Note: Descriptions are shown in the official language in which they were submitted.
~HP-9114 mz
~ 3 ~ ~ 4 ~ ~; PATENT
SUB~ST~UTED 2,3,4,9~ TRAHYDR~lE~ARBAZOLE-l-ACEl~lC ACID
BACKGROUND OF TEIE INV13 NTION
a. Field of Invention
This invention relates to tricyclic acetic acid derivatives, to their
preparation flnd use.
More specifically, this invention relates to tricyclic ace$ic acid derivatives
in which the tricyclic portion thereof is characterized by having an indole
portion fused to a cyclohexane ring. Still more specifically, the compounds of
this invention are characterized as derivatives of the following tricyclic acetic
acid system:
7~2
CH2--COOH
2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid in which the carbons at the 1-, 4-and 8- positions are further substituted.
The tricyclic acetic acid compounds of this invention possess useful
pharmacologic properties;. for instance, they exhibit analgesic and anti-
inflammatory activity at dose levels which do not elicit undesirable side effects.
The foregoing combination of attributes renders the compounds of this invention
useful for the treatment of inflammatory or painful conditions in a mammalO
b. Prior Art
The closest prior art to the present invention is:
~ ;.
.
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Y114 mz
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Mobilio et al, United States Patent No. 4,616,028 issued October 7,
1986, United States Patent No. 4,578,398 and United States Patent No.
~,584,312, and Asselin et al. United stales Patent ~o. 4,057,559.
Mobilio et al, and Asselin et al, disclose analgesic and anti-
inflamnatory agents having the sarne heterocyclic ring system as the
present invention but without the l-, 4- and 8-s~stituents of the
present invention.
Demerson et al, United States Patent No. 3,939,178 discloses 1,3,4,9-
tetrahydropyrano[3,4-b}indoles and 1,3,4,9-tetrahydrothiopyranoE3,4-b]indoles
having analgesic and anti-inflammatory activity. Related United States Patents
are Nos. 3,974,179 and 3,843,681.
Boehringer Mannheim European Patent 42j93 generi~ally dis~loses starting
materials useful for producing cardiotonic and beta-blocking agents. The
starting materials include 1,2,3,4-tetrahydrocarbazoles with substituents selected
from the broad group including hydrogen, ~arboxy, lower alkyl and lower alkenyl.The starting materials are in each case also substituted with a reactive group
which distinguishes them from the compounds of the present invention.
Further removed, related patents that include tetrahydrocarbazoleacetic ~-
acid derivatives useful as analgesic and anti-inflammatory agents are United
States Patents 4,234,487; 4,264,500; 4,193,923; 4,158,007; 4,146,542; 3,896,145 and
3,824,314; Japanese Patent J51032556; Netherland Patent NL 7,100,213 and Great
Britain Patent GB 1385620.
SUMMARY O~ THE IN~ENTION
The compounds of this invention are represented by formula (I)
~7 ~ ;
R5~ ~C 3 1 Rl CH2--COOH
R~ \ 4
.
~ 3~ 1 AHP-9114 mz
--3--
wherein Rl is lower alkyl containing 1 to 4 carbon atoms and R2, R3, R4, R5, R6
and R7 are independently selected from the group consisting of hydrogen and
lower alkyl cont~ining 1 to 4 carbon atoms and the pharmaceutically acceptable
salts thereof.
A preferred aspect of the present invention are the compounds represented
by formula (I) wherein Rl is ethyl and the pharmaceutically acceptable salts
thereof.
A still further preferred aspect of the present invention are the compounds
represented by formula (I) wherein Rl is ethyl, R2, R3, R4, E~S and R6 are
hydrogen and R7 is hydrogen or methyl and the ph~rmaceutically acceptable
salts thereof.
The most preferred compounds of the present invention are designated l-
ethyl-8-~2-propenyl)-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid and l-ethyl-4-
methyl-8-(2-propenyl)-2,3,4,9-tetrahydr~lH-carbazole-l-acetic acid.
The compounds of the present invention are prepared by a process in which
the ketone of structure (II~
o C02CH3
R7
wherein Rl and R7 are as defined above is reacted with orth~
bromophenylhydrazine to form d phenylhydrazone. The hydr~zone is further
reacted in the pre~ence of acetic acid ~nd borontriflouride-etherate to obtain
compounds of structure (III)
, ~
3 ~73 AHP-gl l4 mz
(III)
Br H Rl C2 CH3
wherein Rl and R7 are as defined above.
