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WO2009049028A1 - Composés de pyrrolopyrimidine et leur utilisation en tant qu'inhibiteurs des janus kinases - Google Patents

Composés de pyrrolopyrimidine et leur utilisation en tant qu'inhibiteurs des janus kinases Download PDF

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Publication number
WO2009049028A1
WO2009049028A1 PCT/US2008/079315 US2008079315W WO2009049028A1 WO 2009049028 A1 WO2009049028 A1 WO 2009049028A1 US 2008079315 W US2008079315 W US 2008079315W WO 2009049028 A1 WO2009049028 A1 WO 2009049028A1
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Prior art keywords
pyrrolo
pyrimidin
phenyl
amine
methyl
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PCT/US2008/079315
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English (en)
Inventor
Glenn Noronha
Jianguo Cao
Chun P. Chow
Chi Ching Mak
Moorthy S.S. Palanki
Elena Dneprovskaia
Andrew Mcpherson
Ved Prakash Pathak
Joel Renick
Binqi Zeng
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TargeGen Inc
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TargeGen Inc
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Publication of WO2009049028A1 publication Critical patent/WO2009049028A1/fr
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    • 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

Definitions

  • Aberrant kinase activity has been implicated in many diseases including cancers, in immunological and auto-immune disorders, in inflammatory disorders, in diabetes, fibrosis of the liver and kidney, atherosclerosis and in ocular diseases. Inhibition of such kinase activity may be beneficial in e.g., the treatment of such diseases.
  • JAK kinases have been implicated in ocular diseases such as Age Related Macular Degeneration (AMD), diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR).
  • AMD Age Related Macular Degeneration
  • DME diabetic macular edema
  • PDR proliferative diabetic retinopathy
  • the term "therapeutic effect” is art- recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human.
  • the phrase "therapeutically-effective amount” means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • the therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • certain compositions of the present invention may be administered in a sufficient amount to produce some desired local or systemic effect at a reasonable benefit/risk ratio applicable to such treatment.
  • treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 3 O for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, e.g. from 1 to 6 carbons.
  • alkyl (or “lower alkyl”) includes “substituted alkyls”, which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents may include, for example, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a carbonyl such as a carboxyl, an alkoxy
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylene refers to an organic radical formed from an unsaturated aliphatic hydrocarbon and can include substituted alkylenes using the substituents noted above;
  • alkenylene denotes an acyclic carbon chain which includes a carbon-to-carbon double bond and can include substituted alkylenes using the substituents noted above.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • aryl refers to a mono-, bi-, or other multi-carbocyclic, aromatic ring system.
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, or the like.
  • aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • heteroaryl or “heteroaromatics” are art-recognized and refer to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings.
  • the heteroaryl ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • heteroaryl groups include, but are not limited to, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazo
  • heterocyclyl or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3- to 10-membered ring structures, alternatively 3- to 7- membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems. A heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings.
  • Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, th
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • heterocycloalkyl is art-recognized and refers to a saturated heterocyclyl group as defined above.
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethylthio, and the like.
  • carbonyl is art recognized and includes such moieties as may be represented by the general formulas:
  • compositions of the present invention refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • Inhalation administration or “administered by inhalation” refers to administration of a subject composition, therapeutic or other material by a pulmonary route, e.g. aerosol inhalation or nasal administration.
  • R 1 of Formula I is a heteroaryl, for example, a heteroaryl containing at least one sulfur (S) atom, where the heteraryl can be optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, nitro, formyl, formamido, cyano, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, CF 3 , ureido, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, carbaldehyde oxime, N-alkylsulphamoyl, N-alkylcarbamoyl, -0-R 13 R 11 or -R 13 R 11 .
  • R 1 can be selected, in some embodiments, from the group consisting of: optionally substituted: furanyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, triazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, quinolyl, benzimidazolyl, benzothiophene, or thienopyridine.
  • R 1 may be an optionally substituted monocyclic or bicyclic heteroaryl, e.g.
  • R 2 may be a heteroaryl, e.g. a phenyl or pyridinyl, wherein R 2 can be optionally substituted on a ring carbon by one, two, or three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, amino, amido, -N-alkyl-amino, carbamoyl, sulphamoyl, CF 3 , ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, -N-alkyl-amino-N-alkylcarbamoyl, - OR 11 , -OR 12 R 11 , or -R 12 R 11 .
