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WO1997028161A1 - Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase - Google Patents

Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase Download PDF

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Publication number
WO1997028161A1
WO1997028161A1 PCT/EP1997/000350 EP9700350W WO9728161A1 WO 1997028161 A1 WO1997028161 A1 WO 1997028161A1 EP 9700350 W EP9700350 W EP 9700350W WO 9728161 A1 WO9728161 A1 WO 9728161A1
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Prior art keywords
phenyl
lower alkyl
amino
formula
compound
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PCT/EP1997/000350
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English (en)
Inventor
Eva Altmann
Leo Widler
Martin Missbach
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Novartis Ag
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Priority to AU15951/97A priority Critical patent/AU1595197A/en
Publication of WO1997028161A1 publication Critical patent/WO1997028161A1/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
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease

Definitions

  • the invention relates to compounds of formula I
  • Ri is aryl
  • R 2 and R 4 are simultaneously or each independently of the other hydrogen, lower alkyl or halogen
  • R 3 is unsubstituted or substituted cyclo-lower alkyl or cyclo-lower alkenyl, with the proviso that when R 3 is a free or esterified 2,3-dihydroxycyclopent-4-yl, any further substituent of that radical in the 1 -position must not be selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, hydrocarbyloxycarbonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, azidoaikyl, cyanoalkyl and haloalkyl; and to salts thereof, to processes for the preparation of those compounds, to pharmaceuti ⁇ cal compositions comprising those compounds, to the use of those compounds in the therapeutic treatment of the human or animal body or in the preparation of pharmaceutical compositions.
  • Lower alkyl is, for example, t>propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te/ -butyl, ⁇ -pentyl, isopentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl or methyl.
  • Lower alkylene is, for example, methylene, ethylene or propylene, preferably methylene or ethylene.
  • Halogen is, for example, chlorine, bromine or fluorine, but may also be iodine.
  • Halo-lower alkyl is, for example, halomethyl, for example chloromethyl, or, for example, trifluoromethyl.
  • Lower alkanoyl is, for example, acetyl, propionyl or pivaloyl, but may also be, for example, formyl.
  • Lower alkoxy is, for example, n-propoxy, isopropoxy, # butoxy, isobutoxy, sec-butoxy, tert- butoxy, n-amyloxy or isoamyioxy, preferably methoxy or ethoxy.
  • Lower alkoxycarbonyl denotes the radical lower alkyl-O-C(O)- and is, for example, n-prop- oxycarbonyl, isopropoxycarbonyl, ⁇ -butoxycarbonyl, isobutoxycarbonyl, seo-butoxycarbonyl, tert-butoxycarbonyi, n-amyloxycarbonyl or isoamyloxycarbonyl, preferably methoxycarbonyl or ethoxycarbonyl.
  • Lower alkylamino is, for example, n-propy amino, n-butylamino, isopropylamino or isobutyl- amino, preferably methylamino or ethylamino.
  • Di-lower alkylamino is, for example, dimethylamino, diethylamino, di-n-propylamino, n-butyl ⁇ amino, di-n-butylamino or n-propyl-n-butylamino, preferably dimethylamino, diethylamino or methylethylamino.
  • Aryl is, for example, phenyl or naphthyl, each of which is unsubstituted or substituted, for example as indicated hereinafter for phenyl.
  • Aryl is preferably phenyl unsubstituted or sub ⁇ stituted by one or more, for example from one to three, especially one or two, substituents from the group consisting of lower alkyl, halo-lower alkyl, (hydroxy or lower alkanoyloxy)- lower alkyl, lower alkoxy-lower alkyl, (hydroxy, lower alkoxy or lower alkanoyloxy)-lower alk- oxy-lower alkyl, (amino, lower alkylamino, di-lower alkylamino or lower alkanoylamino)-lower alkoxy-lower alkyl, (amino or lower alkanoylamino)-lower alkyl, lower alkylamino-lower alkyl, di-lower alky
  • Hydroxysulfonyl is the group -SO 3 H.
  • Aminocarbonyl is -CONH 2 .
  • Cyclo-lower alkyl is an aliphatic ring having preferably from 3 up to and including 7 ring members, such as cyclopropyl, cyclobutyl, cydoheptyl, and especially cyclopentyl or cyclo ⁇ hexyl.
  • Cyclo-lower alkenyl is a mono- or, optionally, poly-unsaturated ring having preferably from 3 up to and including 7 ring members, such as cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1- enyl, cyclobut-2-enyl, cyclopent-3-enyl, cyclopenta-1 ,3-dienyl, cyclohex-1-enyl, cyclohexa- 1,3-dienyl or cyclohept-2-enyl, especially cyciopent-2-enyl.
  • Cyclo-lower alkyl and cyclo-lower alkenyl are unsubstituted or substituted by one or more, for example, depending on the size of the ring, from one to four, especially one, two or three, substituents from the group consisting of hydroxy, oxo, lower alkanoyloxy, hydroxy- lower alkyl, lower alkanoyloxy-lower alkyl, carboxy, amino, lower alkanoylamino, amino-lower alkyl, lower alkanoylamino-lower alkyl, carbonyl-lower alkoxy, hydroxy-lower alkyloxy, lower alkanoyloxy-lower alkyloxy, lower alkoxy-lower alkoxy, amino-lower alkoxy, lower alkanoyl ⁇ amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, imida- zolyl-lower alkoxy
  • the two hetero atoms are preferably separated from one another by at least two carbon atoms; in other words, the lower alkyl moiety is preferably so selected that there are at least two carbon atoms between the two hetero atoms.
  • Azacycloalkyl is a cycloalkyl radical having from 3 to 8, especially from 5 to 7, ring atoms, at least one of the ring atoms being a nitrogen atom.
  • Azacycloalkyl may also contain further ring hetero atoms, for example N, O or S; it is, for example, piperidinyl, piperazinyl, mo ⁇ ho ⁇ linyl or pyrrolidinyl.
  • Azaheteroaryl is an aromatic radical having from 3 to 7, especially from 5 to 7, ring atoms, at least one of the ring atoms being a nitrogen atom. Azaheteroaryl may also contain further ring hetero atoms, for example N, O or S. It may also be partially saturated. Azaheteroaryl is, for example, imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrrolyl.
  • Radicals such as piperidinyl, piperazinyl, mo ⁇ holinyl, pyrrolidinyl, imidazolyl, triazolyl and pyrrolyl can be bonded via a ring nitrogen atom or a ring carbon atom, and radicals such as pyridyl or pyrimidinyl are preferably bonded via a carbon atom.
  • the azacycloalkyl radicals bonded via a ring nitrogen atom which are preferred, are re ⁇ ferred to in known manner as piperidino, piperazino, mo ⁇ holino, pyrrolidino, etc..
  • Salts of compounds of formula I are especially pharmaceutically acceptable salts, especially acid addition salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclo- hexylsulfamates (cyclamates), or salts with strong organic carboxyiic acids, such as lower alkanecarboxylic acids or saturated or unsaturated or hydroxylated aliphatic dicarboxylic acids, for example acetates, oxalates, malonates, maleates, fumarates, tartrates or citrates.
  • suitable mineral acids such as hydrohalic acids, sulfuric acid or phospho
  • salts with bases for example corresponding alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts, such as zinc or copper salts, or salts with ammonia or organic amines, such as cyclic amines, mono-, di- or tri-lower alkylamines, hydroxy-lower alkylamines, for example mono-, di- or tri-hydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkyl-amines or poly- hydroxy-lower alkylamines.
