SK154299A3 - N-triazolyl-2-indolecarboxamides and their use as cck-a agonists - Google Patents

Abstract

The invention concerns compounds of formula (I) in which R1, R4, X1, X2, X3, X4, Y1, Y2 and Y3 are as defined in claim 1. These compounds have partial or total agonist activity of CCK-A receptors and are useful for treating eating problems, obesity, tardive dyskinesia and disorders of the gastrointestinal sphere.

Description

N-Triazolyl-2-indolecarboxamides and their use as CCK-A receptor agonists

Technical field

The invention relates to novel triazole derivatives, to a process for their preparation and to medicaments containing them. In particular, the invention relates to novel non-peptide compounds which have an affinity for cholecystokinin (CCK) receptors.

BACKGROUND OF THE INVENTION

CCK is a peptide that is secreted at the peripheral level in response to food digestion and is involved in the regulation of many digestive processes (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735).

Cholecystokinin was later identified in the brain and could be the most commonly occurring neuropeptide acting as a neuromodulator of brain function by a mechanism of stimulating CCK-B receptors (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735). In the central nervous system, cholecystokinin interacts with dopamine-mediated neuronal transmission (Crawley J. N. et al., Isis Atlas of Sci., Pharmac., 1988, 84-90). Cholecystokinin has also been implicated in mechanisms including acetylcholine, gaba (4-aminobutyric acid), serotonin, opioids, somatostatin and substance P, as well as in ion channels.

The administration of cholecystokinin induces physiological responses, including palpebral ptosis, hypothermia, hyperglycemia and catalepsy, as well as behavioral modifications, including decreased locomotion ability, limited exploration capacity, analgesia, modification of learning ability and modification of sexual behavior and satiety.

Cholecystokinin exerts its biological activity through at least two types of receptors, which are receptors

CCK-A localized mainly at the peripheral level, and CCK-B receptors present predominantly in the cerebral cortex. Peripheral type CCK-A receptors are also present in certain central nervous system zones, including the postrema region, the solitary tract nucleus, and the interpedoncular nucleus (Moran T. H. et al., Brain Research,

1986, 362, 175-179; Hill DR et al., J. Neurosci., 1990, 10, 1070-1081), but there are specific differences (Hill DR et al., J. Neurosci., 1990, 10, 1070-1081; Mailleux P. et al., Neurosci. Lett., 1990, 177, 243-247; Barrett RW et al., Mol Pharmacol., 1989, 36, 285-290; Mercer JG et al., Neurosci. Lett., 1992, 137 Moran TH et al., Trends in Pharmacol. Sci., 1991, 12, 232-236).

At the peripheral level, cholecystokinin slows gastrointestinal emptying, modulates intestinal motility, increases bile secretion, and regulates pancreatic secretion (Mc Hugh PR et al., CCM-A receptors (Moran TH et al., Brain Research, 1986, 362, 175-179)). , Fed. Proc., 1986, 45, 1384-1390; Pendleton RG et al., J. Pharmacol. Exp. Ther.

1987, 241,110-116).

Cholecystokinin could in some cases act on arterial pressure and affect immune systems.

The role of cholecystokinin in satiety signaling is supported by the fact that plasma concentrations of cholecystokinin, which depend on food composition (high protein or lipid concentrations), are above mealtime concentrations of cholecystokinin (Izzo RS et al., Regul. Pept. 1984, 9, 21-24; Pfeiffer A. et al., Eur J. Clin Invest., 1993, 23, 57-62; Lieverse RJ, Gut, 1994, 35, 501). Bul persons suffering from bulimia reduce the excretion of food-induced cholecystokinin (Geraciotti TD Jr. et al., N. Engl. J. Med., 1988, 319, 683-688; Devlin MJ et al., Am J. Clin. Nutr., 1997, 65, 114-120), and a decrease in the concentration of cholecystokinin in the cerebrospinal fluid (Lydiard RB et al., Am. J. Psychiatry, 1993, 150, 1099-1101). In T lymphocytes, a cell compartment capable of indicating central neuronal secretions, basal cholecystokinin concentrations are significantly lower in patients suffering from the diagnosis of Bulimia nervosa (Brambilla F. et al., Psychiatry Research, 1995, 37, 51-56).

Treatments (e.g., L-phenylalanine or trypsin inhibitors) that increase secretion of endogenous cholecystokinin induce a reduction in food intake in certain animal species including humans (Hill. AJ et al., Physiol. Behav., 1990, 48, 241-246; Ballinger AB et al., Metabolism, 1994, 43, 735-738). Similarly, administration of exogenous cholecystokinin reduces the need for food intake in many animal species including humans (Crawley J. N. et al., Peptides, 1994, 15, 731-735).

Said cholecystokinin inhibition of food intake is mediated by the CCK-A receptor. In fact, devazepide, which is a selective antagonist of CCK-A receptors, inhibits the anorexigenic effect of CCK, while selective agonists of said receptors, in turn, inhibit the need for food (Asin KE et al., Pharmacol. Biochem. Behav., 1992, 42, 699 Elliott RL et al., J. Med. Chem., 1994, 37, 309-313; Elliott RL et al., J. Med. Chem., 1994, 37, 1562-1568). In addition, Oleft rats that do not express CCK-A receptors are insensitive to the anorexigenic effect of cholecystokinin (Miyasaka K. et al., 1994, 180, 143-146).

In view of the above evidence suggesting a key role for cholecystokinin in peripheral satiety signaling, the utility of cholecystokinin agonists and antagonists as drugs in the treatment of certain digestive disorders, obesity and diabetes seems to be undeniable. The cholecystokinin receptor agonist can also be used therapeutically in the treatment of emotional, sexual and amnesia behavior disorders (Itoh S. et al., Drug Develop. Res., 1990, 21, 257-276), schizophrenia, psychoses (Crawley JN et al. , Isis Atlas of Sci., Pharmac., 1988, 84-90; Crawley JN, Trends in Pharmacol. Sci., 1991, 12, 232-265), Parkinson's Disease (Bednar I. et al., Biogenic Amine, 1996 12 (4), 275-284), late dyskinesia (Nishikawa T. et al., Prog. Neuropsychopharmacol. Biol. Psych., 1988, 12, 803-812; Kampen JV et al., Eur. J. Pharmacol. .

1996, 298, 7-15) and various disorders of the gastrointestinal sphere (Drugs of the Future, 1992, 17 (3), 197-206).

Cholecystokinin CCK-A receptor agonists are described in the literature. For example, some products with these properties are described in EP 383690, WO 90/06937, WO 95/28419, WO 96/11701 and WO 96/11940.

Most of the CCK-A receptor agonists described to date have a peptide character. Thus, FPL 14294 is derived from CCK-7 by a potent CCK-A agonist that is non-selective for CCK-B receptors. This derivative has potent inhibitory capacity against intake of rat and dog in intranasal administration (Simmons RD et al., Pharmacol. Biochem. Behav., 1994, 47 (3), 701-708; Kaiser EF et al., Faseb (1991, 5, A864). It has also been shown that A 71623, which is a tetrapeptide selective agonist of CCK-A receptors, is effective in anorexia models over a period of 11 days and causes a significant reduction in weight gain relative to the control group in rodents and cynomologous monkeys (Asin KE et al. Pharmacol. Biochem. Behav., 1992, 42,

699-704). Likewise, the structural analogues of product A 71623, which have good potency and selectivity to CCK-A receptors, are characterized by marked anorexigenic activity in rats (Elliott RL et al., J. Med. Chem., 1994, 37, 309-313; Elliott RL et al., J. Med. Chem., 37, 1562-1568). The product GW 7854 (Hirst G. C. et al., J. Med. Chem., 1996, 39, 5236-5245), which is 1,5-benzodiazepine, is a CCK-A receptor agonist in vitro. This molecule also has an effect on oral gallbladder contraction in mice and the need for food intake.

It has now surprisingly been found that a number of triazole derivatives are characterized by partial or complete agonizing activity against CCK-A receptors.

Compounds of the invention have been the subject of systematic studies conducted to determine:

their ability to displace [ ¹²⁵ I] -CCK from their binding sites present on rat pancreatic membranes (CCK-A receptor) or on 3T3 cells expressing the recombinant human CCK-A receptor;

their affinity for the CCK-B receptor present on guinea pig cortex membranes, some of which are selective or non-selective CCK-A receptor ligands; and

their antagonistic properties to CCK-A receptors through their ability to induce in vitro mobilization of intracellular calcium in 3T3 cells expressing the human CCK-A receptor.

The triazole derivatives of the present invention are CCK-A receptor agonists because, like CCK, they are able to partially or completely stimulate the mobilization of intracellular calcium in a cell line expressing recombinant human CCK-A. Surprisingly, they have been found to be much more potent agents than the thiazole derivatives described in patent applications EP 518731, EP 611766, the thiadiazole derivatives described in patent application 620 620 and the benzodiazepines derivatives described in patent EP 667344.

In fact, these thiazole, thiadiazole and benzodiazepine derivatives are unable to induce said CCK-A receptor-mediated intracellular calcium mobilization.

The triazole derivatives of the invention are also more potent agents than the thiazole, thiadiazole or benzodiazepine derivatives in terms of their ability to block in vivo gastrointestinal emptying by intraperitoneal administration in mice.

The agonizing properties of CCK-A were thus studied in vivo, assessing the ability of the compounds to block gastrointestinal emptying in mice or to induce, in vivo, gall bladder emptying in mice.

Some of the derivatives also exhibit CCK-B receptor antagonist activity.

SUMMARY OF THE INVENTION

The invention thus relates to compounds of .Y ¹

NH-CII

--Y ² | Y3

R ^{4 of} formula I (I) wherein

R is an alkyl group containing from 2 to about - (CH3) m G wherein m is a number from 0 carbon atoms; to 5 and G is a non-aromatic mono- or polycyclic hydrocarbon group having 3 to 13 carbon atoms optionally substituted by one or more alkyl groups having 1 to 3 carbon atoms; a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms and the phenyl moiety is optionally substituted one or more times with a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms; - (CH ₂ ) _n NR ² R ³ in which n is an integer from 1 to 6 and R ² and R ³ , which are the same or different, represent an alkyl group having 1 to 3 carbon atoms or forming together with the nitrogen atom to which they are attached, a morpholine group, a piperidine group, a pyrrolidinyl group or a piperazinyl group;

X ¹ , X ² , X ³ or X ⁴ each independently represent a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 3 alkoxy group or a tri-7-fluoromethyl group, with only one of X ¹ , X ^2, X ³ and X ⁴ possibly represents a hydrogen atom;

R ⁴ represents a hydrogen atom, a - (CH 2) n COOR ^{5 group} in which n is as defined above and R ⁵ represents a hydrogen atom, a C 1 -C 6 alkyl group or an arylalkyl group in which the aryl radical contains 6 to 10 carbon atoms and the alkyl radical contains 1 to 6 carbon atoms; (C 1 -C 6) alkyl; - (CH 2) OR ⁵ or - (CH ² ) n NR ² R ³ in which R ² , R ³ and R ⁵ are as defined above; - (CH ₂ ) _n -tetrazolyl, in which n is as defined above, or

R ⁴ represents one of these groups in the form of an alkali metal or alkaline earth metal salt;

Y ¹ , Y ² and Y ³ are each independently hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, nitro, cyano, acylamino in which the acyl radical contains up to 6 atoms carbon, carbamoyl, trifluoromethyl, -COOR ⁶ in which R ⁶ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;

or one of their salts or solvates.

Within the scope of the invention, the term "C 1 -C 6 alkyl" or "C 1 -C 6 alkyl" refers to a straight or branched C 1 -C 6 alkyl group, respectively. 2 to 6 carbon atoms.

Alkoxy refers to an alkyloxy group in which the alkyl radical is as previously defined.

Acyl refers to an alkylcarbonyl group in which the alkyl radical is as previously defined. C 1 -C 6 acylamino is C 1 -C 6 alkylcarbonylamino.

Non-aromatic hydrocarbon groups having 3 to 13 carbon atoms include monocyclic or polycyclic fused or bridged, saturated or unsaturated, or terpenic groups. These groups are optionally mono- or polysubstituted with an alkyl group having 1 to 3 carbon atoms. Monocyclic groups include cycloalkyl groups, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclododecyl. Polycyclic groups include, for example, a norbornane group, an adamantane group, a hexahydroindane group, a norbornene group, a dihydrophenalene group, a bicyclo [2.2.1] heptane group, a bicyclo [3.3.1] nonane group, and a tricyclo [5.2.1.0 ^2.6 ] decane group.

In the context of the invention, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

Examples of aryl groups are phenyl and naphthyl.

The alkali metal and alkaline earth metal cations are preferably sodium, potassium or calcium cations.

Where the compound of the invention contains asymmetric carbon or asymmetric carbons, the present invention also encompasses optical isomers of the compound.

When a compound of the invention is characterized by a stereoisomer, for example an axial-equatorial-type stereoisomer, all stereoisomers of the compound are also included.

Salts of the compounds of the formula I according to the invention include salts with mineral or organic acids which allow suitable separation or crystallization of the compounds of the formula I, such as picric acid, oxalic acid or an optically active acid such as tartaric acid, dibenzoyltartaric acid, mandelic acid. or camphorsulfonic acid, as well as acids that form physiologically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen phosphate, maleate, fumarate, 2-naphthalenesulfonate and para-toluenesulfonate.

Salts of the compounds of formula I also include salts with organic or mineral bases, for example alkali metal or alkaline earth metal salts such as sodium or potassium salts or amine salts such as trometamol, or salts with arginine, lysine or salts with any physiologically acceptable amine.

The functional groups optionally present in the molecule of the compounds of formula I or in the reaction intermediates can be protected, either permanently or temporarily, with protecting groups which ensure that the syntheses lead exclusively to the desired products.

A temporary protecting group of amines, alcohols, or carboxylic acids means protecting groups as described, for example, in Protective Groups in Organic Synthesis, Greene TW & Wuts PGM Eds., John Wiley & Sons, 1991 and Kocienski PJ, Protecting Groups, Georg. Thieme Verlag, 1994.

The compounds of formula (I) may contain precursor groups of other groups which are later formed in one or more reaction steps.

Preferred compounds of the invention are those compounds of formula I wherein R ¹ is cyclohexylalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms.

Preferred compounds are also those compounds of formula I wherein the phenyl at the 5-position of the triazole is trisubstituted by the methoxy group at the 2 and 6 positions and the methyl at the 4-position.

Even more preferred are compounds of formula I wherein the phenyl group at the 5-position of the triazole is trisubstituted by the methoxy group at the 2- and 5-positions and the methyl or chlorine atom at the 4-position.

Particular preference is given to compounds of the formula 1.1

wherein R ¹ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ have the meanings defined for formula I, and some of their salts or solvates.

Of these compounds, those in which the group is preferred are those

X ¹

X2-jYúť

X ³ X ³ represents a 2,6-dimethoxy-4-methylphenyl group.

Particularly preferred are compounds of formula 1.2

wherein R ¹ and R ⁴ have the meanings given for formula I, or one of their salts or solvates.

Particularly preferred are compounds of formula 1.3

wherein R ¹ , R ⁴ , Y ¹ , Y ² and Y ³ have the meanings given for formula I and X ² represents a methyl group or a chlorine atom, or some of their salts or solvates.

The present invention also relates to a process for the preparation of compounds of the formula (I), characterized in that the compound of the formula (7)

wherein R ¹ , X ¹ , X ² , X ³ and X ⁴ have the meanings given for formula (I), undergo the reaction

either with an indole carboxylic acid derivative of the formula 8

wherein R ⁴ , Y ¹ , Y ² and Y ³ have the meanings given for formula I,

- or with an indole carboxylic acid derivative of the general formula 8 '

wherein Y ¹ , Y ² and Y ³ have the meanings given for formula I and R ⁴ 'represents a precursor group of the group R ⁴ , in which case a compound of formula I' is obtained

wherein R ¹ , X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² and Y ³ have the meanings given for formula I and R ⁴ 'represents a precursor group of the group R ⁴ , wherein R ⁴ has the meaning given for of formula I to form a compound of formula I and salts or solvates thereof.

The intermediates of formula I 'lead to compounds of formula I by converting the group R ^4' to a group R ^4, which can be determined by a process comprising the conventional procedures of organic chemistry.

Aminotriazoles of formula 7 form novel key intermediates for the preparation of compounds of formula I and are also within the scope of the invention.

Said starting products are either commercially available or can be prepared by the methods described below.

The following Reaction Scheme 1 illustrates the synthesis of compounds of Formula 7.

Further Reaction Scheme 2 illustrates the preparation of compounds of Formula I from aminotriazoles of Formula 7.

Scheme 1: Preparation of substituted 3-aminotriazoles of general formula 7

X ¹ , .COOH

X3 x ⁴

1) COCOCOCl / toluene

-i

2) H 1 -NH-f-NH ₂ , H ₂ CO ₃ / pyridine

NH

3) NaOH aq.

(D

C 6 5 C 6 5 (6) very small fraction

Reaction Scheme 2: Preparation of the 3-amidotriazoles of Formula I

(7) (8) soci ₂ pyridine

When R ⁴ is - (CH 2) _n COOH, the compounds of formula I are obtained from the corresponding esters, which in turn are prepared according to reaction scheme 2.

When R ⁴ is - (CH ₂ ) _n ^- tetrazolyl, the compounds of formula I are obtained from the corresponding nitriles of formula I '/ X

Ύ ¹

X ' ^{1 1} / Y X2-l · w

X ³ x · »

NH-CII

I

R4 '

Y ²

Y 3 (I ') wherein R ⁴ ' is - (CH 2) _n CN, by treatment with azidotrimethylsilane in the presence of dibutyltin oxide as described in J. Org.

