1-phenylpropanone compounds and use thereof

Abstract

The present invention relates to a 1-phenylpropanone compound of formula (I), wherein X is CH.sub.2 or an atom selected from the group consisting of O, S and Se, n is an integer from 4 to 6, A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl, 4-methyl-1-piperazinyl, A being optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl substituent, with the proviso that when X is CH.sub.2, n is equal to 5, for use as an antitumoral agent in the treatment of breast cancer, chronic lymphatic leukemia or neuroblastoma. The invention also concerns new 1-phenylpropanone compounds, and compounds as antitumoral agents. ##STR00001##

Claims

1. A method for the treatment of breast cancer, chronic lymphatic leukemia or neuroblastoma, comprising the step of administering a 1-phenylpropanone compound of formula (I) ##STR00021## or a pharmaceutically acceptable salt thereof wherein: X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se, n is an integer from 4 to 6, A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical, with the proviso that when X is O, A is 4-methyl-1-piperazinyl, and n is equal to 6, when X is S and n is 5, then A is 4-methyl-1-piperazinyl, when X is Se and A is 1-piperidinyl, then n is 6, when X is CH.sub.2, n is equal to 5, and A is 4-methyl-1-piperazinyl or 4-morpholyl.

2. The method of claim 1, wherein X is S, Se or CH.sub.2.

3. The method of claim 1, wherein n is 5 or 6.

4. The method of claim 1, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

5. The method of claim 4, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

6. The method of claim 5, wherein said compound is selected from the group consisting of: Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

7. A 1-phenylpropanone compound of formula (I) ##STR00022## or a pharmaceutically acceptable salt thereof wherein: X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se, n is an integer from 4 to 6, A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical, with the proviso that when X is O, A is 4-methyl-1-piperazinyl, and n is equal to 6, when X is S and n is 5, then A is 4-methyl-1-piperazinyl, when X is Se and A is 1-piperidinyl, then n is 6, when X is CH.sub.2, n is equal to 5, and A is 4-methyl-1-piperazinyl or 4-morpholyl.

8. The compound of claim 7, wherein X is selected from the group consisting of S, Se or CH.sub.2.

9. The compound of claim 7, wherein n is 5 or 6.

10. The compound of claim 8, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

11. The compound of claim 10, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

12. The compound of claim 11, wherein said compound is selected from the group consisting of: Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

13. A pharmaceutical composition comprising a compound of formula (I) ##STR00023## or a pharmaceutically acceptable salt thereof wherein: X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se, n is an integer from 4 to 6, A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical, with the proviso that when X is O, A is 4-methyl-1-piperazinyl, and n is equal to 6, when X is S and n is 5, then A is 4-methyl-1-piperazinyl or 4-morpholyl, when X is Se and A is 1-piperidinyl, then n is 6, when X is CH.sub.2, n is equal to 5, and A is 4-methyl-1-piperazinyl or 4-morpholyl; and a pharmaceutically acceptable vehicle.

14. The pharmaceutical composition of claim 13, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one, Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

15. The pharmaceutical composition of claim 14, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

16. The pharmaceutical composition of claim 15, wherein said compound is selected from the group consisting of: Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

17. A method for treating a tumor comprising the step of administering a compound of formula (I) ##STR00024## or a pharmaceutically acceptable salt thereof wherein: X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se, n is an integer from 4 to 6, A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical, with the proviso that when X is O, A is 4-methyl-1-piperazinyl, and n is equal to 6, when X is S and n is 5, then A is 4-methyl-1-piperazinyl, when X is Se and A is 1-piperidinyl, then n is 6, when X is CH.sub.2, n is equal to 5, and A is 4-methyl-1-piperazinyl or 4-morpholyl.

18. The method of claim 17, wherein the tumor is breast cancer, hepatocarcinoma, chronic lymphatic leukemia or neuroblastoma.

19. The method of claim 17, wherein X is selected from the group consisting of S, Se or CH.sub.2.

20. The method of claim 17, wherein n is 5 or 6.

21. The method of claim 17, wherein the 1-phenylpropanone compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, ene; Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one, Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

22. The method of claim 21, wherein said compound is selected from the group consisting of: Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

23. The method of claim 22, wherein said compound is selected from the group consisting of: Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one, Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one, Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one, Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one, Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

24. The compound of claim 8, wherein X is S.

25. The method of claim 2, wherein X is S.

26. The method of claim 17, wherein X is S.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows the results of tests aimed at assessing the immunosuppression characteristics of compounds of the invention and, by comparison, of a compound of the prior art.

DETAILED DESCRIPTION OF THE INVENTION

(2) In the compounds of the invention, the optional substituent C.sub.3-alkyl of substituent A may be either n-propyl or isopropyl.

(3) The invention relates to a 1-phenylpropanone compound of formula (I)

(4) ##STR00008##
wherein
X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se,
n is an integer from 4 to 6,
A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical,
with the proviso that when X is CH.sub.2, n is equal to 5,
for use as an antitumoral agent in the treatment of breast cancer, chronic lymphatic leukemia (LLC) or neuroblastoma.

(5) In the treatment of breast cancer, chronic lymphatic leukemia (LLC) or neuroblastoma, the compound of the invention is preferably a compound wherein X is S, Se or CH.sub.2, more preferably S; a compound wherein n is 5 or 6.

(6) A is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl substituent.

(7) Preferably, in the treatment of breast cancer, chronic lymphatic leukemia (LLC) or neuroblastoma, the compound of formula (I) is selected from the group consisting of:

(8) ##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##

(9) More preferably, in the treatment of breast cancer, chronic lymphatic leukemia (LLC) or neuroblastoma, the compound of formula (I) is selected from the group consisting of:

(10) Compound 1 (AF08), 1-(4-(hexyloxy)phenyl)-3-morpholinopropan-1-one,

(11) Compound 3 (AF07), 1-(4-(hexyloxy)phenyl)-3-(piperidin-1-yl)propan-1-one,

(12) Compound 4 (CC12), 1-(4-(heptyloxy)phenyl)-3-(piperidin-1-yl)propan-1-one,

(13) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(14) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(15) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(16) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(17) Compound 10 (VP157), 1-(4-(hexylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(18) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(19) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(20) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(21) Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one,

(22) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(23) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(24) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(25) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(26) Compound 25 (GR391), 1-(4-heptylphenyl)-3-(piperidin-1-yl)propan-1-one, and

(27) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(28) Even more preferably, in the treatment of breast cancer, chronic lymphatic leukemia (LLC) or neuroblastoma, the compound of formula (I) is selected from the group consisting of:

(29) Compound 1 (AF08), 1-(4-(hexyloxy)phenyl)-3-morpholinopropan-1-one,

(30) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(31) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(32) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(33) Compound 9 (MC12) 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(34) Compound 10 (VP157), 1-(4-(hexylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(35) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(36) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(37) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(38) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(39) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(40) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(41) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(42) Compound 25 (GR391), 1-(4-heptylphenyl)-3-(piperidin-1-yl)propan-1-one, and

(43) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(44) The inventors also synthesized new 1-phenylpropanone compounds that resulted to have apoptotic activity against tumor cells.

