U.S. patent application number 16/464228 was filed with the patent office on 2019-11-21 for piperidine-2,6-dione derivatives and crohn's disease treating.
The applicant listed for this patent is TIANJIN HEMAY BIO-TECH CO., LTD.. Invention is credited to Guanghuai ZENG, Hesheng ZHANG.
Application Number | 20190352277 16/464228 |
Document ID | / |
Family ID | 62194806 |
Filed Date | 2019-11-21 |
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United States Patent
Application |
20190352277 |
Kind Code |
A1 |
ZHANG; Hesheng ; et
al. |
November 21, 2019 |
PIPERIDINE-2,6-DIONE DERIVATIVES AND CROHN'S DISEASE TREATING
Abstract
Disclosed are piperidine-2,6-dione derivatives and treatment of
Crohn's disease.
Inventors: |
ZHANG; Hesheng; (Tianjin,
CN) ; ZENG; Guanghuai; (Tianjin, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TIANJIN HEMAY BIO-TECH CO., LTD. |
Tianjin |
|
CN |
|
|
Family ID: |
62194806 |
Appl. No.: |
16/464228 |
Filed: |
November 23, 2017 |
PCT Filed: |
November 23, 2017 |
PCT NO: |
PCT/CN2017/112669 |
371 Date: |
May 24, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/00 20180101; A61K
31/454 20130101; A61K 9/2018 20130101; A61P 1/04 20180101; A61K
9/08 20130101; A61K 9/4891 20130101; C07D 209/48 20130101; A61P
37/00 20180101; C07D 211/88 20130101; C07D 401/04 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; A61P 1/00 20060101 A61P001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 24, 2016 |
CN |
201611041317.5 |
Claims
1. A piperidine-2,6-dione derivative of formula (I) and
pharmaceutically acceptable salts thereof: ##STR00014## wherein,
R.sub.1 represents one or more substituents selected from the group
consisting of --H, halogen, --OH, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl; R.sub.2 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and R.sub.3 represents --H or
--C.sub.1-4alkyl.
2. The piperidine-2,6-dione derivative of formula (I) and
pharmaceutically acceptable salts thereof of claim 1: ##STR00015##
wherein, R.sub.1 represents one or more substituents selected from
the group consisting of --H, --F, --Cl, --Br, --OH, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --NHCH.sub.3,
--NH.sub.2, --NHCH.sub.2CH.sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3 and
--NHCOCH.sub.2CH.sub.3; R.sub.2 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and R.sub.3 represents --H,
--CH.sub.3 or --CH.sub.2CH.sub.3.
3. The piperidine-2,6-dione derivative of formula (I) and
pharmaceutically acceptable salts thereof of claim 1: ##STR00016##
wherein, R.sub.1 represents one or more substituents selected from
the group consisting of --H, --F, --OH, --CH.sub.3, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHCOCH.sub.3 and --NH.sub.2; R.sub.2
represents --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and R.sub.3 represents --H,
--CH.sub.3 or --CH.sub.2CH.sub.3.
4. The piperidine-2,6-dione derivative of formula (I) and
pharmaceutically acceptable salts thereof of claim 1, which are
selected from the group consisting of: ##STR00017##
4-acetylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof;
4-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof,
4-dimethylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin--
1,3-dione and pharmaceutically acceptable salts thereof,
4-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof,
4,5,6,7-tetrafluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindo-
lin-1,3-dione and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof,
5-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof,
4-amino-5-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof,
4-amino-5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof,
4-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof,
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof,
4-fluoro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
5-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
and pharmaceutically acceptable salts thereof,
4-fluoro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof,
5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-methoxybutyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof,
4-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
4-methyl-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
4-amino-5-methoxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof, and
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof.
5. A piperidine-2,6-dione derivative of formula (II) and
pharmaceutically acceptable salts thereof: ##STR00018## wherein,
R.sub.4 represents one or more substituents selected from the group
consisting of H, halogen, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl; R.sub.5 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; R.sub.6 represents --S--,
--SO--, --SO.sub.2--, --NH-- or --N(C.sub.1-4alkyl)-; and R.sub.7
represents --H or --C.sub.1-4alkyl.
6. The piperidine-2,6-dione derivative of formula (II) and
pharmaceutically acceptable salts thereof of claim 5: ##STR00019##
wherein, R.sub.4 represents one or more substituents selected from
the group consisting of --H, --F, --Cl, --Br, --OH, --CH.sub.3,
--NHCH.sub.3, --NHCH.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3
and --NHCOCH.sub.2CH.sub.3; R.sub.5 represents
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; R.sub.6 represents --S--,
--SO--, --SO.sub.2--, --NH-- or --N(CH.sub.3)--; and R.sub.7
represents --H, --CH.sub.3 or --CH.sub.2CH.sub.3.
7. The piperidine-2,6-dione derivative of formula (II) and
pharmaceutically acceptable salts thereof of claim 5: ##STR00020##
wherein, R.sub.4 represents --NH.sub.2 or --NHCOCH.sub.3; R.sub.5
represents --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; R.sub.6 represents --S--,
--SO--, --SO.sub.2--, --NH-- or --N(CH.sub.3)--; and R.sub.7
represents --H, --CH.sub.3 or --CH.sub.2CH.sub.3.
8. The piperidine-2,6-dione derivative of formula (II) and
pharmaceutically acceptable salts thereof of claim 5, which are
selected from the group consisting of: ##STR00021##
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-d-
ione and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-methylsulfinylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, and
4-amino-2-(1-(2-methylsulfonylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof.
9. A piperidine-2,6-dione derivative of formula (III) and
pharmaceutically acceptable salts thereof: ##STR00022## wherein,
R.sub.8 represents one or more substituents selected from the group
consisting of H, halogen, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl; R.sub.9 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; R.sub.10 represents --O--,
--S--, --SO--, --SO.sub.2--, --NH-- or --N(C.sub.1-4alkyl)-;
R.sub.11 represents --H or --C.sub.1-4alkyl; and R.sub.12
represents halogen or --C.sub.1-4alkyl.
10. The piperidine-2,6-dione derivative of formula (III) and
pharmaceutically acceptable salts thereof of claim 9: ##STR00023##
wherein, R.sub.8 represents one or more substituents selected from
the group consisting of --H, --F, --Cl, --Br, --OH, --CH.sub.3,
--NHCH.sub.3, --NHCH.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3
and --NHCOCH.sub.2CH.sub.3; R.sub.9 represents
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; R.sub.10 represents --O--,
--S--, --SO--, --SH-- or --N(CH.sub.3)--; R.sub.11 represents --H,
--CH.sub.3 or --CH.sub.2CH.sub.3; and R.sub.12 represents halogen
or --C.sub.1-4alkyl.
11. The piperidine-2,6-dione derivative of formula (III) and
pharmaceutically acceptable salts thereof of claim 9: ##STR00024##
wherein, R.sub.8 represents --NH.sub.2 or --NHCOCH.sub.3; R.sub.9
represents --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; R.sub.10 represents --O--,
--S--, --SO--, --SO.sub.2--, --NH-- or --N(CH.sub.3)--; R.sub.11
represents --H, --CH.sub.3 or --CH.sub.2CH.sub.3; and R.sub.12
represents halogen or --C.sub.1-4alkyl.
12. The piperidine-2,6-dione derivative of formula (III) and
pharmaceutically acceptable salts thereof of claim 9, which are
selected from the group consisting of:
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof; and
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof.
13. A piperidine-2,6-dione derivative and pharmaceutically
acceptable salts thereof, which are selected from the group
consisting of:
4-acetylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof;
4-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof;
4-dimethylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin--
1,3-dione and pharmaceutically acceptable salts thereof;
4-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof;
4,5,6,7-tetrafluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindo-
lin-1,3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof;
5-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof;
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof;
4-amino-5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof;
4-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-d-
ione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methylsulfinylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methylsulfonylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-dimethylaminoethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof;
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof;
4-fluoro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof;
5-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof;
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
and pharmaceutically acceptable salts thereof;
4-fluoro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof;
5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-methoxybutyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof,
4-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
4-methyl-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof,
4-amino-5-methoxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione and pharmaceutically acceptable salts thereof,
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, and
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition comprising the
piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof of claim 1, and a pharmaceutically acceptable
carrier, diluent or excipient.
15. A method for treating Crohn's disease, comprising administering
a therapeutically effective amount of the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof of claim
1.
16. The method of claim 15, wherein the Crohn's disease is mild
Crohn's disease, moderate Crohn's disease, severe Crohn's disease
or Crohn's disease in remission.
17. The method of claim 15, wherein the subject is human.
18. The method of claim 15, wherein the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof is
administered orally.
19. The method of claim 18, wherein the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof is
administered orally in a solid or liquid formulation.
20. The method of claim 19, wherein the solid formulation is a
tablet, capsule or sugar-coated pill.
21. The method of claim 20, wherein the tablet is a plain tablet,
sugar-coated tablet or film-coated tablet.
22. The method of claim 19, wherein the liquid formulation is a
solution or suspension.
23-24. (canceled)
Description
RELATED APPLICATION
[0001] The present disclosure claims all the benefits of the patent
application No. 201611041317.5 which was filed on Nov. 24, 2016
before the State Intellectual Property Office of the People's
Republic of China and was entitled "Use of Piperidine-2,6-dione
Derivatives for Treating Ulcerative Colitis", which is incorporated
herein by reference in its entirety.
FIELD
[0002] The present disclosure relates to organic chemistry and
medicinal chemistry fields.
BACKGROUND
[0003] Crohn's disease is a chronic inflammatory autoimmune disease
of the gastrointestinal tract (GI). Crohn's disease can affect any
part of the digestive tract from the mouth to the anus. Under the
microscope, Crohn's disease affects the entire intestinal wall
(transmural injury). Chronic inflammation can cause fibrosis in the
subgroup of patients with Crohn's disease, who have the
complications including stenosis and fistula, and possibly need
repeated surgery. Crohn's disease is associated with increased risk
of gastrointestinal malignant tumour. It is found by the study on
Crohn's disease that Crohn's disease is associated with TH1 (type 1
T helper cell) and TH17 (type 17 T helper cell) mediated cellular
immunity.
[0004] The clinical manifestations of Crohn's disease are various
and include gastrointestinal manifestations, systemic
manifestations, parenteral manifestations, and complications.
Gastrointestinal manifestations mainly include diarrhea, abdominal
pain, and bloody stool. Systemic manifestations mainly include
weight loss, fever, loss of appetite, fatigue, anemia, and the
like. Growth retardation is commonly found in adolescent patients.
Common complications include fistula, abdominal abscess, intestinal
stenosis, obstruction and perianal lesions. Gastrointestinal
bleeding and acute perforation are rare. The long course of disease
can lead to cancer. Colonoscopy is generally manifested as
segmental and asymmetric various mucosal inflammation, which has
the characterized manifestation of non-continuous lesions,
longitudinal ulcers and pebble-like appearance. The
histopathological changes of Crohn's disease mucosal biopsy samples
include: (1) focal discontinuous infiltration of intrinsic membrane
inflammatory cells; (2) fissuring ulcers; (3) aphthous ulcers; (4)
abnormal crypt structure, glandular hyperplasia, individual crypt
abscess, non-obvious reduction of mucus secretion, visible pyloric
metaplasia or Paneth cell metaplasia; (5) non-cheese-like necrotic
granuloma; (6) chronic inflammatory cell infiltration of
lymphocytes and plasma cells, in which the inflammation at the
bottom of lamina propria and submucosal layer is severe, and
formation of lymph follicle is common; and (7) submucosal lymphatic
dilatation; and (8) ganglion cell proliferation and/or ganglion
inflammation.
[0005] Mildly active Crohn's disease is treated mainly with
5-aminosalicylic acids and budesonide. If the above treatment is
ineffective, Crohn's disease is considered as moderately active.
Moderately active Crohn's disease is preferably treated with
hormone (such as dexamethasone). If the above treatment is
ineffective or becomes dependent, combination with thioglycine or
methotrexate will be considered. TNF-.alpha. monoclonal antibody
can be used if the above hormone therapy and immunotherapy are
ineffective or intolerable. Severely active Crohn's disease is
treated mainly with systemic hormones, TNF-.alpha. monoclonal
antibodies and surgery. Drugs for maintenance treatment for Crohn's
disease in remission include 5-aminosalicylic acids, thioglycines
and TNF-.alpha. monoclonal antibodies.
[0006] It is found during the use of 5-aminosalicylic acid drugs
(such as sulfasalazine and mesalazine) that about 50% of patients
suffer vomiting, anepithymia, liver dysfunction and other digestive
disorders, hemolytic anemia and folic acid deficiency anemia and
other blood disorders. In addition, since there is a salicylic acid
skeleton, there is a possibility that side effects such as
diarrhea, abdominal pain, amylase rise, and renal dysfunction occur
in cases where the patients have allergic symptoms on salicylic
acid agents. Furthermore, because it is discovered that
sulfasalazine has side effects of male infertility and colored
urine, the patients suffer great mental stress. Due to
immunosuppression and short-term efficacy characteristics,
budesonide or azathiopurine can also be used, but only in a short
term. When the patients are not administered with the biological
agents, it will lead to the recurrence of the disease and increase
difficulty to treat the disease. Moreover, the biological agents
will also give patients a greater financial burden. Monoclonal
antibody drugs (such as infliximab and adalimumab) may cause high
blood pressure, chills, rash, fever, headache, eczema and so on. As
infliximab is a chimeric antibody, it is possible to show
antigenicity and sometimes cause acute hypersensitivity.
[0007] Small molecule TNF-.alpha. inhibitors such as lenalidomide
and thalidomide have been shown to be not effective in the
treatment of Crohn's disease (C. Yang et, Aliment Pharmacol Ther
2015; 41:1079-7093.).
[0008] Moreover, Crohn's disease is a chronic disease that requires
a longer duration of drugs. The above data show that there is no
drug for long-term effective treatment of Crohn's disease,
especially drug by oral administration. Therefore, there is a need
for developing better target therapy with optimized chronic use for
Crohn's disease, or drugs with better effectiveness or better
safety.
SUMMARY
[0009] Dinitrobenzene sulfonic acid (DNBS) or trinitrobenzene
sulfonic acid (TNBS)-induced inflammatory models are widely used to
study the mechanism of production of Crohn's disease and the
development and assessment of drugs for treating Crohn's disease.
See the following reference: Establishment of Inflammatory Bowel
Disease Models Induced by 2,4,6-Trinitrobenzenesulfonic, J. Med.
Res., July 2008, Vol. 37, No. 7, which are incorporated herein by
reference in its entirety.
[0010] Small molecular TNF-.alpha. inhibitors such as lenalidomide
and thalidomide have been shown to be not effective in the
treatment of Crohn's disease (C. Yang et, Aliment Pharmacol Ther
2015; 41:1079-7093.).
[0011] In one aspect, some embodiments disclose a
piperidine-2,6-dione derivative of formula (I) and pharmaceutically
acceptable salts thereof:
##STR00001##
[0012] wherein,
[0013] R.sub.1 represents one or more substituents selected from
the group consisting of H, halogen, --OH, --C.sub.1-4alkyl,
--NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl;
[0014] R.sub.2 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and
[0015] R.sub.3 represents --H or --C.sub.1-4alkyl.
[0016] In another aspect, some embodiments disclose a
piperidine-2,6-dione derivative of formula (II) and
pharmaceutically acceptable salts thereof:
##STR00002##
[0017] wherein,
[0018] R.sub.4 represents one or more substituents selected from
the group consisting of H, halogen, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl;
[0019] R.sub.5 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0020] R.sub.6 represents --S--, --SO--, --SO.sub.2--, --NH-- or
--N(C.sub.1-4alkyl)-; and
[0021] R.sub.7 represents --H or --C.sub.1-4alkyl.
[0022] In yet another aspect, some embodiments disclose a
piperidine-2,6-dione derivative of formula (III) and
pharmaceutically acceptable salts thereof:
##STR00003##
[0023] wherein,
[0024] R.sub.8 represents one or more substituents selected from
the group consisting of H, halogen, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl;
[0025] R.sub.9 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0026] R.sub.10 represents --O--, --S--, --SO--, --SO.sub.2--,
--NH-- or --N(C.sub.1-4alkyl)-;
[0027] R.sub.11 represents --H or --C.sub.1-4alkyl; and
[0028] R.sub.12 represents halogen or --C.sub.1-4alkyl.
[0029] All the compounds of formula (I), formula (II) and formula
(III) as mentioned above belong to piperidine-2,6-dione derivatives
as mentioned herein.
[0030] In still another aspect, some embodiments disclose a
piperidine-2,6-dione derivative and pharmaceutically acceptable
salts thereof, which are selected from the group consisting of:
[0031]
4-acetylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof; [0032]
4-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof; [0033]
4-dimethylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindol
in-1,3-dione and pharmaceutically acceptable salts thereof; [0034]
4-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof; [0035]
4,5,6,7-tetrafluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindo-
lin-1,3-dione and pharmaceutically acceptable salts thereof; [0036]
4-amino-2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof; [0037]
5-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof; [0038]
4-amino-5-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof; [0039]
4-amino-5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindol
in-1,3-dione and pharmaceutically acceptable salts thereof; [0040]
4-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof; [0041]
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-d-
ione and pharmaceutically acceptable salts thereof; [0042]
4-amino-2-(1-(2-methyl
sulfinylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione and
pharmaceutically acceptable salts thereof, [0043]
4-amino-2-(1-(2-methylsulfonylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, [0044]
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindol
in-1,3-dione and pharmaceutically acceptable salts thereof, [0045]
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof, [0046]
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, [0047]
4-fluoro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0048]
5-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof, [0049]
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
and pharmaceutically acceptable salts thereof, [0050]
4-fluoro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0051]
5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0052]
4-amino-2-(1-(2-methoxybutyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0053]
4-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0054]
4-methyl-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0055]
4-amino-5-methoxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione and pharmaceutically acceptable salts thereof, [0056]
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, and [0057]
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof.
[0058] In another aspect, some embodiments disclose a
pharmaceutical composition comprising the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein, and a pharmaceutically acceptable carrier,
diluent or excipient.
