SK12742000A3 - Inhibitors of phospholipase enzymes - Google Patents

Abstract

Novel compounds are disclosed which inhibit the activity of phospholipase enzymes, particularly cytosolic phospholipase A2. Pharmaceutical compositions comprising such compounds and methods of treatment using such compositions are also disclosed.

Description

Inhibitors of phospholipase enzymes, pharmaceutical composition containing them and their use

Technical field

The present invention relates to chemical inhibitors of various phospholipase enzymes, in particular phospholipase A ₂ enzymes.

BACKGROUND OF THE INVENTION

Leukotrienes and prostaglandins are important inflammatory mediators, each of these classes of compounds contributing to the development of an inflammatory response in a different way. Leukotrienes collect inflammatory cells, such as neutrophils, into an inflamed site, promote extravasation of these cells and stimulate the release of superoxides and proteases that damage the tissue. Leukotrienes also play a pathophysiological role in asthmatic hypersensitivity [See, for example, B. Samuelson et al., Science, 237: 1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow, i.e. by infiltrating leukocytes into inflamed sites. Prostaglandins also potentiate the pain reactions induced by irritation.

Prostaglandins and leukotrienes are unstable and are not stored in cells, but are synthesized instead [W. L. Smith, Biochem. J. 145: 315-324 (1989)] from arachidonic acid in response to irritation. Prostaglandins are produced from arachidonic acid by COX-1 and COX-2 enzymes. Arachidonic acid is also a substrate for an apparent enzyme mechanism leading to the formation of leukotrienes.

Arachidonic acid that enters these two different inflammatory mechanisms is released from the sn-2 position of membrane phospholipids by phospholipase A ₂ enzymes (hereafter referred to as PLA ₂ ). It is believed that the reaction catalyzed by PLA ₂ is a rate limiting step in the process of lipid mediated biosynthesis and in the formation of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate PLA _{2 is the} phosphotidylcholine class of ether-bonded substances in the sn-1 position, produced by

-2lysophospholipid is a direct precursor of platelet activating factor (hereinafter referred to as PAF), another potent mediator of inflammation [S.I. Wasserman, Hospital Practice, 15: 49-58 (1988)].

Most anti-inflammatory therapies have focused on preventing the formation of either prostaglandins or leukotrienes from these different mechanisms, but not preventing both. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs that inhibit the production of prostaglandins by COX-1 / COX2, but have no effect on the inflammatory formation of leukotrienes from arachidonic acid in other mechanisms. In contrast, zileuton only inhibits the mechanism of conversion of arachidonic acid to leukotrienes, without affecting the formation of prostaglandins. None of these widely used anti-inflammatory agents affect the production of PAF.

Accordingly, direct inhibition of PLA ₂ activity has been suggested as a useful mechanism for the therapeutic agent, ie, to interfere with the inflammatory response. [See, for example, J. Chang et al., Biochem. Pharmacol., 36: 2429-2436 (1987)].

A group of PLA ₂ enzymes characterized by the presence of a secretory signal sequence and finally secreted by the cell was sequenced and structurally defined. These secreted PLA ₂ have a molecular weight of approximately 14 kD and contain the seven disulfide bonds that are required for their activity. These PLA ₂ are found in large quantities in mammalian pancreas, bee venom and various snake venoms. [See, for example, refs. 13-15 in Chang et al, cited above; and EA Dennis, Drug Devel. Res., 10: 205-220 (1987).] However, it is believed that the pancreatic enzyme serves for digestive function and as such should not be important in the formation of inflammatory mediators, the formation of which must be strongly regulated.

The primary structure of the first human non-pancreatic PLA ₂ was determined. This non-pancreatic PLA ₂ is found in platelets, synovial fluid and spleen and is also a secreted enzyme. This enzyme is a member of the above group. [See JJ Seilhamer et al., J. Biol. Chem., 264: 5335-5338 (1989); RM Kramer et al., J. Biol. Chem., 264: 5768-5757 (1989); and A. Kando et al., Biochem. Biophys. Res. Comm., 163: 42-48 (1989)]. However, it is doubtful whether this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF because

-3-non-pancreatic PL7 / ₂ is an extracellular protein that would be difficult to control, and other enzymes in the biosynthetic mechanism of these substances are intracellular proteins. In addition, there is evidence that PLA ₂ is regulated by protein kinase C and G [R. Burch and J Axelrod, Proc. Natl. Acad. Sci. US 84: 6374-6378 (1989)], which are cytosolic proteins that must act on intracellular proteins. It would be impossible for non-pancreatic PI_A ₂ to act in the cytosol, since a high reduction potential would reduce disulfide bonds and inactivate the enzyme.

In mouse macrophage cell strains, mouse PLA ₂ , referred to as RAW 264.7, was identified. The specific activity of 2 mol / min / mg, resistant to reducing conditions, is reported in conjunction with an approximately 60 kD molecule. However, this protein was not purified to a homogeneous substance. [See CC Leslie et al., Biochem. Biophys. Acta., 963: 476-492 (1988)]. The references cited above are incorporated herein by reference as to the function of phospholipase enzymes, in particular PLA ₂ .

Cytosol phospholipase A ₂ (hereinafter referred to as "cPLA ₂ ") was also identified and cloned. See U.S. Pat. 5,322,776 and 5,354,677, which are incorporated herein by reference in their entirety. The enzyme of these patents is an intracellular PLA ₂ enzyme, purified from its natural source or otherwise produced in pure form, which acts intracellularly to produce arachidonic acid in response to inflammatory stimuli.

It is now necessary to identify pharmaceutically useful substances that inhibit the action of these phospholipase enzymes for use in the treatment of inflammatory conditions, particularly where inhibition of the formation of prostaglandins, leukotrienes and PAF are the desired results of action. Thus, there remains a need in the art to identify such anti-inflammatory agents for therapeutic use in a variety of disease states.

SUMMARY OF THE INVENTION

The present invention provides phospholipase enzyme inhibitors of the general formula

where

R ¹ and R ¹ 'are independently selected from H, halogen, -CF ₃ , -OH, -C ₁ -C ₁₀ alkyl, preferably C 1 -C ₆ alkyl, -S-C 1 -C ₆ alkyl, preferably -S-C 1 -C ₆ alkyl, C ₁ -C 10 alkoxy, preferably C 1 -C ₆ alkoxy, -CN, -NO ₂ , -NH ₂ , -NH (C ₁ -C ₆ ), -N (C 1 -C ₆ ) ₂ , phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, - S-benzyl or groups of formulas:

R ⁶ is selected from H, C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, -O-phenyl, benzyl, -Obenzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -NH ₂ , -CN, -CF _3, or -OH;

R ⁷ is selected from -OH, -CF ₃ , C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NH- (C 1 -C ₆ alkyl), -N- (C 1 -C ₆ alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl , phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the rings of these groups may be optionally substituted with 1 to 3 substituents

-5 selected from halogen, -CN, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -NH ₂ , -CF _3, or -OH;

R ² is selected from H, halogen, _-CF3, -OH, -C-C _O alkyl, preferably -C ₆ alkyl, C _r Cioalkoxylu, preferably _Ci-C6 alkoxy, -CHO, -CN, -NO _{2, -NH2, -NHC-C6} alkyl, -N (Ci-6 alkyl) ₂ -N-SO ₂ or -SO ₂ -CrC6alkylu -C 6 alkyl;

R ³ is selected from H, -CF ₃ , C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy, C ₃ -C ₁₀ cycloalkyl, -C 1 -C ₆ alkyl-C ₃ -C ₁₀ cycloalkyl, -CHO, halogen or a group of formula - 1 ' ² -M ² , where

L ² represents a linking and bridging group of the formula - (CH ₂ ) n -, -S-, -O-, -C (O) -, - (CH ₂ ) n - C (O) -, - (CH ₂ ) _n -C (O) - (CH ₂ ) _n -, - (CH ₂ ) n -O- (CH ₂ ) n - or - (CH ₂ ) _n -S- (CH ₂ ) _n -, -C (O) C (O) X wherein X = O, N;

M ² is selected from C 1 -C 6 lower alkyl, C ₁ -C 6 lower alkoxy, C ₃ -C ₁₀ cycloalkyl, phenyl or benzyl, wherein the cycloalkyl, phenyl or benzyl ring may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 10 alkyl, preferably C 1 -C 10 alkyl, C 1 -C ₁₀ alkoxy, preferably C 1 -C ₆ alkoxy, -NO ₂ -NH ₂ , -CN or -CF ₃ ; or

a) a five membered heterocyclic ring containing one or two heteroatoms selected from N, S or O including, but not limited to, furan, pyrrol, thiophene, imidazole, pyrazole, pyrrolidine or tetrazole, wherein the five membered heterocyclic ring may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₁₀ alkyl, preferably C 1 -C ₆ alkyl, C 1 -C ₁₀ alkoxy, preferably C 1 -C ₆ alkoxy, -NO ₂ , -NH ₂ , -CN or -CF ₃ ; or

b) a six-membered heterocyclic ring containing one, two or three heteroatoms selected from N, S or O, including but not limited to pyridine, pyrimidine, piperidine, piperazine or morpholine, wherein the six-membered heterocyclic ring may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₁₀ alkyl, preferably C 1 -C ₆ alkyl, C 1 -C 6 alkoxy, preferably C 1 -C ₆ alkoxy, -CHO, -NO ₂ , -NH ₂ , -CN, -CF _3, or -OH; or

c) a bicyclic ring group having 8 to 10 atoms, preferably containing 1 to 3 heteroatoms selected from N, S or O, including but not limited to benzofuran, indole, indoline, naphthalene, purine or quinoline, wherein the bicyclic ring group may be optionally substituted with 1 to 3 substituents selected

-6 of halogen, C 1 -C ₁₀ alkyl, preferably C 1 -C ₆ alkyl, C ₁ -C ₁₀ alkoxy, preferably C 1 -C ₆ alkoxy, -CHO, -NO ₂ , -NH ₂ , -CN, -CF _3, or -OH; n is an integer from 0 to 3;

R ⁴ is selected from alkyl CrCenižší, CrCenižší alkoxy, - (CH 2) _n -C3Cecykloalkyl, - (CH 2) _n -S- (CH2) n-C3-C5cykloalkyl, - (CH 2) n O- (CH 2) _n -C 3 -C5cycloalkyl, or groups:

a) - _{(CH2) n-phenyl-O-phenyl, (CH2) n-phenyl-CH2-phenyl,} - _{(CH2) n-phenyl-CH2-phenyl,} - (CH _{2) n} phenyl (O-CH 2 -phenyl) 2, -CH ₂ -phenyl-C (O) -benzothiazole or groups of formulas:

(CH ₂ ) 4 wherein n is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C ₅ cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; the rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NH ₂ , -NO _2, or a five membered heterocyclic ring containing one a heteroatom selected from N, S or O, preferably S or O; or

b) groups of formulas - (CH 2) _n -A, - (CH 2) _n -SA, or - (CH 2) _n -OA, wherein A is a group ^D - / - · wherein

D represents H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy or -CF 3;

B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -NO ₂ ; or

(c) groups of formulas:

wherein Z is O or S and the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, -C 1 -C ₆ alkoxy, -NH ₂ or -NO ₂ ;

R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, - (CH ₂₎ ) _n tetrazole,

(C 1 -C 6 -alkyl)

_(Ci-C6-lower haloalkyl)

-8ο

II

-Ρ — ΟΗ ιι Ο or ο

II

-sII ο

-ΟΗ or groups of formula -L ¹ -M ¹ , wherein

L ¹ is a bridging or linking group selected from a chemical bond, - (CH ₂ ) n -,

-S-, -O- -C (O) -, - (CH ₂ ) _n -C (O), - (CH ₂ ) n C (O) - (CH ₂ ) _n -, - (CH ₂ ) _n - O- (CH ₂ ) _n -, - (CH ₂ ) _n -S (CH ₂ ) _n -, -C (Z) -N (R ⁶ ) -, -C (Z) -N (R ⁶ ) - ( CH 2) n -, -C (O) -C (Z) -N (R ⁶ ) -, -C (O) -C (Z) -N (R ⁶ ) (CH 2) _n -, -C (Z) -NH-SO ₂ -, or -C (Z) -NH-SO ₂ - (CH ₂ ) _n -;

M ¹ is selected from the group consisting of -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole,

wherein R ⁸ , R ⁹ or R ¹⁰ may be attached at any point in the cyclic or bicyclic system,

R ⁸ whenever present is independently selected from H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole,

-9ο

II

-Ριι

Ο

-ΟΗ or

ΌΗ

R ⁹ is selected from Η, halogen, _-CF3, -OH, -COOH, - (CH ₂₎ n -COOH, - _(CH2) "- C (O) -COOH, -C COalkyl, -O-C -C ₆ alkyl, -NH (C 1 -C ₆ alkyl) or -N (C 1 -C ₆ alkyl) ₂ ;

R ¹⁰ is selected from the group consisting of H, halogen, -CF 3, -OH, - (CH ₂ ) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, - NH (C 1 -C ₆ alkyl), -N (C 1 -C ₆ alkyl) ₂ ,

- (CH ₂ )

_(Cl-C6 lower alkyl) (lower trickle-haloalkyl)

(C1-C6-lower alkyl)

-N

R ⁸

R ⁹ or

rg

R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, C 1 -C ₆ cycloalkyl, -CF ₃ , -COOH, - (CH ₂ ) _n COOH, - (CH ₂ ) n C (O) -COOH,

provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least one acid group selected from carboxylic acid, tetrazole or a group of the formula:

n is an integer from 0 to 3;

or a pharmaceutically acceptable salt thereof.

It is evident, as noted above, that the substituents R ³ and R ⁴ are attached to the indole or indoline ring at the 2 or 3 position and the R ¹ , R ¹ 'and R ² groups are attached to one of the indole or indoline ring at the 4-position. , 5, 6 or 7 carbon atoms.

One group of compounds of the invention are those in which the R ¹ 'and R ³ groups are hydrogen and the substituents at the other positions of the indole or indoline are described above.

Another group of compounds of the invention are those in which the R ¹ 'and R ³ groups are hydrogen and the groups R ¹ , R ⁴ and R ⁵ are as defined above. Within this group there are two other preferred groups. In the first group, R ¹ is in the 5 position of indole or indoline and in the second group R ¹ is in the 6 position of indole or indoline.

In another preferred group, R ¹ is in the 5-position of indole or indoline and is benzyloxy, R ² and R ⁴ are hydrogen and R ³ and R ⁵ are as defined above.

In another preferred group of the invention, R ¹ is in the 5 or 6 position of indole or indoline and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R ² and R ⁴ are hydrogen and R ³ and R ⁵ are as defined above.

Another preferred group of the invention comprises the R ¹ and R ² groups at the 5 or 6 position of the indole or indoline and each is selected from the group consisting of C 1 -C 6 alkoxy, cyano, sulfonyl and halogen, R ² and R ⁴ are hydrogen and R ³ and R ⁵ are defined above.

It will also be appreciated that another preferred subgroup within each of the groups herein are those compounds wherein the core of the molecule is an indole moiety rather than an indoline moiety. It will also be appreciated that there is a second group within each group where the core of the molecule is an indoline residue.

Preferred phospholipase enzyme inhibitors of the invention also include compounds of the following formula

where

R ¹ is selected from H, halogen, -CF 3, -OH, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -NH 2, -NH (C 1 -C ₆ ), -N (C 1 -C ₆ ) 2, phenyl, -O- phenyl, benzyl, -O-benzyl, or groups of formulas:

R ⁶

C 1 -C 6 alkoxy, phenyl, O-phenyl, benzyl, -Obenzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2, -NO 2, -CF 3 or OH;

R ⁷ is selected from - (CH ₂ ) _n -COOH, - (CH 2) _n -N- (C 1 -C ₆ alkyl) 2, - (CH 2) _n -NH- (C 1 -C ₆ alkyl), -CF ₃ , Ci-C ₆ alkyl, C ₃ -C ₅ cycloalkyl, CrCealkoxylu, -NH-fCrCealkylu), -N _(r C 6 alkyl) 2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, - O-benzyl, adamantyl, or morpholinyl, the rings of these groups being optionally substituted by 1 to 3 substituents selected from halogen, Ci-C ₆ alkyl, C _r C ₆ alkoxy, -NH _2, -N0 _2, -CF _3, or -OH ;

R ² is selected from H, halogen, _-CF3, -OH, -C-C _O alkyl, preferably -C ₆ alkyl, C1C ₁₀ alkoxy, preferably C Cealkoxylu, -CHO, -CN, -NO 2, - NH ₂ , -NH-C ₁ -C ₆ alkyl, -N (C 1 -C ₆ alkyl) ₂₁ -N-SO ₂ -C 1 -C ₆ alkyl or -SO ₂ -C 1 -C ₆ alkyl;

R ³ is selected from C C6nižší alkyl, C Cenižší alkoxy, - (CH _{2) n} -C ₃ -C ₆ cycloalkyl, - _(CH2) ns (CH 2) _n -C ₃ -C6cykloalkyl, or the group:

a) - _{(CH2) n-phenyl-O-phenyl, (CH2)} n-phenyl-CH2-phenyl, - _{(CH2) n-phenyl-CH2-phenyl,} - (CH _{2) n} phenyl ( O-CH ₂ -phenyl) ₂ , -CH ₂ -phenyl-C (O) -benzothiazole or groups of formulas:

'.y o _(CH2) ^ _y

-13 ^ (CH) ^^ _(CH2) rr ^ _Y wherein n is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C 6 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; the rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF 3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH ₂ , -NO ₂ or a five membered heterocyclic ring containing one heteroatom selected from N, S or O, preferably S or O; or

b) groups of formulas - (CH ₂ ) _n -A, - (CH ₂ ) _n -SA, or - (CH ₂ ) _n -OA, where A is a group

B where

D represents H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy or -CF 3;

B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF 3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -NO ₂ ; or

(c) groups of formulas:

or

-14 where the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, -C 1 -C ₆ alkoxy, or -NO ₂ ;

R ⁴ is selected from H, halogen, _-CF3, -OH, Ci-6 alkyl, C _r C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, C (O) benzyl, _-CH2 - (C ₃ -C ₆ cycloalkyl), -C (O) -OH, -CH = O, -C (O) _r -C 6 alkyl, -C (O) -OC _r C ₆ alkyl, -C (O) -CF _3i - (CH ₂ ) n S -CH ₂ - (C ₃ -C ₆ cycloalkyl),

wherein the phenyl and benzyl ring of the respective R ³ group may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -CF ₃ , -C (O) -OH or -OH;

n is an integer from 0 to 3;

R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or

R ⁸

R ⁸ is selected from H, -COOH, - (CH 2) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole, in

/ Y or ₀

ABOUT

II

R ⁹ is selected from H, halogen, _-CF3, -OH, - (CH2) _n-COOH, - _{(CH2) n-C} (O) -COOH, -C _r Cealkylu, -O-C Cealkylu, -NH (C 1 -C 6 alkyl) or -N (C ₁ -C 6 alkyl) 2:

R ¹⁰ is selected from the group consisting of H, halogen, -CF ₃ -OH, - (CH ₂ ) _n COOH, - (CH 2) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl), -γ-C _1-6 alkyl) ₂ ,

R ⁸

_(Cl-C6 lower alkyl)

_(Ci-C6-lower haloalkyl)

-16alebo

R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n C (O) -COOH, or

provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least one acid group selected from carboxylic acid, tetrazole or a group of the formula:

or a pharmaceutically acceptable salt thereof.

