WO2000015645A1

WO2000015645A1 - Phosphonic ester derivatives and process for producing the same

Info

Publication number: WO2000015645A1
Application number: PCT/JP1999/004913
Authority: WO
Inventors: Yasushi Kono; Takayuki Sawada; Masahiro Nomura; Yukie Takahashi; Takeshi Tsubuki; Yasuhiko Sakoe; Kazuhiko Kuriyama
Original assignee: Kyorin Pharmaceutical Co., Ltd.
Priority date: 1998-09-11
Filing date: 1999-09-10
Publication date: 2000-03-23
Also published as: AU5648599A

Abstract

Phosphonic ester derivatives represented by general formula (1) and pharmacologically acceptable salts thereof having an activity of inhibiting a bond between cell adhesion molecules and thus being useful as immunosuppressants, anti-inflammatory agents, antiallergic agents and cancerous metastasis inhibitors.

Description

Satsuki Itoda β phosphonate derivatives and their production

Technical field

The present invention relates to a phosphonate derivative having an activity of inhibiting the binding between cell adhesion molecules and being useful as an immunosuppressant, an anti-inflammatory, an antiallergic, or a cancer metastasis inhibitor, and a method for producing the same.

Background art

In immune and inflammatory responses, adhesion between vascular endothelial cells and leukocytes is a very important process (Mebio, No. 5, Vol. 10 (1993)). The main adhesion molecules on the vascular endothelial cell side involved in this adhesion include ICAM—

1, VC AM-1, E-selectin, P-selectin, etc. have been reported, and the expression of each adhesion molecule differs depending on the time since the inflammation was induced (diagnosis and treatment, 83 Vol., 1164, (1995), Springer Semin Immunopathol, Vol. 11, 13 (1989), Cell, Vol. 76, 301 (1994)). That is, P-selectin shows a peak of expression 5 to 30 minutes after the inflammation is induced (immediately) and the expression decreases thereafter, and a peak of expression 2 to 6 hours (early). E-selectin activity indicates that expression decreases after that, and ICAM-1 and VCAM-1 indicate the peak of expression after 12 to 48 hours (phase I). Among them, adhesion to leukocytes via ICAM_1 and VCAM-1 which are expressed in large amounts in the long term is the strongest, and these two adhesion molecules play an important role even in actual various diseases It is said that. Therefore, I CAM-1 and V CAM—

If it is possible to inhibit adhesion through adhesion molecules such as 1, chronic It is considered to be effective as a remedy for autoimmune diseases such as rheumatoid arthritis, nephritis and knee osteoarthritis and allergic diseases such as chronic inflammatory diseases, asthma and dermatitis, and as a cancer metastasis inhibitor.

Cell adhesion inhibitors that have been reported up to now, so-called expression inhibitors that inhibit adhesion by suppressing the expression of adhesion molecules, and inhibit adhesion by inhibiting the binding between adhesion molecules It is classified as a so-called binding inhibitor. Most of the cell adhesion inhibitors related to IC AM-1 and VC AM_1 are expression inhibitors (Japanese Patent Application Laid-Open Nos. 9-111, 689, 8-28, 156, and 8-8,156). 198,752, JP-A-7-304,667, JP-A-7-258,168), and binding inhibitors, such as antibodies and ligands of adhesion molecules. Except for macromolecules, only non-peptide low molecular weight compounds have been reported in J. Med. Chem., Vol. 38, 1057 (1995). Expression inhibitors often act on the intracellular signal transduction system, and may suppress functions other than expression of adhesion molecules. Unlike such expression suppressors, binding inhibitors only inhibit the binding between adhesion molecules, so they are considered to be excellent drugs in terms of safety, but they are still satisfactory It is not something.

The present invention provides excellent immunosuppressants, anti-inflammatory agents, and the like by providing a substance that inhibits an adhesion pathway mediated by ICAM-1 and VCAM-1 that plays a central role in cell adhesion molecules. An object of the present invention is to provide an antiallergic agent and a cancer metastasis inhibitor. Disclosure of the invention

The present inventors inhibit the binding of human monocyte-like cell line (U933) to human umbilical vein-derived vascular endothelial cells (HUVEC) 24 hours after IL-11 stimulation. As a result of intensive research on compounds, A novel phosphonate ester derivative with a different structure from the known cell adhesion inhibitors is capable of binding between cells via ICAM1-1 and VCAM-1 without inhibiting the expression of adhesion molecules. The inventors have found that the present invention inhibits the present invention and completed the present invention.

That is, the present invention relates to the general formula (1)

Mountain

[Wherein, W is a thiazole ring, an optionally substituted benzothiazolyl ring, a pyridothiazolyl ring, an optionally substituted pyridin ring, an optionally substituted quinoline ring, a substituted Optionally substituted pyridazine ring, optionally substituted phthalazine ring, optionally substituted quinoxaline ring, optionally substituted pyrimidine ring, optionally substituted quinazoline ring An optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, and an optionally substituted indole ring, X Is

-NH (CH 2) m— (m is an integer of 0 to 2), represents one CONH—, or indicates that W and Y may be directly bonded. Y is an optionally substituted benzene ring, an optionally substituted naphthalene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring, a coumarin ring, Chromanone ring, chroman ring, 1,3-thiazolyl ring, Z is — (CH ₂ ) q-(q is an integer of 0 to 2), one CH = CH _, one CH ₂ — ', -0 C (CH ;,) ₂ —, one SCH ₂ -one S〇 CH _2- , — S 0 ₂ CH ₂ —, — NH CO (CH ₂ ) r-(r is an integer from 0 to 2) , R ¹ is a hydrogen atom, and has 1 to 4 carbon atoms. An alkoxycarbonyl group, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms, R ² represents a lower alkyl group having 1 to 4 carbon atoms, and n represents an integer of 0 to 2]. And a pharmacologically acceptable salt thereof, and a cell adhesion inhibitor containing at least one or more of these as an active ingredient.

