US2010196269A1PendingUtilityA1
Spirocyclic heterocyclic derivatives and methods of their use
Est. expiryApr 6, 2026(expired)· nominal 20-yr term from priority
A61P 9/12A61P 9/06A61P 37/00A61P 9/10A61P 43/00A61P 37/02A61P 9/00A61P 25/14A61P 25/18A61P 25/22A61P 29/00A61P 25/36A61P 25/02A61P 25/08A61P 25/24A61P 25/16A61P 25/30A61P 25/00A61P 25/04A61P 25/34A61P 25/32A61P 27/06C07D 491/107A61P 17/06A61P 15/10A61P 1/00A61P 19/02A61P 11/06A61P 1/02A61P 11/00A61P 15/00A61P 13/00A61P 21/00C07D 487/10A61P 15/08A61P 13/10A61K 31/438C07D 221/20
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Claims
Abstract
Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the δ-opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ-opioid receptor-mediated diseases, disorders, and/or conditions.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
wherein:
W is alkylene;
Z is alkoxy, —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) m alkyl;
each R 1 is independently carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl;
R 2 is —NR 5 R 6 or alkoxy;
R 3 and R a are each independently H or alkyl;
R 4 is alkyl or —NR 5 R 6 ;
R 5 and R 6 are each independently H or alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R 7 )—, —N(R 8 )—C(═O)— or —C(═O)—N(R 9 )—;
R 7 , R 8 and R 9 are each independently H or alkyl;
X is —CH 2 —, —S(═O) m — or —O—;
A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond;
each m is independently 0, 1 or 2;
p and t are each independently 0, 1 or 2; and
is 1 or 2; provided that the sum of p+s is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof;
with the proviso that when X is —CH 2 — or —O—, then at least one of p and s is other than 1.
2 . A compound according to claim 1 , wherein A and B are each H.
3 . A compound according to claim 1 , wherein A and B are taken together with the carbon atoms through which they are connected to form a double bond.
4 . A compound according to claim 1 , wherein X is —O—.
5 . A compound according to claim 1 , wherein X is —CH 2 —.
6 . A compound according to claim 1 , wherein R a is H.
7 . A compound according to claim 1 , wherein the sum of p and s is 2 or 3.
8 . A compound according to claim 7 , wherein p and s are each 1.
9 . A compound according to claim 1 , wherein Z is —C(═O)—R 2 .
10 . A compound according to claim 9 , wherein R 2 is —NR 5 R 6 .
11 . A compound according to claim 10 , wherein R 5 and R 6 are each independently H or alkyl.
12 . A compound according to claim 11 , wherein R 5 and R 6 are each independently H or C 1-4 alkyl.
13 . A compound according to claim 12 , wherein R 5 and R 6 are each independently C 1-4 alkyl.
14 . A compound according to claim 13 , wherein R 5 and R 6 are each independently C 2-3 alkyl.
15 . A compound according to claim 6 , having the formula II:
16 . A compound according to claim 15 , wherein A and B are taken together with the carbon atoms through which they are connected to form a double bond.
17 . A compound according to claim 16 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) 2 alkyl.
18 . A compound according to claim 17 , wherein Z is —C(═O)—R 2 .
19 . A compound according to claim 18 , wherein R 2 is —NR 5 R 6 .
20 . A compound according to claim 19 , wherein R 5 and R 6 are each independently C 2-3 alkyl.
21 . A compound according to claim 20 , wherein the sum of p and s is 2 or 3.
22 . A compound according to claim 21 , wherein t is 0.
23 . A compound according to claim 15 , wherein A and B are each H.
24 . A compound according to claim 23 , having the formula III:
wherein:
Q 1 and Q 2 are each independently H, carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl.
25 . A compound according to claim 24 , wherein the sum of p and s is 2 or 3.
26 . A compound according to claim 25 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) 2 alkyl.
27 . A compound according to claim 26 , wherein Z is —C(═O)—R 2 .
28 . A compound according to claim 27 , wherein R 2 is —NR 5 R 6 .
29 . A compound according to claim 28 , wherein R 5 and R 6 are each independently C 2-3 alkyl.
30 . A compound according to claim 29 , wherein at least one of Q 1 and Q 2 is H.
31 . A compound according to claim 30 , wherein Q 1 and Q 2 are each H.
32 . A compound according to claim 30 , wherein one of Q 1 and Q 2 is carboxy, hydroxy, alkoxy, halo, aminocarbonyl or N-alkylaminocarbonyl.
