JP2003522720A - Method for treating apoptosis-related disease using N-heterocyclic glyoxamide compound - Google Patents

Abstract

  (57) [Summary] PROBLEM TO BE SOLVED: To provide a method or an agent for treating apoptosis-related disease using an N-heterocyclic glyoxamide compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for treating an apoptosis-related disease using an N-heterocyclic glyoxamide compound, the use of the N-heterocyclic glyoxamide compound for the treatment of an apoptosis-related disease, and an apoptosis-related disease comprising the N-heterocyclic glyoxamide compound. Regarding therapeutic agents.

[0002]

[Prior art]

In multicellular organisms, homeostasis is maintained by a balance between cell proliferation and cell death. Cell death is roughly divided into necrosis and apoptosis. Apoptosis is observed in physiological development, disease development, or drug effects. Apoptosis, unlike necrosis, is thought to occur on the basis of activation of natural programs in individual cells. Apoptosis is RNA
Apoptosis and necrosis are different from each other in that they may be associated with synthesis and protein synthesis, but not necrosis. The morphological features are common, although the stimuli-induced apoptosis and the mechanism of apoptosis are diverse. The first morphological change is
Most are the formation of chromatin condensations that are associated with DNA fragmentation. After condensation is observed, the cytoplasmic compaction occurs and the cells themselves form cell fragments called apoptotic bodies. The formed apoptotic bodies are immediately phagocytosed, degraded, etc. by adjacent cells or macrophages to guide apoptosis. Brain Research 693 shows that phospholipase A ₂ (PLA ₂ ) has neurotoxicity.
(1995) 101-111 and THE JOURNAL BIOLOGICAL CHEMISTRY Vol. 271, No.51, (1
996) 32722-32728. However, there is no description that the neurotoxicity is related to apoptosis. It has been described in Brain Research 651 (1994) 353-356 that type II PLA ₂ is expressed after severe ischemia of the rat forebrain.
However, there is no description about the relationship between type II PLA ₂ and nerve cell death. Brain Research 752 shows that quinacrine, a phospholipase A ₂ inhibitor, reduces infarct size after short-term middle cerebral artery occlusion in rats.
(1997) 203-208. However, there is no description that this infarction is associated with apoptosis. Although it is described in WO 96/40982 that PLA ₂ inhibitors are useful in the treatment of neurodegenerative diseases, secretory PLA ₂ inhibitors such as the compounds used in the present invention treat such diseases. There is no mention that it can be used to treat. US Pat. No. 5,478,857 that PLA ₂ inhibitors are useful in treating Alzheimer's disease.
However, there is no mention that secretory PLA ₂ inhibitors such as the compounds used in the present invention can be used to treat such diseases.

[0003]

[Problems to be Solved by the Invention]

It is an object of the present invention to provide a method of treating a mammal, including a human, currently suffering from a disease associated with apoptosis, which method comprises treating said mammal in a therapeutically effective amount of N-hetero. Administering a Ring Glyoxamide Compound. It is also an object of the present invention to use the N-heterocyclic glyoxamide compounds for the manufacture of a medicament for the treatment of apoptosis related diseases in mammals, including humans, which are currently suffering from apoptosis related diseases. . It is also an object of the present invention to provide a composition for the treatment of apoptosis-related diseases in mammals, including humans, which are currently suffering from apoptosis-related diseases. The composition is for administering to said mammal a therapeutically effective amount of an N-heterocyclic glyoxamide compound.

[0004]

[Means for Solving the Problems]

The present invention is useful for diseases associated with apoptosis, more specifically, for Alzheimer's disease, a part of sclerosis, ataxia-telangiectasia, chronic diseases such as nerve cell death caused by prions, or acute diseases such as stroke. Is considered to be.

METHODS OF TREATMENT General aspects of the method: It will be apparent to those skilled in the art that the compounds of the invention can be administered in combination with other medically acceptable therapeutic or prophylactic agents and / or medicaments. Is. Since this treatment method lasts for many years, oral administration is preferred from the viewpoint of patient convenience and acceptability. In the case of oral administration, each is about 0.01 to about 50 mg /
kg (body weight), preferably about 0.04 to about 5.0 mg / kg, once a day
~ 3 times administered. The individual dose of the N-heterocyclic glyoxamide compound administered according to the present invention to obtain a therapeutic or prophylactic effect depends on the various circumstances surrounding the case, such as the compound administered, the route of administration, the size of the patient and It will be determined by the age, degree of disease associated with apoptosis, and the condition of the subject being treated. A typical daily dosage might range from about 0.01 mg / kg to about 5 of the active compound of this invention.
A non-toxic dosage level of 0 mg / kg (body weight) is included.

Administration Method The N-heterocyclic glyoxamide compound is usually used in the form of a pharmaceutical preparation in the method of the present invention as shown below. Other dosage forms may be used depending on the situation of humans and livestock. Other forms include suppositories, patches, and buccal or nasal spray formulations such as lozenges, nasal drops, sprays, or patches.

Compounds Used in Methods of Treating Apoptosis-Associated Diseases A method of preventing or treating apoptosis-related diseases comprises administering an effective amount of an N-heterocyclic glyoxamide compound. Suitable 1H-indole-3-glyoxamide compounds for carrying out the methods of treating and preventing apoptosis-related diseases of the present invention are described in EP Application No. 95302166.4, Publication No. 0675110 (published October 4, 1995). Have been described. Suitable 1H-indole-3-glyoxamide compounds are described in US Application No. 08 / 469,954 (filing date: 1995).
6 June), the contents of which are incorporated herein by reference. Formulations containing these 1H-indole-3-glyoxamide compounds and methods for their preparation are also described in EP Application No. 95302166.4 and US Application No. 0.
8 / 469,954. Suitable indolizine compounds are
It is described in WO96 / 03383 (publication date: February 8, 1996).

Definitions: The term "acidic linking group" means a divalent linking group represented by the symbol-(La)-or-(La ')-, and in the usual relationship, at the 4- or 5-position of the indole skeleton. Position or the 7-position or 8-position of the indolizine skeleton has a function of connecting an acidic group.

[Chemical 25]

The term “length of acidic linking group” refers to a linking group — (La) — or — (La ′) that connects the acidic group to the 4-position or 5-position of the indole skeleton or the 7-position or 8-position of the indolizine skeleton. )-Means the number of atoms in the shortest chain (excluding hydrogen). The term "acidic group" group shown below: 5-tetrazolyl, -SO ₃ H,

[Chemical formula 26] Wherein n is 1 to 8, R ₈₉ is a metal or C1-C10 alkyl, and R ₉₉ is hydrogen or C1-C10 alkyl.

[0010]   Preferred compounds for the method of the invention or the formulations of the invention have the general formula (I):

[Chemical 27] (In the formulae, E and F are different from each other, C or N; ----- represents the presence or absence of a double bond; X is independently oxygen or sulfur; R ₁₁ is (a), (b ), And (c), wherein (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, or a carbocyclic group, wherein the carbocyclic group is cycloalkyl, cycloalkyl. Alkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, anthracenyl, biphenyl, bibenzilyl, and formula (bb):

[Chemical 28] (Wherein n is an integer of 1 to 8) and is selected from the group consisting of bibenzilyl derivatives. (B) Component of (a) substituted with one or more independently selected non-interfering substituents. Here, the non-interfering substituents are C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C
3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy,
C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12
Alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C
2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-
C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (
O) O (C1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl)
, Benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino,
Bromo, carbamyl, carboxy, _{carbalkoxy, - (CH 2) n-} COOH
, Chloro, cyano, cyanoguanidyl, fluoro, guanidino, hydrazide (hyd
Razide), hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, in thiocarbonyl, and C1-C6 carbonyl (wherein, n is the group consisting of 1 to 8) Selected from. (C) the - (L ₁₎ a group represented by -R _81, where - (L ₁₎ - has the formula:

[Chemical 29] (Wherein R ₈₄ and R ₈₅ are each independently selected from hydrogen, C 1 -C 10 alkyl, carboxyl, carbalkoxy, or halogen, and p is 1 to 5, Z
It is a single _{bond, - (CH 2) -,} - O -, - N (C1-C10 alkyl) -, - NH
-Or a divalent linking group represented by -S-), R ₈₁ is a group selected from (a) or (b), R ₁₂ is hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3
-C4 cycloalkenyl, -O- (C1-C2 alkyl), or -S- (C
1-C2 alkyl), R ₁₄ is hydrogen or a group represented by — (La) — (acidic group), where — (La)
− Is the expression:

[Chemical 30] (Wherein, Q is _{- (CH 2) -, -} O -, - NH-, and is selected from the group consisting of -S-, hydrogen R ₈₄ and R ₈₅ are each independently, C1-C10 alkyl, aryl , C1-C10 alkaryl, and halogen).
R ₁₅ is a hydrogen atom or a group represented by — (La ′) — (acidic group), where — (
La ')-is the formula:

[Chemical 31] (In the formula, r is an integer from 1 to 7, s is 0 or 1, Q is-(CH ₂ )-, -O-,
Selected from the group consisting of —NH— and —S—, R _{84 ′} and R _{85 ′} are each independently hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C
1-C10 aralkyl, carboxy, carbalkoxy, and halogen)), provided that at least one of R _{14 and} R ₁₅ is a group represented by — (La) — (acidic group) or — (La ′). R ₁₆ is hydrogen, carboxy, or an ester thereof, R ₁₇ is a hydrogen atom or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
Alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl,
Biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6
Alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6. Alkylthio, C2-C12
Alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (O) O (C
1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxy, carbalkoxy, - (CH ₂₎ n -COOH, chloro,
Cyano, cyanoguanidyl, fluoro, guanidino, hydrazide,
Hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, (wherein, n 1 8) thiocarbonyl or C1-C6 carbonyl, noninterfering selected from Or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.

