BG99879A - Inhibitors of hiv reversive transcriptase - Google Patents

Abstract

Indole derivatives inhibit HIV reverse transcriptase and are effective for the prevention and treatment of HIV infections as well as for the treatment of acquired immune deficiency syndrome (AIDS). They are used as pure compounds, as pharmaceutically acceptable salts thereof, as active ingredients of pharmaceutical compositions, alone or in combination with other antiviral agents, anti-infectives, immunomodulators, antibiotics or vaccines. The invention also relates to methods for treating AIDS and for the prevention or treatment of viral infections caused by HIV.

Description

The invention is a continuation of application US No. 07 / 866,765, filed April 9, 1992, related to previous applications US No. 07 / 832,260, filed February 7, 1992 and previously US No. 07 / 756,013, filed September 6, 1991, which now have been abandoned.

The present application relates to compounds that inhibit reversible transcriptase encoded by human immunodeficiency virus (HIV) or to their pharmaceutically acceptable salts, which are useful for the prevention of infections caused by HIV for the treatment of HIV infections, as and for the treatment of Acquired Immune Deficiency Syndrome (AIDS). The invention also relates to pharmaceutical compositions containing the compounds and to a method of using the present compounds and other agents for the treatment of AIDS and viral infections caused by HIV.

BACKGROUND OF THE INVENTION

A retrovirus called human immunodeficiency virus (HIV) is an etiologic agent of a complex disease that manifests itself in the progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous systems. This virus was previously known as LAV, HTLV-III or ARV. Simple transcription of the RNA genome of i

transcriptase characteristic of retroviral replication is reversible until a virus-encoded reverse is created

I

DNA copies of HIV sequences, which is a necessary step in viral replication.

Certain compounds are known to be inhibitors of reverse transcriptase and are effective agents for the treatment of AIDS and similar diseases, e.g. azidothymidine or cidovudine (AZT) compounds.

The nucleotide sequence of HIV includes the presence of ro! freely available gene [Ratner, L. et. al., Nature, 313, 277 (1985)], Homology in the amino acid sequence provides evidence that the semi-sequence encodes reverse transcriptase, endonuclease and HIV protease. [Toh, N. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature 329, 351 (1987)].

The compounds of the invention are inhibitors of HIV reverse transcriptase. In addition, the compounds of the invention do not need bioactivation to be effective.

SUMMARY OF THE INVENTION

The invention relates to new compounds of formula A:

• · ·

as H1V reverse transcriptase inhibitors to prevent

not for HIV infections as well as for the treatment of AIDS and / or compounds or in the form of their treatment for ARC infections or as free!

pharmaceutically acceptable salts (where appropriate) as well as active components of pharmaceutical compositions which may be combined with other antiviral agents, anti-infective agents, immunomodulators, antibiotics or vaccines. The invention also relates to a method of treating AIDS, a method of preventing infection caused by HIV, and methods of treating HIV infection.

Detailed description of the invention and preferred embodiments

The invention relates to the compounds of formula A, described below, to combinations thereof or to their pharmaceutically acceptable salts or esters, which are inhibitors of HIV reverse transcriptase, to the prevention or treatment of infections caused by HIV and to the treatment of acquired immune syndrome

insufficiency (AIDS). have the general formula A: The compounds, according to the invention Y-R A \ R ⁶ in which X is - H, -Cl, -F, -Br, -NO ₂ , -CN, -OR2, -NR2R2, -

NHSO2-C1-6-alkyl or -NHCO-C- C3-alkyl;

Y is -S (O) _n - or -O-, where η is the number 0, 1 or 2;

· · · · · · · · · · · · · · · · · · · · · · · · · · ·

R is: 1) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups

a) -C- .5-alkyl,

b) -Ci-5-alkoxy,

c) -OH or

d) aryl, unsubstituted or substituted by one or more groups

i) -C 1-5 -alkyl,

v) -NR2R2,

2) aryl, unsubstituted or substituted by one or more of the groups:

(a) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups:

i) -OH or

b) -C- .5-alkoxy,

c)

-OH,

d) halogen or

θ)

-NR ² R ² ,

3) heterocycle, unsubstituted or substituted by one or more of the groups:

a) -C- .5-alkyl, unsubstituted or substituted by one or more groups:

i) -OH or ii) -C- .5-alkoxy,

b) -C 1-5 -alkoxy,

c) -OH,

I

d) halogen or

e) -NR2r2 ₍ or

4) the group -NR ² r ³ ', provided that Y is -S (O) _n -;

Z is:

1) -C-NR ² R ³ ,

II

W where W is O, S, -N-CN or -N-OR ² ,

2) -COR ^1a ,

3) -COOR ^1b ,

4) CR ² R ² -S (O) _n -R ^{1 a} , where η has the above meaning,

5) -CR2R2NHR4,

6) -CR2R2.CO-R ^5,

7) -C1-3 alkyl substituted by one or more of the groups:

(a) aryl, unsubstituted or substituted by one or more groups

i) -Ci-5-alkyl,

I) -C- .5-alkoxy, 'iii) -OH, iv) halogen or

v) -NR2r2_ _And whether

b) heterocycle, unsubstituted or substituted by one or more of

group e i) -C- | -5-alkyl, ii) -C- .5-alkoxy, iii) -OH, iv) halogen or v) -NR2r2 ₎ or 8) -CN; R ¹ is: 1) hydrogen.

2) -C 1-5 ^alkyl > unsubstituted or substituted by one or more groups

a) -Ci-5-alkyl,

b) -C 1-6 -alkoxy,

c) -OH or

d) aryl, unsubstituted or substituted by one or more groups

i) -C- | C 1-5 alkyl, ii) -C 1-5 alkoxy, iii) -OH, iv) halogen, or

v) -NR ² R ² , or

e) heterocycle, unsubstituted or substituted by one or more groups

i) -C 1-5 -alkyl, ii) -C 1-5 -alkoxy, iii) -OH, 'iv) halogen or'

v) -NR ² R ² , or

3) aryl, unsubstituted or substituted by one or more of the groups:

a) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups:

i) -OH or ii) -C- .5-alkoxy,

b) -C1-5 alkoxy,

c) -OH,

d) halogen,

e) -CN,

f) -NO2, or

g) -NR2r2 or

4) heterocycle, unsubstituted or substituted by one or more of the following groups:

a) -C- | .5-alkyl, unsubstituted or substituted by one or more of the groups:

i) -OH or ii) θ1 -5-alkoxy,

b) -θ1 - 5-alkoxy,

c) -OH,

d) halogen or

e) -NR ² R 2.

Ria _is;

1) -C1-5-alkyl more than the groups

a) -C 1-5 -alkyl,

b) -Cf. 5-al'coxy,

c) -OH,

d) aryl, unsubstituted or substituted by one or more groups

i) -C 1-5 alkyl,

H) -C 1-5 -alkoxy, iii) -OH, iv) halogen or

v) -NR2r2_ _or

(f) heterocycle unsubstituted or substituted by one or more groups

ί) -Ο-, .5-alkyl,

H) -Cj. 5-alkoxy, iii) -OH, iv) halogen or · · · · · · · · · · · · · · · · · · · · · · ·

v) -NR ² r 2, or

2) aryl, unsubstituted or substituted by one or more of the groups:

a) -C 1-5 alkyl, unsubstituted or substituted by or more than one of the groups:

i) -OH or

B) -C 1-5 -alkoxy,

c)

-OH,

d) halogen,

θ)

-CN,

f) -NO2, or

g) -NR2R2, or

3) heterocycle, unsubstituted or substituted by one or more of the groups:

a) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups: '

C)

-OH,

d) halogen or

-NR2r2, _or

C3-6 cycloalkyl;

R ^1b is:

4)

1) -C 1-5 -alkyl substituted with one or more groups

a) -C 1-5 alkoxy,

B) -OH

i) -C1-5-alkyl, ·· ····

c) -OH,

d) halogen or

e) -NR ² R 2

R 2 is hydrogen or C 1-3 alkyl;

R3 is:

1) -C1-5 alkyl, unsubstituted or substituted by one or more of the groups

a) -C 1-5 alkyl,

b) -C 1-5 -alkoxy, unsubstituted or substituted with -OH

V c) -OH,

d) -OC (O) R ⁷ ;

e) -COOR2,

f) aryl, unsubstituted or substituted by one or more groups

*) C ¹ -C 5 -alkyl unsubstituted or substituted by one or more -OH groups;

I) -C 1-5 -alkoxy, iii) -OH, iv) halogen,

v) -NO ₂ , vi) -NR ² r 2, vii) -NHCO-C 1 -C 3 -alkyl, or viii) -NHSO 2 -C 1-3-alkyl,

g) heterocycle, unsubstituted or substituted by one or more groups

i) -C 1-5 -alkyl,

H) -C 1-5 -alkoxy, iii) -OH, iv) θΐ-C-alkyl- NR2r2 ₍

v) halogen, vi) oxo ii) -C 1-5 alkoxy, iii) -OH, iv) halogen, or

v) -NR ^ R ^, or

d) heterocycle, unsubstituted or substituted by one or more groups

i) -C- | -5-alkyl, ii) -C 1-5 alkoxy, iii) -OH, iv) halogen or

v) -NR2r2, or

2) aryl, unsubstituted or substituted by one or more of the groups:

a) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups:

i) -OH or

ϋ) -C-j.5-alkoxy, t>) -θι.5-alkoxy, '

c) -OH,

d) halogen,

e) -CN,

f) -NO2, or

g) -NR ² R ² , or

3) heterocycle, unsubstituted or substituted by one or more of the groups:

^a ) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups:

i) -OH or ii) -C 1-5 alkoxy,

B) -C- | .5-alkoxy,

• (vii) -NO2, viii) -NR ² R ² , ix) -NHCO-C 1-3 alkyl, or

x) -NHSO2-C1-3-alkyl

h) -NR ² R ² , or '

1) -C3-6-cycloalkyl,

2) aryl, unsubstituted or substituted by one or more of the groups:

a) -C 1-5 alkyl,

b) -Cf. 5 -alkoxy,

c) -OH,

d) halogen, or

e) -NR ² R ² ,

3) heterocycle, unsubstituted or substituted by one of the groups

i) -C- | C 1-5 alkyl,

I) -C- .5-alkoxy, iii) -OH, iv) halogen, or

v) NR ² R ² ,

4) -C- .5-alkoxy,

5) -OH,

6) -C3-6-cycloalkyl or

7) hydrogen;

R ⁴ is:

1) R ¹ or

2) -COR ¹ ;

R ⁵ is:

1) R ¹ ,

2) -C- | .5-alkoxy,

3) -NHR ¹ , or

4) heterocycle

R ⁶

- 12 unsubstituted or substituted for one of the games

i) -C 1-5 alkyl,

j) -C 1-5 -alkoxy iii) iv)

v) NR ² R ²

-OH, halogen, or is:

drink

1) hydrogen,

2) -COR ¹ ,

3) -CONHR ¹ ;

R ⁷ e:

1) aryl, unsubstituted or substituted by one or more substituents -Cl, -Br, -OH, -OCH3 or -CN, or

2) -C 1-5 alkyl, unsubstituted or substituted by one or more of the groups -OH or -NR ² R ² ; and provided that when X is hydrogen, Y is -S, R is unsubstituted phenyl and R ⁶ is hydrogen, το Z is other than -CH 2 -SO-Ph, -COH,

or

or pharmaceutically acceptable salts or esters of the above compounds of formula A.

One embodiment of the present invention encompasses compounds of formula A wherein:

X is -H, -Cl or -F;

Y is -S (O) _n -;

R is phenyl, tolyl, 3-chlorophenyl, 2-pyridyl or 2-thiazolyl;

R 3 is hydrogen; and • · · · ·

- 13 Z is

1) -C-NR 2 R 3, -COOR 11b, -COR 4 -CR ₂ R ² S (O) _n -R ¹ a, II w or -C 1-3 alkyl substituted with a heterocycle.

One class of preferred compounds according to the invention comprises compounds in which:

X is -H or -Cl;

Y is -S (O) _n -;

R is phenyl, tolyl, 3-chlorophenyl or 2-thiazolyl;

R ⁶ is hydrogen; and

Z is

1) -C-NR ² r3,

II

W, wherein R ² is -H and W is -O, -S or -NCN, or

2) -CR ² R 2 -SO-apMn, wherein the aryl group is unsubstituted or substituted by one or more C1-5 alkyl groups;

A subset of compounds in this class are compounds in which:

X is -Cl;

Y is -S (O) _n -, where η is the number 1 or 2;

R is phenyl, 3-chlorophenyl or 2-thiazolyl;

R ⁶ is hydrogen; and

Yes it is

-C-NR2r3,

II

W, wherein R2 is -H and W is -O, -S or -NCN, and

R ³ is:

1) -C 1-5 alkyl, unsubstituted or substituted by one or more groups

a) -C- .5-alkoxy, unsubstituted or substituted by -OH ············

- 14 d) aryl, unsubstituted or substituted by one or more of the groups

i) -C 1-5 alkyl, unsubstituted or substituted by one or more

-OH groups;

iii) -OH, iv) halogen, or

v) -NR ² R ² ,

(f) heterocycle, unsubstituted or substituted by one or more groups

i) -C 1-5 alkyl,

I) -C1-5-alkoxy, iii) -OH, iv) halogen, or

v) -NR ² R ² , or

-C3-6-cycloalkyl,

2) heterocycle, unsubstituted or substituted by one of the groups

i) -C1-5 alkyl,

H) -C- -5-alkoxy, iii) -OH, iv) halogen, or

v) -NR ² R ² ,

3) hydrogen, or

4) -C3-6-cycloalkyl.

A second embodiment of the invention includes compounds of formula A wherein X is selected from the groups:

1) -NR ² R ² ,

2) -NHSO 2 -C 1-3 alkyl, or

3) -NHCO-C 1-3 alkyl.

A third embodiment of the invention comprises compounds of formula A in which:

Z is

-C-NR2R3,

II

W, where R ³ is selected from the following groups:

1) C 1-6 -alkyl substituted with phenyl, wherein the phenyl is substituted by one or more of the groups:

a) -NO ₂ ,

b) -NR2R2,

c) -NHCO-C3-3 alkyl, or

d) -NHSO 2 -C 1-3 alkyl and

2) C 1-3 alkyl substituted with a heterocycle, wherein the heterocycle is substituted by one or more of the groups:

a) halogen,

B) oxo

c) -NO ₂ ,

d) -NR2r2,

e) -NHCO-C 1-3 alkyl, or

f) -NHSO ₂ -C 1-3 alkyl.

A fourth embodiment of the invention encompasses compounds of formula A wherein Y is -S (O) _n - and R is -NR2r3.

The most preferred compounds according to the invention are the compounds 1 to 39 listed below:

···

Compound 1:

NHCH2CH3

N-ethyl-5-chloro-3-phenylthioindole-2-carboxamide,

Compound 2:

NHCH2CH2OH

N-2-hydroxyethyl-5-chloro-3-phenylthioindole-2-carboxamide

Compound 3

NHCH2CH2OCH3

L1-2-methoxyethyl-5-chloro-3-phenylthioindole-2-carboxamide,

Compound 4:

N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2-carboxamide

- 17 Compound 5:

N-4-pyridylmethyl-5 ¹ chloro-3-phenylthioindole-2-carboxamide,

N-3-pyridylmethyl-5-chloro-3-phenylthioindole-2-carboxamide,

Compound 7:

N-2-furanyl methyl-5-chloro-3-phenylthioindole-2-carboxamide,

Compound 8:

NH

L1-3-pyridyl-5-chloro-3-phenylthioindole-2-carboxamide

- 18 Compound 9

SPh Cl D! From h / n 0

N- [1- (2 (R) -hydroxypropyl)] - 5-chloro-3-phenylthioindole-2carboxamide,

Compound 10:

NHCH2

N- (2-pyridyl) methyl-5-chloro-3-phenylthioindole-2-carboxamide,

Compound 11:

N- (3-methoxy-4-pyridyl) methyl-5-chloro-3-phenylthioindole-2carboxamide,

Compound 12:

NHCH2

CH ₂ OH ·· ···· • · · • · • ··· ··· ·· “

- 19 N- (3-hydroxymethyl) benzyl-5-chloro-3-phenylthioindole-2 carboxamide,

13:

Compound

NH ₂

5-chloro-3-phenylthioindole-2-carboxamide,

Compound 1 4:

N- (3-hydroxybenzyl) -5-chloro-3-phenylthioindole-2carboxamide,

Compound 1 5:

N-2-furanylmethyl-5-chloro-3-phenylthioindole-2-thiocarboxamide

- 20 Compound 16:

NH ₂

5-chloro-3-phenylthioindole-2-thiocarboxamide,

Compound 1 7:

NH ₂

5-chloro-3-phenylsulfinylindole-2-carboxamide,%

Compound 18:

NH ₂

5-chloro-3-phenylsulfonylindole-2-carboxamide

Compound 19:

CH3

N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide,

Compound 20:

CH3

N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfinyl-5-chloroindole-2-carboxamide,

Compound 21:

N - [(1-methyl-imidazol-4-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide, • ···

Compound 22:

N - [(1-methylimidazol-5-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide,

Compound 23:

CI

N - [(1-methylimidazol-2-yl) methyl] -3- (3-chlorophenyl-sulfonyl) -5-chloroindole-2-carboxamide,

Compound 24:

carboxamide

N- [2- (1-methylimidazol-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide,

Compound 26:

N-cyclopropyl-5-chloro-3-phenylsulfonylindole-2-carboxamide,

Compound 27:

N-cyclobutyl-5-chloro-3-phenylsulfonylindole-2-carboxamide,

I • ··· • * • · ·

Compound 28:

N- (3-pyridylmethyl) -3-phenylsulfonyl-5-chloroindole-2carboxamide,

Compound 29;

N.

N- (4-pyridyl methyl) -5-chloro-3-phenylsulfinyl indo; > 2carboxamide,

Compound 30:

N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole-2carboxamide,

N- (3-methylsulfonylaminobenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide,

Compound 35:

N-cyano-5-chloro-3-phenylsulfonylindole-2-carboximide-amide,

Compound 36:

CH3SO2NH

Ph nh ₂

3-phenylsulfonyl-5-methylsulfonylaminoindole-2-carboxamide, · · · · · ·

- 25 Compound 31:

N- (3-methoxybenzyl) -5-chloro-3- (2-thiazolyl) sulfonyl-indole-2carboxamide,

Compound 32:

N - [(c) -1-phenyl-2-hydroxyethyl] -5-chloro-3-phenylsulfonylindole-2-carboxamide,

Compound 33:

N - [(R) -1-phenyl ethyl] -5-chloro-3-phenylsul background or ndol-2carboxamide,

The compounds of the invention may have asymmetry centers and exist in the form of racemates, racemic mixtures, individual diastereomers or enantiomers, so that all isomeric forms are within the scope of the present invention.

When some of the variables (eg aryl, heterocycle, R ¹ , R ² , R ³ , etc.) are present more than once in any component of the compound of formula A according to the invention, their significance in each of these cases are irrespective of any other significance when present in the structure. Thus, combinations of substituents and / or variables depend only on whether stable combinations are obtained with these combinations.

As used herein, except where otherwise indicated, the term alkyl includes straight or branched chain saturated aliphatic hydrocarbons having a specified number of carbon atoms; the term alkoxy refers to an alkyl group having a certain number of carbon atoms attached via an oxygen bridge. Halogen or halo means fluoro, chloro, bromo or iodo.

