JPWO2001000217A1 - Pharmaceutical composition for preventing or treating diarrhea - Google Patents

Abstract

(57) [Abstract] A pharmaceutical composition for preventing or treating diarrhea is provided, which is useful as a preventive or therapeutic agent for diarrhea, capable of alleviating diarrhea-related side effects caused by the administration of cancer chemotherapy agents, particularly anticancer camptothecin derivatives that are topoisomerase I inhibitors, to cancer patients. The composition contains as an active ingredient siastatin B or a siastatin B derivative that has β-glucuronidase inhibitory activity. This composition is effective in preventing or treating diarrhea associated with the administration of anticancer camptothecin derivatives.

Description

TECHNICAL FIELD The present invention relates to a novel pharmaceutical composition for preventing or treating diarrhea in cancer-bearing patients undergoing chemotherapy, particularly to a novel pharmaceutical composition for preventing or treating diarrhea that occurs in cancer-bearing patients as a side effect of the administration of cancer chemotherapy agents. The present invention also relates to a medical method for preventing or alleviating diarrhea in cancer-bearing patients who have received cancer chemotherapy agents.

BACKGROUND ART Diarrhea is often a side effect of drugs administered in drug therapy. In particular, diarrhea in cancer patients caused by the administration of cancer chemotherapy drugs is often severe, resulting in the inability to continue cancer treatment by drug administration. Furthermore, severe diarrhea induced by the administration of cancer chemotherapy drugs deteriorates the patient's physical strength and nutritional status, which in turn delays the patient's recovery from leukopenia, thrombocytopenia, and other conditions caused by the administration of cancer chemotherapy drugs. In particular, when anticancer camptothecin derivatives, which are topoisomerase I inhibitors and are one type of cancer chemotherapy drug, are administered, diarrhea caused by the administered drug often becomes severe.

In general, there are still many unknowns about the mechanism of diarrhea. However, in the case of diarrhea caused by the administration of cancer chemotherapy drugs, it is presumed that diarrhea occurs due to direct damage to the gastrointestinal mucosa by the administered cancer chemotherapy drugs, that is, due to biochemical changes in mucosal cells and changes in the intestinal bacterial flora caused by the administered cancer chemotherapy drugs. There is no established treatment method to alleviate diarrhea associated with the administration of cancer chemotherapy drugs. At present, there are several methods to improve the diarrhea caused by the administration of cancer chemotherapy drugs, such as changing the administration method and/or dosage of the cancer chemotherapy drugs, improving the formulation composition,
Alternatively, attempts have been made to reduce diarrhea by chemically modifying compounds used as cancer chemotherapy agents.

DISCLOSURE OF THE INVENTION The first object of the present invention is to provide a pharmaceutical composition for preventing or treating diarrhea, which can alleviate diarrhea that occurs in cancer patients following the administration of cancer chemotherapy drugs, particularly diarrhea that occurs as a side effect when anticancer camptothecin derivatives, which are topoisomerase I inhibitors, are administered to cancer patients.
The present invention provides a medical method capable of alleviating diarrhea that occurs in cancer patients following the administration of cancer chemotherapy agents.

The present inventors have conducted extensive research to achieve the above object. As a result, they have found that the compound represented by the following general formula (I)
It has been found that oral administration of known siastatin B or a siastatin B derivative, which is represented by the formula (I) and has β-glucuronidase inhibitory activity, to a cancer-bearing host prior to administration of an anticancer camptothecin derivative is effective in alleviating diarrhea, which occurs as a side effect accompanying the administration of the camptothecin derivative. Based on this finding, the present invention has been completed.

That is, in the first aspect of the present invention, the following general formula (I) is used:[In the formula, R¹is a hydrogen atom, or is unsubstituted or substituted with a halogen atom
a linear or branched acyl group having 1 to 5 carbon atoms, particularly an alkanoyl group,
Or R¹is represented by the formula -C(=NH)R⁵(However, R⁵is a group -OR⁶or group -
NR⁷R⁸and R⁶, R⁷and R⁸indicates a hydrogen atom or directly
represents a linear or branched alkyl group having 1 to 5 carbon atoms, and R
²and R³may be the same or different, and are each a hydrogen atom or an unsubstituted
a linear or branched alkyl group having 1 to 5 carbon atoms, substituted or substituted with a halogen atom;
R is an alkyl group, particularly an alkanoyl group,⁴is R⁵Independently of the group -OR⁶
or a group —NR⁷R⁸(However, R⁶, R⁷and R⁸indicates a hydrogen atom
or a linear or branched alkyl group having 1 to 5 carbon atoms).
and having β-glucuronidase inhibitory activity.
Astatine B derivatives or their pharmacologically acceptable salts are used as active ingredients.
and a pharmaceutically acceptable carrier mixed with the active ingredient.
The present invention provides a pharmaceutical composition for preventing or treating diarrhea, comprising:

In the above general formula (I), when R ¹ is an acetyl group, R ² and R ³ are each a hydrogen atom, and R ⁴ is an —OH group, the compound is siastatin B itself [
J. Antibiot. 27, 963-969 (1974)].

In the pharmaceutical composition according to the first aspect of the present invention, the pharmacologically acceptable salts of siastatin B or siastatin B derivatives of general formula (I) as an active ingredient include alkali metal salts at the 3-position carboxylic acid group of siastatin B, such as sodium salt, alkaline earth metal salts, such as calcium salt and ammonium salt, as well as addition salts at the imino group of siastatin B or siastatin B derivatives with pharmacologically acceptable inorganic acids, such as hydrochloride, sulfate, phosphate, and addition salts with pharmacologically acceptable organic acids, such as acetate and paratoluenesulfonate.
It is not limited to these.

The pharmaceutical composition of the first invention can be preferably administered when the diarrhea to be prevented or treated is diarrhea that occurs in cancer patients as a side effect of the administration of a cancer chemotherapy agent. In particular, it can be suitably administered to prevent or treat diarrhea associated with the administration of a type of cancer chemotherapy agent that is converted into a glucuronide conjugate form and then excreted in the bile. In a particularly preferred application example, the pharmaceutical composition of the first invention is used to prevent or treat diarrhea that occurs in cancer patients when a topoisomerase I inhibitor is administered as a cancer chemotherapy agent.

It is known that topoisomerase I inhibitors, which are cancer chemotherapy drugs, include camptothecin-related drugs, i.e., anticancer camptothecin derivatives. One example of an anticancer camptothecin derivative is irinotecan, and other examples include topotecan and others (see reference "J.C.
Lin. Oncol., Vol. 10, p. 647 (1992). Irinotecan,
Topotecan and other camptothecin derivatives, once administered to patients,
It is known that the derivative is converted in the liver into a glucuronide conjugate, which is a metabolic product of the derivative, and then excreted in the bile, and then moves to the lower gastrointestinal tract of the patient, i.e., the small intestine and large intestine.

The present inventors believe that the mechanism by which diarrhea can be suppressed by administering Siastatin B or a Siastatin B derivative of general formula (I) having β-glucuronidase inhibitory activity is as follows: After administration, camptothecin derivatives are converted into their metabolic products by the liver in the living body, and the metabolic products are converted into UDs present in the liver.
Camptothecin derivatives are converted into glucuronide conjugates by P-glucuronosyltransferase (UGT) and then excreted in the bile. Many intestinal bacteria exist in the lower gastrointestinal tract, and some intestinal bacteria have β-glucuronidase, which decomposes the converted glucuronide metabolites of camptothecin derivatives into deglucuronide compounds and glucuronic acid. As a result, the deglucuronide compounds (i.e., aglycone compounds derived from the original camptothecin derivatives) regenerated in the intestine are thought to act in the intestine and cause intestinal cytotoxic diarrhea (Xenobiotica).
tica), Vol. 23, pp. 5-10 (1993).

As will be explained later, Siastatin B and Siastatin B derivatives of general formula (I), which are used as active ingredients in the composition of the present invention, are known to have a strong β-glucuronidase inhibitory effect, and this enzyme inhibitory effect can inhibit the decomposition of the glucuronide conjugates by β-glucuronidase in the intestine and the regeneration of the deglucuronide compounds, thereby exhibiting an inhibitory effect on the occurrence of diarrhea. Therefore, Siastatin B or Siastatin B derivatives having β-glucuronidase inhibitory activity that reach the intestine after oral administration can, through their β-glucuronidase inhibitory activity, inhibit the decomposition of the glucuronide conjugates by intestinal bacteria having β-glucuronidase, and can suppress the regeneration of the deglucuronide compounds that cause diarrhea, thereby preventing the onset of diarrhea or alleviating the symptoms of diarrhea that has occurred.

