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PG-type, 1,9-lactones |
| RE30053 |
PG-type, 1,9-lactones
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| Patent Drawings: | |
| Inventor: |
Bundy |
| Date Issued: |
July 24, 1979 |
| Application: |
05/869,900 |
| Filed: |
January 16, 1978 |
| Inventors: |
Bundy; Gordon L. (Kalamazoo, MI)
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| Assignee: |
The Upjohn Company (Kalamazoo, MI) |
| Primary Examiner: |
Ford; John M. |
| Assistant Examiner: |
Fan; Jane T. |
| Attorney Or Agent: |
Armitage; Robert A. |
| U.S. Class: |
549/267; 549/268; 549/269; 556/441; 562/503 |
| Field Of Search: |
260/343.2F; 260/340.2; 260/24R; 260/343.41; 542/426; 542/429 |
| International Class: |
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| U.S Patent Documents: |
3864387; 3935240 |
| Foreign Patent Documents: |
50-13385 |
| Other References: |
Corey, J.A.C.S. 97, p. 653, 1975.. |
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| Abstract: |
The present invention provides novel 1,9 lactones of prostaglandin-type free acids and a process for their preparation. These lactones are useful for the same pharmacological purposes as the corresponding prostaglandin-type free acids. |
| Claim: |
I claim: .[.
1. A prostaglandin-type, 1,9-lactone of the formula ##STR280## wherein W.sub.2 is ##STR281## wherein L.sub.1 is ##STR282## or a mixture of ##STR283## wherein R.sub.3 and R.sub.4 arehydrogen, 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;
wherein M.sub.1 is ##STR284## wherein R.sub.5 is hydrogen or methyl; wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is one to 5, inclusive, cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, or ##STR285## wherein T is chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, and Z.sub.3 is oxa or methylene, with the provisio that not more than two T'sare other than alkyl, and the further proviso that Z.sub.3 is oxa only when R.sub.3 and 4.sub.4 are hydrogen or methyl, being the same or different;
wherein Y.sub.1 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, cis--CH.dbd.CH--, or --C.tbd.C--; and
wherein Z.sub.1 is
2. A compound according to claim 1, wherein W.sub.2 is ##STR287## .[.
3. 11-Deoxy-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 2..]..[.4. A compound according to claim 1, wherein W.sub.2 is ##STR288##
.[.5. A compound according to claim 4, wherein Y.sub.1 is --C.tbd.C--..]..[.6. 13,14-Didehydro-PGD.sub.2, 1,9-lactone, a compound according to claim 5..]..[.7. A compound according to claim 4, wherein Y.sub.1 is cis--CH.dbd.CH--..]..[.8. cis-13-PGD.sub.2, 1,9-lactone..]..[.9. A compound according to claim 4, wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --..]..[.10. 13,14-Dihydro-PGD.sub.2, 1,9-lactone, a compound according to claim 9..]..[.11. A compound according to claim 4, whereinY.sub.1 is trans--CH.dbd.CH--..]..[.12. PGD.sub.2, 1,9-lactone, a compound according to claim 11..]..[.13. A compound according to claim 1, wherein W.sub.2 is ##STR289##
.[.14. A compound according to claim 13, wherein .about. is .alpha...]..[.15. A compound according to claim 14, wherein M.sub.1 ##STR290##
.[.16. 15-epi-PGF.sub.2.alpha., 1,9-lactone, a compound according to 15..]..[.17. A compound according to claim 14, wherein M.sub.1 is ##STR291##
.[.18. A compound according to claim 17, wherein Z.sub.1 is --CH.sub.2 --O--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --..]..[.19. 5-oxa-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 18..]. .[.20. A compound according to claim17, wherein Z.sub.1 is ##STR292##
.[.21. 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 20..]..[.22. A compound according to claim 17, wherein Z.sub.1 is ##STR293##
.[.23. 3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 22..]..[.24. A compound according to claim 17, wherein Z.sub.1 is cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --..]. .[.25. cis-4,5-Didehydro-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 24..]. .[.26. A compound according to claim 17, wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 --..]..[.27. 2,2,16,16-Tetrafluoro-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 26..]..[.28. 2,2-Difluoro-16,16-dimethyl-PGF.sub.2.alpha.,1,9-lactone, a compound according to claim 26..]. .[.29. 2,2-Difluoro-15-methyl-PGF.sub.2.alpha.,1,9-lactones, a compound according to claim 26..]..[.30. 2,2-Difluoro-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 26..]..[.31. A compound according to claim 17, wherein Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2--..]..[.32. 2,2,16,16-Tetrafluoro-PGF.sub.1.alpha., 1,9-lactone, a compound according
to claim 31..]..[.33. 2,2-Difluoro-16,16-dimethyl-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 31..]..[.34. 2,2-Difluoro-15-methyl-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 31..]..[.35. 2,2-Difluoro-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 31..]..[.36. A compound according to claim 17, wherein Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 --..]..[.37. 16,16-Difluoro-PGF.sub.1.alpha., 1,9-lactone, acompound according to claim 36..]..[.38. 16,16-Dimethyl-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 36..]. .[.39. 15-Methyl-PGF.sub.1.alpha., 1,9-lactone, a compound according to claim 36..]..[.40. PGF.sub.1.alpha., 1,9-lactone, acompound according to claim 36..]..[.41. A compound according to claim 17, wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 --..]..[.42. A compound according to claim 41, wherein g is 3..]. .[.43. A compound
according to claim 41, wherein g is 1..]. .[.44. A compound according to claim 43, wherein Y.sub.1 is --C.tbd.C--..]..[.45. 13,14-Didehydro-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 44..]..[.46. A compound according toclaim 43, wherein Y.sub.1 is cis--CH.dbd.CH--..]..[.47. cis-13-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 46..]..[.48. A compound according to claim 43, wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --..]..[.49. 13,14-dihydroPGF.sub.2.alpha., 1,9-lactone, a compound according to claim 48..]..[.50. A compound according to claim 43, wherein Y.sub.1 is trans--CH.dbd.CH--..]..[.51. A compound according to claim 50, wherein R.sub.7 is cis--CH.dbd.CH--CH.sub.2 --CH.sub.3--..]..[.52. PGF.sub.3.alpha., 1,9-lactone, a compound according to claim 51..]..[.53. A compound according to claim 50, wherein 7 is ##STR294##
.[.54. A compound according to claim 53, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl..]..[.55. A compound according to claim 54, wherein Z.sub.3 is methylene..]..[.56. A compound according to claim 55, wherein R.sub.5is methyl..]..[.57. 15-Methyl-17-Phenyl-18,19,20-trinor-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 56..]..[.58. A compound according to claim 55, wherein R.sub.5 is hydrogen..]..[.59. A compound according to claim 58, wherein atleast one of R.sub.3 and R.sub.4 are fluoro..]..[.60. 16,16-Difluoro-17-Phenyl-18,19,20-trinor-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 59..]..[.61. A compound according to claim 58, wherein at least one of R.sub.3 and R.sub.4 ismethyl..]. .[.62. 16,16-Dimethyl-17-phenyl-18,19,20-trinor-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 61..]..[. 63. A compound according to claim
58, wherein R.sub.3 and R.sub.4 are both hydrogen..]..[.64. 17-Phenyl-18,19,20-trinor-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 63..]..[.65. A compound according to claim 54, wherein Z.sub.3 is oxa..]..[.66. A compoundaccording to claim 65, wherein R.sub.5 is methyl..]..[.67. 15-Methyl-16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 66..]..[.68. A compound according to claim 65, wherein R.sub.5 is hydrogen..]..[.69. Acompound according to claim 68, wherein at least one of R.sub.3 and R.sub.4 is methyl..]..[.70. 16-Methyl-16-Phenoxy-18,19,20-trinor-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 69..]..[.71. A compound according to claim 68, whereinR.sub.3 and R.sub.4 are both hydrogen..]..[.72. 16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2.alpha., 1,9-lactone, a compound
according to claim 71..]..[.73. A compound according to claim 50, wherein R.sub.7, is --(CH.sub.2).sub.m --CH.sub.3 --..]..[.74. A compound according to claim 73, wherein m is 30..]..[.75. A compound according to claim 74, wherein R.sub.5 ismethyl..]..[.76. A compound according to claim 75, wherein at least one of R.sub.3 and R.sub.4 is fluoro..]..[.77. 15-Methyl-16,16-difluoro-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 76..]..[.78. A compound according to claim 75,wherein at least one of R.sub.3 and R.sub.4 is methyl..]..[.79. 15,16,16-Trimethyl-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 78..]..[.80. A compound according to claim 75, wherein R.sub.3 and R.sub.4 are both hydrogen..]..[.81. 15-Methyl-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 80..]. .[.82. A compound according to claim 74, wherein R.sub.5 is hydrogen..]..[.83. A compound according to claim 82, wherein at least one of R.sub.3 and R.sub.4 is fluoro..]. .[.84. A compound according to claim 83, wherein R.sub.3 and R.sub.4 are both fluoro..]..[.85. 16,16-Difluoro-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 84..]..[.86. A compound according to claim 82, wherein at least one of R.sub.3and R.sub.4 is methyl..]..[.87. A compound according to claim 86, wherein R.sub.3 and R.sub.4 are both methyl..]..[.88. 16,16-Dimethyl-PGF.sub.2.alpha., 1,9-lactone, a compound according to claim 87..]..[.89. A compound according to claim 82, whereinR.sub.3 and R.sub.4 are both hydrogen..]..[.90. PGF.sub.2.alpha., 1,9-lactone, a compound according to
claim 89..]. .Iadd.91. A prostaglandin-type, 1,9-lactone of the formula ##STR295## wherein W.sub.2 is ##STR296## wherein L.sub.1 is ##STR297## or a mixture of ##STR298## wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being thesame 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;
wherein M.sub.1 is ##STR299## wherein R.sub.5 is hydrogen or methyl; wherein R.sub.7 is --(CH.sub.2).sbsb.m--CH.sub.3, wherein m is one to 5, inclusive, cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, or ##STR300## wherein T is chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl;
wherein Y.sub.1 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, cis--CH.dbd.CH--, or --C.tbd.C--; and
wherein Z.sub.1 is
wherein g is one to 3 inclusive. .Iaddend. .Iadd.92. A compound according to claim 91, wherein W.sub.2 is ##STR302##
.Iaddend. .Iadd.93. 11-Deoxy-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 92. .Iaddend..Iadd.94. A compound according to claim 91, wherein W.sub.2 is ##STR303##
.Iaddend. .Iadd.95. A compound according to claim 94, wherein Y.sub.1 is --C.tbd.C--. .Iaddend..Iadd.96. 13,14-Didehydro-PGD.sub.2, 1,9-lactone, a compound according to claim 95. .Iaddend..Iadd.97. A compound according to claim 94, whereinY.sub.1 is cis--CH.dbd.CH--. .Iaddend..Iadd.98. cis-13-PGD.sub.2, 1,9-lactone, a compound according to claim 97. .Iaddend..Iadd.99. A compound according to claim 94, wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --. .Iaddend..Iadd.100. 13,14-Dihydro-PGD.sub.2, 1,9-lactone, a compound according to claim 99. .Iaddend..Iadd.101. A compound according to claim 94, wherein Y.sub.1 is trans--CH.dbd.CH--. .Iaddend..Iadd.102. PGD.sub.2 1,9-lactone, a compound according to claim 101. .Iaddend..Iadd.103. A compound according to claim 91, wherein W.sub.2 is ##STR304##
.Iaddend. .Iadd.104. A compound according to claim 103, wherein .about. is .alpha...Iaddend..Iadd.105. A compound according to claim 104, wherein M.sub.1 is ##STR305##
.Iaddend. .Iadd.106. 15-epi-16-Methyl-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 105. .Iaddend..Iadd.107. A compound according to claim 104, wherein M.sub.1 is ##STR306##
.Iaddend. .Iadd.108. A compound according to claim 107, wherein Z.sub.1 is --CH.sub.2 --O--CH.sub.2 --(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.109. 5-Oxa-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 108. .Iaddend..Iadd.110. A compound according to claim 107, wherein Z.sub.1 is ##STR307##
.Iaddend. .Iadd.111. 3-Oxa-3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 110. .Iaddend..Iadd.112. A compound according to claim 107, wherein Z.sub.1 is ##STR308##
.Iaddend. .Iadd.113. 3,7-inter-m-phenylene-4,5,6-trinor-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 112. .Iaddend..Iadd.114. A compound according to claim 107, wherein Z.sub.1 is cis--CH.sub.2--CH.dbd.CH--(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.115. cis-4,5-Didehydro-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 114. .Iaddend..Iadd.116. A compound according to claim 107, wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2--(CH.sub.2).sbsb.g--CF.sub.2 --. .Iaddend..Iadd.117. 2,2,16,16-Tetrafluoro-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 116. .Iaddend.. .Iadd.118. 2,2-Difluoro-16,16-dimethyl-PGF.sub.2 .alpha., 1,9-lactone, a compound according toclaim 116. .Iaddend..Iadd.119. 2,2-Difluoro-15-methyl-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 116. .Iaddend..Iadd.120. 2,2-Difluoro-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 116. .Iaddend..Iadd.121. Acompound according to claim 107, wherein Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sbsb.g--CF.sub.2 --. .Iaddend..Iadd.122. 2,2,16,16-Tetrafluoro-PGF.sub.1 .alpha., 1,9-lactone, a compound according
to claim 121. .Iaddend..Iadd.123. 2,2-Difluoro-16,16-dimethyl-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 121. .Iaddend..Iadd.124. 2,2-Difluoro-15-methyl-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 121. .Iaddend..Iadd.125. 2,2-Difluoro-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 121. .Iaddend..Iadd.126. A compound according to claim 107, wherein Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.127. 16,16-Difuoro-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 126. .Iaddend..Iadd.128. 16,16-Dimethyl-PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 126. .Iaddend..Iadd.129. 15-Methyl-PGF.sub.1 .alpha., 1,9-lactone, acompound according to claim 126. .Iaddend..Iadd.130. PGF.sub.1 .alpha., 1,9-lactone, a compound according to claim 126. .Iaddend..Iadd.131. A compound according to claim 107, wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sbsb.g--CH.sub.2--. .Iaddend..Iadd.132. A compound according to claim 131, wherein g is 3. .Iaddend..Iadd.133. A compound according to claim 131, wherein g is one.
