Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

• This invention relates to novel pyrrolo [2, 3-d] - pyrimidines useful for inflammatory diseases.
• sPLA2 human non- pancreatic secretory phospholipase A2
• SPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids .
• compounds which inhibit SPLA2 mediated release of fatty acids e.g., arachidonic acid
• Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA2 ; such as sepsis or rheumatoid arthritis .
• sPLA2 induced diseases It is desirable to develop new compounds and treatments for sPLA2 induced diseases.
• This invention is a novel use of the class of compounds known as pyrrolo [2, 3-d] pyrimidines to inhibit mammalian sPLA2 mediated release of fatty acids.
• This invention is also a novel class of pyrrolo [2,3- d] pyrimidines having potent and selective effectiveness as inhibitors of mammalian sPLA2-
• This invention is also a pyrrolo [2, 3-d] pyrimidine compound in the treatment of Inflammatory Disease.
• This invention is also pharmaceutical compositions containing the pyrrolo [2, 3-d] pyrimidines of the invention.
• This invention is also a method of preventing and treating Inflammatory Diseases in mammals by contact with a therapeutically effective amount of the pyrrolo [2,3- d] pyrimidines of the invention.
• This invention is also the use, in the manufacture of a medicament of pyrrolo [2, 3-d] pyrimidine compound as an active ingredient in an SPLA2 inhibiting composition in admixture with an inert carrier.
• Inflammatory Diseases refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult 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, hyper
• pyrrolo [2, 3-d] pyrimidine nucleus refers to a nucleus (having numbered positions) with the structural formula (X) :
• pyrrolo [2, 3-d] pyrimidine compounds of the invention employ certain defining terms as follows:
• alkyl by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl .
• alkenyl employed alone or in combination with other terms means 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 means an organic group containing only carbon and hydrogen.
• heterocyclic radical refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur.
• Typical heterocyclic radicals are pyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo(1.2- A)pyridinyl, benzotriazolyl, anthranilyl, 1,2- benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridylyl .
• carbocyclic radical refers to radicals 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, thiophenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a) :
• n is a number from 1 to 8.
• non-interfering substituent refers to radicals suitable for substitution at the 2 position of the pyrrolo [2, 3-d] pyrimidine nucleus and on other nucleus substituents (as hereinafter described for Formula I), infra.
• Illustrative non-interfering radicals are Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluoyl, xylenyl, biphenyl, Ci-Cs alkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2 ⁇ c 12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C ⁇ -Ci2 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C8 alkylthio, C2-C12 alkylthiocarbonyl, C ⁇ -C8
• (acidic group) means an organic group which when attached to a pyrrolo [2, 3-d] pyrimidine nucleus, through suitable linking atoms (hereinafter defined as the "acid linker”), acts as a proton donor capable of hydrogen bonding.
• suitable linking atoms hereinafter defined as the “acid linker”
• R41 is a metal or C ⁇ -C8 alkyl.
• acid linker refers to a divalent linking group symbolized as, -(L a )-, which has the function of joining the 4 or 5 position of the pyrrolo [2, 3-d] pyrimidine nucleus to an acidic group in the general relationship:
• acid linker length refers to the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(L a ) ⁇ that connects the 4 position of the pyrrolo [2, 3-d] pyrimidine 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.
• amine includes primary, secondary and tertiary amines .
• alkylene chain of 1 or 2 carbon atoms refers to the divalent radicals, -CH2-CH2- and -CH2-.
