阅读说明：本技术 茶氨酰四氢咪唑并吡啶-6-甲酰碱性氨基酸的制备,活性和应用 (Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl basic amino acid ) 是由 赵明 彭师奇 冯琦琦 易红浪 于 2019-04-30 设计创作，主要内容包括：本发明公开了下式的(6S)-5-茶氨酰-4,5,6,7-四氢-3H-咪唑[4,5-c]并吡啶-6-甲酰-AA(AA为碱性氨基酸残基,即L-赖氨酸残基和L-精氨酸残基),公开了它们的制备方法,公开了它们的抗血栓活性,公开了它们的溶血栓活性以及公开了它们对治疗中风24小时的治疗作用,因而本发明公开了它在制备抗血栓药物,溶血栓药物以及治疗缺血性中风药物中的应用。<Image he="246" wi="366" file="DDA0002047460110000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention discloses (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] of the formula]pyridine-6-formyl-AA (AA is basic amino acid residue, namely L-lysine residue and L-arginine residue), discloses a preparation method thereof, discloses antithrombotic activity thereof, discloses thrombolytic activity thereof and discloses treatment effect thereof on 24 hours of stroke treatment, so that the invention discloses application thereof in preparation of antithrombotic drugs, thrombolytic drugs and drugs for treating ischemic stroke.)

1. theacyltetrahydro-3H-imidazopyridine-6-formyl AA of the formula, wherein AA is a basic amino acid residue, namely an L-lysine residue and an L-arginine residue,

2. a process for the preparation of theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid a according to claim 1, comprising the eight steps of:

(1) preparing (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;

(2) preparing (6S) -methyl 4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylate;

(3) Preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid methyl ester;

(4) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;

(5) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA benzyl ester;

(6) preparing (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-lysine benzyl ester;

(7) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-arginine;

(8) preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA.

3. Use of theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid as defined in claim 1 for the preparation of an antithrombotic medicament.

4. Use of theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid amide according to claim 1 for the preparation of a thrombolytic drug.

5. Use of the theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid amide of claim 1 in the manufacture of a medicament for the treatment of ischemic stroke.

Technical Field

The present invention relates to (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA, to a process for their preparation, to their antithrombotic activity, to their thrombolytic activity and to their therapeutic effect on the treatment of ischemic stroke for 24 hours, and thus to their use in the preparation of antithrombotic agents, thrombolytic agents and agents for the treatment of ischemic stroke. The invention belongs to the field of biological medicine.

Background

Ischemic stroke is a common, severely damaging cerebrovascular disease. Ischemic stroke is characterized by high morbidity, high disability rate, high recurrence rate and high mortality rate, and is one of the most serious fatal diseases for human beings. Currently, rtPA is the only clinically accepted effective drug for the treatment of ischemic stroke. However, rtPA has two difficult problems to overcome in treating ischemic stroke. The first problem is that rtPA is not effective in patients with stroke over 4 h. The second problem is that continued use of rtPA can cause bleeding in the brain, thoracic cavity and abdominal cavity. The invention is a hot spot and a leading edge of research on cerebral vascular medicaments, and is a medicament which is effective on stroke for more than 4h, particularly on stroke for 24h patients and has no bleeding side effect.

The inventors have disclosed that spinacin derivatives of formula I have antithrombotic activity at an oral dose of 10nmol/kg (Pentagon, Zhaoming, Strgerstroemia. amino acid-modified spinacin derivatives, methods of preparation and use thereof, CN 102807600A [ P ]. 2011.). However, at this oral dose they show neither thrombolytic activity nor effect in treating ischemic stroke.

The inventor has disclosed that the intravenous administration of the spinacin derivative of the following formula II at a dose of 1nmol/kg can reduce the cerebral infarction volume of rats with cerebral arterial thrombosis (Peng Shi Qi, Zhao Ming, Wang Yu Ji, Wu Jian Hui, Cao Ye. cyclyl-KAK, the synthesis, the activity and the application related to thrombus, CN 106317186A [ P ] 2017.). However, it has no effect in cases with stroke above 4h at this intravenous dose.

In a further structural modification, the inventors found that a compound obtained by introducing a theanyl group to the amino group of the spinacin derivative of the above formula I and substituting the AA with basic amino acid residues, i.e., L-lysine residue and L-arginine residue, was not only effective in rats with 24h stroke but also had no bleeding side effect. In light of this finding, the inventors have devised the present invention.

Disclosure of Invention

The first aspect of the present invention is to provide (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA (AA is a basic amino acid residue, i.e., an L-lysine residue and an L-arginine residue) of the formula.

In a second aspect of the invention there is provided (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid

-AA (AA is a basic amino acid residue, i.e. a L-lysine residue and a L-arginine residue), comprising:

(1) preparing (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;

(2) preparing (6S) -methyl 4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylate;

(3) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid methyl ester;

(4) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;

(5) Preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA benzyl ester (AA is lysine residue and L-nitroarginine residue);

(6) preparing (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-lysine benzyl ester;

(7) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-arginine;

(8) preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA (AA is L-lysine residue and L-arginine residue).

The third aspect of the present invention is to evaluate antithrombotic activity, thrombolytic activity and activity for treating ischemic stroke of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA (AA is a basic amino acid residue, i.e., an L-lysine residue and an L-arginine residue).

Drawings

FIG. 1(6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ]]A synthetic route to the pyridine-6-formyl-L-lysine (7a) and L-arginine (7 b). i) HCHO, H₂O, concentrated H₂SO₄；ii)CH₃OH,SOCl₂(ii) a iii) anhydrous DMF, Boc-The, HATU, NMM; iv)2N NaOH; v) HCl & Lys (Boc) -OBzl, DCC, HOBt, NMM; vi) a solution of hydrogen chloride in ethyl acetate (4M); vii) H₂/Pd。

Detailed Description

To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.