HK1167090B

HK1167090B - Selective ep4 receptor agonistic substance for treatment of cancer

Info

Publication number: HK1167090B
Application number: HK12107821.6A
Authority: HK
Inventors: 之令武; 信一小泉; 贵子奥村; 和彦野野村
Original assignee: Askat Inc.
Priority date: 2009-04-22
Filing date: 2010-04-22
Publication date: 2017-11-17

Description

Selective EP4 receptor antagonist for cancer therapy

Technical Field

The present invention relates to the use of a compound having inhibitory activity against prostaglandin E2 receptor (EP4 receptor) and represented by the following general formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "the compound of the present invention"), or a pharmaceutical composition comprising the compound or a salt thereof for the manufacture of a medicament for the treatment of cancer. The present invention relates to a method of cancer treatment comprising administering a compound of the present invention or a pharmaceutical composition comprising the same to a human or animal. Also, the present invention relates to a pharmaceutical composition or kit comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

Background

Prostaglandins are mediators involved in a variety of pathologies such as pain, fever and inflammation. Prostaglandin E2(PGE2) is, in particular, the major dodecanoic acid detected in inflammatory states. And, it is also associated with a variety of physiological and/or pathological conditions such as hyperalgesia, uterine contractions, digestive peristalsis, cognition, inhibition of gastric acid secretion, platelet function, bone metabolism, angiogenesis, cancer invasion and metastasis, etc.

There are 4 receptor subtypes, EP1, EP2, EP3 and EP4, which exhibit different pharmacological properties. The EP4 receptor belongs to the G protein-coupled receptor subfamily, is known as a receptor with 7 transmembrane domains, and plays an important role in PGE 2-related biological behaviors by stimulating cAMP production. In the pharmacological studies, compounds having EP4 receptor antagonistic activity were initially tested, and selective antagonists are also known.

PGE2 is the major dodecanoic acid detected in inflammatory states, and is also involved in a variety of physiological and/or pathological conditions such as hyperalgesia, uterine contractions, digestive peristalsis, cognition, inhibition of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis, cancer metastasis, and the like. Non-patent documents 1 to 3 disclose the properties of prostaglandin receptors, the relationship to therapy, and selective agonists and antagonists which are most commonly used for them.

On the other hand, PGE2 was reported to be highly expressed in cancer tissues of different types of cancers, and PGE2 was clearly associated with cancer and the development of disease states. PGE2 is known to be involved in activation of cell proliferation and inhibition of cell death (apoptosis) and plays an important role in cancer progression and metastasis. But due to many reports that vary due to differences in conditions such as cancer type, course, etc., no medically unified insight has been obtained from this point of view as to the PGE receptor mediating such diverse functions of cancer-associated PGE 2.

Regarding the relationship between EP4 and cancer, a report was found at the cellular level indicating that the proliferation of colon cancer cells (HCA-7) is inhibited by EP4 receptor antagonists L-161, 982 (non-patent document 4). As for cancer metastasis, a report has been found which shows that metastasis of breast cancer cells is suppressed by EP4 receptor antagonists AH23848 and ONO-AE3-208 (non-patent document 5).

On the other hand, regarding experiments using animals, it was reported that the EP4 receptor antagonist ONO-AE2-227 showed a reduction in the formation of azomethine-induced aberrant crypt foci of colon and a reduction in the formation of intestinal polyps in APC knockout mice (non-patent document 6).

As described above, EP4 is known to be associated with cancer generation, growth and metastasis, and reports suggesting prevention of cancer, inhibition of growth and inhibition of metastasis by EP4 receptor antagonists have also been verified. However, cancer chemotherapy is based on the reduction of already formed cancer tissues, and examples of EP4 receptor antagonists that show a reduction in cancer tissues already formed in animal organs are not known, and there is a continuing need for such compounds in fact.

Patent document

Non-patent documents:

non-patent document 1: eicosanoids: biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf and Velo eds, Plenum Press, New York, 1996, chapter 14, p.137-154

Non-patent document 2: journal of Lipid Mediators and Cell Signalling, 14: 83-87(1996)

Non-patent document 3: prostagladins and Other Lipid Mediators, 69: 557-573(2002)

Non-patent document 4: experimental Cell Research Volume 313, Issue 14, 15August 2007, Pages 2969-

Non-patent document 5: cancer Research, Volume 66, Issue 6, March 15, 2006

Non-patent document 6: cancer Science Volume 94, Issue 7, 1July 2003, Pages 618-621; cancer Research Volume 62, Issue 1, 1January 2002, Pages 28-32

Disclosure of Invention

The purpose of the present invention is to provide a drug for cancer therapy for reducing cancer tissue.

As a result of intensive studies by the present inventors to solve the above-mentioned problems, the present inventors have found that a compound of the general formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, can significantly reduce cancer tissues in an animal cancer model, thereby completing the present invention.

That is, the present invention is based on the finding that the compounds of the present invention having EP4 selective antagonistic activity reduce tumor mass when the effect of EP4 selective antagonists on spontaneous gastric cancer model in mice (K19-Wnt1/C2mE mice, Gastroenterology Volume 131, Pages 1086-. This model of gastric cancer involves the PGE 2-mediated mechanism of tumor progression, and the above findings have demonstrated for the first time in the world the fact that the compounds of the present invention are effective in PGE 2-mediated tumor tissue shrinkage. In addition, the compounds of the invention also showed effects in models of digestive, prostate, lung and breast cancers.

Effects of the invention

Thus, the compounds of the present invention are effective in patients in need of treatment for cancer associated with PGE 2. "PGE 2-related cancers" include brain tumors, osteosarcomas, epithelial cell-derived neoplasms (epithelial cancers), e.g., basal cell carcinoma, adenocarcinoma, digestive system cancers (e.g., lip cancer, oral cancer, esophageal cancer, intestinal cancer, colon cancer, and gastric cancer), liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancers (e.g., squamous cell and basal cell carcinomas), prostate cancer, renal cell carcinoma, and other well-known cancers that have an effect on epithelial cells in vivo. The cancer is preferably selected from digestive system cancer, prostate cancer, lung cancer and breast cancer.

Drawings

FIG. 1 shows the change in mean tumor area of cross-sections in gastric tumors as determined by X-ray CT scan.

Figure 2 shows a comparison of relative gastric tumor volumes between drug-dosed mice and drug-non-dosed age-matched mice.

FIG. 3 shows the change in mean tumor area of cross-sections in gastric tumors as determined by X-ray CT scan.

Figure 4 shows a comparison of relative colon tumor weight between drug-dosed mice and drug-non-dosed age-matched mice.

Figure 5 shows a comparison of relative lung tumor weight between drug-dosed mice and drug-non-dosed age-matched mice.

Detailed Description

The compounds of the present invention that are effective for the treatment of cancer are compounds of general formula (I), (II), (III) or (IV) or pharmaceutically acceptable salts thereof. The compounds of the present invention include solvates, complexes, polymorphs, prodrugs, isomers and isotopically-labeled compounds.

(in the formula (1), Y¹、Y²、Y³And Y⁴Independently selected from the group consisting of N, CH radicals and C (L) radicals;

R¹is H, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, C_3-7Cycloalkyl radical, C_1-8Alkoxy, halogen substituted C_1-8Alkoxy radical, C_1-8alkyl-S (O)_m-、Q¹-, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, amino, mono-or bis- (C)_1-8Alkyl) amino, C_1-4Alkyl C (═ O) -N (R)³) -or C_1-4alkyl-S (O)_m-N(R³) -; wherein, the C_1-8Alkyl radical, C_2-8Alkenyl and C_2-8Alkynyl optionally substituted by halogen, C_1-3Alkyl, hydroxy, oxo, C_1-4alkoxy-C_1-4alkyl-S (O)_m-、C_3-7Cycloalkyl-, cyano, indanyl, 1, 2, 3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, pyrrolidinyl, piperidinyl, oxopyrrolidinyl, oxopiperidinyl, Q¹-、Q¹-C(＝O)-、Q¹-O-、Q¹-S(O)_m-、Q¹-C_1-4alkyl-O-, Q¹-C_1-4alkyl-S (O)_m-、Q¹-C_1-4alkyl-C (O) -N (R)³)-、Q¹-C_1-4alkyl-N (R)³) -or C_1-4alkyl-C (O) -N (R)³) Substitution;

Q¹is optionally 4 or less heteroatoms selected from O, N and S, and optionally substituted by halogen, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy radical, C_1-4Alkylthio, nitro, amino, mono-or bis- (C)_1-4Alkyl) amino, cyano, HO-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkylsulfonyl, aminosulfonyl, C_1-4Alkyl C (═ O) -, HO (O ═) C-, C_1-4alkyl-O (O ═) C-, R³N(R⁴)C(＝O)-、C_1-4Alkylsulfonylamino group, C_3-7Cycloalkyl radical, R³C(＝O)N(R⁴) -or NH₂(HN ═) C-substituted 5-to 12-membered monocyclic or bicyclic aromatic ring group;

a is a 5-6 membered monocyclic aromatic ring group optionally containing 3 or less heteroatoms selected from O, N and S, wherein the 5-6 membered monocyclic aromatic ring group is substituted with 3 or less heteroatoms selected from halogen, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy radical, C_1-4Alkylthio, nitro, amino, mono-or bis- (C)_1-4Alkyl) amino, cyano, HO-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkylsulfonyl, aminosulfonyl, acetyl, R³N(R⁴)C(＝O)-、HO(O＝)C-、C_1-4alkyl-O (O ═) C-, C_1-4Alkylsulfonylamino group, C_3-7Cycloalkyl radical, R³C(＝O)N(R⁴) -and NH₂(HN ═) C-substituted;

b is halogen-substituted C_1-6Alkylene radical, C_3-7Cycloalkylene radical, C_2-6Alkenylene radical, C_2-6Alkynylene, -O-C_1-5Alkylene radical, C_1-2alkylene-O-C_1-2Alkylene or C_1-6Alkylene, optionally bridged with oxo or C_1-3Alkyl substitution;

w is NH, N-C_1-4Alkyl radical, O, S, N-OR⁵Or a covalent bond;

R²is H, C_1-4Alkyl, OH or C_1-4An alkoxy group;

z is a 5-12 membered monocyclic or bicyclic aromatic ring group optionally containing 3 or less heteroatoms selected from O, N and S, wherein the 5-12 membered monocyclic or bicyclic aromatic ring group is substituted with halogen, C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkenyl radical, C_1-4Alkynyl, hydroxy, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy radical, C_1-4Alkylthio, nitro, amino, mono-or bis- (C)_1-4Alkyl) amino, cyano, HO-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkylsulfonyl, aminosulfonyl, C_1-4Alkyl C (═ O) -, R³C(＝O)N(R⁴)-、HO(O＝)C-、C_1-4alkyl-O (O ═) C-, C_1-4Alkylsulfonylamino group, C_3-7Cycloalkyl, NH₂(HN＝)C-、Q²-S(O)_m-、Q²-O-、Q²-N(R³) -or Q²-substitution;

l is halogen, C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy radical, C_1-4Alkylthio, nitro, amino, mono-or bis- (C)_1-4Alkyl) amino, cyano, HO-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkylsulfonyl, aminosulfonyl, C_1-4Alkyl C (═ O) -, HO (O ═) C-, C_1-4alkyl-O (O ═) C-, C_1-4Alkylsulfonylamino group, C_3-7Cycloalkyl radical, R³C(＝O)N(R⁴)-、NH₂(HN＝)C-、R³N(R⁴)C(＝O)-、R³N(R⁴)S(O)_m-、Q²-、Q²-C(＝O)-、Q₂-O-or Q²-C_1-4alkyl-O-or, alternatively, two adjacent L groups are optionally joined together to form a ring having 3 or 4 members with one of said members in the ringAn alkylene chain in which one or two (non-adjacent) carbon atoms are optionally substituted with an oxygen atom;

m is 0, 1 or 2;

R³and R⁴Independently selected from H and C_1-4An alkyl group;

