JP2011522887A - Thiazole compounds and compositions and methods of use thereof - Google Patents

Abstract

ここで、R₁はアルキレン-R₅-R₆-R₂、-R₆-C(O)-フェニル、-R₆-フェニル、アルキル、アルケニル又はアルキニルからなる群から選択され、ここで、フェニルは、それぞれ独立に、ハロ、アルキル、CN又はNO₂から選択される１以上の基で置換されていてもよい、R₂は、ハロ、CN又はアルキルで１、２又は３つの位置で置換されていてもよいヘテロアリールであり、R₃は、それぞれ独立に、H、ハロ、CN及びNO_２からなる群から選択され、R₄及びR_５は、チオ、スルホニル又はスルフィニルからなる群から選択され及びR_６は、アルキレン又は結合手である。A suitable composition for administration to a patient comprising a) a compound represented by I or a pharmaceutically acceptable salt thereof and b) a pharmaceutically acceptable excipient.

Wherein R ₁ is selected from the group consisting of alkylene-R ₅ -R ₆ -R ₂ , -R ₆ -C (O) -phenyl, -R ₆ -phenyl, alkyl, alkenyl or alkynyl, wherein phenyl Each independently may be substituted with one or more groups selected from halo, alkyl, CN or NO ₂ , R ₂ is substituted at 1, 2 or 3 positions with halo, CN or alkyl R ₃ is independently selected from the group consisting of H, halo, CN and NO ₂ , and R ₄ and R ₅ are selected from the group consisting of thio, sulfonyl or sulfinyl. And R ₆ is alkylene or a bond.

Description

  Cancer is an important health problem around the world. The most frequently diagnosed cancers are colorectal cancer, lung cancer, breast cancer, prostate cancer, liver cancer, stomach cancer, esophageal cancer and kidney cancer. The majority of these cancers are diagnosed in the US population and account for over 90% of cancer-related deaths in the United States.

  For example, in adults, the most common type of kidney cancer is renal cell carcinoma, which begins with cells lining the tubules in the kidney. Children are more likely to develop a type of kidney called Wilms tumor. The American Cancer Society estimates that approximately 51,000 people in the United States are diagnosed with kidney cancer each year. According to the Mayo Clinic, the incidence of kidney cancer is increasing.

  In addition to the solid need for treatments that control or inhibit tumor cell proliferation (eg, kidney cancer growth), treatments that can increase the sensitivity of existing anti-cancer treatments to cancer cells (eg, tumor cells). There is a need for more. For example, various chemotherapies are useful for oncologists and generally reduce the rate of tumor progression. However, intrinsic or acquired tumor-mediated drug resistance represents a major clinical obstacle that can cause a tumor response not to be adequately delivered to the patient being treated.

  Since cytotoxic drugs have become the mainstay treatment for cancer and the oral and gastrointestinal mucosa are often severely damaged by cancer therapy, the management and associated actions of these drugs represent an important challenge for oncologists. Thus, there remains a need for drugs that can minimize such effects even when administered with drugs that minimize side effects and / or cytotoxic drugs.

  As disclosed herein, the present invention provides compounds and compositions. Further disclosed herein are methods of treating cancer (eg, kidney cancer) by administering the disclosed compound or composition to a patient in need thereof.

ここで、
R₁はアルキレン-R₅-R₆-R₂、-R₆-C(O)-フェニル、-R₆-フェニル、アルキル、アルケニル又はアルキニルからなる群から選択され、ここで、フェニルは、それぞれ独立に、ハロ、アルキル、CN又はNO₂から選択される１以上の基で置換されていてもよい、
R₂は、ハロ、CN又はアルキルで１、２又は３つの位置で置換されていてもよいヘテロアリールであり、
R₃は、それぞれ独立に、H、ハロ、CN及びNO_２からなる群から選択され、
R₄は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R_５は、チオ、スルホニル又はスルフィニルからなる群から選択され、及び
R_６は、アルキレン又は結合手である。 For example, provided herein is a composition suitable for administration to a patient. that is,
a) a compound of formula I or a pharmaceutically acceptable salt;
b) a pharmaceutically acceptable excipient.

here,
R ₁ is selected from the group consisting of alkylene-R ₅ -R ₆ -R ₂ , -R ₆ -C (O) -phenyl, -R ₆ -phenyl, alkyl, alkenyl or alkynyl, wherein phenyl is each Independently substituted with one or more groups selected from halo, alkyl, CN or NO ₂ ;
R ₂ is heteroaryl optionally substituted at 1, 2 or 3 positions with halo, CN or alkyl;
Each R ₃ is independently selected from the group consisting of H, halo, CN and NO ₂ ;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl, and
R ₆ is alkylene or a bond.

Examples of R ₂ include a bicyclic or monocyclic heteroaryl group. In one embodiment, R ₂ can be selected from the group consisting of benzothiazole, benzoxazole, isoquinoline and pyridine.

In other embodiments, for example, at least one R ₃ is NO ₂ and / or R ₁ is alkyl or -alkylene-phenyl. For example, R ₁ may be methylbenzene, optionally substituted at one position with halo, or R ₁ may be ethyl or methyl.
In certain embodiments, at least R ₃ is H.
In other embodiments, R ₆ is a bond. R ₅ may be S, for example.
In certain other embodiments, R ₄ is sulfonyl.

  The disclosed composition may comprise, for example, a chemotherapeutic agent selected from the group consisting of cisplatin, 5-fluorouracil and vinblastine.

  Also provided is a packaging material and a product comprising the pharmaceutical composition contained in the packaging material, wherein the packaging material is used alone or in combination with a chemotherapeutic agent to treat cancer and / or gastrointestinal symptoms. Including a label indicating that it can be used, the pharmaceutical composition comprises at least one compound of formula I as described above.