Another group of phospholipase enzyme inhibitors of the invention are compounds of the general formula

R ¹ R ³

N

I

R ⁵ or

-17kde

R ¹ is selected from H, halogen, -CF ₃ , -OH, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -NH ₂₁ phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or formula groups:

R ⁶ R ⁶

R ⁶ is selected from H, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl C _r Cgalkoxylu, -N0 _2, -CF _3, or -OH;

R ⁷ is selected from - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N- (C 1 -C 6 alkyl) ₂ , - (CH ₂ ) n -NH- (C ₁ -C ₆ alkyl), -CF ₃ C 1 - C 6 alkyl, C ₃ -C ₅ cycloalkyl, C 1 -C 6 alkoxy, -NH- (C 1 -C 6 alkyl), -N- (C 1 -C ₆ alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl adamantyl or morpholinyl, wherein the pyridinyl, phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -CF _3, or -OH;

R ² is selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, preferably -C 1 -C ₆ alkyl, C 1 -C 10 alkoxy, preferably C 1 -C ₆ alkoxy, -CHO, -CN, -NO ₂ , -NH ₂₁ -NH -CrCealkylu, -N (CrC6alkylu) _{2, -N-SO2-C r} Cealkylu -CrC6alkylu or _-SO2;

R ³ is selected from H, halogen, -CF ₃ , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) benzyl, -CH ₂ - (C ₃₎ -C ₅ cycloalkyl), -C (O) -OH, -CH = O, -C (O) -C ₁ -C ₆ alkyl, -C (O) -O-C ₁ -C ₆ alkyl, -C (O) -CF ₃ , - (CH ₂ ) _n -S-CH ₂ - (C ₃ -C ₅ cycloalkyl),

wherein the phenyl and benzyl ring of the respective R ³ group may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO 2, -CF ₃ -C (O) -OH or -OH;

n is an integer from 0 to 3;

R ⁴ is selected from the group consisting of C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy, - (CH ₂ ) _n -C 3 C ₅ cycloalkyl, - (CH ₂ ) _n -S- (CH 2) _n -C 3 -C 5 cycloalkyl, - (CH ₂ ) _n -O- (CH 2) n -C 3 -C 5 cycloalkyl or groups:

a) - (CH ₂ ) _n -phenyl-O-phenyl, (CH ₂ ) _n -phenyl-CH 2 -phenyl, - (CH ₂ ) _n -O-phenyl-CH 2 -phenyl, - (CH ₂ ) _n phenyl- (O-CH 2 -phenyl) 2, -CH 2 -phenyl-C (O) -benzothiazole or groups of formulas:

(CH 8) wherein n is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C 6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO _2, or a five membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O; or

b) groups of formulas - (CH ₂ ) _n -A, - (CH ₂ ) _n -SA, or - (CH ₂ ) n OA, wherein A is a group

-19 ^D 7 ^ c

B where

D represents H, C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy or -CF ₃ ;

B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -NO ₂ ; or

(c) groups of formulas:

wherein Z is O or S and the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, -C 1 -C ₆ alkoxy, or -NO ₂ ;

-20R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or

R ⁸

ABOUT

-21 R ⁸ is selected from H, -COOH, - (CH 2) _n -COOH, - (CH 2) _n -C (O) -COOH, tetrazole, o

II —P — OH II O or

IN

FROM\

OH

R ⁹ is selected from H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 - C ₆ alkyl, -NH (C ₁ -C ₆ alkyl) or -N (C 1 -C ₆ alkyl) ₂ ;

R ¹⁰ is selected from the group consisting of H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O- C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl), -N (C 1 -C ₆ -

_(Ci-C6-lower haloalkyl)

R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n C (O) -COOH, or

provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least

-22 one acid group selected from carboxylic acid, tetrazole or a group of the formula:

VO \ _QH or

or a pharmaceutically acceptable salt thereof.

One group of compounds of the invention are those wherein the 3-position of the indole or indoline ring (R ³ ) is substituted only with hydrogen and the substituents at the other positions of the indole or indoline are as defined above.

Another group of compounds of the invention includes compounds wherein R ² is hydrogen and the groups R ¹ , R ³ and R ⁵ are as defined above. Within this group there are two other preferred subgroups. In the first group R ¹ is in the 5 position of indole or indoline and in the second group R ¹ is in the 6 position of indole or indoline.

In another preferred group of compounds wherein R ¹ is at the 5-position of the indole or indoline benzyloxy, R ² and R ⁴ are hydrogen and R ³ and R ⁵ are as defined above.

It will also be appreciated that another preferred subgroup within each of the groups herein are those compounds wherein the core of the molecule is an indole moiety rather than an indoline moiety. It is also evident that there is also a second group within each group where the core of the molecule is an indoline residue.

Another subgroup of phospholipase enzyme inhibitors of the invention are those compounds of formula

where

R ¹ is selected from H, halogen, -CF ₃ , -OH, C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, -NO ₂ , -NH ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl, -S -benzyl or groups of formulas:

R ⁷

R ⁶ is selected from H, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 -C 1-6 alkyl, C _1-6 alkoxy, -NO ₂ , -CF _3, or -OH;

R ⁷ is selected from - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N- (C 1 -C ₆ alkyl) ₂ , - (CH ₂ ) _n -NH- (C 1 -C ₆ alkyl), - CF ₃ , C 1 -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₆ alkoxy, -NH- (C 1 -C ₆ alkyl), -N- (C ₁ -C ₆ alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, - O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, wherein the pyridinyl, phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO 2 ₂₁ -CF ₃ or -OH;

R ² is selected from H, halo, -CF _{3 liters} -OH, -C _r Clo, preferably -C Cgalkylu C _r Cwalkoxylu, preferably CrCealkoxylu, -CHO, -CN, -N0 _2, -NH _2, -NH- C 1 -C 6 alkyl, -N (C 1 -C 6 alkyl) ₂ , -N-SO ₂ -C ₁ -C 6 alkyl or -SO ₂ -C ₁ -C ₆ alkyl;

R ³ is selected from alkyl CrCenižší, CrCenižší alkoxy, - (CH _{2) n} -C ₃ -C ₆ cycloalkyl, - _(CH2) ns (CH _{2) n} -C ₃ -C ₅ cycloalkyl, or the groups of:

a) - (CH ₂ ) _n -phenyl-O-phenyl, (CH ₂ ) _n -phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n phenyl- _{(O-CH2-phenyl) 2, -CH2-phenyl-C} (O) -benzothiazole or a moiety of the formulas:

(CH ₂ ) _n . ^ CH ₂ U

Y ^X O '

-24 ^ χ (ΟΗ ₂ ) π ^

wherein η is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C ₅ cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; the rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF 3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO _2, or a five membered heterocyclic ring containing one heteroatom selected from N, S or O, preferably S or O; or

b) a group of the formula - (CH _{2) n} -A, - _(CH2) "- SA, or - (CH _{2) n} -OA, wherein A is

B where

D represents H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy or -CF ₃ ;

B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF ₃ -OH, -C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy or -NO ₂ ; or

(c) groups of formulas:

s z

wherein Z is O or S and the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, -C 1 -C ₆ alkoxy, or - NO ₂ ;

R ⁴ is selected from H, halogen, -CF ₃ , -OH, C 1 -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) benzyl, -CH ₂ - (C ₃ -C ₅ cycloalkyl), -C (O) -OH, -CH = O, -C (O) -C ₁ -C ₆ alkyl, -C (O) -O-C ₁ -C ₆ alkyl, -C (O) -CF ₃ - (CH ₂ ) _n -S-CH ₂ - (C ₃ -C ₅ cycloalkyl),

wherein the phenyl and benzyl ring of the respective R ³ group may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ , -CF ₃ , -C (O) -OH or -OH;

n is an integer from 0 to 3;

R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH,

-CH = CH-COOH, or

R ⁸

or

R ⁸ is selected from H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole,

with

-š- ° ^H o

or

ΌΗ

R ⁹ is selected from H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl) or -N (C 1 -C 6 alkyl) ₂ ;

R ¹⁰ is selected from the group consisting of H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n COOH - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ ,

or

R ¹¹ is selected from H, C 1 -C 6 lower alkyl, -CF _3, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n C (O) -COOH, or

provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least one acid group selected from carboxylic acid, tetrazole or a group of the formula:

or a pharmaceutically acceptable salt thereof.

Another preferred group of compounds of the invention are those compounds of formula

where

R ¹ is selected from -NH 2, -O-phenyl, benzyl, -O-benzyl, -N-benzyl, N-benzyl-phenyl, -S-benzyl or groups of formulas:

R ⁶ is selected from H, C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -Obenzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO 2 , -CF ₃ or -OH;

R ⁷ is selected from - (CH ₂ ) _n -COOH, - (CH ₂ ) n N - (C ₁ -C ₆ alkyl) 2, - (CH ₂ ) n -NH- (C ₁ -C ₆ alkyl), -CF ₃ , C ₁ -C ₆ alkyl, C ₃ - C 5 cycloalkyl, C 1 -C 6 alkoxy, -NH- (C 1 -C 6 alkyl), -N- (C 1 -C 6 alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these the groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -CF 3, or -OH;

n is an integer from 0 to 3;

R ³ is selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -CF ₃ , -CH = O, -C (O) -C 1 -C ₆ alkyl, -C (O) -O-C 1 -C 6 ₆ alkyl, -C (O) -OH, -C (O) -CF ₃ , -C (O) -phenyl, -C (O) -benzyl, -C (O) -pyrrolyl, -C (O) - thienyl, -C (O) -furanyl or -C (O) -morpholinyl;

R ⁴ is selected from the group consisting of - (CH ₂ ) _n -C 3 -C ₆ cycloalkyl, - (CH ₂ ) _n -S- (CH ₂ ) _n -C ₃ cycloalkyl, - (CH _{2 n} -OCH 4 n -C 5) -Cecykloalkyl, - (CH _{2) n} -S-C ₆ alkyl or the group:

a) -C (O) -O- (CH ₂ ) n C ₃ -C ₅ cycloalkyl, - (CH ₂ ) n -phenyl, - (CH ₂ ) _n -O-phenyl, - (CH ₂ ) _n -S- phenyl, - _(CH2) ns _(CH2) n-phenyl ₁ - _{(CH2) n-phenyl-O-phenyl, (CH2) n-phenyl-CH2-phenyl,} - (CH _{2) n} - _{Ofenyl-CH2-phenyl,} - _{(CH2) n} -phenyl- _{(O-CH2-phenyl) 2,} -C (O) -phenyl, -C (O) -O-benzyl, -C (O) - Opyridinyl, -C (O) -O-naphthyl, - (CH ₂ ) _n -S-naphthyl, - (CH ₂ ) _n -S-pyridinyl, - (CH ₂ ) _n -pyridinyl, or - (CH ₂ ) _n - naphthyl, - (CH ₂ ) _n -O-naphthyl, wherein the phenyl, pyridinyl and naphthyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF 3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, - NO ₂ or a five membered heterocyclic ring containing one heteroatom selected from N, S or O, preferably S or O; or

b) a group of the formula - (CH _{2) n} -A, - _(CH2) "- SA, or - (CH _{2) n} -OA, wherein A is wherein

D represents H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy or -CF ₃ ;

R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or

Ο

-31 R ⁸ is selected from H, -COOH, - (CH 2) _n -COOH, - (CH 2) _n -C (O) -COOH, tetrazole,

or

ΌΗ

R ⁹ is selected from H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -Ο-C ₁ -C ₆ alkyl, -NH (C 1 -C ₆ alkyl) or -N (C ₁ -C 6 alkyl) ₂ ;

R ¹⁰ is selected from the group consisting of H, halogen, -CF 3, -OH, - (CH 2) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 -C ₆ alkyl C ₆ alkyl, -NH (C 1 -C ₆ alkyl), -N (C 1 -C ₆ alkyl) ₂ ,

_(Ci-C6-lower haloalkyl)

R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -

provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least

-32 one acid group selected from carboxylic acid, tetrazole or a group of the formula:

or a pharmaceutically acceptable salt thereof.

As used herein, the term "aryl and" substituted aryl include monocyclic, especially five- and six-membered monocyclic, aromatic and heteroaromatic ring groups, and bicyclic aromatic and heteroaromatic ring groups, especially those having 9 to 10 ring atoms. As aryl groups are meant phenyl rings, which include those found in phenoxy, benzyl, benzyloxy, biphenyl and other such groups. The aryl and heteroaryl groups of the invention also include the following groups:

(a) a five membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to: furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole or oxathiazole; or

b) a six membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including but not limited to: pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadisine, oxazine or morpholine ; or

c) a bicyclic ring moiety optionally containing 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to: benzofuran, chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinoline, phthalazine or naphthyridine.

Groups substituted aryl as used here includes such groups which are optionally substituted by from 1 to 3 substituents selected from halogen, _Ci-Cio alkyl, preferably _Ci-6 alkyl, Ci-Ci ₀ alkoxy, preferably _Ci-C6 alkoxy, - CHO, -COOH or esters thereof, -NO ₂ , -NH ₂ , -CN, -CF ₃ or -OH, or combinations thereof, such as -CH ₂ CF ₃ , -NH (CH ₃ ), etc.

A preferred subgroup of these optionally substituted groups described herein includes those formed from benzene, pyridine, naphthalene, or quinoline rings. Another preferred group includes the rings furan, pyrrole, thiophene, pyrimidine and morpholine. A preferred group of bicyclic aromatic groups includes rings of benzofuran, indole, naphthalene, and quinoline.

The alkyl, alkenyl and alkynyl groups mentioned herein include those having 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless otherwise stated, it is preferred that these groups are straight or branched. Halogens herein include F, Cl, Br and I.

As used herein, the term "phospholipase enzyme activity" means a positive expression in a phospholipid metabolism assay (a preferred assay is described in Example 86 below). A compound has phospholipase enzyme inhibitory activity when it inhibits phospholipase activity (preferably cPLA ₂ ) in any available assay (a preferred assay is described in Example 86 or Example 87 below) of enzyme activity. In preferred embodiments, the compound of (1) has an IC _{50 of} less than about 25 µΜ, preferably less than about 6 µΜ, in the LysoPC assay; (2) an IC50 of less than about 50 μΜ in the blister test; (3) an IC50 of less than about 1 μΜ in the PMN test; (4) an IC50 of less than about 15 μΜ in the Coumarin test; and / or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30% reduction) in the carrageenan-induced paw edema assay.

The compounds of the invention are useful for inhibiting the activity of phospholipase enzymes (preferably cPLA ₂ ) and are therefore useful for treating (ie, treating, preventing or ameliorating) an inflammatory or inflammatory-associated response or condition (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory disease). gut and other diseases mediated by prostaglandins, leukotrienes or PAFs) and other conditions such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.

This invention also encompasses pharmaceutical compositions and therapeutic methods of treatment or use using the compounds of the invention.

The compounds of the invention may be used in a pharmaceutical composition

In association with a pharmaceutically acceptable carrier. Such compositions may also contain (in addition to the substance (s) of the invention and the carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials known in the art. The term pharmaceutically acceptable means a non-toxic material that does not interfere with the effects of the biological activity of the active ingredient (s). The characteristics of the carrier will depend on the mode of administration. The pharmaceutical compositions may further comprise other anti-inflammatory agents. Such additional factors and / or agents may be included in the pharmaceutical composition to cause a synergistic effect with the compounds of the invention or to minimize side effects caused by the compound of the invention.

The pharmaceutical compositions of the invention may be in the form of liposomes in which the compounds of the invention are combined, in addition to pharmaceutically acceptable carriers, with an amphipathic agent, such as lipids that exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers aqueous solution. Suitable lipids for liposome preparations include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids and the like. The preparation of such liposome formulations is within the skill of the art, as described, for example, in U.S. Pat. Patente no. 4,235,871; U. Patente no. 4,501,728; U. Patente no. 4,837,028; and U.S. Pat. Patente no. No. 4,737,323, all of which are incorporated herein by reference.

As used herein, the term "therapeutically effective amount" means the total amount of each active ingredient of a pharmaceutical composition or method that is sufficient to demonstrate significant benefit to a patient, i. for the treatment, healing, prevention or amelioration of an inflammatory response or condition, or to accelerate the treatment, healing, prevention or amelioration of such conditions. When an individual active ingredient is administered alone, the term corresponds to that ingredient alone. When a combination is applied, the term refers to the combined amounts of active ingredients that produce a therapeutic effect when administered in combination, sequentially or simultaneously.

In practicing the method of treatment or use of the invention, a therapeutically effective amount of a compound of the invention is administered to a mammal having a disease to be treated. The compounds of the invention may be administered in a single dose

In accordance with the method of the invention either alone or in combination with other therapeutically active agents, for example, for treatment using other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, the compounds of the invention may be administered either simultaneously with other anti-inflammatory agent (s), cytokine (s), lymphokine (s), other hematopoietic factor (s) ), thrombolytic or anti-thrombotic factor, or sequentially. When administered sequentially, the attending physician will decide on the appropriate sequence of administration of the compound of the invention in combination with other anti-inflammatory agent (s), cytokine (s), lymphokine (s), other hematopoietic factor (s), thrombolytic or antithrombotic factor.

Administration of a compound of the invention used in a pharmaceutical composition or for carrying out the method of the invention can be accomplished by various conventional routes, such as orally, by inhalation, or by cutaneous, subcutaneous or intravenous injection.

When a therapeutically effective amount of a compound of the invention is administered orally, the compounds of the invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in a tablet form, the pharmaceutical composition of the invention may further comprise a solid carrier such as gelatin or a vehicle. The tablet, capsule and powder contain about 5 to 95% by weight of the compound of the invention and preferably about 25 to 90% by weight of the compound of the invention. When administered in liquid form, a liquid carrier such as water, kerosene, oils of animal or vegetable origin, such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils, may be added. The liquid form of the pharmaceutical composition may further comprise physiological saline, dextrose or other carbohydrate solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition comprises about 0.5 to 90% by weight of the compound of the invention and preferably about 1 to 50% by weight of the compound of the invention.

When a therapeutically effective amount of a compound of the invention is administered

By intravenous, cutaneous or subcutaneous injection, the compounds of the invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, which pays the necessary attention to pH, isotonicity, stability, and the like, is within the skill of the art. A preferred pharmaceutical composition for intravenous, cutaneous or subcutaneous injection should contain, in addition to the compound of the invention, an isotonic vehicle such as sodium chloride injection, Ringer injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer injection, or other vehicle known in the art. . The pharmaceutical composition of the invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art.

The amount of the compound (s) of the invention in the pharmaceutical composition of the invention will depend on the nature and severity of the condition being treated and the nature of the prior treatments the patient has undergone. Finally, the attending physician will decide on the amount of compound of the invention to treat each individual patient. Initially, the attending physician will administer low doses of the compound of the invention and observe the patient's response. Larger doses of the compound of the invention may be administered until the optimal therapeutic effect for the patient is attained and from that point on, the dose is not further increased. It is contemplated that the various pharmaceutical compositions used in practicing the method of the invention should contain about 0.1 µg to about 100 mg (preferably about 0.1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of the compound of the invention per kg of body weight.

The duration of intravenous therapy using the pharmaceutical composition of the invention will vary depending upon the severity of the disease being treated and the condition and potential idiosyncratic response in each individual patient. It is contemplated that the duration of each administration of a compound of the invention will be in the range of 12 to 24 hours of continuous intravenous administration. Finally, the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the invention.

The compounds of the invention may be prepared by the methods described below and the methods of the exemplary embodiments also described below. synthesis

Preferred compounds of the invention are described in the examples below.

