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  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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• • A—HUMAN NECESSITIES
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  • 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
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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• • A—HUMAN NECESSITIES
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  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• This invention relates to the field of medicine and specifically to the treatment of Inflammatory Diseases and Respiratory Diseases.
• Lung diseases have been treated with neutrophil elastase inhibitors.
• neutrophil elastase inhibitors For example, clinical trials have been conducted with the compound, Sivelestat, a neutrophil elastase inhibitor, (product of Ono).
• SPLA2 human non-pancreatic secretory phospholipase A2
• SP 2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids .
• SPLA2 fatty acids
• Such compounds are of value in general treatment of Inflammatory Diseases .
• the neutrophil elastase inhibitor and the sPLA2 inhibitor act synergistically to prevent degradation of surfactant damage in the lungs.
• This invention is a pharmaceutical composition comprising: a neutrophil elastase inhibitor, and an sPLA2 inhibitor.
• This invention is also a method of treating or preventing respiratory diseases by administering to a mammal in need thereof a therapeutically effective amount of (a) a neutrophil elastase inhibitor and a therapeutically effective amount of (b) an SP A2 inhibitor; wherein (a) and (b) are both administered within a therapeutically effective interval.
• an sPLA2 inhibitor and a neutrophil elastase inhibitor may be particularly effective in the treatment of diseases associated with surfactant dysfunction such as respiratory distress syndrome in the new born, acute lung injury and/or acute respiratory distress syndrome.
• Surfactant is composed of both lipid and protein and its beneficial physiologic functions can be interfered with by degradation of either component.
• sPLA2 degrades the lipid component of surfactant while neutrophil elastase degrades the protein component of surfactant.
• the combination of both the sPLA2 and neutrophil elastase is synergistically better at maintaining surfactant function.
• Respiratory Diseases - exemplified by lower respiratory diseases such as systemic inflammatory response syndrome, asthma, emphysema, bronchitis, acute lung injury, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, pneumonia, pulmonary edema, pulmonary obstructive disease, endotoxin induced lung damage, non-cell lung cancer, and multiple organ failure resulting from any of the above pathologic processes.
• lower respiratory diseases such as systemic inflammatory response syndrome, asthma, emphysema, bronchitis, acute lung injury, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, pneumonia, pulmonary edema, pulmonary obstructive disease, endotoxin induced lung damage, non-cell lung cancer, and multiple organ failure resulting from any of the above pathologic processes.
• Inflammatory Diseases refers to diseases such as inflammatory bowel disease, sepsis, septic shock, acute respiratory distress syndrome, pancreatitis, trauma- induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathric spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitic syndromes", polyarteritis nodosa, hypersensitivity vasculitis,
• terapéuticaally effective amount is an amount of (a) neutophil elastase inhibitor or an amount of (b) an SPLA2 inhibitor which is effective in preventing or treating Respiratory Diseases or Inflammatory Diseases.
• therapeuticically effective interval is a period of time beginning when one of either (a) the neutophil elastase inhibitor or (b) an SPLA2 inhibitor is administered to a mammal and ending at the limit of the beneficial effect in preventing or ameliorating the Respiratory or Inflammatory Disease or associated organ failure of (a) or (b) .
• terapéuticaally effective combination means administration of both (a) neutrophil elastase inhibitor and (b) an sPLA2 inhibitor, either simultaneously or separately.
• Active Ingredient refers to a combination of (a) neutrophil elastase inhibitor and (b) an sPLA2 inhibitor co-present in a pharmaceutical formulation for the delivery of a treatment regimen that applies this invention.
• injectable liquid carrier refers to a liquid medium containing either or both of (a) neutrophil elastase inhibitor, or (b) an sPLA2 inhibitor; wherein (a) and (b) are independently dissolved, suspended, dispersed, or emulsified in the liquid medium.
• SPLA2 inhibitor - means a compound which inhibits SPLA2 mediated release of fatty acid.
• sepsis - Sepsis is defined as a systemic inflammatory response to infection, associated with and mediated by the activation of a number of host defense mechanisms including the cytokine network, leukocytes, and the complement and coagulation/fibrinolysis systems (Mesters et al . , Blood 88:881-886, 1996).
• Disseminated intravasc lar coagulation (DIC) with widespread deposition of fibrin in the microvasculature of various organs, is an early manifestation of sepsis/septic shock.
• DIC is an important mediator in the development of the multiple organ failure syndrome and contributes to the poor prognosis of patients with septic shock (Fourrier et al . , Chest 101:816-823, 1992).
• septic shock includes severe sepsis, septic shock, septise ia, and related disease states.
• injectable liquid carrier refers to a liquid medium containing either or both of (a) SPLA2 inhibitor, or (b) an sPLA2 inhibitor; wherein (a) and (b) are independently dissolved, suspended, dispersed, or emulsified in the liquid medium.
• alkenyl - a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers .
• hydrocarbyl - an organic group containing only carbon and hydrogen. halo - fluoro, chloro, bromo, or iodo.
• phenylpyridinyl benzylpyridinyl , pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1, 3 , 5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl , oxacanyl, 1, 3-dioxolanyl, 1,3- dioxanyl, 1, 4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1, 3-dithianyl, 1, 4-dithianyl, 1, 4-thioxanyl, azetidinyl, hexamethylenei inium, heptamethyleneiminium, piperazinyl and quinoxalinyl .
• carbocyclic radical - a radical derived from a saturated or unsaturated, substituted or unsubstituted 5- to 14-membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms.
• Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb) ,
• n is o a number from 1 to 8.
• substituent - radicals suitable for substitution at positions 4, 5, 6, and/or 7 on the indole nucleus (as hereinafter depicted in Formula I) and radical (s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above.
• Illustrative non-interfering radicals are C -C ⁇ alkyl, C2-C alkenyl, C2-C5 alkenyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C alkenyloxy, C2-C5 alkenyloxy, C2-C12 alkoxyalkyl, C2- C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl , C1-C12 alkylamino, Ci-C ⁇ alkylthio, C2-C12 alkylthiocarbonyl , Ci-C ⁇ alkylsulfin
• acid linker an organic group which when attached to an indole nucleus, through suitable linking atoms (hereinafter defined as the "acid linker"), acts as a proton donor capable of hydrogen bonding.
• acid linker an organic group which when attached to an indole nucleus, through suitable linking atoms (hereinafter defined as the "acid linker"), acts as a proton donor capable of hydrogen bonding.
• acid linker - a divalent linking group symbolized as, -(L )-, which has the function of joining the 4 or 5 position of the indole nucleus to an acidic group in the general relationship:
• acid linker length the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(La)- that connects the 4 or 5 position of the indole nucleus with the acidic group.
• the presence of a carbocyclic ring in - (L a ) - counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring.
• a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of -(L a )-.
• Illustrative acid linker groups are;
• groups (a) , (b) , and (c) have acid linker lengths of 5, 7, and 2, respectively.
• pharmaceutically acceptable - the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the term, "carbazole SPLA2 inhibitors" includes SPLA2 inhibitors having either a carbazole or a tetrahydrocarbazole nucleus .
• compositions and method of treatment of this invention use compounds known to be active as neutrophil elastase inhibitors .
• Preferred neutrophil elastase inhibitors are those disclosed in United States Patents No. 5,017,610; 5,336,681; and 5 , 403 , 850 ; the disclosures of which are incorporated herein by reference. These patents also teach suitable method of making their respective inhibitors.
• neutrophil elastase inhibitors most preferred in the practice of this invention are those disclosed in United States Patent No. 5,403,850.
• preferred inhibitors are those corresponding to formula (I)
• Y represents sulfonyl (-S0 2 -) or carbonyl
• Rl and R2 which may be the same or different, each represent
• X represents a single-bond, sulfonyl (-S0 2 -) , an alkylene of up to 4 carbon atoms, or an alkylene of up to 4 carbon atoms substituted by -COOH or benzyloxy-carbonyl
• n represents an integer of 1 to 5
• R4 which may be the same or different represents
• R41 and R42 which may be the same or different, each represents hydrogen or alkyl of up to 4 carbon atoms,
• (9) a group of the formula: -Z41-COOR43 wherein Z41 represents a single-bond, an alkylene of up to 4 carbon atoms, or an alkenylene of from 2 to 4 carbon atoms, R43 represents hydrogen, an alkyl of up to 4 carbon atoms or benzyl ,
• (11) a group of the formula: -COO-Z42COOR43 wherein Z42 represents an alkylene of up to 4 carbon atoms, R43 represents hydrogen or an alkyl of up to 4 carbon atoms,
• -N-Z44-CO represents an amino acid residue
• R48 represents hydrogen or alkyl of up to 4 carbon atoms
• R49 represents hydroxy, alkoxy of up to 4 carbon atoms, amino unsubstituted or substituted by one or two alkyls of up to 4 carbon atoms, carbamoylmethoxy unsubstituted or substituted by one or two alkyls of up to 4 carbon atoms at nitrogen of carbamoyl
• R47 represents a single- bond or an alkyl of up to 4 carbon atoms, or
• R47 and R49 each has the same meaning as described hereinbefore,
• (6) an acyloxy of 2 to 5 carbon atoms
• m represents an integer of up to 4, with the proviso that (1) when Rl and R2 represent hydrogen atom or alkyl group of up to 16 carbon atoms, and R3 represents a hydrogen atom or an alkyl group of up to 6 carbon atoms, Y represents carbonyl (-CO-), and that (2) the compounds wherein one of Rl and R2 represents hydrogen or an alkyl group of up to 16 carbon atoms or 2-carboxyethyl and the other of Rl and R2 represents a group of the formula:
• n represents an integer of 1 or 2
• R4 which may be the same or different represents a hydrogen, an alkyl group of up to 8 carbon atoms or a group of the formula: -Z41-COOR43 wherein Z41 and R43 have the same meaning as described hereinbefore, m represents an integer of 1 or 2 and Y and R3 have the same meaning as described hereinbefore, are excluded, or pharmaceutically acceptable salts thereof.
