EA042138B1 - SUBCUTANEOUS ADMINISTRATION OF P2Y12 RECEPTOR ANTAGONIST - Google Patents

Description

1) A first embodiment of the invention relates to a P2Y ₁₂ receptor antagonist, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment (preferably treatment) of a disease, wherein the disease is selected from acute arterial thrombosis and acute venous thrombosis; wherein the P2Y12 receptor antagonist is selected from the group consisting of 4-((R)-2{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3 butyl ester -phosphonopropionyl)piperazine-1-carboxylic acid (compound 1), (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5- (propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor) and (1S,2R ,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5 -d]pyrimidin-3-yl]cyclopentan-1,2,3-triol (ticagrelor-M); and wherein the P2Y ₁₂ receptor antagonist is and/or is to be administered to the patient by intradermal or subcutaneous administration.

2) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1), wherein the disease is selected from acute arterial thrombosis.

3) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to an embodiment of the invention 1), wherein the disease is selected from acute coronary syndromes, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke and transient ischemic attack.

4) An additional embodiment of the invention relates to a P2Y ₁₂ receptor antagonist

- 2 042138 (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1), wherein the disease is selected from acute coronary syndromes, peripheral ischemia, amaurosis, ischemic stroke and transient ischemic attack.

5) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1) wherein the disease is acute coronary syndromes.

6) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1), wherein the disease is myocardial infarction.

7) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1) wherein the disease is peripheral ischemia.

8) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1) wherein the disease is amaurosis.

9) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1) wherein the disease is sudden cardiac death.

10) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 1), wherein the disease is selected from ischemic stroke and transient ischemic attack.

11) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of embodiments 1)-10), wherein the P2Y12 receptor antagonist is and/or is to be administered prior to hospitalization.

12) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 11), wherein the P2Y ₁₂ receptor antagonist is and/or is to be administered by self-administration by the patient.

13) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 11), wherein the P2Y12 receptor antagonist is and/or is to be administered by healthcare professionals.

14) An additional embodiment of the invention relates to a P2Y12 receptor antagonist, or a pharmaceutically acceptable salt thereof, for use in emergency treatment of suspected acute coronary syndromes (ACS) by self-administration by a patient prior to hospitalization; wherein the P2Y12 receptor antagonist is selected from the group consisting of 4-((R)-2-{[6-((S)-3methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-butyl ester carboxylic acid phosphonopropionyl)piperazine-1 (compound 1), (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio )-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2diol (ticagrelor) and (1S,2R,3S,4R )-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine -3-yl]cyclopentan-1,2,3-triol (ticagrelor-M); and wherein the P2Y12 receptor antagonist is and/or is to be administered to the patient by intradermal or subcutaneous administration.

15) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-14), wherein the P2Y12 receptor antagonist is and/or is to be administered to a patient by subcutaneous route. introductions.

16) An additional embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (in particular compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-15), where the P2Y ₁₂ receptor antagonist is administered and/or is to be administered with using an autoinjector.

17) An additional embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (in particular compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-11), where the P2Y 12 receptor antagonist is administered and/or is to be administered to a patient by subcutaneous administration and by self-administration by the patient using an autoinjector device.

18) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of embodiments 1)-17), wherein the patient to be treated is a patient suffering from atherosclerosis.

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19) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of embodiments 1)-17), wherein the patient to be treated is a patient with a known coronary artery disease. artery who had a previous symptomatic episode of acute coronary syndromes.

20) A further embodiment of the invention relates to a P2Y12 receptor antagonist, or a pharmaceutically acceptable salt thereof, for use in any of embodiments 1)-19), wherein the P2Y12 receptor antagonist is 4-((R)-2-{[6 ((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic acid (compound 1), or a pharmaceutically acceptable salt thereof.

21) A further embodiment of the invention relates to a P2Y12 receptor antagonist, or a pharmaceutically acceptable salt thereof, for use according to any of embodiments 1)-19), wherein the P2Y12 receptor antagonist is (1S,2S,3R,5S)-3-[7 -[(1R,2S)-2(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5 -(2hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor) or a pharmaceutically acceptable salt thereof or (1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl )cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentan-1,2,3-triol (ticagrelor-M) or its pharmaceutical acceptable salt. Preferably, the P2Y12 receptor antagonist is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1, 2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2hydroxyethoxy)cyclopentan-1,2-diol (ticagrelor) or a pharmaceutically acceptable salt thereof.

22) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-21), wherein the amount of the P2Y12 receptor antagonist (particularly Compound 1), what is administered and/or should be administered is between 1 and 75 mg per administration.

The lower limits for the amount of the P2Y12 receptor antagonist (particularly Compound 1) are 1, 5, 10 and 20 mg. The upper limits are 35, 40, 50 and 75 mg. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. The preferred amount of the P2Y12 receptor antagonist (particularly Compound 1) is 10 to 40 mg per administration.

In another preferred embodiment, the amount of the P2Y ₁₂ receptor antagonist (particularly Compound 1) is 5 to 20 mg per administration.

23) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1)-22), wherein the P2Y12 receptor antagonist (particularly Compound 1), optionally together with one or more therapeutically inert excipient(s), is dissolved in a pharmaceutically acceptable liquid to form a solution and wherein the volume of solution that is and/or to be administered is between 0.1 and 3.0 ml per administration.

The lower limits of the solution volume are 0.1, 0.2, 0.5 and 0.8 ml. The upper limits are 1.0, 1.4, 2.0 and 3.0 ml. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. The preferred solution volume is 0.5 to 1.4 ml.

24) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 23), wherein the solution is and/or is to be administered within an administration time between 1 to 90 seconds.

The lower limits for administration time are 1, 3, 5, and 8 seconds. The upper limits are 15, 30, 60 and 90 s. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. The preferred administration time is 5 to 30 seconds.

25) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1)-24), wherein the P2Y12 receptor antagonist (particularly Compound 1) is administered and /or must be given as a bolus.

26) An additional embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-24), wherein the P2Y12 receptor antagonist (particularly Compound 1) is administered and/or must be administered at the first subcutaneous injection, which is a bolus injection, and at least one additional subcutaneous injection.

27) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 26), where the further subcutaneous injection is a continuous injection of up to 5 hours.

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It is understood that the continuous injection may last up to 5, up to 4, up to 3, up to 2, up to 1 hour, up to 30 or up to 15 minutes. It is also understood that the continuous injection is and/or should be administered at a lower flow rate than the bolus injection. The continuous flow rate may range from 0.01% to 10% of the bolus flow rate. The lower limits for continuous injection flow rates are 0.01%, 0.05%, 0.1%, and 0.5% of the bolus rate. The upper limits are 0.5, 1, 2, 5 and 10%. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. Continuous injection may begin immediately after the end of the bolus injection, or may begin with a delay of up to 2, up to 1 hour, up to 30 or up to 15 minutes after the end of the bolus injection.

28) A further embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 26), where further subcutaneous injections are from 1 to 10 further bolus injections.

The lower limits for the number of further boluses are 1 and 2. The upper limits are 3, 5, 7, and 10. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. The time between any two consecutive bolus injections can range from 5 to 120 minutes. The lower time limits between any two consecutive bolus injections are 5, 10, 15, and 30 minutes. The upper limits are 30, 60, 90 and 120 minutes. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. The volume that is injected and/or should be injected with a further bolus injection is in the range from 5 to 100% of the volume of the first bolus injection. The lower limits for the additional bolus volume are 5%, 10%, 20%, and 30% of the volume of the first bolus.