  • bases for example corresponding alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts
  • pharmaceutically acceptable transition metal salts such as zinc or copper salts
  • salts with ammonia or organic amines such as cyclic amines, mono-, di- or tri-lower alkylamines, hydroxy-lower alkylamines, for example mono-, di- or tri-hydroxy-low
  • Cyclic amines are, for example, mo ⁇ holine, thiomorpholine, piperidine or pyrrolidine.
  • Suitable mono-lower alkylamines are, for example, ethyl- and ten- butyl-amine;
  • suitable di-lower alkylamines are, for example, diethyl- and diisopropyl-amine and
  • suitable tri-lower alkylamines are, for example, trimethyl- and triethyl-amine.
  • Suitable hydroxy-lower alkylamines are, for example, mono-, di- and tri-ethanolamine; suitable hy ⁇ droxy-lower alkyl-lower alkyl-amines are, for example, N,N-dimethylamino- and N,N-di- ethylamino-ethanol.
  • Compounds of formula I having an acid group, for example carboxy, and a basic group, for example amino may also be in the form of, for example, internal salts, i.e. in zwitterionic form, or part of the molecule may be in the form of an intemal salt and another part in the form of a normal salt.
  • compositions of formula I have valuable pharmacological properties. In particular, they inhibit the activity of tyrosine protein kinase pp60 c src in concentrations of from approximately 0.001 to approximately 10 ⁇ [test description: K. Farley et ai., Anal. Biochem. 203 (1992) 151-157; purified enzyme - as described in N. B. Lydon etai., Biochem. J. 287 (1992) 985- 993 - is used].
  • the compounds of formula I are therefore capable of inhibiting the bone absorption ability of osteoclasts. That can be demonstrated, for example, in the bone slice assay on bovine cortical bone platelets with rat osteoclasts in concentrations of from approx. 0.001 to approx. 10 ⁇ M. [The "bone slice assay” is described, for example, in Biochem. Biophys. Res. Comm. 188 (1992) 1097- 1103]. In that assay, the compounds of formula I inhibit the formation of characteristic ab ⁇ so ⁇ tion holes in bone platelets in vitro.
  • the effectiveness of compounds of formula I can be demonstrated, for example, in the Hock model in the rat.
  • the compounds of formula I - when administered once a day per os in concentrations of from approx. 1 to approx. 100 mg/kg of body weight - for from 3 to 4 weeks completely or at least partially inhibit the bone loss produced as a result of ovariectomy in rats [the "Hock model" is described, for example, in Metab. Bone Dis. 5 (1984) 177-181].
  • the in vivo activity of compounds of formula I can also be demonstrated, for example, via calcium metabolism in intact rats.
  • acute hypocalcaemia is induced within from 1 to 4 hours; it is demonstrated by determining the concentration of calcium in the blood plasma.
  • the observation of acute hypocalcaemia can be interpreted as indirect evidence that the test compound inhibits bone absorption.
  • the compounds of formula I are therefore very suitable for the treatment of diseases that are responsive to inhibition of the activity of tyrosine protein kinase pp60 c src .
  • Special men ⁇ tion may be made here of osteoporosis, and of other diseases in the course of which the absorption of bone by osteoclasts plays a role, such as tumour-induced hypercalcaemia or Paget's disease, or the treatment of bone metastases, and also inflammatory processes in joints and bones and degenerative processes in cartilage tissue.
  • the com ⁇ pounds of formula I are useful in the treatment of benign or malignant tumours that respond to inhibition of tyrosine protein kinase pp ⁇ O 0" " 0 , such as breast cancer (mammary carci ⁇ noma) or intestinal cancer (colon carcinoma).
  • the compounds of formula I are capable of effecting tumour regres ⁇ sion and of preventing the formation of tumour metastases and the growth of micrometas- tases.
  • the compounds of formula I are also useful in the treatment of cardiovascular dis ⁇ eases, such as thrombosis.
  • the compounds of formula I also inhibit the activity of other non-receptor tyrosine protein kinases, such as (a) other members of the src family, for example Ick and fyn, (b) Abl kinase and (c) ZAP70 kinase. Furthermore, the compounds of formula I also inhibit the activity of receptor tyrosine protein kinases, such as (a) the EGF family, for example the EGF receptor, c-erbB2, c-erbB3 and c-erbB4, and (b) the PDGF family, for example the PDGF receptor, CSF- , Kit, VEGF and FGF.
  • other non-receptor tyrosine protein kinases such as (a) other members of the src family, for example Ick and fyn, (b) Abl kinase and (c) ZAP70 kinase.
  • the compounds of formula I also inhibit the activity of receptor tyrosine
  • the compounds of formula I can also be used in immunomodulation and in the treatment of diseases of the immune system, for example in the case of inflammations or organ transplants. They are also suitable for the treatment of (hyper)proliferative diseases, such as psoriasis, tumours, carcinomas and leu ⁇ kaemias, and in fibrosis and restenosis.
  • the compounds of formula I can also be used in the treatment of diseases of the central or the peripheral nervous system where signal transmission by at least one tyrosine protein kinase is involved.
  • the invention relates especially to compounds of formula I wherein
  • R T is phenyl unsubstituted or substituted by one, two or three substituents from the group consisting of lower alkyl, hydroxy-lower alkyl, phenyl, lower alkoxy, phenyl-lower alkoxy,
  • R 2 and R 4 are simultaneously or each independently of the other hydrogen, lower alkyl or halogen; and R 3 is unsubstituted or substituted cyclo-lower alkyl or cyclo-lower alkenyl, with the proviso that when R 3 is a free or esterified 2,3-dihydroxycyclopent-4-yl, any further substituent of that in the 1 -position radical must not be selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, hydrocarbyloxyca ⁇ onylaminoalkyl, mercaptoalkyl, alkylthioalkyl, azidoalkyl, cyanoalkyl and haloalkyl; and to salts thereof.
  • the invention relates more especially to compounds of formula I wherein
  • Ri is phenyl unsubstituted or substituted by one, two or three substituents from the group consisting of lower alkyl, hydroxy-lower alkyl, phenyl, lower alkoxy, phenyl-lower alkoxy,
  • R 2 and R are hydrogen
  • R 3 is unsubstituted or substituted cyclo-lower alkyl or cyclo-lower alkenyl, with the proviso that when R 3 is a free or esterified 2,3-dihydroxycyclopent-4-yl, any further substituent of that radical in the 1 -position must not be selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, hydrocarbyloxycarbonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, azidoalkyl, cyanoalkyl and haloalkyl; and to salts thereof.
  • Ri is phenyl unsubstituted or substituted by one, two or three substituents from the group consisting of lower alkyl, hydroxy-lower alkyl, phenyl, lower alkoxy, phenyl-lower alkoxy,
  • R 2 and R 4 are hydrogen
  • R 3 is unsubstituted or substituted cyclopropyl, cyclopentyl, cyclopentenyl or cyclohexyl, with the proviso that when R 3 is a free or esterified 2,3-dihydroxycyclopent-4-yl, any further substituent of that radical in the 1 -position must not be selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, hydrocarbyloxycarbonylaminoalkyl, mercaptoalkyl, alkylthioalkyl, azidoalkyl, cyanoalkyl and haloalkyl; and to pharmaceutically acceptable salts thereof.
  • the invention relates especially to the specific compounds described in the Examples and to salts thereof.