(45) In another aspect, the invention concerns a 1-phenylpropanone compound of formula (I)

(46) ##STR00018##
wherein:
X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se,
n is an integer from 4 to 6,
A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical,
with the proviso that
when X is O, A is 4-methyl-1-piperazinyl, and n is equal to 6,
when X is S and n is 5, then A is 4-methyl-1-piperazinyl,
when X is Se and A is 1-piperidinyl, then n is 6,
when X is CH.sub.2, n is equal to 5, and A is 4-methyl-1-piperazinyl or 4-morpholyl.

(47) Preferably, in the 1-phenylpropanone compound of the invention, X is selected from the group consisting of S, Se or CH.sub.2, more preferably it is S.

(48) A is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl substituent.

(49) Advantageously, the compound of the invention is a compound wherein n is 5 or 6.

(50) The new compound of formula (I) is preferably a compound selected from the group consisting of:

(51) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(52) Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one,

(53) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(54) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(55) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(56) Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one,

(57) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(58) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(59) Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one,

(60) Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one,

(61) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(62) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(63) Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one,

(64) Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(65) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(66) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(67) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(68) More preferably, the new compound of formula (I) is preferably a compound selected from the group consisting of:

(69) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(70) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(71) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(72) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(73) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(74) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(75) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(76) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(77) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(78) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and

(79) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(80) Even more preferably, the new compound of formula (I) is preferably a compound selected from the group consisting of:

(81) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(82) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(83) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(84) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(85) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(86) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(87) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(88) In a further aspect the invention concerns a compound of formula (I)

(89) ##STR00019##
wherein:
X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se,
n is an integer from 4 to 6,
A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical,
with the proviso that
when X is O, A is 4-methyl-1-piperazinyl and n is equal to 6,
when X is S and n is 5, then A is 4-methyl-1-piperazinyl or 4-morpholyl,
when X is Se and A is 1-piperidinyl, then n is 6,
when X is CH.sub.2, n is equal to 5, and A is 4-methyl-1-piperazinyl or 4-morpholyl for use as a medicament.

(90) Preferably, in the 1-phenylpropanone compound as a medicament of the invention, X is selected from the group consisting of S, Se or CH.sub.2, more preferably it is S.

(91) A is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl substituent.

(92) Advantageously, the compound as a medicament of the invention is a compound wherein n is 5 or 6.

(93) The compound of formula (I) as a medicament is preferably a compound selected from the group consisting of:

(94) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(95) Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one,

(96) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(97) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(98) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(99) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(100) Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one,

(101) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(102) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(103) Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one,

(104) Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one,

(105) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(106) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(107) Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one,

(108) Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(109) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(110) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and

(111) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(112) More preferably, the new compound of formula (I) as a medicament is preferably a compound selected from the group consisting of:

(113) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(114) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(115) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(116) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(117) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(118) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(119) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(120) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(121) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(122) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(123) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one, and

(124) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(125) Even more preferably, the new compound of formula (I) as a medicament is preferably a compound selected from the group consisting of:

(126) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(127) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(128) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(129) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(130) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(131) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(132) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(133) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(134) In a further aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) as a medicament, and a pharmaceutically acceptable vehicle.

(135) The compounds of the invention, as such or a pharmaceutically acceptable salt thereof, may be employed in medicine. They can then be combined with a pharmaceutically acceptable vehicle, and optionally suitable excipients, to obtain pharmaceutical compositions. By the term “pharmaceutically acceptable vehicle” it is meant to include solvents, technological aids, diluents, and the like that are employed in administering compounds of the invention.

(136) Such pharmaceutical compositions may be administered by parenteral, oral, buccal, sublingual, nasal, rectal, topical, or transdermal route.

(137) Compositions of the present invention suitable for oral administration will conveniently be in the form of discrete units, such as tablets, capsules, cachets, powders, or granules, or even as suspensions in a liquid.

(138) The tablets may also contain suitable pharmaceutical excipients, such as pre-gelatinized starch, microcrystalline cellulose, sodium glycol starch, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.

(139) Compositions for parenteral administration will conveniently comprise sterile preparations.

(140) Compositions for topical administration will conveniently be in the form of creams, pastes, oils, ointments, emulsions, foams, gels, drops, spray solutions, and transdermal patches.

(141) In yet a further aspect, the invention concerns a compound of formula (I)

(142) ##STR00020##
wherein:
X is a methylene group (—CH.sub.2—) or an atom selected from the group consisting of O, S and Se,
n is an integer from 4 to 6,
A is a substituent selected from the group consisting of 4-morpholyl, 1-piperidinyl and 4-methyl-1-piperazinyl, and it is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl radical,
with the proviso that
when X is O, A is 4-methyl-1-piperazinyl or 1-piperidinyl, and n is equal to 6,
when X is C, n is 5 for use as an antitumoral agent.

(143) Preferably, the antitumoral treatment is against breast cancer, hepatocarcinoma, chronic lymphatic leukemia (LLC) or neuroblastoma.

(144) Preferably, in the 1-phenylpropanone compound of the invention for use as an antitumoral agent, X is selected from the group consisting of S, Se or CH.sub.2, more preferably it is S.

(145) A is optionally substituted with a (C.sub.1-C.sub.3)alkyl or (C.sub.1-C.sub.3)acyl substituent.

(146) Advantageously, the compound of the invention for use as an antitumoral agent is a compound wherein n is 5 or 6.

(147) Preferably, the 1-phenylpropanone compound of the invention for use as an antitumoral agent is a compound selected from the group consisting of:

(148) Compound 4 (CC12), 1-(4-(heptyloxy)phenyl)-3-(piperidin-1-yl)propan-1-one,

(149) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(150) Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one,

(151) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(152) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(153) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(154) Compound 10 (VP157), 1-(4-(hexylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(155) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(156) Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one,

(157) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(158) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(159) Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one,

(160) Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one,

(161) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(162) Compound 18 (GR378), 1-(4-(pentylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(163) Compound 19 (GR381), 1-(4-(hexylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(164) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(165) Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one,

(166) Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(167) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(168) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(169) Compound 25 (GR391), 1-(4-heptylphenyl)-3-(piperidin-1-yl)propan-1-one, and

(170) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(171) More preferably it is a compound for antitumoral use selected from the group consisting of:

(172) Compound 4 (CC12), 1-(4-(heptyloxy)phenyl)-3-(piperidin-1-yl)propan-1-one,

(173) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(174) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(175) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(176) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(177) Compound 10 (VP157), 1-(4-(hexylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(178) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(179) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(180) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(181) Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one,

(182) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(183) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(184) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(185) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(186) Compound 25 (GR391), 1-(4-heptylphenyl)-3-(piperidin-1-yl)propan-1-one, and

(187) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(188) Even more preferably, the compound of formula (I) for use as an antitumoral agent is selected from the group consisting of:

(189) Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(190) Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one,

(191) Compound 8 (FT017), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one,

(192) Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(193) Compound 10 (VP157), 1-(4-(hexylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(194) Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one,

(195) Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(196) Compound 14 (FT019), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(197) Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one,

(198) Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one,

(199) Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one,

(200) Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one,

(201) Compound 25 (GR391), 1-(4-heptylphenyl)-3-(piperidin-1-yl)propan-1-one, and

(202) Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one.

(203) According to the invention, the novel compounds or the ones for use as a medicament or as antitumoral agents, preferably and specifically for breast cancer, chronic lymphatic leukemia, or neuroblastoma, are obtained through a simple process, of easy industrial scalability, and avoiding the use of lengthy and expensive preparation steps, obtaining high yields of a stable pharmaceutically grade compound.

(204) Now follows the experimental part for the preparation of compounds of the invention, and the assessment of the efficacy thereof, by way of illustration and not limitative of the invention.

EXPERIMENTAL PART

Example 1

(205) Preparation of Compounds of Formula (I)

(206) General Procedure for the Preparation of 1-Phenylpropanone Compounds of Formula (I) Wherein X is Oxygen

(207) The phenyl alkyl ether intermediate was obtained from the reaction between phenol and the appropriate 1-bromoalkane (for example, 1-bromopentane, 1-bromohexane, or 1-bromoheptane, in an amount of 1 equivalent) in acetonitrile in the presence of potassium carbonate (2 equivalents). The mixture was stirred for 5 h at room temperature, the solid thus formed was then removed by filtration, and the solvent evaporated by rotary evaporation. The obtained phenyl alkyl ether intermediate was reacted with 3-bromopropionyl chloride (2 equivalents) and aluminum trichloride (3 equivalents) in 1,2-dichloroethane in ice bath. The reaction was quenched by pouring it into water, and extracting the desired intermediate with diethyl ether. The organic layer was separated and subjected to rotary evaporation to obtain the phenyl alkyl ether derivative acylated in the para position. The intermediate thus synthesized was then treated with an appropriate cyclic amine (morpholine, piperidine or N-methyl piperazine, 2 equivalents), potassium iodide (2 equivalents) and calcium carbonate (3 equivalents) in toluene. The mixture was refluxed for 12 h. After cooling, the solid was removed by filtration, and the solvent evaporated by rotary evaporation. The residue was then dispersed into dichloromethane, and the mixture was washed with 10% sodium hydroxide solution. The organic layer was evaporated by rotary evaporation, affording the desired compound as indicated below. Yields: 68-78%.

Compound 1 (AF08), 1-(4-(hexyloxy)phenyl)-3-morpholinopropan-1-one

(208) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.95 (d, 2H, PhH), 6.92 (d, 2H, PhH), 4.00 (t, 2H, OCH.sub.2), 3.71 (m, 4H, OCH.sub.2), 3.15 (t, 2H, COCH.sub.2), 2.85 (t, 2H, NCH.sub.2), 2.54 (m, 4H, NCH.sub.2), 1.82 (m, 2H, CH.sub.2), 1.4-1.2 (m, 6H, CH.sub.2), 0.92 (t, 3H, CH.sub.3).

(209) .sup.13C-NMR {1H} (100 MHz, CDCl3) δ: 196.5, 162.2, 129.3, 113.2, 76.2, 67.3, 65.9, 52.8, 52.7, 34.5, 30.5, 28.0, 24.6, 21.6, 13.0. m/z (ESI): 320.2.

(210) Yield: 72%. Purity (HPLC): 97%.

Compound 2 (CC11), 1-(4-(heptyloxy)phenyl)-3-morpholinopropan-1-one

(211) .sup.1H-NMR (400 MHz, CDCl3) δ: 7.95 (d, 2H, PhH), 6.94 (d, 2H, PhH), 4.04 (t, 2H, OCH.sub.2), 3.74 (m, 4H, OCH.sub.2), 3.16 (t, 2H, COCH.sub.2), 2.85 (t, 2H, NCH.sub.2), 2.54 (m, 4H, NCH.sub.2), 1.83 (m, 2H, CH.sub.2), 1.5-1.2 (m, 8H, CH.sub.2), 0.92 (t, 3H, CH.sub.3).

(212) .sup.13C-NMR {1H} (100 MHz, CDCl3) δ: 197.5, 163.2, 130.3, 129.7, 114.2, 68.3, 67.0, 53.8, 53.7, 35.6, 31.7, 29.1, 29.0, 25.9, 22.6, 14.1. m/z (ESI): 334.2.

(213) Yield: 68%. Purity (HPLC): 97%.

Compound 3 (AF07), 1-(4-(hexyloxy)phenyl)-3-(piperidin-1-yl)propan-1-one

(214) 1H-NMR (400 MHz, CDCl3) δ: 7.80 (d, 2H, PhH), 6.94 (d, 2H, PhH), 4.04 (t, 2H, OCH.sub.2), 3.18 (m, 4H, NCH.sub.2), 3.11 (t, 2H, COCH.sub.2), 2.82 (t, 2H, CH.sub.2), 1.82 (m, 2H, CH.sub.2), 1.63 (m, 4H, CH.sub.2), 1.49 (m, 4H, CH.sub.2), 1.37 (m, 4H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(215) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 195.5, 161.8, 129.0, 128.5, 12.9, 75.9, 66.9, 53.3, 52.8, 30.3, 27.8, 24.6, 24.7, 21.3, 19.0, 12.8. m/z (ESI): 318.2.

(216) Yield: 75%. Purity (HPLC): 98%.

Compound 4 (CC12), 1-(4-(heptyloxy)phenyl)-3-(piperidin-1-yl)propan-1-one

(217) .sup.1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, 2H, PhH), 6.92 (d, 2H, PhH), 4.01 (t, 2H, OCH.sub.2), 3.18 (m, 4H, NCH.sub.2), 3.10 (t, 2H, COCH.sub.2), 2.83 (t, 2H, CH.sub.2), 1.82 (m, 2H, CH.sub.2), 1.62 (m, 6H, CH.sub.2), 1.50 (m, 4H, CH.sub.2), 1.32 (m, 4H, CH.sub.2), 0.99 (t, 3H, CH.sub.3).