ここで、
Xは、O、NR'及びSから選択され、ここで、R'はH又はアルキルであり、
R₁は、-アルキレン-R₅-R₆-R₁₂、-R₆-C(O)-R₁₂、-R₆-R₁₂、アルキル、アルケニル又はアルキニルからなる群から選択され、
R₄は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R₅は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R₆は、アルケン又は単結合であり、
R₁₂は、ハロ、ヒドロキシ、メルカプト、ニトロ、ホルミル、ホルムアミド、カルボキシ、シアノ、アミノ、アミド、カルバモイル、スルファモイル、ウレイド、アルキル、アルケニル、アルキニル、アルコキシ、アルカノイル又はカルコキシカルボニルで、１、２又は３つの位置で置換されていてもよいアリール又はヘテロアリールであり、
R₃は、それぞれ独立に、H、ハロ、シアノ、ヒドロキシ、カルボキシ、アルキル、アルコキシ及びニトロからなる群から選択される。 Also provided herein is a cancer, eg, renal cancer, ovarian cancer, comprising administering an effective amount of at least one compound represented by Formula II, or a pharmaceutically acceptable salt thereof. Provided is a method of administering leukemia, lung cancer, bladder cancer, breast cancer, liver cancer or thyroid cancer to a patient in need thereof.

here,
X is selected from O, NR ′ and S, wherein R ′ is H or alkyl;
R ₁ is selected from the group consisting of -alkylene-R ₅ -R ₆ -R ₁₂ , -R ₆ -C (O) -R ₁₂ , -R ₆ -R ₁₂ , alkyl, alkenyl or alkynyl;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₆ is an alkene or a single bond,
R ₁₂ is halo, hydroxy, mercapto, nitro, formyl, formamide, carboxy, cyano, amino, amide, carbamoyl, sulfamoyl, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl or chalcoxycarbonyl, 1, 2 or 3 Aryl or heteroaryl optionally substituted at one position,
Each R ₃ is independently selected from the group consisting of H, halo, cyano, hydroxy, carboxy, alkyl, alkoxy and nitro.

R ₁₂ of formula II may be heteroaryl optionally substituted at 1, 2 or 3 positions, for example by halo, CN or alkyl, for example bicyclic or monocyclic heteroaryl. In one embodiment, for example, R ₁₂ can be selected from the group consisting of benzodiazole, benzoxazole, isoquinoline, and pyridine.

In other embodiments, at least one R ₃ is NO ₂ and / or R ₁ is alkyl or -alkylene-phenyl. In yet other embodiments, R ₁ may be methylbenzene optionally substituted at least one position by halo, or may be ethyl or methyl.

In one embodiment, at least one R ₃ is H. In other embodiments, R ₆ is a single bond. In one embodiment, R ₅ may be S and / or R ₄ may be sulfonyl.

  Such methods further comprise administering other chemotherapeutic agents such as cisplatin, 5-fluorouracil or vinblastine. For example, the chemotherapeutic agent and the compound of formula II may be administered together in the same dosage form, may be administered together in separate dosage forms, or may be administered simultaneously or at different times.

  In one embodiment, a method for improving the therapeutic effect of a chemotherapeutic agent is provided, comprising administering a compound of formula II described above to a patient in need thereof.

  Also provided is a method of inhibiting tumor growth comprising administering a compound of formula II to a patient in need thereof.

Detailed Description of the Invention

The disclosure of the present application is directed, in part, to compounds and compositions that inhibit tumor growth, eg, growth of tumor cells such as kidney tumor cells, methods of making and using them.
A. Terms and definitions

  Before further description of the invention, certain terms employed in the specification, examples and claims are collected here. These definitions should be interpreted and understood by one of ordinary skill in the art in view of other disclosures. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

  The term “therapeutic agent” refers to any chemical moiety that is approved in the art and is a physiologically, biologically or pharmacologically active substance that acts locally or systemically in a patient. . The therapeutic agents and what are called “drugs” are described in known literature such as Merck Index, Physicians Desk Reference, and Pharmacological Basis of Therapeutics, and are not limited to drugs, vitamins, minerals. Supplements, substances used in the treatment, prevention, diagnosis, recovery or alleviation of diseases, substances that affect the structure or function of the body or those that become biologically active or more active after they are placed in a physiological environment Includes drag.

  The term “therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and even humans due to pharmacologically active substances. The term thus means any substance used for diagnosis, recovery, alleviation, treatment or disease prevention in animals or humans or for the improvement of desirable physical or mental development and / or symptoms. The phrase “therapeutically effective amount” means the amount of a substance that produces some desired local or systemic effect with a reasonable benefit / risk rate applicable to any treatment. The therapeutically effective amount of such substances can be readily determined by one skilled in the art and will vary with the subject and the condition being treated, the weight and age of the patient, the severity of the condition, the method of administration, etc. Let's go. For example, certain compositions of the invention can be administered in sufficient amounts to provide a reasonable benefit / risk rate that can be applied to such treatment.

  The term “modulation” is art-recognized and refers to an upregulation (ie, activity or stimulation), downregulation (ie, inhibition or suppression) of a response, or a combination thereof or two separate.

  “Patient”, “subject” or “host” to be treated by the subject method means either a human or non-human animal.

  The term “treatment” is art-recognized and refers to treating and ameliorating at least one symptom of any symptom or condition.

  The term “alkyl” is art-recognized and includes saturated aliphatic groups including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Contains groups. In one embodiment, a straight chain or branched chain alkyl group has about 30 or fewer carbon atoms in its backbone (eg, a C1 to C30 straight chain, a C3 to C30 branched chain), or about 20 Having (for example, 1 to 6 carbon atoms). Similarly, cycloalkyls have about 3 to 10 carbon atoms in their ring structure, or contain about 5, 6 or 7 carbon atoms in the ring structure. The term “alkyl” is also defined to include halo-substituted alkyl.

  Furthermore, the term “alkyl” (or “lower alkyl”) includes “substituted alkyl”, which means an alkyl group having a substituent in which one or more carbon atoms of the hydrocarbon backbone are replaced. Such substituents are, for example, hydroxyl, carbonyl (eg carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (eg thioester, thioacetate or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amide, It may contain amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl or aromatic or heterocyclic aromatic groups. It will be appreciated by those skilled in the art that, if appropriate, substituted groups in the hydrocarbon chain may be substituted by themselves. For example, substituted alkyl substituents include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate) and silyl groups, and ether, alkylthio, carbonyl (ketone). Substituted and unsubstituted forms such as -CN, including aldehydes, carboxylates and esters). The substituted alkyl is shown below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, —CN, and the like.