R⁵is H, C_1-4Alkyl radical, C_1-4Alkyl- (O ═) C-or C_1-4alkyl-O- (O ═) C —; and

Q²is a 5-12 membered monocyclic or bicyclic aromatic ring group or a 5-12 membered tricyclic group, optionally containing 3 or less heteroatoms selected from O, N and S, wherein the 5-12 membered monocyclic or bicyclic aromatic ring group is optionally substituted with halogen, C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkenyl radical, C_1-4Alkynyl, hydroxy, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy radical, C_1-4Alkylthio, nitro, amino, mono-or bis- (C)_1-4Alkyl) amino, cyano, HO-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4Alkylsulfonyl, aminosulfonyl, C_1-4Alkyl- (O ═) C-, R³(R⁴)C(＝O)N-、HO(O＝)C-、C_1-4alkyl-O (O ═) C-, C_1-4Alkylsulfonylamino group, C_3-7Cycloalkyl radical, C_1-4alkyl-C (═ O) NH-or NH₂(HN ═) C-substitution; or

When formula (I) includes OH and/or CO₂H, the OH and-COOH can be independently esterified to form a pharmaceutically acceptable ester);

(in the above formula (II), ring A represents a phenyl group or a pyridyl group;

ring B represents aryl or heteroaryl;

ring C represents a 1, 4-phenylene group;

R¹and R²Independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group;

R³and R⁴Independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; or R³And R⁴Can be combined together to form an alkylene chain with 2-6 carbon atoms;

R⁵represents CO₂H、CO₂W、

R⁶Represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 ring atoms, an aryl group or a heteroaryl group;

x represents a methylene group, an oxygen atom or a sulfur atom;

the aryl group has 6 to 10 carbon atoms;

the heteroaryl group is a 5-10 membered aromatic heterocyclic group containing 1-3 heteroatoms selected from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom;

said aryl and said heteroaryl mentioned in the definition of ring B are unsubstituted or substituted by at least 1 substituent selected from the group consisting of substituents α;

said 1, 4-phenylene group mentioned in the definition of ring C is unsubstituted or substituted with at least 1 substituent selected from the group consisting of substituents β;

R⁶and α is unsubstituted or substituted with at least 1 substituent selected from the group consisting of substituents β;

the substituent alpha is selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a cyano group, an alkynyl group having 2 to 6 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 7 ring atoms, a heteroaryl group, an aryl group, an arylalkoxy group having 7 to 10 carbon atoms, an arylcarbonyl group, an aminocarbonyl group, an alkenyl group having 2 to 5 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an aminosulfinyl group, an aminosulfonyl group, a hydroxyl group, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, an alkanoylamino group having 1 to 4 carbon atoms, an alkanoyl (alkyl) amino group having 1 to 6 carbon atoms, An alkanoylaminoalkyl group having 1 to 6 carbon atoms in each of the two alkyl and alkanoyl groups, an alkanoyl (alkyl) aminoalkyl group having 1 to 6 carbon atoms in each of the two alkyl and alkanoyl groups, an alkylsulfonylamino group having 1 to 4 carbon atoms, a mono-or di-alkylaminocarbonyl group having 1 to 6 carbon atoms, a mono-or di-alkylaminosulfinyl group having 1 to 6 carbon atoms, a mono-or di-alkylaminosulfonyl group having 1 to 6 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, a mono-or di-alkylamino group having 1 to 6 carbon atoms, a mono-or di-alkylaminoalkyl group having 1 to 6 carbon atoms in each alkyl group, an arylalkyl group having 7 to 10 carbon atoms, a heteroarylalkylaminoalkyl group having 1 to 4 carbon atoms in the alkyl group, A heteroarylalkoxy group having 1 to 4 carbon atoms in the alkoxy moiety and an alkylsulfonylamino group having 1 to 4 carbon atoms; or, two adjacent a groups may be joined together to form an alkylene or alkenylene chain of 3 or 4 carbon atoms;

the substituent beta is selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms and a cyano group; and

w is a pharmaceutically acceptable ester prodrug group);

(in the formula (III), X represents-CH-or a nitrogen atom;

y represents-NR⁴Oxygen atom or sulfur atom;

R⁴represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;

z represents a hydrogen atom or a halogen atom;

R¹represents an alkyl group having 1 to 6 carbon atoms which is optionally substituted with an alkoxy group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms which is optionally substituted with an alkyl group having 1 to 3 carbon atoms, a phenyl group which is optionally substituted with 1 or more substituents α, or a group Het1 which is optionally substituted with 1 or more substituents α;

het1 represents heterocyclic group having 4 to 7 ring atoms containing 1 to 4 nitrogen ring heteroatoms or containing 0 to 2 nitrogen ring heteroatoms and either 1 oxygen or 1 sulfur ring heteroatom;

R²and R³Independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; or, R²And R³The groups together form an alkylene chain with 3-6 carbon atoms; and

the substituent alpha is selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a cyano group, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms in each of the alkoxy group and the alkyl group, an alkylsulfonyl group having 1 to 4 carbon atoms, and an alkanoyl group having 2 to 5 carbon atoms, alkenyl having 2 to 4 carbon atoms, alkynyl having 2 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, nitro, amino, mono-or di-alkylamino having 1 to 4 carbon atoms, aminosulfonyl, alkoxycarbonyl having 1 to 4 carbon atoms, alkylsulfonylamino having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms and mono-or di-alkylaminocarbonyl having 1 to 6 carbon atoms;

when a hydroxy group is included in formula (III), it may be a pharmaceutically acceptable ester, including CO₂H, independently esterified to form a pharmaceutically acceptable ester); and

(in the formula (IV), X represents-CH or a nitrogen atom;

y represents NR⁴Oxygen atom or sulfur atom;

R⁴represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;

z represents a hydrogen atom or a halogen atom;

R¹represents an alkyl group having 1 to 6 carbon atoms which is optionally substituted with 1 to 2 groups independently selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms, a trifluoromethyl group, an alkanoyl group having 2 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a phenoxy group, a heterocyclic group and a heteroaryl group; a cycloalkyl group having 3 to 7 carbon atoms optionally substituted with an alkyl group having 1 to 3 carbon atoms; or a heterocyclic group;

R²and R³Independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; or, R²And R³The groups together form an alkylene chain with 3-6 carbon atoms;

the heteroaryl group is a 4-to 7-membered aromatic ring system having 1-4 nitrogen ring heteroatoms, or having 0-2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom;

the heterocyclic group is a 4-to 7-membered saturated ring system having 1-4 nitrogen ring heteroatoms, or having 0-2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom;

at R¹Said phenyl, phenoxy and heteroaryl radicals mentioned in the definitions of areUnsubstituted or substituted with at least 1 substituent selected from the group consisting of substituent α;

the substituent alpha is selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, a haloalkoxy group having 1 to 4 carbon atoms, a cyano group, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms in each of the alkoxy group and the alkyl group, an alkylsulfonyl group having 1 to 4 carbon atoms, and an alkanoyl group having 2 to 5 carbon atoms, a C2-4 alkenyl group, a C2-4 alkynyl group, a C1-4 alkylthio group, a nitro group, an amino group, a C1-4 mono-or di-alkylamino group, an aminosulfonyl group, a C1-4 alkoxycarbonyl group, a C1-4 alkylsulfonylamino group, a C3-7 cycloalkyl group, and a C1-6 mono-or di-alkylaminocarbonyl group; or

When OH is included in formula (IV), the OH groups may be independently esterified to form pharmaceutically acceptable esters, including CO₂When H, the CO is₂H may be independently esterified to form a pharmaceutically acceptable ester).

Preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof, which is effective for the treatment of cancer in each formula, is as follows:

general formula (I):

3- [2- (4- { 2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl ] -1- [ (4-methylbenzene) sulfonyl ] urea;

1- (4- { 2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl } phenyl) propan-2-yl N- [ (4-methylbenzene) sulfonyl ] carbamate;

3- [2- (4- { 2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl } phenyl) ethyl ] -1- [ (4-methylbenzene) sulfonyl ] urea;

1- {2- [4- (5-acetyl-2-ethyl-1H-1, 3-benzimidazol-1-yl) phenyl ] ethyl } -3- [ (4-methylbenzene) sulfonyl ] urea;

3- {2- [4- (2-ethyl-5-methoxy-1H-1, 3-benzimidazol-1-yl) phenyl ] ethyl } -1- [ (4-methylbenzene) sulfonyl ] urea;

2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl N- [ (4-methylbenzyl) sulfonyl ] carbamate;

3- {2- [4- (6-chloro-5-cyano-2-ethyl-1H-1, 3-benzimidazol-1-yl) phenyl ] ethyl } -1- [ (4-methylbenzene) sulfonyl ] urea;

2- (4- { 2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl } phenyl) ethyl N- [ (4-methylbenzene) sulfonyl ] carbamate;

2- (4- { 2-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl } phenyl) ethyl N- [ (4-methylbenzene) sulfonyl ] carbamate;

2- (4- { 2-tert-butyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl } phenyl) ethyl N- [ (4-methylbenzene) sulfonyl ] carbamate;

2- (4- { 2-amino-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl } phenyl) ethyl N- [ (4-methylbenzene) sulfonyl ] carbamate;

3- {2- [4- (6-chloro-2-ethyl-5-methanesulfonyl-1H-1, 3-benzimidazol-1-yl) phenyl ] ethyl } -1- [ (4-methylbenzene) sulfonyl ] urea;

2- [4- (5-carbamoyl-6-chloro-2-ethyl-1H-1, 3-benzimidazol-1-yl) phenyl ] ethyl N- [ (4-methylbenzyl) sulfonyl ] carbamate;

1- (2- {4- [ 2-ethyl-5- (1-hydroxyethyl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl) -3- [ (4-methylbenzene) sulfonyl ] urea;

1- (2- {4- [ 2-ethyl-5- (2-hydroxypropan-2-yl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl) -3- [ (4-methylbenzene) sulfonyl ] urea;

1- (2- {4- [ 6-chloro-2- (2-hydroxypropan-2-yl) -5- (trifluoromethyl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl) -3- [ (4-methylbenzene) sulfonyl ] urea;

n- [1- (6-chloro-1- {4- [2- ({ [ (4-methylbenzene) sulfonyl ] carbamoyl } amino) ethyl ] phenyl } -5- (trifluoromethyl) -1H-1, 3-benzimidazol-2-yl) ethyl ] acetamide;

6-chloro-2-ethyl-1- (4- {2- [ methyl ({ [ (4-methylbenzene) sulfonyl ] carbamoyl }) amino ] ethyl } phenyl) -1H-1, 3-benzimidazole-5-carboxamide;

2- {4- [ 6-chloro-2- (pyridin-2-yl) -5- (trifluoromethyl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl N- [ (4-methylbenzyl) sulfonyl ] carbamate;

3- (2- {5- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-1, 3-benzimidazol-1-yl ] pyridin-2-yl } ethyl) -1- [ (4-methylbenzene) sulfonyl ] urea;

2- {4- [ 6-chloro-2-ethyl-5- (trifluoromethyl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl N- [ (2-chlorobenzene) sulfonyl ] carbamate; or

3- (2- {4- [5, 7-dimethyl-2- (methylamino) -3H-imidazo [4, 5-b ] pyridin-3-yl ] phenyl } ethyl) -1- [ (4-methylbenzene) sulfonyl ] urea;

general formula (II):

4- ((1S) -1- { [ 5-chloro-2- (4-fluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (4-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1 ({ [ 5-chloro-2- (3-cyanophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3-chlorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3-fluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3-chlorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (2-chloro-4-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (2, 6-difluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3, 4-difluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (2, 3-difluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (2, 5-difluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (2-chloro-5-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3-methylphenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3, 5-difluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (2, 3-difluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3, 4-difluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3-chloro-5-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3, 5-difluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (2, 5-difluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3-chloro-5-methylphenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3-methylphenoxy) benzoyl ] amino } ethyl) benzoic acid;

((1S) -1- { [ 5-chloro-2- (3-chloro-5-fluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (2, 6-difluorophenoxy) benzoyl ] amino } ethyl) benzoic acid;

4- ((1S) -1- { [ (5-chloro-2-phenoxypyridin-3-yl) carbonyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (2, 3-dichlorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3, 4-dichlorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ [ 5-chloro-2- (3, 5-dichlorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid; or