• the compounds of the invention have the general formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof;
• R2 is selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituent (s) , heterocyclic radicals, and heterocyclic radical substituted with non-interfering substituent (s) ;
• R4 is - (L4 )- (acidic group); wherein -(L4)-, is a divalent acid linker having an acid linker length of 1 to 4; R5 is -(L5)- Z, where -(L5)- is a divalent linker group selected from a bond or a divalent group selected from:
• Z is selected from acetamide, thioacetamide, glyoxylamide, thioglyoxylamide, hydrazide or thiohydrazide groups represented by the formulae,
• R5 and R52 are independently selected from hydrogen, C -Cg alkyl, C -Cg haloalkyl, and C3-C4 cycloalkyl, and X is oxygen or sulfur;
• Rg is hydrogen, or a group containing 1 to 4 non- hydrogen atoms plus any required hydrogen atoms;
• R7 is selected from groups (a) , (b) and (c) wherein;
• (a) is C7-C20 alkyl, C7-C20 haloalkyl, 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 ⁇ ⁇ ; where, -(L7)- is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in -(L7)- is selected from the group consisting of (i) carbon and hydrogen only, (ii) sulfur only, (iii) oxygen only, (iv) nitrogen and hydrogen only, (v) carbon, hydrogen, and sulfur only, and (vi) and carbon, hydrogen, and oxygen only; and where R7 is a group selected from (a) or (b) .
• R2 is preferably selected from the group consisting of hydrogen, cyclopropyl, C_-Cg alkyl, C -Cg haloalkyl, C ⁇ -Cg alkoxy, C ⁇ -C8 thioalkyl, C ⁇ -C8 alkylsulfonyl, C -C ⁇ 2 alkylamino, phenyl, and thiophenyl.
• Particularly preferred R2 groups are hydrogen, methyl, ethyl, propyl, isopropyl,
• a preferred subclass of compounds of formula (I) are those wherein R4 is a substituent having an acid linker with an acid linker length of 2 or 3 and the acid linker group, - (L4)-, is selected from a group represented by the formula;
• Q]_ is selected from the group -(CH2! -0-, -NH-, -C(O)-, -S-, and
• R 0 is independently selected from hydrogen, C ⁇ -Cj alkyl, aryl, C ⁇ -Cs alkaryl, C ⁇ -Cs alkoxy, aralkyl, and halo.
• R4 is selected from the groups;
• R40 is hydrogen or Cx -Cg alkyl.
• Preferred as the (acidic group) in the group R4 are acidic groups selected from:
• R4X is a metal or C ⁇ -C8 alkyl.
• a salt or prodrug derivative of the (acidic group) is also suitable.
• salt derivatives of the (acidic group) R4 are;
• ester prodrug derivatives are of the (acidic group) R4 ;
• the most preferred acidic group in the compounds of the invention is a carboxylic acid group, -CO2H.
• a preferred subclass of compounds of formula (I) are those wherein all X's of group R5 are oxygen.
• Another preferred subclass of compounds of formula (I] are those wherein Z is a group selected from acetamide, glyoxylamide, or hydrazide, represented by the formulae (Va) , (Vb) , and (Vc) ;
• linking group -(L5)- be a bond, particularly when the R5 is a bond in combination with Z being the glyoxylamide group.
• Rg is selected from the group; hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, C1-C3 alkoxy, C ⁇ -C3 alkylthio, C ⁇ -C3 haloalkyl and halo.
• R7 substituents are those wherein Rg is selected from the group; hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, C1-C3 alkoxy, C ⁇ -C3 alkylthio, C ⁇ -C3 haloalkyl and halo.
• Another preferred subclass of compounds of formula (I) wherein the divalent linking group -(L7)- is selected from the formulae (Vila), (Vllb) , (VIIc) , (Vlld) , (Vile), and (Vllf) :
• Q2 is a bond or any of the divalent groups (Vila) , (Vllb), (VIIc), (Vlld), (Vile), and (Vllf) and each R 70 is independently hydrogen, C ⁇ _g alkyl, C ⁇ _g haloalkyl or C ⁇ _g alkoxy.
• linking group -(L7)- of R7 is an alkylene chain of 1 or 2 carbon atoms, namely, - (CH 2 )-, and -(CH 2 -CH 2 )-.
• R7X is a substituted or unsubstituted group selected from the group consisting of C5-CX4 cycloalkyl, C5-CX4 cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl- cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (a) ;
• n is a number from 1 to 8.