33 . A compound according to claim 32 , wherein the halo is fluoro and the N-alkylaminocarbonyl is N—C 1-3 alkylaminocarbonyl.
34 . A compound according to claim 33 , wherein Q 2 is carboxy, hydroxy, alkoxy, fluoro, aminocarbonyl or N—C 1-3 alkylaminocarbonyl.
35 . A compound according to claim 32 , wherein Q 1 is hydroxy or alkoxy.
36 . A compound according to claim 6 , having the formula IV:
37 . A compound according to claim 36 , wherein A and B are taken together with the carbon atoms through which they are connected to form a double bond.
38 . A compound according to claim 37 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) 2 alkyl.
39 . A compound according to claim 38 , wherein Z is —C(═O)—R 2 .
40 . A compound according to claim 39 , wherein R 2 is —NR 5 R 6 .
41 . A compound according to claim 40 , wherein R 5 and R 6 are each independently C 2-3 alkyl.
42 . A compound according to claim 41 , wherein the sum of p and s is 2 or 3.
43 . A compound according to claim 42 , wherein t is 0.
44 . A compound according to claim 36 , wherein A and B are each H.
45 . A compound according to claim 44 , having the formula V:
wherein:
Q 1 and Q 2 are each independently H, carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl.
46 . A compound according to claim 45 , wherein the sum of p and s is 2 or 3.
47 . A compound according to claim 46 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) 2 alkyl.
48 . A compound according to claim 47 , wherein Z is —C(═O)—R 2 .
49 . A compound according to claim 48 , wherein R 2 is —NR 5 R 6 .
50 . A compound according to claim 49 , wherein R 5 and R 6 are each independently C 2-3 alkyl.
51 . A compound according to claim 50 , wherein at least one of Q 1 and Q 2 is H.
52 . A compound according to claim 51 , wherein Q 1 and Q 2 are each H.
53 . A compound according to claim 51 , wherein one of Q 1 and Q 2 is carboxy, hydroxy, alkoxy, halo, aminocarbonyl or N-alkylaminocarbonyl.
54 . A compound according to claim 53 , wherein the halo is fluoro and the N-alkylaminocarbonyl is N—C 1-3 alkylaminocarbonyl.
55 . A compound according to claim 53 , wherein Q 2 is carboxy, hydroxy, alkoxy, fluoro, aminocarbonyl or N—C 1-3 alkylaminocarbonyl.
56 . A compound according to claim 53 , wherein Q 1 is hydroxy or alkoxy.
57 . A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier; and a compound according to claim 1 .
58 . A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier; a compound of formula I:
wherein:
W is alkylene;
Z is alkoxy, —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) m alkyl;
each R 1 is independently carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl;
R 2 is —NR 5 R 6 or alkoxy;
R 3 and R a are each independently H or alkyl;
R 4 is alkyl or —NR 5 R 6 ;
R 5 and R 6 are each independently H or alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R 7 )—, —N(R 8 )—C(═O)— or —C(═O)—N(R 9 )—;
R 7 , R 8 , and R 9 are each independently H or alkyl;
X is —CH 2 —, —S(═O) m — or —O—;
A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond;
each m is independently 0, 1 or 2;
p and t are each independently 0, 1 or 2; and
s is 1 or 2; provided that the sum of p+s is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, an anti-Parkinson's agent or an agent for the treatment of a cardiac disorder.
59 . A pharmaceutical composition according to claim 58 ,
wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine or tramadol or a mixture thereof.
60 . A pharmaceutical composition according to claim 58 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild over-the-counter analgesic, a narcotic analgesic, an anti-seizure medication, or an antidepressant.
61 . A pharmaceutical composition according to claim 58 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor or an antidepressant compound belonging to the heterocyclic class.
62 . A pharmaceutical composition according to claim 58 , wherein said agent for the treatment of urge incontinence is an anti-cholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
63 . A pharmaceutical composition according to claim 58 , wherein said anti-Parkinson's agent is selected from the group consisting of deprenyl, amantadine, levodopa and carbidopa.