4- [ (1S) -1- ({ [ 5-chloro-2- (3-fluoro-4-methylphenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

general formula (III):

4- [ (1S) -1- ({ 5-chloro-2- [ (4-chlorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (4-methylphenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3-chlorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (4-fluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2, 3-difluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3, 4-difluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2, 4-difluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- { (1S) -1- [ ({ 5-chloro-2- [ (3-chlorophenoxy) methyl ] pyridin-3-yl } carbonyl) amino ] ethyl } benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2-chlorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3, 5-difluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- { (1S) -1- [ ({ 5-chloro-2- [ (4-chlorophenoxy) methyl ] pyridin-3-yl } carbonyl) amino ] ethyl } benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3-fluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2, 6-difluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2-fluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2, 5-difluorophenoxy) methyl ] benzoyl } amino) ethyl ] benzoic acid;

4- { (1S) -1- [ ({2- [ (4-chlorophenoxy) methyl ] -5-fluoropyridin-3-yl } carbonyl) amino ] ethyl } benzoic acid; or

4- { (1S) -1- ({ 5-chloro-2- [ (cyclohexylmethoxy) methyl ] benzoyl } amino) ethyl } benzoic acid; and

general formula (IV):

4- [ (1S) -1- ({ 5-chloro-2- [ (2-chlorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [2- (2-methylphenyl) ethoxy ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [2- (4-methylphenyl) ethoxy ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3-chlorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (4-chlorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (cyclobutylmethoxy) benzoyl ] amino } ethyl) benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (cyclohexyloxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2-cyanobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [2- (4-fluorophenyl) ethoxy ] benzoyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3-methylbutoxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (4-fluorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [2- (2-fluorophenyl) ethoxy ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2, 5-difluorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- [ ({ 5-chloro-2- [2- (2-methylphenyl) ethoxy ] benzoyl } amino) methyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (2-chloro-4-fluorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (2-phenoxyethoxy) benzoyl ] amino } ethyl) benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3, 4-difluorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (4-chloro-2-fluorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid;

4- { (1S) -1- [ ({ 5-chloro-2- [ (4-chlorobenzyloxy) ] pyridin-3-yl } carbonyl) amino ] ethyl } benzoic acid;

4- ((1S) -1- { [2- (benzyloxy) -5-chlorobenzoyl ] amino } ethyl) benzoic acid;

4- { (1S) -1- [ ({ 5-chloro-2- [ (2-chlorobenzyloxy) ] pyridin-3-yl } carbonyl) amino ] ethyl } benzoic acid;

4- { (1S) -1- [ ({ 5-chloro-2- [2- (4-chlorophenyl) ethoxy ] pyridin-3-yl } carbonyl) amino ] ethyl } benzoic acid;

4- [ (1S) -1- ({ 5-chloro-2- [ (3, 5-difluorobenzyloxy) ] benzoyl } amino) ethyl ] benzoic acid; or

4- [ (1S) -1- ({ 5-chloro-2- [2- (2, 6-difluorophenyl) ethoxy ] benzoyl } amino) ethyl ] benzoic acid.

More preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof in each formula, which is effective for the treatment of cancer, is as follows:

general formula (I):

2- {4- [ 6-chloro-2- (pyridin-2-yl) -5- (trifluoromethyl) -1H-1, 3-benzimidazol-1-yl ] phenyl } ethyl N- [ (4-methylbenzene) sulfonyl ] carbamate;

general formula (II):

4- [ (1S) -1- ({ [ 5-chloro-2- (3-cyanophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid;

4- ((1S) -1- { [ 5-chloro-2- (3, 4-difluorophenoxy) benzoyl ] amino } ethyl) benzoic acid; or

general formula (III):

general formula (IV):

These compounds are disclosed in WO02/32900, WO2005/021508, WO05/105732 and WO 2005/105733.

Pharmaceutically acceptable salts include their acid addition and base salts. Suitable acid addition salts are typically formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoylphthalate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate or biphosphate, gluconate, stearate, succinate, tartrate, bisulfate, Tosylate and trifluoroacetate.

Suitable basic salts are formed from bases which form non-toxic salts. Those examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, amine (olamine), potassium, sodium, tromethamine and zinc salts.

For the observation of suitable salts, reference is made to the following documents: "Handbook of Pharmaceutical Salts: properties, Selection, and Use "by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The pharmaceutically acceptable salts of the compounds of formula (I), (II), (III) or (IV) can be easily prepared by mixing a solution of the compound of formula (I), (II), (III) or (IV) together with the target acid or base, as necessary. The salt may be collected by precipitation from solution and filtration, or may be recovered by evaporation of the solvent. The degree of ionization in salts can vary from fully ionic to almost non-ionic.

The compounds of the present invention may exist in both unsolvated and solvated forms. In this application, the term "solvate" is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).

Complexes such as clathrates, drug-host inclusion complexes, and the like are included within the scope of the invention, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the aforementioned solvates. Pharmaceutical complexes containing two or more organic and/or inorganic components that may be present in stoichiometric or non-stoichiometric amounts are also included within the scope of the present invention. The resulting complex may be ionized, partially ionized or non-ionized. For the observation of these complexes, reference is made to the following documents: j Pharm Sci.64(8), 1269-1288 by Haleblian (August 1975).

All references to compounds of formula (I), (II), (III) or (IV) include references to their salts, solvates and complexes and references to their salts, solvates and complexes.

The compounds of the invention include the compounds of the invention as defined above, polymorphs, prodrugs and isomers thereof (including optical isomers, geometric isomers and tautomers) as well as the isotopically-labelled compounds of the invention as defined below.

As previously mentioned, the present invention includes all polymorphs of the compounds of the present invention as defined above.

Also, so-called "prodrugs" of compounds of formula (I), (II), (III) or (IV) are included within the scope of the present invention. Thus, a particular derivative of a compound of formula (I), (II), (III) or (IV) which may itself have little or no pharmacological activity is converted, for example by hydrolytic cleavage, to a compound of formula (I), (II), (III) or (IV) having the desired activity when administered to the body or body surface. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in the following documents: pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T.Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(ed.E.B.Roche, American Pharmaceutical Association)

The Prodrugs according to the invention can be prepared, for example, by substituting the appropriate functional groups present in the compounds of the general formula (I), (II), (III) or (IV) with specific moieties well known to the person skilled in the art as "pre-existing groups (pro-moieties)" as described, for example, in "Design of precursors" by h.

Some examples of prodrugs according to the invention include the following:

(i) when the compound of the present invention contains a carboxylic acid function (-COOH), for example, (C) is usable₁-C₈) Esters thereof obtained by substituting hydrogen with an alkyl group;

(ii) when the compound of the present invention contains an alcohol functional group (-OH), for example, (C) is employable₁-C₆) Esters thereof obtained by substituting hydrogen with alkanoyloxymethyl; and

(iii) when the compound of the present invention contains a primary or secondary amine function (-NH)₂or-NHR (wherein R is not H), for example, (C) may be used₁-C₆) An ester thereof obtained by substituting one or both of hydrogens with an alkanoyl group.

Additional examples of substituents other than those described above are known to those skilled in the art and can be found in the foregoing references, but are not limited thereto.

Finally, the particular compounds of formula (I), (II), (III) or (IV) may themselves also act as prodrugs of other compounds of the invention.

The compound of the present invention containing 1 or more asymmetric carbon atoms may exist as 2 or more stereoisomers. When the compounds of the present invention contain an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers can be achieved. When the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ("tautomerism") may occur. It is understood that a single compound may exhibit more than one type of isomerism.

All stereoisomers, geometric isomers and tautomers of the compounds of the invention, including compounds exhibiting more than two types of isomerism, as well as mixtures of more than one of them, are included within the scope of the invention. Also included within the scope of the invention are acid addition or base salts in which the counterion is optically active, such as D-lactate or L-lysine or racemic, such as DL-tartrate or DL-arginine.

The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Common techniques for preparing or isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors and resolution of the racemate (or the racemate of a salt or derivative), for example using chiral High Pressure Liquid Chromatography (HPLC).

In contrast thereto, the racemate (racemic precursor) may be reacted with a suitable optically active compound, for example with an alcohol, or, when the compound of the invention contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereomers may be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers may be converted to the corresponding pure enantiomers by means well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form by chromatography on asymmetric resins based on a mobile layer consisting of a hydrocarbon compound containing 0-50 (w/w)% isopropanol, typically 2-20 (w/w)% and 0-5 (w/w)% alkylamine, typically 0.1 (w/w)% diethylamine, the hydrocarbon being typically heptane or hexane, the chromatography being typically HPLC. The enriched mixture is obtained by concentration of the eluent.

Stereoisomeric assemblies can be isolated by conventional techniques well known to those skilled in the art, for example by reference to the following "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).

Included in the present invention are all pharmaceutically acceptable isotopically-labelled compounds of the present invention, wherein 1 or more atoms are replaced by atoms of the same atomic number, but having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of suitable isotopes that are suitable for inclusion in the compounds of the invention include²H and³h and other hydrogen isotopes,¹¹C、¹³C and¹⁴carbon isotopes of C, etc,³⁶A chlorine isotope such as Cl, a fluorine isotope such as 18F,¹²³I and¹²⁵i and other iodine isotopes,¹³N and¹⁵n, etc. nitrogen isotopes,¹⁵O、¹⁷O and¹⁸oxygen isotope such as O,³²Phosphorus isotopes such as P and³⁵s and other sulfur isotopes.

Certain isotope-labeled compounds of the invention, e.g., isotope-labeled compounds incorporating a radioisotope, are useful in drug and/or stromal tissue distribution studies related to cancer therapy, including diagnosis, symptom alleviation, improvement and prevention of QOL. Tritium as a radioisotope (i.e., tritium) in view of ease of incorporation and rapid detection means³H) And carbon-14 (i.e.¹⁴C) Particularly useful for this purpose.

Heavier isotopes such as heavy hydrogen²Substitution of H may provide specific therapeutic benefits resulting from greater metabolic stabilitySuch as increased in vivo half-life or reduced dosage requirements, and thus such substitutions may be preferred in some circumstances.

For example¹¹C、¹⁸F、¹⁵O and¹³substitution of positron emitting isotopes such as N is useful in Positron Emission Tomography (PET) studies for detecting occupancy of a substrate receptor.

The isotopically-labeled compound of the present invention can be prepared by a conventional technique known to those skilled in the art, or by a similar procedure as described in examples or a preparation section attached to the present application, using an appropriate isotopically-labeled reagent in place of a conventionally used non-labeled reagent.

Pharmaceutically acceptable solvates according to the invention include those solvates in which the crystallization solvent may be isotopically substituted, for example D₂O、d₆-acetone, d₆-solvates of DMSO.

The compounds of the invention for pharmaceutical use purposes may be administered in crystalline or amorphous product form. These can be obtained, for example, by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporation-drying, for example in the form of solid plugs (solid plugs), powders or films. Microwave or high frequency drying may be used for this purpose.

They may be administered alone, or in combination with one or more additional compounds of the invention or one or more additional drugs (therapeutic agent 2 (second active agent)) (or in any combination thereof). Typically, they will be administered in a formulation with one or more pharmaceutically acceptable additives. The term "additive" is used in this application to describe any ingredient other than the compounds of the present invention. The choice of additive will depend on factors such as the particular mode of administration, the effect of the additive on solubility and stability, and the type of dosage form.

Accordingly, the present invention provides a combination of a compound of the invention, a solvate thereof, or a prodrug thereof, and one or more additional pharmaceutically active agents (or chemical combinations, 2 nd therapeutic agent). Furthermore, the present invention provides a pharmaceutical composition comprising such a combination with a pharmaceutically acceptable additive, diluent or carrier for the treatment of cancer, particularly in association with an EP4 antagonist. Also, the present invention provides a kit comprising a 1 st pharmaceutical composition, a 2 nd pharmaceutical composition and a container, the 1 st pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof.

A kit for treating cancer, which comprises a compound of the general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, is also an invention. A pharmaceutical composition containing a compound of the general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, and a product containing the information on the pharmaceutical composition and the information on the purpose of use or application for the treatment of cancer are also one of the inventions.

