RU2190399C2 - Preparation for treating and preventing cachexia - Google Patents

Abstract

FIELD: medicine, oncology. SUBSTANCE: method deals with application of some selective inhibitors of cyclooxygenase-2 for treating and preventing cachexia. The innovation enables to considerably decrease cachexial symptoms, decrease side effects and gives an opportunity to continue treatment by using anti-tumor preparations. EFFECT: higher efficiency. 7 cl, 15 ex, 10 tbl

Description

 The invention relates to the use of certain compounds, especially cyclooxygenase-2 inhibitors (hereinafter referred to as "COX-2 inhibitors") for the treatment and prevention of tumors, disorders associated with tumors and cachexia.

 Cachexia is a systemic disease whose main symptoms are progressive weight loss, anemia, swelling, loss of appetite, etc. It can manifest itself as a side effect of some chronic diseases, such as malignant tumors, tuberculosis, diabetes, blood diseases, diseases of the endocrine system , infections and acquired immunodeficiency syndrome. If cachexia is the result of a malignant tumor, even if the administration of anticancer drugs to a patient with a malignant tumor is effective and an antitumor effect is observed, usually there is no improvement in cachexia due to harmful effects such as myelotoxicity that can be caused by antitumor drugs.

 Treatment of cachexia is often very difficult for the following reasons. Since with the development of cachexia the strength of the patient is significantly weakened, it may not be possible to continue treatment with anticancer drugs (which are usually characterized by a high level of toxicity) and this becomes an obstacle to the treatment of a malignant tumor.

 Dietary supplements are often given to treat cachexia symptoms. However, this often enhances the development of a malignant tumor and can shorten the patient's lifespan.

 There is currently no satisfactory treatment for cachexia, and there is an increasing need for agents that can relieve cachexia symptoms.

The compounds of formulas (I) or (II) below, which along with some other compounds are active ingredients of the compositions of the present invention, are known to selectively inhibit cyclooxygenase-2 (COX-2). It is also known that they inhibit the production of inflammatory cytokines (especially IL-1 and TNF-α), inhibit the production of leukotrienes (in particular, LTB ₄ ), inhibit bone resorption and have analgesic, anti-inflammatory and antipyretic effects (European Patent Publication 799823 A).

Ранее не было известно, что эти соединения могут быть использованы для лечения или профилактики кахексии.

It was not previously known that these compounds can be used to treat or prevent cachexia.

It is also known that some other active ingredients used in the present invention, namely the compounds of formulas (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XII), (XIII) and (XIV), have selective inhibitory activity against cyclooxygenase-2, have an inhibitory effect on the production of leukotrienes (in particular, LTB ₄ ), an inhibitory effect on bone resorption, have an analgesic effect, anti-inflammatory effect and antipyretic effect [international publication WO 95/00501, J.Med. Chem., 40, 1347 (1997), international publication WO 94/13635, Pharmacology, 55, 44 (1997), Prostaglandins, 47, 55 (1994), Japanese publication Hei 9-52882, Jpn. J. Pharmacol, 67, 305 (1995), Inflamm. Res. , 47, Suppl. 3, S257 (1997), J. Med. Chem., 38, 4570 (1995), US patent 5474995, European patent 863134 and international patent publication WO 98/06708], however, it was not previously disclosed that these compounds have anti-cachexia effects.

 From epidemiological studies, it is known that the use of conventional NSAIDS (non-steroidal anti-inflammatory drugs), which are inhibitors of COX-1 and COX-2, the most common of which is aspirin, and cases of colon cancer are inversely proportional. In addition, there are many reports that NSAIDS, such as aspirin and sulindac, have inhibitory activity against tumor metastases and carcinogenesis, as demonstrated in preclinical studies. Some NSAIDS have been used in clinical studies to prevent colon carcinogenesis.

 However, since conventional NSAIDS are not selective for COX-1 or COX-2, harmful effects are inevitable.

 Therefore, it would be desirable to detect a selective cyclooxygenase-2 inhibitor for use as an antitumor agent that would have a low level of side effects.

Among the known selective COX-2 inhibitors, it is known that the MF-tricyclic [Oshima, M. et al. "Suppression of Intestinal Polyposis in APCΔ ⁷¹⁶ Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2)", Cell, 87, 803-809 (1996)], and celecoxib [(Ready RS et a1. "Evaluation of Cyclooxygenase-2 Inhibitor for Potential Chemopreventive Properties in Colon Carcinogenesis ", Cancer Res., 56, 4566-4569 (1996)] inhibit the occurrence of colon polyposis in the experiment and that SC-58125 has an inhibitory effect on the growth of certain types of human colon cancer cell lines [Sheng, H. et al. "Inhibition of Human Colon Cancer Cell Growth by Selective Inhibition of Cyclooxygenase-2", J. Clin. Invest., 99, 2254-2259 (1997)].

 However, in the first case, the experimental system used is not a model of established colon cancer, and these compounds can only prevent polyposis in the first stage of colon cancer.

 On the other hand, in the latter case, the only cell line of colon cancer for which there was an inhibitory effect on the growth of the human colon cancer cell line was a cell line that expresses cyclooxygenase-2 (HCA-7 human colon cancer cell line), and it was found that colon cancer cell lines for which no tumor growth inhibitory activity (HCT-116) was observed in vitro did not exhibit tumor growth inhibitory effects in vivo either. Therefore, whether or not the COX-2-induced inhibitor of tumor growth of colon cancer cells will be induced in vivo will depend on the sensitivity of the used colon cancer cell lines with respect to the COX-2-induced inhibitor of cell growth inhibiting in vitro activity. Thus, it is unlikely that the in vivo effects of COX-2 inhibitors inhibiting tumor growth will be observed in relation to various other cancers, especially those cancers including colon cancers that are resistant to in vitro cell growth inhibition induced by the COX-2 inhibitor and which are not Express cyclooxygenase-2.

