MXPA99000134A

MXPA99000134A - Methods and compositions for the treatment and prevention of tumors, disorders related to tumors and caque

Info

Publication number: MXPA99000134A
Application number: MXPA/A/1999/000134A
Authority: MX
Inventors: Kimura Tomio; Kurakata Shinichi; Hanai Masaharu; Kanai Saori
Original assignee: Sankyo Company Limited
Priority date: 1997-12-24
Filing date: 1999-01-04
Publication date: 2000-06-01

Abstract

Certain cyclooxygenase-2 inhibitors are useful for the treatment and prevention of tumors and disorders related to tumors and cachex

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF TUMORS, DISORDERS RELATED TO TUMORS AND CAQUEXIA BACKGROUND OF THE INVENTION The present invention relates to the use of certain compounds, especially inhibitors of cyclooxygenase-2 (hereinafter referred to as "COX-2 inhibitors") for the treatment and prevention of tumors and disorders related to tumors and cachexia. Cachexia is a systemic disease from which the cardinal symptoms are progressive weight loss, anemia, edema, loss of appetite, etc. It can occur as a side effect of certain chronic diseases such as malignant tumors, tuberculosis, blood diseases, endocrine diseases, infections and acquired immunodeficiency syndrome. When cachexia occurs as a result of the presence of a malignant tumor, even when the administration of antitumor drugs to the patient with a malignant tumor is effective and they experience antitumor effects, there is usually no improvement in cachexia due to the adverse effects such as myelotoxicity that can be caused by the antitumor drug. The treatment of cachexia is often very difficult for the following reasons: Since a patient's resistance is depleted as cachexia progresses, the continuation of treatment using antitumor drugs (which usually have a high level of toxicity) may become impossible, and this consequently becomes an obstacle to the treatment. treatment of the malignant tumor. Nutritional supplements are often given to treat the symptoms of cachexia. However, this often increases the progress of the malignant tumor and may shorten the patient's survival time. At present, satisfactory treatment for cachexia has not been established and there is a need for agents that relieve cachexia symptoms. The compounds of the formula (I) and (II) shown below, which with some other compounds are the active ingredients of the compositions of the present invention, are known to selectively inhibit cyclooxygenase-2 (COX-2). They are also known to inhibit the production of inflammatory cytosines (particularly IL-1 and TNF-a;), which inhibit the production of leukocytes (particularly LTB4), which inhibit bone resorption and which have analgesic, anti-inflammatory and antipyretic effects (Publication of European Patent No. 799 823A). (1! (ID It was not known previously that these compounds could be used for the treatment or prevention of cachexia. Also, although it is known that some other active ingredients employed in the present invention, that is, the compounds of the formulas (III), (IV), (V), (VI), (VII), (VIII), ( IX), (X), (XI), (XII), (XIII) and (XIV), have a selective inhibitory activity against cyclooxygenase-2, an inhibitory effect on the production of inflammatory cytosines (particularly IL-1 and FNT- a), an inhibitory action on the production of leukotrienes (particularly LTB4), an inhibitory action on bone resorption, an analgesic action, an anti-inflammatory action and an antipyretic action [International Publication No. O95 / 00501, J. Med. Chem 40, 1347 (1997), International Publication No. W094 / 13635, Pharmacology, 55, 44 (1997), Prostaglandins, 47, 55 (1994), Japanese Publication No. Hei 9-52882, Jpn. J. Pharmacol., 67, 305 (1995), Inflamm. , Res. 47, Suppl. 3, S247 (1997), J. Med. Chem., 38 4570 (1995), US Patent No. 5 474 995, European Patent No. 863 134 and International Patent Publication No. WO98 / 06708], has not been described. previously that these compounds have an effect against cachexia. From epidemiological studies, it is known that the intake of NSAIDS (non-spheroidal anti-inflammatory drugs, which are conventional COX-1 and COX-2 inhibitors), the most common of which is aspirin, and the incidence of cancer • in the colon they have an inverse correlation. In addition, there have been many reports that NSAIDS, such as aspirin and sulindac, have shown inhibitory activity against tumor metastasis and carcinogenesis in preclinical studies. Some NSAIDS have been used in clinical studies for the prevention of colon carcinogenesis. However, since conventional NSAIDS do not • are selective for COX-1 or COX-2, the occurrence of adverse effects is inevitable. Therefore, it would be convenient to discover a selective cyclooxygenase-2 inhibitor (selective COX-2 inhibitor) to be used as an antitumor agent having a low level of adverse effects. Among the selective COX-2 inhibitors, it is known that "the MF-tricyclic [Oshima, M. et al." Suppression of Intestinal Polyposis in APCA ^ ld Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) ", Cell, 87, 803-809 (1996)] inhibits the occurrence of experimental colonic polyposis, and that SC-58125 shows growth inhibitory effects against certain types of human colon cancer 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 case of the former, the experimental system used is not a model for an established colon cancer, and the compounds are only capable of avoiding the occurrence of polyposis in a preliminary stage of colon cancer On the other hand, with respect to the latter, the only line of colon cancer cells in which the inhibitory effects of growth against cell lines of colon cancer "human, is a line a of cells expressing cyclooxygenase-2 (human colon cancer cell line HCA-7), and it has been described that the colon cancer cell line that does not show tumor growth inhibitory activity (HCT-116) in vitro they have no inhibitory effects on tumor growth in vivo. Thus, whether the inhibitory effects of tumor growth induced by COX-2 inhibitor on colon cancer are expressed or not in vivo depend on the selectivity of the colon cancer cell lines used against growth inhibitory activity. of cells induced by COX-2 inhibitor in vitro. Therefore, the inhibitory effects of tumor growth of COX-2 inhibitors in vivo are unlikely to be observed against several other cancers, especially those cancers, including colon cancers, that are resistant to inhibition induced by COX-inhibitor. 2 of cell growth in vitro and do not express cyclooxygenase-2. Moreover, there has been no prior description of the use of a combination of a selective cyclooxygenase-2 inhibitor and a 5-fluorouracil derivative for the prevention or inhibition of tumor growth. It has now been found that certain derivatives of 1,2-diphenylpyrrole and closely related compounds have excellent activity for the prevention or inhibition of cachexia, and that these derivatives of 1,2-diphenylpyrrole are effective for the treatment or prevention of disorders related to the tumor, alone or in combination with a 5-fluorouracil derivative.

BRIEF DESCRIPTION OF THE INVENTION Therefore, in a first embodiment, the present invention provides a method for the treatment or prevention of cachexia in a mammal, which may be a human, in need of said treatment or prevention, said method comprising administering to said mammal an amount effective 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): (I) (ID 15 twenty (VII) (IX) 15 Wherein R represents a hydrogen atom, a halogen atom or a lower alkyl group; R1 represents a lower alkyl group, an amino group or a group of the formula NHRa (wherein Ra represents a group that can be eliminated in vivo); R 2 represents a phenyl group or a phenyl group having at least one substituent selected from the group consisting of substituents c and substituents β, defined below; R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group having at least one substituent selected from the group consisting of ce substituents; R4 represents a hydrogen atom or an aluqyl group, a lower alkyl group having at least one substituent selected from the group consisting of substituents a, a cycloalkyl group, an aryl group as defined below or an aralkyl group as defined later; said aryl group is a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms is one or more aromatic rings or said group which is fused to a cycloalkyl group having from 3 to 10 carbon atoms, and the group is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents a 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 t-butyl group; Et represents an ethyl group; and Ph represents a phenyl group; said substituents a are selected from the group consisting of hydroxyl group, halogen atoms, lower alkoxy groups and lower alkylthio groups; and said β substituents are selected from the group consisting of lower alkyl groups, alkanoyloxy groups, mercapto groups, alkanoylthio groups, lower alkylsulfonyl groups, lower alkyl groups having at least one substituent selected from the group consisting of substituents or, cycloalkyloxy groups , lower halogenoalkoxy groups and lower alkylenedioxy groups; and pharmaceutically acceptable salts thereof. In addition, the invention provides a method for the treatment or prevention of tumor-related disorders in a mammal, which may be a human being, in need of such treatment or prevention, said method comprising administering to said mammal a effective amount of an active compound selected from the group consisting of compounds of formulas (I) and (II), defined above.

