CN111875558B - Thiazolidine derivative and application thereof in depression resistance - Google Patents

Thiazolidine derivative and application thereof in depression resistance Download PDF

Info

Publication number
CN111875558B
CN111875558B CN202010855736.2A CN202010855736A CN111875558B CN 111875558 B CN111875558 B CN 111875558B CN 202010855736 A CN202010855736 A CN 202010855736A CN 111875558 B CN111875558 B CN 111875558B
Authority
CN
China
Prior art keywords
compound
reaction
pharmaceutically acceptable
antidepressant
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010855736.2A
Other languages
Chinese (zh)
Other versions
CN111875558A (en
Inventor
谭回
李维平
任力杰
俞玉明
高明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Second Peoples Hospital
Original Assignee
Shenzhen Second Peoples Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Second Peoples Hospital filed Critical Shenzhen Second Peoples Hospital
Priority to CN202010855736.2A priority Critical patent/CN111875558B/en
Publication of CN111875558A publication Critical patent/CN111875558A/en
Application granted granted Critical
Publication of CN111875558B publication Critical patent/CN111875558B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a thiazolamine derivative with antidepressant activity, which can be used for preparing antidepressant drugs, widens the range of the existing antidepressant compounds, and can be continuously optimized as a lead compound. Compared with fluoxetine hydrochloride, the compound of the invention has better antidepressant activity. The compound has simple preparation route and mild condition, and is easy for industrialized mass production.