The siastatin B or siastatin B derivative of general formula (I) used as an active ingredient in the composition of the present invention is a siastatin B derivative or siastatin B derivative represented by general formula (I) in which R ¹ , R ² and/or
The compound may be a compound in which ^R3 is the above-mentioned unsubstituted or halogen-substituted linear or branched acyl group having 1 to 5 carbon atoms, and in particular, may be a siastatin B derivative of general formula (I) in which ^R1 , ^R2 and/or ^R3 in general formula (I) are halogen-substituted or unsubstituted linear or branched ( _C1 - _C5 ) alkanoyl groups.

When R ¹ , R ² and/or R ³ in general formula (I) are unsubstituted or halogen-substituted (C ₁ to C ₅ )alkanoyl groups, the alkanoyl groups may preferably be, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, 2-methylbutyryl, 2,2-dimethylpropionyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, iodoacetyl, pentafluoropropionyl, pentachloropropionyl, heptafluorobutyryl or heptachloroisobutyryl.

Furthermore, when R ¹ in the general formula (I) is a group -C(=NH)R ⁵ and R ⁶ , R ⁷ and/or R ⁸ in the R ⁵ group are alkyl groups having 1 to 5 carbon atoms, examples of the alkyl group include, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an ethyl group, an n-propyl group, an i-butyl group, a sec-butyl group, an ethyl group, an ethyl group, an n-butyl group, an i-butyl group, an ethyl ...
Examples of the alkyl group include a t-butyl group, an n-pentyl group, an i-amyl group, and a tert-amyl group. In addition, in general formula (I), when ^R4 is a group ^-OR6 , the alkyl group represented by ^R6 can be the alkyl group exemplified above.

Particularly preferred among the compounds of general formula (I) are siastatin B derivatives in which ^R1 is a hydrogen atom, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, or an amidino group -C(=NH) _NH2 , ^R2 and ^R3 are each a hydrogen atom, and ^R4 is a group -OH.

The ciastatin of the general formula (I) used as an active ingredient in the composition of the present invention
B or a siastatin B derivative is represented by the following general formula (I'):[In the formula, R^1ais a hydrogen atom or (C₁~C₅) an alkanoyl group or
Iwa R^1ais mono-, di- or tri-substituted with chlorine or fluorine atoms (C
₁~C₅) an alkanoyl group, or R^1ais represented by the formula -C(=NH)NH₂
and R^6ais a hydrogen atom or (C₁~C₅) alkyl group
or a pharmacologically acceptable derivative thereof.
Salt is preferred.

Some specific examples of preferred compounds that can be used as active ingredients in the compositions of the present invention are listed below.

(1) The following formula (Ia) Siastatin B represented by the formula:

(2) The following formula (Ib) 6-deacetamido-6-trifluoroacetamido-siastatin B, which is represented by (3S,4S,5R,6R)-6-(trifluoroacetamido)-4
, 5-dihydroxypiperidine-3-carboxylic acid, JP-A-6-157458
The compound is described in Publication No.

(3) The following formula (Ic) 6-deacetamido-6-trichloroacetamido-siastatin B represented by
This is (3S,4S,5R,6R)-6-(trichloroacetamido)-4,
This compound is described in JP-A-9-71565 under the name 5-dihydroxypiperidine-3-carboxylic acid.

(4) The following formula (Id) 6-Deacetamido-6-guanidino-syastatin B, which is represented by (3
S,4S,5R,6R)-6-guanidino-4,5-dihydroxypiperidine-
This compound is described in JP-A-9-71565 under the name 3-carboxylic acid.

(5) The following formula (Ie) 6-Deacetamido-6-amino-siastatin B, which is represented by the formula (Ib
) is a product obtained by detrifluoroacetylating 6-deacetamido-6-trifluoroacetamido-siastatin B in methanol with hydrochloric acid.

It should be noted that the compounds of the above formula (Ia), formula (Ib), formula (Ic) and formula (Id) have β-glucuronidase inhibitory activity as described in "J. Antibiotics"
otics" Vol. 47, pp. 101-107 (1994) and Vol. 49, pp. 321
pp. 325-325 (1996).