  The term “aralkyl” is art-recognized and refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

  The terms “alkenyl” and “alkynyl” are art-recognized and each contain at least one double or triple bond, but with the same length and possible substituents as alkyl described above, Means an unsaturated aliphatic group. The term “alkylene” means an organic radical formed from an unsaturated aliphatic hydrocarbon, and “alkylene” means an acyclic carbon chain containing a carbon-carbon double bond, both of which are described above. As such, it may be substituted like alkyl.

  Unless otherwise indicated, “lower alkyl” means an alkyl group, as described above, but having from 1 to about 10 carbon atoms, alternatively from 1 to about 6 carbon atoms (ie, C1-C6). ). Similarly, “lower alkenyl” and “lower alkynyl” have comparable chain lengths.

  The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “aryl” is art-recognized and is a 5-, 6-, and 7-membered monocyclic aromatic group that may contain from 0 to 4 heteroatoms, such as benzene, pyrrole, It means furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine and the like. An aryl group having a heteroatom in the ring structure may be described as “heteroaryl” or “heteroaromatic”. Aromatic rings can be, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, as described above. Substituents such as silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heterocyclic aromatic group, —CF ₃ , —CN, etc. at one or more ring positions May be substituted. The term “aryl” also means that at least one of the rings is aromatic (eg, the other ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl), 2 The above carbon includes polycyclic systems having two or more rings in which two adjacent rings are common (the ring is a “fused ring”).

  The terms ortho, meta, and para are recognized in the art and refer to 1,2-, 1,3-, and 1,4-disubstituted benzenes, respectively. For example, 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized and their ring structures include from 1 to 4 heteroatoms, from 3 to about 10 membered ring structures, or 3 To about 7-membered ring structure. The heterocycle may be polycyclic. The heterocycle is, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthine, phenoxanthine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, Pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, Phenazine, phenalsazine, phenothiazine, furazane, phenoxazine, pyrrolidine, oxalane, thiolane, oxazole, piperidine, piperazine, Including Ruhorin, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocyclic rings are, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone , Aldehydes, esters, heterocyclyls, aromatic or heterocyclic aromatic groups, —CF ₃ , —CN and the like, may be substituted at one or more positions.

A “polycycle” or “polycyclic group” is art-recognized and is two or more that have two or more carbons common to two adjacent rings (eg, the ring is a “fused ring”) Of the ring (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and heterocycle). Rings that are joined through non-adjacent atoms are termed “bridged” rings. Each of the polycyclic rings can be, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, as described above. It may be substituted with a substituent such as ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heterocyclic aromatic group, —CF ₃ , —CN and the like.

  The term “carbocycle” is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art-recognized and refers to —NO ₂ . The term “halogen” is art-recognized and refers to —F, —Cl, —Br or —I. The term “sulfhydryl” is art-recognized and refers to —SH. The term “hydroxy” means —OH. The term “sulfonyl” is art-recognized and refers to —SO ₂ .

ここで、R50, R51及びR52は、それぞれ独立して、水素、アルキル、アルケニル、-(CH2)m-R61を表すか、R50とR51とは、それらが結合するN原子と共に、環構造において、４から８原子を有する複素環を形成し、
R61は、アリール、シクロアルキル、シクロアルケニル、ヘテロサイクリルまたは多環を表し、
mは、０または１〜８の整数である。
一実施形態では、R50又はR51のうちの１つのみがカルボニルとすることができ、例えば、R50、R51及び窒素が、一緒にイミドを形成しない。他の実施形態では、R50及びR51（及び任意にR52）は、各々独立して、水素、アルキル、アルケニルまたは−（CH2）m-R61を表す。このように、「アルキルアミン」は、上述したように、それらに結合する置換又は非置換アルキルを有する、つまり、R50とR51のうちの少なくとも１つはアルキル基である。 The terms “amine” and “amino” are art-recognized and both refer to unsubstituted and substituted amines, eg, groups that can be represented by the formula:

Here, R50, R51 and R52 each independently represent hydrogen, alkyl, alkenyl,-(CH2) m-R61, or R50 and R51 together with the N atom to which they are bonded, in the ring structure, Forming a heterocycle having 4 to 8 atoms,
R61 represents aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycycle,
m is 0 or an integer of 1-8.
In one embodiment, only one of R50 or R51 can be carbonyl, for example R50, R51 and nitrogen do not form an imide together. In other embodiments, R50 and R51 (and optionally R52) each independently represent hydrogen, alkyl, alkenyl, or-(CH2) m-R61. Thus, an “alkylamine” has a substituted or unsubstituted alkyl attached thereto, as described above, that is, at least one of R50 and R51 is an alkyl group.

ここで、R50及びR51は、上記と同義である。
本発明のアミドの一実施形態は、不安定なイミドは含まないであろう。 The term “amido” is art recognized as an amino-substituted carbonyl and includes a group that may be represented by the formula:

Here, R50 and R51 are as defined above.
One embodiment of the amide of the present invention will not include unstable imides.

ここで、R50は上記と同義であり、
R54は、水素、アルキル、アルケニル又は-(CH2)m-R61で表され、ここでm及びR61は、上記と同義である。 The term “acylamino” is art-recognized and refers to a group that can be represented by the formula:

Where R50 is as defined above,
R54 is represented by hydrogen, alkyl, alkenyl, or — (CH2) m—R61, wherein m and R61 are as defined above.

The term “alkylthio” means an alkyl group having a sulfur group attached thereto, as described above.
In one embodiment, an “alkylthio” group is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S— (CH 2) m —R 61. Here, R61 has the same meaning as described above. Exemplary alkylthio groups include methylthio, ethylthio, and the like.

