CA2002415A1 - Alpha-amino-indole-3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents - Google Patents

Abstract

ABSTRACT
Provided are novel .alpha.-aminoindole-3-acetic acid derivatives having the formula I

wherein R through R9 are ths same as in Claim 1; and pharmacologically acceptable salts of compounds wherein R9 is not OM, which are useful as anti-diabetic, anti-obesity and anti-athero-sclerotic agents.

Description

~-AMINO-INDOLE-3-ACETIC ACIDS USEFUL AS ANTI-DIABETIC.
ANTI-OBESITY AND ANTI-ATHEROSCLEROTIC AGENTS
BACKGROUND OF THE INVENTION
The present invention provides novel compounds. More particularly, the present invention provides novel ~-amino-indole-3-acetic acids, tryptophans and their derivatives. The compounds are useful as antl-diabetic, anti-obesity and anti-atherosclerotic agents.
INFORMATION DISCLOSURE
~-Amino-indole-3-acetic acid, tryptophan and some of their derivatives are described in the literature. Thus, U.S. Patent 3,074,942 discloses ~-amino-indole-3-acetic acid and derivatives thereof that are described as being useful as anaesthetics, CNS
depressants and as antagonists to serotonin, acetylcholine and histamine. Some of these same comp~unds are disclosed in U.S. Patent 4,492,694, Baker, J.W., Journal of Chemical Societv, 458 (1940);
Casnati et al, Gazz Chi~. I~ , 355 (1963); Dawes et ~ ature, 164, 705 (1949); Netherland published application 6,607,754;
Armstrong et al, J. Biol. Chem., 232, 17 (1958).
U.S. Patent 4,492,694 discloses acylated ~-amino derivatives of ~-amino-indole acetic acid.
U.S Patent 3,320,280, Netherland application 6,415,318, U.S.
Patent 3,316,260 and Brltish patent 1,087,359 disc~ose ~-(3-indol-yl)lower aliphatic acid derivatives that contain a methyl substituent at the 2-position oi the indole rin~. Another feature of the compounds disclosed in 3,320,280 is the presence of an aromatic carboxylic acyl radical of less than thres fused rings attached to the nitrogen atom of the indols ring.
U.S. Patent 3,000,888 and Biekert et al, Ber., 97, 363 (1964) discloses a~ ~-amino-indole-3-acetic acid derivatlve in which morpholino has been substituted for the ~-amino group. It is described as being a therapeutic agent and an intermediate for preparing therapeutic agents.
German ~ffen. 2,3~l5,775 and European patent application 7,615 published February 6, 1980 discloses ~-amino-indole-3-acetic acid derivatives having methyl and ethenyl substituent~ respectively, on ~-carbon.
Yoneda, N., Chem. Pharm. Bull. 13, 1231 (1965), Kametani et al, f~ I
- I
, ,: , '~0~

J. Heterocycl. Chem., 5, 799 (1968~, French patent 1,100,016 and Yamada et al, Chem. Pharm. Bull., 13, 88 (1965) disclose tryptophan derivatives in which one or both of the nitrogen atoms have been alkylated.
Preobrazhenskaya et al. Khlm. Geterotslkl. Soedin, ~, 778 (1971) discloses tryptophan derivatives wherein the carboxylic acld group has been replaced by a hydroxyl, alkoxyl or benzyloxy group.
To applicants' knowledge, tryptophan ls the only lndole ~-smino acid Eor which blood sugar altering effects have been reported.
Tryptophan reduced blood sugar levels in normal rats but not in rats with severe alloxan diabetes. Mirsky et al, Endocrinology, 59, 369 (1956) and Endocrinology, 60, 318 (1957).
L-Tryptophan (2.5 mmoles~kg) admlnistered i.p. to fasted rats blocked epinephrine-induced hyperglycemia 7S~-89% and inhlbited eplnephrine-induced hyperglyce~la to the same extent in both intact and diabetic rats indicating that insulin was not involved in preventing the hyperglycemic response. Sanders et al, Pharmacology, 6, 155 (19~1).
Fastlng blood glucose levels were not affected by intra~astric administration (120 mg/rat) of ~L-tryptophan to femAle rats. The rlse in blood glucose following glucose ingestion (1 g/rat) was decreased by DL-tryptophan as compared with rats receiving glucose only. Szigeti et al, Nahrung, 1~, 171 (1969).
It was reported that tryptophan administered through the stomach 25 does not produce hyperglycemis. Bedo et al, Egeszegtudomany, 13, 249 (1969).
Tryptophan facilitated depos~tion of glycogen, increased the liver weight, but decreased the pyruvate incorporation 7.5 times into liver glycogen. Lutkic et alt Bull. Sci., Cons., Acad. Sci. Arts RSF
30 Yougoslavie, Sect. A., 18, 8 (1973~.
The oral administration of lO g L-tryptophan to healthy human sub~ects induced a small but significant rise in blood sugar, a slight increase ln blood insulin, a marked lncrease in plasma glucagon, and delayed increase in plasma growth hormone. This contrasted with the reported hypoglycemic effect of tryptophan in rats and with the well-documcnted inhibition of gluconeogensis by tryptophan and its metabolites in rat liver. Since tryptophan increased the circulsting glucagon ln man, the elevated blood sugar ' ' i`

WAS probably due to enhanced glycogenolysis and/or gluconeogenesis induced by this hormone. Hedo et all Metab., Clin. Exp., 26, 1131 (1977). Derwent 89-089908/12 r~fers to new tryptophan derivatives and their glycosides and their use to prevent or treat.
I.V. glucose tolerance was measured in rats fad various diets of defined L-tryptophan content. Within 14 days, animals which had been fed a tryptophan-deficient diet removed excess glucose from their blood at a reduced rate. The results suggest that dietary L-tryptophan is active in physiological regulation of carbohydrate metabolism. Wittman, J.S., J. Nutr., 106, 631 (1976).
Among the amino acids, all stimulatad the secretion of insulin and some were more active than insulin in inhibiting gluconeogenesis.
The action of tryptophan on inhibiting gluconeogenesis was independent of its action on the secretion of insulin. Carrozza et al, Boll. Soc. Ital. Bio. Sper., 47, 535 (1971).
Oral administration of tryptophan or lysine to rats 30 minutes prior to a subhypoglycemic i.v. injection of hypoglycin A resulted in a potent hypoglycemic effect. Tnnaka et al, Pan-A~. As30c. Biochem.
Soc. Sypm., 3, 163 (1975).
The ~nduction of hypoglycemia in both fed and 36 hour-star~ed rats by tryptophan (750 mg/kg, i.p.) was blocked by pretreatment with MK 486 or p-chlorophenylalanine (inhibitors of tryptophan decarboxylase and tryptophan 5-hydroxylase, respectively) and potentiated by paraglyine (monoamine oxidase inhibitor), suggesting the involvement of 5-hydroxytryptamine or a derivative thereof. I.P.
administration of qulnolate or indol-3-ylacetic acid to untreated rats or of tryptamine to pargyline-treated rats did not produce hypoglycemia. In pargyline-treated rats 5-hydroxytryptamine produced hyperglycemia, whereas 5-hydroxytryptophan had effects llke those of tryptophan. The hypoglycemic response to tryptophan ~as prevented by the specific 5-hydroxytryptamine antagonist, methylsergide, and by experimental diabete6, and was enhanced by adrenalectomy. The response was also dependent on the presence of functional pancreatic ~-celLs, suggest~ng the invol~ement of insulin. Changes in li~er metabolite and glucose concentrations were not rel&ted. The hypoglycemic action of tryptophan was associated with increased plasma ~-hydroxybutyrate/acetoacetate ratios, indicating mediation through formation of intracellular 5-hydroxytryptamine. Smith et al, ". . . ; , . . .
- ' ' : ' ' ' , 2~3LS

Biochem. Soc. Trans., 4, 1049 (1976) and Biochem. J. 168, 495 (1977).
The mPchanisms whereby tryptophan administration leads to hypoglycemia in some groups of rats but not others have been investigated. These results were discussed in relation to previous discrepancies in the literature, and a unifying hypothesis for tryptophan-induced hypoglycemia is proposed. Lloyd et al, Biochem.
Pharmacol., 31, 3563 (1982).
An increase in the rat hepatic level of gluconeogenic intermediates such as malate, aspartate, and citrate occurred after the i.p. administration of 10 mg L-tryptophan/100 g and was associated with 43 ~g liver content of its metabolite quinolinic acid/g liver The clinical implication of these findings are discussed. McDaniel et al, Diabetes, 22, 713 (1973).
The addition of 2.4 mM tryptophan to the medium perfusing isolated rat livers inhibited glucose production from added alanine.
Such livers retained the capacity for converting fructose to glucose.
Veneziale et al, Biochemistry, 6, 2129 (1967).
For examlnation of the theory of Mirsky (C~ 51, s7Sd) that L-tryptoph~n #hows hypoglycemic action because of lts inactivation of the insulin-inhibiting enzyme of the liver, rats were given L-tryptophan 26 mg/100 g after 24 hours of fasting; another group was given tolbutamide ? mg/100 g; another received both and a fourth was a control. Glycemia dropped with ~-tryptophan, tolbutamide, and the mixture during 240 minutes. ~utturini et al, Minerva Med., 1497 (1958).
When ~iven orally, L-tryptophan, DL-kynurenine, anthranilic acid, nicotinic acid, nicotinuric acid, indole-3-acetic acid, 5-hydroxytryptophan and 5-hydroxy-tryptamine creatinine sulfate produces a significant hypoglycemia in normal rats. Rynurenic acid produces a slight and nicotinamide a significant hyperglycemia.
Quinolinic acid, picolinlc acid, 5-hydroxyindoleacetic acid, indole, and skatole do not alter blood sugar levels. Indole-3-acetic acid and nicotinic acid do not reduce blood sugar levels in severely diabetic alloxanized rats. Mirsky et al, Endocrinology, 60, 318 (1957).
The minimum effective dose and the duration of the effect were determined for 37 substances (presumably including tryptophan) found to prevent alloxan diabetes. Okamoto, K., Tohoku J. Exptl. Med., 61, 20~

Suppl. 3, 36 (1955).
The effect of DL-tryptophan on blood sugar levels was studied with normal males as sub;ects. Doses of 0.25, 0.50 and 1.0 g per day for 14 days failed to lower the blood sugar levels. In five of the eleven cases given 0.5 g per day, a significant increase was noted.
An attempt was made to pick up a transient effect of tryptophan on blood sugar levels one to three hours after ingestion, but no effect was found. Howard and Modlinger, Am. J. Physiol., 153, ~25 (1948~.
The intravenous in;ection of 90 cg tryptophan dissolved in 70 cc H20 did not produce hyperglycemia or metabolic changes in normal vs.
diabetic individuals. It did produce a slight lncrease in the alk.
reserve. The intravenous in~ection of 5 cg tyrosine dissolved in 120 cc H20 or in normal serum or the oral administration of 2 g tyrosine showed no hyperglycemia action in diabetes. Barone et al, Bull. Soc.
Ital. Soc. Sper. 6, 834 ~1931).
The compounds of the present invention are able to reduce blood glucose in severely insulln resistant mice. The ma~or effect is on postprandial glucose concentration~ indicating that the ~a~r eff~ct may not be on inhibition of gluconeogenesis as has been suggested as a ma;or mechanism for tryptophan-induced hypoglycemia in the preceding paragraphs. Although it has been hypothesized that metabolites of tryptophan might effect a decrease in fed glucose concentrations in normal rats and mice by a different mechanism (Smith and Pogson, Biochemical J., 168, 495 (1977)), neither tryptophan, 5-fluoro-tryptophan, nor 5-benzoyl-tryptophan at a dose of 100 mg/kg were effective in the insulin resistant model wherein the present invention was discovered. As some tryptophan analogs were effective in lowering fed blood glucose levels in this insulin resistant model, it is possible that extremely large amounts of tryptophan itself might give rise to a similar effect.
SUMMARY OF THE INVENTION
This in~ention relates to met~ods of preventing and treating diabetes, atherosclerosis and obesity in animals, including humans by administering a compound of formula I
wherein R is (a) hydrogen, (b) Cl-C10 alkyl, (c) C2-Cl0 alkenyl, .
,, .. .

2~

(d) C3-C10 alkynyl, (e) phenyl, f) -C(R6)H-phenYl(-R5)b~
(g) -so2-phenyl(-R5)b~
(h) -C(O)Rl, (i) -C(O)ORg, (~ ) - (cH2)qN(R7) (R8) ~
(k) -C(O)N(R7)(R8), (1) -(CH2)m Het, (m) -CH2C(O)R4, (n) -(CH2)mO(CH2)mCH3, (o) -CH2-(C3-C6)cycloalkyl, (p) C3-Cg cycloalkyl, wherein a is 1 to 4, b i~ 1 to 5, m is 1 ar 2, n is O or 1, p 19 4 or 5, q iP 2 or 3, wherein N is a pharmacologically acceptable cation;
wherein Rl is (a) hydrogen, (b) Cl-C10 alkyl, ~c) C2-Clo alk~nyl, (d) C2-Cl0 alkynyl, (e) -phenyl(-Rs)b, (f) -cH2-phenyl(-~5)b;
wherein R2 is (a) -CH(~6)-phenyl-(Rs)b;
(b) -CH2- ~et, (c) Cl-C6 alkyl (d) -CH2)b-phenyl(-R5)b wherein het is a 5- or 6-membered saturated or unsaturated rlng containing from one to three heteroatoms (nitrogen, oxygen, sul*ur);
and including any bicyclic group in ~hich any of the above heterocyclic rings is fused to a benzene ring or ano~her heterocycle;
wherein R3 is (a) hydrogen, ,: ~:
. . . ~ :
::

20~4~S

(b) -C(o)Rl, (C) -C(O)ORl, (d) -(CH2)b-phenyl(R5)b wherein R4 is S (a) hydrogen, (b) -C(O)Rg wherein Rs same or different is (a) hydrogen, (b) halogen, (c) hydroxy, (d) Cl-C10 alkoxy, (e) C3-C10 alkenyloxy, (f) C3-Clo alkynyloxy, (g) nitro, (h) amino, (i) -N(R6)(R7), NHC (03Rl, (k~ -Oc(O~Rl, (1) -C(O)Rl, (~ trifluoromethyl, (n) -S02N(R6)(R7), (o) -SR8 ~
(p) -C~N, (q) -C(O)OR6, (r) Cl-C4 alkyl (s) phenyl (t) -0-CH~-0-, wherein R6 is (a) hydrogen, (b) Cl-Clo alkyl, (C~ -C(O)ORl, (d3 phenyl, wherein R7 is (a) hydrogen, (b3 Cl-Clo alkyl, wherein R8 is (a3 hydrogen, (b3 Cl-C10 alkyl, ;
- , ~ ~ ' ' " ,'' ~

~x~s (c) C3-C10 alkenyl, (d) C3-Cl0 alkynyl, (e) phenyl-(R5)b, (f) -CH2-PhenYl-(R5) (g) CH2-het, and wherein R9 is ~a) hydrogen, (b) hydroxy, (c) OM, (d) -OR8, (e) -N(R6)(R7), and pharmacologically acceptable salts of compounds wherein R9 is not OM;
with the proviso that when n is O, R2 is benzyl, substituted benzyl or alkyl, R is hydrogen, benzyl or substituted benzyl, Rl is hydrogen or methyl, R3 is hydrogen or methyl, R5 is hydrogen, benzyl-oxy or ~ethoxy, and R6 is hydrogen, then R4 cannot be benzyloxycarb-onyl, ethoxycarbonyl, or C(O)OM;
with the further proviso that when n is 1; R is hydrogen or methyl; Rl is hydrogen; R2 is benzyl; R3 is hydrogen; R5 is hydrogen;
and R6 is hydrogen, then R4 cannot be carboxyl or methoxy-carbonyl;
with the further proviso that when n is O; R is hydrogen or 4-;25 substituted benzyl; Rl is hydrogen or methyl; R2 is Cl-C4 alkyl; R3 'is hydrogen or Cl-C2 alkyl; R5 is hydrogen, methoxy, or benzyloxy;
and R6 is hydro~en, then R4 cannot be ethoxycarbonyl, carboxyl, or propoxycarbonyl;
with the further proviso that the compound of Formula I is not:
Methyl ~-[N-methyl-N-3-(trifluoromethyl)benzylamino]-1-benzyl-indole-3-acetate, Methyl ~-[N-methyl-N-3-(trifluoromethyl)benzylamino]-1-benzyl-~: indole-3-acetate hydrochloride, ~-[N-methyl-N-3-(trifluoromethyl)benzylamino]-1-benzylindole-3-35 acetic acid, Methyl ~-[3-(trifluoromethyl)benzylamino]indole-3-acetate hydrochloride, : Ethyl ~-[3-(trifluoromethyl)benzylamino]indole-3-acetate ~' : ,, : , ~ . - , .

Z~gL5 g hydrochloride, ~ -[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid p-phenylphenacyl ester, ~ -[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid l-methyl-3-butenyl ester, 2-[3-(trifluoromethyl)benzylamino]-2-(1-benzyl-3-indolyl)-ethanol, Methyl ~-[3-(trifluoromethyl)benzylamino]-l-acetoxymethylindole-3-acetate, Methyl ~-[3-(trifluoromethyl)benzylamino]-l-acetoxymethylindole-3-acetate hydrochloride, Methyl ~-(benzylamino)-indole-3-acetate, ~ -(phenylpropylamino)-l-benzylindole-3-acetic acid, Methyl ~-[4-~aminosulfonyl)phenylethylamino]-indole-3-acetate, Q-Methylamino-l-benzylindole-3-acetic acid, ~ -(Phenylethylamino)-l-benzylindole-3-acetic acld, ~ -[4-(aminosulfonyl)phenylethylamino]-1-benzylindole-3-acetic acid, ~ -[(tetrahydro-2-furanyl)methylamino]-1-benzylindole-3-acetic acid, ~-[3-(trifluoromethyl)benzylamino]-l-ben7ylindole-3-acetic acid N,~-dimethylamide, Ethyl ~-~3-(trlfluoromethyl)benzylamino]-indole-3-acetate, ~-[(2-iurylmethyl)amino]-indole-3-acetic acid, -benzylamino-indole-3-acetic acid, ~-[3-(tr~fluoromethyl)benzylamino]-1-benzylindole-3-acetic acid amide, ~-[4-(methoxycarbonyl)benzylamino]-l-ben~ylindole-3-acetic acid, ~ethyl ~-[3-(trifluoromethyl)benzylamino]-1-acetoxymethylindole-3-acetate, Methyl o-[3-(trifluoromethyl)benzylamino]-1-acetoxymethylindole-3-acetate hydrochloride.
The compounds of this invention are us~ful as ant~-diabetic, anti-obesity and anti-atherosclerotic agents.
3~ The compounds of this invention may be supplied in capsules, tablets, suppositories, powders, or as fluid solutions and/or suspensions in aqueous or non-aqueous vehicles or can be added to food. The compounds can be administered oxally, intravenously, ' .
.

intramuscularly, intra-arterially, intraperitoneally, subcutaneously, sublingually, bucally to man or to other animals. The dosage of each of the uses is about 0.1-50 mg/kg. The dosage will vary with the route of administration and the physical state of the recipient.
Also, for example, the dosa~e by the oral route will depend on the frequency of admlnistration and the weight of the recipient.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare various compounds of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.
Preferred compounds are those of formula I wherein R is hydrogen or benzyl, Rl is hydrogen, R~ is trifluoromethylbenzyl or furylmethyl and Rg is selected from the group consisting of hydroxy, ~8 and OM
whersin R8 is Cl-Clo alkyl and N is ~ pharmacologically acceptable cation and their preferred utility i9 as anti-diabetic agents.
Particularly preferred are the compounds ~-[3-~tri~luoromethyl)benz-ylamino]-l-benzylindole-3-acetic acid, methyl ~-[3-(trifluoromethyl)-benzylamino]-l-benzylindole-3-acetate hydrochlorida, ~-[3-(trifluoro-methyl)benzylamino]-indole-3-acetic acid, ~-[(2-furylmethyl)amino]-l-benzylindole-3-acetic acid, o-[3-(trifluoromethyl)benzylamino]-1-benzyl-5-methoxyindole-3-acetic acid, ~-[3-(trifluoromethyl)benzyl-amino]-l-benzyl-6-chloro-5-methoxyindole-3-acetic acid, and ~-[3-(trifluoromethyl)benzylamino]-l-benzyl-6-methyl-5-methoxyindole-3-acetic acid.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the preflx (Ci-C;) indicates a moiety of the integer "i" to the integer "~ n carbon atoms, inclusive. Thus (Cl-C4~alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof. C4-C7 cyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms.
Examples of (C3-Clo)cycloalkyl which include alkyl-substitu~ed cycloal~yl containing a total of up to 10 total carbon atoms, are Z~ 5 cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-di-ethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof.
Examples of aryl include phenyl, naphthyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4- 2,3,~-, or 2,4,5-)-trimethylphenyl, (o-, m-, or p-)fluorophenyl, (o-, m-, or p-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (~,4-, 2,5-, 2,6-, 3,4, or 3,5-)difluorophenyl, (o-, m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5- or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3-fluorophenyl, (3- or 4-)chloro-2-fluorophenyl, (o-, m-, or p-)trifluoro-methylphenyl, (o-, m-, or p-)ethoxyphenyl, (4- or 5-)chloro-2-methoxy-phenyl, and 2,4-dichloro-(5- or 6-)methylphenyl, and the like.
Exa~ples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, Nin-formyl-indolyl, Nin-Cl-C5alkyl-C(0)-indolyl, [1,2,4]-triazolyl, 2-, 4-, or 5-pyrimldinyl, ~- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazoli-dilyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazoli-dinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl,benzothiazolyl, benzoxazolyl, furyl, thienyl, phthalimidyl, and benzothienyl. Each of these moieties may be substituted ben~ofuran as noted above.
As would be generally recognized by those skilled in the art of organic chemistry, a heterocycle as defined herein for -Het would not be bonded through oxygen or sulfur or through nitrogen which is within a ring and part of A double bond.
Halo is halogen (fluoro, chloro, bromo, or iodo) or trifluoromethyl. Examples of phar~aceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fwnarate, glucoheptanoate, : . , glycerophosphate, hemisulfate, hept~noate, hexanoate, hydrochlorid~, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
Examples of pharmaceutically acceptable cations include:
pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations. Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., alu~inum, zinc, and ~ron are also within the scope of this invention. Pharma-ceutically acoeptable amine cations are those derived from primary, secondary, or tertlary amines.
EMBODIMENTS OF TH~ INVENTION
l~e ~-amino-indole-3-acetic acids and their derivativ~s wherein n i9 O can be prepared by condensing an indole unsubstituted at the 3-position with glyoxylic acid or esters thereof and a primary or secondary amine. Reactions of this type are described in U.S. patent 3,074,942, the essential parts which are incorporated herein by reference and are illustrated in Charts I and II. A preferred method involves adding 1.1 equivalents of glyoxylic acid monohydrate to a solution of 1.0 equivalent of an appropriate lndole and one equivalent of the appropriate amine. The resulting solution is allowed to stand overnight and then the separated solid is collected by filtratlon, washed wlth methanol and dried to obtain the desired product.
Compounds wherein n - l can be prepared ~rom tryptophan and its known derivatives.
Compounds of this invention having a migrated carboxy group, I', can be prepared by the process illustrated in Chart III. In this process an indole-3-carboxyaldehyde is reacted with an amine such as methyl-phenylglycinate hydrochloride in the presence of a solvent.
The ratio of amine to aldehyde is about 3 to l and the reaction is conducted at a temperature of about 25 to about 40 for a period of about 24 hours to about 72 hours.
The starting materials utilized to prepare the compounds of this ~o~