• Preferred compounds of formula (I) are those wherein wherein the amino acid-residue of R4 is a glycine-residue or an alanine-residue.
• neutrophil elastase inhibitors having an R4 is a glycine-residue are as follows : N-[o-(p- pivaloyloxybenzene) sulfonyla inobenzoyl] glycine,
• neutrophil elastase inhibitors having an R4 is a alanine-residue are as follows :
• acid addition salts of the compound of the general formula (I) are preferred non-toxic and water-soluble salts .
• Suitable acid addition salts include, for example, an inorganic acid addition salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or an organic acid addition salt such as acetate, lactate, tartrate, benzoate, citrate, ethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate.
• the compounds of the present invention of the general formula (I) may be converted into the corresponding salts by known methods. Non-toxic and water-soluble salts are preferable.
• Suitable salts are as follows: salts of alkaline metal (sodium, potassium etc.), salts of alkaline earth metal (calcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amine (tetramethyla monium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidineamine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine etc.).
• Certain compounds used as either neutrophil elastase inhibitors or sPLA2 inhibitors in the composition or method of the invention may possess one or more chiral centers and may thus exist in optically active forms.
• the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans- isomeric forms of the compounds.
• the R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans- isomers, are contemplated by this invention.
• Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention.
• a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods.
• a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers and diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
• Prodrugs are derivatives of the compounds 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.
• double ester type prodrugs such as (acyloxy) alkyl esters or ( (alkoxycarbonyl) oxy) alkyl esters.
• Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido .
• N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA; Item No. 25,099- 6) .
• Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) 4- (2- chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA, Item No. C4, 220-3) .
• SP A2 inhibitors are generally useful in the practice in this invention.
• exemplary of classes of suitable SPLA2 useful in the the method of the invention for treatment of sepsis are the following: lH-indole-3-glyoxylamides lH-indole-3-hydrazides lH-indole-3-acetamides lH-indole-1-glyoxylamides
• No. 09/105381 discloses the following process having steps (a) thru (i) :
• R! is selected from the group consisting of -C7-C20 alkyl
• R!0 is selected from the group consisting of halo, C]_-C]_Q alkyl, C]_-CIQ alkoxy, -S-(C -C ⁇ g alkyl) and halo (C]_-C]_o) alkyl, and t is an integer from 0 to 5 both inclusive;
• R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(C]_-C2 alkyl), -S- (C]_-C2 alkyl), aryl, aryloxy and HET;
• R ⁇ is selected from the group consisting of -CO2H, -SO3H and -P(0) (OH) 2 or salt and prodrug derivatives thereof;
• R5, R6 and R 7 are each independently selected from the group consisting of hydrogen, (C1-C ) alkyl, (C ⁇ C5) alkoxy, halo (C1-C5) alkoxy, halo (C2-C5) alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of: a) halogenating a compound of formula X
• R 8 is (C ⁇ -Cg) alkyl, aryl or HET; with SO2CI2 to form a compound of formula
• the synthesis methodology for making the 1H- indole-3-glyoxylamide SPLA2 inhibitor 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 sepsis.
• the method of the invention is for treatment of a mammal, including a human, afflicted sepsis, 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;
• Rj_ is selected from the group consisting of
• R ] _ Q is a radical independently selected from halo, C]_-C]_o alkyl, C ⁇ -C;j_o alkoxy, -S- (C ⁇ -C;]_o alkyl), and C]_-C o haloalkyl and t is a number from 0 to 5;
• R2 is selected from the group; halo, cyclopropyl, methyl , ethyl , and propyl ;
• R4 and R5 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group) .
• - (L a ) - is an acid linker; provided, the acid linker group, -(L a )-, for R4 is selected from the group consisting of;
• the acid linker, -(L a )-, for R5 is selected from group consisting of;
• R84 and R35 are each independently selected from hydrogen, C -C]_o alkyl, aryl, C -C o 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) (0H) ;
• Rg and R are each independently selected form hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of the following: C ⁇ -Cg alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8
• compositions of the invention are 1H- indole-3-glyoxylamide compounds and all corresponding pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are useful in the method of the invention include the following:
• prodrugs of the compounds of formula (I) and named compounds (A) thru (0) are prodrugs of the compounds of formula (I) and named compounds (A) thru (0) .
• the preferred prodrugs are the aromatic and aliphatic esters, such as the methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec- butyl, tert-butyl ester, N,N-diethylglycolamido ester, and morpholino-N-ethyl ester.
• Methods of making ester prodrugs are disclosed in U.S. Patent No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No.
• 60/063280 filed October 27, 1997 (titled, N,N-diethylglycolamido ester Prodrugs of Indole SPLA2 Inhibitors) , the entire disclosure of which is incorporated herein by reference;
• U.S. Provisional Patent Application Serial No. 60/063646 filed October 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs of Indole SP A2 Inhibitors) , the entire disclosure of which is incorporated herein by reference;
• U.S. Provisional Patent Application Serial No. 60/063284 filed October 27, 1997 (titled, Isopropyl Ester Prodrugs of Indole SPLA2 Inhibitors) , the entire disclosure of which is 'incorporated herein by reference.
• the aniline, 2, on heating with di-tert-butyl dicarbonate in THF at reflux temperature is converted to the N-tert-butylcarbonyl derivative, 3, in good yield.
• the dilithium salt of the dianion of 3 is generated at -40 to -20 °C in THF using sec-butyl lithium and reacted with the appropriately substituted N-methoxy-N-methylalkanamide .
• This product, 4, may be purified by crystallization from hexane, or reacted directly with trifluoroacetic acid in methylene chloride to give the 1, 3-unsubstituted indole 5.
• the 1, 3-unsubstituted indole 5 is reacted with sodium hydride in dimethylformamide at room temperature (20-25 °C) for 0.5-1.0 hour.
• the resulting sodium salt of 5 is treated with an equivalent of arylmethyl halide and the mixture stirred at a temperature range of 0-100 °C, usually at ambient room temperature, for a period of 4 to 36 hours to give the 1-arylmethylindole, 6.
• This indole, 6, is 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.
• the most preferred compound, [ [3- (2-Amino-l, 2- dioxoethyl) -2-ethyl-l- (phenylmethyl) -lH-indol-4- yl] oxy] acetic acid (as well as its sodium salt and methyl ester) useful in the practice of the method of the invention, may be prepared by the following procedure: Preparation of [ [3- (2-Amino-l, 2-dioxoethyl) -2-ethyl- 1- (phenylmethyl) -lH-indol-4-yl] oxy] acetic acid, a compound represented by the formula:
• reaction mixture was stirred 5 minutes, the cooling bath removed and stirred an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HC1. The organic layer was separated, washed with water, brine, dried over MgS ⁇ 4, and concentrated at reduced pressure to give 25.5g of a crude of l-[2-(tert- butoxycarbonylamino) -6-methoxyphenyl] -2-butanone . This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours . The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil.
• 2-ethyl-4-hydroxy-l- (phenylmethyl) -lH-indole (1.56g, 6.2 mmol) was added to a mixture of 248mg (6.2 mmol) of 60% NaH/ ineral oil in 20mL DMF and stirred for 0.67 hour . Then 0.6 mL(6.2 mmol) of methyl bromoacetate was added and stirring was continued for 17 hours . The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgS04) , and concentrated at reduced pressure.
• Oxalyl chloride (0.4 mL, 4.2 mmol) was added to 1.36g (4.2 mmol) of [ [2-ethyl-l- (phenylmethyl) -lH-indol- 4-yl] oxy] acetic acid methyl ester in 10 mL of methylene chloride and the mixture stirred for 1.5 hours. The mixture was concentrated at reduced pressure and residue taken up in 10 mL of methylene chloride. Anhydrous ammonia was bubbled in for 0.25 hours, the mixture stirred for 1.5 hours and evaporated at reduced pressure. The residue was stirred with 20 mL of ethyl acetate and the mixture filtered.