ここで、
X50は、単結合又は酸素又は硫黄を表し、
R55及びR56は、水素、アルキル、アルケニル、-(CH2)m-R61又は薬学的に許容できる塩を表し、R56は、水素、アルキル、アルケニル又は-(CH2)m-R61を表し、m及びR61は、上記と同義である。
X50は酸素であり及びR55又はR56は水素でない場合、この式は「エステル」を表す。
X50は酸素であり、R55は上述したものである場合、この基は、ここではカルボキシ基を表し、特にR55は水素である場合、この式は「カルボン酸」を表す。
X50は酸素、R56は水素である場合、この式は「ホルメート」を表す。
一般に、上記式で酸素原子は硫黄と置き換えられる場合、この式は、「チオカルボニル」基を表す。
X50が硫黄であり、R55又はR56は水素でない場合、この式は「チオエステル」を表す。
X50が硫黄であり、R55が水素である場合、この式は「チオカルボン酸」を表す。
X50が硫黄であり、R56が水素である場合、この式は「チオホルメート」を表す。
一方、X50が単結合であり、R55が水素でない場合、上記式は、「ケトン」基を表す。
X50が単結合であり、R55が水素である場合、上記式は、「アルデヒド」基を表す。 The term “carbonyl” is art-recognized and includes groups that can be represented by the following formulae:

here,
X50 represents a single bond or oxygen or sulfur,
R55 and R56 represent hydrogen, alkyl, alkenyl,-(CH2) m-R61 or a pharmaceutically acceptable salt, R56 represents hydrogen, alkyl, alkenyl or-(CH2) m-R61, m and R61 Is as defined above.
Where X50 is oxygen and R55 or R56 is not hydrogen, this formula represents an “ester”.
When X50 is oxygen and R55 is as described above, this group represents here a carboxy group, especially when R55 is hydrogen, the formula represents a “carboxylic acid”.
Where X50 is oxygen and R56 is hydrogen, the formula represents “formate”.
In general, where the oxygen atom is replaced with sulfur in the above formula, the formula represents a “thiocarbonyl” group.
Where X50 is sulfur and R55 or R56 is not hydrogen, the formula represents a “thioester”.
Where X50 is sulfur and R55 is hydrogen, the formula represents a “thiocarboxylic acid”.
Where X50 is sulfur and R56 is hydrogen, the formula represents a “thioformate”.
On the other hand, when X50 is a single bond and R55 is not hydrogen, the above formula represents a “ketone” group.
Where X50 is a single bond and R55 is hydrogen, the above formula represents an “aldehyde” group.

ここで、R50及びR51は、上記と同義である。
本発明のアミドの一実施形態では、不安定となり得るイミドを含まないであろう。 The term “amido” is art recognized as an amino-substituted carbonyl and includes a group that can be represented by the following formula:

Here, R50 and R51 are as defined above.
One embodiment of the amide of the present invention will not include imides that may be unstable.

The term “alkylthio” refers to an alkyl group having a sulfur group attached thereto, as described above. In one embodiment, an “alkylthio” group refers to S-alkyl, —S-alkenyl, —S-alkynyl, and —S— (CH ₂ ) m—R61. m and R61 are as defined above. Exemplary alkylthio groups include methylthio, ethylthio, and the like.

例えば、R58は、水素、アルキル、アルケニル、アルキニル、アルキレン、シクロアルキル、ヘテロサイクリル、アリール又はヘテロアリールのうちの１つとすることができる。 The term “sulfonyl” is art-recognized and refers to a group that can be represented by the formula:

For example, R58 can be one of hydrogen, alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

R58は上記と同義である。 The term “sulfoxide” or “sulfinyl” is art-recognized and refers to a group that can be represented by the formula:

R58 has the same meaning as above.

  Definitions in each expression, such as alkyl, m, n, etc., are independent of other definitions of the same structure when there are more than one in any structural formula.

  Certain compounds contained in the compositions of the present invention may be present in particular with geometric or stereoisomers. Furthermore, the polymers of the present invention may be optically active. The present invention is within the scope of the present invention, cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, their racemic mixtures and other mixtures thereof. All compounds including are intended. The additional asymmetric carbon atom may be present as a substituent such as an alkyl group. All such isomers and mixtures thereof are intended to be encompassed by the present invention.

  For example, if a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, separating the resulting mixture of diastereomers, where the auxiliary group is Cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains basic functional groups (such as amines) or acidic functional groups (such as carboxyls), diastereomeric salts are formed with the appropriate optically active acid or base and subsequently obtained in this way. The diastereomeric mixture is separated by fractional crystallization or chromatographic means well known in the art to recover the pure enantiomer.

  “Substituted” or “substituted with” is such substituents carried out according to the permissible valence of the substituent atom, substituent, and the substituent results in a stable compound, eg, rearrangement, cyclization , Removal or other reactions, etc., provided that they are not arbitrarily converted.

  The term “substituted” is considered to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen has a hydrogen substituent and / or any permissible substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Also good. The present invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

  For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, back cover. Also, for the purposes of the present invention, the term “hydrocarbon” is intended to include all acceptable compounds with at least one hydrogen and one carbon atom. From a broad perspective, acceptable hydrocarbons may be substituted or unsubstituted, acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents including.

  The term “pharmaceutically acceptable salts” is art-recognized and refers to inorganic and organic acid addition salts of compounds containing them that are relatively non-toxic, for example, those included in the compositions of the present invention. . The disclosed compounds can formulate therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include, for example, inorganic bases (eg, sodium, potassium, ammonium, calcium or iron (III) hydroxide) and isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine Base addition salts (formed with free carboxyl or other anionic groups) that may be derived from organic bases such as. Such salts can be formed as acid addition salts with any free cation group and are usually inorganic acids (eg hydrochloric acid, sulfuric acid, phosphoric acid etc.) or organic acids (acetic acid, citric acid, p-toluenesulfone). Acid, methanesulfonic acid, succinic acid, tartaric acid, mandelic acid, etc.). Salts contemplated herein include salts formed by protonation of amino groups with inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.). The salts may also include amine salts formed by protonation of amino groups with a suitable organic acid (eg, p-toluenesulfonic acid, acetic acid, etc.).