.Iaddend..Iadd.134. A compound according to claim 133 wherein Y.sub.1 is --C.tbd.C--. .Iaddend..Iadd.135. 13,14-Didehydro-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 134. .Iaddend..Iadd.136. A compound according to claim133, wherein Y.sub.1 is cis--CH.dbd.CH--. .Iaddend..Iadd.137. cis-13-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 136. .Iaddend..Iadd.138. A compound according to claim 133, wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --. .Iaddend..Iadd.139. 13,14-Dihydro-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 138. .Iaddend..Iadd.140. A compound according to claim 133, wherein Y.sub.1 is trans--CH.dbd.CH--. .Iaddend..Iadd.141. A compound according to claim 140,wherein R.sub.7 is cis--CH.dbd.CH--CH.sub.2 --CH.sub.3 --. .Iaddend..Iadd.142. PGF.sub.3 .alpha., 1,9-lactone, a compound according to claim 141. .Iaddend..Iadd.143. A compound according to claim 140, wherein R.sub.7 is ##STR309##
.Iaddend. .Iadd.144. A compound according to claim 143, wherein s is zero
or one and T is chloro, fluoro, or trifluoromethyl. .Iaddend..Iadd.145. A compound according to claim 144, wherein R.sub.5 is methyl. .Iaddend..Iadd.146. 15-Methyl-17-phenyl-18,19,20-trinor-PGF.sub.2 .alpha., 1,9-lactone, a compoundaccording to claim 145. .Iaddend..Iadd.147. A compound according to claim 144, wherein R.sub.5 is hydrogen. .Iaddend..Iadd.148. A compound according to claim 147, wherein at least one of R.sub.3 and R.sub.4 is fluoro. .Iaddend..Iadd.149. 16,16-Difluoro-17-phenyl-18,19,20-trinor-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 148. .Iaddend..Iadd.150. A compound according to claim 147, wherein at least one of R.sub.3 and R.sub.4 is methyl. .Iaddend..Iadd.151. 16,16-Dimethyl-17-phenyl-18,19,20-trinor-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 150. .Iaddend..Iadd.152. A compound according to claim 147, wherein R.sub.3 and R.sub.4 are both hydrogen. .Iaddend..Iadd.153. 17-Phenyl-18,19,20-trinor-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 152. .Iaddend..Iadd.154. A compound according to claim 140, wherein R.sub.7 is --(CH.sub.2).sbsb.m--CH.sub.3 --. .Iaddend..Iadd.155. A compound according to claim154, wherein m is 3. .Iaddend..Iadd.156. A compound according to claim 155, wherein R.sub.5 is
methyl. .Iaddend..Iadd.157. A compound according to claim 156, wherein at least one of R.sub.3 and R.sub.4 is fluoro. .Iaddend..Iadd.158. 15-Methyl-16,16-difuoro-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 157. .Iaddend..Iadd.159. A compound according to claim 156, wherein at least one of R.sub.3 and R.sub.4 is methyl. .Iaddend..Iadd.160. 15,16,16-Trimethyl-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 159. .Iaddend..Iadd.161. A compoundaccording to claim 156, wherein R.sub.3 and R.sub.4 are both hydrogen. .Iaddend..Iadd.162. 15-Methyl-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 161. .Iaddend..Iadd.163. A compound according to claim 155, wherein R.sub.5 ishydrogen. .Iaddend..Iadd.164. A compound according to claim 163, wherein at least one of R.sub.3 and R.sub.4 is fluoro. .Iaddend..Iadd.165. A compound according to claim 164, wherein R.sub.3 and R.sub.4 are both fluoro. .Iaddend..Iadd.166. 16,16-Difluoro-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 165.
.Iaddend..Iadd. . A compound according to claim 163, wherein at least one of R.sub.3 and R.sub.4 is methyl. .Iaddend..Iadd.168. A compound according to claim 167, wherein R.sub.3 and R.sub.4 are both methyl. .Iaddend..Iadd.169. 16,16-Dimethyl-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 168. .Iaddend..Iadd.170. A compound according to claim 163, wherein R.sub.3 and R.sub.4 are both hydrogen. .Iaddend..Iadd.171. PGF.sub.2 .alpha., 1,9-lactone, a compoundaccording
to claim 170. .Iaddend..Iadd.172. A prostaglandin-type, 1,9-lactone of the formula ##STR310## wherein W.sub.2 is ##STR311## wherein L.sub.1 is ##STR312## or a mixture of ##STR313## wherein R.sub.3 and R.sub.4 are hydrogen or methyl being thesame or different;
wherein M.sub.1 is ##STR314## wherein R.sub.5 is hydrogen or methyl wherein T is chloro, fluoro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero,one, 2, or 3, with the proviso that not more than two T's are other than alkyl;
wherein Y.sub.1 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, cis--CH.dbd.CH--, or --C.tbd.C--; and
wherein Z.sub.1 is
wherein g is one to 3, inclusive. .Iaddend..Iadd.173. A compound according to claim 172, wherein W.sub.2 is ##STR316##
.Iaddend. .Iadd.174. A compound according to claim 172, wherein W.sub.2 is ##STR317##
.Iaddend. .Iadd.175. A compound according to claim 174, wherein Y.sub.1 is --C.tbd.C--. .Iaddend..Iadd.176. A compound according to claim 174, wherein Y.sub.1 is cis--CH.dbd.CH--. .Iaddend..Iadd.177. A compound according to claim 174,wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --..Iaddend..Iadd.178. A compound according to claim 174, wherein Y.sub.1 is trans--CH.dbd.CH--. .Iaddend..Iadd.179. A compound according to claim 172, wherein W.sub.2 is ##STR318##
.Iaddend. .Iadd.180. A compound according to claim 179, wherein .about. is .alpha...Iaddend..Iadd.181. A compound according to claim 180, wherein M.sub.1 is ##STR319##
.Iaddend. .Iadd.182. A compound according to claim 180, wherein M.sub.1 is ##STR320##
.Iaddend. .Iadd.183. A compound according to claim 182, wherein Z.sub.1 is --CH.sub.2 --O--CH.sub.2 --(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.184. A compound according to claim 182, wherein Z.sub.1 is ##STR321##
.Iaddend. .Iadd.185. A compound according to claim 182, wherein Z.sub.1 is ##STR322##
.Iaddend. .Iadd.186. A compound according to claim 182, wherein Z.sub.1 is cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.187. A compound according to claim 182, wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2--(CH.sub.2).sbsb.g--CF.sub.2 --. .Iaddend..Iadd.188. A compound according to claim 182, wherein Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sbsb.g--CF.sub.2 --. .Iaddend..Iadd.189. A compound according to claim 182, wherein Z.sub.1 is--(CH.sub.2).sub.3 --(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.190. A compound according to claim 182, wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sbsb.g--CH.sub.2 --. .Iaddend..Iadd.191. A compound according to claim 182, wherein gis 3. .Iaddend..Iadd.192. A compound according to claim 182, wherein g is one. .Iaddend..Iadd.193. A compound according to claim 192, wherein Y.sub.1 is --C.tbd.C--. .Iaddend..Iadd.194. A compound according to claim 192, wherein Y.sub.1 iscis--CH.dbd.CH--..Iaddend..Iadd.195. A compound according to claim 192, wherein Y.sub.1 is trans--CH.dbd.CH--. .Iaddend..Iadd.196. A compound according to claim 192, wherein Y.sub.1 is --CH.sub.2 CH.sub.2 --. .Iaddend..Iadd.197. A compound accordingto claim 196, wherein s is zero
or one and T is chloro, fluoro. .Iaddend..Iadd.198. A compound according to claim 197, wherein R.sub.5 is methyl. .Iaddend..Iadd.199. 15-Methyl-16-phenoxy-17,18,19,20-tetranor-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim198. .Iaddend..Iadd.200. A compound according to claim 197, wherein R.sub.5 is hydrogen. .Iaddend..Iadd.201. A compound according to claim 200, wherein at least one of R.sub.3 and R.sub.4 is methyl. .Iaddend..Iadd.202. 16-Methyl-16-pheoxy-18,19,20-trinor-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 201. .Iaddend..Iadd.203. A compound according to claim 200, wherein R.sub.3 and R.sub.4 are both hydrogen. .Iaddend..Iadd.204. 16-Phenoxy-17,18,19,20-tetranor-PGF.sub.2 .alpha., 1,9-lactone, a compound according to claim 203. .Iaddend. |
| Description: |
BACKGROUND OF THE INVENTION
This invention provides novel compositions of matter.
Particularly this invention provides novel lactones of some of the known prostaglandins or prostaglandin analogs.
The known prostaglandins include the PGE compounds, e.g. prostaglandin E.sub.1 (PGE.sub.1), prostaglandin E.sub.2 (PGE.sub.2), prostaglandin E.sub.3 (PGE.sub.3), and dihydroprostaglandin E.sub.1 (dihydro-PGE.sub.1).
The known prostaglandins include PGF.sub..alpha. compounds, e.g. prostaglandin F.sub.1.alpha. (PGF.sub.1.alpha.), prostaglandin F.sub.2.alpha. (PGF.sub.2.alpha.), prostaglandin F.sub.3.alpha. (PGF.sub.3.alpha.), and dihydroprostaglandinF.sub.1.alpha. (dihydro-PGF.sub.1.alpha.).
The known prostaglandins include PGF.sub..beta. compounds, e.g. prostaglandin F.sub.1.beta. (PGF.sub.1.beta.), prostaglandin F.sub.2.beta. (PGE.sub.2.beta.), prostaglandin F.sub.3.beta. (PGE.sub.3.beta.), and dihydroprostaglandinF.sub.1.beta. (dihydro-PGF.sub.1.beta.).
The known prostaglandins include PGA compounds, e.g. prostaglandin A.sub.1 (PGA.sub.1), prostaglandin A.sub.2 (PGA.sub.2), prostaglandin A.sub.3 (PGA.sub.3), and dihydroprostaglandin A.sub.1 (dihydro-PGA.sub.1).
the known prostaglandins include PGB compounds, e.g. prostaglandin B.sub.1 (PGB.sub.1), prostaglandin B.sub.2 (PGB.sub.2), prostaglandin B.sub.3 (PGB.sub.3), and dihydroprostaglandin B.sub.1 (dihydro-PGB.sub.1).
Each of the above mentioned known prostaglandins (PG's) is a derivative of prostanoic acic which has the following structure and carbon atom numbering ##STR1## See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and referencescited therein. A systematic name for prostanoic acid is 7-[(2.beta.-octyl)-cyclopent-1.alpha.-yl]heptanoic acid.