  • the invention relates further to the use of compounds of formula
  • Ri is aryl
  • R 2 and R are simultaneously or each independently of the other hydrogen, lower alkyl or halogen
  • R 3 is unsubstituted or substituted cyclo-lower alkyl or cyclo-lower alkenyl; or pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment of diseases that are responsive to in ⁇ hibition of the activity of tyrosine protein kinase pp60 c'8rc .
  • the invention relates preferably to the use of compounds of formula I wherein Ri is aryl;
  • R 2 and R are simultaneously or each independently of the other hydrogen, lower alkyl or halogen
  • R 3 is unsubstituted or substituted cyclo-lower alkyl or cyclo-lower alkenyl, with the proviso that when R 3 is a free or esterified 2,3-dihydroxycyclopent-4-yl, any further substituent of that radical in the 1 -position must not be selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl and hydrocarbyloxycarbonylamino- alkyl; or pharmaceutically acceptable salts thereof.
  • the compounds of formula I can be prepared in a manner known perse, for example by
  • Process (a) The reaction according to process (a) corresponds to the cyclisation known perse of 2-amino-3-cyano-pyrroles to 4-amino-pyrrolo[2,3-d]pyrimidines (see, for example, H. Pichler et ai, Liebigs Ann. Chem. 1986, 1485-1505).
  • Suitable cyclisation reagents are, for example, (1 ) formamide or (2) 1. trialkyl orthoformate/2. ammonia.
  • the cyclisation of compounds of formula II with formamide is preferably carried out at elevated temperature, for example at 160°C, and advantageously with the addition of a small amount of dimethyl ⁇ formamide and formic acid.
  • the compounds of formula II are preferably prepared using one of the known methods of pyrrole synthesis. They are obtained, for example, by reacting a compound of formula lla
  • malonic acid dinitrile preferably in the presence of a base, for example sodium etha- nolate/ethanol.
  • suitable bases for example sodium ethanolate/- ethanol
  • amidine compounds of formula III can be prepared, for example, from the correspond ⁇ ing amino compounds of formula II in accordance with known methods of amidine synthe ⁇ sis, for example by reaction first with triethyl orthoformate, preferably at elevated tempera ⁇ ture, and then with ammonia, preferably at room temperature.
  • Suitable leaving groups are, for example, methanesulfonates or p-toluenesulf- onates of hydroxy compounds of the formula R 3 -OH, and halogen.
  • Compounds of formula IV are preferably prepared using the methods of synthesis described for compounds of for ⁇ mula I, in which case R 3 is hydrogen.
  • the reaction of compounds of formula IV with com ⁇ pounds of formula V is carried out in a manner known perse.
  • a methane ⁇ sulfonate of formula V is reacted with a pyrrolo[2,3-d]pyrimidine of formula IV in the pres ⁇ ence of a base, for example potassium carbonate.
  • the reaction is preferably carried out at elevated temperature, for example at from 50 C C to the reflux temperature of the reaction mixture, especially at from 60 to 80°C, and advantageously in an inert solvent or solvent mixture.
  • the reaction can be accelerated in an advantageous manner by the addition of a suitable crown ether.
  • the reaction takes place in a manner known per se under the conditions of phase transfer catalysis (E.V. Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis, 3rd ed., VCH, Weinheim, 1993).
  • the reactants of formulae IV and V are dissolved in a suitable inert solvent or solvent mixture, and the second phase is formed by a concentrated aqueous alkali metal hydroxide solution, for example 30% sodium hydroxide solution.
  • a phase transfer catalyst for example a quaternary ammonium halide, such as tetrabutylammonium bromide, is added.
  • the reaction can take place without the addition of a catalyst or auxiliary reagent, as in the case of, for example, a cycloalk-1-en-3-one, or with such an addition; for example the reaction with a cycloalkane epoxide can advantageously be carried out with the addition of an alkali metal hydride, for example lithium hydride, and the reaction with a cycloalkene or cycloalkene ep ⁇ oxide in the presence of a tetra(triarylphosphine)palladium(0) compound, for example tetra(triphenylphosphine)palladium(0).
  • a catalyst or auxiliary reagent as in the case of, for example, a cycloalk-1-en-3-one, or with such an addition
  • the reaction with a cycloalkane epoxide can advantageously be carried out with the addition of an alkali metal hydride, for example lithium hydride
  • halo-lower alkyl e.g. chloromethyl
  • halo-lower alkyl e.g. chloromethyl
  • Hydroxy can be converted, for example, with unsubstituted or substituted halo-lower alk- anes, yielding unsubstituted or substituted lower alkoxy.
  • Hydroxy can, for example, also be reacted initially with a di-halo-lower alkane, for example 1-bromo-2-chloroethane, ⁇ -halo- lower alkoxy being obtained; the latter can be reacted in a manner analogous to that de ⁇ scribed above with unsubstituted or substititued lower alkanols, lower alkanethiols or lower alkylamines in accordance with a nucleophilic substitution reaction, yielding unsubstituted or substituted lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy or lower alkylamino-lower alkoxy, respectively.
  • mercapto can also be alkylated as described in the preceding paragraph.
  • Lower aikylthio groups can be converted by targeted oxidation both into lower alkylsulfinyl groups and into lower alkylsulfonyl groups.
  • Amino groups and hydroxy groups can be acylated in known manner, yielding, for example, lower alkanoylamino or lower alkanoyloxy groups, respectively.
  • Carboxylic acid radicals can be converted in accordance with known derivatisation methods, such as esterification or amide formation, into carboxyiic acid derivatives, such as lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di-lower alkylamino- ca ⁇ onyl, cyano or amidino.
  • carboxyiic acid derivatives can also be converted into free carboxyiic acids, for example by hydrolysis.
  • Substituents in the radical R 3 can be converted in a manner known perse into other sub ⁇ stituents.
  • hydroxy groups can be esterified with organic or inorganic acids or etherified with alcohols or organic halides or they can be removed by reduction.
  • Carbonyl groups can be converted by means of catalytic hydrogenation into methylene groups, or with diols or aminols into heterocyclic spiro-linked radicals.
  • any of the intermediates contain interfering reactive groups, for example carboxy, hy ⁇ droxy, mercapto or amino groups, those groups can be protected temporarily by readily re ⁇ movable protecting groups.
  • suitable protecting groups their introduction and their removal are known perse and are described, for example, in J.F.W. McOmie, Protect ⁇ ive Groups in Organic Chemistry, Plenum Press, London, New York 1973.
  • Salts of compounds I can be prepared in a manner known perse.
  • acid addi ⁇ tion salts of compounds I are obtained by treatment with a suitable acid or a suitable ion ex ⁇ change reagent and salts with bases by treatment with a suitable base or a suitable ion ex ⁇ change reagent.
  • Salts of compounds of formula I can be converted into the free compounds I in customary manner; acid addition salts, for example, by treatment with a suitable basic agent or a suitable ion exchange reagent and salts with bases, for example, by treatment with a suitable acid or a suitable ion exchange reagent.
  • Salts of compounds I can be converted in a manner known perse into other salts of com ⁇ pounds I; acid addition salts can be converted, for example, into other acid addition salts, for example by treatment of a salt of an inorganic acid, such as a hydrochloride, with a suit ⁇ able metal salt, such as a sodium, barium or silver salt, of an acid, for example with silver acetate, in a suitable solvent in which an inorganic salt that forms, for example silver chlo ⁇ ride, is insoluble and thus precipitates from the reaction mixture.