A preferred set of compounds for the method of the invention or the formulation of the invention is represented by the general formula (I
I):

[Chemical 32] (Wherein X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ have the same meanings as described above).

Another preferred set of compounds for the method of the invention or the formulation of the invention is the general formula (III):

[Chemical 33] (Wherein X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ have the same meanings as described above).

A further preferred group of compounds for the method of the present invention or the preparation of the present invention is represented by the general formula (
II) or (III), both X ′ are oxygen, and only one of R _{14 and} R ₁₅ is a group represented by — (La) — (acidic group) or — (La ′) — (
Acidic group), wherein the acidic group is carboxy. Particularly preferred compounds and all their pharmaceutically acceptable salts, solvates, and prodrug derivatives useful as the method of the present invention or the preparation of the present invention are the following compounds: (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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -3 -Ilmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (E) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -4 -Ilmethyl
) -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, (I ') [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, (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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, (L) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -2 -Ilmethyl
) -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-dioxoethyl) -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-
Indole-5-yl] oxy] butanoic acid, (P) A mixture of any of (A) to (O), (Q) (8- (carbomethoxymethyloxy) -2-ethyl-3- (o -Phenylbenzyl) indolizin-1-yl) glyoxamide, (R) [3-benzyl-8- (carbethoxymethyloxy) -2-ethylindolizin-1-
Yl] glyoxamide, (S) [8- (carbethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (T) [3-benzyl-8- (carb Ethoxymethyloxy) -2-methylindolizine-1-
Yl] glyoxamide, (U) [8- (carbethoxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (V) [8-carbethoxymethyloxy-2 -Ethyl-3- (1-naphthylmethyl) indolizin-1-yl] glyoxamide, (W) [3-Benzyl-8- (t-butoxycarbonylmethyloxy) -2-ethylindolizin-1-yl] glyoxamide , (X) [8- (carbmethoxymethyloxy) -2-ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (Y) [8- (carbmethoxymethyloxy)- 2-Cyclopropyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (Z) [3-Benzyl-8- (carboxymethyloxy) -2-ethylindolizin-1-yl]
Glyoxamide, (AA) [8- (Carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (AA ') [8- (Carbomethoxymethyloxy) -2 -Ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (BB) [3-Benzyl-8- (carboxymethyloxy) -2-methylindolizin-1-yl
] Glyoxamide, (CC) [8- (Carboxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (DD) [8- (Carboxymethyloxy) -2- Ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (EE) [8-carboxymethyloxy-2-ethyl-3- (1-naphthylmethyl) indolizin-1-yl] Glyoxamide, (FF) [8- (Carboxymethyloxy) -2-cyclopropyl-3- (o-phenylbenzyl
) Indolizin-1-yl] glyoxamide, (GG) (Q) to (FF) mixture, (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy] -2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (JJ) [3-[(2-amino-1,2-dioxoethyl) -6-ethoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (KK) [3-[(2-amino-1,2-dioxoethyl) -6-n-propoxycarbonyl-2-ethyl-1-benzyl-1H- Indol-4-yl] oxy] acetic acid, (LL) [3-[(2-amino-1,2-dioxoethyl) -6-i-propoxycarbonyl-2-ethyl-1-benzyl-1H-indole-4- Iyl] oxy] acetic acid, (MM) [3-[(2-amino-1,2-dioxoethyl) -6-cyclopropyloxycarbonyl
2-ethyl-1-benzyl-1H-indol-4-yl] oxy] acetic acid, a mixture of (NN) (HH) to (MM) in any combination. The most preferable compound in the practice of the method of the present invention or the preparation of the present invention is
Compounds shown below: (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (I ′ ) [[3- (2-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester is included. Similarly, the most preferable compound in the practice of the method of the present invention or the preparation of the present invention is the following compound: (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenyl Methyl) -1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl] -3-ylmethyl
) -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, (J) [[3- (2-Amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H- Indol-4-yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid. Similarly, the most preferable compound in the practice of the method of the present invention or the preparation of the present invention is the following compound: (AA) [8- (carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizine- 1-yl] glyoxamide, (AA ′) [8- (carbomethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indoridin-1-yl] glyoxamide, and the like. Similarly, the most preferable compound in the practice of the method of the present invention or the practice of the present invention is the compound shown below: (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy-2-ethyl- 1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid.

The most preferable compound in the practice of the method of the present invention or the preparation of the present invention is
1H-indole-3-glyoxamide compound selected from compounds represented by the following formula:

[Chemical 34] Or an indolizine-1-glyoxamide compound selected from the compounds represented by the following formulas:

[Chemical 35] Is mentioned.

A salt of the above-mentioned 1H-indole-3-glyoxamide compound represented by the general formula (II) and represented by the compounds (A) to (P), and a compound represented by the general formula (III) (HH ) To (GG) above indolizine-
Salts of 1-glyoxamide compounds are particularly useful in the method of the invention. In the case of the 1H-indole-3-glyoxamide compound and the indolizine-1-glyoxamide compound having an acidic or basic functional group, various salts having higher water solubility than the original compound and physiologically appropriate salts are used. Can be formed. Representative pharmaceutically acceptable salts include, but are not limited to, alkaline and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or contacting the acid with an ion exchange resin. A relatively non-toxic addition salt of an inorganic base and an organic base of the 1H-indole-3-glyoxamide compound and the indolizine-1-glyoxamide compound used in the method of the present invention or the preparation of the present invention, for example, a salt with the compound of the present invention is formed. Amine cations, ammonium, derived from nitrogen bases that have sufficient basicity to
Quaternary ammonium is included in the definition of pharmaceutically acceptable salts (eg SM Be
rge, et al., "Pharmaceutical Salts", J. Phar. Sci., 66: 119 (1977)). Further, 1H-indole-3-glyoxamide compound and indolizine-
The basic group of the 1-glyoxamide compound is reacted with a suitable organic or inorganic acid to react with acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bittertarate, borate, bromide, camsylate, carbonate,
Chloride, clavulanate, citrate, chloride, edetate, edisylate, estrate, esylate, fluoride, fumarate, glucceptate, gluconate, glutamate, glycolylarsanilate, hexyl resorcinate, bromide, chloride, hydroxynaphthoate, iodide , Isothionate, lactate, lactobionate, laurate, malate, malate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate,
Mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantosenate, phosphate, polygalacturonate, salicylate,
Forms salts such as stearates, subacetates, succinates, tanates, tartarates, tosylates, trifluoroacetates, trifluoromethanesulfonates, and valerates.

When a compound, such as a 1H-indole-3-glyoxamide compound and an indolizine-1-glyoxamide compound, has one or more asymmetric centers,
It may exist as an optically active substance. Further, it is contemplated that mixtures of R and S isomers, and cis, trans isomers, as well as mixtures of R and S isomers, including racemic mixtures, can be used in the methods of the invention or formulations of the invention. Prodrugs are derivatives of 1H-indole-3-glyoxamide compounds or indolizine-1-glyoxamide compounds that have chemically or metabolically degradable groups and are pharmaceutically in vivo by solvolysis or under physiological conditions. Is a compound which becomes the compound of the present invention which is active in. Derivatives of 1H-indole-3-glyoxamide compounds and indolizine-1-glyoxamide compounds are
Although active in both acid and base derivatives, acid derivatives are advantageous in solubility, histocompatibility and controlled release in mammalian organisms (Bundgard, H.,
Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). For example, a ester containing an acidic derivative such as an ester prepared by reacting the underlying acidic compound with a suitable alcohol, or an amide such as an amide prepared by reacting the underlying acidic compound with a suitable amine. Drugs are well known to those of skill in the art. Simple aliphatic or aromatic esters (eg methyl ester, ethyl ester) derived from overhanging acidic groups on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkylesters. The method of the present invention is described in US Pat. 5,296,222 and No. 5,271,
It can be practiced by using a pharmaceutical preparation containing the compound of the present invention, which is transdermally administered by a device such as a patch as described in 940 (the contents of which constitute a part of the present specification). . Aliphatic prodrug derivatives of compounds of general formula (II) are particularly well suited for transdermal absorption and delivery systems. The synthesis of 1H-indole-3-glyoxamide compounds is described in EP Application No. 953.
02166.4, publication number 0675110 (publication date October 4, 1995). Furthermore, the synthesis of indole dicarboxylic acid derivatives is
It can be synthesized as described in JP Application No. 35984/1997. The indolizine-1-glyoxamide compound can be synthesized according to the description in WO96 / 03383 (publication date: February 8, 1996). These synthetic methods also include known methods, methods described in chemical journals, and methods shown in the following reaction schemes.

[0017]

DETAILED DESCRIPTION OF THE INVENTION

  The following abbreviations are used throughout the synthetic schemes and examples.   Et: ethyl   Pr: Propyl   t-Bu: t-butyl   Bn: benzyl   LAH: Lithium aluminum hydride   THF: Tetrahydrofuran   DMF: dimethylformamide   Hex: Hexyl

[0018] Scheme 1

[Chemical 36] (In the formula, R ₁₂ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above, and R ₃ is C1-C5 alkyl, aryl, C1-C6 alkoxy, halogen, aryloxy, aralkyloxy, nitro, hydroxy, amino. , Methylamino, or dimethylamino, R ₅ is hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl,
, C1-C10 aralkyl, or halogen)

Description of Scheme 1 To synthesize a glyoxamide compound in which the 4-position is substituted with an acidic group via an oxygen atom, the reaction outlined in Scheme 1 is used (for the conversion of 1 to 5
Robin D. Clark, Joseph M. Muchowski, Lawrence E. Fisher, Lee A. Flippin
, David B. Repke, Michel Souchet, Synthesis, 1991, 871-878. This content constitutes a part of this specification). The ortho-nitrotoluene 1 is easily reduced to the 2-methylaniline 2 using Pd / C as a catalyst. This reduction can be carried out with hydrogen at low pressure in ethanol or tetrahydrofuran (THF) or a mixture of both. The aniline 2 is heated to reflux temperature in di-tert-butyl dicarbonate in THF to give the N-tert-butylcarbonyl derivative 3 in high yield. -40 to 20 using sec-butyllithium in THF
The dilithium salt of the dianion of 3 is formed at C and reacted with an appropriately substituted N-methoxy-N-methylalkanamide. Reaction product 4, which may be purified by crystallization from hexane, can be obtained by direct reaction with trifluoroacetic acid in methylene chloride to give the 1,3-unsubstituted indole of 5. The 1,3-unsubstituted indole of 5 is reacted with sodium hydride in dimethylformamide at room temperature (20-25 ° C) for 30 minutes to 1 hour. The resulting sodium salt of 5 is treated with an equivalent amount of arylmethyl halide and the mixture is stirred at a temperature range of 0 to 100 ° C., usually at room temperature for 4 to 36 hours to give 1-arylmethylindole of 6 . This indole 6 is o-demethylated by stirring with boron tribromide in methylene chloride for about 5 hours (Tsung-Ying Shem and Charles A Winter, Adv. Drug Res., 1977).
, 12, 176. This content constitutes a part of this specification). 4-hydroxyindole of 7 was prepared by using sodium hydride as a base and dimethylformamide (
Alkylation with α-bromoalkanoic acid ester in DMF) under conditions similar to those described for the conversion of 5 to 6. The α-[(indol-4-yl) oxy] alkanoic acid ester of 8 is reacted with oxalyl chloride in methylene chloride to give 9, which is directly reacted with ammonia without purification to give 10 glyoxamide. The product is hydrolyzed in methanol with 1N sodium hydroxide. 1
The final glyoxylamide compound of 1 separates as the free carboxylic acid, or its sodium salt, or both forms.

[0020] Scheme 2-1

[Chemical 37] (In the formula, R ₁₂ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above, and R ₂ is C6-C20 alkyl, C6-C20 alkenyl, C6-C20 alkynyl or carbocyclic group)

Using sodium hydride and benzyl chloride, compound 23 (N. Desideri F.
Mama, ML Stein, G. Bile, W. Filippeelli, and E. Marmo, Eur. J. Med.
Chem. Chim. Ther., 18 , 295, (1983)) is O-alkylated to give compound 24. N-alkylation of compound 24 was carried out with 1-bromo-2-butanone or chloromethyl cyclopropyl ketone followed by base catalyzed cyclization to give compound 2
5, which is acylated with aroyl halide to give compound 26. The ester functional group of compound 26 is hydrolyzed and then acidified to form an acid which is decarboxylic acid by heating to give compound 27. Compound 27 by LAH
The ketone functional group of is reduced to give indolizine 28.

[0022] Scheme 2-2

[Chemical 38] (In the formula, R ₂ , R ₁₂ , R ₁₅ , R ₁₆ , and R ₁₇ have the same meanings as described above, and R ₅ is hydrogen or C1-C6 alkyl)

Description of Scheme 2-2 Compound 28 is treated sequentially with oxalyl chloride and ammonium hydroxide to form compound 35, which is debenzylated with hydrogen in the presence of Pd / C to give compound Get 36. Indolizine 36 is O-alkylated with sodium hydride and bromoacetate to form compound 37, 38, or 39,
The compound is converted to indolizine 40 by hydrolysis with aqueous base followed by acidification.

Pharmaceutical Formulations A suitable pharmaceutical formulation of the 1H-indole-3-glyoxamide compound may be prepared as disclosed in EP Application No. 95302166.4, Publication No. 0675110 (published October 4, 1995). it can. Suitable pharmaceutical formulations of indolizine-1-glyoxamide compounds are described in WO 96/03383 (February 8, 1996).
It is possible to manufacture it as disclosed in Jpn. The preparation can be obtained by a simple method well known in the pharmaceutical field. The 1H-indole-3-glyoxamide compound or indolizine-1-glyoxamide compound generally comprises a 1H-indole-3-glyoxamide compound or indolizine-1-glyoxamide compound and a therapeutically effective amount of a diluent or carrier. It is administered as a suitable pharmaceutical formulation. The formulation is adapted according to the route of administration chosen. The term "pharmacologically acceptable" is compatible with the 1H-indole-3-glyoxamide compound or the indolizine-1-glyoxamide compound in the formulation and must not be harmful to the patient, a diluent, or Means additive. It is preferable that the pharmaceutical preparation is formulated in a single dose. The unit dose can be the capsule or tablet itself, or an appropriate number of these formulations. The amount of active ingredient in a single dose of the composition may be varied and prepared according to the particular treatment involved, in amounts of about 0.1 to about 1000 mg, or higher. The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intranasal. Any suitable carrier known to those of ordinary skill in the art can be used for this formulation. In such formulations, the carrier is a solid, liquid, or mixture of solids and liquids. A solid carrier is one or more substances that also serve as ingredients for flavoring agents, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents, and encapsulating agents. Tablets for oral administration include calcium carbonate, sodium carbonate with disintegrants such as corn, starch, alginic acid, and / or binders such as gelatin, acacia, and lubricants such as magnesium stearate, stearic acid, or talc. , Lactose, calcium phosphate or the like. In tablets, 1H-indole-3-glyoxamide compound or indolizine-1-
The glyoxamide compound is mixed in a suitable ratio with a carrier having the necessary binding properties, and hardened to the desired shape and size. Powders and tablets preferably contain from about 1% to about 99% by weight of 1H-indole-3-glyoxamide compound or indolizine-1-glyoxamide compound. Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent or a mixture of both.

[0025]

【Example】

Example 1 shown below is [[3- (2-amino-1,2-dioxyethyl) -2.
1 shows the synthesis of -ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, 1H-indole-3-glyoxamide compounds are useful in the practice of the method of the invention.

Example 1 Preparation of [[3- (2-amino-1,2-dioxoethyl) 2-ethyl 1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid represented by the following chemical formula

[Chemical Formula 39]

Part A Synthesis of 2-ethyl-4-methoxy-1H-indole N-tert-butoxy-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in THF
To the solution (250 mL), 140 mL (0.18 mol) of 1.3 M sec-butyllithium in cyclohexane was slowly added in a dry ice-ethanol bath so as to maintain the temperature at -40 ° C or lower. The bath was removed, the temperature was raised to 0 ° C., and then the bath was returned.
After cooling to −60 ° C., a solution of 18.5 g (0.18 mol) N-methoxy-N-methylpropanamide in an equal amount of THF was added. The reaction mixture was stirred for 5 minutes, the bath was removed, and the mixture was further stirred for 18 hours. The reaction solution was poured into a mixed solution of 300 mL of ether and 400 mL of 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, MgSO ₄
Dried in. After concentration under reduced pressure, 25.5 g of a crude product of 1- [2- (tert-butoxycarbonylamino) -6-methoxyphenyl] -2-butanone was obtained. The crude product was dissolved in 250 mL methylene chloride and 50 mL trifluoroacetic acid and combined and stirred for 17 hours. The mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residual oily substance. The ethyl acetate layer was separated, washed with brine, dried (MgSO _4), and concentrated. The residue was purified by silica gel column chromatography eluting with 20% ethyl acetate / hexane 3
After purification, 13.9 g of 2-ethyl-4-methoxy-1H-indole was obtained. Elemental analysis As C ₁₁ H ₁₃ NO: Calculated: C, 75.40; H, 7.48; N, 7.99 Found: C, 74.41; H, 7.64; N, 7.97. Part B 2-Ethyl-4-methoxy-1- Synthesis of (phenylmethyl) -1H-indole 2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL DMF, and 960 mg (24 mmol) of 60% sodium hydride was added. It was After 1.5 hours, 2.9 mL (
(24 mmol) benzyl bromide was added. After 4 hours, the reaction solution was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate layers washed with brine, dried (MgSO _4),
It was concentrated under reduced pressure. The residue was chromatographed on silica gel with 20% ethyl acetate /
From the fraction eluted from hexane, 3.1 g of 2-ethyl-4-methoxy-1- (phenylmethyl) -1H-indole (yield 49%) was obtained. Part C Synthesis of 2-Ethyl-4-hydroxy-1- (phenylmethyl) -1H-indole According to the method used in Example 1, Part D of EP Publication No. 0675110, 3.1 g (11.7 mmol) ) 2-ethyl-4-methoxy-1- (phenylmethyl
)-1H-indole was O- demethylated by treatment with 48.6 mL of 1M BBr ₃ / methylene chloride, purified by silica gel column chromatography (20% elution fraction ethyl acetate / hexane), 1.58 g (yield 54% of 2-ethyl-4-hydroxy-1- (phenylmethyl) -1H-indole was obtained. Melting point: 86-90 ° C Elemental analysis As C ₁₇ H ₁₇ NO: Calculated: C, 81.24; H, 6.82; N, 5.57 Found: C, 81.08; H, 6.92; N, 5.41.