The upper limits are 30, 50, 70 and 100%. It should be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed.

29) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (in particular, compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-28), where inhibition of platelet aggregation by at least 75% is achieved within 30 min after initiation of P2Y ₁₂ receptor antagonist administration in at least 80% of patients.

30) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 29), wherein inhibition of platelet aggregation of at least 80% is achieved.

31) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly compound 1) or a pharmaceutically acceptable salt thereof for use according to embodiment 29), wherein inhibition of platelet aggregation of at least 85% is achieved.

32) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (in particular compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 29)-31), where inhibition of platelet aggregation is achieved within 25 minutes after the start of administration of P2Y12 receptor in at least 80% of patients.

33) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (in particular, compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 29)-31), where inhibition of platelet aggregation is achieved within 20 minutes after the start of administration of the antagonist P2Y12 receptor in at least 80% of patients.

34) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 29)-33), wherein inhibition of platelet aggregation is achieved in at least 85% of patients.

35) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 29)-33), wherein inhibition of platelet aggregation is achieved in at least 90% of patients.

36) An additional embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-35), wherein the platelet aggregation inhibition value is at least 75% (particularly , at least 80%, especially at least 85%) is achieved in at least 80% of patients and continues for at least 3 hours after the start of administration of the P2Y ₁₂ receptor antagonist.

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37) An additional embodiment of the invention relates to a P2Y ₁₂ receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-35), wherein the platelet aggregation inhibition value is at least 75% (in in particular, at least 80%, especially at least 85%) is achieved in at least 80% of patients and continues for an inhibition time between 3 and 12 hours after the start of administration of the P2Y ₁₂ receptor antagonist.

The lower inhibition time limits are 3 and 4 hours. The upper limits are 4, 5, 6, 7, 8, 10, and 12 hours. It will be understood that each lower limit may be combined with each upper limit. Therefore, all combinations must be specifically disclosed. The preferred inhibition time is 4 to 8 hours.

38) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of embodiments 1)-37), wherein the P2Y12 receptor antagonist is administered to a patient by subcutaneous injection.

39) A further embodiment of the invention relates to a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof for use according to any of embodiments 1)-37), wherein the _P2Y12 receptor antagonist is to be administered to a patient by subcutaneous injection.

40) An additional embodiment of the invention relates to a pharmaceutical composition containing as an active principle a P2Y ₁₂ receptor antagonist selected from compound 1, ticagrelor and ticagrelor-M (in particular compound 1) or a pharmaceutically acceptable salt thereof for use according to any of the embodiments of the invention 1)-37), where the pharmaceutical composition is administered and/or to be administered to the patient by subcutaneous administration and where the pharmaceutical composition further comprises at least one therapeutically inert excipient.

Preparation of subcutaneous pharmaceutical compositions of compound 1 (or ticagrelor or ticagrelor-M) can be carried out in a manner that will be familiar to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st ed. (2005) , Part 5, Pharmaceutical Manufacturing [publ. Lippincott Williams & Wilkins]) by making compound 1 (or ticagrelor or ticagrelor-M) or its pharmaceutically acceptable salt in a galenic form for administration along with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier substances and, if necessary, simple pharmaceutical adjuvants/ excipients.

In all cases where a P2Y12 receptor antagonist (compound 1 and/or ticagrelor and/or ticagrelor-M) or a pharmaceutically acceptable salt thereof is described as being useful in the prevention or treatment (in particular treatment) of a disease, it has been found that the P2Y12 receptor antagonist (compound 1 and/or ticagrelor and/or ticagrelor-M) or a pharmaceutically acceptable salt thereof is also useful for the preparation of a medicament for the prevention or treatment (particularly treatment) of said disease. Thus, the present invention covers, in particular, the following additional embodiments of the invention.

41) An additional embodiment of the invention relates to the use of a P2Y ₁₂ receptor antagonist selected from compound 1, ticagrelor and ticagrelor-M, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use according to any of the embodiments of the invention 1)-39).

42) An additional embodiment of the invention relates to the use of compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use according to any of the embodiments of the invention 1)-20) or 22)-39).

43) An additional embodiment of the invention relates to the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease, wherein the disease is selected from acute arterial thrombosis and acute venous thrombosis, and where the drug is and/or is to be administered to a patient by subcutaneous injection.

44) A further embodiment of the invention relates to the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease wherein the disease is selected from acute arterial thrombosis and where the drug is and/or is to be administered to a patient by subcutaneous administration.

45) An additional embodiment of the invention relates to the use of compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease, where the disease is selected from acute coronary syndromes, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke and transient ischemic attack and where the drug is administered and/or to be administered to the patient by subcutaneous administration.

46) An additional embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of

- 6 042138 diseases, where the disease is selected from acute coronary syndromes, peripheral ischemia, amaurosis, ischemic stroke and transient ischemic attack and where the drug is administered and / or should be administered to the patient by subcutaneous injection.

47) An additional embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of acute coronary syndromes, wherein the medicament is and/or to be administered to a patient by subcutaneous administration.

48) A further embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of myocardial infarction, wherein the medicament is and/or to be administered to a patient by subcutaneous administration.

49) An additional embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of peripheral ischemia, wherein the medicament is and/or to be administered to a patient by subcutaneous administration.

50) An additional embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of amaurosis, wherein the medicament is and/or is to be administered to a patient by subcutaneous administration.

51) An additional embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of sudden cardiac death, wherein the medicament is and/or is to be administered to a patient by subcutaneous administration.

52) A further embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease wherein the disease is selected from ischemic stroke and transient ischemic attack and wherein the drug is and/or is to be administered to a patient by subcutaneous administration.

53) An additional embodiment of the invention relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof according to any one of the embodiments of the invention 41)-52), wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient by subcutaneous administration.

54) An additional embodiment of the invention relates to the use of compound 1 or its pharmaceutically acceptable salt according to any of the embodiments of the invention 41)-52); wherein Compound 1, or a pharmaceutically acceptable salt thereof, is to be administered to a patient by subcutaneous injection.

55) An additional embodiment of the invention relates to the use of a P2Y ₁₂ receptor antagonist selected from Compound 1, ticagrelor and ticagrelor-M (preferably Compound 1), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in emergency treatment of suspected acute coronary syndromes (ACS) by self-administration by the patient prior to hospitalization; wherein the P2Y12 receptor antagonist is administered to the patient by subcutaneous injection.

56) An additional embodiment of the invention relates to the use of a P2Y12 receptor antagonist selected from Compound 1, ticagrelor and ticagrelor-M (preferably Compound 1), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in emergency treatment of suspected acute coronary syndromes ( ACS) by self-administration by the patient prior to hospitalization; wherein the P2Y12 receptor antagonist is to be administered to the patient by subcutaneous injection.

