CA1311484C - Substituted 2,3,4,9-tetrahydro-1h-carbazole-1-acetic acid - Google Patents

Abstract

ABSTRACT

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

Description

AHP-~112 mz ~ 31 ~ P~rENT

SUBSl~TUTED 2,3,4,9-TETRAHYDR~lH{~ARBAZOLE-l-ACEII~ ACID

BACE~GROUND O~ THe INVENTION

a. Field of Invention This invention relates to tricyclic acetic acid derivatives, to their preparation and use.

More specifically, this invention relates to tricyclic acetic 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[~,~Q2 2,3,4,9-tetrahydr~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 usef ul pharmacologic properties; for instance, they exhibit analgesic and anti-inflammatory activity at dose levels which do not elicit undesirable side effects.
The foregoin~ combination of attributes renders the compounds of this invention useful for the treatment of inflammatory or painful conditions in a mammal.

b. Prior Art The closest prior art to the present invention is:

.

' -2- ~3~ 1~8~

Mobilio et al, United States Patent No. 4,616,~28 issued CctGber 7, 1986, Unlted States Patent No. 4,578,398 and United States Patent No. 4,584,312, and Asselin et al. United States Patent No. 4,057,559. Mobilio et al, and Asselin et al, disclose analgesic and anti-inflammatory agents having -the same heterocyclic ring system as the present invention but without the 1-, 4- and 8-substituents 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-tetrahydrothiopyrano[3,4-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 42593 generically discloses starting materials useful for producing caraiotoni~ and beta-blocking agents. The starting materiaIs include 1,2,3,4-tetrahydrocarbazoles with substituents selected from the broad group including hydrogen, carboxy, lower alkyl and lower alkenyl.The starting materials are in each case also substituted with a reactive group which distin~uishes them from the compounds of the present invention.

Further removed, related patents that include tetrahydroc rbazoleacetic 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; 4,1463542; 3,896,145 and 3,824,314; Japanese Patent J51032556; Netherland Patent NL 7,100,213 and Great Britain Patent GB 1385620.

SU~IMARY O~ TH~ IN~ENTION
The compounds of this invention are represented by formula (I) R
~ (I) ~jG~ 2 H CH2- COOH
R ~

.
.:

. .

:
, AHP-9112 mz wherein Rl is l~wer alkyl containing I to 4 carbon atoms and R7 R2, R3 and R4 are independently selected from the group consisting of hydrogen and lower alkylcontaining 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 R is hydrogen and 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 R is hydrogen and Rl is ethyl and R2, R3 or R4 is methyl and the pharmaceutically acceptable salts thereof.

The most preferred compounds of the present invention are designated 8-ethenyl-l-ethyl-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid and (Z)-l-ethyl-2~3,4~9-tetrahydro-8-~l-propenyl)-lH-carbazole-l-acetic acid.

The compounds of the present invention are prepared by a process in which the ketone of structure (II) ~R~

wherein R and Rl are as defined above is reacted with ortho-iodophenylhydrazine to form a phenylhydrazone. The hydrazone is further reacted in the presence of acetic acid and borontriflouride-etherate to obtain compounds of structure (III) R

~ ~llU

AHP-9112 mz wherein R and Rl are as defined above.

Compounds of structure tIlI) or their carboxylic acids are reacted with olefins of structure (IV) R5 (IV) wherein R5 is hydrogen, lower alkyl containing 1 to 4 carbon atoms or trimethyl silyl in the presence of palladium catalyst such as tetrakis(triphenylphosphine)-palladium~O) or palladium dichloride with added triphenylphosphine with or without a copper catalyst such as copper iodide to give compounds of structure (I) or their esters, wherein R, Rl, R29 R3 and R4 are as defined above.
Compounds of structure (111) or their carboxylic acids are reacted with acetylenes of structure ~V) R5-C _C - R6 (V) wherein R5 is as defined above and R6 is hydrogen, lithium or copper in the presence or absence of palladium or copper catalyst as described above to obtaincompounds of structure (VI) or their acids ~ (Vl) ,C5 wherein R, Rl and R5 are as defined above.

Compounds of structure (VI) or their acids are reacted with hydrogen gas in the presenee of prllr~dium catrlyst sueh QS pslladium on bsriu~ esrbonate :

.

.

