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Details for Patent: 6,528,688

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Details for Patent: 6,528,688

Title: Prostacyclin derivatives
Abstract:An improved method is described for making 9-deoxy-PGF.sub.1 -type compounds. In contrast to the prior art, the method is stereoselective and requires fewer steps than the known methods for making these compounds.
Inventor(s): Moriarty; Robert M. (Oak Park, IL), Penmasta; Raju (Bolingbrook, IL), Guo; Liang (Chicago, IL), Rao; Munagala S. (Westmont, IL), Staszewski; James P. (Naperville, IL)
Assignee: United Therapeutics Corporation (Washington, DC)
Filing Date:Feb 15, 2002
Application Number:10/075,439
Claims:1. A compound of the formula: ##STR26## wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; wherein X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is alkyl, THP or TBDMS; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1, 2, or 3; wherein n is 0, 1, 2, or 3; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)aikyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.8)alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH with the OH group optionally substituted by an alcohol protecting group, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.

2. A compound as claimed in claim 1, wherein the OH of M.sub.1 is substituted with THP.

3. A compound as claimed in claim 1, wherein Z is O, X is H, n is zero, Y is --CH.sub.2 --CH.sub.2 --, R.sub.5 is hydrogen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.7 is --(CH.sub.2).sub.3 --CH.sub.3.

4. A compound of the formula: ##STR27## wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; wherein X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is alkyl, THP or TBDMS; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1, 2, or 3; wherein n is 0, 1, 2, or 3; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)aikyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5)alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH with the OH group optionally substituted by an alcohol protecting group, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.

5. A compound as claimed in claim 4, wherein the OH of M.sub.1 is substituted with THP.

6. A compound as claimed in claim 4, wherein Z is O, X is H, n is zero, Y is --CH.sub.2 --CH.sub.2 --, R.sub.5 is hydrogen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.7 is --(CH.sub.2).sub.3 --CH.sub.3.

7. A compound of the formula ##STR28## wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; wherein X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is alkyl, THP or TBDMS; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1, 2, or 3; wherein n is 0, 1, 2, or 3; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5)alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH with the OH group optionally substituted by an alcohol protecting group, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.

8. A compound as claimed in claim 7, wherein the OH of M.sub.1 is substituted with THP.

9. A compound as claimed in claim 7, wherein Z is O, X is H, n is zero, Y is --CH.sub.2 --CH.sub.2 --, R.sub.5 is hydrogen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.7 is --(CH.sub.2).sub.3 --CH.sub.3.

10. A compound of the formula ##STR29## wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; wherein X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is alkyl, THP or TBDMS; wherein R.sub.1 is an alcohol protecting group; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2 (CH.sub.2).sub.m --, or --C.ident.C--; m is 1, 2, or 3; wherein R.sub.7 is (1) --C.sub.p H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5)alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH with the OH group optionally substituted by an alcohol protecting group, wherein R.sub.5 is hydrogen or methyl; wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.

11. A compound as claimed in claim 10, wherein the OH of M.sub.1 is substituted with THP.

12. A compound as claimed in claim 10, wherein Z is O, X is H, n is zero, Y is --CH.sub.2 --CH.sub.2 --, R.sub.5 is hydrogen, R.sub.3 and R.sub.4 are hydrogen, and R.sub.7 is --(CH.sub.2).sub.3 --CH.sub.3.
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