Therapeutic Inhibitors of the Reverse Mode of ATP Synthase
20200247758 ยท 2020-08-06
Inventors
Cpc classification
C07D233/56
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
C07D233/61
CHEMISTRY; METALLURGY
C07D403/06
CHEMISTRY; METALLURGY
International classification
Abstract
Compounds of the following formula, and pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, formula (A) are useful to preferentially inhibit the ATP-hydrolysing mode of ATP synthase, and are thereby useful for treating various diseases and orders including cancer, particularly cancers that utilise the Warburg effect.
##STR00001##
Claims
1. A compound having the formula, ##STR00052## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: deuterium (D) enrichment at the chiral centre, and optionally at other locations, exceeds 40% deuterium incorporation; wherein there is an enantiomeric excess (ee) of the S stereoisomer, preferably that exceeds 70%; R.sub.1 is 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 one or more groups selected from 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-hetaroaryl, 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.1-4alkylene-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, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R.sub.3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl; Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl, provided that when R.sub.1 is cyano, Z is not 2-pyridinyl; or Z is selected from 5-membered heteroaryl groups containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; 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, 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 heterocylo 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 C(O)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 substitutes selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto; c) pheyl 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 heterocyle 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.14alkoxy, 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.21 wherein 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.
2. A compound according to claim 1, wherein z is ##STR00053## 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) -A.sub.2-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.7c are independently selected from hydrogen, alkyl, carbamyl, or carbamylalkyl, or R.sub.7a and R.sub.7c join to form an aryl or heteoraryl; 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.1 is (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.
3. A compound according to claim 2 having the formula, ##STR00054## 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.7a and R.sub.7c 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.
4. A compound according to claim 1, wherein one or more of the following applies: R.sub.1 is C(O)R.sub.9, R.sub.9 is aryl optionally substituted with one to three groups selected from trifluoromethyl, hydroxy, cyano, phenyl and pyridinyl; R.sub.2 is hydrogen; R.sub.3 is phenyl optionally substituted with one or more groups selected from C.sub.1-4alkyl, halogen, trifluoromethyl, OCF.sub.3, cyano, nitro, amino, hydroxy, and methoxy; R.sub.3 is phenyl optionally substituted with one or more halogen groups; Z is selected from 5-membered heteroaryl groups containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; or Z is imidazolyl; each R.sub.4 is independently selected from halogen groups; each R.sub.4 is Cl; q is 2.
5. A compound according to claim 2, wherein R.sub.9 is aryl optionally substituted with one to three groups selected from trifluoromethyl, hydroxy, cyano, phenyl and pyridinyl.
6. A compound according to any one of claims 1 to 5, wherein R.sub.2 is hydrogen.
7. A compound according to any one of claims 1 to 6, wherein R.sub.3 is phenyl optionally substituted with one or more groups selected from C.sub.1-4alkyl, halogen, trifluoromethyl, OCF.sub.3, cyano, nitro, amino, hydroxy, and methoxy.
8. A compound according to claim 7, wherein R.sub.3 is phenyl optionally substituted with one or more halogen groups.
9. A compound according to any one of claims 1 to 8, wherein Z is selected from 5-membered heteroaryl groups containing 1, 2 or 3 heteroatoms each independently selected from N, O and S.
10. A compound according to claim 9, wherein Z is imidazolyl.
11. A compound according to any one of claims 1 to 10, wherein each R.sub.4 is independently selected from halogen groups.
12. A compound according to claim 11, wherein each R.sub.4 is Cl.
13. A compound according to any one of claims 1 to 12, wherein q is 2.
14. A compound according to claim 1 having the structure ##STR00055## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: deuterium (D) enrichment at the chiral centre, and optionally at other locations, exceeds 40% deuterium incorporation; and wherein there is an enantiomeric excess (ee) of the S stereoisomer, which preferably exceeds 70%, and more preferably exceeds 90% or greater.
15. A pharmaceutical composition comprising at least one compound selected from claim 1 and a pharmaceutically-acceptable carrier or diluent.
16. A method of treating, ameliorating, preventing or combating a disease or disorder 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 fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm; (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; or (iv) 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; wherein the method comprises administering a therapeutically effective amount to the subject of at least one compound or composition selected from claim 1.