HP-gll2 mz poisoned with lead to give compounds oî structure tI) or their esters wherein R,Rl and R3 are as defined above and R2 and R4 are hydrogenO

Compounds of structure (I), (III) and (YI) are obtained from their esters by hydrolysis.

For basic hydrolysis a preferred 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 example9 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 lû minutes to 48 hours is sufficient for this hydrolysis. The reaction mixture is then rend0red acidic with an acid, for example, acetic acid9 hydrochloric acid, sulfuric acid and the like, to release the free acid as a solid.

Alternatively, the tricyclic ester is hydrolyzed 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 acid9 hydrobromic acid, hydroiodie acid, sulfuric acid, phosphoric acid and the like in a suitable sol~rent at a temperature of at least 60C and preferaMy from 90C to the boiling point of the mixture until the hydrolysis occurs. Usually from 5 to 48 hours are required for this hydrolysis. Suitable solvents include water, acetic acid, aqueous alcohols and the like. If acid hydrolysis is used, the free acid is formed directly. If necessary, the reaction mixture can be diluted with water toprecipitate the product.

.
DETAILED DESCRIPTION O~ T~ I~ENTION

The term "lower alkyl" as used herein represents straight chain alkyl radicalr contrining I to 4 crrbon atoms and branched cht-- rlkyl radicrls .

...... . .
,-~ 3 ~ AHP-9112 rnz containing 3 to 4 carbon atoms and includes rnethyl, ethyl, propyl, isopropyl, butyl, ;sobutyl, and the like.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

The compounds ot formula (I) form salts with suitable pharmaceutical]y 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-allcylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, dl- and triethylamine, methylethylamine, and the like; mono, di- andtrialkanolamines, the alkanol radicals of which contain up to three carbon atoms, such as mon~, di- and triethanolamine; alkylenediamines which contain up to six carbon 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 derivatives7 such asN-methylmorpholine and N-(2-hydroxyethyl)piperidine, as well as pyridine.
Purthermore, there may be mentioned the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl3, alkyl-alkanol (for example methyltrimethanol and trimethyl-monoethanol) and cyclic ammonium salts, for example the N-methyl-pyridinium, N-methyl-N-(2 hydroxyethyl)-morpholinium, N,N-dimethyl~morpholinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylpiperidinium salts, which are characterized by good water-solubility. InprinciL)le, however, there can be used all the ammonium salts which are physiologically compatible.

^- :'' ',,' " .

.
:

HP-9112 m~
_~ 7 The transformations to the salts can be carried out by a variety of methods known in the art. For example, in the case of salts of inorganic bases, it is preferred to dissolve the acid of formula (I) in water containing at least one equivalent amount of a hydroxide, carbonate, or bica~bonat0 . Advantageously, the reaction is performed in a water-miscible organic solvent inert to the reaction conditions, for example, methanol, ethanol, dioxaneg 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 OI a more moderate polarity, for example, a lower alkanol, for instance, butanol, or a 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 example, benzene or petroleum ether, or by evaporation. If th~ amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use equivalent amounts of 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.

~ lso included in this invention are the optical isomers of the compounds of formula (I) which result from asymmetric centers, contained therein. Such .. .

.
' ~8- ~L 3 ~

isomers can be obtained in substantislly pure form by classical separation techniques and by sterically controlled synthesis.

ANTI-INFLAMMA'rORY ACTIVITY
The useful anti-inflammatory activities of the compounds of formula (I) are demonstrated in standald 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 (1~0-200g) are used. The animals have free access to water but food is withdrawn 18 hours before testing.

Dru~ Preparations and Administration:
Freund's Complete Adjuvant is prepared by suspending 5 mg killed and dried ycobacterium butyricum (Difco) in 1 mL mineral oil. The test compounds are dissolved, or suspended in 0.5% Tween 80 in distilled water according to their solubility. For primary screening all drugs are administered by gastric lavage at the arbitrary dosage of 25 mg/kg, p.o. in a volume of 0.5 mL/100 g body weight to groups of 10 animals.

Methodological 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 wlth 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 diference between the hind paw volume on ~day 0 and * Trade mark - , . .

.~, .

HP-9112 mz _g _ day 3 represents the edema volume. Etodolac ~25 mg/kg, p.o.) is ineluded as a positive control.

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 calculated:
% protection = (c-t) 100 c where c is the mean edema volume for the vehicle-treated (0.5% Tween 80 in distilled water) controls and t is the mean edema volume for the drug treated group.

