EP1265607A2 - METHOD FOR THE TREATMENT OF RENAL DYSFUNCTION WITH sPLA 2 INHIBITORS - Google Patents

METHOD FOR THE TREATMENT OF RENAL DYSFUNCTION WITH sPLA 2 INHIBITORS

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Publication number
EP1265607A2
EP1265607A2 EP01956186A EP01956186A EP1265607A2 EP 1265607 A2 EP1265607 A2 EP 1265607A2 EP 01956186 A EP01956186 A EP 01956186A EP 01956186 A EP01956186 A EP 01956186A EP 1265607 A2 EP1265607 A2 EP 1265607A2
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European Patent Office
Prior art keywords
group
alkyl
methyl
acid
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP01956186A
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German (de)
French (fr)
Inventor
William Louis Macias
Vincent Phillip Meador
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Eli Lilly and Co
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Eli Lilly and Co
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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

  • the present invention is directed to a method for treating renal dysfunction. More specifically, the present invention is directed to- a method for treating the symptoms of renal dysfunction by administering a therapeutically effective amount of a SPLA2 inhibitor.
  • Renal failure can be either acute or chronic.
  • Acute renal failure is a very common renal disease affecting about 5% of all hospitalized patients.
  • ARF carries a high mortality of more than 50% and there has been no significant change in the mortality rate over the past four decades.
  • the effects of acute renal failure may be reversible with prompt and proper intervention and treatment .
  • Chronic renal failure on the other hand is often not reversible.
  • Common initiating causes of chronic renal failure (CRF) include glomerulonephritis, diabetes mellitus, and hypertension.
  • CRF chronic renal failure
  • CRF chronic renal failure
  • urea and other toxins encompasses more than just a presumed retention of urea and other toxins but includes the impairment of a host of metabolic and endocrine functions normally subserved by the kidney.
  • Symptoms of uremia include for example, hypothermia- caused possibly by retention of urea and other toxins, impaired glucose metabolism, uremic toxicity caused by an inability to eliminate end products of protein metabolism, fluid and electrolyte imbalance, gastrointestinal disturbances e.g. nausea, anorexia, uremic factors, and peptic ulcer.
  • Other symptoms of CRF include arterial hypertension, congestive heart failure, dermatological disturbances, e.g. itching, neurologic disturbances e.g.
  • previous treatment attempts have focused on pharmaceutical agents that treated the cause of the renal dysfunction.
  • previous methods treated the problem causing renal dysfunction and not, for example, the build up of fluids or cell membrane damage.
  • the present invention is directed to a method of alleviating the symptoms of an animal afflicted with renal dysfunction e.g., acute or chronic renal failure, by administering a therapeutically effective amount of a SP A2 inhibitor compound.
  • the present invention also relates to the use of a SPLA2 inhibitor in combination with a therapeutically effective agent and or medical procedure selected from the group consisting of, dialysis treatment to remove harmful toxins; drugs to restore salt and water balance; and/or other treatment of acute and chronic renal failure.
  • a therapeutically effective agent and or medical procedure selected from the group consisting of, dialysis treatment to remove harmful toxins; drugs to restore salt and water balance; and/or other treatment of acute and chronic renal failure.
  • the invention also relates to the combination of a SPLA2 inhibitor with ANF atrial naturetic factor for the delay or prevention of acute renal failure in a mammal .
  • This invention also relates to the use of a SP A2 inhibitor in combination with erythropoetin to stimulate red cell production in a mammal.
  • the present invention is also the use of a SPLA2 inhibitor in combination with 0KT3TM (a monoclonal antibody used to prevent graft rejection by T3 antigens produced by human T cells) , to reduce the symptoms associated with administration of 0KT3.
  • 0KT3TM a monoclonal antibody used to prevent graft rejection by T3 antigens produced by human T cells
  • Renal dysfunction means a disease state or condition wherein the renal tissues fail to perform their normal functions according to competent medical authority. Renal dysfunction shall also include long term or chronic renal dysfunction also known as renal failure. Renal dysfunction also includes acute renal failure and disease states that lead to renal failure.
  • Examples of disease states leading to renal failure include for example, acute nephritis, nephrotic syndrome, pyuria, auria, oliguria, uremia, bilateral arterial occlusion, acute tubular necrosis, acute uric acid nephropathy, hypovolemia, acute bilateral upper tract obstruction, hypocalcemic nephropathy, hemolytic uremic syndrome, acute urinary retention, scleroderma, hypersensitivity nephropathy, malignant nephrosclerosis, essential and mixed cryoimmunoglobulinemia, and azotemia.
  • uremia means the clinical syndrome of nausea, itching, weight loss, sleep disturbances, altered mentation, and memory loss associated with renal dysfunction .
  • SP A2 inhibitor and “SPLA2 inhibitor compound” as used herein are synonymous.
  • terapéuticaally effective amount is a quantity of SP A2 inhibitor sufficient to ameliorate the symptoms secondary to renal dysfunction in an animal.
  • therapeutically effective interval is a period of time beginning when one of either the SPLA2 inhibitor or the co-agent is administered or practiced on the patient in need thereof, and ending at the limit of the therapeutic effectiveness of either or both.
  • parenteral or parenteral administration mean administration by a route such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, transdermal, transmucosal, transbuccal, transrectal, transvaginal , transnasal or intravenous .
  • animal means any member of the animal kingdom including mammals, reptiles, fishes and fowls.
  • active compound means one or more SPLA2 inhibitors used in the method of the invention.
  • co-agent is a theraputically effective medication or procedure administered in combination with a SPLA2 inhibitor either as a single dose unit or as separate dose units simultaneously or sequentially within a therapeutic interval .
  • a preferred aspect of the invention is the use of a SP A2 inhibitor compound of the invention for the prevention or treatment of uremia.
  • Preclinical studies showed that monkeys and rabbits in renal failure did not develop signs of uremia i.e., the kidneys were failing but the animals were not as clinicallly ill as they should have been.
  • Another preferred aspect of the present invention is the use of a SPL 2 inhibitor in combination with an anti- rejection drug, e.g., OKT3TM for the treatment of chronic or acute inflammation associated with kidney transplant therapy .
  • an anti- rejection drug e.g., OKT3TM
  • SPLA2 inhibitor in combination with erythropoietin to stimulate the production of red cells in renal failure patients.
  • SPLA2 inhibitors in general are useful in the practice of the method of this invention.
  • exemplary of classes of suitable SPLA2 inhibitors useful in the method of the invention for treatment of renal dysfunction includes members selected from the group comprising: lH-indole-3-glyoxylamide, 1H- indole-3-hydrazide, lH-indole-3-acetamide, lH-indole-1- glyoxylamide, lH-indole-1-hydrazide, lH-indole-1- aceta ide, indolizine-1-acetamide, indolizine-1-acetic acid hydrazide, indolizine-1-glyoxylamide, indene-1- acetamide, indene-1-acetic acid hydrazide, indene-1- glyoxylamide, carbazole, tetrahydrocarbazole, pyrazole, phenyl
  • acid linker refers to a divalent linking group of the lH-indole-3-glyoxylamide compounds is symbolized as, ⁇ (L a )-, which has the function of joining the 4 or 5 position of the indole nucleus to an acidic group in the general relationship:
  • acid linker length refers to the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(L )- that connects the 4 or 5 position of the indole nucleus with the acidic group .
  • the method of the invention includes a method for treatment of an animal afflicted with renal dysfunction.
  • This method includes administering to said animal a therapeutically effective amount of a lH-indole-3- glyoxylamide represented by the formula (I) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
  • R ⁇ - is selected from the group consisting of -C7-C20 alkyl ,
  • RIO is selected from the group consisting of halo, c l ⁇ c 10 alkyl, C ⁇ _-C ⁇ _o alkoxy, -S- (C -C ⁇ alkyl) and halo (C -C_o) alkyl, and t is an integer from 0 to 5 both inclusive;
  • R2 is selected from the group consisting of hydrogen, halo, cyclopropyl, methyl, ethyl, and propyl;
  • R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent and the group, - (L a ) - (acidic group) ; where, at least one of R 4 and R 5 is the group, - (L ) - (acidic group) and wherein the (acidic group) is selected from the group consisting of -C0 2 H, -S0 3 H, or -P(0) (0H) 2 ; where,
  • -(L a )- is an acid linker with the proviso that; the acid linker group, -(L a )-, for R is selected from the group consisting of
  • R 103 is a non-interfering substituent
  • the acid linker, -(L a )-, for R5 is selected from the group consisting of
  • R 84 and R 85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 arylkyl, carboxy, carbalkoxy, and halo and, R 6 and R 7 are each independently selected from hydrogen and non-interfering substituents, where non- interfering substituents are selected from the group consisting of Ci-C ⁇ alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C7-C12 arylenalkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3- C ⁇ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C ⁇ C ⁇ alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alky
  • the method of the invention also includes treatment of an animal afflicted by renal dysfunction.
  • This method includes administering to said animal a therapeutically effective amount of a 9H-carbazole compound represented by the formula (II) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
  • ⁇ is selected from the group consisting of -Cy-C2( alkyl,
  • R-O is selected from the group consisting of halo, c l ⁇ c 10 alkyl, C ⁇ -CiQ alkoxy, -S-(C -C ⁇ o alkyl) and halo(C]_-C ⁇ o) alkyl, and t is an integer from 0 to 5 both inclusive; where R 31 , R 32 , R 3 , R 3 ⁇ -, R 32 -, R33 ' , R34 and R 34 . are independently selected from the group consisting of hydrogen, CONR 101 R 102 , alkyl, alkylaryl, aryl, alkylheteroaryl, haloalkyl, alkylCONR 103 ! 102 , a non- interfering substituent and the group, - (L a ) - (acidic group) ⁇ where - (L a ) - is an acid linker selected from the group consisting of
  • R 84 and R 85 are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, aryl, Ci- Cio alkaryl, C ⁇ -C 10 aralkyl, carboxy, carbalkoxy, and halo; and n is 1 or 2 and, where the (acidic group) is selected from the group consisting of -C0 2 H, -S0 3 H, -CO 2 NR 101 R 102 and -P(0)(0H) 2 and, where R 101 and R 102 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and haloalkyl and, where non-interfering substituents are selected from the group consisting of Ci-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C ⁇ alkynyl, C7-C12 arylalkyl, C7-C12 alkylaryl, C3-C8 cycloalkyl, C3-C8 cycloalkyl, pheny
  • the method of the invention also includes treatment of an animal afflicted with renal dysfunction.
  • This method includes administering to said animal in need of such treatment, a therapeutically effective amount of a lH-indole-3-glyoxylamide compound or a 9H-carbazole or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (A) through (AL) :
  • the invention is a method for treatment of an animal afflicted with renal dysfunction. This method includes administering to said animal in need of such treatment a therapeutically effective amount of a composition selected from the group comprising:
  • R is independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl.
  • R! is selected from the group consisting of -C7-C20 alkyl ,
  • R O is selected from the group consisting of halo, alkyl, C -C g alkoxy, -S-(C ⁇ -C ⁇ o alkyl) and halo (C]_-C o) alkyl, and t is an integer from 0 to 5 both inclusive;
  • R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C]_-C2 alkyl), -S- (C ⁇ -C2 alkyl), aryl, aryloxy and HET;
  • R4 is selected from the group consisting of -CO2H,
  • R5 , R6 and R 7 are each independently selected from the group consisting of hydrogen, (C1-C ) alkyl, (C]_-
  • R ⁇ is (C ⁇ -Cg) alkyl, aryl or HET; with SO2CI2 to form a compound of formula IX
  • alkylating agent of the formula XCH2R 4a where X is a leaving group and R 4 is -CO2R 4 ,
  • R 4 -* 3 is an acid protecting group to form a compound of formula III
  • the synthesis methodology for making the 1H- indole-3-glyoxylamide SPLA2 inhibitor starting material may ' be by any suitable means available to one skilled in the chemical arts. However, such methodology is not part of the present invention which is a method of use, specifically, a method of treating mammal afflicted with or susceptible to renal dysfunction.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of the compound represented by formula (la) , or a pharmaceutically acceptable salt or prodrug derivative thereof;
  • RX is selected from the group consisting of
  • R o is a radical independently selected from halo, C ⁇ -C ⁇ o alkyl, C ⁇ -C ⁇ o alkoxy, -S- (C ⁇ -C ⁇ o alkyl), and C -C o- haloalkyl and t is a number from 0 to 5;
  • R2 is selected from the group; halo, cyclopropyl, methyl, ethyl, and propyl;
  • R4 and R5 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group), wherein -(L a )- is an acid linker; provided, the acid linker group, -(L a )-, for R4 is selected from the group consisting of;
  • the acid linker, -(L a )-, for R5 is selected from group consisting of;
  • ⁇ 4 and Rss are each independently selected from hydrogen, C ⁇ -C ⁇ o alkyl, aryl, C ⁇ -C ⁇ o alkaryl, C ⁇ C o aralkyl, carboxy, carbalkoxy, and halo; and provided, that at least one of R4 and R5 must be the group, - (L a ) - (acidic group) and wherein the (acidic group) on the group - (L a ) - (acidic group) of R4 or R5 is selected from -C0 H, -SO3H, or -P(0)(0H) ;
  • Rg and R7 are each independently selected from hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of the following: C -Cg alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C7-CX2 aralkyl, C7-CX2 alkaryl,
  • Preferred for practicing the method of the invention are lH-indole-3-glyoxylamide compounds and all corresponding pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are useful in the method of the invention include the following:
  • Particularly useful prodrugs of the compounds of formula (I) and named compounds (A) thru (0) are the simple aromatic and aliphatic esters, such as the methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n- butyl ester, sec-butyl, tert-butyl ester, N,N- diethylglycolamido ester, and morpholino-N-ethyl ester.
  • Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No.
  • 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 for approximately 5 hours (see 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 described for the conversion of 5 to 6.
  • the - [ (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 glyoxamide 10.
  • This product is hydrolyzed using IN sodium hydroxide in methanol .
  • the final glyoxylamide, 11, is isolated either as the free carboxylic acid or as its sodium salt or in both forms.
  • the most preferred compound, [ [3- (2-Amino-l, 2- dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol-4- yl] oxy] acetic acid (as well as its sodium salt and methyl ester) useful in the practice of the method of the invention, may be prepared by the following procedure: preparation of [ [3- (2-Amino-l, 2-dioxoethyl) -2-ethyl- 1- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid, a compound represented by the formula:
  • IH-indole-3-hydrazide SPLA2 inhibitors useful in practicing the method of the invention are described in U.S. Patent No. 5,578,634; the entire disclosure of which is incorporated herein by reference.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of the compounds described as lH-indole- 3-acetic acid hydrazides represented by the formula (lb), and pharmaceutically acceptable salts, and prodrugs thereof;
  • X is oxygen or sulfur
  • R is selected from groups (i) , (ii) and (iii) where;
  • (i) is C4-C20 alkyl, C4-C20 alkenyl, C4-C20 alkynyl, C4-C20 haloalkyl, C4-C 2 cycloalkyl, or (ii) is aryl or aryl substituted by halo, - CN, -CHO, -OH, -SH, C ⁇ -C 10 alkylthio, C ⁇ -C ⁇ o alkoxy, C ⁇ -C ⁇ o alkyl, carboxyl, amino, or hydroxyamino;
  • R74 is, independently, hydrogen or C ⁇ -C ⁇ o alkyl
  • R75 is aryl or aryl ⁇ substituted by halo, -CN, -CHO, -OH, nitro, phenyl, -SH, C ⁇ -C ⁇ o alkylthio, C ⁇ -C ⁇ o alkoxy, C ⁇ -C ⁇ g alkyl, amino, hydroxyamino or a substituted or unsubstituted 5- to 8- membered heterocyclic ring;
  • R2 is halo, C -C3 alkyl, ethenyl, C -C2 alkylthio, C2 . -C2 alkoxy, -CHO, -CN; each R3 is independently hydrogen, C -C3 alkyl, or halo;
  • R4 R5 , Rg, and R7 are each independently hydrogen
  • Z is a bond, -0-, -N(C ⁇ -C ⁇ alkyl)-, -NH, or -S-;
  • Q is -CON(R 8 2R83) ⁇ -5-tetrazolyl, -SO3H,
  • R8g is independently selected from hydrogen, a metal, or C ⁇ -C ⁇ o alkyl.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of the compound represented by (lib) , and pharmaceutically acceptable salts and prodrug derivatives thereof,
  • X is oxygen or sulfur
  • R ll ⁇ s selected from groups (i) , (ii) (iii) and (iv) where; (i) is C -C20 alkyl, Cg-C20 alkenyl, C -C20 alkynyl, Cg-C20 haloalkyl, C4-C 2 cycloalkyl, or (ii) is aryl or aryl substituted by halo, nitro, -CN, -CHO, -OH, -SH, C ⁇ -C 10 alkyl, CX-CXQ alkylthio, C ⁇ -C ⁇ alkoxyl, carboxyl, amino, or hydroxyamino; or
  • (iii) is -(CH 2 ) n -(R8 ⁇ ) > or - ( NH ) -(R 8 ⁇ ), where n is 1 to 8, and Rso i group recited in (i) , and R8i is selected from a group recited in (i) or (ii) ; (iv) is
  • R87 is hydrogen or C ⁇ -C ⁇ o alkyl
  • R88 is selected from the group; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, -CN, - CHO, -OH, -SH, C ⁇ -C ⁇ o alkylthio, C ⁇ -C ⁇ o alkoxyl, phenyl, nitro, C ⁇ -C ⁇ Q alkyl, C ⁇ -C ⁇ o haloalkyl, carboxyl, amino, hydroxyamino; or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
  • R ⁇ 2 is halo, C -C2 alkylthio, or C -C2 alkoxy; each R 3 is independently hydrogen, halo, or methyl;
  • R ⁇ 4 Rl5 R-16' ano ⁇ R-17 are ea ch independently hydrogen, C ⁇ -C ⁇ Q alkyl, C ⁇ -C ⁇ o alkenyl, C ⁇ -C ⁇ o alkynyl, C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R 4 R15, Rl6 ⁇ - and R 7, combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring; or C ⁇ -C ⁇ o haloalkyl, C ⁇ C o alkoxy, C ⁇ -C g haloalkoxy, C4-C8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl,
  • Z is a bond, -0-, -N(C ⁇ -C ⁇ o alkyl)-, -NH-, or -S-;
  • Q is -CON(R 82 R83) , -5-tetrazolyl, -SO3H, 0
  • Rgg is independently selected from hydrogen, a metal, or C ⁇ -C ⁇ g alkyl, and Rgg is selected from hydrogen or C ⁇ -C ⁇ g alkyl.
  • X is oxygen or sulfur; each R is independently hydrogen, or C -C3 alkyl;
  • R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non- interfering substituents;
  • (c) is the group -(L)-R8 ⁇ ; where, - (L) - is a divalent linking group of 1 to 12 atoms and where Rgo is a group selected from (a) or (b) ; R2 is hydrogen, halo, C -C3 alkyl, C3-C4 cycloalkyl,
  • Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, -(L a )-
  • R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • lH-indole-1-hydrazide compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows: lH-indole-1-hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; is represented by the formula (lie) ;
  • Each R is independently hydrogen, or C -C3 alkyl
  • R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non- interfering substituent;
  • (c) is the group - (h) -RQ Q ; where, -(L)- is a divalent linking group of 1 to 12 atoms and where RQ Q is a group selected from (a) or (b) ; R2 is hydrogen, halo, C ⁇ -C3 alkyl, C3-C4 cycloalkyl,
  • Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) -
  • R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • Indolizine SPLA2 inhibitors and their method of preparation are described in US Patent Application Serial No. 08/765566, filed July 20, 1995 (titled, "Synovial Phospholipase A2 Inhibitor Compounds Having an Indolizine Type Nucleus, Parmaceutical Formulations Containing Said- compounds, and Therapeutic Methods of Using said Compounds"), the entire disclosure of which is incorporated herein by reference; and also in European Patent Publication No. 0772596, published May 14, 1997.
  • the lH-indole-1-functional compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; is represented by the formula (Id);
  • X is oxygen or sulfur; each R is independently hydrogen, C -C3 alkyl, or halo;
  • R ⁇ 3 is selected from groups (a) , (b) and (c) where;
  • (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non- interfering substituents;
  • (c) is the group -(L)-Rg Q .; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R Q Q is a group selected from (a) or (b); R ⁇ 2 is hydrogen, halo, C -C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (C -C2 alkyl), -S- (C ⁇ C2 alkyl) , or a non-interfering substituent having a total of 1 to 3 atoms other than hydroge ,-
  • R ⁇ 7 and R 8 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group), wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R 7 and R ⁇ must be the group, - (L a ) -
  • R ⁇ 5 and R g are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows : an indolizine-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof where said compound is represented by the formula (lid) ;
  • lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows : an indolizine-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (Hid) ;
  • an indolizine-3-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof wherein said compound is represented by the formula (IVd) , as set out below: wherein;
  • X is selected from oxygen or sulfur; each R3 is independently hydrogen, C -C3 alkyl, or halo ;
  • R is selected from groups (a) , (b) and (c) where;
  • (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or (c) is the group -(Lj-Rgo; where, - (L) - is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b) ; R2 is hydrogen, halo, C ⁇ -C3 alkyl, C3-C4 cycloalkyl,
  • R5 and Rg are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group) .
  • -(L a )- is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R5 and Rg must be the group, - (L a ) - (acidic group);
  • R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows : an indolizine-3-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (vid) , as set out below:
  • Patent Application 08/776618 filed July 20 1995, (titled, Synovial Phospholipase A2 Inhibitor Compounds having an Indene Type Nucleus, Pharmaceutical Formulations Containing said Compounds, and Therapeutic Methods of Using Said Compounds"), the entire disclosure of which is incorporated herein by reference, are useful in practicing the method of the invention.
  • indene-1-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof is is represented by the formula (If) ;
  • X is oxygen or sulfur; each R is independently hydrogen, C ⁇ -C3 alkyl, or halo ;
  • R3 is selected from groups (a) , (b) and (c) where;
  • (a) is C7-C2O' alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non- interfering substituents;
  • (c) is the group -(D-Rso where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rso is a group selected from (a) or (b) ; R2 is hydrogen, halo, C ⁇ -C3 alkyl, C3-C4 cycloalkyl,
  • Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) -
  • Suitable indene compounds also include the following: an indene-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (iif) ;
  • X is oxygen or sulfur; each Rx is independently hydrogen, C ⁇ -C alkyl, or halo;
  • R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non- interfering substituents;
  • (c) is the group -(L)-R8o; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R Q Q is a group selected from (a) or (b) ; R2 is hydrogen, halo, C ⁇ -C3 alkyl, C3-C4 cycloalkyl,
  • Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, -(L a )-
  • -(L a )- is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (L a ) - (acidic group) ; and R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents.
  • Suitable indene compounds for use in the method of the invention also include the following: an indene-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (iiif) ;
  • X is oxygen or sulfur
  • R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C 7 -C o alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non- interfering substituents;
  • (c) is the group -(Lj-Rgg; where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rgo is a group selected from (a) or (b) ; R2 is hydrogen, halo, C ⁇ -C3 alkyl, C3-C4 cycloalkyl,
  • Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group), wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (L a ) - (acidic group);
  • R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • Carbazole and tetrahydrocarbazole SPLA2 inhibitors and methods of making these compounds are set out in United States Patent Application SN 09/063066 filed April 21, 1998 (titled, "Substituted Carbazoles and 1, 2 , 3 , 4-Tetrahydrocarbazoles” ) , the entire disclosure of which is incorporated herein by reference.
  • the method of the invention includes treatment of a mammal with these compounds .