Based on the dependencies of the various embodiments that are disclosed above, in particular, the following embodiments, which are specifically disclosed in an individualized form, are possible and thus intended:

1, 2+1, 3+1, 4+1, 5+1, 6+1, 7+1, 8+1, 9+1, 10+1, 11+1, 11+3+1, 11+ 5+1,

12+11 + 1, 12+11+3 + 1, 12+11+5+1, 13 + 11 + 1, 13 + 11+3 + 1, 13 + 11+5+1, 14, 15+1,

15+3 + 1, 15+5+1, 15+11 + 1, 15+11+3 + 1, 15+11+5+1, 15+12+11 + 1, 15+12+11+3 + 1,

15+12+11+5+1, 15+14, 16+1, 16+3 + 1, 16+5+1, 16+11 + 1, 16+11+3 + 1, 16+11+5+ 1,

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16+12+11 + 1, 16+12+11+3 + 1, 16+12+11+5+1, 16+14, 16+15+1, 16+15+3 + 1, 16+15+ 5+1, 16+15+11 + 1, 16+15+11+3 + 1, 16+15+11+5+1, 16+15+12+11 + 1, 16+15+12+11+ 3 + 1, 16+15+12+11+5+1, 16+15+14, 17+1, 17+3 + 1, 17+5+1, 17+11 + 1 17+11+3 + 1 , 17+11+5+1, 18+1, 18+3 + 1, 18+5+1, 18+11 + 1, 18+11+3 + 1, 18+11+5+1, 18+12 +11 + 1, 18+12+11+3 + 1, 18+12+11+5+1, 18+14, 18+15+1, 18+15+3 + 1, 18+15+5+1 , 18+15+11 + 1, 18+15+11+3 + 1, 18+15+11+5+1, 18+15+12+11 + 1, 18+15+12+11+3 + 1 , 18+15+12+11+5+1, 18+15+14, 19+1, 19+3 + 1, 19+5+1, 19+11 + 1 19+11+3 + 1, 19+ 11+5+1, 19+12+11+1, 19+12+11+3+1, 19+12+11+5+1, 19+14, 19+15+1, 19+15+3+ 1, 19+15+5+1, 19+15+11 + 1, 19+15+11+3 + 1, 19+15+11+5+1, 19+15+12+11 + 1, 19+ 15+12+11+3 + 1, 19+15+12+11+5+1, 19+15+14, 19+16+1, 19+16+3 + 1, 19+16+5+1, 19+16+11 + 1, 19+16+11+3 + 1, 19+16+11+5+1, 19+16+12+11 + 1, 19+16+12+11+3 + 1, 19+16+12+11+5+1, 19+16+14, 19+16+15+1, 19+16+15+3 + 1, 19+16+15+5+1, 19+16+ 15+11 + 1, 19+16+15+11+3 + 1, 19+16+15+11+5+1, 19+16+15+12+11+ 1, 19+16+15+12+11+3+1, 19+16+15+12+11+5+1, 19+16+15+14, 20+1, 20+2+1, 20+ 3+1, 20+4+1, 20+5+1, 20+6+1, 20+7+1, 20+8+1, 20+9+1, 20+10+1, 20+11+ 1, 20+11+3 + 1, 20+11+5+1, 20+12+11 + 1, 20+12+11+3 + 1, 20+12+11+5+1, 20+13 + 11 + 1, 20+13 + 11+3 + 1, 20+13 + 11+5+1, 20+14, 20+15+1, 20+15+3 + 1, 20+15+5+1, 20+15+11 + 1, 20+15+11+3 + 1, 20+15+11+5+1, 20+15+12+11 + 1, 20+15+12+11+3 + 1, 20+15+12+11+5+1, 20+15+14, 20+16+1, 20+16+3 + 1, 20+16+5+1, 20+16+11 + 1, 20+ 16+11+3 + 1, 20+16+11+5+1, 20+16+12+11 + 1, 20+16+12+11+3 + 1, 20+16+12+11+5+ 1, 20+16+14, 20+16+15+1, 20+16+15+3 + 1, 20+16+15+5+1, 20+16+15+11 + 1, 20+16+ 15+11+3 + 1, 20+16+15+11+5+1, 20+16+15+12+11 + 1, 20+16+15+12+11+3 + 1, 20+16+ 15+12+11+5+1, 20+16+15+14, 20+17+1, 20+17+3 + 1 20+17+5+1, 20+17+11 + 1, 20+17 +11+3 + 1, 20+17+11+5+1, 20+18+1, 20+18+3 + 1, 20+18+5+1, 20+18+11 + 1, 20+18 +11+3 + 1, 20+18+11+5+1, 20+18+12+11 + 1, 20+18+12+11+3 + 1, 20+18+12+11+5+1 , 20+18+14, 20+18+15+1, 20+18+15+3 + 1, 20+18+15+5+1, 20+18+15+11 + 1, 20 +18+15+11+3 + 1, 20+18+15+11+5+1, 20+18+15+12+11 + 1, 20+18+15+12+11+3 + 1, 20 +18+15+12+11+5+1, 20+18+15+14, 20+19+1, 20+19+3 + 1, 20+19+5+1, 20+19+11 + 1 , 20+19+11+3 + 1, 20+19+11+5+1, 20+19+12+11 + 1, 20+19+12+11+3 + 1, 20+19+12+11 +5+1, 20+19+14, 20+19+15+1, 20+19+15+3 + 1, 20+19+15+5+1, 20+19+15+11 + 1, 20 +19+15+11+3 + 1, 20+19+15+11+5+1, 20+19+15+12+11 + 1, 20+19+15+12+11+3 + 1, 20 +19+15+12+11+5+1, 20+19+15+14, 20+19+16+1, 20+19+16+3 + 1, 20+19+16+5+1

- 8 042138

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39+20+18+15+11+3 + 1, 39+20+18+15+11+5+1, 39+20+18+15+12+11 + 1, 39+20+18+15+ 12+11+3 + 1, 39+20+18+15+12+11+5+1, 39+20+18+15+14, 39+20+19+1, 39+20+19+3 + 1, 39+20+19+5+1, 39+20+19+11 + 1, 39+20+19+11+3 + 1, 39+20+19+11+5+1, 39+20+ 19+12+11 + 1, 39+20+19+12+11+3 + 1, 39+20+19+12+11+5+1, 39+20+19+14, 39+20+19+ 15+1, 39+20+19+15+3 + 1, 39+20+19+15+5+1, 39+20+19+15+11+1, 39+20+19+15+11+ 3 + 1, 39+20+19+15+11+5+1, 39+20+19+15+12+11 + 1, 39+20+19+15+12+11+3 + 1, 39+ 20+19+15+12+11+5+1, 39+20+19+15+14, 39+20+19+16+1, 39+20+19+16+3+1, 39+20+ 19+16+5+1, 39+20+19+16+11 + 1, 39+20+19+16+11+3 + 1, 39+20+19+16+11+5+1, 39+ 20+19+16+12+11 + 1, 39+20+19+16+12+11+3 + 1, 39+20+19+16+12+11+5+1, 39+20+19+ 16+14, 39+20+19+16+15+1, 39+20+19+16+15+3 + 1, 39+20+19+16+15+5+1, 39+20+19+ 16+15+11 + 1, 39+20+19+16+15+11+3 + 1, 39+20+19+16+15+11+5+1, 39+20+19+16+15+ 12+11 + 1, 39+20+19+16+15+12+11+3 + 1, 39+20+19+16+15+12+11+5+1, 39+20+19+16+ 15+14,

