Cell differentiation inducer, benzamide compounds

Abstract

The novel benzamide derivative represented by formula (1) and the novel anilide derivative represented by formula (13) of this invention has differentiation-inducing effect, and are, therefore, useful a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as an anticancer drug, specifically to a hematologic malignancy and a solid carcinoma. ##STR00001##

Description

CROSS REFERENCE

This application claims priority of Foreign Japanese Application #258863 filed Mar. 9, 1996.

wherein e is as defined above,

X in the above formula (1) may be also a moiety having any structure illustrated in formula (7); ##STR00008##

 wherein e, g and R⁴ are as defined above.

X in the above formula (1) may be also a moiety having any structure illustrated in formula (8); ##STR00009##

 wherein g, m and R⁵ are as defined above.

The anilide represented by formula (13) may be one wherein A is an optionally substituted heterocycle; B is an optionally substituted phenyl; and R³ is an amino group.

The anilide may be also one wherein Y has —CO— and is linear, cyclic or their combination.

As used herein, “1 to 4 carbons” means a carbon number per a single substituent; for example, for dialkyl substitution it means 2 to 8 carbons.

A heterocycle in the compound represented by formula (1) or (13) is a monocyclic heterocycle having 5 or 6 members containing 1 to 4 nitrogen, oxygen or sulfur atoms or a bicyclic-fused heterocycle. The monocyclic heterocycle includes pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine, tetrahydrofuran, morpholine, thiomorpholine and the like. The bicyclic fused heterocycle includes quinoline; isoquinoline; naphthyridine; fused pyridines such as furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine and thiazolopyridine; benzofuran; benzothiophene; benzimidazole and the like.

A halogen may be fluorine, chlorine, bromine or iodine.

An alkyl having 1 to 4 carbons includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

An alkoxy having 1 to 4 carbons includes methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

An aminoalkyl having 1 to 4 carbons includes aminomethyl, 1-aminoethyl, 2-aminopropyl and the like.

An alkylamino having 1 to 4 carbons includes N-methylamino, N,N-dimethylamino, N,N-diethylamino, N-methyl-N-ethylamino, N,N-diisopropylamino and the like.

An acyl having 1 to 4 carbons includes acetyl, propanoyl, butanoyl and like.

An acylamino having 1 to 4 carbons includes acetylamino, propanoylamino, butanoylamino and the like.

An alkylthio having 1 to 4 carbons includes methylthio, ethylthio, propylthio and the like.

A perfluoroalkyl having 1 to 4 carbons includes trifluoromethyl, pentafluoroethyl and the like.

A perfluoroalkyloxy having 1 to 4 carbons includes trifluoromethoxy, pentafluoroethoxy and the like.

An alkoxycarbonyl having 1 to 4 carbons includes methoxycarbonyl and ethoxycarbonyl.

An optionally substituted alkyl having 1 to 4 carbons includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl and these having 1 to 4 substituents selected from the group consisting of a halogen, hydroxyl, amino, nitro, cyano, phenyl and a heterocycle.

As described below, important elements in the compound represented by formula (13) are (a) presence of ring A, ring B and oxygen or sulfur atom as a hydrogen bond acceptor, and (b) the distances between them determined by their steric configurations. There may be, therefore, no limitation as long as the structure of Y has a hydrogen bond acceptor and rings A and B have required steric configurations. Specifically, the structure of Y which has —CO—, —CS—, —SO— or —SO₂— and links A and B and which is linear, cyclic or their combination, means either (a) one consisting of carbon and/or hetero atoms linking A and B, whose linear or branched moiety has —CO—, —CS—, —SO— or —SO₂—; (b) one linking A and B, whose cyclic moiety has —CO—, —CS—, —SO— or —SO₂—; and (c) one linking A and B wherein a combination of cyclic and linear moieties form a structural unit having —CO—, —CS—, —SO— or —SO₂—.

A basic cyclic structure includes cyclic moieties having 4 to 7 members containing carbons and/or hetero atoms or their fused cycles. For example it may be cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetane, oxolane, oxane, oxepane, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, indoline, isoindoline, thiolane, thiazolidine and oxazolidine rings, which may contain unsaturated bonds, hydrogen bond acceptors and/or substituents.

Structural analyses considering degree of conformational freedom of the compound represented by formula (13) have indicated that atomic groups possibly involved in an biomolecule-drug interaction such as a hydrophobic interaction and hydrogen bond may have a particular spatial configuration in a compound showing high differentiation-inducing effect.

Specifically, we formed a three-dimensional structure of a high activity compound using a molecular modeling software, SYBYL 6.3, and analyzed conformations for all rotatable bonds to determine the most stable structure, wherein their energy levels were evaluated by using Tripos force field after allocating charge on each atom according to Gasteiger-Huckel method. Then, starting with the most stable structure, we have performed a superimposition taking its conformation into consideration using DISCO/SYBYL and then have found that a particular spatial configuration is necessary for expression of high differentiation-inducing effect.

In the above analyses, other commercially available program packages such as CATALYST(MSI), Cerius 2/QSAR+(MSI) and SYBYL/DISCO(Tripos) may be used, and the information on distance obtained in this invention is not limited to that from a particular calculation program.

The ring centroid used in definition of the spatial configuration may be defined as an average of X, Y and Z axes of the ring-forming atoms. When a ring structure to be calculated is fused-polycyclic, the centroid of either the overall fused ring or of a partial ring may be used as that for defining the space.

“Possibility of formation of a configuration” means that a conformer filling the spatial configuration is within 15 kcal/mol, preferably 8 kcal/mol from the energetically most stable structure.

Specific calculation can be performed as described in the instructions for Sybyl (M.Clark) or J.Comput.Chem. 10, 982(1989).

A pharmaceutically acceptable salt of the compound of this invention includes salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and with an organic acid such as acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluroacetic acid, p-toluenesulfonic acid and methanesulfonic acid. Such a salt includes N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide hydrochloride, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide hydrobromide, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide sulfate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide phosphate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide acetate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide lactate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide tartrate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide malate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide succinate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide fumarate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide maleate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide citrate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide trifluoroacetate, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide p-toluenesulfonate and N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide methanesulfonate.