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount carbazole or tetrahydrocarbazole represented by the following: a compound of the formula (Ie)
  • a is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position; one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at the 1-, 2-, or 3-position, or a 6- membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position;
  • R-20 is selected from groups (a) , (b) and (c) where; (a) is - (C5-C20) alkyl, - (C5-C20) alkenyl,
  • (c) is the group - (L) -R ⁇ O ; where, -(L)- is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in -(L)- are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only,
  • R ⁇ O is a group selected from (a) or (b) ;
  • R21 is a non-interfering substituent;
  • RI' is -NHNH , -NH or -CONH ;
  • R2 ' is selected from the group consisting of -OH, and -0(CH 2 ) t r5' where
  • R 5 ' is H, -CN, -NH2, -CONH 2 -CONR 9 R 10 -NHS0 R 15 ;
  • R 15 is - (C ⁇ -Cg) alkyl or -CF 3 ; phenyl or phenyl substituted with -CO2H or -CO2 (CX-C4) alkyl; and - (L a ) - (acidic group), wherein -(L a )- is an acid linker having an acid linker length of 1 to 7 and t is 1-5;
  • R3 ' is selected from non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable race ate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof; provided that; when R ⁇ ' is H, R ⁇ O ⁇ s benzyl and m is 1 or 2; R ⁇ ' cannot be -0(CH2) h; and
  • the heteroatom of Z is selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the
  • Z is cyclohexenyl, or phenyl
  • R ⁇ l is a non-interfering substituent
  • R 1 is -NHNH 2 or -NH 2 ;
  • R2 is selected from the group consisting of -OH and
  • R 5 is H, -C0 H, -CONH 2 , -C0 (C ⁇ -C 4 alkyl);
  • R 8 is H, -C0NH 2 , -NR 9 R 10 , -CN or phenyl where R 9 and R ⁇ O ar e independently - (C ⁇ C4) alkyl or -phenyl (C -C4) alkyl and n is 1 to 8;
  • R 4 is H, - (C5-C14) alkyl, - (C3-CX4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C ⁇ -Cg) alkyl, halo, -CF 3 , -OCF3, -(C1-C4) alkoxy, -CN, - (0 ⁇ -
  • Preferred specific compounds including all salts and prodrug derivatives thereof, for practicing the method of the invention are as follows: 9-benzyl-5 , 7-dimethoxy-l, 2,3, 4-tetrahydrocarbazole-4- carboxylic acid hydrazide; 9-benzyl-5 , 7-dimethoxy-l, 2,3, 4-tetrahydrocarbazole-4- carboxamide ; [9-benzyl-4-carbamoyl-7-methoxy-l, 2,3,4- tetrahydrocarbazol-5-yl] oxyacetic acid sodium salt; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl] oxyacetic acid;
  • R 1 is -NHNH , or -NH 2 ;
  • R-2 is selected from the group consisting of -OH and - 0(CH 2 ) m r 5 where
  • R 6 and R 7 are H, -C0 H, -C0 (C1-C4 alkyl); ,where R 6 and
  • R ⁇ are each independently -OH or -O (C -C4)alkyl; -S0 3 H, -S0 3 (C ⁇ -C alkyl), tetrazolyl, -CN, -NH 2 '
  • -NHS0 2 R 15 ; -C0NHS0 R 15 , where R 15 is - (C ⁇ -Cg) alkyl or -CF3 , phenyl or phenyl substituted with -C02H or -CO2 (CX-C4) alkyl where m is 1-3;
  • R3 is H, -O (C ⁇ -C4) alkyl, halo, - (C ⁇ -Cg) alkyl, phenyl, - (CX-C4) alkylphenyl; phenyl substituted with
  • R 4 is H, - (C5-CX4) alkyl, - (C3-C 4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C ⁇ -Cg) alkyl, halo, -CF 3 , -OCF3 , -(CX-C ) alkoxy, -CN, - (C ⁇
  • 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 derived from acidic groups 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.
  • Specific preferred prodrugs are ester prodrugs inclusive of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl, tert-butyl ester, N,N-diethylglycolamido ester, and morpholino-N-ethyl ester.
  • Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No.
  • Carbazole and tetrahydrocarbazole SPLA2 inhibitor compounds useful for practicing the method of the invention may be made by the following general methods : the compounds of formula Ie where Z is cyclohexene are prepared according to the following reaction Schemes Ig(a)and (c) .
  • R 1 is -NH 2
  • R 3 (a) is H, -O (C -C4) alkyl, halo, - (C ⁇ Cg ) alkyl , phenyl , - (C ⁇ -C ) alkylphenyl ; phenyl substituted with - (C ⁇ -Cg) alkyl, halo, or -CF3 ; - CH OSi(C ⁇ -Cg) alkyl, furyl, thiophenyl, - (C ⁇ Cg) hydroxyalkyl, - (C ⁇ _Cg) alkoxy (C ⁇ -Cg) alkyl, - (Cx- Cg) alkoxy (C ⁇ _Cg) alkenyl; or -(CH2) n r 8 where R 8 is H,
  • R 9" and R 10 are independently hydrogen, -CF3 , phenyl, - (C ⁇ -C4) alkyl, - (CX-C4) alkylphenyl or -phenyl (C ⁇ -C4) alkyl and n is 1 to 8; when R 1 is -NHNH2 r R 3 (a) is H, -0 (CX-C4) alkyl, halo,
  • R 2 ( a ) ⁇ s -0CH3 or -OH.
  • An appropriately substituted nitrobenzene (1) can be reduced to the aniline (2) by treatment with a reducing agent, such as hydrogen in the presence of Pd/C, preferably at room temperature.
  • a reducing agent such as hydrogen in the presence of Pd/C, preferably at room temperature.
  • Compound (2) is N-alkylated at temperatures of from about 0 to 20 °C using an alkylating agent such as an appropriately substituted aldehyde and sodium cyanoborohydride to form (3).
  • an appropriately substituted benzyl halide may be used for the first alkylation step.
  • the resulting intermediate is further N-alkylated by treatment with 2-carbethoxy- 6-bromocyclohexanone, preferably at temperatures of about 80 °C to yield (4) or by treatment with potassium hexamethyldisilazide and the bromoketoester .
  • the product (4) is cyclized to the tetrahydrocarbazole (5) by refluxing with zncl2 in benzene for from about 1 to 2 days, preferably at 80 C (see Julia, M. ; Lenzi, J. Preparation d'acides tetrahydro-1, 2, 3 , 4-carbazole-l ou -4.
  • Compound (5) is converted to the hydrazide (6) by treatment with hydrazine at temperatures of about 100 °C, or to the amide (7) by reacting with methylchloroaluminum amide in benzene (see Levin, J.I.; Turos, E.; Weinreb, S.M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn . Comm. , 1982, 12, 989-993) .
  • (7) may be produced by treatment of (6) with Raney nickel active catalyst.
  • Compounds (6) and (7) may be dealkylated, preferably at 0 °C to room temperature, with a dealkylating agent, such as boron tribromide or sodium thioethoxide, to give compound (7) where R2 ( a ) ⁇ s _OH, which may then be further converted to compound (9) , by realkylating with a base, such as sodium hydride, and an alkylating agent, such as Br(CH2)m r ⁇ ' where R ⁇ is the carboxylate or phosphonic diester or nitrile as defined above. Conversion of R ⁇ to the carboxylic acid may be accomplished by treatment with an aqueous base.
  • a dealkylating agent such as boron tribromide or sodium thioethoxide
  • R2 is nitrile
  • conversion to the tetrazole may be achieved by reacting with tri-butyl tin azide or conversion to the carboxamide may be achieved by reacting with basic hydrogen peroxide.
  • R ⁇ is the phosphonic diester
  • conversion to the acid may be achieved by reacting with a dealkylating agent such as trimethylsilyl bromide.
  • the monoester may be accomplished by reacting the diester with an aqueous base.
  • R2 and R 3 are both methoxy, selective demethylation can be achieved by treating with sodium ethanethiolate in dimethylformamide at 100 °C.
  • R a is as defined in Scheme 1, above,
  • the aniline (2) is N-alkylated with 2-carbethoxy-6- bromoeyelohexanone in dimethyl formamide in the presence of sodium bicarbonate for 8-24 hours at 50 °C.
  • Preferred protecting, groups include methyl, carbonate, and silyl groups, such as t-butyldimethylsilyl .
  • the reaction product (4') is cyclized to (5') using the zncl2 in benzene conditions described in Scheme 1(a), above.
  • N- alkylation of (5') to yield (5) is accomplished by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours .
  • carbazole (5) is hydrolyzed to the carboxylic acid (10) by treatment with an aqueous base, preferably at room temperature to about 100 °C .
  • the intermediate is then converted to an acid chloride utilizing, for example, oxalyl chloride and dimethylformamide, and then further reacted with a lithium salt of (S) or (R) -4-alkyl-2-oxazolidine at a temperature of about -75 °C, to give (11a) and (lib), which are separable by chromatography.
  • the diastereomers are converted to the corresponding enantiomeric benzyl esters (12) by brief treatment at temperatures of about 0°C to room temperature with lithium benzyl oxide (see Evans, D.A. ; Ennis, M.D.; Mathre, D.J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of alpha- substituted carboxylic acid derivatives J. Am. Chem. Soc . , 1982, 104, 1737-1738) .
  • esters (12) are then converted to (7) preferably by treatment with methylchloroalummum amide (Ref 2, above) or, alternately, by hydrogenation using, for example, hydrogen and palladium on carbon, as described above, to make the acid and then reacting with an acyl azide, such as diphenylphosphoryl azide followed by treatment with ammonia.
  • an acyl azide such as diphenylphosphoryl azide followed by treatment with ammonia.
  • oxidation as described above may result in de-alkylation of the nitrogen.
  • R 3 is substituted at the 8- position with methyl
  • oxidation results in dealkylation of the nitrogen which may be realkylated by treatment with sodium hydride and the appropriate alkyl halide as described in Scheme 1(a) above to prepare the deired product (14) .
  • the reactions are conducted at temperatures from about 0 to 100 °C . Preferably at ambient temperature, and are substantially complete in about 1 to 48 hours depending on conditions.
  • the aniline (25) and dione (15) are condensed under dehydrating conditions, for example, using the general procedure of Iida, et al . , (Ref 5), with or without a noninterfering solvent, such as toluene, benzene, or methylene chloride, under dehydrating conditions at a temperature about 10 to 150 °C .
  • a noninterfering solvent such as toluene, benzene, or methylene chloride
  • the water formed in the process can be removed by distillation, azetropic removal via a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, and the like.
  • the process can be performed with or without a catalytic amount of an acid, such a p-toluenesulfonic acid or methanesulfonic acid.
  • an acid such as a p-toluenesulfonic acid or methanesulfonic acid.
  • suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride, and acetic acid.
  • solvents examples include tetrahydrofuran, ethyl acetate, methanol, ethanol,
  • the condensation of the instant process is preferably carried out neat, at a temperature about 100 to 150 °C with the resultant water removed by distillation via a stream of inert gas, such as, nitrogen or argon.
  • inert gas such as, nitrogen or argon.
  • the reaction is substantially complete in about 30 minutes to 24 hours.
  • Intermediate (26) may then be readily cyclized in the presence of a palladium catalyst, such as Pd(oac)2 or Pd(ppt-3)4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o-tolylphosphine , or tricyclohexylphosphine, and the like, a base, such as, sodium bicarbonate, triethylamine, or diisopropylethylamine, in a noninterfering solvent, such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200°C to form (19) .
  • a palladium catalyst such as Pd(oac)2 or Pd(ppt-3)4 and the like
  • a phosphine preferably a trialkyl- or triarylphosphine, such as triphenylphosphin
  • solvents examples include tetrahydrofuran, benzene, dimethylsulfoxide, or dimethylformamide .
  • Examples of other suitable palladium catalysts include Pd(pph 3 )Cl2, Pd(OCOCF 3 ) , [ (CH CgH4) 3 P] pdcl 2 , [(CH 3 CH2)3P]2Pdcl 2 , [ (C 6 H ⁇ ) 3 P] 2 pdcl 2 , and [(CgH5)3P]2Pdbr 2 .
  • phosphines examples include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2- bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1,4- bis (diphenylphosphino) butane .
  • Examples of other suitable bases include tripropyl amine, 2, 2 , 6, 6-tetramethylpiperidine, 1,5- diazabicyclo [2.2.2] octane (DABCO) , 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5- diazabicyclo [4.3.0]non-5-ene, (DBN) sodium carbonate, potassium carbonate, and potassium bicarbonate.
  • DABCO 1,8- diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5- diazabicyclo [4.3.0]non-5-ene
  • the cyclization of the instant process is preferably carried out with palladium (II) acetate as catalyst in the presence of either triphenylphosphine, tri-o- tolylphosphine, 1, 3-bis (diphenylphosphino) propane, or tricyclohexylphosphine in acetonitrile as solvent and triethylamine as base at a temperature about 50 to 150 °C .
  • the reaction is substantially complete in about 1 hour to 14 days.
  • a preferred process for cyclization consists of the reaction of intermediate (26) with a palladacycle catalyst such as trans-di ( ⁇ -acetato) -bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) in a solvent such as dimethylacetamide (DMAC) at 120-140 °C in the presence of a base such as sodium acetate.
  • a palladacycle catalyst such as trans-di ( ⁇ -acetato) -bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) in a solvent such as dimethylacetamide (DMAC) at 120-140 °C in the presence of a base such as sodium acetate.
  • Intermediate (19) may be alkylated with an alkylating agent XCH2R , where X is halo in the presence of a base to form (20) .
  • Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N- benzyltrimethylammonium hydroxide) .
  • the reaction may or may not be carried out in the presence of a crown ether. Potassium carbonate and Triton B are preferred.
  • the amount of alkylating agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material .
  • a catalytic amount of an iodide such as sodium iodide or lithium iodide may or may not be added to the reaction mixture.
  • the reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile.
  • Suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether.
  • the reaction is conducted at temperatures from about
  • phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed.
  • Intermediate (20) May by dehydrogenated by oxidation with 2 , 3-dichloro-5 , 6-dicyano-l, 4-benzoquinone in a noninterfering solvent to form (21) .
  • Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, diethyl ether, methyl ethyl ketone, and t-butyl methyl ether. Toluene, benzene, dioxane, and tetrahydrofuran are preferred solvents.
  • the reaction is carried out at a temperature about 0 to 120 °C. Temperatures from 50 to 120 °C are preferred.
  • the reaction is substantially complete in about 1 to 48 hours depending on conditions .
  • Intermediate 1 (21) may be animated with ammonia in the presence of a noninterfering solvent to form a (22) .
  • Ammonia may be in the form of ammonia gas or an ammonium salt, such as ammonium hydroxide, ammonium acetate, ammonium trifluoroacetate, ammonium chloride, and the like.
  • Suitable solvents include ethanol, methanol, propanol, butanol, tetrahydrofuran, dioxane, and water. A mixture of concentrated aqueous ammonium hydroxide and tetrahydrofuran or methanol is preferred for the instant process.
  • the reaction is carried out at a temperature about 20 to 100 °C . Temperatures from 50 to 60 °C are preferred.
  • the reaction is substantially complete in about 1 to 48 hours depending on conditions.
  • Alkylation of (22) is achieved by treatment with an alkylating agent of the formula XCH2R 9 where X is halo and R 70 is -C0 R 71 , -SO3R 71 , -P (O) (OR 71 ) 2 , or -
  • Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N-benzyltrimethylammonium hydroxide) .
  • the reaction may or may not be carried out in the presence of a crown ether . Cesium carbonate and Triton B are preferred.
  • the amount of alkylating agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material .
  • the reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile.
  • Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether.
  • the reaction is conducted at temperatures from about -10 to 100 °C . Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions.
  • a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed.
  • Intermediate (23) may be optionally hydrolyzed with a base or acid to form desired product (24) and optionally salified.
  • Hydrolysis of (23) is achieved using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous potassium carbonate, aqueous sodium carbonate, aqueous lithium carbonate, aqueous potassium bicarbonate, aqueous sodium bicarbonate, aqueous lithium bicarbonate, preferably sodium hydroxide and a lower alcohol solvent, such as, methanol, ethanol, isopropanol, and the like.
  • suitable solvents include acetone, tetrahydrofuran, and dioxane .
  • the acid protecting group may be removed by organic and inorganic acids, such as trifluoroacetic acid and hydrochloric acid with or without a noninterferring solvent.
  • Suitable solvents include methylene chloride, tetrahydrofuran, dioxane, and acetone.
  • the t-butyl esters are preferably removed by neat trifluoroacetic acid.
  • the reaction is conducted at temperatures from about -10 to 100°C. Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions .
  • the preferred alkyl halide is methyl iodide.
  • the reaction is conducted at temperatures from about 0 to 100°C. Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions.
  • the starting material (16) may be prepared by condensation with an alcohol HOPG, where PG is an acid protecting group, in the presence of a dehydrating catalyst such as, dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole.
  • a dehydrating catalyst such as, dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole.
  • DCC dicyclohexylcarbodiimide
  • Jpn Jpn.
  • R is as defined in Scheme iiig(b) .
  • X is halo
  • a palladium catalyst such as Pd(Pl-3P)4
  • a base such as sodium bicarbonate
  • Compound (28) is converted to the carbazole product (29) by treatment with a trialkyl or triaryl phosphite or phosphine, such as, triethylphosphite or triphenyl phosphine, according to the general procedure of Cadogan, et al . , J. Chem. Soc, 4831 (1965).
  • a trialkyl or triaryl phosphite or phosphine such as, triethylphosphite or triphenyl phosphine
  • Compound (29) is N-alkylated with an appropriately substituted alkyl or aryl halide XCH2R ⁇ in the presence of a base, such as sodium hydride or potassium carbonate, in a noninterfering solvent, such as toluene, dimethylformamide, or dimethylsulfoxide to afford carbazole (30) .
  • a base such as sodium hydride or potassium carbonate
  • a noninterfering solvent such as toluene, dimethylformamide, or dimethylsulfoxide
  • Compound (30) is converted to the corresponding amide (22) by treatment with boron tribromide or sodium thioethoxide, followed by ammonia or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, or with ethylchloroaluminum amide in an inert solvent, such as toluene, at a temperature between 0 to 110 °C.
  • an inert solvent such as water or alcohol
  • ethylchloroaluminum amide in an inert solvent, such as toluene
  • the aniline is treated with sulfuric acid and sodium nitrite, followed by sodium azide to form an intermediate azide which is cyclized to carbazole (29) by heating in an inert sovent, such as toluene.
  • Compound (29) is converted to carbazole product (24) as described previously in Schemes iiig(b) and iiig(c).
  • reaction is conducted under inert atmosphere such as nitrogen, at room temperature.
  • Sulfonylation may be achieved with an appropriate acylating agent in the presence of an acid scavenger such as triethyl amine.
  • intermediate (50) prepared as described in Scheme 1(a) above, is first activated with an activating agent such as carbonyl diimidazole.
  • the reaction is preferably run in an aprotic polar or non-polar solvent such as tetrahydrofuran.
  • Acylation with the activated intermediate is accomplished by reacting with H2NSOR in the presence of a base, preferably diazabicycloundecene .
  • PG is an acid protecting group
  • R 22 is (C ⁇ -Cg) alkoxy (C ⁇ -Cg) alkyl is (Cl-Cg) alkoxy
  • Starting material (20) is O-alkylated with an alkyl halide or alkenyl halide, using a base such as NaH, in an aprotic polar solvent preferably anhydrous DMF, at ambient temperature under a nitrogen atmosphere.
  • a base such as NaH
  • an aprotic polar solvent preferably anhydrous DMF
  • the process of aromatization from a cyclohexenone functionality to a phenol functionality can be performed by treating the tetrahydrocabazole . intermediate (60) with a base such as NaH in the presence of methyl benzenesulfinate in an anhydrous solvent, such as 1, 4-dioxane or DMF, to form the ketosulfoxide derivative.
  • the ketosulfoxide derivative (60) Upon heating at about 100 °C for 1-2 hours, the ketosulfoxide derivative (60) is converted to the phenol derivative (61). Conversion of the ester (61) to the amide (62) can be achieved by treating a solution of (61) in an aprotic polar solvent such as tetrahydrofuran with ammonia gas . Phenolic 0- alkylation of (62) with, for example, methyl bromoacetate can be carried out in anhydrous DMF at ambient temperature using CS2CO3 or K2CO3 as a base to form (63) . Desired product (64) can be derived from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H 2 0/CH 3 OH/THF solution at 50 °C for 1-2 hours .
  • R 22 is - (C ⁇ -Cg) alkoxy (C ⁇ -Cg) alkenyl
  • hydrogenation of the double bond can be performed by treating (63) in THF using Pt ⁇ 2 as a catalysis under a hydrogen atmosphere. Desired product can then be derived as described above in Scheme I ⁇ I(g) from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H2O/CH3OH/THF solution at 50°C for 1-2 hours.
  • pyrazole s L .2 inhibitors which are described (together with the method of making) in US Patent Application No. 08/984261, filed December 3, 1997, the entire disclosure of which is incorporated herein by reference.
  • Suitable pyrazole compounds are represented by formula (Ih)
  • R 1 is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin- 2-yl, pyridin-2-yl substituted at the 4- position with - (C ⁇ -C4) alkyl, (C ⁇ -C4) alkoxyl, -
  • R 2 is phenyl; phenyl substituted with 1 to 3 substituents selected from the group consisting of -(C ⁇ -C4) alkyl, -CN, halo, -N0 2 , C0 (C ⁇ C4) alkyl and -CF3 ; naphthyl; thiophene or thiophene substituted with 1 to 3 halo groups;
  • R 3 is hydrogen; phenyl; phenyl (C2 ⁇ Cg) alkenyl; pyridyl; naphthyl; quinolinyl; (C ⁇ -C4 ) alkylthiazolyl ; Phenyl substituted with 1 to 2 substituents selected from the group consisting of -(CX-C4) alkyl, -CN, -CONH , -N0 , -CF3 , halo,
  • R ⁇ is cyclopentyl, cyclohexenyl, or phenyl substituted with halo or (CX-C4) alkoxy;
  • pyrazole type SPLA2 inhibitors as follows: a pyrazole compound of formula (I), supra, wherein:
  • R 1 is pyridine-2-yl or pyridine-2-yl substituted at the 4-position with - (C ⁇ -C4) alkyl, (C ⁇ -C4) alkoxy, -CN or
  • R 2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of - (CX-C4) alkyl, -CN, halo, -NO2, CO2 (CX-C4) alkyl and -CF3 ; and
  • R3 is phenyl; phenyl (C2 ⁇ Cg) alkenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of - (C -C4) alkyl, -CN, -CONH2 , -NO2 - CF3, halo, (C -C4) alkoxy, CO2 (CX-C4) alkyl, phenoxy and
  • R ⁇ is - (C -C4) alkyl or halo phenyl; phenyl substituted with one substituent selected from the group consisting of -0(CH2)pr ⁇ where p is 1 to 3 and R 5 is -CN, -CO2H, -CONH2 or tetrazolyl, phenyl and - OR6 where R ⁇ is cyclopentyl, cyclohexenyl or phenyl substituted with halo or (C ⁇ -C4) alkoxy; or phenyl substituted with two substituents which when taken together with the phenyl ring to which they are attached form a methylenedioxy ring.
  • pyrazole type SPLA2 inhibitors useful in the method of the invention are as follows : Compounds selected from the group consisting of 3- (2- chloro-6-methylphenylsulfonylamino) -4- (2- (4- acetamido) pyridyl) -5- (3- (4-fluorophenoxy) benzylthio) -
  • Phenyl glyoxamide SPLA2 inhibitors (and the method of making them) are described in U.S. Patent Application Serial No. 08/979446, filed November 24, 1997 (titled, Phenyl Glyoxamides as SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount a phenyl glyoxamide type SPLA2 inhibitors useful in the method of the invention are as follows: a compound of the formula ( Ii )
  • X is -O- or -(CH2) m -/ where m is 0 or 1;
  • Y is -C0 2 -, -PO3-, -SO3-;
  • R is independently -H or - (C ⁇ -C4) alkyl
  • Ri and R 2 are each independently -H, halo or - (C1-C4) lkyl ; R 3 and R ⁇ are each independently -H, - (C -C4) alkyl,
  • a specific suitable phenyl glyoxamide type SPLA2 inhibitors is 2- (4-carboxybut-l-yl-oxy) -4- (3- phenylphenoxy) phenylglyoxamide .
  • Pyrrole SPLA2 inhibitors and methods of making them are disclosed in U.S. Patent Applicaton Serial No. 08/985518 filed December 5, 1997 (titled, "Pyrroles as SPLA2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount a pyrrole SPLA2 inhibitors useful in the method of the invention as follows : a compound of the formula (Ij)
  • R 1 is hydrogen, (C ⁇ -C4) alkyl, phenyl or phenyl substituted with one or two substituents selected from the group consisting of - (CX-C4) alkyl, (CX-C4) alkoxy, phenyl (C -C4) alkyl, (C -C4) alkylthio, halo and phenyl;
  • R 2 is hydrogen, - (C ⁇ -C4) alkyl, halo, (C ⁇ -C4) alkoxy or (CX-C4) alkylthio;
  • R 5 is - H2 or -NHNH ;
  • R6 and R 7 are each hydrogen or when one of R6 and R 7 is hydrogen, the other is - (C ⁇ -C4) alkyl, -(CH2) n rlO where
  • X is R 8 (C ⁇ -Cg) alkyl; R 8 (C -Cg) alkenyl or phenyl substituted at the ortho position with R 8 where R 8 is
  • R 10 is -C0 R 1:L , -P ⁇ 3(R 1:L )2, -P0 (R 1:L ) or
  • -SO3R I, RH and n is 1 to 4 as defined above, and additionally substituted with one or two substituents selected from the group consisting of hydrogen, - (C1-C4) alkyl, halo, (CX-C4) alkoxy, or two substituents which, when taken together with the phenyl ring to which they are attached, form a naphthyl group; and R9 is hydrogen or methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • Preferred pyrrole SPLA2 inhibitors useful in the method of the invention are compounds of formula Ij wherein;
  • R 1 is phenyl
  • R 2 is methyl or ethyl
  • R 5 is -NH ;
  • R6 and R 7 are each hydrogen; X is RS (C ⁇ -Cg) alkyl or phenyl substituted at the ortho position with R 8 where R 8 is -C0 2 R 1:L ; and R° is methyl or ethyl .
  • a specific suitable pyrrole SPLA2 inhibitors useful in the method of the invention is 2- [l-benzyl-2, 5- dimethyl-4- (2-carboxyphenylmethyl) pyrrol-3-yl] glyoxamide .
  • K) Naphthyl glyoxamide SPL 2 inhibitors and methods of making them are described in U.S. Patent Application Serial No. 09/091079, filed December 9, 1966. (titled, "Naphthyl Glyoxamides as SPLA2 Inhibitors”), the entire disclosure of which is incorporated herein by reference.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount a naphthyl glyoxamide SPLA2 inhibitors useful in the method of the invention are as follows -. a naphthyl glyoxamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula Ik
  • R 1 and R 2 are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R 1 or R 2 must be hydrogen;
  • X is -CH2- or -0-
  • Y is (CH2) n z where n is a number from 1-3 and Z is an acid group selected from the group consisting of CO2H, -SO3H or -PO(OH) 2 -
  • a specific suitable naphthyl glyoxamide SPLA2 inhibitors useful in the method of the invention has the following structural formula:
  • Phenyl acetamide SPLA2 inhibitors and methods of making them are disclosed in US Patent Application 08/976858, filed November 24 1997 (titled, "Phenyl Acetamides as SPLA2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of a phenyl acetamide S LA2 inhibitor represented by formula (II) as follows:
  • R 1 is -H or -0(CH 2 ) n z;
  • R 2 is -H or -OH;
  • R 3 and R ⁇ are each independently -H, halo or
  • R5 and R ⁇ are -YR 7 and the other is -H, where Y is -0- or -CH2- and R 7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, - (CX-C4) alkyl, (C ⁇
  • Z is -CO2R, -PO3R2 or -SO3R where R is -H or - (C1-C4) alkyl; and N is 1-8; or a pharmaceutically acceptable salt, racemate or optical isomer thereof; provided that when R ⁇ is YR 7 , R 1 is hydrogen; and when R 1 , R 2 , R 3 , R ⁇ and R ⁇ are hydrogen and R ⁇ is YR 7 where Y is -O- , R 7 cannot be phenyl; and when Ri, R 2 , R 3 , R 4 and R 6 are hydrogen, R 5 is YR 7 where Y is CH2 , R 7 cannot be phenyl substituted with one methoxy or two chloro groups .
  • Preferred suitable phenyl acetamide SPLA2 inhibitors usef l in the method of the invention are as follows : compounds of formula I wherein R 2 , R 3 and R ⁇ is H, Y is oxygen or CH2 , R 7 is phenyl or phenyl substituted at the meta position with one or two substituents selected from halo, - (CX-C4) alkyl, (CX-C4) alkoxy, phenyl or phenyl substituted with halo and n is 4-5.
  • a specific suitable phenyl acetamide SPLA2 inhibitors useful in the method of the invention is 2- (4- carboxybutoxy) -4- ( 3-phenylphenoxy) phenylacetamide .
  • a naphthyl acetamide SPLA2 inhibitor is represented by formula (Im) as follows: wherein :
  • R 1 and R 2 are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R1 and R 2 must be hydrogen;
  • R 3 is hydrogen, -0(CH2) n Y, " -O ⁇ x )'n -0 n ' ( v ⁇ v) 'n n Y " where n is from 2 to 4 and Y is -CO2H, -PO3H2 or SO3H; and X is -O- or -CH2-.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of pyrrolo[l,2- a]pyrazine derivative SPLA2 inhibitors useful in the method of the invention as follows : a compound of the formula (In)
  • R 1 is a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) -(L x )-R 6 wherein L 1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s) , nitrogen atom(s) , carbon atom(s) , oxygen atom(s) , and sulfur atom(s) , and R 5 is a group selected from the groups (a) and (b) ;
  • R 2 is hydrogen atom, or a group containing 1 to 4 non-hydrogen atoms ;
  • R 3 is - (L 2 ) - (acidic group) wherein L 2 is an acid linker having an acid linker length of 1 to 5;
  • R 4 and R 5 are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent (s) , heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent (s) and;
  • R A is a group represented by the formula:
  • L 7 is a divalent linker group selected from a bond or a divalent group selected from -CH 2 -, -0-, -S-, -NH-, or -CO-
  • R 27 and R 28 are independently hydrogen atom, Cl to C3 alkyl or a halogen
  • X and Y are independently an oxygen atom or a sulfur atom
  • Z is -NH 2 or -NHNH 2 ; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
  • a preferred subclass of compounds of formula (In) are those where for Rx the divalent linking group
  • -(L ⁇ ) ⁇ is a group represented by any one of the following formulae (Ina) or (Inb) or (Inc) :
  • ⁇ is a bond or any of the divalent groups (la) or (lb) and each R is independently hydrogen, C ⁇ _g alkyl, C ⁇ _8 haloalkyl or C ⁇ _g alkoxy.
  • linking group -(L ⁇ ) ⁇ of R is an alkylene chain of 1 or 2 carbon atoms, namely, -(CH 2 ) ⁇ or -(CH 2 -CH2)--
  • Preferred SPLA2 inhibitor compounds of the invention are represented by the formula (Iln)
  • R 7 is -(CH2) m _R wherein m is an integer from
  • R ⁇ 2 is (d) a group represented by the formula :
  • a, c, e, n, q, and t are independently an integer from 0 to 2
  • R ⁇ - 3 and R ⁇ - ⁇ are independently selected from a halogen, 0 ⁇ to C ⁇ o alkyl, Cx to C ⁇ o alkyloxy, Cx to C ⁇ o alkylthio, aryl, heteroaryl, and Cx to C ⁇ haloalkyl
  • ⁇ is an oxygen atom or a sulfur atom
  • v is an integer from 0 to 2
  • ⁇ is -CH2 ⁇ or -(CH2)2 - Y i s an oxygen atom or a sulfur atom
  • b is an integer from 0 to 3
  • d is an integer from 0 to 4
  • f , p, and w are independently an integer from 0 to 5
  • r is an integer
  • R 8 is Cx to C3 alkyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, Cx to C2 haloalkyl, Cx to C3 alkyloxy, or Cx to C3 alkylthio;
  • R9 is -(L 3 )-R1 wherein L 3 is represented by the formula :
  • R 16 and R 17 are independently hydrogen atom, 0 ⁇ to C ⁇ o alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and
  • R 4 is hydrogen atom or O ⁇ to Cg alkyl, and R ⁇ 5 ⁇ s represented by the formula:
  • R-*- 8 ⁇ s hydrogen atom, a metal, or Cx to C ⁇ o alkyl, !9 is independently hydrogen atom, or O ⁇ to C ⁇ o alkyl, and t is an integer from 1 to 8;
  • R!0 and RU are independently hydrogen atom or a non-interfering substituent selected from hydrogen, Cx to
  • Cg alkyl Cx to Cg alkenyl, Cx to Cg alkynyl, C7 to C ⁇ 2 aralkyl, C7 to C ⁇ 2 alkaryl, C3 to Cg cycloalkyl, C3 to Cg cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Cx to Cg alkyloxy, C2 to Cg alkenyloxy, C2 to Cg alkynyloxy, C2 to
  • SPLA2 inhibitors of the invention are [7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, methyl ester;
  • the SPLA2 inhibitors used in the method of the invention may be administered to treat renal dysfunction by any means that produces contact of the active agent with the agent's site of action in the animal body. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents .
  • the SPLA2 inhibitors can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • Suitable formulations are those comprising a therapeutically effective amount of SPLA2 inhibitor 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 SPLA2 inhibitor ("active compound” ) in the formulation and not deleterious to the subject being treated.
  • 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 SPLA2 inhibitor 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 0.01 to about 99 weight percent of the SPLA2 inhibitor.
  • Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
  • the active compound can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, saline, dextrose solution, sterile organic solvent or a mixture of both.
  • the active compound can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. It can also be administered by inhalation in the form of a nasal spray or lung inhaler. It can also be administered topically as an ointment, cream, gel, paste, lotion, solution, spray, aerosol, liposome, or patch. Dosage forms used to administer the active compound usually contain suitable carriers, diluents, preservatives, or other excipients, as described in Remington's Pharmaceutical Sciences, Merck Publishing Company, a standard reference text in the field.
  • Gelatin capsules may be prepared containing the active compound and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets and powders . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets and powders . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance .
  • water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration contain the active compound, suitable stabilizing agents, and if necessary, buffer substances.
  • Anti-oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
  • Topical ointments, creams, gels, and pastes contain with the active compound diluents such as waxes, paraffins, starch, polyethylene glycol, silicones, bentonites, silicic acid, animal and vegetable fats, talc and zinc oxide or mixtures of these or other diluents.
  • Topical solutions and emulsions can, for example, contain with the active compound, customary diluents (with the exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent) , such as solvents, dissolving agents and emulsifiers; specific examples are water, ethanol, 2- propanol, ethyl carbonate, benzyl alcohol, propylene glycol, oils, glycerol, and fatty acid esters of sorbitol or mixtures thereof.
  • Compositions for topical dosing may also contain preservatives or anti-oxidizing agents.
  • Powders and sprays can contain along with the active compound, the usual diluents, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures of these materials. Aerosol sprays can contain the usual propellants.
  • Liposomes can be made from such materials as animal or vegetable fats which will form lipid bilayers in which the active compound can be incorporated.
  • Formulations containing compounds of the invention may be administered through the skin by an appliance such as a transdermal patch.
  • Patches can be made of a matrix such as polyacrylamide and a semipermeable membrane made from a suitable polymer to control the rate at which the material is delivered to the skin.
  • Other suitable transdermal patch formulations and configurations are described in U.S. Patents Nos. 5,296,222 and 5,271,940, the disclosures of which are incorporated herein by reference.
  • Lipophilic prodrug derivatives of the SPLA2 inhibitors are particularly well suited for transdermal absorption administration and delivery systems.
  • the preferred active compound are the lH-indole-3-glyoxylamide compounds as previously described and methods of making as described in n US Patent No. 5,654,326 (the disclosure of which is incorporated herein by reference) .
  • Most preferred compounds within the general class of 1H- indole-3-glyoxylamides are ( (3- (2-amino-l, 2-dioxoethyl) - 2-ethyl-l- (phenylmethyl) -lH-indol-4yl) oxy) acetic acid, sodium salt; and lH-indole-3-glyoxylamides are ((3- (2- amino-1, 2-dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol- 4yl) oxy) acetic acid, methyl ester.
  • the lH-indole-3-glyoxylamide compound may be used at a concentration of 0.1 to 99.9 weight percent of the formulation.
  • 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 compound 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.
  • compositions suitable for internal administration contain from about 1 milligram to about 500 milligrams of active compound per unit.
  • the active compound will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • Capsules may be prepared by filling standard two-piece hard gelatin capsules each with 50 mg of powdered active compound, 175 mg of lactose, 24 mg of talc, and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active compound in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 mg of the active compound. The capsules are washed in petroleum ether and dried.
  • Tablets Tablets may be prepared by conventional procedures so that the dosage unit is 50 mg of active compound, 6 mg of magnesium stearate, 70 mg of microcrystallme cellulose, 11 mg of cornstarch, and 225 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • Suspensions An aqueous suspension is prepared for oral administration so that each 5 ml contain 25 mg of finely divided active compound, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mg of vanillin.
  • injectables A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active compound in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.
  • Nasal Spray An aqueous solution is prepared such that each 1 ml contains 10 mg of active compound, 1.8 mg methylparaben, 0.2 mg propylparaben and 10 mg methylcellulose. The solution is dispensed into 1 ml vials .
  • the active compound may be used at a concentration of 0.01 to 99.9 weight percent of the formulation.
  • Aerosol formulations are capable of dispersing into particle sizes of from about 0.5 to about 10 microns and have sufficient SPLA2 inhibitor to achieve concentrations of the inhibitor on the airway surfaces of from about 10 "10 to 10 "2 moles per liter.
  • SPLA2 inhibitors prevents progressive deterioration by inhibiting or reducing the degree of renal dysfunction that may be a primary pathologic process in renal dysfunction.
  • the method of the invention is preferably used early in the symptomatic-life of the patient afflicted with renal dysfunction.
  • the method of the invention can be practiced using pharmaceutical formulations containing SPLA2 inhibitors
  • the dosage administered will vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; ' nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a daily dosage of active compound can be about 0.1 to 200 milligrams per kilogram of body weight.
  • 0.5 to 50, and preferably 1 to 25 milligrams per kilogram per day given in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.
  • the SPLA2 inhibitor will be administered to an animal so that a therapeutically effective amount is received.
  • a therapeutically effective amount may conventionally be determined for an individual patient by administering the active compound in increasing doses and observing the effect on the patient, for example, improvement in exercise, increased appetite, or a reduction in other symptoms associated with renal dysfunction.
  • the compound must be administered in a manner and a dose to achieve in the animal a blood level concentration of SPLA2 inhibitor of from 10 to 3000 nanograms/ml , and preferably a concentration of 100 to
  • the treatment regimen may stretch over many days to months or to years. Oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four oral doses per day, each from about 0.01 to 25 mg/kg of body weight with preferred doses being from about 0.1 mg/kg to about 2 mg/kg. Parenteral administration (particularly, intravenous administration) is often preferred in instances where rapid alleviation of patient distress is required. With parenteral administration doses of 0.01 to 100 mg/kg/day administered continuously or intermittently throughout the day may be used.
  • the compound may be administered in a physiologic saline vehicle (e.g., 0.9% normal saline, 0.45% normal saline, etc.) a dextrose vehicle (e.g., 5% dextrose in water), or a combination of saline and dextrose vehicle (0.9% normal saline in 5% dextrose) .
  • a physiologic saline vehicle e.g., 0.9% normal saline, 0.45% normal saline, etc.
  • a dextrose vehicle e.g., 5% dextrose in water
  • a combination of saline and dextrose vehicle e.g., 5% dextrose in water
  • Inhalation therapy also may be useful either alone or as an adjunct to other routes of administration. With inhalation therapy, doses necessary to produce a decrease in the clinical symptoms of renal dysfunction are readily determined and used.
  • the diagnostic criteria for renal dysfunction are those found in standard medical references (e.g.,
  • the renal dysfunction patient having renal disease may be evaluated with any conventional measure of renal capacity.
  • the renal dysfunction patient having gastrointestinal disease may be evaluated by conventional criteria for adequate nutrition.
  • the underlying renal dysfunction event may be evaluated and treated according to current standards of good medical practice, where the standard treatment is supplemented with the administration of a compound according to this invention.
  • 374388 is an oralsPLA2 inhibitor compound of the present invention.
  • the purpose of this study was to evaluate the effect of 374388 in a model of chronic renal failure in male Fisher 344 (F344) rats, when administered daily by gavage. Doses of 0, 3 or 30 mg/kg were administered for approximately 2 months (dosing begun approximately 60 days after the nephrectomy performed at Lilly Research Laboratories) . Alterations in live phase, and morphologic and clinical pathology parameters were compared to findings in age-matched control, sham- nephrectomized control, and vehicle-control nephrectomized rats. No compound-related alterations suggestive of toxicity occurred.
  • Body weight and body weight gains were improved in uremic rats given 3 mg/kg 374388 compared to nephrectomized controls. Near the end of the treatment phase (Day 112), mean body weight for rats given 3 mg/kg was significantly increased relative to the nephrectomized control value and was within approximately 5% of the control group mean, as compared to 19% for nephrectomized control rats. Although not statistically analyzed, body weight change data for rats given 30 mg/kg followed the same general trend as that seen in the 3-mg/kg group.
  • nephrectomized rats had minimal increases in cholesterol, total protein, and total carbon dioxide and slight to moderate decreases in BUN, CREAT and IP compared to nephrectomized controls.

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Abstract

A method is disclosed for the treatment of of the symptoms associated with renal dysfunction by administering to an animal in need thereof a therapeutically effective amount of a sPLA2 inhibitor, such as a 1H-indole-3-glyoxylamide.

Description

METHOD FOR THE TREATMENT OF RENAL DYSFUNCTION WITH SPLA2 INHIBITORS
FIELD OF THE INVENTION
The present invention is directed to a method for treating renal dysfunction. More specifically, the present invention is directed to- a method for treating the symptoms of renal dysfunction by administering a therapeutically effective amount of a SPLA2 inhibitor.
BACKGROUND OF THE INVENTION
Renal failure can be either acute or chronic. Acute renal failure (ARF) is a very common renal disease affecting about 5% of all hospitalized patients. ARF carries a high mortality of more than 50% and there has been no significant change in the mortality rate over the past four decades. The effects of acute renal failure may be reversible with prompt and proper intervention and treatment . Chronic renal failure on the other hand is often not reversible. Common initiating causes of chronic renal failure (CRF) include glomerulonephritis, diabetes mellitus, and hypertension. CRF is characterized by progressive reduction in nephron mass, which eventually impacts the operation of virtually every major organ in the body. The clinical syndrome that results from profound loss of renal function is called uremia. The term encompasses more than just a presumed retention of urea and other toxins but includes the impairment of a host of metabolic and endocrine functions normally subserved by the kidney. Symptoms of uremia include for example, hypothermia- caused possibly by retention of urea and other toxins, impaired glucose metabolism, uremic toxicity caused by an inability to eliminate end products of protein metabolism, fluid and electrolyte imbalance, gastrointestinal disturbances e.g. nausea, anorexia, uremic factors, and peptic ulcer. Other symptoms of CRF include arterial hypertension, congestive heart failure, dermatological disturbances, e.g. itching, neurologic disturbances e.g. impaired mentation, headache, seizures, and immunological disturbances such as for example, leukopenia, lymphocytopenia, bleeding diathesis. (See generally, Harrisson's Principles of Internal Medicine, Isselbacher, K. J. et . al . , editors, pages 1259-1284, 13th edition, 1994, McGraw-Hill Publishers, NY, New York.) Because there is neither clear understanding of the cause nor the mechanism of action of ARF, CRF or any of the related renal dysfunctional problems, numerous scientific publications have posited theories .
One theory examines the controversial involvement of sPLA2~induced cell membrane damage (Edelstein, C.L.; Ling, H. ; Schrier, R.W. ; International Society of Nephrology, 51, 1997, 1341-1351). Edelstein et al . propose a dual mode of action for SPLA2 and SPL 2 inhibitors because both cell death and cellular protection are seemingly involved. U.S. Pat. No. 5,654,326 which is incorporated herein by reference, describes lH-indole-3-glyoxylamide SP A2 inhibitors for use in inhibiting SP A2 mediated release of fatty acids in conditions such as septic shock. Major therapies for renal dysfunction include the following: 1. Dialysis treatment to remove harmful toxins
2. Drugs to restore salt and water balance, e.g., ' diuretics 3. Antibiotics
4. Inhaled beta-adrenergic agonists
However, previous treatment attempts have focused on pharmaceutical agents that treated the cause of the renal dysfunction. For example, previous methods treated the problem causing renal dysfunction and not, for example, the build up of fluids or cell membrane damage.
Also of importance are the problems relative to renal organ transplant . Transplantation of kidneys and associated tissues creates additional sepsis and tissue rejection concerns. M. Baur et al . have reported increased PLA levels in patients undergoing major surgery (Baur, M. ; Schmid, T. O . ; Landauer, B.; Klin . Wochenschr. , Vol. 67(3), 1989. Baur et al . further observed that serum PLA levels decrease spontaneously in recovering postsurgical patients.
Accordingly, there i-s a substantial need for an effective treatment for the many symptoms secondary to renal dysfunction including sepsis, inflammation, cell membrane damage, secondary to organ failure and tissue rejection following kidney transplant.
SUMMARY OF THE INVENTION
The present invention is directed to a method of alleviating the symptoms of an animal afflicted with renal dysfunction e.g., acute or chronic renal failure, by administering a therapeutically effective amount of a SP A2 inhibitor compound.
The present invention also relates to the use of a SPLA2 inhibitor in combination with a therapeutically effective agent and or medical procedure selected from the group consisting of, dialysis treatment to remove harmful toxins; drugs to restore salt and water balance; and/or other treatment of acute and chronic renal failure.
The invention also relates to the combination of a SPLA2 inhibitor with ANF atrial naturetic factor for the delay or prevention of acute renal failure in a mammal . This invention also relates to the use of a SP A2 inhibitor in combination with erythropoetin to stimulate red cell production in a mammal. The present invention is also the use of a SPLA2 inhibitor in combination with 0KT3™ (a monoclonal antibody used to prevent graft rejection by T3 antigens produced by human T cells) , to reduce the symptoms associated with administration of 0KT3. DETAILED DESCRIPTION OF THE INVENTION Definitions;
General Definitions:
As used herein "Renal dysfunction" means a disease state or condition wherein the renal tissues fail to perform their normal functions according to competent medical authority. Renal dysfunction shall also include long term or chronic renal dysfunction also known as renal failure. Renal dysfunction also includes acute renal failure and disease states that lead to renal failure. Examples of disease states leading to renal failure include for example, acute nephritis, nephrotic syndrome, pyuria, auria, oliguria, uremia, bilateral arterial occlusion, acute tubular necrosis, acute uric acid nephropathy, hypovolemia, acute bilateral upper tract obstruction, hypocalcemic nephropathy, hemolytic uremic syndrome, acute urinary retention, scleroderma, hypersensitivity nephropathy, malignant nephrosclerosis, essential and mixed cryoimmunoglobulinemia, and azotemia. The term "uremia" means the clinical syndrome of nausea, itching, weight loss, sleep disturbances, altered mentation, and memory loss associated with renal dysfunction .
The terms "SP A2 inhibitor" and "SPLA2 inhibitor compound" as used herein are synonymous.
The term "therapeutically effective amount" is a quantity of SP A2 inhibitor sufficient to ameliorate the symptoms secondary to renal dysfunction in an animal. The term "therapeutically effective interval" is a period of time beginning when one of either the SPLA2 inhibitor or the co-agent is administered or practiced on the patient in need thereof, and ending at the limit of the therapeutic effectiveness of either or both.