Pharmaceutically acceptable salts of the compound represented by the general formula (1) in the present invention include acids such as hydrochloride, hydrobromide, methanesulfonate, citrate and tartrate. Addition salts, and metal salts such as sodium salts and potassium salts.

In the general formula (1) of the present invention, the “lower alkyl group” such as a lower alkyl group, a lower alkoxycarbonyl group and a lower alkoxyphosphoryl group means, for example, a straight chain such as methyl, ethyl, propyl, isopropyl, etc. Represents a chain or branched hydrocarbon having 1 to 4 carbon atoms, and includes `` an optionally substituted benzothiazole ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, Optionally substituted pyridazine ring, optionally substituted phthalazine ring, optionally substituted quinoxaline ring, optionally substituted pyrimidine ring, optionally substituted quinazoline ring, substituted Optionally substituted chenobilimidine ring, optionally substituted benzimidazole ring, optionally substituted pyridine ring, optionally substituted A good indole ring, an optionally substituted benzene ring, an optionally substituted naphthylene ring, and an optionally substituted pyridine ring are lower alkyl groups at any position on the ring. , A lower alkoxy group, a trifluoromethyl group, a lower alkoxymethyl group, a dimethylamino group, a dimethylamino group, etc., a lower dialkylamino group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, Cl, Br, Halogen atoms such as I and F, hydroxy, phenyl, piperidine, acetylamino And those having a lower acetylamino group, an acetyl group or a nitro group such as a group.

According to the present invention, the compound represented by the general formula (1) is produced by condensing the compound represented by the general formula (2) and the compound represented by the general formula (3). Can be.

Wherein W is a thiazolyl ring, an optionally substituted benzothiazolyl ring, a pyridothiazolyl ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, An optionally substituted pyridazine ring, an optionally substituted phthalazine ring, an optionally substituted quinoxaline ring, an optionally substituted pyrimidine ring, an optionally substituted quinazoline ring X represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, or an optionally substituted indole ring;

- NH (CH ₂₎ m- (m is an integer of 0-2), - or shows a C 0 NH-, show that W and Y may be bonded directly. Y is an optionally substituted benzene ring, an optionally substituted naphthylene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring, a coumarin ring , A chromanone ring, a chroman ring, a 1,3-thiazole ring, Z is one (CH ₂ ) q-(q is an integer of 0 to 2), one CH = CH-, one CH _2- , One 0 C (CH 3) _2- , — SCH ₂ — S 0 CH _2- , one S 0 ₂ CH ' ₂ -,-NHC 0 (CH ₂ ) r-(where r is an integer from 0 to 2) R ³ represents a hydroxy group or a halogen atom]

[R ¹ is a hydrogen atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms, R ² is a lower alkyl group having 1 to 4 carbon atoms, and n is 0. In the case of an acid halide in which R ^{3 in} the formula (2) is a halogen atom, methylene chloride and 1,4-dioxane are present in the presence of an organic base such as triethylamine or pyridine. And the like can be used as a solvent at 0 ° C. to room temperature. When R ³ in the formula (2) is a hydroxy group, it can be produced by a mixed acid anhydride method or an active ester method used in a usual peptide bond formation reaction, and preferably a condensing agent. The method using is suitable. Reactions include dicyclohexyl carpoimide (DCC), diisopropyl carbodiimide (DIPC), diphenylphosphonyl azide (DPPA), getylphosphonyl cyanide (DEPC), 1-ethyl 3- (3-dimethylaminopropyl pill) In the presence of a condensing agent such as 1-carbodiimide (WSC), 4-dimethylaminoviridine (DMAP) may optionally be added as a catalyst and the reaction solvent used as a reaction solvent. The reaction can be performed using tetrahydrofuran (THF), methylene chloride, dimethylsulfoxide (DMSO), or dimethylformamide (DMF) at a reaction temperature of 0 ° C to room temperature.

Among the compounds represented by the general formula (1), a compound in which X is —CO NH—, ie, a compound represented by the general formula (9) ′ PO (OFt ² ) _{2 (9)}

[Wherein W, Y, Z, RR ² , and n are as described above], the compound represented by the general formula (7) and the compound represented by the general formula (8) Can also be produced by condensing

[Where Y, Z, RR ² and n are as described above]

[Where W and R ³ are as described above]

In the case of the acid halide in which R ³ in the formula (8) is a halogen atom, the reaction is carried out using methylene chloride, 1,4-dioxane or the like as a solvent in the presence of an organic base such as triethylamine or pyridine. The reaction can be performed at 0 ° C. to room temperature. Further, when R ^{; i} in the formula (8) is a hydroxy group, it can be produced by a mixed acid anhydride method or an active ester method used in a general peptide bond formation reaction, and preferably by condensation. A method using an agent is suitable. The reaction may be carried out in the presence of a condensing agent such as DCC; DIPC; DPPA, DEPC, WSC, etc., in some cases, by adding DMAP as a catalyst, and using THF, methylene chloride, DMSO, Using DMF, The reaction can be carried out at a temperature of 0 ° C to room temperature.

