US2008306085A1PendingUtilityA1
Non-imidazole aryloxyalkylamines
Est. expiryAug 8, 2020(expired)· nominal 20-yr term from priority
Inventors:Richard ApodacaNicholas I. CarruthersCurt A. DvorakDale A. RudolphChandravadan R. ShahWei Xiao
A61P 9/00A61P 37/08A61P 43/00A61P 25/00A61P 3/00A61P 25/24A61P 25/18A61P 25/28A61P 27/16A61P 25/20A61P 25/06A61P 25/08C07D 231/12C07D 239/34C07D 211/58A61K 45/06C07D 235/26C07D 295/112C07D 295/135C07C 217/22C07D 207/335A61K 31/4402A61P 11/00C07D 401/04C07D 295/205C07D 471/08C07D 233/56C07D 233/54C07D 213/36C07D 215/06C07D 277/36C07D 233/42C07D 401/14C07D 317/28C07D 257/04C07D 307/52C07D 233/84C07D 235/06C07D 211/46C07D 233/88C07C 335/32C07D 211/22A61P 11/06A61K 31/4465C07D 401/12C07D 295/096C07D 207/325C07D 213/74C07D 249/08C07D 333/20C07D 295/088C07C 323/25
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Claims
Abstract
Substituted aryloxyalkylamines of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.
Claims
exact text as granted — not AI-modified1 .- 53 . (canceled)
54 . A method of inhibiting histamine H 3 receptor activity in a subject, comprising administering an effective amount of a compound of formula (I) to a subject in need of such inhibition of histamine H 3 receptor activity, wherein the compound of formula (I) is:
wherein R a , and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, phenyl, naphthyl, (naphthyl)C 1-6 alkylene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene,
L 5 is C 1-5 alkylene,
L 6 is C 1-5 alkylene,
L 7 is C 1-5 alkylene or absent;
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-6 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide, C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocycyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl)C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
55 . A method of treating a subject having a disease or condition modulated by histamine H 3 receptor activity, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 , and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent;
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-6 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide, C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
56 . A method of claim 55 , wherein said disease or condition is selected from the group consisting of sleep/wake disorders, arousal/vigilance disorders, migraine, asthma, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, motion sickness, vertigo, attention deficit hyperactivity disorders, learning disorders, memory retention disorders, schizophrenia, nasal congestion, allergic rhinitis, and upper airway allergic response.
57 . A method for treating a disease or condition modulated by at least one receptor selected from the histamine H 1 receptor and the histamine H 3 receptor, said method comprising (a) administering to a subject a jointly effective amount of a histamine H 1 receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of formula (I), said method providing a jointly therapeutically effective amount of said compounds, wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 , and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent;
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-16 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide, C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
58 . The method of claim 57 wherein the histamine H 1 receptor antagonist and the compound of formula (I) are present in the same dosage form.
59 . A method for treating diseases or conditions modulated by at least one receptor selected from the histamine H 2 receptor and the histamine H 3 receptor in a subject, comprising (a) administering to the subject a jointly effective amount of a histamine H 2 receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of formula (I) said method providing a jointly therapeutically effective amount of said compounds, wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 , and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent;
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen C 1-8 alkyl C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-6 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
60 . The method of claim 59 wherein the histamine H 2 receptor antagonist and the compound of formula (I) are present in the same dosage form.
61 . A method for treating one or more disorders or conditions selected from the group consisting of sleep/wake disorders, narcolepsy, and arousal/vigilance disorders, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-3 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent;
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen C 1-8 alkyl, C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-6 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide C 2-6 alkyl, heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
62 . A method for treating attention deficit hyperactivity disorders (ADHD), comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent,
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen C 1-8 alkyl C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-16 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide, C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
63 . A method for treating one or more disorders or conditions selected from the group consisting of dementia, mild cognitive impairment (pre-dementia), cognitive dysfunction, schizophrenia, depression, manic disorders, bipolar disorders, and learning and memory disorders, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 9-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent;
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl, ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen C 1-8 alkyl C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-16 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
64 . A method for treating or preventing upper airway allergic response, nasal congestion, or allergic rhinitis, comprising administering to a subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent,
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-16 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide, C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
L 3 is not phenyl or naphthyl.
65 . A method for studying disorders mediated by the histamine H 3 receptor, comprising using an 18 F-labeled compound of formula (I) as a positron emission tomography (PET) molecular probe, wherein the compound of formula (I) is:
wherein R a and R b are independently C 1-8 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl,
(C 3-8 cycloalkyl) C 1-6 alkyl, or taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclyl optionally including up to 3 additional heteroatoms;
n is 0-4;
one of R 1 , R 2 and R 3 is G, and the remaining two are hydrogen or halo;
G is a nitrogen-containing group selected from one of the following:
—OL 1 Q, -L 2 Q, —N(L 1 Q)R 5 , -L 3 C(L 1 Q)R 6 R 7 , —C(L 1 Q)R 6 R 7 ,
wherein:
L 1 is C 2-6 alkylene, C 3-8 cycloalkylene, C 4-6 alkenylene, C 4-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 2-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, or (C 2-5 heteroaryloxy)C 1-6 alkylene;
L 2 is C 1-6 alkylene, C 3-8 cycloalkylene, C 3-6 alkenylene, C 3-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 alkylene, (naphthyl)C 1-6 alkylene, (C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or (C 1-5 heteroarylthio)C 1-6 alkylene;
L 3 is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 2-5 alkanoyl, (phenyl)C 1-6 allene, C 1-5 heteroaryl)C 1-6 alkylene, (phenoxy)C 1-6 alkylene, (C 1-5 heteroaryloxy)C 1-6 alkylene, or C 2-5 heteroaryl;
L 4 is C 1-5 alkylene;
L 5 is C 1-5 alkylene;
L 6 is C 1-5 alkylene;
L 7 is C 1-5 alkylene or absent,
Q is —NR 8 R 9 or a non-aromatic C 2-15 heterocyclyl ring system containing at least one nitrogen atom and optionally between 1 and 3 additional heteroatoms selected from O, S, and N in each ring;
each of R 5 and R 6 is independently selected from hydrogen, C 1-8 alkyl C 2-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, and (C 2-7 heterocyclyl)C 1-6 alkylene;
R 7 is H, hydroxyl, halo, C 2-6 alkoxy or absent where the carbon linking L 6 and L 7 (or bonded to R 6 ) participates in a double bond;
each of R 8 and R 9 is independently selected from hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, C 2-15 heterocyclyl, phenyl, (C 2-15 heterocyclyl)C 1-6 alkylene, and (phenyl) C 1-6 alkylene;
R 10 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)C 1-6 alkylene, (C 2-15 heterocyclyl)C 1-16 alkylene, or (phenyl) C 1-6 alkylene;
wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents selected from halo, amino, nitro, hydroxyl, and C 1-3 alkyl;
wherein substituents of Q can be further selected from carboxamide, C 2-6 alkyl, C 1-8 heterocyclyl, N(C 1-6 alkyl)(C 1-8 heterocyclyl), NH(C 1-8 heterocyclyl), (C 1-8 heterocyclyl) C 1-3 alkylene, O(C 1-8 heterocyclyl), C 1-6 alkoxy, (phenyl)C 3-6 cycloalkyl-O—, phenyl, (phenyl) C 1-3 alkylene, N(C 1-6 alkyl)[(phenyl)C 1-3 alkylene], and (phenyl)C 1-3 alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from halogen, nitro, cyano, and C 1-3 alkyl;
or a pharmaceutically acceptable salt, ester, or amide thereof, provided that when NR a R b is a six-membered heterocyclyl ring system and G is
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