Lrll~lC AC~
A further test used to determine the utility of the compounds of the present invention is designated: Drug Effects on Phenylbenzoquinone-induced Writhing in Mice The objective 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 0.5%
Tween 80 in distilled water. They are administered 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.

Methodologieal 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 . ~
. ' -' ' :

~ 3 ~ 3 ~ ~HP-9112 m~

compound or vehicle control. Sixty minutes later the animals are injected i.p. with 0.3 mL/20 g body weight of a 0.02% solution of phenylbenzoquinone (PBQ; 2-phenyl-1,4-benzoquinone) and placed in individual observation boxes. The nurnber 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 lO 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-$) lO0 c where c = mean number of writhes in the control group where t = mean number of writhes in the test drug group Typical results obtained for the compounds of the present invention in the aforementioned tests are as followsO

Table I

Substituted 2,3,4,9-Tetrahydro-lH-carbazole-l-acetic Acids R

2-C003 (1~ ~

' ~ 3 ~ HP-9112 mz Preventative Phenylquinone Example Adjuvant Edema * Writhing in Mice *
(102) 2 (10) (43) ~ 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 described by R.A. Turner in 'IScreening Methods in Pharmacology," Academic Press, New York and London, 1965, pp. 152-163 and by prolonged administration of the compound to warm-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 forms, i.e., capsules or tablets, combined with pharmacologically 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 orally in sustained release dosage form or transdermally in ointments or patches.
The compounds of this invention may also be administered in the form o suppositories.

The dosage of the compounds of formula I of this invention will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under tr~atment. Generally, the compounds of this invention are adminlstered 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, wi~h a preferred range of 1.0 llg to 100 mg,kg pcr day. rhe :

~ , .

: :

~L 3 ~ AUY-9112 m~

preferred anti-inflammatory dose range is 1 mg to 20 mg/lcg b.i.d. The preferredanalgesic dose range is 1 ,ug to 4 mg/kg 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 opiate analgesics such as codeine9 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 possess antipyretic activity.

AHP-9112 mz The following examples further illustrate this invention.

8-Ethenyl-l-ethyl-2,3,4,9-tetrahydro-lH-carbazole-l-acetic Acid (I, Rl= -C2Hs, R, R2, R3, 1~4= -H) a) Preparation of 2-Iodophenylhydrazine Hydrochloride A mixture of concentrated hydrochloric acid (115.2 mL~ and distilled water (51~2 mL) was cooled in an ice water bath while 2-iodoaniline (100 g, 0.457 mol)was added slowly with vigorous stirring resuIting in a thick tan suspension. Themixture was cooled to -5C and a solution of sodiurn nitrite (35 g, 0.492 mol) in water (51.2 mL) was added dropwise. The resulting yellow mixture was maintained at 0C while a solution of tin (Il)chloride dihydrate (232 g, 0.9 mol) in 6N HCl (312 mL) was added dropwise over 2 1/2 hours, to form a pale yellow slurry. After stirring at room temperature for 24 hours, the mixture was treatedwith 50% NaOH, added dropwise with vigorous stirring, until the aqueous layer was basic. The free hydrazine was extracted with ether (3 x 1 L). The ether layers were combined, washed with water (1 L), saturated NaCl solution (1 L), concentrated to 500 mL and dried (MgSO4). With cooling and vigorous stirring, HCl (gas) was introduced into the solution to yield an off white precipitate. This was filtered, washed with ether and dried under vacuum at room temperature to give an off-white solid (112 g, 91% yield) m~p. 149-150 C.

b) Preparation of 2-Ethylcyclohexanone 2-Ethylcyclohexanol (1.6 mol, 204 g, 226 mL) was 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 mLj. Isopropanol was then added to turn the solution green after which it was poured into 2 L of ether. The product was weshed with 6 x 500 m L of brme, dried ov<r MgS04 aDd .

