JP2002542148A - Combination therapy for the treatment of sepsis - Google Patents

Abstract

(57) Abstract The present invention provides a method for preventing and treating sepsis in a mammal. The treatment is a combination therapy with activated protein C and sPLA ₂ inhibitors.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to the field of medicine, and specifically to the treatment of sepsis.

BACKGROUND OF THE INVENTION Responses to infections involve a very large number of physical responses. The onset of a systemic inflammatory response to etiologies such as microbial invasion is called sepsis. My body is beaten,
And if the defense mechanisms do not work (ie sepsis, severe sepsis, septic shock), the body is very dangerous.

The prior art has recently disclosed two relatively new drugs (and their associated uses) for the treatment of sepsis. These agents are (a) activated protein C and (b) sPLA ₂ inhibitors.

A. Activated protein C and its role in sepsis Protein C is a serine protease, a naturally occurring anticoagulant, that plays a role in regulating vascular homeostasis by inactivating Factors Va and VIIIa of the coagulation cascade. Play. Human protein C is produced in vivo (mainly in the liver) as a single-chain polypeptide having 461 amino acids.

[0005] Along with other proteins, protein C functions as an important down-regulator of blood coagulation factors that promote thrombosis. In other words, the protein C enzyme system is the major physiological mechanism of anticoagulation.

[0006] The important role of protein C in controlling homeostasis is to increase the rate of thrombosis in heterozygous deficiencies, to prevent protein C resistance (eg, due to common Factor V Leiden mutations). ) And the lethal consequences of untreated homozygous protein C deficiency. Human activated protein C (both plasma-derived and recombinant) has been found to be an effective and safe antithrombotic in a number of animal models in both venous or arterial thrombosis. Activated protein C has been effective in recent clinical studies in treating human thrombotic diseases, such as protein C deficiency and microvascular thrombosis, such as disseminated intravascular coagulation associated with sepsis. It turned out to be.

B. sPLA ₂ and sPLA ₂ inhibitors and non-pancreatic secretory role human in their sepsis phospholipase _{A 2} (which is hereinafter referred to as "sPLA _2") structure and physical properties of the two documents, namely Seilhame
r, Jeffrey J .; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller
, Judy A .; Kloss, Jean; and Johnson, Lorin K.
mbinant Expression of Phospolipase A ₂ Present in Rheumatoid Arthritic Sy
novial Fluid "( The Journal of Biological Chemistry , 264, 10th edition (1989
Published April 5) 5335-5338) and Ruth, M .; Hession, Catherine; Johanse
n, Berit; Hayes, Gretchen; McGray, Paula, Chow, E, Pingchang; Tizard, R
`` Structure and Properties of a Huma '' by Richard and Repinsky, R. Blake
n Non-pancreatic Phospholipase A ₂ "(The Journal of Biological Chemistry, 264, pp. 10 edition (issued on April 5, 1989), pp. 5768-5775) sufficient to (these constitute a part of this specification) Is disclosed. sPLA ₂ inhibitors is the rate-limiting enzyme hydrolyzes arachidonic acid cascade membrane phospholipids. Thus, compounds that inhibit the release of fatty acids sPLA ₂ mediated (e.g., arachidonic acid) it is important to develop. The compound is sP
Or induced by overproduction of LA _2, and / or maintained by the disease (e.g., sepsis) will become important in the conventional treatment of.

[0008] The discovery of the present invention (Summary of the invention) was prevented by (i) activating human Protein C and (ii) sPLA ₂ Inbita advantageously sepsis by combination therapy using a shape or superior manner, And to treat.

[0009] Combination therapy aPC with sPLA ₂ inhibitors, as both anti-inflammatory and anti-coagulant, by initiating attacks from various fields in a timely manner, the body response of human to a disease state of sepsis To improve. With this combination therapy, aP
Obtaining one of effective treatment, or synergistically effective treatment by many mechanisms than the results obtained when using the C pharmaceutical agent or sPLA ₂ drugs separately. The advantages are increased therapeutic or prophylactic efficacy, reduced effective doses, and / or reduced duration of therapy.

[0010] The present invention relates to (a) sPLA ₂ inhibitors and (b) a pharmaceutical composition comprising an activated protein C.

[0011] The present invention also relates to a method of treating or preventing sepsis, the method comprising administering to a mammal in need of treatment for sepsis a therapeutically effective amount of (a) activated protein C and therapeutics. manner by administering an effective (b) sPLA ₂ inhibitors, in time,
This is a method by administering both (a) and (b) within a therapeutically effective interval.

(Detailed Description of the Invention) Definitions: For the purposes of the invention disclosed and claimed herein, the following terms are defined below.

[0013] aPC is activated human protein C, also called activated protein C. APTT is the activated partial thromboplastin time. hPC is human protein C zymogen. rhPC is a recombinant human protein C zymogen.

The terms “aPC”, “activated human protein C”, “activated protein C”, “
"raPC" and "recombinant activated protein C" are synonymous in the purpose and practice of the present invention.

[0015] Protein C activity refers to the properties of activated human protein C or its derivatives involved in proteolytic, amidolytic, esterolytic and biological (eg, anticoagulant and profibrinolytic) activities. It is. Methods for testing protein C anticoagulant and amidolytic activity are well known in the art, see Grinnell et al., 1987, Bio / Technology 5: 1189-1192.

[0016] rhaPC is produced by activating r-HPC in vitro or by directly secreting the activated form of protein C from prokaryotic, eukaryotic or transgenic animals. The recombinant activated human protein C produced.

[0017] Zymogens are enzymatically inactive precursors of proteolytic enzymes. As used herein, protein C zymogen refers to single or double chain protein C in a secreted, inactive form.

[0018] and sPLA ₂ is a secretory phospholipase _{A 2.}

By sPLA ₂ inhibitor is meant a compound that inhibits sPLA ₂ mediated release of fatty acids.

[0020] Sepsis is a systemic inflammatory response associated with and mediated by the defense functions of many hosts, including, for example, cytokine networks, leukocytes and complement, and activation of the coagulation / fibrinolysis system. (Masters
Blood, 88; 881-886, 1996). Disseminated intravascular coagulation (DIC), which involves extensive deposition of fibrin in microvessels of many organs
Is an early manifestation of sepsis and / or septic shock. DIC is
An important mediator in the development of numerous organ dysfunction syndromes, which itself is the cause of poor prognosis in patients with septic shock (Fourrier et al.
Chest, 101: 816-823, 1992). "Sepsis" includes severe sepsis, septic shock, sepsis and related conditions.

[0021] The term "therapeutically effective amount", that is effective to either or alleviate to prevent sepsis, an amount or (b) the amount of aPC of (a) sPLA ₂ inhibitors.

[0022] The term "therapeutically effective interval" is, (a) sPLA ₂ inhibitor, or (
b) beginning when any one of the aPCs is administered to the mammal, wherein (a) or (b)
) Means a period of time that results in the limit of a beneficial effect in preventing or reducing sepsis.

The term “therapeutically effective combination” as used in the practice of the present invention is defined as (
a) sPLA ₂ inhibitors and a (b) activated protein C, refers to the administration simultaneously or separately.

As used herein, the term “active ingredient” refers to (a) activated protein C and (b) sP coexisting in a pharmaceutical composition for delivery of a treatment regimen using the present invention.
It means a combination of LA ₂ inhibitors.

The term "carrier injectable liquid", (a) sPLA ₂ inhibitors and (
b) means a liquid medium containing either or both activated protein C, wherein (a) and (b) are independently dissolved, suspended, dispersed or emulsified in said liquid medium .

Other defined chemical terms are as follows: “Alkyl” means a linear or branched monovalent hydrocarbon group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl And n-hexyl.

“Alkenyl” means a straight or branched chain monovalent hydrocarbon radical having the above range of carbon numbers, typically vinyl, propenyl, crotonyl, isopentenyl and various butenyl isomers. Body.

“Hydrocarbon” means an organic group containing only carbon and hydrogen.

“Halo” means fluoro, chloro, bromo or iodo.

“Heterocyclic group” means a group derived from a monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nucleus, wherein the heterocyclic nucleus is It has -14 ring atoms and contains 1-3 heteroatoms, wherein the heteroatoms are selected from the group consisting of nitrogen, oxygen or sulfur. For example, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,
5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiophenyl, Pentamethylene sulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thiooxanyl, azetidinyl, hexamethyleneiminium.

The “carbocyclic group” is a saturated or unsaturated, substituted or unsubstituted 5- to 14-membered organic nucleus in which atoms forming a ring (excluding hydrogen) are only carbon. Means nucleus. Typical carbocyclics are cycloalkyl, cycloalkenyl, phenyl,
Naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xyenyl,
Indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, anthracenyl, biphenyl, bibenzilyl and formula (bb):

Embedded image (Wherein n is 1 to 8).

“Non-interfering substituents” are at positions 4, 5, 6, and / or 7 on the indole nucleus.
(Shown in Formula I below) and heterocyclic groups as defined above and
And suitable groups for substitution on carbocyclic groups. Examples of non-interfering groups include C₁ ~ C₆Alkyl, C₂~ C₆Alkenyl, C₂~ C₆Alkenyl,
C₇~ C₁₂Aralkyl, C₇~ C₁₂Arkaaryl, C₃~ C₈Cycloal
Kill, C₃~ C₈Cycloalkenyl, phenyl, toluryl, xylenyl, biphe
Nil, C₁~ C₆Alkoxy, C₂~ C₆Alkenyloxy, C₂~ C₆Arche
Nyloxy, C₂~ C₁₂Alkoxyalkyl, C₂~ C₁₂Alkoxyalkyl
Luoxy, C₂~ C₁₂Alkylcarbonyl, C₂~ C₁₂Alkylcarbonyl
Amino, C₂~ C₁₂Alkoxyamino, C₂~ C₁₂Alkoxyaminocarbo
Nil, C₁~ C₁₂Alkylamino, C₁~ C₆Alkylthio, C₂~ C₁₂A
Rukylthiocarbonyl, C₁~ C₆Alkylsulfinyl, C₁~ C₆Alkyl
Sulfonyl, C₂~ C₆Haloalkoxy, C₁~ C₆Haloalkylsulfonyl,
C₁~ C₆Haloalkyl, C₁~ C₆Hydroxyalkyl, -C (O) (C₁~ C
₆Alkyl),-(CH₂)_n-O- (C₁~ C₆Alkyl), benzyloxy,
Enoxy, phenylthio,-(CONHSO₂R), -CHO, amino, amidino
, Bromo, carbamyl, carboxyl, carbalkoxy,-(CH₂)_n-CO₂ H, chloro, cyano, cyanoguanidyl, fluoro, guanidino, hydrazide,
Hydrazino, hydrazide, hydroxy, hydroxyamino, iodo, nitro, e
Suhono, -SO₃H, thioacetal, thiocarbonyl and C₁~ C₆Carbo
And n is 1-8.

An “acid group” is an organic group that is bonded to an indole nucleus by a suitable bonding atom (hereinafter, defined as an “acid linking group”), and acts as a hydrogen-bondable proton donor. Means a group. Examples of acidic groups include -5-tetrazolyl,
-SO ₃ H,

Embedded image

Embedded image Wherein n is 1-8, R ⁸⁹ is a metal or C ₁ -C ₁₀ alkyl, and R ⁹⁹ is hydrogen or C ₁ -C ₁₀ alkyl.

An “acid linking group” is a divalent linking group represented by — (L _a ) —, which links the 4- or 5-position of the indole nucleus in the following general formula with an acidic group. Has functions.

Embedded image

The term “acid-linked chain length” means the number of atoms (excluding hydrogen) in the shortest chain length of the linking group — (La) — that links the 4- or 5-position of the indole nucleus to the acidic group. − (L
a) If there is a carbocycle in-, count the number of atoms approximately equal to the theoretical diameter of the carbocycle. Therefore, the benzene ring or cyclohexane ring in the acid linking group is counted as 2 atoms when calculating the length of-(La)-. Examples of acid linking groups include

Embedded image Wherein the groups (a), (b) and (c) have acid-linked chain lengths of 5, 7 and 2, respectively.

“Amine” means primary, secondary and tertiary amines.

“Mammal” includes humans.

“Mammal” includes humans.

The “alkylene chain having 1 to 2 carbon atoms” refers to a divalent group —CH₂-CH ₂ -And -CH₂It is.

“Pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients in the formulation but must not be harmful to the recipient. .

The term “carbazole sPLA ₂ inhibitor” includes sPLA ₂ inhibitors having either a carbazole nucleus or a tetrahydrocarbazole nucleus.

As used herein, the term “active ingredient” refers to sP present as a compound or as a mixture in a pharmaceutical formulation for delivery of a treatment regimen using the present invention.
LA ₂ means a combination of inhibitors and (b) activated protein C.

II. All kinds of useful sPLA ₂ inhibitors sPLA ₂ inhibitors in the method of the present invention are typically useful in the practice of the present invention.

[0044] Classes of suitable sPLA ₂ inhibitors useful in the methods of the present invention for use in the treatment of sepsis, for example, 1H- indole-3-glyoxylamides 1H- indole-3-hydrazides 1H- indole-3-acetamide 1H -Indole-1-glyoxylamide 1H-indole-1-hydrazide 1H-indole-1-acetamide indolizine-1-acetamide indolizine-1-acetic acid hydrazide indolizine-1-glyoxylamide indene-1-acetamide indene-1- Hydrazide acetate indene-1-glyoxylamide carbazole and tetrahydrocarbazole pyrazole phenylglyoxamide pyrrole naphthylglyoxamide phenylacetamide naphthylacet Amide.

[0045] For each of the above types sPLA ₂ inhibitors, the following items (a) ~
As described in (m), details of their molecular arrangement will be shown together with their production methods.

(A) 1H-indole-3-glyoxylamide sPLA ₂ inhibitors and methods for their preparation are described in US Pat. No. 5,654,326, which forms part of the present specification. 1H-indole-3-glyoxylamide sP
LA ₂ For another preparation of inhibitors, U.S. Patent Application No. 09/105381 (1998
Process for Preparing 4-substituted 1-H-Indole-3-gl
yoxyamides ", which form part of the present specification.

US patent application Ser. No. 09/105381 has the formula (I):

Embedded image "Wherein R ¹ is -C ₇ -C ₂₀ alkyl,

Embedded image Selected from the group consisting of Here, R ¹⁰ is halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, —
It is selected from the group consisting of S (C ₁ -C ₁₀ alkyl) and halo (C ₁ -C ₁₀ ) alkyl, and t is an integer of 0-5. R ² is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl), aryl, selected from the group consisting of aryloxy and HET. R ⁴ is selected from the group consisting of —CO ₂ H, —SO ₃ H, and —P (O) (OH) _2, or salts and prodrug derivatives thereof. R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, (C ₁ -C ₆ alkyl), (C ₁
-C ₆ alkoxy), halo _(C 1 -C ₆₎ alkoxy, halo _(C 2 -C ₆₎ alkyl, bromo, chloro, fluoro, selected from the group consisting of iodo or aryl
Or a process comprising steps (a) to (i) for the production of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug derivative thereof.

The production method includes the following steps. a) Formula X:

Embedded image Wherein R ⁸ is (C ₁ -C ₆ ) alkyl, aryl or HET, wherein the compound of the formula IX is halogenated using SO ₂ Cl _2.

Embedded image Is obtained.

B) Formula IX:

Embedded image Hydrolysis and decarboxylation of a compound of formula VIII:

Embedded image Is obtained.

C) Formula VII:

Embedded image With a compound of formula VIII:

Embedded image Alkylation with a compound of formula VI:

Embedded image Is obtained.

D) Formula VI:

Embedded image The compound of formula V is aminated and dehydrated with an amine of the formula R ¹ —NH _{2 in} the presence of a solvent that forms an azeotrope with water to give a compound of formula V:

E) Formula V:

Embedded image By refluxing a compound of the formula IV in the presence of a catalyst in a polar hydrocarbon solvent having a boiling point of at least 150 ° C. and a dielectric constant of at least 10.

Embedded image Is obtained.

F) Formula IV:

Embedded image A compound of the formula: XCH ₂ R ^{4a wherein} X is a leaving group and R ^4a is —CO ₂ R ^4b , —SO ₃ R ^4b , —P (
O) (OR ^4b ) ₂ or —P (O) (OR ^4b ) H, wherein R ^4b is a protecting group for the acid.

Embedded image Is obtained.

G) Formula III:

Embedded image Is reacted with oxalyl chloride and ammonia to give a compound of formula II:

Embedded image Is obtained.

H) optionally, a compound of formula II:

Embedded image Is hydrolyzed to give a compound of formula I.

I) Optionally, the compound of formula I is salified.

[0057] 1H- indole-3-glyoxylamides sPLA synthetic methodologies for the preparation of ₂ inhibitor, those skilled in the chemical arts may be suitable any of the methods available. However, the methodology is not relevant to the present invention, which is a method of use, specifically a method of treating a mammal suffering from or susceptible to sepsis.

The method of the present invention is a method for the treatment of a mammal (including a human) afflicted with sepsis, wherein the method comprises administering to the human a compound of formula (Ia): Administering a therapeutically effective amount of a pharmaceutically acceptable salt or prodrug derivative.

Embedded image Wherein both X are oxygen. R ₁ is

Embedded image (Where R ₁₀ is halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy,
—S— (C ₁ -C ₁₀ alkyl) and a group independently selected from C ₁ -C ₁₀ haloalkyl, and t is a number from 0 to 5). R ₂ is selected from the group of halo, cyclopropyl, methyl, ethyl and propyl. R ₄ and R ₅ are hydrogen, non-interfering substituents or groups :-( L _a) - (an acidic group) (wherein, - (L _a) - is independently selected from a a) acid linking group . However, for R ₄ , the acid linking group: — (L _a ) —

Embedded image Selected from the group consisting of And, for R ₅ , the acid linking group: — (L _a ) —

Embedded image

Embedded image(Where R₈₄And R₈₅Is each independently hydrogen, C₁~ C₁₀Alkyl,
Aryl, C₁~ C₁₀Arkaaryl, C₁~ C₁₀Aralkyl, carboxy
, Carbalkoxy and halo). Where R₄And R₅At least one of the groups is-(L_a)-(Acidic group)
Not R₄Or R₅Of the group:-(L_a)-(Acidic group) on (acidic group) is -CO₂H
, -SO₃H, or -PO (OH)₂Selected from. R₆And R₇Are each independently selected from hydrogen and a non-interfering substituent. This
Wherein the non-interfering substituent is C₁~ C₆Alkyl, C₂~ C₆Alkenyl, C₂ ~ C₆Alkynyl, C₇~ C₁₂Aralkyl, C₇~ C₁₂Arkaaryl, C ₃ ~ C₈Cycloalkyl, C₃~ C₈Cycloalkenyl, phenyl, torril,
Xylenyl, biphenyl, C₁~ C₆Alkoxy, C₂~ C₆Alkenyloxy
, C₂~ C₆Alkynyloxy, C₂~ C₁₂Alkoxyalkyl, C₂~ C_{1 2} Alkoxyalkyloxy, C₂~ C₁₂Alkylcarbonyl, C₂~ C₁₂ Alkylcarbonylamino, C₂~ C₁₂Alkoxyamino, C₂~ C₁₂Al
Coxyaminocarbonyl, C₂~ C₁₂Alkylamino, C₁~ C₆Alkyl
Oh, C₂~ C₁₂Alkylthiocarbonyl, C₂~ C₁₂Alkylsulfinyl
, C₁~ C₆Alkylsulfonyl, C₂~ C₆Haloalkoxy, C₁~ C₆Halo
Alkylsulfonyl, C₂~ C₆Haloalkyl, C₁~ C₆Hydroxyalkyl
, -C (O) O (C₁~ C₆Alkyl),-(CH₂)_n-O- (C₁~ C₆Alkyl)
, Benzyloxy, phenoxy, phenylthio,-(CONHSO₂R), -CH
O, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,
− (CH₂)_n-CO₂H, chloro, cyano, cyanoguanidyl, fluoro, gua
Nidino, hydrazide, hydrazino, hydrazide, hydroxy, hydroxyamino
, Iodo, nitro, phosphono, -SO₃H, thioacetal, thiocarbonyl and
And C₁~ C₆It is selected from the group consisting of carbonyl. n is 1 to 8]

The 1H-indole-3-glyoxylamide compounds useful in the methods of the invention and all their corresponding pharmaceutically acceptable salts, solvates and prodrug derivatives perform the methods of the invention. Preferred for the preparation of the compositions of the present invention, and include the following: (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl- 1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (B) dl-2-[[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenyl) methyl)-1H-indol-4-yl] oxy] propanoic acid, (C) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl ) -2-Methyl-1H-indol-4-yl ] Oxy]
Acetate, (D) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -3-ylmethyl) -2-methyl -1H- indol-4-yl] Oxy]
Acetate, (E) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -4-ylmethyl) -2-methyl -1H- indol-4-yl] Oxy]
Acetic acid, (F) [[3- (2-amino-1,2-dioxoethyl) -1-[(2,6-dichlorophenyl) methyl] -2-methyl-1H-indol-4-yl] oxy] acetic acid, (G) [[3- (2-Amino-1,2-dioxoethyl) -1- [4 (-fluorophenyl) methyl] -2-methyl-1H-indol-4-yl] oxy] acetic acid, (H) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1-[(
1-naphthalenyl) methyl] -1H-indol-4-yl] oxy] acetic acid, (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H -Indol-4-yl] oxy] acetic acid, (J) [[3- (2-amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H-indole-4 - yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-ethyl -1H- indole -4-yl] oxy]
Acid, (L) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-propyl -1H- indol-4-yl] Oxy] acetic acid, (M) [[3- (2-amino-1,2-dioxoethyl) -2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (N) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-cyclopropyl -1H- indol-4-yl
] Oxy] acetic acid, (O) 4-[[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1
-(Phenylmethyl) -1H-indol-5-yl] oxy] butyric acid, and (P) any combination mixture of (A) to (P).

Compounds of formula (I) and prodrugs of compound names (A)-(O) are represented by sPLA ₂ It is particularly useful as an inhibitor. Preferred prodrugs are aromatic esters
Or aliphatic esters such as methyl esters, ethyl esters, n
-Propyl ester, isopropyl ester, n-butyl ester, sec-butyl ester
Tyl ester, tert-butyl ester, N, N-diethyl glycolamide
Esters and morpholino-N-ethyl esters. Esters and
Methods for making prodrugs are disclosed in US Pat. No. 5,654,326.
For another method of preparing prodrugs, see US Provisional Patent Application No. 60/063280 (1997).
Filed October 27, 2012) (Title is N, N-diethylglycolamido ester Prodrugs of Indol
e sPLA_Two inhibitors) (which form a part of this specification), US Provisional Patent Application 60
/ 063646 (filed on October 27, 1997) (Title is Morpholino-N-ethyl Ester Prodr
ugs of Indole of sPLA_Two inhibitors) (which form part of this specification) and
And US Provisional Patent Application No. 06/063284 (filed October 27, 1997) (titled Isopropyl
Ester Prodrugs of Indole sPLA_Two inhibitors) (this is part of this specification)
To).

In the practice of the method of the present invention, the formula:

Embedded image

Embedded image [[3- (2-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, sodium salt,
Most preferred are the methyl ester and morpholino-N-ethyl ester forms.

Another highly preferred compound has the formula:

Embedded image Indole-3-glyoxylamidomorpholinoethyl ester represented by the formula: U.S. Provisional Patent Application No. 60 / 063,646 (filed October 27, 1997)
Are described further.

The method for synthesizing 1H-indole-3-glyoxylamide sPLA ₂ inhibitor is further shown in the following reaction formula. Reaction formula of 1H-indole-3-glyoxylamide

Embedded image

Embedded image

Description of Reaction Schemes: To obtain 4-substituted glyoxylamides having an acidic function derived from an oxygen atom, the reaction outlined in Scheme 1 is used (see Robin D,
Clark, Joseph M. Muchowski, Lawrence E. Fisher, Lee A. Flippin, David B
See Repke, Synthesis by Michel Souchet, 1991, 871-878. This forms part of the present description). Ortho-nitrotoluene 1 is Pd / C as a catalyst.
And is easily reduced to 2-methylaniline. The reduction reaction can be carried out in ethanol, tetrahydrofuran (THF), or a mixture thereof using low-pressure hydrogen. Aniline 2 with di-tert-butyl dicarbonate in THF
When heated at reflux, it is converted to the N-tert-butylcarbonyl derivative 3 in good yield. A dilithium salt of dianion 3 is formed using sec-butyllithium at -40 ° C to -20 ° C in THF, and appropriately substituted N-methoxy-N-
React with methyl alkanamide. The product 4 is purified by crystallization from hexane or reacted directly with trifluoroacetic acid in dichloromethane to give 1,3-unsubstituted indole 5. The 1,3-unsubstituted indole 5 is reacted with sodium hydride in dimethylformamide at room temperature (20-25 ° C.) for 0.5-1.0 hours. The resulting sodium salt of 5 is treated with an equivalent amount of an arylmethyl halide and the mixture is allowed to stir at a temperature in the range of 0-100 ° C. (typically at ambient room temperature) for 4-36 hours, 1-arylmethylindole 6 is obtained. This indole 6 is combined with boron tribromide in dichloromethane for about 5
Stir for hours to O-demethylate (see Adv. Drug Res., 1977, 12, 176 by Tsuung-Ying Shem and Charles A Winter, which forms part of this specification). Alkylation of 4-hydroxyindole 7 with α-bromoalkanoate in dimethylformamide (DMF) using sodium hydride as base under the same reaction conditions as described for the conversion of 5 to 6. did. The a-[(indol-4-yl) oxy] alkanoate 8 is reacted with oxalyl chloride in dichloromethane to give 9, which is reacted directly with ammonia without purification to give glyoxamide 10. . The product is hydrolyzed using 1N sodium hydroxide in MeOH. The final glyoxylamide 11 is isolated as the free carboxylic acid or as its sodium salt, or both.

The most preferred compound useful in the practice of the method of the present invention is [[3- (2
-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H
-Indol-4-yl] oxy] acetic acid (and its sodium salts and methyl esters) can be prepared by the following method.

