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MXPA06009242A - Analogs exhibiting inhibition of cell proliferation, methods of making, and uses thereof - Google Patents

Analogs exhibiting inhibition of cell proliferation, methods of making, and uses thereof

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Publication number
MXPA06009242A
MXPA06009242A MXPA/A/2006/009242A MXPA06009242A MXPA06009242A MX PA06009242 A MXPA06009242 A MX PA06009242A MX PA06009242 A MXPA06009242 A MX PA06009242A MX PA06009242 A MXPA06009242 A MX PA06009242A
Authority
MX
Mexico
Prior art keywords
hydrocarbon
unsaturated
aliphatic
saturated
straight
Prior art date
Application number
MXPA/A/2006/009242A
Other languages
Spanish (es)
Inventor
Duane D Miller
James T Dalton
Veeresa Gududuru
Eunju Hurh
Original Assignee
James T Dalton
Veeresa Gududuru
Eunju Hurh
Duane D Miller
The Ohio State University Research Foundation
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Publication date
Application filed by James T Dalton, Veeresa Gududuru, Eunju Hurh, Duane D Miller, The Ohio State University Research Foundation filed Critical James T Dalton
Publication of MXPA06009242A publication Critical patent/MXPA06009242A/en

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Abstract

Analogs exhibiting inhibition of cell proliferation are provided. Methods of making the analogs are also included. The analogs can be used to treat cancerous conditions such as prostate, breast, and ovarian cancer.

Description

ANALOGS THAT EXHIBIT INHIBITION OF CELL PROLIFERATION. METHODS OF ELABORATION. AND USES OF THEMSELVES The present application is a continuation in part and claims priority to and benefit from the U.S. Patent Application. Serial No. 10 / 992,175, which claims the priority benefit of the Provisional Patent Application of E.U.A. Serial No. 60 / 523,079, filed on November 18, 2003, both incorporated in the present invention as references in their entirety. The present application claims priority to and the benefit of the Provisional Patent Application of E.U.A. Serial No. 60 / 543,724, filed on February 11, 2004, and the Provisional Patent Application of E.U.A. Serial No. 60 / 555,803, filed March 24, 2004, both incorporated in the present invention as references in their entirety. This request was made, a! less in part, with funds received from the Department of Defense of the United States under the economic support DAMD17-01-1-0830. The government of the United States may have certain rights in this invention.
BACKGROUND OF THE INVENTION Prostate cancer is responsible for 33% of all newly diagnosed malignancies among men in the United States (American Cancer Society: Cancer Facts and Figures (2003)). According to the American Cancer Society, an estimated 230,110 men with prostate cancer will be diagnosed in 2004, and 29,900 will die from this (American Cancer Society: Cancer Facts and Figures (2004)). The incidence of prostate cancer varies worldwide, with the highest ratios found in the United States, Canada, and Scandinavia, and the smaller relationships found in China and other parts of Asia (Quinn and Babb, "Patterns and Trends in Prostate Cancer Incidence, Survival, Prevalence and Mortality, Part: International Comparisons, "BJU Int. 90: 162-173 (2002), Gronberg," Prostate Cancer Epidemiology, "Lancet 361: 859-864 (2003)). These differences are caused by genetic susceptibility, exposure to unknown external risk factors, differences in health care and cancer registration, or a combination of these factors. Prostate cancer is multifocal and it has been commonly observed that the cancer gland contains multiple independent lesions, suggesting the heterogeneity of the disease (Foster et al., "Cellular and Molecular Pathology of Prostate Cancer Precursors", Scand. J. Urol. Nephrol 205: 19-43 (2000)). The determinants responsible for the pathological growth of the prostate remain poorly understood, although steroidal androgens and peptide growth factors have been implicated (Agus et al., "Prostate Cancer Cell Cycle Regulators: Response to Androgen Withdrawal and Development of Androgen Independence ", J. Nati, Cancer, Inst. 91: 1869-1876 (1999), Djakiew," Dysregulated Expression of Growth Factors and Their Receptors in the Development of Prostate Cancer ", Prostate 42: 150-160 (2000)). As long as the cancer is confined to the prostate, it can be successfully controlled by surgery or radiation, but in metastatic disease, few options are available beyond the removal of androgens (Frydenberg et al .. "Prostate Cancer Diagnosis and Management "Lancet 349: 1681-1687 (1997)), the main axis of treatment in the case of involvement of the disseminated lymph node or loci. Once the tumor cells have become refractory to the hormone, standard cytotoxic agents are marginally effective in slowing the progression of the disease, although they do provide some degree of palliative relief. Current chemotherapeutic regimens, typically two or more agents, allow for response ratios in the range of only 20-30% (Beedassy et al., "Chemotherapy Advanced Prostate Cancer", Sem. Oncol. 26: 428-438 ( 1999); Raghavan et al., "Evolving Strategies of Cytotoxic Chemotherapy for Advanced Prostate Cancer", Eur. J. Cancer 33: 566-574 (1997)). A promising strategy for the development of drugs for prostate cancer involves the identification and evaluation of agents that interfere with growth factors and other molecules involved in the signaling pathways of the cancer cell. The G-protein coupled receptors ("GPCRs") are a family of membrane-bound proteins that participate in the proliferation and survival of prostate cancer cells initiated by the binding of lysophospholipids ("LPLs") (Raj et al. , "Guanosine Phosphate Binding Protein Coupled Receptors in Prostate Cancer: A Review," J Urol. 167: 1458-1463 (2002); Kue et al., "Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling", J. Urol. 164: 2162-2167 (2000); Guo et al., "Mitogenic Signaling in Androgen Sensitive and Insensitive Prostate Cancer Cell Lines", J. Urol. 163: 1027-1032 (2000); Barki-Harrington et al., "Bradykinin Induced Mitogenesis of Androgen Independent Prostate Cancer Cells", J. Uroi 165: 2121-2125 (2001)). The importance of the G protein-dependent pathways in the regulation of growth and metastasis in vivo is corroborated by the observation that the growth of androgen-independent prostate cancer cells in mice is attenuated by treatment with pertussis toxin, a inhibitor of Gi / o proteins (Hex et al., "Influence of Pertussis Toxin on Local Progression and Metastasis After Orthotopic Implantation of the Human Prostate Cancer Cell Line PC3 in Nude Mice", Prostate Cancer Prostatic Dis. 2: 36-40 ( 1999)). Lysophosphatidic acid ("LPA") and sphingosine 1 -phosphate ("SIP") are lipid mediators generated via the regulated decomposition of membrane membrane phospholipids that are known to stimulate GPCR signaling.
LPL binds to GPCRs encoded by the Edg gene family, collectively referred to as LPL receptors, to exert various biological effects. LPA stimulates the activity of phospholipase D and the proliferation of the prostate cell PC-3 (Qi et al., "Lysophosphatidic Acid Stimulates Phospholipase D Activity and Cell Proliferation in PC-3 Human Prostate Cancer Cells", J. Cell. Physiol. 174: 261-272 (1998)). In addition, previous studies have shown that LPA is mitogenic in prostate cancer cells and that PC-3 and DU-145 express receptors LPA1, LPA2, and LPA3 (Daaka, "Mitogenic Action of LPA in Prostate", Biochim. Biophys. Acts 1582: 265-269 (2002)). Advanced prostate cancers express LPL receptors and depend on the signaling of phosphatidylinositol 3 kinase ("PI3K") for growth and progression towards androgen independence (Kue and Daaka, "Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling ", J. Ural. 164: 2162-2167 (2000)). Therefore, these routes are widely observed as one of the most promising methods for cancer therapy (Vivanco et al., "The Phosphatidilinositol 3 Kinase AKT Pathway in Human Cancer", Nat. Rev. Cancer 2: 489-501 ( 2002)) and provide a particularly novel method for the treatment of advanced prostate cancer, refractory to androgen. Despite the promise of this method, there are no clinically available therapies that selectively exploit or inhibit LPA or PI3K signaling.
The present invention is directed to overcome these and other deficiencies in the present art.
BRIEF DESCRIPTION OF THE INVENTION A first aspect of the present invention relates to the compounds according to formula (I) and formula (II) where X and X are each optional, and each can be oxygen; X3 and X4 are each optional, and each one can be oxygen or sulfur; / is an integer from 1 to 12; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30 straight or branched chain, or or - (CH2) m-Y1 wherein m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of C1 to Straight or branched chain C30, R10-N (Z) -hydrocarbon- or R10-hydrocarbon-wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C30, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated mixed heterocycle, or or - (CH2) n-Y2 wherein n is an integer from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R3 is hydrogen or an aliphatic or non-aliphatic hydrocarbon of C1 to C10 straight or branched chain; R 4 is optional, or it can be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C 1 to C 10, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haioalkyl, dihaloaikyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N -phenylalkyl-, H (Z) N-phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl-N (Z) -hydrocarbon-, H ( Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to C10, and wherein each alkyl is an alkyl of C1 to C10; and Z is independently hydrogen or t-butoxycarbonyl.
A second aspect of the present invention relates to the compounds according to formula (V) and formula (VI) where X1 and X2 are each optional, and each can be oxygen; X5 is optional, and may be oxygen; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30 straight or branched chain, or or - (CH2) m-Y1 wherein m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C to C30, R10-N (Z) -hydrocarbon- or R10-hydrocarbon-wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to C30 straight or branched chain, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated mixed heterocycle, or or - (CH2) n-Y2 where n is an integer from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated S-heterocycle or unsaturated, or saturated or unsaturated mixed heterocycle; R3 is nothing, hydrogen or an aliphatic or non-aliphatic hydrocarbon of C1 to C10 straight or branched chain; R 4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C 1 to C 10, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R5 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy , aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N -phenylalkyl-, H (Z) N-phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-0-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C 1 to C 10, and wherein each alkyl is a C 1 -C alkyl C10; and Z is independently hydrogen or t-butoxycarbonyl. A third aspect of the present invention relates to the compounds according to the formula (Vll) wherein X3 is optional and may be oxygen; X6 is oxygen or nitrogen; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30 straight or branched chain, or or - (CH2) m-Y1 wherein m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle , or saturated or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C to C30, R10-N (Z) -hydrocarbon- or R 0-hydrocarbon-wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to Straight or branched chain C30, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated mixed heterocycle, or or - (CH2) n-Y2 wherein n is an integer from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R3 is nothing, hydrogen or an aliphatic or non-aliphatic hydrocarbon C1 to C10 straight or branched chain; R4 is optional, or may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of Ci to C10 straight or branched chain, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N- phenylalkyl-, H (Z) N-phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-0-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkylcarbony-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to C10, and wherein each alkyl is a C1 to C alkyl C10; and Z is independently hydrogen or t-butoxycarbonyl. A fourth aspect of the present invention relates to the compounds of formula (VIII) where X8 is O or S; n is between 1 and 30; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons from C1 to C30 straight or branched chain, oo - (CH2) m-Y1 where m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated O-heterocycle or unsaturated, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R 4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C 1 to C 10, aryl, acetyl, or mesyl; and R5, R6, R7, R8, and R9 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro , bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl. A fifth aspect of the present invention relates to the compounds having the formulas (X) (XII) wherein X7 is P03H or O-benzyl; X9 is O or nothing; R16 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted, R17 and R18 are independently none, hydrogen, -S02R19, COR19, and R19; and R19 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted or a substituted or unsubstituted aryl. A sixth aspect of the present invention relates to a compound of formulas (XIV) and (XV) A seventh aspect of the present invention relates to a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound in accordance with the first, second, Iercer, fourth, quinío, and sexío aspecíos of the present invention. A third aspect of the present invention relates to a method for removing a cancer cell that includes the steps of providing a compound in accordance with the first, second, third, fourth, quinine, and sixth aspects of the present invention and putting in contact with a cancerous cell with the compound under effective conditions to deplete the conialated cancer cell. A ninth aspect of the present invention refers to a method for e! It would be the prevention or prevention of a cancerous condition that includes the steps of providing a compost in accordance with the first, second, third, fourth, fifth, and sixth aspects of the present invention and administering a specific type of patient to a patient. to eradicate or prevent a cancerous condition. A tenth aspect of the present invention relates to a method for producing a compound according to formula (I) which includes the steps of: reacting an inmate in accordance with formula (III), where /, R1, X3, and X4 were defined as mentioned above, with either (i) a suitable primary or secondary amine according to the formula (HNR2R3) wherein R2 and R3 were defined as mentioned earlier, or (i) ammonia in the presence of a compound conforming R2-H, under effecive conditions to form the compound according to formula (I). An eleventh aspect of the present invention relates to a method for making a compound according to the formula (II) which includes the steps of: reacting an agent in accordance with formula (IV), wherein R1 and X3 were defined as mentioned above, with a primary or secondary amine according to the formula (HNR2R3) wherein R2 and R3 were defined as mentioned above, under conditions effective to form the compound in accordance with the formula (II).
A twelfth aspect of the present invention relates to intermediates according to formula (III) and formula (IV). The present invention allows a significant improvement over previously identified cancer therapeutics known to be useful for the inhibition of prostate cancer cell growth. In a previous report, it was shown that cytotoxic compounds were obtained by replacing the glycerol base structure in APL with serine amide in five prostate cancer cell lines (Gududuru et al., "Synlhesis and Biological Evaluation of Novel Cytoxicity"). Phospholipids for Cancer Prosthetics, "Borgorg, Med. Chem. Lett., 14: 4919-4923 (2004), which is incorporated in the present invention as a reference in its tolality). The most powerful compounds reported in Gududuru et al. (previously cited) were non-selective and potentially eliminated the cancer cell lines of prostate cancer as well as the conírol cell lines. The present invention produces compounds having similar or even improved potency, but more importantly, improved selectivity, particularly with respect to prostate cancer cell lines. It is shown that the compounds of the present invention are effective against prostate cancer cells and ovarian cancer cells.
BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of modernities of the present invention can be better understood when read in conjunction with the following drawings, wherein the similar language is indicated with similar reference numerals and in which: Figures 1A and 1B illustrate the eiecloforesis in agarose gels of the exiguated ioral DNA from 2 x 10 6 LNCaP cells after travail with thiazolidine 4 compounds (Figure 1A) and 5 (Figure 1B) for 24 to 108 hours. The results show the effects of treatment on DNA fragmentation, indicating progression of cell death. In Figure 1A, the dose and time of exposure are indicated for compound 4 as follows: line 1, 100 bp of the DNA marker; line 2, 5 μM for 36 hours; line 3, 3 μM per 24 hours; line 4, 3 μM for 24 hours; line 5, 3 μM for 48 hours; Line 6, 3 μM for 72 hours; Line 7, 3 μM for 108 hours; and line 8, 50 μM for 36 hours. In Figure 1 B, the dose and time of exposure are indicated for compound 5 as follows: line 1, 100 bp of the DNA marker; line 2, 5 μM per 24 hours; line 3, 5 μM for 48 hours; line 4, 5 μM for 72 hours; line 5, 5 μM for 96 hours; line 6, 3 μM for 96 hours; line 7, 8 μM for 48 hours; and line 8, 8 μM for 72 hours; Figures 2A and 2B demonstrate the AKT inhibitory effects of thiazolidine compounds, as measured by the inhibition of AKT phosphorylation. Figure 2A shows the results of immunobloid using anti-phospho-AKT (5473) or anti-AKT antibodies. Immunoblots were visualized by improved chemiluminescence, and changes in the relative levels of phospho-AKT compared to total AKT by analogous treatment were quantified by densitometry analysis. Figure 2B graphically illustrates the immunological detection of AKT using anti-AKT and anti-phospho-AKT, as shown in Figure 2A.
DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described with occasional reference to the specific embodiments of the invention. However, this invention can be incorporated in different forms and should not be considered as limited to the modalities previously described in the present invention. RatherThese modalities are provided in such a way that this description will be de fi ned and complemented, and will fully communicate the scope of the invention to those experts in the art. Unless defined in a proper manner, all the technical and scientific terms used in the present invention have the same meaning that is commonly understood by an experiment in the technique to which the invention belongs. The terminology used in the description of the invention in the present invention is for the description of particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms "a", "an", and "the" are intended to also include the plural forms, unless the context clearly dictates otherwise. way. All publications, patent applications, patents, and other references mentioned in the present invention are incorporated as references in their tofality. Unless otherwise indicated, all numbers express amounts of ingredients, properties such as molecular weight, reaction conditions, and so on as used in the specification and claims should be understood as being capable of being modified in all cases by the term "approximately". Accordingly, unless otherwise indicated, the numerical properties set forth in the following specifications and claims are approximations that may vary depending on the desired properties desired in the embodiments of the present invention. Although the numerical and parametric ranges establish the broad scope of the invention, these are approximations, the numerical values established in the specific examples are reported as precisely as possible. However, any numerical values inherently contain certain errors that necessarily result from the error found in their respective measurements. One aspect of the invention relates to the compounds according to the formulas (I) and (II) below where X1 and X2 are each optional, and each may be oxygen; X3 and X4 are each optional, and each one can be oxygen or sulfur; / is a year from 1 to 12; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, unsaturated or unsaturated N-heterocyclics, purified or unsaturated O-heterocycles, unsaturated or unsaturated S-helerocycles, mixed or unsaturated heterocyclics, aliphatic or non-aliphatic hydrocarbons of Cl to C30 , strong chain, cyclic or branched, or or - (CH2) m-Y1 wherein m is an ether from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heyerocycle, saturated or unsaturated O-heyerocycle, saturated S-heterocycle or Unsaturated, or saturated or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of C1 to C30 straight or branched chain, R10-N (Z) -hydrocarbon- or R10-hydrocarbon-where the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight or branched chain, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heyerocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a mixed or unsaturated heterocycle, or or - (CH2) n-Y2 wherein n is an ether of 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R3 is hydrogen or an aliphatic or non-aliphatic hydrocarbon of C1 to C10 straight or branched chain; R4 is optional, or it can be hydrogen, an aliphatic or non-aliphatic hydrocarbon of C1 to C10 of straight or branched chain, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N -phenylalkyl-, H (Z) N-phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl-N (Z) -hydrocarbon-, H ( Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to C10, and wherein each alkyl is an alkyl of C1 to C10; and Z is independently hydrogen or t-butoxycarbonyl. As used in the present invention, "straight or branched chain aliphatic or non-aliphatic hydrocarbon" refers to both alkylene groups which contains a particular carbon and has a defined upper limit, as well as alkenyl groups and alkynyl groups which confer two carbons up to the upper limit, whether the carbons are present in a single chain or in a branched chain. Unless specifically identified, a hydrocarbon may contain up to about 30 carbons, or up to about 20 hydrocarbons, or up to about 10 hydrocarbons. As used in the present invention, the term "alkyl" can be any straight or branched chain alkyl group containing up to about 30 carbons unless otherwise specified. The amino group may be a single constituent or may be a component of a larger constituent, such as in an alkoxy, arylalkyl, alkylamino, eic. As used in the present invention, "saturated or unsaturated cyclic hydrocarbons" can be any of said cyclic hydrocarbons, including but not limited to phenyl, biphenyl, niphenyl, naphthyl, cycloalkyl, cycloalkenyl, cyclodienyl, eic; "Sacred or unsaturated N-heterocycles" can be any of said N-containing heterocycles, including but not limited to aza- and diaza-cycloalkyls such as aziridinyl, azeidinyl, diazaidinyl, pyrrolidinyl, piperidinium, piperazinyl, and azocanyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinium, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, unsaturated O-heterocycles can be any of said heterocycles which contain O -including, but are not limited to, oxiranyl, oxyenyl, isohydrofuranyl, teirahydropyranyl, dioxanyl, furanyl, pyryl, benzofuranyl, etc.; "Salicylated or unsaturated heterocycles" may be any of said S-containing heterocarbons, including but not limited to tyranyl, iefanyl, iorahydroiiophenyl, difiolanyl, tetrahydrothiopyranyl, thiophenyl, thiephyl, thianaphtenyl, efe; "Salified or unsaturated blended heterocycles" can be any heterocycles containing two or more S, N, or O heteroatoms, including but not limited to oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolium, oxadiazoyl, etc. Another aspect of the present invention relates to the compounds according to formula (V) and the formula (VI) where X1 and X2 are each optional, and each can be oxygen; X5 is optional, and may be oxygen; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, safe or unsaturated O-helerocycles, saturated or unsaturated S-heterocycles, mixed or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30, straight or branched chain, or or - (CH2) m-Y1 where m is an ether from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heyerocycle, unsaturated or unsaturated O-heterocycle, unsaturated or unsaturated S-heiEROcycle, or mixed or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of C1 to Straight or branched chain C30, R10-N (Z) -hydrocarbon- or R10-hydrocarbon-wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight or branched chain, a saturated or unsaturated cyclic hydrocarbon , a saturated or unsaturated N-heterocycle, a safed or unsaturated O-heterocycle, a unsaturated or unsaturated S-heterocycle, a mixed unsaturated or unsaturated heterocycle, or or - (CH2) p-Y2 wherein n is an integer from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, unsaturated or unsaturated N-heyerocycle, unsaturated or unsaturated O-heterocycle, S-saturated or unsaturated heterocycle , or mixed or unsaturated mixed heterocycle; R3 is nothing, hydrogen or an aliphatic or non-aliphatic hydrocarbon of C1 to C10 of straight or branched chain; R 4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C 1 to C 10, aryl, acetyl, or mesium; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of C1 to C10 of straight or branched chain, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N -phenylalkyl-, H (Z) N-phenylalkylN (Z) -h -drocarbon-, H (Z) N-phenylalkyl-0-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl-N (Z) -hydrocarbon-, H ( Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonii-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to C10, and wherein each alkyl is an alkyl of C1 to C10; and Z is independently hydrogen or t-buloxycarbonyl. Another aspect of the present invention refers to the compounds according to the formula (Vll) wherein X3 is optional and may be oxygen; X6 is oxygen or nihologen; / is an integer from 1 to 12; R1 is selected from the group of unsaturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, unsaturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30, straight or branched chain, or or - (CH2) m-Y1 wherein m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, unsaturated or unsaturated O-heyerocycle, saturated or unsaturated S-heterocycle, or blended or unsaturated mixed material; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C30, R10-N (Z) -hydrocarbon- or R10-hydrocarbon-wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to C30 , of straight or branched chain, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, an unsaturated or unsaturated product, a purified or unsaturated product, a mixed or unsaturated mixed product, or or - (CH2) n-Y2 where n is an ether from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N -heterocycle, safed or unsaturated O-heyerocycle, unsaturated or unsaturated S-heyerocycle , or mixed or sautered mixed or unsaturated product; R3 is nothing, hydrogen or an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10; R 4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C 1 to C 10, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbon-1-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N -phenylalkyl -, H (Z) N-phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenalkyl-0-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl (Z) -hydrocarbon-, H (Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to CI O, and wherein each alkyl is a C1 to C10 alkyl; and Z is independently hydrogen or t-butoxycarbonyl. Even another aspect of the present invention relates to the compounds of formula (VIII) (VUI) where X8 is O or S; n is enire 1 and 30; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, unsaturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30 straight or branched chain, or or ~ (CH2) m-Y1 where m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, N-heterocyclic or unsaturated, unsaturated or unsaturated O-heyerocycle, saturated or unsaturated S-helerocycle , or blended or unsaturated mixed heterocycle; R 4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C 1 to C 10, aryl, acetyl, or mesyl; and R5, R6, R7, R8, and R9 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, niino, cyano, chloro, fluoro , bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl. Another aspect of the present invention refers to the compounds that come with the formulas (X) (XÍ3) wherein X7 is P03H or O-benzyl; X9 is O or nothing; R16 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, unsubstituted or unsubstituted, R17 and R18 are independently hydrogen, -S02R19, COR19, and R19; and R19 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted or a substituted or unsubstituted aryl. In one example, the compound of formula (X) is limited, such that R16 is not C- | 4H2g when X7 is P03H and X8 is O. A further aspect of the present invention relates to a compound of formulas (XIV) ) and (XV) It will be understood that dotted lines in the structures of formulas II and Vll indicate the presence or absence of a link. Preferred R groups include benzyl, furanyl, indolyl, pyridinyl, phenyl, or phenyl susíiuuido (with R5-R9 as defined above). Preferred R2 groups include aliphatic and non-aliphatic straight or branched chain C1 to C30 hydrocarbons, phenyl, phenylalkyl, substituted phenyls and substituted phenylalkyl with R1-R15 groups as defined above. The preferred straight or branched chain aliphatic and non-aliphatic hydrocarbons are C8 to C24 hydrocarbons, including C10 to C20 alkyls, more preferably C14 to C18 alkyls. Preferred R3 groups include hydrogen and C1 to C10 alkyls. Preferred R4 groups include hydrogen, acyl, acetyl, and mesyl. Preferred R1 groups are polyamines.
The integer / is preferably from 1 to 10, more preferably from 1 to 8, 1 to 6, or 1 to 4. The integer In is preferably from 0 to 8, 0 to 6, 0 to 4, or 0 to 2. The whole n is preferably 0 to 8, 0 to 6, 0 to 4, or 0 to 2. Exemplary compounds according to formula (I) include, without limitation: 2- (4-oxo-2-phenylthiazolidin-3) -yl) acetamide (compound 65), N-decyl-2- (4-oxo-2-phenylthiazolidin-3-yl) acetamide (compound 66), N-teradecyl-2- (4-oxo-2-phenylthiazolidin- 3-yl) acetamide (compound 67), N-ocladecii-2- (4-oxo-2-phenylthiazolidin-3-yl) acefamide (compound 68), N-occydecyl-2- (4-oxo-2-biphenyl); thiazolidin-3-yl) acetylamide (compound 69), 2- (2- (1- (dimethylamino) naphthalen-4-yl) -4-oxothiazolidin-3-yl) -N-ociadecylacetamide (compound 70), 2- ( 2- (4-meioxyphenyl) -4-oxothiazolidin-3-yl) -N-octadecylacetamide (compound 71), 2- (2- (2,6-dichlorophenyl) -4-oxothiazolidin-3-yl) -N-octadecylacetamide (compound 72), N-octadecyl-2- (4-oxo-2-phenyl-1-sulfoxide-thiazolidin-3-yl) aceylamide (compound 80), N-occydecyl-2- (4-oxo-2-phenyl-1-sulfonyl! -iazolidin-3-y!) Acelamide (compound 81), N- (3,5-difluoropheni!) - 2- ( 4-oxo-2-phenyllazozolidin-3-yl) acetylamide (compound 73), N- (3,5-difluorophenyl) -2- (4-oxo-2-phenylazolidin-3-yl) ethanedioamide, N- (3,5-bis (trifluoromethyl) phenyl) -2- (4-oxo-2-phenylthiazolidin-3-yl) acetamide (compound 74), N- (3,5-dichlorophenyl) -2- (4-oxo- 2-phenylthiazolidin-3-yl) acetamide (compound 75), N- (2,4-dimethioxyphenyl) -2- (4-oxo-2-phenylazolidin-3-yl) acetylamide (compound 76), N- (naphthalene- 1-yl) -2- (4-oxo-2-phenylthiazolidin-3-yl) acetamide (compound 77), 3- (2- (octadecylamino) ethyl) -2-phenylthiazolidin-4-one (compound 79) , N- (2- (2-phenylthiazolidin-3-yl) eyl) ociadecan-1-amine, and salts thereof.
