REGISTER  |  SIGN IN
United States PatentRE39754
Suzuki , ; et al.July 31, 2007
Title
Benzamide derivatives and pharmaceutical compositions containing same
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##
Inventors:Suzuki; Tsuneji (Ichihara, JP), Ando; Tomoyuki  (Ichihara, JP), Tsuchiya; Katsutoshi  (Ichihara, JP), Nakanishi; Osamu  (Chiba, JP), Saito; Akiko  (Chiba, JP), Yamashita; Takashi  (Nagareyama, JP), Shiraishi; Yoshinori  (Yokohama, JP), Tanaka; Eishi  (Chiba, JP)
Assignee:Schering AG (Berlin, DE)
Appl. No.:10/640,278
Filed:August 14, 2003
PCT Pub Date:July 31, 2007
Foreign Application Priority Data
Sep 30, 1996 [JP] 8-258863
Current U.S. Class:514/346 514/352 544/238 544/242 544/336 546/290 546/342 548/400 548/452 549/200 549/30 549/302 549/49 564/342 514/247 514/277 
Current International Class:A61K 31/44 (20060101) A01N 43/08 (20060101) A01N 43/32 (20060101) C07D 211/70 (20060101) C07D 327/04 (20060101) C07D 327/06 (20060101)
Field of Search:514/346,351,352 546/342,290,341,314,340 544/238,242,336 549/30,49,200,302 548/400,452 564/342
Claims

What is claimed is:
1. A .Iadd.benzamide .Iaddend.compound represented by formula (1): ##STR00570## wherein A is an optionally substituted phenyl group or an optionally substituted heterocyclic group 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, 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; R.sup.4 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 R.sup.6 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; R.sup.5 is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons; n is an integer of 0-4 .[., 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 R.sup.7 and R.sup.8 are independently a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons; R.sup.1 and R.sup.2 are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino 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, 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; R.sup.3 is .[.a hydroxyl or.]. .Iadd.an .Iaddend.amino group.Iadd.; .Iaddend.or a pharmaceutically acceptable salt thereof.
.[.2. A benzamiode 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.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim .[.2.]. .Iadd.1.Iaddend., wherein Q is selected from the structures illustrated in formula (5): ##STR00574## wherein R.sup.7 and R.sup.8 are as defined above.
4. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein A is an optionally substituted hetero ring.
5. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein A is an optionally substituted pyridyl group.
6. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 4, wherein X is a direct bond.
7. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein R.sup.1 and R.sup.2 are a hydrogen atom.
8. A benzamide .[.derivative or a pharmaceutically acceptable salt thereof.]. .Iadd.compound of formula (1) .Iaddend.as claimed in claim 7.[., wherein R.sup.1 is an amino group.]. .
9. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is the structure represented by formula (6): --(CH.sub.2)e-- (6) wherein e is an integer of 1 to 4.
10. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 9, wherein n is 1; and R.sup.1 and R.sup.2 are a hydrogen atom.
11. A benzamide .[.derivative or a pharmaceutically acceptable salt thereof.]. .Iadd.compound of formula (1) .Iaddend.as claimed in claim 10.[., wherein R.sup.3 is an amino group.]. .
12. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is selected from the structure illustrated in formula (7): ##STR00575## wherein e, g and R.sup.4 are as defined above.
13. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 12, wherein n is 1; and R.sup.1 and R.sup.2 are a hydrogen atom.
14. A benzamide .[.derivative or a pharmaceutically acceptable salt thereof.]. .Iadd.compound of formula (1) .Iaddend.as claimed in claim 13.[., wherein R.sup.3 is an amino group.]. .
15. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein X is selected from the structures illustrated in formula (8): ##STR00576## wherein g, m and R.sup.5 are as defined above.
16. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim 15, wherein n is 1; and R.sup.1 and R.sup.2 are a hydrogen atom.
17. A benzamide .[.derivative or a pharmaceutically acceptable salt thereof.]. .Iadd.compound of formula (1) .Iaddend.as claimed in claim 16.[., wherein R.sup.3 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) ##STR00577## .].
.[.20. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 19, wherein A is an optionally substituted hetero ring..].
.[.21. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in claim 20, wherein A is an optionally substituted pyridyl group..].
22. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof as claimed in claim .[.21.]. .Iadd.5.Iaddend., wherein R.sup.1 and R.sup.2 are a hydrogen atom.
23. A benzamide .[.derivative or a pharmaceutically acceptable salt thereof.]. .Iadd.compound of formula (1) .Iaddend.as claimed in claim 22.[., wherein R.sup.1 is an amino group.]. .
24. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof .[.as claimed in claim 1.]. represented by formula (9) ##STR00578##
25. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof .[.as claimed in claim 1.]. represented by formula (10) ##STR00579##
26. A benzamide .[.derivative.]. .Iadd.compound .Iaddend.or a pharmaceutically acceptable salt thereof .[.as claimed in claim 1.]. represented by formula (11) ##STR00580##
.[.27. A benzamide derivative or a pharmaceutically acceptable salt thereof (as claimed in claim 1) represented by formula (12) ##STR00581## .].
.[.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.]. .Iadd.31.Iaddend., 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.]. .Iadd.benzamide compound represented by formula (1): ##STR00582## wherein A is an optionally substituted phenyl group or an optionally substituted heterocyclic group 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, 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): ##STR00583## wherein e is an integer of 1 to 4; g and m are independently an integer of 0 to 4; R.sup.4 is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons, or the acyl group represented by formula (3) ##STR00584## wherein R.sup.6 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; R.sup.5 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) ##STR00585## wherein R.sup.7 and R.sup.8 are independently a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons; R.sup.1 and R.sup.2 are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino 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, 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; R.sup.3 is an amino group; or a pharmaceutically acceptable salt thereof; and ii. a pharmaceutically acceptable carrier or excipient.Iaddend..
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.
.Iadd.33. A benzamide compound of formula (9) ##STR00586## .Iaddend.
.Iadd.34. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound according to claim 33 and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.35. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound or pharmaceutically acceptable salt thereof according to claim 24, and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.36. A benzamide compound of formula (10) ##STR00587## .Iaddend.
.Iadd.37. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound according to claim 36, and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.38. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound or pharmaceutically acceptable salt thereof according to claim 25, and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.39. A benzamide compound of formula (11) ##STR00588## .Iaddend.
.Iadd.40. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound according to claim 39, and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.41. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound or pharmaceutically acceptable salt thereof according to claim 26, and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.42. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound of formula (12) ##STR00589## and a pharmaceutically acceptable carrier or excipient..Iaddend.
.Iadd.43. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound represented by formula (12) ##STR00590## or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient..Iaddend.
Description
CROSS REFERENCE

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

1. Field of the Invention

This invention relates to a differentiation-inducing agent. In particular, this invention relates to the use of a novel benzamide derivative or anilide derivative for an anticancer drug or other drugs based on its differentiation-inducing activity.

2. Description of the Related Art

Cancers have now become a top cause of death, exceeding heart and cerebrovascular diseases, and so many studies have been conducted with enormous expense and time to overcome cancers. They have not been, however, overcome in spite of a variety of investigations for therapy such as a surgical operation, a radiation therapy and thermotherapy. Among those therapies, chemotherapy is one of the main area for cancer treatment. To date, however, no satisfactory drugs have been discovered, and thus an anticancer drug with reduced toxicity and high therapeutic effect has been desired. Many of the conventional anticancer drugs show their effect by affecting mainly DNA to express their cytotoxicity and then injuring carcinoma cells. However, since they do not have sufficient selectivity between carcinoma cells and normal cells, adverse reactions expressed in normal cells have limited their use in therapy.

Meanwhile, differentiation-inducing agents among anticancer drugs are intended to induce differentiation of carcinoma cells for controlling their infinite proliferation, rather than directly kill the cells.

The agents may, therefore, be inferior to the anticancer drugs directly killing carcinoma cells, with regard to involution of a carcinoma, but may be expected to have reduced toxicity and different selectivity. In fact, it is well known that retinoic acid, a differentiation-inducing agent, may be used for treatment of acute promyelogenous leukemia to exhibit a higher effect [Huang et al., Blood, 72, 567-572(1988); Castaign et al., Blood, 76, 1704-1709 (1990); Warrell et al., New Engl. J. Med. 324, 1385-1393(1991) etc.]. In addition, vitamin D derivatives exhibit differentiation-inducing effect, and thus their application for anticancer drugs have been investigated [e.g., Olsson et al, Cancer Res. 43, 5862-5867 (1983) etc.].

As the results of these investigations, there have been reported applications for anticancer drugs, of a variety of differentiation-inducing agents such as vitamin D derivatives (JP-A 6-179622), isoprene derivatives (JP-A6-192073), tocopherol (JP-A6-256181), quinone derivatives (JP-A 6-305955), noncyclic polyisoprenoids (JP-A 6-316520), benzoic acid derivatives (JP-A 7-206765) and glycolipids (JP-A 7-258100). There have been no agents having sufficient level of effect for cancer treatment in spite of the investigations, and thus thee has been greatly desired a highly safe agent effective to a variety of cancers.

SUMMARY OF THE INVENTION

An objective of this invention is to provide a compound which exhibits differentiation-inducing effect and is useful as a pharmaceutical agent such as therapeutic or improving agents for malignant tumors, automimmune diseases, dermatologic diseases and parasitism.

We have intensely attempted to achieve the above objective and have found that a novel benzamide derivative and a novel anilide derivative having differentiation-inducing effect show antitumor effect, leading to this invention. Specifically, this invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. ##STR00002## wherein A is an optionally substituted a phenyl or heterocyclic group which has 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, 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) ##STR00003## wherein e is an integer of 1 to 4; g and m are independently an integer of 0 to 4; R.sup.4 is hydrogen or an optionally substituted alkyl group having 1 to 4 carbons, or the acyl group represented by formula (3) ##STR00004## wherein R.sup.6 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; R.sup.5 is hydrogen 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) ##STR00005## wherein R.sup.7 and R.sup.8 are independently hydrogen or an optionally substituted alkyl having 1 to 4 carbons; R.sup.1 and R.sup.2 are independently a hydrogen atom, a halogen atom, a hydroxyl group, amino 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, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having to 4 carbons, a carboxyl group or an alkoxycarbonyl group having 1 to 4 carbons; R.sup.3 is a hydroxyl or amino group.

This invention also provides an anilide having the structure represented by formula (13) ##STR00006## wherein A and R.sup.3 are as defined above; B is an optionally substituted a phenyl or heterocycle group; Y is a moiety having --CO--, --CS--, --SO-- or --SO.sub.2-- which is linear, cyclic or their combination and links A and B; and in which the distances between the centroid of ring B (W1), the centroid of ring A (W2) and an oxygen or sulfur atom as a hydrogen bond acceptor in the moiety Y (W3) can be as follows; W1-W2=6.0 to 11.0 .ANG., W1-W3=3.0 to 8.0 .ANG., and W2-W3=3.0 to 8.0 .ANG.; preferably W1-W2=7.0 to 9.5 .ANG.; W1-W3 is 3.0 to 5.0 .ANG.; and W2-W3 is 5.0-8.0 .ANG.; or a pharmaceutically acceptable salt thereof.

The novel benzamide derivative and the novel anilide derivative of this invention have differentiation-inducing effect and are useful as a drug such as a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as a carcinostatic agent, specifically to a hematologic malignancy and a solid carcinoma.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a change of the volume of the tumor when the compound of Example 48 was administered against the tumor cell HT-29.

FIG. 2 shows a change of the volume of the tumor when the compound of Example 48 was administered against the tumor cell KB-3-1.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In the above formula (1), n maybe zero or an integer of 1 to 4. Q in the above formula (1) may be any structure illustrated in formula (5); ##STR00007## wherein R.sup.7 and R.sup.8 are as defined above. X in the above formula (1) may be a moiety having the structure represented by formula (6); --(CH.sub.2)e-- (6) 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 R.sup.4 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 R.sup.5 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 R.sup.3is 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 --SO.sub.2-- 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 --SO.sub.2--; (b) one linking A and B, whose cyclic moiety has --CO--, --CS--, --SO-- or --SO.sub.2--; and (c) one linking A and B wherein a combination of cyclic and linear moieties form a structural unit having --CO--, --CS--, --SO-- or --SO.sub.2--.

