Therapeutic Modulators of the Reverse Mode of ATP Synthase
20200306253 ยท 2020-10-01
Inventors
Cpc classification
C07D233/56
CHEMISTRY; METALLURGY
A61K31/53
HUMAN NECESSITIES
C07D233/61
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
International classification
A61K31/53
HUMAN NECESSITIES
Abstract
Compounds of the following formula (I) slow the ATP-hydrolysing mode of ATP synthase and are useful for treating various diseases and disorders including cancer, particularly cancers that utilise the Warburg effect.
##STR00001##
Claims
1. A method of treating, ameliorating, preventing or combating cancer in a subject, or a method of treating a disease or disorder in a subject selected from (i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. .sup.18F-FDG PET); (ii) cachexia or cancer driven cachexia; wherein the method comprises administering to the subject an effective amount of at least one compound, or a composition containing at least one compound, of the following formula: ##STR00090## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein R.sup.A1 and R.sup.A2 are each independently selected from the groups ##STR00091## wherein R.sup.C and R.sup.D are each independently selected from hydrogen, deuterium, halogen and alkyl, and wherein R.sup.E is hydrogen, deuterium, or alkyl; R.sup.B is selected from R.sup.B1, hydrogen and deuterium; wherein R.sup.B1 is selected from phenyl, benzyl, pyridyl, pyrimidyl and pyrazinyl optionally substituted with one or more substituents R.sup.B2; wherein each R.sup.B2 is independently selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and polyhalogen alkyl; or R.sup.B is a phenylalkyl of the formula: ##STR00092## wherein R.sup.F and R.sup.G are hydrogen or alkyl, G is a carbon-carbon double bond or a carbon-carbon single bond, n is 0 or 1 and q is 0 or 1 provided that where q is 0, G is a carbon-carbon double bond and where q is 1, G is a carbon-carbon single bond, or R.sup.B is a diphenylalkyl of the formula ##STR00093## wherein R.sup.H is hydrogen or halogen, and p is 0, 1 or 2; or R.sup.B is the group ##STR00094## wherein R.sup.J and R.sup.K each independently represent 1-5 optional substituents on each ring, and wherein each R.sup.J and each R.sup.K, when present, is independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
2. A method according to claim 1, wherein one or more of the following applies: R.sup.B is the group: ##STR00095## R.sup.B is the group: ##STR00096## wherein R.sup.L and R.sup.M are each independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl; R.sup.L and R.sup.M are each independently selected from halogen; R.sup.L and R.sup.M are the same; R.sup.L and R.sup.M are each F; R.sup.A1and R.sup.A2 are each independently selected from the group ##STR00097## wherein R.sup.C and R.sup.D are each independently selected from hydrogen, deuterium, halogen and alkyl; R.sup.A1 and R.sup.A2 are the same; R.sup.C is hydrogen; R.sup.D is hydrogen;
3. A compound or composition for use according to claim 2, wherein R.sup.B is the group: ##STR00098## wherein R.sup.L and R.sup.M are each independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
4. A compound or composition for use according to claim 3, wherein R.sup.L and R.sup.M are each independently selected from halogen.
5. A compound or composition for use according to claim 3 or 4, wherein R.sup.L and R.sup.M are the same.
6. A compound or composition for use according to claim 3, wherein R.sup.L and R.sup.M are each F.
7. A compound or composition for use according to any one of claims 1 to 6, wherein R.sup.A1 and R.sup.A2 are each independently selected from the group ##STR00099## wherein R.sup.C and le are each independently selected from hydrogen, deuterium, halogen and alkyl.
8. A compound or composition for use according to claim 7, wherein R.sup.A1 and R.sup.A2 are the same.
9. A compound or composition for use according to claim 7 or 8, wherein R.sup.C is hydrogen.
10. A compound or composition for use according to any one of claims 7 to 9, wherein R.sup.D is hydrogen.
11. A method according to claim 1, wherein the compound is: ##STR00100## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof or an isotopologue(s) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
12. A compound or composition for use according to claim 1, wherein the compound is an isotopologue(s) of: ##STR00101## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof.
13. A compound having the formula, ##STR00102## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: L is alkyl, or deuterium, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.) except hydrogen at natural abundance; R.sub.1 is hydrogen, cyano, SO.sub.2R.sub.8, C(O)R.sub.9, or heteroaryl (such as thiazolyl); R.sub.2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R.sub.3 forms a heterocyclo; R.sub.3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, B.sub.B-aryl, B.sub.B-heterocyclo, B.sub.B-heteroaryl, or B.sub.B-cycloalkyl, or (ii) phenyl optionally substituted with C.sub.1-4a1kyl, halogen, trifluoromethyl, OCF.sub.3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from C.sub.1-4alkyl, alkylthio, aminoalkyl, B.sub.B-aryl, B.sub.B-heterocyclo, B.sub.B-cycloalkyl, and B.sub.B heteroaryl, optionally having one to three substituents selected from R.sub.3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R.sub.2 forms a heterocyclo optionally substituted with alkyl or substituted alkyl; B.sub.B is a bond, C.sub.1-4alkylene, C.sub.2-4alkenylene, substituted C.sub.1-4alkylene, substituted C.sub.2-4alkenylene, substituted C.sub.1-4a1kylene-C(O)NH, C(O)NH, C.sub.1-4alkylene-C(O)NH, C(O)NR.sub.19, C.sub.1-4alkylene-C(O)NR.sub.19, or substituted C.sub.1-4alkylene-C(O)NR.sub.19, (CHR.sub.14).sub.m (CR.sub.15R.sub.16).sub.n or (CHR.sub.14).sub.pC(O)NH; R.sub.3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, NR.sub.17R.sub.18, SR.sub.17, OR.sub.17, SO.sub.2R.sub.17a, SO.sub.2NR.sub.17R.sub.18, NR.sub.17C(O)R.sub.18, CO.sub.2R.sub.17, C(O)R.sub.17, cycloalkyl, aryl, heterocyclo, and heteroaryl, wherein when R.sub.3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyclo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl; Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl; or Z is triazolyl optionally substituted with one to two R.sub.7 substituents or imidazolyl optionally substituted with one to two R.sub.7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R.sub.7 substituents; and R.sub.7 is alkyl, carbamyl, or substituted alkyl; R.sub.4 at each occurrence is selected independently of each other R.sub.4 from the group consisting of halogen, trifluoromethyl, OCF.sub.3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR.sub.25, SR.sub.25, NR.sub.25R.sub.26, NR.sub.25SO.sub.2R.sub.27, SO.sub.2R.sub.27, SO.sub.2NR.sub.25R.sub.26, CO.sub.2R.sub.26, C(O)R.sub.26, C(O)NR.sub.25R.sub.26, OC(O)R.sub.25, OCNR.sub.25R.sub.26, NR.sub.25C(O)R.sub.26, NR.sub.25CO.sub.2R.sub.26, aryl, heteroaryl, heterocyclo and cycloalkyl; R.sub.8 is C.sub.1-4alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl; R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or CO.sub.2R.sub.12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C.sub.1-4alkoxy, haloalkoxy, C.sub.1-6alkyl, CO.sub.2alkyl, SO.sub.2alkyl, SO.sub.2NH.sub.2, amino, NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NHC(O)alky, C(O)alkyl, and/or C.sub.1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocyclo in turn optionally substituted with keto or having a benzene ring fused thereto or a) C.sub.1-4alkyl optionally substituted with one to two of: i) SR.sub.13, OR.sub.13, NR.sub.13aR.sub.13b, halogen, trifluoromethyl, CO.sub.2R.sub.13a, and CO)NR.sub.13aR.sub.13b; ii) cycloalkyl optionally substituted with one to two of C(O)H, C.sub.1-4acyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen; iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, C.sub.1-4alkoxy, or having fused thereto a five or six membered heterocyclo; iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or C.sub.1-4alkoxy; b) 3 to 6 membered cycloalkyl optionally having up to four substituents selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto; c) phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C.sub.1-4alkoxy, haloalkoxy, C.sub.1-4alkyl, CO.sub.2alkyl, SO.sub.2alkyl, SO.sub.2NH.sub.2, amino NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NHC(O)alkyl, C(O)alkyl, and/or C.sub.1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocycle in turn optionally substituted with keto or having a benzene ring fused thereto; d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl; R.sub.10 and R.sub.11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or C.sub.1-4alkyl optionally substituted with one to two of CO.sub.2alkyl, C(O)NH(aryl), NH(aryl), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with C.sub.1-4alkyl, hydroxy, C.sub.1-4alkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto; napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with C.sub.1-4alkyl or C.sub.1-4alkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by R.sub.10 and R.sub.11 is optionally substituted with one to two of keto, CO.sub.2H, C.sub.1-4alkoxy, CO.sub.2alkyl, C.sub.1-4carbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or C.sub.1-4 alkoxy; tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; alkyl optionally substituted with amino or NHR.sub.2uwherein R.sub.21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, C.sub.1-4alkoxy, CO.sub.2alkyl, and/or C.sub.1-4carbamyl; R.sub.12 and R.sub.19 are hydrogen or alkyl; R.sub.13 is hydrogen or alkyl; R.sub.13a and R.sub.13b are selected from hydrogen, alkyl, and aryl; R.sub.14, R.sub.15 and R.sub.16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxy, and phenyl, and/or one of R.sub.15 and one of R.sub.16 join together to form a 3 to 6 membered cycloalkyl; R.sub.17 and R.sub.18 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl; R.sub.17a is alkyl or substituted alkyl; R.sub.25 and R.sub.26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring; R.sub.27 is alkyl or substituted alkyl; q is 0, 1, 2, or 3; m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.
14. A compound according to claim 13, of the formula, ##STR00103## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: there is an enantiomeric excess (ee) of the particular stereoisomer shown in the formula.
15. A compound according to claim 13, of the formula, ##STR00104## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: the enantiomeric excess (ee) of the R stereoisomer exceeds 70%;
16. A compound according to claim 13, of the formula, ##STR00105## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: the enantiomeric excess (ee) of the S stereoisomer exceeds 70%;
17. A compound according to claim 13, wherein, ##STR00106## Y is CH, N or CR.sub.7c; R.sub.1 is cyano, SO.sub.2R.sub.8, C(O)R.sub.9, or heteroaryl; R.sub.2 is (i) independently hydrogen, alkyl, or substituted alkyl, or (ii) taken together with R.sub.3 forms a heterocyclo; R.sub.3 is (i) independently selected from (a) alkyl optionally substituted with one to two of hydroxy and alkoxy; (b) alkylthio or aminoalkyl optionally substituted with hydroxy or alkoxy; (c) -A.sub.1-aryl, wherein the aryl is optionally substituted with up to four substituents selected from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, NR.sub.17R.sub.18, SR.sub.17, OR.sub.17, SO.sub.2R.sub.17a, SO.sub.2NR.sub.17R.sub.18, NR.sub.17C(O)R.sub.18, CO.sub.2R.sub.17, C(O)R.sub.17, cycloalkyl, aryl, heterocyclo, and heteroaryl, and/or has fused thereto a five or six membered cycloalkyl ring; (d) -A2-heteroaryl wherein the heteroaryl is a five or six membered monocyclic ring having 1 to 3 heteroatoms selected from N, O, and S, or an eight or nine membered bicyclic ringed system having at least one aromatic ring and 1 to 4 heteroatoms selected from N, O, and S in at least one of the rings, said heteroaryl being optionally substituted with halogen. alkyl, alkoxycarbonyl, sulfonamide, nitro, cyano, trifluoromethyl, alkylthio, alkoxy, keto, C(O)H, acyl, benzyloxy, hydroxy, hydroxyalkyl, or phenyl optionally substituted with alkyl or substituted alkyl; (e) -A.sub.2-heterocyclo wherein the heterocyclo is optionally substituted with one to two groups selected from alkyl, keto, hydroxy, hydroxyalkyl, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, phenyl, and/or benzyl, and/or has a bridged carbon-carbon chain or fused benzene ring joined thereto; (f) -A.sub.2-cycloalkyl wherein the cycloalkyl is optionally substituted with one to two groups selected from alkyl, keto, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, and/or benzyl, and/or has a bridged carbon-carbon chain or fused benzene ring joined thereto; or (ii) taken together with R.sub.2 forms a heterocyclo; R.sub.4 at each occurrence is selected independently of each other R.sub.4 from the group consisting of halogen, alkyl, haloalkyl, cyano, and haloalkoxy; R.sub.7a, R.sub.7b and R.sub.7 are independently selected from hydrogen, alkyl, carbamyl, or carbamylalkyl, or R.sub.7a and R.sub.7c join to form an aryl or heteorarylheteroaryl; R.sub.8 is alkyl, arylalkyl, or aryl; R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, CO.sub.2R.sub.12, or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C.sub.1-4alkoxy, haloalkoxy, C.sub.1-6alkyl, CO.sub.2alkyl, SO.sub.2alkyl, SO.sub.2NH.sub.2, amino, NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NHC(O)alkyl, C(O)alkyl, and/or C.sub.1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocyclo in turn optionally substituted with keto or having a benzene ring fused thereto; R.sub.10 is independently hydrogen, alkyl, or alkoxy; and R.sub.11 is independently hydrogen, alkyl, substituted alkyl, alkoxy heterocyclo cycloalkyl, aryl, or heteroaryl; or R.sub.10 and R.sub.11 taken together form a heterocyclo or heteroaryl optionally substituted with alkyl, keto, CO.sub.2H, alkoxycarbonyl, hydroxy, alkoxy, alkyl, carbamyl, aryl, or substituted alkyl, wherein when the R.sub.10 and R.sub.11 group comprises a phenyl ring, said phenyl ring is optionally substituted with one to two of alkyl, halogen, and alkoxy; R.sub.12 is hydrogen or alkyl; A.sub.1is (CHR.sub.14).sub.mV(CR.sub.15R.sub.16).sub.n or (CHR.sub.14).sub.p(CO)NH; A.sub.2 is (CHR.sub.14).sub.mV(CR.sub.15R.sub.16).sub.n; V is a bond, S, or NR.sub.22; R.sub.14, R.sub.15 and R.sub.16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxy, and phenyl, and/or one of R.sub.15 and one of R.sub.16 join together to form a three to six membered cycloalkyl; R.sub.17 and R.sub.18 are independently selected from hydrogen, alkyl, phenyl, and benzyl, wherein the phenyl and benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl; R.sub.17a is alkyl or substituted alkyl; R.sub.22 is hydrogen or alkyl; m and n are 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
18. A compound according to claim 17 having the formula, ##STR00107## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: R.sub.7a, R.sub.7b and R.sub.7c are independently selected from hydrogen, alkyl, carbamyl or carbamylC.sub.1-4alkyl, or R.sub.7, and R.sub.7, join to form a fused phenyl ring; R.sub.23 is selected from hydrogen, alkyl, hydroxyalkyl, or phenyl; R.sub.24 is selected from alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF.sub.3, methoxy, phenyloxy, benzyloxy, cyano, acyl, or two R.sub.24 groups join to form a fused cycloalkyl or benzene ring; and x is 0, 1, or 2; and y is 0, 1, 2, or 3.
19. A compound according to claim 13 having the structure ##STR00108## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: the enantiomeric excess (ee) of the S stereoisomer exceeds 70%.
20. A compound according to claim 13 having the structure ##STR00109## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: the enantiomeric excess (ee) of the R stereoisomer exceeds 70%.
21. A pharmaceutical composition comprising at least one compound as defined in claim 13 and a pharmaceutically-acceptable carrier or diluent.
22. A compound or composition according to claim 13 for use in a method of treatment of the human or animal body by therapy.
23. A method of treating, ameliorating, preventing or combating a disease or disorder, in a subject, selected from (i) cancer; (ii) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. .sup.18F-FDG PET); (iii) cachexia, cancer driven cachexia or weight loss; (iv) disease or disorder that causes a higher than normal body temperature such as high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, drug or drug withdrawal induced hyperthermia, idiosyncratic drug reaction, fever of unknown or uncertain origin, reaction to incompatible blood product(s), metabolic disorder(s), cancer, injury; (v) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), HIV associated cancers, AIDS-defining cancers, non-AIDS defining cancers; (vi) virus neuroinvasion via macrophages, as used for example by HIV and SARS coronavirus; (vii) neurocognitive or neurodegenerative diseases/disorders, for example those caused by a virus; (viii) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome; (ix) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance, or low or less than desired body weight; (x) disease or disorder treatable by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, deep hypothermic circulatory arrest for surgery, hypothermia for a surgical purpose, hypothermia for cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery), Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage and/or transplant), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, birth asphyxia, haemorrhage, hypovolemia, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, ischemic brain/heart/kidney injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject; (xi) poisoning by a toxic amount of a compound(s) in a subject e.g. carbon monoxide/methanol/heavy metal/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), bacterial toxin(s), endotoxemia or drug/substance overdose e.g. heroin, ethanol, prescription medication(s) or over the counter medication(s); (xii) accelerated aging disease or progeroid syndrome including Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann-Rautenstrauch syndrome, Hutchinson-Gilford progeria syndrome (progeria); (xiii) disease or disorder of aging (incidence increases with increased age/senescence) and/or a disease/disorder associated with elevated reactive oxygen species including degenerative diseases, neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, andropause, sarcopenia, age-related macular degeneration (AMD), hearing loss, movement disability, cancer; (xiv) aging, wherein these compounds slow aging, extend lifespan and healthspan; or (xv) skin aging; wherein the method comprises administering to the subject an effective amount of at least one compound or composition according to claim 13.
24. A cmethod according to claim 23, wherein the subject is further administered with one or more compounds or compositions approved for human use, optionally for anti-cancer use, by the United States Food and Drug Administration (FDA) and/or European Medicines Agency (EMA), optionally in the same pharmaceutical composition.
25. A compound for use according to claim 23, wherein the mg/kg dose administered to the subject is comparable with or larger than the mg/kg dose which would be administered to a subject of smaller bodily size, and optionally the mg/kg dosage administered to adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C.
26. A method according to claim 23 wherein the inflammatory/autoinflammatory/autoimmune disease/disorder/syndrome is selected from acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases (inflammaging), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, appendicitis, acute appendicitis, bursitis, colitis, cystitis, dermatitis, encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis-associated interstitial lung disease and desquamative interstitial pneumonia, interstitial lung disease, Lofgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Bal disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly.
