FIELD OF INVENTION
The present invention relates to a novel compound, which may be used as a hair growth
stimulant and a method for synthesis of the compound and composition comprising the same.
BACKGROUND OF THE INVENTION
Dermatologists recognize different types of hair loss. The most common, by far, being
alopecia, wherein human males begin loosing scalp hair at the temples and on the crown of
the head as they get older while this type of hair loss is largely confined to males, loosing hair
is not uncommon to both sexes. Hair loss is induced by various causes, for example, reduced
functions of hair due to male hormones, reduced metabolic activity of hair roots, reduced
physiological activity of the scalp, local disorders of blood circulation due to abnormal
conditions of the scalp impeding hair growth, which results from decrease in the amount of
blood flowing through the head. Some hair loss is also considered to be genetic in nature and
certain genes are expressed in relation to age, stress, environmental factors and the like.
Recently, several anti-alopecia agents such as minoxidil and cyoctol have gained attention.
However, most of these anti-alopecia agents are only minimally effective in some cases
and/or can cause adverse dermatological or systemic reactions. Minoxidil for instance, is a
therapeutic anti-hypertensive and may cause adverse effects when observed through skin.
There are certain compositions that are obtained from natural resources. However, the
efficiency of such compositions is not proven. Hence, there is a need for a new, safe and
more effective anti-alopecic agent, which can be used without the risk of undesirable side
effects.
Prostaglandins play a vital role in the growth of hair. Prostaglandins are generally present in
the human body as Prostaglandin synthase-1 (PGHS-1) and its inducible form (PGHS-2).
Certain hair growth promoters such as minoxidil have been reported to increase the product
of Prostaglandin E-2. Certain other molecules such as latanoprost, are selective FP Prostanoid
receptor agonist, indicated for glaucoma has a hypertrichotic effect. Application of this
compound in the scalp has been reported to increase the hair growth and the increased length
of lashes on application of latanoprost in the eye demonstrates the capability of this molecule
to prolong the anagen phase of hair cycle. Latanoprost and other prostanoid receptor agonists
have been reported to have side effects, including hypertrichosis and hyper-pigmentation of
3
the eye lashes and peri-occular skin and occasionally psoriasis. Hence, the use of latanoprost
as a topical applicant is not popular.
Certain other compounds such as finasteride, dutasteride are known 5-alpha reductase
inhibitors and such inhibitors have been known to promote the conversion of hairs into the
anagen phase and thereby promote their growth. However, there has been an increasing
concern about permanent sexual adverse effect such as impotence and infertility with use of
these drugs. Several flavonoids, that are naturally found, also possess 5-alpha reductase
inhibitory activity. Flavonoids such as myricetin, quercitin, baicalein and fisetin, Biochanin
A, daidzein, genistein, and kaempferol, all are reported to have 5-alpha reductase activities
and are useful as hair growth promoters, however, the use of the flavonoids alone does not
provide a satisfactory end result.
Hence, there is a need for a novel molecule to provide effective treatment for the stimulation
of hair growth and treatment of hair loss.
OBJECT OF THE INVENTION
An object of the invention is to provide a novel compound for effective treatment of
stimulation of hair growth and prevention of baldness.
SUMMARY OF THE INVENTION
The present invention provides a novel compound of formula (I):
Formula I
HO
R3
COOR5
R2
(CH2)n
R4
R1
4
wherein
is either a single bond or a double bond;
R1 is selected from the group comprising 5 or 6 membered carbocyclic or heterocyclic
or aryloxy or fused ring systems, wherein each ring of fused ring system comprises 6-
10 carbon atoms; the heterocyclic ring comprises 2 to 4 heteroatoms such as O, N or
S; the ring may be further substituted by a group selected from halogen, C1 to C3
halocarbon, C1 to C3 alkoxy or C1 to C3 alkyl group;
R2 and R3 are independently selected from the group comprising carbonyl or
hydroxyl;
n is from 1 to 10;
R4 is selected from the group comprising C1 to C4 alkyl;
R5 is selected from the group comprising iso-flavone, flavone preferably biochanin A,
formononetin, genistein, genistin, daidzein, daidzin, pratensein, pectolinarigenin,
calycosin.
The present invention also provides a process for the preparation of a novel
compound of Formula I comprising the steps of:
i. solubilizing the compound of Formula II in a solvent;
Formula II
wherein
5
is either a single bond or a double bond;
R1 is selected from the group comprising 5 or 6 membered carbocyclic or heterocyclic
or aryloxy or fused ring systems, wherein each ring of fused ring system comprises 6-
10 carbon atoms; the heterocyclic ring comprises 2 to 4 heteroatoms such as O, N or
S; the ring may be further substituted by a group selected from halogen, C1 to C3
halocarbon, C1 to C3 alkoxy or C1 to C3 alkyl group;
R2 and R3 are independently selected from the group comprising carbonyl or
hydroxyl;
n is from 1 to 10;
R4 is selected from the group comprising C1 to C4 alkyl;
ii. esterification of compound of Formula II and R5 in equimolar quantity in the
presence of an acid catalyst to obtain esterified product ; and
iii. isolating the esterified product to obtain the compound of Formula I.
Further, the present invention provides a pharmaceutical composition comprising compound
of Formula I along with pharmaceutically acceptable excipients and use of compound and
composition for prevention of hair fall and restoration of hair growth cycle.
