CA1329611C - Substituted 1,3,4,9-tetrahydropyrano [3,4-b]indole-1-acetic acids - Google Patents

Abstract

ABSTRACT

The compounds having the structure

Description

l 1329~11 SUBSIIrUI`EV 13 ~ 9~ YL~nOPYnl~NO~

B9Ci~ OU~D OF 1`13E IJi~ l`lC)N

a. Field Or Invention This invention relates to novel indole derivatives, and to the processes for their preparation and use.

Notwithstallding the advullces made during the last four decades in the developnent of agents for the treatment of pain-producing and inflammatory collditions, there still re~naills a need for effective agents without the side effects associated with the therapeutic sgents presently used for this purpose.

?llore specifically this invention relates to tricyclic acetic acid derivatives in which the tricyclic portion tllereof is characterized by hsving an indole portion fused to a pyrano ring. Still Inore s;~ecifically, the compounds of thisinvelltion are characterized as derivatives of the following tricyclic acetic acid system:

7 ~Q2 H Cl-: -CO H

1,3,4,9-tetrallydropyrsno[3 ~-~indole-l-acetic acid in which the carbons at tlle 1-, and 9-position, and op~ionnlly at tl~e 5-, 6-, 7-, and 8-positions ~re further subs ti tuted.

I~

-2- ~3296~1 The indole derivatives o~ this invention have been found to exhibit useful pharlnacodynalnic properties without eliciting undesirable side effects. Notableatlributes ot this erfect are anli-inrlalnmatory and analgesic activities.

L). Prior Art The closest prior ~rt Io tlle present invention is:

De;mersorl et al Uni(e(3 Slales Patent No. 3 939178. Demerson et al disclosed 1 3 4 9-telrahy(lroL)yrano[3 4-l:3indoles and 13 4 9-tetral)ydrothio-pyrano[3 4-b]indoles hsving ana] esic and anti-inflammatory activity but not with the sulstituents of tlle present invention. Related United States Patents are Nos. 3 974179 and 3 843 681.

SU~l~]AR~ C)F ~HE lNVE.~ I`IC)N
~ =

The compounds of tllis invention are represented by formula (I) ~l. CH2 R2 ~0 (1~
R5 H Rl C'32--COOH

wherein Rl is lower fllkyl contailling 1 to 4 carbon stoms R2 and R3 are llydrogen or R2 ~nd R3 are joined together to ~ive -Cll=(~ CII=CH-and rorm a benzene ring R4 and R5 are hydrogen alkyl containing 1 to 6 carbon fltoms halogen and the phArlnaceutically acceptable salts thereor.

13296~1 1~ prererred aspect Or lhe present invelltion is the series Or compounds represented by formulP~ (Il). R3 ,~
R4 C}~2 R2 ,~ (Il) R5 I C 11 C~2--C02H

wherein R2 and R3 are hydl ogell or 1~2 and R3 are joined together to give -Cll=(~ CII=CH-snd-form a benzene ring, R4 and R5 are hydrogen, lower fllkyl contflining 1 to 4 -carbon stolns, halogen and tlle pharmaceutiefllly acceptable sfllts thereof.

A still furtller preferred aspect of the present invention is the compounds represented by formula (Il) whereill R2 and R3 are hydrogen or R2 and R3 are joined together to give -Cll=CI1-(;H=CH-and rorm a benzene rin~, n4 is hydrogen, or 5-, 6-, or 7-hfllogen, RS is hydrogen, methyl, ethyl or propyl and the pharmaceutically flcceptable sAlts thereor.

A further aspect of the presenL invention is tlle compounds representrd by formula (XIY) ,~

E~4 CH2 ~, (X~V) R5 ~ll Rl CH2--CoO~
wherein Rl is lower slkyl contQining 1 to 4 carbon stoms, R4 snd R5 are llydrogen, alkyl containing I to 6 carbon atoms or h~logen, and Y is 4-halogen, a-and 4-dihalogen, 3-trifluorornethyl, or 4-methyoxy Qnd the pharmaceutically acceptsble sslts thereof.

The most preferred compounds Or the present invention are desi~nated l-ethyl-1,3,4,9-tetrahj dro-4-(phenylmethyl)-pyrsno[3,4-~3 indole-l-acetic QCid;
7-chloro-1-ethyl-1,3,4,9-telrahydro-8-rnelllyl-4-(2-propenyl)-pyrano[3,4-b]indole-l-acetic scid;
l-ethyl-7-fluoro-1,3,4,9-lell al~ydro-8-melhyl-4-(2-propenyl)-pyrano[3,4,-b]-indole-l-acetic ~cid;
8-cllloro-1-etllyl-1,3,~1,9-lelral)ydro-5-1lletllyl-~-(phenylmetllyl)-pyrarlo[3,4-b]-indo]e-1-scetic acid;
1,8-diethyl-1,3,4,9-lell allydl o-4-(2-propeJlyl)-pyrsno[3~4-b] indole-l-acetic scid;
l-etllyl-1,3,4,9-telral~ydro-8-rllelllyl-4-(2-propenyl)-pyrano[3,4-~3 indole-l-acelic acid;
7-chloro-l-etl3yl-1,3,~1,9-letrall5~dro-4-(pllellylmetllyl)-pyrano[3~4-b] indole-l-scetic ~cid;
G-brorno-l-etllyl-1,3,4,9-telrallydro-4-(pllenylmetllyl)-pyrano[3,4-b] indole-l-acetic acid;

_5_ 1329611 5-cllloro-1-etllyl-1,3,4,9-(etrallydro-8-rnethyl-~-(phenylrnetllyl)-pyrano[3,4-b]-indole-l-acetic acid;
7,8-dichloro-1-etllyl-1,3,4,9-tetrallydro-4-(phenylmetllyl)-pyrallo[3,4-b]indole-I-acetic acid;
7-cHlor~l-etllyl-1,3,4,9-tell ahydro-8-metllyl-4-(211enylmetllyl)-pyrano[3,4-b]-indole-l-acetic acid;
l-ethyl-1,3,4,9-tetrallydlo-8-1nelllyl-4-(pllenylrnethyl)-pyrallo[3,4-b]indole-l-acetic acid;
I-ethyl-1,3,4,9-telrahydlo-4-(2-?ropenyl)-8-propyl-pyrano[3,4-b]indole-1-acetic acid;
1,8-diethyl-1,3,4,9-tetlallydro-4-(2-propenyl)-pyrano[3,4-b]indole-1-acetic acid.

The indole derivatives of this invention of for~nula 1 are prepared b~ the following three processes.

Process A ~
~ 2 R4 0~ 1) LDA R ~ OH R

(III) (1V) (VI) 1) R ~ ~C-OCil3 R4 CH2 R2 2) OCH3 (Vll) NaOH _ ~ ~ N ~
R5 H R CH2-cooH

~32~611 Process B

/~ R2 _~ 0~ CH

H I (IX) Cl H
(VIII) R3 (X) /~ R2 R4 Cl~2 LiAlH4 ~ ~ Follo~ Compound of OH Process A ~ formula 1 R H
(Vl) Process C

R4 ~0 R2 R5 ~ CH - C- Cl g H (XII) R3 (XI) R3 ~ R2 H4 CH2C112 Tl(N03)3 5~H (~) Follow (XlIIj ~ Process B
Compound~ of formula (I) _7_ ~3296 Process V
~Y
4 0 ~, R C~12C-OC1~3 ~ R4 CH2 H5~ CHz 5 H Cl (XV) R
H (XVI) (VlII) ~Y

I,IAlH ~ ~ FolIsY
-4 ~ 5~ N OH Process A Compound of (XVII) Process .~ describes a process for preparing compounds o~ formu1a (1) and (11) which co~n?rises the condensation of a substituted isatin (111), wherein R4 and R5 are as defined in formulrl (I) and (Il), with the enolate of the carboxylic acid ester (IV), wherein R2 and R3 are as defined in formu]a (I~ and (ll), affording the hydroxyester intermediate (-') /~ R
[ ~ CH-Co CH

(v) ~32961~

The inter~rlediate (V), wiLhout isolation, is reduced using a llydride, for example Li/~lH4, to give llle e-substituted tryptophol (VI), wllerein R2, R3, R4and R5 are as de~ine(l above. ReAction of the ~-substituted tryptophol (Vl) Witll 3-me~hox~-2-alkanoic aci l, Illelhyl ester (VII), wherein Rl is as derined in f r lilula (I) alld (Il), in tl)e prcse~ce of a l,ewis acid, for example boron trifluoride elherate, followed by alkalille hydrolysis affords compounds of formula (I) and (Il). Alterllatively, con(lellsl~tioll with a substituted ~-keto ester, followed by llydrolysis, as described by l)e;nerson et al, Vnited States Patent 3,939,178, affords conlpounds of forlllull~ (I) an(3 (Il).