Formula:

Embedded image Production of [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid which is a compound represented by A. Preparation of 2-ethyl-4-methoxy-1H-indole 1.3 M sec-butyllithium in cyclohexane (140 mL, 0.1
8 mol) in N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in THF (250 mL) using a dry ice-ethanol bath at a temperature of -40 ° C. Add slowly, keeping it low. The bath was removed and the temperature was raised to 0 ° C., then the bath was replaced. After cooling the temperature to −60 ° C., N-methoxy-N-methylpropanamide (18.5 g, 0.18 mol) in an equal volume of THF was added dropwise. The reaction mixture was stirred for 5 minutes, the cooling bath was removed and stirred for a further 18 hours. It was then poured into a mixture of ether (300 mL) and 0.5N HCl (400 mL). The organic phase was separated, washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure to give crude 1- [2- (te
rt-butoxycarbonylamino) -6-methoxyphenyl] -2-butanone (2
5.5 g). This material was dissolved in dichloromethane (250 mL) and trifluoroacetic acid (50 mL) and stirred for a total of 17 hours. The mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel chromatography (eluted with 20% EtOAc / hexane) three times to give 2-ethyl-4-methoxy-1H-indole (13.9 g). Elemental analysis _(calculated as C _{11 H} 13 NO) :( theory) C, 75.40; H,
7.48; N, 7.99. (Actual value) C, 74.41; H, 7.64; N, 7.97.
.

Part B. Preparation of 2-ethyl-4-methoxy-l- (phenylmethyl) -lH-indole 2-Ethyl-4-methoxy-lH-indole (4.2 g, 24 mmol) was dissolved in DMF (30 mL) and 60% NaH / mineral oil (960 mg, 24 mmo
l) was added. After 1.5 hours, benzyl bromide (2.9 mL, 24 mmol) was added. After 4 hours, the mixture was diluted with water and extracted twice with ethyl acetate. Washed with brine and the combined the ethyl acetate, dried (MgSO _4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 20% EtOAc / hexane) to give 2-ethyl-4-methoxy-1- (phenylmethyl) -1H-indole (3.1 g, 49% yield). Obtained.

Part C. Preparation of 2-ethyl-4-hydroxy-1- (phenylmethyl) -1H-indole 2-ethyl-4-methoxy-1- (phenylmethyl) -1H-indole (3.
1g, a 11.7 mmol), while stirring at room temperature for 5 hours, depending O- demethylation to be processed using dichloromethane 1M BBr ₃ (48.6mL),
Subsequently, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried (MgSO _4). After concentration under reduced pressure, the residue was purified by silica gel chromatography (eluted with 20% EtOAc / hexane) to give 2-
Ethyl-4-hydroxy-1- (phenylmethyl) -1H-indole (1.58
g, yield 54%). mp, 86-90 ° C. Elemental analysis _(calculated as C _{17 H 17} NO) :( theory) C, 81.24; H,
6.82; N, 5.57. (Actual value) C, 81.08; H, 6.92; N, 5.41.
.

Part D. Preparation of [[2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy] acetic acid methyl ester 2-ethyl-4-hydroxy-1- (phenylmethyl) -1H-indole (1
.56 g, 6.2 mmol) in 60% NaH / mineral oil (248 mg, 6.2 mmol)
Was added to a mixture of DMF (20 mL) and stirred for 0.67 hours.

Then, methyl bromoacetate (0.6 mL, 6.2 mmol) was added, and the mixture was stirred for 17 minutes.
Continued for hours. The mixture was diluted with water and extracted with ethyl acetate. Washed ethyl acetate solution with brine, dried (MgSO _4), and concentrated under reduced pressure. Silica gel chromatography of the residue (eluted with 20% EtOAc / hexane)
After purification, [[2-ethyl-1- (phenylmethyl) -1H-indole-4
[-Yl] oxy] acetic acid (1.37 g, yield 69%) was obtained. 89-92 ° C. Elemental analysis _{(C 20 H} 21 calculated as NO ₃₎ :( theory) C, 74.28; H
, 6.55; N, 4.33. (Found) C, 74.03; H, 7.49; N, 4.6.
0.

Section E. Production of [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester [[2-ethyl-1- (Phenylmethyl) -1H-indol-4-yl] oxy]
Acetic acid methyl ester (1.36 g, 4.2 mmol) in dichloromethane (10 mL)
), Oxalyl chloride (0.4 mL, 4.2 mmol) was added and the mixture was combined with 1.
Stir for 5 hours. The mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (10 mL
). Anhydrous ammonia was bubbled in for 0.25 hours, the mixture was stirred for 1.5 hours and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and the mixture was filtered. The filtrate is concentrated to give [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy.
A mixture of acetic acid methyl ester and ammonium chloride (1.37 g) was obtained. This mixture melted at 172-187 ° C.

Part F. Preparation of [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid [[3- (2-amino-1) , 2-Dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester (788 mg
A mixture of 1N NaOH (10 mL) and MeOH (30 mL) was heated at reflux for 0.5 h, stirred at room temperature for 0.5 h, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and water, the aqueous phase was separated and acidified to pH 2-3 with 1H HCl. The precipitate was filtered, washed with ethyl acetate, and [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-
1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid (559 mg
, Yield 74%). mp, 230-234 ° C. Elemental analysis _{(C 21} H ₂₀ N 2 _O calculated as ₅₎ :( theory) C, 65.96;
H, 5.80; N, 7.33. (Actual value) C, 66.95; H, 5.55; N, 6.
99.

B) 1H-indole-3-hydrazide sP useful for carrying out the method of the invention
For LA ₂ inhibitors are described in U.S. Patent No. 5,578,634 (which is incorporated herein by reference). The method of the present invention is a method of treating a mammal (including a human) suffering from sepsis, wherein the method comprises treating the human with a compound of formula (Ib)
Administering a therapeutically effective amount of H-indole-3-acetic acid hydrazide, a pharmaceutically acceptable salt thereof and a prodrug derivative.

Embedded image Wherein X is oxygen or sulfur. R ₁ is selected from the group of (i), (ii) and (iii). Here, (i) is C ₄ -C ₂₀ alkyl, C ₄ -C ₂₀ alkenyl, C ₄ -C ₂₀ alkynyl, C ₄ -C ₂₀ haloalkyl, and C ₄ -C ₁₂ cycloalkyl. (Ii) is aryl or substituted aryl (the substituent is halo, -CN,-
CHO, a -OH, _-SH, a C 1 _{-C 10 alkylthio,} C 1 _{-C 10 alkoxy,} C 1 _{-C 10} alkyl, carboxyl, amino or hydroxyamino). (Iii)

Embedded image(Where y is 1 to 8; R₇₄Is independently hydrogen or C₁~ C₁₀Archi
It is. R₇₅Is aryl, substituted aryl (the substituent is halo, -CN
, -CHO, -OH, nitro, phenyl, -SH, C₁~ C₁₀Alkylthio,
C₁~ C₁₀Alkoxy, C₁~ C₁₀Alkyl, amino, hydroxyamino
A) or a substituted or unsubstituted 5- to 8-membered heterocycle). R₂Is halo, C₁~ C₃Alkyl, ethenyl, C₁~ C₂Alkylthio, C ₁ ~ C₂Alkoxy, -CHO, and -CN. Each R₃Is independently hydrogen, C₁~ C₃Alkyl or halo. R₄, R₅, R₆And R₇Is each independently hydrogen, C₁~ C₁₀Alkyl,
C₁~ C₁₀Alkenyl, C₁~ C₁₀Alkynyl, C₃~ C₈Cycloalkyl
, Aryl, aralkyl, or R₄, R₅, R₆And R₇Out of the set
Any two adjacent hydrocarbon groups, which are the ring carbons to which they are attached
Forms a 5- or 6-membered substituted or unsubstituted carbocyclic ring together with an elemental atom
), C₁~ C₁₀Haloalkyl, C₁~ C₁₀Alkoxy, C₁~ C₁₀Haloa
Lucoxy, C₄~ C₈Cycloalkoxy, phenoxy, halo, hydroxy, cal
Boxyl, -SN, -CN, -S (C₁~ C₁₀Alkyl), arylthio, thio
Acetal, -C (O) O (C₁~ C₁₀Alkyl), hydrazino, hydrazide,-
NH₂, -NO₂, -NR⁸²R⁸³And -C (O) NR₈₂R₈₃(here,
R₈₂And R₈₃Forms a 5- to 8-membered heterocyclic ring, or N, R₈₂And
And R₈₃Together form a 5- to 8-membered heterocycle), or a formula:

Embedded image Wherein each R ₇₆ is independently hydrogen, C ₁ -C ₁₀ alkyl, hydroxy, or R _{76 taken} together is ＯO. p is 1-8. Z is a _{bond, -O -, - N (C} 1 ~C 10 alkyl) -, NH or -S-. Then, Q _{is, -CON (R 82 R 83)} , - 5- tetrazolyl, _-SO 3 H,

Embedded image Wherein R ₈₆ is independently hydrogen, metal or C ₁ -C ₁₀ alkyl.

The synthesis of 1H-indole-3-acetic acid hydrazide of structure (I) can be accomplished by known methods as outlined in the following reaction scheme. Reaction formula 1

Embedded image

The 1H-indole-3-acetic acid ester is easily alkylated with an alkyl halide or an arylalkyl halide in a solvent such as N, N-dimethylformamide (DMF) in the presence of a base (method a) to give an intermediate 1-Alkyl-1H-indole-3-acetic acid ester III can be obtained. Bases such as potassium t-butoxide and sodium hydride are particularly useful. Indole I
It is advantageous to react I with a base first to form the salt of II and then to add an alkylating agent. Most alkylations can be performed at room temperature. The 1-alkyl-1H-indole-3-acetic ester III is treated with hydrazine or hydrazine hydrate in ethanol (method b) to give the desired 1-alkyl.
An alkyl-1H-indole-3-acetic acid hydrazide I is obtained. This condensation reaction to formula I is usually carried out at the reflux temperature of the solvent for 1 to 24 hours.

For [0076] c) 1H-indole-3-acetamide sPLA ₂ inhibitors and preparation of these inhibitors, are described in U.S. Patent No. 5,684,034 (which is incorporated herein by reference). These inhibitors are components useful in the compositions of the present invention and in the methods of the present invention for the treatment of mammals (eg, including humans) suffering from sepsis.

Useful inhibitors are represented by formula (IIB), and pharmaceutically acceptable salts and prodrug derivatives thereof.

Embedded image Wherein X is oxygen or sulfur. R ₁₁ is selected from the group of (i), (ii), (iii) and (iv). Here, (i) is C ₆ -C ₂₀ alkyl, C ₆ -C ₂₀ alkenyl, C ₆ -C ₂₀ alkynyl, C ₆ -C ₂₀ haloalkyl, and C ₄ -C ₁₂ cycloalkyl. (Ii) is aryl or substituted aryl (the substituent is halo, nitro,-
CN, a _{-CHO, -OH, -SH, C 1} ~C 10 _alkyl, C 1 _{-C 10 alkylthio,} C 1 _{-C 10} alkoxyl, carboxyl, amino or hydroxyamino. (Iii) it _{is, - (CH 2) n -} (R 80) or -NH- _{(R 81)} (where, n
Is 1 to 8, R ₈₀ is a group listed in (i), and R ₈₁ is (i) and (
ii). (Iv)

Embedded image(Where R₈₇Is hydrogen or C₁~ C₁₀Alkyl. And R₈₈ Is unsubstituted or substituted (the substituent is halo, -CN, -CHO, -OH,-
SH, C₁~ C₁₀Alkylthio, C₁~ C₁₀Alkoxy, phenyl, nitro
, C₁~ C₁₀Alkyl, C₁~ C₁₀Haloalkyl, carboxyl, amino
And hydroxyamino) phenyl, naphthyl, indenyl and biphenyl
Or a substituted or unsubstituted 5- to 8-membered heterocyclic ring).
Devour. R¹²Is halo, C₁~ C₂Alkylthio or C₁~ C₂Is alkoxy
. Each R¹³Is independently hydrogen, halo or methyl. R¹⁴, R^Fifteen, R¹⁶And R¹⁷Is each independently hydrogen, C₁~ C₁₀A
Luquil, C₁~ C₁₀Alkenyl, C₁~ C₁₀Alkynyl, C₃~ C₈Cyclo
Alkyl, aryl, aralkyl, or R¹⁴, R^Fifteen, R¹⁶And R¹⁷ Any two adjacent hydrocarbon groups of the set
A 5- or 6-membered substituted or unsubstituted carbon atom together with the joining ring carbon atom
Forms a ring), C₁~ C₁₀Haloalkyl, C₁~ C₁₀Alkoxy, C₁~
C₁₀Haloalkoxy, C₄~ C₈Cycloalkoxy, phenoxy, halo, hide
Roxy, carboxyl, -SN, -CN, C₁~ C₁₀Alkylthio, aryl
Thio, thioacetal, -C (O) O (C₁~ C₁₀Alkyl), hydrazide (hydr
azide), hydrazino, hydrazido, -NH₂, -NO₂, -NR ₈₂ R₈₃And -C (O) NR₈₂R₈₃(Where R₈₂And R₈₃Is independent
And hydrogen, C₁~ C₁₀Alkyl, C₁~ C₁₀Is it hydroxyalkyl
, Or N, R₈₂And R₈₃Together form a 5- to 8-membered heterocycle)
Or the formula:

Embedded image Wherein R ₈₄ and R ₈₅ are each independently hydrogen, C ₁ -C ₁₀ alkyl, hydroxy, or R ₈₄ and R _{85 taken} together are ＯO. p is 1-5. Z is a _{bond, -O -, - N (C} 1 ~C 10 alkyl) -, NH or -S-. Then, Q _{is, -CON (R 82 R 83)} , - 5- tetrazolyl, _-SO 3 H,

Embedded image

Embedded image (Where n is 1-8, R ₈₆ is independently hydrogen, metal or C ₁ -C ₁₀ alkyl, and R ₉₉ is selected from hydrogen or C ₁ -C ₁₀ alkyl]]

The synthesis of 1H-indole-3-acetamide of structure (IIb) useful in the method of the invention is achieved by known methods. A useful method for synthesizing these compounds is shown in the following reaction formula.

Embedded image

The 1H-indole-3-acetamide II is alkylated with an alkyl halide or arylalkyl halide in a solvent such as N, N-dimethylformamide (DMF) in the presence of a base (method a) to give the intermediate Some 1-alkyl-
1H-indole-3-acetic ester III can be obtained. Bases such as potassium t-butoxide and sodium hydride are useful. It is advantageous to react indole II with a base to first form the salt of II and then add the alkylating agent. The desired 1-alkyl-1H-indole-3-acetic acid hydrazide IV can be obtained by treating 1-alkyl-1H-indole-3-acetic acid ester III with hydrazine or hydrazine hydrate in ethanol (method b). Get. This condensation reaction to formula IV can usually be carried out at the reflux temperature of the solvent for 1 to 24 hours. The acetic hydrazide IV is hydrogenated by heating with Raney nickel in ethanol to give acetamide I (method c). The intermediate acetate III is first hydrolyzed to give the acetic acid derivative V (method d), which is treated with an alkyl chloroformate followed by treatment with anhydrous ammonia. (Method e).

[0080] d) U.S. Pat. No. 5,641,800 (which is described in constituting) a part of this specification, hydrazide, amide or glyoxylamide type of IH-1-functionality of sPLA ₂ inhibitors. These inhibitors are components useful in the compositions of the invention and in the methods of the invention for treating mammals (including, for example, humans) suffering from sepsis.

The inhibitor is 1H-indole-1-acetamide, or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof, wherein the compound is of the formula (Ic):

Embedded image Wherein X is oxygen or sulfur. Each R ₁ is independently hydrogen or C ₁ -C ₃ alkyl. R ₃ is selected from the group of (a), (b) or (c). Here, (a) represents _a C 7 _{-C 20 alkyl,} C 7 _{-C 20 alkenyl,} C 7 _{-C 20} alkynyl, carbocyclic or heterocyclic group. (B) is a component of (a) substituted with one or more independently selected non-interfering substituents. (C) the group :-( L) _{-R 80} (where, - (L) - is a divalent linking group having 1 to 12 carbon _{atoms, R 80} is from (a) or (b) Is the group of choice). R ₂ is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R ₆ and R ₇ are independently hydrogen, a non-interfering substituent or group:-(La)-(acid acidic group), wherein-(La)-has an acid-linked chain length of 1 to 10. Is an acid linking group)
It is. However, at least one of R ⁶ and R ⁷ must be a group: — (La) — (acid group). R ₄ and R ₅ are each independently hydrogen, a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a non-interfering substituent. It is a heterocyclic group which has been produced].

The 1H-indole-1-hydrazide compounds useful as sPLA ₂ inhibitors in the practice of the methods of manufacture of the compositions and products of the present invention are 1H-indole-1-hydrazide compounds, or pharmaceutically acceptable salts thereof. A salt, solvate or prodrug derivative, wherein the compound is of the formula (IIc):

Embedded image Wherein X is oxygen or sulfur. Each R ₁ is independently hydrogen or C ₁ -C ₃ alkyl. R ₃ is selected from the group of (a), (b) or (c). Here, (a) represents _a C 7 _{-C 20 alkyl,} C 7 _{-C 20 alkenyl,} C 7 _{-C 20} alkynyl, carbocyclic or heterocyclic group. (B) is an element of (a) substituted with one or more independently selected non-interfering substituents. (C) the group :-( L) _{-R 80} (where, - (L) - is a divalent linking group having 1 to 12 carbon _{atoms, R 80} is from (a) or (b) Is the group of choice). R ₂ is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R ₆ and R ₇ are independently hydrogen, a non-interfering substituent or group:-(La)-(acid acidic group) (where-(La)-is an acid having an acid chain length of 1 to 10). A linking group). However, at least one of R ₆ and R ₇ must be a group: — (La) — (acid group). R ₄ and R ₅ are each independently hydrogen, a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a non-interfering substituent. It is a heterocyclic group which has been produced].

[0083] e) For India lysine sPLA ₂ inhibitors and their preparation, US patent application 08/765566 (filed July 20, 1995) (The title is "Synovial Phospholipase
A2 Inhibitor Compounds Having an Indolizine Type Nucleus, Pharmaceutical
Formations Containing Said compounds, and Therapeutic Methods of Using
said compounds), which form a part of this specification; and EP 0772596 (published May 14, 1997). These inhibitors are useful in the manufacture of compositions of the invention and in the practice of the methods of the invention for treating mammals (including, for example, humans) suffering from sepsis.

Useful 1H-indole-1-functional compounds, or pharmaceutically acceptable salts, solvates or prodrug derivatives thereof, have the formula (Id):

Embedded imageWherein X is oxygen or sulfur. Each R₁₁Is independently hydrogen, C₁~ C₃Alkyl or halo. R₁₃Is selected from the group of (a), (b) or (c). Where (a) is C₇~ C₂₀Alkyl, C₇~ C₂₀Alkenyl, C₇~ C₂₀A
Alkynyl, a carbocyclic group or a heterocyclic group. (B) is a compound of (a) substituted with one or more independently selected non-interfering substituents
Element. (C) is a group:-(L) -R₈₀(Where-(L)-is a divalent group having 1 to 12 carbon atoms)
Is a bonding group of₈₀Is a group selected from (a) and (b)). R₁₂Is hydrogen, halo, C₁~ C₃Alkyl, C₃~ C₄Cycloalkyl, C ₃ ~ C₄Cycloalkenyl, -O- (C₁~ C₂Alkyl), -S- (C₁~ C₂
Alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R₁₇And R₁₈Is independently hydrogen, a non-interfering substituent or group:-(La)-
(Acid acid group) (where-(La)-is an acid linking group having an acid linking chain length of 1 to 10.
). Where R₁₇And R₁₈At least one of the groups:-(La)-(acid
Sex group). R_FifteenAnd R₁₆Each independently represents hydrogen, a non-interfering substituent, a carbocyclic group,
Substituted with carbocyclic, heterocyclic and non-interfering substituents substituted with interfering substituents
Is a substituted heterocyclic group].

Particularly preferred 1H-indole functional compounds useful as sPLA ₂ inhibitors in the practice of the method of the present invention are indolizine-1-acetic acid hydrazide compounds, or pharmaceutically acceptable salts, solvates or prodrugs thereof. A derivative, wherein said compound is of the formula (IId):

Embedded image Indicated by

[0086] In practicing the methods of the present invention useful as sPLA ₂ inhibitors, particularly preferred 1H- indol-1-functional compounds indolizine-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate Or a prodrug derivative, wherein the compound is of the formula (IIId):

Embedded image Indicated by

[0087] In practicing the methods of the present invention useful as sPLA ₂ inhibitors, particularly preferred 1H- indole -1H- functional compound indolizine-3-acetamide compound or a pharmaceutically acceptable salts solvates or A prodrug derivative, wherein the compound is of the following formula (IVd):

Embedded image Wherein X is selected from oxygen or sulfur. Each R ₃ is independently hydrogen, C ₁ -C ₃ alkyl or halo. R ₁ is selected from the group of (a), (b) or (c). Here, (a) represents _a C 7 _{-C 20 alkyl,} C 7 _{-C 20 alkenyl,} C 7 _{-C 20} alkynyl, carbocyclic or heterocyclic group. (B) is an element of (a) substituted with one or more independently selected non-interfering substituents. (C) the group :-( L) _{-R 80} (where, - (L) - is a divalent linking group having 1 to 12 carbon _{atoms, R 80} is from (a) or (b) Is the group of choice). R ₂ is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R ₅ and R ₆ are independently hydrogen, a non-interfering substituent or group:-(La)-(acid acidic group) (where-(La)-has an acid-linked chain length of 1 to 10; Is an acid linking group)
It is. However, at least one of R ₅ and R ₆ must be a group: — (La) — (acid group). R ₇ and R ₈ are each independently hydrogen, a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a non-interfering substituent. It is a heterocyclic group which has been produced].

A particularly preferred 1H-indole-1H-functional compound useful as an sPLA ₂ inhibitor in the practice of the method of the present invention is an indolizine-3-hydrazide compound, or a pharmaceutically acceptable salt, solvate thereof. Or a prodrug derivative, wherein the compound is of the formula (Vd):

Embedded image Indicated by

Particularly preferred 1H-indole-1H-functional compounds useful as sPLA ₂ inhibitors in the practice of the method of the present invention are indolizine-3-glyoxylamide compounds, or pharmaceutically acceptable salts, solvates thereof. Or a prodrug derivative, wherein the compound is of the formula (VId):

Embedded image Indicated by

Particularly preferred 1H-indole-1H-functional compounds useful as sPLA ₂ inhibitors in the practice of the methods of the present invention are indolizine-1-acetamide functional compounds, or pharmaceutically acceptable salts, solvents thereof. A solvate or a prodrug derivative, wherein the compound is

Embedded image

Embedded image

Embedded image

Embedded image And a mixture of the above compounds.

[0091] useful as sPLA ₂ inhibitors in the practice of the method of the present invention, other particularly preferred 1H- indole -1H- functional compound indolizine-1-glyoxylamide functional compound, or may be as their pharmaceutically acceptable A salt, solvate or prodrug derivative, wherein the compound is

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image And a mixture of the above compounds.

[0092] Indolizine compounds can be prepared by one or more of the following reaction schemes. The following abbreviations are used: Bn is benzyl. THF is tetrahydrofuran. LAH is lithium aluminum hydride. LDA is lithium diisopropylamine. DBU is 1,8-diazabicyclo [5.4.0] undec-7-ene.

Reaction formula 1e-1 part

Embedded image The anion of 2-methyl-5-methoxypyridine is generated in lithium diisopropylamide in THF and reacted with benzonitrile to give 2. Alkylation of the 2 nitrogen with 1-bromo-2-butanone is followed by a base-catalyzed cyclization to give 3, which is reduced with LAH to give 4.
By treating 4 continuously with oxalyl chloride and ammonia, 8
Get. Alternatively, 4 is acylated with ethyl oxalyl chloride to give 5, which is converted to 6 with lithium hydroxide and then treated successively with ethyl chloroformate and ammonium hydroxide. To obtain 8.
Demethylation of 8 with BBr ₃ gives 9 which is O-alkylated with base and ethyl 4-bromobutyrate to give 10. Hydrolysis of 10 with aqueous base gives 11;

Reaction formula 2e-1 part

Embedded image Here, in the present specification, the following “cyclo” is “cyclo” and “Naphthyl”
Is "naphthyl";"cyclo-Pr","cyclo-Pro" and "cyclopropyl" are "cyclopropyl";"cyclo-Hex" and "cyclohexyl" are "cyclohexyl"
"Biphenyl" is "biphenyl";"phenyl" is "phenyl";"cyclop
"entyl" is translated as "cyclopentyl". Compound 12 (Ar by N, Desidiri, A. Galli, I. Sestili and ML Stein
ch. Pharm. (Weinheim) 325, 29 (1992)) is reduced with hydrogen in the presence of Pd / C to give 14, which is ammonolysed with ammonium hydroxide to give 15. . By O-alkylation of 15 with benzyl chloride and base,
16 is obtained. Alkylation of 13 or 16 nitrogen atoms with 1-bromo-2-ketone followed by a base-catalyzed cyclization reaction affords indolizine 1
7 is obtained, which is acylated with an aroyl halide to give 18.

Formula 2e-2 part

Embedded image Reduction of 18 with tert-butylamine-borohydride and aluminum chloride gives 19, which is reduced with hydrogen in the presence of Pd / C to give 20. O-alkylation of 20 with benzyl bromoacetate and base gives 21 which is converted to acid 22 by benzylation with hydrogen in the presence of Pd / C.

Reaction formula 3e-1 part

Embedded image Compound 23 (N. Desideri F. Manna, ML Stein, G. Bile, W. Filippeelli
And E. Marmo, Eur. J. Med. Chem. Chim. Ther., 18, 295 (1983))
O-alkylation with sodium hydride and benzyl chloride gives 24.
2 with 1-bromo-2-butanone or chloromethylcyclopropyl ketone
N-alkylation of 4 followed by a base-catalyzed cyclization gives 25, which is acylated with aroyl halide to give 26. The ester function of 26 is hydrolyzed, followed by acidification to give the acid, which is subjected to thermal decarboxylation to give 27. Reduction of the ketone function of 27 with LAH gives indolizine 28.

Reaction Formula 3e-2 parts

Embedded image Heating a mixture of 3-bromo-4-phenyl-butan-2-one or 3-bromo-4-cyclohexyl-butan-2-one and ethyl pyridine-2-ethyl acetate or a substituted derivative thereof in the presence of a base Thus, indolizine 31 is obtained. Treatment of 31 with an aqueous solution of a base at high temperature in DMSO gives 32, which is decarbonated with heat to give 33.