PGE.sub.1 has the following structure: ##STR2##
PGE.sub.2 has the following structure: ##STR3##
PGE.sub.3 has the following structure: ##STR4##
Dihydro-PGE.sub.1 has the following structure: ##STR5##
PGF.sub.1.alpha. has the following structure: ##STR6##
PGF.sub.2.alpha. has the following structure: ##STR7##
PGF.sub.3.alpha. has the following structure: ##STR8##
Dihydro-PGF.sub.1.alpha. has the following structure: ##STR9##
PGF.sub.1.beta. has the following structure: ##STR10##
PGF.sub.2.beta. has the following structure: ##STR11##
PGF.sub.3.beta. has the following structure: ##STR12##
Dihydro-PGF.sub.1.beta. has the following structure: ##STR13##
PGA.sub.1 has the following structure: ##STR14##
PGA.sub.2 has the following structure: ##STR15##
PGA.sub.3 has the following structure: ##STR16##
Dihydro-PGA.sub.1 has the following structure: ##STR17##
PGB.sub.1 has the following structure: ##STR18##
PGB.sub.2 has the following structure: ##STR19##
PGB.sub.3 has the following structure: ##STR20##
Dihydro-PGB.sub.1 has the following structure: ##STR21##
In the above formulas, as well as in the formulas hereinafter given, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration i.e., below the plane of the cyclopentane ring. Heavy solid line attachments tothe cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The use of wavy lines (.about.) herein will represent attachment of substituents in either the alpha or beta configuration or attachmentin a mixture of alpha and beta configurations.
The side-chain hydroxy at C-15 in the above formulas is in S configuration. See, Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins. Expressions such as C-9, C-11, C-15, and the like, refer to the carbon atom inthe prostaglandin analog which is in the position corresponding to the position of the same number in prostanoic acid.
Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory and levorotatory forms. Asdrawn, the above formulas each represent the particular optically active form of the prostaglandin as is obtained from mammalian tissues, for example, sheep vesicular glands, swine lung, or human seminal plasma, from carbonyl and/or double bond reductionof the prostaglandin so obtained. See, for example, Bergstrom et al., cited above. The mirror image of each of these formulas represents the other enantiomer of that prostaglandin. The racemic form of a prostaglandin contains equal numbers of bothenantiomeric molecules, and one of the above formulas and the mirror image of that formula is needed to represent correctly the corresponding racemic prostaglandin.
For convenience hereinafter, use of the term, prostaglandin or "PG" will mean the optically active form of that prostaglandin thereby referred to with the same absolute configuration as PGE.sub.1 obtained from mammalian tissues. When referenceto the racemic form of one of those prostaglandins is intended, the word "racemic" or "d1" will precede the prostaglandin name.
The term "prostaglandin-type" (PG-type) compound, as used herein, refers to any cyclopentane derivative herein which is useful for at least one of the same pharmacological purposes as the prostaglandins, as indicated herein.
The term prostaglandin-type intermediate, as used herein, refers to any cyclopentane derivative useful in preparing a prostaglandin-type compound.
The formulas, as drawn herein, which depict a prostaglandin-type compound or an intermediate useful in preparing a prostaglandin-type compound, each represent the particular stereoisomer of the prostaglandin-type compound which is of the samerelative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues, or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the prostaglandin-type compounds.
The term "prostaglandin analog", as used herein, represents that stereoisomer of a prostaglandin-type compound which is of the same relative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues, a mixturecomprising that stereoisomer and the enantiomer thereof, or the enantiomer thereof. In particular, where a formula is used to depict a prostaglandin- type compound herein, the term prostaglandin analog refers to the compound of that formula, or amixture comprising that compound and the enantiomer thereof.
The term "prostaglandin-type lactone" as used herein refers to a 1,9-; 1,11-; or 1,15-lactone of a prostaglandin or prostaglandin analog, but only to the extent that the C-9, C-11, or C-15 position, respectively, is hydroxylated and thus capableof lactone formation with the PG carboxyl. For example, as applied to a PGE-type compound (e.g. PGE.sub.2) the term "prostaglandin-type lactone" refers only to a 1,11- or 1,15-lactone. Further, where a formula is used to depict a prostaglandin-typelactone herein, or a prostaglandin analog from which the prostaglandin-type lactone is prepared, the term "prostaglandin-type lactone" refers to the compound of that formula (or the lactone prepared therefrom) or a mixture comprising that compound (orthe lactone prepared therefrom) and the enantiomer thereof.
The various PG's named above, their esters, acylates and pharmacologically acceptable salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, forexample, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein.
For the PGE compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests, for example, on guinea pig ileum, rabbit duodenum, or qerbil colon);
b. affecting lipolytic activity (as shown by antagonism of epinephrine induced release of glycerol from isolated rat fat pads);
c. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors;
d. controlling spasm and facilitating breathing in asthmatic conditions;
e. decongesting nasal passages;
f. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombus formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ATP, ADP,serotinin, thrombin, and collagen);
g. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle; and
h. accelerating growth of epidermal cells and keratin in animals.
For the PGF.sub..alpha. compound these biological responses include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon);
b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systemic administration of prostaglandin synthetase inhibitors;
c. decongesting nasal passages;
d. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombus formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ADP, ATP,serotinin, thrombin, and collagen); and
e. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstral cycle.
For the PGF.sub..alpha. compounds these biological response include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon);
b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors;
c. controlling spasm and facilitating breathing in asthmatic conditions;
d. decongesting nasal passages;
e. decreasing blood platelet adhesion (as shown by platelet to glass adhesiveness) and inhibiting blood platelet aggregation and thrombis formation induced by various physical stimuli (e.g., arterial injury) or chemical stimuli (e.g., ADP, ATP,serotinin, thrombin, and collagen); and
f. affecting the reproductive organs of mammals as labor inducers, abortifacients, cervical dilators, regulators of the estrus, and regulators of the menstrual cycle.
For the PGA compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests on quinea pig ileum, rabbit duodenum, or gerbil colon);
b. inhibiting gastric secretion and reducing undesirable gastrointestinal effects from systematic administration of prostaglandin synthetase inhibitors;
d. controlling spasm and facilitating breathing in asthmatic conditions;
d. decongesting nasal passages; and
e. increasing kidney blood flow.
For the PGB compounds these biological responses include:
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit duodenum, or gerbil colon); and
b. accelerating growth of epidermal cells and keratin in animals.
Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, including humans, useful domesticanimals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.
The compounds so cited above as extremely potent in causing stimulation of smooth muscle are also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloidsincluding derivatives and analogs thereof. Therefore, these compounds for example, are useful in place of or in combination wth less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, orto control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the prostaglandin is administered by intravenous infusion immediately after abortion ordelivery at a dose in the range about 0.01 to about 50.mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium inthe range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.
As mentioned above, the PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, includingman, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g. diabetes mellitus, vascular diseases, and hyperthyroidism.
The prostaglandins so cited above as useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secetion, therby reduce or avoid gastrointestinal ulcer formation, and accelerate thehealing of such ulcers already present in the gastrointestinal tract. For this purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 to about 500 .mu.g. per kg. of bodyweight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency androute of administration.
these compounds are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration ofthe prostaglandin and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge et al., U.S. Pat. No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibitedby concomitant oral administration of certain prostaglandins of the E and A series, including PGE.sub.1, PGE.sub.2, PGE.sub.3, 13,14-dihydro-PGE.sub.1, and the corresponding 11-deoxy-PGE and PGA compounds. Prostaglandins are useful, for example, inreducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge et al. as non-steroidal, anti-inflammatory agents. These arealso known to be prostaglandin synthetase inhibitors.
The anti-flammatory synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the knownroutes of systemic administration.
The prostaglandin is administered along with the anti-inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. For example, if the anti-inflammatory substance is being administeredorally, the prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example as describedin U.S. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the prostaglandin is also administered rectally, or, alternatively, orally or, in the case of women, vaginally. It is especially convenientwhen the administration route is to be the same for both anti-inflammatory substance and prostaglandin, to combine both into a single dosage form.
The dosage regimen for the prostaglandin in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatorysynthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effects, and the particular prostaglandin to be administered. For example,not every human in need of an anti-inflammatory substance experienced the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it is within the skill ofthe attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of the prostaglandin to reduceand then substantially to eliminate those undesirable effects.
The prostaglandins so cited above as useful in the treatment of asthma, are useful, for example, as bronchodilators or as inhibitors of mediators, such as SRS-A, and histamine which are released from cells activated by an antigen-antibodycomplex. Thus, these compounds control spasm and facilitate breathing in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia, and emphysema. For these purposes, the compounds are administered in a variety of dosage forms, e.g.,orally in the form of tablets, capsules, or liquids; rectally in the form of suppositories; parenterally; subcutaneously; or intramuscularly; with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosolsor solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 0.1 to 5 mg. per kg. of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on thefrequency and route of administration. For the above use these prostaglandins can be combined advantageously with other antiasthmatic agents, such as sympathomimerics (isoproterenol, phenylephrine, epinephrine, etc.); xanthine derivatives (theophyllineand aminophylline); and corticosteroids (ACTH and prednisolone). Regarding use of these compounds see M. E. Rosenthale, et al., U.S. Pat. No. 3,644,638.
The prostaglandins so cited above as useful in mammals, including man, as nasal decongestants are used for this purpose, in a dose range of about 10 .mu.g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosolspray, both for topical application.
The prostaglandins so cited above as useful whenever it is desired to inhibit platelet aggregation, reduce the adhesive character of platelets, and remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. Forexample, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.005 toabout 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
These compounds are further useful as additives to blood, blood products, blood substitutes, or other fluids which are used in artificial extracorporeal circulation or perfusion of isolated body portions, e.g., limbs and organs, whether attachedto the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. Thisblocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached,to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, forthese purposes in order to develop new methods and techniques for organ and limb transplants.
The prostaglandins so cited above as useful in place of oxytocin to induce labor are used in pregnant female animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20weeks to term. For this purpose, the compound is infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. These compounds areespecially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral.
These compounds are further useful for controlling the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so old thatregular menstruation has ceased. For that purpose the prostaglandin is administered systemically at a dose level in the range 0.01 to about 20 mg. per kg. of body weight of the female mammal, advantageously during a span of time starting approximatelyat the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administration. Additionally, expulsion of an embryo or a fetus is accomplished by similaradministration of the compound during the first or second trimester of the normal mammalian gestation period.
These compounds are further useful in causing cervical dilation in pregnant and nonpregnant female mammals for purposes of gynecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation isalso observed. In cases of infertility, cervical dilation produced by these compounds is useful in assisting sperm movement to the uterus. Cervical dilation by prostaglandins is also useful in operative gynecology such as D and C (Cervical Dilation andUterine Curettage) where mechanical dilation may cause perforation of the uterus, cervical tears, or infections. It is also useful in diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the prostaglandin isadministered locally or systemically.
The prostaglandin, for example, is administered orally or vaginally at doses of about 5 to 50 mg. per treatment of an adult female human, with from one to five treatments per 24 hour period. Alternatively the prostaglandin is administeredintramuscularly or subcutaneously at doses of about one to 25 mg. per treatment. The exact dosages for these purposes depend on the age, weight, and condition of the patient or animal.
These compounds are further useful in domestic animals as an abortifacient (especially for feedlot heifers), as an aid to estrus detection, and for regulation or synchronization of estrus. Domestic animals include horses, cattle, sheep, andswine. The regulation or synchronization of estrus allows for more efficient management of both conception and labor by enabling the herdsman to breed all his females in short pre-defined intervals. This synchronization results in a higher percentageof live births than the percentage achieved by natural control. The prostaglandin is injected or applied in a feed at doses of 0.1-100 mg. per animal and may be combined with other agents such as steroids. Dosing schedules will depend on the speciestreated. For example, mares are given the prostaglandin 5 to 8 days after ovulation and return to estrus. Cattle, are treated at regular intervals over a 3 week period to advantageously bring all into estrus at the same time.
The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renaldysfunction, especially those involving blockage of the renal vascular bed. Illustratively, the PGA compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. Forthese purposes, the PGA compounds are preferably first administered by intravenous injections at a dose in the range 10 to 1000 .mu.g. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 .mu.g. per kg. of body weightper minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.
The compounds so cited above as promoters and acceleraters of growth of epidermal cells and keratin are useful in animals, including humans, useful domestic animals, pets, zoological specimens, and laboratory animals for this purpose. For thisreason, these compounds are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, and abrasions, and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skinautografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
For the above purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solutionin the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, for example, when there is substantial fluid loss as in the case of extensive burns or skin loss dueto other causes, systemic administration in advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. To illustrate, a wet dressing fortopical application to second and/or third degree burns of skin area 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution containing 1 to 500 .mu.g. per ml. of the prostaglandin pound. Especially for topical use,these prostaglandins are useful in combination with antibiotics, for example, gentamycin, neomycin, polymixin, bacitracin, spectinomycin, and oxytetracycline, with other antibacterials, for example, mafenide hydrochloride, sulfadiazine, furazoliumchloride, and nitrofurazone, and with corticoid steroids, for example, hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each of those being used in the combination at the usual concentration suitable for its use alone.
