US2006094720A1PendingUtilityA1
NK1 antagonists
Est. expiryJul 3, 2022(expired)· nominal 20-yr term from priority
A61P 9/10A61P 3/10A61P 25/36A61P 25/00A61P 25/28A61P 25/30A61P 25/20A61P 31/18A61P 3/04A61P 25/32A61P 29/00A61P 25/22A61P 25/04A61P 25/24A61P 25/06A61P 25/08A61P 29/02A61P 25/18A61P 27/02A61P 13/02A61P 11/14A61P 13/10A61P 17/00C07D 417/14A61P 1/04A61P 1/08C07D 211/98A61P 15/00C07D 413/04C07D 417/12C07D 413/12A61P 1/14A61P 11/00C07D 405/12C07D 409/12A61P 19/04C07D 401/12C07D 401/04
51
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Claims
Abstract
Disclosed are NK 1 antagonists having the formula: Also disclosed are methods for treating a number of physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough, using the compounds of formula (I).
Claims
exact text as granted — not AI-modified1 . A compound having the formula (I):
or a pharmaceutically acceptable salt or solvate thereof, wherein
Ar 1 and Ar 2 are each independently selected from the group consisting of (R 19 ) n7 -heteroaryl- and
X 1 is selected from the group consisting of —O—, —S—, —SO—, —SO 2 —, —NR 12 —, —N(COR 12 )— and —N(SO 2 R 15 )—;
R 1 , R 3 and R 5 are each independently selected from the group consisting of H and C 1 -C 6 alkyl;
R 2 , R 4 and R 6 are each independently selected from the group consisting of H, —CONR 13 R 14 and —(CH 2 ) n1 -G; wherein G is selected from the group consisting of H, —CF 3 , —CHF 2 , —CH 2 F, —OH, —O—(C 1 -C 6 )alkyl, —SO 2 R 13 , —O—(C 3 -C 8 cycloalkyl), —NR 13 R 14 , —SO 2 NR 13 R 14 , —NR 13 SO 2 R 15 , —NR 13 COR 12 , —NR 12 (CONR 13 R 14 ), —CONR 13 R 14 , —COOR 12 and C 3 -C 8 cycloalkyl; or
R 1 and R 2 , taken together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl ring; or
R 1 and R 2 , taken together with the carbon to which they are attached, form a
group, provided that X1 is —O— or —NR 12 when said
is formed; or
R 3 and R 4 , taken together with the carbon to which they are attached, form a
group; or
R 5 and R 6 , taken together with the carbon to which they are attached, form a
group;
R 7 and R 11 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, (R 16 ) n7 -aryl-, (R 19 ) n7 -heteroaryl-, —COOR 29 , —CONR 21 R 22 , —CON(R 21 )(CH 2 ) n -G 1 , —S(O) n5 (CH 2 ) n -G 1 , —S(O) n5 R 13 , —CO(CH 2 ) n -G 1 and —(CH 2 ) n1 -G 1 ; wherein
n is 0-4, and
G 1 is selected from the group consisting of H, —OH, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 alkyl), —S(O) n5 R 13 , —O—(C 3 -C 8 cycloalkyl), —NR 13 R 14 , —SO 2 NR 13 R 14 , —NR 13 SO 2 R 15 , —NR 13 COR 12 , —NR 12 (CONR 13 R 14 ), —OC(═O)R 12 , —CONR 13 R 14 , —COOR 12 , C 3 -C 8 cycloalkyl, —CF 3 , (R 16 ) n7 -aryl-O—, (R 16 ) n7 -aryl-, (R 19 ) n7 -heteroaryl-, (R 19 ) n7 -heterocycloalkyl- and alkenyl, and
provided that, when n is 0, then G 1 is selected from the group consisting of H, (C 1 -C 6 )alkyl, alkenyl, —CONR 13 R 14 , —COOR 12 , C 3 -C 8 cycloalkyl, —CF 3 , (R 16 ) n7 -aryl-, (R 19 ) n7 -heteroaryl-, and (R 19 ) n7 -heterocycloalkyl-; and
provided that, when n 1 is 1, then G 1 is selected from the group consisting of H, (C 1 -C 6 )alkyl, alkenyl, —S(O) n5 R 13 , —SO 2 NR 13 R 14 , —CONR 13 R 14 , —COOR 12 , C 3 -C 8 cycloalkyl, —CF 3 , (R 16 ) n7 -aryl-, (R 19 ) n7 -heteroaryl- wherein said heteroaryl ring is bound by a ring carbon to the —(CH 2 ) n1 — group, and (R 19 ) n7 -heterocycloalkyl- wherein said heterocycloalkyl ring is bound by a ring carbon to the —(CH 2 ) n1 — group; or