Preferred compounds according to formula (I) include compounds 68, 71, 80, and 81. Exemplary compounds according to formula (II) include, without imitation: (4R) -2- (4-methoxyphenyl) ) -N-octadecylthiazolidine-4-carboxamide (compound 15); (4R) -2- (4-ethoxyphenyl) -N-octadecylthiazolidin-4-carboxamide; N-octadecyl-2-phenylthiazole-4-carboxamide (compound 34); (4R) -2- (3,5-difluorophenyl) -N-octadecytiotazolidine-4-carboxamide (compound 23); (4R) -2- (4-cyanophenyl) -N-octadecyl-azolidine-4-carboxamide (compound 22); (4R) -N-occydecyl-N-mesyl-2-phenylazozolidine-4-carboxamide (compound 29); (4R) -N-ocladecyl-N-acetyl-2-phenylthiazolidine-4-carboxamide (compound 28); (4R) -N-heptyl-2-phenylthiazolidine-4-carboxamide (compound 3); (4R) -N-ocfadecyl-2-phenylthiazolidine-4-carboxamide (compound 5, R-isomer); (4S) -N-octadecyl-2-phenylazozolidine-4-carboxamide (Compound 5, S-isomer); (4R) -N-ioradecyl-2-phenylliiazole! Idine-4-carboxamide hydrochloride (compound 4); (4R) -N-ocladecyl-2-bipheni! Iazolidine-4-carboxamide (Compound 27); (4R) -2-dodecyl-N-ocyadecyl-aiazolidine-4-carboxamide (compound 7); (4R) -N-octadecyi-2- (pyridin-3-yl) -iazolidine-4-carboxamide (compound 11); 2- (furan-3-ii) -N-octadecylthiazolidine-4-carboxamide (compound 12); (4R) -N-nonadecyl-2-phenylthiazolidine-4-carboxamide (compound 6); (4R) -2- (4-hydroxyphenyl) -N-octadecyl-aiazolidine-4-carboxamide; 2- (3-hydroxyphenyl) -N-ociadecylthiazolidine-4-carboxamide (compound 14); (4R) -2- (2,4,6-dimethoxyphenyl) -N-octadecylthiazolidine-4-carboxamide; 2- (3,4-dimethoxyphenyl) -N-octadecyl-aiazolidine-4-carboxamide (compound 18); (4R) -2- (4-fluorophenyl) -N-octadecylthiazothidine-4-carboxamide (compound 19); (4R) -2- (2,6-dichlorophenyl) -N-octadecylthiazolidine-4-carboxamide (compound 24); (4R) -2- (4-bromophenyl) -N-ocfadecyl-aiazolidine-4-carboxamide (compound 20); (4R) -N-octadecyl-2-p-folylthiazolidine-4-carboxamide (compound 26); (4R) -2-cyclohexyl-N-ocfadecyl-fiazolidine-4-carboxamide (compound 8); 2- (4-nifrophenyl) -N-ociadecyl-fiazolidine-4-carboxamide (compound 21); (4R) -2- (4- (dimethylamino) phenyl) -N -cyanodecyladiazolidine-4-carboxamide (compound 13); (4R) -2- (1 H-indol-3-yl) -N-ocfadecyl-aiazolidine-4-carboxamide (Compound 10); (4R) -2-benzyl-N-ocyadecyl-aiazolidine-4-carboxamide (compound 9); (4R) -2- (3-bromo-4-fluorophenyl) -N-ociadecyl-aiazolidine-4-carboxamide (compound 25); (4R) -2- (3,4,5-uroxy-phenyl) -N, N-diocylyl-aiazolidine-4-carboxamide; and you come out of them. Preferred compounds according to formula (II) include compounds 5 (R-isomer), 13, 14,16, 17, 18, 19, 25, and 26. Compounds of formula V include, but are not limited to : The compounds of formula (VI!) Include, but were not limited to: where n = 6, 13 and 17.
The compounds of formulas (IX), (X), (XI), and (XII) include, but were not limited to, those found in table 9 of the examples section. The compounds of the present invention and their intermediates can be synthesized by using commercially available or readily synthesized reagents. By way of example, the compounds according to formula (I) can be synthesized according to scheme 4.
SCHEME 4 NH NH? HN (C According to a method, an acid intermediate according to the formula (III) fCTt) (where /, R1, X3, and X4 are as defined above) is reacted with the appropriate amines in the presence of EDC / HOBt under standard conditions. Acid intermediates can be initially prepared via the condensation of mercaphoacetic acid, glycine methyl ester, and aromatic aldehydes in a reaction in a vessel, followed by basic hydrolysis of the ester (Holmes et al., "Syriages for Combinatorial Organic Synítesis: Soiuíion and Polymer -Supported Synítesis de 4-thiazolidinones and 4-Metelhiazanones Derived from Amino Acids, "J Org. Chem. 60: 7328-7333 (1995), which is incorporated in the present invention as reference in its iopidad). By suspending glycine meityl ester with analogues containing longer carbon base structures, it became possible to prepare the compounds according to formula (III) and, finally, of formula (I), with / being greater than 1 (for example, containing an alkylene group that is longer than methylene). According to a second method, the thiazolidinone amides of formula (I) can also be prepared by a simple and direct method (Schuemacher et al., "Condensafion beíween Isocyanates and carboxylic acids in the Presence of 4-Dimethylaminopyridine. (DMAP), to Mild and Efficient Synthesis of Amides, "Synítesis 22: 243-246 (2001), which is incorporated in the present invention as reference in its entirety), which includes the reaction of the intermediate acid with desired isocyanates in the presence of a calamicity of DMAP (scheme 5).
SCHEME 5 Further modification of the iazolidinone compounds can be modified by, for example, exhaustively reducing the use of BH3 THF under reflux conditions to remove the carbonyl or sulfoxide groups X3 and X4 (scheme 6 (c)), as well as the oxidation of a compound using H202 and KMn0 to produce sulfoxides or sulfones, respectively, as shown in Scheme 6 (a) and 6 (b).
SCHEME 6 Also by way of example, the compounds according to formula (II) can be prepared by reacting an acid intermediate according to formula (IV), wherein the compound (IV) can be any of the stereoisomers R or S and R1 and X3 are defined as mentioned above, with appropriate amines in the presence of EDC / HOBt under slanting conditions. Acid intermediates can be prepared via the reaction of L-cysteine with desired aldehydes under reported conditions (Seki et al., "A Novel Synthesis of (+) - Bíotin from L-Cysteine, "J. Org. Chem. 67: 5527-5536 (2002), which is incorporated herein by reference in its entirety). The compounds of the present invention can also be modified to contain a polymer conjugate. Suitable polymeric conjugates include, without limitation, poly (alkyl) amines, poly (alkoxy) amine, polyamines, eic. It is also well known that polyamine-containing compounds exhibit numerous biological activities and have been used as chemotherapeutic agents. Exemplary conjugates include those containing the polyamines that occur in naphural ways such as puirescin, spermidine, and spermine, as well as synneial polyamines. According to a method, a compound of the present invention can be conjugated to a polyamine by reacting the acid intermediate or a niiophenyl derivative thereof with a polyamine NH2-R2 wherein R2 is R10"N (Z) -hydrocarbon. - or R10-hydrocarbon-, with R10 and Z being as defined earlier An exemplary synis scheme is illustrated in Scheme A.
SCHEME A ? oo? By way of example, the compounds of formulas (V) and (VI) can be formed in accordance with the exemplary synthesis scheme illustrated in scheme B. The compound can be made in accordance with any other suitable manner.
SCHEME B By way of example, the analogous compounds of the oxazoline of formula (Vll) can be formed according to the scheme illustrated in scheme C. Additionally, the compounds of formula (VI!) Can be formed using the methods previously described with respect to to the compounds of formula (II). The compounds can also be made in accordance with any other suitable manner.
SCHEME C By way of example, the compounds of formula (VIII) can be formed in accordance with the scheme illustrated in scheme D.
Additionally, the compounds can be made in accordance with any other suitable manner.
SCHEME D By way of example, the compounds of formulas (IX) and (X) can be made in accordance with the general synthesis of serine amide phosphates (SAPs), serine amide alcohols (SAAs), and serine diamide phosphates (SDAPs) shown in the EH schemes. The commercially available N-Boc-serine (form R or S) is allowed to react with an appropriate amine in the presence of EDC / HOBt to form an amide. The amide is fused with TFA to produce an SAA analogue. The phosphorylation of the amide and the concurrent removal of the protecting groups under hydrogenolysis conditions using Pd / C in ethylene produced an SAP. The unsaturated analogs of SAA and SAP can be synthesized by similar procedures as shown in Scheme F. Serine diamide phosphates (SDAPs) and other amine derivatives can be synthesized starting from O-benzyl-N-Boc. serine as shown in scheme G. The LAH-mediated reduction of an amine compound produces long-chain N-alkyl amino alcohols as shown in scheme H. The compounds of formulas (XI) and (XII) which have a base structure of the effanolamine amide instead of the base serine amide base can be syntheized according to the procedure reported Lynch, KRH, DW Cariisle, SJ Catalán, JG Zhang, M. MacDonald, TL Mol. Pharmacol. 1997, 52, 75-81, in which it is incorporated as a reference in its entirety.
SCHEME E SCHEME F 0 o or i 11 not '-A * - l - H?' "V HO '" r + hC3H.5 C H ÑHauc Í -) ot NI 13 * C? 301? 03 CHJJ CdH 311 SCHEME G 315 315 SCHEME H 3-? The compounds may also be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically undesirable or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-loluenesulfonic acid, salicylic acid, N-acelylcysteine and the like. Other salts are known to those skilled in the art and can be easily adapted for use in accordance with the present invention. The compounds of the present invention may be present in the form of a racemic mixture, which contains substantially equivalent amounts of stereoisomers. In another embodiment, the compounds of the present invention can be prepared or otherwise isolated, using known methods, to obtain a stereoisomer substantially free of its corresponding stereoisomers (e.g., substantially pure). By substantially pure, it is intended that a stereoisomer be at least about 95% pure, more preferably at least about 98% pure, more preferably at least about 99% pure. Another aspect of the present invention relates to pharmaceutical compositions containing one or more of the above-identified compounds of the present invention. Generally, the pharmaceutical composition of the present invention will include a compound of the present invention or its pharmaceutically acceptable salt, as well as a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvants, carriers, excipients, or stabilizers, and may be in solid or liquid form such as tablets, capsules, powders, solutions, suspensions, or emulsions. In one example, the composition will contain from about 0.01 to about 99 percent or from about 20 to about 75 percent of the active compound (s), along with the adjuvants, vehicles and / or excipients. For example, application to mucous membranes can be achieved with an aerosol spray that contains small particles of a compound of this invention in a spray or dry powder form. The solid unit dose forms can be of any suitable type. The solid form can be a capsule and the like, like an ordinary type of gelatin which contains the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as lactose, sucrose, or corn starch. In other modalities, these compounds are formed into tablets with conventional bases such as lacíosa, saccharose, or corn starch in combination with such binders as acacia, corn starch, or gelaine, disinfectant agents, such as corn starch, starch. of potato, or alginic acid, and a lubricant, similar to stearic acid or magnesium stearate. Tablets, capsules, and the like may also contain a binder such as gum tragacane, acacia, corn starch, or gelatin.; excipieníes them as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above-mentioned type, a liquid carrier such as a fatty oil. Many other materials can be presented as remarks or to modify the physical form of the dose unit. For example, the tablets can be coated with shellac, sugar, or both. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavorings such as cherry or orange flavor, For oral therapeutic administration, these active compounds may be incorporated with excipients and they are used in the form of iableies, capsules, elixirs, suspensions, syrups, and the like. Said compositions and preparations can contain at least 0.1% of the active compound. The percentage of the composition in these compositions may vary, of course, and may conveniently range from approximately 2% to approximately 60% of the weight of the unit. The potentiality of the active compound in such phytoplankically useful compositions is that an adequate dose will be obtained. In one example, the compositions according to the present invention are prepared so that an oral dose unit contains between about 1 mg and 800 mg of the active compound. The active compounds of the present invention can be administered orally, for example, with an inert diluent, or with an edible assimilable carrier, or they can be included in hard or soft-shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the dieia. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that there is a facility for application through the use of a syringe. It must be stable under the conditions of processing and storage and must be preserved in confidence from the action of the microorganisms, such as bacteria and fungi. The carrier may be a solvent medium or dispersion medium containing, for example, water, ethylene, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. The compounds or pharmaceutical compositions of the present invention can also be administered in injectable doses by the solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, vehicle or excipient. Said adjuvants, vehicles and / or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a pharmaceutically and physiologically acceptable agent and other pharmaceutically acceptable components. The ilusíraíivos oils are those of origin of peiróleo, animal, vegetable, or siníélico, for example, peanut aceife, soybean oil, or mineral aceifera. In general, water, saline, aqueous dextrose and sugar-related solution, and glycols, such as propylene glycol or polyethylene glycol, liquid carriers are preferred, particularly for injectable solutions. These active components can also be administered parentally. The solutions or suspensions of these compounds can be prepared in water mixed in a suitable manner with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. The illusionary oils are those of peiróleo origin, animal, vegetable, or synthetic, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dexory and related solution of sugar, and glycols such as propylene glycol or polyethylene glycol, are the preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. For use as aerosols, the compounds of the present invention in solution or suspension can be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants similar to propane, butane, or isobutane with conventional adjuvants. The materials of the present invention can also be administered in a non-pressurized form as in a nebulizer or atomizer. The compounds of the present invention are particularly useful in the treatment or prevention of various forms of cancer, particularly prostate cancer, breast cancer, and ovarian cancer. It is believed that other forms of cancer will be, similarly, irrational or preventable after administration of the compounds or compositions of the present invention to a patient. The preferred compounds of the present invention are selectively destructive of cancer cells, causing removal of cancer cells but not of normal cells. Significantly, damage to normal cells is minimized because the cancer cells are susceptible to destruction at much lower concentrations of the compounds of the present invention. Therefore, a further aspect of the present invention relates to a method for the removal of a cancer cell which includes: providing a compound of the present invention and then contacting a cancer cell with the compound under conditions effective to destroy the cancer. cancer cell contacted. In accordance with the various embodiments for the destruction of cancer cells, the cells to be depleted can be localized either in vivo or ex vivo (for example, in culino). Even a further aspect of the present invention relates to a method of treating or preventing a cancerous condition which includes: providing a compound of the present invention and then administering an effective compound quality to a patient in an effective manner to fray or prevent a cancerous condition. It will be understood that an effective amount refers to an amount of the compound that is effective to reduce, prevent, improve, or benefit at least one symptom of the condition for which the compound is administered. It will further be understood that the term "prevent" should be understood as referring to the prevention of the development of at least one symptom related to the condition for which the compound is administered. According to one embodiment, the patient to be treated is characterized by the presence of a precancerous condition, and the administration of the compound is effective to prevent the development of the precancerous condition towards the cancerous condition. This can occur by destroying the precancerous cell before or concurrent with its further development into a cancerous state. According to another embodiment, the patient to be treated is characterized by the presence of a cancerous condition, and the administration of the compound is effective either to cause the regression of the cancerous condition or to inhibit the growth of the cancerous condition. This preferably occurs through the removal of cancer cells, regardless of their location in the patient's body. That is, whether the cancer cells are located in a primary tumor site or whether the cancer cells have metastasized and created secondary tumors in the patient's body. As used in the present invention, the patient refers to any mammalian patient, including without limitation, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents.
