US2002156076A1PendingUtilityA1
Compounds and method of treatment having agonist-like activity selective at alpha 2B or 2B / 2C adrenergic receptors
Est. expiryDec 4, 2017(expired)· nominal 20-yr term from priority
Inventors:Ken ChowDaniel W. GilJames A. BurkeDale A. HarcourtMichael E. GarstLarry A. WheelerStephen Munk
C07D 233/06C07D 495/04C07D 403/06C07D 233/56A61P 43/00C07D 233/10C07D 233/64C07D 405/06C07D 401/06C07D 409/06C07D 263/28C07D 413/12C07D 233/84
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Claims
Abstract
Compounds having adrenergic activity which are a selective agonists for one or both of the α 2B and α 2c adrenoceptor receptor subtypes in preference to the α 2A adrenoceptor receptor subtype; the active compound being selected from the group consisting of compounds having the formula wherein the dotted lines represent optional bonds provided that two double bonds may not share a common carbon atom; R is H or lower alkyl; X is S or C(H)R 1 , wherein R 1 is H or lower alkyl, but R 1 is absent when the bond between X and the ring represented by is a double bond; Y is O, N, S, (CR 1 2 ) y , wherein y is an integer of from 1 to 3, —CH═CH— or —Y 1 CH 2 —, wherein Y 1 is O, N or S; x is an integer of 1 or 2, wherein x is 1 when R 2 , R 3 or R 4 is bound to an unsaturated carbon atom and x is 2 when R 2 , R 3 or R 4 is bonded to a saturated carbon atom; R 2 is H, lower alkyl, halogen, hydroxy, lower alkoxy, lower alkenyl, acyl or lower alkynyl, or, when attached to a saturated carbon atom, R 2 may be oxo; R 3 and R 4 are, each, H, lower alkyl, halogen, lower alkenyl, acyl, lower alkynyl, aryl, heteroaryl, or sub stituted aryl or heteroaryl, wherein said substituent is halogen, lower alkyl, lower alkoxy, lower alkenyl, acyl, lower alkynyl, nitro, cyano, trifluoromethyl, hydroxy, or phenyl or, together, are —(C(R 2 )x)z—; —Y 1 (C(R 2 )x)z′—; —Y 1 (C(R 2 )x)y Y 1 —; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—(C(R 2 )x)— and —Y 1 —(C(R 2 )x)—Y 1 —(C(R 2 )x)— wherein z is an integer of from 3 to 5, z′ is an integer of from 2 to 4 and x and y are as defined above, and further either end of each of these divalent moieties may attach at either R3 or R4 to form a condensed ring structure and the rings formed may be totally unsaturated, partially unsaturated, or totally saturated; and being useful for treating muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases, memory and cognition deficits, psychoses including manic disorders and anxiety, hypertension, cardiac ischemia, congestive heart failure, and nasal congestion without sedating or cardiovascular side effects.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having selective agonist activity at the α2B or α2B/α2C adrenergic receptor subtype(s) as compared to the 2A adrenergic receptor subtype represented by the formula
wherein the dotted lines represent optional double bonds; R is H or lower alkyl; X is S or C(H)R 1 , wherein R 1 is H or lower alkyl or R 1 is absent when X is S or when the bond between X and the ring represented by
is a double bond; Y is O, N, S, (CR 1 x)y, wherein y is an integer of from 1 to 3, —CH=CH—or —Y 1 CH 2 —, wherein Y 1 is O, N or S; x is an integer of 1 or 2, wherein x is 1 when R 2 , R 3 or R 4 is bound to an unsaturated carbon atom and x is 2 when R 2 , R 3 or R 4 is bonded to a saturated carbon atom; R 2 is H, lower alkyl, halogen, hydroxy, lower alkoxy, lower alkenyl, acyl or lower alkynyl or, when attached to a saturated carbon atom, R 2 may be oxo; R 3 and R 4 are, each, H, lower alkyl, halogen, lower alkenyl, acyl or lower alkynyl, or, when attached to a saturated carbon atom, R 2 may be oxo; R 3 and R 4 are, each, H, lower alkyl, halogen, lower alkenyl, acyl, lower alkynyl, aryl, heteroaryl, or substituted aryl or heteroaryl, wherein said substituent is halogen, lower alkyl, lower alkoxy, lower alkenyl, acyl, lower alkynyl, nitro, cyano, trifluoromethyl, hydroxy, or phenyl or, together, are —(C(R 2 )x)z—; —Y 1 (C(R 2 )x)z′-; —Y 1 (C(R 2 )x)y Y 1 —; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—(C(R 2 )x)—and—Y 1 —(C(R 2 )x)—Y 1 —(C(R 2 )x)—wherein z is an integer of from 3 to 5, z′ is an integer of from 2 to 4 and x and y are as defined above, and further either end of each of these divalent moieties may attach at either R 3 or R 4 to form the condensed ring structure
and the ring thus formed may be totally unsaturated, partially unsaturated, or totally saturated provided that a ring carbon has no more than 4 valences, nitrogen no more than three and O and S have no more than two, and including enantiomers and pharmaceutically acceptable salts thereof.