• X is oxygen or sulfur
• R]_ is selected from groups (i) , (ii) and (iii) where;
• (i) is C4-C20 alkyl, C4-C20 alkenyl, C4-C20 alkynyl, C4-C20 haloalkyl, C4-C12 cycloalkyl, or
• (ii) is aryl or aryl substituted by halo, -CN, -CHO, -OH, -SH, C1-C10 alkylthio, CI-CIQ alkoxy, C ⁇ -C ⁇ o alkyl, carboxyl, amino, or hydroxyamino ; (iii) is
• R74 is, independently, hydrogen or C]_-C]_o alkyl
• R75 is aryl or aryl substituted by halo, -CN, -CHO, -OH, nitro, phenyl, -SH, C]_-C]_o alkylthio, C ] _-C ⁇ Q alkoxy, C ] _-C o 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 ⁇ -C 2 alkoxy, -CHO, -CN; each R3 is independently hydrogen, C . -C3 alkyl, or halo ;
• R4 R5 , Rg, and R7 are each independently hydrogen, C ⁇ -C ⁇ o alkyl, C ⁇ -C Q alkenyl, C ⁇ -CIQ alkynyl, C3-C8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R4 R5, Rg, and R7 combined with the ring carbon atoms to which they are attached to form a 5- or 6-membered substituted or unsubstituted carbocyclic ring; or C]_-C ⁇ o haloalkyl, C ⁇ -C ⁇ o alkoxy, C ⁇ C]_Q haloalkoxy, C4-C8 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN, -S(C ⁇ -C]_o alkyl), arylthio, thioacetal, -C (0) 0 alkyl), hydrazino, hydrazid
• Z is a bond, -0-, -N(C 1 -C 10 alkyl)-, -NH, or -S-;
• Q is -CON(R 8 R 8 3) , -5-tetrazolyl, -S0 H,
• R 8 g is independently selected from hydrogen, a metal, or C]_-C]_Q alkyl.
• the lH-indole-3-acetic acid ester can be readily alkylated by an alkyl halide or arylalkyl halide in a solvent such as N, -dimethy1formamide (DMF) in the presence of a base (meth a) to give the intermediate 1- alkyl-lH-indole-3-acetic acid esters, III.
• a solvent such as N, -dimethy1formamide (DMF)
• a base meth a
• Bases such as potassium t-butoxide and sodium hydride were particularily useful. It is advantageous to react the indole, II, with the base to first form the salt of II and then add the alkylatmg agent. Most alkylations can be carried out at room temperature.
• inhibitors are useful ingredients in the compositons of the invention and the method of the invention for treatment of a mammal, including a human, afflicted with sepsis.
• Useful inhibitors are represented by formula (lib) , and pharmaceutically acceptable salts and prodrug derivatives thereof,
• X is oxygen or sulfur
• R]_2 is selected from groups (i) , (ii) (iii) and (iv) where;
• (i) is C -C20 alkyl, Cg-C20 alkenyl, C -C20 alkynyl, Cg-C20 haloalkyl, C4-C12 cycloalkyl, or (ii) is aryl or aryl substituted by halo, nitro, -CN, -CHO, -OH, -SH, alkyl, C ⁇ -C 10 alkylthio, C]_-CI Q alkoxyl, carboxyl, amino, or hydroxyamino ; or
• (iii) is -(CH2) n -( R 8 ⁇ ) ' or -(NH)-(R 81 ), where n is 1 to 8, and R 8 g is a group recited in (i) , and R 8 ⁇ is selected from a group recited in (i) or (ii) ;
• R 8 7 is hydrogen or C]_-C]_o alkyl
• R 88 is selected from the group; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted or substituted by halo, -CN, - CHO, -OH, -SH, alkylthio, C ⁇ -C o alkoxyl, phenyl, nitro, C ⁇ -C]_o alkyl, CI-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 ] _ R15, R-ig/ and R17 are each independently hydrogen, alkynyl, C3-C 8 cycloalkyl, aryl, aralkyl, or any two adjacent hydrocarbyl groups in the set R]_4 R15, R-lg.
• R17 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 ⁇ Q haloalkyl, C]_- C o alkoxy, C]_-C o haloalkoxy, C4-C3 cycloalkoxy, phenoxy, halo, hydroxy, carboxyl, -SH, -CN, alkylthio, arylthio, thioacetal, -C (0) 0 (C ⁇ -CIQ alkyl), hydrazide, hydrazino, hydrazido, -NH2 , -NO2 , -NR 8 2 R 83' and -C(0)NR 8 2R 8 3' where, R 8 2 and R 8 3 are independently hydrogen, C]_-CIQ alkyl, C ⁇ -C]_o hydroxyalkyl, or taken together with N, R 8 2 and R 8 3
• Z is a bond, -0- , -N(CI-CIQ alkyl)-, -NH- , or -S-;
• Q is -CON(R 8 2R 8 3) , -5-tetrazolyl, -SO3H,
• R 8 g is independently selected from hydrogen, a metal, or alkyl, and R99 is selected from hydrogen or C ⁇ -C Q alkyl.
• the lH-indole-3-acetamide II may be alkylated by an alkyl halide or arylalkyl halide in a solvent such as N,N- dimethylformamide (DMF) in the presence of a base (method a) to give intermediate l-alkyl-lH-indole-3-acetic acid esters, III.
• a solvent such as N,N- dimethylformamide (DMF)
• a base (method a) to give intermediate l-alkyl-lH-indole-3-acetic acid esters, III.
• Bases such as potassium t-butoxide and sodium hydride are useful. It is advantageous to react the indole, II, with the base to first form the salt of II and then add alkylatmg agent.
• the intermediate acetic acid esters, III can be first hydrolyzed to the acetic acid derivatives, V
• lH-indole-1-functional SPLA2 inhibitors of the hydrazide, amide, or glyoxylamide types as described in United States Patent No. 5,641,800, the entire disclosure of which is incorporated herein by reference. These inhibitors are useful ingredients in the co positons of the invention and the method of the invention for treatment of a mammal, including a human, afflicted with sepsis .
• 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)-R 8 g; where, - (L) - is a divalent linking group of 1 to 12 atoms and where R 8 Q is a group selected from (a) or (b) ;
• R2 is hydrogen, halo, C1-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;
• Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group) .
• -(L a )- is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, -(L a )- (acidic group) ;
• R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
• lH-indole-1-hydrazide compounds useful as SPLA2 inhibitors in the practice of the method and formulation of the compositions of the invention are as follows: A IH-indole-l-hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (He) ;
• 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 substituent;
• (c) is the group -(L)-R 8Q ; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R 8 Q is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-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 It to 3 atoms other than hydrogen;
• Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group), wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, -(L a )- (acidic group) ;
• R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
• IH-indole-l-functional compounds or pharmaceutically acceptable salts, solvates or prodrug derivatives are represented by the formula (Id) ;
• X is oxygen or sulfur; each R ] _ ⁇ is independently hydrogen, C1-C3 alkyl, or halo ; 3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
• (c) is the group -(L)-R 8 Q; where, - (L) - is a divalent linking group of 1 to 12 atoms and where R 8 g is a group selected from (a) or (b) ;
• Rl2 i hydrogen, halo, C1-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;
• lH-indole-1-functional compounds useful as SP A2 inhibitors in the practice of the method of the invention are as follows: An indolizine-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof where said compound is represented by the formula (lid) ;
• Another preferred lH-indole-1-functional compounds useful as SPLA2 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)-R 8Q ; where, - (L) - is a divalent linking group of 1 to 12 atoms and where R 8Q is a group selected from (a) or (b) ;
• R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C ⁇ -C 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 R 8 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 indolizine compounds may be made by one of more of the following reaction schemes:
• Compound 12 (N. Desidiri, A. Galli, I. Sestili, and M. L. Stein, Arch. Pharm. (Weinheim) 325, 29, (1992)) is reduced by hydrogen in the presence of Pd/C to 14 which gives 15 on ammonolysis using ammonium hydroxide.
• Compound 23 (N. Desideri F. Manna, M. L. Stein, G. Bile, W. Filippeelli, and E. Marmo, Eur. J. Med. Chem. Chim. Ther., 18, 295, (1983)) is O-alkylated using sodium hydride and benzyl chloride to give 24. N-alkylation of 24 by l-bromo-2-butanone or chloromethylcyclopropyl ketone and subsequent base catalyzed cyclization gives 25 which is acylated by aroyl halide to give 26. Hydrolysis of the ester function of 26 followed by acidification forms an acid which is thermally decarboxylated to give 27. Reduction of the ketone function of 27 by LAH yields indolizines 28.
• R 1 H
• R 2 Ph c: R 0 Bn
• R 2 cyclo-Hex
• the hydroxypyridine is O-alkylated to give 44 which is heated with 2-haloketones to produce 45.
• Treatment of 45 with base causes cyclization to 46 which on heating with acid chlorides yields acylindolizines 47 which are reduced by aluminum hydride to the corresponding alkylindolizines 48.
• Sequential treatment of 48 with oxalyl chloride and then ammonia gives 49.
• Cleavage of the ether functionality of 49 yields 50.
• the oxyacetic ester derivatives 51 are formed by O-alkylation of 50 and then hydrolyzed to the oxyacetic acids 52.
• Pyridine 43 is O-alkylated to produce 53. Heating 53 with 2-haloketones gives intermediate N-alkylated pyridinium compounds which are cyclized to 54 on treatment with base. Heating 54 with acyl chlorides gives the acylindolizines 55 which are reduced to the alkylindolizines 56 by sodium borohydride-aluminum chloride. Alternatively, 56 are produced by C-alkylation of 54 using alkyl halides. Sequential treatment of 56 with oxalyl chloride and then ammonia gives 57 which are hydrolyzed to produce 58. Compound 58b is converted to its sodium salt 59a which yields 59b-k on reaction with the appropriate alkyl halide. Scheme 6e - Part 2
• Compound 36b is O-alkylated to give 591-p.
• Pyridine 60 is N-alkylated by 2-haloketones to produce intermediate pyridinium compounds which are cyclized by base to give 61.
• Reaction of 61 with acyl chlorides produces 62 which are reduced to 63 by tert butylamine-borane and aluminum chloride .
• Sequential treatment of 63 with oxalyl chloride and then ammonia yields 64 which are O-demethylated by BBr3 to give 65.