DETAILED DESCRIPTION OF THE INVENTION Preferred classes of compounds of the present invention are those compounds of formulas (I) and (II) in which: (1) R represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, most preferably a hydrogen atom, (2) R 1 represents a methyl group, an amino group or an acetylamino group, most preferably an amino group or acetylemino group, (3) R 2 represents a phenyl group or a phenyl group having at least one a substituent selected from the group consisting of substituents of α and substituents β1, most preferably a phenyl group or a phenyl group having at least one substituent selected from the group consisting of substituents at and substituents β2, most preferably still a phenyl group at wherein the number of substituents is from 1 to 3, (4) R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group having at least one substituent selected from the group consisting of substituents at, most preferably an atom ? k of hydrogen, a halogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom, (5) R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group having at least one substituent selected from the group consisting of substituents or, a cycloalkyl group, an aryl group, an aryl group having at least one substituent ^^ selected from the group consisting of substituents to and substituents 3, an aralkyl group or an aralkyl group having at least one substituent selected from the group consisting of substituents at and substituents S3, most preferably a hydrogen atom, a group I rent Lower, a lower alkyl group having at least one substituent selected from the group consisting of a2 substituents, a cycloalkyl group, an aryl group, a J aryl group having at least one substituent selected from the group consisting of substituents a2 and Substituents ß4, an aralkyl group or an aralkyl group having at least one substituent selected from the group consisting of a2 substituents and ß4 substituents. Said substituents are selected from the group consisting of halogen atoms, lower alkoxy groups and lower alkylthio groups.

Said substituents a2 are selected from the group consisting of hydroxyl groups, halogen atoms and lower alkoxy groups. Said β substituents are selected from the group consisting of lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups having at least one substituent selected from the group consisting of substituents α, halogenoalkoxy groups and lower alkylenedioxy groups. Said β2 substituents are selected from the group consisting of lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted with a halogen atom, lower halogenoalkoxy groups and lower alkylenedioxy groups. Said β3 substituents are selected from the group consisting of lower alkyl groups, lower alkyl groups having at least one substituent selected from the group consisting of substituents a and cycloalkyloxy groups. Said β4 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 the formulas (I) and (II), wherein R, R3, substituents a, substituents to or substituents a2 represent a halogen atom, or wherein the substituents ß2 or substituents ß4 represent a substituted lower alkyl group with halogen atom, the halogen atom is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom. Where R, R1, R3, R4, substituent ß, substituent ßl, substituent S2, substituent ß3 or substituent 4 represent a lower alkyl group, or R3, R4, substituent ß, substituent ßl or substituent ß3 represent a lower alkyl group having at least one substituent selected from the group consisting of substituents a or substituents β2 or substituents β4 represent a lower alkyl group substutuido with a halogen atom, the alkyl or para alkyl group of the substituted group can be an alkyl group, straight or branched chain having from 1 to 6 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl groups , 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 -di methylbutyl and 2-ethylbutyl. Of these, straight or branched chain groups having 1 to 4 carbon atoms, most preferably the methyl and ethyl groups, are preferred. In R, R1 and R4, the lower alkyl group is particularly preferably the methyl group. Where the β substituent represents an alkanoyloxy group, or substituent β, substituent β1 or substituent β2. represents an alkanoylthio group, the alkanoyl part of those groups can be, for example, a straight or branched chain alkanoyl group having from 1 to 25 carbon atoms, such as the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl groups , isocaleryl, pivaloyl, hexanoyl, heptanoyl, occanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, myristoyl, palmitoyl, stearoyl, icosanoyl, docosanoyl and pentacosanoyl. Of these, alkanoyl groups having from 1 to 12 carbon atoms are preferred, most preferably those alkanoyl groups having from 1 to 6 carbon atoms, most preferably even those alkanoyl groups having from 1 to 4 carbon atoms, and most preferably still the acetyl and propionyl groups. Where R 4 represents a cycloalkyl group, it is preferably a cycloalkyl group having from 3 to 8 carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups. Of these, those cycloalkyl groups having from 3 to 7 carbon atoms are preferred, most preferably those cycloalkyl groups having from 3 to 6 carbon atoms, and most preferably the cyclopropyl group.

