration may be effected for the prevention, i.e. before clinical occurrence of a disease or disorder, or for treatment, i.e. after clinical occurrence of a disease or disorder.
• the present invention is directed to the use of the above- mentioned compounds for preparing a medicament for the treatment of a disease or medical condition selected from the group consisting of selected from the group consisting of cardiovascular diseases, preferably cardiac hypoxia, cardiac infarction, cardiac hypertrophy, arteriosclerosis and hypertension; ischemia-reperfusion injury, inflammatory diseases, preferably asthma or angina; traumatic injury, preferably of the brain, kidney or liver; transplant rejection, preferably allograft and xenograft rejection, platelet aggregation and/or monocyte activation; neuron degeneration of the nervous system, radiation damage, cancer, penile erectile dysfunction, adult respiratory distress syndrome, and disorders of the circadian rhythm of mammals, preferably jet lag.
• cardiovascular diseases preferably cardiac hypoxia, cardiac infarction, cardiac hypertrophy, arteriosclerosis and hypertension
• ischemia-reperfusion injury inflammatory diseases, preferably asthma or angina
• traumatic injury preferably of the brain, kidney or liver
• transplant rejection preferably allograft and x
• the present invention relates to a method of treating and/or protecting patients having or being prone to develop a disease or medical condition responsive to carbon monoxide treatment as discussed above, the method comprising the administration of a therapeutically effective amount of at least one compound of the invention as defined above or a prodrug thereof or an effective amount of the pharmaceutical composition of the invention as defined above to a patient in need thereof.
• an “effective amount” is an amount of a therapeutic agent sufficient to achieve the intended purpose.
• the effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration.
• the effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art.
• the compounds of the invention may be administered in any conventional dosage form in any conventional manner.
• Routes of administration include, but are not limited to, intravenously, intramuscularly, cutaneously, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, or topically.
• the preferred modes of administration is intravenous.
• the compounds may be administered alone or in combination with adjuvants that enhance stability of the compounds, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, provide adjunct therapy, and the like, including other active ingredients.
• combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side-effects incurred when those agents are used as monotherapies.
• the above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is this regard may be made to Cappola et al.: U.S. patent application no. 09/902,822, PCT/US 01/21860 und US provisional application no. 60/313,527, each incorporated by reference herein in their entirety.
• the compounds may then be administered together in a single dosage form.
• the pharmaceutical compositions comprising such combinations of compounds contain at least about 5 %, but more preferably at least about 20 %, of a compound of formula (I) (w/w) or a combination thereof.
• the optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art.
• the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
• dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
• carriers and adjuvants include, for example, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances.
• Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup,
• dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 0.1 - 100 g/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day or more may be required.
• the present invention relates to compounds of formula (I) as described above, preferably non-radioactive compounds, more preferably with the proviso that the compound is not selected from the group explicitly disclosed in the recent publication of the present inventors (Zobi et al., Inorg. Chem. 2009, 48, 8965- 8970), the group preferably consisting of [Re"Br 4 (CO) 2 ] 2" , [Re"Br 2 (CO) 2 (pyridine) 2 ], [Re"Br 2 (CO) 2 (imidazole) 2 ], [Re"(CO) 2 (HOCH 3 )4] 2+ , [Re"Br 3 (CO) 2 (N ⁇ CCH 3 )r,
• Fig. 1 graphically represents a typical absorption spectrum of the conversion of deoxy-myoglobin (Mb) to carbon monoxide myoglobin (MbCO) by a cis-trans-
• Figs. 2 to 7 graphically represent the results of the pH-dependent rate of CO release of different cis-trans-[Re"(CO)2Br 2 L 2 ] n complexes under conditions of 30 ⁇ Mb (myoglobin), 25°C, 0.1 M phosphate buffer, pH 7.4 ( ⁇ ), 6.3 (A), 5.8 ( ⁇ ).
• Fig. 8 Cytoprotective effects of conjugates B 12 -CORM-2 and B 12 CO-RM-4 (30 ⁇ ) against "ischemia-reperfusion" injury (l/R).
• ischemia-reperfusion injury
• NRCs neonatal rat ventricular cardiomyocytes
• CO- RMs or the aliquot of solvent (DMSO) were added to the cell culture medium at the onset of reperfusion period of 9 h at 30 ⁇ concentration.
• Bars indicate the % of Pl-positive (dead) cells. ** denotes p ⁇ 0.01 when l/R B 12 -CORM-2-treated cells are compared to l/R control. # denotes p ⁇ 0.05 when normoxic cells are compared with l/R control.
• Fig. 9 Regulation of oxygen availability and the intracellular reduced glutathione content by Re-CORMs.
• the compounds of the present invention can be prepared without any undue burden or inventive skill by any appropriate conventional synthetic strategy known to those of skill in organic and inorganic chemistry, in particular in view of the recent disclosure of the present inventors in Inorg. Chem. 2009, 48, 8965-8970, the synthetic routes of which are incorporated in toto by reference herewith.
• the release of CO from the compounds of the invention was assessed spectrophoto- metrically by measuring the conversion of deoxymyoglobin (Mb) to carbonmonoxy myoglobin (MbCO) as previously reported (Clark et al., Circ. Res. 2003, 93, e2-8; Motterlini et al., Circ. Res. 2002, 90, E17-24; Motterlini et al., Curr. Pharm. Des. 2003, 9, 2525-2539).