Part D Synthesis of 2-[[2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester Example 1, Part E of EP Publication No. 0675110. 2-ethyl-4-hydroxy-1- (phenylmethyl) -1H-indole (
1.56 g, 6.2 mmol) to 248 mg (6.2 mmol) sodium hydride and 0.6 mL (6.2
mmol) of methyl bromoacetate. The product was purified by silica gel column chromatography, 1.37 from the fraction eluted with 20% ethyl acetate / hexane.
g (yield 69%) of 2-[[2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester was obtained. Melting point: 89-92 ° C Elemental analysis As C ₂₀ H ₂₁ NO ₃ : Calculated: C, 74.28; H, 6.55; N, 4.33 Found: C, 74.03; H, 6.49; N, 4.60. Part E [[3 -(2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl)-
Synthesis of 1H-indol-4-yl] oxy] acetic acid methyl ester Using Example F of EP Publication No. 0675110, 1.36 g (4.2 mm
ol) [[2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester was reacted with 0.4 mL (4.2 mmol) of oxalyl chloride and then reacted with excess ammonia. And a white solid was obtained. The white solid was stirred in ethyl acetate, the insoluble material was separated and dried, and 1.37 g of [[3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H A mixture of -indol-4-yl] oxy] acetic acid methyl ester and ammonium chloride was obtained. This mixture melted at 172-187 ° C. Part F [[3- (2-Amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl)-
Synthesis of 1H-indol-4-yl] oxy] acetic acid 788 mg (2 mmol) of [3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl) -1H-indole-4 A mixture of -yl] oxy] acetic acid methyl ester, 10 mL of 1N sodium hydroxide, and 30 mL of methanol was heated under reflux for 0.5 hours, stirred at room temperature for 0.5 hours, and concentrated under reduced pressure. . The residue was treated with ethyl acetate and water, the aqueous layer was separated, and acidified to pH 2-3 with 1N hydrochloric acid. The precipitated crystals were collected by filtration, washed with ethyl acetate, and 559 mg (yield 74%) of [[3- (2-amino-1,2-dioxyethyl) -2-ethyl-1- (phenylmethyl)- 1H-indol-4-yl] oxy] acetic acid was obtained. Melting point: 230-234 ° C Elemental analysis As C ₂₁ H ₂₀ N ₂ O ₅ : Calculated: C, 65.96; H, 5.80; N, 7.33 Found: C, 66.95; H, 5.55; N, 6.99.

Example 2 shown below is (8- (carbomethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl) glyoxamide, useful in the practice of the method of the invention. 1 shows the synthesis of an indolizine-1-glyoxamide compound. Example 2 (8- (carboxymethyloxy) -2-ethyl-3 represented by the following chemical formula
Preparation of-(o-phenylbenzyl) indolizin-1-yl) glyoxamide

[Chemical 40]

Part A Synthesis of Ethyl 3-benzyloxy-2-pyridine acetate 24 Ethyl 3-hydroxy-2-pyridine acetate (23, 12.0 g, 66.2 mmol) (N.
Desideri, F. Manna, ML Stein, G. Bile, W. Filippeelli, and E. Marmo.
Eur. J. Med. Chem. Chim. Ther., 18, 295 (1983)) dimethylformamide (2
20%) solution was added 60% sodium hydride (2.69 g, 66.2 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 50 minutes. Benzyl chloride (8.4 ml, 72.8 mmol)
Was added to the reaction solution, and the mixture was stirred overnight. Ethyl acetate was added. The mixture was washed with 5% aqueous sodium hydrogen carbonate solution and water and dried over Na ₂ SO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl acetate: toluene (
From the fraction eluted at 1:19 to 1: 1), 16.17 g (yield 90.0%) of the target compound was obtained as an oily compound. _{IR ν max (film) 1736,} 1446, 1278 cm -1. 1 H NMR (CDCl 3) δ 1.21 (3H, t, J = 7.2 Hz), 3.93 (2H, s), 4.14 (2H, q, J = 7
.2 Hz), 5.10 (2H, s), 7.13-7.22 (2H, m), 7.32-7.43 (5H, m), 8.16 (1H, dd
, J = 4.0, 3.0 Hz). Part B Synthesis of ethyl (8-benzyloxy-2-ethylindolizin-1-yl) carboxylate 25a Pyridine derivative (24, 15.15 g, 55.8 mmol), sodium hydrogen carbonate ( 23.45 g,
A solution of a mixture of 279 mmol and 1-bromo-2-butanone (11.4 ml, 113 mmol) in methyl ethyl ketone (250 ml) was heated under reflux for 24 hours, washed with water and dried over Na ₂ SO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography, and 16.66 g (yield 92.0%) of the target compound was obtained as an oily compound from the fraction eluted with ethyl acetate: hexane. _{IR ν max (film) 1690,} 1227, 1092 cm -1. 1 H NMR (CDCl 3) δ 1.15 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.5 Hz), 2.82 (
2H, q, J = 7.5 Hz), 4.11 (2H, q, J = 7.2 Hz), 5.16 (2H, s), 6.22 (1H, d, J = 7
.6 Hz), 6.44 (1H, t, J = 7.1 Hz), 7.07 (1H, s), 7.27-7.57 (6H, m).

Part C Synthesis of ethyl (8-benzyloxy-2-ethyl-3- (o-phenylbenzoyl) indolizin-1-yl) carboxylate 26b Indolizine (25, 1 eq), o-phenylbenzoyl chloride A mixture of (2.0 eq) and triethylamine (5.0 eq) was stirred at 90 ° C (bath temperature) for 2-8 hours. Ethyl acetate was added. The mixture was washed with dilute hydrochloric acid and water, dried over Na ₂ SO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography,
Elution with ethyl acetate: hexane (1: 2) recrystallized (46.0%). Melting point: 110-112 ℃
(Ether-hexane) Part D 8-Benzyloxy-2-ethyl-3- (o-phenylbenzoyl) indolizine
Synthesis of 27b To a solution of the ester (26, 1.0 mmol) in dimethyl sulfoxide (10 ml) was added 50% aqueous potassium hydroxide solution (3 ml). The mixture was heated at 140 ° C. for 2-24 hours. After cooling, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over Na ₂ SO ₄ . After distilling off the solvent under reduced pressure, the residue was purified by recrystallization to obtain a carboxylic acid. A toluene solution of this acid was heated under reflux for 1 hour, and the solvent was distilled off under reduced pressure. The residue was purified by recrystallization to give 27 quantitatively. IR ν _max (nujol) 1735, 1597, 742 cm ^-1 .

Part E 8-Benzyloxy-2-ethyl-3- (o-phenylbenzyl) indolizine 2
Synthesis of 8b Compound 27 was treated in the same manner as in the method of synthesizing compound 4 described in WO96 / 03383 to quantitatively obtain the desired product. IR ν _max (CHCl ₃ ) 1525, 1259 cm ^-1 .Part F (8-benzyloxy-2-ethyl-3- (o-phenylbenzyl) indolizine-
Synthesis of 1-yl) glyoxamide 35d These compounds can be synthesized according to the method described as the synthesis of compounds 4 to 8 of WO96 / 03383. Yield 79.0%. Melting point: 183-185 ° C. Part G Synthesis of (2-ethyl-8-hydroxy-3- (o-phenylbenzyl) indolizin-1-yl) glyoxamide 36d These compounds are the compounds of compounds 19 to 20 of WO 96/03383. It can be synthesized according to the method described as synthesis. Yield 95.0%. Melting point: 195-196
C (decomposition) (ether-hexane) part H (8- (carbomethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl
) Synthesis of indoridin-1-yl) glyoxamide 39d These compounds can be synthesized according to the method described as the synthesis of compounds 20 to 21 of WO96 / 03383. Yield 84%. Melting point: 73-75 ℃ (
Decomposition) (Ether-hexane) Part I (8- (Carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl) glyoxamide 40d Synthesis of ester (37-39, 2 mmol 1N potassium hydroxide aqueous solution (4 ml) was added to a methanol (21 ml) solution of). The solution was stirred at room temperature for 40 minutes, washed with ether,
The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. Wash this extract with water,
It was dried over Na ₂ SO ₄ . After distilling off the solvent under reduced pressure, the residue was recrystallized. Yield 93%. Mp:.. 209-212 C (decomposed) (ether - _{hexane) IR ν max (nujol) 3316} , 1704, 1601, 1493 cm -1 1 H NMR (d 6 -DMSO) δ 1.01 (3H, t, J = 7.5 Hz), 2.67 (2H, q, J = 7.5 Hz), 4.18
(2H, s), 4.71 (2H, s), 6.41 (1H, d, J = 7.8 Hz), 6.57-6.59 (2H, m), 7.14-
7.57 (10H, m), 7.34 (1H, s), 13.09 (1H, br.s). Elemental analysis C ₂₇ H ₂₄ N ₂ O ₅ 0.3H ₂ O: Calculated value: C, 70.21; H, 5.37; N, 6.06. Found: C, 70.17; H, 5.35; N, 5.98.