27. A method of prevention or treatment of a disease or disorder, in a subject, selected from: (i) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. .sup.18F-FDG PET); (ii) cachexia, cancer driven cachexia or weight loss; (iii) disease or disorder that causes a higher than normal body temperature such as high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, drug or drug withdrawal induced hyperthermia, idiosyncratic drug reaction, fever of unknown or uncertain origin, reaction to incompatible blood product(s), metabolic disorder(s), cancer, injury; (iv) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as Macrophage Activation Syndrome (MAS), AIDS, HIV-associated neurocognitive disorders (HAND), HIV associated cancers, AIDS-defining cancers or non-AIDS defining cancers; (v) virus neuroinvasion via macrophages, as used for example by HIV and SARS coronavirus; (vi) neurocognitive or neurodegenerative diseases/disorders, for example those caused by a virus; (vii) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome; (viii) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance, or low or less than desired body weight; (ix) disease or disorder treatable by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, deep hypothermic circulatory arrest for surgery, hypothermia for a surgical purpose, hypothermia for cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery), Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage and/or transplant), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, birth asphyxia, haemorrhage, hypovolemia, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, ischemic brain/heart/kidney injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject; (x) poisoning by a toxic amount of a compound(s) in a subject e.g. carbon monoxide/methanol/heavy metal/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), bacterial toxin(s), endotoxemia or drug/substance overdose e.g. heroin, ethanol, prescription medication(s) or over the counter medication(s); (xi) accelerated aging disease or progeroid syndrome including Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann-Rautenstrauch syndrome, Hutchinson-Gilford progeria syndrome (progeria); (xii) disease or disorder of aging (incidence increases with increased age/senescence) and/or a disease/disorder associated with elevated reactive oxygen species including degenerative diseases, neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, andropause, sarcopenia, age-related macular degeneration (AMD), hearing loss, movement disability, cancer; (xiii) aging, wherein these compounds slow aging, extend lifespan and healthspan; or (xiv) skin aging; wherein the method comprises administering to the subject an effective amount of at least one compound of the following formula: ##STR00110## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof wherein: L is hydrogen; R.sub.1 is hydrogen, cyano, SO.sub.2R.sub.8, C(O)R.sub.9, or heteroaryl (such as thiazolyl); R.sub.2 is (i) independently hydrogen, alkyl, benzyl, or substituted alkyl, or (ii) taken together with R.sub.3 forms a heterocyclo; R.sub.3 is (i) independently alkyl, substituted alkyl, alkylthio, aminoalkyl, carbamyl, B.sub.B-aryl, B.sub.B-heterocyclo, B.sub.B-heteroaryl, or B.sub.B-cycloalkyl, or (ii) phenyl optionally substituted with C.sub.1-4alkyl, halogen, trifluoromethyl, OCF.sub.3, cyano, nitro, amino, hydroxy, or methoxy, or (iii) independently selected from C.sub.1-4alkyl, alkylthio, aminoalkyl, B.sub.B-aryl, B.sub.B-heterocyclo, B.sub.B-cycloalkyl, and B.sub.B heteroaryl, optionally having one to three substituents selected from R3a; and/or having fused thereto a five or six membered carbocyclic ring, or (iv) taken together with R.sub.2 forms a heterocyclo optionally substituted with alkyl or substituted alkyl; B.sub.B is a bond, C.sub.1-4alkylene, C.sub.2-4alkenylene, substituted C.sub.1-4alkylene, substituted C.sub.2-4alkenylene, substituted C.sub.1-4alkylene-C(O)NH, C(O)NH, C.sub.1-4alkylene-C(O)NH, C(O)NR.sub.19, C.sub.1-4alkylene-C(O)NR.sub.19, or substituted C.sub.1-4alkylene-C(O)NR.sub.19, (CHR.sub.14).sub.m(CR.sub.15R.sub.16).sub.n or (CHR.sub.14).sub.pC(O)NH; R.sub.3a at each occurrence is selected independently from alkyl, substituted alkyl, halogen, haloalkoxy, cyano, nitro, keto, trifluoromethyl, NR.sub.17R.sub.18, SR.sub.17, OR.sub.17, SO.sub.2R.sub.17a, SO.sub.2NR.sub.17R.sub.18, NR.sub.17C(O)R.sub.18, CO.sub.2R.sub.17, C(O)R.sub.17, cycloalkyl, aryl, heterocyclo, and heteroaryl, wherein when R.sub.3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyclo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl; Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl; or Z is triazolyl optionally substituted with one to two R.sub.7 substituents or imidazolyl optionally substituted with one to two R.sub.7 substituents and/or having fused thereto a benzene ring in turn optionally substituted with one to two R.sub.7 substituents; and R.sub.7 is alkyl, carbamyl, or substituted alkyl; R.sub.4 at each occurrence is selected independently of each other R.sub.4 from the group consisting of halogen, trifluoromethyl, OCF.sub.3, alkyl, substituted alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR.sub.25, SR.sub.25, NR.sub.25R.sub.26, NR.sub.25SO.sub.2R.sub.27, SO.sub.2R.sub.27, SO.sub.2NR.sub.25R.sub.26, CO.sub.2R.sub.26, C(O)R.sub.26, CO)NR.sub.25R.sub.26, OC(O)R.sub.25, OC(O)NR.sub.25R.sub.26, NR.sub.25C(O)R.sub.26, NR.sub.25CO.sub.2R.sub.26, aryl, heteroaryl, heterocyclo and cycloalkyl; R.sub.8 is C.sub.1-4alkyl or phenyl optionally substituted with alkyl, halogen, haloalkoxy, cyano, nitro, or trifluoromethyl; R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocyclo, or CO.sub.2R.sub.12, alkyl or phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C.sub.1-4alkoxy, haloalkoxy, C.sub.1-6alkyl, CO.sub.2alkyl, SO.sub.2alkyl, SO.sub.2NH.sub.2, amino, NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NHC(O)alky, C(O)alkyl, and/or C.sub.1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or hetcrocyloheterocyclo in turn optionally substituted with keto or having a benzene ring fused thereto or a) C.sub.1-4alkyl optionally substituted with one to two of: i) SR.sub.13, OR.sub.13, NR.sub.13aR.sub.13b, halogen, trifluoromethyl, CO.sub.2R.sub.13a, and CO)NR.sub.13aR.sub.13b; ii) cycloalkyl optionally substituted with one to two of C(O)H, C.sub.1-4acyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen; iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, C.sub.1-4alkoxy, or having fused thereto a five or six membered heterocyclo; iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or C.sub.1-4alkoxy; b) 3 to 6 membered cycloalkyl optionally having up to four substituents selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto; c) phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C.sub.1-4alkoxy, haloalkoxy, C.sub.1-4alkyl, CO.sub.2alkyl, SO.sub.2alkyl, SO.sub.2NH.sub.2, amino NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NHC(O)alkyl, C(O)alkyl, and/or C.sub.1-4alkyl optionally substituted with one to three of trifluoromethyl, hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocycle in turn optionally substituted with keto or having a benzene ring fused thereto; d) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl; R.sub.10 and R.sub.11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, heteroaryl or C.sub.1-4alkyl optionally substituted with one to two of CO.sub.2alkyl, C(O)NH(aryl), NH(aryl), cycloalkyl, phenyloxy, phenyl in turn optionally substituted with C.sub.1-4alkyl, hydroxy, C.sub.1-4alkoxy, halogen, amino, nitro, tetrahydrofuranyl, and/or five or six membered heterocyclo, or having a five or six membered heterocyclo fused thereto; pyrrolidinyl optionally substituted with keto; napthyl, anthracenyl, pyridinyl, thiophenyl, furanyl, imidazolyl, benzimidazolyl, or indolyl in turn optionally substituted with C.sub.1-4alkyl or C.sub.1-4alkoxy; or (ii) taken together form a heteroaryl or heterocyclo selected from pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, tetrahydropyridinyl, and imidazoilidinyl, wherein said heterocyclo formed by R.sub.10 and R.sub.11 is optionally substituted with one to two of keto, CO.sub.2H, C.sub.1-4alkoxy, CO.sub.2alkyl, C.sub.1-4carbamyl, benzyl; phenyl in turn optionally substituted with alkyl, halogen, or C.sub.1-4 alkoxy; tetrahydropyridinyl in turn optionally substituted with keto and/or phenyl; alkyl optionally substituted with amino or NHR.sub.2uwherein R.sub.21 is alkyl or phenyl optionally substituted with alkyl; and/or has a benzene ring fused thereto in turn optionally substituted with one to two of alkyl, C.sub.1-4alkoxy, CO.sub.2alkyl, and/or C.sub.1-4carbamyl; R.sub.12 and R.sub.19 are hydrogen or alkyl; R.sub.13 is hydrogen or alkyl; R.sub.13a and R.sub.13b are selected from hydrogen, alkyl, and aryl; R.sub.14, R.sub.15 and R.sub.16 at each occurrence are independently selected from hydrogen, alkyl, hydroxy, hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxy, and phenyl, and/or one of R.sub.15 and one of R.sub.16 join together to form a 3 to 6 membered cycloalkyl; R.sub.17 and R.sub.18 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, phenyl, or benzyl wherein the phenyl or benzyl is optionally substituted with alkyl, hydroxy, or hydroxyalkyl; R.sub.17a is alkyl or substituted alkyl; R.sub.25 and R.sub.26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring; R.sub.27 is alkyl or substituted alkyl; q is 0, 1, 2, or 3; m and n are 0, 1 or 2; and p is 0, 1, 2, or 3.
28. A compound for use according to claim 27, wherein L is hydrogen.
29. A method according to claim 27 using at least one compound of the formula, ##STR00111## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein there is an enantiomeric excess (ee) of the S stereisomer, preferably that exceeds 70%, and more preferably that exceeds 90%.
30. A compound for use according to claim 29, wherein the enantiomeric excess of S-enantiomer exceeds 70%.
31. A method according to claim 27, using the compound ##STR00112## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: the enantiomeric excess (ee) of the S stereoisomer exceeds 70%, and more preferably exceeds 90%.
32. A method according to claim 27, wherein comparable or larger mg/kg doses are used in, or administered to larger animals, which is very distinct from most drugs, and optionally the mg/kg dosage administered to adult humans is comparable or greater than the No Observed Adverse Effects Level (NOAEL) mg/kg dosage in mice housed at 22 C.
33. A compound that reduces F.sub.1F.sub.0 ATP hydrolysis in a subject, for use in treating, ameliorating, preventing or combating a disease or disorder selected from: (i) cachexia, cancer driven cachexia or weight loss; (ii) disease or disorder that causes a higher than normal body temperature such as high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, drug or drug withdrawal induced hyperthermia, idiosyncratic drug reaction, fever of unknown or uncertain origin, reaction to incompatible blood product(s), metabolic disorder(s), cancer, injury; (iii) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as Macrophage Activation Syndrome (MAS), AIDS, HIV-associated neurocognitive disorders (HAND), HIV associated cancers, AIDS-defining cancers or non-AIDS defining cancers; (iv) virus neuroinvasion via macrophages, as used for example by HIV and SARS coronavirus; (v) neurocognitive or neurodegenerative diseases/disorders, for example those caused by a virus; (vi) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance, or low or less than desired body weight; (vii) to confer hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, deep hypothermic circulatory arrest for surgery, hypothermia for a surgical purpose, hypothermia for cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery), Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage and/or transplant), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, birth asphyxia, haemorrhage, hypovolemia, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, ischemic brain/heart/kidney injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject; (viii) to confer hypothermia to treat/ameliorate/prevent/combat a poisoning by a toxic amount of a compound(s) in a subject e.g. carbon monoxide/methanol/heavy metal/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), bacterial toxin(s), endotoxemia or drug/substance overdose e.g. heroin, ethanol, prescription medication(s) or over the counter medication(s); (ix) accelerated aging disease or progeroid syndrome including Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann-Rautenstrauch syndrome, Hutchinson-Gilford progeria syndrome (progeria); (x) disease or disorder of aging (incidence increases with increased age/senescence) and/or a disease/disorder associated with elevated reactive oxygen species including degenerative diseases, neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, andropause, sarcopenia, age-related macular degeneration (AMD), hearing loss, movement disability, cancer; (xi) aging, wherein these compounds slow ingaging, extend lifespan and healthspan; or (xii) skin aging.
34. A compound according to claim 13, of the formula, ##STR00113## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at position shown [optionally at other H positions also]. The greater the deuterium enrichment at the position shown [chiral carbon], the more preferred); and there is an enantiomeric excess (ee) of the S stereoisomer, preferably exceeding 70%, and more preferably exceeding 90%.
35. A compound according to claim 34, having the structure: ##STR00114## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: there is deuterium (D) enrichment at the chiral centre (optionally at other H positions also), the greater the deuterium enrichment at this position, the more preferred, optionally wherein deuterium incorporation at the chiral centre exceeds 40%; and there is an enantiomeric excess (ee) of the S stereoisomer, preferably exceeding 70% and more preferably exceeding 90%.
36. A compound according to claim 13, of the formula, ##STR00115## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally wherein there is an enantiomeric excess (ee) of the S stereoisomer ##STR00116## optionally exceeding 70%; optionally wherein there is an enantiomeric excess (ee) of the R stereoisomer instead, optionally exceeding 70%.
37. A compound according to claim 36, having the structure: ##STR00117## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally wherein there is an enantiomeric excess (ee) of the S stereoisomer ##STR00118## optionally exceeding 70%; optionally wherein there is an enantiomeric excess (ee) of the R stereoisomer instead, optionally exceeding 70%.
38. A method according to claim 27, wherein an effective amount of compound(s) or composition(s) is administered to the subject topically/locally and/or systemically and optionally the subject is monitored, for example by a healthcare professional(s) and/or machine substitute(s), for sign(s) of reduction in body temperature and/or the subject is located at an ambient temperature that maintains their body temperature within safe limits whilst they have an effective amount of compound(s)/composition(s) in their system and/or the subject wears (and/or is covered by) insulating material(s), e.g. clothing/clothes (and/or bedding/blanket(s)), and/or is in a heated/insulated space and/or hot climate, optionally exceeding 25 C. or 28 C. or 30 C. or 35 C. or 36 C. or 37 C., optionally at or around 37 C., wherein a high (e.g. in the thirties C.), but safe, ambient temperature (and/or greater bodily insulation, for example by clothing/clothes and/or bedding/blanket(s)) can permit a greater compound(s)/composition(s) dose(s) to be safely administered, wherein a preferred ambient temperature is the thermoneutral temperature for the subject with the amount of bodily insulation they have, e.g. the amount of clothing they are wearing, if any, and the amount of the compound(s)/composition(s) in their system.
Description
DESCRIPTION OF THE DRAWINGS
[0251] For purposes of clarity, not every component is labelled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention.
[0252]
[0253]
[0254] NCI-60 tests are performed at a controlled temperature of 37 C. [35].
[0255] To perform the anti-cancer testing reported: BMS-199264 hydrochloride was purchased from Sigma-Aldrich. BTB06584 was purchased from AdooQ Bioscience, Irvine, Calif., USA. Compounds 19a (separated into 6a and 6b stereoisomers) and 31 were synthesized by reaction schemes disclosed herein. Almitrine dimesylate was purchased from Ak Scientific, Palo Alto, Calif., USA. Tested compounds are available from NCI by NSC number which are: BTB06584 (NSC: 794220), BMS-199264 HCI (NSC: 795767), almitrine dimesylate (NSC: 800450), 6b (NSC: 801828), 6a (NSC: 801827), 31 (NSC: 802605).
[0256]
[0257]
[0258]
[0259]
[0260]
[0261]
[0262]
[0263]
[0264]
[0265] 6b and 6a anti-cancer activities are similar because of their epimerization in biological systems, which erodes their enantiomeric excess (ee) during NCI testing, making them converge upon being the racemate, 19a. Thus, during NCI testing, 6b EC.sub.50F.sub.1F.sub.0ATP hydrolase is not constant but in the range 0.033 MEC.sub.50 F.sub.1F.sub.0ATP hydrolase 0.018 M because EC.sub.50 F.sub.1F.sub.0 ATP hydrolase .fwdarw.0.033 M as 6b .fwdarw.19a, as racemization proceeds. Similarly, 6a EC.sub.50 F.sub.1F.sub.0 ATP hydrolase .fwdarw.0.033 M as 6a .fwdarw.19a.
[0266] Mean % cancer growth inhibition for BMS-199264 at 100 M is >100% because for most cancer cell lines tested it doesn't just cause 100% cancer growth inhibition but, in addition, causes cancer regression, wherein the number of cancer cells at experiment end is less than at experiment start. BMS-199264 predominantly exerts anti-cancer activity at 10 M by inhibiting F.sub.1F.sub.0 ATP hydrolase, and at 100 M, by reducing F.sub.1F.sub.0 ATP synthesis.
[0267] 31 has less anti-cancer activity than its EC.sub.50 F.sub.1F.sub.0 ATP hydrolase value would predict because it is broken down by cytochrome P450 enzyme: CYP2C9, which it inhibits competitively (31 being consumed in the process). Average 1og2 transcript intensity of CYP2C9, across all NCI-60 cell lines, is 3.539 [31-32]. Average 1og2 transcript intensity of ATP5A1, the alpha subunit of Fi ATP synthase, across all NCI-60 lines, is 9.871 [31-32]. There are 3 alpha subunits per ATP synthase [ I ]. So, on average, approximately, there is a comparable amount of CYP2C9 and ATP synthase in an NCI-60 cancer cell line: 3.539:(9.871/3=3.29) 1. If we equate EC.sub.50 as some measure of binding affinity then compound 31 has a greater affinity for binding ATP synthase in its reverse mode (EC.sub.50 =0.022 M) than for binding CYP2C9 (EC.sub.50=2 M) (these EC.sub.50 values come from different assays, thence this comparison isn't very robust). However, ATP synthase does not always operate in reverse, it likely has different operating propensities at different stages of the cell cycle, and compound 31 EC.sub.50 F.sub.1F.sub.0 ATP synthesis is >30 M. Thus, CYP2C9 can meaningfully reduce compound 31 inhibition of F.sub.1F.sub.0 ATP hydrolase, and thence its anti-cancer activity. Especially because CYP2C9, a cytochrome P450 enzyme, does not merely bind and sequester compound 31, but metabolises and inactivates compound 31 at a rate set by its kcat for compound 31. Compound 31 as substrate for an enzyme(s) of the cytochrome P450 enzyme, whilst itself having anti-cancer activity, means it can add to the anti-cancer action, for example potentiate the anti-cancer action, of other anti-cancer therapeutics which are also broken down by this system e.g. idarubicin.
[0268] At 10 M, 6b (and 6a) exerts more anti-cancer activity than BMS-199264, despite having less effect on F.sub.1F.sub.0-ATP synthesis, because it inhibits F.sub.1F.sub.0-ATP hydrolysis more potently.
[0269]
[0270]
[0271] Cancers have, and need, lower intracellular [ROS] than normal cells. There are concentrations of F.sub.1F.sub.0 ATP hydrolysis inhibitor(s) that simultaneously raise [ROS] in cancer cells and decrease [ROS] in normal cells. In normal cells, greater F.sub.1F.sub.0 ATP hydrolysis inhibition makes OXPHOS more efficient (less ATP needs to be made because less ATP is hydrolysed), which reduces the OXPHOS rate and [ROS] and increases normal cell lifespan. F.sub.1F.sub.0 ATP hydrolysis inhibitor(s) conferred OXPHOS efficiency gain comes from, and so its maximum is dictated by, proportion of OXPHOS produced ATP hydrolysed by F.sub.1F.sub.0 ATP hydrolysis, which is high, and so lifespan (and healthspan) extension significant, especially if it reduces [ROS] sufficiently to reduce DNA mutation rate below DNA repair rate. Especially, if this [ROS] is sufficient to keep cells differentiated, maintaining tissue and organ function.
[0272]
[0273]
[0274] RESULTS:
[0275] Before 6b dosing experiments, Mouse 1, 2 and 3 had all survived IV injections of 6a. 6a doesn't potently reduce rectal temperature like 6b: the dose-dependent rectal temperature reduction (with hypoactivity reported over same timescale that rectal temperature is reduced) that 6a can cause is because of in vivo epimerization of 6a to 6b. Similarly, when 6b is the administered compound, in vivo epimerization of 6b to 6a reduces the effective dose of 6b and chemical modifications to the 6b compound structure to prevent or slow this epimerization are componentry to this invention: for example, a non-limiting example embodiment is to replace the hydrogen on the chiral carbon of 6b with deuterium. >40 mg/kg doses of 6a weren't trialled because I ran out of 6a compound. Indeed, I only had enough 6a to dose 2 of the 3 test mice with 40 mg/kg.
[0276] Vehicle control can cause a drop in rectal temperature because of its 12.5% ethanol content: 12.5% of 10 ul/g solution administered=1.25 ul/g ethanol=0.000989226 g/g=0.99 g/kg=1 g/kg ethanol (IV). 1.9 g/kg ethanol (intraperitoneal injection, IP) reduced rat body temperature by 1.6 C. (in 24.5 to 25 C. ambient temperature; raising temperature of IP injected ethanol solution to 37 C. didn't have major impact) [100]. Ideally, future studies should not use ethanol as a vehicle component. The problem is not its hypOthermia, which is safely mitigated by a higher ambient temperature [100]. But because at just a slightly higher ambient temperature than this, ethanol can cause hypERthermia [100]. And the ambient temperature that safely mitigates ethanol driven hypothermia, without causing ethanol driven hyperthermia, varies with the ethanol dose [100]. This [ethanol dose/ambient temperature/hypothermia/hyperthermia/safe rectal temperature] matrix can be mapped by experimentation, and indeed there is much in the literature already e.g. non-limiting examples: [100-106], to guide the best use of ethanol as a vehicle component in future studies. However, this experimentation can be avoided: alternative vehicle options, which are not a potent drug in and of themselves, as ethanol is, are well known to those of the art, e.g. see [107-108]: one or more of these can be employed as an alternative. When ethanol as vehicle is used, the fraction of rectal temperature drop accountable to the test drug can be calculated by subtracting any rectal temperature drop observed just with the ethanol containing vehicle control (assumes that ethanol and drug induced rectal temperature drops are additive and not potentiating). Drug induced rectal temperature reductions in this study, when they occur, are dose-dependent and well in excess of any rectal temperature drop observed when only ethanol containing vehicle control is injected.
[0277] The presented data shows that inhibiting the reverse mode of ATP synthase reduces body temperature. 6b potently inhibits the reverse mode of ATP synthase (IC.sub.50=0.018 M [5-6]), 6a does not (IC.sub.50>100 M [5-6]). 6b potently reduces rectal temperature, 6a does not (it does to a minor degree, which is evidence for in vivo epimerization of 6a to 6b, on a faster timescale than 6a clearance). A significant reduction in body temperature is lethal. Thence the maximal tolerated dose (MTD) of 6b, at room temperature=22 C., is lower than the MTD of 6a. Body temperature cannot fall below ambient temperature and so the MTD of 6b is increased by ensuring ambient temperature is closer to the normal mouse body temperature, which ensures that mouse body temperature is maintained at an acceptable value. This brings greater alignment between the MTD of 6a and 6b, which in the case of 6a is very safe: LD.sub.50 >40 mg/kg (IV). This is safer than the FDA approved anti-depressants clomipramine HCl and imipramine HCl: LD.sub.50 {mouse, IV} of 22 mg/kg and LD.sub.50 {mouse, IV} of 27 mg/kg respectively (Register of Toxic Effects of Chemical Substances, RTECS). Some patients take these drugs daily, safely, for years.
[0278] Non-limiting example embodiments to maintain mice, or some other animal, including humans, at a life permissive body temperature, whilst having a compound of this disclosure in their body, include locating them in a temperature-controlled room or confinement. For example, in small animal experiments, a plant growth or egg incubator or similar type device. An embodiment is to administer a compound of this disclosure to an animal(s), including human(s), in a hot country, geography or climate e.g. Dubai or somewhere else in the Middle East, more preferably during summer when it has high daytime and night temperatures. There are many methods in the literature to keep rodents at elevated temperature, easing the cold stress they feel at typical room temperatures [62]: e.g. partially submerging water proof mouse cages into fish tanks, in use as water baths, heated by thermostatic electric fish tank heaters [111 ], or by heating cages with chemical reaction hand warmers [109-110]. Such methods, or any method with equivalent intention, when employed with an animal(s)/human(s) with a compound of this invention in its body, is componentry to this invention. Adaptive heating can be employed, which adjusts the heating element output (e.g. an infrared lamp, or any other heating element(s)) in response to the measured body temperature (e.g. by rectal temperature probe or by thermal imaging, or any other body temperature recording device(s)), to maintain a life-permissive body temperature, when a compound of this invention is in the body. With a compound of this disclosure, the need for (and amplitude of) ambient temperature intervention is more important for smaller than larger animals e.g. more so for a mouse (20 g) than a rat (150 g). If an experimenter has to work with a compound of this disclosure at typical room temperature (20-25 C.) then the test species, and individual(s), chosen should be as large as possible. All methods of maintaining body temperature within a temperature range that permits life, whilst having a compound of this invention in the body, are componentry to this invention. For (non-limiting) example, wearing clothes.
[0279]
[0280]
[0281]
[0282] LogP=3.2 is the optimal compromise for best passing a membrane: its hydrophobic core (selecting for high logP) and hydrophilic boundary layer (selecting for low logP) ([36], herein incorporated in its entirety). The imidazole containing molecules presented in this figure, and in this disclosure's drawings more generally, have logP >3.2 and present increased logP=decreased uncoupling. The uncoupling capability/liability of a molecule actually hinges on its intersection of pKa(s) and logP [36] but for the molecules in this disclosure's drawings, wherein the imidazole pKa values are, generally, all within a fairly narrow range, the more primary determinant to each molecule's uncoupling rate, relative to the others, is the molecule's logP value relative to the others.
[0283] The drawn molecules of this figure do inhibit the reverse mode of ATP synthase. When a respiratory chain inhibitor blocks electron flow, .sub.IM is maintained, not by proton pumping by the respiratory complexes, but by proton pumping by ATP synthase i.e. the reverse mode of ATP synthase. In the presented data, when the respiratory chain is blocked, the presented molecules depolarise .sub.IM because they block the reverse mode of ATP synthase. They do not affect .sub.IM by these means when the respiratory chain is operational. Because .sub.IM is not set/maintained by the reverse mode of ATP synthase in this case. Although the molecules with stronger uncoupling capability, they can shuttle more protons across the IM (dissipate more pmf) than the respiratory chain can increase its rate to replace, and they do depolarise .sub.IM. When the respiratory chain is blocked, a stronger uncoupler in this figure depolarises TIM more. Because not only does it inhibit the generator of .sub.IM (reverse mode ATP synthase), it simultaneously erodes .sub.IM (uncoupling).
[0284] Oligomycin does inhibit the reverse mode of ATP synthase. But distinctly it inhibits its forward mode more [11]. So, using oligomycin, there is no margin to inhibit the reverse mode (anti-cancer), without adversely affecting cells using OXPHOS i.e. most normal cells. Contrast this with molecule VG019 of this figure, for example, which can inhibit the reverse mode of ATP synthase, and yetin observed distinction to oligomycindoes not affect cells using OXPHOS: it does not change their O.sub.2 consumption or .sub.IM (at 100 M). This grants it, in distinction to oligomycin, anti-cancer selectivity. Other molecules of this disclosure have even greater cancer selectivity. For example, a preferred embodiment (refer disclosure section: Preferred Embodiments) inhibits F.sub.1F.sub.0 ATP hydrolysis >5,556 times more than F.sub.1F.sub.0 ATP synthesis, in NADH-linked and NADPH-linked SMP assays [5-6], whilst oligomycininversely-inhibits F.sub.1F.sub.0 ATP hydrolysis less than F.sub.1F0 ATP synthesis in such assays [1 1].
[0285] Computational calculations of logP and pKa were made using [25]. The data presented in this Figure is from [12] (herein incorporated in entirety), but the analysis/(re)interpretation is novel. As is the process/method of using these molecules as anti-cancer therapeutics, which is componentry to this invention. The imidazole of the drawn molecules is 4-yl. Permutations, with 5-yl instead, are also disclosed by this invention as anti-cancer therapeutics.
EXAMPLE EMBODIMENTS OF THE INVENTION
[0286] The Drawings present embodiments of the invention. Further examples are enumerations of Markush Formulas (I), (II), (III), (IV), (V) and (VI), presented henceforth. Note: none of these formulae share Markush symbols, which can be, for example, symbols of the type: Rx, wherein x is an integer, well known to those of the art. They each have their own, as specified for each, in their own sections of this disclosure.
[0287] In this disclosure, the term Formula [X] is used when a statement is true for Formula (I), (II), (III), (IV), (V) and (VI), and all are being referred to independently. A compound of Formula [X] is a compound of Formula (I), or Formula (II), or Formula (III), or Formula (IV), or Formula (V), or Formula (VI), or any compound presented in this disclosure's Drawings.
[0288] This invention is described using these example embodiments but it isn't limited to these. These merely illustrate the invention. Compounds of other structures, which are identified as therapeutic inhibitors by the rationale and methods of the present invention, are also encompassed by the present invention.
[0289] Encompassed by this invention are methods of treating a subject suffering from a medical disease or disorder by administering an effective amount of at least one compound of Formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising one or compounds of Formula (I), (II), (III), (IV), (V) or (VI), for use in a method of treatment of the human or animal body by therapy, particularly for use in a method of treating, ameliorating, preventing or combating a disease or disorder selected from [0290] (i) cancer; [0291] (ii) cancer that metabolizes much of its glucose and/or glutamine to lactate, for example a cancer exhibiting the Warburg effect and/or a cancer that can be discriminated from surrounding tissue by PET imaging (e.g. .sup.18F-FDG PET); [0292] (iii) cachexia, cancer driven cachexia or weight loss; [0293] (iv) disease or disorder that causes a higher than normal body temperature such as high environmental temperature, ingesting an uncoupler (e.g. 2,4-dinitrophenol), infection, sepsis, stroke, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, heatstroke, thermoregulatory disorder(s), Kawasaki syndrome, drug or drug withdrawal induced hyperthermia, idiosyncratic drug reaction, fever of unknown or uncertain origin, reaction to incompatible blood product(s), metabolic disorder(s), cancer, injury; [0294] (v) Tumour Associated Macrophages (TAMs) or any macrophage associated disease or disorder such as Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), HIV associated cancers, AIDS-defining cancers, non-AIDS defining cancers; [0295] (vi) virus neuroinvasion via macrophages, as used for example by HIV and SARS coronavirus; [0296] (vii) neurocognitive or neurodegenerative diseases/disorders, for example those caused by a virus; [0297] (viii) acute or chronic or systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome; [0298] (ix) low or less than desired metabolic/bioenergetic efficiency in a subject, or low or less than desired physical or mental performance, or low or less than desired body weight; [0299] (x) diseases or disorders treatable by conferring hypothermia in a subject for some medical or other purpose which can include slowing a chemical reaction(s) rate in a subject for therapeutic benefit, preventing/minimizing brain and/or tissue damage, deep hypothermic circulatory arrest for surgery, hypothermia for a surgical purpose, hypothermia for cardiac and/or cardiovascular surgery and/or brain surgery (neurosurgery), Emergency Preservation and Resuscitation (EPR), preserving detached body parts such as limbs and/or organs (for example during organ storage and/or transplant), protective hypothermia, targeted temperature management, therapeutic hypothermia, hypothermia therapy for neonatal encephalopathy, birth asphyxia, haemorrhage, hypovolemia, decompression sickness, burn injury(s) including skin burn, inflammation, allergic reaction, anaphylaxis, tissue/organ rejection, hypoxia, hypoxemia, anoxemia, anoxia, anemia, hypervolemia, altitude sickness, obstructed airway, asthma attack, hypoxia in a body/tissue/organ, hypoglycemia, reperfusion injury (ischemia-reperfusion injury), upon release of a ligature or tourniquet, uraemia, crush syndrome, compartment syndrome, traumatic brain and/or spinal cord injury, major trauma, infection, bacterial and/or viral infection(s) (e.g. meningitis), sepsis, septic shock, ischemic brain/heart/kidney injury, neuroprotection and/or cardioprotection and/or tissue protection during/after a stroke and/or ischemia and/or cardiac arrest and/or resuscitation and/or a period(s) of poor blood flow anywhere in a subject; [0300] (xi) poisoning by a toxic amount of a compound(s) in a subject e.g. carbon monoxide/methanol/heavy metal/pesticide poisoning, snake/spider/bee/insect/lizard venom, metabolic poison(s), bacterial toxin(s), endotoxemia or drug/substance overdose e.g. heroin, ethanol, prescription medication(s) or over the counter medication(s); [0301] (xii) accelerated aging disease or progeroid syndrome including Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Cockayne syndrome, xeroderma pigmentosum, trichothiodystrophy, combined xeroderma pigmentosum-Cockayne syndrome, restrictive dermopathy, Wiedemann-Rautenstrauch syndrome, Hutchinson-Gilford progeria syndrome (progeria); [0302] (xiii) disease or disorder of ageing (incidence increases with increased age/senescence) and/or a disease/disorder associated with elevated reactive oxygen species including degenerative diseases, neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, dementia, Batten disease, polyglutamine diseases, osteoporosis, atherosclerosis, cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, heart failure, chronic obstructive pulmonary disease (COPD), hypertension, arthritis, cataracts, type 2 diabetes, andropause, sarcopenia, age-related macular degeneration (AMD), hearing loss, movement disability, cancer; [0303] (xiv) aging, wherein these compounds slow ageing, extend lifespan and healthspan; [0304] (xv) skin aging; [0305] (xvi) cardiovascular diseases and conditions associated with ischemia and associated conditions including, without limitation, ischemia-reperfusion injury, myocardial ischemia, ischemic heart disease, chronic stable angina pectoris, myocardial infarction, congestive heart failure, an acute coronary syndrome, muscle cell damage, necrosis, cardiac arrhythmias, non-Q wave MI, unstable angina, high blood pressure, coronary artery disease, ischemic hypoxia, cyanosis, gangrene, acute limb ischemia, stroke, ischemic stroke, brain ischemia, vascular dementia, transient ischemic attack (TIA), ischemic colitis, mesenteric ischemia, angina pectoris, ischemic heart disease, ischemic neuropathy, hypoxic-ischemic encephalopathy, cerebral hypoxia, brain hypoxia, ischemia resulting from vascular occlusion, cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack), muscle cell damage, necrosis; or [0306] (xvii) acute inflammation, chronic inflammation, systemic inflammation, inflammation because of infection or foreign bodies or injury or chemical or toxin or drug or stress or frostbite or burn or ionising radiation, inflammatory diseases/disorders/syndromes, Macrophage Activation Syndrome (MAS), autoinflammatory diseases/disorders/syndromes, age-related chronic inflammatory diseases (inflammaging), autoimmune diseases/disorders/syndromes, diseases/disorders of the innate immune system, sore throat, sore throat associated with cold or flu or fever, high-intensity exercise associated inflammation, ulcerative colitis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), rheumatoid arthritis, osteoarthritis, psoriatic arthritis, atopic dermatitis, allergic airway inflammation, asthma, inflammation associated depression, exercise-induced acute inflammation, atherosclerosis, allergy, hay fever, anaphylaxis, inflammatory myopathies, drug-induced inflammation, systemic inflammatory response syndrome, sepsis-related multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, acne vulgaris, celiac disease, celiac sprue, chronic prostatitis, colitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Mast Cell Activation Syndrome, mastocytosis, otitis, pelvic inflammatory disease (PID), reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, transplant rejection, parasitosis, eosinophilia, type III hypersensitivity, ischaemia, chronic peptic ulcer, tuberculosis, Crohn's disease, hepatitis, chronic active hepatitis, immune hepatitis, ankylosing spondylitis, diverticulitis, fibromyalgia, systemic lupus erythematous (SLE), Alzheimer's disease, Parkinson's disease, neurodegenerative disease, cardiovascular disease, chronic obstructive pulmonary disease, bronchitis, acute bronchitis, appendicitis, acute appendicitis, bursitis, colitis, cystitis, dermatitis, encephalitis, gingivitis, meningitis, infective meningitis, myelitis, nephritis, neuritis, periodontitis, chronic periodontitis, phlebitis, prostatitis, RSD/CRPS, rhinitis, sinusitis, chronic sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, respiratory bronchiolitis-associated interstitial lung disease and desquamative interstitial pneumonia, interstitial lung disease, Lofgren syndrome, Heerfordt syndrome, monocytosis, liver fibrosis, steatohepatitis, nonalcoholic steatohepatitis, silicosis, histiocytoses, Langerhans' cell histiocytosis, haemophagocytic lymphohistiocytosis, pulmonary langerhans cell histiocytosis, obesity, type II diabetes, gout, pseudogout, organ transplant rejection, epidermal hyperplasia, chronic fatigue syndrome, graft versus host disease (GVHD), lymphadenopathy, familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinemia D with recurrent fever syndrome (HIDS), cryopyrin associated periodic syndrome (CAPS), Blau syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), mevalonate kinase deficiency, pyogenic-arthritis-pyoderma gangrenosum and acne syndrome (PAPA), periodic fever aphthous stomatitis pharyngitis adenitis (PFAPA) syndrome, Behcet's disease, Still's disease, Crohn's disease, Schnitzler's syndrome, Sweet's syndrome, NLRP12-associated autoinflammatory disorders, deficiency of interleukin-1 receptor antagonist (DIRA), pyoderma gangrenosum, cystic acne, aseptic arthritis, periodic Fever Associated with mevalonate kinase deficiency (hyperimmunoglobulin D Syndrome), Pyogenic Arthritis Pyoderma Gangrenosum Acne (PAPA) syndrome, Periodic Fever Aphthous Stomatitis, Pharyngitis and Adenopathy (PFAPA) syndrome, Adult-Onset Still's Disease (AOSD),
[0307] Systemic Juvenile Idiopathic Arthritis (sJIA), Chronic Recurrent Multifocal Osteomyelitis (CRMO), Synovitis Acne Pustulosis Hyperostosis Osteitis (SAPHO) syndrome, Cryopyrin associated Periodic Syndrome (CAPS), Familial cold auto inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), Familial cold urticarial, Neonatal onset multisystemic inflammatory disorder (NOMID), hereditary Periodic Fever Syndromes, Periodic Fever Syndromes, systemic autoinflammatory diseases, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospho lipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Bal disease, Behcet's disease, benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Berger's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, immune hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR) PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, peripheral neuropathy, perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)), idiopathic thrombocytopenia purpura, splenomegaly.
EXAMPLE (I)
[0308] Summary of Formula (I)
[0309] This invention embodiment relates to compounds having the following formula:
##STR00023##
[0310] or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
[0311] L.sup.M, L.sup.N, L.sup.U, L.sup.T and L.sup.R are each independently selected from a single bond or CR.sup.V.sub.2, wherein each R.sup.V is independently selected from hydrogen, alkyl, or substituted alkyl (non-limiting examples: CF.sub.3, CCl.sub.3), or deuterated alkyl (non-limiting example: CD.sub.3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy;
[0312] m, n, u, t, and r are each independently selected from 0, 1, 2, 3 and 4;
[0313] L is independently at each point of its use alkyl, or substituted alkyl (non-limiting examples:
[0314] CF.sub.3, CCl.sub.3), or deuterated alkyl (non-limiting example: CD.sub.3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.);
[0315] R.sub.1 is R.sub.extra, hydrogen, cyano, SO.sub.2R.sub.8, C(O)R.sub.9, or heteroaryl;
[0316] R.sub.extra is selected from L (defined earlier), alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkylene, substituted alkylene, alkynyl, substituted alkynyl, alkoxy, thioalkyl, aminoalkyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, morpholinylalkyl, aryl, arylalkyl, heterocyclo, heteroaryl, (heterocyclo)alkyl, acyl, alkoxycarbonyl, substituted amino;
[0317] R.sub.2 is (i) independently hydrogen, L (defined earlier), alkyl, or substituted alkyl, [0318] or (ii) taken together with R.sub.3 forms a heterocyclo;
[0319] R.sub.3 is (i) independently alkyl, substituted alkyl, L, alkylthio, aminoalkyl, carbamyl, B.sub.B-aryl, B.sub.B-heterocyclo, B.sub.B-heteroaryl, or B.sub.B-cycloalkyl, or (ii) taken together with R.sub.2 forms a heterocyclo;
[0320] Z is heteroaryl;
[0321] B.sub.B is a bond, C.sub.1-4alkylene, C.sub.2-4alkenylene, substituted C.sub.1-4alkylene, substituted C.sub.2-4alkenylene, C(O)NR.sub.19, C.sub.1-4alkylene-C(O)NR.sub.19, or substituted C.sub.1-4alkylene-C(O)NR.sub.19;
[0322] R.sub.4 at each occurrence is selected independently of each other R.sub.4 from the group consisting of halogen, alkyl, haloalkyl, nitro, cyano, haloalkoxy, OR.sub.25, SR.sub.25, NR.sub.25R.sub.26, NR.sub.25SO.sub.2R.sub.27, SO.sub.2R.sub.27, SO.sub.2NR.sub.25R.sub.26, CO.sub.2R.sub.26, C(O)R.sub.26, CHNR.sub.25R.sub.26, OC(O)R.sub.25, OC(O)NR.sub.25R.sub.26, NR.sub.25C(O)R.sub.26, NR.sub.25CO.sub.2R.sub.26, aryl, heteroaryl, heterocyclo and cycloalkyl;
[0323] R.sub.8 is alkyl, substituted alkyl, aryl, or heteroaryl;
[0324] R.sub.9 is NR.sub.1OR.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, or CO.sub.2R.sub.12;
[0325] R.sub.10 and R.sub.11, are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, and heteroaryl; or (ii) taken together form a hetero cyclo or heteroaryl;
[0326] R.sub.12 and R.sub.19 are hydrogen or alkyl;
[0327] R.sub.25 and R.sub.26 are independently selected from hydrogen, alkyl, or substituted alkyl, or taken together form a heterocyclo or heteroaryl ring;
[0328] R.sub.27 is alkyl or substituted alkyl, and
[0329] q is 0, 1, 2, or 3.
