CYCLOPENTENONE DERIVATIVES FOR CANCER THERAPY
Field of Invention
The invention relates to the use of derivatives of cyclopentenone for the inhibition
or prevention of the growth or multiplication of cancer cells, and to therapeutic
compositions containing such compounds. The invention relates more specifically to the
use of derivatives of cyclopentenone for the inhibition and / or prevention of cancer of the
colon, pancreas, larynx, ovary, duodenum, kidney, oral cavity, prostate, lung, endothelial
cells and leukemias.
Background Of The Invention
The treatment of solid-tumor cancers continues to rely on the development of
architecturally new and biologically more potent and anti-tumor, antimitotic agents.
Vincristine, taxol, dolastatin 10 and combretastatin A-4 (CA-4) prodrugs have established
clinical efficacy as antimitotic agents. We have designed (molecular modeling and 3DQSAR)
and synthesized a novel class of compounds viz. cyclopentenone derivatives i.e
2,3-diaryl-4 or 5-substituted cyclopent-2-en-l-one derivatives in particular which could
mimic combretastatin A-4. The lead compounds in our designed molecules demonstrate
remarkable cytotoxic activity against a variety of human cancer cell lines representing
cancer of the colon, pancreas, larynx, ovary, duodenum, kidney, oral cavity, prostate, lung,
endothelial cells and leukemias
Summary Of The Invention
This invention relates to novel cyclopentenone derivatives for cancer therapy said
derivatives having a general structural formula (1)
wherein X is oxygen, hydroxyimino, alkoxyimino, aryloxyimino or arylimino; R is
hydroxy, oxo, amino, alkylamino, hydroxyimino, alkoxyimino, aryloxyimino,
alkylcarbonyloxy, aroyloxy, alkoxy, methoxymethyloxy, 2-methoxyethoxymethyloxy,
tert.- butyldimethylsilyloxy, trimethylsilyloxy, carboxyl, carboxylate salts, or carboxylic
acid esters (preferably Ci-C4 alkyl esters); RI to RIO are the same or different and represent
hydrogen, hydroxy, alkyl, alkoxy, methoxymethyloxy, 2-methoxyethoxymethyloxy, tertbutyldimethylsilyloxy,
trimethylsilyloxy, chloro, fluoro, bromo, mercapto, alkylthio, nitro,
amino, mouoalkylamino, dialkylamino, azido, carboxyl, carbalkoxy, alkylcarbonyloxy,
carboxymethyloxy, NHCOCH3, NHCOCF3, NH-alkyl (preferably, the alkyl of NH-alkyl is
methyl, propyl, butyl, or t-butyl), N-dialkyl (the alkyl groups may be the same or different
and preferably represent C1-C4 alkyl groups), CN, guanidine, NHCOORn,
CH2C-NR12R13; NHNH2, NHCONHo, NHNHCONH2, NHNHC(=S)NH2 and their salts,
preferred salts are HC1, and HBr salts; OPO3H2, OPO3Na2, OPO3K2, SO2NH2, CONHalkyl
( preferably CrC4 ), CHO, CH=NOH, or -(CH2-CH2-N[CH3])- fused at R8, R9
positions respectively, methylenedioxy group fused in lieu of either Rg, Rg or Rp, RIO
position, respectively, and in the latter R8 is alkoxy (preferably methoxy), and R11, R12and
RB are lower alkyl groups selected from C1-C4 alky! groups or a salt thereof.
The present invention also relates to the design and synthesis of novel
cyclopentenones derivatives with anticancer activity.
The present invention also provides pharmaceutical compositions of novel
derivatives of cyclopentenone based compounds or pharmaceutically acceptable salts of
the cyclopentenone based compounds useful for killing or inhibiting multiplication of
cancer cells and for testing their bio-activity using cultured human cancer cells as the
monitor.
Brief Description Of The Figure
Figure 1 shows the percent inhibition of the growth of PTC xenograft using the
compound of formula no. 49 as compared to the control.
Detailed Description Of The Invention
The present invention is directed to the development of cyclopentenone derivatives
as new anticancer agents.
As described herein, the present invention encompasses compounds selected from
a group of compounds represented by the General formula (1 A) and (IB)
wherein X is oxygen, hydroxyimino, alkoxyimino, aryloxyimino or arylimino; R is
hydroxy, oxo, amino, alkylamino, hydroxyimino, alkoxyimino, aryloxyimino,
alkylcarbonyloxy, aroyloxy, alkoxy, methoxymethyloxy, 2-methoxyethoxymethyloxy,
tert- butyldimethylsilyloxy, trimethylsilyloxy, carboxyl, carboxylate salts, carboxylic acid
esters (preferably Ci-C4 alkyl esters); RI to RIO are the same or different and represent
hydrogen, hydroxy, alkyl, alkoxy, methoxymethyloxy, 2-methoxyethoxymethyloxy, tertbutyldimethylsilyloxy,
trimethylsilyloxy, chloro, fluoro, bromo, mercapto, alkylthio, nitro,
ammo, monoalkylainino, dialkylamino, azido, carboxyl, alkylcarbonyloxy, carbalkoxy,
carboxymethyloxy, NHCOCH3, NHCOCF3, Nll-alkyi (preferably, the alkyl of NH-alkyl is
methyl, propyl, butyl, t-butyl), N-dialkyl (the alkyl groups may be the same or different
and preferably represent Ci-C4 alkyl groups), CN, guanidine, NHCOORn,
CH2C=NRi2Ri3; NHNH2, NHCONH2, NHNHCONH2, NHNHC(=S)NH2 and their salts
(preferred salts are HC1 and HBr salts), OPO3H2, OPO3Na2, OP03K2, SO2NH2, CONHalkyl
( preferably d-C4), CHO, or CH=NOH, or -(CH2-CH2-N[CH3])- may be fused at
Rg, RS positions respectively, methylenedioxy group fused in lieu of either Rs, Rg or Rg,
RIO position, respectively, and in the latter Rg = alkoxy (preferably methoxy) and Ra, Ri2
and Ri3 are lower alkyl groups selected from Ci-C4 alkyl groups, derivatives and salts
thereof.
The present invention is directed to the synthesis of compounds having the
(Figure Remove) structural formula 1
having two substituted aryl groups or combinations thereof separated by a bridging unit of
C = C which is a part of C$ cyclic unit. The aryl group(s) are preferably substituted by at
least one or more alkoxy groups. The preferred substitution pattern is 3,4,5-trimethoxy
system in one of the aryl groups.
The present invention contemplates employing compounds of formula 1
R10 R10
having R at C-4 (1A) or C-5 (IB) of the cyclopentenone unit as a free hydroxy group or
derivatives thereof.
A preferred compound of the formula 1
[0011] wherein X is oxygen or hydroxyimino. Hydroxyimino is expected to provide a
more hydrophilic substance required for the biological activity.
As used herein, alkyl is a group having Ci-C4 carbon atoms.
As used herein the term alkoxy refers to 0-alkyl groups wherein the alkyl group
has 1-4 carbon atoms. The preferred alkyl group is methyl.
The aryl group may be phenyl or naphthyl. The aryl group may be substituted.
Preferred substituents are hydrogen, hydroxy, alkyl, alkoxy, methoxymethyloxy, 2-
methoxyethoxymethyloxy, tert-butyldimethylsilyloxy, trimethylsilyloxy, chloro, fluoro,
bromo, mercapto, alkylthio, nitro, amino, alkylamino, dialkylamino, azido, carboxyl,
alkylcarbonyloxy, carbalkoxy, carboxymethyloxy, NHCOCH3, NHCOCF3> NH-alkyl
(preferably, the alkyl of NH-alkyl is methyl, propyl, butyl, t-butyl), N-dialkyl (the alkyl
groups may be the same or different and preferably represent Ci-C4 alkyl groups), CN,
guanidine, NHCOORn, CH2C=NRi2R13; NHNH2, NHCONH2, NHNHCONH2,
NHNHC(=S)NH2 and their salts (preferred salts are HC1 and HBr salts); OP03H2,
OPO3Na2, OPO3K2, SO2NH2, CONH- alkyl ( preferably C!-C4), CHO, or CH=NOH, or -
(CH2-CH2-N[CH3])- may be fused at Rg, R9 positions respectively, methylenedioxy
group fused at adjacent positions of the aryl ring and Rn, Ri2 and Ri3 are lower alkyl
groups selected from Q-C4 alkyl groups,
Alkyl carbonyloxy is a group is the formula O(CO)-alkyl wherein the acyl group
((CO)alkyl) containing 1-4 carbon atoms is bonded to oxygen. The preferred acyl group
has 2 carbon atoms.
"Alkylamino", "monoalkylamino" and "dialkylamino" refer to a group wherein one
alkyl group or two alkyl groups are bonded to an amino nitrogen, i.e., NH(alkyl) or
N(alkyl)2. The NH or N is the bridge connecting the alkyl groups to the aryl/phenyl group
of formulae described in this application. Examples include NHMe, NHEt, or N(Me)2,
N(Et)2 and the like.
As used herein, alkylthio refers to an S-alkyl wherein the alkylthio is attached as a
substituent through the S atom. The S is the bridge connecting the alkyl group to the
aryl/phenyl group.
Aryloxyimino includes groups of the formula Ar-O-N= where AT is aryl.
The "carbalkoxy" is a group wherein the acyl group is bonded to the main
aryl/phenyl unit and alkyl is as defined hereinabove. Examples include COOMe, COOEt
and the like.
Aroyl is ArCO where AT is an aryl group. Aroyloxy is ArC(O)0.
Carboxylate salts may be sodium, potassium or ammonium salts. The esters of
carboxylic acid may have 1 to 4 carbon atoms in the ester group.
Chemistry
A typical synthesis of 2,3-diaryl-4-hydroxycyclopent-2-en-l-one and 2,3-diaryl-5-
hydroxycyclopent-2-en-l-one of General formulae (6A) and (6B) respectively
and other derivatives of formula (1)
(Figure Remove)is shown in Schemes 1 and 2. According to one embodiment of the invention furan was
treated with a strong base selected from methyllithium, n-butyllithium, s- or t-butyl
lithium, lithium diisopropyl amide (LDA) and substituted benzaldehydes of the Formula 2
at -40° to 0°C to obtain substituted furfuryl alcohol of the formula (3)
(Figure Remove) [0012] Treatment of the compound of the formula (3) with a Lewis acid preferably
zinc chloride resulted in the formation of 2-aryl-4-hydroxy-cyclopent-2-en-l-one of
the formula (4)
Unlike the prior art G. Piancatelli , A. Scettri, and S. Barbadoro, Tet. Lett.39,
3555-3558 (1976); G. Piancatelli and A. Scettri, Tet. Lett. 13, 1131-1134 (1977); G.
Piancatelli , A. Scettri, G. David and M. D. Auria, Tetrahedron 34, 2775-2778 (1978); A.
Scettri, G. Piancatelli, M. D. Auria and G. David, Tetrahedron 35, 135-138 (1979); P. W.
Collins, S. W. Kramer and G. W. Gullikson, J. Med. Chem. 30, 1952-1955 (1987); P. W.
Collins, S. W. Kramer, A. F. Gasiecki, R. M. Weier, P. H. Jones, G. W. Gullikson, R. G.
Bianchi, and R. F. Bauer, J. Med. Chem. 30, 193-197 (1987); M. D. Auria, Heterocycles,
52, 185-194 (2000) which disclose a two step process for preparing compounds of formula
(4), in applicant's process to obtain 2-aryl-4-hydroxycyclopent-2-en-l-one of the formula
(4), the double rearrangement of substituted furfuryl alcohols of the formula (3) occurs in
one pot.
Compounds of the formula (4) under Heck reaction conditions using properly
substituted iodobenzenes of the formula (5) provided 2,3-diaryl-4-hydroxycyclopent-2-en-
1-one of the formula (6A).
Standard derivatisation techniques have been employed for converting compounds
