Traitement en cours

Veuillez attendre...

Paramétrages

Paramétrages

Aller à Demande

1. WO2020109420 - PROCÉDÉS DE PRÉPARATION DE PROPANEDIOLS NITROSYLÉS, COMPOSITIONS COMPRENANT CEUX-CI, ET LEURS UTILISATIONS MÉDICALES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

Claims

1. A process for the preparation of a composition comprising one or more compounds of formula I


wherein R1, R2 and R3 each independently represent H or -NO,

wherein n is 0 or 1 ;

wherein when n is 0, R1 is H; and

wherein when n is 1 , R2 is H,

provided that at least one of R1 R2 and R3 represents -NO,

said process comprising the step of:

(i) reacting a corresponding compound of formula I but wherein R1, R2 and R3 represent H with a source of nitrite, optionally in the presence of a suitable acid,

wherein:

(a) when the source of nitrite is an organic nitrite, step (i) is performed in a suitable organic solvent; and

(b) when the source of nitrite is an inorganic nitrite, step (i) is performed in a bi-phasic solvent mixture comprising an aqueous phase and a non-aqueous phase.

2. A process as claimed in Claim 1 , wherein inorganic nitrite is a metal nitrite.

3. A process as claimed in Claim 2, wherein the metal nitrite is an alkali metal nitrite or an alkaline earth metal nitrite.

4. A process as claimed in Claim 3, wherein the metal nitrite is an alkali metal nitrite.

5. A process as claimed in Claim 4, wherein the alkali metal nitrite is sodium nitrite.

6. A process as claimed in Claim 2, wherein the organic nitrite is an alkyl nitrite.

7. A process as claimed in Claim 6, wherein the alkyl nitrite is tert-butyl nitrite.

8. A process as claimed in any one of Claims 1 to 7, wherein the suitable acid is a strong acid, such as a strong mineral acid.

9. A process as claimed in Claim 8, wherein the strong mineral acid is sulphuric acid.

10. A process as claimed in any one of Claims 1 to 9, wherein the non-aqueous phase comprises a water immiscible organic solvent, such as a water immiscible aprotic organic solvent.

1 1. A process as claimed in Claim 10, wherein the water immiscible organic solvent is dichloromethane or tert-butylmethyl ether.

12. A process as claimed in any one of Claims 1 to 1 1 , wherein the solvent mixture further comprises excess of a compound of formula I but wherein R1 , R2 and R3 represent H.

13. A process as claimed in any one of Claims 1 to 12, wherein after step (i) the process further comprises the step of:

(ii) removing substantially all of the aqueous phase from the solvent mixture.

14. A process as claimed any one of Claims 1 to 12, wherein after step (i) the process further comprises the step(s) of:

(ii) removing some or all (e.g. substantially all) of the aqueous phase (i.e. of water);

(iii) washing the remaining organic phase with one or more further aqueous phase;

(iv) optionally repeating steps (ii) and (iii) one or more times;

(v) optionally reducing (i.e. reducing the amount/volume of) the organic phase, and (vi) optionally drying the product,

wherein steps (ii) to (vi) may be performed in any order provided that steps (ii) to (iv) are performed before steps (v) and (vi).

15. A process as claimed in any one of Claims 1 to 12, wherein the process further comprises the step of adding a further amount of a compound of formula I but wherein R1 , R2 and R3 represent H, such that the combined mixture of the one or more compounds of formula I and a compound of formula I but wherein R1 , R2 and R3 represent H comprises from about 0.01 % to about 9% by weight of the one or more compounds of formula I.

16. A product obtained or obtainable by a process as claimed in any one of Claims 1 to 15.

17. A substantially non-aqueous composition comprising:

(a) one or more compounds of formula I


wherein R1 , R2 and R3 each independently represent H or -NO,

wherein n is 0 or 1 ; and

wherein when n is 0, R1 is H and

wherein when n is 1 , R2 is H,

provided that at least one of R1 R2 and R3 represents -NO and

(b) a compound of formula I but wherein R1 , R2 and R3 represent H.

18. A composition as claimed in Claim 17, wherein the composition comprises from about 0.01 % to about 9% by weight of the one or more compounds of formula I.

19. A composition as claimed in any one of Claims 17 and 18, wherein the composition is substantially free of dissolved nitric oxide.

20. A composition as claimed in any one of Claims 17 to 19, wherein the composition consists essentially of the one or more compounds of formula I and a compound of formula I but wherein R1, R2 and R3 represent H.

21. A pharmaceutical formulation comprising a composition as claimed in any one of Claims 17 to 20, and optionally one or more pharmaceutically acceptable excipients.