64 . A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier; a compound of formula I:
wherein:
W is alkylene;
Z is alkoxy, —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) m alkyl;
each R 1 is independently carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl;
R 2 is —NR 5 R 6 or alkoxy;
R 3 and R a are each independently H or alkyl;
R 4 is alkyl or —NR 5 R 6 ;
R 5 and R 6 are each independently H or alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R 7 )—, —N(R 8 )—C(═O)— or —C(═O)—N(R 9 )—;
R 7 , R 8 , and R 9 are each independently H or alkyl;
X is —CH 2 —, —S(═O) m — or —O—;
A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond;
each m is independently 0, 1 or 2;
p and t are each independently 0, 1 or 2; and
s is 1 or 2; provided that the sum of p+s is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof; and
an antibiotic, an antiviral, an antifungal, an anti-inflammatory or an anesthetic or a combination thereof.
65 . A method of binding opioid receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound of formula I:
wherein:
W is alkylene;
Z is alkoxy, —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) m alkyl;
each R 1 is independently carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl;
R 2 is —NR 5 R 6 or alkoxy;
R 3 and R a are each independently H or alkyl;
R 4 is alkyl or —NR 5 R 6 ;
R 5 and R 6 are each independently H or alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R 7 )—, —N(R 8 )—C(═O)— or —C(═O)—N(R 9 )—;
R 7 , R 8 and R 9 are each independently H or alkyl;
X is —CH 2 —, —S(═O) m — or —O—;
A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond;
each m is independently 0, 1 or 2;
p and t are each independently 0, 1 or 2; and
s is 1 or 2; provided that the sum of p+s is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
66 . A method according to claim 65 ,
wherein said compound binds δ-opioid receptors.
67 . A method according to claim 66 ,
wherein said δ-opioid receptors are located in the central nervous system.
68 . A method according to claim 66 ,
wherein said δ-opioid receptors are located peripherally to the central nervous system.
69 . A method according to claim 65 ,
wherein said binding modulates the activity of said opioid receptors.
70 . A method according to claim 69 ,
wherein said binding agonizes the activity of said opioid receptors.
71 . A method according to claim 68 ,
wherein said compound does not substantially cross the blood-brain barrier.
72 . A method according to claim 65 which is for the treatment of a disease, disorder or condition selected from the group consisting of pain, gastrointestinal dysfunction, a urogenital tract disorder, an immunomodulatory disorder, an inflammatory disorder, a respiratory function disorder, anxiety, a mood disorder, a stress-related disorder, attention deficit hyperactivity disorder, sympathetic nervous system disorder, tussis, a motor disorder, a traumatic injury to the central nervous system, stroke, cardiac arrhythmia, glaucoma, sexual dysfunction and substance addiction.
73 . A method according to claim 72 , wherein the disease, disorder or condition is pain.
74 . A method according to claim 73 , further comprising the step of:
administering to said patient an effective amount of an opioid.
75 . A method according to claim 74 ,
wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine or tramadol or a combination thereof.
76 . A method according to claim 72 , wherein the disease, disorder or condition is gastrointestinal dysfunction.
77 . A method according to claim 72 , wherein the disease, disorder or condition is a urogenital tract disorder.
78 . A method according to claim 77 , wherein said urogenital tract disorder is incontinence or overactive bladder.
79 . A method according to claim 78 , wherein said incontinence is stress urinary incontinence or urge urinary incontinence.
80 . A method according to claim 78 , wherein said urogenital tract disorder is overactive bladder.
81 . A method according to claim 78 further comprising the step of:
administering to said patient an effective amount of an agent for the treatment of incontinence.
82 . A method according to claim 72 , wherein the disease, disorder or condition is an immunomodulatory disorder.
83 . A method according to claim 82 , wherein said immunomodulatory disorder is selected from the group consisting of an autoimmune disease, a collagen disease, an allergy, a side effect associated with the administration of an anti-tumor agent and a side effect associated with the administration of an antiviral agent.
84 . A method according to claim 83 ,
wherein said autoimmune disease is selected from the group consisting of arthritis, an autoimmune disorder associated with a skin graft, an autoimmune disorder associated with organ transplant and an autoimmune disorder associated with surgery.
85 . A method according to claim 72 , wherein the disease, disorder or condition is an inflammatory disorder.
86 . A method according to claim 85 , wherein said inflammatory disorder is arthritis, psoriasis, asthma or inflammatory bowel disease.
87 . A method according to claim 72 , wherein the disease, disorder or condition is a respiratory function disorder.
88 . A method according to claim 87 , wherein said respiratory function disorder is asthma or lung edema.
89 . A method according to claim 72 , wherein the disease, disorder or condition is anxiety.
90 . A method according to claim 72 , wherein the disease, disorder or condition is a mood disorder.
91 . A method according to claim 90 , wherein said mood disorder is selected from the group consisting of depression, bipolar manic-depression and seasonal affective disorder.