[ definition of terms ]

Those skilled in the art can readily understand the terms used in this specification and the appended claims, and the following terms have the meanings described below.

The term "EP 4 receptor activity" or "EP 4 activity" as used in the present application refers to the rise of cAMP based on a combination with PGE2 stimulation mediated by EP4 receptor.

The term "selective" EP4 receptor antagonist as used herein refers to a compound having an IC which, when inhibited in EP4 activity, is determined by standard methods well known to those skilled in the art₅₀IC exhibiting activity with EP1, EP2 or EP3₅₀Compared to an EP4 receptor antagonist that is at least 10-fold less, preferably 100-fold less capable.

The terms "halo" and "halogen atom" as used herein refer to F, Cl, Br or I, preferably F or Cl.

The term "alkyl" as used herein refers to a straight or branched chain saturated monovalent hydrocarbon group including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, and the like.

The term "alkenyl" as used herein refers to a hydrocarbon group having at least 1 double bond including vinyl, propenyl, 1-butenyl, 2-butenyl, etc., but is not limited thereto.

The term "alkynyl" as used herein refers to a hydrocarbon group having at least 1 triple bond including ethynyl, propynyl, 1-butynyl, 2-butynyl, etc., but is not limited thereto.

The term "cycloalkyl" as used herein refers to a saturated carbocyclic group including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl.

The term "alkoxy" as used herein refers to, but is not limited to, O-alkyl (wherein "alkyl" is as defined above) within methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

And, for example, C as used in the present application_1-4The alkyl group has the same meaning as the alkyl group having 1 to 4 carbon atoms.

The term "alkylene" as used herein refers to a saturated hydrocarbon (straight or branched chain) in which a hydrogen atom is removed from the respective terminal carbon, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

The term "cycloalkylene" as used herein refers to a divalent cycloalkyl group including, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and the like.

The term "alkenylene" as used herein is meant to include-CH ═ CH-, -CH ═ CHCH (CH) — CHCH (CH)₃) Linear or branched hydrocarbon chain spacer groups having at least 1 double bond, and the like, but are not limited thereto.

In this applicationThe term "alkynylene" as used herein is meant to include-C.ident.C-, -C-C.ident.CCH₂-、-C≡CCH(CH₃) -linear or branched hydrocarbon chain spacer groups having at least 1 triple bond, and the like, but not limited thereto.

The term "alkanoyl" as used herein refers to a compound having the formula R '-C (O) - (wherein R' is C), including formyl, acetyl, ethyl-C (O) -, n-propyl-C (O) -, isopropyl-C (O) -, n-butyl-C (O) -, isobutyl-C (O) -, sec-butyl-C (O) -, tert-butyl-C (O) -, cyclopropyl-C (O) -, cyclobutyl-C (O), and the like_1-4Alkyl radical C_3-4Cycloalkyl), but not limited thereto.

The term "haloalkyl" as used herein refers to an alkyl group substituted with a halogen atom as defined above, including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2, 2, 2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl, and bromomethyl, and the like.

The term "haloalkoxy" as used herein refers to haloalkyl-O-including, but not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 2, 2, 2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy, iodomethoxy, bromomethoxy, and the like.

The term "aryl" as used herein refers to an aromatic group including, but not limited to, phenyl, naphthyl, tetrafluoronaphthyl, indanyl, biphenyl, and the like.

The term "monocyclic aromatic ring group" as used herein refers to a monocyclic aromatic ring carbocyclic or heterocyclic ring (containing 0 to 4 heteroatoms selected from O, N and S) including phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, triazolyl, furazanyl and the like, but is not limited thereto.

The term "bicyclic aromatic ring group" as used herein means a monocyclic or bicyclic aromatic ring carbocyclic or heterocyclic ring (containing 0 to 4 heteroatoms selected from O, N and S) including naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc., but is not limited thereto.

The term "tricyclic aromatic ring group" as used herein refers to a saturated carbocyclic group including adamantyl, tricyclo [5.2.1.02, 6] decyl, and the like, but is not limited thereto.

The term "two contiguous L groups optionally joined together to form an alkylene chain having 3 or 4 members and one or two (non-contiguous) carbon atoms optionally substituted with an oxygen atom" as used herein means-O-CH₂-O-、-CH₂-O-CH₂-、-O-CH₂CH₂-、CH₂CH₂-O-、-O-CH₂CH₂-O-、-CH₂CH₂CH₂-O-、-O-CH₂CH₂CH₂-、-CH₂-O-CH₂CH₂-、-CH₂CH₂-O-CH₂-and the like, but is not limited thereto. The term "two adjacent L groups" refers to two L groups bound at separate carbon atoms adjacent to each other. The above "two non-adjacent carbon atoms" means that they may be two adjacent carbon atoms, or two non-adjacent carbon atoms.

The term "ester" as used herein refers to a protecting group that can be cleaved in vivo by biological means such as hydrolysis and forms the free acid or salt thereof. Whether a compound is that derivative can be determined by examining body fluids of an animal after intravenous administration to a laboratory animal such as rat or mouse to determine whether the compound or a pharmaceutically acceptable salt thereof can be detected.

Preferred examples of the group of the carboxyl group or the ester of the hydroxyl group include the following: (1) aliphatic alkanoyl groups, for example: alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, n-valeryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3, 7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentaneoyl, 14-methylpentaneoyl, 13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptanoyl, nonadecanoyl, eicosanoyl and heneicosanoyl; halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl; alkoxyalkanoyl (alkyalkanoyl), such as methoxyacetyl; and unsaturated alkanoyl groups such as acryloyl, propioyl, methacryloyl, crotonyl, methacryloyl and (E) -2-methyl-2-butenoyl;

(2) aromatic alkanoyl groups, for example: arylcarbonyl groups such as benzoyl, α -naphthoyl and β -naphthoyl; halogenated arylcarbonyls such as 2-bromobenzoyl and 4-chlorobenzoyl; alkylated arylcarbonyl groups such as 2, 4, 6-trimethylbenzoyl and 4-toluoyl; alkoxylated arylcarbonyl groups such as 4-anisoyl; nitrated arylcarbonyls, such as 4-nitrobenzoyl and 2-nitrobenzoyl; alkoxycarbonylated arylcarbonyls such as 2- (methoxycarbonyl) benzoyl; and arylated arylcarbonyls, such as 4-phenylbenzoyl;

(3) alkoxycarbonyl groups, for example: alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and isobutoxycarbonyl; and halogen-or tri (alkyl) silyl-substituted alkoxycarbonyl groups, such as 2, 2, 2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl;

(4) tetrahydropyranyl or tetrahydrothiopyranyl, such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl; and tetrahydrofuranyl or tetrahydrothiofuranyl, such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl;

(5) silicon based, for example: tri (alkyl) silyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl and triisopropylsilyl; and a silicon group substituted with 1 or more aryl groups and alkyl groups, such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl;

(6) alkoxymethyl groups, such as: alkoxymethyl groups such as methoxymethyl, 1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl; alkoxylated alkoxymethyl groups such as 2-methoxyethoxymethyl and halo (alkoxy) methyl groups such as 2, 2, 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl;

(7) substituted ethyl groups, for example: alkoxylated ethyl groups such as 1-ethoxyethyl and 1- (isopropoxy) ethyl; and halogenated ethyl groups such as 2, 2, 2-trichloroethyl; and

(8) aralkyl groups, such as: alkyl substituted with 1 to 3 aryl groups such as benzyl, α -naphthylmethyl, β -naphthylmethyl, diphenylmethyl, triphenylmethyl, α -naphthyldiphenylmethyl and 9-anthrylmethyl; alkyl substituted with 1 to 3 substituted aryl groups (wherein 1 or more of the aryl groups are substituted with 1 or more alkyl, alkoxy, nitro, halogen or cyano substituents), such as 4-methylbenzyl, 2, 4, 6-trimethylbenzyl, 3, 4, 5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; alkenyloxycarbonyl, such as vinyloxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl; and aralkyloxycarbonyl groups (wherein the aryl ring may be substituted with 1 or 2 alkoxy groups or nitro groups), such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

The term "protecting group" as used in this application refers to a hydroxy or amino protecting group selected from the typical hydroxy or amino protecting Groups described in the literature [ Protective Groups in Organic Synthesis identified by T.W.Greene et al (John Wiley & Sons, 1991).

The term "hydrate" as used herein is used when the solvent is water.

The terms "treated" or "treatment" as used herein refer to reversing, alleviating, inhibiting the progression of, or preventing the progression of, a disorder or condition to which the above terms apply or one or more symptoms of such a disorder or condition. The term "treated" or "treatment" as used in this application includes not only shrinking growing tumor tissue, but also alleviating symptoms, improving QOL, and preventing (radiotherapy, prevention of postoperative recurrence, adjuvant chemotherapy, etc.).

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. While particular embodiments of the present invention have been described, numerous other known or commonly practiced variations and modifications of the present invention are within the scope of the appended claims. The invention also includes equivalents, variations, uses, or adaptations of the invention following its spirit.

The compounds of the present invention are administered in an amount sufficient to reduce metastasis, reduce cancer, and/or increase the effectiveness of cancer therapy. The therapeutically effective amount will vary depending on the particular disease being treated, the patient's condition, the route of administration, the formulation, the field determination, and other factors. The amounts are determined by generally optimized techniques, according to the disclosure, based on factors well known to those skilled in the art.

The pharmaceutical composition may comprise a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof. These drugs are mixed with a pharmaceutically acceptable transport medium or carrier.

The term "pharmaceutically acceptable transport medium" as used herein includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, suitable for pharmaceutical administration. The above-described media may also contain other active or inert components and target cancer tissue based on composition.

In light of this disclosure, the therapeutic efficacy of the compounds of the invention can be determined, for example, by standard therapeutic methods in cell culture or experimental animals for determining the ED50 (therapeutically effective dose in 50% of the population).

Data obtained from cell culture assays and animal studies can be used in dosage ranges formulated for use in humans. The dosage may vary depending on the formulation and route of administration. For any EP4 receptor antagonist used in the methods of the invention, the therapeutically effective dose can be calculated early in the cell culture assay. The dose can be formulated as an IC based on determination by cell culture in animal models₅₀To achieve a target circulating plasma concentration range. Such information can be used to more accurately determine useful doses in humans. The level in plasma can be determined, for example, by high performance liquid chromatography or mass spectrometry.

Specific factors, including, but not limited to, the severity of the disease or condition, past treatment history, general health and/or age of the mammal, and other diseases present, will have an effect on the dosage and time required to effectively treat the animal, as is well known to those skilled in the art. Also, treatment of a mammal with a therapeutically effective amount of a compound of the present invention includes, but is not limited to, monotherapy, alternate treatment, and series of treatments.

The precise amount of the compound to be administered to a human patient is especially the responsibility of the attending physician. However, the dosage employed will depend upon a variety of factors including the age and sex of the patient, the precise condition being treated and its severity and the route of administration.

The compounds are conveniently administered in the form of pharmaceutical compositions. Such compositions are conveniently presented for use in admixture with one or more pharmaceutically acceptable carriers or excipients in a conventional manner. Preferably, the pharmaceutical composition is for use in cancer therapy. A pharmaceutical composition for cancer treatment comprising the compound of the present invention is also one of the present invention.

The compounds may be administered as the chemical substance in the raw state, but are preferably provided in a pharmaceutical formulation. The formulations comprise the compound together with one or more carriers or diluents for the compound and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical composition is formulated to meet the intended route of administration. Routes of administration are, for example, non-oral (e.g., intravenous, intradermal, subcutaneous), oral (e.g., ingestion or inhalation), transdermal (topical), mucosal, rectal and topical (including transdermal, buccal and sublingual) administration. Solutions or suspensions can be prepared by methods described in the literature [ Remington's pharmaceutical Sciences, 18^thed.，Gennaro，ed.，Mack Publishing Co.，Easton，PA，(1990)]The method of (1) is carried out.

The most suitable route may vary, for example, depending on the condition or disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, a preparation is prepared by uniformly and homogeneously mixing an active ingredient with both a liquid carrier or a fine powder solid carrier, and then molding the product into a desired preparation as needed.

Formulations of the invention suitable for oral administration may be provided as follows: discrete units such as capsules, cachets, tablets (e.g., chewable tablets for pediatric administration, among others) each containing a predetermined amount of active ingredient; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. The active ingredient may also be provided in the form of a bolus, electuary or paste.

The tablet can be optionally prepared by compressing or molding with 1 or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant (lubricant), inert diluent, lubricant (lubricating), surface active or dispersing agent. Shaped tablets may be prepared by shaping in a machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored to provide slow or controlled release of the active ingredient therein.

Agents for non-oral administration include aqueous or non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous or non-aqueous sterile suspensions which may include suspending agents or thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules or glass vials, and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous preparation of injectable solutions and suspensions may be prepared from sterile powders and tablets of the kind previously described.

The preparation for rectal administration may be provided in the form of a suppository with a usual carrier such as cocoa butter, hard fat or polyethylene glycol.

Formulations for topical administration in the oral cavity, for example for buccal or sublingual administration, include lozenges comprising the active ingredient in a flavoured base (e.g. sucrose and acacia or tragacanth), and pastilles comprising the active ingredient in a base such as gelatin and glycerol or sucrose and acacia.

The compounds of the present invention or pharmaceutically acceptable salts thereof may also be formulated as implants. Such long acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. For example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins or may be formulated as sparingly soluble salts.

In addition to the ingredients particularly mentioned above, the formulations may contain other agents conventional in the art, for example flavouring agents, suitable for oral administration, depending on the type of agent concerned.

Further, it is preferable to use the compound of the present invention or a pharmaceutically acceptable salt thereof in combination with at least one member selected from the group consisting of a steroid or nonsteroidal antiandrogen agent or antiestrogen agent, a chemotherapeutic agent, a GnRH antagonistic peptide, an α -reductase inhibitor, an α -receptor inhibitor, an aromatase inhibitor, a 17 β -hydroxysteroid dehydrogenase inhibitor, an adrenal androgen production inhibitor, a kinase inhibitor, a drug for hormone therapy, and a drug inhibiting a cell growth factor and its receptor.

The above-mentioned "chemotherapeutic agents" include, among others, ifosfamide, doxorubicin, pelomycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, and the like.

The above-mentioned "GnRH antagonist peptide" includes non-oral GnRH antagonist peptides such as cetrorelix, ganirelix, abarelix and the like.

The above-mentioned "adrenal androgen production inhibitor" includes lyase (C17, 20-lyase) inhibitors and the like.

The "kinase inhibitor" mentioned above includes tyrosine kinase inhibitors and the like.

"hormone therapy drugs" include, inter alia, antiestrogens, progestins (e.g., MPA, etc.), androgens, estrogens, and antiandrogens.

The "cell growth factor" mentioned above may be any substance that promotes cell proliferation, and generally includes peptides having a molecular weight of not more than 20,000 that act by binding to a receptor expressed at a low concentration. Specifically, among them, there are (1) EGF (epidermal growth factor) or a substance having substantially the same activity (for example, EGF, heregulin (HER2 ligand), etc.), (2) insulin or a substance having substantially the same activity (for example, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), (3) FGF (fibroblast growth factor) or a substance having substantially the same activity (aFGF, bFGF, KGF (keratinocyte growth factor), HGF (hepatocyte growth factor), FGF-10, etc.), and (4) other growth factors (for example, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF β (transforming growth factor β), etc.).

The "cell growth factor receptor" may be any receptor including EGF receptor, heregulin receptor (HER2), insulin receptor-1, insulin receptor-2, IGF receptor, FGF receptor-1, FGF receptor-2, etc., which is capable of binding to the above cell growth factors.

The above-mentioned cytostatic drugs include, inter alia, herceptin (anti-HER 2 receptor antibody).

The above-mentioned drugs for inhibiting cell growth factors or their receptors include herbimycin, PDl53035[ e.g., Science, 265(5175) p1093, (1994) ] and the like.

Additional classes of agents that inhibit cell growth factor or its receptor include HER2 inhibitors. The HER2 inhibitor may be any substance that inhibits the activity of HER2 (e.g., kinase activity) and thus includes antibodies, low-molecular weight compounds (synthetic or natural products), antisense, HER2 ligands, heregulin, and any of them partially structurally deformed or mutated. Further, the compound may be a substance which inhibits HER2 activity by inhibiting HER2 receptor (for example, an anti-HER 2 receptor antibody).

In the case of prostate cancer, the compound of the present invention is used in combination with a GnRH super agonist, an antiandrogen, an antiestrogen, a chemotherapeutic agent (e.g., ifosfamide, UFT, doxorubicin, perlomycin, cisplatin, etc.), a GnRH antagonistic peptide, an aromatase inhibitor, a 17 β -hydroxysteroid dehydrogenase inhibitor, an adrenal androgen production inhibitor, a kinase inhibitor, a drug for hormone therapy such as an estrogen (e.g., DSB, EMP, etc.), an antiandrogen (e.g., CMA, etc.), a drug that inhibits a cell growth factor or its receptor, and the like.

In the case of breast cancer, the compound of the present invention is used in combination with a GnRH super-agonist, an antiestrogen, a chemotherapeutic agent (e.g., cyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C, mitoxantrone, etc.), a GnRH antagonistic peptide, an aromatase inhibitor, an adrenoandrogen production inhibitor, a kinase inhibitor, a drug for hormone therapy such as an antiestrogen (e.g., tamoxifen, etc.), a progestin (e.g., MPA, etc.), an androgen, an estrogen, a drug for inhibiting a cell growth factor or its receptor, and the like.

In the case of digestive system cancer, the compound of the present invention is used in combination with a chemotherapeutic agent (e.g., cyclophosphamide, 5-FU, UFT, methotrexate, levofolinic acid, gemcitabine, doxorubicin, mitomycin C, mitoxantrone, etc.), a microtubule inhibitor (e.g., vincristine, paclitaxel, etc.), a platinum-containing drug such as cisplatin, etc., a topoisomerase inhibitor (e.g., irinotecan, etoposide, etc.), a COX-2 inhibitor, a kinase inhibitor, a drug that inhibits a cell growth factor or its receptor, etc.

In the case of lung cancer, the compound of the present invention is used in combination with a chemotherapeutic agent (e.g., cyclophosphamide, 5-FU, UFT, methotrexate, adriamycin, mitomycin C, mitoxantrone, etc.), a microtubule inhibitor (e.g., vincristine, taxol, etc.), a palladium-containing drug such as cisplatin, etc., a topoisomerase inhibitor (e.g., irinotecan, etoposide, etc.), a kinase inhibitor, a drug that inhibits a cell growth factor or its receptor, etc.

Small molecule second active agents may also be used to mitigate side effects associated with administration of the compounds of the present invention. However, as with some macromolecules, most provide a synergistic effect when administered with (e.g., before, after, or simultaneously with) a compound of the invention. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

Examples of the anticancer agent include alkylating agents, antitumor agents, antimetabolites (for example, folic acid analogs, purine analogs, adenosine analogs, pyrimidine analogs, and substituted ureas), platinum coordination complexes, topoisomerase II inhibitors, and radiation, but are not limited thereto.

Specific anti-cancer agents include, but are not limited to, the following: acivicin; aclarubicin; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; altretamine; an apramycin; amethone acetate; amsacrine; anastrozole; an atramycin; asparaginase enzyme; a triptyline; azacitidine; azatipipide; (ii) azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; bisnefaede dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; capecitabine; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib (COX-2 inhibitor); chlorambucil; a sirolimus; cisplatin; cladribine; clariatol mesylate; cyclophosphamide; cytarabine; (ii) azotemidine; actinomycin D; daunorubicin hydrochloride; decitabine; (ii) dexomaplatin; tizanoguanine; dizyguanine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotasndrosterone propionate; daptomycin; edatrexae; eflornithine hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; erlotinib; isosbacin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; chloroacetyl pyrimethanil (etoprine); fadrozole hydrochloride; fazarabine; a retinoid amine; uridine; fludarabine phosphate; a pentafluorouracil; (iii) flucitabine; a phosphorus quinolone; fostricin sodium (fosstricin sodium); gefitinib; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; ifosfamide; ilofovir dipivoxil; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium (lomerexol sodium); lomustine; losoxantrone hydrochloride; (ii) maxolone; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; metoprolol; meurtripypde; mitodomide; mitecaxin (mitocarcin); mitorubin; mitoxantrone; mitomacin; mitomycin; mitospirane culturing; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noramycin; ormaplatin; oshuzuren; paclitaxel; a pemetrexed; a pelithromycin; pemetrexed (pemetrexed); nemadectin; pellomycin sulfate; cultivating phosphoramide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin (plicamycin); pramipexole; porfimer sodium; a podomycin; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; (ii) lybodenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium phosphonoaspartate (sparfosate sodium); a sparamycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; streptonigrin; a streptozocin; a sulfochlorophenylurea; a talithromycin; sodium tegaserod (tecogalan sodium); taxotere; tegafur; tiloxanthraquinone hydrochloride; temoporfin; (ii) teniposide; tioxilong; cheese in the testis; (ii) a thiopurine; guanidine mercaptide (thioguanidine); thioguanine; thiotepa; thiazolfurin; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; tritrazol glucuronic acid; triptorelin; tobramzole hydrochloride; uracil mustard; uretipi; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vincristine sulfate; vinorelbine tartrate; vinblastine sulfate; vinzolidine sulfate; (ii) vorozole; zeniplatin; 1, neat setastine; and zorubicin hydrochloride.

Other anticancer drugs include, but are not limited to, 20-epitope-1, 25 dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, doxorubicin, acylfulvene (acetylfulvene), adenosylpentanol, adolesin, aldesleukin, ALL-TK antagonists, altretamine, ammostemin, 2, 4-dichlorophenoxyacetic acid (amidodox), amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonists D, G, enrichine (antalixix), anti-dorsaligenin-1, anti-androgens, prostate cancer, anti-estrogen, anti-onconone, anti-oligonucleotide, alficellin glycinate (aphidicolin glycation), anticonvulsant gene modulators, depurination nucleic acids, ara-DL-arginine, tyrosine-arginine (folate-arginine, benzathine (benzathine, benzathine (benzathinine, ademetine, ademetin, ademet;combretastatin a 4; combretastatin analogs; cohn jiening (concanagenin); cladribine (crambescidin) 816; clinatot; clarthacin (cryptophycin) 8; a cladribine a derivative; curve A; cyclopentanoanthraquinones (cyclopentaanthraquinones); new clauparm (cycloplatam); daptomycin (cyclopycin); cytarabine octadecyl phosphate; a cytolytic factor; hexestrol phosphate; daclizumab; decitabine; dehydromembrane ecteinascidin B; deslorelin; dexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; diazaquinone; a sphingosine B; underpass (didox); diethyl norspermine; dihydro-5-azacytidine; 9-dihydrotaxol; oxamycin (dioxamycin); diphenylspiromustine; docetaxel; docosanol; dolasetron; a deoxyfluorouracil; doxorubicin; droloxifene; dronabinol; duocarmycin SA; drying in the sun; etokomustine; edifulin; epidolumab; eflornithine; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine analogue; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; a retinoid amine; filgrastim; finasteride; frataxinol (flavopiridol); flutemastine; froslet lauren (flashterone); fludarabine; fludoanuronicin hydrochloride; fowler; 2, fulvestrant; fostrexed; fotemustine; motesafine gadolinium (gadolinium texaphyrin); gallium nitrate; galocitabine; ganirelix; (ii) a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; haiss fam (hepsulfam); modulation of protein; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; iloperidone; ilofovir dipivoxil; ilomastat; the amount of imatinib (e.g.,) (ii) a Imiquimod; an immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; an interferon; interleukins; iodobenzylguanidine; indole doxorubicin; 4-sweet potato picrol; iprop; isradine; isofengazole (isobengazole); different from each otherMesorilin B, itasetron, Gelsepraline (jasplakinolide), Kahalalide (kahalalide) F, lamellarin-N triacetate, lanreotide, renomycin (leinamycin), lenetin, lentinan sulfate, leprotine (leptin), letrozole, leukemia inhibitory factor, leukocyte α interferon, leuprorelin + estrogen + progestin, leuprorelin, levamisole, linazole, linear polyamine analogs, lipophilic bis glycopeptide compounds, liscinonide (lissorlinide) 7, lobaplatin, guanidinium ethyl phosphoserine, lomethaxolone, lonidamine, lossoterelin, topotecan, delphacilantrine (lipocalin) texaphyrin, lyxaphyrin (lyxol) N, lipocaline (lipocaline) N-arginine, lipocaline (lipocaline) N-arginine, lipocaline (lipocaline) N-beta-neomycin, lipocaline (lipocaline, lipocaline (lipocaline) N-substituted lipocaline, lipocaline (lipocaline, beta-N-O6-benzylguanosine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; mouth pieceTaking cytokine inducer (oral cytokine inducer); ormaplatin; an oxateclone; oxaliplatin; oxauromycin (oxaauromycin); paclitaxel; a paclitaxel analog; a paclitaxel derivative; palatamine (palauaiamine); palmitoyl tuberculin; pamidronic acid; panaxytriol; panomifen; paracocculin; pazeliptin; a pemetrexed; pedunculing; (iii) a sodium pentosan polysulfate; pentostatin; pentaerythrityl; perfluorobromoalkane; cultivating phosphoramide; perilla alcohol; a phenylazeocin; phenyl acetate; a phosphatase inhibitor; carrying out streptolysin; pilocarpine hydrochloride; pirarubicin; pirtroxine; pascaling A; pascaling B; a pro-plasmodium activator inhibitor; a platinum complex; a platinum compound; platinum-triamine (platinum-triamine) complexes; porfimer sodium; a podomycin; prednisone; propylbisacridone (propyl bis-acridone); prostaglandin J2; a proteasome inhibitor; protein a-based immunomodulators; inhibitors of protein kinase C; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoline acridine; a pyridoxylated hemoglobin polyethylene glycol conjugate; a raf antagonist; raltitrexed; ramosetron; a ras farnesyltransferase inhibitor; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated retetriptine (demethylated); rhenium etidronate [186Re ]](ii) a A tuberculin; a ribozyme; RII isotretinoin amide (retinamide); rohituine (rohitukine); romurtide; loquimex; rubiginone B1; labox (ruboxyl); safrog; saintopin (saintopin); SarCNU; sacochotrol (sarcophylol) A; sargrastim; sdi1 mimetics; semustine; an aging source inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; sisofilan; sobuconazole; sodium boron carbonate; sodium phenylacetate; semvallar (solvol); a growth regulator binding protein; sonaming; phosphono-winteric acid; spicamycin D; spiromustine; spleen pentapeptide; spongistatin 1; shark amine; stilinamide (stiiamide); a matriptase inhibitor; inosine sulfinyl (sulfinosine); a superactive vasoactive intestinal peptide antagonist; (ii) surfasta; shulaming; swainsonine; tamustine; tamoxifenMethiodide (tamoxifen methiodide); taulomustine; tazarotene; sodium tegaserod (tecogalan sodium); tegafur; tellerapalym (tellurophynium); a telomerase inhibitor; temoporfin; (ii) teniposide; tetrachloroundecane (tetrachlorodecaoxide); tetrazomine (tetrazomine); (ii) pinosylvine; thiocoraline (thiocoraline); thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor antagonist; thymotreonam; thyroid stimulating hormone; ethyl tin primary purpurin; tirapazamine; cyclopentadienyl titanium dichloride (titanocene bichloride); daughtenzein (topstein); toremifene; a translation inhibitor; tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; a tyrosine phosphorylation inhibitor; an UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; a urokinase receptor antagonist; vapreotide; varolin (variolin) B; veramine lock (velaresol); veratramine (veramine); waters (verdins); verteporfin; vinorelbine; venzatine (vinxaline); integrin antagonists (vitaxin); (ii) vorozole; zanoteron; zeniplatin; benzal dimension (zilascorb); and a nettastatin analog.

Specific second active agents include, but are not limited to, the following: rituximab; oblimersenRemicade (remicade); docetaxel; celecoxib; melphalan; dexamethasoneA steroid; gemcitabine; cisplatin; temozolomide; etoposide; cyclophosphamide; temodar (temodar); carboplatin; procarbazine; gliadel (gliadel); tamoxifen; topotecan; methotrexate;texol; docetaxel; a pentafluorouracil; leucovorin; yiRitegam, HiratA, CPT-11, interferon α, PEG interferon α (e.g., PEGINTRON-A), capecitabine, cisplatin, thiotepA, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, pamitellarite (palmitronate), bixin (biaxin), busulfan, prednisone, bisphosphate, arsenic trioxide, vincristine, doxorubicin, CimetrA, and paclitaxelPaclitaxel; more coxib; doxorubicin; estramustine sodium phosphateSulindac and etoposide.

In certain embodiments, the second active agent is etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin, carboplatin, pemetrexed, methotrexate, Ara-C, 5-FU, Woltmann-ing, gemcitabine, geldanamycin, or a combination of one or more thereof.

In another embodiment, the second active agent is an adjuvant therapy agent (supportive care agent). An example of the adjuvant therapy agent is emetic. Specific antiemetics include phenothiazine, butyrophenone, benzodiazepine, corticosteroid, serotonin antagonist, cannabinoid and NK₁Receptor antagonists, but are not limited thereto. Examples of phenothiazine antiemetics include prochlorperazine and trimethobenzamide, but are not limited thereto. Examples of the butanolic acid phenolic ketone antiemetic include haloperidol, but are not limited thereto. Examples of benzodiazepine antiemetics include lorazepam, but are not limited thereto. Examples of corticosteroid antiemetics include dexamethasone, but are not limited thereto. Examples of serotonin antagonist antiemetics include, but are not limited to, ondansetron, granisetron, and dolasetron. Examples of cannabinoid antiemetics include, but are not limited to, dronabinol. NK₁Examples of receptor antagonists include, but are not limited to, aprepitant. The dose and administration of the antiemetic agent will depend on the agent to be treatedThe particular symptoms, the age and condition of the patient, and the severity of the side effects, can therefore be adjusted by those skilled in the art. Examples of dosages and usage can be found, for example, in The Physician's Desk Reference.

The invention also comprises the combination of the components of the medicine in a kit form. The kit comprises more than two medicines: the compounds of the present invention and the second active agents described in the present application. Kits typically comprise containers such as vials or foil packets for filling the components, but the components may be contained in a single, undivided container. The kit form is particularly advantageous when the ingredients are preferably administered in different dosage forms (e.g., oral or non-oral) or are administered at different dosing intervals, or when the prescribing physician requires titration of the ingredients of the combination.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). The blister pack is preferably generally formed from a sheet of relatively rigid material wrapped in a foil of transparent plastics material. In the packaging process, recesses are formed in the plastic foil. The recess is of the size and shape of the tablet or capsule to be packaged. Next, the tablet or capsule is placed in the recess, and the plastic foil is sealed with the rigid sheet on the foil surface on the opposite side of the direction in which the recess is formed. As a result, the tablet or capsule is sealed in the recess between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the sheet can be taken out from the blister pack by applying pressure to the recesses by hand to form openings in the sheet at the positions of the recesses. Subsequently, the tablet or capsule can be taken out through the opening.

Exemplary methods of combination therapy

In certain embodiments, the methods for the present application comprise administering a compound of the present invention in combination with one or more second active agents, and/or in combination with radiotherapy or surgery. Administration of the compound of the invention and the second active agent to the patient may occur simultaneously or sequentially by the same or different routes of administration. The appropriateness of a particular route of administration for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without decomposition prior to entering the bloodstream) and the disease being treated. The recommended route of administration for the second active agent is well known to those skilled in the art. For example, see Physicians' Desk Reference.

In one embodiment, the second active agent is administered in an amount of about 1 to about 1,000mg, about 5 to about 500mg, about 10 to about 375mg or about 50 to about 200mg, 1 or 2 intravenous or subcutaneous injections per day. In one embodiment, the second active agent is rituximab, oblimersenGM-CSF, G-CSF, EPO, taxotere, irathimazone, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitors, IL2, IL8, IL18, IFN, cytarabine, vinorelbine, or a combination thereof. In certain embodiments, the second active agent is etoposide, daunomycin, defensin D, mitomycin C, cisplatin, carboplatin, pemetrexed, aminopterin, Ara-C, 5-FU, Woltmann-ing, geldanamycin, gemcitabine, or a combination thereof.

In another embodiment, provided herein is a method of treating, preventing and/or managing a hematologic malignancy, which comprises combining a compound of the invention with conventional therapies including, but not limited to, surgery, immunotherapy, biological therapy, radiotherapy and other non-drug therapies currently used to treat, prevent or manage cancer. Without being bound by theory, it is believed that the compounds of the present invention may provide additive or synergistic effects when given concurrently with conventional therapy.

In certain embodiments, the second active agent is administered with or delayed from the compound of the invention by approximately 1 to 50 hours. In certain embodiments, the administration of the second active agent is delayed by approximately 1 to 50 hours after the administration of the compound of the invention. In another embodiment, the compound of the invention is administered after the first active agent, with a delay of approximately 1 to 50 hours. In some embodiments, the delay is preferably 24 hours.

In one embodiment, the compounds of the present invention may be administered alone or in combination with a second active agent as described herein in an amount of about 1mg to about 5000mg per day, before, during or after conventional therapy.

In another embodiment, a method for the present application comprises: a) administering to a patient in need thereof a 1 day dose of about 1mg to 5000mg of a compound of the invention; b) administering a therapeutically effective amount of a second active agent, such as an adjunctive therapy agent.

In one embodiment, the 2 nd agent is an alkylating agent. In another other embodiment, the alkylating agent is an alkyl sulfonate and the cancer treated is typically leukemia or lymphoma. In another other embodiment, the alkylsulfonate is busulfan. In another other embodiment, the alkyl sulfonate is busulfan, and the therapeutically effective amount is typically a 1 day dose of at least 1 mg. In another other embodiment, the alkyl sulfonate is busulfan, and the therapeutically effective amount is typically a 1 day oral dose of about 2mg to 8 mg. In another other embodiment, the alkyl sulfonate is busulfan, and the therapeutically effective amount is typically a 1 day oral dose of about 1mg to about 3 mg.

In another other embodiment, the alkylating agent is a nitrogen mustard and the cancer treated is typically bladder cancer, breast cancer, hodgkin's disease, leukemia, lung cancer, melanoma, ovarian cancer, or testicular cancer. In another other embodiment, the nitrogen mustard is chlorambucil. In yet other embodiments, the nitrogen mustard is chlorambucil and the therapeutically effective amount is typically at least 0.1 mg/kg. In yet other embodiments, the nitrogen mustard is chlorambucil and the therapeutically effective amount is typically a 1 day oral dose of about 0.1mg/kg to about 0.2mg/kg for 3 to 6 weeks. In another other embodiment, the nitrogen mustard is chlorambucil and the therapeutically effective amount is typically every 3 to 4 weeksDosage of 0.4 mg/kg. In another other embodiment, the nitrogen mustard is cyclophosphamide. In yet other embodiments, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is typically an intravenous dose of at least 10 mg/kg. In yet other embodiments, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is an intravenous dose of about 10mg/kg to 15mg/kg, typically every 7 to 10 days. In yet other embodiments, the nitrogen mustard is cyclophosphamide and the therapeutically effective amount is typically a 1 day oral dose of about 1mg/kg to about 5 mg/kg. In another other embodiment, the nitrogen mustard is melphalan. In yet other embodiments, the nitrogen mustard is melphalan, and the therapeutically effective amount is typically a 1 day oral dose of at least 2 mg. In yet other embodiments, the nitrogen mustard is melphalan, and the therapeutically effective amount is typically a 1 day oral dose of 6mg for 2 to 3 weeks, discontinuing melphalan for 2 to 4 weeks, followed by a 1 day oral dose of about 2mg to about 4 mg. In yet other embodiments, the nitrogen mustard is melphalan, and the therapeutically effective amount is typically 10mg/m for 4 days every 4 to 6 weeks²(body surface area) 1 day oral dose.

In another other embodiment, the alkylating agent is nitrosourea and the cancer treated is typically brain tumor, colorectal cancer, hodgkin's disease, liver cancer, lung cancer, lymphoma or melanoma. In another other embodiment, the nitrosourea is carmustine. In yet other embodiments, the nitrosourea is carmustine, and the therapeutically effective amount is typically at least 150mg/m². In yet other embodiments, the nitrosourea is carmustine and the therapeutically effective amount is typically about 150mg/m every 6 to 8 weeks²～200mg/m²Intravenous dosage of (a).

In another other embodiment, the alkylating agent is a triazene and the cancer treated is typically hodgkin's disease, melanoma, ganglion cell tumor, or soft tissue sarcoma. In another other embodiment, the triazene is azoenamide. In yet other embodiments, the triazene is azoniazole, and the therapeutically effective amount is typically a 1 day intravenous dose of about 2.0mg/kg to about 4.5mg/kg for 10 days every 4 weeks. In another other embodiment, the triazene is azotemidine, aThe therapeutically effective amount is typically about 250mg/m for 5 days every 3 weeks²1 day intravenous dose. In yet other embodiments, the triazene is azoenamide and the therapeutically effective amount is typically 375mg/m every 16 days²Intravenous dosage of (a). In yet other embodiments, the triazene is azotemidine and the therapeutically effective amount is typically about 150mg/m for 5 days every 4 weeks²Intravenous dosage of (a).

In yet other embodiments, the agent of claim 2 is an antitumor antibiotic and the cancer treated is typically bladder cancer, breast cancer, cervical cancer, head and neck cancer, hodgkin's disease, leukemia, multiple myeloma, ganglion cell tumor, ovarian cancer, sarcoma, skin cancer, testicular cancer, or thyroid cancer. In another other embodiment, the antibiotic is bleomycin. In yet other embodiments, the antibiotic is bleomycin and the therapeutically effective amount is typically at least 10 units/m². In yet other embodiments, the antibiotic is bleomycin and the therapeutically effective amount is typically about 10 units/m 1 or 2 times per week²About 20 units/m²Intravenous, subcutaneous or intramuscular dosage. In another other embodiment, the antibiotic is actinomycin D. In yet other embodiments, the antibiotic is actinomycin D and the therapeutically effective amount is typically at least 0.01 mg/kg. In another other embodiment, the antibiotic is actinomycin D and the therapeutically effective amount is typically a 1 day intravenous dose of about 0.010mg/kg to about 0.015mg/kg for 5 days every 3 weeks. In another other embodiment, the antibiotic is actinomycin D and the therapeutically effective amount is typically 2mg/m every 3 or 4 weeks²Intravenous dosage of (a). In another other embodiment, the antibiotic is daunorubicin. In yet other embodiments, the antibiotic is daunorubicin and the therapeutically effective amount is typically at least 30mg/m². In yet other embodiments, the antibiotic is daunorubicin, and the therapeutically effective amount is typically about 30mg/m²About 45mg/m²The 1 day intravenous dose of (a) was continued for 3 days. In yet another embodiment, the antibiotic is a liposomal formulation of daunorubicin, and the therapeutically effective amount is typically 40mg/m every 2 weeks²Intravenous dosage of (a). In another other embodiment, the antibiotic is doxorubicinComparing with star. In yet other embodiments, the antibiotic is doxorubicin and the therapeutically effective amount is typically at least 15mg/m². In yet other embodiments, the antibiotic is doxorubicin and the therapeutically effective amount is typically about 60mg/m every 3 weeks²About 90mg/m²Intravenous dosage of (a). In yet other embodiments, the antibiotic is doxorubicin, and the therapeutically effective amount is typically about 15mg/m²About 20mg/m²Weekly intravenous doses of (c). In yet other embodiments, the antibiotic is doxorubicin and the therapeutically effective amount is typically comprised of 30mg/m²For 2 weeks followed by a 2 week cycle without doxorubicin administration.

In another other embodiment, the agent of claim 2 is an antimetabolite. In another other embodiment, the antimetabolite is a folic acid analog and the cancer treated is typically breast cancer, head and neck cancer, leukemia, lung cancer, non-hodgkin's lymphoma or osteosarcoma. In another other embodiment, the folic acid analog is methotrexate. In another other embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is typically at least 2.5 mg. In another other embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is typically a 1 day oral dose of about 2.5mg to about 5 mg. In yet other embodiments, the folic acid analog is methotrexate and the therapeutically effective amount is typically about 5mg/m²About 25mg/m²2 doses per week (twice-weekly dose). In another other embodiment, the folic acid analog is methotrexate and the therapeutically effective amount is typically 50mg/m every 2 to 3 weeks²Weekly intravenous doses of (c). In another other embodiment, the folic acid analog is pemetrexed. In another other embodiment, the folic acid analog is pemetrexed, and the therapeutically effective amount is typically at least 300mg/m². In another other embodiment, the folic acid analog is pemetrexed and the therapeutically effective amount is typically about 300mg/m every 2 or 3 weeks²About 600mg/m²Intravenous dosage of (a). In another other embodiment, the folic acid analog is pemetrexed and the therapeutically effective amount is typically 500mg/m every 3 weeks²Intravenous dosage of (a).

In another other embodiment, the antimetabolite is a purine analog and the cancer treated is typically colorectal cancer, leukemia, or bone marrow cancer. In another other embodiment, the purine analog is a mercaptopurine. In yet other embodiments, the purine analog is mercaptopurine and the therapeutically effective amount is typically at least 1.5 mg/kg. In yet other embodiments, the purine analog is mercaptopurine and the therapeutically effective amount is generally a 1 day oral dose of about 1.5mg/kg to about 5 mg/kg. In another other embodiment, the purine analog is thioguanine (thioguanidine). In yet other embodiments, the purine analog is thioguanine and the therapeutically effective amount is typically at least 2 mg/kg. In yet other embodiments, the purine analog is thioguanine and the therapeutically effective amount is typically a 1 day oral dose of about 2mg/kg to about 3 mg/kg.

In another other embodiment, the antimetabolite is an adenosine analog and the cancer treated is typically leukemia or lymphoma. In another other embodiment, the adenosine analog is cladribine. In another other embodiment, the adenosine analog is cladribine and the therapeutically effective amount is typically at least 0.09 mg/kg. In another other embodiment, the adenosine analog is cladribine and the therapeutically effective amount is typically a 1 day intravenous dose of 0.09mg/kg for 7 days. In yet other embodiments, the adenosine analog is cladribine and the therapeutically effective amount is typically 4mg/m²The 1 day intravenous dose of (a) was continued for 7 days. In another other embodiment, the adenosine analog is pentostatin. In yet another embodiment, the adenosine analog is pentostatin and the therapeutically effective amount is typically 4mg/m². In yet another embodiment, the adenosine analogue is pentostatin and the therapeutically effective amount is typically 4mg/m every other week²Intravenous dosage of (a). In another other embodiment, the adenosine analogue is pentostatin and the therapeutically effective amount is typically 4mg/m every 3 weeks²Intravenous dosage of (a).

In another other embodiment, the antimetabolite is a pyrimidine analog and the cancer treated is typically bladder cancer, breast cancer, colorectal cancer, esophageal cancerHead and neck cancer, leukemia, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, skin cancer or gastric cancer. In another other embodiment, the pyrimidine analog is cytarabine. In another other embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is typically at least 100mg/m². In another other embodiment, the pyrimidine analog is cytarabine and the therapeutically effective amount is typically 100mg/m²The 1 day intravenous dose of (a) was continued for 7 days. In another other embodiment, the pyrimidine analog is capecitabine. In another other embodiment, the pyrimidine analog is capecitabine and the therapeutically effective amount is typically at least 2000mg/m²1 day dose of (c). In another other embodiment, the pyrimidine analog is capecitabine, and the therapeutically effective amount is typically about 1200mg/m²About 1300mg/m²2 oral doses (twice-daily oral dose) for 14 days. In another other embodiment, the pyrimidine analog is capecitabine, and the therapeutically effective amount is typically about 1250mg/m²For a three week cycle of 14 days followed by rest for one week for 2 doses on day 1. In another other embodiment, the pyrimidine analog is fluorouracil. In another other embodiment, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is typically at least 10 mg/kg. In yet another example, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is typically about 300mg/m²About 500mg/m²The 1 day intravenous dose of (a) is continued for at least 3 days. In another example, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is typically a 1 day intravenous dose of 12mg/kg for 3-5 days. In yet other embodiments, the pyrimidine analog is fluorouracil, and the therapeutically effective amount is generally a weekly intravenous dose of about 10mg/kg to about 15 mg/kg.

In another other embodiment, the antimetabolite is a substituted urea and the cancer treated is typically head and neck cancer, leukemia, melanoma, or ovarian cancer. In another other embodiment, the substituted urea is hydroxyurea. In yet other embodiments, the substituted urea is hydroxyurea and the therapeutically effective amount is typically at least 20 mg/kg. In yet other embodiments, where the substituted urea is hydroxyurea, the therapeutically effective amount is typically an oral dose of 80mg/kg every 3 days. In yet other embodiments, the substituted urea is hydroxyurea and the therapeutically effective amount is typically a 1 day oral dose of about 20mg/kg to about 30 mg/kg.

In yet other embodiments, the agent of claim 2 is a platinum coordination complex and the cancer treated is typically bladder cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, leukemia, lung cancer, lymphoma, ovarian cancer, sarcoma, testicular cancer, or uterine cancer. In another other embodiment, the platinum coordination complex is carboplatin. In yet other embodiments, the platinum coordination complex is carboplatin and the therapeutically effective amount is typically at least 300mg/m². In yet other embodiments, the platinum coordination complex is carboplatin and the therapeutically effective amount is typically at least 300mg/m every 4 weeks². In yet other embodiments, the platinum coordination complex is carboplatin and the therapeutically effective amount is typically 300mg/m every 4 weeks². In yet other embodiments, the platinum coordination complex is carboplatin and the therapeutically effective amount is typically at least 360mg/m every 4 weeks². In another other embodiment, the platinum coordination complex is cisplatin. In yet other embodiments, the platinum coordination complex is cisplatin and the therapeutically effective amount is typically at least 20mg/m². In another embodiment, the platinum coordination complex is cisplatin and the therapeutically effective amount is generally 20mg/m for 4-5 days every 3-4 weeks²1 day intravenous dose. In yet other embodiments, the platinum coordination complex is cisplatin and the therapeutically effective amount is typically 50mg/m every 3 weeks²Intravenous dosage of (a). In another other embodiment, the platinum coordination complex is oxaliplatin. In another other embodiment, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is typically at least 75mg/m². In yet other embodiments, the platinum coordination complex is oxaliplatin, typically in a therapeutically effective amount of about 50mg/m²About 100mg/m². In yet other embodiments, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is typically about 50mg/m every 2 weeks²About 100mg/m²IV injection of (3). In yet other embodiments, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is typically about 80mg/m every 2 weeks²About 90mg/m²IV injection of (3). In another other embodiment, the platinum coordination complex is oxaliplatin, and the therapeutically effective amount is typically 85mg/m every 2 weeks²IV injection for 2 hours.

In yet other embodiments, the agent 2 is a topoisomerase II inhibitor and the cancer treated is typically hodgkin's disease, leukemia, small cell lung cancer, sarcoma, or testicular cancer. In another other embodiment, the topoisomerase II inhibitor is etoposide. In yet other embodiments, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is typically at least 35mg/m². In yet other embodiments, the topoisomerase II inhibitor is etoposide, and the therapeutically effective amount is typically about 50mg/m²About 100mg/m². In another other embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is about 35mg/m at least 3 times a day 1 over a 5 day period of 3 or 4 weeks, typically²About 50mg/m²Intravenous dosage of (a). In another other embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is typically about 50mg/m at least 3 times per 1 day for a 5 day period of 3 or 4 weeks²About 100mg/m²Intravenous dosage of (a). In another other embodiment, the topoisomerase II inhibitor is etoposide and the therapeutically effective amount is typically at least 3 times 100mg/m every 3 or 4 weeks for 1 day during a 5 day period²The oral dosage of (1). In another other embodiment, the topoisomerase II inhibitor is teniposide. In yet other embodiments, the topoisomerase II inhibitor is teniposide and the therapeutically effective amount is typically at least 20mg/m². In yet other embodiments, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is typically 100mg/m²1 dose per week. In yet other embodiments, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is typically 100mg/m²2 doses per week (twice-weekly dose). In yet other embodiments, the topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is typically about 20mg/m²About 60mg/m²The 1 day dose of (c) was continued for 5 days. In yet other embodimentsThe topoisomerase II inhibitor is teniposide, and the therapeutically effective amount is typically about 80mg/m²About 90mg/m²The 1 day dose of (c) was continued for 5 days.