The compound represented by the above general formula (7) can be produced by the following synthetic route.

When V in the general formula (4) is an amino group, a method by condensation with (3), or when V in the general formula (4) is a nitro group, condensation with (3). The obtained compound (5), that is, the compound represented by the general formula (6), is subsequently divided into two methods.

In the above reaction path, the general formula (5)

{ ₅₎

[Wherein, V represents an amino group or a nitro group, and Y, Z, R ′, R ² , and n are as described above]. The compound represented by the general formula (3) The compound can be produced by condensing a compound represented by the general formula (4) with a compound represented by the general formula (4).

(Four)

Wherein, V, Y, Z, R 3 are as described above]

In the case of an acid halide in which R ³ in the formula (4) is a halogen atom, methylene chloride, 1,4-dioxane or the like is used as a solvent in the presence of an organic base such as triethylamine or pyridine. It can be performed at 0 ° C to room temperature. Further, when R ^{: 3} in the formula (4) is a hydroxy group, it can be produced by a mixed acid anhydride method or an active ester method used for a usual peptide bond formation reaction, and is preferably used. A method using a condensing agent is suitable. The reaction may be carried out in the presence of a condensing agent such as DCC, DIPC, DPPA, DEPC; or WSC, in some cases, by adding DMAP as a catalyst, and using THF, methylene chloride, DMSO, DMF as the reaction solvent. The reaction can be performed at a reaction temperature of 0 ° C to room temperature.

In the above synthetic route, the compound represented by the general formula (7) is represented by the general formula:

The compound can also be produced by reducing the compound represented by (6).

PO (OR ² ) _{2 (6)}

[Where Y, Z, RR ² and n are as described above]

The reaction is carried out in a hydrogen atmosphere in the presence of Pd / C, Raney nickel, platinum oxide, etc., using methanol, ethanol, DMF, 1,4-dioxane, THF, etc. as a solvent, and heating from room temperature to room temperature. Can react. In addition, the reaction can be carried out from room temperature to under heating using acetic acid, a mixed solution of ethanol and water, a mixture of THF and the like as a solvent in the presence of iron, zinc and tin tetrachloride.

In the compound represented by the general formula (1), R ¹ is a carboxyl group A compound of the general formula (11)! I)

[Wherein, W, X, Y, Ζ, R ² , and η are as described above], can also be obtained by hydrolyzing the compound represented by the general formula (10). Can be manufactured.

[Wherein R ⁴ represents a lower alkyl group having 1 to 4 carbon atoms, and W, X, Y, Z, R ² and n are as described above]

The reaction is carried out using a solvent such as methanol, ethanol, DMSO, DMF, etc., and an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of lithium hydroxide, etc., and the reaction temperature is adjusted. Although not limited, the reaction can be performed at 0 ° C to room temperature. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

Amethylmethylphosphonate, aminoethylphosphonate and aminopropylphosphonate are described in Org. Synth., 65, 119 (1987, Bull. Chem. Soc. Jpn., 45, 2531 (1972 ^ Helv Chim. Acta, 75, 2545 (1992), ethyl amino (diethoxyphosphoryl) acetate was synthesized by Synthesis, 580 (1996), and aminoethylmethylenebisphosphonate getyl was synthesized by referring to Syn. Commun., 26, 2037 (1996). Reference example 1

4 I (Benzothia 2-yl) Amino 2-Black benzoic acid

A mixture of 2-benzothiazole (2.12 g) and 4-amino-2-ethyl benzoate (2.50 g) was heated and stirred at 140 ° C. for 30 minutes. After cooling, the reaction product was dissolved in ethanol, water was added, and the precipitated crystals were collected by filtration. 4- (Benzothiazol-1-yl) amino-2-chloroethyl benzoate (3.78 g) was obtained as a pale yellow powder. The obtained ester (1.28 g) was dissolved in ethanol (2 () ml), a 10% aqueous sodium hydroxide solution (5 ml) was added, and the mixture was heated under reflux for 1 hour. After cooling, ethanol was distilled off under reduced pressure, water was added to the residue, the reaction solution was converted to PH 3 with diluted hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water and drying, the desired product (l. () 5g) was obtained as a colorless powder. Reference example 2

4 — [(Benzothiazol 2-yl) amino diphenyloxyacetic acid O 0 ₂ H

1-, 3-Dimethyl-2-benzodiazole (19.2 g) and 4-ethylaminophenyl acetate (22.Og) in 1,3-dimethyl-2-imidazolidinone (300 ml) solution Sulfonic acid (2.83 g) was added, and the mixture was stirred at 140 ° C for 2 hours. Water and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the crystals obtained by purification by silica gel column chromatography (developing solvent n—hexane: ethyl acetate = 2: 1) are washed with methanol, and 4— (benzothiazol-1-yl) is removed. 2- (yl) aminophenyloxyethyl acetate (21.5 _g ) was obtained as a colorless powder. The obtained ester was subjected to alkaline hydrolysis in the same manner as in Reference Example 1 to obtain the desired product as a colorless powder. Reference example 3—8 9