of the formula (4) and (6A) into 4-acetoxy, 4-tert.-butyldimethysilyoxy, and 4-
trimethylsilyoxy derivatives (See for example Scheme 3). In order to increase the
solubility of the designed molecules oximation of the cyclic ketone, oxidation of 4-
hydroxy group and further dioximation was conducted by routine procedures.
Derivatisation of the functional groups in the cyclopentenone ring can be earned
out before or after the Heck reaction. However Heck reaction gave better yields when
hydroxy at C-4 of the cyclopenetenone was protected. It was preferred that the compound
of structure 4 was protected as trimethylsilyl or teit-butyldimethylsilyl ether before the
Heck reaction was performed to attach the second aryl group at C-3 position.
Deprotection of silyloxy group at C-4 in the compound of the formula of structure (6A)
was achieved under acidic conditions e.g. acetic acid in aqueous-tetrahydrofuran at 50°C
followed by acylation or oxidation gave the corresponding acyloxy or oxo derivatives.
The 2,3-diaryl-l,4-cyclopent-2-en-dione of the formula (15) was further treated with
hydroxylamine hydrochloride to obtain the dioxime of the formula (18).
Following the protocol as shown in Scheme 1, the compounds (shown in Table 1)
of the formulae (7) to (45) belonging to the General formula (1A) were synthesized.
(Figure Remove)Wherein R1 = R5 = R10 = H
(Figure Remove)OMOM represents methoxymethyloxy
The ter/-butyldimethylsilyl derivative of Compounds of the formula (4) under
Grignard reaction conditions using properly substituted iodobenzenes of the formula (5) or
reaction of aryl lithium from the formula (5) afforded the corresponding l,2-diaryl-4-(terrbutyldimethylsilyloxy)-
cyclopent-2-en-l-ols having the formula (4A),
which are subjected to a pyridinium dichromate catalyzed rearrangement to yield the title
2,3-diaryl-5-(ter/-butyldimernylsilyloxy)-cyclopent-2-en-l-ones of the formula (6B) as
shown in Scheme 2.
Following the protocol as shown in Scheme 2, the compounds (shown in Table 2)
of the formulae (46) to (73) belonging to the of General formula (IB) were synthesized.
OiPr represents isopropyloxy
Representative salts of the compounds of formula 1 include but are not limited to
the following: acetate, ascorbate, benzoate, citrate, oxalate, stearate, trifluoroacetate,
succinate, tartarate, lactate, fumarate, gluconate, glutamate, phosphate/diphosphate, and
valerate. Other salts include Ca, Li, Mg, Na, and K salts, halides, salts of amino acids
such as lysine or arginine; guanidine, ammonium, substituted ammonium salts or
aluminium salts. The salts may be prepared in a conventional manner.
The present invention also provides a composition comprising a compound of
formula 1, a derivative or salt thereof and a pharmaceutically acceptable carrier, diluent,
or solvent. The composition may optionally and preferably contain pharmaceutically
acceptable diluents, excipients, additives, fillers, lubricants, solvents, binders, stabilizers,
and the like. Such diluents may include: RPMI 1649, buffered saline, isotonic NaCl,
Ringer's solution, water, distilled water, polyethylene glycol (neat or in water), 2% Tween
in water, dimethyl-sulfoxide to 50% in water, propylene glycol ( neat or in water),
phosphate buffered saline, balanced salt solution, glycerol, and other conventional fluids
that are suitable for intravenous administration. Pharmaceutical compositions which
provide from about 0.1 to 10 gram (preferably 0.5 to 5.0 gram) of the composition per unit
dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders,
aqueous or oily suspension, syrups, elixirs, and aqueous solutions. The nature of the
pharmaceutical composition employed will, of course, depend on the desired route of
administration.
The invention provides a method of treatment for humans, mammals, or other
animals suffering from cancer or other tumors. The method may suitably comprise,
consist of, or consist essentially of administering a therapeutically effective dose of the
pharmaceutical composition so as to kill or inhibit the multiplication of cancer or tumor
cells. The invention relates more specifically to the use of the compounds of formula (I)
derivatives or salts thereof for the inhibition and/or prevention of cancer of the colon,
pancreas, larynx, ovary, duodenum, kidney, oral cavity, prostate, lung, endothelial cells or
leukemias.
The methods of this invention comprise, consist of, or consist essentially of
administering systematically to the mammal a therapeutically effective combination of cyclopentenone
derivatives. An effective dose of cyclopentenone derivatives or pharmaceutically acceptable salts of the
cyclopentenone derivatives ranges from Img / Kg. B. Wt to 300 mg / Kg. B. Wt (preferably 10 - 100 mg) /
Kg. B. Wt) of the mammal, with the dose dependent on the effects sought, the manner of administration, and
the cancer being treated. Systemic administration refers to oral, rectal, nasal, transdermal, and parental (i.e.,
intramuscular, intravenous and subcutaneous). In accordance with good clinical practice, it is preferred to
administer the composition at a dose that will produce anticancer effects without causing undue harmful side
effects. The composition may be administered either alone or as a mixture with other therapeutic agents
such as 5-fluorouracil, methotrexate, etoposide, paclitaxel, taxotere, doxorubicin, daunarubicin, vincristine,
vinblastine and other such known and established anticancer drugs.
An effective amount means that amount of a drug or pharmaceutical agent that will
elicit the biological or medical response of a tissue, system, animal or human that is being
sought.
Further chemical transformations to obtain the desired molecules were performed
using standard methods and some of them have been presented in the following examples.
To further assist in the understanding of the present invention and not by way of
limitation the following examples are presented to more clearly describe the present
invention.
EXAMPLE 1
Preparation of substituted furfurvl alcohols of the formula (3)
Furyl-(3.4.5-trimethoxvphenoDmethanol
Magnesium (1.68 gm, 70 mmol) was taken in three neck R.B. flask equipped with
condenser, 100 ml ether followed by dibromoethane (9.5 gm, 51.02 mmol) were added
with stirring at 0°C under nitrogen atmosphere. Stirring was continued until all the
magnesium reacted, then the ether was removed under vacuum until a slurry was formed.
(A). In another single neck R.B. flask furan (4.76 gm, 70 mmol) in tetra-hydrofuran (100
ml) was cooled with ice-salt mixture, n-butyl lithium (2M, 35 ml, 70 mmol) was added
dropwise, and the mixture was stirred at 0°C for 45 min. (B)
Furyllithium thus prepared in flask (B) was added to cold mixture in (A) through
cannula, stirred at 0°C for 5 min, brought to room temperature and stirred at room
temperature for 1.5 hrs; then cooled to -20°C (dry ice and CC1j). Substituted
benzaldehyde (51.02 mmol) in tetra-hydrofuran (50 ml) was added and stirred at -20°C for
4 hr (monitored by TLC). After completion of reaction the mixture was quenched with
saturated ammonium chloride solution. The mixture was allowed to warm to room
temperature. Solvent was removed under reduced pressure and residue extracted with
ethyl acetate. The organic layer was washed with water followed by brine, dried over
sodium sulfate and concentrated to dryness under reduced pressure using a rotary
evaporator. The crude residue was purified by column chromatography using silica gel
(petroleum ether : acetone as eluents) to collect pure compounds of the formula of
structure 3 (yield, 93%).
Spectral data of furyl-(3,4,5-trimethoxyphenyl)methanol:
'HNMRCCDCla + CCL,): 5 2.72 (bs, 1H), 3.84 (s,9H),'5.75 (bs, 1H),
6.15(d, J=6Hz, 1H), 6.27-6.32 (m, 1H), 6.66(d, J=2Hz, 2H), 7.40(bs,lH).
Mass (m/e): 264 (M+, 80), 247 (60), 233 (12), 214 (15), 189 (20),
169 (70) 161 (25), 95 (100)
EXAMPLE 2
Preparation of 2-(3.4.5-trimethoxvphenvl)-4-hvdroxv-cyclopent-2-enones
A solution of aryl furfuryl alcohol i.e. compound of the formula of structure 3
wherein RI and R5 are H and R2-R4 are OCH3 (25 gm, 94.69 mmol) and ZnCl2 (51.26 gm,
378.7 mmol) in dioxan (30 ml) and water (206 ml) was refluxed for 24 h at which time
TLC analysis indicated the complete disappearance of starting material. The mixture was
brought to room temperature, acidified to pH 1 with dilute HC1 and extracted with ethyl
acetate. The organic layer was washed with water, followed by brine and dried over
sodium sulphate. The organic layer was concentrated under reduced pressure using rotary
evaporator to collect the required 2-(3,4,5-trimethoxyphenyl)-4-hydroxy-cyclopent-2-enl-
one(21.25gm, 85%).
Spectral data:
'H NMR(CDC13 + CCL,) : 5 2.52 (d, J=18 Hz, 1H), 3.00 (dd, J=18 Hz and 6 Hz,
1H), 3.86 (s, 3H), 3.89 (s,6H), 5.00-5.10 (m, 1H), 6.98 (s,2H), 7.58 (d, 1H).
Mass (m/e): 264 (M+, 100), 249 (57), 233 (10), 221 (22), 205 (32), 189
(15), 177(20), 161(40).
EXAMPLE 3
Preparation of tert-butyldimethylsilyl derivatives
A solution of 2-aryl-4-hydroxy-cyclopent-2-en-l-one of formula (4) (8.7 nimol) in
dry dichloromethane (30 ml) was stirred at 0°C under inert atmosphere (maintained by
using nitrogen or argon gas filled in balloon), a solution of tert-butyl dimethylsilyl
chloride (1.5 gm, 9.95 mmol) and dimethylamino pyridine (0.194 gm, 1.5 g nimol) in
dichloromethane (10 ml) was added drop wise and stirred at the same temperature for 15
min. Then triethylamine (1.77 ml, 12.7 mmol) was added and mixture was warmed to
room temperature and stirred further for 3 h (monitored by TLC). The reaction mixture
was filtered through whatman filter paper, dichloromethane was removed under reduced
pressure and extracted with chloroform. The organic layer was washed with water,
followed by brine, dried over sodium sulphate and concentrated to dryness under reduced
pressure using rotary evaporator. The crude residue was purified by column
chromatography using silica gel (petroleum ether: acetone as eluent) to give the title
derivatives.
Spectral data of 2-(3,4,5-trimethoxyphenyl)-4-tert.-butyldimethylsilyoxycyclopent-
2-en-1 -one:
'H NMR(CDC13 + CCL,) : 5 0.16 (s, 3H), 0.17 (s,3H), 0.94 (s,9H), 2.47 (d, J=18
Hz, 1H), 2.92 (dd, J=18 Hz and 6 Hz, 1H), 3.85 (s,3H), 3.90 (s, 6H), 4.95-5.05 (m, 1H),
6.96 (s, 2H), 7.45 (d, 1H).
Mass (m/e): 378 (M+, 100), 363 (10), 321 (15), 290 (40), 219 (70).