2 . A compound according to claim 1 wherein said compound is represented by the formula
3 . A compound according to claim 2 wherein X is C(H)R 1 .
4 . A compound of claim 3 wherein R 1 is H.
5 . A compound of claim 4 wherein R 2 is H and
represents a furanyl radical.
6 . A compound of claim 5 wherein R 3 and R 4 together are (CH) 4 .
7 . A compound of claim 4 wherein R 2 is H and
represents a thienyl radical.
8 . A compound of claim 7 wherein R 3 and R 4 , together, represent (CH 2 ) 4 .
9 . A compound of claim 7 wherein R 3 is phenyl and R 4 is H.
10 . A compound of claim 7 wherein R 3 and R 4 , together, represent (CH 2 ) 3 S.
11 . A compound of claim 7 wherein R 3 and R 4 , together, represent (CH) 4 .
12 . A compound of claim 4 wherein
represents a cyclohexyl radical.
13 . A compound of claim 12 wherein R 2 is H. and R 3 and R 4 , together, represent (CH) 2 S.
14 . A compound of claim 12 wherein R 2 is H, and R 3 and R 4 , together, represent (CH 2 ) 4 .
15 . A compound of claim 12 wherein R 2 is dimethyl, and R 3 and R 4 , together, represent (CH) 4 .
16 . A compound of claim 12 wherein Y is —CH 2 CH(CH 3 )—, R 2 is hydrogen or oxo, and R 3 and R 4 , together, represent (CH) 4 .
17 . A compound of claim 12 wherein R 2 is oxo or hydrogen, and R 3 and R 4 , together, represent S(CH) 2 or S(CH 2 ) 2 .
18 . A compound of claim 12 wherein Y is —CH2C(CH) 2 —, R 2 is hydrogen or oxo, and R 3 and R 4 , together, represent (CH) 4 .
19 . A compound of claim 4 wherein
represents a cyclopentyl radical.
20 . A compound of claim 19 wherein R 2 is hydrogen, and R 3 and R 4 , together, represent (CH 2 ) 3 .
21 . A compound of claim 4 wherein
represents a phenyl radical.
22 . A compound of claim 1 wherein said compound has the formula
wherein Y is S or O.
23 . A compound of claim 1 wherein said compound has the formula
24 . A compound of claim 23 wherein R 3 and R 4 , together, represent (CH) 4 .
25 . A compound of claim 24 wherein Y 1 is O.
26 . A compound of claim 25 wherein R 2 is oxo.
27 . A compound of claim 26 wherein X is CH.
28 . A compound of claim 26 wherein X is CH 2 .
29 . A compound of claim 24 wherein one of R 2 is hydroxy and the other is H.
30 . A compound of claim 25 wherein R 2 is H.
31 . A compound of claim 24 wherein Y 1 is S.
32 . A compound of claim 31 wherein X is CH 2 .
33 . A compound of claim 32 wherein R 2 is oxo.
34 . A compound of claim 32 wherein R 2 is H.
35 . A compound of claim 31 wherein X is CH and R 2 is oxo.
36 . A compound of claim 3 wherein Y is (CH 2 ) 3 .
37 . A compound of claim 36 wherein X is CH and R 2 is oxo.
38 . A compound of claim 36 wherein X is CH 2 and R 2 is H.
39 . A compound of claim 2 wherein X is S and
is phenyl.
40 . A compound of claim 3 wherein R 1 is methyl and
is furanyl.
41 . A compound of claim 4 wherein Y is CH 2 (CR 1 2 ) 2 wherein R 1 is hydrogen or methyl.
42 . A compound of claim 41 wherein R 2 is H.
43 . A compound of claim 41 wherein R 2 is oxo.
44 . A compound of claim 3 wherein R is CH 3 ,
represents a phenyl radical and R3 and R4, together represent O(CR 2 ) 2 O.
45 . A compound of claim 2 wherein X is CH,
represents a cyclopentyl radical and R 2 is oxo.
46 . A compound represented by the formula
47 . A compound according to claim 1 represented by the formula
wherein Y is (R 1 x) 2 , R 3 +R 4 is (C(R 2 )x) 4 and X attaches at one of the two positions of the ring indicated by the wavy line with the remaining position being occupied by hydrogen, provided that two double bonds may not occupy the same ring atom.
48 . A compound according to claim 47 wherein said compound is represented by the formula
wherein (R 2 ) x is hydrogen or oxo.
49 . A compound of claim 47 wherein the structure is
50 . A compound of claim 50 wherein the structure is
51 . A compound of claim 2 wherein R is hydrogen, R3 and R4 are —(C(R 2 ) x )—N—(C(R 2 ) x)—(C(R 2 ) x )—, and X is CHR 1 as represented by the formula
the CHR 1 group attaches at one of the two positions of the ring indicated by the wavy line with the remaining position being occupied by hydrogen, and provided that two double bonds may not occupy the same ring atom.
52 . A compound of claim 51 wherein said compound has the formula
and (R 2 ) x is hydrogen or oxo.
53 . A compound of claim 51 wherein said compound has the formula
and (R 2 ), is hydrogen or oxo.
54 . A compound of claim 1 wherein R3 and R4 are chosen from the group consisting of —Y 1 —(C(R 2 )x)—(C(R 2 )x)—Y 1 and —Y 1 (C(R 2 )x)—(C(R 2 )x) —(C(R 2 )x)—, and Y 1 is N or O or S as represented by the formula
wherein X and X′ are selected from the group consisting of N, O and C and at least one of X and X′ are N.
55 . A compound according to claim 54 wherein said compound is represented by the formula
wherein (R 2 )x is hydrogen or oxo.
56 . A compounds according to claim 54 wherein said compound is represented by the formula
wherein (R 2 )x is hydrogen or oxo.
57 . A compound having selective agonist activity at the α2B or α2B/2C adrenergic receptor subtype(s) as compared to the α2A adrenergic receptor subtype represented by the
formula and pharmaceutically acceptable salts thereof.
58 . A process for administering to a host mammnal, including a human being, a pharmaceutical composition containing an effective dose of an active compound to treat or prevent glaucoma without sedating or cardiovascular side effects, wherein said compound has adrenergic activity and is a selective agonist of the α2B adrenoceptor subtype or α2B/(α2C adrenoceptor subtype(s) in preference over the α2A adrenoceptor subtype.
59 . A process of claim 58 wherein the active compound has an efficacy relative to a standard full agonist that is at least approximately 0.3 greater at the α2B or α2C adrenoreceptor subtypes than at the α2A adrenoreceptor subtype and its efficacy at the α2A adrenoreceptor subtype is ≦0.4.
60 . A process of claim 58 wherein the active compound is at least ten times more potent at the α2B or α2C adrenoceptor subtype than at the α2A adrenoceptor receptor.
61 . A process of claim 60 wherein approximately 0.001% to 5% by weight of the active compound is administered topically to the host mammal in daily or twice daily doses.
62 . A process of claim 61 wherein approximately 0.01%to 3% byweight of the active compound is administered topically to the host mammnal in daily or twice daily doses.
63 . A process of claimr 58 wherein said compound has no activity at the α2A adrenoreceptor subtype.
64 . A process of claim 58 wherein said compound has no activity at the α2A and α2C adrenoreceptor subtypes.
65 . A process for administering to a host mammal, including a human being, a pharmaceutical composition containing an effective dose of an active compound to treat elevated intraocular pressure without sedating or cardiovascular side effects, wherein the compound has adrenergic activity and is a selective agonist of the α2B or α2B/ α2C adrenoceptor subtype(s) in preference over the α2A adrenoceptor receptor subtype.