• the sodium salt of 65 is reacted with ethyl 4- bromobutyrate to give 66 which is hydrolyzed to the acid 67.
• Compounds 36d and 65c are O-alkylated by omega- bromocarboxylic esters to give 68 which are hydrolyzed to the acids 69.
• Compounds 36d and 65c produce 70 on treatment with propiolactone and base.
• Pyridine 44b reacts with ethyl bromoacetate to produce 72 which is treated with CS2 and base and then with ethyl acrylate to form 73.
• Reaction of 73 with base and ethyl bromoacetate yields a mixture of regioisomers 74a+b, 6- and 8-benzyloxy compounds.
• Base treatment of 74a+b eliminates ethyl acrylate to form 75 which is separated from the isomer of 6-benzyloxy derivative and S-alkylated to give 76. Hydrolysis of 76 forms 77 which is thermally decarboxylated to yield 78.
• Compound 78 is C-alkylated to form 79 which on sequential treatment with oxalyl chloride and then ammonia forms 80.
• Ether cleavage of 80 gives 81 whose sodium salt is alkylated by methyl bromoacetate to form 82 which are hydrolyzed to acids 83.
• Aminopicoline 84 is converted to its N-CBZ derivative 85 whose anion is alkylated by methyl bromoacetate to produce 86.
• Reaction of 86 with methyl alpha-bromoalkyl ketones in the presence of base yields 87.
• Sequential treatment of 87 with oxalyl chloride and then ammonia gives 88 which is converted to 89 by hydrogenolysis of the N-CBZ function. Hydrolysis of 89 yields acids 90.
• Pyridine 24 is N-alkylated by methyl bromoacetate, cyclized with base, and o-methylated using dimethysulfate to give 94.
• Hydrolysis of the ester function of 94 followed by thermal decarboxylation yields 2-methoxy-8- benzyloxyindolizine which is C-alkylated at position 3 and then reacted sequentially with oxalyl chloride and ammonia to produce 95.
• Hydrogenolysis of the 8-benzyloxy group followed by O-alkylation gives 96 which is hydrolyzed to 97.
• the method of the invention is for treatment of a mammal, including a human, afflicted with sepsis, said method comprising administering to said human a therapeutically effective amount of an indene-1-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (If) ;
• 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 -( )-Rgo .
• -( )- is a divalent linking group of 1 to 12 atoms and where Rgo is a group selected from (a) or (b) ;
• R2 is hydrogen, halo, C1-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;
• Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group) .
• -( a )- is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (L a ) - (acidic group); and
• R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
• Suitable indene compounds also include the following: 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) ;
• (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)-Rgo.
• -(L)- is a divalent linking group of 1 to 12 atoms and where Rgg is a group selected from (a) or (b) ;
• R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C1-C2 alkyl), -S-(C ⁇ -C 2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, -(L a )- (acidic group) .
• -(L a )- is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - (L a ) - (acidic group); and
• R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non- interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents .
• Suitable indene compounds for use in the method of the invention also include the following: An indene-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (IHf);
• 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 -(Lj-Rgg; where, - (L) - is a divalent linking group of 1 to 12 atoms and where Rgg is a group selected from (a) or (b) ;
• R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0- (C ⁇ -C2 alkyl), -S- (C -C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group), wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rg and R7 must be the group, - ( a ) - (acidic group);
• R 4 and R 5 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 method of making the indene compounds is as follows :
• Compound 12c is O-alkylated using sodium hydride and methylbromoacetate to product 15 which is reduced by hydrogen in the presence of Pd/C to give a mixture of iso ers 16a and 16b.
• Aqueous base hydrolysis of 16a and 16b gives 17a and 17b, respectively.
• Compound lOd is treated with lithium diisopropylamme, then air is bubbled into the solution to give 18.
• the indene 18 is converted to an active ester using benzotriazo-1- yloxytris (dimethylamino) hexafluorophosphonate and then reacted with ammonium hydroxide to form the hydroxy acetamide 19.
• Compound 19 is oxidized to 20 using N-methylmorpholine N-oxide in the presence of tetrapropylam onium perruthenate .
• Carbazole and tetrahydrocarbazole SPLA2 inhibitors and methods of making these compounds are set out in United ' States Patent Application SN 09/063066 filed April 21, 1998 (titled, "Substituted Carbazoles and 1, 2, 3 , 4-Tetrahydrocarbazoles” ) , the entire disclosure of which is incorporated herein by reference. These inhibitors are useful in making the compositons of the invention and practicing the method of the invention for treating a mammal affliced with sepsis.
• A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position; one of B or D is nitrogen and the other is carbon;
• Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at the 1-, 2-, or 3-position, or a 6- membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position;
• R 20 j_ s selected from groups (a) , (b) and (c) where;
• (a) is - (C5-C20) alkyl, - (C5-C20) lkenyl,
• (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-R80 ; where, - (L) - is a divalent linking group of 1 to 12 atoms 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,
• R ⁇ l is a non-interfering substituent
• Rl' is -NHNH 2 , -NH 2 or -C0NH ;
• R2 ' is selected from the group consisting of -OH, and
• R 5 ' is H, -CN, -NH , -C0NH -CONR 9 R 10 -NHS0 R 15 ;
• R 15 is - (Cx-Cg) alkyl or -CF 3 ; phenyl or phenyl substituted with -CO2H or -CO2 (C1-C4) alkyl; and - ( 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 R3 ' is H, R 2 ⁇ is benzyl and m is 1 or 2; R ' cannot be -0(CH2) m H; and provided that when D is nitrogen, the heteroatom of Z is selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-position.
• compositions and method of the invention are compounds represented by the formula (He) :
• Z is cyclohexenyl, or phenyl;
• R 2 -L is a non-interfering substituent;
• R 1 is -NHNH 2 or -NH 2 ;
• R 2 is selected from the group consisting of -OH and -0(CH ) m R5 where
• R 5 is H, -C0 2 H, -CONH 2 , -C0 2 (C1-C4 alkyl); - p(R ⁇ R7) , where R ⁇ and R "7 are each independently -OH or -0(C ⁇ _C 4 ) alkyl; -SO3H, -SO3 (C1-C4 alkyl), tetrazolyl, - CN > _NH 2 ' -NHS0 2 R15; -CONHS0 2 Rl5, where R15 is - (C- - X alkyl or -CF-, , phenyl or phenyl substituted with -CO ⁇ H or -CO ⁇ (C ⁇ -C.) lkyl where m is 1-3;
• R 3 is H, -0(C!-C4) alkyl, halo, - (C1-C5) alkyl, phenyl, - (C]_-C4)alkylphenyl; phenyl substituted with -(C 1 _C 6 ) alkyl, halo, or -CF 3 ; -CH 2 0Si (C ⁇ Cg) alkyl, furyl, thiophenyl, - (C]_-C5) hydroxyalkyl; or -
• R 8 is H, -CONH 2 , -NR 9 R 10 , -CN or phenyl where R 9 and R ⁇ -0 are independently - (C ⁇ C4) alkyl or -phenyl (C1-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, - (C1-C4) alkoxy, -CN, - (Cj_-
• Preferred specific compounds including all salts and prodrug derivatives thereof, for the compositions and method of the invention are as follows:
• carbazole inhibitors suitable for the compositions and method of thein invention are selected from those represented by the formula (XXX) :
• R 1 is -NHNH , or -NH ;
• R 2 is selected from the group consisting of -OH and - 0(CH 2 ) m R 5 w h ere
• R 5 is H, -CO2H, -C0 2 (C1-C4 alkyl); , where R 6 and
• R "7 are each independently -OH or -0 (C . -C4) alkyl
• R 3 is H, -0(C ⁇ _-C4) alkyl, halo, - (Cx-Cg) alkyl, phenyl,
• R 4 is H, - (C5-C14) alkyl, - (C3-CX4) cycloalkyl, pyridyl, phenyl or phenyl substituted with - (C ⁇ -Cg) alkyl, halo, -CF , -OCF3 , -(C2-C4) alkoxy, -CN, - (C ⁇ C 4 ) alkylthio, phenyl (CI-C4) alkyl, - (C ⁇ C4) alkyIphenyl, phenyl, phenoxy or naphthyl;
• A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position;
• Z is cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1-, 2- or 3-position or a 6-membered
• compositions and method of the invention are selected from the following:
• cabozole/tetrahydrocarbazole inhibitors for the compositions and method of treating sepsis are represented by the formulae (Xe) and (Xle) below:
• Prodrugs are derivatives of SPLA2 inhibitors used in the method of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo.
• Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H. , Design of Prodrugs , pp. 7-9, 21-24, Elsevier, Amsterdam 1985) .
• Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ( (alkoxycarbonyl) oxy) alkyl esters.
• prodrugs are ester prodrugs inclusive of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl, tert-butyl ester,
• Carbazole and tetrahydrocarbazole SPLA2 inhibitor compounds useful for practicing the method of the invention may be made by the following general methods:
• the compounds of formula Ie where Z is cyclohexene are prepared according to the following reaction Schemes Ig(a)and (c) .