Description

Thiazolidine derivative and application thereof in depression resistance
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a series of thiazolamine derivatives, and a preparation method and application thereof.
Background
Depression is a disease clinically manifested as mood disorders or affective disorders due to various causes, and about 15% of patients have suicidal tendency, which greatly affects social stability and economic development. Receptors are currently thought to play an important role in the pathogenesis of depression and the mechanism of antidepressants, and the receptors involved are monoamine transmitter receptors, glutamate receptors, glucocorticoid receptors, neurokinin receptors, and the like. Monoamine transmitter receptors include 5-hydroxytryptamine (5-HT) receptors, adrenergic receptors, and dopamine receptors, among others, which have been most widely studied as the 5-HT system.
The jensen pharmaceutical industry reported thiazole amine derivatives (CN101263130A) with antidepressant activity, which act by modulating α 7 nicotinic receptors and can be used for antidepressant, anxiolytic, hypnotic, etc., said compounds having the general structure as follows:
Figure BDA0002643096120000011
however, no thiazole amine antidepressant on the market exists at present, so that the development of a novel thiazole amine compound with antidepressant activity still has good application prospect.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: a class of thiazolamine derivatives is provided which are useful as antidepressants.
In a first aspect, the present invention provides compounds of formula I and pharmaceutically acceptable salts thereof, having the following structure:
Figure BDA0002643096120000012
Figure BDA0002643096120000021
wherein: r1Each independently selected from H, halogen, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;
R2selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy;
n is selected from 0, 1, 2,3 or 4.
Preferably, R1Each independently selected from H, halogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, more preferably H; n is selected from 0, 1 or 2, preferably 0 or 1.
Preferably, R2Selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, more preferably H.
More preferably, the compounds of formula I according to the invention are selected from the following compounds:
Figure BDA0002643096120000022
in another aspect of the invention there is provided a process for the preparation of a compound of formula I, the reaction scheme being as follows:
Figure BDA0002643096120000023
wherein R is1、R2And n is as defined above.
The preparation method of the invention specifically comprises the following reaction steps:
the method comprises the following steps: adding 3-carboxyphenylthiourea, the compound 1 and glacial acetic acid into a reaction bottle, uniformly stirring, heating to reflux, removing insoluble solids in the reaction bottle when the reaction is finished, rotationally evaporating partial solvent, cooling in a ventilation kitchen at normal temperature, separating out solids, filtering, and drying the obtained solids to obtain the intermediate compound 2.
Step two: adding substituted aniline (compound 3), an intermediate compound 2 and dichloromethane into a reaction bottle, stirring and dissolving at room temperature, adding 4-dimethylaminopyridine, stirring and reacting for 0.5-1h, adding DCC, detecting by TLC, filtering to remove part of dicyclohexylurea after the reaction is finished, and purifying by column chromatography to obtain a target product I.
Preferably, the molar ratio of the 3-carboxyphenylthiourea in step one to the compound 1 is from 1:1 to 1.2, preferably 1:1.
Preferably, the molar ratio of intermediate compound 2 to substituted aniline (compound 3) in step two is 1:1-2, preferably 1: 1.5.
In another aspect of the present invention, a pharmaceutical composition is provided, which comprises the compound represented by formula I or a pharmaceutically acceptable salt thereof described in the present invention, and a pharmaceutically acceptable carrier or excipient.
Another aspect of the invention relates to the use of a compound of the invention, or a pharmaceutical composition comprising said compound, in the manufacture of an antidepressant medicament.
Defining:
"alkyl" means consisting solely of carbon and hydrogen atoms, containing no unsaturation, and may be a C1-6 alkyl group. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Representative saturated straight chain alkyl groups include, but are not limited to-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and-n-hexyl; and saturated branched alkyl groups include, but are not limited to-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methyl-pentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethyl-butyl, and the like. The alkyl group is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl. In a non-limiting embodiment, the substituted alkyl group can be selected from the group consisting of fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.
"alkoxy" means an "alkyl" group attached to the parent molecule through an oxygen atom, wherein "alkyl" has the meaning described above.
"haloalkyl" refers to an alkyl group wherein all hydrogen atoms are partially or fully replaced with a halogen selected from fluoro, chloro, bromo, and iodo. In some embodiments, all hydrogen atoms are each replaced with fluoro groups. In some embodiments, all hydrogen atoms are each replaced with a chloro group. Examples of haloalkyl groups include-CF 3, -CF2CF3, -CF2CF2CF3, -CFCl2, -CF2Cl, and the like.
In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt, which is well known in the art. Examples of pharmaceutically acceptable salts are such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, acetic, oxalic, maleic, tartaric, citric, succinic or malonic, acetic, propionic, glycolic, pyruvic, oxalic, lactic, trifluoroacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like.
"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, isotonic and absorption delaying agents and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a new thiazolamine derivative with antidepressant activity, widens the range of the existing antidepressant compound, and can be continuously optimized as a lead compound;
(2) compared with fluoxetine hydrochloride, the compound of the invention has better antidepressant activity.
(3) The compound has simple preparation route and mild condition, and is easy for industrialized mass production.
Detailed Description
The present invention will be described in detail with reference to examples. In the present invention, the following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials, reagents and the like used in the examples are commercially available unless otherwise specified.
Example 13- [ (5-Ethyl-4-phenylthiazol-2-yl) amino ] benzoic acid
The method comprises the following steps: 3- [ (-4-phenylthiazol-2-yl) amino ] benzoic acid
Figure BDA0002643096120000051
1.96g (0.01mol) of 3-carboxyphenylthiourea, 1.99g (0.01mol) of 2-bromo-1-phenylethanone and 15mL of glacial acetic acid were added to a 100mL inclined-mouth reaction flask with a condenser tube, stirred uniformly, heated to reflux, and reacted for about 24 hours while monitoring the progress of the reaction by TLC (developing agent: ethyl acetate: petroleum ether: 4: 1). The insoluble solid in the reaction flask was removed while hot and part of the solvent was rotary evaporated. The mixture was cooled in a fume hood at room temperature to precipitate a solid, which was then filtered and dried to obtain 2.02g of powder with a yield of 68.2%.1H NMR(DMSO-D6，400MHz)，δ：7.16(s，1H，CH-S)，7.30-8.24(m，9H，C6H4，C6H5)，10.38(s，1H，COOH)。
Step two: preparation of Compounds of formula I
Figure BDA0002643096120000052
Adding aniline (0.28g, 3mmol), intermediate compound 2 (0.59g, 2mmol) and 20mL dichloromethane into a reaction bottle, stirring at room temperature for dissolving, adding 2mmol 4-dimethylaminopyridine, stirring for reacting for 0.5h, adding 2mmol DCC, detecting by TLC (petroleum ether: ethyl acetate: 5:1), filtering to remove part of dicyclohexylurea after the reaction is finished, and purifying by column chromatography to obtain 0.58g of target product I with the yield of 78.4%.
1H NMR(DMSO-D6，400MHz)，δ：7.16(s，1H，CH-S)，7.28-8.27(m，14H，C6H4，C6H5，C6H5)。ESI-MS(m/z)：371.1。
Example 2 antidepressant Activity test
This experiment searches for compounds that act directly on or produce reuptake inhibitory effects through adenosine receptors by creating a high-throughput hoofed segment of fluorescent substance ASP. The fluorescent dye ASP + is a compound with neurotoxicity, can be combined with a monoamine transporter to enter a cell and emit yellow fluorescence (the combination strength is in the sequence of dopamine transporter > epinephrine transporter >5-HT transporter). When other compounds capable of binding to the transporter exist, competition with ASP is performed, so that the number of cells entering the cells is reduced, yellow fluorescence is weakened, and a reuptake inhibitor acting on the 5-HT transporter is screened by comparing the change of fluorescence intensity.
RBL cells are a cell line that can secrete histamine and 5-HT, are immortalized mast cells, and can release transmitters in quanta. And has the ability to undergo 5-HT reuptake.
CACO-2 cells are adenocarcinoma cell strains derived from human small intestines, and research shows that the cells after being cultured and differentiated for a period of time can express various transporters and receptors, such as SERT, adenosine receptors and the like. By establishing a standardized process of cell culture, cells can be well differentiated after being cultured for 6-7 days, a test sample to be selected is added for a period of time, then fluorescent dye is added according to a certain concentration, the dye which does not enter the cells is absorbed, and then the fluorescence intensity of ASP between different samples is compared, so that a sample which directly inhibits SERT activity or indirectly affects the activity of a transporter through the action of activating/inhibiting an adenosine receptor can be found.
1) Cell culture
RBL cell lines were purchased from the China center for type culture Collection. The cell line used was EMEM containing 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acids, 1.0mM sodium pyruvate, 2mM L-glutamine and Earle' BSS, 85%; cell culture was performed with heat-inactivated FBS 15% medium. The cells need to be changed every other day by 1 time, and when the cell proliferation reaches 80%, the cells need to be passaged with the ratio of 1: 3.
Strictly performing aseptic operation, performing cell culture in MEM alpha complete culture medium containing 15% fetal calf serum, performing experiment when the cells reach good logarithmic phase, washing twice with D-hanks solution, adding 0.125% pancreatin digested cells, standing at 37 deg.C for 5min to make intercellular connection and propagation, distributing cells singly, adding equal volume of complete culture medium to stop digestion, blowing gently to blow cells to centrifuge the suspension into a centrifuge tube, discarding supernatant, suspending the cells with complete culture medium, counting, and diluting the cells to 6 × 105one/mL for use.
Cell plating and dosing, addition of fluorescent dye: 4X 105Adding the cell suspension/mL into a 96-well plate according to 0.1 mL/well, performing a high-throughput screening experiment by using the portable fluorescence device when the cells grow well adherent to the wall for more than 10h, reading at the excitation wavelength of 475nm and the emission wavelength of 605nm, and performing result statistics.
CACO-2 cell strain is preserved in the laboratory of the national drug hoof selection center of the institute of medicine of Chinese academy of medical sciences. The cell line used was EMEM containing 1.5g/L sodium bicarbonate, 0.1mM non-essential amino acids, 1.0mM sodium pyruvate, 2mM L-glutamine and Earle' BSS, 80%; cell culture was performed with heat-inactivated FBS 20% medium. The cells need to be changed every other day by 1 time, and when the cell proliferation reaches 80%, the cells need to be passaged with the ratio of 1: 3.
Cell plating and differentiation: 1X 105Adding the cell sap per mL into a 96-pore plate according to 0.1mL per pore, changing the cell sap every other day when the cells do not grow full, changing the cell sap every day when the cells grow fast and grow full at the bottom, growing microvilli when the cells grow for 6-7 days and are unclear in visible cell boundary, and conducting microvilli growth.
2) Data processing
Calculating the fluorescence intensity inhibition rate:
Figure BDA0002643096120000071
at a concentration of 10. mu.g/mL, the compounds of the invention inhibit SERT as follows:
Figure BDA0002643096120000072
the results show that the compound has good inhibitory activity on SERT, can be used for further research and development, and is expected to become a new antidepressant drug.

Claims (7)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:
Figure DEST_PATH_IMAGE002
。
2. a process for the preparation of a compound of formula I according to claim 1, which reaction scheme is as follows:
Figure DEST_PATH_IMAGE004
。
3. the method of claim 2, comprising the reaction steps of:
the method comprises the following steps: adding 3-carboxyphenylthiourea, the compound 1 and glacial acetic acid into a reaction bottle, uniformly stirring, heating to reflux, removing insoluble solids in the reaction bottle when the reaction is finished, rotationally steaming part of the solvent, putting the solvent into a ventilation kitchen, cooling at normal temperature, separating out solids, filtering, and drying the obtained solids to obtain an intermediate compound 2;
step two: adding the aniline compound 3, the intermediate compound 2 and dichloromethane into a reaction bottle, stirring and dissolving at room temperature, adding 4-dimethylaminopyridine, stirring and reacting for 0.5-1h, adding DCC, detecting by TLC, reacting, filtering to remove part of dicyclohexylurea after the reaction is finished, and purifying by column chromatography to obtain a target product I.
4. The method of claim 3, wherein:
the mol ratio of the 3-carboxyl phenylthiourea to the compound 1 in the first step is 1: 1-1.2;
in the second step, the molar ratio of the intermediate compound 2 to the aniline compound 3 is 1: 1-2.
5. The method of claim 4, wherein:
the mol ratio of the 3-carboxyl phenylthiourea to the compound 1 in the first step is 1: 1;
in the second step, the molar ratio of the intermediate compound 2 to the aniline compound 3 is 1: 1.5.
6. A pharmaceutical composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient.
7. Use of a compound of claim 1 or a pharmaceutical composition of claim 6 in the preparation of an antidepressant.
CN202010855736.2A 2020-08-21 2020-08-21 Thiazolidine derivative and application thereof in depression resistance Active CN111875558B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010855736.2A CN111875558B (en) 2020-08-21 2020-08-21 Thiazolidine derivative and application thereof in depression resistance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010855736.2A CN111875558B (en) 2020-08-21 2020-08-21 Thiazolidine derivative and application thereof in depression resistance

