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WO1999024026A2 - Method for the treatment of disorders associated with apoptosis using n-heterocyclic glyoxylamide compounds - Google Patents

Method for the treatment of disorders associated with apoptosis using n-heterocyclic glyoxylamide compounds Download PDF

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Publication number
WO1999024026A2
WO1999024026A2 PCT/JP1998/005042 JP9805042W WO9924026A2 WO 1999024026 A2 WO1999024026 A2 WO 1999024026A2 JP 9805042 W JP9805042 W JP 9805042W WO 9924026 A2 WO9924026 A2 WO 9924026A2
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WO
WIPO (PCT)
Prior art keywords
amino
oxy
indol
dioxoethyl
ethyl
Prior art date
Application number
PCT/JP1998/005042
Other languages
French (fr)
Other versions
WO1999024026A3 (en
Inventor
Tatsurou Yagami
Nobuo Takasu
Original Assignee
Shionogi & Co., Ltd.
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Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU97630/98A priority Critical patent/AU9763098A/en
Priority to JP2000520118A priority patent/JP2003522720A/en
Priority to EP98951749A priority patent/EP1037630A2/en
Priority to CA002308269A priority patent/CA2308269A1/en
Publication of WO1999024026A2 publication Critical patent/WO1999024026A2/en
Publication of WO1999024026A3 publication Critical patent/WO1999024026A3/en
Priority to US10/219,931 priority patent/US20030149000A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a method for the treatment of disorders associated i ith apoptosis using N-heterocyclic glyoxylamide compounds, a use of N-heterocyclic glyoxylamide compounds for th " e tre atment of disorders associated with apoptosis and a composition for the treatme nt of disorders associated with apoptosis comprising N-heterocyclic glyoxylamide compounds.
  • apoptosis-mducing stimulus and the mechanism thereof are various its morphologic features are common
  • the first morphologic change is a formation of condensation of chromatin, which is almost associated with DNA fragmentation.
  • apoptotic bodies are quickly phagocytosed and disintegrated by adjacent cells or macrophages, and the like so as to lead apoptosis.
  • a phospholipase A2 inhibitor quinacrine
  • WO 96/40982 discloses that a PLA2 inhibitor is useful in the treatment of neurodegenerative diseases, but it does not disclose that a secretory PLA2 inhibitor such as compounds used in the present invention can be used to treat such diseases .
  • USP 5478857 discloses that a PLA2 inhibitor is useful in the treatment of Alzheimer ' s diseases, but it does not disclose that a secretory PLA2 inhibitor such as compounds used in the present invention can be used to treat such diseases .
  • N-heterocyclic glyoxylamide compound for the manufacture of a medicament for treatment of a mammal, including a human, currently afflicted with disorders associated with apoptosis.
  • the present invention is considered to be useful for disorders associated with apoptosis, in more detail, chronic diseases such as Alzheimer ' s disease, a number of scleroma, ataxia, talangiectasia, prion- induced neuronal cell death, and the like, or acute diseases such as stroke, and the like.
  • a compound of the present invention can be co-administered with other therapeutic or prophylactic agents and/or medicaments that are not medically incompatible therewith.
  • the regimen for treatment may stretch over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • oral dosing one to three oral doses per day, each from about 0.01 to about
  • 50 mg/kg of body weight are used with preferred doses being from about 0.04 to about 5.0 mg/kg.
  • N-heterocyclic glyoxylamide compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course , be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the size and age of the patient, the severity of disorders associated with apoptosis, and the condition being treated.
  • Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
  • N-heterocyclic glyoxylamide compounds are most often used in the method of the invention in the form of pharmaceutical formulation, as described infra.
  • Other forms of administration may be used in both human and veterinary contexts.
  • Such alternative forms include the use of suppositories, transdermal patches, and compositions for buccal or nasal administration, for example lozenges, nose drops, an aerosol spray, or transdermal patch.
  • the method for treating subjects for the occurrence or prevention of disorders associated with apoptosis comprises administering an effective amount of an N-heterocyclic glyoxylamide compound.
  • Suitable 1H- indole-3-glyoxylamide compounds for the practice of the method of treating and preventing disorders associated with apoptosis as taught herein are those described in European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ. , 4 October 1995) .
  • Suitable lH-indole-3- glyoxylamide compounds are also those disclosed in United States patent application No 08/469, 954 filed 6 June 1995, the disclosure of which is incorporated herein by reference.
  • acid linker refers to a divalent linking group symbolized as, -(L a )- or (La') -, which has the function of joining the 4 or 5 position of the indole nucleus or the 7 or 8 position of the indolizine nucleus to an acidic group in the general relationship: Indole Nucleus -(La)- or -(La)- Acidic Group
  • amino acid linker length refers to the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(L a )-
  • acidic group is selected from -5-tetrazolyl, - S0 3 H,
  • n is from 1 to 8
  • Rgg is a metal or CI-C ⁇ Q alkyl
  • R99 is hydrogen or alkyl.
  • Preferre d compounds for use in the method or composition of the invention are those having the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof;
  • E and F are differently C or N; is prese nce or absence of a double bond; e ach X is independently oxygen or sulfur;
  • R l l is selecte d from groups (a) , (b) and (c) where;
  • (a) is C 7- C20 alkyl, C 7- C20 alkenyl, C7-C20 alkynyl; or carbocyclic radical selected from the group cycloalkyi, cycloalkenyl, phenyl, nap hthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthryl, biphenyl, bibenzylyl and related bibenzylyl homologues represente d by the formula (bb) ,
  • n is a number from 1 to 8.
  • (b) is a me mber of (a) substituted with one or more independently selected non-interfering substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C -C12 alkylcarbonyl, C2- C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio,
  • R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl. carboxyl, carbalkoxy, or halo; p is 1 to 5,
  • Z is a bond, -(CH2)-, -O-, -N(C ⁇ -C ⁇ o alkyl)-, -NH-, or -S-; and where R81 is a group selected from (a) or (b); Rl2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyi, C3-C4 cycloalkenyl, -0-(C ⁇ -C2 alkyl), or -S-(C ⁇ -C2 alkyl);
  • Rl4 is hydrogen or a group, -(L a )-(acidic group) wherein - (L a )- is represented by the formula;
  • R84 and R ⁇ 5 are each independently selected from hydrogen, Ci -C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, and halo;
  • Rl5 is hydrogen or a group, -(La')-(acidic group) wherein - (La')- is represented by the formula;
  • R84' and R ⁇ 5' are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of R ⁇ 4 or R1 must be the group, -(La)-(acidic group)
  • Rl6 is hydrogen, carboxyl or ester thereof
  • Rl7 is selected from hydrogen, non-interfering substituents, selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Ci-C ⁇ alkoxy, C2-C6 alkenyloxy.
  • a preferred class of compounds for the method or composition of the invention are compounds represented by the formula (II):
  • An alternatively preferred class of compounds for the method or composition of the invention are compounds represented by the formula (HI):
  • a further preferred class of compounds for the method or composition of the invention are the compounds represented by the formula (II) or (III) where both X's are oxygen, only one of Ri 4 ⁇ or R15 is -(L a )- (acidic group) or -(La')-(acidic group ), and the acidic group is carboxyl.
  • indolizine- 1-glyoxylamides selected from the formula:
  • the salts of the above lH-indole-3-glyoxylamide compounds represented by formula (II) and named compounds (A) through (P) , (HH) through (NN) and of indolizine- 1 -glyoxylamide compounds represented by the formula (III) and named compounds (Q) through (GG) are particularly useful in the method of the invention.
  • various salts may be formed which are more water soluble and physiologically suitable than the parent compounds.
  • Representative pharmaceutically acceptable salts include but are not limited to, the alkali 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 by exposing the acid to an ion exchange resin.
  • salts include the relatively non-toxic, inorganic and organic base addition salts of the lH-mdole-3-glyoxylam ⁇ de compounds and mdol ⁇ zine- 1 -glyoxylam ⁇ de compounds used in the method or composition of the present invention, for example, ammonium, quaternary ammonium, and amme cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, 15. M. Berge, et al. , " Pharmaceutical Salts , " J. Phar. Sci. , 66. 1 - 19 (1977)) .
  • salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate , esylate, fluoride , fumarate, gluceptate, gluconate, glutamate glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate , lactate, lactobionate, laurate, malate, malate, mandelate, mesylate, methylbromide, methylmtrate, methylsulfate, mucate, napsy
  • Certain lH-mdole-3-glyoxylam ⁇ de compounds and mdol ⁇ z ⁇ ne- 1- glyoxylamide compounds may possess one or more chiral centers and may thus exist in optically active forms Likewise, R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans- isomers, are contemplated for use by the method or composition of this invention.
  • Prodrugs are derivatives of the lH-indole- 3-glyoxylamide compounds or indolizine- 1-glyoxylamide compounds which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
  • Derivatives of the lH-indole-3- glyoxylamide compounds and indolizine- 1 -glyoxylamide compounds have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see , Bundgard, H. , Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine .
  • Simple aliphatic or aromatic esters e. g. , methyl or ethyl esters
  • acidic groups e. g. , carboxyl
  • prodrugs are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
  • the method of the invention can be practiced using pharmaceutical formulations containing compounds of the invention administered through the skin by an appliance such as a transdermal patch, as described in US Patents No. 5, 296, 222 and 5, 271, 940, the disclosures of which are incorporated herein by reference.
  • Lipophilic prodrug derivatives of the compounds for formula II are particularly well suited for transdermal absorption administration and delivery systems.
  • the synthesis of the lH-indole- 3-glyoxylamide compounds may be accomplished as described European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ. , 4 October 1995). Further, the synthesis of the indole dicarboxylic acid derivatives may be accomplished as described Japanese Patent Application No. 35984/1997. The synthesis of the indolizine compounds may be accomplished as described WO 9603383 (Publ. , 8 February 1996) . Such synthetic methods also include well-known methods as recorded in the chemical literature and the procedure illustrated in the following preparative reaction scheme.
  • R ⁇ 2, Rl 5- ⁇ 16 a nu R 17 are as defined above.
  • R3 is C1-C5 alkyl, aryl, C ⁇ -Cg alkoxy, halo, aryloxy, araikyloxy, nitro, hydroxy, amino, methylamino or dimethylamino.
  • R5 is hydrogen, C ⁇ -C ⁇ o a lkyl. aryl, C ⁇ -C ⁇ o alkaryl, C ⁇ - C ⁇ Q aralkyl or halo.
  • the aniline, 2, on heating with di-tert-butyl dicarbonate in THF at reflux temperature is converted to the N-tert-butylcarbonyl derivative, 3, in good yield.
  • the dilithium salt of the dianion of 3 is generated at -40 to -20 ° C in THF using sec-butyl lithium and reacted with the appropriately substituted N-methoxy-N- methylalkanamide .
  • This product, 4, may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 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 hour.
  • the resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0- 100 ° C, usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6.
  • This indole, 6, is O-demethylated by stirring with boron tribromide in methylene chloride
  • R 12 R 2 a: Et Ph b: Et o-Ph-Ph c: Et m-CI-Ph d: Et m-CF 3 -Ph e: Et 1 -Naphthyl f: cyclo- ⁇ Pr o-Ph-Ph
  • R2 is Cg-C20 alkyl, Cg- C20 alkenyl, C -C20 alkynyl or carbocyclic radical.
  • R2 is hydrogen or
  • Suitable pharmaceutical formulation of the lH-indole- 3- glyoxylamide compounds may be made as described European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ. , 4 October 1995) .
  • Suitable pharmaceutical formulation of the indolizine- 1-glyoxylamide compounds may be made as described WO 9603383 (publ. , 8 February 1996) .
  • Formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the lH-indole-3-glyoxylamide compound or indolizine- 1- glyoxylamide compound is generally administered as an appropriate pharmaceutical composition which comprises a therapeutically effective amount of lH-indole-3-glyoxylamide compound or indolizine- 1- glyoxylamide is together with a pharmaceutically acceptable diluent or carrier, the composition being adapted for the particular route of administration chosen.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the 1H- indole-3-glyoxylamide compound or indolizine- 1-glyoxylamide compound in the formulation and not deleterious to the subject being treated.
  • the pharmaceutical formulation is in unit dosage form.
  • the unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these.
  • the quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0. 1 to about 1000 milligrams or more according to the particular treatment involved.
  • the compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • any suitable carrier known in the art can be used.
  • the carrier may be a solid, liquid, or mixture of a solid and a liquid.
  • a solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
  • the lH-indole-3-glyoxylamide compound or indolizine- 1-glyoxylamide compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the lH-indole-3-glyoxylamide compound or indolizine- 1- glyoxylamide compound.
  • Sterile liquid form 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.
  • Example 1 illustrates the preparation of [[3- (2- Amino- l, 2-dioxoethyl)-2-ethyl- l-(phenylmethyl)- lH-indol-4-yl]oxy] acetic acid, a lH-indole-3-glyoxylamide compound useful in the practice of the method of the invention:
  • 2-Ethyl-4-methoxy- lH-indole (4.2g, 24 mmol) was dissolved in 30 mL of DMF and 960mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO ⁇ and concentrated at reduced pressure.
  • Example 2 illustrates the preparation of (8- (Carboxymethyloxy)-2-ethyl-3- (o-phenylbenzyl)indolizin- l- yl)glyoxylamide , a indolizine- 1 -glyoxylamide compound useful in the practice of the method of the invention:
  • Compound 27 was treated by the procedure described for the preparation of 4, WO 9603383.
  • Part H Preparation of (8-(Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin- l-yl) glyoxylamide 39d These compounds were prepared according to the procedure described for the synthesis of compound 21 from 20, WO 9603383. Mp, 73- 75 ° C (dec.) (ether-hexane) . 84% Yield.
  • Example 3 The disorders associated with apoptosis treatment utility of the method of the invention will now be illustrated by the following Example 3 and 4:
  • Example 3 The disorders associated with apoptosis treatment utility of the method of the invention will now be illustrated by the following Example 3 and 4:
  • Example 2 This example illustrates the action of (8- (Carboxymethyloxy)-2- ethyl- 3- (o-p he nylbenzyl)indolizin- l-yl) glyoxylamide (the compound prepared in Example 2, hereinafter called "Ex-2") for neuronal death induced by human PLA2-II (I1PLA2-II)
  • Neuronal cultures were prepared from cerebral cortex of 19-day-old Sprague-Dawley rat embryos .
  • the cerebral cortices were dissociated in isotonic buffer (137mM NaCl, 5.4mM KCl, 0. 17mM Na2HP04, 0.22mM KH2P04. 5.5mM Glucose, 59mM Sucrose; volume of each buffer is 25 ml) with 4 mg/ml trypsin and 0.4 mg/ml deoxyribonuclease I.
  • Cells were plated at a density of 2.5 x 10 ⁇ cells/cm ⁇ on poly-L-lysine coated dishes in conditioning medium, Leibovitz ' s L- 15 medium supplemented with 5 % fetal calf serum and 5 % horse serum. Culture medium was exchanged for conditioning medium containing 0. 1 mM arabinosylcytosine C on day 1 after plating. Cultured neurons were used for the experiments on day 2 of culture.
  • p-BPB 100 ⁇ .
  • M hPLA2-II were preincubated with 0.01, 0. 1 or 1 mM p-bromophenacylbromide for 20 min at 37 ° C. After preincubation, an aliquot was removed and diluted 100-fold in the culture medium of cortical neurons.
  • Vehicle and the compound prepared in Example 2 Cortical neurons were treated with vehicle or 1 /__ M I1PLA2-II in the presence of the compound prepared in Example 2 at the indicated concentrations on day 2 of culture. MTT reducing activity was determined 48 hr after hPLA2-II-treatment. The result was shown in Figure 2.
  • Example 4 This example illustrates the action of [[3-(2-Amino- l, 2- dioxoethyl)-2-ethyl- l-(phenylmethyl)- lH-indol-4-yl] oxy] acetic acid (the compound prepared in Example 1, hereinafter called " Ex- 1 ”) for neuronal death induced by human PLA2-II (hPLA2-II) Analysis of neuronal survival The experiment was carried out in the same method as in Example 3 (3) mentioned above other than adding 3 ⁇ M I1PLA2-II to 48 well-cultured neuron instead of 1 ⁇ M hPLA2-II to 12 well-cultured one . The result was
  • a tablet is prepared using the ingre washers below:
  • An aerosol solution is prepared containing the following components:
  • the active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
  • Tablets each containing 60 mg of active ingredient, are made as follows:
  • the active ingredient, starch and cellulose are passed through a No.45 mesh U. S. sieve and the mixed thoroughly.
  • the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powde r, and the mixture then is passed through a No. 14 mesh U. S. sieve .
  • the granules so produced are dried at 50°C and passed through No. 18 mesh U. S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate and talc previously passed through a No.60 mesh U. S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Capsules each containing 80 mg of active ingredient, are made as follows: Active ingredient 80 mg
  • Suppositories each containing 225 mg of active ingredient, are made as follows:
  • the active ingredient is passed through a No.60 mesh U. S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
  • Suspensions each containing 50 mg of active ingredient per 5 ml dose, are made as follows:
  • An intravenous formulation may be prepared as follows: Active ingredient 100 mg Isotonic saline 1000 ml
  • the solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.
  • Figure IA shows the ultrastructure of untreated neurons.
  • Figure IB shows the ultrastructure of hPLA2-II-treated neurons.
  • Figure 2 shows the concentration-dependent effect of Ex-2 on hPLA2-II-induced neuronal cell death.
  • Figure 3 shows the time-dependent effect of Ex-2 on hPLA2-II-
  • Figure 4 shows the concentration-dependent effect of Ex- 1 on hPLA2-II-induced neuronal cell death.

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Abstract

A method or composition is disclosed for the treatment of disorders associated with apoptosis using N-heterocyclic glyoxylamide compounds.

Description

Description
METHOD FOR THE TREATMENT OF DISORDERS ASSO CIATED WITH APOPTOSIS USING N-HETEROCYCLIC GLYOXYLAMIDE COMPOUNDS
This invention relates to a method for the treatment of disorders associated i ith apoptosis using N-heterocyclic glyoxylamide compounds, a use of N-heterocyclic glyoxylamide compounds for th"e tre atment of disorders associated with apoptosis and a composition for the treatme nt of disorders associated with apoptosis comprising N-heterocyclic glyoxylamide compounds.
BACKGROUND OF THE INVENTION
In multicellular organisms, homeostasis is maintained through a balance between cell proliferation and cell death Cell death is roughly classified into necrosis and apoptosis Apoptosis is observed in a physiological ontogeny, or an appearance of disorders or pharmaceutics effects, and it has been thought to occur on the basis of activation of the nature program in individual cell, which differs from necrosis Apoptosis and necrosis are different from each other in terms of that apoptosis is associated with RNA synthesis and protein synthesis, while necrosis is not. Although apoptosis-mducing stimulus and the mechanism thereof are various its morphologic features are common The first morphologic change is a formation of condensation of chromatin, which is almost associated with DNA fragmentation. Then the condensation is observed, it appears that the compaction of cytoplasm occurs, and cell itself forms cell fragments called apoptotic bodies . The formed apoptotic bodies are quickly phagocytosed and disintegrated by adjacent cells or macrophages, and the like so as to lead apoptosis.
Brain Research 693 (1995) 101- 111 and THE JOURNAL BIOLOGI CAL CHEMISTRY Vol. 271 , No.51 , (1996) 32722- 32728 disclose that secretory phospholipase A2 (sPLA2) has neurotoxicity. but it does not disclose that the neurotoxicity therein is associated with apoptosis . Brain Research 651 (1994) 353-356 discloses that group II PLA2 is expressed in rat brain after severe forebrain ischemia, but it does not disclose any relationship between group II PLA2 and neuronal death. Brain Research 752 (1997) 203-208 discloses that a phospholipase A2 inhibitor, quinacrine, reduces infarct size in rats after transient middle cerebral artery occlusion, but it does not disclose that the infarction therein is associated with apoptosis. WO 96/40982 discloses that a PLA2 inhibitor is useful in the treatment of neurodegenerative diseases, but it does not disclose that a secretory PLA2 inhibitor such as compounds used in the present invention can be used to treat such diseases . USP 5478857 discloses that a PLA2 inhibitor is useful in the treatment of Alzheimer ' s diseases, but it does not disclose that a secretory PLA2 inhibitor such as compounds used in the present invention can be used to treat such diseases .
SUMMARY OF THE INVENTION It is an object of this invention to provide a method of treatment of a mammal, including a human, currently afflicted with disorders associated with apoptosis, said method comprising administering to said mammal a therapeutically effective amount of an N-heterocyclic glyoxylamide compound.
It is also an object of this invention to use an N-heterocyclic glyoxylamide compound for the manufacture of a medicament for treatment of a mammal, including a human, currently afflicted with disorders associated with apoptosis.
It is also an object of this invention to provide a composition for treatment of disorders associated with apoptosis, said composition comprising a therapeutically effective amount of an N-heterocyclic glyoxylamide compound. The present invention is considered to be useful for disorders associated with apoptosis, in more detail, chronic diseases such as Alzheimer ' s disease, a number of scleroma, ataxia, talangiectasia, prion- induced neuronal cell death, and the like, or acute diseases such as stroke, and the like.
TREATMENT METHODS
General Aspects of the Method:
It will be apparent to those skilled in the art that a compound of the present invention can be co-administered with other therapeutic or prophylactic agents and/or medicaments that are not medically incompatible therewith.
The regimen for treatment may stretch over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to three oral doses per day, each from about 0.01 to about
50 mg/kg of body weight are used with preferred doses being from about 0.04 to about 5.0 mg/kg.
The specific dose of N-heterocyclic glyoxylamide compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course , be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the size and age of the patient, the severity of disorders associated with apoptosis, and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
Method of administration.
The N-heterocyclic glyoxylamide compounds are most often used in the method of the invention in the form of pharmaceutical formulation, as described infra. Other forms of administration may be used in both human and veterinary contexts. Such alternative forms include the use of suppositories, transdermal patches, and compositions for buccal or nasal administration, for example lozenges, nose drops, an aerosol spray, or transdermal patch. COMPOUNDS USED IN TREATMENT METHOD OF THE DISORDERS
ASSOCIATED WITH APOPTOSIS
The method for treating subjects for the occurrence or prevention of disorders associated with apoptosis comprises administering an effective amount of an N-heterocyclic glyoxylamide compound. Suitable 1H- indole-3-glyoxylamide compounds for the practice of the method of treating and preventing disorders associated with apoptosis as taught herein are those described in European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ. , 4 October 1995) . Suitable lH-indole-3- glyoxylamide compounds are also those disclosed in United States patent application No 08/469, 954 filed 6 June 1995, the disclosure of which is incorporated herein by reference. Formulations containing these 1H- indole- 3-glyoxylamide compounds and methods of making them are also fully described in European Patent Office Publication European Patent Application No. 95302166.4 and United States patent application No 08/469, 954. Suitable indolizine compounds are disclosed in WO 9603383 (Publ. , 8 February 1996) . Definitions:
The words, "acid linker" refers to a divalent linking group symbolized as, -(La)- or (La') -, which has the function of joining the 4 or 5 position of the indole nucleus or the 7 or 8 position of the indolizine nucleus to an acidic group in the general relationship: Indole Nucleus -(La)- or -(La)- Acidic Group
or
Indolizine Nucleus" -(La)- or -(La)- Acidic Group
The words, "acid linker length", refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(La)-
or (La')- that connects the 4 or 5 position of the indole nucleus or the 7 or 8 position of the indolizine nucleus with the acidic group.
The word "acidic group" is selected from -5-tetrazolyl, - S03H,
o
♦ t
-OH t -OH -P t OH -O P OH
OR ■;89 OR 89 OH OH
0 R 99 0 R, 99
T -P — O (CH2)n N R99 -O P t O (CH2)n N R99
OH R99 ' OH R99 >
Figure imgf000008_0001
where n is from 1 to 8, Rgg is a metal or CI-C^Q alkyl, and R99 is hydrogen or
Figure imgf000008_0002
alkyl. Preferre d compounds for use in the method or composition of the invention are those having the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof;
Figure imgf000009_0001
wherein ;
E and F are differently C or N; is prese nce or absence of a double bond; e ach X is independently oxygen or sulfur;
R l l is selecte d from groups (a) , (b) and (c) where;
(a) is C 7- C20 alkyl, C 7- C20 alkenyl, C7-C20 alkynyl; or carbocyclic radical selected from the group cycloalkyi, cycloalkenyl, phenyl, nap hthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthryl, biphenyl, bibenzylyl and related bibenzylyl homologues represente d by the formula (bb) ,
Figure imgf000009_0002
where n is a number from 1 to 8; or
(b) is a me mber of (a) substituted with one or more independently selected non-interfering substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C -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, C -CQ haloalkylsulfonyl, C2-CQ haloalkyl, Ci-Cρ hydroxyalkyl. -C(O)O(Cι-C6 alkyl), -(CH2)n-0-(Cι-C6 alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)n-Cθ2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8; (c) is the group -(Lι)-R8i; where, -(Li)- is a divalent linking group having the formula;
Figure imgf000010_0001
where,
R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl. carboxyl, carbalkoxy, or halo; p is 1 to 5,
Z is a bond, -(CH2)-, -O-, -N(Cι-Cιo alkyl)-, -NH-, or -S-; and where R81 is a group selected from (a) or (b); Rl2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyi, C3-C4 cycloalkenyl, -0-(Cι-C2 alkyl), or -S-(Cι-C2 alkyl);
Rl4 is hydrogen or a group, -(La)-(acidic group) wherein - (La)- is represented by the formula;
Figure imgf000011_0001
where is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84 and Rδ5 are each independently selected from hydrogen, Ci -C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, and halo;
Rl5 is hydrogen or a group, -(La')-(acidic group) wherein - (La')- is represented by the formula;
- - Q — (CH2)r — (phenylene)s- F
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84' and Rδ5' are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of Rχ4 or R1 must be the group, -(La)-(acidic group)
or -(La')-(acidic group);
Rl6 is hydrogen, carboxyl or ester thereof;
Rl7 is selected from hydrogen, non-interfering substituents, selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Ci-Cβ alkoxy, C2-C6 alkenyloxy. C2-Cρ alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2- C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, Ci-Cβ alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, Ci-Cβ hydroxyalkyl, -C(0)0(Cι-C6 alkyl), -(CH2)n-O-(Cι-C6 alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)n-C02H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Ci-Cρ carbonyl; where n is from 1 to 8.
A preferred class of compounds for the method or composition of the invention are compounds represented by the formula (II):
Figure imgf000012_0001
wherein X. RJI, Ri2> Rl4> ^15- ^16 an(* ^17 are as defined above.
An alternatively preferred class of compounds for the method or composition of the invention are compounds represented by the formula (HI):
Figure imgf000013_0001
wherein X, u, R].2> Rl4> Rl5> ^16 anc ^17 are as defined above.
A further preferred class of compounds for the method or composition of the invention are the compounds represented by the formula (II) or (III) where both X's are oxygen, only one of Ri 4~or R15 is -(La)- (acidic group) or -(La')-(acidic group ), and the acidic group is carboxyl.
Specific preferred compounds and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are useful in the method or composition of the invention include the following:
(A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(B) dl-2-[[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)- lH-indol-4-yl]oxy]propanoic acid,
(C) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,r-biphenyl]-2-ylmethyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(D) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-3-ylmethyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(E) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-4-ylmethyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(F) [[3-(2-Amino-l,2-dioxoethyl)-l-[(2,6-dichlorophenyl)methyl]- 2-methyl-lH-indol-4-yl]oxy]acetic acid,
11 (G) [[3-(2-Amino-l,2-dioxoethyl)-l-[(4-fluorophenyl)methyl]-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(H) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-[(l- naphthalenyl) met hyl]-lH-indol-4-yl]oxy] acetic acid, (I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(I' ) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2- ethyl-lH-indol-4-yl]oxy]acetic acid,
(K) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy] acetic acid,
(L) [[3-(2-amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-2-ylmethyl)-2- propyl-lH-indol-4-yl]oxy]acetic acid, (M) [[3-(2-Amino-l,2-dioxoethyl)-2-cyclopropyl-l-(phenylmethyl)- lH-indol-4-yl]oxy]acetic acid,
(N) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-2-ylmethyl)-2- cyclopropyl-lH-indol-4-yl]oxy] acetic acid,
(0) 4-[[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-5-yl]oxy]butanoic acid,
(P) mixtures of (A) through (0) in any combination, ( ) (8-(Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(R) (3-Benzyl-8-(carbethoxymethyloxy)-2-ethylindolizin-l- yl)glyoxylamide, (S) (8-(Carbethoxymethyloxy)-2-ethyl-3-(o- p he nylbenzyl)indolizin-l-yl) glyoxylamide,
(T) (3-Benzyl-8-(carbethoxymethyloxy)-2-methylindolizin-l- yl)glyoxylamide, (U) (8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2- ethylindolizin-1-yl) glyoxylamide,
(V) (8-Carbethoxymethyloxy-2-ethyl-3-(l- naphthylmethyl)indolizin-l-yl) glyoxylamide,
(W) (3-Benzyl-8-(t-butoxycarbonylmethyloxy)-2-ethylindolizin-l- yl)glyoxylamide.
(X) (8-(Carbmethoxymethyloxy)-2-ethyl-3-(m- trifluoro me thy lbenzyl)indolizin-l-yl) glyoxylamide,
(Y) (8-(Carbmethoxymethyloxy)-2-cyclopropyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide, (Z) (3-Benzyl-8-(carboxymethyloxy)-2-ethylindolizin-l- yl)glyoxylamide,
(AA) (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o-
phe nylbenzyl)indolizin-l-yl) glyoxylamide,
(BB) (3-Benzyl-8-(carboxymethyloxy)-2-methylindolizin-l- yl)glyoxylamide,
(CC) (8-(Carboxymethyloxy)-3-(m-chlorobenzyl)-2-
ethylindolizin-1-yl) glyoxylamide, (DD) (8-(Carboxymethyloxy)-2-ethyl-3-(m- trifluoro me thy lbenzyl)indolizin-l-yl) glyoxylamide,
(EE) (8-Carboxymethyloxy-2-ethyl-3-(l- naphthylmethyl)indolizin-l-yl) glyoxylamide,
(FF) (8-(Carboxymethyloxy)-2-cyclopropyl-3-(o- phe nylbenzyl)indolizin-l-yl) glyoxylamide,
(GG) mixtures of (Q) through (FF) in any combination, (HH) [[3- (2-Amino-l,2-dioxoethyl)-6-carboxyl-2-ethyl-l -benzyl- 1H- indol-4-yl]oxy]acetic acid,
(II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(JJ) [[3-(2-Amino-l,2-dioxoethyl)-6-ethoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(KK) [[3-(2-Amino-l,2-dioxoethyl)-6-n-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid, (LL) [[3-(2-Amino-l,2-dioxoethyl)-6-i-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(MM) [[3-(2-Amino-l,2-dioxoethyl)-6-cyclopropyloxycarbonyl-2- ethyl-l-benzyl-lH-indol-4-yl]oxy] acetic acid,
(NN) mixtures of (HH) through (MM) in any combination. Most preferred in the practice of the method or composition of the invention include the following:
(I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(I') [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester. Similarly, Most preferred in the practice of the method or composition of the invention include the following:
(A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid, (D) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-3-ylmethyl)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(H) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-[(l- naphthalenyl)methyl]-lH-indol-4-yl]oxy]acetic acid,
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlor phenyl)methyl]-2- ethyl-lH-indol-4-yl]oxy]acetic acid,
(K) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy] acetic acid.
Similarly, Most preferred in the practice of the method or composition of the invention include the following: (AA) (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide.
Similarly, Most preferred in the practice of the method or composition of the invention include the following:
(HH) [[3-(2-Amino-l,2-dioxoethyl)-6-carboxyl-2-ethyl-l-benzyl-lH- indol-4-yl]oxy]acetic acid,
(II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid. Most preferred in the practice of the method or composition of the invention are lH-indole- 3-glyoxylamides selected from the formula:
Figure imgf000018_0001
or indolizine- 1-glyoxylamides selected from the formula:
Figure imgf000019_0001
The salts of the above lH-indole-3-glyoxylamide compounds represented by formula (II) and named compounds (A) through (P) , (HH) through (NN) and of indolizine- 1 -glyoxylamide compounds represented by the formula (III) and named compounds (Q) through (GG) are particularly useful in the method of the invention. In those instances where the 1H- indole- 3-glyoxylamide compounds and indolizine- 1-glyoxylamide compounds possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compounds. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali 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 by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of the lH-mdole-3-glyoxylamιde compounds and mdolιzine- 1 -glyoxylamιde compounds used in the method or composition of the present invention, for example, ammonium, quaternary ammonium, and amme cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, 15. M. Berge, et al. , " Pharmaceutical Salts , " J. Phar. Sci. , 66. 1 - 19 (1977)) . Moreover basic group(s) present in the lH-mdole- 3-glyoxylamιde compound may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate , esylate, fluoride , fumarate, gluceptate, gluconate, glutamate glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate , lactate, lactobionate, laurate, malate, malate, mandelate, mesylate, methylbromide, methylmtrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate , pantothenate , phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, tπfluoromethane sulfonate, and valerate.
Certain lH-mdole-3-glyoxylamιde compounds and mdolιzιne- 1- glyoxylamide compounds may possess one or more chiral centers and may thus exist in optically active forms Likewise, R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans- isomers, are contemplated for use by the method or composition of this invention.
Prodrugs are derivatives of the lH-indole- 3-glyoxylamide compounds or indolizine- 1-glyoxylamide compounds which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the lH-indole-3- glyoxylamide compounds and indolizine- 1 -glyoxylamide compounds have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see , Bundgard, H. , Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine . Simple aliphatic or aromatic esters (e. g. , methyl or ethyl esters) derived from acidic groups (e. g. , carboxyl) pendent 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)alkyl esters.
The method of the invention can be practiced using pharmaceutical formulations containing compounds of the invention administered through the skin by an appliance such as a transdermal patch, as described in US Patents No. 5, 296, 222 and 5, 271, 940, the disclosures of which are incorporated herein by reference. Lipophilic prodrug derivatives of the compounds for formula II are particularly well suited for transdermal absorption administration and delivery systems.
The synthesis of the lH-indole- 3-glyoxylamide compounds may be accomplished as described European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ. , 4 October 1995). Further, the synthesis of the indole dicarboxylic acid derivatives may be accomplished as described Japanese Patent Application No. 35984/1997. The synthesis of the indolizine compounds may be accomplished as described WO 9603383 (Publ. , 8 February 1996) . Such synthetic methods also include well-known methods as recorded in the chemical literature and the procedure illustrated in the following preparative reaction scheme.
The following abbreviations are used throughout the synthesis Schemes and Examples. Et ethyl
Pr propyl t-Bu t-butyl
Bn benzyl
LAH lithium aluminum hydride THF tetrahydrofuran
DMF dimethylformamide
Hex hexyl Preparative Reaction Scheme 1
Figure imgf000023_0001
1 2 3
Figure imgf000023_0002
wherein Rχ2, Rl 5- ^16 a nu R17 are as defined above. R3 is C1-C5 alkyl, aryl, Cχ-Cg alkoxy, halo, aryloxy, araikyloxy, nitro, hydroxy, amino, methylamino or dimethylamino. R5 is hydrogen, Cχ-Cχo alkyl. aryl, C χ-Cχo alkaryl, C χ- C χ Q aralkyl or halo.
Explanation of Preparative Reaction Scheme 1 :
To obtain the glyoxylamides substituted in the 4-position with an acidic function through an oxygen atom, the reactions outlined in scheme 1 are used (for conversions 1 through 5, see ref. Robin D. Clark, Joseph M. Muchowski, Lawrence E . Fisher, Lee A. Flippin, David B. Repke, Michel Souchet, Synthesis, 1991, 871-878, the disclosures of which are incorporated herein by reference) . The ortho-nitrotoluene , 1 , is readily reduced to the 2-methylaniline , 2, using Pd/C as catalyst. The reduction can be carried out in ethanol or tetrahydrofuran (THF) or a combination of both, using a low pressure of hydrogen. The aniline, 2, on heating with di-tert-butyl dicarbonate in THF at reflux temperature is converted to the N-tert-butylcarbonyl derivative, 3, in good yield. The dilithium salt of the dianion of 3 is generated at -40 to -20 ° C in THF using sec-butyl lithium and reacted with the appropriately substituted N-methoxy-N- methylalkanamide . This product, 4, may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 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 hour. The resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0- 100 ° C, usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6. This indole, 6, is O-demethylated by stirring with boron tribromide in methylene chloride
29. for approximately 5 hours (see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug Res. , 1977, 12, 176, the disclosure of which is incorporated herein by reference) . The 4-hydroxyindole, 7, is alkylated with an alpha bromoalkanoic acid ester in dimethylformamide (DMF) using sodium hydride as a base, with reactions conditions similar to that describe d for the conversion of 5 to 6. The a- [(indol-4-yl)oxy] alkanoic acid ester, 8, is reacted with oxalyl chloride in methylene chloride to give 9, which is not purified but reacted directly with ammonia to give the glyoxlamide 10. This product is hydrolyzed using IN sodium hydroxide in MeOH. The final glyoxylamide, 11. is isolated either as the free carboxylic acid or as its sodium salt or in both forms. Preparative Reaction Scheme 2 - 1
Figure imgf000026_0001
25a: R12=Et 26a-f b:R12=cyclo-Pr
Figure imgf000026_0002
27a-f 28a-f
26-28 R12 R2 a: Et Ph b: Et o-Ph-Ph c: Et m-CI-Ph d: Et m-CF3-Ph e: Et 1 -Naphthyl f: cyclo- ■Pr o-Ph-Ph
wherein Rχ2> Rl 5> ^16 a n ^17 are defined above. R2 is Cg-C20 alkyl, Cg- C20 alkenyl, C -C20 alkynyl or carbocyclic radical. Explanation of Preparative Reaction Scheme 2 - 1 :
Compound 23 (N. Desideri F. Mama, M. L. Stein, G. Bile, W. Filippeelli, and E . Marmo, Eur. J. Me d. Chem. Chim. Ther. , 18, 295, (1983)) is O-alkylated using sodium hydride and benzyl chloride to give 24. N-alkylation of 24 by l-bromo-2-butanone or chloromethylcyclopropyl ketone and subsequent base catalyzed cyclization gives 25 which is acylated by aroyl halide to give 26. Hydrolysis of the ester function of 26 followed by acidification forms an acid which is thermally decarboxylated to give 27. Reduction of the ketone function of 27 by LAH yields indolizines 28. Preparative Reaction Scheme 2 - 2
Figure imgf000027_0001
35-40 R, a, R 12 R
H H Et Ph H H Et o-Ph-Ph H H Me Ph H H Et m-CI-Ph H H Et m-CF3-Ph H H Et 1 -Naphthyl
H H cyclo-Pr o-Ph-Ph H H Me cyclo-Hex
wherein R2, χ 2> ^15- ^16 a nd Rl 7 are as defined above. R5 is hydrogen or
Cj-Cg alkyl.
Explanation of Preparative Reaction Scheme 2 - 2: Sequential treatment of 28 with oxalyl chloride and ammonium hydroxide forms 35 which is debenzylated by hydrogen in the presence of Pd/C to give 36. Indolizines 36 are O-alkylated using sodium hydride and bromoacetic acid esters to form 37, 38, or 39 which are converted to indolizines 40 by hydrolysis with aqueous base followed by acidification.
Pharmaceutical Formulations
Suitable pharmaceutical formulation of the lH-indole- 3- glyoxylamide compounds may be made as described European Patent Application No. 95302166.4, Publication No. 0 675 110 (publ. , 4 October 1995) . Suitable pharmaceutical formulation of the indolizine- 1-glyoxylamide compounds may be made as described WO 9603383 (publ. , 8 February 1996) . Formulations may be obtained by conventional procedures well known in the pharmaceutical art.
The lH-indole-3-glyoxylamide compound or indolizine- 1- glyoxylamide compound is generally administered as an appropriate pharmaceutical composition which comprises a therapeutically effective amount of lH-indole-3-glyoxylamide compound or indolizine- 1- glyoxylamide is together with a pharmaceutically acceptable diluent or carrier, the composition being adapted for the particular route of administration chosen. By " pharmaceutically acceptable " it is meant the carrier, diluent or excipient must be compatible with the 1H- indole-3-glyoxylamide compound or indolizine- 1-glyoxylamide compound in the formulation and not deleterious to the subject being treated. Preferably the pharmaceutical formulation is in unit dosage form. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0. 1 to about 1000 milligrams or more according to the particular treatment involved.
The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material. Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. In tablets the lH-indole-3-glyoxylamide compound or indolizine- 1-glyoxylamide compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the lH-indole-3-glyoxylamide compound or indolizine- 1- glyoxylamide compound. Sterile liquid form 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.
EXAMPLES The following Example 1 illustrates the preparation of [[3- (2- Amino- l, 2-dioxoethyl)-2-ethyl- l-(phenylmethyl)- lH-indol-4-yl]oxy] acetic acid, a lH-indole-3-glyoxylamide compound useful in the practice of the method of the invention:
Example 1 Preparation of [[3- (2-Amino- l, 2-dioxoethyl)-2-ethyl- l-
(phenylmethyl)-lH-indol-4-yl]oxy]acetic acid, a compound represented by the formula:
Figure imgf000030_0001
Part A. Preparation of 2-Ethyl-4-methoxy- lH-indole.
A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl- 3-methoxy-2- methylaniline (21.3g, 0.09 mol) in 250 mL of THF keeping the temperature below -40 ° C with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0 ° C and then the bath replaced. After the tempera ire had cooled to -60 ° C, 18.5g (0. 18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise . The reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCI. The organic layer was separated, washed with water, brine, dried over M SO and
concentrated at reduced pressure to give 25.5g of a crude of l - [2-(tert- butoxycarbonylamino)-6-methoxyphenyl] -2-butanone . This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO^) and concentrated. The residue was chromatographed
three times on silica eluting with 20% EtOAc/hexane to give 13.9g of 2-ethyl-4-methoxy- lH-indole. Analyses for C ^H^NO:
Calculated: C, 75.40; H, 7.48; N, 7.99
Found: 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 (4.2g, 24 mmol) was dissolved in 30 mL of DMF and 960mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, the mixture was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO^ and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1g (49% yield) of 2- ethyl-4-methoxy-l-(phenylmethyl)-lH-indole.
Part C. Preparation of 2-Ethyl-4-hydroxy-l-(phenylmethyl)- lH-indole.
By the method used in Example 1, Part D, in EP Publication No. 0675110, 3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-l-(phenylmethyl)- lH-indole was O-demethylated by treating it with 48~.6 mL of IM BBr3/CH2Cl_: to give a material that was chromatographed on silica gel (eluted with 20 % EtOAc/hexane) to give 1.58 g (54 % yield) of 2-ethyl- 4-hydroxy-l-(phenylmethyl)-lH-indole, mp, 86-90 °C. Analyses for C17H17NO:
Calculated: C, 81.24; H, 6.82; N, 5.57 Found: C, 81.08; H, 6.92; N, 5.41.
Part D. Preparation of 2-[[2-Ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester.
Using the procedure described in Example 1, Part E, in EP Publication No. 0 675 110, 2-ethyl-4-hydroxy-l-(phenylmethyl)-lH- indole (1.56 g, 6.2 mmol) was treated with 248 mg (6.2 mmol) of 60 % NaH/mineral oil and then 0.6 mL (6.2 mmol ) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20 % EtOAc/hexane, to give 1.37 g (69 % yield) of [[2-ethyl-l- (phenylmethyl)-lH-indol-4-yl]oxyl]acetic acid methyl ester, ; mp 89-92 °c.
Analyses for C20H21NO3:
Calculated: C, 74.28; H, 6.55; N, 4.33 Found: C, 74.03; H, 6.49; N, 4.60.
Part E. Preparation of [[3-(2-Amino-l,2-dioxoethyl)-2- ethyl-l-(phenylmethyl)-lH-indol-4-yl]oxy]acetic acid methyl ester.
Using the procedure in Example F, in EP Publication No.0675 110. 1.36 g (4.2 mmol) of [[2-ethyl-l-(phenylmethyl)- H-indol-4- yl]oxy]acetic acid methyl ester was reacted first with 0.4 mL (4.2 mmol) of oxalyl chloride and then excess ammonia to give a white solid. This was stirred with ethyl acetate and the insoluble material separated and dried to give 1.37 g of a mixture of [[3-(2-amino-l,2-dioxoethyl)-2- ethyl-l-(phenylmethyl)-lH-indol-4-yl]oxy]acetic acid methyl ester and ammonium chloride. This mixture melted at 172-187 °C.
Part F. Preparation of [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl- l-(phenylmethyl)-lH-indol-4-yl]oxy]acetic acid.
A mixture of 788 mg (2mmol) of [3-(2-Amino-l,2-dioxoethyl)- 2-ethyl-l-(phenylmethyl)-lH-indol-4-yl]oxy]acetic acid methyl ester, 10 mL of In NaOH and 30 mL of MeOH was heated to maintain reflux for 0.5 hour, stirred at room temperature for 0.5 hour and concentrated at reduced pressure. The residue was taken up in ethyl acetate and water, the aqueous layer separated and made acidic to pH 2-3 with IN HCI. The precipitate was filtered and washed with ethyl acetate to give 559 mg (74 % yield) of [[3-(2-Amino- l , 2-dioxoethyl)-2-ethyl- l - (phenylmethyl)- lH-indol-4-yl] oxy] acetic acid, mp 230-234 ° C.
Analyses for C2ιH2oN2θ5:
Calculated: C, 65.96; H, 5.80; N, 7.33
Found: C, 66.95; H, 5.55; N, 6.99.
The following Example 2 illustrates the preparation of (8- (Carboxymethyloxy)-2-ethyl-3- (o-phenylbenzyl)indolizin- l- yl)glyoxylamide , a indolizine- 1 -glyoxylamide compound useful in the practice of the method of the invention:
Example2 Preparation of (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin- l-yl)glyoxylamide, a compound represented by the formula:
Figure imgf000034_0001
Part A: Preparation of Ethyl 3-benzyloxy-2-pyridineacetate 24
60% Sodium hydride (2.69 g, 66.2 m mol) was added in small portions to a solution of ethyl 3-hydroxy-2-pyridineacetate (23, 12.0 g, 66.2 mmol) (N. Desideri, F. Manna, M. L. Stein, G. Bile, W. Filippeelli, and E. Marmo. Eur. J. Med. Chem. Chim. Ther. , 18, 295 (1983)) in dimethylformamide (220 ml) at 0 ° C. The mixture was stirre d at 0 ° C for 50 min. Benzyl chloride (8.4 ml, 72.8 mmol) was added dropwise to the mixture, which was stirred overnight. Ethyl acetate was added. The mixture was washed with 5% aqueous sodium hydrogencarbonate and water and dried over Na2SO ι. After removing the solvent at reduced pressure, the residue was chromatographed on silica gel eluting with AcOEt: toluene (1 : 19 to 1 : 1) to give 16. 17 g (90.0% yield) of the titled compound as an oil. IR v m« (film) 1736, 1446, 1278 cm- 1. !H NMR (CD Cla) 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) . Analyses: Calc'd for C16H17NO3: C, 70.83; H, 6.32; N, 5. 16. Found: C, 70.65; H, 6.37; N, 5.20.
Part B: Preparation of Ethyl (8-benzyloxy-2-ethylindolizin- l- yl)carboxylate 25a
A mixture of pyridine derivative (24, 15.15 g, 55.8 mmol) sodium hydrogencarbonate (23.45 g, 279 mmol) and l-bromo-2-butanone (11.4 ml, 113 mmol) in methylethylketone (250 ml) was heated under reflux for 24 hours, washed with water and dried over Na2SO ι. After removing the solvent at reduced pressure, the residue was chromatographed on silica gel eluting with AcOEt: hexane (1 : 19 to 1 : 9) to give 16.66 g, (92.0% yield) of the titled compound as an oil. IR v m a x (film) 1690, 1227, 1092 cm-1. !H NMR (CDCI3) <5 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 (IH, d, J=7.6 Hz), 6.44 (IH, t, J=7. 1 Hz) , 7.07 (IH, s), 7.27-7.57 (6H, m) . Analyses : Calc'd for C20H21NO3 O. IH2O: C, 73.87; H, 6.57; N, 4.31. Found: C, 73.75; H, 6.66; N, 4.30.
Part C: Preparation of Ethyl (8-benzyloxy-2-ethyl-3-(o- phenylbenzoyl)indolizin- l -yl)carboxylate 26b
A mixture of the indolizine (25, 1 eq), o-phenyl benzoyi chloride (2.0 eq) and triethylamine (5.0 eq) was heated at 90 ° C (bath temp .) for 2-8 hours. Ethyl acetate was added. The mixture was washed with dilute hydrochloric acid and water and dried over Na∑SO-i. After removing the solvent at reduced pressure, the residue was chromatographed on silica gel eluting with AcOEt:hexane (1 : 2) and recrystallized. mp, 110- 112 t (ether-hexane) . 46.0% Yield.
Part D: Preparation of 8-Benzyloxy-2-ethyl-3-(o- phenylbenzoyl)indolizine 27b
To a solution of the ester (26, 1.0 mmol) in dimethylsulfoxide (10 ml), 50% aqueous potassium hydroxide (3 ml) was added. 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 extracts were washed with water dried over Na2S04. After removing the solvent under reduced pressure, the residue was purified by recrystallization to give the carboxylic acid. The acid in toluene was heated under reflux for 1 hour and the solvent was removed by distillation at reduced pressure. The residue was purified by recrystallization to give 27.
Quantitative yield. IR v maχ (nujol) 1735, 1597, 742 cm"1.
Part E: Preparation of 8-Benzyloxy-2-ethyl- 3-(o- phenylbenzyl)indolizine 28b
Compound 27 was treated by the procedure described for the preparation of 4, WO 9603383.
Quantitative yield. IR v maχ (CHClj) 1525, 1259 cmA
Part F: Preparation of (8-Benzyloxy-2-ethyl- 3-(o- phenylbenzyl)indolizin- l-yl) glyoxylamide 35d
These compounds were prepared according to the procedure described for the synthesis of compound 8 from compound 4, WO 9603383. Mp, 183- 185 ° C (ether-hexane) . 79.0% Yield.
Part G: Preparation of (2-Ethyl-8-hydroxy-3-(o- phenylbenzyl)indolizin- l-yl) glyoxylamide 36d
These compounds were prepared according to the procedure described for the synthesis of compound 20 from 19, WO 9603383.
Mp, 195- 196 ° C (dec.) (ether-hexane). 95.0% Yield.
Part H: Preparation of (8-(Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin- l-yl) glyoxylamide 39d These compounds were prepared according to the procedure described for the synthesis of compound 21 from 20, WO 9603383. Mp, 73- 75 ° C (dec.) (ether-hexane) . 84% Yield.
Part I: Preparation of (8- (Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin- l-yl)glyoxylamide 40d lN-Aqueous potassium hydroxide (4 ml) was added to a solution of the ester (37- 39, 2 mmol) in methanol (21 ml) . The solution was stirred at room temperature for 40 min, washe d with ether, acidified with 2N- HC1 and extracted with ethyl acetate . The extracts were washed with water and dried over Na2SO _. After removing the solvent at reduced pressure, the residue was recrystallized.
Mp, 209-212 ° C (dec.) (ether-hexane) . 93% Yield. IR v max (nujol) 3316, 1704, 1601, 1493 cm 1. *H NMR (dβ-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 (IH, d, J=7.8 Hz), 6.57-6.59 (2H, m), 7.14-7.57 (10H, m) , 7.34 (IH, s), 13.09 (IH, br.s). Analyses: Calc'd for C27H21N2O5 O.3H2O: C, 70.21 ; H, 5.37; N, 6.06. Found: C, 70.17; H, 5.35; N, 5.98.
The disorders associated with apoptosis treatment utility of the method of the invention will now be illustrated by the following Example 3 and 4: Example 3
This example illustrates the action of (8- (Carboxymethyloxy)-2- ethyl- 3- (o-p he nylbenzyl)indolizin- l-yl) glyoxylamide (the compound prepared in Example 2, hereinafter called "Ex-2") for neuronal death induced by human PLA2-II (I1PLA2-II)
(1) Primary culture of neuron
According to a method disclosed in Neurosci. Lett. 203, 175- 178 Ueda K. et al, Neuronal cultures were prepared from cerebral cortex of 19-day-old Sprague-Dawley rat embryos . The cerebral cortices were dissociated in isotonic buffer (137mM NaCl, 5.4mM KCl, 0. 17mM Na2HP04, 0.22mM KH2P04. 5.5mM Glucose, 59mM Sucrose; volume of each buffer is 25 ml) with 4 mg/ml trypsin and 0.4 mg/ml deoxyribonuclease I. Cells were plated at a density of 2.5 x 10^ cells/cm^ on poly-L-lysine coated dishes in conditioning medium, Leibovitz ' s L- 15 medium supplemented with 5 % fetal calf serum and 5 % horse serum. Culture medium was exchanged for conditioning medium containing 0. 1 mM arabinosylcytosine C on day 1 after plating. Cultured neurons were used for the experiments on day 2 of culture.
(2) Ultrastructural changes in cortical neurons after hPLA2-II treatment Cells were treated with hPLA2-H for 48 h, and fixed in situ in 1-5 %
(especially 2.5 %) glutaraldehyde in PBS for 2 h at 4 ° C and post-fixed in 0.5-2 % (especially 1 % osmium tetraoxide) . To increase contrast, cells were double-fixed in saturated thiocarbohydrazide-osmium. Afterwards, samples were dehydrated using a graded series of ethanol from 50- 100 %. Tissue culture dishes were embedded in Araldite or Epoxy resin (especially Epon 812), cured in vacuo for 48 h at 60 - 70 ° C and sectione d. Afterwards, the culture were double-dyeing with uranium acetate and lead citrate, it was identified the formation by electron microscope . The result was shown in Figure 1. Figure IA shows the ultrastructure of untreated neurons, while Figure IB shows the ultrastructure of I1PLA2-II treated neurons.
Result: We confirmed that untreated neurons had bright and round soma. and extended neurites. On the other hand, hPLA2-II-treated neurons had shrank cell bodies and lost their neurites . In comparison with untreated cells (Figure IA), condensation and fragmentation of nuclear chromatin, lost of intracellular organelle other than mitochondria and blebbing of plasma membranes were observed in hPLA2-II -treated cells
(Figure IB) .
(3) Analysis of neuronal survival
For assessment of neurotoxicity of hPLA2-II according to a method disclosed in Neurosci. Lett. 203, 175- 178 Ueda K. et al, the 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide dye (MTT) reduction assay reflecting mitochondrial activity was employed. MTT (5mg/ml) was applied to the conditioning medium (vol/vol = 1/50 - 1/100) and incubated at 37 O for 1 hour. Supernatant was aspirated and cells were solved by isopropanol containing 0.04 N HCI (100 - 200 ml) . Absorbance at 570 nm were measured with a microplate reader. p-BPB : 100 μ. M hPLA2-II were preincubated with 0.01, 0. 1 or 1 mM p-bromophenacylbromide for 20 min at 37 ° C. After preincubation, an aliquot was removed and diluted 100-fold in the culture medium of cortical neurons. Vehicle and the compound prepared in Example 2: Cortical neurons were treated with vehicle or 1 /__ M I1PLA2-II in the presence of the compound prepared in Example 2 at the indicated concentrations on day 2 of culture. MTT reducing activity was determined 48 hr after hPLA2-II-treatment. The result was shown in Figure 2.
Post-treatment with the compound prepared by Example 2: Cortical neurons were treated with vehicle or 1 M hPLA2-II on day 2 of culture. At the indicated time after the treatment with hPLA2-II (1 P- M), the compound prepared in Example 2 (final concentration = 10 /i M) was added to the culture medium. Data are expressed as mean ± SEM values (n = 4). *P < 0.05, **P < 0.01 , compared with vehicle-treated conditions by ANOVA followed by Dunnett's test. The result was shown in Figure 3.
Result: From Figure 2, we confirmed that the compound prepared in Example 2 suppressed neuronal death in a concentration- dependent manner. From Figure 3, we confirmed that the compound prepared in Example 2 suppressed neuronal death completely within 10 hours after hPLA2-II treatment. Thus, posttreatment with a hPLA2-II inhibitor, as well as co-treatment, could rescue neuron from I1PLA2-II-
induced death. Example 4 This example illustrates the action of [[3-(2-Amino- l, 2- dioxoethyl)-2-ethyl- l-(phenylmethyl)- lH-indol-4-yl] oxy] acetic acid (the compound prepared in Example 1, hereinafter called " Ex- 1 ") for neuronal death induced by human PLA2-II (hPLA2-II) Analysis of neuronal survival The experiment was carried out in the same method as in Example 3 (3) mentioned above other than adding 3 μM I1PLA2-II to 48 well-cultured neuron instead of 1 μM hPLA2-II to 12 well-cultured one . The result was
shown in Figure 4.
Result: From Figure 4, we confirme d that the compound prepared in Example 1 suppressed neuronal death completely depe nding on its concentration.
The following pharmaceutical formulations 1 through 8 are illustrative only and are not intended to limit the scope of the inve ntion in any way. "Active ingredie nt" , refers to a compound according to formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
Formulation 1
Hard gelatin capsules are prep ared using the following ingredients: Quantity (mg/capsule)
Active ingre dient 250
Starch," dried 200
Magnesium ste arate K>
Total 460 mg
Formulation 2
A tablet is prepared using the ingre dients below:
Quantity (mg/tablet) Active ingredient 250 Cellulose , microcrystalline 400 Silicon dioxide, fumed 10
Stearic acid 5.
Total 665
Formulation 3
An aerosol solution is prepared containing the following components:
Weight Active ingredient 0.25 Ethanol 25.75
Propellant 22 74.00
(Chlorodifluoro me thane)
Total 100.00
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
Formulation 4
Tablets, each containing 60 mg of active ingredient, are made as follows:
Active ingredient 60 mg
Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone
(as 10% solution in water ) 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg Talc 1 mg
Total 150 mg
The active ingredient, starch and cellulose are passed through a No.45 mesh U. S. sieve and the mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powde r, and the mixture then is passed through a No. 14 mesh U. S. sieve . The granules so produced are dried at 50°C and passed through No. 18 mesh U. S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No.60 mesh U. S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation 5
Capsules, each containing 80 mg of active ingredient, are made as follows: Active ingredient 80 mg
Starch 59 mg
Microcrystalline cellulose 59 mg
Magnesium stearate 2 mg
Total 200 mg The active ingredient, cellulose, and magnesium stearate are blended, passed through a No.45 mesh U. S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Formulation 6
Suppositories, each containing 225 mg of active ingredient, are made as follows:
Active ingredient 225 mg
Saturated fatty acid glycerides 2000 mg Total 2225 mg
The active ingredient is passed through a No.60 mesh U. S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Formulation 7
Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows:
Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 ml
Benzoic acid solution 0. 10 ml
Flavor q.v.
Color q.v. Purified water to total 5 ml The active ingredient is passed through a No.45 mesh U. S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste . The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
Formulation 8
An intravenous formulation may be prepared as follows: Active ingredient 100 mg Isotonic saline 1000 ml
The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.
While the present invention has been illustrated above by certain specific embodiments, it is not intended that these specific examples should limit the scope of the invention as described in the appended claims.
Brief Description of Drawings
Figure IA shows the ultrastructure of untreated neurons. Figure IB shows the ultrastructure of hPLA2-II-treated neurons. Figure 2 shows the concentration-dependent effect of Ex-2 on hPLA2-II-induced neuronal cell death.
Figure 3 shows the time-dependent effect of Ex-2 on hPLA2-II-
induced neuronal cell death.
Figure 4 shows the concentration-dependent effect of Ex- 1 on hPLA2-II-induced neuronal cell death.

Claims

Claims
1. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal a therapeutically effective amount of an N-heterocyclic glyoxylamide compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000047_0001
wherein ;
E and F are differently C or N; is presence or absence of a double bond; each X is independently oxygen or sulfur; Rl l is selected from groups (a), (b) and (c) where; (a) is C7-C2O alkyl, C7-C2O alkenyl, C7-C20 alkynyl; or carbocyclic radical selected from the group cycloalkyi, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthryl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),
Figure imgf000048_0001
where n is a number from 1 to 8; or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents selected from the group consisting of Ci-Cg alkyl, C2-C alkenyl, C2-Cg alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Ci-Cg alkoxy, C2-C alkenyloxy, C2-Cg alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2- C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, Cχ-Cg alkylthio, C2-C12 alkylthiocarbonyl, Ci-Cg alkylsulfinyl, Ci-Cg alkylsulfonyl, C2-C haloalkoxy, Ci-Cg haloalkylsulfonyl, C2-Cg haloalkyl, C1-C6 hydroxyalkyl, -C(O)O(Cι-C6 alkyl), -(CH2)n-0-(Cι-Cg alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)n-C02H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8;
(c) is the group -(L╬╣)-Rsi; where, -(Li)- is a divalent linking group having the formula;
Figure imgf000048_0002
wh ere, R84 and ╬┤5 are each independently selected from hydrogen, Cl-Cio alkyl, carboxyl, carbalkoxy, or halo; p is 1 to 5,
Z is a bond, -(CH2)-, -0-, -N(C╬╣-C╬╣o alkyl)-, -NH-, or -S-; and where R╬▓l is a group selected from (a) or (b);
Rχ2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyi, C3-C4 cycloalkenyl, -O-(Cι-C2 alkyl), or -S-(Cι-C2 alkyl);
Rχ4 is hydrogen or a group, -(La)-(acidic group) wherein - (La)- is represented by the formula;
Figure imgf000049_0001
where Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and Rβ4 and R85 are each independently selected from hydrogen, Cι-Cχo alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, and halo;
Rχ5 is hydrogen or a group, -(La')-(acidic group) wherein -(La')- is represented by the formula;
• Q — (CH2)r — (phenylene)£ Res'
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84' and R85' are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of R14 or R15 must be the group, -(La)-(acidic group) or -(La')-(acidic group);
Ri is hydrogen, carboxyl or ester thereof;
Rl 7 is selected from hydrogen, non-interfering substituents, selected from the group consisting of Ci -Cg alkyl, C2- C alkenyl, C2- Cg alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C χ- Cg alkoxy, C2- C alkenyloxy, C2-Cg alkynyloxy, C2- C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C 12 alkylcarbonyl, C2-C 12 alkylcarbonylamino, C2- C 12 alkoxvamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino, Ci-Cg alkylthio, C2-C 12 alkylthiocarbonyl, C i -Cg alkylsulfinyl, C χ-Cg alkylsulfonyl, C2-Cg haloalkoxy, C χ-Cg haloalkylsulfonyl, C2-Cg haloalkyl, Cχ-Cg hydroxyalkyl, -C(0)0(C ι-Cg alkyl) , -(CH2)n-0-(Cι-Cg alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2) -C02H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and C i-Cg carbonyl; where n is from 1 to 8.
2. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal a therapeutically effective amount of a lH-indole-3- glyoxylamide compound represented by the formula (II) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000051_0001
wherein X, Rχ ι , Ri2> Rl 4> 15, Ri and Rχ 7 are as defined above.
3. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal a therapeutically effective amount of an indolizine- 1- glyoxylamide compound represented by the formula (III) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000051_0002
wherein X, Ru , Rχ2> Rl4> Rl5> ^16 and &17 are as defined above.
4. The method of claim 2 or 3 wherein for the compound of formula (II) or (III) both X are oxygen, only one of R14 or R 5 are - (La)-
(acidic group) or - (La')-(acidic group) and the (acidic group) is carboxyl.
5. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal in need of such treatment a therapeutically effective amount of an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (A) through (NN): (A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(B) dl-2-[[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)- lH-indol-4-yl]oxy]propanoic acid,
(C) [[3- (2- Amino- l,2-dioxoethyl)-l-([l,l' -biphenyl] -2-ylmethyl)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(D) [[3- (2-Amino-l,2-dioxoethyl)-l- ([1,1 '-biphenyl] -3-ylme thyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(E) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-4-ylmethyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid, (F) [[3-(2-Amino-l,2-dioxoethyl)-l-[(2,6-dichlorophenyl)methyl]-
2-methyl-lH-indol-4-yl]oxy]acetic acid,
(G) [[3-(2-Amino-l,2-dioxoethyl)-l-[(4-fluorophenyl)methyl]-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(H) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-[(l- naphthalenyl)methyl]-lH-indol-4-yl]oxy]acetic acid,
(I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(I') [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester (J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2- ethyl-lH-indol- 4- yl]oxy] acetic acid,
(K) [[3- (2-Amino-l,2-dioxoethyl)-l-([l,l '-biphenyl] -2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy] acetic acid, (L) [[3- (2-amino-l,2-dioxoethyl)-l- ([1,1 '-biphenyl] -2-ylmethyl)-2- propyl-lH-indol-4-yl]oxy]acetic acid,
(M) [[3-(2-Amino-l,2-dioxoethyl)-2-cyclopropyl-l-(phenylmethyl)- lH-indol-4-yl]oxy]acetic acid,
(N) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphe"nyl]-2-ylmethyl)-2- cyclopropyl-lH-indol-4-yl]oxy]acetic acid,
(O) 4-[[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-5-yl]oxy]butanoic acid,
(P) mixtures of (A) through (O),
(Q) (8-(Carbomethoxymethyloxy)-2-ethyl-3-(o- phe nylbenzyl)indolizin-l-yl) glyoxylamide,
(R) (3-Benzyl-8-(carbethoxymethyloxy)-2-ethylindolizin-l- yl)glyoxylamide,
(S) (8-(Carbethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide, (T) (3-Benzyl-8-(carbethoxymethyloxy)-2-methylindolizin-l-
yl)glyoxylamide,
(U) (8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2- ethylindolizin-1-yl) glyoxylamide,
(V) (8-Carbethoxymethyloxy-2-ethyl-3-(l- nap hthylmethyl)indolizin-l-yl) glyoxylamide, (W) (3-Benzyl-8-(t-butoxycarbonylmethyloxy)-2-ethylindolizin-l- yl)glyoxylamide,
(X) (8-(Carbmethoxymethyloxy)-2-ethyl-3-(m- trifluoromethylbenzyl)indolizin-l-yl) glyoxylamide, (Y) (8-(Carbmethoxymethyloxy)-2-cyclopropyl-3-(o- p he nylbenzyl)indolizin-l-yl) glyoxylamide,
(Z) (3-Benzyl-8-(carboxymethyloxy)-2-ethylindolizin-l- yl)glyoxylamide,
(AA) (8-(Carboxymethyloxy)-2-ethyl-3-(6- phe nylbenzyl)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o- p he ny lb enzyl)indolizin-l-yl) glyoxylamide,
(BB) (3-Benzyl-8-(carboxymethyloxy)-2-methylindolizin-l- yl)glyoxylamide, (CC) (8-(Carboxymethyloxy)-3-(m-chlorobenzyl)-2- ethylindolizin-1-yl) glyoxylamide,
(DD) (8-(Carboxymethyloxy)-2-ethyl-3-(m- tr ifluorome thy lbenzyl)indolizin-l-yl) glyoxylamide,
(EE) (8-Carboxymethyloxy-2-ethyl-3-(l- naphthy lme thy l)indolizin-l-yl) glyoxylamide,
(FF) (8-(Carboxymethyloxy)-2-cyclopropyl-3-(o- p he nylbenzyl)indolizin-l-yl) glyoxylamide, (GG) mixtures of (Q) through (FF),
(HH) [[3- (2-Amino-l,2-dioxoethyl)-6-carboxyl-2-ethyl-l -benzyl- 1H- indol-4-yl]oxy]acetic acid, (II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid,
(JJ) [[3-(2-Amino-l,2-dioxoethyl)-6-ethoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid, (KK) [[3-(2-Amino-l,2-dioxoethyl)-6-n-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(LL) [[3-(2-Amino-l,2-dioxoethyl)-6-i-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid,
(MM) [[3-(2-Amino-l,2-dioxoethyl)-6-cyclopropyloxycarbonyl-2- ethyl-l-benzyl-lH-indol-4-yl]oxy]acetic acid,
(NN) mixtures of (HH) through (MM).
6. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal in need of such treatment a therapeutically effective amount of an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (I) and (I'): (I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(I') [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester.
7. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal in need of such treatment a therapeutically effective amount of an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (A), (D), (H), (J) and (K):
(A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid, (D) [[3-(2-Amino-l,2-dioxoethyl)-l-([l,l'-biphenyl]-3-ylmethyl)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(H) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-[(l- naphthalenyl)methyl]-lH-indol-4-yl]oxy]acetic acid,
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2- ethyl-lH-indol-4-yl]oxy]acetic acid,
(K) [[3- (2-Amino-l,2-dioxoethyl)-l- ([1,1 '-biphenyl] - 2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy] acetic acid.
8. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal in need of such treatment a therapeutically effective amount of an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (AA) and (AA'): (AA) (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide.
9. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal in need of such treatment a therapeutically effective amount of an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (HH) and (II):
(HH) [[3- (2-Amino-l,2-dioxoethyl)-6-carboxyl-2-ethyl-l -benzyl- 1H- indol-4-yl]oxy]acetic acid, (II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid.
10. A method of treatment of a mammal currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis, said method comprising administering to said mammal in need of such treatment a therapeutically effective amount of an N-heterocyclic glyoxylamide compound selected from the formula:
Figure imgf000058_0001
Figure imgf000059_0001
or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof.
11. The method of claims 1 or 2 or 3 or 4 or 5 or 6 wherein the therapeutically effective amount of the compound is in the form of a pharmaceutical formulation comprising the compound and a suitable carrier or excipient therefor.
12. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is represented by the formula (I) or a pharmaceutically acceptable salt, solvate , or prodrug derivative thereof:
Figure imgf000060_0001
wherein ;
E and F are differently C or N; is prese nce or abse nce of a double bond; each X is independently oxygen or sulfur;
Rl l is selecte d from groups (a), (b) and (c) where;
(a) is C7- C20 alkyl, C7- C2O alkenyl, C7-C20 alkynyl; or carbocyclic radical selected from the group cycloalkyi, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthryl, biphenyl, bibenzylyl and related bibenzylyl homologues represente d by the formula (bb) ,
Figure imgf000060_0002
where n is a number from 1 to 8; or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents selected from the group consisting of C i - Cg alkyl, C2- Cg alkenyl, C2-Cg alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C i-Cg alkoxy, C2-Cg alkenyloxy, C2- Cg alkynyloxy, C2-C12 alkoxyalkyl, C2-C 12 alkoxyalkyloxy, C2-C 12 alkylcarbonyl, C2- C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, Ci -Cg alkylthio, C2-C12 alkylthiocarbonyl, Ci-Cg alkylsulfinyl, Ci-Cg alkylsulfonyl, C2-C haloalkoxy, C i-Cg haloalkylsulfonyl, C2-C haloalkyl, C i-Cg hydroxyalkyl, -C(0)0(C╬╣ - Cg alkyl), -(CH2)n-0-(C ╬╣- Cg alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)n- C╬╕2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and C i-Cg carbonyl; where n is from 1 to 8;
(c) is the group - (L╬╣)-R╬┤i ; where, -(Li)- is a divalent linking group having the formula;
Figure imgf000061_0001
where,
R84 and R85 are each independently selected from hydrogen, C1 -C10 alkyl, carboxyl, carbalkoxy, or halo;
p is 1 to 5,
Z is a bond, -(CH2)-, -0-, -N(C ι-C ιo alkyl)-, -NH-, or -S-; and where R81 is a group selected from (a) or (b); Rl2 is hydrogen, halo, C 1-C3 alkyl, C3- C4 cycloalkyi, C3-C4 cycloalkenyl, -O- (Cι-C2 alkyl), or -S-(C χ-C2 alkyl);
Rχ4 is hydrogen or a group, -(La)-(acidic group) wherein - (La)- is represented by the formula;
Figure imgf000062_0001
where Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R╬┤4 and R╬┤5 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C 1- C10 alkaryl, C 1-C 10 aralkyl, and halo;
Rχ5 is hydrogen or a group, -(La')-(acidic group) wherein -(La - is represented by the formula;
Q- (CH2)r- (phenylene)s
R╬╣ 85
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84' and R85' are each independently selected from hydrogen, C1-C10 alkyl, aryl, C 1-C10 alkaryl, C1-C 10 aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of Rχ4 or R 5 must be the group, - (La)-(acidic group)
or -(La')-(acidic group);
Rig is hydrogen, carboxyl or ester thereof;
Rl 7 is selected from hydrogen, non-interfering substituents, selected from the group consisting of Ci-Cg alkyl, C2-Cg alkenyl, C2- Cg alkynyl, C7-C 12 aralkyl, C7-C 12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C i-Cg alkoxy, C2-C alkenyloxy, C2-C alkynyloxy, C2-C12 alkoxyalkyl, C2- C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C 12 alkylcarbonylamino, C2- C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C 2 alkylamino, Ci-Cg alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C i -Cg alkylsulfonyl, C2- Cg haloalkoxy, C i -Cg haloalkylsulfonyl, C2-Cg haloalkyl, Ci -Cg hydroxyalkyl, - C(0)0(C ╬╣-Cg alkyl) , -(CH2)n-0-(C ╬╣-Cg alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)rr CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Ci-Cg carbonyl; where n is from 1 to 8.
13. Use of a lH-indole-3-glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is represented by the formula (II) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000063_0001
wherein X, Ru, Ri2> ^14> Rl5> ^16 and ^17 are as defined above.
14. Use of an indolizine-1-glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is represented by the formula (III) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000064_0001
wherein X, Ru, i2> ^14┬╗ &15> ^16 and Rl7 are as defined above.
15. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (A) through (NN): (A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(B) dl-2-[[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)- lH-indol-4-yl]oxy]propanoic acid, (C) [[3-(2-Amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(D) [[3- (2- Amino- 1,2-dioxoethy 1)-1-([1, l'-biphenyl] -3-ylmethyl).2- methyl-lH-indol-4-yl]oxy] acetic acid,
(E) [[3- (2- Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -4-ylmethyl)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(F) [[3-(2-Amino-l,2-dioxoethyl)-l-[(2,6-dichlorophenyl)methyl]- 2-methyl-lH-indol-4-yl]oxy] acetic acid,
(G) [[3-(2-Amino-l,2-dioxoethyl)-l-[(4-fluorophenyl)methyl]-2- methyl-lH-indol-4-yl]oxy]acetic acid, (H) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-[(l- naphthalenyl)methyl]-lH-indol-4-yl]oxy]acetic acid,
(I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(I' ) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2-
ethyl-lH-indol-4-yl]oxy] acetic acid,
(K) [[3-(2-Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy]ace ic acid, (L) [[3-(2-amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- propyl-lH-indol-4-yl]oxy]acetic acid,
(M) [[3-(2-Amino-l,2-dioxoethyl)-2-cyclopropyl-l-(phenylmethyl)- lH-indol-4-yl]oxy]acetic acid, (N) [[3-(2- Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- cyclopropyl-lH-indol-4-yl]oxy] acetic acid,
(0) 4-[[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-5-yl]oxy]butanoic acid,
(P) mixtures of (A) through (O), (Q) (8-(Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(R) (3-Benzyl-8-(carbethoxymethyloxy)-2-ethylindolizin-l- yl)glyoxylamide,
(S) (8-(Carbethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(T) (3-Benzyl-8-(carbethoxymethyloxy)-2-methylindolizin-l- yl)glyoxylamide,
(U) (8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2- ethylindolizin-1-yl) glyoxylamide, (V) (8-Carbethoxymethyloxy-2-ethyl-3-(l- naphthylmethyl)indolizin-l-yl) glyoxylamide,
(W) (3-Benzyl-8-(t-butoxycarbonylmethyloxy)-2-ethylindolizin-l- yl)glyoxylamide,
(X) (8-(Carbmethoxymethyloxy)-2-ethyl-3-(m- trifluoromethylbenzyl)in do lizin-1-yl) glyoxylamide, (Y) (8-(Carbmethoxymethyloxy)-2-cyclopropyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(Z) (3-Benzyl-8-(carboxymethyloxy)-2-ethylindolizin-l- yl)glyoxylamide, (AA) (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(BB) (3-Benzyl-8-(carboxymethyloxy)-2-methylindolizin-l- yl)glyoxylamide,
(CC) (8-(Carboxymethyloxy)-3-(m-chlorobenzyl)-2- ethylindolizin-1-yl) glyoxylamide,
(DD) (8-(Carboxymethyloxy)-2-ethyl-3-(m- trifluorome thy lbenzyl)indolizin-l-yl) glyoxylamide, (EE) (8-Carboxymethyloxy-2-ethyl-3-(l- nap ht hy lm e t hy 1) in do lizin-1-yl) glyoxylamide,
(FF) (8-(Carboxymethyloxy)-2-cyclopropyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide, (GG) mixtures of (Q) through (FF), (HH) [[3-(2-Amino-l,2-dioxoethyl)-6-carboxyl-2-ethyl-l-benzyl-lH- indol-4-yl]oxy]acetic acid,
(II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(JJ) [[3-(2-Amino-l,2-dioxoethyl)-6-ethoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid, (KK) [[3-(2-Amino-l,2-dioxoethyl)-6-n-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid,
(LL) [[3-(2-Amino-l,2-dioxoethyl)-6-i-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid, (MM) [[3-(2-Amino-l,2-dioxoethyl)-6-cyclopropyloxycarbonyl-2- ethyl-1 -be nzyl-lH-indol-4-yl]oxy] acetic acid,
(NN) mixtures of (HH) through (MM).
16. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (I) and (I' ):
(I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(I') [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester.
17. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (A), (D), (H), (J) and (K):
(A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(D) [[3- (2- Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -3-ylmethyl)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(H) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-[(l- naphthalenyl)methyl]-lH-indol-4-yl]oxy]acetic acid,
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2- ethyl-lH-indol-4-yl]oxy]acetic acid, (K) [[3-(2-Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy]acetic acid.
18. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (AA) and (AA'): (AA) (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o-
p he nylbenzyl)indolizin-l-yl) glyoxylamide.
19. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated with apoptosis; where the compound is an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (HH) and (II): (HH) [[3-(2-Amino-l,2-dioxoethyl)-6-carboxyl-2-ethyl-l -benzyl- 1H- indol-4-yl]oxy]acetic acid,
(II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid.
20. Use of an N-heterocyclic glyoxylamide compound for the manufacture of a medicant for treating disorders associated with apoptosis in a mammal, including a human, currently afflicted with disorders associated with apoptosis or previously afflicted with disorders associated
with apoptosis; where the compound is an N-heterocyclic glyoxylamide compound
selected from the formula:
Figure imgf000071_0001
Figure imgf000072_0001
or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof.
21. A composition for treatment of disorders associated with apoptosis; which comprises an N-heterocyclic glyoxylamide compound represented by the formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000072_0002
wherein ; E and F are differently C or N; is presence or absence of a double bond; each X is independently oxygen or sulfur;
Rl l is selected from groups (a), (b) and (c) where; (a) is C7-C2O alkyl, C7-C20 alkenyl, C7-C20 alkynyl; or carbocyclic radical selected from the group cycloalkyi, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthryl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),
Figure imgf000073_0001
where n is a number from 1 to 8; or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents selected from the group consisting of C i-Cg alkyl, C2- C alkenyl, C2- Cg alkynyl, C7-C12 aralkyl, C7-C 12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Ci-Cg alkoxy, C2-Cg alkenyloxy, C2- Cg alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2- C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2- C12 alkoxyaminocarbonyl, C 1- C 12 alkylamino, C i-Cg alkylthio, C2-C12 alkylthiocarbonyl, Ci- Cg alkylsulfinyl, C i-Cg alkylsulfonyl, C2- Cg haloalkoxy, C i-Cg haloalkylsulfonyl, C2-Cg haloalkyl, C i- Cg hydroxyalkyl, -C(0)0(C ╬╣-Cg alkyl) , - (CH2)n-0-(C ╬╣-Cg alkyl), benzyloxy, phenoxy, phenylthio, -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)n-C╬╕2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido. hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Ci-Cg carbonyl; where n is from 1 to 8;
(c) is the group -(L╬╣)-R╬┤i; where, -(Li)- is a divalent linking group having the formula;
Figure imgf000074_0001
where,
R84 and R╬┤5 are each independently selected from hydrogen, C1-C10 alkyl, carboxyl, carbalkoxy, or halo; p is 1 to 5,
Z is a bond, -(CH2)-, -0-, -N(C╬╣-C╬╣o alkyl)-, -NH-, or -S-; and where Rsi is a group selected from (a) or (b);
Rl2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyi, C3-C4 cycloalkenyl, -O-(C╬╣-C2 alkyl), or -S-(Ci-C2 alkyl);
Rl4 is hydrogen or a group, -(La)-(acidic group) wherein - (La)- is represented by the formula;
Figure imgf000074_0002
where Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84 and R╬┤5 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, Ci-Cio aralkyl, and halo; Rl 5 is hydrogen or a group, - (La')- (acidic group) wherein ΓÇó(La')- is represented by the formula;
Q ΓÇö (CH2)r ΓÇö (phenylene)s
Figure imgf000075_0001
where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group - (CH2)-, -0-, -NH-, and -S-, and R84' and R85' are each independently selected from hydrogen, C i- C i o alkyl, aryl, C i -C io alkaryl, C i- C i o aralkyl, carboxy, carbalkoxy, and halo; provided that at least one of R14 or R15 must be the group, - (La)-(acidic group) or -(La')- (acidic group); Ri is hydrogen, carboxyl or ester thereof;
Rl7 is selected from hydrogen, non-interfering substituents, selected from the group consisting of Ci-Cg alkyl, C2-Cg alkenyl, C2- Cg alkynyl, C7- C12 aralkyl, C7- C 12 alkaryl, C3-C8 cycloalkyi, C3-C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Ci-Cg alkoxy, C2- C alkenyloxy, C2-Cg alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2- C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino, Cl-Cg alkylthio, C2- C12 alkylthiocarbonyl, Ci-Cg alkylsulfinyl, Ci-Cg alkylsulfonyl, C2-Cg haloalkoxy, Ci-Cg haloalkylsulfonyl, C2- Cg haloalkyl, Ci -Cg hydroxyalkyl, - C(0)0(C ╬╣- Cg alkyl), -(CH2)n-0-(C ╬╣-Cg alkyl) , benzyloxy, phenoxy, phenylthio, - CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, -(CH2)n-C╬╕2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino , iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl. and C i-Cg carbonyl; where n is from 1 to 8.
22. A composition for treatment of disorders associated with apoptosis; which comprises a lH-indole- 3-glyoxylamide compound represented by the formula (II) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000076_0001
wherein X, u , Ri2> Rl4> ^15* ^16 and Rl7 are as defined above.
23. A composition for treatment of disorders associated with apoptosis; which comprises an indolizine- 1-glyoxylamide compound represented by the formula (III) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof:
Figure imgf000076_0002
wherein X, u, Ri2> ^14- ^15> ^16 an Rl7 are as defined above.
24. A composition for treatment of disorders associated with apoptosis; which comprises an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (A) through (NN):
(A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid, (B) dl-2- [[3-(2- Amino- 1,2-dioxoethyl) -2-methyl-l- (phenylmethy 1)- lH-indol-4-yl]oxy]propanoic acid,
(C) [[3- (2-Amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- methyl-lH-indol-4-yl]oxy] acetic acid,
(D) [[3-(2-Amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -3-ylmethyl)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(E) [ [3- (2- Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -4-ylmethy l)-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(F) [[3-(2-Amino-l,2-dioxoethyl)-l-[(2,6-dichlorophenyl)methyl]- 2-methyl-lH-indol-4-yl]oxy]acetic acid, (G) [[3-(2-Amino-l,2-dioxoethyl)-l-[(4-fluorophenyl)methyl]-2- methyl-lH-indol-4-yl]oxy]acetic acid,
(H) [[3-(2- Amino- 1, 2-dioxoethyl)-2-methyl- 1- [(1- naphthalenyl)methyl]-lH-indol-4-yl]oxy]acetic acid,
(I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid, (I') [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2- ethyl-lH-indol-4-yl]oxy] acetic acid, (K) [[3-(2-Amino- l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy] acetic acid,
(L) [[3- (2-amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- propyl-lH-indol-4-yl]oxy]acetic acid,
(M) [[3-(2-Amino-l,2-dioxoethyl)-2-cyclopropyϊ-l-(phenylmethyl)- lH-indol-4-yl]oxy]acetic acid,
(N) [[3- (2-Amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- cyclopropyl-lH-indol-4-yl]oxy] acetic acid,
(0) 4-[[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-5-yl]oxy]butanoic acid, (P) mixtures of (A) through (0),
(Q) (8-(Carbomethoxymethyloxy)-2-ethyl-3-(o- p he nylbenzyl)indolizin-l-yl) glyoxylamide,
(R) (3-Benzyl-8-(carbethoxymethyloxy)-2-ethylindolizin-l- yl) glyoxylamide, (S) (8-(Carbethoxymethyloxy)-2-ethyl-3-(o- phenylbenzyl)indolizin-l-yl) glyoxylamide,
(T) (3-Benzyl-8-(carbethoxymethyloxy)-2-methylindolizin-l-
yl)glyoxylamide,
(U) (8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2- ethylindolizin-1-yl) glyoxylamide, (V) (8- Carbethoxymethyloxy-2-ethyl-3-(l- naphthylmethyl)indolizin- l -yl) glyoxylamide,
(W) (3-Benzyl-8-(t-butoxycarbonylmethyloxy)-2-ethylindolizin- l- yl)glyoxylamide, (X) (8- (Carbmethoxymethyloxy)-2-ethyl-3-(m- trifluoro me thylbenzyl)indolizin- l-yl) glyoxylamide,
(Y) (8- (Carbmethoxymethyloxy)-2-cyclopropyl- 3-(o- phenylbenzyl)indolizin- l-yl) glyoxylamide,
(Z) (3-Benzyl-8-(carboxymethyloxy)-2-ethylindolizin- l - yl)glyoxylamide,
(AA) (8-(Carboxymethyloxy)-2-ethyl- 3-(o- phenylbenzyl)indolizin- l-yl) glyoxylamide,
(AA' ) (8- Carbomethoxymethyloxy)-2-ethyl- 3-(o- p he ny lbe nzy 1) in dolizin- 1-yl) glyoxylamide, (BB) (3-Benzyl-8-(carboxymethyloxy)-2-methylindolizin- l- yl)glyoxylamide,
(CC) (8-(Carboxymethyloxy)-3- (m-chlorobenzyl)-2- ethylindolizin- 1-yl) glyoxylamide,
(DD) (8-(Carboxymethyloxy)-2-ethyl-3-(m- trifluoromethylbenzyl)indolizin- l-yl) glyoxylamide,
(EE) (8-Carboxymethyloxy-2-ethyl- 3-(l- naphthylme thy l)indolizin- l-yl) glyoxylamide,
(FF) (8-(Carboxymethyloxy)-2-cyclopropyl-3-(o- pheny lbe nzy l)indolizin- l-yl) glyoxylamide, (GG) mixtures of (Q) through (FF), (HH) [[3-(2- Amino- l,2-dioxoethyl)-6-carboxyl-2-ethyl-l -benzyl- 1H- indol-4-yl]oxy]acetic acid,
(II) [[3-(2-Amino-l,2-dioxoethyl)-6-methoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid, (JJ) [[3-(2-Amino-l,2-dioxoethyl)-6-ethoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy] acetic acid,
(KK) [[3-(2-Amino-l,2-dioxoethyl)-6-n-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(LL) [[3-(2-Amino-l,2-dioxoethyl)-6-i-propoxycarbonyl-2-ethyl-l- benzyl-lH-indol-4-yl]oxy]acetic acid,
(MM) [[3-(2-Amino-l,2-dioxoethyl)-6-cyclopropyloxycarbonyl-2- ethyl-l-benzyl-lH-indol-4-yl]oxy]acetic acid,
(NN) mixtures of (HH) through (MM).
25. A composition for treatment of disorders associated with apoptosis; which comprises an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (I) and (I'): (I) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(P) [[3-(2-Amino-l,2-dioxoethyl)-2-ethyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid methyl ester.
26. A composition for treatment of disorders associated with
apoptosis; which comprises an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (A), (D), (H), (J) and (K): (A) [[3-(2-Amino-l,2-dioxoethyl)-2-methyl-l-(phenylmethyl)-lH- indol-4-yl]oxy]acetic acid,
(D) [[3- (2-Amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -3-ylmethy l)-2- methyl-lH-indo 1-4- yl]oxy] acetic acid, (H) [[3-(2-Amino-l,2-d╬╣oxoethyl)-2-methyl-l-[(l- naphthalenyl) methyl] -lH-indol-4-yl]oxy] acetic acid,
(J) [[3-(2-Amino-l,2-dioxoethyl)-l-[(3-chlorophenyl)methyl]-2- ethyl-lH-indol-4-yl]oxy] acetic acid,
(K) [[3-(2-Amino-l,2-dioxoethyl)-l-([l, l'-biphenyl] -2-ylmethyl)-2- ethyl-lH-indol-4-yl]oxy]acetic acid.
27. A composition for treatment of disorders associated with apoptosis; which comprises an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (AA) and (AA'):
(AA) (8-(Carboxymethyloxy)-2-ethyl-3-(o- phenylbe nzy l)indolizin-l-yl) glyoxylamide,
(AA' ) (8-Carbomethoxymethyloxy)-2-ethyl-3-(o-
phenylbenzyl)indolizin-l-yl) glyoxylamide.
28. A composition for treatment of disorders associated with apoptosis; which comprises an N-heterocyclic glyoxylamide compound or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof selected from the group consisting of compounds (HH) and (II):
(HH) [[3- (2- Amino- l, 2-dioxoethyl)-6-carboxyl-2-ethyl- l -benzyl- 1H- indol-4-yl] oxy] acetic acid,
(II) [[3- (2-Amino- l , 2-dioxoethyl)-6-methoxycarbonyl-2-ethyl- l- benzyl- lH-indol-4-yl] oxy] acetic acid.
29. A composition for treatment of disorders associated with apoptosis; which comprises an N-heterocyclic glyoxylamide compound selected from the formula:
Figure imgf000083_0001
Figure imgf000084_0001
or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof.
PCT/JP1998/005042 1997-11-12 1998-11-10 Method for the treatment of disorders associated with apoptosis using n-heterocyclic glyoxylamide compounds WO1999024026A2 (en)

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WO2000011947A1 (en) * 1998-08-28 2000-03-09 Uropath Pty. Ltd. Method of diagnosis of prostate cancer
US6677157B1 (en) * 1998-08-28 2004-01-13 Uropath Pty Ltd., A.C.N. Method of diagnosis of prostate cancer
WO2000067802A1 (en) * 1999-05-10 2000-11-16 Protarga, Inc. Fatty acid-n-substituted indol-3-glyoxyl-amide compositions and uses thereof
US6787545B1 (en) 1999-08-23 2004-09-07 Shiongi & Co., Ltd. Pyrrolotriazine derivatives having spla2-inhibitory activities
JP4623483B2 (en) * 1999-08-23 2011-02-02 塩野義製薬株式会社 Pyrrotriazine derivative having sPLA2 inhibitory action
EP1300159A1 (en) * 2000-06-29 2003-04-09 Shionogi & Co., Ltd. Remedies for cancer
EP1300159A4 (en) * 2000-06-29 2005-08-24 Shionogi & Co Remedies for cancer

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WO1999024026A3 (en) 1999-07-15
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