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CXCR4-antagonistic drugs composed of nitrogen-containing compound

A technology of nitrogen compounds and compounds, applied in the direction of active ingredients of heterocyclic compounds, medical preparations containing active ingredients, antineoplastic drugs, etc., can solve problems such as insufficient

Inactive Publication Date: 2005-06-22
KUREHA KAGAKU KOGYO KK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

AMD3100 and the like (WO00 / 02870) have been known so far among low-molecular-weight compounds, but they are not enough

Method used

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  • CXCR4-antagonistic drugs composed of nitrogen-containing compound
  • CXCR4-antagonistic drugs composed of nitrogen-containing compound
  • CXCR4-antagonistic drugs composed of nitrogen-containing compound

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example 1

[0327] Synthesis Example 1: (S)-2-(4-(N-2-pyridylaminomethyl)benzamido)-5-((imidazol-2-ylmethyl)amino)pentanoic acid 1-naphthalene Preparation of Methylamide [Compound No. 1]

Synthetic example 1-1

[0328] Synthesis Example 1-1: Preparation of methyl 4-(N-Boc-N-2-pyridylaminomethyl)benzoate (compound VI-1)

[0329] Dissolve 1.08 g of commercially available 2-picolylamine in 22.5 ml of DMF, add 1.55 ml of triethylamine, and cool to 0°C. To this solution was added dropwise a solution of 2.52 ml of di-tert-butyl dicarbonate dissolved in 7.5 ml of DMF over 10 minutes. After raising the temperature to room temperature and stirring for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (30 g, chloroform) to obtain 1.71 g of a pale yellow liquid.

[0330] 1.199 g of them were dissolved in 6 ml of THF, and suspended with 46.1 mg of sodium hydride (60% paraffin mixture). After stirring at room temperature for 15 minutes, 241 mg of commercially available methyl 4-bromomethylbenzoate was added, followed by stirring at room temperature for 2 days. After the reaction, adjust the pH to 5-7 with 1 mol / l hydrochl...

Synthetic example 1-2

[0333] Synthesis Example 1-2: Synthesis of 4-(N-Boc-N-2-pyridylaminomethyl)benzoic acid (Compound VII-1)

[0334] To 200.6 mg of the compound obtained in Synthesis Example 1-1 were added 2 ml of methanol, 2 ml of THF, and 2 ml of 1 mol / l sodium hydroxide aqueous solution, and stirred at room temperature for 1 day. After the reaction was completed, the solvent was distilled off, and 5 ml of water was added. 1 mol / l hydrochloric acid aqueous solution was added dropwise thereto to make pH=3. The precipitated crystals were filtered and dried to obtain 123.2 mg of the title compound as colorless crystals.

[0335] MS (Fab, pos.): m / z = 343 [M+1] +

[0336] 1 H-NMR (500MHz, DMSO-d 6): δ=1.35 and 1.54 (9H, brs), 4.41 (1H, brs), 4.51 (2H, s), 4.58 (1H, brs), 7.2-7.4 (4H, m), 7.77 (1H, td, J =7.6, 1.8Hz), 8.52(1H, dd, J=4.9, 1.7Hz), 12.9(1H, s).

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Abstract

Provides novel nitrogen-containing compounds with CXCR4 antagonistic activity and therapeutic drugs for diseases such as rheumatism and cancer metastasis based on CXCR4 antagonistic activity. A nitrogen-containing compound represented by the above general formula and a CXCR4 antagonist containing these compounds as an active ingredient. Representative compound has the compound defined as follows in general formula (I): A1, A2 represent guanidino group or the group shown in formula (ia) above, A3 is the monocyclic or polycyclic ring that contains 1 or 2 heteroatoms A heteroaryl ring of the form, B1 is a single bond or an alkylene group, R1 is hydrogen or an alkyl group, W is an alkylene group with 2-3 carbon atoms, a cyclic alkylene group with 5-10 carbon atoms, a carbon atom An aromatic ring with a number of 6-10, a heteroaromatic ring with a carbon number of 5-10, y represents -C(=O)-, x represents -C(=O)-NH-, n1 represents an integer of 1-2, n2 represents an integer of 2-3, and D represents various substituents.

Description

technical field [0001] The invention relates to a medicine for related diseases such as rheumatism or cancer metastases. The medicine uses nitrogen-containing compounds or pharmacologically acceptable salts thereof as active ingredients, especially based on antagonism to chemokine receptor CXCR4. Background technique [0002] Among the cytokines, the factors that show chemotaxis to leukocytes are called chemokines, which are secreted proteins. According to the N-terminal cysteine ​​(Cys) sequence, they are divided into CXC-chemokines and CC-chemokines. , C-chemokine, CX3C-chemokine, the number is said to be about 30 or so. There are several subtypes of these chemokine receptors, among which CXCR4 is known to be associated with various diseases with the CXC-chemokine SDF-1 as a ligand. For example, rheumatism (WO 00 / 06086, The Journal of Immunology, 165, 659 0 (2000)), cancer metastasis (Nature, 410, 50 (2001)) and the like are reported. As therapeutic drugs for these disea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/40A61K31/4164A61K31/4178A61K31/4402A61K31/4439A61K31/444A61K31/4709A61K31/506A61P29/00A61P35/04A61P43/00C07D207/14C07D213/38C07D215/40C07D233/54C07D233/64C07D233/88C07D235/10C07D235/14C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14C07D409/12C07D409/14
CPCA61K31/40A61K31/4164A61K31/4178A61K31/4402A61K31/4439A61K31/444A61K31/4709A61K31/506C07D207/14C07D213/38C07D215/40C07D233/64C07D235/14C07D401/12C07D401/14C07D403/12C07D405/12C07D405/14C07D409/12C07D409/14A61P29/00A61P35/04A61P43/00
Inventor 谷中干郎山崎彻坂内坚二广濑国孝
Owner KUREHA KAGAKU KOGYO KK
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