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, trifluoroacetic 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-US-00001 TABLE 1 ##STR00010## Compound No. A X Q n R1 R2 R3 1 ##STR00011## Direct bond ##STR00012## 1 H H NH.sub.2 2 ##STR00013## --CH.sub.2-- ##STR00014## 0 H H NH.sub.2 3 ##STR00015## --(CH.sub.2).sub.2-- ##STR00016## 0 H H NH.sub.2 4
##STR00017## --(CH.sub.2).sub.3-- ##STR00018## 0 H H NH.sub.2 5 ##STR00019## --(CH.sub.2).sub.4-- ##STR00020## 0 H H NH.sub.2 6 ##STR00021## --CH.sub.2-- ##STR00022## 1 H H NH.sub.2 7 ##STR00023## --(CH.sub.2).sub.2-- ##STR00024## 1 H H NH.sub.2 8
##STR00025## --CH.sub.2-- ##STR00026## 0 H H NH.sub.2 9 ##STR00027## --(CH.sub.2).sub.2-- ##STR00028## 0 H H NH.sub.2 10 ##STR00029## Direct bond ##STR00030## 1 H H NH.sub.2 11 ##STR00031## --CH.sub.2-- ##STR00032## 1 H H NH.sub.2 12 ##STR00033## Direct bond ##STR00034## 1 H H NH.sub.2 13 ##STR00035## Direct bond ##STR00036## 1 H H NH.sub.2 14 ##STR00037## Direct bond ##STR00038## 1 H H NH.sub.2 15 ##STR00039## --CH.sub.2-- ##STR00040## 0 H H NH.sub.2 16 ##STR00041## Direct bond ##STR00042## 1 H H NH.sub.2 17 ##STR00043## Direct bond ##STR00044## 1 H H NH.sub.2 18 ##STR00045## Direct bond ##STR00046## 1 H H NH.sub.2 19 ##STR00047## --CH.sub.2-- ##STR00048## 0 H H NH.sub.2 20 ##STR00049## Direct bond ##STR00050## 1 H H NH.sub.2 21 ##STR00051## --CH.sub.2-- ##STR00052## 0 H H NH.sub.2 22 ##STR00053## --CH.sub.2-- ##STR00054## 0 H H NH.sub.2 23 ##STR00055## --CH.sub.2-- ##STR00056## 1 H H NH.sub.2 24 ##STR00057## Direct bond ##STR00058## 1 H H NH.sub.2 25 ##STR00059## Direct bond ##STR00060## 1
H H NH.sub.2 26 ##STR00061## --CH.sub.2-- ##STR00062## 0 H H NH.sub.2 27 ##STR00063## Direct bond ##STR00064## 1 H H NH.sub.2 28 ##STR00065## Direct bond ##STR00066## 1 H H NH.sub.2 29 ##STR00067## Direct bond ##STR00068## 1 H H NH.sub.2 30 ##STR00069## Direct bond ##STR00070## 1 H H NH.sub.2 31 ##STR00071## Direct bond ##STR00072## 1 H H NH.sub.2 32 ##STR00073## --CH.sub.2-- ##STR00074## 0 H H NH.sub.2 33 ##STR00075## Direct bond ##STR00076## 1 H H NH.sub.2 34 ##STR00077## --CH.sub.2-- ##STR00078## 1 H H NH.sub.2 35 ##STR00079## Direct bond ##STR00080## 1 H H NH.sub.2 36 ##STR00081## Direct bond ##STR00082## 1 H H NH.sub.2 37 ##STR00083## Direct bond ##STR00084## 1 H H NH.sub.2 38 ##STR00085## --CH.sub.2-- ##STR00086## 1 H H NH.sub.2 39 ##STR00087## --CH.sub.2-- ##STR00088## 1 H H NH.sub.2 40 ##STR00089## Direct bond ##STR00090## 1 H H NH.sub.2 41 ##STR00091## Direct bond ##STR00092## 1 H H NH.sub.2 42 ##STR00093## Direct bond ##STR00094## 1 H H NH.sub.2 43 ##STR00095## --CH.sub.2-- ##STR00096## 0 H H NH.sub.2 44 ##STR00097## Direct bond ##STR00098## 1 H H NH.sub.2 45 ##STR00099## Direct bond ##STR00100## 1 H H NH.sub.2 46 ##STR00101## Direct bond ##STR00102## 1 H H NH.sub.2 47 ##STR00103## --CH.sub.2-- ##STR00104## 1 H H NH.sub.2 48 ##STR00105## --O--CH.sub.2-- ##STR00106## 1 H H NH.sub.2 49 ##STR00107## --S--CH.sub.2-- ##STR00108## 1 H H NH.sub.2 50 ##STR00109## ##STR00110## ##STR00111## 1 H H NH.sub.2 51 ##STR00112## --CH.sub.2-- ##STR00113## 1 H H NH.sub.2 52 ##STR00114## --CH.sub.2-- ##STR00115## 1 H H NH.sub.2 53 ##STR00116## --CH.sub.2-- ##STR00117## 0 H H NH.sub.2 54 ##STR00118## --O--CH.sub.2-- ##STR00119## 0 H H NH.sub.2 55 ##STR00120## --O--CH.sub.2-- ##STR00121## 0 H H NH.sub.2 56 ##STR00122## --O--CH.sub.2-- ##STR00123## 1 H H NH.sub.2 57 ##STR00124## --O--CH.sub.2-- ##STR00125## 1 H 5-F NH.sub.2 58 ##STR00126## --CH.sub.2--O--CH.sub.2-- ##STR00127## 0 H H NH.sub.2 59 ##STR00128## ##STR00129## ##STR00130## 1 H H NH.sub.2 60 ##STR00131## ##STR00132## ##STR00133## 1 H H NH.sub.2 61 ##STR00134## --O--CH.sub.2-- ##STR00135## 1 H H NH.sub.2 62 ##STR00136## --O--(CH.sub.2).sub.2-- ##STR00137## 1 H H NH.sub.2 63 ##STR00138## ##STR00139## ##STR00140## 1 H H NH.sub.2 64 ##STR00141## --S--CH.sub.2-- ##STR00142## 1 H H NH.sub.2
65 ##STR00143## --O--CH.sub.2-- ##STR00144## 0 H H NH.sub.2 66 ##STR00145## --O--(CH.sub.2).sub.2-- ##STR00146## 0 H H NH.sub.2 67 ##STR00147## --O--(CH.sub.2).sub.2-- ##STR00148## 0 H H NH.sub.2 68 ##STR00149## --CH.sub.2-- ##STR00150## 0 H H NH.sub.2
69 ##STR00151## --(CH.sub.2).sub.2-- ##STR00152## 0 H H NH.sub.2 70 ##STR00153## --(CH.sub.2).sub.3-- ##STR00154## 0 H H NH.sub.2 71 ##STR00155## Direct bond ##STR00156## 1 H H NH.sub.2 72 ##STR00157## Direct bond ##STR00158## 2 H H NH.sub.2 73
##STR00159## Direct bond ##STR00160## 3 H H NH.sub.2 74 ##STR00161## --CH.sub.2-- ##STR00162## 1 H H NH.sub.2 75 ##STR00163## --(CH.sub.2).sub.2-- ##STR00164## 1 H H NH.sub.2 76 ##STR00165## --(CH.sub.2).sub.3-- ##STR00166## 1 H H NH.sub.2 77
##STR00167## --CH.sub.2-- ##STR00168## 2 H H NH.sub.2 78 ##STR00169## --CH.sub.2-- ##STR00170## 1 H H NH.sub.2 79 ##STR00171## Direct bond ##STR00172## 2 H H NH.sub.2 80 ##STR00173## --CH.sub.2-- ##STR00174## 2 H H NH.sub.2 81 ##STR00175## Direct bond ##STR00176## 1 H H NH.sub.2 82 ##STR00177## --CH.sub.2-- ##STR00178## 1 H H NH.sub.2 83 ##STR00179## --(CH.sub.2).sub.2-- ##STR00180## 1 H H NH.sub.2 84 ##STR00181## --(CH.sub.2).sub.3-- ##STR00182## 1 H H NH.sub.2 85 ##STR00183## --CH.sub.2-- ##STR00184## 1 H H NH.sub.2 86 ##STR00185## --CH.sub.2-- ##STR00186## 1 H H NH.sub.2 87 ##STR00187## Direct bond ##STR00188## 1 H H NH.sub.2 88 ##STR00189## --CH.sub.2-- ##STR00190## 1 H H NH.sub.2 89 ##STR00191## --(CH.sub.2).sub.2-- ##STR00192## 1 H H NH.sub.2 90 ##STR00193## --CH.sub.2-- ##STR00194## 1 H H NH.sub.2 91 ##STR00195## --O--CH.sub.2-- ##STR00196## 1 H H NH.sub.2 92 ##STR00197## --O--CH.sub.2-- ##STR00198## 1 H H NH.sub.2 93 ##STR00199## --O--CH.sub.2-- ##STR00200## 1 H H OH 94
##STR00201## ##STR00202## ##STR00203## 0 H H NH.sub.2 95 ##STR00204## ##STR00205## ##STR00206## 1 H H NH.sub.2 96 ##STR00207## ##STR00208## ##STR00209## 1 H H NH.sub.2 97 ##STR00210## ##STR00211## ##STR00212## 0 H H NH.sub.2 98 ##STR00213## ##STR00214## ##STR00215## 1 H H NH.sub.2 99 ##STR00216## ##STR00217## ##STR00218## 0 H H NH.sub.2 100 ##STR00219## ##STR00220## ##STR00221## 1 H H NH.sub.2 101 ##STR00222## --CH.sub.2--O--CH.sub.2-- ##STR00223## 0 H H NH.sub.2 102 ##STR00224## --CH.sub.2--O--CH.sub.2-- ##STR00225## 0 3-CH.sub.3 H NH.sub.2 103 ##STR00226## --CH.sub.2--O--CH.sub.2-- ##STR00227## 0 H H NH.sub.2 104 ##STR00228## ##STR00229## ##STR00230## 0 H H NH.sub.2 105 ##STR00231## ##STR00232## ##STR00233## 0 H H NH.sub.2 106
##STR00234## ##STR00235## ##STR00236## 0 H H NH.sub.2 107 ##STR00237## ##STR00238## ##STR00239## 1 H H NH.sub.2 108 ##STR00240## ##STR00241## ##STR00242## 0 H H NH.sub.2 109 ##STR00243## --CH.sub.2-- ##STR00244## 1 H H NH.sub.2 110 ##STR00245## --CH.sub.2-- ##STR00246## 1 H 5-F NH.sub.2 111 ##STR00247## --CH.sub.2-- ##STR00248## 1 H H OH 112 ##STR00249## --CH.sub.2-- ##STR00250## 1 H 5-F NH.sub.2 113 ##STR00251## --CH.sub.2-- ##STR00252## 1 H 4-Cl NH.sub.2 114 ##STR00253## --CH.sub.2-- ##STR00254## 1 H H OH 115 ##STR00255## --CH.sub.2-- ##STR00256## 1 H H OH 116 ##STR00257## --CH.sub.2-- ##STR00258## 1 H 4-OH OH 117 ##STR00259## --CH.sub.2-- ##STR00260## 1 H H OH 118 ##STR00261## --CH.sub.2-- ##STR00262## 1 H 5-CH.sub.3 OH 119
##STR00263## --CH.sub.2-- ##STR00264## 1 H 5-OCH.sub.3 OH 120 ##STR00265## --CH.sub.2-- ##STR00266## 1 H H NH.sub.2 121 ##STR00267## --CH.sub.2-- ##STR00268## 1 H 5-OCH.sub.3 NH.sub.2 122 ##STR00269## --(CH.sub.2).sub.3-- ##STR00270## 0 H 5-F NH.sub.2
123 ##STR00271## --(CH.sub.2).sub.2-- ##STR00272## 0 3-Cl H NH.sub.2 124 ##STR00273## --(CH.sub.2).sub.2-- ##STR00274## 0 H H NH.sub.2 125 ##STR00275## --(CH.sub.2).sub.2-- ##STR00276## 1 H H OH 126 ##STR00277## ##STR00278## ##STR00279## 1 H H NH.sub.2
127 ##STR00280## ##STR00281## ##STR00282## 1 H H NH.sub.2 128 ##STR00283## --O--CH.sub.2-- ##STR00284## 1 2-Cl H NH.sub.2 129 ##STR00285## --O--CH.sub.2-- ##STR00286## 1 H 5-F NH.sub.2 130 ##STR00287## --O--CH.sub.2-- ##STR00288## 1 H 5-OCH.sub.3
NH.sub.2 131 ##STR00289## --CH.sub.2-- ##STR00290## 1 H H NH.sub.2 132 ##STR00291## --O--CH.sub.2-- ##STR00292## 1 H H NH.sub.2 133 ##STR00293## --CH.sub.2--O--CH.sub.2-- ##STR00294## 1 H H NH.sub.2 134 ##STR00295## --CH.sub.2-- ##STR00296## 1 H H NH.sub.2 135 ##STR00297## --O--CH.sub.2-- ##STR00298## 1 H H NH.sub.2 136 ##STR00299## --CH.sub.2--O--CH.sub.2-- ##STR00300## 1 H H NH.sub.2 137 ##STR00301## --CH.sub.2-- ##STR00302## 1 H H NH.sub.2 138 ##STR00303## --O--CH.sub.2-- ##STR00304## 1 H H NH.sub.2 139 ##STR00305## --CH.sub.2--O--CH.sub.2-- ##STR00306## 1 H H NH.sub.2 140 ##STR00307## --CH.sub.2-- ##STR00308## 1 H H NH.sub.2 141 ##STR00309## Direct bond ##STR00310## 1 H H NH.sub.2 142 ##STR00311## --CH.sub.2-- ##STR00312## 1 H H NH.sub.2
143 ##STR00313## Direct bond ##STR00314## 1 H H NH.sub.2 144 ##STR00315## --CH.sub.2-- ##STR00316## 1 H H NH.sub.2 145 ##STR00317## --CH.sub.2-- ##STR00318## 1 H H NH.sub.2 146 ##STR00319## --CH.sub.2-- ##STR00320## 1 H H NH.sub.2 147 ##STR00321## --CH.sub.2-- ##STR00322## 1 H H NH.sub.2 148 ##STR00323## --CH.sub.2-- ##STR00324## 1 H H NH.sub.2 149 ##STR00325## --CH.sub.2-- ##STR00326## 1 H H NH.sub.2 150 ##STR00327## --(CH.sub.2).sub.2-- ##STR00328## 1 H H NH.sub.2 151 ##STR00329## --(CH.sub.2).sub.2-- ##STR00330## 1 H H NH.sub.2 152 ##STR00331## --(CH.sub.2).sub.2-- ##STR00332## 0 H H NH.sub.2 153 ##STR00333## --CH.sub.2-- ##STR00334## 2 H H NH.sub.2 154 ##STR00335## Direct bond ##STR00336## 1 H H NH.sub.2 155 ##STR00337## --CH.sub.2-- ##STR00338## 1 H H NH.sub.2 156 ##STR00339## Direct bond ##STR00340## 1 H H NH.sub.2 157 ##STR00341## --CH.sub.2-- ##STR00342## 1 H H NH.sub.2 158 ##STR00343## --O--CH.sub.2-- ##STR00344## 1 H H NH.sub.2 159 ##STR00345## --O--CH.sub.2-- ##STR00346## 1 H H NH.sub.2 160 ##STR00347## --CH.sub.2-- ##STR00348## 1 H H NH.sub.2 161 ##STR00349## --CH.sub.2-- ##STR00350## 1 H H NH.sub.2 162 ##STR00351## --CH.sub.2-- ##STR00352## 1 H H NH.sub.2 163 ##STR00353## --CH.sub.2-- ##STR00354## 1 H H NH.sub.2 164 ##STR00355## --(CH.sub.2).sub.2-- ##STR00356## 1 H H NH.sub.2 165 ##STR00357## --(CH.sub.2).sub.2-- ##STR00358## 1 H H NH.sub.2 166 ##STR00359## --(CH.sub.2).sub.2-- ##STR00360## 0 H H NH.sub.2 167 ##STR00361## --CH.sub.2-- ##STR00362## 2 H H NH.sub.2 168 ##STR00363## --CH.sub.2-- ##STR00364## 1 H H NH.sub.2 169 ##STR00365## --CH.sub.2-- ##STR00366## 1 H H NH.sub.2 170 ##STR00367## --CH.sub.2-- ##STR00368## 1 H H NH.sub.2 171 ##STR00369## --CH.sub.2-- ##STR00370## 1 H H NH.sub.2 172
##STR00371## --(CH.sub.2).sub.2-- ##STR00372## 1 H H NH.sub.2 173 ##STR00373## Direct bond ##STR00374## 1 H H NH.sub.2 174 ##STR00375## --CH.sub.2-- ##STR00376## 0 H H NH.sub.2 175 ##STR00377## --O--CH.sub.2-- ##STR00378## 1 H 5-OCH.sub.3 NH.sub.2 176
##STR00379## --CH.sub.2--O--CH.sub.2-- ##STR00380## 0 H H NH.sub.2 177 ##STR00381## --CH.sub.2-- ##STR00382## 0 H H NH.sub.2 178 ##STR00383## Direct bond ##STR00384## 1 H H NH.sub.2 179 ##STR00385## --CH.sub.2-- ##STR00386## 1 H H NH.sub.2 180
##STR00387## --CH.sub.2-- ##STR00388## 1 H H NH.sub.2 181 ##STR00389## --CH.sub.2-- ##STR00390## 1 H H NH.sub.2 182 ##STR00391## --(CH.sub.2).sub.2-- ##STR00392## 1 H H NH.sub.2 183 ##STR00393## Direct bond ##STR00394## 1 H H NH.sub.2 184 ##STR00395## --CH.sub.2-- ##STR00396## 0 H H NH.sub.2 185 ##STR00397## --CH.sub.2-- ##STR00398## 0 H H NH.sub.2 186 ##STR00399## --CH.sub.2-- ##STR00400## 1 H H NH.sub.2 187 ##STR00401## --CH.sub.2-- ##STR00402## 0 H H NH.sub.2 188 ##STR00403## Direct bond ##STR00404## 1 H H NH.sub.2 189 ##STR00405## --CH.sub.2-- ##STR00406## 1 H H NH.sub.2 190 ##STR00407## --CH.sub.2-- ##STR00408## 1 H H NH.sub.2 191 ##STR00409## Direct bond ##STR00410## 1 H H NH.sub.2 192 ##STR00411## --CH.sub.2-- ##STR00412## 1 H H NH.sub.2 193 ##STR00413## --CH.sub.2--O--CH.sub.2-- ##STR00414## 1 H H NH.sub.2 194 ##STR00415## --CH.sub.2--O--CH.sub.2-- ##STR00416## 0 H H NH.sub.2 195 ##STR00417## Direct bond ##STR00418## 1 H H NH.sub.2 196 ##STR00419## --CH.sub.2-- ##STR00420## 1 H H NH.sub.2 197 ##STR00421## Direct bond ##STR00422## 1 H H NH.sub.2 198 ##STR00423## --CH.sub.2-- ##STR00424## 1 H H NH.sub.2 199 ##STR00425## --CH.sub.2--O--CH.sub.2-- ##STR00426## 1 H H NH.sub.2 200 ##STR00427## --CH.sub.2--O--CH.sub.2-- ##STR00428## 0
H H NH.sub.2 201 ##STR00429## Direct bond ##STR00430## 1 H H NH.sub.2 202 ##STR00431## --CH.sub.2-- ##STR00432## 1 H H NH.sub.2 203 ##STR00433## --(CH.sub.2).sub.2-- ##STR00434## 1 H H NH.sub.2 204 ##STR00435## --CH.sub.2--O--CH.sub.2-- ##STR00436## 0 H H NH.sub.2 205 ##STR00437## Direct bond ##STR00438## 1 H H NH.sub.2 206 ##STR00439## --CH.sub.2-- ##STR00440## 1 H H NH.sub.2 207 ##STR00441## --CH.sub.2--O--CH.sub.2-- ##STR00442## 1 H H NH.sub.2 208 ##STR00443## CH.sub.2--O--CH.sub.2-- ##STR00444## 0
H H NH.sub.2 209 ##STR00445## Direct bond ##STR00446## 1 H H NH.sub.2 210 ##STR00447## Direct bond ##STR00448## 1 H H NH.sub.2 211 ##STR00449## --CH.sub.2-- ##STR00450## 1 H H NH.sub.2 212 ##STR00451## Direct bond ##STR00452## 1 H H NH.sub.2 213
##STR00453## Direct bond ##STR00454## 1 H H NH.sub.2 214 ##STR00455## Direct bond ##STR00456## 1 H H NH.sub.2 215 ##STR00457## --(CH.sub.2).sub.3-- ##STR00458## 1 H H NH.sub.2 216 ##STR00459## --CH.sub.2-- ##STR00460## 1 H H NH.sub.2 217 ##STR00461## --(CH.sub.2).sub.2-- ##STR00462## 1 H H NH.sub.2 218 ##STR00463## --CH.sub.2-- ##STR00464## 1 H H NH.sub.2 219 ##STR00465## --CH.sub.2-- ##STR00466## 1 H H NH.sub.2 220 ##STR00467## --CH.sub.2-- ##STR00468## 1 H H NH.sub.2 221 ##STR00469## --CH.sub.2-- ##STR00470## 1 H H NH.sub.2 222 ##STR00471## --CH.sub.2--O--CH.sub.2-- ##STR00472## 1 H H NH.sub.2 223 ##STR00473## --CH.sub.2--O--CH.sub.2-- ##STR00474## 1 H H NH.sub.2 224 ##STR00475## Direct bond ##STR00476## 1 H H NH.sub.2 225 ##STR00477## --CH.sub.2-- ##STR00478## 1 H H NH.sub.2 226 ##STR00479## --CH.sub.2--O--CH.sub.2-- ##STR00480## 1 H H NH.sub.2