As used herein, a “drug” includes a therapeutic and/or improving agent to, for example, an autoimmune disease, dermatologic disease or parasitism, in addition to a anticancer drug.

When having asymmetric carbon or carbons, the compound represented by formula (1) or (13) may be obtained as an individual stereoisomer or a mixture of stereoisomers including a racemic modification. This invention encompasses the above-specified different forms, which may be also used as an active ingredient.

Representative compounds of this invention represented by formula (1) or (13) are specifically shown in Tables 1 to 4, but this invention is not intended to be limited to these.

TABLE 1
##STR00010##
Compound No.	A	X	Q	n	R1	R2	R3
1	##STR00011##	Direct bond	##STR00012##	1	H	H	NH2
2	##STR00013##	—CH2—	##STR00014##	0	H	H	NH2
3	##STR00015##	—(CH2)2—	##STR00016##	0	H	H	NH2
4	##STR00017##	—(CH2)3—	##STR00018##	0	H	H	NH2
5	##STR00019##	—(CH2)4—	##STR00020##	0	H	H	NH2
6	##STR00021##	—CH2—	##STR00022##	1	H	H	NH2
7	##STR00023##	—(CH2)2—	##STR00024##	1	H	H	NH2
8	##STR00025##	—CH2—	##STR00026##	0	H	H	NH2
9	##STR00027##	—(CH2)2—	##STR00028##	0	H	H	NH2
10	##STR00029##	Direct bond	##STR00030##	1	H	H	NH2
11	##STR00031##	—CH2—	##STR00032##	1	H	H	NH2
12	##STR00033##	Direct bond	##STR00034##	1	H	H	NH2
13	##STR00035##	Direct bond	##STR00036##	1	H	H	NH2
14	##STR00037##	Direct bond	##STR00038##	1	H	H	NH2
15	##STR00039##	—CH2—	##STR00040##	0	H	H	NH2
16	##STR00041##	Direct bond	##STR00042##	1	H	H	NH2
17	##STR00043##	Direct bond	##STR00044##	1	H	H	NH2
18	##STR00045##	Direct bond	##STR00046##	1	H	H	NH2
19	##STR00047##	—CH2—	##STR00048##	0	H	H	NH2
20	##STR00049##	Direct bond	##STR00050##	1	H	H	NH2
21	##STR00051##	—CH2—	##STR00052##	0	H	H	NH2
22	##STR00053##	—CH2—	##STR00054##	0	H	H	NH2
23	##STR00055##	—CH2—	##STR00056##	1	H	H	NH2
24	##STR00057##	Direct bond	##STR00058##	1	H	H	NH2
25	##STR00059##	Direct bond	##STR00060##	1	H	H	NH2
26	##STR00061##	—CH2—	##STR00062##	0	H	H	NH2
27	##STR00063##	Direct bond	##STR00064##	1	H	H	NH2
28	##STR00065##	Direct bond	##STR00066##	1	H	H	NH2
29	##STR00067##	Direct bond	##STR00068##	1	H	H	NH2
30	##STR00069##	Direct bond	##STR00070##	1	H	H	NH2
31	##STR00071##	Direct bond	##STR00072##	1	H	H	NH2
32	##STR00073##	—CH2—	##STR00074##	0	H	H	NH2
33	##STR00075##	Direct bond	##STR00076##	1	H	H	NH2
34	##STR00077##	—CH2—	##STR00078##	1	H	H	NH2
35	##STR00079##	Direct bond	##STR00080##	1	H	H	NH2
36	##STR00081##	Direct bond	##STR00082##	1	H	H	NH2
37	##STR00083##	Direct bond	##STR00084##	1	H	H	NH2
38	##STR00085##	—CH2—	##STR00086##	1	H	H	NH2
39	##STR00087##	—CH2—	##STR00088##	1	H	H	NH2
40	##STR00089##	Direct bond	##STR00090##	1	H	H	NH2
41	##STR00091##	Direct bond	##STR00092##	1	H	H	NH2
42	##STR00093##	Direct bond	##STR00094##	1	H	H	NH2
43	##STR00095##	—CH2—	##STR00096##	0	H	H	NH2
44	##STR00097##	Direct bond	##STR00098##	1	H	H	NH2
45	##STR00099##	Direct bond	##STR00100##	1	H	H	NH2
46	##STR00101##	Direct bond	##STR00102##	1	H	H	NH2
47	##STR00103##	—CH2—	##STR00104##	1	H	H	NH2
48	##STR00105##	—O—CH2—	##STR00106##	1	H	H	NH2
49	##STR00107##	—S—CH2—	##STR00108##	1	H	H	NH2
50	##STR00109##	##STR00110##	##STR00111##	1	H	H	NH2
51	##STR00112##	—CH2—	##STR00113##	1	H	H	NH2
52	##STR00114##	—CH2—	##STR00115##	1	H	H	NH2
53	##STR00116##	—CH2—	##STR00117##	0	H	H	NH2
54	##STR00118##	—O—CH2—	##STR00119##	0	H	H	NH2
55	##STR00120##	—O—CH2—	##STR00121##	0	H	H	NH2
56	##STR00122##	—O—CH2—	##STR00123##	1	H	H	NH2
57	##STR00124##	—O—CH2—	##STR00125##	1	H	5-F	NH2
58	##STR00126##	—CH2—O—CH2—	##STR00127##	0	H	H	NH2
59	##STR00128##	##STR00129##	##STR00130##	1	H	H	NH2
60	##STR00131##	##STR00132##	##STR00133##	1	H	H	NH2
61	##STR00134##	—O—CH2—	##STR00135##	1	H	H	NH2
62	##STR00136##	—O—(CH2)2—	##STR00137##	1	H	H	NH2
63	##STR00138##	##STR00139##	##STR00140##	1	H	H	NH2
64	##STR00141##	—S—CH2—	##STR00142##	1	H	H	NH2
65	##STR00143##	—O—CH2—	##STR00144##	0	H	H	NH2
66	##STR00145##	—O—(CH2)2—	##STR00146##	0	H	H	NH2
67	##STR00147##	—O—(CH2)2—	##STR00148##	0	H	H	NH2
68	##STR00149##	—CH2—	##STR00150##	0	H	H	NH2
69	##STR00151##	—(CH2)2—	##STR00152##	0	H	H	NH2
70	##STR00153##	—(CH2)3—	##STR00154##	0	H	H	NH2
71	##STR00155##	Direct bond	##STR00156##	1	H	H	NH2