In the same manner as in Reference Examples 1 and 2, various heterocyclic compounds having a chloro group and a methylthio group were reacted with various amine derivatives to synthesize the compounds shown in Table 1.

table 1

To a solution of ammonium thiocyanate (3.80 g) in THF (100 ml) was added benzoyl chloride (7.00 g) while stirring at room temperature, and the mixture was heated under reflux for 5 minutes (preparation of benzoylisothiosinate). 2-Amino 6-methylbenzothiazol (8.2 () g) was added to the reaction mixture, and the mixture was further heated for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with hot ethanol to obtain the desired product (7.71 _g ) as a pale yellow powder.

2) 2 — [(6-Methylbenzothiazoyl 2- 2-yl) amino j-1 3-1-thiazole 4-ethyl acetate

The above thiourea (7.52 g) and lithium hydroxide monohydrate (5.58 g) were dissolved in water (70 ml) and heated under reflux for 20 minutes. After cooling, the reaction mixture was adjusted to pH 1 by adding dilute hydrochloric acid, then adjusted to pH 10 with aqueous ammonia, heated on a water bath, and allowed to cool. The precipitated crystals were collected by filtration and recrystallized from ethyl acetate-THF-DMF-isopropyl ether. N— (6-Methylbenzothiazole-2-yl) thiourea (1.37 g) was obtained as colorless needles. The obtained thiourea (1.30 _g ) was dissolved in THF (50 ml), 4-ethyl acetylacetate (5.00 g) and DMAP (0.05 g) were added, and the mixture was heated under reflux for 20 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained powder, and the mixture was extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. did. The obtained crystals were recrystallized from THF-isopropyl ether-isopropyl alcohol to give the desired product (0.60 g) as milky white needles.

3) 2 — | (6 -Methylbenzothiazoyl 2 _yl) amino] 1, 3 —Thia val-4

The ester was hydrolyzed in the same manner as in Reference Example 1 to obtain the desired product as a colorless powder. Reference Example 9 1

4 '(benzothiazol-2-yl) cinnamic acid

1) 4 I (Benzothiazo-1-yl) Benzaldehyde

2— (p-tolyl) ben Vthiazol (2.42 g), N-bromosuccinimide (2.1 ⁽⁾ g), benzoyl peroxide (0.10 g) in carbon tetrachloride (100 ml) The mixture was heated under reflux for 4 hours. After cooling, the precipitated crystals were removed by filtration, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude 2-'(4-bromomethylphenyl) benzothiazole (3.31 g) as a colorless powder. The obtained bromo compound (3.04 g) and hexamethylenetetramamine (2.80 g) were dissolved in a 5 () ml mixture of acetic acid / water (1: 1), and the mixture was heated and stirred at 100 ° C for 2 hours. . Then, add 2 () ml of concentrated hydrochloric acid and heat at the same temperature for 15 minutes. After stirring _and cooling, water was added, and the precipitated crystals were collected by filtration and dried well. The obtained crystals were purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 1: 3) to give the desired product (1.29 g) as a colorless powder.

2) 4 '1 (benzothiazoyl-2-yl) cinnamic acid

A solution of the above aldehyde (1.29 g) and dimethyl dimethylcarbonylphosphonate (1.46 g) in DMS0 (30 ml) was stirred at room temperature, and thereto was added 60% sodium hydride oil (0.26 _g ). . Then, after stirring at the same temperature for 1 hour, water was added and the precipitated crystals were collected by filtration. After drying, the resulting crystals were purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 1: 3), and 4— (benzothiazol-1-yl) ethyl cinnamate (1.55 _g ) was obtained as a yellow powder. The obtained ester was hydrolyzed in the same manner as in Reference Example 1 to obtain the desired product as a yellow powder. Reference example 9 2

4 '― [(2_black mouth pyridin-5-yl) carbonyl] amino cinnamic acid

WSC (0.86 g) was added to a DMF (20 ml) solution of 2-cyclopyridine pyridin-5-carboxylic acid (0.47 g) and ethyl 4-ethylaminocinnamate (() .63 g), and the mixture was brought to room temperature. And stirred for 8 hours. Water is added to the reaction solution, and the precipitated crystals are filtered. The crystals were taken out, washed with water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried.