Where R4 represents an aryl group, this aryl group can be a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms and can be unsubstituted or can be substituted by at least one substituent selected from the group consisting of substituents a substituents ß. The group may contain an aromatic ring or may contain two or more fused rings. Examples of such groups include phenyl, indenyl, naphthyl, phenanthrenyl and anthracenyl groups. Of these, phenyl and naphthyl groups are preferred, most preferably the phenyl group. The aforementioned aryl group can be condensed with a cycloalkyl group having from 3 to 10 carbon atoms and examples of such condensed groups include for example the 2-indanyl group. Where R4 represents an aralkyl group, this is an alkyl group which can be any of the alkyl groups defined and illustrated above in relation to R, etc., and which is substituted by 1 to 3 aryl groups, as defined and illustrated previously. Said group can be unsubstituted or can be substituted by at least one of the substituents a or β. Examples of such groups include the benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphylmethyl, 2-naphthylmethyl, diphenylmethyl, triphenylmethyl, 1-naphildildylmethyl and 9-anthrylmethyl groups. Of these, the alkyl group having from 1 to 4 carbon atoms is preferred which is substituted with an aryl group having from 6 to 10 carbon atoms. Where the substituent a, substituent or substituent a2 represent a lower alkoxy group, this may be, for example a straight or branched chain alkoxy group having from 1 to 6 carbon atoms, such as methoxy groups, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 4-10 methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, - methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy. Of these, straight or branched chain alkoxy groups having 1 to 4 atoms are preferred carbon, most preferably the methoxy and ethoxy groups. Where the substituent α or the substituent α represents a lower alkylthio group, this may be a straight or branched chain alkylthio group having from 1 to 6 carbon atoms and examples include the methylthio groups, Ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, - methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1- dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio. Of these, straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, most preferably the mecythium and ethylthio groups, are preferred. Where the β-substituent represents a lower alkylsulfinyl group, this may be a straight or branched chain alkylsulfinyl group having from 1 to 6 carbon atoms, such as the methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec- butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, 2-methylbutylsulfinyl, neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, isohexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulphinyl, 3, 3-dimethylbutylsulfinyl, 2,2- dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinium, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl and 2-ethylbutylsulfinyl. Of these, straight or branched chain alkylsulfinyl groups having from 1 to 4 carbon atoms are preferred. Where the β substituent, the β3 substituent or the β4 substituent represents a cycloalkyloxy group, this may be, for example a cycloalkyloxy group having from 3 to 8 carbon atoms, such as the cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy groups. Of these, cycloalkyloxy groups having from 3 to 7 carbon atoms are preferred, most preferably cycloalkyloxy groups having from 5 or 6 carbon atoms, most preferably the cyclopentyloxy group. Where the β substituent, substituent β1 or substituent S2_ represent a lower halogenoalkoxy group, this is an alkoxy group which can be as defined and illustrated above in relation to the substituent a, etc., and which is substituted by or less than a halogen atom, such as those defined and illustrated above. Examples of such groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy groups. , iodomethoxy and bromomethoxy. Of these, lower halogenoalkoxy groups having 1 to 4 carbon atoms are preferred, most preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy and bromomethoxy, and most preferably the fluoromethoxy, difluoromethoxy and trifluoromethoxy groups. Where the β substituent, β substituent or β 2 substituent represent a lower alkylenedioxy group, this may be, for example, a straight or branched chain alkylenedioxy group having from 1 to 6 carbon atoms, such as the methylenedioxy, ethylenedioxy groups, trimethylenedioxy, tetramethylenedioxy, pentamethylenedioxy, hexamethylenedioxy and propylenedioxy. Of these, alkylenedioxy groups having from 1 to 4 carbon atoms, most preferably the methylenedioxy and ethylenedioxy groups, are preferred. Where the β 2 substituent or β 4 substituent represents a lower alkyl group substituted with a halogen atom, this may be any of the alkyl groups defined or illustrated above in relation to R, etc., which is substituted by at least one atom of halogen, and also defined and illustrated 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, halogenoalkoxy groups having from 1 to 4 carbon atoms are preferred, most preferably the fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl and bromomethyl groups, and most preferably the fluoromethyl, difluoromethyl and trifluoromethyl groups. Where Ra represents a group that will be eliminated in vivo a group that can be eliminated in the human body under physiological conditions such as hydrolysis, which is a group that produces a free amino group (-NH2) from a group of the formula -NHRa (where Ra is as defined before). It is easy to determine whether the group may or may not be eliminated in vivo by the following test: a compound to be tested is administered orally or intravenously to an experimental an, such as a rat or a mouse, and the fluid from the an. The body is tested for the presence or absence of the corresponding compound having the free amino group or a pharmaceutically acceptable salt thereof. Such groups include, for example: the alkanoyl groups defined and illustrated above in relation to the β-substituent, etc. , - a lower alkoxycarbonyl group, in which the alkoxy group is as defined and illustrated above in relation to the substituent a, etc., such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and cyclohexyloxycarbonyl groups; an aralkyloxycarbonyl group in which the aryl is as defined above and is unsubstituted or is substituted by one or two lower alkoxy or nitro groups, such as the benzylcycarbonyl, 4-methoxybenzeloxycarbonyl, 3,4-5 dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl groups and 4-nitrobenzyloxycarbonyl; an alkanoyloxymethyl group in which the alkanoyl group is as defined and illustrated above in relation to the substituent β, etc., such as the formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl and hexanoyloxymethyl groups, - an alkoxycarbonyloxymethyl group wherein the alkoxy group is as defined and illustrated above in relation to the substituent a etc., such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyl-oxymethyl, isobutoxycarbonyloxymethyl and pentyloxycarbonyl-oxymethyl groups, and a group (2-oxo-1,3-dioxolen-4-yl) methyl in which the 5-position of the dioxolene ring can be substituted with a lower alkyl group or an aryl group, as defined and illustrated above in relation to R and R4, respectively, such as the groups (5-phenyl-2-oxo-l, 3-dioxolen-4-yl) methyl, [5- (4- methylphenyl) -2 -oxo-1,3-dioxolen-4-ylmethyl, [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-l, 3-dioxolen-4-yl] me ilo , (2-oxo-l, 3-dioxolen-4-yl) methyl, (5-methyl-2-oxo, 1,3-dioxolen-4-yl) methyl, (5-Ethyl-2-oxo-l, 3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1, 3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo) -1,2-dioxolen-4-yl) methyl and (5-butyl-2-oxo-l, 3-dioxolen-4-yl) methyl. Of these, alkanoyl groups having from 1 to 12, alkoxycarbonyl groups having from 2 to 5 carbon atoms, aralkyloxycarbonyl groups having from 7 to 8 carbon atoms, alkanoyloxymethyl groups having from 3 to 6 are preferred. carbon atoms, alkoxycarbonyloxymethyl groups having from 3 to 6 carbon atoms and the 5-substituted group (2-oxo-l, 3-dioxolen-4-yl) methyl, most preferably the acetyl, propionyl, butyryl, isobutyryl groups , valeryl, isovaleryl, pivaloyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, 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 preferably still the acetyl group. Specific examples of R1 preferably include the methyl, ethyl, amino, acetylamino, propionylamino, bu irilamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, methoxycarbonylamino, ethoxycarbonylamino, benzyloxycarbonylamino, acetoximetilamino, propionyloxy-methylamino, metoxicarboniloximetilamino ethoxycarbonyloxy-methylamino, (5- methyl-2-oxo-l, 3-dioxolen-4-yl) methylamino and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methylamino, most preferably the methyl, amino and acetylamino groups, and most preferably even the amino and acetylamino groups Specific examples of R2 preferably include: the unsubstituted phenyl group; phenyl groups of 1 to 3 substituents selected from mercapto groups, alkoxythio groups of C-j_-C ^, halogen atoms, alkyl groups of C-j_-C4, alkoxy groups of < -l_ < -4 'alkylthio groups -j_-C4 alkylsulfinyl groups and C- | _-C4 alkyl, such as 4-mercaptophenyl group, 4-acetiltiofenilo, 4- propioniltiofenilo, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, p-tolyl, 4-ethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl, 4-ethylthiophenyl, 4-methylsulphinylphenyl, 4-etilsulfinilfenilo, 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; the phenyl groups trifluoromethyl-, difluoromethoxy or trifluoromethoxy substituted, such as the groups 4-trifluoromethylphenyl, 4-difluoromethoxyphenyl and 4-trifluoromethoxyphenyl; the substituted phenylenedioxy or ethylenedioxy phenyl group such as the 3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl groups. In the case where R2 is a substituted phenyl group, the number of substituents is preferably 1 to 3, most preferably 1 or 2. Specific examples of R3 preferably include hydrogen atoms; halogen atoms such as the fluorine, chlorine, bromine and iodine atoms; alkyl groups of C-j_-C4, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups; and halogenoalkyl groups of C '_- 1l, c ~ 4, such as the fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropilo, 4-fluorobutyl, 2-chloroethyl and 3-chloropropyl, most preferably hydrogen atoms , halogen atoms, such as the fluorine, chlorine, bromine and iodine atoms; and the methyl, ethyl, fluoromethyl, difluoromethyl, 2-fluoroethyl and 2-chloroethyl groups. Specific examples of R4 preferably include hydrogen atoms; Alkyl groups of C 1 - Cg, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl groups; any of these alkyl groups having a substituent selected from hydroxy, halogen (such as fluorine, chlorine, bromine or iodine) and - ^ - C ^ alkoxy (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy and t -butoxy); C2-C2 cycloalkyl groups such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, Cg-C-J_Q aryl groups such as the phenyl and naphthyl groups, which may be unsubstituted or may have one or more of the following 2.7 substituents; aryl groups of Cg-C ^ Q-C4-C4 alkyl, such as the benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl and 2-naphthylmethyl groups, which may be unsubstituted or may have one or more of the following substituents F in the aryl portion; Substituents F include: halogen atoms, such as fluorine, chlorine, bromine and iodine atoms; alkyl groups of C - ^ - C ^, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups; halogenalkyl groups of C-j_-C4 such as fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, trichloromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 3-fluoropropyl and 4-fluoropropyl; C1-C4 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t -butoxy groups; and C3-C- cycloalkyloxy groups, such as the cyclopropyloxy, cyclobutyloxy, cyclopentyloxycyclohexyloxy and cycloheptyloxy groups. Preferred examples of R4 include: hydrogen atoms; alkyl groups of C -, - C ?, such as the methyl, ethyl, isopropyl, butyl and isobutyl groups; mono-, di- or trihalogenoalkyl groups of C- | _-C4, such as the fluoromethyl, difluoromethyl, chlorodifluoromethyl, bromodifluoromethyl, trifluoromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl groups; hydroxymethyl groups; alkoxymethyl groups of C-j_-C4, such as the methoxymethyl and ethoxymethyl groups; cycloalkyl groups of C ^ -Cg, such as the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups; phenyl groups; mono- or difluorophenyl groups, such as the 4-fluorophenyl and 2,4-difluorophenyl groups; mono or dimethoxyphenyl groups, such as the 4-methoxyphenyl and 3,4-dimethoxyphenyl groups; tolyl groups, such as the p-tolyl and q-tolyl groups; cyclopentyloxy (methoxy) phenyl groups, such as the 3-cyclopentyloxy-4-methoxyphenyl group; trifluoromethylphenyl groups, such as the 4-trifluoromethylphenyl group; benzyl group; substituted benzyl groups, such as the 4-methoxybenzyl and 3-cyclopentyloxy-4-methoxybenzyl groups, phenethyl groups; naphthyl groups, such as the 1-naphthyl and 2-naphthyl groups; and naphthylmethyl groups, such as the 1-naphthylmethyl and 2-naphthylmethyl groups. Some of the compounds of the present invention, specifically the compounds of the formula (I) and (II), possess an acidic group and can therefore form salts with cations. The nature of the salt is not critical to the present invention, so long as it is pharmaceutically acceptable, that is, that the salt is not less active (or unacceptably less active) or more toxic (or unacceptably more toxic) than the free acid. Said salts include, for example, salts with alkali metals, such as sodium, potassium or lithium. Salts with ferrous alkali metals, such as calcium or magnesium; salts with other metals, such as aluminum, iron, zinc, copper, nickel or cobalt; inorganic ot_ra.s_sal.es such as ammonium salt; salts with organic amines such as t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycine alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N__N_-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzyl-N -phenethylamine, piperazine, tetramethylammonium or tris (hydroxymethyl) aminomethane. In addition, when the compounds of the formulas (I) and (II) and salts thereof are allowed to stand in the atmosphere, they can absorb moisture to form hydrates. Said hydrates are also included in the present invention. In addition, the compounds of the formulas (I) and (II) and salts thereof sometimes absorb certain types of solvents to give solvates, and said solvates are also included in the present invention. Some compounds of formulas (I) and (II) of the present invention may have asymmetric carbon atoms in their molecule, and stereoisomers in the R configuration or S configuration would then exist. Each of these stereoisomers and mixtures thereof in any desired ratio are all included in the present invention. Specific examples of the compounds of the formulas (I) and (II) used in the method and composition of the present invention include, for example, those shown in the following Table 1 [compounds of the formula (I)] and Table 2 [ compounds of the formula (II)]. In the Tables, the following abbreviations are used: Ac acetyl; Bu butyl; Byr butyryl; iByr isobutyryl; Bz benzyl; Et ethyl, - For formyl; I metyl; Ph phenyl; Pivaloyl piv; cPn cyclopentyl; Pr propyl cPr cyclopropyl, - iPr isopropyl; Prn propionyl; iVal isovaleryl; and Val valeril.

