The present invention provides benzothiadiazine and chroman derivatives and particularly diazoxide and cromakalim derivatives for use in treating glaucoma, retinopathy, treating age related macular degeneration, treating, stabilizing and/or inhibiting blood and lymph vascularization, and reducing intraocular pressure by administering a pharmaceutically effective amount of a prodrug disposed in an ophthalmically acceptable carrier to the eye, wherein the prodrug specifically modulates a K.sub.ATP channel to reduce an intraocular pressure.

An agent for use in medicine, wherein the agent comprises a compound of Formula (I): wherein Ar is an aryl linker group, for example a 1,4-phenyl group, including individual pharmaceutically acceptable salts, solvates, prodrugs or derivatives thereof. The compounds of Formula (I) are inhibitors of human C-reactive protein (CRP) and may be used for the treatment of medical conditions mediated by CRP. Also provided are methods of making the compounds of Formula (I) and chemical intermediates thereof.

##STR00001##

The disclosure provides compositions and methods for determining the propensity of a subject (e.g., a female human subject) undergoing embryo transfer therapy to benefit from administration of an oxytocin receptor antagonist, as well as for treating such patients accordingly. Using the compositions and methods of the disclosure, a subject undergoing embryo transfer therapy may be selected for treatment with an oxytocin receptor antagonist on the basis of a pre-treatment gene signature. Additionally or alternatively, a subject that is undergoing embryo transfer therapy and that has been administered an oxytocin receptor antagonist may be monitored following treatment to determine whether the subject is responding to the oxytocin receptor antagonist or if subsequent dosing is desirable. Exemplary oxytocin receptor antagonists useful in conjunction with the compositions and methods of the disclosure include pyrrolidin-3-one oxime compounds, such as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, among others.

The disclosure provides compositions and methods for determining the propensity of a subject (e.g., a female human subject) undergoing embryo transfer therapy to benefit from administration of an oxytocin receptor antagonist, as well as for treating such patients accordingly. Using the compositions and methods of the disclosure, a subject undergoing embryo transfer therapy may be selected for treatment with an oxytocin receptor antagonist on the basis of a pre-treatment gene signature. Additionally or alternatively, a subject that is undergoing embryo transfer therapy and that has been administered an oxytocin receptor antagonist may be monitored following treatment to determine whether the subject is responding to the oxytocin receptor antagonist or if subsequent dosing is desirable. Exemplary oxytocin receptor antagonists useful in conjunction with the compositions and methods of the disclosure include pyrrolidin-3-one oxime compounds, such as (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, among others.

There is disclosed herein a composition for treating gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux esophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease or autism, the composition comprising: (i) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (ii) at least one anti-clostridial agent selected from the above combined with an opioid blocking agent. There is also disclosed herein a method of treating various gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease or autism, the method comprising administering orally, via enema or by suppository: (i) a composition of the invention; (ii) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (iii) at least one anti-clostridial agent selected from the above and an opioid blocking agent to a patient in need of such treatment.

There is disclosed herein a composition for treating gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux esophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease or autism, the composition comprising: (i) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (ii) at least one anti-clostridial agent selected from the above combined with an opioid blocking agent. There is also disclosed herein a method of treating various gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinson's disease, MS, Alzheimer's Disease, Motor Neuron Disease or autism, the method comprising administering orally, via enema or by suppository: (i) a composition of the invention; (ii) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, aminoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (iii) at least one anti-clostridial agent selected from the above and an opioid blocking agent to a patient in need of such treatment.

Compounds of the formula I ##STR00001## in which R.sup.1 denotes A, Ar, Cyc, Het, COA or CN, R.sup.2 denotes SO.sub.2A, SOA, SA, SO.sub.2NHA, SO.sub.2NA.sub.2, S(═NH,═O)A, S(═NH).sub.2A, NO.sub.2, Hal, CN, A, Het.sup.1, COOH or COOA, R.sup.3 denotes H or Hal, R.sup.4 denotes H or Hal, n denotes 1, 2 or 3, A denotes unbranched or branched alkyl having 1-6 C-atoms, Cyc denotes cyclic alkyl with 3 to 7 C-atoms, Ar denotes phenyl, Het denotes a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, Het.sup.1 denotes a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, and Hal denotes F, Cl, Br, or I, are inhibitors of HIF-2α, and can be employed for the treatment of diseases such as cancer.

Compounds of the formula I ##STR00001## in which R.sup.1 denotes A, Ar, Cyc, Het, COA or CN, R.sup.2 denotes SO.sub.2A, SOA, SA, SO.sub.2NHA, SO.sub.2NA.sub.2, S(═NH,═O)A, S(═NH).sub.2A, NO.sub.2, Hal, CN, A, Het.sup.1, COOH or COOA, R.sup.3 denotes H or Hal, R.sup.4 denotes H or Hal, n denotes 1, 2 or 3, A denotes unbranched or branched alkyl having 1-6 C-atoms, Cyc denotes cyclic alkyl with 3 to 7 C-atoms, Ar denotes phenyl, Het denotes a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, Het.sup.1 denotes a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, and Hal denotes F, Cl, Br, or I, are inhibitors of HIF-2α, and can be employed for the treatment of diseases such as cancer.

A method of treating cardiac hypertrophy and/or heart failure in a subject includes administering to the subject a therapeutically effective amount of a REV-ERBα agonist.

A method of treating cardiac hypertrophy and/or heart failure in a subject includes administering to the subject a therapeutically effective amount of a REV-ERBα agonist.