66 . A process of claim 65 wherein the active compound has an efficacy relative to a standard full agonist that is at least approximately 0.3 greater at the α2B or 2C adrenoceptor subtypes than at the α2A adrenoceptor subtype, and its efficacy at the α2A adrenoceptor subtype is ≦0.4.
67 . A process of claim 66 wherein approximately 0.001% to 5% by weight of the active compound is administered topically to the host mammal in daily or twice daily doses.
68 . A process of claim 67 wherein approximately 0.01% to 3.0% by weight of the active compound is administered topically to the host mammal in daily or twice daily doses.
69 . A process of claimn 65 wherein said compound has no activity at the α2A adrenoreceptor subtypes.
70 . A process of claim 65 wherein said compound has no activity at the α2A and α2C adrenoreceptor subtypes.
71 . A method of treating a mammal to lower intraocular pressure without having cardiovascular and sedative side effects by selectively agonizing the α2B adrenoceptor subtype or α2B/α2C adrenoceptor subtype(s) in preference to the α2A adrenoceptor subtype.
72 . A method of selectively agonizing the 60 2B adrenoceptor subtype or α2B/α2C adrenoceptor subtypes without agonizing the α2A adrenoceptor subtype comprising administering a therapeutically effective amount of a selective α2B or α2B/α2C receptor subtype agonist(s) respectively.
73 . An alpha adrenergic agonist that selectively activates the α2B or α2B/α2C receptor subtype(s) in preference to the α2A receptor subtype.
74 . A process according to claims 58 , 65 or 71 wherein the active compound is selected from the group consisting of compounds having the formula
wherein the dotted lines represent optional double bonds; R is H or lower alkyl; X is S or C(H)R 1 , wherein R 1 is H or lower alkyl or R 1 is absent when X is S or when the bond between X and the ring represented by
is a double bond; Y is O, N, S, (CR 1 x)y, wherein y is an integer of from 1 to 3, —CH=CH—or —Y 1 CH 2 —, wherein Y 1 is O, N or S; x is an integer of 1 or 2, wherein x is 1 when R 2 , R 3 or R 4 is bound to an unsaturated carbon atom and x is 2 when R 2 , R 3 or R 4 is bonded to a saturated carbon atom; R 2 is H, lower alkyl, halogen, hydroxy or lower alkoxy, or, when attached to a saturated carbon atom, R 2 may be oxo; R 3 and R 4 are, each, H, lower alkyl, hydroxy, lower alkoxy, or phenyl or, together, are —(C(R 2 )x)z—;
—Y 1 (C(R 2 )x)z′—; —Y 1 (C(R 2 )x)y Y 1 —; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—(C(R 2 )x)—and—Y 1 —(C(R 2 )x)—Y 1 —(C(R 2 )x)—wherein z is an integer of from 3 to 5, z′ is an integer of from 2 to 4 and x and y are as defined above, and further either end of each of these divalent moieties may attach at either R3 or R4 to form the condensed ring structure
and the ring thus formed may be totally unsaturated, partially unsaturated, or totally saturated provided that a ring carbon has no more than 4 valences, nitrogen no more than three and O and S have no more than two;
or
wherein W is a bicyclic radical selected from the group consisting of
wherein R 5, R 6 , R 7 and R 8 are selected from the group consisting of H and lower alkyl provided that at least one of R 5 and R 6 or R 6 and R 7 are OC(R 9 )C(R 9 )N(R) to form a condensed ring with
wherein R 9 is H, lower alkyl or oxo and
wherein R 10 is H, lower alkyl, phenyl or lower alkyl substituted phenyl, and Z is O or NH.
75 . A process for administering to a host mammal, including a human being, a pharmaceutical composition containing an effective dose of an active compound, having adrenergic activity, to treat or prevent glaucoma wherein the active compound has the biological property that the compound is a selective agonist of α2B or α2B/α2C receptor subtype(s) in preference over the α2A receptor subtype, said selectivity being measured in an assay using cells that naturally express the individual α2 subtypes or have had one of the subtypes introduced, the receptors being human or from a species that has been shown to have a similar pharmacology, and in which assay the efficacy relative to a standard compound of the active compound at the α2B or α2C receptor subtype is measured to be at least 0.3 greater than the efficacy relative to the standard compound of the active compound at the α2A receptor subtype and its efficacy at the α2A receptor subtype is ≦0.4, and/or the active compound is at least approximately 10 times more potent at the α2B or α2C receptor subtypes than at the α2A receptor subtype.
76 . A process of claim 75 wherein approximately 0.001% to 5% by weight of the active compound is administered topically to the host mammal per day.
77 . A process for administering to a host mammal, including a human being, a pharmaceutical composition containing an effective dose of an active compound to treat or prevent muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases including optic neuropathy, spinal ischemia and stroke, memory and cognition deficits, attention deficit disorder, psychoses including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedating or cardiovascular side effects, wherein said compound has adrenergic activity and is a selective agonist of the α2B or α2B /α2C adrenoceptor receptor subtype(s) in preference over the α2A adrenoceptor receptor subtype.
78 . A process for administering to a host mammal, including a human being, a pharmaceutical composition containing an effective dose of an active compound, having adrenergic activity, to treat muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases including optic neuropathy, spinal ischemia and stroke, memory and cognition deficits, attention deficit disorder, psychoses including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedating or cardiovascular side effects wherein the active compound has the biological property that the compound is a selective agonist of α2B or α2B/α2C receptor subtype(s) in preference over the α2A receptor subtype, said selectivity being measured in an assay using cells that naturally express the individual α2 subtypes or have had one of the subtypes introduced, the receptors being human or from a species that has been shown to have a similar pharmacology, and in which assay the efficacy relative to a standard compound of the active compound at the α2B or the α2C receptor subtype is measured to be at least 0.3 greater than the efficacy relative to the standard compound of the active compound at the α2A receptor subtype and its efficacy at the α2A receptor is ≦0.4, and/or the active compound is at least approximately 10 times more potent at the α2B or α2C receptor subtypes than at the α2A receptor subtype.
79 . A process for administering to a host mammal, including a human being, a pharmaceutical composition containing an effective dose of an active compound, having adrenergic activity, to treat muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases including optic neuropathy, spinal ischemia and stroke, memory and cognition deficits, attention deficit disorder, psychoses including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion without sedating or cardiovascular side effects wherein the active compound has the biological property that the compound is a selective agonist of α2B or α2B/α2C receptor subtype(s) in preference over the α2A receptor subtype, said selectivity being measured in an RSAT assay in which activation of the α2A and α2C receptor subtype by the test compound is compared to brimnonidine and the α2B receptor subtype is compared to oxymetazoline and wherein the respective a2A, a2B and a2C receptor subtypes are expressed in NIH-3T3 cells, and in which assay the efficacy relative to brimonidine of the active compound at the α2C receptor subtype or the efficacy relative to oxymetazoline of the active compound at the α2B receptor subtype is measured to be at least 0.3 greater than the efficacy relative to brimonidine of the active compound at the α2A receptor subtype, and its efficacy at the a2A receptor subtype is <0.4 and/or the active compound is at least approximately 10 times more potent at the α2B or α2C receptor subtypes than at the α2A receptor subtype.
80 . A process of claim 60 wherein the active compound is at least one hundred times more potent at the α2B or α2C adrenoceptor subtype than at the α2A adrenoceptor subtype.
81 . The compound of claim 4 wherein
represents a cyclopentenyl or a cyclohexenyl radical.
82 . The compound of claim 81 wherein
represents a cyclohexenyl radical.
83 . The compound of claim 82 wherein
represents
and R 2 is hydrogen and methyl.
84 . The compound of claim 83 wherein R 3 is hydrogen or methyl and R 4 is hydrogen or methyl or one of R 3 is methyl and the other R 3 and R 4 together represent (CH 2 ) 4 .
85 . The compound of claim 82 wherein
and R 2 is hydrogen.
86 . The compound of claim 85 wherein R 3 is hydrogen or methyl and R 4 is hydrogen, methyl, ethyl or n-pentyl.
87 . The compound of claim 81 wherein
represents a cyclopentenyl radical.Join the waitlist — get patent alerts
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