22. A pharmaceutical formulation as claimed in Claim 21 , wherein the one or more pharmaceutically acceptable excipients are non-aqueous.

23. A kit-of-parts comprising:

(A) a pharmaceutical formulation as claimed in any one of Claims 21 and 22; and

(B) a suitable aqueous buffer,

wherein components (A) and (B) are provided in a form suitable for administration with each other.

24. A combination product formed by mixing together:

(A) a pharmaceutical formulation as claimed in any one of Claims 21 and 22; and

(B) a suitable aqueous buffer.

25. A kit-of-parts as claimed in Claim 23 or a combination product as claimed in Claim

24, wherein the ratio of the pharmaceutical formulation and the suitable buffer is from about 3:7 to about 1 :99 by volume.

26. A kit-of-parts as claimed in any one of Claim 23 and 25, or a combination product as claimed in any one of Claims 24 and 25, wherein the buffer is non-nucleophilic and weakly basic.

27. A kit-of-parts as claimed in any one of Claims 23, 25 and 26, or a combination product as claimed in any one of Claims 24 to 26, wherein the buffer maintains a pH of from about 7.1 to about 10.

28. A kit-of-parts as claimed in any one of Claims 23 and 25 to 27, or a combination product as claimed in any one of Claims 24 to 27, wherein the buffer is a carbonate buffer or a phosphate buffer, or a mixture thereof.

29. A process for preparing a combination product as claimed in any one of Claims 24 and 26 to 28, comprising the step of mixing together:

(A) a pharmaceutical formulation as claimed in any one of Claims 21 and 22; and

(B) a suitable aqueous buffer as defined in any one of Claims 26 to 28.

30. A composition as claimed in any one of Claims 17 to 20, a pharmaceutical formulation as claimed in any one of Claims 21 and 22, a kit-of-parts as claimed in any one of Claims 23 and 25 to 28, or a combination product as claimed in any one of Claims 24 to 28, for use in the treatment of a condition wherein administration of NO has a beneficial effect.

31. A method of treating a condition wherein administration of NO has a beneficial effect comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation as claimed in any one of Claims 21 and 22 or a combination product as claimed in any one of Claims 24 to 28.

32. A method of treating a condition wherein administration of NO has a beneficial effect comprising administering to a patient in need thereof a therapeutically effective amount of components:

(A) a pharmaceutical formulation as claimed in any one of Claims 21 and 22; and

(B) a suitable aqueous buffer as defined in any one of Claims 25 to 28,

wherein the components (A) and (B) are mixed prior to administration.

33. The use as claimed in Claim 30 or the method as claimed in any one of Claims 31 and 32, wherein the condition is selected from the group consisting of:

acute pulmonary vasoconstriction of different genesis; pulmonary hypertension of different genesis, including primary hypertension and secondary hypertension; conditions of different genesis in need of vasodilation; systemic hypertension of different genesis; regional vasoconstriction of different genesis; local vasoconstriction of different genesis; acute heart failure (with or without preserved ejection fraction (HFpEF)); coronary heart disease; myocardial infarction; ischemic heart disease; angina pectoris; instable angina; cardiac arrhythmia; acute pulmonary hypertension in cardiac surgery patients; acidosis; inflammation of the airways; cystic fibrosis; COPD; immotile cilia syndrome; inflammation of the lung; pulmonary fibrosis; adult respiratory distress syndrome; acute pulmonary oedema; acute mountain sickness; asthma; bronchitis; hypoxia of different genesis; stroke; cerebral vasoconstriction; inflammation of the gastrointestinal tract; gastrointestinal dysfunction; gastrointestinal complication; IBD; Crohn’s disease; ulcerous colitis; liver disease; pancreas disease; inflammation of the bladder of the urethral tract; inflammation of the skin; diabetic ulcers; diabetic neuropathy; psoriasis; inflammation of different genesis; wound healing; organ protection in ischemia-reperfusion conditions; organ transplantation; tissue transplantation; cell transplantation; acute kidney disease; uterus relaxation; cervix relaxation; and conditions where smooth muscle relaxation is needed.

34. The method as claimed in any one of Claims 32 and 33, wherein the mixing of components (A) and (B) is performed immediately prior to administration to the patient, such as by co-administration thereof.

35. The method as claimed in any one of Claims 32 to 34, wherein the mixing is performed by a mixed flow process.

36. The method as claimed in Claim 35, wherein the mixed flow process occurs at the point of administration of the components to the patient.

37. The use according to Claim 33, wherein the condition is selected from the group consisting of pulmonary hypertension of different genesis, including primary hypertension and secondary hypertension; and acute heart failure (with or without preserved ejection fraction (HFpEF)).