Method A

Ethyl 5-nitroindole-2-carboxylate is chlorinated at the 3-position with N-chlorosuccinimide in a solvent such as DMF or DMSO at an elevated temperature of 40 ° C to 80 ° C. The resulting ester is then reduced in a three-step process. In a first step, the ester is hydrolyzed under basic conditions with a base, for example sodium hydroxide or potassium hydroxide, in a solvent system such as water: methanol: THF. The acid is then activated by the addition of carbonyldiimidazole in THF and reduced with a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in an alcohol solvent system such as methanol or ethanol. The resulting alcohol is protected as a TBDMS ether with TBDMSCl in a solvent such as DMF, methylene chloride or THF with a base such as triethylamine or imidazole. The indole nitrogen is then alkylated with methyl 4-bromomethylbenzoate in a solvent such as THF, acetonitrile or DMF with a base such as sodium hydride, nBuLi or potassium bis (trimethylsilyl) amide. The 5-nitro group is then reduced by exposure to H 2 in the presence of a catalyst such as Pt / C or Pd / C in a solvent such as ethyl acetate, methanol or THF or in a mixture of two or all three solvents. The amine is then acylated with cyclopentylcarbonyl chloride in a biphasic system of saturated sodium bicarbonate and methylene chloride. R ¹ is then introduced in the second step of the process wherein the TBDMS ether is converted to the bromide by treatment with dibromotriphenyl phosphate in methylene chloride and then the crude bromide is removed with thiols or phenols in a solvent such as THF, methylene chloride or DMF in the presence of a base such as potassium carbonate or cesium carbonate. . The resulting ester is then prepared by hydrolyzing the ester under basic conditions with sodium hydroxide in a solvent system such as water: MeOH: THF.

Scheme A

H

DMF 30 T

H

IINaOH

MtOH.THF

2) CDLTHF

3) NaBHj. EtOH

Cl, OH

TBDMSCI imidizole, DMF

Scheme A - continued

R ¹ = arylthioether alkylthioether and aryl ether alkyl ether

Method B

Acylation at the 3-position of indole I with an acylating agent such as naphthoyl chloride can be carried out using ethylmagnesium bromide in a solvent such as THF to give compound II. The alkylation of the indole nitrogen can be carried out by treatment with a suitable base such as sodium hydride in a suitable solvent. Removal of the hydroxyl protecting group with tetrabutylammonium fluoride and oxidation with a suitable oxidizing agent affords compound IV. A. The Horner-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent, such as tetrahydrofuran, provides an unsaturated ester V from which the indole protecting group at the 1-position is removed by a suitable reagent system such as, for example, hydrofluoric acid in acetonitrile. The saponification of the acid group present gives compound VI.

£

DTBAF

2) ΜηΟ;

1) HF, CH, CN

2) NaOH. MeOH-THF

Method C

Indole I can be converted to compound II in two steps: (1) reduction with LAH in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of compound II, such as ethylmagnesium bromide in a solvent such as THF at -60 ° C, by acylation of the resultant magnesium salt, by the Grignard reagent

-40 with a suitable acyl chloride such as acetyl chloride in ether and finally, alkylation on nitrogen with an alkyl halide such as methyl (4-bromomethyl) benzoate in the presence of a strong base such as NaH in DMF affords ketone III. The silyl group on compound III is removed using tetrabutylammonium fluoride in a solvent such as THF, and the resulting alcohol is then converted to the bromide using carbon bromide and bis (diphenylphosphino) ethane in a solvent such as dichloromethane to give bromide IV. Removal of the bromine from compound IV is accomplished with a thiol compound in the presence of a base such as cesium carbonate, or with an alcohol in the presence of a strong base such as NaH in DMF to give compound V (sulfide or optionally ether).

Scheme C

R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO ₂ , alkyl or aryl R = alkyl acid, benzylic acid, alkenyl, alkynyl X = O, S

Y = halogen, mesylate

-41 Method D

The protected alcohol was deprotected in a suitable solvent, such as THF, and the resulting alcohol was functionalized to a halide using carbon tetrabromide or methanesulfonyl chloride, which was then reacted with an oxygen nucleophile, coupled by prior deprotonation with a strong base such as sodium hydride or sulfur nucleophile. presence of cesium carbonate in DMF or THF. The nitro group was then reduced to the amine Pt / C by hydrogenation or treatment with copper (II) acetate and sodium borohydride. The resulting amine could be hydrolyzed using a standard method using sodium hydroxide in THF / MeOH or coupled using acylating agents such as acid chlorides, chloroformates and isocyanides, wherein reactions are generally carried out in the presence of a base in a solvent such as THF or dichloromethane. The amine can also be acylated with EDCI by coupling with various acids. The starting amines can also be alkylated by reductive amination using various aldehydes and sodium triacetoxyborohydride as a reducing agent. These functionalized amines can be hydrolyzed to give the desired acids, which can be converted to acylsulfonamides by EDCI coupling with sulfonamide. Alternatively, the functionalized amines can be alkylated by further reaction with a strong base and an alkyl halide and then hydrolyzed under standard conditions to provide the desired product.

at

Scheme D

Cl

about

NjOH / THF / MCOI

about

EDCI / H.NSOjR

-42 Scheme D - continued

Method E

The starting indole, with or without C2 substitution, was functionalized at the C3 position using DMF / POCb conditions or the magnesium indole salt was acylated with various acid chlorides to form ketones. These products were then N-alkylated by treatment with a strong base and various alkyl or aryl-halogen esters. When R 'is a nitro group, then the nitro group is reduced with Pt / C and H ₂ or cuprous acetate and sodium borohydride to an amine which is then acylated with various acid chlorides, isocyanates, chloroformates, reductively alkylated with amines or coupled with acids. The resulting ester was hydrolyzed to give the desired acid, which can be further transformed to acylsuflonamide.

Scheme E

CZ

EDCI / H.NSO.R-

H / l- <R-ξ-ΟO

ABOUT

EXAMPLES OF EMBODIMENTS OF THE INVENTION

Example 1

4 - ({3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(phenethylsulfanyl) methyl] -1Hindol-1-yl} methyl) benzoic acid

Step 1

Ethyl 5-nitroindole-2-carboxylate (21.1 g) was dissolved in DMF (500 mL). To this dark brown solution was added a solution of N-chlorosuccinamide (12 g in 125 mL DMF) over 5 minutes. The reaction mixture was heated to 50 ° C for 1.5 hours. The end of the reaction was determined by TLC. The reaction mixture was cooled to room temperature, diluted with water (2 L) and extracted with ethyl acetate (3 x 11). The organic layers were combined, dried over MgSO 4, filtered, and concentrated. This gave the desired ethyl ester (96 g wet with DMF), which was used in the next step without further purification.

Step 2

The ethyl ester was dissolved in methanol (400 mL) and THF (800 mL). To this clear brown solution was added 2N NaOH (450 mL). The black mixture was stirred at room temperature overnight. The reaction was not complete (TLC), so 7.2 g of granulated NaOH was added. After 7 hours the reaction was complete. Approximately 1 L of solvent was removed using a rotary evaporator. The residue was dissolved in ethyl acetate and water and acidified with 2N HCl to pH 2. The mixture was extracted with ethyl acetate (3 x 11). The combined organic layers were dried over MgSO 4, filtered, and concentrated to give the acid (24.3 g, 100%) as a brown solid.

Step 3

The carboxylic acid (24 g) was dissolved in THF (700 mL). To a transparent amber-colored solution was added CDI (16.2 g). The mixture was stirred at room temperature for 1.5 hours, giving a light brown suspension. The reaction mixture was cooled in an ice bath. Sodium borohydride (10.8 g) was then added slowly. Ethanol (140 mL) was then added. Gas evolution was observed. After 2 hours, the reaction was determined to be complete by TLC analysis. 2N was added to adjust the pH to 2

-44HCI. The reaction mixture was then extracted with ethyl acetate (3 x 600 mL). The combined organic layers were dried (MgSO ₄ ), filtered, and concentrated to give the desired alcohol (28.5 g) as a brown solid.

Step 4

The alcohol prepared above (25.4 g), imidazole (18.6 g) and tert-butyldimethylsilyl chloride (13.3 g) were dissolved in DMF (350 mL). The reaction mixture was stirred overnight and the reaction was found to be incomplete. Thus, imidazole (18.7 g) and tert-butyldimethylsilyl chloride (18.6 g) were added. After 1 hour the reaction was complete. Water (1.5 L) was added and the mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were evaporated to dryness to give the crude 5-tert-butyldimethylsilyl protected alcohol. The crude material was dissolved in ethyl acetate, absorbed on silica gel and evaporated to dryness. After loading onto a silica gel column and eluting with 15% ethyl acetate in hexanes, the desired protected alcohol (18.5 g, 69% from step 1) was isolated as pale yellow crystals.

Step 5 tert-Butyldimethylsilyl protected alcohol (1.0 g) was dissolved in DMF (10 mL). The yellow solution was cooled in an ice bath. Sodium hydride (147 mg) was added. After 15 minutes, 4- (bromomethyl) benzoate (807 mg) was added to the dark red solution. After an additional 15 minutes by TLC analysis, the reaction was determined to be complete. The reaction mixture was purified in cold 1N HCl. Water (800 mL) was added and the solution was extracted with ethyl acetate. The combined organic layers were evaporated to dryness to give crude N-alkylated indole as an orange solid. The crude solid absorbed on silica gel, added to a silica gel column and eluted with 15% ethyl acetate in hexanes, gave the desired N -alkylated indole (1.05 g, 73%) as a yellow solid.

Step 6 N-alkylated indole (3.8 g) was dissolved in THF (50 mL) and 5% Pt / C (1.6 g) was added. The reaction mixture was bubbled with hydrogen and stirred at room temperature overnight. The reaction mixture was filtered (celite) and concentrated. column

Chromatography (35% ethyl acetate in hexanes) gave the desired amine (1.7 g) as an off-white solid.

Step 7

To a solution of the above amine (1.6 g, 3.5 mmol) in CH ₂ Cl ₂ (10 mL) and saturated sodium bicarbonate (10 mL) was added cyclopentylcarbonyl chloride (0.467 mL, 1.1 eq). The reaction mixture was stirred for 45 minutes, dissolved in ethyl acetate (100 mL), washed with brine (3 x 20 mL), dried (MgSO 4), filtered and concentrated. Chromatography (20% ethyl acetate / hexanes) gave the desired product (1.55 g, 82%) as a light yellow oil.

Step 8

To a solution of the above amide (0.6 g, 1.1 mmol) in dichloroethane (3 mL) at 0 ° C was added dibromotriphenylphosphorane (0.5 g, 1.1 eq). The reaction mixture was stirred at room temperature for 2 hours, dissolved in ethyl acetate (50 mL), washed with brine (3 x 10 mL), dried (MgSO 4) and concentrated and used immediately in the next step.

Step 9

To a solution of the crude bromide prepared above (0.54 mmol) in DMF (2 mL, degassed) was added phenethyl mercaptan (0.08 g, 1.1 eq.) Followed by cesium carbonate (0.21 g, 1.2 eq.). ). The reaction mixture was stirred for 1 hour, taken up in ethyl acetate (20 mL), washed with brine (3 x 5 mL), dried (MgSO ₄ ), filtered and concentrated. Chromatography (25% ethyl acetate / hexanes) provided the title compound (0.17 g, 56%) as a colorless oil.

Step 10

To a solution of the above ester in THF (1 mL) and MeOH (0.5 mL) was added NaOH (0.28 mL, 5M, 5 eq). The reaction mixture was stirred for 4 hours, acidified with sodium hydrogen phosphate, purified in ethyl acetate, washed with brine and dried (MgSO ₄ ). The title compound (0.157 g, 98%) was triturated from ethyl acetate with hexanes.

Each compound of the following Examples 2-11 was prepared in the first step of step 9 described in Example 1, using the appropriate thiol, and in the second step of step 10 described in Example 1.

Example 2

4 - [(3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - {[(2-furylmethyl) sulfanyl] methyl} -1H-indol-1-yl) methyl] benzoic acid

Example 3

4 - [(3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - {[(4-hydroxy-6-phenyl-2-pyrimidinyl) sulfanyl] methyl} -1H-indol-1-yl) methyl] benzoic acid

Example 4

4 - {[3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - ({[4- (2-thienyl) -2-pyrimidinyljsulfanyl} methyl) -1 H -indol-1-yl] methyl } benzoic acid

Example 5

4 - ({3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2,4-dibromophenoxy) methyl] -1 H -indol-1-yl} methyl) benzoic acid

Example 6

4 - ({3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(cyclopentylsulfanyl) methyl] 1H-indol-1-yl} methyl) benzoic acid

Example 7

4- ({3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(propylsulfanyl) methyl] -1-hindol-1-yl} methyl) benzoic acid

Example 8

4 - ({2 - {[4- (tert -butyl) phenoxy] methyl} -3-chloro-5 - [(cyclopentylcarbonyl) amino] -1 H -indol-1-yl} methyl) benzoic acid

-47Example 9

4 - ({3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2-quinolinylsulfanyl) methyl] 1H-indol-1-yl} methyl) benzoic acid

Example 10

4 - [(3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - {[(cyclopropylmethyl) sulfanyl] methyl} -1H-indol-1-yl) methyl] benzoic acid

Example 11

4 - ({2 - [(Benzhydrylsulfanyl) methyl] -3-chloro-5 - [(cyclopentylcarbonyl) amino] 1H-indol-1-yl} methyl) benzoic acid

The compounds of the following Examples 12-14 were prepared as follows:

Step 1

The product prepared in Example 1, Step 6 was acylated at the 5-amino position using the procedure of Example 1, Step 7 with a suitable acylic reagent.

Step 2

The title compound was prepared from the intermediate of step 1, according to the method of example 1, steps 8 to 10 using the appropriate thiol.

Example 12

4 - ({5 - [(3-Carboxypropanoyl) amino] -3-chloro-2 - [(phenethylsulfanyl) methyl] -1Hindol-1-yl} methyl) benzoic acid

Example 13

4 - [(5 - [(3-Carboxypropanoyl) amino] -3-chloro-2 - {[(3-methylbenzyl) sulfanyl] methyl} -1H-indol-1-yl) methyl] benzoic acid

-48Example 14

4 - ({2 - ({[4- (tert-butyl) benzyl] sulfanyl} methyl) -5 - [(3-carboxypropanoyl) amino] -3-chloro-1H-indol-1-yl} methyl) benzoic acid

Example 15

4 - ({3-Chloro-5- (3-furoylamino) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid

The title compound was prepared as described in Example 43 using a suitable acylating agent.

The following Examples 17 to 21 are prepared according to the method of Example 43 using suitable acylating agents.

Example 17

4 - ({3-Chloro-5 - {[3- (diethylamino) propanoyl] amino} -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid

Example 18

4 - ({3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-thienylcarbonyl) amino] -1H-indol-1-yl} methyl) benzoic acid

Example 19

4 - ({5 - {[(Benzylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] 1H-indol-1-yl} methyl) benzoic acid

Example 20

4 - ({5 - {[(Butylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl) benzoic acid

-49Example 21

3 - [({1- (4-Carboxybenzyl) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-5-yl} amino) carbonyl] benzoic acid

Example 22

4 - {[5- (Benzyloxy) -2 - [(E) -2-carboxyethenyl] -3- (2-naphthoyl) -1H-indol-1-yl] methyl] benzoic acid

Step 1

A solution of 2- (tert-butyldimethylsilyloxymethyl) -5-benzyloxyindole (2.0 g, 5.4 mmol) in anhydrous ether (10 mL) was cooled to -78 ° C and a solution of ethylmagnesium bromide (3.0 M in ether) was added dropwise. , 4.0 mL, 12.0 mmol). The mixture was stirred at -60 ° C to -65 ° C for 2 hours, during which time a homogeneous solution formed a yellow suspension. A solution of naphthoyl chloride (2.28 g, 12.0 mmol) in ether (8 mL) was added. After stirring for 2 hours at -60 ° C to -40 ° C, the reaction was carefully quenched with saturated aqueous sodium bicarbonate and diluted with EtOAc. Flash chromatography (hexane / acetone, 6/1) gave 2.2 g (78%) of compound 17 as a yellow foam.

Step 2

To an ice-cooled solution (0 ° C) of the above intermediate (1.0 g, 1.9 mmol) in DMF (10 mL) was added sodium hydride (0.12 g, 2.1 mmol). After 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 30 minutes, during which bromomethyl SEM ether (0.5 mL, 2.8 mmol) was added dropwise. The mixture was stirred at room temperature for 4 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography (hexane / acetone, 6/1) gave 1.22 g (81%) of the desired intermediate as an off-white foam.

Step 3

To a solution of the above compound (6.6 g, 8.4 mmol) in THF (80 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 21 mL). The reaction mixture was stirred at temperature

-50 rooms for 2 hours, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. Flash chromatography (hexane / EtOAc, 4: 1) afforded 3.8 g (67%) of the alcohol as a thick colorless oil. The alcohol was dissolved in THF (50 mL) and MnO ₂ (5.5 g, 63.2 mmol) was added. The reaction mixture was stirred for 22 hours and filtered through a pad of celite. Concentration and filtration gave 3.7 g (96%) of the desired intermediate as a pale yellow foam.

Step 4

To an ice cold (0 ° C) solution of trimethylphosphonoacetate (0.12 mL, 0.7 mmol) in DMF (5 mL) was added sodium hydride (0.027 g, 0.8 mmol). After 30 minutes, a solution of the above intermediate (0.5 g, 0.7 mmol) in 5 mL of DMF was added. The ice bath was removed and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated. Flash chromatography (hexane / EtOAc, 3/2) gave 0.2 g of the desired intermediate (37%) as a white foam.

Step 5

4 - {[5- (Benzyloxy) -2 - [(E) -2-carboxyethenyl] -3- (2-naphthyl) -1 H -indol-1-yl] methyl} benzoic acid

To a solution of the intermediate prepared above (0.5 g, 0.7 mmol) in acetonitrile (10 mL) was added an aqueous solution of 48% hydrofluoric acid (5 mL). After 2 hours, water was added and the product was extracted with ethyl acetate. The organic layers were washed with water, brine and dried over magnesium sulfate. Concentration gave a crude solid which was dissolved in THF (2 mL) and MeOH (1 mL) and 1N sodium hydroxide solution (2 mL). After stirring overnight at room temperature, the reaction mixture was acidified to pH 3 with 10% HCl solution and extracted with ethyl acetate. Flash chromatography (CH ₂ Cl ₂ / MeOH, 10/1) gave the title compound (0.2 g, 50%) as a white solid.

-51 Example 23

4 - {{3-Acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} benzoic acid

Step 1

Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL THF and cooled to 0 ° C and lithium aluminum hydride (IAH) (255 mL 1.0 M solution in THF) was added via addition funnel. for 40 minutes. The reaction mixture was stirred for an additional 2 hours at 0 ° C and then treated with 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3 x 400 mL), the filtrates were combined and dried over MgSO ₄ and concentrated to give 24.8 g.

Step 2

The crude indolal alcohol prepared in Step 1 (8.3 g, 32.6 mmol) was dissolved in DMF (10.5 mL). To this solution was added imidazole (5.5 g, 81.5 mmol) and tert-butyldimethylsilyl chloride (5.4 g, 35.8 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was purified with water and extracted with ethyl acetate (3x). The organic layers were dried over magnesium sulfate and then concentrated. The crude material was purified on a silica gel column using 19: 1 hexane: ethyl acetate to give the pure product (11.9 g, 31 mmol, 94% yield, TLC - 0.8 Rf in toluene: ethyl acetate 2: 1).

Step 3

A solution of the silyl protected indole prepared in Step 2 (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to ethylmagnesium bromide (2.4 mL of a 3M solution in ether, 7.2 mmol) in ether (10 mL). maintained at -78 ° C. The reaction mixture was stirred at -60 ° C for 2 hours. Acetyl chloride (0.5 mL, 7.2 mmol) in ether (4 mL) was then added slowly. The reaction mixture was maintained at a temperature between -50 ° C and -60 ° C for an additional 2 hours. The reaction was then quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3x). The organic layers were dried over magnesium sulfate and then concentrated. The crude material was purified on a column

-52 Silica gel using 19: 1 hexane: ethyl acetate to give pure product (1.2 g, 50%).

