EP1926487A2 - Amides de thiazolidinone, amides d'acide carboxylique de thiazolidine et amides de sérine, y compris leurs conjugués de polyamines, en tant qu'agents anti-cancéreux sélectifs - Google Patents

Amides de thiazolidinone, amides d'acide carboxylique de thiazolidine et amides de sérine, y compris leurs conjugués de polyamines, en tant qu'agents anti-cancéreux sélectifs

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Publication number
EP1926487A2
EP1926487A2 EP06851619A EP06851619A EP1926487A2 EP 1926487 A2 EP1926487 A2 EP 1926487A2 EP 06851619 A EP06851619 A EP 06851619A EP 06851619 A EP06851619 A EP 06851619A EP 1926487 A2 EP1926487 A2 EP 1926487A2
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EP
European Patent Office
Prior art keywords
hydrocarbon
saturated
unsaturated
aliphatic
phenylalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06851619A
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German (de)
English (en)
Inventor
Duane D. Miller
Veeresa Gududuru
James T. Dalton
Eunju Hurh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ohio State University Research Foundation
University of Tennessee Research Foundation
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Ohio State University Research Foundation
University of Tennessee Research Foundation
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Publication date
Application filed by Ohio State University Research Foundation, University of Tennessee Research Foundation filed Critical Ohio State University Research Foundation
Publication of EP1926487A2 publication Critical patent/EP1926487A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel thiazolidinone amides, novel thiazolidine carboxylic acid amides, methods of making these compounds, and uses thereof, particularly for treating various cancers including but not limited to prostate, breast, ovarian, and skin cancers.
  • Prostate cancer accounts for 33% of all newly diagnosed malignancies among men in the United States (American Cancer Society: Cancer Facts and
  • GPCRs G-protein coupled receptors
  • LPLs lysophospholipids
  • LPL binds to GPCRs encoded by the Edg gene family, collectively referred to as LPL receptors, to exert diverse biological effects.
  • LPA stimulates phospholipase D activity and PC-3 prostate cell proliferation (Qi et al.,
  • Advanced prostate cancers express LPL receptors and depend on phosphatidylinositol 3 -kinase (“PI3K”) signaling for growth and progression to androgen independence (Kue and Daaka, "Essential Role for G Proteins in Prostate Cancer Cell Growth and Signaling,” J. Urol. 164:2162-2167 (2000)).
  • PI3K phosphatidylinositol 3 -kinase
  • stage 0 in situ melanoma
  • stage IV melanoma metastized to major organs
  • FDA Fluorescence-Activated Drug Delivery
  • IFN- ⁇ 2b interferon alpha-2b
  • a first aspect of the present invention relates to compounds according to formula (I) and formula (II)
  • X 1 and X 2 are each optional, and each can be oxygen;
  • X 3 and X 4 are each optional, and each can be oxygen or sulfur;
  • / is an integer from 1 to 12;
  • R 1 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 straight- or branched-chain Cl to C30
  • hydrocarbons or or-(CH 2 ) m — Y ' where m is an integer from 0 to 10 and Y 1 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;
  • R 2 is hydrogen, an aliphatic or non-aliphatic straight- or branched- chain Cl to C30 hydrocarbon, R 10 — N(Z) — hydrocarbon — or R 10 — hydrocarbon — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched- chain Cl to C30 hydrocarbon, 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,
  • n is an integer from 0 to 10 and Y 2 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;
  • R 3 is hydrogen or an aliphatic or non-aliphatic straight- or branched- chain Cl to ClO hydrocarbon
  • R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched-chain Cl to ClO hydrocarbon, acyl, acetyl, or mesyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight- or branched-chain Cl to ClO hydrocarbon, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamino, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalky
  • R 10 is H(Z)N-, H(Z)N- hydrocarbon— ,
  • a second aspect of the present invention relates to a pharmaceutical composition including a pharmaceutically acceptable carrier and a compound according to the first aspect of the present invention.
  • a third aspect of the present invention relates to a method of destroying a cancer cell that includes the steps of: providing a compound according to the first aspect of the present invention and contacting a cancer cell with the compound under conditions effective to destroy the contacted cancer cell.