17. A method of treating/ameliorating/preventing/combating cancer in a subject by their taking, or being administered, a pharmaceutical composition with an effective amount of at least one compound according to claim 1 and a drug(s) that is permitted by the United States Food and Drug Administration (FDA), for example, for anti-cancer use.
18. A method according to claim 16 wherein the subject is monitored, for example by a healthcare professional or machine substitute, for signs 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 in their system.
19. A method according to claim 16 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, Lfgren 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.
20. A compound according to claim 1, for use in a method of treatment of the human or animal body by therapy.
21. A compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15, for use in the prevention or treatment of a disease or disorder 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 fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome or thyroid storm; (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 or 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; or (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.
22. A method of treating, ameliorating, preventing or combating a disease or disorder by administering an effective amount to the subject of at least one compound that preferentially inhibits the ATP-hydrolysing mode of ATP synthase, wherein the disease or disorder is 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 fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome or thyroid storm; (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 or 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; or (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.
23. A compound according to the formula: ##STR00056## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof for use in the prevention or treatment of a disease or disorder 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 fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome or thyroid storm; (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 or 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; or (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; wherein L is alkyl, substituted alkyl or any atom or isotope permitted by valence except hydrogen at natural abundance; R.sub.1 is 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 one or more groups selected from 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-hetaroaryl, 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.1-4alkylene-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, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R.sub.3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl; Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl, provided that when R.sub.1 is cyano, Z is not 2-pyridinyl; or Z is selected from 5-membered heteroaryl groups containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; 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, 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 heterocylo 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 C(O)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 substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto; c) pheyl 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 heterocyle 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.14alkoxy, 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.21 wherein 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.
24. A compound for use according to claim 23, wherein L is hydrogen or deuterium.
25. A compound for use according to claim 24, wherein the S-enantiomer is in enantiomeric excess.
26. A compound for use according to claim 25, wherein the enantiomeric excess of S-enantiomer exceeds 70%.
27. 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 fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome or thyroid storm; (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 or 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; or (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; 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: ##STR00057## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: L is alkyl, substituted alkyl or any atom or isotope permitted by valence except hydrogen at natural abundance; R.sub.1 is 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 one or more groups selected from 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-hetaroaryl, 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.1-4alkylene-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, heterocyolo, and heteroaryl, wherein when R.sub.3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl; Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl, provided that when R.sub.1 is cyano, Z is not 2-pyridinyl; or Z is selected from 5-membered heteroaryl groups containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; 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, 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 heterocylo 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 C(O)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 substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto; c) pheyl 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 heterocyle 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.14alkoxy, 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.21 wherein 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 method according to claim 16, 17, 22 or 27 wherein the cancer is breast, prostate, renal, ovarian, skin, central nervous system, colon or lung cancer or leukaemia.
29. A compound according to any one of claims 1 to 14, or claims 23 to 26, or a pharmaceutical composition according to claim 15, for use in a method of treatment of cancer wherein the cancer is breast, prostate, renal, ovarian, skin, central nervous system, colon or lung cancer or leukaemia.
30. A method according to claim 22 wherein the compound transports protons across the mitochondrial inner membrane, thereby dissipating the proton motive force as heat, and it specifically inhibits the ATP-hydrolysing mode, and not the ATP-synthesising mode, of ATP synthase.
31. A method of treating, ameliorating, preventing or combating 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 fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome or thyroid storm; (iv) 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 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; or (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; 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: ##STR00058## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: R.sub.1 is 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 one or more groups selected from 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-hetaroaryl, 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.1-4alkylene-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, cyoloalkyl, aryl, heterocyolo, and heteroaryl, wherein when R.sub.3a is cycloalkyl, aryl, heterocyclo or heteroaryl, said cycloalkyl, aryl, heterocyolo and heteroaryl in turn is optionally substituted with alkyl or substituted alkyl; Z is a heteroaryl, for example an optionally-substituted bicyclic heteroaryl, provided that when R.sub.1 is cyano, Z is not 2-pyridinyl; or Z is selected from 5-membered heteroaryl groups containing 1, 2 or 3 heteroatoms each independently selected from N, O and S; 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, 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 heterocylo 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 C(O)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 substituetits selected from alkyl, halogen, cyano, alkenyl, acyl, alkylthio, carbamyl, phenyl in turn optionally substituted with halogen; or having an aryl fused thereto; c) pheyl 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 heterocyle 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.14alkoxy, 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.21 wherein 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; R14, 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.
32. A method according to claim 31, wherein there is an enantiomeric excess (ee) of the S stereisomer, preferably that exceeds 70%
33. A method according to claim 32, using the compound: ##STR00059## or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: there is an enantiomeric excess (ee) of the S stereoisomer, which preferably exceeds 70%, and more preferably exceeds 90% or greater.
34. A method according to claim 27 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, Lfgren 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.
35. A method according to claim 32 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, Lfgren 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.
Description
DESCRIPTION OF THE DRAWINGS
[0098] 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.
[0099]
[0100]
[0101]
[0102]
[0103]
[0104]
[0105]
[0106]
[0107]
[0108]
[0109] 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) ([32], 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 [32] 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.
[0110] 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 don't affect .sub.IM by these means when the respiratory chain is operational, because .sub.IM isn't set/maintained by the reverse mode of ATP synthase in this case, but 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 .sub.IM more. Because not only does it inhibit the generator of .sub.IM (reverse mode ATP synthase), it simultaneously erodes .sub.IM (uncoupling).
[0111] 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, the best mode (refer disclosure section of that name) 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 oligomycininverselyinhibits F.sub.1F.sub.0 ATP hydrolysis less than F.sub.1F.sub.0 ATP synthesis in such assays [11].
[0112] Computational calculations of logP and pKa were made using [31]. 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
[0113] The Drawings present embodiments of the invention. Further examples are enumerations of Markush Formulas (I), (II), (III), (IV) and (V), presented henceforth. Note: none of these share Markush symbols, which are symbols of the type: R.sub.x, 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.
[0114] In this disclosure, the term Formula [X] is used when a statement is true for Formula (I), (II), (III), (IV) and (V), 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 any compound presented in this disclosure's Drawings.
[0115] 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.
[0116] 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) or (V) 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) or (V). A very large number of diseases/disorders can be treated using compounds described herein. For example, but not limited to, the compounds described herein can be used to treat/ameliorate/prevent/combat a disease or disorder selected from cancer, cachexia, cancer driven cachexia, weight loss or a disease or disorder that causes a higher than normal body temperature which can include, but isn't limited to, fever, pyrexia, hyperpyrexia, hyperthermia, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, or to treat/ameliorate/prevent/combat Tumour Associated Macrophages (TAMs) or treat/ameliorate/prevent/combat any macrophage associated disease or disorder including, but not limited to, Macrophage Activation Syndrome (MAS), HIV, AIDS, HIV-associated neurocognitive disorders (HAND), HIV associated cancers, AIDS-defining cancers, non-AIDS defining cancers or treat/ameliorate/prevent/combat virus neuroinvasion via macrophages, as used for example by HIV and SARS coronavirus, or treat/ameliorate/prevent/combat neurocognitive and neurodegenerative diseases/disorders, for example those caused by, but not limited to, a virus or treat/ameliorate/prevent/combat acute/chronic/systemic inflammation or any inflammatory disease/disorder/syndrome or any autoinflammatory disease/disorder/syndrome or any autoimmune disease/disorder/syndrome or to treat/ameliorate/prevent/combat 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 and necrosis or to cause greater metabolic/bioenergetic efficiency in a subject, enhancing their physical or mental performance or causing body weight gain.
Example (I)
[0117] Summary of Formula (I)
[0118] This invention embodiment relates to compounds having the following formula:
[0119] Formula (I)
##STR00013##
[0120] or a pharmaceutically-acceptable salt, solvate, hydrate or prodrug thereof, wherein: [0121] L is alkyl, or substituted alkyl, or any atom or isotope permitted by valence; [0122] R.sub.1 is cyano, SO.sub.2R.sub.8, C(O)R.sub.9, or heteroaryl; [0123] R.sub.2 is (i) independently hydrogen, alkyl, or substituted alkyl, or (ii) taken together with R.sub.3 forms a heterocyclo; [0124] 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) taken together with R.sub.2 forms a heterocyclo; [0125] Z is heteroaryl provided that when R.sub.1 is cyano, Z is not 2-pyridinyl; [0126] 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.1-4-alkylene-C(O)NR.sub.19, or substituted C.sub.1-4alkylene-C(O)NR.sub.19; [0127] 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, C()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; [0128] R.sub.8 is alkyl, substituted alkyl, aryl, or heteroaryl; [0129] R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, or CO.sub.2R.sub.12; [0130] 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; [0131] R.sub.12 and R.sub.19 are hydrogen or alkyl; [0132] 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; [0133] R.sub.27 is alkyl or substituted alkyl, and [0134] q is 0, 1, 2, or 3.
[0135] Preferred Compounds of Formula (I)
[0136] Preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00014##
[0137] 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,
##STR00015##
[0138] in which, in the preceding two structures shown:
[0139] L is hydrogen or deuterium;
[0140] D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
[0141] S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
[0142] 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;
[0143] R.sub.1 is cyano or C(O)R.sub.9;
[0144] R.sub.2 is hydrogen, alkyl, or benzyl;
[0145] R.sub.3 is aryl or arylalkyl optionally substituted with alkyl, halogen, trifluoromethyl, OCF.sub.3, cyano, nitro, amino, hydroxy, or methoxy;
[0146] R.sub.4 is halogen, alkyl, trifluoromethyl, or OCF.sub.3;
[0147] R.sub.7 is alkyl, carbamyl or carbamylC.sub.1-4alkyl;
[0148] R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, or CO.sub.2R.sub.12;
[0149] 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;
[0150] R.sub.12 is hydrogen or alkyl; and
[0151] q is 0, 1, 2, or 3.
[0152] Further preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00016##
[0153] and even more preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00017##
[0154] in which, for the preceding two structures shown:
[0155] z is
##STR00018##
[0156] L is hydrogen or deuterium;
[0157] D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
[0158] S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
[0159] Y is N, CH or CR.sub.7c;
[0160] R.sub.1 is cyano or C(O)R.sub.9;
[0161] R.sub.2 is hydrogen or C.sub.1-4alkyl;
[0162] R.sub.4 is halogen, C.sub.1-4alkyl, trifluoromethyl; or OCF.sub.3;
[0163] R.sub.7a, R.sub.7b, and R.sub.7c are 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;
[0164] R.sub.9 is NR.sub.10R.sub.11, alkyl, substituted alkyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl, heterocycle, or CO.sub.2R.sub.12;
[0165] 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;
[0166] R.sub.12 is hydrogen or alkyl;
[0167] R.sub.23 is hydrogen, alkyl, hydroxyalkyl, or phenyl;
[0168] 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;
[0169] q is 1 or 2;
[0170] x is 0, 1, or 2; and
[0171] y is 0, 1, 2, or 3.
[0172] More preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00019##
[0173] and even more preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00020##
[0174] in which, for the preceding two structures shown:
[0175] z is
##STR00021##
[0176] L is hydrogen or deuterium;
[0177] D is deuterium (enrichment, for example, exceeding 40% deuterium incorporation at shown position, and optionally at other positions also);
[0178] S symbolises the S stereoisomer, for example, in enantiomeric excess (ee) exceeding 70%;
[0179] R.sub.1 is cyano or C(O)R.sub.9;
[0180] R.sub.4 is halogen, C.sub.1-4alkyl, trifluoromethyl, or OCF.sub.3;
[0181] R.sub.7c is hydrogen or R.sub.7 and R.sub.7c join to form a fused benzene ring optionally substituted with C.sub.1-4alkyl or (CH.sub.2).sub.1-2NHC(O)C.sub.1-4alkyl,
[0182] R.sub.7b is hydrogen, C.sub.1-4alkyl, or (CH.sub.2).sub.1-2NHC(O)C.sub.1-4alkyl;
[0183] R.sub.9 is a) NR.sub.10R.sub.11 [0184] b) C.sub.1-8alkyl optionally substituted with one to two of:
[0185] 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;
[0186] 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;
[0187] 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;
[0188] 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;
[0189] c) C.sub.1-4alkoxy;
[0190] d) C.sub.1-4alkylthio;
[0191] e) CO.sub.2alkyl;
[0192] 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;
[0193] 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;
[0194] 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;
[0195] R.sub.10 is hydrogen, alkyl, or alkoxy;
[0196] R.sub.11 is alkyl, substituted alkyl, alkoxy, heterocyclo, cycloalkyl, aryl, or heteroaryl;
[0197] or R.sub.10 and R.sub.11, taken together form a heterocyclo or heteroaryl;
[0198] R.sub.23 is hydrogen, alkyl, hydroxyalkyl, or phenyl;
[0199] 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;
[0200] q is 0, 1, or 2;
[0201] x is 0 or 1; and
[0202] y is 0, 1, or 2.
[0203] 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 most preferred structure, its S stereoisomer is preferred. And further preferred is for its L group to be deuterium.
[0204] Example Embodiments of Formula (I)
[0205] 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.
##STR00022##
[0206] 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],
##STR00023##
[0207] Further examples [5]:
TABLE-US-00001 For all: EC.sub.50 F.sub.1F.sub.0ATP synthesis > 100 M EC.sub.50 F.sub.1F.sub.0 ATP hydro- R1 R2 lase (M) 4-Cl CN 8.8
Example (II)
[0208] Summary of Formula (II)
[0209] This invention embodiment relates to compounds having the formula:
##STR00025##
[0210] or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
[0211] L is alkyl, or substituted alkyl, or any atom or isotope permitted by valence, for example hydrogen or deuterium;
[0212] 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 alkyl, substituted alkyl, 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, 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 R.sub.1 and/or two of R.sub.5 join together to form a fused benzo ring;
[0213] R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen, 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 is selected from hydrogen, alkyl, and substituted alkyl;
[0214] 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;
[0215] 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.1O or CN;
[0216] R.sub.6 is selected from alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heterocyclo, and heteroaryl; provided that where R.sub.2 is hydrogen, ZR.sub.6 together are not SO.sub.2-Me or
##STR00026##
[0217] 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, sulfonamidyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
[0218] R.sub.8 and R.sub.9 are independently selected from hydrogen, alkyl, substituted alkyl, 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;
[0219] R.sub.10 and R.sub.11 are independently selected from hydrogen, alkyl, and substituted alkyl;
[0220] m and n are independently selected from 0, 1, 2 and 3
[0221] o, p and q are independently 0, 1 or 2; and
[0222] r and t are 0 or 1.
[0223] Preferred Compounds of Formula (II)
[0224] Preferred methods are to use, and preferred compounds are, compounds with the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00027##
[0225] wherein:
[0226] L is hydrogen or deuterium;
[0227] 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, aralkyl, aminoalkyl, halogen, cyano, nitro, hydroxy, alkoxy, alkylthio, NH.sub.2, NH(alkyl), N(alkyl).sub.2, C(O)H, acyl, CO.sub.2H, alkoxycarbonyl, carbamyl, sulfonyl, sulfonamide, 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;
[0228] R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen and alkyl;
[0229] Z is CO.sub.2, SO.sub.2, or is absent;
[0230] Y, R and T are selected from CH.sub.2 and C(O),
[0231] R.sub.6 is selected from:
[0232] 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;
[0233] 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;
[0234] heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl wherein said heteroaryl is optionally substituted with up to two R.sub.12,
[0235] provided that where R.sub.2 is hydrogen, ZR.sub.6 together are not SO.sub.2-Me or
##STR00028##
[0236] 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;
[0237] 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, five to six membered monocyclic heteroaryl, and phenyloxy or benzyloxy in turn optionally substituted with halogen, C.sub.1-4alkyl, and/or O(C.sub.1-4alkyl);
[0238] m and n are independently selected from 0, 1, 2 or 3; and
[0239] q is 0, 1 or 2; and
[0240] r and t are 0 or 1.
[0241] More preferred are compounds having the following formula, or pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof,
##STR00029##
[0242] wherein
[0243] 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, 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 R.sub.1 and/or two of R.sub.5 join together to form a fused benzo ring;
[0244] R.sub.2, R.sub.3 and R.sub.4 are independently selected from hydrogen and lower alkyl;
[0245] Z is CO.sub.2, SO.sub.2, or is absent;
[0246] R.sub.6 is selected from:
[0247] 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;
[0248] 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;
[0249] heteroaryl selected from thiophenyl, imidazolyl, pyrazolyl, and isoxazolyl, wherein said heteroaryl is optionally substituted with up to two R.sub.12,
[0250] provided that where R.sub.2 is hydrogen, ZR.sub.6 together are not SO.sub.2-Me or
##STR00030##
[0251] 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, five to six membered monocyclic heteroaryl, and phenyloxy or benzyloxy in turn optionally substituted with halogen, C.sub.1-4 alkyl, and/or O(C.sub.1-4 alkyl); and
[0252] m and n are independently selected from 0, 1, or 2.
[0253] 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,
##STR00031##
[0254] wherein:
[0255] 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;
[0256] R.sub.16 is selected from hydrogen, halogen, alkyl, nitro, cyano, hydroxy, alkoxy, NHC(O)alkyl, and phenyloxy or benzyloxy in turn optionally substituted with 1 to 3 of halogen, cyano, and C.sub.1-4alkoxy;
[0257] R.sub.17 is selected from alkyl, alkoxy, CO.sub.2C.sub.1-6alkyl, and SO.sub.2phenyl;
[0258] and u and v are independently 0, 1 or 2.
[0259] Most preferred compounds of Formula (II) are those having the formula:
##STR00032##
[0260] wherein
[0261] L is deuterium;
[0262] R.sub.2 is hydrogen or CH.sub.3;
[0263] Z is CO.sub.2, SO.sub.2, or is absent; and
[0264] R.sub.6 is selected from the groups recited immediately above, most preferably
##STR00033##
[0265] Example Embodiments of Formula (II)
[0266] 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.
##STR00034##
[0267] For all compounds;
TABLE-US-00002 EC.sub.50F.sub.1F.sub.0ATP synthesis > 30 M R6 R5 Imidazole EC.sub.50F.sub.1F.sub.0ATP hydrolase (M) 4-FPh SO.sub.2 5-yl 0.221
Example (III)
[0268] Summary of Formula (III)
[0269] This invention embodiment relates to compounds having the following formula:
##STR00039##
[0270] or their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
[0271] Optionally, one or more places upon the structure have deuterium in place of hydrogen;
[0272] R2 is hydrogen, hydroxy, or OC(O)R14;
[0273] R14 is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or (cycloalkyl)alkyl;
[0274] R3 and R4 are each independently hydrogen, alkyl or arylalkyl;
[0275] or R3 and R4 taken together with the carbon atom to which they are attached form a 3- to 7-membered carbocyclic ring;
[0276] R5 is hydrogen, alkyl, halogen, heterocyclo, nitrile, haloalkyl or aryl;
[0277] R12 is aryl or heterocyclo;
[0278] X is alkyl;
[0279] Y is a single bond, CH2, C(O), O, S or N(R14)-;
[0280] A is nitrogen (N), or N.sup.+, or carbon;
[0281] E is absent, or alkyl, or substituted alkyl, or any atom or isotope permitted by valence, for example hydrogen or deuterium;
[0282] R8 is hydrogen, alkyl, halogen, carbamyl or carbamylC.sub.1-4alkyl, or two R8 groups join to form an optionally substituted fused phenyl ring;
[0283] q is 0, 1, 2 or 3.
[0284] R1 is any chemical group smaller than 300 Daltons, R9, cyano, hydrogen, halogen, alkyl, substituted alkyl, alkenyl, alkylene, alkoxy, thioalkyl, aminoalkyl, carbamyl, sulfonyl, sulfonamide, cycloalkyl, haloalkyl, haloalkoxy, aryl, heterocyclo, heteroaryl;
[0285] R9 is
##STR00040##
[0286] R6 and R7 are independently hydrogen, 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 R6 and R7 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 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 alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, COOR14 or CO-substituted amino;
[0287] or R5 and R6 taken together with the atoms to which they are attached form a 5- to 7-membered ring optionally substituted with aryl;
[0288] Preferred Compounds of Formula (III)
[0289] 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:
[0290] Y is oxygen;
[0291] R2 is hydroxyl;
[0292] R3 and R4 are methyl;
[0293] R6 and R7 are alkyl; or R6 and R7 taken together with the nitrogen atom to which they are attached form a 6-membered ring;
[0294] X is alkyl;
[0295] R12 is aryl or heterocyclo;
[0296] A is N;
[0297] E is absent or hydrogen;
[0298] R5 and R8 are hydrogen;
[0299] Example embodiments of Formula (III) 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.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. 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).
##STR00041##
Example (IV)
[0300] Summary of Formula (IV)
[0301] This invention embodiment relates to compounds having the following formula:
##STR00042##
[0302] or their enantiomers, diastereomers, pharmaceutically-acceptable salts, solvates, hydrates or prodrugs thereof, wherein:
[0303] X is selected from O or S;
[0304] A is selected from hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
[0305] n and m are 0, 1, or 2
[0306] R.sub.1 through R.sub.5 are independently selected from hydrogen, halogen, NO.sub.2, CN, C.sub.1-8alkyl, substituted C.sub.1-8alkyl, 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;
[0307] R.sub.6 and R.sub.7 are independently hydrogen, alkyl or substituted alkyl;
[0308] R.sub.8 is hydrogen, deuterium, C.sub.1-8alkyl, substituted C.sub.1-8alkyl, aryl, heterocyclo or heteroaryl;
[0309] 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.1O;
[0310] 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
[0311] R.sub.11, R.sub.12 and R.sub.13 are independently hydrogen, C.sub.1-8alkyl, substituted C.sub.1-8alkyl, C.sub.3-10cycloalkyl, aryl, heterocyclo or heteroaryl;
[0312] wherein each occurrence of R.sub.9-R.sub.13 is chosen independently.
[0313] Preferred Compounds of Formula (IV)
[0314] 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:
[0315] R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and/or
[0316] R.sub.6 and R.sub.7 are both hydrogen; and/or
[0317] n and m are both 1; and/or
[0318] 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.
[0319] 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:
[0320] Z is C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.1-8haloalkyl, 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.1-8alkyl;
[0321] R.sub.9 is hydrogen;
[0322] R.sub.10 is C.sub.1-8alkyl or C.sub.3-10cycloalkyl; aryl or arylalkyl; and
[0323] R.sub.11 is hydrogen, C.sub.1-8alkyl, C.sub.3-10cycloalkyl, C.sub.3-10heterocycloalkyl, C.sub.3-10aryl or C.sub.3-10 arylalkyl.
[0324] 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:
[0325] A is hydrogen, deuterium, C.sub.1-8alkyl, 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, 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;
[0326] 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-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-;
[0327] 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
[0328] T.sup.8 and T.sup.9 are each independently a single bond, alkylene, alkenylene or alkynylene;
[0329] 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;
[0330] 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).sub.tH or SO.sub.3H;
[0331] 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);
[0332] wherein each occurrence of T.sup.1-T.sup.14 is chosen independently; and
[0333] t is 1 or 2.
[0334] Preferred compounds of the foregoing section are those in which A is hydrogen, deuterium, C.sub.1-8alkyl, 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).sub.tT.sup.12-NT.sup.8T.sup.9 and T.sup.6-N(T.sup.5)T.sup.7NT.sup.8T.sup.9.
[0335] 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).
[0336] 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:
##STR00043##
[0337] wherein:
[0338] 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.5T6 or T.sup.3-N(T.sup.2)T.sup.4NT.sup.5T.sup.6;
[0339] R.sup.1 and R.sup.5 are independently C.sub.1-8alkyl optionally substituted where valence allows;
[0340] R.sup.6 and R.sup.7 are independently hydrogen or C.sub.1-8alkyl;
[0341] R.sup.8 is hydrogen, deuterium, C.sub.1-8alkyl or substituted C.sub.1-8alkyl;
[0342] 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;
[0343] R.sup.9 is hydrogen,
[0344] R.sup.10 is C.sub.1-8alkyl or C.sub.3-10cycloalkyl; aryl or arylalkyl;
[0345] 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.
[0346] 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;
[0347] T.sup.2 and T.sup.3 are each independently a single bond, VS(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-O-T.sup.9-, -T.sup.8-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-;
[0348] 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
[0349] T.sup.8 and T.sup.9 are each independently a single bond, alkylene, alkenylene or alkynylene;
[0350] 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;
[0351] 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;
[0352] 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); and
[0353] t is 1 or 2.
[0354] More preferred methods/compounds use/are:
[0355] 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).
[0356] Especially preferred methods/compounds use/are:
[0357] A is CH(CH.sub.3)CH.sub.2(CH.sub.3), phenyl, CH.sub.2(phenyl) or CH.sub.2(2-indole).
[0358] Also, especially preferred methods/compounds use/are:
[0359] 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.
[0360] Other preferred methods/compounds use/are:
[0361] R.sup.1 and R.sup.5 are both isopropyl; and/or R.sup.6R.sup.7 and 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.
Example (V)
[0362] ##STR00044##
[0363] 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 R.sub.2 (independently in each case of R2), R.sub.3 is selected from the options of R.sub.3 (independently in each case of R3), R.sub.4 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.
[0364] Example Embodiment of Formula (V)
##STR00045##
[0365] Definitions Used to Specify Formulas (I), (II), (III) and (IV)
[0366] 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.
[0367] 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.
[0368] 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.c, SO.sub.2R.sub.c, SO.sub.2NR.sub.aR.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.c 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.c 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).
[0369] 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 (CH2).sub.n-NHC(O)alkyl, Wherein n is 1 to 12.
[0370] 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.
[0371] 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.
[0372] 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.
[0373] 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
##STR00046##
[0374] and so forth.
[0375] 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 O-.sub.C1-12alkyl, C.sub.1-6alkylene-OC.sub.1-6alkyl, C.sub.1-4alkylene-O-phenyl, and so forth.
[0376] 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.
[0377] 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. (where R is hydrogen, alkyl or substituted alkyl as defined above.) Amino refers to the group NH.sub.2.
[0378] 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.
[0379] 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.
[0380] The term acyl refers to a carbonyl
##STR00047##
[0381] linked to an organic group i.e.
##STR00048##
[0382] wherein R.sub.d may be selected from alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, heterocyclo, cycloalkyl, or heteroaryl, as defined herein.
[0383] The term alkoxycarbonyl refers to a group having a carboxy or ester group
##STR00049##
[0384] linked to an organic radical, i.e.,
##STR00050##
[0385] Wherein R.sub.d is as defined above for acyl.
[0386] 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.sub.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.
[0387] The term sulfonyl refers to a sulphoxide group (i.e., S(O).sub.1-2) linked to an organic radical R.sub.c, as defined above.
[0388] 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 R.sub.e 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.
[0389] 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 NR.sub.cSO.sub.2, NR.sub.cSO.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.c, R.sub.d and R.sub.e 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).
[0390] The term halo or halogen refers to chloro, bromo, fluoro and iodo.
[0391] The term haloalkyl means a substituted alkyl having one or more halo substituents. For example, haloalkyl includes mono, bi, and trifluoromethyl.
[0392] The term haloalkoxy means an alkoxy group having one or more halo substituents. For example, haloalkoxy includes OCF.sub.3.
[0393] The term aryl refers to phenyl, biphenyl, 1-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.c, 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.c, 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)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).
[0394] 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, 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, 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.c, 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).
[0395] 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.
[0396] 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.c, 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).sub.n, 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).
[0397] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl
##STR00051##
[0398] thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
[0399] 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.
[0400] Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
[0401] 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.
[0402] 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.
[0403] 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.
[0404] Stereoisomers
[0405] 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.
[0406] For the molecules presented in this invention's Description and Drawings: the present invention contemplates all geometric/conformational isomers, rotamers, atropisomers, stereoisomers, optically active forms, tautomers, keto-enol tautomers, cis- and trans-isomers, E and Z isomers, R- and S-enantiomers, diastereomers, (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/solvates/hydrates/chelates/metal complexes/mixtures/prodrugs/radionuclides/polymorphs/esters/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.
[0407] 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.
[0408] Salts, Solvates, Prodrugs
[0409] Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.
[0410] 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.
[0411] 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.
[0412] 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.
[0413] 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.
[0414] 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.
[0415] 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.
[0416] 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.
[0417] 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.
[0418] 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).
[0419] Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
[0420] 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);
[0421] 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);
[0422] c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992);
[0423] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); and
[0424] e) N. Kakeya, et. al., Chem Phar Bull, Vol. 32, p. 692 (1984).
[0425] 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.
[0426] Chelates, metal complexes, mixtures, radio-nuclides and liposomes of Formula [X] are within the scope of this invention.
[0427] Dosage
[0428] 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.
[0429] 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.
[0430] 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.
[0431] Pharmaceutical Composition
[0432] 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.
[0433] 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].
[0434] Administration
[0435] 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.
[0436] 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.
[0437] 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.
[0438] 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.
[0439] 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.
[0440] Co-Administration
[0441] 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
[0442] [P1] Hamann L G, Pudzianowski A T, inventors; Bristol-Myers Squibb Company, assignee. N-substituted phenylurea inhibitors of mitochondrial F 1F0 ATP hydrolase. U.S. Pat. No. 6,846,836. 2005 Jan. 25.
[0443] [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 F1F0 ATP hydrolase and methods of inhibiting F1F0 ATP hydrolase. U.S. patent application Ser. No. 10/461,736. 2003 Jun. 13.
[0444] [P3] 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 F1F0 ATP hydrolase. U.S. Pat. No. 6,916,813. 2005 Jul. 12.
[0445] [P4] 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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