~ .: .. : - ~ . , :

~ 3 ~ 4 AHP-9112 mz stripped of solvent. Short path distillation (b.p. 80-85C at 25 mm) aforded 184 g (1.46 moles, 91%) of 2-ethylcyclohexanone as a colorless oil.
c) Preparation of 2-Carbomethoxymethyl-2-ethyleyclohexanone According to the procedure of E. Negishi and S. Chatterjee, Tet. Lett., 24, 1341 (1983), potassium hydride (417 mmol, 70 mL, ~ 6M in mineral oil) was placecl under nitrogen in a three-neeked flask equipped with a mechanical stirrer and was washed three times with petroleum ether (this washing can be omitted).
Tetrahydrofuran (200 mL, distilled from sodium/Ph2CO) was then added followed by a solution of 2-ethylcyclohexanone, prepared in Step b) (50 g, 396 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 bromoacetate. The yellow suspension was stirred or 2.5 hours, poured into 80û mL of water (being careful to decant away from excess KH!) 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 was distilled through a 6 inches Vigreux column collecting the material boiling at 10~-118 C 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, 5112 inches of silica gel) to afford 35.33 g (178.2 mmol~ 45%) of colorless oil. The desired product is the lower Rf material of the two overlapping spots on thin layer. Rf=0.23 in 1096 ethyl acetate/petroleum ether.
About 5 10% of the 2,6 regioisomer can be isolated as the top spot.

d) Preparation of l-Ethyl-8-iodo-2,3,4,9-tetrahydro-lH-oarbazole-l-acetic Acid Methyl Ester : ~:
Solid 2-iodophenylhydrazine hydrochloride (25.6 g9 9g.6 mmol), prepared in Step a), was partitioned between lN NaOH (150 mL) and ether (200 mL). The aqueous layer was washed with more ether (200 mL). The combined ether layers were washed with saturated NaCl ~50 mL), dried (MgS04) and concentrated to ', ;', .,,,, ~. ,. ' ' ' ' :

:L 3 ~ AHP-9112 mz -~ -15-give 21.3 g (91 mmol) of a reddish oil. The oil was dissolved in benzene (250 mL) and the ketoesl er, 2-carbom ethoxym ethyl-2-ethylcyclohexanone, prepared in Step (c), (18 g, 91 mmol) was added. The mixture was refluxed using a Dean~tark trap until starting materials were no longer present (usually around 20 hours) to form the intermediate hydrazone (TLC on silica gel in 10% ethyl acetate in hexanes gave hydrazine Rf=0.09; keto-ester Rf=0.18; hydrazone Rf=0.37; indole Rf=0.43). The reaction mixture was then cooled, concentrated to an oil and redissolved in glacial acetic acid (115 mL). According to the procedure of Snyder, H.R. and C.W. Smith, JACS, 46, 2452 (1943), boron trifluoride etherate (20 g, 141 mmol) was added and the reaction mixture was heated at reflux for 30 minutes.
The mixture was cooled and poured into ice water (350 mL) which was extracted with ether (3 x 350 mL). The combined ether layers were washed with saturated sodium bicarbonate solution, dried (MgSO4) and concentrated to give a brown oil.The product was then purified by flash chromatography (silica gel, 15 cm I.D. X
15 cm ht., 5% ethyl acetate in petroleum ether) to give 18.6 g (51%) of a light reddish oil which slowly solidified on standing in the freezer.

NMR (CDC13) ~ 0.87 (3H, t, J=7.7 Hz), 1.55-2.2 (6~, m), 2.55-2.85 (4H, m), 3.75 ~3H, s), 6.91 (lH, t), 7.32-7.65 (2H, 2d), 9.35 (lH, br.s).
IR (neat) 3360, 3060, 3000-2840,1730 cm~l.

e) Preparation of 8-l~thenyl-l~ethyl-2,3,4,9-tetrahydro-lH-carbazole-l-acetic Acid Methyl Ester.

l-Ethyl-8-iodo-2,3,499~tetrahydro-lH-carbazole-l-acetic acid methyl ester~
prepared in Step (d), (7 gms, 17.6 mmol), triphenylphosphine (190 mg, 724 mmol) and palladium (II) acetate (81 mg, 360 mmol) were combined in a glaæs pressure vessel, dissolved in DMF (50 mL) and bubbled with nitrogen gas for fifteen minutes. Triethylamine (9 mL) was added and the solution bubbled with nitrogen gas another two minutes. Vinyltrimethylsilane (9 mL, 5.8 g, 58.3 mmol) was added and the mixture was sealed and heated at 125C for two hours. The reaction mixture was then cooled to room temperature. TLC

~3~ AHP-9112 mz analysis {silica gel, 10% ethyl acetate in petroleum ether) indicated clean formation of two products, A (Rf=0.50) and B (Rf=0.34) and no starting material (Rf=0.42). The mixture was partitioned between water and ether (200 mL each).
The aqueous layer was washed with more ether (50 mL). The combined ether layers were washed with saturated sodium chloride solution ~100 mL), dried (MgSO4~, concentrated and purified by flash chromatography ~silica gel, 7.5 cm I.D. x 15 cm ht., 5% ethyl acetate in hexanes) to give 2.2 g (34%) of the ~E)-l-ethyl-233,4,9-tetrahydr~8-[2-(trimetllylsilyl)etheny~-lH-carbazole-l-acetic acidmethyl ester compound A and 2.15 g (41%) of 8-e~henyl-1-ethyl-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid methyl ester compound B.

NMR of compound A (CDC13, 60 MlIz) ~ 0.25 (9H, s), 0.9 (3H, t), 1.6-2.3 (6H, m),2.6-2.9 (4H, m), 3.75 (3H, s), 6.6 (lH, d, J=18Hz), 6.9-7.5 (4H, m), 10 (lH, br.s).

NMR of compound B (CDC13, 60 MHz) ~ 0.9 (3H, t), 1.6-2.3 (6H, m), 2.6 2.9 (4H, m), 3.75 (3H, s), 5.5 (lH, d, J=12Hz), 5.9 (lH, d, J-18Hz), 6.9-7.6 (4H, m), 9.75 (lH, br.s).

f) Preparation of B-Ethenyl-l-ethyl 2,3,4,9-tetrahydro-lH-carbazole-l-acetic Acid The 8-ethenyl-1-ethyl-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid methyl ester (3.36 mg, 11.3 rnmol) prepared in Step e), was dissolved in methanol (100 mL). Potassium carbonate monohydrate (2.2 g, 13.6 mmol), dissolved in water (10 mL), was added and the mixture refluxed for 16 hours. The reaction mixture was then cooled and concentrated to remove methanol. The residue was partitioned between ether (100 mL) and lN HCl (30 mL). The e$her layer was washed with saturated sodium chloride solution (25 mL), dried (MgSO4), concentrated and purified by flash chromatography (silica gel, 4.8 cm I.D. x 15 cm ht., 3~% ethylacetate in hexanes). The product was then recrystallized from benzene/he2~anes to give 1.3 g t41%) of a tan solid, m.p. 136-13~C. This compound is quite unstable in solution, apparently undergoing acid catalyzed polymerization. It appears to be stable as a salt.

AHP-9112 mz IR (KBr) 3400,1700 cm~l.

NMR (CDC13, 60 MHz) ~ 0085 (lH, t),1.6-2.2 (6H, m), 2.5-2.9 (4H, m), 5.4 (lEI, dd, J=2, 11 Hz), 5.8 (lH, dd, J=2, 18 Hz), 6.7-7.7 (4H, m), 9.25 (lH, br.s), 10.1 (lH, v.br.s).
MS (EI) m/z 283 (M~), 254 (M+- C2Hs)9 224 (M+ - CH2CO~H).

Calculated C 76.30; H 7.47; N 4.93 Found C 76.24; H 7.47; N 4.87 (Z)-l-Ethyl-2,3,4,9-tetrahydro-8-(1-propenyl)-lH-carbazole-l acetic Acid (I, Rl- -C2Hs, R, R2, R4= -H, R3= -CH3) a) Preparation of Copper (I) propyne Propynyl lithium ~3.96 g, 86.1 mmol) was added to THF (300 mL) and stirred to orm a suspension. Copper (I) iodide (16.4 g, 86.1 mmol) was added and the mixture heated at reflux for one hour. The mixture was then cooled and a bright yellow precipitate was collected by filtration. The filtered product was washed with plenty of water, ethanol and finally ether, then dried under vacuum to give5.84 g (66%) of the prownyl copper as a greenish yellow solid.

b) Preparation of l-Ethyl-2,3,4,9-tetrahydro-8~ propynyl)-lH~-carbazole-l-acetic Acid Methyl Ester l-Ethyl-8-iodo-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid methyl ester, prepared in Example 1, Step a) to d~, (5 g 12.6 mmol), copper (I~ propyne9 prepared in Step a), (2.6 g, 25.4 mmol)9 pyridine (100 mL) and Pd(PPh3)2G12 ~10 mg~ were bubbled with nitrogen gas then heated to reflux for 2 ~hours. The reaction mixture was cooled and diluted with~ ether to 250 mL. The ether was . .: . .

-18~
.
*

filtered through Celite, washed with saturated copper sulfate sollltion (3 x 100mL), washed with lN HCl (100 mL), washed witll saturated sodium chloride solution (5û mL), dried (MgSO4) and concentrated to give 3.9 g (100,6~ of a brown oil. The product was purified by flash chromatography (silica gel, 7.5 cm I.D. x15 cm ht., 10% ethyl acetate in petroleum ether) to give 2.61 g (67%) of l-ethyl-2,3,4,9-tetrahydro-8-(1-propynyl)-lH-carbazole-l-acetic acid methyl ester as an oil.

NMR (CDCI3, 200 MHz) ~ 0.83 (3H, t), 1.6-2.1 (6H, m), 2.18 (3H, s), 2.6-2.8 (4H,m), 3.7 (3H, s), 7.01 (lH, t), 7.22 (lH, d), 7.45 (lH, d), 9.18 (lH, br.s).

c) Preparation of (Z)-l-Ethyl-2,3,4,9-tetrahydro-8~1-propenyl)-lH-carbazole-l-acetic Acid Methyl Ester l-Ethyl-2,3,4,9-tetrahydro-8-(1-propynyl)-lH-carbazole-l-acetic acid methyl ester, prepared in Step b), (2.3 g, 7.4 mmol) was dissolved in methanol (50 mL),treated with Lindlar catalyst (Pd/CaCO3/Pb), (250 mg), flushed repeatedly with hydrogen gas and left under hydrogen for 15 hours. TLC analysis indicated no starting material. The reaction mixture was filtered through Celite, concentrated, then purified by flash chromatography (4.8 cm I.D. x 15 cm ht., 5%ethyl acetate in petroleum ether) to give the desired product almost quantitatively.

d) Preparation of ~Z)-1-Ethyl~2,3,4,9-tetrahydro-8~1-propenyl)-lH-carbazole-1-acetic Acid (Z)-l-Ethyl-2,3,4,9-tetrahydro 8-(1-propenyl)-lH-carbazole-l-acetic acid methyl ester, prepared in Step c), (5.1 g, 16.4 mmol) was dissolved in methanol (75 mL), treated with potassium carbonate monohydrate (4 g, 24.2 mmol) dissolved in water (10 mL) and heated at reflux or 16 hours. The reaction mixture was then cooled and concentrated to remove methanol. The residue was partitioned between lN HCl (60 mL) and ether (100 mL). The ether layer was washed with saturated sodium chloride solution (50 mL), dried (MgSO4) and concentrated to :
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~311~ AHP-9112 m~

give 4 g of a yellow oil. The product was purified by flash chromatography (7.5 cm I.D. x 15 cm ht., 40% ethyl acetate in petroleum ether) to give 3.2 g (66%) of an off-white solid. The product was dissolved in ethyl acetate and concentrated to a viscous oil. Dissolution of the oil in petroleum ether (lOU mL) led to cryst~llization of (Z)-l-ethyl-2,3,4,9-tetrahydro-8-(1-propenyl)-lH-carbazole-l-acetic acid as 2.66 g (55%) o a white crystal]ine product, m.p. 114-115Co IR (KBr) 3360, 2200-3400,1600,1130 cm.~l.

NMR (CDC13, 200 MIIz) ~ 0.877 (3H, t, J=7.7Hz~, 1.7-2.2 (6H, m), 1.8 (3H, dd, J=l.9, 7.0 Hz), 2.7-2.9 (4H, m), 6.0 (lH, dq, J=7.0, 11.4Hz), 6.60 (lH, dq, J=l.9, 11.4Hz), 7.0 (2H, m), 7.38 (lH, m), 8.7 (lH, br.s).

MS (EI) m/z 297 (M+), 268 (M~-C2Hs), 238 (M+-CH2C02H) Calculated C 76.~4, H 7.8, N 4.71 Found C 76.82, H 7.99, N 4.71 C 76.59, H 8~05~ N 4~68 (E)-l-Ethyl-2,3,4~9-tetrahydr~8-(1-propenyl)-lH-carbazole-l-acetic Acid ~I, Rl= -~2Hs, R, R2, R4= -H, R3= -CH3) and l-Ethyl-2,3,4,9-tetrahydro-8-(1-methylethenyl)-lH carbazole-l-acetic Acid (I, Rl= -C2Hs, R, R3, R4= -H, R2=-CH3) a) Preparation of l-Ethyl-8-iodo-2,3,4,9-tetrahydro-lH-carbazole-l-acetic Acid l~Ethyl-8-iodo-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid methyl ester, prepared in Example 1, Step a) to d) (45 m, 113 mmol) was dissolved in methanol (665 mL). Potassium carbonate monohydrate (37.5 g, 226 mmol), dissolved in ~ 3 ~