invention are either commercially available or can be prepared by methods well known in the art. For example, se~ K. Sukata, Bull.
Chem. Soc., Japan, 56, 280 (1982)~ Khan et al, Chem. Pharm. ~ull., 25, 3110 (1970), discloses a procedure for preparing l-phenylindole;
1-benzyl-2-phenylindole was prepared by Suvorou et al, J. Org. Chem..
USSR, 16, 766 (1980) by the Fischer indole synthesis. Ehrhart et al, Arch, Pharm., 294, 550 (1961) disclosed a process for preparing 1-benzyl-5-methoxyindole, 1-bsnzyl-5-chloroindole and 1-benzyl-2-methoxyindole and l-benzyl-5-fluoroindole. Rubottom et al., Org.
10 Syn., 54, 60 (1974) discloses a process for preparing l-allylindole.
Kelly et al, Synthesis, 544 (1972) discloses a process for preparing methyl glyoxylate.
DESCRIPTION OF THE PREFERRED ~MBODIMENTS
Preparation 1 l-Benzylindole To a stirred mixture of sodium amide (prepared from 19.6 g, 0.85 mole of sodium and a few mg of Fe(N03)3-9H20) and 800 mL of liquid NH3 (a dry ice condenser was ussd) was added a solution of 100 g (0.85 mole) of indole in 250 mL of dry ether durlng 15 m1nutoD. The mixture was stirred for 30 minutes and then a solution of 107.8 g 20 (0.85 mole) of benzyl chloride in 100 mL of dry ether was added during 30 minutes. The ammonia was allowed to evaporate overnleht.
The sides of the flask were washed down with MeOH and then 500 mL of H20 was added. The mixture was extracted with ether (2x500 mL). The combined ether extracts were washed with 250 mL of H20 and dried over MgS04. The solvent was evaporated. The residue was distllled at 2 mm: fr 1, b.p. 172-183, fr II, b.p. 183-186, 5 ~; fr III, b.p.
186-187~, 10.9 g; fr IV, b.p. 187-191, 121.8 g; fr V, b.p. 191-197, 13.9 g. Fractions III-V solidified upon standing se~eral hours. Fraction IV had m.p. 42-43. Fraction III was crystallized 30 from aqueous MeOH giving 9.9 g o colorless needles, m.p. 42.5-43.5.
Fraction V was crystallized from aqueous MeOH giving 11.6 g of colorless needless, m.p. 43-45.5. The total yield was 143.3 g (81.5%).
Preparation 2 1-(4-Chlorobenzyl)indole A mixture of 11.72 g (0.1 mole) Gf indole, 17.71 g (0.11 mole) of 4-chlorobenzyl chloride, 33 g (0.5 mole) of 85~ KOH, 14 mL of H20, 2.5 g (2.5 ~moles) of PEG-1000 and 100 mL of toluene was stirred and heated at 55-60 for 22 hours. After cooling to room te~perature, 50 mL of H20 was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined organic phases were washed with 2N HCl (2x50 mL), H20 (2x50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 29 g of orange-brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 1:1 CH2C12-Skellysol~e B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (lx4") (25~ CH2C12-Skellysolve B). Fractions 12-19 were combined giving 23.11 g of crude product as a pink oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25~ CH2C12-Skellysolve B and 200 mL fractions were collected. The fractions were assayed as before. Fractions 20-30 were combined giving 20.33 g (84%) of 1-(4-chlorobenzyl)indole as a yellow oil.
Phy~ical characteri~tics are as follows:
NMR (CDC13): ~ 5.22 (s~ 2H), 6.6 (d,J-3Hz, lH~, 6.9-7.4 (m, 8H), 7.57-7.a (m, lH).
Pre~ar~tion 3 l-Phenylindole A mixture of 17.57 g (0.15 mole) of indole, 23.55 g (0.15 mole) 20 of bromobenzene, 21 g of anhydrous potassium carbonate, 0.75 g of CuO, and 30 mL of DMF was stirred and heated under reflux for 43 hours. The cooled mixture was diluted with 200 mL of H20 and extracted with 150 mL of ether. The extract was washed wi~h H20 (2x50 mL) and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 35.7 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25~
CH2C12-Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (lx4n) (25~ CH2C12-Skellysolve B). Fractions 15-22 were combined giving 5.86 g (20~) of l-phenylindole as a yellow oil.
Physical characteristics are as follows:
NMR (CDC13): ~ 6.7 (d,J 3Hz, lH), 7.1-7.9 (m, lOH).
P'f eparatio~ 4 1-Ben~yl-2-phenylindole and 1,3-Dibenzyl-2-phenylindole A mlxture of 19.33 g (0.1 mole) of 2-phenylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O~
2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 55-60 for 24 hours. After cooling to room temperature, ,, , , , ., .. .. . . ., .. .... . . . ~ .. . , .. , , .. . .. ~ .. ... . . . ...

, `

lS

100 mL of H20 was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed with 2N HCl (2x50 mL), H20 (2x50 mL), and 50 ~L of brine and dried over MgS04. Evaporation of the solvent left 32.3 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25~ CH2C12-Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (lx4") (25~ CH2C12-Skellysolve B). Fractions 18-20 were comblned giving 3.74 g (13~) of 1-benzyl-2-phenylindole as a solid.
Physical characteristics are as follows:
NMR (fr 19) (CDC13): 6 5.38 (s,2H), 6.7 (s,lH), 7.0-7.9 (m, 14H).
Fractions 21-25 were combined giving 10.38 g of a mixture of 1-benzyl-2-phenylindole and 1,3-dibenzyl-2-phenylindole as a pale yellow oil which partially solidified upon standing.
Physical characteristics are as follows:
NMR ~fr 28) (CDC13): C 4.1 (s,2H), 5.28 (~,2H), 6.9-7.6 (m,19H).
Prepara~ Benzyl-5-methoxyindole and 1,3-Dibenzyl-5-methoxyindole A mixture of 5 g (33.97 mmoles) of 5-methoxyindole, 4.73 g (37.37 mmoles) of benzyl chloride, 11.2 g (170 mmoles) of 85% KOH, 5 mL of H20, 0.83 g (0.83 mmoles) of PEG-1000, and 50 ~L of toluene was 25 stirred &nd heated at 55-60 for 21 hours. After cooling to room temperature, 100 mL of H20 was added. The layers were separated.
The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed with 2N HCl (2x50 mL), H20 (2x50 ~L), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 30 9.86 g of brown oil. The oil was chromatographed on a 400 g column of silica gel. The column was eluted with 1:1 CH2C12-Skellysolve B
and 100 mL fractions were collected. The fractions were assayed by silica gel tlc (2x8n) (1:1 CH2C12-Skellysolve B). Fraction 15 contained 0.78 g of a mixture of 1-benzyl-5-methoxyindole and 1,3-dlbenzyl-5-methoxyindole as an oil.
Physical characteristics are as follows:
NMR (fr 15) (CDC13): ~ 3.78 and 3.88 (s;s,3H), 4.1 (s,lH), 5.2 and 5.28 (s's,2H), 6.51 (d,J~3Hz,<lH), 6.77-7.4 (m,9.5H).

'' '' ~

,, .

2~ 15 Fraction 16 was crystalli~ed from CH2C12-Skellysolve B giving 1.49 g of 1-benzyl-5-methoxyindole as a white solid. Fractions 17-27 were combined giving 4.44 g of 1-benzyl-5-methoxyindolP as a white solid. The total yield of l-benzyl-5-methoxyindole was 5.93 g (74%).
Physical characteristics are as follows:
NMR (fr 22) (CDCl~ 3.8 (s,3H), 5.25 (s,2H), 6.5(d,J-3Hz, lH), 6.8-7.4 (m,9H).
Preparation 6 l~Benzyl-5-chloroindole To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 mL of dry ether was added 4.39 g (39.12 mmoles) potassium tert-butoxide.
The mixture was stirred while 5.08 g (33.51 mmoles) of 5-chloroindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 6.69 g (39.11 ~moles) of benzyl bromide in 40 mL of ether was added during 0.5 hour. The stirring was continued for 27 hours. Water (100 mL) was added. The layers were separated.
The aqueous layer was extracted with ether (2x75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgS04.
Evaporation of the solvent left 9.17 g of orange oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 1:2 CH2C12-Skellysolve B and 200 mL fractions ware collected. The fractions were assayed by silica gel tlc (2x8n) (1:2 CH2C12-Skellysolve B). Fractions 10-14 were co~bined giving 7.26 g (90~) of 1-benzyl-5-chloroindole as a yellow oil.
Physical characteristics are as follows:
N~R (fr 10) (CDC13): ~ 4.06 (s, trace~, 5.28 (s, 2H), 6.52 (d, J 3Hz, lH), 7.02-7.58 (m,8H), 7.63-7.73 (m, lH).
~ 51~n 7 1-Ben~yl-2-methylindole and 1,3-dibenzyl-2-methylindole A mixture of 13.11 g (0.1 mole) of 2-methylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H20~
2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heatsd at 60 for 23 hours. ~fter cooling to room temperature, 100 mL of H20 was added. The layers were sepsrated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed 2N HCl (2x50 mL), H20 (2x50 mL), and 50 mL of brine and dried over MgS04. Evaporation of the solvent left 26.98 g of dark brown oll. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2C12-Skellysolve B and 200 mL

~: :
- .
:: :

2~

fractions were collected. The fractions were assayed by silica gel tlc (lx4n) (25~ CH2Cl2-Skellysolve B). Fractions 20-22 were combined giving 2.08 g (9~) of 1-benzy1-2-methylindole as a yellow oil which solidified.
Physical characteristics are as follows:
NMR (fr 22) (CDC13): 6 2.32 (s, 3H), 5.23 (s, 2H), 6.2-6.6 (br, lH), 6.9-7.42 (m, 7H), 7.5-7.78 (m, 2H).
Fractions 23-28 were combined giving 7.50 g of yellow oil consisting of l-benæyl-2-methylindole and 1,3-dibenzyl-2-methyl-indole.
Physical characteristics are as follows:
NMR (fr 33)(CDC13): ~ 2.29 (s, 3H), 4.09 (s, 2H), 5.23 (8, 2H), 6.88-7.58 (m, 14H).
Preparation 8 1-Benzyl-2-methylindole and 1,3-dibenzyl-2-methyl-indole To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 mL of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide.
ThQ mixture was stirrsd while 13.11 g (100 ~moles) of 2-methylindole was added. The stirring was continued for 0.5 hour. Most of the 20 solid dissolvad. Then 20 g (116.9 mmoles~ of benzyl chloride in 120 mL of ether was added during 45 minutec. The stirring was continued for 21.5 hours. Water (200 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2x75 mL~.
The rombined ether pha3es were washed ~ith 50 ~L of brine and dri2d 25 over MgS04. Evaporation of the solvent left 25.85 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica g81.
The column was eluted with 25% CH2C12-Skellysolve ~ and 200 mL
fractions were collected. The frsctions wsre assayed by silica gel tlc (lx4n) (25~ CH2Cl2-Skellysolve B). Fractions 22-2S were combined 30 giving 2.28 8 (10%) of slightly impure 1-benzyl-2-methylindole as a pals yellow oil which solidified upon standing. Fractions 26-35 were combined giving 8.42 g of 1-benæyl-2-methylindole snd 1,3-dibenzyl-2-methylindole as a pale yellow oil. The 8.42 g was ~ombined with the 7.50 g of 8 similar mixture from fractions 23-28, and chromatographed 35 on a 1100 g column of silica gel. The column was el~ted with 25%
CH2C12-Skellysolve B and 200 mL fractions were collected. The fractlons were assayed as before. Fractions 21-24 were combined giving 3.59 g oi 1-benzyl-2-methylindole as a pale yellow oil which '' ' - ~ `

:

~o~s solidified. Fractions 25-30 were combined giving 7.66 g of a mixture of l-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as an oil.
Preparation 9 l-Allylindole To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 ml of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide.
The mixture was stirred while 11.72 g (100 mmoles) indole was added.
The stirring was continued for 3 hours. All of the solid did not dissolve. Then 14.1 g (116.5 mmoles) of allyl bromide in 100 ml of ether was added during 0.5 hour. The stirrlng was continued for 67.5 hours. Water (200 ml) was added. The layers were separated. The aqueous layer was extracted with ether (2 x 75 ml). The combined ether phases were washed with 50 ml of brine and dried over MgS04.
~vaporation of the solvent left 16.02 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was 15 eluted with 104 acstone-Skellysolve B ~nd 200 ml fractions were collected. The fractions were assayed by silic8 gel tlc (1 x 4n) (10~ acetone-Skellysolve B). Fractions 17-23 were com~ined giving 11.60 g (74~) of l-allylindole BS a yellow-bro~n oil.
Physical characteristics are as follows:
NMR (fr 22) (CDC13): ~ 4.5-4.8 (m, 2H), 4.9-5.25 (m, 2H), 5.7-6.2 (m, lH), 6.52 (d, J - 3Hz, lH), 7.0-7.48 (~, 4H), 7.58-7.78 (m, lH).
Preparation 10 1-Benzyl-5-methylindole To a stirred mixture of ~odium amide (prepared from O.9 g 39.13 mmoles of sodium) and ca 100 ml of liquid am~onia was added a solution of 5.08 g (38.73 mmoles) of 5-methylindole in 100 ml of ether during 5 minutes. The mixture was stirred for 1.5 hours. Then a solution of 5.15 g (40.68 mmoles) of benzyl chloride in 100 ml of ether was added during 10 minutes. The mixture was stirred for two hours. The ammonia was allowed to evaporate overnight. The inqide of the flask was washed down with MeOH. Then 150 ml of H20 was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether. The combined ether phases were washed with 50 ml of brine and dried over MgS04. Evaporation of the solvent left 35 9.41 g of oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 30% CH2C12-Skellysolve B and 200 ml frac~ions were collected. The fractions were assayed by silica gel tlc (2 x 8n) (25~ CH2C12-Skellysolve B). FraGtions 12-17 2~

were combined giving 4.52 g (53%) of 1-benzyl-5-methylindole as a yellow-green oll.
Physical charac~eristics are as follows:
NMR (CDC13): ~ 2.42 (s, 3H), 5.23 (s, 2H), 6.49 (d, J 4 Hz, lH), 6.91-7.58 (m, 9H).
Preparation 11 1-Benzyl-5-fluoroindole To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 ml of dry ether was added 3.27 g (29.14 mmoles) of potassium tert-butoxide.
The mixture was stirred while a solution of 3.75 g (27.75 mmoles) of 5-fluoroindole in 80 ml of ether was added. The stirring was continued for 0.5 hour. Solid was present. l~en 3.~9 g (29.15 mmoles) of benæyl chloride in 80 ml of ether was added. The mixt~re was stirred for 28 hours. Water (100 ml) was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether.
The combined ether layers were washed with 50 ml of brine and dried over MgS04. Evaporation of the solvent left 6.95 g of orange oil.
The oil was chromatographed on a 600 g column of silica gel. The column was eluted with 30% CH2C12-Skellysolve B and 200 ml fractions were collected. The fractions were assayed by silica gel tlc (1 x 20 4n) (80~ CH2C12-Skellysolve B). Fractions 11-15 were combined giving 0.88 g (14~) of 1-benzyl-5-fluoroindole as a pale yellow oil which contained a small amount of 1,3-dibenzyl-5-fluoroindole.
Physlcal characteristics are as follows:
NMR (CD30D): ~ 5.23 (s, 2H), 6.46 (d, J - 4Hz, lH), 6.7-7.32 (m, 9H). Also present in the spectrum are two small singlets one at 3.98 and the other at 5.13 ~, which are from the 1,3-dibenzyl-5-fluoroindole impurity.
Fractions 19~29 were combined giving 2.28 g of recovered 5-fluoroindole as a solid.
Prepa~ation 12 N,N-Dimethyl-2-oxoacetamide To a solution of 5.21 g (25.51 mmoles) of (L)-N,N-dimethyl-tartramide in 100 ml of MeOH was added 5.82 g ~25.53 mmoles of para-periodic acid. The mixture became warm. The resulting solution was allowed to stand for 24 hours giving a yellow solution. The solvent was evaporated using a rotary evaporator and a water bath at 40 leaving a viscous orange-brown oil. The oil was triturated with 250 ml of ether causing a solid to separate. The mixturs was filtered.
Evaporation of the solvent from the filtrate left 4.97 g of brown .. . ... . . . .. . -- .. . . .

, - 2~ 4~S

oil. The oil was chromatographed on a 300 g column of sillca gel.
The column was eluted with 10% MeOH-CH2C12 and 100 ml fractions were collected. The fractions were assayed by silica ~el tlc (1 x 4n~
(10% MeOH-CH2C12). Fractions 7-11 were combined giving 4.92 g (95%) of N,N-dimethyl-2-oxoaceta~ide as a brown oil.
Physical characteristics are as follows:
NMR (CDC13): ~ 3.11 (s, 3H), 3.19 (s, 3H), 5.08 (s, lH), 9.58 (very small s). A MeOH peak was also present. Since the peak at 9.58 ~ is so small, the compound must exist in a polymeric form.
Preparation 13 Diethoxyacetamide A mixture of 24.85 g of ethyl diethoxyacetate and 140 ml of concentrated am~onium hydroxide was stirred for 3 hours. The ammonia and H20 were evaporated under reduced pressure on a water bath at 50-60 leaving a wet solid. The wet solid was dried in a vacuum oven at 53 for 18 hcurs giving a dark pink solid. The solid was dissolved in CH2C12. The solution ~as filtered to remove a small amount of red insoluble material. The filtrate was concentrated and Skellysolve B
was added. Cooling gave la.O ~ (87~) of diethoxyacetamid~ as orange plates, m.p. 76.5-79.
Preparstion 14 2-(3-Trifluoromethylphenyl)-Q-l-Pyrroline To magnesium metal turnings (2.19 g, 90 mmol) covered with dry ether (40 mL) was added ca. 10% of a solution of 3-trifluoromethyl-bromobenzene (10.13 g, 45 mmol) in Et20 (10 mL). When the reaction had commenced the remaining halide solution was added at such a rate so as to maintain a gentle reflux. Af~er the addition was complete the brown mixture was heated under reflux for 30 minutes; then was cooled to room temperature and transferred via cannula to a flas~
(250 mL, three-neck RB) equipped wi~h a reflux condenser and a~
addition funnel. The Grignard reagent was diluted with Et20 (100 mL) and a solution of freshly distilled 4-chlorooutyron~trile (4.66 g, 45 mmol) in Et20 (50 mL) was added over a period of 20 minutes. The resulting solution was heated under reflux for 30 m~nutes, then was allowed ~o cool to room temperature and stir overnight. The solvent was removed in vacuo and the gummy residue refluxed in o-xylene (100 mL) for one hour, then was allowed to cool to room temperature and was treated with 10~ aqueous NH4Cl (100 mL). The organic phase was separated, the aqueous layer was extracted with Et20 (100 mL~ and the combined organic phases were acidified to pH 1 with 6N aqueous HCl.

. .

.' ~
' ~al0~4~S

The aqueous layer was separated, extracted with Et2O (100 mL) and the pH was adjusted to 14 with 20% aqueous NaOH. The aqueous phase was extracted with Et2O (2 x mL~, the combined organic extracts we~e washed with water (0.25 L), brine (0.25 L), dried (Na2SO4) and then concentrated in vacuo to furnish the title compound (3.43 g, 35%) as a brown oil which was utilized without further purification.
Physical characteristics are as follows:
TLC: (Merck; EtOAc-hexanes, 1:1; W (+); ammoniu~ molybdate): rf _ 0.43.
lH-NMR (300 MHz, CDC13): 5 - 8.12 (s, 1), 8.01 (d, J - 7.8Hz, 1), 7.53(m, 1), 4.10(m, 2), 2.96(m, 2), 2.08(m, 2).
13C-NMR (75.5 MHz), CDC13): ~ ~ 173.2, 136.2, 130.6, 128.8, 126.7, 126.0, 124.2, 122.5, 61.6, 34.8, 22.6.
Preparatio~ 15 2(3-Trifluoromethylphenyl)-pyrrolidine To a solution of 2(3-trifluoromethylphenyl)pyrroline (3.43 g, 16 mmol) in methanol-THF (100 mL, 1:1, v/~) was added ~laeial acetie aeid(5 mL) followed immediately by NaBH3CN (1.31 g, 21 mmol). After stirring for two hours at room tamperature the reaction mixture was concentrated in vacuo and the xesulting rust eolored solid was treated with 20% aqueous NaOH (25 mL) to give a rust eolored solution and suspended solids. The mixture was east into water (100 mL) and EtOAe (100 mL). The organic phase was separated, the aqueous layer was extracted with an additional volume (100 mL) of EtOAc, and the combined organic extracts were washed with ~a~er (0.25 L), brine (0.25 L) and dried (Na2SO4). Concentration in vaeuo provided the crude amine as a brown liquid which was purified by chromatography on a eolumn of silica gel (230-400 mesh, 500 g, 70 mm o.d., EtOAe-hexanes 30:70, 400 mL fractions) using the flash teehnique.
Fraetions 27-50 afforded 2.56 g (74~) of the title eompound as a yellow oil.
Physical characteristics are as follows:
TLC: (MereX; EtOAe-hexanes, 1:1.
W (+); ammonium molybdate): Rf - 0.08.
lH-NMR (300 MHz, CDC13): 6 - 7.39-7.64 (4), 4.18 (t, J ~ 7.7Hz, 1), 3.20 (m, 1), 3.04 (m, 1), 2.20 (m, 1), 2.01 (m, 1~, 1.90 (m, 2), 1.6 (m, 1).
13C-NMR (75.5MHz, CDC13): 6 147.1, 129.9, 128.7, 126.7, 123.5, 123.2, 122.9, 61.9, 46.9, 34.5, 25.5.

~ .

~z~

Preparation 16 1-Phenyl-lH-indole-3-acetonitrile-~-((3-trifluoro-methyl)phenyl)methylamine To a solution of 3-trifluoromethylbenzylamine (4.38 g, 25 mmol) and NaCN (11.23 g, 25 m~ol) in 1.00M aqueous HCl (25 mL) was added one portion N-benæylindole-3-carboxyaldehyde (5.90 g, 25 mmol) in MeOH (25 mL). The mixture was allowed to stir for five hours, then the reaction was cast into Et20 (1.0 L) and 0.3N aqueous NaOH (1.0 L). The organic phase was separated, washed with brine (1.0 L) and dsied (Na2SO4). Concentration in vacuo affo~ded the crude amino-nitrile as an oily red-orange solid which was purified by chroma-tography on a column of silica gel (230-400 mesh, 500 g, 70 mm o.d., Et2O-hexanes 1:4, 300 mL fr) using the flash technique. Fractions 6-12 gave 3.76 g (36~) of 1 as a relatively un~table cream colored solid which was contaminated with the starting aldehyde. Thls compound was utili7ed in the next reaction without further purlfi¢ation. Physical char~cteristics are as follows:
TLC: (Merck; Et2O-hexanes~
W (+); ammonium molybdate): Rf ~ 0.20.
lH-NMR (300 MHz, CDC13): ~ - 1.94 (brm, 1), 4.09 (dq, J - 9.1, 20 1.6 Jz, 2), 5.04 (d, J - 8.7 Hz, 1), 5.29 (s, 2), 7.0-7.8 (14).
IR (neat): 3330, 3050, 2925, 2850, 2210, 1640, 1540, 1440, 1340, 1160 (br), 890, 709, 735 and 695 cm~l.
EI/MS (70eV): 392 (base), 301 (34.1), 281 (4.35), 248 (10.7), 232 (6.8), 220 (22.6), 208 (85.5), 91 (base).
Data attributed to Kalir, A.; Szara, S.J. Med. Chem. 2966, 9, 793.
P~eparation 17 Methyl-3-trifluoromethylphe~ylAcetate Into 8 solution of 3-trifluoromethylphenylscetic acid (20.0 g, 98 mmol) in MeOH (100 mL), cooled in an lce-water bath, was bubbled HCl (g) for 15 min. The mixture was allowed to war~ to room temperature and was then concentrated in vacuo to furnish a clear, yellow-green liquid which was diluted with EtOAc (0.25L) and washed with saturated aqueous NaHCO3 (2X0.25L), brin~ (0.25L), ~nd dried (Na2S04). Concentr~tion in vacuo provlded the crude ester which was 35 purified by chromatography on a column of silica gel (230-400 mesh, 600g, 70m~ o.d., ethyl acetate-hexanes 10:90, 400 mL fractions) using the flash technique. Fractions 6-9 provided 19.08g (89~) of methyl-3-trifluoromethylphenylacetate as a clear colorless liquid.