The therapeutic utility of the methods of the invention in treating apoptosis-related disorders is demonstrated by Examples 3 and 4 set forth below. Example 3 This example is directed against human cell death induced by PLA ₂ -II (hPLA ₂ -II).
(8- (carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizine-
1-yl) glyoxamide (compound prepared in Example 2, hereinafter referred to as “compound 2
")). (1) Primary culture of nerve cells According to the method of Ueda et al. (Neurosci. Lett. 203, 175-178), nerve cells were prepared from the cerebral cortex of Sprague-Dawley rat (embryonic day 19). . The cerebral cortex contains 25 ml of isotonic buffer (137 mM NaCl, 5.
4 mM KCl, 0.17 mM Na ₂ HPO ₄ , 0.22 mM KH ₂ PO ₄ , 5.5 mM glucose, 59 mM sucrose; the volume of each buffer is 25 ml, 4 mg / ml trypsin (Trypsin)
And 0.4 mg / ml deoxyribonuclease I. 5% fetal bovine serum using (fetal calf serum) and 5% horse serum Leibovitz L-15 medium containing (horse serum) (Leivbovitz's L -15 medium), 2.5 x 10 5 cells in culture plates coated with poly-L-lysine Neurons were seeded at a density of / cm ² . On the 1st day, 0.1 mM arabinosylcytosine C (arabinosylcytosine
The medium was replaced with a medium containing C). Cultured neurons were used in the experiment on the second day of culture. (2) Ultrastructural changes in cortical neurons after hPLA ₂ -II treatment Neurons were treated with hPLA ₂ -II for 48 hours and then dissolved in PBS 1-5% (preferably 2.
5%) Fix with glutaraldehyde for 2 hours at 4 ℃, 0.5-2% (
After fixation with osmium tetraoxide (preferably 1%). To increase the contrast, saturated thiocarbohydrazide-osmium (thiocarb
Double fixed with ohydrazide-osmium). The samples were then sequentially dehydrated with 50-100% ethanol. Araldite or an epoxy resin (preferably Epon 812) was poured into the culture dish, and vacuum was applied at 60-70 ° C. for 48 hours to prepare a section. The sections were then cut into uranium acetate and lead citr.
ate) and double-stained and observed with an electron microscope. The results are shown in FIGS. 1 and 2. Figure 1 shows the ultrastructure of untreated neurons and Figure 2 shows the ultrastructure of hPLA ₂ -II treated neurons. Results: Untreated nerve cells showed round cell bodies and extended neurites. On the other hand, in hPLA ₂ -II-treated neurons, the cell bodies were atrophied and the neurites were lost. Compared to untreated neurons (Figure 1), the HPLA ₂ -II treated neurons fragmentation nuclear chromatin, loss of intracellular organelles other than mitochondria, foaming of the cell membrane was observed (Fig. 2
).

(3) Evaluation Method of Neuronal Cell Death In order to evaluate the neuronal toxicity of hPLA ₂ -II according to the method of Ueda et al. (Neurosci. Lett. 203, 175-178), the mitochondrial activity is reflected 3 The-(4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide dye (MTT) reduction assay was used. To the nerve cells, add MTT stock solution (5 mg / ml) to the medium (volume ratio 1/50-1/100).
), And incubated at 37 degrees for 1 hour. The supernatant was aspirated and the cells were lysed in isopropranolol (100-200 μl) containing 0.04N hydrochloric acid. The absorbance at a wavelength of 570 nm was measured with a microplate reader. p-BPB: 100 μM hPLA ₂ -II was pre-incubated with 0.01, 0.1, or 1 mM p-bromophenacyl bromide at 37 ° C for 20 minutes, and then part of it was added to the medium of cerebral cortex neurons.
It was added at 0-fold dilution. Vehicle and Compound 2: Cortical neurons on day 2 of culture were treated with Compound ₂ in vehicle or 1 μM hPLA ₂ -II in the presence of the concentrations shown in the figure for the compound prepared in Example 2. 48 hours after hPLA ₂ -II treatment, MTT reducing activity (MTT reducing activity
) Was measured. The results are shown in FIG. Post-treatment with Compound 2: Cortical neurons on day 2 of culture were treated with 1 μM hPLA ₂ -II. After hPLA ₂ -II treatment, Compound 2 was added to the medium at a final concentration of 10 μM at the time shown in the figure. The data are shown as mean ± standard deviation (4 cases). ANOV
A), Dunnett's test was used to perform a significant difference test. ** indicates that there is a significant difference at P <0.01 with respect to the vehicle treated group. The results are shown in FIG.
Results: From FIG. 3, it was confirmed that Compound 2 suppressed nerve cell death in a concentration-dependent manner. From FIG. 4, it was confirmed that Compound 2 completely suppressed nerve cell death even after 10 hours treatment with hPLA ₂ -II. Thus, compound 2 was able to rescue nerve cells from hPLA ₂ -II-induced cell death not only upon simultaneous application but also after application.

Example 4 This example addresses neuronal cell death induced by human PLA ₂ -II (hPLA ₂ -II).
[[3- (2-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid (the compound prepared in Example 1, (Referred to as "compound 1"). About the evaluation method of nerve cell death The experiment was carried out except that 3 μM hPLA ₂ -II was added to the neurons cultured in the 48-well plate instead of adding 1 μM hPLA ₂ -II to the neurons cultured in the 12-well plate. It carried out by the method similar to Example 3 (3). The result is shown in FIG. Results: From FIG. 5, it was confirmed that Compound 1 completely suppressed nerve cell death in a concentration-dependent manner.

The following Pharmaceutical Formulations 1-8 are merely exemplary and are not intended to limit the scope of the invention in any way. The term "active ingredient" means a compound of formula (I), its pharmaceutically acceptable salts, solvates, or prodrugs thereof. Formulation Example Formulation Example 1 Hard gelatin capsules are manufactured using the following ingredients: Dose (mg / capsule) Active ingredient 250 Starch (dry) 200 Magnesium stearate 10 Total 460 mg Formulation Example 2 Tablets are manufactured using the following ingredients Do: Dose (mg / tablet) Active ingredient 250 Cellulose (microcrystalline) 400 Silicon dioxide (fume) 10 Stearic acid 5 Total 665

Formulation Example 3 An aerosol solution is prepared containing the following ingredients: Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 74.00 Total 100.00 Active ingredient and ethanol are mixed. , This mixture is added to a portion of propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container. Formulation Example 4 A tablet containing 60 mg of the active ingredient is prepared as follows: Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg total 150 mg Active ingredient, starch and cellulose are No. 45 mesh U.S. S. Sift through and mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and then the mixture was mixed with No. 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.S.S. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, which has been passed through a sieve, magnesium stearate, and talc are added to the granules, which are mixed and then compressed with a tableting machine to give tablets each weighing 150 mg.

Formulation Example 5 A capsule containing 80 mg of the active ingredient is produced as follows: Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg Active ingredient, starch, cellulose and magnesium stearate are mixed. No. 45 mesh U.S. S. Pass 200 through hard gelatin capsules through a sieve
Fill with mg. Formulation Example 6 A suppository containing 225 mg of active ingredient is prepared as follows: Active ingredient 225 mg Saturated fatty acid glyceride 2000 mg Total 2225 mg Active ingredient 60 mesh U.S. S. Pass through the sieve of No. 1 and suspend in saturated fatty acid glyceride that has been melted by previously heating it to the minimum required. The mixture is then placed in an apparent 2g mold and allowed to cool.

Formulation Example 7 A suspension containing 50 mg of the active ingredient is prepared as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Perfume q. v. Dye q. v. Purified water was added and a total of 5 ml active ingredient was added. 45 mesh U.S. S. And mix with sodium carboxymethyl cellulose and syrup to a smooth paste. Add benzoic acid solution and perfume diluted with a portion of water and stir. Then add sufficient water to bring it to the required volume. Formulation Example 8 An intravenous formulation is prepared as follows: Active ingredient 100 mg Saturated fatty acid glyceride 1000 ml A solution of the above ingredients is usually administered to a patient intravenously at a rate of 1 ml per minute. Although the present invention has been described in terms of certain specific embodiments described above, these specific examples are not intended to limit the scope of the invention described in the claims herein.