• Substituents for R7 are non-interfering radicals selected from halo, -CF3 C ⁇ -C ⁇ o alkyl, C ⁇ -C ⁇ o alkoxy, -S- (C ⁇ -C ⁇ o alkyl), and C ⁇ -C ⁇ o haloalkyl radicals. Particularly preferred are compounds wherein for R7 the combined group -(I ⁇ 7)-R7 ⁇ is selected from the group consisting of
• R72 is a radical independently selected from hydrogen, halo, -CF3 C ⁇ -C ⁇ o alkyl, C ⁇ -C ⁇ o alkoxy, -S- (C ⁇ -C ⁇ o alkyl), and C ⁇ -C ⁇ o haloalkyl, C ⁇ -C ⁇ o hydroxyalkyl and t is a number from 0 to 5 and u is a number from 0 to 4.
• Preferred compounds of the invention are those having the general formula (II) , or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof;
• R ⁇ 2 is selected from hydrogen, halo, cyclopropyl, C ⁇ -C ⁇ alkyl, C ⁇ -Cs alkoxy, C ⁇ -Cs alkylthio C ⁇ -C8 haloalkyl, C ⁇ -Cs hydroxyalkyl, phenyl, thiophenyl, thiomethyl, diethylamino, dimethylamino, and ethylamino.
• -(L4)- is a divalent group selected from
• R40 is hydrogen C ⁇ -C8 alkyl
• RXg is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, C ⁇ -C3 alkoxy, C ⁇ -C3 alkylthio, and C ⁇ -C3 haloalkyl .
• R72 is and C ⁇ -C8 alkyl, C ⁇ -Cs alkoxy, -S-(C ⁇ -C8 alkyl), C ⁇ -Cs haloalkyl, C ⁇ -C8 hydroxyalkyl, - CF3 and halo, phenyl, biphenyl, thiophenyl and t is an integer from 0 to 5.
• Preferred R72 substituents are -Cl, - CF3, and -F located at a position meta to the linking group attached to the nitrogen atom at the 7 position, for example, as shown in Formula Ila below;
• One set of specific preferred compounds and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are illustrative of the compounds of the invention include the following:
• Another set of specific preferred compounds and all pharmaceutically acceptable salts, solvates and prodrug derivatives thereof which are illustrative of the compounds of the invention include the following:
• Representative pharmaceutically acceptable salts include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from' the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
• the (acidic group) of the substituent R4 of Formula I may be selected as -CO2H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt.
• salts include the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al . , "Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)).
• the basic group (s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate,
• Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when 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 enantio er 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) with 4- (2- chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wisconsin USA, Item No. C4, 220-3).
• RX Cl, RS, CN, RO, R 2 N
• 2-butanone to provide compound IV.
• the ethyl group of the ketone eventually becomes the ethyl substituent at the 6 position of the pyrrolopyrimidine .
• the ketone is treated with an alcohol under mildly acidic conditions generating a ketal, compound V.
• Compound V can then be reacted under basic to neutral conditions with ureas, thioureas, and amidines .
• compound V can be reacted with thiourea under basic conditions to provide compound Via, 2-thiopyrimidone .
• the thio group can be hydrogenolized using Raney Nickel to provide the 2-unsubstituted pyrimidone .
• compound V can be reacted under neutral conditions with acetamidine to provide the 2-methylpyrimidone, compound Vic.
• Compound VI can be cyclized to a pyrrolopyrimidine compound VII, and reacted with POCI3 to produce the 2-substituted 4- chloropyrrolpyrimidine, compound VIII.
• the nitrogen at the 7 position is then alkylated under basic conditions and the chloride displaced with enough glycolate to provide compound X.
• the glyoxamide side chain was incorporated using an excess of oxalyl chloride in the presence of pyridine followed by quench with ammonia.
• This provides the compound of the invention, (C2), supra.
• Straightforward hydrolysis of the methyl ester followed by acidification provides compound I (C4) supra.
• the sulfur group can be oxidized and displaced with a variety of nucleophiles which is described at the bottom as going from compound lid, to compound XI, to compound IIx.
• Pyrrolo [2, 3-d] pyrimidines described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of mammalian (including human) sPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc.