  • R 2 may be substituted with only one moiety other than H.
  • R 2 may be substituted with only one moiety
  • R 3 and R 4 may each be independently selected from the group consisting of: hydrogen, halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N- alkylsulphamoyl, N-alkylcarbamoyl, aryl, heterocycle, cycloalkyl, -OR 13 , -OR 13 R 11 , or - R 13 R 11 , or R 3 and R 4 taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to four substituents each independently selected from the group consisting of: halo, cyano, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido,
  • R 2 can be represented as:
  • X is N or CR 6 ;
  • R 6 is H or alkyl,
  • R 7 and Rg, independently for each occurrence, is chosen from the group consisting of: H, heterocycle, -O-heterocycle, -alkylene-heterocycle, - O-alkylene-heterocycle, -SC ⁇ N-alkylene-heterocycle, or -S ⁇ 2 -heterocycle, wherein said heterocycle is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbamoyl, sulphamoyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, and N-alkylcarbamoyl.
  • R 8 may include a heterocycle substituted with methyl.
  • Rg is H.
  • Rg may be H and R 7 may be an optionally substituted heterocycle, or - O-alkylene-heterocycle, wherein heterocycle may be chosen from the group consisting of: pyrrolidinyl, piperazinyl, or morpholinyl.
  • R 8 may be H and R 7 may be selected from the group consisting of: methylpiperazine, piperazine, -CH 2 - piperdine, -CH 2 -methylimidazole, -CH 2 -morpholine, imidazole, and 2-pyrrolidin-lylethoxy.
  • this disclosure also provides for a compound of Formula I which inhibits JAK2 with an IC 50 at least about ten times lower as compared to a compound represented by Formula A:
  • R 1 and R 2 are defined above.
  • compound B has a IC 50 against JAK2 of 384 nM
  • compound C has an IC 50 against JAK2 >30000 nM.
  • R 1 is thiophene
  • the 3-position on the thiophene is hydrogen.
  • a methyl at this position may result in a loss of JAK2 activity.
  • R 3 and R 4 may each be independently selected from the group consisting of: hydrogen, halo, hydroxyl, cyano, nitro, formyl, formamido, carboxy, amino, amido, acylamino, carbaldehyde oxime, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, or -R 13 R 11 , or R 3 and R 4 taken together with the carbon atoms to which they are attached form a 5 or 6 membered carbocyclic or heterocyclic ring, optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoy
  • R 3 or R 4 can be chosen from:
  • X may be N or CR 6 , where R 6 is H or alkyl.
  • R 11 can independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl, wherein R 11 can be optionally substituted by one to four substituents each independently selected from the group consisting of: halo, alkyl, carbonyl, of halo, hydroxyl, nitro, formyl, formamido, carboxy, amino, amido, carbamoyl, sulphamoyl, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl and R 13 can be alkylene, alkenylene, -C(O)-, or a bond.
  • Pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof of Formula II are contemplated.
  • R 19 independently for each occurrence, chosen from H or halo
  • Rg a independently for each occurrence, is chosen from the group consisting of: H, alkyl, amido, -N-alkyl-sulfamoyl, sulfonyl, alkanoyl, carbamoyl, -C(0)-alkyl-NR2oR2o, -C(O)- heterocycle, and heterocycle, wherein R 2 o is independently selected from H and alkyl.
  • compositions that include the disclosed compounds and a pharmaceutically acceptable carrier.
  • compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
  • An effective dose or amount, and any possible affects on the timing of administration of the formulation may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
  • the effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.
  • Treatment including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
  • compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.
  • Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 and the ED50.
  • the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.
  • the dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.
  • compositions of the present invention may be formulated as tablets, capsules, granules, powders or syrups.
  • formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, suppositories or administration intranasally (for example, to deliver a dosage to the brain via the nose or to deliver a dosage to the nose directly) or by inhalation (e.g. to treat a condition of the respiratory tract or to pretreat or vaccinate via the respiratory tract).
  • compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.
  • Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient.