BRIEF DESCRIPTION OF FIGURES:
Figure 1 depicts aliphatic esterase activity of skin extracts
Figure 2 depicts heat induced inactivation of aliphatic esterase activity of skin extracts
Figure 3 depicts aromatic esterase activity of skin extracts
Figure 4 depicts de-esterification activity of esterase
Figure5 Representative extracted ion chromatograms resulting from the analysis of (a)
blanks, (b) GF2alpha derivative and (c) biochanin
Figure6 Representative MRM chromatograms resulting from the analysis of (a) blank, (b)
Extracted ion chromatogram (overlay) of PGF2alpha derivative (1) and biochanin (2)
Figure7 Representative MRM chromatograms resulting from the analysis of (a) blank and
(b) Extracted ion chromatogram of C101
Figure 8 Representative extracted ion chromatograms of prostaglandin and Biochanin and
C101 levels found in rabbit skin after 18hrs. (a) composition A treated skin; (b) composition
B treated skin
Figure9 FTIR of C101
6
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel compound of Formula-I as hair growth stimulant.
For the purposes of the present invention, it is submitted that the novel compound of
Formula-I, is capable of stimulating hair growth and also preventing and reversing already
lost hair and baldness. All hair, both human and animal passes through a life cycle that
includes three phases, namely, anagen phase, categen phase and the telogen phase. The
anagen phase is the period of active hair growth and the categen phase is a transition phase
between anagen and telogen phase and the final phase, the telogen phase is the resting phase
where all growth ceases and the hair eventually is shed before the follicle grows a new hair.
Generally, it is said that in a scalp around 80% of the hairs are in anagen phase and 1% is in
categen phase and the remainder is in telogen phase. During extensive hair loss, most of the
hair follicles are in the telogen phase and it is in the interest of the subject that the hair growth
stimulant should either activate the anagen phase and/or shift the number of follicles in the
telogen phase to the anagen phase.
The present invention provides a novel compound of formula (I) as a hair growth restorant
and stimulator.
Formula I
wherein
is either a single bond or a double bond;
HO
R3
COOR5
R2
(CH2)n
R4
R1
7
R1 is selected from the group comprising 5 or 6 membered carbocyclic or heterocyclic
or aryloxy or fused ring systems, wherein each ring of fused ring system comprises 6-
10 carbon atoms; the heterocyclic ring comprises 2 to 4 heteroatoms such as O, N or
S; the ring may be further substituted by a group selected from halogen, C1 to C3
halocarbon, C1 to C3 alkoxy or C1 to C3 alkyl group;
R2 and R3 are independently selected from the group comprising carbonyl or
hydroxyl;
n is from 1 to 10;
R4 is selected from the group comprising C1 to C4 alkyl;
R5 is selected from the group comprising iso-flavone, flavone preferably biochanin A,
formononetin, genistein, genistin, daidzein, daidzin, pratensein, pectolinarigenin,
calycosin.
The present invention also provides a process for the preparation of a novel
compound of Formula I comprising the steps of:
i. solubilizing the compound of Formula II in a solvent;
Formula II
wherein
is either a single bond or a double bond;
8
R1 is selected from the group comprising 5 or 6 membered carbocyclic or heterocyclic
or aryloxy or fused ring systems, wherein each ring of fused ring system comprises 6-
10 carbon atoms; the heterocyclic ring comprises 2 to 4 heteroatoms such as O, N or
S; the ring may be further substituted by a group selected from halogen, C1 to C3
halocarbon, C1 to C3 alkoxy or C1 to C3 alkyl group;
R2 and R3 are independently selected from the group comprising carbonyl or
hydroxyl;
n is from 1 to 10;
R4 is selected from the group comprising C1 to C4 alkyl;
ii. esterification of compound of Formula II and R5 in equimolar quantity in the
presence of an acid catalyst to obtain esterified product ; and
iii. isolating the esterified product to obtain the compound of Formula I
HO
R3
COOH
R2
(CH2)n
R4
R1
Esterification
HO
R3
COOR5
R2
(CH2)n
R4
R1
+ R5
isolation
Formula II Formula I
Without being limited by theory, the compound of Formula I of the present invention is a
novel compound obtained by the formation of a chemical ester bond between prostaglandin
compound of Formula II and isoflavone or flavone of R5. It is purposed that the compound of
Formula I on administration will release compound of Formula II and isoflavone or flavones
of R5. Both the isoflavone or flavone and the prostaglandin, act on stimulating the hair growth
through different pathways, hence, the novel compound of the present invention is expected
to act synergistically to enable topical application for the promotion of hair growth.
The compounds of Formula I of the present invention are illustrated below at Table 1
9
Table 1: Illustrative compounds of Formula I of the present invention
No. IUPAC name Structure
C101
(Z)-5-hydroxy-3-(4-methoxyphenyl)-4-
oxo-4H-chromen-7-yl 7-((1R,2R,3R,5S)-
3,5-dihydroxy-2-((R)-3-hydroxy-5-
phenylpentyl)cyclopentyl)hept-5-enoate
C102
(Z)-5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-
4H-chromen-7-yl 7-((1R,2R,3R,5S)-3,5-
dihydroxy-2- ((R)-3-hydroxy-5-
phenylpentyl)cyclopentyl)hept-5-enoate
C103
(Z)-3-(4-hydroxyphenyl)-4-oxo-4Hchromen-
7-yl 7-((1R, 2R, 3R, 5S)-3, 5-
dihydroxy-2- ((R)-3- hydroxy-5-
phenylpentyl) cyclopentyl) hept-5-enoate
Further, compounds of Formula (II) of the present invention are illustrated below at Table 2.
The compounds illustrated at table 2 are capable of formation of an ester bond at the free
carboxyl group by interacting with a compound of R5 preferably at the hydroxyl group.