- 25 042138

39+22+1, 39+22+3 + 1, 39+22+5+1, 39+22+11 + 1, 39+22+11+3 + 1, 39+22+11+5+1, 39+22+12+11 + 1, 39+22+12+11+3 + 1, 39+22+12+11+5+1, 39+22+14, 39+22+16+1 39+22 +16+3 + 1, 39+22+16+5+1, 39+22+16+11 + 1, 39+22+16+11+3 + 1, 39+22+16+11+5+1 , 39+22+16+12+11 + 1, 39+22+16+12+11+3 + 1, 39+22+16+12+11+5+1, 39+22+16+14, 39 +22+16+15+1, 39+22+16+15+3 + 1, 39+22+16+15+5+1, 39+22+16+15+11 + 1, 39+22+16 +15+11+3 + 1, 39+22+16+15+11+5+1, 39+22+16+15+12+11 + 1, 39+22+16+15+12+11+3 + 1, 39+22+16+15+12+11+5+1, 39+22+16+15+14, 39+22+20+1, 39+22+20+2+1, 39+22 +20+3 + 1, 39+22+20+4+1, 39+22+20+5+1, 39+22+20+6+1, 39+22+20+7+1, 39+22 +20+8+1, 39+22+20+9+1, 39+22+20+10+1, 39+22+20+11 + 1, 39+22+20+11+3 + 1, 39 +22+20+11+5+1, 39+22+20+12+11 + 1, 39+22+20+12+11+3 + 1, 39+22+20+12+11+5+1 , 39+22+20+13 + 11 + 1, 39+22+20+13 + 11+3 + 1, 39+22+20+13 + 11+5+1, 39+22+20+14, 39 +22+20+15+1, 39+22+20+15+3 + 1, 39+22+20+15+5+1, 39+22+20+15+11 + 1, 39+22+20 +15+11+3 + 1, 39+22+20+15+11+5+1, 39+22+20+15+12+11 + 1, 39+22+20+15+12+11+ 3+1, 39+22+20+15+12+11+5+1, 39+22+20+15+14, 39+22+20+16+1, 39+22+20+16+3 + 1, 39+22+20+16+5+1, 39+22+20+16+11 + 1, 39+22+20+16+11+3 + 1, 39+22+20+16+11+ 5+1, 39+22+20+16+12+11 + 1, 39+22+20+16+12+11+3 + 1, 39+22+20+16+12+11+5+1, 39+22+20+16+14, 39+22+20+16+15+1, 39+22+20+16+15+3 + 1, 39+22+20+16+15+5+1, 39+22+20+16+15+11 + 1, 39+22+20+16+15+11+3 + 1, 39+22+20+16+15+11+5+1, 39+22+ 20+16+15+12+11 + 1, 39+22+20+16+15+12+11+3 + 1, 39+22+20+16+15+12+11+5+1, 39+ 22+20+16+15+14, 39+22+20+17+1, 39+22+20+17+3 + 1, 39+22+20+17+5+1, 39+22+20+ 17+11 + 1, 39+22+20+17+11+3 + 1, 39+22+20+17+11+5+1, 39+22+20+18+1, 39+22+20+ 18+3 + 1, 39+22+20+18+5+1.39+22+20+18+11 + 1, 39+22+20+18+11+3 + 1, 39+22+20+ 18+11+5+1, 39+22+20+18+12+11 + 1, 39+22+20+18+12+11+3 + 1, 39+22+20+18+12+11+ 5+1, 39+22+20+18+14, 39+22+20+18+15+1, 39+22+20+18+15+3+1, 39+22+20+18+15+ 5+1, 39+22+20+18+15+11 + 1, 39+22+20+18+15+11+3 + 1, 39+22+20+18+15+11+5+1, 39+22+20+18+15+12+11 + 1, 39+22+20+18+15+12+11+3 + 1, 39+22+20+18+15+12+11+5+ 1, 39+ 22+20+18+15+14, 39+22+20+19+1, 39+22+20+19+3 + 1, 39+22+20+19+5+1, 39+22+20+ 19+11 + 1, 39+22+20+19+11+3 + 1, 39+22+20+19+11+5+1, 39+22+20+19+12+11 + 1,

- 26 042138

39+22+20+19+12+11+3 + 1, 39+22+20+19+12+11+5+1, 39+22+20+19+14, 39+22+20+19+ 15+1, 39+22+20+19+15+3 + 1, 39+22+20+19+15+5+1, 39+22+20+19+15+11 + 1, 39+22+ 20+19+15 + 11+3 + 1, 39+22+20+19+15+11+5+1, 39+22+20+19+15+12+11 + 1, 39+22+20+ 19+15+12+11+3 + 1, 39+22+20+19+15+12+11+5+1, 39+22+20+19+15+14, 39+22+20+19+ 16+1, 39+22+20+19+16+3 + 1, 39+22+20+19+16+5+1, 39+22+20+19+16+11 + 1, 39+22+ 20+19+16+11+3 + 1, 39+22+20+19+16+11+5+1, 39+22+20+19+16+12+11 + 1, 39+22+20+ 19+16+12+11+3 + 1, 39+22+20+19+16+12+11+5+1, 39+22+20+19+16+14, 39+22+20+19+ 16+15+1, 39+22+20+19+16+15+3 + 1, 39+22+20+19+16+15+5+1, 39+22+20+19+16+15+ 11+1, 39+22+20+19+16+15+11+3+1, 39+22+20+19+16+15+11+5+1, 39+22+20+19+16+ 15+12+11 + 1, 39+22+20+19+16+15+12+11+3 + 1, 39+22+20+19+16+15+12+11+5+1, 39+ 22+20+19+16+15+14, 40, 41.

In the list above, the numbers refer to the embodiments as numbered above, while + indicates a dependency on another embodiment. Various individualized embodiments are separated by commas. In other words, 11+3+1, for example, refers to option 11) depending on option 3), depending on option 1), i.e. option 11+3+1 corresponds to option 1) further limited by the features of options 3) and 11).

A P2Y ₁₂ receptor antagonist (particularly Compound 1) which is described as being useful in treating or preventing a disease according to any of embodiments 1)-38) has also been found to be useful in a method for treating and/or preventing a disease, wherein the method comprises subcutaneous administration of a pharmaceutically active amount of the P2Y ₁₂ receptor antagonist, or a pharmaceutically acceptable salt thereof, to a person in need thereof.

The present invention particularly relates to a method for the acute treatment of acute coronary syndromes (ACS) by self-administration by a patient prior to hospitalization of a pharmaceutically active amount of Compound 1, ticagrelor or ticagrelor-M (particularly Compound 1), or a pharmaceutically acceptable salt thereof, wherein the method comprises subcutaneous administration to a patient in need.

The present invention also relates to a method of treating a disease that responds to inhibition of platelet activation and/or platelet aggregation, comprising subcutaneously administering a pharmaceutically active amount of compound 1, ticagrelor or ticagrelor-M (particularly compound 1) or a pharmaceutically acceptable salt thereof to a person in need thereof. to a person.

The present invention also relates to a method of treating a disease that is responsive to a P2Y12 receptor antagonist, comprising subcutaneously administering a pharmaceutically active amount of Compound 1, ticagrelor or ticagrelor-M (particularly Compound 1), or a pharmaceutically acceptable salt to a person in need thereof.

