IP Library › Granted Patent US 8,044,055

Granted Patent B2

US 8,044,055 · App. 12/447,039 · Granted Oct 25, 2011

2-phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y12 receptor

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Patent No.: US 8,044,055
App. No.: 12/447,039
Granted: Oct 25, 2011
Kind: B2

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Abstract

The invention relates to 2-phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y 12 receptor antagonists in the treatment and/or prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. Formula (I).

Claims (89)

1. A compound of formula I

wherein

R 1 represents phenyl optionally substituted 1 to 3 times by substituents each independently selected from the group consisting of halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

R 2 represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group, a dimethoxyalkyl group or a (2,2-dimethyl-[1,3]dioxolan-4-yl)-alkyl group;

or R 2 represents a group of the formula

wherein

either m is 1 and n is 2 or 3, or m is 2 and n is 2; and

X represents O, S, NH, NR 3 , SO or SO 2 ;

R 3 represents alkyl or arylalkyl;

or also R 2 represents 2,2,6,6-tetramethyl-piperidin-4-yl;

each of R 4 and R 5 represents independently hydrogen or methyl;

R 6 represents alkoxy; and

Y represents alkylene or phenylalkylene, and Z represents —OH, —COOH, cyano, tetrazolyl or —COOR 7 , R 7 representing alkyl;

or a salt of such a compound.

2. A compound according to claim 1 , wherein R 1 represents phenyl optionally substituted once by halogen, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

3. A compound according to claim 1 , wherein R 2 represents an alkoxyalkoxyalkyl group, a dihydroxyalkyl group, a dimethoxyalkyl group or a (2,2-dimethyl-[1,3]dioxolan-4-yl)-alkyl group.

4. A compound according to claim 1 , wherein R 2 represents group of the formula

or R 2 represents 2,2,6,6-tetramethyl-piperidin-4-yl.

5. A compound according to claim 1 , wherein one of R 4 and R 5 represents hydrogen and the other represents hydrogen or methyl.

6. A compound according to claim 1 , wherein Y represents alkylene or phenylalkylene, and Z represents —OH or —COOH or tetrazolyl.

7. A compound according to claim 6 , wherein Y represents —CH 2 —, —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —, and Z represents —COOH.

8. A compound according to claim 1 , which is selected from the group consisting of:

4-[(S)-4-carboxy-2-({6-[2-(2-methoxy-ethoxy)-ethoxy]-2-phenyl-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-phenyl-pyrimidine-4-carbonyl]amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-((S)-2,3-dihydroxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-((R)-2,3-dimethoxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-pyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-(1-methyl-piperidin-3-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-2-{[6-(1-benzyl-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-4-carboxy-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-(4-fluoro-phenyl)-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

((S)-4-carboxy-2-{[6-(tetrahydro-furan-3-yloxy)-2-p-tolyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-3-methyl-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-3-(4-carboxy-phenyl)-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyrimidine-4-carbonyl]amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-cyano-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-3-hydroxy-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-2-{[2-phenyl-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-4-(1H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[2-phenyl-6-(tetrahydro-pyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[6-(1-methyl-piperidin-3-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-2-{[6-(1-benzyl-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-carbony]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-3-(4-tert-butoxycarbonyl-phenyl)-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-propionyl]-piperazine-1-carboxylic acid ethyl ester;

((S)-4-tert-butoxycarbonyl-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[2-phenyl-6-(2,2,6,6-tetramethyl-piperidin-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-(3-hydroxy-2-hydroxymethyl-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-thiopyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-carboxy-2-({2-phenyl-6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-carboxy-2-({2-phenyl-6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-carboxy-2-({2-phenyl-6-[tetrahydro-furan-3-yloxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-carboxy-2-({2-phenyl-6-[tetrahydro-furan-3-yloxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester;

4-[(S)-4-carboxy-2-({2-phenyl-6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester;

4-[(S)-4-carboxy-2-({2-phenyl-6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-4-carboxylic acid butyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[6-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-2-phenyl-pyrimidine-4-carbonyl]amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-tert-butoxycarbonyl-2-{[2-phenyl-6-(tetrahydro-thiopyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-tert-butoxycarbonyl-2-({2-phenyl-6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-4-tert-butoxycarbonyl-2-({2-phenyl-6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester;

4-[(S)-4-tert-butoxycarbonyl-2-({2-phenyl-6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid butyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(piperidin-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid butyl ester; and

4-((S)-4-tert-butoxycarbonyl-2-{[2-phenyl-6-(piperidin-4-yl)oxy)-pyrimidine-4-carbonyl]amino}-butyryl)-piperazine-1-carboxylic acid butyl ester;

or a pharmaceutically acceptable salt of such a compound.

9. A compound according to claim 1 , which is selected from the group consisting of:

4-[(S)-4-carboxy-2-({6-[2-(2-methoxy-ethoxy)-ethoxy]-2-phenyl-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-((S)-2,3-dihydroxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-((R)-2,3-dimethoxy-propoxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-pyran-4-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[6-(1-methyl-piperidin-3-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

4-((S)-2-{[6-(1-benzyl-piperidin-4-yloxy)-2-phenyl-pyrimidine-4-carbonyl]-amino)-4-carboxy-butyryl}-piperazine-1-carboxylic acid ethyl ester;

4-((S)-4-carboxy-2-{[2-(4-fluoro-phenyl)-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

((S)-4-carboxy-2-{[6-(tetrahydro-furan-3-yloxy)-2-p-tolyl-pyrimidine-4-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester;

((S)-4-carboxy-2-{[2-phenyl-6-(tetrahydro-furan-3-yloxy)-pyrimidine-4-carbonyl]-amino}-butyryl)-3-methyl-piperazine-1-carboxylic acid ethyl ester;

4-[(S)-3-(4-carboxy-phenyl)-2-({2-phenyl-6-[(tetrahydro-furan-3-yl)oxy]-pyrimidine-4-carbonyl}-amino)-propionyl]piperazine-1-carboxylic acid ethyl ester;