72	##STR00157##	Direct bond	##STR00158##	2	H	H	NH2
73	##STR00159##	Direct bond	##STR00160##	3	H	H	NH2
74	##STR00161##	—CH2—	##STR00162##	1	H	H	NH2
75	##STR00163##	—(CH2)2—	##STR00164##	1	H	H	NH2
76	##STR00165##	—(CH2)3—	##STR00166##	1	H	H	NH2
77	##STR00167##	—CH2—	##STR00168##	2	H	H	NH2
78	##STR00169##	—CH2—	##STR00170##	1	H	H	NH2
79	##STR00171##	Direct bond	##STR00172##	2	H	H	NH2
80	##STR00173##	—CH2—	##STR00174##	2	H	H	NH2
81	##STR00175##	Direct bond	##STR00176##	1	H	H	NH2
82	##STR00177##	—CH2—	##STR00178##	1	H	H	NH2
83	##STR00179##	—(CH2)2—	##STR00180##	1	H	H	NH2
84	##STR00181##	—(CH2)3—	##STR00182##	1	H	H	NH2
85	##STR00183##	—CH2—	##STR00184##	1	H	H	NH2
86	##STR00185##	—CH2—	##STR00186##	1	H	H	NH2
87	##STR00187##	Direct bond	##STR00188##	1	H	H	NH2
88	##STR00189##	—CH2—	##STR00190##	1	H	H	NH2
89	##STR00191##	—(CH2)2—	##STR00192##	1	H	H	NH2
90	##STR00193##	—CH2—	##STR00194##	1	H	H	NH2
91	##STR00195##	—O—CH2—	##STR00196##	1	H	H	NH2
92	##STR00197##	—O—CH2—	##STR00198##	1	H	H	NH2
93	##STR00199##	—O—CH2—	##STR00200##	1	H	H	OH
94	##STR00201##	##STR00202##	##STR00203##	0	H	H	NH2
95	##STR00204##	##STR00205##	##STR00206##	1	H	H	NH2
96	##STR00207##	##STR00208##	##STR00209##	1	H	H	NH2
97	##STR00210##	##STR00211##	##STR00212##	0	H	H	NH2
98	##STR00213##	##STR00214##	##STR00215##	1	H	H	NH2
99	##STR00216##	##STR00217##	##STR00218##	0	H	H	NH2
100	##STR00219##	##STR00220##	##STR00221##	1	H	H	NH2
101	##STR00222##	—CH2—O—CH2—	##STR00223##	0	H	H	NH2
102	##STR00224##	—CH2—O—CH2—	##STR00225##	0	3-CH3	H	NH2
103	##STR00226##	—CH2—O—CH2—	##STR00227##	0	H	H	NH2
104	##STR00228##	##STR00229##	##STR00230##	0	H	H	NH2
105	##STR00231##	##STR00232##	##STR00233##	0	H	H	NH2
106	##STR00234##	##STR00235##	##STR00236##	0	H	H	NH2
107	##STR00237##	##STR00238##	##STR00239##	1	H	H	NH2
108	##STR00240##	##STR00241##	##STR00242##	0	H	H	NH2
109	##STR00243##	—CH2—	##STR00244##	1	H	H	NH2
110	##STR00245##	—CH2—	##STR00246##	1	H	5-F	NH2
111	##STR00247##	—CH2—	##STR00248##	1	H	H	OH
112	##STR00249##	—CH2—	##STR00250##	1	H	5-F	NH2
113	##STR00251##	—CH2—	##STR00252##	1	H	4-Cl	NH2
114	##STR00253##	—CH2—	##STR00254##	1	H	H	OH
115	##STR00255##	—CH2—	##STR00256##	1	H	H	OH
116	##STR00257##	—CH2—	##STR00258##	1	H	4-OH	OH
117	##STR00259##	—CH2—	##STR00260##	1	H	H	OH
118	##STR00261##	—CH2—	##STR00262##	1	H	5-CH3	OH
119	##STR00263##	—CH2—	##STR00264##	1	H	5-OCH3	OH
120	##STR00265##	—CH2—	##STR00266##	1	H	H	NH2
121	##STR00267##	—CH2—	##STR00268##	1	H	5-OCH3	NH2
122	##STR00269##	—(CH2)2—	##STR00270##	0	H	5-F	NH2
123	##STR00271##	—(CH2)2—	##STR00272##	0	3-Cl	H	NH2
124	##STR00273##	—(CH2)2—	##STR00274##	0	H	H	NH2
125	##STR00275##	—(CH2)2—	##STR00276##	1	H	H	OH
126	##STR00277##	##STR00278##	##STR00279##	1	H	H	NH2
127	##STR00280##	##STR00281##	##STR00282##	1	H	H	NH2
128	##STR00283##	—O—CH2—	##STR00284##	1	2-Cl	H	NH2
129	##STR00285##	—O—CH2—	##STR00286##	1	H	5-F	NH2
130	##STR00287##	—O—CH2—	##STR00288##	1	H	5-OCH3	NH2
131	##STR00289##	—CH2—	##STR00290##	1	H	H	NH2
132	##STR00291##	—O—CH2—	##STR00292##	1	H	H	NH2
133	##STR00293##	—CH2—O—CH2—	##STR00294##	1	H	H	NH2
134	##STR00295##	—CH2—	##STR00296##	1	H	H	NH2
135	##STR00297##	—O—CH2—	##STR00298##	1	H	H	NH2
136	##STR00299##	—CH2—O—CH2—	##STR00300##	1	H	H	NH2
137	##STR00301##	—CH2—	##STR00302##	1	H	H	NH2
138	##STR00303##	—O—CH2—	##STR00304##	1	H	H	NH2
139	##STR00305##	—CH2—O—CH2—	##STR00306##	1	H	H	NH2
140	##STR00307##	—CH2—	##STR00308##	1	H	5-F	NH2
141	##STR00309##	Direct bond	##STR00310##	1	H	H	NH2
142	##STR00311##	—CH2—	##STR00312##	1	H	H	NH2
143	##STR00313##	Direct bond	##STR00314##	1	H	H	NH2
144	##STR00315##	—CH2—	##STR00316##	1	H	H	NH2
145	##STR00317##	—CH2—	##STR00318##	1	H	H	NH2
146	##STR00319##	—CH2—	##STR00320##	1	H	H	NH2
147	##STR00321##	—CH2—	##STR00322##	1	H	H	NH2
148	##STR00323##	—CH2—	##STR00324##	1	H	H	NH2
149	##STR00325##	—CH2—	##STR00326##	1	H	H	NH2
150	##STR00327##	—(CH2)2—	##STR00328##	1	H	H	NH2
151	##STR00329##	—(CH2)2—	##STR00330##	1	H	H	NH2
152	##STR00331##	—(CH2)2—	##STR00332##	0	H	H	NH2
153	##STR00333##	—CH2—	##STR00334##	2	H	H	NH2
154	##STR00335##	Direct bond	##STR00336##	1	H	H	NH2
155	##STR00337##	—CH2—	##STR00338##	1	H	H	NH2
156	##STR00339##	Direct bond	##STR00340##	1	H	H	NH2