227 ##STR00481## --(CH.sub.2).sub.3-- ##STR00482## 1 H H NH.sub.2 228 ##STR00483## Direct bond ##STR00484## 1 H H NH.sub.2 229 ##STR00485## --CH.sub.2-- ##STR00486## 1 H H NH.sub.2 230 ##STR00487## --CH.sub.2--O--CH.sub.2-- ##STR00488## 1 H H NH.sub.2 231 ##STR00489## Direct bond ##STR00490## 1 H H NH.sub.2 232 ##STR00491## Direct bond ##STR00492## 1 H H NH.sub.2 233 ##STR00493## Direct bond ##STR00494## 1 H H NH.sub.2 234 ##STR00495## Direct bond ##STR00496## 1 H H NH.sub.2 235 ##STR00497## Direct bond ##STR00498## 1 H H NH.sub.2 236 ##STR00499## Direct bond ##STR00500## 1 H H NH.sub.2 237 ##STR00501## Direct bond ##STR00502## 1 H H NH.sub.2 238 ##STR00503## Direct bond ##STR00504## 1 H H NH.sub.2 239 ##STR00505## Direct bond ##STR00506## 1
H H NH.sub.2 240 ##STR00507## Direct bond ##STR00508## 1 H H NH.sub.2

TABLE-US-00002 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-US-00003 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-US-00004 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--R.sup.9 (14) wherein A and X are as defined above; R.sup.9 is --C(.dbd.G)OH (G is an oxygen or sulfur atom) or --NH.sub.2; is condensed with a compound represented by formula (15); ##STR00559## wherein R.sup.1, R.sup.2 and n are as defined above; R.sup.10 is --NH.sub.2 when R.sup.9 is --C(.dbd.G)OH (G is as defined above) and --C(.dbd.G)OH (G is as defined above) when R.sup.9 is --NH.sub.2; R.sup.11 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--R.sup.12 (16) wherein A and X are as defined above; and R.sup.12 is --OH or --NH.sub.2; is condensed with a compound represented by formula (17); ##STR00560## wherein R.sup.1, R.sup.2, R.sup.11 and n are as defined above; R.sup.13 is --OH or --NH.sub.2; 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, R.sup.1, R.sup.2 and R.sup.11 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 R.sup.1, R.sup.10 and n are as defined above; R.sup.14 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 R.sup.1, R.sup.13, R.sup.14 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, R.sup.1 and R.sup.14 are as defined above; which is then hydrolyzed to give a compound represented by formula (22); ##STR00565## wherein A, X, Q, n and R.sup.1 are as defined above. The product is condensed with a compound represented by formula (23); ##STR00566## wherein R.sup.2 and R.sup.11 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 represented with formula (22) is condensed with a compound represented by formula (24); ##STR00567## wherein R.sup.2 and R.sup.3 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 R.sup.1, R.sup.10 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 R.sup.1, R.sup.13 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 R.sup.9 is --C(.dbd.G)OH (G is as defined above) or a compound represented by formula (15) wherein R.sup.10 is --C(.dbd.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 R.sup.9 is --NH.sub.2 or by formula (15) wherein R.sup.10 is --NH.sub.2, to give the desired product.

Alternatively, a carboxylic acid represented by formula (14) wherein R.sup.9 is --C(.dbd.G)OH (G is as defined above) or by formula (15) wherein R.sup.10 is --C(.dbd.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 R.sup.9 is --NH.sub.2 or by formula (15) wherein R.sup.10 is --NH.sub.2, to give the desired product.

Furthermore, a carboxylic acid represented by formula (14) wherein R.sup.9 is --C(.dbd.G)OH (G is as defined above) or by formula (15) wherein R.sup.10 is --C(.dbd.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 R.sup.9 is --NH.sub.2 or by formula (15) wherein R.sup.10 is --NH.sub.2, 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.degree. 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 reactions may be usually conducted at -20 to +50.degree. 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 R.sup.11 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, trifluroacetic 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, adrenocorticol 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 automimmune 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, glucose 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 about 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 .[.mall.]. .Iadd.small .Iaddend.toxicity which is acceptable as the anticancer agent at the dose showing pharmacological effects.

EXAMPLES

This invention will be specifically illustrated with, but is not limited to, the following examples, where the numbers in parentheses indicate those of the compounds shown in the above detailed description.

Example 1

Preparation of N-(2-aminophenyl)-4-(N-benzoylaminomethyl)benzamide hydrochloride (Table 1: hydrochloride of Compound 1):

(1-1) To a suspension of 21.16 g of 4-aminomethylbenzoic acid(140 mmol) in 450 mL of dichloromethane was added 42 mL of triethylamine (300 mmol). Under ice-cooling, 60.4 g of trifluoroacetic anhydride (287 mmol) in 50 mL of dichloromethane were added dropwise, maintaining the inner temperature at 3 to 8.degree. C., and then the mixture was stirred four 3 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and was acidified with 10% hydrochloric acid. The gel precipitate-was collected by filtration and dried to give 30.4 g of 4-(N-trifluoroacetylaminomethyl)benzoic acid (Yield: 87.8%) as an opalescent solid.

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 4.47(2H, d, J=5.8 Hz), 7.39(2H, d, J=8.1 Hz), 7.93(2H, d, J=8.1 Hz), 10.08 (1H, t, J=5.8 Hz), 12.95(1H, br.s.)

(1-2) To a solution of 108 g of o-phenylenediamine (1.0 mol) in 1000 mL of dioxane was added 500 mL of 1N sodium hydroxide aq., and then 218 g of tert-butyldicarbonate (1.1 mol) in 500 mL of dioxane under ice-cooling. After stirring for 6 hours at room temperature, the mixture was left overnight. The mixture was concentrated to 1/2 volume by evaporation, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography (eluent: chloroform) to give a solid, which was then washed with diethyl ether to give 68.4 g of N-tertbutoxycarbonyl-o-phenylenediamine (Yield: 32.8%) as a white solid.

.sup.1H NMR(270 MHz, CDCl.sub.3) .delta. ppm: 1.51(9H, s), 3.75(2H, s), 6.26(1H, s), 6.77(1H, d, J=8.1 Hz), 6.79(1H, dd, J=7.3, 8.1 Hz), 7.00(1H, dd, J=7.3, 8.1 Hz), 7.27(1H, d, J=8.1 Hz)

(1-3) To a suspension of 30 g of the compound from the process (1-1) (121 mmol) in 200 mL of dichloromethane were slowly added dropwise 21 g of oxalyl chloride (165 mmol) with intermittently adding DMF (0.1 mL per 2 mL addition), maintaining the inner temperature within 10 to 15.degree. C. by ice-cooling. After completion of the addition, the mixture was stirred until bubble generation ceased, and then at 40.degree. C. for an additional hour. After evaporation, excess oxalyl chloride was azeotropically removed with toluene, and then the residue was redissolved in 100 mL of dichloroethane. The prepared acid chloride solution was added dropwise to a solution of 22.88 g of the compound from the process (1-2) (110 mmol) in 100 mL of dichloromethane and 200 mL of pyridine, maintaining the inner temperature within 7 to 9.degree. C. by ice-cooling.