Chem. 1993, 58, 4139-4141.

Compounds of formula I 'are prepared according to reaction scheme 2 from compounds of formula 7 and 8'

wherein R ⁴ 'is - (CH 2) _n CN.

The substituted benzoic acids of formula 1 are commercially available or can be prepared by modification of procedures described in the literature, for example:

1) regioselective lithiation of substituted benzenes and subsequent carboxylation of the obtained lithium derivative with carbon dioxide according to the following reaction scheme 3.

Reaction scheme 3

BuLi

WHAT,

Nov ² x 4 x ³ x ⁴ x ² 4W

X3 X ⁴

W ^C0CH

X 2 - X 3 (1) wherein Z ¹ represents a bromine atom or a hydrogen atom according to the nature and / or position of the substituents X ¹ , X ² , X ³ and X ⁴ , see NS Narashiman et al., Indian J. Chem., 1973, 11, 1192; RC Cambie et al.,

Austr. J. Chem., 1991, 44, 1465; T. de Paulis et al., J. Med.

Chem., 1986, 29, 61; or

2) regioselective formylation of substituted benzenes and subsequent oxidation of the substituted benzaldehyde obtained with potassium permanganate according to reaction scheme 4;

Reaction scheme 4

KMnO ₄

(1) according to the method described by S. B. Matin et al. in J. Med. Chem., 1974, 17, 877; or

3) haloform oxidation according to R. Levin et al., J. Am. Chem. Soc., 1959, 72, 1642 aromatic methyl ketones obtained by Friedel-Crafts acylation of substituted benzenes (CA Bartram et al., J. Chem. Soc., 1963, 4691) or Fries rearrangement of substituted acyloxybenzenes according to SE Cremer et al., J. Org . Chem., 1961, 26, 3653 according to the following Reaction Schemes 5 and 6.

Reaction scheme 5

X!

Friedel-Crafts

X3

X ⁴ (CH, CO) _: O or CH ₃ COCl Lewis acid (AlCl ₃ , SnCl ₃ )

NaOH • ^^. COOH B L2 x ² + haloform y reaction X3 X ⁴

(D

Acids substituted at the 2-position with a methoxy group can be prepared from a substituted phenol derivative by reaction with acetic anhydride in pyridine followed by a Fries reaction in the presence of aluminum chloride to give hydroxyacetophenone treated with methyl iodide in an alkaline medium to give the desired acid of formula 1 according to the following reaction scheme 6.

Reaction scheme 6

Ac ₂ O

XO _<% .OCOCH ₃ pyridine

Fries

A1C1 ₃

Δ

COCH3

OH and CH ₃ / OH ^_

COOH

X 2 -I _X 3> OCH ₃

Haloform reaction ^X in CH 2 ^CH 3

NaOH or KOH x * - |

The benzamidoguanidine of formula 2 is obtained by acylating the aminoguanidine hydrogen carbonate with benzoic acid chloride obtained from the benzoic acid of formula 1 by conventional methods (SOCl 2, oxalyl chloride in an inert solvent) using a modification of the method described by E. Hoggarth in J. Chem. Soc., 1950, 612. It can also be obtained using the variant described in the same publication according to the following Reaction Scheme 7.

Reaction scheme 7

n ₂ h ₄ ^Χ ν ^ / Ο-ΝΗ-ΝΗ ₂

X ^{2 *} +

X3 X ⁴ (D

OH

NH

II h ₃ sc-nh ₂

1) C1COCOC1

2) h ₂ n-nh-c-nh ₂ , h ₂ co ₃

3) NaOH (1)

Thermal cyclization of the benzamidoguanidine of formula 2 in a high boiling solvent such as diphenyl ether results in the aryl-5-amino-3-triazole of formula 3 using a modification of the method described by E. Hoggarth in J. Chem. Soc., 1950, 612.

Protection of the primary amino group of the triazole of formula III in the form of diphenylimine results in the N-protected triazole of formula 4 using a modification of the method described by M. J. O'Donnell et al. in J. Org. Chem., 1982, 47, 2663.

The compound of formula 4 can also be obtained using a variant consisting in the reaction of a triazole of formula 3 which has been previously converted to the hydrochloride of formula 3 'with diphenylimine according to the following reaction scheme 8.

Reaction scheme 8

3 '4

N-alkylation of the diphenyliminotriazole of formula 4 with an alkyl halide R ¹ X under phase conditions (strong base in the form of a concentrated aqueous solution in the presence of an immiscible organic cosolvent and a quaternary ammonium catalyst) results predominantly in the triazole of formula 5 accompanied by a small amount of triazole 6. the bases may be aqueous solutions of sodium hydroxide or potassium hydroxide having a concentration of 6-12 M. The cosolvent may be toluene, benzene and the quaternary ammonium compound is selected from the group consisting of all quaternary ammonium salts and especially tetrabutylammonium bromide (TBAB).

a) N-Alkylation of the diphenylaminotriazole 4 can be carried out in a non-aqueous medium (e.g. dimethylformamide or tetrahydrofuran) in the presence of a strong base such as potassium carbonate or sodium hydride.

b) The variant described by E. Akerbl in Acta Chem. Scand., 1965, 19, 1142, which uses an alkylating agent in an alcohol such as ethanol in the presence of a solid strong base such as potassium hydroxide or sodium hydroxide.

The triazole of formula 5 is readily separated from its isomer of formula 6 using silica gel or flash chromatography, depending on the nature of the group R ¹ .

The cleavage of the product of formula (5) obtained after separation from the minor isomer is carried out in an aqueous acid medium such as aqueous 1 N hydrochloric acid using a modification of the method described by J. Yaozhong et al. in Tetrahedron, 1988, 44, 5343 or M.J. O'Donnell et al. in J. Org. Chem., 1982, 47, 2663. This cleavage gives the 3-aminotriazole N-alkylated at the 1-position of formula 7.

The indole carboxylic acids of formula 8 were prepared according to the methods described in patent document EP 611766 according to the following reaction scheme 9.

Reaction scheme 9

Y ¹

XX —Y ²

Y3 c ₆ h ₅ ch ₂ oc ^{b 5} II o

X XX - γ2

Y3

NaH / R ⁴ X

T

R ⁴ xx γι

Y2

C ₆ H ₅ CH ₂ OC b 5 z _(|

ABOUT

I

R ⁴

Y3

The indole carboxylic acids of general formula 8 'in which R ⁴ ' represents a - (CH 2) _n CN group were prepared in an analogous manner to reaction scheme 9a.

Reaction Scheme 9a

Y ¹

O (CH ₂ ) _n CN

C ₂ H ₅ OC 1

NaH

X (CH ₂ ) _n CN

H

C ₂ H ₅ OC zs _h

ABOUT

Y2

Y3

Y ¹ -Y 2 (CH _{2) n} CN

8 '

The indoles of formula 11 are commercially available or are prepared by modification of methods described in the literature, for example, by L. Henn et al. in J. Chem. Soc. Perkin Trans. 1, 1984, 2189 according to the following Reaction Scheme 10,

EtONa

toluene

Δ γι

Y2 saponification

Y ²

A

I

H di:

'COOH

COOC ₂ H ₅ or can be prepared, for example, by Fischer synthesis (V. Prelog et al., Helv. Chim. Acta, 1948, 31, 1178) according to the following reaction scheme 11,

Reaction scheme 11

Y ¹

1) NaNO ₂

HCl

2) SnCl ₂

HCl

Y

Y-V ^^ NHNHo.HCI

EtOH at reflux

CH ₃ COCOOC ₂ H ₅

COOC ₂ H ₅

NaOH 2N EtOH

H para-toluenesulfonic acid · toluene

Y

Xx

Y - cooc ₂ h ₅

CH,

or by Japp-Klingermann synthesis (H. Ishi et al., J Chem. Soc. Perkin Trans. 1, 1989, 2407) according to the following reaction scheme 12.

Reaction scheme 12

1) NaNO ₂ / HCl aq. ->

2) KOH / CH ₃ COCH (CH 3) CO ₂ C ₂ H ₅

Y ¹ CH ₃

NH-N = <^

COOC ₂ H ₅

ZnCl ₂ / AcOH

H

Y3

Y ² -I

H 'COOC ₂ H ₅

Said compounds of the formula I also include those compounds of the formula I in which one or more hydrogen, carbon or halogen atoms, in particular a chlorine atom or a fluorine atom, have been replaced, respectively. have replaced them with radioactive isotopes such as tritium or carbon-14. The radiation-labeled compounds are useful in research studies, metabolism or pharmacokinetic studies, as well as in biochemical assays as receptor ligands.

The compounds of formula (I) have been the subject of in vitro binding studies in which their binding to CCK-A and CCK-B receptors was studied using the method described in Europe. J. Pharmacol., 1993, 232, 13-19.

The agonist activity of these compounds against CCK-A receptors was evaluated in vitro in 3T3 cells expressing the human CCK-A receptor by determining intercellular calcium mobilization [Ca ²⁺ ] using a technique derived from the MF technique

Lignon et al. described in Eur. J. Pharmacol., 1993, 245, 241-245. The calcium concentration [Ca ²⁺ ] is evaluated using the Fura-2 double excitation wavelength method. The ratio of fluorescence emitted at two wavelengths gives [Ca ²⁺ ] concentrations after calibration (G. Grynkiewicz et al., J. Biol. Chem., 1985, 260, 3440-3450).

The compounds of the invention stimulate partially or completely [Ca ²⁺ ] as well as CCK and thus act as CCK-A receptor agonists.

The study of the agonist effect of these compounds on gastrointestinal emptying was performed as follows. Female Swiss albino CD1 mice weighing between 20 and 25 g are maintained in solid fasting mode for 18 hours. On the day of the experiment, they are given intraperitoneally 30 minutes prior to ingestion of the pulverized coal feed (0.3 ml / mouse of a 10% aqueous pulverized carbon suspension containing 5% gum arabic and 1% carboxymethylcellulose) or orally administered testly 1 hour prior to said food. product (as a suspension in a 1% carboxymethylcellulose solution containing 0.6% methylcellulose) or the corresponding vehicle. Mice are sacrificed 5 minutes later by cervical dislocation and determined for gastrointestinal emptying, defined as the presence of coal in the intestine after a site referred to as a pyloric sphincter (European J. Pharmacol., 1993, 232, 13-19). The compounds of formula I partially or completely block gastrointestinal emptying as well as CCK and thus behave as CCK receptor agonists. Some have a DE50 (dose causing 50% CCK effect) of less than 0.1 mg / kg when administered intraperitoneally.

The study of the agonist effect of the compounds on gallbladder contraction was performed as follows. Female Swiss albino CD1 mice weighing between 20 and 25 g are maintained on a solid fasting regimen for 24 hours. On the day of the experiment, they are orally administered the test product (as a suspension in a 1% carboxymethylcellulose solution containing

0.6% methylcellulose) or the corresponding vehicle. Mice are then sacrificed by cervical dislocation 1 hour after administration of the test product and the gall bladder is removed and weighed. The results obtained are expressed in mg / kg body weight (Europa, J. Pharmacol., 1993, 232, 13-19). The compounds of the invention partially or totally cause gall bladder contraction as well as CCK and thus act as CCK receptor agonists. Some of them have a DE50 (effective dose causing a 50% reduction in gallbladder weight due to CCK) of less than 0.1 mg / kg when administered orally.

Accordingly, the compounds of formula I are capable of being used as CCK-A receptor agonists for the preparation of medicaments for the treatment of diseases whose treatment requires stimulation of the CCK-A receptors with cholecystokinin by exerting a full or partial agonizing effect. In particular, the compounds of the formula I are intended for the manufacture of medicaments for the treatment of certain disorders in the gastrointestinal sphere (prevention of gallstones, irritable bowel syndrome), obesity and associated pathological conditions such as diabetes and hypertension. The compounds of formula I indicate a state of satiety and can thus be used to treat digestive disorders, to regulate appetite and reduce food intake, to treat bulimia and obesity, and to induce weight loss. The compounds of formula I are also useful for the treatment of emotional and sexual behavior disorders and memory disorders, psychoses and in particular schizophrenia, Parkinson's disease and late dyskinesia. Said compounds may also serve in the treatment of fasting disorders, i. j. to regulate consumption wishes, in particular to regulate consumption of sugar, carbohydrates, alcohol or drugs and, more generally, all attractive consumption ingredients.

The compounds of the formula I according to the invention are of low toxicity. Their toxicity is compatible with their use as a medicament for the treatment of said disorders and diseases. At the pharmacologically effective dose level, no signs of toxicity have been observed for these compounds and their toxicity is therefore compatible with their medical use as medicaments.

Accordingly, the present invention also provides pharmaceutical compositions comprising an effective dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a suitable excipient. Said excipients are selected according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions according to the invention for oral, sublingual, subcutaneous, intramuscular, transdermal, rectal and intraocular administration, the active compounds of the formula I or their possible salts can be administered in unit dosage form in admixture with conventional pharmaceutical carriers for animals and humans for prophylaxis. or treating said disorders or diseases. Said unit dosages include oral dosage forms such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, as well as sublingual, oral, intracheal, intranasal, subcutaneous, intramuscular, intravenous and rectal dosage forms. For topical use, the compounds of the invention may be administered in the form of creams, ointments, lotions and patches.

In order to achieve the desired prophylactic or therapeutic effect, the dose of active ingredient may be between 0.01 and 50 mg / kg body weight per day.

Each unit dose may contain 0.5 to 100 mg, preferably 1 to 500 mg, of the active ingredients in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times daily to achieve a daily dose ranging from 0.5 to 5000 mg, preferably from 1 to 2500 mg.

In order to prepare a solid pharmaceutical composition in the form of tablets, the main component of the active ingredient composition is admixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The obtained tablet may be encapsulated in a coating of sucrose, a cellulose derivative or other suitable materials, or it may be processed in such a way that it has a prolonged effectiveness, which means that the tablet releases the active ingredient continuously in a predetermined amount per time unit.

In the preparation of gelatin capsules, the active ingredient is mixed with a diluent and the resulting mixture is introduced into gelatin capsules of soft or hard gelatin.

A syrup or elixir formulation or a droplet formulation may contain the active ingredient together with a sweetener, which is preferably non-caloric, methylparaban and propylparaban as an antiseptic additive, and an agent providing the composition with a suitable taste and color. The water dispersible powders or granules may contain the active ingredient in admixture with dispersing or wetting agents or suspending agents such as polyvinylpyrrolidone, sweetening and flavoring agents. For rectal administration, suppositories are used which are prepared using suitable binders melting at rectal temperature, such as cocoa butter or polyethylene glycols. For parenteral administration, injectable aqueous suspensions, isotonic saline solutions or sterile solutions containing dispersing agents and / or pharmacologically compatible wetting agents, such as propylene glycol or butylene glycol, are used.

The active ingredient may also be formulated in the form of microcapsules, optionally with one or more carriers or excipients, or with matrices such as polymer or cyclodextrin (prolonged-release forms, patches).

The pharmaceutical compositions of the invention can be used to treat or prevent various diseases in which cholecystokinin is involved.

The pharmaceutical compositions according to the invention may contain, in addition to the compounds of the formula I, other active substances which may be useful in the treatment of the disorders or diseases mentioned.

Preferred pharmaceutical compositions of the invention comprise a compound of formula 1.1, 1.2 or 1.3 or one of their pharmaceutically acceptable salts, solvates or hydrates.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of synthesis intermediates

A) Preparation of acids of formula 1 (variants)

2,5-Dimethoxy-4-methylbenzoic acid (compound A.l)

a) 2,5-Dimethoxy-4-methylbenzaldehyde

After stirring for 40 minutes with a mixture of 8.5 ml (0.068 mol) of N-methylformanilide and 6.3 ml (0.068 mol) of phosphorus oxychloride at ambient temperature, 17.8 g (0.117 mol) of 2,5-dimethoxytoluene are introduced into this mixture. The reaction mixture is heated at 50 ° C for 6 hours, allowed to cool to 20 ° C, then hydrolysed with 100 ml of 10% aqueous sodium acetate solution, extracted twice with diethyl ether and concentrated. The residue was taken up in aqueous sodium bisulfite solution and extracted twice with diethyl ether. The aqueous phase was made basic (pH = 12) to give white crystals.

Melting point: 83 ° C, yield: 67%.

b) 2,5-Dimethoxy-4-methylbenzoic acid

A solution of 2,5-dimethoxy-4-methylbenzaldehyde (23.86 g, 0.132 mol) in water (500 ml) was heated to 75 ° C and a solution of potassium permanganate (29.3 g, 0.185 mol) in 500 ml was introduced. water. The reaction mixture is left at 75 ° C for 2 hours and after adjusting the pH to 10 with 10% sodium hydroxide solution, the insoluble matter is filtered hot while washing the insoluble material with three times 80 ml of warm water. The filtrate is cooled, the precipitate formed is filtered off and dried under vacuum at 40 ° C to give white crystals. Melting point: 120 DEG C. Yield: 71%.

2,5-Dimethoxy-4-chlorobenzoic acid (compound A.2)

a) (2,5-Dimethoxy-4-chlorophenyl) methyl ketone

To 2 L of carbon tetrachloride is added at ambient temperature

162.5 g (1.2 mol) of aluminum chloride, at 0 ° C, 82 ml (1.2 mol) of acetyl chloride are added dropwise, followed by 200 g (1.2 mol) of 1,4-dimethoxy-2-chlorobenzene . The reaction mixture is left at 0 ° C for 3 hours 30 minutes and hydrolysed with 700 ml of water. The organic phase is washed with 2M sodium hydroxide solution, dried over anhydrous sodium sulphate and concentrated. The semi-crystalline residue was taken up in petroleum ether, filtered and dried to give white crystals.