• R 1 is -NH 2
• R 3 (a) is H, -0 (C1-C4) alkyl, halo, - (C ⁇ C5) alkyl, phenyl, - (C1-C4) alkyIphenyl; phenyl substituted with - (C ⁇ -Cg) alkyl, halo, or -CF3 ; - CH2 ⁇ Si(C ⁇ -C ) alkyl, furyl, thiophenyl, - (C ⁇ _-
• R 8 is H, -NR 9 R 10 , -CN or phenyl where R 9 and R 10 are independently hydrogen, -CF3 , phenyl, - (C ] _-C4) alkyl, - (C1-C4) alkylphenyl or -phenyl (C ⁇ -C4) alkyl and n is 1 to 8;
• R 2 ( a) is -0CH3 or -OH.
• An appropriately substituted nitrobenzene (1) can be reduced to the aniline (2) by treatment with a reducing agent, such as hydrogen in the presence of
• Pd/C preferably at room temperature.
• Compound (2) is N-alkylated at temperatures of from about 0 to 20 °C using an alkylating agent such as an appropriately substituted aldehyde and sodium cyanoborohydride to form (3).
• 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 Z Cl2 in benzene for from about 1 to 2 days, preferably at
• Compounds (6) and (7) may be dealkylated, preferably at 0 °C to room temperature, with a dealkylating agent, such as boron tribromide or sodium thioethoxide, to give compound (7) where R 2 ( a ) s -OH, which may then be further converted to compound (9) , by realkylating with a base, such as sodium hydride, and an alkylatmg agent, such as Br(CH2) m R ⁇ , where R ⁇ is the carboxylate or phosphonic diester or nitrile as defined above. Conversion of R 2 to the carboxylic acid may be accomplished by treatment with an aqueous base.
• a dealkylating agent such as boron tribromide or sodium thioethoxide
• R 2 When R 2 is nitrile, conversion to the tetrazole may be achieved by reacting with tri-butyl tin azide or conversion to the carboxamide may be achieved by reacting with basic hydrogen peroxide.
• R 2 When R 2 is the phosphonic diester, conversion to the acid may be achieved by reacting with a dealkylating agent such as trimethylsilyl bromide. The monoester may be accomplished by reacting the diester with an aqueous base.
• R 2 and R 3 are both methoxy, selective demethylation can be achieved by treating with sodium ethanethiolate in dimethylformamide at 100 °C.
• R a is as defined in Scheme 1, above.
• the aniline (2) is N-alkylated with 2-carbethoxy-6- bromocyclohexanone in dimethyl formamide in the presence of sodium bicarbonate for 8-24 hours at 50 °C .
• Preferred protecting groups include methyl, carbonate, and silyl groups, such as t ⁇ butyldimethylsilyl .
• the reaction product (4') is cyclized to (5') using the ZnCl2 in benzene conditions described in Scheme 1(a), above.
• N- alkylation of (5') to yield (5) is accomplished by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours .
• carbazole (5) is hydrolyzed to the carboxylic acid (10) by treatment with an aqueous base, preferably at room temperature to about 100 °C.
• the intermediate is then converted to an acid chloride utilizing, for example, oxalyl chloride and dimethylformamide, and then further reacted with a lithium salt of (S) or (R) -4-alkyl-2-oxazolidine at a temperature of about -75 °C, to give (11a) and (lib) , which are separable by chromatography.
• the diastereomers are converted to the corresponding enantiomeric benzyl esters (12) by brief treatment at temperatures of about 0 °C to room temperature with lithium benzyl oxide.
• esters (12) are then converted to (7) preferably by treatment with methylchloroaluminum amide (Ref 2, above) or, alternately, by hydrogenation using, for example, hydrogen and palladium on carbon, as described above, to make the acid and then reacting with an acyl azide, such as diphenylphosphoryl azide followed by treatment with ammonia.
• an acyl azide such as diphenylphosphoryl azide followed by treatment with ammonia.
• 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.
• Benzoic acid derivative (16) where X is preferably chlorine, bromine or iodine and the protecting group is preferably -CH3 , are reduced to the corresponding aniline (25) with a reducing agent, such as stannous chloride in the presence of acid under the general conditions of Sakamoto et al, Chem Pharm. Bull . 35 (5), 1823-1828 (1987) .
• a reducing agent such as stannous chloride
• the reactions are conducted at temperatures from about 0 to 100 °C . preferably at ambient temperature, and are substantially complete in about 1 to 48 hours depending on conditions.
• the aniline (25) and dione (15) are condensed under dehydrating conditions, for example, using the general procedure of Iida, et al . , (Ref 5), with or without a noninterfering solvent, such as toluene, benzene, or methylene chloride, under dehydrating conditions at a. temperature about 10 to 150 °C.
• a noninterfering solvent such as toluene, benzene, or methylene chloride
• the water formed in the process can be removed by distillation, azetropic removal via a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, and the like.
• the process can be performed with or without a catalytic amount of an acid, such a p-toluenesulfonic acid or methanesulfonic acid.
• an acid such as a p-toluenesulfonic acid or methanesulfonic acid.
• suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride, and acetic acid.
• solvents examples include tetrahydrofuran, ethyl acetate, methanol, ethanol, 1, 1, 2 , 2-tetrachloroethane, chlorobenzene, bromobenzene, xylenes, and carbotetrachloride .
• the condensation of the instant process is preferably carried out neat, at a temperature about 100 to 150 °C with the resultant water removed by distillation via a stream of inert gas, such as, nitrogen or argon. The reaction is substantially complete in about 30 minutes to 24 hours.
• Intermediate (26) may then be readily cyclized in the presence of a palladium catalyst, such as Pd(0Ac)2 or Pd(PPh3)4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o-tolylphosphine , or tricyclohexylphosphine, and the like, a base, such as, sodium bicarbonate, triethylamine, or diisopropylethylamine, in a noninterfering solvent, such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200°C to form (19) .
• a palladium catalyst such as Pd(0Ac)2 or Pd(PPh3)4 and the like
• a phosphine preferably a trialkyl- or triarylphosphine, such as triphenylphosphine,
• solvents examples include tetrahydrofuran, benzene, dimethylsulfoxide, or dimethylformamide .
• Examples of other suitable palladium catalysts include Pd(PPh 3 )Cl2, Pd(0C0CF 3 ) 2 . [ (CH 3 CgH4) 3P] 2 p dCl 2 ,
• phosphines include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2- bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1,4- bis (diphenylphosphino) butane .
• Examples of other suitable bases include tripropyl amine, 2 , 2 , 6, 6-tetramethylpiperidine, 1,5- diazabicyclo[2.2.2] octane (DABCO) , 1,8- diazabicyclo [5.4.0]undec-7-ene (DBU) , 1,5- diazabicyclo [4.3.0] non-5-ene, (DBN) sodium carbonate, potassium carbonate, and potassium bicarbonate.
• 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 alkylatmg agent CH2R4, 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 alkylatmg agent of the formula XCH ⁇ ⁇ where X is halo and R 70 is -C0 R 71 , -SO3R 71 , -P (0) (OR 71 ) 2. or - P(O) (OR 71 )H, where R ⁇ is an acid protecting group or a prodrug function, in the presence of a base in a noninterfering solvent to form (23).
• Methyl bromoacetate and t-butyl bromoacetate are the preferred alkylatmg agents .
• Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N-benzyltrimethylammonium hydroxide) .
• the reaction may or may not be carried out in the presence of a crown ether. Cesium carbonate and Triton B are preferred.
• the amount of alkylatmg agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material.
• the reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile.
• Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether .
• the reaction is conducted at temperatures from about -10 to 100 °C . preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions.
• a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed.
• Intermediate (23) may be optionally hydrolyzed with a base or acid to form desired product (24) and optionally salified.
• Hydrolysis of (23) is achieved using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous potassium carbonate, aqueous sodium carbonate, aqueous lithium carbonate, aqueous potassium bicarbonate, aqueous sodium bicarbonate, aqueous lithium bicarbonate, preferably sodium hydroxide and a lower alcohol solvent, such as, methanol, ethanol, isopropanol, and the like.
• 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.
• the acid protecting group may be removed by organic and inorganic acids, such as trifluoroacetic acid and hydrochloric acid with or without a noninterferring solvent.
• Suitable solvents include methylene chloride, tetrahydrofuran, dioxane, and acetone.
• the t-butyl esters are preferably removed by neat trifluoroacetic acid.
• the reaction is conducted at temperatures from about -10 to 100 °C. preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions .
• the preferred alkyl halide is methyl iodide.
• the reaction is conducted at temperatures from about 0 to 100 °C . preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions.
• the starting material (16) may be prepared by condensation with an alcohol HOPG, where PG is an acid protecting group, in the presence of a dehydrating catalyst such as, dicyclohexylcarbodiimide
• a palladium catalyst such as Pd(Pl_3P)4
• a base such as sodium bicarbonate
• Compound (28) is converted to the carbazole product (29) by treatment with a trialkyl or triaryl phosphite or phosphine, such as, triethylphosphite or triphenyl phosphine, according to the general procedure of Cadogan, et al . (Ref 6).
• a trialkyl or triaryl phosphite or phosphine such as, triethylphosphite or triphenyl phosphine
• Compound (29) is N-alkylated with an appropriately substituted alkyl or aryl halide C ⁇ R ⁇ in the presence of a base, such as sodium hydride or potassium carbonate, in a noninterfering solvent, such as toluene, dimethylformamide, or dimethylsulfoxide to afford carbazole (30) .
• a base such as sodium hydride or potassium carbonate
• a noninterfering solvent such as toluene, dimethylformamide, or dimethylsulfoxide
• Compound (30) is converted to the corresponding amide (22) by treatment with boron tribromide or sodium thioethoxide, followed by ammonia or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, or with methylchloroaluminum amide in an inert solvent, such as toluene, at a temperature between 0 to 110 °C .