As used herein, unless otherwise indicated, the term aryl means a stable monocyclic, bicyclic or tricyclic carbon ring containing up to 7 members in each ring, wherein at least one of the rings is aromatic. Examples of such aryl substituents are phenyl, naphthyl, tetrahydronaphthyl, biphenyl.

The term heterocycle or heterocyclic, as used herein, unless otherwise indicated, includes a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocycle which is saturated or • · · · · ·

- 27 Compound 37:

4 - [(5-chloro-3-phenylsulfonylindole-2-carboxamido) -methyl] pyridin-2 (1H) -one

Compound 38:

N- (2-amino-4-pyridylmethyl) -5-chloro-3-phenylsulfonyl-indole-

2-carboxamide and

N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-carboxamide.

- 29 unsaturated and containing carbon atoms from one to three heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may be quaternized, and optionally comprising any bicyclic group in which any of the heterocyclic rings defined above may be fused to a benzene ring. Heterocyclic rings may be attached at any of the heteroatoms or carbon atoms to give a stable structure. Examples of such heterocyclic elements are piperidinyl,

piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo- pyrrolidinyl, 2-oxazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,

imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oksazolil.oksazolidinil, isoxazolyl, isoxazol pyrrolidinyl, morfolynil, thiazolyl, thiazolidinyl, izotiazblil, quinuclidinyl, isothiazolidinyl, indolyl, quinolyl, isoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl , tetrahydrofuryl, benzofuranyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.

Other abbreviations that can be found in the description are

the following: Me methyl Ass acetyl Et ethyl Ph phenyl Bu Li butyl lithium η-ΒιΐβΡ tri-p-butylphosphine LAH lithium aluminum hydride

·· ····

• · ·

- 30 DMF dimethylformamide

THF tetrahydrofuran

Et ₃ N triethylamine

MMPP monoperoxyphthalic acid, magnesium salt

BH ₃ , DMS

BOP-boron-dimethylsulfide complex benzotriazol-1-yloxytris- (dimethylamino) phosphonium hexafluorophosphate

etc.

melting point (mp) eq

The pharmaceutically acceptable salts of the novel compounds of the invention which are capable of forming salts (in the form of water- or oil-soluble or dispersible products) include the usual non-toxic salts or quaternary ammonium salts of these compounds which are formed with inorganic or organic acids or bases. Examples of such acid addition salts are acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanethanol, ethyl acetate hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, succinate, succinate, succinate, succinate, sulphate t and undecanoate. Also the basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides, e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain hydrocarbons such as ·· ······

- 32 SCHEME I

CO ₂ H

NaH, PhSSPh

DMF, Δ

As shown in Scheme I, commercially available indole-2 carboxylic acid (or 5-chloro, 5-fluoro or 5-methoxyindole-

2-carboxylic acid) of formula I is reacted with excess sodium hydride in dimethylformamide in the presence of aryldisulfide, such as phenyldisulfide at a temperature of 0 ° C to 60 ° C according to the general procedure described by Atkinson, et al., In Synthesis, page 480- 481 (1988). The resulting product of formula II is reacted with refluxing oxalyl chloride in chloroform for 30 minutes to 1 hour to give the corresponding acid chloride, which is then reacted with primary or secondary amine in chloroform at 0 ° C to 20 ° C to give the amide of formula III. Alternatively, the amide of formula III can be obtained directly from a compound of formula II by reacting with BOP-reagent (benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate) in the presence of • ·· • ···

- 31 decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and others. Esters are also within the scope of the invention and include those which will be easily formed, which is known to those skilled in the art, e.g. C- | .d-alkyl esters.

Below are Schemes I to VIII by which the novel compounds of the invention can be prepared. Tables I to VII following the schemes indicate the compounds which may be obtained by Schemes I to VIII, but these schemes are not limited to the compounds listed in the tables or by the specific substituents indicated in the illustration schemes . The examples specifically illustrate the use of the following schemes for the preparation of specific specific compounds.

In Scheme I below, the basic method for the preparation of the compounds, e.g. of the compounds listed in Table I. The substituent groups (such as X, R, R1, and so on) ν 'used in Scheme I correspond to the substitution groups in Table I, but Scheme I is not limited to the compounds defined in Table I .

· · · · · · · · · · ·

- 33 the desired primary or secondary amine and triethylamine, in a solvent such as dimethylformamide.

Other carboxyl-activating reagents such as, N -carbonyldiimidazole may be used in this step. Saponification of ethyl 5-chloro-3 benzylindole-2-carboxylate (prepared as described below) by methods known to those skilled in the art yields 5 chloro-3-benzylindole-2-carboxylic acid, which can be converted in the desired amides in the manner described for the preparation of the amides of formula III.

The compounds described in Table II were prepared by the general method described in Scheme I, except that R ¹ OH was used instead of R ² R ³ NH, as shown in Scheme II below. The substituent groups used in Scheme II correspond to the substituent groups listed in Table II, but Scheme II is not limited to the substituents or compounds defined in Table II.

SCHEME II '

- 34 As indicated in Scheme II,

3-Phenylthioindole-2-carboxylic acid of formula II may be converted to the corresponding acid chloride under reflux with alcohol to afford the reaction of oxalyl chloride by boiling a compound of formula

IV by reacting the medium with chloroform and then treating an ester of formula IV. Alternatively, 1a may be converted to an ester of the formula N-phenylthio-succinimide in chloroform at room temperature in the presence of a Lewis acid, e.g. of borontrifluoride etherate as a catalyst (as shown in Scheme II). The ethyl-5-chloro-3-benzylindole-2 carboxylate compound was prepared according to the method described by Inaba, et al., In Chem. Pharm. Bull., 24, pp. 1076-1082 (1976).

Scheme III below is the main method of preparation e.g. of the compounds listed in Table III. The substituent groups used in Scheme III correspond to the substituent groups listed in Table III ', but Scheme III is not limited to the substituents or compounds defined in Table III.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 35 SCHEME III

CH ₃

IX

As shown in Scheme III, commercially available ethylindole-

2-carboxylate (compound of formula V in which X is -H) or ethyl 5-chloroindole-2-carboxylate (compound of formula V in which X is -Cl) is reduced to a primary alcohol of formula VI with excess lithium aluminum hydride in tetrahydrofuran at 0 ° C. The compound of formula VI is converted to a sulfide of formula VII by treatment with an excess of tri-n-butylphosphine and aryldisulfide, such as phenyldisulfide in tetrahydrofuran at 0 ° C to 20 ° C for 6 to 24 hours. By reacting a sulfide of formula VII with sodium hydride and aryldisulfide as phenyldisulfide in dimethylformamide at 0 ° C to 20 ° C for 1 to 18 hours ············· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

36 gives bisulphide of formula VIII. Non-commercially available aryldisulfides are prepared by the oxidation of commercially available arylmercaptan with dimethylsulfoxyl and iodine, according to the method described by Orville G. Lowe, in J. Org. Chem., 4θ ', pp. 2096-2098 (1975). The compound of formula VIII may optionally be alkylated by methods analogous to those known in the art, e.g. by treatment with sodium hydride in dimethylformamide at 0 ° C in the presence of an alkylating reagent such as iodomethane to give a compound of formula IX. The compound of formula VIII (or IX) is then reacted with an equivalent of peracid, e.g. mono-peroxyphthalic acid, magnesium salt (MMPP), or meta-chloroperoxy-benzoic acid in methanol or chloroform-methanol at 0 ° C for 30 minutes to 3 hours, to give predominantly sulfoxide of formula X.

Schemes IV-A and IV-B below show the general progress of the process for preparing, for example, the compounds shown in Tables IV-A and IV-B. The substituent groups used in Schemes IVA and IV-B respectively correspond to the substituent groups as defined in Tables IV-A and IV-B respectively, but Schemes IV-A and IVB are not limited by the meanings of the substituents or the compounds specified in Tables IV-A and IV-B.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 37 Scheme IV-A

Scheme IV-B

CH ₂ NH ₂

JI

R ¹ CCI pyridine, CHCI ₃

As shown in Scheme IV-A

The 3-phenylthioindole-2carboxamides of formula XI can be reduced to primary or secondary amines of formula XII by reacting with an excess of borane-dimethylsulfide complex under reflux in tetrahydrofuran medium for 6 to 24 hours. As shown in Scheme IV-B, a primary amine of formula XII-A may be acylated with an acid chloride such as benzoyl chloride in chloroform in the presence of pyridine to give an amide of formula XIII.

Scheme V below shows the basic method for preparing, for example, the compounds listed in Tables V-A and V-B. The substituent groups used in Scheme V correspond to the substituents listed in Tables V-A and V-B, but Scheme V is not limited to the substituents or compounds listed in Tables V-A and V-B.

• ·

- 38 h

Scheme V

NaH, PHSSPh DMF

1) n-BuLi

2) C0 ₂

CO ₂ Li

1) t-BuLi

1) t-BuLi

2) R ¹ -NCO / H ⁺

XVII • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

39 As shown in Scheme V, commercially available 2-methylindole of formula XIV can be treated with sodium hydride in dimethylformamide in the presence of aryldisulfide, such as e.g. phenyldisulfide to give a compound of formula XV. The compound of formula XV can be converted into mono anion with butyllithium in tetrahydrofuran at -78 ° C and then reacted with carbon dioxide to give the carboxylate of formula XVI. The dianion formed by the reaction of a compound of formula XVI with t-butyllithium can be reacted with isocyanate, such as phenylisocyanate, to produce a mixture of a monoacylated product and a diacylated product of formula XVII (see Table V-B). Alternatively, the dianion formed by the reaction of a compound of formula XVI with t-butyllithium can be reacted with N-methoxy-N-methylamide, such as N-methoxy-N-methylfuran-2-carboxamide, (obtained by analogy to those skilled in the art methods, e.g., by the methods described in Scheme 1) to obtain ketones of formula XVIII. The method described above is essentially the one used by

A.J. Katritsky and K. Akutagawa for the Preparation of 2-Indolacetic Acids, Published in J. Am. Chem. Soc., 108, pp. 6808 (1986).

Scheme VI below shows the general method of preparation e.g. of the compounds listed in Table VI. The substituents used in Scheme VI correspond to the substituents listed in Table VI, but Scheme VI is not limited to the substituents or compounds listed in Table VI.

• · · · · · · · ·

Scheme VI

eq R ¹ MgCI THF -78 ° C - 20 ° C

As shown in Scheme VI, GM-methoxy-N-methyl-3-phenylthioindole-2-carboxamide of formula XIX (or Ν-Μβτοκοπ-Νmethyl-5-chloro-3-phenylthioindole-2-carboxamide) (prepared according to Scheme 1) can react with a grignard reagent (when R ¹ is not hydrogen), such as phenylmagnesium chloride, in tetrahydrofuran at -78 ° C to 20 ° C for 18 to 48 hours, or a compound of formula XIX may be reacted with other organometallic reagents, well known to those skilled in the art, to obtain ketones of formula XX. The compounds shown in Table VII can be prepared by methods known in the art according to the methods described in Schemes I to VI, with the exception of 2- (2-benzoxazol-2-ylethyl) -3-phenylthioindole (compound of formula XXIV ), the preparation of which is described below in Scheme VII.

·· ····

Scheme VII

As shown in Scheme VII, N-methoxy-N-methyl-3-phenylthioindole-2-carboxamide of formula XXI can be reduced to an aldehyde of formula XXII with lithium-aluminum hydride in tetrahydrofuran at a temperature of 0 ° C to 20 ° C. for 2 to 4 hours. The aldehyde of formula XXII can be reacted with an aluminum salt of [(benzoxal-2-yl) methyl] diethyl phosphonate to give an olefin of formula XXIII, which is then hydrogenated in the presence of 10% palladium on carbon in methanol under one atmosphere hydrogen pressure, to obtain. a compound of formula XXIV.

The compound 5-chloro-2-cyano-3-phenylthioindole in Table VII can be obtained by dehydrosulfurization of 5-chloro-3-phenylthioindole-2-thiocarboxamide, e.g. with Sun (OAc) 2 ·

Using methods well known to those skilled in the art, compounds of formula A, wherein Y is -SO- or -SO2f · · · · · · · · · · · · · · · · · · ·

- 42 can be obtained by treating compounds in which Y is -S with a suitable oxidizing reagent, such as e.g. meta-chloroperoxybenzoic acid peroxide acid (MCPBA), sodium periodate or hydrogen in a suitable solvent such as methanol, CHCl3 or acetic or potassium persulfate in a solvent such as e.g.

methanol / water.

Alternative Methods for the Preparation of Amide Derivatives of Formula A in which Y is -SO- or -SO2- are shown in Scheme The intermediate of formula II can be oxidized (e.g. meta-chloroperoxy-benzoic acid (MCPBA) in CHCI3) to obtain an acid derivative of formula XXV in which

SO- or -SO2-, which can be converted to the corresponding amide derivative of formula XXVII, using the formation of the amide group described in Scheme I.

VIII.

conditions for

The second is useful

IVa may be the sequence, the intermediate ester of formula oxides, to obtain the intermediate esters of formula XXVI, where

Y is -SO- or -SO2- which, when reacted with ammonia or primary amine, under heating, are converted to compounds of formula XXVII.

Scheme VIII

or

H ₂ O ₂ / NODs

MCPBA / CHCI

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 44 · · · · · · · · · · · · · · · · · · · · · · ·

Table I

X Υ R ² R ³ m.p. Η S CH ₃ CH ₃ Mp 194-195 ° C Η S Η CH ₂ Ph Mp 179-181 ° C Η S Η Ph Mp 194-196 ° C Η S Η P-C ^ Sun. 161-163 ° C Η S Η CH ₂ CH ₂ Ph 147-149 ° C CI S CH ₃ OCH ₃ 57-59 ° C CI S Η Mp 255-256 ° C Η S Η CH ₃ Mp 197-199 ° C CI S Η PSN7 210-212 ° C CI S Η 240-241 ° C

255-256 ° C · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 46 · · · · · · · · · · · · · · ·

Table I (continued)

X Y R ² R ³ m.p. Cl s H CH ₂ CH ₂ CH ₂ OCH3 170-171 ° C , OCH ₃ Cl s H ^CH 2 - ^{base of} 184 ° C Cl s H oUiZ) N H 259-260 ° C (HCI salt) Cl s H ch ₂ ch ₂ -n ^ n W 256 ° C (HCI salt) Cl s H 'CH (CH ₃ ) ₂ 193-194 ° C Cl s CH ₃ Ph 191-192 ° C Cl s H CH ₂ CH ₂ CH ₂ N (CH ₃ ) ₂ 229-230 ° C (HCI coi |

«· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 45 Table I (continued)

X Y R ² R ³ m.p. F s H 239-241 ° C Cl s H OH Mp 232-233 ° C Cl CH ₂ H 243-244 ° C Cl s H 1 HQ OCH ₃ 221 ° C Cl s H -CH ₂ - 214 ° C Cl s H —CH ₂ CH ₂ CH ₂ OH 215 ° C Cl s H - (^) - 00¾ 229 ° C Cl s H CH ₃ 220-221 ° C

• · · · · · · · · · · υ · · · · · · · · · · · · · · · · · · ·

Table I (continued)

-e

X Y R ² R ³ m.p. Cl s H C ₂ H ₅ 210-211 ° C Cl s H Ph 245-246 ° C OCH, / ³ Cl s H chhQ> 172 ° C Cl s H / - \ CHjCHjCH ^ -N ^ __ 0 Mp 162-164 ° C Cl s H ch ₂ —Δ ν ' 219-219.5 ° C Cl s H CH ₂ Ph 222 ° C Cl s H ^CH 2 - O-OCH 3 198 ° C Cl s H CH ₂ CH ₂ OCH ₂ CH ₂ OH 161.5-162.5 ° C

• · · · · · · · · · · · · · · ·

Table I (continued)

XY

Cls

Cls

Cls

Cls

R ² R ³

m.p.

OH

CH ₂ CH ₂ OCH ₃

CH ₂ CH ₂ OC ₂ H ₅

> 300 ° C

216-217.5 ° C

Mp 165.5-167 ° C

182-183 ° C

Cls

Cls

Cls

Cls

Cls

CH3O

CH ₂ (NCH ₃ OH)

Mp 228-229 ° C

222-223.5 ° C

Mp 151-152 ° C

201 ° C

205 ° C

Table I (continued)

X Y R ² R ³ m.p. Cl s H OCH ₃ Mp 179-180 ° C Cl s H - (j) H-CH ₂ CH ₃ CH ₂ OH Mp 153-154 ° C Cl s H 0 II CH ₂ COC ₂ H ₅ 215-215.2 ° C Cl s H - <jlHCH ₂ OCH ₃ CH ₃ Mp 168-169 ° C

OH

Cl . S H - CH ₂ \ 202-203 ° C Cl S H 209-210 ° C Cl S H -CH ₂ CH ₂ CH ₂ -N ^ D * HCl OH -CH ₂ ' ^X ^ ^X 188-189 ° C Cl S H 201-206 ° C Cl s H - CHCH ₂ CH ₃ 1 CH ₂ OH Mp 138-139 ° C

- 50 ··

Table I (continued)

XYR ²

m.p.

Cl s H - CHCH ₂ CH ₃ CH ₂ OH 137.5-139 ° C Cl s H OH —ch ₂ (!) Nch _{2 he} 219-221 ° C Cl s H CH ₃ Mp 208-210 ° C Cl s H -ch CH ₂ OH 223-226 ° C Cl s H -ΐ ^Η -Ο CH ₂ OH 223-226 ° C Cl s H -CH— CH ₃ OCH ₃ ___ / ^ύ Mp 208-210 ° C Cl s H ~ ^cng hg ^ ^m 227-228 ° C

I · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 51 · · · · · · · · · · · · · ·

Table I (continued)

m.p.

229-230 ° C

217-219 ° C

214-216 ° C

193-195.5 ° C

213-215 ° C

Mp 255-257 ° C

249-251 ° C • · · · · ·

Table I (continued).

XYR ²

R ³

m.p.

Cl SO ₂

H -CH ₂ CH ₂ OH

198-200 ° C

Mp 212-215 ° C

211-215 ° C

275-278 ° C

Cl are ₂

Cl are ₂

265-270 ° C

149 ° C

- 53 • · · · · · · · · · · · · · · · · · · · · · · ·

Table I (continued)

Cl SO ₂

278-281 ° C

- 54 Table II

Y-R

X Y R Rib m.p. Η s Ph 1 'CH ₃ Mp 179-180 ° C Η s CH ₃ O CH ₃ Mp 195-197 ° C basic ₃ s Ph CH ₃ 211-212 ° C Cl s Ph CH ₃ Mp 193-196 ° C Cl s Ph CH ₂ Ph Mp 154-155 ° C Cl s Ph C ₂ H ₅ w Mp 163-164 ° C Cl CH ₂ Ph C ₂ H ₅ Mp 196-197 ° C F s Ph C ₂ H ₅ 149 ° C

· · · · · · · · · · · · ·

- 55 • · · · · · ·

Table III

X R R ¹ n R _x m.p. Η Ph Ph 1 H 71-74 ° C Η Ph Ph 0 H - Η Ph Ph 2 H Mp 168-169 ° C Η - th CH ₃ Ph 1 H 166-167 ° C Η - - <^) - ^CHs Ph 1 H 164.5-166.5 ° C basic ₃ Ph Ph 1 H 70-80 ° C Η CH ₃ Ph 1 H 171.5-172.5 ° C Η Ph Ph 0 CH ₃ 98-99 ° C

- 56 · · · · · · · · · · · · · · · · · · · ·

Table III (continued) = l ^1a n R _x

m.p.