A pharmaceutical composition containing a P2Y ₁₂ receptor antagonist (compound 1, ticagrelor or ticagrelor-M) or a pharmaceutically acceptable salt thereof may be in the form of an aqueous or oily solution, suspension or emulsion (preferably an aqueous solution) and may optionally contain one or more additional excipients . An additional excipient may be, for example, a pharmaceutically acceptable acid or base (to adjust the pH value of the pharmaceutical composition) or a pharmaceutically acceptable salt such as sodium chloride (to adapt the tonicity of the pharmaceutical composition).

The pharmaceutical composition may be in the form of a ready-to-use solution, suspension or emulsion, or in the form of an injectable powder containing a P2Y ₁₂ receptor antagonist, where the injectable powder requires dissolution in a pharmaceutically acceptable liquid to form an aqueous or oily solution, suspension or emulsion prior to subcutaneous administration. . Said solid may be in crystalline or amorphous form, or any mixture thereof.

The general terms and expressions used above and/or hereinafter preferably have the following meanings in this disclosure:

The term acute coronary syndromes (ACS) refers to syndromes due to a sudden decrease or interruption in blood flow in certain coronary arteries. Acute coronary syndromes include ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), or unstable angina. It is understood that a P2Y12 receptor antagonist that is disclosed as being useful in the prevention or treatment of ACS is also useful in the prevention or treatment of STEMI, NSTEMI and/or unstable angina.

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The term emergency management of suspected acute coronary syndromes refers to the treatment of a patient during which the patient exhibits ACS symptoms such as sudden onset chest pain, chest discomfort (intermittent or not), persistent chest pressure or heaviness extending to the left arm, neck , back or jaw for at least 10 minutes, nausea/vomiting, shortness of breath, fatigue, palpitations, dizziness, or fainting (and especially prominent ACS symptoms such as sudden onset chest pain, chest discomfort (intermittent or not), or persistent retrosternal pressure or heaviness extending to the left arm, neck, back or jaw, lasting at least 10 minutes); where the patient is to be treated and/or needs to be treated prior to an electrocardiogram, chest x-ray, and/or blood tests. In one embodiment, the patient is a patient who is already known to be at high risk of suffering from ACS prior to the onset of symptoms (especially overt symptoms) of ACS, such as, for example, a patient with established coronary artery disease who has had a previous symptomatic episode of acute coronary syndromes. In an additional embodiment, the treatment is carried out by self-administration by the patient prior to hospitalization; it is preferred that the patient be trained by a healthcare professional to better assess the symptoms of ACS prior to any such self-administration.

The term coronary artery disease (CAD) refers to a group of diseases that include myocardial infarction, unstable angina, stable angina and sudden cardiac death.

The term patient with a previous symptomatic episode of acute coronary syndromes refers to a patient who has had a myocardial infarction (STEMI or NSTEMI) or unstable angina.

The term subcutaneous administration refers to the introduction of a pharmaceutical composition into the subcutaneous layer by injection. Typical injection sites are the outer shoulder, abdomen (avoiding the area close to the navel), anterior thigh, chest, neck, upper back, and upper buttocks; abdomen and anterior thigh are preferred. Subcutaneous administration may be performed using any type of suitable injection device such as, for example, a syringe or an auto-injector device.

The term intradermal administration refers to the administration of a pharmaceutical composition into the dermis by injection. Typical insertion sites are the inner surface of the forearm and upper back under the shoulder blade.

The term bolus injection, when used in the context of subcutaneous administration/injection, refers to the injection of a discrete amount of a P2Y ₁₂ receptor antagonist (particularly in a pharmaceutical composition suitable for subcutaneous administration) over a relatively short period of time (typically 1 to 90 seconds) .

The term patient refers to a mammal, in particular a human, having a disease or disorder that can be prevented or treated with a P2Y12 receptor antagonist. In a preferred embodiment, the patient is a human having a disease or disorder that can be prevented or treated (especially treated) with a P2Y12 receptor antagonist, wherein said individual has previously had a statistically increased risk of developing the disease or disorder.

The term self-administration by a patient refers to the administration of a pharmaceutical composition to a patient by the patient himself or by acquaintances with minimal medical training, such as a relative, friend or neighbor (especially by the patient himself).

The term administration by healthcare professionals refers to the administration of a pharmaceutical composition to a patient by a person who is professionally trained to perform such administrations, such as, for example, a nurse or physician. Preferably, any such administration is performed prior to the patient's hospitalization (eg, in an ambulance or elsewhere prior to the patient being admitted to the hospital).

The term auto-injection device refers to a medical device for automatically administering a pharmaceutical composition after a trigger or activator or the like has been pulled.

Autoinjector devices may be, for example, in the form of a pen device, a patch device, or a patch pump.

Any reference to a P2Y ₁₂ receptor antagonist in this specification is to be understood as referring also to pharmaceutically acceptable salts of such a P2Y 12 antagonist.

The term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the target compound and exhibit minimal undesirable toxicological effects. Such salts include inorganic or organic acid and/or base addition salts, depending on the presence of basic and/or acidic groups in the compound in question. For reference, see, for example, Guide to Pharmaceutical Salts. Properties, Selection and Use, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and Pharmaceutical Salts and Co-crystals, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

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A preferred pharmaceutically acceptable salt of Compound 1 is the hydrochloride salt of Compound 1. Another preferred pharmaceutically acceptable salt of Compound 1 is the 2-amino-2-(hydroxymethyl)-1,3-propanediol or sodium salt of Compound 1.

The term pharmaceutically acceptable liquid refers to a liquid which provides an injectable solution, suspension or emulsion (particularly a solution) when mixed with a P2Y12 receptor antagonist (particularly Compound 1) or a pharmaceutically acceptable salt thereof, optionally together with one or more therapeutically inert excipient(s) that exhibits minimal undesirable toxicological effects. A preferred example of a pharmaceutically acceptable liquid is water, especially water for injection and especially sterile water for injection.

When not used in relation to temperatures, the term approximately given before the numerical value of X refers herein to the range of X minus 10% X to X plus 10% X, and preferably to the range of X minus 5% X to X plus 5% X. In the particular case of temperatures, the term roughly preceded by temperature Y refers herein to the range from temperature Y minus 10°C to Y plus 10°C, and preferably to the range from Y minus 5 °С to Y plus 5°С.

Whenever the word between is used to describe a numeric range, it should be understood that the endpoints of the specified range are explicitly included in the range. For example: if the volume range is described as 0.1-3.0 ml, this means that the endpoints of 0.1 and 3.0 ml are included in the range; or if the variable is defined as an integer between 1 and 4, it means that the variable is an integer 1, 2, 3, or 4.

experimental part

Abbreviations.

The following abbreviations are used in the description and examples:

ACS acute coronary syndromes aq. water ET outdoor temperature FACS sorting of fluorescent activated cells h watch) IPC interoperational control IT internal temperature min minute(s) PBS phosphate buffered saline solution PCI percutaneous coronary intervention PEG400 poly(ethylene glycol) k.t. room temperature sat. saturated With second(s) about. l solvent per kg starting material

Preparation of compound 1 and its HCl salt.

Compound 1 can be prepared according to the procedures as disclosed in WO 2009/069100 (Example 2) or Caroff E. et al., J. Med. Chem. (2015), 58, 9133-9153. Alternatively, Compound 1 and its HCl salt can be prepared according to the following procedure.

