WO2001055108A2 - Methode de traitement d'inflammations au moyen d'inhibiteurs spla¿2? - Google Patents

Methode de traitement d'inflammations au moyen d'inhibiteurs spla¿2? Download PDF

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WO2001055108A2
WO2001055108A2 PCT/US2001/000011 US0100011W WO0155108A2 WO 2001055108 A2 WO2001055108 A2 WO 2001055108A2 US 0100011 W US0100011 W US 0100011W WO 0155108 A2 WO0155108 A2 WO 0155108A2
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alkyl
acid
methyl
ethyl
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WO2001055108A3 (fr
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Jerome Herbert Fleisch
William Louis Macias
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Eli Lilly And Company
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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
    • A61K31/495—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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A61K31/40—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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention is directed to a method for treating inflammation. More specifically, the present invention is directed to a method for treating the symptoms secondary to an inflammatory event by administering a therapeutically effective amount of an SP A2 inhibitor.
  • Inflammation is an organism's natural response to an injury or to the destruction of tissue.
  • Exemplary injuries that trigger an inflammatory event are represented by exposure to certain chemicals, allergic reactions, infection, physical trauma, birth defects, surgical complications, poisoning, shock, and biochemical abnormalities. These inflammatory events result in injurious symptoms to human as well as other mammals.
  • injurious symptoms secondary to an inflammatory event are observed in allergic rhinitis, and asthma.
  • the swelling of the sinus and bronchial membranes secondary to an allergic reaction often causes significant discomfort and inflammation.
  • a further example is observed in allergic conjunctivitis.
  • the swelling of the conjunctiva tissues secondary to an allergic interraction event often causes significant discomfort, inflammation and decreased vision because of swollen membranes.
  • Osteomyelitis Pancreatitis, Pharyngitis, Platelet aggregration, Prostatitis, Renal failure, Reperfusion injury, Rheumatoid arthritis, Sarcoidosis, Sepsis, Severe sepsis, Septic shock, Sickle cell syndrome (acute chest syndrome) , Systemic inflammatory response syndrome, Sjogrens syndrome, Stroke, Systemic Lupus erythematism, Tendonitis, Thrombosis, Tonsillitis, Trauma, Tubulo- interstitial nephritides, Ulcerative colitis, Uveitis, chronic inflammation.
  • Previous treatment attempts have typically focused on pharmaceutical agents that treated the cause of the inflammation instead of the inflammation directly. For example, using antibiotic treatment of an infection can be contrasted with the treatment of the inflammation caused by the infection.
  • This invention is directed to a method of alleviating the symptoms of an animal afflicted with inflammation by administering a therapeutically effective amount of a SPLA2 inhibitor compound of formula I. DETAILED DESCRIPTION OF THE INVENTION
  • Inflammation means a state wherein the body tissues or any one selected tissue displays one or more classic signs of pain, heat, redness, swelling (edema) , and loss of function according to competent medical authority. Inflammation also includes chronic inflammation that may or may not be the result of a determinable cause .
  • inflammation event means an event that triggers the inflammation of one or more tissues of the subject organism.
  • inflammation events include those of the following list:
  • Sickle cell syndrome acute chest syndrome
  • Sjogrens syndrome Stroke
  • Systemic Lupus erythematism Tendonitis
  • Thrombosis Tonsillitis
  • Trauma Tubulo- interstitial nephritides
  • Ulcerative colitis Uveitis and chronic inflammation.
  • terapéuticaally effective amount is a quantity of SPLA2 inhibitor sufficient to ameliorate inflammation in an animal.
  • parenteral or “parenteral administration” means administered 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.
  • SPLA2 Inhibitors Useful in the Method of the Invention
  • SPLA2 phopholipase A2
  • exemplary of classes of suitable SP A2 inhibitors useful in the method of the invention for treatment of inflammation 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- 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 .
  • 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:
  • 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, l ⁇ c 10 alkyl, C]_-C ⁇ o 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, 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 R4 and R5 is the group, -(L a )-
  • (acidic group) and wherein the (acidic group) is selected from the group consisting of -CO2H, -SO3H, or -P(O) (OH) 2; where,
  • -(L a )- is an acid linker with the proviso that; the acid linker group, -(L a )-, for R4 is selected from the group consisting of
  • R103 S a non-interfering substituent
  • the acid linker, -(L a )-, for R5 is selected from the group consisting of
  • R ⁇ and R ⁇ 5 are each independently selected from hydrogen, Ci-Cio alkyl, aryl, C1-C10 alkaryl, Ci- C10 arylkyl, carboxy, carbalkoxy, and halo and, R5 and R7 are each independently selected from hydrogen and non-interfering substituents, where non-interfering substituents are selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C alkynyl, C7-C12 arylenalkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkyl
  • 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 compound represented by the formula (II) , or a pharmaceutically acceptable salt or aliphatic ester prodrug derivative thereof;
  • Y ] _ is selected from the group consisting of 0, NH, NR! and S;
  • R 1 - 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 ⁇ o alkyl) and halo (C ⁇ -C ⁇ o) alkyl , and t is an integer from 0 to 5 both inclusive; where R 31 , R 32 , R33, R31', R32 ' ⁇ R 33'' R 34 and R 34' are independently selected from the group consisting of hydrogen, CONR 101 R 102 , alkyl, alkylaryl, aryl, alkylheteroaryl, haloalkyl, alkylCONR 101 R 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 ⁇ 4 an d R85 are each independently selected from the group consisting of hydrogen, C]_-C ⁇ _ ⁇ alkyl, aryl,
  • R is selected from the group consisting of hydrogen and alkyl and, where at least one of R31, R32' R 33 or R 34 i s the group - (L 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 (U) : (A) [ [3- ( 2-amino-1, 2-dioxoethyl) -2-methyl-l-
  • Particularly useful prodrugs of the compounds of formula (II) and named compounds (A) thru (U) are the simple aromatic and aliphatic esters, such as the methyl ester.
  • a method for treatment of an animal afflicted with inflammation 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 independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl
  • R- is selected from the group consisting of -C7-C20 alkyl
  • R10 i s selected from the group consisting of halo, c l _c 10 alkyl, C ⁇ _-C ⁇ _o alkoxy, -S- (C ⁇ -C ⁇ o alkyl) and halo (C ⁇ -C ⁇ o) lkyl, and t is an integer from 0 to 5 both inclusive;
  • R 2 is selected from the group consisting of hydrogen, halo, C 1. -C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (C ⁇ -C2 alkyl), -S- (C ⁇ -C2 alkyl), aryl, aryloxy and HET;
  • R4 is selected from the group consisting of -CO2H,
  • R5, R6 a nd R 7 are each independently selected from the group consisting of hydrogen, (C ⁇ -Cg) alkyl, (C]_-
  • R 8 is (C ⁇ -Cg) alkyl, aryl or HET; with SO2CI2 to form a compound of formula
  • alkylating agent of the formula XCH2R 4a where X is a leaving group and R 4a is -C0 R b , -S ⁇ 3R b , -P(0) (OR 4b ) , or -
  • the synthesis methodology for making the 1H- indole-3-glyoxylamide SP A2 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 a mammal afflicted with or susceptible to inflammation.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with inflammation, 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;
  • R 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;
  • R84 and R85 are each independently selected from hydrogen, C ⁇ -C ⁇ o alkyl, aryl, C ⁇ -C ⁇ , alkaryl, Cx- 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 -CO2H, -SO3H, or -P(0)(0H)2;
  • Rg and R7 are each independently selected form hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of the following: C ⁇ -Cg alkyl, C2 ⁇ C alkenyl, C2 ⁇ Cg alkynyl, C7-CX2 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C ⁇ -Cg alkoxy, C2 ⁇ Cg alkenyloxy, C2-
  • 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 sP A2 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;
  • U.S. Provisional Patent Application Serial No. 60/063284 filed October 27, 1997 (titled, Isopropyl Ester Prodrugs of Indole SP A2 Inhibitors) , the entire disclosure of which is incorporated herein by reference.
  • Another highly preferred compound is the indole-3- glyoxylamide morpholino ethyl ester represented by the formula :
  • 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
  • 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 (MgS0 ) and concentrated at reduced pressure. The residue is chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with inflammation, said method comprising administering to said human a therapeutically effective amount of the described as lH-indole-3-acetic acid hydrazides represented by the formula (Ib) , and pharmaceutically acceptable salts, and prodrugs thereof;
  • X is oxygen or sulfur
  • Rx 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 ⁇ o 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 ⁇ g alkoxy, C ⁇ -C ⁇ o alkyl, amino, hydroxyamino or a substituted or unsubstituted 5- to 8- membered heterocyclic ring
  • R2 is halo, C ⁇ -C3 alkyl, ethenyl, C ⁇ -C2 alkylthio,
  • each R3 is independently hydrogen, C -C3 alkyl, or halo;
  • R4 R5 , Rg, and R7 are each independently hydrogen
  • Q is -CON(Rs2R83) ' -5-tetrazolyl, -S03H,
  • RQ Q is independently selected from hydrogen, a metal, or C ⁇ -C ⁇ g alkyl.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with inflammation, 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 ⁇ i is selected from groups (i), (ii) (iii) and (iv) where;
  • (i) is Cg-C 2 o alkyl, Cg-C 2 o alkenyl, C -C o alkynyl, Cg-C20 haloalkyl, C4-C 2 cycloalkyl, or (ii) is aryl or aryl substituted by halo, nitro, -CN, -CHO, -OH, -SH, C ⁇ -C ⁇ o alkyl, C ⁇ -C ⁇ o alkylthio, C -C ⁇ Q alkoxyl, carboxyl, amino, or hydroxyamino ; or
  • (iii) is - ( CH 2 ) n -(R8 ⁇ ) > or -(NH)-(R 8 ⁇ ), where n is 1 to 8, and Rso is a group recited in (i) , and Rsi is selected from a group recited in (i) or (ii) ;
  • Rg ⁇ is hydrogen or C ⁇ -C ⁇ o alkyl
  • Rss 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 ⁇ , alkoxyl, phenyl, nitro, C ⁇ -C ⁇ o 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 14, R 15 R 16' anc ⁇ R 17 are ea ch independently hydrogen, C ⁇ -C ⁇ o alkyl, C ⁇ -C ⁇ g alkenyl, C ⁇ -C ⁇ o alkynyl, C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R ⁇ 4, R15, R 16- and R 17 ' 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 ⁇
  • Z is a bond, -0-, -N(C ⁇ -C ⁇ g alkyl)-, -NH- , or -S-;
  • Q is -CON(Rs2 R 83) ' -5-tetrazolyl, -SO3H,
  • Rgg is independently selected from hydrogen, a metal, or C ⁇ -C ⁇ o alkyl
  • R99 is selected from hydrogen or C ⁇ -C ⁇ o 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)-R8o; 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 ) -
  • 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) ;
  • 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 -(L)-R80»' where, - (L) - is a divalent linking group of 1 to 12 atoms and where Rgg is a group selected from (a) or (b) ;
  • R2 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 Itto 3 atoms other than hydrogen;
  • 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 )-
  • 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 .
  • Phospholipase A2 Inhibitor Compounds Having an Indolizine Type Nucleus, Parmaceutical Formulations Containing Said compounds, and Therapeutic Methods of Using said Compounds are represented by the formula (Id) ;
  • 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 -(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) ;
  • R ⁇ 2 is hydrogen, halo, C ⁇ -C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C ⁇ -C2 alkyl), -S- (C ⁇
  • R ⁇ 7 and Rxg 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 R ⁇ 7 and R ⁇ 8 must be the group, - (L a ) - (acidic group); and
  • R ⁇ 5 and Rx 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 .
  • X is selected from oxygen or sulfur; each R3 is independently hydrogen, C -C3 alkyl, or halo;
  • RX 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 RQ Q 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 ) -
  • 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.
  • Synovial Phospholipase A2 Inhibitor Compounds having an Indene Type Nucleus, Pharmaceutical Formulations Containing said Compounds, and Therapeutic Methods of Using Said Compounds 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 Rx is independently hydrogen, C ⁇ -C3 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)-R80'' where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rso i 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) .
  • -(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 also include the following:
  • X is oxygen or sulfur; each Rx is independently hydrogen, C ⁇ -C3 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)-Rsg; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R g 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 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 (Illf);
  • X is oxygen or sulfur
  • R3 is selected from groups (a), (b) and (c) where;
  • (a) is C7 ⁇ C2g alkyl, C7 ⁇ C2 alkenyl, C7 ⁇ C2 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 Rgg 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- (C ⁇ -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, -(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 .
  • 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 inflammation, said method comprising administering to said human a therapeutically effective amount carbazole or tetrahydrocarbazole represented by the following: A compound of the formula (le)
  • 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 ⁇ O is selected from groups (a) , (b) and (c) where;
  • (a) is -(C 5 -C 2 g)alkyl, -(C 5 -C 2 g), -
  • (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
  • (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 -CONH2 ;
  • R2 ' is selected from the group consisting of -OH, and -0(CH 2 ) R5 ' where
  • R 5 ' is H, -CN, -NH 2 , -CONH -CONR 9 R 10 -NHS0 R 15 ;
  • R 15 is - (C ⁇ -Cg) alkyl or -CF3 ; phenyl or phenyl substituted with -CO2H or
  • 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 racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof; provided that; when R ⁇ ' is H, R ⁇ O is benzyl and m is 1 or 2; R 2 ' cannot be -0(CH2) m 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) :
  • Z is cyclohexenyl, or phenyl
  • R 2 i is a non-interfering substituent
  • R 1 is -NHNH2 or -NH ;
  • R 2 is selected from the group consisting of -OH and
  • R 5 is H, -CO2H, -CONH2, -C ⁇ 2(C ⁇ -C4 alkyl);
  • R6 a nd R 7 are each independently -OH or -0(C ⁇ _C4) alkyl; -SO3H, -SO3 (C ⁇ -C4 alkyl), tetrazolyl, ⁇ N ' " NH 2 • -NHS0 2 R15; -CONHS0 2 R15, where R15 is - (C- -C fi ) alkyl or -CF-., phenyl or phenyl substituted with -C0 2 H or -C0 2 (C..-C.) alkyl where m is 1-3; R 3 is H, -0(C ⁇ -C 4 ) alkyl, halo, - (C ⁇ -Cg) alkyl, phenyl, - (C ⁇ -C4> alkylphenyl ; phenyl substituted with -(C ⁇ _Cg) alkyl, halo, or -CF 3 ; -CH 2 OS
  • R 8 is H, -CONH2 , -NR 9 R 10 , -CN or phenyl where R 9 and R ⁇ O are independently - (C ⁇ C4) alkyl or -phenyl (C ⁇ -C4) alkyl and n is 1 to 8;
  • R 4 is H, - (C5-CX4) alkyl, - (C3-CX4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C ⁇ -Cg) alkyl , halo, -CF3, -OCF3, -(C ⁇ -C ) alkoxy, -CN, - (C ⁇
  • Preferred specific compounds including all salts and prodrug derivatives thereof, for practicing the method of the invention are as follows:
  • R 1 is -NHNH , or -NH2 ;
  • R 2 is selected from the group consisting of -OH and - 0(CH 2 ) m R 5 where
  • R 5 is H, -CO2H, -C0 (C1-C4 alkyl); , where R 6 and
  • R 7 are each independently -OH or -0 (C1-C4) alkyl; -SO3H, -S ⁇ 3(C -C4 alkyl), tetrazolyl, -CN, -NH 2 '
  • R 3 is H, -0(C ⁇ -C4) alkyl, halo, - (C ⁇ -Cg) alkyl, phenyl, - (C ⁇ -C4> alkylphenyl; phenyl substituted with - (C ⁇ _Cg) alkyl, halo, or -CF 3 ; -CH OSi (C ⁇ -Cg) alkyl, furyl, thiophenyl, - (C ⁇ -Cg) hydroxyalkyl; or -
  • R 8 is H, -CONH , -NR 9 R 10 , -CN or phenyl where R 9 and R!0 are independently - (C ⁇ C4) alkyl or -phenyl (C ⁇ -C4> alkyl and n is 1 to 8;
  • R 4 is H, - (C5-CX4) alkyl, - (C3-CX4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C ⁇ -Cg) alkyl , halo, -CF3, -OCF3 , -(C ⁇ -C 4 ) alkoxy, -CN, - (C ⁇
  • A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position
  • 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.
  • 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.
  • 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,
  • Carbazole and tetrahydrocarbazole SPLA2 inhibitor compounds useful for practicing the method of the invention may be made by the following general methods:
  • R 1 is -NH2
  • R 3 (a) is H, -0 (C -C4) alkyl, halo, - C ⁇ - Cg)alkyl, phenyl, - (C ⁇ -C4) alkylphenyl ; phenyl substituted with - (C ⁇ -Cg) alkyl, halo, or -CF3 ; - CH2 ⁇ Si(C ⁇ -Cg) alkyl, furyl, thiophenyl, - (C ⁇ Cg) hydroxyalkyl, - (C ⁇ _Cg) alkoxy (C ⁇ -Cg) alkyl, - (C ⁇
  • R 8 is H, -CONH 2 , -NR 9 R 10 , -CN or phenyl where R 9 and R 10 are independently hydrogen, -CF3 , phenyl, - (CX-C4) alkyl, - (CX-C4) alkylphenyl or -phenyl (C ⁇ -C4) alkyl and n is 1 to 8; when R 1 is -NHNH 2 , R 3 (a) is H, -0 (C ⁇ -C4) alkyl, halo, - (C ⁇ -Cg) alkyl, phenyl, - (C ⁇ -C4> alkylphenyl ; phenyl substituted with - (C ⁇ -Cg) alkyl, halo or -CF3 ; -CH2 ⁇ Si (C ⁇ -Cg) alkyl, furyl, thiophenyl
  • 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
  • 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 . Co m . , 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 R 2( 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 2 to the carboxylic acid may be accomplished by treatment with an aqueous base.
  • a dealkylating agent such as boron tribromide or sodium thioethoxide
  • R 2 When R 2 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 2 When R 2 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.
  • R 2 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- bromocyclohexanone 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 Z Cl2 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.
  • R3 ( a ) is a s defined in Scheme lg .
  • 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 dimethy1formamide, 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 (Ila) 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.
  • vans, D.A. ; Ennis, M.D.; Mathre, D.J. Asymmetric alkylation reactions of chiral imide enolates .
  • esters (12) are then converted to (7) preferably by treatment with methylchloroaluminum amide, (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) 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.
  • 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 .
  • a solvent such as carbitol
  • Pd/C a solvent such as Pd/C
  • carbazole-4-carboxamide a solvent such as dioxane
  • 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 . , (J of Org. Chem. 45, 2938 (1980) ) with or without a noninterfering solvent, such as toluene, benzene, or methylene chloride, under dehydrating conditions at a temperature about 10 to
  • 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.
  • 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, 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.
  • 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(0Ac)2 or Pd(PPh3)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(0Ac)2 or Pd(PPh3)4 and the like
  • a phosphine preferably a trialkyl- or triarylphosphine, such as triphenylphosphine,
  • solvents examples include tetrahydrofuran, benzene, dimethylsulfoxide, or dimethylformamide .
  • Examples of other suitable palladium catalysts include Pd(PPh 3 )Cl 2 , Pd(OCOCF 3 ) 2 , [ (CH3C6H4) P] PdCl 2 , [(CH 3 CH 2 )3P]2PdCl 2 , [ (C 6 H ⁇ ) 3 P] 2 PdCl 2 , and [(C 6 H 5 )3P] 2 PdBr2.
  • phosphines examples include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2- bis (diphenylphosphino) ethane,
  • 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 XCH2R4, 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.
  • organic 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.
  • 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 (21) may be aminated 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 XC ⁇ R ⁇ where X is halo and R 70 is -CO2R 71 , -SO3R 71 , -P (0) (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.
  • organic 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.
  • 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.
  • a lower alcohol solvent such as, methanol, ethanol, isopropanol, and the like.
  • suitable solvents include
  • 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 .
  • a base preferably potassium carbonate or sodium cabonate
  • 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.
  • 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.
  • X is halo
  • 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 . (see J. 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) .
  • 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 methylchloroaluminum amide in an inert solvent, such as toluene, at a temperature between 0 to 110 °C .
  • 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.
  • 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 ⁇ NSOR- ⁇ in the presence of a base, preferably diazabicycloundecene .
  • PG is an acid protecting group
  • R 22 is (C ⁇ -C6)alkoxy (C ⁇ -C 6 )alkyl is (Cl-Cg) alkoxy (C ⁇ -C6) 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.
  • 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.
  • anhydrous solvent such as 1,4-dioxane or DMF
  • 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 O- 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 H2O/CH3OH/THF solution at 50 °C for 1-2 hours .
  • R 22 is - (C ⁇ -Cs) 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.
  • X is halo
  • R 3 (a) is H, -0(C ⁇ -C ) alkyl, halo, - (C ⁇ -C6) alkyl, phenyl, - (CX-C4) alkylphenyl ; phenyl substituted with -(Cx-Cg) alkyl, halo or -CF 3 ; -CH 2 OSi(C ⁇ - CsJal yl, furyl, thiophenyl, - (C ⁇ -C5) hydroxyalkyl; or -(CH 2 ) n R8 where R 8 is H, -NR 9 R 10 , -CN or phenyl where R 9 and R ⁇ O are independently - (CX-C4) alkyl or -phenyl (C ⁇ -C4) alkyl and n is 1 to 8; An indole-3-acetic ester (101) , (see Dillard,
  • R. et al., J, Med Chem. Vol 39, No. 26, 5119-5136 is alkylated by treatment with alkalai metal amide and benzyloxymethyl chloride to give (102) which is converted to the alcohol (103) by catalytic hydrogenation.
  • the alcohol is alkylated to provide the formaldehyde acetal (104) which is cyclized by Lewis acid to produce the pyrano [3, 4-b] indole (105).
  • the ester is converted to the amide (106) by methylchloroaluminum amide, and then to the phenol (107) with boron tribromide.
  • the phenol is O-alkylated to give (108) which is hydrolyzed to the acid (109) .
  • PG is an acid protecting group
  • W is halo, alkyl or aryl sulfonyl
  • R 3 (a) is H, -0(C ⁇ -C ) alkyl, halo, - (C ⁇ -C6) alkyl, phenyl, - (C ⁇ -C4> alkylphenyl ; phenyl substituted with
  • Conversion of the hydroxyl function of (103) to a halide or sulfate functionality is achieved by treatment with triphenylphosphine and CH3X (where X is a halogen) to make compounds of formula (111) where X is a halide; or by treatment with triethylamine and methanesulfonyl chloride to make the sulfonate.
  • Displacement with the sodium salt of thiol acetic acid gives (114) which in turn is hydrolyzed by base to the thiol (115) which is reacted with an appropriately substituted aldehyde and acid to produce the thiopyranoindoles (116).
  • Intermediate (111) may also be reacted with sodium azide to give the azido derivative (112) which is reduced by hydrogen catalytically to give the amine which is converted to the carboline (113) with aldehyde and acid.
  • X is halo, p3 ( a ) ⁇ s as defined in Scheme 1(a) above;
  • R is - (CH2)mR 5 .
  • Protection of the oxygen by treatment of (132) with tert-butyldimethylsilyl chloride and imidazole in an aprotic polar solvent such as tetrahydrofuran or methylene chloride accomplishes (133).
  • Alkylation at the 3-position of the indole (133) is achieved by treatment with n-butyllithum then zinc chloride at temperatures starting at about 10 °C and warming to room temperature, followed by reaction with an appropriate haloalkyl ester such as methyl or ethyl bromoacetate.
  • the reaction is preferably conducted at room temperature in an appropriate aprotic polar solvent such as tetrahydrofuran.
  • Alkylation of the indole-nitrogen can then be achieved by reacting (134) with a suitable alkyl halide in the presence of potassium bis (trimethylsilyl) amide to prepare (135) .
  • the ester functionality of (135) is converted to a trimethylsilylketene acetal (136) by treatment with potassium bis (trimethylsilyl) amide and trimethylsilyl chloride.
  • Treatment of the ketene acetal (136) with bis (chloromethyl) sulfide and zinc bromide in methylene chloride affords the cyclized product (137).
  • Conversion to amide (138) can be accomplished by a Weinreb reaction with methylchloroaluminum amide.
  • N-alkylation of commercially available 4-methoxy indole (231) under basic conditions using an alkyl halide affords the N-alkyl indole (232).
  • Acylation with a suitable acid chloride provides the glyoxalate ester product (233) which can be reduced with a variety of hydride reducing agents to give intermediate alcohols (234).
  • Conversion of the alcohol to a suitable leaving group and displacement with sulfur nucleophiles affords the thioether product (235) .
  • Conversion to the acid chloride and spontaneous cyclization affords the thioketone product (236) .
  • Cleavage of the ester can be effected under basic conditions to give the correponding acid which upon formation of the acid chloride and reaction with an appropriate amine gives the amide product (237) .
  • Cleavage of the methyl ether gives the phenol (238) which can be alkylated under basic conditions using alkyl halides to give the O-alkylated product (239) .
  • Cleavage of the ester under basic conditions gives the desired product (240) .
  • Substituted haloaniline (145) is condensed with N-benzyl- 3-piperidone to provide enamine (146) .
  • Ring closure is effected by treatment of (146) with palladium (II) acetate and the resultant product is converted to (147) by treatment with cyanogen bromide.
  • Alkylation of (147) is accomplished by treatment with the appropriate alkyl bromide using sodium hydride as base.
  • Hydrolysis of this N-alkylated product with basic hydrogen peroxide under standard conditions provides (148). Demethylation of (148) is carried out by treatment with boron tribromide in methylene chloride.
  • the resulting phenol (149) is converted by the standard sequence of O-alkylation with methyl bromoacetate in the presence of a base, hydrolysis with hydroxide to provide the intermediate salt which is then protonated in aqueous acid to provide desired 6- carboline (150).
  • X is halo
  • R is as defined in Scheme IV (d) .
  • Ketene acetal (136) is reacted with benzyl bis (methoxymethyl) amine in the presence of zinc chloride to give the tetrahydro- beta-carboline (151).
  • amide (152) (R 2 ⁇ is t-butyldimethylsilyl) which is desilylated with tetra-n-butylammonium fluoride and alkylated with, for example, ethyl bromoacetate to give ester (153).
  • Lithium hydroxide-mediated hydrolysis gives acid (154), which may be hydrogenated over an appropriate catalyst in the presence of hydrochloride acid to give the tetrahydro-beta-carboline as the hydrochloride salt (155) .
  • Compound (155) may in turn be aromatized by refluxing in carbitol with palladium on carbon to provide beta-carboline (156).
  • X is halo
  • indole (133) is successively treated with one equivalent n- butyllithium, carbon dioxide gas, one equivalent of t- butyllithium, and l-dimethylamino-2-nitroethene to give (157) .
  • Nitroalkene (157) is reduced with lithium aluminum hydride to amine (158), which is cyclized with methyl glyoxylate (see L.-C. Chen et al . , Synthesis 385 (1995) ) in refluxing ethanol to give tetrahydrocarboline (159) .
  • Alkylation of both nitrogens of (159) leads to intermediate (160), which is treated with the appropriate Weinreb reagent to provide amide (161).
  • ester (162) Fluoride-assisted desilylation and alkylation with, for example, ethyl iodoacetate gives ester (162), which may be hydrogenated over a suitable catalyst and base-hydrolyzed to give acid (163).
  • Aromatization of (163) to carboline (164) is achieved by refluxing in carbitol in the presence of palladium-on-carbon .
  • AMINE (179) MAY BE AROMATIZED BY REFLUXING IN CARBITOL OR SOME OTHER SUITABLE HIGH BOILING SOLVENT TO GIVE ALPHA-CARBOLINE (183), WHICH
  • R 3(a) is as defined above
  • Scheme V(e) provides ⁇ -carboline (198) by the indicated sequence of reactions.
  • N-alkylation of 2- carboethoxyindole (190) followed by a standard two carbon homologation sequence provides 2- (3-propenoic acid) indoles (194).
  • the condensation of aldehyde (193) with malonic acid utilized a mixture of pyridine and piperidine as the base.
  • ring closure (196) was effected by treatment with bis (2,2,2- trichloroethyl) azodicarboxylate (BTCEAD) followed by zinc in acetic acid.
  • BTCEAD bis (2,2,2- trichloroethyl) azodicarboxylate
  • Reverse indoles i.e., compounds where B is carbon and D is nitrogen can be prepared as described in Scheme VIg, below.
  • Aryl hydrazines (200) are condensed with substituted prpionaldehydes to form hydrazones which are cyclized to indoles (201) by treatment with phosphorous trichloride at room temperature (see Julia, M. ; Lenzi, J. Preparation d'acides tetrahydro-1 , 2 , 3 , 4- carbazole-1 ou -4. Bull . Soc . Chim . France, 1962, 2262- 2263).
  • the indoles are N-alkylated on reaction with a base such as sodium hydride and an alph-bromo ester to give indoles (202) which are cyclized to tetrahydrocarbazoles (203) by Lewis acids (e.g., aluminum chloride) or by radical initiators (e.g., tributyltin hydride).
  • Lewis acids e.g., aluminum chloride
  • radical initiators e.g., tributyltin hydride
  • Compounds (203) can be converted to carbazoles by, for example, refluxing in a solvent such as carbitol in the presence of Pd/C.
  • Compounds of formula I wherein A is pyridyl can be prepared as described in Schemes VIIg(a)-(b), below.
  • X is halo and R is (CH 2 ) m R 5 .
  • R3(a) is as defined in Scheme 1(a), X is halo, and
  • R is (CH )mR 5 .
  • the 1,3-dione structures (228) are either commercially available or readily prepared by known techniques from commercially available starting materials.
  • the amino group of (228) is protected with an appropriate protecting group, such as the, carboethoxyl , benzyl, CBZ (benzyloxycarbonyl) or BOC ( tert-butoxycarbonyl) protecting group, and the like.
  • an appropriate protecting group such as the, carboethoxyl , benzyl, CBZ (benzyloxycarbonyl) or BOC ( tert-butoxycarbonyl) protecting group, and the like.
  • the dione (228) and aniline derivative (220) are condensed according to the general procedure of, L.-C. Chen et al . , Synthesis 385 (1995), or Yang, et al . , S.-C. Yang et al . , Heterocycles, 32, 2399 (1991), with or without a noninterfering solvent, such as methanol, toluene, or methylene chloride, with or without an acid, such as p-toluenesulfonic acid or trifluoroacetic acid, with or without N-chlorosuccinimide and dimethyl sulfide, to afford the coupled product (221) .
  • a noninterfering solvent such as methanol, toluene, or methylene chloride
  • an acid such as p-toluenesulfonic acid or trifluoroacetic acid
  • N-chlorosuccinimide and dimethyl sulfide to afford the coupled product
  • Compound (221) is cyclized under basic conditions with a copper (I) salt in an inert solvent according to the general procedure of Yang, et al . , N. Miyaura, et al., Synth. Commun. 11, 513 (1981),-and F. Trecourt, et al., Tetrahedron, 51, 11743 6).
  • the derivative (221) is treated with a base, such as sodium hydride, in an inert solvent, such as HMPA, at a temperature between 0 and 25 °C.
  • a copper (I) salt, such as copper (I) iodide is added and the resultant mixture stirred at a temperature between 25 and 150 °C for 1 to 48 hours to afford compound (222) .
  • Compound (221) may also be cyclized according to the general procedure of Chen, et al . , Synthesis 385 (1995) .
  • the derivative (221) is treated with a base, such as sodium bicarbonate, and a palladium catalyst, such as Pd(PPh3)4, in an inert solvent, such as HMPA, at a temperature between 25 and 150 °C to afford compound (222).
  • a base such as sodium bicarbonate
  • a palladium catalyst such as Pd(PPh3)4
  • an inert solvent such as HMPA
  • intermediate (171) is treated with a transition metal catalyst, such as Pd(OAc) 2 (O-tol) 3P in the presence of a base such as triethylamine using a cosolvent of DMF/acetonitrile to prepare (222).
  • a transition metal catalyst such as Pd(OAc) 2 (O-tol) 3P
  • a base such as triethylamine
  • Compound (222) is N-alkylated with an appropriately substituted benzyl halide in the presence of a base, such as sodium hydride or potassium carbonate, in a noninterfering solvent, such as dimethylformamide or dimethylsulfoxide to afford ketone (223) .
  • a base such as sodium hydride or potassium carbonate
  • a noninterfering solvent such as dimethylformamide or dimethylsulfoxide to afford ketone (223) .
  • one pot process (222) is aromatized by treatment with acetic acid and palladium on carbon in a noninterfering solvent, such as carbitol or cymene, followed by treatment with hydrogen gas and palladium on carbon to cleave the nitrogen protecting group and produce the phenolic derivative (224) .
  • the ester (224) is converted to the corresponding amide (225) under standard conditions with ammonia (preferably) or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, preferably methanol, or with MeClAlNH2 in an inert solvent, such as toluene, at a temperature between 0 to 110 °C.
  • an inert solvent such as water or alcohol, preferably methanol
  • MeClAlNH2 in an inert solvent, such as toluene
  • Alkylation of the phenolic oxygen of compound 38 with an appropriate haloester, such as methyl bromoacetate, in the presence of a base, such as cesium carbonate, potassium or sodium carbonate, in an inert solvent, such as dimethylformamide or dimethylsulfoxide affords the ester-amide (226) .
  • Other haloesters such as ethyl bromoacetate, propyl bromoa
  • pyrazole SPLA2 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! is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin- 2-yl, pyridin-2-yl substituted at the 4- position with - (C1-C4) alkyl, (C ⁇ -C4) alkoxyl, -
  • R2 is phenyl; phenyl substituted with 1 to 3 substituents selected from the group consisting of - (C1-C4) alkyl, -CN, halo, -N0 2 , CO2 (Ci- 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; (C1-C4 ) alkylthiazolyl ; phenyl substituted with 1 to 2 substituents selected from the group consisting of
  • R ⁇ is cyclopentyl, cyclohexenyl, or phenyl substituted with halo or (C1-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; and m is 1 to 5; or a pharmaceutically acceptable salt thereof.
  • pyrazole type SPLA2 inhibitors as follows: A pyrazole compound of formula (I) , supra, wherein:
  • R! is pyridine-2-yl or pyridine-2-yl substituted at the 4-position with - (C1-C4) alkyl, (C3 . -
  • R2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of - (C]_-
  • R3 is phenyl; phenyl (C2-C5) alkenyl ; phenyl substituted with 1 or 2 substituents selected from the group consisting of - (C1-C4) alkyl , -CN, -CONH2, -NO2 , - CF3, halo, (C1-C4) alkoxy, CO2 (C1-C4) alkyl, phenoxy and
  • R 4 is - (C]_-C4> alkyl or halo phenyl; phenyl substituted with one substituent selected from the group consisting of -0(CH2)pR 5 where p is 1 to 3 and R 5 is -CN, -CO2H, -CONH 2 or tetrazolyl, phenyl and -OR ⁇ where R ⁇ is cyclopentyl, cyclohexenyl or phenyl substituted with halo or (C1-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 pain, 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:
  • X is -O- or -(CH2) _, where m is 0 or 1;
  • Y is -C0 2 -, -PO3-, -SO3-;
  • R is independently -H or - (C1-C4) alkyl
  • R! and R2 are each independently -H, halo or - (C ⁇ -C 4 ) alkyl
  • R 3 and R 4 are each independently -H, - (C1-C4) alkyl
  • a specific suitable phenyl glyoxamide type SPLA2 inhibitors is 2- (4-carboxybut-l-yl-oxy) -4- (3- phenylphenoxy) phenylglyoxamide .
  • the method of the invention is for treatment of a mammal, including a human, afflicted with pain, said method comprising administering to said human a therapeutically effective amount a pyrrole sPLA 2 inhibitors useful in the method of the invention as follows :
  • R 1 is hydrogen, (C1-C4) alkyl, phenyl or phenyl substituted with one or two substituents selected from the group consisting of - (C1-C4) alkyl, (C1-C4) alkoxy, phenyl (C -C4) alkyl, (C1-C4) alkylthio, halo and phenyl;
  • R ⁇ is hydrogen, - (C1-C4) alkyl, halo, (C1-C4) alkoxy or (C1-C4) alkylthio;
  • R 5 is -NH2 or -NHNH2
  • R ⁇ and R 7 are each hydrogen or when one of R ⁇ and R 7 is hydrogen, the other is - (C1-C4) alkyl, -(CH2) n R-'- 0 where R 10 is -C0 2 R 1:L , -P0 3( R 1:L )2, -P ⁇ 4(R 1:L )2 or -SO3R 11 where
  • X is R 8 (Ci-Cg) alkyl; R 8 (C2-C6) alkenyl or phenyl substituted at the ortho position with R 8 where R 8 is
  • R 10 is -CO2R 11 , -P0 3 (R 1:L )2, -P ⁇ 4(R 1:L ) or
  • -SO3RH, R ⁇ -l and n is 1 to 4 as defined above, and additionally substituted with one or two substituents selected from the group consisting of hydrogen,
  • 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 I wherein; R 1 is phenyl ;
  • R ⁇ is methyl or ethyl
  • R 5 is -NH 2 ;
  • R6 and R 7 are each hydrogen
  • X is R 8 (C ⁇ -Cg) alkyl or phenyl substituted at the ortho position with R 8 where R 8 is -CO2R 11 ; and R9 is methyl or ethyl.
  • a specific suitable pyrrole SPLA2 inhibitors useful in the method of the invention is 2- [l-benzyl-2 , 5- dimethy1-4- (2-carboxyphenylmethy1 ) pyrrol-3-y1] glyoxamide .
  • Naphthyl glyoxamide SPLA2 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 sPLA 2 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 pain, said method comprising administering to said human a therapeutically effective amount a naphthyl glyoxamide sPLA 2 inhibitors useful in the method of the invention are as follows: wherein :
  • R! and R ⁇ are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R! or R ⁇ 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 SP A2 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 pain, said method comprising administering to said human a therapeutically effective amount of a phenyl acetamide SPLA2 inhibitor represented by formula (II) as follows:
  • R 1 is -H or -0(CH2)n Z '' R 2 is -H or -OH;
  • R 3 and R 4 are each independently -H, halo or - (C1-C4 ) alkyl
  • R5 and R ⁇ is -YR 7 and the other is -H, where Y is -0- or -CH 2 - and R 7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, - (C1-C4) alkyl, (C . -C4 ) alkoxy, phenyl or phenyl substituted with one or two halo groups;
  • Z is -C0 2 R, -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 4 and R 6 are hydrogen and R 5 is
  • R 7 where Y is -0-, R 7 cannot be phenyl; and when R 1 , 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 sPLA 2 inhibitors useful in the method of the invention are as follows: compounds of formula I wherein R 2 , R 3 and R 4 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, - (C1-C4) alkyl, (C1-C4) alkoxy, phenyl or phenyl substituted with halo and n is 4-5.
  • a specific suitable phenyl acetamide sPLA 2 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:
  • R! and R 2 are each independently hydrogen or a non-interfering substituent with the proviso that at least one of R ⁇ and R 2 must be hydrogen;
  • R 3 is hydrogen, -0(CH 2 ) n Y, "0 where n is from 2 to 4 and Y is -CO2H, -PO3H2 or SO3H;
  • X is -0- or -CH2-.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with pain, 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 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 1 )-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 6 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) ;
  • 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-, -0-, -S-, -NH- , or -CO-
  • R 27 and R 28 are independently hydrogen atom, C]_ to C3 alkyl or a halogen
  • X and Y are independently an oxygen atom or a sulfur atom
  • Z 1 is -NH 2 or -NHNH ; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
  • a preferred subclass of compounds of formula (In) are those where for the divalent linking group
  • -(L ] _)- is a group represented by any one of the following formulae (la) or (Ib) or (Ic) :
  • Q ⁇ is a bond or any of the divalent groups (la) or (Ib)and each R ⁇ o is independently hydrogen, Ci_s alkyl, C ⁇ _8 haloalkyl or C ⁇ -% alkoxy.
  • linking group -( ⁇ ) of Rx is an alkylene chain of 1 or 2 carbon atoms, namely, -(CH 2 )- or -(CH2-CH2)-.
  • Preferred sPLA 2 inhibitor compounds of the invention are represented by the formula (Iln):
  • R 7 is -(CH 2 )m-Rl 2 wherein m is an integer from 1 to 6, and R ⁇ 2 is (d) a group represented by the formula:
  • R ⁇ and R ⁇ - 4 are independently selected from a halogen, C ⁇ to C ⁇ o alkyl, Ci to C]_Q alkyloxy, C ⁇ to C ⁇ g alkylthio, aryl, heteroaryl, and Ci to C ⁇ o haloalkyl
  • ⁇ is an oxygen atom or a sulfur atom
  • v is an integer from 0 to 2
  • ⁇ is -CH 2 - or -(CH 2 ) 2 -
  • ⁇ 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
  • u is
  • R 8 is Ci to C3 alkyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, Ci to C 2 haloalkyl, C ⁇ to C3 alkyloxy, or
  • R ⁇ is -(L 3 )-R15 wherein L 3 is represented by the formula:
  • R 16 and R 17 are independently hydrogen atom, C ⁇ to C ⁇ o alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R 24 is hydrogen atom or C ⁇ to Cg alkyl, and R!5 S represented by the formula :
  • R 18 is hydrogen atom, a metal, or C ⁇ to CIQ alkyl, R ⁇ -9 s independently hydrogen atom, or C ⁇ to C o alkyl, and t is an integer from 1 to 8;
  • R10 and R ⁇ are independently hydrogen atom or a non-interfering substituent selected from hydrogen, C ⁇ to
  • Cg alkyl Ci to Cg alkenyl, Ci to Cg alkynyl, C7 to C ⁇ 2 aralkyl, C7 to C12 alkaryl, C3 to Cg cycloalkyl, C3 to Cg cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C ⁇ to Cg alkyloxy, C2 to Cg alkenyloxy, C2 to Cg alkynyloxy, C2 to
  • R 2 ⁇ is C ] _ to Cg alkyl or aryl, z is an integer from 1 to 8; and R B is a group represented by the formula:
  • Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
  • R-- 3 or R ⁇ -4 may be different from one another.
  • 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 sPLA 2 inhibitor compounds of formula (I) or (II) namely a pyrrolo [1, 2-a]pyrazine compound selected from the group consisting of :
  • sPLA 2 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 sPLA 2 inhibitors used in the method of the invention may be administered to treat inflammation 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 sPLA 2 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 sPLA 2 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 sPLA 2 inhibitor ("active compound” ) in the formulation and not deleterious to the subject being treated.
  • 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.
  • disintegrating agents such as maize, starch, or alginic acid
  • binding agents for example, gelatin or acacia
  • lubricating agents such as magnesium stearate, stearic acid, or talc.
  • the sPLA 2 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 95 weight percent of the sPLA 2 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, Mack 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.
  • 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.
  • 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.
  • 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.
  • 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 sPLA 2 inhibitors are particularly well suited for transdermal absorption administration and delivery systems.
  • Formulations within the scope of this invention include the admixture of sPLA 2 inhibitor with a therapeutically effective amount of any therapeutically effective co-agents for inflammation such as N-acetyl- cysteine, animal recombinant DNAse, antibiotics, etc., as set out in the section "CO-AGENT - COMBINED THERAPY", infra.
  • 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 IH-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 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 microcrystalline 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.
  • 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 99.0 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 sPLA inhibitor to achieve concentrations of the inhibitor on the airway surfaces of from about 10 "10 to 10 "2 moles per liter.
  • sPLA 2 inhibitors prevents progressive deterioration by inhibiting or reducing the degree of inflammation that may be a primary pathologic process in inflammation.
  • the method of the invention is preferably used early in the symptomatic-life of the patient afflicted with inflammation.
  • the method of the invention can be practiced using pharmaceutical formulations containing sPLA 2 inhibitors
  • SPLA2 inhibitors identified as preferred herein
  • formulations containing such SPLA2 inhibitors as taught in the preceding section.
  • 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.
  • 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 inflammation.
  • the compound must be administered in a manner and a dose to achieve in the animal a blood level concentration of SP A2 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 g/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.
  • parenteral administation 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 inflammation are readily determined and used.
  • the sPLA2 inhibitor (viz., active compound in a formulation of the invention) can also be administered in the method of the invention in combination with another pharmacologically active agent known to have utility for alleviating the symptoms of inflammation.
  • the sPLA 2 inhibitors taught herein may be combined with other therapeutic agents for treatment of inflammation: TESTING METHODS FOR INFLAMMATION
  • the diagnostic criteria for inflammation 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.
  • the inflammation patient having renal disease may be evaluated with any conventional measure of renal capacity.
  • the inflammation patient having gastrointestinal disease may be evaluated by conventional criteria for adequate nutrition.
  • the underlying inflammation 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.

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Abstract

L'invention concerne une méthode de traitement d'inflammations consistant à administrer à un animal une quantité efficace sur le plan thérapeutique d'un inhibiteur sPLA2, tel qu'un 1H-indole-3-glyoxylamide.
PCT/US2001/000011 2000-01-25 2001-01-16 Methode de traitement d'inflammations au moyen d'inhibiteurs spla¿2? WO2001055108A2 (fr)

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WO2006002082A2 (fr) 2004-06-16 2006-01-05 Jack Arbiser Formulations de carbazole destinees au traitement du psoriasis et de l'angiogenese
EP2154958A1 (fr) * 2007-05-03 2010-02-24 Anthera Pharmaceuticals, Inc. Traitement des maladies cardiovasculaires et de la dyslipidémie au moyen d'inhibiteurs de la phospholipase a<sb>2</sb>sécrétoire (spla<sb>2</sb>) et thérapies combinées impliquant des inhibiteurs de la spla<sb>2</sb>
US8048880B2 (en) 2007-05-03 2011-11-01 Anthera Pharmaceuticals, Inc. Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase A2 (SPLA2) inhibitors and SPLA2 inhibitor combination therapies
US20210236500A1 (en) * 2017-11-14 2021-08-05 Oregon Health & Science University Inhibition of autophagy using phospholipase a2 inhibitors

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WO2000002561A1 (fr) * 1998-07-13 2000-01-20 University Of South Florida Modulation de la voie de phospholipase a2 utilisee comme procede therapeutique
WO2000007591A1 (fr) * 1998-08-03 2000-02-17 Eli Lilly And Company INHIBITEURS DE sPLA2 DE TYPE INDOLE
WO2000069818A1 (fr) * 1999-05-12 2000-11-23 Eli Lilly And Company DERIVE DE MORPHOLINO-N-ETHYL ESTER D'UN INHIBITEUR INDOLE DE sPLA¿2?
WO2001005731A1 (fr) * 1999-07-19 2001-01-25 Garegin Oganesovich Karapetyan Procede d'immobilisation de composes physiologiquement actifs

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WO1999016453A1 (fr) * 1997-09-26 1999-04-08 Eli Lilly And Company Methode de traitement de la mucoviscidose
WO1999044604A1 (fr) * 1998-03-03 1999-09-10 Shionogi & Co., Ltd. Compositions pharmaceutiques contenant un [[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-phenylmethyl)-1h-indol-4-yl]oxy]acetate sodique, inhibiteur des phospholipases
WO1999057100A1 (fr) * 1998-05-01 1999-11-11 Eli Lilly And Company Composés inhibiteurs de spla2 pour traiter une maladie
WO2000002561A1 (fr) * 1998-07-13 2000-01-20 University Of South Florida Modulation de la voie de phospholipase a2 utilisee comme procede therapeutique
WO2000007591A1 (fr) * 1998-08-03 2000-02-17 Eli Lilly And Company INHIBITEURS DE sPLA2 DE TYPE INDOLE
WO2000069818A1 (fr) * 1999-05-12 2000-11-23 Eli Lilly And Company DERIVE DE MORPHOLINO-N-ETHYL ESTER D'UN INHIBITEUR INDOLE DE sPLA¿2?
WO2001005731A1 (fr) * 1999-07-19 2001-01-25 Garegin Oganesovich Karapetyan Procede d'immobilisation de composes physiologiquement actifs

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006002082A2 (fr) 2004-06-16 2006-01-05 Jack Arbiser Formulations de carbazole destinees au traitement du psoriasis et de l'angiogenese
EP1896035A2 (fr) * 2004-06-16 2008-03-12 Jack Arbiser Formulations de carbazole destinees au traitement du psoriasis et de l' angiogenese
EP1896035B1 (fr) * 2004-06-16 2014-10-15 Jack L. Arbiser Formulations de carbazole destinées au traitement du psoriasis et de l'angiogenèse
US9289414B2 (en) 2004-06-16 2016-03-22 Jack L. Arbiser Carbazole formulations for the treatment of psoriasis and angiogenesis
EP2154958A1 (fr) * 2007-05-03 2010-02-24 Anthera Pharmaceuticals, Inc. Traitement des maladies cardiovasculaires et de la dyslipidémie au moyen d'inhibiteurs de la phospholipase a<sb>2</sb>sécrétoire (spla<sb>2</sb>) et thérapies combinées impliquant des inhibiteurs de la spla<sb>2</sb>
EP2154958A4 (fr) * 2007-05-03 2011-05-04 Anthera Pharmaceuticals Inc Traitement des maladies cardiovasculaires et de la dyslipidémie au moyen d'inhibiteurs de la phospholipase a<sb>2</sb>sécrétoire (spla<sb>2</sb>) et thérapies combinées impliquant des inhibiteurs de la spla<sb>2</sb>
US8048880B2 (en) 2007-05-03 2011-11-01 Anthera Pharmaceuticals, Inc. Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase A2 (SPLA2) inhibitors and SPLA2 inhibitor combination therapies
US20210236500A1 (en) * 2017-11-14 2021-08-05 Oregon Health & Science University Inhibition of autophagy using phospholipase a2 inhibitors

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