  • a salt of an inorganic acid such as a hydrochloride
  • a suit ⁇ able metal salt such as a sodium, barium or silver salt
  • compounds I having salt-forming properties can be obtained in free form or in the form of salts.
  • any reference to the free compound I or its salts should be understood as including also the corresponding salts or the free compound I, respect ⁇ ively, as appropriate and expedient.
  • the compounds I including the salts of salt-forming compounds, can also be obtained in the form of their hydrates and/or may include other solvents, for example solvents that may have been used for the crystallisation of compounds in solid form.
  • the compounds I and their salts may be in the form of one of the possible isomers or in the form of a mixture thereof.
  • isomers for example, pure diastereoisomers.
  • mixtures of isomers may be in the form of, for example, mixtures of diastereoisomers.
  • Iso ⁇ meric mixtures of compounds I in free form or in salt form obtainable in accordance with the process or by another method can be separated into their components in customary man ⁇ ner, for example on the basis of the physico-chemical differences between the constituents in known manner by fractional crystallisation, distillation and/or chromatography. Advanta ⁇ geously, the more active isomer is isolated.
  • the invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a derivative or salt or, es ⁇ pecially, is formed under the reaction conditions. ln the process of the present invention it is preferable to use those starting materials and intermediates, in each case in free form or in salt form, which result in the compounds I de ⁇ scribed at the beginning as being especially valuable or the salts thereof.
  • the invention re ⁇ lates also to novel starting materials and intermediates, in each case in free form or in salt form, for the preparation of compounds I or the salts thereof, to the use thereof and to processes for their preparation, the variable R being as defined for compounds I.
  • the invention relates also to the use of compounds I and their pharmaceutically acceptable salts in the treatment of allergic conditions and diseases, preferably in the form of pharma ⁇ ceutically acceptable preparations, especially in a method for the therapeutic treatment of the animal or human body, and to such a method of treatment.
  • the invention relates also to pharmaceutical compositions comprising as active ingredient a compound I or a pharmaceutically acceptable salt thereof, and to processes for their prepa ⁇ ration.
  • Those pharmaceutical compositions are, for example, for enteral, such as especially oral, also rectal, administration, for parenteral administration and for local administration to warm-blooded animals, especially humans, the compositions comprising the pharmacologi ⁇ cal active ingredient on its own or together with customary pharmaceutical excipients.
  • the pharmaceutical compositions comprise (in percent by weight) for example from approxi ⁇ mately 0.001% to 100%, preferably from approximately 0.1 % to approximately 50%, active ingredient.
  • compositions for enteral or parenteral administration are, for example, those in unit dose forms, such as dragees, tablets, capsules or suppositories, and also am ⁇ poules. They are prepared in a manner known perse, for example by means of conven ⁇ tional mixing, granulating, confectioning, dissolving or lyophilising procedures.
  • pharmaceutical compositions for oral administration can be obtained by combining the ac ⁇ tive ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of appropriate excipients, into tablets or drag ⁇ e cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example trical ⁇ cium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, com, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example trical ⁇ cium phosphate or calcium hydrogen phosphate
  • binders
  • Excipients are especially flow conditioners and lu ⁇ bricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable, op ⁇ tionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium di ⁇ oxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the prepa ⁇ ration of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellu- lose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate dif ⁇ ferent doses of active ingredient.
  • compositions are dry-filled capsules consisting of gelatin, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also have been added.
  • Suitable rectal ly administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material.
  • Suit ⁇ able suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rec ⁇ tal capsules which comprise a combination of the active ingredient with a base material.
  • Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt
  • suspensions of the active ingredient such as corresponding oily injection suspensions
  • suitable lipophilic solvents or vehicles such as fatty oils, for example ses ⁇ ame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilisers.
  • compositions for local administration are, for example for topical treatment of the skin, lotions, creams and ointments, i.e. liquid or semi-solid oil-in-water or water-in-oil emulsions, fatty ointments, which are anhydrous, pastes, i.e. creams and ointments having secretion-absorbing powder constituents, gels, which are aqueous, of low water content or anhydrous and consist of swellable, gel-forming materials, foams, i.e.
  • liquid oil-in-water emulsions in aerosol form which are administered from pressurised containers, and tinc ⁇ tures having an aqueous-ethanolic base and may comprise other customary pharmaceutical excipients, such as preservatives.
  • the pharmaceutical compositions for local administration are prepared in a manner known perse by mixing the active ingredient with the pharma ⁇ ceutical excipients, for example by dissolving or suspending the active ingredient in the base or in a portion thereof, if necessary.
  • the active ingredient In order to prepare emulsions in which the active ingredient is dissolved in one of the liquid phases, the active ingredient is generally dis ⁇ solved therein prior to emulsification; in order to prepare suspensions in which the active in ⁇ gredient is suspended in the emulsion, the active ingredient is mixed with a portion of the base after emulsification and then added to the remainder of the formulation.
  • the dosage of the active ingredient can depend upon various factors, such as the effective ⁇ ness and duration of action of the active ingredient, the severity of the disease to be treated and of its symptoms, the mode of administration, the species of warm-blooded animal, and the sex, age, weight and or individual condition of the warm-blooded animal.
  • the, for example oral, daily dose for a warm-blooded animal weighing approximately 75 kg is estimated to be from approximately 1 mg to approximately 1000 mg, especially from approximately 5 mg to approximately 200 mg. It can be administered, for example, as a single dose or in several part doses of, for example, from 10 to 100 mg.
  • M.p.: melting point
  • DMSO-d ⁇ hexadeuterodimethyl sulfoxide
  • Example 1 5-Phenyl-7H-pyrrolo[2.3-d]pyrimidin-4-yl-amine a) N-(2-Oxo-2-phenyl-ethyl)-acetamide: 25.0 g of phenacylamine hydrochloride are sus ⁇ pended in a mixture of 150 ml of tetrahydrofuran, 40.5 ml of triethylamine and 27.6 ml of acetic anhydride. The suspension is stirred for 2.5 hours at room temperature and then fil ⁇ tered and the solvent is removed using a rotary evaporator. The residue is crystallised from diethyl ether. M.p.: 95-96°C.
  • N-r3-Cyano-4-(4-methoxy-phenyl)-1 H-pyrrol-2-ylj-formamidine 6.0 g of 2-amino-4-phenyl- 1 H-pyrrole-3-carbonitrile are dissolved in 80 ml of triethyl orthoformate and the solution is stirred for 1 hour at 140°C. Triethyl orthoformate is removed under a high vacuum and the residue is dissolved in saturated methanolic ammonia. The solution is stirred for 24 hours at room temperature and then filtered. The product is recrystallised from ethanol.
  • Example 2 5-'3-Methoxy-ohenyl ⁇ -7H-Dyrrolor2.3-dlDyrimidin-4-yl-amine a) 2-Bromo-1-(3-methoxy-phenyO-ethanone: A mixture of 10 ml of diethyl ether and 10 ml of 3-methoxy-acetophenone is cooled to 5°C, then 0.2 g of aluminium chloride is added and the reaction mixture is stirred for 5 minutes at 5°C. Then 3.9 ml of bromine are added drop ⁇ wise at 0-5°C and the mixture is then stirred for a further one hour at 0-5°C.
  • reaction mixture is poured into ethyl acetate and washed with water, saturated aqueous ammonium chloride and saturated sodium chloride solution.
  • the organic layer is dried over sodium sulfate and the solvent is removed using a rotary evaporator.
  • the product is crystallised from ether/petroleum ether. M.p.: 64-65°C.
