Treatment of cardiopulmonary disorders

Patent metadata

Field	Value
Publication number	US-12138256-B2
Application number	US-202318506944-A
Country	US
Kind code	B2
Filing date	Nov 10, 2023
Priority date	Dec 29, 2021
Publication date	Nov 12, 2024
Grant date	Nov 12, 2024

Abstract

The present invention relates to the use 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), prefer-ably in form of one of its salts or solvates or hydrates, preferably (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) or (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 inform of mono hydrate (II) of formula (I-M-II), in the inhalative treatment of cardiopulmonary and pulmonary disorders, such as pulmonary arterial hypertension (P AH), chronic tromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension (PH) associated with chronic lung disease (PH group 3) such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP), characterized in that an inhalative dosage form comprising 240 to 4000 μg, preferably 480 to 2000 μg 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-carboxy lie acid of formula (I), preferably in form of one of its salts or solvates or hydrates, preferably in form of monohydrate I of formula (I-M-I) or (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxy lie acid in form of mono hydrate (II) of formula (I-M-II), is administered to a patient in need thereof once or twice daily for a period of at least two consecutive days, preferably at least 2 to 7 consecutive days, preferably for a period of at least 14 consecutive days, in particular from after onset of treatment for the whole course of the disease, wherein the inhalative dosage form preferably comprises the combination of the active ingredient and a pharmaceutically suitable excipient or carrier, while preferably the active ingredient and a pharmaceutically suitable excipient are filled in a hard capsule.

First claim

The invention claimed is:

1. A method of treating a cardiopulmonary disorder in a subject comprising administering to the subject, about 240 μg to about 4000 μg of a crystalline monohydrate compound 1:

wherein, measured at 25° C. using monochromatic CuKα1 radiation of λ=1.540456 Å, 40 kV, 40 mA, the X-ray powder diffraction reflection pattern of crystalline monohydrate compound 1, expressed as ±0.2 °2θ, has at least one of the following characteristic reflections: 6.9±0.2 °2θ, 7.2±0.2 °2θ, 7.3±0.2 °2θ, 12.8±0.2 °2θ, 15.2±0.2 °2θ, 16.0±0.2 °2θ, 23.0±0.2 °2θ, 25.8±0.2 °2θ and 29.2±0.2 °2θ.

2. The method of claim 1 , wherein the crystalline monohydrate form has X-ray powder diffraction reflections at 12.8±0.2 °2θ and 29.2±0.2 °2θ.

3. The method of claim 2 , wherein the crystalline monohydrate form has at least one additional reflection at 6.9±0.2 °2θ, 7.2±0.2 °2θ, 7.3±0.2 °2θ, 15.2±0.2 °2θ, or 23.0±0.2 °2θ.

4. The method of claim 1 , wherein the crystalline monohydrate form has X-ray powder diffraction reflections at 12.8±0.2 °2θ, 16.0±0.2 °2θ, and 25.8±0.2 °2θ.

5. The method of claim 4 , wherein the crystalline monohydrate form has at least one additional reflection at 6.9±0.2 °2θ, 7.2±0.2 °2θ, 7.3±0.2 °2θ, or 15.2±0.2 °2θ.

6. The method of claim 1 , wherein the crystalline monohydrate form has X-ray powder diffraction reflections at 12.8±0.2 °2θ, 20.5±0.2 °2θ, and 25.8±0.2 °2θ.

7. The method of claim 6 , wherein the crystalline monohydrate form has at least one additional reflection at 6.9±0.2 °2θ, 7.2±0.2 °2θ, 7.3±0.2 °2θ, 15.2±0.2 °2θ, or 25.1±0.2 °2θ.

8. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered at a dose of about 480 μg to about 4000 μg.

9. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered at a dose of about 4000 μg.

10. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered via inhalation.

11. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered once daily.

12. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered twice daily.

13. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered for at least two consecutive days.

14. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered for at least seven consecutive days.

15. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered for at least fourteen consecutive days.

16. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered after onset of the cardiopulmonary disorder.

17. The method of claim 1 , wherein the crystalline monohydrate Compound 1 is administered via dry powder inhaler.

18. The method of claim 1 , wherein the cardiopulmonary disorder is selected from pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH) associated with chronic lung disease (PH group 3).

19. The method of claim 18 , wherein the pulmonary hypertension (PH) associated with chronic lung disease (PH group 3) is pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) or pulmonary hypertension with idiopathic interstitial pneumonia (PH-IIP).

20. A method of treating a cardiopulmonary disorder in a subject comprising administering to the subject, a pharmaceutical composition comprising crystalline monohydrate compound of claim 1 .

21. The method of claim 20 , wherein the crystalline monohydrate form has X-ray powder diffraction reflections at 12.8±0.2 °2θ and 29.2±0.2 °2θ.

22. The method of claim 20 , wherein the crystalline monohydrate form has X-ray powder diffraction reflections at 12.8±0.2 °2θ, 16.0±0.2 °2θ, and 25.8±0.2 °2θ.

23. The method of claim 20 , wherein the crystalline monohydrate form has X-ray powder diffraction reflections at 12.8±0.2 °2θ, 20.5±0.2 °2θ, and 25.8±0.2 °2θ.

24. The method of claim 20 , wherein the crystalline monohydrate Compound 1 is administered at a dose of about 480 μg to about 4000 μg.

25. The method of claim 20 , wherein the crystalline monohydrate Compound 1 is administered at a dose of about 4000 μg.

26. The method of claim 20 , wherein the crystalline monohydrate Compound 1 is administered via inhalation.

27. The method of claim 20 , wherein the crystalline monohydrate Compound 1 is administered once or twice daily.

28. The method of claim 20 , wherein the crystalline monohydrate Compound 1 is administered for at least two consecutive days, at least seven consecutive days, or at least fourteen consecutive days.

29. The method of claim 20 , wherein the crystalline monohydrate Compound 1 is administered via dry powder inhaler.

30. The method of claim 20 , wherein the cardiopulmonary disorder is selected from pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH) associated with chronic lung disease (PH group 3).

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Becker-Pelster Eva Maria
• Tinel Hanna
• Hahn Michael
• Lang Dieter
• Weimann Gerrit
• Nagelschmitz Johannes
• Dietz Lisa
• Saleh Soundos
• Jung David
• Terebesi Ildiko
• Mundry Tobias
• Richter Annett
• Olenik Britta
• Keil Birgit
• Rösler Bernd
• Fey Peter
• Schirmer Heiko
• Becker Guido
• Bothe Clemens
• Faber Helene
• Egger Julian
• Parry Mark
• Ward David
• Vitre Cecile

Classifications

• A61K9/0075

  for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles · CPC title

• A61P9/12

  Antihypertensives · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title