When administering the compounds of the present invention, these may be administered systemically or, alternatively, they may be administered directly to a specific site where cancer cells or precancerous cells are present. Therefore, administration can be accomplished in any effective manner to administer the compounds or pharmaceutical compositions to cancer cells or precancerous cells. Exemplary modes of administration include, without limitation, administering the compositions or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, intracavillary or intravesical instillation, intraocularly, intraarterially, intralesionally , or by applying to mucous membranes, such as, that application of nasal tubes, for the throat, and bronchial tubes. When the compounds or pharmaceutical compositions of the present invention are administered to treat or prevent a cancerous condition, the pharmaceutical composition may also contain, or may be administered in conjunction with, other therapeutic agents or delivery regimen currently known or developed in the present invention for the irradiation of various types of cancer. Examples of other therapeutic agents or treatment regimens include, without limitation, radiation therapy, chemotherapy, surgical intervention, and combinations thereof.
The compositions within the scope of this invention include all compositions wherein the compound of the present invention is contained in an effective amount to achieve its intended purpose. Although the individual needs may vary, the determination of the optimal ranges of the effective amounts of each component is within the capacity of the technique. Typical doses comprise approximately 0.01 to approximately 100 mg / kg coporai weight. The most preferred doses comprise from about 0.1 to about 100 mg / kg body weight. The treatment regime for the administration of the compounds of the present invention can also be easily determined by those skilled in the art. That is, the frequency of administration and the size of the dose can be established by routine opimimization, preferably while minimizing any side effects.
EXAMPLES The examples set forth below are for illusory purposes only and are not intended to limit, in any way, the scope of the present invention.
EXAMPLE 1 Synthesis of thiazolidine carboxylic acid amides All the reactive and solveníes used were reactive grade or were purified by standard methods before use. The moisture sensitive reactions were carried out under an argon atmosphere. The progress of the reactions was followed by thin-layer chromatography (TLC) analysis. Flash column chromatography was carried out using silica gel (200-425 mesh) supplied by Fisher. The melting points were measured in open capillary tubes in a Thomas-Hoover melting point apparatus and were not corrected. All compounds were characterized by NMR and MS (ESI). The 1 H NMR spectra were recorded on a Varian 300 device. Chemical changes were reported as S values in relation to MeaSi as an internal standard. The mass spectra were obtained in the electrospray mode (ES) using the Esquire-LC spectrometer (Broker). Elemental analyzes were carried out using Atlanic Microlab Inc. (Norcross, GA). All the compounds described in this study were prepared following direct chemistry. The reaction of L-cysteine with various aldehydes under reported conditions (Seki et al., "A Novel Synítesis de (+) - Bioíin from L-Cysíeine, "J. Org. Chem. 67: 5527-5536 (2002), which is incorporated herein by reference in its entirety) produced the corresponding acids (Table A and Scheme 1), which were isolated as diastereomeric mixtures. These mixtures were used directly for the formation of the corresponding amides by reaction with appropriate alkyl amines using EDC / HOB, as shown in scheme 1. All the compounds thus prepared were characterized as diastereomeric mixtures (Table 1). Appropriate carboxylic acid (Table A and Scheme 1, 0.3-0.5 g), EDC (1.25 equivalents) and HOBi (1 equivalent) in CH2Cl2 (25-50 mL) was stirred for 10 minutes.To this solution, alkyl amine was added. The reaction mixture was diluted with CH2CI2 (100-150 mL) and washed sequentially with water, saturated NaHC03, brine and dried over Na2 (equivalent) and the stirring was continued at room temperature for 6-8 hours. S04 The solvent was removed under reduced pressure to produce an unpurified solid, which was purified by column chromatography. The purified compounds (3-6, 12, 15-18 and 27) were converted to the corresponding hydrochlorides using 2M HCl / Et20.
SCHEME 1 2a-2v 3-27 TABLE A Hepthylamide hydrochloride of (2RS, 4R) -2-phenylthiazolidine-4-carboxylic acid (compound 3 »HCl): 1H NMR (DMSO-d6) d 8.72 (s, 1 H), 7.65 (m, 2H), 7.43 ( m, 3H), 5.89 (s, 0.6H), 5.84 (s, 0.4H), 4.66 (t, J = 6.3 Hz, 0.6H), 4.46 (t, J = 6.9 Hz, 0.4H), 3.55-3.71 (m, 1H), 3.24-3.34 (m, 1H), 3.13 (d, J = 5.7 Hz, 2H), 1.44 (m, 2H), 1.25 (s, 8H), 0.83 (t, J = 6.9 Hz, 3H); MS (ESI) m / z calculated for C17H27N2OS 307.47 (M + 1), observed 307.10. (2RS, 4R) -2-phenylazolidine-4-carboxylic acid (2RS, 4R) -2-phenylazolidine hydrochloride (Compound 4"HCl): 1H NMR (DMSO-d6) d 8.69 (m, 1 H), 7.64-7J1 (m, 2H), 7.45 (m, 3H), 5.89 (s, 0.6H), 5.84 (s, 0.4H), 4.67 (t, J = 6.6 Hz, 0.6H), 4.47 (i, J = 7.2 Hz, 0.4H), 3.55 -3.71 (m, 1H), 3.25-3.35 (m, 1 H), 3.1, 0-3.16 (m, 2H), 1.44 (m, 2H), 1.23 (s, 22H), 0.85 (í, J = 63) Hz, 3H); MS (ESI) m / z calculated for C 24 H 40 N 2 OS 404.65 (M +), found 427.30 (M + Na).
Octadecylamide hydrochloride of (2RS, 4R) -2-phenylazolidine-4-carboxylic acid (compound 5 »HCl): 1 H NMR (DMSO-d 6) d 8.59 (d, J = 5.1 Hz, 1 H), 7.63 (d, J = 3.9 Hz, 2H), 7.42-7.47 (in, 3H), 5.86 (s, 0.6H), 5.81 (s, 0.4H), 4.60 (i, J = 6.3 Hz, 0.6H), 4.39 (t, J = 6.9 Hz, 0.4H), 3.52-3.66 (m, 1 H), 3.24-3.30 (m, 1 H), 3.10-3.16 (m, 2H), 1.42 (m, 2H), 1.23 (s, 30H ), 0.85 (i, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C28H49N2OS 461.76 (M + 1), observed 461.50.
Nonadecylamide hydrochloride of (2RS, 4R) -2-phenylthiazolidine-4-carboxylic acid (compound 6 «HCl): 1H NMR (DMSO-d6) d 8.51 (s, 1 H), 7.62 (m, 2H), 7.41- 7.46 (in, 3H), 5.83 (s, 0.6H), 5.78 (s, 0.4H), 4.53 (m, 0.6H), 4.32 (m, 0.4H), 3.48-3.61 (m, 1 H), 3.24 -3.29 (m, 1 H), 3.11-3.15 (m, 2H), 1.43 (m, 2H), 1.23 (s, 32H), 0.85 (i, J = 6.3 Hz, 3H); MS (EST) m / z calculated for C29H50N2OS 474.79 (M +), observed 497.40 (M + Na).
Ocydecylamide of the acid (2RS, 4R) -2-Dodecilliazolidine-4-carboxylic acid (compound 7): 1 H NMR (CDCl 3) d 7.18 (m, 1 H), 4.20-4.27 (m, 1 H), 3. 79 (m, 0.3H), 3.54-3.59 (m, 0.7H), 3.08-3.34 (m, 4H), 1.65-1.78 (m, 2H), 1. 43-1.51 (m, 4H), 1.27 (brs, 48H), 0.89 (t, J = 6 Hz, 6H); MS (ES!) M / z calculated for C3 H69N2OS 553.98 (M + 1), found 553.60.
Octadecylamide of (2RS, 4R) -2-Cyclohexylthiazolidine-4-carboxylic acid (compound 8): 1 H NMR (CDCl 3) d 7.17 (m, 1 H), 4.10-4.20 (m, 1 H), 3.76 (m, 0.3 H), 3.54 (dd, J = 11.1, 3.6 Hz, 0.7H), 2.97-3.34 (m, 4H), 2.02 (m, 1 H), 1.68-1.78 (m, 4H), 2 1.48-1.54 (m , 2H), 1.27 (brs, 36H), 0.87 (t, J = 6.9 Hz, 3H); MS (ESI) m / z calculated for C28H55N2OS 467.81 (M + 1), observed 467.60. (2RS, 4R) -2-Benzylthiazolidine-4-carboxylic acid octane acrylamide (compound 9): 1 H NMR (CDCl 3) d 7.28-7.33 (m, 5H), 7.03 (s, 0.7H), 6.48 (s, 0.3H) ), 4.55 (brs, 0.5H), 4.18 (brs, 0.5H), 3.82 (brs, 0.3H), 3.54 (dd, J = 11.1, 3.6 Hz, 0.7H), 2.99-3.31On, 6H), 1.46 -1.51 (m, 2H), 1.27 (brs, 30H), 0.89 (t, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C29H5ON20S 475.79 (M + 1), observed 475.50.
Octadecylamide of (2RS, 4R) -2- (1 H-lndol-3-yl) -thiazolidine-4-carboxylic acid (compound 10): 1 H NMR (CDCl 3) d 7.86 (m, 0.6H), 7.77 (m, 0.4H), 7.41-7.48 (m, 4H), 7.29-7.34 (m, 1 H), 6.0 (s, 0.3H), 5.69 (s, 0.7H), 4.37-4.41 (m, 0.5H), 3.76 (dd, J = 11.1, 4.2 Hz, 0.5H), 3.23-3.52 (m, 3H), 2.79-3.04 (in, 1 H), 1.43 (m, 2H), 1.27 (s, 30H), 0.89 (t , J = 6.6 Hz, 3H); MS (ESI) m / z calculated for C30H50N3OS 500.80 (M + 1), observed 500.60. (2RS, 4R) -2-Pyridin-3-yl-iazolidine-4-carboxylic acid ocladecylamide (Compound 11): 1 H NMR (CDCl 3) d 8.74 (d, J = 2.1 Hz, 1H), 8.60 (d, J) = 4.8 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.31-7.36 (m, 1 H), 7.08 (m, 1 H), 5.44 (s, 0.5 H), 5.40 (s) , 0.5H), 4.28-4.35 (m, 1 H), 3.72 (dd, J = 11.1, 4.2 Hz, 1 H), 3.27-3.45 (m, 3H), 2.57 (m, 1 H), 1.53-1.57 (m, 2H), 1.26 (s, 30H), 0.89 (i, J = 6.6 Hz, 3H); MS (ESL) m / z calculated for C27H49N3OS 462.75 (M + 1), observed 462.40. (2RS, 4R) -2-Furan-3-yl-thiazolidine-4-carboxylic acid hydrochloride (comp. 12.HCl): 1 H NMR (DMSO-4) d 8.59 (d, J = 15.6 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.72 (s, 1 H), 5.86 (s, 0J1-f), 5.78 (s, 0.3H), 4.37-4.56 (m, 1 H), 3.50- 3.63 (nay, 1 H), 3.11-3.23 (m, 3H), 1.43 (m, 2H), 1.23 (s, 30H), 0.85 (f, J = 6.6 Hz, 3H); MS (ESI) m / z calculated for C26H48N202S 451.72 (M + 1), found 451.60.
Ocydecylamide of (2RS, 4R) -2- (4-Dimeylamino-phenyl) -thiazolidine-4-carboxylic acid (compound 13): 1 H NMR (CDCl 3) d 7.34-7.41 (m, 2H), 6.70-6.74 (m, 2H), 5.57 (s, 0.3H), 5.28 (s, 0.7H), 4.34 (m, 0.7H), 3.90 (m, 0.3H), 3.69 (dd, J = 11.1, 4.2 Hz, 1 H), 3.41-3.47 (m, 1 H), 3.20-3.33 (m, 2H), 2.97 (d, J = 3.6 Hz, 6H), 1.48-1.55 (m, 2H), 1.27 (s, 30H), 0.89 (i , J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C3oH54N3OS 504.83 (M + 1), observed 504.60.
Occipdecylamide of (2RS, 4R) -2- (3-Hydroxy-phenyl) -thiazolidine-4-carboxylic acid (compound 14): H NMR (DMSO-d6) d 8.59 (s, 1 H), 7.22 (i, J) = 6.6 • Hz, 1 H), 7.02 (d, J = 6.3 Hz, 2H), 6.82 (d, J = 7.5 Hz, 1H), 5.77 (s, 0.7H), 5.71 (s, 0.3H), 4.545 (m, 0JH), 4.37 (m, 0.3H), 3.49-3.59 (m, 1H), 3.13-327 (m, 3H), 1.43 (brs, 2H), 1.23 (s, 30H), 0.85 (í, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C28H49N202S 477.76 (M + 1), observed 477.60.
Chlorhydrate of (2RS, 4R) -2- (4-Methoxy-phenyl) -iiazolidine-4-carboxylic acid octadecylamide (comp. 15 HCl): 1 H NMR (DMSO-d 6) d 8.61 O, 1 H), 7.57 (d , J = 8.4 Hz, 2H), 6.98 (d, J = 9 Hz, 211), 5.83 (s, 0.711), 5.78 (s, 0.311), 4.61 (t, J = 6.3 Hz, 0.7H), 4.40 ( m, 0.3H), 3.77 (s, 311), 3.51-3J0 (m, 1 H), 3.22-3.31 (m, 1 H), 3.1.1 (m, 2H), 1.43 (m, 2H), 1.23 (s, 30H), 0.84 (í, J = 6.6 Hz, 3H); MS (ESI) m / z calculated for C29H5? N202S 491.79 (M + 1), observed 491.60.
Acid (2RS, 4R) -2- (3,4-D-methoxy-phenyl) -f-azozidine-4-carboxylic acid cyclohydraide (compound 16 HCl): 1 H NMR (DMSO-de) d 8.58 (m, 1 H), 7.33 (d, J = 4.2 Hz, 111), 7.14 (i, J = 7.5 Hz, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 5.81 (s, 0.8H), 5.77 (s, 0.2H), 4.62 (m, 0.711), 4.40 (m, 0.3H), 3.78 (d, J = 7.8 Hz, 6H), 3.52-3.68 (m, 1 H), 3.23-3.29 On, 1 H), 3.12-3.13 (m, 2H), 1.43 (m, 2H), 1.23 (s, 30H), 0.85 (i, J = 6.6 Hz, 3H); MS (ESI) m / z registered for C3oH53N203S 521.81 (Thousand), observed 521.60.