 Moreover, the use of a combination of a selective cyclooxygenase-2 inhibitor and a 5-fluorouracil derivative to prevent or inhibit tumor growth has not been previously disclosed.

 Some 1,2-diphenylpyrrole derivatives and closely related compounds have been found to have excellent activity in preventing or inhibiting cachexia and that these 1,2-diphenylpyrrole derivatives are effective in treating or preventing tumor-related disorders, taken alone or in combination with the derivative 5 fluorouracil.

Thus, in a first embodiment of the present invention, there is provided a method of treating or preventing cachexia in a mammal, which may be a person in need of such treatment or prophylaxis, which comprises administering to said mammal an effective amount of an active compound selected from the group consisting of compounds of formulas (I) , (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and ( XIV) (see the end of the description),
where R represents a hydrogen atom, a halogen atom or a lower alkyl group;
R ¹ represents a lower alkyl group, an amino group or a group of the formula NHR ^a (where R ^a represents a group that can be cleaved in vivo);
R ² represents a phenyl group or a group containing at least one substituent selected from the group consisting of substituents α and substituents β, as defined below;
R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group containing at least one substituent selected from the group consisting of substituents α;
R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkyl group containing at least one substituent selected from the group consisting of substituents α, a cycloalkyl group, an aryl group as defined below, or an aralkyl group as defined below;
said aryl group is a carbocyclic aromatic hydrocarbon group containing from 6 to 14 carbon atoms in one or more aromatic rings, or such a group that is fused to a cycloalkyl group containing from 3 to 10 carbon atoms, and this group is unsubstituted or substituted, at least one substituent selected from the group consisting of substituents α and substituents β;
said aralkyl group is a lower alkyl group which is substituted by one or more of the aryl groups defined above;
tBu represents a tert-butyl group;
Et represents an ethyl group; and
Ph represents a phenyl group;
said substituents α are selected from the group consisting of hydroxy groups, halogen atoms, lower alkoxy groups and lower alkylthio groups; and
said substituents β are selected from the group consisting of lower alkyl groups, alkanoyloxy groups, mercapto groups, alkanoylthio groups, lower alkylsulfinyl groups, lower alkyl groups containing at least one substituent selected from the group consisting of substituents α, cycloalkyloxy groups, lower haloalkoxy groups and lower alkylenedioxy groups;
and their pharmaceutically acceptable salts.

 The present invention further provides a method for treating or preventing tumor-related disorders in a mammal, which may be a person in need of such treatment or prophylaxis, which comprises administering to said mammal an effective amount of an active compound selected from the group consisting of compounds of formula (I) and (Ii) as defined above.

Preferred compounds of the present invention are those compounds of formula (I) and (II) in which:
(1) R represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, more preferably a hydrogen atom,
(2) R ¹ represents a methyl group, an amino group or an acetylamino group, more preferably an amino group or an acetylamino group,
(3) R ² represents a phenyl group or phenyl group containing at least one substituent selected from the group consisting of substituents α ¹ and substituents β ¹ , more preferably a phenyl group or phenyl group containing at least one a substituent selected from the group consisting of substituents α ¹ and substituents β ² , even more preferably a phenyl group in which the number of substituents is from 1 to 3,
(4) R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group containing at least one substituent selected from the group consisting of substituents α ¹ , more preferably a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by a halogen atom,
(5) R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkyl group containing at least one substituent selected from the group consisting of substituents α, a cycloalkyl group, an aryl group, an aryl group containing at least one substituent selected from the group consisting of substituents α ¹ and substituents β ^3, an aralkyl group or an aralkyl group having at least one substituent selected from the group consisting of substituents α ¹ and substituents β ^3, more preferably a vodoro and, a lower alkyl group, a lower alkyl group having at least one substituent selected from the group consisting of substituents α ^2, a cycloalkyl group, an aryl group, an aryl group containing at least one substituent selected from the group consisting of substituents α ² and substituents β ⁴ , an aralkyl group, or an aralkyl group containing at least one substituent selected from the group consisting of substituents α ² and substituents β ⁴ .
These substituents α ¹ are selected from the group consisting of halogen atoms, lower alkoxy groups and lower alkylthio groups.

These substituents α ² are selected from the group consisting of hydroxy groups, halogen atoms and lower alkoxy groups.

These β ¹ substituents are selected from the group consisting of lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups containing at least one substituent selected from the group consisting of α ¹ substituents, lower haloalkoxy groups and lower alkylenedioxy groups.

These β ² substituents are selected from the group consisting of lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted with a halogen atom, lower haloalkoxy groups and lower alkylenedioxy groups.

These β ³ substituents are selected from the group consisting of lower alkyl groups, lower alkyl groups containing at least one substituent selected from the group consisting of α substituents and cycloalkyloxy groups.

These β ⁴ substituents are selected from the group consisting of lower alkyl groups, lower alkyl groups substituted with a halogen atom, and cycloalkyloxy groups.

In the compounds of formulas (I) and (II), where R, R ³ , substituents α, substituents α ¹ or substituents α ² represent a halogen atom, or where substituents β ² or substituents β ⁴ represent a lower alkyl group substituted by a halogen atom, an atom halogen is preferably a chlorine atom, a bromine atom, a fluorine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or an iodine atom.