4,-[(2-Cyropyridin-5-yl) carbonyl] amino ethylethyl cinnamate (() .95 _g ) was obtained as a yellow powder. The obtained crystals were subjected to alkaline hydrolysis in the same manner as in Reference Example 1 to obtain the desired product as a yellow powder. Reference example 9 3

4,-[(5-Chloro-1-phenylindole-1-yl) carbonyl] aminocinnamic acid

The desired product was obtained as a yellow powder by reacting with 5-ethylamine 1-phenylindole-12-carboxylic acid and ethyl 4-ethylaminocinnamate in the same manner as in Reference Example 92. Reference example 9 4

4,-[(6-Methylbenzothiazoyl-2-yl) carbonyl

] Aminocinnamic acid

6-Methylbenzothiazol-1--2-carboxylic acid and 4,4-aminocarboxylic acid The same procedures used in Reference Example 92 were carried out using ethyl cinnamate to give the desired product as a yellow powder. Example 1

[4,1 (benzothiazoyl 2-yl) cinnamoiaminomethanine phosphonate

Reference Example 91 WSC (0.38 g) and DMAP (0.10 g) were added to a DMF (3 () ml) solution of the compound of Example 1 (0.28 g) and dimethyl ethyl phosphonate (0.25 g), and the mixture was added at room temperature. Stirred for hours. After adding water to the reaction mixture, the mixture was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, water, dilute hydrochloric acid, water and saturated saline in this order, and then anhydrous sodium sulfate. And dried over um. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: methylene chloride: ethanol = 15: 1) to obtain the desired product (0.30 g) as a colorless powder. Melting point 182-183 ° C (AcOEt- iPr ₂ O)

Elemental analysis value (%): As C _{2 1} H _{2 3} N ₂ 0 ₄ PS

C H N

Calculated value: 58.60 5.39 6.51

Observed value: 58.81 '5.48 6.56 Examples 2 to 202

Using the reference example compound and various aminophosphonic esters, the procedure was performed in the same manner as in Example 1 to obtain the compounds shown in Table 2.

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€ l6f0 / 66df / 13d Sf9Sl / 00 OW Example 2 0 3

[4- (4-trifluoromethylpyrimidine-1-2-yl) amino

_ 2—methoxyphenyl] oxyacetylamino (diethoxyphosphoryl) acetic acid

Example 18 The compound of 50 (50 _mg ) was added to a mixed solution of ethanol (1 ml) and a 1N aqueous sodium hydroxide solution ((.13 ml)), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, adjusted to pH 3 with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was solidified by adding ethyl persulfate and isopropyl ether, and the precipitated crystals were collected by filtration. Object

(29 mg) as a pale yellow powder.

H RM S: with a _{_{_{C 2 "H 2 5 F 3}}} N 4 0 8 P

Calculated value: 537.1362 Actual value: 537.1338 Example 2 0 4

(4'-amino cinnamoyl) amino methane phosphonate getyl

N ^ PO (OEt) ₂ The reaction was carried out in the same manner as in Example 1 using 4,4-aminocinnamic acid and getyl aminomethanephosphonate to obtain the desired product as a yellow powder. 141 142 ° C (AcOEt).

Elemental analysis (%): In to a _{_{H h 2, N 2 0 4}} P

C H N

: 53.84 6.78 8.97

Found: 53.87 6.76 8.93 Example 2 0 5

(3,12-Trocinnamamoylaminomethanephosphonate getyl

The reaction was carried out in the same manner as in Example 1 using 3, aminoaminocinnamic acid and dimethyl aminophosphonate to obtain the desired product as a colorless powder. 176-177 ° C (AcOEt).

Elemental analysis (%): CHN ₉ ◦ κ P

C H N

Calculated 49.13 5.60 8.18

Measured value 49.00 5.62 8.05 Example 2 06

[4,1- (2-Methanesulfenylpyrimidine-14yl) anocinnamoyl] aminomethane phosphonate getyl

Example 17 The compound of 72 (0.44 g) was dissolved in a mixture of DMF (5 ml) and methylene monochloride (30 ml). Under stirring at C, methylbenzoate perbenzoic acid (0.19 g) was added over 30 minutes. After stirring at the same temperature for 3 hours, an aqueous solution of sodium hydrogencarbonate was added to the reaction solution, and the mixture was extracted with methylene chloride.The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. did. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: methylene chloride: ethanol = 1: 0: 1) to obtain the desired product (.39 g) as a pale yellow oil.

H R M S (FAB): as C H N ^ C ^ P S

Calculated value: 453.1362 Actual value: 453.1367 Example 200-7 to 210

The compounds shown in Table 3 were synthesized in the same manner as in Example 206 using Examples 62, 63, and 173.

Table 3

Elemental analysis point CO

Example w n R 'fusion

Calculated / Actual (Recrystallization solvent) H. N

C ₂₀ H ₂₈ N ₄ O ₅ PS

1 H Et oil HRMS 467.1518

²⁰⁷ MeOS people (FAB) 467.1542

Next, the results supporting the usefulness of the compound of the present invention are shown by experimental examples.

Inhibitory effect of test compound on adhesion between human vascular endothelial cells and U933 cells (human monocyte cell line)

Stimulation of human umbilical vein-derived vascular endothelial cells (HUVEC) with human lipoprotein 1 (IL-1) provides ICAM-1, VCAM-1, ELAM-1, etc. Expression of adhesion molecules is induced. Twenty-four hours after stimulation, ICAM-1 and VCAM-1 are mainly expressed (J. Immunol., 144, 2558 (1990), ibid., 149, 698 (1992)) ₀ IL- By performing cell adhesion test using HUV EC stimulated with 1 for 24 hours, adhesion reaction via ICAM-VCAM-1 can be tested. Furthermore, by dividing the time of addition of the test compound into the time of stimulating HUVEC with IL-11 and the time of adhesion between HUVEC and U937, the adhesion inhibition effect of the test compound is mainly It can be evaluated whether it is due to inhibition of molecule binding or suppression of expression of adhesion molecules. Experimental example 1 Binding inhibition test of adhesion molecule

