U.S. patent number RE47,388 [Application Number 15/684,291] was granted by the patent office on 2019-05-14 for agents for alleviating side effects.
This patent grant is currently assigned to TAIHO PHARMACEUTICAL CO., LTD.. The grantee listed for this patent is TAIHO PHARMACEUTICAL CO., LTD.. Invention is credited to Masakazu Fukushima, Norihiko Suzuki, Noriyuki Yamamoto.
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United States Patent |
RE47,388 |
Fukushima , et al. |
May 14, 2019 |
Agents for alleviating side effects
Abstract
The present invention provides an agent for alleviating side
effects caused by use of an anti-tumor agent, which contains
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H-pyrimidi
nedione (1) represented by formula (1): ##STR00001## or a
pharmaceutically acceptable salt thereof. The
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione
or a pharmaceutically acceptable salt thereof exhibit an
inflammatory-suppressing action in the digestive tract and
advantageously alleviate diarrhea and loss of body weight
concomitant with administration of a chemical for treating cancer
without suppressing the anti-tumor effect. Thus, the compounds of
the present invention are of great value as agents for alleviating
side effects caused by use of an anti-tumor agent, which enable not
only the chemotherapy to be continuedly carried out, but also the
body exhaustion to be effectively prevented.
Inventors: |
Fukushima; Masakazu (Tokyo,
JP), Yamamoto; Noriyuki (Tokyo, JP),
Suzuki; Norihiko (Tokyo, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
TAIHO PHARMACEUTICAL CO., LTD. |
Tokyo |
N/A |
JP |
|
|
Assignee: |
TAIHO PHARMACEUTICAL CO., LTD.
(Tokyo, JP)
|
Family
ID: |
1000003708648 |
Appl.
No.: |
15/684,291 |
Filed: |
August 23, 2017 |
PCT
Filed: |
March 16, 2000 |
PCT No.: |
PCT/JP00/01607 |
371(c)(1),(2),(4) Date: |
November 22, 2000 |
PCT
Pub. No.: |
WO00/56337 |
PCT
Pub. Date: |
September 28, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
09701041 |
Mar 16, 2000 |
6479500 |
Nov 12, 2002 |
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Foreign Application Priority Data
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Mar 23, 1999 [JP] |
|
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11-77579 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
31/513 (20130101); A61K 31/4745 (20130101); A61K
31/7072 (20130101); A61K 31/513 (20130101); A61K
9/02 (20130101); A61K 9/2018 (20130101); A61K
9/0019 (20130101); A61K 45/06 (20130101); A61K
9/0031 (20130101); C07D 403/06 (20130101); A61K
9/1652 (20130101); A61K 9/4858 (20130101); A61P
1/12 (20180101); A61K 9/0019 (20130101); A61P
35/00 (20180101); A61K 31/7072 (20130101); A61P
1/08 (20180101); A61P 3/00 (20180101); A61K
9/2018 (20130101); A61K 9/4858 (20130101); A61K
9/1652 (20130101); A61K 33/243 (20190101); A61K
45/06 (20130101); A61K 9/0031 (20130101); A61P
39/00 (20180101); A61P 43/00 (20180101); A61K
31/4745 (20130101); C07D 403/06 (20130101); A61K
9/02 (20130101); A61K 33/243 (20190101); A61K
31/513 (20130101); A61K 31/513 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
31/7072 (20130101); A61K 31/7072 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
31/4745 (20130101); A61K 31/4745 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
33/24 (20130101); A61K 33/24 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); Y10S
514/867 (20130101); Y10S 514/867 (20130101) |
Current International
Class: |
A61K
31/506 (20060101); A61K 45/06 (20060101); A61K
31/4745 (20060101); A61K 9/00 (20060101); A61K
31/513 (20060101); A61K 31/505 (20060101); C07D
403/06 (20060101); C07D 403/00 (20060101); A61K
33/24 (20190101); A61K 31/7072 (20060101); A61K
9/48 (20060101); A61K 9/20 (20060101); A61K
9/16 (20060101); A61K 9/02 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 884 051 |
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Dec 1998 |
|
EP |
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0884051 |
|
Dec 1998 |
|
EP |
|
96-30346 |
|
Oct 1996 |
|
WO |
|
98-13045 |
|
Apr 1998 |
|
WO |
|
Other References
International Search Report dated Jun. 13, 2000 in PCT/JP00/01607
filed Jun. 2, 2000. cited by applicant .
International Search Report. cited by applicant.
|
Primary Examiner: Diamond; Alan D
Attorney, Agent or Firm: Oblon, McClelland, Maier &
Neustadt, L.L.P.
Claims
What is claimed is:
1. A method for alleviating side effects caused by use of an
anti-tumor agent .Iadd.selected from the group consisting of an
alkylating agent, a plant-derived compound, an antibiotic, or a
platinum containing agent .Iaddend.comprising administering
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione
represented by formula (1): ##STR00003## or a pharmaceutically
acceptable salt thereof to a patient to whom .[.an.]. .Iadd.the
.Iaddend.anti-tumor agent has been administered.
2. A method according to claim 1, wherein the side effect caused by
use of the anti-tumor agent is nausea, vomiting, diarrhea,
anorexia, or loss of body weight.