[0059] In another aspect, some embodiments disclose a method for
treating Crohn's disease, comprising administering a
therapeutically effective amount of the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein, or a therapeutically effective amount of the
pharmaceutical composition as disclosed herein to a subject in need
thereof.
[0060] In another aspect, some embodiments disclose the
piperidine-2,6-dione derivative and pharmaceutically acceptable
salts thereof of as disclosed herein for treating Crohn's
disease.
[0061] In another aspect, some embodiments disclose a
pharmaceutical composition for treating Crohn's disease, comprising
the piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof as disclosed herein, and a pharmaceutically
acceptable carrier, diluent or excipient.
DETAILED DESCRIPTION
[0062] In the following description, certain specific details are
included to provide a thorough understanding for various disclosed
embodiments. One skilled in the relevant art, however, will
recognize that the embodiments may be practiced without one or more
these specific details, or with other methods, components,
materials, etc.
[0063] Unless the context required otherwise, throughout the
specification and claims which follows, the term "comprise" and
variations thereof, such as "comprises" and "comprising" are to be
construed in an open, inclusive sense, which is as "include, but
not limited to".
[0064] Reference throughout this specification to "one embodiment",
or "an embodiment", or "in another embodiment", or "in some
embodiments" means that a particular referent feature, structure or
characteristic described in connection with the embodiments is
included in at least one embodiment. Therefore, the appearance of
the phrases "in one embodiment", or "in the embodiment", or "in
another embodiment", or "in some embodiments" in various places
throughout this specification are not necessarily all referring to
the same embodiment. Moreover, the particular features, structures
or characteristics may be combined in any suitable manner in one or
more embodiments.
Definition
[0065] Accordingly, as used in the specification and appended
claims, unless specified to the contrary, the following terms have
the meanings indicated:
[0066] The term "Crohn's disease" is a nonspecific inflammatory
disease, of which the etiology is not yet clear. The more specific
definition can be found in the following reference: Consensus on
diagnosis and treatment of inflammatory bowel disease (2012,
Guangzhou), Chinese Journal of Gastroenterology, 2012, 51
(12):763-781, which is incorporated herein by reference in its
entirety.
[0067] According to the severity of disease, Crohn's disease can be
mild Crohn's disease, moderate Crohn's disease, or severe Crohn's
disease. According to the activity of disease, Crohn's disease can
be divided into active Crohn's disease or Crohn's disease in
remission.
[0068] The goal of treatment for Crohn's disease is to induce
active Crohn's disease to enter the remission (i.e, induction of
remission) and/or to maintain the disease in remission (i.e.,
maintenance of remission).
[0069] In clinical studies, the Montreal CD phenotype is a
classification method for Crohn's disease. The details are as
follows:
TABLE-US-00001 TABLE 1 Montreal Classification for Crohn's disease
Age at diagnosis (A) A1 16 years or younger A2 between 17 to 40
years A3 over 40 years Location (L) L1 Terminal ileum L1 + L4.sup.b
L2 Colon L2 + L4.sup.b L3 Ileocolon L2 + L4.sup.b L4 Upper
gastrointestinal Behaviour (B) B1.sup.a non-stricturing,
non-penetrating B1P.sup.c B2 stricturing B2p.sup.c B3 penetrating
B3p.sup.c Note: .sup.aB1 may develop into B2 or B3 when time
passes; .sup.bL4 may coexist with L1, L2 or L3; .sup.cp is perianal
disease, which may coexist with B1, B2 or B3
[0070] Clinically, the Crohn's disease activity index (CDAI) can
also be used to assess the severity of disease activity and
evaluate efficacy. Best CDAI calculation can be referred to. The
details are as follows:
TABLE-US-00002 TABLE 2 Best CDAI Calculation Variable Multiplier
Number of liquid stools (in one week) 2 Abdominal pain ratings (in
one week, 0-3 points) 5 General well-being (in one week, 0-4
points) 7 Extraintestinal findings and complications 20 (1 point
for each item) Opiods antidiarrhoeal drugs (no = 0; yes = 1) 30
Abdominal mass (questionalbel = 2; definite = 5) 10 Haematocrit
reduction (Norm.sup.a: Men: 0.40, Women: 0.37) 6 100 .times.
(1-observed body weight/ideal body weight) 1 Note .sup.ahaematocrit
norm is based on Chinese standard; total point = the sum of the
points in each item, where CDAI is <150, the disease is in
remission; where CDAI is .gtoreq.150 the disease is active, where
CDAI is 150-220, disease is mild; where CDAI is 221-450, disease is
moderate; where CDAI is >450, disease is severe.
[0071] The patient's disease was scored according to the Best CDAI
calculation as described above. After scoring, the clinical
remission corresponds to Crohn's disease in remission of the
present disclosure, mild activity corresponds to mild Crohn's
disease of the present disclosure, moderate activity corresponds to
moderate Crohn's disease of the present disclosure, and severe
activity corresponds to severe Crohn's disease of the present
disclosure.
[0072] Certain chemical groups named herein are preceded by a
shorthand notation indicating the total number of carbon atoms that
are to be found in the indicated chemical group. For example,
C.sub.1-C.sub.4alkyl describes an alkyl group, as defined below,
having a total of 1 to 4 carbon atoms, and
C.sub.3-C.sub.10cycloalkyl describes a cycloaklyl group, as defined
below, having a total of 3 to 10 carbon atoms. The total number of
carbon atoms in the shorthand notation does not include the carbons
that may exist in the substituents of the groups described.
[0073] The term "mammal" means animals including, for example,
dogs, cats, cows, sheep, horses, and humans. In some embodiments,
mammals include humans.
[0074] The term "patient" means an animal, such as a human, a
companion animal, such as a dog, cat and horse, and livestock, such
as cattle, swine and sheep. In some embodiments, patients are
mammals, including both males and females. In some embodiments,
patients are humans.
[0075] The term "pharmaceutically acceptable" as used herein means
the carrier, vehicle, diluent, excipient and/or salt must be
compatible with the other ingredients of the formulation, and not
deleterious to the recipient thereof.
[0076] "Optional" or "optionally" means that the subsequently
described event of circumstances may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not.
[0077] "Pharmaceutically acceptable carrier, diluent or excipient"
includes without limitation any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isosmotic agent, solvent, or
emulsifier, etc, which has been approved by the United States Food
and Drug Administration as being acceptable for use in humans or
animals and have no side effects on preparing a pharmaceutical
composition.
[0078] "Pharmaceutically acceptable salts" include both
"pharmaceutically acceptable acid addition salts" and
"pharmaceutically acceptable base addition salts".
[0079] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but not limited to hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphanic acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleinic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid and the like.
[0080] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic or an organic base to the free acid. Salts derived from
inorganic bases include, but are not limited, to sodium, potassium,
lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminium salts and the like. In some embodiments,
inorganic salts are the ammonium, sodium, potassium, calcium, and
magnesium salts. Salts derived from organic bases include, but are
not limited to, salts of primary, secondary and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and s basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,
lysine, arginine, histidine, caffeine, procaine, hydrabamine,
choline, betaine, benethamine, benzathine, ethylenediamine,
glucosamine, methylglucosamine, theobromine, triethanolamine,
trometamol, purine, piperazine, piperidine, N-ethyl piperidine,
polyamine resins and the like. In some embodiments, organic bases
are isopropylamine, diethylamine, ethanolamine, trimethylamine,
dicyclohexylamine, choline and caffeine.
[0081] The term "a solvent or a solvent mixture" refers to any and
all solvents, In some embodiments, a solvent or a solvent mixture
is organic solvents and water, which include, but are not limited
to, water, methanol, ethanol, 2-propanol, n-butanol, iso-butanol,
acetone, methylethylketone, ethylacetate, 1,4-dioxane,
diethylether, MTBE, THF, acetonitrile, dichloromethane, chloroform,
DMF, cyclohexane, cyclopentane, n-hexane, n-heptane, n-pentane,
toluene, o-xylene, p-xylene, DMSO, pyridine, acetic acid, anisole,
butylacetate, cumene, ethylformate, formic acid, iso-butylacetate,
iso-propylacetate, methylacetate, 3-methyl-1-butanol,
methylisobutylketone, 2-methyl-1-propanol, 1-pentanol,
propylacetate, ethylenglycole, and 1-methyl-2-pyrrolidone, as well
as any and all mixtures of two or more such solvents. In some
embodiments, a solvent or a solvent mixture is single solvent and
binary mixtures. In some embodiments, a solvent or a solvent
mixture is water and single solvent of organic solvent and binary
mixtures of water and organic solvent.
[0082] A "pharmaceutical composition" refers to a formulation of a
compound of the present disclosure and a medium generally
acceptable in the art for the delivery of the biologically active
compound to mammals, e.g., humans. Such a medium includes all
pharmaceutically acceptable carriers, diluents or excipients
therefor.
[0083] "Therapeutically effective amount" refers to an amount of a
compound or combination of compounds that ameliorates, attenuates
or eliminates a particular disease or condition or a symptom of a
particular disease or condition, or prevents or delays the onset of
a particular disease or condition or a symptom of a particular
disease or condition. The amount of a compound of the present
disclosure which constitutes a "therapeutically effective amount"
will vary depending on the compound, the condition and its
severity, and the age of the mammal to be treated, but can be
determined routinely by one of ordinary skill in the art having
regard to his own knowledge and to this disclosure.
[0084] "Treating" or "treatment" as used herein covers the
treatment of the disease or condition of interest in a mammal, such
as a human, having the disease or disorder of interest, and
includes:
[0085] (i) preventing the disease or condition from occurring in a
mammal, in particular, when such mammal is predisposed to the
condition but has not yet been diagnosed as having it;
[0086] (ii) inhibiting the disease or condition, i.e., arresting
its development; or
[0087] (iii) relieving the disease or condition, i.e., causing
regression of the disease or condition.
[0088] As used herein, the terms "disease" and "condition" may be
used interchangeably or may be different in that the particular
malady or condition may not have a known causative agent (so that
etiology has not yet been worked out) and it is therefore not yet
recognized as a disease but only as an undesirable condition or
syndrome, wherein a more or less specific set of symptoms have been
identified by clinicians.
[0089] The compounds of the present disclosure or their
pharmaceutically acceptable salt may contain one or more asymmetric
centers and may thus give rise to enantiomers, diastereoisomers,
and other stereoismeric forms that may be defined, in terms of
absolute stereochemistry, as (R)- or (S)-, or (D)- or (L)- for
amino acids. The present disclosure is meant to include all such
possible isomers, as well as their racemic and optically pure
forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and
(L)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques, such as HPLC
using a chiral column. When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0090] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present disclosure contemplates various stereoisomers and mixtures
thereof.
[0091] The substituent position of the compounds disclosed in the
present disclosure is numbered as follows:
##STR00004##
[0092] The substitution site of R.sub.1 in formula (I) can be one
of the sites numbered as 4, 5, 6 and 7 or a combination of several
sites numbered as 4, 5, 6 and 7. The substitution site of R.sub.4
in formula (II) can be one of the sites numbered as 4, 5, 6 and 7
or a combination of several sites numbered as 4, 5, 6 and 7. The
substitution site of R.sub.8 in formula (III) can be one of the
sites numbered as 4, 5, 6 and 7 or a combination of several sites
numbered as 4, 5, 6 and 7.
[0093] These and other features, aspects and advantages of the
present disclosure will become better understood with reference to
the following drawings, description and claims.
Specific Embodiments
[0094] In one aspect, some embodiments disclose a
piperidine-2,6-dione derivative of formula (I) and pharmaceutically
acceptable salts thereof:
##STR00005##
[0095] wherein,
[0096] R.sub.1 represents one or more substituents selected from
the group consisting of H, halogen, --OH, --C.sub.1-4alkyl,
--NH.sub.2, --NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl;
[0097] R.sub.2 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and
[0098] R.sub.3 represents --H or --C.sub.1-4alkyl.
[0099] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (I) and pharmaceutically acceptable salts thereof:
##STR00006##
[0100] wherein,
[0101] R.sub.1 represents one or more substituents selected from
the group consisting of --H, --F, --Cl, --Br, --OH, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, --NHCH.sub.3,
--NH.sub.2, --NHCH.sub.2CH.sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3 and
--NHCOCH.sub.2CH.sub.3;
[0102] R.sub.2 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and
[0103] R.sub.3 represents --H, --CH.sub.3 or
--CH.sub.2CH.sub.3.
[0104] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (I) and pharmaceutically acceptable salts thereof:
##STR00007## [0105] wherein,
[0106] R.sub.1 represents one or more substituents selected from
the group consisting of --H, --F, --OH, --CH.sub.3, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHCOCH.sub.3 and --NH.sub.2;
[0107] R.sub.2 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--; and
[0108] R.sub.3 represents --H, --CH.sub.3 or
--CH.sub.2CH.sub.3.
[0109] Some embodiments disclose a piperidine-2,6-dione derivatives
of formula (I) and pharmaceutically acceptable salts thereof, which
are selected from the group consisting of: [0110]
4-acetylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof; [0111]
4-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof; [0112]
4-dimethylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindol
in-1,3-dione and pharmaceutically acceptable salts thereof; [0113]
4-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof; [0114]
4,5,6,7-tetrafluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindo-
lin-1,3-dione and pharmaceutically acceptable salts thereof, [0115]
4-amino-2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof; [0116]
5-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof; [0117]
4-amino-5-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof; [0118]
4-amino-5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof, [0119]
4-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof, [0120]
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, [0121]
4-fluoro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0122]
5-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof, [0123]
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
and pharmaceutically acceptable salts thereof, [0124]
4-fluoro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0125]
5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0126]
4-amino-2-(1-(2-methoxybutyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0127]
4-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0128]
4-methyl-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0129]
4-amino-5-methoxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione and pharmaceutically acceptable salts thereof, [0130]
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, and [0131]
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof.
[0132] In one aspect, some embodiments disclose a
piperidine-2,6-dione derivative of formula (II) and
pharmaceutically acceptable salts thereof:
##STR00008##
[0133] wherein,
[0134] R.sub.4 represents one or more substituents selected from
the group consisting of H, halogen, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl;
[0135] R.sub.5 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0136] R.sub.6 represents --S--, --SO--, --SO.sub.2--, --NH-- or
--N(C.sub.1-4alkyl)-; and
[0137] R.sub.7 represents --H or --C.sub.1-4alkyl.
[0138] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (II) and pharmaceutically acceptable salts thereof:
##STR00009##
[0139] wherein,
[0140] R.sup.4 represents one or more substituents selected from
the group consisting of --H, --F, --Cl, --Br, --OH, --CH.sub.3,
--NHCH.sub.3, --NHCH.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3
and --NHCOCH.sub.2CH.sub.3;
[0141] R.sub.5 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0142] R.sub.6 represents --S--, --SO--, --SO.sub.2--, --NH-- or
--N(CH.sub.3)--; and
[0143] R.sub.7 represents --H, --CH.sub.3 or
--CH.sub.2CH.sub.3.
[0144] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (II) and pharmaceutically acceptable salts thereof:
##STR00010##
[0145] wherein,
[0146] R.sub.4 represents --NH.sub.2 or --NHCOCH.sub.3;
[0147] R.sub.5 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0148] R.sub.6 represents --S--, --SO--, --SO.sub.2--, --NH-- or
--N(CH.sub.3)--; and
[0149] R.sub.7 represents --H, --CH.sub.3 or
--CH.sub.2CH.sub.3.
[0150] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (II) and pharmaceutically acceptable salts thereof:
[0151]
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-d-
ione and pharmaceutically acceptable salts thereof; [0152]
4-amino-2-(1-(2-methylsulfinylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof; and [0153]
4-amino-2-(1-(2-methylsulfonylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof.
[0154] In yet another aspect, some embodiments disclose a
piperidine-2,6-dione derivative of formula (III) and
pharmaceutically acceptable salts thereof:
##STR00011##
[0155] wherein,
[0156] R.sub.8 represents one or more substituents selected from
the group consisting of H, halogen, --C.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl).sub.2 and
--NHCOC.sub.1-4alkyl;
[0157] R.sub.9 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0158] R.sub.10 represents --O--, --S--, --SO--, --SO.sub.2--,
--NH-- or --N(C.sub.1-4alkyl)-;
[0159] R.sub.11 represents --H or --C.sub.1-4alkyl; and
[0160] R.sub.12 represents halogen or --C.sub.1-4alkyl.
[0161] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (III) and pharmaceutically acceptable salts thereof:
##STR00012##
[0162] wherein,
[0163] R.sub.8 represents one or more substituents selected from
the group consisting of --H, --F, --Cl, --Br, --OH, --CH.sub.3,
--NHCH.sub.3, --NHCH.sub.2CH.sub.3, --NH.sub.2,
--N(CH.sub.3).sub.2, --N(CH.sub.2CH.sub.3).sub.2, --NHCOCH.sub.3
and --NHCOCH.sub.2CH.sub.3;
[0164] R.sub.9 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0165] R.sub.10 represents --O--, --S--, --SO--, --SO.sub.2--,
--NH-- or --N(CH.sub.3)--;
[0166] R.sub.11 represents --H, --CH.sub.3 or --CH.sub.2CH.sub.3;
and
[0167] R.sub.12 represents halogen or --C.sub.1-4alkyl.
[0168] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (III) and pharmaceutically acceptable salts thereof:
##STR00013##
[0169] wherein,
[0170] R.sub.8 represents --NH.sub.2 or --NHCOCH.sub.3;
[0171] R.sub.9 represents --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--;
[0172] R.sub.10 represents --O--, --S--, --SO--, --SO.sub.2--,
--NH-- or --N(CH.sub.3)--;
[0173] R.sup.11 represents --H, --CH.sub.3 or --CH.sub.2CH.sub.3;
and
[0174] R.sub.12 represents halogen or --C.sub.1-4alkyl.
[0175] Some embodiments disclose a piperidine-2,6-dione derivative
of formula (III) and pharmaceutically acceptable salts thereof,
which are selected from the group consisting of: [0176]
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof; and
[0177]
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof.
[0178] All the compounds of formula (I), formula (II) and formula
(III) as mentioned above belong to piperidine-2,6-dione derivatives
as mentioned herein.