Reaction formula 4e-1 part

Embedded image Successive treatment of 28 or 33 with oxalyl chloride and ammonium hydroxide gives 35, which is debenzylated with hydrogen in the presence of Pd / C to give 36. Indolizine 36 is O-alkylated with sodium hydride and bromoacetate to give 37, 38 or 39, which is hydrolyzed by aqueous solution of base followed by acidification to give indolizine 40. Convert to

Reaction formula 4e-2 parts

Embedded image O-alkylation of 36h gives nitrile 41, which is converted to 42 by reaction with trialkyltin azide.

Reaction formula 5e

Embedded image

Embedded image

Embedded image O-alkylation of the hydroxypyridine gives 44, which is heated with a 2-haloketone to give 45. Treatment of 45 with a base caused cyclization to give 46, which was heated with acid chloride to give acylindolizine 47, which was reduced with aluminum hydride. The corresponding alkylindolizine 48 is obtained. Continuous treatment of 48 with oxalyl chloride followed by ammonia gives 49. Cleavage of the ether function of 49 gives 50. O-alkylation of 50 gives oxyacetic acid ester derivative 51, which is then hydrolyzed to give oxyacetic acid 52.

Reaction formula 6e-1 part

Embedded image

Embedded image O-Alkylation of pyridine 43 gives 53. Heating 53 together with the 2-haloketone gives the intermediate N-alkylated pyridinium compound, which is cyclized by base treatment to give 54. Heating 54 with the acyl chloride gives the acyl indolizine 55, which is reduced with sodium borohydride-aluminum chloride to give the alkyl indolizine 56. Alternatively, 56 is obtained by C-alkylation of 54 with an alkyl halide. Continuous treatment of 56 with oxalyl chloride followed by ammonia gives 57, which is hydrolyzed to give 58. Compound 58b
Is converted to its sodium salt, which is reacted with a suitable alkyl halide to give 59b-k.

Reaction Formula 6e-2 parts

Embedded image Compound 36b is O-alkylated to give 591-p.

Reaction formula 7e

Embedded image

Embedded image N-Alkylation of pyridine 60 with a 2-haloketone gives the intermediate pyridinium compound, which is cyclized with a base to give 61. Reaction of 61 with acyl chloride gives 62, which is reduced with tert-butylamine-borane and aluminum chloride to give 63. Consecutive treatment of 63 with oxalyl chloride followed by ammonia gives 64, which is O-demethylated with BBr ₃ to give 65. 65 sodium salts in 4
-Reaction with ethyl bromobutyrate to give 66 which is hydrolyzed to give acid 67.

Reaction formula 8e

Embedded image Compounds 36d and 65c are O-alkylated with ω-bromocarboxylic acid ester to give 68, which is hydrolyzed to give acid 69. Compound 36d
And 65c are treated with propiolactone and a base to give 70.

Reaction formula 9e

Embedded image Compound 66 is reduced with tert-butylamine-borane and aluminum chloride to give 71.

[0106]

Embedded image

Embedded image Pyridine 44b is reacted with ethyl bromoacetate to give 72, which is CS ₂ And treated with a base, then reacted with ethyl acrylate to give 73
. 73 is reacted with a base and ethyl bromoacetate to give the 74a + b position.
A mixture of stereoisomers is obtained, the 6- and 8-benzyloxy compounds. 74a + b salt
By the base treatment, ethyl acrylate was eliminated to obtain 75, which was converted to 6
-Separation from isomers of benzyloxy derivatives and S-alkylation to give 76
. Hydrolysis of 76 gives 77, which is decarbonated by heat to give 78
obtain. C-alkylation of compound 78 to give 79, which is oxalyl chloride
Followed by continuous treatment with ammonia to give 80. Cut 80 ether
To give 81, the sodium salt of which was acetylated with methyl bromoacetate.
The alkylation yields 82, which is hydrolyzed to give acid 83.

Reaction formula 11e-1 part

Embedded image Aminopyridine 84 is converted to its N-CBZ derivative 85 and the anion is alkylated with methyl bromoacetate to give 86. Reacting 86 with methyl α-bromoalkyl ketone in the presence of a base gives 87. Sequential treatment of 87 with oxalyl chloride followed by ammonia gives 88, which is converted to 89 by hydrogenolysis of the N-CBZ function. Hydrolysis of 89 gives acid 90.

Reaction formula 11e-2 parts

Embedded image Compound 88 is reduced with tert-butylamine-borane and aluminum chloride to give 91, which is hydrolyzed to give acid 92.

Reaction formula 12e

Embedded image

Embedded image Pyridine 24 is N-alkylated with methyl bromoacetate, cyclized with a base, and O-methylated with dimethyl sulfate to give 94. Hydrolysis of the ester function of 94 followed by thermal decarboxylation afforded 2-methoxy-8-benzyloxyindolizine, which was C-alkylated at the 3-position and then co-existed with oxalyl chloride and ammonia. To give 95.
A hydrogenolysis reaction of the 8-benzyloxy group is carried out followed by O-alkylation to give 96, which is hydrolyzed to give 97.

F) US Patent Application 08/776618, filed July 20, 1995, entitled “Synovial Ph.
ospholipase A ₂ Inhibitor Compounds having an Indene Type Nucleus, Pharma
ceutical Formulations Containing said Compounds, and Therapeutic Methods
of the Using Said Compounds, ") (indene sPLA ₂ inhibitors described which constitutes a part of this specification). These inhibitors are useful for preparing the compositions of the present invention and for practicing the methods of the present invention for treating sepsis.

The method of the present invention relates to a method of treating a mammal (eg, a human) afflicted with sepsis, wherein the method comprises administering to the human an indene-1-acetamide compound or a pharmaceutically acceptable salt thereof. Administering a therapeutically effective amount of an acceptable salt, solvate or prodrug derivative, wherein the compound comprises a compound of formula (If):

Embedded image Wherein X is oxygen or sulfur. Each R ₁ is independently hydrogen, C ₁ -C ₃ alkyl or halo. R ₃ is selected from the group of (a), (b) or (c). Here, (a) represents _a C 7 _{-C 20 alkyl,} C 7 _{-C 20 alkenyl,} C 7 _{-C 20} alkynyl, carbocyclic or heterocyclic group. (B) is an element of (a) substituted with one or more independently selected non-interfering substituents. (C) the group :-( L) _{-R 80} (where, - (L) - is a divalent linking group having 1 to 12 carbon _{atoms, R 80} is from (a) or (b) Is the group of choice). R ₂ is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R ₆ and R ₇ are independently hydrogen, a non-interfering substituent or group:-(La)-(acid acidic group), wherein-(La)-has an acid-linked chain length of 1 to 10. Is an acid linking group)
It is. However, at least one of R ₆ and R ₇ must be a group: — (La) — (acid group). R ₄ and R ₅ are each independently hydrogen, a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a non-interfering substituent. It is a heterocyclic group which has been produced].

Suitable indene compounds also include the indene-1-acetic acid hydrazide compound, or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof. The compound has the formula (IIf):

Embedded image Wherein X is oxygen or sulfur. Each R ₁ is independently hydrogen, C ₁ -C ₃ alkyl or halo. R ₃ is selected from the group of (a), (b) or (c). Here, (a) represents _a C 7 _{-C 20 alkyl,} C 7 _{-C 20 alkenyl,} C 7 _{-C 20} alkynyl, carbocyclic or heterocyclic group. (B) is an element of (a) substituted with one or more independently selected non-interfering substituents. (C) the group :-( L) _{-R 80} (where, - (L) - is a divalent linking group having 1 to 12 carbon _{atoms, R 80} is from (a) or (b) Is the group of choice). R ₂ is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R ₆ and _{R 7} are independently hydrogen, non-interfering substituents or groups :-( _{L a)} - (acid acidic group) (wherein, - _{(L a)} - is an acid linking chain length 1-10 Is an acid linking group)
It is. However, at least one of R ₆ and R ₇ must be _a group: — (L _a ) — (acid group). And R ₄ and R ₅ are each independently hydrogen, a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a non-interfering substituent. And a heterocyclic group substituted with

Suitable indene compounds useful in the method of the present invention include indene-1-
Glyoxylamide compounds, or pharmaceutically acceptable salts, solvates or prodrug derivatives thereof are also included. The compound has the formula (IIIf):

Embedded image Wherein X is oxygen or sulfur. R ₃ is selected from the group of (a), (b) or (c). Here, (a) represents _a C 7 _{-C 20 alkyl,} C 7 _{-C 20 alkenyl,} C 7 _{-C 20} alkynyl, carbocyclic or heterocyclic group. (B) is an element of (a) substituted with one or more independently selected non-interfering substituents. (C) the group :-( L) _{-R 80} (where, - (L) - is a divalent linking group having 1 to 12 carbon _{atoms, R 80} is from (a) or (b) Is the group of choice). R ₂ is hydrogen, _halo, C 1 -C _{3 alkyl,} C 3 -C _{4 cycloalkyl,} C 3 -C ₄ cycloalkenyl, -O- _(C 1 ~C ₂ alkyl), - S- _(C 1 ~ C ₂ alkyl) or non-interfering substituents having a total of 1-3 atoms other than hydrogen. R ₆ and _{R 7} are independently hydrogen, non-interfering substituents or groups :-( _{L a)} - (acid acidic group) (wherein, - _{(L a)} - is an acid linking chain length 1-10 Is an acid linking group)
It is. However, at least one of R ₆ and R ₇ must be _a group: — (L _a ) — (acid group). And R ₄ and R ₅ are each independently hydrogen, a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a non-interfering substituent. And a heterocyclic group substituted with

The method for producing the indene compound is as follows. Reaction formula-1f

Embedded image

Embedded image A mixture of anisaldehyde 1, propionic anhydride and sodium propionate is heated to give 2, which is reduced by hydrogen in the presence of Pd / C to give 3. 6 is obtained by subjecting 3 to a cyclization reaction with an acid. Alternatively,
The aromatic position at the para position of the methoxy group of 3 is blocked by bromination to give 4.
This is cyclized with acid to give 5, and then debrominated with hydrogen and Pd / C to give 6. Reacting 6 with the anion of triethyl phosphonoacetate gives 7 and / or 8. Radical bromination of 8 gives 9 which is reduced with hydrogen in the presence of PtO ₂ to give 7. Alternatively, 8 is treated with an acid to give 7.

[0115]

Embedded image Compound 7 is condensed with benzaldehyde and its derivatives in the presence of a base to give 10. Indene 10 is converted to the active ester using benzotriazo-1-yloxytris (dimethylamino) hexafluorophosphate and then reacted with ammonium hydroxide to give 11. Demethylation of 11 with BBr3 gives 12 which is O-alkylated with sodium hydride and ω-bromoalkanoate to give 13. Hydrolysis of the base with an aqueous solution gives 14.

Reaction formula-3f

Embedded image Compound 12c is O-alkylated with sodium hydride and methyl bromoacetate to give 15, which is reduced by hydrogen in the presence of Pd / C to give a mixture of isomers 16a and 16b. Hydrolysis of the bases 16a and 16b with aqueous solutions gives 17a and 17b, respectively.

[0117]

Embedded image Compound 10d is treated with lithium diisopropylamide and then the solution is blown with air to give 18. Indene 18 is converted to the active ester using benzotriazo-1-yloxytris (dimethylamino) hexafluorophosphate and then reacted with ammonium hydroxide to give hydroxyacetamide 19
Get. Compound 19 is oxidized with N-methylmorpholine N-oxide in the presence of tetrapropylammonium perruthenate to give 20.

[0118] g) carbazole and tetrahydrocarbazole sPLA ₂ inhibitors, as well as for the preparation of these compounds, U.S. Patent Application No. 09/063066 (1998 8
Filed on March 21) (The title is "Substituted Carbazoles and 1,2,3,4-Tetrahydrocar
bazoles "), which form part of the present specification. These inhibitors are useful for making the compositions of the present invention and for practicing methods for treating mammals (including, for example, humans) suffering from sepsis.

[0119] Useful carbazole or tetrahydrocarbazole inhibitors have the formula:

Embedded image Wherein A is phenyl or pyridyl, wherein the nitrogen is in the 5-, 6-, 7- or 8-position. One of B or D is nitrogen and the other is carbon. Z is cyclohexenyl, phenyl, pyridyl (where the nitrogen is in the 1-, 2- or 3-position) or a 6-membered heterocycle (where the ring is a 1-, 2- or 3-position sulfur or oxygen And one heteroatom selected from the group consisting of nitrogen at the 1-, 2-, 3- or 4-position).

Embedded imageIs a double bond or a single bond. R²⁰Is selected from the group of (a), (b) and (c). Here, (a) is-(C₅~ C₂₀) Alkyl,-(C₅~ C₂₀) Alkenyl,-(C₅
~ C₂₀) Alkynyl, carbocyclic or heterocyclic. (B) is an element of (a) substituted with one or more independently selected non-interfering substituents
It is. (C) is a group:-(L) -R⁸⁰It is. Here,-(L)-means 1 to 12 atoms.
Is a divalent linking group. The atom is selected from carbon, hydrogen, oxygen, nitrogen and sulfur
,-(L)-are (i) only carbon and hydrogen, (ii) one atom
Only sulfur, (iii) only one oxygen, (iv) one or two nitrogen and hydrogen
(V) only carbon, hydrogen and one sulfur, and (vi) only carbon, hydrogen and oxygen
, Selected from. R⁸⁰Is a group selected from (a) and (b). R²¹Is a non-interfering substituent. R^{1 '}Is -NHNH₂, -NH₂Or -CONH₂It is. R^{2 '}Are -OH and -O (CH₂)_tR^{5 '}Selected from the group consisting of Where R^{5 '}Is H, -CN, -NH₂, -CONH₂, -CONR⁹R¹⁰
, -NHSO₂R^Fifteen, -CONHSO₂R^Fifteen(Where R^FifteenIs-(C₁~
C₆) Alkyl or -CF₃), Phenyl, substituted phenyl (the
The substituent is -CO₂H or -CO₂(C₁~ C₄) Alkyl), and-(L
_a)-(Acidic group) (where-(L_a)-Is an acid linking group having 1 to 7 acid linking chain lengths
And t is 1-5. R^{3 '}Is a non-interfering substituent, a carbocyclic group, a carbocyclic ring substituted with a non-interfering substituent
Selected from formula groups, heterocyclic groups and heterocyclic groups substituted with non-interfering substituents
You. Where R^{3 '}Is H and R²⁰Is benzyl and m is 1 or 2
If R^{2 '}Is -O (CH₂)_mNot H. And when D is nitrogen, the heteroatom of Z is 1-, 2- or 3-position sulfur or
Is selected from the group consisting of oxygen and nitrogen at the 1-, 2-, 3- or 4-position.
Indicated by

In the compositions and methods of the present invention, the compound of formula (IIe):

Embedded image Wherein Z is cyclohexenyl or phenyl. R ²¹ is a non-interfering substituent. R ¹ is —NHNH ₂ or —NH ₂ . R ² is selected from the group consisting of -OH and ^{_{-O (CH 2) m R 5}} . here,
R ⁵ is H, —CO ₂ H, —CONH ₂ , —CO (C ₁ -C ₄ alkyl),

Embedded image (Where R ⁶ and R ⁷ are each independently —OH or —O (C ₁ -C ₄ ) alkyl), —SO ₃ H, —SO ₃ (C ₁ -C ₄ alkyl), tetrazolyl ^{_{, -CN, -NH 2, -NHSO 2}} R 15, -CONHSO 2 R 15 ( ^{wherein, R 15} is - _(C 1 ~
C ₆ ) alkyl or —CF ₃ ), phenyl or substituted phenyl (
The substituent is -CO ₂ H or -CO _{2 (C} 1 ~C ₄₎ alkyl), m
Is 1-3. R ³ is H, —O (C ₁ -C ₄ ) alkyl, halo, — (C ₁ -C ₆ ) alkyl, phenyl, — (C ₁ -C ₄ ) alkylphenyl, substituted phenyl (the substituent Is-
_(C 1 ~C ₆₎ alkyl, halo or _{-CF 3), - CH 2 OSi} (C 1 ~
C ₆₎ alkyl, furyl, thiophenyl, - _(C 1 ~C ₆₎ hydroxyalkyl,
Or ^{_{- (CH 2) n R 8}} ( ^wherein, R 8 is _{^{H, -CONH 2, -NR 9 R}} 10,
Is -CN or phenyl, ^{R 9} and ^{R 10} are independently - _(C 1 -C ₄₎ alkyl or - phenyl _(C 1 -C ₄₎ alkyl, n represents a 1 to 8). R ⁴ is H,-(C ₅ -C ₁₄ alkyl),-(C ₃ -C ₁₄ ) cycloalkyl,
Pyridyl, phenyl or substituted phenyl (the substituent - _(C 1 ~C ₆₎ alkyl, _{halo, -CF 3, -OCF 3, -} (C 1 ~C 4) alkoxy, -CN, - (
C ₁ -C ₄ ) alkylthio, phenyl (C ₁ -C ₄ ) alkyl,-(C ₁ -C ₄ ) alkylphenyl, phenyl, phenoxy or naphthyl), or a pharmaceutically acceptable salt thereof. Preferred are racemates, solvates, tautomers, optical isomers, prodrug derivatives or salts which are acceptable.

Specific compounds (including all salts and prodrug derivatives thereof) preferred as compositions and methods of the present invention are as follows. 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid hydrazide; 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4- Carboxamide; [9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid sodium salt; [9-benzyl-4-carbamoyl-7-methoxycarbazole- 5- [5-yl] oxyacetic acid; methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl] oxyacetate; 9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4 -Tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5- (1H-tetrazol-5-ylmethyl) oxy) -1,2, 3,4-tetrahydrocarbazole-4-carboxamide; {9-[(phenyl) methyl] -5-carbamoyl-2-methyl-carbazole-
{9-[(3-fluorophenyl) methyl] -5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid; {9-[(3-methylphenyl) methyl]- 5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid; {9-[(phenyl) methyl] -5-carbamoyl-2- (4-trifluoromethylphenyl) -carbazol-4-yl} oxyacetic acid 9-benzyl-5- (2-methanesulfonamido) ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4- (2-methanesulfonamido) ethyloxy- 2-methoxycarbazole-5-carboxamide; 9-benzyl-4- (2-trifluoromethanesulfonamido) ethyloxy-
2-methoxycarbazole-5-carboxamide; 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-
1,2,3,4-tetrahydrcarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-
5-carboxamide; [5-carbamoyl-2-pentyl-9- (phenylmethyl) carbazole-4
-Yl] oxyacetic acid; [5-carbamoyl-2- (1-methylethyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2- [ (Tri (-1-methylethyl
) Silyl) oxymethyl)] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl) carbazole-4
[5-carbamoyl-2- (4-chlorophenyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2- (2-furyl) -9- ( [Phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2-[(tri (-1-methylethyl)
) Silyl) oxymethyl] carbazol-4-yl] oxyacetic acid lithium salt; {9-[(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(3-fluorophenyl) Methyl] -5-carbamoylcarbazole-4
-Yl} oxyacetic acid; {9-[(3-phenoxyphenyl) methyl] -5-carbamoylcarbazole-
4-yl} oxyacetic acid; {9-[(2-fluorophenyl) methyl] -5-carbamoylcarbazole-4
-9-[(2-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-benzylphenyl) methyl] -5-carbamoylcarbazole -4
-Yl} oxyacetic acid; {9-[(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(1-naphthyl) methyl] -5-carbamoylcarbazole- 4-yl} oxyacetic acid; {9-[(2-cyanophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3-cyanophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(2-methylphenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3-methylphenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3,5-dimethylphenyl) methyl] -5-carbamoylcarbazole-
4-yl} oxyacetic acid; {9-[(3-iodophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(2-chlorophenyl) methyl] -5-carbamoylcarbazole-4-
{9-[(2,3-difluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2,6-difluorophenyl) methyl] -5-carbamoyl Carbazol-4-yl} oxyacetic acid; {9-[(2,6-dichlorophenyl) methyl] -5-carbamoylcarbazole-
{9-[(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl] -5 -Carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl]- 5-carbamoylcarbazol-4-yl}
[9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; {9-[(2-pyridyl) methyl] -5-carbamoylcarbazol-4-yl } Oxyacetic acid; {9-[(3-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydro [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4 -Tetrahydrocarbazol-5-yl} oxyacetic acid; [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl} oxyacetic acid; [9-benzyl-4-carbamoyl-8- [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid; [9-[(cyclohexyl) methyl] chloro-1,2,3,4-tetrahydrocarbazol-5-yl} oxyacetic acid; -5-carbamoylcarbazol-4-yl}
Oxyacetic acid; [9-[(cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl}
Oxyacetic acid; 5-carbamoyl-9- (phenylmethyl) -2-[[(propen-3-yl) oxy] methyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl)- 2-[(propyloxy) methyl]
Carbazol-4-yl] oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -1,2,
3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-
Carboxamide; 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl
) Oxy) -carbazole-4-carboxamide; 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -carbazole-4-carboxamide; [9-benzyl-4-carbamoyl-1,2,3,4 -Tetrahydrocarbazol-5-yl] oxyacetic acid; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer,
Prodrug or salt.

Other desirable carbazole inhibitors suitable for the compositions and methods of the present invention include compounds of formula (XXX):

Embedded image[Where R¹Is -NHNH₂Or -NH₂It is. R²Are -OH and -O (CH₂)_mR⁵Selected from the group consisting of Where R ⁵ Is H, -CO₂H, -CO₂(C₁~ C₄Alkyl),

Embedded image(Where R⁶And R⁷Are each independently -OH or -O (C₁~ C₄) Al
Kill)), -SO₃H, -SO₃(C₁~ C₄Alkyl), tetrazolyl, -CN, -NH ₂ , -NHSO₂R^Fifteen, -CONHSO₂R^Fifteen(Where R^FifteenIs-(C₁
~ C₆) Alkyl or -CF₃), Phenyl or substituted phenyl
(The substituent is -CO₂H or -CO₂(C₁~ C₄Alkyl))
m is 1-3. R³Is H, -O (C₁~ C₄) Alkyl, halo,-(C₁~ C₆) Alkyl,
Enyl,-(C₁~ C₄) Alkylphenyl, substituted phenyl (the substituent is-
(C₁~ C₆Alkyl), halo or -CF₃), -CH₂OSi (C₁~
C₆Alkyl), furyl, thiophenyl,-(C₁~ C₆) Hydroxyalkyl,
Or-(CH₂)_nR⁸(Where R⁸Is H, -CONH₂, -NR⁹NR¹⁰ , -CN or phenyl;⁹And R¹⁰Are independently-(C₁~ C₄A
Alkyl) or -phenyl (C₁~ C₄Alkyl) and n is 1-8)
is there. R⁴Is H,-(C₅~ C₁₄) Alkyl,-(C₃~ C₁₄) Cycloalkyl,
Pyridyl, phenyl or substituted phenyl, wherein the substituent is-(C₁~ C₆) Al
Kill, halo, -CF₃, -OCF₃,-(C₁~ C₄) Alkoxy, -CN,-(
C₁~ C₄) Alkylthio, phenyl (C₁~ C₄) Alkyl,-(C₁~ C₄A)
Alkylphenyl, phenyl, phenoxy or naphthyl). A is phenyl or pyridyl (where nitrogen is at the 5-, 6-, 7- or 8-position
In). Z is cyclohexenyl, phenyl, pyridyl (where nitrogen is 1-, 2-
Or at the 3-position) or a 6-membered heterocycle, wherein the ring is at the 1-, 2- or 3-position
Selected from the group consisting of sulfur or oxygen and nitrogen in the 1-, 2-, 3- or 4-position.
One heteroatom or optionally one carbon atom on the heterocycle
Atoms are replaced with = O). Provided that one of A or Z is a heterocyclic ring, or a pharmaceutically acceptable racemic, solvate or tautomer thereof.
, Optical isomers, prodrugs or salts.

Specific carbazole and tetrahydrocarbazole inhibitors that are more desirable in the compositions and methods of the present invention are compounds: (R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1, Two,
(R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,2,4-tetrahydrocarbazol-5-yl) oxyacetic acid;
3,4-tetrahydrocarbazol-5-yl) oxyacetic acid; [N-benzyl-1-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl) oxyacetic acid; 4-methoxy-6 -Methoxycarbonyl-10-phenylmethyl-6,7,8,
9-tetrahydropyrido [1,2-a] indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,
4-b] indol-5-yl] oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole; 2-[(2, 9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-β-carbolin-5-yl) oxy] acetic acid, or a pharmaceutically acceptable racemic, solvate, tautomer thereof Selected from isomers, optical isomers, prodrug derivatives or salts.

The most preferred carbazole / tetrahydrocarbazole inhibitors in compositions and methods of treating sepsis are represented by formulas (Xe) and (XIe):

Embedded image

Embedded image Indicated by

For all of the carbazole and tetrahydrocarbazole types described above, they may be (i) in acid form or (ii) pharmaceutically acceptable (eg, Na
, K) form or (iii) prodrug derivatives (eg, methyl ester, ethyl ester, n-butyl ester, morpholinoethyl ester).

[0126] Prodrugs are derivatives of sPLA ₂ inhibitor for use in the method of the present invention, this compound has a chemically or metabolically cleavable groups and either or physiologically by solvolysis The compounds of the invention are pharmaceutically active in vivo under typical conditions. Derivatives of the compounds of the invention are active in their acid and base forms, but the acid derivative forms often exhibit advantages such as solubility, tissue compatibility, or slow release in vivo in mammals. (See Design of Prodrugs by Bundgard, H., pp. 7-9, 21-24, Elsevier, Amsterdam 1985)
. Prodrugs include acid derivatives well known to those skilled in the art, for example, esters prepared by reaction of the parent compound with a suitable alcohol,
Or amides prepared by reaction of the parent compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups hanging on the compounds of the invention are preferred prodrugs. Optionally, a prodrug of the double ester type (eg, an (acyloxy) alkyl ester or
It is preferred to produce ((alkoxycarbonyl) oxy) alkyl ester). Particularly preferred prodrugs are ester prodrugs such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, N, N-diethylglycolamide and Morpholino-N-ethyl ester). A method for producing an ester prodrug is disclosed in US Pat. No. 5,654,326. For another method of prodrug synthesis, see US Provisional Patent Application 60/0632.
80 (filed on October 27, 1997) (Title is "N, N-diethylglycolamido ester Prodrug
s of Indole sPLA2 Inhibitors "(which forms part of the present specification).
U.S. Provisional Patent Application No. 60/063646 (filed October 27, 1997) (titled "Morpholino
-N-ethyl Ester Prodrugs of Indole sPLA ₂ Inhibitors "(which forms part of this specification); and U.S. Provisional Patent Application No. 60/063284 (filed October 27, 1997). Is `` Isopropyl Ester Prodrugs of Indole sPLA ₂ Inhibitors ''
Which is part of the present specification.