Chlorhydrate of (2RS, 4R) -2- (3,4,5-Trimeloxy-phenyl) -thiazolidine-4-carboxylic acid ocladecylamide (comp. 17 HCl): 1 H NMR (DMSO-de) d 8.59 (m, 1 H ), 7.01 (d, J = 5.7 Hz, 2H), 5.80 (s, 0.8H), 5.76 (s, 0.2H), 4.63 (m, 0.7H), 4.37 (m, 0.3H), 3.80 (d, J = 5.7 Hz, 611), 3.66 (s, 3H), 3.23-3.28 (m, 1 H), 3.12-3.13 (m, 2H), 1.43 (m, 2H), 1.23 (s, 30H), 0.85 ( f, J = 6 Hz, 3H); MS (ESI) m / z calculated for C3? H55N204S 551.84 (M + 1), observed 551.60.
Acid (2RS, 4R) -2- (4-Acetylamino-phenyl) -yiazolidine-4-carboxylic acid (meth. 18 HCl) hydrochloride: 1 H NMR (DMSO-de) d 10.18 (s, 1 H) , 8.61 (m, 1 H), 7.54-7.64 (m, 4H), 5.82 (s, 0.7H), 5.77 (s, 0.3H), 4.60 (m, 0.8H), 4.42 (m, 0.2H), 3.56-3.64 (m, 1 H), 3.12-3.26 (m, 3H), 2.05 (s, 3H), 1.43 (m, 2H), 1.23 (s, 30H), 0. 84 (t, J = 6 Hz , 3H); MS (ESI) m / z calculated for C3oH52N302S 518.81 (M + 1), observed 518.70.
Ocydecylamide of (2RS, 4R) -2- (4-Fluoro-phenyl) -yiazolidine-4-carboxylic acid (compound 19): 1 H NMR (CDCl 3) d 7.46-7.54 (m, 2H), 7.13-7.20 (m, 1 H), 7.01-7.08 (m, 2H), 5.60 (s, 0.3H), 5.34 (s, 0.7H), 4.76 (m, 0.3H), 4.34 (m, 0.7H), 3.69 (dd, J = 11.1, 6.9 Hz, 1 H), 3.21-3.52 (m, 3H), 1.49 (n, 2H), 1.26 (s, 30H), 0.89 (í, J = 6.3 Hz, 3H); MS (EST) m / z calculated for C28H48FN2OS 479.75 (M + 1), observed 479.60.
Octadecylamide of (2RS, 4R) -2- (4-Bromo-phenyl) -thiazole-4-carboxylic acid (compound 20): 1 H NMR (CDCl 3) d 7.48-7.62 (m, 2H), 7.36-7.42 ( m, 2H), 7.14 (m, 0.7H), 6.40 (m, 0.3), 5.57 (d, J = 10.2 Hz, 0.3H), 5.33 (d, J = 11.1 Hz, 0.7H), 4.32 (m, 0.7H), 3.94 (in, 0.3H), 3.70 (dd, J = 11.1, 4.2 Hz, 1 H), 3.20-3.44 (m, 3H), 1.49 (m, 2H), 1.27 (s, 30H), 0.89 (t, J = 6.3 Hz, 3H); MS (ESL) m / z calculated for C23H47BrN2OS 539.66 (M +), observed 539.70.
Acid cyclodexamide (2RS, 4R) -2- (4-Nifro-fenii) -iazoiidine-4-carboxylic acid (compound 21): 1 H NMR (CDCl 3) d 8.24 (d, J = 8.7 Hz, 2H), 7.67 (d , J = 8.7 Hz, 2H), 6.92 (m, 1 H), 5.54 (s, 0.5H), 5.50 (s, 0.5H), 4.24-4.31 (in, 1 H), 3.67 (dd, J = 10.8 , 4.8 Hz, 1 H), 3.27-3.44 (m, 3H), 1.55 Orí, 2H), 1.26 (s, 30H), 0.89 (í, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C28H47N303S 506.76 (M + 1), observed 506.60.
Octadecylamide of (2RS, 4R) -2- (4-cyano-phenyl) -iazolidine-4-carboxylic acid (compound 22): 1 H NMR (CDCl 3) d 7.60-7.70 (m, 4H), 6.94 (m, 0.6H ), 6.37 (m, 0.4), 5.64 (s, 0.4H), 5.46 (s, 0.6H), 4.27 (m, 0.6H), 3.96 (m, 0.4H), 3.65-3.70 (m, 1 H) , 3.20-3.45 (m, 3H), 1.54 Oñ, 2H), 1.26 (s, 30H), 0.89 (,, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C29H47N3OS 485.77 (M.), observed 508.50 (M + Na).
Octadecylamide of (2RS, 4R) -2- (3,5-Difluoro-phenyl) -thiazolidine-4-carboxylic acid (compound 23): H NMR (CDCl 3) d 7.04-7.08 (in, 2H), 6.97 (m, 1H), 6.79 (m, 1 H), 5.40 (s, 0.5H), 5.36 (s, 0.5H), 4.23-4.30 (m, 1 H), 3.66 (dd, J = 11.1, 4.5 Hz, 1 H ), 3.26-3.42 On, 3H), 1.33 (m, 2H), 1.26 (s, 30H), 0.89 (t, J = 6.3 Hz, 3H); MS (ESI) only calculated for C29H47F2N202S 497.74 (M + 1), observed 497.50.
Ocladecylamide of (2RS, 4R) -2- (2,6-Dichloro-phenyl) -fiazolidine-4-carboxylic acid (compound 24): 1 H NMR (CDCl 3) d 7.34-7.38 (m, 2H), 7.15-7.28 ( m, 2H), 6.29 (s, 0.5H), 6.25 (s, 0.511), 4.25 (t, J = 5.7 Hz, 1 H), 3.94 (dd, J = 10.5, 1.8 Hz, 1H), 3.26 -3.52 (m, 3H), 1.52 (m, 2H), 1.26 (s, 30H), 0.89 (t, J = 6 Hz, 3H); MS (ESI) m / z calculated for C28H46CI2N202S 529.65 (M +), observed 529.70. (2RS, 4R) -2- (3-Bromo-4-fiuoro-phenyl) -thiazolidine-4-carboxylic acid octanecilamide (compound 25): 1 H NMR (CDCl 3) d 7.71 On, 1 H), 7.42 (m, 1 H), 7.06-7.16 (m, 211), 5.56 (d, J = 9.3 Hz, 0.2H), 5.34 (d, J = 10.2 Hz, 0.8H), 4.29 (d, J = 4.5 Hz, 0.811) , 3.94 (m, 0.2H), 3.69 (dd, J = 11.1, 4.2 Hz, 1 H), 3.21-141 (m, 3H), 1.52 (m, 2H), 1.26 (s, 30H), 0.89 (f , J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C28H47BrFN2OS 558.65 (M + 1), found 558.70.
Ocydecylamide of (2RS, 4R) -2p-Tolyl-iazolidine-4-carboxylic acid (Compound 26): 1 H NMR (CDCl 3) d 7.34-7.43 (m, 2H), 7.14-7.21 (m, 3H), 5.59 (s) , 0.2H), 5.32 (s, 0.8H), 4.76 (in, 0.2H), 4.35 (m, 0.8H), 3.70 (dd, J = 11.1, 3.9 Hz, 1 H), 3.21-3.43 (m, 311), 2.36 (d, J = 2.7 Hz, 3H), 1.51 (m, 2H), 1.27 (s, 30H), 0.89 (i, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C29H5? N2OS 475.79 (M + 1), observed 475.60.
Octadecylamide hydrochloride of (2RS, 4R) -2-Biphenyl-4-yl-thiazolidine-4-carboxylic acid (compound 27 «HCl): 1H NMR» (DMSO-d6) d 8.59 (m, 1 H), 7.66- 7.73 (m, 5H), 7.37-7.51 (m, 4H), 5.92 (s, 0JH), 5.87 (s, 0.3H), 4.62 (m, 0JH), 4.41 (m, 0.3H), 3.53-3.64 ( m, 1 H), 3.26-3.32 (m, 1 H), 3.13-3.17 (m, 2H), 1.44 (m, 2H), 1.22 (s, 30H), 0.84 (i, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C34H53N2OS 537.86 (M + 1), observed. 537.70.
EXAMPLE 2 Synthesis of N-Acyl and N-sulfonyl derivatives of thiazolidine carboxylic acid amides The N-Acyl and N-sulfonyl derivatives (compounds 28 and 29) were synthesized from the compound 5 by means of standard procedures (scheme 2). Briefly, ociadecylamide of (2RS, 4R) -2-phenylazolidine-4-carboxylic acid (compound 5) was reacted with any acetic anhydride or meilynylsulfonyl chloride, in pyridine, to produce the desired derivatives.
Ocydecylamide of (2RS, 4R) -3-Acetyl-2-phenylthiazolidine-4-carboxylic acid (compound 28): 1 H NMR (CDCl 3) d 7.31-7.41 (m, 5H), 6.01 (s, 1 H), . 12 (s, 1H), 3.73 (m, 1 H), 3.40 (m, 1 H), 3.31 (m, 1 H), 3.11-3.17 (m, 1 H), 2.00 (s, 3H), 1.27- 1.33 (m, 32H), 0.89 (i, J = 6.3 Hz, 3H); MS (ES!) M / z calculated for C3oH5oN202S 502.80 (M +), observed 502.60.
Ocydecylamide of (2RS, 4R) -3-Menessulfonyl-2-phenylfiazolidine-4-carboxylic acid (compound 29): 1 H NMR (CDCl 3) d 7.65-7.68 (m, 2H), 7.32-7.36 (m, 3H), 6.20 (s, 1H), 4.63 (dd, J = 9.6 Hz, 1 H), 3.67 d, J = 12.6 Hz, 1 H), 3.47 (dd, J = 12.3, 8.1 Hz, 1 H), 3.04-3.13 ( m, 2H), 3.02 (s, 3H), 1.27 (m, 32H), 0.89 (i, J = 6.3 Hz, 3H); MS (ESI) m / z calculated for C29H5oN203S2 538.85 (M +), observed 538.70.
Based on the above synthesis, it is expected that other acyl anhydrides (eg, which contain larger alkyl groups) can also be prepared according to the same synthesis procedures (Badr et al., "Synítesis de Oxazolidines, Thiazolidines, and 5,6,7,8-Tetrahydro-1 H, 3H-pyrrolo [1,2-c] oxazole (or iazole) -1, 3-diones from ß-Hydroxy-or -Mercapto-a-amino Acid Esíers, "Bull. Chem. Soc. Jpn. 54: 1844-1847 (1981), which is incorporated in the present invention as a reference in its entirety).
EXAMPLE 3 Synthesis of thiazole carboxylic acid amides The synthesis of the thiazole derivative (compound 34) was achieved by starting from cisfeine as shown in scheme 3. To a solution of DL-cisiein (3 g, 24.76 mmol) in MeOH (50 mL) at 0 ° C, leniamenie SOCI2 (2.76 mL, 37.14 mmol) was added and heated to ambient temperature and posiioriorly refluxed for 3 hours. The reaction mixture was concentrated in vacuo to yield a residue. This residue was taken in aqueous EfOH (1: 1, 30 mL), NaHCO3 (2.28 g, 27.23 mmol) was added, after 10 min. Benzaldehyde (2.5 mL, 24.76 mmol) was added and stirred coninuously for 3 hours. . CHCl3 (200 L) was added to the reaction mixture and washed with water, brine, dried (Na2SO4) and the solvency was removed in vacuo. The unpurified product was purified by column chromatography to yield 2-phenylthiazo! Idine-4-carboxylic acid methyl ester (compound 31): Yield 4.7 g, 85%; 1 H NMR (CDCl 3) d 7.51-7.62 (m, 2 H), 7.32-7.42 (m, 3 H), 5.84 (s, 0.4 H), 5.58 (x, 0.4 H), 4.24 (i, J = 6.3 Hz, 0.4 H), 4.01 (i, J = 7.5 Hz, 0.6H), 3.83 (s, 3H), 3.39-3.55 (m, 1 H), 3.10-3.26 (m, 1 H); MS (ESI) m / z 224 (M + 1). Starting with compound 31, 2-phenylisiazole-4-carboxylic acid methyl ester (compound 32) was synleized following a reported procedure (Kue ef al .. "Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling" Urol. 164 : 2162-2167 (2000), which is incorporated herein by reference in its entirety). Yield 033 g, 68%; 1 H NMR (CDCl 3) d 8.20 (s, 1 H), 8.0-8.04 (m, 2H), 7.45-7.50 (m, 3H), 4.0 (s, 3H); MS (ESI) m / z 220 (M + 1). To a solution of compound 32 (0.5 g, 2.28 mmol) in MeOH (10 mL) at 0 ° C, 1 N NaOH (5 mL) was added and stirred for 2 hours. EOAc (30 mL) was added to the reaction mixture, and it was acidified with 1N HCl. It was extracted with EtOAc (3X50 mL), the combined extractions were washed with water, brine, dried (Na2SO) and the solveny stirring under vacuum to produce the crude acid (compound 33), which was converted to the octadecylamide of 2-phenylisoxazole-4-carboxylic acid (compound 34) following the general procedure described in Example 1 above. Yield 0.30 g, 68%; 1 H NMR (CDCl 3) d 8.10 (s, 1 H), 7.96.7.93 (m, 2H), 7.46-7.50 (m, 3H), 3.49 (dd, J = 13.5, 6.9 Hz, 2H), 1.69 (m, 2H), 1.27 (m, 301-1), 0.89 (i, J = 6.3 Hz, 3H); MS (BSI) m / z calculated for C28H45N2OS 457.73 (M + 1), observed 457.60. TABLE 1 EXAMPLE 4 Analysis of the selected cell lines of prostate cancer by RT-PCR for the expression of the LPA receptor Human prostate cancer cells DU-145, PC-3, and LNCaP, and RH7777 rat hepatic cells were obtained from American Type Culíure Coiiecíion (Manassas, VA). Dr. Míícheil Síeiner ai Universiíy of Tennessee Healíh Science Ceníer, kindly provided the PPG-1 and TSU-Prl cells. Prostate cancer cells and RH7777 cells were cultured in RPMl 1640 medium and DMEM (Mediaic, Inc., Herndon, VA), respectively, supplemented with 10% fetal bovine serum (Gibco, Grand Island, NY) in a humid atmosphere with 5% C02 / 95% air at 37 ° C. The total RNA was extracted using the Triazol® reagent (Invilrogen Corp., Carlsbad, CA) in accordance with the instructions of! maker. 0.5 μg (LPA-i) or 1 (LPA2 and LPA3) of the total RNA were used to carry out the RT-PCR using SuperScripl ™ One-Síep RT-PCR with Plaíinum® Tag (Invifrogen Corp., Carlsbad, CA) with 0.2 μM of primers. The following pairs of primers were used: LPAT forward d'-GCTCCACACACGGATGAGCAACC-S ' (SEQ ID NO: 1), and LPA, reverse 5'-GTGGTCATTGCTGTGAACTCCAGC-3 '(SEQ ID NO: 2); LPA2 forward 5'-CTGCTCAGCCGCTCCTATTTG-3 '(SEQ ID NO: 3), and reverse LPA2 5'-AGGAGCACCCACAAGTCATCAG-3' (SEQ ID NO: 4); LPA3 forward 5'-CCATAGCAACCTGACCAAAAAGAG-3 ' (SEQ ID NO: 5), and reverse LPA3 d-TCCTTGTAGGAGTAGATGATGGGG-S '(SEQ ID NO: 6); β-actin forward 5'-GCTCGTCGTCGACAACGGCTC-3 '(SEQ ID NO: 7), and reverse β-acin 5'-CAAACATGATCTGGGTCATCTTCTC-3' (SEQ ID NO: 8). The PCR conditions were as follows: After 2 minutes of the denaturation step at 94 ° C, the samples were subjected to 34 to 40 cycles at 94 ° C for 30 seconds, 60 ° C (LPA-,) or 58 ° C (LPA2 and LPA3) for 30 seconds, and 72DC for 1 minute, followed by an additional step of elongation at 72 ° C for 7 minutes. The primers were selected to span at least one inirogen of the genomic sequence to detect contamination of the genomic DNA. The PCR products were separated on 1.5% agarose gels, stained with ethyl bromide, and band intensity quantified using Quantiíy One software (Bio-Rad Laboratories, Inc., Hercules, CA). The expression levels of each receptor subtype in different cell lines were expressed as ratios compared to the i-actin mRNA level. The expression of the LPL receptor in these cell lines was determined to validate its use as in vitro models (see Table 2 below). 1 μg of the total RNA was subjected to RT-PCR, the PCR products were separated on agarose gels, and the level of relative expression of each receptor subtype was quantified in comparison with the β-actin using the Quantity One software (Bio -Rad). LPAT was the LPL receptor predominantly expressed in these cell lines. However, LNCaP cells express it as a sub-type of the receptor. The LPA3 receptor was expressed only in the prostate cancer cell lines. RH7777 cells do not express any of the known LPL receptors.