A 15 L reactor was charged with sodium (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylate (584 g, 1.82 mol) and 1-hydroxybenzotriazole monohydrate (HOBt) (274 g, 1.1 eq.) . Water (1305 ml, 2.0 vol) was added. The pH of the suspension was 5-6. Butyl (R)-4-(2-amino-3-(diethoxyphosphoryl)propanoyl)piperazine-1-carboxylate (665.7 g, 1.0 equiv.) was dissolved in tetrahydrofuran (THF) (1960 ml, 3.0 vol.). The solution was added to the reaction mixture at 20-30°C for 5-10 min. A solution of 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDCI) (389 g, 1.2 equiv.) in water (1305 ml, 2.0 vol.) was added to the reaction mixture at 20-30°C over 15-30 min. The pH of the reaction mixture remained between 6-7. The reaction mixture was stirred for 4 hours at 20-30°C. IPC showed 93% conversion. The reaction mixture was diluted with dichloromethane (DCM) (3265 ml, 5.0 vol.) and _1/2 sat. aq. sodium bicarbonate solution (3265 ml, 5.0 vol.). The layers were separated. The organic layer was washed again with _1/2 sat. aq. sodium bicarbonate solution (3265 ml, 5.0 vol.). The layers were separated. IPC showed complete removal of HOBt. The organic layer was washed again with 10% aq. citric acid (3265 ml, 5.0 vol.). A total of 3.75 liters of solvents were distilled off at a minimum of 800 mbar and ET = 75-80° C. over 40 minutes. The residual solution was cooled to 20-30°C. Added aq. 32% HCl (3 L, 19 eq.) for 5-10 min at 20-30°C. IPC after 4 hours of stirring showed complete hydrolysis. Water (5.2 L, 8 vols) was added at 20-30°C. reaction mixture

- 29 042138 was diluted with DCM (5.2 L, 8 vol). The layers were separated. The aqueous layer was again extracted twice with DCM (5.2 L, 8 vol). All DCM layers were combined and filtered through a Polycap 75 HD filter. A total of 14 liters of solvents were distilled off for 2 hours at atmospheric pressure and ET = 75-80°C. To the reaction mixture under reflux was added acetone (21.6 l, 33 vol.) at ET = 70-75°C. Water (325 ml, 0.5 vol) was added to the boiling thin slurry under reflux. The thin pale suspension was stirred at reflux for 1.5 hours to give a thick white slurry. The suspension was cooled to IT = 25°C for 1 h (linear change). The solid product was isolated by filtration. The filter cake was washed with acetone (4.5 L, 7 vol) and dried by blowing nitrogen through it to give 750 g (69%) of ((R)-3-(4-(butoxycarbonyl)piperazin-1-yl) hydrochloride )-2-(6-((S)-3-methoxypyrrolidin-1yl)-2-phenylpyrimidine-4-carboxamido)-3-oxopropyl)phosphonic acid as a white solid. Purity by LC-MS was >99% a/a, purity by 1H-NMR analysis was 98% w/w.

Composition of compound 1 (lower dose 1 mg/ml).

An aqueous solution of 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris base, 21.6 ml, 1.0 M) was added to 4.80 L of water for injection (WFI) in a glass vial. Butyl ester hydrochloride (6.00 g) 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4carbonyl]amino}-3-phosphonopropionyl)piperazine was added successfully -1-carboxylic acid and mannitol (210 g) and the mixture was stirred until complete dissolution. Additional Tris base was added to pH 7.4±0.1. The solution was diluted to a final volume of 6.00 L with WFI, refilled into glass vials (1.1 ml per vial), dried by lyophilization, and reconstituted with 1.0 ml of WFI before administration to give a subcutaneous solution of Compound 1 .

Composition of compound 1 (higher dose 20 mg/ml).

An aqueous solution of 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris base, 21.6 ml, 1.0 M) was added to 4.80 L of water for injection (WFI) in a glass tube. 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1 butyl ester hydrochloride was added successively α-carboxylic acid (120 g) and mannitol (120 g) and the mixture was stirred until complete dissolution. Additional Tris base was added to pH 7.4±0.1. The solution was diluted to a final volume of 6.00 L with WFI, refilled into glass vials (1.1 ml per vial), dried by lyophilization, and reconstituted with 1.0 ml of WFI before administration to give a subcutaneous solution of Compound 1 .

In vivo measurements of time-dependent platelet inhibition following subcutaneous administration of P2Y ₁₂ receptor antagonists.

Animals.

Balb/c male mice were purchased from Charles River Laboratories (Sulzfeld, Germany). All animals were kept under the same conditions in accordance with the recommendations of the cantonal veterinary department of Basel-Landschaft. Animals were housed in professional animal housing, with group cages provided with standard food/water freely available, as well as standard lighting and climatic conditions. Technical assistants performed at least one check per day.

Sufficient time was given to the animals to get used to the experimental environment. Stress reduction was also provided by arranging cells and providing the possibility of shelter in dark rooms (using color blindness in albino mice in the red range of the light spectrum). Inside the red enclosure, the animals have the impression that they are in the dark, while this enclosure remains visible to normal human vision.

Reagents: The hydrochloride salt of compound 1 was synthesized according to the above procedure. Ticagrelor was extracted from commercially available tablets (Brilique).

Fibrinogen from human plasma conjugate Alexa Fluor TM 488, catalog number F-13191, was purchased from Molecular Probes and processed as described in the supplier's data sheet.

Preparation of test compounds. Compound 1 hydrochloride (0.04 mg/ml), ticagrelor (0.2 mg/ml), elinogrel (6 mg/ml) or cangrelor (0.04 mg/ml) was dissolved in 25% PEG 400/water.

Preparation of test compounds: compound 1 hydrochloride (0.04 mg/ml), ticagrelor (0.2 mg/ml), elinogrel (6 mg/ml) or cangrelor (0.04 mg/ml) were dissolved in 25% PEG 400/ water.

Experimental groups: compounds were administered by subcutaneous injection in the lower abdomen:

Compound 1 hydrochloride, 0.2 mg/kg (corresponding to 5 ml/kg).

Ticagrelor, 1 mg/kg (corresponding to 5 ml/kg).

Elinogrel, 30 mg/kg (corresponding to 5 ml/kg).

Kanglor, 0.2 mg/kg (corresponding to 5 ml/kg).

Animal Preparation: After an acclimatization period of at least 7 days, mice were anesthetized with isoflurane (2-5%). Then the animals were placed on a thermostatically controlled heating table to maintain body temperature at 36-38°C. Polyurethane catheter (BTPU-027)

- 30 042138 was injected into the right jugular vein and advanced into the vena cava for heparin infusion and for blood collection. In order to perform accurate platelet tests, it is necessary to ensure that blood collection does not result in platelet activation. Therefore, heparin (4000 units/kg/2.5 ml) was administered intravenously to prevent blood clotting.

Experimental procedure: 2 minutes after the injection of heparin, 60 μl of whole blood was collected through the vena cava catheter (baseline). After a baseline blood draw, the test compounds were injected subcutaneously into the lower abdomen of the animals. At 10, 20, 30, 40 and 60 minutes after the subcutaneous injection of the test compounds, 60 μl of whole blood was collected via a vena cava catheter for fibrinogen binding analysis.

AF488 fibrinogen binding assay.