HUVEC suspended in M199 medium (for culture) containing 20% fetal serum and 1 ng / ml vascular endothelial cell growth factor (ECGF) was applied to a 96-well collagen-coated plate (flat bottom). X 1 0 ⁴ / Ueru not a One were seeded and cultured in 3 7 ° C, 5% C 0 2 below. After culturing for about 24 hours, HUV ECs were washed twice with M199 medium (for washing) containing no fetal serum and ECGF. Next, Hytointerleukin

(L-1?) Was cultured for 24 hours in a culture medium Ml99 containing 10 U / ml. On the other hand, U 9 3 7 cell suspension ^{(lxl 0 7 / ml) I} mM BCECF- AM solution (Wako Pure Chemical Industries, Ltd.) 1 0〃 1 not a One addition to Ri per 1 ml, 1 hour Lee under ice-cooling It was incubated and fluorescently labeled. Fluorescent marker Identification U 9.3 7 cells,-phosphate buffered saline (PBS (-)) after 2 washes, 1 0% © shea calf serum was suspended in R PM I- 1 640 medium containing (lxl 0 ⁷ / ml). HUVECs were washed three times with M199 medium for washing. The test compound was dissolved in dimethylsulfoxide, and diluted 100-fold with M-99 medium for culture, and added at a concentration of 801 / well. Subsequently, a fluorescence-labeled U933 cell suspension was added at a rate of 201 / well (final concentration of the test compound was 10 / well). Min 1 0 0 0 rotation, at room temperature, was centrifuged for 1 min, and incubated 3 7 ° C, 5% C 0 2 3 0 minutes under. Each well was washed twice with PBS (-) 100 / il to remove unadhered cells. Cells were solubilized by adding 0.1% sodium dodecyl sulfate aqueous solution in 100/1 / well portions. The fluorescence intensity of each well was measured (Excitation 49 () nm, Emission53 () nm), and the number of adhered U933 cells was determined from the calibration curve. The adhesion inhibition rate was calculated according to the following equation.

Contact and suppression rate (¾) X100

Table 4 shows the results. The suppression rate exceeding 100% was shown as 100%. Experimental Example 2 Test for suppressing the expression of adhesion molecules

The HUVE C were suspended in M 1 9 9 culturing medium was inoculated by Ueru 9 6 well collagen Coat Topure preparative (flat bottom), were cultured in 3 7 ° C, 5% C 0 2 below. After culturing for about 24 hours, HUVEC was washed twice with M199 medium for washing. Test compound is dimethylsulfoxy The cells were dissolved in a culture medium and diluted 100-fold with M199 medium for culture, added at 801 / well, and cultured for 1 hour. Next, a culture medium containing IL-1? Was added to the culture medium at a concentration of 20 ずつ / ゥ, and cultured for 24 hours (final concentration of IL-11? Was 10 U / m1. (Final concentration 10 / M). On the other hand, U 9 3 7 cell suspension ^{(lxl 0 7 / ml) 1} mM BCECF- AM solution Ri 1 m 1 per (Wako Junkusurye industry) was added portionwise 1 0 1, 1 hour Lee under ice-cooling The cells were incubated and fluorescently labeled. Fluorescently labeled U933 cells were washed twice with PBS (-), and then suspended in RPMI-164 medium containing 1 °% fetal bovine serum (1 x 107 / m1). After washing HUVEC three times with M199 medium for washing, 801 / well of M199 medium for culture and 20 // 1/1 / well of suspension of fluorescently labeled U933 cells were added. . Min 1 0 0 0 rotation, Atsushi Muro, after centrifugation for 1 min, and incubated 3 7 ° C, 5% C 0 2 3 0 minutes under. Each well was washed twice with PBS (—) 100〃1 to remove non-adherent cells. The cells were solubilized by adding 0.1% sodium dodecyl sulfate aqueous solution in 100/1 / well. The fluorescence intensity of each well was measured (Excitation 49 () nm, Emission 530 nm), and the number of adhered U933 cells was determined from the calibration curve. The adhesion inhibition rate was calculated according to the following equation.

Adhesion percentage (%): Number of cells of test compound — '1

Number of immobilized cells in IP-added control—Ile Number of immobilized cells in control without ip

The results are shown in Table 4. Table 4-Inhibition inhibition rate (%) Expression inhibition inhibition rate (%) Example No. 10μΜ Example No. 0μΜ