If R, R ¹ , R ³ , R ⁴ , Deputy β, Deputy β ¹ , Deputy β ² , Deputy β ³ or Deputy β ⁴ represents a lower alkyl group, or R ³ , R ⁴ , Deputy β, Deputy β ¹ or Deputy β ³ represents a lower alkyl group containing at least one substituent selected from the group consisting of α substituents, or β ² or β ⁴ substituent represents a lower alkyl group substituted by a halogen atom, an alkyl group or an alkyl part of a substituted group be a branched or straight chain alkyl group my chain containing from 1 to 6 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl. Of these, branched or unbranched alkyl groups containing from 1 to 4 carbon atoms are preferred, methyl and ethyl groups are more preferred. In R, R ¹ and R ⁴ , a methyl group is particularly preferred as a lower alkyl group.

If substituent β represents an alkanoyloxy group or substituent β, substituent β ¹ or substituent β ² represents an alkanoylthio group, the alkanoyl part of these groups may be, for example, a branched or unbranched alkanoyl group containing from 1 to 25 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, myristoyl, palmitoyl, stearoyl, icosanoyl, docosanoyl and pentacosanoyl. Of these, those alkanoyl groups which contain from 1 to 12 carbon atoms are preferred, those alkanoyl groups which contain from 1 to 6 carbon atoms are more preferred, and those alkanoyl groups which contain from 1 to 4 carbon atoms are even more preferred, and most acetyl and propionyl groups are preferred.

If R ⁴ represents a cycloalkyl group, a cycloalkyl group containing from 3 to 8 carbon atoms is preferred, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Of these, cycloalkyl groups containing from 3 to 7 carbon atoms are preferred, more preferred cycloalkyl groups containing from 3 to 6 carbon atoms, and the cyclopropyl group is most preferred.

If R ⁴ represents an aryl group, this aryl group may be a carbocyclic aromatic hydrocarbon group containing from 6 to 14 carbon atoms, and may be unsubstituted or may be substituted by at least one substituent selected from the group consisting of substituents α and substituents β. Such a group may contain one aromatic ring or may contain two or more fused rings. Examples of such groups include phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl. Of these, phenyl and naphthyl groups are preferred, and a phenyl group is more preferred. The above aryl group may be fused to a cycloalkyl group containing from 3 to 10 carbon atoms, and examples of such fused groups include, for example, a 2-indanyl group.

If R ⁴ represents an aralkyl group, then the alkyl group may be any of the alkyl groups defined and exemplified above with respect to R, etc., and may be substituted with 1-3 aryl groups as defined and exemplified above. Such a group may be unsubstituted or may be substituted by at least one of the substituents α or β. Examples of such groups include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, diphenylmethyl, triphenylmethyl, 1-naphthyldiphenylmethyl and 9-anthrylmethyl. Of these, an alkyl group containing from 1 to 4 carbon atoms is preferred, which is substituted by one aryl group containing from 6 to 10 carbon atoms.

If substituent α, substituent α ¹ or substituent α ² represents a lower alkoxy group, it may be, for example, a branched or straight chain alkoxy group containing, for example, from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3, 3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dime tilbutoksi, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy. Of these, branched or unbranched alkoxy groups containing from 1 to 4 carbon atoms are preferred, methoxy and ethoxy groups are more preferred.

If substituent α or substituent α ¹ represents a lower alkylthio group, it may be a branched or unbranched alkylthio group containing from 1 to 6 carbon atoms, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio , pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylbutyl dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-d methylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio. Of these, branched or unbranched alkylthio groups containing from 1 to 4 carbon atoms, preferably methylthio and ethylthio groups, are preferred.

 If the substituent β represents a lower alkylsulfinyl group, it may be a branched or unbranched alkylsulfinyl group containing from 1 to 6 carbon atoms, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsilynylsilynylsulfinylphenylsulfinylphenylsilynylsulfinylphenylsulfinylphenylsulfinylphenylsulfinylphenylsulfinylphenylsulfinylphenylsulfinylphenylsulfinylphenylsulfinylphenylsulfinyl , 2-methylbutylsulfinyl, neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, isohexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentyl ulfinil, 1-methylpentylsulfinyl, 3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, and 2-ethylbutylsulfinyl. Of these, branched or unbranched alkylsulfinyl groups containing from 1 to 4 carbon atoms are preferred.

If the substituent β, the substituent β ³ or the substituent β ⁴ represents a cycloalkyloxy group, it can be, for example, a cycloalkyloxy group containing from 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclohepyloxy and cyclooctyloxy. Of these, cycloalkyloxy groups containing from 3 to 7 carbon atoms are preferred, more preferred cycloalkyloxy groups containing from 5 to 6 carbon atoms, and most preferred is cyclopentyloxy group.

If the substituent β, the substituent β ¹ or the substituent β ² represents a lower haloalkoxy group, it is an alkoxy group which may be as defined and exemplified above with respect to the substituent α, etc., and which is substituted by at least one atom halogen, as defined and represented by the examples above. Examples of such
groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy, iodomethoxy and bromomethoxy. Of these, lower haloalkoxy groups are preferred which contain from 1 to 4 carbon atoms, more preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy and bromomethoxy, and fluoromethoxy, difluoromethoxy and trifluoromethoxy groups are most preferred.

If the substituent β, the substituent β ¹ or the substituent β ² represents a lower alkylenedioxy group, it can be, for example, a branched or unbranched alkylenedioxy group containing from 1 to 6 carbon atoms, such as methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy, pentamethylenedioxy, hexamethylenedioxyoxy and propylene. Of these, alkylenedioxy groups which contain from 1 to 4 carbon atoms are preferred, methylenedioxy and ethylenedioxy groups are more preferred.