EXAMPLE 4
Preparation of 4-acetoxy-2-f3A5-trimethoxvphenyl)-cvclopent-2-en-1 -one
A solution of 2-(3,4,5-trimethoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one (3 gm,
11.36 mmol) in dichloromethane (30 ml) was cooled to 0°C using ice-salt bath. To the
cold solution dry pyridine (1.70 gm, 1.73 ml; 26.0 mmol) was added and stirred at 0°C for
10 min. To the stirred solution, acetic anhydride (1.63 gm, 1.50 ml, 16.0 minol) was
added dropwise while maintaining the temperature below 0°C. The reaction mixture was
stirred at room temperature for 15 h (monitored by TLC) then quenched by adding cold,
dilute hydrochloric acid. The organic layer was washed three times with water, 10%
sodium bicarbonate solution and finally brine. The organic layer was dried over sodium
sulfate and concentrated to dryness under reduced pressure using a rotary evaporator. The
crude residue was purified by column chromatography using silica gel (petroleum ether:
acetone as eluent) to collect the pure 4-acetoxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-2-
en-l-one (2.56 gm, 73.47 %).
Spectral data:
1H NMR(CDC13 + CCLt): 8 2.08 (s,3H), 2.54 (d, J=18Hz, 1H), 3.00 ( dd, J=18Hz
and 6Hz, 1H), 3.82 (s,3H), 3.84 (s, 6H), 5.80-5.90 (m, 1H), 6.96 (s, 2H), 7.59 (d, J=4Hz,
1H)
Mass (m/e): 306 (M+, 100), 264 (14), 247 (34), 231 (8), 219 (51).
EXAMPLES
Heck reaction of arvl iodides with cyclopentenone
A mixture of of p-iodo anisole (3.71 gm, 15.87 mmol), 2-(3,4,5-
trimethoxyphenyl)-4-hydroxy-cyclopent-2-enone (7.93 mmol),), palladium acetate (0.230
gm, 1.026 mmol), triphenyl phosphine, (0.400 gm, 1.52 mmol), potassium carbonate (2.20
gm, 15.86 mmol), and catalytic amount of tetrabutylammonium bromide (0.030 gm) in
degassed acetonitrile was refluxed for 36 h. Then the reaction mixture was cooled to room
temperature, and acetonitrile was removed under reduced pressure using a rotary
evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform.
The organic layer was washed with water followed by brine, dried over sodium sulfate and
concentrated to dryness under reduced pressure, using a rotary evaporator. The crude
residue was purified by column chromatography using silica gel (petroleum ether: acetone
as eluent) to collect pure products of the formula of structure (7).
Spectral data of compound of the formula of structure (7)
'H NMR(CDC13 + CC14 ) : 6 2.65 (d, J=18 Hz, 1H), 3.11 ( dd, J=18 Hz and 8 Hz,
1H), 3.72 (s, 6H), 3.83 (s, 3H), 3.86 (s, 3H), 5.45 -5.50 (m, 1H), 6.46 (s, 2H), 6.87 (d,
J=10 Hz, 2H), 7.41 (d, J=10 Hz, 2H).
Mass (m/e) : 370 (M+, 100), 355 (19), 262 (32), 231 (20), 219 (18), 177 (30), 163
(27), 135 (25).
EXAMPLE 6
Preparation of compound of formula of structure (10)
A mixture of p-iodo anisole (3.71 gm, 15.87 mmol), 2-(3,4,5-trimethoxyphenyl)-
4-ter-butyldimethylsilyoxy-cyclopent-2-enone (7.93 mmol),), palladium acetate (0.230
gm, 1.026 mmol), triphenyl phosphine, (0.400 gm, 1.52 mmol), potassium carbonate (2.20
gm, 15.86 mmol), and catalytic amount of tetrabutyl-ammonium bromide (0.030 gm) in
degassed acetonitrile was refluxed for 36 h. Then the reaction mixture was cooled to room
temperature, and acetonitriie was removed under reduced pressure using a rotary
evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform.
The organic layer was washed with water followed by brine, dried over sodium sulfate and
concentrated to dryness under reduced pressure, using a rotary evaporator. The crude
residue was purified by column chromatography using silica gel (petroleum ether : acetone
as eluent) to collect pure products of the formula of structure (10).
Spectral data of compound of the formula of structure (10):
'H NMR(CDC13 + CO,): 6 0.05 (s, 3H), 0.09 (s, 3H), 0.80 (s, 9H), 2.57 (d, J= 16
Hz,lH), 3.02(dd, J=16 Hz and 6 Hz, 1H), 3.69 (s, 6H), 3.82 (s, 3H), 3.84 (s, 3H), 5.30 -
5.40 (m, 1H), 6.44 (s, 2H), 6.82 (d, J=6Hz, 2H), 7.27 (d, J=6 Hz, 2H).
Mass (m/e): 484( M+, 5), 427 (30), 369 (32), 353 (100), 325 (61), 294 (47).
EXAMPLE 7
Preparation of compound of formula of structure (11)
A mixture of iodobenzene (15.87 mmol), 2-(3,4,5-trimethoxyphenyl)-4-terbutyldimethylsilyoxy-
cyclopent-2-enone (7.93 mmol), palladium acetate (0.230 gm, 1.026
mmol), triphenyl phosphine, (0.400 gm, 1.52 mmol), potassium carbonate (2.20 gm, 15.86
mmol), and catalytic amount of tetrabutylammonium bromide (0.030 gm) in degassed
acetonitrile was refluxed for 36 h. Then the reaction mixture was cooled to room
temperature, and acetonitrile was removed under reduced pressure using a rotary
evaporator. The residue was acidified with dilute HC1 and then extracted with chloroform.
The organic layer was washed with water followed by brine, dried over sodium
sulfate and concentrated to dryness under reduced pressure, using a rotary evaporator. The
crude residue was purified by column chromatography using silica gel (petroleum ether :
acetone as eluent) to collect pure products of the formula of structure (11).
Spectral data of compound of the formula structure (11):
JH NMR(CDC13 + CC14 ) : 8 - 0.05 (s, 3H), 0.05 (s,3H ), 0.77 (s, 9H), 2.61 (d,
J=18 Hz, 1H) 3.05 (dd, J=18 Hz and 6 Hz, 1H), 3.63 (s, 6H), 3.82 (s, 3H), 5.27-5.33 (m,
1H), 6.47 (s, 2H), 7.32 (bs, 5H).
Mass (m/e): 454 (M+, 28), 379 (100), 323 (28), 291 (27), 247 (92), 219 (66),
75(83).
EXAMPLE 8
Preparation of compound of formula of structure (12)
A mixture of 3, 5-dimethyl-4-methoxy-l-iodobenzene (15.87 mmol), 2-(3,4,5-
trimethoxyphenyl)-4-ter-butyldimethylsilyoxy-cyclopent-2-enone (7.93 mmol),),
palladium acetate (0.230 gm, 1.026 mmol), triphenyl phosphine, (0.400 gm, 1.52 mmol),
potassium carbonate (2.20 gm, 15.86 mmol), and catalytic amount of tetrabutylammonium
bromide (0.030 gm) in degassed acetonitrile was refluxed for 36 h. Then the
reaction mixture was cooled to room temperature, and acetonitrile was removed under
reduced pressure using a rotary evaporator. The residue was acidified with dilute HC1 and
then extracted with chloroform. The organic layer was washed with water followed by
brine, dried over sodium sulfate and concentrated to dryness under reduced pressure, using
a rotary evaporator. The crude residue was purified by column chromatography using
silica gel (petroleum ether : acetone as eluent) to collect pure products of the formula of
structure 12.
Spectral data of compound of the formula of structure 12:
'H NMR(CDC13 + CCL,) : 8 -0.01 (s, 3H), 0.07(s, 3H), 0.78(s, 9H), 2.20(s,6H),
2.56(d, J= 18Hz, 1H) 3.01(dd, J=18Hz and 6Hz, 1H), 3.68(s,6H), 3.70(s, 3H), 3.83(s, 3H),
5.20-5.30(m, 1H), 6.51(s, 2H), 6.97 (s,2H).
Mass (m/e): 512 (M, 18), 456 (38), 425 (16), 381 (51), 353 (15), 322 (13)
129(100).
EXAMPLE 9
Preparation of compound of formula of structure 13
A mixture of 2,5-dimethoxy-l-iodobenzene (15.87 mmol), 2-(3,4,5-
trimethoxyphenyl)-4-ter-butyldimethylsilyoxy-cyclopent-2-enone (7.93 mmol), palladium
acetate (0.230 gm, 1.026 mmol), triphenyl phosphine, (0.400 gm, 1.52 mmol), potassium
carbonate (2.20 gm, 15.86 mmol), and catalytic amount of tetrabutylammonium bromide
(0.030 gm) in degassed acetonitrile was refluxed for 36 h. Then the reaction mixture was
cooled to room temperature, and acetonitrile was removed under reduced pressure using a
rotary evaporator. The residue was acidified with dilute HC1 and then extracted with
chloroform. The organic layer was washed with water followed by brine, dried over
sodium sulfate and concentrated to dryness under reduced pressure, using a rotary
evaporator. The crude residue was purified by column chromatography using silica gel
(petroleum ether : acetone as eluent) to collect pure products of the formula of structure
13.
Spectral data of compound of the formula of structure 13:
'HNMRtCDCls + CCU): 5 -0.19 (s, 3H),-0.04 (s, 3H), 0.74 (s, 9H), 2.55 (d, J=16
Hz, 1H), 3.02 (dd, J=16 Hz and 6 Hz, 1H), 3.63 (s, 6H), 3.65 (s, 3H), 3.69 (s, 3H), 3.78 (s,
3H), 5.25-5.38 (m, 1H), 6.45-6.72 (m, 3H), 6.75-6.96 (m, 2H).
Mass (m/e): 514 (M+, 71), 458 (87), 443 (30), 384 (40), 154 (70) 75 (100).
Example 10 describes a general method for deprotection of tertbutyldimethylsilyloxy
group used in preparation of various compounds described in this
specification. The compounds of the formula 8 and 9 are specific compounds obtained
using this method from their corresponding TBS derivatives, i.e. compound 8 is obtained
from compound 12 and compound 9 is obtained from compound 13.
EXAMPLE 10
Deprotection of tert-butyldimethylsilvloxy derivatives
A solution of protected 4-tert-butyldimethylsilyloxy-2,3-diarylcyclopent-2-enone
(0.72 mmol) in acetic acid; tetrahydrofuran and water (3:1:1) was heated at 50°C for 20 h
(monitored by TLC). The reaction mixture was cooled to 0°C and neutralized by sodium
bicarbonate and extracted with chloroform. The organic layer was washed with water
followed by brine and dried over sodium sulfate and filtered. The filtrate was
concentrated to dryness under reduced pressure using a rotary evaporator. The crude
residue was purified by column chromatography using silica gel (petroleum ether: acetone
as eluent) to collect the 4-hydroxy-2,3-diarylcyclopentenone of the general formula of
structure 6.
Spectral data of compounds of the formula of structure 8:
'H NMR(CDC13 + CC14 ) : 8 2.21 (s, 6H), 2.63 (d, J=18 Hz, 1H), 3.07 (dd, J=18
Hz and 6 Hz, 1H), 3.69 (s, 6H), 3.71 (s, 3H), 3.84 (s, 3H), 5.35-5.45 (m, 1H), 6.47 (s, 2H),
7.06 (s, 2H).
Mass (m/e): 398 (M, 100), 367 (5), 262 (32), 247 (51), 231 (12), 177 (15), 149
(13).
Spectral data of compounds of the formula of structure 9:
'H NMR(CDC13 + CC14): 8 2.63 (dd, J=18 Hz and 2 Hz, 1H), 3.06 (dd, J=18 Hz
and 6 Hz, 1 H), 3.59 (s, 3H), 3.64 (s, 6 H), 3.71 (s, 3H), 3.80 (s, 3H), 5.35-5.50 (m, 1H),
6.45-6.75 (m, 3H), 6.84-7.00 (m, 2H).
Mass (m/e): 400 (M4,19), 369 (3), 111 (82), 83 (52), 71 (67).
EXAMPLE 11
Preparation of compound of the formula of structure 14
A solution of 2-(3,4,5-trimethoxyphenyl)-3-(4-methoxyphenyl)-4-hydroxycyclopent-
2-en-l-one (0.235gm, 0.63 mmol) in dichloromethane (20 ml) was cooled to
0°C using ice-salt bath. To the cold solution dry pyridine (0.10 gm, 1.46.0 mmol) was
added and stirred at 0°C for 10 min. To the stirred solution, acetic anhydride (0.10 gm,
0.95 mmol) was added drop wise while maintaining the temperature below 0°C. The
reaction mixture was stirred at room temperature for 15 h (monitored by TLC) then