97 55 97 9

9 & 68 98 -5

99 69 99 -20

156 54 156 4

182 88 182 9

Experimental example 3 Rat delayed type hypersensitivity test

A female female rat (Japanese charles 'river'), 8 or 9 weeks old, was divided into 5 animals per group. The rat was injected with .05 ml of 0.6 mg bacterium (Difco) killed in liquid paraffin intradermally into the foot of the right hind limb suspended in liquid paraffin. Seven days later, the back was shaved with an electric hair clipper, and the skin thickness of the back (two places on the left and right) was measured using a dial thickness gauge (Ozaki Seisakusho). Next, the antigen solution 5 () 1 was injected intradermally into the skin thickness measurement part. As an antigen solution, suspend Mycobacterium putilicum killed bacteria in physiological saline to a concentration of 200 g / ml, and centrifuge at 3 () 0 () rpm for 3 minutes at 4 ° C, U). The used supernatant was used. Twenty-four hours after the injection of the antigen solution, the skin thickness at the injection site was measured to determine the amount of increase in skin thickness, and the average of the two sites on the left and right was taken as the data for each individual. The test compounds were 3% arabia gum aqueous solution (Example No. 18 2) containing () .5% ethanol and (). 1% Tween 20 ('No. 18%) or 3% arabia gum aqueous solution (Example No. 18 5) and orally administered once a day, every day, 7 days after the injection of mycobacterium butyricum, at a daily dose of (). The control group received a solvent of the same composition as used for the preparation of the test compound. The results are shown as the increase in skin thickness of the test compound relative to the increase in skin thickness in the control group. Expressed as a percentage of the weight. Table 5 shows the results

Table 5 Effect on delayed type hypersensitivity reaction

Example No. Skin ^ 庳 Increase

n

Percentage of (mg / kg / day, p.o.) (%)

182 30 5 66 **

185 100 5 69 "

Significant difference at p <0.01

Industrial applicability

As described above, the compound of the present invention represented by the general formula (1) does not exhibit the effect of suppressing the expression of cell adhesion molecules such as ICAM-1 and VCAM-1 and inhibits the binding between cells mediated by these compounds. Inhibition and its efficacy were also observed in delayed type hypersensitivity reaction tests.

Claims

Claims General formula (1)

[In the formula, w is a thiazole ring, an optionally substituted benzothiazole ring, a pyridothiazole ring, an optionally substituted pyridin ring, an optionally substituted quinoline ring, An optionally substituted pyridazine ring, an optionally substituted phthalazine ても, an optionally substituted quinoxaline ring, an optionally substituted bilimidine ring, an optionally substituted quinazoline ring, X represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, or an optionally substituted indole ring;

-NH (CH ₂ ) m— (m is an integer of 0 to 2), —CONH—, or indicates that W and Y may be directly bonded. Y is an optionally substituted benzene ring, an optionally substituted naphthalene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring, a coumarin ring , Kuromano down ring, click Roman ring, a 1,3 _ thiazole ring, Z is one (CH ₂ J q - (q is an integer of 0-2), one CH two CH -, _ OCH _2, - 0 C (CH 3) ₂ -,-SCH ₂ -one SOCH ₂ -,-S 0 ₂ CH _2- , one NHCO (CH ₂ ) r-(where r is an integer from 0 to 2), and R ¹ is hydrogen Atom, lower alkoxycarbonyl group having 1 to 4 carbon atoms, carboxyl group, lower alkoxyphosphoryl group having 1 to 4 carbon atoms, R ² is lower alkyl group having 1 to 4 carbon atoms, n is 0 to 2 Which represents an integer]. Ester derivatives and pharmacologically acceptable salts

2 1) 1 formula (1)

[In the formula, w is a thiazole ring, an optionally substituted benzothiazole ring, a pyridothiazole ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, or an optionally substituted quinoline ring. An optionally substituted pyridazine ring, an optionally substituted phthalazine ring, an optionally substituted quinoxaline ring, an optionally substituted pyrimidine ring, an optionally substituted quinazoline ring, an optionally substituted X represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, or an optionally substituted indole ring;

-NH (CH ₂ ) m— (m is an integer of 0 to 2), represents one CONH—, or indicates that W and Y may be directly bonded. Y is an optionally substituted benzene ring, an optionally substituted naphthalene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring, a coumarin ring, Chromanone ring, chroman ring, 1,3-thiazole ring, Z is one (CH ₂ ) q-(q is an integer of 0 to 2), one CH2 CH-, one OCH _2- , one OC ( CH 3) 2, _ SCH ₂ —, — SOCH ₂ —, one S〇 ₂ CH ₂ —, one NHCO (CH ₂ ) r-(wherein represents an integer of 0 to 2), and R ′ is a hydrogen atom, carbon A lower alkoxycarbonyl group of 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group of 1 to 4 carbon atoms, R ² represents a lower alkyl group of 1 to 4 carbon atoms, and n represents an integer of 0 to 2 ] A phosphonate ester characterized by the formula: A cell adhesion inhibitor comprising at least one or more active components of derivatives and pharmacologically acceptable salts.

3. General formula (2)

(2)

[In the formula, w is a thiazolyl ring, an optionally substituted benzothiazole ring, a pyridothiazolyl ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, An optionally substituted pyridazine ring, an optionally substituted phthalazine ring, an optionally substituted quinoxaline ring, an optionally substituted pyrimidine ring, an optionally substituted quinazoline ring X represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, or an optionally substituted indole ring;

-NH (CH ₂ ) m— (m is an integer of 0 to 2), represents one CONH—, or indicates that W and Y may be directly bonded. Y is an optionally substituted benzene ring, an optionally substituted naphthylene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring, a copolymer. Ring, chromanon ring, chroman ring, 1,3-thiazole ring, Z is one (CH ₂ ) q-(q is an integer of 0 to 2), one CH 2 CH-, one OCH ₂ -,-0 C (CH 3) _2- , one SCH ₂ -_ SOCH _2- , one S 0 ₂ CH ₂ -,-N II C 0 (CH ₂ ) r one (where r is an integer from 0 to 2 ) And R ³ represents a hydroxy group or a halogen atom.] A compound represented by the general formula (3)

[In the formula, R ¹ is a hydrogen atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms, and R ² is a lower alkyl group having 1 to 4 carbon atoms. Wherein n represents an integer of 0 to 2], and a compound represented by the general formula (1):

[Wherein, W, X, Y, Z, RR ² , and n are as described above].

4. General formula (4)

[In the formula, V represents an amino group or a nitro group, Y represents an optionally substituted benzene ring, an optionally substituted naphthalene ring, an optionally substituted pyridine ring, or a substituted A quinoline ring, a benzofuran ring, a coumarin ring, a chromanone ring, a chroman ring, a 1,3-thiazole ring, and Z is — (CH ₂ ) q— (q is an integer of 0 to 2) Show),

One CH2 CH, _〇 CH ₂ -',-0 C (CH ;,) ₂ —, One SCH ₂ -One S〇 CH ₂ , One S 0 ₂ CH ₂ , — NHCO (CH ₂ ) r-(r Represents an integer of 0 to 2), and R ³ represents a hydroxy group or a halogen atom. The compound represented by the general formula (3)

[In the formula, R ¹ is a hydrogen atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms, and R ² is a lower alkyl group having 1 to 4 carbon atoms. Wherein n represents an integer of 0 to 2], wherein the compound represented by the general formula (5) PO (OR ² ) ₂ ( ₅ )

[Wherein, V, Υ, Ζ, R ′, and Rη are as described above].

5 General formula (6)

(6)

[In the formula, Y is an optionally substituted benzene ring, an optionally substituted naphthylene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring , A coumarin ring, a chromanone ring, a chroman ring, a 1,3-thia valyl ring, Ζ is one (CH ₂ ) q-(q is an integer of 0 to 2), — CH 2 CH—, — OCH ₂ —, one OC (CH 3) ₂ —, one SCH ₂ _, — SOCH ₂ —, 1 SO, ₂ CH ₂ —, — NH CO (CH 2) r-(r represents an integer of 0 to 2), R ¹ is a hydrogen atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group the lower Arukokishihosuho Li Le group of from 1 to carbon atoms 4, R ² is a lower alkyl group having 1-4 carbon atoms, n represents a child reducing a compound represented by the ί indicating the integer of 0-2 General formula characterized by

(7) PO (OR ² ) _{2 (7)}

H ₂

[Wherein, γ, RRRR ² , and n are as described above].

6. General formula (Ί)

(7)

[In the formula, Y is an optionally substituted benzene ring, an optionally substituted naphthylene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, a benzofuran ring, A coumarin ring, a chromanone ring, a chroman ring, a 1,3-thiazole ring, Z is — (CH ₂ ) q-(q is an integer of 0 to 2), —CH 2 CH—, _ 0 CH ₂ —, one C (CH 3) ₂ —, one SCH _2- , — S 0 CH ₂ ―,

I S 0 ₂ CH ₂ _, — NHC 0 '(CH ₂ ) r-(where r represents an integer of 0 to 2), R' is a hydrogen atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, carboxyl Group, lower alkoxy phosphoryl having 1 to 4 carbon atoms R ² represents a lower alkyl group having 1 to 4 carbon atoms, and n represents an integer of 0 to 2].

[In the formula, w is a thiazole ring, an optionally substituted benzothiazole ring, a pyridothiazole ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, or an optionally substituted quinoline ring. Optionally substituted pyridazine ring, optionally substituted phthalazine ring, optionally substituted quinoxaline ring, optionally substituted pyrimidine ring, optionally substituted quinazoline ring, substituted R ³ represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, an optionally substituted indole ring; A compound represented by the following formula: (9) which represents a hydroxy group or a halogen atom].

PO (OR ² ) _{2 (9)}

[Wherein W, Y, Z, RR ² , and n are as described above].

7. General formula (10)

[Wherein, W is a thiazolyl ring, an optionally substituted benzothiazolyl ring, a pyridothiazole ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, Optionally substituted pyridazine ring, optionally substituted phthalazine ring, optionally substituted quinoxaline ring, optionally substituted pyrimidine ring, optionally substituted quinazoline ring, substituted X represents an optionally substituted chenobilimidine ring, an optionally substituted benzimidazole ring, an optionally substituted purine ring, or an optionally substituted indole ring;

— NH (CH,) m— (m is an integer of 0 to 2), one CONH—, or indicates that W and Y may be directly bonded. Y is an optionally substituted benzene ring, an optionally substituted naphthalene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring; a benzofuran ring, a coumarin Ring, chromanon ring, chroman ring, 1,3-thiazole ring, Z is — (CH ₂ ) q-(q is an integer of 0 to 2). — CH = .CH—, _ OCH _2- one _{OC 2 (CH,.) -} , one _{_{SCH 2 - - SOCH 2 -,}} - S 0 2 CH 2 -, - NHCO and (CH ₂₎ r one (r is an integer of 0 to 2), R ² , and have the same or different carbon numbers

Wherein n represents an integer of 0 to 2; and a compound represented by the formula:

[Wherein X, Y, Z, R ² and n are as described above]. -