One of the compounds represented by formula (I) used as an active ingredient in the composition of the present invention is ciastatin B. It is known that ciastatin B can be isolated from the culture medium of actinomycetes as a fermentation product [see, for example, Japanese Patent Publication No. 55-4024].
No. 6714 and "J. Antibiot.", Vol. 27, pp. 963-969 (1
974)]. Furthermore, ciastatin B can also be produced by chemical total synthesis or semi-synthesis from sugars [see, for example, JP-A-1-294687, Bull. Chem.
Soc. Jpn., vol. 65, p. 978 (1992) and J. Am. Chem.
Soc., Vol. 110, p. 7249 (1988)].

The siastatin B derivatives of general formula (I) used as active ingredients in the composition of the present invention can all be produced by chemical conversion from siastatin B using known methods. The compound in the case where R ¹ = acetyl group, R ² = R ³ = H, and R ⁴ = OH in the above general formula (I), i.e., siastatin B, and other siastatin B derivatives represented by general formula (I) can be produced from siastatin B using known methods, for example, the method described in JP-A-6-1995.
They can be produced by the methods described in Japanese Patent Application Laid-Open No. 57458 and Japanese Patent Application Laid-Open No. 9-71565, or by a method comprising a combination of ordinary protection and deprotection of functional groups, acylation, esterification, amidation, etc. Such siastatin B derivatives can also be produced directly by chemical synthesis without going through siastatin B.

The pharmaceutical composition of the first invention contains a pharmaceutically acceptable carrier mixed with an active ingredient, and can be formulated in a conventional pharmaceutical dosage form. As the pharmaceutically acceptable carrier, various solid carriers commonly used in conventional pharmaceuticals, such as starch, saccharose, lactose, or liquid carriers, such as water, physiological saline, ethanol, or aqueous ethanol, can be used. In addition, the composition of the present invention can contain, if desired, excipients,
Binders, disintegrants, lubricants, colorants, flavoring agents, fragrances, and/or surfactants may be incorporated in a known manner.

The administration preparation of the composition of the present invention can be any form of oral administration preparation, injection or suppository, but oral administration preparation form is preferable.When preparing oral administration preparation, the siastatin B or siastatin B derivative of general formula (I) as the active ingredient of the present invention is mixed with solid carrier, and further, if necessary, excipient, binder, disintegrant, lubricant, colorant, flavoring agent, odorant, surfactant, etc. are added, and then it can be formulated into tablets, granules, powder, capsules, pills, etc. by conventional method.The composition of the present invention or its preparation contains 0.1-100% (by weight), preferably 1-
Siastatin B or a Siastatin B derivative of general formula (I) can be blended in a proportion of 90% (by weight).

In the composition of the present invention, the dosage of the compound of general formula (I) is determined by the judgment of a specialist depending on the age, weight, sex, symptoms, purpose of treatment, etc. of the patient. In general, in the case of parenteral administration, the compound of general formula (I) is administered in an amount of 50 mg/day as an active ingredient.
In the case of oral administration, the active ingredient is 100 to 1000 mg.
The dosage may be once a day or divided into 2 to 4 doses per day.

The pharmaceutical composition according to the first aspect of the present invention can be administered when the diarrhea to be prevented or treated is diarrhea associated with the administration of a cancer chemotherapeutic agent, particularly when the diarrhea to be prevented or treated is diarrhea associated with the administration of a type of cancer chemotherapeutic agent that is excreted in the bile in the form of a glucuronide conjugate after administration.

Furthermore, the pharmaceutical composition according to the first aspect of the present invention can be administered when the diarrhea to be prevented or treated is diarrhea associated with the administration of a topoisomerase I inhibitor as a cancer chemotherapy agent, particularly when the diarrhea to be prevented or treated is diarrhea associated with the intravenous administration of an anticancer camptothecin derivative that is a topoisomerase I inhibitor, particularly irinotecan or topotecan.

Furthermore, the second invention provides use of Siastatin B or a Siastatin B derivative of the above general formula (I), or a pharmacologically acceptable salt thereof, for the manufacture of a pharmaceutical composition for the prevention or treatment of diarrhea.

Furthermore, the third aspect of the present invention provides a method for preventing or treating diarrhea in a cancer-bearing patient, which comprises orally administering to the cancer-bearing patient, who has or is at risk of developing diarrhea after receiving an anticancer camptothecin derivative, a topoisomerase I inhibitor, Siastatin B or a Siastatin B derivative represented by the above general formula (I), in an amount effective to alleviate the diarrheal symptoms.

In the third method of the present invention, to a cancer patient who has received intravenous administration of irinotecan or other anticancer camptothecin derivatives as an anticancer drug and is experiencing diarrhea, Siastatin B or a Siastatin B derivative of general formula (I) can be orally administered before each intravenous injection of irinotecan or other anticancer camptothecin derivative in an amount effective to alleviate diarrhea. The compound of general formula (I) can be orally administered to an adult in a single daily dose of 100 to 1,000 mg, which is an effective amount for alleviating diarrhea. Usually, when an anticancer camptothecin derivative, particularly irinotecan or topotecan, is intravenously injected, it is preferable to orally administer the compound of general formula (I) 10 to 30 minutes before the intravenous injection.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will now be described by way of example with reference to examples showing formulation examples of the pharmaceutical composition of the present invention and test examples showing the treatment of diarrhea, but the present invention is not limited to these examples. Example 1 The following ingredients were thoroughly mixed in a conventional manner to prepare a powder having the following composition.

6-Deacetamido-6-trifluoroacetamido-siastatin B of the above formula (Ib) 100 mg Lactose 175 mg Example 2 A powder consisting of a mixture of the following composition was filled into a capsule container to obtain capsules.

Siastatin B derivative of the above formula (Ib) 100 mg Lactose 175 mg Test Example 1 The diarrhea suppressing effect of the ciastatin B derivative on diarrhea caused by the administration of irinotecan was tested as follows.

Irinotecan (a camptothecin derivative) dissolved in physiological saline was intravenously administered to 6-week-old male ICR mice (6 mice per group) at a dose of 60 mg/kg once a day for 5 consecutive days to create a gastrointestinal disorder model that causes diarrhea. Using this model, 15 minutes before each administration of irinotecan, 6-deacetamido-6-trifluoroacetamido-siastatin B of formula (Ib) was administered as a test drug at a dose of 200 mg/kg or 400 mg/kg once a day.
The mice were orally administered once a day for five consecutive days. The changes in body weight of each mouse group were measured, and the results are shown in Table 1 below.

Furthermore, to evaluate the degree of weight change in each of the above mouse groups (6 mice per group),
The relative body weight ratio was calculated using the following formula and is shown in Table 2 below.

Calculation formula: Relative body weight ratio = body weight on the day of measurement / body weight on the day irinotecan administration was started As shown in Tables 1 and 2, the test drug, the ciastatin B derivative, significantly reduced the weight loss caused by the administration of irinotecan.

Furthermore, to evaluate the degree of gastrointestinal damage in each of the above mouse groups, the degree of diarrhea and histopathological findings of the lower small intestine were examined two days after the end of irinotecan administration (i.e., the end of administration of 6-deacetamido-6-trifluoroacetamido-Siastatin B as the test drug). The results are shown in Table 3 below.

As shown in Table 3 above, in the test in which the test drug, siastatin B derivative, was administered, the degree of diarrhea observed by symptom observation and the degree of gastrointestinal damage by histopathological examination were milder than the degree of gastrointestinal damage observed in the case of administration of irinotecan alone. Test Example 2 In order to examine the effect of the combined use of the test drug, siastatin B derivative, on the anticancer drug efficacy of irinotecan, the following test was conducted.

A colon cancer model was prepared by transplanting tumor fragments of the human colon cancer line HT-29 into the cecum of 8-week-old female KSN nude mice (7-10 mice per group) under anesthesia. Using this model, irinotecan was intravenously administered five times, once every four days, starting three weeks after tumor transplantation (60 mg/kg irinotecan in the first and second doses, and once every three days for the third, fourth, and fifth doses).
The first administration was 45 mg/kg of irinotecan.
Deacetamido-6-trifluoroacetamido-Syastatin B 400 mg
The test drug was administered at a dose of 400 mg/kg once every four days, 15 minutes before each administration of irinotecan, for a total of five times. A group of mice was also treated with the test drug alone at 400 mg/kg.

On the second day after the end of administration of the test drug, the mice in each group were sacrificed under anesthesia, and the tumor masses were excised from the cecum. The tumor weights of each mouse group were measured.
The results are shown in the following Table 4. The influence of the test drug, ciastatin B derivative, on the efficacy of irinotecan was examined using the change in tumor weight as a marker.

As shown in Table 4, the tumor weight observed in the group administered irinotecan alone was lower than the tumor weight observed in the untreated group (administered neither irinotecan nor the test drug siastatin B derivative), demonstrating that irinotecan exhibited a significant growth inhibitory effect on the human colon cancer cell line HT-29 transplanted into the cecum of nude mice.

Furthermore, as shown in Table 4, the tumor weight observed in the irinotecan alone administration group was not significantly different from the tumor weight observed in the irinotecan + test drug combination administration group (irinotecan + siastatin B derivative combination administration group). This indicates that the siastatin B derivative administered as the test drug did not exhibit any interfering effect on the anticancer drug efficacy of irinotecan.

INDUSTRIAL APPLICABILITY As described above, the siastatin B or siastatin B derivative of general formula (I), used as an active ingredient in the pharmaceutical composition for preventing or treating diarrhea according to the present invention, has β-glucuronidase inhibitory activity. Oral administration of the composition of the present invention, which contains siastatin B or a siastatin B derivative of general formula (I) as an active ingredient, can effectively suppress diarrhea in cancer patients receiving anticancer drugs, particularly diarrhea associated with the administration of anticancer drugs such as camptothecin derivatives. Therefore, the composition of the present invention eliminates the need to interrupt cancer chemotherapy due to diarrhea, allows cancer chemotherapy to be continued, and prevents physical fatigue due to diarrhea. Therefore, the composition and method of the present invention can also enhance the effectiveness of cancer treatment using conventional anticancer drugs.

──────────────────────────────────────────────────── Continuation of front page (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP(GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), UA(AM, AZ, BY, KG, KZ, MD, R.U. TJ, TM), AE, AG, AL, AU, BA, BB, BG, BR, BZ, CA, CN, CR, CU, C Z, DM, DZ, EE, GD, GE, HR, HU, ID ,IL,IN,IS,JP,KR,LC,LK,LR, LT, LV, MA, MG, MK, MN, MX, NO, N Z, PL, RO, RU, SG, SI, SK, TR, TT , UA, US, UZ, VN, YU, ZA (72) Inventor Yoshio Nishimura 3-18-21 Iwatominami, Komae City, Tokyo (72) Inventor: Yoshihiko Terayama 788 Kayayama, Odawara City, Kanagawa Prefecture, Meiji Seika Kaisha, Ltd. Pharmaceutical Technology Research Institute (72) Inventor: Mineaki Okada 3-29-15 Shimo, Kita-ku, Tokyo (72) Inventor: Yuji Akiyama 2-336 Kitabukuro-cho, Omiya City, Saitama Prefecture (72) Inventor: Hisao Yokumoto 2-4-5 Shimo, Kita-ku, Tokyo (Note) This publication is based on the publication published internationally by the International Bureau of Patent Publication (WIPO). Please note that the effect of the international publication of the Japanese-language patent application (Japanese-language utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act), and is unrelated to this publication.

Claims (13)

[Claims] Claim 1: The following general formula (I) [In the formula, R¹is a hydrogen atom, or is unsubstituted or substituted with a halogen atom
a linear or branched acyl group having 1 to 5 carbon atoms, particularly an alkanoyl group,
Or R¹is represented by the formula -C(=NH)R⁵(However, R⁵is a group -OR⁶or group -
NR⁷R⁸and R⁶, R⁷and R⁸indicates a hydrogen atom or directly
represents a linear or branched alkyl group having 1 to 5 carbon atoms, and R
²and R³may be the same or different, and are each a hydrogen atom or an unsubstituted
a linear or branched alkyl group having 1 to 5 carbon atoms, substituted or substituted with a halogen atom;
R is an alkyl group, particularly an alkanoyl group,⁴is R⁵Independently of the group -OR⁶
or a group —NR⁷R⁸(However, R⁶, R⁷and R⁸indicates a hydrogen atom
or a linear or branched alkyl group having 1 to 5 carbon atoms).
and having β-glucuronidase inhibitory activity.
Astatine B derivatives or their pharmacologically acceptable salts are used as active ingredients.
A pharmaceutical composition for preventing or treating diarrhea, comprising: Claim 2: In the general formula (I), R ¹ , R ² and/or R ³ are the above-mentioned unsubstituted or halogen-substituted linear or branched (C ₁ -C ₅ )
2. The composition according to claim 1, comprising as an active ingredient a siastatin B derivative of formula (I) or a salt thereof, wherein the siastatin B derivative is an alkanoyl group. [Claim 3] In the general formula (I), R ¹ , R ² and/or R ³ are unsubstituted or halogen atom-substituted (C ₁ -C ₅ ) alkanoyl groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,
3. The composition according to claim 2, comprising as an active ingredient a siastatin B derivative or a salt thereof of general formula (I), wherein the siastatin B derivative is an isovaleryl group, a 2-methylbutyryl group, a 2,2-dimethylpropionyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a bromoacetyl group, an iodoacetyl group, a pentafluoropropionyl group, a pentachloropropionyl group, a heptafluorobutyryl group, or a heptachloroisobutyryl group. 4. The composition according to claim 1, comprising as an active ingredient a compound of general formula (I) or a salt thereof, wherein ^R1 in general formula (I) is a hydrogen atom, an acetyl group, a trifluoroacetyl group, a trichloroacetyl group, or an amidino group -C(=NH) _NH2 , ^R2 and ^R3 are each a hydrogen atom, and ^R4 is a group -OH. Claim 5: Siastatin B or a Siastatin B derivative of general formula (I) is one of the following:
General formula (I’)[In the formula, R^1ais a hydrogen atom or (C₁~C₅) an alkanoyl group or
Iwa R^1ais mono-, di- or tri-substituted with chlorine or fluorine atoms (C
₁~C₅) an alkanoyl group, or R^1ais represented by the formula -C(=NH)NH₂
and R^6ais a hydrogen atom or (C₁~C₅) alkyl group
or a pharmacologically acceptable derivative thereof.
2. The composition of claim 1 which is a salt. Claim 6: A compound represented by the following formula (Ia) as an active ingredient: or siastatin B represented by the following formula (Ib): or 6-deacetamido-6-trifluoroacetamido-siastatin B represented by the following formula (Ic): 6-deacetamido-6-trichloroacetamido-siastatin B represented by
or the following formula (Id): or 6-deacetamido-6-guanidino-syastatin B represented by the following formula (Ie): 2. The composition according to claim 1, comprising 6-deacetamido-6-amino-ciastatin B represented by the formula: or a pharmacologically acceptable salt thereof. 7. The composition according to any one of claims 1 to 6, wherein the diarrhea to be prevented or treated is diarrhea associated with the administration of a cancer chemotherapy agent. [Claim 8] A composition described in any one of claims 1 to 7, wherein the diarrhea to be prevented or treated is diarrhea associated with the administration of a type of cancer chemotherapy agent that is excreted in the bile in the form of a glucuronide conjugate after administration of the cancer chemotherapy agent. 9. The composition according to claim 7 or 8, wherein the diarrhea to be prevented or treated is diarrhea associated with the administration of a topoisomerase I inhibitor as a cancer chemotherapy agent. 10. The composition according to claim 8 or 9, wherein the diarrhea to be prevented or treated is diarrhea associated with intravenous administration of an anticancer camptothecin derivative which is a topoisomerase I inhibitor, particularly irinotecan or topotecan. Claim 11: Use in the manufacture of a pharmaceutical composition for the prevention or treatment of diarrhea.
2. Use of siastatin B or a siastatin B derivative of the general formula (I) described in 1 above, or a pharmacologically acceptable salt thereof. [Claim 12] A method for preventing or treating diarrhea in a cancer-bearing patient, which comprises orally administering to the cancer-bearing patient, who has symptoms of diarrhea or is at risk of developing diarrhea after receiving an anticancer camptothecin derivative, which is a topoisomerase I inhibitor, siastatin B or a siastatin B derivative represented by general formula (I) described in claim 1, in an amount effective to alleviate the symptoms of diarrhea. 13. A method according to claim 1, comprising orally administering to a cancer patient who has symptoms of diarrhea after intravenous administration of irinotecan or other anticancer camptothecin derivatives as an anticancer drug, Siastatin B or a Siastatin B derivative of the general formula (I) according to claim 1, in an amount effective for alleviating the symptoms of diarrhea, before each intravenous injection of irinotecan or other anticancer camptothecin derivatives.
2. The method according to claim 2.