After addition, the mixture was warmed to room temperature, and was left overnight. After adding saturated sodium bicarbonate aq. to the reaction mixture, the resulting mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried and evaporated. To the residue was added methanol-diisopropyl ether, and the precipitated solid was collected by filtration and dried to give 28.1 g of N-([2-(N-tert-butoxycarbonyl)aminophenyl]-4-(N-trifluoroacetylaminomethyl- )benzamide (Yield: 58%) as a light yellow solid.

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 1.44(9H, s), 4.48(2H, d, J=5.9 Hz), 7.12-7.23(2H, m), 7.44(2H, d, J=8.1 Hz), 7.54(2H, d, J=8.1 Hz) 7.94(2H, d, J=8.1 Hz), 8.68(1H, br.s), 9.83(1H, s), 10.10(1H, br.t, J=5.9 Hz)

(1-4) To a suspension of 13.12 g of the compound from the process (1-3) (30 mmol) in 120 mL of methanol and 180 mL of water were added 4.70 g of potassium carbonate (34.0 mmol), and the mixture was heated with stirring at 70.degree. C. for 4
hours. It was extracted with chloroform, and the organic layer was washed with saturated brine, dried, evaporated and dried to give 10.3 g of 4-aminomethyl-N-[2-(N-tertbutoxycarbonyl)aminophenyl]benzamide (Yield: quantitative) as a light yellow amorphous solid.

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 3.80(2H, s), 7.13-7.23(2H, m), 7.48-7.58(4H, m), 7.90(2H, d, J=8.1 Hz), 8.69(1H, br.s), 9.77(1H, br.s)

(1-5) To a solution of 0.11 g of the compound from the process (1-4) (0.44 mmol) in 5 mL of pyridine was added 0.08 g of benzyl chloride (0.53 mmol), and the mixture was gradually warmed to room temperature and then stirred for 8 hours. Saturated sodium bicarbonate aq. was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was washed with diisopropyl ether, and the solid obtained was dried to give 0.14 g of N-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-(N-benzoylaminomethyl)benza- mide (Yield: 71.4%) as a white solid.

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 1.44(9H, s), 4.56(2H, d, J=5.9 Hz), 7.11-7.22(2H, m), 7.46-7.56(7H, m), 7.90-7.94(4H, m), 8.67(1H, s), 9.15(1H, t, J=5.9 Hz), 9.81 (1H, s)

(1-6) To a solution of 0.10 g of the compound from the process (1-5) (0.224 mmol) in 5 mL of dioxane and 1 mL of methanol was added 5 mL of 4N hydrochloric acid-dioxane, and the mixture was stirred at room temperature for 7 hours. To the residue after evaporation was added diisopropyl ether, and the formed solid was collected by filtration and dried to give 0.08 g of N-(2-aminophenyl)-4-(N-benzoylaminomethyl)benzamide hydrochloride (Yield: 93%) as a light brown solid.

mp: 206-209.degree. C.

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 4.57(2H, d, J=5.8 Hz), 7.27-7.38(4H, m), 7.47-7.59(5H, m), 7.92(1H, d, J=8.1 Hz), 8.05(1H, d, J=8.1 Hz), 9.19(1H, t, J=5.8 Hz), 10.38(1H, br.s)

IR(KBr, cm.sup.-1): 3286, 3003(br.), 1630, 1551, 1492, 1306, 1250, 749, 695.

As described in Example 1, the compounds of Examples 2 to 44 were prepared, each of whose melting point (mp), .sup.1H NMR data and/or IR data are described below.

Example 2

N-(2-aminophenyl)-4-[N-(2-chlorobenzoyl)aminomethyl]benzamide (Table 1: Compound 14)

mp: 201-204.degree. C. (dec.)

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 4.52(2H, t, J=5.9 Hz), 4.89(2H, br.s), 6.60(1H, ddd, J=1.5, 7.3, 8.1 Hz), 6.78(1H, dd, J=1.5, 8.1 Hz), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.17(1H, d, J=8.1 Hz), 7.38-7.54(6H, m), 7.97(2H, d, J=8.1
Hz), 9.06(1H, br.t, J=5.9 Hz), 9.63(1H, br.s)

IR (KBr) cm.sup.-1: 3268, 1649, 1458, 1304, 748

Example 3

N-(2-aminophenyl)-4-[N-(2-nitrobenzoyl)aminomethyl]benzamide hydrochloride (Table 1: hydrochloride of Compound 18)

mp: 210-212.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.55(2H, t, J=5.9 Hz), 7.20-7.40(3H, m), 7.50-7.60(1H, m), 7.53(2H, d, J=8.1 Hz), 7.60-7.70(2H, m), 7.83(1H, ddd, J=1.5, 8.1, 8.1 Hz), 8.00-8.10(3H, m), 9.34(1H, t, J=5.9 Hz), 10.43(1H, br.s)

IR(KBr)cm.sup.-1: 3283, 2500-3000(br.), 1648, 1534, 1461, 1362, 1314, 754, 701

Example 4

N-(2-aminophenyl)-4-[N-(4-methylbenzoyl)aminomethyl]benzamide hydrochloride (Table 1: hydrochloride of Compound 28)

mp: (amorphous).

.sup.1H NMR (270 MHz, DMSO-d.sub.6) .delta. ppm: 2.37(3H, s), 4.56(2H, d, J=5.0 Hz), 7.20-7.30(6H, m), 7.47(4H, d, J=8.8 Hz), 7.82(2H, d,J=8.8 Hz), 8.03(2H, d, J=8.8 Hz), 9.09(1H, t, J=5 Hz), 10.36(1H, br.s)

IR(KBr)cm.sup.-1: 3269(br.), 2861(br.), 1743, 1636, 1534, 1505, 1456, 1308, 1120, 753.

Example 5

N-(2-aminophenyl)-4-[N-(3-methoxybenzoyl)aminomethyl]benzamide (Table 1: Compound 30)

mp: 182-185.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.81(3H, s), 4.54(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.60(1H, dd, J=6.6, 7.3 Hz), 6.78(1H, d, J=7.3 Hz), 6.97(1H, dd, J=6.6, 7.3 Hz), 7.11(1H, dd, J=1.5, 8.1 Hz), 7.16(1H, d, J=7.3 Hz),
7.35-7.51(5H, m), 7.94(2H, d, J=8.1 Hz), 9.12(1H, br.t, J=5.9 Hz), 9.63(1H, br.s)

IR(KBr)cm.sup.-1: 3301, 1637, 1524, 1489, 1457, 1314, 1248, 752

Example 6

N-(2-aminophenyl)-4-[N-(4-methoxybenzoyl)aminomethyl]benzamide (Table 1: Compound 31)

mp: 149-151.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.82(3H, s), 4.53(2H, d, J=5.9 Hz), 4.88(2H, s), 6.59(1H, dd, J=7.3, 7.3 Hz), 6.77(1H, d, J=8.1 Hz), 6.94-7.00(1H, m), 7.02(2H, d, J=8.8 Hz), 7.16(1H, d, J=8.1 Hz), 7.43(2H, d, J=8.1 Hz), 7.89(2H, d, J=8.8 Hz), 7.94(2H, d, J=8.1 Hz), 8.98(1H, br.t, J=5.9 Hz), 9.61(1H, br.s)

IR(KBr)cm.sup.-1: 3297, 1630, 1527, 1505, 1457, 1256, 1177, 1024,843, 749

Example 7

N-(2-aminophenyl)-4-[N-(3,4,5-trimethoxybenzoyl)aminomethyl]benzamide (Table 1: Compound 33)

mp: 208-210.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.71(3H, s), 3.83(6H, s), 4.55(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.60(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=6.6, 8.1 Hz), 7.16(1H, d, J=8.1 Hz), 7.26(2H, s), 7.44(2H, d, J=8.1 Hz), 7.95(2H, d, J=8.8 Hz), 9.07(1H, t, J=5.9 Hz), 9.62(1H, br.s)

IR(KBR)cm.sup.-1: 3267, 1635, 1582, 1457, 1237, 1132, 755

Example 8

N-(2-aminophenyl)-4-[N-(N,N-dimethyl)aminobenzoyl]aminomethyl]benzamide (Table 1: Compound 36)

mp: 216-219.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.98(6H, s), 4.51(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.60(1H, dd, J=8.1, 8.1 Hz), 6.71(2H, d, J=8.8 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.16(1H, d, J=7.3 Hz), 7.41(2H, d, J=8.1 Hz), 7.78(2H, d, J=8.8
Hz), 7.93(2H, d, J=8.1 Hz), 8.77(1H, t, J=5.9 Hz), 9.63(1H, br.s).

IR(KBr)cm.sup.-1: 3301, 1632, 1519, 1457, 1298, 754

Example 9

N-(2-aminophenyl)-4-[N-(4-trifluoromethylbenzoyl)aminomethyl]benzamide (Table 1: Compound 42)

mp: 243-246.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.58(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.59(1H, dd, J=6.6, 7.3 Hz), 6.77(1H, d, J=8.1 Hz), 6.94(1H, dd, J=5.9, 6.6 Hz), 7.16(1H, d, J=8.1 Hz), 7.45(2H, d, J=8.1 Hz), 7.88(2H, d, J=8.8 Hz), 7.95(2H, d, J=8.1 Hz), 8.11(2H, d, J=8.1 Hz), 9.38(1H, t, J=5.9 Hz), 9.64 (1H, br.s)

IR(KBr)cm.sup.-1: 3301, 1640, 1549, 1523, 1458, 1334, 1162, 1120, 1070, 856, 750

Example 10

N-(2-aminophenyl)-4-[N-(4-carboxybenzoyl)aminomethyl]benzamide hydrochloride (Table 1: hydrochloride of Compound 45)

mp: (amorphous).

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.58(2H, d, J=5.9 Hz), 7.29-7.37(3H, m), 7.49(3H, d, J=8.1 Hz), 8.02-8.06 (6H, m), 9.36(1H, t, J=5.9 Hz), 10.4(1H, br.s)

IR(KBr)cm.sup.-1: 3432(br.), 1718, 1637, 1542, 1499, 1303 (br.), 1116, 1018, 757

Example 11

N-(2-aminophenyl)-4-(N-(4-.[.methoxycarbonlbenzoyl.]. .Iadd.methoxycarbonylbenzoyl.Iaddend.)aminomethylbenzamide (Table 1: Compound 46)

mp: 204-209.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.89(3H, s), 4.57(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.60(1H, dd, J=6.6, 7.3 Hz), 6.78(2H, d, J=7.3 Hz), 6.97(1H, ddd, J=1.5, 6.6, 7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.45 (2H, d, J=8.1 Hz), 7.95(2H, d, J=8.1 Hz), 8.03(2H, d, J=8.8 Hz), 8.07(2H, d, J=8.8 Hz), 9.35(1H, t, J=5.9 Hz), 9.64(1H, br.s)

IR(KBr)cm.sup.-1: 3287(br.), 1721, 1634, 1281, 1113, 750, 703

Example 12

N-(2-aminophenyl)-4-(N-picolinoylaminomethyl)benzamide (Table 1: Compound 173)

mp: 173-178.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.57(2H, d, J=6.6 Hz), 4.88(2H, br.s), 6.59(1H, dd, J=7.3, 8.1 Hz), 6.77(1H, d, J=8.1 Hz), 6.96(1H, dd, J=7.3, 8.1 Hz), 7.16(1H, d, J=7.3 Hz), 7.44(2H, d, J=8.1 Hz), 7.60-7.65(1H, m), 7.93(2H, d, J=8.1 Hz), 7.98-8.08(2H, m), 8.67(1H, d, J=4.4 Hz), 9.45 (1H, t, J=6.6 Hz), 9.61(1H, br s)

IR(KBr)cm.sup.-1: 3330, 1656, 1634, 1523, 1456, 1294, 752

Example 13

N-(2-aminophenyl)-4-[N-(6-methylpicolinoyl)aminomethyl]benzamide (Table 1: Compound 178)

mp: 172-173.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.51(3H, s), 4.57(2H, d, J=6.6 Hz), 5.0(2H, br.s), 6.61(1H, dd, J=7.3, 8.1 Hz), 6.79(1H, d, J=7.3 Hz), 6.98(1H, dd, J=7.3, 8.1 Hz), 7.17(1H, d, J=7.3 Hz), 7.44(2H, d, J=8.1 Hz), 7.43-7.49(1H, m),
7.84-7.90(2H, m), 7.94(2H, d, J=8.1 Hz), 9.27(1H, t, J=5.9 Hz), 9.64(1H, br.s)

IR(KBr)cm.sup.-1: 3331, 1675, 1634, 1594, 1523, 1454, 1307, 1292, 750

Example 14

N-(2-aminophenyl)-4-(N-nicotinoylaminomethyl)benzamide (Table 1: Compound 71)

mp: 193-196.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.58(2H, d), 4.88(2H, br.s), 6.60(1H, t), 6.78(1H, d), 6.97(1H, t), 7.16 (1H, d), 7.46(2H, d), 7.53(1H, dd), 7.95(2H, d), 8.24(1H, ddd), 8.73(1H, dd), 9.07(1H, d), 9.32(1H, br.t), 9.63(1H, br.s)

IR(KBr)cm.sup.-1: 3301, 1639, 1522, 1457, 1314, 749, 705

Example 15

N-(2-aminophenyl)-4-[N-(2-methylnicotinoyl)aminomethyl]benzamide (Table 1: Compound 141)

mp: 191-194.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.53(3H, s), 4.53(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.60(1H, dd, J=6.6, 8.1 Hz), 6.78(1H, d, J=7.3 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.17(1H, d, J=7.3 Hz), 7.29(1H, dd, J=5.1, 8.1 Hz), 7.47(2H, d, J=8.1 Hz), 7.77(1H, dd, J=1.5, 8.1 Hz), 7.97(2H, d, J=8.1 Hz), 8.51(1H, dd, J=1.5, 5.1 Hz), 9.06(1H, t, J=5.9 Hz), 9.64(1H, s)

IR(KBr)cm.sup.-1: 3261, 1642, 1523, 1310, 753

Example 16

N-(2-aminophenyl)-4-[N-(6-methylnicotinoyl)aminomethyl]benzamide (Table 1: Compound 143)

mp: 186-190.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.36(3H, s), 4.56(2H, d, J=5.9 Hz), 4.88(2H, s), 6.60(1H, dd, J=7.4, 7.8 Hz), 6.78(1H, d, J=7.8 Hz), 6.97(1H, dd, J=6.9, 6.9 Hz), 7.16(1H, d, J=7.4 Hz), 7.37(1H, d, J=8.3 Hz), 7.45(2H, d, J=8.3
Hz), 7.95(2H, d, J=8.3 Hz), 8.13(1H, dd, J=2.0, 8.3 Hz), 8.96(1H, s), 9.24(1H, t, J=5.9 Hz), 9.63(1H, br.s)

IR(KBr)cm.sup.-1: 3302, 1636, 1602, 1523, 1489, 1457, 1313, 751

Example 17

N-(2-aminophenyl)-4-[N-(2-chloronicotinoyl)aminomethyl]benzamide (Table 1: Compound 154)

mp: 176-178.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.54(2H, t, J=5.9 Hz), 4.90(2H, br.s), 6.60(1H, ddd, J=1.5, 7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, ddd, J=1.5, 7.3, 7.3 Hz), 7.18(1H, d, J=8.1 Hz), 7.48-7.54(3H, m), 7.94-7.99(3H, m),
8.49(1H, dd, J=2.1, 5.1 Hz), 9.23(1H, br.t, J=5.9 Hz), 9.65(1H, br.s)

IR(KBr)cm.sup.-1: 3264, 1649, 1524, 1400, 1309, 751

Example 18

N-(2-aminophenyl)-4-[N-(6-chloronicotinoyl)aminomethyl]benzamide (Table 1: Compound 156)

mp: 205-208.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 5.57(2H, d, J=5.9 Hz), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.96(1H, dd, J=7.3, 8.1 Hz), 7.16(1H, d, J=8.1 Hz), 7.45(2H, d, J=8.1 Hz), 7.66(1H, d, J=8.8 Hz), 7.95(2H, d, J=8.1 Hz),
8.27-8.32(1H, m), 8.90(1H, d, J=2.1 Hz), 9.38(1H, t, J=5.9 Hz), 9.63(1H, s)

IR(KBr)cm.sup.-1: 3318(br.), 2929, 1646, 1590, 1525, 1503, 1454, 1108, 745

Example 19

N-(2-aminophenyl)-4-(N-isonicotinoylaminomethyl)benzamide (Table 1: Compound 183)

mp: 234-237.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.57(2H, t, J=5.9 Hz), 4.88(2H, br.s), 6.59(1H, dd, J=6.6, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.96(1H, dd, J=7.3, 7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.45(2H, d, J=8.1 Hz), 7.81(2H, d, J=1.5, 4.4 Hz),
7.95(2H, d, J=8.1 Hz), 8.75(2H, d, J=6.6 Hz), 9.41(1H, t, J=5.9 Hz), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3298, 1646, 1550, 1525, 1457, 1304, 843, 760, 695

Example 20

N-(2-aminophenyl)-4-[N-(pyrazin-2-yl)carbonylaminomethyl]benzamide (Table 1: Compound 191)

mp: 207.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.58(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.59(1H, dd, J=7.3, 7.3 Hz), 6.77(1H, d, J=8.1 Hz), 6.94(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.15(1H, d, J=7.3 Hz), 7.45(2H, d, J=8.1 Hz), 7.93(2H, d, J=8.1 Hz),
8.77(1H, d, J=1.5 Hz), 8.90(1H, d, J=2.1 Hz), 9.21(1H, s), 9.55-9.61(2H, m)

IR(KBr)cm.sup.-1: 3368(br.), 1657, 1524, 1455, 1295, 1023, 751

Example 21

N-(2-aminophenyl)-4-[N-(thiophen-2-yl)carbonylaminomethyl]benzamide (Table 1: Compound 201)

mp: 202-205.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.52(2H, t, J=5.9 Hz), 4.88(3H, br.s), 6.60(1H, dd, J=6.6.7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.15-7.18(2H, m), 7.43(2H,d, J=8.1 Hz), 7.78(1H, d, J=4.4), 7.82(1H, d, J=3.7
Hz), 7.95(2H, d, J=8.1 Hz), 9.12(1H, br.t, J=5.9 Hz), 9.62 (1H, br.s)

IR(KBr)cm.sup.-1: 3306, 1633, 1523, 1456, 1297, 750, 716

Example 22

N-(2-aminophenyl)-4-[N-(furan-2-yl)carbonylaminomethyl]benzamide (Table 1: Compound 205)

mp: 197.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.59(2H, d, J=6.6 Hz), 4.86(2H, br.s), 6.59(1H, dd, J=6.6, 6.6 Hz), 6.63(1H, dd, J=1.5, 3.6 Hz), 6.78(1H, d, J=8.1 Hz), 6.96(1H, dd, J=7.3, 6.6 Hz), 7.10-7.20(2H, m), 7.41(2H, d, J=8.1 Hz),
7.84(1H, s), 7.94(2H, d, J=8.1 Hz), 9.00(1H, br.t, J=5.9 Hz), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3245, 1651, 1573, 1545, 1323, 1241, 745

Example 23

N-(2-aminophenyl)-4-[N-(pyrrol-2-yl)carbonylaminomethyl]benzamide (Table 1: Compound 209)

mp: 216-220.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.50(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.10(1H, dd, J=2.1, 5.9 Hz), 6.59(1H, dd, J=7.3, 7.3 Hz), 6.77(1H, dd, J=1.5, 8.1 Hz), 6.84-6.88 (2H, m), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16(1H, d, J=7.3
Hz), 7.41(2H, d, J=8.1 Hz), 7.94(2H, d, J=8.1 Hz), 8.62(1H, br.t, J=5.9 Hz), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3275, 1655, 1584, 1534, 1458, 1316, 747

Example 24

N-(2-aminophenyl)-4-[N-(N'-methyl-1H-pyrrol-2-yl)carbonylaminomethyl]benza- mide (Table 1: Compound 210)

mp: 177-179.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.84(3H, s), 4.46(2H, d, J=5.9 Hz), 4.88(2H, br.s), 6.03(1H, dd, J=2.1, 4.4 Hz), 6.59(1H, dd, J=8.1, 8.1 Hz), 6.77(1H, d, J=8.1 Hz), 6.84-6.97(2H, m), 7.16(1H, d, J=7.3 Hz), 7.41(2H, d, J=8.1 Hz),
7.93(2H, d, J=8.1 Hz), 8.61(1H, t, J=5.9 Hz), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3325(br.), 1630, 1551, 1520, 1507, 1324, 1265, 1154, 740

Example 25

N-(2-aminophenyl)-4-[N-(isoxazol-5-yl)carbonylaminomethyl]benzamide (Table 1: Compound 212)

mp: 183-185.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.53(2H, d, J=6.6 Hz), 4.89(2H, br.s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=7.3 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.12(1H, d, J=2.1 Hz), 7.16(1H, d, J=8.1 Hz), 7.44(2H, d, J=8.1 Hz), 7.95(2H, d, J=8.1 Hz), 8.76(1H, d, J=1.5 Hz), 9.61(1H, t, J=5.9 Hz), 9.64(1H, br.s)

IR(KBr)cm.sup.-1: 3278(br.), 1636, 1576, 1522, 1458, 1220, 749

Example 26

N-(2-aminophenyl)-4-[N-(3-methylisothiazol-5-yl)carbonylaminomethyl]benzam- ide (Table 1: Compound 213)

mp: 168-169.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.47(3H, s), 4.54(2H, d, J=5.9 Hz), 4.89(2H, br.s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=7.3 Hz), 6.97(1H, ddd, J=1.0, 7.3, 8.1 Hz), 7.17(1H, d, J=7.3 Hz), 7.44 (2H, d, J=8.1 Hz), 7.73(1H, s), 7.96(2H, d, J=8.1 Hz), 9.44(1H, t, J=5.9 Hz), 9.64(1H, br.s)

IR(KBr)cm.sup.-1: 3310, 1637, 1503, 1294, 751

Example 27

N-(2-aminophenyl)-4-[N-(imidazol-4-yl)carbonylaminomethyl]benzamide (Table 1: Compound 214)

mp: (amorphous).

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.49(2H, d, J=6.4 Hz), 4.87(2H, br.s), 6.59(1H, dd, J=6.9, 6.9 Hz), 6.77(1H, d, J=6.9 Hz), 6.96(1H, dd, J=7.4, 7.4 Hz), 7.16(1H, d, J=6.9 Hz), 7.41(2H, d, J=6.9 Hz), 7.64(1H, br.s), 7.73(1H, br.s),
7.92(2H, d, J=6.9 Hz), 8.56(1H, br.t, J=6.4 Hz), 9.61(1H, s), 12.5(1H, br.s)

IR(KBr)cm.sup.-1: 3278(br.), 1636, 1576, 1522, 1458, 1220, 749

Example 28

N-(2-aminophenyl)-4-[N-(3-aminophenyl)acetylaminomethyl]benzamide (Table 1: Compound 23)

mp: 171-176.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.34(2H, d, J=5.9 Hz), 5.24(4H, br.s), 6.48-6.63(4H, m), 6.78-6.81(1H, m), 6.94-7.00(2H, m), 7.18(1H, d, J=8.1 Hz), 7.34(2H, d, J=8.1 Hz), 7.92(2H, d, J=8.1 Hz), 8.50(1H, t, J=5.9 Hz), 9.61(1H, s)

Example 29

N-(2-aminophenyl)-4-[N-(pyridin-3-yl)acetylaminomethyl]benzamide (Table 1: Compound 74)

mp: 127.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.84(2H, s), 4.40(2H, d, J=5.8 Hz), 7.15-7.29(3H, m), 7.37(1H, d, J=6.6 Hz), 7.43(2H, d, J=8.8 Hz), 7.96(1H, m), 7.98(2H, d, J=8.8 Hz), 8.40(1H, d, J=8.8 Hz), 8.79-8.87(3H, m), 10.20(1H, s)

Example 30

N-(2-aminophenyl)-4-[N-[3-(pyridin-3-yl)propionyl]aminomethyl]benzamide (Table 1: Compound 75)

mp: 183-186.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.51(2H, t, J=7.3 Hz), 2.88(2H, d, J=7.3 Hz), 4.31(2H, d, J=5.9 Hz), 4.89(2H, br.s), 6.60(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16(1H, d, J=8.1 Hz),
7.23(2H, d, J=8.8 Hz), 7.28-7.33(1H, m), 7.63(1H, d, J=8.1 Hz), 7.89(2H, d, J=8.1 Hz), 8.41-8.45(3H, m), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3407, 3313, 1640, 1552, 1522, 1456, 1309, 746, 717

Example 31

N-(2-aminophenyl)-4-[N-[4-(pyridin-3-yl)-1,4-dioxobutyl]aminomethyl]benzam- ide (Table 1: Compound 100)

mp: 145-147.degree. C.(dec..Iadd.).Iaddend.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.37-2.50(2H, m), 2.62-2.68(2H, m), 4.13(2H, s), 4.86(2H, s), 6.56-6.61 (1H, m), 6.76-6.79(1H, m), 6.94-6.99(1H, m), 7.10-7.39 (4H, m), 7.43-7.46(1H, m), 7.78(2H, d, J=8.1 Hz), 8.60-8.64(1H, m),
9.58(1H, s)

IR(KBr)cm.sup.-1: 3348, 1691, 1655, 1534, 1508, 1458, 1395, 1315, 1083, 746

Example 32

N-(2-aminophenyl)-4-[N-(5-chloropyridin-3-yl)oxyacetylaminomethyl]benzamid- e (Table 1: Compound 158)

mp: 199-201.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.43(2H, d, J=6.6 Hz), 4.75(2H, s), 4.87(2H, br. s), 6.60(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.16(1H, d, J=8.1 Hz), 7.37(2H, d, J=8.1 Hz), 7.59(1H, d, J=2.2 Hz), 7.93(2H, d, J=8.1 Hz), 8.25(1H, d, J=1.5 Hz), 8.81(1H, t, J=6.6 Hz), 9.64(1H, s)

IR(KBr)cm.sup.-1: 3288, 3058, 1675, 1633, 1523, 1457, 1314, 912, 755

Example 33

N-(2-amino-5-methoxyphenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzam- ide (Table 1: Compound 175)

mp: 141-144.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.66(3H, s), 4.43(2H, d, J=5.9 Hz), 4.49(2H, br.s), 4.68(2H, s), 6.62(1H, dd, J=2.9, 8.8 Hz), 6.75(1H, d, J=8.8 Hz), 6.91(1H, d, J=2.2 Hz), 7.37(4H, m), 7.92(2H, d, J=8.8 Hz), 8.21(1H, dd, J=1.5,
4.4 Hz), 8.35(1H, d, J=2.7 Hz), 8.81(1H, s), 9.65(1H, s)

Example 34

N-(2-aminophenyl)-4-[N-[3-(pyridin-3-yl)-1,3-dioxopropyl]aminomethyl]benza- mide (Table 1: Compound 98)

mp: 204-206.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.08( 4/3H, s), 4.39( 4/3H, d, J=5.9 Hz), 4.49(2/3H, d, J=5.9 Hz), 4.90(2H, br.s), 5.93(1/3H, s), 6.60(1H, t, J=7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, t, J=7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.3-7.7
(3H, m), 7.8-8.4(3H, m), 8.6-9.2(3H, m), 9.64(1H, s), 14.74(1/3H, s). (2:1 equilibrium mixture)

IR(KBr)cm.sup.-1: 3282, 1690, 1645, 1527, 1421, 1314, 1217, 1028, 994, 911, 753, 701

Example 35

N-(2-aminophenyl)-4-[N-[N-(pyridin-3-yl)aminoacetyl]aminomethyl]benzamide (Table 1: Compound 96)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.77(2H, d, J=6.6 Hz), 4.37(2H, d, J=5.9 Hz), 4.87(2H, br.s), 6.27(1H, t, J=5.9 Hz), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, 7.3 Hz), 6.87(1H, d, J=8.1 Hz), 6.96(1H, dd, J=7.3, 8.1 Hz), 7.09(1H, d, J=4.4 Hz), 7.12(1H, d, J=4.4 Hz), 7.16(1H, d, J=8.1 Hz), 7.33(2H, d, J=8.8 Hz), 7.81(1H, d, J=4.4 Hz), 7.91(2H, d, J=7.3 Hz), 7.99(1H, d, J=2.9 Hz), 8.59(1H, br.t, J=5.1 Hz), 9.63(1H, br.s)

IR(KBr)cm.sup.-1: 3350, 1658, 1525, 1502, 1314, 750

Example 36

N-(2-aminophenyl)-4-[N-(2-aminothiazol-4-yl)acetylaminomethyl]benzamide (Table 1: Compound 220)

mp: (amorphous).

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.34(2H, s), 4.35(2H, d, J=5.9 Hz), 4.87(2H, s), 6.25(1H, s), 6.59(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=7.3 Hz), 6.87(2H, s), 6.96(1H, dd, J=7.3, 7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.37(2H, d, J=8.1
Hz), 7.93(2H, d, J=8.1 Hz), 8.44(1H, t, J=5.9 Hz), 9.62(1H, s)

Example 37

N-(2-aminophenyl)-4-[N-(quinolin-6-yl)carbonylaminomethyl]benzamide (Table 1: Compound 231)

mp: 209-210.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.62(2H, d, J=5.9 Hz), 4.88(2H, s), 6.60(1H, t, J=7.7 Hz), 6.78(1H, d, J=7.3 Hz), 6.95(1H, d, J=7.3 Hz), 7.17(1H, d, J=7.3 Hz), 7.49(2H, d, J=8.8 Hz), 7.62(1H, dd, J=4.4, 8.1 Hz), 7.96(2H, d, J=8.8
Hz), 8.10(1H, d, J=8.8 Hz), 8.23(1H, dd, J=2.2, 8.8 Hz), 8.38(1H, m), 8.49(1H, d, J=8.1 Hz), 8.58(1H, s), 8.99(1H, s), 9.64(1H, s)

IR(KBr)cm.sup.-1: 3301, 1640, 1614, 1545, 1496, 1312, 910, 853, 745

Example 38

N-(2-aminophenyl)-4-[N-(furo[3,2-b]pyridin-2-yl)carbonylaminomethyl]benzam- ide (Table 1: Compound 233)

mp: 191.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.58(2H, d, J=5.9 Hz), 4.88(2H, s), 6.57-6.62(1H m), 6.76-6.79(1H, m), 6.93-6.99(1H, m), 7.15-7.25(1H, m), 7.45-7.52(3H, m), 7.74(1H, s), 7.95(2H, d, J=8.1 Hz), 8.13(1H, d, J=8.8 Hz), 8.63(1H, d, J=3.7 Hz), 9.54(1H, t, J=5.9 Hz), 9.64(1H, s)

IR(KBr)cm.sup.-1: 3406, 1662, 1529, 1507, 1420, 1313, 1209, 1139, 1170, 1139, 924, 741

Example 39

N-(2-aminophenyl)-4-[N-(furo[2,3-c]pyridin-2-yl)carbonylaminomethyl]benzam- ide (Table 1: Compound 234)

mp: 210.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.58(2H, J=6.6 Hz), 4.87(2H, s), 6.57-6.62(1H, m), 6.76-6.79(1H, m), 6.93-6.99(1H, m), 7.14-7.17(1H, m), 7.47(2H, d, J=8.1 Hz), 7.66(1H, s), 7.82(1H, d, J=4.4 Hz), 7.96(2H, d, J=8.1 Hz), 8.48(1H, d, J=5.1 Hz), 9.06(1H, s), 9.60-9.64(2H, m)

IR(KBr)cm.sup.-1: 3320, 1653, 1632, 1598, 1457, 1424, 1308, 1187, 1033, 853, 749

Example 40

N-(2-hydroxyphenyl)-4-[N-[3-(pyridin-3-yl)propionyl]aminomethyl]benzamide (Table 1: Compound 125)

mp: (amorphous)

.sup.1H NMR(270 MHz, CD.sub.3OD) .delta. ppm: 2.61(2H, t, J=7.3 Hz), 3.00(2H, t, J=7.3 Hz), 4.39(2H, s), 7.04(1H, ddd, J=1.5, 8.1, 8.1 Hz), 7.25(2H, d, J=8.1 Hz), 7.33(1H, dd, J=5.1, 8.1 Hz), 7.69(1H, d, J=8.1 Hz), 7.85(2H, d, J=8.1 Hz),
7.86(1H, d, J=8.1 Hz), 8.41(2H, br.s)

IR(neat)cm.sup.-1: 3276, 1645, 1614, 1536, 1509, 1435, 1415, 1385, 1333, 1280, 1247, 1091, 737

Example 41

N-(2-hydroxyphenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide (Table 1: Compound 93)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) 4.43(2H, d, J=6.6 Hz), 4.69(2H, s), 6.83(1H, t, J=6.6 Hz), 6.91(1H, d, J=8.1 Hz), 7.68(1H, d, J=6.6 Hz), 7.82(2H, d, J=8.1 Hz), 8.21(1H, d, J=4.4 Hz), 8.35(1H, d, J=2.2 Hz), 8.81(1H, t, J=6.6 Hz), 9.48(1H, s),
9.75(1H, s)

IR(KBr)cm.sup.-1: 3399, 1664, 1535, 1236, 1064

Example 42

N-(2-hydroxyphenyl)-4-[N-(pyridin-3-yl)acetylaminomethyl]benzamide (Table 1: Compound 117)

mp: 201-202.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.56(2H, s), 4.37(2H, d, J=5.9 Hz), 6.83(1H, ddd, J=1.5, 8.1, 8.1 Hz), 6.92(1H, br.d, J=8.1 Hz), 7.03(1H, ddd, J=1.5, 8.1, 8.1 Hz), 7.34(1H, dd, J=3.7, 8.1 Hz), 7.37(2H, d, J=8.1 Hz), 7.70(2H, d, J=8.1 Hz), 7.91(2H, d, J=8.1 Hz), 8.45(1H, br.d, J=3.7 Hz), 8.49(1H, s), 8.73(1H, t, J=5.9 Hz), 9.47(1H, s), 9.73 (1H, br.s)

IR(KBr)cm.sup.-1: 3272, 3067, 1661, 1647, 1598, 1536, 1455, 1334, 1288, 1194, 1024, 742

Example 43

N-(2-aminophenyl)-4-[N-(pyridin-3-yl)oxyacetyl-N-[3-(pyridin-3-yl-)propyl]- aminomethyl]benzamide (Table 1: Compound 91)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.77-1.93(2H, m), 2.50-2.63(2H, m), 3.16-3.30(2H, m), 4.63(1.2H, s), 4.71(0.8H, s), 4.88(1.2H, s), 4.95(0.8H, s), 5.05(2H, s), 6.57-6.63(1H, m), 6.77-6.79(1H, m), 6.94-7.00(1H, m), 7.11-7.42(5H, m), 7.58-7.64(1H, m), 7.92-8.02(2H, m), 8.15-8.43(5H, m), 9.65(0.6H, s), 9.69(0.4H, s)(a mixture of rotational isomers)

Example 44

N-(2-aminophenyl)-4-[N-methyl-N-(pyridin-3-yl)oxyacetyl]aminomethylbenzami- de (Table 1: Compound 92)

mp: 117-120.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.84 and 2.99(total 3H, s), 4.60 and 4.69(total 2H, s), 4.90(2H, br.s), 4.99 and 5.08(total 2H, s), 6.60(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=7.3, 7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.30-7.43(4H, m), 7.95 and 8.01(total 2H, d, J=8.1 Hz), 8.17(1H, d, J=4.4 Hz), 8.31(1H, d, J=2.9 Hz), 9.65 and 9.68(total 1H, br.s) (a mixture of rotational isomers)

IR(KBr)cm.sup.-1: 3298, 1665, 1501, 1425, 1310, 1276, 1254, 1078, 799, 746, 703

Example 45

Preparation of N-(2-aminophenyl)-4-[N-(pyridin-3-yl)oxamoylaminomethyl]benzamide (Table 1: Compound 95)

(45-1) Ethyl N-(pyridin-3-yl)oxamate (388 mg, 2 mmol) and 638 mg of the compound from the process (1-4) (2 mmol) were dissolved in ethanol, and the mixture was heated with stirring at 40 to 50.degree. C. for 2.5 hours. The precipitated crystals were collected by filtration and washed with 2 mL of ethanol and 3 mL of diethyl ether. The crystals were dried to give 724 mg of N-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)oxamoylaminom- ethyl]benzamide (Yield: 74%).

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.44(9H, s), 4.49(2H, d, J=5.9 Hz), 7.10-7.30(2H, m), 7.35-7.57(5H, m), 7.93(2H, d, J=8.1 Hz), 8.21(1H, br.d, J=5.1 Hz), 8.35(1H, dd, J=1.5, 5.1 Hz), 8.68(1H, br.s), 9.00(1H, d, J=2.9 Hz), 9.70(1H, t, J=5.9 Hz), 9.82(1H, s), 10.98(1H, br.s)

(45-2) To a suspension of 720 mg of the compound from the process (45-1) in 8 mL of methanol was added 8 mL of 4N hydrochloric acid-dioxane solution. After stirring for 3 hours, the mixture was poured into a diluted sodium hydroxide aq. to be basified, and the precipitated crystals were collected by filtration. The crystals were recrystallized from THF/methanol=1:1, to give 280 mg of the desired product.

mp: 254-258.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.67(2H, d, J=5.9 Hz), 4.89(2H, br.s), 6.59(1H, dd, J=7.3 Hz), 6.77(1H, d, J=8.1 Hz), 6.97(1H, dd, J=6.6, 7.3 Hz), 7.16(1H, d, J=8.1 Hz), 7.38-7.44(1H, m), 7.43(2H, d, J=8.1 Hz), 7.95(2H, d, J=8.1
Hz), 8.18-8.24(1H, m), 8.34(1H, dd, J=1.5, 4.4 Hz), 9.00(1H, d, J=2.1 Hz), 9.63(1H, s), 9.69(1H, br.t, J=6.6 Hz), 10.97(1H, br.s)

IR(KBr.cm.sup.-1): 3312, 3270, 1663, 1636, 1521, 1312, 1296, 1019

Example 46

Preparation of N-(2-aminophenyl)-4-[N-(pyridin-3-yl)oxyacetylaminomethyl]benzamide (Table 1: Compound 61)

(46-1) To a suspension of 0.22 g of sodium hydride (60% oil dispersion, 5.5 mmol) in 2 mL of DMF was added dropwise a solution of 0.48 g of 3-hydroxypyridine (5.0 mmol) in 2 mL of DMF at room temperature, and the mixture was stirred for an hour. The resulting brown solution was ice-cooled, 0.81 mL of tert-butyl bromoacetate (5.5 mmol) was added, and the mixture was stirred under ice-cooling for an hour followed by stirring at room temperature for 2 hours. After addition of water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: chloroform:ethyl acetate=5:1), to give 0.34 g of tert-butyl
3-pyridyloxyacetate (Yield: 32.5%) as a clear oil.

.sup.1H NMR(270 MHz, CDCl.sub.3) .delta. ppm: 1.49(9H, s), 4.56(2H, s), 7.18-7.24(2H, m), 8.26(1H, dd, J=1.5, 3.6 Hz), 8.32(1H, d, J=2.9 Hz)

(46-2) To a solution of 0.14 g of the compound from the process (46-1) (0.67 mmol) in 2 mL of dichloromethane was added 2 mL of trifluoroacetic acid, and the solution was stirred at room temperature for 3 hours. After evaporation, diisopropyl ether was added, and the precipitated solid was collected by filtration and dried to give 0.15 g of 3-pyridyloxyacetic acid trifluoroacetate (Yield: 83.8%) as a light yellow solid.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.86(2H, s), 7.57(1H, dd, J=4.4, 8.1 Hz), 7.67(1H, ddd, J=1.5, 1.5, 8.8 Hz), 8.31(1H, d, J=5.1 Hz), 8.46(1H, d, J=2.1 Hz), 13.00 (1H, br.s)

(46-3) To a suspension of 100 mg of the compound from the process (46-2) (0.37 mmol) and 255 mg of the compound from Example 1, the process (1-4) (0.75 mmol) in 5 mL of dichloromethane was added 0.14 mL of triethylamine (1.0 mmol), and the mixture was cooled with ice. Under ice-cooling, to the mixture was added a solution of 140 mg of 2-chloro-1,3-dimethylimidazolinium chloride (0.83 mmol) in 6 mL of dichloromethane, and the mixture was warmed to room temperature with stirring for 7
hours, and left at room temperature overnight. After adding water and saturated brine, the mixture was extracted with chloroform.

The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate:methanol=10:1) to give 0.37 g of N-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl)oxyacetylamin- omethyl]benzamide (Yield: quantitative) as a clear oil.