Melting point: 96 DEG C. Yield: 70%.

b) 2,5-Dimethoxy-4-chlorobenzoic acid

To 800 ml of water was added 278 g (4.96 mol) of potassium hydroxide and then dropwise 84 ml (1.6 mol) of bromine at 5 ° C. The reaction mixture is left at ambient temperature for 1 hour. The obtained aqueous sodium bromate solution was added to a solution of 107 g (0.494 mol) of (2,5-dimethoxy-4-chlorophenyl) methyl ketone in 1.5 L of 1,4-dioxane. After 1 hour at 20 ° C, the reaction mixture was heated to reflux for 1 hour. When the reaction is complete, 100 ml of aqueous sodium bisulfite solution are introduced into the reaction mixture and the solvent is evaporated. The residue was acidified with 6 N hydrochloric acid solution and extracted twice with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and concentrated. The residue was precipitated with diisopropyl ether to give white crystals.

Melting point: 160 ° C, yield: 91%.

2,6-Dimethoxy-4-methylphenylbenzoic acid (Compound A.3)

231.6 g (1.5 mol) of 3,5-dimethoxytoluene are dissolved in 1 ml of diethyl ether and 1 L (1.6 mol) of a 1.6 N solution of butyllithium in hexane is added dropwise under nitrogen at ambient temperature. The reaction mixture is left for 18 hours at ambient temperature, after cooling to -30 ° C, 1 L of diethyl ether is added and the reaction mixture is bubbled with carbon dioxide for 1 hour while maintaining a temperature of -30 ° C. The reaction mixture is taken up in 6 L of 1 M sodium hydroxide solution, the aqueous phase is decanted and acidified with 6 N hydrochloric acid solution. The precipitate formed is filtered off, washed with water and dried under vacuum at 40 ° C to give white crystals.

Mp .: 187 ° C, yield: 88%.

B) Preparation of substituted indoles and variants thereof

Preparation of ethyl 5-methyl-1H-2-indolecarboxylate (compound B.l)

1. method (Japp-Klingermann method):

To a mixture of 10.7 g (0.1 mol) of 4-methylaniline, 74 ml of 12N hydrochloric acid and 140 ml of water at -5 ° C was added a solution of 7.2 g (0.104 mol) of sodium nitrite in 40 ml of water. The reaction mixture was stirred at -5 ° C for 15 minutes and neutralized by addition of 8.1 g of sodium acetate. 12.33 g (0.085 mol) of ethyl .alpha.-methylacetoacetate, 80 ml of ethanol, and then a solution of 4.8 g (0.085 mol) of potassium hydroxide in 20 ml of water and 100 g of ice are introduced into a three-necked flask. To this reaction mixture, a previously prepared diazonium solution was added dropwise at 0 ° C, and the mixture was left at 0 ° C for 18 hours. The aqueous phase is extracted four times with 50 ml of ethyl acetate, the organic phases are combined and dried over anhydrous sodium sulfate. The residue is taken up in 100 ml of toluene and 16.3 g (0.085 mol) of para-toluenesulfonic acid monohydrate. The mixture is slowly heated to 110 ° C and maintained at this temperature for 5 hours. After cooling and subsequent addition of saturated sodium carbonate solution, the insoluble matter is removed by filtration, the organic phase is decanted, dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane / cyclohexane (30/70; v / v) mixture to give beige crystals.

Melting point: 94 DEG C. Yield: 25%.

Preparation of ethyl 4-methyl-1 H -2-indolecarboxylate (compound B.2)

2. method:

- step 1: preparation of azide

To 200 ml of ethanol was added portionwise 9.3 g (0.405 mol) of sodium. A solution of 16.2 g (0.135 mol) of ortho-tolualdehyde in 52.2 g (0.405 mol) of ethylazidoacetate was added dropwise to this solution of sodium ethoxide in ethanol at -20 ° C. After 2 hours at -10 ° C, the reaction mixture is poured into 400 ml of water and the precipitate formed is filtered off. After drying under vacuum at 40 ° C for 18 hours, white crystals are obtained.

Melting point: 55 ° C, yield: 78%.

- Step 2: Azide cyclization

To 19.5 g (0.0844 mol) of the azide prepared in Step 1 was added portionwise 100 ml of xylene heated to 140 ° C. After the addition is complete, the reaction mixture is left at 140 ° C for 1 hour. The xylene is distilled off and the residue is taken up in diisopropyl ether, filtered and dried under vacuum at 40 ° C for 18 hours to give white crystals.

Melting point: 141 ° C, yield: 62%.

Preparation of 5-ethyl-1H-2-indolecarboxylic acid (according to the Fischer method) (compound B.3)

Method 3

- step 1: 4-ethylphenylhydrazine hydrochloride

To 24.2 g (0.2 mol) of 4-ethylaniline are added 150 ml of water and 160 ml of 12 N hydrochloric acid. The mixture was cooled to 0 ° C and a solution of 14 g (0.2 mol) of sodium nitrite in 140 ml of water was added dropwise. After 1 hour at 0 ° C, a solution of 112 g (0.496 mol) of tin (II) chloride hydrate in 90 ml of 12 N hydrochloric acid was added to the reaction mixture at -10 ° C. After 1 hour 30 minutes at -10 ° C, the reaction mixture was filtered to give a brown solid. Melting point: 198 ° C, yield: 95%.

step 2: ethyl 2- [2- (4-ethylphenyl) hydrazono] propanoate

To 34.5 g (0.2 mol) of 4-ethylphenylhydrazine hydrochloride prepared in the preceding step and suspended in 500 ml of ethanol is added 23 ml (0.2 mol) of ethyl pyruvate and the reaction mixture is heated at reflux for 3 hours 30 minutes. under reflux. The mixture was then allowed to cool to 20 ° C and the ethanol was evaporated. The solid residue is washed with pentane, dried under vacuum at 40 ° C to give a colorless liquid.

Yield: 94%.

step 3: ethyl 5-ethyl-11-indolecarboxylate

To 44 g (0.188 mol) of ethyl 2- [2- (4-ethylphenyl) hydrazono] propanoate prepared in the previous step and suspended in 300 ml of toluene is added, in portions over 7 hours, at reflux temperature 19 g. (0.1 mol) para-toluenesulfonic acid monohydrate. The reaction mixture was allowed to cool to 20 ° C and the insoluble material was collected by filtration and washed with toluene. The filtrate was washed with saturated aqueous potassium carbonate solution, decanted, dried over anhydrous potassium sulfate and concentrated. The residue was purified by silica gel column chromatography using a 5: 5 by volume mixture of dichloromethane and cyclohexane to give beige crystals.

Melting point: 94 DEG C. Yield: 51%.

step 4: 5-ethyl-1H-2-indolecarboxylic acid

To 150 ml of 1,4-dioxane was added 15.8 g (0.073 mol) of ethyl 536

of ethyl-1H-2-indolecarboxylate prepared in step 3 and then 45 ml (0.09 mol) of 2 M sodium hydroxide solution. The reaction mixture is left for 48 hours at ambient temperature. After evaporation of 1,4-dioxane, the residue is taken up in 6 N hydrochloric acid, the precipitate formed is filtered off and dried under vacuum at 60 ° C to give 5-ethyl-1H-2-indolecarboxylic acid as white crystals.

Melting point: 184 DEG C. Yield: 92%.

Preparation of N-alkyl-1H-2-indolecarboxylic acids

5-Ethyl-1- (methoxycarbonylmethyl) -1H-2-indolecarboxylic acid (Compound B.4)

step 1: benzyl 5-ethyl-1H-2-indolecarboxylate

To 70 ml of dimethylformamide was gradually added 12.7 g (0.067 mol) of 5-ethyl-1H-2-indolecarboxylic acid and 10 ml (0.067 mol) of 1,8-diazabicyclo [5.4.0] undec-7-ene. The reaction mixture was left for 40 minutes at 0 ° C and 10.6 ml (0.089 mol) of benzyl bromide was added dropwise. After 18 hours at ambient temperature, the reaction mixture is poured into 300 ml of water, the precipitate formed is washed with water and dried under vacuum at 50 ° C for 18 hours to give yellow crystals.

Melting point: 99 ° C, yield: 90%.

- Step 2: benzyl 5-ethyl-1- (methoxycarbonylmethyl) -2-indolecarboxylate

To 1.5 g (0.031 mol) of 50% sodium hydride in suspension in oil was added 75 ml of dimethylformamide and then portionwise 7.9 g (0.0283 mol) of benzyl 5-ethyl-1H-2-indolecarboxylate prepared in step 1. After 40 minutes at 0 ° C, 2.5 ml (0.0315 mol) of methyl bromoacetate is added dropwise and the reaction mixture is left at 20 ° C for 2 hours. Ethyl acetate (300 ml) was added, washed with water (2 x 300 ml), the mixture was decanted and the organic phases were dried over anhydrous sodium sulfate and concentrated.

- level 3:

9.5 g of a colorless oil are obtained.

%.

5-ethyl-1- (methoxycarbonylmethyl) -2-indolecarboxylic acid

To a solution of 9.5 g (0.0269 mol) of benzyl 5-ethyl-1- (methoxycarbonylmethyl) -1H-2-indolecarboxylate prepared in step 2 in 150 ml of ethanol is added 2.5 g of 10% palladium on carbon and then 40 ml (0.395 mol) of cyclohexene. The reaction mixture is heated at 70 ° C for 2 hours and cooled to 20 ° C. The reaction mixture is then filtered through talc and the filtrate is evaporated to dryness. The residue was dried under vacuum at 40 ° C for 18 hours to give beige crystals.

Melting point: 181 ° C, yield: 90%.

If the appropriate compounds B.5 to B.70 described above are used, the synthesis intermediates are obtained in the following Table I.

Table I

compound no. Y ¹ Y ² Y ³ R ⁴ M.p. B5 5-C ₂ H ₅ H H - (CH ₂ ) ₂ CO ₂ CH ₃ 128 B6 5-C ₂ H ₅ H H - (CH ₂ ) ₃ co ₂ c ₂ h ₅ 94 B7 5-C ₂ H ₅ H H - (CH ₂ ) ₄ CO ₂ C ₂ H ₅ oil B8 4-CH3 5-CH3 H -ch ₂ co ₂ ch ₃ 208 B9 4-CH3 5-CH3 H - (CH ₂ ) ₂ CO ₂ CH ₃ 170 B10 4-CH3 5-CH3 H - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 163 Bil 5-C ₂ H ₅ H H - (CH ₂ ) ₅ CO ₂ C ₂ H ₅ oil B12 5-C1 H H -ch ₂ co ₂ ch ₃ 207 B13 5-C1 H H - (CH ₂ ) ₂ CO ₂ CH ₃ 175 B14 5-C1 H H - (CH ₂ ) ₃ CO ₂ c ₂ h ₅ 152 B15 5-C1 H H - (CH ₂ ) ₄ CO ₂ C ₂ H ₅ 99 B16 5-C1 H H - (CH ₂ ) ₅ co ₂ c ₂ h ₅ 93 B17 5-CH3 H H -ch ₂ co ₂ ch ₃ 211 B18 5-CH3 H H - (CH ₂ ) ₂ CO ₂ CH ₃ 174 B19 5-CH3 H H - (CH ₂ ) ₃ CO ₂ c ₂ h ₅ 146 B20 5-CH3 H H - (CH 2) ₄ CO ₂ C ₂ H ₅ 186 B21 5-CH3 H H - (CH _{2) 5} CO ₂ C ₂ H ₅ 91

Table 1 (continued 1)

compound no. Y ¹ Y ² Y ³ R ⁴ M.p. B22 _4-OCH3 5-CH3 6-OCH3 -CH2CO2CH3 220 B23 4-OCH ₃ 5-CH3 6-OCH3 - (CH ₂ ) ₂ CO ₂ CH ₃ 200 B24 4-OCH3 5-CH3 6-OCH3 - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 134 B25 5-OCH3 H H -CH2CO2CH3 195 B26 5-OCH3 H H - (CHJ ₂ co ₂ ch ₃ 157 B27 5-OCH3 H H - (CHzbCOzCzHs 119 B28 5-OCH3 H H - (CH ₂ ) ₄ CO ₂ C ₂ H 5 87 B29 5-OCH3 H H - (CH ₅ CO ₂ C ₂ H 5 70 B30 5-CH3 H H -ch ₃ 230 B31 5-CH3 H H -CH2CH3 206 B32 5-CH3 H H - (CH ₂ ) ₂ OCH ₃ 158 B33 5-OCH3 H H - (CH ₂ ) ₂ OCH ₃ 170 B34 4-CH3 H H -CH2CO2CH3 206 B35 4-CH3 H H - (CH ₂ ) ₂ CO ₂ CH ₃ 118 B36 5-OC2H5 H H -CH2CO2CH3 186 B37 5-OC2H5 H H - (CH ₂ ) ₂ CO ₂ CH ₃ 158 B38 5-OC2H5 H H - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 131 B39 4-OCH3 6-OCH3 H -ch ₂ co ₂ ch ₃ 195 B40 4-OCH3 6-OCH3 H - (CH ₂ CO ₂ CH ₃ 191 B41 4-OCH3 6-OCH3 H - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 154 B42 4-OCH3 5-CH3 6-OCH3 - (CHzhCOzCzHs 132 B43 5-C1 H H -ch ₃ 248

Table 1 (continued 2)

compound no. Y ¹ Y ² Y ³ R ⁴ M.p. B44 _5-CH3 H 7-CH3 -CH ₂ CO ₂ CH ₃ 209 B45 5-CH3 H 7-CH3 - (CH ₂ ) ₂ CO ₂ CH 3 - B4 6 5-CH3 H 7-CH3 - (CH ₂ ) 3 CO ₂ C ₂ H ₅ 183 B47 5-C1 H H - (CH ₂ ) ₂ OCH ₃ 162 B48 4-CH3 5-CH3 6-OCH3 -CH2CO2CH3 185 B49 4-CH3 5-CH3 6-OCH3 - (CH ₂ ) ₂ CO ₂ CH ₃ 197 B50 4-CH3 5-CH3 6-OCH3 - (CH ₂ ) 3 CO ₂ C ₂ H ₅ 143 B51 4-CH3 H 7-CH3 -CH2CO2CH3 118 B52 4-CH3 H 7-CH3 - (CH ₂ ) 3 CO ₂ C ₂ H ₅ 108 B53 5-OCH3 H 7-CH3 -ch ₂ co ₂ ch ₃ 215 B54 4-CH3 6-CH3 H -CH2CO2CH3 112 B55 4-CH3 6-CH3 H - (CH ₂ ) ₃ co ₂ c ₂ h ₅ 152 B56 6-C ₂ H ₅ H H -CH2CO2CH3 158 B57 6-C2H5 H H - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 142 B58 5-OCH3 H 7-CH3 - (CH ₂ ) ₃ co ₂ c ₂ h ₅ oil B59 6-C2H5 H H - (CH ₂ ) ₂ CO ₂ CH ₃ 166 B60 5-C1 H 7-CH3 -ch ₂ co ₂ ch ₃ 209 B61 5-OCH3 H 7-OCH 3 -ch ₂ co ₂ ch ₃ 186 B62 5-OCH3 H 7-OCH 3 - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 138 B63 5-OCH3 6-OCH3 H -ch ₂ co ₂ ch ₃ 202 B64 5-F H 7-CH3 -ch ₂ co ₂ ch ₃ 242 B65 5-F H 7-CH3 - (CH ₂ ) ₃ co ₂ c ₂ h ₅ 142

Table 1 (continued 3)

compound no. Y ¹ Y ² Y ³ R ⁴ T. t .; ° C B66 5-C1 H 7-CH3 - (CH ₂ ) 3 CO ₂ C ₂ H ₅ 181 B67 5-OCH ₃ 6-OCH3 H - (CH ₂ ) ₂ CO ₂ CH ₃ 166 B68 5-OCH3 6-OCH3 H - (CH ₂ ) ₃ CO ₂ C ₂ H ₅ oil B69 5-CH3 7-C1 H -ch ₂ co ₂ ch ₃ 210 B70 4-CH3 6-OCH3 7-CH3 -ch ₂ co ₂ ch ₃ 211

4,5-Dimethyl-1- (3-cyanopropyl) -1H-2-indolecarboxylic acid (Compound B.71)

- Step 1: ethyl 4,5-dimethyl-1- (3-cyanopropyl) -1H-2-indolecarboxylate

To 1.92 g (0.040 mol) of 50% sodium hydride as a suspension in oil was added 75 ml of dimethylformamide followed by 7.9 g (0.0363 mol) of ethyl 4,5-dimethyl-1H-2 in portions. -indolkarboxylátu. After stirring at 0 ° C for 40 min, 4 ml (0.040 mol) of 4-bromobutyronitrile was added dropwise and the reaction mixture was then kept at 20 ° C for 2 hours. Ethyl acetate (300 ml) was added, the mixture was washed with water (2 x 300 ml) and then decanted. The organic phase is dried over anhydrous sodium sulphate and concentrated. 9.8 g of a colorless oil are obtained.

Yield: 95%.

- Step 2: 4,5-Dimethyl-1- (3-cyanopropyl) -2-indolecarboxylic acid

To 150 ml of 1,4-dioxane was added 9.8 g (0.0345 mol) of ethyl 4,5-dimethyl-1- (3-cyanopropyl) -ΙΗ-2-indolecarboxylate followed by 25 ml (0.05 mol). 2 M sodium hydroxide solution. The reaction mixture is then maintained at ambient temperature for 48 hours. After evaporation of dioxane, the residue is taken up in 6M hydrochloric acid, the precipitate formed is filtered off and dried under reduced pressure at 60 ° C to give 4,5-dimethyl-1- (3-cyanopropyl) -ΙΗ-2- acid. indolecarboxylic acid in the form of white crystals.