Compounds of structur0 (III) are further reacted [as described by M. Kosugi
et al, Chem. Lett., 301(1977)~ with compounds of structure (IV)
R5 R4
~ R2 :`
6 / \ I (IV)
R C -M
R3
wherein R2, R3, R4, R5 and R6 are as defined above and M is trialkylstannyl:
[prepared according to D. Seyferth et al, J. Org. Chem., 4797 (1961)] to ~ive ~ ~
compound of structure (V) : .
~ ':
R5 ~ C2c~3 (V)
R R4
:
wherein Rl, R2, R3, R4, R5, R6 E.nd R~ are as defined above.
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Compounds of structure (I) are obtained from compounds of structure (~
by hydrolysis.
For basic hydrolysis a pre~erred embodiment involves subjecting the
tricyclic ester to the action of a base, for example, sodium or potassium
carbonate, in the presence of sufficient water to effect hydrolysis of the ester.
The hydrolysis is performed using a suitable solvent, for example, methanol or
ethanol under a nitrogen atmosphere.
The reaction mixture is maintained at a temperature of from 25C to the
reflux temperature until hydrolysis occurs. Usually from 10 minutes to 48 hours
is sufficient for this hydrolysis. The reaction mixture is then rendered acidic
with an aeid, for example, acetic acid, hydrochloric acid, sulfuric acid and thelike, to release the free acid as a solid.
Alternativelyy the tricyclic ester is hydroly~ed by subjecting the ester to
the action of a hydrolyzing agent which is a strong organic or inorganic acid, for
example, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like in a
suitable solvent at a temperature of at least 60C and preferably from 90C to
the boiling point of the mixture until the hydrolysis occurs. Usually from 5 to 48
hours are required for this hydrolysis. Suitab~e solvents include water, acetic
acid, aqueous alcohols and the like. If acid hydrolysis is used, the ~ree acid is
forrned directly. If necessary, the reaction mixture can be diluted with water to
precipitate the product.
DETAILI~D DESS:~RIPTION OF THE INVENTION
The term "lower alkyll' as used herein represents straight chain alkyl
radicals containing l to 4 carbon atoms and branched chain alkyl radicals
containing 3 to 4 carbon atoms and includes methyl, ethyI, propyl, isopropyl,
butyl, isobutyl, and the like.
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AllP-91 14 mz
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The term "halogen" as used herein includes fluorine, chlorine, bromine and
iodine
The compounds of formula (I) form salts with suitable pharmaceutically
acceptable inorganic and organic bases. These derived salts possess the same
activity as the parent acid and are included within the scope of this invention.The acid of formula (I) is transformed in excellent yield into the correspondingpharmaceutically acceptable salts by neutralization of said acid with the
appropriate inorganic or organic base. The salts are administered in the same
manner as the parent acid compounds. Suitable inorganic bases to form these
salts include, for example, the hydroxides, carbonates, bicarbonates or alkoxides
of the alkali metals or alkaline earth metals, for example, sodium, potassium,
magnesium, calcium and the like. Suitable organic bases include the following
amines; lower mono-, di- and tri-alkylamines, the alkyl radicals of which contain
up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine,
ethylamine, di- and triethylarnine, methylethylamine, and the like; mono, di- and
trialkanolamines, the alkanol radicals of which contain up to three carbon atoms,
such as mono-, di- and triethanolamine; alkylenediamines which contain up to sixcarbon atoms, such as hexamethylenediamine; cyclic saturated or unsaturated
bases containing up to six carbon atoms, such as pyrrolidine, piperidine,
morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such asN-methylmorpholine and N-(2-hydroxyethyl)piperidine, as well as pyridine.
Furthermore, there may be mentioned the corresponding quaternary salts, such
as the tetraalkyl (for example tetramethyl), alkyl-alkanol tfor example
methyltrimethunol and trimethyl-monoethanol) and cyclic ammonium salts, for
example the N-methyl-pyridinium~ N-methyl-N-(2-hydroxyethyl)-morpholinium,
N,N-dimethyl-morpholiniumJ N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-
dimethylpiperidinium salts, which are characterized by good water-solubility. Inprinciple, however, there can be used all the ammonium salts which are
physiologically compatible.
The transformations to the salts can be carried out by a variety of methods
known in the art. ~or example, in the case of salts of inorganic bases, it is
:;
L 3 ~ AHY-9114 mz
--7--
preferred to dissolve the acid of formula (I~ in water containing at least one
equivalent amount of a hydroxide, carbonate, or bicarbonate . Advantageously,
the reaction is performed in a water-miscible organic solvent inert to the
reaction conditions, for example, methanol, ethanol, dioxane, and the like in the
presence of water. For example, such use of sodium hydroxide, sodium
carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporationof the solution or addition of a water-miscible solvent of a more moderate
polarity, for example, a lower alkanol, for instance, butanol, or ~ lower alkanone,
for instance, ethyl methyl ketone, gives the solid salt if that form is desired.
To produce an amine salt, the acid of formula (I) is dissolved in a suitable
solvent of either moderate or low polarity, for example, ethanol, acetone, ethylacetate, diethyl ether and benzene. At least an equivalent amount of the amine
corresponding to the desired cation is then added to that solution. If the
resulting salt does not precipitate, it can usually be obtained in solid form byaddition of a miscible diluent of low polarity, for e~ample, benzene or petroleum
ether, or by evaporation. If the amine is relatively volatile, any excess can
easily be removed by evaporation. It is preferred to use equivalent amounts OI
the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by mixing
the acid of formula (I) with an equivalent amount of the corresponding
quaternary ammonium hydroxide in water solution, followed by evaporation of
the water.
Included in the present invention are the diastereoisomers wherein the 4-
substituent other than hydrogen is either cis or trans to the acetic acid chain at
position one.
Also included in this invention are the optical isomers of the compounds of
formula (I) which result from asymmetric centers, contained therein. Such
isomers can be obtained in substantially pure form by classical separation
techniques.
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ANTI-INFLAMMATORY ACTIVITY
The useful anti-inflammatory activities of the compounds of formula (I) are
demonstrated in standard pharmacologic tests, for example, the test designated:
Preventative Adjuvant Edema
The objective of this test is to determine the ability of test drugs to
exhibit an acute anti-inflammatory effect in rats. This test is a primary screenfor anti-inflammatory drugs.
Species:
Male Sprague Dawley rats (180-200g) are used. The animals have free
access to water but food is withdrawn 18 hours before testing.
Drug Preparations and Administration:
Freund's Complete Adjuvant ;s prepared by suspending S mg killed and
dried Mycobacterium butyricum (Difco) in 1 mL mineral oil. The test
compounds are dissolved, or suspended in 0.5% Tween 80 }n distilled water
according to their solubility. For primary screening Pll drugs are
administered by gastric lavage at the arbitrary dosage of 25 mg/kg, p.o. in
a volume of 0.5 mL/10û g body weight to groups of lû animals.
hlethodolo~ical Details:
The method is essentially that described by Wax et al., J. Pharmacol. Exp.
Ther., 192, 166-171 ~1975). Groups of rats are injected intradermally in the
left hind paw with 0.1 mL of Freund's Complete Adjuvant. The test
compound or vehicle is administered immediately before the adjuvant, 24
hours and 48 hours after the adjuvant (day 0, 1 and 2). The injected hind
paw volume is measured before the injection of adjuvant and 24 hours after
the last drug administration (day 3) by means of a plethysmometer (Buxco
Electronics Inc). The difference between the hind paw volume on day 0 and
day 3 represents the edema volume. Etodolac (25 mg/kg, p.o.) is included
as a positive control.
* Trade-mark
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AHP-9114 mz
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Presentation of Results:
The mean edema volume (expressed as mL + SEM) is calculated for each
group and the percentage protection conferred by the drug is calculatedO
% protection = (c-t) 100
c
where c is the mean edema volume for the vehicle-~reated (0.5% Tween 80
in distilled water) controls and t is the mean edema volume for the drug
treated group.
ANALGESIC ACTIVITY
A further test used to determine the utility of the compounds of the
present invention is designated: Drug Effects on Phenylbenzoquinone-
induced Writhing in Miee
The obiective of this test is to determine the ability of test drugs to inhibit
the nociceptive (pain) response of mice injected with a chemical irritant. This
test is a primary screen for both peripheral and centrally acting analgesic drugs.
Species:
Male Swiss albino mice (15-25 g). The animals are fasted for 18 hours prior
to use but have free access to water.
Drug Preparation and Administration:
Drugs are dissolved or suspended according to their solubility in U.5%
Tween 80 in distilled water. They are administersd by gastric gavage in a
volume of 5 mL/kg. For primary screening all drugs are administered at
the arbitary dosage of 25 mg/kg, p.o. to a group of 10 mice.
Methodological Details:
A modification of the method of Siegmund et al, Proc. Soc. Exp. Biol.
Med., 95, 729-731 (1957) is used. Groups of 5 mice are dosed with the test
compound or vehicle control. Sixty minutes later the animals are injected
i.p. with 0.3 mLI20 g body weight of a 0.02% solution of
. . , ; :
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AHP-9114 mz
-10-
phenylbenzoquinone (PBQ; 2 phenyl-1,4-benzoquinone) and placed in
individual observation boxes. The number of writhing or abdominal
squirming movements made by each mouse during the following 15 minutes
period is counted. The experiment is repeated with another group of 5
mice and the mean number of writhes per mouse for a group of 10 mice is
calculated.
Presentation of Results:
Drug treated and vehicle-treated control groups are compared and the
percentage protection conferred by the drug is calculated:
Percentage protection = (c-t) 100
c
where c = mean number of writhes in the control group
where t = mean number of writhes in the test drug group
An additional test used to determine the utility of the compound of the
present inventlon is designated: Randall Selitto Test in the Rat
The objective of this test is to assess the potency of peripheral and central
acting drugs in inhibiting the reaction of rats to painful stimulation applied to an
inflamed paw.
Species:
Male Sprague Dawley rats (180-200g) are used. The animals are fasted
overnight prior to drug administration.
Drug preparation and Administration:
Freund's complete Adjuvant (FCA) is prepared by suspending 5 mg killed
and dried mycobacterium butyricum (Difco) in 1 mL mineral oil. The test ,;J
compounds are dissolved or suspended in 0.59b Tween 80 in distilled water
according to their solubility. They are administered by gastric gavage in a
volume of 0.5 mL/lOOg body weight to groups of 10 animals.
~ 3~ AHP-9114 mz
--11--
Methodolo~ical details:
Ten rats are used per group. The method is essentially that described by
Randall and Selitto, Arch. Int. Pharmacodyn. 111, 409 (1957) and the
apparatus which is used to apply pressure to the paw (Analgesi-meter for
the rat paw, Ugo Basile, Comeria, Italy) is a modification of that described
by Gilfoil et al, J. Pharmacol. 142,1(1963). The instrument is basically a
device which exerts a orce that increases at a constant rate. The force is
continuously monitored by a pointer moving along a linear seale and is
measured in grams. The inflammatory reaction is induced in the left hind
paw of rats by injecting 0.1 mL of ~reundls adjuvant intradermally. The test
compound or vehicle is administered 24 hours after the adjuvant. The pain
threshold (vocalization) is determined 1 hour later in the inflamed paw of
the treated and control groups.
Presentation of Results and Criteria for Activity:
Each animal which has a reading 1.5 times greater than the mean reading of
the control-group will be considered as responsive (haivng an analgesic
effect) to treatment. The number of anirnals showing an analgesic effect is
then determined in each group.
The EDso (dose which causes analgesia in 5~% of the animals) using at
least 3 doses is then determined, by the method described in Litchfield and
Wilcoson, J. Pharmacol. Exp. Ther., 96, 99-113 ~1949).
Typical results obtained for the compounds of the present invention in the
aforementioned tests are as follows:
A~P-91 14 mz
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--12--
Table I
Substituted 1,3,4,9-Tetrahydropyrano[3,4-b3indole-1-acetic Acids
~ (I~
R ~ ~ 3 CH2--COOH
C= C ~R
B6' ~R4
Preventative Phenylquinone Randall Selitto
Example Adjuvant Edema~ Writhing in Mice* Test in the Rat*
(13) (48) (0~1)
2 42 25
3 0 (5.2) (1.1)
* The numbers quoted are either percent inhibition at 25 mg/kg or the EDso in
mg/kg given in parentheses.
.: .
The lack of side effects for the compounds of this invention are
demonstrated by standard acute toxicity tests as described by R.A. Turner in
"Screening Methods in Pharrnacology," Academic Press, New York and London,
1965, pp. 152-163, and by prolonged administration of the compound to w~rm-
blooded animals.
When the compounds of this invention are employed as anti inflammatory
and analgesic agents~in warm-blooded animals, they are administered orally,
alone or in ~dosage iorms, ~ i.e., capsules~ or ta~lets~ combined with
pharmacologicalIy acceptable excipients, such as starch, milk sugar and so forth,
or they are administered orally in the form of solutions in suitable vehicles such
as vegetable oils or water. The compounds of this invention may be administered
L 3 ~ HP-9114 mz
--13--
orally in sustained release dosage form or transdermally in ointments or patches.
The compounds of this invention may also be administered in the form of
suppositories.
The dosage of the compounds of formula (I) of this invention will vary with
the particular compound chosen and form of administration. ~urthermore, it will
vary with the particular host under treatment. Generally, the compounds of this
invention are administered at a concentration level that affords efficacy without
any deleterious side effects. These effective anti-inflammatorily and analgesic
concentration levels are usually obtained within a therapeutic range of 1.0 ~g to
500 mg/kg per day, with a preferred range of 1.0 ug to 100 mg/kg per day. The
preferred antiinflammatory dose range is 1 mg to 20 mg/kg b.i.d. The preferred
analgesic dose range is 1 llg to 4 mg/lcg b.i.d.
The compounds of this invention may be administered in conjunction with
nonsteroid anti-inflammatory drugs such as acetaminophen, ibuprofen and aspirin
and/or with OpiQte analgesics such as codeine, oxycodone and morphine together
with the usual doses of caffeine. When used in combination with other drugs, thedosage of the compounds of the present invention is adjusted accordingly.
The compounds of this present invention also pOSS2SS antipyretic activity.
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The following examples further illustrate this invention.
EXAMPLE 1
l-Ethyl-8-(2-propenyl)-2,3,4,g-tetrahydro-lH-carbazol~l-acetic Acid
(I, 3~1= -C2H5, R2, R3, R4, R5, R6, R7= -H~
a) Preparation of 2-Ethylcyclohexanone
2-Ethylcyclohexanol (1.6 mol, 204 g, 226 mL) WQS stirred in 3.2 L of
acetone at 0C and treated with Jones reagent (prepared from 106.8 g of CrO3
suspended in 92 mL of concentrated sulfuric acid and diluted to 400 mL with
water) until the orange color persisted ( ~ 430 mL). Isopropanol was then added
to turn the solution green after which it was poured into 2 L of ether. The
product was washed with 6 x 500 mL of brine, dried over MgSO4 and stripped of
solvent. Short path distillation (b.p. 80-85C at 25 mm) afforded 184 g (1.46
moles, 91%) of 2-ethylcyclohexanone as a colorless oil~
b) Preparation of l-Ethyl-2-oxocyclohexaneacetic Acid Methyl Ester
According to the procedure of E. Negishi and S. Chatterjee, Tet. Lett., 24,
1341 (1983), potassium hydride (417 mmol7 70 mL, ~ 6M in mineral oil) was placedunder nitrogen in a three-necked flask equipped with a mechanical stirrer and
was washed three times with petroleum ether (this washing can be omitted).
Tetrahydrofuran (200 mL, diitilled from sodium/Ph2CO) was then added followed
by a solution of 2-ethylcyclohexanone, prepared in Step a) (50 g, 39f~ mmol) in
200 mL of tetrahydrofuran added as a slow stream over ~15 minutes. The
addition was followed one minute later by 495 mL of lM Et3B in tetrahydrofuran
followed 1 hour later by 594 mmol (91 g, 56 mL) :of methyl brornoacetate. The
yellow suspension was stirred for 2.5 hours, poured into 800 mL of water (being
:
careful to decant away from excess KII!) and extracted with 4 x 300 mL of
petroleum ether. The combined organic phases were dried over sodium sulfate
and concentrated in vacuo. The product WRS distilled through a 6 inches Vigreux ~ ~
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column collecting the material boiling at 107-118C at 0.8 mm (the two
regioisomers from the alkylation). This material was then purified by flash
chromatography (4 inches diameter column, 7.5% ethyl acetate in petroleum
ether eluent, 5 1/2 inches of sil;ca gel) to afford 35.33 g (178.2 mmol, 45%) Oecolorless oil. The desired product is the lower Rf material of the two
overlapping spots on thin layer. Rf=0.23 in 10% ethyl acetate/petroleum ether.
About 5-10% of the 2,6 regioisomer can be isolated as the top spot.
c) Preparation of 8-Bromo-l-ethyl-2,3,4,9-tetrahydr~lH-cm bazole-l-
acetic Acid Methyl Ester
.
2-Bromophenylhydrazine hydrochloride (30 g, 134 mmol) was partitioned
between lN NaOEl (250 mL) and ether (3ûO mL). The ether layer was separated,
dried (MgS04) and concentrated to give a brown oil. The free hydrazine was
dissolved in benzene (370 mL), treated with l-ethyl-2-oxocyclohexaneacetic acid
methyl ester, prepared in Step ~b), (26.5 g, 134 mmol) and refluxed for three days
with a Dean~tark trap. The mixture was then cooled and concentrated to yield
the crude hydrazone as a brown oil. The crude hydrazone was dissolved in glacialacetic acid (96 mL), treated with B~3-OEt2 (24.6 mL, 28.4 g, 200 mmol) and
refluxed for twenty minutes. The reaction was then cooled and slowly poured
into water (1,000 mL) which was extracted with ether (2 x 250 mL). The
combined ether layers were washed with a saturated sodium bicarbonate solution
(lOQ mL), dried (MgS04) and concentrated to give 35.3 g (75%) of a dark brown
oil. The 8-bromo-1-ethyl-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid m~thyl
ester was purified by flash chromatography (silica gel, 15 cm. I.D. x 15 cm. ht.,
7.5% ethyl acetate in hexanes) to give 25.2 g (50%) of the product as an orange
oil.
IR (CHC13) 3410, 3360, 2800-3100,1720 cm~l.
NMR (CDC13, 200 MHz) ~ 0.85 (3H, t, J=7.7Hz), 1.8-2.2 (6H, m), 2.6-2.8 (4H, m3,
3.72 (3H, s), 6.93 (lH, pseudo t, J=7.7 Hz), 7.2 (lH, dd, J-7.7, 0.7 Hz), 7.40 (lH, dd,
J=7.7, 0.7 Hz), 9.4 (lH, br.s).
. .: ,
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3 3~ HP-9114 mz
~16-
MS (EI) m/z 349 (M~), 320 (M+-c2Hs)7 290 (M~-CH2CO2H~-
d) Preparation of l-Ethyl-2,3,4,9-tetrahydro-8-(2-propenyl~-lH-earbazole-l-
acetic Acid
8-Bromo-l-ethyl-2,3,4,9-tetrahydr~lH-carbazol~l-acetic acid methyl
ester, prepared in Step c), (5 g, 14.3 mmol), allyltributyltin (5.92 g, 18 mmol).
benzene (10 mL) and Pd(PPh3)4 (200 mg, 173 mmol) were mixed and heated in a
sealed system at 100C for 48 hours according to the procedure of M. Kosugi9 et
al, Chem. Lett., 301, (19~7). TLC analysis (silica gel plates dipped in 10% aqueous
AgNO3 and dried at 160C for one hour, then at RT for one day7 10~6 ethyl
acetate in petroleum ether) indicated clean formation of a new product (Rf =
0.17) and no starting material ~Rf = 0.52). The reaction mixture was partitionedbetween water (50 mL) and ether (120 mL~. The ether layer was washed with
saturated sodium chloride solution (50 mL), dried (MgSO4), concentrated and
chromatographed (silica gel, 7.5 cm. I.D. x 15 cm. ht., 5% ethyl acetate in
petroleum ether) to give 3.4 g (76%) of 1-ethyl-2,3,4,9-tetrahydro-3-(2-propenyl)-
lH-carbazole-l-acetic acid methyl ester as a yellowish oil. The oil was dissolved
in methanol (50 mL) and treated with potassium carbonate monohydrate (2.7 g,
16.4 mmol) dissolved in water (5 mL). The mixture was then heated at reflux for
16 hours. After cooling, the reaction mixture was concentrated to remove
methanol and partitioned between ether (175 mL) and lN HCl (50 mL). The ether
layer was dried (MgSO4), concentrated, and puri~ied by chromatography (silica
gel, 4.8 cm. I.D. x 15 cm. ht., 40% ethyl acetate in petroleum ether). The active
fractions were concentrated to a viscous oil (3.4 g), then dissolved in petroleum
ether. The crystals which grew from the solution were collected and air dried togive 2.2 g (529~ from the iodide~ o~ 1-ethyl-2,3,4,9-tetrahydro-8-(2-propenyl~lH-
carbazole-l-acetic acid as white needles, m.p. llO-111C.
IR (CHC13) 3450, 3400, 3550-2400,170091460,1230 cm~l.
NMR (CDCL3, 20û MHz) ~ 0.88 (3H, t, J=7.7 Hz), 1.7-2.1 ~6H, m), 2.6-2.8 (4H, m),3.60 (2H, d, J=6.6 Hz), 5.12 (IH, dd, J=1.5) 9.9 Hz), 5.23 (lN, dd, J=16.8, 1.47 Hz),
~'
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-17-
6.04 (lH, ddt, J=6.6, 9.9, 16.8 Hz), 6.96 (lH, d, J=6.6 Hz), 7.03 ~lH, dd, J=6.6, 7.7
Hz), 7.37 (lH, d, J=7.7 EIz), 8.86 (lH, br.s~.
MS (EI) m/z 297 (M+), 268 (M~-C2EIs), 23~ (M+-C~2C02H)-
MA Calculated: C 76.74, N 7.80, H 4.71
Pound:C 76.38, N 7.73, H 4.60
EXAMPLE 2
l-Ethyl-2,3,4,9-tetrahydro-4-methyl-8-(2-propenyl)-
lH-carbazole-l-acetic Acid (Isomer A)
(1~ Rl= -C2H5, R2, R3, R4, R5, R6= -H, R7= -CH3)
a) Preparation of l-Ethyl-2-oxo-3-cyclohexeneacetic Acid Methyl Ester
The l-ethyl-2-oxocyclohexaneacetic acid methyl ester, prepared in
Example 1, Step b), (28 g, 141 mmol) was stirred in 1.25 1 of ethyl acetate (dried
over 3A molecular sieves) and treated with 169 mmol (32.5 g) of PhSeCl. The
reaction was stirred under nitrogen for 4 hours then treated with 250 ml. of
water. The mixture was shaken vigorously in a separatory funnel and the organic
phase was returned to the reaction flask. Tetrahydrofuran (550 mL) was then
added followed by 35 mL of 30% H22 (aq.) added dropwise. The reaction
mixture was stirred for one hour then washed with 500 mL of water and 500 mL
of saturated Na2CO3 (aq.). The product was then dried over MgSO4 and
concentrated in vacuo. Flash chromatography (~ inches diameter column, 20%
ethyl acetate in petroleum ether eluent, 5 1/2 inches of silica gel) afforded 15.3 g
(78.0 mmol, 55%) of the product as a pale yellow oil. Rf=0.9 in 15% ethyl
acetate/petroleum ether on TLC.
b) Preparation o~ l-Ethyl-4-methyl-2-oxocyclohexaneacetic Acid Methyl
Ester
:., ~ :. .:
~31L1~3~ ~\HP-9l14 mz
-18-
A solution of l-ethyl-2-oxo-3-cy(!lohexeneacetic acid methyl ester,
prepared in Step a), (14 g, 71.47 mmol), copper (I) bromide-dimethyl sulfide
complex (1.47 g, 7.15 mmol) and methyl sul~ide (14.3 mL) in dry tetrahydrofuran
(210 mL) was cooled under nitrogen to _a,oo C and treated dropwise with a solution
of methyl magnesium iodide (23.8 mL of a 3M solution in ether, 71.5 mmol). The
reaction was then quenched with lN HCl (200 mL) and extracted with ether (3 x
100 mI,) and petroleum ether (100 mL). The combined organic layers were dried
(MgS04), concentrated, and chromatographed (silica gel, 9.5 cm. I.D. x 15 em.
ht., 15% ethyl acetate in petroleum ether) to give 22.5 g (106 mmol, 74%) of oil.
The diastereomers were separated by chromatography on silica gel. The
more rapidly eluting isomer is Isomer A.
NMR (CDC13/TMS; 200MHz) ~ 0.78 (t, 3H, J=7.62), 1.01 (d, 3H, J=6.35), 1.4-2.4
~m, 9H), 2.34 and 2.66 (2d, ABq, 2H, J=15.87~, 3.65 (s, 3H).
The more slowly eluting isomer is Isomer B.
NMR (CDC13/TMS, 200MHz) ~ 0.81 (t, 3H, J=7D46)~ 1.04 (d, 3H, J-6.66), 1.4-2.8
(m, 9H), 2.56 (s, 2H), 3.64 (s, 3H).
c) Preparation of l-Ethyl-2,3,4,9-tetrahydro-4-methyl-8-(2-propenyl)-lH-
carbazole-l-acetic Acid (Isomer A)
The A isomer of l-ethyl-4-methyl-2-oxocyclohexaneactic acid methyl
ester, (2.04 g, g.6 mmol) prepared in Step b), (2.04 g, 9.6 mmol) and o-
bromophenylhydrazine (1.9 g, 9.6 mmol) were combined in benzene (26 mL) and
heated at reflux with a Dean Stark trap for 18 hours to form the hydrazone. The
mixture was then concentrated, dissolved in glacial acetic acid (7 mL), treated
with BF3-OEt2 (1.77 g, 1.53 mL, 12.5 mmol3 and heated at reflux for thirty
mintues. The reaction mixture was allow2d to cool9 poured into water (30 mL)
and extracted with ether (4 x 25 mL)~ The combined ether layers were washed
with saturated sodium bicarbonate solution (25 mL~, saturated sodium chloride
.
AHP-9114 mz
~ 3 ~
--19--
solution ~25 m1), dried (MgSOa~) and concentrated. The crude 8-bromo-1-ethyl-
2,3,4,9-tetrahydro-4-methyl-lH-carbazole-l-acetic acid methyl ester was then
purified by chromatography (silica gel, 4.8 x 15 cm, 5% ethyl acetate in hexane)to give 1.69 g (48%) of product.