The terms "parenteral" or "parenteral administration" mean administration by a route such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, transdermal, transmucosal, transbuccal, transrectal, transvaginal , transnasal or intravenous .
The term "animal" means any member of the animal kingdom including mammals, reptiles, fishes and fowls.
The term "active compound" means one or more SPLA2 inhibitors used in the method of the invention.
The term "in combination with" denotes the co- administration of a SPLA2 inhibitor and a co-agent therapy or procdeure. The term further means simultaneous co-administration either as a single formulation or as separate formulations or sequential administration of a SPLA2 inhibitor and co-agent or other therapeutically effective procedure. The term "co-agent" is a theraputically effective medication or procedure administered in combination with a SPLA2 inhibitor either as a single dose unit or as separate dose units simultaneously or sequentially within a therapeutic interval . PREFERRED ASPECTS OF THE INVENTION
A preferred aspect of the invention is the use of a SP A2 inhibitor compound of the invention for the prevention or treatment of uremia. Preclinical studies showed that monkeys and rabbits in renal failure did not develop signs of uremia i.e., the kidneys were failing but the animals were not as clinicallly ill as they should have been.
Another preferred aspect of the present invention is the use of a SPL 2 inhibitor in combination with an anti- rejection drug, e.g., OKT3™ for the treatment of chronic or acute inflammation associated with kidney transplant therapy .
Also preferred is the use of SPLA2 inhibitor in combination with erythropoietin to stimulate the production of red cells in renal failure patients.
I. SPLA2 INHIBITORS USEFUL IN THE METHOD OF THE INVENTION:
Secretary phopholipase A (SPLA2) inhibitors in general are useful in the practice of the method of this invention. Exemplary of classes of suitable SPLA2 inhibitors useful in the method of the invention for treatment of renal dysfunction includes members selected from the group comprising: lH-indole-3-glyoxylamide, 1H- indole-3-hydrazide, lH-indole-3-acetamide, lH-indole-1- glyoxylamide, lH-indole-1-hydrazide, lH-indole-1- aceta ide, indolizine-1-acetamide, indolizine-1-acetic acid hydrazide, indolizine-1-glyoxylamide, indene-1- acetamide, indene-1-acetic acid hydrazide, indene-1- glyoxylamide, carbazole, tetrahydrocarbazole, pyrazole, phenyl glyoxamide, pyrrole, naphthyl glyoxamide, naphthyl acetamide, phenyl acetamide, pyrrolo [1, 2-a]pyrazine, 9H- carbazole, 9-benzylcarbazole and mixtures thereof.
Each of the above SPL 2 inhibitor types is discussed in the following sections (a) through (n) wherein details of their molecular configuration are given along with methods for their preparation.
A) THE 1H-INDOLE-3-GLYOXYLAMIDE INHIBITORS
The lH-indole-3-glyoxylamide SPLA2 inhibitors and method of making them are described in U.S. Patent
5,654,326, the disclosure of which is incorporated herein by reference. These lH-indole-3-glyoxylamide compounds are also described in European Patent Application No . 95302166.4, Publication No.067511Q (publ . , 4 October 1995) .
DEFINITIONS FOR 1H-INDOLE-3-GLYOXYLAMIDE COMPOUNDS:
The words, "acid linker" refers to a divalent linking group of the lH-indole-3-glyoxylamide compounds is symbolized as, ~(La)-, which has the function of joining the 4 or 5 position of the indole nucleus to an acidic group in the general relationship:
Indole Nucleus "(La)" Acidic Group
The words, "acid linker length", refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(L )- that connects the 4 or 5 position of the indole nucleus with the acidic group . DETAILED DESCRIPTION OF THE INVENTION
The method of the invention includes a method for treatment of an animal afflicted with renal dysfunction.
This method includes administering to said animal a therapeutically effective amount of a lH-indole-3- glyoxylamide represented by the formula (I) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
where;
X is oxygen,
R^- is selected from the group consisting of -C7-C20 alkyl ,
where RIO is selected from the group consisting of halo, cl~c10 alkyl, Cτ_-Cη_o alkoxy, -S- (C -Cχ alkyl) and halo (C -C_o) alkyl, and t is an integer from 0 to 5 both inclusive;
R2 is selected from the group consisting of hydrogen, halo, cyclopropyl, methyl, ethyl, and propyl; R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent and the group, - (La) - (acidic group); where, at least one of R4 and R5 is the group, - (L ) - (acidic group) and wherein the (acidic group) is selected from the group consisting of -C02H, -S03H, or -P(0) (0H)2; where,
-(La)- is an acid linker with the proviso that; the acid linker group, -(La)-, for R is selected from the group consisting of
where R103 is a non-interfering substituent, and where, the acid linker, -(La)-, for R5 is selected from the group consisting of
84 R 84
H -N- ■(CHa)n- "CH; ■(CH2)n- and
D 85 .85
where R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 arylkyl, carboxy, carbalkoxy, and halo and, R6 and R7 are each independently selected from hydrogen and non-interfering substituents, where non- interfering substituents are selected from the group consisting of Ci-Cς alkyl, C2-Cg alkenyl, C2-C6 alkynyl, C7-C12 arylenalkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3- Cβ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, Cι~ Cβ alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl , C2_Ci2 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino, C1-C6 alkylthio, C2_Ci2 alkylthiocarbonyl, Ci-Cδ alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl , -C(0)0(Cι-C6 alkyl), - (CH2) n_0- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, - (CONHSO2R) , -CHO, amino, amidino, bro o, carbamyl, carboxyl, carbalkoxy, - (CH2 )n~C02H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Ci-Cζ carbonyl and where n is between 1 and 8.
The method of the invention also includes treatment of an animal afflicted by renal dysfunction. This method includes administering to said animal a therapeutically effective amount of a 9H-carbazole compound represented by the formula (II) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
(II) where Yi is selected from the group consisting of 0,
NH, NR and S; ^ is selected from the group consisting of -Cy-C2( alkyl,
C
where
R-O is selected from the group consisting of halo, cl~c10 alkyl, Cχ-CiQ alkoxy, -S-(C -Cιo alkyl) and halo(C]_-Cιo) alkyl, and t is an integer from 0 to 5 both inclusive; where R31, R32, R3, R3ι-, R32-, R33', R34 and R34. are independently selected from the group consisting of hydrogen, CONR101R102, alkyl, alkylaryl, aryl, alkylheteroaryl, haloalkyl, alkylCONR103!102, a non- interfering substituent and the group, - (La) - (acidic group) ■ where - (La) - is an acid linker selected from the group consisting of
where R84 and R85 are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, aryl, Ci- Cio alkaryl, Cι-C10 aralkyl, carboxy, carbalkoxy, and halo; and n is 1 or 2 and, where the (acidic group) is selected from the group consisting of -C02H, -S03H, -CO2NR101R102 and -P(0)(0H)2 and, where R101 and R102 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and haloalkyl and, where non-interfering substituents are selected from the group consisting of Ci-Cβ alkyl, C2-Cβ alkenyl, C2-Cβ alkynyl, C7-C12 arylalkyl, C7-C12 alkylaryl, C3-C8 cycloalkyl, C3-C8 cycloalkyl, phenyl, tolulyl, xylyl, biphenyl, C1-C5 alkoxy, C2-C6 alkyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxya ino, C2-C12 alkoxyaminocarbonyl , C2-C12 alkylamino, Ci-Cς alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, Cχ-C6 haloalkylsulfonyl, C2-C6 haloalkyl, Ci- C6 hydroxyalkyl, -C(0)0(Cι-C6 alkyl), - (CH2)n-0- (Ci-Ce alkyl), benzyloxy, phenoxy, phenylthio, - (C0NHS02 (R) ) , - CHO, amino, amidino, bro o, carbamyl, carboxyl, carbalkoxy, - (CH2 )n~C02H, chloro, cyano, cyanoguanidinyl , fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and C1-C5 carbonyl and where n is between about 1 and 8 and, R is selected from the group consisting of hydrogen and alkyl and, where at least one of R3ι, R3 , R33 or R3 is the group - ( a) - (acidic group) . The method of the invention also includes treatment of an animal afflicted with renal dysfunction. This method includes administering to said animal in need of such treatment, a therapeutically effective amount of a lH-indole-3-glyoxylamide compound or a 9H-carbazole or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (A) through (AL) :
(A) [ [3- (2-amino-l, 2-dioxoethyl) -2-methyl-l- (phenylmethyl) -IH indol-4-yl] oxy] acetic acid,
(B) dl-2-[ [3- (2-amino-l, 2-dioxoethyl) -2- methyl-1- (phenylmethyl) -IH indol-4-yl] oxy]propanoic acid,
(C) [ [3-(2-amino-l,2-dioxoethyl)-l-( [1,1'- biphenyl] -2-ylmethyl) -2 methyl-lH-indol-4-yl] oxy] cetic acid,
(D) [ [3- (2-amino-l, 2-dioxoethyl) -l-( [1,1'- biphenyl] -3-ylmethyl) -2-methyl-lH-indol-4-yl] oxy] acetic acid,
(Ξ) [ [3-(2-amino-l,2-dioxoethyl)-l-( [1,1'- 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) -1- [4 (- fluorophenyl) ethyl] -2-methyl-lH-indol-4-yl] oxy] acetic acid,
(H) [ [3- (2-amino-l, 2-dioxoethyl) -2-methyl-l- [ (1-naphthalenyl) methyl] -lH-indol-4-yl] oxy] acetic acid, (I) [ [3- (2-amino-l, 2-dioxoethyl) -2-ethyl-1-
(phenylmethyl) -lH-indol-4-yl] oxy] acetic acid, (J) [ [3- (2-amino-l, 2-dioxoethyl) -1- [ (3- chlorophenyl) methyl] -2-ethyl-lH-indol-4-yl] oxy] acetic acid,
(K) [[3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -2-ylmethyl) -2-ethyl-lH-indol-4-yl] oxy] acetic acid,
(L) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -2-ylmethyl) -2-propyl-lH-indol-4-yl] oxy] acetic acid, (M) [ [3- (2-amino-l, 2-dioxoethyl) -2- cyclopropyl-1- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid,
(N) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -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) 9H-carbazole,
(Q-) 9-benzylcarbazole, (AG) l-(9H-benzylcarbazol-l-halo-4-yloxy-5- alkylamido) alkylacetate,
(AH) 1- (9H-benzylcarbazol-4-yloxy-5-alkylamido) alkylacetate,
(Al) 1- (9H-benzylcarbazol-l-halo-4-yloxy-5- alkyla ido) acetic acid,
(AJ) 1- (9H-benzylcarbazol-4-yloxy-5-alkylamido) acetic acid and
(AK) mixtures of (AG) through (AJ) and
(AL) mixtures of (A) through (AK) combined with an additional treatment composition. Particularly useful prodrugs of the compounds of formula (II) and named compounds (A) thru (AL) are the simple aromatic and aliphatic esters, such as the methyl ester.
The invention is a method for treatment of an animal afflicted with renal dysfunction. This method includes administering to said animal in need of such treatment a therapeutically effective amount of a composition selected from the group comprising:
where R is independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl. PREPARATION OF sPLA2 INHIBITORS
The methyl ester of (Va) a) The lH-indole-3-glyoxylamide SPLA2 inhibitors and method of making them are described in U.S. Patent 5,654,326, the entire disclosure of which is incorporated herein by reference. Another method of making lH-indole-3-glyoxylamide SPLA2 inhibitors is described in United States Patent Application Serial No. 09/105381, filed June 26, 1998 and titled, "Process for Preparing 4-substituted l-H-Indole-3-glyoxyamides" the entire disclosure of which is incorporated herein by reference. United States Patent Application Serial No. 09/105381 discloses the following process having steps (a) thru (i) : preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof
wherein :
R! is selected from the group consisting of -C7-C20 alkyl ,
where
R O is selected from the group consisting of halo, alkyl, C -C g alkoxy, -S-(Cχ-Cχo alkyl) and halo (C]_-C o) alkyl, and t is an integer from 0 to 5 both inclusive;
R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C]_-C2 alkyl), -S- (Cχ-C2 alkyl), aryl, aryloxy and HET;
R4 is selected from the group consisting of -CO2H,
-SO3H and -P(0) (OH) 2 or salt and prodrug derivatives thereof; and
R5 , R6 and R7 are each independently selected from the group consisting of hydrogen, (C1-C ) alkyl, (C]_-
C5) alkoxy, halo (C1-C5) alkoxy, halo (C2-C5) alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of:
a) halogenating a compound of formula X
X where R^ is (Cχ-Cg) alkyl, aryl or HET; with SO2CI2 to form a compound of formula IX
b) Hydrolyzing and decarboxylating a compound of formula IX
to form a compound of formula VIII
; c) alkylating a compound of formula VII
with a compound of formula VIII
to form a compound of formula VI d) aminating and dehydrating a compound of formula VI
with an amine of the formula R^NH2 in the presence of a solvent that forms and azeotrope with water to form a compound of formula V;
e) oxidizing a compound of formula V
by refluxing in a polar hydrocarbon solvent having a boiling point of at least 150 °C and a dielectric constant of at least 10 in the presence of a catalyst to form a compound of formula IV
f) alkylating a compound of the formula IV
with an alkylating agent of the formula XCH2R4a where X is a leaving group and R4 is -CO2R4 ,
-S0 R b, -P(O) (0R4b)2, or -P (O) (0R4b)H, where
R4-*3 is an acid protecting group to form a compound of formula III
g) reacting a compound of formula III
with oxalyl chloride and ammonia to form a compound of formula II h) optionally hydrolyzing a compound of formula II
to form a compound of formula I; and i) optionally salifying a compound of formula I.
The synthesis methodology for making the 1H- indole-3-glyoxylamide SPLA2 inhibitor starting material may' be by any suitable means available to one skilled in the chemical arts. However, such methodology is not part of the present invention which is a method of use, specifically, a method of treating mammal afflicted with or susceptible to renal dysfunction.
The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of the compound represented by formula (la) , or a pharmaceutically acceptable salt or prodrug derivative thereof;
wherein ;
Both X are oxygen;
RX is selected from the group consisting of
Where R o is a radical independently selected from halo, Cχ-Cχo alkyl, Cχ-Cχo alkoxy, -S- (Cχ-Cχo alkyl), and C -C o- haloalkyl and t is a number from 0 to 5;
R2 is selected from the group; halo, cyclopropyl, methyl, ethyl, and propyl;
R4 and R5 are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) - (acidic group), wherein -(La)- is an acid linker; provided, the acid linker group, -(La)-, for R4 is selected from the group consisting of;
and provided, the acid linker, -(La)-, for R5 is selected from group consisting of;
wherein β4 and Rss are each independently selected from hydrogen, Cχ-Cχo alkyl, aryl, Cχ-Cχo alkaryl, Cχ~ C o aralkyl, carboxy, carbalkoxy, and halo; and provided, that at least one of R4 and R5 must be the group, - (La) - (acidic group) and wherein the (acidic group) on the group - (La) - (acidic group) of R4 or R5 is selected from -C0 H, -SO3H, or -P(0)(0H) ; Rg and R7 are each independently selected from hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of the following: C -Cg alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C7-CX2 aralkyl, C7-CX2 alkaryl,
C3-C8 cycloalkyl, C3-C8 cycloalkenyl , phenyl, tolulyl, xylenyl, biphenyl, C -Cg alkoxy, C2~C alkenyloxy, C2-
Cg alkynyloxy, C2~C 2 alkoxyalkyl, C2~C 2 alkoxyalkyloxy, C2~C 2 alkylcarbonyl , C2~C 2 alkylcarbonylamino, C2~C 2 alkoxyamino, C2~C 2 alkoxyaminocarbonyl , C2~C 2 alkylamino, Cχ-Cg alkylthio, C2~C 2 alkylthiocarbonyl, Cχ-Cg alkylsulfinyl, Cχ-Cg alkylsulfonyl, C2~Cg haloalkoxy, Cχ-Cg haloalkylsulfonyl, C2~C haloalkyl, Cχ-Cg hydroxyalkyl , -C(0)0(Cχ-Cg alkyl), - (CH2) n-0- (Cχ-Cg alkyl), benzyloxy, phenoxy, phenylthio, - (CONHSO2R) , - 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
Cχ-Cg carbonyl; where n is from 1 to 8.
Preferred for practicing the method of the invention are lH-indole-3-glyoxylamide compounds and all corresponding pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are useful in the method 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-1-
(phenylmethyl) -lH-indol-4-yl] oxy]propanoic acid,
(C) [ [3- (2-Amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -2-ylmethyl) -2-methyl-lH-indol-4- yl] oxy] acetic acid,
(D) [ [3- (2-Amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl}-3-ylmethyl) -2-methyl-lH-indol-4- yl] oxy] acetic acid, (E) [ [3- (2-Amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -4-ylmethyl) -2-methyl-lH-indol-4- yl] oxy] acetic acid,
(F) [ [3- (2-Amino-l, 2-dioxoethyl) -1- [ (2, 6- dichlorophenyl) methyl] -2-methyl-lH-indol-4- yl] oxy] acetic acid
(G) [ [3- (2-Amino-l, 2-dioxoethyl) -1- [4 (- fluorophenyl) ethyl] -2-methyl-lH-indol-4- yl] oxy] acetic acid,
(H) [ [3- (2-Amino-l, 2-dioxoethyl) -2-methyl-l- [ (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, (J) [ [3- (2-Amino-l, 2-dioxoethyl) -1- [ (3- chlorophenyl) methyl] -2-ethyl-lH-indol-4- yl] oxy] acetic acid, (K) [ [3- (2-Amino-l, 2-dioxoethyl) -1- ( [1,1'- 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-proρyl-lH-indol-4- yl] oxy] acetic acid, (M) [ [3- (2-Amino-l, 2-dioxoethyl) -2-cyclopropyl-l- (phenylmethyl) -lH-indol-4-yl] oxy] cetic acid,
(N) [ [3- (2-Amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -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 (P) in any combination.
Particularly useful prodrugs of the compounds of formula (I) and named compounds (A) thru (0) are the simple aromatic and aliphatic esters, such as the methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n- butyl ester, sec-butyl, tert-butyl ester, N,N- diethylglycolamido ester, and morpholino-N-ethyl ester. Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No. 60/063280 filed October 27, 1997 (titled, N,N-diethylglycolamido ester Prodrugs of Indole SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference; U.S. Provisional Patent Application Serial No. 60/063646 filed October 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs of Indole SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference; and U.S. Provisional Patent Application Serial No. 60/063284 filed October 27,. 1997 (titled, Isopropyl Ester Prodrugs of Indole SPLA2
Inhibitors) , the entire disclosure of which is incorporated herein by reference.
Most preferred in the practice of the method of the invention are the acid, sodium salt, methyl ester, and morpholino-N-ethyl ester forms of [ [3- (2-amino-l, 2- dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol-4- yl] oxy] acetic acid as represented by the following formulae :
another highly preferred compound is the indole-3- glyoxylamide morpholino ethyl ester of represented by the formula :
The preparation of which is further described in United States provisional patent application SN 60/063,646 filed October 27, 1997.
Synthesis methods for IH-indole-3-glyoxylamide SPLA2 inhibitors are additionally depicted in the following reaction scheme:
lH-indole-3-glyoxylamide Reaction Scheme
3
Explanation of Reaction Scheme: 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 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 for approximately 5 hours (see 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 described for the conversion of 5 to 6. The - [ (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 glyoxamide 10. This product is hydrolyzed using IN sodium hydroxide in methanol . The final glyoxylamide, 11, is isolated either as the free carboxylic acid or as its sodium salt or in both forms. The most preferred compound, [ [3- (2-Amino-l, 2- dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol-4- yl] oxy] acetic acid (as well as its sodium salt and methyl ester) useful in the practice of the method of the invention, may be prepared by the following procedure: preparation of [ [3- (2-Amino-l, 2-dioxoethyl) -2-ethyl- 1- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid, a compound represented by the formula:
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 is 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 is removed and the temperature allowed to rise to 0 °C and then the bath replaced. After the temperature has cooled to - 60 °C, 18.5 g (0.18 mmol) of N-methoxy-N- methylpropanamide in an equal volume of THF iss added dropwise. The reaction mixture is stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It is then poured into a mixture of 300 ml of ether and 400 ml of 0.5N HCl. The organic layer is separated, washing with water, brine, dried over MgSθ4, and concentrated at reduced pressure to give 25.5g of a crude of 1- [2- (tert-butoxycarbonylamino) -6-methoxyphenyl] -2- butanone. This material is dissolved in 250 ml of methylene chloride and 50 ml of trifluoroacetic acid and stirred for a total of 17 hours. The mixture is concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate is separated, washed with brine, dried (MgS04) and concentrated. The residue is chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9g of 2-ethyl-4-methoxy-lH-indole . Analysis for C11H13NO:
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) is dissolved in 30 ml- of DMF and 960mg (24 mmol) of 60% NAH/mineral oil is added. After 1.5 hours, 2.9 ml (24 mmol) of benzyl bromide is added. After 4 hours, the mixture is diluted with water extracting twice with ethyl acetate. The combined ethyl acetate is washed with brine, dried (MgS04) and concentrated at reduced pressure. The residue is chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3. Ig (49% yield) of 2-ethyl-4-methoxy-l- (phenylmethyl) -IH-indole.
Part C. Preparation of 2-Ethyl-4-hydroxy-l- ( henylmethyl) -IH-indole. A solution of 3. Ig (11.7 mmol) of 2-ethyl-4-methoxy- 1- (phenylmethyl) -IH-indole and 48.6 ml of 1M BBr3/CH2Cl in 50 ml of methylene chloride is stirred at room temperature for 5 hours and concentrated at reduced pressure. The residue is dissolved in ethyl acetate, washed with brine and dried (mgso4) . After concentrating at reduced pressure, the residue is chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.58g (54% yield) of 2-ethyl-4-hydroxy-l- (phenylmethyl) -1H- indole, mp, 86-90 °C . Analysis for CX7H 7NO:
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-Ethyl-l- (phenylmethyl) -1H- indol-4-yl] oxy] acetic acid tert-butyl ester.
2-Ethyl-4-hydroxy-l- (phenylmethyl) -IH-indole (5.82 g, 20 mmol) is added to 7.82g (24 mmol) cesium carbonate in 25 ml DMF and the mixture is stirred at 35 °C for 30 minutes. After cooling to 20 °C, a solution of tert-butyl bromoacetate (4.65 g, 23.8 mmol) in 5 ml DMF is added and stirring maintained until the reaction is judged complete by TLC analysis (several hours) . The mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgS04) and concentrated at reduced pressure to give 6.8g of solid. Mass spectrum: 365 Analyses for C23H27NO3 :
Calculated: C, 75 . 59 ; H, 7 . 75 ; N, 3 . 83 ; Found: C, 75 . 87 ; H, 7 . 48 ; N, 3 . 94 .
Part E. Preparation of [ [2-Ethyl-l- (phenylmethyl) -3- ureido-lH-indol-4-yl] oxy] acetic acid tert-butyl ester. A solution of 2.3g (6.3 mmol) [ [2-ethyl-l- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid tert-butyl ester and 4.8g (12.6 mmol) bis (2 , 2 , 2-trichloroethyl) - azodicarboxylate in diethyl ether is stirred for 24 hours at room temperature. The resulting solid is filtered and vacuum dried. This adduct (Ig, 1.3 mmol) is dissolved in 10 ml of THF and treated with zinc (1 g) and glacial acetic acid (0.5 ml). After stirring for 30 minutes at room temperature an excess of trimethylsilylisocyanate in 1 ml of THF is added and stirring is continued at room temperature for 18 hours. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over MgS04 and concentrated to dryness to give 0.385g (69% yield) of the subtitled material. Mass spectrum: 423. Analyses for C24H29N3O4:
Calculated: C, 68.07; H, 6.90; N, 9.92; Found: C, 67.92; H, 6.84; N, 9.70.