[0179] Some embodiments disclose a piperidine-2,6-dione derivatives
and pharmaceutically acceptable salts thereof, which are selected
from the group consisting of: [0180]
4-acetylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof, [0181]
4-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione and pharmaceutically acceptable salts thereof, [0182]
4-dimethylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindol
in-1,3-dione and pharmaceutically acceptable salts thereof, [0183]
4-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof, [0184]
4,5,6,7-tetrafluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindo-
lin-1,3-dione and pharmaceutically acceptable salts thereof, [0185]
4-amino-2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0186]
5-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0187]
4-amino-5-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof, [0188]
4-amino-5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof, [0189]
4-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione and pharmaceutically acceptable salts thereof, [0190]
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-d-
ione and pharmaceutically acceptable salts thereof, [0191]
4-amino-2-(1-(2-methylsulfinylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, [0192]
4-amino-2-(1-(2-methylsulfonylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, [0193]
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindol
in-1,3-dione and pharmaceutically acceptable salts thereof, [0194]
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione and pharmaceutically acceptable salts thereof, [0195]
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione and pharmaceutically acceptable salts thereof, [0196]
4-fluoro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0197]
5-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof, [0198]
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
and pharmaceutically acceptable salts thereof, [0199]
4-fluoro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0200]
5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0201]
4-amino-2-(1-(2-methoxybutyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, [0202]
4-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0203]
4-methyl-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one and pharmaceutically acceptable salts thereof, [0204]
4-amino-5-methoxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione and pharmaceutically acceptable salts thereof, [0205]
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e and pharmaceutically acceptable salts thereof, and [0206]
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne and pharmaceutically acceptable salts thereof.
[0207] In still another aspect, some embodiments disclose a
pharmaceutical composition comprising the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein, and a pharmaceutically acceptable carrier,
diluent or excipient.
[0208] In yet another aspect, some embodiments disclose a method
for treating Crohn's disease, comprising administering a
therapeutically effective amount of the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein, or a therapeutically effective amount of the
pharmaceutical composition as disclosed herein to a subject in need
thereof.
[0209] Some embodiments disclose a method for treating Crohn's
disease, comprising administering 1 mg-10 g of the
piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof as disclosed herein to a subject in need thereof.
[0210] Some embodiments disclose a method for treating Crohn's
disease, comprising administering 10 mg-3000 mg of the
piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof as disclosed herein to a subject in need thereof.
[0211] Some embodiments disclose a method for treating Crohn's
disease, comprising administering 100 mg-1000 mg of the
piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof as disclosed herein to a subject in need thereof.
[0212] Some embodiments disclose a method for treating Crohn's
disease, comprising administering 100 mg, 150 mg, 200 mg, 250 mg,
300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700
mg, 750 mg, 800 mg, 850 mg, 900 mg or 1000 mg of the
piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof as disclosed herein to a subject in need thereof.
[0213] Some embodiments disclose a method for treating Crohn's
disease, wherein the Crohn's disease is mild Crohn's disease,
moderate Crohn's disease, severe Crohn's disease or Crohn's disease
in remission.
[0214] Some embodiments disclose a method for treating Crohn's
disease, wherein the subject in need thereof is a mammal.
[0215] Some embodiments disclose a method for treating Crohn's
disease, wherein the subject in need thereof is human.
[0216] Some embodiments disclose of a method of maintenance
treatment of Crohn's disease, comprising administering a
therapeutically effective amount of the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein, or a therapeutically effective amount of the
pharmaceutical composition as disclosed herein to a subject in need
thereof.
[0217] Some embodiments disclose a method for treating Crohn's
disease, wherein the piperidine-2,6-dione derivative or
pharmaceutically acceptable salts thereof as disclosed herein, or
the pharmaceutical composition comprising the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein is administered orally.
[0218] Some embodiments disclose a method for treating Crohn's
disease, wherein the piperidine-2,6-dione derivative or
pharmaceutically acceptable salts thereof as disclosed herein, or
the pharmaceutical composition comprising the piperidine-2,6-dione
derivative or pharmaceutically acceptable salts thereof as
disclosed herein is administered orally in a solid or liquid
formulation.
[0219] Exemplary examples of the solid formulation that can be used
in the method for treating Crohn's disease as disclosed herein
comprise, but are not limited to, a tablet, capsule and
sugar-coated pill.
[0220] Exemplary examples of the tablet that can be used in the
method for treating Crohn's disease as disclosed herein comprise,
but are not limited to, a plain tablet, sugar-coated tablet and
film-coated tablet.
[0221] Exemplary examples of the liquid formulation that can be
used in the method for treating Crohn's disease as disclosed herein
comprise, but are not limited to, a solution and suspension.
[0222] In yet another aspect, some embodiments disclose a
piperidine-2,6-dione derivative and pharmaceutically acceptable
salts thereof for treating Crohn's disease.
[0223] In still another aspect, some embodiments disclose a
pharmaceutical composition for treating Crohn's disease, comprising
the piperidine-2,6-dione derivative or pharmaceutically acceptable
salts thereof as disclosed herein, and a pharmaceutically
acceptable carrier, diluent or excipient.
[0224] The piperidine-2,6-dione derivatives as disclosed herein
have good therapeutical effects.
[0225] The piperidine-2,6-dione derivatives as disclosed herein
have better safety.
[0226] The piperidine-2,6-dione derivatives as disclosed herein
have better tolerance.
Pharmaceutical Compositions
[0227] Some embodiments disclose a pharmaceutical composition
comprising the piperidine-2,6-dione derivative or pharmaceutically
acceptable salts thereof as disclosed herein, and a
pharmaceutically acceptable carrier, diluent or excipient.
[0228] In some embodiments, the route of administration of the
piperidine-2,6-dione derivatives as disclosed herein to the mammals
can be non-parenteral route.
[0229] In some embodiments, the route of administration of the
piperidine-2,6-dione derivatives as disclosed herein to the mammals
can be oral route.
[0230] In some embodiments, the route of administration of the
piperidine-2,6-dione derivatives as disclosed herein to the mammals
can be intrarectal route.
[0231] The piperidine-2,6-dione derivatives as described herein may
be obtained in any suitable form such as tablet, capsule, powder,
oral solution, suspension, rectal gel, rectal foam, rectal enema or
suppository and the like. Exemplary examples of tablets comprise,
but are not limited to, plain tablets, sugar-coated tablets and
film-coated tablets.
[0232] Examples of a pharmaceutically acceptable carrier that can
be used in the pharmaceutical composition of the present disclosure
include, but are not limited to, any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enchancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isosmotic agent, solvent or
emulsifier, which has been approved by the United States Food and
Drug Administration as being acceptable for use in humans or
animals. Acceptable carriers or diluents for therapeutic use are
well-known in the art, and are described, for example, in
Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co.,
Easton, Pa. (1990), which is incorporated herein by reference in
its entirety.
[0233] The pharmaceutical compositions of the present disclosure
may be administered by any means that achieve their intended
purpose. For example, administration may be by oral, parenteral,
topical, enteral, intravenous, intramuscular, inhalant, nasal,
intraarticular, intraspinal, transtracheal, transocular,
subcutaneous, intraperitoneal, transdermal, or buccal routes. The
route of administration can be non-parenteral route, oral route and
intrarectal route. The dosage administered will be dependent upon
the age, health, and weight of the recipient, kind of concurrent
treatment, if any, frequency of treatment, and the nature of the
effect desired.
[0234] Suitable dosage forms include, but are not limited to
capsules, tablets, pellets, dragees, semi-solids, powders,
granules, suppositories, ointments, creams, lotions, inhalants,
injections, cataplasms, gels, tapes, eye drops, solution, syrups,
aerosols, suspension, emulsion, which can be produced according to
methods known in the art.
[0235] Particularly suitable for oral use are ordinary tablets
(plain tablets), sugar-coated tablet, film-coated tablets, pills,
coated tablets, capsules, powders, granules, syrups, juices or
drops, suitable for rectal use are suppositories, suitable for
parenteral use are solutions, or oil-based or aqueous solutions,
furthermore suspensions, emulsions or implants, and suitable for
topical use are ointments, creams or powders. The compounds of the
present disclosure may also be lyophilised and the resultant
lyophilisates used, for example, for the preparation of injection
preparations. The preparations indicated may be sterilised and/or
comprise assistants, such as lubricants, preservatives, stabilisers
and/or wetting agents, emulsifiers, salts for modifying the osmotic
pressure, buffer substances, dyes, flavours and/or a plurality of
further active ingredients, for example one or more vitamins.
[0236] In some embodiments, a pharmaceutical composition of the
present disclosure is formulated as tablet, solution, granule,
patch, ointment, capsule, aerosol or suppository administered via
parenteral, transdermal, mucosa, nasal, buccal, sublingual or oral
route.
[0237] Preservatives, stabilizers, dyes, sweeteners, flavoring
agents, fragrances, and the like, may be provided in the
pharmaceutical composition. For example, sodium benzoate, ascorbic
acid and esters of p-hydroxybenzoic acid may be added as
preservatives. Furthermore, antioxidants and suspending agents may
be used.
[0238] In various embodiments, alcohols, esters, sulfating
aliphatic alcohols, and the like may be used as surfactants;
sucrose, glucose, lactose, starch, crystalline cellulose, mannitol,
light anhydrous silicate, magnesium aluminate, methyl magnesium
silicate aluminate, synthetic aluminum silicate, calcium carbonate,
calcium bicarbonate, calcium hydrogenphosphate, calcium
hydroxymethyl cellulose and the like may be used as excipients;
magnesium stearate, talc, hardened oil may be used as smoothing
agents; coconut oil, olive oil, sesame oil, peanut oil, soybean may
be used as suspending agents or lubricants; cellulose acetate
phthalate as a derivative of a carbohydrate such as cellulose or
sugar, or methylacetate-metharylate copolymer as a derivative of
polyethylene may be used as suspending agents; and plasticizers
such as ester phthalates and the like may be used as suspending
agents.
[0239] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, topical, or intestinal administration;
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intranasal or intraocular
injections. The compound can be administered in sustained or
controlled release dosage forms, including depot injections,
osmotic pumps, pills, transdermal (including electromigrating)
patches, and the like for prolonged and/or timed, pulsed
administration at a predetermined rate.
[0240] Pharmaceutical compositions of the present disclosure may be
manufacture in manner that is itself known, for example, by means
of conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping, or tabletting
processes.
[0241] Pharmaceutical compositions for use in accordance with the
present disclosure thus may be formulated by a conventional manner
using one or more physiologically acceptable carriers comprising
excipienst and auxiliaries which facilitate processing the active
compounds into preparation which can be used pharmaceutically.
Proper formulation is dependent on the route of administration
chosen. Any of the well-known techniques, carriers and excipients
may be used as suitable and as understood in the art.
[0242] Injectables can be prepared in conventional forms, either as
liquid solutions or suspensions, solid forms suitable for solution
or suspension in liquid prior to injection, or as emulsions.
Suitable excipients are, for example, water, saline, glucose,
mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine
hydrochloride, and the like. Furthermore, if desired, the
injectable pharmaceutical compositions may contain minor amounts of
nontoxic auxiliary substances, such as wetting agents, pH buffering
agents, and the like. Physiologically compatible buffers include,
but are not limited to, Hank's solution, Ringer's solution or
physiological saline buffer. If desired, absorption enhancing
preparations (such as liposomes) may be used.
[0243] For oral administration, the compound can be formulated
readily by combining the active compound with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compound of the disclosure to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, ointments, suspensions,
and the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparation for oral use can be obtained by
combining the active compound with solid excipient, optionally
grinding a resultant mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, saccharose, mannitol or
sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If
desired, disintegrating agents may be added, such as the
crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt
thereof such as sodium alginate. Dragee cores are provided with
suitable coatings. For this purpose, concentrated sugar solutions
may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or
titanium dioxide, lacquer solution, and suitable organic solvents
or solvent mixtures. Dyestuffs or pigments may be added into the
tablets or dagree coatings for identification or to characterizing
different combinations of active compound doses. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solution, and
suitable organic solvents or solvent mixtures.
[0244] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer such as glycerol or sorbitol. The
push-fit capsules can contain active ingredients in admixture with
filler such as sugar, binders such as starches, and/or lubricants
such as talc or magnesium stearate and, optionally, stabilizers. In
soft capsules, the active ingredients may be dissolved or suspended
in suitable liquids, such as fatty oil, liquid paraffin, or liquid
polyethylene glycols. Furthermore, stabilizers may be added. All
formulations for oral administration should be in dosages suitable
for such administration.
[0245] In some embodiments, the pharmaceutical composition of the
present disclosure may comprise 0.1%-95% of the
piperidine-2,6-dione derivatives as disclosed herein.
[0246] In some embodiments, the pharmaceutical composition of the
present disclosure may comprise 1%-70% of the piperidine-2,6-dione
derivatives as disclosed herein.
[0247] Under any circumstances, the composition or formulation to
be administered may comprise some amount of the
piperidine-2,6-dione derivatives as disclosed herein, which is
effective to treat the disease/condition of a study subject to be
treated.
Methods of Administration
[0248] At least one of the compounds of the present disclosure or
the pharmaceutical compositions comprising at least one of the
compounds of the present disclosure may be administered to the
patient by any suitable means and/or by any means that topically
delivers the compounds of the present disclosure. Non-limiting
examples of methods of administration include, among others, (a)
administration though oral pathways, which administration includes
administration in capsule, tablet, granule, spray, syrup, or other
such forms; (b) administration through non-oral pathways such as
rectal, vaginal, intraurethral, intraocular, intranasal, or
intraauricular, which administration includes administration as an
aqueous suspension, an oily preparation or the like or as a drip,
spray, suppository, salve, ointment or the like; (c) administration
via injection, subcutaneously, intraperitoneally, intravenously,
intramuscularly, intradermally, intraorbitally, intracapsularly,
intraspinally, intrasternally, or the like, including infusion pump
delivery; (d) administration locally such as by injection directly
in the renal or cardiac area, e.g., by depot implantation; as well
as (e) administration topically; as deemed appropriate by those of
skill in the art for bringing the compound of the present
disclosure into contact with living tissue.
[0249] The most suitable route depends on the nature and severity
of the condition to be treated. A person having ordinary skill in
the art also knows determination of methods of administration
(buccal, intravenous, inhalation subcutaneous, rectal and the
like), dosage form, suitable pharmaceutical excipients and other
events regarding delivering the compound to a subject in need
thereof.
[0250] Pharmaceutical compositions suitable for administration
include compositions where the active ingredients are contained in
an amount effective to achieve its intended purpose. The
therapeutically effective amount of the compounds disclosed herein
required as a dose will depend on the route of administration, the
type of animal, including human, being treated, and the physical
characteristics of the specific animal under consideration. The
dose can be tailored to achieve a desired effect, but will depend
on such factors as weight, diet, concurrent medication and other
factors which those skilled in the medical arts will recognize.
More specifically, a therapeutically effective amount means an
amount of compound effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated. Determination of a therapeutically effective amount is
well within the capability of those skilled in the art, especially
in light of the detailed disclosure provided herein.
[0251] As will be readily apparent to one skilled in the art, the
useful in vivo dosage to be administered and the particular mode of
administration will vary depending upon the age, weight and
mammalian species treated, the particular compounds employed, and
the specific use for which these compounds are employed. The
determination of effective dosage levels, that is the dosage levels
necessary to achieve the desired result, can be accomplished by one
skilled in the art using routine pharmacological methods.
Typically, human clinical applications of products are commenced at
lower dosage levels, with dosage level being increased until the
desired effect is achieved. Alternatively, acceptable in vitro
studies can be used to establish useful doses and routes of
administration of the compositions identified by the present
methods using established pharmacological methods.
[0252] In non-human animal studies, applications of potential
products are commenced at higher dosage levels, with dosage being
decreased until the desired effect is no longer achieved or adverse
side effects disappear. The dosage may range broadly, depending
upon the desired affects and the therapeutic indication. Typically,
dosages may be between about 10 microgram/kg and 1000 mg/kg body
weight, in some embodiments, between about 100 microgram/kg and 300
mg/kg body weight. Alternatively dosages may be based and
calculated upon the surface area of the patient, as understood by
those of skill in the art.
[0253] The exact formulation, route of administration and dosage
for the pharmaceutical compositions of the present disclosure can
be chosen by the individual physician in view of the patient's
condition. Typically, the dose range of the composition
administered to the patient can be from about 0.5 to 1000 mg/kg of
the patient's body weight. The dosage may be a single one or a
series of two or more given in the course of one or more days, as
is needed by the patient. In instances where human dosages for
compounds have been established for at least some condition, the
present disclosure will use those same dosages, or dosages that are
between about 0.1% and 500%, in some embodiments, between about 25%
and 250% of the established human dosage. Where no human dosage is
established, as will be the case for newly-discovered
pharmaceutical compounds, a suitable human dosage can be inferred
from ED.sub.50 or ID.sub.50 values, or other appropriate values
derived from in vitro or in vivo studies, as qualified by toxicity
studies and efficacy studies in animals.
[0254] It should be noted that the attending physician would know
how to and when to terminate, interrupt, or adjust administration
due to toxicity or organ dysfunctions. Conversely, the attending
physician would also know to adjust treatment to higher levels if
the clinical response were not adequate (precluding toxicity). The
magnitude of an administrated dose in the management of the
disorder of interest will vary with the severity of the condition
to be treated and to the route of administration. The severity of
the condition may, for example, be evaluated, in part, by standard
prognostic evaluation methods. Further, the dose and perhaps dose
frequency, will also vary according to the age, body weight, and
response of the individual patient. A program comparable to that
discussed above may be used in veterinary medicine.