(218) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 198.0, 163.1, 130.3, 129.8, 114.2, 68.2, 54.6, 54.2, 36.1, 31.7, 29.1, 29.0, 26.0, 25.9, 24.3, 22.6, 14.1. m/z (ESI): 332.3.

(219) Yield: 76%. Purity (HPLC): 97%.

Compound 5 (AI01), 1-(4-(heptyloxy)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one

(220) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.89 (d, 2H, PhH), 6.90 (d, 2H, PhH), 4.03 (t, 2H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 2.83 (t, 2H, NCH.sub.2), 2.62 (m, 4H, NCH.sub.2), 2.50 (m, 4H, NCH.sub.2), 2.33 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2), 1.4-1.2 (m, 8H, CH.sub.2), 0.92 (t, 3H, CH.sub.3).

(221) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 196.2, 162.2, 129.1, 114.1, 76.9, 66.7, 65.1, 52.8, 51.1, 45.1, 32.5, 33.2, 29.4, 28.7, 24.6, 21.2, 13.1. m/z (ESI): 347.3.

(222) Yield: 70%. Purity (HPLC): 97%.

(223) General Procedure for the Preparation of 1-Phenylpropanone Compounds of Formula (I) Wherein X is Sulfur

(224) The phenyl alkyl thioether intermediate was obtained from the reaction between thiophenol and the appropriate 1-bromoalkane (for example, 1-bromopentane, 1-bromohexane, or 1-bromoheptane, 1 equivalent) in the presence of potassium hydroxide (2 equivalents) in ethanol at room temperature. The mixture was stirred for 5 h at room temperature, the solid thus formed was then removed by filtration, and the solvent evaporated by rotary evaporation. The obtained phenyl alkyl thioether intermediate was then reacted with 3-bromopropionyl chloride (2 equivalents) and aluminum trichloride (3 equivalents) in 1,2-dichloroethane in ice bath. The reaction was quenched by pouring it into water, and extracting the desired intermediate with diethyl ether. The organic layer was separated and subjected to rotary evaporation to obtain the phenyl alkyl thioether acylated in the para position. The intermediate thus synthesized was treated with an appropriate cyclic amine (morpholine, piperidine or N-methyl piperazine, 2 equivalents), potassium iodide (2 equivalents) and calcium carbonate (3 equivalents) in toluene. The mixture was refluxed for 12 h. After cooling, the solid was removed by filtration, and the solvent evaporated by rotary evaporation. The residue was dispersed into dichloromethane, and the mixture was washed with 10% sodium hydroxide solution. The organic layer was evaporated by rotary evaporation to afford the desired compound. Yields: 65-75%.

Compound 6 (MD63), 3-morpholino-1-(4-(pentylthio)phenyl)propan-1-one

(225) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.83 (d, 2H, PhH), 7.28 (d, 2H, PhH), 3.69 (t, 4H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 2.97 (t, 2H, CH.sub.2), 2.81 (t, 2H, SCH.sub.2), 2.49 (m, 4H, NCH.sub.2), 1.69 (m, 4H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.90 (t, 3H, CH.sub.3).

(226) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 197.9, 145.1, 133.5, 128.4, 126.3, 66.8, 53.7, 53.6, 35.8, 31.8, 31.0, 28.4, 22.1, 13.8. m/z (ESI): 322.2.

(227) Yield: 72%. Purity (HPLC): 98%.

Compound 7 (VP158), 1-(4-(hexylthio)phenyl)-3-morpholinopropan-1-one

(228) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.84 (d, 2H, PhH), 7.19 (d, 2H, PhH), 3.69 (t, 4H, OCH.sub.2), 3.10 (t, 2H, COCH.sub.2), 2.98 (t, 2H, CH.sub.2), 2.81 (t, 2H, SCH.sub.2), 2.44 (m, 4H, NCH.sub.2), 1.7-1.5 (m, 6H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.90 (t, 3H, CH.sub.3).

(229) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 197.9, 145.2, 137.1, 133.4, 128.8, 68.9, 53.7, 35.7, 33.6, 31.9, 31.3, 30.5, 29.1, 28.5, 22.5. m/z (ESI): 336.2.

(230) Yield: 69%. Purity (HPLC): 97%.

Compound 8 (FT17), 1-(4-(heptylthio)phenyl)-3-morpholinopropan-1-one

(231) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.82 (d, 2H, PhH), 7.22 (d, 2H, PhH), 3.66 (t, 4H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 2.92 (t, 2H, CH.sub.2), 2.79 (t, 2H, SCH.sub.2), 2.44 (m, 4H, NCH.sub.2), 1.6-1.5 (m, 8H, CH.sub.2), 1.34 (m, 2H, CH.sub.2), 0.98 (t, 3H, CH.sub.3).

(232) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 197.7, 145.1, 136.1, 133.2, 128.9, 69.9, 54.7, 36.7, 35.4, 33.6, 31.9, 31.0, 30.1, 29.4, 28.4, 22.5. m/z (ESI): 350.2.

(233) Yield: 65%. Purity (HPLC): 97%.

Compound 9 (MC12), 1-(4-(pentylthio)phenyl)-3-(piperidin-1-yl)propan-1-one

(234) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.94 (d, 2H, PhH), 3.13 (m, 4H, NCH.sub.2), 3.11 (t, 2H, COCH.sub.2), 3.04 (t, 2H, SCH.sub.2), 2.72 (t, 2H, CH.sub.2), 1.82 (m, 2H, CH.sub.2), 1.63 (m, 4H, CH.sub.2), 1.49 (m, 2H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(235) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 198.0, 163.1, 130.3, 129.8, 14.2, 68.2, 54.6, 54.2, 34.1, 31.7, 29.3, 26.7, 24.3, 22.6, 14.1 m/z (ESI): 320.2.

(236) Yield: 72%. Purity (HPLC): 98%.

Compound 10 (VP157), 1-(4-(hexylthio)phenyl)-3-(piperidin-1-yl)propan-1-one

(237) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.70 (d, 2H, PhH), 6.94 (d, 2H, PhH), 3.12 (m, 4H, NCH.sub.2), 3.09 (t, 2H, COCH.sub.2), 3.04 (t, 2H, SCH.sub.2), 2.71 (t, 2H, CH.sub.2), 1.81 (m, 2H, CH.sub.2), 1.6-1.5 (m, 4H, CH.sub.2), 1.49 (m, 4H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(238) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 198.2, 145.1, 133.4, 128.8, 126.3, 54.5, 53.9, 45.1, 36.0, 33.6, 31.9, 31.3, 28.9, 28.5, 25.7, 22.5. m/z (ESI): 334.2.

(239) Yield: 71%. Purity (HPLC): 97%.

Compound 11 (FT018), 1-(4-(heptylthio)phenyl)-3-(piperidin-1-yl)propan-1-one

(240) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.72 (d, 2H, PhH), 6.93 (d, 2H, PhH), 3.11 (m, 4H, NCH.sub.2), 3.08 (t, 2H, COCH.sub.2), 3.00 (t, 2H, SCH.sub.2), 2.72 (t, 2H, CH.sub.2), 1.81 (m, 2H, CH.sub.2), 1.6-1.5 (m, 4H, CH.sub.2), 1.49 (m, 6H, CH.sub.2), 1.33 (m, 2H, CH.sub.2), 0.90 (t, 3H, CH.sub.3).

(241) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 197.9, 145.0, 136.0, 133.1, 128.8, 69.9, 62.3, 54.7, 36.2, 35.8, 33.5, 31.8, 31.1, 30.2, 29.7, 28.2, 22.4. m/z (ESI): 349.2.

(242) Yield: 68%. Purity (HPLC): 97%.

Compound 12 (FT013), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylthio)phenyl)propan-1-one

(243) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.75 (d, 2H, PhH), 6.90 (d, 2H, PhH), 3.16 (t, 2H, COCH.sub.2), 3.03 (t, 2H, SCH.sub.2), 2.84 (t, 2H, NCH.sub.2), 2.60 (m, 4H, NCH.sub.2), 2.51 (m, 4H, NCH.sub.2), 2.23 (s, 3H, CH.sub.3), 1.82 (m, 2H, CH.sub.2), 1.4-1.2 (m, 4H, CH.sub.2), 0.97 (t, 3H, CH.sub.3).

(244) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 193.2, 161.2, 132.3, 111.6, 75.3, 67.9, 65.1, 52.7, 51.6, 45.2, 34.5, 31.6, 29.2, 22.2, 13.8. m/z (ESI): 335.2.

(245) Yield: 75%. Purity (HPLC): 98%.

Compound 13 (FT016), 1-(4-(hexylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one

(246) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.75 (d, 2H, PhH), 6.92 (d, 2H, PhH), 3.15 (t, 2H, COCH.sub.2), 3.03 (t, 2H, SCH.sub.2), 2.84 (t, 2H, NCH.sub.2), 2.64 (m, 4H, NCH.sub.2), 2.52 (m, 4H, NCH.sub.2), 2.27 (s, 3H, CH.sub.3), 1.82 (m, 2H, CH.sub.2), 1.4-1.2 (m, 6H, CH.sub.2), 0.92 (t, 3H, CH.sub.3).

(247) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 196.1, 164.1, 130.3, 112.1, 75.2, 68.9, 65.3, 52.1, 51.7, 45.5, 34.9, 31.2, 28.0, 23.2, 21.2, 14.6. m/z (ESI): 349.2.

(248) Yield: 72%. Purity (HPLC): 97%.

Compound 14 (FT19), 1-(4-(heptylthio)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one

(249) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.78 (d, 2H, PhH), 6.90 (d, 2H, PhH), 3.11 (t, 2H, COCH.sub.2), 3.01 (t, 2H, SCH.sub.2), 2.87 (t, 2H, NCH.sub.2), 2.63 (m, 4H, NCH.sub.2), 2.52 (m, 4H, NCH.sub.2), 2.23 (s, 3H, CH.sub.3), 1.82 (m, 2H, CH.sub.2), 1.4-1.2 (m, 8H, CH.sub.2), 0.99 (t, 3H, CH.sub.3).

(250) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 190.3, 168.2, 130.1, 111.4, 75.4, 69.0, 65.4, 52.8, 51.2, 49.3, 34.8, 31.0, 29.9, 28.4, 23.7, 21.2, 13.9. m/z (ESI): 363.2.

(251) Yield: 70%. Purity (HPLC): 97%.

(252) General Procedure for the Preparation of 1-phenylpropanone Compounds of Formula (I) Wherein X is Selenium

(253) An appropriate amount of diphenyl diselenide was dissolved in ethanol, and the obtained solution was placed in an ice bath. Sodium borohydride (4 equivalents) was added cautiously, while keeping it cold and under stirring. After 20 minutes, the appropriate 1-bromoalkane (for example, 1-bromopentane, 1-bromohexane, or 1-bromoheptane, 1 equivalent) was added to the mixture. After 5 h, the reaction was quenched by adding water, and ethanol was removed by rotary evaporation. The resulting residue was dispersed in diethyl ether, and the organic layer was washed with water. Diethyl ether was removed by rotary evaporation to obtain phenyl alkyl selenoether. Such an intermediate was reacted with 3-bromopropionyl chloride (2 equivalents) and aluminum trichloride (3 equivalents) in 1,2-dichloroethane in an ice bath. The reaction was quenched by pouring it into water, and extracting the desired intermediate with diethyl ether. The organic layer was separated and subjected to rotary evaporation to obtain the phenyl alkyl selenoether acylated in the para position. The intermediate thus synthesized was treated with an appropriate cyclic amine (morpholine, piperidine or N-methyl piperazine, 2 equivalents), potassium iodide (2 equivalents) and calcium carbonate (3 equivalents) in toluene. The mixture was refluxed for 12 h. After cooling, the solid was removed by filtration, and the solvent evaporated by rotary evaporation. The residue was then dispersed into dichloromethane, and the mixture was washed with 10% sodium hydroxide solution. The organic layer was evaporated by rotary evaporation to obtain the desired compound. Yields: 72-80%.

Compound 15 (GR376), 3-morpholino-1-(4-(pentylselenyl)phenyl)propan-1-one

(254) .sup.1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, 2H, PhH), 7.28 (d, 2H, PhH), 3.69 (t, 4H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 3.01 (t, 2H, SeCH.sub.2), 2.92 (t, 2H, NCH.sub.2), 2.49 (m, 4H, NCH.sub.2), 1.69 (m, 4H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.90 (t, 3H, CH.sub.3).

(255) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 196.2, 145.4, 133.5, 128.2, 126.3, 66.7, 53.2, 53.1, 35.2, 31.2, 31.1, 28.7, 22.2, 13.9. m/z (ESI): 370.2.

(256) Yield: 73%. Purity (HPLC): 98%.

Compound 16 (GR377), 1-(4-(hexylselenyl)phenyl)-3-morpholinopropan-1-one

(257) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.75 (d, 2H, PhH), 7.29 (d, 2H, PhH), 3.64 (t, 4H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 3.02 (t, 2H, SeCH.sub.2), 2.91 (t, 2H, NCH.sub.2), 2.49 (m, 4H, NCH.sub.2), 1.69 (m, 6H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.90 (t, 3H, CH.sub.3).

(258) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 196.2, 145.4, 132.5, 128.2, 125.2, 66.7, 53.6, 53.1, 35.1, 31.2, 31.1, 28.7, 25.2, 22.2, 13.9. m/z (ESI): 384.1.

(259) Yield: 79%. Purity (HPLC): 97%.

Compound 17 (GR386), 1-(4-(heptylselenyl)phenyl)-3-morpholinopropan-1-one

(260) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.73 (d, 2H, PhH), 7.29 (d, 2H, PhH), 3.62 (t, 4H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 3.03 (t, 2H, SeCH.sub.2), 2.91 (t, 2H, NCH.sub.2), 2.47 (m, 4H, NCH.sub.2), 1.7-1.5 (m, 8H, CH.sub.2), 1.38 (m, 2H, CH.sub.2), 0.91 (t, 3H, CH.sub.3).

(261) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 198.1, 145.2, 132.1, 128.6, 125.1, 66.8, 53.2, 49.5, 35.3, 31.0, 31.2, 28.9, 25.1, 22.0, 14.2. m/z (ESI): 398.2.

(262) Yield: 80%. Purity (HPLC): 97%.

Compound 18 (GR378), 1-(4-(pentylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one

(263) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.94 (d, 2H, PhH), 3.15 (m, 4H, NCH.sub.2), 3.11 (t, 2H, COCH.sub.2), 3.01 (m, 2H, SeCH.sub.2), 2.82 (t, 2H, CH.sub.2), 1.80 (m, 2H, CH.sub.2), 1.63 (m, 2H, CH.sub.2), 1.46 (m, 4H, CH.sub.2), 1.37 (m, 2H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(264) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 198.0, 162.1, 131.2, 129.3, 140.1, 68.1, 53.2, 54.6, 34.2, 30.5, 29.2, 26.7, 24.2, 22.1, 14.0. m/z (ESI): 368.1.

(265) Yield: 72%. Purity (HPLC): 97%.

Compound 19 (GR381), 1-(4-(hexylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one

(266) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.92 (d, 2H, PhH), 3.11 (m, 4H, NCH.sub.2) 3.08 (t, 2H, COCH.sub.2), 3.02 (m, 2H, SeCH.sub.2), 2.81 (t, 2H, CH.sub.2), 1.79 (m, 2H, CH.sub.2), 1.62 (m, 4H, CH.sub.2), 1.45 (m, 6H, CH.sub.2), 1.32 (m, 2H, CH.sub.2), 0.91 (t, 3H, CH.sub.3).

(267) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 195.2, 161.6, 132.1, 130.2, 141.1, 67.4, 53.1, 51.4, 38.2, 33.1, 30.5, 29.8, 26.1, 23.9, 19.8, 14.1. m/z (ESI): 382.2.

(268) Yield: 76%. Purity (HPLC): 98%.

Compound 20 (GR387), 1-(4-(heptylselenyl)phenyl)-3-(piperidin-1-yl)propan-1-one

(269) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.92 (d, 2H, PhH), 3.12 (m, 4H, NCH.sub.2), 3.09 (t, 2H, COCH.sub.2), 3.01 (t, 2H, SeCH.sub.2), 2.81 (t, 2H, CH.sub.2), 1.79 (m, 4H, CH.sub.2), 1.7-1.4 (m, 10H, CH.sub.2), 0.91 (t, 3H, CH.sub.3).

(270) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 191.2, 162.2, 131.5, 132.1, 142.2, 68.2, 51.0, 50.4, 38.1, 35.2, 32.4, 31.5, 29.0, 26.2, 23.8, 19.7, 14.2. m/z (ESI): 396.2.

(271) Yield: 75%. Purity (HPLC): 96%.

Compound 21 (GR379), 3-(4-methylpiperazin-1-yl)-1-(4-(pentylselenyl)phenyl)propan-1-one

(272) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.75 (d, 2H, PhH), 6.90 (d, 2H, PhH), 3.16 (t, 2H, COCH.sub.2), 3.01 (t, 2H, SeCH.sub.2), 2.84 (t, 2H, NCH.sub.2), 2.60 (m, 4H, NCH.sub.2), 2.51 (m, 4H, NCH.sub.2), 2.21 (s, 3H, CH.sub.3), 1.82 (m, 2H, CH.sub.2), 1.4-1.2 (m, 4H, CH.sub.2), 0.97 (t, 3H, CH.sub.3).

(273) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 195.8, 161.1, 132.2, 111.6, 75.2, 68.1, 64.2, 51.7, 51.5, 45.1, 33.2, 31.4, 29.1, 22.1, 14.8. m/z (ESI): 383.2.

(274) Yield: 72%. Purity (HPLC): 97%.

Compound 22 (GR383), 1-(4-(hexylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one

(275) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.91 (d, 2H, PhH), 3.13 (t, 2H, COCH.sub.2), 3.01 (t, 2H, SeCH.sub.2), 2.81 (t, 2H, NCH.sub.2), 2.60 (m, 4H, NCH.sub.2), 2.48 (m, 4H, NCH.sub.2), 2.22 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2), 1.5-1.2 (m, 6H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(276) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 193.2, 161.0, 132.0, 111.5, 75.1, 68.4, 64.9, 52.9, 51.0, 45.2, 37.1, 33.1, 31.7, 29.1, 22.0, 13.8. m/z (ESI): 397.2.

(277) Yield: 79%. Purity (HPLC): 98%.

Compound 23 (GR388), 1-(4-(heptylselenyl)phenyl)-3-(4-methylpiperazin-1-yl)propan-1-one

(278) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.91 (d, 2H, PhH), 3.13 (t, 2H, COCH.sub.2), 3.01 (t, 2H, SeCH.sub.2), 2.81 (t, 2H, NCH.sub.2), 2.60 (m, 4H, NCH.sub.2), 2.48 (m, 4H, NCH.sub.2), 2.22 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2), 1.5-1.2 (m, 8H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(279) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 196.4, 160.2, 131.2, 111.2, 75.3, 68.2, 64.3, 52.1, 51.9, 45.1, 37.5, 33.3, 32.7, 31.4, 29.8, 22.2, 13.9. m/z (ESI): 411.2.

(280) Yield: 76%. Purity (HPLC): 97%.

(281) General Procedure for the Preparation of 1-phenylpropanone Compounds of Formula (I) Wherein X is Methylene, CH.sub.2

(282) The appropriate alkylbenzene (for example, pentylbenzene, hexylbenzene, or heptylbenzene) was reacted with 3-bromopropionyl chloride (2 equivalents) and aluminum trichloride (3 equivalents) in 1,2-dichloroethane in ice bath. The reaction was quenched by pouring it into water, and extracting the desired intermediate with diethyl ether. The organic layer was separated and subjected to rotary evaporation. The intermediate thus synthesized was then treated with an appropriate cyclic amine (morpholine, piperidine or N-methyl piperazine, 2 equivalents), potassium iodide (2 equivalents) and calcium carbonate (3 equivalents) in toluene. The mixture was refluxed for 12 h. After cooling, the solid was removed by filtration, and the solvent evaporated by rotary evaporation. The residue was dispersed into dichloromethane, and the mixture was washed with 10% sodium hydroxide solution. The organic layer was evaporated by rotary evaporation to afford the desired compound. Yields: 61-75%.

Compound 24 (GR390), 1-(4-heptylphenyl)-3-morpholinopropan-1-one

(283) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.75 (d, 2H, PhH), 7.08 (d, 2H, PhH), 3.69 (t, 4H, OCH.sub.2), 3.12 (t, 2H, COCH.sub.2), 2.87 (t, 2H, NCH.sub.2), 2.62 (t, 2H, PhCH.sub.2), 2.48 (m, 4H, NCH.sub.2), 1.74 (m, 6H, CH.sub.2), 1.30 (m, 4H, CH.sub.2), 0.90 (t, 3H, CH.sub.3).

(284) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 191.5, 157.2, 143.1, 131.6, 124.3, 67.5, 53.2, 51.4, 34.3, 32.0, 31.3, 28.4, 25.6, 23.0, 22.8, 14.1. m/z (ESI): 318.2.

(285) Yield: 61%. Purity (HPLC): 97%.

Compound 25 (GR391), 1-(4-heptylphenyl)-3-(piperidin-1-yl)propan-1-one

(286) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.74 (d, 2H, PhH), 6.91 (d, 2H, PhH), 3.09 (t, 2H, COCH.sub.2), 2.99 (m, 4H, NCH.sub.2), 2.55 (t, 2H, PhCH.sub.2), 2.84 (t, 2H, CH.sub.2), 1.75 (m, 4H, CH.sub.2), 1.62 (m, 4H, CH.sub.2), 1.41 (m, 6H, CH.sub.2), 1.31 (m, 4H, CH.sub.2), 0.96 (t, 3H, CH.sub.3).

(287) .sup.13C-NMR (100 MHz, CDCl.sub.3) δ: 190.4, 157.5, 142.2, 133.1, 125.2, 68.7, 54.1, 52.2, 37.0, 32.1, 31.5, 29.7, 28.4, 27.2, 25.0, 24.2, 13.5. m/z (ESI): 316.3.

(288) Yield: 72%. Purity (HPLC): 98%.

Compound 26 (GR392), 1-(4-heptylphenyl)-3-(4-methylpiperazin-1-yl)propan-1-one

(289) .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.72 (d, 2H, PhH), 6.90 (d, 2H, PhH), 3.12 (t, 2H, COCH.sub.2), 2.82 (t, 2H, NCH.sub.2), 2.62 (m, 4H, NCH.sub.2), 2.49 (t, 2H, PhCH.sub.2), 2.43 (m, 4H, NCH.sub.2), 2.21 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2), 1.5-1.2 (m, 8H, CH.sub.2), 0.93 (t, 3H, CH.sub.3).

(290) .sup.13C-NMR {1H} (100 MHz, CDCl.sub.3) δ: 196.3, 161.4, 131.3, 111.6, 78.2, 67.1, 66.2, 54.2, 51.7, 45.2, 34.5, 33.3, 31.7, 31.5, 29.7, 21.2, 15.1. m/z (ESI): 331.3.

(291) Yield: 75%. Purity (HPLC): 97%.

Example 2

(292) Evaluation of the Proapoptotic Effect on Tumor Cells In Vitro

(293) Flow cytofluorometry was used to evaluate the ability of some compounds of the invention to induce cell death, with particular reference to apoptosis. This latter phenomenon is characterized by morphological modification of the plasmatic membrane as a result of the translocation of the phospholipid phosphatidylserine (PS) in the plasmatic membrane from the cytoplasmic side to the outer surface of the cell. In the presence of calcium ions, the annexin V protein exhibits high affinity for PS, becoming a reliable marker for apoptosis detection. Annexin is detected because it is conjugated to a specific fluorochrome, thus allowing to distinguish apoptosis from necrotic phenomena, which are instead measured by the fluorescent dye propidium iodide, which penetrates freely in the cell having a damaged plasmatic membrane.

(294) Both primary lymphocytic tumor cells taken from patients with chronic lymphatic leukemia (LLC) and humanized cell lines of neuroblastoma (SK-N-BE), hepatocarcinoma (HepG2 and HUH7.5) and breast cancer (MDA-MB-231) were used.

(295) HepG2 (2×10.sup.5 cells per well), HUH7.5 and MDA-MB-231 (1.5×10.sup.5 cells per well) cells were seeded on a 6-well plate in Dulbecco's Modified Eagle Medium (DMEM), 10% FBS and cultured at 37° C. in a 5% CO.sub.2 atmosphere. After 24 hours, the medium was removed and replaced by DMEM containing the test compounds, previously dissolved in 100% dimethylsulfoxide, and diluted such that the final concentration of the same in cell incubation solutions was 0.5% (v/v). After 30 minutes incubation, 10% FBS was added, and the cells were incubated for 24 hours, then detached with trypsin, and analyzed by cytofluorimeter. LLC cells (1×10.sup.6 cells per well) were seeded and cultured on 12-well plates in RPMI-1640 medium, 10% FBS, at 37° C. in a humified atmosphere containing 5% CO.sub.2. To this medium, test compounds were added, and incubation was carried out for 24 hours, after which time the cells were analyzed by cytofluorimeter.

(296) Leukemic lymphocytes were isolated, following heparinized venous withdrawal from peripheral blood of LLC patients, diluted with saline in a 1:3 ratio, layered on a Ficoll/Hypaque (F/H) density gradient, centrifuged at 900 rpm for 20 minutes, at 20° C. without brakes. Mononuclear cells and platelets, concentrating on top of the F/H gradient, were separated after 2 further washings, with centrifugation at 400 rpm at room temperature. The mononuclear cells thus obtained were washed 3 times with PBS, centrifuged for 10 minutes at 400 rpm, at 20° C. with brakes, and resuspended in RPMI 1640.

(297) In most LLC cases, the percentage of leukemic B cells was higher than 85% with respect to all mononuclear cells from peripheral blood.

(298) The results obtained by cytofluorometry from three separate experiments executed in triplicate were tabulated, estimating the concentration required to cause 50% apoptosis (IC.sub.50), and standard deviation. The results are shown in Table 1 below.

(299) TABLE-US-00001 TABLE 1 IC.sub.50 ± S.D. (μM) Compound LLC SK-N-BE HepG2 HUH7.5 MDA-MB-231  1 (AF08) 1.61 ± 0.10 1.85 ± 0.09 1.67 ± 0.15 1.58 ± 0.07 1.61 ± 0.08  2 (CC11) 1.62 ± 0.15 1.64 ± 0.09 1.55 ± 0.13 1.58 ± 0.10 1.61 ± 0.07  3 (AF07) 2.53 ± 0.15 3.00 ± 0.17 3.07 ± 0.09 2.75 ± 0.09 2.60 ± 0.10  4 (CC12) 3.03 ± 0.07 2.93 ± 0.08 3.00 ± 0.15 2.78 ± 0.13 3.01 ± 0.15  5 (AI01) 1.45 ± 0.06 1.55 ± 0.10 1.60 ± 0.05 1.61 ± 0.08 1.48 ± 0.09  6 (MD63) 8.50 ± 0.08 8.20 ± 0.10 8.00 ± 0.10 8.25 ± 0.12 8.00 ± 0.07  7 (VP158) 0.50 ± 0.20 0.53 ± 0.09 0.49 ± 0.11 0.56 ± 0.20 0.50 ± 0.20  8 (FT017) 0.55 ± 0.09 0.60 ± 0.05 0.57 ± 0.08 0.63 ± 0.08 0.66 ± 0.12  9 (MC12) 1.75 ± 0.04 1.85 ± 0.14 1.66 ± 0.10 1.73 ± 0.09 1.80 ± 0.06 10 (VP157) 1.87 ± 0.07 1.67 ± 0.05 1.70 ± 0.05 1.80 ± 0.11 1.80 ± 0.09 11 (FT018) 0.50 ± 0.04 0.54 ± 0.09 0.59 ± 0.01 0.49 ± 0.07 0.56 ± 0.06 12 (FT013) 12.20 ± 0.11  13.17 ± 0.12  12.95 ± 0.05  14.54 ± 0.12  11.85 ± 0.07  13 (FT016) 0.65 ± 0.01 0.67 ± 0.09 0.59 ± 0.06 0.60 ± 0.12 0.65 ± 0.01 14 (FT019) 0.44 ± 0.06 0.45 ± 0.07 0.50 ± 0.09 0.52 ± 0.10 0.47 ± 0.10 15 (GR376) 14.22 ± 0.17  15.71 ± 0.13  11.11 ± 0.07  12.20 ± 0.08  13.86 ± 0.14  16 (GR377) 2.53 ± 0.09 2.47 ± 0.06 2.62 ± 0.08 2.60 ± 0.10 2.58 ± 0.09 17 (GR386) 0.55 ± 0.04 0.50 ± 0.06 0.60 ± 0.07 0.50 ± 0.10 0.55 ± 0.07 18 (GR378) 8.50 ± 0.15 8.00 ± 0.10 7.50 ± 0.15 8.30 ± 0.08 7.90 ± 0.10 19 (GR381) 10.10 ± 0.08  11.65 ± 0.06  12.48 ± 0.12  11.98 ± 0.11  13.01 ± 0.12  20 (GR387) 1.70 ± 0.05 1.68 ± 0.13 1.74 ± 0.05 1.73 ± 0.09 1.75 ± 0.10 21 (GR379) 14.16 ± 0.09  13.88 ± 0.13  15.57 ± 0.03  13.60 ± 0.09  14.23 ± 0.14  22 (GR383) 8.15 ± 0.07 8.20 ± 0.07 8.10 ± 0.10 8.00 ± 0.06 8.10 ± 0.07 23 (GR388) 1.77 ± 0.05 1.75 ± 0.09 1.70 ± 0.05 1.69 ± 0.08 1.70 ± 0.09 24 (GR390) 0.50 ± 0.15 0.50 ± 0.17 0.50 ± 0.08  0.50 ± 0.065 0.55 ± 0.08 25 (GR391) 1.50 ± 0.08 1.60 ± 0.10 1.55 ± 0.09 1.50 ± 0.10 1.65 ± 0.75 26 (GR392) 0.85 ± 0.06 0.75 ± 0.13 0.80 ± 0.07 0.95 ± 0.06 0.90 ± 0.05

(300) As shown in Table 1, the exposure of cells to the compounds reveals that: the ideal alkyl chain is represented by 6 or 7 carbon atoms, thus n is preferably 5 or 6; for compound with heteroatom represented by Se, a higher efficacy is observed when the carbon chain contains 7 C atoms, i.e. with n equal to 6; the heteroatom conferring highest efficacy to the molecules is S, equally capable of inducing apoptosis irrespective from the piperidine, morpholine, and methylpiperazine groups; in compounds wherein the heteroatom is not S, the morpholine group is the one conferring a more effective apoptotic action.

(301) In addition, as discussed above, the two articles cited in the name of D. Ju et al. discuss the properties of dyclonine, a compound analogous to some compounds of the present invention, but with an alkoxyl chain of only 4 carbon atoms. These articles highlight the role of dyclonine solely as enhancer of the proteasome inhibitors effect in inducing apoptosis in breast cancer and multiple myeloma cells, and show efficacy in the induction of caspase-dependent apoptosis (IC.sub.50 values) only at concentration in the range 15-30 μM, much higher than the concentrations to which the compounds of the present invention are active (IC.sub.50 values from 0.55 up to a maximum of 14.23 μM, with most of the compounds showing IC.sub.50 values lower than 3).

Example 3

(302) Evaluation of the Immunosuppressive Effect of the Compounds of the Invention

(303) As discussed in the introduction, the compound FTY720 exerts a cytotoxic action on tumor cells, while maintaining the molecular mechanism underlying the immunosuppressive effect that consists in the degradation of the S1P receptor. In order to evaluate whether this mechanism, undesirable for a potential use in antitumoral treatments, persisted in the presence of compounds of the present invention, some of these were tested by comparing them with FTY720 under the same conditions. To this end, LLC cells (5×10.sup.5 per well) were seeded and cultured on 12-well plates in RPMI-1640 medium, 10% FBS, at 37° C. in a humidified atmosphere containing 5% CO.sub.2, adding to the culture the various test compounds. Incubation was conducted for discrete times, at the end of which the cells were lysed to submit the protein content to Western blot analysis with antibodies that specifically recognize the S1P1 receptor. The results shown in FIG. 1 clearly show that FTY720 induces a rapid decrease of S1P1 receptor, clear already at 3 hours and even more significant after 12 hours of incubation (S1P1 concentration decrease is the cause of immunosuppression); conversely, the compounds of the invention tested leave unchanged the expression profile of the same receptor at all time points of the test.