JPH0971564A - Benzamidoxime derivative and its use in medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzamidoxime derivative having an excellent cell adhesion-inhibiting action, extremely low in toxicity, and useful for anti- inflammatory agents, ischemic reperfusion disorder-treating agents, organ transplantation rejection-depressing agents, etc. SOLUTION: A benzamidoxime derivative of formula I [R<1> is H, an alkyl, an aralkyl, an acyl; R<2> , R<3> are H, an alkyl, an acyl; A is oxygen atom, carbonyl, etc.; B is a group of formula II (j is 0,1,2), a group of formula III, etc.; X is H, a halogen; n is an integer of 1-3] or its pharmacologically acceptable salt. For example, 4-(4-cyclohexyl-1-piperazinyl) benzamidoxime. The compound of formula I is obtained e.g. by aminating a compound of formula IV by an aromatic nucleophilic substitution reaction and subsequently adding a hydroxylamine to the cyano group to convert the group into an amidoxime group.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to novel benzamide oxime derivatives and cell adhesion inhibitors containing these compounds. More specifically, prevention and treatment of various diseases based on cell adhesion inhibitory action, for example, inflammation, ischemia-reperfusion injury, organ transplant rejection, autoimmune diseases such as collagen disease represented by rheumatoid arthritis, and cancer metastasis inhibition. , Allergies,
Novel benzamide oxime derivatives useful for prevention and treatment of asthma, atopic contact dermatitis, bone marrow transplant rejection, arteriosclerosis, etc., and various therapeutic agents for diseases including anti-inflammatory agents containing these benzamide oxime derivatives as active ingredients To a useful medicine.

[0002]

2. Description of the Related Art Inflammation is a defense reaction of a tissue to an external stimulus, and its process is roughly divided into three stages (Tetsuo Sato, "Essence Pharmacology", 190-1).
91). In the first stage of inflammation, physical and chemical stimuli cause disorders such as degeneration and necrosis in cells and tissues. At this time, chemical substances such as histamine, serotonin and prostaglandins are produced and released. In addition, these chemical substances may be produced or released without any morphological change, which may trigger the development of inflammatory reaction. The released chemicals cause a vascular reaction, a local circulatory disturbance. First, the arterioles in the tissue contract transiently, and then the arteries are in a continuous dilated state, which is accompanied by passive dilation of the capillaries and veins. Therefore, the blood flow at this site increases and becomes hyperemic, and if the inflammation is just under the skin or mucous membrane, it is recognized as a symptom of redness. Next, the permeability of blood vessels is increased, and blood components are leached into tissues, resulting in inflammatory edema. This is divided into an immediate reaction period (phase 1) that lasts 15 to 30 minutes after stimulation, and a delayed reaction period (phase 2) that lasts several hours to several days.

In the second stage of inflammation, leukocytes start to migrate into the tissue from venules following the emigration of body fluid, and histiocytes and plasma cells are added thereto. In this process, vascular endothelial cells adhere to various cells in the bloodstream and then infiltrate into the tissue. This cellular infiltration is the most important finding of inflammation.
In the early days, neutrophils occupy the mainstream, but monocytes start to exude a few hours later, and if inflammation is prolonged, many lymphocytes and plasma cells become visible. At this time, a blood clot is formed due to a change in blood vessels or a stagnation of blood flow, and if it is severe, local necrosis also occurs.

Inflammation stage III is the stage of tissue repair against inflammation, in which new formation of capillaries and proliferation of fibroblasts are newly observed. These are called granulation tissues, which show cleaning action and repair action, absorb necrotic tissue, and proceed with tissue repair.
Furthermore, collagen fibers increase in the tissue, and fibrosis progresses, and gradually, capillaries and cell components are reduced and disappear to become scars and heal.

Phenomena such as adhesion and infiltration of leukocytes and the like observed in the second stage of the inflammatory process include autoimmune diseases such as collagen disease represented by rheumatoid arthritis, ischemia-reperfusion injury, organ transplant rejection, bone marrow. This phenomenon is also observed in transplant rejection, arteriosclerosis, or cancer metastasis. The adhesion phenomenon of these white blood cells, lymphocytes, cancer cells and the like to vascular endothelial cells and cells such as organs has a significant influence on these various diseases and is also a cause of symptom progression. Adhesion molecules that control the interaction between cells include integrin family, Ig superfamily, selectin family,
There are a series of adhesion molecule groups called the CD44 family and the cadherin family. Among these, integrin is a membrane protein in which an α subunit having a molecular weight of 120 to 180 kDa and a β subunit having a molecular weight of 90 to 110 kDa are non-covalently associated with each other, and the α subunit is CD11a,
It is known that at least 14 types such as CD11b and CD49a and at least 8 types of β subunit are present.

[0006] As described above, integrins are αβ heterodimers that have β _{1 in the} β subunit (β ₁
The family) is distributed in many cells and uses extracellular matrix (ECM) or fibronectin, collagen, laminin, etc. on the cell surface as ligands. On the other hand, those belonging to the β ₂ family are mainly present in lymphocytes and myeloid cells, and are ICA, which is a cell adhesion molecule of the immunoglobulin superfamily.
Using M-1, ICAM-2, etc. as a ligand, it mediates adhesion of these cells to vascular endothelial cells, adhesion between antigen presenting cells and helper cells, and the like.

[0007] Integrins can be roughly classified into two types, those that mediate adhesion of cells to ECM and those that mediate cell-cell adhesion. The former is mainly
Receptors for ECM-constituting proteins, collagen receptors α ₁ β ₁ , α ₂ β ₁ , and laminin receptor α
₃ β ₁ , α ₆ β ₁ , α ₄ β _{1 of} fibronectin receptor,
There are α ₅ β ₁ etc. These have a β ₁ subunit in common, so β ₁ integrin, or VL from the common name
Also called A integrin. The latter is a family of β ₂ integrins present in lymphoid / myeloid cells, and α _L β ₂ (LFA-1), α _M β ₂ (Mac-1), α
Three types of _X β ₂ (p150,95) are known. α _L β ₂
Uses molecules of the immunoglobulin superfamily such as ICAM-1 and ICAM-2 as ligands to mediate adhesion of leukocytes to vascular endothelial cells, adhesion between antigen-presenting cells and helper cells, and α _M β ₂ , α _X β ₂ is mainly the complement component iC
It is considered that 3b is used as a ligand to enhance the adhesion of macrophages to bacteria that have entered the body [Mevio,
Volume 10, May issue, pp. 19-22 (1993) [Mebio, 10
(5), 19-22 (1993)]].

During the inflammatory process, neutrophils and macrophages adhere to vascular endothelial cells in the postcapillaries and infiltrate into tissues. In ischemia-reperfusion injury, neutrophils infiltrate the tissue and damage the tissue by a similar mechanism [Proceeding of National Academy of Science USA, 87, 2643-2646 (1990).
Year) [Proc. Natl. Acad. Sci. USA, 87 , 2643-2646 (19
90)]]. In organ transplant rejection, at the same time as antigen presenting cells and T cells adhere to major histocompatibility antigens via T cell receptors, ICAM-1 / LFA-1 or VC
Stimulation by adhesion between adhesion molecules such as AM-1 / VLA-4 (costimulatory signal) induces antibody production by B lymphocytes and tissue damage via killer T cells and natural killer cells. [Transplantation, 55 volumes, 766-77
Page 3 (1993) [Transplantation, 55 , 766-773 (1
993)]]. In autoimmune diseases such as collagen disease typified by rheumatoid arthritis, VLA-4 is expressed on lymphocytes, specific adhesion molecules called LFA-1, MAC-1 are expressed on neutrophils, and leukocytes are vascularized. Adhesion migration via these integrins on endothelial cells and joint synovium is considered to be one of the causes of tissue damage [Journal of Immunology, 147, 4167-4171 (1991).
Y.) [J. Immunol., 147 , 4167-4171 (1991)]]. In cancer metastasis, cancer cells that have penetrated into the blood vessel from the primary cancer tissue adhere to vascular endothelial cells and extracellular matrix, resulting in distant metastasis of the cancer [Japanese Journal of Cancer Research, 83, 1317-1326].
Page (1992) [Jpn. J. Cancer Res., 83 , 1317-132
6 (1992)]].

In the process of cancer metastasis, a wide variety of adhesion molecules such as cadherin, integrin, immunoglobulin, selectin, and lymphocyte homing receptor on cancer cells are transferred from cell to cell (cancer cell-cancer cell, cancer cell- For adhesion of vascular endothelial cells, cancer cells-immune cells, cancer cells-platelets, etc. and between cells-extracellular matrix (cancer cells-fibronectin, cancer cells-laminin, cancer cells-collagen, cancer cells-heparan sulfate proteoglycans, etc.) It is said to be involved. Most of them are transmembrane proteins that regulate cell function by transducing information into cells through adhesion and are thought to be deeply involved in the complex cascade of metastasis. Focusing on the function, controlling adhesion and migration of cancer cells has been studied as one useful means for preventing cancer metastasis. In fact, β on cancer cells
₁ Integrin (VLA-4) and VC on vascular endothelial cells
AM-1 has been shown to be involved in metastasis, and it is considered that β ₁ integrin plays an important role in the process of infiltration of extracellular matrix (basement membrane and stroma) by cancer cells [ Mevio, Vol. 10, May, 102-10
P. 3 (1993) [Mebio, 10 (5), 102-103 (199)
3)]].

Therefore, inflammation can be suppressed if adhesion between leukocytes, lymphocytes, cancer cells and the like and vascular endothelial cells can be suppressed.
Ischemia-reperfusion injury, organ transplant rejection, autoimmune disease, cancer metastasis, allergy, asthma, atopic contact dermatitis,
It can suppress bone marrow transplant rejection, arteriosclerosis, etc., anti-inflammatory agent, ischemia / reperfusion injury therapeutic agent, bone marrow transplant rejection inhibitor, autoimmune disease therapeutic agent, cancer metastasis inhibitor, anti-allergic agent, anti-asthma It can be used as an agent, a therapeutic agent for atopic contact dermatitis, a therapeutic agent for organ transplant rejection reaction, a therapeutic agent for arteriosclerosis and the like.

On the other hand, the benzamide oxime derivative is represented by the general formula in JP-A-7-500327.

Embedded image (R1 represents a hydrogen atom, a hydroxyl group or the like) is disclosed for use as a platelet aggregation inhibitor, and no benzamide oxime derivative is described as a specific compound, but cis-4- [4- [4- ( Aminoiminomethyl) phenyl-
1-piperazinyl] -1-hydroxycyclohexaneacetic acid / trifluoroacetic acid salt or cis-4- [4- [4-
(Aminoiminomethyl) phenyl-1-piperidinyl]
Compounds such as -1-hydroxycyclohexane acetic acid and trifluoroacetic acid salt are described. In addition, special table flat 7-50
No. 1063 and Japanese Patent Publication No. 7-503459 have general formulas.

Embedded image Is disclosed for use as a platelet aggregation inhibitor, and specifically 4- [4- [4- [amino (hydroxyimino))
Methyl] phenyl-1-piperazinyl] -1-piperidine acetate 1,1-dimethylethyl, 4- [4- [4- [amino (hydroxyimino) methyl] phenyl-1-piperazinyl] -1-piperidine acetic acid trifluoroacetic acid Salt 1 '-[4- [amino (hydroxyimino) methyl] phenyl] -α-phenyl [4,4'-bipiperidine] -1-methyl acetate or 4- [4- [4- [amino [hydroxyimino]) Benzamido oxime-acetic acid derivatives such as methyl] phenyl-1-piperazinyl] -α- (4-methoxyphenyl) -1-piperidine methyl acetate are described.

[0012] However, these compounds do not belong to the specific α _IIb β ₃ (GpIIb / III) group of the integrin family.
Although it is a platelet aggregation inhibitor based on the antagonism of a), it has no inhibitory activity against β ₂ integrin. on the other hand,
Although the compound of the present invention has excellent safety and excellent anti-inflammatory action, it does not have such an action of inhibiting platelet aggregation, and the difference is clear from this point as well. The compounds of the present invention are
Of course, treatment of diseases associated with cell adhesion, such as ischemia / reperfusion injury treatment, suppression of organ transplant rejection, suppression of bone marrow transplant rejection, autoimmune diseases such as collagen disease represented by rheumatoid arthritis. It is also effective for treatment, cancer metastasis suppression, arteriosclerosis treatment, etc., but not for treating diseases associated with platelet aggregation. Further, the compounds described in the above-mentioned documents essentially have an acetic acid residue or an ester thereof as a substituent, and this is also structurally different.

Achief Der Pharmacy (Weinheim), Volume 323, 915-918 (1990)
Year) [Arch. Pharm. (Weinheim), 323 , 915-918 (1990)]
To

Embedded image Is described, but it is only described as a synthetic intermediate of a quinazolinone oxime compound, and there is no description of its use and no description suggesting a change in the substitution position of piperidine. Also, Journal of Heterocyclic Chemistry, Vol. 30, 497-500 (1993).
[J. Heterocyclic Chem., 30 , 497-500 (1993)]

[Chemical 12] Is described, but this is also only described as a synthetic intermediate of an oxadiazole compound, and there is no description of use and no description suggesting conversion of a heterocycle.

The benzamidine derivative is disclosed in Japanese Patent Publication No. 7-503718.

Embedded image Etc. in WO94 / 21616

Embedded image Etc. are disclosed, but these relate to anti-inflammatory agents and anti-allergic agents based on leukotriene B ₄ antagonism.

[0015]

Currently, various researches and developments are being carried out on anti-inflammatory agents whose mechanism of action is an adhesion inhibitory action. However, in the integrin family, specific α _M β ₂ (aka Mac- 1, CR3) Currently, no drug that specifically inhibits adhesion molecules has been developed. If a drug based on such a mechanism of action is developed, inflammation, ischemia-reperfusion injury, organ transplant rejection, autoimmune diseases such as collagen disease represented by rheumatoid arthritis, and cancer metastasis inhibition as described above. In addition to prevention and treatment of arteriosclerosis, etc., as a new medicinal product that has never existed as an anti-allergic agent, anti-asthma agent, therapeutic agent for atopic contact dermatitis, bone marrow transplant rejection inhibitor, therapeutic agent for arteriosclerosis, etc. Expected to be very useful

[0016]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that a novel benzamido oxime derivative inhibits adhesion of leukocytes to vascular endothelial cells, The present invention has been completed.

Since the compound of the present invention has a mechanism of action that inhibits cell adhesion, which is not present in conventional anti-inflammatory agents, it is effective even after the migration of leukocytes and the like in the second stage of inflammation, and at the same time, For prevention and treatment of ischemia-reperfusion injury involving cell adhesion, organ transplant rejection, bone marrow transplant rejection, autologous diseases such as collagen disease represented by rheumatoid arthritis, arteriosclerosis or cancer metastasis. Its usefulness is expected.

That is, the present invention provides a drug represented by the following general formula [I], specifically a cell adhesion inhibitor, an anti-inflammatory agent, an ischemia / reperfusion injury therapeutic agent, an organ transplant rejection inhibitor, a chronic joint. As a therapeutic agent for autoimmune diseases such as collagen disease represented by rheumatism, cancer metastasis inhibitor, antiallergic agent, antiasthma agent, atopic contact dermatitis therapeutic agent, bone marrow transplant rejection inhibitor, arteriosclerosis therapeutic agent, etc. Another useful invention relates to a novel benzamide oxime derivative, and another invention relates to a medicament comprising such a novel benzamide oxime derivative. More specifically, it is as shown in the following (1) to (13).

(1) General formula [I]

[Chemical 15] [In the formula, R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group or an acyl group, R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group or an acyl group, A is an oxygen atom, a carbonyl group,

Embedded image Or A′-R ⁴ [R ⁴ is a hydrogen atom; a hydroxyl group, an amino group, an alkoxy group, an alkyl group which may be substituted with an alkyl-substituted amino group or an oxo group; an alkyl group, a hydroxyl group, an alkoxy group, an amino group or an alkyl group Aryl group optionally substituted with amino group; Aralkyl group optionally substituted with alkyl group, hydroxyl group, alkoxy group, amino group or alkyl substituted amino group; Substituted with hydroxyl group, amino group, alkyl substituted amino group or oxo group Optionally an alkoxycarbonyl group or

Embedded image << R ⁵ represents a hydrogen atom or an alkyl group which may be substituted with a hydroxyl group, A ¹ is an oxygen atom or A ¹ ′ -R ⁶ <R ⁶ is a hydrogen atom, an alkyl group which may be substituted with a hydroxyl group or R ^Five
Be with

Embedded image {A ² represents an oxygen atom or A ² ′ -R ⁷ (R ⁷ represents a hydrogen atom, an alkyl group, an acyl group or an alkoxycarbonyl group, and A ² ′ represents a nitrogen atom or a CH group),
s and t are the same or different and each represents an integer of 1 to 3. Represents｝. >, And r represents an integer of 0 or 1 to 3. >>, A'represents a nitrogen atom or a CH group. ]
And B is

Embedded image (J represents 0 or an integer of 1 to 2),

Embedded image (J has the same meaning as described above),

[Chemical 21] (K represents an integer of 1 to ₂ ) _or- (CH2) _m-.
(M represents an integer of 1 to 3), X represents a hydrogen atom or a halogen atom, and n represents an integer of 1 to 3. ] The benzamido oxime derivative shown by these, or its pharmacologically acceptable salt.

