阅读说明：本技术 异喹啉衍生物用于伤口愈合的新颖用途 (Novel use of isoquinoline derivatives for wound healing ) 是由 苏铭嘉 李水盛 徐兆民 于 2019-01-22 设计创作，主要内容包括：本发明涉及一种用于伤口愈合的方法,包括向有需要的个体投用一药物组合物,其包含药学上可接受的载剂及治疗有效量的具式I的化合物,较佳为去甲猪毛菜碱(salsolinol)。(The present invention relates to a method for wound healing comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, preferably norsalsolinol.)

1. A method for wound healing comprising administering to an individual in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I:

r, R therein₁And R₂Each independently is H, alkyl or acyl (R)_aCO)；R₃Is H, alkyl or substituted benzyl; wherein R is_aIs H or alkyl.

2. The method of claim 1, wherein the substituted benzyl is of formula II:

wherein X and Y are each independently H, OH, methoxy (OMe) or acyloxy (R)_bCO-O-); wherein R is_bIs H or alkyl.

3. The method of claim 1, wherein the compound is norsalsoline (salsolinol).

4. The method of claim 1, wherein the effective amount of the compound is 0.001mg/g to 0.03 mg/g.

5. The method of claim 1, wherein the effective amount of the compound is 0.01 mg/g.

6. Use of a compound of formula I for the preparation of a medicament for wound healing:

r, R therein₁And R₂Each independently is H, alkyl or acyl (R)_aCO)；R₃Is H, alkyl or substituted benzyl; wherein R is_aIs H or alkyl.

7. The use of claim 6, wherein the substituted benzyl is of formula II:

wherein X and Y are each independently H, OH, methoxy (OMe) or acyloxy (R)_bCO-O-); wherein Rb is H or alkyl.

8. The use of claim 6, wherein the compound is norsalsoline (salsolinol).

9. The use of claim 6, wherein the effective amount of the compound is 0.001mg/g to 0.03 mg/g.

10. The use of claim 6, wherein the effective amount of the compound is 0.01 mg/g.

Technical Field

The present invention provides a method for wound healing. In particular, the present invention provides a novel use of isoquinoline derivatives for wound healing.

Background

Isoquinoline derivatives are a class of nitrogen-containing organic compounds that occur naturally in plants and animals. Most have complex ring structures with the nitrogen atom contained within the ring. The isoquinoline derivatives, including norsalsoline (salsolinol) and reticuline (reticuline), have significant biological activity. Norsalsoline is known to be mainly used for regulating blood pressure, while reticuline is mainly used as an active ingredient for treating malaria and also as an ingredient of analgesics.

U.S. Pat. No.9,707,222 discloses that isoquinoline derivatives, norsalsoline and reticuline, can activate phosphorylated adenosine-dependent protein kinase (AMPK) and are useful in the treatment of AMPK-dependent diseases. In particular, norsalsoline or reticuline has effects of lowering blood sugar and treating diabetes.

In addition, U.S. patent No.9,655,891 discloses a method for healing a diabetic wound in an individual comprising administering to the diabetic wound of the individual a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of isoquinoline derivatives, including norsalsoline and reticuline. However, none of the prior art references report the role of such isoquinoline derivatives, such as norsalsoline, in wound healing.

Disclosure of Invention

Certain isoquinoline derivatives, such as norsalsolinol, have unexpectedly been found to be efficacious in wound healing in the present invention.

In one aspect, the present invention provides a method for wound healing, comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I:

r, R therein₁And R₂Each independently is H, alkyl or acyl (R)_aCO)；R₃Is H, alkyl or substituted benzyl; wherein R is_aIs H or alkyl.

In a particular embodiment of the invention, the substituted benzyl is of formula II:

wherein X and Y are each independently H, OH, methoxy (OMe) or acyloxy (R)_bCO-O-); wherein R is_bIs H or alkyl.

In one embodiment of the invention, the compound of formula I is norsalsoline.

In another aspect, the present invention provides the use of a compound of formula I of the present invention for the preparation of a medicament for wound healing.

These and other aspects of the invention will become apparent from the following description of the preferred embodiments and the accompanying drawings; even though variations or modifications may be made therein without departing from the spirit and scope of the novel concepts of the disclosure.

Drawings

The accompanying drawings, which present preferred embodiments of the invention, are intended to illustrate the invention. It should be understood that the invention is not limited to the preferred embodiments shown. Data in the figures and examples are shown as MEAN ± standard deviation (MEAN ± SD), determined by paired t-assays. Significant differences are shown below: p < 0.01; p < 0.05.

Figure 1 shows the wound recovery rate (: p <0.01) for animals treated with 0.01mg/g norsalsolinol) on days 1, 3, 5, 7, 10 and 14 compared to the control group (treated with vehicle).

Figure 2 shows the wound recovery of animals treated with 0.03mg/g norsalsoline on days 1, 3, 5, 7, 10 and 14 compared to the control group (treated with vehicle) (.: p < 0.05).

Fig. 3 provides wound images of one representative animal in each experimental and control group on days 1, 3, 5, 7, 10 and 14.

Figure 4 provides the wound recovery of animals treated with 0.001mg/g norsalsoline on days 1, 3, 5, 7, 10 and 14 compared to the control group (treated with vehicle).

Figure 5 provides the wound recovery of guinea pigs treated with 0.01mg/g norsalsoline on days 1, 3, 5, 7, 10 and 14 (.: p <0.05) compared to the control group (treated with vehicle).

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

The articles "a", "an" and "the" are intended to mean a plurality including "more than one" unless the context clearly indicates otherwise. Thus, for example, when the term "an ingredient" is used, a plurality of such ingredients and equivalents thereof known to those skilled in the art are included.

As used herein, the term "substituted" or "substitution" refers to where a functional group in a compound is replaced with another group.

As used herein, the term "individual" refers to a human or a mammal, such as: patients, companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), or laboratory animals (e.g., rats, mice, rabbits, and the like).

The term "alkyl" as used herein refers to a straight or branched chain monovalent hydrocarbon containing 1 to 20 carbon atoms, such as an alkyl group having 1 to 10 carbons, preferably an alkyl group having 1 to 6 carbons, more preferably an alkyl group having 1 to 3 carbons. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

Accordingly, in one aspect, the present invention provides a method for wound healing. The method comprises administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I:

r, R therein₁And R₂Each independently is H, alkyl or acyl (R)_aCO)；R₃Is H, alkyl or substituted benzyl; wherein R is_aIs H or alkyl.

In a particular embodiment of the invention, the substituted benzyl is of formula II:

wherein X and Y are each independently H, OH, methoxy (OMe) or acyloxy (R)_bCO-O-); wherein R is_bIs H or alkyl.

A particular embodiment of the active compounds of the invention has the formula I, wherein R ═ R₁＝R₂H and R₃Me (methyl), this compound has the formula norsalsoline.

As shown in the specific embodiment of the invention, the compound with the formula I of the invention, such as norsalsoline, has the effect of treating wounds.

An effective amount of norsalsoline of 0.001mg/g to 0.03mg/g, preferably 0.01mg/g, is unexpectedly found in the present invention.

According to the present invention, the compounds of formula I may be formulated into any form of medicament well known or commonly used in the medical arts, and may be prepared according to techniques well known in the medical arts into a composition comprising a therapeutically effective amount of the compound in combination with a commonly used carrier or a pharmaceutically acceptable carrier.

As used herein, the term "carrier" or "pharmaceutically acceptable carrier" includes, but is not limited to, pharmaceutically acceptable excipients, fillers, diluents, or the like, including those well known to those skilled in the medical arts.

The invention is illustrated in the above description of the invention and in the following examples, which should not be taken to limit the scope of the invention.