  • Compositions of the present invention may also be administered as a bolus, electuary, or paste.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing
  • Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Dosages for administration by nasal delivery can be applied as drops, ointments, gels, mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders), powders, or combinations thereof.
  • Such delivery can be achieved by commercially available devices such as droppers, nasal sprayers, metered dose aerosols, or other mechanisms known in the art.
  • Pharmaceutical formulations for inhalation and/or delivery to the nose may contain from 1% to 20% by weight of a penetrator enhancer (for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters) which may allow enhanced nose permeability of the active agent.
  • a penetrator enhancer for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters
  • Dosages for administration by inhalation or by delivered to or via the lung can be applied as mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders), liquids or suspensions (aqueous or nonaqueous), powders, or combinations thereof.
  • Such delivery can be achieved by commercially available devices such as 1) nebulizers, 2) metered dose inhalers, 3) dry powder inhalers, 4) soft mist inhalers, or by instillation or insufflation, or other mechanisms and/or devices known in the art.
  • compositions of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.
  • compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Treatment or amelioration of disease states and pathological conditions that implicate JAK, e.g. JAK2, pathways comprises administering one or more of the disclosed compounds, such as those recited in Formulas I, II, or III, or a composition as described herein comprising a disclosed compound.
  • the disclosed compounds may inhibit or modulate one or more of the JAK family, e.g, JAKl, JAK2, JAK3, and/or TYK2, and/or may inhibit or modulate KDR.
  • the disclosed compounds may for example inhibit JAK2 but may not substantially modulate JAK3 and/or KDR.
  • Methods of treating a patient in need thereof e.g. suffering from a disease where inihibition of kinases are useful, for example, immunological and autoimmune disorders, inflammatory disease, diabetes, fibrosis of the liver and/or kidney, atherosclerosis, and ocular diseases are contemplated.
  • JAKs appear to play a crucial role in regulating cell behavior induced by a number of cytokines
  • treatment of indications driven by a dysregulation of signaling pathways normally associated with cytokine regulation may include compounds which modulate the activity of the JAKs, such as those recited in Formulas I, II or III is contemplated, such as the treatment of immune and inflammatory diseases, e.g.
  • RA rheumatoid arthritis
  • COPD chronic obstructive pulmonary disease
  • Somatic mutations in the hematopoietic system leading to activation of the JAK pathway has been linked to the myeloproliferative disorders polycythemia vera, essential thrombocythemia and myeloid metaplasia with myelofibrosis.
  • upregulation of the JAK pathway may contribute to the myeloproliferative disorders chronic myelogenous leukemia, chronic myelomomocytic leukemia, thallasemia gravis, hypereosinophilic syndrome, and systemic mast cell disease.
  • methods for treating cancers e.g.
  • cancers are associated with activation of Janus kinases including acute myeloid leukemia, hepatocellular carcinoma, multiple myeloma, Hodgkin's lymphomas and T cell leukemia/lymphoma, wherein the method includes administrating a disclosed compound.
  • angiogenic role of JAK2 downstream of the EPO receptor has been implicated in ocular diseases such as Age Related Macular Degeneration (AMD), diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), and treatement of one or more of these diseases is contemplated.
  • a method of treating an ocular or other disease includes administration of a disclosed compound that modulates JAK and in some embodiments, inhibits VEGFr.
  • Also contemplated herein is a method for treating or ameliorating transplant rejection that includes administering an instantly disclosed compound.
  • a method for treating or ameliorating rheumatoid arthritis that includes administering an instantly disclosed compound is contemplated.
  • Dysregulation in the hematopoietic stem cells of the myeloid compartment may lead to related myeloproliferative disorders (MPDs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), and to acute myeloid leukemia (AML) Underlying each of these myeloid diseases may be a cytokine-independent activation of molecular signaling pathways critical for the proliferation and aberrant survival of the cells associated with the disease's pathology.
  • MPDs myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocythemia
  • MF myelofibrosis
  • AML acute myeloid leukemia
  • JAK2 V617F Janus kinase 2
  • JAK2 T875N tyrosine kinase mutations
  • JAK2 activation leads to phosphorylation of signal transducer and activator of transcription (STAT) proteins, transcription factors that stimulate the cell's genetic machinery to induce proliferation and prevent apoptosis.
  • STAT signal transducer and activator of transcription
  • AML features ligand-independent activation of the JAK-STAT pathway in the majority of patients. Although there is no predominant known mutation that leads to activation of the JAK-STAT pathway in AML, approximately 30% of AML patients appear to have this activation mediated through mutations in the FMS-like receptor tyrosine kinase 3 (FLT3).
  • FLT3 FMS-like receptor tyrosine kinase 3
  • Methods of treating a patient suffering from acute leukaemias, myeloid and lymphoid malignancies or myeloproliferative disorders such as polycythemia vera, myelofibrosis and essential thrombocythemia are contemplated and may comprise administering an effective amount of a disclosed compound, such as those recited in Formulas I, II, or III or a composition comprising a disclosed compound.
  • a method of treatment of AML, PV, ET and MT for example, in patients with mutations in FLT3, is contemplated, comprising administering a disclosed compound, e.g. a compound of Formulas I, II, or III.
  • Treatment of other cancers comprising administering an effective amount of a disclosed compound.
  • the treatment of cancers can include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.
  • Examples of some additional diseases and disorders that can be treated using a disclosed include cell mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Vims, Hepatitis B, Hepatitis C, HIV, HTLVl, Vaiceila- Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
  • SLE systemic lupus erythematosus
  • rheumatic diseases e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondy
  • One embodiment provides for a process for forming a compound of Formula I comprising reacting a compound of Formula IV:
  • R 2 is
  • Another embodiment provides a process for forming a compound of formula II comprising reacting a compound of formula V:
  • the compound of Formula II is a compound of Formula Ilia or IHb.
  • Example 4 Preparation of 4-[4-(4-Methyl-thiophen-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-ylamino] -/V-(2-pyrrolidin- 1 -yl-ethyl)-benzenesulfonamide
  • the filtrate was concentrated and the residue purified by ⁇ PLC.
  • the fractions were combined and poured into saturated NaHCO 3 solution (30 mL).
  • the combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered.
  • the filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a yellow solid (10 mg, 3%).
  • the filtrate was concentrated and the residue purified by ⁇ PLC.
  • the fractions were combined and poured into saturated NaHCO 3 solution (30 mL).
  • the combined aqueous layers were extracted with EtOAc (2 x 30 rnL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered.
  • the filtrate was concentrated and the residue re-dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a beige solid (15 mg, 9%).
  • the compound 13 was treated with tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 5 rnL, 5 mmol). The mixture was heated under reflux for 20 min. The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with saturated NaHCO 3 (2 x 50 mL). The crude product was purified by using HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO 3 (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na 2 SO 4 ). The solvent was removed in vacuo. The title compound (19 mg, 18%) was afforded as a yellow solid.
  • TBAF tetrabutylammonium fluoride
  • reaction mixture was filtered through 0.2 u syringe filter and purified by reverse-phase preparative ⁇ PLC in C ⁇ 3 CN/ ⁇ 2 O system containing 0.1% of TFA.
  • Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO 3 (50 mL). The organic layer was washed with brine (1 x 30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the Ts- protected compound as a yellow solid (130 mg, 25%). To this solid was added 6 mL of 1.0 M solution of TBAF in THF.
  • a microwave vial was charged with 16 (0.14 g, 0.32 mmol), thiazolidine-2,4-dione (60 mg, 0.51 mmol), and Cs 2 CO 3 (0.16 g, 0.49 mmol) in ethanol (4 mL).
  • the reaction mixture was heated for 40 min at 140 0 C in a Biotage microwave reactor.
  • the resulting reaction mixture was concentrated and the residue triturated in water.
  • the resulting solid was filtered and purified by ⁇ PLC.
  • the fractions were combined and poured into saturated NaHCO 3 solution (30 mL).
  • the combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2 SO 4 and filtered.
  • the filtrate was concentrated and the residue triturated in a mixture of EtOAc/hexanes (1/3, 20 mL). After filtration, the title compound was obtained as a red solid (20 mg, 12%).
  • the organic solution was separated and dried (Na 2 SO 4 ). The solvent was removed in vacuo.
