Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the overall most common strategy is to formulate an active ingredient with inactive carrier compounds into a dry powder blend where the micronized drug particles adhere to an inactive carrier which in most cases is lactose or other sugar related compounds e.g. sugar alcohols as mannitol.
• Basic mechanism of drug delivery is here the temporary adhesion of micronized drug particles on inactive larger carrier material particles and the subsequent deagglomeration or release of the active miconized drug particles from carrier affected by the airflow energy created within a dry powder inhaler use for application of the formulation.
• the majority of the carrier material is not intended to be inhaled and due to its size will settle down in the upper airways, mainly mouth and throat.
• the compound of the formula (I) can be prepared via its NS A salt, characterized in that in a first step [D] the dibutylester has to be released from the NSA salt of formula (XII -NSA) which is than further transformed into the free acid via two steps (basic saponification of the dibutylester (step [A]) and thereafter inverse addition to acid to release the free acid of formula (I) (step [B]).
• the pseudopolymorphic form of compound of formula (I), the monohydrate I of formula (I-M-I) can be characterized by a X-Ray powder diffractogram (at 25 °C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 12.8, 20.5 and 25.8 or at least 6.9, 7.2 and 7.3 or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2 and 25.1 or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1 and 23.7 or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1, 23.7, 9.9, 5.7 and 11.5, each quoted as 20 value ⁇ 0.2°.
• the pseudopolymorphic form of compound of formula (I), the monohydrate I of formula (I-M-I) can additionally be characterized by a X-Ray powder diffractogram (at 25 °C and with Cu-K alpha 1 as radiation source) which does not display at least the following reflections: 7.6 each quoted as 20 value ⁇ 0.2°.
• the pseudopolymorphic form of compound of formula (I), the monohydrate I of formula (I-M-I) can additionally be characterized by a X-Ray powder diffractogram (at 25 °C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 12.8 and 29.2 or at least 6.9, 7.2 and 7.3 or at least 6.9, 7.2, 7.3, 12.8 and 29.2 or at least 6.9, 7.2, 7.3 12.8, 29.2, 23.0 and 15.2, or at least the following reflections: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8 and 25.1 or at least the following reflections: 6.9, 7.2, 7.3 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7 and 23.7, or at least the following reflections: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7 and 23.7, or at least the following reflections: 6.9, 7.2
• the pseudopolymorphic form of compound of formula (I), the monohydrate I of formula (I-M-I) can additionally be characterized by a X-Ray powder diffractogram (at 25 °C and with Cu-K alpha 1 as radiation source) which displays at least the following reflections: 12.8, 20.5 and 25.8 or at least 6.9, 7.2 and 7.3 or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2 and 25.1 or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8,
• the compound of formula (I) in the pseudopolymorphic form monohydrate II can also be characterized unambiguously by the X-Ray powder diffractogram (at 25 °C and with Cu-K alpha 1 as radiation source) as shown in Figure 7.
• the pseudopolymorphic form of compound of formula (I), the diydrate can additionally be characterized by a X-Ray powder diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) which does not display at least the following reflections: 29.2 each quoted as 20 value ⁇ 0.2°.
• the treatment or the prevention of a disease, a condition, a disorder, an injury or a health impairment may take place partially or completely.
• “Local administration” or “local control” in connection with cardiopulmonary disorders means for the purposes of the invention - in contrast to oral administration of dosage forms intended for absorption via the gastrointestinal tract, and in contrast to intravenous administration, both leading to systemic drug distribution via bloodstream - administration of the active ingredient by inhalation in inhalable dosage form to primarily cover the lung as target organ, which requires a lower dose and causes a lower general drug exposure.
• the preparation in powder form or powder-containing suspensions to be used according to the invention are preparations which are inhaled.
• HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway
• HASMC from severe asthma donors might possess inherent defects in their sGC or in redox enzymes that support sGC function.
• a majority of the severe asthma donor HASMC (12/17) and lung samples primarily expressed a dysfunctional sGC that was NO-unresponsive and had low heterodimer content and high Hsp90 association.