157	##STR00341##	—CH2—	##STR00342##	1	H	H	NH2
158	##STR00343##	—O—CH2—	##STR00344##	1	H	H	NH2
159	##STR00345##	—O—CH2—	##STR00346##	1	H	H	NH2
160	##STR00347##	—CH2—	##STR00348##	1	H	H	NH2
161	##STR00349##	—CH2—	##STR00350##	1	H	H	NH2
162	##STR00351##	—CH2—	##STR00352##	1	H	H	NH2
163	##STR00353##	—CH2—	##STR00354##	1	H	H	NH2
164	##STR00355##	—(CH2)2—	##STR00356##	1	H	H	NH2
165	##STR00357##	—(CH2)2—	##STR00358##	1	H	H	NH2
166	##STR00359##	—(CH2)2—	##STR00360##	0	H	H	NH2
167	##STR00361##	—CH2—	##STR00362##	2	H	H	NH2
168	##STR00363##	—CH2—	##STR00364##	1	H	H	NH2
169	##STR00365##	—CH2—	##STR00366##	1	H	H	NH2
170	##STR00367##	—CH2—	##STR00368##	1	H	H	NH2
171	##STR00369##	—CH2—	##STR00370##	1	H	H	NH2
172	##STR00371##	—(CH2)2—	##STR00372##	1	H	H	NH2
173	##STR00373##	Direct bond	##STR00374##	1	H	H	NH2
174	##STR00375##	—CH2—	##STR00376##	0	H	H	NH2
175	##STR00377##	—O—CH2—	##STR00378##	1	H	5-OCH3	NH2
176	##STR00379##	—CH2—O—CH2—	##STR00380##	0	H	H	NH2
177	##STR00381##	—CH2—	##STR00382##	0	H	H	NH2
178	##STR00383##	Direct bond	##STR00384##	1	H	H	NH2
179	##STR00385##	—CH2—	##STR00386##	1	H	H	NH2
180	##STR00387##	—CH2—	##STR00388##	1	H	H	NH2
181	##STR00389##	—CH2—	##STR00390##	1	H	H	NH2
182	##STR00391##	—(CH2)2—	##STR00392##	1	H	H	NH2
183	##STR00393##	Direct bond	##STR00394##	1	H	H	NH2
184	##STR00395##	—CH2—	##STR00396##	0	H	H	NH2
185	##STR00397##	—CH2—	##STR00398##	0	H	H	NH2
186	##STR00399##	—CH2—	##STR00400##	1	H	H	NH2
187	##STR00401##	—CH2—	##STR00402##	0	H	H	NH2
188	##STR00403##	Direct bond	##STR00404##	1	H	H	NH2
189	##STR00405##	—CH2—	##STR00406##	1	H	H	NH2
190	##STR00407##	—CH2—	##STR00408##	1	H	H	NH2
191	##STR00409##	Direct bond	##STR00410##	1	H	H	NH2
192	##STR00411##	—CH2—	##STR00412##	1	H	H	NH2
193	##STR00413##	—CH2—O—CH2—	##STR00414##	1	H	H	NH2
194	##STR00415##	—CH2—O—CH2—	##STR00416##	0	H	H	NH2
195	##STR00417##	Direct bond	##STR00418##	1	H	H	NH2
196	##STR00419##	—CH2—	##STR00420##	1	H	H	NH2
197	##STR00421##	Direct bond	##STR00422##	1	H	H	NH2
198	##STR00423##	—CH2—	##STR00424##	1	H	H	NH2
199	##STR00425##	—CH2—O—CH2—	##STR00426##	1	H	H	NH2
200	##STR00427##	—CH2—O—CH2—	##STR00428##	0	H	H	NH2
201	##STR00429##	Direct bond	##STR00430##	1	H	H	NH2
202	##STR00431##	—CH2—	##STR00432##	1	H	H	NH2
203	##STR00433##	—(CH2)2—	##STR00434##	1	H	H	NH2
204	##STR00435##	—CH2—O—CH2	##STR00436##	0	H	H	NH2
205	##STR00437##	Direct bond	##STR00438##	1	H	H	NH2
206	##STR00439##	—CH2—	##STR00440##	1	H	H	NH2
207	##STR00441##	—CH2—O—CH2—	##STR00442##	1	H	H	NH2
208	##STR00443##	CH2—O—CH2—	##STR00444##	0	H	H	NH2
209	##STR00445##	Direct bond	##STR00446##	1	H	H	NH2
210	##STR00447##	Direct bond	##STR00448##	1	H	H	NH2
211	##STR00449##	—CH2—	##STR00450##	1	H	H	NH2
212	##STR00451##	Direct bond	##STR00452##	1	H	H	NH2
213	##STR00453##	Direct bond	##STR00454##	1	H	H	NH2
214	##STR00455##	Direct bond	##STR00456##	1	H	H	NH2
215	##STR00457##	—(CH2)3—	##STR00458##	1	H	H	NH2
216	##STR00459##	—CH2—	##STR00460##	1	H	H	NH2
217	##STR00461##	—(CH2)2—	##STR00462##	1	H	H	NH2
218	##STR00463##	—CH2—	##STR00464##	1	H	H	NH2
219	##STR00465##	—CH2—	##STR00466##	1	H	H	NH2
220	##STR00467##	—CH2—	##STR00468##	1	H	H	NH2
221	##STR00469##	—CH2—	##STR00470##	1	H	H	NH2
222	##STR00471##	—CH2—O—CH2—	##STR00472##	1	H	H	NH2
223	##STR00473##	—CH2—O—CH2—	##STR00474##	1	H	H	NH2
224	##STR00475##	Direct bond	##STR00476##	1	H	H	NH2
225	##STR00477##	—CH2—	##STR00478##	1	H	H	NH2
226	##STR00479##	—CH2—O—CH2—	##STR00480##	1	H	H	NH2
227	##STR00481##	—(CH2)3—	##STR00482##	1	H	H	NH2
228	##STR00483##	Direct bond	##STR00484##	1	H	H	NH2
229	##STR00485##	—CH2—	##STR00486##	1	H	H	NH2
230	##STR00487##	—CH2—O—CH2—	##STR00488##	1	H	H	NH2
231	##STR00489##	Direct bond	##STR00490##	1	H	H	NH2
232	##STR00491##	Direct bond	##STR00492##	1	H	H	NH2
233	##STR00493##	Direct bond	##STR00494##	1	H	H	NH2
234	##STR00495##	Direct bond	##STR00496##	1	H	H	NH2
235	##STR00497##	Direct bond	##STR00498##	1	H	H	NH2
236	##STR00499##	Direct bond	##STR00500##	1	H	H	NH2
237	##STR00501##	Direct bond	##STR00502##	1	H	H	NH2
238	##STR00503##	Direct bond	##STR00504##	1	H	H	NH2
239	##STR00505##	Direct bond	##STR00506##	1	H	H	NH2
240	##STR00507##	Direct bond	##STR00508##	1	H	H	NH2