  • the crude product was purified by using ⁇ PLC. The ⁇ PLC fractions containing product were combined and neutralized with saturated NaHCO 3 (50 mL). The free base was extracted with EtOAc (2 x 100 mL). The organic layers were combined and dried (Na 2 SO 4 ). The solvent was removed in vacuo. The residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.2 mL, 0.8 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then solvent was removed in vacuo. The residue was dissolved in MeOH (1 mL) and anhydrous Et 2 O (20 mL) was added. The solid was collected by centrifuging. The title compound (8 mg, 6%) was afforded as an orange solid.
  • the solvent was removed in vacuo.
  • the crude product was purified by ⁇ PLC.
  • the ⁇ PLC fractions containing product were combined and neutralized with saturated NaHCO 3 (50 mL).
  • the free base was extracted with EtOAc (2 x 100 mL).
  • the organic layers were combined and dried (Na 2 SO 4 ).
  • the solvent was removed in vacuo.
  • the residue was dissolved in MeOH (2 mL) and 4.0 M HCl solution (0.3 mL, 1.2 mmol) in dioxane was added. The solution was stirred for 5 min at room temperature and then concentrated in vacuo.
  • the residue was dissolved in MeOH (1 mL) and anhydrous Et 2 O (20 mL) was added.
  • the solid was collected by centrifuging.
  • the reaction mixture was purged with argon gas for 5 min, and then the vial was sealed and irradiated in a microwave (Initiator, Biotage) at 110 0 C for 90 min. After cooling to room temperature, the formed dark-red solution was diluted with EtOAc (200 mL), washed with water (3 x 50 mL), brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for purification using 20 to 100% EtOAc gradient in hexanes. Fractions, containing the product, were concentrated in vacuo to give a dark- yellow solid.
  • reaction mixture was filtered through 0.2 u syringe filter and purified by reverse-phase preparative ⁇ PLC in C ⁇ 3 CN/ ⁇ 2 O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (100 mL) and saturated aqueous NaHCO 3 (50 mL). The organic layer was washed with brine (1 x 30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the title product as a bright-orange solid (110 mg, 40% yield).
  • EtOAc layer was washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was dissolved in 2 mL of DMF and purified by reverse-phase preparative HPLC in CH 3 CN/H 2 O system containing 0.1% of TFA. Fractions, containing the product, were combined and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO 3 (50 mL). The organic layer was washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give the title product as a yellow solid (24 mg, 30% yield).

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Abstract

La présente invention concerne des composés de pyrrolopyrimidine représentés par la formule (I), dans laquelle R1 désigne un hétéroaryle contenant au moins un atome de S, et éventuellement substitué sur un cycle de carbone par un, deux ou trois substituants chacun indépendamment sélectionnés dans le groupe constitué de: halo, hydroxyle, nitro, formyle, formamido, cyano, sulfonyle, carboxy, amino, amido, acylamino, carbamoyle, sulfamoyle, alkyle, alcényle, CF3, uréido, alcynyle, alcoxy, alcanoyle, alcoxycarbonyle, oxime de carbaldéhyde, N -alkylsulfamoyle, N-alkylcarbamoyle, -OR13R11 ou -R13R11; R2 désigne phényle ou pyrdinyle, R2 étant éventuellement substitué sur un cycle de carbone par un, deux ou trois substituants chacun indépendamment sélectionnés dans le groupe constitué de: halo, hydroxyle, cyano, nitro, formyle, formamido, carboxy, sulfonyle, amino, amido, -N- alkyl -amino, carbamoyle, sulfamoyle, CF3, uréido, alkyle, alcényle, alcynyle, alcoxy, alcanoyle, alcoxycarbonyle, N-alkylsulfamoyle, N-alkylcarbamoyle, -OR11, -OR12R11, ou -R12R11; ainsi que des procédés de production et d'utilisation de ceux-ci. Lesdits composés peuvent être utilisés dans le traitement de troubles inflammatoires ou myéloprolifératifs. La description concerne également le traitement du cancer.
PCT/US2008/079315 2007-10-09 2008-10-09 Composés de pyrrolopyrimidine et leur utilisation en tant qu'inhibiteurs des janus kinases Ceased WO2009049028A1 (fr)

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