  • a fourth aspect of the present invention relates to a method of treating or preventing a cancerous condition that includes the steps of: providing a compound according to the first aspect of the present invention and administering an amount of the compound to a patient in a manner effective to treat or prevent a cancerous condition.
  • a fifth aspect of the present invention relates to a method of making a compound according to formula (I) that includes the steps of: reacting an intermediate according to formula (III),
  • a sixth aspect of the present invention relates to a method of making a compound according to formula (II) that includes the steps of: reacting an intermediate according to formula (IV),
  • a seventh aspect of the present invention relates to intermediate compounds according to formula (III) and formula (IV).
  • An eighth aspect of the present invention relates to the use of the carboxylic acid intermediates of formula (III) or (IV) in the formation of a polymeric conjugate that includes at least one reactive amine group.
  • the polymeric conjugate constitutes a polyamine in accordance with the definitions of R 2 and R 10 above.
  • a ninth aspect of the present invention relates to polymeric conjugates of serine amide alcohols, phosphates, thiophosphates, or phosphonates according to formula (V) where R 16 is a hydroxyl, phosphate, thiophosphate, or phosphonate; and R 17 is a polymeric conjugated as described herein.
  • the present invention affords a significant improvement over previously identified cancer therapeutics that are known to be useful for the inhibition of prostate cancer cell growth.
  • Figure 1 illustrates one approach (scheme 1) for the synthesis of thiazolidine carboxylic acid amides.
  • the thiazolidine carboxylic acid intermediate (2a-v) is formed upon reacting L-cysteine with various aldehydes under reported conditions (Seki et al., "A Novel Synthesis of (+)-Biotin from L-Cysteine," J. Org. Chem. 67:5527-5536 (2002), which is hereby incorporated by reference in its entirety).
  • the intermediate carboxylic acid is reacted with an amine to form the corresponding amide (3-27).
  • Figure 2 illustrates one approach (scheme 2) for the synthesis of N- acyl and N-sulfonyl derivatives of the thiazolidine carboxylic acid amides.
  • the N- acyl and N-sulfonyl derivatives (compounds 28 and 29) were synthesized from compound 5 by standard procedures.
  • Figure 3 illustrates one approach (scheme 3) for the synthesis of thiazole carboxylic acid amides.
  • the thiazolidine carboxylic acid methyl ester was converted to the thiazole carboxylic acid methyl ester following a reported procedure (Badr et al., "Synthesis of Oxazolidines, Thiazolidines, and 5,6,7,8-Tetrahydro-lH, 3//-pyrrolo[l,2-c] Oxazole (or Thiazole)- 1,3 -diones from ⁇ - ⁇ ydroxy- or ⁇ -Mercapto- ⁇ -amino Acid Esters," Bull. Chem. Soc. Jpn.
  • Figures 4A-B illustrate agarose gel electrophoresis of total DNA extracted from 2 x 10 6 LNCaP cells following treatment with thiazolidine compounds 4 (Figure 4A) and 5 ( Figure 4B) for 24 to 108 hours.
  • the results show the effects of treatment on DNA fragmentation, indicating progression of cell death, hi Figure 4A, the dose and exposure time are indicated for compound 4 as follows: lane 1, 100 bp DNA marker; lane 2, 5 ⁇ M for 36 h; lane 3, 3 ⁇ M for 24 h; lane 4, 3 ⁇ M for 24 h; lane 5, 3 ⁇ M for 48 h; lane 6, 3 ⁇ M for 72 h; lane 7, 3 ⁇ M for 108 h; and lane 8, 50 ⁇ M for 36 h.
  • the dose and exposure time are indicated for compound 5 as follows: lane 1, 100 bp DNA marker; lane 2, 5 ⁇ M for 24 h; lane 3, 5 ⁇ M for 48 h; lane 4, 5 ⁇ M for 72 h; lane 5, 5 ⁇ M for 96 h; lane 6, 3 ⁇ M for 96 h; lane 7, 8 ⁇ M for 48 h; and lane 8, 8 ⁇ M for 72 h.
  • Figures 5A-B demonstrate AKT inhibitory effects of thiazolidine compounds, as measured by inhibition of AKT phosphorylation.