Table 2: Illustrative compounds of Formula (II) of the present invention
No. IUPAC name Structure
A201
(Z)-7-((1R,2R,3f, R,5S)-3,5-dihydroxy-
2-((S,E)-3-hydroxy-4-phenylbut-1-en-
1-yl)cyclopentyl)hept-5-enoic acid
10
A202
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A203
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((E)-3-oxo-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A204
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((R,E)-3-hydroxy-4-phenoxybut-1-en-
1-yl)cyclopentyl)hept-5-enoic acid
A205
(Z)-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-
3-hydroxy-5-phenylpent-1-en-1-yl)-5-
oxocyclopentyl)hept-5-enoic acid
A206
(Z)-7-((1R,2R,3R)-3-hydroxy-2-((R)-3-
hydroxy-5-phenylpentyl)-5-
oxocyclopentyl)hept-5-enoic acid
11
A207
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((R,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
HO
HO
COOH
HO
A208
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(4-
methoxyphenyl)pent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A209
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((R)-3-hydroxy-5-
phenylpentyl)cyclopentyl)hept-5-enoic
acid
A2010
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S)-3-hydroxy-6-
phenylhexyl)cyclopentyl)hept-5-enoic
acid
12
A2011
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S)-3-hydroxy-7-
phenylheptyl)cyclopentyl)hept-5-enoic
acid
A2012
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S)-3-hydroxy-8-
phenyloctyl)cyclopentyl)hept-5-enoic
acid
A2013
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S)-3-hydroxy-12-
phenyldodecyl)cyclopentyl)hept-5-
enoic acid HO
HO
COOH
OH
A2014
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((R)-3-hydroxy-5-(thiophen-2-
yl)pentyl)cyclopentyl)hept-5-enoic acid
A2015
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((R)-3-hydroxy-5-(thiophen-3-
yl)pentyl)cyclopentyl)hept-5-enoic acid
13
A2016
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((3S,5R,E)-3-hydroxy-5-phenylhex-1-
en-1-yl)cyclopentyl)hept-5-enoic acid
A2017
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((3S,5S,E)-3-hydroxy-5-phenylhex-1-
en-1-yl)cyclopentyl)hept-5-enoic acid
A2018
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(4-
(trifluoromethyl)phenyl)pent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A2019
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((E)-3-oxo-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A2020
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(p-tolyl)pent-1-en-
1-yl)cyclopentyl)hept-5-enoic acid
14
A2021
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(o-tolyl)pent-1-en-
1-yl)cyclopentyl)hept-5-enoic acid
A2022
(Z)-7-((1R,2R,3R,5S)-2-((S,E)-5-(4-
fluorophenyl)-3-hydroxypent-1-en-1-
yl)-3,5-dihydroxycyclopentyl)hept-5-
enoic acid
A2023
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-9-phenylnon-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A2024
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(naphthalen-1-
yl)pent-1-en-1-yl)cyclopentyl)hept-5-
enoic acid
A2025
(Z)-7-((1R,2R,3R,5S)-2-((S,E)-5-
cyclohexyl-3-hydroxypent-1-en-1-yl)-
3,5-dihydroxycyclopentyl)hept-5-enoic
acid
15
A2026
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(4-
methoxyphenyl)pent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A2027
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-(3-
methoxyphenyl)pent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A2028
(Z)-7-((1R,2R,3R,5S)-2-((S,E)-3-
cyclohexyl-3-hydroxyprop-1-en-1-yl)-
3,5-dihydroxycyclopentyl)hept-5-enoic
acid
A2029
(Z)-7-((1R,2R,3R,5R)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
A2030
(Z)-7-((1R,2R,3S,5S)-3,5-dihydroxy-2-
((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid
16
The preferred prostaglandin derivatives are included herein. The omega chain of
prostaglandin has the 18, 19, 20 trinor form and especially includes the 17 phenyl analogs,
such as the 15-(R)-, 15-dehydro and 13, 14-dihydro-17-phenyl-18, 19, 20-trinor forms. In the
Formula-II given above, the preferred prostaglandin is 13-14 dihydro-15-dehydro-17-phenyl-
18, 19, 20-trinor-PGF2α isopropyl ester, also known as latanoprost and sold under the name
Xalatan by Pharmacia and Upjohn Company.
R5 is a flavone or isoflavone which may comprise an O-methylated isoflavone, and the Omethylated
isoflavone may comprise at least one compound selected from the group
comprising biochanin A, calycosin, formononetin, pratensein, and any combination thereof.
In an embodiment, the isoflavone is selected from the group comprising biochanin A,
formononetin, genistein, genistin, daidzein, daidzin, pratensein, pectolinarigenin, calycosin.
Without being limited by theory, isoflavones or phytoestrogens are plant-based compounds
that produce estrogen-like effects in the human body. O-methylated isoflavones or methoxy
isoflavones comprise isoflavones with methylations on hydroxyl (-OH) groups, i.e., methoxy
(-OCH3) groups. The presence of the methoxy groups has an effect on the solubility of the
isoflavones, e.g., the O- methylated isoflavones are less soluble in water than the isoflavones
with similar structure but lacking the methoxy groups. Such soluble iso-flavones are
preferred compounds within the scope of this invention.
The process of the present invention involves the solubilization of the compound of formula
II in a solvent followed by esterification of compound of Formula II and R5 in equimolar
quantity using an acid catalyst to get an esterified product and then further isolating the
esterified product from the solution to obtain the compound of Formula I. The solvent is
selected from the group comprising dichloromethane, 2-Methyltetrahydrofuran, hexane,
toluene, diethyl ether and the acid catalyst is selected from the group comprising hydrochloric
acid, sulfuric acid, tosic acid.