• the method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with an therapeutically effective amount of pyrrolo [2 , 3-d] pyrimidines corresponding to Formulae (I) or (II) as described herein including salt or a prodrug derivative thereof.
• Another aspect of this invention is a method for treating Inflammatory Diseases such as inflammatory bowel disease, septic shock, adult respiratory distress syndrome, panceatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, osteoarthritis, and related diseases which comprises administering to a mammal (including a human) a therapeutically effective dose pyrrolo [2,3- d] pyrimidines of the invention (see, formulae I and II) .
• a mammal including a human
• pyrrolo [2,3- d] pyrimidines of the invention see, formulae I and II
• the compounds of this invention are useful for inhibiting sPLA2 mediated release of fatty acids such as arachidonic acid.
• inhibiting is meant the prevention or therapeutically significant reduction in release of sPLA2 initiated fatty acids by the compounds of the invention.
• pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention.
• Preferably compounds of the invention (per Formulae I or II) or pharmaceutical formulations containing these co pounds are in unit dosage form for administration to a mammal.
• the unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these.
• the quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
• the compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
• compositions of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the pyrrolo [2, 3-d] pyrimidines of the invention together with a pharmaceutically acceptable carrier or diluent therefor.
• the present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
• the Active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
• a carrier which may be in the form of a capsule, sachet, paper or other container.
• the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , or ointment, containing, for example, up to 10% by weight of the active compound.
• the compounds of the present invention are preferably formulated prior to administration.
• the carrier may be a solid, liquid, or mixture of a solid and a liquid.
• the compounds of the invention may be dissolved in at a concentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueous solution.
• Solid form formulations include powders, tablets and capsules.
• a solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
• Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.
• suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate
• disintegrating agents such as maize, starch, or alginic acid
• binding agents for example, gelatin or acacia
• lubricating agents such as magnesium stearate, stearic acid, or talc.
• the carrier is a finely divided solid which is in admixture with the finely divided Active ingredient.
• the Active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain from about 1 to about 99 weight percent of the Active ingredient which is the novel compound of this invention.
• Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
• Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.
• the Active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
• a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent or a mixture of both.
• the Active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol.
• suitable organic solvent for instance aqueous propylene glycol.
• Other compositions can be made by dispersing the finely divided Active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
• the following pharmaceutical formulations 1 thru 8 are illustrative only and are not intended to limit the scope of the invention in any way.
• "Active ingredient” refers to a compound according to Formula (I) or (II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
• Hard gelatin capsules are prepared using the following ingredients :
• Formulation 2 A tablet is prepared using the ingredients below:
• the active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to - 30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
• Formulation 4 Tablets each containing 60 mg of Active ingredient, are made as follows:
• the Active ingredient, starch and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly.
• the aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No . 14 mesh U.S. sieve.
• the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
• the sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
• Capsules each containing 80 mg of Active ingredient, are made as follows:
• the Active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities .
• Formulation 6 Suppositories, each containing 225 mg of Active ingredient, are made as follows:
• the Active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
• the benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume.
• An intravenous formulation may be prepared as follows : Active ingredient 100 mg
• the solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.
• Example 1 This example illustrates the preparation of five pyrrolo [2, 3-d] pyrimidine compounds having utility as SPLA2 inhibitors. These compounds are represented by the following structural formulae:
• a solution of sodium ethoxide (prepared from 0.96 g (40 mmol) of sodium hydride and 40 mL of ethanol) was treated with 3.78 g (40 mmol) of acetamidine hydrochloride and 9.09 g (40 mmol) of a-cyano-2-ethyl-l, 3-dioxolane-2- propanoic acid ethyl ester.
• the mixture was heated to reflux for 150 minutes, cooled to ambient temperature and concentrated under vacuum.
• the solid residue was dissolved in 50 mL of water and the resulting solution washed with ethyl ether.
• Phosphorous oxychloride (21 mL) was carefully added to a mixture of 5.66 g (27.0 mmol) of 1, 7-dihydro-6-ethyl-2- (methylthio) -4H-pyrrolo [2, 3-d] pyrimidin-4-one and 1.70 mL of N,N-dimethylaniline .