.[.3. A method according to claim 1 or 2, wherein the anti-tumor
agent is an antimetabolite, an alkylating agent, a plant-derived
compound, an antibiotic, or a platinum-containing agent..].
4. A method according to claim 1 or 2, wherein the anti-tumor agent
is .[.5-trifluoromethyl-2'-deoxyuridine, 5-fluorouracil,.].
irinotecan hydrochloride.[.,.]. or cisplatin.
.Iadd.5. The method of claim 4, wherein the anti-tumor agent is
irinotecan hydrochloride..Iaddend.
.Iadd.6. The method of claim 4, wherein the anti-tumor agent is
cisplatin..Iaddend.
Description
This application is a .Iadd.Reissue of U.S. Pat. No. 6,479,500,
filed Nov. 22, 2000 as U.S. Ser. No. 09/701,041, which is a
.Iaddend.371 of PCT/JP00/01607 filed Mar. 16, 2000 .Iadd.which is
based upon and claims benefit of priority from the prior Japanese
Application 11-77579 filed Mar. 23, 1999, the entire contents of
which are incorporated herein by reference.Iaddend..
TECHNICAL FIELD
The present invention relates to an agent for alleviating side
effects caused by use of an anti-tumor agent.
BACKGROUND ART
Most drugs employed in chemotherapy to treat cancers act upon
proliferating cells to arrest the cell cycle and prevent
proliferation of the cells, to thereby terminate proliferation of
the cancer tissue or reduce the cancer tissue. However, such drugs
also act upon the mucosal cells of the digestive tract, where cell
proliferation is active. Therefore, it is well-known that
proliferation of mucosal cells in the digestive tract is also
prevented, thereby causing shrinkage of mucosal villi; reducing the
resistance of the digestive tract against external stimulation such
as food; causing inflammatory conditions; and inducing disorders of
the digestive tract such as diarrhea and inhibition of nutrient
absorption.
When cancer is treated through the administration of an anti-tumor
agent, side effects such as nausea, vomiting, diarrhea, and loss of
body weight make these drugs very difficult for patients to
tolerate. Thus, it is not uncommon in clinical practice that drug
administration must be intermitted. In order to alleviate such side
effects, compounds have been employed in combination.
For example, a dithiobis (2,2-dimethylpropionamide) derivative is
employed with a fluoropyrimidine anti-tumoragent (Japanese Patent
Application Laid-Open (kokal) No. 10-158163); a
dithiobis(carboxylic acid) derivative is employed with a
fluoropyrimidine anti-tumor agent (Japanese Patent Application
Laid-Open (kokai) No.10-158159); conagenin is employed with cancer
chemotherapeutic agents such as antimetabolites, alkylating agents,
and plant-derived compounds (Japanese Patent Application Laid-Open
(kokai) No. 8-165236); a pyrimidine nucleocide phosphorylase
inhibitor is employed with 5'-deoxy-5-fluorouridine (Japanese
Patent Application Laid-Open (kokai) No. 5-213761); and oxonic acid
is employed with a fluoropyrimidine anti-tumor agent (Japanese
Patent Application Laid-Open (kokai) No. 5-78249). Of these, only
oxonic acid is actually employed in clinic. In a clinical setting,
administration of Hange Shashin Tou is discussed so as to prevent
delayed diarrhea caused by irinotecan hydrochloride (CPT-11).
However, the capacity of the aforementioned means to alleviate side
effects is less than satisfactory.
Thus, an object of the present invention is to provide a drug which
can considerably reduce side effects, e.g., such as nausea,
vomiting, diarrhea, loss of body weight, and anorexia, caused by
administering an anti-tumor agent to an organism, thereby
alleviating the side effects suffered by patients and allowing
cancer treatment by the use of an anti-tumor agent to continue,
which treatment must be intermitted by these side effects.
Disclosure of the Invention
In view of the foregoing, the present inventors have carried out
extensive studies from various points of view on
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidi
nedione or a pharmaceutically acceptable salt thereof, and have
found that these compounds can effectively alleviate
digestive-tract-related side effects such as nausea, vomiting,
diarrhea, loss of body weight, and anorexia, which side effects are
caused by an anti-tumor agent. The present invention has been
accomplished on the basis of this finding.
Accordingly, the present invention provides an agent for
alleviating side effects caused by use of an anti-tumor agent,
which comprises, as an active ingredient,
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione
represented by formula (1):
##STR00002## and a pharmaceutically acceptable salt thereof.
The present invention also provides use of the aforementioned
compound represented by formula (1) or a pharmaceutically
acceptable salt thereof for producing an agent for alleviating side
effects caused by use of an anti-tumor agent.
In addition, the present invention also provides a method for
alleviating side effects caused by an anti-tumor agent, which
comprises administering the aforementioned compound represented by
formula (1) or a pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a chart showing the relationship between cumulative
diarrhea occurrence and the number of administration days.
BEST MODE FOR CARRYING OUT THE INVENTION
5-Chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-py
rimidinedione is a known compound, and its pharmacological action
such as enhancing anti-tumor effects (see International Patent
Publication WO/9630346) and cancer metastasis suppressing actions
(see International Patent Publication WO/9813045) are known.