[Brief description of drawings]

FIG. 1 shows the ultrastructure of untreated neurons.

FIG. 2 shows the ultrastructure of hPLA ₂ -II treated neurons.

FIG. 3 shows the concentration-dependent effect of Compound 2 on hPLA ₂ -II-induced neuronal cell death.

FIG. 4 shows the time-dependent effect of Compound 2 on hPLA ₂ -II-induced neuronal cell death.

FIG. 5 shows the concentration-dependent effect of Compound 1 on hPLA ₂ -II-induced neuronal cell death.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 209/18 C07D 209/18 471/04 104 471/04 104A (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, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV , MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, U S, UZ, VN, YU, ZW F terms (reference) 4C065 AA03 BB04 CC01 DD01 EE02 HH08 JJ03 KK02 KK04 PP03 4C086 AA01 AA02 BC13 CB05 MA01 MA04 NA14 NA15 ZA02 ZA02 BB01 DB21 CB01 DB21 CB01 DB03 CB01 DB03 CB01 DB03 CB03 BB01 CB03 BB01 CB03 BB01 CB03 DB03 CB01

Claims (29)

[Claims] 1. A compound represented by the general formula (I): [Wherein E and F are different from each other and are C or N; ----- represents the presence or absence of a double bond; X is independently oxygen or sulfur; R ₁₁ is (a), (b ), And (c). Here, (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, or a carbocyclic group. The carbocyclic group is cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, anthracenyl, biphenyl, bibenzilyl, And formula (bb): (Wherein n is an integer of 1 to 8) and is selected from the group consisting of bibenzilyl derivatives. (B) Component of (a) substituted with one or more independently selected non-interfering substituents. Here, the non-interfering substituents are C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C
3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy,
C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12
Alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C
2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-
C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (
O) O (C1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl)
, Benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino,
Bromo, carbamyl, carboxy, _{carbalkoxy, - (CH 2) n-} COOH
, Chloro, cyano, cyanoguanidyl, fluoro, guanidino, hydrazide (hyd
Razide), hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, in thiocarbonyl, and C1-C6 carbonyl (wherein, n is the group consisting of 1 to 8) Selected from. (C) the - (L ₁₎ a group represented by -R _81, where - (L ₁₎ - has the formula: ## STR3 ## (Wherein R ₈₄ and R ₈₅ are each independently selected from hydrogen, C 1 -C 10 alkyl, carboxyl, carbalkoxy, or halogen, and p is 1 to 5, Z
It is a single _{bond, - (CH 2) -,} - O -, - N (C1-C10 alkyl) -, - NH
-Or a divalent linking group represented by -S-), R ₈₁ is a group selected from (a) or (b), R ₁₂ is hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3
-C4 cycloalkenyl, -O- (C1-C2 alkyl), or -S- (C
1-C2 alkyl), R ₁₄ is hydrogen or a group represented by — (La) — (acidic group), where — (La)
-Is the formula: (Wherein, Q is _{- (CH 2) -, -} O -, - NH-, and is selected from the group consisting of -S-, hydrogen R ₈₄ and R ₈₅ are each independently, C1-C10 alkyl, aryl , C1-C10 alkaryl, and halogen).
R ₁₅ is a hydrogen atom or a group represented by — (La ′) — (acidic group), where — (
La ')-is of the formula: (In the formula, r is an integer from 1 to 7, s is 0 or 1, Q is-(CH ₂ )-, -O-,
Selected from the group consisting of —NH— and —S—, R _{84 ′} and R _{85 ′} are each independently hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C
1-C10 aralkyl, carboxy, carbalkoxy, and halogen)), provided that at least one of R _{14 and} R ₁₅ is a group represented by — (La) — (acidic group) or — (La ′). R ₁₆ is hydrogen, carboxy, or an ester thereof, R ₁₇ is a hydrogen atom or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
Alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl,
Biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6
Alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6. Alkylthio, C2-C12
Alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (O) O (C
1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxy, carbalkoxy, - (CH ₂₎ n -COOH, chloro,
Cyano, cyanoguanidyl, fluoro, guanidino, hydrazide,
Hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, (wherein, n 1 8) thiocarbonyl or C1-C6 carbonyl, noninterfering selected from Substituent]], a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof is administered, and the present invention relates to an apoptosis-related disease. A method of treating a mammal suffering from or previously suffering from an apoptosis-related disease. 2. General formula (II): (Wherein X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above) in a therapeutically effective amount of a 1H-indole-3-glyoxamide compound,
Alternatively, a method for treating a mammal currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease, which comprises administering a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. 3. General formula (III): (Wherein X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ have the same meanings as defined above), or a therapeutically effective amount of the indolizine-1-glyoxamide compound, or a pharmaceutical. A method for treating a mammal currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease, which comprises administering an acceptable salt, solvate, or prodrug derivative thereof. 4. A compound represented by the general formula (II) or (III) is X ′.
Are both oxygen, R ₁₄ or R ₁₅ is a group represented by — (La) — (acidic group) or — (La ′) — (acidic group), and (acidic group) is carboxy. The method according to claim 2 or 3, which is a compound. 5. From compound (A) to compound (NN): (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indole-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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -3 -Ilmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (E) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -4 -Ilmethyl
) -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, (I ') [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, (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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, (L) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -2 -Ilmethyl
) -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-dioxoethyl) -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-
Indole-5-yl] oxy] butanoic acid, (P) A mixture of any of (A) to (O), (Q) (8- (carbomethoxymethyloxy) -2-ethyl-3- (o -Phenylbenzyl) indolizin-1-yl) glyoxamide, (R) [3-benzyl-8- (carbethoxymethyloxy) -2-ethylindolizin-1-
Yl] glyoxamide, (S) [8- (carbethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (T) [3-benzyl-8- (carb Ethoxymethyloxy) -2-methylindolizine-1-
Yl] glyoxamide, (U) [8- (carbethoxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (V) [8-carbethoxymethyloxy-2 -Ethyl-3- (1-naphthylmethyl) indolizin-1-yl] glyoxamide, (W) [3-Benzyl-8- (t-butoxycarbonylmethyloxy) -2-ethylindolizin-1-yl] glyoxamide , (X) [8- (carbmethoxymethyloxy) -2-ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (Y) [8- (carbmethoxymethyloxy)- 2-Cyclopropyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (Z) [3-Benzyl-8- (carboxymethyloxy) -2-ethylindolizin-1-yl]
Glyoxamide, (AA) [8- (Carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (AA ') [8- (Carbomethoxymethyloxy) -2 -Ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (BB) [3-Benzyl-8- (carboxymethyloxy) -2-methylindolizin-1-yl
] Glyoxamide, (CC) [8- (Carboxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (DD) [8- (Carboxymethyloxy) -2- Ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (EE) [8-carboxymethyloxy-2-ethyl-3- (1-naphthylmethyl) indolizin-1-yl] Glyoxamide, (FF) [8- (Carboxymethyloxy) -2-cyclopropyl-3- (o-phenylbenzyl
) Indolizin-1-yl] glyoxamide, (GG) (Q) to (FF) mixture, (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy] -2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (JJ) [3-[(2-amino-1,2-dioxoethyl) -6-ethoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (KK) [3-[(2-amino-1,2-dioxoethyl) -6-n-propoxycarbonyl-2-ethyl-1-benzyl-1H- Indol-4-yl] oxy] acetic acid, (LL) [3-[(2-amino-1,2-dioxoethyl) -6-i-propoxycarbonyl-2-ethyl-1-benzyl-1H-indole-4- Iyl] oxy] acetic acid, (MM) [3-[(2-amino-1,2-dioxoethyl) -6-cyclopropyloxycarbonyl
2-ethyl-1-benzyl-1H-indol-4-yl] oxy] acetic acid, a mixture of any of (NN) (HH) to (MM), and a therapeutically effective compound selected from the group consisting of: Suffering from an apoptosis-related disease, which comprises administering to a mammal in need thereof an amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof, Alternatively, a method of treating a mammal previously suffering from an apoptosis-related disease. 6. Compound (I) and compound (I ′): (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indole- 4-yl] oxy] acetic acid, (I ') [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. Is administered to a mammal in need thereof, and a method for treating a mammal currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease. 7. Compounds (A), (D), (H), (J), and (K): (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl- 1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl]- 3-ylmethyl
) -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, (J) [[3- (2-Amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H- Indol-4-yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, Alternatively, a method for treating a mammal currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease, which comprises administering a prodrug derivative thereof to a mammal in need thereof. 8. A compound (AA) and a compound (AA ′): (AA) [8- (carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indoridin-1-yl] glyoxamide, AA ') [8- (carbomethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, a therapeutically effective amount of N-hetero. A ring glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof, which is administered to a mammal in need thereof, is currently suffering from an apoptosis-related disease, or is a previous apoptosis-related disease. For treating a mammal afflicted with. 9. Compound (HH) and compound (II): (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy-2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prod thereof thereof. A method for treating a mammal currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease, which comprises administering the drug derivative to a mammal in need thereof. 10. The following formula: From the administration of a therapeutically effective amount of a N-heterocyclic glyoxamide compound selected from compounds represented by: or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof to a mammal in need thereof A method of treating a mammal currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease. 11. A therapeutically effective amount of a compound in the form of a pharmaceutical formulation comprising the compound and a suitable carrier or excipient, 1, 2, 3, 4, 5, or 6.