  • N-2-r2-(3-Methoxy-Dhenyl ⁇ -2-oxo-ethyllacetamide 7.60 g of 2-amino-1 -(3-methoxy- phenyl)-ethanone hydrochloride are suspended in a mixture of 60 ml of tetrahydrofuran, 10.5 ml of triethylamine and 7.1 ml of acetic anhydride and the suspension is stirred for
  • N-r3-Cyano-4-(3-methoxy-phenyl)-1H-pyrrol-2-yl]-formamidine N-[3-Cyano-4-(3-methoxy- phenyl)-1H-pyrrol-2-yl]-formamidine is dissolved in 50 ml of triethyl orthoformate and the solution is stirred for 1 hour at 140°C. Excess triethyl orthoformate is removed under a high vacuum and the residue is dissolved with saturated methanolic ammonia solution. The re ⁇ sulting solution is stirred for 20 hours at room temperature and then filtered. The product is recrystallised from ethanol. M.p.: 188-190°C.
  • Example 3 5-(4-Benzyloxy-Phenyl)-7H-pyrrolof2.3-dlpyrimidin-4-yl-amine a) 1 -f4-(Benzyloxy ⁇ phenyllethanone: 48 ml of benzyl bromide are added dropwise to a sus ⁇ pension of 50.0 g of 4-hydroxyacetophenone and 76.0 g of potassium carbonate in 600 ml of acetone. The reaction mixture is stirred for.20 hours under reflux and then filtered. The filtrate is concentrated by evaporation and the residue is triturated with petroleum ether.
  • N-2-f2-(4-Benzyloxy-phenyl)-2-oxo-ethyl1-acetamide 28.2 g of 2-amino-1 -(4-benzyloxy- phenyl)-ethanone hydrochloride are suspended in 300 ml of tetrahydrofuran, and 28.2 ml of triethylamine and 11.5 ml of acetic anhydride are added thereto. The reaction mixture is stirred for 3 hours at room temperature and filtered and the mother liquor is concentrated by evaporation using a rotary evaporator.
  • Example 16 4-(4-Amino-5-phenyl-pyrrolof2.3-dlpyrimidin-7-y0-cyclopent-2-en-ol 0.25 g of tetrakis(triphenylphosphine)palladium(0) and 1.09 g of 5-phenyl-7H-pyrrolo[2,3-d]- pyrimidin-4-yl-amine (Example 1 ) are dissolved in 12 ml of tetrahydrofuran dimethyl sulfox ⁇ ide (1:1) and the reaction mixture is stirred for 2 minutes at room temperature and then cooled to 0°C.
  • Cyclopentadiene monoepoxide [CAS Reg. No.: 7129-41 -1] ⁇ s prepared according to V. Merio etai., J. Chem. Soc. Perkin Transaction 11994, 1477.
  • Example 3 Prepared analogously to Example 1 , starting from 5-(4-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]- pyrimidin-4-yl-amine (Example 3) and cyclopentadiene monoepoxide.
  • 'H-NMR CD 3 OD, ppm: 8.1 (s, 1H), 7.32 (m, 7H), 7.1 (s, 1H), 7.0 (d, 2H), 6.18 (m, 1H), 5.9 (m, 1H), 5.75 (m,
  • Example 20 3-(4-Amino-5-Phenyl-Pyrrolof2.3-dlPyrimidin-7-v ⁇ -cvclopentanol
  • a solution of 4-(4-amino-5-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclopent-2-en-ol (Example 16) in 15 ml of dimethylformamide is hydrogenated over 30 mg of palladium-on-carbon (10%) under normal pressure with hydrogen.
  • the catalyst is filtered off and the filtrate is taken up in ethyl acetate.
  • the organic layer is extracted three times with water and dried over sodium sulfate and the solvent is removed using a rotary evaporator. The residue is triturated with ether.
  • Example 23 3-(4-Amino-5-(4-hvdroxy-Phenvn-pvrrolor2.3-dlpyrimidin-7-vn-cvclopentanol 50 mg of palladium-on-carbon (10%) are added to a solution of 0.2 g of 4-(4-amino- 5-(4-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclopent-2-en-ol (Example 19) in 12 ml of methanol and the reaction mixture is hydrogenated with hydrogen analogously to Exam ⁇ ple 3. The catalyst is filtered off and methanol is removed using a rotary evaporator. The residue is triturated with ether.
  • the synthesis of the cyclopentenol derivatives can also be carried out starting from 3-acetoxy-5-hydroxycyclopent-1-ene (c/s-3-acetoxy-5-hydroxycyclopent-1-ene: [CAS Reg. No.: 60410-18-6] an ⁇ frans-3-acetoxy-5-hydroxycyclopent-1-ene: [CAS Reg. No.: 60410-15-3]).
  • the hydroxy group of the corresponding 3-acetoxy-5-hydroxycyclopent-1-ene is p-toluenesulfonated or methanesulfonated, followed by alkylation with the desired 5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl-amine.
  • Example 24 3-f4-Amino-5-(3-hvdroxy-Phenyli-Pyrrolof2.3-dlPyrimidin-7-yli-cvclopentanol
  • Example 25 5-(4-Amino-5-phenyl-pyrrolof2.3-dlPyrimidin-7-yl ⁇ -3-benzyloxy-2-benzyloxy- methyl-cyclopentanol
  • Example 26 4- 4-Amino-5-Phenyl-pyrrolof2.3-dlDyrimidin-7-yl ⁇ -2-hvdroxymethyl-cyclo- pentane-1 ,3-diol
  • Example 27 4-f4-Amino-5-(4-methoxy-phenyl)-pyrrolof2.3-dlpyrimidin-7-yl]-2-hydroxy- methvi-cvclopentane-1 ,3-diol
  • Examole 28 4-f4-Amino-5-f3-methoxy-phenvn-pyrrolor2.3-dlPyrimidin-7-yll-2-hvdroxy- methyl-cyclopentane-1 ,3-diol
  • Example 31 4- 4-Amino-5-phenyl-pyrrolor2.3-dlPyrimidin-7-v ⁇ -2-hvdroxymethyl-cyclo- pentanol a) f7-f4-Benzyloxy-3-benzyloxymethyl-2-(tert-butyl-dimethyl-silanyloxyl-cvclopentyll-5- phenyl-7H-pyrrolor2.3-dlpyrimidin-4-yl)-amine: 0.250 g of 5-(4-am ⁇ no-5-phenyl-pyrrolo- [2,3-d]pyrimidin-7-yl)-3-benzyloxy-2-benzyloxymethyl-cyclopentanol (Example 26), 0.270 g of tert-butyldimethylsilyl chloride and 0.125 g of imidazole are dissolved in 8 mi of dichloro ⁇ methane and the reaction mixture is stirred for 10 hours at room temperature.
  • the reaction mixture is taken up in dichloromethane and washed with saturated aqueous ammonium chloride and water.
  • the organic layer is separated off and dried over sodium sulfate and the solvent is removed using a rotary evaporator.
  • the product is purified by flash chromato ⁇ graphy (dichloromethane).
  • the reaction mixture is stirred for 4 hours at 40°C and for 18 hours at room temperature, taken up in ethyl acetate and ex ⁇ tracted with water.
  • the organic layer is separated off and dried over sodium sulfate and the solvent is removed using a rotary evaporator.
  • the product is purified by flash chromato ⁇ graphy (dichloromethane/methanol 10:0.3).
  • the reaction mixture is stirred for 3 hours at 75°C and then taken up in ethyl acetate and ex ⁇ tracted with aqueous ammonium chloride and water.
  • the organic layer is separated off and dried over sodium sulfate and the solvent is removed using a rotary evaporator.
  • the residue is partitioned between acetonitrile and hexane and the acetonitrile layer is extracted twice with hexane.
  • the acetonitrile layer is concentrated by evaporation using a rotary evaporator and the residue is dried under a high vacuum.
  • the crude product is dissolved in 5 ml of methanol, and 4 drops of 4N hydrochloric acid and 0.010 g of palladium-on-carbon (10%) are added thereto. Hydrogenation is carried out under normal pressure with hydrogen, the catalyst is filtered off and the filtrate is concentrated. The prod ⁇ uct is purified by flash chromatography with dichloromethane/methanol (10:1 ) as eluant.
  • Example 36 4-Amino-7-cvclopentyl-5-phenyl-pyrrolof2.3-dlpyrimidine
  • 2-Cyclopentylamino-acetophenone A mixture of 2.0 g of cyclopentylamine, 4.67 g of phenacyl bromide and 7.46 g of powdered potassium carbonate is stirred in 40 ml of etha ⁇ nol for 1 hour under argon at room temperature. Undissolved potassium carbonate is fil ⁇ tered off and washed with ether. The organic layer is washed with water and sodium chlo ⁇ ride solution, dried over sodium sulfate and concentrated and yields an orange-brown oil which solidifies on being left to stand. The product is used in the following step without be ⁇ ing purified further.
  • reaction mixture After 15 minutes the reaction mixture is cooled to 0°C and 182 mg of (4aR * ,7aR * )-4,4a,5,7a-tetrahydrocyclopenta[1,3]dioxin-2-one, dissolved in 3 ml of tetrahy ⁇ drofuran (distilled under argon over potassium), are added dropwise thereto. After 2 hours at 0°C the reaction mixture is allowed to rise to room temperature and is stirred for 2 days at room temperature. The reaction solution is then partitioned between water and ethyl acetate and the aqueous layer is extracted twice with ethyl acetate. The organic layer is washed with saturated sodium chloride solution.
  • Example 46 4- 4-Amino-5-phenvl-pvrrolo,2.3-dlPvrimidin-7-vl,-(1.2.4/0,-cvclopentane-1.2- diol
  • Methanesulfonic acid [2,2-dimethyl-tetrahydro-(1 ,2/4)-cyclopenta[1 ,3]dioxol-5-yl] ester can be prepared by methanesulfonating 2,2-dimethyl-tetrahydro-(1 ,2/4)-cyclopenta[1 ,3]dioxol-5- ol (R. Steyn, H.Z. Sabble, Tetrahedron 25, 3579 (1969)).
  • 3-Methanesulfonyloxy-cyciobutanecarboxylic acid methyl ester can be prepared by esteri ⁇ fying with methanol and subsequent methanesulfonating starting from 3-hydroxy-cyclo- butanecarboxylic acid (see K. B. Wiberg et ai., Tetrahedron 2 , 2763 (1965)).
  • the reaction mixture is cooled to 0°C and then 42 ⁇ l of water, 42 ⁇ l of 15 percent sodium hydroxide solution and a further 218 ⁇ l of water are added in succession thereto. After half an hour the solid material is separated off and the filtrate is partitioned between water and ethyl acetate. Drying over magnesium sulfate, concentrating in vacuo and purifying by coiumn chromatography (ethyl acetate/methanol 95:5) yield the pure diastereoisomers (cis/trans) in a ratio of approx. 3:4. M.p.: 138-140°C ( ⁇ s-isomer), m.p.: 146-148°C (frans-isomer).
  • Methanesulfonic acid (3-benzyloxy)cyclobutyl ester can be prepared by reduction of 3-benzyloxy-cyclobutanone (see K. Ogura et al. Bull. Chem. Soc. Jpn. ⁇ 7, 1637 (1 4)) with lithium aluminium hydride and subsequent methanesulfonation.
  • Example 49 c/s-f3-f4-Amino-5-phenyl-pyrrolof2.3-dlPyrimidin-7-yl)-cyclobutvn-methanol. m.p.: 200-204°C
  • Example 50 rran5-f3-(4-Amino-5-phenyl-pyrrolo[2.3-d1pyrimidin-7-y ⁇ -cyclobutyl1-methanol. m.p.: 163-165°C
  • Example 51 4-(4-Amino-5-phenyl-pyrrolor2.3-d)pyrimidin-7-ylH1.2/4)-cyclooentane-1 ,2-diol. m.p.: 189-191 °C
  • Example 61 4-Amino-7-cvclobutyl-5-f3-methoxyphenv ⁇ -Pyrrolof2.3-dlPyrimidine. m.p.: 167-169°C
  • Example 65 Acetic acid-2-acetoxv-4-(4-amino-5-phenvl-Pvrrolof2.3-dlovrimidin-7-vn-(1.4/2.- cyclopentyl ester, m.p.: 154-157°C
  • Example 66 4-(4-Amino-5-phenyl-pyrrolof2.3-d]pyrimidin-7-ylH1.4/2)-cyclopentane-1.2-dio . m.p.: 140-145°C
  • Example 70 rtans-3-r4-Amino-5-(3-hvdroxy-phenyl)-pyrrolo[2.3-dlpyrimidin-7-vn-cyclo- butanecarboxylic acid methyl ester, m.p.: 176-180°C
  • Example 71 3-f4-Amino-5-(3-methoxy-phenyl.-Pyrrolor2.3-dlPyrimidin-7-yn-cvclobutane- carboxylic acid methyl ester, m.p.: 159-161 °C
  • Example 72 f3-[4-Amino-5-(3-methoxy-phenyl ⁇ -Pyrrolof2.3-dlPyrimidin-7-yll-cvclobutyl)- methanol. m.p.: 151-153°C
  • Example A Tablets each comorisin ⁇ 50 m ⁇ of active in ⁇ redient:
  • composition (10000 tablets) active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly dispersed) 20.0 g ethanol q.s.
  • the active ingredient is mixed with the lactose and 292 g of the potato starch and the mix ⁇ ture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remaining potato starch, the magnesium stearate, the talc and the silica are mixed in and the mixture is compressed to form tablets each weighing 145 mg and comprising 50 mg of active ingredient, which may, if desired, be provided with dividing notches for finer adaptation of the dose.
  • Example B Film-coated tablets, each comprising 100 mg of active ingredient:
  • composition 1000 film-coated tablets
  • active ingredient 100.0 g lactose 100-O g com starch 70.0 g talc 8.5 g calcium stearate 1.5 g hydroxypropyl methylcellulose 2.36 g shellac 0.64 g water q.s. dichloromethane q.s.
  • the active ingredient, the lactose and 40 g of the corn starch are mixed, and the mixture is moistened with a paste, prepared from 15 g of the com starch and water (with heating), and granulated.
  • the granules are dried, and the remaining com starch, the talc and the calcium stearate are mixed with the granules.
  • the mixture is compressed to form tablets (each weighing 280 mg), which are then coated with a solution of the hydroxypropylmethylcellul- ose and the shellac in dichloromethane (final weight of each film-coated tablet: 283 mg).

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Abstract

Cette invention concerne des pyrrolo(2,3-d)pyrimidines représentées par la formule (I) dans laquelle R1, R2, R3 et R4 sont définis dans le descriptif de l'invention. Ces composés possèdent d'intéressantes propriétés pharmaceutiques et s'avèrent particulièrement efficaces en tant qu'inhibiteurs de tyrosine protéine kinase. Ils peuvent permettre de traiter, chez des animaux à sang chaud, des maladies des os et d'autres maladies qui sont favorablement influencées par l'inhibition d'une tyrosine protéine kinase.
PCT/EP1997/000350 1996-02-01 1997-01-27 Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase WO1997028161A1 (fr)

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CH257/96 1996-02-01
CH00257/96A CH690773A5 (de) 1996-02-01 1996-02-01 Pyrrolo(2,3-d)pyrimide und ihre Verwendung.

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Cited By (124)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998041525A1 (fr) * 1997-03-19 1998-09-24 Basf Aktiengesellschaft Pyrrolo [2,3] pyrimidines et leur utilisation comme inhibiteurs de la tyrosine kinase
WO2000017203A1 (fr) * 1998-09-18 2000-03-30 Basf Aktiengesellschaft Pyrrolopyrimidines utilisees comme inhibiteurs de proteines kinases
US6184225B1 (en) 1996-02-13 2001-02-06 Zeneca Limited Quinazoline derivatives as VEGF inhibitors
US6201004B1 (en) 1997-03-11 2001-03-13 Knoll Aktiengesellschaft Dioxino derivatives and their use as therapeutic agents
US6265411B1 (en) 1996-05-06 2001-07-24 Zeneca Limited Oxindole derivatives
US6291455B1 (en) 1996-03-05 2001-09-18 Zeneca Limited 4-anilinoquinazoline derivatives
US6294532B1 (en) 1997-08-22 2001-09-25 Zeneca Limited Oxindolylquinazoline derivatives as angiogenesis inhibitors
WO2001072751A1 (fr) * 2000-03-29 2001-10-04 Knoll Gesellschaft Mit Beschraenkter Haftung Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases
US6610847B2 (en) 1998-06-19 2003-08-26 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6627754B2 (en) 1999-12-10 2003-09-30 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6635762B1 (en) 1998-06-19 2003-10-21 Pfizer Inc. Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use
US6660744B1 (en) 1999-09-17 2003-12-09 Abbott Gmbh & Co. Kg Pyrazolopyrimidines as therapeutic agents
US6673803B2 (en) 1996-09-25 2004-01-06 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6696567B2 (en) 2000-06-26 2004-02-24 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6713474B2 (en) 1998-09-18 2004-03-30 Abbott Gmbh & Co. Kg Pyrrolopyrimidines as therapeutic agents
WO2004043962A1 (fr) * 2002-11-12 2004-05-27 Novartis Ag Derives de 4-amino-5-phenyl-7-cyclohexyl-pyrrolo[2,3-d]pyrimidine
US6809097B1 (en) 1996-09-25 2004-10-26 Zeneca Limited Quinoline derivatives inhibiting the effect of growth factors such as VEGF
WO2006012422A1 (fr) 2004-07-20 2006-02-02 Osi Pharmaceuticals, Inc. Imidazotriazines comme inhibiteurs de la tyrosine kinase
US7071199B1 (en) 1999-09-17 2006-07-04 Abbott Gmbh & Cco. Kg Kinase inhibitors as therapeutic agents
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7160889B2 (en) 2000-04-07 2007-01-09 Astrazeneca Ab Quinazoline compounds
US7173038B1 (en) 1999-11-05 2007-02-06 Astrazeneca Ab Quinazoline derivatives as VEGF inhibitors
WO2007035744A1 (fr) 2005-09-20 2007-03-29 Osi Pharmaceuticals, Inc. Marqueurs biologiques predictifs d'une reaction anticancereuse aux inhibiteurs kinase du recepteur du facteur de croissance 1 analogue a l'insuline
WO2007064993A2 (fr) 2005-12-02 2007-06-07 Osi Pharmaceuticals, Inc. Inhibiteurs bicycliques de la proteine kinase
US7250420B2 (en) 2002-11-26 2007-07-31 Pfizer Inc. Method of treatment of transplant rejection
WO2007079164A3 (fr) * 2005-12-29 2007-09-27 Abbott Lab Inhibiteurs de protéines kinases
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
WO2007115620A3 (fr) * 2006-04-07 2007-11-29 Merck Patent Gmbh Nouveaux composés de cyclobutyle en tant qu'inhibiteurs de kinase
WO2007116025A3 (fr) * 2006-04-07 2007-12-13 Novartis Ag Utilisation d'inhibiteurs de c-src en combinaison avec un composé pyrimidylaminobenzamide pour traiter la leucémie
US7326699B2 (en) 2001-05-14 2008-02-05 Novartis Ag 4-Amino-5-phenyl-7-cyclobutyl-pyrrolo(2,3-d)pyrimidine derivatives
US7429596B2 (en) * 2003-06-20 2008-09-30 The Regents Of The University Of California 1H-pyrrolo [2,3-D] pyrimidine derivatives and methods of use thereof
US7459554B2 (en) 2003-10-15 2008-12-02 Osi Pharmaceuticals, Inc. Imidazopyrazine tyrosine kinase inhibitors
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
US7514444B2 (en) 2006-09-22 2009-04-07 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US7534797B2 (en) 2004-04-02 2009-05-19 Osi Pharmaceuticals, Inc. 6,6-Bicyclic ring substituted heterobicyclic protein kinase inhibitors
US7566721B2 (en) 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
WO2009098715A2 (fr) 2008-01-11 2009-08-13 Natco Pharma Limited Nouveaux dérivés de pyrazolo [3, 4 -d] pyrimidine en tant qu’agents anticancéreux
US7585868B2 (en) 2006-04-04 2009-09-08 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines as kinase antagonists
US7625880B2 (en) 2006-01-13 2009-12-01 Pharmacyclics, Inc. Inhibitors of tyrosine kinases and uses thereof
WO2010099363A1 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
WO2010099137A2 (fr) 2009-02-26 2010-09-02 Osi Pharmaceuticals, Inc. Procédés in situ pour surveiller l'état emt de cellules tumorales in vivo
WO2010099139A2 (fr) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Thérapie anti-cancer combinée
WO2010099138A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Procédés pour l'identification d'agents qui inhibent les cellules tumorales de type mésenchymateuses ou leur formation
WO2010099364A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
EP2258371A1 (fr) 2001-08-10 2010-12-08 Novartis AG Utilisation d'inhibiteurs c-Src seuls ou en combinaison avec STI571 pour le traitement de leucemies
US7863444B2 (en) 1997-03-19 2011-01-04 Abbott Laboratories 4-aminopyrrolopyrimidines as kinase inhibitors
WO2011029915A1 (fr) 2009-09-10 2011-03-17 Novartis Ag Dérivés éthers d'hétéroaryles bicycliques
EP2308855A1 (fr) 2002-03-15 2011-04-13 Novartis AG Dérivés de 2,4-Diaminopyrimidine
WO2011064211A1 (fr) 2009-11-25 2011-06-03 Novartis Ag Dérivés hétérocycliques d'hétéroaryles bicycliques à 6 cycles benzéniques accolés de benzène contenant de l'oxygène
WO2011109572A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011109584A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011112666A1 (fr) 2010-03-09 2011-09-15 OSI Pharmaceuticals, LLC Thérapie anticancéreuse combinatoire
JP4842929B2 (ja) * 2004-05-27 2011-12-21 ファイザー・プロダクツ・インク 癌治療に有用なピロロピリミジン誘導体
WO2011157793A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle
WO2011157787A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution biphényle
EP2409969A1 (fr) 2004-06-24 2012-01-25 Novartis AG Dérivés d'urée de pyrimidine en tant qu'inhibiteurs de kinase
US8133899B2 (en) 2008-08-20 2012-03-13 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