  • Figure 5 A shows the immunoblot results using anti-phospho AKT (S473) or anti-AKT antibodies. The immunoblots were visualized by enhanced chemiluminescence, and changes of relative levels of phospho-AKT compared to total AKT by analog treatment were quantified by densitometric analysis.
  • Figure 5B graphically illustrates the immunological detection of AKT using anti-AKT and anti-phospo-AKT, shown in Figure 5A.
  • Figure 6 illustrates one approach (scheme 4) for the synthesis of 4- thiazolidinone carboxylic acids, and their conversion to corresponding amides by reaction with primary or secondary amines (FfNR 2 R 3 ). As shown in this reaction scheme, different starting materials (where / differs) can be used to prepare various compounds of the invention.
  • Figure 7 illustrates a second approach (scheme 5) for the synthesis of
  • Figure 8 illustrates three approaches for modifying the core structure of the thiazolidinone compounds of the present invention (scheme 6) to afford ring- bound sulfone or sulfoxide groups (steps a and b, respectively), as well as the complete reduction of carbonyl groups (step c).
  • Figure 9 illustrates a process for the synthesis of polyamine conjugates of thiazolidinone amides (scheme 7).
  • Figure 1 OA illustrates a process for the synthesis of polyamine reactants and carboxylic acid intermediates (scheme 8).
  • Figure 1OB illustrates a process for the synthesis of polyamine derivatives of serine alcohols, serine amides, and 2-arylthiazolidine-4-carboxylic acid amides.
  • Figures 1 IA-B illustrate that Compound 4 (R enantiomer) causes necrotic cell death.
  • SKMEL-188 melanoma cells were incubated with Compound 4(R) at 60 ⁇ M for 48 hours.
  • Figure 1 IB is a pair of graphs that show the DNA content, as measured by flow cytometry, of cells that were exposed to control (left) and Compound 4(R) (right).
  • X 1 and X 2 are each optional, and each can be oxygen;
  • X 3 and X 4 are each optional, and each can be oxygen or sulfur;
  • / is an integer from 1 to 12;
  • R 1 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 straight- or branched-chain Cl to C30
  • hydrocarbons or or -(CH 2 ) m — Y 1 where m is an integer from 0 to 10 and Y 1 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;
  • R is hydrogen, an aliphatic or non-aliphatic straight- or branched- chain Cl to C30 hydrocarbon, R 10 — N(Z) — hydrocarbon — or R 10 — hydrocarbon- — where the hydrocarbon group is an aliphatic or non-aliphatic straight- or branched- chain Cl to C30 hydrocarbon, a saturated or unsaturated cyclic hydrocarbons, 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 - ⁇
  • R 4 is optional, or can be hydrogen, an aliphatic or non-aliphatic straight- or branched-chain Cl to ClO hydrocarbon, acyl, acetyl, or mesyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , and R 15 are independently selected from the group of hydrogen, hydroxyl, an aliphatic or non-aliphatic straight- or branched-chain Cl to ClO hydrocarbon, alkoxy, aryloxy, nitro, cyano, chloro, fluoro, bromo, iodo, haloalkyl, dihaloalkyl, trihaloalkyl, amino, alkylamino, dialkylamino, acylamino, arylamino, amido, alkylamido, dialkylamido, arylamido, aryl, C5 to C7 cycloalkyl, arylalkyl; R 10 is H(Z)N-, H(Z)N- hydrocarbon— ,
  • aliphatic or non-aliphatic straight- or branched-chain hydrocarbon refers to both alkylene groups that contain a single carbon and up to a defined upper limit, as well as alkenyl groups and alkynyl groups that contain two carbons up to the upper limit, whether the carbons are present in a single chain or a branched chain.
  • a hydrocarbon can include up to about 30 carbons, or up to about 20 hydrocarbons, or up to about 10 hydrocarbons.
  • alkyl can be any straight- or branched-chain alkyl group containing up to about 30 carbons unless otherwise specified.
  • the alkyl group can be a sole constituent or it can be a component of a larger constituent, such as in an alkoxy, arylalkyl, alkylamino, etc.
  • saturated or unsaturated cyclic hydrocarbons can be any such cyclic hydrocarbon, including but not limited to phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl, cycloalkenyl, cyclodienyl, etc.
  • saturated or unsaturated N- heterocycles can be any such N-containing heterocycle, including but not limited to aza- and diaza-cycloalkyls such as aziridinyl, azetidinyl, diazatidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azocanyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl
  • Preferred R groups include aliphatic or non-aliphatic straight- or branched-chain Cl to C30 hydrocarbons, phenyl, phenylalkyls, substituted phenyls and substituted phenylalkyls with R 11 -R 15 groups as defined above.
  • Preferred aliphatic or non-aliphatic straight- or branched-chain hydrocarbons are C8 to C24 hydrocarbons, including ClO to C20 alkyls, more preferably C14 to Cl 8 alkyls.
  • Preferred R 3 groups include hydrogen and Cl to ClO alkyls.
  • Preferred R 4 groups include hydrogen, acyl, acetyl, and mesyl.
  • Preferred R groups are polyamines.
  • the integer / is preferably from 1 to 10, more preferably 1 to 8, 1 to 6, or 1 to 4.
  • the integer m is preferably from 0 to 8, 0 to 6, 0 to 4, or 0 to 2.
  • the integer n is preferably from 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-tetradecyl-2-(4-oxo-2- phenylthiazolidin-3-yl)acetamide (compound 67), N-octadecyl-2-(4-oxo-2- phenylthiazolidin-3-yl)acetamide (compound 68), N-octadecyl-2-(4-oxo-2- biphenylthiazolidin-3-yl)acetamide (compound 69), 2-(2-(l- (dimethylamino)naphthalen-4-yl)-4-oxothiazolidin-3-yl)-N-octadecylace
  • Exemplary compounds according to formula (II) include, without limitation: (4R)-2-(4-methoxyphenyl)-N-octadecylthiazolidine-4-carboxamide (compound 15); (4R)-2-(4-ethoxyphenyl)-N-octadecylthiazolidine-4-carboxamide; N- octadecyl-2-phenylthiazole-4-carboxamide (compound 34); (4R)-2-(3,5- difluorophenyl)-N-octadecylthiazolidine-4-carboxamide (compound 23); (4R)-2-(4- cyanophenyl)-N-octadecylthiazolidine-4-carboxamide (compound 22); (4R)-N- octadecyl-N-mesyl-2-phenylthiazolidine-4-carboxamide (compound 29); (4R)-N- oc
  • Preferred compounds according to formula (II) include compounds 4
  • the intermediate acids can be prepared initially via condensing mercaptoacetic acid, glycine methyl ester, and aromatic aldehydes in a one-pot reaction, followed by basic hydrolysis of the ester (Holmes et al., "Strategies for Combinatorial Organic Synthesis: Solution and Polymer-Supported Synthesis of 4-Thiazolidinones and 4-Metathiazanones Derived from Amino Acids," J Org. Chem. 60:7328-7333 (1995), which is hereby incorporated by reference in its entirety).
  • thiazolidinone amides of formula (I) can also be prepared by a simple and direct method (Schuemacher et al., "Condensation Between Isocyanates and Carboxylic Acids in the Presence of 4-Dimethylaminopyridine
  • compound (IV) where compound (IV) can be either the R- or S-stereoisomer and R 1 and X 3 are defined as above, with appropriate amines in the presence of EDC/HOBt under standard conditions.
  • the intermediate acids can be prepared via reaction of L- cysteine with desired aldehydes under reported conditions (Seki et al., "A Novel Synthesis of (+)-Biotin from L-Cysteine," J. Org. Chem. 67:5527-5536 (2002), which is hereby incorporated by reference in its entirety).
  • the compounds of the present invention can also be modified to contain a polymeric conjugate (i.e., as defined by the substituents R 2 and Ri 0 ).
  • Suitable polymeric conjugates include, without limitation, poly(alkyl)amines, poly(alkoxy)amine, polyamines, etc. It is also well known that polyamine containing compounds exhibit a number of biological activities and have been utilized as chemotherapeutic agents. Exemplary conjugates include those containing the naturally occurring polyamines like putrescine, spermidine, and spermine, as well as synthetic polyamines.
  • a further aspect of the present invention relates to polymeric conjugates of a third class of compounds, polymeric conjugates of the serine amide alcohols and serine amide phosphates. These compounds are characterized by the structure according to formula (V)
  • R 16 is a hydroxyl group, phosphate group (H 2 O 2 PO-O- or HO 2 PO "
  • R 17 is defined above as R 2 contain an R 10 substituent (i.e., R 10 —
  • R 18 is defined as hydrogen, a straight or branched-chain Cl to C30 alkyl, a straight or branched-chain C2 to C30 alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri-substitutions of the ring, an acyl including a Cl to C30 alkyl or an aromatic or heteroaromatic ring, an arylalkyl including straight or branched-chain Cl to C30 alkyl, an aryloxyalkyl including straight or branched-chain
  • R , 19 and R >20 are independently hydrogen, a straight or branched-chain Cl to C30 alkyl, a straight or branched-chain C2 to C30 alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri-substitutions of the ring, an acyl including a Cl to C30 alkyl or aromatic or heteroaromatic ring, an aryl alkyl including straight or branched-chain Cl to C30 alkyl, or an aryloxyalkyl including straight or branched- chain Cl to C30 alkyl.
  • a compound of the present invention can be conjugated to a polyamine by reacting the intermediate acid or a nitrophenyl derivative thereof with a polyamine NH 2 -R 2 where R z is any of the R 2 /R 10 groups defined above. Exemplary synthesis schemes are illustrated in Figures 9-11.
  • the compounds can also be in the form of a salt, preferably a pharmaceutically acceptable salt.
  • salts refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically 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-toluenesulfonic acid, salicylic acid, N- acetyl cysteine and the like.
  • the compounds of the present invention can be present in the form of a racemic mixture, containing substantially equivalent amounts of stereoisomers.
  • the compounds of the present invention can be prepared or otherwise isolated, using known procedures, to obtain a stereoisomer substantially free of its corresponding stereoisomer (i.e., substantially pure).
  • substantially pure it is intended that a stereoisomer is at least about 95% pure, more preferably at least about 98% pure, most preferably at least about 99% pure.
  • Another aspect of the present invention relates to pharmaceutical compositions that contain one or more of the above-identified compounds of the present invention.
  • 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.
  • pharmaceutically acceptable carrier refers to any suitable adjuvants, carriers, excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
  • the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the adjuvants, carriers and/or excipients.
  • active compound(s) preferably from about 20 to 75 percent
  • application to mucous membranes can be achieved with an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form.
  • the solid unit dosage forms can be of the conventional type.
  • the solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds of the present invention and a carrier, for example, lubricants and inert fillers such as, lactose, sucrose, or cornstarch.
  • these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.
  • the tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such 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.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin.
  • a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with
  • a syrup can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
  • these active compounds can be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 mg and 800 mg of active compound.
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions, hi all cases, the form should be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • polyol e.g., glycerol, propylene glycol, and liquid polyethylene glycol
  • the compounds or pharmaceutical compositions of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier or excipient.
  • a pharmaceutical adjuvant, carrier or excipient include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.
  • active compounds may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are 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.
  • the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
  • the materials of the present invention also may be administered in a non-pressurized form such 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, ovarian, and skin cancer (e.g., melanoma). It is believed that other forms of cancer will likewise be treatable or preventable upon administration of the compounds or compositions of the present invention to a patient.
  • Preferred compounds of the present invention are selectively disruptive to cancer cells, causing ablation of cancer cells but not normal cells. Significantly, harm to normal cells is minimized because the cancer cells are susceptible
  • a further aspect of the present invention relates to a method of destroying a cancerous cell that includes: providing a compound of the present invention and then contacting a cancerous cell with the compound under conditions effective to destroy the contacted cancerous cell.
  • the cells to be destroyed can be located either in vivo or ex vivo (i.e., in culture).
  • a still further aspect of the present invention relates to a method of treating or preventing a cancerous condition that includes: providing a compound of the present invention and then administering an effective amount of the compound to a patient in a manner effective to treat or prevent a cancerous condition.
  • the patient to be treated is characterized by the presence of a precancerous condition, and the administering of the compound is effective to prevent development of the precancerous condition into the cancerous condition. This can occur by destroying the precancerous cell prior to or concurrent with its further development into a cancerous state.
  • the patient to be treated is characterized by the presence of a cancerous condition, and the administering of the compound is effective either to cause regression of the cancerous condition or to inhibit growth of the cancerous condition. This preferably occurs by destroying cancer cells, regardless of their location in the patient body. That is, whether the cancer cells are located at a primary tumor site or whether the cancer cells have metastasized and created secondary tumors within the patient body.
  • patient refers to any mammalian patient, including without limitation, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents.
  • administering can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer cells or precancerous cells.
  • Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes.
  • compositions within the scope of this invention include all compositions wherein the compound of the present invention is contained in an amount effective to achieve its intended purpose. While individual needs may vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typical dosages comprise about 0.01 to about 100 mg/kg-body wt. The preferred dosages comprise about 0.1 to about 100 mg/kg-body wt.
  • the most preferred dosages comprise about 1 to about 100 mg/kg-body wt.
  • Treatment regimen for the administration of the compounds of the present invention can also be determined readily by those with ordinary skill in art. That is, the frequency of administration and size of the dose can be established by routine optimization, preferably while minimizing any side effects.
  • N-Acyl and N-sulfonyl derivatives were synthesized from compound 5 by standard procedures (scheme 2). Briefly, (2RS, 4R)- 2-phenylthiazolidine-4-carboxylic acid octadecylamide (compound 5) was reacted with either acetic anhydride or methyl sulfonyl chloride, in pyridine, to afford the desired derivatives.
  • DU-145, PC-3, and LNCaP human prostate cancer cells, and RH7777 rat hepatoma cells were obtained from American Type Culture Collection (Manassas, VA). Dr. Mitchell Steiner at University of Tennessee Health Science Center, kindly provided PPC-I and TSU-PrI cells. Prostate cancer cells and RH7777 cells were maintained in RPMI 1640 medium and DMEM (Mediatech, Inc., Herndon, VA), respectively, supplemented with 10% fetal bovine serum (Gibco, Grand Island, NY) in 5% CO 2 / 95% air humidified atmosphere at 37 °C.
  • DMEM Mediatech, Inc., Herndon, VA
  • LPA 1 forward 5'-GCTCCACACACGGATGAGCAACC-S' (SEQ ID NO: 1), and LPA 1 reverse 5'-GTGGTCATTGCTGTGAACTCCAGC-S' (SEQ ID NO: 2);
  • LPA 2 forward 5'-CTGCTCAGCCGCTCCTATTTG-S' (SEQ ID NO: 3), and LPA 2 reverse 5'-AGGAGCACCCACAAGTCATCAG-S' (SEQ ID NO: 4);
  • LPA 3 forward 5'-CCATAGCAACCTGACCAAAAAGAG-S' (SEQ ID NO: 5), and LPA 3 reverse 5'-TCCTTGTAGGAGTAGATGATGGGG-S' (SEQ ID NO: 6);
  • PCR conditions were as follows: After 2 min denaturation step at 94 °C, samples were subjected to 34 to 40 cycles at 94 °C for 30 sec, 60 °C (LPA 1 ) or 58 °C (LPA 2 and
  • LPA 3 LPA 3 for 30 sec, and 72 °C for 1 min, followed by an additional elongation step at 72 0 C for 7 min.
  • Primers were selected to span at least one intron of the genomic sequence to detect genomic DNA contamination.
  • the PCR products were separated on 1.5% agarose gels, stained with ethidium bromide, and the band intensity was quantified using Quantity One Software (Bio-Rad Laboratories, Inc., Hercules, CA). Expression levels of each receptor subtype in different cell lines were expressed as ratios compared to ⁇ -actin mRNA level.
  • LPL receptor expression in these cell lines was determined to validate their use as in vitro models (see Table 2 below). 1 ⁇ g of total RNA was subjected to RT-PCR, the PCR products were separated on agarose gels, and relative expression level of each receptor subtype compared to ⁇ -actin was quantified by Quantity One Software (Bio-Rad). LPA 1 was the predominant LPL receptor expressed in these cell lines. However, LNCaP cells did not express this receptor subtype. LPA 3 receptor was uniquely expressed in prostate cancer cell lines. RH7777 cells do not express any of the known LPL receptors.
  • IC 50 concentration that inhibited cell growth by 50% of untreated control
  • IC 50 concentration that inhibited cell growth by 50% of untreated control
  • 5-fluorouracil was used as a positive control to compare potencies of the new compounds.
  • a sandwich ELISA (Roche, Mannheim, Germany) utilizing monoclonal antibodies specific for DNA and histones was used to quantify degree of apoptosis induced by the analogs after 72 h exposure. This assay measures DNA-histone complexes (mono- and oligonucleosomes) released into cytoplasm from the nucleus during apoptosis.
  • RH7777 cells were employed because of nonspecific cytotoxicity of compound 4 in receptor-negative cells as well as receptor-positive prostate cancer cells.
  • ATCAAs 2-aryl-thiazolidine derivatives
  • SRB sulforhodamine B
  • a control cell line (RH7777) that does not express LPL receptors (Svetlov et al., "EDG Receptors and Hepatic Pathophysiology of LPA and SlP: EDG-ology of Liver Injury,” Biochimica et Biophysica ACT 1582:251 -256 (2002), which is hereby incorporated by reference in its entirety) was also utilized to understand whether the antiproliferative activity of these derivatives is mediated through inhibition of LPL receptors.
  • N-Acyl and N-sulfonyl derivatives were less cytotoxic than parent compound 5.
  • Replacement of the phenyl ring with an alkyl or cyclohexyl group reduced the potency (compounds 7 and 8) relative to the thiazolidine (compound 5) derivative.
  • Introduction of a methylene spacer separating the phenyl ring and the thiazolidine ring furnished a compound 9, which was less active than the parent compound 5.
  • the furanyl derivative (compound 12) showed equivalent cytotoxicity as compound 5, but was 3-fold less selective against RH7777 cells.
  • the cytotoxicity data of compounds 13-27 provides a summary of a broad survey of phenyl ring substituted analogs. Examination of the IC 50 values of these analogs demonstrates a greater tolerance for diverse substituents in the phenyl ring. In general, the most potent analogues possessed electron-donating substituents, as exemplified by comparison of compound 13, and compounds 16-18, relative to compound 5. One of the most active compounds (compound 18) with an IC 50 of 0.55 ⁇ M was 38-fold more selective in PPC-I cells compared to RH7777 cells.
  • the enrichment factor calculated (as ratio of OD405 in treated and un-treated cells) provides a quantitative assessment of the degree of apoptosis induced. Initially, only two compounds (4 & 5) were used for this study. Apoptotic activity of analog (compound 4) was selective in prostate cancer cells despite nonselective cytotoxicity in RH7777 negative control cells (see Table 5 below). Analog compound 5 induced apoptosis in PC-3 and LNCaP cells, but to a lesser extent in PC-3 cells perhaps due to lower potency in this cell line. This data suggests that thiazolidine analogs may act as potent inducers of apoptosis and selectively kill a variety of prostate cancer cell lines.
  • 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 total DNA was extracted from 2 x 10 6 cells by simple centrifugation method, treated with RNase and Proteinase K. After precipication in ethanol, DNA was reconstituted in Tris- EDTA buffer, separated on agarose gels, and visualized by ethidium bromide staining (Herrmann et al., "A Rapid and Simple Method for the Isolation of Apoptotic DNA Fragments," Nucl. Acids Res. 22:5506-5507 (1994), which is hereby incorporated by reference in its entirety).
  • FIG. 5B graphically illustrates fhe immunological detection of AKT using anti-AKT and anti-phospo-AKT, shown in Figure 5A.
  • Control cell line b Prostate cancer cell lines.
  • Control cell line b Prostate cancer cell lines.
  • the reaction mixture was diluted with CH 2 Cl 2 , washed sequentially with cold 5% HCl, saturated NaHCO 3 , water, brine, and dried (anhydrous) Na 2 SO 4 , and solvent was removed in vacuo.
  • the nitrophenyl ester product (compound 100) was purified by flash chromatography (silica gel) using EtOAc/Hexanes to afford 1.76 g (78%).
  • Compound 101 demonstrated more potent activity against prostate cancer cells compared to ovarian and MCF-7 breast cancer cells, with IC 50 ( ⁇ M) values as follows: RH7777 (>100), DU145 (12.4), PC-3 (11.1), LNCaP (26.2), PPC-I (11.7), TSU-PrI (5.0), MCF-7 (>100), CaOv-3 (39.3), OVCAR-3 (39.7), and SKOv-3 (>100).
  • IC 50 ( ⁇ M) values as follows: RH7777 (>100), DU145 (12.4), PC-3 (11.1), LNCaP (26.2), PPC-I (11.7), TSU-PrI (5.0), MCF-7 (>100), CaOv-3 (39.3), OVCAR-3 (39.7), and SKOv-3 (>100).
  • IC 50 ( ⁇ M) values as follows: RH7777 (>100), DU145 (12.4), PC-3 (11.1), LNCaP (26.2), PPC-I (11.7), TSU
  • Carboxylic acids 64a and 21 were synthesized as described in the preceding examples ⁇ see also Gududuru et al., Bioorg. Med. Chem. Lett. 14:5289- 5293 (2004); Gududuru et al., J. Med. Chem. 48:2584-2588 (2005), each of which is hereby incorporated by reference in its entirety).
  • Commercially available (L)-N-BoC- serine was converted to TBDMS ether (207) as shown in Scheme 8 ( Figure 10A).
  • the antiproliferative effects of synthesized compounds were assessed against five human prostate cancer cell lines DU- 145, PC-3, LNCaP, PPC-I, and TSU-PrI using sulforhodamine B (SRB) assay ⁇ see Example 5 above).
  • the IC 50 value was defined as the concentration of analogue required inhibiting cell growth by 50% of untreated control.
  • RH7777 and CV-I cells were used as negative controls and MCF-7 cell line (breast cancer) was included to examine the selectivity.
  • 5- Fluorouracil was used as reference drug.
  • the structures of polyamine conjugates and their IC 50 values are listed in Table 9 below.
  • SKMEL-188 cells were cultured in Ham's FlO medium (Gibco).
  • the IC 50 values of seventeen compounds with 50% or more growth inhibition at 10 ⁇ M were subsequently measured on both cancer cell lines as well as on the control cells (fibroblast cells). DTIC and Taxol were assayed in the same way for comparison and served as internal quality controls in the different batches of assay. For comparison, the activities of 5R and 5S were measured. While these compounds showed very good activity in prostate cancer, they failed to demonstrate high activity against the two melanoma cell lines. The results for all three cell types are summarized in Table 10 below.
  • amides were less active than the corresponding alcohols. Heteroatoms on the sidechain substantially increase the potency, but unsaturation on the side chain decreased potency. Second, alkyl amine was about equipotent to the unsubstituted amine, suggesting that cyclization of the amine and alcohol may be possible. However, none of the open chain compounds displayed acceptable selectivity against cancer cells. Third, the presence of the aromatic ring in the heterocyclic compounds improves selectivity and cytotoxicity for the arylthiazolidine- carboxylic acid amides. Fourth, the potency of the compound depends strongly on the chirality at the C-4 position, the substitution on the aromatic ring, and the chain length.
  • the most potent compound identified in this assay is compound 4R, with an IC 50 value of about 0.5 ⁇ M and selectivity over 10- fold against both neoplastic cell lines.
  • LDH release was measured by colorimetric assay and DNA content was analyzed by flow cytometry.
  • LDH is a stable cytosolic enzyme that is released upon cell lysis.
  • Treatment of cells with compound 4R resulted in dramatic does-dependent increase of LDH released to cellular environment (Figure HA).
  • Analysis of the DNA content of control cells shows peaks corresponding to the cells in G 1/0 phase (62%), S phase (32%), and G2/M phase (6%). This is a typical distribution of cells in culture (Ormerod, Flow Cytometry, 3d edition, Oxford University Press

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Abstract

L'invention concerne des amides d'acide carboxylique de thiazolidinone substitués et des amides d'acide carboxylique de thiazolidine substitués selon les formules (I) et (II), dans lesquelles les divers groupes de substitution sont tels que définis dans la description. L'invention concerne également des procédés destinés à fabriquer ces composés, des compositions pharmaceutiques contenant les composés, et leur utilisation, particulièrement dans le traitement ou la prévention du cancer.
EP06851619A 2005-07-19 2006-07-19 Amides de thiazolidinone, amides d'acide carboxylique de thiazolidine et amides de sérine, y compris leurs conjugués de polyamines, en tant qu'agents anti-cancéreux sélectifs Withdrawn EP1926487A2 (fr)

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