The method described in any one of. 12. A compound of general formula (I) for the manufacture of a medicament for the treatment of an apoptosis related disease in a mammal, including a human, who is currently suffering from an apoptosis related disease or previously suffered from an apoptosis related disease. [Chemical 9] [Wherein E and F are different from each other and are C or N; ----- represents the presence or absence of a double bond; X is independently oxygen or sulfur; R ₁₁ is (a), (b ), And (c). Here, (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, or a carbocyclic group. The carbocyclic group is cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, anthracenyl, biphenyl, bibenzilyl, And formula (bb): (Wherein n is an integer of 1 to 8) and is selected from the group consisting of bibenzilyl derivatives. (B) Component of (a) substituted with one or more independently selected non-interfering substituents. Here, the non-interfering substituents are C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C
3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy,
C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12
Alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C
2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-
C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (
O) O (C1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl)
, Benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino,
Bromo, carbamyl, carboxy, _{carbalkoxy, - (CH 2) n-} COOH
, Chloro, cyano, cyanoguanidyl, fluoro, guanidino, hydrazide (hyd
Razide), hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, in thiocarbonyl, and C1-C6 carbonyl (wherein, n is the group consisting of 1 to 8) Selected from. (C) the - (L ₁₎ a group represented by -R _81, where - (L ₁₎ - is formula: 11] (Wherein R ₈₄ and R ₈₅ are each independently selected from hydrogen, C 1 -C 10 alkyl, carboxyl, carbalkoxy, or halogen, and p is 1 to 5, Z
It is a single _{bond, - (CH 2) -,} - O -, - N (C1-C10 alkyl) -, - NH
-Or a divalent linking group represented by -S-), R ₈₁ is a group selected from (a) or (b), R ₁₂ is hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3
-C4 cycloalkenyl, -O- (C1-C2 alkyl), or -S- (C
1-C2 alkyl), R ₁₄ is hydrogen or a group represented by — (La) — (acidic group), where — (La)
-Is the formula: (Wherein, Q is _{- (CH 2) -, -} O -, - NH-, and is selected from the group consisting of -S-, hydrogen R ₈₄ and R ₈₅ are each independently, C1-C10 alkyl, aryl , C1-C10 alkaryl, and halogen).
R ₁₅ is a hydrogen atom or a group represented by — (La ′) — (acidic group), where — (
La ')-is of the formula: (In the formula, r is an integer from 1 to 7, s is 0 or 1, Q is-(CH ₂ )-, -O-,
Selected from the group consisting of —NH— and —S—, R _{84 ′} and R _{85 ′} are each independently hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C
1-C10 aralkyl, carboxy, carbalkoxy, and halogen)), provided that at least one of R _{14 and} R ₁₅ is a group represented by — (La) — (acidic group) or — (La ′). R ₁₆ is hydrogen, carboxy, or an ester thereof, R ₁₇ is a hydrogen atom or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
Alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl,
Biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6
Alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6. Alkylthio, C2-C12
Alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (O) O (C
1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxy, carbalkoxy, - (CH ₂₎ n -COOH, chloro,
Cyano, cyanoguanidyl, fluoro, guanidino, hydrazide,
Hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, (wherein, n 1 8) thiocarbonyl or C1-C6 carbonyl, noninterfering selected from N-heterocyclic glyoxamide compound represented by the formula: or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. 13. A compound of the general formula (II) for the manufacture of a medicament for the treatment of an apoptosis related disease in a mammal, including a human, who is currently suffering from an apoptosis related disease or has been previously affected by an apoptosis related disease: [Chemical 14] (In the formula, X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above), or a 1H-indole-3-glyoxamide compound, or a pharmaceutically acceptable salt thereof, Use of solvates or their prodrug derivatives. 14. A compound of the general formula (III): for the manufacture of a medicament for the treatment of an apoptosis related disease in a mammal, including a human, who is currently suffering from an apoptosis related disease or has been previously affected by an apoptosis related disease. [Chemical 15] (In the formula, X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above), an indolizine-1-glyoxamide compound, or a pharmaceutically acceptable salt or solvent. Use of Japanese products or prodrug derivatives thereof. 15. A compound (A) for the manufacture of a medicament for the treatment of an apoptosis-related disease in a mammal, including a human, who is currently suffering from an apoptosis-related disease or has been previously affected by an apoptosis-related disease. NN): (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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -3 -Ilmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (E) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -4 -Ilmethyl
) -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, (I ') [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, (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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, (L) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -2 -Ilmethyl
) -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-dioxoethyl) -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-
Indole-5-yl] oxy] butanoic acid, (P) A mixture of any of (A) to (O), (Q) (8- (carbomethoxymethyloxy) -2-ethyl-3- (o -Phenylbenzyl) indolizin-1-yl) glyoxamide, (R) [3-benzyl-8- (carbethoxymethyloxy) -2-ethylindolizin-1-
Yl] glyoxamide, (S) [8- (carbethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (T) [3-benzyl-8- (carb Ethoxymethyloxy) -2-methylindolizine-1-
Yl] glyoxamide, (U) [8- (carbethoxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (V) [8-carbethoxymethyloxy-2 -Ethyl-3- (1-naphthylmethyl) indolizin-1-yl] glyoxamide, (W) [3-Benzyl-8- (t-butoxycarbonylmethyloxy) -2-ethylindolizin-1-yl] glyoxamide , (X) [8- (carbmethoxymethyloxy) -2-ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (Y) [8- (carbmethoxymethyloxy)- 2-Cyclopropyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (Z) [3-Benzyl-8- (carboxymethyloxy) -2-ethylindolizin-1-yl]
Glyoxamide, (AA) [8- (Carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (AA ') [8- (Carbomethoxymethyloxy) -2 -Ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (BB) [3-Benzyl-8- (carboxymethyloxy) -2-methylindolizin-1-yl
] Glyoxamide, (CC) [8- (Carboxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (DD) [8- (Carboxymethyloxy) -2- Ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (EE) [8-carboxymethyloxy-2-ethyl-3- (1-naphthylmethyl) indolizin-1-yl] Glyoxamide, (FF) [8- (Carboxymethyloxy) -2-cyclopropyl-3- (o-phenylbenzyl
) Indolizin-1-yl] glyoxamide, (GG) (Q) to (FF) mixture, (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy] -2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (JJ) [3-[(2-amino-1,2-dioxoethyl) -6-ethoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (KK) [3-[(2-amino-1,2-dioxoethyl) -6-n-propoxycarbonyl-2-ethyl-1-benzyl-1H- Indol-4-yl] oxy] acetic acid, (LL) [3-[(2-amino-1,2-dioxoethyl) -6-i-propoxycarbonyl-2-ethyl-1-benzyl-1H-indole-4- Iyl] oxy] acetic acid, (MM) [3-[(2-amino-1,2-dioxoethyl) -6-cyclopropyloxycarbonyl
2-ethyl-1-benzyl-1H-indol-4-yl] oxy] acetic acid, a mixture of any of (NN) (HH) to (MM), and a therapeutically effective compound selected from the group consisting of: Use of an amount of N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. 16. Compound (I) and compound (I) for producing a medicament for the treatment of an apoptosis-related disease in a mammal, including a human, who is currently suffering from an apoptosis-related disease or has been previously affected by an apoptosis-related disease. I '): (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (I') [[3- (2-Amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. Use of. 17. A compound (A), (D) for producing a medicament for the treatment of an apoptosis-related disease in a mammal, including a human, who is currently suffering from an apoptosis-related disease or has been previously affected by an apoptosis-related disease. ), (H), (J), and (K)
: (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl] -3-ylmethyl
