U.S. patent application number 16/935531 was filed with the patent office on 2021-05-06 for prophylactic or therapeutic agent for autism spectrum disorder.
The applicant listed for this patent is TAKEDA PHARMACEUTICAL COMPANY LIMITED. Invention is credited to Keisuke HIRAI, Takashi ISHIKAWA.
Application Number | 20210130305 16/935531 |
Document ID | / |
Family ID | 1000005332938 |
Filed Date | 2021-05-06 |
United States Patent
Application |
20210130305 |
Kind Code |
A1 |
HIRAI; Keisuke ; et
al. |
May 6, 2021 |
PROPHYLACTIC OR THERAPEUTIC AGENT FOR AUTISM SPECTRUM DISORDER
Abstract
The present invention provides a prophylactic or therapeutic
agent for an autism spectrum disorder containing compound (I)
having melatonin receptor affinity. A compound represented by the
formula: ##STR00001## wherein each symbol is as described in the
specification, or a salt thereof.
Inventors: |
HIRAI; Keisuke; (Kanagawa,
JP) ; ISHIKAWA; Takashi; (Kanagawa, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TAKEDA PHARMACEUTICAL COMPANY LIMITED |
Osaka |
|
JP |
|
|
Family ID: |
1000005332938 |
Appl. No.: |
16/935531 |
Filed: |
July 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16068553 |
Jul 6, 2018 |
10759768 |
|
|
PCT/JP2017/000166 |
Jan 5, 2017 |
|
|
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16935531 |
|
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62276354 |
Jan 8, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/423 20130101;
A61K 31/428 20130101; C07D 413/06 20130101; C07D 263/52 20130101;
A61P 25/00 20180101; C07D 277/60 20130101 |
International
Class: |
C07D 263/52 20060101
C07D263/52; A61K 31/428 20060101 A61K031/428; A61K 31/423 20060101
A61K031/423; A61P 25/00 20060101 A61P025/00; C07D 277/60 20060101
C07D277/60; C07D 413/06 20060101 C07D413/06 |
Claims
1-2. (canceled)
3. A method for preventing or treating an autism spectrum disorder
comprising administering an effective amount of a compound selected
from
(N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]a-
cetamide,
N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide,
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]pr-
opionamide,
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene-
]ethyl}acetamide,
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]a-
cetamide,
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethy-
l]acetamide,
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide,
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)-
ethyl]acetamide,
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propion-
amide,
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)et-
hyl]propionamide,
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide,
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetam-
ide,
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)eth-
yl]acetamide,
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide,
N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl-
]acetamide,
(R)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide,
(S)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)et-
hyl]acetamide,
N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetam-
ide,
(R)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)eth-
yl]acetamide, and
(S)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide, or a salt thereof to a mammal.
4. A method for preventing or treating an autism spectrum disorder
comprising administering an effective amount of
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide or a salt thereof to a mammal.
5-8. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 16/068,553, filed on Jul. 6, 2018, which is a U.S.
National Phase of International Patent Application No.
PCT/JP2017/000166, filed on Jan. 5, 2017, which claims priority to
U.S. Provisional Patent Application No. 62/276,354, filed on Jan.
8, 2016, the contents of each of which is incorporated by reference
herein in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to a medicament containing a
compound possibly having melatonin receptor affinity and expected
to be effective for the prophylaxis or treatment of an autism
spectrum disorder.
BACKGROUND OF THE INVENTION
[0003] Autistic spectrum disorder is said to be one of
neurodevelopmental disorders characterized by the symptoms of
social disorder (e.g., social communication disturbance,
interpersonal mutual reaction disorder and the like), restricted
repetitive modalities (e.g., behavior, interests, activities and
the like) and the like (non-patent document 1). At present, a
treatment method has not been established yet, and improvement of
life has been attempted by prescribing drugs. For example,
antipsychotic drugs are used for preventing aggressive behaviors
and self-injurious behaviors, which are behavioral disorders
associated with autism spectrum disorder. However, it is a
symptomatic treatment and does not aim at permanent cure.
[0004] Therefore, a therapeutic drug effective for an autism
spectrum disorder (particularly, medicament effective for social
disorder) has been awaited at the medical site.
[0005] Non-patent document 2 discloses that ramelteon was
administered to two patients with insomnia accompanied by autism to
confirm a therapeutic effect of ramelteon on sleep disorder, and
evaluates items relating to sleep disorder.
[0006] Patent document 1 discloses a combined use of 5HTR agent and
the like and ramelteon and discloses autism as an application.
[0007] Patent document 2 discloses
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide.
[0008] Non-patent document 3 suggests that the amount of melatonin
decreases in patients with an autistic spectrum disorder and that
ASMT involved in melatonin synthesis in the body is involved.
[0009] Non-patent document 4 discloses the results that melatonin
metabolite (6-SM) in the urine of autism patients decreases during
daytime, in the night and throughout the day, the results that the
amount of urinary 6-SM at night and the severity of autism such as
language ability and the like show a negative correlation, and the
results that the amount of urinary 6-SM during the day and the IQ
score and the like show a positive correlation.
[0010] Non-patent document 5 suggests that melatonin has a
therapeutic effect on sleep disorder in children with insomnia and
sleep disorder accompanied by autism spectrum disorder and
vulnerability X (Fragile X) syndrome.
[0011] Non-patent document 6 reports that there are six tests in
the past in which improvement of day-to-day behavior by nocturnal
administration of melatonin was reported in autistic spectrum
disorder patients, and the like.
DOCUMENT LIST
Patent Documents
[0012] Patent Document 1: WO 2007/134077 [0013] Patent Document 2:
WO 2007/148808
Non-Patent Documents
[0013] [0014] Non-patent Document 1: Diagnostic and Statistical
Manual of Psychiatric disorders, 5.sup.th Edition [DSM-5], p.
50-59. [0015] Non-patent Document 2: Stigler K. A., et al., J.