The term “pharmaceutically acceptable carrier” is art-recognized and carries any subject composition or component from one organ or body part to another organ or body part or Refers to a pharmaceutically acceptable material, composition, excipient (eg, liquid, solid filler, diluent, excipient, solvent or encapsulating material) involved in transport. Each carrier should be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Materials that can serve as pharmaceutically acceptable carriers include the following. (1) sugar (eg lactose, glucose and sucrose), (2) starch (eg corn starch and potato starch), (3) cellulose and its derivatives (eg sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), (4) Powdered tragacanth gum, (5) malt, (6) gelatin, (7) talc, (8) excipients (eg cocoa butter and suppository wax), (9) oils (eg peanut oil, cottonseed oil, safflower) Oil, sesame oil, olive oil, corn oil and soybean oil), (10) glycol (eg propylene glycol), (11) polyhydric alcohols (eg glycerin, sorbitol, mannitol and polyethylene glycol), (12) esters (eg , Ethyl oleate and ethyl laurate), (13) agar, (14) buffer (eg, magnesium hydroxide) And aluminum hydroxide), (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer and (21) Other non-toxic compatible materials used in pharmaceutical compositions.
B. Compounds and compositions

ここで、
R₁はアルキレン-R₅-R₆-R₂、-R₆-C(O)-フェニル、-R₆-フェニル、アルキル、アルケニル又はアルキニルからなる群から選択され、ここで、フェニルは、それぞれ独立に、ハロ、アルキル、CN又はNO₂から選択される１以上の基で置換されていてもよい、
R₂は、ハロ、CN又はアルキルで１、２又は３つの位置で置換されていてもよいヘテロアリールであり、
R₃は、それぞれ独立に、H、ハロ、CN及びNO_２からなる群から選択され、
R₄は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R_５は、チオ、スルホニル又はスルフィニルからなる群から選択され、及び
R_６は、アルキレン又は結合手である。 In part, this disclosure provides individual diastereomers of compounds having structure (I) or pharmaceutically acceptable salts thereof.

here,
R ₁ is selected from the group consisting of alkylene-R ₅ -R ₆ -R ₂ , -R ₆ -C (O) -phenyl, -R ₆ -phenyl, alkyl, alkenyl or alkynyl, wherein phenyl is each Independently substituted with one or more groups selected from halo, alkyl, CN or NO ₂ ;
R ₂ is heteroaryl optionally substituted at 1, 2 or 3 positions with halo, CN or alkyl;
Each R ₃ is independently selected from the group consisting of H, halo, CN and NO ₂ ;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl, and
R ₆ is alkylene or a bond.

In one embodiment, as described above, any alkylene group may be a substituted alkylene group. In other embodiments, R ₂ can be, for example, a bicyclic or monocyclic heteroaryl group, such as benzothiazole, benzoxazole, isoquinoline, or pyridine.

In one embodiment, R ₃ may be NO ₂ and R ₃ may be H. In other embodiments, R ₄ is sulfonyl, eg, —S (O) ₂ —.

In one embodiment, R ₁ is alkylene-S-heteroaryl, such as —CH ₂ —CH ₂ —S-heteroaryl, where heteroaryl is 1, 2 or, depending on halo, alkyl, CN or NO ₂ For example, it can be a heteroaryl which can be substituted at only one position with cyano. In other embodiments, R ₁ may be -alkylene-C (O) -phenyl, such as -CH ₂ -C (O) -phenyl, or R ₁ is -alkylene-phenyl, such as It may be —CH ₂ -phenyl. Such phenyl groups are each independent and optionally substituted with one or two groups selected from the group consisting of halo, alkyl, CN or NO ₂ . In still other embodiments, R ₁ can be selected from alkyl, alkenyl, or alkynyl.

In one embodiment, R ₆ is a single bond.

ここで、
Xは、O、NR'及びSから選択され、ここで、R'はH又はアルキルであり、
R₁は、-アルキレン-R₅-R₆-R₁₂、-R₆-C(O)-R₁₂、-R₆-R₁₂、アルキル、アルケニル又はアルキニルからなる群から選択され、
R₄は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R₅は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R₆は、アルケン又は単結合であり、
R₁₂は、ハロ、ヒドロキシ、メルカプト、ニトロ、ホルミル、ホルムアミド、カルボキシ、シアノ、アミノ、アミド、カルバモイル、スルファモイル、ウレイド、アルキル、アルケニル、アルキニル、アルコキシ、アルカノイル又はカルコキシカルボニルで、１、２又は３つの位置で置換されていてもよいアリール又はヘテロアリールであり、
R₃は、それぞれ独立に、H、ハロ、シアノ、ヒドロキシ、カルボキシ、アルキル、アルコキシ及びニトロからなる群から選択される。 Also provided are compounds of formula II or pharmaceutically acceptable salts.

here,
X is selected from O, NR ′ and S, wherein R ′ is H or alkyl;
R ₁ is selected from the group consisting of -alkylene-R ₅ -R ₆ -R ₁₂ , -R ₆ -C (O) -R ₁₂ , -R ₆ -R ₁₂ , alkyl, alkenyl or alkynyl;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₆ is an alkene or a single bond,
R ₁₂ is halo, hydroxy, mercapto, nitro, formyl, formamide, carboxy, cyano, amino, amide, carbamoyl, sulfamoyl, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl or chalcoxycarbonyl, 1, 2 or 3 Aryl or heteroaryl optionally substituted at one position,
Each R ₃ is independently selected from the group consisting of H, halo, cyano, hydroxy, carboxy, alkyl, alkoxy and nitro.

In one embodiment, R ₁₂ may be bicyclic or monocyclic heteroaryl, such as benzothiazole, benzoxazole, quinoline, isoquinoline or pyridine.

In one embodiment, R ₁ may be alkylene-S-heteroaryl, eg, —CH ₂ —CH ₂ —S-heteroaryl, wherein heteroaryl is any as defined above for R ₁₂ May be substituted.

ここで、R3はH又はNO₂から選択され、
R₁は、t-ブチル、エチル、メチル、

から選択される。 Compounds that form part of this disclosure include those represented below.