[0330] Preferred Compounds of Formula (I)
[0331] Preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00024##
[0332] and even more preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00025##
[0333] other preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00026##
[0334] in which, in the preceding three structures shown:
[0335] L is hydrogen, or methyl, or CF.sub.3, or CD.sub.3, or deuterium (D);
[0336] D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
[0337] S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
[0338] R symbolises the R stereoisomer, for example, in enantiomeric excess (ee) exceeding 70% (following IUPAC naming rules the chiral carbon of the fluorine (F) analogue is labelled R rather than S, but note that the arrangement of which bond is up, bold wedge, and down, dashed, around the stereogenic carbon is the same as the preceeding structures labelled S at their chiral carbon, it is this molecule arrangement that is salient, and that is disclosed, rather than a mere label in a naming convention. This clarification won't be repeated at every place to which it applies in this disclosure, at every point at which there is an F in place of an H on the chiral carbon, or any other higher order of priority atom (by IUPAC rules), e.g. (non-limiting) any other halogen, because this clarification here itself is likely superfluous: all this is very clear to someone of the art. So, when there is said to be an enantiomeric excess (ee) in this disclosure in relation to this example embodiment, Formula (I), it applies to this molecular configuration, this arrangement of solid/dashed wedges, about the chiral carbon, whether this be S or R by IUPAC naming rules);
[0339] Z is triazolyl optionally substituted with one to two R.sub.7 or imidazolyl optionally substituted with one to two R.sub.7 and/or having fused thereto a benzene ring in turn optionally substituted with one to two R.sub.7;
[0340] R.sub.1 is cyano or C(O)R.sub.9;
[0341] R.sub.2 is hydrogen, alkyl, or benzyl;
[0342] R.sub.3 is aryl or arylalkyl optionally substituted with alkyl, halogen, trifluoromethyl, OCF.sub.3, cyano, nitro, amino, hydroxy, or methoxy;
[0343] R.sub.4 is halogen, alkyl, trifluoromethyl, or OCF.sub.3;
[0344] R.sub.7 is alkyl, carbamyl or carbamylC.sub.1-4alkyl;
[0345] R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, or CO.sub.2R.sub.12;
[0346] R.sub.10 and R.sub.11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, and heteroaryl; or (ii) taken together form a heterocyclo or heteroaryl;
[0347] R.sub.12 is hydrogen or alkyl; and
[0348] q is 0, 1, 2, or 3.
[0349] Further preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00027##
[0350] and even more preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00028##
[0351] other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00029##
[0352] in which, for the preceding three structures shown:
##STR00030##
[0353] and more preferably
##STR00031##
[0354] L is hydrogen, or methyl, or CF.sub.3, or CD.sub.3, or deuterium (D);
[0355] D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
[0356] S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
[0357] A is nitrogen (N), or N.sup.+, or carbon;
[0358] E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.), for example hydrogen, deuterium or fluorine;
[0359] Y is N, CH or CR.sub.7c;
[0360] Ri is cyano or C(O)R.sub.9;
[0361] R.sub.2 is hydrogen or C.sub.1-4alkyl;
[0362] R.sub.4 is halogen, C.sub.1-4alkyl, trifluoromethyl; or OCF.sub.3;
[0363] R.sub.7a, R.sub.7b, and R.sub.7c are independently E (defined earlier), hydrogen, alkyl, carbamyl or carbamylC.sub.1-4alkyl, or R.sub.7a and R.sub.7c join to form an optionally substituted fused phenyl ring;
[0364] R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, or CO.sub.2R.sub.12;
[0365] R.sub.10 and R.sub.11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, and heteroaryl; or (ii) taken together form a heterocyclo or heteroaryl;
[0366] R.sub.12 is hydrogen or alkyl;
[0367] R.sub.23 is hydrogen, alkyl, hydroxyalkyl, or phenyl;
[0368] R.sub.24 is alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF.sub.3, methoxy, phenyloxy, benzyloxy, cyano, or acyl, or two R.sub.24 groups join to form a fused cycloalkyl or benzene ring;
[0369] q is 1 or 2;
[0370] x is 0, 1, or 2; and
[0371] y is 0, 1, 2, or 3.
[0372] More preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00032##
[0373] and even more preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00033##
[0374] other preferred compounds are those with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00034##
[0375] in which, for the preceding three structures shown:
##STR00035##
[0376] L is hydrogen, or methyl or deuterium;
[0377] D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
[0378] S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
[0379] R.sub.1 is cyano or C(O)R.sub.9;
[0380] R.sub.4 is halogen, C.sub.1-4alkyl, trifluoromethyl, or OCF.sub.3;
[0381] R.sub.7c is hydrogen or R.sub.7 and R.sub.7c join to form a fused benzene ring optionally substituted with
[0382] C.sub.1-4alkyl or (CH.sub.2).sub.1-2NHC(O)C.sub.1-4alkyl,
[0383] R.sub.7b is hydrogen, C.sub.1-4alkyl, or (CH.sub.2).sub.1-2NHC(O)C.sub.1-4alkyl;
[0384] R.sub.9 is a) NR.sub.10R.sub.11 [0385] b) C.sub.1-8salkyl optionally substituted with one to two of:
[0386] i) SR.sub.13, OR.sub.13, NR.sub.13aR.sub.13b, halogen, trifluoromethyl, CO.sub.2R.sub.13a, and C(O)NR.sub.13aR.sub.13b;
[0387] ii) cycloalkyl optionally substituted with one to two of C(O)H, C.sub.1-4acyl, alkenyl, carbamyl, and/or phenyl in turn optionally substituted with halogen;
[0388] iii) phenyl or napthyl optionally substituted with one to two of halogen, nitro, amino, alkyl, hydroxy, C.sub.1-4alkoxy, or having fused thereto a five or six membered heterocyclo;
[0389] iv) pyridinyl, thiophenyl, furanyl, tetrahydrofuranyl, or azepinyl, optionally substituted with alkyl or having fused thereto a five to six membered carbocyclic ring optionally substituted with keto or C.sub.1-4alkoxy;
[0390] c) C.sub.1-4alkoxy;
[0391] d) C.sub.1-4alkylthio;
[0392] e) CO.sub.2alkyl;
[0393] f) 3 to 6 membered cycloalkyl optionally having up to four substituents selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, and/or phenyl in turn optionally substituted with halogen; or having an aryl fused thereto;
[0394] g) phenyl optionally substituted with one to four of halogen, cyano, trifluoromethyl, nitro, hydroxy, C.sub.1-4alkoxy, haloalkoxy, C.sub.1-6alkyl, CO.sub.2alkyl, SO.sub.2alkyl, SO.sub.2NH.sub.2, amino, NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, NHC(O)alkyl, C(O)alkyl, and/or C.sub.1-4 alkyl in turn optionally substituted with one to three of trifluoromethyl; hydroxy, cyano, phenyl, pyridinyl; and/or a five or six membered heteroaryl or heterocyle in turn optionally substituted with keto or having a benzene ring fused thereto;
[0395] h) pyridinyl, thiazolyl, furanyl, thiophenyl, and pyrrolyl optionally substituted with one to two of halogen, alkyl, and phenyl in turn optionally substituted with halogen or trifluoromethyl;
[0396] R.sub.10 is hydrogen, alkyl, or alkoxy;
[0397] R.sub.11 is alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, or heteroaryl;
[0398] or R.sub.10 and R.sub.11, taken together form a heterocyclo or heteroaryl;
[0399] R.sub.23 is hydrogen, alkyl, hydroxyalkyl, or phenyl;
[0400] R.sub.24 is alkyl, halogen, trifluoromethyl, cyano, halogen, hydroxy, OCF.sub.3, methoxy, phenyloxy, benzyloxy, cyano, or acyl, or two R.sub.24 groups join to form a fused cycloalkyl or benzene ring;
[0401] q is 0, 1, or 2;
[0402] x is 0 or 1; and
[0403] y is 0, 1, or 2.
[0404] Most preferred are compounds as immediately defined above wherein, R.sub.1 is cyano or C(O)R.sub.9; R.sub.9 is optionally substituted phenyl or phenyl C.sub.1-4alkyl; x is 0 or 1; and q and y are 1 or 2. For this preferred structure, its S stereoisomer is preferred. And further preferred is for its L group to be deuterium.
[0405] Example Embodiments of Formula (I)
[0406] Compounds from [5-6], selected as specific anti-cancer therapeutics by the invention of this disclosure, selected because they inhibit the reverse, more than the forward, mode of ATP synthase. EC.sub.50 and IC.sub.50 used interchangeably. EC.sub.50 values for F.sub.1F.sub.0 ATP hydrolysis, and F.sub.1F.sub.0 ATP synthesis, in NADH-linked and NADPH-linked sub-mitochondrial (SMP) assays respectively, sourced from [5-6], are presented. [5-6] refer to these EC.sub.50 values as IC.sub.50 values for inhibiting F.sub.1F.sub.0 ATP hydrolase (reverse mode) and F.sub.1F.sub.0 ATP synthase (forward mode). However, this in incorrect. Because, as identified by the invention of this disclosure, explained herein, although these molecules inhibit F.sub.1F.sub.0 ATP hydrolase, their reducing of F.sub.1F.sub.0 ATP synthesis is not (predominantly) because of inhibiting F.sub.1F.sub.0 ATP synthase, but by uncoupling. More preferred molecules of this invention have a low EC.sub.50 for F.sub.1F.sub.0 ATP hydrolysis, and a higher EC.sub.50 for F.sub.1F.sub.0 ATP synthesis, and their ratio difference is large.
##STR00036##
[0407] Further example embodiments of Formula (I), with SMP data, reinterpreted (as aforementioned, these molecules don't significantly inhibit F.sub.1F.sub.0 ATP synthase but do reduce F.sub.1F.sub.0 ATP synthesis by uncoupling), from [5],
##STR00037##
[0408] Further examples [5]:
TABLE-US-00002 R1 R2 EC.sub.50 F.sub.1F.sub.0 ATP hydrolase (M) 4-Cl 2-Cl 2,3-Cl.sub.2 3-Cl 4-Cl 4-Cl CN CN CN CN C(O)4-CNPh C(O)Et 8.8 2.23 2.49 0.72 9.17 0.28 2.27
[0409] Further example, with synthesis step, effectively without a protonable element in its imidazole, which diminishes the molecule's ability to uncouple the proton motive force:
##STR00039##
[0410] General Compound Synthesis
[0411] A general synthetic route applicable to some compounds of the invention is set out in Scheme 1 below.
##STR00040##
[0412] The person skilled in the art is able to make modifications to this general synthetic route, based on the common general knowledge, the chemical reaction literature, and/or the content of prior art disclosures cited herein, in order to synthesise compounds of the invention where necessary.
[0413] Specific Compound Synthesis
[0414] Racemate 19a [5] was synthesised by the following synthesis route, Scheme 2, and separated into component stereoisomers using superfluid chromatography (SFC). Starting reagents for this synthesis were sourced commercially using the LabNetwork (www.labnetwork.com), which is a website that permits one to search for chemical suppliers for inputted structures/chemical names e.g. there are numerous suppliers listed on LabNetwork for the starting compound, Compound 1.
##STR00041## ##STR00042##
[0415] The reaction scheme below, Scheme 3, is modified from that presented above, in order to produce a deuterated analogue, with deuterium in place of hydrogen on the chiral carbon. The scheme is provided for the purpose of illustrating the invention, and should not be regarded in any manner as limiting the scope or the spirit of the invention. This illustrating, not limiting, feature applies to all the compound synthesis schemes of this disclosure. The starting compound in the scheme below, Compound 1, is available from multiple suppliers listed on LabNetwork (e.g. Manchester Organics Ltd., UK).
##STR00043## ##STR00044##
[0416] Compound 4 in Scheme 3 is of the form of Compound 1, the starting compound, in the molecule synthesis embodiments of [P1] (presented in its Process of Preparation section), BUT with the exception that is deuterated on its chiral carbon. This deuterated form can be substituted into the synthesis schemes described in [P 1 ] to produce deuterated molecules, with deuterium on their chiral carbon, which are componentry to the present invention, and in a non-limiting embodiment, one of more of these new compositions of matter are used as anti-cancer medicines. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods. Further methods to synthesize Compound 4, of Scheme 3 above, are given below in Scheme 4.
##STR00045##
[0417] Compound 1 in Scheme 4 is available from multiple suppliers listed on LabNetwork (e.g. Apollo Scientific Ltd., Stockport, UK). Conducting Scheme 4, the aim is to obtain a higher degree of deuterium incorporation on the chiral carbon than natural abundance: for Compound 4 ultimately, and for Compound 1 first if the lower arm of the synthesis route is used. In both cases, the greater the deuterium incorporation, the better. Deuterium incorporation at other positions of each molecule is permissible and within the scope of the invention, as is elevated deuterium incorporation only at the chiral carbon. Reactions described in [L, H, G, K, M, J1, J2, J3, I, F, S] deuterate (herein defined as replace hydrogen with deuterium) the -carbon to a secondary alcohol and so the chiral carbon of Compound 1.
[0418] Reactions described in [A, B, P, E1, E2, F] deuterate the -carbon to primary amines, thence can deuterate the chiral carbon of Compound 4. Reactions described in [N] deuterate sp3 carbons, thence can deuterate the chiral carbon of Compounds 1 and 4. Reactions described in [O1, O2] can deuterate the -carbon to phenyl groups and so can deuterate the chiral carbon of Compounds 1 and 4. Reactions described in [R1, R2, Q1, Q2] can deuterate widely, upon aromatic and alkyl molecular components, and thence can deuterate the chiral carbon of Compounds 1 and 4. Reactions described in [D] deuterate the -carbon to tertiary amines, thence can deuterate the chiral carbon of Compounds 1 and 4. The teaching of [D] is especially preferred for use in the present context. Whichever option(s) is chosen, solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. The level of deuteration can be modulated by modulating the reaction time: greater deuterium incorporation by longer reaction time. One can do multiple cycles of one or more of these reactions until the desired level of deuterium incorporation occurs, monitored by .sup.1H and/or .sup.2H NMR (e.g. deuterium incorporation quantified by decrease of .sup.1H NMR integral intensity at specified position(s) compared to starting material) and/or mass spectrometry. Some of the reactions cited herein use commercially available catalysts e.g.
[0419] 10% Pd/C catalyst [O1, O2, Q1, R1, R2], and/or Pt/C catalyst [R1, R2, Q1, Q2], or shvo catalyst [D], or RuCl.sub.2(P(Ph).sub.3).sub.3 (CAS no: 15529-49-4) [A], or 5% Ru/C catalyst [K], or Ru-macho catalyst [G, M], all available from Sigma-Aldrich. Others teach, or cite literature teaching, how to prepare the catalyst to use. The aforementioned list of synthesis options, to make Compound 4 in Scheme 4, is not exhaustive. A person skilled in the art will know how to find further options. For example using computational tools, including artificial intelligence (A1, non-limiting e.g. [A11, A12, A13]), to search the chemical reaction literature/databases, e.g. (non-limiting) the Reaxys or CAS databases, and their own skill in the art to find, plan and prioritise synthesis routes. 2-(1H-imidazol-1-yl)-1-phenylethanamine is commercially available on LabNetwork and can be deuterated at its chiral carbon (and optionally at other positions also) by one or more of the aforementioned methods disclosed herein for deuterating the chiral carbon of 1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)ethanamine. Before or after deuteration, its phenyl group can be (non-limiting) alkylated, halogenated, or CF.sub.3 added (non-limiting example: at the IUPAC 2.5 positions), at desired position(s) by methods well known to those of the art. Then it can be a starting compound in the synthesis schemes of [P1] and used to produce deuterated compositions of matter that are componentry to this invention, which in non-limiting embodiments, are used singly or in a combination in anti-cancer therapy, in an animal or human. Alternatively, the final products, rather than starting materials, of the synthesis schemes of [P1] can be deuterated, to produce deuterated compositions of matter that are componentry to this invention, which in non-limiting embodiments, are used singly or in a combination in anti-cancer therapy, in an animal or human. Reactions described in [A, B, E1, E2, F] can deuterate the -carbon to secondary amines, and thence the chiral carbon of Compound 19a, in Scheme 2 presented previously, and the chiral carbon of other molecules with the scaffold of [P1], as presented in the abstract of [P1]. These compounds can also be deuterated at their chiral carbon, and in further embodiments at further or other position(s), by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [O1, O2], which can deuterate the -carbon to phenyl groups. And/or by reactions described in [R1, R2, Q1, Q2], which deuterate aromatic and alkyl molecular components. And/or by reactions described in [D], which can deuterate the -carbon to tertiary amines. Some of these reactions are stereoretentive [F, N, E1, E2] and thus can be used, optionally, after stereoisomer enrichment. Others are not, e.g. [Q1, Q2], and so should be used before any enantiomeric excess (ee) enrichment step. All patents and papers cited by the present disclosure, and their supplementary materials, are herein incorporated by reference, and are componentry, to the present disclosure.
[0420] The reaction scheme below, Scheme 5, differs from Scheme 2 in order to produce methylated analogues, with methyl in place of hydrogen on the chiral carbon.
##STR00046## ##STR00047## ##STR00048##
[0421] Compound 5 in Scheme 5 is of the form of Compound 1, the starting compound, in the molecule synthesis embodiments of [P 1 ] (presented in its Process of Preparation section), BUT with the exception that is methylated on its chiral carbon. This methylated form can be substituted into the synthesis schemes described in [P1] to produce methylated molecules, with methyl on their chiral carbon, that are componentry to the present invention, and in a non-limiting embodiment, one of more of these new compositions of matter are used as anti-cancer medicines. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods.
[0422] The reaction scheme below, Scheme 6, differs from Scheme 2 in order to produce fluorinated analogues, with fluorine in place of hydrogen on the chiral carbon.
##STR00049##
[0423] Compound 6 in Scheme 6 is of the form of Compound 1, the starting compound, in the molecule synthesis embodiments of [P1] (presented in its Process of Preparation section), BUT with the exception that is fluorinated on its chiral carbon. This fluorinated form can be substituted into the synthesis schemes described in [P1] to produce fluorinated molecules, with fluorine on their chiral carbon, that are componentry to the present invention, and in a non-limiting embodiment, one of more of these new compositions of matter are used as anti-cancer medicines. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods.
EXAMPLE (II)
[0424] Summary of Formula (II)
[0425] This invention embodiment relates to compounds having the formula:
##STR00050##
[0426] or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
[0427] L is independently at each point of use alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.), for example hydrogen, or deuterium, or fluorine;
[0428] A is nitrogen (N), or N.sup.+, or carbon;
[0429] E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.), for example hydrogen, or deuterium or fluorine;
[0430] C is carbon;
[0431] x, w, f, g are independently selected to be 0, 1, 2 or 3;
[0432] d is a selected integer between 0 and 7;
[0433] k and s are independently selected to be 1, 2, or 3;
[0434] The 5-sided ring structure is attached by any one of its available ring atoms, and none, one or two of its bonds can be a double bond, for example at locations shown by the single or double bond symbol;
[0435] R.sub.1 and R.sub.5 are attached to any available carbon atom of phenyl rings A and B, respectively, and at each occurrence are independently selected from hydrogen, deuterium, alkyl, substituted alkyl, trifluoromethoxy, halogen, cyano, nitro, OR.sub.8, NR.sub.8R.sub.9, C(O)R.sub.8, CO.sub.2R.sub.8, C(O)NR.sub.8R.sub.9, NR.sub.8C(O)R.sub.9, NR.sub.8C(O)OR.sub.9,
[0436] S(O).sub.oR.sub.9, NR.sub.8SO.sub.2R.sub.9, SO.sub.2NR.sub.8R.sub.9, cycloalkyl, heterocycle, aryl, and heteroaryl, and/or two of
[0437] R.sub.1 and/or two of R.sub.5 join together to form a fused benzo ring; R.sub.2, R.sub.3 and R.sub.4 are independently selected from E (defined earlier), hydrogen, or deuterium, or alkyl, or deuterated alkyl, and substituted alkyl, or one of R.sub.2, R.sub.3 and R.sub.4 is a bond to R, T or Y and the other of R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen, alkyl, and substituted alkyl;
[0438] Z and Y are independently selected from C(O),CO.sub.2, SO.sub.2, CH.sub.2, CH.sub.2C(O), and C(O)C(O), or Z may be absent;
[0439] R and T are selected from CH.sub.2, C(O), and CH[(CH.sub.2).sub.p(Q)], wherein Q is NR.sub.10R.sub.11, OR.sub.10 or CN;
[0440] R.sub.6 is selected from thienyl, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, heterocyclo, heteroaryl and aryl optionally substituted with a lower aliphatic group or one or more functional groups selected independently from the group consisting of NH.sub.2, OH, phenyl, halogen, (C.sub.1-C.sub.4)alkoxy or NHCOCH.sub.3;
[0441] R.sub.7 is selected from L (defined earlier), hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aminoalkyl, halogen, cyano, nitro, keto (O), hydroxy, alkoxy, alkylthio, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
[0442] R.sub.8 and R.sub.9 are independently selected from hydrogen, alkyl, substituted alkyl, C.sub.2-4alkenyl optionally substituted, cycloalkyl, heterocycle, aryl, and heteroaryl, or R.sub.8 and R.sub.9 taken together to form a heterocycle or heteroaryl, except R.sub.9 is not hydrogen when attached to a sulfonyl group as in SO.sub.2R.sub.9;
[0443] R.sub.10 and R.sub.11 are independently selected from hydrogen, alkyl, and substituted alkyl;
[0444] m and n are independently selected from 0, 1, 2 and 3
[0445] o, p and q are independently 0, 1 or 2; and
[0446] r and t are 0 or 1.