Child Adolesc. Psychopharmacol. 2006 October; 16(5):631-6. [0016]
Non-patent document 3: Melke J et al., Abnormal melatonin synthesis
in autism spectrum disorders., Mol. Psychiatry. 2008 January;
13(1):90-8. [0017] Non-patent Document 4: Tordjman S, et al., Day
and nighttime excretion of 6-sulphatoxymelatonin in adolescents and
young adults with autistic disorder., Psychoneuroendocrinology.
2012 December; 37(12):1990-7. [0018] Non-patent Document 5:
Wirojanan J et al., The efficacy of melatonin for sleep problems in
children with autism, fragile X syndrome, or autism and fragile X
syndrome., J. Clin. Sleep Med. 2009 Apr. 15; 5(2):145-50. [0019]
Non-patent Document 6: Rossignol D A et al., Melatonin in autism
spectrum disorders: a systematic review and meta-analysis. Dev.
Med. Child Neurol., 2011 September; 53(9):783-92.
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0020] An object of the present invention is to provide a
medicament containing a compound possibly having melatonin receptor
affinity and expected to be effective for the prophylaxis or
treatment of an autism spectrum disorder.
Means of Solving the Problems
[0021] The present inventors have conducted intensive studies and
found that the below-mentioned compound of the present invention
may be effective for the prophylaxis or treatment of an autism
spectrum disorder, which resulted in the completion of the present
invention.
[0022] That is, the present invention relates to:
[1] A prophylactic or therapeutic agent for an autism spectrum
disorder comprising a compound selected from: [0023]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]ac-
etamide, [0024]
N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide,
[0025]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]pr-
opionamide, [0026]
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene-
]ethyl}acetamide, [0027]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]a-
cetamide, [0028]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetami-
de, [0029]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-y-
l)ethyl]acetamide, [0030]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide, [0031]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propion-
amide, [0032]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0033]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0034]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetam-
ide, [0035]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0036]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0037]
N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e, [0038]
(R)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)-
ethyl]acetamide, [0039]
(S)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide, [0040]
N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetam-
ide, [0041]
(R)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide, and [0042]
(S)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide or a salt thereof (sometimes to be abbreviated as "the
compound of the present invention" in the present specification) as
an active ingredient (sometimes to be abbreviated as "the agent of
the present invention" in the present specification). [2] A
prophylactic or therapeutic agent for an autism spectrum disorder
comprising
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide or a salt thereof as an active ingredient. [3] A method for
preventing or treating an autism spectrum disorder comprising
administering an effective amount of a compound selected from:
[0043]
(N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]a-
cetamide, [0044]
N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide,
[0045]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]pr-
opionamide, [0046]
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene-
]ethyl}acetamide, [0047]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]a-
cetamide, [0048]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetami-
de, [0049]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-y-
l)ethyl]acetamide, [0050]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide, [0051]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propion-
amide, [0052]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0053]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0054]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetam-
ide, [0055]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0056]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0057]
N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e, [0058]
(R)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)-
ethyl]acetamide, [0059]
(S)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide, [0060]
N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetam-
ide, [0061]
(R)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide, and [0062]
(S)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide, or a salt thereof to a mammal. [4] A method for
preventing or treating an autism spectrum disorder comprising
administering an effective amount of
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide or a salt thereof to a mammal. [5] A compound selected
from: [0063]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)e-
thyl]acetamide, [0064]
N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide,
[0065]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]pr-
opionamide, [0066]
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene-
]ethyl}acetamide, [0067]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]a-
cetamide, [0068]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetami-
de, [0069]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-y-
l)ethyl]acetamide, [0070]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide, [0071]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propion-
amide, [0072]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0073]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0074]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetam-
ide, [0075]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0076]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0077]
N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e, [0078]
(R)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)-
ethyl]acetamide, [0079]
(S)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide, [0080]
N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetam-
ide, [0081]
(R)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide, and [0082]
(S)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide or a salt thereof for use as a prophylactic or therapeutic
agent for an autism spectrum disorder. [6]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide or a salt thereof for use in the prophylaxis or treatment
of an autism spectrum disorder. [7] Use of a compound selected from
[0083]
(N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]a-
cetamide, [0084]
N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide,
[0085]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]pr-
opionamide, [0086]
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene-
]ethyl}acetamide, [0087]
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]a-
cetamide, [0088]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetami-
de, [0089]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-y-
l)ethyl]acetamide, [0090]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide, [0091]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propion-
amide, [0092]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0093]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pr-
opionamide, [0094]
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetam-
ide, [0095]
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0096]
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]a-
cetamide, [0097]
N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e, [0098]
(R)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)-
ethyl]acetamide, [0099]
(S)--N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide, [0100]
N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetam-
ide, [0101]
(R)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide, and [0102]
(S)--N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]a-
cetamide or a salt thereof in the production of a prophylactic or
therapeutic drug for an autism spectrum disorder. [8] Use of
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide or a salt thereof in the production of a prophylactic or
therapeutic drug for an autism spectrum disorder; and the like.
Effect of the Invention
[0103] According to the present invention, a medicament containing
a compound possibly having melatonin receptor affinity as an active
ingredient and expected to be effective for the prophylaxis or
treatment of an autism spectrum disorder can be provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0104] FIG. 1 is a graph showing the effect of the compound of the
present invention on the social disorders of rat valproic
acid-exposed autism model (Sniffing index and Sniffing time to
cylinder with object (inanimate object) (Sniffing time to
object)).
DETAILED DESCRIPTION OF THE INVENTION
[0105] Of the compounds of the present invention,
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide is preferable.
[0106] As the salt of the compound of the present invention, a
pharmacologically acceptable salt and the like are used. Examples
thereof include salts with inorganic bases, salts with organic
bases, salts with inorganic acids, salts with organic acids, salts
with basic or acidic amino acids and the like. Preferable examples
of the salts with inorganic bases include alkali metal salts such
as sodium salt, potassium salt and the like, alkaline earth metal
salts such as calcium salt, magnesium salt and the like, aluminum
salt, ammonium salt and the like. Preferable examples of the salts
with organic bases include salts with trimethylamine,
triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine,
diethanolamine, triethanolamine, cyclohexylamine,
dicyclohexylamine, N,N'-dibenzylethylenediamine and the like.
Preferable examples of the salts with inorganic acids include salts
with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid, phosphoric acid and the like. Preferable examples of the
salts with organic acids include salts with formic acid, acetic
acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic
acid, tartaric acid, maleic acid, citric acid, succinic acid, malic
acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
acid and the like. Preferable examples of the salts with basic
amino acids include salts with arginine, lysine, ornithine, and the
like and preferable examples of the salts with acidic amino acids
include salts with aspartic acid, glutamic acid and the like.
[0107] Particularly, a pharmaceutically acceptable salt is
preferable. Examples thereof when the compound of the present
invention has a basic functional group include salts with inorganic
acids such as hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid and the like, and salts with organic
acids such as acetic acid, phthalic acid, fumaric acid, tartaric
acid, maleic acid, citric acid, succinic acid, methanesulfonic
acid, p-toluenesulfonic acid and the like. Examples thereof when
the compound of the present invention has an acidic functional
group include alkali metal salts such as sodium salt, potassium
salt and the like, alkaline earth metal salts such as calcium salt,
magnesium salt and the like, ammonium salt and the like.
[0108] The compound of the present invention may be a hydrate or a
non-hydrate.
[0109] The compound of the present invention can be produced
according to a method known per se, for example, the production
method described in WO 2007/148808 filed on Jun. 18, 2007 as a PCT
application and published or a method analogous thereto.
[0110] The compound of the present invention may be a crystal, and
both a single crystal and crystal mixtures are encompassed in the
compound of the present invention. The crystal can be produced by
crystallization by applying a crystallization method known per
se.
[0111] The compound of the present invention or a salt thereof may
be a pharmaceutically acceptable cocrystal or cocrystal salt. Here,
the cocrystal or cocrystal salt means a crystalline substance
consisting of two or more particular substances which are solids at
room temperature, each having different physical properties (e.g.,
structure, melting point, heat of melting, hygroscopicity,
solubility, stability etc.). The cocrystal and cocrystal salt can
be produced by cocrystallization method known per se.
[0112] The compound of the present invention encompasses solvates
(e.g., hydrate) and non-solvates within the scope thereof. The
compound of the present invention may be a compound labeled or
substituted with an isotope (e.g., .sup.2H, .sup.3H, .sup.11C,
.sup.14C .sup.18F, .sup.35S, .sup.125I). A compound labeled with or
substituted by an isotope may be used, for example, as a tracer
used for Positron Emission Tomography (PET) (PET tracer) and may be
useful in the field of medical diagnosis and the like.
[0113] When the compound of the present invention has an asymmetric
center, isomers such as enantiomer, diastereomer and the like may
be present. Such isomers and a mixture thereof are all encompassed
within the scope of the present invention. When an isomer is formed
due to the conformation or tautomerism, such isomers and a mixture
thereof are also encompassed in the compound of the present
invention.
[0114] In the compound of the present invention, stereoisomers may
be generated depending on the kind of the substituent. Such isomers
singly or a mixture thereof are also encompassed in the present
invention.
[0115] The compound of the present invention may be used as a
prodrug. The prodrug of the compound of the present invention means
a compound which can be converted into the compound of the present
invention by reaction with an enzyme, gastric acid, or the like
under physiological conditions in the living body. In other words,
it means a compound which can be converted into the compound of the
present invention by enzymatic oxidation, reduction, hydrolysis or
the like, or a compound which can be converted into the compound of
the present invention by hydrolysis with gastric acid or the
like.
[0116] The compound of the present invention may be useful as a
prophylactic or therapeutic agent for an autism spectrum disorder
[e.g., autism spectrum disorders with social disability (e.g.,
social communication impairments, interpersonal mutual reaction
disorder etc.), autism spectrum disorders with restricted
repetitive patterns (e.g., behavior, interests, activities etc.),
pervasive developmental disorders, autism (e.g., childhood autism,
infantile autism, high functioning autism, childhood psychosis,
Kanner syndrome, atypical autism, etc.), Rett syndrome, Asperger
syndrome (e.g., autistic psychopathy, schizophrenia disorder,
etc.), childhood disintegrative disorder (e.g., infantile dementia,
disintegrative psychosis, Heller's syndrome, symbiotic psychosis,
etc.), Down's syndrome, Kabuki syndrome, fragile Syndrome X
syndrome, Kleefstra syndrome, Rubinstein-Taybi syndrome,
neurofibromatosis type 1 (NF1), Noonan syndrome, tuberous
sclerosis, Coffin-Lowry syndrome, Sotos syndrome, Smith-Magenis
syndrome, Weaver's syndrome, Cornelia de Lange syndrome,
Beckwith-Wiedemann syndrome, Angelman's syndrome, 5p syndrome, 4p
syndrome, 18 trisomy syndrome, 13 trisomy syndrome, chromosomal
abnormality syndrome, CFC syndrome, Marfan syndrome, Costello
syndrome, CHARGE syndrome, Werdnig-Hoffman disease, Dubowitz
disease, Kugelberg-Welander disease, intellectual disability group
(e.g., intellectual disability, global developmental delay, wisdom
delay, intelligence low rank, mental retardation, stupidity,
foolishness, idiocy, intelligence defect etc.), communication
disorders (e.g., language disorder, speech sound disorder,
childhood-onset fluency disorder, social communication disorder
etc.), specific learning disorder, motor disorders (e.g.,
developmental coordination disorder, stereotypic movement disorder
etc.), tic disorder group (e.g., Tourette's disorder, persistent
motor or vocal tic disorder, provisional tic disorder etc.),
learning disorder (e.g., dyslexia, dyscalculia, dysgraphia etc.),
selective mutism, boundary intelligence, autism spectrum disorder
with intellectual disorder, autism spectrum disorder with language
disorder, autism spectrum disorder with tension, other
neurodevelopment, autism spectrum disorder with mental disease or
behavior disorder (e.g., attention deficit/hyperactivity disorder,
coordination disorder, destructive behavior, impulse control
disorder, behavior disorder, anxiety, depression, bipolar disorder,
tic disorder, Tourette disorder, aggressive behavior, self-injury
behavior, eating disorder, excretory disorders, sleeping disorders,
etc.), autism spectrum disorder with epilepsy] in mammals (e.g.,
mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human
and the like).
[0117] The compound of the present invention may have high affinity
for melatonin receptors (MT1 receptor, MT2 receptor). The compound
of the present invention may act as a melatonin agonist and may be
useful as a composition having melatonin receptor affinity,
particularly, a melatonin receptor agonist. Therefore, superior
treatment effects for the above-mentioned diseases can be
expected.
[0118] The compounds having melatonin receptor affinity and
described in the specifications as filed of WO 96/08466 filed on
Sep. 11, 1995 and published, WO 97/01539 filed on Jun. 26, 1996 and
published, WO 97/05098 filed on Jul. 25, 1996 and published, WO
97/32871 filed on Mar. 5, 1997 and published, WO 2008/069311 filed
on Dec. 7, 2007 and published, WO 2008/084717 filed on Dec. 27,
2007 and published, and WO 2008/136382 filed on Apr. 25, 2008 and
published may also be useful for the prophylaxis, improvement of
the symptoms, suppression of progression or treatment of the
diseases described above, specifically, an autism spectrum disorder
and the like.
[0119] Furthermore, a compound represented by the formula:
##STR00002##
wherein
[0120] R.sup.1 is a hydrocarbon group optionally having
substituent(s), amino optionally having substituent(s), hydroxy
optionally having substituent(s) or a heterocyclic group optionally
having substituent(s);
[0121] R.sup.5 is a hydrogen atom, a halogen atom, a hydrocarbon
group optionally having substituent(s), amino optionally having
substituent(s), hydroxy optionally having substituent(s) or
mercapto optionally having substituent(s);
[0122] R.sup.6 is a hydrogen atom or a hydrocarbon group optionally
having substituent(s);
[0123] X is an oxygen atom or a sulfur atom;
[0124] m is 0, 1 or 2;
[0125] ring A is a 5-membered ring optionally having
substituent(s);
[0126] ring B is a 6-membered ring optionally having
substituent(s);
[0127] ring C is a 5-membered ring optionally having
substituent(s); and
is a single bond or a double bond, or a salt thereof (sometimes to
be abbreviated as "compound (I)" in the present specification),
which is described in WO 2007/148808, may also be useful for the
prophylaxis or treatment of an autism spectrum disorder.
[0128] Of compounds (1), a compound represented by the formula:
##STR00003##
wherein:
[0129] R.sup.1 is C.sub.1-6 alkyl optionally having substituent(s),
C.sub.3-6 cycloalkyl optionally having substituent(s) or C.sub.2-6
alkenyl optionally having substituent(s);
[0130] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally
having substituent(s) or a heterocyclic group optionally having
substituent(s);
[0131] R.sup.3 is a hydrogen atom, C.sub.1-6 alkyl optionally
having substituent(s), C.sub.2-6 alkenyl optionally having
substituent(s) or amino optionally having substituent(s);
[0132] R.sup.4a and R.sup.4b are the same or different and each is
a hydrogen atom, a halogen atom, hydroxy optionally having
substituent(s) or C.sub.1-6 alkyl optionally having
substituent(s);
[0133] R.sup.5 is a hydrogen atom or C.sub.1-6 alkyl optionally
having substituent(s); and
[0134] R.sup.6 is a hydrogen atom or C.sub.1-6 alkyl optionally
having substituent(s), or a salt thereof is preferable.
[0135] In the aforementioned formula, the ring represented by:
##STR00004##
[0136] Of compounds (I), particularly a compound represented by the
formula:
##STR00005##
wherein:
[0137] R.sup.1a is (a) C.sub.1-6 alkyl optionally having 1 to 3
substituents selected from C.sub.1-6 alkyl-carbonyloxy, hydroxy and
halogen atom, (b) C.sub.3-6 cycloalkyl, (c) phenyl or (d) mono- or
di-C.sub.1-6 alkylamino;
[0138] R.sup.2a is a hydrogen atom or C.sub.1-6 alkyl;
[0139] R.sup.2b is a hydrogen atom or hydroxy; and
[0140] R.sup.3a is (a) a hydrogen atom, (b) C.sub.1-6 alkyl
optionally having 1 to 3 substituents selected from phenyl,
hydroxy, a halogen atom, C.sub.1-6 alkyl-carbonyl, C.sub.7-13
aralkyloxy and pyridyl, (c) C.sub.3-6 cycloalkyl, (d) phenyl, (e)
C.sub.1-6 alkoxy, (f) mercapto, (g) C.sub.1-6 alkylthio or (h)
mono- or di-C.sub.1-6 alkylamino, or a salt thereof is
preferable.
[0141] In the aforementioned formula, the ring represented by
##STR00006##
[0142] In addition, medicaments such as tasimelteon, agomelatine,
melatonin sustained release preparation, melatonin sustained
release preparation for children and the like may also be useful
for the prophylaxis or treatment of an autism spectrum
disorder.
[0143] The compound of the present invention may have superior
properties as a pharmaceutical product since it can be expected to
be superior in solubility in water, the Japanese Pharmacopoeia
dissolution test 2nd fluid or the Japanese Pharmacopoeia
disintegration test 2nd fluid, can be expected to be superior in
pharmacokinetics (e.g., drug half-life in blood, intracerebral
transferability, metabolic stability, CYP inhibition), can be
expected to have low toxicity (e.g., more superior as medicament in
terms of acute toxicity, chronic toxicity, genetic toxicity,
reproductive toxicity, cardiotoxicity, drug interaction,
carcinogenicity, phototoxicity and the like), can be expected to
show few side effects and the like. Therefore, the compound of the
present invention can be safely administered orally or parenterally
to mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine,
sheep, monkey, human and the like). The "parenteral" includes
intravenous, intramuscular, subcutaneous, intraorgan, intranasal,
intradermal, instillation, intracerebral, intrarectal,
intravaginal, intraperitoneal and intratumor administrations,
administration to the vicinity of tumor, and direct administration
to the lesion.
[0144] The agent of the present invention may take any form of a
solid preparation such as powder, granule, tablet, capsule, orally
disintegrable film or the like, or liquid such as syrup, emulsion,
injection, or the like.
[0145] The agent of the present invention can be produced by a
conventionally used method, for example, blending, kneading,
granulation, tableting, coating, sterilization treatment,
emulsification or the like according to the form thereof. As for
the production of the preparation, for example, each section of the
Japanese Pharmacopoeia preparation General Rules and the like can
be referred to. The agent of the present invention may also be
formulated as a sustained-release preparation containing the active
ingredient and a biodegradable polymer compound. Such
sustained-release preparation can be formulated according to the
method described in JP-A-9-263545.
[0146] In the agent of the present invention, the content of the
compound of the present invention varies depending on the form of
the preparation. It is generally about 0.01-100 wt %, preferably
about 0.1-50 wt %, further preferably about 0.5-20 wt %, as the
amount of the compound of the present invention or a salt thereof
relative to the whole preparation (whole medicament).
[0147] The compound of the present invention may be administered
orally or parenterally as it is or in the form of a solid agent
such as powder, fine granule, granule, tablet, capsule or the like
or a liquid agent such as injection or the like by mixing with an
appropriate pharmacologically acceptable carrier, for example,
excipient (e.g., starch, lactose, sucrose, calcium carbonate,
calcium phosphate, and the like), binder (e.g., starch, gum arabic,
carboxymethylcellulose, hydroxypropylcellulose, crystalline
cellulose, alginic acid, gelatin, polyvinylpyrrolidone, and the
like), lubricant (e.g., stearic acid, magnesium stearate, calcium
stearate, talc, and the like), disintegrant (e.g., calcium
carboxymethylcellulose, talc and the like), diluent (e.g., water
for injection, saline and the like), additive (e.g., stabilizer,
preservative, colorant, flavor, solubilizing agent, emulsifier,
buffering agent, isotonic agent, and the like) as necessary and the
like by a conventional method. When the compound of the present
invention or a salt thereof is formulated as a preparation for
topical administration, it can be directly administered to the
affected parts of an articular disease and the like. In this case,
it is preferable to form an injection. The compound can be
administered as a parenteral agent for topical administration
(e.g., intramuscular injection, subcutaneous injection, organ
injection, injection into joint part, and the like, a solid
preparation such as implant, granule, powder and the like, liquid
such as suspension, and the like, ointment etc.) or the like.
[0148] For example, when an injection is formed, the compound of
the present invention is formulated into an aqueous suspension
together with dispersing agent (e.g., surfactant such as Tween 80,
HCO-60 and the like, polysaccharide such as carboxymethylcellulose,
sodium alginate, hyaluronic acid and the like, polysorbate etc.),
preservative (e.g., methylparaben, propylparaben etc.), isotonic
agent (e.g., sodium chloride, mannitol, sorbitol, glucose etc.),
buffering agent (e.g., calcium carbonate etc.), pH adjuster (e.g.,
sodium phosphate, potassium phosphate etc.) and the like, whereby a
practical preparation for injection can be obtained. Alternatively,
the compound is dispersed together with a vegetable oil such as
sesame oil, corn oil etc., or a mixture thereof with phospholipid
such as lecithin and the like or medium-chain fatty acid
triglyceride (e.g., miglyol 812 etc.) to obtain an oily suspension
to give an injection that can be used in practice.
[0149] The dose of the compound of the present invention varies
depending on the subject of administration, administration route,
target disease, symptom and the like. For example, for oral
administration to an adult, the single dose is generally about
0.01-100 mg/kg body weight, preferably 0.1-50 mg/kg body weight,
further preferably 0.5-20 mg/kg body weight. This amount may be
administered in one to three portions per day.
[0150] The agent of the present invention may be used solely or in
the form of a pharmaceutical composition obtained by mixing with a
pharmacologically acceptable carrier according to a method known
per se (e.g., the method described in the Japanese Pharmacopoeia
etc.) as the production method of a pharmaceutical preparation. The
agent of the present invention may be safely administered as a
pharmaceutical composition, for example, tablet (including
sugar-coated tablet, film-coated tablet, sublingual tablet, orally
disintegrating tablet, buccal and the like), pill, powder, granule,
capsule (including soft capsule, microcapsule), troche, syrup,
liquid, emulsion, suspension, release control preparation (e.g.,
immediate-release preparation, sustained-release preparation,
sustained-release microcapsule), aerosol, film (e.g., orally
disintegrating film, oral mucosa-adhesive film), injection (e.g.,
subcutaneous injection, intravenous injection, intramuscular
injection, intraperitoneal injection), drip infusion, transdermal
absorption type preparation, ointment, lotion, adhesive
preparation, suppository (e.g., rectal suppository, vaginal
suppository), pellet, nasal preparation, pulmonary preparation
(inhalant), eye drop or the like, orally or parenterally (e.g.,
intravenous, intramuscular, subcutaneous, intraorgan, intranasal,
intradermal, instillation, intracerebral, intrarectal, intravaginal
and intraperitoneal administrations, and administration to lesion,
and the like).
[0151] As the aforementioned "pharmacologically acceptable
carrier," various organic or inorganic carriers conventionally used
as preparation materials (starting materials) may be used. For
example, excipient, lubricant, binder and disintegrant and the like
may be used for solid preparations, and solvent, solubilizing
agent, suspending agent, isotonic agent, buffering agent, and
soothing agent and the like may be used for liquid preparations.
Where necessary, preparation additives such as preservative,
antioxidant, colorant, sweetening agent and the like may be
used.
[0152] Examples of the excipient include lactose, white sugar,
D-mannitol, starch, corn starch, crystalline cellulose, light
anhydrous silicic acid and the like.
[0153] Examples of the lubricant include magnesium stearate,
calcium stearate, talc, colloidal silica and the like.
[0154] Examples of the binding agent include crystalline cellulose,
white sugar, D-mannitol, dextrin, hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch,
sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium
and the like.
[0155] Examples of the disintegrant include starch,
carboxymethylcellulose, carboxymethylcellulose calcium,
carboxymethyl starch sodium, L-hydroxypropylcellulose and the
like.
[0156] Examples of the solvent include water for injection,
alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive
oil and the like.
[0157] Examples of the solubilizing agent include polyethylene
glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
sodium citrate and the like.
[0158] Examples of the suspending agent include surfactants such as
stearyl triethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride,
benzetonium chloride, glycerin monostearate and the like;
hydrophilic polymers such as poly(vinyl alcohol),
polyvinylpyrrolidone, carboxymethylcellulose sodium,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and the like; and the like.
[0159] Examples of the isotonic agent include glucose, D-sorbitol,
sodium chloride, glycerin, D-mannitol and the like.
[0160] Examples of the buffering agent include buffer solutions
such as phosphates, acetates, carbonates, citrates and the
like.
[0161] Examples of the soothing agent include benzyl alcohol and
the like.
[0162] Examples of the preservative include parahydroxybenzoates,
chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic
acid, sorbic acid and the like.
[0163] Examples of the antioxidant include sulfites, ascorbic acid,
.alpha.-tocopherol and the like.
[0164] The pharmaceutical composition can be produced according to
a conventional method by adding the compound of the present
invention in a proportion of generally 0.01-100% (w/w), preferably
0.1-95% (w/w), relative to the total amount of the preparation,
though subject to change depending on the dosage form,
administration method, carrier and the like.
[0165] The compound of the present invention can be expected to
have extremely low toxicity, can be used for the prophylaxis or
treatment of an autism spectrum disorder by combining with other
medicament, and can be expected to show a superior prophylactic or
therapeutic effect by such combined use with said other medicament.
It can also be expected to reduce side effects of other
prophylactic or therapeutic agents for an autism spectrum disorder
by reducing the dose thereof by such combination therapy.
[0166] As such medicaments that can be used in combination with the
compound of the present invention (hereinafter to be abbreviated as
concomitant drug), for example, "other prophylactic or therapeutic
agents for an autism spectrum disorder" (e.g., serotonin-dopamine
antagonist (risperidone, olanzapine, quetiapine, clozapine,
ziprasidone and the like), dopamine partial agonist (aripiprazole
and the like) and the like) can be mentioned.
[0167] In the following, combined use of the compound of the
present invention and a concomitant drug is indicated by "the
combination agent of the present invention."
[0168] Two or more kinds of the above-mentioned concomitant drugs
may be used in combination at an appropriately ratio.
[0169] When the compound of the present invention is used in
combination with concomitant drugs, the amounts of the drugs may be
decreased within a safe range in consideration of the counter
effect of the drugs. Therefore, the counter effect presumably
induced by these drugs can be prevented safely.
[0170] The compound of the present invention may be used in
combination with a non-drug therapy. Specific examples of the
non-drug therapy include (1) surgery; (2) pressurized chemotherapy
using angiotensin II and the like; (3) gene therapy; (4)
hyperthermia therapy; (5) cryotherapy; (6) laser ablation method;
(7) radiation therapy; (8) immunotherapy; (9) regenerative therapy;
(10) cell therapy method; (11) psychotherapy or psychosocial
therapy.
[0171] These concomitant drugs may be free forms or
pharmaceutically acceptable salts. Examples of such salt when the
drug has an acidic functional group include inorganic salts such as
alkali metal salt (e.g., sodium salt, potassium salt and the like),
alkaline earth metal salt (e.g., calcium salt, magnesium salt,
barium salt and the like) and the like, ammonium salt and the like.
Examples thereof when the drug has a basic functional group include
salts with inorganic acids such as hydrochloric acid, hydrobromic
acid, nitric acid, sulfuric acid, phosphoric acid and the like, and
salts with organic acids such as acetic acid, phthalic acid,
fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,
succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the
like. The concomitant drugs exemplified here can be easily obtained
as commercially available products or can be produced according to
a known method.
[0172] When the compound of the present invention and a concomitant
drug are used in combination, examples of the administration mode
include the following: [0173] (1) administration of a single
preparation obtained by simultaneously processing the compound of
the present invention and the concomitant drug; [0174] (2)
simultaneous administration of two kinds of preparations of the
compound of the present invention and the concomitant drug, which
have been separately produced, by the same administration route;
[0175] (3) administration of two kinds of preparations of the
compound of the present invention and the concomitant drug, which
have been separately produced, by the same administration route in
a staggered manner; [0176] (4) simultaneous administration of two
kinds of preparations of the compound of the present invention and
the concomitant drug, which have been separately produced, by
different administration routes; [0177] (5) administration of two
kinds of preparations of the compound of the present invention and
the concomitant drug, which have been separately produced, by
different administration routes in a staggered manner (e.g.,
administration in the order of the compound of the present
invention; the concomitant drug, or in the reverse order) and the
like.
[0178] From the aspect of convenience of the patients,
administration of a single preparation obtained by simultaneously
processing the compound of the present invention and the
concomitant drug is a particularly preferable embodiment.
