CN105418576B - A kind of pseudoephedrine analog derivative and its antiallergy application - Google Patents

A kind of pseudoephedrine analog derivative and its antiallergy application Download PDF

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CN105418576B
CN105418576B CN201510782844.0A CN201510782844A CN105418576B CN 105418576 B CN105418576 B CN 105418576B CN 201510782844 A CN201510782844 A CN 201510782844A CN 105418576 B CN105418576 B CN 105418576B
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isochroman
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methylamino
pseudoephedrine
propyl
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CN105418576A (en
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刘国华
张景红
曹化云
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Tianchang Yifan Pharmaceutical Co ltd
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Beijing New Line Medical Science And Technology Development Co Ltd
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a kind of pseudoephedrine analog derivative, belong to organic synthesis field.A kind of pseudoephedrine analog derivative as shown in general structure I of the present invention, or its pharmaceutically acceptable salt, ester or prodrug, its preparation method and application of the composition in allergic drug is treated and prevented containing one or more such compounds.

Description

Pseudoephedrine derivative and anti-allergic application thereof
Technical Field
The invention relates to an organic matter, in particular to a pseudoephedrine derivative and a preparation method and application thereof.
Background
Allergy is a series of hypersensitivity phenomena caused by contacting part of allergen factors which have little influence on ordinary people in the environment of immune system, and comprises allergic rhinitis, food allergy, urticaria, atopic dermatitis, asthma, systemic anaphylactic reaction and the like; symptoms may be redness, rashes causing itching, runny nose, dyspnea and swelling.
Allergy is a fairly common symptom. In developing countries, about 20% of people are afflicted with allergic rhinitis, about 6% of people have at least one experience of food allergy, and nearly 20% of people experience at least one atopic dermatitis throughout their life. Depending on the country, 1% to 18% of people have symptoms of asthma, and 0.05% to 2% of people experience systemic allergies. The proportion of many allergic diseases tends to rise, and therefore, it is of great importance to develop novel and highly effective antiallergic drugs.
Disclosure of Invention
The invention aims to: aiming at the existing problems, the pseudoephedrine derivative, the preparation method thereof and the application of the pseudoephedrine derivative in preparing antiallergic drugs are provided.
The technical scheme adopted by the invention is as follows:
the invention relates to a pseudoephedrine derivative, or pharmaceutically acceptable salt, ester or prodrug thereof, and the structural general formula I is as follows:
wherein,
ar is a six-membered aromatic heterocycle with various structures; x1，X2，X3，X4Each independently is O, S, N, NH or CH;
heterocyclic ring Ar is optionally substituted by (C)1-4) Alkyl, (C)3-7) Cycloalkyl group, (C)3-7) Cycloalkyl- (C)1-3) Alkyl substituted, wherein the alkyl, cycloalkyl or cycloalkylalkyl may be monosubstituted with-OH.
R1，R2Each independently of the other is H, (C)1-4) Alkyl, halogen, CF3，NO2、（C1-8) Alkoxy radical
The pseudoephedrine derivative of the invention is the following compounds:
the pseudoephedrine derivative is one of the following compounds:
1, 6-bis ((S) -2- (methylamino) propyl) isochroman-3-one,
1, 6-bis ((S) -2- (methylamino) butyl) isochroman-3-one,
1, 6-bis ((S) -2- (ethylamino) butyl) isochroman-3-one,
1, 6-bis ((S) -2- (ethylamino) propyl) isochroman-3-one,
1- ((S) -2- (tert-butylamino) propyl) -6- ((R) -2- (ethylamino) -3, 3-dimethylbutyl) isochroman-3-one,
1, 6-bis ((R) -3-methyl-2- (methylamino) butyl) isochroman-3-one,
1, 6-bis ((R) -3,3, 3-trifluoro-2- (methylamino) propyl) isochroman-3-one,
1, 6-bis ((S) -2- (methylamino) -2-nitroethyl) isochroman-3-one,
1, 6-bis ((S) -2-bromo-2- (ethylamino) ethyl) isochroman-3-one,
1, 6-bis ((S) -2-chloro-2- (methylamino) ethyl) isochroman-3-one.
The invention relates to a preparation method of pseudoephedrine derivatives, which comprises the following steps:
reagents and conditions: heating and refluxing sodium ethoxide and DMF;
wherein Ar, X1，X2，X3，X4，R1And R2The definition of (A) is described in general formula I.
The invention relates to a pseudoephedrine derivative, and a preparation method of a compound with a general formula Ia comprises the following steps:
the reagent and the conditions are (Ia-i) periodic acid, chromium trioxide, glucose isomerase, acetonitrile and room temperature, (Ia-ii) sodium hydride, ethanol and α -amylase and room temperature, (Ia-iii) sodium borohydride and DMF, and the mixture is heated and refluxed, (Ia-iv) sodium ethoxide and DMF;
wherein R is1And R2The definition of (A) is described in general formula I.
An antiallergic composition comprising a compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
The invention relates to application of pseudoephedrine derivatives in preparing antiallergic drugs.
Experiments show that the compound has the biological activity of antianaphylaxis and can be applied to antianaphylaxis drugs. The compounds of the present invention may be used either as such or in the form of their pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts of the compounds of formula I include conventional salts with pharmaceutically acceptable inorganic or organic acids or bases. Examples of suitable acid addition salts include salts formed with hydrochloric, sulfuric, phosphoric, nitric, hydrobromic, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic, hydroxybenzoic, hydroiodic, malic acid, and the like. Suitable ions of base addition salts include salts with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine, and the like. Reference herein to the compounds of the invention includes reference to the compounds of formula I and pharmaceutically acceptable salts or solvates thereof.
The compound of the invention with the general formula I can be combined with conventional drug carriers or excipients to form a drug composition. The pharmaceutical composition can be administered orally or via the parenteral route. The pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, etc. according to conventional methods in the art, and can be administered orally or via parenteral routes.
The novel structural modification and intensive research on the compound of the present invention also contribute to the development of novel antiallergic drugs.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
1, 6-bis ((S) -2- (methylamino) propyl) isochroman-3-one (Ia-1, R)1=R2=CH3）
Weighing 1.71g of 2- (5-chloro-2-methylphenyl) ethan-1-ol, placing the 2- (5-chloro-2-methylphenyl) ethan-1-ol in a 150mL three-necked bottle, measuring 20mL of acetonitrile, stirring and dissolving at room temperature, adding 0.4g of glucose isomerase and 0.2g of chromium trioxide, continuing stirring at room temperature for 10min, weighing 2.28g of periodic acid, dissolving in 10mL of acetonitrile, gradually and slowly dropwise adding the mixture to a reaction system, and continuing to react at room temperature for 36 h. Stopping the reaction after the Ia-1 reaction is completed, concentrating the solvent under reduced pressure, and performing column chromatography by using acetone as a developing agent: diethyl ether =1:5, yielding Ia-2, 1.32g (66.3% yield).
Weighing 1.99g of 2- (5-chloro-2-formylphenyl) acetic acid (Ia-2) and placing the 2- (5-chloro-2-formylphenyl) acetic acid in a 150mL round-bottom flask, measuring 20mL of ethanol, stirring and dissolving the mixture at room temperature, adding 1.83g of N-dimethylpropan-2-amine, adding 0.5g of α -amylase, continuing stirring the mixture at room temperature for 10min, weighing 0.48g of sodium hydride, stirring the mixture at room temperature for 18h, heating and refluxing the mixture for 10h after the Ia-2 reaction is completed, stopping the reaction, rapidly cooling the mixture to 0 ℃ under an ice bath condition to generate white precipitate, filtering the white precipitate, washing the white precipitate with ethanol and drying the white precipitate to obtain Ia-3 and 1.48g (the yield is 48.
Weighing 3.07g of 2- (2- ((S) -3- (methylamino) butyryl) -5- ((S) -2- (methylamino) propyl) phenyl) acetic acid (Ia-3), placing the mixture in a 150mL round-bottom flask, measuring 15mL of DMF, stirring and dissolving the mixture at room temperature, weighing 0.57g of sodium borohydride, dissolving the sodium borohydride in 5mL of DMF, slowly dropwise adding the mixture into the round-bottom flask under the ice bath condition, stirring the mixture for 30min under the ice bath condition, naturally returning the mixture to the room temperature, and heating and refluxing the mixture for 5 h. Stopping the reaction after the Ia-3 reaction is completed, and performing column chromatography by using a developing solvent of methanol: dichloromethane =1:4, yielding Ia-4, 0.64g (20.7% yield).
Weighing 3.08g of 2- (2- ((3S) -1-hydroxy-3- (methylamino) butyl) -5- ((S) -2- (methylamino) propyl) phenyl) acetic acid (Ia-4), placing the mixture in a 150mL round-bottom flask, measuring 15mL of DMF, stirring and dissolving the mixture at room temperature, weighing 1.02g of sodium ethoxide, dissolving the sodium ethoxide in 5mL of DMF, slowly dropwise adding the mixture into the round-bottom flask under the ice bath condition, stirring the mixture for 30min under the ice bath, naturally returning the mixture to the room temperature, and heating and refluxing the mixture for 18 h. Stopping the reaction after the Ia-4 reaction is completed, and performing column chromatography by using ethanol as a developing agent: ethyl acetate =1:10, yielding Ia-5, 0.68g (yield 23.4%). White solid, mp: 215-221 ℃, MSm/z: 291.31 (M + H), 313.32 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.42~7.08（m，3H），5.85（d，1H），3.52~3.32（m，4H），3.26（m，2H），3.11（m，1H），2.79~2.54（m，4H），1.92（s，2H），1.11~1.06（m，2H）；13C-NMR（DMSO-d6，ppm）δ：168.6,，137.5，136.4，132.8，130.5，128.6,136.7，66.3,59.2，52.0,44.7，42.4，36.9,33.7,21.2,20.8.
example 2
1, 6-bis ((S) -2- (methylamino) butyl) isochroman-3-one (R)1= CH3，R2=CH2CH3）
The procedure is as in example 1, except that N-methylbutan-2-amine is used. White solid, mp: 216-220 ℃, MSm/z: 341.46 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.42~7.09（m，3H），6.85（m，1H），3.52~3.49（d，2H），3.12~3.06（m，4H），2.93~2.54（m，4H），1.92~1.48（m，2H），0.87（t，2H）；13C-NMR（DMSO-d6，ppm）δ：167.4，138.1，137.3，135.4，132.5，130.9，125.3，68.9，67.9，66.4，58.4，42.2，39.9，36.9，34.0，27.8，10.7。
example 3
1, 6-bis ((S) -2- (ethylamino) butyl) isochroman-3-one (R)1=R2=CH2CH3）
The procedure is as in example 1, except that N-diethylbutyl-2-amine is used. White solid, mp: 201-215 ℃, MSm/z: 347.09 (M + H), 369.26 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.37~7.18(m，3H)，5.72（m，1H），3.52~3.38（m，4H），2.91(d，1H)，2.79(d，1H)，2.59~2.54(m，3H)，2.13(m，1H)，1.97~1.53(m，4H) ，1.11(s，2H)，0.84(t，2H)；13C-NMR（DMSO-d6，ppm）δ：169.4，138.1，136.7，135.4，130.5，128.7，126.9，66.6，62.4，55.9，42.2，40.1，36.9，28.6，27.4，15.9，10.3。
example 4
1, 6-bis ((S) -2- (ethylamino) propyl) isochroman-3-one (R)1= CH2CH3，R2=CH3）
The procedure is as in example 1, except that N-diethylpropyl-2-amine is used. White solid, mp: 226-241 ℃, MSm/z: 319.39 (M + H);1H-NMR（DMSO-d6，ppm）δ：7.61~7.20(m，3H)，6.41（m，1H），3.56~3.11（m，5H），2.79~2.54（m，5H），1.92~1.11（m，6H）；13C-NMR（DMSO-d6，ppm）δ：169.5，167.9，138.2，134.6，131.2，127.6，126.9，67.5，56.7，49.2，45.0，43.5，42.6，36.1，22.9，15.4。
example 5
1- ((S) -2- (tert-butylamino) propyl) -6- ((R) -2- (ethylamino) -3, 3-dimethylbutyl) isochroman-3-one (R)1= CH3，R2= isopropyl)
The procedure is as in example 1, except that N-isopropyl-2-methylpropan-2-amine is used. White solid, mp: 267-281 ℃, MSm/z: 411.07 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.52~7.09(m，3H)，5.64（d，1H），3.47~3.21（m，2H），2.71（m，2H），2.64（s，1H），2.57~2.31（m，2H），1.92（m，2H），1.22~1.06（m，5H），0.89（t，3H）；13C-NMR（DMSO-d6，ppm）δ：172.5，150.9，148.2，141.6，132.7，128.9，127.1，75.9，64.1，60.2，43.7，42.5，39.7，37.4，36.2，30.5，27.3，22.4，16.1。
example 6
1, 6-bis ((R) -3-methyl-2- (methylamino) butyl) isochroman-3-one (R)1= isopropyl, R2=CH3）
The procedure is as in example 1, except that N-3-dimethylbut-2-amine is used. White solid, mp: 261-273 ℃, MSm/z: 347.09 (M + H), 369.26 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.45~7.16(m，3H)，5.82（m，1H），3.62~3.40（m，4H），2.93(d，1H)，2.71(d，1H)，2.63~2.52(m，3H)，2.21(m，1H)，1.97~1.54(m，4H) ，1.30(s，2H)，0.87(t，2H)；13C-NMR（DMSO-d6，ppm）δ：168.4，138.7，136.4，135.9，131.5，129.6，127.8，67.1，64.9，57.9，43.2，41.6，37.9，29.3，28.0，16.9，10.3。
example 7
1, 6-bis ((R) -3,3, 3-trifluoro-2- (methylamino) propyl) isochroman-3-one (R)1= trifluoromethyl, R2=CH3）
The procedure is as in example 1, except that 1,1, 1-trifluoro-N-methylpropan-2-amine is used. White solid, mp: 317-326 ℃, MSm/z: 421.42 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.73~7.64(m，3H)，5.84（m，1H），5.11（d，1H），4.61（m，1H），3.59~3.34（m，6H），2.74~2.28（m，4H）；13C-NMR（DMSO-d6，ppm）δ：172.6，147.3，137.9，134.2，132.6，129.1，128.3，127.5，124.8，72.6，68.6，65.8，37.8，33.7，24.3，22.0。
example 8
1, 6-bis ((S) -2- (methylamino) -2-nitroethyl) isochroman-3-one (R)1=NO2，R2=CH3）
The procedure is as in example 1, except that N-methyl-1-ethylnitro-1-amine is used. White solid, mp: 284-295 ℃, MSm/z: 353.16 (M + H), 374.26 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.36~7.09(m，3H)，5.46~5.32（t，2H），4.84（d，1H），3.52~3.38（m，3H），3.17~3.10（m，7H），2.56（d，2H）；13C-NMR（DMSO-d6，ppm）δ：175.4，160.4，139.2，137.6，132.6，128.1，126.7，108.9，100.4，63.4，38.5，36.9，35.1，31.6。
example 9
1,6-Bis ((S) -2-bromo-2- (ethylamino) ethyl) isochroman-3-one (R)1=Br，R2=CH2CH3）
The procedure is as in example 1, except that 1-bromo-N-diethyl-1-amine is used. White solid, mp: 326-331 ℃, MSm/z: 449.01 (M + H), 471.38 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.48~7.26(m，3H)，6.71（d，1H），5.31（m，1H），4.16（s，1H），3.47~3.00（m，6H），2.59~2.44（t，3H），1.54（s，2H）；13C-NMR（DMSO-d6，ppm）δ：173.8，137.6，136.9，134.1，130.8，129.4，128.6，67.1，66.4，58.4，48.3，46.0，42.9，36.7，14.8。
example 10
1, 6-bis ((S) -2-chloro-2- (methylamino) ethyl) isochroman-3-one (R)1=Cl，R2=CH3）
The procedure is as in example 1, except that 1-chloro-N-dimethyl-1-amine is used. White solid, mp: 313-328 ℃, MSm/z: 354.18 (M + Na);1H-NMR（DMSO-d6，ppm）δ：7.48~7.19(m，3H)，5.83（m，1H），4.99~4.62（t，2H），3.57~3.17（m，4H），3.24（s，2H），3.04（s，1H），2.79（m，1H），2.22（d，2H）；13C-NMR（DMSO-d6，ppm）δ：170.6，137.1，133.7，132.6，130.8，128.6，126.3，81.1，72.6，64.8，45.8，37.5，31.1。
example 11
The experimental contents are as follows: test for determining antiallergic Activity
Testing materials:
1. experimental mice: the weight of Kunming mouse is 18-22 g, the male and female are half and half, and the weight is provided by the experimental animal center of Sichuan university, and the animal grade is as follows: one stage.
The test method comprises the following steps:
effect of Compounds on Histamine-induced capillary Permeability in mice
The experimental method comprises the following steps: 10 mice in each group are orally administered with 8mg/kg/10ml of test drug for a single time, loratadine is orally administered to a positive drug group, 0.2% of CMC-Na with the same volume is administered to a blank control group, 1h after administration, 0.1% of histamine phosphate is immediately injected into the tail vein of the mice after 10ml/kg of Evans blue with 1% is injected, a small skin dune is formed, the mice are killed after 30min by removing cervical vertebrae, the skin is blue-stained on the abdomen, cut into pieces with surgical scissors and placed in a test tube, soaked with 2ml (7: 3) of acetone-physiological saline for 24h, centrifuged at 2000r/min for 10min, the supernatant is taken to be subjected to color comparison at 610nm, the OD value is recorded, and the concentration is calculated through the standard curve of Evans blue. The results of the biological evaluation are shown in Table 1
TABLE 1
Effect of Compounds on the Effect of xylene on the rate of swelling of the ear Mass in mice
132 qualified mice are taken and randomly divided into 22 groups according to the weight, wherein each group comprises 6 mice, and the number of the mice is half of that of the mice. Taking the compound 1-10 positive control ibuprofen group and the model control group. The dose of the compound is 4mg/kg, the dose of the ibuprofen group is 30mg/kg, and the model group is given 0.5% CMC-Na with equal volume. The administration volume was 0.4ml/20g, once daily for 5 consecutive days. 0.5 hour after the last administration, xylene (0.1 ml per mouse) was uniformly applied to the front and back sides of the right auricle. One hour later, animals were sacrificed, and both ears were cut along the base line of auricle (left ear as control), and both ears were punched at the same site with a punch of 9mm diameter and weighed (g), and the swelling degree and swelling inhibition (%) were determined. The results of the biological evaluation are shown in Table 2
Swelling degree ═ weight of right ear (g) -weight of left ear (g)
Swelling inhibition ratio (%) (mean value of model swelling degree-mean value of administered swelling degree)/swelling ratio of model group × 100%
TABLE 2
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (4)

1. A pseudoephedrine derivative is characterized in that the pseudoephedrine derivative is a compound represented by a structural general formula Ia, and the structural general formula Ia is as follows:
wherein R is1，R2Each independently of the other is H, (C)1-4) Alkyl, halogen, CF3，NO2Or (C)1-8) One of the alkoxy groups.
2. The pseudoephedrine derivative according to claim 1, which is one of the following compounds:
1, 6-bis ((S) -2- (methylamino) propyl) isochroman-3-one,
1, 6-bis ((S) -2- (methylamino) butyl) isochroman-3-one,
1, 6-bis ((S) -2- (ethylamino) butyl) isochroman-3-one,
1, 6-bis ((S) -2- (ethylamino) propyl) isochroman-3-one,
1- ((S) -2- (tert-butylamino) propyl) -6- ((R) -2- (ethylamino) -3, 3-dimethylbutyl) isochroman-3-one,
1, 6-bis ((R) -3-methyl-2- (methylamino) butyl) isochroman-3-one,
1, 6-bis ((R) -3,3, 3-trifluoro-2- (methylamino) propyl) isochroman-3-one,
1, 6-bis ((S) -2- (methylamino) -2-nitroethyl) isochroman-3-one,
1, 6-bis ((S) -2-bromo-2- (ethylamino) ethyl) isochroman-3-one,
1, 6-bis ((S) -2-chloro-2- (methylamino) ethyl) isochroman-3-one.
3. An antiallergic composition which comprises the pseudoephedrine derivative as set forth in claim 1 or 2 and one or more pharmaceutically acceptable carriers.
4. Use of pseudoephedrine derivatives as claimed in claim 1 or 2 for the preparation of antiallergic drugs.
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