In addition to the discovery of the prostaglandins cited above, various prostaglandin analogs have likewise been discovered. In particular, there are known prostaglandin analogs of the formula ##STR22## wherein D is ##STR23## wherein R.sub.8 ishydrogen or hydroxy;
wherein L.sub.1 is ##STR24## or a mixture of ##STR25## and ##STR26## 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 ishydrogen or fluoro;
wherein M.sub.1 is ##STR27## or ##STR28## wherein R.sub.5 is hydrogen or methyl; wherein R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is one to 5, inclusive, cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, or ##STR29## wherein T is chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, and Z.sub.3 is oxa or methylene, with the proviso that not more than two T'sare other than alkyl, and the further proviso that Z.sub.3 is oxa only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different;
wherein Y.sub.1 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, cis--CH.dbd.CH--, or --C.tbd.C--; and
wherein Z.sub.1 is
While the use and preparation of many of the prostaglandin analogs described above is widely known in the art, the Appendix, hereto provides a discussion of the preparation of each of the various compounds depicted by formula I above.
For the prostaglandin analogs described in formula I above, a convenient classification system according to cyclopentane ring structure is effected by referencing:
a. PGF.sub..alpha. -type compounds when D is ##STR31##
b. 11-deoxy-PGF.sub..alpha. -type compounds when D is ##STR32##
c. PGE-type compounds when D is ##STR33##
d. 11-deoxy-PGE-type compounds when D is ##STR34##
e. PGF.sub..beta. -type compounds when D is ##STR35##
f. PGD-type or 9.beta.-PGD-type compounds when D is ##STR36## and
g. 9-deoxy-PGD-type compounds when D is ##STR37##
h. 9-deoxy-9,10-didehydro-PGD-type compounds when D is ##STR38## and
i. PGA-type compounds when D is ##STR39##
j. PGB-type compounds when D is ##STR40##
k. 8.beta.,12.alpha.-PGF.sub..alpha. -type compounds when D is ##STR41##
l. 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -type compounds when D is ##STR42##
m. 8.beta.,12.alpha.-PGE-type compounds when D is ##STR43##
n. 8.beta.,12.alpha.-11-deoxy-PGE-type compounds when D is ##STR44##
o. 8.beta.,12.alpha.-PGF.sub..beta. -type compounds when D is ##STR45##
p. 8.beta.,12.alpha.-PGD-type or 8.beta.,9.beta.,12.alpha.-PGD-type compounds when D is ##STR46##
q. 8.beta.,12.alpha.-9-deoxy-PGD-type compounds when D is ##STR47## and
s. 8.beta.,12.alpha.-PGA-type compounds when D is ##STR48##
Those prostaglandin analogs wherein Z.sub.1 is cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -- or cis--CH.dbd.CH--CH.sub.2 --(CH.sub.2).sub.g --CF.sub.2 -- are named as "PG.sub.2 " compounds. The latter compounds are furthercharacterized as "2,2-difluoro" PG.sub.2 -type compounds. When g is 2 or 3, the prostaglandin analogs so described are "2a-homo" or "2a,2b-dihomo" compounds, since in this event the carboxy terminated side chain contains 8 or 9 carbon atoms,respectively, in place of the 7 carbon atoms contained in PGE.sub.1. These additional carbon atoms are considered as though they were inserted between the C-2 and C-3 positions. Accordingly, these additional carbon atoms are referred to as C-2a andC-2b, counting from the C-2 to the C-3 position.
Further when Z.sub.1 is --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CH.sub.2 -- or --(CH.sub.2).sub.3 --(CH.sub.2).sub.g --CF.sub.2, wherein g is as defined above, the PG analogs so described are "PG.sub.1 " compounds. When g is 2 or 3, the"2a-homo" and "2a, 2b-dihomo" compounds are described as is discussed in the preceding paragraph.
When Z.sub.1 is --CH.sub.2 13 0--CH.sub.2 --(CH.sub.2).sub.g --CH.sub.2 -- the PG analogs so described are named as "5-oxa-PG.sub.1 " compounds. When g is 2 or 3, the compounds so described are "2a-homo" or "2a, 2b-dihomo" compounds,respectively, as discussed above.
When Z.sub.1 is cis--CH.sub.2 --CH.dbd.CH--(CH.sub.2).sub.g --CH.sub.2 --, wherein g is as defined above, the PG analogs so described are named "cis-4,5-didehydro-PG.sub.1 " compounds. When g is 2 or 3, the compounds so described are furthercharacterized as "2a-homo" or "2a,2b-dihomo" compounds, respectively, as discussed above.
For the PG analogs wherein Z.sub.1 is ##STR49## there are described, respectively, 3-oxa-3,7-inter-m-phenylene-4,5,6-trinor or 3,7-inter-m-phenylene-4,5,6-trinor-PG-type compounds, when g is one. When g is 2 or 3, the above compounds areadditionally described as "2a-homo" or "2a,2b-dihomo" PG-type compounds, respectively.
The prostaglandin analogs described herein which contain a cis--CH.dbd.CH-- moiety at the C-13 to C-14, the compounds so described are "13-cis" compounds.
Further when the C-13 to C-14 moiety is --C.tbd.C-- or --CH.sub.2 CH.sub.2 -- the compounds so described are named as "13,14-didehydro" or "13,14-dihydro" compounds, respectively.
When R.sub.7 is --(CH.sub.2).sub.m --CH.sub.3, wherein m is as defined above, the PG analogs so described are named as "19,20-dinor", "20-nor", "20-methyl", or "20-ethyl" compounds when m is one, 2,4, or 5, respectively. When R.sub.7 is##STR50## wherein T and s are as defined above, the PG analogs so described are named as "17-phenyl-18,19,20-trinor" compounds, when s is 0. When s is one, 2, or 3, the corresponding compounds are named as "17-(substituted phenyl)-18,19,20-trinor"compounds.
When R.sub.7 is ##STR51## wherein T and s are as defined above, and neither R.sub.3 nor R.sub.4 is methyl, the PG analogs so described are named as "16-phenoxy-17,18,19,20-tetranor" compounds, when s is zero. When s is one, 2, or 3, thecorresponding compounds are named as "16-(substituted phenoxy)-17,18,19,20-tetranor" compounds. When one and only one of R.sub.3 and R.sub.4 is methyl or both R.sub.3 and R.sub.4 are methyl, then the corresponding compounds wherein R.sub.7 is as definedin this paragraph are named as "16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds or "16-methyl-16-phenoxy or 16-(substituted phenoxy)-18,19,20-trinor" compounds, respectively.
When R.sub.7 is cis--CH.dbd.CH--CH.sub.2 --CH.sub.3, the compounds so described are "PG.sub.3 " or "cis-17,18-didehydro" compounds depending on whether Z.sub.1 is cis--CH.dbd.CH--(CH.sub.2).sub.g --C(R.sub.2).sub.2, wherein R.sub.2 is hydrogen orfluoro, or another moiety, respectively.
When at least one of R.sub.3 and R.sub.4 is not hydrogen then (except for the 16-phenoxy compounds discussed above) there are described the "16-methyl" (one and only one of R.sub.3 and R.sub.4 is methyl), "16,16-dimethyl" (R.sub.3 and R.sub.4 areboth methyl), "16-fluoro" (one and only one of R.sub.3 and R.sub.4 is fluoro), "16,16-difluoro" (R.sub.3 and R.sub.4 are both fluoro) compounds. For those compounds wherein R.sub.3 and R.sub.4 are different, the prostaglandin analogs so representedcontain an asymmetric carbon atom at C-16. Accordingly, two epimeric configurations are possible: "(16S)" and "(16R)". Further, there is described by this invention the C-16 epimeric mixture: "(16RS)".
When R.sub.5 is methyl, the compounds so described are named as "15-methyl" compounds.
Some formulas of 13-cis-cyclopentane derivatives described hereinafter contain a moiety of the formula: ##STR52## wherein the cyclopentane ring is variously substituted, wherein M is variously defined according to the subscripts provided herein;wherein L.sub.1 and R.sub.7 are as defined above; and wherein Y.sub.4 is cis--CH.dbd.CH--. Optionally the above formula is depicted with one or both of L.sub.1 and M above the carbon atom to which it is attached, e.g., as follows: ##STR53## When eitherof the above representations is employed, it is hereby defined to indicate the following convention with respect to the representation of the cis-13 double bond: ##STR54## Further in employing this convention when M is, for example, ##STR55## or##STR56## then the corresponding representations: ##STR57## or ##STR58## are intended, respectively. Accordingly all the formulas herein which represent 13-cis cyclopentane derivatives are depicted by the same convention as that for the cis-13-PGE.sub.1when drawn as follows: ##STR59## Thus, by this convention the (15S)-hydroxy of cis-13-PGE.sub.1 is in the beta configuration.
cis-13-PG-type compounds as drawn herein which have an hydroxy or methoxy at C-15 in the alpha configuration are of the opposite relative stereochemical configuration at C-15 as that of cis-13-PGE.sub.1, and are therefore named as "15-epi"compounds. When the beta hydroxy or methoxy configuration is present, no special designation of this stereochemistry is provided.
Accordingly, 15-epi-16,16-difluoro-cis-13-PGD.sub.2 is depicted herein as follows: ##STR60##
Alternate representations of cis-13-PGE.sub.1 affect the depiction of C-15 as an alpha or beta hydroxy. Thus, by a representation contrary to the instant convention, cis-13-PGE.sub.1 appears as follows: ##STR61##
Accordingly, care must be taken to consistently draw the formulas of cis-13-PG-type compounds herein such that the C-15 carbon atoms is properly represented, i.e., all cis-13-15-epic-PG's are of the 15.alpha.-hydroxy configuration.
13,14-trans-13,14-dihydro, or 13,14-didehydro cyclopentane derivatives which contain the moiety ##STR62## wherein the cyclopentane ring is variously substituted, wherein M is variously defined according to the subscripts provided herein; whereinL.sub.1 and R.sub.7 are as defined above; and wherein Y.sub.3 is trans--CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, or --C.tbd.C-- respectively. When this representation is employed, it is hereby defined to indicate the following convention with respect to therepresentation of the C-13 to C-14 moiety: ##STR63## or ##STR64## respectively. Likewise in employing this convention when M is, for example ##STR65## or ##STR66## then the corresponding representation for the trans-13 compounds: ##STR67## or ##STR68##the 13,14-dihydro compounds: ##STR69## or ##STR70## and the 13,14-didehydro compounds: ##STR71## or ##STR72## are intended, respectively. Accordingly all the formulas herein which represent trans-13, 13,14-dihydro, or 13,14-didehydro-cyclopentanederivatives are depicted by the same convention as that for PGE.sub.1 when drawn as above, i.e., ##STR73##
Thus, for all trans-13, 13,14-dihydro, or 13,14-didehydro-PG-type compounds, as drawn herein the 15.alpha.-hydroxy configuration corresponds to the relative C-15 stereochemical configuration of PGE.sub.1 as obtained from mammalian tissues. Nospecial designation of the C-15 stereochemistry is provided in naming these compounds. For compounds of the opposite stereochemical configuration at C-15 (i.e., 15.beta.-hydroxy), the description "15-epi" will be employed.
The prostaglandin analogs of formula I are known to correspond to the prostaglandins described above, in that these prostaglandin analogs exhibit prostaglandin-like activity.
Specifically the PGE-, 8.beta.,12.alpha.-PGE-, 8.beta.,12.alpha.-11-deoxy-PGE-, and 11-deoxy-PGE-type compounds correspond to the PGE compounds described above, in that these PGE-, 8.beta.,12.alpha.-PGE-, 8.beta.,12.alpha.-11-deoxy-PGE-, and11-deoxy-PGE-type compounds are useful for each of the above-described purposes for which the PGE compounds are used, and are used in the same manner as the PGE compounds, as described above.
The PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.sub..alpha. -type compounds correspond to the PGF.sub..alpha. compounds described above, in that these PGF.sub.60 -,8.beta.,12.alpha.-PGF.sub..alpha., 8.beta.,12.alpha.-11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.sub..alpha. -type compounds are useful for each of the above-described purposes for which the PGF.sub..alpha. compounds are used, and are used in thesame manner as the PGF compounds, as described above.
The PGD-, 9.beta.-PGD-, 8.beta.,12.alpha.-PGD-, 8.beta.,9.beta.,12.alpha.-PGD-, 9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-PGD-, 8.beta.,12.alpha.-9,10-didehydro-9-deoxy-PGD-, and 9,10-didehydro-9-deoxy-PGD-type compounds of formula I correspond tothe PGE or PGF.sub..alpha. compounds described above, in that these PGD-, 8.beta.,12.alpha.-PGD-, 9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-PGD-, 8.beta.,12.alpha.-9-deoxy-9,10-didehydro-PGD-, or 9-deoxy-9,10-didehydro-PGD-type compounds are useful foreach of the above-described purposes for which either the PGE or PGF.sub..alpha. compounds are used, and are used in the same manner as the PGE and PGF.alpha. compounds, as described above.
