CA1311485C - Substituted 2,3,4-9-tetrahydro-1h-carbazole-1-acetic acid - Google Patents

Abstract

ABSTRACT

Substituted 2,3,4,9-tetrahydro-1H-carba-zole-1-acetic acid derivatives and methods for their preparation and use are disclosed. The compounds are useful analgesic and anti-inflammatory agents. The compounds have the structure:

Description

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SUB~ST~UTED 2,3,4,9~ TRAHYDR~lE~ARBAZOLE-l-ACEl~lC ACID

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 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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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 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 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) ~ R2 :`
6 / \ I (IV) R C -M

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) : .

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R5 ~ C2c~3 (V) :
wherein Rl, R2, R3, R4, R5, R6 E.nd R~ are as defined above.

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~ 33 ~ 3 AHP-9114 mz 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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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 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.

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, AHP-9114 mz _g _ 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 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 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:

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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) 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.
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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 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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~ , , ~31~ 4~5 A~IP-9114 mz The following examples further illustrate this invention.

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), ~' :
:' ~L 3 ~ AHP~ mz 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 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 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 ~

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 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 ~ ., :

--.

-

Claims (9)

1. The compounds having the structure (I) (I) wherein R1 is lower alkyl containing 1 to 4 carbon atoms and R2, R3, R4, R5, R6 and R7 are hydrogen or lower alkyl containing 1 to 4 carbon atoms and the pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1 having the structure (I) wherein R1 is ethyl, R2, R3, R4, R5 and R6 are hydrogen and R7 is hydrogen or methyl and the pharmaceutically acceptable salts thereof.

3. The compounds according to claim 2 designated 1-ethyl-8-(2-propenyl)-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid and the pharma-ceutically acceptable salts thereof.

4. A compound according of claim 2 designated 1-ethyl-2,3,4,9-tetrahydro-4-methyl-8-(2-propenyl)1H-carbazole-1-acetic acid where the 4-methyl and 1-acetic acid substituents are cis or trans and the pharma-ceutically acceptable salts thereof.

5. The process for producing compounds of formula (I) (I) AHP-9114 mz wherein R1 is lower alkyl containing 1 to 4 carbon atoms and R2, R3, R4, R5, R6 and R7 are hydrogen or lower alkyl containing 1 to 4 carbon atoms and the pharmaceutically acceptable salts thereof which comprises a) reacting the ketone of structure (II) (II) wherein R1 and R7 are as defined above with ortho-bromophenylhydrazine to form a phenylhydrazone and further reacting the hydrazone in the presence of acetic acid and borontriflouride-etherate to obtain compounds of structure (III) (III) wherein R1 and R7 are as defined above b) reacting compounds of structure (III) with compounds of structure (IV) (IV) wherein R2, R3, R4, R5 and R6 are as defined above and M is trialkylstannyl to give compounds of structure (V) (V) c) hydrolyzing the esters of compounds of structure (V) to obtain compounds of structure (I) and optionally forming a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of structure (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound of structure (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, a nonsteroid anti-inflammatory drug selected from the group consisting of acetaminophen, ibuprofen and aspirin? an opiate analgesic selected from the group consisting of codeine, oxycodone and morphine and a pharmaceutically acceptable carrier.

8. The use of an effective amount of a compound selected from those of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, for treating inflammatory or painful conditions in a mammal.

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9. The use of an effective amount of a compound selected from those of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in conjunc-tion with nonsteroid anti-inflammatory drugs and opiate analgesics, for treating inflammatory or painful conditions in a mammal.