Publications (2)

Publication Number Publication Date
CN111875558A CN111875558A (en) 2020-11-03
CN111875558B true CN111875558B (en) 2022-07-01

Family

ID=73204087

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010855736.2A Active CN111875558B (en) 2020-08-21 2020-08-21 Thiazolidine derivative and application thereof in depression resistance

Country Status (1)

Country Link
CN (1) CN111875558B (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2566104A1 (en) * 2004-05-18 2005-12-01 Ab Science Use of mast cells inhibitors for treating patients exposed to chemical or biological weapons
CN101263130B (en) * 2005-09-13 2011-03-09 詹森药业有限公司 2-aniline-4-aryl substituted thiazole derivatives
CN109320473B (en) * 2018-10-17 2022-11-22 南华大学 Thiazolylaminobenzamide acetic acid derivatives and uses thereof

Also Published As

Publication number Publication date
CN111875558A (en) 2020-11-03

Similar Documents

Publication Publication Date Title
JP2021130700A (en) Combination therapy for treating cancer
EP4140487A1 (en) Combination therapy for treating cancer
CN107922425A (en) Method for preparing PARP inhibitor, crystal form and application thereof
EP3070089A1 (en) N-benzyl tryptanthrin derivative, and preparation method and application thereof
JP7324144B2 (en) cancer treatment modalities
CN110099900A (en) For the hedgehog pathway inhibitor of Smoothened mutant strain
Heinrich et al. Dual 5-HT1A agonists and 5-HT re-uptake inhibitors by combination of indole-butyl-amine and chromenonyl-piperazine structural elements in a single molecular entity
TW201938558A (en) Crystal form, salt type of pyridoimidazole compound and preparation method thereof
US11236112B2 (en) Crystal form and salt form of TGF-βRI inhibitor and preparation method therefor
CN109320473B (en) Thiazolylaminobenzamide acetic acid derivatives and uses thereof
CN111875558B (en) Thiazolidine derivative and application thereof in depression resistance
BR112013031121B1 (en) Compound for modulating a kinase
CN111909111B (en) 5-alkyl thiazolamine derivative and application thereof in depression resistance
EP1400510B1 (en) Cyclic diamine compounds having fused-ring groups
CN108530337B (en) Indoleamide compound capable of selectively inhibiting gastric cancer cells
CN110143893A (en) A kind of compound, Its Preparation Method And Use that can combine alpha-synuclein aggregation body by force
CN109456279B (en) Thiazolylaminobenzamide acetate derivatives and uses thereof
EP3287459B1 (en) Purinyl-n-hydroxyl pyrimidine formamide derivatives, preparation method therefor and use thereof
JP6695875B2 (en) Novel 1,3,5-triazine PI3K inhibitor as anticancer agent and method for producing the same
JP7450017B2 (en) Predominant salt forms of pyrimidine derivatives and their crystal forms
CN110872263B (en) Compound, preparation method and application
CN108912035B (en) Indole amide compound with anti-tumor activity
CN102786515A (en) 2-(2, 2-dimethyl-2, 3-dihydrobenzofuran-5-group)morpholine and preparation method and application
CN102633791A (en) Application of 4-alkyl-6-aryl-5-(1,2,4-triazole-1-yl)-2-amino-1,3-thiazine to preparation of antidepressants
CN115475253B (en) Lapatinib-cancer cell stem inhibitor conjugate, preparation method, pharmaceutical composition and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant