# US 9,518,038 B2 · Condensation product of theanine derivative and carboxylic acid coumarin derivative, its intermediate, preparation method and use thereof

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- Number: US 9,518,038 B2
- Document ID: US9518038B2
- Status: Granted
- Kind: B2
- Application number: 14/431,707
- Filed: 2013-09-25
- Published: 2015-08-27
- Granted: 2016-12-13
- Earliest claimed: 2012-09-27
- Assignees: Shandong Yingdong Yinghao Biotechnology, Inc.
- Applicants: Shandong Yingdong Yinghao Biotechnology, Inc.
- Inventors: Guoying Zhang; Ying Zhang; Benhao Wu; Guohua Zhang
- Web page: https://patentgrep.com/patent/US9518038B2

## CPC

- C07D 311/12: substituted in position 3 and unsubstituted in position 7
- A61K 31/223: of alpha-aminoacids
- A61K 31/37: Coumarins, e.g. psoralen
- A61K 49/0039: {Coumarin dyes}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 229/22: the carbon skeleton being further substituted by oxygen atoms
- C07C 237/06: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 311/74: Benzo[b]pyrans, hydrogenated in the carbocyclic ring
- C07B 2200/07: Optical isomers
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a compound as represented by formula (I), which is a condensation product of a theanine derivative and a carboxylic acid coumarin derivative, compounds as represented by formula (II) and formula (III), both of which are intermediates of the condensation product, a method for preparing these compounds, a pharmaceutical composition comprising the compounds, and a use thereof in preparing a medicament for prevention and treatment of tumors, inflammation, cardiovascular diseases, immune deficiency diseases and the like. Wherein, (Ia) R═CH3 R1═H R2═H (Ib) R═CH2CH3 R1═H R2═H (Ic) R═CH2CH3 R1═Cl R2═H (Id) R═CH2CH3 R1═Br R2═H (Ie) R═CH2CH3 R1═F R2═H (If) R═CH2CH3 R1═NO2 R2═H (Ig) R═CH2CH3 R1═Cl R2═Cl (Ih) R═CH2CH3 R1═Br R2═Br (Ii) R═CH2CH3 R1═NH2 R2═H Wherein, (IIa) R═CH3 (IIb) R═CH2CH3 Wherein, (IIIc) R1═Cl R2═H (IIId) R1═Br R2═H (IIIe) R1═F R2═H (IIIf) R1═NO2 R2═H (IIIg) R1═Cl R2═Cl (IIIh) R1═Br R2═Br

## Claims

### Claim 1

A compound as represented by formula (I):
wherein Formula (I) has variables and bonds selected from (Ib) to (Ii), wherein;
R=CH2CH3, and
(Ib) R1=H, R2=H and =;
(Ic) R1=Cl, R2=H and =;
(Id) R1=Br, R2=H and =;
(Ie) R1=F, R2=H and =;
(If) R1=NO2, R2=H and =;
(Ig) R1=Cl, R2=Cl and =;
(Ih) R1=Br, R2=Br and =; or
(Ii) R1=NH2, R2=H and =.

### Claim 2

A method for preparing a compound as represented by formula (I):
wherein
R=CH2CH3, and
R1=H, R2=H and =;
comprising:
wherein
according to the formula and procedures above.

### Claim 3

A method for preparing a compound as represented by formula (I):
wherein Formula (I) has variables and bonds selected from (Ie) to (Ih), wherein;
R=CH2CH3, and
(Ic) R1=Cl, R2=H and =;
(Id) R1=Br, R2=H and =;
(Ie) R1=F, R2=H and =;
(If) R1=NO2, R2=H and =;
(Ig) R1=Cl, R2=Cl and =;
(Ih) R1=Br, R2=Br and =;
comprising:
or alternatively comprising:
according to the formula and procedures above.

### Claim 4 (depends on 1)

A pharmaceutical composition, comprising a compound according to claim 1 and optionally, a pharmaceutically acceptable excipient.

### Claim 5

A pharmaceutical composition comprising a compound as represented by formula (I):
wherein Formula (I) has variables and bonds selected from (Ib) to (Ii), wherein
R=CH2CH3, and
(Ib) R1=H, R2=H and =;
(Ic) R1=Cl, R2=H and =;
(Id) R1=Br, R2=H and =;
(Ie) R1=F, R2=H and =;
(If) R1=NO2, R2=H and =;
(Ig) R1=Cl, R2=Cl and =;
(Ih) R1=Br, R2=Br and =; or
(Ii) R1=NH2, R2=H and ,
and a pharmaceutically acceptable excipient wherein the pharmaceutical composition is in the forms of deglutible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, injection, spreadable pastes, gels, ointments or soaps, emulsive liposomes, microspheres and nanospheres.

### Claim 6 (depends on 1, 5)

A method for treating a patient with human cancer, comprising administering to the patient to be treated a therapeutically effective amount of the compound according to claim 1, or the pharmaceutical composition of claim 5.

### Claim 7 (depends on 1, 5)

A method for inhibiting histone methyltransferase EZH2, in a patient suffering from cancer comprising administering the compound according to claim 1, or the pharmaceutical composition of claim 5.

### Claim 8 (depends on 6)

The method according to claim 6, wherein the human cancer is in the form of tumors.

### Claim 9 (depends on 1, 5)

A method for treatment of tumors in synergy with radiotherapy, or in cooperation with radiotherapy, chemotherapy, surgical treatment, thermal therapy, and multimodality therapy, comprising administering to the subject in need a therapeutically effective amount of the compound according to claim 1 or the pharmaceutical composition of claim 5.