• N-alkylation using for example a base such as sodium hydride and an appropriately substituted alkyl or aryl halide in dimethoxy formamide.
• Compound (22) can be converted to product carbazole product (24) as described previously in Scheme I ⁇ Ig(b) above.
• Conversion to the desired prodrug may be accomplished by techniques known to the skilled artisan, such as for example, by treatment with a primary or secondary halide to make an ester prodrug.
• 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.
• 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 H2NS0R 1 ⁇ in the presence of a base, preferably diazabicycloundecene .
• PG is an acid protecting group
• R 22 is (Ci-Cg) alkoxy (C ⁇ Cg) alkyl is (Cl-Cg) alkoxy
• Starting material (20) is O-alkylated with an alkyl halide or alkenyl halide, using a base such as NaH, in an aprotic polar solvent preferably anhydrous DMF, at ambient temperature under a nitrogen atmosphere.
• a base such as NaH
• an aprotic polar solvent preferably anhydrous DMF
• the process of aromatization from a cyclohexenone functionality to a phenol functionality can be performed by treating the tetrahydrocabazole intermediate (60) with a base such as NaH in the presence of methyl benzenesulfinate in an anhydrous solvent, such as 1,4-dioxane or DMF, to form the ketosulfoxide derivative.
• the ketosulfoxide derivative (60) Upon heating at about 100 °C for 1-2 hours, the ketosulfoxide derivative (60) is converted to the phenol derivative (61) .
• Conversion of the ester (61) to the amide (62) can be achieved by treating a solution of (61) in an aprotic polar solvent such as tetrahydrofuran with ammonia gas.
• Phenolic O-alkylation of (62) with, for example, methyl bromoacetate can be carried out in anhydrous DMF at ambient temperature using CS2CO3 or K2CO3 as a base to form (63) .
• Desired product (64) can be derived from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H 2 0/CH 3 OH/THF solution at 50 °C for 1-2 hours .
• R 22 is - (C ⁇ -Cg) alkoxy (C -Cg) alkenyl
• hydrogenation of the double bond can be performed by treating (63) in THF using Pt ⁇ 2 as a catalysis under a hydrogen atmosphere. Desired product can then be derived as described above in Scheme I ⁇ I(g) from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H 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(02-04) alkyl, halo, - (C j _-Cg) alkyl, phenyl, - (C -C4) alkylphenyl; phenyl substituted with -(C j _-Cg) alkyl, halo or -CF 3 ; -CH OSi (C ⁇
• 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 sulf onyl
• R 3 (a) is H, -0(C ] _-C4) alkyl, halo, - (C ⁇ -Cg) alkyl, phenyl, - (C1-C4) alkylphenyl; phenyl substituted with -(Ci-Cg) alkyl, halo or -CF 3 ; -CH 2 OSi (Ci-C ) alkyl, furyl, thiophenyl, - (C ⁇ -Cg) hydroxyalkyl; or -
• R9 and R ⁇ -O are independently - (C . -C4) alkyl or
• Conversion of the hydroxyl function of (103) to a halide or sulfate functionality is achieved by treatment with triphenylphosphine and CH3X (where X is a halogen) to make compounds of formula (111) where X is a halide; or by treatment with triethylamine and methanesulfonyl chloride to make the sulfonate.
• Displacement with the sodium salt of thiol acetic acid gives (114) which in turn is hydrolyzed by base to the thiol (115) which is reacted with an appropriately substituted aldehyde and acid to produce the thiopyranoindoles (116) .
• Intermediate (111) may also be reacted with sodium azide to give the azido derivative (112) which is reduced by hydrogen catalytically to give the amine which is converted to the carboline (113) with aldehyde and acid.
• Intermediates (113), (110) and (116) may be N-alkylated, using sodium hydride and an appropriately substituted alkylhalide XCH2R ⁇ .
• Lewis acids convert (126) to the thiopyrano [3 , -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, p3 ( a ) s as defined in Scheme 1(a) above;
• R is -(CH 2 )mR 5 .
• Alkylation at the 3-position of the indole (133) is achieved by treatment with n-butyllithum then zinc chloride at temperatures starting at about 10 °C and warming to room temperature, followed by reaction with an appropriate haloalkyl ester such as methyl or ethyl bromoacetate.
• the reaction is preferably conducted at room temperature in an appropriate aprotic polar solvent such as tetrahydrofuran.
• Alkylation of the indole-nitrogen can then be achieved by reacting (134) with a suitable alkyl halide in the presence of potassium bis (trimethylsilyl) mide to prepare (135) .
• the ester functionality of (135) is converted to a trimethylsilylketene acetal (136) by treatment with potassium bis (trimethylsilyl) amide and trimethylsilyl chloride.
• Treatment of the ketene acetal (136) with bis (chloromethyl) sulfide and zinc bromide in methylene chloride affords the cyclized product (137) .
• Conversion to amide (138) can be accomplished by a Weinreb reaction with methylchloroaluminum amide.
• N-alkylation of commercially available 4-methoxy indole (231) under basic conditions using an alkyl halide affords the N-alkyl indole (232) .
• Acylation with a suitable acid chloride provides the glyoxalate ester product (233) which can be reduced with a variety of hydride reducing agents to give intermediate alcohols (234) .
• Conversion of the alcohol to a suitable leaving group and displacement with sulfur nucleophiles affords the thioether product (235) .
• Conversion to the acid chloride and spontaneous cyclization affords the thioketone product (236) .
• Cleavage of the ester can be effected under basic conditions to give the correponding acid which upon formation of the acid chloride and reaction with an appropriate amine gives the amide product (237) .
• Cleavage of the methyl ether gives the phenol (238) which can be alkylated under basic conditions using alkyl halides to give the O-alkylated product (239) .
• Cleavage of the ester under basic conditions gives the desired product (240) .
• 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 methyl bromoacetate in the presence of a base, hydrolysis with hydroxide to provide the intermediate salt which is then protonated in aqueous acid to provide desired ⁇ - carboline (150) .
• X is halo
• R is as defined in Scheme IV (d)
• Ketene acetal (136) is reacted with benzyl bis (methoxymethyl) amine in the presence of zinc chloride to give the tetrahydro-beta-carboline (151) .
• amide (152) (R ⁇ 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) ; and R3 ( a ) ig as defined in Scheme 1(a).
• 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 (Ref. 9) in refluxing ethanol to give tetrahydrocarboline (159) .
• X is halo
• R 3 ( a ) is as defined above Scheme V(e) provides ⁇ -carboline (198) by the indicated sequence of reactions.
• N-alkylation of 2- carboethoxyindole (190) followed by a standard two carbon homologation sequence provides 2- (3-propenoic acid) indoles (194).
• the condensation of aldehyde (193) with malonic acid utilized a mixture of pyridine and piperidine as the base.
• ring closure (196) was effected by treatment with bis (2,2,2- trichloroethyl) azodicarboxylate (BTCEAD) followed by zinc in acetic acid.
• BTCEAD bis (2,2,2- trichloroethyl) azodicarboxylate
• Reverse indoles i.e., compounds where B is carbon and D is nitrogen can be prepared as described in Scheme VIg, below.
• Aryl hydrazines (200) are condensed with substituted prpionaldehydes to form hydrazones which are cyclized to indoles (201) by treatment with phosphorous trichloride at room temperature (Ref 1) .
• 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 .
• Commercially available 4-chloroindole (210) is treated with 3 equivalents of t-butyllithium followed by carbon dioxide, 1 equivalent of n-butyllithium, l-dimethylamino-2-nitroethene, and acid to provide carboxylic acid (211) , which may be esterified to give (212) .
• Alkylation at the 1-position followed by hydrogenation provides aminoethyl indole (214) .
• Cyclization with phosgene to (215) followed by aromatization gives carboline (216) .
• Treatment of (216) with the appropriate Weinreb reagent provides amide (217), which may be alkylated with, for example, ethyl bromoacetate and saponified with sodium hydroxide to give the carboline (218) .
• 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.
• the amino group of (228) is protected with an appropriate protecting group, such as the, carboethoxyl , benzyl, CBZ (benzyloxycarbonyl) or BOC (tert-butoxycarbonyl) protecting group, and the like.
• an appropriate protecting group such as the, carboethoxyl , benzyl, CBZ (benzyloxycarbonyl) or BOC (tert-butoxycarbonyl) protecting group, and the like.
• the dione (228) and aniline derivative (220) are condensed according to the general procedure of Chen, et al . , (Ref 10) or Yang, et al . , (Ref 11), 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 . , (Reff8) .
• 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) .
• Co pound (221) may also be cyclized according to the general procedure of Chen, et al . , (Ref 10) .
• the derivative (221) is treated with a base, such as sodium bicarbonate, and a palladium catalyst, such as Pd(PPb.3)4, in an inert solvent, such as HMPA, at a temperature between 25 and 150 °C to afford compound (222) .
• a base such as sodium bicarbonate
• a palladium catalyst such as Pd(PPb.3)4
• an inert solvent such as HMPA
• intermediate (171) is treated with a transition metal catalyst, such as Pd(OAc) 2 (O-tol) 3P in the presence of a base such as triethylamine using a cosolvent of DMF/acetonitrile to prepare (222) .