[0127] Useful carbazole and tetrahydrocarbazole sPLA ₂ inhibitor compounds for performing the method of the present invention can be prepared by the following general methods.

Compounds of formula Ie wherein Z is cyclohexene are prepared according to the following schemes Ig (a) and I
g (b). Reaction formula Ig (a)

Embedded image Where R¹Is -NH₂If R³(a) is H, -O (C₁~ C₄ ) Alkyl, halo,-(C₁~ C₆) Alkyl, phenyl,-(C₁~ C₄) Archi
Phenyl, substituted phenyl (the substituent is-(C₁~ C₆) Alkyl, halo
Or -CF₃), -CH₂OSi (C₁~ C₆) Alkyl, furyl, thiof
Enyl,-(C₁~ C₆) Hydroxyalkyl or-(CH₂)_nR⁸(here,
R⁸Is H, -CONH₂, -NR⁹R¹⁰, -CN or phenyl;⁹ And R¹⁰Are independently-(C₁~ C₄) Alkyl or -phenyl (C₁~ C₄)
Alkyl and n is 1-8). Also, R¹Is -NHNH₂If R³(a) is H, -O (C₁~ C ₄ ) Alkyl, halo,-(C₁~ C₆) Alkyl, phenyl,-(C₁~ C₄) Al
Killphenyl, substituted phenyl (the substituent is-(C₁~ C₆) Alkyl, halo
Or -CF₃), -CH₂OSi (C₁~ C₆) Alkyl, furyl, thio
Phenyl,-(C₁~ C₆) Hydroxyalkyl or-(CH₂)_nR⁸(here
, R⁸Is H, -CONH₂, -NR⁹R¹⁰, -CN or phenyl; ⁹ And R¹⁰Are independently-(C₁~ C₄) Alkyl or -phenyl (C₁~ C
₄) Alkyl, and n is 1-8). R²(a) is -OCH₃Or -OH.

The aniline (2) is treated by treating a suitable substituted nitrobenzene (1) with a reducing agent (eg, hydrogen) in the presence of Pd / C (preferably at room temperature).
).

Compound (2) can be N-alkylated with an alkylating agent (eg, a suitably substituted aldehyde) and sodium cyanoborohydride at a temperature of about 0 ° C to 20 ° C. Alternatively, an appropriately substituted benzyl halide can be used first in the alkylation step. The obtained intermediate was 2-carboethoxy-
(4) is obtained by treatment with 6-bromocyclohexanone (preferably at a temperature of about 80 ° C.) or by treatment with potassium hexamethyldisilazide and bromoketoester.

The product (4) can be cyclized in benzene by refluxing with ZnCl ₂ for about 1-2 days, preferably at 80 ° C., to give the tetrahydrocarbazole (5) (Ref. 1). See). Compound (5) is converted to hydrazide (6) by treatment with hydrazine at a temperature of about 100 ° C., or is reacted with methylchloroaluminamide in benzene to give amide (
7) (see Document 2). Alternatively, (7) can be obtained by treating (6) with a Raney nickel active catalyst.

R ^{3 (a)} has the formula:

Embedded image In this case, conversion to the amide will also be achieved with this procedure.

Compounds (6) and (7) are preferably dealkylated at 0 ° C. to room temperature (eg,
Dealkylation using boron tribromide or sodium thioethoxy)
Compound (7) (where R^{2 (a)}Is -OH), which is then converted to a base
(Eg, sodium hydride) and an alkylating agent (eg, Br (CH₂)_mR ⁵ (Where R⁵Is a carboxylate or phosphonate die, as defined above.
(Which is luster or nitrile). R ² Is converted to a carboxylic acid by treatment with an aqueous solution of a base.
Can be R²When is a nitrile, the conversion to tetrazole is
Can be achieved using Libutyltin Azide or to Carboxamide
Can be achieved by reaction with basic hydrogen peroxide.
R²When is a phosphonate diester, the conversion to the acid is effected by a dealkylating agent (eg,
, Trimethylsilyl bromide).
.

When R ² and R ³ are both methoxy, selective demethylation can be achieved by treatment with sodium ethanethiolate in dimethylformamide at 100 ° C.

Reference 1 is “J. Preparation d 'acides tetrahy” by Julia, M .; Lenzi, J.
dro-1,2,3,4-carbazole-1 ou -4 ", Bull Soc. Chim. France, 1962, 2262-2263
It is. Reference 2 is “An alternativ” by Levin, JL; Turos, E ,; Weinreb, SM.
e procedure for the aluminum-mediated conversion of esters to amides '',
Syn. Comm., 1982, 12, 989-993.

Another synthesis of intermediate (5) is shown in the following reaction formula I (b). Reaction formula Ig (b)

Embedded image Here, PG is a protecting group. R ^3a is as defined in Reaction Scheme 1 above. Aniline (2) in dimethylformamide in the presence of sodium bicarbonate
N-alkylation by reaction with 2-carboethoxy-6-bromocyclohexanone at 0 ° C for 8-24 hours. Preferred protecting groups include, for example, methyl, carbonate and silyl groups (eg, t-butyldimethylsilyl). Reaction product (4 '
) Is cyclized with ZnCl ₂ under the benzene conditions described in Reaction Scheme I (a) above to give (5 ′). The formation of (5) by N-alkylation of (5 ′) is achieved by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours.

Reaction Scheme IIg

Embedded image R ^{3 (a)} is as defined in Reaction Formula Ig. As described in Reaction Scheme I above, carbazole (5) is hydrolyzed by treatment with an aqueous base solution (preferably at room temperature to about 100 ° C.) to give carboxylic acid (10). The intermediate is then converted to a useful acid chloride using, for example, oxalyl chloride and dimethylformamide, and then the temperature is reduced to about -75 ° C.
To further react with the lithium salt of (S) or (R) -4-alkyl-2-oxazolidine to give (11a) and (11b). This can be separated by chromatography.

The diastereomer is obtained by simple treatment with lithium benzyl oxide at a temperature of about 0 ° C. to room temperature to give the corresponding enantiomeric benzyl ester (12) (see ref. 3). The ester (12) is then treated, preferably with methylchloroaluminum amide (see reference 2 above),
Alternatively, a hydrogenation reaction is performed using hydrogen and palladium-carbon, as described above, followed by an acyl azide (eg, diphenylphosphoryl azide)
And then treated with ammonia to convert to (7). Compound (9a) or (9b) can be obtained using the method described in Reaction Scheme I above.

Reference 3 is “Asymmet, by Evans, DA; Ennis, MD; Mathre, DJ.
ric alkylation reactions of chiral imide enolates.A practical approach
to the enantioselective synthesis of alpha-substituted carboxylic acid d
erivatives. ", J. Am. Chem. Soc., 1982, 104, 1737-1738.

Compounds of formula Ie wherein Z is phenyl can be prepared as described in Schemes III (a)-(f) below. Reaction formula III (a)

Embedded image 1,2,3,4-tetrahydrocarbazole or 4-carboxyhydrazide (
13) is refluxed in a solvent such as carbitol in the presence of Pd / C to carry out a dehydrogenation reaction to obtain carbazole-4-carboxamide. Alternatively, (13)
By treating with DDQ in a suitable solvent (eg, dioxane)
The carbazole (14) is obtained.

Following the oxidation reaction according to the substituent patterns described above, dealkylation on nitrogen can occur. For example, if R ³ is substituted by methyl at the 8-position, the oxidation reaction will result in dealkylation on the nitrogen, and the nitrogen will be converted to sodium hydride as described in Scheme I (a) above. And by treating with a suitable alkylating agent, the desired product (14) can be obtained by alkylation again.

Reaction formula III (b)

Embedded image R ^{3 (a)} is as defined in Reaction Scheme I (a) above. PG is an acid protecting group. X is halo. Benzoic acid derivative (16) (where X is preferably chlorine, bromine or iodine,
The protecting group is preferably -CH _3), Chem by general conditions (Sakamoto et al Pha
rm. Bull, 35 (5), 1823-1828 (1987)), reducing to the corresponding aniline (25) using a reducing agent (eg tin (II) chloride) in the presence of an acid.

Alternatively, the starting material may be reduced with sodium dithionite in a non-interfering solvent (eg, water, ethanol and / or tetrahydrofuran) in the presence of a base (eg, sodium carbonate) (16) is obtained.

Alternatively, the reduction reaction is carried out by a hydrogenation reaction (1 to 60 pressure) over a sulfided platinum catalyst supported on carbon in a non-interfering solvent (preferably ethyl acetate), The starting material (16) is obtained.

The reaction is carried out at about 0 ° C. to 100 ° C. (preferably at ambient temperature) and is substantially complete in about 1 to 48 hours, depending on conditions.

The aniline (25) and the dione (15) can be treated, for example, under dehydration conditions at a temperature of about 1
The condensation reaction is carried out under dehydrating conditions at 0 to 150 ° C. with or without a non-interfering solvent (eg toluene, benzene or dichloromethane) using the general procedure by Iida et al. The water formed in the process can be removed by distillation, azeotropic removal with a Dean-Stark apparatus, or by adding desiccants (eg, molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, etc.). .

The process can be performed with or without a catalytic amount of an acid (eg, p-toluenesulfonic acid or methanesulfonic acid). Other examples of suitable catalysts include hydrochloric, phenylsulfonic, calcium chloride and acetic acid.

Examples of other suitable solvents include, for example, tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,1,2,2-tetrachloroethane, chlorobenzene, bromobenzene, xylene and carbon tetrachloride.

The condensation of the present process is preferably performed neat at a temperature of about 100-150 ° C., and the resulting water is removed by distillation under flowing inert gas (eg, nitrogen or argon).

The reaction is substantially complete in about 30 minutes to about 24 hours.

Then, the intermediate (26) is converted to a palladium catalyst (for example, Pd (OAc) ₂ or P
d like (PPh _{3) 4),} phosphine (triphenylphosphine, tri alkyl tris -o- tolyl phosphine or tricyclohexylphosphine - or triarylphosphine is preferred), a base (e.g., sodium hydrogen carbonate,
About 25-2 in a non-interfering solvent (eg, acetonitrile, triethylamine or toluene) in the presence of triethylamine or tridiisopropylamine).
It can be easily cyclized at a temperature of 00 ° C. to give (19).

[0152] Examples of other suitable solvents include tetrahydrofuran, benzene, dimethylsulfoxide or dimethylformamide.

Examples of other suitable palladium catalysts include Pd (PPh ₃ ) Cl ₂ , Pd (OC
_{OCF 3) 2, [(CH} 3 C 6 H 4) P] 2 PdCl 2, [(CH 3 CH 2) P] 2 Pd
Cl _2, containing _{[(C 6 H 11) 3} P] 2 PdCl 2 and _{[(C 6 H 5) 3} P] PdBr 2.

Examples of other suitable phosphines include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane and 4-bis (
Diphenylphosphino) butane.

Examples of other suitable bases include tripropylamine, 2,2,6,6-tetramethylpiperidine, 1,5-diazabicyclo [2.2.2] octane (DABCO),
1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), sodium carbonate, potassium carbonate and hydrogen carbonate Contains potassium.

The cyclization reaction of this method is carried out in the presence of palladium (II) acetate as a catalyst, using any of triphenylphosphine, tri-o-tolylphosphine, 1,3-bis (diphenylphosphino) propane or tricyclohexylphosphine. In the presence of triethylamine as a base in acetonitrile as solvent,
It is preferably carried out at a temperature of about 150 ° C. The reaction is substantially complete in about 1 hour to 14 days.

Alternatively, a preferred method for cyclization is to use a paradacycle catalyst (eg, trans-di (μ) in a solvent such as dimethylacetamide (DMAC) at 120-140 ° C. in the presence of a base such as sodium acetate. -Acetato) -bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) with intermediate (26).

Intermediate (19) can be alkylated with an alkylating agent, XCH ₂ R _4, where X is halo, in the presence of a base. Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride and Triton B (N -Benzyltrimethylammonium hydroxide).

The reaction may or may not be carried out in the presence of a crown ether. Potassium carbonate and Triton B are preferred. However, the amount of alkylating agent is not critical and the reaction is best achieved with an excess of alkyl halide relative to the starting material.

A catalytic amount of iodide (eg, sodium or lithium iodide) may or may not be added to the reaction mixture. The reaction is preferably performed in an organic solvent (for example, acetone, dimethylformamide, dimethylsulfoxide or acetonitrile). Other suitable solvents include, for example, tetrahydrofuran, methyl ethyl ketone and t-butyl methyl ether.

The reaction is preferably carried out at a temperature of about -10 to 100 ° C (preferably at ambient temperature) and is preferably substantially complete in about 1 to 48 hours, depending on the conditions. Optionally, a phase transfer reagent (eg, tetrabutylammonium bromide or tetrabutylammonium chloride) can be used.

Intermediate (20) was prepared in a non-interfering solvent using 2,3-dichloro-5,6-dicyano-1
(21) can be obtained by dehydrogenation with 2,4-benzoquinone.

[0163] Suitable solvents include dichloromethane, chloroform, carbon tetrachloride, diethyl ether, methyl ethyl ketone and t-butyl methyl ether. Toluene, benzene, dioxane and tetrahydrofuran are preferred solvents. The reaction is carried out at a temperature from about 0C to 120. Temperatures between 50 and 120C are preferred. The reaction is substantially complete in about 1 to 48 hours, depending on the conditions.

Intermediate (21) can be aminated with ammonia in the presence of a non-interfering solvent to give (229. Ammonia can be in the form of ammonia gas or an ammonium salt (eg, Ammonium hydroxide, ammonium acetate, ammonium trifluoroacetate, ammonium chloride, etc. Suitable solvents include, for example, ethanol, methanol, propanol, butanol,
Contains tetrahydrofuran, dioxane and water. A mixture of concentrated aqueous ammonium hydroxide and tetrahydrofuran or methanol is preferred for the present method. The reaction is performed at a temperature of about 20-100C. Temperatures of 50-60 ° C are preferred.
The reaction is substantially complete in about 1 to 48 hours, depending on the conditions.

The alkylation of (22) can be carried out in a non-interfering solvent in the presence of a base in the presence of a base of the formula: XCH₂R ⁹ (Where X is halo and R⁷⁰Is -CO₂R⁷¹, -SO₃R⁷¹, -P
(O) (OR⁷¹)₂Or -P (O) (OR⁷¹) H and R⁷¹Is an acid protecting group
Or a prodrug functional group).
To obtain (23). Methyl bromoacetate and t-butyl bromoacetate
Is a preferred alkylating agent.

Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride and triton B
(N-benzyltrimethylammonium hydroxide). The reaction may or may not be performed in the presence of a crown ether. Cesium carbonate and Triton B are preferred.

However, the amount of the alkylating agent is not critical, and the reaction is best achieved by using an excess of the alkyl halide relative to the starting materials. The reaction is preferably performed in an organic solvent (for example, acetone, dimethylformamide or acetonitrile). Other applicable solvents include tetrahydrofuran, methyl ethyl ketone and t-butyl methyl ether.

The reaction is carried out at a temperature of about -10 ° C to 100 ° C (preferably at ambient temperature) and is substantially complete in about 1 to 48 hours depending on the conditions. Optionally, a phase transfer catalyst (eg, tetrabutylammonium bromide or tetrabutylammonium chloride) can be used.

Intermediate (23) is optionally hydrolyzed with a base or acid to give the desired product (2
4) can be obtained and optionally salified.

The hydrolysis of the intermediate (23) is carried out by a base (for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate aqueous solution, sodium carbonate aqueous solution, lithium carbonate aqueous solution, potassium hydrogencarbonate aqueous solution, sodium hydrogencarbonate aqueous solution , An aqueous lithium hydrogen carbonate solution, preferably sodium hydroxide) and a lower alcohol solvent (eg, methanol, ethanol, isopropanol, etc.). Other suitable solvents include acetone, tetrahydrofuran and dioxane.

Alternatively, acid protecting groups can be removed by organic and inorganic acids (eg, trifluoroacetic acid and hydrochloric acid), with or without non-interfering solvents.
Suitable solvents include dichloromethane, tetrahydrofuran, dioxane and acetone. The t-butyl ester is preferably removed by neat trifluoroacetic acid.

The reaction is carried out at a temperature of about -10 to 100 ° C (preferably at ambient temperature) and is substantially complete in about 1 to 48 hours depending on the conditions.

The starting material (16) is an alkyl halide in the presence of a base (preferably potassium carbonate or sodium carbonate) in a non-interfering solvent (preferably dimethylformamide or dimethylsulfoxide). XPG (where
X is halo and PG is an acid protecting group). The preferred alkyl halide is methyl iodide. The reaction is about 0
C. to 100.degree. C. (preferably ambient temperature), depending on the conditions,
It is virtually complete in 8 hours.

Alternatively, the starting material (16) may be treated with an alcohol, HOPG, where PG is an acid protecting group, in the presence of a dehydration catalyst (eg, dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole). And by condensation.

In addition, US Pat. No. 4,885,338 and US Pat. No. 5,286,912 (November 1993) teach methods for making 2-fluoro-5-methoxyaniline derivatives. Reaction formula IIIg (c)

Embedded image R is as defined in Reaction Scheme IIIg (b). R ^{3 (a)} is as defined in Reaction Formula Ig (a) above. And X is halo.

The benzoic acid derivative (16) (where X = Cl, Br or I) and the boronic acid derivative (27), which are either commercially available or from commercially available starting materials A palladium catalyst (eg, Pd (PPh ₃ ) ₄ ), a base (eg, sodium bicarbonate),
Miyaura in the presence of an inert solvent (eg, THF, toluene or ethanol)
The compound (28) is obtained by condensation under the general preparation method of U.S.A. et al. (References 8a) or Trecourt et al. (References 8b).

Compound (28) can be treated with a trialkyl or triaryl phosphite or phosphine (eg, triethyl phosphite or triphenyl phosphine) according to the general procedure by Cadogan et al. Converted to carbazole product (29).

Compound (29) is optionally substituted with an alkyl halide or aryl in a non-interfering solvent (eg, toluene, dimethylformamide or dimethyl sulfoxide) in the presence of a base (eg, sodium hydride or potassium carbonate). N-alkylation is performed using XCH ₂ R ⁴ which is a halide.

Compound (30) is treated with boron tribromide or sodium thioethoxy, followed by treatment with ammonia or an ammonium salt (eg, ammonium acetate) in an inert solvent (eg, water or alcohol). Alternatively, it is converted to the corresponding amide (22) by treatment with methylchloroalminum amide in an inert solvent (eg, toluene) at a temperature of 0 to 110 ° C.

When R ^{3 (a)} is substituted with chloro at the 8-position, (30)
) With boron tribromide results in debenzylation on nitrogen. Alkylation can be easily achieved in a two step process. First, O-alkylation is performed by treatment with a haloalkyl acetate (eg, methyl bromoacetate) using sodium hydride in tetrahydrofuran, followed by a base (eg, sodium hydride) in, for example, dimethoxyformamide. ) And appropriately substituted alkyl and aryl halides
Perform alkylation. Compound (22) as described in Reaction Scheme IIIg (b) above.
Can be converted to give the carbazole product (24).

Conversion to the desired prodrug can be accomplished by methods known to those skilled in the art, for example, by treatment with a primary or secondary halide to produce an ester prodrug. Reaction formula IIIg (d)

Embedded image Alternatively, in a non-interfering solvent (eg, ethanol) at 1 to 60 atm, 0 to
Performing a reduction reaction of the nitro group of compound (28) using a reducing agent (eg, hydrogen in the presence of palladium-carbon) at a temperature of 60 ° C. gives the corresponding aniline (
32) is obtained. Compound (32) is converted to carbazole (29) according to the general procedure described by Trecourt et al. (Reference 8b). The aniline is treated with sulfuric acid and sodium nitrite, followed by treatment with sodium azide to give the intermediate azide, which is heated by heating in an inert solvent (eg, toluene). Obtain carbazole (29). Compound (29)
Conversion to the carbazole product (24) as described in Schemes IIIg (b) and IIIg (c) above.

References 8) a) are Synth. Commun. 11, 513, (1981) by N. Miyaura et al., And b) are Tetrahedron, 51, 11743 by F. Trecourt et al. Reference 6) is J. Chem. Soc., 4831 (1965) by J. Cadogan et al.

Reaction Scheme IIIg (e)

Embedded image The reduction reaction of (40) in an aprotic solvent (preferably tetrahydrofuran) is achieved using a reducing agent (eg, aluminum trihydride). The reaction is preferably performed at room temperature under an inert atmosphere (for example, nitrogen).

The sulfonylation reaction can be accomplished using a suitable acylating agent in the presence of an acid scavenger (eg, triethylamine).

Reaction Formula IIIg (f)

Embedded image In a two-step one-pot process, intermediate (50), prepared as described in Scheme I (a) above, is first activated with an activating agent (eg, carbonyldiimidazole). The reaction is preferably performed in an aprotic polar or non-polar solvent (eg, tetrahydrofuran). The acylation reaction on the activated intermediate is carried out in the presence of H ₂ NS in the presence of a base (preferably diazabicycloundecene).
It is accomplished by reaction with OR ^15.

Reaction Formula IIIg (g)

Embedded image PG is an acid protecting group. R ²² is (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl is (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkenyl. O-alkylation of the starting material (20) with an alkyl halide or alkenyl halide in an aprotic polar solvent (preferably anhydrous DMF) under a nitrogen atmosphere at ambient temperature with a base (e.g. NaH). I do. A method of aromatizing a cyclohexenone functionality to a phenol functionality involves the preparation of a tetrahydrocarbazole intermediate (16) in an anhydrous solvent (eg, 1,4-dioxane or DMF) in the presence of methyl benzenesulfinate. (For example, NaH) to obtain a ketosulfoxide derivative. After heating at about 100 ° C for 1 to 2 hours, the ketosulfoxide derivative (60) was converted to a phenol derivative (6).
Convert to 1). The conversion of the ester (61) to the amide (62) is performed using ammonia gas in an aprotic polar solvent (eg, tetrahydrofuran) (
61) can be achieved by treating the solution. For example, O- alkylation of phenol with methyl bromoacetate (62), in anhydrous DMF, performed using _Cs 2 CO ₃ or _K 2 CO ₃ as base at ambient temperature, to obtain the (63) it can. The desired product _(64), 3 OH / THF solution H ₂ O / CH, 5
It can be derived from carrying out base hydrolysis of ester (63) with LiOH or NaOH at 0 ° C. for 1-2 hours.

When R ²² is — (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkenyl,
The hydrogenation reaction of the double bond can be carried out by treating (63) with PtO ₂ as a catalyst in a hydrogen atmosphere in THF. Then, the target compound was dissolved in a H ₂ O / CH ₃ OH / THF solution as described in the above Reaction Scheme III (g).
Ester (63) using LiOH or NaOH as base at 1-2 ° C. for 1-2 hours
Can be derived from performing a hydrolysis reaction with a base.

Compounds of Formula Ie (where Ring A is phenyl and the heteroatom of Z is sulfur, oxygen or nitrogen) are prepared as described in Schemes IV (a)-(f) below. can do.

Reaction Formula IVg (a)

Embedded image PG is an acid protecting group. X is halo. R ^{3 (a)} _{is, H, -O (C 1 ~C} 4) alkyl, halo, -O _(C 1 ~C ₆₎ alkyl, phenyl, - _(C 1 ~C ₄₎ alkyl phenyl, substituted phenyl (the substituents, - _(C 1 ~C ₆₎ alkyl, halo or -CF _3), - _CH 2 OS
i _(C 1 ~C ₆₎ alkyl, furyl, thiophenyl, - _(C 1 ~C ₄₎ hydroxyalkyl or ^{_{- (CH 2) n R 8}} ( wherein, ^{R 8} is ^{H, -NR} 9 R 10, -CN Or phenyl, and R ⁹ and R ¹⁰ are independently-(C ₁ -C ₄ ) alkyl or -phenyl (C ₁ -C ₄ ) alkyl, and n is 1-8.

The indole-3-acetic ester (101) (Cited Document 10) is alkylated by treatment with an alkali metal amide and benzyloxymethyl chloride to give (102), which is catalytically hydrogenated. Alcohol (1
03). The alcohol is alkylated to give the acetal of formaldehyde (104), which is cyclized with Lewis acid to give pyrano [3,4-b
] Indole (105) is obtained. The ester is converted to amide (106) by methylchloroaluminum amide and then to phenol (107) using boron tribromide. O-alkylation of the phenol to give (108),
This is hydrolyzed to obtain the acid (109).

10) J. Med. Chem. 39, 26th edition, 5119-5136 by Dillard, R. et al.

Reaction Formula IVg (b)

Embedded image PG is an acid protecting group. W is halo, alkylsulfonyl or arylsulfonyl. R ^{3 (a)} _{is, H, -O (C 1 ~C} 4) alkyl, halo, -O _(C 1 ~C ₆₎ alkyl, phenyl, - _(C 1 ~C ₄₎ alkyl phenyl, substituted phenyl (the substituents, - _(C 1 ~C ₆₎ alkyl, halo or -CF _3), - _CH 2 OS
i _(C 1 ~C ₆₎ alkyl, furyl, thiophenyl, - _(C 1 ~C ₆₎ hydroxyalkyl or ^{_{- (CH 2) n R 8}} ( wherein, ^{R 8} is ^{H, -NR} 9 R 10, -CN Or phenyl, and R ⁹ and R ¹⁰ are independently-(C ₁ -C ₄ ) alkyl or -phenyl (C ₁ -C ₄ ) alkyl, and n is 1-8.

By reacting the alcohol (103) with an aldehyde and an acid,
Pyranoindole (110) is obtained.

The conversion of the hydroxyl function of (103) to a halide or sulfate functionality can be treated with triphenylphosphine and CH ₃ X, where X is a halogen, to form a compound of formula (111) (where X is a halogen). Where X is a halide), or by treatment with triethylamine and methanesulfonyl chloride to give the sulfonate. Substitution reaction using the sodium salt of thiolacetic acid gave (114), which in turn was hydrolyzed with a base to give thiol (115), which was reacted with an appropriately substituted aldehyde and acid. Thiopyranoindole (116) is obtained.

Intermediate (111) is reacted with sodium azide to give azide derivative (112)
Which can be reduced by catalytic hydrogenation to give the amine, which can also be converted to carboline (113) using aldehydes and acids.