Ph

Ph

OCH ₃

Η Ph

CH ₃ 1

Η Ph

Ph

Ph

CH ₃

177-178 ° C

164-168 ° C · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 57 Table III (continued)

H Ph —0 H H Ph —Oh ° ^{h 1} H 219-220 ° C

Cl Ph p.h

H 158-162 ° C

OH

Table IV-A

SPh ir CH ₂ NHR ¹ H R ¹ m.p. -CH ₂ Ph 199-201 ° C -Ph Mp 167-170 ° C -N-C4H9 177-179 ° C -H

Table IV-B

-Ph

64-65 ° C ·· ····

· · · · · · · · · · · · · · · · · ·

Table V-A

X R ⁵ R ⁶ m.p. Η -CH ₂ Ph Η - Η • Ph Η 154-155'C Η -CH ₃ Η 101.5-103.5'0 Η Η 87-90'C Η Η 127-129'C CI -axis ₂ n ₅ Η 99-103 ° C

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

XR ¹

Table V-B

R ⁶ mp

H -Ph H 66-68 ° C H -Ph -jJNHPh 0 123-125 ° C

X ^R x R ⁶ m.p. Η -Sn ₃ H 128-130 ° C Η -Sn ₃ -CNHPh Mp 157-159 ° C II 0 Η -Sn ₃ r 0 124-125 ° C Η -CH ₂ CH ₂ Ph H 117-120.5 ° C Η -CH2CH2-IFO) H Mp 92-193 ° C CI -CN H 172-174 ° C CI -C-NHCH ₂ - ^ j) II o- ^ s H Mp 143-144 ° C CI - <fl-MH ₂ s H 217 (decomposition)

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 61 Table VI

X Y R13 m.p. Cl s -Ph Mp 154-155 ° C Cl s -CH ₂ Ph 219-220 ° C Η s -Ph 121.5-123.5 ° C Η s ~ O ^ci 142-149 ° C Cl s . '-c ₂ h ₅ Mp 196-197 ° C Huh? Cl s 214-215 ° C Cl s -CH ₃ 178 ° C Cl CH ₂ -C ₂ H ₅ 203-205 ° C Cl CH ₂ -Ph 161-163 ° C Cl are ₂ cyclopropyl 224-226 ° C Cl are ₂ -C ₂ H ₅ 226-227 ° C Cl are ₂ -CH ₃ Mp 184-187.5 ° C

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 64 intravenously, intramuscularly, by intrasternal injection or by various routes of infusion), by inhalation spray or rectally,) in single dosage forms containing the usual non-toxic pharmaceutically acceptable nose

I Aids and Thinners.

want,

In addition, a method of treatment and pharmaceutical composition for the treatment of HIV infection and AIDS have been devised according to the invention. The method of treatment comprises administering to patients in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention.

These pharmaceutical compositions may be in the form of orally administered suspensions or tablets, nasal sprays, sterile injectable forms, e.g. sterile aqueous or oily injectable suspensions or suppositories.

When administered orally as suspensions, the compositions of the invention are prepared using techniques well known in the art for the preparation of pharmaceutical forms and may contain microcrystalline cellulose as a filler, alginic acid or sodium alginate as a suspending agent, methylcellulose to change viscosity as well as sweeteners or flavoring agents well known in the art. For use as fast acting tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other additives, binders, fillers, diluents, solvents and lubricants well known to those skilled in the art. .

«.J ····

63 The compounds of the invention are useful for inhibiting HIV reverse transcriptase, i

for the prevention or treatment of human immunodeficiency virus (HIV) infections and for the treatment of subsequent pathological conditions such as AIDS. The treatment of AIDS or the prevention or treatment of HIV infections includes, but is not limited to, the treatment of a wide range of HIV infections, such as AIDS, ARC (AIDS-related complex), both symptomatic and asymptomatic, as well as treatment in actual or potential exposure of HIV. For example, the compounds of the invention may be used in the treatment of HIV infections at the suspected subsequent exposure to HIV infection, e.g. in case of impending blood transfusion, organ transplantation, change of body fluids, bites, accidental stabbing or transfusion of the patient during surgery.

The compounds of the invention are also useful in the preparation of and screening for antiviral activity testing of compounds. Thus, for example, the compounds of the invention are useful for isolating enzyme mutants, which are excellent tools for the study of more potent antiviral compounds. In addition, the compounds of the invention are useful for identifying and determining the binding center of other antiviral agents to HIV reverse transcriptase, e.g. by comparative inhibition. Thus, the compounds of the invention are commercial products that are manufactured for these purposes.

For the inhibition of HIV reverse transcriptase, for the prevention of HIV infection and for the treatment of an AIDS or AIDS-related complex, the compounds of the invention may be administered orally, parenterally (including subcutaneously,

administration varies individually for each patient, depending on many factors, including the activity of the particular compound being used, the metabolic stability and duration of action of this compound, age, weight, general health, gender, diet , the route and timing of administration, the rate of its excretion, the combination of drugs used, the severity of the condition, and the effect of therapy on the body.

The present invention also relates to combinations of HIV-reverse transcriptase inhibiting compounds with one or more agents useful in the treatment of AIDS. The compounds of the invention may be administered in combination with other compounds that are inhibitors of HIV reverse transcriptase and / or with compounds that are inhibitors of HIV protease. For example, the compounds of the invention may be administered more effectively either in the pre-administration and / or post-administration periods in combination with effective amounts of antiviral agents for the treatment of AIDS, such as. those listed in Table VIII below.

When used in combination with the compounds of the present invention, the dosage of HIV protease inhibitors is in the range of 0.02 to 5.0 or 10.0 grams per day and is useful for treating or preventing the conditions mentioned above, such that when administered orally, the doses are two to five times higher. For example, HIV infections are effectively treated by administering 10 to 50 milligrams of an HIV protease inhibitor per kilogram of body weight one to three times a day. However, it should be understood that the specific dose level and frequency of dosing in each individual patient may vary and depend on

• · · ·

When administered as nasal aerosols or by inhalation, the compositions are prepared using techniques well known to those skilled in the art of pharmaceutical formulation and can be prepared as solutions in physiological

I solution using benzyl alcohol or other suitable stabilizers, absorption promoters or bioavailability enhancers, fluorocarbon compounds and / or other dissolution enhancers or dispersants known to those skilled in the art.

Injectable solutions or suspensions may be prepared by methods known in the art using suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing, wetting and suspending agents, sterile, softening, fixing oils' including synthetic mono or diglycerides and fatty acids such as oleic acid.

When administered rectally in the form of suppositories, the compositions may be prepared by mixing the active substance with a suitable non-irritating carrier such as cocoa butter, synthetic glyceride esters or polyethylene glycols which are solid at room temperature but liquefy and / or dissolve under rectal conditions. until release of the active substance.

The compounds of the invention may be administered orally to humans at doses of 1 to 100 mg / kg body weight in divided doses. Preferred dosages are in the range of 1 to 10 mg / kg body weight for oral administration in divided doses.

Other preferred doses are in the range of 1 to 20 mg / kg body weight for oral administration in divided doses. It must be understood, however, that the specific dose level and frequency of · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 68 Table VIII (continued)

Zidovudine; AZT Burroughs Wellcome AIDS, ARC, baby (Rsch. Triangle Park, AIDS, sarcoma of NC) Hoods, asymptomatic HIV infections, milder HIV diseases, neurological effects in combination with other therapy. L-697,661 Merck AIDS, ARC (Rahway, NJ) asymptomatic HIV also in combination with AZT. L-696,229 Merck AIDS, ARC (Rahway, NJ) asymptomatic HIV

also in combination with

AZT. L-735,524 Merck AIDS, ARC (Rahway, NJ) asymptomatic HIV also in combination with AZT. L-738,372 Merck AIDS, ARC (Rahway, NJ) asymptomatic HIV also in combination with AZT. L-738,872 Merck AIDS, ARC (Rahway, NJ) asymptomatic HIV also in combination with

AZT.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 67 multiple factors, including the activity of the specific compound used, the metabolic stability and duration of action of that compound by age, body weight, general health, sex, diet, type and timing of administration, rate of elimination of the substance, combination medicines, the severity of the disease, and the specific impact of the therapy.

The doses of HIV reverse transcriptase inhibitors when used for treatment in combination with the compounds of the invention are comparable to those indicated above as suitable for use in administering the compounds of the invention.

It is to be understood that the scope of combinations of the compounds of the invention with AIDS antiviral agents is not limited to those listed in Table VIII below, but generally includes any combination with any pharmaceutical composition useful for the treatment of AIDS.

Table VIII

Name of the drug Manufacturer

Indication ddl

Bristol-Mayers

AIDS, ARC

Dideoxyinosine (New York)

Dideoxycytidine Hoffman-La Roche AIDS, ARC ddC (Nutley, NJ) • · · · · ·

- 70 RTr in tubes. The mixture was incubated at 37 ° C for minutes.

After icing for 5 minutes. Add incubation The tubes were cooled in ice-cooled TCA containing 10 mM

NaPPj (200 μΙ) and the mixture was incubated in ice for 30 minutes. The precipitated cDNA was removed by filtration through compression glass filters [TCA, NaPPj]. The precipitate was then washed with 1N hydrochloric acid, 10 mM NaPPj.

The resulting filter plates are then counted in a scintillation counter.

Under these conditions, dGTP and polyg (C) »oligo d (G) - | 2-18 ^are each approximately equal in value to the corresponding K _m value. Approximately 5-6,000 cpm of [ ³ H] dGMP are incorporated into the acid-precipitated material. The RT reaction is concentration and time dependent. Dimethyl sulfoxide (DMSO) (from zero to 5%) did not affect the activity of the enzyme. The calculated IC 50 values for the test compounds of the present invention range from about 3 nM to more than 300 μΜ. The IC50 values of the more preferred compounds range from 3 nM to about 35 nM.

Inhibition of viral spread

A. Preparation of a suspension of HIV-infected MT-4 cells

MT cells were infected on the day indicated as zero (Day 0) at a concentration of 250,000 per ml with a diluted 1: 2000 solution of HIV-1 virus type 11llb (final concentration 125 pg p 24 / ml; sufficient to cause received 1% infected cells on the first day (Day 1) and 25-100% on the fourth day (Day 4). Cells were infected and developed in the following medium: RPMI 1640 (product made by Whittaker BioProducts), 10% fetal

- 69 The abbreviations used in Table VIII are as follows:

L-697,661 is 3 - ([(4,7-dichloro-1,3-benzoxazol-2-yl) methyl] aminotyl-6-methylpyridin-2 (1H) -one;

5th

L-696,229 is 3- [2- (1,3-benzoxazol-2-yl) ethyl] -5-ethyl-6 methylpyridin-2 (1H) -one;

L-735,524 is an HIV protease inhibitor of the chemical name N-1- (2 (R) -hydroxy-1 (S) -indanyl) -2 (R) -phenylmethyl-4- (8) hydroxy-5- (1 - (4- (3-pyridylmethyl) -2 (S) -N '- (1-butylcarboxamido) piperazinyl)) pentanamide;

L-738,372 is 6-chloro-4 (S) -cyclopropyl-3,4-dihydro-4 - ((2 pyridyl) ethynyl) quinazolin-2- (1H) -one;

L-738.872 is N-tert-butyl-1- [2 '- (D) -hydroxy-4'-phenyl-3' (3) [3 "(R) - [1" ', 1 "' -dioxo- 2 "'(R) -methylethyl] tetrahydrothienyloxycarbonylamino] butyl] -4- [4' - (2-chloro-6" -methyl) pyridylmethyl] piperazine-2 (S) -carboxamide.

Attempts to inhibit reverse transcriptase

The trial measured the incorporation of tritium deoxyguanosine monophosphate activated by recombinant HIV reverse transcriptase (HIV RTr) (or other reverse transcriptase RT) into acid-cDNA (DNA) at a K _t value of dGTP and poly g (C) * oligo d (G) - | 2-18- The inhibitors of the invention inhibit this incorporation.

Thirty µl of the reaction mixture containing equal volumes of: 500 mM Tris * HCl (pH 8.2), 300 mM MgCl 2> 1200 KCI, 10 mM DTT, 400 µg / m 1 poly g (C) oligo d (G) (obtained by dissolving 1.5 mg (25U) of poly g (C) * oligo d (G) in 1.5 ml of sterile distilled water and diluting to 400 µg / ml), 0.1 μΟί / μΙ [ ³ H] dGTP, 160 μΜ dGTP was added to 10 μΙ sterile distilled water, 2.5 μΙ from the potential inhibitor tested and 10 μΙ 5 nM purified HIV ···············

- 71 bovine serum, 4 mM glutamine (production by Gibco Labs) and 1: 100 penicillin-streptomycin (production by Gibco Labs).

The resulting mixture was incubated! overnight at 37 ° C in an atmosphere containing 5% CO ₂ .

B. Treatment with inhibitors

A series of solutions of the compounds in cell culture medium are prepared by double dilutions. On Day 1, commensurate portions of 125 μΙ of the compound were added to an equal volume of HIV-infected MT-4 cells (50,000 per well) on a 96-well microtiter plate. The incubation was continued for three days at 37 ° C in an atmosphere containing 5% CO ₂ .

C. Measurement of viral spread

Using a multichannel pipette, part of the infected cells from the wells were resuspended and 125 μΙ of each well was placed on a separate microtiter plate. After seeding, the plates were frozen for use in the next attempt to measure the supernatant for HIV p24 antigens.

The concentration of HIV p24 antigens was measured using an enzyme immunoassay as described below. Comparable portions of the p24 antigens to be tested are added to micrografts coated with monoclonal antibodies specific for HIV nuclear antigen. The micro-wells are washed at this point and at another appropriate stage as follows. Biotin-treated HIV-specific antibodies and then conjugated streptavidin-horseradish peroxidase were then added. The color reaction that occurs after the addition of hydrogen peroxide and tetramethylbenzidine substrate is made. The color intensity is proportional to the concentration of HIV p24 antigens.

The cell culture inhibitory concentration (CIC95) for each compound tested is defined as the concentration at which infection is inhibited, which is more than 95% tested by the prevalence of detection greater than

I% reduction in the production of p24 antigens compared with untreated controls. Test compounds according to the invention show values for CIC95 ranging from about 3 nM to about 400 nM for the preferred species, and up to about 40 μΜ for other compounds.

Examples of carrying out the invention

Example 1

Preparation of N- (3-pyridylmethyl) -5-chloro-3-phenylthioindole-2carboxamide

Step A: 5-Chloro-3-phenylthioindole-2-carboxylic acid

To a suspension of sodium hydride (3.0 g, 60% dispersion in oil, 0.076 mol) in dimethyl) formamide (125 mL) was added 5 chloroindole-2-carboxylic acid (5.0 g, 0.0255 mol) and phenyldisulfide (6.1 g, 0.028 mol) . The reaction mixture was heated under a nitrogen atmosphere at 50 ° C overnight. The mixture was cooled and additional sodium hydride (1.8 g) and phenyldisulfide (3.6 g) added and heating continued for another 1 hour. The reaction mixture was cooled and the dimethylformamide removed by vacuum distillation. The residue was treated with ethyl acetate and water, whereby two layers were separated. The aqueous layer was separated and acidified with 10% aqueous hydrochloric acid solution to pH 1. The aqueous phase was extracted with ethyl acetate and the ethyl acetate extract was washed with water and saturated sodium chloride solution, then dried over magnesium sulfate. The crude product was recrystallized from ethyl acetate in hexane to

- 73 obtaining the title compound as an off-white solid.

Stage B:

N- (3-ππ ridylmethyl) -5-chloro-3-phenylthioindole

2carboxamide

Benzotriazol-1-ylo xitr is (d and methyl amino) phosphorous hexachlorophosphate (0.73 g, 1.6 mmol) was added to a solution of 5chloro-3-phenylthioindole-2-carboxylic acid (0.50 g, 1.6 mmol).

3-Aminomethylpyridine (0.35 g, 3.2 mmol) and triethylamine (0.50 mL, 3.2 mmol) in degassed dimethylformamide (25 mL). The reaction mixture was stirred at room temperature overnight. The precipitated product was filtered off and the filter residue was washed thoroughly with water. The solid was treated with 30% ethyl acetate in hexane, filtered and dried at 60 ° C in vacuo for 72 hours. The title compound was obtained as an off-white solid, m.p. 240-241 ° C.

I ^;

Analysis calculated for C21 H- | θΟΙΝ3θ5 · 0.25 H2O:

ν '

C, 63.31; H, 4.17; Ν, 10.54

Found: C, 63.34; H, 4.06; Ν, 10.71.

NMR (DMSO-d ₆ ): δ 12.54 (1H, s), 8.91 (1H, t, J = 6 Hz), 8.51 (1H, s), 8.42 (1H, d, J = 5 Hz), 7.58 (2H, m), 7.45 (1H, m), 7.25 (4H, m), 7.15 (1H, t, J = 7 Hz), 7.04 (2H, d, J = 8 Hz), 4.58 (2H, d. J = 6 Hz).

Example 2

Preparation of methyl 5-chloro-3-phenylthioindole-2-carboxylate Oxalyl chloride (0.70 mL, 9.6 mmol) was added to a solution of 5-chloro-3-phenylthioindole-2-carboxylic acid (0.97 g, 3.2 mmol) in chloroform (50 mL) under a nitrogen atmosphere. The reaction mixture was heated to reflux for 3 hours, cooled and concentrated in vacuo to dryness. The resulting solid was dissolved in chloroform and added to methanol at 0 ° C. The methanol was removed in vacuo

74 and the crude product is chromatographed on silica gel with 20% ethyl acetate in hexane. The title compound was obtained

Analysis:

for C- | solid θH12CINO2S:

mp

193-196 ° C.

C, 60.47; H, 3.81; N, 4.42

Found: C, 60.09

H, 3.50; N, 4.67.

Example 3

Preparation of ethyl 5-chloro-3-benzylindole-2-carboxylate The title compound was prepared by the method described by Inaba, S., et al., Chem. Pharm. Bull., 24, 1076-1082 (1976) After recrystallization from benzene, the title compound was obtained as pale yellow needle crystals, m.p. 196-1 97 ° C.

Analysis: calculated for C3 Η- | θΰ IN O 2:

C, 68.90; H, 5.13; N, 4.46

Found: C, 68.64; H, 5.10; N, 4.56.

Example 4

Preparation of 2-phenylsulfinylmethyl-3-phenylthioindole

Step A: 2-Hydroxymethylindole

A suspension of lithium aluminum hydride (2.0 g, 0.20 mol) in THF (100 mL) was cooled with stirring to 0 ° C under a nitrogen atmosphere. A solution of ethyl indole-2carboxylate (10.0 g, 0.052 mol) in tetrahydrofuran was added dropwise while maintaining the temperature of the reaction mixture in the range of 0 to 5 ° C. After 1 hour, the reaction was quenched by the addition of saturated sodium potassium tartrate solution. The resulting precipitate was separated by filtration and washed well with tetrahydrofuran. The tetrahydrofuran was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate solution was washed with water, saturated sodium chloride solution, dried over ········

- 75 Magnesium sulfate, filtered and released from the solvent.

The title compound was obtained as a yellowish solid.

NMR (CDCl3): δ 8.18 (1H, bs), 7.57 (1H, d, J = 8 Hz), 7.35 (1H, d,

J = 8 Hz), 7.26 (1H, s), 7.18 (1H, dt, J = 1.8 Hz), 7.10 (1H, dt, J = 1.8)

Hz), 6.41 (1H, bs), 4.84 (2H, s).