: ~ .
:

. :

20(~ 1S

Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 25:75.
W (+)) Rf - 0.44.
lH-NMR: ~ - 7.35-7.55 (4), 3.70 (s, 3), 3.67 (s, 2).
Preparation 18 Methyl-2-(3-trifluoromethylphenyl)-2-bromo-acetate To a solution of methyl 3 trifluoromethylphenylacetate (37.79g, 173mmol) in CC14 (0.3L) was added N~S (33.91 g, 191 mmol) in six portions at one hour intervals. After the first addition of NBS, two drops of 48~ HBr were added and the mixture was warmed to reflux and maintained at reflux during the course of the NBS additions and for an additional 18 hours after the additions were completed. The mixture was cooled to room temperature and filtered through a pad of silica gel (230-400 mesh, 250 g, eluted with EtOAc-hexanes, 50:50, 0.75 L). Concentration in vacuo afforded the crude bromide as a clear yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 600 g, 70 mm o.d., ethyl a~etate-hexanes 25:75, 400 mL fractions) using the flash technique. Fractions 4-6 provided 39.6 g (774) of methyl-2-(3-trifluoromethylphenyl)2-bromo-acetate as a clear colorless liquid.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 25:75.
W (+); ammoniu~ molybdate) Rf - O.45.
lH-NMR: ~ - 7.40-7.85 (4), 5.38 (s, 1), 3.81 (s, 3).
EI/MS (70eV): 298 (M+, 1.93), 296 (M-~, 2.7), 239 (22.2), 237 25 (22.2), 217 (base), 189 (36.2), 159 (34.3).
Preparation l9 3-Trifluoromethylphenylglycine Methyl Ester To a solution of methyl 3-trifluoromethylphenyl-2~bromo-acetate (22.38 g, 75.3 m~ol) in CHCl3 (0.1 L), cooled (0C internal, cryo-cool~ in a -10~C methanol bath, was added a solution of tetramethyl 30 guanidinium azide (13.11 g, 82.9 mmol) in CHC13 (0.15 L) over one hour. After the addition was completed the solvent was removed in vacuo (no heat!) to afford a pale yellow solid. The crude yellow material was placed in Et20 and the dissolved organic materials were separated frGm the tetramethylguanldinium hydrobromide by filtration through a pad of cellte. The filter cake was rinsed with Et20 (0.2 L) and the combined flltrates were concentrated in vacuo (no heatl~
to furnish the desired azide (16.56 g, 85~) as a pale brown oil which was i~mediately utilized without further purification.

!
': ; . '~, ., ~ , ~ .

Physical characterlstics are as follows:
TLC (Merck; EtOAc-hexanes, 25:75.
W (+); ammonium molybdate) Rf - 0.23.
lH-NMR: ~ - 8.33 (brs, l), 8.25 (d, J - 8Hz, 1), 7.92 (d, J -8Hz, 1), 7.60-7.70 (1), 5.11 (s, 1), 4.01 (s, 3).
Infrared (neat): 3173, 3150, 2933, 2112, 1752, 1721, 1610, 1452, 1331, 1247, 1207, 1182, 1169, 1126, 1096, 1077, 805, 792, and 700 cm~l The crude azlde (16.56 g, 63.9 mmol) was dissolved in MeOH (0.1 L) and hydrogenated at 50 psi of }12 over 10~ Pd-C (1.5 g) in a Parr apparatus until hydrogen uptake cPased. The catalyst was removed by filtration through a pad of celite, the filter cake was rinsed with MeOH (0.2L) and the combined filtrates were concentrated in vacuo to give the crude amino acid ester a~ a an oily semi-solid. This material was partitioned between water (0.5 L) and EtOAc (0.5 L). The organic phase was discarded, the aqueous phase WA8 made basic (20%
aquaous NaOH) and extracted with EtOAc (2 X 0.25 L). The combined organic phases were dried (Na2SO4), and concentrated in vacuo to give the crude ester as a pale green oil. The crude product was purlfied by chromatography on a column of silica gel (230-400 mesh, 500g , 70 mm o.d., packed-ethyl acetate-hexanes 30:70, eluted ethyl acetate-hexanes 50:50, 400 mL fractions) using the flash technique.
Fractions 6-10 provided 9.24 g (53~) of the desired 3-trifluoro-methylphenylglycin~ methyl ester as a clear, colorless liquid.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 25:75.
W ~+); ammonium molybdate) Rf - 0.10.
lH-NMR: ~ - 7.69( brs, 1), 7.59 (brt, J - 8Hz, 2), 7.47 (d, J
8Hz, 1), 4.70 (s, 1), 3.72 (s, 3), 1.98( s, 2).
Infrared (neat): 338S, 3320, 2958, 1741, 1451, 1438, 1331, 1271, 1223, 1167, 1125, 1097, 1074, 987, 906, 812, 786, and 701 cm~l.
EI/MS (70eV): 233 (M+, 3.0), 174 (base), 127 (9.3).
Analysis: Calcd. for CloH21F3N02: C, 51.51; H, 4.32; N, 6.01.
Found: C, 51.74; H, 4.35, N, 6.08.
Example 1 ~-[-(Trifluorome~hyl)benzylamino]-l]benzylindole-3-acetic acid To a stirred solution of 5.52 g (0.06 mole) of glyoxylic acid monohydrate in 150 mL of MeOH was added 10.36 g (0.05 mole) of 1-.

:
.

2~2a~

benzylindole. To the result~ng solution was added a solution of 8.76 g (0.05 mole) of 3-(trifluoromethyl)benzylamine in 50 mL of MeOH and l mL of acetic acid. The mixture was stirred for 20 hours. The solid which had separated was collected by filtration and washed with MeOH glving 16.97 g (77~) o~ the title compound as an ivory solid, m.p. 171-172.5(dec.).
Physical characteristics are as follows:
Analysis: Calcd. for C25H21F3N2O2 C, 68-48; H~ 4-83; N~ 6-39-Found: C, 68.61; H, 4.75; N, 6.40.
Mass Spectrum: Ions at (m/e): 393,392, 208, 174, 159, 91, 69, 65, 57, 55.
Infrared: vmax (mull) 3106, 3061, 3030, 2519, 2396, 2345, 2252, 1637, 1608, 1541, 1497, 1389, 1360, 1333, 1288, 1246, 1210, 1184, 1116, 1079, 908, 802, 743, 729, 702 cm~l.
Utilizing a procedure similar to that of Example 1 but substituting the approprlately substituted indole and amine for 1-benzylindole and 3-(trifluromethyl)benzylamine, there are obtained the followin~ compounds:
~-[3-(Trlfluoromethyl)benzylamino]-l-methylindole-3-acetic acid as a white solid, m.p. 163 (dec.).
Physical characteristics are as follows:
Analysis: Calcd. for ClgHl7F3N2O2: 62.98; H, 4.73; N. 7.73.
Found: C, 62.73; H, 4.53; N, 7.70.
Mass Spectrum: Ions at (mJe): 317, 159, 158, 157, 145, 144, 25 132, 127, 109, 77.
NMR (DMSO-d6): 6 3.74 (s, 3H), 3.94 (s, 2H), 4.58 (s, l~), 6.9-7.88 (br m, 9H).
Infrared: vmax (mull) 3117, 3070, 3057, 3025, 2368, 2300, 2225, 2165, 1598, 1549, 1395, 1371, 1356, 1331, 1256, 1205, 117~, 1133, 30 1121, 1075, 910, 814, 806, 772, 742, 734, 706 cm~l.
~ -Benzylamino-l-benzylindole-3-acetic Acid as a whi~e solid, m.p. 180 (dec.).
Physical characteristics are as follows:
Analysis: Calcd. for C24H22N2O2: C, 77.81; ~, 5.99; N, 7.55.
35 Found: C, 77.87; H, 6.04; N, 7.54.
Mass Spectrum: Ions at (m/e): 326, 325, 324, 235, 220, 107, 106, 92, 91, 65.
Infrared: ~max (mull) 3103, 3088, 3079, 3066, 3045, 3035, 2526, .... ~ ... . .. .

. , .

z~

2447, 2384, 2258, 2197, 1636, 1609, 1542, 1496, 1353, 1294, 1248, 741, 734, 695 cm~l.
~-(4-Chlorobenzylamino)-l-benzylindole-3-acetic acid as a pale pink solid, m.p. 171 (dec.).
Physical characteristics are as follows:
Analysis: Calcd. for C24H21ClN202: C, 71.19; H. 5.23; Cl, 8.76; N, 6.92. Found: C, 71.16; H, 5.28; Cl, 8.80; N, 6.99.
Mass Spectrum: Ions at (m/e): 360, 359, 235, 220, 140, 127, 125, 106, 91, 77.
Infrared: vmax (mull) 3110, 3100, 3064, 3032, 2670, 2567, 2370, 1634, 1597, 1539, 1493, 1375, 1368, 1353, 1301, 804, 743 cm~l.
~-[(3-Pyridinylmethyl)amino]-l-benzylindole-3-acetic acid as a pale orange solid, m.p. 183 (dec).
Physical characteristics are as follows:
AnalysiS: Calcd. for C23~21N32 C~ 74-37; H~ 5-70; ~ 31-Mass Spectrum: Ions at (m/e3: 327, 326, 325, 235, 2~1, 220, 92, 91, 90, 65.
Infrar~d: ~max (mull) 3108, 3088, 3063, 3051, 3029, Z668, 2642, 2380, 2327, 2282, 1614, 1607, 1578, 1544, 1495, 1479, 1466, 1456, 1360, 1346, 802, 762, 750, 735, 697, cm~l.
~-[(3-Phenylpropyl)amino]-l-benzylindole-3-aceeic acid as a w~ite solid, m.p. 178 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C26H26N202: C, 78,36; H, 6.58; N, 7.03.
Found: C, 78.66; H, 6.61; N, 7.19.
Mass Spectrum: Ions at (m/e): 354, 353, 248, 235, 221, 220, 118, 92, 91, 65.
Infrared: ~max (mull) 3109, 3085, 3056, 3029, 2788, 2763, 2664, 258~3, 2543, 2429, 1627, 1605, 1544, 1495, 1483, 1393, 1367, 742, 716, 701 cm~l.
~-(4-Methoxybenzylamino~-l-benzylindole-3-acetic acid as a white solid, m.p. 170(dec.) Physical character~stics are as follows:
Analysis: Calcd. for C2sH24N203: C, 74.98; H, 6.04; N, 7-00-Found: C, 75.17; H, 6.22; N, 6.95.
Mass Spectrum: Ions at (m/e): 355, 235, 221, 220, 137, 136, 121, 106, 91, 77.
Infrared: ~max (mull) 3102, 3089, 3061, 2590, 2398, 1639, 1612, "

.. . . .

2~Z~

1592, 1585, 1538, 1518, 1496, 1480, 1377, 1311, 1252, 1187, 1174, 1031, 1015, 823, 815, 743 cm~l.
~-Morpholino-l-benzylindol¢-3-acetic acid as a white solid, m.p.
202~ (dsc).
Physical characteristics are as follows:
Analysi5: Calcd- for C21H22N2O3: C, 71.98; H, 6.33; N, 8.00.
Found: C, 72.05; H, 6.43; N, 8.13.
Mass Spectrum: Ions at (m/e): 306, 305, 265, 264, 248, 220, 91, 69, 57, 55.
Infrared: ~max (mull) 3121, 3101, 3090, 3069, 3033, 3024, 2118, 1614, 1587, 1546, 1497, 1485, 1344, 1251, 1172, 1124, 1087, 753, cm~

~-[(4-Phenylbutyl)amino]-l-benzylindole-3-acetic acid as an ivory solid, m.p. 171 (dec).
Physical characteristlcs are as follows:
Analysis: Calcd. ~or C27H2gN202: C, 78.61; H, 6.84; N, 6.79.
Found: C, 78.02; H, 7.08; N, 6.66.
Mass Spectrum: Ions at (m/e): 368, 335, 221, 220, 149, 129, 104, 92, 91, 77, 65, 57.
Infrared: ~max (mull) 3106, 3084, 3060, 3025, 2810, 2772, 2700, 2591, 2446, 1605, 1542, 1496, 1354, 1383, 1379, 1365, 783, 759, 740, 721, 699 cm~l.
~-Methyl~mino-l-benzylindole-3-acetic Acid as a pale pink solid, m.p. 159 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for Clg~lgN2O2: C, 73,45; H, 6.16; N, 9.52.
Found: C, 73.45; H, 6.25; N, 9.25.
M&ss Spectrum: Ions at (m/e): 250, 249, 235, 220 ! 158, 130, 129, 92, 91, 65.
Infrared: vmax (mull) 3111, 3072, 3034, 3020, 1615, 1606, 1574, 1550, 1497, 1384, 1355, 742, 727, 717 cm~l.

-[3-(Trifluoromethyl)benzylamino]-1-(4-chlorobenzyl)lnd~le-3-aceti~ acid as an i~ory solid, m.p. 186 (dec).
PhyQical characteristlcs are as follows:
Analysis: C~cld. for C25H20ClF3N2O2: C, 63.49; H, 4.26; Cl, 7.50; N, 5.93. Found: C, 63.62; H, 4.55; Cl, 7.39; N, 5.91.
Mass Spectrum: Ions at (m~e): 429, 423, 427, 426, 269, 254, 174, 159, 127, 125.

:- . ~ , :
.: - :~; . .:.
, , : , -; ~ :~ ~...... :

:

Infrared. vmax (mull) 3061, 3036, 2511, 2495, 2395, 2242, 1637, 1608, 1542, 1492, 1389, 1358, 1335, 1290, 1247, 1211, 1166, 1118, 1078, 1015, 908, 813, 802, 777, 744, 729, 701 cm~l.
~ -[3-(Trifluoromethyl)benzylamino]-l-phenylindole-3-acetic acid as a white solid, m.p. 172 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C24HlgF3N202: C, 67.92; H, 4.51; N, 6.60.
Found: C, 67.92; H, 4.70; N, 6.49.
Mass Spectrum: Ions at (m/e): 380, 379, 221, 220, 219, 206, 194, 193, 159, 77.
Infrared: ~max (mull) 3120, 3062, 3047, 2644, 2529, 2341, 2195, 2122, 2091, 1641 sh. 1613, 1597, 1575, 1557, 1502, 1362, 1330, 1203, 1174, 1128, 1077, 877, 808, 773, 769, 755, 748, 743, 697 cm~l.
~ -[(2-Phenylethyl)amino]-l-benzylindole-3-acetic acid hydrate (1:1) as a whLte solid, m.p. lS3 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C25H24N2O2 H2O: C, 74.60; H, 6.51; N, 6.96. Found: C, 74.50; H, 6.14; N, 6.75.
Mass Spectrum: Ions at (m/e): 340, 335, 247,221, 220, 92, 91, 65.
NMR (DMSO-d6): ~ 2.9 (s, 4H), 4.72 (s, lH), 5.38 ~s, 2H), 6.9-7.92 (m, 15H).
Infrared: vmax (mull) 3596, 3511, 3246, 3340, 3106, 3057, 3031, 3026, 2730, 2608, 2519, 2425, 1621, 1582, 1604, 1540, 1419, 1483, 1378, 1351, 1340, 1176, 1169, 751, 747, 739, 727, 702 cm~l.
~-[3-~Trifluoromethyl)benzylamino]-l-benzyl-2-phenylindole-3-acetic Acid as a white solid, m.p. 186 (dec).
Physic~l characteri~tics are a~ follows:
Analysis: Calcd. for C31H25F3N22 C, 72-36; H~ 4.90; N~ 5.45.
Found: C, 72.67; H, 5.06; N, 5.30.
Mass Spectrum: lons at (m/e): 469, 312, 311, 309, 219, 218, 204, 159, 92, 91.
NMR (DMS0-d6): ~ 3.9 (s, 2H), 4.3 (s, lH), 5.3 (s, 2H), 5.8 (s, lH~, 6.8-7.7 (m, 17H), 7.9-8.1 (m, lH).
Infrared: Ymax (mull) 3064, 3049, 3035, 3027, 2669, 2529, 2337, 1642, 1563, 1495, 1335, 1165, 1127, 1075, 806, 762, 759, 740, 714, 704, 696 cm~l.
~-[(2-(4-Aminosulfonylphenyl)ethyl)amino]-l-benzylindole-3-20C~2~5 acetic acid hydrate (2:1) as a buff solid, m.p. 201 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C25H25N304S05 H20: C, 63.54; H, 5.55; N, 8.89; S, 6.79. Found: C, 63.67; H, 5.48; N, 9.03; S, 7.10.
Mass Spectru~: Ions at (m/e): 427, 426, 425, 335, 247, 220, 92, 91, 90, 57.
Infrared: vmax (mull) 3369, 3211, 3129, 3082, 3054, 3035, 3024, 2689, 2636, 2609, 2340, 2200, 1614, 1574, 1554, 1497, 1482, 1386, 1377, 1352, 1333, 1315, 1169, 1161, 855, 821, 750, 741, 730, 694 cm~
~-~3-(Trifluoromethyl~benzylamino]-l-benzyl-S-methoxyindole-3-acetic acid as a white solid, m.p. 168 (dec).
Physlcal characteristics are as follows:
Analysis: Calcd. for C26H23F3N203: C, ~6.66; H, 4.95; N, 5.98.
Found: C, 66.61; H, 5.00; N. 6.13.
Mass Spectrum: Ions at (m/e): 424, 422, 251, 150, 160, 159, g2, 91, 65.
Infrared: vmax (mull) 3112, 3059, 3028, 2504, 2397, 2322, 1605, 1540, 1487, 1389, 1376, 1358, 1332, 1252, 1230, 1204, 1171, 1123, 1076, 826, 813, 799, 734, 705 cm~l.
~-(N-Methyl-benzylamino)-l-benzylindole-3-acetic acid hydrate (4:1) as a white solid, m.p. 117 (dec).
Physical characteristics are as follow4:
Analysis: Calcd. for C2sH24N202-0Ø25H20: C, 77.19; H, 6.35; N, 7.20. Found: C, 77.30; H, 6.27; N, 7.10.
Mass Spectrum: Ions at (~/e): 340, 339, 249, 220, 134, 121, 92, 91, 65.
NMR (DMSO-d6): 6 2.2 (s, 3H), 3.7 (d, J - 3Hz, 2H), 4.65 (s, lH), 5.45 (s, 2H), 7.05-7.7 (m, 14H), 7.78-7.98 (m, lH).
Infrared: ~max (mull) 3644, 3370, 3111, 3056, 3028, 2680, 1622, 1543, 1496, 1366, 1341, 1331, 1179, 907, 747, 723, 699 c~-l.
~-[3-(Trifluoromethyl)benzylamino]-l-ben7yl-5-chloroindole-3-acetic acid as a whlte solid, m.p. 192 (dec).
Physical character~stics are as follows:
Analysis Calcd. for C2sH20ClF3N202: C, 63.49; H, 4.26; Cl, 7.50; N, 5.93. Found: C, 63.36; H, 4.45; Cl, 7.24; N, 5.86.
Mass Spectrum: Ions at (m/e): 473 ~M +), 427, 301, 300, 299, 298, 269, 159, 193, 91.

, : -Z~lS

Infrared: vmax (mull) 3112, 2102, 3066, 3028, 2513, 2407, 2368, 2248, 1637, 1607, 1540, 1497, 1336, 1290, 1246, 1212, 1168, 1122, 1114, 1079, 909, 859, 800, 734, 728, 702 cm~l.
~ -[3-(Trifluoromethyl)benzylamino]-l-allylindole-3-acetic acid as a very pale oran~e solid, m.p. 163 (dec).
Physical characteristics are as follows:
Analysis: Calcd. ~or C21HlgF3N202: C, 64.94; H, 4.93; N, 7.21.
Found: C, 65.22; H, 4.85; N, 6.94.
Mass Spectrum: Iorls at (m/e): 388 (M +), 344, 343, 185, 183, lO 174, 170, 159, 158, 156, 106.
Infrared: vmax (mull) 3118, 3081, 3058, 2484, 2387, 2337, 2236, 1641, 1599, 1541, 1388, 1359, 1335, 1289, 1240, 1210, 1176, 1118, 1080, 908, 803, 738, 701 cm~l.
~ -~2-(Trifluoromethyl)benzylamino]-l-benzylindole-3-acetic acid as a whlte solid, m.p. 180 (dec).
Physical charactaristics are as follows:
Analysis: Calcd. ~or C25HzlF3N202: C, 68.48; H, 4.83; N, 6.39.
Found: C, S8.08; H, 4.81; N. 6.43.
Mass Spectrum: Ions at (m/e): 393, 392, 235, 175, 174, 159, 134, 20 106, 9]., 57.
Infrared: vmax (mull) 3129, 3085, 3071, 3064, 3054, 3032, 2773, 2623, 2424, 1612, 1598, 1573, 1496, 1317, 1175, 1163, 1124, 1033, 771, 742, 736, 696 cm~l.
~-[4-(Trifluoromethyl)benzylamino~-l-benzylindole-3-acetic acid as a pale orange solid, m.p. 170 (dec).
Physical characteristics are as iollows:
Analysis: Calcd. for C24H21F3N22 C, 68-48; H~ 4-~3; N~ 6-39-Found: C, 68.09; ~, 4.79; N, 6.19.
Mass Spectrum: Ions at (m/e): 394, 393, 392, 235, 221, 220, 208, 30174, 159, 91.
Infrared: ~max (mull) 3089, 3065, 3029, 2539, 2496, 2401, 2247, 1636, 1607, 1542, 1497, 1356, 1327, 1248, 1170, 1125, 1070, 893, 825,779, 745, 734, 727, 695 cm~l.
~ -(3-Chlorobenzylamino)-l-benzylindole-3-acetic acid as a pale orange solid, m.p. 162 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C24H21ClN202: C, 71.19; H, 5.23; Cl, 8.76; N, 6.92. Found: C, 71.39; H, 5.13; C~, 8.61; N, 6.67.

.. _ .. . .. . .. . . . .. . . . .. . . .
.~

,' ' ~` ' , ;~0024~

Mass Spectrum: Ions at (m/e): 407, 405, 359, 266, 265, 264, 236, 235, 125, 91.
Infrared: vmax (mull) 3120, 3065, 3055, 3030, 2608, 2526, 2476, 2405, 2316, 2266, 2153, 1596, 1545, 1496, 1388, 1362, 1249, 900, 846, 797, 738, 705 cm~l.
~-(2-Chlorobenzylamino)-l-benzylindole-3-acetic acid as a white solid, m.p. 164 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C24H21ClN202: C, 71.19; H, 5.23; Cl, 10 8.76; N, 6.92. Found: C, 71.00; H, 5.26; Cl, 8.73; N, 6.88.
Mass Speetrum: Ions at (m/e): 405, 359, 266, 265, 264, 236, 235, 125, 91, 45.
Infrared ~max (mull) 3061, 3049, 3030, 2730, 2601, 2411, 1629, 1592, 1542, 1497, 1378, 1367, 1313, 1178, 770, 759, 744, 700 cm~l.
~-[3,5-Bis(trifluoromethyl)benzylamino]-l-benzylindole-3-acetic acid as a white solid, m.p. 17Q (dee).
Physical eharacteristies are as follows:
Analysis: Calcd. for C26H20F6N202 C, 61-66; H~ 3-98; H~ 5.53.
Found: C, 61.79; H, 3.97; N, 5.60.
Mass Spectrum: Ions at (m/e): 505, 462, 461, 398, 265, 264, 244, 236, 235, 227, 91.
Infrared: vmax (mull) 3115, 3092, 3066, 3035, 2317, 2146, 1607, 1541, 1497, 1359, 1285, 1180, 1137, 908, 738, 683 cm~l.
~-(4-Nethylben~ylamino)-l-benzylindole-3-actie acid as a white solid, m.p. 170 (dec).
Physical characteristlcs are as follows:
Analysis: Calcd. for C2sH24N202: C, 7B.lO; H, 6.29; N- 7-29-Found: C, 77.91; H, 6.30; N, 7.30.
Mass Speetrum: Ions at (m~e): 386, 385, 340, 339, 265, 264, 30 236, 235, lOS. 91.
Infrar~d: ~max (mull) 3115, 3061, 3024, 2608, 2529, 2467, 2391, 2313, 2161, 1604, 1598, 1545, 1519, 1495, 1364, 1253, 891, 815, 808, 744, 735, 699 cm~l.
~-!(2-Furylmethyl)amino]-l-benzylindole-3-acetic aeid as a white solid, m.p. 172 (dec).
Physieal eharacteristics are as follows:
Analysis: Calcd. for C22H20N2o3: C, 73.31; H, Found: C, 73.38; H, 5.85; N. 7.80.

.

