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Last Updated: January 18, 2020

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Claims for Patent: 10,138,260

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Summary for Patent: 10,138,260
Title:Compounds of phosphinanes and azaphosphinanes, a process for their preparation and pharmaceutical compositions containing them
Abstract: Compounds of formula (I) ##STR00001## wherein: Ak.sub.1 represents an alkyl chain, X represents --(CH.sub.2).sub.m--, --CH(R)--, --N(R)--, --CH.sub.2--N(R)--, --N(R)--CH.sub.2-- or --CH.sub.2--N(R)--CH.sub.2--, m and R are as defined in the description, R.sub.1 and R.sub.2 each represent H when X represents --(CH.sub.2).sub.m--, --CH(R)--, --N(R)--, --CH.sub.2--N(R)-- or --N(R)--CH.sub.2--, or together form a bond when X represents --CH.sub.2--N(R)--CH.sub.2--, R.sub.3 represents NH.sub.2, Cy-NH.sub.2, Cy-Ak.sub.3-NH.sub.2 or piperidin-4-yl, Cy and Ak.sub.3 are as defined in the description, R.sub.4 and R.sub.5, which may be identical or different, each represent H or F, their optical isomers, and addition salts thereof with a pharmaceutically acceptable acid. Medicinal products containing the same which are useful in treating conditions requiring a TAFIa inhibitor.
Inventor(s): Gloanec; Philippe (Marly le Roi, FR), Schaffner; Arnaud-Pierre (Marly le Roi, FR), Sansilvestri-Morel; Patricia (Antony, FR), Rupin; Alain (Savonnieres, FR), Mennecier; Philippe (Conflans Sainte Honorine, FR), Vallez; Marie-Odile (Montreuil, FR)
Assignee: LES LABORATOIRES SERVIER (Suresnes, FR)
Application Number:15/548,533
Patent Claims:1. A compound of formula (I): ##STR00134## wherein: Ak.sub.1 represents a C.sub.1-C.sub.6-alkyl chain; X represents --(CH.sub.2).sub.m--, --CH(R)--, --N(R)--, --CH.sub.2--N(R)--, --N(R)--CH.sub.2-- or --CH.sub.2--N(R)--CH.sub.2--; m represents 0 or an integer from 1 to 4; R represents a hydrogen atom, C.sub.1-C.sub.6-alkyl, -Ak.sub.2-Ar.sub.1, -Ak.sub.2-Ar.sub.1-Ar.sub.2, -Ak.sub.2-Ar.sub.1-O--Ar.sub.2, -Ak.sub.2-cycloalkyl or -Ak.sub.2-OH; Ak.sub.2 represents a linear or branched C.sub.1-C.sub.6-alkyl chain; Ar.sub.1 and Ar.sub.2, which may be identical or different, each represent an aryl or heteroaryl group; R.sub.1 and R.sub.2 each represent a hydrogen atom when X represents --(CH.sub.2).sub.m--, --CH(R)--, --N(R)--, --CH.sub.2--N(R)-- or --N(R)--CH.sub.2--, or together form a bond when X represents --CH.sub.2--N(R)--CH.sub.2--; R.sub.3 represents NH.sub.2, Cy-NH.sub.2, Cy-Ak.sub.3-NH.sub.2 or piperidin-4-yl; Cy represents cycloalkyl, aryl or heteroaryl; Ak.sub.3 represents a C.sub.1-C.sub.3-alkyl chain; R.sub.4 and R.sub.5, which may be identical or different, each represent a hydrogen atom or a fluorine atom; its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

2. The compound according to claim 1, wherein R.sub.1, R.sub.2, R.sub.4 and R.sub.5 each represent a hydrogen atom; R.sub.3 represents NH.sub.2; X represents --N(R)--, --CH.sub.2--N(R)--, --N(R)--CH.sub.2-- or --CH.sub.2--N(R)--CH.sub.2--; and R represents a group selected from -Ak.sub.2-Ar.sub.1, -Ak.sub.2-Ar.sub.1-Ar.sub.2 and -Ak.sub.2-Ar.sub.1-O--Ar.sub.2.

3. The compound according to claim 1, which is a compound of formula (Ia): ##STR00135## wherein Ra represents --CH.sub.2-Ar.sub.1 or --CH.sub.2-Ar.sub.1-Ar.sub.2, wherein Ar.sub.1 and Ar.sub.2, which may be identical or different, each represent an aryl or heteroaryl group.

4. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[[2-(3,4-dimethoxyphenyl)-4-fluorophenyl]methyl]-- 4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

5. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(4-methylphenyl)phenyl]methyl]-4-hyd- roxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

6. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(4-methoxyphenyl)phenyl]methyl]-4-hy- droxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

7. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[[4-fluoro-2-(4-fluorophenyl)phenyl]methyl]-4-hyd- roxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

8. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-4-hydroxy-1-[(4-hydroxy-2-phenylphenyl)methyl]-4-ox- o-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

9. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-4-hydroxy-1-[2-(6-methoxypyridin-3-yl)benzyl]-4-oxo- -1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

10. The compound according to claim 7, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[[2-(4-chlorophenyl)-4-fluorophenyl]methyl]-4-hyd- roxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

11. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[4-fluoro-2-(1-methyl-1H-imidazol-5-yl)benzyl]-4-- hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

12. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-1-[2-(1,2-dimethyl-1H-imidazol-5-yl)-4-fluorobenzyl- ]-4-hydroxy-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

13. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-4-hydroxy-1-[[4-hydroxy-2-(4-methylphenyl)phenyl]me- thyl]-4-oxo-1,4-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

14. The compound according to claim 1, which is selected from the group consisting of (3S)-3-(4-aminobutyl)-4-hydroxy-1-[4-hydroxy-2-(imidazo[1,2-a]pyridin-3-y- l)benzyl]-4-oxo-14-azaphosphinane-3-carboxylic acid, and its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.

15. A pharmaceutical composition comprising the compound according to claim 1, in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

16. The pharmaceutical composition according to claim 15, which further comprises a fibrinolytic, an anticoagulant or an anti-platelet agent.

17. A method for the treatment, prevention or secondary prevention of cerebrovascular accidents, myocardial infarction, angina pectoris, arteritis of the lower limbs, thromboses, including venous thromboses, pulmonary embolism, aortic aneurysms or vascular dementia, in a subject in need thereof, comprising administration of an effective amount of the compound of formula (I) according to claim 1, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

18. The method according to claim 17, wherein the compound of formula (I) is administered in combination with a fibrinolytic, an anticoagulant or an anti-platelet agent.

19. The method according to claim 18, wherein the fibrinolytic is an injectable fibrinolytic selected from the group consisting of alteplase and tenecteplase.

Summary for Patent:   Start Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
France16 70004Jan 14, 2016
PCT Information
PCT FiledJanuary 13, 2017PCT Application Number:PCT/FR2017/050075
PCT Publication Date:July 20, 2017PCT Publication Number:WO2017/121969

Details for Patent 10,138,260

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Genentech ACTIVASE alteplase VIAL; SINGLE-USE 103172 001 1987-11-13   Start Trial LES LABORATOIRES SERVIER (Suresnes, FR) 2036-01-14 RX search
Genentech ACTIVASE alteplase VIAL; SINGLE-USE 103172 002 1987-11-13   Start Trial LES LABORATOIRES SERVIER (Suresnes, FR) 2036-01-14 RX search
Genentech CATHFLO ACTIVASE alteplase VIAL 103172 003 1987-11-13   Start Trial LES LABORATOIRES SERVIER (Suresnes, FR) 2036-01-14 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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