Part F. Preparation of [ [3- (2-Amino-l, 2-dioxoethyl) -2- ethyl-1- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid. A mixture of 788mg (2 mmol) 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 methanol is heated to maintain reflux for 0.5 hour, stirred at room temperature for 0.5 hour and concentrated at reduced pressure. The residue is taken up in ethyl acetate and water, the aqueous layer separated and made acidic to pH 2-3 with IN HCl. The precipitate is 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, 23 - 234 °C.
Analyses for C2χH20N2°5: Calculated: C, 65.96; H, 5.80; N, 7.33; Found: C, 66.95; H, 5.55; N, 6.99.
B) IH-indole-3-hydrazide SPLA2 inhibitors useful in practicing the method of the invention are described in U.S. Patent No. 5,578,634; the entire disclosure of which is incorporated herein by reference. The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of the compounds described as lH-indole- 3-acetic acid hydrazides represented by the formula (lb), and pharmaceutically acceptable salts, and prodrugs thereof;
wherein;
X is oxygen or sulfur;
R is selected from groups (i) , (ii) and (iii) where;
(i) is C4-C20 alkyl, C4-C20 alkenyl, C4-C20 alkynyl, C4-C20 haloalkyl, C4-C 2 cycloalkyl, or (ii) is aryl or aryl substituted by halo, - CN, -CHO, -OH, -SH, Cχ-C10 alkylthio, Cχ-Cχo alkoxy, Cχ-Cχo alkyl, carboxyl, amino, or hydroxyamino;
(iii) is
where y is from 1 to 8, R74 is, independently, hydrogen or Cχ-Cχo alkyl, and R75 is aryl or aryl ■ substituted by halo, -CN, -CHO, -OH, nitro, phenyl, -SH, Cχ-Cχo alkylthio, Cχ-Cχo alkoxy, Cχ-Cχg alkyl, amino, hydroxyamino or a substituted or unsubstituted 5- to 8- membered heterocyclic ring;
R2 is halo, C -C3 alkyl, ethenyl, C -C2 alkylthio, C2.-C2 alkoxy, -CHO, -CN; each R3 is independently hydrogen, C -C3 alkyl, or halo;
R4 R5 , Rg, and R7 are each independently hydrogen,
Cχ-Cχo alkyl, Cχ-Cχo alkenyl, Cχ-Cχø alkynyl, C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R4 R5 , Rg , and R7 combined with the ring carbon atoms to which they are attached to form a 5- or 6-membered substituted or unsubstituted carbocyclic ring; or Cχ-Cχo haloalkyl, Cχ-Cχo alkoxy, Cχ~ Cχo haloalkoxy, C4-C8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN, -S(Cχ-Cχo alkyl), arylthio, thioacetal, -C (0) 0 (Cχ-Cχo alkyl), hydrazino, hydrazido, - H2, - O2, -NRg2Rδ3' and -C(0) Rs2R83' where, Rβ2 and Rg3 are independently hydrogen, Cχ-Cχo alkyl, Cχ-Cχo hydroxyalkyl, or taken together with N, R82 and R 3 form a 5- to 8'-membered heterocyclic ring; or a group having the formula;
where, each R7g is independently selected from Hydrogen, Cχ-Cχo alkyl, hydroxy, or both R7g taken together are =0 ; P is 1 to 8,
Z is a bond, -0-, -N(Cχ-Cχ alkyl)-, -NH, or -S-; and
Q is -CON(R82R83) ■ -5-tetrazolyl, -SO3H,
O
■0- ■OR 86
OR 86
o
-c- OR85
where R8g is independently selected from hydrogen, a metal, or Cχ-Cχo alkyl.
C) lH-indole-3-acetamide SPLA2 inhibitors and methods of making these inhibitors are set out in U.S. Patent No. 5,684,034, the entire disclosure of which is incorporated herein by reference. The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of the compound represented by (lib) , and pharmaceutically acceptable salts and prodrug derivatives thereof,
wherein ;
X is oxygen or sulfur;
Rll ^s selected from groups (i) , (ii) (iii) and (iv) where; (i) is C -C20 alkyl, Cg-C20 alkenyl, C -C20 alkynyl, Cg-C20 haloalkyl, C4-C 2 cycloalkyl, or (ii) is aryl or aryl substituted by halo, nitro, -CN, -CHO, -OH, -SH, Cχ-C10 alkyl, CX-CXQ alkylthio, Cχ-Cχø alkoxyl, carboxyl, amino, or hydroxyamino; or
(iii) is -(CH2)n-(R8θ) > or -(NH)-(R8ι), where n is 1 to 8, and Rso i group recited in (i) , and R8i is selected from a group recited in (i) or (ii) ; (iv) is
R87
R 87
where R87 is hydrogen or Cχ-Cχo alkyl, and R88 is selected from the group; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, -CN, - CHO, -OH, -SH, Cχ-Cχo alkylthio, Cχ-Cχo alkoxyl, phenyl, nitro, Cχ-CχQ alkyl, Cχ-Cχo haloalkyl, carboxyl, amino, hydroxyamino; or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
Rχ2 is halo, C -C2 alkylthio, or C -C2 alkoxy; each R 3 is independently hydrogen, halo, or methyl; Rχ4 Rl5 R-16' ano^ R-17 are each independently hydrogen, Cχ-CχQ alkyl, Cχ-Cχo alkenyl, Cχ-Cχo alkynyl, C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R 4 R15, Rl6<- and R 7, combine with the ring carbon atoms to which they are attached to form a 5 or 6 membered substituted or unsubstituted carbocyclic ring; or Cχ-Cχo haloalkyl, Cχ~ C o alkoxy, Cχ-C g haloalkoxy, C4-C8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN, Cχ-Cχg alkylthio, arylthio, thioacetal, -C (0) 0 (Cχ-Cχo alkyl), hydrazide, hydrazino, hydrazido, -NH2 , -NO2 , -NR82R83 and -C (0)NR82R83 ' where, β2 and R83 are independently hydrogen, Cχ-Cχo alkyl, Cχ-Cχo hydroxyalkyl, or taken together with N, R82 and R83 form a 5- to 8-membered heterocyclic ring; or a group having the formula;
where,
R84 and R85 are each independently selected from Hydrogen, Cχ-Cχg alkyl, hydroxy, or R84 and R85 taken together are =0; P is 1 to 5,
Z is a bond, -0-, -N(Cχ-Cχo alkyl)-, -NH-, or -S-; and
Q is -CON(R82R83) , -5-tetrazolyl, -SO3H, 0
-p. ORse
OR86 0
o- ■OR86
OR86
0
V R-99
■0 P 0 (CH2)H N R99
OR, 86 R 9.9
where n is 1 to 8, Rgg is independently selected from hydrogen, a metal, or Cχ-Cχg alkyl, and Rgg is selected from hydrogen or Cχ-Cχg alkyl.
D) lH-indole-1-functional SPLA2 inhibitors of the hydrazide, amide, or glyoxylamide types as described in United States Patent No. 5,641,800, the entire disclosure of which is incorporated herein by reference are useful for treatment of a mammal, including a human afflicted with renal dysfunction. IH-indole-l-acetamide or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (Ic) ;
wherein for Formula (Ic) ;
X is oxygen or sulfur; each R is independently hydrogen, or C -C3 alkyl;
R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or
(c) is the group -(L)-R8ø; where, - (L) - is a divalent linking group of 1 to 12 atoms and where Rgo is a group selected from (a) or (b) ; R2 is hydrogen, halo, C -C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -0- (C -C2 alkyl), -S- (Cχ-C alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, -(La)-
(acidic group), wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (La) - (acidic group);
R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents . lH-indole-1-hydrazide compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows: lH-indole-1-hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; is represented by the formula (lie) ;
wherein for formula (lie) ; X is oxygen or sulfur;
Each R is independently hydrogen, or C -C3 alkyl;
R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non- interfering substituent; or
(c) is the group - (h) -RQ Q ; where, -(L)- is a divalent linking group of 1 to 12 atoms and where RQ Q is a group selected from (a) or (b) ; R2 is hydrogen, halo, Cχ-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -0- (Cχ-C alkyl), -S- (Cχ-C alkyl), or a non-interfering substituent having a total of Itto 3 atoms other than hydrogen;
Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) -
(acidic group), wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (La) - (acidic group);
R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents . E) Indolizine SPLA2 inhibitors and their method of preparation are described in US Patent Application Serial No. 08/765566, filed July 20, 1995 (titled, "Synovial Phospholipase A2 Inhibitor Compounds Having an Indolizine Type Nucleus, Parmaceutical Formulations Containing Said- compounds, and Therapeutic Methods of Using said Compounds"), the entire disclosure of which is incorporated herein by reference; and also in European Patent Publication No. 0772596, published May 14, 1997. The lH-indole-1-functional compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; is represented by the formula (Id);
wherein;
X is oxygen or sulfur; each R is independently hydrogen, C -C3 alkyl, or halo;
Rχ3 is selected from groups (a) , (b) and (c) where;
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or
(c) is the group -(L)-RgQ.; where, -(L)- is a divalent linking group of 1 to 12 atoms and where RQQ is a group selected from (a) or (b); Rχ2 is hydrogen, halo, C -C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (C -C2 alkyl), -S- (Cχ~ C2 alkyl) , or a non-interfering substituent having a total of 1 to 3 atoms other than hydroge ,-
Rχ7 and R 8 are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) - (acidic group), wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R 7 and R § must be the group, - (La) -
(acidic group) ; and
Rχ5 and R g are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
Particularly preferred lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows : an indolizine-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof where said compound is represented by the formula (lid) ;
particularly preferred lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows : an indolizine-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (Hid) ;
another preferred lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows: an indolizine-3-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (IVd) , as set out below: wherein;
X is selected from oxygen or sulfur; each R3 is independently hydrogen, C -C3 alkyl, or halo ;
R is selected from groups (a) , (b) and (c) where;
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or (c) is the group -(Lj-Rgo; where, - (L) - is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b) ; R2 is hydrogen, halo, Cχ-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -O- (Cχ-C2 alkyl), -S-(Cχ-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
R5 and Rg are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) - (acidic group) . wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R5 and Rg must be the group, - (La) - (acidic group); R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
Particularly preferred lH-indole-1-functional compounds useful as S LA2 inhibitors in the practice of the method of the invention are as follows: an indolizine-3-hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (Vd) , as set out below:
Particularly preferred lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows : an indolizine-3-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (vid) , as set out below:
particularly preferred lH-indole-1-functional compounds useful as SPLA2 inhibitors in the practice of the method of the invention are as follows: an indolizine-1-acetamide functional compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is selected from the group represented by the following formulae:
and mixtures of the above compounds , F) Indene SP A2 inhibitors as described in US
Patent Application 08/776618 filed July 20 1995, (titled, Synovial Phospholipase A2 Inhibitor Compounds having an Indene Type Nucleus, Pharmaceutical Formulations Containing said Compounds, and Therapeutic Methods of Using Said Compounds"), the entire disclosure of which is incorporated herein by reference, are useful in practicing the method of the invention.
An indene-1-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; is is represented by the formula (If) ;
wherein;
X is oxygen or sulfur; each R is independently hydrogen, Cχ-C3 alkyl, or halo ;
R3 is selected from groups (a) , (b) and (c) where;
(a) is C7-C2O' alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or
(c) is the group -(D-Rso where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rso is a group selected from (a) or (b) ; R2 is hydrogen, halo, Cχ-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -0- (Cχ-C2 alkyl), -S- (Cχ-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) -
(acidic group), wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (La) - (acidic group); and R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
Suitable indene compounds also include the following: an indene-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (iif) ;
wherein : X is oxygen or sulfur; each Rx is independently hydrogen, Cχ-C alkyl, or halo;
R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or
(c) is the group -(L)-R8o; where, -(L)- is a divalent linking group of 1 to 12 atoms and where RQ Q is a group selected from (a) or (b) ; R2 is hydrogen, halo, Cχ-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -0- (Cχ-C alkyl), -S- (Cχ-C alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, -(La)-
(acidic group) . wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (La) - (acidic group) ; and R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents. Suitable indene compounds for use in the method of the invention also include the following: an indene-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (iiif) ;
X is oxygen or sulfur;
R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C o alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non- interfering substituents; or
(c) is the group -(Lj-Rgg; where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rgo is a group selected from (a) or (b) ; R2 is hydrogen, halo, Cχ-C3 alkyl, C3-C4 cycloalkyl,
C3-C4 cycloalkenyl, -0- (Cχ-C alkyl), -S- (Cχ-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) - (acidic group), wherein -(La)-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (La) - (acidic group);
R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
6) Carbazole and tetrahydrocarbazole SPLA2 inhibitors and methods of making these compounds are set out in United States Patent Application SN 09/063066 filed April 21, 1998 (titled, "Substituted Carbazoles and 1, 2 , 3 , 4-Tetrahydrocarbazoles" ) , the entire disclosure of which is incorporated herein by reference. The method of the invention includes treatment of a mammal with these compounds .
The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount carbazole or tetrahydrocarbazole represented by the following: a compound of the formula (Ie)
wherein; a is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position; one of B or D is nitrogen and the other is carbon; Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at the 1-, 2-, or 3-position, or a 6- membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position;
is a double or single bond;
R-20 is selected from groups (a) , (b) and (c) where; (a) is - (C5-C20) alkyl, - (C5-C20) alkenyl,
- (C5-C20) alkynyl, carbocyclic radicals, or heterocyclic radicals, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group - (L) -R^O ; where, -(L)- is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in -(L)- are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only,
(v) carbon, hydrogen, and one sulfur only, and (vi) and carbon, hydrogen, and oxygen only; and where R^O is a group selected from (a) or (b) ; R21 is a non-interfering substituent; RI' is -NHNH , -NH or -CONH ; R2 ' is selected from the group consisting of -OH, and -0(CH2)tr5' where
R5' is H, -CN, -NH2, -CONH2 -CONR9R10 -NHS0 R15;
-CONHSQ2R15, where R15 is - (Cχ-Cg) alkyl or -CF3 ; phenyl or phenyl substituted with -CO2H or -CO2 (CX-C4) alkyl; and - (La) - (acidic group), wherein -(La)- is an acid linker having an acid linker length of 1 to 7 and t is 1-5;
R3 ' is selected from non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable race ate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof; provided that; when R^ ' is H, R^O χs benzyl and m is 1 or 2; R^ ' cannot be -0(CH2) h; and
Provided that when D is nitrogen, the heteroatom of Z is selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the
1-, 2-, 3- or 4-position.
Preferred in the practice of the method of the invention are compounds represented by the formula (He) :
wherein;
Z is cyclohexenyl, or phenyl;
R^l is a non-interfering substituent; R1 is -NHNH2 or -NH2 ;
R2 is selected from the group consisting of -OH and
-0(CH )m r5 where
R5 is H, -C0 H, -CONH2, -C0 (Cχ-C4 alkyl);
O
-P (R R ) (r WχLere R6 an(χ p7 are each independently -OH or -0 ( Cχ_C4 ) alkyl ; -S03H, -SO3 ( Cχ-C alkyl ) , tetrazolyl, ~CN' "NH2 ' -NHS02 R15; ~CO HS02R15, where R15 is - (C- -C X alkyl or -CF-. , phenyl or phenyl substituted with -CO„H or -CO„ (C^ -C-) alkyl where m is 1-3; R3 is H, -0(Cχ-C4) alkyl, halo, - (Cχ-Cg.) alkyl, phenyl, - (CX-C4) alkylphenyl; phenyl substituted with - (Cχ_Cg) alkyl, halo, or -CF3; -CH OSi (Cχ-Cg) alkyl, furyl, thiophenyl, - (Cχ-Cg) hydroxyalkyl ; or -
(CH2)nr8 where R8 is H, -C0NH2, -NR9R10, -CN or phenyl where R9 and R^O are independently - (Cχ~ C4) alkyl or -phenyl (C -C4) alkyl and n is 1 to 8; R4 is H, - (C5-C14) alkyl, - (C3-CX4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (Cχ-Cg) alkyl, halo, -CF3, -OCF3, -(C1-C4) alkoxy, -CN, - (0χ-
C4) alkylthio, phenyl (CI-C4) alkyl, - (Cχ~ C4) alkylphenyl, phenyl, phenoxy or naphthyl; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof.
Preferred specific compounds including all salts and prodrug derivatives thereof, for practicing the method of the invention are as follows: 9-benzyl-5 , 7-dimethoxy-l, 2,3, 4-tetrahydrocarbazole-4- carboxylic acid hydrazide; 9-benzyl-5 , 7-dimethoxy-l, 2,3, 4-tetrahydrocarbazole-4- carboxamide ; [9-benzyl-4-carbamoyl-7-methoxy-l, 2,3,4- tetrahydrocarbazol-5-yl] oxyacetic acid sodium salt; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl] oxyacetic acid;
Methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5- yl] oxyacetic acid; 9-benzyl-7-methoxy-5-cyanomethyloxy-l, 2,3,4- tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5- (lH-tetrazol-5-yl-methyl) oxy) - 1,2,3, 4-tetrahydrocarbazole-4-carboxamide; {9- [ (phenyl) methyl] -5-carbamoyl-2-methyl-carbazol-4- yl} oxyacetic acid; {9- [ (3-fluorophenyl)methyl] -5-carbamoyl-2-methyl- carbazol-4-yl}oxyacetic acid; {9- [ (3-methylphenyl) ethyl] -5-carbamoyl-2-methyl- carbazol-4-yl} oxyacetic acid; {9- [ (phenyl) methyl] -5-carbamoyl-2- (4- trifluoromethylphenyl) -carbazol-4-yl}oxyacetic acid; 9-benzyl-5— (2-methanesulfonamido) ethyloxy-7-methoxy-
1,2,3, 4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4- (2-methanesulfonamido) ethyloxy-2- methoxycarbazole-5-carboxamide; 9-benzyl-4- (2-trifluoromethanesulfonamido) ethyloxy-2- methoxycarbazole-5-carboxamide;
9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-
1,2,3, 4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-5- carboxamide; [5-carbamoyl-2-pentyl-9- (phenylmethyl) carbazol-4- yl] oxyacetic acid; [5-carbamoyl-2- (1-methylethyl) -9- (phenylmethyl) carbazol-
4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2- [ (tri (-1- methylethyl) silyl) oxymethyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl) carbazol-4- yl] oxyacetic acid[5-carbamoyl-2- (4-chlorophenyl) -9-
(phenylmethyl) carbazol-4-yl] oxyacetic acid; [5-carbamoyl-2- (2-furyl) -9- (phenylmethyl) carbazol-4- yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2- [ (tri (-1- methylethyl) silyl) oxymethyl} carbazol-4-yl] oxyacetic acid, lithium salt; {9- [ (phenyl) methyl] -5-carbamoylcarbazol-4-yl}oxyacetic acid; {9- [ (3-fluorophenyl)methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9- [ ( 3-phenoxyphenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9- [ (2-Fluorophenyl) ethyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9- [ (2-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-
4-yl}oxyacetic acid; {9- [ ( 2-benzylphenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid;
{9- [ (3-trifluoromethylphenyl)methyl] -5-carbamoylcarbazol-
4-yl}oxyacetic acid; {9- [ (1-nap thyl) ethyl] -5-carbamoylcarbazol-4- yl} oxyacetic acid; (9- [ (2-cyanophenyl) ethyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; .{9- [ (3-cyanophenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9- [ ( 2-methylphenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid;
{9- [ (3-methylphenyl) methyl] -5-carbamoylcarbazol-4- yl} oxyacetic acid; {9- [ (3 , 5-dimethylphenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9-[ (3-iodophenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9- [ (2-Chlorophenyl) methyl] -5-carbamoylcarbazol-4- yl} oxyacetic acid; {9- [ (2 , 3-difluorophenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid;
{9- [ (2, 6-difluorophenyl) ethyl] -5-carbamoylcarbazol-4- yl} oxyacetic acid; {9- [ (2, 6-dichlorophenyl)methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid; {9- [ (3-trifluoromethoxyphenyl) methyl] -5- carbamoylcarbazol-4-yl}oxyacetic acid; (9- [ (2-biphenyl) methyl] -5-carbamoylcarbazol-4- yl} oxyacetic acid; {9- [ (2-Biphenyl) ethyl] -5-carbamoylcarbazol-4- yl} oxyacetic acid; the {9- [ (2-Biphenyl) methyl] -5-carbamoylcarbazol-4- yl}oxyacetic acid;
[9-Benzyl-4-carbamoyl-l, 2,3, 4-tetrahydrocarbaole-5- yl] oxyacetic acid; {9- [ (2-Pyridyl) methyl] -5-carbamoylcarbazol-4-yl}oxyacetic acid; {9- [ (3-Pyridyl) methyl] -5-carbamoylcarbazol-4-yl}oxyacetic acid; [9-benzyl-4-carbamoyl-8-methyl-l, 2,3,4- tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-l-methylcarbazol-4-yl] oxyacetic acid;
[9-benzyl-4-carbamoyl-8-fluoro-1, 2,3,4- tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-l-fluorocarbazol-4-yl] oxyacetic acid; [9-benzyl-4-carbamoyl-8-chloro-l, 2, 3, 4- tetrahydrocarbazol-5-yl] oxyacetic acid; [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl] oxyacetic acid; [9- [ (Cyclohexyl) methyl] -5-carbamoylcarbazo1-4- yl] oxyacetic acid;
[9- [ (Cyclopentyl) methyl] -5-carbamoylcarbazol-4- yl] oxyacetic acid; 5-carbamoyl-9- (phenylmethyl) -2- [ [ (propen-3- yl) oxy]methyl] carbazol-4-yl] oxyacetic acid; [5-carbamoyl-9- (phenylmethyl) -2-
[ (propyloxy) methyl ] carbazol-4-yl] oxyacetic acid; 9-benzyl-7-methoxy-5- ( (carboxamidomethyl) oxy) -1,2,3,4- tetrahydrocarbazole-4-carboxamide; 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4- carboxamide,- 9-benzyl-7-methoxy-5- ( (lH-tetrazol-5-yl-methyl) oxy) - carbazole-4-carboxamide; 9-benzyl-7-methoxy-5- ( (carboxamidomethyl) oxy) -carbazole-
4-carboxamide; and [9-Benzyl-4-carbamoyl-l, 2,3, 4-tetrahydrocarbaole-5- yl] oxyacetic acid or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof.
Other desirable carbazole compounds suitable for practicing the method of thein invention are selected from those represented by the formula (XXX) :
(XXX) wherein :
R1 is -NHNH , or -NH2; R-2 is selected from the group consisting of -OH and - 0(CH2)mr5 where
0
-P (R6R7) R5 is H, -C0 H, -C0 (C1-C4 alkyl); ,where R6 and
R^ are each independently -OH or -O (C -C4)alkyl; -S03H, -S03(Cχ-C alkyl), tetrazolyl, -CN, -NH2 '
-NHS02R15; -C0NHS0 R15, where R15 is - (Cχ-Cg) alkyl or -CF3 , phenyl or phenyl substituted with -C02H or -CO2 (CX-C4) alkyl where m is 1-3;
R3 is H, -O (Cχ-C4) alkyl, halo, - (Cχ-Cg) alkyl, phenyl, - (CX-C4) alkylphenyl; phenyl substituted with
-(Cχ_Cg) alkyl, halo, or -CF3 ; -CH20Si (Cχ-Cg) alkyl, furyl, thiophenyl, - (Cχ-Cg) hydroxyalkyl; or -
(CH )nr8 where R8 is H, -CONH , -NR9R10, -CN or phenyl where R° and R^O are independently -(Cχ~ C4) alkyl or -phenyl (CX-C4) alkyl and n is 1 to 8;
R4 is H, - (C5-CX4) alkyl, - (C3-C 4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (Cχ-Cg) alkyl, halo, -CF3, -OCF3 , -(CX-C ) alkoxy, -CN, - (Cχ~
C4) alkylthio, phenyl (CI-C4) alkyl, - (Cχ~ C4) alkylphenyl, phenyl, phenoxy or naphthyl; a is phenyl or pyridyl wherein the nitrogen is at the
5-, 6-, 7- or 8-position; Z is cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1-, 2- or 3-position or a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-position, or wherein one carbon on the heterocyclic ring is optionally substituted with =0; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof ,- provided that one of A or Z is a heterocyclic ring.
Further desirable specific compounds suitable for the method of the invention are selected from the following:
(R, S) - (9-benzyl-4-carbamoyl-l-oxo-3-thia-l,2,3,4- tetrahydrocarbazol-5-yl) oxyacetic acid; (R, S) - ( 9- benzyl-4-carbamoyl-l-oxo-3-thia-l , 2,3,4- tetrahydrocarbazol-5-yl) oxyacetic acid; [N-benzyl-1- carbamoyl-l-aza-1 , 2,3, 4-tetrahydrocarbazol-8- yl] oxyacetic acid; 4-methoxy-6-methoxycarbonyl-10- phenylmethyl-6, 7,8, 9-tetrahydropyrido [1, 2-a] indole; (4- carboxamido-9-phenylmethyl-4 , 5-dihydrothiopyrano [3,4- b] indol-5-yl) oxyacetic acid; 3, 4-dihydro-4- carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4- b] indole; 2- [(2, 9 bis-benzyl-4-carbamoyl-l, 2 , 3 , 4- tetrahydro-beta-carbolin-5-yl) oxy] cetic acid or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof .
Particularly preferred compounds for the treatment of renal dysfunction are represented by the formulae (Xe) and (xie) below: and
For all of the above compounds of the carbazole or tetrahydrocarbazole type it is advantageous to use them in their (i) acid form, or (ii) pharmaceutically acceptable (e.g., Na, K) form, or (iii) and prodrugs derivatives (e.g., Methyl ester, ethyl ester, n-butyl ester, morpholino ethyl ester) . Prodrugs are derivatives of SPLA2 inhibitors used in the method of the invention 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 compounds of this invention 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 derived from acidic groups 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. Specific preferred prodrugs are ester prodrugs inclusive of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl, tert-butyl ester, N,N-diethylglycolamido ester, and morpholino-N-ethyl ester. Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No. 60/063280 filed October 27, 1997 (titled, N,N-diethylglycolamido ester Prodrugs of Indole SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference; U.S. Provisional Patent Application Serial No. 60/063646 filed October 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs of Indole SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference; and US Provisional Patent Application Serial No. 60/063284 filed October 27, 1997 (titled, Isopropyl Ester Prodrugs of Indole SPLA2
Inhibitors) , the entire disclosure of which is incorporated herein by reference.
Carbazole and tetrahydrocarbazole SPLA2 inhibitor compounds useful for practicing the method of the invention may be made by the following general methods : the compounds of formula Ie where Z is cyclohexene are prepared according to the following reaction Schemes Ig(a)and (c) .
Scheme Ig(a)
wherein;
R1 is -NH2, R3(a) is H, -O (C -C4) alkyl, halo, - (Cχ~ Cg ) alkyl , phenyl , - (Cχ-C ) alkylphenyl ; phenyl substituted with - (Cχ-Cg) alkyl, halo, or -CF3 ; - CH OSi(Cχ-Cg) alkyl, furyl, thiophenyl, - (Cχ~ Cg) hydroxyalkyl, - (Cχ_Cg) alkoxy (Cχ-Cg) alkyl, - (Cx- Cg) alkoxy (Cχ_Cg) alkenyl; or -(CH2)nr8 where R8 is H,
-CONH2, -NR9R10, -CN or phenyl where R9" and R10 are independently hydrogen, -CF3 , phenyl, - (Cχ-C4) alkyl, - (CX-C4) alkylphenyl or -phenyl (Cχ-C4) alkyl and n is 1 to 8; when R1 is -NHNH2 r R3 (a) is H, -0 (CX-C4) alkyl, halo,
- (Cχ-Cg) alkyl, phenyl, - (CX-C4) alkylphenyl; phenyl substituted with - (Cχ-Cg) alkyl, halo or -CF3 ; -CH2θSi (Cχ-Cg) alkyl, furyl, thiophenyl, - (Cχ-Cg) hydroxyalkyl, - (Cχ-Cg) alkoxy (Cχ-Cg) alkyl,
- (Cχ-Cg) alkoxy (Cχ-Cg) alkenyl; or -(CH2)nr8 where R8 is H, -NR9R10, -CN or phenyl where R9 and R10 are independently hydrogen, -CF3 , phenyl, - (Cχ-C4) alkyl,
- (CX-C4) alkylphenyl or -phenyl (Cχ-C4) alkyl and n is 1 to 8;
R2(a) χs -0CH3 or -OH.
An appropriately substituted nitrobenzene (1) can be reduced to the aniline (2) by treatment with a reducing agent, such as hydrogen in the presence of Pd/C, preferably at room temperature.
Compound (2) is N-alkylated at temperatures of from about 0 to 20 °C using an alkylating agent such as an appropriately substituted aldehyde and sodium cyanoborohydride to form (3). Alternately, an appropriately substituted benzyl halide may be used for the first alkylation step. The resulting intermediate is further N-alkylated by treatment with 2-carbethoxy- 6-bromocyclohexanone, preferably at temperatures of about 80 °C to yield (4) or by treatment with potassium hexamethyldisilazide and the bromoketoester .
The product (4) is cyclized to the tetrahydrocarbazole (5) by refluxing with zncl2 in benzene for from about 1 to 2 days, preferably at 80 C (see Julia, M. ; Lenzi, J. Preparation d'acides tetrahydro-1, 2, 3 , 4-carbazole-l ou -4.
Bull . Soc . Chim. France, 1962, 2262-2263). Compound (5) is converted to the hydrazide (6) by treatment with hydrazine at temperatures of about 100 °C, or to the amide (7) by reacting with methylchloroaluminum amide in benzene (see Levin, J.I.; Turos, E.; Weinreb, S.M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn . Comm. , 1982, 12, 989-993) . Alternatively, (7) may be produced by treatment of (6) with Raney nickel active catalyst.
It will be readily appreciated that when R3 (a) χS:
0 -(CH2)nCO (C-^^ alkyl),
Conversion to the amide will also be achieved in this procedure.
Compounds (6) and (7) may be dealkylated, preferably at 0 °C to room temperature, with a dealkylating agent, such as boron tribromide or sodium thioethoxide, to give compound (7) where R2 (a) χs _OH, which may then be further converted to compound (9) , by realkylating with a base, such as sodium hydride, and an alkylating agent, such as Br(CH2)mr^' where R^ is the carboxylate or phosphonic diester or nitrile as defined above. Conversion of R^ to the carboxylic acid may be accomplished by treatment with an aqueous base. When R2 is nitrile, conversion to the tetrazole may be achieved by reacting with tri-butyl tin azide or conversion to the carboxamide may be achieved by reacting with basic hydrogen peroxide. When R^ is the phosphonic diester, conversion to the acid may be achieved by reacting with a dealkylating agent such as trimethylsilyl bromide. The monoester may be accomplished by reacting the diester with an aqueous base.
When R2 and R3 are both methoxy, selective demethylation can be achieved by treating with sodium ethanethiolate in dimethylformamide at 100 °C.
An alternative synthesis of intermediate (5) is shown in Scheme 1(b), as follows.
Scheme Ig(b)
(2; (4')
where PG is a protecting group;
R a is as defined in Scheme 1, above, The aniline (2) is N-alkylated with 2-carbethoxy-6- bromoeyelohexanone in dimethyl formamide in the presence of sodium bicarbonate for 8-24 hours at 50 °C. Preferred protecting, groups include methyl, carbonate, and silyl groups, such as t-butyldimethylsilyl . The reaction product (4') is cyclized to (5') using the zncl2 in benzene conditions described in Scheme 1(a), above. N- alkylation of (5') to yield (5) is accomplished by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours .
Scheme iig
R3 (a) χs as defined in Scheme Ig.
As discussed in Scheme I above, carbazole (5) is hydrolyzed to the carboxylic acid (10) by treatment with an aqueous base, preferably at room temperature to about 100 °C . The intermediate is then converted to an acid chloride utilizing, for example, oxalyl chloride and dimethylformamide, and then further reacted with a lithium salt of (S) or (R) -4-alkyl-2-oxazolidine at a temperature of about -75 °C, to give (11a) and (lib), which are separable by chromatography.
The diastereomers are converted to the corresponding enantiomeric benzyl esters (12) by brief treatment at temperatures of about 0°C to room temperature with lithium benzyl oxide (see Evans, D.A. ; Ennis, M.D.; Mathre, D.J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of alpha- substituted carboxylic acid derivatives J. Am. Chem. Soc . , 1982, 104, 1737-1738) .
The esters (12) are then converted to (7) preferably by treatment with methylchloroalummum amide (Ref 2, above) or, alternately, by hydrogenation using, for example, hydrogen and palladium on carbon, as described above, to make the acid and then reacting with an acyl azide, such as diphenylphosphoryl azide followed by treatment with ammonia. Using the procedure described above in Scheme I, compound (9a) or (9b) may be accomplished.
Compounds of formula Ie where Z is phenyl can be prepared as follows in Schemes III (a) -(f), below.
Scheme III (a)
(13) (14) A 1, 2 , 3 , 4-tetrahydrocarbazole-4-carboxamide or 4- carboxhydrazide (13) is dehydrogenated by refluxing in a solvent such as carbitol in the presence of Pd/C to produce the carbazole-4-carboxamide. Alternately, treatment of (13) with DDQ in an appropriate solvent such as dioxane yields carbozole (14) .
Depending on the substituent pattern oxidation as described above may result in de-alkylation of the nitrogen. For example when R3 is substituted at the 8- position with methyl, oxidation results in dealkylation of the nitrogen which may be realkylated by treatment with sodium hydride and the appropriate alkyl halide as described in Scheme 1(a) above to prepare the deired product (14) .
Scheme Ill(b)
(15) (15) (25)
,
(20) (21)
(22) (23)
ined in Scheme I (a) above protecting group
(24) Benzoic acid derivative (16) where X is preferably chlorine, bromine or iodine and the protecting group is preferably -CH3, are reduced to the corresponding aniline
(25) with a reducing agent, such as stannous chloride in the presence of acid under the general conditions of Sakamoto et al, Chem Pharm. Bull. 35 (5), 1823-1828 (1987) .
Alternatively, reduction with sodium dithionite in the presence of a base, such as sodium carbonate in a noninterferring solvent, such as water, ethanol, and/or tetrahydrofuran affords starting material (16) .
Alternatively, reduction by hydrogenation over a sulfided platinum catalyst supported on carbon with hydrogen at 1 to 60 atmospheres in a noninterfering solvent, preferably ethyl acetate, to form a starting material (16) .
The reactions are conducted at temperatures from about 0 to 100 °C . Preferably at ambient temperature, and are substantially complete in about 1 to 48 hours depending on conditions.
The aniline (25) and dione (15) are condensed under dehydrating conditions, for example, using the general procedure of Iida, et al . , (Ref 5), with or without a noninterfering solvent, such as toluene, benzene, or methylene chloride, under dehydrating conditions at a temperature about 10 to 150 °C . The water formed in the process can be removed by distillation, azetropic removal via a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, and the like.
The process can be performed with or without a catalytic amount of an acid, such a p-toluenesulfonic acid or methanesulfonic acid. Other examples of suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride, and acetic acid.
Examples of other suitable solvents include tetrahydrofuran, ethyl acetate, methanol, ethanol,
1, 1, 2, 2-tetrachloroethane, chlorobenzene, bromobenzene, xylenes, and carbotetrachloride.
The condensation of the instant process is preferably carried out neat, at a temperature about 100 to 150 °C with the resultant water removed by distillation via a stream of inert gas, such as, nitrogen or argon.
The reaction is substantially complete in about 30 minutes to 24 hours.
Intermediate (26) may then be readily cyclized in the presence of a palladium catalyst, such as Pd(oac)2 or Pd(ppt-3)4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o-tolylphosphine , or tricyclohexylphosphine, and the like, a base, such as, sodium bicarbonate, triethylamine, or diisopropylethylamine, in a noninterfering solvent, such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200°C to form (19) .
Examples of other suitable solvents include tetrahydrofuran, benzene, dimethylsulfoxide, or dimethylformamide .
Examples of other suitable palladium catalysts include Pd(pph3)Cl2, Pd(OCOCF3) , [ (CH CgH4) 3P] pdcl2 , [(CH3CH2)3P]2Pdcl2, [ (C6Hχχ) 3P] 2pdcl2 , and [(CgH5)3P]2Pdbr2. Examples of other suitable phosphines include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2- bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1,4- bis (diphenylphosphino) butane .
Examples of other suitable bases include tripropyl amine, 2, 2 , 6, 6-tetramethylpiperidine, 1,5- diazabicyclo [2.2.2] octane (DABCO) , 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5- diazabicyclo [4.3.0]non-5-ene, (DBN) sodium carbonate, potassium carbonate, and potassium bicarbonate.
The cyclization of the instant process is preferably carried out with palladium (II) acetate as catalyst in the presence of either triphenylphosphine, tri-o- tolylphosphine, 1, 3-bis (diphenylphosphino) propane, or tricyclohexylphosphine in acetonitrile as solvent and triethylamine as base at a temperature about 50 to 150 °C . The reaction is substantially complete in about 1 hour to 14 days.
Alternatively, a preferred process for cyclization consists of the reaction of intermediate (26) with a palladacycle catalyst such as trans-di (μ-acetato) -bis [o- (di-o-tolylphosphino) benzyl] dipalladium (II) in a solvent such as dimethylacetamide (DMAC) at 120-140 °C in the presence of a base such as sodium acetate.
Intermediate (19) may be alkylated with an alkylating agent XCH2R , where X is halo in the presence of a base to form (20) . Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N- benzyltrimethylammonium hydroxide) .
The reaction may or may not be carried out in the presence of a crown ether. Potassium carbonate and Triton B are preferred. The amount of alkylating agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material .
A catalytic amount of an iodide, such as sodium iodide or lithium iodide may or may not be added to the reaction mixture. The reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile.
Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether.
The reaction is conducted at temperatures from about
-10 to 100 °C . Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions. Optionally, a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed.
Intermediate (20) May by dehydrogenated by oxidation with 2 , 3-dichloro-5 , 6-dicyano-l, 4-benzoquinone in a noninterfering solvent to form (21) . Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, diethyl ether, methyl ethyl ketone, and t-butyl methyl ether. Toluene, benzene, dioxane, and tetrahydrofuran are preferred solvents. The reaction is carried out at a temperature about 0 to 120 °C. Temperatures from 50 to 120 °C are preferred. The reaction is substantially complete in about 1 to 48 hours depending on conditions . Intermediate1 (21) may be animated with ammonia in the presence of a noninterfering solvent to form a (22) . Ammonia may be in the form of ammonia gas or an ammonium salt, such as ammonium hydroxide, ammonium acetate, ammonium trifluoroacetate, ammonium chloride, and the like. Suitable solvents include ethanol, methanol, propanol, butanol, tetrahydrofuran, dioxane, and water. A mixture of concentrated aqueous ammonium hydroxide and tetrahydrofuran or methanol is preferred for the instant process. The reaction is carried out at a temperature about 20 to 100 °C . Temperatures from 50 to 60 °C are preferred. The reaction is substantially complete in about 1 to 48 hours depending on conditions.
Alkylation of (22) is achieved by treatment with an alkylating agent of the formula XCH2R9 where X is halo and R70 is -C0 R71, -SO3R71, -P (O) (OR71) 2 , or -
P(0) (0R i)H, where R71 is an acid protecting group or a prodrug function, in the presence of a base in a noninterfering solvent to form (23). Methyl bromoacetate and t-butyl bromoacetate are the preferred alkylating agents .
Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N-benzyltrimethylammonium hydroxide) . The reaction may or may not be carried out in the presence of a crown ether . Cesium carbonate and Triton B are preferred. The amount of alkylating agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material . The reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether.
The reaction is conducted at temperatures from about -10 to 100 °C . Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions. Optionally, a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed.
Intermediate (23) may be optionally hydrolyzed with a base or acid to form desired product (24) and optionally salified.
Hydrolysis of (23) is achieved using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous potassium carbonate, aqueous sodium carbonate, aqueous lithium carbonate, aqueous potassium bicarbonate, aqueous sodium bicarbonate, aqueous lithium bicarbonate, preferably sodium hydroxide and a lower alcohol solvent, such as, methanol, ethanol, isopropanol, and the like. Other suitable solvents include acetone, tetrahydrofuran, and dioxane . Alternatively, the acid protecting group may be removed by organic and inorganic acids, such as trifluoroacetic acid and hydrochloric acid with or without a noninterferring solvent. Suitable solvents include methylene chloride, tetrahydrofuran, dioxane, and acetone. The t-butyl esters are preferably removed by neat trifluoroacetic acid. The reaction is conducted at temperatures from about -10 to 100°C. Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions . The starting material (16) is prepared by esterifying compound (15) with a alkyl halide = XPG; where X is halo and PG is an acid protecting group, in the presence of a base, preferably potassium carbonate or sodium cabonate, in a noninterferring solvent, preferably dimethylformamide or dimethylsulfoxide. The preferred alkyl halide is methyl iodide. The reaction is conducted at temperatures from about 0 to 100°C. Preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions. Alternatively the starting material (16) may be prepared by condensation with an alcohol HOPG, where PG is an acid protecting group, in the presence of a dehydrating catalyst such as, dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole. In addition, U.S. Patent No. 4,885,338 and Jpn.
Kokai Tokkyo Koho 05286912, Nov 1993 Hesei teach a method for preparing 2-fluoro-5-methoxyaniline derivatives.
Scheme iiig (c)
( 22 ) ( 23 )
R is as defined in Scheme iiig(b) ,
R3 (a) χs as defined in Scheme Ig(a), above; and
X is halo.
Benzoic acid derivatives (16) (X= Cl, Br, or I) and boronic acid derivative (27) (either commercially available or readily prepared by known techniques from commercially available starting materials) are condensed under the general procedure of Miyaura, et al., (Ref 8a) or Trecourt, et al . , (Ref 8b) in the presence of a palladium catalyst, such as Pd(Pl-3P)4, a base, such as sodium bicarbonate, in an inert solvent, such as THF, toluene or ethanol, to afford compound (28) .
Compound (28) is converted to the carbazole product (29) by treatment with a trialkyl or triaryl phosphite or phosphine, such as, triethylphosphite or triphenyl phosphine, according to the general procedure of Cadogan, et al . , J. Chem. Soc, 4831 (1965).
Compound (29) is N-alkylated with an appropriately substituted alkyl or aryl halide XCH2R^ in the presence of a base, such as sodium hydride or potassium carbonate, in a noninterfering solvent, such as toluene, dimethylformamide, or dimethylsulfoxide to afford carbazole (30) . Compound (30) is converted to the corresponding amide (22) by treatment with boron tribromide or sodium thioethoxide, followed by ammonia or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, or with ethylchloroaluminum amide in an inert solvent, such as toluene, at a temperature between 0 to 110 °C.
When R (a) is substituted at the 8-position with chloro, de-alkylation of (30) with boron tribromide results in de-benzylation of the nitrogen as described above. Alkylation may be readily accomplished in a two step process. First, an O-alkylation by treatment with a haloalkyl acetate such as methyl bromo acetate using sodium hydride in tetrahydrofuran, followed by N-alkylation using for example a base such as sodium hydride and an appropriately substituted alkyl or aryl halide in dimethoxy formamide. Compound (22) can be converted to product carbazole product (24) as described previously in Scheme iiig(b) above. Conversion to the desired prodrug may be accomplished by techniques known to the skilled artisan, such as for example, by treatment with a primary or secondary halide to make an ester prodrug.
Scheme iiig(d)
(29)
Alternatively, reduction of the nitro group of compound (28) with a reducing, agent, such as hydrogen in the presence of palladium on carbon, in a noninterfering solvent, such as ethanol, at 1 to 60 atmospheres, at a temperature of 0 to 60°C affords the corresponding aniline (32). Compound (32) is converted to the carbazole (29) according to the general procedure described by Miyaura, et al . , Synthetic
Communications 11, 523(1981). The aniline is treated with sulfuric acid and sodium nitrite, followed by sodium azide to form an intermediate azide which is cyclized to carbazole (29) by heating in an inert sovent, such as toluene. Compound (29) is converted to carbazole product (24) as described previously in Schemes iiig(b) and iiig(c).
Scheme iiig(e)
(40) (41)
In an aprotic solvent, preferably tetrahydrofuran, reduction of (40) is achieved using a reducing agent such as aluminum trihydride. Preferably, the reaction is conducted under inert atmosphere such as nitrogen, at room temperature. Sulfonylation may be achieved with an appropriate acylating agent in the presence of an acid scavenger such as triethyl amine. Scheme iiig(f)
activating agent iysrSO2 L
(50 )
( 51)
In a two-step, one-pot process, intermediate (50) , prepared as described in Scheme 1(a) above, is first activated with an activating agent such as carbonyl diimidazole. The reaction is preferably run in an aprotic polar or non-polar solvent such as tetrahydrofuran. Acylation with the activated intermediate is accomplished by reacting with H2NSOR in the presence of a base, preferably diazabicycloundecene . Scheme iiig (g)
( 61 ) ( 62 )
(63) (64)
PG is an acid protecting group;
R22 is (Cχ-Cg) alkoxy (Cχ-Cg) alkyl is (Cl-Cg) alkoxy
(Cχ-Cg) alkenyl.
Starting material (20) is O-alkylated with an alkyl halide or alkenyl halide, using a base such as NaH, in an aprotic polar solvent preferably anhydrous DMF, at ambient temperature under a nitrogen atmosphere. The process of aromatization from a cyclohexenone functionality to a phenol functionality can be performed by treating the tetrahydrocabazole . intermediate (60) with a base such as NaH in the presence of methyl benzenesulfinate in an anhydrous solvent, such as 1, 4-dioxane or DMF, to form the ketosulfoxide derivative. Upon heating at about 100 °C for 1-2 hours, the ketosulfoxide derivative (60) is converted to the phenol derivative (61). Conversion of the ester (61) to the amide (62) can be achieved by treating a solution of (61) in an aprotic polar solvent such as tetrahydrofuran with ammonia gas . Phenolic 0- alkylation of (62) with, for example, methyl bromoacetate can be carried out in anhydrous DMF at ambient temperature using CS2CO3 or K2CO3 as a base to form (63) . Desired product (64) can be derived from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H20/CH3OH/THF solution at 50 °C for 1-2 hours .
When R22 is - (Cχ-Cg) alkoxy (Cχ-Cg) alkenyl, hydrogenation of the double bond can be performed by treating (63) in THF using Ptθ2 as a catalysis under a hydrogen atmosphere. Desired product can then be derived as described above in Scheme IΙI(g) from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H2O/CH3OH/THF solution at 50°C for 1-2 hours.
H) Pyrazole SP A2 inhibitors
The method of the invention may be practiced using pyrazole s L .2 inhibitors, which are described (together with the method of making) in US Patent Application No. 08/984261, filed December 3, 1997, the entire disclosure of which is incorporated herein by reference. Suitable pyrazole compounds are represented by formula (Ih)
wherein:
R1 is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin- 2-yl, pyridin-2-yl substituted at the 4- position with - (Cχ-C4) alkyl, (Cχ-C4) alkoxyl, -
CN or - (CH2)nconh.2 where n is 0-2;
R2 is phenyl; phenyl substituted with 1 to 3 substituents selected from the group consisting of -(Cχ-C4) alkyl, -CN, halo, -N02 , C0 (Cχ~ C4) alkyl and -CF3 ; naphthyl; thiophene or thiophene substituted with 1 to 3 halo groups;
R3 is hydrogen; phenyl; phenyl (C2~Cg) alkenyl; pyridyl; naphthyl; quinolinyl; (Cχ-C4 ) alkylthiazolyl ; Phenyl substituted with 1 to 2 substituents selected from the group consisting of -(CX-C4) alkyl, -CN, -CONH , -N0 , -CF3 , halo,
(C1-C4) alkoxy, CO2 (C1-C4) alkyl, phenoxy and SR4 where R^ is - (C1-C4) alkyl or halophenyl; Phenyl substituted with one substituent selected from the group consisting, of -0(CH2) r5 where p is 1 to 3 and R^ is - CN, -CO2H, -CONH2, or tetrazolyl, Phenyl and
-ORS where R^ is cyclopentyl, cyclohexenyl, or phenyl substituted with halo or (CX-C4) alkoxy;
Or phenyl substituted with two substituents which, when taken together with the phenyl ring to which they are attached form a ethylenedioxy ring; and M is 1 to 5; or a pharmaceutically acceptable salt thereof.
Particularly preferred are pyrazole type SPLA2 inhibitors as follows: a pyrazole compound of formula (I), supra, wherein:
R1 is pyridine-2-yl or pyridine-2-yl substituted at the 4-position with - (Cχ-C4) alkyl, (Cχ-C4) alkoxy, -CN or
-(CH )nCONH2 where n is 0-2;
R2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of - (CX-C4) alkyl, -CN, halo, -NO2, CO2 (CX-C4) alkyl and -CF3 ; and
R3 is phenyl; phenyl (C2~Cg) alkenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of - (C -C4) alkyl, -CN, -CONH2 , -NO2 - CF3, halo, (C -C4) alkoxy, CO2 (CX-C4) alkyl, phenoxy and
SR4 where R^ is - (C -C4) alkyl or halo phenyl; phenyl substituted with one substituent selected from the group consisting of -0(CH2)pr^ where p is 1 to 3 and R5 is -CN, -CO2H, -CONH2 or tetrazolyl, phenyl and - OR6 where R^ is cyclopentyl, cyclohexenyl or phenyl substituted with halo or (Cχ-C4) alkoxy; or phenyl substituted with two substituents which when taken together with the phenyl ring to which they are attached form a methylenedioxy ring.
Specific suitable pyrazole type SPLA2 inhibitors useful in the method of the invention are as follows : Compounds selected from the group consisting of 3- (2- chloro-6-methylphenylsulfonylamino) -4- (2- (4- acetamido) pyridyl) -5- (3- (4-fluorophenoxy) benzylthio) -
(IH) -pyrazole and 3- (2 , 6-dichlorophenylsulfonylamino) -4-
(2- (4-acetamido) pyridyl) -5- (3- (4- fluorophenoxy) benzylthio) - (IH) -pyrazole.
I) Phenyl glyoxamide SPLA2 inhibitors (and the method of making them) are described in U.S. Patent Application Serial No. 08/979446, filed November 24, 1997 (titled, Phenyl Glyoxamides as SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference.
The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount a phenyl glyoxamide type SPLA2 inhibitors useful in the method of the invention are as follows: a compound of the formula ( Ii )
wherein: X is -O- or -(CH2)m-/ where m is 0 or 1;
Y is -C02-, -PO3-, -SO3-;
R is independently -H or - (Cχ-C4) alkyl;
Ri and R2 are each independently -H, halo or - (C1-C4) lkyl ; R3 and R^ are each independently -H, - (C -C4) alkyl,
(C -C4) alkoxy, (CX-C4) alkylthio, halo, phenyl or phenyl substituted with halo; N is 1-8; and P is 1 when Y is -CO2- or -SO3- and 1 or 2 when Y is -PO3-;. or a pharmaceutically acceptable salt thereof.
A specific suitable phenyl glyoxamide type SPLA2 inhibitors is 2- (4-carboxybut-l-yl-oxy) -4- (3- phenylphenoxy) phenylglyoxamide . ) Pyrrole SPLA2 inhibitors and methods of making them are disclosed in U.S. Patent Applicaton Serial No. 08/985518 filed December 5, 1997 (titled, "Pyrroles as SPLA2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount a pyrrole SPLA2 inhibitors useful in the method of the invention as follows : a compound of the formula (Ij)
R1 is hydrogen, (Cχ-C4) alkyl, phenyl or phenyl substituted with one or two substituents selected from the group consisting of - (CX-C4) alkyl, (CX-C4) alkoxy, phenyl (C -C4) alkyl, (C -C4) alkylthio, halo and phenyl;
R2 is hydrogen, - (Cχ-C4) alkyl, halo, (Cχ-C4) alkoxy or (CX-C4) alkylthio;
R3 and R^ are each hydrogen or when taken together are =0; R5 is - H2 or -NHNH ; R6 and R7 are each hydrogen or when one of R6 and R7 is hydrogen, the other is - (Cχ-C4) alkyl, -(CH2)nrlO where
R10 is -C0 R1:L, -PO3 (R11)^, -P04(R1:L)2 or -SO3R11 where RU is independently hydrogen or - (C -C4) alkyl and n is 0 to 4; or R6 and R7 , taken together, are =0 or =S;
X is R8(Cχ-Cg) alkyl; R8 (C -Cg) alkenyl or phenyl substituted at the ortho position with R8 where R8 is
(CH2)nr10 where R10 is -C0 R1:L, -Pθ3(R1:L)2, -P0 (R1:L) or
-SO3R I, RH and n is 1 to 4 as defined above, and additionally substituted with one or two substituents selected from the group consisting of hydrogen, - (C1-C4) alkyl, halo, (CX-C4) alkoxy, or two substituents which, when taken together with the phenyl ring to which they are attached, form a naphthyl group; and R9 is hydrogen or methyl or ethyl; or a pharmaceutically acceptable salt thereof. Preferred pyrrole SPLA2 inhibitors useful in the method of the invention are compounds of formula Ij wherein;
R1 is phenyl ;
R2 is methyl or ethyl;
R5 is -NH ;
R6 and R7 are each hydrogen; X is RS (Cχ-Cg) alkyl or phenyl substituted at the ortho position with R8 where R8 is -C02R1:L; and R° is methyl or ethyl . A specific suitable pyrrole SPLA2 inhibitors useful in the method of the invention is 2- [l-benzyl-2, 5- dimethyl-4- (2-carboxyphenylmethyl) pyrrol-3-yl] glyoxamide . K) Naphthyl glyoxamide SPL 2 inhibitors and methods of making them are described in U.S. Patent Application Serial No. 09/091079, filed December 9, 1966. (titled, "Naphthyl Glyoxamides as SPLA2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount a naphthyl glyoxamide SPLA2 inhibitors useful in the method of the invention are as follows -. a naphthyl glyoxamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula Ik
wherein : R1 and R2 are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R1 or R2 must be hydrogen;
X is -CH2- or -0-; and
Y is (CH2)nz where n is a number from 1-3 and Z is an acid group selected from the group consisting of CO2H, -SO3H or -PO(OH)2-
A specific suitable naphthyl glyoxamide SPLA2 inhibitors useful in the method of the invention has the following structural formula:
L) Phenyl acetamide SPLA2 inhibitors and methods of making them are disclosed in US Patent Application 08/976858, filed November 24 1997 (titled, "Phenyl Acetamides as SPLA2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of a phenyl acetamide S LA2 inhibitor represented by formula (II) as follows:
wherein:
R1 is -H or -0(CH2)nz;
R2 is -H or -OH; R3 and R^ are each independently -H, halo or
- (Cχ-C ) alkyl; one of R5 and R^ is -YR7 and the other is -H, where Y is -0- or -CH2- and R7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, - (CX-C4) alkyl, (Cχ~
C4) alkoxy, phenyl or phenyl substituted with one or two halo groups ;
Z is -CO2R, -PO3R2 or -SO3R where R is -H or - (C1-C4) alkyl; and N is 1-8; or a pharmaceutically acceptable salt, racemate or optical isomer thereof; provided that when R^ is YR7 , R1 is hydrogen; and when R1, R2 , R3 , R^ and R^ are hydrogen and R^ is YR7 where Y is -O- , R7 cannot be phenyl; and when Ri, R2 , R3 , R4 and R6 are hydrogen, R5 is YR7 where Y is CH2 , R7 cannot be phenyl substituted with one methoxy or two chloro groups .
Preferred suitable phenyl acetamide SPLA2 inhibitors usef l in the method of the invention are as follows : compounds of formula I wherein R2 , R3 and R^ is H, Y is oxygen or CH2 , R7 is phenyl or phenyl substituted at the meta position with one or two substituents selected from halo, - (CX-C4) alkyl, (CX-C4) alkoxy, phenyl or phenyl substituted with halo and n is 4-5.
A specific suitable phenyl acetamide SPLA2 inhibitors useful in the method of the invention is 2- (4- carboxybutoxy) -4- ( 3-phenylphenoxy) phenylacetamide .
M) Naphthyl acetamide SPLA2 inhibitors and the method of making them are described in U.S. Patent Application Serial No. 09/091077, filed December 9, 1996 (titled, "Benzyl naphthalene SPLA2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
A naphthyl acetamide SPLA2 inhibitor is represented by formula (Im) as follows: wherein :
R1 and R2 are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R1 and R2 must be hydrogen;
CH, o
R3 is hydrogen, -0(CH2)nY, " -O ^ x )'n -0 n ' (vΛv)'nnY" where n is from 2 to 4 and Y is -CO2H, -PO3H2 or SO3H; and X is -O- or -CH2-.
N) The method of the invention is for treatment of a mammal, including a human, afflicted with renal dysfunction, said method comprising administering to said human a therapeutically effective amount of pyrrolo[l,2- a]pyrazine derivative SPLA2 inhibitors useful in the method of the invention as follows : a compound of the formula (In)
wherein R1 is a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) -(Lx)-R6 wherein L1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s) , nitrogen atom(s) , carbon atom(s) , oxygen atom(s) , and sulfur atom(s) , and R5 is a group selected from the groups (a) and (b) ;
R2 is hydrogen atom, or a group containing 1 to 4 non-hydrogen atoms ;
R3 is - (L2) - (acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 5; R4 and R5 are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent (s) , heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent (s) and;
RA is a group represented by the formula:
wherein L7 is a divalent linker group selected from a bond or a divalent group selected from -CH2-, -0-, -S-, -NH-, or -CO-, R27 and R28 are independently hydrogen atom, Cl to C3 alkyl or a halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is -NH2 or -NHNH2; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
A preferred subclass of compounds of formula (In) are those where for Rx the divalent linking group
-(Lχ)~ is a group represented by any one of the following formulae (Ina) or (Inb) or (Inc) :
(la)
H„
or
where ζχ is a bond or any of the divalent groups (la) or (lb) and each R is independently hydrogen, Cχ_g alkyl, Cχ_8 haloalkyl or Cχ_g alkoxy.
Particularly preferred as the linking group -(Lχ)~ of R is an alkylene chain of 1 or 2 carbon atoms, namely, -(CH2)~ or -(CH2-CH2)--
Preferred SPLA2 inhibitor compounds of the invention are represented by the formula (Iln)
(Iln) wherein R7 is -(CH2)m _R wherein m is an integer from
1 to 6, and R^2 is (d) a group represented by the formula :
wherein a, c, e, n, q, and t are independently an integer from 0 to 2 , R^-3 and R^-^ are independently selected from a halogen, 0χ to Cχo alkyl, Cx to Cχo alkyloxy, Cx to Cχo alkylthio, aryl, heteroaryl, and Cx to Cχø haloalkyl, α is an oxygen atom or a sulfur atom, L^ is a bond, - (CH2) -, -C=C-, -CC-, -0-, or -S-, v is an integer from 0 to 2, β is -CH2~ or -(CH2)2 - Y is an oxygen atom or a sulfur atom, b is an integer from 0 to 3 , d is an integer from 0 to 4, f , p, and w are independently an integer from 0 to 5, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of 0χ to Cg alkyl, C to Cg alkyloxy, 0χ to Cg haloalkyloxy, Cx to Cg haloalkyl, aryl, and a halogen;
R8 is Cx to C3 alkyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, Cx to C2 haloalkyl, Cx to C3 alkyloxy, or Cx to C3 alkylthio;
R9 is -(L3)-R1 wherein L3 is represented by the formula :
wherein M is -CH -, -0-, -N(R24)-, or -S-, R16 and R17 are independently hydrogen atom, 0χ to Cχo alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and
R 4 is hydrogen atom or Oχ to Cg alkyl, and R^5 ±s represented by the formula:
wherein R-*-8 χs hydrogen atom, a metal, or Cx to Cχo alkyl, !9 is independently hydrogen atom, or Oχ to Cχo alkyl, and t is an integer from 1 to 8;
R!0 and RU are independently hydrogen atom or a non-interfering substituent selected from hydrogen, Cx to
Cg alkyl, Cx to Cg alkenyl, Cx to Cg alkynyl, C7 to Cχ2 aralkyl, C7 to Cχ2 alkaryl, C3 to Cg cycloalkyl, C3 to Cg cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, Cx to Cg alkyloxy, C2 to Cg alkenyloxy, C2 to Cg alkynyloxy, C2 to
C 2 alkyloxyalkyl, C2 to C 2 alkyloxyalkyloxy, C2 to Cχ2 alkylcarbonyl, C2 to Cχ2 alkylcarbonylamino, C2 to Cχ2 alkyloxyamino, C2 to Cχ2 alkyloxyaminocarbonyl, C2 to Cχ2 alkylamino, Cx to Cg alkylthio, C2 to C 2 alkylthiocarbonyl, Cx to Cg alkylsulfinyl, C to Cg alkylsulfonyl, C2 to Cg haloalkyloxy, Cx to Cg haloalkylsulfonyl, C2 to Cg haloalkyl, C to Cg hydroxyalkyl, -C(0)0(Cχ to Cg alkyl), -(CH2)z-0-( Cx to
Cg alkyl), benzyloxy, aryloxy, arylthio, - (CONHSO2R25) , CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, - (CH2 ) z~C02H, cyano, cyanoguanidinyl , guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, or carbonyl, R2^ is Cx to Cg alkyl or aryl, z is an integer from 1 to 8; and R^ is a group represented by the formula:
wherein Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R^3 or R^- may be different from one another. When R^3 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. The invention further relates to specific preferred SPLA2 inhibitor compounds of formule (I) or (II) namely a pyrrolo [1, 2-a]pyrazine compound selected from the group consisting of :
[6-Benzyl-7-ethyl-8—oxamoylpyrrolo [1, 2-a]pyrazin-l- yl] oxyacetic acid,
[ 6-Cyclohexylmethyl-7-ethyl-8-oxamoylpyrrolo [1,2- a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-6- (3-methoxybenzyl) -8-oxamoylpyrrolo [1, 2- a]pyrazin-l-yl] oxyacetic acid, [6- (Benzo[b] thiophen-6-ylmethyl) -7-ethyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[ 6-Benzyl-7-ethyl-3-methyl-8-oxamoylpyrrolo [1,2- a]pyrazin-l-yl] oxyacetic acid, [7-Ethyl-6- (4-fluorobenzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[6- (2-Biphenylmethyl) -7-ethyl-3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[6-Cyclopentylmethyl-7-ethyl-3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[6- (2-Benzyl)benzyl-7-ethyl-3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid, [7-Ethyl-6- (3-fluorobenzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-1-yl] oxyacetic acid,
[6-Benzyl-7-ethyl-3-isopropyl-8-oxamoylpyrrolo [1,2- a]pyrazin-l-yl] oxyacetic acid,
[6-Benzyl-3 , 7-diethyl-8-oxamoylpyrrolo [1,2- a] pyrazin-1-yl] oxyacetic acid,
[6-Benzyl-7-ethyl-8-oxamoyl-3-phenylpyrrolo [1,2- a]pyrazin-l-yl] oxyacetic acid,
[6-Benzyl-7-ethyl-3-isobutyl-8-oxamoylpyrrolo [1, 2- a]pyrazin-l-yl] oxyacetic acid, [3 , 6-Dibenzyl-7-ethyl-8-oxamoylpyrrolo [1,2- a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl)pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6-(2- phenylethynylbenzyl)pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid, [7-Ethyl-3-methyl-8-oxamoy1-6- (2-phenyloxybenzyl ) pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6- (2- (3- thienyl) benzyl) pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid, [7-Ethyl-3-methyl-6- (2- (5-methylthien-2-yl)benzyl) - 8-oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-6- (2- (4-methoxyphenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-3-methyl-6- (2- (4-methylphenyl) benzyl ) -8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6- (2- (2- phenylethyl) benzyl) pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[6-Benzyl-7-cyclopropyl-3-methyl-8- oxamoylpyrrolo [1, 2-a] pyrazin-1-yl] oxyacetic acid,
[7-Cyclopropyl-6- (4-fluorobenzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[6-Benzyl-3-cyclohexyl-7-ethyl-8-oxamoylpyrrolo [1,2- a] pyrazin-1-yl] oxyacetic acid, [6- (2-Biphenylmethyl) -3-cyclohexyl-7-ethyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid, [6-Benzyl-3 , 7-dimethyl-8-oxamoylpyrrolo [1, 2-a]pyrazin-1- yl] oxyacetic acid,
[7-Ethyl-3-methyl-6- (5-methylthien-2-ylmethyl) -8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
[6- (Benzo [b] thiophen-3-ylmethyl) -7-ethyl-3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid,
Sodium [7-ethyl-6- (4-fluorobenzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl]oxyacetate, Sodium [7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3- methyl-8-oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, Sodium [7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl)pyrrolo [1, 2-a].pyrazin-l-yl] oxyacetate,
Sodium [7-ethyl-3-methyl-8-oxamoyl-6- (2- (3- thienyl) benzyl)pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, and the prodrugs thereof; the parent acids thereof, or their pharmaceutically acceptable salts; or their solvates .
Most preferred as SPLA2 inhibitors of the invention are [7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, methyl ester;
[7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxa oylpyrrolo [1, 2-a] pyrazin-1-yl] oxyacetate, ethyl ester;
[7 -ethyl-6- (2- (4-fluorophenyl)benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, morpholinylethyl ester;
[7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, sodium salt;
[7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl)pyrrolo [1, 2-a] pyrazin-1-yl] oxyacetic acid, methy1 ester; [7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) pyrrolo [1, 2-a] pyrazin-1-yl] oxyacetic acid, ethyl ester;
[7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) pyrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid, morpholinylethyl ester; [7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) pyrrolo [1, 2-a]pyrazin-1-yl] oxyacetic acid, sodium salt.
FORMULATIONS SUITABLE FOR USE IN THE METHOD OF THE INVENTION
The SPLA2 inhibitors used in the method of the invention may be administered to treat renal dysfunction by any means that produces contact of the active agent with the agent's site of action in the animal body. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents . The SPLA2 inhibitors can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
Suitable formulations are those comprising a therapeutically effective amount of SPLA2 inhibitor 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 SPLA2 inhibitor ("active compound" ) in the formulation and not deleterious to the subject being treated.
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 SPLA2 inhibitor 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 0.01 to about 99 weight percent of the SPLA2 inhibitor.
Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The active compound can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, saline, dextrose solution, sterile organic solvent or a mixture of both.
The active compound can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms. It can also be administered by inhalation in the form of a nasal spray or lung inhaler. It can also be administered topically as an ointment, cream, gel, paste, lotion, solution, spray, aerosol, liposome, or patch. Dosage forms used to administer the active compound usually contain suitable carriers, diluents, preservatives, or other excipients, as described in Remington's Pharmaceutical Sciences, Merck Publishing Company, a standard reference text in the field. Gelatin capsules may be prepared containing the active compound and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets and powders . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance . For parenteral solutions, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain the active compound, suitable stabilizing agents, and if necessary, buffer substances. Anti-oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Topical ointments, creams, gels, and pastes contain with the active compound diluents such as waxes, paraffins, starch, polyethylene glycol, silicones, bentonites, silicic acid, animal and vegetable fats, talc and zinc oxide or mixtures of these or other diluents. Topical solutions and emulsions can, for example, contain with the active compound, customary diluents (with the exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent) , such as solvents, dissolving agents and emulsifiers; specific examples are water, ethanol, 2- propanol, ethyl carbonate, benzyl alcohol, propylene glycol, oils, glycerol, and fatty acid esters of sorbitol or mixtures thereof. Compositions for topical dosing may also contain preservatives or anti-oxidizing agents.
Powders and sprays can contain along with the active compound, the usual diluents, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures of these materials. Aerosol sprays can contain the usual propellants.
Liposomes can be made from such materials as animal or vegetable fats which will form lipid bilayers in which the active compound can be incorporated.
Formulations containing compounds of the invention may be administered through the skin by an appliance such as a transdermal patch. Patches can be made of a matrix such as polyacrylamide and a semipermeable membrane made from a suitable polymer to control the rate at which the material is delivered to the skin. Other suitable transdermal patch formulations and configurations are described in U.S. Patents Nos. 5,296,222 and 5,271,940, the disclosures of which are incorporated herein by reference. Lipophilic prodrug derivatives of the SPLA2 inhibitors are particularly well suited for transdermal absorption administration and delivery systems.
For all of the above formulations the preferred active compound are the lH-indole-3-glyoxylamide compounds as previously described and methods of making as described in n US Patent No. 5,654,326 (the disclosure of which is incorporated herein by reference) . Most preferred compounds within the general class of 1H- indole-3-glyoxylamides are ( (3- (2-amino-l, 2-dioxoethyl) - 2-ethyl-l- (phenylmethyl) -lH-indol-4yl) oxy) acetic acid, sodium salt; and lH-indole-3-glyoxylamides are ((3- (2- amino-1, 2-dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol- 4yl) oxy) acetic acid, methyl ester.
PROPORTION AND WEIGHT OF ACTIVE COMPOUNDS USED IN THE METHOD OF THE INVENTION
The lH-indole-3-glyoxylamide compound may be used at a concentration of 0.1 to 99.9 weight percent of the formulation.
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 compound 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.
Compositions (dosage forms) suitable for internal administration contain from about 1 milligram to about 500 milligrams of active compound per unit. In these pharmaceutical compositions the active compound will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
Examples of useful pharmaceutical compositions and their proportions of ingredients are illustrated as follows:
Capsules: Capsules may be prepared by filling standard two-piece hard gelatin capsules each with 50 mg of powdered active compound, 175 mg of lactose, 24 mg of talc, and 6 mg of magnesium stearate. Soft Gelatin Capsules: A mixture of active compound in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 mg of the active compound. The capsules are washed in petroleum ether and dried. Tablets: Tablets may be prepared by conventional procedures so that the dosage unit is 50 mg of active compound, 6 mg of magnesium stearate, 70 mg of microcrystallme cellulose, 11 mg of cornstarch, and 225 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Suspensions: An aqueous suspension is prepared for oral administration so that each 5 ml contain 25 mg of finely divided active compound, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mg of vanillin. Injectables: A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active compound in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.
Nasal Spray: An aqueous solution is prepared such that each 1 ml contains 10 mg of active compound, 1.8 mg methylparaben, 0.2 mg propylparaben and 10 mg methylcellulose. The solution is dispensed into 1 ml vials .
The active compound may be used at a concentration of 0.01 to 99.9 weight percent of the formulation.
Aerosol formulations are capable of dispersing into particle sizes of from about 0.5 to about 10 microns and have sufficient SPLA2 inhibitor to achieve concentrations of the inhibitor on the airway surfaces of from about 10"10 to 10"2 moles per liter.
THE PRACTICE OF THE METHOD OF THE INVENTION
The use of SPLA2 inhibitors in the method of the invention prevents progressive deterioration by inhibiting or reducing the degree of renal dysfunction that may be a primary pathologic process in renal dysfunction. The method of the invention is preferably used early in the symptomatic-life of the patient afflicted with renal dysfunction. The method of the invention can be practiced using pharmaceutical formulations containing SPLA2 inhibitors
(preferably, SPLA2 inhibitors identified as preferred herein) or formulations containing such ΞPLA2 inhibitors as taught in the preceding section. Although it is believed that the underlying causes of renal dysfunction will not be prevented by the method of this invention, the symptoms will be reduced in severity or extent by administration of SPL 2 inhibitors
(and their formulations) . The dosage administered will vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; ' nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active compound can be about 0.1 to 200 milligrams per kilogram of body weight. Ordinarily 0.5 to 50, and preferably 1 to 25 milligrams per kilogram per day given in divided doses 1 to 6 times a day or in sustained release form is effective to obtain desired results.
In general, the SPLA2 inhibitor will be administered to an animal so that a therapeutically effective amount is received. A therapeutically effective amount may conventionally be determined for an individual patient by administering the active compound in increasing doses and observing the effect on the patient, for example, improvement in exercise, increased appetite, or a reduction in other symptoms associated with renal dysfunction.
Generally, the compound must be administered in a manner and a dose to achieve in the animal a blood level concentration of SPLA2 inhibitor of from 10 to 3000 nanograms/ml , and preferably a concentration of 100 to
800 nanograms/ml .
The treatment regimen may stretch over many days to months or to years. Oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four oral doses per day, each from about 0.01 to 25 mg/kg of body weight with preferred doses being from about 0.1 mg/kg to about 2 mg/kg. Parenteral administration (particularly, intravenous administration) is often preferred in instances where rapid alleviation of patient distress is required. With parenteral administration doses of 0.01 to 100 mg/kg/day administered continuously or intermittently throughout the day may be used. For parenteral administration, the compound may be administered in a physiologic saline vehicle (e.g., 0.9% normal saline, 0.45% normal saline, etc.) a dextrose vehicle (e.g., 5% dextrose in water), or a combination of saline and dextrose vehicle (0.9% normal saline in 5% dextrose) .
Inhalation therapy also may be useful either alone or as an adjunct to other routes of administration. With inhalation therapy, doses necessary to produce a decrease in the clinical symptoms of renal dysfunction are readily determined and used.
TESTING METHODS FOR RENAL DYSFUNCTION
The diagnostic criteria for renal dysfunction are those found in standard medical references (e.g.,
Harrison's Principles of Internal Medicine, thirteenth ed., 1994, by McGraw-Hill, Inc., ISBN 0-07-032370-4) . These criteria, or criteria designated by competent medical opinion may be used to determine when to begin using the method of the invention, the frequency and degree of treatment, and the time for cessation of treatment .
For example, the renal dysfunction patient having renal disease may be evaluated with any conventional measure of renal capacity. The renal dysfunction patient having gastrointestinal disease may be evaluated by conventional criteria for adequate nutrition.
The underlying renal dysfunction event may be evaluated and treated according to current standards of good medical practice, where the standard treatment is supplemented with the administration of a compound according to this invention. Results of a To Evaluate the Effects of Compound 374388 in Fischer 344 Rats with Surgically Induced Chronic Renal
Failure
Study R09199
374388 is an oralsPLA2 inhibitor compound of the present invention. The purpose of this study was to evaluate the effect of 374388 in a model of chronic renal failure in male Fisher 344 (F344) rats, when administered daily by gavage. Doses of 0, 3 or 30 mg/kg were administered for approximately 2 months (dosing begun approximately 60 days after the nephrectomy performed at Lilly Research Laboratories) . Alterations in live phase, and morphologic and clinical pathology parameters were compared to findings in age-matched control, sham- nephrectomized control, and vehicle-control nephrectomized rats. No compound-related alterations suggestive of toxicity occurred.
Chronic renal failure was successfully induced in nephrectomized rats. The only remarkable difference in mortality among the nephrectomized groups was an increased number of rats in the 30mg/kg group that died during the pretreatment phase . The high pretreatment mortality in this group was likely due to the increased area of renal infarction seen in most rats in the 30- mg/kg group at necropsy, resulting in a more rapid onset of renal failure. Due to the mortality in this group, data from this group were not analyzed statistically.
Body weight and body weight gains were improved in uremic rats given 3 mg/kg 374388 compared to nephrectomized controls. Near the end of the treatment phase (Day 112), mean body weight for rats given 3 mg/kg was significantly increased relative to the nephrectomized control value and was within approximately 5% of the control group mean, as compared to 19% for nephrectomized control rats. Although not statistically analyzed, body weight change data for rats given 30 mg/kg followed the same general trend as that seen in the 3-mg/kg group.
Alterations in clinical and morphologic pathology parameters in nephrectomized rats were attributed to the model (chronic renal failure-uremia) . Alterations in these parameters, in general, were less pronounced in nephrectomized rats given 374388, suggesting that this compound may ameliorate the effects of uremia. On Day 117, nephrectomized rats given 3mg/kg had minimal increases in cholesterol, total protein, and total carbon dioxide and slight to moderate decreases in BUN, CREAT and IP compared to nephrectomized controls.
Nephrectomized control rats surviving to study termination had more severe nephropathy, and a higher incidence of secondary parathyroid hyperplasia, fibrous osteodystrophy and periarteritis nodusus, compared to nephrectomized rats given 3 mg/kg.
In conclusion, this, study demonstrated a reliable model of chronic renal failure in the rat. Data from this preliminary study suggest that daily doses of 3 mg/kg of 374388 ameliorated the effects of uremia in rats with surgically induced chronic renal failure. Therefore, 374388 and other members of the class of compounds of formula I may be potential therapeutic agents for the treatment of chronic renal failure (uremia) in human beings.
While the present invention has been illustrated by certain specific embodiments, these are not intended to limit the scope of the invention.

Claims

CLAIMS :
1. A method for treatment of an animal afflicted with renal dysfunction, said method comprising administering to said animal a therapeutically effective amount of a composition including members selected from the group comprising: lH-indole-3-glyoxylamide, 1H- indole-3-hydrazide, lH-indole-3-acetamide, lH-indole-1- glyoxylamide, lH-indole-1-hydrazide, lH-indole-1- acetamide, indolizine-1-acetamide, indolizine-1-acetic acid hydrazide, indolizine-1-glyoxylamide, indene-1- acetamide, indene-1-acetic acid hydrazide, indene-1- glyoxylamide, carbazole, tetrahydrocarbazole, pyrazole, phenyl glyoxamide, pyrrole, naphthyl glyoxamide, naphthyl acetamide, phenyl acetamide, 9H-carbazole, 9- benzylcarbazole and mixtures thereof.
2. A method for treatment of an animal afflicted with renal dysfunction, said method comprising administering to said animal a therapeutically effective amount of a lH-indole-3-glyoxylamide represented by the formula (I) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
where;
X is oxygen, R! is selected from the group consisting of -C7-C20 alkyl ,
where
RIO is selected from the group consisting of halo, Cχ-Cχo alkyl, Cχ-Cχo alkoxy, -S-(Cχ-Cχo alkyl) and halo (Cχ-Cχo) lkyl, and t is an integer from 0 to 5 both inclusive; R2 is selected from the group consisting of hydrogen, halo, cyclopropyl, methyl, ethyl, and propyl; R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent and the group, - (La) - (acidic group); where, at least one of R4 and R5 is the group, - (La) -
(acidic group) and wherein the (acidic group) is selected from the group consisting of -CO2H, -SO3H, or -P(O) (OH) 2; where,
- (La) - s an acid linker with the proviso that; the acid linker group, -(La)-, for R4 is selected from the group consisting of
where R^3 χs a non-interfering substituent, and where, the acid linker, -(La)-, for R5 is selected from the group consisting of
where
R8 and R85 are each independently selected from hydrogen, Cχ-Cχo alkyl, aryl, Cχ-Cχo alkaryl, Cχ-Cχo arylkyl, carboxy, carbalkoxy, and halo where n is between 1 and 8 and, Rg and R7 are each independently selected from hydrogen and non-interfering substituents, where non-interfering substituents are selected from the group consisting of Cχ-Cg alkyl, C2~Cg alkenyl, C2~Cg alkynyl, C7-C12 arylenalkyl, C7-C12 alkaryl, C3~Cg cycloalkyl, C3~C cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, Cχ-Cg alkoxy, C2-C alkenyloxy, C2~Cg alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-Cχ2 alkylcarbonyl, C2-Cχ2 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl , C2-CX2 alkylamino, Cχ-Cg alkylthio, C2-C12 alkylthiocarbonyl, Cl-Cg alkylsulfinyl, Cχ-Cg alkylsulfonyl, C2-Cg haloalkoxy, Cχ-Cg haloalkylsulfonyl, C2-Cg haloalkyl, Cχ-Cg hydroxyalkyl, -C(0)0(Cχ-Cg alkyl), - (CH2)n-0- (Cχ-Cg alkyl), benzyloxy, phenoxy, phenylthio, - (CONHSO2R) / - CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, - (CH2)rι~C02H, chloro, cyano, cyanoguanidinyl , fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Cχ-Cg carbonyl.
3. A method for treatment of an animal afflicted with renal dysfunction, said method comprising administering to said animal a therapeutically effective amount of a compound represented by the formula (II) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
(II) where Yx is selected from the group consisting of O,
R-L is selected from the group consisting of -C7-C20 alkyl ,
where
R!0 is selected from the group consisting of halo, Cχ-Cχo alkyl, Cχ-Cχ alkoxy, -S- (Cχ-Cχo alkyl) and halo (Cχ-Cχo) alkyl, and t is an integer from 0 to 5 both inclusive; where R31, R32, R33, R31', R32 ' < ^33'' R34 and R34' are independently selected from the group consisting of hydrogen, CONR101R102, alkyl, alkylaryl, aryl, alkylheteroaryl, haloalkyl, alkylCONR101R102, a non- interfering substituent and the group - (L ) - (acidic group) ; where at least one of R31, R32' R33 or R34 ^s the group - (La) - (acidic group) where -(La)- is an acid linker selected from the group consisting of
84 84
H -N- ■(CH2)n- -CHP -(CH2)n- and
R 85
R' 85
where R^4 and R^^ are each independently selected from the group consisting of hydrogen, Cχ-Cχg alkyl, aryl, Cχ-Cχo alkaryl, Cχ-Cχg aralkyl, carboxy, carbalkoxy, and halo; and n is 1 or 2 and, where the (acidic group) is selected from the group consisting of -C02H, -S03H, -Cθ2NR101R102 and -P(0)(OH)2 and, where R^-d and R^2 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl and haloalkyl and, where non-interfering substituents are selected from the group consisting of Cχ-Cg alkyl, C2-C alkenyl, C2~Cg alkynyl, C7-C12 arylalkyl, C7-C12 alkylaryl, C3-Cg cycloalkyl, C3-Cg cycloalkyl, phenyl, tolulyl, xylyl, biphenyl, Cχ-Cg alkoxy, C2~Cg alkyloxy, C2~Cg alkynyloxy, C2~Cχ2 alkoxyalkyl, C2~Cχ2 alkoxyalkyloxy, C2-Cχ2 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-CX2 alkoxyamino, C2-C12 alkoxya inocarbonyl , C2-C12 alkylamino, Cχ-Cg alkylthio, C2-C12 alkylthiocarbonyl, Cl-Cg alkylsulfinyl, Cχ-Cg alkylsulfonyl, C2~C haloalkoxy, Cχ-Cg haloalkylsulfonyl, C2~Cg haloalkyl, Cχ-Cg hydroxyalkyl, -C (0) O (Cχ-Cg alkyl) , - (CH2 )n-0- (Cχ-Cg alkyl), benzyloxy, phenoxy, phenylthio, - (CONHSO2 (R) ) , - 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 Cχ-Cg carbonyl and where n is between about 1 and 8 and,
R is selected from the group consisting of hydrogen and alkyl .
4. A method for treatment of an animal afflicted with renal dysfunction, said method comprising administering to said animal in need of such treatment, a therapeutically effective amount of a lH-indole-3- glyoxylamide compound or a 9H-carbazole or a pharmaceutically acceptable salt, solvate, or a prodrug derivative thereof selected from the group consisting of compounds (A) through (AL) :
(A) [ [3- (2-amino-l, 2-dioxoethyl) -2-methyl-l- (phenylmethyl) -IH indol-4-yl] oxy] acetic acid,
(B) ' dl-2- [ [3- (2-amino-l, 2-dioxoethyl) -2- methyl-1- (phenylmethyl) -IH indol-4-yl] oxy]propanoic acid,
(C) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -2-ylmethyl) -2 methyl-lH-indol-4-yl] oxy] acetic acid,
(D) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -3-ylmethyl) -2-methyl-lH-indol-4-yl] oxy] acetic acid,
(E) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -4-ylmethyl) -2-methyl-lH-indol-4-yl] oxy] acetic acid,
(F) [ [3- (2-amino-l, 2-dioxoethyl) -1- [ (2, 6- dichlorophenyl)methyl] -2-methyl-lH-indol-4-yl] oxy] acetic acid (G) [ [3- (2-amino-l, 2-dioxoethyl) -1- [4 (- fluorophenyl) methyl] -2-methyl-lH-indol-4-yl] oxy] acetic acid,
(H) [ [3- (2-amino-l , 2-dioxoethyl) -2-methyl-l-
[ ( 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, (J) [ [3- (2-amino-l, 2-dioxoethyl) -1- [ (3- chlorophenyl) methyl] -2-ethyl-lH-indol-4-yl] oxy] acetic acid,
(K) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -2-ylmethyl) -2-ethyl-lH-indol-4-yl] oxy] acetic acid,
(L) [[3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- biphenyl] -2-ylmethyl) -2-propyl-lH-indol-4-yl] oxy] acetic acid, (M) [ [3- (2-amino-l, 2-dioxoethyl) -2- cyclopropyl-1- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid,
(N) [ [3- (2-amino-l, 2-dioxoethyl) -1- ( [1,1'- 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,
(AG) 1- (9H-benzylcarbazol-l-halo-4-yloxy-5- alkylamido) alkylacetate, (AH) 1- (9H-benzylcarbazol-4-yloxy-5-alkylamido) alkylacetate,
(Al) 1- (9H-benzylcarbazol-l-halo-4-yloxy-5- alkylamido) acetic acid,
(AJ) 1- (9H-benzylcarbazol-4-yloxy-5-alkylamido) acetic acid and
(AK) mixtures of (AG) through (AJ) and
(AL) mixtures of (A) through (AK) combined with an additional treatment composition.
5. A method for treatment of an animal afflicted with renal dysfunction, said method comprising administering to said animal in need of such treatment a therapeutically effective amount of a composition selected from the group comprising:
where R is independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl.
R!05 is selected from the group consisting of H2 , NHNH2 and alkylamino and,
RU is selected from groups (a) , (b) and (c) where;
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group -(L)- R^O; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R^O is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3- C4 cycloalkenyl, -0- (Cχ-C2 alkyl), -S- (Cχ-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
R--6 and R17 are independently selected from hydrogen, a non-interfering substituent, or the group, - (La) - (acidic group); wherein -(La)-, is an acid linker having an acid linker length of 1 to 10-; provided, that at least one of R!6 and R^7 must be the group, - (La) - (acidic group) ; and
Rl4 and R^-5 are each independently selected from hydrogen, non-interfering substituents, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
6. A method for treatment of an animal afflicted with renal dysfunction, said method comprising administering to said animal in need of such treatment, a therapeutically effective amount of a compound of the formula (XII)
where :
R-L05 χs selected from the group consisting of NH2 , NHNH2 and alkylamino and, R50 is -OH, or -0(CH2)m R53 where
R^3 is selected from the group consisting of H, - o II
C02H, -Cθ2(Cχ-C4 alkyl), -P( R54 R55), phenyl, -CO2H substituted phenyl and -CO2 (C1-C4 alkyl) where R^4 and R^5 are each independently selected from the group consisting of -OH and -0(Cχ-C4 alkyl) and, m is 1, 2 or 3 ;
R51 is selected from the group consisting of H, - 0(Cχ-C4 alkyl), and -(CH2)nR56 where R56 is selected from the group consisting of H, -N
0 II and phenyl where,
R^7 and R^δ are independently selected from the group consisting of - (C1-C4) alkyl, and phenyl (C1-C4) alkyl and, n is between about 0 and 9;
R^2 is selected from the group consisting of H, - (C5-C14) alkyl, - (C3-C14) cycloalkyl, phenyl, or phenyl substituted with 1 or 2 substituents selected from the group consisting of - (C1-C4) alkyl, (C1-C4) alkoxy, phenyl (C1-C4) lkyl, (C1-C4) alkylthio, halo or phenyl; and
Z is cyclohexenyl or phenyl; or a pharmaceutically acceptable salt, racemate or optical isomer thereof; provided that when R51 is H, R^2 is phenyl, m is 1 or 2 and R50 is a substituent at the 6 position, R^3 cannot be H; and 0 II when R105 is NHNH2 , R8 cannot be - CκH2.
7. A method for treatment of an animal afflicted with renal dysfunction, wherein the method comprises administering to said animal in need of such treatment, a therapeutically effective amount of a compound selected from the group consisting of; 4- [ (9-benzyl-4-carbamoyl- 1, 2, 3 , 4-tetrahydrocarbazol-6-yl) oxy]butyric acid; 3-[(9- benzyl-4-carbamoyl-l, 2,3, 4-tetrahydrocarbazol-6- yl) oxy]propylphosphonic acid; 2- [ (9-benzyl-4-carbamoyl- 1, 2 , 3 , 4-tetrahydrocarbazol-6-yl) oxy]methylbenzoic acid; 3- [ (9-benzyl-4-carbamoyl-7-n-octyl-l, 2,3,4- tetrahydrocarbazol-6-yl) oxy]propylphosphonic acid; 4-[(9- benzyl-4-carbamoyl-7-ethyl-l, 2,3, 4-tetrahydrocarbazol-6- yl) oxy] butyric acid; 3- [ (9-benzyl-4-carbamoyl-7-ethyl- 1,2,3, 4-tetrahydrocarbaz'ol-6-yl) oxy]propylphosphonic acid; 3- [ (9-benzyl-4-carbamoyl-7-ethyl-l, 2 , 3 , 4- tetrahydrocarbazol-6-yl) oxy]propylphosphonic acid; (S)- (+) -4- [ (9-benzyl-4-carbamoyl-7-ethyl-l, 2, 3, 4- tetrahydrocarbazol-6-yl) oxy] butyric acid; 4- [9-benzyl-4- carbamoyl-6- (2-cyanoethyl) -1,2,3, 4-tetrahydrocarbazol-6- yl] oxybutyric acid; 4- [9-benzyl-4-carboxamido-7- (2- phenylethyl) -1,2,3, 4-tetrahydrocarbazol-6-yl] oxybutyric acid; and 4- [9-benzyl-4-carboxamidocarbazol-6- yl] oxybutyric acid. •
8. A method for treatment of an animal afflicted with renal dysfunction, wherein the method comprises administering to said animal in need of such treatment, a therapeutically effective amount of a compound represented by the formula (In) :
(In) wherein R is a group selected from (a) Cg to C20 alkyl, Cg to C20 alkenyl, Cg to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) - L^)-R6 wherein L^ is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s) , nitrogen atom(s) , carbon atom(s) , oxygen atom(s) , and sulfur atom(s) , and R^ is a group selected from the groups (a) and (b) ;
R2 is hydrogen atom, or a group containing 1 to 4 non-hydrogen atoms ;
R3 is - (L2) - (acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 5 ;
R4 and R5 are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent (s) , heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent (s) ; and
RA is a group represented by the formula: wherein L7 is a divalent linker group selected from a bond or a divalent group selected from -CH2-, -0-, -S-,
-NH- , or -CO-, R27 and R28 are independently hydrogen atom, Cx to C3 alkyl or a halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is - NH2 OR -NHNH2 ; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
9. A method for treatment of an animal afflicted with renal dysfunction, wherein the method comprises administering to said animal in need of such treatment, a therapeutically effective amount of a pyrrolo [1,2- a]pyrazine compound selected from the group consisting of:
[7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a] pyrazin-1-yl] oxyacetate, methyl ester;
[7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, ethyl ester;
[7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, morpholinylethyl ester; [7-ethyl-6- (2- (4-fluorophenyl) benzyl) -3-methyl-8- oxamoylpyrrolo [1, 2-a]pyrazin-l-yl] oxyacetate, sodium salt; [7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) yrrolo [1, 2-a]pyrazin-l-yl] oxyacetic acid, methyl ester;
[7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) yrrolo [1, 2-a] pyrazin-1-yl] oxyacetic acid, ethyl ester;
[7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) yrrolo [1, 2-a] pyrazin-1-yl] oxyacetic acid, morpholinylethyl ester; and
[7-ethyl-3-methyl-8-oxamoyl-6- (2- (2- thienyl) benzyl) pyrrolo [1, 2-a] pyrazin-1-yl] oxyacetic acid, sodium salt.
10. A pharmaceutical composition comprising of a SPLA2 inhibitor useful for the treatment of renal dysfunction.
11. The use of a SP A2 inhibitor in combination with therapeutically effective agents and or procedures selected from the group consisting of dialysis treatment to remove harmful toxins; drugs to restore salt and water balance; for the delay, prevention and/or treatment of acute or chronic renal failure.
12. The use of a sPLA2 inhibitor in combination with atrial naturetic factor (ANF) for the delay, prevention and/or treatment of acute and chronic renal failure in a mammal.
13. The use of a SPL 2 in combination with erythropoetin to stimulate red cell production in a mammal .
14. The present invention is also the use of a SPL 2 inhibitor in combination with 0KT3™ to prevent kidney rejection or reduce the symotoms assocaited with administration of 0KT3™.
15. A method as in any one of Claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 wherein the administration of SPLA2 inhibitor compound is in an amount of from 0.01 mg/kg/day to 100 mg/kg/day.
16. The method as in any one of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 wherein the administration of SPL 2 compound is oral.
17. The method as in any one of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 wherein treatment is of an animal afflicted with renal dysfunction and the SPL 2 inhibitor is administered in a therapeutically effective amount to achieve an animal blood level inhibitor concentration of from 10 to 3000 nanograms/ml .
18. The method as in any one of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 wherein the therapeutically effective amount is in the form of a pharmaceutical formulation comprising the SPL 2 inhibitor and a suitable carrier or excipient therefor.
19. The method as in Claim 11 wherein the therapeutically effective amount is in the form of a pharmaceutical formulation comprising: a SPL 2 inhibitor compound and a suitable carrier or excipient therefor.
20. Use of a SPL 2 inhibitor selected from 1H- indole-3-glyoxylamide, lH-indole-3-hydrazide, iH-indole- 3-acetamide, IH-indole-l-glyoxylamide, IH-indole-l- hydrazide, lH-indole-1-acetamide, indolizine-1-acetamide, indolizine-1-acetic acid hydrazide, indolizine-1- glyoxyla ide, indene-1-acetamides, indene-1-acetic acid hydrazide, indene-1-glyoxylamide, carbazoles, tetrahydrocarbazoles, pyrazoles, phenyl glyoxamides, pyrroles, naphthyl glyoxamides, naphthyl acetamide, and phenyl acetamide for the manufacture of a medicament for therapeutic treatment of renal dysfunction.
21. Use of a compound selected from compounds represented by one of one of the following formulae
wherein R is independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl for the manufacture of a medicament for therapeutic treatment of renal' dysfunction.
22. The method as in any one of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 wherein the administration is transdermal.
23. The method as in any one of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 wherein the administration is intramuscular.
24. Use of a composition including members selected from the group comprising: lH-indole-3-glyoxylamide, 1H- indole-3-hydrazide, lH-indole-3-acetamide, lH-indole-1- glyoxylamide, lH-indole-1-hydrazide, lH-indole-1- acetamide, indolizine-1-acetamide, indolizine-1-acetic acid hydrazide, indolizine-1-glyoxylamide, indene-1- acetamide, indene-1-acetic acid hydrazide, indene-1- glyoxylamide, carbazole, tetrahydrocarbazole, pyrazole, phenyl glyoxamide, pyrrole, naphthyl glyoxamide, naphthyl acetamide, phenyl acetamide, 9H-carbazole, 9- benzylcarbazole, 1- (9H-benzylcarbazol-l-halo-4-yloxy-5- alkylamido) alkylacetate, 1- (9H-benzylcarbazol-4-yloxy-5- alkyla ido) alkylacetate, 1- (9H-benzylcarbazol-l-halo-4- yloxy-5-alkylamido) acetic acid, 1- (9H-benzylcarbazol-4- yloxy-5-alkylamido) acetic acid and mixtures thereof for the manufacture of a medicament for the therapeutic treatment of renal dysfunction.
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