TABLE 2 Expression of LPL receptor mRNA 3UD = low detection limit EXAMPLE 5 Cytotoxicity assay in prostate cancer cells For the selection of in vitro cytotoxicity, 1000 to 5000 cells were seeded into each well of 96 well plates depending on the growth rate, and were exposed to different concentrations of a test compound for 96 hours in three to five cycles. . All compounds were dissolved in 5 to 20 mM dimethyl sulfoxide, and diluted to the desired concentrations in complete culture medium. Cell numbers were measured at the end of the treatment with the drug by the SRB assay (Gududuru et al., "Synthesis and Biological Evaluation of Novel Cytoxicity Phospholipids for Cancer Prospects", Bioorg, Med. Chem. Lei., 14: 4919-4923. (2004); Rubinsiein et al., "Comparison of in vitro Anticancer-Drug-Screening Dala Generaíed wifh to Teírazolium Assay Versus a Prolein Assay Againsí a Diverse Pane! Of Human Tumor Cell Lines", J. Nati, Cancer Inst. 82: 1113-1118 (1990), each of which is incorporated in the present invention as reference in its identity). Briefly, the cells were fixed with 10% rubricoacetic acid, stained with 0.4% SRB, and absorbances were measured at 540 nm using a plate reader (DYNEX Technologies, Chanfilly, VA). The percentage of cell survival was plotted against the drug concentrations and the IC50 values (concentration that inhibited cellular growth by 50% of the non-treated serum) were determined by a non-linear regression analysis using WinNonlin (Pharsighí Corporaíion, Mouníain View, AC). 5-fluorouracil was used as a positive control to compare the potencies of the novel compounds. An intercalated ELISA (Roche, Mannheim, Germany) was used using monoclonal antibodies specific for DNA and histones to quantify the degree of apoptosis induced by the analogues after a 72-hour exposure. This assay measures DNA-histone complexes (mono- and oligonucleosomes) released in the cytoplasm from the nucleus during apoptosis. The RH7777 cells were used due to the non-specific cytotoxicity of compound 4 in the negave cells to the receptor as well as in the prostaglandin cells posilive to the receptor. The ability of 2-aryl-aiazolidine derivatives (ATCAAs) to inhibit the growth of five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPG-1, and TSU-Prl) was evaluated using the assay of sulforhodamine B (SRB) (previously described). A control cell line (RH7777) that does not express LPL receptors (Sveilov et al., "EDG Receptors and Hepalic Pathophysiology of LPA and EDG-ology of Liver Injury", Biochimica et Biophysica ACT 1582: 251-256 (2002), which is incorporated in the present invention as a reference in its entirety) was also used to understand whether the antiproliferative activity of derived spheres is mediated through the inhibition of LPL receptors. The diamelereomeric mixtures of the white compounds 3-29 were used as such to evaluate their inhibitory activity in vitro in conir of the prostate cancer cell lines, and the results are summarized in Tables 3 and 4 below. 5-Fluorouracil was used as the reference drug. To deduce the structure-activity relationships, the IC50 must be determined in principle on pure isomers. A disadvantage of the evaluation of the mixtures of stereoisomers, which could not be avoided in this case, was the fact that each stereoisomer could not be evaluated on the biological activity. On the other hand, the calculated IC50 values can be used as a selection method to select promising selective cytoxic agents and to identify the diastereomeric mixture with the best ability to inhibit the growth of prostate cancer cells. Many of these thiazolidine analogues were very effective in the elimination of prostate cancer cell lines with IC50 values in the low / sub micromolar interval (Table 3). Examination of the cytotoxic effects of compounds 3-5 shows that as the chain length increases from C7 to C8, also increased the power. However, a further increase in the length of the alkyl chain of a carbon unit (eg, C18 to C-? 9) caused a significant loss in cytoxicity. Interestingly, the derivative of C-4 (compound 4) showed a higher potency compared to compound 5, but was 8 times less effective against the cell line RH7777. Therefore, an alkyl chain with a C? 8 unit is optimal for the manipulation of the power and selectivity observed in this series of compounds. The N-Acyl and N-sulfonyl derivatives (compounds 28 and 29) were less cytotoxic than the parent compound 5. The replacement of the phenyl ring with an alkyl or cyclohexyl group reduced potency (compounds 7 and 8) relative to the thiazolidine derivative (compound 5). The introduction of a methylene spacer separating the phenyl ring and the iazolidine ring produced a compound 9, which was less active than the parenteral compound 5.
TABLE 3 Cell line conírol. bProsy cancer cell lines. ND = not deible. NA = without acíividad.
TABLE 4 Antiproliferative effects of compounds 18-29 and 34 on the prostate cancer cell line 3 Cell line conírol. bPelstatic cancer cell lines.
To understand the effect of unsaturation on potency and selectivity, and to overcome the problems associated with stereoisomers, the nucleus of core thiazolidine core in compound 5 was replaced with a thiazole ring. Notwithstanding, the Iiazole derivative (compound 34) showed no activity below 20 μM in both prostate cells and RH7777 cells, indicating that the thiazolidine ring with two chiral centers plays an important role in the provision of power and selectivity. Replacements of the phenyl ring with a heterocycle, such as an indole, pyridine or furan ring were investigated by the synthesis of analogs (compounds 10-12). The furanyl derivative (compound 12) showed equivalent cytotoxicity compared to compound 5, but was 3 times less selective against RH7777 cells. The cytotoxicity data of compounds 13-27 provide a summary of a broad search for substituted analogues of the phenyl ring. Examination of the IC50 values of these analogues demonstrates a greater tolerance for the various substituents on the phenyl ring. In general, the most potent analogs have electron donor substrates, as exemplified in comparison to compound 13, and compounds 16-18, in relation to compound 5. One of the most active compounds (compound 18) with a IC 0 of 0.55 μM was 38 times more selective in PPC-1 cells compared to RH7777 cells. On the other hand, the thiazolidine analogs (compounds 19-25), with electron acceptor substituents, showed less cytotoxicity. The comparison of the powers of compound 26 and compound 27 suggests that the substitution of the phenyl ring with a bulky group reduces the activity. From the expression studies of the LPL receptor mRNA (Table 2), it was evident that these cell lines serve as a model system to explore the effects of the LPL receptor. Given the structural similarity of SAPs to ceramide (and the known ability of ceramide to induce apoptosis), it was then determined whether the antiproliferative effects of thiazolidine analogues were mediated via apoptotic events. The ability of the analogs to induce apoptosis in LNCaP, PC-3, and RH7777 cells was examined using a quantitative sandwich ELISA that measures the DNA-histone complex released during apoptosis. The calculated enrichment factor (as the ratio of OD405 in treated and untreated cells) provides a quantitative evaluation of the degree of apoptosis induced. Initially, only two chapters (4 and 5) were used for this study. The apophotic activity of the analogue (compound 4) was selective in the prostate cancer cells despite the non-selective cytotoxicity in the negative control RH7777 cells (see Table 5 below). Analogous compound 5 induced apoptosis in PC-3 and LNCaP cells, but to a lesser degree in PC-3 cells perhaps due to the low potency in this cell line. These data suggest that thiazolidine analogues can act as potent inducers of apoptosis and selectively eliminate a variety of prostate cancer cell lines.
TABLE 5 Apoptosis induced by thiazolidine amides These results are consistent with the evaluation assay of LNCaP cells for DNA fragmentation by agarose gel electrophoresis. LNCaP cells were treated with a thiazolidine derivative (compound 4 or 5) for 24 to 108 hours, and then the whole DNA was extracted from 2 x 10 6 cells by a simple centrifugation method, treated with RNase and Proteinase K. After precipitation in ethanol, the DNA was reconsti- tuted in Tris-EDTA pH buffer, separated on agarose gels, and visualized by staining with ethidium bromide (Herrmann et al., " A Rapid and Simple Method for the Isolation of Apopíotic DNA Fragments ", Nucí Acids Res. 22: 5506-5507 (1994), which is incorporated in the present invention as a reference in its entirety). The results, shown in Figures 1A and 1B, demonstrate that both compounds induce cellular apoptosis in the LNCaP cell line of prostate cancer. As another evaluation of cytotoxicity, AKT inhibition was measured. 30 pg of cellular protein tola! from untreated control cells and cells treated with the compound were separated by SDS-PAGE, transferred to a nitrocellulose membrane, and AKT tota! and phospho-AKT with anti-AKT antibody and anti-phospho AKT specific for AKT phosphorylated at Ser 473, respectively (Cell Signaling Technology, Beverly, MA). Immunoblots were visualized by enhanced chemiluminescence, and changes in the relative levels of phospho-AKT compared to total AKT were quantified by analogous treatment by densitometry analysis. Figure 2B graphically illustrates the immunological detection of AKT using anti-AKT and anti-phospho-AKT, as shown in Figure 2A.
From the present, it can be seen that the introduction of ring activating groups on the phenyl ring resulted in increased potencies for the prostate cancer cell lines. The aforementioned results demonstrate several novel anticancer agents (represented by compounds 16, 17, and 18) with low / submicromolar cytotoxicity and alias selectivity. From this study, compound 18 emerged as one of the most potent and selective cytotoxic agents with a 1C50 of 0.55 μM and 38 times the selectivity in PPC-1 cells. In addition, the ability of these analogs to induce apoptosis in LNCaP, PC-3 and RH7777 cells provides an important key to understanding their mechanism of action.
EXAMPLE 6 Synthesis of thiazolidinone amides The synthesis of iazolidinone derivatives (compounds 65-72) was used for chemical guidance as shown in scheme 4, where / is 1. Various 4-thiazolidinones were synthesized following a reported procedure of the condensation of mercaptoacetic acid, glycine methyl ester, and aromatic aldehydes in a reaction in a vessel, followed by basic hydrolysis of the ester (Holmes et al., "Straighties for Combinatorial Organic Synthesis: Solution and Polymer-supporied Synítesis of 4-fiazolidinones and 4-metahiazanones Derived from AminoAcids", J Org Chem. 60: 7328-7333 (1995), which is incorporated herein by reference in its entirety). The iazolidinone amides were obtained by means of the amine with appropriate amines in the presence of EDC / HOBi under standard conditions. The compound 65 that does not have a lamellar chain was synthesized from the corresponding acid as shown in scheme 4. Iiazolidinone amides (compounds 73-77) were synthesized by a simple and direct method (Schuemacher et al., "Condensation beineween isocyanates"). and Carboxylic Acids n fhe Presence of 4-dimethylaminopyridine (DMAP), to Mild and Efficiení Synítesis de amides ", Synítesis 22: 243-246 (2001), which is incorporated in the present invention as a reference in its íoality), which involves the reaction of the acidic compound 64a with different isocyanals in the presence of a catalytic amount of DMAP (scheme 5). The exhaustive reduction of compound 68 by using BH3 THF under reflux conditions yielded compound 79 (scheme 6). Oxidation of 68 using H202 and KMn04 yielded sulphoxide (compound 80) and sulfone (compound 81), respectively, as shown in scheme 6. All compounds were characterized by 1H and 13C NMR, mass spectroscopy and, in certain cases, elemental analysis. The compounds were made as mixtures of diastereomers and used as such for biological studies. Characteristic data for the exemplary compounds 68, 71, 72, and 81 are provided in confinement.