[0255] Although the exact dosage will be determined on a
drug-by-drug basis, in most cases, some generalizations regarding
the dosage can be made. The daily dosage regimen for an adult human
patient may be, for example, an oral dose of between 0.1 mg and
2000 mg of each active ingredient, in some embodiments, between 1
mg and 2000 mg, e.g. 5 to 1500 mg. In other embodiments, an
intravenous, subcutaneous, or intramuscular dose of each active
ingredient of between 0.01 mg and 1000 mg, in some embodiments,
between 0.1 mg and 1000 mg, e.g. 1 to 800 mg is used. In cases of
administration of a pharmaceutically acceptable salt, dosages may
be calculated as the free base. In some embodiments, the
composition is administered 1 to 4 times per day. Alternatively the
compositions of the disclosure may be administered by continuous
intravenous infusion, in some embodiments, at a dose of each active
ingredient up to 2000 mg per day. As will be understood by those of
skill in the art, in certain situations it may be necessary to
administer the compounds disclosed herein in amounts that exceed,
or even far exceed, the above-stated dosage range in order to
effectively and aggressively treat particularly aggressive diseases
or infections. In some embodiments, the compounds will be
administered for a period of continuous therapy, for example for a
week or more, or for months or years.
[0256] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety which are sufficient to
maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics and route of administration.
However, HPLC assays or bioassays can be used to determine plasma
concentrations.
[0257] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, in some
embodiments, between 30-90% and in some embodiments, between
50-90%.
[0258] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0259] The amount of composition administered will, of course, be
dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0260] Compounds disclosed herein can be evaluated for efficacy and
toxicity using known methods. For example, the toxicology of a
particular compound, or of a subset of the compounds, sharing
certain chemical moieties, may be established by determining in
vitro toxicity towards a cell line, such as a mammalian, and in
some embodiments, human, cell line. The results of such studies are
often predictive of toxicity in animals, such as mammals, or more
specifically, humans. Alternatively, the toxicity of particular
compounds in an animal model, such as mice, rats, rabbits, or
monkeys, may be determined using known methods. The efficacy of a
particular compound may be established using several recognized
methods, such as in vitro methods, animal models, or human clinical
trials. Recognized in vitro models exist for nearly every class of
condition, including but not limited to cancer, cardiovascular
disease, and various immune dysfunction. Similarly, acceptable
animal models may be used to establish efficacy of chemicals to
treat such conditions. When selecting a model to determine
efficacy, the skilled artisan can be guided by the state of the art
to choose an appropriate model, dose, and route of administration,
and regime. Of course, human clinical trials can also be used to
determine the efficacy of a compound in humans.
[0261] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions comprising a
compound of the disclosure formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
EXAMPLES
[0262] The following abbreviations were used in the discussion,
examples and preparations.
[0263] LPS: lipopolysaccharide;
[0264] PBS: phosphate buffered saline;
[0265] Tween-20
[0266] PBST: 0.05% of Tween-20 in phosphate buffered saline;
[0267] HRP: horseradish peroxidase;
[0268] TMB: 3,3',5,5'-tetramethylbenzidine;
[0269] DSS: dextra sulfate sodium;
[0270] 5-ASA: 5-aminosalicylic acid;
[0271] CMC-Na: sodium carboxymethyl cellulose;
[0272] DNBS: dinitrobenzenesulfonic acid;
[0273] 1% CMC-Na: 1% (weight/volume) of CMC-Na in water;
[0274] 1.6% DSS: 1.6% (weight/volume) of DSS in water;
[0275] 0.9% DSS: 0.9% (weight/volume) of DSS in water;
[0276] mg/Kg: milligram/kilogram;
[0277] mg/Kg/d: milligram/kilogram/day;
[0278] ml/Kg: milliliter/kilogram;
[0279] cm: centimeter;
[0280] Mean.+-.SD: Mean.+-.standard deviation;
[0281] 30% ethanol: 30% (volume/volume) of ethanol in water;
[0282] cm.sup.2: square centimeter;
[0283] U/mg: unit/milligram;
[0284] g: gram;
[0285] mmol: millimole;
[0286] mol/L: mole/liter;
[0287] i.g: intragastric administration;
[0288] ml: milliliter;
[0289] MPO: myeloperoxidase;
[0290] .mu.L: microliter;
[0291] nm: nanometer;
[0292] s: second;
[0293] OD value: optical density value;
[0294] .mu.m: micron;
[0295] Qd, QD, Q.D or qd: once a day;
[0296] The following instruments or devices may be used in the
experiments:
TABLE-US-00003 Instruments Type Company Animal Endoscopy VET-6011
Shanghai Aohua Endoscopy Co., Ltd. Fully Automated Cobas c 311
Roche Biochemical Analyzer ELIASA Multiskan GO Thermo Scientific
ELIASA Model 680 Biorad Microplate Washer Model 1575 Biorad Animal
Fixator Chinese Suzhou Monkey Animal Patent No. Experimental
Equipment ZL200800089997.7 Technology Co., Ltd. High-speed
Centrifuge TGL-16B Shanghai Anting Scientific Instrument Factory
Triple Quadrupole Mass API3000 Applied Biosystems Spectrometer
(TQMS) High Performance Liquid LC-20A Shimadzu Corporation
Chromatography (HPLC) Vortex Mixer QL901 Haimen Kylin-Bell Lab
Instruments Co., Ltd. Low-temperature Heraeus Thermo Scientific
High-speed Centrifuge Multifuge X3R Fully Automated Leica ASP200S
Leica Instruments Vacuum Processor Germany GmbH Embedding Machine
Leica Leica Instruments EG1150H + C Germany GmbH Manual Microtome
Leica RM2235 Leica Instruments Germany GmbH Water Bath for Paraffin
Leica-HI1210 Leica Instruments Sections Germany GmbH Fully
Automated Stainer Leica-ST5020 Leica Instruments Germany GmbH Fully
Automated Glass Leica CV5030 Leica Instruments Coverslipper Germany
GmbH
[0297] The Chinese patent No. ZL200510013292.3 discloses the
preparation process of
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e, which is incorporated herein by reference in its entirety.
Example 1
Preparation of
4-acetylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione
[0298]
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione was prepared in accordance with the process disclosed in
the Chinese patent No. ZL200510013292.3.
[0299] In dichloromethane (DCM) (30 mL) was dissolved
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e (3.0 g). Triethylamine (TEA) (2.75 g, 3.77 mL) and
4-dimethylaminopyridine (DMAP) (0.126 g) were added into the
solution. The air was replaced with argon. The temperature of the
reaction system was lowered to 0.degree. C. To the reaction system
was added acetyl chloride (4.59 g, 4.16 mL) with stirring. The
temperature of the reaction system was slowly heated to the room
temperature until the reaction was complete. To the reaction
solution was added water (60 mL) to quench the reaction. The
solution was extracted once with dichloromethane. The organic phase
was washed once with saturated aqueous solution of sodium chloride,
dried over anhydrous magnesium sulfate and filtered. The solvent
was evaporated under reduced pressure to give a crude product. The
crude product was purified with silica gel column chromatography to
give a solid product (1.8 g). The solid product was dissolved with
dichloromethane. To the solution was added dropwise diethyl ether
to separate out a product. The resultant product was dissolved with
dichloromethane. To the solution was added diethyl ether to
separate out a product. The resultant product was dried under
reduced pressure to give the title compound of Example 1 as a white
solid (1.3 g) (HPLC purity: 98.06%). Yield: 38.3%.
[0300] .sup.1HNMR (deuterated chloroform (CDCl.sub.3), 400 MHz)
.delta. 9.411 (bs, 1H), 8.823-8.802 (d, 1H), 7.730-7.690 (dd, 1H),
7.557-7.537 (dd, 1H), 4.995-4.950 (m, 1H), 4.146-4.001 (m, 2H),
3.555-3.521 (m, 2H), 3.345 (s, 3H), 3.048-2.956 (m, 1H),
2.848-2.719 (m, 2H), 2.267 (s, 3H), 2.186-2.086 (m, 1H). MS(m/e):
374.21 (M+H+).
Example 2
Preparation of 4-methyl
amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
[0301] To a reaction flask were added
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e (4.0 g), di-tert-butyl dicarbonate (10.528 g) and
4-dimethylaminopyridine (0.147 g). To the reaction flask was added
tetrahydrofuran (40 mL). The solution was stirred at the room
temperature overnight. The reaction solution was concentrated under
reduced pressure to give a crude product. The crude product was
purified with silica gel column chromatography to give
4-di-BOC-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin--
1,3-dione (3.3 g) as a white solid. Yield: 74.1%. MS(m/e): 554.40
(M+Na.sup.+).
[0302]
4-di-BOC-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoin-
dolin-1,3-dione (2.05 g) was dissolved in dichloromethane (600 mL).
To the solution was added tetrahydrofuran (3 mL). The reaction
solution was stirred at the room temperature until the reaction was
complete. To the resultant solution was added saturated aqueous
solution of sodium carbonate to quench the reaction. The solution
was separated. The organic phase was dried over anhydrous magnesium
sulfate and filtered to give a filtrate. The filtrate was
concentrated under reduced pressure to give
4-BOC-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-
-dione (1.66 g) (HPLC purity: 98.62%). Yield: 100%. MS(m/e): 454.29
(M+Na.sup.+).
[0303] To a reaction flask were added
4-Boc-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-
-dione (3.0 g), methyl iodide (2.96 g) and potassium carbonate
(2.88 g). To the reaction flask was added N,N-dimethylformamide (30
mL). The reaction solution was stirred at the room temperature
overnight. The reaction solution was diluted with dichloromethane
(100 mL). The organic phase was washed with water. The aqueous
phase was extracted with dichloromethane. The organic phases were
combined. The combined organic phase was washed with saturated
aqueous solution of sodium chloride, dried over anhydrous magnesium
sulfate and filtered to give a filtrate. The filtrate was
concentrated under reduced pressure to give a crude product. The
crude product was purified with silica gel column chromatography to
give
4-BOC-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione as a yellow oil (2.91 g) (HPLC purity: 96.43%). Yield:
94.0%. MS(m/e): 468.31 (M+Na.sup.+).
[0304]
4-BOC-methylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-is-
o indolin-1,3-dione (2.9 g) was dissolved in dichloromethane (30
mL). To the solution was added tetrahydrofuran (6 mL). The reaction
solution was stirred at the room temperature over 2 hours. The
resultant solution was concentrated under reduced pressure to give
a crude product. The crude product was dissolved in methyl
tert-butyl ether (35 mL). The solution was stirred overnight to
separate out a yellow solid product and filtered. The product was
dried under reduced pressure to give the title compound as a yellow
solid (1.83 g) (HPLC purity: 98.62%). Yield: 81.6%.
[0305] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.538-7.499 (dd,
1H), 7.112-7.094 (d, 1H), 6.887-6.866 (d, 1H), 4.949-4.904 (m, 1H),
4.122-3.999 (m, 2H), 3.543-3.510 (m, 2H), 3.341 (s, 3H),
2.989-2.950 (m, 1H), 2.981 (s, 3H), 2.820-2.700 (m, 2H),
2.115-2.060 (m, 1H). MS(m/e): 346.24 (M+H+).
Example 3
Preparation of
4-dimethylamino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin--
1,3-dione
[0306] To a pressure-resistant reaction tube were added
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e (3.0 g), methyl iodide (14.2 g) and potassium carbonate (6.25 g).
To the pressure-resistant reaction tube was added
N,N-dimethylformamide (20 mL). The reaction tube was sealed and
heated to 80.degree. C. in an oil bath. The reaction solution was
stirred over 80 hours. The resultant solution was diluted with
dichloromethane (200 mL) and filtered to give a filtrate. The
filtrate was concentrated under reduced pressure to give a black
oily crude product. The crude product was purified with silica gel
column chromatography to give a brown solid (3.2 g). The brown
solid was dissolved in ethyl acetate (20 mL) and stirred overnight.
The resultant solution was filtered to give a solid. The solid was
dried under reduced pressure to give the title compound as a yellow
powdery solid (1.67 g) (HPLC purity: 97.22%). Yield: 51.4%.
[0307] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.543-7.504 (dd,
1H), 7.308-7.287 (d, 1H), 7.121-7.100 (d, 1H), 5.004-4.959 (m, 1H),
4.115-3.999 (m, 2H), 3.537-3.507 (m, 2H), 3.337 (s, 3H), 3.108 (s,
6H), 2.982-2.944 (m, 1H), 2.803-2.751 (m, 2H), 2.094-2.079 (m, 1H).
MS(m/e): 360.27 (M+H+).
Example 4
Preparation of
4-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne
[0308] To a reaction flask were added
1-(2-methoxyethyl)-3-benzyloxyamido-2,6-piperidinedione acetate (35
g), palladium on carbon (3.5 g, content of palladium: 10%) and
acetic acid (13 mL). The air in the flask was replaced with
hydrogen three times. The reaction solution was stirred at the room
temperature over 72 hours. The resultant solution was filtered to
give a filtrate, which was directly used in the next step.
[0309] To a reaction flask were added the above filtrate
(comprising 2.0 g (calculated) of
1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate),
3-fluorophthalic anhydride (1.35 g), sodium acetate (0.67 g) and
acetic acid (43 mL). The solution was heated to 140.degree. C. in
an oil bath and stirred to react over 5 hours. The resultant
solution was concentrated under reduced pressure to give a black
crude product. The crude product was purified with silica gel
column chromatography to give the title compound as a white solid
(1.56 g) (HPLC purity: 99.88%). Yield: 57.4%.
[0310] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.796-7.746 (m, 1H),
7.717-7.700 (d, 1H), 7.447-7.403 (m, 1H), 5.028-4.982 (m, 1H),
4.127-3.998 (m, 2H), 3.541-3.510 (m, 2H), 3.340 (s, 3H),
3.019-2.951 (m, 1H), 2.895-2.739 (m, 2H), 2.171-2.085 (m, 1H).
MS(m/e): 357.19 (M+Na.sup.+).
Example 5
Preparation of
4,5,6,7-tetrafluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindo-
lin-1,3-dione
[0311] Using the preparation process in Example 4,
2,3,4,5-tetrafluorophthalic anhydride and
1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate were reacted
to give the title compound as a white solid (2.93 g) (HPLC purity:
97.58%). Yield: 78.6%.
[0312] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 4.999-4.953 (m, 1H),
4.118-3.984 (m, 2H), 3.530-3.500 (m, 2H), 3.333 (s, 3H),
3.029-2.991 (m, 1H), 2.803-2.764 (m, 2H), 2.136-2.117 (m, 1H).
MS(m/e): 389.22 (M+H.sup.+).
Example 6
Preparation of
4-amino-2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e
[0313] To a reaction flask were added
3-amino-N-(2,6-dioxo-3-piperidinyl) phthalimide (3.5 g),
2-bromoethanol (4.8 g), potassium carbonate (1.77 g) and
N,N-dimethylformamide (35 mL). The reaction flask was heated to
40.degree. C. in an oil bath. The reaction solution was stirred
over 80 hours. The reaction system was cooled to the room
temperature. To the reaction system was added water (80 mL) to
quench the reaction. To the solution was added ethyl acetate. The
resultant solution was stirred to separate out a solid. The
resultant mixture was filtered under reduced pressure. The filter
cake was discarded and the filtrate was collected and separated.
The aqueous phase was back-extracted with ethyl acetate four times.
The organic phases were combined. The combined organic phase was
washed with saturated aqueous solution of sodium chloride, dried
over anhydrous magnesium sulfate and filtered. The organic phase
was concentrated under reduced pressure to give a crude product.
The crude product was purified with silica gel column
chromatography to give the title compound as a yellow solid (2.0 g)
(HPLC purity: 95.53%). Yield: 49.2%.
[0314] .sup.1HNMR(CDCl.sub.3, 400 MHzz) .delta. 7.457-7.419 (t,
1H), 7.176-7.158 (d, 1H), 6.886-6.865 (d, 1H), 4.990-4.945 (m, 1H),
4.135-4.065 (m, 2H), 3.813-3.785 (m, 2H), 3.006-2.966 (m, 1H),
2.829-2.714 (m, 2H), 2.153-2.114 (m, 1H). MS(m/e): 340.18
(M+Na.sup.+).
Example 7
Preparation of
5-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e
[0315] Using the preparation process in Example 4, 4-nitrophthalic
anhydride and 1-(2-methoxyethyl)-3-amino-2,6-piperidinedione
acetate were reacted to give
5-nitro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-dio-
ne as a white solid (2.8 g) (HPLC purity: 99.62%). Yield: 54.5.
MS(m/e): 384.18 (M+Na.sup.+).
[0316] To a reaction flask were added
5-nitro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-dio-
ne (2.6 g), palladium on carbon (0.26 g) and tetrahydrofuran (30
mL). The air in the flask was replaced with hydrogen three times.
The reaction solution was stirred at the room temperature over 20
hours until the reaction was complete. The resultant solution was
filtered to give a filtrate. The filtrate was concentrated under
reduced pressure with water pump to give a crude product. The crude
product was dissolved and purified with ethyl acetate to give the
title compound as a yellow solid (1.56 g) (HPLC purity: 95.74%).
Yield: 65.4%.
[0317] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.607-7.587 (d, 1H),
7.012-7.007 (d, 1H), 6.846-6.820 (dd, 1H), 4.970-4.925 (m, 1H),
4.135-3.982 (m, 2H), 3.540-3.509 (m, 2H), 3.340 (s, 3H),
3.024-2.903 (m, 1H), 2.829-2.710 (m, 2H), 2.117-2.062 (m, 1H).
MS(m/e): 354.22 (M+Na.sup.+).
Example 8
Preparation of
4-amino-5-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoli-
n-1,3-dione
[0318] To a reaction flask were added 4-hydroxyphthalate dimethyl
(125 g) and concentrated sulfuric acid (600 mL). The solution was
stirred and cooled to 0.degree. C. To the reaction system was
slowly added dropwise fuming nitric acid (39.44 g). The temperature
of the reaction system was controlled to be below 5.degree. C. The
addition of fuming nitric acid was complete in about 1 hour. The
ice bath was removed. The solution was heated to the room
temperature and stirred over 22 hours until the reaction was
complete. The resultant solution was slowly poured into ice water
to quench the reaction. The aqueous phase was extracted with ethyl
acetate five times. The organic phases were combined. The combined
organic phase was dried over anhydrous magnesium sulfate and
filtered. The filtrate was collected and concentrated under reduced
pressure with water pump and oil pump successively to give
4-hydroxy-3-nitrophthalate dimethyl (169 g) (HPLC purity: 36.54%),
which was directly used in the next step. MS(m/e): 254.07
(M-H).sup.-.
[0319] To a reaction flask were added 4-hydroxy-3-nitrophthalate
dimethyl (164 g), benzyl bromide (135.9 g), potassium carbonate
(400 g) and acetone (1730 mL). The reaction flask was heated to
70.degree. C. in an oil bath. The solution was stirred over 23
hours until the reaction was complete. The reaction system was
cooled to the room temperature and concentrated under reduced
pressure. The filter cake was washed with dichloromethane. The
filtrate was collected and concentrated under reduced pressure. To
the concentrate were added dichloromethane (2000 mL) and saturated
aqueous solution of sodium chloride (1000 mL). The resultant
solution was extracted. The organic phase was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced pressure
to give a yellow solid crude product. The crude product was
recrystallized and purified with ethyl acetate to give
4-benzyloxy-3-nitrophthalate dimethyl as a white solid (40 g) (HPLC
purity: 96.96%). Yield: 18.1%. MS(m/e): 346.14 (M+H.sup.+).
[0320] To a reaction flask were added 4-benzyloxy-3-nitrophthalate
dimethyl (30 g) and ethanol (300 mL). To the reaction flask was
added preformulated aqueous solution of sodium hydroxide (24 g of
sodium hydroxide in 300 mL of water). The reaction flask was heated
to 70.degree. C. in an oil bath. The solution was stirred over 7
hours until the reaction was complete. The reaction system was
cooled to the room temperature and concentrated under reduced
pressure to evaporate most of ethanol. To the concentrate was added
4 N hydrochloric acid at the room temperature until the pH of the
solution was adjusted to 2 such that a lot of white solids were
separated out. The resultant mixture was filtered under reduced
pressure. The filter cake was collected and dried under reduced
pressure with oil pump to give 4-benzyloxy-3-nitrophthalic acid as
a white solid (27.5 g) (HPLC purity: 99.55%). Yield: 100%. MS(m/e):
316.15 (M-H).sup.-.
[0321] To a reaction flask were added 4-benzyloxy-3-nitrophthalic
acid (19.1 g) and acetic anhydride (120 mL). The flask was heated
to 140.degree. C. in an oil bath. The solution was stirred over 6
hours. The reaction system was cooled to the room temperature. The
resultant solution was concentrated under reduced pressure to give
a crude product. The crude product was dissolved and purified with
methyl tert-butyl ether and n-hexane to give
4-benzyloxy-3-nitrophthalic anhydride as a brown solid (16.8 g).
Yield: 93.3%.
[0322] Using the preparation process in Example 4,
4-benzyloxy-3-nitrophthalic anhydride and
1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate were reacted
to prepare
4-nitro-5-benzyloxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl-
)-isoindolin-1,3-dione as a white solid (22.3 g) (HPLC purity:
99.69%). Yield: 85.0%. MS(m/e): 468.22 (M+H.sup.+).
[0323] Using the preparation process in Example 7,
4-nitro-5-benzyloxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoind-
olin-1,3-dione was used to give the title compound as a yellow
solid (18.4 g) (HPLC purity: 99.03%). Yield: 86.8%.
[0324] .sup.1HNMR (dimethyl sulfoxide (DMSO), 400 MHz) .delta.
10.820 (s, 1H), 6.974-6.955 (d, 1H), 6.915-6.896 (d, 1H),
5.936-5.935 (bs, 2H), 5.099-5.053 (q, 1H), 3.917-3.730 (m, 2H),
3.363-3.331 (t, 2H), 3.217 (s, 3H), 3.002-2.911 (m, 1H),
2.762-2.702 (m, 1H), 2.560-2.450 (m, 1H), 2.027-1.963 (m, 1H).
MS(m/e): 348.17 (M+H+).
Example 9
Preparation of
4-amino-5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione
[0325] To a reaction flask were added 4-fluorophthalic acid (1.0 g)
and concentrated sulfuric acid (5 mL). The solution was stirred and
cooled to 0.degree. C. To the reaction system was slowly added
dropwise concentrated nitric acid (1.05 g, content: 65%). After the
addition was complete, the resultant solution was heated to
80.degree. C. in an oil bath. The solution was stirred over 7
hours. HPLC was used to monitor the reaction until the reaction was
complete. The resultant solution was slowly poured into ice water
(20 g) to quench the reaction. The aqueous phase was extracted with
ethyl acetate. The organic phases were combined. The combined
organic phase was washed with saturated aqueous solution of sodium
chloride, dried over anhydrous magnesium sulfate and filtered. The
filtrate was collected and concentrated under reduced pressure with
water pump and oil pump successively to give a yellow solid (1.3
g), which was directly used in the next step.
[0326] To a reaction flask was added thionyl chloride (5 mL). The
reaction system was heated to 90.degree. C. in an oil bath and
stirred over 11 hours. The reaction system was then cooled to the
room temperature. The reaction solution was concentrated under
reduced pressure with water pump to give a crude product as a
yellow oil (0.56 g), which was directly used in the next step.
[0327] Using the preparation process in Example 4,
4-fluoro-3-nitrophthalic anhydride and
1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate were reacted
to prepare
5-fluoro-4-nitro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-i-
soindolin-1,3-dione as a black solid (0.3 g) (HPLC purity: 90.63%).
MS(m/e): 380.21 (M+H.sup.+).
[0328] Using the preparation process in Example 7,
5-fluoro-4-nitro-2-(1-(2-methoxyethyl)-2,6-di
oxopiperidin-3-yl)-isoindolin-1,3-dione was used to give the title
compound as a yellow solid (0.137 g) (HPLC purity: 97.59%). Yield:
57.2%.
[0329] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.256-7.208 (dd,
1H), 7.158-7.129 (dd, 1H), 5.269 (bs, 2H), 4.959-4.914 (m, 1H),
4.140-3.988 (m, 2H), 3.544-3.512 (m, 2H), 3.341 (s, 3H),
3.000-2.961 (m, 1H), 2.795-2.745 (m, 2H), 2.121-2.081 (m, 1H).
MS(m/e): 350.2 (M+H+).
Example 10
Preparation of
4-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindol--
1,3-dione
[0330] 4-BOC-amino-7-hydroxyphthalate dimethyl was prepared in
accordance with Journal of Organic Chemistry, 62(12), 4088-4096;
1997.
[0331] To a reaction flask were added
3-BOC-amino-6-hydroxyphthalate dimethyl (3.0 g),
1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate (4.5 g) and
pyridine (60 mL). The reaction flask was heated to 100.degree. C.
in an oil bath. The reaction solution was stirred over 40 hours and
then cooled to the room temperature. The resultant solution was
concentrated to give a crude product. The crude product was
purified with silica gel column chromatography to give
4-BOC-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoi-
ndolin-1,3-dione as a yellow solid (2.35 g) (HPLC purity: 95.96%).
Yield: 48.8%. MS(m/e): 470.28 (M+Na.sup.+).
[0332]
4-BOC-amino-7-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl-
)-isoindolin-1,3-dione (2.25 g) was dissolved in dichloromethane
(20 mL). To the solution was added tetrahydrofuran (4 mL). The
resultant solution was stirred at the room temperature over 6 hours
until the reaction was complete. The solution was concentrated
under reduced pressure to give a crude product. The crude product
was dissolved and purified with methyl tert-butyl ether to give the
title compound as brown solid (1.413 g) (HPLC purity: 95.35%).
Yield: 77.4%.
[0333] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.020-6.998 (d, 1H),
6.858-6.835 (d, 1H), 4.934-4.889 (m, 1H), 4.145-3.995 (m, 2H),
3.555-3.521 (m, 2H), 3.346 (s, 3H), 3.031-2.926 (m, 1H),
2.827-2.742 (m, 2H), 2.140-2.059 (m, 1H). MS(m/e): 348.22
(M+H.sup.+).
Example 11
Preparation of
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-d-
ione
[0334] To a reaction flask were added
3-amino-N-(2,6-dioxo-3-piperidinyl) phthalimide (2.5 g),
2-chloroethyl methyl sulfide (2.55 g), potassium carbonate (3.8 g),
sodium iodide (0.28 g) and N,N-dimethylformamide (35 mL). The
reaction flask was heated to 50.degree. C. in an oil bath. The
reaction solution was stirred over 20 hours until the reaction was
complete. To the reaction solution were added dichloromethane and
water to extract. The aqueous phase was back-extracted with
dichloromethane twice. The organic phases were combined. The
combined organic phase was dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure to give a crude
product. The crude product was purified with silica gel column
chromatography to give the title compound as a yellow solid (2.111
g) (HPLC purity: 96.68%). Yield: 55.3%.
[0335] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.457-7.418 (dd,
1H), 7.180-7.161 (dd, 1H), 6.885-6.863 (dd, 1H), 4.966-4.921 (m,
1H), 4.110-3.973 (m, 2H), 2.994-2.926 (m, 1H), 2.820-2.753 (m, 2H),
2.683-2.646 (t, 2H), 2.144 (s, 3H), 2.125-2.079 (m, 1H). MS(m/e):
348.19 (M+H+).
Example 12
Preparation of
4-amino-2-(1-(2-methylsulfinylethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione
[0336] To a reaction flask were added
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3--
dione (4.85 g), m-chloroperoxybenzoic acid (3.13 g) and
dichloromethane (170 mL). The solution was stirred at the room
temperature over 18 hours. To the reaction system was added
saturated aqueous solution of sodium bicarbonate (100 mL) to
extract. The aqueous phase was back-extracted with dichloromethane
(150 mL.times.3). The organic phases were combined. The combined
organic phase was dried over anhydrous magnesium sulfate, filtered
and concentrated under reduced pressure to give a crude product.
The crude product was purified with silica gel column
chromatography to give the title compound
4-amino-2-(1-(2-methylsulfinylethyl)-2,6-dioxopiperidin-3-yl)-isoindolin--
1,3-dione (0.846 g) (HPLC purity: 95.09%). Yield: 16.7%.
[0337] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.462-7.423 (dd,
1H), 7.172-7.155 (d, 1H), 6.895-6.874 (d, 1H), 4.974-4.931 (m, 1H),
4.371-4.192 (m, 2H), 3.073-2.909 (m, 3H), 2.827-2.696 (m, 2H),
2.650-2.647 (d, 3H), 2.144-2.104 (m, 1H). MS(m/e): 364.22
(M+H.sup.+).
Example 13
Preparation of 4-amino-2-(1-(2-methyl
sulfonylethyl)-2,6-dixopiperidin-3-yl)isoindolin-1,3-dione
[0338] In accordance with the preparation process in Example 12,
4-amino-2-(1-(2-methylthioethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3--
dione was used to give the title compound as a yellow solid (1.78
g) (HPLC purity: 99.47%). Yield: 33.6%.
[0339] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.470-7.431 (dd,
1H), 7.184-7.167 (d, 1H), 6.896-6.876 (d, 1H), 4.988-4.943 (m, 1H),
4.400-4.231 (m, 2H), 3.311-3.277 (t, 2H), 2.999 (s, 3H),
3.012-2.932 (m, 1H), 2.834-2.697 (m, 2H), 2.153-2.110 (m, 1H).
MS(m/e): 380.23 (M+H.sup.+).
Example 14
Preparation of
4-amino-2-(1-(2-methoxyethyl)-3-fluoro-2,6-dioxopiperidin-3-yl)isoindolin-
-1,3-dione
[0340]
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1-
,3-dione was prepared in accordance with PCT Int. Appl.,
2006105697, 12 Oct. 2006.
[0341]
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1-
,3-dione (5 g) was dissolved in tetrahydrofuran (100 mLl) under
argon atmosphere. The solution was cooled to -78.degree. C. To the
solution was slowly added dropwise lithium hexamethyldisilazide (40
mL). After addition, the resultant solution was stirred over 1
hour. To the solution was added N-fluorobenzenesulfonimide (11.67 g
in 30 mL of tetrahydrofuran). After addition, the resultant
solution was stirred over 1 hour. The resultant solution was slowly
heated to the room temperature and reacted overnight. To the
reaction mixture were added saturated aqueous solution of ammonium
chloride (150 mL) and ethyl acetate (150 mL). The solution was
separated. The aqueous phase was extracted with ethyl acetate (100
mL). The organic phases were combined. The combined organic phase
was washed with saturated aqueous solution of sodium chloride (200
mL), dried over anhydrous sodium sulfate and filtered. The organic
phase was concentrated. The residue was purified with column
chromatography (ethyl acetate/petroleum ether=1/3) to give the
title compound as a yellow solid (968 mg) (HPLC purity: 97.20%).
Yield: 18.4%.
[0342] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.461-7.499 (dd,
1H), 7.171-7.153 (d, 1H), 6.931-6.899 (d, 1H), 4.193-4.024 (m, 2H),
3.670-3.640 (t, 2H), 3.606-3.5558 (m, 1H), 3.020 (s, 3H),
2.371-2.960 (m, 1H), 2.656-2.555 (m, 1H), 2.433-2.342 (m, 1H).
MS(m/e): 372.22 (M+Na.sup.+).
Example 15
Preparation of
4-amino-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)isoindolin-
-1)isoindolin-1,3-dione
[0343] 3-amino-3-methylpiperidin-2,6-dione hydrochloride was
prepared in accordance with PCT Int. Appl., 2006081251, 3 Aug.
2006.
[0344] Using the preparation process in Example 4,
3-amino-3-methylpiperidin-2,6-dione hydrochloride and
3-nitrophthalic anhydride were reacted to give 2-(3-methyl-2,6-di
oxopiperidin-3-yl)-4-nitroisoindolin-1,3-dione as a white solid
(2.7 g) (HPLC purity: 66.03%). Yield: 69.1%. MS(m/e): 318.12
(M+H+).
[0345] Using the preparation process in Example 11,
2-(3-methyl-2,6-dioxopiperidin-3-yl)-4-nitroisoindolin-1,3-dione
was used to prepare
4-nitro-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)-isoindoli-
n-1,3-dion e as a yellow solid (0.736 g) (HPLC purity: 96.45%).
Yield: 28.3%. MS(m/e): 376.26 (M+H+).
[0346] Using the preparation process in Example 7,
4-nitro-2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxopiperidin-3-yl)-isoindoli-
n-1,3-dion e was used to give the title compound as yellow solid
(0.572 g) (HPLC purity: 94.51%). Yield: 84.1%.
[0347] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.430-7.391 (t, 1H),
7.104-7.086 (d, 1H), 6.854-6.833 (d, 1H), 4.112-4.074 (m, 2H),
3.615-3.580 (m, 2H), 3.373 (s, 3H), 2.844-2.793 (m, 1H),
2.734-2.690 (m, 2H), 2.046-1.993 (m, 1H), 1.969 (s, 3H). MS(m/e):
368.22 (M+Na.sup.+). MS(m/e): 368.22 (M+Na.sup.+).
Example 16
Preparation of
4-acetylamino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1-
,3-dione
[0348] N-((benzyloxy)carbonyl)-glutamic anhydride was prepared in
accordance with Archives of Pharmacal Research, 31(7), 834-837;
2008.
[0349] To a reaction flask were added
N-((benzyloxy)carbonyl)-glutamic anhydride (19 g),
3-methoxypropylamine (6.4 g), triethylamine (7.3 g),
4-dimethylaminopyridine (0.88 g) and tetrahydrofuran (270 mL). The
reaction solution was stirred at the room temperature over 40 hours
until the reaction was complete. The resultant reaction was the
tetrahydrofuran solution of the product, which was directly used in
the next step.
[0350] N,N'-carbonyldiiazole (23.4 g) was added into the above
reaction solution in batch. The resultant solution was stirred at
the room temperature over 72 hours until the reaction was complete.
The solution was concentrated under reduced pressure. To the
concentrate was added dichloromethane (500 mL). The resultant
solution was washed with 1 N hydrochloric acid (250 mL), saturated
aqueous solution of sodium bicarbonate (250 mL) and saturated
aqueous solution of sodium chloride (250 mL). The organic phase was
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure to give
1-(2-methoxypropyl)-3-benzyloxyamido-2,6-piperidinedione as a brown
oil (23.7 g), which was directly used in the next step. MS(m/e):
357.24 (M+Na+).
[0351] Using the preparation process in Example 4,
1-(2-methoxypropyl)-3-benzyloxyamido-2,6-pi peridinedione was used
to prepare the title compound as a white solid (0.434 g) (HPLC
purity: 97.71%). Yield: 12.5%.
[0352] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 9.411 (bs, 1H),
8.822-8.801 (d, 1H), 7.729-7.689 (dd, 1H), 7.555-7.535 (dd, 1H),
4.943-4.987 (m, 1H), 3.993-3.879 (m, 2H), 3.428-3.397 (t, 2H),
3.304 (s, 3H), 3.005-2.936 (m, 1H), 2.825-2.705 (m, 2H), 2.266 (s,
3H), 2.146-2.092 (m, 1H), 1.880-1.802 (m, 2H). MS(m/e): 410.31
(M+Na.sup.+).
Example 17
Preparation of
4-fluoro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one
[0353] Using the preparation process in Example 4,
1-(2-methoxypropyl)-3-amino-2,6-piperidinedione acetate and
3-fluorophthalic anhydride were reacted to give the title compound
as a yellowish sticky product (0.631 g) (HPLC purity: 97.42%).
Yield: 31.1%.
[0354] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.792-7.743 (m, 1H),
7.715-7.697 (d, 1H), 7.444-7.400 (m, 1H), 4.978-4.932 (m, 1H),
3.988-3.871 (m, 2H), 3.421-3.390 (t, 2H), 3.300 (s, 3H),
3.000-2.938 (m, 1H), 2.851-2.691 (m, 2H), 2.142-2.091 (m, 1H),
1.872-1.797 (m, 2H). MS(m/e): 349.22 (M+H+).
Example 18
Preparation of
5-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne
[0355] Using the preparation process in Example 4, 5-nitrophthalic
anhydride and 1-(2-methoxypropyl)-3-amino-2,6-piperidinedione
acetate were reacted to prepare
5-nitro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one as a yellowish oily product (1.118 g) (HPLC purity: 98.44%).
Yield: 20%. MS(m/e): 376.25 (M+H.sup.+).
[0356] Using the preparation process in Example 7,
5-nitro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one was used to give the title compound as a yellowish solid (0.697
g) (HPLC purity: 97.79%). Yield: 67.7%.
[0357] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.624-7.603 (d, 1H),
7.031-7.027 (d, 1H), 6.861-6.835 (dd, 1H), 4.925-4.879 (m, 1H),
3.977-3.863 (m, 2H), 3.421-3.390 (t, 2H), 3.301 (s, 3H),
2.969-2.922 (m, 1H), 2.820-2.676 (m, 2H), 2.108-2.056 (m, 1H),
1.869-1.794 (m, 2H). MS(m/e): 346.24 (M+H+).
Example 19
Preparation of
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione
[0358] Using the preparation process in Example 16,
N-((benzyloxy)carbonyl)-glutamic anhydride was used to prepare
1-(2-ethoxyethyl)-3-benzyloxyamido-2,6-piperidinedione as a brown
oily crude product (17.2 g).
[0359] Using the preparation process in Example 4,
1-(2-ethoxyethyl)-3-amino-2,6-piperidinedione acetate and
3-nitrophthalic anhydride were reacted to prepare
4-nitro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-dion-
e as an off-white solid (1.326 g) (HPLC purity: 95.24%). Yield:
39.4%. MS(m/e): 376.23 (M+H+).
[0360] Using the preparation process in Example 7,
4-nitro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-dion-
e was used to prepare
4-amino-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-dion-
e as a yellow solid (0.631 g) (HPLC purity: 94.95%). Yield:
51.7%.
[0361] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.450-7.411 (dd,
1H), 7.174-7.156 (d, 1H), 6.881-6.860 (d, 1H), 4.963-4.918 (m, 1H),
4.119-3.994 (m, 2H), 3.575-3.480 (m, 4H), 3.023-2.921 (m, 1H),
2.839-2.714 (m, 2H), 2.140-2.035 (m, 1H), 1.180-1.145 (t, 3H).
MS(m/e): 346.24 (M+H.sup.+).
Example 20
Preparation of
4-fluoro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e
[0362] Using the preparation process in Example 4,
1-(2-ethoxyethyl)-3-amino-2.6-piperidinedione acetate and
3-fluorophthalic anhydride were reacted to give the title compound
as a yellowish sticky product (1.566 g) (HPLC purity: 98.63%).
Yield: 74.7%.
[0363] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.792-7.743 (m, 1H),
7.715-7.698 (d, 1H), 7.444-7.400 (m, 1H), 5.019-4.974 (m, 1H),
4.147-3.984 (m, 2H), 3.570-3.475 (m, 4H), 3.045-2.941 (m, 1H),
2.862-2.733 (m, 2H), 2.167-2.087 (m, 1H), 1.178-1.143 (t, 3H).
MS(m/e): 349.23 (M+H.sup.+).
Example 21
Preparation of
5-fluoro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one
[0364] Using the preparation process in Example 4, 4-fluorophthalic
anhydride and 1-(2-methoxyethyl)-3-amino-2,6-piperidinedione
acetate were reacted to give the title compound as a white solid
(2.905 g) (HPLC purity: 99.64%). Yield: 77.9%.
[0365] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.912-7.880 (dd,
1H), 7.572-7.549 (dd, 1H), 7.457-7.408 (dt, 1H), 5.023-4.978 (m,
1H), 4.144-3.988 (m, 2H), 3.544-3.512 (m, 2H), 3.342 (s, 3H),
3.056-2.933 (m, 1H), 2.859-2.738 (m, 2H), 2.175-2.080 (m, 1H).
MS(m/e): 357.20 (M+Na.sup.+).
Example 22
Preparation of
4-amino-2-(1-(2-methoxybutyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e
[0366] Using the preparation process in Example 11,
3-amino-N-(2,6-dioxo-3-piperidinyl)-phthalimide and
1-bromo-4-methoxybutane were reacted to give the title compound as
a yellow solid (2.625 g) (HPLC purity: 99.02%). Yield: 79.9%.
[0367] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.455-7.416 (dd,
1H), 7.178-7.160 (dd, 1H), 6.884-6.863 (dd, 1H), 4.927-4.882 (m,
1H), 3.858-3.816 (m, 2H), 3.402-3.371 (t, 2H), 3.317 (s, 3H),
3.007-2.916 (m, 1H), 2.819-2.685 (m, 2H), 2.117-2.067 (m, 1H),
1.651-1.571 (m, 4H). MS(m/e): 360.28 (M+H+).
Example 23
Preparation of
4-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-di-
one
[0368] Using the preparation process in Example 4,
3-hydroxyphthalic anhydride and
1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate were reacted
to give the title compound as a white solid (2.833 g) (HPLC purity:
99.54%). Yield: 80.1%.
[0369] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.649-7.609 (dd,
1H), 7.539 (bs, 1H), 7.430-7.412 (d, 1H), 7.214-7.193 (d, 1H),
4.980-4.934 (m, 1H), 4.146-3.991 (m, 2H), 3.549-3.516 (m, 2H),
3.342 (s, 3H), 3.048-2.941 (m, 1H), 2.843-2.724 (m, 2H),
2.165-2.083 (m, 1H). MS(m/e): 333.19 (M+H.sup.+).
Example 24
Preparation of
4-methyl-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindolin-1,3-di-
one
[0370] Using the preparation process in Example 4, 3-methylphthalic
anhydride and 1-(2-methoxyethyl)-3-amino-2,6-piperidinedione
acetate were reacted to give the title compound as a white solid
(2.348 g) (HPLC purity: 98.36%). Yield: 68.1%.
[0371] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.716-7.697 (d, 1H),
7.623-7.586 (t, 1H), 7.508-7.489 (d, 1H), 5.017-4.972 (m, 1H),
4.143-3.996 (m, 2H), 3.547-3.516 (t, 2H), 3.344 (s, 3H),
3.006-2.944 (m, 1H), 2.855-2.732 (m, 2H), 2.698 (s, 3H),
2.153-2.084 (m, 1H). MS(m/e): 353.23 (M+Na.sup.+).
Example 25
Preparation of
4-amino-5-methoxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione
[0372] To a reaction flask were added
4-amino-5-hydroxy-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindol-
in-1,3-dione (2.5 g), methyl iodide (1.02 g), potassium carbonate
(1.99 g) and N,N-dimethylformamide (25 mL). The solution was
stirred at the room temperature over 16 hours until the reaction
was complete. The solution was added into water at the room
temperature. The resultant solution was stirred and filtered. The
filter cake was collected as crude product. The crude product was
dissolved and purified with methyl tert-butyl ether/ethyl acetate
to give the title compound as a yellow solid (1.94 g) (HPLC purity:
96.08%). Yield: 74.6%.
[0373] .sup.1HNMR(CDCl.sub.3, 400 MHz) .delta. 7.180-7.160 (d, 1H),
6.891-6.871 (d, 1H), 5.388 (bs, 2H), 4.954-4.909 (m, 1H),
4.136-3.987 (m, 2H), 3.943 (s, 3H), 3.541-3.511 (t, 2H), 3.340 (s,
3H), 2.983-2.944 (m, 1H), 2.793-2.744 (m, 2H), 2.130-2.035 (m, 1H).
MS(m/e): 362.22 (M+H.sup.+).
Example 26
Preparation of
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne
[0374] To a three-neck flask (100 mL) were added 3-nitrophthalic
anhydride (5 g, 25.9 mmol), L-glutamine (3.782 g, 25.9 mmol), and
acetonitrile (45 mL). The reaction solution was magnetically
stirred under argon atmosphere. The reaction solution was refluxed
at 90.degree. C. over 14 hours. After the reaction was complete,
the solution was cooled. To the solution was added
N,N'-carbonyldiiazole (12.591 g, 77.7 mmol) at the room
temperature. The solution was stirred at the room temperature until
no bubble was released. The resultant solution was reacted over 1
hour in an oil bath of 84.degree. C. The solution was cooled to the
room temperature. The solution was added into hydrochloric acid
(225 mL, 1 mol/L) with vigorously stirring. The resultant solution
was stirred and filtered. The filter cake was dissolved in absolute
ethanol (25 mL). The solution was filtered. The resultant solid was
dried in vacuo to give
2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindolin-1,3-dione (5.125 g)
as a yellow product. Yield: 65.3%.
[0375] To a single-neck flask (100 mL) were added
2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindolin-1,3-dione (3 g, 9.9
mmol) and N,N-dimethylformamide (45 mL). Sodium hydride (content:
60%, 0.872 g, 21.8 mmol) was added in one portion. The solution was
stirred at the room temperature over 15 minutes. To the solution
was slowly added dropwise 3-bromopropyl methyl ether (1.8 g, 12
mmol) in N,N-dimethylformamide (4 mL). After addition, the reaction
continued over 2.5 hours. The reaction solution was poured into
saturated aqueous solution of ammonium chloride (400 mL). The
resultant solution was extracted with ethyl acetate (200
mL.times.3). The organic phases were combined. The combined organic
phase was dried over anhydrous sodium sulfate and filtered. The
filtrate was concentrated. The residue was separated with column
chromatography to give
4-nitro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,-
3-dione (1.211 g). Yield: 32.3%.
[0376] To a single-neck flask were added
4-nitro-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne (1.875 g, 5 mmol), palladium on carbon (10%, 0.4 g), methanol
(10 mL), tetrahydrofuran (10 mL). The air was replaced with
hydrogen. The solution was stirred at the room temperature and
under atmospheric pressure overnight. After the reaction was
complete, the solution was filtered with diatomite. The filtrate
was concentrated. The residue was separated with column
chromatography to give the title compound
4-amino-2-(1-(2-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dio-
ne (1.135 g). HPLC purity: 96.51%. Yield: 65.8%.
[0377] MS(m/e): 346 (M+H.sup.+)
Example 27
Preparation of
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e
[0378] The Chinese patent No. ZL200510013292.3 discloses the
preparation process of
4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dion-
e, which is incorporated herein by reference in its entirety.
[0379] Alternatively, in accordance with the preparation process in
Example 27, 3-bromopropyl methyl ether was replaced with
3-bromoethyl methyl ether to prepare the title compound.
[0380] .sup.1HNMR(CDCl.sub.3, 600 MHz) .delta. 7.38 (t, 1H), 7.11
(d, 1H), 6.85 (d, 1H), 5.30 (bs, 2H), 4.95-4.98 (m, 1H), 4.09-4.13
(m, 1H), 4.00-4.04 (m, 1H), 3.52-3.54 (m, 2H), 3.34 (s, 3H),
2.96-2.99 (m, 1H), 2.76-2.75 (m, 1H), 2.78-2.80 (m, 1H), 2.08-2.11
(m, 1H). MS(m/e): 332 (M+H+).
Biological Example 1
Effects of Piperidine-2,6-Dione Derivatives on Treatment of
DNBS-Induced Inflammatory Bowel Disease Models in Rats
Experimental Animals:
[0381] Wistar rats, male, body weight of 100-120 g.
Methods:
[0382] 90 male Wistar rats were fasted for 40 hours. A 5% glucose
injection was administered subcutaneously during fasting. 60 rats
with normal conditions and moderate body weight were selected from
the fasting rats. The animals were randomly divided into 6 groups
according to the body weight: normal control group, model control
group, sulfasalazine group (300 mg/Kg), and the compound in Example
27 groups consisting of 5, 15 and 30 mg/Kg dose groups. There were
10 rats in each group. The animals were anesthetized with ether. A
specially made gavage device (made by a rat gavage device having
the diameter of 2 mm, which was nested on a mouse gavage device
having the diameter of 1 mm) was slowly inserted into the enteric
cavity at 8 cm from the anus. The model control group, the
sulfasalazine group and the compound in Example 27 groups were
administered with 0.5 mL of 50 mg/mL DNBS in 30% ethanol solution.
The normal control group was administered with 0.5 mL of 30%
ethanol solution. The animals were inverted in anesthesia for 15
minutes after the gavage device was removed. The day when the model
was prepared was the first day of the experiment. After 4 hours of
DNBS induction, the corresponding drug or the corresponding volume
of 1% CMC-Na was administered once per day. The body weights were
recorded and the stool characteristics were scored. On the sixth
day of the experiment colon tissues were taken from the animals to
observe the results of each index.
[0383] The compound in Example 27 and sulfasalazine: Preparation
Method: Suspended with 1% CMC-Na, and prepared when it was
needed.
TABLE-US-00004 TABLE 3 Grouped Table DNBS Clysis Administration
DNBS Concentration Volume Administration Dose Administration Groups
Solvent (mg/mL) (mL/rat) Route (mg/Kg) Regimen Normal Control 30% 0
0.5 i.g 0 qd .times. 6 Group ethanol Model Control 30% 50 0.5 i.g 0
qd .times. 6 Group ethanol Sulfasalazine 30% 50 0.5 i.g 300 qd
.times. 6 Group ethanol Compound in 30% 50 0.5 i.g 5 qd .times. 6
Example 27 ethanol Group 30% 50 0.5 i.g 15 qd .times. 6 ethanol 30%
50 0.5 i.g 30 qd .times. 6 ethanol Note: i.g: intragastric
administration; qd .times. 6: once per day, a total of 6 times.
[0384] Animals were euthanized on the sixth day of the experiment
to observe the results of each index. After the animals were
sacrificed, colons were obtained. The adhesion degree of colon was
observed and the length of the colon was measured. The ulcer area
was calculated after removing the contents in the colon and the
weight of the colon tissue was weighed. The colon tissue was
longitudinally divided into two parts. One part of the colon tissue
was fixed in 10% formalin solution for later use. The other part of
the colon tissue was put into the liquid nitrogen to quickly
frozen, and then was reserved at -80.degree. C. for the detection
of MPO.
TABLE-US-00005 TABLE 4 Criteria for Adhesion Degree of Colon in
Rats Adhesion Degree Point None 0 Mild 1 Severe 2
[0385] Reference: Videla S, Vilaseca J, Medina C, et al. Selective
inhibition of phosphodiesterase-4 ameliorates chronic colitis and
prevents intestinal fibrosis [J]. Journal of Pharmacology and
Experimental Therapeutics, 2006, 316(2): 940-945.
[0386] Calculation method for ulcer area: length of ulcer point
(cm).times.width of ulcer point (cm).
[0387] The frozen tissue was ground into powder in liquid nitrogen.
An appropriate amount of the powder was weighed and was added into
50 mM potassium phosphate solution (containing 0.5%
cetyltrimethylammonium bromide) to give a 25 mg/mL solution. The
resultant solution was homogenized by an electric homogenizer. 1 mL
of suspension was centrifuged to give a supernatant. 7 .mu.L of the
supernatant was added into a 96-well plate and 200 .mu.L of
o-dianisidine mixture (containing 0.167 mg/mL o-dianisidine and
0.0006% H.sub.2O.sub.2 potassium phosphate buffer). OD values of
the resultant solution at 0, 30, 60, and 90 s were detected at 450
nm of the microplate reader.
Statistical Analysis of Data:
[0388] Test for homogeneity of variance was performed with
Spss13.0. Where variance of data was homogeneous (P>0.05),
one-way ANOVA LSD test was performed. Where the analysis of
variance was significant (P.ltoreq.0.05), then Dunnett's multiple
comparison (parameter method) or Kruskal-Wallis non-parametric test
was performed. Where the results of Kruskal-Wallis non-parametric
test were significant (P.ltoreq.0.05), the Mann-Whitney U test was
performed for pairwise comparison.
Experimental Results:
TABLE-US-00006 [0389] TABLE 5 Results of Animal Colon Indexes in
Each Group (Mean .+-. SD) Adhesion Degree Colon Weight Groups
(Point) (mg) Normal Control Group 0.0 .+-. 0.0 1454.3 .+-. 177.9
Model Control Group 0.7 .+-. 0.8 2026.1 .+-. 781.0 Sulfasalazine
Group- 0.2 .+-. 0.4 1794.9 .+-. 242.3 300 mg/Kg Compound in Example
0.4 .+-. 0.7 1775.7 .+-. 321.0 27 Group-5 mg/Kg Compound in Example
0.1 .+-. 0.3 1668.7 .+-. 245.3 27 Group-15 mg/Kg Compound in
Example 0.1 .+-. 0.3 1534.7 .+-. 156.2 27 Group-30 mg/Kg Note: *
compared with normal control group, P < 0.01; #: compared with
model control group, P < 0.05.
TABLE-US-00007 TABLE 6 Results of Animal Colon Indexes in Each
Group (Mean .+-. SD) Colon weight to Colon MPO length ratio Ulcer
Area Activity Groups (mg/cm) (cm.sup.2) (U/mg) Normal Control Group
90.0 .+-. 9.5 0.0 .+-. 0.0 1.7 .+-. 1.2 Model Control Group 145.4
.+-. 50.1 1.8 .+-. 1.9 33.4 .+-. 19.6* Sulfasalazine Group- 140.6
.+-. 27.9 0.7 .+-. 0.6 26.0 .+-. 14.8 300 mg/Kg Compound in Example
144.2 .+-. 30.5 0.8 .+-. 0.9 20.3 .+-. 19.8 27 Group-5 mg/Kg
Compound in Example 127.1 .+-. 13.7 0.7 .+-. 0.9 16.7 .+-. 9.8# 27
Group-15 mg/Kg Compound in Example 117.7 .+-. 19.4 0.3 .+-. 0.5
15.1 .+-. 13.0# 27 Group-30 mg/Kg Note: *compared with normal
control group, P < 0.05; #compared with model control group, P
< 0.05.
[0390] Results of colonic tissue-related indexes showed that
compared with the normal control group, the colon of the model
control group was significantly shortened, the colon tissue was
abnormally proliferated and the colon weight was increased. At the
same time, the MPO activity of colon tissue was significantly
increased, the colon had a larger area of ulcer injury.
Sulfasalazine as positive drug at the dose of 300 mg/Kg reduced the
colon abnormal proliferation and reduced the colon weight, and had
some improvement on colonic ulcers with the reduction of the ulcer
area by 60.degree. %. The compound in Example 27 at the dose of 5
mg/Kg, 15 mg/Kg and 30 mg/Kg reduced the adhesion degree of colons,
reduced the weight of colon tissue and the ulcer degree, and
reduced the MPO activity of colon tissue, and thus showed a certain
dose effect and a good therapeutic effect without the weight loss
of animals. The compound in Example 27 at the dose of 30 mg/Kg
reduced the ulcer degree of colon with a reduction of the ulcer
area by about 80%, while the MPO activity of colon tissue was
significantly reduced (P<0.05), of which the therapeutic effects
are better than those of sulfasalazine as positive drug at the dose
of 300 mg/Kg.