TABLE 1 TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) TABLE 1. (CONTINUED) TABLE 1 (CONTINUED) TABLE 1 (CONTINUED) Cpd. No. R R * R ^ 4-MeS-Ph 1-188 H NH [(5-Me-2-oxo-1, 3- dioxolen ^ l-yl) CH] 1-189 I H I NH [(5-Ph-2-oxol.3-4-MeS-Ph dioxolen-4-yl) CH] TABLE 2 TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) TABLE 2 (CONTINUED) Of the compounds listed above, the preferred compounds 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-fluoro-l- (4-fluorofeml) -2- (4-methylsulfonylphenyl) pyrrole, 6) 2- (4-methoxyphenyl) -4-met? Ll- (4-sulfamoylphenyl) pyrrole, 7) 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) irol, 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-l- (4-methoxyphenyl) -2- (4-sulfamoylphenyl) pyrrole, 19) 1- (3, 4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, ) 5-chloro-l- (4-ethoxyphenyl) -2- (4-sulfamoylphenyl) pyrrole, 21) 5-chloro-1- (4-methylthiophenyl) -2- (4 -suifamoylphenyl) 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, ) 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-dimethylphene) pyrrole. Of these, the most preferred compounds are: 2) 4-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) inulin, 6) 2- (4-methoxyphenyl) -4-methyl-1- (4 -sulfamoylphenyl) indole, 9) 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) irrol, 10) 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfonylphenyl) pyrrole, 11) 2- (4-ethoxyphenyl) -4-phenyl-1- (4-sulfamoylphenyl) inorgan, 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-dimethylphene) irrol.

Of these, the most preferred compounds are: 11) 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, * f 15) 2- (3,4-dimethylphenyl) -4-methyl- l- (4-Sulfamoylphenyl) pyrrole, 17) 4-methyl-1- (4-methylthiophenyl) -2- (4-sulphamoylphenyl) eneol, 5 26) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- ( 4-methoxyphenyl) -pyrrole, and 27) 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole. The compounds of the formula (I), compounds of the? Formula (II) and pharmaceutically acceptable salts of these compounds are known compounds and a method for preparing these compounds is described in Patent Publication.

European EP-799823A, the description of which is incorporated herein by reference. The chemical names of the compounds of formulas (III) to (XIV), respectively, are: (III): 3- (3,4-difluorophenyl) -4- (4-methanesulfonylmethyl) -5H-furan- ^ 2 - ona, (IV): 4- (5-p-tolyl-3-trifluoromethyl-1H-pyrazol-1-yl) benzensul- 20 fonamide, (V): N- [6- (2, 4-difluorof enylthio ) -l-oxoindan-5-yl] methansul-fonamide, (VI): 4-hydroxy-2-methyl-N- (5-methylthiazol-2-yl) -2H-1, 2-benzothiazine-1,1-dioxide 3 -carboxamide, 25 (VII): N- (4-nitro-2-f enoxyphenyl) methanesulfonamide, (VIII): 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide , (IX): N- (3-formylamino-4-oxo-6-phenoxy-4H-l-benzopyran-7-yl) methanesulfonamide, (X): (E) -2-ethyl- 1,1-dioxide 5- (3,5-di-t-butyl-4-hydroxy) benzylidine-1,2-isothiazolidine. (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) benzensulfonamide. These compounds are described in International Publication No. O95 / 00501, J. Med. Chem., 40, 1347 (1997), International Publication No. 094/13635, Pharmacology, 55, 44 (1997), Prostaglandins, 47, 55 (1994). ), Japanese Publication number Hei 9-52882, Jpn. J. Pharmacol., 67, 305 (1995), Inflamm. Res., 47, Suppl. 3, S257 (1997), J. Med. Chem., 38, 4570 (1995), EP 863 134, EUA 5 474 995 or O98 / 06708, the disclosures of which are incorporated herein by reference. Since the compounds of the present invention have excellent activity for the prevention or inhibition of cachexia and very low toxicity, they are useful as preventive and therapeutic agents for cachexia. They are also useful for the treatment of tumor-related disorders, and can be used to inhibit the growth and / or metastasis of tumors. In addition, if desired, one or more of the compounds of the present invention [ie, the compounds of the formulas (I) to (XIV) inclusive] may be used in association with one or more other agents for the prevention or inhibition for tumor growth, and the compounds of the present invention and other agents can be administered simultaneously, separately or in sequence. The other antitumor agent is preferably selected from a group consisting of 5-fluorouracil, cisplatin, tamoxifen, paclitaxel, docetaxel and irinotecan. Especially, in the case of simultaneous administration, the compound of the formulas (I) or (II) or a pharmaceutically acceptable salt thereof and other antitumor agent may be contained in a single composition. The composition of the present invention may be in any conventional form, depending on the route of administration. 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 injections or suppositories, these formulations are prepared according to known methods and may include additives such as those well known in the art, for example, excipients (eg, organic excipients including derivatives of sugar, such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives, such as corn starch, potato starch, α-starch and dextrin; cellulose derivatives, such as crystalline cellulose; gum arabic, - dextran and swarming, inorganic excipients including silicate derivatives, such as light silicic acid anhydride, synthetic aluminum silicate, calcium silicate and magnesium metasilicate-aluminate, phosphates, such as calcium acid phosphate; carbonates, such as calcium carbonate; and sulfates, such as sulfate, calcium), lubricants (e.g., stearic acid and metal salts thereof, including stearic acid). co, calcium stearate and magnesium stearate; talcum powder; colloidal silica, 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 acid; lauryl sulfates, such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids, such as silicic acid anhydride and hydrated silicic acid; and derivatives aforementioned starch), binders (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, Macrogol and compounds similar to the above excipients), disintegrators (for example, cellulose derivatives such as hydroxypropylcellulose substituted with low molecular weight, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose internal bridge; starch chemically modified celluloses such as carboxymethyl starch, sodium carboxymethyl starch and polyvinylpyrrolidone bridge), stabilizers (e.g. paraoxybenzoates, such as methylparaben and propylparaben; alcohols such as chlorobutanol , benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; deshidroacé ico acid; and sorbic acid), corrigents (e.g., sweeteners, vinegars and perfumes) and diluents. The dose varies, depending on many factors, including the condition and age of the patients, 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 0.001 mg / kg (preferably 0.1 mg / kg) as a lower limit and 50 mg / kg (preferably 10 mg / kg) as an upper limit for an adult per day, in a single dose or in 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 a lower limit and 10 mg / kg (preferably 5 mg / kg) as an upper limit for an adult, in a single dose or in divided doses, depending on the symptoms. The present invention is further illustrated by the following non-limiting examples and formulation examples.

EXAMPLE 1 Anticaccexia Effect Test in Crue Mice Have Colon Colon Cancer Cells 26 The test animals were CDF1 mice (8-week-old females). They were used in groups of 10 for each test. 1 x 10 ^ colon cells from mouse colon cancer were transplanted subcutaneously to each animal. The test compounds were Bo compounds. 1-94 and 2-78 as shown above in Tables 1 and 2, respectively, and having the following formulas: Compound No. 2-78 Compound No. 1-94 Each test compound was suspended in sterile distilled water containing 0.5% w / v carboxymethylcellulose (CMC) and orally administered once daily beginning the day of cell transplantation. tumor Each test animal was weighed immediately after the transplantation of tumor cells and the weight was recorded (A g). Each animal was then weighed on day 19 after transplantation of tumor cells and weight was recorded (B g). The gain in weight on day 19 after tumor cell transplantation was calculated as B-A = Difference of gt for each test animal. The experiment was repeated with two control groups: the first control group (control group 1) were transplanted tumor cells but not treated with any test compound, and the weight gain was reported as Difference of 9c; to the second control group (control group 2) no tumor cells were transplanted and no test compound was treated, and the test gain was reported as the gc2 difference. The rate of recovery of body weight was determined according to the following formula based on weight gain on day 19 after transplantation of tumor cells, and this value was used as an indicator of the anticaquexia effect.

