US 4,666,907 AGranted

Phenothiazine and derivatives and analogs and use as leukotriene biosynthesis inhibitors

AssigneeMerck Frosst Canada, Inc.

InventorsRejean Fortin, Cheuk K. Lau, Yvan Guindon, Joshua Rokach, Christiane Yoakim

Life of this patent

Estimating the term…

Abstract

Phenothiazine derivatives and analogs thereof having the Formula I are useful as inhibitors of the biosynthesis of mammalian leukotrienes. As such, these compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders and inflammation, and are useful as cytoprotective agents. ##STR1##

Claims21

Dependent claims

The compounds having the Formula:

##STR87## wherein the substituents are:
______________________________________ Compound X R.sup.1 R.sup.2 R.sup.3 ______________________________________ 3 S Me 4-Cl H 8 S Ac 4-Cl H 9 S Ac 4-Cl H 27 S Ac H 4-Cl 28 S Ac H 4-Cl 29 S Me H 4-Cl 30 S H H 2-OEt 32 SO.sub.2 H H H 33 SO.sub.2 H H 4-Cl 34 SO.sub.2 H H 4-Cl 39 S H 1-OMe 2-OMe 40 S H 1-OMe 2-OMe 41 SO.sub.2 H 1-OMe 2-OMe 43 S H 1-OH 2-C(Me).sub.3 49 SO H 1-OMe 2-OMe 50 SO H 1-OMe 2-OMe 51 SO.sub.2 H 1-OMe 2-OMe 52 S H 2-OMe 3-OH 53 S H 2-OMe 3-OH 54 S H 2-OMe 3-OAc 55 S H 2-OMe 3-OAc 56 SO.sub.2 H 2-OMe 3-OH 58 SO.sub.2 H 2-OMe 3-OAc 59 O Ac 2-OMe 3-OH 60 O Ac 2-OMe 3-OAc 61 O CO.sub.2 CH(Me)OAc 2-OMe 3-OH 62 O CO.sub.2 CH(Me)OAc 2-OMe 3-OAc 63 S H 2-OMe 3-OH 64 S H 2-OMe 3-OAc 65 S H 2-OMe 3-OH 66 S H 2-OMe 3-OAc 67 SO H 2-OMe 3-OAc 68 SO.sub.2 H 2-OMe 3-OH 69 SO.sub.2 H 2-OMe 3-OAc 70 S Ac 2-OMe 4-Br 71 S Ac 2-OMe 4-Cl 72 S Ac 2-OMe 4-F 73 S Ac 2-OMe 4-I 74 S Ac 2-OMe 4-CF.sub.3 75 S Ac 2-OMe 4-CN 76 S Ac 2-OEt 4-Br 77 S Ac 2-OEt 4-Cl 78 S Ac 2-OMe 4-Br 79 S Ac 2-OMe 4-Cl 80 S Ac 2-OMe 4-F 81 S Ac 2-OEt 4-Br 82 S Ac 2-OEt 4-Cl 83 S Ac 2-OEt 4-F 84 S Ac 2-OEt 4-CF.sub.3 85 S H 2-OMe 4-Br 86 S H 2-OMe 4-Cl 87 S H 2-OMe 4-F 88 S H 2-OMe 4-CF.sub.3 89 S H 2-OMe 4-Br 90 S H 2-OMe 4-Br 91 S H 2-OMe 4-Br 92 S H 2-OMe 4-Br 93 S Ac 2-OMe 4-Br 94 S Ac 2-OMe 4-Br 95 S Ac 2-OMe 4-Br 96 S Ac 2-OMe 4-Cl 97 S CH.sub.2 OAc 2-OMe 4-Br 98 S CH.sub.2 OAc 2-OMe 4-Cl 99 S CH.sub.2 OAc 2-OMe 4-Br 100 S CH.sub.2 OAc 2-OMe 4-Br 101 S CH.sub.2 OAc 2-OMe 4-Br 102 S CH.sub.3 2-OMe 4-Br 103 S CH.sub.3 2-OMe 4-Br 104 S CH.sub.3 2-OMe 4-Cl 105 S Me 2-OMe 4-F 106 S Me 2-OMe 4-CF.sub.3 107 S CH(Me)OAc 2-OMe 4-Br 108 S CH(Me)OCOC(Me).sub.3 2-OMe 4-Br 109 S CH(Me)OAc 2-OMe 4-Cl 110 S CH(Me)OAc 2-OMe 4-F 111 S CH(Me)OAc 2-OMe 4-CF.sub.3 112 S H 2-OMe 4-Br 113 S H 2-OMe 4-Br 114 S H 2-OMe 4-Br 115 S H 2-OMe 4-Cl 116 S CO.sub.2 Me 2-OMe 4-Br 117 S CO.sub.2 Et 2-OMe 4-Br 118 S CO.sub.2 CH(Me)OAc 2-OMe 4-Br 119 S CO.sub.2 CH(Me)OAc 2-OMe 4-Cl 120 S CO.sub.2 CH(Me)OAc 2-OMe 4-F 121 S CO.sub.2 CH(Me)OAc 2-OMe 4-Br 122 S CO.sub.2 CH(Me)OAc 2-OMe 4-Br 123 S Ac 2-OMe 4-Br 124 S Ac 2-OMe 4-Cl 125 S Me 2-OMe 4-Br 126 S H 2-OMe 4-Br 127 S CH(Me)OAc 4-Cl H 128 SO.sub.2 Ac 4-Cl H 129 SO.sub.2 Ac 4-Cl H 130 S Ac 2-OEt 4-Cl 131 S Ac 2-OEt 4-Cl 132 S Ac 2-OMe 4-Br 133 S Ac 2-OMe 4-Br 134 SO.sub.2 Ac 2-OMe 4-Br 135 SO.sub.2 Ac 2-OMe 4-Br 136 SO.sub.2 CO.sub.2 CH(Me)OAc 2-OMe 4-Br 137 S ##STR88## H 4-Br 138 S H 2-OMe 4-I 139 S H 2-OMe 4-CN 140 S H 2-OEt 4-Br 141 S H 2-OEt 4-Cl 142 S H 2-OMe 4-Br 143 S H 2-OMe 4-Cl 144 S H 2-OMe 4-F 145 S H 2-OEt 4-Br 146 S H 2-OEt 4-Cl 147 S H 2-OEt 4-F 148 S H 2-OEt 4-CF.sub.3 149 S H 2-Cl 3-Ac 150 S H 2-OMe H 151 SO H 2-OMe H ______________________________________ Compound R.sup.4 R.sup.5 T ______________________________________ 3 H H 3-OMe 8 H H 3-OAc 9 H H 3-OH 27 7-F H 3-OMe 28 7-F H 3-OH 29 7-F H 3-OMe 30 4-Cl H 3-OH 32 H H 3-OAc 33 H H 3-OAc 34 H H 3-OH 39 4-Me H 3-OH 40 4-Me H 3-OAc 41 4-Me H 3-OH 43 H 4-C(Me).sub.3 H 49 4-Me H 3-OH 50 4-Me H 3-OAc 51 4-Me H 3-OAc 52 4-Br 7-OMe H 53 4-Cl 7-OMe H 54 4-Br 7-OMe H 55 4-Cl 7-OMe H 56 4-Br 7-OMe H 58 4-Br 7-OMe H 59 4-Br 7-OMe H 60 4-Br 7-OMe H 61 4-Br 7-OMe H 62 4-Br 7-OMe H 63 4-Br 7-Me H 64 4-Br 7-Me H 65 4-Br 7-F H 66 4-Br 7-F H 67 4-Br 7-OMe H 68 H 7-OMe H 69 H 7-OMe H 70 7-OMe H 3-OAc 71 7-OMe H 3-OAc 72 7-OMe H 3-OAc 73 7-OMe H 3-OAc 74 7-OMe H 3-OAc 75 7-OMe H 3-OAc 76 7-OEt H 3-OAc 77 7-OEt H 3-OAc 78 7-OEt H 3-OAc 79 7-OEt H 3-OAc 80 7-OEt H 3-OAc 81 7-OMe H 3-OAc 82 7-OMe H 3-OAc 83 7-OMe H 3-OAc 84 7-OMe H 3-OAc 85 7-OMe H 3-OH 86 7-OMe H 3-OH 87 7-OMe H 3-OH 88 7-OMe H 3-OH 89 7-OMe H 3-OAc 90 7-OMe H 3-OBz 91 7-OMe H 3-OCOCHMe.sub.2 92 7-OMe 3-OCH.sub.2 CO.sub.2 H H 93 7-OMe H 3-OBz 94 7-OMe H 3-OMe 95 7-OMe 3-OCH.sub.2 CO.sub.2 H H 96 7-OMe 3-OCH.sub.2 CO.sub.2 H H 97 7-OMe H 3-OH 98 7-OMe H 3-OH 99 7-OMe H 3-OAc 100 7-OMe H 3-OBz 101 7-OMe H 3-OMe 102 7-OMe H 3-OH 103 7-OMe H 3-OAc 104 7-OMe H 3-OH 105 7-OMe H 3-OH 106 7-OMe H 3-OH 107 7-OMe H 3-OH 108 7-OMe H 3-OH 109 7-OMe H 3-OH 110 7-OMe H 3-OH 111 7-OMe H 3-OH 112 7-OMe 3-OCO.sub.2 Me H 113 7-OMe 3-OCO.sub.2 Et H 114 7-OMe 3-OCO.sub.2 CH(Me)OAc H 115 7-OMe 3-OCO.sub.2 CH(Me)OAC H 116 7-OMe H 3-OH 117 7-OMe H 3-OH 118 7-OMe H 3-OH 119 7-OMe H 3-OH 120 7-OMe H 3-OH 121 7-OMe H 3-OAc 122 7-OMe 3-OCO.sub.2 CH(Me)OAc H 123 7-OMe H 3-OH 124 7-OMe H 3-OH 125 7-OMe H 3-OMe 126 7-OMe H 3-OMe 127 H H 3-OAc 128 H H 3-OH 129 H H 3-OAc 130 H H 3-OH 131 H H 3-OAc 132 7-OH H 3-OH 133 7-OAc H 3-OH 134 7-OMe H 3-OH 135 7-OMe H 3-OAc 136 7-OMe H 3-OH 137 7-OMe 2-OMe 3-OH 138 7-OMe H 3-OH 139 7-OMe H 3-OH 140 7-OEt H 3-OH 141 7-OEt H 3-OH 142 7-OEt H 3-OH 143 7-OEt H 3-OH 144 7-OEt H 3-OH 145 7-OMe H 3-OH 146 7-OMe H 3-OH 147 7-OMe H 3-OH 148 7-OMe H 3-OH 149 7-Ac H H 150 7-OMe H 3-OAc 151 7-OMe H 3-OAc ______________________________________

Dependencies are inferred from the claim text.

Facts

Application: 06/654,991Filed 26 Sep 1986 · continuation in part
Priority: 5 Oct 1983
Granted: 19 May 1987
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 265/38
Condensed with carbocyclic rings: [b, e]-condensed with two six-membered rings
C07D 279/20
[b, e]-condensed with two six-membered rings: with hydrogen atoms directly attached to the ring nitrogen atom
C07D 279/22
[b, e]-condensed with two six-membered rings: with carbon atoms directly attached to the ring nitrogen atom
C07D 279/30
With carbon atoms directly attached to the ring nitrogen atom: with acyl radicals attached to the ring nitrogen atom

Family

Serial539,342Parent of this continuation-in-part · filed 5 Oct 1983
US 4,666,907 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The compounds having the Formula:

##STR87## wherein the substituents are:
______________________________________ Compound X R.sup.1 R.sup.2 R.sup.3 ______________________________________ 3 S Me 4-Cl H 8 S Ac 4-Cl H 9 S Ac 4-Cl H 27 S Ac H 4-Cl 28 S Ac H 4-Cl 29 S Me H 4-Cl 30 S H H 2-OEt 32 SO.sub.2 H H H 33 SO.sub.2 H H 4-Cl 34 SO.sub.2 H H 4-Cl 39 S H 1-OMe 2-OMe 40 S H 1-OMe 2-OMe 41 SO.sub.2 H 1-OMe 2-OMe 43 S H 1-OH 2-C(Me).sub.3 49 SO H 1-OMe 2-OMe 50 SO H 1-OMe 2-OMe 51 SO.sub.2 H 1-OMe 2-OMe 52 S H 2-OMe 3-OH 53 S H 2-OMe 3-OH 54 S H 2-OMe 3-OAc 55 S H 2-OMe 3-OAc 56 SO.sub.2 H 2-OMe 3-OH 58 SO.sub.2 H 2-OMe 3-OAc 59 O Ac 2-OMe 3-OH 60 O Ac 2-OMe 3-OAc 61 O CO.sub.2 CH(Me)OAc 2-OMe 3-OH 62 O CO.sub.2 CH(Me)OAc 2-OMe 3-OAc 63 S H 2-OMe 3-OH 64 S H 2-OMe 3-OAc 65 S H 2-OMe 3-OH 66 S H 2-OMe 3-OAc 67 SO H 2-OMe 3-OAc 68 SO.sub.2 H 2-OMe 3-OH 69 SO.sub.2 H 2-OMe 3-OAc 70 S Ac 2-OMe 4-Br 71 S Ac 2-OMe 4-Cl 72 S Ac 2-OMe 4-F 73 S Ac 2-OMe 4-I 74 S Ac 2-OMe 4-CF.sub.3 75 S Ac 2-OMe 4-CN 76 S Ac 2-OEt 4-Br 77 S Ac 2-OEt 4-Cl 78 S Ac 2-OMe 4-Br 79 S Ac 2-OMe 4-Cl 80 S Ac 2-OMe 4-F 81 S Ac 2-OEt 4-Br 82 S Ac 2-OEt 4-Cl 83 S Ac 2-OEt 4-F 84 S Ac 2-OEt 4-CF.sub.3 85 S H 2-OMe 4-Br 86 S H 2-OMe 4-Cl 87 S H 2-OMe 4-F 88 S H 2-OMe 4-CF.sub.3 89 S H 2-OMe 4-Br 90 S H 2-OMe 4-Br 91 S H 2-OMe 4-Br 92 S H 2-OMe 4-Br 93 S Ac 2-OMe 4-Br 94 S Ac 2-OMe 4-Br 95 S Ac 2-OMe 4-Br 96 S Ac 2-OMe 4-Cl 97 S CH.sub.2 OAc 2-OMe 4-Br 98 S CH.sub.2 OAc 2-OMe 4-Cl 99 S CH.sub.2 OAc 2-OMe 4-Br 100 S CH.sub.2 OAc 2-OMe 4-Br 101 S CH.sub.2 OAc 2-OMe 4-Br 102 S CH.sub.3 2-OMe 4-Br 103 S CH.sub.3 2-OMe 4-Br 104 S CH.sub.3 2-OMe 4-Cl 105 S Me 2-OMe 4-F 106 S Me 2-OMe 4-CF.sub.3 107 S CH(Me)OAc 2-OMe 4-Br 108 S CH(Me)OCOC(Me).sub.3 2-OMe 4-Br 109 S CH(Me)OAc 2-OMe 4-Cl 110 S CH(Me)OAc 2-OMe 4-F 111 S CH(Me)OAc 2-OMe 4-CF.sub.3 112 S H 2-OMe 4-Br 113 S H 2-OMe 4-Br 114 S H 2-OMe 4-Br 115 S H 2-OMe 4-Cl 116 S CO.sub.2 Me 2-OMe 4-Br 117 S CO.sub.2 Et 2-OMe 4-Br 118 S CO.sub.2 CH(Me)OAc 2-OMe 4-Br 119 S CO.sub.2 CH(Me)OAc 2-OMe 4-Cl 120 S CO.sub.2 CH(Me)OAc 2-OMe 4-F 121 S CO.sub.2 CH(Me)OAc 2-OMe 4-Br 122 S CO.sub.2 CH(Me)OAc 2-OMe 4-Br 123 S Ac 2-OMe 4-Br 124 S Ac 2-OMe 4-Cl 125 S Me 2-OMe 4-Br 126 S H 2-OMe 4-Br 127 S CH(Me)OAc 4-Cl H 128 SO.sub.2 Ac 4-Cl H 129 SO.sub.2 Ac 4-Cl H 130 S Ac 2-OEt 4-Cl 131 S Ac 2-OEt 4-Cl 132 S Ac 2-OMe 4-Br 133 S Ac 2-OMe 4-Br 134 SO.sub.2 Ac 2-OMe 4-Br 135 SO.sub.2 Ac 2-OMe 4-Br 136 SO.sub.2 CO.sub.2 CH(Me)OAc 2-OMe 4-Br 137 S ##STR88## H 4-Br 138 S H 2-OMe 4-I 139 S H 2-OMe 4-CN 140 S H 2-OEt 4-Br 141 S H 2-OEt 4-Cl 142 S H 2-OMe 4-Br 143 S H 2-OMe 4-Cl 144 S H 2-OMe 4-F 145 S H 2-OEt 4-Br 146 S H 2-OEt 4-Cl 147 S H 2-OEt 4-F 148 S H 2-OEt 4-CF.sub.3 149 S H 2-Cl 3-Ac 150 S H 2-OMe H 151 SO H 2-OMe H ______________________________________ Compound R.sup.4 R.sup.5 T ______________________________________ 3 H H 3-OMe 8 H H 3-OAc 9 H H 3-OH 27 7-F H 3-OMe 28 7-F H 3-OH 29 7-F H 3-OMe 30 4-Cl H 3-OH 32 H H 3-OAc 33 H H 3-OAc 34 H H 3-OH 39 4-Me H 3-OH 40 4-Me H 3-OAc 41 4-Me H 3-OH 43 H 4-C(Me).sub.3 H 49 4-Me H 3-OH 50 4-Me H 3-OAc 51 4-Me H 3-OAc 52 4-Br 7-OMe H 53 4-Cl 7-OMe H 54 4-Br 7-OMe H 55 4-Cl 7-OMe H 56 4-Br 7-OMe H 58 4-Br 7-OMe H 59 4-Br 7-OMe H 60 4-Br 7-OMe H 61 4-Br 7-OMe H 62 4-Br 7-OMe H 63 4-Br 7-Me H 64 4-Br 7-Me H 65 4-Br 7-F H 66 4-Br 7-F H 67 4-Br 7-OMe H 68 H 7-OMe H 69 H 7-OMe H 70 7-OMe H 3-OAc 71 7-OMe H 3-OAc 72 7-OMe H 3-OAc 73 7-OMe