• the reaction was heated to 95 °C for 12 hours. At this time the reaction was cooled and concentrated under vacuum. The residue was combined with 60 g of ice and stirred for 1 hour. The solids were collected by filtration, washed with 30 mL of water and suspended in 100 L of water.
• the organic phase was washed with 40 mL of water, dried with sodium sulfate, and concentrated to 5.90 g of yellow solid.
• the solid was first purified by flash chromatography (500 g of silica, ethyl acetate) and the product obtained was then slurried in 100 mL of methyl tert-butyl ether to provide
• the crude oil was dissolved in 30 mL of ethanol, treated with 2.28 g of Raney Ni, then the mixture heated to reflux. After 18 hours, the solids were removed by filtration through a filter aid and the reaction concentrated to an oil.
• the oil was purified by flash chromatography ( 46 g silica, hexanes-ethyl acetate gradient 100:0 to 2:1) to provide 203 mg (quantitative yield for 2 steps) of [ [6-ethyl-7- ( [1, 1 ' -biphenyl] -2-ylmethyl) -7H- pyrrolo [2, 3-d] pyrimidin-4-yl] oxy] acetic acid methyl ester as an oil.
• reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate.
• the aqueous phase was extracted twice with 7 mL portions of ethyl acetate.
• the combined organic phases were dried with sodium sulfate and concentrated 600 mg of solid.
• CDCI3 ⁇ 1.20 (t, 3H) , 2.62 (q, 2H) , 3.79 (s, 3H) , 5.09 (s, 2H) , 5.45 (s, 2H) , 6.42 (s, IH) , 6.72 (d, IH) , 6.82 (d, IH) , 6.93 (dt, IH) , 7.26 (dt, IH) , 8.37 (s, IH) AK.
• the reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate.
• the aqueous phase was extracted twice with 7 mL portions of ethyl acetate.
• the combined organic phases were dried with sodium sulfate and concentrated.
• the product was purified by flash chromatography (53 g silica, hexanes-ethyl acetate gradient 100:0 to 85:15) to provide 187 mg (47%) of [ [2- (methylthio) - 6-ethyl-7- ([1,1' -biphenyl] -2-ylmethyl) -7H-pyrrolo [2, 3- d] pyrimidin-4-yl] oxy] acetic acid methyl ester as a solid.
• nmr 300 MHz, CDCI3 ⁇ 1.10 (t, 3H) , 2.16 (q, 2H) , 2.52 (s, 3H) , 3.80 (s, 3H) , 5.03 (s, 2H) , 5.32 (s, 2H) , 6.25 (s, IH) , 6.62 (d, IH), 7.1-7.6 (m, 8H)
• reaction was partitioned by the addition of 2 mL of 2 M sodium hydrogen sulfate and 20 mL of ethyl acetate. The organic phase was washed with 10 mL of water, dried with sodium sulfate and concentrated.
• CaCl2-2H2 ⁇ (1.47 g/L) KCl (7.455 g/L) Bovine Serum Albumin (fatty acid free) (1 g/L) (Sigma A-7030, product of Sigma Chemical Co. St. Louis MO, USA) TRIS HCl (3.94 g/L) pH 7.5 (adjust with NaOH)
• a measured volume of racemic dipheptanoyl thio PC supplied in chloroform at a concentration of 100 mg/ml is taken to dryness and redissolved in 10 millimolar TRITON X-100TM nonionic detergent aqueous solution.
• Reaction Buffer is added to the solution, then DTNB to give the Reaction Mixture .
• the reaction mixture thus obtained contains ImM diheptanoly thio-PC substrate, 0.29 mm Triton X- 100TM detergent, and 0.12 mm DTMB in a buffered aqueous solution at pH 7.5.
• % inhibition measured at 405 nanometers generated by enzyme reactions containing inhibitors relative to the uninhibited control reactions was determined. Each sample was titrated in triplicate and result values were averaged for plotting and calculation of IC50 values. IC50 were determined by plotting log concentration versus inhibition values in the range from 10-90% inhibition.

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