TABLE 2

Compound No. Structural formula


1            ##STR00509##
2            ##STR00510##
3            ##STR00511##
4            ##STR00512##
5            ##STR00513##
6            ##STR00514##
7            ##STR00515##
8            ##STR00516##
9            ##STR00517##
10           ##STR00518##
11           ##STR00519##
12           ##STR00520##
13           ##STR00521##
14           ##STR00522##
15           ##STR00523##
16           ##STR00524##
17           ##STR00525##
18           ##STR00526##
19           ##STR00527##
20           ##STR00528##

TABLE 3

Compound No. Structural formula


1            ##STR00529##
2            ##STR00530##
3            ##STR00531##
4            ##STR00532##
5            ##STR00533##
6            ##STR00534##
7            ##STR00535##
8            ##STR00536##
9            ##STR00537##
10           ##STR00538##
11           ##STR00539##
12           ##STR00540##
13           ##STR00541##
14           ##STR00542##
15           ##STR00543##
16           ##STR00544##

TABLE 4

Compound No. Structural formula


1            ##STR00545##
2            ##STR00546##
3            ##STR00547##
4            ##STR00548##
5            ##STR00549##
6            ##STR00550##
7            ##STR00551##
8            ##STR00552##
9            ##STR00553##
10           ##STR00554##
11           ##STR00555##
12           ##STR00556##
13           ##STR00557##
14           ##STR00558##

The compound of this invention may be prepared as described below.

(a) A compound represented by formula (14);
A—X—R⁹   (14)
wherein A and X are as defined above; R⁹ is —C(═G)OH (G is an oxygen or sulfur atom) or —NH₂; is condensed with a compound represented by formula (15); ##STR00559##
wherein R¹, R² and n are as defined above; R¹⁰ is —NH₂ when R⁹ is —C(═G)OH (G is as defined above) and —C(═G)OH (G is as defined above) when R⁹ is —NH₂; R¹¹ is an amino group protected with a protective group used in a common peptide-forming reaction, e.g., tert-butoxycarbonyl or a hydroxyl group protected with a protecting group commonly used in a peptide-forming reaction, including benzyl.

(b) A compound represented by formula (16)
A—X—R¹²   (16)
where A and X are as defined above; and R¹² is —OH or —NH₂; is condensed with a compound represented by formula (17); ##STR00560##
wherein R¹, R², R¹¹ and n are as defined above; R¹³ is —OH or —NH₂; using an agent such as N,N′-carbonyldiimidazole, N,N′-thiocarbonyldiimidazole, phosgene or thiophosgene, to give a compound represented by formula (18); ##STR00561##
wherein A, X, Q, n, R¹, R² and R¹¹ are as defined above, whose protecting group is then removed to give the compound of this invention.

(c) A compound represented by formula (14) is condensed with a compound represented by formula (19); ##STR00562##
wherein R¹, R¹⁰ and n are as defined above; R¹⁴ is a methyl, ethyl or tert-butyl group.

(d) A compound represented by formula (16) is condensed with a compound represented by formula (20); ##STR00563##
wherein R¹, R¹³, R¹⁴ and n are as defined above; using an agent such as N,N′-carbonyldiimidazole, N,N′-thiocarbonyldiimidazole, phosgene or thiophosgene to give a compound represented by formula (21); ##STR00564##
wherein A, X, Q, n, R¹ and R¹⁴ are as defined above; which is then hydrolyzed to give a compound represented by formula (22); ##STR00565##
wherein A, X, Q, n and R¹ are as defined above. The product is condensed with a compound represented by formula (23); ##STR00566##
wherein R² and R¹¹ are as defined above; to give a compound represented by formula (18) whose protecting group is then removed to give the compound of this invention.