Melting point: 175 ° C, yield: 92%.

Compounds B.72 to B were prepared in the same manner.

Table la

Y ¹ Y2—

Y3 7

COOH

R ⁴ '

compound no. Y ¹ Y ² Y ³ R ⁴ ' Mp, ° C B72 5-C ₂ H ₅ H H - (ch ₂ ) ₃ cn 137 B73 5-C2H5 H H -ch ₂ cn 229 B74 5-OCH3 H H -ch ₂ cn 190 B75 5-CH3 6-CH3 7-OCH 3 - (CH ₂ ) ₃ CN 181

C) Preparation of benzamidoguanidine derivatives

Preparation of 2,6-dimethoxy-4-methylbenzamidoguanidine (compound C.l)

To a suspension of 2,6-dimethoxy-4-methylbenzoic acid (353 g, 1.8 mol) in toluene (1.5 L) was added dimethylformamide (1 ml) followed by dropwise addition of oxalyl chloride (190 ml, 2.16 mol). The reaction mixture is left for 2 hours at ambient temperature and evaporated to dryness. The crystalline residue was added portionwise to a suspension of 293.8 g (2.16 mol) of aminoguanidine hydrogen carbonate in 2.5 L of pyridine maintained at about 5 ° C and the resulting mixture was left at 20 ° C for 18 hours. The reaction mixture was evaporated to dryness and the residue was taken up in 1 L of 2M sodium hydroxide solution. The precipitate formed is filtered off, washed with a minimum of water and dried under vacuum at 60 ° C to give a crystalline residue.

Melting point: 222 ° C, Yield: 81%.

D) Preparation of 3-aminotriazole derivatives

3-Amino-5- (2,6-dimethoxy-4-methylphenyl) -1,2,4-triazole (Compound D.l)

To 230 g (0.91 mol) of 2,6-dimethoxy-4-methylbenzamidoguanidine was added 2 L of diphenyl ether and the reaction mixture was heated at 220 ° C for 5 minutes. The temperature of the reaction mixture is then reduced to 80 ° C, the precipitate formed is filtered off, washed with diisopropyl ether and dried under vacuum at 60 ° C to give a crystalline product.

Melting point: 286 DEG C. Yield: 93%.

Using this procedure and the appropriate starting materials, compounds D.2 to D.11 listed in the following table are prepared

Second

Table 2

compound no. X ¹ X ² X ³ X ⁴ T. t. ° C D2 2-OCH ₃ 4-OCH3 6-OCH3 H 297 D3 2-OCH3 4-OCH3 5-OCH3 H 240 D4 2-OCH3 4-CH3 5-OCH3 H 248 D5 2-OCH3 4-C1 5-OCH3 H 262 D6 2-OCH3 4-CH3 6-CH3 H 266 D7 2-OCH3 4-OCH3 5-CH3 H 248 D8 2-OCH3 4-CH3 5-CH3 H 286 D9 2-OCH3 3-C1 6-OCH3 H 215 D10 2-OCH3 3-CH3 6-OCH3 H 236 dll 2-OCH3 4-CH3 5-CH3 6-OCH3 237

E) Preparation of diphenyliminoderivatives

preparation

N- [3- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazol-5-yl] -N-diphenylmethyleneamine (compound E.l)

A suspension of 105 g (0.45 mol) of 3-amino-5- (2,6-dimethoxy-4-methylphenyl-1,2,4-triazole in 200 ml of xylene and 150 g (0.9 mol) of benzophenoneimine is heated under The reaction mixture was then lowered to 80 ° C, poured into 4 L of diisopropyl ether and the precipitate formed was filtered off, washed with diisopropyl ether and dried at 50 ° C for 18 hours.

Melting point: 126 ° C, yield: 90%.

Table 3

compound no. X ¹ X ² X ³ X ⁴ T. t. ° C E2 2-OCH ₃ 4-OCH3 6-OCH3 H 143 E3 2-OCH3 4-OCH3 5-OCH3 H 235 E4 2-OCH3 4-CH3 5-OCH3 H 228 E5 2-OCH 4-C1 5-OCH3 H 236 E6 2-OCH3 4-CH3 6-CH3 H 171 E7 2-OCH3 4-CH3 5-CH3 H 240 E8 2-OCH3 3-C1 6-OCH3 H 152 E9 2-OCH3 3-CH3 6-OCH3 H 169 E10 2-OCH3 4-CH3 5-CH3 6-OCH3 110

F) Preparation of 1-substituted 3-aminotriazoles

Preparation of 1- (2-cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1HI

-1,2,4-triazol-3-amine (compound F.l)

a) N-Alkylation of triazole

To 400 ml of toluene was added successively 300 ml of 6 N aqueous sodium hydroxide solution, 24 g (0.06 mol) of N- [3- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazole. -5-yl] -N-diphenylmethyleneamine and 2.7 g of tetrabutylammonium bromide. To the reaction mixture heated to 70 ° C was then added dropwise 17 g (0.09 mol) of 2-bromomethylcyclohexane. The reaction mixture is maintained at 80 ° C for 2 hours. The organic phase is decanted, dried over anhydrous sodium sulphate and evaporated to dryness. The residue is chromatographed on a column of silica gel, eluting with a toluene / ethyl acetate (90/10; v / v) mixture to give 21.4 g of a colorless oil.

Yield: 70%.

b)

Hydrolysis of diphenylimino group

To a solution of 10.3 g (0.02 mol) of N- [1- (2-cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazol-3-yl 1-N-Diphenylmethyleneamine in 200 mL of methanol was added 100 mL of 1 N hydrochloric acid. The reaction mixture is left for 18 hours at ambient temperature and evaporated to dryness. The oily residue is precipitated with diethyl ether and the precipitate formed is filtered off and dried under vacuum at 40 ° C.

M.p .: 136 ° C (hydrochloride), yield: 90%.

Table 4

compound no. X ¹ X ² X ³ R ¹ Mp, ° C hydro- chloride F2 2-OCH 4-CH 6-OCH 135 F3 2-OCH 4-CH 6-OCH • CH-cghj 215 F4 2-OCH 4-CH 6-OCH - {CH-CH, 143 F5 2-OCH 4-CH 6-OCH -CH "0 236 F6 2-OCH 4-CH 6-OCH -CHjCHrCgHj 200 F7 2-OCH 4-CH 6-OCH - (CHJrCH- (CH,), 172 F3 2-OCH 4-CH 6-OCH 187 F9 2-OCH 4-CH 6-OCH ry —CH.CH ₂ - N 0 \ __ / 160 F10 2-OCH 4-CH 6-OCH - {CH,) r -N (CH,), 148 F11 2-OCH 4-CH 6-OCH 190

Table 4 (continued 1)

compound no. X ¹ X ² X ³ R ¹ MP: , C hydro- chloride F12 2-OCH 4-CH 6-OCH - (CHdrCH, 212 F13 2-OCH 4-CH 6-OCH 198 F14 2-OCH 4-CH 6-OCH ABOUT 219 F15 2-OCH 4-CH 6-OCH 132 F16 2-OCH 4-CH 6-OCH OCH] 197 F17 2-OCH 4-CH 6-OCH 217 F18 2-OCH 4-CH 6-OCH 208 F19 2-OCH 4-CH 6-OCH C! 136 F20 2-OCH 4-CH 6-OCH CH - Cl 204 F21 2-OCH 4-CH 6-OCH CH] - 202 F22 2-OCH 4-Cl 5-OCH CH, C] -C 196

Table 4 (continued 2)

compound No. X ¹ X ² X ³ R ¹ Mp, ° C hydro- chloride F23 2-OCH 4-Cl 5-OCH - ° HHQ 148 F24 2-OCH 4-CH 5-OCH 192 F25 2-OCH 4-CH 5-OCH -οπ, -Ο 186 F26 2-OCH 4-CH 5-OCH -ΟΗ, ΟΗ, -ζ ^ 166 F27 2-OCH 4-OCH 6-OCH -CHPV - ^^ 189 F28 2-OCH 4-OCH 6-OCH -about 180 F29 2-OCH 4-CH 6-CH -about 168 F30 2-OCH 4-CH 6-CH —Ch, ch _iH 3 188 F31 2-OCH ₃ 4-CH 5-CH 200 F32 2-OCH 4-CH 5-CH -CH ^ chhQ 206 F33 2-OCH 4-OCH 6-OCH ch, ch, cn 244 F34 2-OCH 4-CH 5-OCH -CH CHj- 218

Table 4 (continued 3)

compound no. X ¹ X ² X ³ R ¹ Mp, ° C hydro- chloride F3S 2-OCH 4-C1 5-OCH -ΟΗ, ΟΗ, -θ 127 F36 2-OCH 3-C1 6-OCH 159 F37 2-OCH 3-CH 6-OCH —Ch ₂ chhQ ^ 168

1- (2-Cyclohexylethyl-5- (2,6-dimethoxy-4,5-dimethylphenyl) -1H-1,2,4-triazol-5-amine) was prepared in the same manner from compound E.10 (compound F.38). ).

Melting point: 180 ° C.

G) Preparation of amidotriazole derivatives with unsubstituted indoles

Synthesis of N- [1- (2-chlorobenzyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazol-3-yl] -5-chloro-1H-2-indolecarboxamide (Compound G.1)

To a solution of pyridine (1 mL, 0.013 mol) in dichloromethane (30 mL) was added thionyl chloride (0.2 mL, 0.0028 mol) at 0 ° C. After 15 minutes at 0 ° C, 500 mg (0.0025 mol) of 5-chloroindolecarboxylic acid was added and the reaction mixture was left at 0 ° C for 30 minutes. 0.91 g (0.0028 mol) of 1 - [(2-chlorophenyl) methyl] -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazole- 3-amine and the resulting mixture is left at 20 ° C for 18 hours. The reaction mixture was then washed with 1M sodium hydroxide solution. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a dichloromethane / methanol (5: v / v) mixture, to give 0.980 g of a crystalline product. M.p .: 262 ° C; yield: 73%.

Table 5

X3 X ⁴

compound no. X > < - \ R ¹ HYδΟδ HY ³ T. t. C G2 OCH, \ ^X C H ₃ OCH ^^ _j CH - ά ° W ' H 271 G3 och ₃ h ₃ (J 2 _{O 3)} CH - 1 0 W H 301 G4 OCH x δ W ' H 251 G5 och ₃ x CFE = ï W H 248 G6 x about about about" UCR H 283

Table 5 (continued 1)

compound no. And X ³ X ⁴ R ¹ W T. t. C G7 OCH Λ CH.- ABOUT -στ H 253 GS OCH "A», chl = á ° H 229 G9 OCH A. CH - ï Joca N H 262 G10 OCH A OCH CH - ABOUT here H 270 G11 OCH, A ³ OCH, δ ' CH, 245 G12 OCH A OCH CH, CHR- ABOUT ^ Y CH, CH, 139 G13 OCH, A. ^HjC7 OCH CHjCHj- ABOUT xxT H 210 (HCl)

Table 5 (continued 2)

H) Preparation of aminotriazole derivatives with N-substituted indoles

Example 1

Methyl 2- [2 - ({[1- (2-cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazol-3-yl] amino} carbonyl) -5-ethyl-lH-indol-l-yl] acetate

To 15 ml of dichloromethane was gradually added 1 ml (0.013 mol) of pyridine and 0.21 ml (0.0029 mol) of thionyl chloride. After 15 minutes at 0 ° C, 0.627 g of 5-ethyl-1-methoxycarbonylmethyl-1H-2-indolecarboxylic acid is added followed by 0.9 g of 1- (2-cyclohexylethyl) -5- (2,6-dimethoxy). 4-Methylphenyl-1H-1,2,4-triazol-3-amine hydrochloride The reaction mixture is then left for 18 hours at ambient temperature, followed by an acidic wash followed by an alkaline wash of the reaction mixture, and the organic phase is dried over anhydrous sulfate. The oily residue is chromatographed on silica gel, eluting with a dichloromethane / methanol (98.5: 1.5; v / v) mixture to give a white powdery product.

Melting point: 191 ° C, yield: 87%.

Example 2

2- [2 - ({[1- (2-Cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-triazol-3-yl] amino} carbonyl) - 5-ethyl-1H-indol-1-yl] -acetic acid

To a solution of 530 mg (0.0009 mol) of methyl 2- [2 - ({[1- (2-cyclohexylethyl) -5- (2,6-dimethoxy-4-methylphenyl) -1H-1,2,4-] triazol-3-yl] amino} carbonyl) -5-ethyl-1H-indol-1-yl] acetate prepared according to Example 1 in 50 ml of methanol is added 1.8 ml (0.0018 mol) of 1 N sodium hydroxide solution . After 18 hours at ambient temperature, the reaction mixture was evaporated to dryness. The residue was taken up in ethyl acetate and 0.5 N hydrochloric acid solution. The organic phase is decanted, dried over anhydrous sodium sulphate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 92: 8 mixture of dichloromethane and methanol, to give white crystals.

Melting point: 198 ° C, yield: 91%.

Using the procedure of Examples 1 and 2, the compounds shown in Tables 6 and 7 were prepared in the same manner from the corresponding intermediates in Examples 3 to 511.

Table 6

Pr. no. A X ³ x * R ¹ R ⁴ T. t. C (Salt) 3 OCH Ä Η, Ο ^^^^ ΟΟΗ. CH.- ABOUT -CHjCOjCHj 185 4 OCH A about" -CHjCOjH 226 5 OCH A h ^^^^ oh, δ -CHjCOzCH. 118 6 OCH A Η, Ο ^^^ ΟΟΗ. X -CHjCOjH 230 7 OCH A Η, Ο ^^^ ΟΟΗ. CH.- ABOUT -CHjCHjCO ^ CH 101 8 OCH XX η, ο ^ '^' ^ οοη. jCHz) <CH C ^ CH ^ CH 192

Table 6 (continued 1)

Pr. no. X ³ X ⁴ R ¹ R ⁴ MP: C (Salt) 9 OCH Λ CH - ABOUT -ΟΗϊϋΗ, ΟΟ, Η 210 10 OCH A • (CHJ4CH3 -ΟΗ, ΟΟίΗ 205 11 OCH (IN : H £ h - • CHjCOjCH. 189 12 OCH A ΟΗ, ΟΗ - ABOUT CH, CO, H 218 13 OCH A C : HjCh ₂ -CHjCOjCHj 138 14 OCH A - < »f- <] -CH ₂ CO ₃ CH, 115 15 OCH A CH - ABOUT CH, CO, CH, 167

Table 6 (continued 2)

Pr. no. X ³ X ⁴ R ¹ R ⁴ T. t. C (Salt) 16 OCH. A pH = CH, - 0 -CH ₂ CO ₂ CH 3 180 17 OCH A 0 CH _and CO 3 CH 3 203 18 OCH, ch ₃ -CH ₂ CO _from CH, 158 19 OCH A ρΗ, ΟΗ - 0 -CHjCOzH 217 (HCl) 20 OCH J? CH CH - ABOUT -CHjCOíH 169 21 QY ' about r> x - 'Hr-O -ch ₂ every ₂ h 271 22 OCH. A H ₃ C ^{x Z} 2 ^{X X} CH ₃ CH - ABOUT -CHjCOíH 181

Table 6 (continued 3)

Pr. no. A X3 X ⁴ R ¹ R ⁴ T. t. C (Salt) 23 OCH A - (CHjJaCHj -CH ₂ CO ₂ CH 3 220 24 OCH Λ 0 -CHjCOíH 220 (HCl) 25 OCH A Η, ο ^^^ οεΗ. from ^{CH 3} - (oy / i ₃₎ -CHjCOjCH. 168 26 OCH, 4 and ₃ ch - about -ch, what ₂ hours 198 27 OCH, oh ₃ δ ' -CHjCOjCHj 132 28 och ₃ Ä - (CHabCHa -CHzCOjH 220 29 OCH A Η, Ο ^^^ ΟΗ. C ^ CHj- ABOUT • CHjCOaCH. 144

Table 6 (continued 4)

Pr. no. X ³ X * R ¹ R ⁴ MP: C (Salt) 30 OCH A C SHjCH - -CHjCOiH 169 31 OCH, ÄH ₃ C ' ^X ^ ^{X <} OCH ₃ / CH - (CH / I CH, -CHjCOzH 203 (HCl) 32 OCH A HJC - ^^ OCH XjCH - ) -CHzCOjH 180 33 OCH A H CH, ABOUT • CH2CO2CH3 172 34 OCH A Η, Ο ^^^ ΟΟΗ. ABOUT -CHzCOjH 216 35 OCH , .Ψ ' OCH C XjCH - -CHjCOjCHj 126 36 OCH CH, CHjCH - ABOUT -CHjCOzCH. 158

Table 6 (continued 5)

Pr. no. A X ³ x * R ¹ R ⁴ MP: C (Salt) 37 OCH A (CHJiCHtCHjJj -CHjCOjH 272 38 OCH A -CHjCHÍCHj) -CHjCOaCHj 206 39 OCH Ä -CH 2 CH (CH 3) ₂ -ch ₂ every ₂ h 189 40 OCH OCH -ch ₂ every ₂ h 175 41 OCH CH, CH £ H, - ABOUT -CHjCOzH 156 42 OCH A HjCO ^^^ OCH CH - ABOUT -CHjCOjCHj 160 43 OCH tris Η, Ο ^^ ΟΟΗ, ΟΗ, ΟΗΧΗ. 0 -CHjCOjCHa 161

Table 6 (continued 6)