However, no action to alleviate side effects caused by an
anti-tumor agent has been disclosed.
Examples of anti-tumor agents upon which the agent for alleviating
side effects of the present invention can act include
antimetabolites such as 5-fluorouracil (5-FU), tegafur, carmofur,
tegafur-uracil composition (UFT, product of Taiho Pharmaceutical
Co., Ltd.), 5-trifluoromethyl-2'-deoxyuridine,
5-fluoro-2'-deoxyuridine, capecitabine, gemcitabine hydrochloride,
and methotrexate; plant-derived compounds such as irinotecan
hydrochloride (CPT-11), etoposide, vindensine, vincrystine,
paclitaxel, and docetaxel; alkylating agents such as
cyclophosphamide, itostamide, and ranimustine; anti-cancer
antibiotics such as daunorubicin, doxorubicin, pirarubicin,
neocarzinostatin, mitomycin C; platinum-containing compounds such
as cisplatin (CDDP) and carboplatin; and pharmaceutically
acceptable salts thereof. Of these, 5-fluorouracil, tegafur,
carmofur, tegafur-uracil composition,
5-trifluoromethyl-2'-deoxyuridine, cisplatin, etoposide, and
irinotecan are preferred. Particularly, 5-fluorouracil,
5-trifluoromethyl-2'-deoxyuridine, irinotecan hydrocloride, and
cisplastin are most preferred.
No particular limitation is imposed on the pharmaceutically
acceptable salts of the compound (1) of the present invention,
however, acid-adduct salts reacted with a pharmaceutically
acceptable acid are preferred. Examples of acid-adduct salts
include salts of an inorganic acid such as hydrochloric acid,
sulfuric acid, phosphoric acid, or hydrobromic acid; and salts of
an organic acid such as oxalic acid, maleic acid, fumaric acid,
malic acid, tartaric acid, citric acid, benzoic acid, acetic acid,
p-toluenesulfonic acid, and methanesulfonic acid. Of these, salts
of hydrochloric acid orp-toluenesulfonic acid are preferred.
Examples of particularly preferred compounds (1) of the present
invention or salts thereof include
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidi
nedione hydrochloride and
5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidi neone
tosylate.
The compound (1) of the present invention or a salt thereof may be
formulated singly into a preparation in accordance with the form of
administration and may be administered simultaneously or
non-simultaneously with an anti-tumor agent which is also
formulated into a preparation in accordance with the form of
administration. Alternatively, the compound (1) or the salt thereof
and the anti-tumor agent may be mixed in advance, formulated into a
preparation in accordance with the form of administration, and then
administered. When these are administered individually, the
compound (1) or the salt there of may be administered arbitrarily
before or after administration of the anti-tumor agent.
In the present invention, when the agent for alleviating side
effects and the anti-tumor agent are used to treat malignant tumors
in mammals including humans, the agent for alleviating side effects
and the anti-tumor agent may be formulated into any of the
pharmaceutically administrative forms depending on the therapeutic
purpose. Examples include oral preparations such as tablets,
capsulated tablets, pills, powders, granules, capsules, liquid
preparations, suspension preparations, and emulsions; and non-oral
preparations such as injections and suppositories. These
preparations can be formulated using a pharmaceutically acceptable
carrier through a customary method generally known in the art. When
the agent is formed into tablets, examples of carriers include
vehicles such as lactose, sucrose, sodium chloride, glucose, urea,
starch, calcium carbonate, kaolin, crystalline cellulose, and
silicic acid; binders such as water, ethanol, propanol, cornstarch,
single syrup, glucose liquid, starch liquid, a gelatin solution,
carboxymethyl cellulose, shellac, methyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, potassium phosphate, and
polyvinyl pyrrolidone; disintegrators such as dry starch, sodium
alginate, agar powder, laminaran powder, sodium hydrogen carbonate,
calcium carbonate, polyoxyethylene sorbitan fatty acidesters,
sodium lauryl sulfate, stearic acid monoglyceride, and lactose;
disintegration-inhibitors such as sucrose, stearic acid, cacao
butter, and hydrogenated oil; absorption-promoting agents such as
quaternary ammonium salts and sodium lauryl sulfate; humectants
such as glycerin and starch; absorbents such as starch, lactose,
kaolin, bentonite, colloidal silicic acid; lubricants such as
purified talc, stearic acid salts, boric acid powder, and
polyethylene glycol. Optionally, tablets may be formed into typical
coated tablets such as sugar-coated tablets, gelatin-coated
tablets, enteric coated tablets, film-coated tablets,
double-layered tablets, and multi-layered tablets. When the
preparation is formed into pills, examples of carriers include
vehicles such as glucose, lactose, starch, cacao butter,
hydrogenated vegetable oils, kaolin, and talc; binders such as gum
arabic powders, tragacanth powders, gelatin, and ethanol;
disintegrators such as laminaran and agar. Capsules are produced
using a customary method. For example, the preparation and any of
the above carriers are mixed, and the mixture is charged into hard
gelatin capsules or soft capsules. When a liquid preparation for
oral administration is produced, agents for internal use, syrup
agents, and elixirs may be prepared through a customary method
using additives such as taste-modifying agents, buffers,
stabilizers, and flavoring agents. Examples of taste modifying
agents include sucrose, orange peal, citric acid, and tartaric
acid. Examples of buffers include sodium citrate. Examples of
stabilizers include tragacanth gum, gum arabic, and gelatin.
