Note: Descriptions are shown in the official language in which they were submitted.
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PREGNANE GLUCURON1DES
BACKGROUND OF THE INVENTION
The use of naturally occurnng estrogenic compositions of substantial
purity and low toxicity such as PREMARIN (conjugated equine estrogens) has
become a preferred medical treatment for alleviating the symptoms of
menopausal
syndrome, osteoporosis/osteopenia in estrogen deficient women and in other
hormone related disorders. The estrogenic components of the naturally
occurring
estrogenic compositions have been generally identified as sulfate esters of
estrone,
equilin, equilenin, 17-p-estradiol, dihydroequilenin and 17-~3-
dihydroequilenin
(U.S. Patent 2,834,712). The estrogenic compositions are usually buffered or
stabilized with alkali metal salts of organic or inorganic acids at a
substantially
neutral pH of about 6.5 to 7.5. Urea has also been used as a stabilizer (U.S.
3,608,077). The incorporation of antioxidants to stabilize synthetic
conjugated
estrogens and the failure of pH control with tris(hydroxymethyl)aminomethane
(TRIS} to prevent hydrolysis is discussed in U.S. 4,154,820.
Two of the compounds described herein, Sa-Pregnane-3~i,(20S), 21 triol
20-O-~i-glucuronide sodium salt and Sa-Pregnane-3(3,20R-diol 20-O-j3
glucuronide sodium salt are minor components of PREMARIN (conjugated
equine estrogens).
DESCRIPTION OF THE INVENTION
In accordance with this invention, there is provided Sa-Pregnane-3~,(20S),
21-triol, 20-O-(3-glucuronide and Sa-Pregnane-3~i,20R-diol, 20-O-(3-
glucuronide and
pharmaceutically acceptable salts thereof which are useful as progestational
agents.
The preparation of pregnane glucuronides 7 and 12 is shown in schemes I and
II,
respectively. Additionally, a conversion of the glucuronides to the naturally
occurring sodium salt forms 8 and 13 is also shown.
Pharmaceutically acceptable salts of Sa-Pregnane-3R>(20S), 21-triol 20-O-~i-
glucuronide and Sa-Pregnane-3~i,20R-diol 20-O-(3-glucuronide are not limited
to the
naturally occurring form, but also include the alkali metal salts, alkaline
earth metal
salts, ammonium salts, alkylamrnonium salts containing 1-6 carbon atoms or
dialkylammonium salts containing 1-6 carbon atoms in each alkyl group, and
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trialkylammonium salts containing 1-6 carbon atoms in each alkyl group as well
as
any other atom or molecules which have a positive charge.
As Sa-Pregnane-3~i,(20S), 21 trial 20-O-(3-glucuronide and Sa-Pregnane-
3~i,20R-dial 20-O-~i-glucuronide are minor components of PREMARIN (conjugated
equine estrogens), this invention also provides Sa-Pregnane-3~,(20S), 21-trial
20-O-
~i-glucuronide and Sa-Pregnane-3~3,20R-dial 20-O-(3-glucuronide and their
pharmaceutically acceptable salts in greater than 1 percent purity.
This invention also provides compounds consisting essentially of Sa-
Pregnane-3~3,(20S), 21-trial 20-O-~i-glucuronide or a pharmaceutically
acceptable salt
thereof or Sa-Pregnane-3(3,20R-dial 20-O-(3-glucuronide or pharmaceutically
acceptable salt thereof.
This invention further provides a method of using Sa-Pregnane-3a,(20S), 21-
triol glucuronide and Sa-Pregnane-3(3,20R-dial glucuronide or a
pharmaceutically
acceptable salt of the related glucuronides as progestational agents.
The starting materials used in this synthesis are either commercially
available
or can be prepared using standard chemical methodology.
The compounds of this invention can be prepared from readily available
starting materials according to the processes in Scheme I, as shown for Sa-
Pregnane-
3p,(20S), 21-trial 20-O-(3-glucuronide (and corresponding monobasic sodium
salt) or
according to the process in Scheme II, as shown for the synthesis of Sa-
Pregnane-
3~i,20R-diol 20-O-(3-glucuronide (and corresponding monobasic sodium salt).
In Scheme I, pregnenolone 3-acetate 1 was used as the starting material.
Reaction of 1 with lead tetraacetate in acetic acid according to the procedure
described by Purdy, et al, Journal of Medicinal Chemistry 33(6), 1572-1581
(1990)
yields 2. Hydrogenation of 2 over Pt02 in acetic acid yields compounds 3 and 4
in an
approximate ratio of 3:1. Compound 3 is subsequently heated with excess
equivalents of the acetobromo glucuronic acid methyl ester 5. The protected
glucuronide is subsequently saponified with LiOH and reprotonated with acid to
yield
the desired 20-glucuronic acid conjugate 7. The free acid can be titrated with
a slight
excess of NaOH solution which generates the monosodium salt 8.
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Scbame 1
Pb(OAc)4, AcOH
PregnenolonE
. ..
off
OAc
Pt02, AcOH
H2, 40 psi
H
3 4
'~.GOZMe
s
~N
OAc
\COtAIb 7
g + Ag2C03, CHCIs Aco pAc
OAc
OAc
5
OZH
dN,
OH
1 - LiOH,THF,H20,MeOf HO
6
2-2 N HCI
7
~COO~Na+
dw~
OH
HO
MaOH, 1.05 eg Nai
H
8
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In Scheme II, compound 10 was reacted with acetobromo glucuronic acid
methyl ester 5 and Ag~C03 to yield the protected conjugate 11. This material
was
subsequently saponified and then protonated with acid to yield the deprotected
glucuronic acid derivative 12. This material was then titrated with NaOI-i to
yield the
sodium glucuronate 13.
s~ner"e a
off Ag2C03 0"~. ~,aco~H3
6 ~MC02~H OAc OAc
Z
OAc
Ac0 OAc
H
OAc
6 11
LiOH
THF/MeOH/HZO
o,~, e~cozr~, o,,,~ o ,,vca~H
io off NaOH Ho y ~oH
off MeOH
HO
H 12
13
10 The compounds of this invention are progestational agents, and are
therefore
useful as oral contraceptives (male and female), in hormone replacement
therapy
(particularly when combined with an estrogen), in the treatment of
endometriosis,
luteal phase defects, benign breast and prostatic diseases and prostatic and
endometrial cancers. The compounds of this invention are also useful in
protecting
I S against epileptic seizures, in cognition enhancement, in treating
Alzheimer's disease,
dementias, vasomotor symptoms related to menopause, and other central nervous
system disorders The compounds of this invention are further useful in
stimulating
erythropoieses.
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The compounds of this invention can be used alone as a sole therapeutic agent
or can be used in combination with other agents, such as other estrogens,
progestins,
or androgens.
The compounds of this invention can be formulated neat or with a
pharmaceutical carrier for administration, the proportion of which is
determined by
the solubility and chemical nature of the compound, chosen route of
administration
and standard pharmacological practice. The pharmaceutical carrier may be solid
or
liquid.
A solid carrier can include one or more substances which may also act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers,
glidants,
compression aids, binders or tablet-disintegrating agents; it can also be an
encapsulating material. In powders, the carrier is a finely divided solid
which is in
admixture with the finely divided active ingredient. In tablets, the active
ingredient is
mixed with a carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The powders and
tablets
preferably contain up to 99°l0 of the active ingredient. Suitable solid
carriers include,
for example, calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin,
starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions,
syrups, elixirs and pressurized compositions. The active ingredient can be
dissolved
or suspended in a pharmaceutically acceptable liquid carrier such as water, an
organic
solvent, a mixture of both or pharmaceutically acceptable oils or fats. The
liquid
carrier can contain other suitable pharmaceutical additives such as
solubilizers,
emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending
agents,
thickening agents, colors, viscosity regulators, stabilizers or osmo-
regulators.
Suitable examples of liquid carriers for oral and parenteral administration
include
water (partially containing additives as above, e.g. cellulose derivatives,
preferably
sodium carboxymethyl cellulose solution), alcohols (including monohydric
alcohols
and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and
oils (e.g.
fractionated coconut oil and arachis oil). For parenteral administration, the
carrier
can also be an oily ester such as ethyl oleate and isopropyl myristate.
Sterile liquid
carriers are useful in sterile liquid form compositions for parenteral
administration.
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The liquid carrier for pressurized compositions can be halogenated hydrocarbon
or
other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions which are sterile solutions or suspensions
can be utilized by, for example, intramuscular, intraperitoneal or
subcutaneous
injection. Sterile solutions can also be administered intravenously. The
compounds
of this invention can also be administered orally either in liquid or solid
composition
form.
The compounds of this invention may be administered rectally or vaginally in
the form of a conventional suppository. For administration by intranasal or
intrabronchial inhalation or insufflation, the compounds of this invention may
be
formulated into an aqueous or partially aqueous solution, which can then be
utilized
in the form of an aerosol. The compounds of this invention may also be
administered
transdermally through the use of a transdermal patch containing the active
compound
and a carrier that is inert to the active compound, is non toxic to the skin,
and allows
delivery of the agent for systemic absorption into the blood stream via the
skin. The
carrier may take any number of forms such as creams and ointments, pastes,
gels, and
occlusive devices. The creams and ointments may be viscous liquid or semisolid
emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of
absorptive powders dispersed in petroleum or hydrophilic petroleum containing
the
active ingredient may also be suitable. A variety of occlusive devices may be
used to
release the active ingredient into the blood stream such as a semipermeable
membrane covering a reservoir containing the active ingredient with or without
a
carrier, or a matrix containing the active ingredient. Other occlusive devices
are
known in the literature.
The dosage requirements vary with the particular compositions employed, the
route of administration, the severity of the symptoms presented and the
particular
subject being treated. Based on the results obtained in the standard
pharmacological
test procedures, projected daily dosages of active compound would be 0.02
~,g/kg -
750 ~g/kg. Treatment will generally be initiated with small dosages less than
the
optimum dose of the compound. Thereafter the dosage is increased until the
optimum effect under the circumstances is reached; precise dosages for oral,
parenteral, nasal, or intrabronchial administration will be determined by the
administering physician based on experience with the individual subject
treated.
Preferably, the pharmaceutical composition is in unit dosage form, e.g. as
tablets or
capsules. In such form, the composition is sub-divided in unit dose containing
appropriate quantities of the active ingredient; the unit dosage forms can be
packaged
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compositions, for example, packaged powders, vials, ampoules, pre filled
syringes or
sachets containing liquids. The unit dosage form can be, for example, a
capsule or
tablet itself, or it can be the appropriate number of any such compositions in
package
form.
The following provides the preparation of representative compounds of this
invention.
Example 1
Pregnane-3(3.20R.21-triol 3.21-diacetate 3
Compound 2 (6.0 g, 14.4 mmol) in 0.2 L AcOH was treated with PtO~ (1.75
g, 7.7 rnmol) and the solution was hydrogenated under 40 PSI of H:. After 18
h, the
catalyst was filtered and the crude reaction mixture was concentrated and
chromatographed on silica gel using EtOAc/hexanes ( 1:4) to yield the two
products
(3 and 4). The first product to elute was the major (desired) material 3 which
was
isolated as 2.40 g of a white solid: Mp = 164 - 166°C; 'H NMR (CDCl3)
4.75 - 4.60
(m, 1 H), 4.16 (dd, 1 H, J = 11.4 Hz, 2.2 Hz), 3.94 - 3.87 (m, 1 H), 3.81 -
3.73 (m, 1
H), 2.10 (s, 3 H), 2.10 - 2.05 (m, 1 H), 2.02 (s, 3 H), I .84 (d, 1 H, J = 5.2
Hz), 1.82 -
0.88 (m, 21 H), 0.83 (s, 3 H), 0.76 (s, 3 H), 0.68 (dt, 1 H, J = 10.6 Hz); MS
(+ESI)
421 (M+H)'; IR (KBr) 3520, 2920, 2880, 1740, 1710 cm~'.
Example 2
Pre; nane-3g.20R.21-triol 3,20-diacetate 4
The second product 4 to elute was the minor product which was isolated as
0.73 g of a white solid: Mp = 189 - 191°C; 'H NMR (DMSO) 4.91 (dq, 1 H,
J = 5.5
Hz, 2.2 Hz), 4.74 - 4.63 (m, 1 H), 3.81 - 3.74 (m, 1 H), 3.57 - 3.49 (m, 1 H),
2.09 (s,
3 H), 2.02 (s, 3 H), 1.91 (dd, 1 H, J = 7.2 Hz, S.0 Hz), 1.85 - 0.83 (m, 22
H), 0.82 (s,
3 H), 0.72 - 0.61 (m, 1 H), 0.65 (s, 3 H); MS EI 420 (M+); IR (KBr) 3410,
2920,
1730, 1700 cm~'.
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_g_
Example 3
2.3.4-O-Triacetvl -1-O-(3[3.21-diacetoxv-5a-pregnan-205-yl)-~3-D-~lu~uronic
acid
methyl ester 6
Compound 3 (6.6 g, 15.7 mmol) was dissolved in CHCI, (125 mL) and treated
with Ag2C0, (4.3 g, 15.7 mmol) and the glucuronyl bromide 5 [21085-72-3] (6.2
g,
15.7 mmol). After refluxing for 1.5 h, an additional 0.5 eq of Ag2C03 and 0.5
eq of
the glucuronyl bromide were added. After an additional 1.5 h this addition of
reagents was repeated and after another 1.5 h it was repeated once more. The
reaction was allowed to reflux for a total of 5.5 h. The reaction was allowed
to cool
down and the inorganic salts were filtered off. The filtrate was concentrated
and
chromatographed on silica gel (3:7, EtOAc/hexanes) and the fractions
containing
product were concentrated and rechromatographed under the same conditions to
yield
4.1 g of 6 which was triturated with MeOH to give 3.05 g of 6 as a white
solid: Mp =
180 - 183°C; MS (APCI) 754 (M+ NH4'); 'H NMR (DMSO} 5.36 (t, 1 H, J =
9.6
Hz), 5.06 (d, 1 H, J = 8.0 Hz), 4.91 (t, 1 H, J = 9.8 Hz), 4.70 (dd, 1 H, J =
9.5 Hz, 8.1
Hz), 4.63 - 4.50 (m, 1 H), 4.47 (d, 1 H, J = 10.0 Hz), 4.16 (d, 1 H, J = 11.3
Hz), 3.92
- 3.75 (m, 2 H), 3.63 (s, 3 H), 2.16 - 2.07 (m, 1 H), 2.04 (s, 3 H), 1.99 (s,
3 H), 1.97
(s, 3 H), 1.95 (s, 3 H), 1.93 (s, 3 H), 1.78 - 1.63 (m, 3 H), 1.62 - 1.39 {m,
6 H), 1.36 -
1.10 (m, 8H), 1.06 - 0.85 (m, 5 H), 0.79 (s, 3 H), 0.68 (s, 3 H).
Example 4
5a-Pre,~nane -3fi.20S.21-triol 20-O-[i-D-glucuronide 7
Compound 6 (3.76 g, 5.1 mmol) was dissolved in THF (25 mL) and treated
with a solution consisting of LiOH ( 1.35 g, 56.1 mmol) in H20 ( 13 mL). MeOH
(4
mL) was added to this solution and the reaction was heated to 75°C for
2 h. The
solution was then cooled and concentrated. The aqueous residue was taken up
with
an additional 15 mL of H20. To this residue was then added a 2N HCl solution
(43
mL). Solid formation was induced by scratching the glass. Filtration yielded
2.6 g
of 7 as a white solid:
Mp = 231 - 235°C; "C NMR (75 MHz, MeOD) (C=O missing), 102.6,
82.i, 77.6,
76.8, 75.3, 73.1, 71.9, 63.6, 57.6, 56.1, 51.5, 49.9, 46.3, 43.6, 40.3, 39.0,
38.3, 36.9,
36.7, 33.5, 32.2, 30.0, 25.9, 25.4, 22.3, 12.8, 11.9; 'H NMR (300 MHz, MeOD)
4.54
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(d, 1 H, J = 7.7 Hz), 3.82 - 3.71 (m, 3 H), 3.59 - 3.22 (m, 5 H), 2.30 (d, 1
H, J = 12.6
Hz), 1.75 - 1.66 (m, 6 H), 1.53 - 1.18 (m, 9 H), 1.17 - 0.88 (m, 6 H), 0.83
(s, 3 H),
0.78 (s, 3 H), 0.7U - 0.58 (m, 1 H); MS (-)ESI 511 (M-H)-; IR (KBr) 3410,
2910,
2830, 1730, 1700 cm''.
Example 5
5a-Pre ng ane-3~i,20S.21-triol 20-O-~3-D-~lucuronide sodium salt 8
Compound 7 (1.57 g, 1.7 mmol) was suspended in MeOH (20 mL) and treated with
an aqueous solution of NaOH (6.4 mL, 0.5 N) and stirred for 5 minutes which
allowed all of the starting material to go into solution. The solution was
then mixed
with 0.65 g of product from a previous run and the combination stripped onto
silica
gel and column chromatographed on silica gel (MeOH:CH,Ch, 4:6 then 5:5). The
product was then triturated once with a 1:1 mixture of MeOH and Dioxane (total
volume equal 60 mL) to yield 1.57 g of 8 as a white solid: Mp = 240 -
244°C; '3C
NMR (75 MHz, DMSO) (C=O missing), 100.4, 79.8, 76.7, 73.9, 73.7, 72.2, 69.3,
66.3, 62.0, 55.6, 54.0, 49.8, 44.3, 41.9, 38.1, 36.6, 35.1, 35.0> 31.8, 31.3,
28.4, 24.4,
23.9, 20.8, 12.1, 11.4; IR (KBr) 3400 (H20), 2920, 2870, 1610 cni'.
Example 6
Pre ng ane-3[3.205.21-triol9
Compound 3 (1.6 g, 3.8 mmol) was dissolved in THF (8 mL). A solution of
LiOH (0.27 g, 11.4 mmol) in 3 mL of H,O was added. In order to make the
solution
one phase, 1 mL of MeOH was added to the reaction mixture. After 30 minutes at
reflux, the reaction mixture was treated with 1.1 mL of AcOH and partitioned
between an organic layer consisting of 100 mL EtOAc, 20 mL CH2C1" 10 mL
MeOH, and 60 mL H20. The organic layer was then washed with brine and dried
over MgSO,. The solution was concentrated and the resulting solid triturated
with
ether to yield 1.1 g of 9 as a white solid: Mp = 210 - 212°C; 'H NMR
(DMSO) (3
OH protons missing) 4.43 (d, 1 H, J = 4.6 Hz), 4.31 (t, I H, J = 5.5 Hz), 4.05
(d, 1 H,
J = 5.2 Hz), 3.16 - 3.05 (m, 1 H), 2.10 {d, 1 H, J = 12.4 Hz), 1.65 - 0.78 (m,
21 H),
0.75 (s, 3 H), 0.68 (s, 3 H), 0.65 - U.54 (m, 1 H); MS EI 336 M+; IR (KBr)
3400,
2930, 2880 cm''.
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Example 7
1-O-(3ti-Acetoxv-nre~n-20-vl)-2 3 4-triacetyl ~3-D-~lucuronic acid rnethvl
ester 11
Sa-Pregnan-3(3, 20[3-diol 3-acetate 10 (3.0g, 11.0 mmol), glucuronyl bromide
5 [21085-72-3) (S.Sg, 13.8 mmol) and Ag2C03 (4.Sg, 16.1 mmol) were stirred in
toluene (40 mL) at rt (flask protected from light with aluminum foil). After
18 h the
reaction was diluted with CHzCIz, filtered, concentrated and chromatographed
on
silica gel (EtOAc:Hex, 2:8 then EtOAc:Hex, 4:6) to yield a solid which was
triturated
with MeOH to give 3.0 g of 11 as a white solid:
Mp = 248 - 251°C; 'H NMR (DMSO) 5.33 (t, 1 H, J = 9.6 Hz), 4.95 - 4.88
(m, 2 H),
4.68 (dd, 1 H, J = 9.5 Hz, 8.1 Hz), 4.62 - 4.49 (m, 1 H), 4.44 (d, 1 H, J =
10.0 Hz),
3.71 - 3.65 (m, 1 H), 3.63 (s, 3 H), 2.11 (d, 1 H, J = 12.6 Hz), 1.98 (s, 3
H), 1.97 (s, 3
H), 1.96 (s, 3 H), 1.95 (s, 3 H), 1.77 - 1.64 (m, 2 H), 1.63 - 1.10 (m, 14 H),
0.99 (d, 3
H, J = 5.8 Hz), 0.95 - 0.83 (m, 5 H), 0.78 (s, 3 H), 0.66 (s, 3 H), 0.65 -
0.58 (m, 1 H);
IR (KBr) 2930, 2900, 2830, 1750, 1730 cm~'; MS (+)ESI 696 (M+NH,)'.
Example 8
Sa-Pre~nane-3~3.20R-diol 20-O~i-D-glucuronide 12
Compound 11 (2.5 g, 3.7 mmol) was dissolved in a solution of THF (25 mL)
and MeOH (15 mL) and treated with a solution of LiOH (0.9g, 37.5 mmol) in H20
(10 mL). The reaction was heated at reflux for 1 h. The reaction was allowed
to cool
to room temperature and concentrated. The product was taken up in water (20
mL)
and acidified with aqueous 2 N HCI. A precipitate' formed which was filtered
yielding 1.5 g of 12 as a white solid: Mp = 255 - 260°; 'H NMR (DMSO)
(3 H
buried) 4.98 (d, 1 H, J = 3.8 Hz), 4.91 (d, 1 H, J = 4.6 Hz), 4.42 (br s, 1
H), 4.25 (d, 1
H, J = 7.7 Hz), 3.71 - 3.62 (m, 1 H), 3.58 (d, 1 H, J = 9.7 Hz), 3.23 - 3.12
(m, 1 H),
2.96 - 2.87 (m, 1 H), 2.15 (d, 1 H, J = 12.3 Hz), 1.67 - 1.46 (m, 5 H), 1.45 -
0.80 (m,
17 H), 1.01 (d, 3 H, J = 5.8 Hzl, 0.74 (s, 3 H), 0.65 (s, 3 H), 0.65 - 0.52
(m, 1 H); IR
(KBr) 3520, 3400, 2920, 2820, 2800, 1710 cm~'; MS (-) ESI 495 (M-H)-.
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Example 9
5a-Pregnane-3~i.20R-diol 20-O-~i-D-~lucuronide sodium salt 13
A suspension of Compound 12 ( 1.5 g, 3.0 mmol) in MeOH (25 mL) and
treated with an aqueous solution of NaOH (0.5 N, 6.0 mL, 3.0 mmol) and stirred
for
5 minutes during which time everything went into solution. The solution was
concentrated to dryness and the residue was triturated with EtOH to obtain 1.1
g of 13
as a white solid:
Mp = 223 - 226°C (dec); 'H NMR (DMSO) 7.26 (s, 1 H), 4.76 (d, 1 H, J =
3.6 Hz),
4.67 (d, 1 H, J = 3.6 Hz), 4.43 (d, 1 H, ~J = approx 4 Hz), 4.12 (d, 1 H, J =
7.6 Hz),
3.78 - 3.71 (m, 1 H), 3.45 - 3.35 (m, 1 H), 3.17 - 3.03 (m, 3 H), 3.38 - 3.29
(m, 1 H),
2.17 (d, 1 H, J = 12.4 Hz), 1.67 - 1.49 (m, 5 H), 1.45 - 0.80 (m, 17 H), 0.99
(d, 3 H, J
= 5.9 Hz), 0.76 (s, 3 H), 0.75 (s, 3 H), 0.65 - 0.53 (m, 1 H); IR (KBr) 3400,
2920,
2830, 1610 cm~'; MS (-) ESI 495 (M-H)~.