(e) A compound is represented with formula (22) is condensed with a compound represented by formula (24); ##STR00567##
wherein R² and R³ are as defined above; to give the compound of this invention.

Preparation procedures for typical intermediates are shown below.

A compound represented by formula (15) may be prepared by introducing an appropriate protecting group to a benzoic acid derivative represented by formula (25); ##STR00568##
wherein R¹, R¹⁰ and n are as defined above; condensing the product with a compound represented by formula (23), and removing the protecting group of the condensation product.

A compound represented by formula (17) may be prepared by introducing an appropriate protecting group to a benzoic acid derivative represented by formula (26); ##STR00569##
wherein R¹, R¹³ and n are as defined above; condensing the product with a compound represented by formula (23), and removing the protecting group of the condensation product.

A compound represented by formula (23) may be prepared by introducing a protecting group to a compound represented by formula (24).

Next, reactions used for preparation of the compound of this invention will be described.

The condensation reaction in (a) may be an amide-bond forming reaction for a usual peptide using, for example, an activated ester, a mixed acid anhydride or an acid halide. For example, a carboxylic acid, i.e., a compound represented by formula (14) wherein R⁹ is —C(═G)OH (G is as defined above) or a compound represented by formula (15) wherein R¹⁰ is —C(═G)OH (G is as defined above), may be condensed with a phenol derivative such as 2,4,5-trichlorophenol, pentachlorophenol and 4-nitrophenol, or an N-hydroxy compound such as N-hydroxysuccinimide and N-hydroxybenzotriazole, in the presence of dicyclohexylcarbodiimide, to be converted into an activated ester, which is then condensed with an amine represented by formula (14) wherein R⁹ is —NH₂ or by formula (15) wherein R¹⁰ is —NH₂, to give the desired product.

Alternatively, a carboxylic acid represented by formula (14) wherein R⁹ is —C(═G)OH (G is as defined above) or by formula (15) wherein R¹⁰ is —C(═G)OH (G is as defined above), may be reacted with, for example, oxalyl chloride, thionyl chloride or phosphorus oxychloride to be converted into an acid chloride, which is then condensed with an amine represented by formula (14) wherein R⁹ is —NH₂ or by formula (15) wherein R¹⁰ is —NH₂, to give the desired product.

Furthermore, a carboxylic acid represented by formula (14) wherein R⁹ is —C(═G)OH (G is as defined above) or by formula (15) wherein R¹⁰ is —C(═G)OH (G is as defined above), may be reacted with, for example, isobutyl chlorocarbonate or methanesulfonyl chloride to be converted into a mixed acid anhydride, which is then condensed with an amine represented by formula (14) wherein R⁹ is —NH₂ or by formula (15) wherein R¹⁴ is —NH₂, to give the desired product.

The above condensation reaction may be conducted solely using a peptide condensing agent such as dicyclohexylcarbodiimide, N,N′-carbonyldiimidazole, diphenyl phosphoric azide, diethylphosphorylcyanide, 2-chloro-1,3-dimethylimidazolonium chloride, etc.

The reaction may be usually conducted at −20 to +50° C. for 0.5 to 48 hours. Solvents which may be used include aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; N,N-dimethylformamide; alcohols such as methanol, ethanol and the like; and a mixture thereof. If necessary, an organic base such as triethylamine and pyridine may be added.

The condensation reaction in (b) may be conducted by activating a compound represented by either formula (16) or (17) with, for example, phosgene, thiophosgene, N,N′-carbonyldiimidazole, N,N′-thiocarbonyldiimidazole or the like and then reacting the activated product with the other compound. The reaction may be usually conducted at −20 to +50° C. for 0.5 to 48 hours. Solvents which may be used include aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; N,N-dimethylformamide; and a mixture thereof. If necessary, an organic base such as triethylamine, pyridine and the like may be added.

The condensation reaction in (c) may be conducted as the condensation in (a).

The condensation reaction in (d) may be conducted as the condensation in (b).

The protecting group of the compound represented by formula (17) may be removed under the conditions used in a common peptide-forming reaction. For example, when R¹¹ in formula (18) is the amino group protected with tert-butoxycarbonyl, it may be deprotected by treatment with an acid such as hydrochloric acid, trifluoroacetic acid or the like.

A salt of a compound represented by formula (1) or (13) may be formed during preparation of the compound, but is usually formed by treating the compound with a pharmaceutically acceptable acid. Such an acid includes inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; and organic acids such as acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like. These salts may be also used as an active ingredient in this invention, as the free base, the compound represented by formula (1) or (13).

A compound represented by formula (1) or (13) may be purified or isolated by a usual separation method such as extraction, recrystallization, column chromatography and the like.

The novel benzamide or anilide derivative of this invention has differentiation-inducing effect and thus is useful as a therapeutic and/or improving agent to a variety of diseases such as malignant tumors, autoimmune diseases, dermatologic diseases and parasitism.

As used herein, a “malignant tumor” includes hematologic malignancy such as acute leukemia, malignant lymphoma, multiple myeloma and macroglobulinemia as well as solid tumors such as colon cancer, cerebral tumor, head and neck tumor, breast carcinoma, pulmonary cancer, esophageal cancer, gastric cancer, hepatic cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, nesidioblastoma, renal cell carcinoma, adrenocortical cancer, urinary bladder carcinoma, prostatic cancer, testicular tumor, ovarian carcinoma, uterine cancer, chorionic carcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer, malignant melanoma, osteogenic sarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor and retinoblastoma.

An autoimmune disease includes rheumatism, diabetes, systemic lupus erythematodes, human autoimmune lymphocytotic lymphadenopathy, immunoblastic lymphadenopathy, Crohn disease and ulcerative colitis.

A dermatologic disease includes psoriasis, acne, eczema and atopic dermatitis.

Parasitism includes diseases such as malaria caused through vermination.