Step 4

To indole (1.2 g, 2.9 mmol, prepared in step 3 above) in 10.5 mL DMF, was added sodium hydride (0.13 g, 60% dispersion in oil, 3.23 mmol) at room temperature. . The reaction mixture was stirred for 30 minutes. At this time, methyl (4-bromomethyl) benzoate (0.81 g, 3.53 mmol) was added and the reaction mixture was stirred overnight. After completion of the reaction (determined by TLC), quench the reaction with water, extract the reaction mixture with ethyl acetate (3x). The organic layers were dried over magnesium sulfate, concentrated and used in the next step.

Step 5

A mixture of the silyl protected indole prepared in step 4 above (0.65 g, 1.2 mmol) and tetrabutylammonium fluoride (2.9 mL of a 1M solution in tetrahydrofuran, 2.9 mmol) in tetrahydrofuran (6 mL) was stirred at room temperature for 1 hour. . At this time, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (3x), dried with magnesium sulfate and concentrated. The crude material was purified on silica gel using 1: 1 hexane: ethyl acetate to give pure alcohol (0.47 g, 91%)

Step 6

Indolal alcohol (0.3 g, 0.68 mmol), tetrabromomethane (0.27 g, 0.81 mmol) and 1,3bis (diphenylphosphino) propane (0.21 g, 0.51 mmol) were dissolved in dichloromethane (8 mL). (4 ml) and stirred for 16 hours, then the reaction mixture was diluted with dichloromethane and half-saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3x), dried over magnesium sulfate, and concentrated. The crude material was purified on silica gel using 2: 1 hexane: ethyl acetate to give pure alcohol (0.27 g, 78%).

-53Krokľ

The indol bromide prepared in step 6 (0.1 g, 0.2 mmol) was dissolved in dimethylformamide (0.4 mL, degassing of the solvent is highly recommended) and cesium carbonate (0.2 g, 0.6 mmol) was added followed by ethyl 2-naphthalenethiol (0.034 g, 0.22 mmol) was added and the mixture was stirred for 1 day, then the reaction mixture was purified in half-saturated (1/2) ammonium chloride and extracted with ethyl acetate (3x), dried and concentrated ( hexane-ethyl acetate 3: 1) to give 0.05 g (57%) of pure product.

Step 8

The ester (0.2 g, 0.34 mmol) prepared in step 7 was dissolved in 4.0 mL of 1/1 THF / methanol and then 1N sodium hydroxide (2.5 mL) was added and the resulting mixture was stirred for 16 hours at room temperature to give the crude product which was purified by chromatography (1: 1, hexane: ethyl acetate with 1% acetic acid) to give (0.17 g, 85%) a solid.

Example 24

4 - {[5- (Benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -3- (2,2,2-trifluoroacetyl) -1Hindol-1-yl] methyl} -benzoic acid

Step 1

This intermediate was prepared from the indole prepared in Step 2 of Example 23 and trifluoroacetic anhydride according to the method described in Step 3 of Example 23.

Step 2

The intermediate was prepared according to the method described in Step 4 of Example 23, but using the indole derivative prepared in Step 1 above and methyl (4-bromomethyl) benzoate.

Step 3

To a solution of indole alcohol in step 2 (0.1 g, 0.2 mmol) and triethylamine (0.04 mL, 0.3 mmol) in dichloromethane (0.4 mL) was added dropwise methanesulfonyl chloride (0.02 mL, 0.24 mmol) at 0 ° C. The reaction mixture was stirred for 1.5 hours and then

The dichloromethane was removed. To the residue in 0.4 mL of DMF at 0 ° C was added 2-naphthalenethiol (0.034 g, 0.22 mmol). Next, CsCO ₃ (0.96 g, 0.3 mmol) was added and the reaction mixture was stirred at room temperature overnight, then the reaction mixture was purified with brine and extracted with ethyl acetate (3x), dried and concentrated and chromatographed (hexane: ethyl acetate, 3: 1) gave 0.064 g (50%) of pure product.

Step 4

The title compound was prepared from the ester prepared in Step 3 above according to the method described in Step 8 of Example 23.

Example 25

4 - {{5 - [(4-aminobutanoyl) amino]] - 3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid

Step 1 tert-Butylsilyl protected alcohol (25 g) from Step 6 of Example 1 was dissolved in THF (200 mL) and then tetrabutylammonium fluoride (125 mL of a 1M solution) was added and the mixture was stirred for 10 minutes at room temperature. diluted with water and THF was concentrated, ethyl acetate was added and the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated to give the desired alcohol (21.5 g).

Step 2

The alcohol (13.1 g) from step 1 was suspended in dichloromethane (450 mL), cooled to 0 ° C and triethylamine (10 mL) and methanesulfonyl chloride (4.0 mL) were added and the resulting mixture was warmed to room temperature over The reaction mixture was diluted with dichloromethane, the layers separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated to give the desired chloride (13.5 g).

-55Step 3

To the chloride (13.5 g) produced in step 2 was added DMF (150 mL), cesium carbonate (33.5 g), and then the solution was degassed with argon, which was bubbled through the solution for 20 minutes, and then 2 -naphthalenethiol and the reaction mixture was stirred at room temperature for 20 minutes, then water and ethyl acetate were added, the layers were separated and the combined organic layers were concentrated to a slurry which was stirred overnight and the resulting slurry was filtered and the solid triturated with 40% ethyl acetate. in hexane to give the desired disulfide (12.2 g) in 69% yield.

Step 4

The product of Step 3 (11.25 g) was dissolved in THF (500 mL), methanol (500 mL) was added, followed by copper (II) acetate (29.2 g) as a suspension in water (300 mL) as well as a little THF ( 100 ml) and then sodium borohydride (11.2 g) was added portionwise. After stirring at room temperature for 2.5 hours, the foaming black solution was diluted with saturated sodium bicarbonate and the layers were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and chromatographed to give the desired amine (9.0 g) in 85% yield.

Step 5

The amine from step 4 above was coupled to the fmoc protected 4-aminobutyric acid as described in step 43 of Example 43, followed by trituration with dichloromethane to afford the amide in 43% yield.

Step 6

The amide (1.0 equivalent) from step 5 was dissolved in methanol (5 mg / ml) and piperidine (0.024 ml / mg) and then the reaction mixture was stirred at room temperature for two hours, concentrated and chromatographed to give the desired product in quantitative yield. .

Step 7

The amino ester of step 6 was hydrolyzed using the conditions described in step 43 of Example 43 to give the title compound in 54% yield.

-56Example 26

4 - {{3-Chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl} benzoic acid

Step 1

The amine (1 equivalent) from step 4 of Example 25 was dissolved in CH ₂ Cl ₂ (0.3 M) and then an equivalent amount of saturated sodium bicarbonate was added followed by the addition of the appropriate acid chloride (1.2 eq). The biphasic reaction mixture was stirred vigorously until TLC analysis indicated that the reaction was complete (usually several hours) and then the reaction mixture was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed or used crude to give the desired amide in 50% yield.

Step 2

The ester from the previous step was dissolved in THF / MeOH (3: 1) and then 1N NaOH (3 equivalents) was added and the reaction stirred until TLC analysis indicated that the reaction was complete. The reaction mixture was then concentrated, diluted with water, acidified to pH 2 with concentrated HCl, extracted with ethyl acetate 3 times, the combined organic layers were dried over magnesium sulfate and purified by chromatography to give the desired acid in 69% yield.

Example 27

4 - {{3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(2-quinoxalinylcarbonyl) amino] 1H-indol-1-yl} methyl] benzoic acid

Step 1

The amine from Step 4 of Example 25 was treated with the appropriate acid chloride according to the general method of Example 71, Step 1, to give the amide in 76% yield.

-57Krok2

The ester of step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid in 53% yield.

Example 28

4 - {{3-Chloro-5 - [(2,2-dimethylpropanolyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl] benzoic acid

Step 1

The amine from Step 4 of Example 25 was treated with the appropriate acid chloride according to the general method of Example 71, Step 1 to give the amide in 100% yield.

Step 2

The ester of step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid in 79% yield.

Example 29

4 - {{5 - {[(Benzyloxy) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl} benzoic acid

Step 1

The amine from Step 4 of Example 25 was treated with the appropriate acid chloride according to the method described in Example 71, Step 1 to give the amide in 96% yield.

Step 2

The ester from step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid.

Example 30

4 - {{3-Chloro-5 - {[(cyclopentyloxy) carbonyl] amino} -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} benzoic acid

-58Step 1

The amine from Step 4 of Example 25 was treated with acetic anhydride according to the general method of Example 71, Step 1 to afford the amide in 92% yield.

Step 2

The ester from step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid.

Example 31

4 - {{5- (acetylamino) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} benzoic acid

Step 1

The amine from Step 4 of Example 25 was treated with acetic anhydride according to the general method of Example 71, Step 1 to give the amide in 77% yield.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 29% yield.

Example 32

4 - {{5 - {[(butylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl} benzoic acid

Step 1

To the amine (1 equivalent) produced in Step 4 was added THF (0.12 M) and the reaction mixture was cooled to 0 ° C and then butyl isocyanate (1.1 eq) was added and the mixture was warmed to room temperature overnight and then the reaction mixture was diluted with half-saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried, concentrated and purified by chromatography to give the desired urea in 57% yield.

-59Krok2

The ester from step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid in 41% yield.

Example 33

4 - {{5 - {[(butylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl] benzoic acid

Step 1

According to the method of Example 32, Step 1, the amine was treated with benzyl isocyanate to give the title compound in 16% yield.

Step 2

The ester of Step 1 was hydrolyzed under the conditions described for Step 2 of Example 26 to give the desired acid in 100% yield.

Example 34

4 - {{3-Chloro-5 - [(morpholinocarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl} methyl] benzoic acid

Step 1

The amine (1 equivalent) produced above in step 4 was weighed into a flask together with

With 4-dimethylaminopyridine (1.5 eq) and then added to dichloroethane (0.08 M) followed by the addition of 4-morpholinecarbonyl chloride (1.5 eq) and the reaction mixture was stirred overnight at room temperature and then warmed at 40 ° C for 4 hours and worked up by adding ethyl acetate and half-saturated (1/2) ammonium chloride. The layers were then separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried, concentrated and purified by chromatography to give the desired urea in 100% yield.

-60Step 2

The ester of Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 79% yield.

Example 35

4 - {{5- (Benzylamino) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} benzoic acid

Step 1

The amine (1 equivalent) from step 1 was dissolved in dichloroethane and then benzaldehyde (1 equivalent) and acetic acid (1.0 mL / 1 mmol) were added and the reaction stirred for 20 minutes before sodium triacetoxyborohydride (1.3) was added. eq) and the reaction mixture was stirred overnight at room temperature, quenched by addition of aqueous diethanolamine and dichloromethane. The layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and purified by chromatography to give the desired urea in 74% yield.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 49% yield.

Example 36

4 - {{3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-phenoxybenzyl) amino] -1H-indol-1-yl} methyl] benzoic acid

Step 1

By the method of Example 35, Step 1, the amine from Step 4 of Example 25 was treated with the appropriate aldehyde to give the desired secondary amine in 38% yield.

-61 Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Example 26, Step 2 to give the desired acid in 87% yield.

Example 37

4 - {{3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1Hindol-1-yl] methyl] benzoic acid

Step 1

DMF (0.05 M) was added to the ester produced in Step 1 by the synthesis of Example 27, the reaction mixture was cooled to 0 ° C, and then sodium hydride (10 eq.) Was added and the mixture was stirred for 30 minutes, then methyl iodide was added. (10 eq.) And the resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate and half-saturated (1/2) ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried, concentrated and purified by chromatography to give the desired amide in 56% yield.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 57% yield.

Example 38

4 - {{5- [acetyl- (benzyl) amino] -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid

Step 1

The amide prepared in Step 1 of Example 31 was benzylated according to the procedure of Step 1 of Example 37 to give the tertiary amide in 90% yield.

Step 2

The ester from step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid in 41% yield.

-62Example 39

4 - {{3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(tetrahydro-3-furanylcarbonyl) amino] -1H-indol-1-yl} methyl] benzoic acid

Step 1

To Indolamine (1 equivalent) was added acid (1.2 eq), dimethylaminopyridine (10 mol%), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.5 eq) and then DMF ( 0.3 M) and the reaction mixture was stirred under nitrogen for 24 hours at room temperature and then poured into a semi-saturated (1/2) solution of ammonium chloride and ethyl acetate, and then the layers were separated. The aqueous layer was extracted 3x, the combined organic layers were washed with water 2x, dried, concentrated and chromatographed to give 55% of the title compound.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 55% yield.

Example 40

4 - {{3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-thienylcarbonyl) amino] -1H-indol-1-yl] methyl] benzoic acid

Step 1

According to the method of Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the prescribed acid to give the amide in 100% yield.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 21 yield.

Example 41

4 - {{3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(1-adamantylcarbonyl) amino] -1Hindol-1-yl} methyl] benzoic acid

-63Step 1

According to the method of Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the desired acid to give the amide in 100% yield.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 35% yield.

Example 42

3 - {{[1- (4-Carboxybenzyl) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-5-yl] amino} carbonyl} benzoic acid

Step 1

By the method of Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the desired acid to give the amide in 100% yield.

Step 2

The ester from Step 1 was hydrolyzed under the conditions described in Step 2 of Example 26 to give the desired acid in 20% yield.

Example 43

4 - {{3-Chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-phenylpropanoyl) amino] -1Hindol-1-yl} methyl] benzoic acid

Step 1

By the method of Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the desired acid to give the amide in 100% yield.

Step 2

The ester from step 1 was hydrolyzed under the conditions described in step 2 of example 26 to give the desired acid in 32% yield.

-64Example 44

4 - {{5-amino-3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} benzoic acid

Step 1

The amine produced in step 4 was hydrolyzed by the method of step 2 of Example 26 to give the title compound in 79% yield.

Example 45 N- {3-Chloro-1- {4 - {[(methylsulfonyl) amino] carbonyl} benzyl} -2 - [(2-naphthylsulfanyl) methyl] 1H-indol-5-yl} cyclopentane carboxamide

Step 1

To the product of Example 26 (1.0 equiv), EDCI (1.5 equiv), DMAP (1.0 equiv), methanesulfonamide (1.0 equiv) in a flask under nitrogen was added DMF (0.08 M) and the reaction mixture was stirred overnight at room temperature and then a half-saturated (1/2) ammonium chloride solution and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous layer was extracted 3x, the combined organic layers were washed with water 2x, dried, concentrated and chromatographed to give 27% of the title compound.

Example 46 N- {3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1- [4 - {{[(4-nitrophenyl) sulfonyl] amino} carbonyl} benzyl] -1 H -indole-5 -yl} cyclopentanecarboxamide

Step 1

To the compound of Example 26 was added the appropriate sulfonamide under the conditions described in Step 1 of Example 45 to give the desired acylsulfonamide in 43% yield.

EXAMPLE 47 N- {3-Chloro-1- [4 - {{[[(2-methylphenyl) sulfonyl] amino} carbonyl} benzyl] -2 - [(2-naphthylsulfanyl) methyl] -1H-indole-5 yl} cyclopentanecarboxamide

Step 1

To the compound of Example 26 was added the appropriate sulfonamide under the conditions described in Step 1 of Example 45 to give the desired acylsulfonamide in 40% yield.

Example 48

N- {3-chloro-2 - [(2naphthylsulfanyl) methyl] -1- [4 - [[(phenylsulfonyl) amino] carbonyl] benzyl] 1 / - / - indol-5-yl} cyclopentanecarboxamide

Step 1

To the compound of Example 26 was added the appropriate sulfonamide under the conditions described in Step 1 of Example 45 to give the desired acylsulfonamide in 40% yield.

Example 49 N- {3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1- [4 - {[[(trifluoromethyl) sulfonyl] amino] carbonyl} benzyl] -1H-indol-5-yl} cyclopentanecarboxamide

Step 1

To the compound of Example 26, a suitable sulfonamide was added under the conditions described in Step 1 of Example 45 to give the desired acylsulfonamide in 67% yield.

Example 50

4- {5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indol-1-yl} butanoic acid

-66Step 1

Ethyl 5-nitroindole-2-carboxylate (1 equivalent) was dissolved in THF / MeOH / H ₂ O (3: 1: 1, 0.21 M) followed by addition of LiOH.H ₂ O (1.3 eq.). The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was then acidified to pH 1 with 1N HCl solution and extracted with ethyl acetate. Treatment with water, brine, drying and concentration gave the crude product in 99% yield.

Step 2

The crude acid (1 equivalent) from step 1 was dissolved in THF (0.14 M) and carbonyldiimidazole (1 equivalent) was added, the mixture was stirred at 25 ° C for 1.5 hours. The reaction mixture was then cooled to 0 ° C. Sodium borohydride (2.86 eq.) Was then added in several portions followed by addition of EtOH (0.71 M), the mixture was stirred at 25 ° C overnight. The reaction mixture was then acidified to pH 2 with 2N HCl and extracted with ethyl acetate. Treatment with water, brine, drying and concentration gave the crude product in 95% yield.

Step 3

To the dry flask was added crude indolal alcohol (1 equivalent) from step 2 followed by anhydrous DMF (0.135 M). To this was then added imidazole (1.3 eq.) And TBSCl (1.2 eq.), The mixture was stirred at 25 ° C for 1 hour. Treatment with ethyl acetate / water followed by chromatographic purification gave the desired product in 70% yield.

Step 4

The silyl protected indole (1 equivalent) from step 3 was dissolved in anhydrous DMF (0.13 M) in a dry flask. To this was added NaH (60% dispersion in mineral oil, 1.2 eq.) And the mixture was stirred at 25 ° C for 1 hour, after which ethyl 4-bromobutyrate (1.2 eq.) And KI (1 eq.) Were added. , 2 eq). The reaction mixture was heated at 60 ° C for 2 hours. Treatment with ethyl acetate / water followed by chromatographic purification gave the desired product in 93% yield.

-67Krok5

The alkylated indole (1 equivalent) from step 4 was dissolved in THF (0.05 M) and to this was added dropwise TBAF (1M / THF, 1.1 eq) at 25 ° C. The mixture was stirred for 1 hour. Treatment of the ethyl acetate / water mixture with chromatographic purification afforded the desired product in quantitative yield.

Step 6

The indole alcohol (1 equivalent) from step 5 was dissolved in anhydrous DMF (0.16 M) followed by dropwise addition of POCl 3 (10 eq) at 0 ° C. The mixture was heated to 80 ° C overnight. Treatment with ethyl acetate / water and washing the organic layer with 1N NaOH, water, brine, followed by concentration and chromatographic purification gave the desired product in 64% yield.

Step 7

A mixture of the chloraldehyde derivative (1 equivalent) from step 6, 325 mesh K ₂ CO ₃ (2.4 eq), 2-naphthol (1.2 eq) and KI (1.2 eq) was suspended in anhydrous acetonitrile ( 0.2 M) and heated to 70 ° C for 1.5 hours. Treatment with ethyl acetate / water followed by chromatographic purification afforded the desired product in 65% yield.

Step 8

The naphthyloxyindole derivative (1 equivalent) from step 7 was dissolved in anhydrous THF (0.023 M) and to this solution was added 5% Pt / C (40 wt%) under nitrogen and hydrogenated by bubbling H ₂ for 2.5 hours. The reaction mixture was then filtered through celite and concentrated to give the crude product in 96% yield.

Step 9

The aminoindole derivative (1 equivalent) from step 8 was dissolved in anhydrous CH 2 Cl 2 (0.07 M) and then Et ₃ N (1.4 eq) and cyclopentanecarbonyl chloride (1.2 eq) were added dropwise at 0 ° C. The mixture was stirred at 25 ° C for 0.5 h and then quenched with saturated NaHCO ₃ solution and allowed to cool.

-68 Stir overnight. The organic layer was separated, washed with brine and dried. The product was obtained in 66% yield after recrystallization from 30% ethyl acetate / hexane.