Intermediates (113), (110) and (116) can be N-alkylated with sodium hydride and an appropriately substituted alkyl halide XCH ₂ R ⁴ . Reaction formula Ivg (c)

Embedded image

Embedded image PG is an acid protecting group. R ^{3 (a)} is as defined above. The 4-methoxyindole (117) is converted to the indoleacetic acid derivative (118) by alkylation with epoxy propionate. (118
) Is treated with a brominating reagent to give a mixture of the bromo isomers (119) and (120), which is treated with a base to give the spiro compound (121).
Get. Heating (121) together with benzyl bromide gives a mixture of isomers of the bromo compounds (122) and (123), which is reacted with potassium thioacetate to give a mixture of isomers. (124) can be separated from this. The thioester is solvolyzed to give the thiol (125), which is alkylated to give (126). The Lewis acid converts (126) to thiopyrano [3,4-b] indole (127). The ester function is converted to an amide using methylchloroaluminum amide, the methyl ether is cleaved with boron tribromide, and the product phenol is O-alkylated with bromoacetate (130). And hydrolyzing it (13).
Obtain 1).

Reaction Formula IVg (d)

Embedded image X is halo. R ^{3 (a)} is as defined above Scheme I (a), R is - (CH _{2) m} R ^5. Oxygen protection is achieved by treatment of (132) with tert-butyldimethylsilyl chloride and imidazole in an aprotic polar solvent (eg, tetrahydrofuran or dichloromethane) to give (133).

Alkylation at the 3-position of indole (133) can be accomplished by starting the temperature at about 10 ° C., warming to room temperature, treating with n-butyllithium, then zinc chloride, followed by the appropriate haloalkyl This is accomplished by reacting with an ester (eg, methyl or ethyl bromoacetate). The reaction is preferably performed in a suitable aprotic polar solvent (eg, tetrahydrofuran) at room temperature.

The alkylation of the nitrogen of the indole can then be accomplished by reacting (134) with a suitable alkyl halide in the presence of potassium bis (trimethylsilyl) amide to give compound (135).

The ester functionality of (135) is converted to the trimethylsilyl ketene acetal (136) by treatment with bis (trimethylsilyl) amide and trimethylsilyl chloride. Treatment of the ketene acetal (136) with bis (chloromethyl) sulfide and zinc bromide in dichloromethane gives the cyclic product (137). Conversion to the amide (138) can be achieved by a Weinreb reaction using methylcycloaluminamide. An oxygen protecting group can be added to a fluoride source (eg, tetrabutylammonium fluoride (TBA)
F)) and reacting the resulting anion with, for example, ethyl bromoacetate to give the ester (139). The desired acid (140) is obtained by the deprotection reaction of the ester.

Reaction Formula IVg (e)

Embedded image R ^{3 (a)} is as described in Reaction Formula I (a), and R is as described in Reaction Formula IV (d). Treatment of the ketene acetal (136) with bis (chloromethyl) ether and zinc bromide in dichloromethane gives the cyclic product (141). Conversion to the amide (142) was performed using methylchloroaluminum amide
It can be achieved by an inreb reaction. The oxygen protecting group is removed using a fluoride source (eg, tetrabutylammonium fluoride) and the resulting anion is reacted with ethyl bromoacetate to give ester (143). Deprotection of the ester gives the desired acid (144).

Reaction Formula IVg (f)

Embedded image

Embedded image N-alkylation with commercially available 4-methoxyindole (231) using an alkyl halide under basic conditions gives N-alkylindole (232). Glyoxylate product (233) is obtained by acylation using a suitable acid chloride, and this product is reduced using various hydride reducing agents, whereby alcohol (234) as an intermediate is obtained. Obtainable. Conversion of the alcohol to a suitable leaving group and displacement with a sulfur nucleophile gives the thioether product (235). Conversion to the acid chloride and simultaneous cyclization gives the thioketone product (236). The cleavage of the ester can be carried out effectively under basic conditions to give the corresponding acid, which produces the acid chloride and reacts with the appropriate amine to give the amide product (237). By cleaving the methyl ether, phenol (
238), which is alkylated under basic conditions with an alkyl halide to give the O-alkylated product (239). The desired product (140) is obtained by cleaving the ester under basic conditions. Alternatively, the benzyl ketone is reduced with a hydride reducing agent, followed by deoxygenation of the resulting alcohol to give the deoxygenated product (244). Cleavage of the oxyacetic acid ester under basic conditions gives the desired oxyacetic acid (242).

A compound wherein Z is an aromatic ring or a nitrogen-containing heterocyclic ring can be produced as described in the following reaction formulas Vg (a) to (e). Reaction formula Vg (a)

Embedded image Condensation of the substituted haloaniline (145) with N-benzyl-3-piperidone gives the enamine (146). In the ring closure reaction, (146) is converted to palladium acetate
It is effective by treating with (II) and converting the obtained product to (147) by treating with cyanogen bromide. The alkylation of (147) is accomplished by treatment with the appropriate alkyl bromide using sodium hydride as the base. Hydrolysis of this N-alkylated product with basic hydrogen peroxide under standard conditions gives (148). (1
The demethylation reaction of 48) is carried out by treating with boron tribromide in dichloroethane. The resulting phenol (149) is O-alkylated with methyl bromoacetate in the presence of a base and hydrolyzed with a hydroxide to give the intermediate salt, which is then added to an aqueous acid solution To give the desired δ-carboline (150).

Reaction formula Vg (b)

Embedded image X is halo; R is as defined in Reaction Formula IV (d); R ^{3 (a)} is as defined in Reaction Formula I (a). The ketene acetal (136) prepared as described in Scheme IV (d) is reacted with benzylbis (methoxymethyl) amine in the presence of zinc chloride to give tetrahydro-β-carboline (151).

(151) was treated with lithium hydroxide, neutralized with hydrochloric acid, and then treated with 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and ammonia to give the desilylated amide (152) (wherein
R ²⁰ is hydrogen), which can be alkylated using, for example, ethyl bromoacetate to give ester (153).

Alternatively, treatment of (115) with an appropriate Weinreb reagent provides
Amide (152) (R ²⁰ is a is t- butyldimethylsilyl) to give a tetra this thing - n - desilylated with tetrabutylammonium fluoride, for example alkylated by ester using Buroo ethyl acetate ( 153) is obtained. Lithium hydroxide-mediated hydrolysis gives acid (154), which is subjected to a hydrogenation reaction on a suitable catalyst in the presence of hydrochloric acid to give the hydrochloride tetrahydro-β-carboline (155). Can be obtained. Compound (155) can be aromatized by refluxing in sequence with palladium and carbon in carbitol to give β-carboline (156).

Reaction formula Vg (c)

Embedded image X is halo; R is as defined in Reaction Formula IV (d); R ^{3 (a)} is as defined in Reaction Formula I (a). In a one-pot reaction, the indole (133) was treated successively with one equivalent of n -butyllithium, carbon dioxide gas, one equivalent of t -butyllithium and 1-dimethylamino-2-nitroethene (157). The dinitroalkene (157) is reduced with lithium aluminum hydride to give the amine (157), which is cyclized in refluxing ethanol with methyl glyoxylate to give tetrahydrocarboline. (159) (Reference 9)
). Alkylation of both nitrogens of (159) leads to intermediate (160), which is treated with the appropriate Weinreb reagent to give amide (161). Ester (162) is obtained by desilylation reaction with fluoride and alkylation using, for example, ethyl iodoacetate, which is subjected to a hydrogenation reaction over a suitable catalyst, followed by hydrolysis with a base. , Acid (163). (16
Aromatization of 3) to carboline (164) is achieved by refluxing in carbitol in the presence of palladium-carbon.

Reference 9: Aconv by Kelley, TR; Schmidt, TE; Haggerty, JG
enient preparation of methyl and ethyl glyoxylate, Synthesis, 1972, 544-
Five.

Reaction formula Vg (d)

Embedded image

Embedded image The commercially available acid (170) is reduced using lithium aluminum hydride, oxidized using pyridinium chlorochromate, and silylated using t-butyldimethylsilyl chloride to give (171). . Treatment with sodium azide affords the azide (172), which is reacted with nitromethane and potassium hydroxide in ethanol, followed by treatment with acetic anhydride and pyridine to give the nitroolefin (172). 173) is obtained. Heating in xylene causes a cyclization reaction to give indole (174). For example, alkylation with benzyl iodide and sodium hydride gives (17
5) is obtained, and this is subjected to a hydrogenation reaction in the presence of palladium-carbon to obtain an amine (176). Acylation of the commercially available acid chloride of oxaloacetic acid monoethyl ester gives (177), which is thermally cyclized to give the lactam (178). The selective reduction reaction of the lactam carbonyl is
Accomplished by treatment process _using NaBH ₂ S3, it is possible to obtain the amine (179).

The amine (179) was protected with di- t -butyl dicarbonate and pyridine to give (180), which was conjugated to the amide (1) with a suitable Weinreb reagent.
80). A desilylation reaction with fluoride, for example, an alkylation reaction with ethyl iodoacetate and potassium carbonate, a hydrolysis reaction with a base, and a hydrolysis reaction with an acid give tetrahydro-α-carboline (182).

Alternatively, amine (179) can be aromatized by refluxing in carbitol or some other suitable high boiling solvent to form α-carboline (183)
Which can be converted to the amide (184) using the appropriate Weinreb reagent. As described above, desilylation with fluoride, alkylation with ethyl iodoacetate and potassium carbonate, and hydrolysis with a base gives α-carboline (185).

Reaction formula Vg (e)

Embedded image X is halo and R ^{3 (a)} is as defined above. Reaction formula V (e) gives δ-carboline (198) by the above series of reactions. An N-alkylation reaction of 2-carbethoxyindole (190) is performed,
Subsequent homologation of standard two carbons gives 2- (3-propenoic acid) indole (194). In this series of operations, the condensation reaction of aldehyde (193) with malonic acid used a mixture of pyridine and piperidine as base. Ring formation (196) after formation with methyl ester and hydrogenation reaction of (195)
Is bis (2,2,2-trichloroethyl) azodicarboxylate (BTCEAD
) Followed by treatment with zinc in acetic acid. Reduction of the cyclic amide with lithium aluminum hydride followed by treatment with trimethylsilyl isocyanate provided urea (197). Conversion to the desired d-carboline (198) was achieved under the usual conditions of a demethylation step followed by an alkylation step and an ester hydrolysis step.

The reverse indole, ie, a compound wherein B is carbon and D is nitrogen, can be prepared as described in Scheme VIg below. Reaction formula VIg

Embedded image Arylhydrazine (200) is condensed with substituted propionaldehyde to give hydrazone, which is cyclized by treatment with phosphorus trichloride at room temperature to give indole (201) (Cited Document 1). . The indole is N-alkylated by reaction with a base (eg, sodium hydride) and an α-bromoester to give indole (202), which can be reacted with a Lewis acid (eg, aluminum chloride) or with a radical Cyclization with an initiator (eg, tributyltin hydride) gives tetrahydrocarbazole (203). Compound (20
3) can be converted to carbazole by refluxing in a solvent such as carbitol, for example, in the presence of Pd / C.

Compounds of formula I wherein A is pyridyl can be prepared as described in Schemes VIIg (a)-(b) below. Reaction formula VIIg (a)

Embedded image X is halo, and R is (CH ² ) _m R ⁵ . Commercially available 4-chloroindole (210) is prepared by using 3 equivalents of t -butyllithium, followed by carbon dioxide, 1 equivalent of n -butyllithium, 1-dimethylamino-2-nitroethene and an acid. Treatment with carboxylic acid (21
After obtaining 1), this can be esterified to obtain (212). Alkylation at the 1-position followed by hydrogenation gives aminoethylindole (214). Cyclization with phosgene to give (215) followed by aromatization gives carboline (216). (216) to a suitable Weinreb
Treatment with a reagent gives the amide (217), which is alkylated using, for example, ethyl bromoacetate and saponified using sodium hydroxide to give the carboline (218).

Reaction formula VIIg (b)

Embedded image R ^{3 (a)} is as defined in Scheme I (a), X is halo, and R is (CH ₂ ) _m R ⁵ . The 1,3-dione structure (228) is commercially available or can be easily prepared from commercially available starting materials using known techniques.
The preparation of the aniline derivative (220) (where X is Cl, Br or I) involves the preparation of an appropriately substituted benzoic acid derivative in a solution of hydrochloric acid in an inert solvent (eg, ethanol) with a reducing agent (eg, SnCl 2). ₂ ) or the corresponding aniline is obtained and treated with a reducing agent (eg SnCl ₂ ) in a solution of hydrochloric acid in an inert solvent (eg ethanol), or with hydrogen gas and sulfide It is achieved by reducing to the corresponding aniline by performing a hydrogenation reaction with platinum or carbon or palladium-carbon. The amino group of (228) is protected using a suitable protecting group such as, for example, carbethoxy, benzyl, CBZ (benzyloxycarbonyl) or BOC (tert-butoxycarbonyl) protecting group.

Dione (228) and the aniline derivative (220) were prepared according to Chen et al.
) Or according to the general procedure of Yang et al. (Ref. 11) to give the coupled product (221), with or without non-interfering solvents (eg methanol, toluene, dichloroethane). With or without an acid (e.g., p-toluenesulfonic acid or methanesulfonic acid), with or without N-chlorosuccinimide and dimethyl sulfide.

Compound (221) is cyclized using a copper (I) salt in an inert solvent under basic conditions according to the general procedure by Yang et al. (Reference 8). Derivative (221)
Treat with a base (eg, sodium hydride) in an inert solvent (eg, HMPA) at a temperature of 0-25 ° C. A copper (I) salt (eg, copper (I) iodide) is added, and the resulting mixture is stirred at a temperature of 25 to 150 ° C. for 1 to 48 hours to give compound (2
22) is obtained.

Compound (221) can be cyclized according to the general procedure by Chen et al. (Cited Document 10). Derivative (221) is prepared in an inert solvent (eg, HMPA)
Treatment with a base (eg, sodium bicarbonate) and a palladium catalyst (eg, Pd (PPh ₃ ) ₄ ) at a temperature of 25-150 ° C. gives compound (222).
.

In a preferred method, intermediate (171) is converted to a base (eg, triethylamine)
A transition metal catalyst (for example, P) using a DMF / acetonitrile cosolvent in the presence of
Treat with d (OAc) (O-tolyl) ₃ P) to produce (222).

Compound (222) is converted to a base (eg, sodium hydride or potassium carbonate)
N-alkylation with an appropriately substituted benzyl halide in a non-interfering solvent (e.g., dimethylformamide or dimethylsulfoxide) in the presence of
The ketone (223) is obtained. In a two-step, one-pot process, (222) is aromatized by treatment with acetic acid and palladium-carbon in a non-interfering solvent (eg, carbitol or cymene), followed by hydrogen gas and palladium-carbon. Cleavage of the nitrogen protecting group by treatment with carbon gives the phenol derivative (224).

The ester (224) can be prepared using ammonia (preferred) or an ammonium salt (eg, ammonium acetate) in an inert solvent (eg, water or alcohol, preferably methanol) under standard conditions, or inert solvent (e.g., toluene) in, by using MeClAlNH ₂ at a temperature of 0 to 110 ° C., is converted to the corresponding amide (225). Bases (eg, cesium carbonate,
Alkylating the phenol oxygen in compound 38 with a suitable haloester (eg, methyl bromoacetate) in an inert solvent (eg, dimethylformamide or dimethylsulfoxide) in the presence of potassium carbonate or sodium carbonate). Yields the ester-amide (226). The corresponding ester can be prepared using other haloesters (eg, ethyl bromoacetate, propyl bromoacetate, butyl bromoacetate, etc.).

The compound (226) is saponified with lithium hydroxide in an inert solvent (eg, methanol-water) to give (227). Intermediates and end products are isolated by conventional techniques (eg, chromatography or recrystallization)
It can be purified. Regioisomeric products and their intermediates can be prepared by standard methods (
For example, recrystallization or chromatography).

References: 10) Synthesis 385 (1995) by L.-C. Chen et al. 11) Heterocycles, 32, 2399 (1991) by S.-C. Yang et al.

[0224] h) pyrazole sPLA ₂ inhibitor composition and method of the present invention are described in U.S. Patent Application 08/984261 (filed December 3, 1997) (which constitutes a part of this specification) pyrazole sPLA (also described their preparation) ₂ inhibitors produced using, can be performed. Suitable pyrazole compounds are of the formula (Ih):

Embedded image [Wherein R ¹ is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin-2-yl, pyridin-2-yl substituted in the 4-position (the substituent is-(C ₁ -C ₄ ) alkyl ,-(C ₁ -C ₄ ) alkoxyl, -CN or-(CH ₂ ) _n CONH ₂ , wherein n is 1-2. R ² is phenyl, phenyl substituted with 1 to 3 substituents (the substituent is-(
C ₁ -C ₄₎ alkyl, -CN, halo, selected from the group consisting of _{-NO 2, CO 2 (C 1} ~C 4) alkyl and -CF _3), naphthyl, thiophene or 1-3
Thiophene substituted with two halo groups. R ³ is hydrogen, phenyl, phenyl (C ₂ -C ₆ ) alkenyl, pyridyl, naphthyl, quinolinyl, (C ₁ -C ₄ ) alkylthiazolyl, phenyl substituted with 1 to 2 substituents (the substituents, - _(C 1 ~C _{4) alkyl, -CN, -CONH 2, -NO 2} , -CF 3, halo, _(C 1 ~C _{4) alkoxy, CO 2 (C 1 ~C 4} ) alkyl , Phenoxy and SR ⁴ (where R ⁴ is-
(C ₁ -C ₄ ) alkyl or halophenyl), phenyl substituted with one substituent, wherein the substituent is —O (CH ₂ ) _p R ^5, wherein p is 1 to ^3, R 5 is _-CN, -CO ₂ H, -CONH 2 or tetrazolyl) phenyl and -OR ⁶ (wherein, ^{R 6} is cyclopentyl, cyclohexenyl or halo or (C, ₁ -C ₄₎ selected from the group consisting been phenyl) substituted with an alkoxy), or two substituted with a substituent phenyl (the substituents methylene combine with the phenyl ring to which they are attached To form a dioxy ring). m is 1 to 5], or a pharmaceutically acceptable salt thereof.

Pyrazole-type sPLA₂Inhibitors are particularly preferred, which are
[I] wherein R is¹Is pyridin-2-yl, 4-position substituted
Pyridin-2-yl (the substituent is-(C₁~ C₄) Alkyl,-(C₁~ C₄) Al
Coxy, -CN or-(CH₂)_nCONH₂And n is 1-2.
You. R²Is phenyl substituted with 1 to 3 substituents (the substituent is-(C₁~ C₄)
Alkyl, -CN, halo, -NO₂, CO₂(C₁~ C₄) Alkyl and -CF ₃ Is). R³Is phenyl, phenyl (C₂~ C₆) Alkenyl, phenyl substituted with one or two substituents, wherein the substituent is-(C₁~ C₄) Archi
, -CN, -CONH₂, -NO₂, -CF₃, Halo, (C₁~ C₄) Alkoki
Si, CO₂(C₁~ C₄) Alkyl, phenoxy and SR⁴(Where R⁴Is-
(C₁~ C₄) Alkyl or halophenyl)), phenyl substituted with one substituent, wherein the substituent is -O (CH₂)_pR⁵(here
Where p is 1-3 and R⁵Is -CN, -CO₂H, -CONH₂Or tetra
Zolyl), phenyl and -OR⁶(Where R⁶Is cyclopentyl,
Clohexenyl or halo or (C₁~ C₄) Phenyl substituted by alkoxy
Phenyl) substituted with two substituents (the substituents being the phenyl to which they are attached).
To form a methylenedioxy ring together with the ring).

[0226] Useful specifically suitable pyrazole type sPLA ₂ inhibitors in the method of the present invention, 3- (2-chloro-6-methyl-phenylsulfonyl) -4- (2- (4-acetamido) pyridyl) -5- (3- (4-fluorophenoxy) benzylthio)-(
1H) -pyrazole and 3- (2,6-dichlorophenylsulfonylamino) -4- (2- (4-acetamido) pyridyl) -5- (3- (4-fluorophenoxy) benzylthio)-(1H)-
And a compound selected from the group consisting of pyrazoles.

The pyrazole compounds of formula Ih are as described in Scheme Ih below. Reaction formula Ih

Embedded image The acetonitrile compound (1) is treated with an excess of a strong base (eg, sodium hydride) (preferably under an inert gas such as nitrogen) in an aprotic polar solvent (eg, tetrahydrofuran). Deprotonation. The deprotonated intermediate is treated with carbon disulfide and then an appropriately substituted alkyl halide, R ³ (CH ₂ ) _m L, where L is a leaving group (preferably bromine). And R ³ and m are as defined above) to provide an intermediate of formula (3). The reaction is carried out at ambient temperature and is substantially complete in 1 to 24 hours.

The formation of the amino-substituted pyrazole (4) by cyclization is achieved by reacting intermediate (3) with hydrazine at room temperature for about 1 to 24 hours.

The selective sulfonylation of the amino group of intermediate (4) is effected by treatment with a sulfonyl chloride of the formula R ² SO ₂ Cl, wherein R ² is as defined above. This can be achieved to obtain the product (6). The reaction is preferably performed in a solvent such as pyridine at ambient temperature for 1 to 24 hours. 2,6-Dimethylsulfonyl chloride can be achieved as described in J. Org. Chem., 25, 1996 (1960). All other sulfonyl chlorides are commercially available.

[0230] i) For phenyl glyoxamides sPLA ₂ inhibitors (and their preparation), filed U.S. Patent Application No. 08/979446 (November 24, 1997) (The title is "Phen
yl Glyoxamides as sPLA ₂ Inhibitors "), which form part of the present specification.

The compositions and methods of the present invention are methods of treating a mammal (eg, including a human) suffering from sepsis, comprising a compound of formula (Ii):

Embedded image[Wherein X is -O- or-(CH₂)_mAnd m is 0 or 1. Y is -CO₂-, -PO₃-Or -SO₃R is independently -H or-(C₁~ C₄) Alkyl. R¹And R²Are each independently -H, halo or-(C₁~ C₄) With alkyl
is there. R³And R⁴Are each independently -H,-(C₁~ C₄) Alkyl, (C₁~ C
₄) Alkoxy, (C₁~ C₄) Substituted with alkylthio, halo, phenyl or halo
Phenyl. n is 1-8. And Y is -CO₂-Or -SO₃When p is 1, p is 1 and Y is -PO₃Or p is 1 or 2 when it is-), or a pharmaceutically acceptable salt thereof, phenylglyoxamide
Ip sPLA₂It can be performed using an inhibitor.

[0232] Specifically suitable phenyl glyoxamides type sPLA ₂ inhibitors,
2- (4-carboxybut-1-yl-oxy) -4- (3-phenylphenoxy)
Phenylglyoxamide.

The phenylglyoxamide compounds useful in the compositions and methods of the present invention include:
It is manufactured as follows. Compounds wherein R ¹ , R ² , R ³ and R ⁴ are H and X, Y, n and p are as defined above can be prepared according to the following Scheme Ii. Reaction formula Ii

Embedded image

Embedded image

[0234] alkyl halide solvent (e.g., chloroform) in, by refluxing with 4-N, the N ^{'dimethylaminopyridine} as a catalyst (1) with oxalyl chloride to give intermediate (2).

Under Friedel-Crafts conditions, a suitable Lewis acid (eg, aluminum chloride)
Is used to give intramolecular cyclization of compound (2) to give compound (3). The reaction is preferably performed at about 0 ° C. to room temperature, and can proceed in about 24 hours.

Aminolysis of (3) to amide (4) can be achieved by treatment with concentrated ammonium hydroxide.

Alkylation of the hydroxyl of compound (4) can be carried out using a suitable alkylating agent (eg,
Br (CH₂)_nY, where Y is -CO₂R, -PO₃R₂Or SO ₃ And R is-(C₁~ C₄) Is an alkyl)
To easily obtain the intermediate (5). The reaction involves potassium carbonate and
Aprotic polar solvent in the presence of a suitable catalyst (eg, potassium iodide)
(Eg, dimethylformamide).

Conversion of (5) to (6) which is a carboxylic acid or a sulfonic acid or an acid salt thereof is carried out in a protic polar solvent (eg, methanol) with a suitable base (eg, aqueous sodium hydroxide solution). ).

When n is 2, the carboxylic acid (6) must be obtained using bromoacetal as the alkylating agent. The alkylated molecule (5) is then converted to the acid (6) by oxidizing it under aqueous conditions using sodium dichromatate.

When Y is —PO ₃ —, the conversion to (6) is performed by using an alkyl halide solvent (
Preference is given to using a dealkylating agent (for example trimethylsilyl bromide) and an excess of potassium carbonate in dichloromethane) followed by treatment with methanol.

When R ¹ , R ² , R ³ or R ⁴ is other than hydrogen, the preparation proceeds as described in Scheme IIi on the following page.

Embedded image R ^′ is as defined in Reaction Formula Ii.

The phenol (7) substituted with the appropriate R ¹ and R ² is converted to the lactone (8) according to the method described in the above reaction scheme Ii, step (ab).

Conversion to intermediate (9) is accomplished by reacting (2a) with an aqueous acid solution (eg, hydrochloric acid, which is used to remove aluminum chloride from the reaction). The acid (9) is converted to the corresponding acid chloride using oxalyl chloride together with dimethylformamide as catalyst. The acid chloride is reclosed by removing the solvent (preferably under vacuum) to give the lactone (10).
The lactone (10) is converted to glyoxamide (11) by treatment with excess ammonia as described in step (c) of Scheme I above.

The alkylation of (11) to produce (12) and subsequent conversion to the acid is accomplished according to the method described in Scheme I, steps (d) and (e).

Alternatively, the conversion of (10) to (12) is carried out using sodium amide in an aprotic polar solvent such as dimethylformamide (preferably at a temperature of about 0-20 ° C.). This can be accomplished in a one-pot process by treating lactone (10) followed by alkylation with a suitable alkyl halide.

J) For pyrrole sPLA ₂ inhibitors and methods for their preparation, see US patent application Ser. No. 08/985518, filed Dec. 5, 1997, entitled “Pyrroles as sPLA ₂ Inhib”.
itors ", which forms part of the present specification.