Process A was use 3 for tlle l)reparation of the compounds of Example I and 8-37, Table 11. The required isutills III were prepared as described by Frank D.Popp, in Advances in Tletel ocyclic Cllelnistry, 18, pp 1-58 (1975).

Process B describes a process for preparing compounds of formula (I) and (Il) which colnprises alk~lation of a substituted indole-3-acetic acid metllyl ester Vlll, wherein R4 and R5 are as defined in formula (I) and (Il), with an organic halide (IX), wherein R2 and R3 are as defined in formula (1) and (Il), to give tlle c;-substituted indole-3-ucetic acid ester (X), wherein R2, R3, R4 and R5 are as defined above. Tlle ester (X) is reduced, for example with LiAlH4, to afford thee -substituted tryptophol (Vl), described in Process A above. The compound (Vl) is converted to the conlpoulld Or formula (I) and (Il) by Process A described above.

Process B was used for tl~e preparation of tlle colnpound of Example 2, Table 11.

Process C describes a process for preparing connpounds of formula (I) and (Il) whicll colnprises the reactiol1 Or a substituted indole (Xl), wherein ~4 and R5 are as defined in forn~u]n (I) and (Il), and a substituted acid cl~loride (Xll),wl)ereill l~2 and n3 are ns defined in formllls (1) and (Il), affording tlle substituted 3-ucylindole (Xlll), wllerein 1~2, R3, R4 and R5 are as defined above.
Resrrangelnent of conlpolllld (Xlll) to the intermediate ~-substituted indole-3-acetic acid ester (X), described in Process B is accomplished using thallium (lll) nitr2te by a lnetllod Or E.(_. I`a~lor et al, J. Amer. Cheln. Soc. 98, 3037 (1976).

9 132961~

Process C was used for ~he preparation of the compounds of Example 4 and 5, Table II.
Process D describes a process for preparing compounds of formula (XIV) which co~nprises alkylation of a sub5tituted indole-3-acetic acid methyl ester VIII, wherein R4 and R5 are as defined in formula (XIY), with a substituted benzyl halide (XV), wherein X is as defined in ~ormula (XIY), to give the -substituted indole-3-acetic acid ester (XVI), wherein R4, ~5 and X are as defined above. The ester (XVI) is reduced, for example with LiAlH4, to afford ~he ~ -substituted tryptophol (XVII)- The compound (XVII) is converted to the compound of formu]a (XIV) by Process A described above.

Process D was used for the preparation of the compounds 40 to 45 of Table n.
Alternatively, the process described in United 5~ates Patent No. .

4,585,872 issued April 29, 1986 may be adapted for the production of the compounds of the present invention of formula (I3 and (II).
DETAILED DESCRIPTlON OF THE INvENTlON

The term "alkyl" as used herein represents straight chain P1kyl radicals containing from one to si~ carbon atoms and branched chain alkyl radicals containing from three to four cRrbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.

The term "lower alkyl" as used herein represents strai~ht chain slkyl radicals containing l to 4 carbon atoms and branched chain alkyl radicals containillg three to four carbon atoms and includes Inethyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.

The term "11alogen" as used herein includes fluorine, chlorine, bro.-nine and iodine.

-lo- 1 32~61~

rhe colnpounds Or rorll)uln (I) form s~lts with suit~ble ph~rln~ceutically acceptable inorganic and orgal)ic bases. These derived salts possess the same activities as the parent acid and are included within tl~e scope oS this invention.
The acid oî forlnula (I) is transrormed in excellent yield into the corresponding pharmaceutically acceptable salts by neutralization of said acid with the appro?riate inorganic or organic base. The salts are adlninistered in the same manner as the parent acid compounds. Suitable inorganic bases to form these sAlts include, for example"l)e hydl oxides, carbonates, bicarbonates or alkoxides of the alkali Inetsls or alkaline earth metals, for example, sodium, potassium, magnesium, calcium and the like. The preferred salt is the sodium salt. Suitableorganic bases include the following amines; lower mono-, di- and tri-alkylamines, the alkyl radicals of which contain up to three carbon stoms, such as metl)ylalnine, dimetl)ylnlnir)e, trimetllylamine, ethylamine, di- and triethylamine, mettlyletllylamine, and the like; mono, di- and trialkanolamines, the alkanol radicals of which ccntain up to three carbon atoms, such 8S mono-, di- and triethanolamine; alkylenediflll)ines which contain up to six carbon atoms, such as hexamethylenediamine; cyclic snturated or unsaturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyAlkyl derivatives, such as N-methylmorpholine and N-(2-11ydroxyethyllpiperidine, as well as pyridine. Furtherlnore, there may be mentioned the correspon(3illg quaternary salts, such as the tetraalkyl (for example tetramethyl), alkyl-alkanol (~or example methyltrimethanol and trimethyl-monoethanol) and cyclic ammonium salts, for example the N-methyl-pyridinium, N-methyl-N-(2-hydroxyetllyl)-rnorpllolinium, N,N-dimethyl-morpholillium, N-methyl-lN-(2-hydroxyethyl)-1norpholinium, N,N-dimethyl-piperidinium salts, which are cl)aracterized by good water~olubility. ln principle, however, there can be used all the alnmonjum salts which are ptlysiologically compatible.

132~611 The transforlllations ~o lhe salls can be carried out by a variety of methods knowll in the art. ~or exunll)le, in the case of salts of inorganic bases, it isprererred to dissolve the acid Or rormula (I) hl water containing at least one equivale1lt amoullt of a hydloYide, carbollate, or bicarbonate. Advantageously, the reaction is performe(l in a ~ aler-miscible or~anlc solvent inert to the reaction conditions, for exaulL>le~ nletllanol, ethanol, dioxane, and the like in the presence of water. ~or example, such use of sodium hydroxide, sodium carl)onate or sodiuln bicarl~onute gives a solutioll Or tl)e sodium salt. E;vaporation of the solution or addilioll Or a water-miscible solvent Or a Inore moderate polarity, for example, a lower all~flnol, for instance, butanol, or a lower alkanone, for instance, ethyl metllyl kelone, gives tl-e solid salt if that forln is desired.

To produce an amille salt, the acid of formula (I) is dissolved in a suitable solvent of either moderate or low polarity, for example, ethanol, acetonej ethylacetate, diethyl ether and bell7el)e. At least an equivalent amount of the aminecorresponding to tlle desired cation is then added to that solution. If the resultilla salt does not ~)reci~itate, it can usually be obtained in solid form by nddition of a miscible diluelll Or low polarity, for example, l~enzene or petroleum ether, or l)y evaporatiom Ir tlle amine is relatively volatile, any excess can easily be removed by evaL)oratioll. It is preferred to use substantially equivalent amounts of the less volntile umil)es.

Salts wherein the cnlion is quaternary ammonium are produced by mixing the acid of formula (I) witll an equivalent amount of the corresponding quaternary arnmonium llydloxide in water solution, followed by evaporation of the wat~r.

Included in the presenl invention are the diastereoisolners wherein the 4-substituent is either cis or trulls to tlle acetic acid chain at position one.

132961~

Also included in this invention are the optical isomers of the compounds of forlnula (I) which result from asymmetric centers, contained therein. Such isomers can be obtained in substantially pure form by classical se?aration techniques and by stericAlly c~ntrolled synthesis. Included is the specific case of the resolution of l-ethyl-1,3,4,9-tetrahydro-4-(?henylrnethyl)-pyrano[3,4-b]indole-l-acetic acid into its optical isomers by separation of the corresponding [~
endo]-1,7,7-trimethyl-bicyclo[2-2.~ heptan-2-yl ester followed by basic hydrolysis.

