Inhibitor for immune cell migration

An immune cell and inhibitor technology, which can be used in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., and can solve problems such as skin side effects

Active Publication Date: 2019-05-07
VIVA VISION SHANGHAI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Internationally, there are only a few options for dry eye patients (cyclosporine, Lifitegrast, etc.), but there is no topical drug approved for the treatmen

Method used

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  • Inhibitor for immune cell migration
  • Inhibitor for immune cell migration
  • Inhibitor for immune cell migration

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117]

[0118] (S)-2-(8-Chloro-2-(benzofuran-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]quinazoline-7-carboxamide base)-3-(3-(methylsulfonyl)phenyl)propionic acid

[0119] The specific reaction equation is as follows:

[0120]

[0121] Step A: Dimethyl 2-amino-5-chloroterephthalate (Compound 1-1)

[0122]To a vigorously stirred solution of dimethyl 2-aminoterephthalate (10 g, 48 mmol) in isopropanol (1.5 L) was added NCS (7.34 g, 55 mmol) over a period of 5 minutes at room temperature. After the addition was complete, the reaction mixture was heated to reflux for 48 hours. After cooling to room temperature, the solvent was concentrated and the residue was purified by flash chromatography eluting with 5% ethyl acetate in petroleum jelly to give the desired product (6.4 g, 55%) as a pale yellow crystalline solid. LCMS ESI (+) m / z: 244 (M+1). 1 H NMR (600MHz, CDCl3) δ7.92(s,1H),7.10(s,1H),5.71(brs,2H),3.92(s,3H),3.90(s,3H).

[0123] Step B: Dimethyl 2-amino-3-bromo-5...

Embodiment 2

[0150]

[0151] (S)-2-(8-Chloro-2-(1H-indole-6-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij]quinazoline-7- Formamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid

[0152] The title compound was prepared according to the procedure of Example 1, Steps M and N, using 1H-indole-6-carboxylic acid instead of compound benzofuran-6-carboxylic acid to give a white solid. LCMS ESI (+) m / z: 605 (M+1). 1 H NMR(600MHz,DMSO)δ12.89(brs,1H),11.39(s,1H),8.78(d,J=8.2Hz,1H),7.89(s,1H),7.79(d,J=7.8Hz ,1H),7.70(d,J=7.5Hz,1H),7.63(d,J=8.1Hz,1H),7.59(t,J=7.7Hz,1H),7.52(s,1H),7.53–7.46 (m,1H),7.46(s,1H),7.04(d,J=8.2Hz,1H),7.03–6.93(m,1H),6.52(s,1H),6.13(s,1H),5.99– 5.78(m,2H),5.14–4.95(m,2H),4.85–4.69(m,1H),3.30–3.26(m,1H),3.12(s,3H),3.10–3.03(m,1H).

Embodiment 3

[0154]

[0155] (S)-2-(8-chloro-2-(pyrazol[1,5-a]pyridine-2-carbonyl)-2,3-dihydro-1H-pyrrole[3,2,1-ij] Quinazoline-7-carboxamido)-3-(3-(methylsulfonyl)phenyl)propionic acid

[0156] The title compound was prepared according to the method of Steps M and N of Example 1, using pyrazol[1,5-a]pyridine-2-carboxylic acid instead of compound benzofuran-6-carboxylic acid to obtain a white solid. LCMS ESI (+) m / z: 606 (M+1). 1 H NMR (600MHz, DMSO) δ12.89(brs, 1H), 8.76(d, J=8.0Hz, 1H), 8.75(d, J=6.5Hz, 1H), 7.88(s, 1H), 7.79(d ,J=8.3Hz,1H),7.77(d,J=10.1Hz,1H),7.69(d,J=7.6Hz,1H),7.58(t,J=7.7Hz,1H),7.63–7.40(m ,1H),7.33(t,J=7.7Hz,1H),7.10–7.01(m,1H),7.15–6.92(m,1H),6.90(s,1H),6.30–6.18(m,1H), 6.17–6.06(m,1H),,6.06–5.93(m,1H),5.44–5.31(m,1H),5.23–5.08(m,1H),4.82–4.74(m,1H),3.32(dd, J=14.3,4.3Hz,1H),3.11(s,3H),3.05(dd,J=13.5,11.4Hz,1H).

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Abstract

The invention discloses an inhibitor for immune cell migration. The inhibitor has the characteristic of a structure as shown in a following formula. The inhibitor has balanced hydrophilicity and lipotropy, can be developed into eyedrops easily and external applied plaster, has a high inhibitory effect on immune cell migration, and can alleviate most dry eye diseases and eczematous dermatitis and psoriasis.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to an immune cell migration inhibitor. Background technique [0002] Many local diseases are related to inflammation, such as irritant contact dermatitis, eczematous dermatitis, seborrheic dermatitis, scar formation, atopic dermatitis, psoriasis, etc. in skin care diseases; Immune disorders such as intraocular inflammation, periocular inflammation, ocular surface inflammation, keratoconjunctivitis, keratoconjunctivitis sicca (KCS, also known as dry eye), KCS in patients with Sjogren syndrome, allergic conjunctivitis, uvea Inflammation of the eye, inflammation of the eye caused by wearing a contact lens, inflammation of the cornea caused by wearing a contact lens, inflammation of the tissues around the eye caused by wearing a contact lens, inflammation of the eye after surgery, inflammation of the eye, retinitis, edema, retinopathy, inflammation of the cornea , Graves' disease (Basedow's dis...

Claims

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Application Information

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IPC IPC(8): C07D487/06C07D519/00C07D209/08C07D405/12A61K31/519A61K31/404A61K31/551A61P29/00A61P27/04A61P17/08A61P17/00A61P27/02
CPCA61K31/404A61K31/519A61K31/551A61P17/00A61P17/08A61P27/02A61P27/04A61P29/00C07D209/08C07D405/12C07D487/04C07D487/06C07D519/00Y02P20/55
Inventor 沈旺丁悦汪江峰姜浩陈福利吴兴龙李寸飞杨立国胡彪
Owner VIVA VISION SHANGHAI LTD
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