N-Octadecyl-2- (4-oxo-2-phenylthiazolidin-3-yl) acefamide (Compound 68): 1 H NMR (300 MHz, CDCl 3): d 0.89 (f, J = 6.0 Hz, 3H), 1.26 (br s, 30H), 1.46 (m, 2H), 3.16-3.29 (m, 3H), 3.82 (d, J = 1.5 Hz, 2H), 4.20 (s, 0.5H), 4.25 (s, 0.5H) , 5.83-5.85 (m, 2H), 7.27-7.41 (m, 5H); 13 C NMR (300 MHz, CDCl 3): d 13.55, 22.13, 26.30, 28.69, 28.80, 28.88, 28.99, 29.03, 29.10, 29.14, 31.37, 32.13, 39.08, 45.88, 63.67, 127.05, 128.58, 128.96, 137.61, 166.30, 171.61; MS (ESI) m / z 511 [M + Na]. Analysis calculated for C29H48N202S; C, 71.26; H, 9.90; N, 5.73. Found: C, 71.18; H, 10.03; N, 5.79. 2- (2-4-methoxyphenyl) -4-oxothiazolidin-3-yl) -N-ocacydecylacetamide (compound 71): 1 H NMR (300 MHz, CDCl 3): d 0.89 (t, J = 6.0 Hz, 3 H), 1.26 (br s, 30 H), 1.33 (s, 2 H), 3.16-3.19 (m, 1 H ), 3.2-3.29 (m, 2H), 3.80 (d, J = 0.9 Hz, 2H), 3.83 (s, 3H), 4.16 (s, 0.5H), 4.21 (s, 0.47H), 5.82 (s, 1 H), 6.9 (dd, J = 1.8 Hz, 2H), 7.29 (dd, J = 1.5 Hz, 2H); 13 C NMR (300 MHz, CDCl 3): d 13.53, 22.12, 26.31, 28.70, 28.74, 28.79, 28.89, 28.99, 29.03, 29.09, 29.13, 31.36, 32.23, 39.06, 45.74, 54.79, 63.44, 128.64, 129.11, 159.97, 166.41, 171.47; MS (ESI) m / z 541 [M + Na]. Analysis calculated for C3oH5oN203S: C, 69.45; H, 9.71; N, 5.40. Found: C, 69.30; H, 9.86; N, 5.43. 2- (2- (2,6-Dichlorophenyl) -4-oxothiazolidin-3-yl) -N-ocladecyl-alamide (compound 72): 1 H NMR (300 MHz, CDCl 3): d 3.54 (d, J = 15.3 Hz, 1 H), 3.87 (s, 2 H), 4.25 (d, J = 15.3 Hz, 1 H), 5.88 ( s, 1 H), 7.10 (i, J = 1.8 Hz, 1 H), 7.36-7.43 (m, 7H), 8.29 (s, 1 H); 13 C NMR (300 MHz, CDCl 3): d 32.35, 46.73, 64.40, 1 17.37, 123.85, 127.29, 128.74, 129.32, 134.59, 136.87, 138.61, 165.14, 172.60; MS (ESI) m / z 403 [M + Na]. Analysis calculated for C17H14C? 2N202S: C, 53.55; H, 3.70; N, 7.35. Found: C, 53.39; H, 3.47; N, 7.36.
N-ocfadecyl-2- (4-oxo-2-phenyl-1-sulfonyl-thiazolidin-3-yl) acetylamide (compound 81): 1 H NMR (300 MHz, CDCl 3): d 0.89 (,, J = 6.0 Hz, 3H), 1.26 (br s, 32H), 3.19-3.34 (m, 3H), 3.88-4.03 (dd, J = 16.5 Hz, 2H), 4.66 (s, 0.51), 4.72 (s, 0.5H), 5.67 (br s, 1H), 5.95 (s, 1 H), 7.38 (m, 2H), 7.50-7.53 ( m, 3H); 13C NMR (300 MHz, CDCi3): d 13.54, 22.12, 26.26, 28.66, 28.79, 28.96, 29.02, 29.09, 29.14, 31.36, 39.30, 44.35, 49.85, 81.32, 125.77, 128.43, 128.91, 130.55, 163.23, 165.30; MS (ESI) m / z 519 [M-H]. Analysis calculated for C29H48N204S: C, 66.88; H, 9.29; N, 5.38. Found: C, 66.68; H, 9.27; N, 5.41.
EXAMPLE 7 Cytotoxicity test The antiproliferative activity of all synthesized compounds was evaluated in the five human prostate cancer cell lines and in the RH7777 cells (negative control) using the sulforhodamine B (SRB) assay (see description in Example 5 above). mentioned). 5-Fluorouracil (5-FU) was used as a reference drug. As shown in Table 6, the 4-thiazolidinone carboxylic acids (compounds 64a and 64b) were unable to inhibit the growth of any of the five prostate cancer cell lines below 50 μM. However, the corresponding amides (compounds 66-68) showed higher activities. It was observed that an increase in the length of the alkyl chain [compounds 66 (10), 67 (C14), and 68 (C18)] improves the antiproliferative activity of analogous strains in prostate cancer cells. Interestingly, the simple amide 65 without any long alkyl chain is not cytotoxic below 100 μM, which indicates that the absence of an alkyl side chain causes a considerable decrease in the antiproliferative effect. On the other hand, the replacement of the alkyl chain with various lamellar aryl chains (compounds 73-78) reduced the biological activity. Among this series, compound 73 is moderately cylotoxic, while analogs (compounds 76-78) exhibited low cytotoxicity in several prostate cancer cell lines. However, it should be mentioned that thiazoiidinone amides (compounds 74 and 75), with electron acceptor substituents in the aryl ring, showed cytotoxicity in the range of 13-29 μM against the five prostate cancer cell lines.
TABLE 6 Antiproliferative effects of compounds 64a-64b and 65-78 00 prostate cancer cell lines.
TABLE 7 Antiproliferative effects of compounds 79-81 a Cell line control. bProsstatic cancer cell lines. ND = not deceptible. NA = no activity.
Thiazolidinone derivatives (compounds 69 and 70) with bulky biphenyl or naphialene groups showed low cytotoxicity compared to compound 68 (Table 6). Compounds 71 and 72 were synthesized to understand the effects of the substitution of the aromatic ring on compound 68. It was observed that the electron donor substituents maintained a good activity while the ortho accepting electron withdrawants substantially decreased the antiproliferal activity of these derivatives. (table 6). Compound 79, which did not contain amide groups, significantly showed good potency in all five prostate cancer cell lines. Notably, compounds 80 and 81 that confer a sulfoxide or sulfone portion exhibited a higher cytotoxic potency comparable to that of the reference drug 5-FU against both cell lines PC-3 and PPC-I (Table 7).
Briefly, a series of novel and cyclo-toxic 4-iazolidinone amides was prepared and idenified. In this series, the de fi ned esíudios of the relationship between the acidity of the compounds of type I (scheme 4) were carried out to evaluate their antiproliferative activity against the five cell lines of prostate cancer and of the RH7777 cells (confiçal negaíivos) . The cyclo-toxicity test shows that the aniiproiiferative activity is sensitive to the suspensions in the 2-aryl ring, the length of the alkyl alkyl chain, and the removal or suspension of the lipophilic alkyl side chain. Oxidation of sulfur is well tolerated since compounds 80 and 81 showed significant cytotoxicity compared to 5-FU. This study resulted in the discovery of potent cytoxic 4-thiazolidinones (compounds 68, 80, and 81), which inhibit the growth of all five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, and TSU) with a 2-5 fold lower selectivity compared to the line of RH7777 cells. These 4-thiazolidinone derivatives are a significant improvement in the SAP portion in fluoride which are less cytoioxic but showed improved selectivity in non-tissue cells.
EXAMPLE 8 Cytotoxicity assay in breast and ovarian cancer cells The most potent compounds from each squirt formula were selected and evaluated for their growth inhibitory activity in a human breast cancer cell line (MCF-7) and in human ovarian cancer cell lines (CHO-1, CaOv-3, SKOv-3, and OVCAR-3). The in vitro cytotoxicity test was carried out by means of the same assay of sulforhodamine B (SRB) (previously described). The mosyrate compounds in Table 8 below were evaluated for conical activity of the breast cancer and ovarian cancer cell lines.
TABLE 8 Antiproliferative effects of the compounds on breast and ovarian cancer cell lines 3 Breast cancer cell line. b Ovarian cancer cell lines. NT = not evaluated.
The stereoselectivity of the compounds (compared to the (R) and (S) isomers) was observed in the CaOV-3 and SKOv-3 cells. Substitutions on the 2-phenyl ring generally increased the cytotoxicity of the compounds.
EXAMPLE 9 Synthesis and evaluation of thiazolidine amide conjugated to spermine As illustrated in Scheme A, a mixture of 4-thiazolidinone acid (wherein R 1 is phenyl and / is 1) (1.5 g, 6.32 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.51 g) , 7.9 mmol) and 1-hydroxybenzotriazole (0.85 g, 6.32 mmol) in CH 2 Cl 2 was cooled in an ice bath, stirred for 10 minutes. To this solution was added 4-nitrofen! (0.78 g, 5.61 mmol) and stirred for 2 hours. The reaction mixture was diluted with CH2C! 2, washed sequentially with HC! to! 5% cold, saturated NaHCO3, water, brine, dried (anhydrous Na2SO4) and the solvent was removed N vacuous. The nitrophenyl ester product (compound 100) was purified by flash chromatography (silica gel) using EtOAc / Hexanes to yield 1.76 g (78%). 1 H NMR (CDCl 3) d 3.70 (d, J = 18 Hz, 1 H), 3.85 (d, J = 1.2 Hz, 2 H), 4.64 (d, J = 17.7 Hz, 1 H), 5.88 (s, 1 H) ), 7.24 (d, J = 2.1 Hz, 1 H), 7. 26 (d, .J = 2.4 Hz, 1 H), 7.40-7.46 (m, 5H), 8.26 (d, J = 1.8 Hz, 1 H), 8.28 (d, J = 2. 1 Hz, 1 H).
To a solution of the nitrophenyl ester (compound 100) (0.5 g, 1.39 mmol) in CH3OH (35 mL) at room temperature, a solution of spermine (0.33 g, 1.63 mmol, in CH OH) was added slowly and stirred by 1 hour. The reaction mixture was concentrated in vacuo, and was added to the concentrated reaction mixture 1: 1 (CHCl 3: CH 3 OH) and filtered through celite. The solvent was removed in vacuo and the residue was purified by insanitary column chromatography (silica gel) using CHCl3: CH3OH / i-PrNH2 to yield 0.2 g (50%) of the spermine conjugate (compound 101), which was converted to the corresponding hydrochloride salt using 2M HCl / Et20. 1 H NMR (DMSO-d 6) d 1.71-1.76 (m, 6H), L95-2.0 (m, 2H), 2.89-3.0 (m, 10H), 3.0-3.15 (m, 4H), 3.74 (d, J = 15.6 Hz, 1 H), 3.87 (d, J = 15.3 Hz, 1 H), 4.10 (d, J = 16.5 Hz, 1 H), 7.35-7.44 (m, 5H), 8.0-8.18 (m, 4H) , 8.89 (Ins, 2H), 9.15 (brs, 2H). ESI MS m / z 422.4 (M ++ 1). Compound 101 demonstrated more potent activity against prostate cancer cells compared to MCF-7 ovarian and breast cancer cells, with IC50 values (μM) as follows: RH7777 (>100), DU145 (12.4), PC-3 (11.1), LNCaP (26.2), PPC-1 (11.7), TSU-Prl (5.0), MCF-7 (> 100), CaOv-3 (39.3) , OVCAR-3 (39.7), and SKOv-3 (> 100).
EXAMPLE 10 The antiproliferative effects of 3, 4, 5R, and 5S were compared with those observed with the four active derivatives of serine amide phosphates (SAPs) and 5-fluorouracil (5-FU, positive control) in human prostate cancer cell lines (PC-3, DU 145, LNCaP, PPC-1, TSU-Prl). A conírol cell line (RH7777) that does not express the receptors of LPL4 and MCF-7 (a human breast cancer cell line) was included to measure its selectivity. The cell lines chosen represent different basal levels of expression of AKT acfivo and LPL receptor (discussed later). The cells were exposed to a wide range of concentrations (0 to 100 μM) of the indicated compound for 96 hours. Cell numbers were measured at the end of the treatment using the sulforhodamine B (SRB) 5 assay. The IC 50 values (for example, concentration that inhibited cell growth in 50% of the non-treated conírol) were obviated by non-linear regression analysis (WinNonlin, Pharsighí Corp.). As previously observed in the inventors' laboratory, the SAP derivatives (compounds S1-S4 in the table below were potent inhibitors of the proliferation of the tissue cell with IC5o values having a range of 1.1 to -20 μM (ND = Not determined.) Differences in the antiproliferative activity of SAP and of Iiazolidine were observed.Tiazolidine derivatives (3, 4, 5R, and 5S) also potentially inhibited the growth of the prostate and breast cancer cell, but were 2 to 12 times less important in the RH7777 cells negative to the LPL receptor, suggesting that the iazolidine analogues showed greater potency and selective amphiproliferative activity.Two significant relationships between expression and activity were suggested in this small series of compounds. containing long alkyl chains (eg, C18; 5R, and 5S) were more selective and selective than those derived with long shorter chain chains (for example, C7 and C1, 3 and 4). Second, the IC50 for the R-isomer (5R) were less than the IC50 for the S-isomer (5S) in all tumor cell lines, except for RH7777. This suggests a stereospecific infection with a molecular target that is absent or that is less critical in RH7777 cells. Importantly, analogues 4, 5R, and 5S were as potent inhibitors of tumor cell proliferation as 5-FU was, and were better measured in many cell lines.
OO EXAMPLE 11 The cytotoxicity of thiazolidine and SAP derivatives in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, TSU-Pr1) and in a negative control cell line (RH7777) that is lacking of the LPL receptor was examined using the sulforhodamine B (SRB) assay. The cells were exposed to a wide range of concentrations (0 to 100 μM) of the particular compound for 96 hours in 96-well plates. The cells were fixed with 10% rubricoacetic acid, washed five times with water. The plates were air-dried overnight and the fixed cells were stained with an SRB solution. The SRB bound to the cellular protein was measured at 540 nm using a platelet. Cell numbers were measured at the end of the procedure. The IC50 values (for example, concentration that inhibited cell growth in 50% of the non-circulated confrol) were measured by non-linear regression analysis using WinNonlin. For comparison purposes and to understand the degree of cytotoxicity, 5-fluorouracil (5-FU) was evaluated against the five prostate cancer cell lines. Compounds that showed more potent amphiproliferaive activity will exhibit lower IC 50 values compared to those of 5-fluorouracil. The results are summarized below.
EXAMPLE 12 The LNCaP cells of the prostate cell line were irradiated with 30 μM of the compound of formula: For the indicated period and time. The active form of AKT (Pi-AKT) and ß-acyin were quantified by analysis of Wesíern bloí. The compound inhibited 50% AKT phosphorylation for 12 hours of the tra y. The compound of formula VIII had an IC 50 equal to 10.3 μM. The results of the experiment are given below.
EXAMPLE 13 The LNCaP cells of the prostate cell line were boarded with 10 μM of the compound of the formula: HCl For the period and time indicated. The active form of AKT (Pi- AKT) and AKT were quantified by Western blot analysis. The compound of formula IX almost completely inhibited the phosphorylation of AKT in the 6 hours of the year. The compound had an IC 50 equal to 3.3 μM. The results of the experiment are given in confinement.
EXAMPLE 14 The LNCaP cells of the prostate cell line were irradiated with 10 μM of the compound of formula HCl for the period and time indicated. The active form of AKT (P¡-AKT), AKT and ß-actin were quantified by Western Bloí analysis. The compound almost completely inhibited AKT phosphorylation for 1 hour of irradiation. The compound had an IC 50 equal to 3.3 μM. The results of the experiment are given below.
EXAMPLE 15 The cyto-toxicity of the syngeneic compounds was examined in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, and TSU) and in two conirol negaíivo cell lines (CHO and RH7777) using the sulforhodamine B (SRB) assay (Rubinstein, L.V.S., R. H. Paull, K. D. Simon, R. M. Tosini, S. Skehan, P. Scudiero, D. A. Monks, A. Boyd, M. R. J. Nati. Cancer. Inst. 1990, 82, 1113-1118, which is incorporated by reference in the present invention). The cells were exposed to a broad concentration inervance (0 to 100 μM) of the particular compound for 96 hours in 96-well plates. The cells were fixed with 10% trichloroacetic acid, washed five times with water. The plates were air dried overnight and the fixed cells were stained with SRB solution. The SRB bound to the cell line was measured at 540 nm using a platelet. Numerous cell phones were calculated at the end of the fraternity as a percentage of the unframed conírol. IC50 values were obtained (for example, concentration that inhibited cell growth in 50% of the nonradiol conirol) by means of nonlinear regression analysis using WinNonlin. For purposes of comparison and to understand the degree of cyto-toxicity, 5-fluorouracil was evaluated against the five prostate cancer cell lines. The results are summarized in Table 1. From the damage of cytotoxicity, it is evident that most of the compounds evaluated showed a better cancer activity in the five prostate cancer cell lines. SAAs (306b, 306e, 306f) without a phosphate group are as effective as SAPs. A direct relationship was observed between the length of the alkyl chain and the cyto-toxicity of the compounds evaluated. Consequently, all these compounds showed a cyclicity dependent on the length of the alkyl chain. Compounds with shorter alkyl chains (302a, 306b, 315d, 316d) are less cycloxic than analogs with longer alkyl chains (see Table 1). The 302f compound emerged as one of the most potent SAPs evaluated so far with an IC50 of 1.8 μM against the PPC-1 cell line. However, SAAs are more potent than the corresponding SAPs when the length of the alkyl chain is below 18C, but no significant difference in cyto-toxicity was observed between SAAs and SAPs with an alkyl chain greater than 18C. The 1C50 values for the enantiomers of SAAs (306c, 306d) and SAPs (302b, 302c) are approximately equivalent which suggests that chirality is not important for the antiproliferative activity of compound strands in prostate cancer. The inroduction of a double bond in the alkyl chain decreased the strength of both SAA 309 and SAP 311. To understand the importance of the amine functionality, the inventors derived the amine group to the corresponding B-amide derivatives., sulfonamide and urea. Serine diamide phosphate 316d phosphate with a shorter alkyl chain could not demonstrate cytotoxicity below 100 μM in four prostate cancer cell lines except in the TSU prostate cell line. The inhibitory activity of the sulfonamide derivatives 315b and 316b and the urea derivative 315c in all five prostate cancer cell lines showed a general tendency to decrease suggesting that the derivatization of the C2 amine group is not irrelevant due to its ability to eliminate the prostate cancer cells. To further investigate the degree of perilidal srucural tolerance in the region of the serine amide base, the inventors replaced the serine amide group with simple amide amide amine via the syn- thesis of compounds 319 and 320. Notwithstanding, these analogs of efanolamine amide were less potent and particularly compound 319 showed no activity against the prostate cancer cell lines DU-145, PC-3, and LNCaP. When the amide group in SAAs was reduced to produce long chain N-alkyl amino alcohols 317 and 318, these analogs retained cytoxicity and were very effective in eliminating prostate cancer cell lines with low micromolar cytotoxicity. To determine the selectivity, several of the syntheized compounds were also examined for their cytotoxicity in the CHO and RH7777 cells as negative controls. Many of the potent compounds showed similar cytotoxicity and were not selective in their action against the prostate cancer cell lines and the non-tumor control negative cells.
TABLE 9 ICgn (μM) of various compounds Although several embodiments have been illustrated and described in detail in the present invention, it will be apparent to those skilled in the art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and therefore these are consider the scope of the invention as defined in the claims below.

Claims (2)

  1. NOVELTY OF THE INVENTION CLAIMS 1. A compound according to formula (V) or formula (SAW) wherein X1 and X2 are each optional, and each may be oxygen; X5 is optional, and may be oxygen; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, unsaturated or unsaturated O-heterocycles, saturated or unsaturated S-heyerocycles, mixed saturated or unsaturated heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30 of straight or branched chain, or or - (CH2) m-Y1 wherein m is an ether from 0 to 10 and Y1 is a sauced or unsaturated cyclic hydrocarbon, unsaturated or unsaturated N-helerocycle, unsaturated or unsaturated O-heterocycle, unsaturated or unsaturated S-heiEROcycle, or saturated or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C to C30, R10-N (Z) -hydrocarbon- or R10-hydrocarbon- wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to C30 of straight or branched chain, a saturated or unsaturated cyclic hydrocarbon, a saturated or unsaturated N-heterocycle, a saturated or unsaturated O-heterocycle, a saturated or unsaturated S-heyerocycle, a saturated or unsaturated mixed heterocycle, or or - (CH2) n-Y2 wherein n is an ether from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, unsaturated or unsaturated O-heyerocycle, unsaturated or unsaturated S-heyerocycle, or blended or unsaturated mixed material; R3 is nothing, hydrogen or an aliphatic or non-aliphatic hydrocarbon of C1 to C10 straight or branched chain; R4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of C1 to C10 of straight or branched chain, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, haloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N- hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N- hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl- hydrocarbon, H (Z) N -phenyl-, H (Z) N -pheniachiaium-, H (Z) N-yenylalkyl-N (Z) - hydrocarbon-, H (Z) N-phenylalkyl-0-hydrocarbon-, phenylalkyl-O-hydrocarbon-, phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to C10, and wherein each alkyl is an alkyl of C1 to C10; and Z is independently hydrogen or t-butoxycarbonyl.
  2. 2. The compound according to claim 1, further characterized by having the formula 3. - A compound according to the formula (Vll) wherein X3 is optional and may be oxygen; X6 is oxygen or nitrogen; R1 is selected from the group of saturated cyclic hydrocarbons or Unsaturated, saturated or unsaturated N-heterocycles, saturated or unsaturated O-heterocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic straight or branched chain C1 to C30 hydrocarbons, or or - (CH2) m-Y1 wherein m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heyerocycle, saturated or unsaturated S-heterocycle, or saturated or unsaturated mixed heterocycle; R2 is hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C30, R10-N (Z) -hydrocarbon- or R10-hydrocarbon- wherein the hydrocarbon group is an aliphatic or non-aliphatic hydrocarbon of C1 to C30 straight or branched chain, a saturated or unsaturated cyclic hydrocarbon, a N-saturated or unsaturated N-heyerocycle, a unsaturated or unsaturated O-heterocycle, a saturated or unsaturated S-heterocycle, a saturated or unsaturated mixed heterocycle, or or - (CH2) n-Y2 where n is an integer from 0 to 10 and Y2 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle , or saturated or unsaturated mixed heterocycle; R3 is nothing, hydrogen or an aliphatic or non-aliphatic hydrocarbon of C1 to C10 straight or branched chain; R4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of C-i to C10 of straight or branched chain, aryl, acetyl, or mesyl; R5, R6, R7, R8, R9, R11, R12, R13, R14, and R15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, akoxy , aryioxy, niiio, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, iohaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R10 is H (Z) N-, H (Z) N-hydrocarbon-, H (Z) N-hydrocarbon-N (Z) -hydrocarbon-, H (Z) N-hydrocarbon-, O hydrocarbon-, hydrocarbon-O -hydrocarbon-, hydrocarbon-N (Z) hydrocarbon-, H (Z) N-hydrocarbon-carbonyl-hydrocarbon-, hydrocarbon-carbonyl-hydrocarbon, H (Z) N -phenyl-, H (Z) N -phenylalkyou-, H (Z) N-phenylalkyl-N (Z) -hydrocarbon-, H (Z) N-phenylalkyl-0-hydrocarbon-, phenyla! -i-0-hydrocarbon-, phenylalkyl-N (Z) -h Hydrocarbon-, H (Z) N-phenylalkyl-carbonyl-hydrocarbon-, or phenylalkyl-carbonyl-hydrocarbon-, wherein each hydrocarbon is independently an aliphatic or non-aliphatic group of straight or branched chain C1 to C10, and wherein each alkyl is a C1 to C10 alkyl; and Z is independently hydrogen or β-buloxycarbonyl. 4. The compound according to claim 3, further characterized in that it has the formula wherein n = 6, 13, or 17. 5.- A compound according to the formula (VIII) where X8 is O or S; n is between 1 and 30; R1 is selected from the group of saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated N-heterocycles, saturated or unsaturated O-helerocycles, saturated or unsaturated S-heterocycles, saturated or unsaturated mixed heterocycles, aliphatic or non-aliphatic hydrocarbons of C1 to C30 straight or branched chain, or or - (CH2) m-Y1 wherein m is an integer from 0 to 10 and Y1 is a saturated or unsaturated cyclic hydrocarbon, saturated or unsaturated N-heterocycle, saturated or unsaturated O-heterocycle, saturated or unsaturated S-heterocycle, or blended or unsaturated mixed material; R4 is optional, or it may be hydrogen, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain, C1 to C10, aryl, acetyl, or mesyl; and R5, R6, R7, R8, and R9 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic hydrocarbon of straight or branched chain C1 to C10, alkoxy, aryloxy, nitro, cyano, chloro, fluoro , bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamido, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl. 6. A compound according to formula (IX), formula (X), formula (XI), or formula (XII) / Vi (x where X7 is P03H or O-benzyl, X9 is O or nothing, R16 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted, R17 and R18 are independently, hydrogen, -S02R19, COR19, and R19, and R19 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight-chain, cyclic or branched, susi-substituted or unsubstituted or a substituted or unsubstituted aryl, with the proviso that R16 is not C? H2g when X7 is P03H and X8 is O. 7. The compound according to claim 6, further characterized in that X9 is O, X7 is P03H, and R6 is an aliphatic or non-aliphatic hydrocarbon from C7 to C20 straight or branched chain 8. The compound according to claim 6, further characterized in that X9 is O. 9. The compound according to claim 6, further characterized in that X7 is P03H. - The composite according to claim 6, further characterized by R16 is an aliphatic or non-aliphatic hydrocarbon of C7 to C20 straight or branched chain. 11. The compound according to claim 6, further characterized in that R17 and R18 are hydrogen. 12. A compound according to formula (XIV) and formula (XV) 13. - A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a compound according to any of claims 1, 3, 5, and 12 or salt thereof. 14. - A pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a compound according to formula (IX), formula (X), formula (XI), or formula (XII) (X > CXI! wherein X7 is P03H or O-benzyl; X9 is O or nothing; R16 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted, R17 and R18 are independently none, hydrogen, -S02R19, COR19, and R19; and R19 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted or a substituted or unsubstituted aryl or salt thereof. 15. A method for destroying a cancer cell comprising: providing a compound according to any of claims 1, 3, 5, and 12 and counteracting a cancer cell with the compound under effective conditions to destroy the contacted cancer cell . 16. - The method according to claim 15, further characterized in that said contact occurs ex vivo. 17. The method according to claim 15, further characterized in that said cancer cell is selected from a prostate cancer cell, a breast cancer cell, and an ovarian cancer cell. 18. A method for destroying a cancer cell comprising: providing a compound according to formula (IX), formula (X), formula (XI), or formula (XII) (X) (Xii) wherein X7 is P03H or O-benzyl; X9 is O or nothing; R16 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted, R17 and R18 are independently none, hydrogen, -S02R19, COR19, and R19; and R19 is an aliphatic or non-aliphatic hydrocarbon of C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted or a substituted or unsubstituted aryl; and contacting a cancer cell with the compound under conditions effective to destroy the contacted cancer cell. 19. The method according to claim 18, further characterized because said conjoint occurs ex vivo. 20. The method according to claim 18, further characterized in that said cancer cell is selected from a prostate cancer cell, a breast cancer cell, and an ovarian cancer cell. 21. The use of at least one compound of claims 1, 3, 5, and 12; in the manufacture of a medicament to fratate or prevent a cancerous condition in a patient. 22. The use as claimed in claim 21, wherein the cancerous condition is prostate cancer, breast cancer, or ovarian cancer. 23. The use as claimed in claim 21, wherein the patient is in the presence of a precancerous condition, and said medication is effective to prevent or decrease the rate of development of the precancerous condition towards the cancerous condition. 24. The use as claimed in claim 21, wherein the patient is in the presence of a cancerous condition, and said medication is effective either to cause the regression of the cancerous condition or to inhibit the progression of the cancerous condition. 25. - The use of a compound according to formula (IX), formula (X), formula (XI), or formula (XII) (X) ((X? Aliphatic or non-aliphatic C1 to C30, straight chain, cyclic or branched, substituted or unsubstituted, R17 and R18 are independently hydrogen, -S02R19, COR19, and R19, and R19 is an aliphatic hydrocarbon or not aliphatic from C1 to C30, straight chain, cyclic or branched, substituted or unsuitable, or a solid or non-solid aryl, in the manufacture of a medicinal product to prevent or prevent a cancerous condition in a patient. it is claimed in claim 25, where the cancerous condition is prostate cancer, breast cancer, or ovarian cancer. 27. The use as claimed in claim 25, wherein the patient is in the presence of a precancerous condition, and said medication is effective to prevent the development of the precancerous condition towards the cancerous condition. 28. The use as claimed in claim 25, wherein the patient is in the presence of a cancerous condition, and said medication is effective either to cause the regression of the cancerous condition or to inhibit the growth of the cancerous condition.
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