If the substituent β ² or the substituent β ⁴ represents a lower alkyl group substituted by a halogen atom, it may be an alkyl group as defined and exemplified above with respect to R and the like, which are substituted by at least one halogen atom, as well defined and represented by the examples above. Examples of such groups include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, 2- chloroethyl, 3-chloropropyl, bromomethyl, 2-bromoethyl, iodomethyl, 2-iodoethyl, chlorodifluoromethyl and bromodifluoromethyl. Of these, haloalkyl groups containing from 1 to 4 carbon atoms are preferred, more preferred are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl and bromomethyl, and most preferred are fluoromethyl, difluoromethyl and trifluoromethyl.

If R ^a represents a group that is cleaved in vivo, it is a group that can be cleaved in the human body under physiological conditions, such as hydrolysis, that is, it is a group that produces a free amino group (-NH ₂ ) from the group of the formula -NHR ^a ( where R ^a has the above meanings). Using the following test, it is easy to determine whether or not a group can be split off in vivo: the compound to be tested is administered orally or intravenously to an experimental animal such as a rat or mouse, and body fluid is tested for the presence or absence of the corresponding compound containing a free amino group, or its pharmaceutically acceptable salt.

Such groups include, for example:
alkanoyl groups defined and exemplified above for substituent β and the like;
lower alkoxy groups in which the alkoxy group is defined and exemplified above for substituent α and the like, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and cyclo;
an aralkyloxycarbonyl group in which aryl is defined above and may be unsubstituted or may be substituted with one or two lower alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxy;
an alkanoyloxymethyl group in which an alkanoyl group is defined and exemplified above for substituent β and the like, such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl and hexanoyloxymethyl;
a lower alkoxycarbonyloxymethyl group in which the alkoxy group defined and exemplified above for the substituent α etc., such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl and pentiloksikarboniloksimetil; and
(2-oxo-l, 3-dioxolen-4-yl) methyl group, which at the 5-position of the dioxolene ring may be substituted with a lower alkyl group or an aryl group, as defined and exemplified above for R and R ^4, respectively, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- ( 4-methoxyphenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl] -2-oxo-1,3-dioxolen-4-yl] methyl, [5- ( 4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3 -dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5 -propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl and (5-butyl-2-oxo-1 , 3-dioxolen-4-yl) methyl.

 Of these, alkanoyl groups containing from 1 to 12 carbon atoms, alkoxycarbonyl groups containing from 2 to 5 carbon atoms, aralkyloxycarbonyl groups containing from 7 to 8 carbon atoms, alkanoyloxymethyl groups containing from 3 to 6 carbon atoms, alkoxycarbonyloxymethyl groups are preferred, containing from 3 to 6 carbon atoms and a 5-substituted (2-oxo-1,3-dioxolen-4-yl) methyl group, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovalenil, pivaloyl, methoxycarbonyl, ethoxycarbonyl, benzyl are more preferred xicarbonyl, acetoxymethyl, propionyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, and (5-phenyl-2-oxo-1,3-dioxolen-4-yl ) methyl, and most preferred is an acetyl group.

Specific examples of R ¹ preferably include the methyl, ethyl, amino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, atsetoksimetilamino, propioniloksimetilamino, metoksikarboniloksimetilamino, etoksikarboniloksimetilamino, (5-methyl-2-oxo -1,3-dioxolen-4-yl) methylamino and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methylamino groups, more preferably methyl, amino and acetylamino groups and most preferred amino and acetone laminogruppy.

Specific examples of R ² preferably include:
unsubstituted phenyl group;
phenyl groups containing from 1 to 3 substituents selected from mercapto groups, C ₁ -C ₄ alkanoylthio groups, halogen atoms, C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio and C ₁ -C ₄ alkylsulfinyl groups such as 4-mercaptophenyl, 4-acetylthiophenyl, 4-propionylthiophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, p-toluyl, 4-ethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 4-methylsulfinyl phenyl, 4-ethylsulfinyl phenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dimethylphenyl, 3,4-dimethoxyphenyl, 3- chloro 4- fluorophenyl, 3-chloro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-methyl-4-methoxyphenyl, 3,5-dichloro-4-methoxyphenyl and 4-methoxy-3,5-dimethylphenyl groups;
trifluoromethyl, difluoromethoxy or trifluoromethoxy substituted phenyl groups such as 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl and 4-trifluoromethoxyphenyl groups;
a methylenedioxy or ethylenedioxy substituted phenyl group such as 3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl groups.

In the case where R ² represents a substituted phenyl group, the number of substituents is preferably 1-3, more preferably 1 or 2.

Specific examples of R ³ preferably include hydrogen atoms, halogen atoms such as fluorine, chlorine, bromine and iodine; C ₁ -C ₄ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; and C ₁ -C ₄ haloalkyl groups such as fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 2-chloroethyl and 3-chloropropyl, more preferred are hydrogen atoms; halogen atoms such as fluorine, chlorine, bromine and iodine; and methyl, ethyl, fluoromethyl, difluoromethyl, 2-fluoroethyl and 2-chloroethyl.

Specific examples of R ⁴ preferably include hydrogen atoms; C ₁ -C ₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl; wherein any of these alkyl groups contain a substituent selected from hydroxy, halogen (such as fluoro, chloro, bromo and iodo) and C ₁ -C ₄ alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy); C ₃ -C ₇ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C ₆ -C ₁₀ aryl groups, such as phenyl and naphthyl, which may be unsubstituted or may contain one or more of the following substituents γ; C ₆ -C ₁₀ aryl C ₁ -C ₄ alkyl groups such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl and 2-naphthylmethyl, which may be unsubstituted or may have one or more of the following substituents γ in the aryl part;
γ substituents include: halogen atoms such as fluorine, chlorine, bromine and iodine; C ₁ -C ₄ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; C ₁ -C ₄ haloalkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 3-fluoropropyl and 4-fluoropropyl; C ₁ -C ₄ alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy; and C ₃ -C ₇ cycloalkyloxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

Preferred examples of R ⁴ include: hydrogen atoms; C ₁ -C ₄ alkyl groups such as methyl, ethyl, isopropyl, butyl and isobutyl; C ₁ -C ₄ mono-, di- or trihaloalkyl groups such as fluoromethyl, difluoromethyl, chlorodifluoromethyl, bromodifluoromethyl, trifluoromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl; hydroxymethyl groups; C ₁ -C ₄ alkoxymethyl groups such as methoxymethyl and ethoxymethyl; C ₃ -C ₆ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; phenyl groups; mono- or difluorophenyl groups such as 4-fluorophenyl and 2,4-difluorophenyl; mono- or dimethoxyphenyl groups such as 4-methoxyphenyl and 3,4-dimethoxyphenyl; tolyl groups such as p-tolyl and o-tolyl; cyclopentyloxy (methoxy) phenyl groups such as 3-cyclopentyloxy-4-methoxyphenyl; trifluoromethylphenyl groups such as 4-trifluoromethylphenyl; benzyl groups; substituted benzyl groups such as 4-methoxyphenyl and 3-cyclopentyloxy-4-methoxybenzyl; phenethyl groups; naphthyl groups such as 1-naphthyl and 2-naphthyl; and naphthylmethyl groups such as 1-naphthylmethyl and 2-naphthylmethyl.

 Some compounds of the present invention, especially compounds of formula (I) and (II), have an acid group and, thus, can form salts with cations. The nature of the salt is not critical to the present invention, provided that it is pharmaceutically acceptable, that is, that the salt is not less active (or unacceptably less active), more toxic (or unacceptably more toxic) than the free acid. Such salts include, for example, alkali metal salts such as sodium, potassium or lithium; alkaline earth metal salts such as calcium or magnesium; salts of other metals, such as aluminum, iron, copper, zinc, nickel or cobalt; other inorganic salts, such as ammonium salts; salts of organic amines, such as tert.-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, pro-chloro-ethanol diamine -benzyl-N-phenethylamine, piperazine, tetramethylammonium or tris (hydroxymethyl) aminomethane.

 Further, when the compounds of formula (I) and (II) and their salts are left open in air, they can adsorb moisture and form hydrates. Such hydrates are also included in the scope of the invention.

 Further, the compounds of formula (I) and (II) and their salts sometimes absorb some types of solvents to form solvates, and such solvates are also included in the scope of the present invention.

 Some compounds of formulas (I) and (II) of the present invention may contain asymmetric carbon atoms in the molecule, and then stereoisomers of the R configuration or S configuration exist. Each of these stereoisomers and mixtures thereof in any desired proportions are also included in the scope of the present invention.

 Specific examples of compounds of formula (I) and (II) used in the method and compositions of the present invention include, for example, those shown in Table 1 [compounds of formula (1)] and table 2 [compounds of formula (II)].

The following abbreviations are adopted in these tables:
Ace acetyl; Wu butyl; Byr butyryl; iByr isobutyryl; Bz benzyl; Et ethyl; For form; Me methyl; Ph phenyl; Piv pivaloyl; CPn cyclopentyl; Pr propyl; CPr cyclopropyl; iPr isopropyl; Prn propionyl; iVal isovaleryl; and Val Valery.

Of the above compounds, preferred are:
1) 3-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole;
2) 4-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole;
3) 1- (4-fluorophenyl) -2- (4-sulfamoylphenyl) pyrrole;
4) 1- (4-fluorophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole,
5) 5-fluoro-1- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) pyrrole;
6) 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
7) 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole;
8) 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) pyrrole;
9) 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
10) 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole;
11) 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
12) 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
13) 2- (3-fluoro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
14) 4-methyl-2-phenyl-1- (4-sulfamoylphenyl) pyrrole;
15) 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
16) 2- (3-chloro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
17) 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;
18) 5-chloro-1- (4-methoxyphenyl) -2- (4-sulfamoylphenyl) pyrrole;
19) 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole;
20) 5-chloro-1- (4-ethoxyphenyl) -2- (4-sulfamoylphenyl) pyrrole;
21) 5-chloro-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;
22) 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole;
23) 2- (3,5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
24) 1- (4-mercaptophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole;
25) 1- (4-acetylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole;
26) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and
27) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole.

Of these, more preferred compounds are:
2) 4-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole;
6) 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
9) 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
10) 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole;
11) 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
12) 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
13) 2- (3-fluoro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
15) 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
17) 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;
26) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and
27) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole.

Of these, the most preferred compounds are:
11) 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
15) 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole;
17) 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole;
26) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole and
27) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole.

 Compounds of formula (I), compounds of formula (II) and pharmaceutically acceptable salts of these compounds are known compounds, and a process for preparing these compounds is disclosed in European Patent Publication EP 799823 A, which is incorporated herein by reference.

The compounds of formulas (III) - (XIV) have the following chemical names:
(III) 3- (3,4-difluorophenyl) -4- (4-methanesulfonylphenyl) -5H-furan-2-one,
(IV) 4- (5-tolyl-3-trifluoromethyl-1H-pyrazol-1-yl) benzenesulfonamide,
(V) N- [6- (2,4-Difluorophenylthio) -1-oxoindan-5-yl] methanesulfonamide,
(VI) 4-hydroxy-2-methyl-N- (5-methylthiazol-2-yl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide,
(VII) N- (4-nitro-2-phenoxyphenyl) methanesulfonamide,
(VIII) 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide,
(IX) N- (3-formylamino-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl) methanesulfonamide,
(X) (E) -2-ethyl-5- (3,5-di-tert-butyl-4-hydroxy) benzylidene-1,2-isothiazolidine-1,1-dioxide,
(XI) 1- (4-methanesulfonylphenyl) -2- (4-fluorophenyl) cyclopentene,
(XII) 3-phenyl-4- (4-methanesulfonylphenyl) -5H-furan-2-one, and
(XIII) 2- (3,5-difluorophenyl) -3- (4-methanesulfonylphenyl) -2-cyclopenten-1-one,
(XIV) 4- [5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide.

 These compounds are disclosed in WO 95/00501, J. Med. Chem. 40, 1347 (1997), in international publication WO 94/13635, Pharmacology 55, 44 (1997), Prostaglandins, 47, 55 (1994), in Japanese publication Hei 9-52882, Jpn. J. Pharmacol. 67, 305 (1995), Inflamm. Res., 47, Suppl. 3, S257 (1997), J. Med. Chem., 38, 4570 (1995), EP 863134, US 5474995 or WO 98/06708, which are incorporated herein by reference.

 Since the compounds of the present invention have excellent activity against the prevention or inhibition of cachexia and very low toxicity, they can be used as prophylactic and therapeutic agents for cachexia. They can be used to treat tumor-related disorders and to inhibit the growth and / or metastasis of tumors.

 Moreover, if desired, one or more compounds of the present invention [t. ie, compounds of formulas (I) to (XIV) inclusive] can be used together with one or more other agents for the prevention or inhibition of tumor growth, and the compounds of the present invention and other agents can be administered simultaneously, separately or sequentially.

 Another antitumor agent is preferably selected from the group consisting of 5-fluorouracil, cisplatin, tamoxifen, paclitaxel, docetaxel and irinotecan. Especially when administered simultaneously, a compound of formula (I) or (II) or their pharmaceutically acceptable salts and another antitumor agent can be included in one composition.

 The composition of the present invention may be in any convenient form depending on the route of administration. So, for example, for oral administration, it may be in the form of tablets, capsules, granules, powders or syrups. For non-oral administration, it may be in the form of suppositories or injectable preparations. The compositions are prepared according to known methods and may include additives well known to those skilled in the art, such as, for example, excipients (e.g., organic excipients, including derivatives of sugars such as lactose, sucrose, glucose, mannitol and sorbitol; derivatives of starch such as corn starch, potato starch, α-starch and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; and Pullulan, inorganic excipients, including silicate derivatives such as light silicic acid anhydride, synthetic aluminosilicate, calcium silicate and magnesium metaaluminosilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricants (e.g. stearic acid and its metal salts, including stearic acid, calcium stearate and magnesium stearate; talc, colloidal silicon dioxide; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine, sodium salts of fatty acids; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid, for example silicic anhydride and silicic acid hydrate; and the above starch derivatives), binding agents (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, Macrogol and compounds similar to the above excipients), disintegrating agents (e.g., cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose) internal carbohydrate sodium carboxymethyl cellulose; chemically modified starch cellulose such as carboxymethyl starch, sodium carbo simethyl starch and polyvinylpyrrolidone with bridges), stabilizers (for example, paraoxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phonols such as phenol and cresol; dehydroxybenzoic acid) flavoring agents (e.g. sweeteners, vinegar and perfumes) and diluents.

 Doses vary depending on many factors, including the condition and age of the patient, the severity and nature of the disorder, and the route of administration. For example, in the case of oral administration, it is desirable to administer 0.01 mg / kg (preferably 0.1 mg / kg) as the lower limit and 50 mg / kg (preferably 10 mg / kg) as the upper limit for an adult patient per day as a single dose or as several divided doses, depending on the symptoms. In the case of intravenous administration, it is desirable to administer 0.001 mg / kg (preferably 0.01 mg / kg) as the lower limit and 10 mg / kg (preferably 5 mg / kg) as the upper limit for adult patients as a single dose or as divided doses depending on the symptoms.

 Further, the present invention is illustrated by the following non-limiting examples and formulation examples.

EXAMPLE 1
Testing anti-cachexia action in mice with Colon 26 mouse colon cancer cells
As test animals used mice of strain CDF1 (females, 8 weeks). They were used in groups of 10 for each test. 1 × 10 ⁶ mouse Colon 26 colon cancer cells were transplanted subcutaneously to each animal.

Каждое тестируемое соединение суспендируют в стерилизованной дистиллированной воде, содержащей 0,5% вес/объем карбоксиметилцеллюлозы (CMC), и его вводят перорально один раз в день, начиная со дня трансплантации раковых клеток.As the tested compounds used compounds 1-94 and 2-78, are presented in tables 1 and 2, respectively, and having the formula

Each test compound is suspended in sterilized distilled water containing 0.5% w / v carboxymethyl cellulose (CMC) and is administered orally once a day, starting from the day of the cancer cell transplant.

Each test animal is weighed immediately after tumor cell transplantation and weight (A g) is recorded. Then, each animal was weighed on day 19 after tumor cell transplantation, and weight (g) was recorded. Weight gain on day 19 after cancer cell transplantation is calculated as BA = Δg _t for the test animals. The experiment is repeated for two control groups: tumor cells are transplanted to the first control group (control group 1), but they are not treated with any of the tested compounds and the weight gain is designated as Δg _c1 ; the second control group (control group 2) did not transplant tumor cells and were not treated with any test compounds, and weight gain was designated as Δg _c2 . The degree of recovery of body weight is determined in accordance with the following formula, based on weight gain on day 19 after transplantation of tumor cells, and this value is used as an indicator of anti-cachexial action.

The degree of recovery of body weight (%) = (Δg _t -Δg _c1 ) / (Δg _c2 -Δg _c1 ) × 100.
The results are shown in table 4.

 From the above results, it is obvious that these compounds inhibit tumor associated cachexia in mice and reduce weight loss.

EXAMPLE 2
Colon 26 mouse colon cancer mouse anti-cachexia test
The procedure of Example 1 is repeated, but the compound of formula (III) is used as the test compound, and the weight increase (Δg _t ) of the test group of animals to which the compound of formula (III) is administered is compared with the increase in the weight of the control group (Δg _c ) to which the tumors were transplanted cells but no antitumor compound is administered. As test animals using female mice of strain CDF1 at the age of 16 weeks. Weight gain is determined 22 days after transplantation of tumor cells. The average body weight of animals in each group immediately after transplantation of tumor cells is from 25 to 26 g. The results are shown in table 4.

 From the presented results it is clearly seen that the compound of formula (III) inhibits tumor-associated cachexia in mice and reduces weight loss.

EXAMPLE 3
Colon 26 mouse colon cancer mouse anti-cachexia test
The procedure of Example 2 is repeated, but the compound of formula (IV) is used as the test compound and the weight gain (Δg _t ) in the test group of animals to which the compound of formula (IV) is administered is compared with the weight increase in the control group of animals (Δg _c ), which tumor cells are transplanted, but to which the antitumor compound is not administered. As test animals used female mice of strain CDF1 at the age of 7 weeks. Weight gain is measured 15 days after tumor cell transplantation. The average weight of animals in each group immediately after transplantation of tumor cells ranged from 20 to 21 g. The results obtained are shown in table 5.

 From the presented results, it is clear that the compound of formula (IV) inhibits tumor-associated cachexia in mice and reduces weight loss.

EXAMPLE 4
Colon 26 mouse colon cancer mouse anti-cachexia test
Test compounds (compounds of formulas (V), (IV), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV)) are administered according to the scheme described in example 2. These compounds inhibit cachexia in mice associated with the tumor and reduce the loss of average body weight.

EXAMPLE 5
Life Test for Life Extension
Observations of the mice used in example 1 continue. The life extension indicator is determined based on the number of days the mouse survives, and then this value is used as an indicator of the extension of the life of the test compounds. It should be noted that in the case of a group of mice treated with the test compound, oral administration of the corresponding compound once a day is continued for 20 days after the transplantation of tumor cells, and also after that.

Life extension rate (%) = (S _t / S _c -1) (100
S _t is the average survival time (days) for a group of mice treated with the test compound.

S _c is the average survival time (days) for the control group of mice that did not have tumor cells transplanted.

 The results are presented in table 6.

 As follows from the data of table 6, the compounds of the present invention demonstrate a noticeable effect in relation to prolonging life.

EXAMPLE 6
Life Test for Life Extension
The experiment described in Example 5 is repeated with the animals used in Example 2. In the case of a group of mice treated with the test compound, oral administration of the corresponding compound once a day continues on day 23 after tumor cell transplantation and also thereafter. The results are shown in table 7.

EXAMPLE 7
Life Test for Life Extension
The experiment described in example 5 is repeated with the animals used in examples 3 and 4. The compounds of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI ), (XII), (XIII) and (XIV) all inhibit tumor associated cachexia in mice and show a marked extension of their lifespan.

EXAMPLE 8
Test with the simultaneous use of an antitumor agent
Mouse colon cancer cells transplant CDF1 into mice in the same manner as in Example 1, followed by administration of test compounds (compounds 2-78 and 1-94) and compounds of formulas (III), (IV), (V), (VI) , (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) and an antitumor agent (5-fluorouracil or cisplatin).

 The simultaneous use of one of the compounds of the present invention and an antitumor agent markedly inhibits tumor growth and cachexia, showing a significant effect on prolonging the life span.

EXAMPLE 9
Inhibitory effect on pulmonary cell metastases of murine malignant melanoma B16-BL6
Groups of mice, each of which includes ten mice of strain C57BL / 6 (females, age 8 weeks) are transplanted intravenously into the tail vein of 3 • 10 ⁴ cells of murine malignant melanoma B16-BL6.

 If necessary, mice are injected intravenously into the tail vein with bacterial lipopolysaccharide (LPS) in an amount of 3 μg each 1 hour before melanoma cell transplantation in order to accelerate the formation of melanoma metastases in the lungs. [M. J. Anasagasti et al., J. Natl. Cancer Research, 89, 645-651 (1997)].

 Compounds 2-118, a compound of formula (IV), a compound of formula (V) and indomethacin are each used as test compounds and each is suspended in distilled water containing 0.5% w / v% carboxymethyl cellulose (CMC), and this suspension is orally administered in a dose 1 mg / kg / day for 5 days, starting from the day of melanoma cell transplantation.

 Compound 2-118 is 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole.

 Inhibitory activity against pulmonary metastases of melanoma cells is evaluated in units of the degree of inhibition of metastases in the lungs (LMI%) by counting the number of colonies of lung metastases on day 10 after intravenous transplantation of murine malignant melanoma B16-BL6 cells into the tail vein.

LMI (%) = (lN _t / N _c ) • 100
N _t is the number of colonies of lung metastases on day 10 in the group of mice injected with the tested compounds; and
N _c is the number of colonies of lung metastases on day 10 in the group of mice to which the test compounds were not administered. The results obtained are presented in table 8.

 From the data of table 8 it is obvious that the compounds of the present invention successfully inhibit pulmonary metastases of cells of murine mouse B16-BL6 malignant melanoma, regardless of whether or not the formation of metastases in the lungs is accelerated by the introduction of LPS (induction of an inflammatory response).

 In particular, the compound of the present invention exhibits marked inhibition of lung metastases, although the compound of formula (IV) and the compound of formula (V), which are COX-2 selective inhibitors, and indomethacin, which is a typical NSAID, do not exhibit such inhibitory activity under conditions accelerating the formation of metastases in the lungs induced inflammatory response (which reflects the acceleration of the formation of tumor metastases during surgical removal of the tumor).

EXAMPLE 10
Antitumor effect against murine sarcoma cells S-180
1 • 10 ⁶ S-180 mouse sarcoma cells are transplanted subcutaneously in nude mice of strain Ba1b / s (females, age 8 weeks) in groups of 10 mice each.

 The test compound, compound 2-118, is suspended in sterilized distilled water containing 0.5% w / v carboxymethyl cellulose (CMC) and is administered orally once a day for 5 days starting from the day of tumor cell transplantation.

Antitumor activity is evaluated in accordance with the following equation to determine the degree of inhibition of tumor growth (GI%) on day 7 after transplantation
GI (%) = (lV _t / V _s ) • 100
V _t is the average tumor volume on day 7 in the group of mice that were injected with the test compound.

V _c - average tumor volume on day 7 in the control group of untreated mice.

Tumor volume is determined as 1/2 g • [long axis of the tumor] • [short axis of the tumor] ²
The test results are shown in table 9.

 From the results of table 9 it is obvious that the compound of the present invention inhibits the growth of murine tumor cells.

EXAMPLE 11
Antitumor effect against human colon cancer cells KM12-HX
Human colon cancer KM12-HX cells are orthotopically transplanted into the cecum of a naked mouse according to the method of Fu et al., [X. Fu et al., Anticancer Res., 12 (1992)] using naked Balb / c mice (females, age 7 weeks) in groups of 10 each.

 More specifically, in the lower left abdominal region, each of the mice is dissected with an abacin anesthesia, after which a thin section of the tumor with a size of 5 mm is sutured to the cecum from the side of the cecum using absorbable surgical sutures to perform orthotopic transplantation. The incision is sutured using absorbable surgical sutures, and the mice are warmed and awakened accordingly from anesthesia.

 The test compound is suspended in sterilized distilled water containing 0.5% w / v carboxymethyl cellulose (CMC) and orally administered in a total of 9 doses, one dose per day, from 3 to 7 days after tumor cell transplantation and from 10 to 13 after transplantation .

 Antitumor activity was evaluated in accordance with the following equation to assess the degree of inhibition of tumor growth (GI%) on day 14 after transplantation.

GI (%) = (lV _t '/ V _c ') • 100
V ' _t is the average tumor weight on day 14 in the group of mice that were injected with the test compound.

V ' _c is the average tumor weight on day 14 in mice of the untreated control group.

 The results are presented in table 10.

 From the data in Table 10, it is apparent that the compound of the present invention inhibits the growth of human colon cancer cells at the site of orthotopic transplantation.

 The following illustrates the preparation of formulations containing the compounds of the present invention with the following non-limiting examples.

EXAMPLE 12
EXAMPLE OF DRUG FORM 1
Capsules
A mixture of a compound of the present invention, such as a compound of formula (III), compounds 1-94, 2-78 or 2-118, is prepared in a digestible oil substance, such as soybean oil, cottonseed oil or olive oil, and placed in gelatin using a pump with positive displacement, getting soft gelatin capsules containing 100 mg of the active ingredient. Then, the obtained capsules are washed and dried.

EXAMPLE 13
EXAMPLE OF DRUG FORM 2
Tablets
Tablets are prepared according to conventional methods using 100 mg of a compound of the present invention, such as a compound of formula (III), compounds 1-94, 2-78 or 2-118, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose.

 In this case, tablets can be coated if desired.

EXAMPLE 14
EXAMPLE OF DRUG FORM 3
Infections
1.5 wt.% Of a compound of the present invention, such as a compound of formula (III), compound 1-94, 2-78 or 2-118, is mixed in 10 vol.% Propylene glycol, and then brought to a constant volume by adding water for injection and then sterilized, receiving the drug for injection.

EXAMPLE 15
EXAMPLE OF DRUG FORM 4
Suspensions
Suspensions are prepared so that they contain 100 mg of a compound of the present invention, such as a compound of formula (III), compounds 1-94, 2-78 or 2-118, which are ground to a fine powder, 100 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1 , 0 g of a solution of sorbitol (Japanese Pharmacopoeia) and 0.025 ml of vanillin in 5 ml of suspension.

Claims (7)

1. Use of a compound selected from 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole , 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, the compounds of formula (III)

compounds of formula (IV)

compounds of formula (V)

or a pharmaceutically acceptable salt thereof as an active ingredient for the manufacture of a medicament for the treatment or prevention of cachexia in mammals.  2. The use according to claim 1, wherein said active ingredient is 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole or a pharmaceutically acceptable salt thereof.  3. The use of claim 1, wherein said active ingredient is 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole or a pharmaceutically acceptable salt thereof.  4. The use of claim 1, wherein said active ingredient is 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole or a pharmaceutically acceptable salt thereof.  5. The use of claim 1, wherein said active ingredient is a compound of formula (III) or a pharmaceutically acceptable salt thereof.  6. The use of claim 1, wherein said active ingredient is a compound of formula (IV) or a pharmaceutically acceptable salt thereof.  7. The use of claim 1, wherein said active ingredient is a compound of formula (V) or a pharmaceutically acceptable salt thereof. Priority on points and signs:
07/21/1998. according to claim 1, compounds: 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole , 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, according to claims 2-4;
09.24.1998 pp. 1, 5-7 other signs.

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