The compositions and methods of the present invention for the treatment of a mammal (eg, a human) afflicted with sepsis are described in Formula (Ij):

Embedded image[Where R¹Is hydrogen, (C₁~ C₄) Alkyl, phenyl, or one or two
Phenyl substituted with a substituent (the substituent is-(C₁~ C₄) Alkyl,-(C₁
~ C₄) Alkoxy, -phenyl (C₁~ C₄) Alkyl,-(C₁~ C₄) Archi
Selected from the group consisting of luthio, halo and phenyl). R²Is hydrogen,-(C₁~ C₄) Alkyl, halo,-(C₁~ C₄) Alkoxy
Or-(C₁~ C₄) Alkylthio. R³And R⁴Are each hydrogen or together 一 緒 O. R⁵Is -NH₂Or -NHNH₂It is. R⁶And R⁷Are each hydrogen or R⁶And R⁷One of them is hydrogen
The other is-(C₁~ C₄) Alkyl,-(CH₂)_nR¹⁰(Where R ¹⁰ Is -CO₂R¹¹, -PO₃(R¹¹)₂, -PO₄(R¹¹)₂Or -S
O₃R¹¹And R¹¹Is independently hydrogen or-(C₁~ C₄) And n is 0
４4) or R⁶And R⁷Are together = O or = S
It is. X is R⁸(C₁~ C₆) Alkyl, R⁸(C₂~ C₆) Alkenyl or ortho
Rank is R⁸Substituted phenyl (the R⁸Is (CH₂)_nR¹⁰And R¹⁰Is
-CO₂R¹¹, -PO₃(R¹¹)₂, -PO₄(R¹¹) Or -SO₃(R^1
1) And R¹¹Is as defined above, and n is 1-4.
Phenyl further has one or two substituents, wherein the substituent is hydrogen,-(C₁~ C₄) Al
Kill, halo, (C₁~ C₄) Selected from the group consisting of alkoxy)) or two
A substituent (in this case, naphthyl together with the phenyl ring to which the substituent is attached)
Which forms a ring). R⁹Is hydrogen, methyl or ethyl], or a pharmaceutically acceptable salt thereof, pyrrole sPLA₂Inhi
It can be performed using bitter.

[0248] Preferred pyrrole sPLA ₂ inhibitors useful in the methods of the invention is a compound of formula Ij (wherein, ^{R 1} is phenyl, ^{R 2} is methyl or ethyl, ^{R 5} is -NH _2, ^{R 6} And R ⁷ are each hydrogen; X is R ⁸ (C ₁ -C ₆ ) alkyl or phenyl (ortho-substituted R ⁸ )
Wherein R ⁸ is —CO ₂ R ¹¹ ) and R ⁹ is ethyl or ethyl).

Particularly suitable pyrrole sPLA ₂ inhibitors in the method of the invention are 2
-[1-benzyl-2,5-dimethyl-4- (2-carboxyphenylmethyl) pyrrol-3-yl] glyoxamide.

The pyrrole compound is produced as follows. The compound of the formula R ⁵ is -NH ₂ I, can be prepared as shown in the following reaction formula Ij. Reaction formula Ij

Embedded image

The appropriately substituted γ-diketone (1) is reacted with an alkylamine of the formula NHCH ₂ R ¹ to give pyrrole (2). Under Friedel-Crafts conditions using a suitable Lewis acid catalyst (eg, stannic chloride, aluminum chloride or titanium tetrachloride, with stannic chloride being preferred), the formula ZCR ⁶ R ⁷ X for pyrrole (2)
(Where Z is a suitable halogen and R ⁸ of X is a protected acid or ester) using an alkyl halide or arylalkyl halide compound. The reaction is preferably carried out in a halogenated hydrocarbon solvent (eg, dichloromethane) at ambient temperature, and the reaction can proceed for about 1 to about 24 hours.

Intermediate (3) is converted to (4) by successive treatment with oxalyl chloride followed by ammonia. The selective reduction reaction of (4) is achieved by a two-step reaction. For example, in the case of a hydride reduction reaction using sodium borohydride, a hydroxy intermediate (5) is produced, and this is further subjected to a catalytic reduction reaction or a hydride reduction reaction (palladium-carbon is preferable). Reduce (
6) is obtained. Generation of the acid by deprotection of R ⁸ can be easily achieved by conventional techniques. For example, when using an alkyl ester as a protecting group,
The deprotection reaction can be achieved by treating with a base (eg, sodium hydroxide).

[0253] k) For naphthylene Legris oxamide sPLA ₂ inhibitors and their preparation, filed in US Patent Application No. 09/091079 (1966, December 9, 2009) (The title is, "Naphthy
l Glyoxamides as sPLA ₂ Inhibitors "(this forms part of the present description)
Is disclosed.

[0254] mammal suffering from sepsis (for example, including humans) can be performed using the compositions and methods naphthyl Legris oxamide sPLA ₂ inhibitors of the present invention for the treatment of, the inhibitor, Formula Ik:

Embedded image[Where R¹And R²Is each independently hydrogen or a non-interfering substituent. Where R ¹ Or R²At least one of them must be hydrogen. X is -CH₂— Or —O—, and Y is (CH₂)_nZ (where n is a number from 1 to 3 and Z is CO₂H, -SO₃ H and -PO (OH)₂A naphthylglyoxamide compound represented by the formula: or a pharmaceutically acceptable salt thereof, a solvent
It is a derivative or a prodrug derivative.

[0255] The method of the present invention are useful, specifically suitable naphthyl Legris oxamide sPLA ₂ inhibitors structural formula:

Embedded image Having.

The naphthylglyoxamide compound is produced as follows. Compounds of Formula I where X is oxygen can be prepared by the following Scheme Ik. Reaction formula Ik

Embedded image

Embedded image

In the above reaction scheme, the 1,5-dihydroxynaphthalene starting material (1) is dispersed in water and then treated with 2 equivalents of potassium hydroxide. The resulting solution is cooled in an ice bath and 1 equivalent of a strong mineral acid (eg, hydrochloric acid) is added to add the potassium salt (2).
Get.

Then, the alkylation of the group (2) can be achieved using a methylating agent (eg, dimethyl sulfate) to produce the ether (3).

The production of (4) can be achieved by reacting (3) with an appropriately substituted phenol in an Ullmann-type reaction using potassium carbonate and copper (II) oxide.

In the demethylation reaction (4), (4) is converted to a protic polar solvent (for example, acetic acid).
Achieved by treating with a 40% HBr / HOAc solution in
5) can be manufactured.

The compound (5) is refluxed together with oxalyl chloride and 4-dimethylaminopyridine in an alkyl halide solvent (for example, dichloromethane) to obtain an oxalyl chloride (6).

The intramolecular cyclization of (6) can be achieved under Friedel-Crafts reaction conditions using aluminum chloride or other similar metal halide as a catalyst.
The reaction is usually performed in an alkyl halide solvent (for example, 1,2-dichloroethane).

The alkylation and hydrolysis of the cyclic compound (7) is carried out by reacting (7) with an alkali amide base (eg, sodium amide), and subsequently using potassium iodide as a catalyst to form an alkylating agent (eg, (Methyl bromoacetate).

Finally, the acid (9) is treated with the ester (8) using an alkali base (eg, aqueous sodium hydroxide) followed by treatment with a dilute aqueous mineral acid (eg, hydrochloric acid). Achieved by. Next, the acid compound (9) is added to an organic solvent (for example,
(Ethyl acetate).

The final product (9) is converted to a suitable organic solvent (eg, dichloromethane / hexane)
In which it can be purified using standard recrystallization methods.

Compounds of Formula I where X is methylene can be prepared as shown in Scheme IIk below. Reaction formula IIk

Embedded image

The Grignard reagent is prepared using appropriately substituted phenyl bromide. The phenyl Grignard reagent is then reacted with 4-methoxynaphthylnitrile,
The obtained compound is hydrolyzed using a dilute acid (for example, hydrochloric acid) to obtain a benzoylnaphthylene compound (1a).

The production of compound (2a) by reducing (1a) is achieved by treating with a reducing agent (for example, sodium borohydride). The reaction is performed in a solvent-catalyst (eg, trifluoroacetic acid) and starts in an ice bath and is allowed to warm to room temperature as the reaction proceeds.

The desired naphthylglyoxamide can then be prepared from (2a) according to the method of reaction formula I starting from the chloromethylation step.

The substituted benzyl bromide, substituted phenol and substituted naphthyl nitriles of Schemes I and II are commercially available or can be obtained by known techniques from commercially available starting materials. It will be readily recognized by those skilled in the art that it can be easily manufactured.

[0271] l) For phenylacetamide sPLA ₂ inhibitors and their preparation, U.S. Patent Application No. 08/976858 (filed November 4, 1997) (The title is "Phenyl Ac
etamides as sPLA ₂ Inhibitors, which are incorporated herein by reference.

[0272] mammal suffering from sepsis (for example, including a human) compositions and methods of the present invention for the treatment of may be carried out using phenylacetamide sPLA ₂ inhibitors, the inhibitor has the formula ( II):

Embedded image Wherein R ¹ is —H or —O (CH ₂ ) _n Z, R ² is —H or —OH, and R ³ and R ⁴ are each independently —H, halo, or — ( C ₁ -C ₄ ) alkyl. One of R ⁵ and R ⁶ is -YR ⁷ and the other is -H. Wherein Y is —O— or —CH ₂ —, and R ⁷ is phenyl or phenyl substituted with one or two substituents, wherein the substituents are halo, — (C ₁ -C ₄ ) Alkyl,
-(C ₁ -C ₄ ) alkoxy, phenyl, or phenyl substituted with one or two halo groups). Z is _-CO ^{2 R,} _-PO 3 R 2 or -SO ₃ R, where R is -H or - a _(C 1 _{~C 4)} alkyl. And n is 1-8. Provided that when R ⁶ is YR ⁷ , R ¹ is hydrogen. And when R ¹ , R ² , R ³ , R ⁴ and R ⁶ are hydrogen and R ⁵ is YR ⁷ (where Y is —O—), then R ⁷ is phenyl It is not possible. And if R ¹ , R ² , R ³ , R ⁴ and R ⁶ are hydrogen and R ⁵ is YR ⁷ (where Y is CH ₂ ), then R ⁷ is one of Phenyl substituted with a methoxy group and two chloro groups] or a pharmaceutically acceptable salt, racemate or optical isomer thereof.

[0273] useful in the compositions and methods of the present invention, preferred suitable phenyl acetamide sPLA ₂ inhibitor, formula I: (wherein ^,, R 2, ^{R 3} and ^{R 4} is H, Y is oxygen or CH ₂ and
R ⁷ is phenyl or phenyl substituted at the meta position with one or two substituents (the substituents are halo, — (C ₁ -C ₄ alkyl), (C ₁ -C ₄ ) alkoxy, phenyl or halo Is a substituted phenyl), and n is 4-5).

Specifically Suitable Phenylacetamide sPLA Useful in the Methods of the Invention ₂ The inhibitor is 2- (4-carboxybutoxy) -4- (3-phenylpheno
Xy) phenylacetamide.

A phenylacetamide inhibitor is produced as follows. Compounds wherein R ¹ and R ² are H, R ⁵ or R ⁶ is YR ⁷ , R ⁷ is phenyl or substituted phenyl, and Y is oxygen are represented by the following reaction formula Il
It can be manufactured as exemplified in (a).

Reaction Scheme Il (a)

Embedded image X is halo, ^{R 8} and ^{R 9} are each independently, -H, halo, - _(C 1 -C ₄₎ alkyl, - (
C ₁ -C ₄ ) alkoxy, phenyl, phenyl substituted by one or two halo groups. PG is a carboxyl protecting group.

An appropriately substituted carboxy-protected halophenyl compound (1) (preferably halogen is bromine) is reacted with an appropriately substituted phenol (under preferred Ullmann reaction conditions)
2), and refluxed with potassium carbonate and copper (II) oxide in an aprotic polar solvent (eg, pyridine) under an inert gas (eg, argon). The reaction is completed substantially in 1 to 24 hours.

Intermediate (3) is deprotected by treatment with a base (eg, aqueous potassium hydroxide solution) using a solvent such as diethylene glycol. The reaction is about 1
The reaction is preferably carried out at a temperature of from about 00 to about 150 ° C, and is substantially completed in 1 to 24 hours.

The conversion to the amide (5) is then first carried out in an alkyl halide solvent (eg dichloromethane) at a temperature of about 0 ° C. to ambient temperature using dimethylformamide as catalyst and oxalyl chloride, Subsequently, it can be easily achieved by treating again with an excess amount of ammonia gas in an alkyl halide solvent.

Alternatively, compounds of formula I can be prepared according to the methods in Scheme I (b) below.

The substituted phenol (2) is reacted with an appropriately substituted benzyl halide (6) as described in Scheme I (a) above to give (7).

In the halogenation reaction (7), an alkyl halide solvent (eg, chloroform)
In a halogenating agent (eg, N-bromosuccinimide) and a catalyst (eg,
2,2 ^'- accomplished using azobisisobutyronitrile), producing (8).

Treatment of (8) with sodium cyanide in an aprotic polar solvent (eg, dimethylformamide) gives the nitrile (9), which is converted to an aqueous acid solution (eg, hydrochloric acid). ) Can be easily converted to amide (10). Reaction formula Il (b)

Embedded image R ⁸ and R ⁹ are as shown in Scheme I (a), and X is halo.

In another process, compounds of Formula I wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen, Y is —O— or —CH ₂ —, and R ⁷ is phenyl, Can be prepared as described in Formula II. Reaction formula II1

Embedded image

The appropriately substituted diphenyl compound (11) is treated with paraformaldehyde and a halogenating agent (eg, 40% hydrogen bromide / acetic acid). The two regioisomers have an X substituent at either the meta or para position of the phenyl ring to which it is attached.

The preparation of the nitrile isomer (13) by halogen substitution is described in Scheme I (b) above.
This can be achieved by treating (12) with sodium cyanide in dimethylformamide as described in step (c) of (a). The isomers can then be easily separated by conventional chromatographic purification methods, and each isomer is treated with hydrogen peroxide and potassium carbonate in an aprotic polar solvent (eg, dimethyl sulfoxide). By their respective amides (1
4) can be converted.

Compounds wherein R ¹ is —O (CH ₂ ) _n Z can be prepared as illustrated in Reaction Scheme III1 below. Reaction formula III1

Embedded image

Embedded image R is-(C ₁ -C ₄ ) alkyl, and p is 1 or 2.

An appropriately substituted diphenyl compound (15) is converted to an alkyl halide solvent (eg,
By refluxing with oxalyl chloride in chloroform), the intermediate (1
6) is manufactured.

The cyclization reaction to lactone (17) can be carried out by using a metal halide (for example,
(Aluminum chloride) under Friedel-Crafts reaction conditions. Conversion to glyoxamide (18) can be achieved by aminolysis of the lactone ring with concentrated ammonium hydroxide.

The preparation of the desired alkyl-linked ester by alkylation of a hydroxy group comprises
(18) is converted to a suitable alkylating agent (eg, (X) (CH ₂ ) _n B (where
B is _CO 2 PG, _-PO 3 PG or _-SO 3 PG, X is halo, P
G results from treatment with an acid protecting group (preferably methyl).

The reduction reaction of one of the carbonyl groups in glyoxamide (19) is performed using a suitable reducing agent (eg, sodium borohydride) in methanol (at a temperature of 0 to 2).
(Preferably 0 ° C.) to give intermediate (20). The desired acid or acid salt (21) can be obtained by treating with a suitable base (for example, sodium hydroxide).

A further reduction reaction of the intermediate (20) is carried out under an inert gas (eg, argon)
Achieved by treatment with triethylsilane in a strong acid (eg, trifluoroacetic acid) to give (22), which is subsequently treated again with a strong base to give the acid or salt (23) Can be converted to

M) For naphthyl acetamide sPLA ₂ inhibitors and methods for their preparation,
U.S. patent application Ser. No. 09/090977, filed Dec. 9, 1996, entitled "Benzyl naphth
alene sPLA ₂ Inhibitors "), which form part of the present specification.

The compositions and methods of the present invention for the treatment of mammals (including, for example, humans) suffering from sepsis comprise a compound of formula (Im):

Embedded image[Where R¹And R²Is each independently hydrogen or a non-interfering substituent. Where R ¹ And R²At least one must be hydrogen. R³Is hydrogen,-(CH₂)_nY,

Embedded image

Embedded image (Where, n is 2 to 4, Y is _{-CO 2 H, -PO} 3 H 2 or _-SO 3 H
In it, X is -O- or -CH ₂ - indicated by a is) performed using a naphthyl acetamide sPLA ₂ inhibitors.

Compounds wherein X is oxygen can be prepared according to Scheme Im. Reaction formula Im

Embedded image

Embedded image

In the first step of the above reaction scheme, an appropriately substituted 1-bromo-4-methylnaphthalene and an appropriately substituted phenol are converted to an aprotic polar solvent (for example,
Pyridine). The mixture is treated with excess potassium carbonate and excess bronze and refluxed under a nitrogen blanket to give (1).

[0297] Production of (2) by bromination of compound (1) is a non-polar alkyl halide solvent (e.g., carbon tetrachloride) 2,2 ^'as catalyst in - azobisisobutyronitrile using brominating agent ( For example, by refluxing with N-bromosuccinimide).

(3) is obtained by treating (2) with sodium cyanide.
The reaction is carried out in an aprotic polar solvent such as dimethyl sulfoxide (DMSO
)) Is best carried out while maintaining the temperature at about 60 ° C.

The production of the acid (4) by hydrolyzing the cyano compound (3) is achieved in two steps. If a polar protic solvent (e.g., diethylene glycol) is used as the co-solvent, the cyano compound (3) is treated with an alkali metal base (e.g., potassium hydroxide) and then the mixture is treated with 90-95. Heat to ° C. The resulting product is then reacted with a strong mineral acid (eg, hydrochloric acid).

Conversion of (4) to the desired naphthyl acetamide compound (5) is achieved by another two-step method. First, the acid (4) is dissolved in an alkali halide solvent (eg, dichloromethane). The acid / alkyl halide solution is cooled in an ice bath and then treated with oxalyl chloride using dimethylformamide as a catalyst to give the acid chloride. The solution is warmed to room temperature and then treated with ammonia gas to give (5).

The target compound (5) can be purified by using a standard recrystallization method in a suitable organic solvent (for example, dichloromethane / hexane).

Compounds wherein X is methylene can be prepared according to the following Scheme IIm. Reaction formula IIm

Embedded image

Embedded image

Compound (1a) is produced by Grignard reaction. The starting material for the Grignard reagent is prepared by reacting an appropriately substituted phenyl bromide with magnesium and ether. The reagent is then reacted with an appropriately substituted naphthylnitrile, and the resulting compound is hydrolyzed using an aqueous acid solution (eg, hydrochloric acid) to give benzoylnaphthyl (1a).

The reduction reaction of (1a) is achieved by treating with a molar excess of a reducing agent (for example, sodium borohydride). The reaction is carried out in an ice bath in a solvent-catalyst (
(E.g., trifluoroacetic acid) and then raised to room temperature as the reduction reaction proceeds.

The chloromethylation of (2a) is achieved by treatment with an excess of formaldehyde and concentrated hydrochloric acid in a polar acidic solvent (eg a mixture of acetic acid / phosphoric acid). The reaction is best carried out at a temperature of about 90 ° C.

The nitrile (4a) is produced by subjecting the compound (13a), which is a chloride, to a nucleophilic substitution reaction using cyanide. The reaction is carried out by refluxing (3a) in an aprotic polar solvent (eg, dimethylformamide (DMF)) with a slight molar excess of sodium cyanide for about 5 hours and then cooling to room temperature. It is performed by continuing the reaction.

Then, the desired naphthylamide (5a) was converted into the nitrile (4a) in three steps.
Manufacture from. The nitrile solution is made slightly basic by adding potassium carbonate to a solution of the nitrile (4a) dissolved in an aprotic polar solvent (eg, DMSO). The nitrile hydrolysis is then achieved by treatment with an aqueous solution of hydrogen peroxide. Crystallization of naphthyl acetamide can be achieved by adding water to the peroxide solution.

Compounds wherein R ³ is other than hydrogen can be prepared by using 1-bromo-4-methyl-naphthalene at the 6-position of the starting naphthalene ring together with a protected (eg, methoxy) phenol. , Can be easily manufactured. The reaction is performed as described above to give compounds (1)-(3). Hydrolysis of the cyano group (3) with an acid and deprotection of the protected phenol can be achieved by treating (3) with a 40% hydrogen bromide / acetic acid solution. Then, the deprotected phenol is reacted to prepare an appropriate substituent at the 6-position of the naphthyl ring. For example, the preparation of compounds where R ³ is —O (CH ₂ ) _n COOH involves alkylating the phenol with a suitable alkyl halide, followed by a base (eg,
(Aqueous sodium hydroxide solution) followed by conversion to an acid by treatment with dilute hydrochloric acid.

The fact that the substituted phenol and phenyl bromide starting materials are commercially available or can be easily prepared from commercially available starting materials by known methods is not It will be readily appreciated by those skilled in the art. All other reactants and reagents used to make the compounds of the present invention are commercially available. The most preferred sPLA ₂ inhibitors, 1H
- an indole-3-glyoxylamides sPLA ₂ inhibitor (are as described above), carbazole sPLA ₂ inhibitors are most preferred for the compositions and methods of the present invention.

[0310] III. Preparation of Activated Protein C Component a. Preparation of Human Protein C Recombinant human protein C (r-hPC) can be obtained using techniques well known to those skilled in the art (eg, US Pat. No. 4,981,952 to Yan, which is incorporated herein by reference). Produced in human kidney 293 cells. The genetic code for human protein C is disclosed and claimed in US Patent No. 4,755,624 to Bang et al., Which is incorporated herein by reference. The plasmid used to express human protein C in 293 cells is plasmid pLPC, which is US Pat. No. 4,992,373 to Bang et al., Which are incorporated herein by reference.
Is disclosed. The construction of plasmid pLPC is described in European Patent Publication 04.
No. 45939, which form part of the present specification, and also in Bio / Technology 5: 1189-1192, 1987 by Grinnell et al., Which form part of the present specification. Briefly, the plasmid is transfected into 293 cells, then stable transformants are identified, subcultured, and grown in serum-free medium. After fermentation, a cell-free medium is obtained by microfiltration.

[0311] Human protein C is separated from the culture by applying the teaching of US Patent No. 4,981,952 to Yan, which forms part of the present specification. Prior to absorption on an anion exchange resin (Fast-Flow Q, Pharmacia), the clarified medium was
Bring to 4 mM in DTA. Four column volumes of 20 mM Tris, 200 mM N
aCl, pH 7.4, and 2 column volumes of 20 mM Tris, 150 mM
NaCl, pH 7.4, then washed with 20 mM Tris, 150 mM N
NaCl, using 10mM of CaCl _2, pH 7.4, the bound recombinant human protein C Chi - eluting the Mogen. The eluted protein after elution was analyzed by SDS-
Purity is greater than 95% as determined by polyacrylamide gel electrophoresis.

For further purification of the protein, a 3 M protein NaCl solution was prepared, followed by a hydrophobic interaction resin (Toyopearl Phenyl 650 M, TosoHaas) (20 mM Tris, 3 M NaCl, 10 mM CaCl ₂ , pH 7). .4 equilibrated). After washing the column _twice with the equilibration buffer containing no CaCl ₂ , the recombinant human protein C was washed with 20 mM Tris (pH 7.0).
Elute using 4). The eluted protein is prepared for activation by removing residual calcium. The recombinant human protein C is passed through a metal affinity column (Chelex-100, Bio-Rad) to remove calcium, and is bound again to an anion exchanger (Fast Flow Q, Pharmacia). Both columns were placed in series, 20 mM Tris, 150 mM NaCl, 5 mM EDTA.
Equilibrate in pH 7.4. After loading the protein, the Chelex-100 column is washed with one column volume of the same buffer and the column is removed from the series. After washing the anion exchange column with 3 column volumes of equilibration buffer, the protein was washed with 0.4 M NaCl, 20 mM Tris-acetate,
Elute with pH 6.5. The absorbance at 280 nm of the protein concentration of each of the recombinant human protein C solution and the recombinant active protein C solution was measured, and E ^0.1% = 1.81 or 1.85, respectively, was obtained.

B. Activation of Recombinant Human Protein C Bovine thrombin is bound to activated CH-Sepharose 4B (Pharmacia) in the presence of 50 mM HEPES (pH 7.5, 4 ° C.). The binding reaction is performed on the resin already packed in the column using about 5000 units of thrombin / mL of resin. After circulating the thrombin solution through the column for about 3 hours, MEA is added until the concentration of the circulating solution is 0.6 mL / L. The solution containing the MEA is circulated for an additional 10-12 hours to ensure complete blocking of unreacted amine on the resin. After blocking, thrombin-bound resin was added to 10 times the column volume of 1
Wash with M NaCl, 20 mM Tris, pH 6.5 to remove any non-specifically bound protein and use in the activity reaction after equilibration in the activity buffer.

Purified rHPC was adjusted to 5 mM in EDTA (to chelate residual calcium) and 2 mg / min using 20 mM Tris (pH 7.4) or 20 mM Tris-acetate (pH 6.5). Dilute to a concentration of mL. This substance
50 mM NaCl and 20 mM Tris (pH 7.4) or 20 mM
Through a thrombin column equilibrated at 37 ° C. with Tris-acetate (pH 6.5). The flow rate is adjusted so that the contact time between rHPC and thrombin resin is about 20 minutes. Collect the effluent and immediately assay for amidolytic activity. If the substance does not have a specific activity (amidolytic) comparable to the established aPC standard,
Recycle to the thrombin column to complete the activation of the rHPC. Following this, while waiting for the next processing step, the material was reduced to 1 with 20 mM buffer (pH 7.4 or 6.5) as described above to keep the aPC at a lower concentration.
: 1 dilution.

Activation buffer (20 mM Tris, pH 7) with 150 mM NaCl
Leached thrombin was removed from aPC material by coupling aPC to an anion exchange resin (Fast Flow Q, Pharmacia) equilibrated in .4) or 20 mM Tris-acetate (pH 6.5). . Thrombin does not interact with the anion exchange resin under these conditions and passes through the column into the effluent to which the sample is applied. When aPC is loaded onto the column, washing is performed using 2-6 volumes of a 20 mM equilibration buffer, followed by 5 mM Tris-acetate (pH 6.5) or 20 mM Tris (pH 7.5). 4) 0.4M Na in
The bound aPC is eluted by sequential elution with Cl solution. A higher volume wash of the column facilitates more complete removal of the dodecapeptide. The material eluted from this column is stored as a refrigerated solution (−20 ° C.) or a lyophilized powder.