• a transition metal catalyst such as Pd(OAc) 2 (O-tol) 3P
• a base such as triethylamine
• Compound (222) is N-alkylated with an appropriately substituted benzyl halide in the presence of a base, such as sodium hydride or potassium carbonate, in a noninterfering solvent, such as dimethylformamide or dimethylsulfoxide to afford ketone (223) .
• a base such as sodium hydride or potassium carbonate
• a noninterfering solvent such as dimethylformamide or dimethylsulfoxide to afford ketone (223) .
• one pot process (222) is aromatized by treatment with acetic acid and palladium on carbon in a noninterfering solvent, such as carbitol or cymene, followed by treatment with hydrogen gas and palladium on carbon to cleave the nitrogen protecting group and produce the phenolic derivative (224) .
• the ester (224) is converted to the corresponding amide (225) under standard conditions with ammonia (preferably) or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, preferably methanol, or with MeClAlNH2 in an inert solvent, such as toluene, at a temperature between 0 to 110 °C.
• ammonia preferably
• an ammonium salt such as ammonium acetate
• an inert solvent such as water or alcohol, preferably methanol
• MeClAlNH2 inert solvent, such as toluene
• haloester such as methyl bromoacetate
• a base such as cesium carbonate, potassium or sodium carbonate
• an inert solvent such as dimethylformamide or dimethylsulfoxide
• ester-amide 226
• haloesters such as ethyl bromoacetate, propyl bromoacetate, butyl bromoacetate, and the like can also be used to prepare the corresponding esters .
• compositions and method of the invention may be prepared and practiced using pyrazole sPLA 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 CONH 2 where n is 0-2; R ⁇ is phenyl; phenyl substituted with 1 to 3 substituents selected from the group consisting of -(C3 .
• -C4 alkyl, -CN, halo, -N0 , C0 2 (C ⁇ C4) lkyl and -CF3 ; naphthyl; thiophene or thiophene substituted with 1 to 3 halo groups;
• R 3 is hydrogen; phenyl; phenyl (C2-C5) alkenyl; pyridyl; naphthyl; quinolinyl; (C1-C4) alkylthiazolyl; phenyl substituted with 1 to 2 substituents selected from the group consisting of - ⁇ C1-C4) alkyl, -CN, -C0NH , -N0 2 , -CF3 , halo,
• R ⁇ is cyclopentyl, cyclohexenyl, or phenyl substituted with halo or (Ci ⁇ C ) 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; pharmaceutically acceptable salt thereof.
• Particularly preferred are pyrazole type sPLA 2 inhibitors as follows:
• R-L is pyridine-2-yl or pyridine-2-yl substituted at the 4-position with - (C ⁇ C4) alkyl, (C]_- C 4 )alkoxy, -CN or -(CH 2 ) n CONH2 where n is 0-2;
• R2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of - (C]_- C4) alkyl, -CN, halo, -N0 2 , C0 2 (C1-C4) alkyl and -CF3 ; and
• R3 is phenyl; phenyl (C 2 -C5) alkenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of - (C1-C4) alkyl, -CN, -C0NH 2 , -N0 2 , - CF3, halo, (C ] _-
• pyrazole type sPLA inhibitors useful in the method of the invention are as follows: Compounds selected from the group consisting of 3- (2- chloro-6-methylphenylsulfonylamino) -4- (2- (4- acetamido) pyridyl) -5- (3- (4-fluorophenoxy) benzylthio) - (IH) -pyrazole and 3- (2 , 6-dichlorophenylsulfonylamino) -4- (2- ( 4-acetamido) pyridyl) -5- (3- (4- fluorophenoxy) benzylthio) - (IH) -pyrazole.
• the pyrazole compounds of formula Ih are prepared as described in Scheme Ih below.
• L is a leaving group
• an acetonitrile compound (1) is deprotonated by treatment with an excess of a strong base, such as sodium hydride, preferably under an inert gas, such as nitrogen.
• a strong base such as sodium hydride
• the deprotonated intermediate is treated with carbon disulfide and then alkylated twice with an appropriately substituted alkyl halide (2) of the formula R (CH 2 ) m L, where L is a leaving group, preferably bromine, and R 3 and m are as defined above, to prepare intermediate compound (3).
• the reaction is conducted at ambient temperatures and is substantially complete in 1 to 24 hours.
• Cyclization to form the amino substituted pyrazole (4) is achieved by reacting intermediate (3) with hydrazine at room temperature for from about 1 to 24 hours .
• Selective sulfonylation of the amino group of intermediate (4) can be accomplished by treatment with a sulfonyl chloride (5) of the formula R2S0 C1, where R ⁇ is as defined above, to prepare product (6) .
• the reaction is preferably conducted in a solvent, such as pyridine, at ambient temperature for a period of time of from 1 to 24 hours.
• Preparation of 2 , 6-dimethyIphenylsulfonyl chloride can be accomplished as described in J. Org.
• Phenyl glyoxamide sPLA 2 inhibitors (and the method of making them) are described in U.S. Patent Application Serial No. 08/979446, filed November 24, 1997 (titled, Phenyl Glyoxamides as sPLA 2 Inhibitors) , the entire disclosure of which is incorporated herein by reference.
• the compositions and method of the invention is for treatment of a mammal, including a human, afflicted with sepsis may be practiced using phenyl glyoxamide type sPLA2 inhibitors described as follows:
• X is -O- or -(CH 2 ) m -, where m is 0 or 1; Y is -CO2-, -PO3-, -SO3-; R is independently -H or - (C -C4) alkyl ; l and R ⁇ are each independently -H, halo or - (C1-C4) alkyl; R 3 and R 4 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 -C0 2 - or -SO3- and 1 or 2 when Y is -PO3-; or a pharmaceutically acceptable salt thereof.
• Phenyl glyoxylamide compounds useful in the compositons and method of the invention are prepared as follows:
• R' IS (Ci-C ) alkyl
• compound (2) is internally cyclized to form compound (3) .
• the reaction is preferably conducted at temperatures from about 0 °C to room temperature and allowed to proceed for about 24 hours.
• Aminolysis of (3) to amide (4) can be achieved by treatment with concentrated ammonium hydroxide.
• Alkylation of the hydroxyl of compound (4) can be readily achieved by treatment with an appropriate alkylating agent, such as Br(CH 2 ) n Y, where Y is -CO2R, - P ⁇ 3R 2 or SO3R and R is - (C . -C4) alkyl, to form intermediate (5) .
• the reaction is preferably conducted in an aprotic polar solvent, such as dimethyl formamide, in the presence of potassium carbonate and a suitable catalyst, such as potassium iodide.
• Conversion of (5) to the carboxylic or sulfonic acid or acid salt (6) may be achieved by treatment with an appropriate base, such as aqueous sodium hydroxide, in a polar protic solvent, such as methanol.
• a base such as aqueous sodium hydroxide
• a polar protic solvent such as methanol.
• n 2
• a bromoacetal must be employed as an alkylating agent to achieve the carboxylic acid (6) .
• the alkylated moiety (5) is then converted to the acid (6) by oxidizing with sodium dichromatate in aqueous conditions.
• conversion to the acid (6) is preferably conducted in an alkyl halide solvent, such as methylene chloride, using a dealkylating agent, such as trimethylsilyl bromide, and an excess of potassium carbonate, followed by treatment with methanol.
• alkyl halide solvent such as methylene chloride
• dealkylating agent such as trimethylsilyl bromide
• R' is as defined in Scheme Ii.
• Conversion to the intermediate (9) is accomplished by reacting (2a) with an aqueous acid, such as hydrochloric acid which affords removal of aluminum chloride from the reaction.
• Acid (9) is converted to the corresponding acid chloride using oxalyl chloride with dimethyl formamide as a catalyst.
• the acid chloride is recyclized to the lactone (10) on removal of the solvent, preferably under vacuum.
• the lactone (10) is converted to the glyoxamide (11) by treatment with an excess of ammonia as described in Schemetl, step (c) , above.
• conversion of (10) to (12) can be accomplished in a one-pot procedure by treating the lactone (10) with sodium amide in an aprotic polar solvent, such as dimethylformamide, preferably at temperatures of from about 0 °C to 20 °C, followed by alkylation with an appropriate alkyl halide .
• an aprotic polar solvent such as dimethylformamide
• compositions and method of the invention for treatment of a mammal, including a human, afflicted with sepsis may be practiced with a pyrrole sPLA 2 described as follows :
• Rl is hydrogen, (C1-C ) alkyl, phenyl or phenyl substituted with one or two substituents selected from the group consisting of - (C1-C4) alkyl, (C2 . -C4) alkoxy, phenyl (C1-C4) alkyl, (C1-C ) alkylthio, halo and phenyl;
• R 2 is hydrogen, - (C . -C4) alkyl, halo, (C -C4) alkoxy or (C1-C4) alkylthio;
• R 5 is -NH 2 or -NHNH ;
• X is R 8 (C 1 -C 6 ) alkyl; R 8 (C 2 -C5) alkenyl or phenyl substituted at the ortho position with R 8 where R 8 is
• R 10 is -C0 2 R 1:L , -P0 3 (R 1:L ) , -RO t ⁇ ⁇ R 11 ) 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, - (C1-C ) alkyl, halo, (C1-C4) alkoxy, or two substituents which, when taken together with the phenyl ring to which they are attached, form a naphthyl group; and R9 is hydrogen or methyl or ethyl; or a pharmaceutically acceptable salt thereof.