Biological Example 2
Effects of Piperidine-2,6-Dione Derivatives on Treatment of
DNBS-Induced Inflammatory Bowel Disease Models in Rats
Experimental Grouping and Modeling:
[0391] 110 male Wistar rats were fasted for 40 hours. A 5% glucose
injection (10 mL/Kg) was administered subcutaneously during
fasting. 48 rats with normal conditions and moderate body weight
were selected from the fasting rats. The animals were randomly
divided into 5 groups according to the body weight: normal control
group, model control group, sulfasalazine group (300 mg/Kg),
dexamethasone group (0.1 mg/Kg), the compound in Example 26 group
(30 mg/kg) and the compound in Example 27 group (30 mg/kg), with 8
rats in each group. The animals were anesthetized with isoflurane.
A specially made gavage device (made by a rat gavage device having
the diameter of 2 mm, which was nested on a mouse gavage device
having the diameter of 1 mm) was slowly inserted into the enteric
cavity at 8 cm from the anus. The model control group, the compound
in Example 26 group and the compound in Example 27 group were
administered with 0.5 mL of 50 mg/mL DNBS in 30% ethanol solution.
The normal control group was administered with 0.5 mL of 30%
ethanol solution. The animals were inverted in anesthesia for 15
minutes after the gavage device was removed. The day when the model
was prepared was the first day of the experiment. After 4 hours of
DNBS induction, the corresponding drug or the corresponding volume
of 1% CMC-Na was administered once per day. On the sixth day of the
experiment, the animals were euthanized to observe the results of
each index so as to score the colon adhesion degree, measure the
length of colon and ulcer area, weigh colon and calculate the colon
weight to length ratio.
[0392] The compound in Example 26 and Example 27, sulfasalazine and
dexamethasone: Preparation Method: Suspended with 1% CMC-Na, and
prepared when it was needed.
TABLE-US-00008 TABLE 7 Grouped Table DNBS Clysis Administration
Number Concentration Volume Administration Dose Administration of
Groups (mg/mL) (mL/rat) Route (mg/Kg) Regimen Animals Normal
Control 0 0.5 i.g 0 qd .times. 6 8 Group Model Control 50 0.5 i.g 0
qd .times. 6 8 Group Sulfasalazine 50 0.5 i.g 300 qd .times. 6 8
Group Dexamethasone 50 0.5 i.g 0.1 qd .times. 6 8 Group Compound in
50 0.5 i.g 30 qd .times. 6 8 Example 27 Group Compound in 50 0.5
i.g 30 qd .times. 6 8 Example 26 Group Note: qd .times. 6: once per
day, a total of 6 times.
Statistical Analysis of Data:
[0393] Levene's Test for homogeneity of data was performed with
Spss. Where the data were homogeneous (P>0.05), one-way ANOVA
LSD test was performed. Where the analysis of variance was
significant (P.ltoreq.0.05), Dunnett's multiple comparison
(parameter method) was performed. Where the results of Levene's
Test were significant (P.ltoreq.0.05), Kruskal-Wallis nonparametric
test was performed. Where the results of Kruskal-Wallis
nonparametric test were significant (P.ltoreq.0.05), Mann-Whitney U
test was performed for pairwise comparison.
Experimental Results:
TABLE-US-00009 [0394] TABLE 8 Results of Animal Colon Indexes in
Each Group (Mean .+-. SD) Colon Adhesion Length Colon Weight Degree
Ulcer Area Groups (cm) (mg) (Points) (cm.sup.2) Normal Control
Group 15.1 .+-. 0.9 1406.3 .+-. 83.7 0.0 .+-. 0.0 0.0 .+-. 0.0
Model Control Group 12.6 .+-. 1.3** 1863.3 .+-. 406.0* 0.9 .+-. 0.6
3.3 .+-. 1.4** Sulfasalazine Group 13.2 .+-. 2.5 1776.1 .+-. 280.7
0.8 .+-. 0.7 1.6 .+-. 1.2# Dexamethasone Group 14.2 .+-. 0.9 1496.0
.+-. 450.0# 0.3 .+-. 0.5 1.4 .+-. 1.5# Compound in Example 13.7
.+-. 1.4 1628.3 .+-. 185.5 0.3 .+-. 0.5 1.1 .+-. 0.9## 26 Group
Compound in Example 12.9 .+-. 2.3 1737.9 .+-. 410.6 0.9 .+-. 0.8
2.0 .+-. 1.9 27 Group Note: *compared with normal control group, P
< 0.05; **compared with normal control group, P < 0.01;
#compared with model control group, P < 0.05, ##compared with
model control group, P < 0.01.
[0395] The results of this experiment showed that after the animals
were induced by DNBS in ethanol solution, the growth rate of the
body weight was lower than that of the normal control group. On the
fourth day of the experiment, the growth rate of the body weight of
the animals in the sulfasalazine group and the compound in Example
26 group and the compound in Example 27 group was higher than that
in the model control group, while the growth of the body weight of
the animals in the dexamethasone group were slower, which
indirectly implied the improvement effects of the drugs on the
colonic injury.
[0396] The results of fecal characteristics showed that diarrhea
symptoms were observed in all groups of DNBS-induced animals. On
the fifth day of experiment, symptoms of diarrhea and liquid stools
of animals in each administration group were slightly improved
compared with the model control group.
[0397] Colon indexes showed that the area of colonic ulcer and the
weight of colon of model control group were significantly higher
than those of normal control group (P<0.05), and the colon was
significantly shortened. Compared with model control group, there
was significant reduction in the area of colonic ulcer in each
administration group (P<0.05).
[0398] In view of the above results, the compound in Example 26 and
the compound in Example 27 have good therapeutic effects on the
improved model.
Biological Example 3
Effects of Piperidine-2,6-Dione Derivatives on Treatment of
DNBS-Induced Inflammatory Bowel Disease Models in Rats
Experimental Grouping and Modeling:
[0399] 102 male Wistar rats were fasted for 40 hours. A 5% glucose
injection (10 mL/Kg) was administered subcutaneously during
fasting. 72 rats with normal conditions and moderate body weight
were selected from the fasting rats. The animals were randomly
divided into 9 groups according to the body weight (see Table 9.
Grouped Table).
[0400] The animals were anesthetized with ether after 40 hours
fasting. A specially made gavage device was slowly inserted into
the enteric cavity at 8 cm from the anus. The model control group
and each test group were administered with 0.5 mL of 50 mg/mL DNBS
in 30% ethanol solution. The normal control group was administered
with 0.5 mL of 30% ethanol solution. The animals were inverted in
anesthesia for 15 minutes. The day when the model was prepared was
day 0 of the experiment. After 4 hours of DNBS induction, the
corresponding drug or the corresponding volume of 1% CMC-Na was
administered once per day. On day 7 of the experiment, the animals
were euthanized to score the colon adhesion degree, measure the
length of colon and ulcer area, weigh colon and calculate the colon
weight to length ratio.
TABLE-US-00010 TABLE 9 Grouped Table DNBS Clysis Administration
Number DNBS Concentration Volume Administration Dose Administration
of Groups Solvent (mg/ml) (ml/rat) Route (mg/Kg) Regimen Animals
Normal Control 30% 0 0.5 -- -- -- 8 Group ethanol Model Control 50
0.5 ig -- qd .times. 7 Group Example 27 30 Example 7 Example 4
Example 21 Example 22 Example 6 Example 16 Note: The compound in
each Example was suspended with 1% CMC-Na to prepare a 3 mg/mL of
homogenous suspension. The administration volume was 10 mL/Kg. qd
.times. 7: once per day, a total of 7 times. i.g: intragastric
administration.
[0401] One-way ANOVA analysis of the length of colon and colon
weight per length of rats was performed by SPSS22. Statistical
analyses between groups were performed. The adhesion degree was
scored. Mann-Whitney U non-parametric test was performed on ulcer
area. Statistical analyses between groups were performed.
TABLE-US-00011 TABLE 10 Criteria for Adhesion Degree of Colon in
Rats Adhesion Degree Point None 0 Mild 1 Severe 2
Experimental Results:
TABLE-US-00012 [0402] TABLE 11 Table of Body Weights Changes of
Experimental Rats over 7 Days (g, Mean .+-. SD) Day 0 Day 1 Day 2
Day 3 Day 4 Day 5 Day 6 Day 7 Blank Control 135.7 .+-. 4.1 150.4
.+-. 7.4 162.7 .+-. 12.0 168.1 .+-. 15.5 172.3 .+-. 12.8 180.5 .+-.
15.7 182.7 .+-. 12.9 197.0 .+-. 13.1 Group Model Control 139.9 .+-.
6.6 141.6 .+-. 10.4 140.8 .+-. 11.0 137.9 .+-. 6.6 143.8 .+-. 7.9
154.0 .+-. 4.6 158.3 .+-. 7.7 168.2 .+-. 14.3 Group Example 27
135.4 .+-. 4.9 135.2 .+-. 4.2 136.7 .+-. 5.0 141.7 .+-. 7.5 150.1
.+-. 9.2 159.1 .+-. 10.3 165.2 .+-. 10.0 175.8 .+-. 8.2 Example 7
136.1 .+-. 2.5 136.7 .+-. 3.7 137.0 .+-. 8.7 141.6 .+-. 11.9 148.2
.+-. 12.7 159.2 .+-. 13.2 168.0 .+-. 15.7 173.5 .+-. 18.5 Example 4
137.1 .+-. 6.2 136.2 .+-. 4.1 138.2 .+-. 6.9 141.1 .+-. 8.8 151.8
.+-. 13.4 162.5 .+-. 13.0 170.8 .+-. 13.0 181.0 .+-. 12.2 Example
21 135.6 .+-. 6.9 134.4 .+-. 6.8 133.9 .+-. 6.8 138.7 .+-. 6.8
146.4 .+-. 6.9 157.9 .+-. 8.9 168.3 .+-. 4.6 173.5 .+-. 7.4 Example
22 137.5 .+-. 7.2 137.0 .+-. 9.0 139.7 .+-. 11.2 144.1 .+-. 12.7
152.6 .+-. 20.0 162.7 .+-. 19.0 170.5 .+-. 17.7 178.3 .+-. 20.7
Example 6 137.5 .+-. 5.6 138.1 .+-. 8.0 141.8 .+-. 13.1 147.4 .+-.
16.5 154.5 .+-. 17.7 164.2 .+-. 16.2 169.3 .+-. 18.4 180.9 .+-.
15.5 Example 16 137.3 .+-. 1.7 135.9 .+-. 3.7 137.6 .+-. 7.0 145.0
.+-. 9.2 155.2 .+-. 10.9 166.8 .+-. 10.2 171.5 .+-. 15.1 184.3 .+-.
13.8
TABLE-US-00013 TABLE 12 Colonic Data of Rats in Each Group
Inhibitory Adhesion Inhibitory rate of weight Inhibitory Degree of
rate of colon Colon weight increase Ulcer area rate of ulcer Colon
adhesion to length ratio per length of colon area of colon (unit:
point) (%) (unit: mg/cm) (%) (unit: cm.sup.2) (%) Blank Control 0.0
.+-. 0.0 76 .+-. 13 0.00 .+-. 0.00 Group Model Control 1.7 .+-.
0.5*** 155 .+-. 56*** 3.09 .+-. 2.23*** Group Example 27 0.9 .+-.
0.4# 47.1# 109 .+-. 12## 58.2## 0.01 .+-. 0.02## 99.7## Example 22
0.8 .+-. 0.9# 52.9# 112 .+-. 40# 54.4# 1.84 .+-. 2.59 40.5 Example
21 0.9 .+-. 0.7# 47.1# 104 .+-. 17## 64.6## 0.93 .+-. 1.52 70.0
Example 16 1.1 .+-. 0.8 35.3 114 .+-. 23# 51.9# 0.84 .+-. 1.25#
72.8# Example 7 0.9 .+-. 0.8# 47.1# 127 .+-. 52 35.4 0.77 .+-. 1.05
75.1 Example 6 0.6 .+-. 0.5## 64.7# 99 .+-. 21## 70.9## 0.34 .+-.
0.54# 89.0# Example 4 0.6 .+-. 0.7## 64.7## 125 .+-. 34 38.0 0.58
.+-. 0.78# 81.2# Note: ***compared with blank control group, P <
0.001; #compared with model control group, P < 0.05; ##compared
with model control group, 0.001 .ltoreq. P < 0.01.
[0403] Calculation Formula of Inhibitory rate of weight increase
per length: (Colon weight to length ratio in model group-Colon
weight to length ratio in administration group)/(Colon weight to
length ratio in model group-Colon weight to length ratio in blank
group)
[0404] The pathological changes of the colon (adhesion, hyperplasia
and ulcer) in the animals can be effectively relieved by the
treatment in each experimental group.
Biological Example 4
Effects of Piperidine-2,6-Dione Derivatives on Treatment of
DNBS-Induced Inflammatory Bowel Disease Models in Rats
Experimental Grouping and Modeling:
[0405] 102 male Wistar rats were fasted for 72 hours. A 5% glucose
injection was administered subcutaneously twice during fasting. 88
rats with normal conditions and moderate body weight were selected
from the fasting rats. The animals were randomly divided into 11
groups according to the body weight (see Table 11. Grouped
Table).
[0406] The animals were anesthetized with ether after 72 hours
fasting. A specially made gavage device was slowly inserted into
the enteric cavity at 8 cm from the anus. The model control group
and each test group were administered with 0.5 mL of 50 mg/mL DNBS
in 30% ethanol solution. The normal control group was administered
with 0.5 mL of 30% ethanol solution. The animals were inverted in
anesthesia for 15 minutes. The day when the model was prepared was
day 0 of the experiment. After 4 hours of DNBS induction, the
corresponding drug or the corresponding volume of 1% CMC-Na was
administered once per day. On day 7 of the experiment, the animals
were euthanized to score the colon adhesion degree, measure the
length of colon and ulcer area, weigh colon and calculate the colon
weight to length ratio.
TABLE-US-00014 TABLE 13 Grouped Table DNBS Clysis Administration
Number DNBS Concentration Volume Administration Dose Administration
of Groups Solvent (mg/ml) (ml/rat) Route (mg/Kg) Regimen Animals
Normal Control 30% 0 0.5 -- -- -- 8 Group ethanol Model Control 50
0.5 i.g -- qd .times. 7 Group Example 27 30 Example 8 Example 14
Example 24 Example 5 Example 23 Example 10 Example 2 Example 12
Note: The drug in the experiment was suspended with 1% CMC-Na to
prepare a 3 mg/mL of homogenous suspension. The administration
volume was 10 mL/Kg. i.g: intragastric administration. qd .times.
7: once per day, a total of 7 times.
TABLE-US-00015 TABLE 14 Criteria for Adhesion Degree of Colon in
Rats Adhesion Degree Point None 0 Mild 1 Severe 2
[0407] One-way ANOVA analysis of the length of colon and colon
weight per length of rats was performed by SPSS22. Statistical
analyses between groups were performed. The adhesion degree was
scored. Mann-Whitney U non-parametric test was performed on ulcer
area. Statistical analyses between groups were performed.
Experimental Results:
TABLE-US-00016 [0408] TABLE 15 Table of Body Weights Changes of
Experimental Rats over 7 Days (g, Mean .+-. SD) Day 0 Day 1 Day 2
Day 3 Day 4 Day 5 Day 6 Day 7 Blank Control 117.4 .+-. 1.6 132.2
.+-. 3.7 143.1 .+-. 7.7 153.6 .+-. 7.7 160.7 .+-. 7.2 172.3 .+-.
5.4 170.3 .+-. 4.3 185.0 .+-. 5.6 Group Model Control 121.1 .+-.
4.9 125.7 .+-. 6.3 121.4 .+-. 11.6 123.0 .+-. 8.1 125.3 .+-. 9.4
129.2 .+-. 12.5 134.7 .+-. 9.7 153.9 .+-. 12.7 Group Example 27
121.7 .+-. 7.0 125.5 .+-. 8.4 124.4 .+-. 8.1 125.8 .+-. 8.2 133.1
.+-. 9.2 141.6 .+-. 12.0 146.7 .+-. 11.8 156.3 .+-. 11.0 Example 8
125.3 .+-. 5.4 128.6 .+-. 5.3 128.2 .+-. 9.2 131.6 .+-. 13.5 136.8
.+-. 17.4 149.1 .+-. 16.7 149.7 .+-. 16.8 164.1 .+-. 17.9 Example
14 119.3 .+-. 6.4 126.2 .+-. 8.7 125.1 .+-. 10.5 129.5 .+-. 17.8
136.5 .+-. 19.7 146.4 .+-. 19.4 147.6 .+-. 19.9 165.7 .+-. 20.8
Example 24 123.5 .+-. 4.8 129.1 .+-. 5.5 130.9 .+-. 10.4 133.2 .+-.
14.5 135.3 .+-. 13.6 144.9 .+-. 12.6 145.9 .+-. 13.3 165.6 .+-.
12.1 Example 5 123.4 .+-. 5.5 126.7 .+-. 8.9 125.0 .+-. 11.0 126.9
.+-. 14.0 133.9 .+-. 13.3 141.9 .+-. 14.9 146.9 .+-. 13.9 159.7
.+-. 14.3 Example 23 121.9 .+-. 7.0 126.6 .+-. 8.5 123.2 .+-. 9.0
123.9 .+-. 7.6 136.5 .+-. 11.8 148.1 .+-. 14.5 152.1 .+-. 15.9
166.8 .+-. 12.8 Example 10 119.7 .+-. 4.2 122.4 .+-. 6.7 122.1 .+-.
8.0 126.6 .+-. 9.8 136.9 .+-. 12.5 143.7 .+-. 18.2 144.9 .+-. 19.7
160.8 .+-. 25.7 Example 2 117.9 .+-. 4.6 122.1 .+-. 4.6 123.0 .+-.