Indications for the compound of this invention are not limited to these specific examples.

The active ingredient of this invention useful as a drug may be used in the form of a general pharmaceutical composition. The pharmaceutical composition may be prepared with generally used diluents or excipients such as filler, extender, binder, moisturizing agent, disintegrator, surfactant and lubricant. The pharmaceutical composition may have a variety of dosage forms depending on its therapeutic purpose; typically tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injection (e.g., solution, suspension) and suppository.

For preparing tablets, a variety of carriers well-known in the art may be used. Such a carrier includes excipients such as lactose, glucose, starch, calcium carbonate, kaoline, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup, glycose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and polyvinyl pyrrolidone; disintegrators such as dried starch, sodium alginate, powdered agar, calcium carmelose, starch and lactose; disintegration retarders such as sucrose, cocoa butter and hydrogenated oil; absorption promoters such as quaternary ammonium base and sodium lauryl sulfate; moisturizing agents such as glycerin and starch; adsorbents such as starch, lactose, kaoline, bentonite, colloidal silicic acid; and glidants such as talc, stearates and polyethylene glycol. The tablet may be, if necessary, one coated with a common coating; for example, sugar-coated tablet, gelatin-coated tablet, enteric coated tablet, film-coated tablet, double-layer tablet and multilayer tablet.

In forming pills, a variety of carriers well-known in the art may be used. Such a carrier includes excipients such as crystalline cellulose, lactose, starch, hydrogenated vegetable oil, kaoline and talc; binders such as powdered acacia, powdered tragacanth gum and gelatin; disintegrators such as calcium carmelose and agar.

Capsule may be prepared by blending an active ingredient with a variety of the above carriers as usual and filling the resulting blend into, for example, a hard or soft gelatin capsule or the like.

For preparing injection, solution, emulsion and suspension are sterilized and preferably isotonic with blood. It may be prepared using diluents commonly used in the art; for example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. The pharmaceutical preparation may contain sodium chloride necessary to prepare an isotonic solution, glucose or glycerin, as well as usual solubilizers, buffers and soothing agents.

Suppository may be formed using a variety of well-known carriers; for example, semi-synthetic glyceride, cocoa butter, higher alcohols, higher alcohol esters and polyethylene glycol.

Furthermore, the pharmaceutical composition may contain coloring agents, preservatives, perfumes, flavors, sweeteners and/or other drugs.

The amount of the active ingredient in the pharmaceutical composition of this invention may be, as appropriate, selected from a wide range with no limitations, and is generally from 1 to 70% by weight in the composition, preferably about 5 to 50% by weight.

An administration route of the pharmaceutical composition is not limited, and selected depending on patient's age, sex, severity of disease and other conditions. For example, tablet, pill, solution, suspension, emulsion, granule and capsule may be orally administered; injection may be intravenously administered solely or in combination with a common infusion fluid such as glucose, amino acids and the like, or if necessary, intramuscularly, subcutaneously or intraperitoneally as a sole preparation. Suppository may be intrarectally administered.

Dose of the pharmaceutical preparation of this invention may be selected, depending on their dosage form, patient's age, sex and severity of disease, and other conditions, as appropriate, but the amount of the active ingredient may be generally about 0.0001 to 100 mg/kg a day. It is recommended that a unit dosage form may contain about 0.001 to 1000 mg of the active ingredient.

The compound represented by formula (1) or (13) of this invention or a salt thereof exhibits no or a d, J=5.9
Results

The results for the compound of Example 48 (dose: 66 μmol/kg) against HT-29 are shown in FIG. 1.

The results for the compound of Example 48 (dose: 66 μmol/kg) against KB-3-1 are shown in FIG. 2.

Calculation Example

Model Construction of Superposition Using High Activity Compounds

Three dimensional structure was superimposed using the compounds of Examples 45, 46 and 48 which exhibit a high differentiation-inducing activity, to extract information on spatial configurations of atomic groups necessary for expression of their activity.

For this purpose, any of commercially available program packages, e.g., CATALYST(MSI), Cerius2/QSAR+(MSI) and SYBYL/DISCO(Tripos), may be used to perform a similar level of analysis. Here, SYBYL/DISCO(Tripos) was used for construction of a superimposed structure and analyses.

For the compound of Example 48, a three-dimensional structure was generated using the sketch function of SYBYL, a point charge was allocated on each atom by Gasteiger-Huckel method, and the structure was optimized using Tripos force field. A dummy atom was placed at sites possibly interacting with a biomolecule in order to determine the sites where such an interaction may occur and which may be important for an interaction between a drug and a biomolecule, e.g., a hydrophobic-interaction site (e.g., an aromatic ring and an aliphatic side chain) and a hydrogen-bonding site (e.g., a carbonyl oxygen, hydroxyl and amino). The interactions were categorized in order to identify the types of interaction, e.g., hydrophobic interaction, hydrogen bond and electrostatic interaction, and a different type of dummy atom was allocated to each of the interactions. Furthermore, conformers were generated by rotating the molecule at a rotatable bond to retain a conformation in which there was a change of the distance between dummy atoms allocated at the possible interaction sites, in a conformation file as a candidate conformation. For the compounds of Examples 45 and 46, three dimensional structures were constructed and conformations were generated as described for the compound of Example 48.

Using the compound of Example 48 as a template, for each of its conformations a superimposed structure was constructed so that the dummy atoms showing the same type of interaction were superimposed for both conformations of Examples 45 and 46.

For the superimposed structures, the optimal superimposed structure was selected according to the analysis results of the three dimensional QSAR using the number of the dummy atoms used in the superimposition (the number of common interactions), the degree of steric superimposition (volume of superimposition) and the activity values.

It was found that in the superimposed structure obtained, the centroid of ring B (W1), the centroid of ring A (W2) and hydrogen bond acceptor (e.g., carbonyl oxygen)(W3) in formula (13) are positioned in a manner that there are the following relationships between them; W1−W2=8.34 Å, W1−W3=3.80 Å and W2−W3=5.55 Å.