ANTI-I~FL.~MI~]ATORY ACrlVl~t The useful anti-inflammatory activities of the pyranoindole acetic acid derivatives of ~ormula (I) are demonstrated in standard pharmacologic tests, forexample, the test designated: Preventative Adjuvant Edema The objective of this test is to determine the ability of test drugs to exhibit an acute anti-inflamlnatory effect in rats. This test is a primary screen for anti-inflammatory drugs.

Speci es:
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 is prepared by suspending 5 mg of killed and dried ;~lycobacterium butvricum (Difco~ in 1 mL miner~l oil. The test compounds are dissolved, or suspended in 0.5% Tween 80 in distilled water according to their solubility- For 2rifnary 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/lOU g body weight to groups of 10 animals.

Methodolo~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 adrninistered immediately before the adjuvant, 24 hours and 48 hours after the adjuvant (days 0, 1 and 2). The injected hind paw volume is measured before the injection of adiuvant and 24 hrs. after * Trade-mark the last drug fldlnillis~ratioll (day 3) by means Or a pletllysmollleter (Buxco Electrollics Inc.). Ihe dirrerence between the hilld paw volulne on day U
and day 3 represellls tlle edelna volume. Etodolac (2s mg/kg p.o.) is inclu ied as a posiliYe col~trol.

P~ eselltat o l~f Results:
The meAn edema volume (e~pressed as mL + SE.~) is cRlculated for each group and the perce~ ge pro~ec~ion conferred by the drug is calculated:
% prolectioll = _(c-t) lUU
c where c is the Inenll c(3elna volume for tlle vehicle-treated (0.5% Tween 8() in distilled water) collLrols and t is tlle Inean edelna volulne for the drug treated group.

ANAL(;ESIC ACrlVlrY
A further test used to determine the utility of the compounds of the present invention is desigl1a~ed: I)rug Effects on Phenylbenzoquinone-induced Writhing in Mice Tlle objective of tllis test is to determine the ability of test drugs to inhibit the nociceptive (pain) res~onse of mice injected with a chemical irritant. This tes~ is a primary screen for botll peripl-eral and centrally acting analgesic drugs.

Species:
Male Swiss albino nlice (15-25 g). ~he anilnals are fasted for 18 hours prior to use but have free flccess ~o wster.

Drua Preparation and Adnlillistratioll:
r.
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 dosnge Or 25 n g/kg p.o. to a group of 10 mice.

Methodolo~ical Details:
A modiricatioll of the nlethod of Sieglnund et al Proc. Soc. Exp. Biol.
Med. 95 729-731 (1957) is used. Groups of S Inice are dosed with the test compound or vehicle control. Sixty minutes later the anilnals are injected -14- 1~29611 i.p. with 0.3 mL/2U g body weight Or a 0.02% solution of pllellylbell~oquinolle (1'13~; 2-pllellyl-1,4-benzoquillone) and placed in indlvidual observatioll boxes. The nulnber of writhing or abdominal squirming movelllellts made by eacll mouse during tl)e following 15 m;n.
period is counted. Ille experilnent is repeated with another group of 5 mice and the meAn m~ ber o~ writhes per mouse for ~ group of 10 mice is calculated.

Presentatioll of Results:
I)rug treated and ve1licle-lreated control groups are compared and the percentage protection conrel red by the drug is calculated:

Percentage proleclion = (c-t) 100 c where c = meall nulllber Or writhes in the control group where t = mean number of writhes in the test drug group An additional test used l~ dctermine the utility of the compounds of the present invention is designated: Randall Selitto Test in the Rat Tlle objective of tllis test is to assess the potency of peripheral and central acting drugs in inllibitillg tlle r eaction of rats to painful stimulation applied to an intlamed paw.

Species:
Male Sprague Dawley rats (180-200g) are used. The animals are fasted overnig)lt prior to drug adll~ istration.

Drug Preparation and Adlllillislratioll:
Freund's Complete AdjuvAIlt (FCA) is ?repared by suspending 5 mg killed and dried mycobacterium l~utyricum (Difco) in 1 mL mineral oil. The test compounds are dissolved or suspended in 0.59~ Tween 80 in distilled water according to their solubility. They are administered by gastric gavage in a volume of 0.5 mL/II)0 g body weigllt to groups of 10 animals.

Methodolo~ical details:
l`en 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 npply pressure to the paw lAnalgesi-meter for the rat paw, Ugo Bnsile, Con)eriA, lt~ly) is a modification of that described by Gilfoil et al, J. Pll~rmacol. 142,1 (1963). The instrument is basically a device which exerts a force that increases at a constant rate. The force is continuously mollitored by a pointer moving along a linear scale and is measured in grams. Ihe inrla~ nrltory reaction is induced in the left hind paw Or rats by injeclillg 1).1 mL of Freund's adjuvant intradermally. The test compound or vehicle is adlninistered 24 hours after the adjuvant. The pain threshold (vocalizatiorl) is determined 1 hour later in the inflamed paw of the treated And control groups.

Presentation of Results and Criteria for Activity:
Each animal wllicll hns a rending 1.5 tilnes greater than the mean reading of the control~roup will be considered AS responsive (h~vin~ an anPl~esic effect) to trestmellt. T!le number of anilnals showing an analgesic effect is then determined in each group.

The EDso (dose whicll causes analgesia in 50% of the animals) using at least 3 doses is thell delerlnined, by the method described in Litchfield and l~ilcoxon, J. Pharlllacol. Exp. Ther., 96, g9-113 (1949).

Typical results obtnilled for the colnpourds of the present invention in the aforementioned tests are as follows:
Table I

Substituted 1,3,4,9-Tetr~llydropyrano[3,4-~3indole-1-acetic Acids R H Rl CH2--COOH

-]6- 1329~1 Preventutive Phenylquinone Xandall Selitto Exsnlple Aàjuvant Ede~lla * I~ritlling in :~1ice * Test in the Rat 4 37 (1.9) (0.003) 2 -- -- _ 4 15 86 (0.5) 6 (3.2) (18) 7 37 1~ --(7.8) (7) 60b 12 32a (9.5) (1) 16 (3) (~.5) (0.012) 18 15 (3.2) (0.8) 19 52 (3.3) ~1.6) Preventative Phenylquinone Randall Selitto Example ~djuvant Edenla * Writ~ g in i~lice * Test in the Rat *

22 47 ~4.7) (0.25) 23 0 (1.9) -- (3.1) 29 -- (3.2) 34 -- (1.4) -16a- 1329611 Substituted 1,3,4,9-'l'elrallydropyrano~3,4-~3indole-1-acetic Acids ~1' R5 l Rl CH2--COOH
Preventative - Phen~lquinone Randall Selitto Example Adjuv~nt Edema ~ ~rithing in Mice Test in the Rat - 41 ~ 30 42 l8a 2~la 43 25a 47a 44 25a 22~ --4Sa 2~a * The numbers quoted are eitller percent inhibition at 25 mg/kg or the EDso in mg/kg given in parentlleses.

a Tested at 10 mg/kg.
b 1`ested at 5 mg/kg.

~'7~ 1329611 The lack of side effeets associated witll the compounds of this invention are demons~rated by standard acule toxicity tests as described by R.A. Turner inScreening Methods in PharlnAcology, Academic Press, New York and London, 1965, pp. 152-163, and by plolonged adm}nistration of tlle compound to warm-blooded anilnals.

~ ell the compourids Or this invelltion are employed as anti-inflammatory and analgesic agents in warm-bloo(led animals, they are administered orally, alone or in dosage forms, i.e., capsules or tablets, cornbined with pharmacologically accept~ble excipients, sucll as starch, milk sugar and so forth, or they are adrninistere(3 orally in the form of solutions in suitable vehicles such as vegetable oils or water. l he compounds of this invention may be administeredorally in sustained release dosage form or transdermslly in ointments or patches.
The compounds of this h~ventioll may Hlso be administered in the form of supposi tories.

