TECHNICAL FIELD

The present invention relates to the technical field of chemically synthetic drugs, in particular to a 10H-phenothiazine ferroptosis inhibitor as well as the preparative method and the use thereof.

BACKGROUND ART

Cell ferroptosis is a new mode of cell death caused by iron-dependent oxidative damage that has only been discovered in recent years, and it is different from the traditional death modes of apoptosis, necrosis and autophagy, whose typical features are the increase of reactive oxygen free radicals in cytoplasm and lipid, the shrinkage of mitochondria, and the density increase of the mitochondrial bilayer membrane. Since this mode of cell death depends on the presence of iron, Dixon et al. named it “Ferroptosis” in 2012.

Cell ferroptosis is closely related to the occurrence and development of neurodegeneration, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, renal failure, and diabetic complications, and ferroptosis inhibitors are considered to be potential drugs for treatment of these diseases.

At present, most of the small molecule inhibitors of ferroptosis are antioxidants or iron chelating agents. Here, we mainly introduce three kinds of compounds with specific anti-ferroptosis activity:

Ferrostatin: the first generation of Ferrostatin is called Ferrostatin-1, which inhibits the formation of iron ions induced by Erastin- and RSL3 in HT1080 cells. The activity of Ferrostain-1 mainly depends on aromatic amines, which specifically inhibit the accumulation of ROS caused by lipid oxidation.

Compared with Ferrostatin-1, the second generation (called SRS11-92) and the third generation of Ferrostatins (called SRS16-86) have better plasma stability and metabolic stability, and can significantly prevent the damage of tissues in vivo (such as acute kidney injury and ischemia-reperfusion injury).

Liproxstatin-1: Liproxstatin-1 can prevent ROS accumulation and cell death in GPX4−/− cells. In addition, Liproxstatin-1 inhibits ferroptosis induced by FINs (such as Erastin, RSL3, and BSO). In inducible GPX4−/− mice, intraperitoneal administration of Liproxstatin-1 (10 mg/kg) can increase the survival rate of the animals against kidney injury. Liproxstatin-1 can also protect mice from liver injury caused by ischemia-reperfusion.

Zileuton: Zileuton is an active specific inhibitor of oral 5-LOX, but not an inhibitor of 12/15-LOX.

Zileuton inhibits the production of ROS in cytosol and provides significant protection against the increase of iron ions induced by glutamate and ergosporin in HT22 cells (mouse hippocampal cell line).



The above-mentioned ferroptosis inhibitors have strong targeted activity, but the activity is not high, and there is no application for stroke genes. Therefore, how to prepare a ferroptosis inhibitor with high activity, which can be used as a drug for treatment of stroke, is a problem that urgently needs to be solved.

CONTENT OF THE INVENTION

In order to solve above problems, the present invention provides the compound of formula I, or a pharmaceutically acceptable salt, or crystal, or solvate thereof:



Wherein,

When the dotted line is a bond,

R1is selected from 3-10 membered saturated cycloalkyl, 3-10 membered unsaturated cycloalkyl, 3-10 membered saturated heterocyclic group, and 3-10 membered unsaturated heterocyclic group, all of which are substituted by m R2;

m is an integer of 0-5;

R2is selected from the group consisting of substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8alkoxy, substituted or unsubstituted 3-10 membered saturated cycloalkyl, substituted or unsubstituted 3-10 membered saturated heterocyclic group, substituted or unsubstituted 3-10 membered unsaturated cycloalkyl, carbazolyl, amino, hydroxyl, nitro, cyano, halogen, —C(O)OR51, —N(H)C(O)R51, —C(O)R51, —S(O)(O)R51, —C(O)N(H)R51; R51is selected from the group consisting of H, C1-C8alkyl, amino, substituted or unsubstituted 3-10 membered unsaturated cycloalkyl, substituted or unsubstituted 3-10 membered saturated heterocyclic group, —NR52R53;

R52and R53are each independently selected from H, substituted or unsubstituted 5-10 membered saturated heterocyclic group, substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted 3-8 membered saturated cycloalkyl;