• Mb deoxymyoglobin
• MbCO carbonmonoxy myoglobin
• Cyanocobalamin 400 mg, 0.3 mmol was dissolved in 10 mL of anhydrous DMSO and carbonyldiimidazole (CDI, 1 g, 6.2 mmol) was added. The solution was stirred and heated to 60 °C for 12 h. The solution was allowed to cool to room temperature (RT) and then slowly added to a rapidly stirring mixture of 300 mL 1 :1 diethyl etherchloroform. The red precipitate was collected by vacuum filtration, washed with 50 mL of acetone and vacuum dried. Yield: 395 mg. This product was not purified but used directly for the next reaction.
• CDI carbonyldiimidazole
• the derivatives a) are fully water soluble and biocompatible, b) show improved stability in aqueous aerobic media over the metal complex alone, c) are non-toxic towards cultured cardiomyocytes, d) protect these cells against ischemia-reperfusion injury and e) after CO release, in water under aerobic conditions, the rhenium complex is oxidized to Re0 4 " which is among the least toxic of all of the rare inorganic compounds.
• Complexes 3-5 are soluble in common organic solvents like methanol, CH 2 CI 2 , acetonitrile or DMSO and even under aerobic conditions are stable for days. X-ray quality crystals of 3, 4 and 5 could be grown from CH 2 CI 2 .
• the ligands L substituted the two bromides trans to the CO's resulting in [Re"(CO) 2 Br 2 L 2 ] complexes with a cis-trans-cis arrangement of the ligands. Since the cis arrangement of the two COs is the only structural compulsion, other isomers are expected as well .
• a common feature of the compounds 3-5 is the bending of the two trans bromides away from the CO's with an average Br-Re-Br angle of 171.5°.
• Bond lengths and angles of 3 and 5 were found similar to the related imidazole and pyridine complexes cis-trans- [Re"(CO) 2 Br 2 (lm) 2 ] (6) and c/s-fraA7s-[Re"(CO) 2 Br 2 (py) 2 ] (7) previously described (Zobiet al., Inorg. Chem. 2009, 48, 8965-8970.). When reacted with others
• heterocyclic aromatic ligands like THF or thiophene, 2 was always recovered unreacted indicating that, under similar experimental conditions, these ligands are not strong enough to replace the bound bromides even if present in large excess.
• the bases were found to be able to freely rotate around the metal center and we have shown that the different head-to-head (HH) or HT conformers observed in the solid state structures of the adducts are a result of packing effects (Zobi et al., Inorg. Chem. 2004, 43, 2087-2096).
• the Bzlm and other purine-type ligands are expected to be able to freely rotate around the cis- [Re"(CO) 2 ] 2+ core.
• the HT conformer observed in the solid state structure of 4 is unlikely to be the predominant form in solution.
• Example 2 Biological properties CO-releasing properties of c/s-fra/7S-fRe"(CO) z Br U1 n complexes.
• the carbon monoxide releasing properties of complexes were evaluated by the myoglobin assay (Fig. 2A).
• This assay has been shown to be a reliable method for assessing the amount and kinetic of CO liberation from CO- releasing molecules (Clark et al., Circ. Res. 2003, 93, e2-8, Motterlini et al., Circ. Res. 2002, 90, E17-24, Motterlini et al., Curr. Pharm. Des. 2003, 9, 2525-2539).
• Mb carbon monoxide myoglobin
• B 12 -CORM-2 and 4 were tested for their cytotoxic and their cytoprotective effects using the neonatal rat cardiomyocyte (NRC) cell-based model of ischemia- reperfusion injury (l/R) as previously described (Zobi et at., Inorg. Chem. 2010, 49, 7313-7322).
• NRC neonatal rat cardiomyocyte
• l/R ischemia- reperfusion injury
• the membrane-impermeable Rell-CORMs studied so far were non-toxic in the micromolar concentration range.
• Atomic absorption spectres- copy (AAS) measurements showed that the rhenium concentration in the medium supplemented with B 12 -CORM-2 and B 12 -CORM-4 did not change over time. This observation implies that complexes (or the dissociated Re fragment) did not enter the cells through the cell surface membrane during a 3 h incubation period (data not shown). The fraction of dead cells tended to decrease in the presence of CORMs, but, due to the high variability, the differences were not statistically significant (2.7 ⁇ 1.7 % in control vs 1.1 ⁇ 0.3 and 1.0 ⁇ 0.2 in the presence of B 12 -CORM-2 and B 12 -CORM-4 respectively).
• Oxidative stress triggered by acute hyperoxygenation is a hallmark of reperfusion injury.
• CORMs may be viewed as oxygen scavengers which, when applied early on during reperfusion, may reduce the cellular oxidative damage.
• intracellular reduced glutathione (GSH) levels were determined in cells 10 min after the "onset of reperfusion" in the presence or absence of 30 ⁇ 2, 6 and B 12 -CORM-2.
• GSH reduced glutathione
• FIG 9B presence of 2 complex at reperfusion resulted in an increase in the intracellular reduced glutathione (GSH) levels reflecting its antioxidative action.
• This acute antioxidative effect of 2 most likely reflects the ability of the intermediates formed upon CO release to react with oxygen forming Re0 4 " .

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