Recovery speed of (%) = (Dif .gfc-Dif .gcl) / (Dif .gc2-Dif .gcl) x 100 body weight The results are shown in the following table 3 TABLE 3 COMPOSITION Dose Gain Speed recovery administered (mg / kg) weight ((Di f.g) body weight (%) Comp. 2-78 10 2.6 88 Comp. 2-78 3 2.5 85 Comp. 2-78 1 2.5 85 Comp. 2-94 10 3.1 98 Comp. 2-94 3 2.7 89 Comp. 2-94 1 2.2 78 gpo contr 1 - -1.4 0 gpo contr 2 - 3.2 100 From the above results, it is clear that these compounds inhibited cachexia by tumor in mice and reduced weight loss.

EXAMPLE 2 Test of anticaguexia effects in mice having mouse colon cancer colon cells 26 The procedure described in Example 1 was repeated, but using the compound of the formula (III) as the test compound, and comparing the weight gain (Dif. Gt) of the test group of animals to which the test compound had been administered. compound of the formula (III) with a control group (Dif. g) in which cancer cells had been transplanted but to which no antitumor compound had been administered. The test animals were 16-week-old female CDF1 mice. Also, the weight gain was measured 22 days after the tumor transplant. The average body weight of each group of animals immediately after transplantation was 25 to 26 g. The results are shown in table 4.

TABLE 4 Compound Dosage Weight gain (mg / kg) Average (Dif. G) Compound (III) 10 0.9 Compound (III) 3 0.3 Compound (III) 1 0.0 None (control group) - -4.2 From the above results, it is clear that the compound of the formula (III) inhibited cachexia by tumor in mice and reduced weight loss.

EXAMPLE 3 Test of anti-cachexia effects in mice having mouse colon cancer colon cells 26 The procedure described in Example 2 was repeated, but using the compound of the formula (IV) as the test compound, and comparing the weight gain (Dif. Gt) of the test group of animals to which the test compound had been administered. compound of formula (IV) with a control group (Difc gc) in which cancer cells had been transplanted but to which no antitumor compound had been administered. The test animals were 7-week-old female CDFl mice. Also, the weight gain was measured 15 days after the tumor transplant. The average body weight of each group of animals immediately after transplantation was 20 to 21 g. The results are shown in table 5.

TABLE 5 Compound Dosage Weight gain (mg / kg) Average (Dif. G) Compound (IV) 10 -0.6 Compound (IV) 3 -1.3 Compound (IV) 1 -1.2 None (control group) - -3.4 From the above results, it is clear that the compound of the formula (IV) inhibited cachexia by tumor in mice and reduced weight loss.

EXAMPLE 4 Test of anti-cachexia effects in mice having mouse colon cancer colon cells 26 Test compounds [the compounds of formulas (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV)] they are administered in the same manner as described in example 2. These compounds inhibit tumor cachexia in mice and recover average body weight loss. EXAMPLE 5 Proof of life extension activity Observation of the mice used in Example 1 was continued. The life extension index was determined, based on the number of days that each mouse survived, and this value was then used as an indicator of the effects of prolongation of life of the test compounds. It should be noted that, in the case of the group of mice treated with a test compound, oral administration of the respective compound once a day was continued on day 20 after transplantation of tumor cells and thereafter. life extension index (%) = (St / Sc-1) x 100 St: Average survival time value (days) of the group of mice treated with a test compound. Sc: Average survival time value (days) of the control group to which no tumor cells were transplanted. The results are shown in table 6. TABLE 6 Name Dose Survival period prolonged index of comp. (mg / kg) expired (median days) of life (%) Comp. 2-78 10 48.5 73 Comp. 2-78 3 50.5 80 Comp. 2-78 1 45.0 61 Comp. 1-94 10 45.0 61 Comp. 1-94 3 35.0 25 Comp. 1-94 1 48.5 73 None - 28.0 0 As is clear, from table 6, the compounds of the present invention showed a prominent effect of prolongation of life.

EXAMPLE 6 Proof of life extension activity The experiment reported in example 5 was repeated with the animals used in example 2. In the case of the group of mice treated with a test compound, oral administration of the respective compound once a day was continued on day 23 after transplantation of tumor cells and in the subsequent. The results are shown in table 7.

TABLE 7 Name Dose Survival period prolonged index of comp. (mg / kg) expired (median: days) of life (%) Comp. (III) 10 43.5 91 Comp. (III) 37.5 63 Comp. (III) 40.0 76 None 23.0 EXAMPLE 7 Proof of life extension activity The experiment reported in example 5 was 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 showed cachexia by mouse tumor and showed pronounced prolongation of life.

EXAMPLE 8 Proof of concomitant use of antitumor agent Mouse colon cancer cells transplanted into CDF1 mice in the same manner as in Example 1 followed by administration of the test compounds [Compounds No. 2-78 and 1-94, and the compounds of the formulas (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) and an agent antitumor (5-fluorouracil or cisplatin). The concomitant use of the compounds of the present invention and an antitumor agent remarkably inhibits tumor growth and cachexia, to give a pronounced life extension effect.

EXAMPLE 9 Inhibitory effect on lung metastasis of mouse malignant melanoma cells B16-BL6 Groups of mice, each containing ten C57BL / 6 mice (8-week-old females), were transplanted intravenously into the tail vein 3 × 10 4 mouse malignant melanoma cells B16-BL6. When necessary, the mice were then k administered intravenously to the tail vein bacterial lipopolysaccharide (LPS) in an amount of 3 μg each within one hour before transplantation of melanoma cells to accelerate lung metastasis of melanoma [M.J. Anasagasti et al., J. Nati. Cancer Research, 89, 645-651 (1997)]. As a test compound, compound No. 2-118, a compound of the formula (IV) and indomethacin was employed, and each ^ One was suspended in distilled sterilized water containing 0. 5% w / v carboxymethylcellulose (CMC), and the suspensions are administered orally at a dose of 1 mg / kg per day for five days starting from the day of melanoma cell transplantation. Compound No. 2-118 is 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) irol. 25 The inhibitory activities on pulmonary metastasis of melanoma cells were evaluated in terms of the rate of inhibition of pulmonary metastasis (% of LMI) by counting the number of metastatic colonies in the lung on day 10 after intravenous transplantation of melanoma cells mouse malignant B16-BL6 in the tail.

LMI (%) = (1 - Nt / Nc) x 100 Nt: Number of pulmonary metastatic colonies on day 10 in groups to which the test compounds were administered: and N, Number of pulmonary metastatic colonies on day 10 in control groups to which the test compounds were not administered.

The results are given in table 8 TABLE 8 Comp. of Aministr. LMI test dose of LPS (mg / kg) (%) Comp. 2-118 No 1 64 Comp. 2-118 Yes 1 34 Comp. (VI) Yes 1 9 Comp. (V) Yes 1 1 Indomethacin Yes 1 -1 It is clear, from table 8, that the present composition was successful in inhibiting metastasis of malignant melanoma cells of B16-BL6 mouse to the lung whether the metastasis is accelerated or not by administration of LPS (induction of inflammation reaction). In particular, the present compositions showed marked inhibition of pulmonary metastasis, while the compound of the formula (IV) and the compound of the formula (V), which are selective inhibitors of COX-2, and indomethacin, which is an NSAID typical, it did not have such inhibitory activity under the conditions of acceleration of pulmonary metastasis caused by inducing inflammation reaction (reflecting the acceleration of tumor metastasis in a surgical operation of tumor excision).

EXAMPLE 10 Anti-umoral effect against mouse sarcoma cells S-180 1 x 10 6 S-180 mouse sarcoma cells were transplanted subcutaneously to hairless Balb / c mice (8-week-old females) in groups of 10 each. The test compound, compound No. 2-118, was suspended in sterilized distilled water containing 0.5% w / v carboxymethylcellulose (CMC), and the suspensions were orally administered once a day for five days starting from the day when the tumor cells were transplanted. The antitumor activity was evaluated according to the following equation to determine the rate of inhibition of tumor growth (% Gl) on day 7 after transplantation. GI (%) = (1 - Vt / Vc) x 100 Vt: Mean tumor volume on day 7 in a group given test compound (*) Vc: Mean tumor volume on day 7 in a control group (*) * Tumor volume is defined as 1/2 x [long axis of the tumor] x [short axis of the tumor] 2 The results are shown in table 9.

TABLE 9 Comp. Test dose (mg / kg) Gl (%) Compound 2-118 54 It is clear from Table 9 that the composition of the present application inhibited the growth of mouse tumor cells.

EXAMPLE 11 Antitumor effect against human colon cancer cells KM12-HX Human colon cancer cells KM12-HX were orthotopically transplanted into the caecum of hairless mice according to the method of Fu "et al [X. Fu et al., Anticancer Res., 12 (1992)] using Balb / c mice hairless (7-week-old females) in groups of 10. Specifically, an incision was made in the lower left abdominal region of each mouse under anesthesia with Abacin, after which a thin section of tumor measuring 5 mm on one side it was sutured to the blind using absorbable surgical sutures for orthotopic transplantation.The incision was sutured using absorbable surgical sutures and the mice were warmed and promptly awakened from anesthesia.The test compound was suspended in sterile distilled water containing 0.5% p / v of carboxymethylcellulose (CMC) and was administered orally in a total of 9 doses consisting of one dose per day from 3 to 7 days after transplantation of tumorale cells s and 10 to 13 days after transplant. The antitumor activity was evaluated according to the following equation to determine the rate of inhibition of tumor growth (% Gl) on day 14 after transplantation.

GI (%) = (1 - Vf. '/ V') x 100 Vt ': Mean tumor weight on day 14 in a group given test compound Vc': Mean tumor weight on day 14 in a control group The results are shown in Table 10 TABLE 10 Comp. Test dose (mg / kg) Gl (%) Compound 2-118 0.3 12 Compound 2-118 1 35 Compound 2-118 3 '45 Compound 2-118 10 59 It is clear, from Table 10, that the composition of the present invention inhibited the growth of human colon cancer cells at the orthotopic transplantation site. The preparation of pharmaceutical formulations containing flfc compounds of the present invention is further illustrated by the following non-limiting formulation.

EXAMPLE OF FORMULATION 1 Capsules A mixture of a compound of the present invention, such as the compound of the formula (III), Compound No. 1-94, 2-78 or 2-118, is prepared in a digestive oil substance, such as oil soybean, cottonseed oil or olive oil and filled in gelatin with a positive replacement pump to obtain soft capsules containing 100 mg of active ingredient. The resulting capsules are washed and dried.

EXAMPLE OF FORMULATION 2 Tablets Tablets are manufactured according to conventional methods using 100 mg of a compound of the present invention, such as the compound of formula (III), Compound No. 1-94, 2-78 or 2-118, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. In this case, the tablets may be coated with a preparation coating if desired.

EXAMPLE OF FORMULATION 3 Inventions 1.5% by weight of a compound of the present invention, such as the compound of the formula (III), Compound No. 1-94, 2-78 or 2-118, is stirred in 10% by volume of propylene glycol, and it is adjusted to a constant volume by adding water for injection, after which it is sterilized to prepare injections.

EXAMPLE OF FORMULATION 4 Suspensions A suspension is produced to contain 100 mg of compound of the present invention, such as the compound of the formula (III), Compound No. 1-94, 2-78 or 2-118, which is milled into a fine powder, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (Farmacopeya Japonesa) and 0.025 ml of vanillin in 5 ml of the suspension.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound of the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (IX) wherein: R represents a hydrogen atom, a halogen atom or a lower alkyl group; R1 represents a lower alkyl group, an amino group or a group of the formula NHRa (in which Ra represents a group that can be eliminated in vivo); R 2 represents a phenyl group or a phenyl group substituted by at least one of the substituents a or substituents β, defined below; R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the substituents a; R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group as defined below, or an alkyl group as defined below; said aryl group is a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms in one or more aromatic rings or said group is fused to a cycloalkyl group having from 3 to 10 carbon atoms, and the group is unsubstituted or is substituted by at least one of the substituents a or 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 t-butyl group, • Et represents an ethyl group; and Ph represents a phenyl group; said substituents a are selected from hydroxyl groups, halogen atoms, lower alkoxy groups and lower alkylthio groups; and said β substituents are selected from lower alkyl groups, alkanoyloxy groups, mercapto groups, alkanoylthio groups, lower alkylsulfinyl groups, lower alkyl groups substituted by at least one of the substituents, cycloalkoxy groups, lower halogenoalkoxy groups and alkynedioxy groups, - or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of cachexia in a mammal.

2. The use according to claim 1, wherein the active compound is a compound of the formula (I) or (II).

3. The use according to claim 2, wherein R represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.

4. The use according to claim 3, wherein R represents a hydrogen atom.

5. The use according to claim 2 or 4, in which RI represents a methyl group, an amino group or an acetylamino group. ^

6. The use according to claim 5, wherein R1 represents an amino group or an acetylamino group.

7. The use according to any of claims 2 to 6, wherein R1 represents a phenyl group or a phenyl group substituted by at least one of the substituents a1 or substituents ß1, substituents a1 are selected from atoms of halogen, lower alkoxy groups and B lower alkylthio groups; and the β1 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted by at least one of the a1 substituents, lower halogenoalkoxy groups and lower alkylenedioxy groups.

8. Use according to claim 2 or 7, in which R2 represents a phenyl group or a phenyl group substituted by at least one of the substituents a1 or ^ substituents ß2, substituents a2 are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups; and the β2 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted with a halogen atom, lower halogenoalkoxy groups and lower alkylenedioxy groups.

9. - The use according to any of the 25 claims 2 to 8, wherein R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the substituents ^, the a ^ substituents are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups.

10. The use according to claim 2 or 9, wherein R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom.

11. The use according to any of claims 2 to 10, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group, an aryl group substituted by at least one of the substituents a ^ or substituents β3, an aralkyl group or an aralkyl group substituted by at least one of the substituents ^ or substituents β3; the a1 substituents are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted by at least one of the a substituents and cycloalkyloxy groups.

12. The use according to claim 2 or 11, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the a2 substituents, a cycloalkyl group, a group aryl, an aryl group substiuid with at least one of the substituents a2 or substituents ß4, an aralkyl group or an aralkyl group substituted by at least one of the substituents Qf "substituents ß4, - substituents a1 are selected from hydroxyl groups, halogen atoms and lower alkoxy groups, and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted with a halogen atom or cycloalkyloxy groups

13. The use according to claim 2, wherein said active compound is: 3-methyl-2 - (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 4-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 1- (4-fluorophenyl) ) -2- (4-sulfamoylphenyl) -pyrrole, 1- (4-fluorophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 5-fluoro-1- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) pyrrole, 2- (4-methoxyphenyl) - 4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4 -sulfamoylphenyl) pyrrole, 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) eneol, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- ( 4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4- sulfamoylphenyl) -pyrrole, 2- (3-fluoro) -4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 4-methyl-2-phenyl-1- (4-sulfamoyl-phenylDpyrrole, 2- (3,4-dimethylphenyl) -4-methyl -l- (4-sulfamoyl-phenyl) -rolol, 2- (3-chloro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoyl-phenyl) -pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) -pyrrole, 5-chloro-1- (4-methoxyphenyl) -2- (4-sulfamoylphenyl) pyrrole, 1- (3,4-dimethylphenyl) -4-methyl-2- (4 -sulfamoylphenyl) pyrrole, 5-chloro-1- (4-etox ifenyl) -2- (4-sulfamoylphenyl) iriol, 5-chloro-l- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, 1- (4-ethylthio-phenyl) -4-methyl -2- ( 4-sulfamoylphenyl) pyrrole, 2- (3,5-dimethyl-phenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-mercaptophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 1- (4-acetylthiophenyl) -4-methyl -2- (4-sulfamoylphenyl) pyrrole, 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) irriole, or 1- (4- acetylaminosulfonyl-phenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole, or a pharmaceutically acceptable salt thereof.

14. The use according to claim 2, wherein said active compound is: 2- (4-chlorosphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4 -methyl-1- (4-sulfamoylphenyl) inulin, 2- (3, 4-dimethylphenyl) -4-methyl-1- (4-sulfamo'ylphenyl) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2 - (4-sulfamoylphenyl) pyrrole, or 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole, or a pharmaceutically acceptable salt thereof.

15. The use according to claim 1, wherein the active compound is a compound of the formulas (III), (IV), (V), (VI), (VII), (VIII), (IX) ), (X), (XI).

16. The use according to claim 15, wherein the active compound is 3- (3,4-difluorophenyl) -4 (4-methanesulfonylphenyl) -5H-furan-2 -one or a pharmaceutically acceptable salt thereof .

17. The use according to claim 15, wherein the active compound is 4- (5-p-tolyl-3-trifkuoromethyl-1-Hpyrazol-1-yl) benzenesulfonamide or a pharmaceutically acceptable salt thereof.

18. The use according to claim 15, wherein the active compound is N- [6- (2,4-difluorophenylthio) -1-oxoindan-5-yl] methanesulfonamide or a pharmaceutically acceptable salt thereof.

19. The use according to claim 15, in which the active compound is 1,1-4-hydroxy-2-methyl-N- (5-methylthiazol-2-yl) -2H-1, 2-benzothiazino-3-carboxamide dioxide or a pharmaceutically acceptable salt of the same.

20. The use according to claim 15, wherein the active compound is N- (4-Nitro-2-phenoxyphenyl) methanesulfonamide or a pharmaceutically acceptable salt thereof.

21. The use according to claim 15, wherein the active compound is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof.

22. The use according to claim 15, wherein the active compound is N- (3-formylamino-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl) methanesulfonamide or a pharmaceutically acceptable salt of the same.

23. The use according to claim 15, wherein the active compound is (E) -2-ethyl-5- (3,5-di-t-butyl-4-hydroxy) 1,1-dioxide. nemciliden-1, 2-isothiazolidine or a pharmaceutically acceptable salt thereof.

24. The use according to claim 15, wherein the active compound is 1- (4-methansuldonylphenyl) -2- (4-fluorophenyl) cyclopentene or a pharmaceutically acceptable salt thereof.

25. The use according to claim 1, wherein the active compound is a compound of the formulas (XII), (XIII) or (XIV).

26. The use according to claim 25, wherein the active compound is 3-phenyl-4- (4-methanesulfonylphenyl) -5H-furan-2 -one or a pharmaceutically acceptable salt thereof.

27. The use according to claim 25, wherein the active compound is 2- (3,5-difluorophenyl) -3- (4-methanesulfonylphenyl) -2-cyclopenten-1-one or a pharmaceutically acceptable salt of the same.

28. The use according to claim 25, wherein the active compound is 4- [5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide or a pharmaceutically acceptable salt thereof.

29. - The use of a compound of the formula (I) or (II) (11) (i) in which: R represents a hydrogen atom, a halogen atom or a lower alkyl group; R1 represents a lower alkyl group, an amino group or a group of the formula NHRa ! | áfc (in which Ra represents a group that can be eliminated in vivo); R 2 represents a phenyl group or a phenyl group substituted by at least one of the substituents a or substituents β, defined below; R3 represents a hydrogen atom, a halogen atom, an alkyl group Lower or a lower alkyl group substituted by at least one of the substituents a; R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group ^ substituted by at least one of the substituents a, a cycloalkyl group, an aryl group as defined below, 20 or an alkyl group as defined below; said aryl group is a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms in one or more aromatic rings or said group is fused to a cycloalkyl group having from 3 to 10 carbon atoms, and the group is unsubstituted or is 25 substituted by at least one of the substituents α or β substituents; said aralkyl group is a lower alkyl group which is substituted by one or more of the aryl groups ^ P defined above, - said substituents a are selected from hydroxyl groups, halogen atoms, groups 5 lower alkoxy and lower alkylthio groups; and said β substituents are selected from lower alkyl groups, alkanoyloxy groups, mercapto groups, alkanoylthio groups, lower alkylsulfinyl groups, lower alkyl groups substituted by at least one of the a substituents, cycloalkoxy groups, lower halogenoalkoxy groups and alkynedioxy groups; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of tumor-related disorders in a mammal.

30. The use according to claim 29, wherein R represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group. ^

31. The use according to claim 30, wherein R represents a hydrogen atom.

32. The use according to any of claims 29 to 31, wherein R1 represents a methyl group, an amino group or an acetylamino group.

33. The use according to claim 32, wherein R1 represents an amino group or an acetylamino group.

34. The use according to any of claims 29 to 33, wherein R2 represents a phenyl group or a phenyl group substituted by at least one of the substituents a1 or substituents ß1, substituents a1 are selected from atoms of halogen, lower alkoxy groups and lower alkylthio groups; and the β1 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted by at least one of the a1 substituents, lower halogenoalkoxy groups and lower alkylenedioxy groups.

35. The use according to claim 34, wherein R2 represents a phenyl group or a phenyl group substi- tuted by at least one of the substituents a1 or substituents ß2, substituents a2 are selected from halogen atoms, alkoxy groups lower and lower alkylthio groups; and the β2 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted with a halogen atom, lower halogenoalkoxy groups and lower alkylenedioxy groups.

36. The use according to any of claims 29 to 35, in which R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the substituents? -, substituents a ^ are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups.

37. The use according to claim 36, wherein R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom.

38. The use according to any of claims 29 to 37, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group, an aryl group substi- tuted by at least one of the substituents a ^ or substituents β3, an aralkyl group or an aralkyl group substituted by at least one of the substituents a1- or substituents ß3; the a1 substituents are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted by at least one of the substituents a and cycloalkyloxy groups.

39. The use according to claim 38, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group, an aryl group substiuid with at least one of the a2 substituents or β4 substituents, an aralkyl group or an aralkyl group substituted by at least one of the substituents a2 or substituents ß4; the a1 substituents are selected from hydroxyl groups, halogen atoms and lower alkoxy groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted with a halogen atom or cycloalkyloxy groups.

40. The use according to claim 29, wherein said active compound is: 3-methyl-2 - (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 4-methyl-2- (4- methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 1- (4-fluorophenyl) -2- (4-sulfamoylphenyl) -pyrrole, 1- (4-fluorophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole , 5-fluoro-1- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl -2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-chlorophenyl) -4-methyl-1- ( 4-Sulfamoylphenyl) pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulphamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) ene, 2 - (4-methoxy -3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 2- (3-fluoro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole , 4-methyl-2-phenyl-1- (4-sulfamoylphene) pyrrole, 2- (3, 4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 2- (3-cl) gold-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) irrol, 5-chloro-1- (4 -methoxyphenyl) -2- (4-sulfamoylphenyl) irol, 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 5-chloro-l- (4-ethoxyphenyl) -2- (4-sulfamoylf nyl) pyrrole, 5-chloro-l- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3,5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) iriol, 1- (4-mercaptophenyl) -4-methyl-2- (4-sulfamoylphenyl) irrol, 1- (4-acetylthiophenyl) ) -4-Methyl-2- (4-sulfamoylphenyl) eneol, 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) eneol, or 1- (4-acetylaminosulfonylphenyl) -4-methyl-2 - (3, 4-dimethylphenyl) irrol, or a pharmaceutically acceptable salt thereof.

41. The use according to claim 29, wherein said active compound is: 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4 -methyl-1- (4-sul-famoylphenyl) pyrrole, 2- (3, 4-dimethylphenyl) -4-methyl-1- (4-sulfa-moylphenyl) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulphamoyl-phenyl) pyrrole, or "1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole, or a pharmaceutically acceptable salt thereof.

Use of a compound of the formula (I) or (II): (I) (II) wherein: R represents a hydrogen atom, a halogen atom or a lower alkyl group; R1 represents a lower alkyl group, an amino group or a group of the formula NHRa (in which Ra represents a group that can be eliminated in vivo); R 2 represents a phenyl group or a phenyl group substituted by at least one of the substituents a or substituents β, defined below; R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the substituents; R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group as defined below, or an alkyl group as defined below; said aryl group is a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms in one or more aromatic rings or said group is fused to a cycloalkyl group having from 3 to 10 carbon atoms, and the group is unsubstituted or is substituted by at least one of the substituents a or substituents β; said aralkyl group is a lower alkyl group which is substituted by one or more of the aryl groups defined above; said substituents a are selected from hydroxyl groups, halogen atoms, lower alkoxy groups and lower alkylthio groups; and said β substituents are selected from lower alkyl groups, alkanoyloxy groups, mercapto groups, alkanoylthio groups, lower alkylsulfinyl groups, lower alkyl groups substituted by at least one of the a substituents, cycloalkoxy groups, lower halogenoalkoxy groups and alkynedioxy groups; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting tumor growth in a mammal.

43. The use according to claim 42, wherein R represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.

44. The use according to claim 43, wherein R represents a hydrogen atom.

45. The use according to any of claims 42 to 44, wherein R 1 represents a methyl group, an amino group or an acetylamino group.

46. The use according to claim 45, wherein R1 represents an amino group or an acetylamino group.

47. The use according to any of claims 42 to 46, wherein R2 represents a phenyl group or a phenyl group substi- tuted by at least one of the substituents a1 or substituents ß1, substituents a1 are selected from halogen, lower alkoxy groups and lower alkylthio groups; and the β1 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted by at least one of the substituents, lower halogenoalkoxy groups and lower alkylenedioxy groups.

48. - The use according to claim 47, wherein R2 represents a phenyl group or a phenyl group substi- tuted by at least one of the substituents a1 or substituents ß2, substituents a2 are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups; and the β2 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted with a halogen atom, lower halogenoalkoxy groups and lower alkylenedioxy groups.

49. The use according to any of claims 42 to 48, in which R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the substituents a1 , the substituents a1 are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups.

50.- The use according to claim 49, wherein R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom.

51. The use according to any of claims 42 to 50, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group, an aryl group substi- tuted by at least one of the substituents 1 or substituents ß3, an aralkyl group or an aralkyl group substituted by at least one of the a1 substituents or β3 substituents; the a1 substituents are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted by at least one of the a substituents and cycloalkyloxy groups.

52. The use according to claim 51, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the a2 substituents, a cycloalkyl group, an aryl group, an aryl group substiuid with at least one of the substituents a2 or substituents ß4, an aralkyl group or an aralkyl group substituted by at least one of the substituents a- 'or substituents ß4; the substituents ai are selected from hydroxyl groups, halogen atoms and lower alkoxy groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted with a halogen atom or cycloalkyloxy groups.

53. The use according to claim 42, wherein said active compound is: 3-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 4-methyl-2- (4- methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 1- (4-fluorophenyl) -2- (4-sulfamoylphenyl) -pyrrole, 1- (4-fluorophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole , 5-fluoro-l- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-methoxyphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-chlorophenyl) -4-methyl-1- ( 4-sulfamoylphenyl) pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 2- (3-fluoro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 4-methyl-2-phenyl-1- (4-sulfamoylphene) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 2- (3-chloro) 4-met oxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, 5-chloro-1- (4-methoxyphenyl) - 2- (4-sulfamoylphenyl) pyrrole, 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 5-chloro-1- (4-ethoxyphenyl) -2- (4-sulfamoylphenyl) ) pyrrole, 5-chloro-l- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) iriol, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3, 5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-mercaptophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 1- (4-acetylthiophenyl) -4-methyl -2- (4-Sulfamoylphenyl) pyrrole, 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) indole, • or 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3, 4-dimethylphenyl) pyrrole, or a pharmaceutically acceptable salt thereof.

54. The use according to claim 42, wherein said active compound is: 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4 -methyl-1- (4-sulfaoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) eneol, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, or 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4-dimethylphenyl) pyrrole, or a pharmaceutically acceptable salt thereof.

55.- The use of a compound of the formula (I) or (II): (I) (II) In which: R represents a hydrogen atom, a halogen atom or a lower alkyl group; R1 represents a lower alkyl group, an amino group or a group of the formula NHRa ^ (in which Ra represents a group that can be eliminated in vivo); R2 represents a phenyl group or a phenyl group 20 substituted by at least one of the substituents a or substituents β, defined below; R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the substituents a; R4 represents an atom of Hydrogen, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group as defined below, or an alkyl group as defined below; said aryl group is a carbocyclic aromatic hydrocarbon group having from 6 to 14 carbon atoms in one or more aromatic rings or said group is fused to a cycloalkyl group having from 3 to 10 carbon atoms, and the group is unsubstituted or is substituted by at least one of the substituents a or substituents β; said aralkyl group is a lower alkyl group which is substituted by one or more of the aryl groups defined above; said substituents a are selected from hydroxyl groups, halogen atoms, lower alkoxy groups and lower alkylthio groups; and said β substituents are selected from lower alkyl groups, alkanoyloxy groups, mercapto groups, alkanoylthio groups, lower alkylsulfinyl groups, lower alkyl groups substituted by at least one of the a substituents, cycloalkoxy groups, lower halogenoalkoxy groups and alkynedioxy groups; and a pharmaceutically acceptable salt thereof for preparing a medicament for inhibiting tumor metastasis in a mammal.

56. The use according to claim 55, wherein R represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.

57. The use according to claim 56, wherein R represents a hydrogen atom.

58. The use according to any of claims 55 to 57, wherein R1 represents a methyl group, an amino group or an acetylamino group.

59. The use according to claim 58, in which RI represents an amino group or an acetylamino group.

60. The use according to any of claims 55 to 59, wherein R 2 represents a phenyl group or a phenyl group substi- tuted by at least one of the substituents or substituents β 1, substituents 1 are selected from halogen, lower alkoxy groups and lower alkylthio groups; and the ßi substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted by at least one of the a1 substituents, lower halogenoalkoxy groups and lower alkylenedioxy groups.

61. The use according to claim 60, wherein R2 represents a phenyl group or a phenyl group substi- tuted by at least one of the substituents a1 or substituents ß2, substituents a2 are selected from halogen atoms, alkoxy groups lower and lower alkylthio groups; and the β2 substituents are selected from lower alkyl groups, mercapto groups, alkanoylthio groups, lower alkyl groups substituted with a halogen atom, lower halogenoalkoxy groups and lower alkylenedioxy groups.

62. - The use according to any of claims 55 to 61, wherein R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by at least one of the a1 substituents, substituents a1 are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups.

63.- The use according to claim 62, wherein R3 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted with a halogen atom.

64. The use according to any of claims 55 to 63, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group, an aryl group substi- tuted by at least one of the substituents a1 or substituents ß3, an aralkyl group or an aralkyl group substi- tuted by at least one of the a1 substituents or β3 substituents; the a1 substituents are selected from halogen atoms, lower alkoxy groups and lower alkylthio groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted by at least one of the a substituents and cycloalkyloxy groups.

65. The use according to claim 64, wherein R4 represents a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by at least one of the substituents a, a cycloalkyl group, an aryl group, an aryl group substiuid with at least one of the a2 substituents or β4 substituents, an aralkyl group or an aralkyl group substituted by at least one of the substituents a2 or substituents ß4; the substituents ^ are selected from hydroxyl groups, halogen atoms and lower alkoxy groups; and the β3 substituents are selected from lower alkyl groups, lower alkyl groups substituted with a halogen atom or cycloalkyloxy groups.

66. The use according to claim 55, wherein said active compound is: 3-methyl-2- (4-methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 4-methyl-2- (4- methylphenyl) -1- (4-sulfamoylphenyl) pyrrole, 1- (4-fluorophenyl) -2- (4-sulfamoylphenyl) -pyrrole, 1- (4-fluorophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole *, 5-fluoro-l- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) pyrrole, 2- (4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-methoxyphenyl) ) -4-methyl-2- (4-sulfonylphenyl) pyrrole, 4-ethyl-2- (4-methoxyphenyl) -1- (4-sulfamoylphenyl) pyrrole, 2- (4-chlorophenyl) -4-methyl-1 - (4-sulfamoylphenyl) pyrrole, 4-methyl-2- (4-methylthiophenyl) -1- (4-sulfamoylphenyl) irol, 2- (4-ethoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-methoxy-3-methylphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 2- (3-fluoro-4-methoxyphenyl) -4-methyl-1- (4-sulfamoylphenyl) - pyrrole, 4-methyl-2-phenyl-1- (4-sulfamoylphene) pyrrole, 2- (3, 4-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 2- (3- chlorine-4-methoxy enyl) -4-methyl-1- (4-sulfamoylphenyl) -pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, 5-chloro-1- (4-methoxyphenyl) - 2- (4-sulfamoylphenyl) pyrrole, 1- (3,4-dimethylphenyl) -4-methyl-2- (4-sulfamoylphenyl) eneol, 5-chloro-1- (4-ethoxyphenyl) -2- (4-sulfamoylphenyl) ) pyrrole, 5-chloro-l- (4-methylthiophenyl) -2- (4-sulfamoylphenyl) pyrrole, 1- (4-ethylthiophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 2- (3, 5-dimethylphenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 1- (4-mercaptophenyl) -4-methyl-2- (4-sulfamoylphenyl) pyrrole, 1- (4-acetylthiophenyl) -4-methyl -2- (4-sulfamoylphenyl) pyrrole, 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (4-methoxyphenyl) pyrrole, or 1- (4-acetylaminosulfonylphenyl) -4-methyl-2- (3,4) -dimethylphenyl) pyrrole or a pharmaceutically acceptable salt thereof.

67. The use according to claim 55, wherein said active compound is: 2- (4-chlorophenyl) -4-methyl-1- (4-sulfamoylphenyl) pyrrole, 2- (4-ethoxyphenyl) -4 -methyl-1- (4-sul-famoylphenyl) pyrrole, 2- (3,4-dimethylphenyl) -4-methyl-1- (4-sulfa-moylphenyl) pyrrole, 2- (3-chloro-4-methoxyphenyl) -4-methyl-l- (4-sulfa-moylphenyl) pyrrole, 4-methyl-1- (4-methylthiophenyl) -2- (4-sulfamoyl-phenyl) pyrrole, or 1- (4-acetylaminosulfonylphenyl) -4- methyl-2- (3,4-dimethylphenyl) pyrrole, or a pharmaceutically acceptable salt thereof.