Here, R3 is selected from H or NO _2,
R ₁ is t-butyl, ethyl, methyl,

Selected from.

  In certain embodiments, a composition is provided comprising one or more compounds of Formula I or Formula II and a pharmaceutically acceptable excipient.

In one embodiment, the compound of formula I or formula II may inhibit H ⁺ , K ⁺ -ATPase, eg, have proton pump inhibitory properties.

  The compositions disclosed herein may, in certain embodiments, contain a buffer that may protect the compound against acid degradation. In certain embodiments, such buffering agents may include weak or strong bases and / or one or more of sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, glucomate magnesium, Aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, amino acid and buffer mixture, aluminum glycinate and buffer mixture, amino acid acid salt and buffer mixture, amino acid alkali salt and buffer mixture May be included. Additional buffers include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate , Tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate And other calcium salts.

  In one embodiment, the compositions disclosed herein include other chemotherapeutic agents such as anthracyclines (eg, doxorubicin and mitoxantrone), fluoropyrimidines (eg, 5-FU, 5-fluorouracil), folic acid antagonists (Eg, methotrexate), podophylotoxins (eg, etoposide), camptothecin, hydroxyurea or platinum complexes (eg, cisplatin)). Certain other chemotherapeutic agents include cisplatin, 5-fluorouracil, vinblastine and irinotecan. Other chemotherapeutic agents may include taxol, such as docetaxel or paclitaxel, etoposide, hormone antineoplastic agents such as leuprolide or tamoxifen, IL-2, vinblastine and vincristine.

  The method of the invention contemplates a composition comprising a compound of formula I administered alone or in combination with other agents (eg, chemotherapeutic or protein therapeutics described below).

  The composition of the present invention may contain other therapeutic agents, for example, conventional solid or liquid excipients or diluents and pharmaceutical additives suitable for the desired dosage form according to techniques known in the pharmaceutical field. It can be formulated by employing an agent (for example, excipient, binder, preservative, stabilizer, flavoring, etc.).

  Depending on the condition being treated, these pharmaceutical compositions can be formulated or administered systemically or locally. Formulation and administration techniques can be found in the latest edition of “Remington's Pharmaceutical Sciences” (Mack Publishing Co, Easton Pa.). Suitable routes can include, for example, oral or transmucosal administration as well as parenteral delivery, intramuscular, subcutaneous, intrathecal, intrathecal, intraventricular, intravenous, intraperitoneal or intranasal administration. For injection, the pharmaceutical compositions of the invention can be formulated as aqueous solutions, preferably Hank's solution, Ringer's solution, or physiologically buffered sarin. For administration to tissues or cells, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or excipients include fatty oils or liposomes such as sesame oil or synthetic fatty acid esters (eg, ethyl oleate or triglycerides). Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may contain suitable stabilizers or agents that increase the solubility of the compound in order to prepare a highly concentrated solution.

  For topical use, it may be a cream, ointment, jelly, solution or suspension containing the compound of the invention. In one embodiment, the compositions contemplated herein may be in the form of eye drops.

  The compounds or compositions disclosed herein may, in one embodiment, be administered in close association with other chemotherapy schedules. For example, administration can occur before, simultaneously with, or immediately after other therapies.

ここで、
R₁はアルキレン-R₅-R₆-R₂、-R₆-C(O)-フェニル、-R₆-フェニル、アルキル、アルケニル又はアルキニルからなる群から選択され、ここで、フェニルは、それぞれ独立に、ハロ、アルキル、CN又はNO₂から選択される１以上の基で置換されていてもよい、
R₂は、ハロ、CN又はアルキルで１、２又は３つの位置で置換されていてもよいヘテロアリールであり、
R₃は、それぞれ独立に、H、ハロ、CN及びNO_２からなる群から選択され、
R₄は、チオ、スルホニル又はスルフィニルからなる群から選択され、
R_５は、チオ、スルホニル又はスルフィニルからなる群から選択され、及び
R_６は、アルキレン又は結合手である。
Ｃ．方法 In other embodiments, a product comprising a packaging material and a pharmaceutical composition contained in the packaging material is provided, the packaging material comprising the pharmaceutical composition, alone or in combination with a chemotherapeutic agent, cancer and / or Including a label indicating that it can be used for the treatment of gastrointestinal symptoms, the pharmaceutical composition comprises at least one compound of formula I or pharmaceutically acceptable salts.

here,
R ₁ is selected from the group consisting of alkylene-R ₅ -R ₆ -R ₂ , -R ₆ -C (O) -phenyl, -R ₆ -phenyl, alkyl, alkenyl or alkynyl, wherein phenyl is each Independently substituted with one or more groups selected from halo, alkyl, CN or NO ₂ ;
R ₂ is heteroaryl optionally substituted at 1, 2 or 3 positions with halo, CN or alkyl;
Each R ₃ is independently selected from the group consisting of H, halo, CN and NO ₂ ;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl, and
R ₆ is alkylene or a bond.
C. Method

  A method of treating cancer in a patient in need thereof provided herein comprises a composition comprising at least one compound of formula II or I and / or a compound of formula II or I as described above Administration of an effective amount of the product. The intended methods for treating cancer are kidney cancer, ovarian cancer, leukemia, lung cancer, bladder cancer, breast cancer, liver cancer, thyroid cancer, lymphoma, Hodgkin lymphoma, melanoma, myeloma, brain cancer, colon Includes methods of treating cancer, prostate cancer, bone cancer, kidney cancer and cervical cancer. Exemplary methods include methods for treating kidney cancer, small cell lung cancer, non-small cell lung cancer and glioblastoma.

  Such a method of treating cancer may also include administering other chemotherapeutic agents as described above. For example, the contemplated method involves administering (substantially simultaneously or sequentially) an effective amount of at least one compound represented by Formula II or I and the chemotherapeutic agent in the same dosage form or in separate dosage forms. Including that. Furthermore, when administered in separate dosage forms, one compound or formulation may be administered by one route, while other active ingredients, eg, other chemotherapeutic agents may be administered by different routes. Good. Alternatively, all compounds may be administered by the same route.

