WO2000015604A1 - Derives de diesters maloniques et leur procede d'obtention - Google Patents

Derives de diesters maloniques et leur procede d'obtention Download PDF

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Publication number
WO2000015604A1
WO2000015604A1 PCT/JP1999/004914 JP9904914W WO0015604A1 WO 2000015604 A1 WO2000015604 A1 WO 2000015604A1 JP 9904914 W JP9904914 W JP 9904914W WO 0015604 A1 WO0015604 A1 WO 0015604A1
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WIPO (PCT)
Prior art keywords
ring
optionally substituted
carbon atoms
general formula
lower alkyl
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PCT/JP1999/004914
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English (en)
Japanese (ja)
Inventor
Yasushi Kono
Masahiro Nomura
Takayuki Sawada
Naoki Ando
Yukie Takahashi
Kazuhiko Kuriyama
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to AU56486/99A priority Critical patent/AU5648699A/en
Publication of WO2000015604A1 publication Critical patent/WO2000015604A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to a malonic acid diester derivative which has a binding inhibitory activity between cell adhesion molecules and is useful as an immunosuppressant, an anti-inflammatory agent, an anti-allergic agent, and a cancer metastasis inhibitor, and a method for producing the same.
  • adhesion between vascular endothelial cells and leukocytes is an extremely important process (Mebio, ⁇ ⁇ 5, Vol. 10, (1993)).
  • the main adhesion molecules on the vascular endothelial cell side involved in this adhesion are reported to be ICAM-1, VCAM-1, E-selectin, P-selectin, etc., and the expression of each adhesion molecule is inflammatory. (Diagnosis and treatment, Vol. 83, 1164, (1995)), Springer Semin Immunopathol, Vol. 11 163, (1989), Cell, Vol. 76, 301 (1994)).
  • adhesion molecules such as ICAM-1 and VCAM-1 which play a central role in inflammation
  • chronic It is considered to be effective as a therapeutic drug for autoimmune diseases such as arthritis, nephritis and knee osteoarthritis, allergic diseases such as chronic inflammatory diseases, asthma and dermatitis, and as a cancer metastasis inhibitor.
  • Cell adhesion inhibitors that have been reported to date include so-called expression inhibitors that inhibit adhesion by suppressing the expression of adhesion molecules, and so-called expression inhibitors that inhibit adhesion by inhibiting the bonding between adhesion molecules. Classified as a binding inhibitor. Most of the cell adhesion inhibitors for ICAM-1 and VCAM-1 are expression inhibitors (JP-A-9-110689, JP-A-8-28316, JP-A-8-156).
  • the present invention provides an excellent immunosuppressant, anti-inflammatory agent by providing a substance that inhibits the binding between ICAM-1, VCAM-1 and leukocytes, which plays a central role in cell adhesion molecules.
  • the present inventors have developed a compound that inhibits the binding between human monocyte-like cell line (U933) and human umbilical vein-derived vascular endothelial cells (HUVEC) 24 hours after IL-1 stimulation.
  • U933 human monocyte-like cell line
  • VCAM human umbilical vein-derived vascular endothelial cells
  • the present invention relates to the general formula (1)
  • W is an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, an optionally substituted benzothiazole ring, or an optionally substituted benzothiazole ring;
  • X represents an amino group, One CONH—
  • Y is an optionally substituted benzene ring, naphthalene ring, pyridine ring, chroman ring, 1,3-thiazolyl ring
  • Z is one CH2 CH—, — OCH 2 —, -0 C (CH 3) 2- , one NHC 0 (CH 2 ) 2- , one (CH 2) n-(n is an integer of 0 to 3)
  • R 1 is a lower alkyl group having 1 to 4 carbon
  • Pharmaceutically acceptable salts of the compound represented by the general formula (1) ′ in the present invention include, for example, hydrochloride, hydrobromide, methanesulfonate, citrate, and tartrate. Acid addition salts.
  • the “lower alkyl group” such as a lower alkyl group and a lower alkoxycarbonyl group refers to, for example, a linear or branched chain such as methyl, ethyl, propyl, and isoprovir.
  • ⁇ ring '' means a halogen atom such as a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a methoxymethyl group, a Cl atom, a Br atom, an I atom, a F atom, a nitro group, an a C Group, a lower Ashiruami amino group such as Asechiruami amino group, piperidine group, Jimechiruami amino group, can be mentioned, et al are those having a lower Jiarukiruami amino
  • the compound represented by the general formula (1) is a compound represented by the general formula (5)
  • W is an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted quinoline ring, an optionally substituted benzothiazole ring, or an optionally substituted benzothiazole ring.
  • An optionally substituted pyrimidine ring, an optionally substituted quinazoline ring, an optionally substituted chenopyrimidine ring, an optionally substituted benzimidazole ring, X represents an amino group, one CONH —, And Y is an optionally substituted benzene ring, naphthylene ring, pyridine ring, chroman ring, 1,3 —thiazole ring , Z is one CH CH—, _ 0 CH 2 —, 0 C (CH 3 ) 2 —, NHCO (CH 2 ) 2 —, one (CH 2) n-(n is an integer of 0 to 3) R 3 represents a hydroxy group or a halogen atom], and a compound represented by the general formula (6) is condensed. '
  • R 1 represents a lower alkyl group having 1 to 4 carbon atoms
  • R 2 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms.
  • R 3 in the formula (5) is a halogen atom
  • the reaction is carried out by using methylene chloride, 1,4-dioxane or the like as a solvent in the presence of an organic base such as triethylamine or pyridine. C to room temperature.
  • R 3 in the formula (5) is a hydroxy group
  • the compound can be produced by a mixed acid anhydride method or an active ester method used in a general peptide bond formation reaction, and preferably a condensing agent is used. The method used is appropriate.
  • Reactions include dihexyl carbyl imide (DCC), diisopropyl carbodiimide (DIPC), diphenylphosphonyl azide (DPPA), getyl phosphonyl cyanide (DEPC), and 1-ethyl.
  • DCC dihexyl carbyl imide
  • DIPC diisopropyl carbodiimide
  • DPPA diphenylphosphonyl azide
  • DEPC getyl phosphonyl cyanide
  • 1-ethyl 1-ethyl.
  • a condensing agent such as 1-carposimid (WSC)
  • WSC 1-carposimid
  • DMAP 4-dimethylaminoviridine
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • the reaction can be carried out at a reaction temperature of 0 ° C. to room temperature.
  • R 2 is a lower alkoxycarbonyl group having 1 to 4 carbon atoms in the general formula (6), that is, a compound represented by the general formula (4)
  • R 4 represents a hydroxy group or a halogen atom
  • W represents the above-mentioned ⁇
  • the reaction is carried out by using methylene chloride, 1,4-dioxane or the like as a solvent in the presence of an organic base such as triethylamine or pyridine. It can be carried out at a temperature between ° C and room temperature.
  • R 4 in the formula (7) 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, preferably using a condensing agent. The method is suitable.
  • the reaction is DCC, DIPC ;, DPPA, DEPC, WS
  • DMAP is added as a catalyst in the presence of a condensing agent such as C, and THF, methylene chloride, DMSO, and DMF are used as reaction solvents, and the reaction temperature is 0. C to room temperature.
  • Examples 3 to 63 The compounds of Reference Example and the compound of Example 1 were reacted in the same manner as in Example 2 to synthesize the compounds shown in Table 2 (Examples 3 to 63).
  • Example 64 to 67 after reacting in the same manner as in Example 2, crystals precipitated when the organic layer extracted in the post-treatment stage was washed with diluted hydrochloric acid were collected by filtration.
  • ICAM-1 By stimulating human umbilical vein-derived vascular endothelial cells (HUVEC) with human IL-1 (IL-1), ICAM-1, VCAM-1, ELAM-1 And the like are induced. At 24 hours after stimulation, expression of ICAM-1 and VCAM-1 is mainly observed (J. Immunol. 144, 2558 (1990), ibid, 149, 698 (1992)) 0 IL-1
  • HUV EC human umbilical vein-derived vascular endothelial cells
  • the adhesion inhibitory effect of the test compound is mainly It can be evaluated whether it is due to inhibition of the binding of the adhesion molecule or suppression of the expression of the adhesion molecule.
  • Experimental example 1 Binding inhibition test of adhesion molecule
  • HUVEC suspended in M199 medium (culture) containing 20% fetal serum and 1 ng / ml vascular endothelial cell growth factor (ECGF) was transferred to a 96-well collagen plate (flat bottom). Seed 2 x 10 4 / ⁇ wells and 37. C, and cultured under 5% C 2 . After culturing for about 24 hours, HUV ECs were washed twice with M199 medium (for washing) containing no fetal serum and ECGF. Next, Hytointer and Leukin
  • the test compound was dissolved in dimethyl sulfoxide, and diluted 100-fold with M199 medium for culture, and added in 80/1 / well. Subsequently, the fluorescence-labeled U933 cell suspension was added at a concentration of 201 / well (final concentration of the test compound was 10 ⁇ M). 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 (-) 1001 to remove non-adherent cells. The cells were solubilized by adding 0.1% aqueous sodium dodecyl sulfate at 100 / l / well. The fluorescence intensity of each well was measured (Excitation 490 nm, Emission 530 nm), and the number of adhered U933 cells was determined from the calibration curve force. The adhesion inhibition rate was calculated according to the following equation.
  • the HUV EC were suspended in M 1 9 9 culturing medium, 9 6 seeded well collagen Coat plate (flat bottom) one by 2 x 1 0 4 / Ueru were cultured at 3 7 ° C, 5% C 0 2 below . After culturing for about 24 hours, wash M 199 medium The HUVEC was washed twice. The test compound was dissolved in dimethylsulfoxide, and a 100-fold dilution in M199 medium for culture was added at 80 81 / ⁇ , and the mixture was cultured for 1 hour. Next, a culture medium containing IL-11 was added at a rate of 20 1 / well, and cultured for 24 hours (final concentration of IL-11 was 10 U / m 1, Final concentration 10 ⁇ M).
  • the culture M199 medium was added at 80 ⁇ 1 / ⁇ and the fluorescently labeled U937 cell suspension was added at 201 1 / ⁇ . After centrifugation at 100 rpm, room temperature and 1 minute per minute, 37. C, and cultured 5% C_ ⁇ 3 0 minutes at 2 under.
  • Each well was washed twice with PBS (—) 100 ⁇ 1 to remove non-adherent cells. The cells were solubilized by the addition of 0.1% sodium dodecyl sulfate aqueous solution at 100 / l / well.
  • the fluorescence intensity of each well was measured (Excitation 490 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.
  • Table 4 shows the results. Table 3.Adhesion molecule binding inhibition test
  • the antigen solution use the supernatant obtained by suspending Mycobacterium butyricum at a concentration of 200 ⁇ g / ml in physiological saline and centrifuging at 3,000 rpm for 10 minutes at 4 ° C. did.
  • the skin thickness at the injection site was measured, and the amount of increase in skin thickness was calculated.
  • the test compound was suspended in a 3% aqueous solution of gum arabic and orally administered once daily, 0.5 ml per 100 g of rat weight once a day from the day of injection of the killed Mycobacterium petilicum. .
  • the control group received only a 3% gum arabic aqueous solution.
  • the results were expressed as a percentage of the increase in skin thickness of the test compound relative to the increase in skin thickness of the control group. Table 5 shows the results.
  • the compound of the present invention represented by the general formula (1) does not exhibit the inhibitory effect on the expression of cell adhesion molecules such as ICAM-1 and VCAM-1 and inhibits the cell-mediated binding therebetween. However, its efficacy was also confirmed in a delayed type hypersensitivity reaction test.

Abstract

L'invention porte sur des dérivés de diesters maloniques de formule générale (1) et leurs sels pharmacocompatibles capables d'empêcher l'ICAM-1 et le VCAM-1, qui jouent des rôles majeurs parmi les molécules d'adhésion cellulaire, de se fixer aux leucocytes. Elle porte en outre sur des inhibiteurs de l'adhésion cellulaire comprenant comme principe actif au moins l'un des susdits composés et s'avérant être d'excellents immunosuppresseurs, agents anti-inflammatoires, agents anti-allergiques, et inhibiteurs des métastases tumorales.
PCT/JP1999/004914 1998-09-11 1999-09-10 Derives de diesters maloniques et leur procede d'obtention WO2000015604A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56486/99A AU5648699A (en) 1998-09-11 1999-09-10 Malonic diester derivatives and process for producing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP25884098 1998-09-11
JP10/258840 1998-09-11

Publications (1)

Publication Number Publication Date
WO2000015604A1 true WO2000015604A1 (fr) 2000-03-23

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021598A1 (fr) * 1999-09-23 2001-03-29 Astrazeneca Ab Composes therapeutiques de quinazoline
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
JP2003522751A (ja) * 2000-02-09 2003-07-29 エフ．ホフマン−ラ ロシュ アーゲー デヒドロアミノ酸
US6787542B2 (en) 2000-06-29 2004-09-07 Icos Corporation Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6878700B1 (en) 1998-12-29 2005-04-12 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
USRE39197E1 (en) 1998-12-29 2006-07-18 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
JP2008517897A (ja) * 2004-10-22 2008-05-29 ビオプロジェ 新規なジカルボン酸誘導体
CN102702135A (zh) * 2012-06-15 2012-10-03 中国农业大学 一种含苯并噻唑结构的苯甲酰基硫脲类化合物及其制备方法和应用
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2014174745A1 (fr) * 2013-04-26 2014-10-30 国立大学法人京都大学 INHIBITEUR D'Eg5

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4836199A (fr) * 1971-09-15 1973-05-28

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4836199A (fr) * 1971-09-15 1973-05-28

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANFILIPPO P.J. ET AL.: "Novel Thiazole Based Heterocycles as Inhibitors of LFA-1/ICAM-1 Mediated Cell Adhesion", J. MED. CHEM.,, vol. 38, no. 7, 1995, pages 1057 - 1059, XP002925822 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878700B1 (en) 1998-12-29 2005-04-12 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
USRE39197E1 (en) 1998-12-29 2006-07-18 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
US6399603B1 (en) 1999-09-23 2002-06-04 Astrazeneca Ab Therapeutic heterocycles
WO2001021598A1 (fr) * 1999-09-23 2001-03-29 Astrazeneca Ab Composes therapeutiques de quinazoline
JP2003522751A (ja) * 2000-02-09 2003-07-29 エフ．ホフマン−ラ ロシュ アーゲー デヒドロアミノ酸
US6787542B2 (en) 2000-06-29 2004-09-07 Icos Corporation Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
US6521619B2 (en) 2000-06-29 2003-02-18 Icos Corporation Aryl phenylcyclopropyl sulfide derivatives and their use as cell adhesion inhibiting anti-inflammatory and immune suppressive agents
US7129247B2 (en) 2000-06-29 2006-10-31 Abbott Laboratories Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
JP2008517897A (ja) * 2004-10-22 2008-05-29 ビオプロジェ 新規なジカルボン酸誘導体
CN102702135A (zh) * 2012-06-15 2012-10-03 中国农业大学 一种含苯并噻唑结构的苯甲酰基硫脲类化合物及其制备方法和应用
CN102702135B (zh) * 2012-06-15 2014-05-28 中国农业大学 一种含苯并噻唑结构的苯甲酰基硫脲类化合物及其制备方法和应用
WO2014174745A1 (fr) * 2013-04-26 2014-10-30 国立大学法人京都大学 INHIBITEUR D'Eg5

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