In one embodiment, the present invention provides a pharmaceutical composition comprising
compound of Formula I along with pharmaceutically acceptable excipients.
The composition comprising the novel compound of the present invention may be applied
topically. The topical form of the composition includes a solution, gel, lotion, cream,
17
ointment, oil-in-water emulsion, water-in-oil emulsion, stick, spray, aerosol, paste, mousse,
tonic, liposome or other cosmetically and topically suitable form, and the like, and may be
applied in patches or impregnated dressings or by spraying, dabbing, swabbing, rubbing, or
combinations thereof on the part of the body to be treated.
The compound of the present invention may also be present in concentrated form as
previously described herein and may be added to any shampoo, conditioner, styling product,
or any other suitable hair care composition that is commercially available or commonly used.
For example, the compound may be mixed with fatty acid esters of sorbitol and sorbitol
anhydrides (e.g., polysorbates). These compounds have nonionic properties that inhibit
shedding of hair. Without being limited by theory, polysorbates are nonionic surfactants
obtained by esterification of sorbitol with one or three molecules of a fatty acid (e.g. stearic,
lauric, oleic, palmitic, etc.).
The compound and/or composition may be topically administered on a daily basis or twice
daily basis for a period of time sufficient to bring about the desired level of improvement in
modulation of hair growth or re-growth. For example, a user may topically administer
directly to a balding area or other area where increased hair growth is desired by gently
massaging the composition of the present invention into the desired area. This process may
be repeated later the same day. The composition may be left on the scalp or other area where
increased hair growth is desired between applications occurring on the same day or on
different days.
The present invention finds application in all mammalian species, including both humans and
animals. In humans, the compounds of the subject invention can be applied for example, to
the scalp, face, beard, head, upper lip, eyebrows and eyelids. In animals raised for their pelts,
e.g., mink, the compounds can be applied over the entire surface of the body to improve the
overall pelt for commercial reasons. The process can also be used for cosmetic reasons in
animals, e.g., applied to the skin of dogs and cats having bald patches due to mange or other
diseases causing a degree of alopecia.
The compound of the present invention may remain on the scalp for a period of time of about
1 week, alternatively about 1 day, alternatively about 12 h, alternatively about 4 h,
alternatively about 1 h, alternatively about 30 min, alternatively about 5 min, or alternatively
18
about 1 min. The compound and/or the composition may be removed at any desired point in
time by washing and/or rinsing the scalp.
The compound of the present invention may continue for any suitable period of time. For
example, within a few weeks to a few months of the initial application, a user may notice a
reduction in hair loss and/or an increase in hair growth or regrowth. It should be appreciated
that the frequency of application will vary depending on the desired effect.
The composition for the treatment of hair loss such as that of the present invention may be
advantageously used to diminish hair loss and/or promote hair growth and/or regrowth. For
example, as disclosed herein, a composition for the treatment of hair loss such as CTHL may
diminish and/or stop hair loss in a time period of from about 7 days to about 80 days,
alternatively from about 10 days to about 28 days, or alternatively from about 14 days to
about 21 days. The compound of the present invention may advantageously regrow hair in a
time period of from about 4 weeks to about 20 weeks, alternatively from about 6 weeks to
about 16 weeks, or alternatively from about 8 weeks to about 12 weeks.
The compound of the present invention may advantageously diminish and/or stop the itching
of the scalp when topically applied to the scalp, which may be due in some embodiments to
the use of an alcohol free carrier fluid along with one or more optional ingredients.
The compound of the present invention may advantageously promote hair growth from
dormant and/or injured hair follicles, e.g., may have a rejuvenating effect on the hair follicles.
However, if the hair follicle is dead, it is believed that the hair follicle cannot become
functional again.
Without being limited by theory, biochanin A is believed to negatively regulate
dihydrotestosterone (DHT) levels, and consequently to positively regulate hair growth by
inhibiting the activity of 5ot-reductase, an enzyme responsible for converting testosterone to
DHT. An increased level of DHT is associated with alopecia (i.e., hair loss) in men, and to
some extent, in women. The inhibitory effect of biochanin A on 5ot-reductase is described in
more detail in J. Endocrinology (1995), volume 147(2), pages 295-302, which is incorporated
by reference herein in its entirety.
19
EXAMPLES:
Example 1: Preparation of skin extracts.
Rabbit’s abdominal skin is harvested and 0.5g is weighed and placed in 5ml of buffered
saline. It is then homogenized using tissue homogenizer under ice cold conditions. It is then
subjected to centrifugation at 10000 RPM for 20 minutes in a cold centrifuge. The skin
supernatant is subjected for analysis as per further examples below using the said extracts.
Example 2: Determination of aliphatic esterase activity of the skin extract using
prostaglandin ester probe.
50μl to 50 mg/ml of sample prostaglandin ester probe (Fig. 1) having aliphatic ester
(2.5mcg) is added to 250μl of rabbit abdominal skin extract and incubated at 37 ºC for the
duration of 6 h in a carbon-di-oxide incubator. A 50μl of aliquot is collected at various time
points (0, 30, 60, 120, 240, 360 min). Immediately after the removal of 250μl of extraction
solvent i.e. 80% ACN with sulpha-di-methoxine as internal standard is added to stop the
reaction. It is vortexed for 2 minutes and subjected to centrifugation to remove the
supernatant quantified for the content latanoprost using LC-MS/MS. Control samples are
processed in the same way except replacing skin extract with distilled water.
This experiment shows the de-esterification of the prostaglandin leading to the loss of probe
concentration up to 96% within 30 minutes of incubation with skin extract (Figure.1)
Example 3: Inability of heat deactivated skin extract on the de-esterificaiton of aliphatic
prostaglandin ester probe.
Known amount of aliphatic ester derivative PG-F2 alpha is incubated with the heat
deactivated rat skin extract (deactivating by heating the extract for a period of 15 min. at 95⁰
C) for the period of one hour. For comparison control samples use methanolic solution to
avoid any degradation. This study shows the lack of degradation of the probe at the
concentrations varying from 125ng to 1 mg. The extraction efficiency of the method is
attributed to 80% in lower concentrations as shown in the figure 2.
This study shows the lack of degradation (up to 96% within 30min as noticed by Exp 1) after
deactivation of skin esterases.
20
Example 4: Determination of aromatic esterase activity of the skin extract using
prostaglandin ester probe
In order to validate the data for aromatic esterase activity in the skin extract a test probe 2
(MEM)-morpholinoethyl ester of mycophenolic acid (Fig.4) chemically (4E)-6-(4-Hydroxy-
6-methoxy-7-methyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid is
used. Skin extract as per Example 1 is used for the incubation of MEM at the concentration of
10μg/ml for 4 hrs. The incubation is stopped by the addition of acetonitrile and the mixture
is vortexed and centrifuged to get the clear supernatant.
The clear supernatant is subjected for gradient HPLC with the identification of molecular
spectrum using IDA protocol of the tandem mass spectroscopy.
The result clearly shows that the esterases are non-specific towards aliphatic or aromatic
linkage and are capable of cleaving the linkage in de-esterification process (Fig-3).
Example 5:
The above experiment is repeated for aromatic esterase activity in the skin extract a test probe
2 (MEM)-morpholinoethyl ester of mycophenolic acid (Fig.4). Chemically (4E)-6-(4-
Hydroxy-6-methoxy-7-methyl-3-oxo-1, 3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic
acid is used. Skin extract as per Example 1 is used for the incubation of MEM at the
concentration of 70ngs for the period of 4 hrs. Periodical sampling is carried out and the
incubation is stopped by the addition of acetonitrile along with internal standard and the
mixture is vortexed and centrifuged to get the clear supernatant. The supernatant is subjected
for the quantification of MEM.
This experiment shows that the esterases are capable of reducing the molecular weight of
MEM along with time (Fig 4) and at the end of 4 hrs almost 80% of the probe is de-esterified.
Example 6: Preparation of linkage between prostaglandin and flavonoid
A prototype prostaglandin acid is esterified with a flavonoid and its property to increase the
lipophilicity is calculated using CACHE software on appropriate 3D platform. Individually
the compound part A substituted with phenyl ring and part B substituted at 6 with –OH and at
4’ with OCH3 is subjected for linkage through ester bond by the elimination of water
molecule. The resultant molecule is subjected for the analysis of molecular characteristics to
list the effect on logP value as represented at Example 10 and Table 3.
21
Example 7: Synthesis of novel compound C101 of Formula I
Scheme 1
Prostaglandin F2 alpha with free carboxylic group (A209) is dissolved in dichloromethane
(DCM) and added with equimolar quantity of biochanin A (B301) i.e. (A209) of equimolar
quantity is added with 0.1 equivalent of (B301). The resulting reaction mixture is vortexed
and is kept overnight at room temperature. The esterified final product is isolated as a white
precipitate. The precipitate is washed three times with (DCM) and the final product is
obtained after the removal of DCM under vacuum. The product is again washed with 0.1M
HCl to remove catalysts and the other water soluble impurities. This process yields the final
product C101 and yield varies from 50-60%.
22
Example 8: Synthesis of novel compound C102 of Formula I
Scheme 2
The compound of Formula (C102) is synthesized as per procedure of Example 7, but using
different starting material as in scheme 1. The compound of formula (A209) is esterified with
compound B302 to obtain the compound (C102). This process yields the final product C102
and FTIR is represented at Figure 9. The yield varies from 60-70%.
23
Example 9: Synthesis of novel compound C103 of Formula I
Scheme 3
The compound of Formula (C103) is synthesized as per procedure of example 7, but using
different starting material as in scheme 1. The compound of formula (A209) is esterified with
compound B303 to obtain the compound (C103). This process yields the final product C103
and yield varyies from 60-70%.
24
EXAMPLE 10: Determination of various parameters of the compound of the present
invention
Various parameters of the compound of the present invention are tested and compared with
prostaglandin and biochanin
The parameters of the reactants prostaglandin (part A) and biochanin (part B) and final
product (C101) are in the table 3.
Table-3: Various parameters of the reactants and final product
Parameters Part A (mean) Part B (mean) Final compound
Log P 2.2 3.14 5.85
Mass (Avg) 390.51 284.26 658.7
Density 1.159 1.42 1.251
Polarizability (x 10-
24cm3)
43.43± 0.5 29.59±0.5 71.64 ±0.5
Surface tension
(dyne/cm)
50 ± 3 63.4 56± 3
Molar volume (cm3) 336.7 ± 3 200.1±3 526.2± 3
Based on such comparison, it can be seen that the formula C101 has higher logP than the
compounds part A and Part B and hence increased lipophilicty value of C101 enabling its
retention in the skin and releases its part A and B upon the action of esterases.
EXAMPLE: 11 Comparison of composition of the present invention with the
composition of the prior art
The composition of the individual compounds of the Prostaglandin and biochanin is made
according to the composition A presented at Table 4.
25
Table 4: Composition of composition A
S.
No. Ingredient For 100ml
1
PGF2 alpha
derivative
3.2mg
(0.0032%w/v)
2 Flavone
4.4mg
(0.0044%w/v)
3 Isopropyl myristate 10ml
4 Kernel oil 20ml
5 Isopropyl alcohol 70ml
Further, the composition comprising the compound C101 of the present invention is made
according to composition B presented at Table 5.
Table 5: Composition of composition B
S.
No. Ingredient For 100ml
1 C101
7.6mg
(0.0076%w/v)
2 Isopropyl myristate 10ml
3 Kernel oil 20ml
4 Isopropyl alcohol 70ml
Both the compositions are compared in various studies as set out below:
(a) Evaluation of delivery volume per spray
Both compositions A and B are transferred to 50ml spray bottle and delivery volume is
measured by gravimetric analysis. The pumps of spray bottles containing composition A and
B are activated by spraying 3 times. After getting activated, the compositions are sprayed 3
times in pre-weight glass bottle and delivered weights are calculated.
I) Animal experiment
New Zealand albino rabbits of either sex weighing 1.5–2.0 kg are used for the study. The
rabbits are maintained with standard fresh diet in a light and dark cycle. In each rabbit, hair
removal cream is applied on the abdominal skin (5x5cm) and after 7-9 minutes hair is
26
removed using plastic scalpel. The skin is wiped with 70%v/v alcohol. 24 hrs later they are
subjected for the present study. Composition A and B are applied (one spray per rabbit; n=3).
After 18 hours, the rabbits are sacrificed and the skin is excised. The skin tissues are kept at -
20°C until analysis.
A) LC-MS/MS bio-analytical method for PGF2alpha derivative and biochanin and
C101
Instrumentation
UHPLC-MS/MS experiments are performed using a triple quadrupole tandem mass
spectrometer (4000 Q-Trap, AB Sciex, Foster City, CA, USA) coupled with ultrahigh
performance liquid chromatography system (UHPLC, Accela, Thermo Electron Corp,
Waltham, MA, USA) connected with a photodiode array detector, autosampler and online
degasser. All the parameters of tandem mass spectrometer and UHPLC are controlled by
Analyst software, version 1.5.2 (AB Sciex, Foster City, CA, USA) and ChromQuest
software, version 4.5 (Thermo Fisher, Waltham, MA, USA), respectively.
B) LC-MS/MS bio-analytical method for PGF2alpha derivative and biochanin
Chromatographic separation is done using Purospher star C18 column (55 x4 mm, 3.5 μm,
Merck, Darmstadt, Germany). An isocratic method is used for quantification of PGF2-alpha
derivative and flavones (biochanin). Mobile phase consisting of (solvent A; 45%) 5mM
Ammonium acetate with 0.1%formic acid (FA) and (solvent B; 55%) Acetonitrile with
0.1%FA. The mobile phase is pumped at a flow rate of 0.5ml/min. Ten microlitre of sample
is injected into UHPLC every time for standards and samples.
Electrospray ionization in negative ion mode for the analytes is optimized using Turbo Ion
Spray source (AB Sciex, Foster City, CA, USA). Compound dependent parameters for each
analyte such as Declustering Potential (DP), Entrance Potential (EP), Collision Energy (CE)
and Cell Exit Potential (CXP) are manually optimized by infusing individual standard
solutions at 100 ng/mL into the ion source of the mass spectrometer at a flow rate of
10μL/min using a Harvard pump (Harvard Company, Reno, NV, USA) connected with a
Hamilton syringe (Holliston, MA, USA). Compound dependent parameters for each analyte
are given in the table 6. Source dependent parameters are optimized: curtain gas (20 psi); ion
spray voltage (5000 eV), temperature (500°C), gas 1 (30 psi) and gas 2 (60 psi). The dwell
27
time for each MRM transition is set at 100ms. Multiple Reaction Monitoring (MRM) mode
are used for quantification of PGF2 alpha derivative and biochanin as given in table 6.
Table 6: Optimized chromatography conditions of PGF2alpha derivative and biochanin
Time
(min)
Solvent A*
(%)
Solvent B*
(%)
Flow rate
(mL/min)
0.0 45.0 55.0 0.5
4.0 45.0 55.0 0.5
Table 7: MRM transitions, retention time and optimized ESI-MS/MS parameters of
PGF2 alpha derivative and biochanin
S.
No.
Analytes &
Molecular
Mass (Da)
Q1 mass
(Dalton)
Q3 mass
(Dalton)
Retention
Time
(min)
DP
(V)
EP
(V)
CE
(V)
CXP
(V)
Dwell
time
(ms)
1. PGF2alpha
derivative
(390.2)
389.2 371.2 1.43 -110 -10 -33 -9 100
345.2 -110 -10 -36 -7 100
2. Biochanin
(284.0)
283.0 268.0 3.20 -100 -10 -30 -6 100
239.0 -100 -10 -45 -4 100
C) LC-MS/MS bio-analytical method for C101
Chromatographic separation is done using Purospher star C18 column (55x4 mm, 3.5 μm,
Merck, Darmstadt, Germany). An isocratic method is used for quantification of C101. Mobile
phase consisting of (solvent A; 10%) MilliQ with 0.1%formic acid (FA) and (solvent B;
90%) Acetonitrile with 0.1%FA. The mobile phase is pumped at a flow rate of 0.5ml/min.
Ten microlitre of sample is injected into UHPLC every time for standards and samples.
Electrospray ionization in negative ion mode for the analyte is optimized using Turbo Ion
Spray source (AB Sciex, Foster City, CA, USA). Selected ion mode (SIM) is used for
quantification of C101 as given in table 9. Compound dependent parameters for each analyte
such as Declustering Potential (DP) and Entrance Potential (EP) are manually optimized
given in the table 6. Source dependent parameters are optimized: curtain gas (20 psi); ion
spray voltage (5000 eV), temperature (500°C), gas 1 (30 psi) and gas 2 (60 psi). The dwell
time for each MRM transition is set at 50ms.
28
Table 8: Optimized chromatography conditions for C101
Time
(min)
Solvent A*
(%)
Solvent B*
(%)
Flow rate
(mL/min)
0.0 10.0 90.0 0.5
4.0 10.0 90.0 0.5
Table 9: MRM transitions, retention time and optimized ESI-MS/MS parameters of
C101
S.
No.
Analytes &
Molecular
Mass (Da)
Q1 mass
(Dalton)
Retention
Time
(min)
DP
(V)
EP
(V)
Dwell time
(ms)
1. C101 (656.0) 655.0 2.4 -100 -10 50
Calibration standards and samples preparation
A) For PGF2alpha derivative and biochanin
To obtain calibration standards, PGF2 alpha derivative and biochanin are weighed accurately
and dissolved in acetonitrile to get 1mg/ml concentration of each analyte. Calibration
standards are prepared by diluting this standard stock solution with acetonitrile to reach
concentrations ranging 1.56-100ng/ml. Fifty microlitre of each standards are taken into
microcentrifuge tubes and subjected for drying using Rotavac at 40°C followed by
reconstitution with 200ul of acetonitrile. This solution is vortexed for 1min and 10ul is
injected into LC-MS/MS for analysis.
B) For C101
To obtain calibration standards, C101 powder is weighed accurately and dissolved in
dichloromethane to get 1mg/ml concentration of each analyte. Calibration standards are
prepared by diluting this standard stock solution with acetonitrile to reach concentrations
ranging 1.56-100ng/ml. fifty microlitre of each standards are taken into microcentrifuge tubes
and subjected for drying using Rotavac at 40°C followed by reconstitution with 200ul of
acetonitrile. This solution is vortexed for 1min and 10ul is injected into LC-MS/MS for
analysis.
29
C) Skin tissue sample extraction protocol
The weight of the skin in each rabbit is noted. Skin is chopped and added 2ml of normal
saline followed by homogenization. After homogenization, 8 ml acetonitrile is added. The
mixture is then vortexed for 1min and sonicated for 1 min followed by centrifugation at
7000rpm for 10min. The supernatant is collected and subjected for rotavac at 40°C. The dried
tissue extract is reconstituted with 200ul of acetonitrile, vortexed and sonicated for 5min.
10ul of this solution is used for quantification using LC-MS/MS.
Results:
Skin reactions
After 18 hrs, the exposed is anlysed for any change in color, sign of inflammation or
irritation. This study observes no significant changes on the skin as compared to the
unexposed area in both of the compositions.
Evaluation of delivery volume
Delivery volume is measured by gravimetry. Table 10 shows the results of delivery volume.
It is found that approximately 100ul is delivered in one spray. Drug content of composition A
and B is also evaluated and found within range.
Table 10: Delivery volume of compositions
Composition A C101
weight measured
(g) weight measured (g)
1 spray 0.102 0.109
2 spray 0.106 0.104
3 spray 0.107 0.101
Mean 0.105 0.104
LC-MS/MS method for the analysis of biochanin, PGF2 alpha derivative and C101
analytes
The bio-analytical methods are developed for the analysis of biochanin, PGF2 alpha
derivative and C101 analytes. Standard calibration curve are plotted by using peak height of
respective standards on y-axis and concentrations on x-axis. It is found to be linear for
biochanin ranging from 1.56-100ng/ml with linear regression correlation coefficient (r2) of
30
0.9992. It is found to be linear for C101 ranging from 1.56-50ng/ml with r2 of 0.9989 and
representative extracted ion chromatograms resulting from the analysis of (a) blanks, (b)
GF2alpha derivative and (c) biochanin are as shown in Figure 5 and representative MRM
chromatograms resulting from the analysis of (a) blank, (b) Extracted ion chromatogram
(overlay) of PGF2alpha derivative (1) and biochanin (2) are as shown in Figure 6 and
representative MRM chromatograms resulting from the analysis of (a) blank and (b)
Extracted ion chromatogram of C101 are as shown in Figure 7.
Skin levels of PGF2 alpha derivative, biochanin and C101
Both Compositions A and B are applied on abdominal skin of rabbit. After 18hrs of contact
with skin, the skin are excised and analyzed for the levels of C101 and prostaglandin and
biochanin. The results were given in table 11 and 12. Representative extracted ion
chromatograms of prostaglandin and Biochanin and C101 levels found in rabbit skin after
18hrs. (a) Composition A treated skin; (b) composition B treated skin are shown at figures 8.
Table 11: Skin levels of biochanin and PGF2 alpha derivative concentration 18 hours
after application of composition A and B (C101)
ND= not detectable or less than the LOD
Conclusion
C101 derivative shows persistent presence in the skin than its physical mixture and undergoes
slow desertification in vivo to release both of the compounds.
Code Components Biochannin
level
( ng/gm)
PGF2 alpha
derivative
(ng/gm)
C101
Composition A Mixture of
Biochannin and
PA
114± 17 ND ND
Composition B C101 249 ± 45 46 ±6 ng/gm 41.5 ng/gm

We Claim:
1. A novel compound of formula (I):
Formula I
wherein
is either a single bond or a double bond;
R1 is selected from the group comprising 5 or 6 membered carbocyclic or heterocyclic
or aryloxy or fused ring systems, wherein each ring of fused ring system comprises 6-
10 carbon atoms; the heterocyclic ring comprises 2 to 4 heteroatoms such as O, N or
S; the ring may be further substituted by a group selected from halogen, C1 to C3
halocarbon, C1 to C3 alkoxy or C1 to C3 alkyl group;
R2 and R3 are independently selected from the group comprising carbonyl or
hydroxyl;
n is from 1 to 10;
R4 is selected from the group comprising C1 to C4 alkyl;
R5 is selected from the group comprising iso-flavone, flavone preferably biochanin A,
formononetin, genistein, genistin, daidzein, daidzin, pratensein, pectolinarigenin,
calycosin.
2. The compounds as claimed in claim 1, selected from the group comprising:
HO
R3
COOR5
R2
(CH2)n
R4
R1
32
3. The compounds as claimed in claim 1, selected from the group comprising:
(Z)-5-hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl 7-((1R,2R,3R,5S)-3,5-
dihydroxy-2- ((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate;
(Z)-5-hydroxy-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yl 7-((1R,2R,3R,5S)-3,5-
dihydroxy-2- ((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate; and
(Z)-3-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yl 7-((1R, 2R, 3R, 5S)-3, 5-
dihydroxy-2- ((R)-3- hydroxy-5-phenylpentyl) cyclopentyl) hept-5-enoate.
4. A process for the preparation of a novel compound of Formula I as claimed in
claim 1 comprising the steps of:
33
iv. solubilizing the compound of Formula II in a solvent;
Formula II
wherein
is either a single bond or a double bond;
R1 is selected from the group comprising 5 or 6 membered carbocyclic or heterocyclic
or aryloxy or fused ring systems, wherein each ring of fused ring system comprises 6-
10 carbon atoms; the heterocyclic ring comprises 2 to 4 heteroatoms such as O, N or
S; the ring may be further substituted by a group selected from halogen, C1 to C3
halocarbon, C1 to C3 alkoxy or C1 to C3 alkyl group;
R2 and R3 are independently selected from the group comprising carbonyl or
hydroxyl;
n is from 1 to 10;
R4 is selected from the group comprising C1 to C4 alkyl;
i. esterification of compound of Formula II and R5 in equimolar quantity using
an acid catalyst to get esterified product ; and
ii. isolating the esterified product from the solution to obtain the compound of
Formula I.
5. A process as claimed in claim 4, wherein the compound of Formula II is selected
from the group comprising:
34
(Z)-7-((1R,2R,3f,R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-4-phenylbut-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-3-oxo-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-phenoxybut-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-en-1-yl)-5-
oxocyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R)-3-hydroxy-2-((R)-3-hydroxy-5-phenylpentyl)-5-
oxocyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(4-methoxyphenyl)pent-
1-en-1-yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-
phenylpentyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-3-hydroxy-6-
phenylhexyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-3-hydroxy-7-
phenylheptyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-3-hydroxy-8-
phenyloctyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S)-3-hydroxy-12-
phenyldodecyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-(thiophen-2-
yl)pentyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-(thiophen-3-
yl)pentyl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((3S,5R,E)-3-hydroxy-5-phenylhex-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((3S,5S,E)-3-hydroxy-5-phenylhex-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
35
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(4-
(trifluoromethyl)phenyl)pent-1-en-1-yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((E)-3-oxo-5-phenylpent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(p-tolyl)pent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(o-tolyl)pent-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-2-((S,E)-5-(4-fluorophenyl)-3-hydroxypent-1-en-1-yl)-3,5-
dihydroxycyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-9-phenylnon-1-en-1-
yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(naphthalen-1-yl)pent-1-
en-1-yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-2-((S,E)-5-cyclohexyl-3-hydroxypent-1-en-1-yl)-3,5-
dihydroxycyclopentyl)hept-5-enoic acid
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(4-methoxyphenyl)pent-
1-en-1-yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-(3-methoxyphenyl)pent-
1-en- 1-yl)cyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5S)-2-((S,E)-3-cyclohexyl-3-hydroxyprop-1-en-1-yl)-3,5-
dihydroxycyclopentyl)hept-5-enoic acid;
(Z)-7-((1R,2R,3R,5R)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept- 5-enoic acid; and
(Z)-7-((1R,2R,3S,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-en-1-
yl)cyclopentyl)hept- 5-enoic acid.
6. A process as claimed in claim 4, wherein the solvent is selected from the group
comprising dichloromethane, 2-Methyltetrahydrofuran, hexane, toluene, diethyl
ether and the acid catalyst is selected from the group comprising hydrochloric
acid, sulfuric acid, tosic acid.
7. A pharmaceutical composition of the compound as claimed in claim1 along with
pharmaceutically acceptable excipients.
36
8. A pharmaceutical composition as claimed in claim 7, wherein the composition is
selected from the group comprising solution, gel, lotion, cream, ointment, oil-inwater
emulsion, water-in-oil emulsion, stick, spray, aerosol, paste, mousse, tonic,
liposome, concentrated form for shampoo, conditioner, styling products, hair care
formulations.
9. A pharmaceutical composition as claimed in claim 7, wherein the composition is
mixed with non-ionic fatty acid esters.
10. Use of the compounds as claimed in claim 1 for prevention of hair fall and
restoration of hair growth cycle.
11. Use of the composition as claimed in claim 7 for prevention of hair fall and
restoration of hair growth cycle.