The anticoagulant activity of active protein C was measured by the activated partial thromboplastin time (AP
TT) Measured by measuring the extension of the clotting time of the clotting assay. Dilution buffer (radioimmunoassay grade BSA in 1 mg / mL, 20 mM Tris (pH 7.4), 150 mM of NaCl, 0.02% of NaN ₃₎ to prepare a standard curve in the concentration of protein C 125~1000ng / ML range, while preparing samples at several dilutions within this concentration range. To each sample cuvette, add 50 μL of cold hose plasma and 50 μL of reconstituted active partial thromboplastin time reagent (APTT reagent, Sigma) and incubate at 37 ° C. for 5 minutes. After incubation, add 50 μL of the appropriate samples and standards to each cuvette. To determine the basal clotting time, a dilution buffer is used in the presence of a sample or standard. CaCl ₂ (50 μL) was added to each sample or standard solution.
, 37 ° C, 30 mM) immediately after the addition of a fibrometer (fibrometer).
Start the timer of the CoA Screener Hemostasis Analyzer (American Laboratory). The concentration of active protein C in the sample is calculated from a linear regression equation of a standard curve. The clotting times reported herein are based on three replicates (including samples for the standard curve)
Is the average of the minimum values of

IV. The pharmaceutical compositions of the pharmaceutical compositions of the Invention The present invention comprises (a) sPLA ₂ inhibitors as an essential component, and (b) activated protein C.

When these two components are combined as a pharmaceutical composition, the composition comprises (
i) must themselves be in a liquid form suitable for injectable administration, or (ii) be readily soluble, suspended, dispersed, or emulsified in a liquid medium suitable for injectable administration at a later time. . In case of producing as injectable form a pharmaceutical composition of the present invention, the composition comprises (a) sPLA ₂ inhibitors, (b) activated protein C, and (c) injectable liquid carrier.

A. The ratio and amount essential component of the active ingredient in the compositions of the present invention (a) sPLA ₂ inhibitors and (b) activated protein C, the pharmaceutical of each active ingredient to a patient in treatment doses of the formulation in the formulation Present in such a ratio as to provide an effective amount. Typically, the weight ratio to activated protein C of sPLA ₂ inhibitor is 1000: 1 to 10,000,000: 1, 10
It is preferably 0: 1 to 1,000,000: 1.

The effective amount of activated protein C in human patients is between 0.1 and 100 μg /
kg / day. Preferably, the dose is between 1 and 50 μg / kg / day. The most preferred dose of activated protein C is 1-25 μg / kg / day. Effective amount of sPLA ₂ inhibitor in human patients, 0.1 to 20
It is believed to be 00 mg / kg / day. Preferably, the dose is about 1-100 mg / kg / day.

In preparing the compositions of the present invention, the essential components (a) sPLA ₂ inhibitor and (b) activated protein C are co-present and they are made in a homogeneous or heterogeneous manner. It may be mixed, adjacent, or otherwise close together in discrete dosage units suitable for practicing the methods of the present invention.

[0322] dosage units sPLA ₂ inhibitors usually be mixed with a carrier or inert ingredients, or diluted by a carrier, or ampoule, capsule, dosage device which released over time, sachet, paper agents or other May be enclosed in a carrier that can take the form of a container. If the carrier functions as a diluent, it may be a solid, semi-solid, paste or liquid material acting as a vehicle, or for example, tablets, pills, powders containing up to 10% by weight of active compound. Lozenges, troches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium) or ointments.

The dosage unit of activated protein C is usually mixed with a liquid carrier and / or other inert ingredients or may be in the form of an ampoule, a bottle, a dispensing device or other container which releases over time. It may be enclosed in a carrier. When the carrier functions as a diluent, it can be a liquid material that acts as a vehicle or can be in the form of a solution containing, for example, up to 10% by weight of active compound. The activated protein C component should be in an injectable liquid form immediately before use, but it is possible to produce it in a storable form that is not liquid but can be easily converted to a liquid.

[0324] In the case of pharmaceutical formulations containing both (a) sPLA ₂ inhibitors and (b) activated protein C, the carrier may be a pourable liquid medium are well known in the art. The injectable liquid must be capable of parenteral administration, ie, capable of introducing the substance to the mammal to be treated by intravenous, subcutaneous, intramuscular, or intramedullary injection.

The activating ingredient is dissolved in a pharmaceutically acceptable carrier (eg, sterile water, sterile water containing saline and / or saccharides, or a mixture of both); Or they can be suspended. For example, for intravenous injection, a compound of the invention can be dissolved in a 4% dextrose / 0.5% aqueous sodium citrate solution at about 2 mg / mL.

[0326] sPLA ₂ inhibitor (if separate from the activated protein C) include powders,
It may take the form of tablets or capsules. A solid carrier can be one or more substances, which can also function as flavoring agents, lubricants, solubilizers, suspending agents, binders, tablet disintegrants, and encapsulating substances. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes and cocoa butter.

[0327] The following pharmaceutical formulations, in the case of sPLA ₂ inhibitor alone (as above),
Or useful in the case of the active ingredient is a combination of (a) sPLA ₂ inhibitors and (b) activated protein C.

[0328] Typically, the 10mg~1000mg of sPLA ₂ inhibitor, 1 of the preparation
Use as a single dose.

Formulation Example 1 A hard capsule is prepared using the following components.

[Table 1]

Formulation Example 2 A tablet is prepared using the following ingredients.

[Table 2]

The ingredients are mixed and compressed to give tablets weighing 655 mg each.

Formulation Example 3 An aerosol solution containing the following components is prepared.

[Table 3]

[0333] The sPLA ₂ inhibitor is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30 ° C., transfer the mixture to a filling device. The required amount is then fed to a stainless steel container and diluted with the rest of the propellant. Next, a valve unit is installed in the container.

[0334] Formulation Example 4 Each, sPLA tablets containing 60mg of ₂ inhibitor be formulated as follows.

[Table 4]

[0335] sPLA ₂ inhibitors, starch and cellulose, No. 45 mesh U
Sift using a sieve and mix thoroughly. The solution containing polyvinylpyrrolidone is mixed with the remaining powder, and the mixture is then sieved using a # 14 mesh US sieve. The granules so obtained are dried at 50 ° C. and sieved using a No. 18 mesh US sieve. Next, the 60th US
The sodium carboxymethyl starch, magnesium stearate and talc, which have been sieved using a sieve, are added to the granules which, after mixing, are compressed on a tablet machine to give tablets weighing 150 mg each.

[0336] Formulation Example 5 Each of formulated as follows Capsules 80mg containing sPLA ₂ inhibitors.

[Table 5]

[0337] sPLA ₂ inhibitors, cellulose, starch, and magnesium stearate, sieved using U.S. Sieve No. 45 mesh, 200 meters
Fill g amount into hard capsules.

[0338] Formulation Example 6 Each of the suppository containing 225mg of sPLA ₂ inhibitors, formulated as follows.

[Table 6]

[0339] sPLA ₂ inhibitors sieved using U.S. Sieve No. 60 mesh and suspended in the saturated fatty acid glycerides melted by performing only necessary preheating minimum. The mixture is then poured into a suppository mold of nominal 2 g capacity and cooled.

Formulation Example 7 A suspension containing 50 mg of active ingredient per 5 mL dose is prepared as follows.

[Table 7]

The active ingredients are mixed with sodium carboxymethylcellulose and syrup to give a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Then add enough water to get the required amount.

Formulation Example 8 An intravenous formulation is prepared as follows.

[Table 8]

The solution of the active ingredient is administered to a subject intravenously at a rate of 1 mL per minute.

Typically, from 10 mg to 100 mg of active ingredient are used in a unit dose formulation.

Unit dose formulations suitable for administration by continuous infusion include activated protein C, sPLA ₂ Inhibitors, salts (NaCl), bulking agents (sucrose) and buffers (eg,
(For example, citrate) at pH 6.0. Active ingredients,
Salt and bulking agent may be used in an amount of about 7 to 8 parts salt to about 1 part by weight of active ingredient.
And the bulking agent are mixed in a proportion of about 5 to 6 parts.

After mixing, transfer 4 mL of the solution to a vial and freeze-dry. The vial containing the active ingredient is sealed and stored until used.

V. Treatment invention of sepsis according to the method of the present invention relates to treatment or prophylaxis of septicemia, the method a therapeutically effective amount of (a) sPLA ₂ inhibitors and the treatment thereof is required mammal By administering a therapeutically effective amount of (b) activated protein C, wherein both (a) and (b) are administered within a therapeutically effective interval.
Administration of (a) or (b) to a septic patient may be continuous or intermittent.

A. METHOD activated protein C and sPLA ₂ Inbita of the present invention using the simultaneous delivery of activated protein C and sPLA ₂ inhibitors can be transported at the same time. One convenient method of co-delivery is to use the compositions of the present invention described in Part IV, above, wherein the active ingredient has the essential ingredients, which coexist in unit dosage form. If desired, the mixed essential component solution or suspension can be delivered from a liquid holding sachet of Part IV.

[0349] Another method of simultaneous delivery of activated protein C and sPLA ₂ inhibitors, they but separate to the patient is to transport simultaneously. Thus, for example, the activated protein C at the same time parenterally provide, can give sPLA ₂ inhibitor as an oral preparation.

[0350] Administration of sPLA ₂ inhibitors can be started concurrently with the administration of activated protein C. administration period of sPLA ₂ inhibitors may be extended until after the administration of activated protein C.

B. Each method essential component of the present invention using a non-simultaneous delivery of activated protein C and sPLA ₂ inhibitors, i.e. therapeutically effective amount of (a) sPLA ₂ inhibitors and a therapeutically effective amount of (b) Activated protein C has a therapeutically effective interval, ie, an interval of time such that each component provides benefit to a patient treating sepsis. The method of the present invention provides a therapeutically effective amount of (a) s for a patient with sepsis.
This can be accomplished by separately administering the PLA ₂ inhibitor and a therapeutically effective amount of (b) activated protein C in any order. However, each component is provided within a period during which the other component is therapeutically effective against sepsis.

[0352] Typically, an intravenous form of sPLA ₂ inhibitor (e.g., ((3- (2-amino-1,2-Jiokisoechiru) -2-ethyl-1- (phenylmethyl)-1H-indol-4 Il) oxy) acetic acid-sodium salt) is therapeutically effective immediately after administration or up to 5 days after administration, with time intervals ranging from 5 minutes after administration to 72 days after administration.
It is preferable until after the time. Oral forms typically sPLA ₂ inhibitors (e.g.,
((3- (2-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid methyl ester) was administered at about 1 dose.
From 0 minutes to about 5 days is therapeutically effective, from about half an hour after administration to about 72 days.
It is preferable until after the time.

[0353] Administration transportation of sPLA ₂ inhibitor, can be started at least 48 hours prior to injection of activated protein C, preferably beginning 24 hours, 12
Most preferably, start by the hour. Starting Alternatively, administration of sPLA ₂ inhibitor can be initiated before the start 48 hours after infusion of activated protein C, and it is preferable to begin by about 24 hours after the start, until 12 hours after the start Is most preferred.

[0354] sPLA ₂ inhibitors may be administered by infusion solutions various paths (e.g., including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal). The activated protein C compound can be administered as an injectable solution. The activated protein C and sPLA ₂ inhibitors,
Parenteral administration to septic patients is preferred to ensure that they are transported into the bloodstream as quickly as possible in an effective form.

VI. The amount and the ratio of activated protein C and sPLA ₂ inhibitors for use in the practice of the method of the method treatment period invention sepsis patients using the present invention are described in (V) of the above. It will be readily apparent to those skilled in the art that the dosage of any of the components may be varied mechanically depending on the age and medical condition of the patient.

The decision to start the therapy may be in the laboratory indicating the appearance of clinical signs of sepsis, or the onset of a sepsis cascade, including, for example, renal complications, coagulopathies or multiple organ failures. Will be based on testing. Typical clinical signs are fever, chills, tachycardia, tachypnea, changes in mental status, hypothermia, hyperthermia, accelerated or suppressed respiratory or heart rate, increased or decreased white blood cell counts and hypotension Is mentioned. These and other conditions are well known in the art and can be found in standard literature, for example, Harrison's Principles of Internal Medicine (ISBN 0-07-032370-4) 1994.
, Pp. 511-515.

The decision to determine the duration of therapy is supported by standard clinical laboratory results from commercially available assays or instruments that support the elimination of the symptoms that define sepsis. You. The method of the present invention provides a therapeutically effective amount of the essential activated protein C for a period considered to be effective for the treatment of an episode of sepsis.
It can be performed by the components and sPLA ₂ inhibitor component or continuous administration, or intermittent administration. The administration can last up to about 60 days in total, with a preferred course of therapy lasting up to 10 days.

Determination of the end of therapy according to the methods of the present invention is supported by standard clinical laboratory results from commercially available assays or instruments, or by the disappearance of clinical symptoms specific to sepsis. Can be done. The determination to end may be based on a measurement that the patient's baseline protein C concentration has returned to a value within the normal range.

The therapy can be restarted when sepsis recurs.

[0360] Combination therapy with activated protein C and sPLA ₂ inhibitors also
It is a safe and effective treatment in the prevention and treatment of sepsis in children.

Although the invention has been illustrated above by certain specific embodiments, these specific examples are not intended to limit the scope of the invention as set forth in the claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 123 A61K 37/547 (81) Designated country EP (AT, BE, CH, CY, DE, DK) , ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR) , NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, K, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF Term (reference) 4C084 AA02 AA19 CA59 DC03 MA02 ZB35 4C086 AA01 AA02 BC12 BC13 MA02 ZB35

Claims (35)