Pr. no. A X ³ X ⁴ R ¹ R ⁴ T. t. ° C (Salt) 51 OCH, R h _d c ^{'of K} ^ ^of Oh, CH - A -CH ₂ CO ₂ CH ₃ 129 52 OCH, Η, ^{Ζ χΖ} ^ ^{Ζ <} ΟΟΗ ₃ CH - A -CH ₂ CO ₂ H 213 53 OCH A Η, Ο '^^ ΟΟΗ. 1 CH, A -ch ₂ every ₂ h 182 54 OCH A CHjCH. 1 CH, CH CH, CH, -ch ₂ every ₂ h 151 55 OCH ΧΪ HJC - ^^^ OCH CH - ï -ch ₂ cooch ₃ 192 56 OCH A Η, Ο ^^^ ΟΟΗ. CH - A -ch ₂ co ₂ ch ₃ 173 57 OCH η, ο ^^ όοη. A -ch ₂ every ₂ h 229

Table 6 (continued 7)

Pr. no. A X ³ X ⁴ R ¹ R ⁴ MP: C (Salt) 58 OCH A H ^- ά -CH ₂ COaH 195 59 OCH A h ^^^ oh, F CI -CHjCOjCHj 133 60 OCH, A h ₃ c ^^ and ₃ CH - Φ Cl -CH ₂ CO ₂ H 175 61 OCH A HJC ^^^ OCH ¾ ^1- ά -CH ₂ CH ₂ CO ₂ CH 3 178 62 oh, A HJC ^^^ OCH CH - ï -ch ₂ ch ₂ every ₂ h 235 63 OCH A η, ο ^^^ οοη. & - (CH ₂ ) ₃ CO2C ₂ H _p 144 64 OCH A - (CH ₂ ) ₃ CO ₂ H 141

Table 6 (continued 8)

Pr. no. X ^{1 x} 4 rr ✓ R ¹ R ⁴ T. t. C (Salt) x ³ X ⁴ 65 r OCH Ar from CH - tris ° • {CH ^ COjCaHs 95 J H-Y << X · OCH U 66 I ' OCH lT FROM CH - about - (CH ₂ ) ₄ CO ₂ C ₂ H ₅ 101 h ₃ cY ^ χχ OCH M 67 F OCH FROM CH, - ^a - (CH ₂ ) ₄ CO ₂ H 266 H, C X ^ X OCH IN 68 OCH FROM CH - Λ - (CH 2) ₄ CO ₂ H 157 HJC ^ OCH ABOUT 69 OCH H FROM δ ' - (CH ₂ ) jCO ₂ C ₂ Hj 114 HJC ^ OCH 70 OCH 4 FROM p- ΓΎ ^α - (CH ₂ ) _s CO, C, H _s 76 HJC · ^ << x OCH M 71 OCH h with CH - about (CHjJsCOjCjHs 85 H. cr XX 'OCH, about

Table 6 (continued 9)

Pr. no. X X ³ x * R ¹ R ⁴ MP: C (Salt) 72 OCH Af Η, Ο Χ ^ ^ ΟΟΗ, - (CH 2) _with CO ₂ H 243 73 OCH A á - <CH ₂ ) _with CO ₂ H 138 74 OCH Ä HJC ^^^ OCH á - (CH ₂ ) ₃ CO ₂ H 150 75 OCH A h ^ XX ^ oh, 1 CH, Ί © -ch ₂ co ₂ ch ₃ 201 76 OCH A HjcXX'OCH. ΟΛ CH-FH -ch ₂ co ₂ ch ₃ 162 77 OCH Η, Ο'ΧΧΟΟΗ. about -ch ₂ cooh 200 78 OCH x OCH 0 -CHíCOOH 168 (HCl)

Table 6 (continued 10)

Pr. no. X ³ x ⁴ R ¹ R ⁴ Tt ^e c (salt) 79 OCH OCH CH - ABOUT -CH ₂ COOH 211 and OCH A HJC - ^^^ OCH (CHU " 0 -CHjCOOH 243 (HCl) 81 OCH OCH ό -CHíCOOH 188 (2HCl) 82 OCH A H,> Y OCH (CH,), - ABOUT -CHjCOOCHj 200 83 OCH Λ OCH ό -CH ₂ COOCH ₃ 170 84 OCH A OCH P ¥ = h> - -CHjCOOCHj 137

Table 6 (continued 11)

Pr. no. X ³ X ⁴ R ¹ R ⁴ MP: C (Salt) 79 OCH xr OCH CH - ABOUT -CHzCOOH 211 80 OCH Λ (CHU - 0 -CHjCOOH 243 (HCl) 81 OCH Λ OCH about -CH ₂ COOH 188 (2HCl) 82 OCH Λ OCH (CH,), " ABOUT -CHjCOOCH. 200 83 OCH Λ OCH ό -CH ₂ COOCH ₃ 170 84 OCH 7 ' OCH CHjCH - 0 -CH ₂ COOCH ₃ 137

Table 6 (continued 12)

Table 7

Pr. X1 R ¹ MP: no. * T, J i jQ- * C X ³ X ⁴ (Salt) R ⁴ OCH CH] - X ^ -CI and? Ä r ír Cl x Cr 145 H, C; OCH (Ιη]) ₅ 00] 0] Η] OCH CH - , x ^ x ^cl B8 Ä X Λ Cl χΠ 147 HJC · ' OCH] M (!) H] ₁₄ C0H1 _s OCH CH - 89 Ä WITH CI aí> 155 H, C OCH] (1 H) 1] CO] C 1 H _p OCH 90 Ä X ír .it XV 221 H, C OCH ÍhjCOjCH. OCH, I ³ CH-- , ^ x ^cl 91 h ₃ c · Λ OCH ά .it AIX 1 (CH]) _with CO, H 243

Table 7 (continued 1)

Pr. no. A X ³ X ⁴ R ¹ AÁ 'R ⁴ MP: C (Salt) 92 OCH A á χσ ' 1 CHjCOjCH. 207 93 OCH A á XXJ · 1 CH ₃ CO ₃ CH ₃ 196 94 OCH, AH, C ' ^{Z Z /} ^OCH ₃ CH - á " xu 1 CH ₂ COO'Na ⁺ 310 (sára salt) 95 OCH ₃ and H, C ^'/ ^ ^/ ^ _OCH3 CH - ï W 1 (CH ₃ ) ₃ CO ₃ H 221 96 OCH A CH - á ' w 1 CH, CO ₃ CH ₃ 214 97 OCH A Γ á " xu 1 (CH ₂ ) j CO ₃ CH ₃ 202 98 OCH. A Η, Ο ^^^ ΟΟΗ. CH - ABOUT W 1 (CH ₂ ) ₂ CO ₂ CH ₃ 194

Table 7 (continued 2)

Pr. no. A X ³ x * R ¹ δδ R ⁴ MP: C (Salt) 99 A CH - A 1 (CH 3) ₄ CO, H 286 100 OCH Ä HJC ^ '^' ^ OCH δ AU 1 (CH ₂ ) ₂ COO-Na ⁺ 194 (sodium salt) 101 oh, ΧΪ η, οΑ ^^ οοη. δ au (CH ₂ ), CO, C, H _p 132 102 OCH Af HJC ^^^ OCH δ Λυ 1 (CH ··· gCOCNa 277 (thrush salt) 103 OCH / T Η, Ο - ^^^ ΟΟΗ. CH - δ W 1 (CH 3) ₄ CO, H 195 104 OCH A δ ° AU 1 (CH,), COjH 264 105 OCH A Η, Ο ^^^ ΟΟΗ. δ A? X 1 CH ₂ COO-Na + 266 (plaster salt)

Table 7 (continued 3)

Table 7 (continued 4)

Pr. no. X x- \ R ¹ Y ¹ T. t. C (Salt) JQU 1 R ⁴ H Y3 och ₃ CH - / C 113 H, C '' ú OCH ABOUT XZO 1 CH, CO, H 205 OCH CH - / C 114 H, C; XX OCH ABOUT xO 1 (CH,), CO, H 191 OCH, I ³ CH - = H, 115 H, Λ OCH ï 1 (CH 2), CO, C, H _S 154 OCH, I ³ CH - xC, H _p 116 H, C; Λ 'OCH, á " li il T 1 CH, CO, H 233 OCH CH - _z ^/ v <Z _X C, H _$ 117 H, Λ oh, about w 1 (CH,), CO, C, H, 82 OCH. I ³ CH - ζΑ « 118 h, c- Λ 'OCH, about Λϋ 1 CH, CO, H 257 OCH CH - 119 H, C; XX 'OCH, about xO 1 (Oy, CO, H 181

Table 7 (continued 5)

Pr. no. A X ³ X ⁴ R ¹ aa R ⁴ MP: C (Salt) 120 OCH Ä CH - ï AU 1 (CH,), CO, H 275 121 OCH. A CH - ABOUT AU 1 (CH,), CO, CH, 132 122 OCH RT χυ 1 (CH,), CO, CH, 135 123 OCH rt Η, Ο ^^^ ΟΟΗ. CH - ABOUT W 1 (CH,), CO, H 263 124 OCH. A Η, Ο - ^^^ ΟΟΗ. CH - A AU 1 (CH,), CO, H 250 125 OCH A Η, Ο ^^ ΟΟΗ, CH - A AU 1 (CH,), CO, H 154 126 OCH Η, Ο ^^^ ΟΟΗ. CH - A AU ' 1 ΟΗ, ΟΟ, Η 184

Table 7 (continued 6)

Pr. no. x ³ x * R ¹ χΧ5χ i Y ³ R ⁴ MP: C (Salt) 127 H ₃ C ^Z OCH XX OCH OH, - á ΛΧ5 1 (CHJjCOjCHj 5CH ₃ 207 OCH _and also ³ CH - 5CH. 128 H ₃ C ' XX och ₃ ï XX5 I (CH COjCjH, 179 OCH _and also ³ ΟΠχ- ) CH ₃ 129 HJC XX och ₃ á " AX2 1 (CH ^ COjCjHj 175 130 OCH Λ with RX " ) CK, 188 'SCAA RJC ' och ₃ at 1 (CH ₂ ) ₃ COO'Na ⁺ salt) 131 OCH _S A x * ¾ ^1- yy ) CH 235 H ₃ C ' χ ^ χΧ 'OCH, at 1 (CH ₄ CO ₃ H) OCH I CHj- 3CHj 132 Ä x * Λ XX ^ 177 l-LjC- • OCH 1 (CH ₂ CO ₃ CH ₃ OCH CH - ) CH 133 Ä x * Λ ad 141 HJC ' OCH ABOUT I (CHJjCOjCjH.

Table 7 (continued 7)

Pr. no. A X ³ X ⁴ R ¹ 1 Y ³ R ⁴ MP: C (Salt) 134 OCH Ä Η, Ο - ^^ ΟΟΗ, CH - ABOUT 1 (CH,) ₃ CO, _(S; H 108 135 OCH Λ δ 1 (CH 2) ₄ CO, C, H _p 144 136 OCH A η, ο ^^ Όοη. δ ' AIX 1 CH, 196 137 OCH Ä Η, Ο '^^' ^ ΟΟΗ. Jux ' 1 (CH COO'Na * 249 (sxrá salt) 138 OCH A Η, Ο - ^^^ ΟΟΗ. δ ^- X 1 (CH ₂ ) g COONa ⁺ 176. (sľriru salt) 139 OCH A Η, Ο - ^^ ΟΟΗ, CH - A J 1 X (CH ₂ ) ₂ COO-Na ⁺ 198 140 OCH A & / X 1 CHjCOjCjH. 212

Table 7 (continued 8)

Pr. no. A X ³ X ⁴ R ¹ xA i Y ³ R ⁴ MP: C (Salt) 141 OCH JA Η, Ο - ^^^ ΟΟΗ. á JXT 1 (ΟΗ ΟΟ ^, Ο, Η. 140 142 OCH JA Η, Ο ^^^ ΟΟΗ. δ A 1 CH, CO, C C ^ _S 159 143 OCH JA h ^ / ^^ Oh, w 1 CHjCOjCH. 121 144 OCH. A Η, Ο ^^^ ΟΟΗ. CH - á " w 1 (ΟΗ,) ₄ 00.0, Η ₅ 153 145 OCH JA Η, Ο '^^^ ΟΟΗ. CH - A λΧΧ 1 CH, 220 146 OCH, JA H, C- ^Z> ^ ^{X <} 'OCH, CH - A Al 1 (CH ₂ ) ₄ COONa ⁺ 266 147 OCH JA Η, Ο - ^^^ ΟΟΗ. A A 1 CH ₂ COO'Na ⁺ 206

Table 7 (continued 9)

Pr. no. A X ³ X ⁴ R ¹ äXV 1 Y R ⁴ T. t. C (Salt) 148 OCH JA HJC ^^ OCH CH - ABOUT 1 (CH ₂ ) ₂ COO-Na ⁺ 210 (Saza AOL) 149 OCH JA Η, Ο ^^^ ΟΟΗ. 2 ? 7 '1 (CH ₂ ) ₃ CO ₂ H 213 150 OCH JA HJC ^^^ OCH CH - ABOUT 1 1 (CH ₂ ) ₄ CO ₂ H 247 151 OCH JA HJC - ^^^ OCH CH - A A 1 (CH ₂ ) ₅ CO ₂ C ₂ H _s 163 152 OCH A Η, Ο ^^^ ΟΟΗ. ^ OH, - w 1 C * ^ COO'Na 230 (Saxa salt) 153 OCH A HJC - ^^^ OCH CH - ABOUT W 1 CH ₂ COO'Na ⁺ 252 (SCAA SALT) 154 oh, Η, Ο - ^^^ ΟΟΗ. CH - A W 1 (CH ₂ ) g CO ₂ C ₂ H 2 132

Table 7 (continued 10)

Pr. no. A X ³ X ⁴ R ¹ Λΰ; i Y ³ R ⁴ T. t. "C. (Salt) 155 OCH Af Η, Ο - ^^^ ΟΟΗ. CH - ABOUT ΤίΤ 1 (CH 2) ₅ CO ₂ C ₂ H ₅ 138 156 OCH LL η, ο - ^^^ οοη. about ΛΧΤ · 1 (CHjfeOCHg 188 157 OCH Λ Η, Ο ^^ ΟΟΗ, CH.- á ΛΧΤ 1 (CH ₂ ) ₂ OCH ₃ 196 158 OCH rt Η, Ο ^^^ ΟΟΗ. ΡΗζΟΗ - ABOUT ΤίΤ 1 (CH ₂ ) ₃ CO ₂ C ₂ H ₅ 82 159 OCH, A h ₃ c ^x ' ^zzK och, xcr 1 (CH ₂ ) ₃ CO ₂ H 215 160 OCH, ^AH , C ' ^X = 5 ^x OCH _i CH - A ΛΧΓ 1 (CH ₂ ) ₂ CO ₂ CH ₃ 177 161 OCH A Η, Ο - ^^^ ΟΟΗ. CH - A AV 1 (CH ₂ ) ₅ CO 2 H 233

Table 7 (continued 11)

Pr. X ³ X ⁴ R ¹ IXI; R ⁴ T. t. ° C (Salt) 162 OCH, H yy, C '^ ^X? ^ ^{Z <} OCH3 CH-- ABOUT XXJ '1 (CH ₂ ) ₂ CO ₂ CH ₃ 131 163 OCH Ä CH - ï yO 1 (CH ^ CO ^ 241 164 OCH Λ Η, Ο ^^^ ΟΟΗ. CH - ABOUT 1 1 (CH ₂ ) ₅ CO ₂ C ₂ H _S 120 165 OCH. A f H, C, - 0 '7' 1 (CH ₂ ) ₃ CO ₂ C ₂ Hg 145 16S OCH Λ Η, Ο '^^ ΟΟΗ. CH - á ° 1ίΤ '1 (CH ₂ ) ₅ COOW · 144 (sodium salt) 167 OCH Ä Η, Ο - ^^^ ΟΟΗ. J = CH, - 0 1 '1 (CH ₂ ) ₂ CO ₂ CH ₃ 114 168 OCH XX Η, Ο ^^^ ΟΟΗ. pdjCHj- 0 äXT 1 ^CH 2 ^CO 2 ^C 2 ^H 5 148

Table 7 (continued 12)

Pr. no. X ³ X ⁴ R ¹ xXV R ⁴ MP: C (Salt) 169 OCH Λ J = CH, - 0 ÄJ 1 CH ₂ CO ₂ CH ₃ 202 170 OCH Λ pH ₂ CH ₂ - 0 XXX ' 1 CHgCOgH 231 (HCl) 171 OCH IV enzyme Η, Ο ^^ ΟΟΗ, Phichit - 0 xw 1 ch ₂ co ₂ hr 237 (2HCl) 172 OCH Ä H ^ - ^^ OCH pHjCH - 0 XXX '1 ch ₂ co ₂ ch ₃ 208 173 OCH Λ HJC - ^^^ OCH <3H ₂ CH ₂ - 0 XXX '1 ch ₂ every ₂ h 231 (2HC1) 174 OCH Λ HaC ^^^ OCH CH - ABOUT xn 1 (CH ₂ ) ₂ COO'Na ⁺ 268 (sxté salt) 175 OCH Ar Η, Ο ^^ ΟΟΗ, CHjCHj- 0 XXX 1 ch ₂ co ₂ ch ₃ 195

Table 7 (continued 13)

Pr. no. A X ³ X ⁴ R ¹ aa R ⁴ T. t. ^e c (sol) 176 OCH IV enzyme Η, Ο ^^ ΟΟΗ, PW- 1 CH ₂ CO ₂ CH ₃ 164 177 OCH A Η, Ο ^^^ ΟΟΗ. PW " w 1 CH, CO, -Na * 2-15 178 ° CH χχ Η, Ο ^^^ ΟΟΗ. A ΛΧΤ 1 CH, CO, H 232 179 OCH A Η, Ο ^^^ ΟΟΗ. δ ΑΠ 1 (CH,) _with COGNa * 200 (astra · sal ') 180 OCH rx Η, Ο '^^ ΟΟΗ. CH - A ΛΧ7 ' 1 (Ohms. 199 181 OCH xX Η, Ο - ^^^ ΟΟΗ. J = CH, - 0 ΛΧ7 ' 1 (CH, CO ^ 233 (HCl) 182 OCH xX HJC ^^^ OCH J = CH, - 0 A 1 (CHJjCOjCH. 101

Table 7 (continued 14)

Pr. no. A X ³ X ⁴ R ¹ xXJ * 1 Y * R ⁴ MP: C (Salt) 183 OCH A pHjCHj- 0 XW 1 (CH ^ COjH 246 (HCl) 184 OCH A CH - ABOUT XX7-1 (CH3 _with CO3H2O) 217 185 OCH JA HJC ^^^ OCH δ ^- AA C ^ H _S 108 186 OCH A Η, Ο - ^^^ ΟΟΗ. CH - A xiT C ^ _s 219 187 OCH, A H ₃ C ^{x Z} 2 ^{X X} OCH _J CHjCH - ABOUT C1 ^ XXX 1 (CH) _{CO, the} CJH 87 188 OCH, A h ₃ c ^^^ och ₃ C ^ CH, - ABOUT XXJ · 1 (CH ₂ ) ₂ CO ₂ H 263 189 OCH A CH - 0 xjX 1 (CHU Coon * 184 (sxtá salt)

Table 7 (continued 15)

Pr. no. x ³ x * R ¹ jXV 1 Y ³ R4 T. t. C (Salt) 190 OCH A η, ο ^^^ οοη. ch, ch ₂ -o XXJ '1 (CH ₂ ), CO ₂ C ₂ H _S 140 191 OCH χΥ HJC '^^^ OCH P = CH - ABOUT w 1 (CH ₂ ) ₂ CO ₂ CH 187 192 OCH A Η, Ο ^^^ ΟΟΗ. 0 xX 1 (CH COjH 208 (HCl) 193 OCH A Η, Ο ^^^ ΟΟΗ. CH ₂ CH ₂ - 0 xo 1 (CH ₂ ), CO ₂ H 200 (HCl) 194 OCH ΧΪ Η, Ο '^^ ΟΟΗ. jSHjCH - 0 xu 1 (CH jCOjH 197 (2HCl) 195 OCH Ä Η, Ο '^^^ ΟΟΗ. pHjCHj- 0 xit 1 (CHJjCOjH 186 (2HCl) 196 OCH A Η, Ο - ^^^ ΟΟΗ. fHjCHa- 0 XIR (^ 2), 00 ^^, 148

Table 7 (continued 16)

Pr. no. A x ³ x * R ¹ R ⁴ T. t. C (SOI) / 197 OCH A C SHjCH - ΛΟ 1 (Chy ₃ cojCjHs 136 198 OCH A h ^ X '- ^ oh, ΖΗ, ΟΗ - s 1 (CH,) ₃ COO * 170 199 OCH A Η, ^ οΧΧ ΟΟΗ, CH - A α 1 1 (CH 3) ₄ CO, C 4 H 5 _s 130 200 OCH, A h ₃ cX * Xoch ₃ CH - ABOUT w 1 (CH3) ₄ COO-Na * 282 (sodium SAL) 201 OCH A h ^ XX ^ oh, CH CHj- ABOUT ^ / Vc · ^Hs 1 (CH 3 C 3 CH 3, 101 202 och ₃ A HjcXXoch, C ÍHjCH - αχτ · 1 (CH,) ₂ 273 (sodium SQL *) 203 och ₃ A HjcX ^ X ^ OCH, CH - ABOUT W 1 CH, 231

Table 7 (continued 17)

Pr. no. A X ³ X ⁴ R ¹ i Y ³ R ⁴ T. t. C (Salt) 204 OCH Ar pHzCH - 0 W 1 (CHU, COQNa * 225 sodium sal *) 205 OCH A Η, Ο - ^^^ ΟΟΗ. CH.- ABOUT W 1 (CH ₂ ) ₂ OCH 112 206 OCH A Η, Ο - ^^^ ΟΟΗ. I ^ CH, - 0 w 1 CHjCOjCH. 108 207 OCH A Η, Ο ^^^ ΟΟΗ. δ ' xa ' 1 (CHJjOCH. 122 208 OCH A <W ABOUT W 1 (CH 2) ₂ CO ₂ H 155 209 OCH A η, ο ^^^ οοη. CH.CM - W 1 (CHjJjCOO-N a 162 (sodium SQI) 210 OCH, iX h, c ^{xZi! 5zZ <} och, CH.— ï ¹ XU 1 (CH? COO-Na + 225 (sodium salt)

Table 7 (continued 18)

Pr. no. X ³ x ⁴ R ¹ Y ³ R ⁴ MP: C (Salt) 211 OCH Juf CH - ά CH, - ^{/ Z} ^ N ^X ^ ^S ^ 1 CH, CO, CH, 130 212 OCH Ä h ^ / ^^ Oh, CH - ABOUT x6 1 CH, CO ₂ CH, 141 213 OCH rI Η, Ο Η ^^^. pH CHj- 0 C 1 CH, CO, CH, 177 214 OCH A Η, Ο ^^^ ΟΟΗ. ABOUT CH, x6 1 CH, CO ₂ CH, 126 21S OCH A Η, Ο ^^ ΟΟΗ, ľ ¹ ď CH 2 X 1 CH 3 CO ₂ H 213

Table 7 (continued 19)

Pr. no. A X ³ X ⁴ R ¹ xA i Y ³ R ⁴ MP: C (Salt) 216 OCH A CH - δ CH ₃ CO 1 CH, CO, H 241 217 och ₃ Ä HaC ^^^ OCH ΟΗ, ΟΗ - ABOUT ch, x6 1 CH ₂ CO ₂ H 257 218 OCH A 0 CH, xo 1 ΟΗ, ΟΟ, Η 221 (2HCl!) 21S OCH A Η, Ο - ^^^ ΟΟΗ. A ά x6 (CH ₂ ), CO ₂ C ₂ H _s 152 220 OCH Ä HJC ^^ OCH CH - ABOUT xo 1 (CH COjCjHj 87 221 OCH ΓΪ HJC ^^^ OCH jíHjCHj- 0 ch ₃ x 6 (CH 3 Cl 2 H) 182 (2HCl)

Table 7 (continued 20)

Pr. no. X ³ X ⁴ R ¹ tQ · R ⁴ T. t. C (Salt) 222 OCH CH - ï CH, xo (H,), CO, H 168 223 OCH A ^^^ to ties OCH ABOUT W 1 CHjCOCCH. 205 224 OCH A J = CH, - 0 / X 1 CH ₂ CO ₂ H 255 (HCl) 225 OCH A OCH J = CH, - ABOUT - / xx ^c H w 1 CH 2 COOCH, 196 226 OCH A OCH Y 1 CH ₂ CH ₂ COOCH, 95 227 OCH A OCH (PCH - W 1 CH ₂ CO 2 Na * 198 (sodium SALT)

Table 7 (continued 21)

Pr. no. A X ³ X ⁴ R ¹ AXh | Y3 R ⁴ MP: 'C (Salt) 228 OCH A OCH ť ^ CH, - AU 1 CHjCHjCOO-Na · 200 (aodbá salt) 229 OCH A CH, A 1 CHjCOOCH. 145 230 OCH A HJC ^^^ OCH C : HJCH - CH, A 1 CH, CO, H 256 231 OCH A Η, Ο ^^^ ΟΟΗ. CH - ABOUT CH, A H, CO, CH, 157 232 OCH rI Η, Ο ^^^ ΟΟΗ. 5 CH, A 1 CHjCO ^ I 265

Table 7 (continued 22)

Pr. no. A X ³ X ⁴ R ¹ R ⁴ T. t. C (Salt) 233 OCH Λ OCH CH - ABOUT / A 1 CH ₂ CO ₂ CH 157 234 OCH Ä η, ο ^^^ οοη. ρΗ, ΟΗ - 0 AJ 1 (CHjJjCOjCH. 211 (HCl) 235 OCH A Η, Ο ^^^ ΟΟΗ. ^ CH, - 0 W 1 CHjCOjCH. 209 (HCl) 236 OCH, ^AH ₃ C ' ^X ^ ^{tX <} OCH ₃ ρΗ, ΟΗ - ABOUT AU 1 CH ₂ CO ₂ H 222 (2HCl) 237 OCH rx Η, Ο ^^^ ΟΟΗ. jSHjCH - 0 xit 1 (CH ^ CO ^ H, 240 (HCl) 238 OCH 4 OCH CH.- ABOUT AIT ' 1 C ^ COjH 217

Table 7 (continued 23)

Pr. no. A X ³ X ⁴ R ¹ | Y3 R ⁴ MP: C (Salt) 239 OCH A Η, Ο ^^^^ ΟΟΗ. δ w 1 (CHjJjCOjCjHj 129 240 OCH. JA HJC ^^^ OCH δ xu 1 (CH _{z) 5} CO, H 136 241 OCH. A ρΗ, ΟΗ - 0 xu 1 CHjCOjH 215 (2HCl) 242 OCH JA HJC ^^^ OCH 0 A 1 (οη ₂ ), οο _? ο, η, 83 243 OCH A HJC ^^ OCH J = CH, - 0 XV 1 (Οη ^ οο, η 205 (2HCl) 244 OCH. A Η, Ο ^^^ ΟΟΗ. pH ₂ CH 3 - O CH, A 1 (CH 2), CO, C, H _S 125

Table 7 (continued 24)

Pr. no. A X ³ X ⁴ R ¹ Αδ 'R ⁴ MP: C (Salt) 245 OCH OC CHjCH - ABOUT CH, A 1 (CH, CO, C, H, 94 246 OCH A CH, A 1 (CH,), CO, H 234 247 OCH, R H, ^{X ^? Ix <OCH} CH ~ 0 A 1 (CH,), CO, H 170 246 OCH rI Η, Ο ^ '^^ ΧΟΗ. CH \FROM CH, A 1 (CH,), CO, CH, 143 249 OCH JA HJC ^^^ OCH CH - ABOUT CH, A 1 (CH,), CO, CH, 107

Table 7 (continued 25)

Pr. no. A X ³ X ⁴ R ¹ and X ³ = Y ³ R ⁴ T. t. 'C (Salt) 250 OCH A pHjCHj- 0 A ¹ 1 (CH ^{3 C} 3 H 3 H) 206 (2HCl) 251 OCH A m- , Χ ^ θΟΗ, Λθ 1 (ChyjCOO-N a 240 (sodium salt) 252 OCH A Η, Ο '^^^' ΟΟΗ. A 1 (CHJjCOjH 184 253 OCH A PH - ABOUT CH, A 1 (CH) jCOO-In ' 238 (Saxa salt) 254 OCH A Η, Ο ^^ ΟΟΗ, H CH, - ABOUT and 1 (CHJjCOjCH. 122 255 OCH A HJC ^^^ OCH p-IjCHj- 0 CH, A 1 (CHjJjCOjCH. 121

Table 7 (continued 26)

Pr. A A X ³ X ⁴ R ¹ iQt i Y ³ R ⁴ MP: C (Salt) 256 OCH JUC Η, Ο ^^^ ΟΟΗ. ΟΗ, ΟΗ - ABOUT CH, AO 1 (CHU, Cognis * 251 (Soo salt) 257 OCH Λ OCH c ¹ H, CH - AU 1 CH-COjCH, 200 258 OCH Λ OCH SHjCHj- A0 1 CHjCOjH 151 (2HCl) 259 OCH A Η, Ο ^^ ΟΟΗ, CH - ABOUT OCH A 1 CH, CO, CH 241 260 OCH A η, ο - ^ ^^ Α οοη, C : HjCh ₂ OCH, aA, 1 CH, CO _of CH ₃ 157 261 OCH XI ' Η, Ο ^^^ ΟΟΗ. δ OCH, JCf A '^ N ^{X <s} ^ ^A ^ OCH, 1 ¹ CH 3 CO ³ CH, 170

Table 7 (continued 27)

Pr. no. A X ³ X ⁴ R ¹ R ⁴ MP: C (Salt) 262 OCH Λ Η, Ο ^^ ΟΟΗ, CHjC ^ - ABOUT OCH, Joyce - ^Χ ^ '^ ^Ν χΑχ ^{Χ ΟΟΗ,} 1 ³ _CH2 CH ₂ CO, 191 263 OCH A ρΗ, ΟΗ - 0 W 1 CHjCHjCOO-On * · 193 264 OCH A 0 ΛΧ 1 (CH ₂ ), CO ₂ H 196 265 OCH A CH, CH - ABOUT - w 1 CH ₂ CO ₂ CH, 163 266 OCH RC HJC ^^^^ OCH ô ^- XW ' 1 CHjCOjCH. 205 267 OCH Λ OCH pH, CH ₂ - 0 rY about x CJ 114

Table 7 (continued 28)

Pr. No. A X ³ X ⁴ R ¹ -ΆΑ R ⁴ MP: C (Salt) 268 OCH OCH ^ CH, - 0 l · xA 1 CHjCOjH 223 (HCl) 269 OCH OCH Chachi - ABOUT xiT 1 (CH 2), CO, C _Z H, 159 270 OCH Λ OCH CH-- ABOUT xo 1 CHjCOO-On * 295 (sára salt) 271 OCH Η, Ο ^^^ ΌΟΗ. δ OCH, xA Α ^ννΆΑΆοοη 1 ³ CH ³ COOH 227 272 OCH Ä Η, Ο ^^^ ΟΟΗ. CH - ABOUT OCH, xA 1 (CH 2), CO, C, H _S 102 273 OCH A Η, Ο - '^^ ΟΟΗ. CHjCHj- ABOUT OCH Jaola (CH ^ COjCjH, 162

Table 7 (continued 29)

Pr. no. Yr X ³ X ⁴ R ¹ and Q 'R ⁴ MP: C (Salt) OCH CHjCHj- R / W ^{C S} ^ 274 1 1 B ¾ T 240 x Λ A _n x ^ i (sxra OCH at salt) H ₃ C ' CHjCOQNa * OCH CH - X @ ₅ ° C _{for 2} hours 275 1 X White 1 250 rY rj AY (saar h ₃ c- OCH ABOUT 1 CHjCOO'Na * salt) OCH CH - AP 276 1 1 161 rY X A χΧχ.-Χ <Χ OCH ABOUT 1 h ₃ c- X ΧξχΧ (CHjljCOjCjHj OCH. 1 ³ CHjCHj- X ^ OCA 277 Λ FROM X rXX 177 | 1 'N zX zX 'OCH, at 1 h ₃ c- S \ Z XX (CHJjCOjCjHj OCH CHj- OCH 278 1 X JL CH. 297 fy X rY ΓΪ Ύ (sora h ₃ c- "Oh, ABOUT X ^ N ^^^ OCH | The SDL) CHjCOONa » OCH CH - OCH 279 1 JL CH, 127 ILT from* YJ l! L L J Jj JL xJL H, OCH \ x ^{/ x} r ⁱⁿ xjch. 1 CHjCHjCOjCH,

100

Table 7 (continued 30)

Pr. no. X ³ X4 R ¹ 1 Y3 R ⁴ MP: C (Salt) 280 OCH. A Η, Ο ^^ ΟΟΗ, CH - ABOUT OCH IA 1 CHjCHjCO ^ i 303 281 OCH Λ H, C ^^ OCH CH, xx ' 1 CH, CH, CO, CH, 111 282 OCH A CH - ABOUT CH, Xa ' 1 CHjCHjCOjCH. 191 283 OCH Ä CH, CH - xX 1 ΟΗ, ΟΗ, ΟΟ, Η 289 284 OCH A Η, Ο - ^ ^^^ ΟΟ CH - ABOUT CH, XX ' 1 CHjCHjCOjH 273 285 OCH A OCH CHjCHj- ABOUT xX ' 1 (CH,), CO, H 131 (HCl)

101

Table 7 (continued 31)

Pr. no. A X ³ X ⁴ R ¹ aa R ⁴ MP: C (Salt) 286 OCH A cHjCiy- A * | 156 H, C ^X IN OCH kA 1 CHjCHjCOjCH. 287 F OCH IN CH.- about I 160 A h ₃ A X ^ oh, 1 CH, CH ₂ CO ₂ CH, 288 OCH A £ ^ CH, - , AV ^oca A 181 A HJC · ^ X'Xch. kA 1 CHjCHjCOjCH. 289 Η, Α OCH A AA-oh, CH - ABOUT , _AX ΛΑ 1 (CH,), CO, H 157 290 Η, Ο ^ OCH AAoch. CHjCHj- ABOUT α 1 (CH ₂ ), COO * Na * 140 (SRRA salt) 291 HJC ^ OCH A <Aochi. CH.- ABOUT jA CH ₂ CH, COQNa ' 174 (sodium salt) 292 HJC ^ OCH A AAqch. Aa 1 CHjCHjCOQNa * 170 (Soda salt)

102

Table 7 (continued 32)

Pr. no. R ¹ 1 R ⁴ Y ¹ -Y ² Y ³ MP: C (Salt) X ^{: /} ^ _χ4 293 J H, C ^ OCH Ύ CH - ABOUT OCH, AU '1 (CH _S ,, COO-Na' 247 (sodium salt) 294 OCH CH, CH ₂ - , x CH, 220 (sodium salt) J ₃ cr  I '^' OCH about / M 1 (CHJCOO-Na OCH 295 r x OCH and: CH, 151 J h ₃ c ^ I ' ^^^ OCH 0 II II I ^ N ^^^ Oh, (CH,), COOC, H, _S OCH jCHjCH - _ .c ₂ h ₅ 296 H, '' ä OCH 0 w 1 (CHJjCOaNa * 216 (sodium salt) 297 X CH, CH - CH, "CH. 104 H, O ^ D, ABOUT W 1 (CH ₃ , COOC ₂ H ₅ 298 HJC ^ OCH about: '^^ OCH CH - ABOUT CH, yr 1 (CH, COOC, H, 111