Step B: 2-Phenylthiomethylindole

2-Hydroxymethylindole (6.94 g, 0.047 mol) and phenyldisulfide (10.8 g, 0.049 mol) were dissolved in tetrahydrofuran (200 mL) and the solution was cooled to 0 ° C under a nitrogen atmosphere. Tri-n-butylphosphine (11.7 mL, 0.047 mol) was added and the reaction mixture was stirred for 1 hour. An additional amount of phenyldisulfide (1.5 g, 0.007 mol) and tri-n-butylphosphine (5.1 mL, 0.20 mol) was then added and the reaction mixture was stirred at room temperature until the reaction was complete. The tetrahydrofuran was removed in vacuo and the residue was purified by chromatography on silica gel and eluent 5% ethyl acetate in hexane. The title compound is obtained as clear colorless plates, m.p. 100-101.5 ° C.

Analysis calculated for C-15H13NS:

C, 75.27; H, 5.47; N, 5.85;

Found: C, 74.52; H, 5.39, N, 5.95,

Step C: 3-Phenylthio-2-phenylthiomethylindole

A suspension of sodium hydride (0.37 g, 60% dispersion in oil, 9.4 mmol) in dimethylformamide (50 mL) was cooled to 0 ° C. 2-Phenylthiomethylindole (1.5 g, 6.3 mmol) was added in portions and the mixture was stirred at 0 ° C for 15 minutes. Phenyldisulfide (1.5 g, 6.9 mmol) was added and the reaction mixture was stirred for 6 hours at 20 ° C. The reaction was then quenched with water and the reaction mixture extracted with ethyl acetate.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 76 The organic extract is washed with water, saturated sodium chloride solution and dried over magnesium sulfate. After filtration and evaporation of the solvent, an oil was left which was purified by chromatography under ordinary pressure over silica gel using 5% ethyl acetate in hexane as eluent. The title compound was obtained as an oil.

Analysis: calculated for C21H- 7NS2, »H2O * 0.1 5 · ΰ4Ηθθ2:

C, 68.50; H, 5.33; Ν, 3.60;

Found: C, 68.40; H, 4.65; Ν, 3.86

Step D: 2-Phenylsulfinylmethyl-3-phenylthioindole

A solution of 3-phenylthio-2-phenylthiomethylindole (0.750 g, 2.94 mmol) in methanol (100 mL) was cooled to 0 ° C with stirring. A solution of monoperoxyphthalic acid, magnesium salt (0.908 g, 80% peracid) in methanol (50 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred for another 30 minutes and quenched with 10% aqueous sodium thiosulfate (2 mL). The methanol was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed successively with water, then with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and concentration of the filtrate in vacuo afforded an oil which was purified by chromatography on silica gel using 20-30% ethyl acetate in hexane as the eluent. The title compound was obtained as a foam, m.p. 71 -74 ° C.

Exact mass calculated for C21H17NOS2: 364.082982.

Found: 364.084549.

NMR (DMSO-dg): δ 11.82 (1H, s), 7.50 (6H, m), 7.23 (1H, d, J = 8 Hz), 7.15 (3H, m), 7.05 (2H, m). 6.90 (2H, m), 4.43 (1H, d, J = 13 Hz), 4.38 (1H, d, J = 1 3 Hz).

I

- ^Ύ 8 hydrochloric acid. The layers were separated and the organic phase was washed sequentially with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The chloroform solution was dried over magnesium sulfate, filtered and evaporated to dryness. The resulting oil was purified by chromatography on silica gel and eluent 5% ethyl acetate in methylene chloride. The title compound was obtained as a solid, m.p. 64-65 ° C.

Analysis: calculated for C22H1 qN2OS »0.2 H2O

C, 73.00; H, 5.08; N, 7.74;

Found: C, 72.93; H, 5.02; N, 7.66.

Example 6

Preparation of 2- (N-phenylacetamido) -3-phenyl-thioindole and 2- (N-phenylacetamido) -1- (phenylcarbamoyl) -3-phenylthioindole 2-Methyl-3-phenylthioindole (0.50 g, 2.1 mmol) (obtained by The method described by Atkinson, JG et al., Synthesis, 480-481 (1988)) was dissolved in dry tetrahydrofuran and cooled under nitrogen to -78 ° C. A solution of n-butyllithium in hexane (0.83 ml_, 2.5 M) was added by injection. Carbon dioxide was bubbled through the solution for several minutes and the unreacted carbon dioxide was removed by freezing the reaction mixture to liquid nitrogen under high vacuum and warming to -78 ° C. A solution of t-butyllithium in hexane (1.35 mL, 1.7 M) was added and the reaction mixture was stirred for 20 minutes. Phenylisocyanate (0.23 mL, 2.1 mmol) in tetrahydrofuran (1.5 mL) was added and the reaction mixture was stirred at 20 ° C overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and evaporation of the solvent gave a yellow

· · · · · · · · · · · · · · · · · · · · · · · · • * w 5 ··· · ···· • · · · · · · · · · · · · · · · · · · · · - 77 -

Example 5

Preparation of 2-phenylcarboxamidomethyl-3-phenylthioindole

Step A: 3-Phenylthioindole-2-carboxamide

The title compound was obtained from 3-phenylthioindole-2-carboxylic acid (prepared by the method described by Atkinson, J. G. et al., Synthesis, 480-481 (1988), (4.01 g,

0.015 mol), ammonia (large excess) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (7.2 g, 0.016 mol) in dimethylformamide according to the basic method described in Example 1 to give N- (3-pyridylmethyl) -5 -chloro-3-phenylthio-2carboxamide. The title compound was obtained as a pale yellow solid.

Step B: 2-Aminomethyl-3-phenylthioindole

A solution of 3-phenylthioindole-2-carboxamide (1.9 g, 7.1 mmol) in tetrahydrofuran was cooled under nitrogen to 0 ° C and treated with pure borandimethyl sulfide complex (7.1 mL, 0.070 mol). The reaction mixture was heated to reflux under ^'v for 7 hours, cooled to 0 ° C and quenched with 10% aqueous hydrochloric acid solution. The solution was basified to pH 8 with 20% aqueous sodium hydroxide solution. The reaction mixture was extracted with ethyl acetate and the organic extract was washed with saturated sodium chloride solution and dried over magnesium sulfate. The title compound was obtained as a pale yellow solid.

Step C: 2-Phenylcarboxamidomethyl-3-phenylthioindole

2-Aminomethyl-3-phenylthioindole (0.85 g, 3.3 mmol) was dissolved in chloroform (15 mL) and cooled under nitrogen to 0 ° C. Pyridine (2.7 mL, 33 mmol) was added followed by benzoyl chloride (1.1 mL, 10 mmol). The reaction mixture was stirred at 20 ° C for 1 hour and a 10% aqueous oil solution was added. The harsh

The product was chromatographed on silica gel eluting successively with 15%, 20% and 40% ether in hexane.

2- (N-Phenylacetamido) -3-phenylthioindole is obtained as a solid, m.p. 66-68 ° C.

Analysis calculated for C ₂₂ HiqN ₂ OS:

C, 72.98; H, 5.01; Ν, 7.73;

Found: C, 72.99; H, 4.87; 7.5, 7.52.

The following fraction contains 2- (N-phenylacetamido) -!

(phenylcarbamoyl) -3-phenylthioindole, m.p. 123-125 ° C.

Analysis calculated for C ₂ gH ₂ 3N ₃ O ₂ S:

C, 70.28; H, 4.67; N, 8.47;

Found: C, 70.37; H, 4.61; N, 8.34.

Example 7

Preparation of 2- (2-oxo-2-furan-3-yl) ethyl-3-phenylthioindole

Step A: N-Methoxy-N-methylfuran-3-carboxamide

The title compound was obtained from furan-3-carboxylic acid (3.4 0.030 mol), N, N-dimethylhydroxylamine hydrochloride (2.9 g, 0.030 mol), triethylamine (8.3 mL, 0.060 mol) and benzotriazol-1-yloxytris (dimethylamino) ) phosphonium hexafluorophosphate (13.3 g, 0.030 mol) by a method analogous to that described in Example 1 to give N- (3-pyridyl methyl) -5-chloro-3-phenylthio-2-carboxamide.

NMR (DMSO-dg): δ 8.25 (1H, s), 7.75 (1H, s), 3.70 (3H, s), 3.22 (3H, s).

Step B: 2- (2-Oxo-2-furan-3-yl) ethyl-3-phenylthioindole

The title compound was obtained from N-methoxy-N-methylfuran-3-carboxamide (0.32 g, 2.1 mmol) and 2-methyl-

3-Phenylthioindole (0.50 g, 2.1 mmol) according to the general method described in Example 6 to give 2- (N-phenylacetamido) -3-phenylthioindole. The crude product is chromatographed on silica gel, i

• · ·

using chloroform as eluent. The title compound was obtained as a pale yellow solid, m.p. 127-129 ° C.

Analysis calculated for C20H15NO2S:

C, 72.05; H, 4.54; N, 4.20;

Found: C, 72.08; H, 4.57; N, 4.24.

Example 8

Preparation of 2-benzoyl-5-chloro-3-phenylthioindole

Step A: N-Methoxy-N-methyl-5-chloro-3-phenylthioindole-2carboxamide

The title compound was obtained from 5chloro-3-phenylthioindole-2-carboxylic acid (1.0 g, 3.30 mmol), N, N-dimethylhydroxylamine hydrochloride (0.64 g, 6.6 mmol), triethylamine (1.0 mL, 7 mmol) and benzotriazole -1-Iloxytris (dimethylamino) phosphonium hexafluorophosphate (1.64 g, 3.6 mmol) in dimethylformamide according to the general method described in Example 1 to give N- (3-pyridylmethyl) -5-chloro-3-phenylthio-2carboxamide. '

Step B: 2-Benzoyl-5-chloro-3-phenylthioindole

N-Methoxy-N-methyl-5-chloro-3-phenylthio and ndol-2carboxamide (0.24 g, 0.69 mmol) was dissolved in dry tetrahydrofuran (5 mL) and cooled to -78 ° C under a nitrogen atmosphere. A solution of phenylmagnesium chloride in tetrahydrofuran (0.81 mL, 2M) was added by injection and the reaction mixture was heated to 20 ° C overnight. Water and ethyl acetate were added to the reaction mixture and the resulting layers were separated.

The organic phase was washed successively with water, 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. After filtration and evaporation of the solvent i

·· which is chromatographed on hexane. The compound, obtained as a solid with m.p. 154-155 ° gave the crude product, silica gel, with eluent 10% ether in ί

indicated in the heading as

P

Analysis calculated for C21H14CINOS

C, 69.32; H, 3.88; Ν, 3.85 Found: C, 68.61; H, 3.83; Ν, 3.83.

Example 9

Preparation of 2- (2-benzoxazol-2-ylethyl) -3-phenylthioindole Step A: N-Methoxy-N-methyl-3-phenylthioindole-2carboxamide

The title compound was obtained from 3-phenylthioindole-2-carboxylic acid (1.0 g, 3.7 mmol), N, N-dimethylhydroxylamine hydrochloride (0.54 g, 5.5 mmol), triethylamine (1.5 mL, 11 mmol) and benzotriazol-1-yloxytris (dimethylaminosetris). ) phosphonium hexafluorophosphate (1.64 g, 3.7 mmol) by the method described in Example 1 to give N- (3-pyridylmethyl) -5-chloro 3-phenylthio-2-carboxamide.

Step B: 3-Phenylthioindole-2-carboxaldehyde N-Methoxy-N-methyl-3-phenylthioindole-2-carboxamide (1.57 g, 5.26 mmol) was dissolved in tetrahydrofuran (150 mL) and cooled to 0 ° C under an atmosphere of nitrogen. A solution of lithium aluminum hydride in tetrahydrofuran (5.76 mL, 1M) was added slowly by injection and the reaction mixture was stirred for a total of one and a half hours. Ethyl acetate (30 mL) was added to the reaction mixture and then sodium potassium tartrate solution. The layers were separated and the organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. Filtration and evaporation of the solvent gave the title compound as a yellow solid.

···· • · I • · • ·· • · · · · ·

- 82 Step C: Trans-2- (2-benzoxazol-2-ylethenyl) -3-phenylthioindole n-butyllithium in hexane (3.47 mL, 2.5 M) was added to a solution of [(benzoxal-2-yl) -methyl] diethylphosphonate ( 2.34 g, 8.68 mmol) in tetrahydrofuran (50 mL) at -78 ° C under a nitrogen atmosphere. The reaction mixture was stirred for 20 minutes and warmed to -20 ° C. A solution of 3-phenylthioindole-2 carboxaldehyde (1.10 g, 4.34 mmol) in tetrahydrofuran (30 mL) was added and the reaction mixture was stirred at 20 ° C overnight.

Ethyl acetate and water were added and the resulting layers separated.

The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product is treated with a mixture

1: 1 from hexane and ethyl acetate and separated by filtration.

The title compound was obtained as a yellow solid, m.p. 260 ° C.

Analysis: calculated for 023Η · | θΝ2θ8

C, 72.32; H, 4.58; 7.3, 7.33;

Found: C, 72.41; H, 4.50; N, 7.44;

Step D: 2- (2-Benzoxazol-2-ylethyl) -3-phenylthioindole

A solution of trans-2- (2-benzoxazol-2-yl-ethenyl) -3-phenylthioindole (0.420 g, 1.14 mmol) in a 1: 1 mixture of methanol and tetrahydrofuran (250 mL) was stirred under 1 atmosphere of hydrogen pressure in the presence of catalyst 10% palladium on carbon (100 mg). An additional amount of catalyst is added if necessary so that the reaction is complete. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The resulting solid was treated with 10% ethyl acetate in hexane and the resulting precipitate was separated by filtration to give the title compound, m.p. Mp 192-193 ° C.

- 83 Analysis: Calculated for C23H13N2OS

C, 72.80; H, 5.04; N, 7.38;

Found: C, 72.78; N.

4.95 Ratio; N, 7.45;

Example 10

Preparation of N-2-furanylmethyl-5-chloro-3-phenylthioindole2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 2aminomethylfuran instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, then the resulting precipitate was separated by filtration. Recrystallization from acetonitrile afforded the title compound, m.p. 214 ° C.

Analysis calculated for C20H15CIN2O2S:

C, 62.74; H, 3.95; N, 7.32

Found: C, 62.27; H, 3.88; N, 7.41.

NMR (DMSO-γθ): δ 12.55 (1 H, s), 8.72 (1 H, t, J = 6 Hz), 7.55 (1 Η, m), 7.54 (1 Η, d, J = 8 Hz). 7.45 (1H, d, J = 2 Hz), 7.15 (1H, tt, J = 7.1 Hz), 7.08 (1H, s), 7.06 (1H, d, J = 8 Hz), 6.35 (1H, m). 6.18 (1H, m), 4.56 (2H, d, J = 6 Hz).

Example 11

Preparation of N-3-pyridyl-5-chloro-3-phenylthioindole2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 3-aminopyridine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, then the resulting precipitate was separated by filtration. After purification by chromatography · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

84 with silica gel and eluent 40% ethyl acetate in hexane to give the title compound, m.p. Mp 255-256 ° C.

Analysis calculated for C20H1 5CIN3OS:

C, 63:24; H, 3.98; N, 10.74

Found: C, 62.59; H, 3.86; N, 11.06.

NMR (DMSO-dg): δ 12.72 (1H, s), 10.55 (1Η, s), 8.85 (1H, d, J = 3 Hz), 8.35 (1H, dd, J = 5.1 Hz), 8.14 ( 1H, dm, Jtf = 8 Hz), 7.60 (1H, d, J = 9 Hz), 7.48 (1H, d, J = 2 Hz), 7.40 (1H, dd, J = 9.2 Hz), 7.25 (2H. t, J = 7 Hz), 7.16 (1H, m), 7.11 (2H, t, J = 7 Hz).

Example 12

Preparation of N-ethyl-5-chloro-3-phenylthioindole-2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using ethylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, then the resulting precipitate was separated by filtration. Purification by recrystallization from 2% methanol in ethyl acetate afforded the title compound, m.p. 210-211 ° C.

Analysis calculated for C 7 H 7 H 15 CIN 2 OS 0.5 H 2 O:

C, 60.08; H, 4.74; N, 8.24

Found: C, 60.00; H, 4.18; N, 8.52.

NMR (DMSO-dg): δ 12.49 (1H, s), 8.31 (1 H, t, J = 6 Hz), 754 (1 H, d, J = 9 Hz), 7.43 (1H, d, J = 2 Hz), 7.27 (3H, m), 7.15 (1H, tt, J = 7.2 Hz), 7.07 (2H, m), 3.35 (4H, m), 1.06 (3H, t, J = 7 Hz).

Example 1 3

Preparation of N-3-methoxybenzyl-5-chloro-3-phenylthioindole-2carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 3-methoxy-

benzylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, then the resulting precipitate was separated by filtration. After purification by recrystallization i

acetonitrile yields the title compound, m.p. Mp 72 ° C.

Analysis calculated for C23H-1 gCl2OgS4O.S.S HgO:

C, 64.48; H, 4.61; N, 6.54

Found: C, 64.41; H, 4.38; N, 6.75.

NMR (DMSO-dg): δ 12.55 (1H, s), 8.80 (1H, m), 7.55 (1H, d, J = 8 Hz), 7.44 (1H, s), 7.25 (3H, m). 7.15 (2H, m), 7.05 (2H, d, J = 7 Hz), 6.80 (3H, m), 4.54 (2H, d, J = 6 Hz).

Example 14

Preparation of N-2-methoxyethyl-5-chloro-3-phenylthioindole-2carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 2-methoxyethylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, after which the resulting precipitate was filtered off to give the title compound, m.p. 216-217 ° C.

Analysis calculated for C- (θΗ- | 7CIN2O2S * 0.25 H2O:

C, 59.1 7; H, 4.83; N, 7.67

Found: C, 59.11; H, 4.75; N, 7.82.

NMR (DMSO-dg): δ 12.54 (1H, s), 8.44 (1H, t, J = 6 Hz), 7.54 (1H, d, J = 9 Hz), 7.48 (1H, d, J = 2 Hz) ), 7.28 (3H, m), 7.17 (1H, t, J = 7 Hz), 7.10 (2H, m), 3.49 (2H, q, J = 6 Hz), 3.37 (2H, t, J = 6 Hz) ), 3.16 (3H, s).

• · · · ·

- 86 Example 1 5 '

Preparation of N-4-pyridylmethyl-5-chloro-3-phenylthioindole-2carboxamide

The title compound was prepared by the (ί method described in Example 1, Step B, using 4aminomethylpyridine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, after After recrystallization from acetonitrile, the title compound is mp 228-229 ° C.

Analysis calculated for C21H-j gCIN3OS * 0.2 H2O:

C, 63.45; H, 4.16; N, 10.57

Found: C, 63.33; H, 4.02; N, 10.50.

NMR (DMSO-d ₆ ): δ 12.56 (1 H, s), 8.92 (1 H, t, J = 6 Hz), 8.38 (1H, d, J-4 Hz), 7.55 (1H, d, J = 8 Hz), 7.47 (1H, s), 7.31 (1H, dd, J = 8.2 Hz), 7.25 (1H, d, J = 7 Hz), 7.17 (2H, m), 7.05 (1H, d, J = 7 Hz), 4.58 (2H, d, J = 6 Hz).

Example 1 6

Preparation of GM-2-hydroxyethyl-5-chloro-3-phenylthioindole-2carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 2-hydroxyethylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with a mixture of ethyl acetate and hexane 1: 1, then the resulting precipitate was separated by filtration. The product was chromatographed on silica gel eluting with 2% methanol in chloroform to give the title compound, m.p. 222-223 ° C.