• the active ingredient needs to have suitable physicochemical, pharmacokinetic and pharmacodynamic properties, e. g. the drug substance needs to be suitable for an inhalative treatment and it needs to have sufficient efficacy to treat cardiopulmonary disorders. Furthermore the active ingredient should have clear efficieacy in the envisaged PH forms, also on top of standard of care (SoC e.g. endothelin antagonists such as bosentan, PDE5 inhibitors e.g. sildenafil, IP agonists e.g. Ilomedin, calcium channel blockers e.g. and sGC stimulators e.g. riociguat).
• SoC e.g. endothelin antagonists such as bosentan, PDE5 inhibitors e.g. sildenafil, IP agonists e.g. Ilomedin, calcium channel blockers e.g. and sGC stimulators e.g. riociguat).
• Comparative example 11 esp. in monohydrate form I of formula (I-M-I) not only shows effective reduction of the PAP via selective vasodilation in the lungs but also showed longer lasting bronchodilatory properties compared to cinaciguat which may be beneficial in the once or twice daily inhalative treatment of PH patients with chronic lung diseases (PH group 3) or even have a potential in the treatment of patients with restricted lung function, e.g. asthmatics.
• the present inventors found that the excellent aerosol performance of the formulations for inhalation according to the present invention is achieved by adjusting a specific content of fine lactose and a specific content of coarse lactose within the dry powder blend.
• the present inventors identified the fine lactose content of the lactose carrier as an important critical parameter.
• the content of fine lactose should be selected within a certain range. For example a higher content of fine lactose in the powder blend / lactose carrier, e.g. a content of 20% or more was found to have a negative impact on the blend uniformity (see e.g. comparative example 20).
• the fine lactose portion was weighed and layered in between two layers of coarse lactose prior to start of mixing.
• the inhalative dosage form comprises 480 to 4000 pg of (5S)- ⁇ [2-(4- carboxyphcnyl (ethyl
• a method of treating a cardiopulmonary disorder comprising administering an inhalative dosage form, comprising 240 to 4000 pg of (5S)- ⁇ [2-(4-carboxyphenyl)ethyl][2-(2- ⁇ [3-chloro-4'- (trifluoromethyl)biphenyl-4-yl]methoxy ⁇ - , phenyl)-ethyl]-amino ⁇ -5,6,7,8-tetrahydroquinoline-2- carboxylic acid of formula I in form of one of its crystalline modifications selected from the list consisting of monohydrate I of formula (I-M-I) or monohydrate II of formula (I-M-II) or sesquihydrate, wherein the X-ray powder diffractogram (measured at 25 °C and with Cu-K alpha 1 as radiation source) of the compound of formula (I-M-I) comprises at least peaks at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2 quoted
• a packaged pharmaceutical composition for use in the inhalative treatment of a cardiopulmonary disorder according to any one of claims 81 to 88 characterized in that the X-ray powder diffractogram (measured at 25 °C and with Cu-K alpha 1 as radiation source) of the compound comprises a peak at least at 12.8 and 5.7 and lacks peaks at 8.5 and 6.1, at diffraction angle 20 value ⁇ 0.2°.
• a packaged pharmaceutical composition for use in the inhalative treatment of a cardiopulmonary disorder according to any one of claims 81 to 89 characterized in that the compound in form of monohydrate II has an X-ray powder diffraction pattern as shown in FIG. 7 (measured at 25 °C and with Cu-K alpha 1 as radiation source).
• a formulation for inhalation according to any one of claims 1 to 40 characterized in that it contains a nominal dose of 480-4000 pg of (5S)- ⁇ [2-(4-carboxyphenyl)ethyl][2-(2- ⁇ [3-chloro-4'- (trifluoromethyl)biphenyl-4-yl]methoxy ⁇ phenyl)ethyl]-amino ⁇ -5,6,7,8-tetrahydroquinoline-2- carboxylic acid in form of monohydrate I of formula (I-M-I).
• a formulation for inhalation according to to any one of claims 1 to 44 characterized in that the coarse lactose content in the dry powder blend is 98.25% to 75% or preferably between 94.25% and 75% or more preferably from 90.00% to 75% or more preferably from 90% to 85% and the fine lactose content in the dry powder blend is from LO.% up to 15% or preferably 1% up to 10%, preferably between 5% and 10%, or more preferably 2.5%-7.5%, preferably between 5% and 7.5% or more preferably 3-7% or more preferably 4%-6%
• a formulation for inhalation according to any one or more of claims 1 to 49 for the production of a medicament for the use in the treatment of cardiopulmonary disorders, characterized in that the medicament comprising an inhalative dosage form, which comprises 240 to 4000 pg of (5 S)- ⁇ [2-(4-carboxyphenyl)ethyl][2-(2- ⁇ [3-chloro-4'-(trifluoromethyl)biphenyl-4- yl]methoxy ⁇ -phenyl)-ethyl]-amino ⁇ -5,6,7,8-tetrahydroquinoline-2-carboxylic acid in form of monohydrate I of formula (I-M-I), wherein the x-ray diffractogram (at 25 °C and with Cu-K alpha 1 as radiation source) of the monohydrate form I of formula (I-M-I) displays at least the following reflections 6.9, 7.2, 7.3, 12.8 and 29.2 quoted as 20 value ⁇ 0.2°, is
• an inhalative dosage form which comprises 240 to 4000 pg of (5S)- ⁇ [2-(4-carboxyphenyl)ethyl][2-(2- ⁇ [3-chloro-4'-(trifluoromethyl)biphenyl- 4-yl]methoxy ⁇ -phenyl)-ethyl]-amino ⁇ -5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in form of its crystalline modification monohydrate I of formula (I-M-I), wherein the X-ray powder diffractogram (measured at 25 °C and with Cu-K alpha 1 as radiation source) of the compound comprises at least peaks at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2 quoted as 20 value ⁇ 0.2°, is administered to a patient in need thereof once or
• an inhalative dosage form which comprises 240 to 4000 pg of (5S)- ⁇ [2-(4-carboxyphenyl)ethyl][2-(2- ⁇ [3-chloro-4'- (trifluoromethyl)biphenyl-4-yl]methoxy ⁇ -phenyl)-ethyl]-amino ⁇ -5,6,7,8-tetrahydroquinoline-2- carboxylic acid of formula I in form of its crystalline modification monohydrate I of formula (I-M- I), wherein the X-ray powder diffractogram (measured at 25 °C and with Cu-K alpha 1 as radiation source) of the compound comprises at least peaks at 12.8 and 29.2, preferably at 6.9, 7.2, 7.3, 12.8 and 29.2 quoted as 20 value ⁇ 0.2°, is administered to a patient in need thereof once or
• thermograms were recorded using thermobalances (model TGA7 and Pyris 1) from Perkin -Elmer. The measurements were performed with a heating rate of 10 Kmin 1 using open platinum pans. Flow gas was nitrogen. There was no sample preparation.
• Example 22A 15 g (21.42 mmol) of the racemic ethyl 5- ⁇ (/ert-butoxycarbonyl)[2-(2- ⁇ [3-chloro-4'-(trifluoromethyl)- biphenyl-4-yl]methoxy ⁇ phenyl)ethyl]amino ⁇ -5,6,7,8-tetrahydroquinoline-2 -carboxylate (Example 22A) were separated by supercritical fluid chromatography (SFC) on a chiral phase into the enantiomers [column: Chiralpak OD-H, 20 pm, 400 mm x 50 mm; mobile phase: carbon dioxide/isopropanol 70:30 (v/v); flow rate: 400 ml/min; pressure: 80 bar; UV detection: 220 nm; temperature: 37°C]:
• SFC supercritical fluid chromatography
• the residue was diluted with 2500 g of water and a portion of the disodium salt solution (1178 g) was added dropwise to a mixture of 1095 g of tetrahydrofuran and 137 g of 10% hydrochloric acid until a pH of 4.0 was reached.
• the combined solids were heated to 50 °C with a mixture of 1020 g acetone and 1020 g methanol and cooled to 20 °C.
• the solution obtained was filtered through a Seitz filter plate, heated to 50 °C and 460 g of water were added dropwise over a period of 30 minutes. It was inoculated with 1.5 g of seed crystals of monohydrate I (example 3), stirred for 30 min, cooled to 20 °C in at least 30 min and the solid was filtered off with suction.
• the moist product was stirred with 2550 g of water for 12 hours, then filtered off with suction and washed twice with 510 g of water.
• the moist product was dried to constant weight at 20 °C in a stream of nitrogen under vacuum.

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