US2009099164A1PendingUtilityA1
Phenylaminopropanol Derivatives and Methods of Their Use
Est. expiryMar 30, 2024(expired)· nominal 20-yr term from priority
Inventors:Callain KimPaige Erin MahaneyEugene J. TrybulskiPuwen ZhangEugene A. TerefenkoCasey Cameron MccomasMichael Anthony MarellaRichard CoghlanGavin David HeffernanStephen Todd CohnAn Thien VuJoseph Peter SabatucciFei Ye
A61P 43/00A61P 25/22A61P 25/00A61P 29/00A61P 25/24A61P 1/00A61P 15/00A61P 15/10A61P 13/02A61P 13/00C07D 209/30C07D 209/08C07D 209/42C07D 241/42C07D 265/36C07D 471/04C07D 235/06C07D 401/06C07D 413/06C07D 209/14
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Claims
Abstract
The present invention is directed to phenylaminopropanol derivatives of formula I: or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.
Claims
exact text as granted — not AI-modified1 - 28 . (canceled)
29 . A method for treating or preventing a condition ameliorated by monoamine reuptake in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
the dotted line between Y and Z represents an optional double bond;
the dotted line between the two R 4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R 4 groups, together with the nitrogen through which they are attached;
Y is N, CR 6 , or C═O;
Z is N, NR 7 , CR 5 , or C(R 5 ) 2 ;
R 1 is, independently at each occurrence, alkyl, alkoxy, halo, CF 3 , OCF 3 , arylalkyloxy substituted with 0-3 R 11 , aryloxy substituted with 0-3 R 11 , aryl substituted with 0-3 R 11 , heteroaryl substituted with 0-3 R 11 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R 11 , alkylsulfone, phenylsulfone substituted with 0-3 R 11 , alkylsulfonamide, phenylsulfonamide substituted with 0-3 R 11 , heteroaryloxy substituted with 0-3 R 11 , heteroarylmethyloxy substituted with 0-3 R 11 , alkylamido, or arylamido substituted with 0-3 R 11 ,; or two adjacent R 1 also represent methylenedioxy;
R 2 is aryl substituted with 0-3 R 1 or heteroaryl substituted with 0-3 R 1 ;
R 3 is H or C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, H, C 1 -C 4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or
both R 4 groups, together with the nitrogen through which they are attached, form a heterocyclic ring of 4 to 6 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , and where any carbon ring atom or additional N atom may be optionally substituted with C 1 -C 4 alkyl, F, or CF 3 ;
R 5 is, independently at each occurrence, H, C 1 -C 4 alkyl, aryl substituted with 0-3 R 1 , or cyano; or when two R 5 are present, they form a carbocyclic ring of 3-7 carbons;
R 6 is H, C 1 -C 4 alkyl, or cyano;
R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl substituted with 0-3 R 1 ;
R 8 is H, or C 1 -C 4 alkyl;
R 9 is H, or C 1 -C 4 alkyl
R 10 is, independently at each occurrence, H, or C 1 -C 4 alkyl; or R 10 and R 4 together with the nitrogen to which R 4 is attached form a nitrogen-containing ring containing 3-6 carbon atoms;
n is an integer from 0 to 4;
x is an integer from 1 to 2; and
R 11 is alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R 11 also represent methylenedioxy;
wherein 1-3 carbon atoms in ring A may optionally be replaced with N.
30 . A method according to claim 29 ,
wherein said condition ameliorated by monoamine reuptake is selected from the group consisting of vasomotor symptoms, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof.
31 . A method according to claim 30 ,
wherein said condition ameliorated by monoamine reuptake is selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.
32 . A method for treating or preventing at least one vasomotor symptom in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
the dotted line between Y and Z represents an optional double bond;
the dotted line between the two R 4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R 4 groups, together with the nitrogen through which they are attached;
Y is N, CR 6 , or C═O;
Z is N, NR 7 , CR 5 , or C(R 5 ) 2 ;
R 1 is, independently at each occurrence, alkyl, alkoxy, halo, CF 3 , OCF 3 , arylalkyloxy substituted with 0-3 R 11 , aryloxy substituted with 0-3 R 11 , aryl substituted with 0-3 R 11 , heteroaryl substituted with 0-3 R 11 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R 11 , alkylsulfone, phenylsulfone substituted with 0-3 R 11 , alkylsulfonamide, phenylsulfonamide substituted with 0-3 R 11 , heteroaryloxy substituted with 0-3 R 11 , heteroarylmethyloxy substituted with 0-3 R 11 , alkylamido, or arylamido substituted with 0-3 R 11 ; or two adjacent R 1 also represent methylenedioxy;
R 2 is aryl substituted with 0-3 R 1 or heteroaryl substituted with 0-3 R 1 ;
R 3 is H or C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, H, C 1 -C 4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or
both R 4 groups, together with the nitrogen through which they are attached, form a heterocyclic ring of 4 to 6 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , and where any carbon ring atom or additional N atom may be optionally substituted with C 1 -C 4 alkyl, F, or CF 3 ;
R 5 is, independently at each occurrence, H, C 1 -C 4 alkyl, aryl substituted with 0-3 R 1 , or cyano; or when two R 5 are present, they form a carbocyclic ring of 3-7 carbons;
R 6 is H, C 1 -C 4 alkyl, or cyano;
R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl substituted with 0-3 R 1 ;
R 8 is H, or C 1 -C 4 alkyl;
R 9 is H, or C 1 -C 4 alkyl
R 10 is, independently at each occurrence, H, or C 1 -C 4 alkyl; or R 10 and R 4 together with the nitrogen to which R 4 is attached form a nitrogen-containing ring containing 3-6 carbon atoms;
n is an integer from 0 to 4;
x is an integer from 1 to 2; and
R 11 is alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R 11 also represent methylenedioxy;
wherein 1-3 carbon atoms in ring A may optionally be replaced with N.
33 . A method according to claim 32 ,
wherein said vasomotor symptom is hot flush.
34 . A method according to claim 33 ,
wherein said subject is human.
35 . A method according to claim 34 ,
wherein said human is a female.
36 . A method according to claim 35 ,
wherein said female is pre-menopausal.
37 . A method according to claim 35 ,
wherein said female is peri-menopausal.
38 . A method according to claim 35 ,
wherein said female is post-menopausal.
39 . A method according to claim 34 ,
wherein said human is a male.
40 . A method according to claim 39 ,
wherein said male is naturally, chemically or surgically andropausal.
41 . A method for treating or preventing at least one depression disorder in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
the dotted line between Y and Z represents an optional double bond;
the dotted line between the two R 4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R 4 groups, together with the nitrogen through which they are attached;
Y is N, CR 6 , or C═O;
Z is N, NR 7 , CR 5 , or C(R 5 ) 2 ;
R 1 is, independently at each occurrence, alkyl, alkoxy, halo, CF 3 , OCF 3 , arylalkyloxy substituted with 0-3 R 11 , aryloxy substituted with 0-3 R 11 , aryl substituted with 0-3 R 11 , heteroaryl substituted with 0-3 R 11 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R 11 , alkylsulfone, phenylsulfone substituted with 0-3 R 11 , alkylsulfonamide, phenylsulfonamide substituted with 0-3 R 11 , heteroaryloxy substituted with 0-3 R 11 , heteroarylmethyloxy substituted with 0-3 R 11 , alkylamido, or arylamido substituted with 0-3 R 11 ; or two adjacent R 1 also represent methylenedioxy;
R 2 is aryl substituted with 0-3 R 1 or heteroaryl substituted with 0-3 R 1 ;
R 3 is H or C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, H, C 1 -C 4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or
both R 4 groups, together with the nitrogen through which they are attached, form a heterocyclic ring of 4 to 6 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , and where any carbon ring atom or additional N atom may be optionally substituted with C 1 -C 4 alkyl, F, or CF 3 ,
R 5 is, independently at each occurrence, H, C 1 -C 4 alkyl, aryl substituted with 0-3 R 1 , or cyano; or when two R 5 are present, they form a carbocyclic ring of 3-7 carbons;
R 6 is H, C 1 -C 4 alkyl, or cyano;
R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl substituted with 0-3 R 1 ;
R 8 is H, or C 1 -C 4 alkyl;
R 2 is H, or C 1 -C 4 alkyl;
R 10 is, independently at each occurrence, H. or C 1 -C 4 alkyl; or R 10 and R 4 together with the nitrogen to which R 4 is attached form a nitrogen-containing ring containing 3-6 carbon atoms;
n is an integer from 0 to 4;
x is an integer from 1 to 2; and
R 11 is alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R 11 also represent methylenedioxy;
wherein 1-3 carbon atoms in ring A may optionally be replaced with N.
42 . A method according to claim 41 ,
wherein said depression disorder is major depressive disorder, anxiety, sleep disturbance, or social phobia.
43 . A method according to claim 42 ,
wherein said subject is human.
44 . A method for treating or preventing at least one sexual dysfunction in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
the dotted line between Y and Z represents an optional double bond;
the dotted line between the two R 4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R 4 groups, together with the nitrogen through which they are attached;
Y is N, CR 6 , or C═O;
Z is N, NR 7 , CR 5 , or C(R 5 ) 2 ;
R 1 is, independently at each occurrence, alkyl, alkoxy, halo, CF 3 , OCF 3 , arylalkyloxy substituted with 0-3 R 11 , aryloxy substituted with 0-3 R 11 , aryl substituted with 0-3 R 11 , heteroaryl substituted with 0-3 R 1 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R 11 , alkylsulfone, phenylsulfone substituted with 0-3 R 11 , alkylsulfonamide, phenylsulfonamide substituted with 0-3 R 11 , heteroaryloxy substituted with 0-3 R 11 , heteroarylmethyloxy substituted with 0-3 R 11 , alkylamido, or arylamido substituted with 0-3 R 11 ; or two adjacent R 1 also represent methylenedioxy;
R 2 is aryl substituted with 0-3 R 1 or heteroaryl substituted with 0-3 R 1 ;
R 3 is H or C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, H, C 1 -C 4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or
both R 4 groups, together with the nitrogen through which they are attached, form a heterocyclic ring of 4 to 6 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , and where any carbon ring atom or additional N atom may be optionally substituted with C 1 -C 4 alkyl, F, or CF 3 ;
R 5 is, independently at each occurrence, H, C 1 -C 4 alkyl, aryl substituted with 0-3 R 1 , or cyano; or when two R 5 are present, they form a carbocyclic ring of 3-7 carbons;
R 6 is H, C 1 -C 4 alkyl, or cyano;
R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl substituted with 0-3 R 1 ;
R 8 is H. or C 1 -C 4 alkyl;
R 2 is H. or C 1 -C 4 alkyl;
R 10 is, independently at each occurrence, H. or C 1 -C 4 alkyl; or R 10 and R 4 together with the nitrogen to which R 4 is attached form a nitrogen-containing ring containing 3-6 carbon atoms;
n is an integer from 0 to 4;
x is an integer from 1 to 2; and
R 11 is alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R 11 also represent methylenedioxy;
wherein 1-3 carbon atoms in ring A may optionally be replaced with N.
45 . A method according to claim 44 ,
wherein said sexual dysfunction is desire-related or arousal-related.
46 . A method according to claim 45 ,
wherein said subject is human.
47 . A method for treating or preventing pain in a subject in need thereof, comprising the step of:
administering to said subject an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
the dotted line between Y and Z represents an optional double bond;
the dotted line between the two R 4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R 4 groups, together with the nitrogen through which they are attached;
Y is N, CR 6 , or C═O;
Z is N, NR 7 , CR 5 , or C(R 5 ) 2 ;
R 1 is, independently at each occurrence, alkyl, alkoxy, halo, CF 3 , OCF 3 , arylalkyloxy substituted with 0-3 R 11 , aryloxy substituted with 0-3 R 11 , aryl substituted with 0-3 R 11 , heteroaryl substituted with 0-3 R 11 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, phenylsulfoxide substituted with 0-3 R 11 , alkylsulfone, phenylsulfone substituted with 0-3 R 11 , alkylsulfonamide, phenylsulfonamide substituted with 0-3 R 11 , heteroaryloxy substituted with 0-3 R 11 , heteroarylmethyloxy substituted with 0-3 R 1 , alkylamido, or arylamido substituted with 0-3 R 11 ; or two adjacent R 1 also represent methylenedioxy;
R 2 is aryl substituted with 0-3 R 1 or heteroaryl substituted with 0-3 R 1 ;
R 3 is H or C 1 -C 4 alkyl;
R 4 is, independently at each occurrence, H, C 1 -C 4 alkyl, arylalkyl, heteroarylmethyl, cycloheptylmethyl, cyclohexylmethyl, cyclopentylmethyl, or cyclobutylmethyl, or
both R 4 groups, together with the nitrogen through which they are attached, form a heterocyclic ring of 4 to 6 ring atoms, where one carbon may be optionally replaced with N, O, S, or SO 2 , and where any carbon ring atom or additional N atom may be optionally substituted with C 1 -C 4 alkyl, F, or CF 3 ,
R 5 is, independently at each occurrence, H, C 1 -C 4 alkyl, aryl substituted with 0-3 R 1 or cyano; or when two R 5 are present, they form a carbocyclic ring of 3-7 carbons;
R 6 is H, C 1 -C 4 alkyl, or cyano;
R 7 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or aryl substituted with 0-3 R 1 ;
R 8 is H, or C 1 -C 4 alkyl;
R 9 is H, or C 1 -C 4 alkyl;
R 10 is, independently at each occurrence, H, or C 1 -C 4 alkyl; or R 10 and R 4 together with the nitrogen to which R 4 is attached form a nitrogen-containing ring containing 3-6 carbon atoms;
n is an integer from 0 to 4;
x is an integer from 1 to 2; and
R 11 is alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido; or two adjacent R 11 also represent methylenedioxy;
wherein 1-3 carbon atoms in ring A may optionally be replaced with N.
48 . A method according to claim 47 ,
wherein said pain is acute centralized pain, acute peripheral pain, or a combination thereof.
49 . A method according to claim 47 ,
wherein said pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.
50 . A method according to claim 47 ,
wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.
51 . A method according to claim 50 ,
wherein said neuropathic pain is associated with diabetes, post traumatic pain of amputation, lower back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection, metastatic infiltration, adiposis dolorosa, bums, central pain conditions related to thalamic conditions, and combinations thereof.
52 . A method according to claim 50 ,
wherein said visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, and combinations thereof.
53 . A method according to claim 47 ,
wherein said pain is female-specific pain.
54 . A method according to claim 47 ,
wherein said subject is human.Join the waitlist — get patent alerts
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