92 . A method according to claim 90 further comprising the step of:
administering to said patient an effective amount of an agent for the treatment of depression.
93 . A method according to claim 72 , wherein the disease, disorder or condition is a stress-related disorder.
94 . A method according to claim 101 , wherein said stress-related disorder is selected from the group consisting of post-traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia and obsessive-compulsive disorder.
95 . A method according to claim 72 , wherein the disease, disorder or condition is attention deficit hyperactivity disorder.
96 . A method according to claim 72 , wherein the disease, disorder or condition is sympathetic nervous system disorder.
97 . A method according to claim 96 , wherein said sympathetic nervous system disorder is hypertension.
98 . A method according to claim 72 , wherein the disease, disorder or condition is tussis.
99 . A method according to claim 72 , wherein the disease, disorder or condition is a motor disorder.
100 . A method according to claim 99 , wherein said motor disorder is tremors, Parkinson's disease, Tourette's syndrome or dyskinesia.
101 . A method according to claim 100 wherein said motor disorder is tremors.
102 . A method according to claim 101 , further comprising the step of:
administering to said patient an effective amount of an anti-Parkinson's agent.
103 . A method according to claim 72 , wherein the disease, disorder or condition is a traumatic injury to the central nervous system.
104 . A method according to claim 103 , wherein said traumatic injury is traumatic injury to the spinal cord or brain.
105 . A method according to claim 72 , wherein the disease, disorder or condition is stroke.
106 . A method according to claim 72 , wherein the disease, disorder or condition is cardiac arrhythmia.
107 . A method according to claim 72 , wherein the disease, disorder or condition is glaucoma.
108 . A method according to claim 72 , wherein the disease, disorder or condition is sexual dysfunction.
109 . A method according to claim 108 , wherein said sexual dysfunction is premature ejaculation.
110 . A method according to claim 72 , wherein the disease, disorder or condition is substance addiction.
111 . A method according to claim 110 , wherein said substance addiction is alcohol addiction, nicotine addiction or drug addiction.
112 . A method according to claim 111 , wherein said drug addiction is addiction to opioids.
113 . A method according to claim 65 , which is for the treatment of a disease, disorder or condition selected from the group consisting of shock, brain edema, cerebral ischemia, cerebral deficits subsequent to cardiac bypass surgery and grafting, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts.
114 . A method according to claim 65 , which is for improving organ and cell survival.
115 . A method according to claim 65 , which is for providing cardioprotection.
116 . A method according to claim 115 , further comprising administering to said patient an effective amount of an agent for treating a cardiac disorder.
117 . A method according to claim 116 , wherein the cardiac disorder agent is selected from the group consisting of nitrates, beta-adrenergic blockers, calcium channel antagonists, ACE inhibitors, non-peptide angiotension II antagonists, IIb/IIIa antagonists and aspirin.
118 . A method according to claim 65 , which is for reducing the need for anesthesia.
119 . A method according to claim 65 , which is for producing or maintaining an anesthetic state.
120 . A method according to claim 119 , further comprising the step of:
administering to said patient an anesthetic agent selected from the group consisting of an inhaled anesthetic, an hypnotic, an anxiolytic, a neuromuscular blocker and an opioid.
121 . A method according to claim 120 , wherein said compound of formula I and said anesthetic agent are co-administered.
122 . A radio-labeled derivative of a compound of formula I:
wherein:
W is alkylene;
Z is alkoxy, —C(═O)—R 2 , —NR 3 —C(═O)—R 4 or —NR 3 S(═O) m alkyl;
each R 1 is independently carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl or N,N-dialkylaminocarbonyl;
R 2 is —NR 5 R 6 or alkoxy;
R 3 and R a are each independently H or alkyl;
R 4 is alkyl or —NR 5 R 6 ;
R 5 and R 6 are each independently H or alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R 7 )—, —N(R 8 )—C(═O)— or —C(═O)—N(R 9 )—;
R 7 , R 8 and R 9 are each independently H or alkyl;
X is —CH 2 —, —S(═O) m — or —O—;
A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond;
each m is independently 0, 1 or 2;
p and t are each independently 0, 1 or 2; and
s is 1 or 2; provided that the sum of p+s is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
123 . A method of diagnostic imaging comprising administering to a patient a compound according to claim 122 , and imaging the patient.
124 . A method according to claim 123 wherein said imaging comprises positron emission tomography.Cited by (0)
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