The dosage of ~he conlpoullds of formula I of this invention will vary with the particular compound chosell and form of administration. Furthermore, it willvary 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. Tllese e~fective anti-inflammatory and analgesic concentration levels are usually obtail-ed within a therapeutic range of 1.0 ~g to 50U mg/kg per day, with a preferred range of 1.0 ~g to 100 mg/kg per day. The prererred anti-inflammatory dose range is I mg to 20 mg/kg b.i.d. The preferred analgesic dose range is I IJg to 4 mg/kg b.i.d.

lhe compounds of lhis invention may be administered in conjunction with nonsleroid anti-inflamlnatory drugs such as acetaminophen, ibuprofen and aspirinand/or with opiate analgesics such as codeine, oxycodone and morphine to~ether with the usual doses of caffeine. When used in combination with other drugs, thedosage of the compounds of tl-e present inven~ion is adjusted accordingly.

The compounds of the presellt invention also possess antipyretic activity.

-18- 132~611 I`lle following exaln p le~s rul lller Ulustrale tl~is inVentiOIl.

LX~MPLE l l-Ethyl-1,3,4,'~-(elr:llly(ll o-~-(pl)enyllnetllyl)-pyrano[3,4-b]-hl(]ole-l-acetic Acid (Isomel A) (1 Rl = -C21~s R2 anà 1~3 = -Cll=(~ll-CIl=C~I~- R4 and R5 = -H) Step 1. Preparatioll o~ 3-Pl enylpropionic Acid Metl~yl Ester A mixture of 3-plienylpropiollic acid (118.2 g 788 m mol) sulfuric acid (5.9 g) and lU0 mL of metllal)ol was heated to reflux overnight. TLC analysis indicated the absence of slartillg material nnd the reaclion was concentrated inv~cuo. The residue u as ~iissolve l in 2U0 mL of ethyl ether washed with sodium bicarbonate (100 mL) dried over nlagJIlesiuln sulfate filtered and concel~trated to give 124.4 g (96.396) of the es~er as a tan oil.

IR (neat) 3020 2940 1730cm~l S tep 2. Prepsration of B -(Phellylln ethyl)-lll-indole-ethallol To a solutioll Or litlliuln diisopropylalnine in tetrahydroruran/cyclohexane (2.2 M 13G.4 mL 30U nllllol) cooled to - 8C under a nitrogen atmosphere was added a solution of 3-phell;/111ropiollic acid Inethyl ester (~4.6 g 272 mmol) (prepared in Step 1) in 15U n)L of dry tetrahydroruran. The mixture was allowed to stir for 30 Ininutes. A solution of isatin (21).0 g 136 mmol) in 300 mL of tetrahydrofurall ~as as3ded dlopwise and the mixture was allowed to warm to room temperature for 3 hours. l he Inixture was quenched with 500 mL of saturated amlno)liulll chloli(3e and the layers were separated; the aqueous layer wns washed with elher (2 x 15U mL). ïhe combined organic extracts were dried over n agnesiuln sulrate rillel ed all(l concelllrated to give 71.8 g of a brown oil.
3-Phel)ylpropiol)ic acid metl)yl ester was relnoved by distillation (95C!L5 mm)alld the residue (50.G g) was dissolved in 300 mL of dry tetrallydrofuran and -l9- 1329611 ad iecl slowly to a cooled (UC) ~l~ixture of lithium alulninum hydride (18.56 g, 489 1) in 225 InL of tetlally i~ of urall. Tl~e mixture was allowed to Warln to roomtelllperature and was tl~en llealed under reflux ror 3 hours. The mixture was then cooled in an ice water ball~, and 250 mL of water was slowly added. The salts were collected by filtralio~l allcl w~slled willl ether (3 x 400 mL). The organic layel was separated froll~ llle ~illrste and dried over magnesiuln sulfate, fUtered alld concentr~ted to give 35.5 g Or a red-brown oil. Tllis material was purified by flasll chrolnatoJraplly (3U'~ etllyl acetate/llexane, silica gel) to give the tryptophol as Q brown oil (IG.(J2 g, 46.9%).

1 H NI~IR(CDCl3) ~ 8.08 (s, 111), 7.65 (d, lli, J=7.5 Hz), 7.36 (d, lI-i, J=7.5 Hz), 7.18 (m, 7H), 7.01 (d, IH, J=2.U 11%), 3.84 (d, 2H, J=5.0 Hz), 3.43 (dt, ill, J=7.5 Hz), 3.10 (d, 2H, J=8.0 Hz), 1.79 (s, lfl) IR (neat) 3420, 3020cm~l Step 3. Preparation Or l-Etl~yl-1,3,4,9-tetrallydr~4-(pl~ellyllnetl~yl)-pyrano-[3,4-b]indole-1-acetic Acid, ~letllyl Ester - A solution of B-(pl~en~ letllyl)-lH-indole-etllanol (1~.97 g, 63.6 mmol) (prepared in Step 2), metllyl ~ropionyl acetste (9.95 g, 76 mmol), and p-toluenesulfollic acid (I.fiO g) in 500 mL of bemene was heated under reflux for 3 llours, and water collected witll a L)ean ~ Stark receiver. Tl~e reaction mixture was cooled to room telllperalure snd washed with 55~ aqueous sodium bicarbollate (20U mL), waler (200 InL), dried over magnesium sulfate, filtered and concelltraled to give 21.37 g of the crude product. The diastereomers were separated by flash chroll~Alograplly (13~ ethyl acetate/llexane, silics gel) to give Isoner A (higller nf, 2.26 g, 9.8%) and Jsomer B (lower Rf, 2.23 g, 9.8%) as yellow oils.

lSOl~lEn A

lH N~]R(CDC13) ~ 9.17 (s, 111), 7.42-7.00 (m, 9H), 3.80 (m, 2H), 3.72 (s, 3H), 3.20 (m, 211), 3.01 (d, 111, J=17 llz), 2.80 (d, lH, d=17 Hz), 2.85 (m, IH), 2.05 (q, 2H, J=7.5 Hz), 0.90 (t, 311, J=7.5 Hz) IK (kBr) 3420,1725cm~l ISOi~IEI~ B

11 NMI~(CL)C13) o 8.88 (s, 111), 7.38-7.U0 (rn, 9H), 3.84 (m, 2H), 3.70 (s, 3H), 3.04 (d, 111, J=17.5 llz), 2.78 (d, 111, J=17.5 IlZ), 3.15 (m, 211), 2.82 (m, 111), 2.20 (q, 2H, J=7.5 l~z), 0.82 (t, 311, J=7.5 llz) 11~ (hBr) 3440,1725cm~l Step 4. Preparatioll of l-Etilyl-1,3,4,9-telrah~dr~4-(phellylmethyl)-pyrano-[3,4-b]il~dole-1-acetic ~cid l-Etilyl-4-(?llellylllle~llyl)-1,3,4,9-telrah5~dropyrallo(3,4-b)indole-1-acetic acid, metllyl ester Iso;mer ~ (prepal ed in Slep 3) (3.0 g, 8.25 mlllol) ~vas dissolved in 100 mL of ethanol, al~d IU0 mL of 1096 aqueous sodium hydroxide was added.
The mixture was heated ullder reflux for 2 hours, and was then concentrated to acloudt,y aqueous solution. Collcentrated hydrocllloric scid was added until the mixture was acidic. It was then washed with ether (2 x 100 mL) and the combined ether extracts were dried over msgnesium sulrate, filtered and concelltrated to give 2.8 g Or an off-white foam. This msterial was recrystallized from benzelle/pelroleum ether to give 2.30 g (80%) of the pure acid as a white solid, m.p. 14~-146C.