2~1~24~

Mass Spectrum: Ions at (m/e): 361, 315, 266, 265, 264, 236, 235, 91, 81, 45.
Infrared: vmax (mull) 3124, 3101, 3063, 3046, 3030, 2507, 2386, 2248, 1629, 1606, 1544, 1497, 1376, 1354, 1337, 1267, 1174, 1149, 1015, 930, 737, 695 cm~l.
~-[(2-Thienylmethyl)amino]-l-benzylindole-3-acetic acid as a white solid, m.p. 181 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C22H20N2O2S: C, 70.18; H, 5.36; N. 7.44;
S, 8.52. Found: C, 70.06; H, 5.44; N, 7.52; S, 8.51.
Mass Spectrum: Ions at (m/e): 378, 377, 331, 265, 264, 235, 217, 97, 91. 45.
Infrared: vmax (mull) 3103, 3064, 3044, 3030, 2535, 2403, 1631, 1606, 1544, 1496, 1363t 1354, 1337, 1330, 747, 736, 703, 695 cm~l.
~-(3-Methylbenzylamino)^l-benzylindole-3-acetic acid as a white solid, m.p. 166 (dec).
Physical characte~istics are as follows:
Analysis: Calcd. for C2sH24N2O2: C, 78.10; H, 6.29; N, 7.29.
Found: C, 78.36; ~, 6.52; N, 7.24.
Mass Spectrum: Ions at (m/e): 386, 385, 339, 266, 265, 264, 236, 235, 105, 91.
Infrared: ~max (mull) 3118, 3054, 3026, 2605, 2522, 2476, 2422, 2361, 2317, 2267, 2151, 1604, 1598, 1545, 1496, 1387, 1361, 1253, 797, 738, 726, 707, 701 cm~l.
~-(3,4-Dichlorobenzylamlno)-l-benzylindole-3-acetic acid as an ivory solid, m.p. 180 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C2~H20C12N2O2: C, 65.61; H, 4.59, Cl, 16.14; N, 6.38. Found: C, 65.86; H, 4.46; Cl, 15.90; N, 6.46.
Mass Spectrum: Ions at (m/e): 439, 395, 393, 266, 265, 264, 236, 235, 231, 91.
Infrared: vmax (mull) 3091, 3061, 3030, 2502, 2388, 2251, 1636, 1606, 1540, 1497, 1378, 1356, 1310, 1279, 1244, 1213, 902, 821, 778, 744, 728, 692 cm~l.
~-(Tetrahydrofurfurylamino)-l-benzylindole-3-acetic acid as a pale pink solid, m.p. 170 ~dec).
Physical characteristics are as follows:
Analysis: Calcd- for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69.

. :
, 2~

Found: C, 72.68; H, 6.35; N, 7.39.
Mass Spectrum: Ions at (m/e): 319, 247, 235, 220, 91, 71, 69, 65, 57, 55.
Infrared: vmax (mull) 3117, 3087, 3061, 3050, 3033, 3024, 2696, 2630, 2552, 2264, 1625, 1579, 1538, 1496, 1356, 1339, 1266, 1173, 1089, 1038, 763, 748, 696 cm~l.
~-~3-Fluorobenzylamino)-l-benzylindole-3-acetic acid as a white solid, m.p. 164 (dec), Physical characteristics are as follows:
Analysis: Calcd. for C24H21FN202: C, 74.21; H, 5.45; N, 7.21.
Found: C, 74.17; H, 5.40: N, 7.15.
Mass Spectrum: Ions at (m/e): 344, 343, 342, 235, 221, 220, 208, 124, 109, 91.
Infrared: vmax (mull) 3120, 3058, 3031, 2607, 2522, 2478, 2387, 2324, 1605, 1595, 1544, 1495, 13~7, 13~3, 1251, 801, 737, 701, 697 cm~l ~-(4-Fluorobenzylamino)-l-benzylindole-3-acetic acid as a white solid, m.p. 185 (dec).
Physical characteristics are a~ follows:
Analysis: Calcd. for C24H21FN202: C, 74.21; H, 5.45; N. 7.21.
Found: C, 73.96; H, 5.27; N. 7.19.
Mass Spectrum: Ion~ at (m/e): 343, 342, 235, 220, 124, 109, 92, 91, 65.
Infrared: vmax (mull) 3091, 3071, 3058, 3050, 3031, 2534, 2491, 2394, 2335, 2268, 2170, 1634, 1608, 1603, 1542, 1515, 1497, 1355, 1337, 1308, 1288, 1247, 1224, 1209, 890, 826, 778, 747, 735, 724, 697 cm-l ~-(3-Methoxybenzylamino)-l-benzylindole-3-acetic acid as a white solid, m.p. 174 (dec).
Physlcal characteristics are as follows:
Analysis: Calcd. ~or C25H24N203: C, 74.98; H, 6.04; N, 7.00.
Found: C, 74.92: H, 6.11; N, 6.91.
Mass Spectrum: Ions at (m/e): 355, 354, 235, 221, 220, 136, 1~2, 121, 91, 65.
Infrared: v~ax (mull) 3106, 3087, 3059, 2609, 2526, 2472, 2416, 2362, 1607, 1598, 1588, 1542, 1490, 1386, 1362, 1~99 7 1260, 1178, 1155, 1036, 898, 780, 749, 738, 701, cm~l.
~-[3-(Trifluoromethyl)benzylamino)-l-benzyl-5-methylindole-3-... . . .. .

~ ' , . , . .

2~ LS

acetic ~cid as a pink solid, m.p. 180 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C26H23F3N202 C, 69-01; H~ 5-12; N~ 6-19-Found: C, 68.94; H, 5.09; N, 6.20.
Mass Spectrum: Ions at (m/c): 453, 451, 407, 278, 249, 234, 159, 91.
Infrared: vmax (mull) 3122, 3088, 3063, 3028, 2607, 2532, 2500, 2426, 2394, 2324, 2222, 2152, 1593, 1542, 1497, 1487, 1389, 1332, 1253, 1203, 1175, 1123, 1076, 813, 791, 736, 707 cm~l.
~-[3-(Trifluoromethyl)benzylamino)-l-benzyl-5-fluorolndole-3-acetic acid as an ivory solid, m.p. 183 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C25H20F4N2O2: C, 65.78; H, 442; N, 6.14.
Found: C, 65.98; H, 4.54; N, 5.98.
Mass Spectrum: Ions ~t (m/e): 457, 411, 309, 284, 2B3, 282, 253, 231, 159, 91.
Infrared: vmax (mull) 3109, 3033, 2543, 2395, 2256, 1637, 1609, 1579, 1541, 1497, 1486, 1335, 1287, 1247, 1209, 1178, 1166, 1121, 901, 852, 801, 728, 701 cm~l.
~-(Benzylamino)-indole-3-acetic acid as a whlte solid, m.p. 195 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C17H16N202: C, 72.83; H, 5.75; N, 10.00.
Found: C, 73.12; H, 5.97; N, 10.12.
Mass Spectrum: Ions at (m/e): 235, 173, 145, 117, 107, 106, 91, 79, 77, 51.
Infrared: vmax (mull) 3183, 3109, 3034, 2648, 2569, 2495, 2446, 1630, 1619, 1556, 1540, 1498, 1377, 1343, 1230, 755, 738, 697 cm~l.
~-(Diphenylmethylamino)-l-benzylindole-3-acstic acid hydrate (1:0:7) as a white solid, m.p. 123 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C30H26N202Ø7H2O: C, 78.47; H, 6.02; N, 6.10. Found: C, 78,92; H, 6.52; N, 6.33.
Mass Spectrum: Ions at (m/e): 400, 183, 167, 165, 120, 106, 105, 104, 91, 77.
Infrared: vmax (mull) 3636, 3250, 3107, 3087, 3064, 2718, 2664, 2645, 2523, 2442, 2341, 1700 w, sh, 1640, 1613, 1605, 1587, 1547, 1493, 1359, 1348, 747, 741, 735, 715, 696 cm~l.

....
-:: :
., .
:

. ~: : ~:
' :: :

~2~S

~-[(2-Furylmethyl)amino]indole-3-acetic acid as a yellow solid, m.p. 149D (dec).
Physical characteristics are as follows:
Analysis: Calcd. for Cl5Hl4N2O3: C, 66.65; H, 5.22; N, 10.37.
Found: C, 66.26; H, 5.30; N, 10.39.
Mass Spectrum: Ions at (m/e): 225, 130, 97, 96, 81, 71, 69, 57, 55, 53.
Infrared: vmax (mull) 3179, 3108, 3074, 3055, 3033, -2607, 2320, - 2191, 1641, 157~, 1539, 1500, 1492, 1349, 1292, 1034, 771, 751 cm~
~-[4-(Methoxycarbonyl)benzylamino]-l-benzylindole-3-acetic acid as an ivory solid, m.p. 183 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C26H24N2O4: C, 72.88; H, 5.65; N, 6.54.
Found: C, 72.58; H, 5.57; N, 6.76.
Nass Spectrum: Ions at (m/e): 429, 383, 266, 265, 264, 236, 235, 149, 91, 18.
Infrar~d: vmax (mull) 3343, 3108, 3090, 3069, 2952, 2~1~, 2869, 2855, 1729, 1718, 1630, 1614, 1598, 1469, 1459, 1437, 1429, 1417, 1375, 1370, 1360, 1315, 1296, 1282, 1170, 1111, 1017, 758, 744 cm~l.
~-[3-(trifluoromethyl)benzylamino]-1-benzyl-5-methoxy-6-methyl-indole-3-acetic acid, ~.p. 176C.
Physical characteristics are as follows:
Analysis: Calcd. for C27H25F3N203: C, 67.21; H, 5.22; N, 5,81.
Found: C, 67.00; H, 5.39; N, 5.70.
~-[3-~Trifluoromethyl)benzylamino]-l-benzyl-5,6-methylenedioxy-~ndole-3-acetic acid, 178-180C.
~hysiral characterlstics are as follows:
Analysis: Calcd. for C26H21F3N2O4: C, 64.73; H, 4.39; N, 5.81.
Found: C, 64.51; H, 4.61; N, 6.03.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-S-methoxy-6-iso-propylindole-3-acetic acid, m.p. 166C.
Physical characteristics are as follows:
Analysis: Calcd. for C2gH2gF3N2O3: C, 68.22; H, 5.73; N, 5.49.
Found: C, 68.07; H, 5.46; N, 5.61.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-5-methoxy-4-methyl-indole-3-acetic acid, m.p. 154-155~C.
Physical characteristics are as follows:

.: . . . . . .

: .
.
.

Analysis: Calc~- for C27H25F3N203: C, 67.21; H, 5.22; N, 5.81.
Found: C, 66.90; H, 5.09; N, 5.95.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-5-methoxy-6-chloro-indole-3-acetic acid, m.p. 160.5-161C.
Physical characteristics are as follows:
Analysis: Calcd. for C26M22ClF3~203: 503.1349 (M++H). Found:
503.1335.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-6-methylindole-3-acetic acid, m.p. 182.5-184.5C (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C26H23F3N202: C, 69.02; H, 5.12; N, 6.19.
Found: C, 68.72; H, 5.25; N, 6.07.
~-~3-(Trifluoromethyl)benzylamino]-l-benzyl-5,6-dimethoxyindole-3-acetic acid, m.p. 157-158C.
Physical characteristics are as follows:
Analysis: Calcd. for C27~35F3N24 498.1766. Found:
498.1743.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-5-methoxy-7-methyl-indole-3-acetLc acid, m.p. 170-171C.
Physical characteristics are as follows:
Analysis: Calcd. for C27H25F3N203: C, 67.21; H, 5.22; N, 5.81.
Found: C, 67.88; H, 5.51; N, 5.93.
~-[3-(Trifluoromethyl)benzylamino]-1-~(2-diethyla~ino)ethyl]-indole-3-acetic acid, m.p. 135.5-137C.
Physical characteristics are as follows:
Analysis: Calcd. for C24H28F3N32 C, 64-41; H, 6-31; N, 9.39.
Found: C, 64.15; H, 6.33; N, 9.33.
~-[3-(Trifluoromethyl)benzyl~mino]-1,2-diphenylindole-3-acetic acid, ~.p. 209C (dec).
Physical characteristics are as follows:
AnalysiS: Calcd. fQr C30H23F3~22 C~ 71-99; H~ ;
Found: C, 71.99; H, 4.97; N, 5.72.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-6-methoxyindole-3-acetic acid, m.p. lgO-191C.
Physical characteristics are as follows:
Analysis: Calcd. for C26~23F3N23 C, 66-67; H~ 4-91; N~ 5.9~.
Found: C, 66.69; H, 5.08; N, 5.90.
~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-5-acetoxyindole-3-' ':

,, z~

acetic acid, m.p. 187-188C (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C27H23F3N24 C, 65-32; H, 4-64; N, 5.65.
Found: C, 65.08; H, 4.57; N, 5.66.
~-[3-(Trifluoromethyl~benzylamino]-l-benzyl-5-hydroxyindole-3-acetic acid, m.p. 190~C (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C25H21F3N2O: C, 66.08; H, 4.63; N, 6.17.
Found: C, 66.57; H, 5.03; N, 6.48.
~-[3-(Trifluoromethyl~benzylamino]-l-benzyl-5-ethoxyindole-3-acetic acid, m.p. 171-172C.
Physical characteristics are as follows:
Analysis: Calcd. for C27H25F3N203: C, 67.22; H, 5.19; N, 5.81.
Found: C, 66.76; H, 5.44; N, 6.27.
~-[3-(Trifluoromethyl~benzylamino]-l-benzyl-5-benzyloxyindole-3-acetic scid, m.p. 173-174C.
Physical characteristlcs ar~ as follows:
Analysis: Calcd. for C32H27F~N2O3: C, 70.59; H, 4.96; N, 5-15-Found: C, 70.44; H, 5.27; N, 5.74.
Exam~le ~ ~-[3-(Trifluoromethyl~-ben2ylamino]-l-ben~ylindole-3-acetic Acid Hydrochlo~ide.
A 2.0 g portion of ~-[3-(trifluoromethyl)benzylamlno]-1-benzylindole 3-acetic acid was added to 150 ml of THF containing an excess anhydrous hydrogen chloride. Withn a fPw minutes a pink solution was obtained. The solvent was evaporated leaving a pink glassy solid. The solid was crystallized from acetone-hexane giving a pale pink solid which after dryin~ at S6~ in a vac~um oven for 22 hours be~ame pale yellow. The solid was crystallized from EtOH-hexane glving 1.37 g (63~) of the title compound as a yellow solid, 30 m.p. 163 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C25H21F3N2O2 HCl: C, 63.22; H, 4.67; Cl, 7.47; N. 5.90. Found: C, 63.00; H, 4.93; Cl, 7.40; N, 5.80.
Ma~s Sp~ctrum: Ions at (~/e): 439, 394, 393, 265, 264, 236, 159, 103, 91.
NMR (DMSO-~6): ~ 4.24 ~d, J ~ 7Hz, 2H), 5.48 and 5.51 (s's, 3H), 7.13-8.07 (m, 15H).
Infrared: vmax (mull) 3156, 3107, 3075, 3052, 3038, 3032, 2783, 20~

2668, 2607, 2555, 2501, 2461, 2401, 1739, 1621, 1602, 1580, 1536, 1500, 1486, 1330, 1270, 1252, 1226, 1204, 1191, 1179, 1170, 1162, 1155, 1114, 1077, 883, 801, 741, 731, 702, 596 cm~l.
Exa~ple 3 Sodium ~-[3-(Trifluoromethyl)benzylamino]-l-ben7ylindole-3-acetate A mixture of 3 g (6.84 mmoles) of ~-[3-(trifluoromethyl)-benzylamino]-l-benzylindole 3-acetic acid, 3.4 ml (6.80 mmoles) of 2N
NaOH, and 100 ml of MeOH was warmed until a solution was obtained (one to two hours). The solvent was evaporated. The residue was dried in a vacuum oven at 66 for 70 hours giving 2.70 (86%) of the title compound as an orange solid, m.p. 210~-215.
Physical characteristics are as follows:
Analysis: Calcd. for C25H20F3NaN2O2: C, 65.21; H, 4.38; N, 6 09. Found: C, 65.57; H, 4.46; N, 6.12.
Ma.ss Spectrum (FAB): Ions at (m/e): 484, 483 (M + Na)+, 393, 287, 286, 264, 235, 159, 91, 23.
Infrared: vmax (~ull) 3109, 3088, 3060, 3030, 1613, 1550, 1497, 1482, 1583, 1393, 1330, 1167, 1122, 1075, 915, 802, 791, 739, 700 c~~

Example 4 ~-~3-(Trifluoromethyl)benzyl~mino]-l-benzylindole-3-acetic acid and methyl ~-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate hydrochloride To a stirred solution of 7.24 g (41.34 mmoles) of 3-(trifluoro-methyl)benzylamine and 4 mL (4.2 g, 69.8A ~moles) acetic acld in 50 mL of NeOH was added 7.14 g (34.45 mmoles) of l-benzylindole followed by a solution of 3.64 g (41.34 mmoles) of methyl glyoxylate in 50 mL
of MeOH. The resulting solid was collected by filtration, washed with MeOH, and dried giving 4.28 g of pale pink solid. The solid and 50 mL of MeOH were heat~d to boiling. The ma~ority of the solid did not dissolve. After cooling to room temperature, the solid was collected by filtration, and dried giving 4.07 ~ (27~) of ~-[3-tri-fluoromethyl)benzyl]-l-benzylindole-3-acstic acid eompound as a pale pink solid, m.p. 176-178~ (dec).
Physieal characteristies are as follows:
Analysis: Calcd. for C2sH21F3N202: C, 63.84; H, 4.83; N, 6.39.
Found: C, 68.55; H, ~.79; N. 6.28.
Nass Spectru~: Ions at (m/e): 438 (M +), 394, 393, 392, 235, 220, 175, 174, 159, 92, 91.

.
, :, Infrared: vmax (mull) 3109, 3061, 3029, 2516, 2395, 2248, 1637, 1606, 1541, 1496, 1337, 1166, 1114, 802, 743, 729, 701 cm~l.
The solvent was evaporated from the combined original filtrate and washing. The residue was treated with 200 ml of H2O and then NaHCO3 was added until the CO2 evolution ceased. The mixture was extracted with CH2C12 (3x100 ml) (some insoluble ~olid was present).
The combined extacts were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 10.97 g of brown oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 2~ MeOH-CH2C12 and 200 ml fractions were collected.
The fractions were assayed by silica gel tlc (lx4")(25% acetone-Skellysolve B). Fractions 23-30 were combined giving 5.8 g of brown oil. The oil was slurried with 50 ml of 25~ acetone-Skellysolve B
and then filtered to remove some insoluble solid. The filtrate was appliad to a 400 g column of ilica gel. The column was eluted wlth 25% acetone-Skellysolve B and 100 ml fractions were collected. The fractions were assayed as before. Fractions 14-15 were combined giving 2.06 ~ of methyl ester as a yellow-brown oil. The 2.n6 g (4.55 mmoles) was dissolved in 50 ml of acetone and added to a 20 solution of 0.53 g (4.57 mmoles) of fumaric acid in 10 ml of EtOH.
The resulting solution was concentrated and then hexane was added.
Cooling gave 2.22 g of white solid. The 0.89 g (1.97 mmoles) of methyl ester from fraction 16 was dissolved ln 25 ml of acetone and then added to a solution of 0.23 g (1.98 mmoles) of fumaric acid in 5 ml of EtOH. The resulting solution was concentrated and then hexane was added. Cooling overnight gave 0.79 g of white solid. The 0.79 g and the 2.22 g were combined in acetone. The solution was concentrated. The solid (ca 0.53 g, m.p. ca 290 dec? which separated and which was removed by filtration was probably fumaric acid. The filtrate was concentrated and hex~ne was added. The solid which ssparated was removed by filtration. The filtrate was concentrated and hexane was added. Only a small amount of solid separated.
The solid was remov~d by filtration. The solvent was evaporated 35 leaving 2.19 g of oll. A solution of the oil in 100 ml of ether was washed with NaHC03 solution and then with brine and dried over MgSO4.
Evaporation of the solvent left 1.90 g of yellow oil.
~MR (CDC13): ~ 2.22-2.4 (br s, lH), 3.72 (s, 3H), 3.88 (s, 2H), ,-- . ., ~.
, ~ :

2~

4.75 (s, lH), 5.28 (s, 2H), 7.1-7.9 (m, 13H). Also peaks for EtOH
were present.
The 1.90 g of oil was dissolved in ether. An excess of a solution of anhydrous hydrogen chloride in ether was added. Nothing separated. The solution was concentrated and hexane was added. An oil separated which after standing several days at room temperature began solidifying. The supernatant liquid was decanted. The remaitlin~ oil solidified within a few minutes. The solid was crystallized from CH2C12-hexane. After several hours a sticky solid had formed. The supernatant liquid was decanted. Upon rubbing, crushin~ and drying 1.10 g (7~) of ~-[3-(trifluoromethyl)benzyl-amino]-l-benzylindole-3-acetic acid hydrochloride was obtained as an ivory free-flowing powder, m.p. 138 (dec).
Physical characteristics are as follows:
Analysis: Calcd. for C26H23F3N202 HCl: C, 63.87; H, 4.95; Cl, 7.25; N, 5.73. Found: C, 64.01; H, 4.76; Cl, 7.05; N, 5.71.
Mass Spectrum: Ions at (m/e): 452, 395, 394, 393, 234, 233, 159, 92, 91, 65.
NMR (CDC13): ~ 3.7 (s, 3H), 4.0 (d, J 13Hz, lH), 4.7 (d, J -20 13Hz, lH), 5-12 (s, lH), 5.38 (s, 2H), 7.12-7.83 (m, 13H), 7.9-8.18 (m, 3H).
Infrared: vmax (mull) 3092, 3067, 3052, 3027, 2603, 2551, 2512, 2434, 2384, 1745, 1605, 1559, 1541, 1496, 1331, 1206, 1168, 1129, 1076, 806, 741, 702 cm~l The second supernatant liquid was concen~rated and then cooled in the refrigerator for several days giving 0.55 g (3~) of ~-[3-(tri1uoromethyl)benzyla~ino]-1-benzylindo~e-3-acetic acid hydrochloride as an ivory solid.
Utilizing a procedure similar to that of Example 4 but sub-stituting the appropriately substituted indole and amine for 1-benzylindole and 3-(trifluromethyl)benzylamine, there is obtained the following compounds:
Methyl ~-[3-(trifluoromethyl)benzylamino]-1,2-dimethylindole-3-acetate hydrochloxide as a purple solid, m.p. 141 (dec), Physical characteristics are as iollows:
Analysis: Galcd. for C21H21F3N202 HCl: C, 59,08, H, 5.20, Cl, 8.31; N, 6.56. Found C, 59.05; H, 5.46; Cl, 8.18; N, 6.50.
Mass Spectrum: Ions at (m/e): 390, 332, 331, 172, 171, 159, ., , : ' . ~
.

"

157, 156, 145, 144.
NMR (D~SO-d6): ~ 2.42 (s, 3H), 3.41 (br s, 3H), 3.69 ~s, 3H), 4.23 ~br s, 2H); 5.51 (br s, lH), 6.99-8.12 (m, 8H).
Infrared: vmax (mull) 3071, 3050, 2698, 2637, 2611, 2581, 2252, 1747, 1614, 1584, 1563, 1326, 1289, 1278, 1226, 1176, 1161, 1119, 1079, 853, 808, 749, 745, 703 cm~l.
Methyl ~-[3-(trifluoromethyl)benzylamino]-1-benzyl-2-methyl-indole-3-acetate hydrochloride as a pale grey solid, m.p, 138-141.
Physical characteristics are as follows:
Analysis: Calcd for C27H25F3N2O2 HCl: C, 64.47; H, 5.21; Cl, 7.06; N, 5.57. Found: C, 64.38; H, 5.34; Cl, 7.01; N, 5.42.
Mass Spectrum: Ions at (m/e): 466, 409, 408, 407, 316, 248, 247, 159, 157, 130, gl.
NMR (CDC13): 6 2.08 (s, 3H), 3.71 (s, 3H), 3.92 (d, J - 14 Hæ, 15 lH), 4.5 (d, J - 14 Hz, lH), 5.1 (s, lH), 5.25 (s, 2H), 7.0-7.7 (m, llH), 7.9-8.14 (m, 2H).
Infrared: vmax (mull) 3066, 3027, 2718, 2625, 2606, 2588, 2496, 2410, 1754, 1741, 1616, 1605, 1592, 1573, 1557, 1497, 1350, 1330, 1271, 1228, 1206, 1170, 1163, 1155, 1123, 1078, 880, 804, 793, 744, 20 740, 704, 69S cm~l.
~-[N-tert-butoxycarbonyl-3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetic Acid Hydrate (1:1) as a buff sol~d, m.p. 108-111 .
Physical characteristics are as follows:
Analysis: Calcd. for C30H29F3N2o4-H2o: C, 64.74; H, 5.61; N, 5.03. Found: C, 64.62; H, 5.21; N, 5.04.
Mass Spectrum: Ions at (mte): 539~ 538, 494, 483, 438, 437, 393, 340, ~64, 159, 91, 57, 45, 41, 29.
~MR (CDC13): ~ 0.9-1.5 (br, 9H), 4.2-4.5 (br, 2H), 4.6-4.9 (br, 30 3H), 6.2-7.3 (br, 14H), 7.4-7.7 (br, lH).
Infrared: ~max ~mull) 3430, 3113, 3062, 3031, 1689, 1651, 1616, 1551, 1497, 1330, 1163, 1125, 1074, 741, 701 c~
F,xample 5 ~-[3 (Trifluoromethyl)benzylamino]-l-benzylindole-3-N,N-dimethylacetamide hydrochlor~de A solution of 9.98 g (48.15 mmoles) of l-benzylindole, 8.44 g (48.18 mmoles) of 3-(trifluoromethyl)benzylamlne, 6 mL (6.29 g, 104.8 mmoles) of acetic acid, and 4.87 g (43.17 mmoles~ of N,N-dimethyl-2-oxoacetamide in 150 mL of MeOH was stirred and then allowed to s~and , , , .

~o~

for four days. Then the solution wa~ refluxed for one day. The solvent was evaporated. The residue was shaken with 100 mL of CH2C12 and 100 mL of dilute NaOH solution. The layers were separated. The aqueous layer was extracted with 100 mL of CH2C12. The combined organic phases were washed with 50 mL of brine and dried over MgSO4.
Evaporation of the solvent left 21.79 g of yellow oil. The oil was chromatographed on a 1100 g column o silica gel. The column was eluted with 5~ MeOH-CH2C12 and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (lx4n) (5~ MeOH-CH2C12).
Fractions 26-30 were combined giving 7.61 g of crude ~-[3-(tri-fluoromethyl)-ben~ylamino)-l-benzylindole-3-N,N-dimethylacetamide as a yellow-brown oil. Fractions 23-25 were combined giving 6.86 g of a ~-[3-(trifluoromethyl)-benzylamino]-1-benzylindole-3-N,N-dimethyl-acetam-de as a yellow oil. A solution of the oil in ether was mixed with a ~olution of excess anhydrous HCl in ethsr. A pink oil separat~d. The solvent was ev~porated (on a steam bath) until the oil had changed to a solid. The solid was collected by filtration and washed with ether giving 5.91 g (24~) of the titled compound as a pink solid, m.p. 187 (dec).
Physical characteristics are a~ follows:
Analysis: Calcd. for C27H27H16F3N3O HCl: C, 64.60; H, 5.42;
Cl, 7.06; N, 8.37. Found: C, 64.46; H, 5.54; Cl, 6.94; N, 8.34.
Mass Spectrum: Ions at (m/e): 465, 426, 395, 394, 393, 234, 233, 159, 92, 91, 72, 65.
NNR (CD30D): ~ 2.81 (s, 3H), 2.96 (s, 3H), 4.34 (s, 2H), 4.73-4.98 (br, 2H), 5.43 (s, 2H), 5.91 (s, lH), 7.15-8.0 (m, 14H).
Infrared: vQax (mull) 3097, 3049, 2655, 2516, 2470, 2430, 2406, 2368, 1643, 1615, 1582, 1535, 1495, 1331, 1182, 1173, 1155, 1122, 1079, 794, 746, 732, 701 cm~l.
Example 6 Ethyl ~-[3-(trifluoromethyl)benzylamino]-1-ben~ylindole-3 acetate To a magnetically stirred suspension of ~-[3-(trifluoromethyl)-ben~ylamino]-l-benzylindole-3-acetic acid ~21.9 g, 0.05 mol) in 250 mL of methanol st room temperature was treated with 11.34 g of sodiu~
methoxide (25~ in methanol) at once. The resulting solution was stirred for two hours, concentrated directly on a rotary evaporator and finally the resulting white residue was pumped do~n under high vacuu~ using a warm wa~er bath at ca 50~C. The dry sodium salt was .

dissolved in 100 mL of dimethylformamide, charged at once with ethyl iodide (9.36 g, 0.06 mol, 1.20 eq) and stlrred in the dark for 48 hours with an additional 50 mL of dimethylformamide being added after 20 hours to facilitate stlrrin~ of the gelatinous precipitate wh~ch formed. The contents ware diluted with ethQr and poured into 125 mL
of ice water plus 125 ml of saturated brine. The aqueous phase was separated from the organic layer and extracted once more with ether.
The comblned organic extracts were drled with anhydrous Na2SO4 and concentrated ~t reduced pressure. Flash chromatography with 250 g of silica gel packed and eluted with ethyl acetate-hexane (1:4) gave the title compound as a yellow oil.
Substitution of methyl iodide for ethyl iodide afforded methyl-~-[3-(trifluoromethyl)benzylamino-1-benzylindole-3-acetate in 51 yield.
Example ~ Ethyl ~-[3-(trifluoromethyl)-benzylamino]-1-ethoxy-carbonyl-indole-3-acetate hydrochloride To a magnetically stirred solution of ethyl ~-[3(trifluoro-methyl)-benzylam~no]-indole-3-acetate (1.00 g, 2.66 mmol) in 15 mL of DMF was added under nitro~en 0.112 g (2.79 mmol) of sodium hydride (60~ oil dispersion). After stirring at room temperature for 10 minutes, 0.26 ml (2.79 mmol) of ethyl chloroformate was added.
Stirring was continued for two hours at room te~perature. At the end of this time, the reaction contents were poured into ice water, the aqueous solution extracted with ether and the ether solution washed with satura~e~ brine and dried over anhydrous Na2S04. Removal of the solvent in vacuo gave the crude product ~hich was chromatographed with 80 g of silica gel using hexane-ethyl acet~te (4:1~ to yield 0.857 ~ of the title compound.
Physical characteristics are as follows:
TLC (Skellysolve B - EtOAc, Rf 0.65).
NMR (CDC13, C) 8.18 ~m, lH), 7.67-7.23 ~m, 8H), 4.60 ~s, lH), 4.47 (m, 2H), 4.21 (m, 2H), 3.86 (m. 2H), 1.47 and 1.22 (2 triplets, 6H).
The absve product was treated with etherèal-HCl to a~ford after 35 crystallization from ether-hexane 0.797 g of HCl salt, m.p. 153-155C.
Physical characteristics are as follows:
Analysls: Calcd. for C23H23F3N204 HCl: C, 57.0~; H, 4.96; N, .
' ., ' ' 5.79. Found: C, 57.25; H, 5.09; N, 5.85.
NMR (CDC13, ~) 8.31 (s, lH), 8.75 (m, lH), 8.00 (m, lH), 7.62-7.26 (m, 6H), 4.97 (s, lH), 4.77 (m, lH), 4.50 (m, 2H), 4.27-4.04 (m, 3H), 1.4~ and 1.15 (2 triplets, 6H).
Utilizing a procedure similar to that in Example 7, but sub-stituting the appropriate chloroformate for ethyl formate, there is obtained ethyl ~-[3-(trifluoromethyl)-benzylamino]-1-benzyloxycar-bonyl-indole-3-acetate hydrochloride, m.p. 150-152C. and methyl-~-[N-methyl-3-(trifluoromethyl)benzylamino]-1-benzyl-indole-3-acetate hydrochloride, m.p. 151-154C.
Exam~le 8 Methyl ~-[3-(trifluoromethyl)benzylamino]-1-benzyllndole-3-acetate To a magnetically stirred solution of 100 ml of methanol cooled in an ice-acetone bath at ca -15C., was treated dropwise with acetyl chloride (27.3 g, 350 mmol, 35 aq) over a six-minute period as a convenient way to generete HCl in situ. The solution was stirred at ambient temperature for 45 minutes, then solid ~-[3-(trifluoro-methyl)benzylamino]-l-ben7.ylindole-3-acetic acid was added wh~ch formed a dark rose colored solution. After stirring for 22 hours the reaction mixture was poured into lO0 mL of saturated ~aHCO3 solutlon containing 100 mL of crushed ice, basified with additional solid NeHCO3 powder ~ntll the rose color dissipated and extracted twice with ether. The combined organic extracts were washed with saturated NaHC03 ~lx75 mL), saturated brine tlxlOO mL), dried with anhydrous NaS04 and concentrated in vacuo. Flash chromatography with 100 g of silica gel using ethyl acetate-hexane ~1:2) afforded 4.07 g of the title compound as a golden oil.
Example 2 Methyl ~-[3-(trifluoromethyl)benzylamino-1-ben~ylindole-3-acetate To a magnetically stirred solution of ethyl ~[3-(trifluoro-methyl)benzylamino-l-benzylindole-3-acetate ester (7.76 g, 16.7 mmol) in 125 mL of methanol was added 3.80 mL ~16.7 mmol~ of 25~ sodlum methoxide in methanol solution. Stirring was continued at room temperature for 15 hours. At the end of this time, the methanolic solution was poured onto 150 mL of crushed ice, thoroughly extracted with methylene chloride and the organic layer dried over anhydrous sodium sulfate. Concentration of the solvent in vacuo gave the crude product which was chromatographed over 150 g of silica gel using ;

.
, ~. . . . ,., :

.: .
...

~72~5 hexane-ethyl acetate (4:1) to afford the title compound as an oil in quantitative yield.
Example 10 Ethyl ~-[3^(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate To a ma~netically stirred solution of methyl ~-[3-ttrifluoro-methyl)benzylamino]-l-benzylindole-3-acetate hydrochloride (100 mg) in 8 mL of ethanol was added 70 ~L of 25~ sodium methoxide in methanol. After stirring at room temperature for two hours, TLC
analysis showed 90~ conversion to the title compound.
Example 11 Methyl ~-[3-(trifluoromethyl)benzylamino]-l-benzylindole-3-acetate hydrochloride A magnetically stirred solution of methyl ~-[3-(trifluoro-methyl)benzylamino]-l-benzylindole-3-acetate (4.07 g, 9.0 mmol) in 65 mL of ether cooled at 0-5C was treated dropwise over a four-minute period with a stock solution of hydrogen chloride in ether (3.8 mL, 11.71 mmol, 1.3 eq, 3.1 mmol per mL). The cooling bath was removed after addition was completed and the mixture stirred at room temperature overnight. The precipitated white solid was collected, washed with ether-hexane (1:1) and recrystallized from acetone-ethyl 20 acetate-ether solvent mixture to yield 4.18 g (95~) of the title compound.
Example 12 Preparation of Ethyl ~-[3-(trifluoromethyl)benzylamino]-l-ethylindole-3-acetate, hydrochloride Ethyl ~-[3-(trifluoromethyl) benzylamino]-1-ethyllndole-3-25 acetate (1.50 g, 3.70 mmol) was placed in 25 mL of ether, saturated with HCl gas and stirred under nitrogen for 30 minutes. The contents were concentrated to dryness in vacuo and the resulting solid recrystallized from acetone-ether (1:5) to give 1.30 g of the title compound as a crystalline white solid, m.p. 141-143C.
Physical characteristics are as follows:
Analysis: Calcd. for C22H24F3N202Cl C~ 59-93; H~ 5-49; N~ 6-35;
F, 12.93; Cl 8.04. Found: C, 59.68; H, 5.68; N, 6.30; F, 12.99; Cl 7.90.
NMR (CDC13, ~) 7.94-7.17 (m, 9H), 5.00 (s, lH), 4.30-3.90 (m, 35 4H), 1.60-1.50 (m, 5H), 1.16 (t, 3H, J - 7 Hz~.
Example 13 Ethyl ~-[N-ethyl-3-(trifluoromethylbenzylamino]-l-benzylindole-3-acetate, ethyl ~-[N-ethyl-3-~trifluoromethyl)benzyl-amino]-indole-3-acetate, and ethyl ~-[3-(trifluoromethyl)-4~

benzylamino]-indole-3-acetate To a magnetically stirred suspension of ~-[3-(trifluromethyl)-benzylamino]-indole-3-acetic acid (20,88 g, 60 mmol) in 350 mL of methanol was added 16.46 mL (72 mmol) of 25% sodium methoxide in methanol solution. The contents were allowed to stir under nitrogen at room temperature for one hour. At the end of this period the methanol was removed in vacuo and replaced with 150 mL of dimethyl-formamide (DMF). The reaction mixture was cooled in an ice-water bath, 5.76 mL (72 mmol) o~ ethyl iodide added, and the reaction stirred overnight in the dark at room temperature. The reaction was diluted with one liter of water, the aqueous phase thoroughly extracted 3x with ether, the ether extract washed with saturated brine and dried over anhydrous sodium sulfate. Removal of the ether in vacuo gave the crude product which was purified by flash chromato~raphy (600 g silica gel). Elution with hexane-ethyl acetate (4:1) afforded 1.22 g of ethyl ~-[N-ethyl-3-(trifluoro-methyl)-benzylamino]-l-ethylindole-3-acetate (lea~t polar), 2.76 g of ethyl ~-[N-ethyl-3-(trifluoromethyl)-benzylamino]-indole-3-acetate, 2.62 g of ethyl ~-[3-(trifluoromethyl)-benzylamino]-1-ethylindole-3-acetate and 8.67 g of ethyl ~-[3-(trifluoromethyl)-benzylamino]-lndole-3-acetate (most polar).
Physical characteristics are as follows:
TLC 1:2 EtOAc-Hexane Ethyl ~-[N-ethyl-3-(trifluoromethyl)-benzylamino]-1-ethylindole-3-acetate Physical characteristics are as follows:
Rf: 0.78 NMR (CDC13, 6) 4.99 (S, lH), 4.32-4.08, (m, 4H), 3.95 (lH), 3.70 (d, lH, J - 12 Hz~, 2.68 (m, 2H) 1.44, 1.28, 1.09 (3 triplets, 9H).
Analysis: Calcd. for C24H27F3N22 432 (M+). Found 432-Infrared (Neat cm-l) 1330, 1124, 1164, 1175, 1731, 741, 1072, 1197, 702, 1463.
Ethyl ~-[N-ethyl-3-(trifluoromethyl)-benzylamino]-indole-3-acetate Phy~ical characteristics are as follow~:
Rf: 0.64.
NMR (CDC13, ~) 5.00 ~s, lH), 4.32-4.19 (m, 4H), 3.96 td, lH, J -15 Hz), 3.70 (d, lH, J - 15 Hz, 2.70 (m, 2H), 1.30 and 1.09 (2 trip-.:' :

.

L~

lets, 6H).
Analysis: Calcd. for C22H23F3N202: 404 (M+).
Infrared (Neat cm-l) 1330, 1124, 1164, 1176, 1729, 1072, 744, 1096l 703, 1457.
Ethyl ~-[N-ethyl-3-(trifluoromethyl)-benzylamino]-indole-3-acetate hydrochloride Physical characteristics are as follows:
Rf: 0.50.
NMR (CDC13, ~) 4.65 (s, lH), 4.30-4.07 (m, 4H), 3.86 (dd, 2H, J
10 - 12Hz, 1.45 and 1.23 (2 tripletsl 6H).
Analysis: Calcd. for C22H23F3N202 404 (M+). Found 404.
Infrared (Neat cm-l) 1330l 1124, 1164, 1731, 1176, 118~, 742, 1073, 704, 1463.
Ethyl ~-[3-(trifluoromethyl)-benzylamino]-indole-3-acetate Physlcal characteristics are as follows:
Rf: 0.31.
NMR (CDC13, ~) 4.68 (s, lH), 4.27-4.10 (m, 2H), 3.92-3.82 (m, 2H), 1.22 (t, 3H, J - 7 Hz).
Analysis: Calcd. for C20HlgF3N203: 376 (~). Found: 376.
Infrared (Neat cm~l) 1330, 1124, 1166, 1730, 1177, 1189, 745, 1073, 703, 1097.
Example 14 Methyl ~-[N-methyl-3-(trifluoromethyl)benzylamino]-1-(4-chlorobenzyl)indole-3-acetate To a magnetically stirred suspension of sodium hydride (60% oil 25 dispersion washed two times with hexane, 80 mg, 2.0 mmol) in 5 mL of dimethylformamide (DMF) under nitrogen was added methyl ~-[3-(tri-fluromethyl)benzylamino]-indole-3-acetate (752 mg, 2.0 mmol) dissolved in 2 mL DMF. Stirring was continued at room temperature for 10 minutes. At ~he end of this time. 0.322 g (2.0 mmol) o~
parachlorobenzyl chloride was added and the reaction stirred at room temperature for one hour. The reaction was diluted with ether and the ether solution was washed two times with water. The ether extract was then washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product.
Flash chromatography of the crude product with 100 g of silica gel and usin~ hexane-ethyl acetate (4:10) as the eluent afforded 419 mg of the title compound.
Physical characteristics are as follows:

,, ,, : . .

" :

TLC: 1:1 Hexans-ethyl acetate, Rf 0.58.
NMR (CDC13, ~) 7.72-7.03 (m, 13H), 5.25 (s, 2H), 4.69 (s, lH), 3.86 (s, 2H), 3.72 (s, 3H).
Hi~h Resolution Mass Spectru~
Calcd for C26H22ClF3~22: 486.1322. Found: 486.1346.
Infrared (neat, cm-l) 1330, 1165, 1124, 1736, 744, 1197, 1073, 703, 1467, 1493.
Example 15 Methyl ~-(3-Trifluoromethylphenylmethylamino)-5-methoxy-3-indoleacetate To a stirred solut~on of 7.24 g (41.34 mmoles) of 3-(trifluoro-methyl)benzylamine and 4mL (4.2 g, 69.88 mmoles) of acetic acid in 50 mL of MeOH was added a solution of 3.65 g ~41.34 mmoles) of glyoxylic acid monohydrate in 50 mL of MeOH followed by 5.07 g (34.45 mmoles) of 5-methoxyindole. The resulting solution was allowed to stand for three days. Solid separatad during this period. The solid was collected by filtration, washed with MeOH, and dried giving 3.02 g of white solid, m.p. ca. 192C. (dec). The solvent was evaporated from the combin~d filtrate and washing. The residue was treat~d with 200 mL of H2O. Sodium bicarbonate was added until the C2 evolution 20 ceased. The mixture was extracted with CH2C12 (3x100 mL). The combined extracts were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 8.71 g of brown oil which slowly solidified. The solid was chromatographed on a 700 g column of silica gel. The column was eluted with 30~ acetone-Skellysolve B
and 203 mL fractions were collected. The fractions were assayed by silica gel TLC (lx4")(40~ acetone-Skellysolve B). Fractlons 14-20 were combined and crystallized from CH2C12-hexane giving 5.14 g of ivory-buff solid. The solid was recrystallized from acetone-h~xane giving 4.8 g (36%) of the title compound as ivory needles, m.p. 109-30 110.5C.
Physical characteristics are as follows:
Analysis: Calcd. for C20HlgF3N203: C, 61.22; H. 4.88; N 7.14.
Found: C, 61.27; H, 4.96; N, 7.17.
Mass Spectrum: Ions at (m/e): 392 (M~), 334, 333, 174, 173, 35 160, 159, 147, 144l 131.
NNR (CDC13): ~ 2.2-2.45 (br, lH), 3.72 (s, 3H), 3.84 (s, 3H), 3.89 (s, 2Hj, 4.7 (s, lH), 6.85-7.02 (~, lH), 7.13-7.4 (m, 3H), 7.48-7.8 (m, 4H), 8.2-8.4 (br, lH).

:' :
:

4~L~

Infrared: ~max(mull), 3324, 3309, 3130, 3077, 3040, 1746, 1725, 1626, 1587, 1492, 1332, 1233, 1199, 1162, 1120, 1071, 811, 793, 706 cm-l Example 16 ~-Aminoindole-3-acetic Acid A mixture of 2 g of ethyl ~-aminoindole-3-acetate, excess dilute NaOH solution, and a few mL oE MeOH WAS stirred oceasionally for 25 minutes. Since a solution had not been obtained, the mixture was heated on a steam bath for ten minutes. The resulting solution was allowed to stand at ambient temperature for 50 minutes. The solution was acidified with acetic acid. The solid which separated was collected by filtration and washed with H2O givin~ 1.50 g (86~) of the title compound as small buff plates, m.p. 217 (dec).
Physical eharaeteristies are as follows:
Analysis: Caled. for CloHloN2O2: C, 63.14; H, 5.30; N, 14.73.
15 Found: C, 62.63; H, 5.63; N, 14.65.
Mass Spectrum: Ions st (m.e): 190, 173, 146, 145, 143, 129, 118, 117, 91, 89, 44.
Infrared: ~max (~ull) 3402, 3114, 3069 - 3000b, 2660, 1633, 1618, 1579, 1575, 1545, 1522, 1490, 1402, 1366, 746 em~l.
~xample 1~ ~-[2-(4-Amino~ulfonylph~nyl)ethylamino~-3-lndoleaeetie aeid Hydrate (1:1) To a stixred solution of 6.01 ~ (0.03 m~ole) of 4-(2-amino-ethyl)benzenesulfona~ide and 2.5 mL (2.62 g 0.Q44 mole) of acetie aeid in 150 mL of MeOH was added a solution of 2.64 g (0.03 mole) of 25 methyl glyoxylate in 50 mL of MeOH followed by 2.93 g (0.025 mole) of indole. Initially a solution was obtained. Soon solid began separating. The resulting mixturs was allowed to stand for four days. The solid was eollected by filtra~ion, washed with ether and dried give 3.72 g (38~) of the title eompound as a buff solid, m.p.
30 226C. (dee). The solid was insoluble in CH2C12, MeOH, DMSO, DMF and aeetie aeid.
Phy~ieal eharaeteristies are as follows:
Analysis: Caled. for C18HlgN3O4S-H2O: C, 55.23; H, 5.41; N, 10.73; S, 8.19. Found: C, 55.06; H, 5.27; N, 10.74; S, 8.50.
Mass Speetrum: Ions at (m/e): 374, 328, 201, 188, 175, 174, 145, 130, 118, 103.
Infrared: vmax(mull), 3394, 3357, 3270, 3133,3033, - 3000 br, 2713, 2619, 2522, 2422, 1594, 1490, 1340, 1328, 1167, 1098, 821, 769, .
:- :
.

4~5i 755 cm~l.
Example 18 ~-[(S-~-Methylbenzylamino]-l-benzylindole-3-acetic Acid To a solution of 4 g (19.3 mmoles) of l-benzyllndole and 1.95 g (21.18 mmoles) of glyoxylic acid monohydrate in 125 mL of MeOH was added 2.35 g (19.39 mmoles) of (S)-(-)-~-methylbenzylamine. The solution was stirred and then allowed to stand for 22 hours. The gelantinous solid which separated was collected by filtration and washed with MeOH giving 3.38 g (46~) of the title compound as an orange solid, m.p. 188C. (dec).
Physical characteristics are as follows:
AnalysiS: Calcd- for C25H24N22 C~ 78-10; H~ 6-29; N~ 7-29-Found: C, 77.62; H, 6.52; N, 7.14.
Mass Spectrum: Ions at (m/e): 339, 338, 323, 235, 120, 106, 105, 91, 79, 77, 65, 50.
Infrared: vmax(mull) 3060,3032, 2669, ~529, 2409, 2175, 1620, 1583, 1552, 1497, 1375, 1355, 1346, 768, 746, 741, 727, 701 cm-l.
Exampl_ 12 1-Phenylmethyl-~-(2-(3-(trifluoromethyl)phenyl)-1-pyrrolidinyl)lH-~ndole-3-acetic acid To a solution of 2-(3-trifluoromethylphenyl)-1-pyrrolidine (2.56 g, 11.9 nmol) in methanol (100 mL) was added N-benzyl-indole (2.45 ~, 11.8 mmol) and glyoxylic acid mono-hydrate (1.20 g, 13.3 mmol). A
white precipitate began to form within one hour, the mixture was allowed to stir overnight, after which time the precipitate WA5 isolated by filtration. The solid was washed with methanol (3 x 50 mL), and dried in vacuo at 40C. to provide 2.76 g, 49% of the title compound as a white powdery solid.
Physicsl characterlstics are as follows:
MP: 137C. (dec).
Infrared: (nu~ol): 3373, 2955, 1612, 1496, 1482, 132g, 1167, 30 1122, and 704 cm~l.
EI/MS (70eV): 433 (M+-C02, 68.8), 220 (10.4), 186 (27.5), 118 (11.8), 91 (base).
Analysis: Calcd. for C28H25F3N22 C, 70-28; ~, 5-27; N~ 5-85-Found: C, 69.78; H, 5.08; N, 5.89.
35 ~ 20 lH-Indole-3-acetic acid, 1-[(4-chlorophenyl)methyl]-~-[[[3-~trifluoromethyl)phenyl]methyl]amino]methyl ester To a magnetically stirred suspension of sodium hydride (60% oil dispersion washed 2X with hexane, 80 mg, 2.0 mmol) in 5 mL of , ..
.

, ~0~4~

dimethylformamide (DMF) under nitrogen w~s added methyl ~-[3-(trifluoromethyl)benzylamin]-indole-3-acetate (752 mg, 2.0 mmol) dissolved in 2 mL DMF. Stirring was continued at room temperature for 10 minutes. At the end of this time, 0.322 g (2.0 mmol) of para-chlorobenzyl chloride was added and the reaction stirred at roomtemperature ior one hour. The reaction was diluted with ether and the ether solution was washed 2~ with water. The ether extract was then washed with saturated brins, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Flash chromatography of the crude product with 100 g of silica gel and using hexane-Pthyl acetate (4:1) as the eluent afforded 419 mg of the title compound.
Physical characteristics are as follows:
Analysis: Cal~d. for C26H22ClF3N202: 486.1322.
Found: 486.1346.
Utiliæing a procedure similar to that used in Example 20 there is obtained the following compounds:
lH-Indole-3-acetic acld, l-butyl ~-[[[3-(trifluorom~thyl)-phenyl]methyl]amino], cthyl ester, m.p. 153-155C.
Physical characteristics are as follows:
Analysis calcd- for C23H23F3N204-HCl: C, 57.02; H, 4.96; N, 5.74. Found: C, 57.25; H, S.09 lH-Indole-3-acetic acid, 1-(2-ethoxyethyl~-~-[[[3-(trifluoro-methyl)]phenyl]methyl]aminoethyl ester.
Physical charscteristics are as follows:
Analysis: Calcd. for 524H273F2N23 448.1974. Found:
448.1986.
lH-Indole-3-acetic acid, 1-(2-ethoxyethyl)-~-[[[3-(trifluoro-methyl)phenyl]methyl]am~no]ethyl ester, monohydrochloride, m.p. 139-141C, Physical characterlstics ars as follows:
Analysis: Calcd. for C24H27F3N2O3 HCl: C, 59.44; H, 5.82; ~,5.78; Cl, 7.31. Found: C, 59.90; H, 5.~5; Cl, 7.21.
lH-Indole-3-acetic acld, 1-~(4-chlorophenyl)methyl]~-[[[3-(trifluoromethyl)phenyl]methyl]amino]ethyl ester.
Physical chsracteristics are as follows:
Analysis: Calcd- for C24H24F3N202Cl 500.1478.
Found: 500.1439.

:: ~
: .
: : -zoa~

lH-Indole-3-acetlc acid, 1-[(4-chlorophenyl)methyl)-~-[[[3-(trifluoromethyl)phenyl]methyl]a~ino]ethyl ester, monohydrochloride, m.p. 146-148C.
Physical characteristics are as follows:
Analysis: Calcd. for C2~H24C12N202 HCl: C, 60.35; H, 4.69; N, 5.21; Cl, 13.20. Found: C, 60.16; H, 4.84; Cl, 12.70.
lH-Indole-3-acetic acid, 1-(cyclohexylmethyl~-~-[[[3-(trifluoro-mathyl)phenyl]methyl]amino]ethyl ester.
Physical characteristics are as follows:
Analysis: Calcd. for C27H21F3N202: 472.2337. Found: 472.2330.
lH-Indole-3-acetic acid, 1-(cyclohexylmethyl)-~-[[[3-(trifluoro-methyl)phenyl]methyl]amino]ethyl ester, monohydrochloride, m.p. 151-153C.
Physical characteristics are as follows:
Analysis: Calcd. for C27H31F3N202 HCl: C, 63.71; H, 6.34; N, 5.50; Cl, 6.97. Found: C, 63.67; H, 6.49; N, 5.41; Cl, 6.27.
lH-Indole-3-acetic acid, 1-acetyl-~-[[[3-(trifluoromethyl)-phenyl]~ethyi]amino]ethyl ester.
Physical characteristics are as follows:
Analysis: Calcd. for C22H21F303N2: 418.1504. Found: 418.1510.
lH-Indole-3-acetic acid, 1-benzoyl-~-[[[3-(trifluoromethyl)-phenyl]methyl]a~ino]ethyl ester.
PhyBiG~l characteristics are as follows:
Analy3is: Calcd- for C27H23F303N2: 480.1661. Found: 480.1672.
lH-Indole-3-acetic acid, 1-benzoyl-~-[[[3-(trifluoromethyl)-phenyl]methyl]smino]ethyl ester, monohydrochloride, m.p. 118-139C.
(dec.).
Physical characteristics are as ~OllOWR:
Analysis: Calcd. for C27H23F3~3Nz HCl: C, 62.73; ~, 4.68; N, 5.42; Cl, 6.86. Found: C, 61.17; H, 4.93; N, 5.26; Cl. 6.44.
lH-Indole-3-acetic acid, 1-acetyl-~-[acetyl[[[3-~trifluoro-methyl)phenyl]methyl]smino]ethyl ester.
Phy31cal characteristics are as follows:
Analysis: Calcd. for C24H2304F3N2: 460.1610. Found: 460.1616.
lH-Indole-3-acetic acid, ~-[acetyl[[3-(trifluoromethyl)phenyl]-methyl]amino]ethyl ester.
Physical characteristics are as follows:
Anslysis: Calcd. for C22H21F303N2: 418.1504. Found: 418.1504.

.
; ,, ' ~ .
.
.

;~030~4~

lH-Indole-3-acetic acid, 1-[(2-chlorophenyl)methyl]-~-[[[3-(trifluoromethyl)pheny]]methyl]amino]methyl ester.
Physical charactPristics are as follows:
Analysis Calcd. for C26H22ClF3N22 486-1322-Found: 486.1332.
lH-Indole-3-acetic acid, 1-[(2,4-dimethylphenyl)methyl]-~-[[[3-(triEluoromethyl)phenyl]methyl]amino]methyl ester.
Physical characteristics are as follows:
Analysis: Calcd. for C2gH27F3N202: 480.2024. Found: 480.2019.
lH-Indole-3-acetic acid, 1-[(3-methoxyphenyl)methyl]-~-[~[3-(trifluoromethyl)phenyl]methyl]amino]methyl ester.
Physical characteristics are as follows:
Analysis: Calcd. for C27H25F3N203: 48~.1817. Found: 482.1839.
lH-Indole-3-acetic acid, 1-[(4-methoxyphenyl)methyl]--[[[3-(trifluoromethyl)phenyl]methyl]amino]methyl ester.
Physical charact~ristlcs ara as follows:
Analysis: Calcd. for C27H25F3N2O3: 482.1817. Found: 482.1847.
lH-Indole-3-acetic acid, 1-~(3-chlorophenyl)me~hyl]-~- L [ [3-(trifluoromethyl)phenyl]methyl]amino-methyl e~ter.
Physical characteristics are ~s follows:
Analysis: Calcd. for C26H22ClF3N2O2: 486.1322.
Found: 486.1327.
lH-Indole-3-acetic acid, 1-(4-pyridlnylmethyl)-~-[[[3-~tri-fluoromethyl)phenyl]methyl]a~ino]methyl ester.
Physical characteristics are as follows:
Analysis: Calcd. for C2sH22F3N3O2: 453.1564. Found: 453.1663.
ExamRle 21 Methyl ~-(phenylmethylamino)-3-indol~acetate To a stirred solution of 6.43 g (0.06 mole) of benyzlamine and 5 mL (S.25 g, 0.09 mole) of acetic acid in 50 mL of MeOH was added a solut~on of 5.28 g (0.06 mole) of methyl glyoxylate in 50 mL of MeOH
followed by 5.86 g (0.05 mole) of indole. The resultlng solution was allowed to stand for 69 hours. The solvent was evaporated. The residue was treated with 200 mL of H2O. Sodium bicarbonate was added until C2 evolution ceased. The mlxture was extracted with CH~C12 (3 x 100 mL). The combined extracts were wa~hed wi~h 50 mL brine and dried over MgSO4. Evaporation of the solvent left 16.2 g of orange-brown oil which solidified upon standing. Th~ solid was chromatographed on a 700 g column of silica gel. The column was :

2(~4~

eluted with 7.5% MeOH-CH2C12 and 200 mL fractions were collected.
The fractions were assayed by silica gel (TLC (lx4n) (5~ MeOH-CH2C12). Fractions 10-14 were combined giving 12.7 g of red oil.
The oil was chromatographed on A 700 g column of silica gel. The column was eluted with 404 acetone-Skellysolve B and 200 mL fractions were collected. The fractions were assayed by ~ilica gel TLC (lx4~) (40~ acetone-Skellysolve B). Fractions 11-14 were combined and crystalli~ed from ether-THF-hexane giving 8.07 g (55%) of the title compound as a pale pink solid, m.p. gl.5-93C.
Physical characteristics are as follows:
Analysis: Calcd. for ClgH18N2O2: C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.27; ~, 6.24; N, 9.52.
M~ss Spectrum: Ions at (m/e): 294 (M+), 236, 235, 144, 143, 130, 128, 106, 92, 91, 65.
NMR (CDC13): ~ 2.28 (s, lH), 3.68 (s, 3H), 3.Bl (s, 2H), 4.71 (s, lH), 6.9-7.45 (m, 9H3, 7.6-7.85 (m, lH), 8.4-8.7 (br, lH).
Infrared: vmax ~mull) 3275, 3205, 3166, 3151, 3130, 3112, 3089, 3065, 3029, 1732, 1619, 1586, 1580, 1539, 1498, 1312, 1238, 1193, 1167, 1118, 1109, 989, 764, 753, 738, 703 cm~l.
~E~lQ ~2 1-Phenylmethyl-lH-indole-3-acetamide-~-((3-~rifluoro-methyl)phenyl)methylamine To a solution of 3-trifluoromethylbenzyl amine (4.38 g, 55 ~mol) and NaCN (1.23 g, 25 mmol) in 1.00 N aqueous HCl (25 mL) was added in one portion N-benzylindole-3-carboxaldehyde (5.90 g, 25 ~mol) in MeOH
(25 ml)~ The mixture was allowed to stir for 5 hours, then the reaction was cast into Et2O (1.0 L), and dried (Na2SO4).
Concentration in Yacuo afforded the crude amino-nitrile as an oily red-orange solid which was purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm o.d., Et20-hexanes 1:4, 300 mL
30 fr) using the flash technique. Fractions 6-12 gave 3.76 g (36~) of l-phenylmethyl-lH-indole-3-acetonitrile-~ 3-trifluoromethyl~-phenyl)methyla~ine AS a relatively unstable cream colored solid w~ich was contaminated with the starting aldehyde. This compound was utilized ln the next reaction without further purification.
To a solution of the above amino nitrile (3.50 g, 8.34 mmol~ in CH2C12 (10 mL), cooled in an ice water bath, was added 30~ H2O2 (3 9 mL) followed immediatPly by n-Bu4NHS04 (0.616 g, 1.66 mmol) and 20~
aqueous NaOH (3.1 mL). The two-phase mixture ~as allowed to stir for 2~0Z4~5 flve hours at room temperature then was c~st into CH2C12-H2O (0.5 L
each). The organic phase was separated, washed with brine (0.5 L), dried (Na2SO4), and then concentrated in vacuo to furnish the crude amide as a pale yellow viscous oil. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm. o.d., EtOAc-hexanes 40:60, 500 mL fractions, usin~ the flash technique. Fractions 16-24 afforded 1.49 g (41~ ) of the title compound as an extremely viscous, pale yellow oil which provided a white powdery solid after trituratlon with Et20.
Physical characteristics are as follows:
M.P.: 112-113C.
TLC: (Merck, EtOAc-hexanes, 1:1; W (+); ammonium molybdate: Rf - 0.19.
lH-NMR (300Hz, CDC13): C - 7.0-7.7(14); 6.82 (brs, 1), 5.89 (brs, 1), 5.26 (s, 2), 4.54 (s, 2~, 3.39 (s, 2), 2.27 (brs, 1).
13C ~MR ~75.5 MHz, CDC13): ~ ~ 175.1, 140,7, 137,0, 131.6, 128.9, 128.8, 127,~, 127.1, 126.~, 12~.4, 125.0, 124.0, 122.4, 119.9, 119.5, 112.6, 110.1, 59.2, 51.9, 50.1.
Infrared (neat): 3368, 2957, 2868, 1705(w), 1656, 1465, 1455, 1378, 1330, 1188, 1173, 1162, 1123, 1074, 804, 745 ~nd 703 cm~l.
EI/MS (70eV): 437 (M+, 0.2), 393 (base), 159 (12.9), 91 (65.6).
~nalysis: Calcd- for C2sH22F3N3O: C, 68.64; H, 5.07; N, 9.60;
Found: C, 68.26; H, 4.70; N, 9.68.
ample 23 1-Phenylmethyl-N-3-(trifluoromethyl)phenylmethyl-L-tryptophan methyl ester To a stirring, ice-water cooled, suspension of (S)-(-)-l-benzyl-tryptophan methyl ester (2.50 g, 8.11 mmol) and 4A molecular sieves (1.50 g) in CH2C12 (100 mL) was added 3-trifluoromethyl benzaldehyde (1.4 mL, 10.5 mmol) via syringe followed by CF3COOH (two drops). The mixture was allowed to warm to 10C and was stirred overnlght. The suspended solids were removed by filtration through a pad of celite and the filtrate was concentrated in vacuo to provide a clear, viscous, yellow oil. The crude imine was dissolved in ~ethanol ~75 mL), cooled in an ice-water bath, and NaBH4 (0.34 g, 8.92 mmol) was added in portions over 20 minutes. After the sddition was complete the cooling bath was removed and the mixture was stirred at room temperature for four hours. The solvent was removed in vacuo and the resulting pale yellow, viscous o$1 was purified by chromatography on 20~

a column of silica gel (230-400 mesh, 500 g, 70 mm o.d., packed EtOAc-hexanes 10:90; eluted EtOAc-hexanes 20:80; 400 mL fractions) using the flash technique. Fractions 10-13 afforded 3.55 g, 97% of the title compound as a viscous oil.
Physical characteristics are as follows:
TLC: (Merck; EtOAc-hexanes, 1:3.
W (+); ammonium molybdate): Rf - 0.17.
lH-NMR (300 MHz, CDC13): ~ - 7.05-7.61 (14), 5.26 (s, 2), 3.88 (d, J - 13.7 Hz, 1), 3.62 (t, J - 6.6 Hz, 1), 3.59 (s, 3), 3.18 (m, 2), 2.10 (brs, 1).
13C-NMR (75.5 MHz, CDCl3): 6 174.8, 140.5, 137.4, 136.5, 131.4, 128.7, 127.6, 126.9, 126.7, 124.7, 123.7, 121.9, 119.3, 119.0, 110.0, 109.7, 61.4, 51.7, 51.6, 49.9, 29.3.
Infrared (neat): 3109, 2951, 1735, 1467, 1330, 1197, 1165, 1124, and 702 cu~l.
El/MS (70eV): 467 (M~, 5.5), 407 (7.6), 220 (base), Analysis: Calcd. for C27H25F3N202: C, 69.52, H, 5.40; N, 6.01.
Found: C, 69.28; H, 5.15; N, 5.55.
Example ~ (D,L)-1-Phenylmethyltryptophan A three-neck, one-liter flask equipped with a magnetic stir bath and placed in a dry ice-acetone bath was cooled ~o -78C. while 370 mL of ammonia was condensed into the flask containing 163 mg of ferric nitrate nonahydrate. The external cooling bath was then removed and pieces of sodium metal (2.62 g, 114.3 mmol) were added portionwise over 30 minutes. After stirring for an additional 10 minutes (d,l)-tryptophan (10.0 g, 49.0 mmol) suspended in 110 mL of ether was added to the dark solution over a ten-minute period. The reaction mixture was allowed to stir for another 30 minutes at refluxing liquid ammonia temperature, treated with benzyl chloride (8.23 g, 65.3 mmol) over a five-minute period. The dry ice-acetone condenscr was removed and the contents stirred o~ernight while a gentle stream of nitrogen was used to slowly remove th0 ammonia. The remaining residue was dissolved in 50 mL of hot water, acidified to pH 5 with 5 mL of acetic acid whlch produced a viscous ~hite slurry.
35 An additional 50 mL of water and 60 mL of 95~ ethanol were added and the mixture was heated to reflux. The contents which remained mostly insoluble was cooled in an ice bath, the white solids collected and successively washed with cold ethanol-watsr (1:1~, cold 95% ethanol '' ' ' '~

and finally ether ~o provide 14.45 g of the title compound. This mixture was used in the next reaction without purification.
Example 25 (D,L)-l-Phenylmethyltryptophan methyl ester Hydrogen chloride gas was bubbled through 200 mL of methanol, cooled in an ice-acetone bath, over a 30-minute period. To this solution was added the title compound obtained in Example 24 (9.58 g) and the contents heated to reflux for five hours. The reaction mixture was cooled in an ice bath, the precipitated solids collected by filtration and washed with methanol-ether (1:1) to obtain 1.76 g of esters as their HCl salts. Concentration of the filtrate afforded an additional 8.60 g of product. The combined salts were treated with lN aqueous NaOH and the aqueous solution was thoroughly extracted with ethyl ac0tate. The ethyl acetate was washed with brine, dried and concentrated in vacuo. Chromatography of the crude product ucing 125 g of silica gel and acetone-hexane as the eluent yielded 6.10 g of the title compound as a golden colored oil.
Physical characteristics are as follows:
Analysis: Calcd. for ClgH20N202: 308. Found: 308.
Example ~ ~D,L)-l-Phenylmethyl-N-(3-tr~fluoromethyl)phenyl)methyl-tryptophan methyl ester To 3.05 g of the (D,L)-l-phenylmethyl tryptophan methyl ester obtained in Example 24 dissolved in 100 mL of methanol, 1.60 mL of acetic acid, 1.72 e of ~e~a-tri1uoromethyleolualdehyde, cooled to 15~C with a cold water bath, was added 0.657 g of sodium cyanoboro-hydride. The cooling bath was removed after 15 m~nutes, the contentsstirred at ambient temperature for an additional three hours and then treated with crushed ice after cooling the reaction mixture in an ice bath. The mixture was made basic with 100 mL of saturated sodium bicarbonate solution, extracted once with ethyl acetate, the ethyl acetate dried and then conc0ntrated in ~acuo. Chromatography of this crude product using 75 g of silica gel and ethyl acetste as the eluent afforded 2.10 g of the title compound.
Physical characteristics are as follows:
Analysis: Calcd. for C27H25F3N202: C, 69.53; H, 5.36; N, 6.01.
Found: C, 69.30; H, 5.44; N, 5.87.
Example 27 (D,L)-l-Phenylmethyl-N-(3-(trifluoromethyl)phenyl)methyl-tryptophan methyl ester HCl Salt To a magnetically stirred ~olution of (D,L)-l-phenylmethyl-N-(3-~ .

4~

trifluoromethyl)phenyl)methyl-tryptophan methyl ester obtained in ExamplP 26 (0.465 g) in 40 mL of ether cooled in a 00-5DC. bath was bubbled HCl gas for two to three minutes. The white mass which precipitated W8S diluted with 10 mL of hexane, allowed to cool to 0-5C. and collected to give 478 mg of the title compound. A smallsample was recrystallized with ethyl acetate-methanol-ether to give the tltle compound, m.p. 201-203C.
Physical characteristics are as follows:
Analysis: Calcd. for C27H2sN202.HCl: C, 64.54; H, 4.98; N, 5.58. Found: C, 64.24; H, 5.41; ~, 5.25.
Exa~ple ~8 (D,L)-l-Phenylmethyl-N-(3-(trifluoromethyl)phenyl)methyl-Tryptophan The methyl ester (1.00 g) isolated in Example 26 was treated with 20 mL of methanol and 4.00 mL of lN sodiu~ hydroxide and stirred at room temperature for 15 hours. The reaction was worked up in the usual way and chromatographed using 40 g of silica gel and chloroform-m~thanol ~85:15) as the eluent to afford 808 Mg of the title ~ompound, ~.p. 125C.
Physical characteristics are as follows:
Analysis: Calcd. for C26H~3F3N202.H2O: C, 66.38; H, 5.32; ~, 5.96. Found: C, 66.20; H, 5.05; N, 5.74.
~E~l~ 29 (D,L)-l-Ethylthiocarboxy-N-(3-(trifluoromethyl)phenyl)-methyl-tryptophan methyl ester A magnetically stirred solution of (D,L)-N-(3-(trifluoromethyl)-~ethyl-tryptophan methyl ester (1.15 g, 3.06 ~mol) in 15 mL of dimethylformamide, cooled to 18C was treated with 3.21 mmol of sodium hydride. The cooling bath was removed after five min~tes, the contents stlrred for another 45 minutes at room temperature, then reacted with ethyl thiolchloroformate (0.419 g, 3.21 mmol) for an additional 40 minutes. The reaction mixture was ~hen poured into 50 mL of crushed ice, extracted with ethyl acetate, the combined organic extracts dried over anhydrous sodium sulfate and concentrated ln vacuo. The crude product was chromatographed using 150 g of silica gel and elution with ethyl acetate-hexane afforded 457 g of the title compound.
Physical characteristlcs are as follows:
H NMR (CDC13) 3.84 (d, lH0, 7.58 (s, lH), 7.53-7.22 (m, 7H), 3.93 (d, lh), 3.76-3.66 (m, lH), 3.68 (s, 3H), 3.S6-3.58 (m, lH), .. . .

-s9-3.18-2.98 (m, 4H), 1.43 (t, 3H).
Example 30 (D,L)-l-Ethylthiocarboxy-N-(3-(trifluoromethyl)phenyl)-methyl-tryptophan methyl ester HCl Salt Utilizing a procedure similar to that described in Example 27 5 0.457 g of the methyl ester yielded 0.474 g of the title compound, m p 180-181C
Physical characteristics are as follows:
Analysis: Calcd. for C23H23F3N203S HCl: C, 55.20; H, 4.80; N, 5.60. Found: C, 55.05; H, 4.62; N, 5.62.
Utilizing a procedure similar to those described previously thcre are obtained the following compounds:
DL-Methyl-l-(phenylme~hyl)-tryptophan-methyl ester monohydro-chloride.
Physical characteristics are as follows:
Analysis: Calcd. for ClgH2oN202-308: Found: M+308.
DL-N-l-bis(phenylmethyl)-tryptophan-methyl ester.
Physical characteristics are as follows:
An~ly~is: Calcd. for C26H26N2O2-398 Found Physical characteristics are as follows:
DL-l-(phenylmethyl)-tryptophan-N-[[3-(trifluoromethyl)phenyl]-methyl]methyl ester.
Physical characteristics are as follows:
Analysis: Calcd. for C27H25F3N22 C, 69-53; H~ 5-36; ~, 6-01-Found: C, 69.30; H, 5.44; N, 5.87.
DL-~-(l-methylethyl)-tryptophan-l-(phenylmethyl)methyl ester.
Physical haracteristics are as follows:
Analysis: Calcd. for C22H26N202: C, 75.43; H, 7.43; ~, 8-00-Found: C, 74.62; H, 7.41; N, 7.63.
DL-N-~l-methylethyl)-l-(phenylmthyl)-tryptophan-methyl ester, monohydrochloride, m.p. 207-208C.
Physical characterlstics are as follows:
Analysis: Calcd. for C22H26N2O2 HCl: C, 68.39; H, 6.74; N, 7.25. Found: C, 68.19; H, 7.20; N, 7.01.
DL-l-(phenylmethyl)-~-[[[3-(trifluoromethyl)phenyl]methyl]-tryptophan-methyl es~er, monohydrochloride, m.p. 201-203C. (dec.).
Physical characteristics are as follows:
Analysis: Calcd. for C27~25F3N2~2-HCl C, 64-54; H, 4-98; N~
5.58. Found: C, 64.24; H, 5.41; N, 5.25.

4~S

DL-N-l-bis(phenylmethyl)-tryptophan, m.p. lB5C.
Physical characteristics are as follows:
Analysis: Calcd. for C25H24N22 H20 C~ 7~-63; H~ 6.47; N~
6.97; Found: C, 74.50; H, 5.85; N, 6.59.
DL-l-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan, m.p. 125C.
Physical characte.ristics are as follows:
.~nalysis: Calcd. for C25H23F3N22 H2 C, 66-38; H~ 5-32; N~
5.96. Found: C, 66.20; H, 5.05; N, 5.74.
DL-Nethylester-tryptophan monohydrochloride DL-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan methyl ester Physical characteristlcs are as follows:
Analysis: Calcd. for ClgHlgF3N202 - 376. Found: M~ 376.
DL-l-p-(4-chlorophenyl)methyl]-N-[[3-(trifluoromethyl)phenyl]-methyl-tryptophan-methyl ester Physical characteristics are as follows:
Analysis: Calcd. for C26H24F3N202Cl - 500. Found M+ 500.
DL-1-[(4-chlorophenyl)methyl]-N-[[3-(trifluorom0thyl)phenyl]-methyl]-tryptophan- methyl ester, m.p. 171-172C.
Physical characteristlcs are as follows:
Analysis: Calcd. for C2~H24ClF3N2O2 HCl: C, 60.45; H, 4.66; N, 5.22. Found: C, 60.05; H, 4.64; N, S.05.
DL-N-[[(3-(trifluoromethyl)phenyl]methyl]-tryptophan-methyl ester, monohydrochloride, m.p. 172-173C.
Physical characteristics are as follows:
Analysis: Calcd. for C20HlgF3N202 HCl: C, 58.25; H, 4.85; N, 6.80. Found: C, 58.21; H, 4.89; N, 6.82.
~L-l-[(ethylthio)carbonyl]-N-[[3(tr~fluoromethyl)phenyl]methyl]-tryptophan DL-l-[ethylthiocarbonyl]-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan monohydochloride, m.p. 180 ~81.5C.
Physical characteristics are as follows: -Analysis: Calcd. for C23H23F3N2O3S HCl: C, 55.20; H, 4.80; N, 5.60. Found: C, 55.05; H, 4.62; N, 5.61.
DL-l-(ethoxycarbonyl)-N-[[3-(trifluoromethyl)ph~nyl]methyl]-tryptophan methyl ester.
DL-l-(ethoxycarbonyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan-methyl ester, monohydrochloride, m.p. 189-190C.

' ', , , , ; i 41~

Physical characteristics are as follows:
Analysis: Calcd. for C23H23F3N2O4 HCl: C, 57.02; H, 4.96; N, 5.79. Found: C, 56.85; H, 5.08; N, 5.92.
DL-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan, m.p. 227C.
Physical characteristics are as follows:
Analysis: Calcd. for ClgH17F3N2O2 H2O: C, 60.00; H, 5.00; N, 7.37. Found: C, 60.43; H, 4.80; N, 7.27.
D-N-(phenylmethyl)-tryptophan.
D-N-(phenylmethyl)-tryptophan-methyl ester.
D-l-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-trypto-phan-methyl ester.
D-l-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-trypto-phan-methylester monohydrochloride, m.p. 171-172C.
Physical characteristics are as follows:
Analy~is: Calcd. for C27H25F3N2O2 HCl: C, 64.54; H, 4.98; N, 5.58. Found: C, 64.28; H, 5.13; N, 5.19 D-l-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl-trypto-phan, ~.p. 170-173C.
Physical characteristics are as follows:
Analysis: Calcd. for C26H23F3N22 C~ 69-03; H, 5-09; N~ 6-19-Found: C, 68.70; H, 5.29; N, 6.37.
Example 31 Methyl (+/-)-~-(l-phenylmethyl-3-indolylmethyl)amino-phenylacetate (see Chart III for preparation of Examples 31-40) To a ~uspension of methyl (+/-)-phenylglycinate hydrochlor$de (4.00 g, 19.8 mmol) in MeOH (50 mL), and HOAc (4 mL) was added 1-phenylmethyl-indole-3-carboxaldehyde (2.85 g, 12.1 mmol). The resulting mixture was allowed to stir at room temperature for 20 minutes; then NaB~3CN (1.98 g, 31.5 mmol) was added in one portion.
The suspension was allow~d to stir at room temperature for 18 hours, thsn was concentrated in vacuo to furnish a sticky white semi-solid.
The crude reaction mixture was partitioned between 20% aqueous NaOH
(0.25 L) and EtOAc ~0.25 L); the organic phase was separated, washed wlth brine (0.25 L), and dried (Na2SO4). Concent~at~on in vacuo afforded the crude product as a pale green o~l which was purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm o~d., EtOAc-hexanes 25:75, 400 mL fractions) using the flash technique. Fractions 8-13 ~ere combined to provide 2.0g (43~3 of the title compound as a white solid. Recrystalli~ation from EtOAc-i~ ' '' ' ' :

:
:' s hexanes provided white needles, m.p. 109-110C.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 25:75.
W (+); ammonium molybdate) Rf 0.48.
lH-NMR: 6 - 7.67 (d, J - 7.23Hz, 1), 7.05-7.45 (15), 5.28 (s,2), 4.49 (s, 1), 3.94 (s, 2), 3.67 (s, 3).
Infrared (nuJol): 2925, 2855, 1733, 1453, 1442, 1333, 1208, 1176, 790, and 737 cm~l.
EI/MS (70eV): 384 (N+, 17.8), 325 (6.0), 235 (7.9), 220 (base), 10 129 (14.2), 91 (75.8).
Analysis: Calcd. for C25H2~N~02: C, 78.10; H, 6.29; N, 7.29.
Found: C, 7S.07; H, 6.48, N, 7.23.
Example 3~ Methyl (R)-~-(l-phenylmethyl-3-indolylmethyl)amino-phenylac2t~te According to the general procedure dascribed for the preparation of Example 31, methyl (R)-phenylglycinste-hydrochloride (4.00 g, 19.8 mmol), 1-benzyl-indole-3-carboxaldshyde (2.33 g, 9.9 mmol) and NaBH3CN (0.81 g, 12.9 ~mol) provided cruda tltle compound a~ a pale yellow oil. The crude materisl was purified by chromatography on a 20 column of silica gel (230-400 mesh, 500 g, 70mm o.d., packed-~thyl acetate-hax~nes 20:80, elut~d ethyl acetate-hexanes 25:75, 400 mL
fractions) using th~ flash t~chnique. Fractions 8-13 provided 2.82 g (74~) of the title compound as a pale yellow oil which slowly crystall~zed to an ivory solid, m.p. 72-75C.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 35:65.
W (+); ammonium molybdate) Rf - 0.30.
lH-NMR: 6 - 7.67 (d, J ~ 7.23Hz, 1), 7.05-7.45 (15), 5.27 (s, 2), 4.48 (s, 1), 3.94 (s, 2), 3.66 ~s, 3).
13C-NMR: ~ - 173.1, 138.1, 137.5, 136.6, 128.7, 128.6, 128.0, 127.6, 126.B, 121.9, 119.3, 113.5, 109.7, 64.6, 52.1, 49.9, 42.5.
Infrared (nu~ol): 2924, 2855, 1733, 1453, 1443, 1333, 1208, 1176, 790, and 737 cm~l.
EI/MS (70eV): 384 (M+, 11.9), 325 (6.1), 235 (8.0), 220 (base), 35 129 (10.9), gl (76.5).
Analysis: Calcd. for C25H24N2O2: C, 78.10; H, 6.29; N, 7.29.
Found: C, 77.82; H, 6.15, N, 7.28.
Example 33 Methyl ~S)-~-(l-phenylmethyl-3-indolylmethyl)amino-phenylacetate According to the general procedure dPscribed for the preparation of Example 31, methyl (S)-phenylglycinate-hydrochloride (4.00 g, 19.8 mmol), 1-benzyl-indole-3-carboxaldehyde (2.33 g, 9.9 mmol) and NaBH3C~ (0.81 g, 12.9 m~ol) provided crude title compound as a pale yellow oil. The crude material was purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70mm o.d., packed-ethyl acetate-hexanes 20:80, eluted ethyl acetate-hexanes 25:75, 400 mL
fractions) usin~ the flash technique. Fractions 7-12 pro~ided 1.44 g (38~) of the title compound as a clear, pale yellow oil.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 35:65.
W (+); ammonium molybdate) Rf ~ 0.30.
lH-NMR: ~ 7.67 (d, J 7.23Hz, 1), 7.05-7.45 (15), 5.24 15 (s,2), 4.48 (9, 1), 3.97 (s, 2), 3.66 (s, 3).
13C-NNR: 6 - 173.1, 138.1, 137.5, 136.6, 128.7, 128.6, 128.0, 127.6, 126.8, 121.9, 119.3, 113.5, 109.7, 64.6, 52.1, 49.9, 42.5.
Infrared (nu~ol): 2954, 2855, 1734, 1453, 1443, 1333, 1208, 1176, 790, and 737 cm~l.
EI/MS (70eV): 384 (M+, 12.4), 325 (6.9), 235 (8.3), 220 (base), 129 (9.5), 91 (70.4).
Analysis: Calcd. for C25H24~2O2: C, 78.10; H, 6.29; N, 7.29.
Found: C, 77.79; H, 6.47, N, 7.24.
Example ~4 ~ethyl (+/-)-~ phenylmethyl-3-indolylmethyl~amlno-(3-trifluoromethylphenyl)acetate According to the general procedure described for the preparatlon of Example 31, (+/-)-3-trifluoromethyl phenylglyclne methyl ester (2.74 g, 11.~ mmol), l-ben7yl-indole-3-carboxaldehyde (1.38 g, 5.88 mmol) and NaBH3CN (0.48 g, 7.64 mmol) provided crude title compound as a cl0ar, pale yellow oil. The crude material was purlfied by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm o.d., ethyl acetate-hexanes 25:75, 400 mL fraetions) using the flash technique. Fractions 8-12 afforded 2.29 g (86%) of the title compound as a clear, pale yellow oil.
Physical character~stics are as follows:
TLC (Merck; EtOAc-hexanes, 50:50.
W (+); ~mmonium molybdate) Rf - 0.12.
lH-NMR: ~ - 7.00-7.70 (14), 5.26 ~s, 2), 4.53 (s, 1), 3.97 (d, .

J - 13.3Hz, 1), 3.92 (d, J - 13.3Hz, 1), 3.66 (5, 3), 2.31 (br, 1).
13C-NMR: ~ - 173.0, 139.7, 137.4, 136.7, 131.1, 130.5, 129.1, 128.7, 127.7, 127.0, 126.9, 124.9, 124.6, 122.0, 119.4, 119.2, 112.4, 109.8, 64.~, 52.4, 50.0, 42.6.
Infrared (CHC13): 3060, 3032, 2954, 2925, 1739, 1496, 1467, 1454, 1437, 1331, 1200, 1167, 1125, 1074, 812, 790, snd 742 cm~l.
EI/MS (70eV): 452 (M+, 20.7), 235 (10.6), 220 (base), 129 (16.8), 91 (96.6).
Analysis: Calcd. for C26H23F3N202: C, 69.02; H, 5.12; N, 6.19.
Found: C, 68.79: H, 5.19, N, 6.09.
Example 35 Methyl (R)-~-(3-indolylmethyl)amino-phenylacetate According to the general procedure described for the preparation of Example 31, methyl (R)-phenylglycinate-hydrochloride (2.50 g, 12.4 mmol), indole-3-carboxaldehyde (0.81 g, 6.2 mmol) and NaBH3CN
(0.51 g, 8.06 mmol) provlded crude title compound as a cloudy, pale brown oil. The crude material was purified by chromatography on a column of silica gel (230-400 mesh, 400 g, 70 mm o.d., packed-ethyl acetate-hexanes 10:90, ~luted ethyl acetate-hexanes (10:90 2 L), (20:80, 2 L), (30:70, 2 L), (40:60, 2 ~), (50:50, 2 L), (60:40, 2 L), 400 mL fractions) using the flash technique. Fractions 28-29 provided 0.19 g (10~) of the title compound as a tan solid, m.p.
115-118C.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 35:65.
W (+); ammonium molybdate) Rf 0.15.
lH-NMR: 6 - 8.20 (brs, 1), 7.65 (d, J - 7.7Hz, 1), 7.0-7.45 (9), 4.49 (8, 2), 3.94 (6, 2), 3.66 (8, 3), 2.16 (br, 1).
13C-NMR: ~ - 173.7, 138.1, 136.5, 128.7, 128.1, 127.7, 126.9, 122.9, 122.1, 119.6, 119.0, 114.0, 111.2, 64.6, 52.2, 42.6.
Infrared (CHC13): 2955, 2925, 2871, 2857, 1733, 1717, 1456, 1452, 1435, 1347, 1283, 1242, 1171, 1108, 1017, 838, 744, and 737 cm-l EI/MS (70eV): 294 (M+, 8.1), 235 (22.2), 130 (base), 106 (62.8).
Analysis: Calcd. for ClgHlgN2O2: C, 73.45; H, 6.16; N, 9.5~.
Found: C, 73.46; H, 6.37, N, 9.49.
Example 36 Methyl (S)-~-(3-indolylmethyl)amino-phenylacetate According to the general procedure described for the preparation of Example 31, methyl (S)-phPnylglycinate-hydrochloride (2.50 g, 12.4 ~.
.

s mmol)l indole-3-carboxaldehyde (0.81 g, 6.2 mmol) and NaBH3CN (0.51 g, 8.06 mmol) provided crude title compound as a cloudy, pale brown oil. The crude materlal was purified by chromatography on a column of silica ~el (230-400 mesh, 400 B. 70 mm o.d., packed-ethyl scetate-hexanes 30:70, eluted ethyl acetate-hexanes 40:60, 400 mL fractions) using the flash technique. Fractions 12-13 provided 0.13g (7~) of the title compound as a tan solid, m.p. 120C (dec.). Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 35:65.
W (+); ammonium molybdate) Rf - 0.15.
lH-~MR: ~ ~ 8.15 (brs, 1), 7.65 (d, J - 7.7Hz, 1), 7.0-7.45 (9), 4.49 (s, 2), 3.94 (s, 2), 3.67 (s, 3), 1.97 (br, 1).
13C-NMR: 6 - 173.5, 138.4, 136.5, 128.4, 127.8, 127.4, 126.7, 122.6, 121.9, 119.3, 118.8, 113.7, 110.9, 64.2, 51.8, 42.3.
Infrared (nu~ol): 295~, 2926, 2868, 2855, 1727, 1694, 1455, 1429, 1349, 1281, 1171, 1108, 1017, 834, and 743 cm~l.
EI/MS (70eV): 294 (M+, 5.7), 235 (21.8), 130 (base), 106 (77.6).
Analy~ Calcd. for ClgHlgN2O2: C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.43; H, 6.31, N, 9.60.
Example 37 Methyl t+~ -(l-phenylmethyl-5-methoxy-3-indolylme~h-yl)amino-(3-trifluoromethylph~nyl)acetate According to the general proc~dure described for the preparation of Example 31, ~+/-)-3-trifluoromethyl-phenylglycine methyl ester (2.66 ~, 11.4 mmol), 1-benzyl-5-methoxyindole-3-carboxaldehyde (1.00 g, 5.71 mmol) and NaBH3CN (0.47 g, 7.42 mmol) provided crude title compound as a clear, pale yellow oil. The crude material was purified by chrometography on a column of silica gPl ~230-400 mesh, 500 g, 70 mm o.d., ethyl acetate-hexanes 35:65, 400 mL fractions) using the flash technique. Fra~tions 4-5 afforded 1.22 g ~54%) of the title compound as a clear, viscous, pale yellow oil.
PhysLcal characteristics are as follows:
TLC (Merck; EtOAc-hexa~es, 35:65.
W (+); ammonium molybdate) Rf 0.35.
lH-NMR: ~ - 7.59 (s, 1), 7.57 (brt, J - 8Hz, 2), 7.45 (t, J -8Hz, 1), 7.27 (m, 3), 7.11 (m, 4), 7.00 (s, 1), 6.83 (dd, J - 8.8, 2.5Hz, 1), 5.23 (s, 2), 4.54 (s, 1), 3.91 (brs, 2), 3.84 (s, 3), 3.68 (s, 3).
13C-N~R: 6 172.7, 154.0, 139.3, 137.6, 132.2, 130.9, 128.9, ': , ' ~ ' ' . . .
:

128.6, 127.5, 126.7, 125.0, 124.6, 112.2, 110.5, 100.8, 63.9, 55.7, 52.3, 50.1, 42.6.
Infrared (CHC13): 2952, 2926, 2835, 1738, 1621, 1581, 1488, 1453, 1437, 1354, 1330, 1261, 1227. 1207, 1167, 1125, 1098, 1074, 1042, 796, 780, 736, and 702 cm~l.
EI/MS (70eV): 482 (M+, 22.9), 250 (base), 159 (16.2), 91 (86.1).
Analysis: Calcd. for C27H2sF3N203: C, 67.21; H, 5.22; N, 5-81-Found: C, 67.27; H, 5.30, N, 5.86.
10 ~ PlQ 38 Methyl-(~/-)-a-(5-methoxy-3-indolylmethyl)amino-(3-trifluoromethylphenyl)acetate According to the general procedure described for the preparation of Example 31, (t/-)-3-trifluoromethyl-phenylglycine methyl ester (5.99 g, 25.7 mmol), 5-methoxyindole-3-carboxaldehyde (1.50 g, 8.56 15 mmol) and NaBH3CN (0.70 g, 11.1 mmol) provided crude title compound as a clear, pale yellow oll. The crude material was purifled by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm o.d., packed cthyl acetate-hexanes 30:70, eluted ethyl acetate-hexanes 40:60, 400 mL fractions) uslng the flash technique. Fractions 20 5-8 afforded 2.50 g (74%) oi` the title compound as a clear, viscous, pale yellow oil.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 50:50.
W (+); a~monium molybdate) Rf - 0.35.
25 lH-NMR: ~ - 7.70 (s, 1), 7.57 (dd, J 10.0, 7.6Hz, 2), 7.45 (m, 2), 7.21 (d, J - 8.80Hz, 1), 7.21 (dd, J - 11.2, 2.46Hz, 1), 6 86 (dd, J - 8.80, 2.46Hz, 1), 4.54 (s, 1), 3.91 (s, 2), 3.84 (s, 3), 3.68(s, 3).
13C-NMR: ~ - 172.8, 154.0, 139.3, 131.4, 130.9, 129.O, 127.3, 30124.8, 124.4, 123.6, 122.3, 113.4, 112.5, 11$.8, 100.6, 63.9, 55.7, 52.3, 50.1, 42.7.

Infrared (CHC13): 3409, 2953, ~833, 1738, 16214, 1586, 1487, 1454, 1441, 1331, 1301, 1239, 1214, 1167, 1125, 1098, 1073, 1028, 922, 831, 800, and 703 cm~l.
35EI/MS (70eV): 392 (M-~, 7.2), 174 (9.3), 160 (base), 145 (12.1), 117 (10.5).
Analysis: Calcd- for C27H2sF3N2O3: 392.1348. Fo~nd: 392.1336.
Example 39 Methyl (R)-~-(l-phenylmethyl-5-methoxy-3-indolylmeth-`

~2a~

yl)amino-phenylacetate According to the general procedure described for the preparation of Example 31, methyl (R)-phenylglycinate-hydrochloride ~1.52 g, 7.54 mmol), l-benzyl-5-methoxy-indole-3-carboxaldehyde (1.00 8, 3.77 mmol) and NaBH3CN (0.31 g, 4.91 mmol) provided crude title compound as a pale yellow oil. The crude material was purified by chromatography on a column of silica gel (230-400 mesh, 500 g, 70 mm o.d., ethyl acetate-hexanes 35:65, 400 mL fractions) using the flaqh technique.
Fractions 6-10 provided 0.74 g (47~) of the title compound as a pale yellow, viscous oil.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 35:65.
W (~; ammonium molybdate) Rf ~ 0.27.
lH-NMR: ~ - 7.05-7.45 (12), 7.02 ~s, l), 6.82 (dd, J - 8.8, 15 2.5Hz, 1), 5.22 (s,2), 4.49 (5, 1), 3.90 (s, 2), 3.83 (s, 3~, 3.67 (s, 3), 2.08(br, 1).
13C-NMR: ~ - 173.6, 154.2, 138.3, 137.3, 132.0, 128.6, 128.5, 127.9, 127.5, 127.4, ~26.7, 112.3, 112.1, llO.~, lOO.9, 64.~, 55.
52.0, 50.1, 42.4.
Infrared (CHC13): 3030~ 2950, 2924, 1736, 1581, 1488, 1453, 1436, 1313, 1262, 1227, 1210, 1176, 1130, 1041, 1029, 796, 77~, 735, and 702 cm~l.
EI/MS (70eV): 414 (N+, 18.0), 250 ~base), 91 (63.5).
Analy8i8: Calcd. for C26H26N2O3: C, 75.34; H, 6.32; N, 6.76.
25 Found: C, 75.12; H, 6.48, N, 6.78.
Example 40 Methyl-(S)-a-(l-phenylmethyl-5-methoxy-3-indolyl-m0thyl)amino-phenylacetate According to the general procedure described for the preparation of Example 31, methyl (S)-phenylglycinate-hydrochloride (3.04 g, 15.1 30 ~mol), 1-benzyl-5-methoxy-lndole-3-carboxaldehyde (2.00 g, 7.54 mmol) and NaBH3CN (0.62 g, 9.80 mmol) provided crude title compound as a pale yellow oil. The crude material ~as purified by chromatography on A column of slllca gel (230-400 mesh, 500 g, 70 mm o.d., packed ethyl acetate-hexanes 25:75, eluted ethyl ace~ate-hexanes 30:70, 400 mL fractions) using the flash technique. Fractlons 8-14 provided 2.18 g (70~) of the title compound as a pale yellow, viscous oil.
Physical characteristics are as follows:
TLC (Merck; EtOAc-hexanes, 50:50.

2~

W (~); ammonium molybdate) Rf - 0.42.
lH-NMR: ~ 7.05-7.45 (12), 7.02 (s, 1), 6.82 (dd, J - 8.8, 2.5H~, 1), 5.21 (s,2), 4.49 (s, 1), 3.90 (s, 2), 3.83 (s, 3), 3.66 (s, 3), 2.23 (br, 1).
13C-NMR: ~ - 173.5, 153.8, 138.2, 137.5, 132.0, 128.6, 128.5, 127.9, 127.6, 127.5, 126.7, 112.7, 112.1, 110.4, 100.9, 64.4, 55.7, 52.1, 50.0, 42.5.
Infrared (CHC13): 3030, 2950, 2925, 1735, 1581, 1488, 1453, 1436, 1313, 1262, 1227, 1209, 1176, 1130, 1042, 1029, 796, 778, 735, and 700 cm~l.
EI/MS (70eV): 414 (M~, 15.5), 250 (base), 91 (63.5).
Analysis: Calcd. for C26H26N2O3: C, 75.34; H, 6.32; N, 6.76.
Found: C, 75.06; H, 6.22, N, 6.80.
The compounds of this inYention are useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents. While all of the compounds do not have all of the activities the utility of a particular compound can be determined by one skilled in the art utilizing the various eests. -Anti-diabetic A. Testin~ For Blood Glucose Lowerin~ In the KKRY_~Q~
All KKAY mice used for screening are produced and select~d by methods outlined by T. Fu~ita et al., Diabetes, 32, pp. 804-10 (1983). The screening is done in groups of six animals per group.
Pre-treat~ent non-fasting blood glucose (NFBG3 sample~- ~re--~
measured five days prior to the start of a screening run bypreviously dsscribed methodologie~. Thsse blood sugar values are used to place animals into groups with equal mean blood glucose concentrations and to ellminate any mice with a NFBG value <250 mg/dl. On day 0, compounds ~hosen to be run are incorporated into ground mouse chow (Purina 5015). Compounds are included at ~ rate of 1 mg/gram of chow. Generally, 300 g of drugs con~aining diet is prepared for each group. Mice receivin~ ground chow only are the negative control.
Each screening run also uses ciglitazone (T. Fu~ita ct al., supra) as a positlve control (0.5 to 1.O mg/gram chow).
Initial body and food weights are taken on day one. Food is placed in a crock which contains an adequate amount to last for the length of the study. In order to acclimate the mice from pelleted '~ ' : . , . ' , s -~9-mouse chow to ground mouse chow, they are fed the ground chow for nine days prior to use in the screen. On day four of treatment, a NFBG sample is again measured, as well as food and body weights.
Food consumption measurements are used to determine an average mg/kg dose the mice received over the testing period, and to evaluate the compound's effect on food consumption.
Acceptance and activity are determined by the following criteria:
A. Negative Control This group must not ~how a significant change (p<.05) from pre- to post-treatment. If there is a significant decrease in blood sugar, the run is not valid.
B. Positive Control This group must show a significant depression in blood sugar mean levels from pre- to post-treatment. A lack of activity in this group would also invalidate the run.
C. Negative Control vs. Positive Control Thi~ contrast ~st be significant. It is a further assurance th~t both control groups performed as expected.
D. Compound A compound's activity is based on several criteria:
1. A significant decrease in blood sugar mean levels from pre- to post-treatment.
2. Negative control vs. compound: This contrast allows one to determine if these groups are dissimilar, which is required for the compound to be considered active.
II. Anti-obesitv Activity --Up~ohn Sprague-Dawley rats are housed individually and given food and water ad libitum. Food consumption is m~asured daily. The animals are orally dosed with 100 mg~kg or 200 mg/kg of the compound in Tween 80. Controls receive an equivalent volume Df Tween 80. If the daily food consumption of the treated animal~ is ln the range-of 4 gr~ms less than that o~ the control animal~ the compound is con--sidered to have anorexic activity.
III. Anti-atherosclerotic activity Normocholesterolemic Ouail Lipoprotein Test Male SEA Japanese quail, approximately four to six weeks of age are used from a colony of animals originally derived at The Up~ohn .