  Also contemplated herein is a method for improving the therapeutic effect of a chemotherapeutic agent, comprising administering a compound of formula I or II to a patient in need thereof. For example, the compounds disclosed herein may have proton pump inhibitory properties, which may reduce cancer cell resistance to cytotoxic agents. In other embodiments, the method comprises administering to a patient in need thereof (e.g., a patient to whom a particular chemotherapeutic agent has been administered), wherein the method reduces side effects, e.g., a particular chemotherapeutic agent. Methods for reducing the incidence of serious side effects or side effects associated with administration, eg, reducing the incidence of oral and / or gastrointestinal disorders are contemplated.

Provided herein is a method for inhibiting tumor growth, eg, reducing tumor size, comprising administering a compound of formula I or II, eg, reducing tumor size . In one embodiment, for a compound of formula I or II, the survival rate of patients in need thereof is greater than about 15% compared to patients receiving placebo. Also provided herein is a method for inhibiting tumor cell growth by administering a compound disclosed herein. Examples of tumor cells that can be inhibited by such administration include: IGROVl (ovary), OVCAR 8 (ovary), ES-2 (ovary), CA0V3 (ovary), 0VCAR5 (ovary), SUDHL4 (lymphoma), RPMI8226 (myeloma), RPMI6666 (Hodgkin lymphoma), NC37 (lymphoma) , GDMI (leukemia), MC / CAR (prostate), DU-145 (prostate), J45-01 (leukemia), M0LT3 (leukemia), HUT78, J-gamma-1 (leukemia), MCF7 (leukemia), COLO205 ( Colon), HL60 CLONE 15 (leukemia), T47D (chest), place 16 (intestine), KU812 (leukemia), SW620 (colon), MK92-M1 (lymphoma), MV-4-11 (leukemia), HS578T (chest) ), HT29 (colon), HCT 116 (colon), CAKII (kidney), A549 (lung), H460 (lung), A3 (colon), MDA-MB231 (melanoma), MALME 3M (melanoma), RXF393 ( Kidney), RS4.11 (leukemia), PC3 (prostate), 0VCAR3 (ovary), MDA-MB435 (melanoma), HUT102 (lymphoma), HL60 (leukemia) CCRF-CEM (leukemia), HUT78 (lymphoma) 786-0 (kidney), ACHN (kidney), A498 (kidney), H226 (lung), H522 (lung), HO P92 (lung), SNB 19 (brain), 0VCAR4 (ovarian), H9 (lymphoma), UO-31 (kidney), HH (lymphoma), DAUDI (leukemia), LOXIMVI (melanoma), NAMALW A (lymphoma), EKVX (lung), D0HH2 (lymphoma), SNB75 (brain), SKMEL28 (melanoma), SKMEL5 (melanoma), SKMEL2 (melanoma), M14 (melanoma), UACC 257 (melanoma), H332M (lung), KM12 (colon), HCC2998 (colon), G401 (kidney), RSl 184 (lymphoma) , MCl 16 (leukemia), M0LT4 (leukemia), JMI (liver), HOP-62 (lung), HCT-15 (colon), SF-539 (brain), SF295 (brain), ST486 (lymphoma), U251 ( Brain), UACC-62 (melanoma).
Compound production

Possible production methods for the compounds disclosed herein are shown below.

The benzothiazole compound of formula I and / or II can be prepared using 2-thiol compound 1. In one embodiment, 1 is reacted with another source material 2. Here, Q is halogen, and R ₁ and R ₃ are as defined above. The reaction can be performed at room temperature in an organic solvent such as ethanol or DMF.

  The disclosed compounds can also be prepared by an acid catalyzed reaction of compound 1 with, for example, 2-aminobenzyl alcohol.

Sulfoxide and sulfonyl-containing compounds can be prepared by oxidation of benzothiazole. Commonly used oxidizing agents include, for example, peracis (eg m-chloroperoxybenzene acid), perestes, peroxides (eg hydrogen peroxide), mtaperiodiate sodium, selenium dioxide, manganese dioxide, including idosobenze. Such agents can be used in the reaction at temperatures from about 0 to about room temperature. The oxidation can be terminated by adding dimethyl sulfide. The disclosed compounds can also be prepared utilizing the methods described in US Pat. No. 6,906,078, incorporated herein by reference in its entirety.
Example

  The following examples are provided to further illustrate the advantages and features of the present invention and are not intended to limit the scope of the invention.

  Example 2: Inhibition of renal tumor cell lines

Adherent cells are fixed in 180 μl growth media for approximately 16-24 hours prior to the day of the experiment. On the day of the experiment, the fixed adherent cells are analyzed and counted and the suspended cells are fixed in 180 μl growth media. Prepare compound and diluent. The resulting solution is added to the cells. Cells are incubated for 48 hours at 37 ° C. with 5% CO ₂ . Next, the medium is sucked. The plate containing the cell suspension is spun at 1500 RPM for 10 minutes. Remove media slowly using a multi-channel pipettor. 200 μl of MTT is added to each well to a concentration of 0.863 mg / ml MTT in the growth media. Cells are incubated for 4 hours at 37 ° C., 5% CO ₂ and aspirated. The plate containing the cell suspension is spun at 1500 RPM for 10 minutes. Remove media slowly using a multi-channel pipettor. Add 100 μl DMSO to each well. Cells are incubated for 5 minutes at 37 ° C., 5% CO ₂ and absorbance is obtained at 560 nm using a Dynex Opsys MR plate reader.

  Tables Ia and Ib show the percent inhibition of the G401 rhabdoid (kidney) cell line using the various compounds disclosed herein. For some compounds, as shown below, the analysis is performed multiple times, each result is reported and associated with a particular compound.

reference

  All publications and patents mentioned herein, including those listed below, are hereby incorporated by reference in their entirety so that each publication or patent is specifically and individually incorporated by reference. In case of conflict, the present application, including any defined herein, will control.

  While specific embodiments of the subject invention have been discussed, the details described above are illustrative only and not limiting. Many variations of the invention will become apparent to those skilled in the art from this detailed perspective. The full scope of the invention, together with such variations, should be determined by reference to the claims, along with the equivalents and the specification.