Step 10

The indole from step 9 (1 equivalent) was weighed into a flask along with NaH ₂ PO ₄ (12 eq), tert-butyl alcohol (0.13 M), water (0.13 M), 2-methyl-2-butene ( 46 eq) when NaO 2 Cl (12 eq) was added at 25 ° C. The reaction mixture was heated to 65 ° C overnight. Treatment with ethyl acetate / water followed by trituration with CH ₂ Cl ₂ / hexane (4: 6) at 0 ° C for 1 hour gave the desired product in 63% yield.

Step 11

The acid from step 10 (1 equivalent) was weighed into a flask to which was added EDCI (3 equivalents), DMAP (1.2 equivalents), pyrrolidine (1.2 equivalents) and finally anhydrous THF (0.018 M) and the reaction mixture was then refluxed for 18 hours. The mixture was treated with ethyl acetate / water and then washed with an organic layer of 1N HCl, saturated sodium bicarbonate, and brine. Recrystallization from ethyl acetate / hexane (3: 7) gave the desired product in 89% yield.

Step 12

To the dissolved amide (1 equivalent) from step 11 in THF / MeOH / water (3: 1: 1, 0.025 M) was added LiOH.H ₂ O (1.2 eq) and the mixture was stirred at 25 ° C over night. Treatment with ethyl acetate / water followed by recrystallization from CH ₂ Cl ₂ / hexane (1: 1) gave the product in 98% yield.

Example 51

4- {5 - [(cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl] butanoic acid

-69Step 1

Following the procedure of Example 11 step 11 and using morpholine, 87% of the desired product was obtained after recrystallization.

Step 2

Following the procedure of Example 12 step 12 and using the corresponding morpholinamide, 96% of the desired product was obtained after recrystallization.

Example 52

A / - [2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 - {[(trifluoromethyl) sulfonyl] amino} butyl) -3- (1-pyrrolidinylcarbonyl) -1 / - / - indole 5-yl} cyclopentanecarboxamide

The acid of Example 50 (1 equivalent) was weighed into a flask and then EDCI (3 equivalents), DMAP (1.2 eq), trifluoromethanesulfonamide (1.2 eq) and finally anhydrous THF (0.04 M) were added. The reaction mixture was stirred at 25 ° C overnight. The mixture was treated with ethyl acetate / water, the organic layer was washed with 1 N HCl), saturated bicarbonate and brine. Trituration of the crude product with CH ₂ Cl ₂ / hexane (1: 2) at 0 ° C for 1 hour afforded the desired product in 96% yield.

Example 53 N- [3- (Morpholinocarbonyl) -2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 - {[(trifluoromethyl) sulfonyl] amino} butyl) -1H-indole-5- yl] cyclopentanecarboxamide

Using the procedure of Example 1, Step 1, and using the corresponding acid of Example 51 (Step 4, Scheme 4), the desired product was obtained in 96% yield.

Example 53A

4- {5 - [(cyclopentylcarbonyl) amino] -3-formyl-2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoic acid

-70Step 1

The indole (1 equivalent) from Step 9 of Example 50 was dissolved in THF / MeOH / H ₂ O (3: 1: 1, 0.025 M) and then LiOH · H ₂ O (1.2 eq) was added followed by stirring at 25 ° C for 4 hours. Treatment with ethyl acetate / 1 N HCl followed by trituration with CH ₂ Cl 2 / hexane gave the desired product in 74% yield.

Example 53B

A / - [3-formyl-2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 - {[(trifluoromethyl) sulfonyl] amino} butyl) -1H-indol-5-yl] cyclopentanecarboxamide

Step 1

The acid (1 equivalent) from step 1 of Example 53A was weighed into a flask and EDCI (1.35 eq.), DMAP (1.1 eq.), Trifluoromethanesulfonamide (1.05 eq.), And finally anhydrous THF ( 0.026 M) and the reaction mixture was stirred at 25 ° C for 3 hours. After treatment with ethyl acetate / water, the organic layer was washed with 0.05 N HCl, saturated bicarbonate, and brine. Chromatographic purification gave the desired product in 94% yield.

Example 54

5 - [(Cyclopentylcarbonyl) amino] -2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 - {[(trifluoromethyl) sulfonyl] amino} butyl) -1H-indole-3-carboxylic acid

Step 1

The product from Step 1 of Example 53B (1 equivalent) was weighed into a flask together with NaH ₂ PO ₄ (12 eq), tert-butyl alcohol (0.12 M), water (0.12 M), 2-methyl-2-butene (50 mL). eq) when the mixture was then added NaO 2 Cl (11.8 eq) at 25 ° C. The reaction mixture was then heated to 60 ° C for 3 hours and allowed to stand overnight at 25 ° C. Treatment with ethyl acetate / water followed by chromatographic purification and trituration with CH ₂ Cl ₂ / hexane (1: 1) gave the desired product in 57% yield.

-71 Example 55

3 - {{4- [5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indol-1-yl] butanoyl} amino} benzoic acid

Step 1

Example 50 (1 equivalent) was weighed into a flask and EDCI (3 equivalents), DMAP (1.2 eq), methyl 3-aminobenzoate (1.2 eq) was added followed by THF (0.04 M The reaction mixture was then stirred at 25 ° C for 2 days. Then, the mixture was treated with ethyl acetate, and then the organic layer was washed with 1N HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate / hexane gave the desired product in 88% yield.

Step 2

The ester (1 equivalent) from step 1 was dissolved in THF / MeOH / water (3: 1: 1, 0.024 M) when LiOH.H ₂ O (1.2 eq) was added thereto, the mixture was stirred at 25 ° C overnight and then 1.2 eq. LiOH.H ₂ O and stirred for 2 hours. Treatment with ethyl acetate / 1 N HCl followed by trituration with CH ₂ Cl ₂ / hexane (1: 1) at 0 ° C gave the desired product in 92% yield.

Example 56

3 - {{4- [5 - [(cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl] butanoyl} amino} benzoic acid

Step 1

Following the procedure of Step 1 of Example 55 using the product of Example 51 (see Scheme 4 for synthesis), the desired product was obtained in 85% yield after chromatographic purification.

Step 2

Following the procedure of Step 2 of Example 55 using the corresponding morpholine of Step 1, the desired product was obtained in 91% yield.

-72Example 57

A / - [2 - [(2-naphthyloxy) methyl] -1- {4-oxo-4- [3 - [[[(trifluoromethyl) sulfonyl] amino] carbonyl] anilino] butyl} -3- (1-pyrrolidinylcarbonyl ) -1 H-indol-5-yl] cyclopentanecarboxamide

Step 1

The compound of Example 51 (1 equivalent) was weighed into a flask when EDCI (3 equivalents), DMAP (1.2 eq), trifluoromethanesulfonamide (1.2 eq) was added followed by anhydrous THF (0.04 M) and the reaction mixture was then stirred at 25 ° C overnight. The mixture was then treated with ethyl acetate / water and then the organic layer was washed with 1N HCl, saturated bicarbonate and brine. Trituration with CH ₂ Cl ₂ / hexane (8: 2) gave the desired product in 84% yield.

Example 58

A / - {3- (morpholinocarbonyl) - [2 - [(2-naphthyloxy) methyl] -1- {4-oxo-4- [3 - [[[(trifluoromethyl) sulfonyl] amino] carbonyl] anilino] butyl} -1 / - / - indol-5-yl] cyclopentanecarboxamide

Following the procedure of Step 1 of Example 57 using the compound of Example 56, the desired product was obtained in 84% yield.

Example 59

2- {4 - {[5- (Benzyloxy) -3- (1-naphthoyl) -1 H -indol-1-yl] methyl} phenyl} acetic acid

Step 1

A solution of MeMgBr in butyl ether (1M, 1.2 eq) was ice-cooled. 4benzyloxyindole (1 equivalent) in CH ₂ Cl ₂ (0.5 M) was added and the reaction mixture was then warmed to 25 ° C. Then, 1-naphthoyl chloride (1 equivalent) in CH ₂ Cl ₂ (1 M) was added and the reaction mixture was heated to reflux for 3 hours. Stopping the reaction with aqueous NH ₄ Cl and extraction with CHCl 3 gave a crude ketone which was purified by recrystallization from hexane / CHCl 3 / MeOH (53% yield).

-73Krok2

The ice-cooled solution of the ketone (1 equivalent) from step 1 in DMF (0.2 M) was treated with NaH (60% in mineral oil, 2.5 eq). After 15 minutes, 4-bromophenylacetic acid (1.1 eq) in DMF (0.4 M) was added and the resulting mixture was stirred at 25 ° C overnight. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic extracts were dried and concentrated. The desired product was obtained in 68% yield after purification by chromatography and recrystallization from hexane / EtOAc.

Example 60

2- {4 - {[5- (Benzyloxy) -3- (2-naphthoyl) -1H-indol-1-yl] methyl} phenyl} acetic acid

Step 1

Following the procedure of Step 1 of Example 59 using the appropriate acyl chloride, 42% of the desired ketone was obtained after recrystallization from hexane / CHCl 3.

Step 2

In analogy to Example 59, Step 2, 35% of the title compound was obtained after chromatographic purification and recrystallization from acetone / pentane.

Example 61

2- {4 - {[5- (Benzyloxy) -3- [3,5-bis (trifluoromethyl) benzoyl] -1H-indol-1-yl] methyl} phenyl} acetic acid

Step 1

Following the procedure of Step 59 of Example 59 using the appropriate acyl chloride, 30% of the desired ketone was obtained after recrystallization from hexane / CH 2 Cl 2 / EtOAc.

-74Krok2

Analogous to step 2 of Example 59, 73% of the title compound was obtained after chromatographic purification and recrystallization from CHCl 3 / MeOH.

Example 62

4 - {{3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} benzoic acid

Step 1

The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, Step 1) was treated with LAH (1.3 eq) in THF (0.27 M) at 0 ° C under nitrogen for 1 hour. Treatment with NaOH and water and subsequent concentration gave the crude product (100%).

Step 2

The crude product from Step 1 was dissolved in DMF (0.38 M) and treated with tert-butyldimethylsuilyl chloride (1.16 eq) and imidazole (1.26 eq) at 25 ° C for 1 day. Chromatographic purification gave the crude product (93%).

Step 3

The silyl ether from step 2 was dissolved in methylene chloride (0.26 M) and treated with BOC anhydride (1.24 eq.), Triethylamine (1.53 eq.) And DMAP (0.21 eq.) At 25 ° C. for 3 days. Chromatographic purification gave the pure product (99%).

Step 4

The N-BOC silyl ether from step 3 was treated with acetic acid / water / THF (3: 1: 1) (0.04 M) at 25 ° C for 1 day. Chromatographic purification gave the pure product (100%).

-75Step 5

The alcohol from step 4 was dissolved in methylene chloride (0.2 M) and treated under nitrogen at -40 ° C with triethylamine (1.33 eq.) And mesyl chloride (1.23 eq.) For 1 hour. To another dry flask was weighed naphthalene-2-thiol (1.31 eq) and THF (1 M) was added followed by lithium hexamethyldisilazide (1N in THF, 1 eq) and the mixture was stirred at 25 ° C for 30 minutes . The resulting mixture was then added dropwise over 30 minutes to the above prepared mesylate solution at -40 ° C. The reaction mixture was then warmed to 25 ° C and stirred for 4.5 hours. Chromatographic purification gave the BOC thioether.

Step 6

The purified BOC thioether of step 5 was heated under nitrogen at 160-170 ° C for 1.25 hours and recrystallization from ethyl acetate-hexanes afforded the free indol dioether in 64% yield.

Step 7

The product of step 6 (1 eq.) In CH ₂ Cl ₂ (0.125 M) was ice-cooled. A solution of MeMgBr (1.2 eq) in butyl ether (1 M) was added and the resulting mixture was stirred for 30 minutes. After heating to 25 ° C, benzoyl chloride was added dropwise. The reaction mixture was then heated to reflux for 3 hours, then stirred at 25 ° C overnight. After stopping the reaction with NH ₄ Cl, the mixture was extracted with CH ₂ Cl ₂ . The organic extracts were washed with brine, dried and concentrated. The desired ketone was obtained in 55% yield after chromatographic purification.

Step 8

A solution of the product of Step 1 (1 eq.) In dry DMF (0.1 M) was treated with NaH (60% in mineral oil, 1.05 eq.). After 1 hour, methyl 4-bromomethylbenzoate (1.2 eq) was added at 25 ° C and the resulting mixture was stirred overnight. Treatment with EtOAc / water gave the desired crude material, which was purified by chromatography (56% yield).

-76Krok9

The material from step 2 (1 eq.) Was hydrolyzed by LiOH.H 2 O (1.2 eq.) In THF / MeOH / water (3/1/1, 0.07 M). After stirring at 25 ° C overnight, the reaction was quenched with AcOH and the solvent was evaporated. Workup with EtOAc / water and chromatographic purification gave the title compound in 78% yield.

Example 63

4 - {[5- (Benzyloxy) -3-isobutyryl-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl] methyl} benzoic acid

Step 1

Following the procedure of Step 7 of Example 62 and using isopropyl chloride, the desired ketone was obtained after chromatography.

Step 2

Analogous to the procedure of Example 8, Step 8, 50% of the N-alkylated material was obtained after chromatographic purification.

Step 3

Following the procedure of Step 9 of Example 62, the methyl ester was hydrolyzed to give the title compound in 67% yield after chromatography.

Example 64

2- {3-Acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl] acetic acid

Step 1

The product of Example 80, Step 1, was alkylated with methyl bromoacetate in an analogous manner to that described in Example 62, Step 8, and recrystallized from EtOAc to give a 65% yield of the title compound.

-77Krok2

Following the procedure of Step 9 of Example 62, the previous methyl ester was hydrolyzed to give the title compound in 84% yield after subsequent chromatography.

Example 65

2- {5- (Benzyloxy) -3-isobutyryl-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} acetic acid

Step 1

In an analogous manner to the step 63 of Example 63, starting from the methyl bromoacetate and the isopropyl ketone described in the step 1 of Example 63 (step 1, see above), 66% of the N-alkylated material was obtained after chromatographic purification.

Step 2

Following the procedure of Step 3 of Example 63, the methyl ester was hydrolyzed to give the title compound in 50% yield after chromatography.

Example 66

4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoic acid

Step 1

A solution of EtMgBr in ether (3N, 2.17 eq) was cooled to -10 ° C. The product of Step 2 of Example 62 (1 eq) in ether (0.55M) was added and the reaction mixture was stirred at -70 ° C for 2 hours. After addition of benzoyl chloride (3 eq) in ether (1.5 M), the reaction mixture was stirred at -40 ° C for 2 hours, quenched with saturated NaHCO ₃ at -40 ° C and allowed to warm to 25 ° C. Treatment with EtOAc / water and crystallization from hexane / EtOAc gave 89% of the desired ketone.

Step 2

Step 1 material (1 eq.) In CH ₂ Cl ₂ (0.25 M) was treated with NEt ₃ (2 eq.) Followed by BOC anhydride (1.24 eq.) And DMAP (0.21 eq.) . After stirring for 20 minutes at

At -78 ° C, the reaction mixture was treated with CH 2 Cl 2 and water. Pure desired material was obtained in 97% yield by trituration with hexane.

Step 3

The material from the previous step (1 eq.) In THF (0.3 M) was mixed with pyridine (excess) and pyridine hydrofluoride (excess) at 0 ° C. The reaction mixture was stirred at 25 ° C for 1.5 hours. Treatment with EtOAc / water followed by chromatographic purification gave the desired alcohol in 86% yield.

Step 4

The alcohol from Step 3 (1 eq) in CH ₂ Cl ₂ (0.4 M) was treated with 2,6-lutidine (2.5 eq) followed by SOCl 2 (1.2 eq). After 30 minutes at 25 ° C, the reaction mixture was treated with EtOAc and water. The crude product was purified by chromatography and trituration with hexane to give the corresponding chloride in 75% yield.

Step 5

A mixture of the material from the previous step (1 eq), 325 mesh K ₂ CO ₃ (2.4 eq), b-naphthol (1.2 eq) and KI (1.2 eq) in CH ₃ CN (0 (3 M) was heated to reflux for 2 hours. Treatment with EtOAc / water followed by trituration in hexane / EtOAc and chromatography of the mother liquor gave 70% of the expected ether.

Step 6

A solution of NaOMe in MeOH was prepared by dissolving Na (3 eq) in MeOH (0.2 M). The product of Step 5 (1 eq) in THF (0.04 M) was added and the reaction mixture was stirred at 25 ° C for 3 hours. Treatment with EtOAc / water followed by trituration with hexane / EtOAc gave the indole compound in 93% yield.

Step 7

A solution of the product of Step 6 (1 eq.) In dry DMF) was treated with NaH (60% in mineral oil, 1.1 eq.) After 1 hour, methyl 4-bromobutyrate (1.2 eq.) And KI were added. (1.2 eq.) And the reaction mixture was stirred at 75 ° C for 3 hours. the action

A mixture of EtOAc / water followed by chromatographic purification gave the desired ester in 96% yield.

Step 8

The material from step 7 (1 eq.) Was hydrolyzed by LiOH.H 2 O (1.2 eq.) In THF / MeOH / water (3/1/1, 0.2 M). After stirring at 25 ° C for 2 hours, the reaction was quenched with 1N HCl and the reaction mixture was extracted with EtOAc and CH 2 Cl 2. The organic extracts were combined, washed with water, dried and concentrated. The crude material was purified by trituration in hexane / EtOAc to give the title compound in 86% yield.

Example 67

3 - [(4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1,7-indol-1-yl} butanoyl) amino] benzoic acid

Step 1

The product of Example 66 (1 eq) was treated with EDCI (1.37 eq) and methyl 3-aminobenzoate (1.05 eq) in DMF (0.09 M) in the presence of DMAP (0.2 eq). The reaction mixture was stirred at 25 ° C for 1.5 hours. Treatment with EtOAc / water followed by flash chromatography gave the desired amine in 81% yield.

Step 2

In an analogous manner to step 2 of Example 66, 98% of the title compound was obtained after purification by trituration in hexane / EtOac.

Example 68

4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} - / V- [3 - ({[(trifluoromethyl) sulfonyl] amino} carbonyl ) phenyl] butanamide

-80Step 1

Following the procedure of Step 1 of Example 67 and using the acid of Example 67 and the appropriate sulfonamide overnight and analogous work-up gave the desired product. Trituration with hexane / EtOAc gave 100% of the title compound.

Example 69

4 - [(4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) amino] benzoic acid

Step 1

The method of Step 1 of Example 67 using the acid of Example 66 and the appropriate aniline yielded a 76% yield of the expected amide.

Step 2

In analogy to Example 67, Step 2, 78% of the title compound is obtained after purification by trituration in hexane / EtOAc.

Example 70

2 - [(4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) amino] benzoic acid

Step 1

The procedure of Example 67 Cork and using the acid of Example 66 and the appropriate aniline yielded 36% of the expected amide after chromatography.

Step 2

In an analogous manner to Example 67, Step 2, 67% of the title compound was obtained after purification by trituration in hexane / EtOAc.

-81 Example 71

3 - [(4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) amino] propanoic acid

Step 1

The method of Example 67 step 1 and using the acid of Example 66 and the appropriate aniline gave 96% of the expected amide after chromatography.

Step 2

In analogy to Example 67, Step 2, 90% of the title compound was obtained after purification by trituration in hexane / EtOAc.

Example 72

3 - [(4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) amino] propanoic acid

The method of Example 67 step 1 and the acid of Example 66 and the appropriate sulfonamide gave 100% of the title compound.

Example 73

A / - (4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) -2metylbenzénsulfónamid

Following the procedure of Example 67 Step 1 and using the acid of Example 66 and the appropriate sulfonamide, 80% of the title compound was obtained after chromatography.

Example 74

5- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} pentanoic acid

-82Step 1

A solution of the product of Step 6 of Example 66 (1 eq.) In dry DMF (0.1 M) was treated with NaH (60% in mineral oil, 1.1 eq.). After 1 hour, ethyl 4-bromopentanoate (1.2 eq) and KI (1.2 eq) were added and the reaction mixture was stirred at 75 ° C for 2 hours. Treatment with EtOAc / water followed by chromatographic purification gave 92% of the desired ester.

Step 2

The material from Step 1 (1 eq.) Was hydrolyzed with LiOH.H ₂ O (1.3 eq.) In THF / MeOH / water (3/1/1, 0.2 M). After stirring at 25 ° C for 3.5 hours, the reaction was quenched with 1N HCl and the reaction mixture was extracted with EtOAc and CH ₂ Cl ₂ . The organic extracts were combined, washed, dried and concentrated. The crude material was purified by trituration in hexane / EtOAc to give the title compound in 95% yield.

Example 75

3 - [(5- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl] pentanoyl) amino] benzoic acid

Step 1

The acid of Example 74 (1 eq) was treated with EDCI (1.37 eq) and methyl 3-aminobenzoate (1.05 eq) in DMF (0.09 M) in the presence of DMAP (0.2 eq). The reaction mixture was stirred at 25 ° C for 2.5 hours. Treatment with EtOAc / water followed by chromatography gave the desired amide in 78% yield.

Step 2

In analogy to Example 74, Step 2, 83% of the title compound was obtained after trituration in hexane / EtOAc.

-83Example 76

5- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1 / - / - indol-1-yl} - / V- [3 - ({[trifluoromethyl) sulfonyl] amino } carbonyl) phenyl] pentanamide

Step I.

Following the procedure of Example 68, Step 1, using the acid of Example 75 and the appropriate sulfonamide, 83% of the title compound was obtained after an overnight reaction and work-up analogously.

Example 77

2- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} acetic acid

Step I.

The method of Example 74 Step 1 gave 80% of the expected amide using the appropriate bromide after chromatography.

Step 2

In analogy to Example 74, Step 2, 70% of the title compound was obtained after trituration in hexane / EtOAc.

Example 78

(E) -4- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} -2-butenoic acid

Step 1

The method of Example 74 Step 1 gave 33% of the expected amide using the appropriate bromide after chromatography.

Step 2

In analogy to Example 74, Step 2, 70% of the title compound was obtained after trituration in hexane / EtOAc.

-84Example 79

3 - ({3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} methyl) benzoic acid

Step 1

The method of Example 74, Step 1, gave 75% of the expected amide using the appropriate bromide after chromatography.

Step 2

In analogy to Example 74, Step 2, 92% of the title compound was obtained after trituration in hexane / EtOAc.

Example 80

1- {1- [4- (1,3-Benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) 2 - [(2-naphthylsulfanyl) methyl] -1H-indol-3-yl} -1- ethanone

Step 1

The thioether from step 6 of Example 62 was dissolved in methylene chloride (0.12 M) and treated under nitrogen at 0 ° C with magnesium bromide (1.1 eq) and stirred at 0 to 25 ° C for 1 hour . The mixture was cooled to 0 ° C and acetyl chloride (1.17 eq) was added. After 1 hour at 0 ° C, the reaction was quenched by the addition of semi-saturated ammonium chloride solution and the reaction mixture was treated with methylene chloride. Chromatographic purification gave pure product (37%) ·

Step 2

Following the procedure of Example 81 Step 1 and using p-toluoyl chloride, the corresponding para-amide was obtained.

Step 3

By the method of step 2 of Example 81 and using the product of step 1 above, the desired product was obtained.

-85Krok4

By the method of step 3 of Example 81 and using the material of step 3, the desired benzyl bromide was obtained.

Step 5

By the method of step 4 of Example 81, the material of step 4 was coupled with the material of step 1 to give the title compound.

Example 81

1- {1- [4- (1,3-Benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-3-yl} -1 -ethanone

Step 1 m-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethylamine hydrochloride (1.1 eq) dissolved in methylene chloride at 0 ° C for 20 minutes. The reaction mixture was allowed to warm to 25 ° C. After stirring at 25 ° C for 1 day, it was treated with methylene chloride and water to give the crude product in approximately 100% yield.

Step 2

Under anhydrous conditions, the benzothiazole was dissolved in THF (0.35 M). BuLi (1.1 eq) was added at -78 ° C. After 1 hour at -78 ° C, the amide from step 1 in THF was added over 15 min. The reaction mixture was allowed to warm to 25 ° C. After stirring at 25 ° C for 1 day, work-up with ethyl acetate and water and chromatography gave pure tolylketone product (52%).

Step 3

The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0.19 M) and NBS (1.2 eq) and AIBN (0.11 eq) were added. After 1 day at 60 ° C, approximately 1: 1 starting material and product were present. Repeating the procedure under the same conditions, followed by filtration and recrystallization from ethyl acetate, afforded the bromobenzyl ketone product (28%).

-86Krok4

The indole from step 1 of Example 80 was dissolved in dry DMF (0.04 M) followed by NaH (1.25 eq). After 45 minutes at 25 ° C, the bromobenzyl ketone from step 3 (1.25 eq.) Was added and stirred for 1 hour at 25 ° C. Workup, chromatography and recrystallization from ethyl acetate / hexanes gave pure the title compound (45%).

Example 82

2- [3 - ({3-Acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoyl] -1,3-benzothiazole-6- carboxylic acid

Step 1

Ethyl 4-aminobenzoate was dissolved in 95% HOAc / water (0.4 M) and treated at 25 ° C with sodium thiocyanate (4.1 eq) and stirred at 25 ° C. ° C 20 minutes. The mixture was cooled to 5 ° C and bromine (1.17 eq) in 95% v / v HOAc / water was added. After 1 hour at 0 ° C, the reaction mixture was quenched by addition of water and filtered. Treatment with ethyl acetate and sodium bicarbonate solution gave 81% pure thiocyanate product.

Step 2

The arylthiocyanate of step 1 was treated with sodium sulfide nonahydrate dissolved in water (1.2 eq, 1.3 M) and the mixture was heated at reflux for 45 minutes. The cooled mixture was filtered, acidified to pH 6 with HOAc, extracted with ethyl acetate and concentrated to give the thiophenol product (91%).

Step 3

The thiophenol from step 2 was dissolved in 90% (v / v) HCOOH / water (3.3 M) and zinc powder was added as a catalyst. After 3 hours reflux and treatment with ethyl acetate and an alkaline compound, pure benzothiazole ester (60%) was formed.

-87Step 4

Benzothiazole ester (step 3) was dissolved in THF / methanol / water (8: 3: 3), (0.34 M), lithium hydroxide (2 eq) was added, and the mixture was stirred for 2 hours at 25 ° C. Treatment with ethyl acetate / aqueous acid gave pure benzothiazolic acid (100%).

Step 5

Under anhydrous conditions, the benzothiazolic acid (step 4) was dissolved in THF (0.052 M). BuLi (2.2 eq) was added at -78 ° C. After 1 hour, the amide (1.28 eq.) From step 1 of Example 81 in THF was added at -78 ° C to 0 ° C over 5 minutes. After 0.5 h at -78 ° C, the reaction mixture was allowed to warm to 25 ° C. After stirring at 25 ° C for 2 hours, treatment with ethyl acetate and water and chromatography gave pure tolylketonic acid (64%).

Step 6

The tolylketonic acid from step 5 was suspended in a 1: 1 mixture of THF / ethanol (0.075 M) and concentrated sulfuric acid (excess) was added. After refluxing for 1 day, treatment with a solution of ethyl acetate and sodium bicarbonate and purification by chromatography gave pure tolylketone ester (69%).

Step 7

The tolyl ketone ester from step 6 was dissolved in carbon tetrachloride (0.05 M) and NBS (1.2 eq) and AIBN (0.15 eq) were added. After 1.25 hours at reflux, additional amounts of NBS (0.3 eq) and AIBN (0.07 eq) were added. Filtration and recrystallization from ethyl acetate gave pure bromobenzyl ketone product (22%).

Step 8

The indole from step 1 of Example 80 was dissolved in dry DMF (0.06 M), and then NaH (1.11 eq) was added. After 45 minutes at 25 ° C, the bromobenzyl ketone from step 7 above (1.25 eq) was added and stirred for 1 hour at 25 ° C. Workup gave the crude ester used in the next step.

-88Step 9

The crude ester from step 8 was dissolved in THF / methanol / water (8: 2: 2), (0.013 M), lithium hydroxide (4.3 eq.) Was added portionwise, and the mixture was stirred for 3 to 4 days. at 25 ° C. Treatment with ethyl acetate / aqueous HCl and purification by chromatography gave pure benzothiazolic acid (31%).

Example 83

5- {3-Benzoyl-5- (benzyloxy) 2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} -2-oxopentanoic acid

Step 1

The indole from step 6 of Example 66 was dissolved in dry DMF (0.17 M), and NaH (1.2 eq) was added. After 1.5 hours at 25 ° C, 3-iodo-1-chloropropane was added and the mixture was stirred for 4 hours at 25 ° C. Treatment with ethyl acetate / hexanes gave the product in 89% yield.

Step 2

The alkyl chloride of step 1 was dissolved in methyl ethyl ketone (0.036 M), and NaI (1.6 eq) was added. After stirring for 1 day under reflux in the dark, treatment with ethyl acetate / water gave the iodide product in 97% yield.

Step 3

NaH (1.0 eq) was weighed into a dry flask under nitrogen and dry benzene (0.14 M) was added. At 0 ° C, dry DMF (0.4 M), ethyl 2-carboxy-1,3-dithiane (1.0 eq.) And iodide from step 2 (1.0 eq.) Were charged to another dry flask. . This DMF solution was then added to the benzene suspension at 0 ° C and the mixture was allowed to warm to 25 ° C and stirred for 3 hours at 25 ° C. Treatment with ethyl acetate / water and chromatography gave the dithianyl ester in 54% yield.

Step 4

Silver nitrate (4.5 eq.) And NCS (4.0 eq.) Were dissolved in a 4: 1 (v / v) acetonitrile / water (approximately 0.04 M) solution and a solution was added at 25 ° C.

Of the 89-dithianyl ester of step 3 (1 eq) in acetonitrile (0.03 M). After stirring for 5 minutes at 25 ° C, sodium sulfite solution was added, followed by sodium carbonate solution for one minute. Treatment with ethyl acetate / water and chromatography gave the ketoester in 17% yield.

Step 5

The ketoester of step 4 was dissolved in THF / water (8: 1), (0.03 M), lithium hydroxide (1.5 eq) was added, and the mixture was stirred for 2 hours at 25 ° C. Treatment with ethyl acetate / aqueous HCl and purification by chromatography gave pure keto acid (64%).

Example 84

3 - [(5- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} -2-oxopentanoyl) amino] bezoic acid

Step 1

The dithianyl ester from step 3 of Example 83 was dissolved in THF / ethanol / water (5: 2: 2) (0.008 M) and lithium hydroxide (11 eq) was added and the mixture was stirred for 1 day at 50 ° C. Treatment with ethyl acetate / aqueous HCl and chromatography gave pure dithianylic acid (90%).

Step 2

The dithianylic acid from step 1 was dissolved in dry methylene chloride (0.08 M) and DMF (as a catalyst). Oxalyl chloride (1.2 eq) was added and the reaction mixture was stirred at 25 ° C for 0.5 hours. Concentration was followed by redissolution in dry methylene chloride and addition of methyl 3-aminobenzoate (1.05 eq) and triethylamine (1.0 eq) at 0 ° C. The reaction mixture was warmed to 25 ° C and stirred there for 3 hours. Treatment with ethyl acetate / aqueous acid and purification by chromatography gave the dithianyl ester in 89% yield.

-90Step 3

The dithianyl ester from step 2 was dissolved in THF / methanol / water (6: 4: 3) (0.02 M) and lithium hydroxide (4.3 eq) was added and the mixture was stirred for 3 hours at 25 ° C. Treatment with ethyl acetate / aqueous HCl gave dithianylic acid (R = 3-COOH) (91%).

Step 4

Silver nitrate (4.6 eq.) And NCS (0.4 eq.) Were dissolved in a 4: 1 mixture (v / v) of acetonitrile / water (about 0.03 M) and a solution of dithianylic acid was added at 25 ° C. from step 3 (1 eq.) in acetonitrile (0.009 M). After stirring for 10 minutes at 25 ° C, sodium sulfite solution was added, followed by sodium carbonate solution for one minute. Treatment with ethyl acetate / aqueous acid and chromatography gave the title compound in 82% yield.

Example 85

4 - [(5- {3-Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} -2-oxopentanoyl) amino] benzoic acid

Step 1

The dithianylic acid from Step 1 of Example 84 was treated as in Step 2 of Example 84 except that ethyl 4-aminobenzoate was used. Purification by chromatography afforded the dithianyl ester (R = 4-COOC ₂ H ₅ ) in 30% yield.

Step 2

The dithianyl ester of step 1 was treated according to the procedure of step 3 of Example 84. Purification by chromatography gave dithianylic acid (R = 4-COOH) in 89% yield.

Step 3

The dithianyl of step 2 was treated according to the method of step 4 of Example 84. Repeated purification by chromatography followed by trituration in pentane afforded the title compound in 30% yield.

-91 Example 86

Table I shows data on the compounds described in the examples above in the cPLA ₂ inhibition assays (described below). The columns of the tables show the results of the assays at IC ₅₀ values, which is the concentration of compound that inhibits 50% of the phospholipase enzyme activity in these assays. Where there is no numerical IC50. NA means that the inhibitory activity of such a compound did not appear in the respective assay and an empty box means that the compound was not tested by this assay at the time of filing this patent application.

Activity tests

(a) Blister test

1-Palmytoil-2- [ ¹⁴ C] arachidonylphosphotidylcholine (58 mCi / mmol) (final concentration 6 mol / l) and 1,2-dioleyolglycerol (final concentration 3 mol / l) were mixed and dried under a stream of nitrogen. 50 mM Hepes pH 7.5 (2x final lipid concentration) was added to the lipids and the suspension was sonicated at 4 ° C for 3 minutes. To the suspension was added 50 mmol / l Hepes pH 7.5, 300 mmol / l NaCl, 2 mmol DTT, 2 mmol / l CaCl ₂ and 2 mg / ml bovine serum albumin (BSA) (Sigma A7511) (1.2x final lipid concentration). A typical test consisted of adding inhibitor (5 μΙ in DMSO) and cPLA ₂ , 10 ng for the automated system and 1 ng for the manual assay in 10 μΙ BSA buffer, respectively, to the lipid mixture (85 μΙ). This test was performed using either the manual test procedure or the automatic test both described below.

(b) Soluble substrate test (LysoPC)

1- [ ¹⁴ C] -Palmitoyl-2-hydroxyphosphotidylcholine (57 mCi / mmol) (final concentration 4.4 mol / L) was dried under a stream of nitrogen. The lipid was resuspended by vortexing 80 mM Hepes pH 7.5, 1 mM EDTA (1.2x final concentration). A typical test consisted of sequentially adding inhibitor (5 μΙ in DMSO) and cPLA ₂ to the lipid suspension (85 μΙ). 200 ng in 80 mmol / l Hepes pH 7.5, 2 mmol / l DTT and 1 mol / l EDTA.

This test was performed using either the manual test procedure or the automatic test procedure described below.

c) Automatic test

The lipid suspension and inhibitor were preincubated for 7 minutes at 37 ° C. The enzyme was added and incubation continued for a further 30 minutes. The reaction was quenched by the addition of decane / isopropanol / trifluoroacetic acid (192: 8: 1 w / v), 150 L). A portion of the quenched mixture (50 L) was passed through a Rainin Spheric-5 silica gel column (5, 30 x 2.1 mm) eluting with heptane / methanol / TFA (97: 3: 0.1 v / v). The [ ¹⁴ C] -arachidonic acid level was analyzed using a Radiomatic Flo-One / Beta linear counter (Packard).

d) Manual test

The mixture of lipid, inhibitor and enzyme was incubated at 37 ° C for 30 minutes. The reaction was quenched by the addition of heptane / isopropanol / 0.5 mmol / L sulfuric acid (105: 20: 1 v / v, 200 L). Half of the quenched mixture was applied to a disposable silica gel column (Whatman SIL, 1 mL) placed under a scintillation vessel in vacuo. The free [ ¹⁴ C] -arachidonic acid was eluted by addition of ethyl ether (1 mL). The level of radioactivity was measured using a liquid scintillation counter.

(e) PMN test

PMN-γ were isolated using Ficoll-Hypaque as described. Red blood cells contaminating PMN-γ were removed by hypotonic lysis, and the PMN pellet was washed once and resuspended in Hanks saline buffer at a concentration of 2 x 10 6 cells / ml. Cells were preincubated with inhibitors for 15 minutes at 37 ° C and then stimulated with 2 pmol / L of A23187. When LTB ₄ production appeared as a measure of CPLA2 inhibition, the reaction was quenched with an equal volume of ice-cold phosphate buffered saline. Cells were removed by centrifugation and LTB ₄ present in the cell supernatant was measured using the LTB ₄ scintillation proximation assay provided by Amersham according to the protocol. LTB ₄ was measured in the tests listed in the tables below. When arachidonic acid production occurred, the reaction was quenched with methanol containing D8-arachidonic acid as internal

-93štandard. Lipids were extracted by the method of Bligh et al. ((1959) Can. J. Biochem. Physiol., 37, 911-917) and fatty acids were converted to pentafluorobenzyl ester and analyzed by GC-MS in a manner similar to that described in Ramesha and Taylor ((1991) Anal. Biochem. 192, 173-180.

f) RBL test

RBL-2H3 cells were cultured in a conventional manner at 37 ° C in an atmosphere of 5% CO ₂ in minimally essential medium containing non-essential amino acids and 12% fetal calf serum. The day before the experiment, cells were seeded in flasks at a density of 3 x 10 ⁵ cells / ml and 100 ng / ml specific-IgE DNP was added. After 20 hours, cells were harvested by centrifugation and washed once in serum-free minimal essential medium and resuspended at 2 x 10 ⁶ cells / ml in serum-free medium. Cells were then preincubated with either inhibitor in DMSO (1% v / v) or DMSO (1% v / v) for 15 minutes at 37 ° C, followed by stimulation with DNP-BSA (300 ng / ml). After 6 minutes, cells were removed by centrifugation and the supernatant was assayed for PGD ₂ content by known methods.

g) Coumarin test

7-Hydroxycoumarin-6-heptenoate was used as the monomeric substrate for cPLA ₂ as described above (Huang, Z. et al., 1994, Analytical Biochemistry 222, 110-115). The inhibitors were mixed with 200 µL of assay buffer (80 mmol / l Hepes, pH 7.5, 1 mmol / l EDTA) containing 60 µl of β 7-hydroxycoumarinyl-6-heptenoate. The reaction was initiated by the addition of 4 µg cPLA ₂ in 50 µL assay buffer. Hydrolysis of the 7-hydroxycoumarinyl-6-heptenoate ester was monitored in a fluorometer by excitation at 360 nm and emission monitoring at 460 nm. The enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of a cPLA ₂ inhibitor, the rate of increase is less.

Example 87

The compounds of the invention were also tested for in vivo activity in the rat paw edema assay as described below. The results are shown in Table II.

-94 Carrageenan-induced paw edema test

The individual substances were suspended in 0.3 ml absolute ethanol, 0.1 ml

Tween-80 and 2.0 ml Dulbecco's PBS (without calcium or magnesium). To this mixture was added 0.1 mL of a 1 M NaOH solution. When dissolution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg / ml. All substances remained in solution. The compounds were administered intravenously in a volume of 5 ml / kg to male Sprague Dawley rats at the same time as edema was induced by injecting 0.05 ml of a 1% w / w type carrageenan solution into the hindpaw. Paw volume was measured before compound administration and 3 hours after carrageenan administration.

All patents and literature are incorporated herein by reference, as if fully explained herein.

Claims (105)

PATENT CLAIMS A phospholipase enzyme inhibitor of the general formula wherein R ¹ and R ¹ 'are independently selected from H, halogen, -CF 3, -OH, -C 1 -C 10 alkyl, preferably C 1 -C ₆ alkyl, -S-C 1 -C ₆ alkyl, preferably -S-C 1 -C ₆ alkyl, C 1 -C ₁₀ alkoxy , preferably C Cealkoxylu _r, -CN, -NO 2, -NH 2, -NH (C 1 -C 6), -N (C 1 -C 6) 2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or groups of formulas: R ⁶ R ⁶ is selected from H, C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, phenyl, -O-phenyl, benzyl, -Obenzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 C ₆ alkyl, C ₁ -C ₆ alkoxy, -NO 2, -NH 2, -CN, -CF _3, or -OH; -96R ⁷ is selected from -OH, -CF 3, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH- (C 1 -C 6 alkyl), -N- (C 1 -C 6 alkyl) 2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, wherein the rings of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, -CN, C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, -ΝΟ ₂ , -NH ₂ , -CF 3, or -OH; R ² is selected from H, halogen, -CF ₃ -OH, -C 1 -C ₁₀ alkyl, preferably -C 1 -C ₆ alkyl, C 1 -C ₁₀ alkoxy, preferably C 1 -C ₆ alkoxy, -CHO, -CN, -NO ₂₁ -NH ₂ , -NHC 1 - C ₆ alkyl, -N (C ₁ -C ₆ alkyl) ₂ , -N-SO ₂ -C 1 -C 6 alkyl or -SO ₂ -C 1 -C ₆ alkyl; R ³ is selected from H, -CF ₃ , C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy, C ₃ C ₁ -Cycloalkyl, -C 1 -C 6 alkyl-C ₃ -Ciocycloalkyl, -CHO, halogen or a group of formula -L ² - M ² , where L ² represents a linking and bridging group of the formula - (CH ₂ ) _n -, -S-, -O-, -C (O) -, - (CH ₂ ) n C (O) -, - (CH ₂ ) n C (O ) - (CH ₂₎ n - (CH ₂₎ n O- _(CH2) n- or - (CH _{2) n} -S- (CH _{2) n} -, -C (O) C (O) X, wherein X = O, N; M ² is selected from C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy, C ₃ -C ₁₀ cycloalkyl, phenyl or benzyl, wherein the cycloalkyl, phenyl or benzyl ring may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 10 alkyl, preferably C 1 -C ₆ alkyl, C 1 -C ₁₀ alkoxy, preferably C 1 -C ₆ alkoxy, -NO ₂ , -NH ₂ , -CN or -CF ₃ ; or a) a five membered heterocyclic ring containing one or two heteroatoms selected from N, S or O, including but not limited to furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine or tetrazole, wherein the five membered heterocyclic ring may be optionally substituted with 1 to 3 substituents selected from halogen, C ₁ -C ₁₀ alkyl, preferably C ₁ -C ₆ alkyl, C ₁ -C ₁₀ alkoxy, preferably C ₁ -C ₆ alkoxy, -NO ₂ , -NH ₂ , -CN or -CF ₃ ; or b) a six membered heterocyclic ring containing one, two or three heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrimidine, piperidine, piperazine or morpholine, wherein the six membered heterocyclic ring may be optionally substituted with 1 to 3 substituents selected from halogen, C ₁ -C ₁₀ alkyl, preferably C ₁ -C ₆ alkyl, C ₁ -C ₁₀ alkoxy, preferably C ₁ -C ₆ alkoxy, -CHO, -NO ₂ , -NH ₂ , -CN, -CF _3, or -OH; or (97c) a bicyclic ring group having 8 to 10 atoms, preferably containing 1 to 3 heteroatoms selected from N, S or O, including but not limited to benzofuran, indole, indoline, naphthalene, purine, or quinoline, wherein the bicyclic ring group may be optionally substituted by 1 to 3 substituents selected from halogen, CrCwalkylu preferably CrCealkylu, CRCI ₀ alkoxy, preferably C _r C ₆ alkoxy, -CHO, _{-NO2, -NH2,} -CN, _-CF3 or-OH; n is an integer from 0 to 3; R ⁴ is selected from -C ₆ lower alkyl, -C ₆ lower alkoxy, - (CH _{2) n} -C ₃ Cecykloalkyl, - _(CH2) ns (CH ₂₎ n C ₃ -C5cykloalkyl, - (CH ₂₎ n O - (CH ₂ ) n C ₃ -C ₅ cycloalkyl, or groups: a) - (CH ₂ ) _n -phenyl-O-phenyl, (CH ₂ ) _n -phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n phenyl- _{(O-CH2-phenyl) 2, -CH2-phenyl-C} (O) -benzothiazole or a moiety of the formulas: / (0Η ₂₎ π \ / ^(CH2) n \ _(CH2) n \ ^ (CH) ^ (ΟΗ ₂₎ ^ _γ wherein n is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C ₃ -C ₅ cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF ₃ , -OH, -CrCealkyl, C 1 -C 6 alkoxy, -NH ₂ , -NO ₂ or a five membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O; or (b) - (CH ₂ ) _n -A, - (CH ₂ ) n -SA, or - (CH ₂ ) _n -OA, where A is a group B where -98D represents H, C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy or -CF ₃ ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF 3, -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy or - NO2; or (c) groups of formulas: wherein Z is O or S and the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, -NH 2 or -NO 2; R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, - (CH ₂₎ ) ntetrazole, θ nn X. N &quot; (C -C lower alkyl) (C _r -C ₆ -lower haloalkyl) or of the formula -L ¹ -M ^1, wherein L ¹ is a bridging or linking group selected from a chemical bond, - (ΟΗ 2) n -, -S-, -O- -C (O) -, - (CH 2) n C (O), - (CH 2) n C (O) - (CH 2) n -, - (CH 2) n O- (CH 2) n -, - (CH 2) n S (CH 2) n -, -C (Z) -N (R ⁶ ) -, -C (Z) -N (R ⁶ ) - (CH 2) _n -, -C (O) -C (Z) -N (R ⁶ ) -, -C (O) -C (Z) -N (R ⁶ ) (CH ₂ ) _n -, -C (Z) -NH-SO ₂ -, or -C (Z) -NH-SO ₂ - (CH ₂ ) _n -; M ¹ is selected from the group consisting of -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole, or -100 wherein R ⁸ , R ⁹ or R ¹⁰ may be attached at any point in the cyclic or bicyclic system, R ^8, whenever present, is independently selected from H, -COOH, - (CH 2) _n -COOH, - (CH ₂ ) n C (O) -COOH, tetrazole, O-P-OH, or -O; t> h R ⁹ is selected from H, halogen, -CF 3, -OH, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) n -C (O) COOH, -C 1 -C ₆ alkyl, -O- C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl) or -N (C 1 -C ₆ alkyl) 4 R ¹⁰ is selected from the group consisting of H, halogen, -CF 3, -OH, - (CH ₂ ) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 -C ₆ alkyl , -NH _(C-C6 alkyl), -N _(Ci-C6 alkyl) _2, (C _r C ₆ lower alkyl) (lower trickle-haloalkyl) -101 - R ⁹ rg R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, C 1 -C ₆ cycloalkyl, -CF ₃ , -COOH, - (CH ₂ ) _n COOH, - (CH ₂ ) _n -C (O) -COOH, for provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least one acid group selected from carboxylic acid, tetrazole or a group of the formula: n is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof. -1022. The phospholipase enzyme inhibitors of claim 1 having the formula wherein R ³ is hydrogen and R ¹ , R ² , R ⁴ and R ⁵ are as defined in claim 1, or a pharmaceutically acceptable salt thereof. Phospholipase enzyme inhibitors according to claim 2 of the general formula wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 2, or a pharmaceutically acceptable salt thereof. A phospholipase enzyme inhibitor according to claim 2 of the general formula wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 2, or a pharmaceutically acceptable salt thereof. 1035. Inhibitors of phospholipase enzymes of the general formula wherein R ¹ is selected from H, halogen, -CF 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ , -NH ₂ , -NH (C 1 -C ₆ ), -N (C 1 -C ₆ ) ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl, or groups of formulas: R ⁶ is selected from H, C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NH ₂ , -NO ₂ , -CF _3, or -OH; R ⁷ is selected from - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -N- (C 1 -C 6 alkyl) ₂ , - (CH ₂ ) _n -NH- (C 1 -C 6 alkyl), -CF ₃ , C 1 -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, C 1 -C ₆ alkoxy, -NH- (C 1 -C ₆ alkyl), -N- (C 1 -C 6 alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O -phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, wherein the rings of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NH ₂ , -NO ₂ , -CF _3, or - OH; -104 R ² is selected from H, halo, -CF _{3 liters} -OH, _-C-C10 alkyl, preferably -C ₆ alkyl, C _r Cwalkoxylu, preferably C Cealkoxylu, -CHO, -CN, _-NO2 , -NH ₂ , -NH-C 1 -C ₆ alkyl, -N (C 1 -C ₆ alkyl) ₂₁ -N-SO ₂ -C 1 -C ₆ alkyl or -SO ₂ -C 1 -C ₆ alkyl; R ³ is selected from the group consisting of C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, - (CH ₂ ) _n -C ₃ C ₆ cycloalkyl, - (CH ₂ ) _n -S- (CH ₂ ) _n -C ₃ -C ₆ cycloalkyl, or groups: a) - (CH ₂ ) _n -phenyl-O-phenyl, (CH ₂ ) _n -phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n phenyl- _{(O-CH2-phenyl) 2, -CH2-phenyl-C} (O) -benzothiazole or a moiety of the formulas: x _z (CH ₂ ) r T 5 JCHK (CH ₂ ) n - wherein n is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C ₃ -C ₆ cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; the rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NH ₂ , -NO _2, or a five membered heterocyclic ring containing one a heteroatom selected from N, S or O, preferably S or O; or b) groups of formulas - (CH ₂ ) _n -A, - (CH ₂ ) _n -SA, or - (CH ₂ ) _n -OA, wherein A is a group b 'wherein D represents H, C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy or -CF ₃ ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C ₆ alkoxy or -NO ₂ ; or - 105c) groups of formulas: wherein the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF 3, -OH, -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -NO ₂ ; R ⁴ is selected from H, halogen, -CF 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) benzyl, -CH ₂ - (C 3 -C 6 cycloalkyl) ), -C (O) -OH, -CH = O, -C (O) -C ₁ -C ₆ alkyl, -C (O) -O-C ₁ -C ₆ alkyl, -C (O) -CF ₃ , - (CH ₂₎ IS-CH ₂ - (C 3 -C 6 cycloalkyl) wherein the phenyl and benzyl ring of the respective R ³ group may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ , -CF 3, -C (O) - OH or -OH; n is an integer from 0 to 3; R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or -106- - 107 R ⁸ is selected from H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole, ABOUT II In ^0H or ΌΗ R ⁹ is selected from H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 - C ₆ alkyl, -NH (C 1 -C ₆ alkyl) or -N (C 1 -C ₆ alkyl) ₂ ; R ¹⁰ is selected from the group consisting of H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O- C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl), -N (C 1 -C ₆ alkyl) ₂ , Or q. .o 2s: (C1-C6-lower alkyl) q. .o S _{'(Cl-C6-lower} haloalkyl) _(Ci-C6 lower alkyl) R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n C (O) -COOH, or - 108 provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ contains at least one acid group selected from carboxylic acid, tetrazole or a group of the formula: or a pharmaceutically acceptable salt thereof. 6. Inhibitors of phospholipase enzymes of general formula R ⁴ or wherein R ¹ is selected from H, halogen, -CF 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO 2, -NH ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or groups formulas: R ⁷ R ^s NR ⁷ 'or R ⁷ > R ⁶ I R ⁶ I -N. -109 R ⁶ is selected from H, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -Obenzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C ₁ -C ₆ alkyl C _r Cealkoxylu, -NO 2, CF 3 or OH; R ⁷ is selected from - _{(CH2) n-COOH,} - _(CH2) nN- (Ci-6 alkyl) _2, - (CH ₂₎ n -NH- _(C-C6 alkyl), -CF _{3 R} C C ₆ alkyl, C ₃ -C ₅ cycloalkyl, C 1 -C ₆ alkoxy, -NH- (C ₁ -C ₆ alkyl), -N- (C 1 -C 6 alkyl) 2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, wherein the pyridinyl, phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C 6 alkoxy, -NO 2, -CF ₃ or - OH; R ² is selected from H, halogen, _-CF3, -OH, -C-C _O alkyl, preferably -C 6 alkyl, Cr C ^ alkoxy, preferably CrCealkoxylu, -CHO, -CN, -NO 2, -NH _2, -ΝΗ-C 1 -C 6 alkyl, -N (C 1 -C 6 alkyl) 2, -N-SO ₂ -C 1 -C 6 alkyl or -SO ₂ -C 1 -C ₆ alkyl; R ³ is selected from H, halogen, -CF ₃ , -OH, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) benzyl, -CH ₂ - (C ₃ -C ₅ cycloalkyl), -C (O) -OH, -CH = O, -C (O) -C 1 -C ₆ alkyl, -C (O) -O-C 1 -C ₆ alkyl, - C (O) -CF ₃ - (CH ₂ ) _n -S-CH ₂ - (C ₃ -C ₅ cycloalkyl), or wherein the phenyl and benzyl ring of the respective R ³ group may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -CF ₃ -C (O) -OH or -OH; n is an integer from 0 to 3; R ⁴ is selected from the group consisting of C 1 -C 6 lower alkyl, C 1 -C 8 lower alkoxy, - (CH ₂ ) n C ₃ C ₅ cycloalkyl, - (CH ₂ ) _n -S- (CH ₂ ) n C ₃ -C ₅ cycloalkyl, - ( CH ₂ ) n O- (CH ₂ ) _n -C ₃ -C ₅ cycloalkyl or groups: a) - (CH ₂ ) _n -phenyl-O-phenyl, (CH ₂ ) _n -phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n phenyl- _{(O-CH2-phenyl) 2, -CH2-phenyl-C} (O) -benzothiazole or a moiety of the formulas: -110ο • Υ Ό (CH3) (CH3) ^ (CH3) wherein η is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3 -C 6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO _2, or a five membered heterocyclic ring containing one heteroatom selected from N , S or O, preferably S or O; b) groups of the formulas - _(CH2) "- A, - (CH _{2) n} -SA, or - (CH _{2) n} -OA, wherein A is B where D represents H, C 1 -C 8 lower alkyl, C 1 -C 8 lower alkoxy or -CF ₃ ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -NO ₂ ; or (c) groups of formulas: Wherein Z is O or S and the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, -C 1 -C ₆ alkoxy, or -NO ₂ ; R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or 112- R ⁹ is selected from H, halogen, -CF 3, -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O-C 1 -C ₆ alkyl, -NH (C 1 -C 6 alkyl) or -N (C ₁ -C ₆ alkyl) 2; R ¹⁰ is selected from H, halogen, _-CF3, -OH, - (CH _{2) n} COOH, - _{(CH2) n-C} (O) -COOH _t -C ₆ alkyl, -Ο- (C 1 -C ₆ alkyl, -NH 1 -C ₆ alkyl), -N (C 1 -C ₆ alkyl) ₂ , -1130 ".0 S '' (C 1 -C ₆ -lower alkyl) (C 1 -C ₆ -lower haloalkyl) R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) n -COOH, - (CH ₂ ) _n C (O) -COOH, or provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ will contain at least one acid group selected from carboxylic acid, tetrazole or a group of the formula: W / \ _θΗ or or a pharmaceutically acceptable salt thereof. 7. Inhibitors of phospholipase enzymes of the general formula or -114 where R ¹ is selected from H, halogen, -CF ₃ , -OH, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -NH ₂ , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or groups of formulas: R ⁶ is selected from H, C 1 -C ₆ alkyl, C ₁ -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -O-benzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C _r -C ₆ alkoxy, -N0 _2, -CF _3, or -OH; R ⁷ is selected from - (CH ₂ ) n -COOH, - (CH ₂ ) _n -N- (C 1 -C ₆ alkyl) ₂ , - (CH ₂ ) _n -NH- (C 1 -C ₆ alkyl), - CF ₃ , C 1 -C ₆ alkyl, C ₃ -C ₅ cycloalkyl, C ₁ -C ₆ alkoxy, -NH- (C 1 -C ₆ alkyl), -N- (C 1 -C ₆ alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, wherein the pyridinyl, phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ , -CF ₃ or -OH; R ² is selected from H, halogen, -CF ₃ , -OH, -C 1 -C 10 alkyl, preferably -C 1 -C ₆ alkyl, C 1 -C ₁₀ alkoxy, preferably C 1 -C ₆ alkoxy, -CHO, -CN, -NO ₂ , -NH ₂ , - NH-C ₁ -C ₆ alkyl, -N (C ₁ -C ₆ alkyl) ₂ , -N-SO ₂ -C ₁ -C ₆ alkyl, or -SO ₂ -C ₁ -C ₆ alkyl; R ³ is selected from the group consisting of C ₁ -C ₆ lower alkyl, C ₁ -C ₆ lower alkoxy, - (CH ₂ ) _n -C ₃ C ₆ cycloalkyl, - (CH ₂ ) _n -S- (CH ₂ ) _n -C ₃ -C ₅ cycloalkyl, or groups: a) - (CH ₂ ) _n -phenyl-O-phenyl, (CH ₂ ) _n -phenyl-CH ₂ -phenyl, - (CH ₂ ) _n -O-phenyl-CH ₂ -phenyl, - (CH ₂ ) _n phenyl- _{(O-CH2-phenyl) 2, -CH2-phenyl-C} (O) -benzothiazole or a moiety of the formulas: -115 ο -Y ^ χ (θΗ2) σ \ ^ γ Ο Υ (CH ₂ ) rf wherein η is an integer of 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C ₃ -C ₅ cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; the rings of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF 3, -OH, -C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ or a five membered heterocyclic ring containing one heteroatom selected from N, S or O, preferably S or O; or b) groups of formulas - (CH ₂ ) _n -A, - (CH ₂ ) _n -SA, or - (CH ₂ ) _n -OA, where A is a group Dkde D represents H, C 1 -C ₆ lower alkyl, C 1 -C ₆ lower alkoxy or -CF ₃ ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl, optionally each ring may be substituted with 1 to 3, preferably 1 to 2 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy or -NO ₂ ; or (c) groups of formulas: from Wherein Z is O or S and the phenyl and pyrimidinyl ring of each group may be optionally and independently substituted with from 1 to 3 substituents selected from halogen, -CF ₃ , -OH, -C 1 -C ₆ alkyl, -C 1 -C ₆ alkoxy, or -NO ₂ ; R ⁴ is selected from H, halogen, -CF ₃ , -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) benzyl, -CH ₂ - (C ₃₎ -C ₅ cycloalkyl), -C (O) -OH, -CH = O, -C (O) -C ₁ -C ₆ alkyl, -C (O) -O-C ₁ -C ₆ alkyl, -C (O) -CF ₃ , - (CH ₂ ) n -CH ₂ - (C ₃ -C ₅ cycloalkyl), wherein the phenyl and benzyl ring of the respective R ³ group may be optionally substituted with 1 to 3 substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -NO ₂ , -CF ₃₁ -C (O) -OH or -OH; n is an integer from 0 to 3; R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or -117 - or ABOUT -118 R ⁸ is selected from H, -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, tetrazole, o -R-OH O or R ⁹ is selected from H, halogen, -CF ₃ -OH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n -C (O) -COOH, -C ₁ -C 6 alkyl, -O-C ₁ -C 6 alkyl, -NH ( (C 1 -C 6 alkyl) or -N (C 1 -C 6 alkyl) ₂ ; R ¹⁰ is selected from the group consisting of H, halogen, -CF ₃ , -OH, - (CH ₂ ) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, -O- C 1 -C ₆ alkyl, -NH (C 1 -C ₆ alkyl), -N (C 1 -C ₆ alkyl) ₂ , o x, or '(C1-C6-lower alkyl) R ¹¹ is selected from H, C 1 -C 6 lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) _n -COOH, - (CH ₂ ) _n C (O) -COOH, or provided that the complete group at the 1-position of the indole or indoline formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ will contain at least -119one acid group selected from carboxylic acid, tetrazole or a group of the formula: or a pharmaceutically acceptable salt thereof. 8. Inhibitors of phospholipase enzymes of the general formula wherein R ¹ is selected from -NH 2, -O-phenyl, benzyl, -O-benzyl, -N-benzyl, N-benzyl-phenyl, -S-benzyl or groups of formulas: -120R ^e I R ⁷ Sv or ý% O Ό R ⁶ is selected from H, C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, phenyl, O-phenyl, benzyl, -Obenzyl, wherein the phenyl and benzyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, -NO ₂ , -CF ₃ or -OH; R ⁷ is selected from - _{(CH2) n-COOH,} - _(CH2) nN- (-C ₆ alkyl) 2, - (CH _{2) n} -NH- (-C ₆ alkyl), -CF _3, CrCealkylu C C ₃ -C ₅ cycloalkyl, C ₁ -C ₆ alkoxy, -NH- (C ₁ -C ₆ alkyl), -N- (C ₁ -C ₆ alkyl) ₂ , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, the rings of these groups may be optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ , -CF _3, or -OH; n is an integer from 0 to 3; R ³ is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -CF ₃ , -CH = O, -C (O) -C 1 -C ₆ alkyl, -C (O) -O-C ₁ -C ₆ alkyl, -C (O) -OH, - C (O) -CF ₃ , -C (O) -phenyl, -C (O) -benzyl, -C (O) -pyrrolyl, -C (O) -thienyl, -C (O) -furanyl or -C (O) morpholinyl; R ⁴ is selected from - (CH ₂₎ n C ₃ -Cecykloalkyl, - (CH _{2) n} -S- (CH _{2) n} -C ₃ Cecykloalkyl, - (CH ₂₎ n O- (CH ₂₎ n C ₃ - C 6 cycloalkyl, - (CH ₂ ) _n -S-C ₁ -C 6 alkyl or groups: a) -C (O) -O- (CH ₂ ) n C ₃ -C ₅ cycloalkyl, - (CH ₂ ) _n -phenyl, - (CH ₂ ) _n -O-phenyl, - (CH ₂ ) _n -S- phenyl, - (CH _{2) n} -S- (CH ₂₎ n -phenyl, - _(CH2) "- phenyl-O-phenyl, _{(CH2) n-phenyl-CH2-phenyl,} - _(CH2) -Ophenyl _{n-CH2-phenyl,} - _(CH2) "- phenyl- _{(O-CH2-phenyl) 2,} -C (O) -phenyl, -C (O) -O-benzyl, -C (O -Opyridinyl, -C (O) -O-naphthyl, - (CH ₂ ) _n -S-naphthyl, - (CH ₂ ) _n -S-pyridinyl, - (CH ₂ ) _n -pyridinyl, or - (CH ₂ ) _n -naphthyl, - (CH ₂ ) _n -O-naphthyl, wherein the phenyl, pyridinyl and naphthyl ring of these groups may be optionally substituted with 1 to 3 substituents selected from H, halogen, -CF ₃ , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ or a five membered heterocyclic ring containing one heteroatom selected from N, S or O, preferably S or O; or b) groups of formulas - (CH ₂ ) _n -A, - (CH ₂ ) _n -SA, or - (CH ₂ ) _n -OA, where A is a group -121 - where D represents H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy or -CF ₃ ; R ⁵ is selected from -COOH, -C (O) -COOH, - (CH ₂ ) _n -C (O) -COOH, - (CH ₂ ) _n -COOH, -CH = CH-COOH, or -122 - R ⁹ is selected from H, halogen, -CF 3, -OH, - (CH 2) _n -COOH, - (ΟΗ 2) _Π -Ο (O) -ΟΟΟΗ, -C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -NH ₍ C ₁ -C ₆ alkyl) or -N (C ₁ -C ₆ alkyl) 2; R ¹⁰ is selected from the group consisting of H, halogen, -CF 3, -OH, - (CH 2) _n COOH, - (CH ₂ ) _n -C (O) -COOH, -C 1 -C ₆ alkyl, alkyl) ₂ , -O-C Cealkylu, -NH (C 1 -C ₆ alkyl), -N (C ₁ -C ₆ - (C 1 -C ₆ lower haloalkyl) or N (C 1 -C 6 -alkyl) -123R ¹¹ is selected from H, C 1 -C ₆ lower alkyl, -CF ₃ , -COOH, - (CH ₂ ) n -COOH, - (CH ₂ ) _n C (O) -COOH, or provided that the complete the indole or indoline position in position 1 formed by any combination of R ⁵ , R ⁸ , R ⁹ , R ¹⁰ and / or R ¹¹ will contain at least one acid group selected from carboxylic acid, tetrazole or a group of the formula: or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1, which is 4 - ({3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(phenethylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid or a pharmaceutical thereof acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 4 [(3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - {[(2-furylmethyl) sulfanyl] methyl} -1H-indol-1-yl (methyl) benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 [(3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - {[(4-hydroxy-6-phenyl-2-pyrimidinyl) sulfanyl] methyl} - 1- (7-indol-1-yl) methyl] benzoic acid or a pharmaceutically acceptable salt thereof. 12412. A phospholipase enzyme inhibitor according to claim 1 which is 4 {[3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - ({[4- (2-thienyl) -2-pyrimidinyl] sulfanyl} methyl) -1 H -indol-1-yl] methyl} benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 ({3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2,4-dibromophenoxy) methyl] -1H-indol-1yl} methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1, which is 4 ({3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(cyclopentylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid or a benzoic acid thereof. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 4 ({3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(propylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid or a benzoic acid thereof. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 4 ({2 - {[4- (tert-butyl) phenoxy] methyl} -3-chloro-5 - [(cyclopentylcarbonyl) amino] -1 H -indole acid. 1-yl} methyl) benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 ({3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2-quinolinylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 [(3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - {[(cyclopropylmethyl) sulfanyl] methyl} -1Hindol-1-yl) methyl] benzoic acid or a benzoic acid thereof. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 4 ({2 - [(benzhydrylsulfanyl) methyl] -3-chloro-5 - [(cyclopentylcarbonyl) amino] -1 H -indol-1yl} methyl) benzoic acid or a pharmaceutically acceptable salt thereof. -125 The phospholipase enzyme inhibitor of claim 1 which is 4 ({5 - [(3-carboxypropanoyl) amino] -3-chloro-2 - [(phenethylsulfanyl) methyl] -1H-indol-1-yl] methyl] benzoic acid or a pharmaceutically acceptable salt thereof. salt. The phospholipase enzyme inhibitor according to claim 1, which is 4 [(5 - [(3-carboxypropanoyl) amino] -3-chloro-2 - {[(3-methylbenzyl) sulfanyl] methyl] -1 H -indol-1-yl] methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 ({2 - ({[4- (tert-butyl) benzyl] sulfanyl) methyl) -5 - [(3-carboxypropanoyl) amino] -3-chloro-1H-indole- 1-yl} methyl) benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1 which is 4 ({3-chloro-5- (3-furoylamino) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoic acid. or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 ({5- (acetylamino) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl] methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 ({3-chloro-5 - {[3- (diethylamino) propanoyl] amino} -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl] methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 ({3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-thienylcarbonyl) amino] -1 H -indol-1-yl] methyl benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1, which is 4 ({5 - {[(benzylamino) carbonyl] amino) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-ylmethylbenzoic acid or a pharmaceutically acceptable salt thereof. salt. -126 The phospholipase enzyme inhibitor of claim 1 which is 4 ({5 - {[(butylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1yl} methyl) benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 3 [({1- (4-carboxybenzyl) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-5-yl} amino) carbonyl or benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1 which is 4 {[5- (benzyloxy) -2 - [(E) -2-carboxyethenyl] -3- (2-naphthoyl) -1 H -indole-1- yl] methyl} -benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1 which is 4 {{3-acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1 H -indol-1-yl} methyl} benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {[5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -3- (2,2,2-trifluoroacetyl) -1 H -indole- 1-yl] methyl} -benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{5 - [(4-aminobutanoyl) amino)] - 3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1 H -indole-1 -yl} methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid or a benzoic acid inhibitor thereof. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor according to claim 1 which is 4 {{3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(2-quinoxalinylcarbonyl) amino] -1 H -indol-1yl} acid. methyl} benzoic acid or a pharmaceutically acceptable salt thereof. -12736. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-5 - [(2,2-dimethylpropanolyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{5 - {[(benzyloxy) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl i-benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-5 - {[(cyclopentyloxy) carbonyl] amino} -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1 which is 4 {{5- (acetylamino) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid or a pharmaceutical thereof acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 4 {{5 - {[(butylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl i-benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{5 - {[(butylamino) carbonyl] amino} -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl i-benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-5 - [(morpholinocarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1 H -indol-1-yl} acid. methyl i-benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{5- (benzylamino) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid or a pharmaceutical thereof acceptable salt. - 128 The phospholipase enzyme inhibitor according to claim 1, which is 4 {{3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-phenoxybenzyl) amino] -1H-indol-1-yl} methyl i-benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -1 H -indol-1-yl] methyl] benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{5- [acetyl- (benzyl) amino] -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl] benzoic acid. or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(tetrahydro-3-furanylcarbonyl) amino] -1Hindol-1-yl} methyl} benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {{3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-thienylcarbonyl) amino] -1H-indol-1-yl} methyl i-benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1 which is 4 {{3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(1-adamantylcarbonyl) amino] -1 H -indole-1- or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 3 {{[[1- (4-carboxybenzyl) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-5-yl] amino} carbonyl] benzoic acid. or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1, which is 4 {{3-chloro-2 - [(2-naphthylsulfanyl) methyl] -5 - [(3-phenylpropanoyl) amino] -1H-indol-1-yl} methyl] benzoic acid. or a pharmaceutically acceptable salt thereof. -129 The phospholipase enzyme inhibitor of claim 1 which is 4 {{5-amino-3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl} -benzoic acid or a pharmaceutically acceptable salt thereof. salt. 53. The phospholipase enzyme inhibitor of claim 1 which is N- {3-chloro-1 {4 - {[(methylsulfonyl) amino] carbonyl} benzyl} -2 - [(2-naphthylsulfanyl) methyl] -1H-indole- 5-ylcyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. A phospholipase enzyme inhibitor according to claim 1 which is N- {3-chloro-2 [(2-naphthylsulfanyl) methyl] -1- [4 - {{[(4-nitrophenyl) sulfonyl] amino} carbonyl} -benzyl 1-1Hindol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 55. The phospholipase enzyme inhibitor according to claim 1, which is N- {3-chloro-1- [4 - {{[(2-methylphenyl) sulfonyl] amino} carbonyl} benzyl] -2 - [(2-naphthylsulfanyl). (methyl) -1H-indol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1, which is N - {3-chloro-2 [(2-naphthylsulfanyl) methyl] -1- [4 - [[(phenylsulfonyl) amino] carbonyl] benzyl] -1H-indole- 5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. A phospholipase enzyme inhibitor according to claim 1 which is N - {3-chloro-2 [(2-naphthylsulfanyl) methyl] -1- [4 - {[[(trifluoromethyl) sulfonyl] amino] carbonyl} -benzyl] - 1Hindol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1, which is 4 {5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1 H -indole- 1-yl} butane or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 {5 - [(cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2 - [(2-naphthyloxy) methyl] -1Hindol-1-yl} butanoic acid or its a pharmaceutically acceptable salt. -13060. A phospholipase enzyme inhibitor according to claim 1 which is N - [2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 - {[(trifluoromethyl) sulfonyl] amino} butyl) -3- (1-pyrrolidinylcarbonyl) -1H-indol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. A phospholipase enzyme inhibitor according to claim 1 which is N- [3 (morpholinocarbonyl) -2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 {[(trifluoromethyl) sulfonyl] amino} -butyl) -1 H -indol-5-yl] cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1, which is 5 [(cyclopentylcarbonyl) amino] -2 - [(2-naphthyloxy) methyl] -1- (4-oxo-4 - {[(trifluoromethyl) sulfonyl] amino} butyl 1H-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 63. The phospholipase enzyme inhibitor of claim 1 which is 2 {4 - {[5- (benzyloxy) -3- (1-naphthoyl) -1H-indol-1-yl] methyl} phenyl} acetic acid or a pharmaceutically acceptable salt thereof. . 64. The phospholipase enzyme inhibitor according to claim 1 which is 2 {4 - {[5- (benzyloxy) -3- (2-naphthoyl) -1H-indol-1-yl] methyl} phenyl} acetic acid or its acid. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 2 {4 - {[5- (benzyloxy) -3- [3,5-bis (trifluoromethyl) benzoyl] -1H-indol-1-yl] methyl} phenyl {acetate} or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor according to claim 1, which is 4 {{3-benzoyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1 H -indol-1-yl} methyl} benzoic acid. or a pharmaceutically acceptable salt thereof. -131 The phospholipase enzyme inhibitor according to claim 1, which is 4 {[5- (benzyloxy) -3-isobutyryl-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl] methyl} benzoic acid or a pharmaceutical salt thereof. acceptable salt. 68. The phospholipase enzyme inhibitor of claim 1 which is 2- {3-acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} acetic acid or a pharmaceutically acceptable salt thereof. . 69. A phospholipase enzyme inhibitor according to claim 1 which is 2- {5- (benzyloxy) -3-isobutyryl-2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} acetic acid or a salt thereof. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1B-indol-1-yl} butanoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 3 [(4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1B-indol-1-yl} butanoyl) amino acid. benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1B-indol-1-yl} -N- [3 - ({ [(trifluoromethyl) sulfonyl] amino} carbonyl) phenyl] butanamide or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4 [(4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1B-indol-1-yl} butanoyl) amino acid. benzoic acid or a pharmaceutically acceptable salt thereof. 74. A phospholipase enzyme inhibitor according to claim 1 which is 2 [(4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} acid. butanoyl) amino] benzoic acid or a pharmaceutically acceptable salt thereof. - 132 75. The phospholipase enzyme inhibitor of claim 1 which is 3 [(4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) amino acid. propane or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 3 [(4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl) amino acid. propane or a pharmaceutically acceptable salt thereof. 77. A phospholipase enzyme inhibitor according to claim 1 which is N- (4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} butanoyl). -2-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 5- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} pentanoic acid or a pharmaceutically acceptable salt thereof. . The phospholipase enzyme inhibitor of claim 1 which is 3 [(5- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} pentanoyl) amino acid benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} - N - [3 - ({ [(trifluoromethyl) sulfonyl] amino} carbonyl) phenyl] butanamide or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 2- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1 H -indol-1-yl] acetic acid or a pharmaceutically acceptable salt thereof. . The phospholipase enzyme inhibitor of claim 1 which is (E) 4- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1 H -indol-1-yl} acid. -2-butene or a pharmaceutically acceptable salt thereof. -133 83. The phospholipase enzyme inhibitor of claim 1 which is 3 ({3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} methyl) benzoic acid or a benzoic acid thereof. a pharmaceutically acceptable salt. The phospholipase enzyme inhibitor of claim 1 which is 1- {1- [4- (1,3-benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) 2 - [(2-naphthylsulfanyl) methyl] 1H- indol-3-yl} -1-ethanone or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1 which is 1- {1- [4- (1,3-benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) -2 - [(2-naphthylsulfanyl) methyl] - 1 H -indol-3-yl} -1-ethanone or a pharmaceutically acceptable salt thereof. 86. A phospholipase enzyme inhibitor according to claim 1 which is 2 [3 - ({3-acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -1H-indol-1-yl} methyl) benzoyl] 1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. 87. The phospholipase enzyme inhibitor of claim 1 which is 5- {3-benzoyl-5- (benzyloxy) 2 - [(2-naphthyloxy) methyl] -1B-indol-1-yl} -2-oxo-pentanoic acid or its a pharmaceutically acceptable salt. 88. The phospholipase enzyme inhibitor of claim 1 which is 3 [(5- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1B-indol-1-yl} -2- oxopentanoyl) aminobenzoic acid or a pharmaceutically acceptable salt thereof. 89. The phospholipase enzyme inhibitor of claim 1 which is 4 [(5- {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -1H-indol-1-yl} acid. -2-oxopentanoyl) aminobenzoic acid or a pharmaceutically acceptable salt thereof. 90. The phospholipase enzyme inhibitor of claim 1 which is 3 {{4- [5 - [(cyclopentylcarbonyl) amino] -2 - [(2-naphthyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indole. -1-yl] butanoyl} amino} benzoic acid or a pharmaceutically acceptable salt thereof. - 134 The phospholipase enzyme inhibitor according to claim 1, which is 3 {{4- [5 - [(cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2 - [(2-naphthyloxy) methyl] -1 H -indole- 1-yl] butanoyl} amino} benzoic acid or a pharmaceutically acceptable salt thereof. The phospholipase enzyme inhibitor of claim 1, which is N- [2 - [(2-naphthyloxy) methyl] -1- {4-oxo-4- [3 - [[[(trifluoromethyl) sulfonyl] amino] carbonyl] anilino] butyl } -3- (1-pyrrolidinylcarbonyl) -1H-indol-5-yl] cyclopentanecarboxamide and a pharmaceutically acceptable salt thereof. 93. The phospholipase enzyme inhibitor according to claim 1 which is N - {3- (morpholinocarbonyl) - [2 - [(2-naphthyloxy) methyl] -1- {4-oxo-4- [3 - [[[(trifluoromethyl)] sulfonyl] amino] carbonyl] anilino] butyl} -1 H -indol-5-yl] cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 94. The phospholipase enzyme inhibitor of claim 1 which is 2 {4 - {[5- (benzyloxy) -3- (1-naphthoyl) -1H-indol-1-yl] methyl} phenyl} acetic acid or a pharmaceutically acceptable salt thereof. . 95. A pharmaceutical composition comprising the phospholipase enzyme inhibitor of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 96. A pharmaceutical composition comprising the phospholipase enzyme inhibitor of claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 97. A pharmaceutical composition comprising the phospholipase enzyme inhibitor of claim 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. - 135 98. A pharmaceutical composition comprising the phospholipase enzyme inhibitor of claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 99. A pharmaceutical composition comprising the phospholipase enzyme inhibitor of claim 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The phospholipase enzyme inhibitors of claim 9 for use in inhibiting the activity of phospholipase enzymes in a mammal. The phospholipase enzyme inhibitors of claim 10 for use in inhibiting the activity of phospholipase enzymes in a mammal. The phospholipase enzyme inhibitors of claim 11 for use in inhibiting the activity of phospholipase enzymes in a mammal. The phospholipase enzyme inhibitors of claim 12 for use in inhibiting the activity of phospholipase enzymes in a mammal. 104. The phospholipase enzyme inhibitors of claim 13 for use in inhibiting the activity of phospholipase enzymes in a mammal. 105. The phospholipase enzyme inhibitors of claim 9 for use in treating an inflammatory response in a mammal. on the 106. The phospholipase enzyme inhibitors of claim 10 for treating an inflammatory response in a mammal. use for 107. The phospholipase enzyme inhibitors of claim 11, for treating an inflammatory response in a mammal. for use on -136 108. The phospholipase enzyme inhibitors of claim 12 for use in treating an inflammatory response in a mammal. 109. The phospholipase enzyme inhibitors of claim 13 for use in treating an inflammatory response in a mammal.