The substituent of the alkyl is halogen, substituted or unsubstituted 4-10 membered saturated heterocyclic group;

The substituent of the alkoxyl is halogen, 3-10 membered unsaturated cycloalkyl;

The substituent of the saturated cycloalkyl is C1-C8alkyl;

The substituent of the unsaturated cycloalkyl is C1-C8alkyl;

The substituent of the saturated heterocyclic group is C1-C8alkyl;

The heteroatom of the unsaturated heterocyclic group is N, O, and S, and the number of heteroatoms is 1 or 2;

The heteroatom of the saturated heterocyclic group is N, O, and S, and the number of heteroatoms is 1 or 2;

When the dotted line is none,

R1is selected from the group consisting of 3-10 membered unsaturated cycloalkyl, benzo(3-8 membered saturated)heterocyclic group, benzo(3-8 membered unsaturated)heterocyclic group, naphthyl, anthryl, 3-10 membered unsaturated heterocyclic group, 3-10 membered saturated cycloalkyl, all of which are substituted by n R3and —S(O)(O)R1′;

n is an integer of 0-5;

R3is selected from the group consisting of halogen, cyano, hydroxyl, amino, nitro, substituted or unsubstituted 3-10 membered unsaturated cycloalkyl, phenoxyl, substituted or unsubstituted 3-10 membered saturated heterocyclic group, substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C1-C8alkoxy, —C(O)OR51, —N(H)C(O)R51, —NR52R53;

R1′ is selected from 3-10 membered saturated heterocyclic group, 3-10 membered saturated cycloalkyl, 3-10 membered unsaturated cycloalkyl, and 3-10 membered unsaturated heterocyclic group, all of which are substituted by p R4;

p is an integer of 0-5;

R4is selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C8alkyl, —C(O)R51, —N(H)C(O)OR51, —S(O)(O)R51, —C(O)OR51, substituted or unsubstituted 3-10 membered unsaturated heterocyclic group, substituted or unsubstituted 3-10 membered saturated heterocyclic group, and substituted or unsubstituted 3-10 membered unsaturated cycloalkyl;

R51is selected from the group consisting of C1-C10alkyl, amino, 3-8 membered saturated heterocyclic group, and benzo(3-8 membered saturated)heterocyclic group;

R52and R53are each independently selected from 3-10 membered unsaturated cycloalkyl, C1-C8alkyl;

The substituent of the alkyl is halogen, benzo(5-10 membered saturated)heterocyclic group, substituted or unsubstituted 3-10 membered unsaturated cycloalkyl, 5-10 membered saturated heterocyclic group, hydroxyl, —N(H)C(O)OR51, —C(O)R51, —NR52R53;

The substituent of the alkoxyl is 3-10 membered unsaturated cycloalkyl, halogen;

The substituent of the unsaturated cycloalkyl is halogen, C1-C6alkoxyl, cyano, nitro, substituted or unsubstituted C1-C8alkyl;

The substituent of the saturated heterocyclic group is C1-C8alkyl;

The substituent of the unsaturated heterocyclic group is C1-C8alkyl;

The heteroatom of the saturated heterocyclic group is O, N, and S, and the number of heteroatoms is 1 or 2;

The heteroatom of the unsaturated heterocyclic group is N, O, and S, and the number of heteroatoms is 1 or 2.

Further,

When the dotted line is a bond,

R1is selected from 3-8 membered unsaturated cycloalkyl, and 3-8 membered unsaturated heterocyclic group, all of which are substituted by m R2;

m is an integer of 0-4;

R2is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, 3-8 membered saturated cycloalkyl, substituted or unsubstituted 3-8 membered saturated heterocyclic group, 3-8 membered unsaturated cycloalkyl, carbazolyl, amino, hydroxyl, nitro, cyano, halogen, —C(O)OR51, —N(H)C(O)R51, —C(O)R51, —S(O)(O)R51, —C(O)N(H)R51;