[0179] The dose of the concomitant drug may be appropriately
selected using the clinically used dose as the standard. In
addition, the mixing ratio of the compound of the present invention
and the concomitant drugs may be appropriately selected according
to the subject of administration, administration route, symptom,
the kind of the concomitant drug used and the like. Generally, it
may be determined using the general dose of the concomitant drug
used as the standard. When the subject of administration is human,
for example, 0.01-100 parts by weight of the concomitant drug is
used per part by weight of the compound of the present
invention.
[0180] The combination agent in the present invention may be used
as a pharmaceutical composition, like the agent of the present
invention, which is obtained by mixing the compound of the present
invention or(and) the above-mentioned concomitant drug is mixed
with a pharmacologically acceptable carrier.
[0181] The mixing ratio of the compound of the present invention
and a concomitant drug in the combination agent of the present
invention may be appropriately selected based on the subject of
administration, administration route, target disease, symptom,
combination and the like.
[0182] For example, while the content of the compound of the
present invention in the combination agent of the present invention
varies depending on the preparation form, it is generally about
0.01 to about 100 wt %, preferably about 0.1 to about 50 wt %, more
preferably about 0.5 to about 20 wt %, of the whole
preparation.
[0183] The content of the concomitant drug in the combination agent
of the present invention varies depending on the preparation form,
and generally about 0.01 to about 100 wt %, preferably about 0.1 to
about 50 wt %, further preferably about 0.5 to about 20 wt %, of
the whole preparation.
[0184] While the content of the additive such as a carrier and the
like in the combination agent of the present invention varies
depending on the form of a preparation, it is generally about 1 to
about 99.99 wt %, preferably about 10 to about 90 wt %, based on
the whole preparation.
[0185] When the compound of the present invention and the
concomitant drug are separately prepared, the contents thereof are
the same as above.
EXAMPLES
[0186] While the present invention is explained in detail by
further referring to the following Production Examples, Examples
and Preparation Example, they are mere Production Examples,
Examples and Preparation Example and do not limit the present
invention.
[0187] The compounds in the following Production Examples can be
produced by a method known per se, for example, Reference Examples
and Examples described in WO 2007/148808 filed on Jun. 18, 2007 as
a PCT application and published or a method analogous thereto.
[0188] In the following Examples and Preparation Example,
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ac-
etamide (compound of Production Example 12) is compound A.
Production Example 1
N-[2-(6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide
##STR00007##
[0189] Production Example 2
N-[2-(6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]propionamide
##STR00008##
[0190] Production Example 3
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]ace-
tamide
##STR00009##
[0191] Production Example 4
N-[2-(2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide
##STR00010##
[0192] Production Example 5
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]pro-
pionamide
##STR00011##
[0193] Production Example 6
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene]-
ethyl}acetamide
##STR00012##
[0194] Production Example 7
N-{2-[2-(4-phenylbutyl)-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene]-
ethyl}propionamide
##STR00013##
[0195] Production Example 8
N-[2-(2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]thiazol-8-ylidene)ethyl]ac-
etamide
##STR00014##
[0196] Production Example 9
N-[2-(7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide
##STR00015##
[0197] Production Example 10
N-[2-(7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propionamide
##STR00016##
[0198] Production Example 11
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e
##STR00017##
[0199] Production Example 12
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide
##STR00018##
[0200] Production Example 13
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide
##STR00019##
[0201] Production Example 14
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]propiona-
mide
##STR00020##
[0202] Production Example 15
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pro-
pionamide
##STR00021##
[0203] Production Example 16
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]pro-
pionamide
##STR00022##
[0204] Production Example 17
N-{2-[2-(4-phenylbutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl-
}acetamide
##STR00023##
[0205] Production Example 18
N-{2-[2-(4-phenylbutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl-
}propionamide
##STR00024##
[0206] Production Example 19
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetami-
de
##STR00025##
[0207] Production Example 20
(S)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]ac-
etamide
##STR00026##
[0208] Production Example 21
(R)--N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]ac-
etamide
##STR00027##
[0209] Production Example 22
N-[2-(2-ethyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide
##STR00028##
[0210] Production Example 23
N-{2-[2-(hydroxymethyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl-
}acetamide
##STR00029##
[0211] Production Example 24
N-[2-(2-isopropyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]aceta-
mide
##STR00030##
[0212] Production Example 25
N-{2-[2-(trifluoromethyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]eth-
yl}acetamide
##STR00031##
[0213] Production Example 26
N-{2-[2-(4-hydroxybutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethy-
l}acetamide
##STR00032##
[0214] Production Example 27
N-{2-[2-(3-hydroxybutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethy-
l}acetamide
##STR00033##
[0215] Production Example 28
N-{2-[2-(3-oxobutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl}ac-
etamide
##STR00034##
[0216] Production Example 29
N-[2-(2-cyclopropyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]ace-
tamide
##STR00035##
[0217] Production Example 30
N-[2-(2-phenyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e
##STR00036##
[0218] Production Example 31
N-[2-(2-benzyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e
##STR00037##
[0219] Production Example 32
N-{2-[2-(2-phenylethyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl-
}acetamide
##STR00038##
[0220] Production Example 33
N-{2-[2-(3-phenylpropyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethy-
l}acetamide
##STR00039##
[0221] Production Example 34