This assay is particularly well suited for robust studies of the effects of P2Y ₁₂ antagonists on mouse platelets in vitro and in vivo. The assay measures ADP-induced AF488 fibrinogen binding on mouse platelets in only 6 µl of whole blood and without washing steps.

First, the blood was incubated with 4 μl of vehicle or 4 μl of Compound 1 hydrochloride (to obtain a final concentration of 2 μM in diluted blood) for 15 min at room temperature. This compound 1 hydrochloride concentration has been determined in previous experiments to inhibit 100% ADP-induced AF488 fibrinogen binding on platelets and represents a non-specific signal. Then, 10 µl of fibrinogen AF488 (to obtain a final concentration of 0.5 mg/ml) was added, followed by incubation for 5 minutes. To induce AF488 fibrinogen binding, platelets were then incubated with 10 µl of ADP (to a final concentration of 20 µM) for 5 min. In addition, incubation with platelet antibody against allophycocyanin (APC) against mouse CD61 (integrin beta 3) (clone 2C9.G2) was performed for 10 min. The platelets were then fixed by adding 34 µl of cold paraformaldehyde solution (to give a final concentration of 0.1%) and stored at 4°C for about 20 minutes. Finally, the samples were diluted with 1.8 ml of cold PBS and kept at 4°C for at least 2 hours, the time required for the mild lysis of erythrocytes, before being measured by flow cytometry.

Receiving data.

Flow cytometry was performed using a FACSCanto II instrument (BD Bioscience). Fluorescence compensation adjustment was not required due to the use of two different lasers. Platelets were first detected using the APC-CD61 platelet specific fluorescent signal (APC settings for fluorescent peak at 660 nm). The platelet population was then subjected to forward scatter (FSC) and side scatter (SSC) gating and their FITC-labeled fibrinogen signal (FITC settings for peak fluorescent emission at 525 nm) was determined as the mean fluorescence intensity (MFI) of 5000 platelets. For each sample, the MFI was subtracted from the corresponding non-specific sample.

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Table 1

Mean fluorescence intensity of AF488 fibrinogen binding to platelets

Time [Minutes] 0 10 20 40 60 Compound 1 0.2 mg/kg sc [MFI] [MFI] [MFI] [MFI] [MFI] Experiment 1 6037 1721 1229 1315 Experiment 2 9042 2909 2542 2544 Experiment 3 8234 1655 1126 997 Experiment 4 7711 2509 1697 1495 1235 Experiment 5 10574 4175 2882 2638 1914 Experiment 6 13675 5806 3763 2582 2375 Ticagrelor 1 mg/kg sc [MFI] [MFI] [MFI] [MFI] [MFI] Experiment 1 8449 3351 1576 1067 Experiment 2 5864 911 510 554 Experiment 3 8707 3061 970 549 Experiment 4 8218 2001 1224 683 917 Experiment 5 6904 6537 4292 2181 1761 Experiment 6 11749 5771 3473 2340 2261 Experiment 7 6073 5625 3840 1937 1148 Elinogrel 30 mg/kg sc [MFI] [MFI] [MFI] [MFI] [MFI] Experiment 1 8124 4403 2374 1644 2034 Experiment 2 5370 4712 3847 1768 1503 Experiment 3 7045 3842 2177 1652 1515 Experiment 4 7097 3840 4078 2619 2191 Cangrelor 0.2 mg/kg s.c. [MFI] [MFI] [MFI] [MFI] [MFI] Experiment 1 6200 1596 713 765 1048 Experiment 2 7453 1628 1364 732 682 Experiment 3 5476 2550 1012 921 961

In vivo measurements of time-dependent inhibition of platelet aggregation (IPA) after subcutaneous administration of Compound 1 to healthy volunteers.

The dependence of plasma concentration on time and dose and inhibition of platelet aggregation (IPA) after subcutaneous administration of compound 1 was investigated in a clinical phase I study in healthy males.

Research plan.

In a randomized, double-blind, placebo-controlled trial, 48 fasting subjects were exposed to single subcutaneous doses ranging from 1 to 32 mg (1, 2, 4, 8, 16, and 32 mg) of Compound 1 (n=6 for Compound 1 and n =2 for placebo per dose level).

Subcutaneous composition of compound 1.

Compound 1 for SC administration was available as sealed glass vials in 20 mg quantities. The tubes contained lyophilized compound 1 to dilute with 1 ml water for injection to prepare stock solutions of 20 mg/ml (see above: composition of compound 1 (higher dose 20 mg/ml)). These stock solutions were further diluted with 0.9% sodium chloride to prepare solutions of 2, 4, 8, 16 and 20 mg/ml. The volume injected was 0.5 ml for dose levels of 1, 2, 4 and 8 mg. For dose levels of 16 and 32 mg, 1 or 2 injection(s) of 0.8 ml of a 20 mg/ml solution were given.

The solution for injection was prepared for administration in a syringe suitable for SC injection. The solution was administered as an injection into the thigh.

Assessment of pharmacokinetic (PK) parameters.

Compound 1 plasma PK parameters were obtained by non-compartmental analysis of plasma concentration profiles over time. The following parameters were obtained:

maximum plasma concentration (Cmax);

time to reach Cmax (tmax);

the area under the plasma concentration/time curve (AUC) from zero to the time t of the last measured concentration above the limit of quantitation (AUC0-t); and terminal half-life (tV ₂ ).

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1) Blood sampling.

Blood was collected by direct venipuncture or through an intravenous catheter placed in the lateral saphenous vein of the arm into a 4 ml Monovette® or equivalent tube containing ethylenediaminetetraacetic acid. Immediately after collecting the required volume of blood, the Monovette® was slowly tilted back and forth (without shaking) to introduce the anticoagulant into the solution and immediately cooled on ice. Within 30 minutes of collection, the Monovette® was centrifuged at approximately 1500g for 10 minutes at 4°C. Plasma was transferred into one labeled polypropylene tube to avoid transfer of RBCs. All samples were stored upright at temperatures below -70°C.

2) Bioanalysis.

Plasma analysis of Compound 1 was performed using validated liquid chromatography coupled with tandem mass spectrometric analysis. The lower limit of quantification (LLOQ) was 1 ng/mL. Concentrations were calculated by interpolation from a standard curve. Quality control (QC) samples were analyzed throughout the study. Their measured concentrations were used to determine the intermediate and overall accuracy and accuracy of the analysis.

3) Results.

table 2

Summary table of pharmacokinetic parameters of compound 1 after subcutaneous doses from 1 to 32 mg

Parameter [unit] 1 mg (n=6) 2 mg (N=6) 4 mg (N=6) 8 mg (N=6) 16 mg (N=6) 32 mg (N=6) C _max [ng/ml] G.S. 95%CI 33.654 25.4, 44.7 58.437 48.5, 70.4 128.394 76.5, 215 272.731 211, 353 435.035 335.565 929.632 786.1100 tmax [h] Average Min, Max 0.500 0.25, 1.00 0.500 0.42, 1.00 0.500 0.37, 1.00 0.500 0.33, 1.00 0.750 0.25, 1.00 0.750 0.50, 1.00 AUC0-t [ng*h/ml] G.S. 95%CI 56.053 45.3, 69.4 115.599 89.8, 149 260.652 181.375 585.336 449.763 1119.438 951, 1317 2343.485 1956.2807 1½ [h] G.S. 95%CI 1.337 1.09, 1.64 1.916 1.18, 3.11 2.663 2.02, 3.51 3.975 2.38, 6.63 7.204 4.89, 10.6 9.203 6.15, 13.8

G.S: geometric mean;

95% CI: 95% confidence interval of the geometric mean.