quenched by adding cold, dilute hydrochloric acid. The organic layer was washed three
times with water, 10% sodium bicarbonate solution and finally brine. The organic layer
was dried over sodium sulfate and concentrated to dryness under reduced pressure using a
rotary evaporator. The crude residue was purified by column chromatography using silica
gel (petroleum ether: acetone as eluent) to collect the pure 2-(3,4,5-trimethoxyphenyl)-3-
(4-methoxyphenyl)-4-acetoxy-cyclopent-2-en-l-one (0.21 gm, 80.45 %).
Spectral data:
'H NMR(CDC13 + CC14 ) : 8 2.01 (s, 3H), 2.52 (d, J=18Hz, 1H), 3.15 (dd, J=18 Hz
and 6 Hz, 1H), 3.71 (s, 6H), 3.81 (s, 3H), 3.85 (s, 3H), 6.40 (m, 1H), 6.44 (s, 2H), 6.81 (d,
J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H).
Mass (m/e): 412 (M+, 100), 397 (8), 352 (13), 337 (17).
EXAMPLE 12
Preparation of diketone of the structure 15
A solution of pyridinium chlorochromate (0.300 gm) in dichloromethane (20 ml)
was cooled to 0°C, stirred for 5 minutes, then a solution of 2,3-diaryl-4-hydroxy
cyclopentenone of the formula 7, (0.200 gm, 0.54 mmol) in dichloromethane (5 ml) was
added and stirred for 2 hours at room temperature (monitored by TLC). The reaction
mixture was filtered through celite. The filtrate was washed with water followed by brine
and dried over sodium sulfate, and concentrated to dryness under reduced pressure using a
rotary evaporator. The crude residue was purified by column chromatography using silica
gel (petroleum ether: acetone as eluents) to collect pure cyclopentenedione of the structure
15 (0.060 gm, 30.16%).
Spectral data:
!H NMR(CDC13 + CCL,) : 6 3.17 (s, 2H), 3.69 (s, 6H), 3.83 (s, 3H), 3.88 (s, 3H),
6.63 (s, 2H), 6.88 (d, J= 6Hz, 2H), 7.38 (d, J=6Hz, 2H).
Mass (m/e): 368 (M, 100), 353 (30), 283 (23), 169 (20), 111 (46) 69 (70).
EXAMPLE 13
Preparation of oxime of the structure 16
A mixture of ketone of the formula 7 (0.100 gm, 0.20 mmol), hydroxyl amine
hydrochloride (0.02 gm, 0.30 mmol) and sodium acetate (0.025 gm, 0.30 mmol) in ethanol
(5 ml) was refluxed on water bath for 3 h. The reaction was monitored by TLC and after
completion of reaction the solvent was removed under reduced pressure using a rotary
evaporator. The residue was extracted with chloroform. The organic layer was washed
with water followed by brine and dried over sodium sulfate and concentrated to dryness
under reduced pressure using a rotary evaporator. The crude residue was purified by
column chromatography using silica gel (petroleum ether: acetone as eluent) to collect
pure oxime of the structure 16 (0.086 gm, 83.50 %).
Spectral data:
H NMR(CDC13 + CC14) : 8 2.80 (d, J=18 Hz, 1H), 3.36 (dd, J=18 Hz and 8 Hz,
1H), 3.73 (s, 6H), 3.79 (s, 3H), 3.87 (s, 3H), 5.30-5.40 (m, 1H), 6.47 (s, 2H), 6.80 (d, J=8
Hz, 2H), 7.26 (d, J=8 Hz, 2H).
21
Mass (m/e) : 385 (M+, 100), 368 (40), 336 (12).
EXAMPLE 14
Preparation of oxime of structure 17 from compound of structure 16
A solution of pyridinium chlorochromate (0.080 gm) in dichloromethane (10 ml)
was cooled to 0°C, stirred for 5 minutes, then a solution of 2,3-diaryl-4-hydroxy
cyclopentenone of the formula 16, (0.075 gm, 0.19 mmol) in dichloromethane (5 ml) was
added and stirred for 2 hours at room temperature (monitored by TLC). The reaction
mixture was filtered through celite and the filtrate was washed with water followed by
brine and dried over sodium sulfate, and concentrated to dryness under reduced pressure
using rotary evaporator. The crude residue was purified by a column chromatography
using silica gel (petroleum ether: acetone as eluents) to collect pure cyclopentenedione of
the structure 17 (0.026 gm, 35 %).
Spectral data compound of the structure 17:
!H NMR(CDC13 + CCL4) : 5 3.41 (s, 2H), 3.69 (s, 6H), 3.80 (s, 3H), 3.89 (s, 3H),
6.58 (s, 2H), 6.83 (d, J=9 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 8.60 (bs, 1H).
Mass (m/e): 384 (M*. 100), 367 (37), 336 (34), 307 (12).
EXAMPLE 15
Preparation of oxime of the structure 19
A mixture of ketone of the formula 10 (0.100 gm, 0.20 mmol), hydroxyl amine
hydrochloride (0.02 gm, 0.30 mmol) and sodium acetate (0.025 gm, 0.30 mmol) in ethanol
(5 ml) was refluxed on water bath for 3 h. The reaction was monitored by TLC and after
completion of the reaction the solvent was removed under reduced pressure using rotary
evaporator. The residue was extracted with chloroform, the organic layer was washed
with water followed by brine and dried over sodium sulfate and concentrated to dryness
under reduced pressure using a rotary evaporator. The crude residue was purified by
column chromatography using silica gel (petroleum ether: acetone as eluent) to collect
pure oxime of the structure 19 (0.086 gm, 83.50 %).
Spectral data:
H NMR(CDC13 + CCL,) : 6 -0.01 (s, 3H), 0.08 (s, 3H), 0.82 (s, 9H), 2.70 (d, J=18
Hz, 1H),3.32 (dd, J=18 Hz and 6 Hz, 1H), 3.69 (s, 6H), 3.78 (s, 3H), 3.84 (s, 3H), 5.24-
5.30 (m, 1H), 6.46 (s, 2H), 6.76 (d, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 7.85 (bs, 1H).
22
Mass (m/e): 499 (M+, 68), 442 (67), 368 (100), 320 (12), 74 (60).
EXAMPLE 16
Preparation of dioxime of the structure 18
A mixture of diketone of the formula 15 (0.060 gm, 0.16 nimol), hydroxylamine
hydrochloride (0.026 gm, 0.40 rnmol) and sodium acetate (0.033 gm, 0.40 mmol) in
ethanol (5 ml) was refluxed on a water bath for 3 hrs. (monitored by TLC). Then the
solvent was removed under reduced pressure using a rotary evaporator and the residue
obtained was extracted with chloroform. The organic layer was washed with water
followed by brine and dried over sodium sulfate, concentrated to dryness under reduced
pressure using a rotary evaporator. The crude residue was purified by column
chromatography using silica gel (petroleum ether: acetone as eluent) to collect pure
dioxime of the structure 18 (0.033 gm, 51.6%).
Spectral data:
H NMR(CDC13 + CCL,): 6 3.42 (s, 2H), 3.47 (s, 6H), 3.61 (s, 3H), 3.64 (s, 3H),
6.36 (s, 2H), 6.60 (d, 3=6 Hz, 2H), 7.06 (d, J=6 Hz, 2H).
EXAMPLE 17
Preparation of compound of the structure 20
A mixture of ketone of the formula 14 (0.100 gm, 0.24 rnmol), hydroxylamine
hydrochloride (0.023 gm, 0.36 mmol) and sodium acetate (0.03 gm, 0.36 mmol) in ethanol
(5 ml) was refluxed on a water bath for 3 h. The reaction was monitored by TLC and after
completion of reaction the solvent was removed under reduced pressure using a rotary
evaporator. The residue was extracted with chloroform, the organic layer was washed
with water followed by brine and dried over sodium sulfate and concentrated to dryness
under reduced pressure using a rotary evaporator. The crude residue was purified by
column chromatography using silica gel (petroleum ether: acetone as eluent) to collect
pure oxime of the structure 20 (0.088 gm, 85.40 %).
Spectral data of compound of structure 20:
H NMR(CDC13 + CCL,): 8 2.02 (s, 3H), 2.72 (d, J=18Hz, 1H), 3.40 (dd, J=18 Hz
and 6 Hz, 1H), 3.72 (s, 6H), 3.78 (s, 3H), 3.87 (s, 3H), 6.25-6.35 (m, 1H), 6.46 (s, 2H),
6.75 (d, J=10 Hz, 2H), 7.12 (d, J=10 Hz, 2H).
Mass (m/e): 427 (M, 100), 412 (7), 369 (47), 351 (25), 320 (31), 305 (7).
The compound of the formula of structure 21 was prepared from a compound of
the formula of structure 13 by using the same procedure as above.
Spectral data of compound of the formula of structure (21):
'H NMR(CDC13 + CCU): 5 - 0.21 (s, 3H), - 0.06 (s, 3H), 0.76 (s, 9H), 2.69 (d,
J=18 Hz, 1H), 3.36 (dd, J=18 Hz and 6 Hz, 1H), 3.64 (s, 3H), 3.66 (s, 6H), 3.70 (s, 3H),
3.80 (s, 3H), 5.20-5.30 (m, 1H), 6.50-6.57 (m, 3H), 6.76 (bs, 2H), 7.99 (bs, 1H).
Mass (m/e): 529 (M+, 63), 512 (71), 472 (100), 398 (68), 75 (60).
EXAMPLE 18
Preparation of 5-tert-Buryldimethvlsilvloxv-3-(4-methoxv-3-i-propoxvphenvlV2-('3.4,5-
trirnethoxvphenvl)-cvclopent-2-en-l-one of the formula (56)
4-Iodo-2-i-propoxyanisole (1.94 g, 7.90 mmol) in dry tetrahydrofuran (10 ml) was
stirred under nitrogen at -78°C and n-butyl lithium (3.45 ml of 2.3 M solution, 7.90
mmol) was added dropwise. The reaction mixture was stirred at -78°C for 1.5 h. 4-tert-
Butyldimethylsilyloxy-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-l-one (2.00 g, 5.29
mmol) in dry tetrahydrofuran (10 ml) was added and the reaction mixture was stirred at -
78°C for 12 h. It was then quenched with saturated ammonium chloride solution (30 ml),
tetrahydrofuran was removed under reduced pressure, extracted with dichloro-methane (3
X 50 ml), washed with water (2 X 20 ml) followed by brine (1 X 20 ml), dried (sodium
sulfate), concentrated and purified by column chromatography over silica gel (eluent- 8%
acetone in pet ether) to afford the compound of the formula (4 A) wherein RI = Rs = Re =
R7 =Rio =H, R2= RS = R4 = Rg = OMe, R9 = Oi-Pr (1.28 g, 45%) as yellowish semisolid.
The above alcohol of the formula (4A) wherein RI = RS = Re = R? =Rio =H, R2=
R3 = R} = R8 = OMe, R9 = Oi-Pr (0.50 g, 0.92 mmol) in dry dichloromethane (15 ml)
was stirred with pyridinium dichromate (0.69 g, 1.83 mmol) under nitrogen at room
temperature for 4 h. It was then filtered through celite (3.00 g), washed with
dichloromethane (50 ml), concentrated and purified by column chromatography over silica
gel (eluent- 5% acetone in pet ether) to afford the title compound of the formula (56)
(0.42 g, 79 %).
Spectral data of compound of the formula of structure (56)
'H NMR (CDC13 + CCU): 5 0.21 (s, 6H), 0.96 (s, 9H), 1.13 (d, J=6Hz, 3H), 1.16
(d, J=6Hz, 3H), 2. 92(dd,J = 18 Hz,and 6Hz, 1H), 3.33 (dd, J=18 Hz and 6 Hz, 1H) 3.74
s, 6H), 3.81 (s,6H), 3.85 (s, 3H), 4.01-4.06 (m, 1H), 4.45-4.50 (m, 1H), 6.41 (s, 2H), 6.80
(d, J=SHz, 1H), 6.83 (d, J=2Hz, 1H), 7.08 (dd, J=SHz and 2Hz, 1H).
13C NMR(CDC13+ CC14): 8 -5.19, -4.42, 18.30, 21.61, 21.75, 25.76 (3C), 39.07,
55.61, 55.79 (2C), 60.46, 71.05, 106.33 (2C), 111.04, 115.71, 121.62, 127.21, 128.39,
135.78, 137.65, 146.51,152.17,153.42 (2C), 162.39, 204.77,205.00
EXAMPLE 19
Preparation of O-tert-Butvldimethvlsilyloxv-S -('4-methoxvphenvD-2-(3,4.5-
trimethoxyphenvl)-cyclopent-2-en-l-one of formula (52)
Magnesium turnings (0.19 g, 7.93 mmol) were taken in a 100 ml round bottom
flask under nitrogen atmosphere. Dry tetrahydrofuran (25 ml) was added followed by
dropwise addition of p-bromoanisole (1.48 g, 7.90 mmol). The reaction mixture was
stirred at room temperature for 2 h by which tune all the magnesium reacted to form 4-
methoxyphenyl magnesium bromide. 4-tert-Butyldimethylsilyloxy-2-(3,4,5-