water (70 mL), was added and the mixture refluxed for 16 hours. The reaction mixture was then cooled and concentrated to remove methanol. The residue was partioned between ether (1700 mL) and lN HCl (700 mL). The ether layer was dried (MgS04), then concent~ated to give 41.6 g (96%) of crude acid. The acid was purified by flash chromatography (silica gel, 15 cm I.D. x 15 cm ht., 409~
ethyl acetate in petroleum ethèr) and recrystallized from ether-petroleum ether to give 3 0 .6 g (71%) of a tan solidt m .p. 17 3-17 5 C .

a) l-Ethyl-8~iodo-2,3,4,9-tetrahydro-lH-carbazole-l-acetic acid, prepared in Step a), (7.00 g, 18.3 mmol)g palladium (II) acetate (112 mg, 0.5 mmol), triphenylphosphine (262 mg, 1.0 mmol), triethylamine (12 m1), copper (I) iodide (225 mg, 1.2 mmol) and DMF (44 mL) were mixed in a Parr hydrogenation bottle, put on a Parr shaker, saturated with propylene gas, and then shaken at 60 C at 53 psi. for 9 days. The reaction mixture was then treated with lN HCl (to pH=l) and extracted with ether (2 x 100 mL). The combined ether layers were washed with saturated sodium chloride solution (50 mL), dried (MgS04) and concentrated to an oil. The oil was purified by flash chromatography (silica gel, 9.5 cm I.D. x 15 cm ht., 40% ethyl acetate in hexanes) to give 4.73 g (87~6) of a yellow oil containing two compounds. The two compounds were dissolved in ether (100 mL) and treated with diazomethane. The ester products were partially separated by flash chromatography (silica gel, 15 cm I.I~. x 15 cm ht., 5% ethyl acetate in hexanes) to give 800 mg (14~6) of the upper spot (Rf=0.33) and 2.87 g (50~6) of the lower spot (Rf=0.26).

The lower Rf compound (Rf=0.26), (2.87 g, 9.2 mmol) was dissolved in methanol (55 mL)~ treated with potassium carbonate monohydrate (2.5 g, 15.5 mmol) dissolved in water (5 mL) and heated at reflux for 16 hours. The mixture was then cooled and concentrated to remove methanol. The residue was partitioned between lN HCl (25 mL) and ether (100 mL). The ether layer was dried (MgS04j, concentrated and purified by flash chromatography (silica gel, 7.5 cm I.D. x 15 cm ht., 40% ethyl acetate in petroleum ether) to gi~/e 2.6 g (47%) of (E)-l-ethyl-293,4,9-tetrahydro-8-(l-propenyl)-lH-carbazole-l-acetic acid. The product was recrystalli~ed from ethyl acetatetpetroleum ether to give 1.9 g ~3596) as a tan solid, m.p. 140-142C.
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~ 3~ AHP-9112 rnz IR (KBr) 3390, 2300-3500, 1685, 1445, 1465cm~l.

NMR (CDC13, 200 MHz) ~ 0.897 (3H, t, J-7.3Hz), 1.6-2.1 (6H9 m), 1.96 (3H, dd, J=1.3, 6.3 Hz), 2.7-2.8 (4H, m), 6.2S ~lH, dq, J=6.3, 15.9), 6.63 (lH, dq, J=1.3, 15.9Hz), 7.02-7.07 (2H, d + pseudo t), 7.3S (lH, d, J=7.0 Hz), 9.23 (lH, br.s).