H 3-OAc 74 7-OMe H 3-OAc 75 7-OMe H 3-OAc 76 7-OEt H 3-OAc 77 7-OEt H 3-OAc 78 7-OEt H 3-OAc 79 7-OEt H 3-OAc 80 7-OEt H 3-OAc 81 7-OMe H 3-OAc 82 7-OMe H 3-OAc 83 7-OMe H 3-OAc 84 7-OMe H 3-OAc 85 7-OMe H 3-OH 86 7-OMe H 3-OH 87 7-OMe H 3-OH 88 7-OMe H 3-OH 89 7-OMe H 3-OAc 90 7-OMe H 3-OBz 91 7-OMe H 3-OCOCHMe.sub.2 92 7-OMe 3-OCH.sub.2 CO.sub.2 H H 93 7-OMe H 3-OBz 94 7-OMe H 3-OMe 95 7-OMe 3-OCH.sub.2 CO.sub.2 H H 96 7-OMe 3-OCH.sub.2 CO.sub.2 H H 97 7-OMe H 3-OH 98 7-OMe H 3-OH 99 7-OMe H 3-OAc 100 7-OMe H 3-OBz 101 7-OMe H 3-OMe 102 7-OMe H 3-OH 103 7-OMe H 3-OAc 104 7-OMe H 3-OH 105 7-OMe H 3-OH 106 7-OMe H 3-OH 107 7-OMe H 3-OH 108 7-OMe H 3-OH 109 7-OMe H 3-OH 110 7-OMe H 3-OH 111 7-OMe H 3-OH 112 7-OMe 3-OCO.sub.2 Me H 113 7-OMe 3-OCO.sub.2 Et H 114 7-OMe 3-OCO.sub.2 CH(Me)OAc H 115 7-OMe 3-OCO.sub.2 CH(Me)OAC H 116 7-OMe H 3-OH 117 7-OMe H 3-OH 118 7-OMe H 3-OH 119 7-OMe H 3-OH 120 7-OMe H 3-OH 121 7-OMe H 3-OAc 122 7-OMe 3-OCO.sub.2 CH(Me)OAc H 123 7-OMe H 3-OH 124 7-OMe H 3-OH 125 7-OMe H 3-OMe 126 7-OMe H 3-OMe 127 H H 3-OAc 128 H H 3-OH 129 H H 3-OAc 130 H H 3-OH 131 H H 3-OAc 132 7-OH H 3-OH 133 7-OAc H 3-OH 134 7-OMe H 3-OH 135 7-OMe H 3-OAc 136 7-OMe H 3-OH 137 7-OMe 2-OMe 3-OH 138 7-OMe H 3-OH 139 7-OMe H 3-OH 140 7-OEt H 3-OH 141 7-OEt H 3-OH 142 7-OEt H 3-OH 143 7-OEt H 3-OH 144 7-OEt H 3-OH 145 7-OMe H 3-OH 146 7-OMe H 3-OH 147 7-OMe H 3-OH 148 7-OMe H 3-OH 149 7-Ac H H 150 7-OMe H 3-OAc 151 7-OMe H 3-OAc ______________________________________

Facts

Application

06/654,991Filed 26 Sep 1986 · continuation in part

Priority

5 Oct 1983

Granted

19 May 1987

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 265/38
Condensed with carbocyclic rings: [b, e]-condensed with two six-membered rings
C07D 279/20
[b, e]-condensed with two six-membered rings: with hydrogen atoms directly attached to the ring nitrogen atom
C07D 279/22
[b, e]-condensed with two six-membered rings: with carbon atoms directly attached to the ring nitrogen atom
C07D 279/30
With carbon atoms directly attached to the ring nitrogen atom: with acyl radicals attached to the ring nitrogen atom