R51is selected from the group consisting of H, C1-C4alkyl, amino, substituted or unsubstituted 3-8 membered unsaturated cycloalkyl, substituted or unsubstituted 5-8 membered saturated heterocyclic group, —NR52R53;

R52and R53are each independently selected from H, substituted or unsubstituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted C1-C6alkyl, 3-6 membered saturated cycloalkyl;

The substituent of the alkyl is halogen, substituted or unsubstituted 5-8 membered saturated heterocyclic group;

The substituent of the alkoxyl is halogen, 3-8 membered unsaturated cycloalkyl;

The substituent of the unsaturated cycloalkyl is C1-C4alkyl;

The substituent of the saturated heterocyclic group is C1-C4alkyl;

The heteroatom of the unsaturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2;

The heteroatom of the saturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2; When the dotted line is none, R1is selected from the group consisting of 3-8 membered unsaturated cycloalkyl, benzo(5-8 membered saturated)heterocyclic group, benzo(5-8 membered unsaturated)heterocyclic group, naphthyl, anthryl, 3-8 membered unsaturated heterocyclic group, 3-8 membered saturated cycloalkyl, all of which are substituted by n R3, and —S(O)(O)R1′;

n is an integer of 0-4;

R3is selected from the group consisting of halogen, cyano, hydroxyl, amino, nitro, 3-8 membered unsaturated cycloalkyl, phenoxyl, substituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, —C(O)OR51, —N(H)C(O)R51, —NR52R53;

R1′ is selected from 3-8 membered saturated heterocyclic group substituted by p R4;

p is an integer of 0-4;

R4is selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C6alkyl, —C(O)R51, —N(H)C(O)OR51, —S(O)(O)R51, —C(O)OR51, 3-8 membered unsaturated heterocyclic group, 3-8 membered saturated heterocyclic group, and substituted or unsubstituted 3-8 membered unsaturated cycloalkyl;

R51is selected from the group consisting of C1-C8alkyl, amino, 5-8 membered saturated heterocyclic group, and benzo(5-8 membered saturated)heterocyclic group;

R52and R53are each independently selected from 3-8 membered unsaturated cycloalkyl, C1-C4alkyl;

The substituent of the alkyl is halogen, benzo(5-8 membered saturated)heterocyclic group, substituted or unsubstituted 3-8 membered unsaturated cycloalkyl, 5-10 membered saturated heterocyclic group, hydroxyl, —N(H)C(O)OR51, —C(O)R51, —NR52R53;

The substituent of the alkoxyl is 3-8 membered unsaturated cycloalkyl, halogen;

The substituent of the unsaturated cycloalkyl is halogen, C1-C4alkoxyl, cyano, nitro, substituted or unsubstituted C1-C4alkyl;

The substituent of the saturated heterocyclic group is C1-C4alkyl;

The heteroatom of the saturated heterocyclic group is O, N, and S, and the number of heteroatoms is 1 or 2;

The heteroatom of the unsaturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2.

Further, said compound has a structure of formula II



Wherein, ring A is selected from aryl or heteroaryl substituted by m R2; the heteroatom of said heteroaryl is N, and the number of heteroatoms is 1 or 2.

m is an integer of 0-4;

R2is selected from the group consisting of H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C3alkoxy, 6-8 membered saturated cycloalkyl, substituted or unsubstituted 6-7 membered saturated heterocyclic group, carbazolyl, amino, hydroxyl, nitro, aryl, cyano, halogen, —C(O)OR51, —N(H)C(O)R51, —C(O)R51, —S(O)(O)R51, —C(O)N(H)R51;

R51is selected from the group consisting of H, C1-C2alkyl, amino, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered saturated heterocyclic group, —NR52R53;

R52and R53are each independently selected from H, substituted or unsubstituted 6-8 membered saturated heterocyclic group, substituted or unsubstituted C1-C4alkyl, 4-5 membered saturated cycloalkyl;

The substituent of the alkyl is halogen, substituted or unsubstituted 6-8 membered saturated heterocyclic group;

The substituent of the alkoxyl is halogen, aryl;

The substituent of the aryl is substituted C1-C3alkyl;

The substituent of the saturated heterocyclic group is C1-C3alkyl; the heteroatom of said heterocyclic group is N and O, and the number of heteroatoms is 1 or 2.

Or, said compound has a structure of formula III:



Wherein, ring Bis selected from the group consisting of aryl benzo(5-6 membered saturated)heterocyclic group, benzo(5 membered unsaturated)heterocyclic group, naphthyl, anthryl, 6-8 membered unsaturated heterocyclic group or 6-8 membered saturated cycloalkyl, all of which are substituted by n R3;

n is an integer of 0-3;

R3is selected from the group consisting of H, halogen, cyano, hydroxyl, amino, nitro, aryl, phenoxy, substituted 6-8 membered saturated heterocyclic group, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C3alkoxy, —C(O)OR51, —N(H)C(O)R51, —NR52R53;

R51is selected from C1-C4alkyl;

R52and R53are each independently selected from aryl;

The substituent of the alkyl is halogen;

The substituent of the alkoxyl is aryl, halogen;

The substituent of the saturated heterocyclic group is C1-C2alkyl;

The heteroatom of the saturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2;

The heteroatom of the unsaturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2;

Or, said compound has a structure of formula IV:



Wherein, ring C is a 5-8 membered saturated heterocyclic group substituted by p R4;

p is an integer of 0-4;

R4is selected from the group consisting of H, hydroxyl, substituted or unsubstituted C1-C4alkyl, —C(O)R51, —N(H)C(O)OR51, —S(O)(O)R51, —C(O)OR51, 6-8 membered unsaturated heterocyclic group, 6-8 membered saturated heterocyclic group, substituted or unsubstituted aryl;

R51is selected from C1-C4alkyl, amino, 5 membered saturated heterocyclic group, benzo(6 membered saturated)heterocyclic group;

The substituent of the alkyl is halogen, benzo(5 membered saturated)heterocyclic group, substituted or unsubstituted aryl, 6 membered saturated heterocyclic group, hydroxyl, —N(H)C(O)OR51, —C(O)R51, —NR52R53;

The substituent of the aryl is halogen, C1alkoxyl, cyano, nitro, substituted or unsubstituted C1alkyl;

R52and R53are each independently selected from C1-C1alkyl;

The heteroatom of the saturated heterocyclic group is O, N and S, and the number of heteroatoms is 1 or 2;

The heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 1 or 2.

Further, said compound has a structure of formula IIA:



Wherein, R21, R22, R23, and R24are each independently selected from the group consisting of H, —C(O)OR51, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C3alkoxy, —N(H)C(O)R51, 6 membered saturated cycloalkyl, —C(O)R51, 6 membered saturated heterocyclic group, carbazolyl, amino, hydroxyl, nitro, —S(O)(O)R51, aryl, cyano, halogen, —C(O)N(H)R51;

R51is selected from the group consisting of H, C1-C2alkyl, amino, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered saturated heterocyclic group, —NR52R53;

R52and R53are each independently selected from H, substituted or unsubstituted 6 membered saturated heterocyclic group, substituted or unsubstituted C1-C4alkyl, 4 membered cycloalkyl;

The substituent of the alkyl is halogen, substituted or unsubstituted 6 membered saturated heterocyclic group;

The substituent of the alkoxyl is halogen, aryl;

The substituent of the aryl is substituted C1alkyl;

The substituent of the saturated heterocyclic group is C1alkyl; the heteroatom of said saturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2.

Or, said compound has a structure of formula IIB:



Wherein, R25is selected from substituted or unsubstituted 6-7 membered saturated heterocyclic group;

The substituent of the saturated heterocyclic group is C1alkyl;

The heteroatom of said heterocyclic group is N and O, and the number of heteroatoms is 2;

Or, said compound has a structure of formula IIC:



Wherein, R26is selected from —N(H)C(O)R51, amino, 6 membered saturated heterocyclic group;

The heteroatom of said saturated heterocyclic group is N and O, and the number of heteroatoms is 2;

R51is selected from C1alkyl;

Or, said compound has a structure of formula IIIA:



Wherein, R31, R32, R33are each independently selected from the group consisting of H, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C3alkoxy, —C(O)OR51, —N(H)C(O)R51, aryl, phenoxy, —NR52R53, substituted 6 membered saturated heterocyclic group, nitro;

R51is selected from C1-C4alkyl;

The substituent of the alkyl is halogen;

The substituent of the alkoxyl is aryl, halogen;

The substituent of the saturated heterocyclic group is C1alkyl;

The heteroatom of the saturated heterocyclic group is N, and the number of heteroatoms is 2;

R52and R53are each independently selected from aryl;

Or, said compound has a structure of formula IIIB:



Wherein,

Ring B is selected from the group consisting of benzo(5-6 membered saturated)heterocyclic group, benzo(5 membered unsaturated)heterocyclic group, substituted or unsubstituted naphthyl, anthryl, substituted 6 membered unsaturated heterocyclic group or 6 membered saturated cycloalkyl;

The substituent of the unsaturated heterocyclic group is cyano, C1alkyl, C2alkoxyl;

The substituent of the naphthyl is C1-C2alkoxyl;

The heteroatom of the saturated heterocyclic group is O, and the number of heteroatoms is 1 or 2;

The heteroatom of the unsaturated heterocyclic group is O and N, and the number of heteroatoms is 1;

Or, said compound has a structure of formula IVA:



Wherein, R41, R42, R43, and R44are each independently selected from the group consisting of H, hydroxyl, —N(H)C(O)OR51, substituted or unsubstituted C1alkyl;

R51is selected from C4alkyl;

The substituent of the alkyl is —N(H)C(O)OR51;

Or, said compound has a structure of formula IVB:



Wherein, R41′, R42′, R43′, and R44′ are each independently selected from H, hydroxyl;

Or, said compound has a structure of formula IVC:



Wherein, R41″, R42″, R43″, and R44″ are each independently selected from H, C1alkyl, —C(O)R51;

R51is selected from C1alkyl;

Or, said compound has a structure of formula IVD:



Wherein, R45, R46, R47, and R48are each independently selected from the group consisting of H, substituted or unsubstituted C1-C4alkyl, —C(O)R51, —S(O)(O)R51, 6 membered unsaturated heterocyclic group, —C(O)OR51, substituted or unsubstituted aryl;

R51is selected from 5 membered saturated heterocyclic group, C1-C4alkyl, benzo(6 membered saturated)heterocyclic group;

R52and R53are each independently selected from C1alkyl;

The substituent of the alkyl is halogen, benzo(5 membered saturated)heterocyclic group, —C(O)R51, —NR52R53, substituted or unsubstituted aryl, 6 membered saturated heterocyclic group, hydroxyl;

The substituent of the aryl is C1alkoxyl, halogen, cyano, nitro, substituted or unsubstituted C1alkyl;

The heteroatom of the saturated heterocyclic group is O and N, and the number of heteroatoms is 1 or 2;

The heteroatom of the unsaturated heterocyclic group is N, and the number of heteroatoms is 1 or 2;

Or, said compound has a structure of formula IVE:



Wherein, R45′, R46′, R47′, and R48′ are each independently selected from H, C1alkyl;

Or, said compound has a structure of formula IVF:



Wherein, R45″, R46″, R47″, and R48″ are each independently selected from H, C1alkyl;

Or, said compound has a structure of formula IVG:



Wherein, R45′″, R46′″, R47′″, and R48′″ are each independently selected from H, hydroxyl, —C(O)OR51, —N(H)C(O)OR51, substituted aryl, substituted or unsubstituted C1alkyl, 6 membered saturated heterocyclic group, —C(O)R51;

R51is selected from C2-C4alkyl, amino;

The substituent of the aryl is halogen;

The substituent of the alkyl is —N(H)C(O)OR51, hydroxyl;

The heteroatom of the saturated heterocyclic group is N, and the number of heteroatoms is 1.

Further, said compounds are:



The present invention also provides the preparative method for the compound mentioned above, or a pharmaceutically acceptable salt, or crystal, or solvate thereof, that includes the following steps:

(1) 2-Acetylphenothiazine and 4-methylbenzenesulfonyl hydrazide are used as starting materials, and dissolved in MeOH, to which is then added the catalyst HOAc. The mixture is heated to 60° C. for reaction, and the progress of the reaction is monitored. After completion of the reaction, the reaction is cooled to room temperature, filtered under reduced pressure, and the filtrate is rinsed to be colorless, then dried in vacuo to obtain intermediate I;

(2) Intermediate I, starting material A, and anhydrous K2CO3are dissolved in 1,4-dioxane, and then reacted at 110° C. The progress of the reaction is monitored. And after completion of the reaction, the mixture is cooled to room temperature and concentrated under reduced pressure to remove 1,4-dioxane.

The residue is extracted, and the organic layer is concentrated and then separated by column chromatography to obtain the target product;

Or, the method includes the following steps:

(1) 2-Acetylphenothiazine and 4-methylbenzenesulfonyl hydrazide are used as starting materials, that are dissolved in MeOH, to which is then added the catalyst HOAc. The mixture is heated to 60° C. for reaction, and the progress of the reaction is monitored. After completion of the reaction, the reaction is cooled to room temperature, filtered under reduced pressure, and the filtrate is rinsed to be colorless, then dried in vacuo to obtain intermediate I;

(2) Intermediate I, starting material A, tris(dibenzylidene-BASE acetone)dipalladium, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl and anhydrous t-BuOLi are dissolved in 1,4-dioxane, to which argon is purged and exchanged for 3 times. The resultant mixture is heated to 70° C. for reaction, and the reaction is monitored by TLC. After about 4 h, the reaction is completed, cooled to room temperature, filtered, concentrated under reduced pressure, and the residue is extracted. The organic layer is concentrated and separated by column chromatography to obtain the target compound;

Or, the method includes the following steps:

(1) 2-Acetylphenothiazine and 4-methylbenzenesulfonyl hydrazide are used as starting materials, that are dissolved in MeOH, to which is then added the catalyst HOAc. The mixture is heated to 60° C. for reaction, and the progress of the reaction is monitored. After completion of the reaction, the reactions are cooled to room temperature, filtered under reduced pressure, and the filtrate is rinsed to be colorless, then dried in vacuo to provide intermediate I;

(2) Intermediate I, starting material A, and DABSO are dissolved in DMSO, to which argon is purged and exchanged for 3 times. The resultant mixture is heated to 100° C. for reaction, and the reaction is monitored. After about 12 h, the reaction is completed, cooled to room temperature, filtered, concentrated under reduced pressure, and the residue is extracted. The organic layer is concentrated and separated by column chromatography to obtain the target compound.

Further, in said step (2), starting material A includes the compounds having following structures:



Or, in said step (2), starting material A includes the compounds having following structures:



Or, in said step (2), starting material A includes the compounds having following structures:



Further, in said step (1), during the rinsing process after completion of the reaction, MeOH and ethyl ether are used to wash; and/or in the step (2), during the extraction process after completion of the reaction, the extraction is carried out with saturated NaHCO3/DCM; and/or, the reaction process is detected all by TLC.

The present invention provides the use of the compound mentioned above, or a pharmaceutically acceptable salt, or crystal, or solvate thereof in the preparation of ferroptosis inhibitor and/or in the preparation of drugs for treatment of stroke; wherein, said ferroptosis inhibitor is a targeted drug for inhibiting cell ferroptosis.

The present invention also provides a drug that is a preparation obtained by using the compound mentioned above, or a pharmaceutically acceptable salt, or crystal, or solvate thereof as active ingredients, with the addition of pharmaceutically acceptable excipients; wherein, said preparations are oral preparations and intravenous injection preparations.

The compounds and derivatives provided in the present invention can be named according to IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracting Service, Columbus, Ohio) naming system.

For the definition of term used in the present the invention: unless otherwise specified, the initial definition provided for the group or the term herein is applicable to those in the whole specification; for terms not specifically defined herein, according to the disclosure content and the context, the term should have the meaning commonly given by those skilled in the field.

“Substitution” means that the hydrogen in a molecule is substituted by other different atoms or molecules.

The structure of the compound mentioned in the present invention all denotes the one that can exist stably.

In the present invention, the structure of substituent “—C(O)R51” is


the structure of substituent “—C(O)OR51” is


the structure of substituent “—C(O)N(H)R51” is


the structure of substituent “—S(O)(O)R51” is


the structure of substituent “—N(H)C(O)R51” is


the structure of substituent “—NR52R53” is


the structure of substituent “—N(H)C(O)OR51” is



In the present invention, the minimum and the maximum for the content of carbon atoms in hydrocarbon groups are represented by prefixes, for example, the prefix (Ca-Cb) alkyls mean any alkyls containing “a”-“b” carbon atoms. Therefore, for example, C1-C8alkyls denotes the straight or branched alkyls containing 1-8 carbon atoms. C1-C8alkoxyls denote the alkoxyls containing 1-8 carbon atoms. In the present invention, “3-8-membered saturated cycloalkyls” denote a monocyclic or polycyclic cycloalkyl consisting of 3-8 carbon atoms, in which there isn't a double bond; 3-8 membered unsaturated cycloalkyls denote a monocyclic cycloalkyl consisting of 3-8 carbon atoms, in which there are one or more double bonds; 3-8-membered saturated heterocyclic groups denote a saturated monocyclic heterocyclic group without double bonds, in which there is at least one heteroatom selected from O, S or substituted nitrogen atom, and the remained atoms in the ring are carbons; 3-8-membered unsaturated heterocyclic groups mean an unsaturated monocyclic heterocyclic group containing double bonds, in which there is at least one heteroatom selected from O, S or substituted nitrogen atom, and the remained atoms in the ring are carbons; a benzo(saturated)heterocyclic group means a saturated heterocyclic group fused with a benzene; a benzo(unsaturated)heterocyclic group means an unsaturated heterocyclic group fused with a benzene.

In the present invention, halogen is fluorine, chlorine, bromine or iodine.

10H-phenothiazine derivatives prepared in the present invention have the effect of inhibiting ferroptosis, and ferroptosis is related to various diseases such as stroke, Parkinson's syndrome and pancreatic cancer, and it has been found that the development of the disease can be intervened by activating or inhibiting ferroptosis. Therefore, 10H-phenothiazine derivatives including bio-pharmaceutically acceptable salts, crystals, and solvates thereof can be used as the main active ingredient, together with the addition of bio-pharmaceutically acceptable excipients, to prepare the inhibitors of ferroptosis. 10H-phenothiazine derivatives or the prepared ferroptosis inhibitors can be used as the main active ingredient of the drugs for treatment of stroke.

In the present invention, a new 10H-phenothiazine derivative has been synthesized that can inhibit ferroptosis, and by study on its structure optimization and structure-activity relationship, it is confirmed that in some embodiments 10H-phenothiazine derivatives can have a better inhibitory effect on body death, and there are compounds that show better therapeutic effects on the rat focal cerebral ischemia model, which can be used as the main active ingredient for the preparation of body death inhibitors. The compounds and the inhibitors prepared by said compounds have good medicinal potential and are expected to become a new candidate drug for treatment of stroke; at the same time, the preparative method of the new compound provided by the present invention is simple, and the reaction conditions are mild, that are convenient for the operation and control. Moreover, the reactions have low consumption, high yield and low cost, and are suitable for industrialized production. The prepared compound has higher biological activity, strong selectivity, and remarkable drug-like properties, and has broad market prospects.

Obviously, based on above content of the present invention, according to the common technical knowledge and the conventional means in the field, without department from above basic technical spirits, other various modifications, alternations or changes can further be made.

By following specific examples of said embodiments, above content of the present invention is further illustrated. But it should not be construed that the scope of above subject of the present invention is limited to following examples. The techniques realized based on above content of the present invention are all within the scope of the present invention.