trimethoxyphenyl)-cyclopent-2-en-l-one (2.00 g, 5.29 mmol) in dry tetrahydrofuran (15
ml) was added and stirred at room temperature for 2 h. It was then quenched with dil
hydrochloric acid (25 ml), tetrahydrofuran was removed under reduced pressure, reaction
mixture was extracted with ethyl acetate (3 X 25 ml), washed with water (2 X 25 ml),
dried over sodium sulfate, concentrated and purified by column chromatography over
silica gel (eluent- 7% acetone in pet ether) to yield the alcohol of the formula (4A)
wherein RI = R5 = R* = R7 = R9 = RIO = H, R2= R3 = R4 = Rg = OMe (1.28 g, 52%).
The above alcohol of the formula (4A) wherein Rj = Rs = Re = R? = Rg = RIO =
H, R2= RS = R4 = Rg = OMe (1.15 g, 2.36 mmol) was dissolved in dry dichloromethane
(30 ml) and stirred under nitrogen with pyridinium dichromate (1.73 g, 7.38 mmol) under
nitrogen at room temperature for 12 h. Workup as in example 1 and purification by
column chromatography over silica gel (eluent- 3% acetone in pet ether afforded the title
compound of the formula (52) (0.52 g, 45%).
Spectral data of compound of the formula of structure (52)
'H NMR (CDC13 + CCL,): 8 0.23 (s, 6H), 0.97 (s, 9H), 2.94 (dd, J=16 Hz and 4
Hz, 1H), 3.30 (dd, J=16 Hz and 8 Hz, 1H), 3.74 (s, 6H), 3.81 (s, 3H), 3.85 (s, 3H), 4.45-
4.52 (m, 1H), 6.44 (s, 2H), 6.80 (d, J=8Hz, 2H), 7.35 (d, J=8Hz, 2H)
EXAMPLE 20
Preparation of 5-tert-Butvldimethvlsilvloxv-3-(4-thiomethvlphenvl)-2-G.4.5
trimethoxyphenyiVcvclopent-2-en-l-one of formula (55)
[0100] 4- Bromothioanisole (1.07 g, 5.28 mmol) and magnesium metal (0.12 g,
5.28 mmol) were placed in a 100 ml two-necked round bottom flask under argon
atmosphere. Dry tetrahydrofuran (10 ml) was added and the mixture was stirred at room
temperature for 2 h. It was then cooled to 0°C, 4-tert-butyldimethysilyloxy-2-(3,4,5-
trimethoxyphenyl)-cyclopent-2-en-l-one (1.00 g, 2.64 mmol) in dry tetrahydrofuran (10
ml) was added dropwise, stirred at 0°C for 1A h and then at room temperature for 2 h. The
reaction was then quenched with saturated ammonium chloride solution (50 ml) and
tetrahydrofuran was removed under reduced pressure. The residual reaction mixture was
extracted with ethyl acetate (3 X 50 ml), washed with water (2 X 20 ml) followed by brine
(10 ml), dried (sodium sulfate) and concentrated. Purification by column chroma-tography
over silica gel (eluent-7% acetone in pet ether) afforded the compound of formula (4A)
wherein RI = R5 = Re = Ry =R9 =Rio =H, R2= R3 = Rj = OMe, Rg = SMe (0.95 g, 72 %).
The above compound of formula (4A) wherein RI = RS = Re = R? =Rg =Rio -H,
R2= R3 = R» = OMe, Rs = SMe (0.65 g, 1.29 mmol) in dry dichloromethane (10 ml) was
cooled to 0°C, pyridinium dichromate (0.96g, 2.5 mmol) was added, the mixture was
stirred at the same temperature for 1 h and then stirred at room temperature for 10 h. It was
then filtered through celite (2.00 g) and washed with dichloromethane (20 ml).The
combined dichloromethane layer was washed with water (2X10 ml) followed by brine (5
ml), dried (sodium sulfate), concentrated and purified by column chromatography over
silica gel ( eluent- 2-5 % acetone in pet ether) to afford the compound of formula (55)
(0.30 g, 46%).
Spectral data of compound of the formula of structure (55)
!H NMR (CDC13 + CC14) : 5 0.23 (s, 6H), 0.98 (s, 9H), 2.48 (s, 3H), 2.96 (dd, J=16
Hz and 4 Hz, 1H), 3.30 (dd, J=16 Hz and 6 Hz, 1H), 3.74 (s, 6H ),3.86 (s, 3H), 4.45-4.60
(m, 1H), 6.44 (s, 2H), 7.13 (d, J=8Hz, 2H), 7.31 (d, J=8Hz, 2H).
13C NMR(CDC13) : 5 -5.23, -4.53, 14.70, 18.22, 25.69 (3C), 39.25, 55.83 (2C),
60.57, 72.84, 106.44 (2C), 125.12 (2C), 127.01, 128.57( 2C ), 131.11, 136.40, 137.80,
142.06, 153.16 (2C), 162.13, 204.92
Mass(m/z) :500(M4)
EXAMPLE 21
Preparation of S-Hvdroxv-S-O-cliloro-methoxvphenv-CS-ti-imethoxvphenvl)-
cycIopent-2-en-l-one of formula (67)
A mixture of magnesium turnings (0.31 g, 13.1 mmol), 2-chloro-4-bromoanisole
(3.00 g, 13.5 mmol), 4-tert-butyldimethysilyloxy-2-(3,4,5-trimethoxy-phenyl)-cyclopent-
2-en-l-one (2.58 g, 6.84 mmol) and dry teuahydrofuran (35 ml) under nitrogen was stirred
at room temperature for 4 h. Reaction was then quenched with dil hydrochloric acid (30
ml), tetrahydrofuran was removed under reduced pressure and the residual reaction
mixture was extracted with ethyl acetate (3X35 ml), washed with water (2 X 20 ml) and
dried over sodium sulfate. Concentration and purification by column chromatography over
silica gel (eluent- 6 % acetone in pet ether) afforded the alcohol of the formula (4 A)
wherein RI = R5 = R* = R7 =Rio = H, R2= R3 = R» = Rg = OMe, R9 = Cl (1.32 g,
37 %).
A solution of the above alcohol of the formula (4A) wherein RI = RS = Re = R?
=Rio = H, R2= R3 = R4 = Rg = OMe, R9 = Cl wherein (0.95 g, 1.83 mmol) in dry
dichloromethane (15 ml) was cooled to 0°C, pyridinium dichromate (1.92 g, 8.17 mmol)
was added and the mixture was stirred at room temperature for 3 h. Filtration through
celite (3.00 g), washing with dichloromethane (30 ml) and concentration afforded the
crude product which was purified by silica gel column chromatography (eluent- 3 %
acetone in pet ether) to yield the title compound of the formula (IB) wherein R = OTBS,
R! = R5 = Re = R7 =RW = H, R2= R3 = R4 = Rg = OMe, R9 = Cl (0.32 g, 34%), which
on deprotection of TBDMS group using the procedure described in example 10 furnished
the compound of formula (67).
Spectral data of compound of the formula of structure (67)
'H-NMR (CDC13 + CCU) : 5 2.96 (dd, J = 18 Hz and 2 Hz,lH), 3.33 (dd, J = 18
Hz and 6 Hz, IH), 3.75 (s, 6H), 3.86 (s, 3H), 3.91 (s, 3H), 4.45-4.54 (m, IH), 6.42 (s, 2H),
6.81 (d, J = S Hz, IH), 7.21 - 7.29 (m, IH), 7.48 (bs, IH).
13C-NMR (CDC13+ CC14 ) : 5 37.79/55.87 (2C)3 60.58, , 71.57, 106.23 (2c),
111.31,122.41,126.82, 127.59,128.58 (2C), 130.05,135.90,138.07,153.36 (2C), 156.48,
162,51,206.95
EXAMPLE 22
Preparation of 5 -Hvdroxv-3 -(3 -fluoro-4-methoxvphenyl)-2-(3,4,5-trimethoxyphenyl)-
cyclopent-2-en-l-one of fonnula (64)
4- Bromo-2-fluoroanisole (1.08 g, 5.29 mmol) and magnesium metal (0.13 g, 5.29
mmol) were placed in a 100 ml t\vo-necked round bottom flask under argon atmosphere.
Dry tetrahydrofuran (10 ml) was added and the mixture was stirred at room temperature
for 2 h. It was then cooled to 0°C, 4-tert-butyldimethysilyloxy-2-(3,4,5-
trimethoxyphenyl)-cyclopent-2-en-l-one (1.00 g, 2.64 mmol) in dry tetrahydrofuran (10
ml) was added dropwise, stirred at 0°C for Ih and then at room temperature for 2 h. The
reaction was then quenched with saturated ammonium chloride solution (50 ml) and
tetrahydrofuran was removed under reduced pressure. The residual reaction mixture was
extracted with ethyl acetate (3 X 50 ml), washed with water (2 X 20 ml) followed by brine
(10 ml), dried (sodium sulfate) and concentrated. Purification by column chroma-tography
over silica gel (eluent-5-8% acetone in pet ether) afforded the compound of fonnula (4A)
wherein Rj = R5 = Re = R7 =R10 = H, R2 = RS = R4 = Rg = OMe, R9 = F (1.20 g, 90 %).
The above compound of formula (4A) wherein Rj = Rs = Re = R? =Rio = H, Ra =
R3 = R4 = R8 = OMe, R9 = F (0.50 g, 1.00 mmol) in dry dichloromethane (10 ml) was
cooled to 0°C, pyridinium dichromate (0.47 g, 2.00 mmol) was added, the mixture was
stirred at the same temperature for 1 h and then stirred at room temperature for 8 h. It was
then filtered through celite (2.00 g) and washed with dichloromethane (20 ml). The
combined dichloromethane layer was washed with water (2X10 ml) followed by brine (5
ml), dried ( sodium sulfate), concentrated and purified by column chromatography over
silica gel ( eluent- 2-5 % acetone in pet ether) to afford the compound of formula (IB)
wherein R = OTBS, RI = R5 = Re - R7 =R,0 = H, R2 = R3 = R» = RS ~ OMe, R9 - F (
0.24 g, 48%), which on deprotection of TBDMS group using the procedure described in
example 10 furnished the compound of fonnula (64)
Spectral data of compound of the formula of structure (64)
'H-NMR (CDC13 + CCU): 5 2.93 (dd, J = 16 Hz and 4 Hz, IH), 3.30 (dd, J = 16
Hz and 6 Hz, IH), 3.70 (s, 6H), 3.82 (s, 3H), 3.85 (s, 3H), 4.45-4.60 (m, IH), 6.40 (s, 2H),
6.78-6.91 (m, IH), 7.00-7.20 (m, 2H).
13C-NMR (CDC13): 5 37.86, 55.84 (2C), 60.58, 71.50, 106.16 (2C), 112.56,
115.72, 116.12, 125.35, 127.00 (2C), 136.01, 137.92, 149.28, 149.50, 153.32 (2C), 162.80,
207.17.
Mass (m/z): 388 (M+).
EXAMPLE 23
Preparation of 5-Hvdroxv-2-(4-methoxy-3-nitrophenvl)-3-(3,4.5-trimethoxvphenvcyclopent-
2-en-1 -one of formula (46)
3,4,5-Trimethoxyiodobenzene (0.20 g, 0.68 mmol) in dry tetrahydrofuran (7 ml)
was stirred under nitrogen at -78°C and n-butyl lithium (0.3 ml of 2.3 M solution, 0.68
mmol) was added dropwise. The reaction mixture was stirred at the same temperature for
1.5 h and then 4-tert-butyldunethysilyloxy-2-(3,4,5-trimethoxyphenyl)-cyclopent-2-en-lone
(0.25 g, 0.68 mmol) in dry tetrahydrofuran (5 ml) was added dropwise. The reaction
mixture was stirred at -78 °C for 1A h and at RT for 1 h. It was then quenched with
saturated ammonium chloride solution (10 ml), tetrahydrofuran was removed under
reduced pressure, product was extracted with ethyl acetate (2X15 ml) washed with water
(1X10 ml), dried (sodium sulfate), concentrated and purified by column chromatography
over silica gel (eluent- 10% acetone in pet ether) to afford the compound of the formula
(4A) wherein R! = R4 = R5 = RS = RIO = H, R3 = R7 = RS = RP = OMe, R2 = N02 (0.14 g,
40%).
The above alcohol of formula (4A) wherein RI = RI = RS = Re = RIO = H, R3 =
R7 = Rg = RP = OMe, R2 = NO2 (0.10 g, 0.19 mmol) in dry dichloromethane (10 ml) was
refluxed with pyridinium dichromate (0.14 g, 0.37 mmol) for 18 h under nitrogen
atmosphere. It was then filtered through celite (2.00 g) and washed with dichloromethane
(30 ml). The combined dichloromethane layer was washed with water (2 X 10 ml)
followed by brine (5 ml), dried (sodium sulfate), concentrated and purified by column
chromatography over silica gel (eluent- 10 % acetone in pet ether) to afford the compound
of formula (IB) wherein R = OTBS, RI = R = R5 = Re = RIO = H, R3 = R7 = R8 = R9 =
OMe, R2 = NO2 (0.06 g, 52%), which on deprotection of TBDMS group using the
procedure described in example 10 furnished the compound of formula (46)
Spectral data of compound of the formula of structure (46)
1E NMR (CDC13 + CCU): 6 3.02 (bd, J = 16 Hz, 1H), 3.27 (dd, J= 16 Hz and 6
Hz, 1H) 3.68 (s, 6H), 3.88 (s, 3H), 3.97 (s, 3H), 4.53 (bs, 1H, D2O exchangeable), 5.28-
5.30 (m, 1H), 6.59 (s, 2H), 7.07 (d, JNSHz, 1H), 7.45 (bd, J=8Hz, 1H), 7.79 (bs, 1H)
EXAMPLE 24
Preparation of compound of the formula (58) from the compound of the formula (51)
A mixture of compound of the formula (51) (0.300 gm, 0.67 mmol), aluminium
chloride (0.180 gm, 1.35 mmol) and benzene (10 ml) was stirred at 50EC under argon
atmosphere. It was then cooled and quenched with cold dilute hydrochloric acid (10 ml)
and extracted with ethyl acetate (2X2 0 ml). The organic layer was washed with water
(2X15 ml) followed by brine (10 ml), dried over sodium sulfate and concentrated under
reduced pressure. Purification by column chromatography over silica gel (eluent 8%, 10 %
acetone in petroleum ether) afforded pure compound of the formula (58) (0.180 gm, 66
%).
Spectral data of compound of the formula of structure (58)
H NMR (CDC13 + CCU) : 5 2.94 (bd, J = 18 Hz, 1H), 3.32 (dd, J= 18 Hz and 8
Hz, 1H), 3.76 (s, 6H), 3.88 (s, 6H),5.29-5.40 (m, 1H), 6.44 (s, 2H), 6.65-6.75 (m, 2H),
6.84 (bs, 1H)
Mass (m/z): 401 (M).
EXAMPLE 25
Preparation of compound of the formula (42) from the compound of the formula (40)
A mixture of compound of the formula (40) (O.lOOgm) and tetrahydro-furan-acetic
acid -water (3:1:1, 20 ml) was heated at 50EC for 20 hr. It was then neutralized by aq.
ammonia and extracted with ethyl acetate, dried over sodium sulfate, concentrated and
purified by column chromatography to yield pure compound of the formula (42) (0.070
gm, 77 %).
Spectral data of compound of the formula of structure (42)
!H NMR (CDC13 + CC14): 5 2. 68 (bd,J = 18 Hz, 1H), 3.00 (dd, J=18 Hz and 6 Hz,
1H) , 3.70 (s, 6H), 3.84 (s, 6H), 5.18 -5.35 (m, 1H), 6.43 (s, 2H), 6.62 -6.80 (m, 2H), 6.88
(bs, 1H).
EXAMPLE 26
In Vitro Cytotoxicity of the Cyclopentenone derivatives
A number of the cyclopentenone derivatives were tested for cytotoxicity against 9
human tumor cell lines. Briefly, a three day MTT cytotoxicity assay was performed,
which is based on the principle of uptake of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide), a tetrazolium salt, by the metabolically active cells where
it is metabolized by active mitochondria into a blue colored formazan product that is read
spectrophotometrically. MTT was dissolved in phosphate buffered saline with a pH of 7.4
to obtain an MTT concentration of 5mg/mi; the resulting mixture was filtered through a
0.22 micron filter to sterilize and remove a small amount of insoluble residue. For each
type of tumor cell, 10000 to 15000 cells were seeded in a 96-well culture plate and
incubated with the individual cyclopentenone derivatives in a C02 incubator for a total of
72 hours. Control cells not treated with the cyclopentenone derivatives were similarly
incubated. The assay was terminated by adding 100 ug (20 ul) of MTT to each well, then
incubating for additional one hour, and finally adding 50 ul of 10% SDS-0.01N HC1 to
each well to lyse the cells and dissolve formazan. After incubating for one hour, the plate
was read spectrophotometrically at 540 nm and the percentage of cytotoxicity calculated
using the following formula:
Cytotoxicity percentage = 100 x [l-(X/Ri)],
where X = (absorbance of treated sample at 540 nm) - (absorbance of blank at 540
nm)
RI = absorbance of control sample at 540 nm.
The EDso Values of the cytotoxicity defined as the concentration at which 50 % of
the cells are killed in vitro was calculated for each cell line treated with each of the
cyclopentenone derivatives.
The cell lines are PTC (all colon), MOLT-4 (leukemia), SW620 (ovary), DU145
(prostate), KB (oral squamous cell), LI32 (lung), MIAPaCa2 (Pancreas), Hep2, (larynx),
PA-1 (ovary), HuTuSO (duodenum), ECV 304 (endothelial), and 293 (kidney).
The ED5o values of hi vitro cytotoxicity of the cyclopentenone derivatives of this
invention are shown hi the Table 3.
(Table Remove)Example 27
The cyclopentenone derivatives were checked for their effects on tubulin
polymerization in vitro. Briefly, the tubulin assembly reaction was performed at 37°C in
buffer containing 80 mM PIPES, ImM EGTA, 1.0 mM GTP and ImM MgCl2 (pH 6.9) at
a tubulin concentration of Img/ml in the presence or absence of the cyclopentenone
derivatives. The final concentration of the cyclopentenone derivatives in the reaction
mixture varied from l-5uM. The derivatives were dissolved in 0.1% DMSO. The control
experiments were carried out with 0.1% DMSO. The tubulin polymerization was
followed by measurement of the absorbance of the solution at 340 nm every 30 seconds.
The IC50 values for the inhibition of Tubulin Polymerization by the cyclopentenone
derivative are shown in Table 4. As shown below the cyclopentenones derivatives
inhibited the Tubulin polymerization with IC50 values ranging from 1.4 -2.9uM in vitro.
Thus the cyclopentenone derivatives mediated their observed anticancer activities by
tubulin depolymerization.
EXAMPLE 28
Human squamous cell carcinoma (KB) were plated in a 25 cm2 flask. When
cultures achieved confluence, the cyclopentenone derivative of structure 20 was added to
the cells. The final concentration of derivative of the structure 20 in the flask was 5ug/ml.
The untreated wells served as controls. The cells were incubated with the drug for 2
different time points of 6 and 16 hours at 37°C. The cells were collected by centrifugation
at 2000 r.p.m. for 10 minutes. The supernatant was gently removed and discarded while
Lysis Buffer was added to the cell pellet (25ul of lysis buffer per 1x104 cells). The cell
lysate was incubated on ice for 10 minutes and centrifuged at 10,000-x g for 1 minute. The
supernatant was transferred to a new tube and kept on ice. 50ul of the cell lysate was
added in a 96 well plate. To this was added 2x Reaction Buffer. Prior to using reaction
35
buffer, l Oul of fresh DTT stock per 1 ml of 2x Reaction Buffer was added. To each well
5ul of Caspase-3 colorimetric substrate (DEVD-pNA) was added. The plate was
Incubated for 1-2 hours at 37EC. and read at 405nm.
The level of caspase enzymatic activity in the cell lysate is directly proportional to
the absorbance at 405nm. Table 5 shows the level of induction of Caspase 3 in KB cells
treated with one of the cyclopentenone derivatives.
EXAMPLE 29
Human endothelial cells (ECV304) were plated at the density of 8-10 xlO5 cells
per 2 ml in a six well plate. After an overnight incubation of cells at 37°C, cyclopentenone
derivatives at a concentration of 5ug/ml was added to the wells. The untreated wells
served as controls. The plates were incubated for 4 hours at 37°C. The medium was
collected from all the wells (control and treated) and spun down at 2000 r.p.m to remove
the cellular material. The supernatant was collected and used for ELISA (Quantikine
human VEGF, R&D Systems). The assay employs the quantitative sandwich enzyme
immunoassay technique. A monoclonal antibody specific for VEGF has been pre-coated
onto a microplate. Standards and samples were pipetted into the wells and VEGF present
was bound by the immobilized antibody. After washing away the unbound substances, an
enzyme-linked polyclonal antibody specific for VEGF was added to the wells. Following
a wash to remove any unbound antibody-enzyme reagent, a substrate solution was added
to the wells and color developed in proportion to the amount of VEGF bound in the initial
step. The optical density of each well was determined within 30 minutes using a
microplate reader set to 450nm and reference wavelength at 540nm.
The VEGF levels were inhibited by the addition of cyclopentenone derivatives in vitro.
36
The percent reduction in the inhibition of VEGF by the cyclopentenone derivatives is
shown in Table 6.
A PubMed search of the National Library of Medicine was carried out to determine
the relevance of cell lines used by us for determining the anticancer activity of the
peptides. While HT29 (human colon) showed 2021 "hits" when searched with reference to
cancer, other human cancer cell lines used by us also showed large number of hits (6848
for K562, 2532 for MOLT-4, 542 for DU145, 1063 for MCF-7, 542 for DU145 and 182
for PA-1). This clearly shows the extensive use of these cell lines in cancer research.
Further, it is a common and standard practice and norm for testing molecules for
anticancer activity in vitro on human tumor cell lines. (Br J Cancer. 2001 May 18;
84(10): 1289-90 (Flasks, Fibres and Flanks - Preclinical tumor models for predicting
clinical antitumor activity). The authors report that in vitro activity against 6 or more lung
or breast cancer cell lines does predict xenograft activity against these tumor types. In
articles "Semin Oncol 1992 Dec.; 19(6):622-38 (The National Cancer Institute: cancer
drug discovery and development program) and "Jpn J Antibiot 1977 Dec.;30 Suppl:35-40
(Antitumor screening procedures of the National Cancer Institute)" extensive use of
human tumor cell lines for identification of potential cytotoxic drugs is described."
EXAMPLE 30
In vivo anti-tumor activitv of compound of formula no. 49 on primary tumor (colon)
xenografted mice
PTC tumor xenografts were grown in Balb/c athymic mice by subcutaneous
inoculation of a single cell suspension of PTC cells (15 X 106 cells/100L). The tumor
bearing animals were divided into 2 groups of three animals each including one group
comprising untreated control animals. Treatment with compound of formula no. 49 was
initiated when the average tumor volumes, as measured using a vernier caliper, were
between 500 nun3. Compound of formula no. 49 was administered intravenously to the
assigned group of tumor bearing animals at a dose of 0.5 mg/100 uL once a day and the
treatment was continued for a period of 14 days.
The antitumor activity of the compound was monitored by measuring tumor
volumes every fourth day using the formula W*W*L*0.4 (W = smaller diameter, L =
larger diameter). The percentage inhibition of tumor growth was calculated using the
formula (1- tumor volume-treated / tumor volume-control) 100. Figure 1 shows the
tumor kinetics till day 23 in the treated and untreated animals. Compound of formula no.
49 showed significant antitumor activity on PTC xenografts. The percentage inhibition of
tumor growth caused compound of formula no. 49 as compared to controls on day 23 was
45.8%.

We claim:
1. Cyclopentenone derivatives of formula 1 having anti-tumor activity
(Formula Removed)

or salts thereof, wherein X is oxygen, hydroxyimino, alkoxyimino, aryloxyimino or arylimino; R is hydroxy, oxo, amino, alkylamino, hydroxyimino, alkoxyimino, aryloxyimino alkylcarbonyloxy, aroyloxy, alkoxy, methoxymethyloxy, 2-methoxyethoxymethyloxy, tert-butyldimethylsilyloxy, trimethylsilyloxy, carboxyl acid, carboxylate salt, or carboxylic acid ester; R1 R2 and R4 to R10 are the same or different and represent hydrogen, hydroxy, alkyl, alkoxy, methoxymethyloxy, 2-methoxyethoxymethyloxy, tert-butyldimethylsilyloxy, trimethylsilyloxy, chloro, fluoro, bromo, mcrcapto, alkylthio, nitro, amino, monoalkylamino, dialkylamino, azido, carboxyl, carbalkoxy, alkylcarbonyloxy, carboxymethyloxy, NHCOCH3, NHCOCF2, NH-alkyl, NH-dialkyl, CN, guanidine, NHCOOR11, CH2C=NR12 NR13; NHNH2, NHCONH2, NHHNCONH2, NHNHC(=S)NH2 and their salts; ; POP3H2, OPO3Na2, OPO3K2, SO2NH2, CONH-alkyl (preferably C1-C4), CHO, CH=NOH, or-KCH2-CH2-N[CH3])-fused at R8, R9 positions respectively, or methylenedioxy group fused in lieu of either Rs, R9, or R9, Rio position, respectively, and in the latter R8 is alkoxy and R11, R12, and R13, are selected from C1-C4 alkyl groups; and R3 is alkoxy.
2. Cyclopentenone derivatives as claimed in claim 1, wherein the cyclopenetenone is a c:yclopent-2-en-l-one derivative.

3. Cyclopentenone derivatives as claimed in claim 1, wherein the cyclopenetenone is a cyclopent-2-en-l-one derivative with R at C-4 position represented by formula (1A).

(Formula Removed)

4. Cyclopentenone derivatives as claimed in claim 1, wherein the cyciopenelenone is a cyclopent-2-en-l-one derivative with R at C-5 position represented by formula (IB).

(Formula Removed)

5. Cyclopentenone derivatives as claimed in claim 1, of the formula (20)

(Formula Removed)

and is 2-(3,4/5-trimethoxyphenyl)-3-(4-methoxyphenyl)-4-acetoxy-cyclopent-2-en-l-one oxime, and is 2,3-diphenyl-4-(tert, butyldimethysilyloxy)cyclopent-2-en-l-one.
6. Cyclopentenone derivatives as claimed in claim 1, having formula (39)
(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one.
7. Cyclopentenone derivatives as claimed in claim 1, having formula (40)

(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(3-methoxymethyloxy-4-methoxyphenyl)-4-(tert. Butyldimethysilyioxy)-cy- cyclopent-2-en-l-one oxime.

8. Cyclopentenone derivatives as claimed in claim 1, having formula (42)

(Formula Removed)

andis2-(34,5-trimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)-4-hydroxy-cyclopent-2-en-l-one oxime.
9. Cyclopentenone derivatives as claimed in claim 1, having formula (48)
(Formula Removed)

and is2-(3,4,5-trimethoxyphenyl)-3-(4-methoxyphenyl)-5-hydroxy-cyclopent-2-en-l-one.
10. Cyclopentenone derivatives as claimed in claim 1, having formula (49)
(Formula Removed)

andis2-(3,4,5-trimethoxyphenyl)-3-(4-methoxyphenyl)-5-hydroxy-cyclopent-2-en-l-
one oxime.
11. Cyclopentenone derivatives as claimed in claim 1, having formula (52)

(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(4-methoxyphenyl)-5-(tert. Butyldimethysilyloxy)-cyclopent-2-en-l-one.
12. Cyclopentenone derivatives as claimed in claim 1, having formula (53)

(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(4-methyphenyl)-5-acetoxy-cyclopent -2-en-l-one.

13. Cyclopentenone derivatives as claimed in claim 1, having formula (54)

(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(4-methoxyphenyl)-5-acetoxy-cyclopent -2-en-l-
one oxime.
14. Cyclopentenone derivatives as claimed in claim 1, having formula (55)

(Formula Removed)


and is 2-(3A5-trirnemoxyphenyl)-3-(4-memylsulphanylphenyl)-5-(tert.Butyldimethy silyloxy)-cyclopent -2-en-l-one.
15. Cyclopentenone derivatives as claimed in claim 1, having formula (56)

(Formula Removed)

and is 2-(3,4,5-ttimethoxyphenyl)-3-(3-isopropyloxy-4-methoxyphenyl)-5-(tert. butyldimethysilyloxy-cyclopent-2-en-l-one
16. Cyclopentenone derivatives as claimed in claim 1, having formula (59)
(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(3-isopropyloxy-4-methoxyphenyl)-5-acetoxy cyclopent-2-en-l-one acetoxy-limine.

17. Cyclopentenone derivatives as claimed in claim 1, having formula (60)

(Formula Removed)

and is 2-(3-anTLno-4-methosyphenyl-3-(3,4,5-trimethoxyphenyl)-5-hydroxycyclopent-2-en-1-one.
18. Cyclopentenone derivatives as claimed in claim 1, having formula (63)

(Formula Removed)
and is 2-(3,4,5-trimethoxyphenyl)-3-(3-chloro-4-methoxyphenyl)-5-hydroxycyclopent-2-

en-l-one oxime.

19. Cyclopentenone derivatives as claimed in claim 1, having formula (64)

(Formula Removed)


andis2-(34,5-trirnethoxyphenyl)-3-(3-fluoro-4-methoxyphenyl)-5-hydroxycyclopent-2-en-l-one.
20. Cyclopentenone derivatives as claimed in claim 1, having formula (65)
(Formula Removed)

andis2-(3,4,5-trimethoxyphenyl)-3-(3-fluoro-4-methoxyphenyl)-5-acetoxycyclopent-2-en-l-one.
21. Cyclopentenone derivatives as claimed in claim 1, having formula (66)
(Formula Removed)

andis2-(3,4,5-trimethoxyphenyl)-3-(3-fluoro-4-methoxyphenyl)-5-hydroxycyclopent-2-en-one-oxime.

22. Cyclopentenone derivatives as claimed in claim 1, having formula (67)
(Formula Removed)

and is 2-(3,4/5-trimethoxyphenyl)-3-(3-chloro-4-methoxyphenyl)-5-hydroxycyclopent-2-en-l-one.
23. Cyclopentenone derivatives as claimed in claim 1, having formula (70)

(Formula Removed)


and is 2-(34,5-trimethoxyphenyl)-3-(3-chloro-4-methoxyphenyl)-5-acetoxycyclopent-2-en-l-one oxime.

24. Cyclopentenone derivatives as claimed in claim 1, having formula (71)

(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)-5-acetoxycyclopent-2-en-l-one
25. Cyclopentenone derivatives as claimed in claim 1, having formula (72)
(Formula Removed)

and is 2-(3,4,5-tiimethoxyphenyl)-3-(3-acetarnido-4-methoxyphenyl)-5-hydroxycyclo pent-2-en-l-one

26. Cyclopentenone derivatives as claimed in claim 1, having formula (73)
(Formula Removed)

and is 2-(3,4,5-trimethoxyphenyl)-3-(3-acetamido-4-methoxyphenyl)-5-hydroxycyclo pent-2-en-l-one oxime.

27. Cyclopentenone derivatives as claimed in claim 1, having formula (75)
(Formula Removed)
i

28. Cyclopentenone derivatives as claimed in claim 1, of the Formula 1A, wherein R1, R5
and R10 are hydrogen R3 is OMe and R, R2, R4, R6, R7, R8, R9, and X are as follows.
(Table Removed)

where OMOM represents methoxymethyloxy.
29. Cyclopentenone derivatives as claimed in claim 1, of the Formula 1B wherein R1, R5 R6 and R1o are hydrogen R3 is OMe and R, R2, R4, R7, R8, R9, and X are as follows.
(Table Removed)

where OiPr represents isopropyloxy.
30. A composition whenever comprising cyclopentenone derivatives of formula (1) as claimed in claims 1-29 for the treatment of carcinoma of the colon, pancreas, larynx, ovary, duodenum, kidney, oral cavity, prostate, lung, or endothelial cells or leukemia .