[Claims] 1. A (a) sPLA ₂ inhibitors and (b) a pharmaceutical composition comprising an activated protein C. 2. sPLA₂The inhibitor of the present invention, which is represented by the formula (Ia):
Indole-3-glyoxylamide, or a pharmaceutically acceptable salt or salt thereof
Is the aliphatic ester prodrug derivative thereof.
. Embedded imageWherein both X are oxygen. R₁Is(Where R₁₀Is halo, C₁~ C₁₀Alkyl, C₁~ C₁₀Alkoxy,
-S- (C₁~ C₁₀Alkyl) and C₁~ C₁₀Independently selected from haloalkyl
And t is a number from 0 to 5). R₂Is selected from the group of halo, cyclopropyl, methyl, ethyl and propyl
It is. R₄And R₅Is hydrogen, a non-interfering substituent or group:-(L_a)-(Acidic group) (this
Here,-(L_a)-Is an acid linking group). Where R₄For the acid linking group:-(L_a)-IsSelected from the group consisting of And R₅For the acid linking group:-(L_a)-IsEmbedded image(Where R₈₄And R₈₅Is each independently hydrogen, C₁~ C₁₀Alkyl,
Aryl, C₁~ C₁₀Arkaaryl, C₁~ C₁₀Aralkyl, carboxy
, Carbalkoxy and halo). Where R₄And R₅At least one of the groups is-(L_a)-(Acidic group)
Not R₄Or R₅Of the group:-(L_a)-(Acidic group) on (acidic group) is -CO₂ H, -SO₃H, or -PO (OH)₂Selected from. R₆And R₇Are each independently selected from hydrogen and a non-interfering substituent. The
The non-interfering substituent is C₁~ C₆Alkyl, C₂~ C₆Alkenyl, C₂~ C₆A
Lucinyl, C₇~ C₁₂Aralkyl, C₇~ C₁₂Arkaaryl, C₃~ C₈ Cycloalkyl, C₃~ C₈Cycloalkenyl, phenyl, torril, xyleni
Le, biphenyl, C₁~ C₆Alkoxy, C₂~ C₆Alkenyloxy, C₂~
C₆Alkynyloxy, C₂~ C₁₂Alkoxyalkyl, C₂~ C₁₂Arco
Xyalkyloxy, C₂~ C₁₂Alkylcarbonyl, C₂~ C₁₂Alkyl
Carbonylamino, C₂~ C₁₂Alkoxyamino, C₂~ C₁₂Alkoxya
Minocarbonyl, C₂~ C₁₂Alkylamino, C₁~ C₆Alkylthio, C₂ ~ C₁₂Alkylthiocarbonyl, C₂~ C₁₂Alkylsulfinyl, C₁~
C₆Alkylsulfonyl, C₂~ C₆Haloalkoxy, C₁~ C₆Haloalkyl
Sulfonyl, C₂~ C₆Haloalkyl, C₁~ C₆Hydroxyalkyl, -C (
O) O (C₁~ C₆Alkyl),-(CH₂)_n-O- (C₁~ C₆Alkyl), ben
Jiloxy, phenoxy, phenylthio,-(CONHSO₂R), -CHO, a
Mino, amidino, bromo, carbamyl, carboxy, carbalkoxy,-(CH
₂)_n-CO₂H, chloro, cyano, cyanoguanidinyl, fluoro, quanidi
, Hydrazide, hydrazino, hydrazide, hydroxy, hydroxyamino, yo
Card, nitro, phosphono, -SO₃H, thioacetal, thiocarbonyl and
C₁~ C₆It is selected from the group consisting of carbonyl. n is 1 to 8] 3. sPLA ₂ inhibitor, the following compounds (A) ~ (P) 1H- indole-3-glyoxylamides compound selected from the group consisting of or a pharmaceutically acceptable salt, or solvate The pharmaceutical composition according to claim 1, which is a prodrug derivative: (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indole- 4-Byl] oxy] acetic acid, (B) dl-2-[[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] propanoic acid, (C) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl) -2-methyl -1H- indol -4 -Yl] oxy]
Acetate, (D) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -3-ylmethyl) -2-methyl -1H- indol-4-yl] Oxy]
Acetate, (E) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -4-ylmethyl) -2-methyl -1H- indol-4-yl] Oxy]
Acetic acid, (F) [[3- (2-amino-1,2-dioxoethyl) -1-[(2,6-dichlorophenyl) methyl] -2-methyl-1H-indol-4-yl] oxy] acetic acid, (G) [[3- (2-Amino-1,2-dioxoethyl) -1- [4 (-fluorophenyl) methyl] -2-methyl-1H-indol-4-yl] oxy] acetic acid, (H) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1-[(
1-naphthalenyl) methyl] -1H-indol-4-yl] oxy] acetic acid, (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H -Indol-4-yl] oxy] acetic acid, (J) [[3- (2-amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H-indole-4 - yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-ethyl -1H- indole -4-yl] oxy]
Acid, (L) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-propyl -1H- indol-4-yl] Oxy] acetic acid, (M) [[3- (2-amino-1,2-dioxoethyl) -2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (N) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-cyclopropyl -1H- indol-4-yl
] Oxy] acetic acid, (O) 4-[[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1
-(Phenylmethyl) -1H-indol-5-yl] oxy] butyric acid, and (P) a mixture of (A) to (P). 4. sPLA ₂ inhibitor, the following compounds (A) ~ (D) 1H- indole-3-glyoxylamides compound selected from the group consisting of or a pharmaceutically acceptable salt, or solvate The pharmaceutical composition according to claim 1, which is a prodrug derivative: Embedded image Embedded image 5. sPLA ₂ inhibitor carbazole compound of the formula (Ie), or a pharmaceutically acceptable racemate thereof, solvates, tautomers, optical isomers, prodrugs derivative or salt thereof, wherein Item 7. The pharmaceutical composition according to Item 1. Embedded image Wherein A is phenyl or pyridyl, wherein the nitrogen is in the 5-, 6-, 7- or 8-position. One of B or D is nitrogen and the other is carbon. Z is cyclohexenyl, phenyl, pyridyl (where the nitrogen is in the 1-, 2- or 3-position) or a 6-membered heterocycle (where the ring is a sulfur or oxygen in the 1-, 2- or 3-position) And one heteroatom selected from the group consisting of nitrogen at the 1-, 2-, 3- or 4-position). Embedded image Is a double bond or a single bond. R ²⁰ is selected from the group of (a), (b) and (c). Here, (a) represents _{- (C} 5 _{~C 20)} alkyl, - _(C 5 ~C ₂₀₎ alkenyl, - _{(C 5}
ＣC ₂₀ ) alkynyl, carbocyclic or heterocyclic. (B) is the element of (a) substituted with one or more independently selected non-interfering substituents. And (c) is a group :-( L) ^{-R 80.} Here,-(L)-means that the number of atoms is 1 to 1
2 is a divalent linking group. The atom is selected from carbon, hydrogen, oxygen, nitrogen and sulfur, and the combination of atoms in-(L)-is (i) only carbon and hydrogen, (ii) only one sulfur, (iii) only one oxygen, (IV) selected from only one or two nitrogen and hydrogen, (v) carbon, only hydrogen and one sulfur, and (vi) only carbon, hydrogen and oxygen. R ⁸⁰ is a group selected from (a) and (b). R ²¹ is a non-interfering substituent. R ^{1 ′} is —NHNH ₂ , —NH ₂ or —CONH ₂ . R ^{2 ′} is selected from the group consisting of —OH and —O (CH ₂ ) _t R ^{5 ′} . Here, R ^{5 ′} is H, —CN, —NH ₂ , —CONH ₂ , —CONR ⁹ R ¹⁰ , —NH
^{_{SO 2 R 15, -CONHSO 2 R}} 15 ( ^{wherein, R 15} is - _(C 1 ~C ₆₎ alkyl or -CF _3), phenyl, substituted phenyl (the substituent -C
O ₂ H or —CO ₂ (C ₁ -C ₄ ) alkyl), and — (L _a ) — (acid group), wherein — (L _a ) — has an acid-linked chain length of 1 to 7. And t is 1-5. R ^{3 ′} is selected from a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a heterocyclic group substituted with a non-interfering substituent. It is. However, when R ^{3 ′} is H, R ²⁰ is benzyl, and m is 1 or 2, R ^{2 ′} is not —O (CH ₂ ) _m H. And when D is nitrogen, the heteroatom of Z is selected from the group consisting of 1-, 2- or 3-position sulfur or oxygen and 1-, 2-, 3- or 4-position nitrogen ] 6. sPLA ₂ inhibitor carbazole compound shown by the formula I (IIe), or a pharmaceutically acceptable racemate thereof, solvates, tautomers, optical isomers, is a prodrug derivative or salt The pharmaceutical composition according to claim 1. Embedded image Wherein Z is cyclohexenyl or phenyl. R ²¹ is a non-interfering substituent. R ¹ is —NHNH ₂ or —NH ₂ . R ² is selected from the group consisting of -OH and ^{_{-O (CH 2) m R 5}} . here,
R ⁵ is H, —CO ₂ H, —CONH ₂ , —CO (C ₁ -C ₄ alkyl), (Where R ⁶ and R ⁷ are each independently —OH or —O (C ₁ -C ₄ ) alkyl), —SO ₃ H, —SO ₃ (C ₁ -C ₄ alkyl), tetrazolyl ^{_{, -CN, -NH 2, -NHSO 2}} R 15, -CONHSO 2 R 15 ( ^{wherein, R 15} is - _(C 1 ~
C ₆ ) alkyl or —CF ₃ ), phenyl or substituted phenyl (
The substituent is -CO ₂ H or -CO _{2 (C} 1 ~C ₄₎ alkyl), m
Is 1-3. R ³ is H, —O (C ₁ -C ₄ ) alkyl, halo, — (C ₁ -C ₆ ) alkyl, phenyl, — (C ₁ -C ₄ ) alkylphenyl, substituted phenyl (the substituent Is-
_(C 1 ~C ₆₎ alkyl, halo or _{-CF 3), - CH 2 OSi} (C 1 ~
C ₆₎ alkyl, furyl, thiophenyl, - _(C 1 ~C ₆₎ hydroxyalkyl or ^{_{- (CH 2) n R 8}} ( ^wherein, R 8 is ^{_{H, -CONH 2, -NR 9 R}} 10, -
Is CN or phenyl, and R ⁹ and R ¹⁰ are independently-(C ₁ -C ₄ ) alkyl or -phenyl (C ₁ -C ₄ ) alkyl, and n is 1-8. R ⁴ is H,-(C ₅ -C ₁₄ alkyl),-(C ₃ -C ₁₄ ) cycloalkyl,
Pyridyl, phenyl or substituted phenyl (the substituent - _(C 1 ~C ₆₎ alkyl, _{halo, -CF 3, -OCF 3, -} (C 1 ~C 4) alkoxy, -CN, - (
C ₁ -C ₄ ) alkylthio, phenyl (C ₁ -C ₄ ) alkyl, — (C ₁ -C ₄ ) alkylphenyl, phenyl, phenoxy or naphthyl. 7. sPLA₂Wherein the inhibitor is a compound represented by the formula (XXX):
The selected carbazole compound, or a pharmaceutically acceptable racemic or solvate thereof
Product, a tautomer, an optical isomer, a prodrug derivative or a salt.
A pharmaceutical composition according to claim 1. Embedded image[Where R¹Is -NHNH₂Or -NH₂It is. R²Are -OH and -O (CH₂)_mR⁵Selected from the group consisting of Where R ⁵ Is H, -CO₂H, -CO₂(C₁~ C₄Alkyl),(Where R⁶And R⁷Are each independently -OH or -O (C₁~ C₄) Al
Kill)), -SO₃H, -SO₃(C₁~ C₄Alkyl), tetrazolyl, -CN, -NH ₂ , -NHSO₂R^Fifteen, -CONHSO₂R^Fifteen(Where R^FifteenIs-(C
₁~ C₆) Alkyl or -CF₃), Phenyl or substituted phenyl
(The substituent is -CO₂H or -CO₂(C₁~ C₄Alkyl))
, M is 1-3. R³Is H, -O (C₁~ C₄) Alkyl, halo,-(C₁~ C₆) Alkyl,
Enyl,-(C₁~ C₄) Alkylphenyl, substituted phenyl (the substituent is-
(C₁~ C₆) Alkyl, halo or -CF₃), -CH₂OSi (C₁~
C₆Alkyl), furyl, thiophenyl,-(C₁~ C₆) Hydroxyalkyl,
Or-(CH₂)_nR⁸(Where R⁸Is H, -CONH₂, -NR⁹NR¹⁰ , -CN or phenyl;⁹And R¹⁰Are independently-(C₁~ C₄A
Alkyl) or -phenyl (C₁~ C₄Alkyl) and n is 1-8)
is there. R⁴Is H,-(C₅~ C₁₄) Alkyl,-(C₃~ C₁₄) Cycloalkyl,
Pyridyl, phenyl or substituted phenyl, wherein the substituent is-(C₁~ C₆) Al
Kill, halo, -CF₃, -OCF₃,-(C₁~ C₄) Alkoxy, -CN,-(
C₁~ C₄) Alkylthio, phenyl (C₁~ C₄) Alkyl,-(C₁~ C₄A)
Alkylphenyl, phenyl, phenoxy or naphthyl). A is phenyl or pyridyl (where nitrogen is at the 5-, 6-, 7- or 8-position
In). Z is cyclohexenyl, phenyl, pyridyl (where nitrogen is 1-, 2-
Or at the 3-position) or a 6-membered heterocycle, wherein the ring is at the 1-, 2- or 3-position
Selected from the group consisting of sulfur or oxygen and nitrogen in the 1-, 2-, 3- or 4-position.
One heteroatom, or optionally one carbon atom on the heterocycle
Are replaced with = O). With the proviso that one of A or Z is a heterocycle. 8. sPLA ₂ inhibitor carbazole compound selected from the following compounds, or a pharmaceutically acceptable racemate thereof, solvates, tautomers, optical isomers, prodrugs or salt, wherein Item 1. The pharmaceutical composition according to item 1, 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid hydrazide; 9-benzyl-5,7-dimethoxy-1,2, 3,4-tetrahydrocarbazole-4-carboxamide; [9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, sodium salt; [9-benzyl- [4-carbamoyl-7-methoxycarbazol-5-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-i] ] Methyl oxyacetate; 9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5- (1H-tetrazole-5 -Ylmethyl) oxy) -1,2,3,4-tetrahydrocarbazole-4-carboxamide; {9-[(phenyl) methyl] -5-carbamoyl-2-methyl-carbazole-
{9-[(3-fluorophenyl) methyl] -5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid; {9-[(3-methylphenyl) methyl]- 5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid; {9-[(phenyl) methyl] -5-carbamoyl-2- (4-trifluoromethylphenyl) -carbazol-4-yl} oxyacetic acid 9-benzyl-5- (2-methanesulfonamido) ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4- (2-methanesulfonamido) ethyloxy- 2-methoxycarbazole-5-carboxamide; 9-benzyl-4- (2-trifluoromethanesulfonamido) ethyloxy-
2-methoxycarbazole-5-carboxamide; 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-
1,2,3,4-tetrahydrcarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-
5-carboxamide; [5-carbamoyl-2-pentyl-9- (phenylmethyl) carbazole-4
-Yl] oxyacetic acid; [5-carbamoyl-2- (1-methylethyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2- [ (Tri (-1-methylethyl
) Silyl) oxymethyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl) carbazole-4
[5-carbamoyl-2- (4-chlorophenyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2- (2-furyl) -9- ( [Phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2-[(tri (-1-methylethyl)
) Silyl) oxymethyl] carbazol-4-yl] oxyacetic acid lithium salt; {9-[(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(3-fluorophenyl) Methyl] -5-carbamoylcarbazole-4
-Yl} oxyacetic acid; {9-[(3-phenoxyphenyl) methyl] -5-carbamoylcarbazole-
4-yl} oxyacetic acid; {9-[(2-fluorophenyl) methyl] -5-carbamoylcarbazole-4
-9-[(2-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-benzylphenyl) methyl] -5-carbamoylcarbazole -4
-Yl} oxyacetic acid; {9-[(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(1-naphthyl) methyl] -5-carbamoylcarbazole- 4-yl} oxyacetic acid; {9-[(2-cyanophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3-cyanophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(2-methylphenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3-methylphenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3,5-dimethylphenyl) methyl] -5-carbamoylcarbazole-
4-yl} oxyacetic acid; {9-[(3-iodophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(2-chlorophenyl) methyl] -5-carbamoylcarbazole-4-
{9-[(2,3-difluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2,6-difluorophenyl) methyl] -5-carbamoyl Carbazol-4-yl} oxyacetic acid; {9-[(2,6-dichlorophenyl) methyl] -5-carbamoylcarbazole-
{9-[(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl] -5 -Carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl]- 5-carbamoylcarbazol-4-yl}
[9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; {9-[(2-pyridyl) methyl] -5-carbamoylcarbazol-4-yl } Oxyacetic acid; {9-[(3-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydro [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4] -Tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-8- Chloro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid; [9-[(cyclohexyl) methyl] -5-carbamoylcarbazol-4-yl}
Oxyacetic acid; [9-[(cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl}
Oxyacetic acid; 5-carbamoyl-9- (phenylmethyl) -2-[[(propen-3-yl) oxy] methyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl)- 2-[(propyloxy) methyl]
Carbazol-4-yl] oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -1,2,
3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-
Carboxamide; 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl
) Oxy) -carbazole-4-carboxamide; 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -carbazole-4-carboxamide; [9-benzyl-4-carbamoyl-1,2,3,4 -(Tetrahydrocarbazol-5-yl) oxyacetic acid; (R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,2,
(R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid;
3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; [N-benzyl-1-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid; 4-methoxy-6 -Methoxycarbonyl-10-phenylmethyl-6,7,8,
9-tetrahydropyrido [1,2-a] indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,
4-b] indol-5-yl) oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole; 2-[(2, 9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-β-carbolin-5-yl) oxy] acetic acid. 9. sPLA ₂ inhibitor is formula (Xe) or (XIe): embedded image Embedded image The pharmaceutical composition according to claim 1, which is a carbazole compound represented by the formula: or a pharmaceutically acceptable salt or ester prodrug derivative thereof. 10. A therapeutically effective include amounts of (a) sPLA ₂ inhibitors and (b) activated protein C, the pharmaceutical composition according to any one of claims 1 to 9. 11. (a) sPLA ₂ weight ratio of inhibitor and (b) activating the protein C of (a) :( b) is 1000: 1 to 10,000,000: 1, any one of claims 1 to 10, A pharmaceutical composition according to one of the preceding claims. 12. the weight ratio of (a) sPLA ₂ inhibitor and (b) activating the protein C of (a) :( b) is 100: 1 to 1,000,000: a is, any one of claims 1 to 10, 1 A pharmaceutical composition according to one of the preceding claims. 13. (a) sPLA ₂ weight inhibitor 0.1mg~20
And (b) the weight of activated protein C is from 1.0 μg to 100 μg.
The pharmaceutical composition according to any one of claims 1 to 10, which is in μg. Weight 14. (a) sPLA ₂ inhibitors 50mg~100
The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition ranges from 0 mg and (b) the weight of activated protein C ranges from 1 g to 25 g. 15. The pharmaceutical composition according to claim 1, comprising a suitable carrier, diluent or excipient. 16. A therapeutic or prophylactic method of septicemia, the method of their treatment a mammal in need a therapeutically effective amount of (a) sPLA ₂ inhibitors and (b) activated protein A method comprising administering C within a therapeutically effective interval. 17. A method of treating a human suffering from or susceptible to sepsis, comprising the step of activating the activated protein C and the 1H-indole-3-glyoxylamide sPLA of the present invention of formula (Ia) in said human. A method comprising administering a therapeutically effective combination of the _two inhibitors, or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof. Embedded image Wherein both X are oxygen. R ₁ is (Where R ₁₀ is halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy,
—S— (C ₁ -C ₁₀ alkyl) and a group independently selected from C ₁ -C ₁₀ haloalkyl, and t is a number from 0 to 5). R ₂ is selected from the group of halo, cyclopropyl, methyl, ethyl and propyl. R ₄ and R ₅ are hydrogen, non-interfering substituents or groups :-( L _a) - (an acidic group) (wherein, - (L _a) - is independently selected from a a) acid linking group . However, for R ₄ , the acid linking group: — (L _a ) — is Selected from the group consisting of For R ₅ , the acid linking group: — (L _a ) — is Embedded image (Where R ₈₄ and R ₈₅ are each independently hydrogen, C ₁ -C ₁₀ alkyl,
Aryl, C ₁ -C ₁₀ alkaryl, C ₁ -C ₁₀ aralkyl, carboxy, carboxy, and halo). However, at least one of R ₄ and R ₅ must be _a group: — (L _a ) — (acidic group), and the group of R ₄ and R ₅ : — (L _a ) — (acidic group) (acidic group) on the _-CO 2 H, are selected from _-SO 3 H or -PO (OH) _2,. R ₆ and R ₇ are each independently selected from hydrogen and non-interfering substituents. The non-interfering substituent may be C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₇ -C ₁₂ aralkyl, C ₇ -C ₁₂ alkaryl, C ₃ -C ₈ cycloalkyl. , _C 3 -C ₈ cycloalkenyl, phenyl, Toruriru, xylenyl, _biphenyl, C 1 -C _{6 alkoxy,} C 2 -C _{6 alkenyloxy, C} 2 ~
C _{6 alkynyloxy,} C 2 _{-C 12 alkoxyalkyl,} C 2 _{-C 12 alkoxyalkyloxy,} C 2 _{-C 12 alkylcarbonyl,} C 2 _{-C 12 alkylcarbonylamino,} C 2 _{-C 12 alkoxyamino, C} 2 ~ C ₁₂ alkoxycarbonyl _{aminocarbonyl,} C 2 _{-C 12 alkylamino,} C 1 -C _{6 alkylthio,} C 2 _{-C 12 alkylthiocarbonyl,} C 2 _{-C 12 alkylsulfinyl, C} 1 ~
C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, C ₁ -C ₆ haloalkylsulfonyl, C ₂ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, —C (
O) O _(C 1 ~C _{6 alkyl), - (CH 2) n} -O- (C 1 ~C 6 alkyl), benzyloxy, phenoxy, _{phenylthio, - (CONHSO 2 R),} - CHO, amino, amidino , Bromo, carbamyl, carboxyl, carbalkoxy,-(C
H _{2) n} -CO ₂ H, chloro, cyano, Shianoguanijiru, fluoro, guanidino, hydrazide, hydrazino, hydrazide, hydroxy, hydroxyamino, iodo, nitro, phosphono, _-SO 3 H, thioacetal, thiocarbonyl, and _C 1 ~ selected from the group consisting of C ₆ carbonyl. n is 1 to 8] 18. A method of treating a human suffering from or susceptible to sepsis, said method comprising in a human in need of such treatment activated protein C and the following compounds (A) to (P): 1H- indole-3-glyoxylamides sPLA ₂ inhibitors selected from or a method comprising administering a pharmaceutically acceptable salt, solvate or prodrug derivatives thereof therapeutically effective combination,: (a ) [[3- (2-Amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (B) dl-2-[[3 -(2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] propanoic acid, (C) [[3- (2-amino-1 , 2-dioxoe Le) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl) -2-methyl -1H- indol-4-yl] oxy]
Acetate, (D) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -3-ylmethyl) -2-methyl -1H- indol-4-yl] Oxy]
Acetate, (E) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -4-ylmethyl) -2-methyl -1H- indol-4-yl] Oxy]
Acetic acid, (F) [[3- (2-amino-1,2-dioxoethyl) -1-[(2,6-dichlorophenyl) methyl] -2-methyl-1H-indol-4-yl] oxy] acetic acid, (G) [[3- (2-amino-1,2-dioxoethyl) -1- [4 (-fluorophenyl) methyl] -2-ethyl-1H-indol-4-yl] oxy] acetic acid, (H) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1-[(
1-naphthalenyl) methyl] -1H-indol-4-yl] oxy] acetic acid, (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H -Indol-4-yl] oxy] acetic acid, (J) [[3- (2-amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H-indole-4 - yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-ethyl -1H- indole -4-yl] oxy]
Acid, (L) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-propyl -1H- indol-4-yl] Oxy] acetic acid, (M) [[3- (2-amino-1,2-dioxoethyl) -2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (N) [[3- (2-amino-1,2-Jiokisoechiru) -1 - ([1,1 ^'- biphenyl] -2-ylmethyl] -2-cyclopropyl -1H- indol-4-yl
] Oxy] acetic acid, (O) 4-[[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1
-(Phenylmethyl) -1H-indol-5-yl] oxy] butyric acid, and (P) a mixture of (A) to (P). 19. A method of treating a human who is currently suffering from or susceptible to sepsis, the method comprising the steps of providing activated human protein C and 1H-indole of any of the following formulas to a human in need of such treatment. 3-Griot sill amide sPLA method comprises administering a therapeutically effective combination of ₂ inhibitors: embedded image Embedded image Embedded image 20. A method of treating a mammal for or preventing alleviate pathological effects of sepsis, the method is activated protein C and sPLA ₂ inhibitor to the mammal [[3- (2-amino-1,2-dioxoethyl)
A method comprising administering a therapeutically effective combination of 2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester compound. 21. A method of treating a human suffering from or susceptible to sepsis, the method comprising activating protein C and a compound of formula (I) in a human in need of such treatment.
A method comprising administering a compound of e), or a therapeutically effective combination of a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof. Embedded image Wherein A is phenyl or pyridyl, wherein the nitrogen is in the 5-, 6-, 7- or 8-position. One of B or D is nitrogen and the other is carbon. Z is cyclohexenyl, phenyl, pyridyl (where the nitrogen is in the 1-, 2- or 3-position) or a 6-membered heterocycle (where the ring is 1-, 2- or 3-position sulfur or Oxygen and one heteroatom selected from the group consisting of nitrogen at the 1-, 2-, 3- or 4-position). Embedded image Is a double bond or a single bond. R ²⁰ is selected from the group of (a), (b) and (c). Here, (a) represents _{- (C} 5 _{~C 20)} alkyl, - _(C 5 ~C ₂₀₎ alkenyl, - _{(C 5}
ＣC ₂₀ ) alkynyl, carbocyclic or heterocyclic. (B) is the element of (a) substituted with one or more independently selected non-interfering substituents. (C) is a group :-( L) ^{-R 80.} Here,-(L)-means 1 to 12 atoms.
Is a divalent linking group. The atom is selected from carbon, hydrogen, oxygen, nitrogen and sulfur, and the combination of atoms in-(L)-is (i) only carbon and hydrogen, (ii) only one sulfur, (iii) only one oxygen, (IV) selected from only one or two nitrogen and hydrogen, (v) carbon, only hydrogen and one sulfur, and (vi) only carbon, hydrogen and oxygen. R ⁸⁰ is a group selected from (a) and (b). R ²¹ is a non-interfering substituent. R ^{1 ′} is —NHNH ₂ , —NH ₂ or —CONH ₂ . R ^{2 ′} is selected from the group consisting of —OH and —O (CH ₂ ) _t R ^{5 ′} . Here, R ^{5 ′} is H, —CN, —NH ₂ , —CONH ₂ , —CONR ⁹ R ¹⁰ , —NH
^{_{SO 2 R 15, -CONHSO 2 R}} 15 ( ^{wherein, R 15} is - _(C 1 ~C ₆₎ alkyl or -CF _3), phenyl, substituted phenyl (the substituent -C
O ₂ H or —CO ₂ (C ₁ -C ₄ ) alkyl), and — (L _a ) — (acid group), wherein — (L _a ) — has an acid-linked chain length of 1 to 7. And t is 1 to 5.
It is. R ^{3 ′} is selected from a non-interfering substituent, a carbocyclic group, a carbocyclic group substituted with a non-interfering substituent, a heterocyclic group, and a heterocyclic group substituted with a non-interfering substituent. It is. However, when R ^{3 ′} is H, R ²⁰ is benzyl, and m is 1 or 2, R ^{2 ′} is not —O (CH ₂ ) _m H. And when D is nitrogen, the heteroatom of Z is selected from the group consisting of sulfur or oxygen at 1-, 2- or 3-position, and nitrogen at 1-, 2-, 3- or 4-position. Be] 22. A method of treating a human suffering from or susceptible to septic pain, the method comprising activating protein C and a compound of formula (IIe), or a pharmaceutical thereof, in a human in need of such treatment. A method comprising administering a therapeutically effective combination of a racemic, solvate, tautomer, optical isomer, prodrug derivative or salt that is chemically acceptable. Embedded image Wherein Z is cyclohexenyl or phenyl. R ²¹ is a non-interfering substituent. R ¹ is —NHNH ₂ or —NH ₂ . R ² is selected from the group consisting of -OH and ^{_{-O (CH 2) m R 5}} . ^Wherein, R 5 is _{H, -CO 2 H, -CONH 2} , -CO (C 1 ~C 4 alkyl)
, Embedded image (Where R ⁶ and R ⁷ are each independently —OH or —O (C ₁ -C ₄ ) alkyl), —SO ₃ H, —SO ₃ (C ₁ -C ₄ alkyl), tetrazolyl ^{_{, -CN, -NH 2, -NHSO 2}} R 15, -CONHSO 2 R 15 ( ^{wherein, R 15} is - _(C 1 ~
C ₆ ) alkyl or —CF ₃ ), phenyl or substituted phenyl (
The substituent is -CO ₂ H or -CO _{2 (C} 1 ~C ₄₎ alkyl), m
Is 1-3. R ³ is H, —O (C ₁ -C ₄ ) alkyl, halo, — (C ₁ -C ₆ ) alkyl, phenyl, — (C ₁ -C ₄ ) alkylphenyl, substituted phenyl (the substituent Is-
_(C 1 ~C ₆₎ alkyl, halo or _{-CF 3), - CH 2 OSi} (C 1 ~
C ₆₎ alkyl, furyl, thiophenyl, - _(C 1 ~C ₆₎ hydroxyalkyl or ^{_{- (CH 2) n R 8}} ( ^wherein, R 8 is ^{_{H, -CONH 2, -NR 9 R}} 10, -
R ⁹ and R ¹⁰ are independently-(C ₁ -C ₄ ) alkyl or -phenyl (C ₁ -C ₄ ) alkyl, and n is 1-8. R ⁴ is H,-(C ₅ -C ₁₄ alkyl),-(C ₃ -C ₁₄ ) cycloalkyl,
Pyridyl, phenyl or substituted phenyl (the substituent - _(C 1 ~C ₆₎ alkyl, _{halo, -CF 3, -OCF 3, -} (C 1 ~C 4) alkoxy, -CN, - (
C ₁ -C ₄ ) alkylthio, phenyl (C ₁ -C ₄ ) alkyl, — (C ₁ -C ₄ ) alkylphenyl, phenyl, phenoxy or naphthyl. 23. A method of treating a human suffering from or susceptible to sepsis.
Thus, the method provides humans in need of such treatment with activated protein C and formula (X
A carbazole compound selected from the compounds represented by XX), or a pharmaceutically acceptable compound thereof;
Racemates, solvates, tautomers, optical isomers, prodrug derivatives
Or a therapeutically effective combination of salts. Embedded image[Where R¹Is -NHNH₂Or -NH₂It is. R²Are -OH and -O (CH₂)_mR⁵Selected from the group consisting of Where R ⁵ Is H, -CO₂H, -CO₂(C₁~ C₄Alkyl), embedded image(Where R⁶And R⁷Are each independently -OH or -O (C₁~ C₄) Al
Kill)), -SO₃H, -SO₃(C₁~ C₄Alkyl), tetrazolyl, -CN, -NH ₂ , -NHSO₂R^Fifteen, -CONHSO₂R^Fifteen(Where R^FifteenIs-(C
₁~ C₆) Alkyl or -CF₃), Phenyl or substituted phenyl
(The substituent is -CO₂H or -CO₂(C₁~ C₄Alkyl))
, M is 1-3. R³Is H, -O (C₁~ C₄) Alkyl, halo,-(C₁~ C₆) Alkyl,
Enyl,-(C₁~ C₄) Alkylphenyl, substituted phenyl (the substituent is-
(C₁~ C₆Alkyl) phenyl, halo or -CF₃), -CH₂OSi
(C₁~ C₆Alkyl), furyl, thiophenyl,-(C₁~ C₆) Hydroxyal
Kill or-(CH₂)_nR⁸(Where R⁸Is H, -CONH₂, -NR⁹NR ¹⁰ , -CN or phenyl;⁹And R¹⁰Are independently-(C₁~ C
₄Alkyl) or -phenyl (C₁~ C₄Alkyl), and n is 1-8
). R⁴Is H,-(C₅~ C₁₄) Alkyl,-(C₃~ C₁₄) Cycloalkyl,
Pyridyl, phenyl or substituted phenyl, wherein the substituent is-(C₁~ C₆) Al
Kill, halo, -CF₃, -OCF₃,-(C₁~ C₄) Alkoxy, -CN,-(
C₁~ C₄) Alkylthio, phenyl (C₁~ C₄) Alkyl,-(C₁~ C₄A)
Alkylphenyl, phenyl, phenoxy or naphthyl). A is phenyl or pyridyl (where nitrogen is at the 5-, 6-, 7- or 8-position
In). Z is cyclohexenyl, phenyl, pyridyl (where nitrogen is 1-, 2-
Or at the 3-position) or a 6-membered heterocycle, wherein the ring is at the 1-, 2- or 3-position
Selected from the group consisting of sulfur or oxygen and nitrogen in the 1-, 2-, 3- or 4-position.
One heteroatom or optionally one carbon on the heterocycle
Prime is replaced by = O). With the proviso that one of A or Z is a heterocycle. 24. A method of treating a human suffering from or susceptible to sepsis, which comprises treating a human in need of such treatment with an activated protein C and a compound selected from the following compounds, or a pharmaceutically acceptable compound thereof. A method comprising administering a therapeutically effective combination of an acceptable racemate, solvate, tautomer, optical isomer, prodrug or salt: 9-benzyl-5,7-dimethoxy-1 9,2,3,4-tetrahydrocarbazole-4-carboxylic acid hydrazide; 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; [9-benzyl-4-carbamoyl- 7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, sodium salt; [9-benzyl-4-carbamoyl-7-methoxy] Carbazol-5-yl] oxyacetic acid; methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl] oxyacetate; 9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3 9,4-Tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5- (1H-tetrazol-5-ylmethyl) oxy) -1,2,3,4-tetrahydrocarbazole-4-carboxamide; {9- [(Phenyl) methyl] -5-carbamoyl-2-methyl-carbazole-
{9-[(3-fluorophenyl) methyl] -5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid; {9-[(3-methylphenyl) methyl]- 5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid; {9-[(phenyl) methyl] -5-carbamoyl-2- (4-trifluoromethylphenyl) -carbazol-4-yl} oxyacetic acid 9-benzyl-5- (2-methanesulfonamido) ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4- (2-methanesulfonamido) ethyloxy- 2-methoxycarbazole-5-carboxamide; 9-benzyl-4- (2-trifluoromethanesulfonamido) ethyloxy-
2-methoxycarbazole-5-carboxamide; 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-
1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-
5-carboxamide; [5-carbamoyl-2-pentyl-9- (phenylmethyl) carbazole-4
-Yl] oxyacetic acid; [5-carbamoyl-2- (1-methylethyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2- [ (Tri (-1-methylethyl
) Silyl) oxymethyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl) carbazole-4
[5-carbamoyl-2- (4-chlorophenyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2- (2-furyl) -9- ( [Phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2-[(tri (-1-methylethyl)
) Silyl) oxymethyl] carbazol-4-yl] oxyacetic acid lithium salt; {9-[(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(3-fluorophenyl) Methyl] -5-carbamoylcarbazole-4
-Yl} oxyacetic acid; {9-[(3-phenoxyphenyl) methyl] -5-carbamoylcarbazole-
4-yl} oxyacetic acid; {9-[(2-fluorophenyl) methyl] -5-carbamoylcarbazole-4
-9-[(2-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-benzylphenyl) methyl] -5-carbamoylcarbazole -4
-Yl} oxyacetic acid; {9-[(3-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(1-naphthyl) methyl] -5-carbamoylcarbazole- 4-yl} oxyacetic acid; {9-[(2-cyanophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3-cyanophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(2-methylphenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3-methylphenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(3,5-dimethylphenyl) methyl] -5-carbamoylcarbazole-
4-yl} oxyacetic acid; {9-[(3-iodophenyl) methyl] -5-carbamoylcarbazole-4-
Yl} oxyacetic acid; {9-[(2-chlorophenyl) methyl] -5-carbamoylcarbazole-4-
{9-[(2,3-difluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2,6-difluorophenyl) methyl] -5-carbamoyl Carbazol-4-yl} oxyacetic acid; {9-[(2,6-dichlorophenyl) methyl] -5-carbamoylcarbazole-
{9-[(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl] -5 -Carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; {9-[(2-biphenyl) methyl]- 5-carbamoylcarbazol-4-yl}
[9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; {9-[(2-pyridyl) methyl] -5-carbamoylcarbazol-4-yl } Oxyacetic acid; {9-[(3-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydro [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4] -Tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-8- Chloro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid; [9-[(cyclohexyl) methyl] -5-carbamoylcarbazol-4-yl]
Oxyacetic acid; [9-[(cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl]
Oxyacetic acid; 5-carbamoyl-9- (phenylmethyl) -2-[[(propen-3-yl) oxy] methyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl)- 2-[(propyloxy) methyl]
Carbazol-4-yl] oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -1,2,
3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-
Carboxamide; 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl
) Oxy) -carbazole-4-carboxamide; 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -carbazole-4-carboxamide; [9-benzyl-4-carbamoyl-1,2,3,4 -(Tetrahydrocarbazol-5-yl) oxyacetic acid; (R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,2,
(R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid;
3,4-tetrahydrocarbazol-5-yl] oxyacetic acid; [N-benzyl-1-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid; 4-methoxy-6 -Methoxycarbonyl-10-phenylmethyl-6,7,8,
9-tetrahydropyrido [1,2-a] indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,
4-b] indol-5-yl) oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole; 2-[(2, 9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-β-carbolin-5-yl) oxy] acetic acid. 25. sPLA ₂ inhibitor, the following formula (Xe) or (X
The pharmaceutical composition according to claim 1, which is a carbazole compound represented by Ie), or a pharmaceutically acceptable salt or ester prodrug derivative thereof. Embedded image 26. The method of claim 16, wherein the activated protein C is delivered parenterally.
25. The method according to any of 25. 27. sPLA ₂ inhibitors parenterally, orally, intranasally, as a suppository, carrying a patch, the method according to any one of claims 16 to 25. 28. transporting sPLA ₂ inhibitors parenterally, claim 1
26. The method according to any of 6 to 25. The 29. sPLA ₂ inhibitor is administered prior to activated protein C, Method according to any one of claims 16 to 25. 30. administering activated protein C before the sPLA ₂ inhibitors A method according to any one of claims 16 to 25. 31. sPLA ₂ inhibitor is administered simultaneously with activated protein C A method according to any one of claims 16 to 25. 32. The dose of activated protein C is from 1 μg to 100 μg / kg /
26. The method according to any of claims 16 to 25, which is a day. 33. The method according to claim 16, wherein the dose of activated protein C is 1 μg to 25 μg / kg / day. Dose of 34. sPLA ₂ inhibitors 10mg~2000mg
2. The method of claim 1, wherein the method is / kg / day. 35. or suffer easily mammal suffering currently sepsis (e.g., including a human) in the manufacture of a medicament for the treatment of sepsis, the use of sPLA ₂ inhibitor in combination with activated protein C.