The mode of administration of the compound of the present invention and the concomitant drug are not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration modes include: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and an accompanying drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and an accompanying drug by the same route, (3) continuous and intermittent administration of two preparations obtained by separately formulating the compound of the present invention and an accompanying drug by the same route, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and an accompanying drug by different routes, (5) continuous and intermittent administration of two preparations obtained by separately formulating the compound of the present invention and an accompanying drug by different routes (for example, administration of the compound of the present invention followed by administration of the accompanying drug, or vice versa), and the like.

When the compound of the present invention is used in combination with more than one 2 nd agent (second active agent), the compounds may be administered sequentially or simultaneously by any convenient route.

The combinations referred to above are conveniently presented for use in the form of a pharmaceutical formulation and thus the use of a pharmaceutical formulation comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient is an add-on to the present invention. The individual components of that combination may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations.

When the compounds of the present invention are used in combination with a 2 nd therapeutic agent that exhibits activity against the same disease, the dose of each compound may be different from the dose when the compound is used alone. Appropriate dosages can be readily appreciated by those skilled in the art.

Similarly, when a compound of the invention is used in combination with a 2 nd therapeutic agent that exhibits activity against the same disease, the dosage of each compound may be different from that when the compound is used alone, and the appropriate dosage can be determined by one skilled in the art, as will be apparent to those skilled in the art.

Preferred unit dosage forms are those containing a 1 day effective dose of the active ingredients specified above in this application, or an appropriate fraction thereof. For example, the recommended 1-day dose of a compound of the invention is preferably about 1mg to 5000mg for 1 day, more preferably 10mg to 500mg for 1 day. As described above, the dose varies depending on individual patients, and thus is not limited thereto.

The subject to which the compound of the present invention or the pharmaceutical composition containing the same is administered is preferably a mammalian subject including a human. Among them, mammals diagnosed with cancer are preferred. More preferably a mammal diagnosed with a PGE 2-related cancer. PGE 2-related cancers include brain tumors, osteosarcomas, epithelial cell-derived neoplasms (epithelial cancers), such as basal cell carcinoma, adenocarcinoma, digestive system cancers (e.g., lip cancer, oral cancer, esophageal cancer, intestinal cancer, colon cancer, and gastric cancer), liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancers (e.g., squamous cell and basal cell carcinomas), prostate cancer, renal cell carcinoma, and other well-known cancers that have an effect on epithelial cells in vivo. The mammal is preferably a human, more preferably a human diagnosed with a cancer selected from at least one of digestive system cancer, prostate cancer, lung cancer, and breast cancer.

The invention includes methods of reducing cancer cells by contacting the cancer cells with a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof. Preferred embodiments of the compounds of the present invention are the same as described above. The method for reducing cancer cells by contacting cancer cells with a compound of the general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof is selected depending on the type of cancer or the like, and typically can be carried out by oral administration or non-oral administration of the aforementioned dose of the compound represented by the general formula (I), (II), (III) or (IV). A second active agent can be used in the methods of the invention.

Examples

Example 1(EP4 receptor-selective antagonist Compound A: 4- ((1S) -1- { [ 5-chloro-2- (4-fluorophenoxy) benzoyl ] amino } ethyl) benzoic acid)

Tumors were generated in the stomach of K19-Wnt1/C2mE mice (Gastroenterology Volume 131, Pages 1086-. In human gastric cancer patients, Wnt upregulation can be observed at 30% to 50% and COX-2 induction can be observed at more than 70%. Therefore, from the viewpoint of molecular mechanism, K19-Wnt1/C2mE was used as a mouse model for inferring human gastric Cancer (Nature Review Cancer, Volume 7, Pages 645-.

Experiments were performed using 5 spontaneous gastric cancer model mice 50 weeks old (K19-Wnt1/C2mE mice). Mice develop large tumors at 50 weeks of age, and the tumor size can be determined by X-ray CT. Tumor sizes were determined before and after dosing with X-ray CT at weeks 1, 2 and 3 and compared. Compound A was administered continuously at a dose of 100mg/kg 2 times 1 day over a 3 week period. Methylcellulose is used as the vehicle. In particular, in two individuals with an oversized tumor formed prior to dosing, a significant reduction in tumor size was observed in the first week (see figure 1). As illustrated in FIG. 1, the mean area of the tumor was about 1500 to about 5000mm in pre-dosed mice²In contrast, after 3 weeks of treatment, the average area was greatly reduced to about 300 to about 1100mm²Range, clearly indicates tumor shrinkage by compound a. At 3 weeks after administration, in 5 mice administered with the compound, the effectiveness was confirmed by almost complete disappearance of tumor tissue in CT images. As clearly shown in fig. 2, it was confirmed that the tumor was effectively shrunk by administration of compound a, compared to 55-60 weeks old K19-Wnt1/C2mE mice (n ═ 7) which were not treated with any compound (refer to fig. 2). In other words, as shown in the figure2, tumors were greatly reduced by administration of EP4 receptor antagonists. In histological analysis of the ex vivo tissue after treatment, the disappearance of atactic glandular branches in the tumor epithelium was visually observed.

In the graph of fig. 2, the vertical axis represents the relative tumor volume, and the "EP inhibitor" refers to the compound a-administered group.

Example 2(EP4 receptor-selective antagonist Compound B4- [ (1S) -1- { [ 5-chloro-2- (3-fluorophenoxy) pyridin-3-yl ] carbonyl } amino) ethyl ] benzoic acid)

Experiments were performed using 6 gastric cancer model mice (K19-Wnt1/C2mE mice) aged 46 to 68 weeks. Compound B was administered continuously 1 day 1 time during 5 weeks at doses of 3mg/kg (n-2), 30mg/kg (n-2) and vehicle control (n-2). The tumor size was measured by the same method as in example 1. It was confirmed by X-ray CT scan that in both vehicle control groups, the tumor size increased in a time-dependent manner during the experiment. On the other hand, the tumor size was decreased in a dose-dependent manner in the compound B-administered group, and an effective decrease in tumor size was observed in the group administered at a dose of 3mg/kg (refer to fig. 3). The values of the mean tumor area after treatment versus the tumor area value before treatment (0w) set to 100 are shown over time in fig. 3. Solid (solid) quadrangles (■) and solid diamonds (□) represent control model mice. The dashed triangles (. tangle-solidup.) and dashed crosses (X) indicate model mice administered compound B at a dose of 3mg/kg, respectively. Filled asterisks and filled circles (●) indicate model mice administered compound B at a dose of 30mg/kg, respectively. Although the tumor size increased in the vehicle-administered group, the tumor size decreased greatly at any dose in the compound B-administered group. Also, significant shrinkage of tumor lesions was also observed at necropsy compared to vehicle control group. Therefore, it was confirmed that the tumor size was greatly reduced in the compound B-administered group compared to the vehicle group.

Example 3 (Compound C3- [2- (4- { 2-Ethyl-4, 6-dimethyl-1H-imidazo [4, 5-C ] pyridin-1-yl } phenyl) ethyl ] -1- [ (4-methylbenzene) sulfonyl ] urea)

An experiment was performed by the same method as example 2, except that compound C was used instead of compound B. As a result, compound C also showed similar effects to compound B, confirming that the tumor size was greatly reduced compared to the vehicle-administered group.

Example 4

The change in tumor size was examined by treating compound A, B or C in a human prostate cancer xenograft animal model (tumor-bearing mice prepared by transplanting human prostate cancer cells into nude mice). In this experimental system, similar tumor shrinkage as previously described was observed in animals treated with compounds A, B and C.

Example 5

In a xenograft animal model of human breast cancer (tumor-bearing mice prepared by transplanting human breast cancer cells to nude mice), change in tumor size was examined by treatment with compound A, B or C. In this experimental system, similar tumor shrinkage as previously described was observed in animals treated with compounds A, B and C.

Example 6

The mouse colon cancer-derived cell line colon26 was subcutaneously transplanted into CD2F1 mice. (based on the method described in int.j. cancer, Volume 121, Pages 878-883, 2007, which model infers colon cancer production and growth from a molecular mechanism point of view.) if the average tumor weight reaches 100mg, compound B is administered with vehicle (n-10) at a dose of 30mg/kg for 1 day 1 (n-10), compound B, or compound C at a dose of 200mg/kg for 1 day 2 (n-10) over a 20 day period. Using the measured values, the tumor weight was calculated as (major axis) × (minor axis) 2 × 0.5. Fig. 4 shows the change in tumor size over time in each group. In fig. 4, the solid quadrangle (■), the solid triangle (a-solidup), and the solid circle (●) represent the vehicle (control group) -administered group, the compound B-administered group, and the compound C-administered group, respectively. A significant reduction in tumor size was observed in all groups administered compound compared to the change in tumor size in the vehicle group.

Example 7

In an experimental system using a xenograft animal model of human colon cancer (tumor-bearing mice prepared by transplanting human colon cancer cells to nude mice), similar tumor shrinkage as described above was observed in animals treated with compound A, B and C.

Example 8

Subcutaneous transplantation of mouse lung Cancer-derived cell line LL/2 into C57BL/6 mice (this model concludes lung Cancer development and growth, based on the method described in Cancer research, volume 58, Pages 2583, 2587, 1998). if the mean tumor weight reaches 100mg, compound B is administered 1 time (n-10) at a dose of 0.3mg/kg 1 day, compound B is administered 1 time (n-10), or compound C is administered 2 times (n-10) at a dose of 10mg/kg 1 day over a 25-day period²× 0.5.5 tumor weight was calculated, FIG. 5 shows the change in tumor size with time in each group, and in FIG. 5, solid quadrangles (■), solid triangles (▲) and solid circles (●) represent vehicle (control group) -administered group, compound B-administered group and compound C-administered group, respectively.

Example 9

In an experimental system using a xenograft animal model of human lung cancer (tumor-bearing mice prepared by xenografting human lung cancer cells into nude mice), similar tumor shrinkage as described above was observed in animals treated with compound A, B and C.

Finally, although examples of the antitumor effect (reduction of cancer tissue) of the compound of the present invention are described, the present invention is not limited to these examples. Thus, as previously described, it was observed that cancer was narrowed by the use of the compounds of the present invention in a PGE 2-associated cancer model. PGE 2-related cancers include brain tumors, osteosarcomas, epithelial cell-derived neoplasms (epithelial cancers), e.g., basal cell carcinoma, adenocarcinoma, digestive system cancers (e.g., lip cancer, oral cancer, esophageal cancer, intestinal cancer, colon cancer, and gastric cancer), liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancers (e.g., squamous cell and basal cell carcinoma), prostate cancer, renal cell carcinoma, and other well-known cancers that have an effect on epithelial cells in vivo.

Therefore, the therapeutic effect can be confirmed by detecting the change in tumor size in the aforementioned human cancer xenograft animal model (tumor-bearing mice prepared by transplanting the aforementioned human cancer cells into nude mice) treated with the compound of the present invention.

Claims

1. Use of 3- [2- (4- { 2-ethyl-4, 6-dimethyl-1H-imidazo [4, 5-c ] pyridin-1-yl } phenyl) ethyl ] -1- [ (4-methylbenzene) sulfonyl ] urea, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in reducing the relative tumor volume of cancerous tissue in a human or animal relative to a control,

wherein the cancer is at least one selected from the group consisting of digestive system cancer, prostate cancer, lung cancer, and breast cancer.

2. The use according to claim 1, wherein the cancer is digestive cancer or lung cancer.