[0447] Preferred Compounds of Formula (II)
[0448] Preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00051##
[0449] wherein:
[0450] L is hydrogen, or deuterium, or methyl, or fluorine;
[0451] A is nitrogen (N), or N.sup.+, or carbon;
[0452] E is absent, or alkyl, or substituted alkyl, or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.), for example hydrogen or deuterium;
[0453] R.sub.1 and R.sub.5 are attached to any available carbon atom of phenyl ring A and phenyl ring B, respectively, and at each occurrence are independently selected from hydrogen, deuterium, alkyl, aralkyl, aminoalkyl, halogen, cyano, nitro, hydroxy, alkoxy, trifluoromethoxy, alkylthio, NH.sub.2, NH(alkyl), N(alkyl).sub.2, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide,
[0454] cycloalkyl, heterocycle, aryl, and heteroaryl, and/or two of R.sub.1 and/or two of R.sub.5 join together to form a fused benzo ring;
[0455] R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen and alkyl;
[0456] Z is CO.sub.2, SO.sub.2, or is absent;
[0457] Y, R and T are selected from CH.sub.2 and C(O),
[0458] R.sub.6 is selected from:
[0459] C.sub.1-4alkyl or C.sub.1-4alkenyl optionally substituted with up to three of halogen, aryl and CO.sub.2C.sub.1-6alkyl;
[0460] phenyl optionally substituted with up to three Rig and/or having fused thereto a benzo-ring or
[0461] a five to six membered heteroaryl;
[0462] heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl wherein said heteroaryl is optionally substituted with up to two R.sub.12,
[0463] R.sub.7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aminoalkyl, halogen, cyano, nitro, keto (O), hydroxy, alkoxy, alkylthio, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, heterocycle, aryl, and heteroaryl;
[0464] R.sub.12 at each occurrence is independently selected from each other R.sub.12 from the group consisting of C.sub.1-6alkyl, halogen, nitro, cyano, hydroxy, alkoxy, NHC(O)alkyl, CO.sub.2alkyl, SO.sub.2phenyl, aryl, five to six membered monocyclic heteroaryl, and phenyloxy or benzyloxy in turn optionally substituted with halogen, hydroxyl, C.sub.1-4alkyl, and/or O(C.sub.1-4alkyl); m and n are independently selected from 0, 1, 2 or 3; and
[0465] q is 0, 1 or 2; and
[0466] r and t are 0 or 1.
[0467] More preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00052##
[0468] wherein
[0469] R.sub.1 and R.sub.5 are attached to any available carbon atom of phenyl ring A and phenyl ring B, respectively, and at each occurrence are independently selected from alkyl,
[0470] halogen, cyano, hydroxy, alkoxy, NH.sub.2, NH(alkyl), N(alkyl).sub.2, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, and/or two of Ri and/or two of R.sub.5 join together to form a fused benzo ring;
[0471] R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen and lower alkyl;
[0472] Z is CO.sub.2, SO.sub.2, or is absent;
[0473] R.sub.6 is selected from: C.sub.1-4alkyl or C.sub.1-4alkenyl optionally substituted with up to three of halogen, aryl and CO.sub.2C.sub.1-6alkyl;
[0474] phenyl optionally substituted with up to three R.sub.12 and/or having fused thereto a benzo ring or a five to six membered heteroaryl;
[0475] heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl, wherein said heteroaryl is optionally substituted with up to two R.sub.12,
[0476] R.sub.12 at each occurrence is independently selected from each other R.sub.12 from the group consisting of C.sub.1-6 alkyl, halogen, nitro, cyano, hydroxy, alkoxy, NHC(O)alkyl, CO.sub.2alkyl, SO.sub.2phenyl, aryl, five to six membered monocyclic heteroaryl, and phenyloxy or benzyloxy in turn optionally substituted with halogen, hydroxyl, C.sub.1-4 alkyl, and/or O(C.sub.1-4 alkyl); and
[0477] m and n are independently selected from 0, 1, or 2.
[0478] Even more preferred are compounds as immediately defined above wherein R.sub.6 is selected from C.sub.1-4alkyl, trifluoromethyl, benzyl, C.sub.2-3alkenyl substituted with phenyl,
##STR00053##
[0479] wherein:
[0480] R.sub.15 is halogen, alkyl, nitro, cyano, hydroxy, alkoxy, NHC(O)alkyl, and/or two R.sub.15 groups are taken together to form a fused benzo ring or a five to six membered heteroaryl;
[0481] R.sub.16 is selected from hydrogen, deuterium, halogen, alkyl, nitro, cyano, hydroxy, alkoxy, NHC(O)alkyl, and phenyloxy or benzyloxy in turn optionally substituted with 1 to 3 of hydrogen, deuterium, halogen, cyano, and C.sub.1-4alkoxy;
[0482] R.sub.17 is selected from alkyl, alkoxy, CO.sub.2C.sub.1-6alkyl, and SO.sub.2phenyl; and u and v are independently 0, 1 or 2.
[0483] Most preferred compounds of Formula (II) are those having the formula:
##STR00054##
[0484] wherein
[0485] L is deuterium;
[0486] R.sub.2 is hydrogen or CH.sub.3;
[0487] Z is CO.sub.2, SO.sub.2, or is absent; and
[0488] R.sub.6 is selected from the groups recited immediately above, most preferably
##STR00055##
[0489] Example Embodiments of Formula (II)
[0490] Compounds from [8, 12], selected as specific anti-cancer therapeutics by the invention of this disclosure, selected because they inhibit the reverse, more than the forward, mode of ATP synthase. EC.sub.50 and IC.sub.50 used interchangeably. EC.sub.50 values for F.sub.1F.sub.0 ATP hydrolysis, and F.sub.1F.sub.0 ATP synthesis, in NADH-linked and NADPH-linked sub-mitochondrial (SMP) assays respectively, sourced from [8], are presented. [8] refer to these EC.sub.50 values as IC.sub.50 values for inhibiting F.sub.1F.sub.0 ATP hydrolase (reverse mode) and F.sub.1F.sub.0 ATP synthase (forward mode). However, this in incorrect. Because, as identified by the invention of this disclosure, explained herein, although these molecules inhibit F.sub.1F.sub.0 ATP hydrolase, their reducing of F.sub.1F.sub.0 ATP synthesis is not (predominantly) because of inhibiting F.sub.1F.sub.0 ATP synthase, but by uncoupling.
##STR00056##
TABLE-US-00003 R6 R5 Imidazole EC.sub.50 F.sub.1F.sub.0 ATP hydrolase (M) 4-FPh Ph 4-OHPh 4-OMePh 2,5-di-ClPh 4-(AcNH)Ph 4-CNPh 2-Cl-4-CNPh 3-NO.sub.2Ph Naphth-1-y1 Thiophen-2-yl Benzofurazan-7-yl Quinolin-8-yl Bn CF.sub.3 4-t-BuPh 4-t-BuPh SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 SO.sub.2 CH.sub.2 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 5-yl 0.221 0.282 0.667 0.077 0.158 2.981 0.255 0.939 0.423 0.338 0.636 1.777 2.935 2.405 0.077 0.008 2.138
[0491] Further examples [ 2],
##STR00058##
[0492] Scheme IIa is route used for synthesizing Compound 31 [8], starting reagents were sourced commercially using the LabNetwork (www.labnetwork.com).
##STR00059## ##STR00060##
[0493] Compound 31, in Scheme IIa, can be deuterated at its chiral carbon, and in further embodiments at further or other position(s), by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [R1, R2, Q1, Q2], which deuterate aromatic and alkyl molecular components. And/or by reactions described in [D], which deuterate and -carbons to tertiary amines. And/or by reactions described in [F, E1, E2, Ex1], which deuterate carbons to tertiary amines. Alternatively, to produce a Compound 31 isotopologue, deuterated on its chiral carbon, and in further embodiments at further or other position(s), an intermediate in Compound 31 synthesis, presented in Scheme IIa, can be deuterated. For (non-limiting) example, Compound 6 in Scheme IIa can be deuterated by reactions described in [A, B, E1, E2, F], which can deuterate the -carbon to secondary amines. And/or by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [R1, R.sub.2, Q1, Q2], which deuterate aromatic and alkyl molecular components. A deuterated Compound 6 can be inputted into synthesis schemes of [P2], in place of Compound 10 in Scheme III in the Process of Preparation section of [P2], to make deuterated isotopologues with the scaffold of [P2]. These are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics. Throughout this disclosure, deuteration methods conveyed are illustrative rather than limiting. All stereoisomers of all the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form.
EXAMPLE (III)
[0494] Summary of Formula (III)
[0495] This invention embodiment relates to compounds having the following formula:
##STR00061##
[0496] or their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
[0497] Optionally, one or more places have deuterium in place of hydrogen, at an artificially high level of deuterium incorporation, in excess of the naturally occuring abundance;
[0498] Optionally, one or more places have fluorine, or other halogen, or methyl, or alkyl, or substituted alkyl, in place of hydrogen;
[0499] Z is heteroaryl;
[0500] g is selected from 0, 1, 2, 3, 4;
[0501] L is independently at each point of its use hydrogen, alkyl, or substituted alkyl (non-limiting example: CF.sub.3), or deuterated alkyl (non-limiting example: CD.sub.3), or aminoalkyl, or thioalkyl, or alkoxy, or halogen, or haloalkyl, or haloalkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.); G1 is N or C;
[0502] c is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9;
[0503] m is independently at each point of use selected from 0, 1, 2, 3, 4, 5, 6, as valence permits;
[0504] R.sub.2 is hydrogen, L (defined earlier), hydroxy, or OC(O)R.sub.14;
[0505] R.sub.14 is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl;
[0506] R.sub.3 and R.sub.4 are each independently hydrogen, or L (defined earlier), or CF.sub.3, or chlorine or other halogen, or alkyl, or substituted alkyl, or deuterated alkyl, or arylalkyl, or R.sub.3 and R.sub.4 taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring;
[0507] R.sub.5 is independently at each point of use hydrogen, L (defined earlier), alkyl, halogen, heterocyclo, nitrile, haloalkyl or aryl;
[0508] R.sub.12 is selected from hydrogen, aryl, heteroaryl, heterocyclo;
[0509] X is alkyl;
[0510] Y is a single bond, CH.sub.2, C(O) O, S or N(R.sub.14);
[0511] A is nitrogen (N), or N.sup.+, or carbon;
[0512] E is absent, or alkyl, or substituted alkyl (non-limiting example: CF.sub.3), or deuterated alkyl, or aminoalkyl, or thioalkyl, or alkoxy or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.), for example hydrogen, or deuterium, or fluorine;
[0513] R.sub.8 is independently selected at each point of use from E (defined earlier), hydrogen, alkyl, halogen, carbamyl, carbamylC.sub.1-4alkyl, substituted alkyl or two R.sub.8 groups join to form an optionally substituted fused phenyl ring;
[0514] q is 0, 1, 2, 3 or 4.
[0515] R.sub.1 is selected from L (defined earlier), hydrogen, deuterium, CN, SO.sub.2-piperidine, SO.sub.2-piperidine substituted with 0-10 of R.sub.5, R.sub.9, cyano, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkylene, substituted alkylene, alkynyl, substituted alkynyl, alkoxy, thioalkyl, aminoalkyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, haloalkyl, haloalkoxy, alkoxyalkyl, morpholinylalkyl, aryl, arylalkyl, heterocyclo, heteroaryl, (heterocyclo)alkyl, acyl, alkoxycarbonyl, substituted amino; Most preferably R.sub.1 is smaller than 300 Daltons;
[0516] R.sub.9 is
##STR00062##
[0517] R.sub.6 and R.sub.7 are independently hydrogen, L (defined earlier), R.sub.1 (provided R.sub.1 is not R.sub.9), alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, hydroxyalkyl substituted with a carboxylic ester or carboxylic acid, alkoxyalkyl, thioalkyl, (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl; or R.sub.6 and R.sub.7 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered mono or bicyclic ring including fused rings such as
[0518] 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 4-thiamorpholine dioxide, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl; or 1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl substituted with one or more L (defined earlier), alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, COOR.sub.14 or CO-substituted amino;
[0519] or R.sub.5 and R.sub.6 taken together with the atoms to which they are attached form a 5- to 7-membered ring optionally substituted with aryl;
[0520] Encompassed by this invention are methods of administering a therapeutically effective amount of any compound(s) of [P6], or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, optionally in a pharmaceutical composition(s), optionally in co-therapy with another anti-cancer treatment(s), to treat/ameliorate/prevent/combat cancer in a subject. Especially preferred for this use are compounds of [P6] with 3S, 4R stereochemistry.
[0521] Preferred Compounds of Formula (III)
[0522] Preferred methods are to use, and preferred compounds are, compounds of Formula (III), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
[0523] Z is triazolyl optionally substituted with one to two R.sub.8 or imidazolyl optionally substituted with one to two R.sub.8 and/or having fused thereto a benzene ring in turn optionally substituted with one to two R.sub.8;
[0524] Y is oxygen;
[0525] R.sub.2 is hydroxyl;
[0526] R.sub.3 and R.sub.4 are methyl or chlorine;
[0527] R.sub.1 is R.sub.9;
[0528] G.sub.1 is nitrogen;
[0529] R.sub.6 and R.sub.7 are alkyl; or R.sub.6 and R.sub.7 taken together with the nitrogen atom to which they are attached (G.sub.1=N) form a 6-membered ring;
[0530] X is alkyl;
[0531] R.sub.12 is aryl or heterocyclo;
[0532] A is N;
[0533] E is absent, or deuterium, or hydrogen;
[0534] R.sub.5 and R.sub.8 are hydrogen;
[0535] Stereochemistry is 3S, 4R;
[0536] Example Embodiments of Formula (III)
[0537] Immediately below, compounds from [7], selected as specific anti-cancer therapeutics by the invention of this disclosure. EC.sub.50 values for F.sub.1F.sub.0 ATP hydrolysis, and F.sub.1F.sub.0 ATP synthesis, in NADH-linked and NADPH-linked sub-mitochondrial (SMP) assays respectively. [7] refers to these EC.sub.50 values as IC.sub.50 values for inhibiting F.sub.1F.sub.0 ATP hydrolase (reverse mode) and F.sub.1F.sub.0ATP synthase (forward mode). However, this in incorrect. Because, as identified by the invention of this disclosure, explained herein, although these molecules inhibit F.sub.1F.sub.0 ATP hydrolase, their reducing of F.sub.1F.sub.0 ATP synthesis is not (predominantly) because of inhibiting F.sub.1F.sub.0 ATP synthase, but by uncoupling. The structure on the left is BMS-199264. It does not harm ex vivo rat heart at a concentration (10 M [11]) that it exerts anti-cancer activity (discovery of this disclosure).
##STR00063##
[0538] For the following example embodiment, with synthesis scheme (as 2 possible salts shown, Scheme Ilia), the starting material is BMS-199264, which is available commercially. For example from Sigma-Aldrich, a chemical and reagents vender well known to those of the art.
##STR00064##
[0539] Further Example Embodiment:
##STR00065##
[0540] The following example embodiment does not uncouple the proton motive force (pmf) because its imidazole group, unlike BMS-199264, for example, does not have a protonable element.
##STR00066##
[0541] The following example embodiment (logP=3.79, calculated from structure [31]) uncouples the proton motive force (pmf) less than BMS-199264 (logP=4.35, calculated from structure [31]) because its logP is further removed from the logP=-3,2 optimum for uncoupling [32].
##STR00067##
[0542] BMS-199264, and/or its analogues, can be deuterated by reactions described in [R1, R2, Q1, Q2], which deuterate aromatic and alkyl molecular components. Furthermore, there is a great wealth of reactions available to deuterate their aromatic rings, and those skilled in the art will know these. For (non-limiting) example, refer [Ex2]. Carbon 1 of BMS-199264, a chiral centre, can be deuterated by reactions described in [D, F, E1, E2, Ex1], which deuterate a carbons to tertiary amines, and/or by reactions described in [N], which deuterate sp3 carbons, and/or by reactions described in [I, M, G, H], which deuterate and -carbons to an OH group. Carbon 6 of BMS-199264, a chiral centre, can be deuterated by reactions described in [L, H, G, A, K, M, J1, J2, J3, I, F, S], which deuterate the -carbon to an OH group, and/or by reactions described in [D], which deuterate and I3-carbons to tertiary amines, and/or by reactions described in [N], which deuterate sp3 carbons. The scaffold of [P6] is presented in its abstract. Deuterated isotopologues of this [P6] scaffold, for (non-limiting) example deuterated BMS-199264, are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics.
EXAMPLE (IV)
[0543] Background
[0544] Well known to those of the art: amino acids have the following structure, wherein the R group is different in different amino acids.
##STR00068##
[0545] Summary of Formula (IV)
[0546] This invention embodiment relates to compounds having the following formula:
##STR00069##
[0547] or their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
[0548] X is selected from O or S;
[0549] A is selected from hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aminoalkyl, thioalkyl, alkoxy and an R group of a proteogenic amino acid, or other amino acid synthesized or used by a living system (non-limiting example of such a system: a human), which is optionally isotopically enriched, and/or substituted by alkyl, substituted alkyl, deuterated alkyl, halogen, cycloalkyl, heterocycle, aryl, heteroaryl, aminoalkyl, thioalkyl, alkoxy, haloalkyl, haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.);
[0550] n and m are 0, 1, or 2;
[0551] R.sub.1 through R.sub.5 are independently selected from hydrogen, halogen, NO.sub.2, CN, C.sub.1-8salkyl, substituted C.sub.1-8salkyl, C.sub.3-8cycloalkyl, aryl, heterocyclo, heteroaryl, OR.sub.9, SR.sub.9, COR.sub.11, CO.sub.2R.sub.11, CONR.sub.9R.sub.10 or NR.sub.9R.sub.10;
[0552] R.sub.6 and R.sub.7 are independently hydrogen, alkyl or substituted alkyl;
[0553] R.sub.8 is hydrogen, deuterium, C.sub.1-8alkyl, substituted C.sub.1-8alkyl, deuterated C.sub.1-8alkyl, aryl, heterocyclo, heteroaryl, aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.);
[0554] Z is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, COR.sub.11, CO.sub.2R.sub.11, SO.sub.2R.sub.11, S(O)R.sub.11 or CONR.sub.9R.sub.10;
[0555] R.sub.9 and R.sub.10 are independently hydrogen, C.sub.1-8alkyl, substituted C.sub.1-8alkyl, C.sub.3-10cycloalkyl, aryl, heterocyclo, heteroaryl, COR.sub.13, SO.sub.2R.sub.13 or S(O)R.sub.13; and
[0556] R.sub.11, R.sub.12 and R.sub.13 are independently hydrogen, C.sub.1-8alkyl, substituted C.sub.1-8alkyl, C.sub.3-10iocycloalkyl, aryl, heterocyclo or heteroaryl;
[0557] wherein each occurrence of R.sub.9-R.sub.13 is chosen independently.
[0558] Preferred Compounds of Formula (IV)
[0559] Preferred methods are to use, and preferred compounds are, compounds of Formula (IV), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
[0560] R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and/or
[0561] R.sub.6 and R.sub.7 are both hydrogen; and/or
[0562] n and m are both 1; and/or
[0563] R.sub.1 and R.sub.5 are both C.sub.1-8 alkyl, preferably both R.sub.1 and R.sub.5 are isopropyl groups.
[0564] Other preferred methods use, and preferred compounds are, compounds of Formula (IV), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
[0565] Z is C.sub.1-8salkyl, C.sub.2-8alkenyl, C.sub.1-8shalo alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl COR.sub.11, CO.sub.2R.sub.11, SO.sub.2R.sub.11, S(O)R.sub.11 or CONR.sub.9R.sub.10; especially preferable is benzyl, C(O).sub.2H or C(O).sub.2C.sub.1-8salkyl;
[0566] R.sub.9 is hydrogen;
[0567] R.sub.10 is C.sub.1-8alkyl or C.sub.3-10cycloalkyl; aryl or arylalkyl; and
[0568] R.sub.11 is hydrogen, C.sub.1-8alkyl, C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl, C.sub.3-10aryl or C.sub.3-10arylalkyl.
[0569] Other preferred methods use, and preferred compounds are, compounds of Formula (IV), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
[0570] A is hydrogen, deuterium, C.sub.1-8salkyl, heteroaryl, aryl, or alkyl substituted with heterocyclo, aryl, OH, SH, ST.sup.1, C(O), H, T.sup.3-NT.sup.5T.sup.6, -T.sup.8-C(O).sub.tT.sup.9-NT.sup.5T.sup.6 or T.sup.3-N(T.sup.2)T.sup.4NT.sup.5T.sup.6,
[0571] T.sup.1 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
[0572] T.sup.2 and T.sup.3 are each independently a single bond, -T.sup.8-S(O).sub.t-T.sup.9-, -T.sup.8-C(O)-T.sup.9-, -T.sup.18-C(S)-T.sup.9, -T.sup.8-OC(O)-T.sup.9-, -T.sup.8-C(O).sub.tT.sup.9-T.sup.8-C(NT.sup.10-T.sup.9- or -T.sup.8-C(O) C(O)-T.sup.9-;
[0573] T.sup.5, T.sup.6, T.sup.7, T.sup.8 and T.sup.9 are independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alky, each group optionally substituted where valence allows by one to three groups selected from halo, cyano, nitro, OH, oxo, SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, OT.sup.11, ST.sup.11, C(O).sub.tH, C(O).sub.tT.sup.11, OC(O)T.sup.11, T.sup.8C(O).sub.tN(T.sup.12)T.sup.11, SO.sub.3H, S(O).sub.tT.sup.11, S(O).sub.tN(T.sup.12)T.sup.11, -T.sup.13-NT.sup.11T.sup.12, -T.sup.13-N(T.sup.12)-T.sup.4-NT.sup.11T.sup.22, -T.sup.13-N(T.sup.11)-T.sup.12-T.sup.11 and -T.sup.13-N(T.sup.18)-T.sup.14-H; or
[0574] T.sup.8 and T.sup.9 are each independently a single bond, alkylene, alkenylene or alkynylene;
[0575] T.sup.11 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
[0576] T.sup.12 is halo, cyano, nitro, OH, oxo, SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, C(O)tH or SO.sub.3H;
[0577] T.sup.13 and T.sup.14 are each independently a single bond, S(O).sub.t, C(O), C(S), O, S, OC(O), C(O).sub.t, C(NT.sup.13) or C(O)C(O);
[0578] wherein each occurrence of T.sup.1-T.sup.14 is chosen independently; and
[0579] t is 1 or 2.
[0580] Preferred compounds of the foregoing section are those in which A is hydrogen, deuterium, C.sub.1-8salkyl, hydroxyalkyl, heterocycloalkyl, heteroaryl alkyl, aryl, arylalkyl, or alkyl substituted with a group selected from SH, ST.sup.4, C(O).sub.tH, T.sup.6-NT.sup.8T.sup.9, -T.sup.11-C(O)tT.sup.12-NT.sup.8T.sup.9 and T.sup.6-N(T.sup.5)T.sup.7NT.sup.8T.sup.9.
[0581] More preferred are those compounds in which A is hydrogen, deuterium, methyl, CH.sub.2(CH.sub.3).sub.2, (CH.sub.2).sub.2(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2(CH.sub.3), (CH.sub.2)OH, hydroxyethyl, (CH.sub.2).sub.2SCH.sub.3, CH.sub.2SH, phenyl, CH.sub.2(phenyl), CH.sub.2(p-hydroxyphenyl), CH.sub.2(indole), (CH.sub.2)C(O)NH.sub.2, (CH.sub.2).sub.2C(O)NH.sub.2, (CH.sub.2).sub.2C(O)OH, CH.sub.2C(O)OH, (CH.sub.2).sub.4NH.sub.2, (CH.sub.2).sub.3(NH)CNH.sub.2, or CH.sub.2(imidazole). Especially preferred A groups are CH(CH.sub.3)CH.sub.2(CH.sub.3), phenyl, phenyl alkyl or CH.sub.2(2-indole).
[0582] Alternatively preferred methods use, and preferred compounds are, compounds of Formula (IVb), their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, in which:
##STR00070##
[0583] wherein:
[0584] A is hydrogen, deuterium, C.sub.1-8alkyl, heteroaryl, aryl, or alkyl substituted with heterocyclo, aryl, OH, SH, ST.sup.1, C(O).sub.tH, T.sup.3-NT.sup.5T.sup.6, -T.sup.8-C(O).sub.tT.sup.9-NT.sup.5T.sup.6 or T.sup.3-N(T.sup.2)T.sup.4NT.sup.5T.sup.6; R.sup.1 and R.sup.5 are independently C.sub.1-8alkyl optionally substituted where valence allows;
[0585] R.sup.6 and R.sup.7 are independently hydrogen or C.sub.1-8alkyl;
[0586] R.sup.8 is hydrogen, halogen, deuterium, C.sub.1-8alkyl or substituted C.sub.1-8alkyl;
[0587] Z is hydrogen, C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.1-8haloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl COR.sup.11, CO.sub.2R.sup.11, SO.sub.2R.sup.11, S(O)R.sup.11 or CONR.sup.9R.sup.10;
[0588] R.sup.9 is hydrogen,
[0589] R.sup.10 is C.sub.1-8alkyl or C.sub.3-10cycloalkyl; aryl or arylalkyl;
[0590] R.sup.11 is hydrogen, C.sub.1-8alkyl, C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl, C.sub.3-10aryl or C.sub.3-10arylalkyl.
[0591] T.sup.1 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
[0592] T.sup.2 and T.sup.3 are each independently a single bond, -T.sup.8-S(O).sub.t-T.sup.9-, -T.sup.8-C(O)-T.sup.9-, -T.sup.18-C(S)-T.sup.9-, -T.sup.8-OC(O)-T.sup.9-, -T.sup.8-C(O).sub.tT.sup.9-,)-T.sup.8-C(NT.sup.10-T.sup.9- or -T.sup.8-C(O)C(O)-T.sup.9-;
[0593] T.sup.5, T.sup.6, T.sup.7, T.sup.8 and T.sup.9 are independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alky, each group optionally substituted where valence allows by one to three groups selected from halo, cyano, nitro, OH, oxo, SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, OT.sup.11, C(O).sub.tH, C(O).sub.tT.sup.11, OC(O)T.sup.11, T.sup.8C(O).sub.tN(T.sup.12)T.sup.11, SO.sub.3H, S(O).sub.tT.sup.11, S(O).sub.tN(T.sup.12)T.sup.11, -T.sup.13-NT.sup.11T.sup.12, -T.sup.13-N(T.sup.12)-T.sup.4-NT.sup.11T.sup.22, -T.sup.13-N(T.sup.11)-T.sup.12-T.sup.11 and -T.sup.13-N(T.sup.18)-T.sup.14-H; or
[0594] T.sup.8 and T.sup.9 are each independently a single bond, alkylene, alkenylene or alkynylene;
[0595] T.sup.11 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl;
[0596] T.sup.12 is halo, cyano, nitro, OH, oxo, SH, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, C(O).sub.tH or SO.sub.3H;
[0597] T.sup.13 and T.sup.14 are each independently a single bond, S(O)S, C(O), C(S), O, S, OC(O), C(O).sub.t, C(NT.sup.13)- or C(O)C(O); and
[0598] t is 1 or 2.
[0599] More preferred methods/compounds use/are:
[0600] A is hydrogen, deuterium, methyl, CH.sub.2(CH.sub.3).sub.2, (CH.sub.2).sub.2(CH.sub.3).sub.2, CH(CH.sub.3)CH.sub.2(CH.sub.3), (CH.sub.2)OH, hydroxyethyl, (CH.sub.2).sub.2SCH.sub.3, CH.sub.2SH, phenyl, CH.sub.2(phenyl), CH.sub.2(p-hydroxyphenyl), CH.sub.2(indole), (CH.sub.2)C(O)NH.sub.2, (CH.sub.2).sub.2C(O)NH.sub.2, (CH.sub.2).sub.2C(O)OH, CH.sub.2C(O)OH, (CH.sub.2).sub.4NH.sub.2, (CH.sub.2).sub.3(NH)CNH.sub.2 or CH.sub.2(imidazole).
[0601] Especially preferred methods/compounds use/are:
[0602] A is CH(CH.sub.3)CH.sub.2(CH.sub.3), phenyl, CH.sub.2(phenyl) or CH.sub.2(2-indole).
[0603] Also, especially preferred methods/compounds use/are:
[0604] R.sup.8 is hydrogen and the configuration about the carbon marked with the * is S, provided A is not H. Also preferred: R.sup.8 is deuterium and the configuration about the carbon marked with the * is S, provided A is not H or deuterium.
[0605] Other preferred methods/compounds use/are:
[0606] R.sup.1 and R.sup.5 are both isopropyl; and/or R.sup.6R.sup.7and R.sup.9 are all hydrogen; and/or Z is CH.sub.2(phenyl), C(O).sub.2H or C(O).sub.2C.sub.1-8alkyl.
[0607] Example Embodiments of Formula (IV)
[0608] In the following scheme, Scheme X, all reactants are commercially available e.g. Compound 2 is available from Oxchem Corporation, IL, USA.
##STR00071##
[0609] Using Scheme X, above, with different amino acids as the Compound 2 input, gives different Compound 5 products (all reactants are commercially available e.g. Compound 2b is available from Aurora Fine Chemicals LLC, San Diego, USA, Compound 2c and 2d from Sigma-Aldrich).
##STR00072##
[0610] Following is Structure IV, from Scheme I, in the Process of Preparation section of [P3], symbol definitions are as in [P3]. Scheme I in [P3] is a more general form of Scheme X above.
##STR00073##
[0611] This Structure IV can be deuterated, as can final compounds of the scaffold of [P3] (scaffold presented in its abstract), at its chiral carbon, and in further embodiments at further or other position(s), by reactions described in [A, B, E1, E2, F], which can deuterate the -carbon to secondary amines. And/or by reactions described in [Ex3], which can deuterate the -carbon to a carbonyl, using pyrrolidine (available from Sigma-Aldrich) as catalyst, and/or by reactions described in [Ex4], which deuterate ketones. And/or by reactions described in [N], which deuterate sp3 carbons. And/or by reactions described in [R1, R2, Q1, Q2], which deuterate aromatic and alkyl molecular components. Deuterated Compound IV structure(s) can be inputted into the synthesis Scheme I of [P3], in place of an undeuterated Compound IV form compound(s), to make deuterated isotopologue(s) with the scaffold of [P3], its scaffold is shown in its abstract. Alternatively, to achieve this aim, a compound(s) of Structure III form in Scheme I of [P3] can be deuterated at its chiral carbon, and in further embodiments at further or other position(s), by reactions described in [A, B, P, E1, E2, F], which deuterate the -carbon to primary amines. And/or by a methodology used to deuterate amino acids, of which many are known to those of the art (non-limiting e.g. [AA1-AA6, B]), because Structure III (of [P3]) is of the amino acid form. Indeed, deuterated (and/or other isotopically enriched e.g. .sup.13C and/or .sup.15N) amino acids can be sourced commercially, e.g. (non-limiting) from Sigma-Aldrich or Cambridge Isotope Laboratories Inc., and used in Scheme I of [P3] to produce isotopically enriched compound embodiments of the present invention. For (illustrative, non-limiting) example, Cambridge Isotope Laboratories Inc. sell histidine enriched (97-99%) for .sup.13C, .sup.15N, .sup.2H at the respective positions of C, N and H in histidine (item number: CDNLM-6806-PK). Sigma-aldrich sell this also (item number: 750158 ALDRICH). Deuterated (and other isotopically enriched) compound embodiments of the scaffold of [P3] (scaffold presented in its abstract), most preferably deuterated at their chiral carbon (which in an embodiment is .sup.13C at enriched, non-natural abundance, e.g. {non-limiting}>70% .sup.13C incorporation), are componentry to the present invention as new compositions of matter. And in non-limiting embodiments, these are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics.
EXAMPLE (V)
[0612] ##STR00074##
[0613] Molecular permutations of BTB06584. Enumerations of this Markush structure, and their pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, are disclosed as anti-cancer molecules: the process/method of their use as anti-cancer molecules is disclosed by this invention. As valence permits: R1 is selected from the options of R1 (independently in each case of R1), X is selected from the options of X (independently in each case of X), R2 is selected from the options of R2 (independently in each case of R2), R3 is selected from the options of R3 (independently in each case of R3), R4 is selected from the options of R4 (independently in each case of R4). In other embodiments one or more phenyl groups has one or more of its double bonds replaced with a single bond. In other embodiments, one or more phenyl groups is replaced with cyclohexane, each with the same possible substitutions as the phenyl it replaces. Hydrogen atoms aren't shown in this figure, but in further embodiments one or more hydrogen atoms is replaced with deuterium. In further embodiments: any possible isotopic substitution at one or more places.
[0614] Example Embodiments of Formula (V)
##STR00075##
[0615] BTB06584, and/or its analogues, can be deuterated by reactions described in [R1, R.sub.2, Q1, Q2], which deuterate aromatic and alkyl molecular components. Furthermore, there is a great wealth of reactions available to deuterate their aromatic rings, and those skilled in the art will know these. For (non-limiting) example, refer [Ex2]. Deuterated isotopologues of Formula (V), for (non-limiting) example deuterated BTB06584, are componentry to the present invention as new compositions of matter, and in non-limiting embodiments are used singly or in combination, optionally in co-therapy with an FDA and/or EMA approved medicine(s) and/or treatment(s), for example a licensed cancer treatment, as anti-cancer therapeutics.
EXAMPLE (VI)
[0616] Encompassed by this embodiment are methods of treating a subject suffering from cancer by administering an effective amount of at least one compound of Formula (VI) or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising one or compounds of Formula (VI).
[0617] Summary of Formula (VI)
[0618] This invention embodiment relates to compounds having the following formula:
##STR00076##
[0619] or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein:
[0620] each Q.sup.A is independently selected from N and CH;
[0621] each Q.sup.B is independently selected from NH and CH.sub.2;
[0622] M is independently selected from O, NH and CH.sub.2;
[0623] x.sup.a is independently at each point of use selected from 1, 2, 3, 4, or 5; x.sup.b is independently at each point of use selected from 0, 1, 2, 3, 4, or 5; L represents 0-5 optional substituents on the ring independently selected from alkyl, substituted alkyl, deuterated alkyl, aminoalkyl, thioalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, or any atom or isotope permitted by valence (including any accompanying hydrogens by valence e.g. (non-limiting) OH, NH.sub.2, SH, SiH.sub.3, PH.sub.2 etc.);
[0624] R.sup.A1 and R.sup.A2 are each independently selected from the groups
##STR00077##
[0625] wherein R.sup.C and RP are each independently selected from hydrogen, deuterium, halogen and alkyl, and wherein R.sup.E is hydrogen, deuterium, or alkyl;
[0626] R.sup.B is selected from R.sup.B1, hydrogen and deuterium;
[0627] wherein R.sup.B1 is selected from phenyl, benzyl, heteroaryl, pyridyl, pyrimidyl and pyrazinyl optionally substituted with one or more substituents R.sup.B2;
[0628] wherein each R.sup.B2 is independently selected from halogen, alkyl, alkoxy, nitro, amino, methoxy and polyhalogen alkyl;
[0629] or R.sup.B is a phenylalkyl of the formula:
##STR00078##
[0630] wherein R.sup.F and R.sup.G are hydrogen or alkyl, G is a carbon-carbon double bond or a carbon-carbon single bond, n is 0 or 1 and q is 0 or 1 provided that where q is 0, G is a carbon-carbon double bond and where q is 1, G is a carbon-carbon single bond,
[0631] or R.sup.B is a diphenylalkyl of the formula
##STR00079##
[0632] wherein R.sup.H1 and R.sup.H2 each independently represent 1-5 optional substituents on each ring, and wherein each R.sup.H1 and R.sup.H2, when present, is independently selected at each point of use from hydrogen, L (defined earlier) or halogen, and p is 0, 1 or 2;
[0633] or R.sup.B is the group
##STR00080##
[0634] Wherein Q is CH or N, R.sup.J and R.sup.K each independently represent 1-5 optional substituents on each ring, and wherein each R.sup.J and each R.sup.K, when present, is independently selected from L (defined earlier), halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
[0635] In some embodiments, when one or both of R.sup.J and R.sup.K is alkoxy, this alkoxy group may be methoxy.
[0636] It is to be understood that in the compounds of general Formula (VI), wherein R.sup.A1 and/or R.sup.A2 are alkenyl moieties having different substituents at the position R.sup.C and R.sup.D, that compound may exist in cis or trans isomeric forms both of which are considered to be within the scope of the present invention. All isotopic forms of Formula (VI) are within the scope of the present invention.
[0637] Preferred Embodiments of Formula (VI)
[0638] For Formula (VI), the symbols R.sup.C and R.sup.D as defined in subgroups R.sup.A1 and R.sup.A2, may be hydrogen, halogen (suitably fluorine, chlorine or bromine), alkyl, suitably lower alkyl (herein now defined) having from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl and the like, most preferably methyl;
[0639] and the moiety R.sup.E may be hydrogen, or lower alkyl having from 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, or pentyl, most suitably methyl.
[0640] The subgroup R.sup.B may be hydrogen; phenyl; or substituted phenyl. The substituted phenyl group may include one or more of the preferred substituents in any of the available positions for substitution, however, mono substitution in the 4-position of the phenyl nucleus is especially preferred. Suitable substituents for the phenyl nucleus include halogen, preferably fluorine, chlorine or bromine; lower alkyl, lower alkoxy, and poly halogen lower alkyl (i.e. substituted alkyl) wherein the alkyl moiety contains from 1 to 5 carbon atoms, especially preferred however are methyl, methoxy, and trifluoromethyl; and nitro and amino.
[0641] Where the subgroup R.sup.B represents substituted pyridyl, substituted pyrimidyl, or substituted pyrazinyl, the substituting group may be located on one or more of the available carbon atoms in the nucleus, and may be the same or different. Preferred among the substituting groups are lower alkyl or lower alkoxy having from 1 to 5 carbon atoms such as methyl, ethyl, butyl or penty; or methoxy, propoxy, butoxy or pentoxy.
[0642] Where the moiety R.sup.B represents substituted benzyl, the benzyl moiety may be substituted in one or more of the available positions on the phenyl nucleus thereof. Among the preferred substituents are halogen (suitably fluorine, chlorine or bromine), lower alkoxy having from 1 to 5 carbon atoms, especially preferred is methoxy and most preferred being di- and tri-methoxy; or alkylenedioxy suitably lower alkylenedioxy such as methylenedioxy, ethylenedioxy, propylenedioxy and the like, most suitably, the alkylenedioxy moiety is attached across the 3- and 4-positions of the phenyl nucleus, although the bridging of other carbon atoms in the phenyl nucleus is to be considered within the scope of the present invention.
[0643] The moieties R.sup.F and R.sup.G may be hydrogen, or lower alkyl of 1 to 5 carbon atoms, most preferred however being methyl.
[0644] The groups R.sup.H1 and R.sup.H2 may be independently hydrogen, or halogen suitably fluorine, chlorine or bromine.
[0645] Preferred embodiments of Formula (VI) include wherein R.sup.C and R.sup.D are methyl, R.sup.E is methyl and R.sup.B is selected from chlorophenyl, methylphenyl, methoxyphenyl, trifluorophenyl, chlorophenyl, dimethoxybenzyl, trimethoxybenzyl, methylenedioxybenzyl and ethylenedioxybenzyl.
[0646] In some embodiments R.sup.B is the group
##STR00081##
[0647] In some embodiments, R.sup.B is the group
##STR00082##
[0648] wherein R.sup.L and R.sup.M are each independently selected from halogen, alkyl, alkoxy, nitro, amino and polyhalogen alkyl.
[0649] Synthesis of Structures of Formula (VI)
[0650] Synthesis routes for example embodiments of Formula (VI) are in [P7], which is herein incorporated in entirety by reference. One or more chemical enumerations/structures from [P7], in use as an anti-cancer therapeutic, is componentry to the present invention. Indeed, encompassed by this embodiment are methods of treating a subject suffering from cancer by administering an effective amount of at least one compound from [P7] or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising one or compounds from [P7].
[0651] Example Embodiments of Formula (VI)
[0652] Invention embodiments include compounds of Formula (VI), whether a decoupler or not, and any compound(s) of any formula, which has decoupling activity (changes F.sub.1F.sub.0 ATP synthase stoichiometry), in use for anti-cancer therapy.
[0653] Decoupler Drugs as Anti-Cancer Medicines
[0654] Enumerations of Formulas I-V exert anti-cancer activity by inhibiting, and so reducing, F.sub.1F.sub.0
[0655] ATP hydrolysis. The present embodiment also exerts anti-cancer activity by reducing F.sub.1F.sub.0ATP hydrolysis. However, not by inhibition of F.sub.1F.sub.0 ATP hydrolysis, but by making F.sub.1F.sub.0ATP hydrolysis more efficient! Such that less ATP is hydrolysed per unit proton motive force (pmf) generated i.e. F.sub.1F.sub.0 ATP hydrolysis is reduced. The shared feature of these embodiments is that cancer function is impaired, and cancer danger reduced, by reducing F.sub.1F.sub.0 ATP hydrolysis in cancer cells. The present embodiment relates to and discloses the method/use of a decoupler drug(s) as an anti-cancer therapeutic e.g. (non-limiting) almitrine, which is a compound of Formula (VI). Disclosed experimental data shows that almitrine exerts anti-cancer activity (
##STR00083##
[0656] Decoupler drugs modify the H.sup.+/ATP stoichiometry of ATP synthase, so modifying the ATP/O ratio, without significantly changing .sub.IM [113-116]. Such drugs symmetrically modify the forward and reverse modes of ATP synthase: they make the forward mode less efficient (less ATP synthesized per protons passed) and the reverse mode more efficient (more protons pumped per ATP hydrolysed). In other words, they reduce the (fractional) ATP yield/cost of a proton passing through ATP synthase energetically downhill/uphill, in relation to the direction of the proton motive force (pmf). In isolated mitochondria, the almitrine conferred decrease in F.sub.1F.sub.0 ATP synthesis and hydrolysis is maximal at 60%, no matter how great the almitrine concentration [114]. Almitrine can double the stoichiometry: double the number of protons required/pumped for/by ATP synthesis/hydrolysis. Almitrine reduces the amount of ATP that F.sub.1F.sub.0 ATP synthase synthesizes, but it also reduces the amount of ATP that F.sub.1F.sub.0 ATP synthase hydrolyses, which is normally, without almitrine, significant. Indeed, this disclosure discloses a new fundamental biological discovery, with supporting in vivo experimental data (
[0657] In normal cells, almitrine decreases ATP synthesis, but decreases ATP hydrolysis also, and so [ATP] is maintained. In cancer cells residing in hypoxia, thence forced to survive with a lower OXPHOS rate, which already rely upon high IF.sub.1 expression (many cancers overexpress IF.sub.1 [23-24]) to block ATP hydrolysis and buoy [ATP], almitrine conferred decrease in ATP synthesis strikes them disproportionally.
[0658] Comparing
[0659] In humans, 200 mg per day of oral almitrine dimesylate has been trialled for sleep apnea, which is a drive to snoring [119]. In humans, oral almitrine dimesylate has been used for decades, totalling millions of patient months of almitrine administration, for chronic obstructive pulmonary disease (COPD), often at 200 mg oral almitrine dimesylate per day [120, 121]. A single 200 mg oral almitrine dimesylate dose (70% orally bioavailable) renders a mean cmax plasma concentration of 286 ng/m1=0.6 M [121]. Because almitrine volume of distribution (VD)=17 1/kg [121], and human volume=1 1/kg [122], corresponding almitrine tissue concentration (assuming uniform)=(0.6*17)=10 M, which is an almitrine concentration that exerts anti-cancer activity in NCI testing (
[0660] recorded mean cmax plasma concentration, post a single 150 mg oral almitrine dimesylate dose, to be 379 ng/ml, and an even higher volume of distribution for almitrine. In clinical use for COPD, a plasma concentration of 300 ng/ml almitrine is the directive [120], which corresponds to an anti-cancer tissue concentration (10 M) of almitrine. Non-limiting anti-cancer embodiments of this invention are almitrine dosages/formulations/compositions/salts/patterns of administration (e.g. sequential administration scheme) already used in humans (for example, as reported in the literature). Furthermore, higher or lower almitrine doses for anti-cancer therapy, optionally administered intravenously and/or with layoff periods (no drug administered), are further embodiments of this invention. An invention embodiment is a method of trialling almitrine as an anti-cancer drug in human cancer patients without first performing Phase I trials with almitrine or first trialling almitrine in healthy human subjects.
[0661] Almitrine acts upon BK potassium channels in chemoreceptors, within the caratoid bodies, and acts as a respiratory stimulant, which increases blood and tissue oxygenation, decreasing their [CO.sub.2] [125, 126]. This respiratory stimulation should exert an additional anti-cancer effect in vivo because increasing [O.sub.2] in blood and tissues increases their [ROS], especially in combination with ROS inducing [chemo/radio] therapies (permitting their use at lower doses, reducing their side effects). This synergises with the almitrine conferred reduction in F.sub.1F.sub.0ATP hydrolysis in cancer cells, which corrupts the system cancers use to maintain low intracellular [ROS] at key stage(s) of the cell cycle, which is paramount to their limitless replicative potential (Hallmark of cancer [26]) and thence danger. Almitrine will be especially valuable against cancers (e.g. lung, breast) that can disrupt breathing and/or reduce O.sub.2 delivery to tissues. Embodiments of this invention are to use almitrine, or any other drug(s) that modifies ATP synthase stoichiometry (a decoupler), as an anti-cancer medicine, optionally in co-therapy with one or more FDA and/or EMA approved drug(s), e.g. a cancer drug(s), and/or in co-therapy with any other compound(s) embodiments of the present invention e.g. a compound(s) of Formula (I-V) herein. Almitrine dimesylate is also known as almitrine bismesylate or almitrine dimethanesulfonate. All pharmaceutical salts of almitrine are contemplated as anti-cancer therapeutics, as is almitrine in complex with another drug(s) e.g. almitrine-raubasine.
[0662] When used chronically, almitrine can have side effects [120]. A 30 year national pharmacovigilance survey in France, representing several million patient months of almitrine treatment [124], showed that upon multi-year use (mean onset of adverse reactions=11 months), some patients receiving oral almitrine exhibited weight loss (795 cases) and peripheral neuropathy (2,304 cases) [120]. Although these side effects didn't present in all patients and only in a minority of cases that they did present were they categorised as serious (<10%) [120]. Almitrine has never been FDA approved. Almitrine has now been withdrawn from use in France, Portugal and Poland, where it was previously approved to treat chronic obstructive pulmonary disease (COPD). This withdrawal was because of the aforementioned two side effects and because alternative treatments emerged and because available efficacy data, including data which became available since the initial marketing authorisation, showed only very limited clinical efficacy of almitrine in its approved indications [120]. Although almitrine does increase arterial p02, this does not translate to significant clinical benefit for COPD sufferers [120].
[0663] Almitrine's anti-cancer activity was unknown prior to this disclosure, despite almitrine being around since the early 1970 s. Its anti-cancer activity is unexpected to a person of the art.
[0664] Especially because another respiratory stimulant, doxapram, has been publically shown by others to have no anti-cancer activity in the same one-dose (10 M) NCI-60 test in which, disclosed herein, almitrine dimesylate (10 M) exerts anti-cancer activity. Doxapram in NCI-60 (10 M) testing: mean % cancer growth inhibition=3.7% (median=2.3%) i.e. negative numbers show cancer growth promotion (!) rather inhibition, as compared to no drug control, NSC: 760347 in [16]. Thence, the discovery of almitrine conferred anticancer activity, disclosed herein, is unforeseen by a person of the art, novel and componentry to the invention of this disclosure. The risk-reward axis for almitrine is sufficient for an anti-cancer drug. Especially when used acutely, because most of almitrine's side-effects only occur with chronic use. Acute almitrine use for cancer treatment has a different risk-reward axis than chronic almitrine use for COPD treatment (for which it is ineffective [120]), especially because almitrine's side-effects are mostly associated with chronic use, and because cancer can be an immediately life-threatening disease for too many patients, with too few life-saving options. Indeed, the merit of anti-cancer treatment merits the risk of higher almitrine dosages than 200 mg per day.
[0665] Intravenous delivery of 459155 mg almitrine, infused within 24 hours, caused reversible lactic acidosis and hepatic dysfunction in 30% of 25 patients [127]. The other 70% of patients had no ill effects, and unaltered plasma [lactate]. The side-affected minority correlated with an impaired liver function parameter, increased plasma [bilirubin], prior to almitrine administration. Thus, this side-affected cohort is largely predictable. Most side-affected were women, but not all women were affected (N.B. women can have a smaller liver relative to body size e.g. refer [128]). The liver converts lactate to glucose by the Cori cycle [1] and an impaired/overwhelmed liver cannot process the elevated plasma lactate that almitrine administration can cause [115], which renders lactate acidosis. An embodiment of this invention is to select a cancer patient's almitrine dosage dependent upon their liver function. That is, in a further (non-limiting) embodiment, assessed by measuring plasma [bilirubin]. For non-limiting example: if (plasma [bilirubin]>17 M) {the patient should not be administered high almitrine dosage(s)}. Patients with better liver function are at less risk of almitrine driven lactic acidosis [127] and can endure higher almitrine dosages. Another embodiment is to record plasma [lactate], and/or a liver function assay chemical(s) (non-limiting e.g. bilirubin), whilst a cancer patient is administered with almitrine, or a course of almitrine administrations, and to lower the administered almitrine dosage/frequency if these plasma concentrations become abnormal. An invention embodiment is to use almitrine, and a drug(s)/treatment(s) treating/mitigating lactic acidosis, in anti-cancer therapy. Another embodiment is almitrine for anti-cancer therapy, given with a dosage adjustment dependent upon initial body weight, before treatment, and optionally reducing the dosage if significant weight loss occurs. Almitrine in co-therapy with a high(er) calorie diet, as an anti-cancer treatment, is another embodiment. Almitrine in co-therapy with a drug to treat or mitigate peripheral neuropathy (e.g. {non-limiting} gabapentin, duloxetine, pregabalin etc.), as an anti-cancer treatment, is an embodiment of this invention. An embodiment is to use almitrine for anti-cancer therapy and to monitor the almitrine recipient, or for the almitrine recipient to self-monitor, for weight loss and/or signs of neuropathy, and/or odd neurological sensations, especially in the body periphery e.g. the limbs. An embodiment is to use almitrine for anti-cancer therapy under medical supervision. Wherein, in animal or human, almitrine dosage, frequency, route and duration of administration is directed/recommended, and/or almitrine is administered, by a medically qualified professional(s) e.g. a doctor or vet or nurse or pharmacist. In an embodiment, an oncologist or other cancer specialist or a medically qualified professional that has undergone additional training and/or qualification and/or residency in oncology beyond a degree in human and/or veterinary medicine. And optionally wherein one or more of the dosage, frequency, route and duration of almitrine administration is modulated in the light of cancer progression/regression/stasis during the course of almitrine administration.
[0666] Mechanistic studies in animals [129-130] have identified that it might not be almitrine itself that causes almitrine associated neuropathy but instead difluorobenzhydrylpiperadine (DFBP), which is the major almitrine metabolite formed in humans. DFBP also causes weight loss in [129] and so DFBP could also be the basis to almitrine associated weight loss (reported in [120]), or this could just be a function of altered feeding behaviour as a function of the DFBP generated neuropathy. To render DFBP from almitrine, the bond between almitrine's nitrogen, at atom number 11, and carbon, at atom number 9, must be broken. An embodiment of this invention is almitrine isotopically enriched (greater than natural abundance, e.g. {non-limiting}>70%) for .sup.15N at Atom Number 11, and/or isotopically enriched for .sup.13C at Atom Number 9, which will make this bond stronger by the kinetic isotope effect (KIE), which will reduce the rate of DFBP formation, and reduce neuropathy (Atom Numbers as labelled by [25]). Kinetic isotope effect (KIE) is the change in the rate of a chemical reaction when one (or more) of the atoms in the reactants is replaced with its isotope. Heavier isotopes form stronger bonds that require higher energy to break them, which ultimately slows down the chemical reaction rate. Other atom(s) of almitrine enriched (greater than natural abundance, e.g. {non-limiting}>70%) with their heavier, stable respective isotope(s) (e.g. {non-limiting} .sup.2H replacements of .sup.1H) is also componentry to the present invention. As is one or more hydrogen atom(s) upon almitrine, or an aforementioned almitrine isotopologue, replaced by fluorine (or other halogen), especially near the N11-C9 bond that breaks to release DFBP, preferably upon the piperazine ring. The use of one or more of the new compositions of matter of this disclosure, to treat a condition for which almitrine has been used in humans, for (non-limiting) example, chronic obstructive pulmonary disease (COPD), is componentry to this invention. As is their use as an anti-cancer treatment.
[0667] Following reactions are illustrative, not restrictive: almitrine could be deuterated, upon its piperazine ring and/or other loci, by reactions described in [N], which deuterate sp3 carbons.
[0668] And/or by reactions described in [R1, R.sub.2, Q1, Q2] which deuterate widely, upon aromatic and alkyl molecular components. And/or by reactions described in [O1, O2], which deuterate a- and I3-carbons to phenyl groups. And/or by reactions described in [D], which deuterate - and -carbons to tertiary amines. And/or by reactions described in [F, E1, E2, Ex1], which deuterate -carbons to tertiary amines. And/or by reactions described in [A, B, E1, E2, F], which deuterate -carbons to secondary amines. Whichever option(s) is chosen, solvents, temperatures, pressures, and other reaction conditions can be selected by one of ordinary skill in the art. Deuteration can be modulated by modulating reaction time: greater deuterium incorporation by longer reaction time. One can do multiple cycles of one or more of these reactions until the desired level of deuterium incorporation occurs, monitored by .sup.1H and/or .sup.2H NMR and/or mass spectrometry.
[0669] Encompassed by this invention are methods of administering an effective amount of almitrine (and/or one or more of its metabolites), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising almitrine (and/or one or more of its metabolites), optionally in co-therapy with another anti-cancer treatment(s), to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of GAL021 [125-126] and/or any compound(s) of [P8], or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising GAL021 [125-126] and/or any compound(s) of [P8], optionally in co-therapy with another anti-cancer treatment(s), to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of a (e.g. chemoreceptor) respiratory stimulant(s), or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising a respiratory stimulant(s), optionally in co-therapy with another anti-cancer treatment(s), to treat/ameliorate/prevent/combat cancer in a subject. Encompassed by this invention are methods of administering an effective amount of a compound(s) that increases pO2 in the subject's blood, or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, or a pharmaceutical composition(s) comprising a compound(s) that increases pO2 in the subject's blood, optionally in co-therapy with another anti-cancer treatment(s), to treat/ameliorate/prevent/combat cancer in the subject.
[0670] A method of treating, ameliorating, preventing or combating cancer in a subject wherein the method comprises the subject taking, or being administered, a therapeutically effective amount of almitrine and/or other compound(s) of Formula VI (and/or a pharmaceutical composition(s) containing a therapeutically effective amount of almitrine and/or other compound(s) of Formula VI herein). Almitrine and/or other compound(s) of Formula VI, (and/or a pharmaceutical composition(s) containing almitrine and/or other compound(s) of Formula VI) for use in the treatment/amelioration/prevention/combat of cancer in a subject. The use of almitrine, and/or other compound(s) of Formula VI, in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of cancer, optionally in a ready-to-use drug form, optionally in a package together with instructions for its anti-cancer use. Almitrine, and/or other compound(s) of Formula VI, for use in a method for the treatment/amelioration/prevention/combat of cancer and/or ischemia and/or stroke (reduces ATP hydrolysis and maintains intracellular [ATP] when O.sub.2 and glucose is in short supply because of a vascular occlusion or similar) in a subject.
[0671] Definitions Used to Specify Formulas (I), (II), (III), (IV), (V) and (VI)
[0672] The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
[0673] The term alkyl refers to straight or branched chain hydrocarbon groups having 1 to 21 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred.
[0674] The term substituted alkyl refers to an alkyl group as defined above having one, two, three, or four substituents selected from the group consisting of halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (O), OR.sub.a, SR.sub.a, NR.sub.aR.sub.b, NR.sub.aSO.sub.2, NR.sub.aSO.sub.2R.sub.e, SO.sub.2R.sub.e, SO.sub.2NR.sub.1R.sub.b, CO.sub.2R.sub.a, C(O)R.sub.a, C(O)NR.sub.aR.sub.b, OC(O)R.sub.a, OC(O)NR.sub.aR.sub.b, NR.sub.aC(O)R.sub.b, NR.sub.aCO.sub.2R.sub.b, NOH,NO-alkyl, aryl, heteroaryl, heterocyclo and cycloalkyl, wherein R.sub.a and R.sub.b are selected from hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R.sub.e is selected from hydrogen, alkyl, cycloalkyl, heterocyclo aryl and heteroaryl. When a substituted alkyl includes an aryl, heterocyclo, heteroaryl, or cycloalkyl substituent, said ringed systems are as defined below and thus may in turn have zero to four substituents (preferably 0-2 substituents), also as defined below. When either R.sub.a, R.sub.b or R.sub.e is an alkyl, said alkyl may optionally be substituted with 1-2 of halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (O), OH, O(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH.sub.2, NH(alkyl), N(alkyl).sub.2, NHSO.sub.2, NHSO.sub.2(alkyl), SO.sub.2(alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(O)H, C(O)alkyl, C(O)NH.sub.2, C(O)NH(alkyl), C(O)N(alkyl).sub.2, OC(O)alkyl, OC(O)NH.sub.2, OC(O)NH(alkyl), NHC(O)alkyl, and/or NHCO.sub.2(alkyl).
[0675] Alkyl when used in conjunction with another group such as in arylalkyl refers to a substituted alkyl in which at least one of the substituents is the specifically named group. For example, the term arylalkyl includes benzyl, or any other straight or branched chain alkyl having at least one aryl group attached at any point of the alkyl chain. As a further example, the term carbamylalkyl includes the group (CH.sub.2).sub.nNHC(O)alkyl, Wherein n is 1 to 12.
[0676] The term alkenyl refers to straight or branched chain hydrocarbon groups having 2 to 21 carbon atoms and at least one double bond. Alkenyl groups of 2 to 6 carbon atoms and having one double bond are most preferred.
[0677] The term alkynyl refers to straight or branched chain hydrocarbon groups having 2 to 21 carbon atoms and at least one triple bond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bond are most preferred.
[0678] The term alkylene refers to bivalent straight or branched chain hydrocarbon groups having 1 to 21 carbon atoms, preferably 1 to 8 carbon atoms, e.g., {CH.sub.2}.sub.n, Wherein n is 1 to 12, preferably 1-8. Lower alkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, are most preferred. The terms alkenylene and alkynylene refer to bivalent radicals of alkenyl and alknyl groups, respectively, as defined above.