.sup.1H NMR(270 MHz, CDCl.sub.3) .delta. ppm: 1.52(9H, s), 4.62(2H, s), 4.63(2H, d, J=7.3 Hz), 6.76(1H, br.s), 6.90-7.00(1H, br.s), 7.15-7.35(5H, m), 7.40(2H, d, J=8.1 Hz), 7.82(1H, d, J=8.1 Hz), 7.95(2H, d, J=8.1 Hz), 8.32(1H, dd, J=2.1, 4.4
Hz), 8.37(1H, d, J=2.8 Hz), 9.20(1H, br.s)

(46-4) To a solution of 175 mg of the compound from the process (46-3) (0.37 mmol) in 2 mL of dioxane and 2 mL of methanol was added 2 mL of 4N hydrochloric acid-dioxane, and the mixture was stirred at room temperature for 2 hours. After adding saturated sodium bicarbonate aq., the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. To the residue was added methanol and diisopropyl ether, and the precipitated solid was collected by filtration and dried to give 90 mg of N-(2-aminophenyl)-4-[N-(pyridin-3-yl) oxyacetylaminomethyl]benzamide (Yield: 64.6%) as an opalescent solid.

mp: 154-155.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.42(2H, d, J=5.9 Hz), 4.69(2H, s), 4.89(2H, br.s), 6.59(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=6.6, 7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.33-7.39(4H, m), 7.92(2H, d, J=8.1 Hz),
8.21(1H, dd, J=1.5, 4.4 Hz), 8.35(1H, d, J=2.9 Hz), 8.80(1H, br.t, J=5.9 Hz), 9.63(1H, br.s)

IR(KBr)cm.sup.-1: 3307, 1672, 1631, 1523, 1456, 1429, 1269, 1231, 803, 756

Example 47

Preparation of N-(2-aminophenyl)-4-[N-[2-(pyridin-3-yl)oxy]propionylaminomethyl]benzamid- e (Table 4: Compound 3)

(47-1) To a suspension of 1.20 g of sodium hydride (60% oil dispersion; 30.0 mmol) in 10 mL of dry DMF at room temperature were added dropwise 2.85 g of 3-hydroxypyridine (30 mmol) in 10 mL of dry DMF, maintaining the temperature below 40.degree. C., and the mixture was stirred at room temperature for 90 min. Under ice-cooling, 6.28 g of tert-butyl-2-bromopropionate (30 mmol) in 10 mL of dry DMF were slowly added dropwise, maintaining the inner temperature within 5 to 10.degree. C., and then the mixture was warmed to room temperature with stirring for 4 hours. After neutralizing with saturated sodium bicarbonate aq., the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=2:1) to give 4.15 g of tert-butyl 2-(pyridin-3-yl)oxypropionate (Yield: 62%) as a brown oil.

.sup.1H NMR(270 MHz, CDCl.sub.3) .delta. ppm: 1.44(9H, s), 1.61(3H, d, J=7.3 Hz), 4.66(1H, q, J=7.3 Hz), 7.13-7.23(2H, m), 8.24(1H, dd, J=1.5, 4.4 Hz), 8.29(1H, d, J=2.1 Hz)

(47-2) To a solution of 1.65 g of the compound from the process (47-1) (7.4 mmol) in 9 mL of dichloromethane was added 9 mL of trifluoroacetic acid, maintaining the temperature below 30.degree. C., and then the mixture was stirred at room temperature for 8 hours. After evaporation, diisopropyl ether was added and the precipitated solid was collected by filtration and dried to give 1.86 g of 2-(pyridin-3-yl) oxypropionic acid trifluoroacetate (Yield: 43.5%) as a light brown solid.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.53(3H, d, J=6.6 Hz), 5.12(1H, q, J=6.6 Hz), 7.60-7.75(2H, m), 8.35(1H, d, J=5.1 Hz), 8.47(1H, s), 12.9(1H, br.s)

(47-3) To a suspension of 0.98 g of the compound from the process (47-2) (3.5 mmol) in 1.02 g of the compound from Example 1, the process (1-4) (3.0 mmol) in 20 mL of dichloromethane was added 1.3 mL of triethylamine (9.0 mmol) and then the mixture was ice-cooled. Under ice-cooling, 0.59 g of 2-chloro-1,3-dimethylimidazolidinium chloride (3.5 mmol) in 5 mL of dichloromethane was added dropwise, and the mixture was stirred for additional 2 hours. The mixture was neutralized with saturated sodium bicarbonate aq., and then extracted with chloroform. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate:methanol=10:1) to give 1.64 g of N-[2-(N-tert-butoxycarbonylamino)phenyl]-4-[N-[2-(pyridin-3-yl)oxypropion- yl]aminomethyl]benzamide as a mixture with 1,3-di-methyl-2-imidazolinone.

.sup.1H NMR(270 MHz, CDCl.sub.3) .delta. ppm: 1.51(9H, s), 1.64(3H, d, J=7.3 Hz), 4.54(2H, m), 4.78(1H, q, J=6.6 Hz), 6.87(2H, br.s), 7.13-7.30(6H, m), 7.81(1H, d, J=7.3 Hz), 7.90(2H, d, J=8.1 Hz), 8.29(1H, dd, J=1.5, 4.4 Hz), 8.33(1H, d, J=2.1
Hz), 9.22(1H, br.s)

(47-4) The compound from the process (47-3) (1.64 g) was dissolved in 10 mL of dioxane and 4 mL of methanol. To the solution was added 10 mL of 4N hydrochloric acid-dioxane solution at room temperature, and the mixture was stirred for 2 hours. The mixture was neutralized with saturated sodium bicarbonate aq. and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. To the residue were added methanol and diisopropyl ether, and the precipitated solid was collected by filtration and dried to give 0.71 g of N-(2-aminophenyl)-4-[N-[2-(pyridin-3-yl)oxy]propionylaminomethyl]benzamid- e (Yield: 60.5% for the 2 steps) as a white solid.

mp: 171-173.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.51(3H, d, J=6.6 Hz), 4.36(2H, d, J=5.9 Hz), 4.89(2H, br.s), 4.90(1H, t, J=6.6 Hz), 6.60(1H, dd, J=6.6, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=6.6, 7.3 Hz), 7.15(1H, d, J=7.3 Hz), 7.27(2H, d, J=8.1 Hz), 7.33-7.37(2H, m), 7.89(2H, d, J=8.1 Hz), 8.21(1H, dd, J=2.9, 2.9 Hz), 8.32(1H, d, J=1.5 Hz), 8.82(1H, t, J=5.9 Hz), 9.63(1H, br.s)

Example 48

Preparation of N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide (Table 1: Compound 82)

(48-1) To a solution of 384 mg of 3-pyridinemethanol (3.52 mmol) in 5 mL of dry THF were added 523 mg of N,N'-carbonyldiimidazole (3.22 mmol) at room temperature. After stirring for an hour, to the mixture was added 1.0 g of the compound from Example 1, the process (1-4) (2.93 mmol) in 6 mL of dry THF.

After being left at room temperature overnight, to the mixture was added 100 mL of chloroform, and the mixture was washed with water (3.times.20 mL) and then saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: chloroform:methanol=30:1) to give 1.27 g of N-[2-(N-tert-butoxycarbonyl)aminophenyl]-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide (Yield: quantitative) as an amorphous solid.

.sup.1H NMR(270 MHz, CDCl.sub.3) .delta. ppm: 1.51(9H, s), 4.45(2H, d, J=5.9 Hz), 5.16(1H, s), 7.10-7.50(7H, m), 7.70(1H, d, J=8.1 Hz), 7.80(1H, d, J=7.3 Hz), 7.93(1H, d, J=8.1 Hz), 8.57(1H, d, J=4.4 Hz), 8.63(1H, s), 9.17(1H, s).

(48-2) The compound from the process (48-1)(1.2 g, 2.8 mmol) was dissolved in 10 mL of methanol. To the solution was added 20 mL of 4N-hydrochloric acid-dioxane. The mixture was stirred at room temperature for 1.5 hours, and then poured into diluted sodium hydroxide aq. and extracted with chloroform (3.times.60 mL). The combined organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 0.88 g of crystals, which were then recrystallized from 16 mL of ethanol, to give 668 mg of N-(2-aminophenyl)-4-[N-(pyridin-3-yl)methoxycarbonylaminomethyl]benzamide (Yield: 73%).

mp: 159-160.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.28(2H, d, J=5.9 Hz), 4.86(2H, s), 5.10(2H, s), 6.60(1H, t, J=7.3 Hz), 6.78 (1H, d, J=7 Hz), 6.97(1H, t, J=7 Hz), 7.17(1H, d, J=8 Hz), 7.30-7.50(3H, m), 7.78(1H, d, J=8 Hz), 7.93(2H, d, J=8 Hz),
8.53(1H, d, J=3.7 Hz), 8.59(1H, s), 9.16(1H, s).

IR(KBr)cm.sup.-1: 3295, 1648, 1541, 1508, 1457, 1309, 1183, 742

As described in Example 48, the compounds of Examples 49 to 87 were prepared, each of whose melting point (mp), .sup.1H NMR data and/or IR data are shown below.

Example 49

N-(2-aminophenyl)-4-[N-(benzyloxycarbonyl) aminomethyl]benzamide (Table 1: Compound 11)

mp: 174-178.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.28(2H, d, J=5.9 Hz), 4.89(2H, br.s), 5.06(2H, s), 6.59(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.16(1H, d, J=7.3 Hz), 7.30-7.40(6H, m), 7.93(3H, m), 9.63(1H, s).

IR(KBr)cm.sup.-1: 3332, 1687, 1652, 1536, 1456, 1279, 747

Example 50

N-(2-aminophenyl)-4-[N-(4-(imidazol-1-yl)benzyl) oxycarbonylaminomethyl]benzamide (Table 1: Compound 47)

mp: 195-198.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.29(2H, d, J=6.6 Hz), 4.88(2H, s), 5.10(2H, s), 6.60-6.63(1H, m), 6.78(1H, d, J=8.1 Hz), 6.97(1H, t, J=7.3 Hz), 7.11(1H, s), 7.16(1H, d, J=7.3 Hz), 7.37(2H, d, J=8.1 Hz), 7.49(2H, d, J=8.8 Hz),
7.66(2H, d, J=8.1 Hz), 7.74(1H, s), 7.92-7.96(3H, m), 8.25(1H, s), 9.62(1H, s)

Example 51

N-(2-aminophenyl)-4-[N-(pyridin-2-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 171)

mp: 166-167.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.30(2H, d, J=5.9 Hz), 4.88(2H, br.s), 5.12(2H, s), 6.60(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16(1H, d, J=7.3 Hz), 7.33(1H, dd, J=3.7, 7.3 Hz),
7.40(3H, d, J=8.1 Hz), 7.83(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.94(2H, d, J=8.1 Hz), 8.03(1H, t, J=5.9 Hz), 8.55(1H, d, J=5.1 Hz), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3334, 1694, 1632, 1580, 1276, 755

Example 52

N-(2-aminophenyl)-4-[N-[2-(pyridin-2-yl) ethoxycarbonyl]aminomethyl]benzamide (Table 1: Compound 172)

mp: 146-148.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 3.04(2H, t, J=6.6 Hz), 4.23(2H, d, J=5.9 Hz), 4.36(2H, t, J=6.6 Hz), 4.88(2H, br.s), 6.60(1H, dd, J=7.3, 8.1 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.15-7.30(3H, m), 7.34(2H, d, J=8.1 Hz), 7.69-7.77(2H, m), 7.92(2H, d, J=7.3 Hz), 8.50 (1H, d, J=4.4 Hz), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3330, 1690, 1633, 1594, 1524, 1277, 760

Example 53

N-(2-aminophenyl)-4-[N-(6-methylpyridin-2-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 179)

mp: 138.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.47(3H, s), 4.30(2H, d, J=5.9 Hz), 5.07(4H, s), 6.63(1H, t, J=8.1 Hz), 6.80(1H, d, J=7.34), 6.98(1H, t, J=8.1 Hz), 7.18(3H, d, J=7.3 Hz), 7.40(2H, d, J=8.1 Hz), 7.71(1H, t, J=8.1 Hz), 7.94(2H, d, J=8.1 Hz), 8.03(1H, t, J=5.9 Hz), 9.66(1H, s)

IR(KBr)cm.sup.-1: 3335, 1693, 1634, 1259

Example 54

N-(2-aminophenyl)-4-[N-[2-(pyridin-3-yl) ethoxycarbonyl]aminomethyl]benzamide (Table 1: Compound 83)

mp: 120-125.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.91(2H, t, J=6.6 Hz), 4.22(4H, t, J=6.6 Hz), 4.89(2H, s), 6.55-6.63(1H, m), 6.78(1H, dd, J=8.1, 1.5 Hz), 6.97(1H, t, J=6.6 Hz), 7.17(1H, d, J=6.6 Hz), 7.33(3H, d, J=8.1 Hz), 7.69(1H, d, J=8.1 Hz),
7.79(1H, t, J=6.6 Hz), 7.93(2H, d, J=8.0 Hz), 8.43-8.49(2H, m), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3234, 1705, 1655, 1260

Example 55

N-(2-aminophenyl)-4-[N-[3-(pyridin-3-yl) propyloxycarbonyl]aminomethyl]benzamide (Table 1: Compound 84)

mp: 121-124.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.83-1.94(2H, m), 2.67(2H, t, J=7.3 Hz), 3.98(2H, t, J=6.6 Hz), 4.26(2H, d, J=5.9 Hz), 4.89(2H, br.s), 6.60(1H, dd, J=8.1, 8.1 Hz), 6.78(1H, d, J=7.3 Hz), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz),
7.16(1H, d, J=8.1 Hz), 7.29-7.33(1H, m), 7.37(1H, d, J=8.1 Hz), 7.64(1H, d, J=8.1 Hz), 7.81(1H, dd, J=5.9, 6.6 Hz), 7.94(2H, d, J=8.1 Hz), 8.40-8.44(2H, m), 9.63(1H, br.s)

IR(KBr)cm.sup.-1: 3348, 1696, 1635, 1523, 1458, 1302, 1272, 1141, 1019, 754, 713

Example 56

N-(2-aminophenyl)-4-[N-(2-methylpyridin-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 142)

mp: 164-165.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.49(3H, s), 4.28(2H,d, J=6.6 Hz), 4.89(2H, s), 5.10(2H, s), 6.60(1H, t, J=6.6 Hz), 6.78(1H, d, J=8.1 Hz), 6.90(1H, t, J=7.3 Hz), 7.17(1H, d, J=7.3 Hz), 7.21-7.26(1H, m), 7.37(2H, d, J=8.1 Hz),
7.68(1H, d, J=6.6 Hz), 7.92-8.00(3H, m), 8.39(1H, d, J=4.4 Hz), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3332, 1719, 1630, 1260

Example 57

N-(2-aminophenyl)-4-[N-(6-methylpyridin-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 144)

mp: 164-165.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.46(3H, s), 4.27(2H, d, J=6.6 Hz), 4.88(2H, s), 5.05(2H, s), 6.59(1H, dt, J=1.5, 8.1 Hz), 6.78(1H, dd, J=1.5, 8.1 Hz), 6.97(1H, dt, J=1.5, 7.3 Hz), 7.17(1H, d, J=7.3 Hz), 7.26(1H, d, J=8.1 Hz),
7.36(2H, d, J=8.1 Hz), 7.67(1H, dd, J=2.2, 8.1 Hz), 7.93(3H, d, J=8.1 Hz), 8.45(1H, d, J=1.5 Hz), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3293, 1701, 1632, 1260

Example 58

N-(2-aminophenyl)-4-[N-(2-chloropyridin-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 155)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.30(2H, d, J=5.9 Hz), 5.00(2H, s), 5.13(2H, s), 6.61(1H, t, J=7.3 Hz), 6.79 (1H, dd, J=1.5, 8.1 Hz), 6.98(1H, dt, J=1.5, 7.3 Hz), 7.17 (1H, d, J=6.6 Hz), 7.39(2H, d, J=8.8 Hz), 7.47-7.52(1H, m),
7.91-7.96(3H, m), 8.08(1H, t, J=5.9 Hz), 8.40(1H, dd, J=4.4, 1.5 Hz), 9.64(1H, s)

IR(KBr)cm.sup.-1: 3340, 1702, 1632, 1273

Example 59

N-(2-aminophenyl)-4-[N-(6-chloropyridin-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 157)

mp: 180-185.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.24(2H, d, J=5.9 Hz), 4.89(2H, br.s), 5.10(2H, s), 6.60(1H, t, J=7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dt, J=1.5, 8.1 Hz), 7.16(1H, d, J=6.6 Hz), 7.37(2H, d, J=8.1 Hz), 7.56(1H, d, J=8.1 Hz),
7.85-8.02(4H, m), 8.44(1H, d, J=2.2 Hz), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3346, 3282, 1696, 1533, 1271

Example 60

N-(2-aminophenyl)-4-[N-(pyridin-4-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 181)

mp: 180-183.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.30(2H, d, J=6.6 Hz), 4.89 (2H, s), 5.12(2H, s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, dd, J=1.5, 7.3 Hz), 6.97(1H, ddd, J=1.5, 7.3, 8.1 Hz), 7.16(1H, d, J=7.3 Hz), 7.34(2H, d, J=5.9 Hz), 7.39(2H, d, J=8.1 Hz), 7.94(2H, d, J=8.1 Hz), 8.09(1H, t, J=5.9 Hz), 8.57(1H, d), 9.64(1H, br.s)

IR(KBr)cm.sup.-1: 3394, 3290, 1711, 1645, 1624, 1535, 1504, 1321, 1251, 1138, 1049, 763

Example 61

N-(2-aminophenyl)-4-[N-[2-(thiophen-3-yl) ethoxycarbonyl]aminomethyl]benzamide (Table 1: Compound 203)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.90(2H, t, J=7.3 Hz), 4.17-4.26(4H, m), 4.89(2H, s), 6.60(1H, t, J=8.1 Hz), 6.78(1H, d, J=6.6 Hz), 6.97(1H, t, J=7.3 Hz), 7.06(1H, d, J=5.1 Hz), 7.17(1H, d, J=7.3 Hz), 7.26(1H, s), 7.36(2H, d, J=8.1 Hz), 7.47(1H, t, J=2.2 Hz), 7.81(1H, t, J=5.9 Hz), 7.93(2H, d, J=8.1 Hz), 9.63(1H, s).

IR(KBr)cm.sup.-1: 3314, 1716, 1638, 1252

Example 62

N-(2-aminophenyl)-4-[N-(3-phenyloxazol-5-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 211)

mp: 192-195.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.30(2H, d, J=5.9 Hz), 4.89(2H, s), 5.25(2H, s), 6.60(1H, t, J=6.6 Hz), 6.68 (1H, d, J=8.1 Hz), 6.94(1H, t, J=7.3 Hz), 7.09(1H, s), 7.16(1H, d, J=7.3 Hz), 7.39(2H, d, J=8.1 Hz), 7.51(4H, d, J=2.2
Hz), 7.87-7.96(5H, m), 8.12(1H, t, J=5.9 Hz), 9.63 (1H, s)

IR(KBr)cm.sup.-1: 3292, 1718, 1630, 1262

Example 63

N-(2-aminophenyl)-4-[N-(thiazol-5-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 216)

mp: 168-175.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.28(2H, d, J=5.9 Hz), 4.91(2H, br.s), 5.30(2H, s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, dd, J=7.3, 8.1 Hz), 7.16(1H, d, J=7.3 Hz), 7.36(2H, d, J=8.1 Hz), 7.91-8.00(4H, m),
9.09(1H, s), 9.63(1H, s)

IR(KBr)cm.sup.-1: 3346(br.), 1697, 1636, 1525, 1456, 1271, 873, 753

Example 64

N-(2-aminophenyl)-4-[N-[2-(4-methylthiazol-5-yl) ethoxycarbonyl]aminomethyl]benzamide (Table 1: Compound 217)

mp: 130-133.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 2.32(3H, s), 3.07(2H, t, J=5.9 Hz), 4.15(2H, t, J=5.9 Hz), 4.25(2H, d, J=6.6 Hz), 4.89(2H, s), 6.60(1H, t, J=5.9 Hz), 6.78(1H, dd, J=7.3, 1.5 Hz), 6.97(1H, dt, J=1.5, 7.3 Hz), 7.16(1H, d, J=8.1
Hz), 7.35(2H, d, J=8.1 Hz), 7.83(1H, t, J=5.9 Hz), 7.94(2H, d, J=8.1 Hz), 8.85(1H, s), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3350, 1691, 1635, 1270

Example 65

N-(2-aminophenyl)-4-[N-(1-methylpiperidin-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 225)

mp: 130-135.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.49-1.78(3H, m), 1.83-2.01(3H, m), 2.30(3H, s), 2.85(2H, t), 3.74-3.94 (2H, m), 4.25(2H, d, J=5.8 Hz), 6.55-6.62(3H, m), 6.78(1H, d, J=8.1 Hz), 6.97(1H, t, J=7.3 Hz), 7.16(1H, d, J=8.1 Hz),
7.37(2H, d, J=8.1 Hz), 7.79(1H, t, J=6.6 Hz), 7.93(2H, d, J=8.0 Hz), 9.66(1H, s)

IR(KBr)cm.sup.-1: 3323, 2722, 1702, 1648, 1263

Example 66

N-(2-aminophenyl)-4-[N-(4-methylpiperazin-1-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 227)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.73(2H, t, J=6.6 Hz), 2.36-2.63(13H, m), 4.00(2H, t, J=6.6 Hz), 4.30(2H, d, J=5.8 Hz), 6.55-6.63(4H, m), 6.78(1H, d, J=6.6 Hz), 6.97 (1H, t, J=7.3 Hz), 7.16(1H, d, J=7.3 Hz), 7.37(2H, d, J=8.7
Hz), 7.73(1H, t, J=5.9 Hz), 7.94(2H, d, J=8.0 Hz), 9.66(1H, s)

IR(KBr)cm.sup.-1: 3341, 2706, 1701, 1262

Example 67

N-(2-aminophenyl)-4-[N-(tetrahydrofuran-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 221)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.50-1.60(1H, m), 1.88-2.00(1H, m), 2.44-2.54(1H, m), 3.41-3.47(1H, m), 3.56-3.77(3H, m), 3.85-4.04(2H, m), 4.25(2H, d, J=5.9 Hz), 4.89(2H, s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz),
6.97(1H, dd, J=7.3, 8.1 Hz), 7.17(1H, d, J=8.1 Hz), 7.37(2H, d, J=8.1 Hz), 7.81(1H, t, J=5.9 Hz), 7.94(2H, d, J=8.1 Hz), 9.62(1H, br.s)

IR(KBr)cm.sup.-1: 3349, 1695, 1635, 1523, 1457, 1259, 754

Example 68

N-(2-aminophenyl)-4-[N-(phenoxycarbonyl) aminomethyl]benzamide (Table 1: Compound 12)

mp: 174-175.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.36(2H, d, J=5.9 Hz), 4.90(2H, br.s), 6.60(1H, dd, J=7.3, 7.3 Hz), 6.77(1H, dd, J=7.3, 7.3 Hz), 6.98(1H, ddd, J=1.5, 7.3, 7.3 Hz), 7.05-7.24(4H, m), 7.39-7.46(4H, m), 7.97(2H, d, J=8.1 Hz),
8.41(1H, t, J=5.9 Hz), 9.65(1H, br.s)

IR(KBr)cm.sup.-1: 3443, 3362, 3313, 1732, 1706, 1636, 1527, 1493, 1458, 1305, 1217, 748

Example 69

N-(2-aminophenyl)-4-[N-(pyridin-3-yl) oxycarbonylaminomethyl]benzamide (Table 1: Compound 81)

mp: 209.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.38(2H, d, J=6.6 Hz), 4.90(2H, br.s), 6.55-6.63(1H, m), 6.78(1H, d, J=8.1 Hz), 7.00(1H, dd, J=7.3, 7.3 Hz), 7.17(1H, d, J=8.8 Hz), 7.37-7.47(3H, m), 7.64(1H, d, J=8.8 Hz), 7.97(2H, d, J=8.1 Hz),
8.43(2H, d, J=3.1 Hz), 8.59(1H, t, J=5.9 Hz), 9.66(1H, br.s)

Example 70

N-(2-amino-5-fluorophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 110)

mp: 160-162.degree. C.

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.28(2H, d, J=6.6 Hz), 4.81(2H, s), 5.10(2H, s), 6.70-6.90(2H, m), 7.10-8.00 (8H, m), 8.53(1H, d, J=3.6 Hz), 8.59(1H, s), 9.61(1H, s)

IR(KBr)cm.sup.-1: 3269, 1716, 1638, 1488, 1436, 1247, 1141, 1043, 744

Example 71

N-(2-aminophenyl)-4-[N-(2-aminophenyl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 51)

mp: 149-151.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.28(2H, d, J=5.9 Hz), 4.88(2H, s), 4.96(2H, s), 5.06(2H, s), 6.53(1H, dd, J=7.3, 7.3 Hz), 6.56-6.67(2H, m), 6.78(1H, dd, J=1.5, 8.1 Hz), 6.93-7.12(3H, m), 7.16(1H, d, J=6.6 Hz), 7.38(2H, d, J=8.1
Hz), 7.86(1H, t-like, J=5.9 Hz), 7.93(2H, d, J=8.1 Hz), 9.61(1H, s)

IR(KBr)cm.sup.-1: 3336, 1685, 1632, 1527, 1276, 748

Example 72

N-(2-aminophenyl)-4-[N-(quinuclidin-3-yl) oxycarbonylaminomethyl]benzamide (Table 1: Compound 228)

mp: (amorphous)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 1.30-1.90(4H, m), 1.90(1H, br.s), 2.45-2.80(6H, m), 3.04-3.13(1H, m), 4.15(2H, d, J=5.9 Hz), 4.55-4.60(1H, m), 4.88(2H, br.s), 6.60(1H, ddd, J=1.5, 7.3, 7.3 Hz), 6.78(1H, d, J=8.1 Hz), 6.97(1H, ddd, J=1.5, 7.3, 7.3 Hz), 7.17(1H, d, J=6.6 Hz), 7.37(2H, d, J=8.1 Hz), 7.78(1H, t, J=5.9 Hz), 7.94(1H, d, J=7.3 Hz), 9.62(1H, s)

IR(KBr)cm.sup.-1: 3328, 2942, 1700, 1648, 1504, 1259, 749

Example 73

N-(2-aminophenyl)-4-[N-(3-aminophenyl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 52)

mp: 149-153.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta. ppm: 4.27(2H, d, J=5.9 Hz), 4.88 and 4.89(total 4H, each br.s), 5.08(2H, s), 6.47-6.63(3H, m), 6.78(1H, d, J=8.1 Hz), 6.94-7.02(2H, m), 7.15(1H, dd, J=7.3, 8.8 Hz), 7.37(2H, d, J=8.1 Hz), 7.84(1H, t, J=5.9 Hz), 7.93(2H, d, J=8.8 Hz), 9.61(1H, br.s)

IR(KBr)cm.sup.-1: 3367, 1682, 1632, 1523, 1457, 1261, 754

Example 74

N-(2-aminophenyl)-4-[N-(1-methylimidazol-5-yl) methoxycarbonylaminomethyl]benzamide (Table 1: Compound 218)

mp: 162-165.degree. C.(dec.)

.sup.1H NMR(270 MHz, DMSO-d.sub.6) .delta.