Analysis: calculated for C- | 7H-1 5θΝ2θ2δ · 0.3 H2O:

···· ··

87 C, 57.96; 4., 4.46; Ν, 7.95

Found: C, 57.99; 4.2, 4.26; Ν, 7.90.

NMR (DMSO-θθ): δ 12.50 (1 Η. S) and 8.46 (1Η, m), 7.55 (1 H, d, J = 9 Hz), 7.45 (1H, d, J = 1 Hz), 7.28 ( 3H, m), 7.17 (1H, t, J = 6 Hz), 7.13 (2H, m), 4.85 (1H, t), 3.49 (1H, m), 3.43 (1H, m).

Example 1 7

Preparation of 5-chloro-3-phenylthioindole-2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using excess ammonia gas instead of 3-aminomethylpyridine and triethylamine. The dimethylformamide and excess ammonia are removed in vacuo and the resulting residue is treated with ethyl acetate and 10% hydrochloric acid to form two layers. The organic phase was washed with water, 5% sodium hydroxide and saturated sodium chloride solution, then dried over magnesium sulfate. Filtration and evaporation of the solvent give a crude product? which was purified by chromatography on silica gel and 30% ethyl acetate in hexane as eluent. The title compound was obtained as a white solid, m.p. 213-215 ° C.

Analysis: calculated for C- | 5H1 CIN2OS · 1/3 H2O:

C, 58.35; H, 3.81; N, 9.07

Found: C, 58.33; H, 3.64; N, 9.11.

NMR (DMSO-d _6): δ 12.52 (1H, bs), 8.06 (1H, s), 7.76 (1H, s), 7.55 ( 1 H, d, J = 9 Hz), 7.44 (1H, s ) , 7.28 (3H, m), 7.15 (1H, t, J = 6 Hz), 7.06 (2H, d, J = 8 Hz).

Example 18

Preparation of 5-chloro-3-phenylthioindole-2-thiocarboxamide

A solution of 5-chloro-3-phenylthioindole-2-carboxamide (3.8 g,

12.5 mmol) and [2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethane · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 90 NMR (DMSO-d ₆ ): δ

12.58 (1H, S), 9.15 (1H, t, J = 5 Hz), 8.46 (1H,

J = 8 Hz), 7.57 (1H, d, J = 8 Hz), 7.50 (1H, s),

m), 4.68 (1H, d, J = 5 Hz).

Example 22 i i

Preparation of N- (3-methoxy-4-pyridyl) methyl-5-chloro-3-phenylthioindole-2-carboxamide

Step 1: Preparation of 4-cyano-2-methoxypyridine

A solution of 2-chloro-4-cyanopyridine (1.25 g, 9.1 mmol) obtained by the method described by D.

Grumbach,

France, 694 (1958), in methanol was treated with sodium methoxide (0.58 g, 10.9 mmol) and refluxed for 30 minutes.

The reaction mixture was cooled, filtered, and the filtrate was concentrated in vacuo to give the crude product as an off-white solid, which was purified by chromatography;

graphite with silica gel and 20% ethyl acetate in hexane as eluent. The title compound was obtained as a white powder.

Step 2: Preparation of 4-Aminomethyl-2-methoxypyridine

A solution of 4-cyano-2-methoxypyridine (0.55 g, 4.1 mmol) in ethanol was hydrogenated under hydrogen pressure of 60 psi in the presence of 10% palladium on charcoal (100 mg). After 3.5 hours, the catalyst was removed by filtration through a supercell and the filtrate was evaporated to give the title compound as a foam.

Step 3: Preparation of N- (3-methoxy-4-pyridylmethyl-5-chloro-3-phenylthioindole-2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 4aminomethyl-2-methoxypyridine instead of 3-aminomethylpyridine.

· · · · · · · · · · · · · · · · · · · · · · ·

- 89 Example 20

Preparation of N- [1- (2 (B) -hydroxypropyl)] - 5-chloro-3-phenylthioindole-2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 2 (R) hydroxy-1-propylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with 20% ethyl acetate in hexane and then with acetonitrile. The title compound was obtained as an off-white solid, m.p. 202-203 ° C.

Analysis calculated for Cf qH-j 7CIN2O2S * 0.3 H2O:

C, 59.01; 4., 4.67; 7.6, 7.65

Found: C, 58.91; Η, 4.59; 7., 7.50.

NMR (DMSO-dg): δ 12.52 (1H, s), 8.45 (1Η, t, J = 5 Hz), 7.55 (1H, d, J = 8 Hz), 7.46 (1H, s), 7.25 (3H , m), 7.15 (3H, m), 4.89 (1H, d, J = 5 Hz), 3.74 (1H, m), 3.38 (1H, m), 3.23 (1H, m), 1.00 (3H /. d, J = 6 Hz).

Example 21

Preparation of N- (2-pyridyl) methyl) -5-chloro-3-phenylthioindole2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 2 pyridylmethylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the resulting residue was treated with 30% ethyl acetate in hexane and then with acetonitrile. The title compound was obtained as a white solid, m.p. 209-210 ° C.

Analysis: calculated for C21H- θΟΝθΟε:

C, 64.03; H, 4.10; Ν, 10.67

Found: C, 63.51; H, 3.97; Ν, 10.41.

· · · · · · · · · · · · · · · · · · · ·

- 92 (The title compound was prepared by the method described in Example 1, Step B, using 3-hydroxybenzyl. 1-1 ammonium instead of 3-aminomethylpyridine. Dimethylformamide was

I was removed by chromatography under vacuum and the crude product obtained was purified silica gel and eluentT 10% methanol in chloroform. The title compound was obtained as a white solid, m.p. Mp 214-216 ° C.

Analysis calculated for C22H1 7CIN2C> 2S »0.3 H2O:

C, 63.77; H, 4.04; N, 6.76

Found: C, 63.92; H, 3.88; N, 6.49.

NMR (DMSO-dg): δ 12.55 (1H, s), 9.34 (1H, s), 8.75 (1H, t, J = 5 Hz), 7.53 (1H, d, J = 8 Hz), 7.45 (1H , s), 7.1-7.65 (4H, m), 7.06 (2H, d, J = 7 Hz), 7.01 (1H, t, J = 8 Hz), 6.70 (1H, s), 6.62 (2H, m) , 4.48 (2H, d, J = 5 Hz).

Example 25

Preparation of 5-chloro-3-phenylsulfonylindole-2-carboxamide (Compound 1 8)

5-Chloro-3-phenylthioindole-2-carboxamide (0.177 g, 0.584 mmol) was dissolved in 25 mL of chloroform and cooled to 0 ° C. 50 wt. % meta-chloroperoxybenzoic acid (503 mg, 1.46 mmol) and the reaction mixture was stirred at 20 ° C for 6 hours. A 10% aqueous solution of sodium thiosulfate was added and the mixture was stirred vigorously for 10 minutes. The layers were separated and the organic phase was washed with saturated sodium chloride solution and then dried over magnesium sulfate. The crude product obtained was purified by chromatography on silica gel and eluent 40% ethyl acetate in hexane. The title compound was obtained as a white powder, m.p. Mp 255-257 ° C.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

91 Dimethylformamide is removed in vacuo and the crude product obtained is purified by chromatography on silica gel and eluent 20-40% ethyl acetate in hexane. The title compound was obtained as a white solid, m.p. Mp 227-228 ° C.

Analysis calculated for C22H1 3CIN3O2S:

C, 62.33; H, 4.28; N, 9.91

Found: C, 62.63; H, 4.21; N, 9.92.

NMR (DMSO-dg): δ 12.58 (1H, s), 8.93 (1H), 8.37 (2H, d), 7.56 (1H, d), 7.47 (1H, s), 7.27 (3H, m). 7.18 (2H, m), 7.05 (2H, d), 4.59 (2H, d), 3.30 (3H, s).

Example 23

Preparation of N- (3-hydroxymethyl) benzyl-5-chloro-3-phenylthioindole-2-carboxamide

The title compound was prepared by the method described in Example 1, Step B, using 3-hydroxymethylbenzylamine instead of 3-aminomethylpyridine. The dimethylformamide was removed in vacuo and the crude product obtained was purified by recrystallization from acetonitrile. The title compound was obtained as a white solid, m.p. Mp 229-230 ° C.

Analysis calculated for C22H1 7CIN2O2S:

C, 64.61; H, 4.19; N, 6.85

Found: C, 64.20; H, 4.09; N, 6.85.

NMR (DMSO-dg): δ 12.69 (1H, s), 10.33 (1Η, s), 7.60 (3H, m), 7.49 (1H, s), 7.30 (4H, m), 7.15 (4H. m), 5.22 (1 H, t, J = 7 Hz), 4.50 (2H, d, J = 7 Hz).

Example 24

Preparation of N- (3-hydroxybenzyl) -5-chloro-3-phenylthioindole-2-carboxamide ·· ···· ·

· · · · · ·

Step A: 5-Chloro-3-phenylsulfonylindole-2-carboxylic acid

To a suspension of 5-chloro-3-phenylthioindole-2-carboxylic acid (4.84 g, 0.016 mol) | chloroform (1200 mL) was added 55% m-chloroperoxybenzoic acid (12.5 G, 0.04 mol). The mixture was allowed to stir at room temperature for 40 hours. Filtration gave the title compound as a colorless solid, m.p. 277-280 ° C (dec). Concentration of the filtrate by evaporation gave an additional amount of product.

Step B: Reaction product of 5-chloro-3-phenyl-sulfonylindole-2-carboxylic acid with oxalyl chloride

Oxalyl chloride (3.81 g, 0.03 mol) was added to a suspension of 5-chloro-3-phenylsulfonylindole-2carboxylic acid (5.04 g, 0.015 mol) in chloroform (200 mL). After the addition of a catalytic amount of dimethylformamide (0.1 mL), the mixture was heated in a bath at 20 DEG C. for 50 minutes. After cooling, the solid obtained, m.p. > 300 ° C is used directly without purification. Based on the mass and NMR data, it is assumed that this product is a symmetric dimer and is referred to as a typical acid chloride when reacted with primary amines.

Step C: N- (2,6-difluorobenzyl) -5-chloro-3-phenylsulfonylindole-2-carboxamide

2,6-Difluorobenzylamine (0.430 g, 3.0 mmol) was added dropwise to a solution of the acid chloride equivalent obtained in step B (0.354 g, 1.0 mmol) in a solution of tetrahydrofuran (10 mL) cooled in an ice bath. acetone. The reaction mixture was allowed to warm to room temperature and left overnight. When developing the mixture

NMR (300 MHz, DMSO-d ₆ ): δ 13.05 (1H, s), 8.48 (1H, s), 8.25 (1H,

s), 8.03 (2H, d, J = 8 Hz), 7.95 (1H, s), 7.60 (4H, m), 7.34 (1H, d, J = 8)

Hz).

Analysis: calculated for C- | 5H1 CIN2O3S:

C, 53.82; Ή, 3.31; 8, 8.37

Found: C, 53.74; Η, 3.29; Ν, 8.34.

Example 26

Preparation of 5-chloro-3-phenylsulfinylindole-2-carboxamide (Compound 1 7)

A solution of the magnesium salt of monoperoxyphthalic acid (85% peracid) (11.8 mg, 0.024 mmol) in methanol (2 mL) was added dropwise to a solution of 5-chloro-3-phenylthioindole-2-carboxamide (14.5 mg, 0.048 mmol) in methanol (2 mL) at 0 ° C and the reaction mixture was stirred at 20 ° C for 4 hours. A 10% aqueous solution of sodium thiosulfate was added and the mixture was stirred vigorously for 10 minutes. The methanol was removed in vacuo and the residue treated with ethyl acetate and water. The layers were separated and the organic phase was washed with sodium chloride solution and then dried over magnesium sulfate. The crude product obtained was purified by silica gel column chromatography eluting with 30-40% ethyl acetate in hexane. The title compound was obtained as a white solid.

NMR (DMSO-d ₆ ): δ 12.53 (1H, s), 8.35 (1H, br s), 8.08 (1H, br s), 7.83 (1H, d, J = 2 Hz), 7.71 (2H. d, J = 8 Hz), 7.52 (4H, m), 7.30 (1H, dd, J = 9.2 Hz).

Example 27

Preparation of N- (2,6-difluorobenzyl-5-chloro-3-phenylsulfonyl indole-2-carboxamide ···········

- 96 ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Dimethylformamide was added benzotriazol-1-yl-oxy-rice (dimethylamino) phosphorous hexafluorophosphate (BOP reagent) (0.1 55 g, 0.35 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for three days. Evaporation gave a residue which was treated with ethyl acetate and water. The ethyl acetate phase was separated and washed with dilute hydrochloric acid. The acid extract was neutralized with aqueous sodium bicarbonate solution and the product extracted with ethyl acetate. The ethyl acetate extract was washed thoroughly with aqueous sodium bicarbonate solution, then with saturated sodium chloride solution and dried over magnesium sulfate. Evaporation gave a solid residue which was recrystallized from ethyl acetate to give the title compound, m.p. 233-235 ° C.

Analysis: calculated for C21H- 6CIN3O2S:

C, 61.54; H, 3.93; N, 10.25. Found: C, 61.39; H, 3.95; N, 10.36.

NMR (DMSO-d _6):

δ 9.62 (1 N, t,

7.67 (2H, m),

7.64 (2H, d, J = 9 Hz), 7.44-7.54 (3H, m), 7.33 (3H, m),

4.60 (2H, dq,

Example 29

Preparation of N - [(S) -1-phenyl-2-hydroxyethyl] -5-chloro-3-phenylsulfonylindole-2-carboxamide (Compound 32)

To a solution of the acid chloride dimer product of Example 27, Step B (0.354 g, 1.0 mmol) in tetrahydrofuran (10 mL) cooled in an ice-acetone bath was added a solution of (S) - (+) phenylglycinol (0.343 g, 2.5 mmol). After gradient warming to room temperature, the reaction mixture was allowed to stand overnight. Ethyl acetate and water were added. The ethyl acetate phase was washed sequentially with diluted ·· ···· · · · ·. · · · · · · · · · · · · · · · · · · · · · · · · ·

- 95 added ethyl acetate and water. The separated ethyl acetate phase was washed thoroughly with dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and pd sodium chloride solution. After drying over magnesium sulfate and evaporation of the solvent, the residue was dispersed in ethyl acetate and filtered to give the title compound,

mp Mp 274-280 ° C.

Analysis: calculated for ¢ 22 ^ 150 ^ 2 ^ 038 ^ 0.5 H2O (3H,

C, 56.24;

H, 3.43; N

5.96

Found: C, 56.1 2

NMR (DMSO-d ₆ ): δ; 3., 3.31N,

13.06 (1 n,

5.97.

s), 9.41 (1H, t, J = 5.5, 7.95 (2H, t, J = 8)

Hz),

Example 28

Preparation of N- (4-pyridylmethyl) -5-chloro-3-phenylsulfinylindole-2-carboxamide (Compound 29)

Step A: Preparation of 5-chloro-3-phenylsulfinylindole-2 carboxylic acid

To a suspension of 5-chloro-3-phenylthioindole-2-carboxylic acid (2.14 g, 0.007 mol) in chloroform (600 mL) was added 55% m-chloroperoxybenzoic acid (2.32 g, 0.0074 mol). The mixture soon cleared and solid particles formed. After stirring overnight at room temperature and filtration, the title compound is obtained in pure form, m.p. 183-185 ° C.

Step B: N- (4-Pyridylmethyl) -5-chloro-3-phenylsulfinylindole-2carboxamide

To a solution of 5-chloro-3-phenylsulfinylindole-2carboxylic acid (0.096 g, 0.3 mmol), triethylamine (0.061 g, 0.6 mmol) and 4-aminomethylpyridine (0.043 g, 0.4 mmol) in dry solution · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

98 Indole-2-carboxylic acid gives the title compound, m.p. 260-261 ° C.

Stage

C: Product of reaction of 5-chloro-3- (2-thiazolyl) sulfonylindole-2-carboxylic acid with oxalyl chloride

I

Using the procedure described in Example 27, Step B, but using 5-chloro-3- (2-thiazolyl) sulfonylindole-2-carboxylic acid instead of 5-chloro-3-phenylsulfonylindole-2-carboxylic acid a solid product is obtained, m.p. >

290 °, which is used directly in the next step.

V Step D: N- (3-Methoxybenzyl) -5-chloro-3- (2-thiazolylsulfonyl) indole-2-carboxamide

To a solution of the acid chloride product of Step C (0.181 g, 0.5 mmol) in tetrahydrofuran (5 mL) cooled in an ice-acetone bath was added 3-methoxybenzylamine (0.205 g, 1.5 mmol). The mixture was allowed to warm to room temperature and then allowed to stir overnight. Ethyl acetate and water were added. The ethyl acetate layer was separated and washed with dilute hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying (over magnesium sulfate) and evaporation gave a solid residue which was allowed to stand in a small amount of ethyl acetate. Filtration gave the title compound, m.p. 205-209 ° C.

Analysis calculated for C20H1 6CIN3O4S2:

C, 52.00; H, 3.49; N, 9.10

Found: C, 51.88; H, 3.42; N, 9.07.

NMR (DMSO-d ₆ ): δ 9.43 (1H, t, J = 6 Hz), 8.18 (1H, d, J = 3 Hz), 8.02 (1H, d, J = 3 Hz), 8.00 (1H. d, J = 2 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.40 (1H, dd, J = 8.5.2 Hz), 7.28 (1H, t, J = 8 Hz), 6.98-7.05 ( 2H, m), 6.85 (1H, dd, J = 8, 2.5 Hz), 4.54 (2H, d, J = 3.76 Hz).

I 9 • · · · · ·

- 97 hydrochloric acid, water, quenching solution

- ---- - -, ~.

bicarbonate and saturated sodium chloride solution.

of sodium

After drying over magnesium sulfate and evaporation, the product was chromatographed on a 20 mm diameter column containing 6 inches (1 i 230-400 mesh size) eluting with 40% ethyl acetate 5.24 cm) silica gel methylene chloride to give the pure compound. which, after evaporation of the eluent, was recrystallized from ethyl acetate-hexane to give the title compound, m.p. Mp 155-160 ° C.

ν '

Analysis calculated for C23H-1CIN2O4S:

C, 60.72; H, 4.21; N, 6.16

Found: C, 60.33; H, 4.13; N, 6.16.

NMR (DMSO-dg): δ 13.05 (1H, s), 9.52 (1H, d, J = 7.5 Hz), 7.958.48 (3H, m), 7.26-7.68 (10H, m), 5.13 (2H , q, J = 7.5 Hz), 5.07 (1H, t, J = 6 Hz), 3.75 (2H, 6Hz).

Example 30,

N- (3-Methoxybenzyl) -5-chloro-3- (2-thiazolyl) sulfonylindole-2carboxamide (Compound 31) '

Step A: Preparation of 5-chloro-3- (2-thiazolyl) thioindole-2 carboxylic acid

Using the procedure described in Example 1, Step A, but using di- (2-thiazolyl) disulfide instead of phenyldisulfide, the title compound was obtained, m.p. 242-244 °.

Step B: Preparation of 5-chloro-3- (2-thiazolyl) -sulfonylindole2-carboxylic acid

Using the procedure described in Example 27, Step A, but using 5-chloro-3- (2-thiazolyl) thioindole-2-carboxylic acid instead of 5-chloro-3-phenylthio 99 Example 31

5-Chloro-3- (2-thiazolyl) sulfonylindole-2-carboxamide

Acid chloride product solution from Example 30 Step

C (0.50 g, 1.4 mmol) in tetrahydrofuran (25 ml_) was added slowly

I;

to a solution of tetrahydrofuran, saturated with ammonia at -10 ° C.