N-(2-{2-[(benzyloxy)methyl]-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl}e-
thyl)acetamide
##STR00040##
[0222] Production Example 35
N-(2-{2-[4-(benzyloxy)butyl]-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl}-
ethyl)acetamide
##STR00041##
[0223] Production Example 36
N-(2-{2-[3-(benzyloxy)butyl]-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl}-
ethyl)acetamide
##STR00042##
[0224] Production Example 37
N-{2-[2-(4-pyridin-2-ylbutyl)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl-
]ethyl}acetamide
##STR00043##
[0225] Production Example 38
N-[2-(2-methoxy-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetami-
de
##STR00044##
[0226] Production Example 39
N-{2-[2-(methylthio)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl}ac-
etamide
##STR00045##
[0227] Production Example 40
N-{2-[2-(dimethylamino)-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl]ethyl-
}acetamide
##STR00046##
[0228] Production Example 41
1-methyl-2-{[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethy-
l]amino}-2-oxoethyl acetate
##STR00047##
[0229] Production Example 42
2-hydroxy-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethy-
l]propanamide
##STR00048##
[0230] Production Example 43
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]cyclopro-
panecarboxamide
##STR00049##
[0231] Production Example 44
N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]benzamid-
e
##STR00050##
[0232] Production Example 45
2,2,2-trifluoro-N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-y-
l)ethyl]acetamide
##STR00051##
[0233] Production Example 46
1-ethyl-3-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]-
urea
##STR00052##
[0234] Production Example 47
N-[2-(2-mercapto-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetam-
ide
##STR00053##
[0235] Production Example 48
N-[2-(8-hydroxy-7-isopropyl-2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxaz-
ol-8-yl)ethyl]acetamide
##STR00054##
[0236] Production Example 49
N-[2-(7-isopropyl-2-methyl-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamid-
e
##STR00055##
[0237] Example 1
Effect of the Compound of the Present Invention on Social Disorders
in Rat Valproic Acid-Exposed Autism Model
[0238] Rat embryonic valproic acid-exposed autism model was used
for the test. Sodium valproate (VPA) 500 mg/kg (mpk) was
intraperitoneally administered to Sprague-Dawley pregnant rats on
the 12.5th day in the embryonic stage. The offspring was weaned on
the 21st day after birth, and only the male rat was used for the
experiment. Compound A (0.2 or 1 mg/kg) was orally administered
once a day at 18 o'clock for 14 days from 3 weeks of age after
weaning and a behavioral test was conducted at 5 weeks of age. As
unknown rat (Stranger rat), a purchased male rat of the same strain
and the same week of age was used with no contact with the rat to
be tested (test rat) until the day of the test.
[0239] In the experiment, a black plastic 3 chamber experimental
apparatus (90.times.60.times.34 cm, each chamber
30.times.60.times.34 cm) was used. The partition of each chamber
was made of transparent plastic, with an opening of 10.times.12 cm
at the bottom, through which the rats were allowed to freely move
between compartments. One transparent acrylic cylinder (diameter 12
cm, height 25 cm, holes (diameter 1.5 cm) on the side at equal
intervals, with black hemispherical metal lid) was installed in the
left and right compartments in the experimental apparatus, thereby
inhibiting direct contact with the unknown rat.
[0240] On the day of the test, the rats to be tested and unknown
rats were acclimated to the test environment for 1 hour or more and
then the test was started. In the 3-chamber apparatus, a
transparent partition plate with no opening was placed to prevent
entry into the left and right compartments and the test rats were
put in the central compartment for 5 min. After 5 min, the unknown
rat was put in one cylinder and an object (white sphere) was put in
the other cylinder. The transparent partition plate without opening
was gently removed so that the test rats can freely come and go
between the left and right compartments. The sniffing to each
cylinder (action of sniffing an object or an animal) was visually
measured for 10 min. A sniffing index, which is an indicator of
interest to other animal, was calculated by the following formula
based on the sniffing time to each cylinder for 10 min. The results
are shown in FIG. 1.
Sniffing index=((sniffing time (sec) to cylinder with unknown
rat)-(sniffing time (sec) to cylinder with object)/((sniffing time
(sec) to cylinder with unknown rat))+(sniffing time (sec) to
cylinder with object))
[0241] In a Sociability test, embryonic valproic acid-exposed rat
showed a significant (***P<0.001) decrease in Sniffing Index,
which is an indicator of an interest in other animal and a
significant (**P<0.01) increase in sniffing time to cylinder
containing object (inanimate object) as compared to the control,
based on which asocial disorder was acknowledged. In contrast,
chronic administration of compound A (0.2 or 1 mg/kg) showed a
significant (#P<0.025) improvement effect on social
performance.
[0242] Chronic administration of compound A showed effectiveness on
the social disorder of the embryonic rat valproic acid-exposed
autism model.
Preparation Example 1
[0243] Compound A (160 g), lactose (4064 g), and cornstarch (640 g)
were uniformly mixed in a fluid bed dryer granulator, and the
mixture was granulated while spraying an aqueous solution of
hydroxypropylcellulose (160 g) therein and dried therein. The
obtained granulated product was crushed using a power mill with a
1.5 mm.phi. punching screen to give a sieved powder. The sieved
powder (3894 g) was measured, cornstarch (124 g) and magnesium
stearate (12.4 g) were added thereto, and they were mixed to give
granules for tableting. The granules were tableted by a tableting
machine with a 7.0 mm.phi. pounder to a weight of 130 mg to give
uncoated tablets. A solution of titanium oxide, yellow ferric oxide
dispersed in hydroxypropylmethylcellulose 2910, copolyvidone was
sprayed on the obtained uncoated tablets in the film coating
machine to give about 25000 film-coated tablets containing 4 mg of
compound A per tablet and having the formulation shown in Table
1.
TABLE-US-00001 TABLE 1 Composition Amount (mg) Compound A 4.0
lactose 101.6 cornstarch 20.0 hydroxypropylcellulose 4.0 magnesium
stearate 0.4 Uncoated tablet 130.0 hydroxypropylmethylcellulose
2910 3.74 copolyvidone 0.75 titanium oxide 0.5 yellow ferric oxide
0.01 Total 135.0
INDUSTRIAL APPLICABILITY
[0244] According to the present invention, a medicament containing
a compound possibly having melatonin receptor affinity as an active
ingredient and expected to be effective for the prophylaxis or
treatment of an autism spectrum disorder can be provided.
* * * * *