Synthesis of prostanoids
AssigneeIrix Pharmaceuticals, Inc.
InventorsGeorge Petros Yiannikouros, Panos Kalaritis, Chaminda Priyapushpa Gamage, Stephanie Bosse Abernathy
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Abstract
The presently disclosed subject matter provides a method of synthesizing prostaglandins and prostaglandin analogs comprising the ring closing metathesis of compounds of Formula (I). Also provided are novel compounds of Formula (I) and Formula (II). In addition to their use as synthetic intermediates in the presently disclosed methods, compounds of Formula (II) can be used as prostaglandin and/or prostaglandin analog prodrugs.
Claims22
A method of preparing a prostaglandin or prostaglandin analog, the method comprising:
- providing a compound of Formula (I):
- wherein:
- n and m are integers between 0 and 4, wherein n+m is 3 or 4;
- R1 is H or a hydroxyl protecting group;
- R2 is H, alkyl or aralkyl, optionally wherein the alkyl or aralkyl group further comprises one or more alkyl or aryl group substituents;
- R3 and R4 are independently H or alkyl;
- and the substituents at carbons 1 and 2 of the cyclopentane ring are oriented cis to one another and trans to the substituent at carbon 3;
- reacting the compound of Formula (I) with a transition metal carbene complex catalyst to perform a ring closing metathesis reaction, thereby forming a lactone;
- and
- reacting the lactone with a nucleophile to form a ring-opened product, wherein said ring-opened product is a prostaglandin, prostaglandin analog or synthetic intermediate thereof, wherein said prostaglandin or prostaglandin analog has the formula:
- wherein m, n, R1, R2, R3, and R4 are as defined above;
- X′ is selected from the group consisting of —OH, —SH, —NH2, —O-alkyl, —O-aryl, —S-alkyl, —S-aryl, —NH-alkyl, —NH-aryl, —NH-aralkyl, —NH-sulfonyl-alkyl, —NH-sulfonyl-aryl, —N(alkyl)2, —N(aryl)2, and —N(alkyl)(aryl);
- and the substituents at carbons 1 and 2 of the cyclopentane ring are oriented cis to one another and trans to the substituent at carbon 3.
A method of preparing a prostaglandin analog, the method comprising:
- providing a compound of Formula (I):
- wherein:
- n and m are integers between 0 and 4, wherein n+m is 3 or 4;
- R1 is a hydroxyl protecting group;
- R2 is H, alkyl or aralkyl, optionally wherein the alkyl or aralkyl group further comprises one or more alkyl or aryl group substituents;
- R3 and R4 are independently H or alkyl;
- and
- the substituents at carbons 1 and 2 of the cyclopentane ring are oriented cis to one another and trans to the substituent at carbon 3;
- reacting the compound of Formula (I) with a transition metal carbene complex catalyst to perform a ring closing metathesis reaction, thereby forming a lactone;
- reacting the lactone with a nucleophile to form a ring-opened product comprising a hydroxyl group;
- oxidizing the hydroxyl group of the ring-opened product to form a ketone;
- and
- removing the hydroxyl protecting group R1, thereby forming a prostaglandin analog having the formula:
- wherein m, n, R2, R3, and R4 are as defined above and wherein X′ is selected from the group consisting of —OH, —SH, —NH2, —O-alkyl, —O-aryl, —S-alkyl, —S-aryl, —NH-alkyl, —NH-aryl, —NH-aralkyl, —NH-sulfonyl-alkyl, —NH-sulfonyl-aryl, —N(alkyl)2, —N(aryl)2, and —N(alkyl)(aryl).
Dependencies are inferred from the claim text.