8.4 127.1 .+-. 11.3 132.0 .+-. 12.4 143.9 .+-. 11.9 141.5 .+-. 11.5
162.8 .+-. 15.8 Example 12 123.7 .+-. 3.3 129.1 .+-. 5.1 128.7 .+-.
6.6 133.9 .+-. 9.8 141.8 .+-. 12.0 149.2 .+-. 11.0 149.5 .+-. 11.2
167.3 .+-. 11.3
TABLE-US-00017 TABLE 16 Colonic Data of Animals in Each
Experimental Group Inhibitory Adhesion Inhibitory rate of weight
Inhibitory Degree of rate of colon Colon weight increase Ulcer area
rate of ulcer Colon adhesion to length ratio per length of colon
area of colon (unit: point) (%) (unit: mg/cm) (%) (unit: cm.sup.2)
(%) Blank Control 0.3 .+-. 0.5 77 .+-. 8 0 .+-. 0 Group Model
Control 1.6 .+-. 0.5*** 162 .+-. 84*** 2.4 .+-. 3.2** Group Example
27 -- -- 106 .+-. 14 65.9 0.4 .+-. 0.6 83.3 Example 24 0.8 .+-.
0.7# 62.2# 99 .+-. 18 74.1 0.3 .+-. 0.3 87.5 Example 23 0.8 .+-.
0.7# 62.2# 105 .+-. 12 67.1 0.2 .+-. 0.3# 91.7# Example 14 0.8 .+-.
0.5# 62.2 102 .+-. 18 70.6 0.1 .+-. 0.4# 95.8# Example 12 0.8 .+-.
0.7# 62.2# 92 .+-. 16# 82.4# 0.4 .+-. 0.9 83.3 Example 10 0.5 .+-.
0.5## 81.1## 93 .+-. 12# 81.2# 0.2 .+-. 0.5# 91.7## Example 8 0.9
.+-. 0.6 52.7 106 .+-. 13 65.9 0.2 .+-. 0.4 91.7 Example 5 0.8 .+-.
0.5# 62.2# 99 .+-. 14 74.1 0.2 .+-. 0.5 91.7 Example 2 0.8 .+-. 0.9
66.9# 120 .+-. 25 57.6 1.0 .+-. 1.6 83.3 Note: ***compared with
blank control group, P < 0.001; **compared with blank control
group, 0.001 .ltoreq. P < 0.01; #compared with model control
group, P < 0.05; ##compared with model control group, 0.001
.ltoreq. P < 0.01.
[0409] Calculation Formula of Inhibitory rate of weight increase
per length: (Colon weight to length ratio in model group-Colon
weight to length ratio in administration group)/(Colon weight to
length ratio in model group-Colon weight to length ratio in blank
group)
[0410] The pathological changes of the colon (adhesion, hyperplasia
and ulcer) in the animals can be effectively relieved by the
treatment in each experimental group.
Biological Example 5
Acute Toxicity Experiment of Single Oral Administration of
Piperidine-2,6-Dione Derivatives in Mice
Experimental Process
[0411] The mice were fasted one day before the experiment. On the
day of the experiment, 6 mice (ICR mice, body weight of 19-21 g,
three females and three males) were selected in each experiment
group. First of all, one female and one male were selected to
orally give 1000 mg/Kg, and observed for 5-10 minutes. If there
were no obvious side effects, the remaining 4 animals were orally
given the same dose, and observed for 10-15 minutes. If no animal
died, the animals were placed in a box to balancedly feed for 7
days. The state was observed and the body weight was recorded
daily. The animal grouping plan and the initial dose of the drug
were shown in the table below:
TABLE-US-00018 TABLE 17 Information Table of Animal Groups
Administration Administration Drug Number Dose Volume Concentration
of Schedule Groups mg/Kg ml/Kg mg/mL Solvent Animals Day 1 Blank --
15 -- 1% CMC-Na Three Control females Example 1 1000 66.67 and
three Example 8 males Example 3 Example 2 Example 4 Example 24 Day
2 Example 23 Example 10 Example 2 Example 11 Example 20 Example 17
Example 13 Example 12 Day 3 Example 19 Example 26 Example 6 Example
3 Example 9
Observation Indexes within 0-15 Minutes after Administration
[0412] Activity: restlessness, hyperactivity
[0413] Nervous system response: tremor, spasm, convulsion, ataxia,
posture abnormality, etc.
[0414] Autonomic nerve: exophthalmos, salivation, tears, urination
(hematuria), diarrhea, piloerection, breathing, etc.
Observation Indexes Over 7 Days
[0415] Body weight
[0416] State of Animal: lethargy, hyperactivity, excitement, hair
loss, diarrhea, abnormal behavior, death, etc.
Experimental Results
TABLE-US-00019 [0417] TABLE 18 Summary Table of Toxic Response of
Tested Animals in 7 Days Group Sex Summary of toxic response of
tested animals in 7 Days Example 23 Male Abnormality was not
observed in 7 days of the test Female Abnormality was not observed
in 7 days of the test Example 10 Male Decrease of activity was
observed in all the animals within 30 minutes after administration
but activity was recovered within this period. Abnormality was not
observed in all the animals from day 2 to 7. Female Decrease of
activity was observed in all the animals within 30 minutes after
administration but activity was recovered within this period.
Abnormality was not observed in all the animals from day 2 to 7.
Example 2 Male Slight abnormality of activity was occasionally
observed in two animals but activity was recovered within in 30
minutes. Abnormality was not observed in all the animals from day 2
to 7. Female Abnormality was not observed in 7 days of the test
Example 11 Male Abnormality was not observed in 7 days of the test
Decrease of activity was observed in one animal after
administration but activity was recovered within 3 minutes. Female
Abnormality was not observed in all the animals from day 2 to 7.
Example 20 Male Decrease of activity was observed in one animal 11
minutes after administration but activity was recovered later.
Abnormality was not observed in all the animals from day 2 to 7.
Female Decrease of activity was observed in two animals in 10
minutes after administration but activity was recovered later.
Abnormality was not observed in all the animals from day 2 to 7.
Example 17 Male Motor dysfunction in two animals was observed 30
minutes after administration and function was recovered later.
Abnormality was not observed in all the animals from day 2 to 7.
Female Motor dysfunction in one animal was observed 10 minutes
after administration and function was recovered later. Abnormality
was not observed in all the animals from day 2 to 7. Example 13
Male Abnormality was not observed in 7 days of the test Female
Abnormality was not observed in 7 days of the test Example 12 Male
Abnormality was not observed in 7 days of the test Female
Abnormality was not observed in 7 days of the test Example 19 Male
Severe motor dysfunction in two animals was observed 30 minutes
after administration and function was recovered in about 2 hours.
Abnormality was not observed in all the animals from day 2 to 7.
Female Severe motor dysfunction in three animals was observed 30
minutes after administration and function was recovered in about 2
hours. Abnormality was not observed in all the animals from day 2
to 7. Example 26 Male Abnormality was not observed in 7 days of the
test Female Abnormality was not observed in 7 days of the test
Example 6 Male Abnormality was not observed in 7 days of the test
Female Abnormality was not observed in 7 days of the test Example 3
Male Abnormality was not observed in 7 days of the test Female
Abnormality was not observed in 7 days of the test Example 9 Male
Abnormality was not observed in 7 days of the test Female
Abnormality was not observed in 7 days of the test Note: The dosage
is 1000 mg/Kg in Table 18 unless indicated otherwise. "n = 1"
indicate the number of the tested animal in the group is one. The
number of the tested animal is 3 where "n = 1" is not indicated in
the group. Abnormality is not observed where the observation index
is not mentioned.
TABLE-US-00020 TABLE 19 Table of Daily Body Weight of Tested Male
Mice (g, Mean .+-. SD) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Blank Control 17.4 .+-. 1.4 23.1 .+-. 1.5 24.6 .+-. 2.0 25.9 .+-.
1.5 26.9 .+-. 0.7 27.9 .+-. 1.5 28.7 .+-. 1.7 Group Example 1 20.1
.+-. 1.4 23.8 .+-. 1.4 24.9 .+-. 1.0 26.3 .+-. 1.2 27.7 .+-. 1.3
29.2 .+-. 1.4 29.4 .+-. 1.4 Example 8 18.0 .+-. 1.3 23.1 .+-. 0.9
24.6 .+-. 1.0 25.6 .+-. 1.7 27.2 .+-. 2.2 28.2 .+-. 2.2 29.2 .+-.
2.6 Example 3 18.0 .+-. 0.2 22.9 .+-. 0.3 24.3 .+-. 0.9 25.2 .+-.
1.1 27.0 .+-. 1.3 28.2 .+-. 1.9 28.5 .+-. 2.7 Example 4 17.6 .+-.
0.2 22.2 .+-. 0.3 23.6 .+-. 0.6 24.7 .+-. 0.6 26.7 .+-. 0.4 27.6
.+-. 0.8 28.2 .+-. 0.1 Example 22 17.1 .+-. 0.3 22.9 .+-. 0.8 23.5
.+-. 0.9 25.2 .+-. 0.5 27.2 .+-. 1.9 27.1 .+-. 1.8 27.4 .+-. 1.9
Example 18 18.2 .+-. 0.4 23.0 .+-. 0.7 24.1 .+-. 0.4 25.6 .+-. 0.8
28.1 .+-. 1.1 29.0 .+-. 1.4 29.0 .+-. 1.0 Example 24 17.7 .+-. 0.2
22.3 .+-. 0.7 24.5 .+-. 1.0 25.2 .+-. 1.0 27.2 .+-. 1.3 28.1 .+-.
2.0 28.9 .+-. 1.9 Example 23 19.4 .+-. 0.8 24.6 .+-. 1.2 24.5 .+-.
0.6 24.5 .+-. 0.6 25.4 .+-. 1.2 28.1 .+-. 0.8 29.0 .+-. 0.8 Example
10 19.4 .+-. 0.3 24.4 .+-. 0.6 25.5 .+-. 0.9 25.5 .+-. 0.9 26.8
.+-. 0.9 29.2 .+-. 0.7 30.3 .+-. 0.7 Example 2 18.6 .+-. 0.5 24.1
.+-. 0.4 24.7 .+-. 0.2 24.7 .+-. 0.2 26.2 .+-. 0.6 28.8 .+-. 0.5
29.2 .+-. 0.8 Example 11 19.5 .+-. 0.6 23.7 .+-. 0.8 25.4 .+-. 0.4
25.4 .+-. 0.4 27.0 .+-. 0.5 29.0 .+-. 0.7 29.8 .+-. 1.0 Example 20
18.8 .+-. 1.0 24.0 .+-. 1.1 25.3 .+-. 1.2 25.3 .+-. 1.2 26.7 .+-.
1.2 29.0 .+-. 1.1 29.3 .+-. 0.7 Example 17 19.0 .+-. 0.7 24.0 .+-.
0.7 24.6 .+-. 0.8 24.6 .+-. 0.8 26.1 .+-. 0.7 28.1 .+-. 0.6 29.3
.+-. 1.0 Example 13 19.6 .+-. 0.7 23.1 .+-. 0.6 24.4 .+-. 0.9 24.4
.+-. 0.9 26.5 .+-. 0.5 28.3 .+-. 1.3 28.4 .+-. 0.8 Example 12 18.5
.+-. 0.2 24.3 .+-. 0.6 24.9 .+-. 0.1 24.9 .+-. 0.1 26.1 .+-. 0.7
27.8 .+-. 0.7 28.5 .+-. 0.7 Example 19 18.9 .+-. 1.2 20.7 .+-. 1.1
21.3 .+-. 0.6 25.0 .+-. 2.0 24.8 .+-. 1.9 26.5 .+-. 1.9 27.7 .+-.
2.2 Example 26 18.7 .+-. 0.8 23.4 .+-. 0.5 25.0 .+-. 0.6 26.6 .+-.
1.4 27.3 .+-. 1.3 28.3 .+-. 1.3 28.8 .+-. 1.4 Example 6 18.4 .+-.
0.6 21.5 .+-. 0.9 21.6 .+-. 1.3 25.5 .+-. 0.5 25.9 .+-. 0.9 26.9
.+-. 1.1 27.1 .+-. 1.1 Example 3 18.8 .+-. 0.7 23.3 .+-. 0.1 24.3
.+-. 0.1 25.6 .+-. 0.7 26.9 .+-. 0.8 27.9 .+-. 0.9 28.6 .+-. 0.4
Example 9 18.3 .+-. 0.7 23.6 .+-. 0.7 24.1 .+-. 1.0 25.9 .+-. 1.1
27.2 .+-. 0.5 26.9 .+-. 1.4 27.9 .+-. 1.5
TABLE-US-00021 TABLE 20 Table of Daily Body Weight of Tested Female
Mice (g, Mean .+-. SD) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Blank Control 17.4 .+-. 1.4 22.2 .+-. 0.3 23.4 .+-. 0.7 23.0 .+-.
0.2 24.3 .+-. 1.6 24.7 .+-. 1.6 24.1 .+-. 1.1 Group Example 1 18.5
.+-. 0.1 22.8 .+-. 0.3 23.2 .+-. 0.7 24.0 .+-. 0.2 25.3 .+-. 1.6
25.7 .+-. 1.6 27.1 .+-. 1.1 Example 8 18.9 .+-. 0.9 22.9 .+-. 0.9
24.3 .+-. 0.7 24.3 .+-. 1.1 25.3 .+-. 1.4 25.8 .+-. 1.5 26.0 .+-.
2.5 Example 3 18.8 .+-. 0.4 22.1 .+-. 1.2 22.7 .+-. 0.8 23.0 .+-.
1.4 23.7 .+-. 1.9 24.1 .+-. 1.2 24.4 .+-. 1.8 Example 4 18.4 .+-.
0.4 21.8 .+-. 0.5 23.2 .+-. 0.6 23.5 .+-. 1.2 24.7 .+-. 0.9 24.2
.+-. 1.2 24.0 .+-. 0.8 Example 22 18.5 .+-. 0.6 21.8 .+-. 0.3 22.9
.+-. 0.4 24.0 .+-. 1.0 25.0 .+-. 0.4 25.3 .+-. 0.6 25.6 .+-. 0.2
Example 18 18.4 .+-. 0.7 22.5 .+-. 0.8 23.8 .+-. 1.1 24.8 .+-. 1.5
24.8 .+-. 0.6 25.4 .+-. 0.7 25.2 .+-. 1.1 Example 24 18.4 .+-. 0.7
22.4 .+-. 1.0 23.4 .+-. 1.0 23.6 .+-. 0.9 24.3 .+-. 0.6 24.7 .+-.
0.6 24.8 .+-. 1.5 Example 23 19.1 .+-. 0.6 22.4 .+-. 0.4 23.0 .+-.
0.1 23.0 .+-. 0.1 24.6 .+-. 0.4 24.8 .+-. 0.7 24.6 .+-. 0.4 Example
10 19.2 .+-. 0.5 21.9 .+-. 0.4 22.4 .+-. 0.2 22.4 .+-. 0.2 22.9
.+-. 0.6 24.1 .+-. 1.5 24.2 .+-. 1.8 Example 2 19.2 .+-. 0.5 22.7
.+-. 0.6 23.2 .+-. 0.5 23.2 .+-. 0.5 24.4 .+-. 0.2 24.6 .+-. 1.1
24.5 .+-. 1.9 Example 11 18.1 .+-. 0.2 21.7 .+-. 0.2 22.4 .+-. 0.1
22.4 .+-. 0.1 23.5 .+-. 0.4 23.2 .+-. 0.8 23.2 .+-. 0.9 Example 20
18.7 .+-. 0.4 21.6 .+-. 1.0 22.1 .+-. 1.0 22.1 .+-. 1.0 23.0 .+-.
1.4 23.3 .+-. 0.2 23.7 .+-. 0.8 Example 17 18.6 .+-. 1.0 21.9 .+-.
0.4 22.7 .+-. 0.4 22.7 .+-. 0.4 23.0 .+-. 0.4 23.1 .+-. 1.0 22.7
.+-. 1.2 Example 13 18.8 .+-. 1.1 21.3 .+-. 0.3 21.8 .+-. 0.4 21.8
.+-. 0.4 23.0 .+-. 0.5 23.2 .+-. 0.9 23.6 .+-. 0.9 Example 12 18.7
.+-. 0.7 21.8 .+-. 0.6 22.6 .+-. 0.1 22.6 .+-. 0.0 23.7 .+-. 0.6
25.3 .+-. 1.0 25.7 .+-. 1.6 Example 19 18.0 .+-. 0.6 20.7 .+-. 1.1
21.3 .+-. 0.6 22.8 .+-. 0.3 23.2 .+-. 0.7 23.3 .+-. 1.2 23.0 .+-.
1.7 Example 26 18.0 .+-. 0.7 21.9 .+-. 0.3 22.1 .+-. 0.5 22.4 .+-.
0.2 22.7 .+-. 0.3 22.6 .+-. 0.3 22.4 .+-. 0.2 Example 6 17.5 .+-.
0.9 21.5 .+-. 0.9 21.6 .+-. 1.3 22.0 .+-. 1.2 22.3 .+-. 1.9 22.4
.+-. 2.3 22.9 .+-. 2.0 Example 3 18.3 .+-. 0.4 21.7 .+-. 0.2 22.3
.+-. 0.2 22.6 .+-. 0.8 23.0 .+-. 1.4 22.6 .+-. 1.3 22.7 .+-. 0.4
Example 9 17.5 .+-. 0.6 22.1 .+-. 0.9 22.1 .+-. 0.7 22.8 .+-. 0.8
22.8 .+-. 1.0 22.7 .+-. 1.6 23.6 .+-. 1.7
[0418] The body weight of the animals in each group had a trend of
increase with slight fluctuations. Each compound had no side
effects on the change of the body weights of the mice at the dosage
of 1000 mg/Kg.
[0419] All the patents, patent application publications, patent
applications and non-patent literatures as cited in the present
disclosure are incorporated herein by reference in their
entirety.
[0420] It is to be understood that the foregoing description
relates to exemplary embodiments of the present application and
that modifications may be made without departing from the spirit
and scope of the present application as set forth in the
claims.
* * * * *