The mixture was allowed to warm gradually to room temperature and then allowed to stir overnight.

After evaporation of the solvent, ethyl acetate and water were added to the residue. The ethyl acetate extract was separated and washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution. Drying over magnesium sulfate and evaporation of the solvent gave a solid residue which was dispersed in ethyl acetate. Filtration gave the title compound, m.p. 292-294 ° C (dec.).

Analysis calculated for C- | 2H3CIN3O3S2:

C, 42.17; H, 2.36; N, 12.29

Found: C, 42.23; H, 2.35; N, 11.85.

NMR (DMSO-θθ): δ 8.39 (1 H, br s), 8.34 (1 H, br s), 8.24 (1H, d, J = 3 Hz), 8.07 (1 H, d, J = 3 Hz) , 8.00 (1H, dd, J = 2, 0.6 Hz), 7.57 (1H, dd, J = 9, 0.6 Hz), 7.40 (1H, dd, J = 9, 2 Hz).

Example 32

5-Chloro-3-phenylsulfonylindole-2-thiocarboxamide

In the method described in Example 18, 5-chloro-3-phenylsulfonylindole-2-carboxamide was reacted with 2,4-bis (4-methoxyphenyl) 1,3-dithia-2,4-diphosphetane (Lawesson's reagent) to give the compound indicated in the title. Purification of the product was performed by chromatography on silica gel, using as eluent 30% ethyl acetate-methylene chloride and then 50% ethyl acetate-methylene chloride. The pure product has a melting point. 207-210 ° C.

Analysis: calculated for C- | 5 H- | 1 SIN 2O 2 S2 ^:

- 100 C, 51 .35; 3.1, 3.16; Ν, 7.98

Found: C, 50.84; 3, 3.08; Ν, 8.04.

NMR (DMSO-dgi): δ 12.90 (1Η, s), 10.71 (1Η, s), 10.70 (1Η, s), 8.0 - 8.6 (2Η, m), 7.84 (! L Η, d, J = 2 Hz), 7.54-7.66 (3H, m), 7.46 (1H, d,

J = 8.5 Hz), 7.30 (1 H, dd, J = 8.5, 2 Hz).

Example 33

Preparation of 3-phenylsulfonyl-5-chloroindole-2-carboxamide

Step A: N- (phenylthio) succinimide

Thiophenol (2.05 mL, 20 mmol) was added to a partial solution in dry methylene chloride (30 mL) of N-chlorosuccinimide (3.34 g, 25 mmol) after cooling in an ice bath under an inert atmosphere. After stirring for 1 hour, an additional amount of N-chlorosuccinimide (0.40 g, 3 mmol) was added. After stirring for an hour and a half, triethylamine (3.9 mL, 28 mmol) was added dropwise. Within 15 minutes, the reaction mixture was diluted with methylene chloride and the organic phase was washed with dilute aqueous hydrochloric acid and dried (over sodium sulfate), then filtered through a layer of activated carbon and evaporated. The residue was triturated with diethyl ether and the product separated by filtration to give the title compound, m.p. 115-116 ° C [lit. data m.p. is 11 5-116 ° C, as seen by J. Org. Chem., 34, 51 (1969)]. This product is used directly in the next step.

Step B: Ethyl 3-phenylthio-5-chloroindole-2-carboxylate

To a partial suspension of ethyl 5-chloroindole-2carboxylate (698 mg, 3.3 mmol) and N- (phenylthio) succinimide (683 mg, 3.3 mmol) in anhydrous methylene chloride (20 mL) at room temperature under an inert gas atmosphere was added boron trifluoride. etherate (0.12 mL, 1.0 mmol). The reaction is monitored by thin layer chromatography until complete flow. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

After 101 hours, the reaction mixture was diluted with chloroform and neutralized with aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered through a layer of activated carbon and the solvents evaporated. The residue is triturated with hexane to crystallize the product which has m.p. 160-162 ° C [see Table II, m.p. Mp 163-162 ° C]. The product is used without further purification.

Step C: Ethyl 3-phenylsulfonyl-5-chloroindole-2-carboxylate

Ethyl 3-phenylthio-5-chloroindole-2-carboxylate (642 mg, 1.94 mmol) was dissolved in chloroform (35 mL) and dried (over sodium sulfate), then a solution of t-chloroperoxybenzoic acid (55) was added dropwise. % purity, 1.30 g, 4.1 mmol) in chloroform (20 mL). The reaction was monitored by thin layer chromatography until complete. After 5 hours, the mixture was diluted with chloroform and a little methanol, and the solution was washed with aqueous sodium bicarbonate and aqueous sodium carbonate. The dried organic layer (over sodium sulfate) is filtered through a layer of activated carbon and the solvent is evaporated. The residue was treated with diethyl ether to yield the product. Recrystallization from methylene chloride and diethyl ether yields the compound of analytical purity, which has a m.p. 201-202 ° C.

¹ H NMR (CDCI ₃ ): δ 9.63 (1 H, br S), 10.58 (t, 1 H, J = 0.7 Hz), 8.07 (d, 2H, J = 7 Hz), 7.46-7.56 (m, 3H ), 7.40 (m, 2H), 4.39 (ABq, 2H, J = 7 Hz), 1.35 (t, 3H, J = 7 Hz).

Analysis calculated for Cf7H14CINO4S:

C, 56.12; H, 3.88; N, 3.85

Found; C, 55.91; H, 3.95; N, 3.91.

Step D: 3-Phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 18) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 102 Suspension of ethyl 3-phenylsulfonyl-5-chloroindole-2carboxylate (596 mg, 1.64 mmOI) in aqueous concentrated ammonium hydroxide solution (10 mL) containing ammonium chloride (28 mg) was heated at 100 ° C for 3 hours in a screw-closed container. The vessel is then cooled in an ice bath and the product crystallizes. It was filtered off, washed with ice water and dried to give the title compound, m.p. 253-254 ° C.

Example 34

Preparation of N - [(imidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

Suspension of 2-aminomethylimidazole dihydrochloride (256 mg, 1.5 mmol) [prepared by the method described in J. Org. Chem., 43, 1603 (1978)] in dry tetrahydrofuran (6 mL) containing triethylamine (0.42 mL, 3.0 mmol) was stirred at room temperature under inert atmosphere for one hour. Dimeric acid chloride (179 mg, 0.25 mmol) was added [prepared according to Example 27, Step *

B] and then additional triethylamine (0.07 mL, 0.5 mmol) and the mixture was stirred for 12 to 20 hours. The reaction mixture was diluted with water and the product extracted into ethyl acetate. The organic layer was dried (over sodium sulfate), filtered and the solvent was evaporated. The residue was treated with ethyl acetate until the product precipitated. Recrystallization from ethyl acetate afforded an analytically pure product, m.p. 276-278 ° C.

¹ H NMR (DMSO-dg): δ 9.50 (br t, 1H, J = 5.4 Hz), 8.07 (s, 1H), 8.05 (s, 1H), 8.00 (d, 1H, J = 1.2 Hz), 7.52 -7.67 (m, 4H), 7.34 (dd, 1H, J = 1.5, 9 Hz), 7.03 (br s, 2H), 4.61 (d, 2H, J = 5.4 Hz).

Analysis: calculated for C- | gH-J 5CIN4O3S:

C, 55.00; H, 3.64; N, 13.50

Found: C, 54.67; H, 3.36; N, 13.37.

·· ····

104 The residue was treated with ethyl acetate to remove a precipitate from the product which was isolated by filtration. Recrystallization from hot methanol / ethyl acetate afforded the product of analytical purity, m.p. 273-275 ° C.

1 H NMR (DMSO-d ₆ ): δ 9.48 (br t, 1H, J = 5 Hz), 8.05 (d, 2H, J = 7 Hz), 7.98 (d, 1H, J = 2 Hz), 7.52-7.67 (m, 4H), 7.35 (dd, 1H, J = 2.9 Hz), 7.18 (d, 1H, J = 1 Hz), 6.88 (d, 1H, J = 1 Hz), 4.66 (d, 2H, J = 5 Hz), 3.71 (s, 3H).

Analysis calculated for C20H1 7CIN4O3S:

C, 56.00; 4., 4.00; N, 13.06

Found: C, 55.77; Η, 3.97; N, 13.41.

The hydrochloride salt is obtained by adding one equivalent of ethanol HCl to the free base and has m.p. 284-285 ° C (decomposition).

Analysis: calculated for C ₂ q H - 7CIN4O3S «HCI:

C, 51.62; H, 3.90; N, 12.04

Found: C, 51.21; H, 3.92; N, 11.55.

Example 36

An alternative method for the preparation of N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

To a partial suspension of N - [(imidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Example 35) (42 mg, 0.1 mmol) in a 1: 1 mixture of methanol / tetrahydrofuran (4 mL) iodomethane (0.05 mL, 0.8 mmol) was added. The reaction mixture was stirred for three days at room temperature. The solvents were removed under reduced pressure and the product extracted with ethyl acetate / methanol. The organic layer was dried (over magnesium sulfate), filtered and the solvent was evaporated. The residue was purified by chromatography eluting with 3% methanol in chloroform. Appropriate fractions are • ·

•:.

• · · · · · · ·

- 103

Example 35

Preparation of N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 19)

Step A: 2-Aminomethyl-1-methylimidazole

To a suspension of lithium aluminum hydride (114 mg, 3.0 mmol) in dry tetrahydrofuran (15 mL) was added in portions at room temperature and solid 1-methylimidazole-2-carboxamide (185 mg, 1.5 mmol) in an inert atmosphere. of the method described in J. Org. Chem., 52, 4379 (1987)]. After stirring the reaction mixture for half an hour, the reaction mixture was left for three and a half hours, raising the temperature to 50 ° C. After cooling the mixture, saturated aqueous sodium sulfate (2 mL) was added until the reaction was stopped and then powdered anhydrous sodium sulfate was added. Filtration of the salt removal mixture yields a water-free solution of 2aminomethyl-1-methylimidazole in tetrahydrofuran (~ 25 mL), which is used in this form. '

Step B: N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

A solution of dimeric indole-acid chloride (see Example 27, Step B) (358 mg, 0.5 mmol) in dry tetrahydrofuran (7 mL) was added dropwise to a solution of the 2-aminomethyl-1-methylimidazole in tetrahydrofuran obtained in the above step. which is pre-cooled in an ice bath. After 15 minutes triethylamine (0.2 mL, 1.4 mmol) was added and the reaction mixture was slowly warmed to room temperature for 12 to 20 hours. The mixture was diluted with water and the product extracted with 10% methanol / ethyl acetate. The extract was dried (over sodium sulfate), filtered through charcoal and the solvent was evaporated.

105 fumes were combined, the solvents were evaporated and the residue was taken up in methylene chloride to give a pure product.

Example

Preparation of N- [2- (imidazol-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 24)

Carbonyldiimidazole (180 mg, 1.11 mmol) was added to a solution of 5-chloro-3-phenylsulfonylindole-2-carboxylic acid (Example 27, Step A) (336 mg, 0.5 mmol) pre-cooled in an ice bath under an inert atmosphere. After 0.5 hours, histamine (125 mg, 1.12 mmol) was added to the resulting yellow solution.

After 5 hours, the reaction mixture was diluted with water and the product extracted with ethyl acetate. This organic extract was washed with dilute aqueous sodium bicarbonate and dried (over sodium sulfate), filtered through charcoal and the solvent evaporated. Treatment of the residue with methylene chloride yields the crude product. Crystallization from hot ethyl acetate afforded an analytically pure product, m.p. 220-221.5 ° C.

¹ H NMR (DMSO-d ₆ ): δ 9.11 (br t, 1H, J = 5.4 Hz), 8.00 (s, 1H),

7.98 (s, 1H), 7.95 (d, 1H, J = 2.1 Hz), 7.52-7.67 (m, 5H), 7.35 (dd, 1H,

J = 2.1, 8.7 Hz), 6.94 (s, 1H), 3.60 (q, 2H, J = 7.2 Hz), 2.83 (t, 2H,

J = 7.2 Hz).

Analysis calculated for C20H1 7CIN4O3S:

C, 56.00; 4., 4.00; Ν, 13.05

Found: C, 55.74; Η, 4.04; 13, 13.35.

Example 38

Preparation of N- (3-methoxybenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

Dimeric acid chloride solution (see Example 27, Step B) (1.77 mg, 2.5 mmol) in dry tetrahydrofuran (25 mL) was added dropwise to a solution of 3-methoxybenzylamine (1.3 mL, 10 mmol) in •

dry tetrahydrofuran (20 mL) pre-cooled in an ice-acetone bath. The reaction mixture was stirred for 12 to 20 hours. The mixture was diluted with 10% methanol ethyl acetate. The organic layer was washed with dilute hydrochloric acid solution, dried (over sodium sulfate), filtered and the solvents evaporated. The residue was treated with ethyl acetate to remove a coarse white precipitate from the product which was isolated by filtration. Recrystallization from methanol / ethyl acetate afforded the product of analytical purity, m.p. 203-204 ° C.

1 H NMR (DMSO-d ₆ ): δ 9.47 (br t, 1H, J = 6 Hz), 8.03 (s, 1H), 8.01 (s, 1H), 7.94 (d, 1H, J = 2.1 Hz), 7.63 (t, 1H, J = 6.9 Hz), 7.52-7.58 (m, 3H), 7.35 (dd, 1H, J = 2.1, 8.7 Hz), 7.29 (t, 1H, J = 7.8 Hz), 7.06 (s. 1H), 7.05 (d, 1H, J = 6.6 Hz), 6.86 (dd, 1 H, J = 2.7, 7.5 Hz), 4.57 (q, 2H, J = 6 Hz), 3.76 (s, 3H).

Analysis calculated for C23H19CIN2O4S:

C, 60.72; Η, 4 <21; N, 6.16

Found: C, 60.60; Η, 4.17; N, 6.12.

Example 39

Preparation of N- (3-hydroxybenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

To a saturated solution of N- (3-methoxybenzyl) -3-phenylsulfonyl5-chloroindole-2-carboxamide (1.37 g, 3.0 mmol) in dry methylene chloride (140 mL), boron tribromide in hexane (1 M, was added). 10 mL, 10 mmol). After stirring for 12 to 20 hours, the reaction mixture was neutralized by the addition of aqueous sodium bicarbonate solution. After two hours, the solution was made slightly acidic by the addition of dilute hydrochloric acid. The precipitated product was removed by filtration and the aqueous filtrate was extracted with ethyl acetate. The organic layer is

108 methanol (10 mL) containing palladium oxide (70 mg) was hydrogenated with hydrogen at atmospheric pressure for 3 hours. After degassing the solution, it is filtered off to remove the catalyst and the solvents are evaporated. The residue was treated with diethyl ether until the product was obtained. Crystallization from acetonitrile yields an analytically pure product, m.p. Mp 247-249 ° C.

1H NMR (DMSO-θθ): δ 9.38 (t, 1H, J = 6 Hz), 7.98 (s, 1H), 7.96 (d,

1H, J = 2.1 Hz), 7.53-7.63 (m, 4H), 7.35 (dd, 1H, J = 2.1, 9 Hz), 7.02 (t,

1H, J = 7.5 Hz), 6.61 (s, 1H), 6.60 (d, 1H, J = 6 Hz), 6.50 (dd, 1H, J = 2.1, 8.1 Hz), 4.43 (d, 2H, J = 6 Hz).

Analysis: Calculated for C22H1 with ClM3O3 8 0.25 H2O:

C, 59.45; H, 4.20; N, 9.46

Found: C, 59.43; H, 4.08; N, 9.54.

Example 42

Preparation of N- (2-methoxybenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

Using the method described in Example 38, but using 2-methoxybenzylamine instead of 3-methoxybenzylamine, the title compound was obtained, m.p. Mp 235-237 ° C.

¹ H NMR (DMSO-dg): δ 9.39 (t, 1H, J = 6 Hz), 7.99 (d, 1H , J = 2.1 Hz), 7.95 (s, 1H), 7.93 (s, 1H), 7.63 (t, 1H, J = 7.2 Hz), 7.50-7.57 (m, 3H), 7.29-7.44 (m, 3H), 7.06 (d, 1H, J = 7.5 Hz), 6.97 (dt, 1H, J = 0.9 , 7.2 Hz), 4.55 (d, 1H, J = 5.7 Hz), 3.85 (s, 3H).

Analysis calculated for C23H1 9CIN2O4S 0.2 H 2 O:

C, 60.24; H, 4.26; N, 6.11

Found: C, 60.19; H, 4.40; N, 6.11.

Example 43

Preparation of N- (2-hydroxybenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide ··

107 dried (over sodium sulfate), filtered and the solvent evaporated. The residue was triturated with diethyl ether to give an additional amount of product. The combined amounts of the resulting solid were recrystallized from methanol / ethyl acetate to give the product of analytical purity, m.p. 273.5

274.5 ° C.

1H NMR (DMSO-dg): δ 9.43 (t, 1H, J = 6 Hz), 8.01 (s, 1H), 7.98 (s,

1H), 7.97 (d, 1H, J = 2.1 Hz), 7.63 (t, 1H, J = 6 Hz), 7.52-7.58 (m, 3H), 7.35 (dd, 1H, J = 2.1, 9 Hz). 7.17 (t, 1H, J = 7.8 Hz), 6.89 (s, 1H), 6.86 (s, 1H), 6.84 (s, 1H), 6.70 (dd, 1H, J = 2.1, 8.4 Hz), 4.50 (d , 2H, J = 6

Hz).

Analysis calculated for C22 * ~ h 7CIN2O4S:

C, 59.93; Η, 3.89; N, 6.36

Found: C, 59.91; Η, 3.86; N, 6.51.

Example 40

Preparation of N- (3-nitrobenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide *

Work was done according to the method described in Example 34, but 3nitrobenzylamine hydrochloride was used instead of 2-aminomethylimidazole dihydrochloride and a corresponding appropriate amount of triethylamine to give the title compound, m.p. 253-254 ° C.

Analysis calculated for C22H1 6CIN3O5S:

C, 56.23; H, 3.43; N, 8.94

Found: C, 55.98; H, 3.37; N, 8.85.

Example 41

Preparation of N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 30).

A solution of N- (3-nitrobenzyl) -3-phenylsulfonyl-5-chloroindole2-carboxamide (353 mg, 0.75 mmol) in tetrahydrofuran (25 mL) and ···· · ··········· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 1 -ώ used there to obtain the title compound, m.p. Mp 249-250 ° C.

¹ H NMR (DMSO-dg): δ 9.35 (t, 1H, J = 6 Hz), 7.95-7.99 (m, 3H ), 7.62 (t, 1H, J = 6.9 Hz), 7.52-7.57 (m, 3H ), 7.35 (dd, 1H, J = 1.8, 8.7 Hz), 7.25 (d, 2H, J = 8.7 Hz), 6.76 (d, 2H, J = 8.1 Hz), 4.46 (d, 2H, J = 6 Hz) ).

Analysis calculated for C22H1 7CIN2O4S:

C, 59.93; Η, 3.89; 6.3, 6.36

Found: C, 59.37; Η, 3.85; 6.2, 6.25.

Example 46

Preparation of N- (3-acetylaminobenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

A solution of N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole2-carboxamide (Example 41) (176 mg, 0.4 mmol) in dry tetrahydrofuran (7 mL) containing acetic anhydride (0.05 mL, 0.5 mmol) was stirred. at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (sodium sulfate), filtered through charcoal and the solvents evaporated. The residue was treated with methylene chloride and the product was isolated by filtration. M.P. Mp 249-250 ° C.