H Ni~lR(Cl~C13) ~ 8.70 (s, IH), 7.43-7.03 (In, 9H), 3.87 (d, 211, J-2.5 Hz), 3.23 (m, 21-1), 2.97 (d, 21-1, J=3.0 llz), 2.8j (m, 111), 2.04 (m, 2H), 0.93 (t, 3H, J=7.5 Hz) 11~ (N~Br) 3380, 3260,174Ucm~l Anal. Calcd- for C221123N3 C, 75.62;11, 6.63; N, 4.01 Found: C, 75.96; Il, 6.43; N, 3.99 Preparation Or l-Etllyl-1,3,4,9-tetrahydro-4~phenyllnethyl!-pyrano[3,4-b] inclole-l-acetic Acid, Sodiuln Salt (Isomer A) -21- 1~29611 Aqueous NaO~I (2.6 mL of IN solution) was added to a stirred solution of l-elhy~ 3~4J9-tetrQllydro-4-(pl~elly~ et~ )-pyrano[3~4-b]indole-l-acetic acid (0.965 g, 2.76 Inmol) in meLI1s~l1ol (5U mL). The pH was sdjusted to 7.75 by theportionwise addition of l-elhyl-1,3,4,9-tetrahydro-4-(pllenyllnethyl)-pyrano[3,4-L~indole-l-acetic acid. Tl1e rcsullillg solution was evaporated to dryness and then taken into benzene and evaporated (2 x). The residue was dissolved in ethyl acetate (8 mL), stirred, and pelroleum ether (30-60~, 30 mL) was added slowly.
The precipitate whicll formed was stirred for 1 hour, filtered, washed with petroleum ether, alld dried lo afror(3 1.0 g (98~) of tl1e salt as a white solid, m.p.
180-190C (dec.).

lSO-d6): No. of_~t ololls l vpe Cl1emical Shift ( ~ ) 3 CH3 0.84 (t, J=8) 2 C112 2.0 (2q, J=8) 7 3CH2,CH 2.2-3.9 (m) 9 aromatic 6.9-7.2 (m) Anal. Calcd.: C, 71.14;11, 5.97; N, 3.77%
Found: C, 7U.41; Il, G.U3; N, 3.64~6 E7~AhlPLE 2 l-thyl-1,3,4,9-lelrallydro-4-(~llenyllnethyl)-pyrano[3,4-b] -indole-l-acelic ~cid, ?,letl1yl Ester (Isomer A) Step 1. Prepflratioll Or lndole-3-scetic Acid, Methyl Ester lndole-3-acetic acid (25 g, 143 mmol) was dissolved in 500 mL of Inethanol an(3 5 mL of conce1ltlaled sulfuric acid was added. The resulting solution was heated un(3er reflux overl1igllt. I`LC analysis indicated the absence of starting mnteï ;A1 and the reaction mixture was concentrated ~n vacuo. The residue was dissolved in 3UU mL ~f elllyl etller, was11ed with 5~6 aqueous sodium bicarbonate - -22- 132961~

(2 .x 15U mL), dried over mngnesium sulfate, riltered and concentrated to 24.09 g (89.1~6) o~ the ester as ~ blll v~ (ly colored oil.

11~ (neat) 340(),1720cnl~l Ni~ (CDC13) ~ 8.17 (s, 111), 7.fi2 (-3,111, J=6.7 Hz), 7.32-7.07 (m, 4H), 3.79 (s, 311), 3.70 (s, 3H) Step 2. Prepara;ion of tl-(Phenyllnetllyl)-lH-indole-3-acetic Acid, Metllyl ~s~er To a 2-liter three neeked roul)d bottom flask equipped Wit]l an addition funnel uas added, under ni~rogerl, 3UU mL of dry tetrahydrofuran (rHF) and 68.75mL of lithium diisoproL)ylalllide (1.92M in cyclohexane/THF, 132 mmol). The mixture was cooled to -78C, and a solution of indole-3-acetic acid, Inethyl ester (11.36 g, 6U rnlnol) in 3()U mL of dry tetrahydrofurLIll was added dropwise. Themixlure was lhell allowe(3 lo sit flt -78C for 15 minutes, and then a solution o~
benzyl cllloride (7.59 g, GU nllrlol) in 300 mL of tetrahydrofuran was added dropwise. The reactioll nlixlure must be stirred vigorously so that the precipitated dianion Or in(lole-3-acetic acid, methyl ester reacts completely with tlle bemyl chloride. Arter 3 hours, TLC analysis indicated complete conslllllption Or startin~g nlalerial, and 2U0 mL of aqueous saturated ammonium chloride wns added. rhe n~ eous layer was separated and washed with ether (2 x 100 mL). rhe conlbilled elhel extracts were added to the orgsnic layer which was dried over Inagnesiuln sulfate, filtered ~nd concentrated to 15.0 g (quunlitative yield) Or red-brown oil. this material was reduced to the corresponding tryptopllol witllout rurtller puriîication.

11 NI~IR(CDC13) ~ 8.09 (s, 111), 7.73 (d, lH, J=7 Hz), 7.40-7.09 (m, 91~), 4.19 (dd, IH), 3.59 (s, 3H), 3.47 (dd, 111), 3.20 (dd, lH) IR (neat) 340U, 1730cm~l Step 3. Prepara ~ion Or ~ -(Pllenylmetllyl)-lH-indole-ethanol - -23- 132~611 l'he crude cl-(phenyll1~el)~ lH~ dole-3-acetic acid, methyl ester obtained ill Step 2 (15 g, 60 mlllol) wns dissolved in IU~ mL of dry tetrahydrofuran and adcled dropwise to a cooled susper1sion of lithium alulninum hydride (2.73 g, 72nlnol) in 30U mL of tetl ahy(3rorlli an. The mixture was allowed to warln to room telaperature and was tllell rerllIxed for 1.5 hours (llenting is usually not requirec3 i~ tllis renetioll). 'I`l~e Illix~lrc ~v~lS coole(3 ill ~n ice water bfltll ~nd 15(J mL of lN
ll~drocllloric acid was ad(led droL)wise. Tlle aqueous layer was removed and theorganic layer was was11ed ~illl sn1urated sodium bicarbonate (2 x lU0 mL), driedover Inagnesiuln sulfate, fil(ered and evaporated to produce 15.06 g (quantitative yield) of a brown oil llavin~ the same physical properties as the product obtainéd in Examp]e 1, Step 2. 'I'his Inalerial was cyclized to the pyralloilldole in Step 4 wilhout furtl)er purificalion.

Step 4. Preparation Or l-Ethyl-1,3,4,9-tetrahydr~4-(phenylrnethyl~-pyrano13,4-b]indol2-l-acelic Acid, Methyl Ester The crude B-(pl~eI~yllnetllyl)-lH-illdole-etllallol obtained in Step 3 (15.()6 g, 6U n~lnol) was dissolve(l in 25U InL of Inethylene chloride. 3-Methoxy-2-pentelloic acid, methyl es~er (1~.68 g, 72 mmol) was added followed by 2.5 mL ofboron trifluoride etllerate and the mixture was allowed to stir at room telnperature overnight. '1'1(~ flnAlysis indicated that the reaction was complete and 200 mL of saturated sodiuIn l~icarbonate was added. The organic layer was separated and washed witll water (2 x 100 mL), dried over magnesium sulfatej filtered and concell~rsted ~o give a crude product which was purified by flash chrolllatogrHplly (13% el!lyl acetste/llexane, silica ~el). 2.5 g (11.5% based on 3 steps) of almost pure Isomer A wus obtained. The proton NMR of this colnpound lnalclled that Or the salnple prepared by the procedure described in Example 1, Step 3.

E~AMPLE 3 I-Ethyl-1,3,~1,'J-telrahydro-4-(pl)enyllnetllyl)-pyrano-[3,4-b]illdole-1-acetic Acid (Isomer B) (1, Rl = -C2H5, R2 and R3 = -(~Il=(~ll-CH=CH-, R4 and R5 = -H) The l-ethyl-1,3, 1,9-lelrnhydro-4-(pllenylrnethyl)-pyrano[3,4-b]-indole-acetic acid, Inethyl ester Isolnel ~3, tpr2pared in Example 1, Step 3) (2.19 g, 6.0 mmol) was udded to a n)ixture Or 65 nlL of lU% aqueous sodium hydroxide and 65 mL of elhanol and the reaclion I~ lure was l~ea~ed under reflux ror 2 hours. The n~ixture was tl~en eoll~elllrAled to drylless and a 1:1 mixture of 10% sodium hydro~i~e/elller ~ns n(l(ll ~] lo the resi(3ue. Ille aqueous layer was separated, acidiried wilh concellllale~] llydrocllloric acid, and extracted several tilnes with elher. I`he colnbined elhel exllncts were dried over magnesium sulrate, filteredand concentrated to give l.G8 g (80~) of a tan-yellow solid. lhis Inaterial was purified by flash cl)rolnlllograplly (30~6 ethyl acetate/hexane, silica gel~ to give 41U Ing of Inaterial whicll was recrystallized from benzene/petroleum ether to give 315 mg ~15~6) of lhe acid ns a white solid, m.p. 171-173C.

11 NAIR(Cl)C13) ~ 8.48 (s, 111), 7.39-7.01 (1ll, 91~), 3.90 (dd, 2H, J=7.5 Hz, J=2.5 Hz), 3.19 (m, 21~), 3.U~ (d, 211, J=3 Hz), 2.88 (m, IH), 2.15 (rn, 2H), 0.89 (t, 3H, J=7.5 Hz) IR (KBr) 339U, 1722cnl~l Anal. Calcd- for C221323Nc)3 C, 75.62; H, 6.63; N, 4.01 Found: C, 75.76; H, 6.35; N, 3.95 E~ PLE 4 l,8-Diethyl-1,3,4,9-telr~hy~]lo-4-(pllellyllnethyl)-pyral7O[3~4-b]indole-l-acetic Acid (1, Rl = -C21is, R2 nlld R3 = -Cll=Cil-CII=CH-, R4 = -Il, R5 = 8-C2115) Step 1. Preparation of 1-(7-E~hyl-lH-indol-3-yl)-3-phenylpropalloJ)e rO a vigorously slir r ed solulion of etllyl magnesium l)romide (2.85M in etller, 0.07 nlol, 24.6 IIIL) in allhydrous etl~er (50 mL), was added a so]ution of 7-ethyl-lil-illdole (7.25 g, U.()5 nlol) in benzene (25 mL), dropwise over the course of 10 mil)utes. The resultil)g pnle green mixture was heated at reflux for 2 hours, ~n(3 lhell cooled to -IU(~ wilh a dry ice/melhanol bath. A solution of hydrocillllalnoyl chloride (8.~3 g, U.05 mol) in benzene (20 mL) was added drop~ise (45 minutes). I he r eaction mixture was allowed to w~rm to room lemperature; after an n(lllilollnl 2 11ours, no starting material ;vas detected by 'I LC allalysis. Aqueous nll~ ollillln cllloride (10~6, 30 mL) w~s ~dded to the rea~tioll mixture and n wllite plecipita~e forlned, which was collected by filtrntion, wnshed witll elher, mld dried n vacuo to yield 7.78 g (56~6) Or the desired ketone, In.p. 14U-111.5C.

C13) 3g65, 1645cl~

N1~ C13) ~ 9.39 (s, 111), 8.3() (d, 11~), 7.8U (d, 111), 3.12 (s, 4H), 2.88 (q, 2~1), 1.32 (t, 311) Step 2. Preparatioll of l-Etllyl-ci -(phellyllllethyl)-lH-indole-3-acetic Acid l~letllyl Ester According to the procedure of E.C. Taylor et al, J. Amer. Chem. Soc., 98, 3037 (1976), a solutiorl of 1-(7-etllyl-lHilldol-3-yl)-3-phenylpropanone (2.77 g, 10 nmol) in a 1:1 mixture of nletllallol and trilnethylorthoformate (25 mL) was added to thalliu~n (111) nitrate lrih~drate (4.88 g, 11 mmol), and the mixture was heated under reflux wltil precipitatioll Or thsllium (1) nitrate was co;nplete (sbout 3hours). The dark browll n~ixlure was diluted with 25 mL Or ether, and the thalliuln (I) nitrate was renloved by filtration. The filtr~te was washed successively with I x 5U mL portions Or water, 5~6 aqueous sodium bicarbonate, and water and was thell dl ied over anhydrous l~lgSO4. Concentration Or the filtrate and flssl) chl onlnlograpl~y Or the crude product (20% ethyl acetate/hexalle, silica gel) gave the ester as a red-brown oil (0.98 g, 31.9%).

IR(CllC13) 348j, 1735cm~l Nl~lll(CL)C13) ~ 8.35 (s, 111), 7.7U (~d, lH), 7.15 (m, 3H), 4.28 (m, IH), 3.75 (s, 3H), 3.3j (s, 3H), 2.8U (q, 211),1.25 (m, 3H) Step 3. Preparation of 7-Etl)yl- e-(phenylmetllyl)-lll-indole-etllanol To a stirred suspellsioll Or lilhiuln ~lumilluln hydride (0.702 g, 18.5 mmol) in80 mL of Allllydrous tetlal)y(llorllral- under nitrogen at 0C was slowly added (about 1.5 hours) a solution of 7-etllyl- ~phellylmetllyl)-lH-indole-3-acetic acid metllyl ester (prepared in Step 2) (5.17 g, 16.8 mmol) in 30 mL of anhydrous tetrahy lrorurrlll. Tlle resullil~ dr~ red Inixture was heated ullder rerlux for 2 hours. It was cooled to 0C, alld (luenched by the dropwise addition of 40 mL ofwater. The precipitated alulninum salts were removed by filtration and washed with e~her. The layers of the filtrate were separated, and the aqueous layer waswashed with ether. The combined ether layers were washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give the desired alcohol as a brown oil (4.51 g, 96%).

CHC13) 3570, 3~80cm~l NMR(CDC13) ~ 6.8-8.40 (In, IU}I), 3.0-4.10 (m, 51~), 2.80 (q, 2H), 1.32 (t, 3H) Step 4. Preparation of 1,8-Diethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)-pyranoE3,4-h]indole-1-acetic Acid (Isomer A) 7-Ethyl- B-(phenylmethyl)-11~ dole-etllanol (prepared in Step 3) (5.86 g, 21.0 mmol), methyl propionyl acetate t4.69 g, 36.0 mmol) and p-toluenesulfonic acid (0.49 g, 2.6 mmol) were dissolved in 175 mL of benzene and heated under reflux for 5 hours, and water collected with a Dean ~ Stark receiver. The mixture was washed with snturated sodium bicarbonate (2 x 50 mL), dried (MgSO4), filtered and evaporated to give the crude methyl ester. This material was dissolved in a mixture of 125 mL of ethanol and 125 mL of 10% aqueous sodium hydroxide, alld tlle mixture was heated under reflux for 2 1~2 hours. It was then concentrated to dryness, and a Inixture of 100 mL of ether and 50 mL of10~6 aqueous sodiwn hydl oxide was added to the residue. The layers were separated, alld the aqueous layer was acidified with concentrated hydrochloric acid and extracted with elher (2 :c 100 mL). The combined ether extracts were dried over anl)ydrous MgSO4, fillered and evaporated to give the crude product as a tan solid (44% yield). The diastereomers were partially separated by flash chromatography (30% ethyl acetate/hexane, H3PO4 treated silica gel), and a portion of the mixed fracliolls from the column were separated by HPLC (Waters Assoc. C18, Prep 50U). 'I'he isonler whictl eluted first on the C18 column was designated Iso~ner A and had a In.p. 147-148.5C; tlle otl-er isomer was designated Isolner B and had a m.p. 158-15Y.5C. Each isolner was recrystallized from 1:3 benzel)e/petroleuin ether.

ISOl~lEn A

IR(KBr) 360U-260U, 333(1,174Uc~ . Analytical HPLC: 97.98~6 isomeric purity.

Anal. Calcd. for C241127NO3: C, 76.35;11, 7.22; N, 3.71 Found: ;, 76.28; H, 7.25; N, 3.81 1,8-Diethyl-1,3,4,9-lell ahydro-~-(;)llellylmetll~l-pyrallo[3,4-b]-indole-l-acetic Acid (Isomer B) ISOMER B

Prepared in Exanlple 4, Step 4.

IR(I~Br) 3600-26UU, 3460,17UOcln~l. Analytichl HPLC: 96.90~ isolneric purity.