) -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, (J) [[3- (2-Amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H- Indol-4-yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, a therapeutically effective amount of a N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, Or use of their prodrug derivatives. 18. A compound (AA) and a compound (AA) for producing a medicament for the treatment of an apoptosis-related disease in a mammal, including a human, who is currently suffering from an apoptosis-related disease or has been previously affected by an apoptosis-related disease. AA '): (AA) [8- (Carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (AA') [8- (Carbomethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, a therapeutically effective amount of an N-heterocyclic glyoxamide compound selected from the group consisting of: Use of solvates or their prodrug derivatives. 19. A compound (HH) and a compound (HH) for producing a medicament for the treatment of an apoptosis-related disease in a mammal, including a human, currently suffering from an apoptosis-related disease or previously suffering from an apoptosis-related disease. II): (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy-2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or prod thereof thereof. Use of drug derivatives. 20. The following formula for the manufacture of a medicament for the treatment of an apoptosis related disease in a mammal, including a human, who is currently suffering from an apoptosis related disease or previously suffered from an apoptosis related disease: ] Use of a therapeutically effective amount of an N-heterocyclic glyoxamide compound selected from the compounds represented by: or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. 21. General formula (I): [Wherein E and F are different from each other and are C or N; ----- represents the presence or absence of a double bond; X is independently oxygen or sulfur; R ₁₁ is (a), (b ), And (c). Here, (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, or a carbocyclic group. The carbocyclic group is cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, anthracenyl, biphenyl, bibenzilyl, And formula (bb): (Wherein n is an integer of 1 to 8) and is selected from the group consisting of bibenzilyl derivatives. (B) Component of (a) substituted with one or more independently selected non-interfering substituents. Here, the non-interfering substituents are C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C
3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy,
C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12
Alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C
2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-
C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (
O) O (C1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl)
, Benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino,
Bromo, carbamyl, carboxy, _{carbalkoxy, - (CH 2) n-} COOH
, Chloro, cyano, cyanoguanidyl, fluoro, guanidino, hydrazide (hyd
Razide), hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, in thiocarbonyl, and C1-C6 carbonyl (wherein, n is the group consisting of 1 to 8) Selected from. (C) the - (L ₁₎ a group represented by -R _81, where - (L ₁₎ - is formula: 19] (Wherein R ₈₄ and R ₈₅ are each independently selected from hydrogen, C 1 -C 10 alkyl, carboxyl, carbalkoxy, or halogen, and p is 1 to 5, Z
It is a single _{bond, - (CH 2) -,} - O -, - N (C1-C10 alkyl) -, - NH
-Or a divalent linking group represented by -S-), R ₈₁ is a group selected from (a) or (b), R ₁₂ is hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, C3
-C4 cycloalkenyl, -O- (C1-C2 alkyl), or -S- (C
1-C2 alkyl), R ₁₄ is hydrogen or a group represented by — (La) — (acidic group), where — (La)
-Is the formula: (Wherein, Q is _{- (CH 2) -, -} O -, - NH-, and is selected from the group consisting of -S-, hydrogen R ₈₄ and R ₈₅ are each independently, C1-C10 alkyl, aryl , C1-C10 alkaryl, and halogen).
R ₁₅ is a hydrogen atom or a group represented by — (La ′) — (acidic group), where — (
La ')-is of the formula: (In the formula, r is an integer from 1 to 7, s is 0 or 1, Q is-(CH ₂ )-, -O-,
Selected from the group consisting of —NH— and —S—, R _{84 ′} and R _{85 ′} are each independently hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C
1-C10 aralkyl, carboxy, carbalkoxy, and halogen)), provided that at least one of R _{14 and} R ₁₅ is a group represented by — (La) — (acidic group) or — (La ′). R ₁₆ is hydrogen, carboxy, or an ester thereof, R ₁₇ is a hydrogen atom or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6
Alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolyl, xylenyl,
Biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6
Alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkoxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6. Alkylthio, C2-C12
Alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C (O) O (C
1-C6 _{alkyl), - (CH 2) n} -O- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxy, carbalkoxy, - (CH ₂₎ n -COOH, chloro,
Cyano, cyanoguanidyl, fluoro, guanidino, hydrazide,
Hydrazino, hydrazide (Hydrazido), hydroxy, hydroxyamino, iodo, nitro, Fosufono, -SO ₃ H, thioacetal, (wherein, n 1 8) thiocarbonyl or C1-C6 carbonyl, noninterfering selected from And a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug derivative thereof. 22. General formula (II): (Wherein X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ have the same meanings as defined above), or a 1H-indole-3-glyoxamide compound, or a pharmaceutically acceptable salt thereof, An apoptosis-related disease therapeutic agent comprising a solvate or a prodrug derivative thereof. 23. General formula (III): (In the formula, X, R ₁₁ , R ₁₂ , R ₁₄ , R ₁₅ , R ₁₆ and R ₁₇ are as defined above), an indolizine-1-glyoxamide compound, or a pharmaceutically acceptable salt or solvent. An agent for treating apoptosis-related diseases, which comprises a solvate or a prodrug derivative thereof. 24. From compound (A) to compound (NN): (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indole-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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -3 -Ilmethyl
) -2-Methyl-1H-indol-4-yl] oxy] acetic acid, (E) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -4 -Ilmethyl
) -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, (I ') [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, (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-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, (L) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1′-biphenyl] -2 -Ilmethyl
) -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-dioxoethyl) -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-
Indole-5-yl] oxy] butanoic acid, (P) A mixture of any of (A) to (O), (Q) (8- (carbomethoxymethyloxy) -2-ethyl-3- (o -Phenylbenzyl) indolizin-1-yl) glyoxamide, (R) [3-benzyl-8- (carbethoxymethyloxy) -2-ethylindolizin-1-
Yl] glyoxamide, (S) [8- (carbethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (T) [3-benzyl-8- (carb Ethoxymethyloxy) -2-methylindolizine-1-
Yl] glyoxamide, (U) [8- (carbethoxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (V) [8-carbethoxymethyloxy-2 -Ethyl-3- (1-naphthylmethyl) indolizin-1-yl] glyoxamide, (W) [3-Benzyl-8- (t-butoxycarbonylmethyloxy) -2-ethylindolizin-1-yl] glyoxamide , (X) [8- (carbmethoxymethyloxy) -2-ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (Y) [8- (carbmethoxymethyloxy)- 2-Cyclopropyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (Z) [3-Benzyl-8- (carboxymethyloxy) -2-ethylindolizin-1-yl]
Glyoxamide, (AA) [8- (Carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (AA ') [8- (Carbomethoxymethyloxy) -2 -Ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, (BB) [3-Benzyl-8- (carboxymethyloxy) -2-methylindolizin-1-yl
] Glyoxamide, (CC) [8- (Carboxymethyloxy) -3- (m-chlorobenzyl) -2-ethylindolizin-1-yl] glyoxamide, (DD) [8- (Carboxymethyloxy) -2- Ethyl-3- (m-trifluoromethylbenzyl) indolizin-1-yl] glyoxamide, (EE) [8-carboxymethyloxy-2-ethyl-3- (1-naphthylmethyl) indolizin-1-yl] Glyoxamide, (FF) [8- (Carboxymethyloxy) -2-cyclopropyl-3- (o-phenylbenzyl
) Indolizin-1-yl] glyoxamide, (GG) (Q) to (FF) mixture, (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy] -2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (JJ) [3-[(2-amino-1,2-dioxoethyl) -6-ethoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, (KK) [3-[(2-amino-1,2-dioxoethyl) -6-n-propoxycarbonyl-2-ethyl-1-benzyl-1H- Indol-4-yl] oxy] acetic acid, (LL) [3-[(2-amino-1,2-dioxoethyl) -6-i-propoxycarbonyl-2-ethyl-1-benzyl-1H-indole-4- Iyl] oxy] acetic acid, (MM) [3-[(2-amino-1,2-dioxoethyl) -6-cyclopropyloxycarbonyl
N-heterocycle selected from the group consisting of 2-ethyl-1-benzyl-1H-indol-4-yl] oxy] acetic acid, a mixture of (NN) (HH) to (MM) in any combination, An apoptotic disease therapeutic agent comprising a glyoxamide compound, a pharmaceutically acceptable salt, a solvate, or a prodrug derivative thereof. 25. Compound (I) and compound (I ′): (I) [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indole- 4-yl] oxy] acetic acid, (I ') [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-
Indole-4-yl] oxy] acetic acid methyl ester, N-heterocyclic glyoxamide compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof Agent. 26. Compounds (A), (D), (H), (J), and (K): (A) [[3- (2-amino-1,2-dioxoethyl) -2-methyl- 1- (phenylmethyl) -1H-indol-4-yl] oxy] acetic acid, (D) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl]- 3-ylmethyl
) -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, (J) [[3- (2-Amino-1,2-dioxoethyl) -1-[(3-chlorophenyl) methyl] -2-ethyl-1H- Indol-4-yl] oxy] acetic acid, (K) [[3- (2-amino-1,2-dioxoethyl) -1-([1,1'-biphenyl] -2-ylmethyl
) -2-Ethyl-1H-indol-4-yl] oxy] acetic acid, an N-heterocyclic glyoxamide compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. A therapeutic agent for an apoptosis-related disease consisting of: 27. Compound (AA) and compound (AA ′): (AA) [8- (carboxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, AA ′) [8- (carbomethoxymethyloxy) -2-ethyl-3- (o-phenylbenzyl) indolizin-1-yl] glyoxamide, an N-heterocyclic glyoxamide compound selected from the group consisting of: A therapeutic agent for apoptosis-related diseases, which comprises an upper acceptable salt, a solvate, or a prodrug derivative thereof. 28. Compound (HH) and compound (II): (HH) [3-[(2-amino-1,2-dioxoethyl) -6-carboxy-2-ethyl-1-benzyl
-1H-Indol-4-yl] oxy] acetic acid, (II) [3-[(2-amino-1,2-dioxoethyl) -6-methoxycarbonyl-2-ethyl-1-
Benzyl-1H-indol-4-yl] oxy] acetic acid, an N-heterocyclic glyoxamide compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof Disease treatment agent. 29. The following formula: embedded image A therapeutic agent for apoptosis-related diseases, which comprises a therapeutically effective amount of an N-heterocyclic glyoxamide compound, or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the compounds represented by: