RU2020129648A - 10H-PHENOTHIAZINE FERROPTOSE INHIBITORS, METHOD FOR THEIR PRODUCTION AND THEIR APPLICATION - Google Patents

Claims (269)

1. A compound of formula I, or a pharmaceutically acceptable salt or crystal or solvate thereof:

, where if the dotted line represents a connection, R ₁ is 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 with mR ₂ ; m is an integer in the range 0-5; R ₂ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkoxy, 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)R ₅₁ , -C(O)R ₅₁ , -S(O)(O)R ₅₁ , -C(O)N(H)R ₅₁ ; R ₅₁ is selected from the group consisting of H, C ₁ -C ₈ alkyl, amino, substituted or unsubstituted 3-10 membered unsaturated cycloalkyl, substituted or unsubstituted 3-10 membered saturated heterocyclic group, -NR ₅₂ R ₅₃ ; R ₅₂ and R ₅₃ are each independently selected from H, substituted or unsubstituted 5-10 membered saturated heterocyclic group, substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted 3-8 membered saturated cycloalkyl; the alkyl substituent is halogen substituted or unsubstituted with a 4-10 membered saturated heterocyclic group; the alkoxy substituent is halogen, 3-10 membered unsaturated cycloalkyl; a saturated cycloalkyl substituent is C ₁ -C ₈ alkyl; an unsaturated cycloalkyl substituent is C ₁ -C ₈ alkyl; the substituent of the saturated heterocyclic group is C ₁ -C ₈ alkyl; 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 missing, R ₁ is 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 a heterocyclic group, a 3-10 membered saturated cycloalkyl, all of which are substituted with nR ₃ , and -S(O)(O)R ₁ '; n is an integer in the range 0-5; R ₂ is selected from the group consisting of halo, 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 C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkoxy, -C(O)OR ₅₁ , -N(H)C(O)R ₅₁ , -NR ₅₂ R ₅₃ ; R ₁ ' is selected from a 3-10 membered saturated heterocyclic group, a 3-10 membered saturated cycloalkyl group, a 3-10 membered unsaturated cycloalkyl group, and a 3-10 membered unsaturated heterocyclic group, all of which are substituted with pR ₄ ; p is an integer in the range 0-5; R ₄ is selected from the group consisting of hydroxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, -C(O)R ₅₁ , -N(H)C(O)OR ₅₁ , -S(O)(O)R ₅₁ , -C(O)OR ₅₁ , a substituted or unsubstituted 3-10 membered unsaturated heterocyclic group, a substituted or unsubstituted 3-10 membered saturated heterocyclic group, and a substituted or unsubstituted 3-10 membered unsaturated cycloalkyl group; R ₅₁ is selected from the group consisting of C ₁ -C ₁₀ alkyl, amino, 3-8 membered saturated heterocyclic group and benzo(3-8 membered saturated)heterocyclic group; R ₅₂ and R ₅₃ are each independently selected from 3-10 membered unsaturated cycloalkyl, C ₁ -C ₈ alkyl; alkyl substituent 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)OR ₅₁ , -C(O)R ₅₁ , -NR ₅₂ R ₅₃ ; the alkoxy substituent is a 3-10 membered unsaturated cycloalkyl, halogen; the unsaturated cycloalkyl substituent is halogen, C ₁ -C ₆ alkoxy, cyano, nitro, substituted or unsubstituted C ₁ -C ₈ alkyl; the substituent of the saturated heterocyclic group is C ₁ -C ₈ alkyl; the substituent of the unsaturated heterocyclic group is C ₁ -C ₈ alkyl; 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. 2. A compound according to claim 1, or a pharmaceutically acceptable salt or crystal or solvate thereof, wherein: if the dotted line represents a connection, R ₁ is selected from a 3-8 membered unsaturated cycloalkyl and a 3-8 membered unsaturated heterocyclic group, all of which are substituted with mR ₂ ; m is an integer in the range 0-4; R ₂ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, 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)OR ₅₁ , -N(H)C(O)R ₅₁ , -C(O)R ₅₁ , -S(O )(O)R ₅₁ , -C(O)N(H)R ₅₁ ; R ₅₁ is selected from the group consisting of H, C ₁ -C ₄ alkyl, amino, substituted or unsubstituted 3-8 membered unsaturated cycloalkyl, substituted or unsubstituted 5-8 membered saturated heterocyclic group, -NR ₅₂ R ₅₃ ; R ₅₂ and R ₅₃ are each independently selected from H, substituted or unsubstituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted C ₁ -C ₆ alkyl, 3-6 membered saturated cycloalkyl; an alkyl substituent is a halogen, substituted or unsubstituted 5-8 membered saturated heterocyclic group; the alkoxy substituent is halogen, 3-8 membered unsaturated cycloalkyl; an unsaturated cycloalkyl substituent is C ₁ -C ₄ alkyl; the substituent of the saturated heterocyclic group is C ₁ -C ₄ alkyl; the heteroatom of the unsaturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2; the heteroatom of a saturated heterocyclic group is N and O, and the amount heteroatoms equal to 1 or 2; when the dotted line is missing, R ₁ is 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 a heterocyclic group, a 3-8 membered saturated cycloalkyl, all of which are substituted with nR ₃ , and S(O)(O)R ₁ '; n is an integer in the range 0-4; R ₃ is selected from the group consisting of halo, cyano, hydroxyl, amino, nitro, 3-8 membered unsaturated cycloalkyl, phenoxyl, substituted 5-8 membered saturated heterocyclic group, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, -C(O)OR ₅₁ , -N(H)C(O)R ₅₁ , -NR ₅₂ R ₅₃ ; R ₁ ' is selected from a 3-8 membered saturated heterocyclic group substituted with pR ₄ ; p is an integer in the range 0-4; R ₄ is selected from the group consisting of hydroxyl, substituted or unsubstituted C ₁ -C ₆ alkyl, -C(O)R ₅₁ , -N(H)C(O)OR ₅₁ , -S(O)(O)R ₅₁ , -C(O)OR ₅₁ , 3-8-membered unsaturated heterocyclic group, 3-8-membered saturated heterocyclic group and substituted or unsubstituted 3-8-membered unsaturated cycloalkyl; R ₅₁ is selected from the group consisting of C ₁ -C ₈ alkyl, amino, 5-8 membered saturated heterocyclic group, and benzo(5-8 membered saturated)heterocyclic group; R ₅₂ and R ₅₃ are each independently selected from 3-8 membered unsaturated cycloalkyl, C ₁ -C ₄ alkyl; alkyl substituent 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)OR ₅₁ , -C(O)R ₅₁ , -NR ₅₂ R ₅₃ ; the alkoxy substituent is a 3-8 membered unsaturated cycloalkyl, halogen; the unsaturated cycloalkyl substituent is halogen, C ₁ -C ₄ alkoxy, cyano, nitro, substituted or unsubstituted C ₁ -C ₄ alkyl; the substituent of the saturated heterocyclic group is C ₁ -C ₄ alkyl; 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. 3. The compound according to p. 2, or its pharmaceutically acceptable salt, or crystal, or solvate, where the specified compound has the structure of formula II:

, where ring A is selected from aryl or heteroaryl substituted with mR ₂ ; wherein the heteroatom of said heteroaryl is N and the number of heteroatoms is 1 or 2; m is an integer in the range 0-4; R ₂ is selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₃ alkoxy, 6-8 membered saturated cycloalkyl, substituted or unsubstituted 6-7 membered saturated heterocyclic group, carbazolyl, amino, hydroxyl, nitro, aryl, cyano, halogen, -C(O)OR ₅₁ , -N(H)C(O)R ₅₁ , -C(O)R ₅₁ , -S(O)(O) R ₅₁ , -C(O)N(H)R ₅₁ ; R ₅₁ is selected from the group consisting of H, C ₁ -C ₂ alkyl, amino, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered saturated heterocyclic group, -NR ₅₂ R ₅₃ ; R ₅₂ and R ₅₃ are each independently selected from H, substituted or unsubstituted 6-8 membered saturated heterocyclic group, substituted or unsubstituted C ₁ -C ₄ alkyl, 4-5 membered saturated cycloalkyl; an alkyl substituent is a halogen, substituted or unsubstituted 6-8 membered saturated heterocyclic group; the alkoxy substituent is halogen, aryl; the aryl substituent is a substituted C ₁ -C ₃ alkyl; the substituent of the saturated heterocyclic group is C ₁ -C ₃ alkyl; the heteroatom of said heterocyclic group is N and O, and the number of heteroatoms is 1 or 2; or said compound has the structure of formula III:

, where ring B is 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- a membered saturated cycloalkyl, all of which are substituted with nR ₃ ; n is an integer in the range 0-3; R ₃ is selected from the group consisting of H, halogen, cyano, hydroxyl, amino, nitro, aryl, phenoxy, substituted 6-8 membered saturated heterocyclic group, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ - C ₃ alkoxy, -C(O)OR ₅₁ , -N(H)C(O)R ₅₁ , -NR ₅₂ R ₅₃ ; R ₅₁ is selected from C ₁ -C ₄ alkyl; R ₅₂ and R ₅₃ are each independently selected from aryl; the alkyl substituent is halogen; the alkoxy substituent is aryl, halogen; the substituent of the saturated heterocyclic group is C ₁ -C ₂ alkyl; the heteroatom of the saturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2; the heteroatom of an unsaturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2; or said compound has the structure of formula IV:

, where ring C is a 5-8 membered saturated heterocyclic group, substituted by pR ₄ ; p is an integer in the range 0-4; R ₄ is selected from the group consisting of H, hydroxyl, substituted or unsubstituted C ₁ -C ₄ alkyl, -C(O)R ₅₁ , -N(H)C(O)OR ₅₁ , -S(O)(O) R ₅₁ , -C(O)OR ₅₁ , 6-8 membered unsaturated heterocyclic group, 6-8 membered saturated heterocyclic group, substituted or unsubstituted aryl; R ₅₁ is selected from C ₁ -C ₄ alkyl, amino, 5-membered saturated heterocyclic group, benzo(6-membered saturated)heterocyclic group; alkyl substituent is halogen, benzo(5-membered saturated)heterocyclic group, substituted or unsubstituted aryl, 6-membered saturated heterocyclic group, hydroxyl, -N(H)C(O)OR ₅₁ , -C(O)R ₅₁ , -NR ₅₂ R ₅₃ ; the aryl substituent is halogen, C ₁ alkoxy, cyano, nitro, substituted or unsubstituted C ₁ alkyl; R ₅₂ and R ₅₃ are each independently selected from C ₁ -C ₁ alkyl; 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. 4. The compound according to claim 3, or a pharmaceutically acceptable salt or crystal or solvate thereof, wherein said compound has the structure of formula IIA:

, where R ₂₁ , R ₂₂ , R ₂₃ and R ₂₄ are each independently selected from the group consisting of H, -C(O)OR ₅₁ , substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₃ alkoxy, -N(H)C(O)R ₅₁ , 6-membered saturated cycloalkyl, -C(O)R ₅₁ , 6-membered saturated heterocyclic group, carbazolyl, amino, hydroxyl, nitro, -S(O)(O)R ₅₁ , aryl, cyano, halogen, -C(O)N(H)R ₅₁ ; R ₅₁ is selected from the group consisting of H, C ₁ -C ₂ alkyl, amino, substituted or unsubstituted aryl, substituted or unsubstituted 5-6 membered saturated heterocyclic group, -NR ₅₂ R ₅₃ ; R ₅₂ and R ₅₃ are each independently selected from H, substituted or unsubstituted 6-membered saturated heterocyclic group, substituted or unsubstituted C ₁ -C ₄ alkyl, 4-membered cycloalkyl; an alkyl substituent is a halogen, substituted or unsubstituted 6-membered saturated heterocyclic group; the alkoxy substituent is halogen, aryl; the aryl substituent is a substituted C ₁ alkyl; the substituent of the saturated heterocyclic group is C ₁ alkyl; the heteroatom of said saturated heterocyclic group is N and O, and the number of heteroatoms is 1 or 2; or said compound has the structure of formula IIB:

, where R ₂₅ is selected from a substituted or unsubstituted 6-7 membered saturated heterocyclic group; the substituent of the saturated heterocyclic group is C ₁ alkyl; the heteroatom of said heterocyclic group is N and O, and the number of heteroatoms is 2; or said compound has the structure of formula IIC:

, where R ₂₆ is selected from -N(H)C(O)R ₅₁ , amino, 6-membered saturated heterocyclic group; the heteroatom of said saturated heterocyclic group is N and O, and the number of heteroatoms is 2; R ₅₁ is selected from C ₁ alkyl; or said compound has the structure of formula IIIA:

, where R ₃₁ , R ₃₂ , R ₃₃ are each independently selected from the group consisting of H, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₃ alkoxy, -C( O)OR ₅₁ , -N(H)C(O)R ₅₁ , aryl, phenoxy, -NR ₅₂ R ₅₃ , substituted 6-membered saturated heterocyclic group, nitro; R ₅₁ is selected from C ₁ -C ₄ alkyl; the alkyl substituent is halogen; the alkoxy substituent is aryl, halogen; the substituent of the saturated heterocyclic group is C ₁ alkyl; the heteroatom of the saturated heterocyclic group is N and the number of heteroatoms is 2; R ₅₂ and R ₅₃ are each independently selected from aryl; or said compound has the structure of formula IIIB:

, where Ring B is selected from the group consisting of a benzo(5-6 membered saturated)heterocyclic group, a benzo(5 membered unsaturated)heterocyclic group, a substituted or unsubstituted naphthyl, anthryl, a substituted 6 membered unsaturated heterocyclic group, or a 6 membered saturated cycloalkyl; the substituent of the unsaturated heterocyclic group is cyano, C ₁ alkyl, C ₂ alkoxy; the naphthyl substituent is C ₁ -C ₂ alkoxy; 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 the structure of formula IVA:

one where R ₄₁ , R ₄₂ , R ₄₃ and R ₄₄ are each independently selected from the group consisting of H, hydroxyl, - N(H)C(O)OR ₅₁ , substituted or unsubstituted C ₁ alkyl; R ₅₁ is selected from C ₄ alkyl; an alkyl substituent is -N(H)C(O)OR ₅₁ ; or said compound has the structure of formula IVB:

, where R ₄₁ ', R ₄₂ ', R ₄₃ ' and R ₄₄ ' each independently selected from H, hydroxyl; or said compound has the structure of the IVC formula:

, where R ₄₁ '', R ₄₂ '', R ₄₃ '' and R ₄₄ '' are each independently selected from H, C ₁ alkyl, -C(O)R ₅₁ ; R ₅₁ is selected from C ₁ alkyl; or said compound has the structure of formula IVD:

5 where R ₄₅ , R ₄₆ , R ₄₇ and R ₄₈ are each independently selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₄ alkyl, -C(O)R ₅₁ , -S(O)(O)R ₅₁ , 6-membered unsaturated heterocyclic group, -C(O)OR ₅₁ , substituted or unsubstituted aryl; R ₅₁ is selected from 5-membered saturated heterocyclic group, C ₁ -C ₄ alkyl, benzene-membered saturated heterocyclic group; R ₅₂ and R ₅₃ are each independently selected from C ₁ alkyl; an alkyl substituent is halogen, a benzo(5-membered saturated)heterocyclic group, -C(O)R ₅₁ , -NR ₅₂ R ₅₃ , substituted or unsubstituted aryl, a 6-membered saturated heterocyclic group, hydroxyl; the aryl substituent is C ₁ alkoxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ alkyl; 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 the specified compound has the structure of the IVE formula:

, where R ₄₅ ', R ₄₆ ', R ₄₇ ' and R ₄₈ ' each independently selected from H, C ₁ alkyl; or said compound has the structure of formula IVF:

, where R ₄₅ '', R ₄₆ '', R ₄₇ '' and R ₄₈ '' are each independently selected from H, C ₁ alkyl; or said compound has the structure of formula IVG:

, IVG where R ₄₅ ''', R ₄₆ ''', R ₄₇ ''' and R ₄₈ ''' are each independently selected from H, hydroxyl, -C(O)OR ₅₁ , -N(H)C(O)OR ₅₁ , substituted aryl, substituted or unsubstituted C ₁ alkyl, 6-membered saturated heterocyclic group, -C(O)R ₅₁ ; R ₅₁ is selected from C ₂ -C ₄ alkyl, amino; the aryl substituent is halogen; an alkyl substituent is -N(H)C(O)OR ₅₁ , hydroxyl; the heteroatom of a saturated heterocyclic group is N, and the number of heteroatoms is 1. 5. A compound according to claim 1, or a pharmaceutically acceptable salt or crystal or solvate thereof, wherein said compound is selected from:

6. A method for preparing a compound according to claim 1, or a pharmaceutically acceptable salt or crystal or solvate thereof, comprising the following steps: (1) 2-acetylphenothiazine and 4-methylbenzenesulfonylhydrazide are used as starting materials, they are dissolved in MeOH, and then the HOAc catalyst is added; the mixture is heated to 60°C to carry out the reaction and control the progress of the reaction; after completion of the reaction, the reaction mixture is cooled to room temperature, filtered under reduced pressure, the filtrate is washed until colorless, and then dried under vacuum to obtain intermediate I; (2) intermediate I, starting compound A and anhydrous K ₂ CO ₃ are dissolved in 1,4-dioxane and then reacted at 110°C; the progress of the reaction is monitored, 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 subjected to extraction, the organic layer is concentrated and then separated by column chromatography to obtain the target product; or including the following steps: (1) 2-acetylphenothiazine and 4-methylbenzenesulfonylhydrazide are used as starting materials, they are dissolved in MeOH and then HOAc catalyst is added; the mixture is heated to 60°C to carry out the reaction and control the progress of the reaction; after completion of the reaction, the reaction mixture is cooled to room temperature, filtered under reduced pressure, the filtrate is washed until colorless and then dried under vacuum to obtain intermediate I; (2) Intermediate I, starting compound A, tris(dibenzylidene-acetone)dipalladium, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl and anhydrous d-BuOLi are dissolved in 1,4-dioxane, purged with argon and replaced with 3 times; the resulting mixture is heated to 70°C to carry out the reaction and control the progress of the reaction by TLC; after about 4 hours the reaction is complete, cooled to room temperature, filtered, concentrated under reduced pressure and the residue is subjected to extraction; the organic layer is concentrated and separated by column chromatography to obtain the target compound; or including the following steps: (1) 2-acetylphenothiazine and 4-methylbenzenesulfonylhydrazide are used as starting materials, they are dissolved in MeOH and then HOAc catalyst is added; the mixture is heated to 60°C to carry out the reaction and control the progress of the reaction; after completion of the reaction, the reaction mixture is cooled to room temperature, filtered under reduced pressure, the filtrate is washed until colorless and then dried under vacuum to obtain intermediate I; (2) Intermediate I, parent compound A and DABSO were dissolved in DMSO, purged with argon and replaced 3 times; the resulting mixture is heated to 100°C to carry out the reaction and control the progress of the reaction; after about 12 hours the reaction is complete, cooled to room temperature, filtered, concentrated under reduced pressure and the residue is subjected to extraction; the organic layer is concentrated and separated using column chromatography to obtain the target compound. 7. The method of production according to p. 6, in which in the specified stage (2) the starting compound A is selected from:

And

8. The method of obtaining according to p. 6, in which at the specified stage (1) in the washing process after completion of the reaction for washing using MeOH and ethyl ether; and/or in step (2) in the extraction process after completion of the reaction, the extraction is carried out with saturated NaHCO ₃ /DCM; and/or the progress of the reaction is monitored by TLC. 9. A method for inhibiting cell ferroptosis, comprising administering a pharmaceutically acceptable amount of a compound according to claim 1, or a pharmaceutically acceptable salt or crystal or solvate thereof, to a subject in need thereof. 10. A pharmaceutical preparation containing a compound according to claim 1, or a pharmaceutically acceptable salt or crystal or solvate thereof, as active ingredients and one or more pharmaceutically acceptable excipients; wherein said pharmaceutical preparation is an oral preparation or an intravenous injection preparation.