Tamoxifen derivatives for treatment of neoplastic diseases, especially with high HER2 protein level

1. A mitochondrially targeted E/Z isomer of an aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA,

wherein n=8 to 12,

wherein Z is selected from the group consisting of anions of organic salts, anions of inorganic salts, and mixtures thereof, and

wherein the crossed double bond in general formula I indicates that the double bond may have E and/or Z configuration,

wherein n=6 to 10,

wherein Z is as defined above, and

wherein the crossed double bond in general formula IA indicates that the double bond may have E and/or Z configuration.

2. The mitochondrially targeted E/Z isomer of the aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA according to claim 1 , wherein Z is selected from the group consisting of citrate, acetate, lactate, tartrate, oxalate, ascorbate, mesylate, tosylate, sulphate, halogenide, phosphate, and mixtures thereof.

3. A method of preparing the mitochondrially targeted E/Z isomer of an alkyl triphenylphosphonium derivative of tamoxifen of general formula I according to claim 1 , the method comprising the steps of:

generating, under the treatment of an organic base in tetrahydrofuran under an argon atmosphere at a temperature of −78° C., an ylide from tert-butyldimethylsilyl-oxy-alkyl-triphenylphosphonium of general formula II:

wherein n=5 to 9, and

wherein X is I, Br, Cl or mesyl,

condensing the ylide with an aldehyde of general formula III to form a silylated derivative of general formula IV:

treating the silylated derivative of general formula IV with tetrabutylammonium fluoride to form an alkenol of general formula V:

reducing the alkenol of general formula V in a hydrogen atmosphere in the presence of a catalyst to form an alcohol of general formula VI,

substituting the alcohol of general formula VI to form a derivative of general formula VII,

 and

converting the derivative of general formula VII to the mitochondrially targeted E/Z isomer of an alkyl triphenylphosphonium derivative of tamoxifen of general formula I by heating with triphenylphosphine.

4. A method of preparing the mitochondrially targeted E/Z isomer of an alkyl triphenylphosphonium derivative of tamoxifen of general formula I according to claim 1 , the method comprising the steps of:

condensing a (hydroxyalkyl)triphenylphosphonium bromide with an aldehyde of general formula III under the treatment of a base in a mixture tetrahydrofuran and dimethylsulphoxide at room temperature to form an alkenol of general formula V:

wherein n=5 to 9, and

wherein X is I, Br, Cl or mesyl,

reducing the alkenol of general formula V in a hydrogen atmosphere in the presence of a catalyst to form an alcohol of general formula VI,

substituting the alcohol of general formula VI to form a derivative of general formula VII,

 and

converting the derivative of general formula VII to the mitochondrially targeted E/Z isomer of an alkyl triphenylphosphonium derivative of tamoxifen of general formula I by heating with triphenylphosphine.

5. A method of preparing the mitochondrially targeted E/Z isomer of an alkylenyl triphenylphosphonium derivative of tamoxifen of general formula IA according to claim 1 , the method comprising the steps of:

generating, in a mixture of tetrahydrofuran and dimethylsulphoxide in an argon atmosphere at room temperature under the treatment of organic base, an ylide from alkyl bis(triphenylphosphonium) with the general Formula XII:

wherein n=7 to 11, and

wherein X is I, Br, Cl or mesyl or their combination, and

subsequently condensing the ylide with an aldehyde of formula III to form the mitochondrially targeted E/Z isomer of an alkylenyl triphenylphosphonium derivative of tamoxifen of general formula IA:

6. A method of treating neoplastic disease comprising administering the mitochondrially targeted E/Z isomer of an aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA according to claim 1 , wherein the neoplastic disease is selected from the group consisting of carcinoma, sarcoma, lymphoma and leukemia.

7. A method of treating neoplastic disease comprising administering the mitochondrially targeted E/Z isomer of an aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA according to claim 1 , wherein the neoplastic disease is selected from the group consisting of astrocytoma, neuroblastoma, glioblastoma, mesothelioma, breast cancer, prostate cancer, non-small cell lung cancer, cervical cancer, osteosarcoma, colorectal cancer, hepatocarcinoma, and leukemia.

8. A method of killing cancer cells in various regions of breast tumors, regardless of expression levels of HER2, ERα, GATA3 and Ki67 proteins comprising administering the mitochondrially targeted E/Z isomer of an aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA according to claim 1 .

9. A method of inhibiting respiration via the mitochondrial complex I comprising administering the mitochondrially targeted E/Z isomer of an aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA according to claim 1 .

10. A drug for the treatment of neoplastic disease, the drug comprising at least one mitochondrially targeted E/Z isomer of an aliphatic triphenylphosphonium derivative of tamoxifen of general formula I or IA according to claim 1 .

11. The drug according to claim 10 , wherein the neoplastic disease is breast cancer with a high HER2 protein level.

12. The drug according to claim 10 , wherein the neoplastic disease is breast cancer with a low HER2 protein level.

13. The drug according to claim 10 , wherein the drug is efficient against neoplastic disease with either low or high HER2 protein levels.