¹ H NMR (DMSO-dg): δ 9.98 (br s, 1 Η), 9.39 (v br s , 1 Η), 7.96-8.00 (m, H), 7.51-7.62 (m, 6H) , 7.30 (t , 2H, J = 8 Hz), 7.14 (d, 1H, J = 8 Hz), 4.53 (br s, 2H), 2.04 (s, 3H).

Analysis; calculated for C24H20CIN3O4S:

C, 59.81; Η, 4.18; Ν, 8.72

Found: C, 59.41; Η, 4.09; Ν, 8.62.

Example 47

Preparation of 1- {1- (3-methylsulfonylaminobenzyl) -3phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 34)

109 The method described in Example 39 was used but 2 methoxy isomers (Example 42) were used instead of the 3 methoxy isomer to give the title compound, m.p. 243

244.5 ° C.

¹ H NMR (DMSO-d ₆ ): δ 7.99 (d, 1 H, J = 3 Hz), 7.98 (s, 1H), 7.97 (s, 1H), 7.63 (t, 1H, J = 6 Hz). 7.51-7.57 (m, 3H), 7.33-7.38 (m, 2H), 7.14 (dt, 1H, J = 1.2, 7.8 Hz), 6.89 (d, 1H, J = 7.2 Hz), 6.81 (t, 1 H) , J = 7.2 Hz), 4.52 (s, 2H).

Analysis calculated for C 22 H 17 FIN 2 O 4 S 0.2 H 2 O:

C, 59.44; H, 3.95; N, 6.30

Found: C, 59.38; H, 3.70; N, 6.39.

Example 44

Preparation of N- (4-methoxybenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

It was done analogously to the method described in Example 38, but 4-methoxybenzylamine was used instead of 3-methoxybenzylamine to give the title compound, m.p. 205206 ° C.

¹ H NMR (DMSO-d ₆ ): δ 9.42 (br t, 1H, J = 6 Hz), 8.01 (s, 1H), 7.98 (s, 1H), 7.95 (d, 1H, J = 1.8 Hz). 7.64 (t, 1H, J = 7.2 Hz), 7.52-7.58 (m, 3H), 7.33-7.40 (m, 3H), 6.95 (d, 2H, J = 9 Hz), 4.51 (d, 2H, J = 6 Hz), 3.76 (s, 3H).

Analysis calculated for C23H19CIN2O4S:

C, 60.72; 4.2, 4.21; N, 6.16

Found; C, 60.59; 4.1, 4.14; N, 6.11.

Example 45

Preparation of N- (4-hydroxybenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

The method described in Example 39 was used, but the 4methoxy isomer (Example 44) was used instead of the methoxy isomer. · · · · · · · · ·

111 To a solution of N- (3-aminobenzyl) -3-phenylsulfonyl-5 chloroindole-2-carboxamide (174 mg, 0.4 mmol) in dry tetrahydrofuran (7 mL) was added at room temperature and methanesulfonyl chloride (0.035 mL) under inert atmosphere. , 0.45 mmol) and triethylamine (0.7 mL, 0.50 mmol). The reaction was monitored for 20 hours by thin layer chromatography. During this period, additionally equivalent amounts of methanesulfonyl chloride and triethylamine were added twice until the reaction with the carboxamide was complete. The reaction mixture was diluted with water, acidified with dilute hydrochloric acid and the product extracted with chloroform. The organic layer was dried (sodium sulfate), filtered and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 1% methanol / chloroform. A bisulfonylated product was obtained, which is evident from the resonances at two methyl groups in the NMR spectrum at δ 3.47 and 2.98.

This product was dissolved in dimethoxyether (3 mL) and water (2 mL) and lithium hydroxide monohydrate (66 mg, 1.57 mmol) was added. The solution was heated at 60 ° C for two hours. After cooling, the mixture was acidified with dilute hydrochloric acid. The solution was stirred for 2-3 hours, during which time the product crystallized, separated by filtration and dried. Recrystallization from methanol / ethyl acetate afforded an analytically pure product, m.p. Mp 252-253 ° C.

¹ H NMR (DMSO-θθ): δ 9.48 (br t, 1 H, J = 5.4 Hz), 8.01 (s, 1H), 7.98 (s, 1H), 7.95 (d, 1H, J = 1.8 Hz). 7.63 (t, 1H, J = 7.2 Hz), 7.52-7.58 (m, 3H), 7.33-7.38 (m, 2H), 7.27 (br s, 1H), 7.23 (br d, 1H, J = 7.8 Hz) , 7.15 (d, 1H, J = 7.8 Hz), 4.55 (d, 2H, J = 5.4 Hz), 3.00 (s, 3H).

Analysis calculated for C23H20CIN3O5S2:

C, 53.33; Η, 3.89; N, 8.11

- 112 Found: C, 53.26; H, 3.86; N, 8.12.

Example 48

Preparation of N-benzyl-3-phenylsulfonyl-5 -: loroindole-2carboxamide

A solution of dimeric acid chloride (Example 27, Step B) (170 mg, 0.25 mmol) in dry tetrahydrofuran (2 mL) was added dropwise to a solution of benzylamine (0.28 mL, 2.5 mmol) in dry tetrahydrofuran (3 mL), cooled in an ice-acetone bath.

The reaction mixture was allowed to stir for up to 20 hours, raising the temperature to room temperature.

The solvents were removed in vacuo and the residue treated with ethyl acetate and water, separating two layers.

The ethyl acetate layer was washed with sodium chloride solution, dried (over sodium sulfate) and the solvent was evaporated. The residue was crystallized from a mixture of ethyl acetate and methanol to give an analytically pure product, m.p. 249-251 ° C ¹ H NMR (DMSO-d ₆ ): δ 9.47 (t, 1 H, J = 6 Hz), 8.02 (s, 1 H), 8.00 (s, 1 H), 7.95 (d, 1 H, J = 2.1 Hz), 7.33-7.57 (m. 1 OH), 4.59 (d, 2H, J = 6 Hz).

Analysis calculated for C ₂₂ H 1 7 CIN 2 O 3 S:

C, 62.19; 4, 4.03; 6.5, 6.59

Found: C, 62.14; 4, 4.13; 6.6, 6.62.

Example 49

Preparation of N- (3-pyridylmethyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 28)

Work was done according to the method described in Example 48 using 3aminomethylpyridine instead of benzylamine. The title compound was obtained, m.p. 263-264 ° C.

Analysis calculated for C22H1IN3O3S:

C, 59.22; H, 3.79; Ν, 9.87

Found: C, 59.01; H, 3.79; Ν, 9.87.

· · · · · · · ·

114 The procedure described in Example 48 was performed using ethylamine instead of benzylamine. The title compound was obtained, m.p. Mp 259-260 ° C.

Analysis: calculated for C- | 7H1 5CIN2O3S:

C, 56.28; H, 4.17; N, 7.72

Found: C, 56.07; H, 4.11; N, 7.73.

Example 54

Preparation of N - [(2-chloropyridin-4-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

Work was done according to the procedure described in Example 35, Step B, using 2-chloro-4-aminomethylpyridine instead of 2-aminomethyl-1 methylimidazole. The title compound was obtained, m.p. 263-265 ° C.

Analysis calculated for C 21 H- 5CI 2 N 3 O 3 S:

C, 54.79; H, 3.28; N, 9.13

Found: C, 54.38; H, 3.18; N, 9.03.

Example 55

Preparation of GM-cyclopropyl-6-chloro-3-phenylsulfonylindole2-carboxamide (Compound 26)

The procedure described in Example 48 was performed using cyclopropylamine instead of benzylamine. The title compound was obtained, m.p. Mp 242-243 ° C.

Analysis: calculated for C- | θΗ- | 5CIN2O3S:

C, 57.68; H, 4.03; 7.4, 7.47

Found: C, 57.40; H, 3.94; 7.4, 7.43.

Example 56

Preparation of N- (cyclopropylmethyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide ······

- 113 Example 50

Preparation of N- (2-pyridylmethyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

The procedure was described in Example 48 using 2aminomethylpyridine instead of benzylamine. The title compound was obtained, m.p. 250-251 ° C.

Analysis calculated for C21 H-J (5CIN3O3S:

C, 59.22; H, 3.79; N, 9.87

Found: C, 59.04; H, 3.73; N, 10.06.

Example 51

Preparation of N- [2- (pyridin-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

The method described in Example 48 was applied using 4- (2-aminoethyl) pyridine instead of benzylamine. The title compound was obtained, m.p. 258-260 ° C.

Analysis calculated for C22H13CIN3O3S:

C, 60.07; H, 4.12; N, 9.55

Found: C, 59.68; H, 3.84; N, 9.30.

Example 52

Preparation of N- (2-hydroxyethyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide

The method described in Example 48 was applied using 2hydroxyethylamine instead of benzylamine. The title compound was obtained, m.p. 198-200 ° C.

Analysis calculated for Cj 7H-1 5CIN2O4S:

C, 53.90; H, 3.99; N, 7.39

Found: C, 54.09; H, 3.94; N, 7.25.

Example 53

Preparation of (M-ethyl-3-phenylsulfonyl-5-chloroindole-2carboxamide · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-116 Work according to the method described in Examples 30 and 31 using bis (3,5-dichlorophenyl) disulfide instead of di (2-thiazolyl) -

disulfide. A meal is obtained the title mentioned in the title, m.p. 258-260 ° C. Analysis: calculated for C- | 5H9Cl3N ₂ O3S: C, 44.63; H, 2 .25; N, 6.94

Found: C, 44.49; H, 2.24; N, 7.04.

Example 60

Preparation of 3- (2-chlorophenylsulfonyl) -5-chloroindole-2carboxamide

The procedure described in Example 33 was performed using 2-chlorothiophenol instead of thiophenol. The title compound was obtained, m.p. 267 ° C.

Analysis calculated for C-5H10CI2N2O3S:

C, 48.79; H, 2.73; N, 7.59

Found: C, 48.69; H, 2.73; N, 7.62.

Example 61

Preparation of 3- (pyridin-2-ylsulfonyl) -5-chloroindole-2carboxamide

The procedure described in Examples 30 and 31 was performed using bis (pyridin-2-yl) disulfide instead of di (2-thiazolyl) disulfide. The title compound was obtained, m.p. Mp 244-246 ° C.

Analysis calculated for C4 4H4 qCIN3O3S:

C, 50.08; H, 3.00; N, 12.51

Found: C, 50.31; H, 3.00; N, 12.55.

Example 62

Preparation of 3- (pyridin-3-ylsulfonyl) -5-chloroindole-2carboxamide

115 The procedure described in Example 48 was performed using cyclopropylmethylamine instead of benzylamine. The title compound was obtained, m.p. Mp 232-234 ° C.

Analysis: calculated for C- | gH- | 7CIN2O3S:

C, 57.88; H, 4.50; N, 7.11

Found: C, 57.92; H, 4.34; N, 7.09.

Example 57

Preparation of 3- (4-chlorophenylsulfonyl-5-chloroindole-2carboxamide

The procedure described in Examples 30 and 31 was performed using bis (4-chlorophenyl) disulfide instead of di (2-thiazolyl) disulfide. The title compound was obtained, m.p. 275-277 ° C.

Analysis: Calculated for CC 5H1QCI2N2O3S:

C, 48.32; H, 2.81; N, 7.51

Found: C, 48.23; H, 2.84; N, 7.91.

Example 58

Preparation of 3- (3-chlorophenylsulfonyl) -5-chloroindole-2carboxamide

The procedure described in Examples 30 and 31 was performed using bis (3-chlorophenyl) disulfide instead of di (2-thiazolyl) disulfide. The title compound was obtained, m.p. Mp 272-273 ° C.

Analysis calculated for C-J5H10CI2N2O3S:

C, 48.79; H, 2.73; N, 7.59

Found: C, 48.39; H, 2.70; N, 7.44.

Example 59

Preparation of 3- (3,5-dichlorophenylsulfonyl-5-chloroindole-2carboxamide)

- 118 acid. The title compound was obtained, m.p. 225-226.5 ° C.

Analysis: and | Calculated for C2H- | 3CI2N2O4S:

C, 56.45; H, 3.71; N, 5.73

Found: C, 56.52; H, 3.70; N, 5.83.

Example 66

Preparation of N- (3-hydroxybenzyl) -3- (3-chlorophenylsulfonyl) -5-chloroindole-2-carboxamide

The method described in Example 39 was followed, but N- (3 (methoxybenzyl) -3- (3-chlorophenylsulfonyl) -5-chloroindole-2carboxamide was used, which was demethylated to give the title compound, m.p. Mp 230-231 ° C.

Analysis calculated for C22H16Cl2N2O4S:

C, 55.58; H, 3.39; N, 5.89

Found: C, 55.59; H, 3.36; N, 5.66.

Example 67 '

Preparation of N - [(1-methylimidazol-2-yl) methyl] -3- (3-chlorophenylsulfonyl) -5-chloroindole-2-carboxamide (Compound 23)

The method described in Example 35 was applied but dimeric acid chloride derived from 3- (3-chlorophenylsulfonyl) 5-chloroindole-2-carboxylic acid was used instead of the 3 (phenylsulfonyl) -5-chloroindole-2-carboxylic acid derivative to obtain the title compound, m.p. 232-234 ° C.

Analysis calculated for C20H1bC3O3S3:

C, 51.84; H, 3.48; N, 12.09

Found: C, 51.46; H, 3.38; N, 11.78.

Example 68

Preparation of 2-carboxamido-5-chloroindole-3-cyclopropylsulfonamide · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

117 The procedure described in Examples 30 and 31 was performed using bis (pyridin-3-yl) disulfide instead of di (2-thiazolyl) disulfide / IL. The title compound was obtained, m.p.

300 ° C (dec.).

Mass spectrum (FAB): m / e = 336 (M + 1).

Example 63

Preparation of 3- (pyridin-4-ylsulfonyl) -5-chloroindole-2carboxamide

The procedure described in Examples 30 and 31 was performed using bis (pyridin-4-yl) disulfide instead of di (2-thiazolyl) disulfide. The title compound was obtained, m.p.

> 260 ° C (decomposition).

Mass spectrum (FAB): m / e = 336 (M + 1).

Example 64

Preparation of 3 - [(1-methylimidazol-2-yl) sulfonyl] -5chloroindole-2-carboxamide

The method described in Examples 30 and 31 as <? bis (1-methylimidazol-2-yl) disulfide is used instead of di (2-thiazolyl) disulfide. The title compound was obtained, m.p. Mp 255-256 ° C (dec.).

Analysis calculated for C-3H-J - CIN4O3S:

C, 46.09; H, 3.27; N, 16.54

Found: C, 46.02; H, 3.28; N, 16.27.

Example 65

Preparation of N- (3-methoxybenzyl) -3- (3-chlorophenylsulfonyl) 5-chloroindole-2-carboxamide

The method described in Example 38 was applied, but the dimeric acid chloride obtained from 3- (3-chlorophenylsulfonyl) -5-chloroindole-2-carboxylic acid was used instead of the one obtained from 3- (phenylsulfonyl) -5-chloroindole- 2-carboxyl • · · · ···· ·· ···· • I · ····

- 120 sulfonyl chloride as a red solid.

It was dissolved in dichloromethane (15 mL) and cyclopropylamine (0.94 mL, 13.56 mmol) and pyridine (0.5 mL) were added. The solution was heated to reflux and after 15 minutes cooled, diluted with ethyl acetate and washed with a 1 M hydrochloric acid solution, sodium bicarbonate solution and sodium chloride solution, dried (over sodium sulfate) and evaporated in vacuum to give a gummy residue. Methanol (5 mL) was added to give a colorless solid and the mixture was stirred and refluxed for 5 minutes. After cooling, the solid was separated by filtration, washed with cooled methanol (3x5 mL) and dried in vacuo to give the title compound as colorless crystals, m.p. 189-191 ° C.

¹ H NMR (DMSO-d ₆ ): δ 0.61 (m, 4H), 1.48 (t, 3H, J = 7.1 Hz), 2.26 (m, 1H), 4.58 (q, 7.1 Hz, 2H), 5.06 (br s, 1H), 7.42 (dd, J = 9.0 and 2.0 Hz, 1H), 7.54 (t, 2H, J = 7.6 Hz), 7.66 (t, J = 7.5 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 7.6 Hz, 2H).

Step C: 2-Carboxamido-5-chloroindole-3-cyclopropylsulfonamide

A mixture of 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3cyclopropylsulfonamide (0.42 g, 0.870 mmol) and a mixture of 2: 1: 1 in a 10% solution of potassium hydroxide, methanol and tetrahydrofuran (20 mL total) was heated at reflux until a clear reddish-brown solution is obtained. After boiling the solution for another half hour, it was cooled and concentrated in vacuo to half volume. The solution was acidified with 1 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate, washed with sodium chloride solution, dried (over sodium sulfate) and evaporated in vacuo to give a gummy substance.

·· ····

- 119Stage A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3sulfonic acid

Concentrated sulfuric acid (2.50 mL, 90 mmol) was added dropwise with stirring at 0 ° C for 5 minutes to a solution of 2-carboethoxy-5-chloro-1 phenylsulfonyl-indole (7.28 g, 20.0 mmol) in acetic acid. anhydride (10 mL) and dry dichloromethane (50 mL). The resulting reddish-brown solution was warmed to room temperature and poured into ice after 3 hours and the mixture extracted with ethyl acetate. The ethyl acetate layer was washed with sodium chloride solution, dried over sodium sulfate and evaporated in vacuo to give a syrupy residue. The residual acetic anhydride was removed by azeotropic distillation with toluene (3 x 50 mL) and the residue was crystallized from dichloromethane. The dichloromethane was evaporated in vacuo to give the title compound as a reddish-brown powder.

¹ H NMR (DMSO-d ₆ ): δ 1.33 (t, 3H, J = 7.1 Hz), 4.33 (g, 7.1 Hz, 2H), 7.44 (dd, J = 8.9 and 2.2 Hz, 1H), 7.63 (t , 2H, J = 7.6 Hz), 7.73 (t, J = 7.4 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H).

Step B: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3cyclopropylsulfonamide

Oxalyl chloride (0.90 mL, 10.3 mmol) was added to a solution of 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3 sulfonic acid (1.505 g, 3.39 mmol) in dry dichloromethane (15 mL) with stirring at 0 ° C. Dimethylformamide (2 drops) was added and the solution warmed to room temperature. More dimethylformamide (one drop) was added and the reaction mixture was heated to reflux. After two hours, the solution was cooled and evaporated in vacuo to give the solution. · · · · · · · · · · · · · · · · · · · · · · ·

- 122 Step A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3-phenylsulfonamide

It was proceeded as described in Example 68, Step B, by adding aniline (0.63 mL, 6.91 mmol) to 2-carboethoxy-5-chloro-1 phenylsulfonylindole-3-sulfonyl chloride. Purification by flash column chromatography over silica (dry and eluting with ethyl acetate / hexanes at a gradient of 20% to 30% ethyl acetate) gave the title compound as colorless crystals.

1 H NMR (DMSO-d ₆ ): δ 1.47 (t, J = 7.1 Hz, 3H), 4.58 (q, J = 7.1 Hz, 2H), 6.74 (br s, 1H), 7.11 (m, 5H), 7.31 (dd, J = 9.0 and 2.2 Hz, 1H), 7.51 (t, J = 8.1 Hz, 2H), 7.57 (d, J = 1.7 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 7.6 Hz, 2H).