R 7 and R 11 , taken together with the nitrogen to which they are attached, form a 5-7 membered heterocycloalkyl ring of the following formula:
R 7 and R 11 , taken together with the nitrogen to which they are attached, form a 5-membered ring having the formula (A) or (B):
X is selected from the group consisting of —NR 20 —, —N(CONR 13 R 14 )—, —N(CO 2 R 13 )—, —N(SO 2 R 15 )—, —N(COR 12 )—, —N(SO 2 NHR 13 )—, —O—, —S—, —SO—, —SO 2 —, —CF 2 —, —CH 2 —, and —C(R 12 )F—;
R 8 , R 9 and R 10 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —OR 12 , halogen, —CN, —NO 2 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —COOR 12 , —CONR 21 R 22 , —NR 21 COR 12 , —NR 21 CO 2 R 15 , —NR 21 CONR 21 R 22 , —NR 21 SO 2 R 15 , —NR 21 R 22 , —SO 2 NR 21 R 22 , —S(O) n5 R 15 , (R 16 ) n7 -aryl- and (R 19 ) n7 -heteroaryl-;
R 12 is selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
R 13 and R 14 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 3 alkyl-O—CH 3 , C 3 -C 8 cycloalkyl, (R 19 ) n7 -aryl(CH 2 ) n6 — and (R 19 ) n7 -heteroaryl-(CH 2 ) n6 —; or
R 13 and R 14 , taken together with the nitrogen to which they are attached, form a 4-7 membered ring containing from 0-3 additional heteroatoms selected from the group consisting of —O—, —S— and —NR 12 —;
R 15 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or —CF 3 ;
R 16 is 1 to 3 substituents each independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, halogen and —CF 3 ;
R 19 is 1 to 3 substituents each independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —OH, halogen, —CN, —NO 2 , —C(O)CF 3 , —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —O—(C 1 -C 6 alkyl), —O—(C 3 -C 8 cycloalkyl), —COOR 12 —CONR 21 R 22 , —NR 21 R 22 , —NR 21 COR 12 , —NR 21 CO 2 R 12 , —NR 21 CONR 21 R 22 , —NR 21 SO 2 R 15 and —S(O) n5 R 15 ;
R 20 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, —(CH 2 ) n6 -heterocycloalkyl, (R 19 ) n7 -aryl(CH 2 ) n6 — or (R 19 ) n7 -heteroaryl-(CH 2 ) n6 —;
R 21 and R 22 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and benzyl; or
R 21 and R 22 , taken together with the nitrogen to which they are attached, form a 4-7 membered heteroaryl ring containing from 0-3 additional heteroatoms selected from the group consisting of —O—, —S— and —NR 12 —;
R 23 and R 24 are each independently selected from the group consisting of H, C 1 -C 6 alkyl and —CONR 13 R 14 ; or
R 23 and R 24 , taken together with the carbon atom to which they are attached, form a
group;
R 25 , R 26 , R 27 and R 28 are each independently selected from the group consisting of H and C 1 -C 6 alkyl; or
R 25 and R 26 , taken together with the carbon atom to which they are attached, form a
group; or
R 27 and R 28 , taken together with the carbon atom to which they are attached, form a
group;
R 29 is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
n 1 is 1-4;
n 2 and n 3 are each independently 0-3, provided that a sum of n 2 and n 3 is 0-4;
n 4 is 0-2;
n 5 is 0-2;
n 6 is 0-3; and
n 7 is 0-3; and
provided that, when n 4 is 0, and R 25 and R 26 are each H, then X is not —O—, —NR 20 — or —S—.
2 . The compound of claim 1 wherein X 1 is —O—.
3 . The compound of claim 1 wherein Ar 1 and Ar 2 are each independently
4 . The compound of claim 3 wherein R 8 , R 9 and R 10 are each independently selected from the group consisting of H, —CH 3 , halogen and —CF 3 .
5 . The compound of claim 1 wherein
X 1 is —O—; and Ar 1 and Ar 2 are each independently wherein R 8 , R 9 and R 10 are each independently selected from the group consisting of H, —CH 3 , halogen and —CF 3 .
6 . The compound of claim 1 wherein
wherein,
R 8 is selected from the group consisting of H and F, and
R 9 and R 10 are each independently selected from the group consisting of H, —CH 3 , F, Cl and —CF 3 .
7 . The compound of claim 6 wherein
X 1 is —O—; and R 3 , R 4 , R 27 and R 28 are each H.
8 . The compound of claim 6 wherein R 5 and R 6 are H.
9 . The compound of claim 7 wherein R 7 and R 11 , taken together with the nitrogen to which they are attached, form a 5-7 membered ring having the following formula:
10 . The compound of claim 1 having the formula
wherein R 7 , R 8 and R 11 are selected from the group consisting of:
R 8
R 7
R 11
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
F
H
H
F
H
F
H
F
H
F
H
F
H
F
H
F
H
H
H
H
H
F
H
F
H
H
H
H
H
H
H
H
H
11 . The compound of claim 1 having the formula:
wherein R 1 , R 2 , R 7 , R 8 and R 11 are selected from the group consisting of:
R 8
R 1
R 2
—NR 7 R 11
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
F
H
H
F
H
H
H
H
H
H
H
CH 3
H
H
CH 2 OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
12 . The compound of claim 11 or the pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 7 , R 8 and R 11 are selected from the group consisting of
R 8
R 1
R 2
—NR 7 R 11
H
H
H
H
H
H
H
H
CH 3
H
H
CH 2 OH
H
H
H
13 . The compound of claim 12 having the formula:
14 . The compound of claim 12 having the formula:
15 . The compound of claim 12 having the formula:
16 . The compound of claim 12 having the formula:
17 . The compound of claim 12 having the formula:
18 . A pharmaceutical composition comprising at least one compound of claim 1 , and a pharmaceutically acceptable carrier.
19 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, at least one serotonin reuptake inhibitor, and at least one compound of claim 1 .
20 . A method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of claim 1 , wherein said physiological disorder, symptom or disease is selected from the group consisting of: respiratory diseases, inflammatory diseases, skin disorders, ophthalmological disorders, central nervous system conditions, addictions, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia, Towne's disease, stress related disorders, obsessive/compulsive disorders, eating disorders, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, atherosclerosis, fibrosing disorders, obesity, Type II diabetes, pain related disorders, bladder and genitourinary disorders, and nausea.
21 . A method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of claim 1 , wherein said physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulemia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis and nausea.
22 . A method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of claim 1 , and an effective amount of at least one active ingredient selected from the group consisting of: other NK 1 receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 5-HT 3 receptor antagonists, serotonin 5-HT 2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5, wherein said physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulemia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis and nausea.
23 . A method of treating emesis and/or nausea in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound having the formula (I) in combination with an effective amount of at least one serotonin 5-HT 3 receptor antagonist and/or at least one glucocorticoid.
24 . The method of claim 23 wherein said serotonin 5-HT 3 receptor antagonist is ondansetron and said glucocorticoid is dexamethasone.
25 . The method of claim 21 , wherein the physiological disorder, symptom or disease is emesis, depression, anxiety or cough.
26 . The method of claim 25 wherein the physiological disorder, symptom or disease is depression or anxiety.
27 . The method of claim 26 , further comprising administering to the patient an effective amount of at least one anti-depressant agent and/or at least one anti-anxiety agent.
28 . The method of claim 25 wherein depression is being treated and said method further comprises administering to the patient an effective amount of at least one selective serotonin reuptake inhibitor.
29 . A method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for blocking at least one neurokinin-1 receptor, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of claim 1 .
30 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NK 1 receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, said therapeutic agent being selected from the group consisting of: SSRIs, other types of NK 1 receptor antagonists, prostanoids, H 1 receptor antagonists, α-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ET A antagonists, renin inhibitors, serotonin 5-HT 3 receptor antagonists, serotonin 5-HT 2c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5.
31 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an antidepressant agent in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising an antianxiety agent in a pharmaceutically acceptable carrier.
32 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NK 1 receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier.
33 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier.
34 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, j wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a serotonin 5-HT 3 receptor antagonist in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising a glucocorticoid in a pharmaceutically acceptable carrier.
35 . A kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, a separate container comprises ondansetron, and/or wherein a separate container comprises dexamethasone.Join the waitlist — get patent alerts
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