(2) R ¹ , R ² and R ³ are all hydrogen atoms, and A is A′-H (A ′ has the same meaning as above).
Or

Embedded image (A ′, A ¹ ′, R ⁵ and R ⁶ have the same meanings as described above.) The benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to (1) above.

(3) The benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to the above (1) or (2), wherein A is a CH ₂ group.

(4) 4- (4-cyclohexyl-1-)
Piperazinyl) benzamide oxime, 4- (4-piperidinopiperidino) benzamide oxime, 4- [4-
(Tert-Butoxycarbonyl) -1-piperazinyl] benzamido oxime, 4- (4-isopropyl-
1-piperazinyl) benzamido oxime, 4- [4-
(3-pentyl) -1-piperazinyl] benzamide oxime, 4- [4-[(1-pyrrolidinyl) carbonylmethyl] -1-piperazinyl] benzamide oxime,
4- [4- [1- (tert-butoxycarbonyl)-
4-piperidyl] -1-piperazinyl] benzamide oxime, 4- [4- (1-pivaloyl-4-piperidinyl) -1-piperazinyl] benzamide oxime, 4-
(1-pyrrolidinyl) benzamido oxime, 4- [4
-(1-Pyrrolidinyl) piperidino] benzamide oxime, 4- (4-morpholinopiperidino) benzamide oxime, 4-morpholinobenzamide oxime, 4-
(4-Methyl-1-piperazinyl) benzamide oxime, 4- (4-ethyl-1-piperazinyl) benzamide oxime, 4- (4-propyl-1-piperazinyl)
Benzamido oxime, 4- (4-cyclopentyl-1)
-Piperazinyl) benzamido oxime, 4- [4-
(3,4,5,6-tetrahydro-2H-pyran-4-
1-piperazinyl] benzamido oxime, 4
-[4- (2-Hydroxyethyl) -1-piperazinyl] benzamide oxime, 4- [4- (2,3-dihydroxypropyl) -1-piperazinyl] benzamide oxime, 4- [4- (5-hydroxy-3) -Oxapentyl) -1-piperazinyl] benzamidoxime,
4- [4- (isopropylaminocarbonylmethyl)-
1-piperazinyl] benzamido oxime, 4- [4-
(2-Dimethylaminoethyl) -1-piperazinyl] benzamide oxime, 4- [4- (3-dimethylaminopropyl) -1-piperazinyl] benzamide oxime, 4- [4- (1-methyl-4-piperidinyl)- 1
-Piperazinyl] benzamido oxime, 4- [4-
(Ethoxycarbonyl) -1-piperazinyl] benzamidoxime, 4- (4-acetyl-1-piperazinyl) benzamidoxime, 4- (4-phenyl-1-)
Piperazinyl) benzamido oxime, 4-piperidinobenzamido oxime, 4- [4- [4- (tert-
Butoxycarbonyl) -1-piperazinyl] piperidino] benzamide oxime, 4- (4-methylpiperidino) benzamide oxime, 4- (1-piperazinyl)
Benzamido oxime, 4- [4- (4-piperidyl)
-1-Piperazinyl] benzamido oxime, 4- [4
-(1-Piperazinyl) piperidino] benzamido oxime, 4- (4-cyclohexyl-1-piperazinyl)
Benzamide O -acetyloxime, 3-bromo-4
-(4-piperidinopiperidino) benzamide oxime, 3-bromo-4- (4-isopropyl-1-piperazinyl) benzamide oxime, 4- (3-hydroxypiperidino) benzamide oxime, 4- (4- Hydroxypiperidino) benzamide oxime, 4- (2-methylpiperidino) benzamide oxime, 4- (4-diethylaminopiperidino) benzamide oxime, 4-
(4-Hydroxyiminopiperidino) benzamide oxime, 4- (2-oxopiperidino) benzamide oxime, 4-piperidinobenzamide O -benzyloxime, 4-piperidinobenzamide O -methyloxime, N -acetyl-4- Piperidinobenzamide O −
The above-mentioned (1) selected from benzyl oxime, N-methyl-4-piperidinobenzamide oxime, N-ethyl-4-piperidinobenzamide oxime, and N, N-dimethyl-4-piperidinobenzamide oxime. A benzamide oxime derivative or a pharmacologically acceptable salt thereof.

(5) 4- (4-piperidinopiperidino) benzamide oxime, 4- [4- (3-pentyl) -1-piperazinyl] benzamide oxime, 4-
The above (1) selected from (4-methyl-1-piperazinyl) benzamide oxime, 4- (4-cyclopentyl-1-piperazinyl) benzamide oxime, 4-piperidinobenzamide oxime, and 4- (1-piperazinyl) benzamide oxime. The benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (2) and (4).

(6) The benzamide oxime derivative or pharmacologically acceptable salt thereof according to any one of (1) to (5) above, which is 4-piperidinobenzamide oxime.

(7) A pharmaceutical composition comprising the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) above and a pharmaceutically acceptable carrier.

(8) A cell adhesion inhibitor comprising the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) above.

(9) An anti-inflammatory agent containing the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) above.

(10) An ischemia-reperfusion injury therapeutic agent comprising the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) above.

(11) An organ transplant rejection inhibitor containing the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6).

(12) An agent for treating autoimmune diseases, which comprises the benzamide oxime derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (6) above.

(13) A cancer metastasis inhibitor comprising the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) above.

The compound of the present invention includes stereoisomers, tautomers and optical isomers, and the present invention includes all of them. These various isomers can be separated and purified or optically resolved by a known method, and can also be converted into each other.

The meanings of the terms used in this specification are as follows. The “alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, te
rt-butyl group, n-pentyl group, isopentyl group, t
ert-pentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, isohexyl group, 2-hexyl group and the like, and preferably methyl group, ethyl group, n-propyl group, isopropyl group. , N-
Butyl group, isobutyl group, sec-butyl group, tert
-Butyl group, n-pentyl group, 2-pentyl group, 3-pentyl group, tert-pentyl group, n-hexyl group, 2-hexyl group and the like. R ¹ , R ² or R ³ is particularly preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group, and as R ⁴ , R ⁵ , R ⁶ or R ^7. A methyl group, an ethyl group, an n-propyl group or an isopropyl group is particularly preferable, and a methyl group or an ethyl group is particularly preferable when used as a substituent. When it has a substituent, it may have two or more kinds or two or more kinds at the same time, and the substitution position and the number are not particularly limited as long as it is chemically acceptable.

The "acyl group" is an alkanoyl group having 1 to 6 carbon atoms which may be linear or branched, or an aroyl group having 6 to 14 carbon atoms, for example, a formyl group, an acetyl group, a propionyl group, Examples thereof include butyroyl group, valeroyl group, pivaloyl group, benzoyl group and the like, preferably formyl group, acetyl group, propionyl group or pivaloyl group and the like, particularly preferably formyl group or acetyl group as R ¹ , R ² or R ^3. And R ⁷ is particularly preferably an acetyl group, a propionyl group or a pivaloyl group.

The "aryl group" means a phenyl group having 6 to 14 carbon atoms, a naphthyl group, a biphenyl group, a fluorenyl group, an anthranyl group or the like, preferably a phenyl group or a naphthyl group, and particularly preferably a phenyl group. Is. When it has a substituent, it may have two or more kinds or two or more kinds at the same time, and the substitution position and the number are not particularly limited as long as it is chemically acceptable.

The "aralkyl group" is an arylalkyl group consisting of an aryl group and an alkyl group as described above, and examples thereof include a benzyl group, a phenethyl group, a phenylpropyl group, a phenylbutyl group and a phenylhexyl group. Is a benzyl group or a phenethyl group. When it has a substituent, it may have two or more kinds or two or more kinds at the same time, and the substitution position and the number are not particularly limited as long as it is chemically acceptable.

The "alkoxycarbonyl group" is an alkoxycarbonyl group having an alkyl part which has 1 to 6 carbon atoms and may be linear or branched, and includes, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, Isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-
Examples thereof include a pentoxycarbonyl group, an isopentoxycarbonyl group, a tert-pentoxycarbonyl group, a neopentoxycarbonyl group, an n-hexoxycarbonyl group and an isohexoxycarbonyl group, and the like, and the alkyl part preferably has 1 carbon atom. To methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group or tert-butoxycarbonyl group, etc., and particularly preferred. Is a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, or the like. When it has a substituent, it may have two or more kinds or two or more kinds at the same time, and the substitution position and the number are not particularly limited as long as it is chemically acceptable.

The "alkoxy group" is a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group. , Isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group,
Examples thereof include an isopentoxy group, a tert-pentoxy group, a neopentoxy group, an n-hexoxy group, an isohexoxy group and the like, preferably a methoxy group having 1 to 4 carbon atoms, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-
A butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group and the like are preferable, and a methoxy group and an ethoxy group are particularly preferable.

The "alkyl-substituted amino group" is an amino group which is mono- or di-substituted with an alkyl group, and examples of the alkyl group include those mentioned above for the "alkyl group". Further, it may be annular depending on the case.

Specifically, methylamino group, ethylamino group, propylamino group, isopropylamino group, dimethylamino group, diethylamino group, dipropylamino group,
A diisopropylamino group, a methylethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidino group or the like can be mentioned, and a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, a pyrrolidinyl group or a piperidino group is particularly preferable. Is a dimethylamino group, a diethylamino group, a pyrrolidinyl group or the like.

The "halogen atom" specifically includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, and particularly preferably a chlorine atom or a bromine atom. Is an atom.

The "pharmacologically acceptable salt" may be any salt as long as it forms a non-toxic salt with the benzamide oxime derivative represented by the general formula [I].
For example, inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or hydrobromic acid, or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, gluconic acid or ascorbic acid. Examples thereof include organic acid salts and the like. Further, depending on the case, it may be a hydrate or a hydrate.

[0044]

Next, an example of a method for producing a compound for carrying out the present invention will be described. However, the method for producing the compound of the present invention is not limited to these. In each step, the reaction treatment may be carried out by a commonly used method, and isolation and purification may be carried out by appropriately selecting and combining commonly used methods such as crystallization, recrystallization, silica gel column chromatography and preparative HPLC. You can do it.

Reaction Process Diagram 1

Embedded image

First Step This step is a step of aminating a compound represented by the general formula (ii) (X represents a hydrogen atom or a halogen atom) by an aromatic nucleophilic substitution reaction. The compound represented by the general formula (ii) is treated with benzene, toluene, xylene, N, N-dimethylformamide, dimethylsulfoxide, a mixed solvent thereof or the like, and sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, In the presence of a base such as potassium carbonate, triethylamine or N, N-diisopropylethylamine, depending on the reaction substrate, at a temperature of 80 ° C to 180 ° C,

Embedded image [A is an oxygen atom, a carbonyl group,

Embedded image Or A′-R ⁴ [R ⁴ is a hydrogen atom; a hydroxyl group, an amino group, an alkoxy group, an alkyl group which may be substituted with an alkyl-substituted amino group or an oxo group; an alkyl group, a hydroxyl group, an alkoxy group, an amino group or an alkyl group Aryl group optionally substituted with amino group; Aralkyl group optionally substituted with alkyl group, hydroxyl group, alkoxy group, amino group or alkyl substituted amino group; Substituted with hydroxyl group, amino group, alkyl substituted amino group or oxo group Optionally an alkoxycarbonyl group or

[Chemical formula 26] << R ⁵ represents a hydrogen atom or an alkyl group which may be substituted with a hydroxyl group, A ¹ is an oxygen atom or A ¹ ′ -R ⁶ <R ⁶ is a hydrogen atom, an alkyl group which may be substituted with a hydroxyl group or R ^Five
Be with

Embedded image {A ² represents an oxygen atom or A ² ′ -R ⁷ (R ⁷ represents a hydrogen atom, an alkyl group, an acyl group or an alkoxycarbonyl group, and A ² ′ represents a nitrogen atom or a CH group),
s and t are the same or different and each represents an integer of 1 to 3. Represents｝. >, And r represents an integer of 0 or 1 to 3. >>, A'represents a nitrogen atom or a CH group. ]
And B is

Embedded image (J represents 0 or an integer of 1 to 2),

[Chemical 29] (J has the same meaning as described above),

Embedded image (K represents an integer of 1 to ₂ ) _or- (CH2) _m-.
(M represents an integer of 1 to 3), and n is 1 to 3
Represents the integer. ] By reacting with an amine compound represented by the following or a salt thereof, a compound of the general formula (iii) (A, B,
X and n have the same meanings as described above. ) The compound represented by this is obtained.

First Step 2 This step is a step of preparing the compound represented by the general formula (iii):
A is N—R ⁴ ′ [R ⁴ ′ is an alkyl group which may be substituted with a hydroxyl group, an amino group, an alkoxy group, an alkyl-substituted amino group or an oxo group; an alkyl group, a hydroxyl group, an alkoxy group, an amino group or an alkyl-substituted amino group. An aryl group which may be substituted with a group; an aralkyl group which may be substituted with an alkyl group, a hydroxyl group, an alkoxy group, an amino group or an alkyl substituted amino group; a hydroxyl group, an amino group, an alkyl substituted amino group or an oxo group Good alkoxycarbonyl group or

[Chemical 31] (R ⁵ , A ¹ , and r have the same meanings as described above.)
Represents ] A method suitable for producing the compound represented by

Reaction Process Diagram 2

Embedded image

Among the compounds represented by the general formula (iii) obtained in the first step, compounds in which A represents an NH group (iii
-2) (B, X and n have the same meanings as described above), methanol, ethanol, n-propanol,
Isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1,2
-Sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, dichloroethane, chloroform, water or a mixed solvent thereof
Sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, triethylamine or N, N-
In the presence of a base such as diisopropylethylamine, depending on the reaction substrate, at a temperature of 20 ° C to 150 ° C,

[Chemical 33] (R ⁴ 'represents the same meaning as described above, and Hal represents a halogen atom.) By reacting with a compound represented by the general formula (iii-3) (R ⁴ ', B, X, n are A compound represented by the same meaning as described above) is obtained.

[0050] 3 This step of the first step, among the compounds represented by the general formula (iii-3), the R ⁴ '

Embedded image [R ⁵ 'represents an alkyl group which may be substituted with a hydroxyl group, R ⁶ ' is an alkyl group which may be substituted with a hydroxyl group or R ⁵ '

Embedded image (A ² , s, and t have the same meanings as described above.)
Represents ] A method suitable for producing the compound represented by

Reaction Process Diagram 3

Embedded image

The compound represented by the general formula (iii-2) is hydrogenated with sodium triacetoxyborohydride or hydrogenated using a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, methanol, ethanol, n-propanol or isopropanol. In the presence of a reducing agent such as sodium cyanoboron, depending on the reaction quality, 0 ℃
To room temperature

Embedded image (R ⁵ 'and R ⁶ ' have the same meanings as described above.)
By reductively condensing with a compound represented by
A compound represented by the general formula (iii-4) (R ⁵ ′, R ⁶ ′, B, X and n each have the same meaning as described above) can be obtained. In this reaction, it may be preferable to add a Lewis acid such as titanium tetraisopropoxide.

Step 1 of Step 4 This step is a step of preparing the compound represented by the general formula (iii):
A is

Embedded image (R ⁵ 'and R ⁶ ' have the same meanings as described above.)
A suitable method for producing the compound represented by

Reaction Process Diagram 4

Embedded image

A compound (iii-5) in which A is a carbonyl group in the general formula (iii) (B, X and n have the same meanings as described above);

[Chemical 40] (R ⁵ 'and R ⁶ ' have the same meanings as described above.)
By carrying out the method similar to the method shown in 3 of the first step for the compound represented by or a salt thereof, among the compounds represented by the general formula (iii), A

Embedded image (R ⁵ 'and R ⁶ ' have the same meanings as described above.)
A compound (iii-6) represented by

Embedded image (R ⁵ 'and R ⁶ ' have the same meanings as described above.)
When a salt of the compound represented by is used, it may be neutralized with an equivalent amount of a base.

5 of the first step Reaction step diagram 5

Embedded image

Among the compounds represented by the general formula (iii-3), the compound (iii in which R ⁴ 'is an alkoxycarbonyl group
-7) (Ak represents an alkyl group, B, X and n have the same meanings as described above), if desired, methyl chlorocarbonate, ethyl chlorocarbonate, butyl chlorocarbonate, isopropyl chlorocarbonate or the like,

Embedded image The method shown in 2 of the first step using an alkoxycarbonylating agent represented by can be carried out, but the reaction is carried out by using an alkoxycarbonylating agent such as di-tert-butyldicarbonate in place of these. Good.

First Step 6 In this step and the following first step 7, in the compound represented by the general formula (iii), B is

Embedded image (J represents 0 or an integer of 1 to 2) A method suitable for producing the compound represented by the following is shown.

Reaction Process Diagram 6

Embedded image

A compound represented by the general formula (ii) (where X has the same meaning as described above),

Embedded image (A, j, and n have the same meanings as described above.) The compound represented by the general formula (iii-8 ′) (A , J,
Each n has the same meaning as described above. ) The compound represented by this is obtained.

Step 1 of Step 7 The compound represented by the general formula (iii-8 ') is converted into dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, or the like. In the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide or diphenylphosphoryl azide. By performing the general formula (iii-8)
(A, X, j, and n have the same meanings as described above.) The compound represented by the above is obtained.

Second Step This step is a step of adding hydroxylamine to the cyano group of the compound represented by the general formula (iii) obtained in the first step to convert it into an amidoxime. General formula (ii
i) the compound represented by methanol, ethanol, n-
Propanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethylsulfoxide, water or a mixed solvent thereof is used, and hydroxylamine or a salt thereof varies depending on the reaction substrate, but at 50 ° C. To 130 ° C
By reacting at the temperature of, the compound of the general formula [I-2] (A, B, X, n in which R ¹ , R ² and R ³ are hydrogen atoms among the compounds represented by the general formula [I] is respectively The compound having the same meaning as described above) is obtained. When using a salt of hydroxylamine, sodium hydrogen carbonate,
It is preferable to neutralize with a base such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide.

At this time, when a compound represented by the general formula (iii) in which A is a carbonyl group is used, A is

Embedded image A compound is obtained. When a compound in which A is a carbonyl group is desired, after protecting the carbonyl group by a known method, this step is performed, and deprotection is performed.
A compound represented by the general formula (iii) in which A is a carbonyl group is obtained.

Third Step In this step, among the compounds represented by the general formula [I-2], the compound in which A is an NH group or A is

Embedded image When a compound in which A ² represents an NH group is desired, among the compounds represented by the general formula [I-2], A or A ² is N
-A method for carrying out a reaction using a compound represented by an alkoxycarbonyl group is shown.

Reaction Process Diagram 7

Embedded image

General formula [I-5] (B, X, n and Ak have the same meanings as described above) or general formula [I-
7] (wherein A ′, A ¹ ′, B, X, n, r, s, t, and Ak have the same meanings as described above), the compound represented by the formula is dichloromethane, dichloromethane, chloroform, diethyl ether, or tetrahydrofuran. , 1,4-dioxane, water or a mixed solvent thereof, or in some cases, the following acid itself is used as a solvent, and an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, trifluoroacetic acid or methanesulfonic acid is used. By carrying out the reaction by the general formula [I-
6] (B, X and n have the same meanings as described above) or the general formula [I-8] (A ′, A ¹ ′, B, X,
n, r, s, and t have the same meanings as described above. )
The compound represented by is obtained.

Fourth Step This step is represented by the general formula [I-2] (or general formula [I-7] or general formula [I-8]) obtained in the second step (or the third step). Is a step of introducing a group other than hydrogen as R ¹ into the compound. If a compound in which R ¹ is hydrogen is desired, this step can be skipped. General formula [I-2] (or general formula [I-7] or general formula [I
-8]) is converted to dichloromethane, 1,2
-Dichloroethane, chloroform, pyridine, tetrahydrofuran, N, N-dimethylformamide or 1,4
-Using a solvent such as dioxane, triethylamine, N,
Presence of a base such as N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride or potassium hydride. Under ice cooling to a temperature of 80 ° C., depending on the reaction substrate,

[Chemical 51] (R ¹ 'represents an alkyl group, an aralkyl group or an acyl group, and Hal has the same meaning as described above.) To react with a compound represented by the general formula [I-3] (R
¹ ', A, B, X and n have the same meanings as described above. ) The compound represented by this is obtained. Here, general formula [I-2] (or general formula [I-7] or general formula [I
-8]) has a reactive group in the compound, the group is protected with a protecting group by a known method before carrying out this step, and after carrying out this step, it is carried out at an appropriate stage. The protecting group may be removed by a known method. When an acyl group is desired as R ¹ ',

Embedded image The reaction may be performed using an acid anhydride such as acetic anhydride instead of the acyl halide represented by.

Fifth Step In this step, a group other than hydrogen is introduced into at least one of R ² and R ^{3 in the} compound represented by the general formula [I-3] obtained in the fourth step. Formula [I] (R ¹ , R ² ,
R ³ , A, B, X and n have the same meanings as described above. ) Is a process of obtaining. If a compound in which R ² and R ³ simultaneously represent a hydrogen atom is desired, this step can be omitted. The compound represented by the general formula [I-3] is used at a temperature of −80 ° C. to room temperature using a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, N, N-dimethylformamide, acetone, methyl ethyl ketone or acetonitrile. n-butyl lithium, sec
-In the presence of a base such as -butyllithium, tert-butyllithium, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide or lithium hydroxide,

Embedded image (R ² 'represents an alkyl group or an acyl group, and Hal has the same meaning as described above.), Whereby R ² and R ³ are R ² ' at the same time. The compound represented by I] is obtained. Here, when R ² 'is an acyl group, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran,
When the reaction is performed in 1,4-dioxane, water or a mixed solvent thereof in the presence of a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, one acyl group is eliminated and R ² is an acyl group. , R ³ is a hydrogen atom to obtain a compound represented by the general formula [I]. Then

Embedded image (R ³ 'represents an alkyl group or an acyl group and Hal has the same meaning as described above.) When a reaction similar to the above is carried out using a compound represented by the formula [I] A compound is obtained. When a compound represented by the general formula [I] in which one of them is an alkyl group and the other is a hydrogen atom is desired, the amino group is replaced with an amino protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group. After protection with, the alkylation reaction similar to the above is carried out, and the protecting group is removed to obtain the desired compound. When a compound representing a hydrogen atom as R ¹ is desired, deprotection may be carried out by performing this step after introducing an operation for introducing a hydroxyl-protecting group instead of the fourth step.

Sixth Step This step and the following seventh step are suitable methods for producing a compound in which an alkyl group is represented as R ^{2 and a} hydrogen atom is represented as R ¹ and R ³ . Reaction process diagram 8

Embedded image

A compound represented by the general formula [I-2] (or general formula [I-7] or general formula [I-8]) obtained in the second step (or the third step)

Embedded image (R ² ″ represents a hydrogen atom or an alkyl group, and Acy represents an acyl group) or

Embedded image By reacting an aldehyde compound represented by (R ² ″ has the same meaning as described above) at a temperature of 60 ° C. to 180 ° C., a compound of the general formula (iv) (

Embedded image Represents a single bond or a double bond, and R ² ″, A, B, and n each have the same meaning as described above.) Are obtained. The solvent used is water, tetrahydrofuran, N,
N-dimethylformamide, dimethyl sulfoxide, a mixed solvent thereof, or an acid anhydride or an aldehyde compound to be reacted may be used as the solvent.

Step 7 The compound represented by the general formula (iv) obtained in Step 6 is
Using a solvent such as tetrahydrofuran, diethyl ether or 1,4-dioxane, and using a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride or diborane under ice cooling to room temperature. Of the compound represented by the general formula [I] by carrying out a reduction reaction with the general formula [I-9]
A compound represented by (R ² ″, A, B, and n has the same meanings as described above) is obtained.

The eighth to eleventh steps are other methods for introducing R ² and R ³ . Reaction process diagram 9

Embedded image

Step 8 This step is a step of aminating the compound represented by the general formula (v) (X represents a hydrogen atom or a halogen atom) by an aromatic nucleophilic substitution reaction, and the first step In some cases, by performing a method similar to the method shown in the first step 2 to the first step 7, the general formula (vi) (A, B,
X and n have the same meanings as described above. ) The compound represented by this is obtained.

Step 9 This step is a step in which the compound represented by the general formula (vi) obtained in Step 8 is reacted with hydroxylamine, and a method similar to the method shown in Step 2 is used. By carrying out, a compound represented by the general formula (vii) (A, B, X and n have the same meanings as described above) can be obtained.

Step 10 This step is a step of halogenating the compound represented by the general formula (vii) obtained in Step 9. General formula (vi
The compound represented by i) is used in a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene or toluene, and tert-butyl hypochlorite, tert-butyl hypobromite, chlorine, By carrying out the halogenation reaction using a halogenating agent such as bromine, thionyl chloride, oxalyl chloride or carbon tetrabromide, the general formula (viii) (A, B, X, n and Hal respectively have the same meanings as described above. A compound represented by the formula (1) is obtained. This compound may proceed to the next step without isolation and purification.

Step 11 This step is a step of aminating the compound represented by the general formula (viii) obtained in Step 10. General formula (vii
The compound represented by i) is converted into methanol, ethanol, n
-Propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N
-Using dimethylformamide, dimethyl sulfoxide or water or a mixed solvent thereof,

Embedded image (R ² and R ³ have the same meanings as described above.) The compound represented by the general formula [I] is prepared by reacting the compound under ice-cooling to 100 ° C., though it varies depending on the reaction substrate.
Among the compounds represented by the general formula [I-10] (R ² ,
R ³ , A, B and n have the same meanings as described above. ) The compound represented by this is obtained.

When the free form of the compound represented by the general formula [I] is used as an acid addition salt or when a weak acid salt is converted into a strong acid salt, the compound is water, methanol, ethanol, n.
-Dissolved in propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane or chloroform or a mixed solvent thereof, etc., and added the solvent in which the desired acid is dissolved, The precipitated crystals are collected by filtration or concentrated under reduced pressure to obtain an acid addition salt of the compound represented by the general formula [I].

When converting the acid addition salt of the compound represented by the general formula [I], the compound is converted to sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide. It is dissolved or suspended in an aqueous solution of a base such as, and extracted with ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, a mixed solvent thereof or the like. Then, this residue is dissolved in water, methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, 1,2-dichloroethane or chloroform, or a mixed solvent thereof or the like, The above-mentioned solvent in which the acid is dissolved is added, and the precipitated crystal is filtered or concentrated under reduced pressure to convert it to the desired salt of the general formula [I].
An acid addition salt of the compound represented by

The thus-obtained compound of the present invention represented by the general formula [I] has an anti-inflammatory effect based on the cell adhesion inhibitory effect,
Ischemia-reperfusion injury inhibitory effect, organ transplant rejection inhibitory effect,
It has an autoimmune disease inhibitory action, cancer metastasis inhibitory action, anti-allergic action, anti-asthma action, bone marrow transplant rejection inhibitory action, anti-atherogenic action and the like. When the compound of the present invention is used as an anti-inflammatory agent, a therapeutic agent for ischemia-reperfusion injury, an agent for suppressing organ transplant rejection, an agent for suppressing autoimmune disease or an agent for suppressing cancer metastasis, it is usually systemically or locally, orally or parenterally. Administered in.

The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but in the case of an anti-inflammatory agent per adult, ischemia-reperfusion injury is usually within the range of 10 mg to 1 g per adult. 0.01 mg to 1 for inhibitors
In the range of 0 mg, 1 m for organ transplant rejection inhibitors
In the range of 1 g to 1 g, it is 0.
In the range of 01 mg to 100 mg, and in the case of a cancer metastasis inhibitor, the range of 0.1 mg to 100 mg is orally or parenterally administered once to several times a day.

When the compound of the present invention is made into a solid composition for oral administration, it may be in the form of tablets, pills, powders, granules and the like. In such solid compositions, the one or more active substances are at least one inert diluent, dispersant or adsorbent, such as lactose, mannitol,
It is mixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylhydrin, magnesium aluminometasilicate, anhydrous silicic acid powder or the like. Further, the composition may be mixed with additives other than the diluent according to a conventional method.

In the case of preparing tablets or pills, it may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose or hydroxymethyl cellulose phthalate, if necessary, or in two or more layers. You may coat. In addition, the capsule may be made of a substance such as gelatin or ethyl cellulose.

When the composition is a liquid composition for oral administration, it can be in the form of a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir. The diluent used includes, for example, purified water, ethanol, vegetable oil and emulsifier. In addition to the diluent, this composition may be mixed with an auxiliary agent such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent or a preservative.

When preparing an injection for parenteral administration,
Sterile aqueous or non-aqueous solutions, solubilizers, suspensions or emulsifiers are used. Examples of the water-soluble solution, solubilizer, and suspension include distilled water for injection, physiological saline cyclodextrin and its derivatives, triethanolamine, diethanolamine, monoethanolamine, triethylamine, and other organic amines or inorganic alkalis. There is a solution etc.

In the case of making a water-soluble solution, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol and the like may be used. As the solubilizing agent, for example, a surfactant such as polyoxyethylene hydrogenated castor oil and sucrose fatty acid ester (mixed micelle formation), or lecithin or hydrogenated lecithin (liposome formation) is also used. or,
It is also possible to prepare an emulsion preparation comprising a water-insoluble solubilizer such as vegetable oil and lecithin, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol or the like.

Other compositions for parenteral administration include external preparations containing one or more active substances and prepared by a method known per se, coating agents such as ointments, suppositories or pessaries. Etc.

[0087]

EXAMPLES Next, the compounds represented by the general formula [I] according to the present invention and the method for producing the same will be specifically described with reference to Examples. However, it goes without saying that the present invention is not limited by these examples.

Reference Example 1 (Step 1) 4- (1-piperazinyl) benzonitrile

[Chemical formula 61] 4-Fluorobenzonitrile (10.0 g) in toluene (165 ml)
, Anhydrous potassium carbonate (11.4 g) and anhydrous piperazine (35.6 g) were added, and the mixture was heated under reflux under a nitrogen atmosphere overnight.
After cooling, the insoluble matter in the reaction mixture was filtered off, and unreacted piperazine precipitated in the process of concentrating the filtrate was filtered off. After repeating the operations of concentration and filtration again, the title compound (14.
0 g) was obtained as colorless crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.68 (1H, s), 2.97-3.09
(4H, m), 3.21-3.35 (4H, m), 6.86 (2H, dt, J = 9.1, 2.1Hz),
7.49 (2H, dt, J = 9.1, 2.1Hz) FAB (+) MS (low resolution) 188

Reference Example 2 (First Step) 4- (4-piperidinopiperidino) benzonitrile

Embedded image A reaction was carried out in the same manner as in Reference Example 1 from 4-fluorobenzonitrile (2.42 g) and 4-piperidinopiperidine (2.24 g). However, xylene (27 ml) instead of toluene
Instead of anhydrous potassium carbonate, anhydrous sodium carbonate
(1.41 g) was used. The reaction treatment was performed as follows. After the reaction mixture was allowed to cool, concentrated hydrochloric acid was added to separate the acidic aqueous layer and the organic layer. The organic layer was extracted twice with 1N hydrochloric acid, the acidic aqueous portions were combined, washed twice with ethyl acetate, made basic with 1N aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration and thoroughly washed with water. Washed with. The obtained crude crystals were recrystallized from ethanol to give the title compound (1.13 g) as colorless crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.37-1.73 (8H, m), 1.84
-1.98 (2H, m), 2.39-2.60 (5H, m), 2.79-2.91 (2H, m), 3.8
2-3.95 (2H, m), 6.85 (2H, dd, J = 9.1, 2.0Hz), 7.45 (2H, d
d, J = 9.0, 2.0Hz) FAB (+) MS (low resolution) 270

Reference Examples 3 to 20 (First Step) In the same manner as in Reference Example 2, compounds of Reference Examples 3 to 20 were obtained. These are shown in Table 1 and Table 2.

[Table 1]

¹ H NMR of Reference Example 3 (300 MHz, δ ppm, CDCl ₃ ).
2.00-2.10 (4H, m), 3.28-3.39 (4H, m), 6.50 (2H, dd, J = 9.
1, 2.0Hz), 7.44 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 173

¹ H NMR of Reference Example 4 (300 MHz, δppm, CDCl ₃ )
1.51-1.70 (2H, m), 1.72-1.87 (4H, m), 1.91-2.04 (2H, m
m), 2.16-2.28 (1H, m), 2.50-2.66 (4H, m), 2.85-3.00 (2
H, m), 3.73-3.87 (2H, m), 6.85 (2H, dd, J = 9.1, 2.0Hz),
7.46 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 256

¹ H NMR of Reference Example 5 (300 MHz, δ ppm, CDCl ₃ )
1.48-1.73 (2H, m), 1.86-2.00 (2H, m), 2.32-2.44 (1H,
m), 2.46-2.62 (4H, m), 2.81-2.98 (2H, m), 3.60-3.78 (4
H, m), 3.80-3.97 (2H, m), 6.85 (2H, dd, J = 9.1, 2.0Hz),
7.46 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 272

¹ H NMR of Reference Example 6 (300 MHz, δ ppm, CDCl ₃ )
3.28 (4H, t, J = 6.0Hz), 3.85 (4H, t, J = 6.0Hz), 6.86 (2H, d
d, J = 9.1, 2.0Hz), 7.52 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 189

¹ H NMR of Reference Example 7 (300 MHz, δ ppm, CDCl ₃ ).
2.36 (3H, s), 2.47-2.60 (4H, m), 3.19-3.40 (4H, m), 6.8
7 (2H, dd, J = 9.1, 2.0Hz), 7.50 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 202

¹ H NMR of Reference Example 8 (300 MHz, δ ppm, CDCl ₃ ).
1.13 (3H, t, J = 5.4Hz), 2.47 (2H, q, J = 5.4Hz), 2.58 (4H,
t, J = 3.8Hz), 3.34 (4H, t, J = 3.8Hz), 6.86 (2H, dd, J = 9.1,
2.0Hz), 7.49 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 216

¹ H NMR of Reference Example 9 (300 MHz, δ ppm, CDCl ₃ ).
0.93 (3H, t, J = 7.9Hz), 1.55 (2H, sextet, J = 7.9Hz), 2.35
(2H, t, J = 7.9Hz), 2.57 (4H, t, J = 5.3Hz), 3.33 (4H, t, J = 5.
3Hz), 6.85 (2H, dd, J = 9.1, 2.0Hz), 7.48 (2H, dd, J = 9.1,
2.0Hz) FAB (+) MS (low resolution) 230

¹ H NMR of Reference Example 10 (300 MHz, δ ppm, CDCl
₃ ) 1.08 (6H, d, J = 6.0Hz), 2.64-2.67 (4H, m), 2.73 (1H, se
ptet, J = 6.0Hz), 3.31-3.35 (4H, m), 6.86 (2H, dd, J = 9.1,
2.0Hz), 7.49 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 230

¹ H NMR of Reference Example 11 (300 MHz, δ ppm, CDCl
₃ ) 1.63 (1H, broad s), 2.58-2.71 (6H, m), 3.35 (4H, t, J =
5.0Hz), 3.68 (2H, t, J = 5.0Hz), 6.86 (2H, dd, J = 9.1, 2.0H
z), 7.49 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 232

[0100]

[Table 2]

¹ H NMR of Reference Example 12 (300 MHz, δ ppm, CDCl
₃ ) 1.81 (2H, broad s), 2.42 (1H, dd, J = 12.5, 3.8Hz), 2.
53-2.70 (3H, m), 2.75-2.85 (2H, m), 3.25-3.42 (4H, m),
3.53 (1H, dd, J = 11.4, 4.3Hz), 3.78 (1H, dd, J = 11.4, 3.7H
z), 3.81-3.91 (1H, m), 6.85 (2H, dd, J = 9.1, 2.0Hz), 7.4
9 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 262

¹ H NMR of Reference Example 13 (300 MHz, δ ppm, CDCl
₃ ) 2.57-2.72 (6H, m), 3.29-3.41 (4H, m), 3.57-3.78 (6H,
m), 6.86 (2H, dd, J = 9.1, 2.0Hz), 7.49 (2H, dd, J = 9.1, 2.
0Hz) FAB (+) MS (low resolution) 276

¹ H NMR of Reference Example 14 (300 MHz, δ ppm, CDCl
₃ ) 1.81-1.90 (2H, m), 1.92-2.02 (2H, m), 2.70-2.73 (4H,
m), 3.19 (2H, s), 3.35-3.39 (4H, m), 3.46-3.52 (4H, m),
6.86 (2H, dd, J = 9.1, 2.0Hz), 7.48 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 299

¹ H NMR of Reference Example 15 (300 MHz, δ ppm, CDCl
₃ ) 1.18 (6H, d, J = 6.0Hz), 2.60-2.71 (4H, m), 3.05 (2H,
s), 3.29-3.40 (4H, m), 4.03-4.19 (1H, m), 6.87 (2H, dd, J
= 9.1,2.0Hz), 7.50 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 287

¹ H NMR of Reference Example 16 (300 MHz, δ ppm, CDCl
₃ ) 2.27 (6H, s), 2.43-2.67 (8H, m), 3.25-3.40 (4H, m), 6.
85 (2H, dd, J = 9.1, 2.0Hz), 7.50 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 259

¹ H NMR of Reference Example 17 (300 MHz, δ ppm, CDCl
₃ ) 1.62-1.78 (2H, m), 2.25 (6H, s), 2.33 (2H, t, J = 6Hz),
2.43 (2H, t, J = 6Hz), 2.50-2.63 (4H, m), 3.26-3.39 (4H,
m), 6.86 (2H, dd, J = 9.1, 2.0Hz), 7.49 (2H, dd, J = 9.1, 2.
0Hz) FAB (+) MS (low resolution) 273

¹ H NMR of Reference Example 18 (300 MHz, δ ppm, CDCl
₃ ) 1.29 (3H, t, J = 6.0Hz), 3.30-3.34 (4H, m), 3.62-3.65
(4H, m), 4.18 (2H, q, J = 6.0Hz), 6.87 (2H, dd, J = 9.1, 2.0H
z), 7.52 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 260

¹ H NMR of Reference Example 19 (300 MHz, δ ppm, CDCl
₃ ) 2.15 (3H, s), 3.31-3.39 (4H, m), 3.62-3.66 (2H, m), 3.
76-3.80 (2H, m), 6.87 (2H, dd, J = 9.1, 2.0Hz), 7.53 (2H, d
d, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 230

¹ H NMR of Reference Example 20 (300 MHz, δ ppm, CDCl
₃ ) 3.32-3.35 (4H, m), 3.47-3.51 (4H, m), 6.89-6.98 (5H,
m), 7.28-7.33 (2H, m), 7.52 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 264

Reference Example 21 (first step) 4-piperidinobenzonitrile

Embedded image 4-Fluorobenzonitrile (2.42 g) and piperidine (1.
From 70 g), the reaction was carried out in the same manner as in Reference Example 1. However,
Dimethyl sulfoxide (25 ml) was used instead of toluene, and stirring was performed at 100 ° C. for 6 hours. The reaction treatment was performed as follows. The reaction mixture was allowed to cool and then poured into ice water, and the precipitated crystals were collected by filtration. The obtained crude crystals were dried under reduced pressure and then recrystallized from a mixed solution of diethyl ether and n-hexane to give the title compound (2.73 g) as colorless crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.55-1.72 (6H, m), 3.22
-3.39 (4H, m), 6.83 (2H, dt, J = 9.0, 2.1Hz), 7.46 (2H, dt,
(J = 9.0, 2.1Hz)

Reference Example 22 (Step 1) 4- (4-methylpiperidino) benzonitrile

Embedded image The title compound (1.39 g) was obtained from 4-fluorobenzonitrile (1.21 g) and 4-methylpiperidine (0.99 g) in the same manner as in Reference Example 21. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 0.97 (3 H, d, J = 6.0 Hz),
1.18-1.35 (2H, m), 1.50-1.80 (3H, m), 2.79-2.91 (2H, m),
3.75-3.88 (2H, m), 6.84 (2H, dd, J = 9.1, 2.0Hz), 7.46 (2
H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 201

Reference Example 23 (2 of the first step) 4- [4- (3-pentyl) -1-piperazinyl] benzonitrile

Embedded image 4- (1-Piperazinyl) benzonitrile (2.0 g) obtained in Reference Example 1 was suspended in ethanol (15 ml), triethylamine (1.56 ml) and 3-bromopentane (1.39 ml) were added, and the mixture was heated for 24 hours. Refluxed. Triethylamine in the reaction solution
(1.56 ml) and 3-bromopentane (1.39 ml) were added, and the mixture was heated under reflux for 15 hr. The reaction solution was allowed to cool and concentrated under reduced pressure, and the obtained residue was dissolved in chloroform, washed successively with 5% aqueous acetic acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then depressurized. Concentrated. The title compound (775 mg) was obtained as colorless crystals by crystallizing the obtained residue with methanol. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 0.92 (6H, t, J = 6.0Hz),
1.33 (2H, d quintet, J = 12.0, 6.0Hz), 1.50 (2H, d quinte
t, J = 12.0, 6.0Hz), 2.21 (1H, quintet, J = 6.0Hz), 2.63-2.
66 (4H, m), 3.27-3.30 (4H, m), 6.85 (2H, dd, J = 9.1, 2.0H
z), 7.48 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 258

Reference Example 24 (3 in the first step) 4- (4-cyclohexyl-1-piperazinyl) benzonitrile

Embedded image 4- (1-Piperazinyl) benzonitrile (1.0 g) obtained in Reference Example 1 was dissolved in dichloromethane (12 ml), and sodium triacetoxyborohydride (2.25 g) and acetic acid (636 m) were dissolved.
g) Cyclohexanone (520 mg) was added thereto, and the mixture was stirred overnight at room temperature under an argon atmosphere. Water was added to the reaction solution to decompose unreacted sodium triacetoxyborohydride and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.29 g). ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.03-1.38 (4H, m), 1.57
-1.70 (2H, m), 1.72-1.98 (4H, m), 2.30 (1H, broad s), 2.
62-2.77 (4H, m), 3.24-3.40 (4H, m), 6.85 (2H, dd, J = 9.1,
2.0Hz), 7.48 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 270

Reference Examples 25 to 29 (3 of the first step) In the same manner as in Reference Example 24, the compounds of Reference Examples 25 to 29 were obtained. These are shown in Table 3.

[Table 3]

¹ H NMR of Reference Example 25 (300 MHz, δ ppm, CDCl
₃ ) 1.33-1.79 (6H, m), 1.80-1.98 (2H, m), 2.53 (1H, quint
et, J = 9.0Hz), 2.62-2.65 (4H, m), 3.32-3.36 (4H, m), 6.8
5 (2H, dd, J = 9.1, 2.0Hz), 7.49 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 256

¹ H NMR of Reference Example 26 (300 MHz, δ ppm, CDCl
₃ ) 1.55-1.64 (2H, m), 1.76-1.80 (2H, m), 2.40-2.51 (1H,
m), 2.68-2.70 (4H, m), 3.31-3.34 (4H, m), 3.35-3.42 (2
H, m), 4.01-4.05 (2H, m), 6.85 (2H, dd, J = 9.1, 2.0Hz), 7.
48 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 272

¹ H NMR of Reference Example 27 (300 MHz, δ ppm, CDCl
₃ ) 1.35-1.51 (11H, m), 1.77-1.88 (2H, m), 2.37-2.50 (1
H, m), 2.65-2.79 (6H, m), 3.32 (4H, t, J = 6.0Hz), 4.08-4.
24 (2H, m), 6.86 (2H, dd, J = 9.1, 2.0Hz), 7.49 (2H, dd, J =
9.1, 2.0Hz) FAB (+) MS (low resolution) 371

¹ H NMR of Reference Example 28 (300 MHz, δ ppm, CDCl
₃ ) 1.28 (9H, s), 1.37-1.52 (2H, m), 1.85-1.96 (2H, m), 2.
45-2.57 (1H, m), 2.70 (4H, t, J = 6.0Hz), 2.73-2.87 (2H,
m), 3.33 (4H, t, J = 6.0Hz), 4.42-4.53 (2H, m), 6.86 (2H, d
d, J = 9.1, 2.0Hz), 7.49 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 355

¹ H NMR of Reference Example 29 (300 MHz, δ ppm, CDCl
₃ ) 1.54-1.68 (2H, m), 1.76-1.84 (2H, m), 1.90-1.99 (2H, m
m), 2.23-2.33 (4H, m), 2.69 (4H, t, J = 3.9Hz), 2.88-2.94
(2H, m), 3.32 (4H, t, J = 3.9Hz), 6.84 (2H, dd, J = 9.1, 2.0H
z), 7.47 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 285

Reference Example 30 (Step 1) 4- (4-oxopiperidino) benzonitrile

Embedded image A reaction was performed in the same manner as in Reference Example 1 from 4-fluorobenzonitrile (4.84 g) and 4-piperidone hydrochloride hydrate (3.07 g). However, dimethyl sulfoxide (10 ml) was used instead of toluene, and stirring was performed at 95 ° C. for 12 hours.
The reaction treatment was performed as follows. After allowing the reaction mixture to cool,
It was poured into water (300 ml) and extracted twice with chloroform (100 ml). The organic layer was washed twice with saturated aqueous sodium chloride solution,
The residue obtained by concentration under reduced pressure after drying over anhydrous sodium sulfate was subjected to silica gel flash column chromatography, and n-hexane: ethyl acetate = 1: 1 eluate
The title compound (573 mg) was obtained as a colorless solid. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 2.59 (4H, t, J = 6.0Hz),
3.75 (4H, t, J = 6.0Hz), 6.90 (2H, dt, J = 9.0, 2.1Hz), 7.54
(2H, dt, J = 9.0, 2.1Hz) FAB (+) MS (Low resolution) 201

Reference Example 31 (4 in the first step) 4- [4- [4- (tert-butoxycarbonyl)-
1-piperazinyl] piperidino] benzonitrile

Embedded image A mixture of 4- (4-oxopiperidino) benzonitrile (573 mg), 1- (tert-butoxycarbonyl) piperazine (533 mg) and titanium tetraisopropoxide (1.06 ml) obtained in Reference Example 30 under an argon atmosphere at room temperature. It was stirred for 1 hour. The mixture was diluted with ethanol, sodium cyanoborohydride (120 mg) was added, and the mixture was stirred at room temperature overnight. Water (1 ml) was added to the reaction mixture, and the deposited precipitate was filtered off and washed with several ml of ethanol.
The filtrate and washings were combined, and the oil obtained by concentration under reduced pressure was subjected to silica gel flash column chromatography,
The title compound (456 mg) was obtained from the eluate of ethyl acetate: methanol = 9: 1. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.46 (9H, s), 1.50-1.70
(2H, m), 1.88-1.99 (2H, m), 2.41-2.58 (5H, m), 2.81-2.9
5 (2H, m), 3.38-3.50 (4H, m), 3.81-3.96 (2H, m), 6.86 (2H,
dd, J = 9.1, 2.0Hz), 7.47 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 371

Reference Example 32 (5 in the first step) 4- [4- (tert-butoxycarbonyl) -1-piperazinyl] benzonitrile

Embedded image 4- (1-Piperazinyl) benzonitrile (1.0 g) obtained in Reference Example 1 was dissolved in dichloromethane (10 ml) to give di-t.
ert-Butyl dicarbonate (1.28 g) was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, petroleum ether was added to the obtained residue, and the precipitated crystals were collected by filtration to give the title compound (1.44 g) as colorless crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.49 (9H, s), 3.25-3.36
(4H, m), 3.53-3.62 (4H, m), 6.85 (2H, dd, J = 9.1, 2.0Hz),
7.51 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 288

Reference Example 33 (Step 1) 3-Bromo-4- (4-piperidinopiperidino) benzonitrile

Embedded image A reaction was carried out in the same manner as in Reference Example 1 from 3-bromo-4-fluorobenzonitrile (4.70 g) and 4-piperidinopiperidine (2.93 g). However, xylene (32 ml) was used instead of toluene, and anhydrous sodium carbonate (2.17 g) was used instead of anhydrous potassium carbonate. The reaction treatment was performed as follows. After allowing the reaction mixture to cool, water was added and the aqueous layer and the organic layer were separated. The organic layer was extracted twice with 1N hydrochloric acid, the aqueous layer was added with 10% sodium hydroxide to make it basic, and then extracted twice with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate,
The title compound (2.47 g) was obtained as colorless crystals by concentrating under reduced pressure. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.40-1.51 (2H, m), 1.57
-1.67 (4H, m), 1.70-1.88 (2H, m), 1.89-1.99 (2H, m), 2.3
6-2.48 (1H, m), 2.50-2.61 (4H, m), 2.64-2.77 (2H, m), 3.
50-3.59 (2H, m), 7.02 (1H, d, J = 9.1Hz), 7.52 (1H, dd, J = 9.
0, 3.0Hz), 7.80 (1H, d, J = 3.0Hz) FAB (+) MS (low resolution) 348, 350

Reference Example 34 (Step 1) 3-Bromo-4- (4-isopropyl-1-piperidino) benzonitrile

Embedded image The title compound was obtained in the same manner as in Reference Example 33. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.10 (6H, d, J = 6.0Hz),
2.68-2.83 (5H, m), 3.16 (3H, t, J = 6.0Hz), 7.04 (1H, d, J =
9.0Hz), 7.54 (1H, dd, J = 9.0, 3.0Hz), 7.81 (1H, d, J = 3.0H
z) FAB (+) MS (low resolution) 308, 310

Reference Example 35 (Step 1) 4- (3-hydroxypiperidino) benzonitrile

Embedded image A reaction was carried out in the same manner as in Reference Example 1 from 4-fluorobenzonitrile (6.00 g) and 3-hydroxypiperidine hydrochloride (7.50 g). However, dimethyl sulfoxide (40 ml) was used instead of toluene, and stirring was performed at 100 ° C. overnight. The reaction treatment was performed as follows. The reaction mixture was allowed to cool, water (200 ml) was added, and the precipitated crystals were collected by filtration to give the title compound (9.27 g) as colorless crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.52-1.75 (2H, m), 1.81
-2.03 (2H, m), 3.02-3.21 (2H, m), 3.33-3.44 (1H, m), 3.5
2-3.63 (1H, m), 3.80-3.98 (1H, m), 6.87 (2H, dd, J = 9.3,
1.8Hz), 7.47 (2H, dd, J = 9.3, 1.8Hz) FAB (+) MS (low resolution) 203

Reference Example 36 (Step 1) 4- (4-hydroxypiperidino) benzonitrile

Embedded image The title compound (7.80 g) was obtained as colorless crystals from 4-fluorobenzonitrile (5.40 g) and 4-hydroxypiperidine (5.00 g) in the same manner as in Reference Example 35. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.53-1.72 (2H, m), 1.91
-2.03 (2H, m), 3.03-3.19 (2H, m), 3.62-3.76 (2H, m), 3.8
8-4.01 (1H, m), 6.86 (2H, dd, J = 9.0, 1.8Hz), 7.48 (2H, d
d, J = 9.0, 1.8Hz) FAB (+) MS (low resolution) 203

Reference Example 37 (first step) 4- (2-methylpiperidino) benzonitrile

Embedded image 4-fluorobenzonitrile (4.00g), 2-pipecoline
From (3.60 g), the reaction was carried out in the same manner as in Reference Example 1. However, dimethyl sulfoxide (28 ml) was used instead of toluene, and stirring was performed at 100 ° C. overnight. The reaction treatment was performed as follows. The reaction mixture was allowed to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layers are combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate,
The residue obtained by concentration under reduced pressure was subjected to silica gel flash column chromatography, and the title compound (2.15 g) was obtained as an oil from the elution part of n-hexane: ethyl acetate = 8: 1. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.12 (3 H, d, J = 6.9 Hz),
1.47-1.90 (6H, m), 2.90-3.06 (1H, m), 3.48-3.60 (1H, m),
4.15-4.29 (1H, m), 6.80 (2H, dt, J = 9.3, 2.4Hz), 7.45 (2
H, dt, J = 9.3, 2.4Hz) FAB (+) MS (low resolution) 201

Reference Example 38 (Step 1) 4- (4-diethylaminopiperidino) benzonitrile

Embedded image A reaction was carried out in the same manner as in Reference Example 1 from 4-fluorobenzonitrile (188 mg) and 4-diethylaminopiperidine dihydrochloride (357 mg). However, dimethyl sulfoxide (2 ml) was used instead of toluene, and stirring was performed at 100 ° C. for 5 hours. The reaction treatment was performed as follows. The reaction mixture was allowed to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel flash column chromatography, and chloroform: methanol = 1.
The title compound (327 mg) was obtained as colorless crystals from the 5: 1 eluate. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.05 (6H, t, J
= 7.1Hz), 1.51-1.94 (4H, m), 2.58 (4H, q, J = 7.1Hz), 2.66-
2.94 (3H, m), 3.82-3.99 (2H, m), 6.85 (2H, dd, J = 9.1,2.0H
z), 7.46 (2H, dd, J = 9.1, 2.0Hz) FAB (+) MS (low resolution) 258

Reference Example 39 (6 in the first step) 5- (4-cyanophenylamino) pentanoic acid

[Chemical 76] The reaction was carried out in the same manner as in Reference Example 1 from 4-fluorobenzonitrile (10.0 g) and 5-aminopentanoic acid (9.70 g). However, instead of toluene, dimethyl sulfoxide (2
ml) and stirring was carried out at 130 ° C. for 12 hours. The reaction treatment was performed as follows. The reaction solution was allowed to cool, poured into ice water, and the insoluble material was filtered off. Concentrated hydrochloric acid was added to the filtrate to adjust the pH to 5
After that, the precipitated crystals were collected by filtration and washed with water to obtain the title compound (5.10 g) as colorless crystals. Melting point 144-147 ° C ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.43-1.65 (4H, m), 2.
20-2.35 (2H.m), 2.95-3.15 (2H, m), 3.32 (1H, broad s),
6.61 (2H, d, J = 8.7Hz), 7.43 (2H, d, J = 8.4Hz), 12.03 (1H, b
road s) FAB (+) MS (low resolution) 219

Reference Example 40 (7 of the first step) 4- (2-oxopiperidino) benzonitrile

Embedded image 5- (4-Cyanophenylamino) pentanoic acid (1.20 g) obtained in Reference Example 39 was suspended in dichloromethane (12 ml) to give 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.20). g) and add 2 at room temperature
After stirring for an hour, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (834 mg) as a colorless amorphous solid. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.49-2.08 (4H, m), 2.59
(2H, t, J = 6.3Hz), 3.69 (2H, t, J = 6.0Hz), 7.39-7.46 (2H,
m), 7.61-7.70 (2H, m) FAB (+) MS (low resolution) 200

Example 1 (second step) 4- (4-cyclohexyl-1-piperazinyl) benzamido oxime

Embedded image Hydroxylamine hydrochloride (1.44 g) was added to anhydrous methanol (13 m
l) and dissolve in potassium te under an argon atmosphere under ice cooling.
After adding rt-butoxide (2.56 g), the mixture was stirred at room temperature for 10 minutes. Then, 4- (4-cyclohexyl-1-piperazinyl) benzonitrile (1.12 obtained in Reference Example 24)
g) was added at room temperature and then stirred at 50 ° C. overnight. After allowing the reaction mixture to cool, the precipitated solid was collected by filtration and washed with methanol and then water. The title compound (996 mg) was obtained as colorless crystals by recrystallizing the obtained solid from methanol. Melting point 183 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.00-1.31 (5H, m), 1.
52-1.62 (1H.m), 1.66-1.87 (4H, m), 2.18-2.33 (1H, m),
2.55-2.69 (4H, m), 3.04-3.20 (4H, m), 5.60 (2H, s), 6.87
(2H, d, J = 9.0Hz), 7.50 (2H, d, J = 9.0Hz), 9.31 (1H, s) FAB (+) MS (low resolution) 303

The compounds of Examples 2 to 8 were obtained in the same manner as in Example 1. These are shown in Table 4. Example 2 4- (4-Piperidinopiperidino) benzamide oxime Example 3 4- [4- (tert-Butoxycarbonyl) -1-piperazinyl] benzamide oxime Example 4 4- (4-Isopropyl-1-) Piperazinyl) benzamido oxime Example 5 4- [4- (3-Pentyl) -1-piperazinyl] benzamido oxime Example 6 4- [4-[(1-pyrrolidinyl) carbonylmethyl]
-1-Piperazinyl] benzamido oxime Example 7 4- [4- [1- (tert-Butoxycarbonyl)-
4-Piperidyl] -1-piperazinyl] benzamido oxime Example 8 4- [4- (1-Pivaloyl-4-piperidyl) -1-
Piperazinyl] benzamido oxime

[0133]

[Table 4]

¹ H NMR of Example 2 (300 MHz, δ ppm, DMSO-d
₆ ) 1.30-1.59 (8H, m), 1.70-1.81 (2H.m), 2.26-2.73 (7H,
m), 3.68-3.83 (2H, m), 5.59 (2H, s), 6.88 (2H, d, J = 9.0H
z), 9.31 (1H, s) IR (cm ^-1 ,, KBr) 3557, 3463, 3374, 3276, 2941, 2927,
2820, 1635, 1613, 1523 FAB (+) MS (low resolution) 303 Elemental analysis C ₁₇ H ₂₆ N ₄₀ / H ₂ O: Calculated value C, 63.72; H, 8.81; N,
17.48: Measured value C, 64.01; H, 9.00; N, 17.53 The compound of Example 2 was confirmed to be a syn-adduct by X-ray crystal structure analysis.

¹ H NMR of Example 3 (300 MHz, δ ppm, DMSO-d
₆ ) 1.41 (9H, s), 3.09-3.18 (4H, m), 3.38-3.47 (4H, m), 5.
63 (2H, s), 6.91 (2H, d, J = 9.0Hz), 7.51 (2H, d, J = 9.0Hz),
9.35 (1H, s) FAB (+) MS (low resolution) 321

¹ H NMR of Example 4 (300 MHz, δ ppm, DMSO-d
₆ ) 0.99 (6H, d, J = 6.0Hz), 2.50-2.59 (4H, m), 2.66 (1H, se
ptet, J = 6.0Hz), 3.07-3.18 (4H, m), 5.61 (2H, s), 6.88 (2
H, d, J = 9.0Hz), 7.50 (2H, d, J = 9.0Hz), 9.32 (1H, s) FAB (+) MS (low resolution) 263

¹ H NMR of Example 5 (300 MHz, δ ppm, DMSO-d
₆ ) 0.88 (6H, t, J = 7.4Hz), 1.20-1.38 (2H.m), 1.40-1.59
(2H, m), 2.19 (1H, quintet, J = 6.6Hz), 2.57-2.63 (4H, m),
3.04-3.19 (4H, m), 5.62 (2H, s), 6.89 (2H, d, J = 9.0Hz),
7.51 (2H, d, J = 9.0Hz), 9.33 (1H, s) IR (cm ^-1 ,, KBr) 3494, 3358, 2957, 2872, 1666, 1610,
1523 FAB (+) MS (low resolution) 291 Elemental analysis C ₁₆ H ₂₆ N ₄₀ : Calculated value C, 66.17; H, 9.02; N, 19.2
9: Measured value C, 66.16; H, 9.22; N, 19.55

¹ H NMR of Example 6 (300 MHz, δ ppm, DMSO-d
₆ ) 1.68-1.93 (4H, m), 2.52-2.63 (4H, m), 3.07-3.54 (10
H, m), 5.62 (2H, s), 6.89 (2H, d, J = 9.0Hz), 7.50 (2H, d, J =
9.0Hz), 9.33 (1H, s) FAB (+) MS (low resolution) 332

¹ H NMR of Example 7 (300 MHz, δ ppm, DMSO-d
₆ ) 1.16-1.35 (2H, m), 1.38 (9H, s), 1.70-1.81 (2H, m), 2.
32-2.45 (1H, m), 2.60 (4H, t, J = 6.0Hz), 2.64-2.80 (2H,
m), 3.14 (4H, t, J = 6.0Hz), 3.88-4.01 (2H, m), 5.61 (2H,
s), 6.88 (2H, d, J = 9.0Hz), 7.50 (2H, d, J = 9.0Hz), 9.32 (1
H, s) FAB (+) MS (low resolution) 404

¹ H NMR of Example 8 (300 MHz, δ ppm, DMSO-d
₆ ) 1.12-1.35 (2H, m), 1.22 (9H, s), 1.76-1.88 (2H, m), 2.
39-2.52 (1H, m), 2.56-2.67 (4H, m), 2.70-2.84 (2H, m),
3.08-3.18 (4H, m), 4.21-4.35 (2H, m), 5.60 (2H, s), 6.88
(2H, d, J = 9.0Hz), 7.50 (2H, d, J = 9.0Hz), 9.32 (1H, s) IR (cm ^-1 ,, KBr) 3496, 3395, 3317, 2973, 2831, 1636,
1612, 1592, 1576, 1522 FAB (+) MS (low resolution) 388 Elemental analysis C ₂₁ H ₃₃ N ₅ 0 ₂ : Calculated value C, 65.09; H, 8.58; N, 18.
07: Measured value C, 65.21; H, 8.42; N, 17.92

Example 9 (second step) 4- (4-piperidinopiperidino) benzamido oxime trihydrochloride

Embedded image 4- (4-piperidinopiperidino) obtained in Reference Example 2
By performing the same method as in Example 1 using benzonitrile (520 mg), 4- (4-piperidinopiperidino) was obtained.
Benzamido oxime was obtained. This was dissolved in a mixed solvent of methanol: chloroform 1: 1 and hydrochloric acid-1,4-
Acidified with dioxane solution. This solution is cooled with ice,
The precipitated crystals were collected by filtration to give the title compound (634m
g) was obtained as colorless crystals. Melting point 186 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.28-1.49 (1H, m), 1.
60-1.99 (7H, m), 2.10-2.25 (2H, m), 2.75-2.98 (4H, m),
3.30-3.46 (3H, m), 4.05-4.20 (2H, m), 7.10 (2H, d, J = 9.0H
z), 7.64 (2H, d, J = 9.0Hz), 8.65 (1H, broad s), 9.09 (1H,
broad s), 10.79 (1H, broad s) IR (cm ^-1 ,, KBr) 3334, 2974, 2813, 2510, 1683, 1627 FAB (+) MS (low resolution) 303 Elemental analysis C ₁₇ H ₂₆ N ₄₀・3HCl ・ H ₂ O: Calculated C, 47.51; H, 7.2
7; N, 13.04: Measured value C, 47.49; H, 7.42; N, 12.16

Example 10 was carried out in the same manner as in Example 9.
Thus, the compound of Example 33 was obtained. These are shown in Table 5 and Table 6.
It was shown to. Example 10 4- (1-Pyrrolidinyl) benzamide oxime dihydrochloride Example 11 4- [4- (1-Pyrrolidinyl) piperidino] benzamide oxime trihydrochloride Example 12 4- (4-Morpholinopiperidino) benzamide oxime Trihydrochloride Example 13 4-morpholinobenzamide oxime dihydrochloride Example 14 4- (4-Methyl-1-piperazinyl) benzamide oxime trihydrochloride Example 15 4- (4-Ethyl-1-piperazinyl) benzamide oxime 3 Hydrochloride Example 16 4- (4-Propyl-1-piperazinyl) benzamide oxime trihydrochloride Example 17 4- (4-Isopropyl-1-piperazinyl) benzamide oxime trihydrochloride Example 18 4- [4- (3 -Pentyl) -1-piperazinyl] benzamidoxime trisalt Salt Example 19 4- (4-Cyclopentyl-1-piperazinyl) benzamide oxime trihydrochloride Example 20 4- (4-Cyclohexyl-1-piperazinyl) benzamide oxime trihydrochloride Example 21 4- [4- (3,3 4,5,6-Tetrahydro-2H-pyran-4-yl) -1-piperazinyl]] benzamidoxime trihydrochloride

[0143]

[Table 5]

¹ H NMR of Example 10 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.90-2.07 (4H, m), 3.23-3.40 (4H, m), 6.64 (2H, d, J
= 9.0Hz), 7.63 (2H, d, J = 9.0Hz), 8.55 (1H, s,), 9.00 (1H,
s), 12.41 (1H, s) IR (cm ^-1 ,, KBr) 3393, 3298, 2966, 2828, 1668, 1646,
1609, 1540 FAB (+) MS (low resolution) 206

¹ H NMR of Example 11 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.62-2.15 (8H, m), 2.70-3.55 (7H, m), 4.00-4.20 (2
H, m), 7.12 (2H, d, J = 9.0Hz), 7.63 (2H, d, J = 9.0Hz), 8.68
(1H, broad s), 9.10 (1H, broad s), 11.20 (1H, broad s),
12.53 (1H, broad s) IR (cm ^-1 , KBr) 3434, 2852, 2555, 2470, 1677, 1629 FAB (+) MS (low resolution) 289

¹ H NMR of Example 12 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.66-1.80 (2H, m), 2.10-2.25 (2H, m), 2.78-3.18 (4
H, m), 3.30-3.47 (3H, m), 3.78-4.25 (6H, m), 7.11 (2H, d,
J = 9.0Hz), 7.63 (2H, d, J = 9.0Hz), 8.68 (1H, broad s), 9.
09 (1H, broad s), 11.49 (1H, broad s), 12.53 (1H, broad
s) IR (cm ^-1 ,, KBr) 3428, 2431, 1670, 1608 FAB (+) MS (low resolution) 305

¹ H NMR of Example 13 (300 MHz, δ ppm, DMSO
-d ₆ ) 3.20-3.38 (4H, m), 3.68-3.80 (4H, m), 7.08 (2H, d, J
= 9.0Hz), 7.66 (2H, d, J = 9.0Hz), 8.68 (1H, s), 9.11 (1H,
s), 12.59 (1H, s) IR (cm ^-1 , KBr) 3289, 2982, 2712, 2575, 2457, 1671,
1619 FAB (+) MS (low resolution) 222

¹ H NMR of Example 14 (300 MHz, δ ppm, DMSO
-d ₆ ) 2.78 (3H, d, J = 3.0Hz), 2.99-3.51 (6H, m), 3.98-4.1
7 (2H, m), 7.15 (2H, d, J = 9.0Hz), 7.69 (2H, d, J = 9.0Hz),
8.71 (1H, broad s), 9.13 (1H, broad s), 11.03 (1H, broad
s), 11.39 (1H, broad s), 12.66 (1H, broad s) IR (cm ^-1 , KBr) 3424, 2966, 2594, 1650, 1611 FAB (+) MS (low resolution) 235

¹ H NMR of Example 15 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.29 (3H, t, J = 6.0Hz), 2.90-3.65 (8H, m), 3.95-4.1
9 (2H, m), 7.16 (2H, d, J = 9.0Hz), 7.70 (2H, d, J = 9.0Hz),
8.86 (2H, broad s), 11.03 (1H, s), 11.31 (1H, broad s),
12.65 (1H, broad s) IR (cm ^-1 ,, KBr) 3448, 3075, 2980, 2730, 1664, 1607,
1501 FAB (+) MS (low resolution) 249

¹ H NMR of Example 16 (300 MHz, δ ppm, DMSO
-d ₆ ) 0.92 (3H, t, J = 6.0Hz), 1.70-1.87 (2H, m), 2.98-3.1
5 (4H, m), 3.27-3.60 (4H, m), 3.90-4.36 (4H, m), 7.16 (2
H, d, J = 9.0Hz), 7.70 (2H, d, J = 9.0Hz), 8.72 (1H, broad
s), 9.15 (1H, broad s), 11.06 (1H, broad s), 11.34 (1H,
broad s), 12.67 (1H, broad s) IR (cm ^-1 ,, KBr) 3528, 3447, 3057, 2967, 2798, 2727,
1665, 1608, 1504 FAB (+) MS (low resolution) 263

¹ H NMR of Example 17 (400 MHz, δ ppm, DMSO
-d ₆ ) 1.32 (6H, d, J = 5.0Hz), 3.00-3.19 (2H, m), 3.30-3.8
5 (5H, m), 4.00-4.15 (2H, m), 7.14 (2H, d, J = 6.5Hz), 7.70
(2H, d, J = 6.5Hz), 8.33 (1H, broad s), 9.13 (1H, broad
s), 11.07 (1H, broad s), 11.43 (1H, broad s), 12.70 (1
H, broad s) FAB (+) MS (low resolution) 263

¹ H NMR of Example 18 (300 MHz, δ ppm, DMSO
-d ₆ ) 0.98 (6H, t, J = 7.5Hz), 1.58-1.75 (2H, m), 1.82-1.9
7 (2H, m), 3.02-3.58 (7H, m), 3.96-4.11 (2H, m), 7.14 (2
H, d, J = 9.0Hz), 7.68 (2H, d, J = 9.0Hz), 8.81 (1H, broad
s), 10.86 (1H, broad s), 10.98 (1H, broad s), 12.63 (1
H, broad s) FAB (+) MS (low resolution) 291

¹ H NMR of Example 19 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.45-2.10 (8H, m), 3.00-3.65 (7H, m), 3.80-4.20 (2
H, m), 7.15 (2H, d, J = 9.2Hz), 7.70 (2H, d, J = 9.2Hz), 8.85
(1H, broad s), 11.04 (1H, broad s), 11.62 (1H, broad
s), 12.73 (1H, broad s) FAB (+) MS (low resolution) 289

¹ H NMR of Example 20 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.00-1.69 (6H, m), 1.72-1.85 (2H, m), 2.04-2.25 (2
H, m), 3.00-3.27 (3H, m), 3.35-3.58 (4H, m), 3.95-4.10
(2H, m), 7.14 (2H, d, J = 9.0Hz), 7.69 (2H, d, J = 9.0Hz), 8.
69 (1H, broad s), 9.15 (1H, broad s), 11.43 (1H, broad
s), 12.69 (1H, broad s) IR (cm ^-1 ,, KBr) 3432, 2938, 2858, 1655, 1608 FAB (+) MS (low resolution) 303

¹ H NMR of Example 21 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.70-1.88 (2H, m), 2.00-2.11 (2H, m), 3.00-3.65 (9
H, m), 3.92-4.14 (4H, m), 8.80 (1H, broad s), 11.05 (1H,
broad s), 12.63 (1H, broad s) IR (cm ^-1 ,, KBr) 3406, 2963, 2851, 1660, 1608 FAB (+) MS (low resolution) 305

Example 22 4- [4- (2-Hydroxyethyl) -1-piperazinyl] benzamide oxime Trihydrochloride Example 23 4- [4- (2,3-Dihydroxypropyl) -1-piperazinyl] benzamide oxime Trihydrochloride Example 24 4- [4- (5-Hydroxy-3-oxapentyl)-
1-Piperazinyl] benzamidoxime trihydrochloride Example 25 4- [4-[(1-pyrrolidinyl) carbonylmethyl]
-1-Piperazinyl] benzamido oxime trihydrochloride Example 26 4- [4- (isopropylaminocarbonylmethyl)-
1-Piperazinyl] benzamidooxime trihydrochloride Example 27 4- [4- (2-Dimethylaminoethyl) -1-piperazinyl] benzamidooxime trihydrochloride Example 28 4- [4- (3-Dimethylaminopropyl)- 1-Piperazinyl] benzamido oxime tetrahydrochloride Example 29 4- [4- (1-Pivaloyl-4-piperidinyl) -1
-Piperazinyl]] benzamidoxime trihydrochloride Example 30 4- [4- (1-Methyl-4-piperidinyl) -1-piperazinyl] benzamidoxime tetrahydrochloride Example 31 4- [4- (Ethoxycarbonyl) -1 -Piperazinyl] benzamidoxime dihydrochloride Example 32 4- (4-Acetyl-1-piperazinyl) benzamidoxime dihydrochloride Example 33 4- (4-Phenyl-1-piperazinyl) benzamidoxime dihydrochloride

[0157]

[Table 6]

¹ H NMR of Example 22 (300 MHz, δ ppm, DMSO
-d ₆ ) 3.03-4.20 (12H, m), 7.16 (2H, d, J = 9.0Hz), 7.70 (2
H, d, J = 9.0Hz), 8.80 (1H, broad s), 10.86 (1H, broad s),
11.03 (1H, broad s), 12.60 (1H, broad s) IR (cm ^-1 , KBr) 3325, 3180, 2965, 2814, 2563, 2467,
1661, 1613, 1508 FAB (+) MS (low resolution) 265

¹ H NMR of Example 23 (300 MHz, δ ppm, DMSO
-d ₆ ) 3.00-4.15 (13H, m), 7.14 (2H, d, J = 9.0Hz), 7.68 (2
H, d, J = 9.0Hz), 10.25 (1H, broad s), 11.02 (1H, broad
s), 12.60 (1H, broad s) IR (cm ^-1 ,, KBr) 3376, 2970, 2822, 1661, 1610, 1505 FAB (+) MS (low resolution) 295

¹ H NMR of Example 24 (300 MHz, δ ppm, DMSO
-d ₆ ) 3.04-4.20 (16H, m), 7.15 (2H, d, J = 9.0Hz), 7.68 (2
H, d, J = 9.0Hz), 8.73 (1H, broad s), 9.13 (1H, broad s),
11.03 (1H, broad s), 12.64 (1H, broad s) IR (cm ^-1 ,, KBr) 3404, 2959, 1660, 1610 FAB (+) MS (low resolution) 309

¹ H NMR of Example 25 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.75-1.98 (4H, m), 3.14-4.17 (12H, m), 4.29 (2H, m
s), 7.14 (2H, d, J = 9.0Hz), 7.71 (2H, d, J = 9.0Hz), 8.73 (1
H, broad s), 9.10 (1H, s), 10.46 (1H, broad s), 11.07 (1
H, broad s), 12.70 (1H, broad s) IR (cm ^-1 ,, KBr) 3410, 2972, 2843, 1654, 1608 FAB (+) MS (low resolution) 332

¹ H NMR of Example 26 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.09 (6H, d, J = 6.0Hz), 3.20-4.25 (11H, m), 7.12 (2
H, d, J = 9.2Hz), 7.70 (2H, d, J = 9.2Hz), 8.67 (1H, d, J = 9.0H
z), 9.15 (1H, broad s), 10.70 (1H, broad s), 11.09 (1H,
broad s), 12.70 (1H, broad s) FAB (+) MS (low resolution) 320

¹ H NMR of Example 27 (300 MHz, δppm, D ₂ O)
2.90 (6H, s), 3.40-3.68 (12H, m), 7.08 (2H, d, J = 9.0Hz),
7.56 (2H, d, J = 9.0Hz) IR (cm ^-1 ,, KBr) 3410, 2962, 2849, 2440, 1663, 1610 FAB (+) MS (low resolution) 292

¹ H NMR of Example 28 (300 MHz, δ ppm, DMSO
-d ₆ ) 2.15-2.30 (2H, m), 2.74 (3H, s), 2.75 (3H, s), 3.00
-3.70 (10H, m), 3.97-4.18 (2H, m), 7.16 (2H, d, J = 9.0Hz),
7.70 (2H, d, J = 9.0Hz), 10.83 (1H, broad s), 11.05 (1H, b
road s), 11.59 (1H, broad s), 12.69 (1H, broad s) IR (cm ^-1 ,, KBr) 3334, 3182, 2964, 2674, 2595, 1661,
1611 FAB (+) MS (low resolution) 306

¹ H NMR of Example 29 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.42 (9H, s), 1.54-1.70 (2H, m), 2.13-2.25 (2H, m),
2.70-2.84 (2H, m), 3.04-3.66 (7H, m), 4.00-4.15 (2H,
m), 4.39-4.48 (2H, m), 7.16 (2H, d, J = 9.2Hz), 7.69 (2H,
d, J = 9.2Hz), 8.88 (1H, broad s), 11.00 (1H, broad s), 1
1.63 (1H, broad s), 12.65 (1H, broad s) FAB (+) MS (low resolution) 388

¹ H NMR of Example 30 (300 MHz, δ ppm, DMSO
-d ₆ ) 2.05-2.46 (4H, m), 2.71 (3H, s), 2.80-4.25 (13H,
m), 7.15 (2H, d, J = 9.0Hz), 7.70 (2H, d, J = 9.0Hz), 10.89
(2H, broad s), 11.05 (1H, broad s) IR (cm ^-1 ,, KBr) 3422, 2957, 2667, 1654, 1610 FAB (+) MS (low resolution) 318

¹ H NMR of Example 31 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.19 (3H, t, J = 6.0Hz), 3.35-3.60 (8H, m), 4.06 (2H,
q, J = 6.0Hz), 7.06 (2H, d, J = 9.2Hz), 7.63 (2H, d, J = 9.2H
z), 8.68 (1H, broad s), 9.09 (1H, broad s), 10.90 (1H, b
road s), 12.51 (1H, broad s) FAB (+) MS (low resolution) 293

¹ H NMR of Example 32 (300 MHz, δ ppm, DMSO
-d ₆ ) 2.04 (3H, s), 3.25-3.64 (8H, m), 7.08 (2H, d, J = 9.0H
z), 7.66 (2H, d, J = 9.0Hz), 8.67 (1H, broad s), 9.10 (1H,
broad s), 12.58 (1H, broad s) FAB (+) MS (low resolution) 263

¹ H NMR of Example 33 (300 MHz, δ ppm, DMSO
-d ₆ ) 3.27-3.46 (4H, m), 3.50-3.60 (4H, m), 6.91-6.98 (1
H, m), 7.10-7.23 (4H, m), 7.26-7.35 (2H, m), 7.66 (2H, d,
J = 9.0Hz), 8.69 (1H, broad s), 9.11 (1H, broad s), 12.5
6 (1H, broad s) IR (cm ^-1 ,, KBr) 3410, 3062, 2848, 1659, 1608 FAB (+) MS (low resolution) 297

Example 34 (second step) 4-piperidinobenzamido oxime

Embedded image Hydroxylamine hydrochloride (417 mg) was dissolved in water (2 ml), sodium hydrogen carbonate (505 mg) was added, and an ethanol (4 ml) solution of 4-piperidinobenzonitrile (559 mg) obtained in Reference Example 21 was added thereto. In addition, the mixture was heated under reflux for 7 hours. The reaction solution was allowed to cool, and the precipitated crystals were collected by filtration to give the title compound (506 mg) as colorless crystals. Melting point 175 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.47-1.70 (6H, m), 3.
09-3.26 (4H, m), 5.61 (2H, s), 6.88 (2H, d, J = 9.0Hz), 7.4
9 (2H, d, J = 9.0Hz), 9.31 (1H, s) IR (cm ^-1 ,, KBr) 3491, 3361, 2938, 2830, 1662, 1609,
1589, 1522 FAB (+) MS (low resolution) 220 Elemental analysis C ₁₂ H ₁₇ N ₃₀ : Calculated value C, 65.73; H, 7.81; N, 19.1
6: Measured value C, 65.92; H, 7.86; N, 19.25

Example 35 (2nd step) 4- [4- [4- (tert-butoxycarbonyl)-
1-piperazinyl] piperidino] benzamide oxime

Embedded image 4- [4- [4- (tert-butoxycarbonyl) -1-piperazinyl] piperidino] obtained in Reference Example 31
The title compound (417 mg) was obtained as colorless crystals by a method similar to that of Example 34 using benzonitrile (456 mg). ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.38 (9H, s), 1.33-1.
55 (2H, m), 1.72-1.86 (2H, m), 2.30-2.56 (5H, m), 2.60-
2.77 (2H, m), 3.20-3.40 (4H, m), 3.70-3.83 (2H, m), 5.60
(2H, broad s), 6.89 (2H, d, J = 9.0Hz), 7.49 (2H, d, J = 9.0H
z), 9.31 (1H, s) FAB (+) MS (low resolution) 404

Example 36 4-Piperidinobenzamide oxime dihydrochloride

[Chemical formula 82] 4-Piperidinobenzamido oxime (1.41 g) obtained in Example 34 was dissolved in 3N hydrochloric acid (10 ml). This was concentrated under reduced pressure, the resulting residue was dissolved in ethanol, and then concentrated under reduced pressure, which was repeated twice. The crystalline residue was washed with diethyl ether to give the title compound
(1.80 g) was obtained as colorless crystals. Melting point 164-166 ° C ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.45-1.73 (6H, m), 3.
30-3.50 (4H, m), 7.18 (2H, d, J = 9.0Hz), 7.67 (2H, d, J = 9.0
Hz), 8.69 (1H, broad s), 9.09 (1H, broad s) IR (cm ^-1 ,, KBr) 2974, 2710, 2534, 1674, 1620 FAB (+) MS (low resolution) 220 Elemental analysis C ₁₂ H ₁₇ N ₃ 0 · 2HCl: calculated C, 49.33; H, 6.55;
N, 14.38: Measured C, 49.31; H, 6.71; N, 14.40

Example 37 (second step) 4- (4-methylpiperidino) benzamide oxime
Dihydrochloride

[Chemical 83] From 4- (4-methylpiperidino) benzonitrile (1.20 g) obtained in Reference Example 22, Example 34 and Example 36 were obtained.
The title compound (1.14 g) was obtained as colorless crystals in the same manner as. Melting point 163-165 ° C. ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 0.91 (3 H, d, J = 6.0 Hz),
1.08-1.36 (2H, m), 1.50-1.75 (3H, m), 2.75-3.00 (2H,
m), 3.77-3.99 (2H, m), 7.15 (2H, d, J = 9.0Hz), 7.65 (2H,
d, J = 9.0Hz), 8.60 (1H, broad s), 9.07 (1H, broad s), 1
2.60 (1H, broad s) IR (cm ^-1 ,, KBr) 3076, 2954, 2839, 2722, 2525, 1666,
1619, 1588 FAB (+) MS ( low resolution) 234 Elemental analysis _{C 13 H 19 N 3 0 ·} 2HCl: Calculated C, 50.99; H, 6.91;
N, 13.72: Measured C, 50.92; H, 6.99; N, 13.69

Example 38 (Third Step) 4- (1-Piperazinyl) benzamido oxime trihydrochloride

Embedded image 4- [4- (tert-Butoxycarbonyl) -1-piperazinyl] benzamide oxime obtained in Example 3
(1.0 g) was dissolved in 5N hydrochloric acid (30 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in methanol and diethyl ether, and the precipitated crystals were collected by filtration to give the title compound (861 mg). Melting point 194 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 3.02-3.24 (4H, m), 3.
47-3.70 (4H, m), 7.12 (2H, d, J = 9.0Hz), 7.69 (2H, d, J = 9.0
Hz), 8.68 (1H, broad s), 9.14 (1H, broad s), 9.65 (2H, b
road s), 12.69 (1H, broad s) IR (cm ^-1 ,, KBr) 3424, 3317, 3020, 2692, 2489, 1670,
1609, 1592 FAB (+) MS (low resolution) 221

The compounds of Example 39 and Example 40 were obtained in the same manner as in Example 38. These are shown in Table 7. Example 39 4- [4- (4-Piperidyl) -1-piperazinyl] benzamide oxime tetrahydrochloride Example 40 4- [4- (1-Piperazinyl) piperidino] benzamide oxime tetrahydrochloride

[0176]

[Table 7]

¹ H NMR of Example 39 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.90-2.18 (2H, m), 2.23-2.45 (2H, m), 2.77-3.75 (1
1H, m), 3.90-4.25 (2H, m), 7.15 (2H, d, J = 9.0Hz), 7.70 (2
H, d, J = 9.0Hz), 8.53-9.50 (3H, m), 11.07 (1H, broad s),
11.93 (1H, broad s), 12.70 (1H, broad s) IR (cm ^-1 ,, KBr) 3404, 3143, 2724, 2450, 1664, 1610 FAB (+) MS (low resolution) 304

¹ H NMR of Example 40 (300 MHz, δ ppm, DMSO
-d ₆ ) 1.60-1.78 (2H, m), 2.10-2.25 (2H, m), 2.77-2.95 (2
H, m), 3.30-4.20 (11H, m), 7.11 (2H, d, J = 9.0Hz), 7.63 (2
H, d, J = 9.0Hz), 8.67 (1H, broad s), 9.09 (1H, broad s),
9.72 (1H, broad s), 10.06 (2H, broad s), 12.25 (1H, broa
ds), 12.54 (1H, broad s) IR (cm ^-1 ,, KBr) 3339, 3003, 2955, 2724, 2562, 1672,
1632 FAB (+) MS (low resolution) 304 Elemental analysis _{C 16 H 25 N 5 0 ·} 4HCl · 3 / 2H 2 O: Calculated C, 40.35; H,
6.77; N, 14.70: Measured C, 40.22; H, 6.92; N, 14.47

Example 41 (4th step) 4- (4-cyclohexyl-1-piperazinyl) benzamide O -acetyloxime

Embedded image 4- (4-cyclohexyl-1-piperazinyl) benzamide oxime (790 mg) obtained in Example 1 was added to pyridine.
It was dissolved in (20 ml), acetic anhydride (0.8 ml) was added, and the mixture was left standing overnight at room temperature. The crystals precipitated in the reaction mixture were collected by filtration and washed with methanol to give the title compound (303 mg). Further, the filtrate and the washing solution are combined and concentrated under reduced pressure to obtain a solid,
By recrystallizing from N-dimethylformamide,
The title compound (262 mg) was obtained as colorless needle crystals. Melting point 171-172 ° C ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.00-1.31 (6H, m), 1.
50-1.88 (4H, m), 2.16-2.33 (1H, m), 2.55-2.67 (4H, m),
3.07-3.22 (4H, m), 6.56 (2H, s), 6.93 (2H, d, J = 9.0Hz),
7.56 (2H, d, J = 9.0Hz) IR (cm ^-1 , KBr) 3514, 3402, 2924, 2852, 2811, 1743,
1612, 1526 FAB (+) MS (low resolution) 344

Example 42 (Second Step) 3-Bromo-4- (4-piperidinopiperidino) benzamido oxime dihydrochloride

Embedded image Using 3-bromo-4- (4-piperidinopiperidino) benzonitrile (1.39 g) obtained in Reference Example 33 and performing a method similar to Example 1, 3-bromo-4-
(4-piperidinopiperidino) benzamido oxime (5
05 mg) was obtained. Methanol: chloroform = 1:
It was dissolved in a mixed solvent of 2 and acidified with a 4N hydrochloric acid-1,4-dioxane solution. Diethyl ether was added to this solution, and the precipitated crystals were collected by filtration to give the title compound (500 mg) as colorless crystals. Melting point 174 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.25-1.50 (1H, m), 1.
60-2.01 (9H, m), 2.20-2.30 (2H, m), 2.64-3.00 (4H, m),
3.23-3.80 (2H, m), 7.30 (1H, d, J = 8.1Hz), 7.74 (1H, dd, J =
8.1, 2.4Hz), 8.01 (1H, d, J = 2.4Hz), 9.02 (1H, broad s),
10.72 (1H, broads), 11.25 (1H, broad s) IR (cm ^-1 ,, KBr) 3432, 2957, 1654 FAB (+) MS (low resolution) 381, 383 Elemental analysis C ₁₇ H ₂₅ BrN ₄₀・ 2HCl・ 2H ₂ O: Calculated value C, 41.65; H,
6.37; N, 11.43: Measured C, 41.68; H, 6.34; N, 11.25

Example 43 (Step 2) 3-Bromo-4- (4-isopropyl-1-piperazinyl) benzamido oxime dihydrochloride

Embedded image The title compound (341 mg) was obtained as colorless crystals in the same manner as in Example 42 from 3-bromo-4- (4-isopropyl-1-piperazinyl) benzonitrile (920 mg) obtained in Reference Example 34. Melting point 232 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.34 (6H, d, J = 6.0Hz),
3.02-3.70 (9H, m), 7.36 (1H, d, J = 8.2Hz), 7.77 (1H, dd, J
= 8.2, 2.5Hz), 8.04 (1H, d, J = 2.5Hz), 8.95 (2H, broad
s), 11.20-11.43 (3H, m) IR (cm ^-1 , KBr) 3424, 3044, 2706, 1668, 1598 FAB (+) MS (low resolution) 341, 343 Elemental analysis C ₁₄ H ₂₁ BrN ₄₀・2HCl ・ 1 / 2H ₂ O: Calculated value C, 39.74;
H, 5.72; N, 13.24: Measured value C, 40.05; H, 5.67; N, 13.02

Example 44 (2nd step) 4- (3-hydroxypiperidino) benzamide oxime

Embedded image 4- (3-Hydroxypiperidino) benzonitrile (5.0 g) obtained in Reference Example 35 was mixed with ethanol (23 ml) and water (12 m).
It was suspended in the mixed solvent of l), 50% hydroxylamine aqueous solution (3.30 g) was added, and the mixture was heated under reflux for 5 hours. After cooling down,
The precipitated crystals were collected by filtration to give the title compound (4.62
g) was obtained as colorless crystals. Melting point 158-160 ° C ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.09-1.94 (4H, m), 2.
42-2.68 (2H, m), 3.43-3.70 (3H, m), 4.80 (1H, d, J = 4.2H
z), 5.60 (2H, s), 6.86 (2H, d, J = 9.3Hz), 7.49 (2H, d, J = 9.
3Hz), 9.31 (1H, s) FAB (+) MS (low resolution) 236

Example 45 (2nd step) 4- (4-hydroxypiperidino) benzamide oxime

Embedded image The title compound (5.30 g) was obtained as colorless crystals from 4- (4-hydroxypiperidino) benzonitrile (7.00 g) obtained in Reference Example 36 and in the same manner as in Example 44. Melting point 179 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.33-1.50 (2H, m), 1.
72-1.83 (2H, m), 2.79-2.92 (2H, m), 3.47-3.69 (3H, m),
4.65 (1H, d, J = 4.2Hz), 5.60 (1H, s), 6.88 (2H, d, J = 9.0H
z), 7.48 (2H, d, J = 9.0Hz), 9.30 (1H, s) FAB (+) MS (low resolution) 236

Example 46 (Second Step) 4- (2-Methylpiperidino) benzamide oxime

Embedded image A reaction was carried out from 4- (2-methylpiperidino) benzonitrile (1.90 g) obtained in Reference Example 37 in the same manner as in Example 44. However, the reaction treatment was performed as follows. The reaction mixture was allowed to cool, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.92 g) as an amorphous solid. ¹ H NMR (300 MHz, δ ppm, DMSO-d ₆ ) 0.95 (3 H, d, J = 6.3 Hz),
1.38-1.82 (6H, m), 2.76-2.91 (1H, m), 3.27-3.39 (1H,
m), 4.03-4.16 (1H, m), 5.58 (2H, s), 6.84 (2H, d, J = 9.0H
z), 7.48 (2H, d, J = 9.0Hz), 9.29 (1H, s) FAB (+) MS (low resolution) 234

Example 47 (2nd step) 4- (4-diethylaminopiperidino) benzamide oxime

Embedded image 4- (4-Diethylaminopiperidino) benzonitrile (320 mg) obtained in Reference Example 38, hydroxylamine hydrochloride (173 mg) and sodium hydrogencarbonate (209 mg) were added to ethanol.
It was suspended in a mixed solvent of (2 ml) and water (1 ml), and heated under reflux for 6 hours. The reaction solution was allowed to cool, water (5 ml) was added, and the precipitated crystals were collected by filtration to give the title compound (104 mg) as colorless crystals. Melting point 159-160 ° C ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 0.94 (6H, t, J = 7.2Hz),
1.36-1.55 (2H, m), 1.63-1.78 (2H, m), 2.48 (4H, q, J = 7.2
Hz), 2.52-2.77 (3H, m), 3.66-3.84 (2H, m), 2.58 (2H, s),
6.88 (2H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 9.31 (1H,
s) IR (cm ^-1 ,, KBr) 3473, 3366, 2972, 2809, 1643, 1610,
1522 FAB (+) MS (low resolution) 291 Elemental analysis _{C 16 H 26 N 4 0 ·} 1 / 4H 2 O: Calcd C, 65.16; H, 9.06;
N, 19.00: Measured C, 65.35; H, 9.21; N, 18.88

Example 48 (2nd step) 4- (4-hydroxyiminopiperidino) benzamide oxime

Embedded image The title compound (260 mg) was obtained as colorless crystals from 4- (4-oxopiperidino) benzonitrile (750 mg) obtained in Reference Example 30 and in the same manner as in Example 44. However, the reaction time was 1 hour, and the purification was performed by recrystallization from a mixed solvent of methanol and acetonitrile. Melting point 193 ° C (decomposition) ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 2.32 (2H, t, J = 6.0Hz),
2.54 (2H, t, J = 6.0Hz), 3.21-3.43 (4H, m), 5.61 (2H, d, J =
8.7Hz), 6.90 (2H, d, J = 8.7Hz), 9.31 (1H, s), 10.36 (1H,
s) IR (cm ^-1 ,, KBr) 3439, 3376, 3180, 2911, 2829, 1643,
1610, 1524 FAB (+) MS (low resolution) 249

Example 49 (2nd step) 4- (2-oxopiperidino) benzamide oxime

Embedded image From 4- (2-oxopiperidino) benzonitrile (834 mg) obtained in Reference Example 40, in the same manner as in Example 44,
The title compound (851 mg) was obtained as colorless crystals. However, the stirring time was 2 hours, and the crystals collected by filtration were washed with a 50% ethanol aqueous solution. Melting point 248-249 ° C ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.78-1.90 (4H, m), 2.
38 (2H, t, J = 6.6Hz), 3.60 (2H, t, J = 5.7Hz), 5.78 (2H, broa
ds), 7.26 (2H, dd, J = 8.4, 2.1Hz), 7.64 (2H, dd, J = 8.4,
1.5Hz), 9.60 (1H, s) FAB (+) MS (low resolution) 234

Example 50 (Step 4) 4-piperidinobenzamide O -benzyl oxime

Embedded image Sodium hydride (60% oily) (1.00 g) was suspended in anhydrous tetrahydrofuran (20 ml) and the 4-piperidinobenzamide oxime (5.00 g) obtained in Example 34 was cooled under ice cooling.
Anhydrous tetrahydrofuran solution of was added and stirred at 60 ° C. for 1 hour. After allowing the reaction solution to reach room temperature, benzyl bromide (2.8
ml) was added and the mixture was heated under reflux for 3 hours. Allow the reaction solution to cool,
The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was dissolved in a small amount of ethyl acetate, and n-hexane was added for crystallization. The crystals were collected by filtration and washed with n-hexane to give the title compound (5.30 g) as colorless crystals. Melting point 101-104 ° C ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.41-1.75 (6H, m), 3.18
-3.27 (4H, m), 4.76 (2H, broad s), 5.12 (2H, s), 6.85-6.
94 (2H, m), 7.23-7.52 (7H, m) IR (cm ^-1 ,, KBr) 3460, 3326, 2940, 2862, 1615 FAB (+) MS (low resolution) 310

Example 51 (4th step) 4-piperidinobenzamide O -methyloxime

Embedded image The title compound (800 mg) was obtained as a pale-yellow amorphous solid from 4-piperidinobenzamido oxime (1.00 g) obtained in Example 34 in the same manner as in Example 50. However, methyl iodide (0.31 ml) was used instead of benzyl bromide, and purification was performed by silica gel flash column chromatography (n
-Hexane: ethyl acetate = 2: 1). ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.50-1.74 (6H, m), 3.17
-3.26 (4H, m), 3.90 (3H, s), 4.72 (2H, broad s), 6.89 (2
H, dd, J = 8.7, 1.7Hz), 7.50 (2H, dd, J = 8.7, 1.7Hz) IR (cm ^-1 , KBr) 3440, 2923, 2807, 1615, 1522 FAB (+) MS (low resolution) ) 234 Elemental analysis C ₁₃ H ₁₉ N ₃₀ : Calculated value C, 66.92; H, 8.21; N, 18.0
1: Measured value C, 66.93; H, 8.41; N, 17.95

Example 52 (Step 5) N -acetyl-4-piperidinobenzamide O -benzyl oxime

[Chemical 96] 4-Piperidinobenzamide O obtained in Example 50
-Benzyl oxime (1.00 g) was added to anhydrous tetrahydrofuran
It was dissolved in (10 ml) and cooled to -70 ° C. Then, n-butyllithium (1.6M n-hexane solution) (2.1 ml)
Was added dropwise, the mixture was stirred for 30 minutes, acetyl chloride (0.26 ml) was added dropwise, and the mixture was stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (10 ml), 1N aqueous sodium hydroxide solution was added under ice-cooling, the mixture was stirred for 30 min, concentrated under reduced pressure, ethyl acetate and water were added to the obtained residue, and ethyl acetate was added. It was extracted with. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel flash column chromatography, and n-hexane: ethyl acetate = 5: 1 to 2: From the 1 elution part, the title compound (302m
g) was obtained as a colorless amorphous solid. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.52-1.74 (6H, m), 2.04
(3H, s), 3.18-3.29 (4H, m), 5.16 (2H, s), 6.82-6.90 (2H,
m), 7.29-7.45 (7H, m), 7.80 (1H, broad s) IR (cm ^-1 ,, KBr) 3432, 3167, 2924, 2874, 2850, 1664,
1598, 1517 FAB (+) MS (low resolution) 352

Reference Example 41 (Sixth Step) 1- [4- (4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] piperidine 1- [4- (Δ ² -1) , 2,4-oxadiazoline-3
-Yl) phenyl] piperidine

Embedded image 4-Piperidinobenzamido oxime (20.0 g) obtained in Example 34 was suspended in dimethyl sulfoxide (18 ml) and formalin solution (11 g), and the mixture was stirred at 100 ° C. overnight.
The reaction solution was allowed to cool, water was added, and the mixture was extracted twice with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to recrystallize the obtained crude crystal to recrystallize with ethanol (230 ml) to give the title compound (16.0 g) as a colorless compound. Obtained as crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.52-1.77 (6H, m), 3.19
-3.33 (4H, m), 4.40-4.55 (1H, m), 5.35 (2H, d, J = 5.1Hz),
6.89 (2H, dt, J = 9.0, 2.1Hz), 7.57 (2H, dt, J = 9.0, 2.1Hz)

Reference Example 42 (Sixth Step) 1- [4- (3-Methyl-1,2,4-oxadiazol-3-yl) phenyl] piperidine

Embedded image The title compound (3.50 g) was obtained as a colorless amorphous solid from the 4-piperidinobenzamide oxime (5.00 g) obtained in Example 34 in the same manner as in Reference Example 41. However, acetic anhydride (30 ml) was used in place of the formalin solution, acetic anhydride itself was used as the solvent, and dimethyl sulfoxide was not used. Further, the purification was performed by silica gel flash column chromatography (n-hexane: ethyl acetate = 5:
1) was performed. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.57-1.75 (6H, m), 2.62
(3H, s), 3.25-3.35 (4H, m), 6.95 (2H, dt, J = 9.0, 2.1Hz),
7.91 (2H, dt, J = 9.0, 1.8Hz)

Example 53 (Seventh Step) N-methyl-4-piperidinobenzamide oxime

Embedded image Lithium aluminum hydride (164 m
g) was suspended in dry tetrahydrofuran (7 ml), and 1- [4- (4,5-dihydro-1,2,4-oxadiazol-3-yl) obtained in Reference Example 41 under ice cooling. Phenyl] piperidine (1.00 g) was added, and the mixture was stirred for 1 hour while gradually returning to room temperature. Water (0.17 ml), 15% aqueous sodium hydroxide solution (0.17 ml) and water (0.5 ml) were sequentially added to the reaction solution, and the insoluble material was filtered off, and washed with tetrahydrofuran. The filtrate and washings were combined, concentrated under reduced pressure, and the obtained residue was subjected to silica gel flash column chromatography to obtain the title compound (640 mg) as colorless crystals from an elution part of ethyl acetate: methanol = 15: 1. Melting point 146-14
9 ℃ ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.51-1.78 (6H, m), 2.76
(3H, s), 3.12-3.31 (4H, m), 5.22 (1H, broad s), 6.91 (2
H, dd, J = 8.7, 1.8Hz), 7.33 (2H, dd, J = 8.7, 1.8Hz) IR (cm ^-1 , KBr) 3379, 2933, 2852, 1643, 1609, 1524 FAB (+) MS ( (Low resolution) 234 Elemental analysis C ₁₃ H ₁₉ N ₃₀ : Calculated value C, 66.92; H, 8.21; N, 18.0
1: Measured value C, 66.94; H, 8.33; N, 17.94

Example 54 (Seventh Step) N-ethyl-4-piperidinobenzamide oxime

[Chemical 100] 1- [4- (3-methyl-4,5, obtained in Reference Example 42)
The title compound (841 mg) was obtained as a pale-yellow amorphous solid from —dihydro-1,2,4-oxadiazol-3-yl) phenyl] piperidine (1.00 g) in the same manner as in Example 53. ¹ H NMR (300 MHz, δ ppm, CDCl ₃ ) 1.08 (3 H, t, J = 7.1 Hz),
1.55-1.76 (6H, m), 3.02-3.28 (8H, m), 5.16 (1H, broad
s), 6.90 (2H, dd, J = 8.9, 2.1Hz), 7.34 (2H, dd, J = 9.0, 2.
1Hz) IR (cm ^-1 ,, KBr) 3366, 2934, 2852, 1643, 1609, 1523 FAB (+) MS (low resolution) 248 Elemental analysis C ₁₄ H ₂₁ N ₃ 0: Calculated value C, 67.99; H, 8.56 ; N, 16.9
9: Measured value C, 68.08; H, 8.71; N, 16.92

Reference Example 43 (8th step) 4-piperidinobenzaldehyde

Embedded image 4-Fluorobenzaldehyde (6.20 g), piperidine (5.
3 ml) and reacted in the same manner as in Reference Example 1. However,
Dimethyl sulfoxide (35 ml) was used instead of toluene, and stirring was performed at 100 ° C. for 5 hours. The reaction treatment was performed as follows. After allowing the reaction solution to cool, pour it into water (200 ml) and
By stirring for 0 minutes and collecting the precipitated crystals by filtration,
The title compound (9.70 g) was obtained as colorless crystals. ¹ H NMR (300MHz, δppm, DMSO-d ₆ ) 1.54-1.75 (6H, m), 3.
30-3.50 (4H.m), 6.89 (2H, d, J = 9.0Hz), 7.73 (2H, d, J = 9.0
Hz), 9.75 (1H, s) FAB (+) MS (low resolution) 190

Reference Example 44 (Step 9) 4-piperidinobenzaldehyde oxime

Embedded image 4-piperidinobenzaldehyde obtained in Reference Example 43
From (7.74 g), the title compound (7.
13 g) was obtained as pale yellow crystals. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.52-1.78 (6H, m), 3.17
-3.32 (4H, m), 6.83-6.95 (2H, m), 7.39-7.50 (2H, m), 7.7
0 (1H, broad s), 8.05 (1H, broad s) FAB (+) MS (low resolution) 205

Example 55 (10th step, 11th step) N, N-dimethyl-4-piperidinobenzamide oxime

Embedded image 4-Piperidinobenzaldehyde oxime (3.00 g) obtained in Reference Example 44 was suspended in carbon tetrachloride (12 ml), and a solution of tert-butyl hypochlorite (1.79 ml) in carbon tetrachloride (3 ml) was added. The mixture was added dropwise and stirred at room temperature for 3 hours. Carbon tetrachloride (20 ml) was added to the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue is ethanol (1.0 ml)
50% dimethylamine aqueous solution (10 ml) was added, and the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. The reaction solution was allowed to cool, water was added, and the mixture was extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel flash column chromatography, and chloroform: methanol = 1.
The title compound (162 mg) was obtained as a brown powder from the 00: 1 eluate. ¹ H NMR (300MHz, δppm, CDCl ₃ ) 1.53-1.81 (6H, m), 2.67
(6H, s), 3.16-3.27 (4H, m), 6.94 (2H, dd, J = 11.6, 2.9H
z), 7.28 (2H, dd, J = 11.6, 2.9Hz) FAB (+) MS (low resolution) 248

[Test Example] Next, the cell adhesion-inhibiting effect of the compound of the present invention was tested. Test Example 1 Inhibition activity of hydrogen peroxide (H ₂ O ₂ ) production by human peripheral blood polymorphonuclear leukocytes (PMN) Method of Karl Nathan [Journal of Clinical Investigation,
80, 1550-1560 (1987) [J. Cli
n. Invest., 80 , 1550-1560 (1987)].
Polymorphonuclear leukocytes (PMN) separated from human heparin-added venous blood by density gradient centrifugation with Ficoll and hypotonic treatment with sodium chloride were added to Krebs-Ringer phosphate buffer wi
th glucose: Abbreviated as KRPG below. ). A reaction containing 24 μM scopoletin, 1 mM sodium azide, 1 μg / ml horseradish peroxidase (HRP) was added to a 96-well plate in which fibrinogen was adhered to the solid phase in advance by adding a fibrinogen aqueous solution (1 mg / ml) and allowing it to stand at room temperature for 3 hours. Liquid, test substance and 10
ng / ml tumor necrosis factor α (TNFα) or 100 ng
/ Ml Phorbol myristate ace
tate (PMA) and 7.5 × 10 ⁵ cells /
After adding ml PMN, the mixture was incubated at 37 ° C. for 1.5 hours, and the amount of H ₂ O ₂ produced was measured with a fluorescence plate reader at an excitation wavelength of 360 nm and a measurement wavelength of 460 nm. The difference between the fluorescence value (b) of the well to which no inhibitor is added and the fluorescence value (a) of the control to which no cells are added is the amount of H ₂ O ₂ produced. The fluorescence value (c) of the well to which the test substance was added was measured, and the H ₂ O ₂ production inhibition rate was calculated from the following formula.

[Equation 1] The inhibition rate of each concentration of the test substance was calculated, and the T
The 50% inhibitory concentration (IC ₅₀ ) when NFα was added was calculated.

Table 8 shows the results of Test Example 1.

[Table 8]

Test Example 2 Inhibitory Effect of Test Substance on Thioglycollate-Induced Peritonitis The method of Rasky et al. [Science, 258, 964-9]
Page 69 (1992) [Science, 258 , 964-969 (199
2)]] was partially modified and tested. Six-week-old male Charles River Don Ryu rats from 6 to 8 groups were used.
The animals were divided into groups, and an aqueous solution of thioglycolate was added to the positive control group and the test substance administration group at 145 mg / 5 ml per individual
Injected intraperitoneally. 1 hour after administration of thioglycollate, 0.5% methylcellulose was administered to the positive and negative control groups, and 0.5% methylcellulose in which the test substance was dissolved was administered to the test substance administration group by tail vein administration at a volume of 1 ml / kg and 5 ml.
Orally administered in a dose of / kg. Thioglycolate administration 5
After a lapse of time, the rat was killed by exsanguination, and immediately thereafter, the abdominal cavity was washed with 5 ml of a phosphate buffered saline containing 0.5% bovine serum albumin and 10 units / ml of heparin sodium to remove leukocytes exuded into the abdominal cavity. Recovered. The number of white blood cells in the lavage fluid was measured using an automatic blood cell counter. From the following formula, the inhibition rate of leukocyte infiltration by the thioglycolate of the test substance was calculated. In addition, in the oral administration group, from the calculated inhibition rate, a 30% effective dose (E
D ₃₀₎ was determined.

[Equation 2] F _x : Number of exudate cells in the test substance group (mean value) F _max : Number of exudate cells in the positive control group (mean value) F ₀ : Number of exudate cells in the negative control group (mean value)

The results of Test Example 2 are shown in Tables 9 and 10.

[Table 9]

[0202]

[Table 10]

Test Example 3 Cell Adhesion Inhibitory Activity of Test Substance by Rat Mesenteric Microcirculation Assay Method Suematsu et al. [American Journal of Physiology, 266, H2410 to H2415 (19)
44) [Am. J. Physiol., 266 , H2410-H2415 (199
4)]]. Using Wistar male rats (body weight: 200-400 g), a midline laparotomy was performed under Nembutal anesthesia to expose the ileocecal mesentery to the outside of the abdominal cavity, carefully developed on a microcirculation observation stage, and kept at 37 ° C. While dripping the Krebslinger solution heated in the bath onto the mesentery, observe the microcirculation of the posterior capillary veins without a branch with a thickness of about 25 to 50 microns with a biomicroscope, and at the same time, use a CCD camera to view the image. Recorded in video. A catheter was placed in the vein, and the test substance and anesthesia solution were additionally administered through the catheter. FMLP used as a leukocyte stimulant
(Final concentration 100 μM) was directly dissolved in Krebs Ringer solution and added dropwise. After 10 minutes from the start of the observation, dropwise addition of fMLP was started, and after 10 minutes, it was confirmed that the leukocytes started to adhere to the vascular endothelium by the stimulation of fMLP, and then the test substance was started to be dropwise added. Then, the observation was continued for 30 minutes. After administration of the test substance, the adherent cells (30
The number of cells remaining in the site for more than 2 seconds was counted. Those that significantly suppressed the number of adherent cells 30 minutes after the start of dropping of the test substance compared to the value of 0 minutes were judged to have cell adhesion inhibitory activity.

Table 11 shows the results of Test Example 3.

[Table 11]

[0205]

As is clear from the above test results, the compound of the present invention not only has an excellent cell adhesion inhibitory action,
Since its toxicity is also extremely low, it is used as an anti-inflammatory agent having a different mechanism of action from the anti-inflammatory agent currently used in clinical practice, a therapeutic agent for ischemia-reperfusion injury, an agent for inhibiting organ transplant rejection, a therapeutic agent for autoimmune diseases, etc. It is useful. It is also expected to be used as a cancer metastasis inhibitor, an anti-allergic agent, an anti-asthma agent, atopic contact dermatitis, a bone marrow transplant rejection inhibitor, an arteriosclerosis therapeutic agent and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/495 ADU A61K 31/495 ADU 31/535 ABN 31/535 ABN C07D 211/14 C07D 211 / 14 211/42 211/42 211/44 211/44 211/62 211/62 211/72 211/72 211/76 211/76 295/12 295/12 AZ

Claims (13)

[Claims] 1. A compound of the general formula [I] [In the formula, R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group or an acyl group, R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group or an acyl group, A is an oxygen atom, a carbonyl group, [Chemical 2] Or A′-R ⁴ [R ⁴ is a hydrogen atom; a hydroxyl group, an amino group, an alkoxy group, an alkyl group which may be substituted with an alkyl-substituted amino group or an oxo group; an alkyl group, a hydroxyl group, an alkoxy group, an amino group or an alkyl group Aryl group optionally substituted with amino group; Aralkyl group optionally substituted with alkyl group, hydroxyl group, alkoxy group, amino group or alkyl substituted amino group; Substituted with hydroxyl group, amino group, alkyl substituted amino group or oxo group Optionally an alkoxycarbonyl group or << R ⁵ represents a hydrogen atom or an alkyl group which may be substituted with a hydroxyl group, A ¹ is an oxygen atom or A ¹ ′ -R ⁶ <R ⁶ is a hydrogen atom, an alkyl group which may be substituted with a hydroxyl group or R ^Five
Together with {A ² represents an oxygen atom or A ² ′ -R ⁷ (R ⁷ represents a hydrogen atom, an alkyl group, an acyl group or an alkoxycarbonyl group, and A ² ′ represents a nitrogen atom or a CH group),
s and t are the same or different and each represents an integer of 1 to 3. Represents｝. >, And r represents an integer of 0 or 1 to 3. >>, A'represents a nitrogen atom or a CH group. ]
And B is (J represents 0 or an integer of 1 to 2), and (J represents the same meaning as described above.), (K represents an integer of 1 to ₂ ) _or- (CH2) _m-.
(M represents an integer of 1 to 3), X represents a hydrogen atom or a halogen atom, and n represents an integer of 1 to 3. ] The benzamido oxime derivative shown by these, or its pharmacologically acceptable salt. 2. R ¹ , R ² and R ³ are all hydrogen atoms, and A is A′-H (A ′ has the same meaning as described above) or embedded image (A ′, A ¹ ′, R ⁵ and R ⁶ have the same meanings as described above.) The benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to claim 1. 3. The benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein A is a CH ₂ group. 4. 4- (4-Cyclohexyl-1-piperazinyl) benzamide oxime, 4- (4-piperidinopiperidino) benzamide oxime, 4- [4- (tert-butoxycarbonyl) -1-piperazinyl] Benzamide oxime, 4- (4-isopropyl-1-piperazinyl) benzamide oxime, 4- [4- (3-pentyl) -1-piperazinyl] benzamide oxime, 4- [4-[(1-pyrrolidinyl) carbonylmethyl]
-1-Piperazinyl] benzamido oxime, 4- [4- [1- (tert-butoxycarbonyl)-
4-piperidyl] -1-piperazinyl] benzamido oxime, 4- [4- (1-pivaloyl-4-piperidinyl) -1
-Piperazinyl] benzamide oxime, 4- (1-pyrrolidinyl) benzamide oxime, 4- [4- (1-pyrrolidinyl) piperidino] benzamide oxime, 4- (4-morpholinopiperidino) benzamide oxime, 4-morpholinobenzamide oxime, 4- (4-methyl-1-piperazinyl) benzamide oxime, 4- (4-ethyl-1-piperazinyl) benzamide oxime, 4- (4-propyl-1-piperazinyl) benzamide oxime, 4- (4-cyclopentyl-1) -Piperazinyl) benzamidoxime, 4- [4- (3,4,5,6-tetrahydro-2H-pyran-4-yl) -1-piperazinyl] benzamidoxime, 4- [4- (2-hydroxyethyl)- 1-piperazinyl] benzamidooxy 4- [4- (2,3-dihydroxypropyl) -1-piperazinyl] benzamide oxime, 4- [4- (5-hydroxy-3-oxapentyl)-
1-piperazinyl] benzamido oxime, 4- [4- (isopropylaminocarbonylmethyl)-
1-piperazinyl] benzamide oxime, 4- [4- (2-dimethylaminoethyl) -1-piperazinyl] benzamide oxime, 4- [4- (3-dimethylaminopropyl) -1-piperazinyl] benzamide oxime, 4- [ 4- (1-methyl-4-piperidinyl) -1-piperazinyl] benzamide oxime, 4- [4- (ethoxycarbonyl) -1-piperazinyl] benzamide oxime, 4- (4-acetyl-1-piperazinyl) benzamide oxime, 4- (4-phenyl-1-piperazinyl) benzamide oxime, 4-piperidinobenzamide oxime, 4- [4- [4- (tert-butoxycarbonyl)-
1-piperazinyl] piperidino] benzamide oxime, 4- (4-methylpiperidino) benzamide oxime, 4- (1-piperazinyl) benzamide oxime, 4- [4- (4-piperidyl) -1-piperazinyl] benzamide oxime, 4- [ 4- (1-piperazinyl) piperidino] benzamide oxime, 4- (4-cyclohexyl-1-piperazinyl) benzamide O -acetyloxime, 3-bromo-4- (4-piperidinopiperidino) benzamide oxime, 3- Bromo-4- (4-isopropyl-1-piperazinyl) benzamide oxime, 4- (3-hydroxypiperidino) benzamide oxime, 4- (4-hydroxypiperidino) benzamide oxime, 4- (2-methylpiperidino) benzamide Oxime 4- (4-diethylamino-piperidinophenyl) benzamide oxime, 4- (4-hydroxyimino-piperidinoethoxy) benzamide oxime, 4- (2-Okisopiperijino) benzamide oxime, 4-piperidinocarbonyl benzamide O - benzyl oxime, 4- Piperidinobenzamide O -methyl oxime, N -acetyl-4-piperidinobenzamide O -benzyl oxime, N-methyl-4-piperidinobenzamide oxime, N-ethyl-4-piperidinobenzamide oxime, N, The benzamide oxime derivative according to claim 1, which is selected from N-dimethyl-4-piperidinobenzamide oxime, or a pharmaceutically acceptable salt thereof. 5. 4- (4-Piperidinopiperidino) benzamide oxime, 4- [4- (3-pentyl) -1-piperazinyl] benzamide oxime, 4- (4-methyl-1-piperazinyl) benzamide An oxime, 4- (4-cyclopentyl-1-piperazinyl) benzamide oxime, 4-piperidinobenzamide oxime, 4- (1-piperazinyl) benzamide oxime, or a benzamide oxime derivative according to claim 1, 2 or 4. A pharmacologically acceptable salt thereof. 6. A benzamide oxime derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 4-piperidinobenzamido oxime. 7. A pharmaceutical composition comprising the benzamide oxime derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. 8. A cell adhesion inhibitor comprising the benzamide oxime derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof. 9. An anti-inflammatory agent comprising the benzamide oxime derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof. 10. An agent for treating ischemia-reperfusion injury comprising the benzamide oxime derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof. 11. An organ transplant rejection inhibitor comprising the benzamide oxime derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof. 12. An agent for treating an autoimmune disease, which comprises the benzamide oxime derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof. 13. A cancer metastasis inhibitor comprising the benzamide oxime derivative according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof. [0001]