[0679] When reference is made to a substituted alkylene, alkenylene, or alkynylene group, these groups are substituted with one to four substituents as defined above for alkyl groups. A substituted alkylene, alkenylene, or alkynylene may have a ringed substituent attached in a spiro fashion as in
##STR00084##
[0680] and so forth.
[0681] The term alkoxy refers to an alkyl or substituted alkyl group as defined above having one, two or three oxygen atoms (O) in the alkyl chain. For example, the term alkoxy includes the groups OC.sub.1-12alkyl, C.sub.1-6alkylene-OC.sub.1-6alkyl, C.sub.1-4alkylene-O-phenyl, and so forth.
[0682] The term thioalkyl or alkylthio refers to an alkyl or substituted alkyl group as defined above having one or more sulphur (S) atoms in the alkyl chain. For example, the term thioalkyl or alkylthio includes the groups (CH.sub.2).sub.nSCH.sub.2aryl, (CH.sub.2).sub.nS-aryl, etc. etc.
[0683] The term aminoalkyl or alkylamino refers to an alkyl or substituted alkyl group as defined above having one or more nitrogen (NR) atoms in the alkyl chain. For example, the term aminoalkyl includes the groups NRC.sub.1-12alkyl and CH.sub.2NR-aryl, etc.
[0684] (where R is hydrogen, alkyl or substituted alkyl as defined above.) Amino refers to the group NH.sub.2.
[0685] When a subscript is used as in C.sub.1-8alkyl, the subscript refers to the number of carbon atoms the group may contain. Zero when used in a subscript denotes a bond, e.g., C.sub.0-4 alkyl refers to a bond or an alkyl of 1 to 4 carbon atoms. When used with alkoxy, thioalkyl or aminoalkyl, a subscript refers to the number of carbon atoms that the group may contain in addition to heteroatoms. Thus, for example, monovalent. C.sub.1-2aminoalkyl includes the groups CH.sub.2NH.sub.2, NHCH.sub.3, (CH.sub.2).sub.2NH.sub.2, NHCH.sub.2CH.sub.3, CH.sub.2NH.sub.2CH.sub.3, and N(CH.sub.3).sub.2. A lower aminoalkyl comprises an aminoalkyl having one to four carbon atoms.
[0686] The alkoxy, thioalkyl, or aminoalkyl groups may be monovalent or bivalent. By monovalent it is meant that the group has a valency (i.e., power to combine with another group), of one, and by bivalent it is meant that the group has a valency of two. For example, a monovalent alkoxy includes groups such as OC.sub.1-12alkyl, C.sub.1-6alkylene-OC.sub.1-6alkyl, etc., whereas a bivalent alkoxy includes groups such as OC.sub.1-2alkylene-, C.sub.1-6alkylene-OC.sub.1-6alkylene- , etc.
[0687] The term acyl refers to a carbonyl
##STR00085##
[0688] linked to an organic group i.e.
##STR00086##
[0689] wherein R.sub.d may be selected from alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, heterocyclo, cycloalkyl, or heteroaryl, as defined herein.
[0690] The term alkoxycarbonyl refers to a group having a carboxy or ester group
##STR00087##
[0691] linked to an organic radical, i.e.,
##STR00088##
[0692] Wherein R.sub.d is as defined above for acyl.
[0693] The term carbamyl refers to a functional group in which a nitrogen atom is directly bonded to a carbonyl, i.e., as in NR.sub.eC(O)R.sup.f or C(O)NR.sub.eR.sub.f, wherein R.sub.e and R.sub.f can be hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, cycloalkyl, aryl, heterocyclo, or heteroaryl, or they may join to form a ring.
[0694] The term sulfonyl refers to a sulphoxide group (i.e., S(O).sub.1-2) linked to an organic radical R.sub.e, as defined above.
[0695] The term sulfonamide or sulfonamido refers to the group S(O).sub.2NR.sub.eR.sub.f, wherein R.sub.e and R.sub.f are as defined above. Preferably when one of Re and R.sub.f is optionally substituted heteroaryl or heterocycle (as defined below), the other of R.sub.e and R.sub.f is hydrogen or alkyl.
[0696] The term cycloalkyl refers to fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. The term cycloalkyl includes such rings having zero to four substituents (preferably 0-2 substituents), selected from the group consisting of halogen, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, keto, OR.sub.d, SR.sub.d NR.sub.dR.sub.e NReSO.sub.2, NR.sub.eSO.sub.2R.sub.e, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, OC(O)R.sub.d, NOH, NO-alkyl, aryl, heteroaryl, heterocyclo, a 4 to 7 membered carbocyclic ring, and a five or six membered ketal, e.g., 1,3-dioxolane or 1,3-dioxane, wherein R.sub.e, Rd and Re are defined as above. The term cycloalkyl also includes such rings having a phenyl ring fused thereto or having a carbon-carbon bridge of 3 to 4 carbon atoms. Additionally, when a cycloalkyl is substituted with a further ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl, cycloalkylalkyl, or a further cycloalkyl ring, such ring in turn may be substituted with one to two of C.sub.0-4alkyl optionally substituted with halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (O), OH, O(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH.sub.2, NH(alkyl), N(alkyl).sub.2, NHSO.sub.2, NHSO.sub.2(alkyl), SO.sub.2(alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(O)H, C(O)alkyl, C(O)NH.sub.2, C(O)NH(alkyl), C(O)N(alkyl).sub.2, OC(O)alkyl, OC(O)NH.sub.2, OC(O)NH(alkyl), NHC(O)alkyl, and NHCO.sub.2(alkyl).
[0697] The term halo or halogen refers to chloro, bromo, fluoro and iodo.
[0698] The term haloalkyl means a substituted alkyl having one or more halo substituents. For example, haloalkyl includes mono, bi, and trifluoromethyl.
[0699] The term haloalkoxy means an alkoxy group having one or more halo substituents. For example, haloalkoxy includes OCF.sub.3.
[0700] The term aryl refers to phenyl, biphenyl, l-naphthyl, 2-naphthyl, and anthracenyl, with phenyl being preferred. The term aryl includes such rings having zero to four substituents (preferably 0-2 substituents), selected from the group consisting of halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, OR.sub.d, SR.sub.d, NR.sub.dR.sub.e, NR.sub.dSO.sub.2, NR.sub.dSO.sub.2R.sub.e, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, OC(O)R.sub.d, heteroaryl, heterocyclo, cycloalkyl, phenyl, benzyl, napthyl, including phenylethyl, phenyloxy, and phenylthio, wherein R.sub.e, R.sub.d and R.sub.e are defined as above. Additionally, two substituents attached to an aryl, particularly a phenyl group, may join to form a further ring such as a fused or spiro-ring, e.g., cyclopentyl or cyclohexyl or fused heterocycle or heteroaryl. When an aryl is substituted with a further ring, such ring in turn may be substituted with one to two of C.sub.0-4alkyl optionally substituted with halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (O), OH, O(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH.sub.2, NH(alkyl), N(alkyl).sub.2, NHSO.sub.2, NHSO.sub.2(alkyl), SO.sub.2(alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(O)H, C(O)alkyl, C(O)NH.sub.2, C(O)NH(alkyl), C(O)N(alkyl).sub.2, OC(O)alkyl, OC(O)NH.sub.2, OC(O)NH(alkyl), NHC(O)alkyl, and NHCO.sub.2(alkyl).
[0701] The term heterocyclo refers to substituted and unsubstituted non-aromatic 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15 membered tricyclic groups, in which at least one of the rings has at least one heteroatom selected from O, S and N. Each ring of the heterocyclo group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The fused rings completing bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may contain zero to four substituents (preferably 0-2 substituents), selected from the group consisting of halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, keto, OR.sub.d, SR.sub.d, NR.sub.dR.sub.e, NRdSO.sub.2, NRdSO.sub.2R.sub.c, SO.sub.2R.sub.d, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, OC(O)R.sub.d, NOH, NO-alkyl, aryl, heteroaryl, cycloalkyl, a five or six membered ketal, e.g., 1,3-dioxolane or 1,3-dioxane, or a monocyclic 4 to 7 membered non aromatic ring having one to four heteroatoms, wherein R.sub.e, R.sub.d and R.sub.e are defined as above. The term heterocyclo also includes such rings having a phenyl ring fused thereto or having a carbon-carbon bridge of 3 to 4 carbon atoms. Additionally, when a heterocyclo is substituted with a further ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or a further heterocyclo ring, such ring in turn may be substituted with one to two of C.sub.0-4alkyl optionally substituted with halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (O), OH, O(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH.sub.2, NH(alkyl), N(alkyl).sub.2, NHSO.sub.2, NHSO.sub.2(alkyl), SO.sub.2(alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(O)H, C(O)alkyl, C(O)NH.sub.2, C(O)NH(alkyl), C(O)N(alkyl).sub.2, OC(O)alkyl, OC(O)NH.sub.2, OC(O)NH (alkyl), NHC(O)alkyl, and NHCO.sub.2(alkyl).
[0702] Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl.
[0703] The term heteroaryl refers to substituted and unsubstituted aromatic 5 to 7 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom selected from O, S and N in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may contain zero to four substituents (preferably 0-2 substituents), selected from the group consisting of halo, alkyl, substituted alkyl (e.g., trifluoromethyl), alkenyl, substituted alkenyl, alkynyl, nitro, cyano, OR.sub.d, SR.sub.d, NR.sub.dR.sub.e, NR.sub.dSO.sub.2, NR.sub.dSO.sub.2R.sub.c, SO.sub.2R.sub.d, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, OC(O)R.sub.d, heterocyclo, cycloalkyl, aryl, or a monocyclic 4 to 7 membered aromatic ring having one to four heteroatoms, including phenylethyl, phenyloxy, and phenylthio, wherein R.sub.e, R.sub.d and R.sub.e are defined as above. Additionally, when a heteroaryl is substituted with a further ring, i.e., aryl, arylalkyl, heterocyclo, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, or a further heteroaryl ring, such ring in turn may be substituted with one to two of C.sub.0-4 alkyl optionally substituted with halogen, trifluoromethyl, alkenyl, alkynyl, nitro, cyano, keto (O), OH, O(alkyl), phenyloxy, benzyloxy, SH, S(alkyl), NH.sub.2, NH(alkyl), N(alkyl).sub.2, NHSO.sub.2, NHSO.sub.2(alkyl)., SO.sub.2(alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(alkyl), CO.sub.2H, CO.sub.2(alkyl), C(O)H, C(O)alkyl, C(O)NH.sub.2, C(O)NH(alkyl), C(O)N(alkyl).sub.2, OC(O)alkyl, OC(O)NH.sub.2, OC(O)NH(alkyl), NHC(O)alkyl, and NHCO.sub.2(alkyl).
[0704] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl
##STR00089##
[0705] thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
[0706] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
[0707] Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
[0708] When the term unsaturated is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.
[0709] The phrase optionally substituted is intended to include substituted or unsubstituted possibilities. Accordingly, the phrase each group of which may be optionally substituted means that each group includes both substituted and unsubstituted groups.
[0710] The use of the phrase Where valence allows means that the groups may be substituted only to the degree and nature allowed by valency of the group. This is commonly understood by those of skill in the art. For example, a hydrogen substituent cannot be further substituted nor can a phenyl group be directly substituted by an oxo group due to limits on valency.
[0711] The term substituted amino refers to a group of the formula NZ.sup.2Z.sup.3 wherein Z.sup.2 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl and Z.sup.3 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, (cycloalkyl)alkyl or hydroxyalkyl further substituted with a carboxylic ester or carboxylic acid, with the proviso that when Z.sup.2 is hydrogen, then Z.sup.3 is other than hydrogen; or Z.sup.2 and Z.sup.3 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl; or 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
[0712] The term heterocyclo or hetero also includes such monocyclic and bicyclic rings wherein an available carbon atom is substituted with a (C.sub.1-C.sub.4)-alkyl, aryl, (C.sub.1-C.sub.4)-alkylthio, (C.sub.1-C.sub.4)-alkoxy, halo, nitro, keto, cyano, hydroxy, azo, thiazo, amino, NH(C.sub.1-C.sub.4)-alkyl, N((C.sub.1-C.sub.4)-alkyl).sub.2, CF.sub.3, (aminoester)alkyl, carboxylic acid, carboxylic ester, OCHF.sub.2 or (C.sub.1-C.sub.4)-alkoxy further substituted with a carboxylic acid or such monocyclic and bicyclic rings wherein two or three available carbons have substituents selected from methyl, methoxy, methylthio, halo, CF.sub.3, nitro, hydroxy, amino and OCHF.sub.2.
[0713] Stereoisomers
[0714] All stereoisomers of Formula [X], such as those, for example, which may exist due to asymmetric carbons, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated and within the scope of this invention. Individual stereoisomers of the compounds of this invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
[0715] For the molecules presented in this invention's Description and Drawings: the present invention contemplates all polymorphs, metabolites, isotopologues, geometric/conformational isomers, rotamers, atropisomers, stereoisomers, optically active forms, tautomers, keto-enol tautomers, cis- and trans- isomers, E and Z isomers, R- and 5-enantiomers, diastereomers, isomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, other mixtures thereof and isotopic variants (e.g. deuterium in place of hydrogen in some or all places upon the molecule {s}) as falling within the scope of the invention. All such isomers, as well as mixtures thereof, are intended to be included in this invention. As well as analogues and pharmaceutically/physiologically acceptable salts/ethers/esters/solvates/hydrates/chelates/complexes/metal complexes/mixtures/prodrugs/particles/radionuclides/derivatives/carriers/crystalline forms/liposomes thereof. Unless indicated otherwise, chemical structures and graphical representations of compounds herein encompass all stereoisomers. Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration wherein the terms Z and E are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the E and Z isomers. The present invention is not limited to any particular mechanism, nor to any understanding of the action of the agents being administered.
[0716] The invention also embraces isotopically labelled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
[0717] Salts, Solvates, Prodrugs
[0718] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.
[0719] The compounds of Formula [X] form salts which are also within the scope of this invention. Reference to a compound of the Formula [X] herein is understood to include reference to salts thereof, unless otherwise indicated.
[0720] As used herein, the term pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of ordinary skill in the art, salts of the compounds of the present invention may be derived from inorganic or organic acids and bases. For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable). However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation, isolation or purification of a pharmaceutically acceptable compound.
[0721] The term salt(s), as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of Formula [X] contains both a basic moiety, such as, but not limited to an amine or a pyridine or imidazole ring, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (inner salts) may be formed and are included within the term salt(s) as used herein.
[0722] Salts of the compounds of the Formula [X] may be formed, for example, by reacting a compound of the Formula [X] with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
[0723] The compounds of Formula [X] which contain a basic moiety, such as, but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihalo acetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methane-sulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
[0724] The compounds of Formula [X] which contain an acidic moiety, such as, but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines [formed with N,N-bis(dehydro-abietyl)ethylenediamine], N-methyl D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e. g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
[0725] Compounds of the Formula [X], and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
[0726] In addition, compounds of the Formulas [X] may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of Formula [X]) is a prodrug within the scope and spirit of the invention.
[0727] For example, pro-drug compounds of the Formulas [X] may be carboxylate ester moieties. A carboxylate ester may be conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure(s).
[0728] Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
[0729] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et. al. (Academic Press, 1985);
[0730] b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, Design and Application of Prodrugs, by H. Bundgaard, p. 113-191 (1991);
[0731] c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992);
[0732] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and
[0733] e) N. Kakeya, et. al., Chem. Phar. Bull., Vol. 32, p. 692 (1984).
[0734] It should further be understood that solvates (e.g., hydrates) of the compounds of Formula [X] are also within the scope of the present invention. Methods of solvation are generally known in the art.
[0735] Chelates, metal complexes, mixtures, radio-nuclides and liposomes of Formula [X] are within the scope of this invention.
[0736] Dosage
[0737] As used herein, the term effective amount refers to the amount of a compound sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
[0738] The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art. The specific dose level and frequency of dosage for any particular subject may vary and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
[0739] An exemplary effective amount of compounds of Formula [X] may be within the dosage range of about 0.001 to about 300 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses. But more exactly it depends upon the compound used, the condition and its advancement/severity, the route of administration, type of dosing (e.g. pulse or consistent etc.), what other treatments are undertaken alongside or previously (e.g. chemotherapeutics, surgery, radiotherapy etc.), the age, sex, condition, previous/other diseases of the patient, pharmacokinetics of compound in that patient, response to treatment and exceptions to this dosage range may be contemplated by the present invention, and they might be changed during treatment to find the optimum. Optimal dosages to be administered to a subject may be determined by those skilled in the art. When the compounds described herein are co-administered with another agent, the effective amount may be less than when the agent is used alone.
[0740] Pharmaceutical Composition
[0741] As used herein, the term pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo. Disclosed is a pharmaceutical composition of a therapeutically effective amount of a compound(s) of Formula [X] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, additives and/or diluents.
[0742] As used herein, the term pharmaceutically acceptable carrier refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].
[0743] Administration
[0744] The compounds of Formula [X] may be administered by any means suitable for the condition to be treated. For example: oral, parenteral, enteral, infusion, injection, sub-lingual, topical, rectal, transdermal, intramuscular and inhalation. The compound may be delivered orally, such as in the form of tablets, capsules, granules, microgranules, pellets, soft-gels, powders, or liquid formulations including syrups, liquids, solutions, elixirs, suspensions, emulsions or magmas; sublingually; bucally; transdermally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
[0745] Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystal line cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavouring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934). Lubricants, glidants, flavours, colouring agents and stabilizers may also be added for ease of fabrication and use.
[0746] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
[0747] Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
[0748] Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
[0749] Co-Administration
[0750] As used herein, the term co-administration refers to the administration of at least two agent(s) (e.g., a compound of the present invention) or therapies to a subject. In some embodiments, the co-administration of two or more agents/therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy. Those of skill in the art understand that the formulations and/or routes of administration of the various agents/therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents/therapies are co-administered, the respective agents/therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents/therapies lowers the requisite dosage of a known potentially harmful (e.g., toxic) agent(s).
PATENTS, OR PATENT APPLICATIONS, CITED
[0751] [P1] Atwal K S, Grover G J, Ding C Z, Stein P D, Lloyd J, Ahmad S, Hamann L G, Green D, Ferrara F N, inventors; Bristol-Myers Squibb Co., assignee. (1-phenyl-2-heteoaryl) ethyl-guanidine compounds as inhibitors of mitochondrial FIFO ATP hydrolase. U.S. Pat. No. 6,916,813. 2005 Jul. 12.
[0752] [P2] Ding C, Hamann L, Stein P, Pudzianowski A, inventors; Ding Charles Z., Hamann Lawrence G., Stein Philip D., Pudzianowski Andrew T., assignee. Benzodiazepine inhibitors of mitochondial FIFO ATP hydrolase and methods of inhibiting FIFO ATP hydrolase. U.S. patent application Ser. No. 10/461,736. 2003 Jun. 13.
[0753] [P3] Hamann L G, Pudzianowski A T, inventors; Bristol-Myers Squibb Company, assignee. N-substituted phenylurea inhibitors of mitochondrial FIFO ATP hydrolase. U.S. Pat. No. 6,846,836. 2005 Jan. 25.
[0754] [P4] Glick G D, inventor; University of Michigan, assignee. Methods and compositions for treating diseases and conditions associated with mitochondrial function. U.S. patent application Ser. No. 11/726,219. 2009 Nov. 5.
[0755] [P5] Glick G, inventor; University of Michigan, assignee. Methods and compositions for treating diseases and conditions associated with mitochondrial function. U.S. patent application Ser. No. 11/110,228. 2005 Dec. 8.
[0756] [P6] Ding C Z, Atwal K S, inventors; Bristol-Myers Squibb Company, assignee. Sulfonamido substituted benzopyran derivatives. U S Pat. No. 5,869,478. 1999 Feb. 9.
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[0758] [P8] Dax S L, Woodward R, Peng S, inventors; Galleon Pharmaceuticals Inc, assignee. Compounds as respiratory stimulants for treatment of breathing control disorders or diseases. U.S. Pat. No. 9,351,972. 2016 May 31.
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