103

Table 7 (continued 33)

Pr. no. A X ³ X ⁴ R ¹ AA R ⁴ MP: C (Salt) 299 OCH A PV * - CH, xA 1 (CHJaCOO'Na * 159 (sxtá salt) 300 OCH JA HJC '^^ OCH CH.- ABOUT CH, xA 1 (CHa) ₃ COOH 218 301 OCH JA HJC ^^^ OCH CH, CH - ABOUT OCH, Ar A _N AA _OC w 1 (CH 3), COOC, H _S 142 302 OCH A Η, Ο ^^^ ΟΟΗ. CH - ABOUT OCH A: 1 (CH,) COOH 254 303 OCH A CHjCHj- ABOUT XJ I N-N (CH), - (/ || N-N H 240 304 OCH JA HJC ^ '^' ^ OCH C ^ CH, - XU I N-N (CHA— {| A-N-N 204 (dcasel- rasol)

104

Table 7 (continued 34)

Pr. no. A X ³ X ⁴ R ¹ aa · R ⁴ MP: C (Salt) 305 OCH XX Η, Ο - ^^^ ΟΟΗ. ΟΗ, ΟΗ - ABOUT OCH AXXoch. 1 (CH) COO-Na + 262 SCCT salt) 306 OCH XX Η, Ο '^^' ΟΟΗ. JHjCHj- ABOUT OCH xA 1 (CH,), COOCH, 159 307 OCH, A H, C ^{/ <V} _Ac4! CH, CH ABOUT OCH And, 1 (CH,), COOCH, 103 308 OCH A Η, Ο'Ά'ΆοΗ. CH, CH - ABOUT OCH Ac 1 (CH,) COOH 242 309 OCH x OCH pHjCH, ^- 0 CH, xA 1 (CH,), COOCH, 104 310 OCH XX Η, Ο - ^^ ΟΟΗ, CH, CH ABOUT OCH xA 1 ΟΗ, ΟΟΟΗ 235 (HCl)

105

Table 7 (continued 35)

Pr. no. A X ³ X ⁴ R ¹ R ⁴ T. t. C (Salt) 311 OCH heehaw Η, ^ οΧ ΧοΟΗ, CH - ABOUT OCH, χά 1 (CH 2), COOCH ₃ 196 312 OCH JA H ^ XX ^ OCH CHjCH - ABOUT OCH xv 1 (CH? COO-Na + 259 (sodium salt) 313 OCH A H ^ X ^ OCH J = CH, - 0 W t (CH,) ₃ CO, C ₂ H ₅ 130 314 OCH ₃ CX ^ h xochu, CHjCH - ABOUT w 1 (CHjJjCOjCH. 92 315 OCH X OCH CH, CH - about W 1 (CH ₃ COOC, H _S 170 316 OCH A η, οΧΧόοη. A Wil A-N-N 187 (Čfcaasl · salt)

106

Table 7 (continued 36)

Pr. no. A X ³ X ⁴ R ¹ i Y ³ R ⁴ T. t. C (Salt) 317 OCH η, ο ^^^ οοη. CH.CH - ABOUT xA , N — N (CH3), - (/ || Na * · N — N 260 sodium SALT) 318 OCH A CJ, OCH CH-CH. ^- Oh A 1 (CH) COOH 132 319 OCH Η, Ο ^^^ ΟΟΗ. ChLCH-CH ABOUT CH, xA 1 CH, CO, CH, 112 320 OCH CH - ABOUT CH, X 1 CHjCO ^3, CH 258 321 OCH Η, Ο - ^^^ ΟΟΗ. CH-CH, - ABOUT CH, xA: CHjCOjCH. 188 322 OCH HJC ^^^ OCH CH - CH, ^- δ OCH jxx CHjCHjCOOH 293

107

Table 7 (continued 37)

Pr. no. A X ³ X ⁴ R ¹ xA. R ⁴ MP: 'c (Salt) 323 OCH Λ OCH CH ₂ CH _r 0 CH, XV 'CH ₂ CH ₂ COOH 258 2 HCl 324 OCH A Η, Ο ^^^ ΟΟΗ. ch ₂ - ó W | CH, CHjCOOCH. 149 325 OCH, xX H, C ' ^X ^ ^{X <} OCH, CHjCHj- ABOUT XV | CH, CH3COOCH, 118 32S OCH xX Η, Ο ^^ ΟΟΗ, CH - ABOUT xV I CH, (CH 3 JCOCO 3 H 3 97 327 OCH A HJC - ^^^ OCH W »- XVI CH, (CH ₂ ), COOC ₂ H _p 138 328 OCH xX Η, Ο ^^ ΟΟΗ, X xV | CH, CH ₂ COOH 179

108

Table 7 (continued 38)

Pr. no. A X ³ X ⁴ R ¹ xA R r. t. C salt) 329 OCH A Η, Ο ^^^ ΟΟΗ. 34jCH _2-0 XV ¹ 1 CH, CH ₂ COOH 189 330 OCH A Η, Ο ^^ ΟΟΗ, CH - ABOUT xV | CH, (CH3), COOH 200 331 OCH A > ^ ch ₂ - ô XV 1 CH, (CH3COOH 151 332 OCH A Η, Ο ^^^ ΧΟΗ. CH, CH, CH, ABOUT' XV 1 CHjCOOCH. 119 333 OCH I ZA HjC- ^ XXoch, CH, CH, CH, ABOUT XV 1 (CH COOCH, 102 334 OCH A HJC ^ '^^ OCH CH-CH, CH, δ ¹ XV 1 (CH ₂ ), COOH 143 335 OCH A HJC ^^ Z ^ OCH CH-C-LCH, delta ¹ XV 1 (CHJjCOOCjH. 135

109

Table 7 (continued 39)

Pr. no. A X ³ X ⁴ R ¹ 1 Y3 R ⁴ MP: "c (Salt) 336 OCH A CH.CH _and CH. ô ¹ A 1 CHjCOOH 151 337 OCH A CH-CH-CH. ABOUT' AU 1 (CH, COOH 138 338 OCH XX á au .; CH, COOH 195 (HCl) 339 OCH A Η, Ο - ^^^ ΟΟΗ. CHjCHj- 0 AU, ¹¹ CH ³ COOH 185 340 OCH A CH-CH-CH, O ¹ CH, _A ^<ch 'and H 1 (CHJjCOOCH, 116 341 OCH A Η, Ο ^^^ ΟΟΗ. CH-CH-CH- ABOUT' CH, A 1 (ChyjCOoCjH. 96

110

Table 7 (continued 40)

Pr. no. A X ³ X ⁴ R ¹ xA iy ³ R ⁴ T. t. C (Salt) 342 OCH A CH.CH.CH. about' CH, A 1 (CH,) COOH 149 343 OCH A CHjCHjCH. about' CH, xA 1 (CH,) COOH 146 344 OCH A Η, Ο '^^^' ΟΟΗ. δ ' OCH X 1 (CHJjCOOH 273 (HCl) 345 OCH H, C ^ I ^ OCH ČKCH - ABOUT AU. i · (CH,), COOCH, 202 346 OCH H, C ^ icchāmi, CH - A w 1 (CH COjH 167 347 OCH HJC '^^^ oh, CH.CH - ABOUT CH, xA 1 (CH 2), COO-Na♦ 279 [sala salt)

111

Table 7 (continued 41)

Pr. no. \ - ^> < > <* x R ¹ Ά R ⁴ MP: C (Salt) 348 OCH HJC ^^^ OCH CH.CH, ^- Ô CH, λXX, I (CH 3) j COOC 3 H _s 80 349 OCH HJC ^^ i ^ OCH á CH, A 1 (CH,), COOC, H, 134 350 OCH A OCH CH.CH, ^- Oh CH, A ' 1 CHjCOOCH. 130 351 OCH A OCH CH.CH, ^- Oh CH, ΛΧΤ 1 (CH,), COOCH, 122 352 OCH A. CH.CH - ABOUT CH, A | CH, CHjCOOCH. 99

112

Table 7 (continued 42)

Pr. no. A X ³ X ⁴ R ¹ 1 Y ³ R ⁴ MP: ° C (Salt) 353 OCH Η, Ο ^^^ ΟΟΗ. CH - ABOUT CH, A | CH, CH, COOCH, 218 354 OCH 1 Η, Ο ^^^ ΟΟΗ. δ A CH, (CH _a ), COOC, H _p 96 355 OCH Η, Ο ^^ ΑοΗ, CH-CH, - ABOUT CH, A | CH, (CH,), COOC, H, 168 356 OCH Η, Ο '^^ ζίΟΗ. CPLCH - ABOUT A M'Lila N-N H 248 357 OCH η, ο ^^^ Αοη. CH, CH - δ AX M'Lila N-N H 196

113

Table 7 (continued 43)

Pr. no. A X ³ X ⁴ R ¹ A R ⁴ T. t. C (Salt) 353 OCH CH.CH.CH, oh ^! CH, A CHjCOO'Na * 174th soba salt) 359 OCH Η, Ι Ο- ^ ^^ ΟΟΗ, CH-CH, ^- O JA 1 CH, CHjCOOCH. 198 360 OCH HJC ^^^ OCH δ I CH, CH, COOCH, 186 361 OCH H, ^^^ AD. CH-CH, - δ CH, aA 7 N — N (CH 2), - (| N — N H 1 233 362 OCH Λ CH-CH-- ABOUT CH,,, AsA ^H 'αΠ 7 N — N (CHJ, - || Na * · N — N 216 (statue salt)

114

Table 7 (continued 44)

Pr. no. A X ³ X ⁴ R ¹ Αδ. ' R ⁴ T. t. C (Salt) 363 OCH Η, Ο - ^^^ ΟΟΗ. CH-CH. " ABOUT CH, -¾ A-N-N 191 drase.- iá sal) 364 Ά cr och, CH-CH. " ABOUT CH, A ' CHjCOOH 240 365 Ά cr och, CH-CH-- ABOUT CH, A 1 (CH) jCOOH 198 366 OCH, H, C ^'Z ^^ Oh, CH, CH-- ABOUT CH, A: 1 (CH,) COOH 247 (HCl) 367 OCH HJC ^^^ OCH δ ' CH, A: 1 (CH,) COOH 185 (HCl)

115

Table 7 (continued 45)

116

Table 7 (continued 46)

Pr. no. A X ³ X ⁴ R ¹ xA iy ³ R ⁴ T. t. 'c (Salt) 375 OCH rV 34.04 - ABOUT CH, A> CH, CO, H 199 376 OCH Η, Ο - ^^^ ΟΟΗ. CH - ABOUT (CH ₂ ), COO * Na * 214 (HCI and SCAA salt) 377 OCH, H, C ' ^Z ^^ OCH, 04,0 "- CH, A 1 CH, (CH ₂ ), COO-Na * 147 (HCI and S ± 33 salt) 378 OCH Η, Ο ^^^ ΟΟΗ. ΟΗ, ΟΗ - 0 xA 1 CH, CH, COO-Na * 156 (Soane SALT) 379 OCH Η, Ο ^^^ ΟΟΗ. 5 xA 1 CH, CH ₂ COO'Na * 219 380 OCH A. W £ H, - XA '| CH, (CH 2), COOC, H _S 131

117

Table 7 (continued 47)

Pr. no. A X ³ X ⁴ R ¹ χΰ; 1 Y ³ R ⁴ T. t. 'C (Salt) 381 OCH Η, Ο Ι ^^ ^ ζίΟΗ, CH.- ABOUT | CH, (CH 3, COOC, H ₅ 148 382 OCH cn, 1 (CH 3) ₄ COOC ₂ H _S 85 383 OCH A Η, Ο - ^^^ ΟΟΗ. Χ, ΟΗ - 0 XV | CH, (CH ₂ ), CO ₂ H 141 384 OCH Η, Ο '^^^ ΟΟΗ. CH - ABOUT , N ^oh 'Ά 1 CH {CH,), CO, H 161 385 OCH η, ο - ^^^ οοη. (CH, COOC, H, 151 386 OCH H, C ^ I ^ OCH A χΑ- CHjCOO · Na * 268 sxtá salt)

118

Table 7 (continued 48)

? R. no. X ³ X ⁴ R ¹ xXA 1 Y ³ R ⁴ MP: C (Salt) 387 OCH η, ο ^^^ οοη. H, CH - about xx " 1 (CH,) COOH 155 388 OCH H. C '^^^ OCH δ ^- CH, ¹¹ CH, COO-Na * 195 (S3ÍB blended) 389 OCH Η, Ο ^^^ ΟΟΗ. δ CH, xÓQ 1 (CH, COOCH, 214 390 OCH δ CH, XCC, 1 (CH,) COOH 293 (HCl, 391 OCH Λ CH - ABOUT χδ I CH, CH, COO 271 392 OCH HJC ^^ I ^ OCH xQ M (1 N-jl 177

119

Table 7 (continued 49)

120

Table 7 (continued 50)

Pr. no. A X ³ X ⁴ R ¹ aa R ⁴ MP: C (Salt) 399 OCH A FROM CH-- rs Aa 220 sjäá H, C '' N, OCH J, Ϊ (CH) COO-Na + salt) 400 OCH Λ from CH, CH _Z - xA '' 246 H, C N, OCH 0 1, w,> .J (Chy, COO-Na + CHjCHj- Z ^ Cl 401 Ä FROM* Λ xA 202 H, · * N, OCH U I CH, CHjCOOCH. ch ₂ ch- AA ^ 402 Ä WITH Λ 266 sxta H, N, OCH A I CH, SAL) CH, COO-Na + OCH ρΗ, ΟΗ - » 403 A from- X 128 H, AaA "Oh, A 1 OCH, CH, COOCH, CHjCH - ^ Z-OCH 404 A with X xA 144 H, 'OCH, A 1 OCH, (CH ₂ ), COOC, H ₅ 405 OCH Λ from· CH - X xA. " 224 SDA H, C ' 'OCH, AA 1 » SALT) 1 IjW CH, COO -Na-

121

Table 7 (continued 51)

Pr. no. X X ³ X ⁴ R ¹ | Y3 R ⁴ MP: C (Salt) 406 OCH Η, Ο - '^^ ΟΟΗ. δ ' XV 1 CH, CHjCOOCH. 158 407 OCH HJC ^^ I ^ OCH ρςοΗ- 0 CH, yr 1 CHjCOOCH. 117 408 OCH Η, Ο - ^^^ ΟΟΗ. f H ^ H, - 0 CH, xxr 1 (CHJCOOCH. 134 409 OCH PW " ? X? Yochi, | OCH CHjCOjH 185 (HCl) 410 OCH HJC ^^^ OCH xy ' | OCH (CH,) COOH 144 (HCl) 411 OCH H. C ^^^ OCH δ? OCH, xá ™ 1 (CH3) ₃ COO-Na * 178 (statue salt)

122

Table 7 (continued 52)

123

Table Ί (continued 53)

Pr. no. A X ³ X ⁴ R ¹ i Y ³ R ⁴ MP: C (Salt) 418 OCH Η, Ο - ^^^ ΟΟΗ. CH - ABOUT x ^ oon, AX I CHjCOOCH ,. 228 419 OCH Η, Ο ^^^ ΟΟΗ. X 1¾ ABOUT 217 420 OCH, H _and C c ^ ^OCH. δ ' r — AA- ° ^CH and A? 1 OCH, (CH 2), COOC, H, 168 421 OCH H, C ^ I ^ OCH p- and X 1 CH, CO, CH, 113 422 OCH x , AA 'OCH' ^A10CH , CH ₂ COOH 201 (HCl) 423 OCH Η, Α ο ^^ ^ ΟΟΗ, x | OCH, (CH3) ₃ COOH 146 (HCl)

124

Table 7 (continued 54)

Pr. no. X ' ^X Á X R ¹ JOC Y ¹ MP: C A X ³ X ⁴ l Y ³ (Salt) R ⁴

424

CH, CH, C

H,

OCH

OCH

3H, CH, 425

OCH

H ₃ C 'and ₃

426

H ₃ C

OCH

OCH _S

_: CH, -

427

HJC

OCH

OCH

CH -

428

H,

OCH

OCH

CH -

429

H,

OCH

CH -

CH, COOH

X,

CH, COOH

Ac

OCH

N I

CH, COO'Na "

OCH

X ^ OCH, ^ OCH,

N I

CH, COO-C '

CH, CH3COOCH,

CH, COOCH,

198 (HCI)

167

244 (set

SQL)

245 (dcaselre salt)

151

157

125

Table 7 (continued 55)

Pr. no. A X ³ X ⁴ R ¹ 1 Y ³ R ⁴ T. t. C (Salt) 430 OCH Η, Ο ^ ^ ΟΟΗ ύ. OCH aA ml N-N H 205 431 OCH H. C '^^^ OCH CHjCHj- ABOUT OCH, Xn 1 ^{N -} 1 (CH 3), - j Na * · N - N WITH 248 (sodium salt) 432 OCH, H ₃ C - ^^ I ^ _OCH3 CHjCHj- ABOUT OCH aJ: J N — N (CH,), - | A-N-N 240 (sodium SQLj 433 OCH Η, Ο ^^^ ΟΟΗ. CHjCHj- ABOUT (CH3) jCOO 'Na * 144 [sodium salt) 434 OCH, H, C 1 ^Z 2 O 2 OCH, 5 A7 | CH _(CH3), C00 * ♦ Na 220 ! sodium salt)

126

Table 7 (continued 56)

Pr. no. A X ³ X ⁴ R ¹ xA i Y ³ R ⁴ MP: ° C (Salt) 435 OCH Η, Ο ^^^ ΟΟΗ. C ^ CH, - ABOUT CH, A 1 (CH,), COOCH, 108 436 OCH h ^^ IaXoch, CH-CH, - ABOUT CH, XQ '1 (CH 2), COOC 3 H _s 77 437 OCH HJC ^^^ OCH CH-CH, - ABOUT CH, xA 1 (CH,) COOH 270 (HCl) 438 OCH Η, Ο ^^^ ΟΟΗ. CH-CH, - ABOUT CH, xA First (CH,) COOH 278 (HCl) 439 OCH H, C ^ I ^ OCH 5 CH, xA, 1 * (CH,), COO · Na · 179 (9ΟΪΥ salt)

127

Table 7 (continued 57)

Pr. no. x \ Ά X ³ X ⁴ R ¹ A 'R ⁴ T. t. C (Salt) 440 OCH HR '^^^ oh fHjCH - 0 CH, Al 1 (CH 2), COOC ₂ H ₅ 167 (HCl) 441 OCH, H, C ^{x Z} ^^ OCH, O ^ H, - AJ 1 CH, (CH 2), COOC, H _S 164 442 OCH HJC - ^^ I ^ OCH SHjCH - ABOUT JoQi ^C1 1 CH, (CHj), COO Na ' 150 'herself SAL) 443 OCH fl HJC - '^^ OCH ch - about r = A ^ ^OCH 1 Al (CH 2), COOC 1 H _S 113 444 OCH HJC ^^^ OCH CH. " ABOUT joCC N AA _and 1 CH 3 COOH 185 445 OCH Η, Ο '^^^ ΑοΗ. AA 1 (CH,) COOH 209

128

Table 7 (continued 58)

Pr. no. A X ³ X ⁴ R ¹ A R ⁴ Rt 'C salt) 446 OCH CH - ABOUT XV 1 CH, CH ₂ COONa 296 [33XB salt) 447 OCH A η, ο ^^^ οοη. 3HjCH ₂ - O xA | CH, CH ₂ COO'Na * 221 (sodium salt) 448 OCH Η, Ο '^^^ θΟΗ. fH ₂ CH ₂ O CH, Xia 1 (CH) COOH 190 449 OCH HJC ^^^ OCH CH - δ aaA ^ch 3 xA ', 1 (CH 2), COOH 246 450 OCH H ^ Z ^^ OCH CH.- δ r_ / V ⁰⁰ "1 and ³ (CH ₂₎ jCOOCH, 196 451 OCH A. > ^ yX ^0CH 3 xA 1 (CH3JCOOCH, 139

129

Table 7 (continued 59)

Pr. no. A X ³ X ⁴ R ¹ Αδ ' R4 T. t. C (Salt) 452 OCH A XjCH - AX 1 (CH,), COOC, H, 109 453 OCH H, C ^ I ^ OCH D A 1 (CHJ, COO) 217 (sxta SOI ¹ ) 454 OCH A Η, Ο - ^^ ΟΟΗ, ,, Z ^ X 1 AX 3 ^0CH (CH,) COOH 245 455 OCH A HJC ^^^ OCH CH, CH - ABOUT CH, XX 1 ³ CH, COO · Na · 238 Saia salt) 455 OCH A OCH C SHjCH - CH, A ' 1 CH, CO, CH 173 457 OCH A OCH C χ, α-ι - P A ' 1 (CH,), COOC, H, 169

130

Table 7 (continued 60)

Pr. no. A X ³ X ⁴ R ¹ xA R ⁴ MP: C (Salt) 458 OCH A OCH XjCH - CH, AU 1 ΟΗ, ΟΟ, Η 164 (HCl) 459 OCH A OCH C WJCh - CH, AU 1 (CH) jCOOCH. 116 460 OCH H, C ^ I ^ OCH CH ³ 1 HC-CH ² CHR 1, CH, AU ' 1 CHjCOjCH. 243 461 OCH Η, Ο - ^^^ ΟΟΗ. CH, ^HC-3 1 CHjCH, CH, AV 1 (CH ₂ ), COOC, H _p 159 462 OCH H, C ^ I ^ OCH CH1 ³ H — CH — CH, CH, A 1 CHjCOOH 227

131

Table 7 (continued 61)

Pr. no. A X ³ X ⁴ R ¹ xA 'R ⁴ MP: C (Salt) 463 OCH CH, 1 'HC-CH ² CHR 1, CH, xA ' (Ih), COOH 150 464 OCH A OCH ; HjCHj- CH, xA 1 (CH,) COOH 208 (HCl) 465 OCH A OCH ^ CH, - CH, XV 1 (CH,) COOH 254 466 OCH A and ΟΗ, ΟΗ - ABOUT CH, XV 1 CHjCOOCH. 108 467 OCH A. and ZHjCH - CH, XV 1 (CH COOCH, 91

132

Table 7 (continued 62)

Pr. no. A X ³ X ⁴ R ¹ A; R ⁴ T. t. C (Salt) 468 OCH A. J34, CH - 0 OCH A: 1 (CH,), COOCH, 139 469 OCH ρΗ ^ Η - 0 OCH xA (L,), COO-Na♦ 265 Saxa salt) 470 OCH fHjCH - 0 OCH Until, 1 CHjCOOCH. 188 471 OCH A Cl C XjCH - r A 1 ΟΗ, ΟΟ, Η 190 (HCl) 472 OCH A Cl LHjCH - CH, A 1 (CH) COOH 243 (HCl)

133

Table 7 (continued 63)

Pr. no. A X ³ X ⁴ R ¹ xA R ⁴ T. t. C (Salt) 473 OCH A CH, CH-CH-- ABOUT r · A 1 CH, COOCH, " 98 474 OCH A CH, CH-CH.- ABOUT Ih A 1 (CH,), COOCH, 86 475 OCH Η, Ο - '^^' ΟΟΗ. PCH - 0 CH, A: 1 (CH ₂ ), COOH 275 476 OCH HJC '^^^ OCH J = CH, - 0 CH, A: 1 (CH, COOH 175 477 OCH HJC - ^^^ Aichi, <1 H, HC - CH _r CH, n ^- ifi ^CHi A ^ _n Ά 1 (CH,), COOCH, 205

134

Table 7 (continued 64)

Pr. no. A X ³ X ⁴ R ¹ xA; R ⁴ MP: C (Salt) 478 OCH "A CH, ^ CH, - CH, xA 1 CH, COOCH, 132 479 OCH HJC ^^^ OCH CH, (W CH, XV 1 (CH jjRead, 33 480 OCH, h ₃ c ^^^ Ach ₃ CH, (PCH - CH, xA 1 (CH ₂ ), COOC 3 H _s 97 481 OCH HJC '^^^ OCH CH, , _ / VA A 1A 1 (CHJjCOOC ss, 82 482 OCH HJC ^^^ OCH CH, PtPt.- CH, XV 1 CHjCOO'Na * 274 (sodium salt)

135

Table 7 (continued 65)

Pr. no. A X ³ X ⁴ R ¹ 1 Y ³ R ⁴ MP: C (Salt) 483 OCH Αδ CH, ^ 01 - CH, A 1 (CH,) COOH 271 484 OCH A. CH, CHjCH - ABOUT L * aA 1 CHjCOOH 237 (HCl) 485 OCH A CH, CHjCHj- 0 CH, aa 1 (CH) jCOOH 144 (HCl) 486 OCH Η, Ο ^^^ ΟΟΗ. pHjCHj- 0 OCH AAZ. 1 CHjCOO- Na * 228 (S3XB salt and HCl) 487 OCH, H, ^"x ^ C) CH, CH, aA I (CH) COO-Na + 166 - -à salt)

136

Table 7 (continued 66)

Pr. no. A X ³ X ⁴ R ¹ xX R ⁴ MP: C (Salt) 488 OCH Η, Ο Ι ^ ^^ ΟΟΗ, CH, A A _n AXoch, 1 (CHJ, COOH 138 48S OCH Η, Ο ^^^ ΟΟΗ. £ J 3 H- 0 OCH, XCR Χ ^ Ν ^'Χχ Χ ^ ΟΟΗ ₅ 1 (CH ₂₎ COOC, H _p 124 490 OCH A CH, ΟΗ, ΟΗ - 0 and _n -OA _h I CH, COOCH, 138 491 OCH Η, Ο ^^^ ΟΟΗ. CH, ΟΗ, ΟΗ - ABOUT A CXoch, _Z 1 CH COOH 224 492 OCH HJC ^^^ OCH X ' 1 Cl CHjCOOCH. 197 493 OCH HJC '^' ^ OCH tw XV 1 Cl CH, COO'Na * 210 statue salt)

137

Table 7 (continued 67)

138

Table 7 (continued 68)

X!

X ²

X ³ X ⁴

R ¹ JCX IN T. t. C 1 (Salt) R ⁴

CH ^

500

OCH

H,

OCH

OCH

OCH

CH COO'K *

139 draaslrá SALT)

501

H,

OCH

OCH

502

OCH

OCH

503

OCH

OCH

504

OCH

OCH

505

OCH

X, C, -

CHjCH -

OCH

CH ₂ COO'Na ·

οη, οοο-κ *

CH, CH, COOCH

ch ₂ coo-k ·

190 salt salts)

237 (potassium salt)

230 (potassium salt ¹ )

208

202 (potassium salt)

139

Table 7 (continued 69)

140

Example 512

2- {N- [5- (4-Chloro-2,5-dimethoxyphenyl) -1- (2-cyclohexylethyl) -1H-1,2,4-triazol-3-yl] carbamoyl} -4,5-dimethyl -1- [3- (2H-1,2,3,4-tetrazol-5-yl) propyl] -1H-indole

- step 1: 4- [2 - ({[1- (2-cyclohexylethyl) -5- (2,5-dimethoxy-4-chlorophenyl) -1H-1,2,4-triazol-3-yl] amino} carbamoyl) -4,5-dimethyl-1H-indolyl] butyronitrile

To 15 ml of dichloromethane was gradually added 1 ml (0.013 mol) of pyridine and 0.21 ml (0.0029 mol) of thionyl chloride. After 15 minutes at 0 ° C, add 0.615 g (0.0024 mol) of 4,5-dimethyl-1- (3-cyanopropyl) -1H-2-indolecarboxylic acid followed by 0.9 g of 1- (2-cyclohexylethyl) 1- (2,5-Dimethoxy-4-chloro-phenyl) -1H-1,2,4-triazol-3-amine hydrochloride. The reaction mixture is maintained for 18 hours at ambient temperature and an acidic and then alkaline wash of the reaction mixture is performed. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. The oily residue is chromatographed on a column of silica gel, eluting with a dichloromethane / methanol (98.5: 1.5; v / v) mixture to give a white powdery product.

Melting point: 178 ° C, yield: 87%.

- Step 2: 2- {N- [5- (4-Chloro-2,5-dimethoxyphenyl) -1- (2-cyclohexylethyl) -1H-1,2,4-triazol-3-yl] carbamoyl} -4 , 5-dimethyl-1- [3- (2H-1,2,3,4-tetrazol-5-yl) propyl] -lH-indole

K 0.720 g (0.0012 mol) 4- [2 - ({[1- (2-cyclohexylethyl) -5- (2,5-dimethoxy-4-chlorophenyl) -1H-1,2,4-triazole-3] -yl] amino] carbamoyl) -4,5-dimethyl-1H-indolyl] butyronitrile dissolved in 15 ml of tetrahydrofuran was added 0.5 ml of azidotrimethylsilane and 0.030 g of dibutyltin oxide and the resulting mixture was heated to boiling below

141 reflux condenser for 18 hours. The reaction mixture was then allowed to cool to ambient temperature, tetrahydrofuran was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with a dichloromethane / methanol (95/5; v / v) mixture to give a white solid. Mp .: 233 ° C, yield: 78%.

The procedure described for Example 512 was also used for Examples 303, 304, 317, 356, 357, 361, 362, 363, 368, 369, 392, 394, 395, 430, 431 and 432.

The potassium and sodium salts of these compounds are obtained in acetonitrile by addition of an equivalent of a base at ambient temperature followed by evaporation of the solvent under reduced pressure and drying.

Claims (16)

A compound of formula I wherein: R ¹ represents an alkyl group having 2 to 6 carbon atoms; a - (CH ₂ ) _m -G group wherein m is an integer from 0 to 5 and G is a non-aromatic mono- or polycyclic hydrocarbon group having 3 to 13 carbon atoms optionally substituted by one or more alkyl groups having 1 to 3 carbon atoms; a phenylalkyl group in which the alkyl radical contains 1 to 3 carbon atoms and the phenyl radical is optionally substituted one or more times with a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms; - (CH ₂ ) _n NR ² R ³ in which n is an integer from 1 to 6 and R ² and R ³ , which are the same or different, represent an alkyl group having 1 to 3 carbon atoms or forming together with the nitrogen atom to which they are attached, a morpholine group, a piperidine group, a pyrrolidinyl group or a piperazine group; X ¹ , X ² , X ³ or X ⁴ each independently represent a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 3 alkoxy group or a trifluoromethyl group, with only one of X ¹ , X ² , X ³ or X ⁴ optionally represents a hydrogen atom; R ⁴ represents a hydrogen atom, a - (CH ₂ ) _n COOR ^{5 group} in which n is as defined above, and R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an arylalkyl group in which the aryl radical contains 6 to 6 carbon atoms; 10 carbon atoms and the alkyl radical contains 1 to 6 carbon atoms; (C 1 -C 6) alkyl; - (CH 2) OR ⁵ or - (CH ² ) n NR ² R ³ in which R ² , R ³ and R ⁵ are as defined above; - (CH 2) _n -tetrazolyl, in which n is as defined above, or R ⁴ represents one of these groups in the form of an alkali metal or alkaline earth metal salt; Y ¹ , Y ² and Y ³ are each independently hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, nitro, cyano, acylamino in which the acyl radical is 1 to 6 carbon atoms, a carbamoyl group, a trifluoromethyl group, a group -COOR ^6, wherein R ⁶ is H or alkyl of 1 to 3 carbon atoms; or one of their salts or solvates. Compound of formula I according to claim 1, in which R ¹ , R ⁴ , X ¹ , X ² , X ³ and X ⁴ have the meanings specified in claim 1 and Y ¹ , Y ² and Y ³ represent a hydrogen atom, or one of its salts or solvates. A compound of formula I according to claim 1, wherein R ¹ and R ⁴ are as defined in claim 1, Y ¹ , Y ² and Y ³ represent a hydrogen atom and a group X ² —X ³ x * represents a 2,6-dimethoxy-4-methylphenyl group, or one of its salts or solvates. 144 A compound of the formula I as claimed in claim 1, wherein R ¹ , R ⁴ , Y ¹ , Y ² and Y ³ have the meanings given in claim 1 and the group represents 2,6-dimethoxy-4-methylphenyl or any one of them salts or solvates. A compound of formula I according to claim 1, wherein R ¹ , R ⁴ , Y ¹ , Y ² and Y ³ have the meanings given in claim 1 and a group X ¹ AV x ² —IΆ X ³ X stands for wherein X ² represents a methyl group or a chlorine atom, or one of its salts or solvates. A compound of formula 7 wherein R ¹ , X ¹ , X ² , X ³ and X ⁴ have the meanings given in claim 1 for formula I. Process for the preparation of a compound of the formula I according to any one of claims 1 to 5, characterized in that the aminotriazole of the formula 7 145 wherein R ¹ , X ¹ , X ² , X ³ and X ⁴ have the meanings given in claim 1 for formula (I), react with an indole carboxylic acid of formula (8) HO-CII R ⁴ A —Y ² Y 3 (8) wherein R ⁴ , Y ¹ , Y ² and Y ³ have the meanings given in claim 1 for formula (I) to give compounds of formula (I) or one of their salts or solvates. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 5, characterized in that the aminotriazole of formula (7) wherein R ¹ , X ¹ , X ² , X ³ and X ⁴ have the meanings given in claim 1 for formula I, reacts either with an indole carboxylic acid derivative of the general formula 8 146 .Y HO-ΟΙΙ O —Y IYR ⁴ (8: wherein R ⁴ , Y ¹ , Y ² and Y ³ are as defined in claim 1 for formula (I), or with an indole carboxylic acid derivative of the general formula 8 ': 8') in which Y ¹ , Y ² and Y ³ have the meanings given in claim 1 for the general formula I and R ⁴ 'represents a precursor group of R ⁴ to form an intermediate compound of general formula of formula I ' R ⁴ ' Y XX-Y wherein R ¹ , X ¹ , X ² , X ³ , X ⁴ , Y ¹ , Y ² and Y ³ have the meanings set forth in claim 1 for formula I and R ⁴ 'represents a precursor group of the group R ⁴ , wherein R ⁴ is as defined in claim 1 for formula I. Pharmaceutical composition, characterized in that it contains a compound of the general formula as active substance 147 The compound of claim 1 or one of its pharmaceutically acceptable salts. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound according to claim 2 or one of its pharmaceutically acceptable salts. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound according to claim 3 or one of its pharmaceutically acceptable salts. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound according to claim 4 or one of its pharmaceutically acceptable salts. 13. A pharmaceutical composition comprising as active ingredient a compound according to claim 5 or one of its pharmaceutically acceptable salts. Use of a compound according to any one of claims 1 to 5 for the preparation of medicaments for treating nutritional and obesity disorders and for reducing food intake. Use of a compound according to any one of claims 1 to 5 for the preparation of medicaments for the treatment of late dyskinesia. Use of a compound according to any one of claims 1 to 5 for the preparation of medicaments for treating disorders in the gastrointestinal region.