Step B: 5-Chloro-3-phenylsulfonylaminoindole-2-carboxylic acid

2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3-phenylsulfonamide (0.39 g, 0.75 mmol) was dissolved in a 2: 1: 1 mixture of 10% sodium hydroxide, methanol and tetrahydrofuran (20 mL total) and after 2 The solution was acidified with 1 M hydrochloric acid for 1 hour and the resulting mixture extracted with ethyl acetate, washed with sodium chloride solution, dried (over sodium sulfate) and evaporated in vacuo to give a glassy substance. Dichloromethane (5 mL) was added to give a colorless substance and the reaction mixture was stirred and refluxed for 5 minutes. The resulting solid was removed by filtration after cooling, washed with cooled dichloromethane and dried in vacuo to give the title compound as colorless crystals.

121 The crude product was dissolved in a 2% solution of sodium ⁵ hydroxide, which was then acidified with a 1 M hydrochloric acid solution.

The resulting solid was filtered off, washed with 1M hydrochloric acid solution and dried in vacuo to give 3-cyclopropylsulfonamido-5-chloroindole-2 carboxylic acid. To a suspension of this acid in dry dichloromethane (10 mL) was added with stirring oxalic yl chloride (0.58 mL, 6.65 mmol) and dimethylformamide (1 drop). After staying at room temperature for one hour, the mixture was heated at reflux for one hour, then cooled and evaporated in vacuo to give a tan solid. The product was suspended in acetone (10 mL) and a 9: 1 solution of ammonium hydroxide and acetone (20 mL) was added. After 15 minutes the solution was evaporated in vacuo to a volume of 2 mL, the residue was acidified with 1M hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with sodium bicarbonate solution, dried (sodium sulfate) and%

evaporates in a vacuum. The reddish-brown solid obtained was purified by flash chromatography on silica (dry and eluting with chloroform / methanol at a gradient of 2 to 10% methanol concentration). The title compound was obtained as colorless crystals (ethyl acetate / hexanes), m.p. 236-238 ^P S.

¹ H NMR (DMSO-d ₆ ): δ 0.40 (m, 4H), 2.07 (m, 1 Η), 7.35 (dd, J = 8.7 and 2.1 Hz, 1 Η), 7.56 (d, J = 8.7 Hz. 1H), 8.01 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 8.22 (br s, 1H), 8.47 (br s, 1H).

Example 69

Preparation of 2-carboxamido-5-chloroindole-3-phenylsulfonamide

123 H NMR (DMSO-dg): δ 7.28 (t, J = 7.1 Hz, 1H), 7.4 (d, J = 7.2 Hz, 2H), 7.51 (t, J = 7.1 Hz, 2H), 7.72 (dd , J = 8.8 and 2.1 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 8.43 (d, J = 2.1 Hz, 1H), 10.25 (br s, 1H).

Step C: 2-Carboxamido-5-chloroindole-3-phenylsulfonamide

Oxalyl chloride (0.087 mL, 1.00 mmol) and dimethylformamide (1 drop) were added to a solution of 5-chloro-3-phenylsulfonylamidoindole-2-carboxylic acid (123 mg, 0.35 mmol) in dry tetrahydrofuran (3 mL) with stirring at 0 ° C. After standing for one hour at room temperature, the solution was evaporated in vacuo to give a reddish-brown solid. It was dissolved in acetone (1 mL) and a 9: 1 mixture of ammonium hydroxide and acetone (2 mL) was added. The solution was left for half an hour, then evaporated in vacuo to give a gummy residue, which was dissolved in ethyl acetate, washed with 1 M hydrochloric acid and sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The reddish-brown solid obtained was purified by flash column chromatography on silica (dry and eluting with ethyl acetate / hexanes at a gradient of 20 to 70% ethyl acetate) to give the title compound as crystalline (recrystallization from dichloromethane) m.p. Mp 225-227 ° C.

¹ H NMR (DMSO-d ₆ ): δ 7.00 (m, 3H), 7.17 (t, 2H, J = 7.3 Hz), 7.30 (dd, J = 8.8 and 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 8.21 (br s, 1H), 8.28 (br s, 1H), 10.34 (br s, 1H).

Example 70

Preparation of 2-carboxamido-5-chloroindole-3-methyl- (phenyl) sulfonamide · · · ·

- 124 Step A: 2-Carboethoxy-5-chloro-1-phenylsulfonylindole-3methyl (phenyl) sulfonamide

This was done as described in Example 68, Step B, by adding N-methylaniline to 2-carboethoxy-5-chloro-1-phenylsulfonylindole-3-sulfonyl chloride. Purification by flash column chromatography on silica (dry and eluting with ethyl acetate / hexanes at a gradient of 10 to 30% ethyl acetate concentration) gave the title compound as colorless crystals (dichloromethane / hexane / hexane) ).

¹ H NMR (DMSO-dg): δ 1.46 (t, J = 7.1 Hz, 3H), 3.30 (s, 3H), 4.55 (q, J = 7.1 Hz, 2H), 6.69 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 7.0 Hz, 2H), 7.26 (m, 4H), 7.54 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 7.4 Hz, 1H), 7.87 (d. J = 8.8 Hz, 1H), 8.08 (d, J = 7.6 Hz, 2H).

Step B: 5-Chloro-3-methyl (phenyl) sulfonamidoindole-2 carboxylic acid

In the manner described in Example 69, Step B, 2'carboethoxy-5-chloro-1-phenylsulfonylin dol-3-ethyl (phenyl) sulfonamide (0.39 g, 0.75 mmol) was hydrolyzed into a mixture of 2 : 1: 1 of a 10% solution of sodium hydroxide, methanol and tetrahydrofuran (20 mL total) for 14 hours at room temperature, followed by reflux for 5 minutes. The title compound (recrystallization from ethyl acetate) was obtained.

¹ H NMR (DMSO-dg): δ 3.26 (s, H), 7.03 (d, 1H, J = 2 = 2 Hz), 7.21 (m, 6H ), 7.46 (d, J = 8.8 Hz, 1H) .

Step C: 2-Carboxamido-5-chloroindole-3-methyl (phenyl) sulfonamide

- 126 Example 74

Preparation of N- [3- (imidazol-1-yl) propyl] -3-phenylsulfonyl5-chloroindole-2-carboxamide

Reaction of 3-phenylsulfonyl-5-chloroindole-2 carboxylic acid with 1- (3-aminopropyl) imidazole under the conditions described in Example 37 gave the title compound, m.p. 216-217.5 ° C.

Example 75

Preparation of 3-phenylsulfonyl-5-methylsulfonylamino-indole2-carboxamide (Compound 36)

Step A: 3-Phenylsulfonyl-5-nitroindole-2-carboxamide

By reacting 5-nitroindole-2-carboxylate (J. Amer. Chem. Soc. 80, 4621 (1958) with N- (phenylthio) succinimide under the conditions described in Example 33, Step B, followed by oxidation to a sulfonyl derivative ( Step C) a product is obtained which can be converted to the title compound by reaction with ammonium hydroxide at elevated temperature and pressure.

Step B: 3-Phenylsulfonyl-5-aminoindole-2-carboxamide

Reduction of 3-phenylsulfonyl-5-nitroindole-2carboxamide with hydrogen under the conditions described in Example 41 gave the title compound.

Step C: 3-Phenylsulfonyl-5-methylsulfonylaminoindole-2carboxamide

Reaction of 3-phenylsulfonyl-5-aminoindole-2carboxamide with methanesulfonyl chloride gave the title compound under the conditions described in Example 47.

Example 76

Preparation of 4 - [(5-chloro-3-phenylsulfonylindole-2carboxamido) methyl] pyridin-2 (1H) -one (Compound 37)

125 Work as described in Example 69, Step C using 5-chloro-3-methyl (phenyl) sulfoamidoindole-2-carboxylic acid. Purification by flash column chromatography on silica (dry and eluting with 2% meta, nol / chloroform) gave the title compound as colorless crystals (ethyl acetate), m.p. 240-242 ° C.

¹ H NMR (DMSO-d ₆ ): δ 3.13 (s, 3H), 7.06 (d, J = 2.1 Hz, 1H), 7.09 (m, 2H), 7.23 (dd, J = 8.8 and 2.1 Hz, 1H) , 7.26 (m, 3H), 7.48 (d, J = 8.8 Hz, 1H), 8.01 (br s, 1H), 8.06 (br s, 1H).

Example 71

Preparation of N- [2- (1-methylimidazol-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 25)

Reaction of 3-phenylsulfonyl-5-chloroindole-2 carboxylic acid with 1-methylhistamine under the conditions described in Example 37 gave the title compound.

Example 72

Preparation of N- [2- (3-methylimidazol-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

Reaction of 3-phenylsulfonyl-5-chloroindole-2-carboxylic acid with 3-methylhistamine under the conditions described in Example 37 gave the title compound with

mp 257-258.5 ° C.

Example 73

Preparation of N - [(imidazol-4-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide

By the reaction of dimeric acid chloride (Ex

27, Step B) with 4-aminomethylimidazole under the conditions described in

Example 34 gave the title compound.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 128 Example 78

Preparation of N- (2-aminothiazol-4-ylmethyl) -5-chloro-3-phenylsulfonyl (dol-2-carboxamide

By reacting 2-aminothiazol-4-ylmethylamine (Chem. Ab. 58, 4534 (1962)) with the dimeric acid chloride obtained according to Example 27, Step B, using the method of operation described in Example 27, step C is obtains the title compound.

Example 79

Preparation of N-cyano-5-chloro-3-phenylsulfonylindole-2carboximide-amide (Compound 35)

Step A: 5-Chloro-3-phenylsulfonylindole-2-carbonitrile 5-Chloro-3-phenylsulfonylindole-2-carboxamide was reacted with methyl (carboxysulfamoyl) triethylammonium hydroxide, an internal salt (Burgess reagent) in tetrahydroacetammonac and V.T. Phillips (Tetrahedron Lett., 29, 2155 (1988)) to afford the title compound.

Step B: Ethyl 5-chloro-3-phenylsulfonylindole-2-carboximidate 5-Chloro-3-phenylsulfonylindole-2-carbonitrile was allowed to react with hydrogen chloride-saturated ethanol at 0-10 ° C for 7 days. Evaporation of the reaction mixture to dryness gave the title compound as the hydrochloride salt. Addition of the reaction mixture to an ice-cooled solution of potassium carbonate in excess and extraction of the product with chloroform afforded the title compound as the free base.

Step C: M-Cyano-5-chloro-3-phenylsulfonylindole-2carboximidamide ··············

- 127 Step A: N- (2-Methoxy-4-pyridylmethyl) -5-chloro-3-phenylsulfonylindole-2-carboxamide

By reacting the dimeric acid chloride obtained in Example 27, Step B with 2-methoxy-4-pyridylmethylamine, subject to the reaction conditions described in Example 27, Step C yields the title compound.

Step B: 4 - [(5-Chloro-3-phenylsulfonylindole-2carboxamido) methyl] pyridin-2 (1H) -one

By reacting N- (2-methoxy-4-pyridylmethyl) -5chloro-3-phenylsulfonylindole-2-carboxamide with boron tribromide in methylene chloride medium at 0 ° C, subject to the reaction conditions described in Example 39, obtains the title compound.

Example 77

Preparation of N- (2-amino-4-pyridylmethyl) -5-chloro-3-phenylsulfonylindole-2-carboxamide (Compound 38)

Step A: 2-Amino-4-aminomethylpyridine

2-Aminopyridine-4-carbonitrile (L.W. Deady et dl., Aust. J. Chem., 35, 2025 (1982)) is subjected to catalytic reduction by the method described by D.E. Beattie et al. to obtain 2-amino -aminomethyl pyridine (J. Med. Chem., 20, 718, (1977)) to give the title compound.

Step B: N- (2-amino-4-pyridylmethyl) -5-chloro-3-phenylsulfonylindole-2-carboxamide

By reacting 2-amino-4-aminomethylpyridine with the dimeric acid chloride prepared according to Example 27, Step B, using the method of operation described in Example 27, Step C, the title compound was obtained.

• · · · · · · ·

I · · · · · · ·

- 130 N - [(1-methyl imidazol-5-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2carboxamide (Compound 22)

Step A: N - [(imidazol-4 (or 5) -yl) methyl] -3-phenylsulfonyl-5i chloroindole-2-carboxamide

The method described in Example 34 was used but used

4- (or 5-) aminomethylimidazole instead of 2-aminomethylimidazole dihydrochloride to give the title compound.

Step B: N - [(1-methylimidazol-4-yl) methyl] -3-phenylsulfonylindole-5-chloroindole-2-carboxamide; N - [(1-methylimidazol-5-yl) methyl] -3-phenylsulfonyl-5-chloro and ndol-2-carboxamide

The procedure described in Example 36 was performed but N [(imidazol-4 (or 5) -yl) methyl] -3-phenylsulfonyl-5-chloroindole-2carboxamide was used instead of 1M - [(imidazol-2-yl) methyl] -3-phenylsulfonyl-

5-chloroindole-2-carboxamide to give the title compound in pure form after purification by chromatography on silica gel column chromatography.

Example 84

Preparation of N - [(R) -1-phenylethyl] -5-chloro-3-phenylsulfonylindole-2-carboxamide (Compound 33)

Work was done according to the method described in Example 29, but (P) - (+) -α-methylbenzylamine was used instead of (2) - (+) -2-phenylglycinol to give the title compound, m.p. t. 149 ° C.

Analysis: Calculated for C23H1gClCl3OgC3O.1I 5C2H4C> 2 * 0.1 5H2O: C, 62.32; H, 4.54; N, 6.16

Found: C, 62.39; H, 4.54; N, 6.01.

¹ H NMR (DMSO-dg): δ 3.06 (s, 1 Η), 9.43 (1Η, d , J = 8 Hz), 7.948.02 (m, 3H ), 7.46-7.67 (m, 6H), 7.25- 7.42 (m, 4H), 5.21 (q, 1H, J = 7 Hz), 1.53 (d, 3H, J = 7 Hz).

I ·· ····

129 Ethyl 5-chloro-3-phenylsulfonyl indole-2-carboximidate is reacted with an equimolar amount of cyanamide in absolute methanol (according to the method described by K.R. Huffman and F.C.

Schaefer (J. Org. Chem., 28, 1812 (1963)). After 30-60 minutes, the solvent was removed and the residue was purified by silica gel chromatography to give the title compound.

Example 80

Preparation of N-Cyclobutyl-5-chloro-3-phenylsulfonylindole-2carboxamide (Compound 27)

Work was done according to the method described in Example 48, but cyclobutylamine was used instead of benzylamine to give the title compound.

Example 81

Preparation of N-cyclopropyl-5-chloro-3-phenylsulfinylindole2-carboxamide (Compound 39)

Work was done according to the method described in Example 28, Step B, 10 -cyclopropylamine was used instead of 4-aminomethylpyridine to give the title compound.

Example 82

Preparation of N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfinyl-5-chloroindole-2-carboxamide (Compound 20)

Work was done according to the method described in Example 28, Step B, but 2-aminomethyl-1-methylimidazole was used instead of 4-amino methylpyridine to give the title compound.

Example 83

Preparation of N - [(1-methylimidazol-4-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide (Compound 21) and ··············

132 -

Claims (6)

1. A compound selected from the group consisting of: N - [(1-methyl imidazol-2-yl) methyl] -3-phenyl sulfonyl-5-chloroindole-2-carboxamide, N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfinyl-5-chloroindole-2-carboxamide, N - [(1-methylimidazol-4-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide, N - [(1-methylimidazol-5-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide, N - [(1-methyl-imidazol-2-yl) methyl] -3- (3-chlorophenyl-sulfonyl) -5-chloroindole-2-carboxamide, - V N- [2- (imidazol-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2carboxamide, N- [2- (1-methylimidazol-4-yl) ethyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-Cycle opro p yl-5-chloro-3-phenyl sulfonyl and ndol-2-carboxamide, The N-cycle is l-5-chloro-3-phenylsulfonyl indole-2-carboxamide, N- (3-pyridyl methyl) -3-phenyl sulfonyl-5-chloroin dol-2carboxamide, N- (4-pyridyl methyl) -5-chloro-3-phenylsulfinyl and ndol-2carboxamide, N- (3-aminobenzyl) -3-phenylsulfonyl-5-chloroindole-2carboxamide, N- (3-methoxybenzyl) -5-chloro-3- (2-thiazolyl) sulfonylindole-2carboxamide, ··········· - 134 - A compound of general formula A wherein X is -H, -Cl, -F, -Br, -NO ₂ , -CN. -OR2, -NR2r2, -NHSO ₂ C1-3-alkyl or -NHCO-C- | C 1-3 alkyl; Y is -S (O) _n - or -Ο-, where η is the number 0, 1 or 2; R is: 1) -C 1-5 alkyl, unsubstituted or substituted by one or more groups a) - C 1-5 alkyl, b) -C- | -5-alkoxy-, " c) -OH or d) aryl, unsubstituted or substituted by one or more groups i) -C 1 -C 5 -alkyl, I) -C 1-5 -alkoxy, iii) -OH, iv) halogen or v) -NR2r2, 2. The compound N - [(1-methylimidazol-2-yl) methyl] -3-phenylsulfonyl-1-5-chloroindole-2-carboxamide or a pharmaceutically acceptable salt thereof. ' 2) aryl, unsubstituted or substituted by one or more of the groups: a) -C 1-5 -alkyl, unsubstituted or substituted by one or more of the groups: i) -OH or ·· ···· ♦ · ·· ·· ···· • • • •••••• a • · · · · · · · · · · · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 131 Example 85 Preparation of N - [(1-ethylimidazol-2-yl) methyl] -3-phenylsulfonyl-5-chloroindole-2-carboxamide Work was done according to the method described in Example 35, but 2aminomethyl-1-ethylimidazole was used instead of 2-aminomethyl-1-methylimidazole (Step A) to give the title compound, m.p. 204-205.5 ° C. The description given above describes the embodiments of the present invention and exemplary embodiments that are intended to illustrate the invention, therefore, it should be clear that in the application of the present invention all the usual variants, adaptations and modifications are included which fall within the scope of the invention as defined by the following claims and their equivalent solutions. A method of inhibiting HIV reverse transcriptase, wherein an effective amount of a compound is administered to the mammal according to claim 3-phenyl sulfonyl-5-methyl sulfonylaminoindole-2-carboxamide, 4. A method of preventing or treating HIV infection or treating HIV infection An AIDS or AIDS-linked complex (ARC) characterized in that an effective amount of a compound according to claim 1 is applied to the mammal. 4- [(5-chloro-3-phenylsulfonylindole-2-carboxamido) -methyl] pyridin-2 (1H) -one N- (2-amino-4-pyridyl methyl) -5-chloro-3-phenylsulfonyl indole-2 carboxamide and N-cyclopropyl-5-chloro-3-phenylsulfinylindole-2-carboxamide or a pharmaceutically acceptable salt or ester thereof. ⁴ ·· · · · · · · - 133 ···· ·· ·· • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · N - [(S) -1-phenyl-1-hydroxyethyl-6-chloro-3-phenyl-sulfonylindole-carboxamide, N - [(R) -1-Phenylethyl] -5-chloro-3-phenylsulfonylindole-2carboxamide, N- (3-methylsulfonylaminobenzyl) -3-phenylsulfonyl-5-chloroindole-2-carboxamide, N-cyano-5-chloro-3-phenylsulfonylindole-2-carboximidamide, and e A pharmaceutical composition useful for inhibiting HIV reverse transcriptase, characterized in that it contains an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · - 132 A-432/95-PC Redesigned pages in response to the MPE Report: Patent Claims A pharmaceutical composition useful for preventing or treating HIV infection or for treating an AIDS or AIDS-related complex comprising an effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier.