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WO2001066111A1 - Compositions contenant des inhibiteurs potentiels de spla2 afin de traiter la douleur - Google Patents

Compositions contenant des inhibiteurs potentiels de spla2 afin de traiter la douleur Download PDF

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Publication number
WO2001066111A1
WO2001066111A1 PCT/US2001/000009 US0100009W WO0166111A1 WO 2001066111 A1 WO2001066111 A1 WO 2001066111A1 US 0100009 W US0100009 W US 0100009W WO 0166111 A1 WO0166111 A1 WO 0166111A1
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group
alkyl
acid
methyl
treatment
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PCT/US2001/000009
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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 pain. More specifically, the present invention is directed to a method for treating the transmission and sensation of pain secondary to a pain resultant event by administering a therapeutically effective amount of a sPLAschreib inhibitor.
  • a nociceptor identifies one of the nonadapting free nerve endings typically found in the skin and in the deeper tissues such as the arterial walls, periosteum, and surfaces of joints which responds to one or more types of noxious or damaging stimuli .
  • Such stimuli include extreme temperature and mechanical trauma which are mediated by various chemical agents. Signals from these receptors are perceived primarily within the spinal cord of the Central Nervous System (“CNS”) as pain; and the duration of effect is perceived as acute or chronic pain.
  • CNS Central Nervous System
  • a nociceptive response is thus mediated by a sensory receptor that responds to noxious and damaging stimuli, which are perceived as painful sensations; it is also a term used to describe a reflex or response to such a noxious stimulus . Accordingly, nociception or pain is a protective mechanism that occurs when living tissues are threatened or are in the process of being damaged which causes the living individual to react to remove the painful stimulus .
  • Pain is an organism's natural response to an abnormality.
  • exemplary abnormalities that trigger a pain event are represented by the classes such as Injury, Infection, Emotional trauma, Old age, birth defects, Surgery, Surgical complications, Poisoning, Shock, Acne, Acute bronchitis, bronchiolitis, Acute CHF, Acute lung injury, Allergic conjunctivitis, Allergic rhinitis, Allograft rejection, Alzheimer's disease, AMI/reperfusion injury, Angina, Ankylosing spopndylitis, Apoptosis, ARDS, Asthma, Atherosclerosis, Atopic eczema, Baloon angioplasty, Blood preservative, Burns, Bursitis, Cancer, Cerebritis, Cholecystitis, Bronchitis including acute exacerbations of bronchitis, Cirrhosis, Cluster headache, Contact determatitis, obstructive pulmonary disease, Crohn's disease,
  • Previous treatment attempts typically have focused on pharmaceutical agents that treated the sensation of the pain or the cause of the pain instead of the pain directly.
  • Two examples include treating a broken bone by stabilizing it in a cast and the antibiotic treatment of an infection contrasted with the treatment of the pain caused by these events.
  • pain has been treated through administeration of analgesics which decrease sensitivity but do not decrease the transimision of pain signals to the brain.
  • this invention relates to the relief of pain. More particularly, this invention relates to the relief of pain generally deemed (by others than the sufferer) mild to moderate, such as headache, muscle ache, menstrual cramps, low back pain, arthralgia and the like through the administration of a medicament containing a sPLA 2 inhibitor according to this invention.
  • This invention also relates to the relief of acknowledged severe pain through the administration of a medicament containing a sPLAschreib inhibitor according to this invention.
  • This invention also relates to the relief of pain generally deemed (by others than the sufferer) mild to moderate, such as headache, muscle ache, menstrual cramps, low back pain, arthralgia and the like through the combined administration of a sPLA 2 inhibitor and one or more synergistic and therapeutically effective pain medication (co-agent) such as propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM according to this invention.
  • a sPLA 2 inhibitor and one or more synergistic and therapeutically effective pain medication (co-agent) such as propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM according to this invention.
  • co-agent such as propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM according to this invention.
  • This invention also relates to the relief of acknowledged severe pain through the combined administration of a sPLA 2 inhibitor and one or more synergistic and therapeutically effective pain medication such as propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM or non steroidal anti-inflammatory agents including for example COX I and COX II inhibitors, according to this invention.
  • This invention is also a pharmaceutical composition comprising:
  • This invention is a method of treating or relieving acknowledged pain by administering to a mammal in need thereof a therapeutically effective amount of (a) a sPLA 2 inhibitor singly or in combination with a therapeutically effective amount of (b) propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM; wherein (a) and (b) where applicable are both administered within a therapeutically effective interval .
  • this invention relates to the relief of pain in one or more of a person's joints through the administration of a medicament containing a sPLA 2 inhibitor singly or in combination with propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM, non steroidal anti inflammatory drugs including for example Cox I and and/or Cox II inhibitors.
  • This invention relates to the relief of pain in a mammal through the administration of a medicament containing a sPLA 2 inhibitor or a sPLA 2 inhibitor in combination with aspirin, acetaminophen or other therapeutically effective pain medication according to this invention.
  • this invention relates to the relief of pain associated with those musculoskeletal disorders that primarily affect the joints.
  • Joint disorders are further classified into the periarticular tissue disorders (eg tennis elbow) and the true articular or joint diseases (eg osteoarthritis) .
  • Pain event means an event that triggers pain in the subject animal. Examples of pain events include those of the following list.
  • Exemplary abnormalities that trigger a pain event are represented by classes such as Injury, Infection, Emotional trauma, Old age, birth defects, Surgery,
  • terapéuticaally effective amount is an amount of sPLA 2 inhibitor or an amount of (a) a sPLA 2 inhibitor in combination with an amount of (b) propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, or an amount of (a) a sPLA 2 inhibitor in combination with an amount of
  • therapeutically effective interval is a period of time beginning when one of either (a) the sPLA 2 inhibitor or (b) a sPLA 2 inhibitor in combination with propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM or (c) a sPLA 2 inhibitor in combination with acetaminophen or aspirin, is administered to a mammal and ending at the limit of the therapeutic effectiveness of (a) or (b) or (c) .
  • parenteral or “parenteral administration” mean 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 ingredient means one or more sPLA 2 inhibitors used in the method of the invention or one or more sPLA 2 inhibitors in combination with propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM, or optionally one or more sPLA 2 inhibitors in combination with acetaminophen or aspirin or other pain medication used in the method of the invention.
  • the term “in combination with” denotes the co- administration of a sPLA 2 compound and propoxyphene, its isomers and pharmaceutically acceptable acid salts thereof, for example DarvonTM or the co-administration of sPLA 2 and acetaminophen or aspirin.
  • the term “in combination with” further defines simultaneous co- administration either as a single formulation or separate formulations or sequential adminstration of either SPLA2 followed by administration of propoxyphene or acetaminophen or aspirin within a therapeutically effective window.
  • co-agent is a therapeutically effective pain medication or analgesic administered in combination with a sPLA 2 inhibitor either as a single dosage unit or separate dosage units simultaneously or sequentially within a therapeutic interval .
  • sPLA 2 Secretory phospholipase A 2 (sPLA 2 ) inhibitors in general are useful in the practice of the method of this invention.
  • exemplary of classes of suitable sPLA 2 inhibitors useful in the method of the invention for treatment of pain include members selected from the group comprising: lH-indole-3-glyoxylamide, lH-indole-3- hydrazide, lH-indole-3-acetamide, IH-indole-l- glyoxylamide, IH-indole-l-hydrazide, lH-indole-1- acetamide, indolizine-1- acetamide, indolizine-1-acetic acid hydrazide, indolizine-1-glyoxylamide, indene-1-acetamide, indene-1- acetic acid hydrazide, indene-1-glyoxylamide, indene-1-acetamide, inden
  • R! is selected from the group consisting of -C 7 -C 20 alkyl ,
  • R10 is selected from the group consisting of halo, l ⁇ c 10 alkyl, C ⁇ -CI alkoxy, -S- (C_-C ⁇ o alkyl) and halo alkyl, and t is an integer from 0 to 5 both inclusive;
  • R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(C ⁇ -C2 alkyl), -S- (C1-C2 alkyl), aryl, aryloxy and HET;
  • R4 is selected from the group consisting of -CO2H,
  • R5, R6 and R ⁇ are each independently selected from the group consisting of hydrogen, (C1-C ) alkyl, (C ⁇ -
  • R 8 is (C1-C5) 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 -CO2 4 ,
  • R 4b is an acid protecting group to form a compound of formula III
  • the synthesis methodology for making the 1H- indole-3-glyoxylamide sPLA 2 inhibitor starting material may be by any suitable means available to one skilled in the chemical arts. However, such methodology is not part of the present invention which is a method of use, specifically, a method of treating mammal afflicted or susceptible to pain.
  • 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 the compound represented by formula (la) , or a pharmaceutically acceptable salt or prodrug derivative thereof; wherein ; both X are oxygen;
  • R j _ is selected from the group consisting of
  • R]_Q is a radical independently selected from halo, C ⁇ -C o alkyl, CI-CIQ alkoxy, -S- (C ⁇ -C ⁇ o alkyl), and CI-CIQ haloalkyl and t is a number from 0 to 5;
  • R2 is selected from the group; halo, cyclopropyl, methyl, ethyl, and propyl; 4 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;
  • Rg4 and Rss are each independently selected from hydrogen, CI-C]_Q alkyl, aryl, alkaryl, C]_- C ] _ Q aralkyl, carboxy, carbalkoxy, and halo; and provided, that at least one of R4 and R5 must be the group, - (L a ) - (acidic group) and wherein the (acidic group) on the group - (L a ) - (acidic group) of R4 or R5 is selected from -C0 2 H, -SO3H, or -P(0)(OH)2;
  • Rg and R7 are each independently selected from hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of the following: C]_-Cg alkyl, C2-C alkenyl, C2-C5 alkynyl, C7-C 2 aralkyl, C7-C12 alkaryl,
  • Preferred for practicing the method of the invention are lH-indole-3-glyoxylamide compounds and all corresponding pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are useful in the method of the invention and include the following: (A) [ [3-(2-Amino-l,2-dioxoethyl)-2-methyl-l- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid, (B) dl-2-[ [3- (2-Amino-l, 2-dioxoethyl) -2-methyl-l-
  • Particularly useful prodrugs of the compounds of formula (I) and named compounds (A) thru (0) are the simple aromatic and aliphatic esters, such as the methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n- butyl ester, sec-butyl, tert-butyl ester, N,N- diethylglycolamido ester, and morpholino-N-ethyl ester.
  • Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No.
  • the aniline, 2, on heating with di-tert-butyl dicarbonate in THF at reflux temperature is converted to the N-tert-butylcarbonyl derivative, 3, in good yield.
  • the dilithium salt of the dianion of 3 is generated at -40 to -20 °C in THF using sec-butyl lithium and reacted with the appropriately substituted N-methoxy-N-methylalkanamide .
  • This product, 4, may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 1, 3-unsubstituted indole 5.
  • 1, 3-unsubstituted indole 5 is reacted with sodium hydride in dimethylformamide at room temperature (20-25 °C) for 0.5-1.0 hour.
  • the resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0-100 °C, usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6.
  • This indole, 6, is 0- demethylated by stirring with boron tribromide in methylene chloride for approximately 5 hours (see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug Res., 1977, 12, 176, the disclosure of which is incorporated herein by reference).
  • the 4-hydroxyindole, 7, is alkylated with an alpha bromoalkanoic acid ester in dimethylformamide (DMF) using sodium hydride as a base, with reactions conditions similar to that described for the conversion of 5 to 6.
  • the a-[(indol-4- yl) oxy] alkanoic acid ester, 8, is reacted with oxalyl chloride in methylene chloride to give 9, which is not purified but reacted directly with ammonia to give the glyoxamide 10.
  • This product is hydrolyzed using IN sodium hydroxide in MeOH.
  • the final glyoxylamide, 11, is isolated either as the free carboxylic acid or as its sodium salt or in both forms .
  • reaction mixture is stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It is then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HC1. The organic layer is separated, washing with water, brine, dried over MgS ⁇ , and concentrated at reduced pressure to give 25.5g of a crude of 1- [2- (tert-butoxycarbonylamino) -6-methoxyphenyl] -2- butanone. This material is dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture is concentrated at reduced pressure and ethyl acetate and water added to the remaining oil.
  • 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 ) anc ⁇ concentrated at reduced pressure. The residue is chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3. Ig (49% yield) of 2-ethyl-4-methoxy-l- (phenylmethyl) -lH-indole.
  • lH-indole-3-hydrazide sPLA 2 inhibitors useful in practicing the method of the invention are described in U.S. Patent No. 5,578,634; the entire disclosure of which is incorporated herein by reference.
  • the method of the invention is for treatment of a mammal, including a human, afflicted with pain, said method comprising administering to said human a therapeutically effective amount of the compounds described as lH-indole-3-acetic acid hydrazides represented by the formula (lb) , and pharmaceutically acceptable salts, and prodrugs thereof;
  • X is oxygen or sulfur
  • Rl is selected from groups (i) , (ii) and (iii) where ; (i) is C4-C20 alkyl, C4-C20 alkenyl, C4-C20 alkynyl, C4-C20 haloalkyl, C4-C12 cycloalkyl, or
  • (ii) is aryl or aryl substituted by halo, -CN, -CHO, -OH, -SH, C1-C10 alkylthio, CI-C]_Q alkoxy, CI-CIQ alkyl, carboxyl, amino, or hydroxyamino;
  • R74 is, independently, hydrogen or C;]_-C;LQ alkyl, and R75 is aryl or aryl substituted by halo, -CN, -CHO, -OH, nitro, phenyl, -SH, alkylthio, C ⁇ -C ⁇ Q alkoxy, C -C ⁇ Q alkyl, amino, hydroxyamino or a substituted or unsubstituted 5- to 8- membered heterocyclic ring; R2 is halo, C1-C3 alkyl, ethenyl, C]_-C2 alkylthio, c l ⁇ c 2 alkoxy, -CHO, -CN; each R3 is independently hydrogen, C1-C3 alkyl, or halo;
  • R4 R5 , Rg, and R7 are each independently hydrogen, C1-C10 alkyl, C ⁇ -CiQ alkenyl, CI-CI alkynyl, C3-Cg cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R4 R5, Rg, and R7 combined with the ring carbon atoms to which they are attached to form a 5- or 6-membered substituted or unsubstituted carbocyclic ring; or C ⁇ -C]_Q haloalkyl, alkoxy, C]_- C]_Q haloalkoxy, C4 ⁇ Cg cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN, -S (CI-CIQ alkyl), arylthio, thioacetal, -C (0) 0 (C ⁇ -Ci Q alkyl), hydrazino, hydrazido
  • R 2 and Rg 3 are independently hydrogen, C -C Q alkyl, C]_-CI hydroxyalkyl, or taken together with N, Rg2 and Rg3 form a 5- to 8-membered heterocyclic ring; or a group having the formula;
  • Z is a bond, -0-, - (C ⁇ -C ⁇ o alkyl)-, -NH, or -S-;
  • Q is -CON(Rg2Rg3) , -5-tetrazolyl, -SO3H,
  • Rgg is independently selected from hydrogen, a metal, or C ⁇ -C ⁇ Q alkyl.
  • 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 the compound represented by (lib) , and pharmaceutically acceptable salts and prodrug derivatives thereof,
  • X is oxygen or sulfur
  • R ⁇ is selected from groups (i) , (ii) (iii) and (iv) where ;
  • (i) is Cg-C o alkyl, Cg-C 2 o alkenyl, Cg-C 2 o alkynyl, Cg-C20 haloalkyl, C4-C12 cycloalkyl, or ( ⁇ ) is aryl or aryl substituted by halo, nitro, -CN, -CHO, -OH, -SH, CX-CXQ alkyl, CX-CIQ alkylthio, C ⁇ -C Q alkoxyl, carboxyl, amino, or hydroxyamino ; or
  • (iii) is -(CH 2 ) n -(R8 ⁇ ) ⁇ or -(NH)-(Rg ⁇ ), where n is 1 to 8, and R80 is a group recited in (i) , and R8i is selected from a group recited in (i) or (ii) ; (iv) is
  • R87 is hydrogen or C -C Q alkyl
  • Rg8 is selected from the group; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, -CN, - CHO, -OH, -SH, C ⁇ -C o alkylthio, C -C ⁇ o alkoxyl, phenyl, nitro, C ⁇ -C Q alkyl, C ⁇ -C Q haloalkyl, carboxyl, amino, hydroxyamino; or a substituted or unsubstituted 5 to 8 membered heterocyclic ring;
  • R ⁇ 2 is halo, C1-C2 alkylthio, or C ⁇ -C2 alkoxy; each R 3 is independently hydrogen, halo, or methyl ;
  • R 4 R15, Rig and R 7 are each independently hydrogen, C ⁇ -C ⁇ Q alkyl, C -C ⁇ Q alkenyl, C -C ⁇ Q alkynyl,
  • C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R 4 R15/ Rig and 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 g haloalkyl, C ⁇
  • Z is a bond, -0-, -N(C ⁇ -C o alkyl)-, -NH-, or -S-;
  • Q is -CON(Rg2R83) , -5-tetrazolyl, -SO3H,
  • Rgg is independently selected from hydrogen, a metal, or C -C ⁇ Q alkyl
  • R99 is selected from hydrogen or C -C ⁇ Q alkyl
  • lH-indole-1-functional sPLA 2 inhibitors of the hydrazide, amide, or glyoxylamide types as described in United States Patent No. 5,641,800, the entire disclosure of which is incorporated herein by reference are useful for treatment of a mammal, including a human afflicted with renal dysfunction.
  • X is oxygen or sulfur; each R ⁇ is independently hydrogen, or C1-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)-RgQ; where, -(L)- is a divalent linking group of 1 to 12 atoms and where RgQ is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-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 sPLA 2 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)-Rgo; 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, C3-C4 cycloalkenyl, -0- (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 )-
  • 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.
  • the IH-indole-l-functional compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; is represented by the formula (Id) ,-
  • X is oxygen or sulfur; each R ⁇ is independently hydrogen, C1-C3 alkyl, or • halo;
  • R ⁇ 3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C 7 -C 2 o alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-R8o; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R80 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 ⁇ C2 alkyl) , or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
  • R 7 and R ⁇ 8 are independently selected from hydrogen, a non-interfering substituent, or the group, -
  • R 5 and R ⁇ g are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • Particularly preferred lH-indole-1-functional compounds useful as sPLA 2 inhibitors in the practice of the method of the invention are as follows :
  • lH-indole-1-functional compounds useful as sPLA 2 inhibitors in the practice of the method of the invention are as follows:
  • IH-indole-l-functional compounds useful as sPLA 2 inhibitors in the practice of the method of the invention are as follows :
  • X is selected from oxygen or sulfur; each R3 is independently hydrogen, C1-C3 alkyl, or halo;
  • R]_ is selected from groups (a) , (b) and (c) where;
  • (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
  • (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(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, C3-C4 cycloalkenyl, -0- (C1-C2 alkyl), -S- (C ⁇ -C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
  • R5 and Rg are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group) .
  • -(L a )- is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R5 and Rg must be the group, - (L a ) - (acidic group);
  • R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
  • lH-indole-1-functional compounds useful as sPLA 2 inhibitors in the practice of the method of the invention are as follows:
  • Particularly preferred lH-indole-1-functional compounds useful as sPLA 2 inhibitors in the practice of the method of the invention are as follows -.
  • IH-indole-1-functional compounds useful as sPLA 2 inhibitors in the practice of the method of the invention are as follows :
  • Patent Application 08/776618 filed July 20 1995, (titled, Synovial Phospholipase A2 Inhibitor Compounds having an Indene Type Nucleus, Pharmaceutical, Formulations Containing said Compounds, and Therapeutic Methods of Using Said Compounds"), the entire disclosure of which is incorporated herein by reference, are useful in practicing the method of the invention.
  • indene-1-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof is represented by the formula (If) ;
  • X is oxygen or sulfur; each R]_ is independently hydrogen, C1-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)-R8o; where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rg Q is a group selected from (a) or (b) ;
  • R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl,
  • Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) -
  • Suitable indene compounds also include the following: An indene-1-acetic acid 'hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (Ilf) ;
  • 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)-Rg Q ; where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rg Q is a group selected from (a) or (b) ;
  • R2 is hydrogen, halo, C1-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 .
  • Suitable indene compounds for use in the method of the invention also include the following:
  • X is oxygen or sulfur
  • 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)-RgQ,- where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rg Q is a group selected from (a) or (b) ; 2 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 .
  • Carbazole and tetrahydrocarbazole sPLA 2 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 pain, said method comprising administering to said human a therapeutically effective amount carbazole or tetrahydrocarbazole represented by the following:
  • 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;
  • R20 is selected from groups (a) , (b) and (c) where; (a) is -(C5-C20) alkyl, - (C 5 -C o) alkenyl,
  • (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
  • (c) is the group -(L)-R80 ; 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 i s a group selected from (a) or (b) ; R21 is a non-interfering substituent; Rl' is -NHNH , -NH or -CONH 2 ; R2 ' is selected from the group consisting of -OH, and -0 (CH 2 ) fc R5 ⁇ where
  • R 5 ' is H, -CN, -NH 2 , -CONH 2/ -CONR 9 R 10 -NHS0 2 R 15 ;
  • R 15 is - (C -C ) alkyl or -CF 3 ; phenyl or phenyl substituted with -CO2H or -CO2 (C -C4) alkyl; and - (L a ) - (acidic group), wherein -(L a )- is an acid linker having an acid linker length of 1 to 7 and t is 1-5;
  • R3 ' is selected from non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof; provided that; when R ⁇ ' is H, R ⁇ O S benzyl and m is 1 or 2; R 2 ' cannot be -0(CH2) m H; and provided that when D is nitrogen, the heteroatom of Z is selected from he group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-position.
  • Z is cyclohexenyl, or phenyl; R21 is a non-interfering substituent;
  • R 1 is -NHNH or -NH ;
  • R2 is selected from the group consisting of -OH and
  • R 5 is H, -CO2H, -CONH , -C0 2 (C ⁇ -C4 alkyl);
  • 0 -P ( RR ) /W j ⁇ ere R6 anc j R7 are ea . ch independently - O H or -0(C ⁇ _C 4 ) alkyl; -SO3H, -SO3 (C ⁇ -C4 alkyl), tetrazolyl, " CN ' _NH 2 ' - NHS0 2 Rl5; - CONHS0 2 R15, where R15 is - (C, -C,-) alkyl or -CF., , phenyl or phenyl substituted with -CO ⁇ H or -CO p (C, -C.) alkyl where m is 1-3; R 3 is H, -0(C -C4) alkyl, halo, - (Ci-Cg) alkyl, phenyl, - (C1-C4) lkylphenyl; phenyl substituted with -(C ⁇ _Cg) alky
  • R 4 is H, - (C5-C14) alkyl, - (C3-C14) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C ⁇ Cg) alkyl, halo, -CF 3 , -OCF3, -(C1-C4) alkoxy, -CN, - (C ⁇
  • R 1 is -NHNH 2 , or -NH ;
  • R is selected from the group consisting of -OH and - 0(CH 2 ) m R 5 where
  • R 6 R 7 is H, -CO2H, -C02(C1-C4 alkyl); ,where R 6 and R 7 are each independently -OH or -0 (C1-C4) alkyl;
  • -S0 3 H -SO3 (C ⁇ -C4 alkyl), tetrazolyl, -CN, -NH 2 ' -NHS0 2 R 15 ; -CONHS0 R 15 , where R 15 is - (Ci-Cg) alkyl or -CF3, phenyl or phenyl substituted with -C02H or -CO2 (C1-C4) alkyl where m is 1-3;
  • R 3 is H, -0(C ⁇ -C ) alkyl, halo, - (Ci-Cg) alkyl, phenyl, - (C1-C4) alkylphenyl; phenyl substituted with
  • R 8 is H, -CONH 2 , -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-C14) alkyl, - (C3-C14) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C -Cg) alkyl, halo, -CF3, -OCF3 , -(C ⁇ -C4) alkoxy, -CN, - (Cx-
  • alkylthio phenyl (CI-C4) alkyl, - (C ⁇ C4) alkylphenyl, phenyl, phenoxy or naphthyl;
  • A is phenyl or pyridyl wherein the nitrogen is at the
  • Further desirable specific compounds suitable for the method of the invention are selected from the following:
  • Prodrugs are derivatives of sPLA 2 inhibitors used in the method of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
  • Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985) .
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ( (alkoxycarbonyl) oxy) alkyl esters.
  • Specific preferred prodrugs are ester prodrugs inclusive of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl, tert-butyl ester, N,N-diethylglycolamido ester, and morpholino-N-ethyl ester.
  • Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No.
  • 60/063280 filed October 27, 1997 (titled, N,N-diethylglycolamido ester Prodrugs of Indole sPLA 2 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 sPLA 2 Inhibitors) , the entire disclosure of which is incorporated herein by reference;
  • US Provisional Patent Application Serial No. 60/063284 filed October 27, 1997 (titled, Isopropyl Ester Prodrugs of Indole sPLA 2 Inhibitors) , the entire disclosure of which is incorporated herein by reference.
  • Carbazole and tetrahydrocarbazole sPLA 2 inhibitor compounds useful for practicing the method of the invention may be made by the following general methods:
  • the compounds of formula le where Z is cyclohexene are prepared according to the following reaction Schemes Ig(a)and (c) .
  • R 1 is -NH 2/ R 3 (a) is H, -0 (C1-C4) alkyl, halo, -(C ⁇ Cg ) alkyl , phenyl , - (C1-C4 ) alkylphenyl ; phenyl substituted with - (C ⁇ Cg) alkyl, halo, or -CF3 ; - CH2 ⁇ Si (Ci-Cg) alkyl, furyl, thiophenyl, - (C ⁇ Cg) hydroxyalkyl, - (C ⁇ _Cg) alkoxy (C ⁇ Cg) alkyl, -(C ⁇ - Cg) alkoxy (C ⁇ _Cg) alkenyl; or -(CH2) n R 8 where R 8 is H,
  • R 9 and R 10 are independently hydrogen, -CF3, phenyl, - (C1-C4) alkyl, - (C1-C4) alkylphenyl or -phenyl (C1-C4) alkyl and n is 1 to 8; when R 1 is -NHNH 2 , R 3 (a) is H, -0 (C1-C4) alkyl, halo,
  • 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.
  • (7) may be produced by treatment of (6) with Raney nickel active catalyst.
  • Compounds (6) and (7) may be dealkylated, preferably at 0 °C to room temperature, with a dealkylating agent, such as boron tribromide or sodium thioethoxide, to give compound (7) where R2 (a) j 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 is the carboxylate or phosphonic diester or nitrile as defined above. Conversion of R to the carboxylic acid may be accomplished by treatment with an aqueous base.
  • a dealkylating agent such as boron tribromide or sodium thioethoxide
  • R When R 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 When R is the phosphonic diester, conversion to the acid may be achieved by reacting with a dealkylating agent such as trimethylsilyl bromide. The monoester may be accomplished by reacting the diester with an aqueous base.
  • R and R 3 are both methoxy, selective demethylation can be achieved by treating with sodium ethanethiolate in dimethylformamide at 100 °C. (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).
  • 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 ZnCl2 in benzene conditions described in Scheme 1(a), above.
  • N- alkylation of (5') to yield (5) is accomplished by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours .
  • carbazole (5) is hydrolyzed to the carboxylic acid (10) by treatment with an aqueous base, preferably at room temperature to about
  • the intermediate is then converted to an acid chloride utilizing, for example, oxalyl chloride and dimethylformamide, and then further reacted with a lithium salt of (S) or (R) -4-alkyl-2-oxazolidine at a temperature of about -75 °C, to give (11a) and (lib) , which are separable by chromatography.
  • the diastereomers are converted to the corresponding enantio eric benzyl esters (12) by brief treatment at temperatures of about 0 °C to room temperature with lithium benzyl oxide.
  • 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 carbitol
  • treatment of (13) with DDQ in an appropriate solvent such as dioxane yields carbozole (14) .
  • oxidation as described above may result in de-alkylation of the nitrogen.
  • R- 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) .
  • Benzoic acid derivative (16) where X is preferably chlorine, bromine or iodine and the protecting group is preferably -CH3, are reduced to the corresponding aniline
  • 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.
  • 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
  • a noninterfering solvent such as toluene, benzene, or methylene chloride
  • dehydrating conditions at a temperature about 10 to 150 °C .
  • the water formed in the process can be removed by distillation, azetropic removal via a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, and the like.
  • the process can be performed with or without a catalytic amount of an acid, such a p-toluenesulfonic acid or methanesulfonic acid.
  • an acid such as a p-toluenesulfonic acid or methanesulfonic acid.
  • suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride, and acetic acid.
  • solvents examples include tetrahydrofuran, ethyl acetate, methanol, ethanol,
  • the condensation of the instant process is preferably carried out neat, at a temperature about 100 to 150 °C with the resultant water removed by distillation via a stream of inert gas, such as, nitrogen or argon.
  • inert gas such as, nitrogen or argon.
  • the reaction is substantially complete in about 30 minutes to 24 hours.
  • Intermediate (26) may then be readily cyclized in the presence of a palladium catalyst, such as Pd(OAc)2 or Pd(PPt_3)4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o-tolylphosphine , or tricyclohexylphosphine, and the like, a base, such as, sodium bicarbonate, triethylamine, or diisopropylethylamine, in a noninterfering solvent, such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200°C to form (19) .
  • a noninterfering solvent such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200°C to form (19) .
  • suitable solvents include tetrahydrofuran, benzen
  • Examples of other suitable palladium catalysts include Pd(PPh 3 )Cl2, Pd(OCOCF 3 ) 2 , [ (CH3C6H4) P] 2 PdCl2 , [(CH 3 CH 2 )3 ]2PdCl2, [ (C 6 H 1:L ) 3 P] 2 PdCl 2 , and [(C 6 H5) 3 P] 2 PdBr2.
  • phosphines examples include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2- bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1,4- bis (diphenylphosphino) butane .
  • Examples of other suitable bases include tripropyl amine, 2 , 2 , 6, 6-tetramethylpiperidine, 1,5- diazabicyclo[2.2.2] octane (DABCO) , 1,8- diazabicyclo [5.4.0]undec-7-ene (DBU) , 1,5- diazabicyclo [4.3.0]non-5-ene, (DBN) sodium carbonate, potassium carbonate, and potassium bicarbonate.
  • DABCO 1,8- diazabicyclo [5.4.0]undec-7-ene
  • DBN 1,5- diazabicyclo [4.3.0]non-5-ene
  • the cyclization of the instant process is preferably carried out with palladium(II) acetate as catalyst in the presence of either triphenylphosphine, tri-o- tolylphosphine, 1, 3-bis (diphenylphosphino) propane, or tricyclohexylphosphine in acetonitrile as solvent and triethylamine as base at a temperature about 50 to 150 °C .
  • the reaction is substantially complete in about 1 hour to 14 days.
  • a preferred process for cyclization consists of the reaction of intermediate (26) with a palladacycle catalyst such as trans-di ( ⁇ -acetato) -bis [o- (di-o-tolylphosphino)benzyl] dipalladium (II) in a solvent such as dimethylacetamide (DMAC) at 120-140 °C in the presence of a base such as sodium acetate.
  • a palladacycle catalyst such as trans-di ( ⁇ -acetato) -bis [o- (di-o-tolylphosphino)benzyl] dipalladium (II) in a solvent such as dimethylacetamide (DMAC) at 120-140 °C in the presence of a base such as sodium acetate.
  • Intermediate (19) may be alkylated with an alkylating agent 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.
  • Intermediate (20) may by dehydrogenated by oxidation with 2, 3-dichloro-5, 6-dicyano-l, 4-benzoquinone in a noninterfering solvent to form (21) .
  • Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, diethyl ether, methyl ethyl ketone, and t-butyl methyl ether. Toluene, benzene, dioxane, and tetrahydrofuran are preferred solvents.
  • the reaction is carried out at a temperature about 0 to 120 °C. Temperatures from 50 to 120 °C are preferred. The reaction is substantially complete in about 1 to 48 hours depending on conditions.
  • Intermediate (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 where X is halo and R 70 is -CO2R 71 , -SO3R 71 , -P (O) (OR 71 ) , 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
  • a palladium catalyst such as Pd(Ph 3 P)4
  • a base such as sodium bicarbonate
  • Compound (28) is converted to the carbazole product (29) by treatment with a trialkyl or triaryl phosphite or phosphine, such as, triethylphosphite or triphenyl phosphine, according to the general procedure of
  • 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 methylchloroaluminu amide in an inert solvent, such as toluene, at a temperature between 0 to 110 °C.
  • an inert solvent such as water or alcohol
  • methylchloroaluminu amide in an inert solvent, such as toluene
  • 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.
  • reduction of (40) is achieved using a reducing agent such as aluminum trihydride.
  • a reducing agent such as aluminum trihydride.
  • the reaction is conducted under inert atmosphere such as nitrogen, at room temperature.
  • Sulfonylation may be achieved with an appropriate acylating agent in the presence of an acid scavenger such as triethyl amine.
  • 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 1 ⁇ in the presence of a base, preferably diazabicycloundecene .
  • PG is an acid protecting group
  • R 22 is (Ci-Cg) alkoxy (Ci-Cg) alkyl is (Cl-
  • Starting material (20) is O-alkylated with an alkyl halide or alkenyl halide, using a base such as NaH, in an aprotic polar solvent preferably anhydrous DMF, at ambient temperature under a nitrogen atmosphere.
  • a base such as NaH
  • an aprotic polar solvent preferably anhydrous DMF
  • the process of aromatization from a cyclohexenone functionality to a phenol functionality can be performed by treating the tetrahydrocabazole intermediate (60) with a base such as NaH in the presence of methyl benzenesulfinate in an anhydrous solvent, such as 1,4-dioxane or DMF, to form the ketosulfoxide derivative.
  • the ketosulfoxide derivative (60) is converted to the phenol derivative (61) .
  • Conversion of the ester (61) to the amide (62) can be achieved by treating a solution of (61) in an aprotic polar solvent such as tetrahydrofuran with ammonia gas.
  • Phenolic 0- alkylation of (62) with, for example, methyl bromoacetate can be carried out in anhydrous DMF at ambient temperature using CS2C0 3 or K2C0 as a base to form (63) .
  • Desired product (64) can be derived from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H 2 0/CH 3 OH/THF solution at 50 °C for 1-2 hours .
  • R 22 is - (C ⁇ -C 6 ) alkoxy (Ci-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 H 2 0/CH 3 OH/THF solution at 50°C for 1-2 hours.
  • PG is an acid protecting group.
  • X is halo.
  • R 3 (a) is H, -0(C ⁇ -C 4 ) alkyl, halo, - (C]_- Cg) alkyl, phenyl, - (C1-C ) lkylphenyl; phenyl substituted with - (C ⁇ -Cg) alkyl, halo or -CF 3 ; - CH2 ⁇ Si (C1-C5) alkyl, furyl, thiophenyl, - (C ⁇ Cg) hydroxyalkyl; or -(CH2) n R ⁇ where R ⁇ is H, -
  • NR 9 R 10 -CN or phenyl where R 9 and R!° are independently - (C1-C4) alkyl or -phenyl (C1-C4) alkyl and n is 1 to 8;
  • An indole-3-acetic ester (101) (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 ⁇ -C4) alkyl, halo, - (Ci-Cg) alkyl, phenyl, - (C1-C4) alkylphenyl; phenyl substituted with -(Ci-Cg) alkyl, halo or -CF 3 ; -CH 2 OSi(C!-
  • Conversion of the hydroxyl function of (103) to a halide or sulfate functionality is achieved by treatment with triphenylphosphine and CH 3 X (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.
  • Intermediates (113) , (110) and (116) may be N-alkylated, using sodium hydride and an appropriately substituted alkylhalide XCH2R 4 •
  • 4-Methoxyindole (117) is converted to the indole acetic acid derivative (118) by alkylation with an epoxy propionate.
  • Treatment of (118) with a brominating reagent affords the mixture of bromo isomers (119) and (120) which give the spiro compound (121) upon basic treatment.
  • Heating (121) with benzyl bromide provides a mixture of the iso eric bromo compounds (122) and (123) which react with potassium thioacetate to give a mixture of isomers from which (124) may be separated.
  • Solvolysis of the thioester produces the thiol (125) which is alkylated to give (126) .
  • Lewis acids convert (126) to the thiopyrano [3 , 4-b] indole (127).
  • the ester function is converted to amide using methylchloroaluminum amide, the methyl ether cleaved by boron tribromide, and the product phenol O-alkylated with bromoacetic ester to give (130) which is hydrolyzed to (131) .
  • X is halo
  • R is -(CH ) R 5 .
  • 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) .
  • Acylatiori 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) .
  • reduction of the benzylic ketone with a hydride reducing agent and subsequent deoxygenation of the resulting alcohol gives the deoxygenated product (244) .
  • Cleavage of the oxyacetic ester proceeds under basic conditions to give the desired oxyacetic acid (242) .
  • 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 methy1 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 ⁇ - carboline (150) .
  • X is halo
  • R is as defined in Scheme IV (d)
  • R3 (a ) is as defined in Scheme 1(a).
  • Ketene acetal (136) is reacted with benzyl bis (methoxymethy1) amine in the presence of zinc chloride to give the tetrahydro- beta-carboline (151) .
  • amide (152) (R ⁇ O 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
  • R is as defined in Scheme IV(d) ;
  • 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 Kelley, T. R. ; Schmidt, T. E. ; Haggerty, J. G. A convenient preparation of methyl and ethyl glyoxylate, Synthesis, 1972, 544-5) in refluxing ethanol to give tetrahydrocarboline (159) .
  • the commercially available acid (170) is reduced with lithium aluminum hydride, oxidized with pyridinium chlorochromate, and silylated with t-butyldimethylsilyl chloride to give (171) .
  • Treatment with sodium azide provides azide (172), which is reacted with nitromethane and potassium hydroxide in ethanol, followed by treatment with acetic anhydride and pyridine to give nitroolefin (173).
  • Heating in xylene induces cyclization to produce indole (174) .
  • Alkylation with, for example, benzyl iodide and sodium hydride gives (175) , which is hydrogenated in the presence of palladium-on-carbon to give amine (176) .
  • amine (179) may be aromatized by refluxing in carbitol or some other suitable high boiling solvent to give alpha-carboline (183), which is converted via the appropriate Weinreb reagent to amide (184) .
  • Fluoride-assisted desilylation, alkylation with ethyl iodoacetate and potassium carbonate, and base hydrolysis as described above provides alpha-carboline (185) .
  • X is halo
  • R3 ( ) 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.
  • 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 2 )mR 5 .
  • the 1,3-dione structures (228) are either commercially available or readily prepared by known techniques from commercially available starting materials.
  • a reducing agent such as SnCl2 in hydrochloric acid in an inert solvent such as ethanol
  • 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.
  • the dione (228) and aniline derivative (220) are condensed according to the general procedure of Chen, L. -C. et al . , Synthesis 385 (1995) or Yang S. -C. 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 (221) .
  • 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 . , (Reft8) .
  • 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 .
  • 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
  • (221) is treated with a base, such as sodium bicarbonate, and a palladium catalyst, such as
  • 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 sPLA 2 inhibitors which are described (together with the method of making) in US Patent Application No. 08/984261, filed December 3, 1997, the entire disclosure of which is incorporated herein by reference.
  • Suitable pyrazole compounds are represented by formula (Ih)
  • R! is phenyl, isoquinolin-3-yl, pyrazinyl, pyridin- 2-yl, pyridin-2-yl substituted at the 4- position with - (C1-C4) alkyl, (C1-C4) alkoxyl, - CN or -(CH 2 ) n CONH2 where n is 0-2;
  • R2 is phenyl; phenyl substituted with 1 to 3 substituents selected from the group consisting of -(C!-C4) alkyl, -CN, halo, - O2 , C0 2 (C]_- C4) alkyl and -CF3 ; naphthyl; thiophene or thiophene substituted with 1 to 3 halo groups;
  • R3 is hydrogen; phenyl; phenyl (C2-C ) alkenyl; pyridyl; naphthyl; quinolihyl; (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 sPLA 2 inhibitors as follows:
  • R! is pyridine-2-yl or pyridine-2-yl substituted at the 4-position with - (C1-C4) alkyl, (C]_-
  • R2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of - (C]_-
  • C 4 alkyl, -CN, halo, -NO2 , C0 2 (C1-C4) alkyl and -CF3 ; and R3 is phenyl; phenyl (C2-C5) alkenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of - (C -C4) alkyl, -CN, -CONH2 , - O2 , -
  • R ⁇ is - (C1-C4) alkyl or halo phenyl; Phenyl substituted with one substituent selected from the group consisting of -0(CH2)pR ⁇ where p is 1 to 3 and R5 is -CN, -CO2H, -CONH2 or tetrazolyl, phenyl and -
  • pyrazole type sPLA satin inhibitors usef l 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 sPLA staining inhibitors are described in U.S. Patent Application Serial No. 08/979446, filed November 24, 1997 (titled, Phenyl Glyoxamides as sPLA availability 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 sPLA 2 inhibitors useful in the method of the invention are as follows :
  • X is -0- or ⁇ (CH2) m _ where is 0 or 1;
  • Y is -CO2-, -PO3-, -SO3-;
  • R is independently -H or - (C1-C4) alkyl
  • R! and R2 are each independently -H, halo or - (C1-C4) alkyl; R ⁇ and R ⁇ are each independently -H, - (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, halo, phenyl or phenyl substituted with halo; n is 1-8; and p is 1 when Y is -CO2- or -SO3- and 1 or 2 when Y is -PO3-; or a pharmaceutically acceptable salt thereof.
  • a specific suitable phenyl glyoxamide type sPLA 2 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! is hydrogen, (C1-C4) alkyl, phenyl or phenyl substituted with one or two substituents selected from the group consisting of - (C . -C4) alkyl, (C1-C4) alkoxy, phenyl (C1-C4) alkyl, (C1-C4) alkylthio, halo and phenyl;
  • R ⁇ is hydrogen, - (C1-C4) alkyl, halo, (C1-C4) alkoxy or (C1-C ) alkylthio;
  • R 5 is -NH 2 or -NHNH 2 ;
  • X is R 8 (C ⁇ -Cg) alkyl; R 8 (C2-Cg) alkenyl or phenyl substituted at the ortho position with R 8 where R° is
  • R 10 is -C0 2 R 1:L , -P0 3 (R 1:L )2/ -P04(R 1:L ) or
  • -SO3RH, RU and n is 1 to 4 as defined above, and additionally substituted with one or two substituents selected from the group consisting of hydrogen, - (C -C4) alkyl, halo, (C -C ) alkoxy, or two substituents which, when taken together with the phenyl ring to which they are attached, form a naphthyl group; and R9 is hydrogen or methyl or ethyl; or a pharmaceutically acceptable salt thereof.
  • Preferred pyrrole sPLA 2 inhibitors useful in the method of the invention are compounds of formula Ij wherein; l - is phenyl ;
  • R ⁇ is methyl or ethyl
  • R 5 is -NH ;
  • R° and R 7 are each hydrogen; X is R 8 (C]_-C ) 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 sPLA- inhibitors useful in the method of the invention is 2- [l-benzyl-2 , 5- dimethyl-4- (2-carboxyphenylmethyl) pyrrol-3-yl] glyoxamide .
  • 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:
  • R! and R2 are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R! or R2 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) .
  • a specific suitable naphthyl glyoxamide sPLAschreib inhibitors useful in the method of the invention has the following structural formula:
  • Phenyl acetamide sPLA 2 inhibitors and methods of making them are disclosed in US Patent Application 08/976858, filed November 24 1997 (titled, "Phenyl Acetamides as sP A thorough 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 sPLA 2 inhibitor represented by formula (II) as follows:
  • R 1 is -H or -0(CH 2 ) n Z;
  • R 2 is -H or -OH;
  • R3 and R ⁇ are each independently -H, halo or - (C1-C4 ) alkyl
  • R 5 and R 6 is -YR 7 and the other is -H, where Y is -0- or -CH2- and R 7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, - (C . -C4) alkyl, (C ⁇ -
  • Z is -CO2R, -PO3R2 or -SO3R where R is -H or
  • R ⁇ is YR 7 , R-*- is hydrogen; and when R1, R 2 , R3 , R4 anc j p>6 are hydrogen and R ⁇ is YR 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 :
  • a specific suitable phenyl acetamide sPLA 2 inhibitors useful in the method of the invention is 2- (4- carboxybutoxy) -4- (3-phenylphenoxy)phenylacetamide.
  • m) Naphthyl acetamide sP A 2 inhibitors and the method of making them are described in U-S. Patent Application Serial No. 09/091077, filed December 9, 1996 (titled, "Benzyl naphthalene sPLA 2 Inhibitors”), the entire disclosure of which is incorporated herein by reference.
  • a naphthyl acetamide sPLA 2 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(CH2) n Y, -0 where n is from 2 to 4 and Y is -CO2H, -PO3H2 or SO3H;
  • X is -O- 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 sPLA 2 inhibitors useful in the method of the invention as follows:
  • R 1 is a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) -(L 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 5 is a group selected from the groups (a) and (b) ;
  • R 2 is hydrogen atom, or a group containing 1 to 4 non-hydrogen atoms ;
  • R 3 is - (L 2 ) - (acidic group) wherein L 2 is an acid linker having an acid linker length of 1 to 5;
  • R 4 and R 5 are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent (s) , heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent (s) ;
  • R A is a group represented by the formula:
  • L 7 is a divalent linker group selected from a bond or a divalent group selected from -CH 2 -, -0-, -S-, -NH- , or -CO-
  • R 27 and R 28 are independently hydrogen atom, Cl to C3 alkyl or a halogen
  • X and Y are independently an oxygen atom or a sulfur atom
  • Z is -NH 2 or -NHNH 2 ; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
  • a preferred subclass of compounds of formula (In) are those where for R ⁇ the divalent linking group
  • -( ⁇ )- is a group represented by any one of the following formulae (la) or (lb) or (Ic) :
  • each R ] _Q is independently hydrogen, C]__g alkyl, ,C ⁇ _8 haloalkyl or C ⁇ _g alkoxy.
  • Particularly preferred as the linking group -(L ⁇ )- of R ⁇ is an alkylene chain of 1 or 2 carbon atoms, namely, -(CH )- or -(CH -CH 2 )-.
  • Preferred sPLA 2 inhibitor compounds of the invention are represented by the formula (Iln) :
  • R 7 is - (CH2) m -R-*- 2 wherein m is an integer from 1 to 6, and R ⁇ 2 i s (£) a group represented by the formula :
  • R!3 anc j R14 are independently selected from a halogen, C]_ to C]_Q alkyl, C]_ to C ⁇ Q alkyloxy, C ⁇ to C ⁇ Q alkylthio, aryl, heteroaryl, and .
  • C ⁇ Q haloalkyl ⁇ is an oxygen atom or a sulfur atom, L ⁇ is a bond, -
  • R 8 is C to C3 alkyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C ⁇ _ to C2 haloalkyl, C ⁇ to C3 alkyloxy, or C ⁇ to C3 alkylthio;
  • R9 is -(I_3)-R15 wherein L 3 is represented by the formula :
  • R 16 and R 17 are independently hydrogen atom, C]_ to Ci ⁇ alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R 24 is hydrogen atom or C]_ to C5 alkyl, and R ⁇ 5 is represented by the formula:
  • R ⁇ 8 is hydrogen atom, a metal, or 0 to C ⁇ g alkyl
  • R ⁇ -9 is independently hydrogen atom, or C]_ to C]_ Q alkyl
  • t is an integer from 1 to 8;
  • R O and R ⁇ are independently hydrogen atom or a non-interfering substituent selected from hydrogen, C ⁇ to
  • alkylthiocarbonyl C]_ to Cg alkylsulfinyl, C ⁇ to Cg alkylsulfonyl, C2 to Cg haloalkyloxy, Cj_ to Cg haloalkylsulfonyl, C2 to Cg haloalkyl, C ⁇ to Cg hydroxyalkyl, -C(0)0(C ⁇ to Cg alkyl), -(CH2)z"0-( Ci to Cg alkyl), benzyloxy, aryloxy, aylthio, - (CONHS02R 2 ⁇ ) , -
  • Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
  • R 13 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 :
  • the sPLA 2 inhibitors used in the method of the invention may be administered to treat pain 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 inhibitor or sPLA 2 inhibitor in combination with other therapeutic analgesic agents 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 ingredient") in the formulation and not deleterious to the subject being treated.
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising from about 1% to about 95% by weight of a sPLA compound, associated with a pharmaceutically acceptable carrier, excipient, or diluent .
  • the present invention provides a method of causing analgesia in mammals employing a sPLA 2 inhibitor in combination with dextropropoxyphene, optionally a sP A 2 inhibitor in combination with aspirin, acetaminophen or other therapeutically effective pain medications (co- agents) .
  • the method comprises administering the compounds by any number of routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes .
  • the compounds are usually employed in the form of a pharmaceutical composition.
  • the compounds may be administered individually at the same time or different times within a theraputically effective time or together.
  • the compounds may be administered by the same route or by different routes. In a preferred embodiment, the compounds are administered orally and together.
  • a preferred regimen is the co-administration of both sPLA 2 inhibitor and dextropropoxyphene .
  • this co-administration can advantageously be accomplished by the administration of a pharmaceutical formulation comprising both compounds.
  • this invention also provides a pharmaceutical composition comprising from about 1% to about 95% by weight of a mixture of dextropropoxy-phene and a sPLA 2 compound, associated with a pharmaceutically acceptable carrier, excipient, or diluent.
  • This invention also provides a pharmaceutical composition comprising from about 1% to about 95% by weight of a mixture of sPLA 2 inhibitor in combination with aspirin or acetaminophen, associated with a pharmaceutically acceptable carrier, excipient, or diluent.
  • 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 sP A satin inhibitor is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 0.01 to about 99 weight percent of the sP A 2 inhibitor or the sPLA 2 inhibitor and propoxyphene, its isomers and pharmaceutically acceptable salts thereof .
  • Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, saline, dextrose solution, sterile organic solvent or a mixture of both.
  • the active ingredient 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 ingredient 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 ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets and powders . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets and powders . Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • 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 ingredient, 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 ingredient 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 ingredient 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 ingredient, 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 ingredient, 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 form lipid bilayers in which the active ingredient 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 contro the rate at which the material is delivered to the skin.
  • Other suitable transdermal patch formulations and configurations are described in U.S. Patents Nos. 5,296,222 and 5,271,940, the disclosures of which are incorporated herein by reference.
  • Lipophilic prodrug derivatives of the 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 pain such propoxyphene, its isomers and pharmaceutically acceptable salts thereof, or acetaminophen or aspirin, etc., as set out in the section "CO-AGENT - COMBINED THERAPY", infra.
  • the preferred active ingredient are the lH-indole-3-glyoxylamide compounds as previously described and methods of making as described in n US Patent No. 5,654,326 (the disclosure of which is incorporated herein by reference) .
  • Most preferred compounds within the general class of 1H- indole-3-glyoxylamides are ( (3- (2-amino-l, 2-dioxoethyl) - 2-ethyl-l- (phenylmethyl) -lH-indol-4yl) oxy) acetic acid, sodium salt; and lH-indole-3-glyoxylamides are ((3- (2- amino-1, 2-dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol- 4yl) oxy) acetic acid, methyl ester.
  • the lH-indole-3-glyoxylamide compound may be used at a concentration of 0.1 to 99.9 weight percent of the formulation.
  • the pharmaceutical formulation is in unit dosage form.
  • the unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these.
  • the quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
  • compositions suitable for internal administration contain from about 1 milligram to about 500 milligrams of active ingredient per unit.
  • the active ingredient 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 ingredient, 175 mg of lactose, 24 mg of talc, and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient 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 ingredient . 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 ingredient, 6 mg of magnesium stearate, 70 mg of microcrystallme cellulose, 11 mg of cornstarch, and 225 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • Suspensions An aqueous suspension is prepared for oral administration so that each 5 ml contain 25 mg of finely divided active ingredient, 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 ingredient 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 ingredient, 1.8 mg methylparaben, 0.2 mg propylparaben and 10 mg methylcellulose. The solution is dispensed into 1 ml vials .
  • the active ingredient may be used at a concentration of 0.1 to 99.9 weight percent of the formulation.
  • Aerosol formulations are capable of dispersing into particle sizes of from about 0.5 to about 10 microns and have sufficient sPLA 2 inhibitor to achieve concentrations of the inhibitor on the airway surfaces of from about 10 "10 to 10 "2 moles per liter.
  • the ratio of the components by weight is preferably from about 100:1 to 1:100 sPLA 2 inhibitor
  • An especially preferred ratio is approximately 2:5 sPLA 2 inhibitor /dextropropoxyphene.
  • the ratio of sPLA 2 inhibitor to acetaminophen or aspirin is similarly 100:1 to 1:100.
  • the compositions are preferably formulated in a unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
  • the preferred unit dosage forms of the present invention contain from about 1 to about 1000 mg of sPLA 2 inhibitor and from about 30 to about 200 mg of dextropropoxyphene.
  • the unit dosage form may contain about 1 to about 200 mg of sPLA 2 inhibitor and up to 1000 mg of aspirin or acetaminophen, preferably 100-500 mg of aspirin or 100-650 mg of acetaminophen.
  • the specific amount of compounds actually administered will be determined by a physician, in the light of the relevant circumstances including the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • sPLA 2 inhibitors in the method of the invention or a combination of sPLA 2 inhibitors and propoxyphene, its isomers and therapeutically effective acid salts thereof, for example DarvonTM or optionally a combination of sPLA 2 inhibitors and acetaminophen, aspirin or other therapeutically effective pain medications, prevents progressive deterioration by inhibiting or reducing the degree of pain that may be a primary pathologic process in pain.
  • the method of the invention is preferably used early in the symptomatic- life of the patient afflicted with pain.
  • the method of the invention can be practiced using pharmaceutical formulations containing sPLA 2 inhibitors (preferably, sPLA 2 inhibitors identified as preferred herein) or formulations containing such sPLA 2 inhibitors singly or in combination with propoxyphene, its isomers and salts or optionally sPLA 2 inhibitors in combination with acetaminophen or aspirin as taught in the preceding section.
  • sPLA 2 inhibitors preferably, sPLA 2 inhibitors identified as preferred herein
  • formulations containing such sPLA 2 inhibitors singly or in combination with propoxyphene, its isomers and salts or optionally sPLA 2 inhibitors in combination with acetaminophen or aspirin as taught in the preceding section.
  • sPLA ⁇ inhibitors and their formulations
  • sPLA 2 inhibitors in combination with propoxyphene, its isomers and salts
  • optionally sPLA 2 inhibitors in combination with acetaminophen or aspirin are not particularly limited.
  • the dosage administered will vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a daily dosage of active ingredient can be about 0.1 to 200 milligrams per kilogram of body weight.
  • 0.5 to 50, and preferably 1 to 25 milligrams per kilogram per day given in divided doses 1 5 to 6 times a day or in sustained release form is effective to obtain desired results.
  • the sPLA- inhibitor will be administered to an animal so that a therapeutically effective amount 10. is received.
  • a therapeutically effective amount may conventionally be determined for an individual patient by administering the active ingredient in increasing doses and observing the effect on the patient, for example, improvement in exercise, increased appetite, or a 15 reduction in other symptoms associated with pain.
  • the compound may be administered in a manner and a dose to achieve in the animal a blood level concentration of sPLA 2 inhibitor of from 10 to 3000
  • the active ingredient may be administered in a manner and a dose to achieve in the animal a blood level concentration of sPLA 2 inhibitor in combination
  • the treatment regimen may stretch over many days to months or to years .
  • Oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four oral doses per day, each from about 0.01 to 25 mg/kg of body weight with preferred doses being from about 0.1 mg/kg to about 2 mg/kg.
  • parenteral administration (particularly, intravenous administration) is often preferred in instances where rapid alleviation of patient distress is required. With parenteral administration doses of 0.01 to 100 mg/kg/day administered continuously or intermittently throughout the day may be used.
  • the compound (s) 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 pain are readily determined and used.
  • the sPLA 2 inhibitor (viz., active ingredient 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 pain.
  • the sPLA 2 inhibitors taught herein may be combined with a therapeutic agent (s) selected from the group consisiting of methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, sulindac, etodolac tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, piroxicam.
  • a therapeutic agent selected from the group consisiting of methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, sulindac, etodolac tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen,
  • the diagnostic criteria for pain 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 pain patient having renal disease may be evaluated with any conventional measure of renal capacity.
  • the pain patient having gastrointestinal disease may be evaluated by conventional criteria for adequate nutrition.
  • the underlying pain 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 un procédé servant à traiter la douleur et consistant à administrer à un patient animal une quantité efficace sur le plan thérapeutique d'un inhibiteur de sPLA2, tel que 1H-indole-3-glyoxylamide, ou un inhibiteur de sPLA2 combiné à propoxyphène.
PCT/US2001/000009 2000-03-09 2001-01-16 Compositions contenant des inhibiteurs potentiels de spla2 afin de traiter la douleur WO2001066111A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2682119A1 (fr) * 2012-07-03 2014-01-08 Université Libre de Bruxelles Dérivés N-hétérocycles aromatiques à utiliser comme médicament
CN117618430A (zh) * 2023-12-05 2024-03-01 湖南巴德医药科技有限公司 一种包括过氧化玉米油的烧烫伤敷料

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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?
WO2001005761A1 (fr) * 1999-07-19 2001-01-25 Eli Lilly And Company INHIBITEURS DE sPLA¿2?

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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?
WO2001005761A1 (fr) * 1999-07-19 2001-01-25 Eli Lilly And Company INHIBITEURS DE sPLA¿2?

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2682119A1 (fr) * 2012-07-03 2014-01-08 Université Libre de Bruxelles Dérivés N-hétérocycles aromatiques à utiliser comme médicament
CN117618430A (zh) * 2023-12-05 2024-03-01 湖南巴德医药科技有限公司 一种包括过氧化玉米油的烧烫伤敷料
CN117618430B (zh) * 2023-12-05 2024-04-30 湖南巴德医药科技有限公司 一种包括过氧化玉米油的烧烫伤敷料

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