Enlarged-hetero-ring prostacyclin analogs
First Claim
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1. A cyclic ether of the formula ##STR85## wherein L is (1) --(CH2)d -- wherein d is one to 5, inclusive, (2) --(CH2)t --CF2 -- wherein t is one, 2, or 3, (3) --CH═
- CH--, (4) --CH2 --O--CH2 Y-- wherein Y is a valance bond or --(CH2)k -- wherein k is one or 2;
wherein Q2 is ##STR86## wherein R3 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein R4 is hydrogen;
wherein ○
R22 is ##STR87## wherein R5 and R6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R5 and R6 is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R5 nor R6 is fluoro when Z is oxa (--0--);
wherein Z represents an oxa atom (--0--) or Cj H2j wherein Cj H2j is a valence bond or alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive between --CR5 R6 -- and the phenyl ring;
wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR7 -- wherein R7 is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, one 3, with the proviso that not more than two T'"'"'s are other than alkyl and when s is 2 or 3 the T'"'"'s are either the same or different;
wherein R27 is (a) alkyl of one to 12 carbon atoms, inclusive, (b) cycloalkyl of 3 to 10 carbon atoms, inclusive, (c) aralkyl of 7 to 12 carbon atoms, inclusive, (d) phenyl, (e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive;
##STR88## (1) hydrogen, or (m) a pharmacologically acceptable cation;
wherein X is cis- or trans-CH═
CH--, --C═
C--, or --CH2 CH2 --;
wherein ˜
indicates attachment in alpha or beta configuration;
including the lower alkanoates thereof.
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Abstract
Processes for preparing dihydro-prostacyclin analogs, which are 9-deoxy-5,9-cyclic ethers of prostaglandin F1 α-type compounds, illustrated, for example, by a compound of the formula ##STR1## wherein ˜ indicates alpha or beta configuration; including the products and intermediates produced therein, said products having pharmacological utility.
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Citations
67 Claims
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1. A cyclic ether of the formula ##STR85## wherein L is (1) --(CH2)d -- wherein d is one to 5, inclusive, (2) --(CH2)t --CF2 -- wherein t is one, 2, or 3, (3) --CH═
- CH--, (4) --CH2 --O--CH2 Y-- wherein Y is a valance bond or --(CH2)k -- wherein k is one or 2;
wherein Q2 is ##STR86## wherein R3 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein R4 is hydrogen;
wherein ○
R22 is ##STR87## wherein R5 and R6 are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R5 and R6 is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R5 nor R6 is fluoro when Z is oxa (--0--);
wherein Z represents an oxa atom (--0--) or Cj H2j wherein Cj H2j is a valence bond or alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive between --CR5 R6 -- and the phenyl ring;
wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR7 -- wherein R7 is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, one 3, with the proviso that not more than two T'"'"'s are other than alkyl and when s is 2 or 3 the T'"'"'s are either the same or different;wherein R27 is (a) alkyl of one to 12 carbon atoms, inclusive, (b) cycloalkyl of 3 to 10 carbon atoms, inclusive, (c) aralkyl of 7 to 12 carbon atoms, inclusive, (d) phenyl, (e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive;
##STR88## (1) hydrogen, or (m) a pharmacologically acceptable cation;wherein X is cis- or trans-CH═
CH--, --C═
C--, or --CH2 CH2 --;
wherein ˜
indicates attachment in alpha or beta configuration;
including the lower alkanoates thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66)
- CH--, (4) --CH2 --O--CH2 Y-- wherein Y is a valance bond or --(CH2)k -- wherein k is one or 2;
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67. A cyclic ether of the formula ##STR97## wherein L is (1) --(CH2)d --, wherein d is one to 5, inclusive, (2) --(CH2)t --CF2 --, wherein t is one, 2, or 3, (3) --CH═
- CH--, (4) --CH2 --O--CH2 --Y--, wherein Y is a valance bond or --(CH2)k --, wherein K is one or 2;
wherein Q2 is ##STR98## wherein R3 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein R4 is hydrogen;
wherin ○
R22 is ##STR99## wherein R5 and R6 are hydrogen, alkyl of one to 4 atoms, inclusive, or fluoro, being the same of different, with the proviso that one of R5 and R6 is fluoro only when the other is hydrogen or fluoro and the fluoro proviso that neither R5 nor R6 is fluoro when Z is oxa (--0--);
wherein Z represents an oxa atom (--013 ) or Cj H2j wherein Cj H2j is a valence bond or alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one or 2 fluoro, with one to 6 carbon atoms, inclusive between --CR5 R6 -- and the phenyl ring;
wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR7 --, wherein R7 is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T'"'"'s are other than alkyl and when s is 2 or 3 the T'"'"'s are either the same or different;
wherein R27 is(a) alkyl of one to 12 carbon atoms, inclusive, (b) cycloalkyl of 3 to 10 carbon atoms, inclusive, (c) aralkyl of 7 to 12 carbon atoms, inclusive, (d) phenyl, (e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR100## (l) hydrogen, or (m) a pharmacologically acceptable cation; wherein X is cis- or trans-CH--CH--, --C|C--, or --CH2 CH2 --; and
wherein ˜
indicates attachment in alpha or beta configuration;
including the lower alkanoates thereof.
- CH--, (4) --CH2 --O--CH2 --Y--, wherein Y is a valance bond or --(CH2)k --, wherein K is one or 2;
Specification
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Current AssigneeThe Upjohn Company (Pharmacia Corp.)
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Original AssigneeThe Upjohn Company (Pharmacia Corp.)
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InventorsJohnson, Roy A.
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Primary Examiner(s)Gerstl, Robert
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Application NumberUS06/023,552Time in Patent Office2,101 DaysField of Search260/345.2, 549/396US Class Current549/396CPC Class CodesC07C 405/0016 containing only hydroxy, et...C07C 405/0041 containing nitrogenC07D 307/935 Not further condensed cyclo...C07D 311/94 condensed with rings other ...