MS (EI) mtz 297 (M~), 268 (M+-C2Hs), 238 (M+-CH2cO2H)-Calculated C 76.72, H 7.80, N 4.71 ~ound C 76.46, H 7.67, N 4.68 C 76.61, H 7.77, N 4.69 c) 1-Ethyl-2,3,4,9-tetrahydro-8-(1-methylethenyl)-lH-carbazole-l-acetic acid methyl ester obtained by chromatography in Step b), (upper spot Rf=0.33, 800 mg, 2.6 mmol) was dissolved in methanol (16 mL), treated with potassium carbonate monohydrate (710 mg, 4.3 mmol) dissolved in water (2 mL) and heated at reflux for 16 hours. The reaction mixture was then cooled and concentrated toremove methanol. The residue was partitioned between lN HCl (10 mL) and ether (50 mL). The ether layer was dried (MgSO,~), concentrated and purified by flash chromatography (silica gel, 3.1 cm I.D. 2~ 15 cm ht., 40% ethyl acetate in petroleum ether). The product was then recrystallized from ethyl acetate/petroleum ether to give 430 mg (8%) of 1-ethyl-2,3,4,9-tetrahydro-8 methylethenyl)-lH-carbazole-l-acetic acid as a white solid, m.p. 148-150 C.

IR (KBr) 3450, 2400-3500, 1695, 1230 cm~l.

NMR (CDC13, 200 NlHz) ~ 0.89 (3H, t, J=7.3Hz), 1.4-2.0 (6H, m), 2~22 (3H, s), 2.68-2.77 (4H, m), 5.34 (2H, sl. br.s), 7.05-7.08 (2H, m), 7.39 (lH, dd9 J=2.4, 6.5Hz), 9.2 (lH, br.s).

MS (EI) m/z 297 (M+), 268 (M+-C2Hs), 238 (M~-CH2CO2H).

Calculated C 76.72, H 7.80, N 4.71 Found C 76.54, H 7.85, N 4.68

Claims (12)

1. The compounds having the structure (I) wherein R1 is lower alkyl containing 1 to 4 carbon atoms and R, R2, R3 and R4 are independently selected from the group consisting of hydrogen and lower alkylcontaining 1 to 4 carbon atoms and the pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1 having the structure (I) wherein R is hydrogen and R1 is ethyl and the pharmaceutically acceptable salts thereof.

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

4. A compound according to claim 3 designated (Z)-1-ethyl-2,3,4,9-tetrahydro-8-(1-propenyl)-1H-carbazole-1-acetic acid and the pharmaceutically acceptable salts thereof.

5. A compound according to claim 3 designated 8-ethenyl-1-ethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid and the pharmaceutically acceptable salts thereof.

6. A compound according to claim 3 designated 1-ethyl-2,3,4,9-tetrahydro-8-(1-methylethenyl)-1H-carbazole-1-acetic acid and the pharmaceutically acceptable salts thereof.

AHP-9112 mz

7. A compound according to claim 3 designated (E)-1-ethyl-2,3,4,9-tetrahydro-8-(1-propenyl)-1H-carbazole-1-acetic acid and the pharmaceutically acceptable salts thereof.

8. The process for producing compounds of formula (I) (I) wherein R1 is lower alkyl containing 1 to 4 carbon atoms and R, R2, R3 and R4 are independently selected from the group consisting of hydrogen and lower alkylcontaining 1 to 4 carbon atoms and the pharmaceutically acceptable salts thereofwhich comprises a) reacting the ketone of structure (II) (II) wherein R and R1 are defined as above with ortho-iodophenylhydrazine 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) AHP-9112 mz wherein R and R1 are defined above.

b) reacting compounds of structure (III) or their carboxylic acids with olefins of structure (IV) (IV) wherein R5 is hydrogen, lower alkyl containing 1 to 4 carbon atoms or trimethylsilyl in the presence of palladium catalyst such as tetrakis(triphenylphosphine)palladium(O) or palladium dichloride with added triphenylphosphine with or without a copper catalyst such as copper iodide to give compounds of structure (I) c) reacting compounds of structure (III) or their carboxylic acids with acetylenes of structure (V) R5-C?CH-R6 (V) wherein R5 is defined as above and R6 is hydrogen, lithium or copper in the presence of absence of palladium or copper catalyst such as copper iodide to obtain compounds of structure (VI) or their acids (VI) wherein R, R1 and R5 are defined as above d) reacting compounds of structure (VI) or their acids with hydrogen gas in the prsence of palladium catalyst such as palladium on barium carbonate poisoned with lead to give compounds of structure (I) or their esters wherein R,R1 and R3 are as defined above and R2 and R4 are hydrogen e) hydrolyzing the esters of compounds of structure (I) to obtain the compounds of structure (I) and forming a pharmaceutically acceptable salt thereof.

9. 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.

10. 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.

11. 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.

12. 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 conjunction with nonsteroid anti-inflammatory drugs and opiate analgesics, for treating inflammatory or painful conditions in a mammal.

* Trade mark