Assessment of pharmacodynamic (PD) parameters (inhibition of platelet aggregation).

1) Blood sampling.

PD blood samples were collected by direct venipuncture or through an intravenous catheter placed in the lateral saphenous vein of the arm using 18-21 gauge needles. The first 2 ml of blood was discarded, after which the blood was carefully drawn into two open tubes to collect 3.5 ml. Tubes for analysis LTA (light transmission aggregometry) contained phenylalanine-prolinarginine-cholormethyl ketone (PPACK) as an anticoagulant.

2) Bioanalysis.

Adenosine diphosphate (ADP)-induced platelet aggregation was assessed using the LTA assay, which measures platelet aggregation as an increase in light transmittance (Michelson A.D., Methods for the measurement of platelet function (2009), Am. J. Cardiol. 103(3):20A -26A).

LTA analysis: two 3.5 ml blood samples were centrifuged to prepare platelet-rich plasma (PRP) and platelet-poor plasma (PPP). If necessary, PRP was adjusted to a final platelet count of 260x109 platelets per liter by diluting PPP from the same donor. The analysis was performed using an 8-channel platelet aggregometer, recording aggregation after the addition of 20 μM ADP as an agonist for 6 min. Results are expressed as percent change in light transmittance at maximum (peak) platelet aggregation (MPA) calculated relative to a baseline signal of 0%. The measurements were carried out in duplicate.

3) Results.

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Table 3

Summary table of pharmacodynamic parameters (% IPA (inhibition of platelet aggregation) calculated using maximum values of platelet aggregation) after subcutaneous doses of 1 to 32 mg

Time [h] 1 mg (n=6) 2 mg (n=6) 4 mg (n=6) 8 mg (n=6) 16 mg (n=6) 32 mg (n=6) mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD mean ± SD 0.25 61.4± 60.3± 79.7 ± 6.0 88.9 ± 8.4 92.8 ± 5.5 95.5 ± 2.7 15.1 48.3 0.5 64.4± 12.8 79.5± 10.8 84.7 ± 5.4 90.0 ± 8.5 93.1 ± 3.6 94.5 ± 2.0 3 15.8± 20.0 36.8± 30.0 58.5 ± 7.2 77.9± 19.5 95.0 ± 1.2 94.5 ± 2.0 4 -10.0 ± 24.2 35.5± 18.9 50.6± 22.1 70.9± 12.5 88.2 ± 4.7 91.2 ± 1.9 5 -6.1 ± 26.0 14.1± 28.4 47.9± 17.9 75.2± 11.5 87.6 ± 5.5 92.1 ± 2.6 12 -4.5 ± 24.7 31.3± 28.9 37.4± 16.7 64.0 ± 10.4 76.0 ± 13.8 83.5± 12.9 48 -47.7± 29.9 11.3± 38.5 2.1 ± 16.3 -1.3 ± 33.7 -1.6 ± 43.8 29.8± 20.9

SD: standard deviation.

As can be seen from Table. 3, at each dose level, the peak % IPA was reached approximately 15-30 minutes post-dose. Peak % IPA reached values above 85% at doses >4 mg (at doses >8 mg even in less than 15 minutes). The duration of PD effects was dose dependent. Average % IPA >85% was maintained for approximately 5 and 12 hours after administration of 16 and 32 mg of Compound 1, respectively.

Claims (16)

1. The use of a P2Y ₁₂ receptor antagonist or a pharmaceutically acceptable salt thereof for the prevention or treatment of a disease, wherein the disease is selected from acute coronary syndromes, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke, and transient ischemic attack, wherein the P2Y ₁₂ receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carbonyl]amino}-3phosphonopropionyl)piperazine-1-carboxylic acid butyl ester and wherein the P2Y12 receptor antagonist is administered to the patient by subcutaneous injection. 2. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to claim 1, wherein the disease is acute coronary syndromes. 3. Use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to claim 1, wherein the disease is a myocardial infarction. 4. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the P2Y12 receptor antagonist is administered prior to hospitalization. 5. Use of the P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to claim 4, wherein the _P2Y12 receptor antagonist is administered by self-administration by the patient. 6. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof for emergency treatment of suspected acute coronary syndromes by self-administration by a patient prior to hospitalization, where the P2Y12 receptor antagonist is 4-((R)-2-{[6-(( S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic acid, and wherein the P2Y12 receptor antagonist is administered to the patient by subcutaneous injection. 7. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the amount of butyl ester administered is 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl )-2phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic acid is between 1 and 75 mg per administration. 8. Use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the amount of butyl ester administered is 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl )-2phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic acid is between 5 and 35 mg per administration. 9. The use of a P2Y12 receptor antagonist, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein the P2Y12 receptor antagonist, optionally together with one or more therapeutically inert excipient(s), is dissolved in a pharmaceutically acceptable liquid to form a solution, and wherein the volume administered is solution is between 0.1 and 3.0 ml per injection. 10. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to claim 9, - 34 042138 where the pharmaceutically acceptable liquid is water. 11. Use of a P2Y ₁₂ receptor antagonist or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the P2Y 12 receptor antagonist is administered by bolus. 12. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein a platelet aggregation inhibition value of at least 75% is achieved within 30 minutes of initiation of administration of the P2Y12 receptor antagonist in at least 80% of patients. 13. The use of a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein a platelet aggregation inhibition value of at least 80% is achieved within 30 minutes of initiation of administration of the P2Y12 receptor antagonist in at least 80% of patients. 14. Use of 4-((R)-2-{[6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1 butyl ester -carboxylic acid or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease, wherein the disease is selected from acute coronary syndromes, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke, and transient ischemic attack, and wherein the drug is administered to a patient by subcutaneous introductions. 15. Application of P2Y12 receptor antagonist - butyl ester 4-((R)-2-{[6-((S)-3methoxypyrrolidin-1 -yl)-2-phenylpyrimidine-4-carbonyl]amino } -3-phosphonopropionyl)piperazine -1 carboxylic acid or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in emergency treatment of suspected acute coronary syndromes by self-administration by the patient prior to hospitalization, where the P2Y ₁₂ receptor antagonist is to be administered to the patient by subcutaneous injection. 16. A method for the emergency treatment of acute coronary syndromes by self-administration by the patient before hospitalization of a pharmaceutically active amount of butyl ester 4-((R)-2-{[6((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidin-4 -carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the method comprises subcutaneous administration to a patient in need thereof. The intensity of AF488 fibrinogen binding after subcutaneous injection of compound 1 hydrochloride (0.2 mg/kg) in Balb/c male mice Fig. 1 Intensity of AF488 fibrinogen binding after subcutaneous administration of ticagrelor (1.0 mg/kg) in Balb/c male mice Fig. 2 - 35 042138 The intensity of AF488 fibrinogen binding after subcutaneous injection of elinogrel (30 mg/kg) in Balb/c male mice AF488 fibrinogen binding intensity after subcutaneous administration of cangrelor (0.2 mg/kg)