Company. Prior to drug ~esting, birds are randomly distributed into 10-15 groups of 10 quail each. They are housed individually in 10-cage units and fed a commercial diet (Purina Game Bird Layena, Ralston Purina Co., St. Louls, M0) for seven days. Compounds (0.5 g S for 50 mg/kg dose, 0.15 g for 15 mg/kg dose, 0.05 g for 5 mg/kg dose, etc.) are dlssolved or dispersed ln 50 mL of 954 ethanol and mlxed wlth 1.2 kg of the dlot. Control groups receive dlet mixed with ethanol alone, and positive control groups receive diet mixed with 1-propyl-2(1H)-pyrldlnone at 50 mg/kg.
After one week on the dlets, each blrd ls bled from the right jugular vein and serum samples are obtalned after low speed centri-fugation. Food intake ls dete~mlned for each group by subtracting the welght of dlet remalnlng at the end of the experiment from the welght of the startlng dlet.
~eta- ~nd alpha-lipoprotelns are i~olated from indlvidual serum sampl3s using PEG-8000 and glycine buffer, pH 9. Three hundred microliter~ of serum are mlxed with 300 ~icroliters of solution A (20 gram of PEG-8000 ~ loo ~L of glycina buffer, pH 9) using a Micromedic automatic pipett~. Samplqs are allowed to stand at room te~perature 20 for 10 minutes and are centrifug~d for 20 minute~ at 2000 x g at 4C.
The beta-lipoprotein pellet is dissolved in 300 mlcroliters of solution B (10 mL Triton X-100 ~ 1000 ~L Milll Q water~. Choles-terol, triglycerldes and total protein in alpha- and beta-lipo-proteins ar~ measured uslng the ~emand Autoanalyæer system Model AU
500 (Cooper Blomedicnl Inc.) and Worehington Demand Enzymatic reagsnts (Pearson, G.W. et al, Biometrika 38, (1951) pp. 112-130).
All data is statistlcally ~nalyzed using a one-way classifi-cation de ign. All value~ are transfor~ed to logarithms to achieve more homogenous within-group variances. The mean response for each test compound is comp~red wlth the mean observed in the control animals by the LSD test (Snedecor, G.W. et al (1969), Statistical Methods, ISV Press, A~es, Iowa, pp. 258-296). Treatsd/control ratios of antilogs of the log means are presented. A P-value less than 0.004 is significantly different from control.
Compounds that reduce beta-lipoproteins and/or increase alpha-lipoproteins are considered to be lndicative of anti-atherosclerotic activity .

. . . :

~2~

KKay Mouse Single Body Ueight Insulin Dose in Change in Name Sensitizing KKAy KKAy mouse d Screen Mouse c 1st 2nd S1ngle Normal Normal 1st 2nd (50 mg/ Stage Dose Quail e Rat e Stage a~Stage b kg) HDL LDL HDL LDL
1 + + 1 t 3 + ~ ~
4 + + + I ~ t t ~ t t +

15 7 + + ~ t 8 + + ~ ~ t 9 + + ~ ~ t +
11 + ~ t 2012 + t `

16 + ~ ~ I

18 +

19 +
+ t 3022 +
23 ~, 24 +

35 27 +
28 + ~, 2~ ~ ~
+ + ~ I
31 + +
4032 ~, ... ~ . ~ . ... .............. ..

:
``

-7~-33 -t 34 +
+
36 +
5 37 -~
39 +
39 +
+

43 +
44 +
46 +
15 47 +
~9 a + si~nifios a T/C value of 0.85 or lower.
- signified a T/C value of 0.85 or higher.
b + signified a T/C stage 1 x T/C stage 2 value of 0.61 or lower.
- signifies a T/C stage 1 x T/C stage 2 ~alue of 0.62 or higher.
c ~ signifies a significant lowering of blood glucose compared to non-treated control animals.
signifies a modest lowering of blood glucose compared to non-treated control anlmals.
- qignifles no change or an increase of blood glucose compared to non-treated control animals.
30 d t signifies an increase in body weight from before treat~ent to after treatment.
signifies a decrease in body weight from before treatment to after treatment.
e t si~nifies an increase in HDL or IDL compared to non-treated control animals.
signifies a decrease in HDL or LDL compared to non-treated control animals.
signifies no change in HDL or LDL compared to non-treated ~, :, control animals.
KEY TO NAME OF COMPOUND:
l. Methyl ~-aminoindole-3-acetate 2. Methyl ~-[(2-(4-aminosulfonylphenyl)-ethylamino]-indole-3-acetate hydrste (1:1) 3. Methyl ~-[3-(trifluoromethyl)benzylamino]-5-methoxyindole-3-acetate 4. ~-[3-(Trifluoromethyl)benzylamino]-l-benzylindole-3-acetic acid 5. ~-[3-(Trifluoromethyl)benzylamino]-l benzylindole-3-acetic acid hydrochloride 6. Sodium ~-[3-(trifluoromethyl)benzyl-amino]-1-benzylindole-3-acetate 7. Methyl ~-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate hydrochloride 8. ~-[3-(Trifluoromethyl)benæylamino]-l-methylindole-3-acetic acid 9. ~-Benzyl&mino-l-benzylindole-3-acetic acid 10. ~-(4-Chlorobenzylamino)-l-benzylindole-3-acetic acid 11. ~-[(3-Pyridinylmethyl)~mino-l-bonzylindole-3-acetic acid 12. ~-(4-Methoxybenzylamino)-l-benzylindole-3-acetic acid 13. ~-[(4-Phenylbutyl)amino]-l-benzylindole-3-acetic acid 14. ~-[(S)-~-methylbenzylamino]-l-benzylindole-3-acetic acid -15. ~-[3-(Trifluoromethyl)benzylamino]-1-(4-chlorobenzyl)-indole-3-acet$c acid 16. ~-[3-~Trifluoromethyl)benzylamino]-l-phenylindole-3-acetic acid 17. N-Benzyl-l-benzyltryptophan hydrate (l:l) 18. N-Benzyl-l-benzyltryptophan methyl ester 19. N-[3-(Trifluoromethyl)benzyl]-l-benzyltryptophan methyl ester hydrochloride 20. ~-[(2-Phenylethyl)amino]-l-benzylindole-3-acetic acid hydrate (1:1) 21. ~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-2-phenylindole-3-acetic acid 22. ~-[3-(Trifluoromethyl)benzylamino]-l-benzyl-5-methoxyindole-3-acetic acid 5 23. ~-(N-Methylbenzylamino)-l-benzylindole-3-acetic acid hydrate (4:1) 24. ~-[3-~Trifluoromethyl)benzylamino]-l-benzyl-5-chloroindole-3-acetic acid 4~i 25. Methyl ~-[3-(trifluoromethyl)benzylaminO]-l-methyl-2-methyl-indole-3-acetate hydrochloride 26. Methyl ~-[3-(trifluoromethyl)benzylamino]-1-benzyl-2-methyl-indole-3-~cetate hydrochloride 27. ~-[3-(Trifluoromethyl)benzylamino]-l-allylindole-3-acetic acid 28. Ethyl-~-[3-(trifluoromethyl)b~nzylamino]-1-benzylindole-3-acetate hydrochloride 29. Methyl ~-[N-methyl-3-(trifluoromethyl)benzylamino]-1-benzyl-indole-3-acetate hydrochloride 30. ~-[3~(Trifluoromethyl)benzylamino]indole-3-acetic acid 31. Ethyl ~-[3-(Trifluoromethyl)bcnzylamino]-indole-3-acetate 32. Ethyl ~-[3-Trifluoromethyl)benzylamino]-indole-3-acetate hydrochloride 33. Benzyl ~-[3-(Trifluoromethyl)benzylamlno]-l-benzylindole-3-acetate hydrochloride 34. Ethyl ~-[3-(trifluoromethyl)banzylamino]-1-ethoxycarbonylindole-3-acatat~ hydrochloride 35. ~-[4-(Trifluoro~ethyl)benzylamino~-l-bcnzylindol~-3acetic acid ~6. ~-[3,5-bis(Trifluoromethyl)benzyl~mino]-l-benzylindole-3-ac~tic acid 37. ~-(4-M~thylbenzyl&mino)-l-benzyli~dole-3-acetic acid 38. ~-[(2-Furylmethyl)amino]-l-benzylindole-3-acetic acid 39. ~-[(2-Thienylmethyl)amino]-l-benzylindole-3-ac~tic ~cid 40. ~-(3,4-Dichlorobenzylamino)-l-be~zyllndole-3-acetlc acid 41. Methyl ~-[3-(t~ifluoromethyl)benzylamlno]-indole-3-acetate hydrochloride 42. 4'-Phenylphenacyl -[3-(trifluoromethyl)benzyla~ino]-1-benzyl-indolc-3-acetate 43. 3,4,5-Trimethoxybenzyl ~-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate hydrochloride 44. ~-(3-Fluorobenzylamino)-l-benzylindole-3-acetic acid 45. ~-[3-(Trifluoromethyl)benzyl~mino)-l-benzyl-5-methylindole-3-acetic acid 46. ~-[3-(Trifluoromethyl)benzylamino)-l-benzyl-5-fluoroindole-3-acetic acid 47. Ethyl~-[3-(trifluoromethyl)benzylamino]-1-acetylindole-3-acetate 49. Ethylo-[3-(trifluoromethyl)benzylamino]-1-benzoylindole-3-- ~
,~
.

:

acetate - 7 ~ -CHART I

,~
(R5)a + ll ll + NH(R2)(R3) + R6C(O)CO2H H20 ~/\ N~ R

(Rs)a~cR6N(R2) (R3)C02H

2~ Rl 4~

CHART I I

~ + NH(R2) (R3) + R6C(O)CO2R8 (R5)a~3~ ~R

~CR6N(R2) (E~3)C02R8 (R5 ) a ~,JI~ Nl R

.

CHART I I I

(R5)a~ Rl + H N/
R

CH2 ~NH--1~2 /

(R5)a~R

I' : - ; , `' ' ' ~ ,~

Claims (15)

1. A compound of Formula I

I

wherein R is (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkenyl, (d) C3-C10 alkynyl, (e) phenyl, (f) -C(R6)H-phenyl(-R5)b, (g) -SO2-phenyl(-R5)b, (h) -C(O)R1, (i) -C(O)OR9, (j) - (CH2)qN(R7)(R8), (k) -C(O)N(R7)(R8), (l) -(CH2)m Het, (m) -CH2C(O)R4, (n) -(CH2)mO(CH2)mCH3, (o) -CH2-(C3-C6)cycloalkyl, (p) -C3-C8 cycloalkyl, wherein a is 1 to 4, b is 1 to 5, m is 1 or 2, n is 0 or 1, p is 4 or 5, q is 2 or 3, wherein M is a pharmacologically acceptable cation;
wherein R1 is (a) hydrogen, (b) C1-C10 alkyl, (c) C2-C10 alkenyl, (d) C2-C10 alkynyl, (e) -phenyl(-R5)b, (f) -CH2-phenyl(-R5)b;
wherein R2 is (a) -CH(R6)-phenyl-(R5)b;
(b) -CH2- Het, (c) C1-C6 alkyl, (d) (CH2)b-phenyl-(R5)b, wherein het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms (nitrogen, oxygen, sulfur);
and including any bicyclic group in which any of the above hetero-cyclic rings is fused to a benzene ring or another heterocycle;
wherein R3 is (a) hydrogen, (b) -C(O)R1, (C) -C(O)OR1, (d) -CH2)b-phenyl(-R5)b wherein R4 is (a) hydrogen, (b) -C(O)R9 wherein R5 same or different is (a) hydrogen, (b) halogen, (c) hydroxy, (d) C1-C10 alkoxy, (e) C3-C10 alkenyloxy, (f) C3-C10 alkynyloxy, (g) nitro, (h) amino, (i) -N(R6)(R7), (j) -NHC(O)R1, (k) -OC(O)R1, (l) -C(O)R1, (m) trifluoromethyl, (n) -SO2N(R6)(R7), (o) - SR8, (p) -C=N, (q) -C(O)OR6, (r) -C1-C4 alkyl, (s) phenyl, (t) -O-CH2-O, wherein R6 is (a) hydrogen, (b) C1-C10 alkyl, (C) -C(O)OR1, (d) phenyl wherein R7 is (a) hydrogen, (b) C1-C10 alkyl, wherein R8 is (a) hydrogen, (b) C1-C10 alkyl, (c) C3-C10 alkenyl, (d) C3-C10 alkynyl, (e) phenyl-(R5)b, (f) -CH2-PhenYl-(R5)b, (g) CH2-het, and wherein R9 is (a) hydrogen, (b) hydroxy, (c) OM, (d) -OR8, (e) -N(R6)(R7), (f) phenyl, and pharmacologically acceptable salts of compounds wherein R9 is not OM; with the proviso that when n is O; R2 is benzyl, substituted benzyl or alkyl substituted benzyl; R is hydrogen, benzyl or substituted benzyl; R1 is hydrogen or methyl; R3 is hydrogen or methyl; R5 is hydrogen, benzyloxy or methoxy; and R6 is hydrogen, then R4 cannot be benzyloxycarbonyl, ethoxycarbonyl, or C(O)OM;
with the further proviso that when n is 1; R is hydrogen or methyl; R1 is hydrogen; R2 is benzyl; R3 is hydrogen; R5 is hydrogen;
and R6 is hydrogen, then R4 cannot be carboxyl or methoxycarbonyl;
with the further proviso that when n is O; R is hydrogsn or 4-substituted benzyl; R1 is hydrogen or methyl; R2 is C1-C4 alkyl; R3 is hydrogen or C1-C2 alkyl; R5 is hydrogen, methoxy, or benzyloxy;
and R6 is hydrogen, then R4 cannot be ethoxycarbonyl, carboxyl, or propoxycarbonyl;
with the further proviso that the compound of Formula I is not:
Methyl .alpha.-[N-methyl-N-3-(trifluoromethyl)benzylamino]-1-benzyl-indole-3-acetate, Methyl .alpha.-[N-methyl-N-3-(trifluoromethyl)benzylamino]-1-benzyl-indole-3-acetate hydrochloride, .alpha.-[N-methyl-N-3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid, Methyl .alpha.-[3-(trifluoromethyl)benzylamino]indole-3-acetate hydro-chloride, Ethyl .alpha.-[3-(trifluoromethyl)benzylamino]indole-3-acetate hydro-chloride, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid p-phenylphenscyl ester, .alpha.- [3-(Trifluoronethyl)benzylamlno]-1-benzylindole-3-acetic acid 1-methyl-3-butenyl ester,

2-[3-(Trifluoromethyl)benzylamino]-2-(1-benzyl-3-indolyl)ethanol, Methyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-acetoxymethylindole-

3-acetate, Methyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-acetoxymethylindole-3-acetate hydrochloride, Methyl .alpha.-(benzylamino)-indole-3-acetate, .alpha.-(Phenylpropylamino)-1-benzylindole-3-acetic acid, Methyl .alpha.-[4-(aminosulfonyl)phenylethylamino]-indole-3-acetate, .alpha.-Methylamino-1-benzylindole-3-acetic acid, .alpha.-(Phenylethylamino)-1-benzylindole-3-acetic acid, .alpha.-[4-(Aminosulfonyl)phenylethylamino]-1-benzylindsle-3-acetic acid, .alpha.-[(Tetrahydro-2-furanyl)methylamino]-1-benzylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid N,N-dimethylamide, Ethyl .alpha.-[3-(trifluoromethyl)benzylamino]-indole-3-acetate, .alpha.-[(2-Furylmethyl)amino]-indole-3-acetic acid, .alpha.-Benzylamino-indole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid amide, .alpha.-[4-(Methoxycarbonyl)benzylamino]-1-benzylindole-3-acetic acid, Methyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-acetoxymethylindole-3-acetate, Methyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-acetoxymethylindole-3-acetate hydrochloride.

2. A compound according to claim 1 having the formula wherein R, R1, R2, R5 and R9 are the same as in claim 1.

3 A compound according to claim 2 wherein R is hydrogen or benzyl, R1 is hydrogen, R2 is trifluoromethylbenzyl or furylmethyl and R9 is selected from the group consisting of hydroxy, OR8 and OM wherein R8 is C1-C10 alkyl and M is a pharmacologically acceptable cation.

4. A compound according to claim 3 wherein R2 is trifluoromethyl-benzyl.

5. A compound according to claim 4 selected from the group consisting of Methyl .alpha.-[3-(trifluoromethyl)benzylamino]-5-methoxyindole-3-acetate, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid hydrochloride, Sodium .alpha.-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate, Methyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate hydrochloride, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-phenylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-methoxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-chloroindole-3-acetic acid, Ethyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate, Ethyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate oxalate (1:1), Ethyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate hydrochloride, .alpha.- [3-(Trifluoromethyl)benzylamino]-indole-3-acetic acid, Ethyl .alpha.-[3-(Trifluoromethyl)-benzylamino]-indole-3-acetate, .alpha.-[3-(Trifluoromethyl)benzylamino)-1-benzyl-5-methylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzyl-amino]-1-benzyl-5-methoxy-6-methylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5,6-methylene-dioxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-methoxy-6-iso-propylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-methoxy-4-methyl-indole-3-acetic acid, .alpha.-13-(Trifluoromethyl)benzylamino]-1-benzyl-5-methoxy-6-chloro-indole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-6-methylindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5,6-dimethoxy-indole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzyl mino]-1-benzyl-5-methoxy-7-methyl-indole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-6-methoxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-acetoxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-hydroxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-ethoxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-benzyloxyindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzyl-5-methoxyindole-3-acetic acid, Ethyl .alpha.-[3-(trifluoromethyl)benzylamino]-1-benzylindole-3-acetate maleic acid salt, .alpha.-[3-(Trifluoromethyl)benzylamino]-indole-3-acetate hydro-chloride, .alpha.-[3-(Trifluoromethyl)benzylzmino]-1-benzyl-5-fluoroindole-3-acetic acid, .alpha.-[3-(Trifluoromethyl)benzylamino]-1-benzylindole-3-acetic acid 1-methyl-3-butenyl ester.

6. A compound according to claim 5, .alpha.-[3-trifluoromethyl)benzyl-amino]-1-benzylindole-5-methoxyindole-3-acetic acid.

7. A compound according to claim 5, .alpha.-[3-(trifluoromethyl)benzyl-amino]-indole-3-acetic acid.

8. A compound according to claim 5, methyl .alpha.-[3-(trifluoromethyl)-benzylamino]-1-benzylindole-3-acetate hydrochloride.

9. A compound according to claim 3, wherein R2 is furylmethyl.

10. A compound according to claim 9, .alpha.-[(2-furylmethyl)amino]-1-benzylindole-3-acetic acid.

11. A compound according to claim 2 selected from the group consisting of .alpha.-Benzylamino-1-benzylindole-3-acetic acid, .alpha.-[(3-Pyridinylmethyl)amino-1-benzylindole-3-acetic acid, .alpha.-(4-Methoxybenzylamino)-1-benzylindole-3-acetic acid, .alpha.-[(Phenylbutyl)amino]-1-benzylindole-3-acetic acid, .alpha.-[(S)-.alpha.-methylbenzylamino]-1-benzylindole-3-acetic acid, .alpha.-(N-Methylbenzylamino)-1-benzylindole-3-acetic acid hydrate (4:1), .alpha.-(3-Chlorobenzylamino)-1-benzylindole-3-acetic acid, .alpha.-(2-Chlorobenzylamino)-1-benzylindole-3-acetic acid, .alpha.-[(2-Thienylmethyl)amino]-1-benzylindole-3-acetic acid, .alpha.-(3-Fluorobenzylamino)-1-benzylindole-3-acetic acid, .alpha.-(4-Fluorobenzylamino-1-benzylindole-3-acetic acid, .alpha.-(3-Methoxybenzylamino-1-benzylindole-3-acetic acid, .alpha.-(3-Methylbenzylamino)-1-benzylindole-3-acetic acid, .alpha.-(3,4-Dichlorobenzylamino)-1-benzylindole-3-acetic acid .alpha.-(Diphenylmethylamino)-indola-3-acetic acid hydrate (1:0:7).

12. A compound according to claim 1 having the formula wherein R, R1, R2, R3, R4, R5 and R6 are the same as in claim 1.

13. A compound according to claim 12 selected from the group consisting of N-Benzyl-1-benzyltryptophan hydrate (1:1), N-Benzyl-1-benæyltryptophan methyl ester, N-(Dibenzyl)-1-benzyltryptophan methyl ester, N-[3-(Trifluoromethyl)benzyl]-1-benzyltryptophan hydrate (1:1), N-[3-(Trifluoromethyl)benzyl]-1-benzyltryptophan methyl ester, N-[3-(Trifluoromethyl)benzyl-1-benzyltryptophan methyl ester hydrochloride, N-(Isopropyl)-1-benzyltryptophan methyl ester, N-(Isopropyl)-1-benzyltryptophan methyl ester hydrochloride, 1-phenylmethyl-N-3-(trifluoromethyl)phenylmethyl-L-tryptophan methyl ester, DL-methyl-1-(phenylmethyl)-tryptophan-methyl ester monohydro-chloride, DL-N-1-bis(phenylmethyl)-tryptophan-methyl ester, DL-1-(phenylmethyl)-tryptophan-N-[[3-(trifluoromethyl)phenyl]-methyl]methyl ester, DL-N-(1-methylethyl)-tryptophan-1-(phenylmethyl)methyl ester, DL-N-(1-methylethyl)-1-(phenylmethyl)-tryptophan-methyl ester, monohydrochloride, DL-1-(phenylmethyl)-N-[[[3-(trifluoromethyl)phenyl]methyl]-tryptophan-methyl ester, monohydrochloride, DL-N-1-bis(phenylmethyl)-tryptophan, DL-1-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan, DL-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan methyl ester, DL-1-p(4-chlorophenyl)methyl]-N-[[3-(trifluoromethyl)phenyl]-methyl-tryptophan methyl ester, DL-1-[(4-chlorophenyl)methyl]-N-[[3-(trifluoromethyl)phenyl]-methyl]-tryptophan methyl ester, DL-N-[[(3-(trifluoromethyl)phenyl]methyl]-tryptophan methyl ester, monohydrochloride, DL-[(ethylthio)cArbonyl]-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan, DL-1-[ethylthiocsrbonyl]-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan monohydochloride, DL-1-(ethoxycarbonyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan methyl ester, DL-1-(ethoxycarbonyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan methyl ester, monohydrochloride, DL-N-[[3-(trifluoromethyl)phenyl]methyl]tryptophan, D-1-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan methyl ester, D-1-(phenylmethyl)-N-[[3-(trifluoromethyl)phenyl]methyl]-tryptophan-methyl ester monohydrochloride, (D,L)-1-ethylthiocarboxy-N-(3-(trlfluoromethyl)phenyl)methyl-tryptophan methyl ester, (D,L)-1-ethylthiocarboxy-N-(3-(trifluoromethyl)phenyl)methyl-tryptophan methyl ester HC1,

14. A compound according to claim 1 having the formula I
wherein R, R1, R2 and R5 are the same as in claim 1.

15. A compound according to claim 14 selected from the group of Methyl (+)-.alpha.-(1-phenylmethyl-3-indolylmethyl)amino-phenyl-acetate, Methyl (R)-.alpha.-(1-phenylmethyl-3-indolylmethyl)amino-phenyl-acetate, Methyl (S)-.alpha.-(1-phenylmethyl-3-indolylmethyl)amino-phwnyl-acetate, Methyl (+)-.alpha.-(1-phenylmethyl-3-indolylmethyl)amino-(3-tri-fluoromethylphenyl)acetate, Methyl (R)-.alpha.-(3-indolylmethyl)amino-phenylacetate, Methyl (S)-.alpha.-(3-indolylmethyl)amino-phenylacetate, Methyl (+)-.alpha.-(1-phenylmethyl-5-methoxy-3-indolylmethyl)amino-(3-trifluoromethylphenyl)acetate, Methyl (+)-.alpha.-(5-methoxy-3-indolylmethyl)amino-(3-trifluoro-methylphenyl)acetate, Methyl (R)-.alpha.-(1-phenylmethyl-5-methoxy-3-indolylmethyl)amino-phenylacetate, and Methyl (S)-.alpha.-(1-phenylmethyl-5-methoxy-3-indolylmethyl)amino-phenylacetate.