  Unless otherwise stated, it is understood that the numbers, reaction conditions, etc., representing the many components used in the specification and claims are modified in all implementations by the term “about”. Accordingly, unless indicated otherwise, the number of parameters set forth in the specification and claims is an approximation that can be varied depending on the specifics desired to be obtained by the present invention.

Claims (33)

a) a compound represented by I or a pharmaceutically acceptable salt thereof;
b) A suitable composition for administration to a patient comprising a pharmaceutically acceptable excipient.

here,
R ₁ is selected from the group consisting of alkylene-R ₅ -R ₆ -R ₂ , -R ₆ -C (O) -phenyl, -R ₆ -phenyl, alkyl, alkenyl or alkynyl, wherein phenyl is each Independently substituted with one or more groups selected from halo, alkyl, CN or NO ₂ ;
R ₂ is heteroaryl optionally substituted at 1, 2 or 3 positions with halo, CN or alkyl;
Each R ₃ is independently selected from the group consisting of H, halo, CN and NO ₂ ;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl, and
R ₆ is alkylene or a bond. The composition of claim 1, wherein R ₂ is bicyclic or monocyclic heteroaryl. The composition of claim 1 or 2, wherein R ₂ is selected from the group consisting of benzothiazole, benzoxazole, isoquinoline and pyridine. The composition of claim 1 wherein R ₃ is NO ₂ and R ₁ is alkyl or -alkylene-phenyl. The composition of claim 4, wherein R ₁ is methylbenzene optionally substituted at one position by halo. The composition of claim 4, wherein R ₁ is ethyl or methyl. At least one R ₃ is the composition of any one of claims 1-5 is H. The composition according to claim 2 or 3, wherein R ₆ is a single bond. R ₅ is The composition of claim 2, 3 or 8 is S. R ₄ is claim 2, 3 or 9 of the composition sulfonyl.   The composition according to any one of claims 1 to 9, further comprising a chemotherapeutic agent.   12. The composition of claim 11, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, 5-fluorouracil and vinblastine. a)

Here, R3 is selected from H or NO _2,
R1 is t-butyl, ethyl, methyl,

Or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable excipient. Packaging materials;
A product comprising a pharmaceutical composition contained in the packaging material,
The packaging material includes a label indicating that the pharmaceutical composition can be used alone or in combination with a chemotherapeutic agent for the treatment of cancer and / or gastrointestinal symptoms;
Said pharmaceutical composition comprises at least one compound of formula I or a pharmaceutically acceptable salt.

here,
R ₁ is selected from the group consisting of alkylene-R ₅ -R ₆ -R ₂ , -R ₆ -C (O) -phenyl, -R ₆ -phenyl, alkyl, alkenyl or alkynyl, wherein phenyl is each Independently substituted with one or more groups selected from halo, alkyl, CN or NO ₂ ;
R ₂ is heteroaryl optionally substituted at 1, 2 or 3 positions with halo, CN or alkyl;
Each R ₃ is independently selected from the group consisting of H, halo, CN and NO ₂ ;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl, and
R ₆ is alkylene or a bond. A method of treating cancer in a patient in need thereof comprising administering an effective amount of at least one compound of formula II or a pharmaceutically acceptable salt.

here,
X is selected from O, NR ′ and S, wherein R ′ is H or alkyl;
R ₁ is selected from the group consisting of -alkylene-R ₅ -R ₆ -R ₁₂ , -R ₆ -C (O) -R ₁₂ , -R ₆ -R ₁₂ , alkyl, alkenyl or alkynyl;
R ₄ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₅ is selected from the group consisting of thio, sulfonyl or sulfinyl;
R ₆ is an alkene or a single bond,
R ₁₂ is halo, hydroxy, mercapto, nitro, formyl, formamide, carboxy, cyano, amino, amide, carbamoyl, sulfamoyl, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl or chalcoxycarbonyl, 1, 2 or 3 Aryl or heteroaryl optionally substituted at one position,
Each R ₃ is independently selected from the group consisting of H, halo, cyano, hydroxy, carboxy, alkyl, alkoxy and nitro.   16. The method of claim 15, further comprising administering another chemotherapeutic agent.   17. The method of claim 16, wherein the chemotherapeutic agent and the compound of formula II are administered in the same dosage form.   17. The method of claim 16, wherein the chemotherapeutic agent and the compound of formula II are administered in separate dosage forms.   16. The method of claim 15, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, 5-fluorouracil and vinblastine. R ₁₂ is halo, method of claim 15 optionally substituted with one, two or three positions by CN or alkyl is heteroaryl. R ₁₂ is The method of claim 15 which is a bicyclic or monocyclic heteroaryl. R ₁₂ is The method of claim 21 which is selected from the group consisting of benzo oxadiazole, benzoxazole, isoquinoline, and pyridine. R ₃ is NO _2, R ₁ is alkyl or - alkylene - The method of claim 15 is phenyl. R ₁ is The method of claim 15 wherein at least one of methyl benzene substituted with position by halo. R ₁ is The method of claim 15 which is ethyl or methyl. At least one R ₃ is any one method of claims 15 25 is H. The method of claim 16 or 17, wherein R ₆ is a single bond. The method of claim 16 or 17, wherein R ₅ is S. R ₄ The method of claim 16 or 17 which is a sulfonyl.   30. The method of any one of claims 15 to 29, wherein X is S.   31. The method according to any one of claims 15 to 30, wherein the cancer is selected from the group consisting of kidney cancer, ovarian cancer, leukemia, lung cancer, bladder cancer, breast cancer, liver cancer or thyroid cancer. A method for improving the therapeutic effect of a chemotherapeutic agent comprising administering a compound represented by formula II to a patient in need thereof.

Here, R ₃ , R ₄ and R ₁ are the same as defined in claim 15. A method of inhibiting tumor growth comprising administering a compound of formula II to a patient in need thereof.

Here, R ₃ , R ₄ and R ₁ are the same as defined in claim 15.