Process for the preparation of a PDE4 inhibitor
Inventors
Falchi, Alessandro • Lutero, Emilio • Ferrari, Emanuele • Pivetti, Fausto • BUSSOLATI, Rocco • Mariani, Edoardo • VECCHI, Orsola • Bappert, Erhard • VENTRICI, Caterina
Assignees
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Publication Number
US-11981639-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present invention relates to a process for the preparation of compounds endowed with phosphodiesterase (PDE4) inhibitory activity having formula (I). The invention also relates to the process for the isolation by crystallization of the compound (I) and to its use for the preparation of pharmaceutical compositions for inhalation in combination with suitable carriers or vehicles. The present invention also relates to solvates and crystal forms of a compound of formula (I). The synthesized product is suitable for use in pharmaceutical applications for instance in the treatment of respiratory diseases.
Core Innovation
The invention provides a pharmaceutical formulation comprising a crystal form of a compound of formula (I) where n is 1, together with a pharmaceutically acceptable carrier. The crystal form is defined by a characteristic XRPD pattern measured as peaks at specified 2θ values (CuKα1/2), and the formulation and crystal-form definition are linked to identification and control of the solid form using XRPD peak characteristics.
The invention also provides a process for preparing the same crystal form of the compound of formula (I) where n is 1. The process comprises heating a suspension of compound of formula (I) to obtain a solution and cooling the solution to obtain crystals, and the crystal form obtained is characterized by the same characteristic XRPD peaks.
In the disclosed description, the compound work includes conversion between intermediates and formation of a target compound of formula (I) for n equal to 0 or 1. It further describes alternative stereoselective routes, including oxidation to keto derivatives, enantioselective reduction, chiral separation using intermediates VI–VIII, recyclable conversion/reconversion via the recyclable intermediate VI, and mesylation of carboxylic-acid/activated derivatives to form (I).
Claims Coverage
The claim set includes two independent claims. The inventive features center on a specific XRPD-characterized crystal form of compound formula (I) where n is 1, formulation of that crystal form with a pharmaceutically acceptable carrier, and a process for preparing the same crystal form by heating a suspension to obtain a solution followed by cooling to obtain crystals.
Xrpd-defined crystal form in a pharmaceutical formulation
A pharmaceutical formulation comprising a crystal form of a compound of formula (I) wherein n is 1 and said crystal form exhibits characteristic XRPD peaks at specified 2θ values for CuKα1/2, together with a pharmaceutically acceptable carrier.
Heating-and-cooling process to obtain xrpd-defined crystals
A process for preparing a crystal form of a compound of formula (I) wherein n is 1 and said crystal form exhibits the characteristic XRPD peaks at specified 2θ values for CuKα1/2, the process comprising heating a suspension of the compound of formula (I) to obtain a solution and cooling the solution to obtain crystals.
Overall claim coverage is grounded in a specific crystal form of compound formula (I) where n is 1, defined by a characteristic XRPD peak list, with the formulation claiming the crystal form plus a pharmaceutically acceptable carrier and the process claim using heating followed by cooling to obtain crystals of the same XRPD-defined crystal form.
Stated Advantages
Simpler and safer manufacture.
Fewer steps and fewer solvent use.
Higher yields.
Lower impurities.
Suitable for industrial scale.
Thermodynamically stable crystalline Form A (n=1).
Enables a pharmaceutical formulation comprising a crystal form of compound (I) with a defined XRPD peak pattern.
Enables preparation of a crystal form of compound (I) characterized by a defined XRPD peak pattern.
Documented Applications
Treating an inflammatory or obstructive respiratory disease by administering an effective amount of the claimed pharmaceutical formulation.
Treating asthma or chronic obstructive pulmonary disease (COPD) by administering to a subject an effective amount of the claimed pharmaceutical formulation.
Inhalation pharmaceutical compositions, including formulation suitability for inhalation and dry powder for inhalation, and intranasal administration suitability.
Inhalation or intranasal administration for inflammatory or obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease.
Treatment of an inflammatory or obstructive respiratory disease by administering an effective amount of the pharmaceutical formulation comprising the crystal form of compound (I) (n=1).
Treatment of asthma by administering an effective amount of the pharmaceutical formulation defined in claim 1.
Treatment of chronic obstructive pulmonary disease (COPD) by administering an effective amount of the pharmaceutical formulation defined in claim 1.
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