Examples of carriers which can be employed for producing
suppositories include polyethylene glycol, cacao butter, higher
alcohols, higher alcohol esters, gelatin, and semi-synthesized
glycerides. When the preparation is formed into injections, liquid
preparations, emulsions, and suspensions are preferably sterilized
and made isotonic with blood. When injections are formed, adiluent
may be used. Examples of diluents includes water, an aqueous
solution of lactic acid, ethyl alcohol, propylene glycol, Macrogol,
ethoxylated isostearyl alcohol, polyoxyethylene-modified isostearyl
alcohol, and polyoxyethylene sorbitan fatty acid esters. In this
case, a sufficient amount of sodium chloride, glucose, or glycerin
may be incorporated into the pharmaceutical preparation so as to
prepare an isotonic solution, and typical solubilizing agent,
buffers, and an esthetics may also be added. In addition, the
aforementioned preparations may contain colorants, preservatives,
perfumes, flavoring agents, and sweetening agents as well as other
pharmaceuticals where desired in accordance with need. No
particular limitation is imposed on the amounts of an anti-tumor
agent and the compound (1) of the present invention or a salt
thereof incorporated into the pharmaceutical preparation of the
present invention. The amounts are appropriately predetermined, and
each component is incorporated in an amount of approximately
0.01-70 wt. %.
The method for administering the agent for alleviating side effects
of the present invention is not particularly limited, and it is
appropriately predetermined in accordance with the form of
preparation; patient condition, e.g., age and sex; and gravity of
the patient's symptoms. For example, tablets, pills, powders,
granules, capsules, liquids, suspensions, and emulsions are
perorally administered. Injection preparations are intravenously
administered singly or in combination with typical auxiliary agents
such as glucose and amino acid. Furthermore, injection preparations
per se are administered intravenously, arterially, intramuscularly,
intradermally, subcutaneously, or intraperitoneally in accordance
with need. Suppositories are administered intrarectally.
The dose of the active ingredient of the agent for alleviating side
effects of the present invention is appropriately selected in
accordance with the directions for use; patient profile, e.g., age
and sex; and gravity of the disease. Typically, the compound (1) of
the present invention or the pharmaceutically acceptable salt
thereof is administered in an amount of approximately 0.01-1000
mg/kg/day, preferably 0.1-100 mg/kg/day. When an anti-tumor agent
is incorporated in advance, the target dose of the anti-tumor agent
may be approximately 0.01-100 mg/kg/day, preferably 0.05-50
mg/kg/day. The pharmaceutical preparation according to the present
invention may be administered in single or divided doses, i.e., 1
to approximately 2-4 doses per day.
Malignant tumors which can be treated by the agent for alleviating
side effects of the present invention may be those which can be
treated by an anti-tumor agent used in combination with the agent
for alleviating side effects of the present invention. Examples of
malignant tumors include esophageal cancer, stomach cancer, hepatic
cancer, cholecystis-cystic duct cancer, pancreatic cancer, colon
cancer, rectal cancer, head and neck cancer, lung cancer, breast
cancer, cervical cancer, ovarian cancer, bladder cancer, prostatic
cancer, orchioncus, osteo- and soft-part-sarcoma, skin cancer,
malignant lymphoma, leukemia, and brain tumors.
EXAMPLES
The present invention will next be described in more detail by way
of examples, which should not be construed as limiting the
invention thereto.
REFERENTIAL EXAMPLE 1
Preparation of
5-Chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4-(1H,3H)-pyrimidinedione
Hydrochloride (Compound 1)
(1) Sulfuryl chloride (120 ml) was added dropwise to a suspension
of 6-chloromethyluracil (163 g) in acetic acid (500 ml) over 20
minutes at room temperature, and the mixture was stirred for an
additional 3 hours at room temperature. The resultant solution was
poured into iced water (500 ml), and then precipitated crystals
were collected through filtration, to there by obtain 182.3 g of
5-chloro-6-chloromethyluracil (92% yield).
Melting Point: .gtoreq.225.degree. C. (Decomposed), NMR spectral
data (DMSO-d.sub.6) .delta. 4.46 (2H, s), 11.57 (1H, s), 11.71 (1H,
s).
(2) 5-Chloro-6-chloromethyluracil (5.0 g), 2-iminopyrrolidine (6.14
g), and sodium ethoxide (5.24 g) were dissolved in
N,N-dimethylformamide (50 ml) and the resultant solution was
stirred for 14 hours at room temperature. Subsequently,
precipitated crystals were collected through filtration, and the
crystals were suspended in water (30 ml). The resultant suspension
was neutralized with acetic acid and washed. Subsequently,
insoluble matter was collected through filtration and was dissolved
in 1N HCl (60 ml). Activated carbon was added to the resultant
solution and the mixture was subjected to filtration. The filtrate
was concentrated under reduced pressure, and the residue was washed
with ethanol, followed by filtration, to thereby obtain 2.68 g of
the title compound (38% yield).
Melting Point: .gtoreq.255.degree. C. (decomposed)
NMR spectral data (DMSO-d.sub.6) .delta. 2.04 (2H, quintet, J=7.6
Hz), 2.87 (2H, t, J=7.6 Hz), 3.59 (2H, t, J=7.6 Hz), 4.69 (2H, s),
9.40 (1H, s), 11.46 (1H, s), 11.73 (1H, s).
REFERENTIAL EXAMPLE 2
Preparation of
5-Chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4-(1H,3H)-pyrimidinedione
Tosylate (Compound 2)
The procedure described in Reference Example 1 was repeated, except
that p-toluenesulfonic acid was used instead of 1N HCl, to thereby
obtain the title compound (26% yield).
melting point: .gtoreq.210.degree. C. (decomposed)
NMR spectral data (DMSO-d.sub.6) .delta. 2.05 (2H, quintet, J=7.7
Hz), 2.29 (3H, s), 2.87 (2H, t, J=7.7 Hz), 3.60 (2H, t, J=7.7 Hz),
4.56 (2H, s), 7.11 (2H, d, J=7.3 Hz), 7.47 (2H, d, J=7.3 Hz), 9.51
(1H, br-s), 11.0-11.8 (2H, very broad).
PREPARATION EXAMPLE 1
TABLE-US-00001 Compound 1 25.0 mg lactose 8.0 mg crystalline
cellulose 4.0 mg magnesium stearate 1.0 mg talc 1.0 mg cornstarch
3.5 mg hydroxypropylmethyl cellulose 2.5 mg weight per tablet 45.0
mg
Tablets of the above-described formulation were prepared through a
routine method.
PREPARATION EXAMPLE 2
TABLE-US-00002 Compound 2 50.0 mg lactose 85.0 mg cornstarch 100.0
mg hydroxypropylmethyl cellulose 3.0 mg weight per sachet 238.0
mg
Granules of the above-described formulation were prepared through a
routine method.
PREPARATION EXAMPLE 3
TABLE-US-00003 Compound 2 50.0 mg lactose 24.0 mg crystalline
cellulose 13.0 mg magnesium stearate 1.0 mg weight per capsule 88.0
mg
Capsules of the above-described formulation were prepared through a
routine method.
PREPARATION EXAMPLE 4
TABLE-US-00004 Injection Compound 1 50.0 mg water for injection
suitable amount volume per ample 5 ml
Injections of the above-described formulation per ample were
prepared through a routine method.
PREPARATION EXAMPLE 5
TABLE-US-00005 Suppositories Compound I 100.0 mg Witepsol W-35
(Trademark; product of 1400.0 mg Dynamit Nobel A.G.) weight per
suppository 1500.0 mg
Suppositories of the above-described formulation per suppository
were prepared through a routine method.
PREPARATION EXAMPLE 6
TABLE-US-00006 Anti-tumor Composition for Injection Compound 2 10.0
mg cisplatin 25.0 mg water for injection suitable amount weight per
ample 50 ml
Injections of the above-described formulation per ample were
prepared through a routine method.
PREPARATION EXAMPLE 7
TABLE-US-00007 Anti-tumor composition for oral administration
Compound I 50.0 mg 5-trifluoromethyl-2'-deoxyuridine (FTD) 12.5 mg
lactose 85.0 mg cornstarch 100.0 mg hydroxypropylmethyl cellulose
2.5 mg weight per sachet 250.0 mg
Granules of the above-described formulation were prepared through a
routine method.
TEST 1
Alleviating Effect on Suppression of Body Weight Increase
(a) Preparation of Test Solution--I:
5-Fluorouracil (hereinafter referred to as "5-FU") was suspended in
saline so as to obtain a 2.0 mg/ml suspension, and the suspension
was stirred by use of a stirrer for about 20 minutes at room
temperature. The suspension was treated with sonication for 5
minutes while being cooled with ice, to thereby obtain a test
solution containing 5-FU for administration at 20 mg/kg/day.
(b) Preparation of Test Solution--II:
Cisplatin (hereinafter referred to as "CDDP") was suspended in
saline so as to obtain a 0.1 mg/ml suspension, and the suspension
was stirred by use of a stirrer for about 20 minutes at room
temperature. The suspension was treated with sonication for 5
minutes while being cooled with ice, to thereby obtain a test
solution containing CDDP for administration at 1.0 mg/kg/day.
(c) Preparation of Test Solution--III:
Compound 1 was suspended in water so as to obtain a 10 mg/ml
suspension, and the suspension was stirred by use of a stirrer for
about 20 minutes at room temperature. The suspension was treated
with sonication for 5 minutes while being cooled with ice, to
thereby obtain a test solution containing Compound 1 for
administration at 100 mg/kg/day.
(d) Test:
Five-week-old Donryu male rats were divided into a control group
and treatment groups so that the average body weights of the groups
and the standard deviations (S.D.) of the groups were made to be as
close to one another as possible. To each rat of the
anti-tumor-agent treatment alone groups, the 5-FU solution or the
CDDP solution was intravenously administered once a day for four
consecutive days at a daily dose of 1.0 ml per 100 g of body
weight. Simultaneously, water was orally administered once a day
for four consecutive days at a daily dose of 1.0 ml per 100 g of
body weight. To each rat of the combination-administration
treatment groups, the 5-FU solution or the CDDP solution was
intravenously administered once a day for four consecutive days at
a daily dose of 1.0 ml per 100 g of body weight. Simultaneously, to
each rat of the combination-administration groups, the solution of
Compound 1 was orally administered once a day for four consecutive
days at a daily dose of 1.0 ml per 100 g of body weight. To each
rat of the control group, saline was intravenously administered
once a day for four consecutive days at a daily dose of 1.0 ml per
100 g of body weight. Simultaneously, water was orally administered
once a day for four consecutive days at a daily dose of 1.0 ml per
100 g of body weight.
The rats were weighed prior to initiation of administration (day 1)
and on the day following the day of final administration (day 5),
and the ratio of suppression of body weight increase was calculated
by use of the following equation. The results are shown in Table
1.
Test results were statistically analyzed using the Student's "T"
test. The marks "*" and "**" mean statistically significant
differences from the control groups ((*;p<0.05) and (**;
p<0.01)), and the marks "#" and "##" mean statistically
significant differences from the anti-tumor-agent-administration
alone groups ((#; p<0.05) and (##; p<0.01)). Ratio of
suppression of body weight increase (%)=(1-body weight changes of
one treatment group/body weight changes of the control
group).times.100
TABLE-US-00008 TABLE 1 Compounds No. of Body weight Suppression
(dose, mg/kg) animals change (g) ratio (%) Control 8 29.3 .+-. 3.7
5-FU(20) 8 15.6 .+-. 3.6** 46.7 5-FU(20) + 8 23.3 .+-. 4.8*## 20.7
Compound 1(100) CDDP(1.0) 8 11.9 .+-. 5.4** 59.4 CDDP(1.0) + 8 17.3
.+-. 5.7**# 41.1 Compound 1 (100)
Suppression of body weight increase was confirmed in the rats in
the anti-tumor-agent-administration alone groups, in which 5-FU in
an amount of 20 mg/kg/day or CDDP in an amount of 1.0 mg/kg/day was
administered to each rat for 4 consecutive days. It became apparent
that suppression of body weight increase due to the anti-tumor
agent was alleviated when Compound 1 was administered in an amount
of 100 mg/kg/day in combination with the anti-tumor agent.
Moreover, it was confirmed that the occurrence of diarrhea as
observed in the combination-administration groups was lower than
that of diarrhea as observed in the anti-tumor-agent-administration
alone groups.
TEST 2
Delaying Effect on Diarrhea Occurence
(a) Preparation of Test Solution--I:
Irinotecan hydrochloride (hereinafter referred to as "CPT-11";
KAMPTO Injection 100 mg/5 ml; product of Yakult Co., Ltd.) was
diluted with saline so as to obtain a 6 mg/ml solution for
administration at 60 mg/kg/day.
(b) Preparation of Test Solution--II:
Compound 1 was suspended in a 0.5% hydroxypropylmethyl cellulose
solution (hereinafter referred to as "0.5% HPMC") so as to obtain a
3 mg/ml suspension, and the suspension was stirred by use of a
stirrer for about 20 minutes at room temperature. The suspension
was subjected to ultrasound treatment for 5 minutes while being
cooled with ice, to thereby obtain a test solution containing
Compound 1 for administration at 30 mg/kg/day.
(c) Test:
Five-week-old Donryu male rats were divided into a control group
and treatment groups so that the average body weights of the groups
and the standard deviations (S.D.) of the groups were made to be as
close to one another as possible. To each rat of the
anti-tumor-agent treatment alone groups, the CPT-11 solution was
intravenously administered once a day for five consecutive days at
a daily dose of 1.0 ml per 100 g of body weight. Simultaneously, a
0.5% HPMC solution was orally administered once a day for five
consecutive days at a daily dose of 1.0 ml per 100 g of body
weight. To each rat of the combination-administration treatment
groups, the CPT-11 solution was intravenously administered once a
day for five consecutive days at a daily dose of 1.0 ml per 100 g
of body weight. Simultaneously, to each rat of the
combination-administration groups, the solution of Compound 1 was
orally administered once a day for five consecutive days at a daily
dose of 1.0 ml per 100 g of body weight. To each rat of the control
group, saline was intravenously administered for five consecutive
days at a daily dose of 1.0 ml per 100 g of body weight.
Simultaneously, a 0.5% HPMC solution was orally administered for
five consecutive days at a daily dose of 1.0 ml per 100 g of body
weight. Prior to each administration, the stool and anal fecal
matter of each rat were observed in order to check the occurrence
of diarrhea. The number of rats which had diarrhea at least once
during the test period were counted as "diarrhea-rats". The
accumulated occurrence of diarrhea was calculated by use of the
following equation: accumulated occurrence of diarrhea (%)=(the
number of rats which had diarrhea/the total number of
rats).times.100
As shown in FIG. 1, diarrhea occurred after the third
administration day in rats in the anti-tumor agent administration
group, in which CPT-11 in an amount of 60 mg/kg/day was
administered every day. It was shown that the event of diarrhea is
delayed when Compound 1 was concomitantly administered in an amount
of 30 mg/kg/day.
TEST 3
Action on Anti-tumor Action of Cancer Drug
(a) Preparation of Test Solution--I:
CDDP was suspended in saline so as to obtain a 0.6 mg/ml
suspension, and the suspension was stirred by use of a stirrer for
about 20 minutes at room temperature. The suspension was subjected
to sonication for 5 minutes while being cooled with ice to thereby
obtain a test solution containing CDDP for administration at 6.0
mg/kg/day.
(b) Preparation of Test Solution--II:
Compound 1 was suspended in 0.5% HPMC so as to obtain a 3 mg/ml
suspension, 10 mg/ml suspension, and 30 mg/ml suspension,
respectively, and each suspension was stirred by use of a stirrer
for about 20 minutes at room temperature. Each suspension was
subjected to sonication for 5 minutes while being cooled with ice
to thereby obtain test solutions containing Compound 1 for
administration at 30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day,
respectively.
(c) Test:
Five-week-old Donryu male rats were divided into a control group
and treatment groups so that the average body weights of the groups
and the standard deviations (S.D.) of the groups were made to be as
close to one another as possible. Yoshida sarcoma (2.times.10.sup.4
cells/0.1 ml/rat) was subcutaneously transplanted on the back of
each rat, and administration was started the day following the day
of transplant. To each rat of the CDDP treatment alone groups, the
CDDP solution of 6.0 mg/kg was intravenously administered on the
first administration day, and a 0.5% HPMC solution was orally
administered for seven consecutive days at a daily dose of 1.0 ml
per 100 g of body weight. In a similar manner, to each rat of the
combination-administration treatment groups, the aforementioned
CDDP solution at 6.0 mg/kg was intravenously administered on the
first administration day, and a solution of Compound 1 (30
mg/kg/day, 100 mg/kg/day, or 300 mg/kg/day) was orally administered
once a day for seven consecutive days at a daily dose of 1.0 ml per
100 g of body weight. To each rat of the control group, saline was
intravenously administered on the first administration day in a
dose of 1.0 ml per 100 g of body weight. Simultaneously, a 0.5%
HPMC solution was orally administered once a day for five
consecutive days at a daily dose of 1.0 ml per 100 g of body
weight. In order to observe the action of Compound 1 per se,
Compound-1-administration alone groups were provided for
administration at 30 mg/kg/day, 100 mg/kg/day, and 300 mg/kg/day,
respectively.
The rats were weighed on the day of transplantation (day 0) and the
day following the day of final administration (day 8), and the
suppression ratio of body weight increase was calculated by use of
the following equation. Ratio of suppression of body weight
increase (%)=(1-body weight changes of one treatment group/body
weight changes of the control group).times.100
The weight of the tumor was measured by weighing rats sacrificed on
the day following the day of the final administration, and the
tumor shrinkage ratio was calculated by use of the following
formula. Ratio of tumor shrinkage (%)=(1-tumor weight changes of
one treatment group/tumor weight changes of the control
group).times.100 The results are shown in Table 2.
TABLE-US-00009 TABLE 2 Inhi- Body Weight bition weight change
Compounds No. of Tumor ratio change ratio (dose, mg/kg) animals
weight (g) (%) (g) (%) Control 8 0.666 .+-. 0.244 25.9 .+-. 9.2
CDDP(6.0) + 8 0.162 .+-. 0.155 75.7 -19.4 .+-. 8.6 174.9 0.5% DPW
CDDP(6.0) + 8 0.167 .+-. 0.147 74.9 -2.7 .+-. 12.8 110.4 Compound 1
(30) CDDP(6.0) + 7 0.139 .+-. 0.130 79.1 -9.1 .+-. 18.9 135.1
Compound 1 (100) CDDP(6.0) + 8 0.158 .+-. 0.122 76.3 -7.4 .+-. 16.3
128.6 Compound 1 (300) Saline + 7 0.787 .+-. 0.307 -18.1 29.3 .+-.
10.2 -13.1 Compound 1 (30) Saline + 8 0.816 .+-. 0.329 -22.4 23.9
.+-. 6.6 7.7 Compound 1 (100) Saline + 7 0.829 .+-. 0.281 -24.5
28.1 .+-. 6.0 -8.5 Compound 1 (300)
Significant inhibition of tumor weight and body weight to the
control group has been proven when CDDP alone was administered at a
dose of 6 mg/kg. When Compound 1 was administered for seven
consecutive days, suppression of body weight was alleviated without
affecting the anti-tumor action.
TEST 4
Suppression of Body Weight, and Variation of Inflammatory Cytokine
Level in the Small Intestine and the Large Intestine
(a) Preparation of Test Solution--I:
5-Trifluoromethyl-2'-deoxyuridine (hereinafter abbreviated as FTD)
was suspended in a 0.5% HPMC solution so as to obtain a 20 mg/ml
suspension, and the suspension was stirred by use of a stirrer for
about 20 minutes at room temperature. The suspension was subjected
to sonication for 5 minutes under ice cooling, to thereby obtain a
test solution containing HD for administration of 200
mg/kg/day.
(b) Preparation of Test Solution--II:
FTD was suspended in a 0.5% HPMC solution so as to obtain a 20
mg/ml suspension. To the suspension, Compound 1 was added so as to
attain a concentration of 9.4 mg/ml. The resultant mixture was
stirred by use of a stirrer for about 20 minutes at room
temperature, and then subjected to sonication under ice cooling, to
thereby obtain a test solution containing FTD and Compound 1 (mol
ratio 1:0.5).
(c) Preparation of Test Solution--III:
Compound 1 was suspended in a 0.5% HPMC solution so as to obtain a
10 mg/ml suspension, and the suspension was stirred by use of a
stirrer for about 20 minutes at room temperature. The suspension
was subjected to sonication for 5 minutes under ice cooling, to
thereby obtain a test solution containing Compound 1 for
administration of 100 mg/kg/day.
(d) Test:
Eight-week-old male ICR rats were divided into a control group and
treatment groups so that the average body weights of the groups and
the standard deviations (S.D.) of the groups were made to be as
close to one another as possible. To each rat of the FTD treatment
alone groups, the FTD solution of 200 mg/kg/day (1.0 ml) was orally
administered once a day for eight consecutive days (per 100 g body
weight of each rat). To each rat of combination-administration
treatment groups, a mixture solution of FTD and Compound 1 was
perorally administered once a day for eight consecutive days at a
daily dose of 1.0 ml per 100 g of body weight. To each rat of the
control group, a 0.5% HPMC solution was perorally administered for
eight consecutive days. In order to observe the action of Compound
1 per se, Compound 1-administration alone groups were provided for
administration of 100 mg/kg/day.
Measurement of Body Weight Change
The rats were weighed at the previous day of the first
administration (day 0) and the following day of the day of final
administration (day 9), and the ratio of body weight ratio was
calculated by use of the following equation. There sults are shown
in Table 3. Ratio of body weight change (%)=body weight
changes/body weight before administration.times.100
Test results were statistically analyzed in accordance with the
Dunnett method ((*; p<0.05) and (**; p<0.01)).
TABLE-US-00010 TABLE 3 Compounds No. of Body weight weight change
(dose, mg/kg) animals change (g) ratio (%) Control 6 1.4 .+-. 0.9
3.9 FTD(200) 6 -1.6 .+-. 4.7** -17.6 VID(200) + 6 0.3 .+-. 0.7 0.7
Compound 1 (94) Compound 1 (100) 6 2.4 .+-. 1.1 6.8
Administration of solo FTD at a daily dose of 200 mg/kg for eight
consecutive days resulted in a decrease ratio of the body weight at
the following day of the final administration to that before
administration of approximately 18%. The decrease in the body
weight was protected by incorporating Compound 1 at a dose of 94
mg/kg/day.
Measurement of Cytokines in the Small Intestine and the Large
Intestine
After the aforementioned body weight measurement on the following
day of final administration was completed, each rat was
anesthetized with ether, and a region of the large intestine 3-6 cm
from the anus and the whole jejunoileal portion, i.e., the small
intestine from which the duodenum was removed, were collected.
Immediately after the collected region were washed with saline, the
portions were frozen to preserve at -80.degree. C. Each sample
preparation was diluted with a 0.05M phosphate buffer (pH 7.4) so
as to attain a tissue concentration of approximately 10% (W/V), and
the resultant mixture was homogenized, subjected to sonication, and
subjected twice to freeze-thawing. The thus-treated matter was
centrifuged at 12,000 g for 15 minutes, and the supernatant was
collected to serve as a sample for cytokine measurement.
Cytokines, i.e., IL-1.beta. and mouse IL-6 were measured by use of
an ELISA kit for mouse (product of Endogen, Inc.), and the results
are shown in Table 4.
Test results were statistically analyzed in accordance with the
Dunnett method ((*; p<0.05) and (**; p<0.01)).
TABLE-US-00011 TABLE 4 (pg/mg protein) Small Compounds intestine
Large intestine (dose, mg/kg) IL-6 IL-1.beta. IL-6 Control 16.2
.+-. 5.9 23.6 .+-. 10.0 11.1 .+-. 5.7 FTD(200) 95.5 .+-. 19.2**
77.3 .+-. 42.1** 118.0 .+-. 47.6** FID(200) + 17.2 .+-. 11.9 14.0
.+-. 4.0 11.3 .+-. 4.6 Compound 1 (94) Compound 1 (100) 19.8 .+-.
9.9 23.7 .+-. 4.6 10.7 .+-. 4.7
Administration of FTD at a daily dose of 200 mg/kg/day for eight
consecutive days resulted in a high level of inflammatory cytokine
IL-6 both in the small intestine and the large intestine as
compared with the control group. In addition, the level of
IL-1.beta. was elevated in the large intestine. The increase in
level of the inflammatory cytokines was inhibited by incorporating
Compound 1 at a dose of 94 mg/kg, which is a nearly same level
observed in the control group.
INDUSTRIAL APPLICABILITY
5-Chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione
(1) or a pharmaceutically acceptable salt thereof exhibit a
suppressing action against inflammations evoked in the digestive
tract after administration of an anti-tumor agent, and
advantageously alleviate diarrhea and loss of body weight
concomitant with administration of a chemical for treating cancer
without suppressing the anti-tumor effect. Thus, the compounds of
the present invention are of great value as agents for alleviating
side effects caused by use of an anti-tumor agent, which enable not
only the chemotherapy to be continuedly carried out, but also the
body exhaustion to be effectively prevented.
* * * * *