Anal. Calcd. for C241127NO3: C, 76.35; H, 7.22; N, 3.71 Found: C, 76.28; H, 7.25; N, 3.81 E,YAI~lPLE 6 I-Ethyl-7-rluol o-1,3,4,9-tetrahydro-8-methyl-4-(2-propenyl)-pyrano[3,4,-L)] indole-l-acetic Acid (Iso)ner A) (1, Rl = ~21~;" R2 and R3 = -11, R4 = 7-F, R5 = 8-CH3) Step 1. Prcparation Or G-l~luoro-7-1nethylisatin A mixtule consislinv of 3-fluoro-2-rnethyl aniline lIydrocllloride (21.9 g), water (5U0 mL), hydroxylalllil)e llydrochloride (29 g) sodium sulfate (120 g) and a few (1l'OPS of GN 11('1 u as h(-aled to boiling with vigorous stirrillg. 'I'o this was added a boiling solutioll of clllol al hydrate (21.9 g in 330 mL of water) ~nd boiling contillued for 4;~ nlillutes.

T~e reacLion was cooled an(l filtered. Tlle precipitate was dissolved in ether, dried over sodiulll slllfale and evaporated to afford 18.7 g of the oxime(8 8 ?6 yi eld).

Tlle oxime was a(](led pOl lionwise to 300 mL of 9U~6 sulfuric acid at 65C.
1'11e nlixture was hea~e(J lo 8U(~ for 15 mil~utes and then poured over ice water while stirring. Filtralion an(l dlyillg affolded Il.7 ~ (6096 yield) of 6-fluoro-7-netllylisatin, m.p. 20~-2U6C.

Step 2. Preparatiol) o~ (;-FIIJoro-7-methylindole-3-~2-sllyl)etllanol A solution Or lithiuill dii.coplopylalnille (l DA) (2.2 M in cyclohexane, 110 mL) was cooled to -78C in flll isopropylamille (IPA) dry ice bath. ~lethyl 4-pen~el-oate (24.0 v 0.206 n~ol) in dry tetrahydrofuran (100 mL) was introduced, and the reaction slirred for U.S hours. A solution of 6-fluoro-7-methylisatin (prepnred in Step 1) (IY g, ().106 mol) in tetrahydrorurAn (150 ml ) containing 2-metllylp~rrolidol7e (22 mlllol) ~as added slowly while keeping the temperature of the reactioll below -6UC. 'Ihe reaction was stirred at -78C for 2 hours and then allowes3 to rEach room lemperature. The excess LDA was quenched using saturated amllloniull- cllk~l ide solulion. 'I'l~e organic layer was extracted with etl-er (2 x 2UU m1.), dried (Na2S04) and concentrated to afford 40.0 g of crude intermediate hydroxyester.

A solution of this hydloxyester interlnediate in tetrahydrofuran (500 mL) was added dropwise to a stirred suspension of LiAlH4 (9.8 g 0.258 mol) in tetrahydrofuran (2U0 nlL) ancl refluxed for 2 hours. Tl-e reaction was cooled in -29- 1329~11 an ice balh, the excess h~(lli(le dcslroyed using 1:1 tetrahydrofuran/112O, filtered, ~ried (Na2S04) und cou e ulllllecl to give 30 g of crude tryptophol. ~lash chrolnalography using 25 ~, elhyl acetate/llexane followed by 30% ethyl acetale/l~exflne flfforde(l 11.~ g (~8 ~ yield) of litle colnpound. This material was imllledialely used in Slep 3.

Step 3. Preparali(7ll of 1-Ell~yl-7-fluoro-1,3,4,9-tetrahydro-8-methyl-4~2-propenyl)-pyrano[3,4-b]illdole-]-ncetic Acid (Isomer A) A mixture consislill ~ of 6-fluoro-7-metllylindole-3-(2-allyl)etllanol (prepared in Step 2) (11.0 ~, ().U98 mol), 3-rnethox~-2-pentenoic acid, Inethyl ester (11 g), l~F3-El20 ~1 mll) nll 1 diclllorolrlelllane (500 mL) was slirred at rooln temperature for 2 bollls, dilllle(3 with dichlorolnetllane, washed with 5~
Nal~CC)~, uater, drie(l ~i~lgSI~.l) an(l concelllrated to give 21 g of oil. This was wnslled througll a silica gel colulnll using hexane followed by 5~ ethyl acetate-hexane. Preparative ]iquid cln omato~Jraphy on a l~aters Assoc. Prep 500 instrulnenl using 3.59~ etllyl f~cet~te-l~exane as eluant afforded the esters (5 g of Isomer A and 6.5 g of Isolller 1~).

Isomer 1~ ester was ll~drolyzed by refluxing with a mixture of X~H (5 g), nletharlol (500 mL), nnd wnter (10 mL) for 2.5 hours. The reaction was concelltrated, diluted willl waler, alld exlracted witll etller. The aqueous phase was acidified with 5~ IICI all(i exlracte(3 with ch]oroforln (3 x 200 mL). The combilled extracts were wnslled wilh water, dried (l~lgSO4) and concentrated to give 3 g of solid acid. Ilecr)stallizatioll froln toluene-petro]euln elher afforded 2.U g (12.69~ yield) of tille conlpoulld, m.p. 159-16U~.

N!~lR(D.;lSC)-dtj): No. of l~lotons Iype Cllenlical Sllift ( 3 CH3 0.72 (t, J=7) 2 C~2 1.95 (m) 3 (~1~3 2.35 (s) 2 =C112 5.1 (In) l~-C=C 5.8 (m) 2 arolnatic 10.6,11.9 (s) ll~ (hl~r, cm~l) 3U7U (Nll/(:)ll), 171U (CO) Anal. Calcd.: C, 68.87; Il, G.69; N, 4.23%
Foun(l:C, 68.94; 13, G.fil; N, 4.15~

1i1PLE 7 I-Ethyl-7-fluoro-1,3,4,9-tetrallydro-8-metilyl-4-(2-propenyl)-pyralloL3,~ 3illdole-1-acetic Acid (Isomer B) l-Ethyl-7-fluoro-1,3,4,Y-~etl allydro-8-1nethyl-4~2-prQpenyl)pyrano[3,4-b]-indole-l-acetic acid Isolner 1~ ester, prepared in Exsmple 6, Step 3, was ydrolyzed as descril~ed in Exalllple 6, Step 3, to afford 2.1 g of white solid.
Recrystallization froln tollJelle-petroleum ether afforded 1.3 g (8.1% yield) oflitle compoulld, m.p. 138-14UC.

Ni~lR(VJ~lSO-d6): No. Or l'rotolls 1~pe Chenlic~l Shift ( 3 (~3 U.62 (t, J=7) CH3 2.35 (s) 2 CH2 2.06 (m) 2 =CH2 5.1 (m) Il-C=C 5.8 (m) 2 nrolnatic 10.6, 11.9 (s) 111 (KBr, cln~l) 3U70 (NlJ/(JiJ), 171U (CO) Anal. Calcd.: C, 68.87; 13, 6.G9; N, 4.23 Found: C, 68.98; IJ, 6.77; N, 4.18%

EX~MPLE 8 Resolution of (+/-)-I-I tllyl-1,3,4,9-tetrallydro-4-(pllenylmethyl)-pyrano-[3,4-L~]indole-l-acetic Acid -31- 13296~1 Step 1. Prepa1alio1l of l-Ethyl-1,3,4,9-tetralIydro-4-(pllellylmetl7yl)-pyrano[3,4-b] indole-l-nceli(~ id, L(lS)-EIIdo]-1,7,7-'l'rilllethyl-l~icyclo~2.2.U-hepta1l-2-yl Esler 5() mL Or metllylene cllloride was added to a mixture of l-ethyl-1,3,4,9-tetrahydro-4-(phellyll1lelh~ pylano[3,4-b]indole-l-acetic acid (3.50 g, 10 mmol), L(lS)-endo]~ borneol (1.7U g, 11 mmol), 1,3-dicyclohexylcarbodii1nide (2.27 g, 11 mlnol) and 4-(N,N-dimel1Iyl~lllino)pyridine (70 mg, 0.57 mmol). The mixture was allowed to stir at room tempe1ature overnigllt under a stream of nitrogen. The mixture was passed through a sintered glass funnel and the precipitate was wasl~ed wit11 50 mL of melllylene cl~loride. 'rhe filtrate was youred into 100 mL
Or ether and wus washed wilh lN hydrocllloric acid (2 x 50 mL) and saturated sodium bicarL)onate (I x 5U nlL), dried over magnesium sulfate, filtered and concentrated to give 3.~5 g Or the crude mixture of esters. Flash chromatography (IU~ elh$1 acetnte/hexalle, silica gel) gave 2.65 g of the diastereo,meric mixture of esters as a wllite foam. The esters were separated byIIPLC (I~'aters Prep. 50()A, 4~ etllyl acetate/hexane, silica gel) to give 1.2 g of lsomer A (first eluting isoll~er) m.p. 63~6C, and 1.15 g of Isomer B (second eluting isomer) m.p. 58-61VC.

Step 2. Preparation ot (+)-l-Ethyl-1,3,4,9-tetrahydro-4-(?hellylmethyl)-pyrano[3,4-b]indole-1-acetic Acid The l-ethyl-1~3~4~9-tetrallydro-4-(pllenylrnetllyl)-pyralIo[3~4-~3 indole-l-acetic acid, [(IS)-endo]-1,7,7-trill)ethyl-bicyclo[2.2.1~heptan-2-yl ester (Isomer A, 1.20 g, 2.5 mmol) was dissolved in a mixture of 65 mL of ethanol and 65 mL of 10~ sodium hydroxide~ Hnd the mixture was heated under reflux for 5 hours. The mixture was then concenlrated to a cloudy aqueous solution, cooled in an ice water bath, alId acidi~ied with concentrated hydrochloric acid. It was then extracted with ether (2 x 5U mL) and the combined ether extracts were dried over magnesiullI sulfste, fillre(3 alId concelltraed to give 900 mg of a yellow oil.
This material W85 recrysl~llli7e(1 froln toluene to give 397 mg ~46%) Or the pure acid as a white solid, m.p. 170-171.5C.

-32- 132~

Anal. Calcd- fol C22l~23N3 C, 75.62; H, 6.63; N, 4.01 Found: C, 75.63; H, 6.44; N, 4.17 [Q]~ = +62 9 EX/~MPLI~ 9 Prepsration of ( - )~ thyl-1,3,4,9-tetrallydro-4-(phenyllnethyl)-pyrano[3,4-b] indole-l-acetic Acid l-Ethyl-1,3,4,9-telrally(ll o-4-(pl~enylrnetllyl)-pyranoL3~4-b]indole-1-acetic acid, L(lS)-elldo]-1,7,7-lrill)elllyl-l~i~yclo[2.2.1]lleptall-2-yl ester, lsolner B, prepared in ~xample 8, Slep 1, was saponified as described in Example 2, Step 2,to give 327 mg (41.3~6) Or tlle pure acid as a white solid, m.p.111-172C.

Anl. Calcd- for C22~123N3 C, 75.62; H, 6.63; N, 4.01 Found: C, 75.55; H, 6.42; N, 4.31 [ ~:~]1) = -60.3 ~33~ 1329611 Table H

Substitu~ed 1,3,4,9-'l elral~ydrop~raIlo[3~4-b]indole Acetic Acids R5 1~ ~ CHz_ COOH

M elting Exalnple Rl R2 R3 ~4 R5 Isomer Point C
Et CH=(~H-CH=CII H H A 145-147 2 E;t Cll=CH-CII=CH H H A
3 ~t CII=CH-ClI=CH H H B 171-173 4 Et CH=CIl-C}I=CH H 8-C2H j A 147-148.5 Et CH=CH-C}I=CII }I 3-C2H; B 158-159.5 6 Et H 11 7-F 8-C113 A 159-160 7 Et H 11 7-F 8-CH3 B 138-140 8 Et CII=CII-CH=CH H H A(~) 170-171.

9 Et CH=CH-CH=CII H H A(-) 171-172 Et H H 7-F 8-C2Hs A 91-93.5 11 Et H 11 11 8-C2Hi B 118-119.5 12 Et H H H 8-n-C3H~ A 99.5-101.i 13 Et H H H 8-n-C3H7 B 117-120 14 Et H H H H A 133-138 li Et H H H H B 136-141 16 Et 11 11 7-C1 8-CH3 A 168-169 17 Et H 11 7-C1 8-CH3 B 124-126 18 Et CH=CII-CI-I=CH 7-C1 8-CI A 154-15i M elting Example ~1 n2 ~3 R4 R5 Isomer Point C
19 Et Cli=CII-Cll=CEl 7-C18-CH3 A 158-159 Et Cll=Cll-CIl=CIl 7-C18-CH3 B 218-220 21 Et CEI=Cll-CEl=CEI H 8-CH3 B 174-176 22 Et CH=CII-CH=CH H 8-CH3 A 141-143 23 Et Cl-l=Cll-CH=ClI 5-CH3 8-Cl A 151-152 24 Et CH=CII-CH=CH 5-CH3 8-Cl B 250-252 Et CH=Cll-(:lll=CH 6-Br ~1 A 154-155.5 26 Et CH=CII-CII=CII 6-Br H B 156-158.5 27 Et H 11 6-F H B 145-147 28 Et CEI=Cll-CII=CEl 6-F H B 190-192 29 Et CEI=CII-CEI=CH 5-C1 8-CH3 A 172-173 3U Et CH=CII-CH=CEI 5-C1 8-CH3 B 248-250 31 Propyl CEI=CH-CH=CH H H A 139.5-141 32 Propyl Cll=Cll-CII=CH H H B 172-173 33 Et CH=Cll-Cli=CEI H 7-Cl B 186.5-188 34 Et CII=CII-CII=CII El7-Cl A 152.5-154 Et CII=CII-C}I=CII 5-CH3 8-CH3 A 175-177 3G Et CH=CII-(,'II=CI~ 5-CH3 8-CH3 B 230-232 37 Et ll 11 H 8-CH3 A 135-137 38 Et 13 11 H 8-CH3 B 138-139 39 Methyl CII=(,'Il-CH=CII H H A 157-158 _35_ 1329611 Subs~ituted 1,3,4,9~'eLrallydropyrano[3,4-~indoleAceticAeids tY
' .

R4 C~2 R5 l Al CH2-COo~

Melting Example Rl Y R4 R5 ~omer PointC
C21~5 4-C1 H H A 182-184 41 C2H5 4~DCII3 H H B 163.5-164.5 42 C2H5 4-C1 H H B 187.5-190 43 C21I5 4-P . H H A 126-128 44 C21~5 3-CF3 H H B 164.5-166 C2~5 2,4~iP fI H A 150-151.5 This application is a division of Canadian Patent Application Serial No. 530,801 filed February 27, 1987.

Claims (4)

1. The compounds having the structure (XIV) wherein R1 is lower alkyl containing 1 to 4 carbon atoms, R4 and R5 are hydrogen, alkyl containing 1 to 6 carbon atoms or halogen, and Y is 4-halogen, 2- and 4-dihalogen, 3-trifluoromethyl or 4-methoxy and the pharmaceutically acceptable salts thereof.

2. A process for preparing the compounds of formula (XIV) (XIV) wherein R1 is lower alkyl containing 1 to 4 carbon atoms, R4 and R5 are hydrogen, alkyl containing 1 to 6 carbon atoms or halogen, and Y is 4-halogen, 2- and 4-dihalogen, 3-trifluoromethyl or 4-methoxy and the pharmaceutically acceptable salts thereof which comprises the steps 1) condensing a substituted indole-3-acetic acid, methyl ester of formula (VIII) (VIII) wherein R4 and R5 are as defined above with the halide of formula (XV) (XV) wherein Y is as defined above and X is halogen selected from the group consisting of chlorine, bromine and iodine to produce the .alpha.-substituted indole-3-acetic acid ester of formula (XVI) (XVI) wherein R4, R5 and Y are as defined above 2) reducing said compound of formula (XVI) to produce the compound of formula (XVII) (XVII) wherein R4 and R5 are as defined above and converting the compound of formula (XVII) to the compound of formula (XIV) as claimed in claim 1.

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

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