The PGA- or 8.beta.,12.alpha.-PGA-type compounds of formula I correspond to the PGA compounds described above, in that these PGA- or 8.beta.,12.alpha.-PGA-type compounds are useful for each of the above described purposes for which the PGAcompounds are used, and are used in the same manner as the PGA compounds, as described above. The PGB-type compounds of formula I correspond to the PGB compounds described above in that the PGB compounds are useful for each of the above describedpurposes for which PGB compounds are used, and are used in the same manner as the PGB compounds described above.
The prostaglandins described above, ar all known to be potent in causing multiple biological responses even at low doses. Moreover, for many applications, there prostaglandins are known to exhibit a relatively short duration of biologicalactivity. Significantly, the prostaglandin analogs of formula I are known to be substantially more selective with regard to potency in causing prostaglandin-like biological responses, and have a somewhat longer duration of biological activity. Thus,each of these prostaglandin analogs is known to be equally or even more useful than one of the corresponding prostaglandins described above for at least one of the pharmacological purposes indicated above for the latter.
Another property of the prostaglandin analogs of formula I, compared with the corresponding prostaglandins, is that these PG analogs are known to be capable of effective administration orally, sublingually, intravaginally, buccally, or rectallyin many cases where the corresponding prostaglandin is known to be effective only by the intravenous, intramuscular, or subcutaneous injection or infusion methods of administration indicated above as used of these prostaglandins. When alternate routesof administration are employed, they are known to facilitate maintaining unilevels of these compounds in the body with fewer, shorter, or smaller doses, and to make possible self-administration by the patient.
Accordingly, the prostaglandin analogs of formula I are known to be capable of administration in various ways for various purposes: e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually,topically, and in the form of sterile implants for prolonged action. For intravenous injection or infusion, sterile aqueous isotonic solutions are known to be preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions areused. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral sublingual administration. For rectal or vaginal administration, suppositories prepared as known inthe art are used. For tissue implants, the use of sterile tablets or silicone rubber capsules or other objects containing or impregnated with the substance is known.
Methods for the preparation of large ringed lactones are known in the art. See, for example, E. J. Corey, et al., Journal of the American Chemical Society 96: 5614 (1974). Further, certain 1,9 lactones of cyclopentane containing carboxylicacids are known in the art. See Sourth African Application No. 737,357, Derwent Farmdoc CPI No. 28414V, which discloses 1,9-lactones of .mu.-heterocyclic prostaglandin analogs; Japanese Application No. 50-0037-793, Derwent Farmdoc CPI No. 61147W, whichdiscloses 15-deoxy-15-methyl-PGF.sub.2.alpha., 1,9-lactone; and E. J. Corey, et al., Journal of the American Chemical Society 97: 653 (1975), which discloses PGF.sub.2.alpha. 1,9-lactone. Further, the latter reference additionally disclosesPGF.sub.2.alpha., 1,15-lactone.
Finally, see Japanese Patent Application No. 50013-385, Derwent Farmdoc CPI No. 56267W, which discloses 1,9lactones of PGF.sub.2.alpha. and (15RS)-15-methyl-PGF.sub.2.alpha..
SUMMARY OF THE INVENTION
This invention provides novel bicyclic, cyclopentane-containing lactones.
This invention further provides novel processes for preparing these lactones.
In particular, this specification discloses:
1. a 1,9-, 1,11-, or 1,15-lactone of a prostaglandin analog of the formula ##STR74## or ##STR75## wherein L.sub.1, M.sub.1, R.sub.7, Y.sub.1, and Z.sub.1 are as defined above;
2. a 1,9- or 1,15-lactone of a prostaglandin analog of the formula ##STR76## or ##STR77## wherein L.sub.1, M.sub.1, R.sub.7, Y.sub.1, and Z.sub.1 are as defined above;
and
wherein W.sub.2 is ##STR78##
3. a 1,11 or 1,15-lactone of a prostaglandin analog of the formula ##STR79## or ##STR80## wherein L.sub.1, M.sub.1, R.sub.7, Y.sub.1, and Z.sub.1 are as defined above;
4. a 1,15-lactone of a prostaglandin analog of the ##STR81## wherein L.sub.1, M.sub.1, R.sub.7, Y.sub.1, and Z.sub.1 are as defined above.
The charts herein describe methods whereby the prostaglandins or prostaglandin analogs, hereinabove described, are transformed to 1,9-, 1,11-, or 1,15-lactones. Since each of these prostaglandins or prostaglandin analogs exhibits an hydroxyl atC-15, each is therefore capable of forming a 1,15-lactone. Further, 1,9- or 1,11-lactones of each of the prostaglandins or prostaglandin analogs hereinabove described is likewise capable of formation, depending upon whether the cyclopentane ringstructure exhibits a 9-hydroxyl or an 11-hydroxyl, respectively. Thus, the PGA-, PGB-, 9-deoxy-PGD-, 9-deoxy-9,10-didehydro-PGD-, and 11-deoxy-PGE-type compounds or their 8.beta.,12.alpha.-isomers are capable of forming only 1,15-lactones. The PGD-,9.beta.-PGD-, 11-deoxy-PGF.sub..alpha. -, and 11-deoxy-PGF.beta.-type compounds or their 8.beta.,12.alpha.-isomers are capable only of forming 1,9- or 1,15-lactones. The PGE-type compounds or their 8.beta.,12.alpha.-isomers are capable of forming only1,11- or 1,15-lactones. Finally, the PGF.sub..alpha. - or PGF.sub..beta. -type compounds or their 8.beta.,12.alpha.-isomers are capable of forming 1,9-, 1,11-, or 1,15-lactones. ##STR82##
Whereas the present specification describes each of the various lactones of each of the various prostaglandins or prostaglandin analogs described above, the charts below describe methods whereby the desired lactone product is obtained with highselectivity. In each case, the lactonization step itself proceeds by methods known in the art.
For example, South African Pat. No. 737,357 (Derwent Farmdoc CPI No. 28,414V) teaches the preparation of 1,9-lactones of certain PG-type compounds by application of heat to neat samples of the PG-type product. However, for the purposes of thepresent invention, the method described therein is unsuitable in that only complex mixtures of products are thereby produced.
A further method for lactonization of PG-type compounds is described by Japanese Patent Application No. 5-0037-793 (Derwent Farmdoc CPl No. 61147W) and Japanese Patent Application No. 5-0013-385 (Derwent Farmdoc CPl No. 56267W) whereintrifluoroacetic acid and trifluoroacetic anhydride are employed as lactonization agents. Further, lactonization for prostaglandin-type products is accomplished by the lactonization procedure of S. Masaume, Journal of the American Chemical Society 97,3515 (1975). By this procedure a mercuric trifluoroacetate catalyzed ring closure of an .omega.-hydroxy-t-butythiol ester is employed.
However, the preferred procedure of lactonization of the prostaglandin analog described herein proceeds by transformation of the carboxyl of the prostaglandin type compound to a corresponding 2-pyridinethiol ester, followed by ring closure. Thegeneral method for this preferred lactonization process is described by E. J. Corey, Journal of the American Chemical Society 96, 5614 (1974), and its application to PGF.sub.2.alpha. is described by E. J. Corey, et al., Journal of the American ChemicalSociety 97, 653 (1975). By this preferred procedure the formation of the 2-pyridinethiol ester proceeds by reaction of the prostaglandin type free acid with 1.5 equivalents of 2,2'-dipyridyl disulfide and 1.5 equivalents of triphenylphosphine in a dry(anhydrous) oxygen free xylene or benzene diluent. The 2-pyridinethiol esterification proceeds at room temperature, in about 2-24 hr. The ring closure then proceeds by first diluting the thiol ester obtained above with dry, oxygen free xylene orbenzene and thereafter heating to reflux for 1-24 hr.
A modification of the preferred procedure for lactonization is described by H. Gerlach, et al., Helv. Chim. Acta. 57 (8) 2661 (1974). This modification involves ring closure of an .omega.-hydroxy-2-pyridine thiol ester with silver ion(perchlorate or fluoroborate) catalysis in benzene at room temperature.
With respect to the charts below:
L.sub.1, m.sub.1, y.sub.1, and R.sub.7 are as defined above.
R.sub.8 is hydrogen or hydroxy.
R.sub.9 is an acyl protecting group.
R.sub.10 is a blocking group.
R.sub.33 is --O--Si--(G.sub.1).sub.3 wherein G.sub.1 is alkyl, cycloakyl, aralkyl, phenyl, or phenyl substituted with alkyl or halogen, the various G.sub.1 's of a --Si--(G.sub.1).sub.3 moiety being the same or different.
Z.sub.4 is ##STR83## wherein T and s are as defined above, and
wherein h is 2 to 4, inclusive, preferably 3.
M.sub.7 is ##STR84## or ##STR85##
M.sub.8 is ##STR86## or ##STR87## wherein R.sub.5 and R.sub.10 are as defined above. M.sub.11 is ##STR88## or ##STR89##
M.sub.15 is ##STR90## or
M.sub.16 is ##STR91## or
M.sub.18 is ##STR92## or
Acyl protecting groups, according to R.sub.9, include:
a. benzoyl;
b. benzoyl substituted with one, 2, 3, 4, or 5 alkyl of one to 4 carbon atoms, inclusive, phenyl alkyl of 7 to 10 carbon atoms, inclusive, phenyl, or nitro, with the proviso that not more than 2 substituents are other than alkyl, and that thetotal number of carbon atoms in the substituents does not exceed 10 carbon atoms, with the further proviso that the substituents may be the same or different;
c. benzoyl substituted with alkoxy carbonyl wherein the alkoxy carbonyl moiety is of 2 to 5 carbon atoms, inclusive;
d. naphthoyl;
e. naphthoyl substituted with one to 9, inclusive, alkyl of one to 4 carbon atoms, inclusive, phenyl alkyl of 7 to 10 carbon atoms, inclusive, or nitro, with the proviso that not more than 2 substituents on either of the naphthyl rings does notexceed 10 carbon atoms, with the further proviso that the various substituents are the same or different; or
f. alkanoyl of 2 to 12 carbon atoms, inclusive.
In preparing these acyl derivatives of the hydroxy-containing compounds herein methods generally known in the art are employed. Thus, for example, an aromatic acid of the formula R.sub.9 OH, wherein R.sub.9 is as defined above (e.g., benzoicacid), is reacted with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. sulfuric acid, zinc chloride, or phosphoryl chloride; or alternatively an anhydride of the aromatic acid of the formula (R.sub.9).sub.2 O (e.g., benzoicanhydride) is used.
Preferably, however, the process described in the above paragraph proceeds by use of the appropriate acyl halide, e.g., R.sub.9 Hal, wherein Hal is chloro, bromo, or iodo. For example, benzoyl chloride is reacted with the hydroxy-containingcompound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine, triethylamine, or the like. The reaction is carried out under a variety of conditions, using procedures generally known in the art. Generally mildconditions are employed: 20.degree.-60.degree. C., contacting the reactants in a liquid medium (e.g., excess pyridine or an inert solvent such as benzene, toluene, or chloroform). The acylating agent is used either in stoichiometric amount or insubstantial stoichiometric excess.
As examples of R.sub.9, the following compounds are available as acids (R.sub.9 OH), anhydrides (R.sub.9).sub.2 O, or acyl chlorides (R.sub.9 Cl): benzoyl; substituted benzoyl, e.g., p-phenylbenzoyl, (2-, 3-, or 4-)-methylbenzoyl, (2-, 3-, or4-)-ethylbenzoyl, (2-, 3-, or 4-)-isopropylbenzoyl, (2-, 3-, or 4-)-tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,5-trimethylbenzoyl, pentamethylbenzoyl, alpha-phenyl(2-, 3-, or 4-)-toluyl, (2-, 3-, or4-)-phenethylbenzoyl, (2-, 3-, or 4-)-nitrobenzoyl, (2,4-, 2,5-, or 2,3-)-dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl,3-nitro-2-phenethylbenzoyl; mono esterified phthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl; substituted naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or 7-)-methyl-1-naphthoyl, (2- or 4 -) ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl,4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 8-)-nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or 8-)methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-)nitro-2-naphthoyl; and acetyl.
There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R.sub.9 Cl compounds corresponding to the above R.sub.9 groups. If the acyl chloride is not available, it is preparedfrom the corresponding acid and phosphorus pentachloride as is known in the art. It is preferred that the R.sub.9 OH, (R.sub.9).sub.2 O, or R.sub.9 Cl reactant does not have bulky hindering substituents, e.g. tert-butyl on both of the ring carbon atomsadjacent to the carbonyl attaching site.