The puriiied 8-brom o-1-ethyl-2,3,4,9 -tetrahydr~4-m ethyl-lH-carbazole-l-
acetic acid methyl ester (1.7 g, 4.6 mmol), allyltributyltin (1.92 g, 5.8 mmol),benzene (0.1 mL) and tetrakis(triphenylphosphine) palladium(0) (64.3 mg) were
combined in a sealed tube and heated at 100C for 72 hours. The reaction
mixture was cooled and partitioned between ether (60 mL) and water (50 mL).
The ether layer was washed with saturated sodium chloride (25 mL), dried
(MgSO4) and concentrated to an oil. The oil was chromatographed (silic~ gel, 7.5x 15 cm, 5% ethyl acetate in petroleum ether) to give 1.26 g (83%) of the l-ethyl-
2,3,4,9-tetrahydro-4-methyl-8-(2-propenyl)~lH-carbazole-l~acetic acid methyl
ester as a yellowish oil.
The l-ethyl-2,3,4,9-tetrahydr~4-methyl-8-(2-propenyl)-lH-carbazole-l-
acetic acid methyl ester (1.26 g, 3.9 mmol) was dissolved in ethanol (20 mL),
treated with potassium carbonate (1.08 g, 7.8 mmol) dissolved in water ~3 mL)
and heated at reflux for 18 hours. The reaction mixture was cooled,
concentrated to remove methanol and portioned between ether (50 mL) and lN
HCl (30 mL). The ether layer was washed with saturated sodium chloride
solution, dried tMgSo4), and concentrated. The product was purified by
chromatography (silica gel, 3.9 x 15 cm, 40% ethyl acetate in hexanes) to give
703 mg (58%), m.p. 107-109C, of the l-ethyl-2,3,4,9-tetrahydro-4-methyl-8-(2-
propenyl)-lH-carbazole-l-acetic acid af ter recrystallization from m ethylene
chloride hexanes. The yield was 23.5% overall from 1-ethyl-4-methyl-2-
oxocyclohexane~cetic acid methyl ester.
IR (KBr) 3390, 3500-2400, 1690 cm~l
NMR (C1)C13, 200MHz) ~ 0.87 (3H, t), 1.33 (3H, d9 J=6.0~, 1.6 (2H, m), 1.89-2.0
(4H, m), 2.72 (2H, 2d), 3.1 (lH, m), 3.6 (2H, d), 5.14-5.27 (2H, 2dd), 6.0 (lH, ddt),
6.93 (lH, d), 7.02 (lH, t), 7.45 (lH~ d)3 8.80 (lH, br.s.)
.
.
~: .
~3~ ~ 4~ AHP-9114 mz
-20-
MS (EI) m/z 311 ~M+), 296 (M~-CH3~, 282 (M+-CH2CH3), 252 (IN~-CH2CO2H).
MA Calculated C 77.12; H 8.10; N 4.50
Found C 76.91; H 7.93; N 4.38
PL~ 3
I-Ethyl-2,3,4,9-tetrahydro-4-methyl-8-
t2-propenyl)-lH-carbazole-l-acetic Acid (Isomer 13)
(I, Rl= -C2Hs; R2, R3, R4, R5, R~= -H, R7- -CH3)
The B isomer of l-ethyl-4-methyl-2-oxocyclohexaneacetic acid methyl
ester, prepared in Example 2, Step b) was reacted in a similar manner as
Example 2, Step c) to give l-ethyl-2,3,4,9-tetrahydro-4-methyl-8-(2-propenyl)-
lH-carbazole-l-acetic acid (Isomer B), m.p. 130-132 C, in 29.2% overall yield.
IR (KBr) 3430, 3500-2400,1690 cm~l
NMR (CDC13, 20ûMHz) ~ 0.85 (3H, t), 1.37 ~3H, d, J=6.98Hz),1.55 (lH, m), 1.7-2.1(4H, m), 2.75 (2H, br.s.), 3.1 (lH, m), 3.5 (2H, d), 5.1-5.3 (2H, 2dd), 5.9-6.1 (lH,
ddt), 6.94 (lH, d), 7.01 (lH, t), 7.48 (lH, d), 8.9 (lH, br.s.)
MS (EI) m/z 311 (M+), 296 (M ~-CH3), 282 (M+-CH2CH3), 252 ~M+-CH2CO2H)
MA Calculated C 77.12; H 8.10; N 4.50
Found C 77.28; H 8.09; N 4.44
~ .,
:
-
-.
-