Calculation Example 1

The Compound of Example 130

Appropriate 7 atoms were selected from the possible interaction sites and the constituent atoms of the benzamide structure of the compound of Example 130, and optimization was performed by applying restrained potential to the compound of Example 130, using the compounds of Examples 45, 46 and 48 used in the above superimposition as target structures. Then, optimization was performed without restrained potential to obtain an active conformation of the compound of Example 130. For this active conformation, the centroid of the benzene ring in the benzamide (W1), the centroid of the pyridine ring (W2) and the carbonyl carbon (W3) were determined to extract the parameters on its spatial configuration.

All conformations were generated for the rotatable bonds, and for each of the conformations, an energy level was calculated to determine the most stable structure. The energy level of the most stable structure was calculated to determine the difference from the active conformation. As a result, it was found that the structure obtained may have a configuration in which W1−W2=8.43 Å, W1−W3=3.82 Å and W2−W3=5.88 Å (energy difference from the most stable structure=2.86 kcal/mol).

With analysis using the dummy atoms obtained in the construction of the above superimposed structure model, the same results were obtained.

Results

The results of the calculation are shown in Table 7.

TABLE 7
Calculation results of the parameters on the
spatial configurations
	Compound	W1-W2 (Å)	W1-W3 (Å)	W2-W3 (Å)
	Example 39	8.29	3.95	5.49
	Example 45	8.54	3.85	5.55
	Example 46	7.42	3.97	5.93
	Example 47	8.52	3.88	5.96
	Example 48	8.43	3.94	5.51
	Example 79	7.09	5.20	5.48
	Example 80	8.59	4.37	5.51
	Example 87	6.80	3.80	3.63
	Example 88	8.67	3.50	6.22
	Example 124	8.29	3.75	5.90
	Example 128	8.64	3.76	5.88
	Example 130	8.43	3.82	5.47
	Example 131	8.59	4.88	7.27
	Example 136	7.59	3.94	7.27
	Example 137	7.58	3.94	7.47
	Example 138	9.07	3.94	7.29
	Example 139	7.64	3.94	7.50
	Example 140	9.11	3.94	7.50
	Example 141	7.60	3.94	7.28
	Example 142	9.02	3.94	7.44
	Example 143	7.62	3.94	7.29
	Example 145	8.48	4.40	5.69

Claims

1. A compound benzamide compound represented by formula (1): ##STR00570##

wherein A is an optionally substituted phenyl group or an optionally substituted heterocyclic group wherein the heterocycle part in the optionally substituted heterocyclic group is selected from the group consisting of pyridine, pyrazine, pyridazine, thiophene and furan, and wherein the substituent(s) for the phenyl group or the heterocyclic group is (are) 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, and a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbons, a phenyl group and a heterocyclic group ;

X is a bond or a moiety having a structure selected from those illustrated in formula (2): ##STR00571##

 wherein e is an integer of 1 to 4; g and m are independently an integer of 0 to 4; R⁴ is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons, or the acyl group represented by formula (3) ##STR00572##

 wherein R⁶ is an optionally substituted alkyl group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a phenyl group or a heterocyclic group; pyridyl group; R⁵ is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons ;

n is an integer of 0 to 4, provided that when X is a bond, n is not zero ;

Q is a moiety having a structure selected from those illustrated in formula (4) ##STR00573##

 wherein R⁷ and R⁸ are independently is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons;

R¹ and R² are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group or an alkoxycarbonyl group having 1 to 4 carbons ;

R³ is a hydroxyl or an amino group or a pharmaceutically acceptable salt thereof.

2. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein n is an integer of 1 to 4.

3. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 2, wherein Q is selected from the structures illustrated in formula (5): ##STR00574##

4. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein A is an optionally substituted hetero ring.

5. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein A is an optionally substituted pyridyl group.

6. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein X is a direct bond.

7. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein R¹ and R² are a hydrogen atom.

8. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 7, wherein R³ is an amino group.

9. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is the structure represented by formula (6):

—(CH₂)e—  (6)

10. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 9, wherein n is 1; and R¹ and R² are a hydrogen atom.

11. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 10, wherein R³ is an amino group.

12. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is selected from the structures illustrated in formula (7): ##STR00575##

13. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 12, wherein n is 1; and R¹ and R² are a hydrogen atom.

14. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 13, wherein R³ is an amino group.

15. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is selected from the structures illustrated in formula (8): ##STR00576##

16. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 15, wherein n is 1; and R¹ and R² are a hydrogen atom.

17. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 16, wherein R³ is an amino group.

18. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein n is zero.

19. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 18, wherein Q is selected from the structures illustrated in formula (5).

20. A benzamide derivative compound or a pharmaceutically acceptable salt thereof as claimed in claim 19 1, wherein A is an optionally substituted hetero ring heterocyclic group.

21. A benzamide derivative compound or a pharmaceutically acceptable salt thereof as claimed in claim 20, wherein A is an optionally substituted pyridyl group.

22. A benzamide derivative compound or a pharmaceutically acceptable salt thereof as claimed in claim 21, wherein R¹ and R² are a hydrogen atom.

23. A benzamide derivative or a pharmaceutically acceptable salt thereof compound of formula (1) as claimed in claim 22, wherein R³ is an amino group .

24. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (9) ##STR00577##

25. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (10) ##STR00578##

26. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (11) ##STR00579##

27. A benzamide derivative compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 represented by formula (12) ##STR00580##

28. A composition suitable for the treatment of cancer which comprises a therapeutic effectively amount of a compound as set forth in claim 1, and a pharmaceutically acceptable carrier or excipient.

29. The composition of claim 28, wherein said carrier or excipient is selected from the group consisting of lactose, glucose, starch, calcium carbonate, kaoline, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quarternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates, and polyethylene glycol.

30. The composition of claim 28, which is in the form of a dosage formulation selected from the group consisting of a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injectable solution or suspension, and suppository.

31. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound according to claim 1.

32. The composition of claim 31, which is a pharmaceutically acceptable formulation selected from the group consisting of a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injectable solution or suspension, and suppository.

33. A benzamide compound of formula (12) ##STR00581##