The acyl protecting groups, according to R.sub.9, are removed by deacylation. Alkali metal carbonates are employed effectively at ambient temperature for this purpose. For example, potassium carbonate in methanol at about 25.degree. C. isadvantageously employed. By the preferred process herein, however, an alkali metal hydroxide is employed in aqueous methanol, e.g. potassium hydroxide.
Those blocking groups within the scope of R.sub.10 are any group which replaces a hydroxy hydrogen and is neither attacked by nor as reactive to the reagents used in the transformations used herein as an hydroxy is and which is subsequentlyreplaceable with hydrogen in the preparation of the prostaglandin-type compounds. Several blocking groups ae known in the art, e.g. tetrahydropyranyl and substituted tetrahydropyranyl. See for reference E. J. Corey, Proceedings of the Robert A. WelchFoundation Conferences on Chemical Research, 12, Organic Synthesis, pgs. 51-79 (1969). Those blocking groups which have been found useful include:
a. tetrahydropyranyl;
b. tetrahydrofuranyl; and
c. a group of the formula
wherein R.sub.11 is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl or phenyl substituted with one to 3 alkyl of one to 4 carbon atoms, inclusive,wherein R.sub.12 and R.sub.13 are alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or when R.sub.12 and R.sub.13 are taken together --(CH.sub.2).sub.a -- or--(CH.sub.2).sub.b -- O --(CH.sub.2).sub.c wherein a is 3, 4, or 5, or b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3, or 4, with the further proviso that R.sub.12 and R.sub.13 may be the same or different, and whereinR.sub.14 is hydrogen or phenyl.
When the blocking group R.sub.10 is tetrahydropyranyl, the tetrahydropyranyl ether derivative of any hydroxy moieties of the PG-type intermediates herein is obtained by reaction of the hydroxy-containing compound with 2,3-dihydropyran in an inertsolvent, e.g. dichloromethane, in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. The dihydropyran is used in large stoichiometric excess, preferably 4 to 100 times the stoichiometric amount. Thereaction is normally complete in less than an hour at 20.degree. to 50.degree. C.
When the blocking group is tetrahydrofuranyl, 2,3-dihydrofuran is used, as described in the preceding paragraph, in place of the 2,3-dihydropyran.
When the blocking group is of the formula
wherein R.sub.11, R.sub.12 R.sub.13, and R.sub.14 are as defined above, the appropriate reagent is a vinyl ether, e.g. isobutyl vinyl ether or any vinyl ether of the formula
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are as defined above; or an unsaturated cyclic or heterocyclic compound, e.g. 1-cyclohexen-1-yl methyl ether, or 5,6-dihydro-4-methoxy-2H-pyran. See C. B. Reese, et al., Journal of the ChemicalSociety 89, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for dihydropyran above.
The blocking groups according to R.sub.10 are removed by mild acidic hydrolysis. For example, by reaction with (1) hydrochloric acid in methanol; (2) a mixture of acetic acid, water, and tetrahydrofuran, or (3) aqueous citric acid or aqueousphosphoric acid in tetrahydrofuran, at temperatures below 55.degree. C., hydrolysis of the blocking groups is achieved.
Various reactions in the succeeding charts introduce silyl groups of the formula --Si(G.sub.1).sub.3. In some cases, such silylations are general, in that they silylate all hydroxy hydrogens, while in other cases they are selective, in thatwhile one or more hydroxyls are silylated, at least one other hydroxyl remains unaffected. For any of these silylations, silyl groups within the scope of --Si(G.sub.1).sub.3 include trimethylsilyl, dimethylphenylsilyl, triphenylsilyl,t-butyldimethylsilyl, or methylphenylbenzylsilyl. With regard to G.sub.1, examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl, pentyl, and the like. Examples of aralkyl are benzyl, phenethyl, .alpha.-phenylethyl,3-phenylpropyl, .alpha.-naphthylmethyl, and 2-(.beta.-naphthyl)ethyl. Examples of phenyl substituted with halo or alkyl are p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3-methylphenyl.
These silyl groups are known in the art. See for example, Pierce "Silylation of Organic Compounds," Pierce Chemical Company, Rockford, Ill. (1968). When silylated products of the charts below are intended to be subject to chromatographicpurification, then the use of silyl groups known to be unstable to chromatography (e.g. trimethylsilyl) should be avoided. Further, when silyl groups are to be introduced selectively, silylating agents which are readily available and known to be usefulin selective silylations are employed. For example, triphenylsilyl groups and t-butyldimethylsilyl groups are employed when selective introduction is required. Further, when silyl groups are to be selectively hydrolyzed over protecting groups accordingto R.sub.10 or acyl protecting groups, then the use of silyl groups which are readily available and known to be easily hydrolyzable with tetran-butylammonium fluoride are employed. A particularly useful silyl group for this purpose ist-butyldimethylsilyl, although other silyl groups (e.g. trimethylsilyl) are likewise employed.
With respect to Chart A, a method is provided where the formula XXI PGF.sub..alpha. -, 11-deoxy-PGF.sub..alpha. -, PFG.sub..beta. -, or 11-deoxyPGF.sub.62 -type compound is transformed to a formula XXII 1,9-lactone or formula XXV 1,15-lactone. Further, Chart A provides a method whereby the formula XXIII 8.beta.,12.alpha.-PGF.sub..alpha. -, 11-deoxy-8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..beta. -,, or 11-deoxy-8.beta.,12.alpha.-PGF.sub..beta. -type compound istransformed to a corresponding formula XXIV 1,9 or formula XXVI 1,15-lactone.
The lactonization of Chart A (XXI to XXII or XXV and XXIII to XXIV and XXVI) proceeds as is described above. The product of lactonization is recovered as a mixture of 1,9- and 1,15-lactones. The predominant product is the 1,9-lactone, theproportion of which is increased by the use of benzene rather than xylene, in the lactonization.
Chart B provides a method whereby the formula XXXVII PGD-type, 1,9-lactone is prepared from the formula XXXI PGF.sub..alpha. -type compound. Likewise, the 8.beta.,12.alpha.-PGF.sub..alpha. -type compound corresponding to formula XXXI isemployed to prepare a corresponding 8.beta.,12.alpha.-PGD-type compound corresponding to formula XXXVII.
The formula XXXII compound is prepared from the formula XXXI compound by cyclo(alkyl or arylboronization). Accordingly, the bycicylic formula XXXII compound is prepared by reaction of the formula XXXI compound with a slight stoichiometric excessof a corresponding alkyl or arylboronic acid. The course of the reaction is conveniently monitored gas chromatography and the reaction is preferably carried forth under vigorous stirring at reflux temperature. The preferred reaction diluent for thistransformation is methylene chloride, although other suitable organic solvents are alternatively employed. The formula XXXII compound so formed is then etherified at the C-15 position by replacing the hydroxyl hydrogen with a blocking group according toR.sub.10. Procedures described above for the use of such blocking groups are employed. Thereafter the formula XXXIV compound is prepared from the formula XXXIII compound by decycloboronization. For this purpose an alkali hydroxide (e.g. sodium,lithium, or potassium hydroxide) is combined with the formula XXXIII compound in a water miscible diluent capable of yielding a homogeneous reaction mixture (e.g. methanol or ethanol). The resulting solution is thereafter treated with dilute aqueoushydrogen peroxide. Thereafter the formula XXXV compound is prepared from the formula XXXIV compound by the lactonization procedure described above. This formula XXXV PGF.sub..alpha. -type, 1,9-lactone is then transformed to the corresponding PGD-type1,9-lactone by oxidation of the C-11 hydroxy to an oxo. Methods known in the art for such an oxidation are employed. Thus, for example, a slight stoichiometric excess of Jones reagent is reacted with the formula XXXV compound at a temperature of-20.degree. to -40.degree. C. The formula XXXVII compound is then prepared from the formula XXXVI compound by hydrolysis of the blocking group, employing methods hereinabove described.
Chart C provides a method whereby the formula XLI PGF.sub..alpha. - or 11-deoxy-PGF.sub..alpha. -type compound is transformed to a formula XLVIII PGF.sub..alpha. -, 11-deoxy-PFG.sub..alpha. -, or 11-deoxy-PGF.sub..beta. -type, 1,15-lactoneor a formula L PGE- or 11-deoxy-PGE-type, 1,15-lactone or a formula LII PGD-type, 1,15-lactone.
By the procedure of Chart C the formula XLI compound is transformed to the formula XLII compound by selective silylation at C-11 and C-15 over C-9. Silyl groups according to the formula --Si(G.sub.1).sub.3, wherein G.sub.1 is defined above, areadvantageously employed. For selective monosilylation procedures see U.S. Pat. No. 3,822,303, issued July 2, 1974, German Offenlegungsschrift No. 2,259,195 (Derwent Farmdoc CPI No. 36457U-B) or Netherlands Pat. No. 7,214,142 (Derwent Farmdoc CPI No.26221U-B). Subsequently, there are performed the optional transformations of the formula XLII compound to the formula XLIII compound, and thereafter the formula XLIV compound. The formula XLIII compound is prepared from the formula XLII compound byoxidation of the 9-hydroxy to an oxo. Methods known in the art are employed. For example, the use of the Jones reagent or the Collins reagent or such additional reagents as are known to transform PGF.sub..alpha. -type compounds to correspondingPGE-type compounds is known and employed herein. Subsequently, the formula XLIII compound is transformed to the formula XLIV compound by reduction of the 9-oxo of the formula XLIII compound to the corresponding 9-hydroxy compound and separation of the9.beta.-hydroxy isomer from the isomeric mixture so formed. This reduction is performed by methods known in the art. For example, the use of sodium, potassium, or lithium borohydride reducing agents and such other agents as is known in the art forreduction of PGE-type compounds to mixtures of PGF.sub..alpha. and PGF.sub..beta. -type compounds is known and employed herein. The 9-epimeric mixture is conveniently separated by silica gel chromatography, yielding the formula XLIV product.
Thereafter, the formula XLII or formula XLIV compounds are transformed to the formula XLV compound by replacing the 9-hydroxy hydrogen with a blocking group according to R.sub.10. Methods known in the art and hereinabove described are employed. Thereafter the formula XLV compound is transformed to the formula XLVI compound by selective hydrolysis of any silyl groups over any blocking groups according to R.sub.10. This selective removal of any silyl groups is accomplished by methods known inthe art. See for reference Corey, et al., Journal of the American Chemical Society 94, 6190 (1972). An especially useful reagent for this purpose is tetra-n-butyl-ammonium fluoride in tetrahydrofuran.
Thereafter the formula XLVI compound is transformed to the formula XLVII compound by 1,15-lactonization. Lactonization methods described above are employed.
The formula XLVIII PGF.sub..alpha. -, 11-deoxy-PGF.sub..alpha. -, PGF.sub..beta. -, or 11-deoxy-PGF.sub..beta. -type, 1,15-lactones are then prepared from the formula XLVII compound by hydrolysis of the blocking group according to R.sub.10. This hydrolysis proceeds by methods hereinabove described.
The formula L PGE- or 11-deoxy-PGE-type, 1,15-lactone is then prepared from the formula XLVIII PGF.sub..alpha. - or 11-deoxy-PGF.sub..alpha. -type, 1,15-lactone by first selective silylation at C-11 over C-9 (formula XLIX) employing methodsdescribed in the transformation of the formula XLI compound to the formula XLII compound; oxidizing the formula XLIX silylated compounds so formed to a corresponding 9-oxo compound, employing methods known in the art for transformation of PGF.sub..alpha. -type compounds to PGE-type compounds as described above; and thereafter optionally hydrolyzing any silyl group employing methods and procedures known in the art.
Alternatively the formula XLVII compound is employed in the preparation of the formula LI compound. In this transformation the 11-hydroxy of the formula XLVII compound is oxidized to the corresponding formula LI 11-oxo compound. Proceduresknown in the art are employed. For example, see Tetrahedron Letters, 2235 (1974). Useful reagents for this purpose include those oxidizing reagents described above as useful in the transformation of PGF-type compounds to PGE-type compounds. Theformula LI compound is then hydrolyzed at C-9, preparing the formula LII PGD-type, 1,15-lactone.
Chart D provides a method whereby the formula LXI 8.beta.,12.alpha.-PGF.sub..alpha. -type compound is transformed to a formula LXIV 8.beta.,12.alpha.-PGF.sub..alpha. -type, 1,15-lactone; a formula LXIX 8.beta.,12.alpha.-PGE-type, 1,15-lactone;a formula LXXI 8.beta.,12.alpha.-PGF.sub..beta. -type, 1,15-lactone; or a formula LXXIII 8.beta.,12.alpha.-PGD-type, 1,15-lactone. Additionally, the transformations of the formula LXI compound to the formula LXII compound are optionally employed on the8,12-isomers of those depicted by formulas LXI to LXIV, respectively, thereby preparing the PGF.sub..alpha. -type, 1,15-lactone corresponding to formula LXIV.
The transformation of the formula LXI compound to the formula LXII compound of Chart D proceeds by the method described in Chart B for the preparation of the formula XXXII compound from the formula XXXI compound. Thereafter, the formula LXXIIcompound is 1,15-lactonized, forming the formula LXIII compound. This lactonization proceeds by the methods hereinabove described. Thereafter, the formula LXIII compound is decyclo(alkylboronized) employing the procedure described in Chart B for thetransformation of the formula XXXIII compound to the formula XXXIV compound. Accordingly, the 8.beta.,12 .alpha.-PGF.sub..alpha. -type, 1,15-lactones are prepared.
Thereafter, the formula XLIV compound is transformed to the formula LXV compound by selective silylation of the C-9 hydroxy over the C-11 hydroxy. This selective silylation proceeds by methods known in the art. For example, see U.S. Pat. No.3,822,303, issued July 2, 1974, German Offenlegungsschrift, No. 2,259,195 (Derwent Farmdoc CPI No. 36457U-B) or Netherlands Pat. No. 7,214,142 (Derwent Farmdoc CIP No. 26221U-B). Thereafter, the formula LXV compound is employed in the preparation ofeither the formula LXVI compound or the formula LXXII compound.
The formula compound is transformed to the formula LXVI compound by replacing the 11-hydroxy hydrogen with a blocking group according to R.sub.10. Methods known in the art, hereinabove described, are employed.
The formula LXVI compound is then transformed to the formula LXVII compound by selective hydrolysis of the silyl group over the blocking group according to R.sub.10. Methods hereinabove described for such selective hydrolysis are employed. Seethe transformation of the formula XLIV compound to the formula XLVI compound of Chart C.
Thereafter, the formula LXVII compound is transformed to the formula LXVIII compound by oxidation of the 9-hydroxy to a corresponding 9-oxo compound. Reagents and procedures known in the art for transformation of PGF.sub..alpha. -type compoundsto PGE-type compounds are employed. The formula LXVIII compound is then hydrolyzed, whereby blocking groups according to R.sub.10 are removed, thereby preparing the formula LXIX 8.beta.,12.alpha.-PGE-type, 1,15-lactone. Methods of hydrolysis ofblocking groups according to R.sub.10 hereinabove described are employed.
Thereafter the formula LXIX compound is transformed to the formula LXXI compound by a ring carbonyl reduction, employing methods known in the art for the transformation of PGE-type compounds to the corresponding PGF.sub..beta. compounds. Accordingly, sodium, potassium, or lithium borohydride is employed in the reduction, followed by chromatographic separation of the 9.beta.-hydroxy epimer from the 9-epimeric mixture so formed. Accordingly, there is prepared8.beta.,12.alpha.-PGF.sub..beta. -type, 1,15-lactones of formula LXXI.
The formula LXV compound is employed in the preparation of the formula LXXII compound by selective oxidation of the C-11 hydroxy to a corresponding oxo. Methods described in Chart G and the transformation of formula LXVII compound to the formulaformula LI compound are employed. Thereafter the formula LXXII compound is transformed to the formula LXXIII 8.beta.,12.alpha.-PGD-type, 1,15-lactone following procedures described above for hydrolysis of silyl groups.
Chart E provides a method whereby the formula LXXXI PGE- or 11-deoxy-PGE-type starting material is transformed to the formula Ixxxii PGE- or 11-deoxy-PGE-type, 1,15-lactones, or the formula LXXXV PGF.sub..alpha. -, 11-deoxy-PGF.sub..alpha. -,PGF.sub..beta. -, or 11-deoxy-PGF.sub..beta. -type, 1,15-lactones. Further, Chart E describes the use of the formula LXXXIII 8.beta.,12.alpha.-PGE- or 11-deoxy-8.beta.,12.alpha.-PGE-type compound in the preparation of the formula LXXXIV8.beta.,12.alpha.-PGE- or 11-deoxy-8.beta.,12.alpha.-PGE-type, 1,15-lactones or the formula LXXXVI 8.beta.,12.alpha.-PGF.sub..alpha. -, 11-deoxy-8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..beta. -, or11-deoxy-8.beta.,12.alpha.-PGF.sub..beta. -type, 1,15-lactones.
For the transformation of the formula LXXXI or LXXXIII compound to the formula LXXXII or formula LXXXIV compound, respectively, lactonization methods hereinabove described are employed. Thereafter, the formula LXXXIV or formula LXXXVI compoundis prepared from the formula LXXXIII compound, respectively, by a ring carbonyl reduction, followed by separation of C-15 epimers. These ring carbonyl reductions and epimeric separations are performed by methods described hereinabove. See thetransformation of the formula XLIII compound to the formula LXIV compound of Chart C.
Chart F provides a method whereby the formula XCI PGE-type compound is transformed to the formula XCII PGA-type, 1,15-lactone; the formula XCIII 8.beta.,12.alpha.-PGE-type, 1,15-lactone is transformed to the formula XCIV8.beta.,12.alpha.-PGA-type, 1,15-lactone; a formula XCV PGD-type, 1,15-lactone is transformed to a formula XCVI 9-deoxy-9,10-didehydroPGD-type, 1,15-lactone; or a formula XCVII 8.beta.,12.alpha.-PGD-type, 1,15-lactone is transformed to a formula XCVIII9-deoxy-9,10-didehydro-8.beta.,12.alpha.-PGD-type, 1,15-lactone.
For each of the above transformations of Chart F, the hydroxyl on the cyclopentane ring is dehydrated to the corresponding compound with .alpha.,.beta.-unsaturation to the ketone employing mild acidic dehydration. For example, methods known inthe art for the transformation of PGE-type compounds to PGA-type compounds are employed. Alternatively, the various starting materials of Chart F are transformed to corresponding acetates (e.g. employing acetic anhydride), and thereafter chromatographedon silica gel to effect the desired dehydration.
Chart G provides a method whereby the formula CI PGA-type compound, formula CII PGB-type compound, formula CIII, formula CV 11-deoxy-PGE-type compound, or their respective 8.beta.,12.alpha.-isomers, are transformed to a corresponding formula CVIPG-type, 1,15-lactone wherein the cyclopentane ring structure of the starting material is preserved. Since each of the formula CI to formula CV compounds is monohydroxylated, lactonization proceeds by the general methods described hereinabove withoutthe use of any selective blocking.
With respect to Chart H, a method is provded whereby the formula CXI PGF.sub..alpha. -type compound is transformed to a formula CXIX PGF.sub..alpha. -type, 1,11-lactone, formula CXXII PGE-type, 1,11-lactone, or formula CXXIII PGF.sub..beta. -type, 1,11-lactone.
With respect to Chart H, the transformation of the formula CI compound to the formula CIV compound employs the methods hereinabove described in Chart B for the transformation of the formula XXXI compound to the formula XXXIV compound. Thereafter, the formula CXV compound is prepared from the formula CXIV compound by selective silylation. Accordingly, methods described in Chart C for the transformation of the formula XLI compound to the formula XLII compound are employed.
Thereafter the formula CXV compound is transformed to the formula CXVI compound by transformation of the 9-hydroxy hydrogen to a blocking group according to R.sub.10. Methods described hereinabove are employed. Thereafter, the formula CXVcompound is transformed to the formula CXVI compound by selective hydrolysis of the 11-silyl group. Methods described hereinabove are employed. See, the transformation of the formula XLV compound to the formula XLVI compound in Chart C.
Thereafter, the formula CXVII compound is 1,11-lactonized, thereby forming the formula CXVIII compound. This lactonization proceeds by methods known in the art and described hereinabove.
Thereafter, the formula CXIX PGF.sub..alpha. -type, 1,11-lactone is prepared from the formula CXVIII compound by hydrolysis of a blocking groups according to R.sub.10. Methods known in the art and hereinabove described are employed.
Thereafter, the formula CXX compound is prepared from the formula CXIX compound by selective silylation. This selective silylation of the C-15 hydroxyl over the C-9 hydroxyl is accomplished by methods known in the art and described andreferenced in Chart C for the transformation of the formula CXLI compound to the formula CXLII compound. Thereafter, the formula CXX compound is oxidized at the C-9 position to the corresponding formula CXXI compound employing methods known in the artfor the transformation of PGF.sub..alpha. -type compounds to corresponding PGE-type compounds. Thereafter, the formula CXXII PGE-type, 1,11-lactone is prepared by hydrolysis of the silyl group, employing methods known in the art.
Finally, the formula CXXIII PGF.sub..beta. -type, 1,11-lactones are prepared from the formula CXXII PGE-type, 1,11-lactones by ring carbonyl reduction and separation of the 9-epimeric mixture thereby obtained. Accordingly, methods describedhereinabove, i.e. the transformation of the formula XLIII compound to the formula XLIV compound of Chart C, are employed.
Chart J provides a method whereby formula CXXXI 8.beta.,12.alpha.-PGF.sub..alpha. -type compound is transformed to a formula CXXXVI 8.beta.,12.alpha.-PGF.sub..alpha. -, 8.beta.,12.alpha.-PGF.sub..beta. -, or 8.beta.,12.alpha.-PGE-type,1,11-lactone.
With respect to Chart J, the formula CXXXI compound is transformed to the formula CXXXII compound by a selective etherification at C-15. Methods described in proceeding charts are employed. See the transformation of the formula XXXI compound tothe formula XXXIV compound of Chart B. Thereafter, the formula CXXXII compound is selectively silylated at the C-9 position, thereby preparing the formula CXXXIII compound. This selective silylation proceeds by the method described in the transformationof the formula LXIV compound to the formula LXV compound of Chart D.
Thereafter, the formula CXXXIII compound is transformed to the formula CXXXIV compound by 1,11-lactonization, employing the lactonization procedures described hereinabove. Thereafter the formula CXXXV compound is prepared from the formula CXXXIVcompound by selective hydrolysis of the silyl group in the presence of a blocking group according to R.sub.10. Methods described in Chart C in the transformation of the formula CXLV compound to the formula CXLVI compound are employed.
Thereafter, the formula CXXXV compound is transformed to the formula CXXXVI compound employing methods hereinabove described in the transformation of PGF.sub..alpha. -type lactones to corresponding PGE-type and PGF.sub..beta. -type lactones.
Chart K provides a method whereby the formula CXLI compound or its 8.beta.,12.alpha.-isomer is transformed to the corresponding formula CXLVIII PG-type 1,11-lactone or its 8.beta.,12.alpha.-epimer.
With respect to Chart K the formula CXLI starting material is prepared in the manner of the formula XXXV compound of Chart B when M.sub.15 is the same as M.sub.8. The 8.beta.,12.alpha.-compound wherein M.sub.15 is the same as M.sub.8corresponding to formula CXLI is prepared in the manner of the formula XXXV compound of Chart B employing 8.beta.,12.alpha.-PGF.sub..alpha. -type starting material corresponding to formula XXXI.
When M.sub.15 is the same as M.sub.7 for the formula CXLI compound of Chart K, then the formula CXLI compound is prepared by selective silylation employing the method described in Chart H for the preparation of the formula CXX compound from theformula CXIX compound.
The formula CXLII compound is prepared from the formula CXLI compound by silylation at C-9. Methods known in the art for the introduction of silyl groups are employed. Thereafter, the formula CXLIII compound is prepared from the formula CXLIIcompound by reduction of the 11-oxo to an 11-hydroxy. This reduction proceeds by methods herein described for the transformation of PGE-type compounds to corresponding PGF-type compounds. Finally, the formula CXLIV compound is prepared from the formulaCXLIII compound by separation of the 11-epimeric mixture employing silica gel chromatography.
The formula CXLIV compound is then 1,11-lactonized forming the formula CXLV compound. This is lactonization proceeds by the general methods hereinabove described. Thereafter, the formula CXXXV compound is transformed to CXXXVI compound byhydrolysis of the silyl groups. When M.sub.15 is the same as M.sub.8, this hydrolysis proceeds selectively by methods hereinabove described. See the transformation of the formula CXLV compound to the formula CXLVI compound of Chart C. Otherwise,methods generally known in the art for removal of silyl groups, without hydrolyzing ester linkages, are employed.
Thereafter, the formula CXLVI compound wherein M.sub.16 is the same as M.sub.8 is transformed to the formula CXLVII compound, employing methods hereinabove described for the transformation of PGF.sub..alpha. -type compounds to PGE-typecompounds. Finally, the formula CXLVII compound is transformed to the various formula CXLVIII PG-type, 1,11-lactones employing ring transformations hereinabove described and hydrolyzing the blocking group according to R.sub.10, following procedureshereinabove described.
Chart L provides a method whereby the formula CLI PGE-type 1,15-lactone, or its 8.beta.,12.alpha.-isomer is transformed to a corresponding formula CLVII 9.beta.-PGD- or PGD-type, 1,15-lactone or its 8.beta.,12.alpha.-isomer, respectively.
With respect to Chart L the formula CXLII compound is prepared from the formula CXLI compound by silylation. Methods known in the art and hereinabove described are employed. The formula CXLIII is then prepared from the formula CXLII compound bya ring carbonyl reduction, employing methods hereinabove described. The 9-epimeric mixture thusly prepared is then separated by silica gel chromatography, preparing the separated formula CLIII epimers.
The formula CLIV compound is then prepared from the formula CLIII compound by transforming the 9-hydroxy hydrogen to a blocking group according to R.sub.10. Methods described hereinabove are employed.
Thereafter the silyl groups are selectively hydrolyzed over the blocking groups according to R.sub.10, following procedures described in Chart B for the transformation of the formula CXLV compound to the formula CXLVI compound. Thereupon, theformula CXLV compound is oxidized at the C-11 position to the corresponding 11-oxo compound. Methods hereinabove described, particularly the transformation of the formula XXXV compound to the formula XXXVI compound of Chart B are employed.
Thereafter, the 9.beta.-PGD- or PGD-type, 1,15-lactones of formula CXLVII are prepared from the formula CXLVI compound by hydrolysis of the blocking groups according to R.sub.10. Methods known in the art and hereinabove discussed are employed.
Chart M provides a method whereby the formula CLXI PGF.sub..alpha. -type compound is transformed to a formula CLXVII 9.beta.-PGD-type, 1,9-lactone.
With respect to Chart M the formula CLXI compound is available as formula XXXIV of Chart B. Thereafter, this compound is transformed to the formula CLXII compound by selective silylation of the C-11 hydroxy over the C-9 hydroxy, employing methodsdescribed in Chart C (the transformation of the formula XLI compound to the formula XLII compound).
Thereafter, the formula CLXII compound undergoes a 9-epimerization to form the formula CLXIII PGF.sub..beta. -type compound. This epimerization is accomplished by one of several methods known in the art. For example, the formula CLXII compoundis optionally oxidized to a 9-oxo compound, and thereafter the 9-oxo compound reduced to the corresponding 9-hydroxy epimeric mixture. Alternatively, the method of E. J. Corey, et al., J. Chem. Soc., Chemical Communications 658 (1975) is employed.
Thereafter the formula CLXIII compound is 1,9-lactonized to the formula CLXIV compound. Lactonization procedures described hereinabove are employed. Thereafter the formula CLXV compound is prepared from the formula CLXIV compound by selectivehydrolysis of the silyl group in the presence of blocking groups according to R.sub.10. Procedures employed in Chart C for the transformation of the formula LXV compound to the formula LXVI compound are employed. Thereafter, the formula CLXVI compoundis prepared from the formula CLXV compound by oxidation of the 11-hydroxy to an 11-oxo. This oxidation proceeds by methods described in Chart B for the transformation of the formula XXXV to the formula XXXVI compound.
Thereafter, formula CXXXVII PGD-type, 1,9-lactone is prepared from the formula CXXXVI compound by hydrolysis of the blocking group according to R.sub.10 employing methods hereinabove described.
Chart N provides a method whereby the formula CLXXI 8.beta.,9.beta.,12.alpha.-PGF-type, 1,9-lactone is transformed to the corresponding 8.beta.,9.beta.,12.alpha.-PGD-type, 1,9-lactone of formula CLXXIV.
With respect to Chart N the formula CLXXII compound is prepared from the formula CLXXI compound by selective silylation of the C-15 hydroxy. This selective silylation accomplished by the procedure described in Chart J for the transformation ofthe formula CLXIX compound to the formula CLXX compound. Thereafter the formula CLXXIII compound is prepared from the formula CLXXII compound by oxidation of the 11-hydroxy to an 11-oxo. This oxidation is accomplished by methods described in Chart B inthe transformation of the formula XXXV compound to the formula XXXVI compound.
Thereafter, the formula CLXXIV 8.beta.,9.beta.,12.alpha.-PGD-type, 1,9-lactone is then prepared from the formula CLXXIII compound by hydrolysis of the silyl group at C-15. The hydrolysis proceeds by those methods known in the art to remove silylgroups while not affecting ester linkages.
Chart O provides a method whereby the formula CLXXVI 9-deoxy-9,10-didehydro-PGD-type, 1,15-lactone is transformed to a corresponding formula CLXXVIII 9-deoxy-PGD-type, 1,15-lactone. Alternatively,9,10-didehydro-9-deoxy-8.beta.,12.alpha.-PGD-type compounds are employed in place of the formula CLXXVI starting material preparing corresponding 9-deoxy-8.beta.,12.alpha.-PGD-type products.
The formula CLXXVII starting material or its 8.beta.,12.alpha.-isomer is prepared by dehydration of a corresponding PGD- or 8.beta.,12.alpha.-PGD-type, 1,15-lactone. This dehydration proceeds by mild acid catalysis, employing organic acids suchas acetic acid, trifluoroacetic acid, citric acid, oxalic acid, or p-toluenesulfonic acid. This dehydration proceeds rapidly at temperatures between ambient temperature at about 40.degree. C. Alternatively, the dehydration is affected by allowing theformula CLXXVI starting material (or its 8.beta.,12.alpha.-isomer) to stand on a column of acid washed silicagel.
The reaction sequence of Chart O proceeds by methods known in the art for transforming PGA-type compounds to corresponding 11-deoxy-PGE-type compounds . Accordingly, the formula CLXXVI starting material is subjected to a potassium, sodium, orlithium borohydride reduction as is known in the art. For this purpose, for example, the reaction is carried out at about -20.degree. C., and is ordinarily complete within a few mintues. Thereafter, the formula CLXXVII compound, thusly obtained, isoxidized to the formula CLXXVIII 9-deoxy-PGD-type, 1,15-lactone employing oxidation agents known in the art for this purpose. Thus, for example, the Jones or Collins reagent as described above, are employed.
Chart P provides a method whereby the formula CLXXXIII 11.beta.-PGF .sub..beta. -type compound ( or its 8.beta.,12.alpha.-isomer) is transformed to a formula CLXXXVIII 9.beta.-PGD-type, 1,9-lactone (or a corresponding 8.beta.,9.beta.,12.alpha.-PGD-type, 1,9-lactone).
With respect to Chart P the formula CLXXXIII compound is known in the art or prepared by methods known in the art. For example, its preparation proceeds from the formula CLXXXI PGA-type compound by 9,10-epoxidation, reduction of the expoxide toan (11RS)-hydroxy mixture and chromatographic separation of the 11.beta.-hydroxy compound from the epimeric mixture. This reaction sequence, preparing the formula CLXXXII compound, is then followed by a ring carbonyl reduction, yielding the formulaCLXXXIII starting material. When the 8.beta., 12.alpha.-isomer of the formula CLXXXIII compound is desired, such compounds are known in the art or prepared by methods known in the art as enantiomers or 15-epi enantiomers of PGF.sub.2.alpha. -typecompounds. Methods for epoxidation, reduction of the epoxide, and separation of the epimeric mixture of alcohol so formed are described in Belgium Pat. No. 804,837 (Derwent Farmdoc CPI No. 22865V).
This formula CLXXXIII compound is then cyclo(alkylboronized) to the formula CLXXXIV compound, following the procedure described in Chart B for the preparation of the formula XXXII compound from the formula CXXXI compound. Thereafter, the formulaCLXXXIV compound is transformed to the formula CLXXXV compound by the procedure described in Chart B for the preparation of the formula CXXXIV compound from the formula CXXXII compound. This C-15 selectively protected formula CLXXXV compounds is then1,9-lactonized to a corresponding formula CLXXXVI compound, employing the lactonization procedures described hereinabove. Thereafter, the formula CLXXXVI compound is converted to the formula CLXXXVIII compound employing the method described in Chart Bfor the preparation of the formula XXXVII compound from the formula XXXV compound.
Chart R provides a method whereby the formula CXCVI 15-methyl-PGF.sub.60 ,1,11-lactone is conveniently prepared from the formula CXCI 15-methyl-PGF.sub.60 -type compound.
With regard to Chart R, the formula CXCII compounds is prepared from the formula CXCI compound by selective acylation. This selective acylation is achieved by employing a single equivalent of the acylating agent (e.g. acyl chloride) andterminating the reaction promptly after the selective C-11 protection is effected. General methods described above for the introduction of acyl protecting groups are employed.
Thereafter, the formula CXCIII compound is prepared from the formula CXCII compound by silylation. Silylation procedures known in the art are employed. Thereafter, the formula CXCIV compound is prepared from the formula CXCIII compound byselective removal of the acyl protecting group according to R.sub.9. This selective removal of the acyl protecting group is accomplished employing potassium, sodium, or lithium hydroxide in aqueous methanol, as described above.
Thereafter, the formula CXCV compound is prepared from the formula CXCIV compound by 1,11-lactonization. This lactonization proceeds as hereinabove described.Finally, formula CVI compound is prepared from the formula CXV compound by removal ofthe silyl groups, as hereinabove described.
With the exception of the procedure in Chart R, where the 15-hydroxy hydrogen is replaced on a 15-methyl-PG-type compound, or, in Charts H, J, and K where PG-type, 1,11-lactones are prepared, the introduction of silyl groups or blocking groupsaccording to R.sub.10 in place of the hydroxy hydrogen at C-15 is not required for the various transformations of the above charts when the 15-methyl compounds are employed. Accordingly, when the 15-hydroxy hydrogen is the only hydroxy hydrogen to beblocked or silylated, then such blocking or silylation may be omitted. Further, when one or both of any secondary hydroxyls at C-9 or C-11 are to be blocked or silylated in addition to the C-15 tertiary hydroxyl, then the transformation effecting theblocking or silylation need only be carried out until any secondary hydroxyls have been so transformed.
However, when the hydroxy hydrogen of a 15-methyl-PG-type compound is replaced with a blocking group according to R.sub.10, then the subsequent hydrolysis of the blocking group in many cases epimerizes the C-15 hydroxyl. In such cases, epimericpurity of the product then requires separation employing silica gel chromatography, high pressure liquid chromatography, or other techniques known to separate prostaglandin-type diastereomers.
The present invention particularly provides a prostaglandin-type 1,9-lactone of the formula ##STR93## wherein Z.sub.1, W.sub.2, Y.sub.1, M.sub.1, L.sub.1, and R.sub.7 are as defined above.
Each of the various prostaglandin-type, 1,9-lactones of the present invention is useful for each of the corresponding purposes for which the corresponding free acid of each of these lactones is used. In particular, these protaglandin-type,1,9-lactones are administered by the same routes as the corresponding free acids and for each particular purpose are administered in doses of about 5 to 1000 times the dosage at which the corresponding free acid is admistered by the same route.
Surprisingly and unexpectedly, however, in administering various prostaglandin-type, 1,9-lactones herein the host experiences increased tolerance of drug and fewer undesirable sideeffects associated with each respective route of administration. For example, when the prostaglandin-type, 1,9-lactones of the present invention are administered intravenously, higher infusion rates are successfully employed with reduction or elimination of undesirable local effects associated with administration ofthe corresponding free acid.
Additionally, when intramuscular administration is employed, the present PG-type, 1,9-lactones provide more consistent release rates from the injection site and in particular a more prolonged duration of release than the corresponding free acid. Accordingly, the present prostaglandin-type, 1,9-lactones exhibit surprisingly and unexpectedly prolonged activity when administered by this route.
The PGD-type, 1,9-lactones and 8.beta., 12.alpha.-PGD-type, 1,9-lactones are accordingly surprisingly and unexpectedly more useful blood pressure lowering agents, gastric antisecretory agents, and platelet aggregation inhibiting agents, than thecorresponding free acids. Most particularly these lactones exhibit surprisingly improved stability, both as bulk chemicals and finished pharmaceutical formulations. Further, when administered at therapeutic doses, these lactones exhibit a surprisinglyand unexpectedly more sustained duration of action than the corresponding free acids, an improved therapeutic ratio, and a lower incidence of prostaglandin-related gastrointestinal and bronchopulmonary side effects than the correspnding free acids. Accordingly, these compounds are surprisingly and unexpectedly more useful than the corresponding free acids in the treatment of hypertension, gastrointestinal hyperacidity, gastrointestinal ulcers and coagulative disorders of the cardiovascular system.
The PGF.sub..alpha. -type, 1,9-lactones; 8.beta.,12.alpha.-PGF.sub..alpha. -type, 1,9-lactones; 11-deoxy-PGF.sub..alpha. -type, 1,9-lactones; 11-deoxy-8.beta.,12.alpha.-PGF.sub..alpha. -type, 1,9-lactones; PGF.sub..bet | | | |