• Preferred pyrrole sPLA 2 inhibitors useful in the method of the invention are compounds of formula Ij wherein;
• R-L is phenyl
• R 2 is methyl or ethyl
• R 5 is -NH ;
• R ⁇ and R ⁇ are each hydrogen;
• X is R 8 (C2 . -C5) alkyl or phenyl substituted at the ortho position with R 8 where
• R 8 is -CO2R 11 ;
• R9 is methyl or ethyl.
• a specific suitable pyrrole sPLA 2 inhibitors useful in the method of the invention is 2- [l-benzyl-2 , 5-dimethyl- 4- (2-carboxyphenylmethyl) pyrrol-3-yl] glyoxamide.
• the pyrrole compounds are prepared as follows:
• a suitable Lewis-acid catalyst such as stannic chloride, aluminum chloride, or titanium tetrachloride (preferably stannic chloride)
• pyrrole (2) is ring alkylated with an alkyl or arylalkyl halide compound of the formula where Z is a suitable halogen and R 8 of X is a protected acid or ester.
• the reaction is preferably conducted in a halogenated hydrocarbon solvent, such as dichloromethane, at ambient temperatures and allowed to proceed for from about 1 to about 24 hours.
• Intermediate (3) is converted to (4) by sequential treatment with oxalyl chloride followed by ammonia.
• Selective reduction of (4) is accomplished in a two step process.
• a hydride reduction using, for example, sodium borohydride the hydroxy intermediate (5) is prepared which can be further reduced using either catalytic or hydride reduction (preferably palladium on carbon) to prepare (6) .
• Deprotection of R 8 to the acid may be readily achieved by conventional techniques. For example, when an alkyl ester is used as a protecting group, deprotection can be accomplished by treatment with a base, such as sodium hydroxide.
• compositions and method of the invention for treatment of a mammal, including a human, afflicted with sepsis may be practiced with a naphthyl glyoxamide sPLA 2 inhibitors described as follows:
• R-L and R 2 are each independently hydrogen or a non- interfering substituent with the proviso that at least one of R-L or R 2 must be hydrogen;
• X is -CH 2 - or -0-; and Y is (CH ) n Z where n is a number from 1-3 and Z is an acid group selected from the group consisting of C0 H, -SO3H or -P0(0H) 2 .
• a specific suitable naphthyl glyoxamide sPLA 2 inhibitors useful in the method of the invention has the following structural formula:
• the naphthyl glyoxamide compounds are prepared as follows:
• the 1, 5-dihydroxy napthalene starting material (1) is dispersed in water and then treated with 2 equivalents of potassium hydroxide.
• the resultant solution is chilled in an ice bath and one equivalent of a strong mineral acid, such as hydrochloric acid, is added to produce the potassium saltt (2) .
• Alkylation of the radical (2) can then be accomplished by treatment with a methylating agent such as dimethyl sulfate to prepare the ether (3) .
• Preparation of (4) is achieved by reacting the ether (3) with an appropriately substituted phenol in an Ullman-type reaction using potassium carbonate and cupric oxide .
• De-methylation of (4) can be accomplished by treating (4) with a 40% HBr/HOAC solution at reflux in a protic polar solvent such as acetic acid, to prepare (5) . Reflux of compound (5) with oxalyl chloride and
• Alkylation and hydrolysis of the cyclized compound (7) can be achieved by reacting (7) with an alkaliamide base, such as sodium amide, followed by treatment with an alkylating agent, such as methyl bromoacetate, using potassium iodide as a catalyst.
• an alkaliamide base such as sodium amide
• an alkylating agent such as methyl bromoacetate
• the acid (9) is achieved by treating the ester (8) with an alkali base, such as aqueous sodium hydroxide, followed by treatment with a dilute aqueous mineral acid such as hydrochloric acid.
• an alkali base such as aqueous sodium hydroxide
• a dilute aqueous mineral acid such as hydrochloric acid
• the final product (9) is then extracted with an organic solvent such as ethyl acetate .
• the final product (9) can be purified using standard recrystallization procedures in a suitable organic solvent such as methylene chloride/hexane .
• a Grignard reagent is prepared.
• the phenyl Grignard is then reacted with 4-methoxy naphthylnitrile and the resultant compound is hydrolyzed with a dilute acid such as hydrochloric acid to form the benzoyl naphthylene compound (la) .
• Reduction of (la) to form compound (2a) is accomplished by treatment with a reducing agent such as sodium borohydride.
• a reducing agent such as sodium borohydride.
• the reaction is conducted in a solvent-catalyst such as trifluoroacetic acid and initiated in an ice bath which is allowed to warm to room temperature as the reaction proceeds .
• the desired naphthyl glyoxamide may then be prepared from (2a) according to the procedure in Scheme I starting with the chloromethylation step.
• Phenyl acetamide sPLA inhibitors and methods of making them are disclosed in US Patent Application 08/976858, filed November 24 1997 (titled, "Phenyl Acetamides as sPLA 2 Inhibitors"), the entire disclosure of which is incorporated herein by reference.
• compositions and method of the invention for treatment of a mammal, including a human, afflicted with sepsis may be practiced using a phenyl acetamide sPLA 2 inhibitor represented by formula (II) as follows:
• R 1 is -H or -0(CH ) n Z;
• R 2 is -H or -OH;
• R 3 and R ⁇ are each independently -H, halo or - (Cj_-C ) alkyl
• R ⁇ and R ⁇ is -YR 7 and the other is -H, where Y is -0- or -CH 2 - and R 7 is phenyl or phenyl substituted with one or two substituents selected from the group consisting of halo, - (C2 . -C4) alkyl, (C -C4) alkoxy, phenyl or phenyl substituted with one or two halo groups;
• Z is -C0 2 R, -P ⁇ 3R or -SO3R where R is -H or - (C1-C4) alkyl; and n is 1-8; or a pharmaceutically acceptable salt, racemate or optical isomer thereof; provided that when R ⁇ is YR 7 , R ⁇ is hydrogen; and when R 1 , R 2 , R , R 4 and R ⁇ are hydrogen and R 5 is YR 7 where Y is -0-, X 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 CH 2 , 7 cannot be phenyl substituted with one methoxy or two chloro groups .
• Preferred suitable phenyl acetamide sPLA 2 inhibitors useful in the composition and method of the invention are as follows:
• a specific suitable phenyl acetamide sPLA 2 inhibitor useful in the method of the invention is 2- (4- carboxybutoxy) -4- (3-phenylphenoxy) phenylacetamide .
• phenyl acetamide inhibitors are prepared as follows:
• X is halo
• R 8 and R ⁇ are each independently -H, halo, - (C1-C4) alkyl, (C1-C4) alkoxy, phenyl or phenyl substituted with one or two halo groups; and PG is a carboxyl protecting group
• An appropriately substituted carboxy-protected halophenyl compound (1) where the halogen is preferably bromine, is coupled with an appropriately substituted phenol (2) under modified Ullmann conditions, by refluxing with potassium carbonate and cupric oxide in an aprotic polar solvent, such as pyridine, under an inert gas such as argon. The reaction is substantially complete in 1-24 hours.
• Intermediate (3) is deprotected by treatment with a base such as aqueous potassium hydroxide using a solvent, such as diethylene glycol.
• a base such as aqueous potassium hydroxide
• a solvent such as diethylene glycol.
• amide (5) Conversion to the amide (5) can then be readily achieved by treatment first with oxalyl chloride in an alkyl halide solvent, such as methylene chloride, using dimethylformamide as a catalyst, at temperatures of from about 0 °C to ambient temperature, followed by treatment with an excess of ammonia gas, again in an alkyl halide solvent .
• alkyl halide solvent such as methylene chloride
• dimethylformamide as a catalyst
• compounds of formula I can be prepared according to the procedure of Scheme 1(b), below.
• the substituted phenol (2) is coupled with an appropriately substituted benzyl halide (6) as described in Scheme 1(a), step a, above, to prepare (7).
• Halogenation of (7) is achieved using a halogenating agent, such as N-bromosuccinimide and a catalyst, such as
• R 8 and R ⁇ are as shown in Scheme 1(a) , X is halo.
• X is a halogen
• diphenyl compound (11) is treated with paraformaldehyde and a halogenating agent, such as 40% hydrogen bromide in acetic acid.
• a halogenating agent such as 40% hydrogen bromide in acetic acid.
• Two positional isomers result with the X substituent at either the meta or para position of the phenyl ring to which it is attached.
• Displacement of the halogen to prepare the nitrile isomers (13) can be achieved by treatment of (12) with sodium cyanide in dimethylformamide as described in Schemetl(b), step (c) , above.
• the isomers can then be readily separated by conventional chromatographic techniques and each isomer may be converted to its respective amide (14) by treatment with hydrogen peroxide and potassium carbonate in an aprotic polar solvent, such as dimethylsulfoxide .
• Intermediate (16) is prepared by refluxing an appropriately substituted diphenyl compound (15) with oxalyl chloride in an alkyl halide solvent, such as chloroform.
• an alkyl halide solvent such as chloroform.
• the reaction is catalyzed with 4 , 4-N-dimethylaminopyridine .
• Cyclization to the lactone (17) can be achieved under Friedel-Crafts conditions using a suitable metal halide, such as aluminum chloride, as the catalyst.
• Conversion to the glyoxamide (18) can be achieved by aminolysis of the lactone ring using concentrated ammonium hydroxide .
• Alkylation of the hydroxy group to prepare the desired alkyl-linked ester (19) occurs by treatment of

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