Spirocyclic compounds as tryptophan hydroxylase inhibitors
Inventors
De Lombaert, Stéphane • Goldberg, Daniel R. • Brameld, Kenneth • Sjogren, Eric Brian
Assignees
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Publication Number
US-9199994-B2
Publication Date
2015-12-01
Expiration Date
Abstract
The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.
Core Innovation
The disclosure is directed to stereochemically defined compounds of the 2,8-diazaspiro[4.5]decane-3-carboxylate or 2,8-diazaspiro[4.5]decane-3-carboxylic acid scaffold, including pharmaceutically acceptable salts thereof. The compounds share a substituted pyrimidin-4-yl core and an (R)-configured 2,2,2-trifluoroethoxy or related trifluoroethoxy-linked aryl or heteroaryl side chain, with (S) configuration on the spiro framework.
The compound set includes substituted biphenyl, pyrazolyl phenyl, chlorinated aryl, quinolinyl, indolyl, benzo[d]isothiazolyl, and related aryl or heteroaryl motifs, together with corresponding ethyl carboxylate and carboxylic acid variants. Example structures are repeatedly supported by LCMS and 1H NMR characterization, and the disclosed members are presented as specific chemical entities with structure representations and related analytical outputs.
The patent further presents pharmaceutical compositions comprising the compounds with at least one pharmaceutically acceptable carrier and treatment methods in which a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof is administered to a patient. The described uses include selected diseases from an enumerated list, and the document also describes TPH1 inhibitor compounds that lower peripheral serotonin.
Claims Coverage
The consolidated independent claims cover specific stereochemically defined 2,8-diazaspiro[4.5]decane compounds, generally in ethyl carboxylate or carboxylic acid form, with the inventive features focused on exact compound identity, (S)/(R) stereochemistry, and optional pharmaceutically acceptable salts. The claim coverage reflects 16 distinct compound definitions and is extended by dependent claims to pharmaceutical compositions and treatment methods.
Stereochemically defined diazaspiro carboxylate with 5-chloro biphenyl trifluoroethoxy pyrimidinyl group
A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylic acid with 5-chloro biphenyl trifluoroethoxy pyrimidinyl group
A compound which is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylate with dimethyl pyrazolyl biphenyl trifluoroethoxy pyrimidinyl group
A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylic acid with dimethyl pyrazolyl biphenyl trifluoroethoxy pyrimidinyl group
A compound which is (S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylate with 4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl trifluoroethoxy pyrimidinyl group
A compound which is (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylic acid with 4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl trifluoroethoxy pyrimidinyl group
A compound which is (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylate with fluoro pyrazolyl propoxy biphenyl ethoxy pyrimidinyl group
A compound which is (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, or a pharmaceutically acceptable salt thereof.
Stereochemically defined diazaspiro carboxylic acid with fluoro pyrazolyl propoxy biphenyl ethoxy pyrimidinyl group
A compound which is (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-fluoro-3-(3-methyl-1H-pyrazol-1-yl)-4′-propoxy-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage centers on specific stereochemically defined 2,8-diazaspiro[4.5]decane carboxylate and carboxylic acid compounds with substituted pyrimidin-4-yl, trifluoroethoxy-linked aromatic substituents, and pharmaceutically acceptable salts. Dependent claims further cover pharmaceutical compositions comprising pharmaceutically acceptable carriers and methods of treating a patient by administering a therapeutically effective amount for diseases selected from an enumerated list.
Stated Advantages
Selective lower peripheral serotonin (5-HT) by inhibiting TPH1.
Avoid central/brain serotonin effects while targeting peripheral 5-HT dysregulation.
Support for structural identification and biological activity is provided by NMR, LCMS, in vitro TPH1/TPH2 inhibition assay results, and in vivo intestinal 5-HT depletion efficacy assays.
Documented Applications
Pharmaceutical compositions comprising the claimed compound or salt together with at least one pharmaceutically acceptable carrier.
Treating a patient by administering a therapeutically effective amount of the claimed compound or salt for diseases selected from an enumerated list, including osteoporosis, osteoporosis pseudoglioma syndrome (OPPG), osteopenia, osteomalacia, renal osteodystrophy, Paget’s disease, bone fractures, bone metastasis, pulmonary arterial hypertension (PAH), associated pulmonary arterial hypertension (APAH), diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), pulmonary embolism, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colitis, chemotherapy-induced emesis, diarrhea, carcinoid syndrome, celiac disease, Crohn’s disease, abdominal pain, dyspepsia, constipation, lactose intolerance, MEN types I and II, Ogilvie’s syndrome, pancreatic cholera syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, Zollinger-Ellison Syndrome, chronic liver disease, liver cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, neuroendocrine tumors, pancreatic cancer, prostate cancer, bone cancer, blood cancer, and allergic airway inflammation.
In vitro TPH1/TPH2 inhibition assay with activity thresholding using IC50 rating categories.
In vivo intestinal 5-HT (serotonin) depletion efficacy assays using selected examples and associated result tables.
Treating and/or preventing diseases associated with peripheral 5-HT dysregulation, including gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass conditions.
Treating serotonin syndrome.
Treating cancer.
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