Spirocyclic compounds as tryptophan hydroxylase inhibitors

Inventors

De Lombaert, Stéphane • Goldberg, Daniel R. • Brameld, Kenneth • Sjogren, Eric Brian • Scribner, Andrew

Assignees

Altavant Sciences GmbH • Scynexis Inc

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 invention relates to pharmaceutical compositions comprising (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, together with a pharmaceutically acceptable excipient. The compositions are suitable for administration to a patient by inhalation, injection or infusion, topical administration, or oral administration, depending on the claim family.

The disclosed compound includes the 2,2,2-trifluoroethoxy group, the pyrimidin-4-yl moiety, and the 2,8-diazaspiro[4.5]decane-3-carboxylic acid framework. The document also enumerates stereodefined analogs and derivative families of the same core spirocyclic pyrimidine scaffold, including substituted biaryl, aryl, and heteroaryl variants, as well as prodrug, ester, and carboxylate forms.

The problem being addressed is lowering peripheral serotonin and treating pulmonary arterial hypertension (PAH). The claims further specify PAH associated pulmonary arterial hypertension (APAH), and the disclosure associates the same compound family with route-specific pharmaceutical administration across inhalation, injection or infusion, topical administration, and oral administration.

Claims Coverage

The independent claims cover four pharmaceutical composition formats and one method of treating pulmonary arterial hypertension (PAH). Across the claims, the central inventive features are the specified (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 pharmaceutically acceptable salt), a pharmaceutically acceptable excipient, route-specific administration, and therapeutic use for lowering peripheral serotonin and treating PAH.

The claim coverage centers on the same specified active compound or salt formulated with a pharmaceutically acceptable excipient for inhalation, injection or infusion, topical, and oral administration, together with a method claim for treating PAH. Dependent and related claim language also ties the compositions and methods to lowering peripheral serotonin and to PAH associated pulmonary arterial hypertension (APAH).

Stated Advantages

Documented Applications