WO2012116040A1 (fr) 2011-02-22 2012-08-30 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de la kinase du récepteur du facteur de croissance 1 analogue à l'insuline dans le carcinome hépatocellulaire
WO2012120469A1 (fr) 2011-03-08 2012-09-13 Novartis Ag Composés hétéroaryliques bicycliques de type fluorophényle
WO2012122499A2 (fr) 2011-03-09 2012-09-13 Pestell Richard G Lignées de cellules du cancer de la prostate, signatures géniques et leurs utilisations
WO2012149014A1 (fr) 2011-04-25 2012-11-01 OSI Pharmaceuticals, LLC Utilisation de signatures de gènes de tem dans la découverte de médicaments contre le cancer, diagnostics et traitement du cancer
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
US8481733B2 (en) 2008-05-19 2013-07-09 OSI Pharmaceuticals, LLC Substituted imidazopyr- and imidazotri-azines
US8513415B2 (en) 2009-04-20 2013-08-20 OSI Pharmaceuticals, LLC Preparation of C-pyrazine-methylamines
WO2013152252A1 (fr) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Polythérapie antinéoplasique
US8569323B2 (en) 2009-07-15 2013-10-29 Intellikine, Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US8575164B2 (en) 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
US8604032B2 (en) 2010-05-21 2013-12-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US8697709B2 (en) 2008-10-16 2014-04-15 The Regents Of The University Of California Fused ring heteroaryl kinase inhibitors
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
US8703777B2 (en) 2008-01-04 2014-04-22 Intellikine Llc Certain chemical entities, compositions and methods
US8754090B2 (en) 2010-06-03 2014-06-17 Pharmacyclics, Inc. Use of inhibitors of bruton's tyrosine kinase (Btk)
US8785454B2 (en) 2009-05-07 2014-07-22 Intellikine Llc Heterocyclic compounds and uses thereof
US8785470B2 (en) 2011-08-29 2014-07-22 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US8809273B2 (en) 2007-03-28 2014-08-19 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US8883803B2 (en) 2008-07-16 2014-11-11 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase for the treatment of solid tumors
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8969363B2 (en) 2011-07-19 2015-03-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8980899B2 (en) 2009-10-16 2015-03-17 The Regents Of The University Of California Methods of inhibiting Ire1
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US9096604B2 (en) 2012-11-15 2015-08-04 Pharmacyclics, Inc. Pyrrolopyrimidine compounds as kinase inhibitors
WO2016016894A1 (fr) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Milieux pour la culture de cellules souches pluripotentes
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
US9296753B2 (en) 2012-06-04 2016-03-29 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US9321772B2 (en) 2011-09-02 2016-04-26 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9359349B2 (en) 2007-10-04 2016-06-07 Intellikine Llc Substituted quinazolines as kinase inhibitors
US9359365B2 (en) 2013-10-04 2016-06-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9381246B2 (en) 2013-09-09 2016-07-05 Triact Therapeutics, Inc. Cancer therapy
US9415050B2 (en) 2013-08-12 2016-08-16 Pharmacyclics Llc Methods for the treatment of HER2 amplified cancer
US9421208B2 (en) 2013-08-02 2016-08-23 Pharmacyclics Llc Methods for the treatment of solid tumors
US9453836B2 (en) 2012-05-14 2016-09-27 Richard G. Pestell Use of modulators of CCR5 in the treatment of cancer and cancer metastasis
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US9512125B2 (en) 2004-11-19 2016-12-06 The Regents Of The University Of California Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents
US9533991B2 (en) 2014-08-01 2017-01-03 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9545407B2 (en) 2014-08-07 2017-01-17 Pharmacyclics Llc Formulations of a bruton's tyrosine kinase inhibitor
US9624224B2 (en) 2013-09-30 2017-04-18 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9629843B2 (en) 2008-07-08 2017-04-25 The Regents Of The University Of California MTOR modulators and uses thereof
US9655857B2 (en) 2015-03-03 2017-05-23 Pharmacyclics Llc Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9775844B2 (en) 2014-03-19 2017-10-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9834575B2 (en) 2013-02-26 2017-12-05 Triact Therapeutics, Inc. Cancer therapy
US9862722B2 (en) 2011-07-13 2018-01-09 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9885086B2 (en) 2014-03-20 2018-02-06 Pharmacyclics Llc Phospholipase C gamma 2 and resistance associated mutations
US10131668B2 (en) 2012-09-26 2018-11-20 The Regents Of The University Of California Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1
US10160761B2 (en) 2015-09-14 2018-12-25 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
WO2019119486A1 (fr) 2017-12-21 2019-06-27 中国科学院合肥物质科学研究院 Classe d'inhibiteurs de kinase dérivés de pyrimidine
US10463668B2 (en) 2013-10-25 2019-11-05 Pharmacyclics Llc Methods of treating and preventing graft versus host disease
WO2020152686A1 (fr) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Milieux de culture pour cellules souches pluripotentes
US10759806B2 (en) 2016-03-17 2020-09-01 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
US10919914B2 (en) 2016-06-08 2021-02-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10954567B2 (en) 2012-07-24 2021-03-23 Pharmacyclics Llc Mutations associated with resistance to inhibitors of Bruton's Tyrosine Kinase (BTK)
WO2021097256A1 (fr) 2019-11-14 2021-05-20 Cohbar, Inc. Peptides antagonistes de cxcr4
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US12202834B2 (en) 2019-01-29 2025-01-21 Vationpharma B.V. Solid state forms of oclacitinib maleate
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0682027A1 (fr) * 1994-05-03 1995-11-15 Ciba-Geigy Ag Dérivés de la pyrrolopyrimidine avec une activité anti-proliférative
WO1996040686A1 (fr) * 1995-06-07 1996-12-19 Abbott Laboratories Composes de cyclopentane substitue heterocycliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0682027A1 (fr) * 1994-05-03 1995-11-15 Ciba-Geigy Ag Dérivés de la pyrrolopyrimidine avec une activité anti-proliférative
WO1996040686A1 (fr) * 1995-06-07 1996-12-19 Abbott Laboratories Composes de cyclopentane substitue heterocycliques

Cited By (291)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6184225B1 (en) 1996-02-13 2001-02-06 Zeneca Limited Quinazoline derivatives as VEGF inhibitors
US6291455B1 (en) 1996-03-05 2001-09-18 Zeneca Limited 4-anilinoquinazoline derivatives
US6265411B1 (en) 1996-05-06 2001-07-24 Zeneca Limited Oxindole derivatives
US6673803B2 (en) 1996-09-25 2004-01-06 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6897210B2 (en) 1996-09-25 2005-05-24 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6809097B1 (en) 1996-09-25 2004-10-26 Zeneca Limited Quinoline derivatives inhibiting the effect of growth factors such as VEGF
USRE42353E1 (en) 1996-09-25 2011-05-10 Astrazeneca Uk Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6201004B1 (en) 1997-03-11 2001-03-13 Knoll Aktiengesellschaft Dioxino derivatives and their use as therapeutic agents
US7863444B2 (en) 1997-03-19 2011-01-04 Abbott Laboratories 4-aminopyrrolopyrimidines as kinase inhibitors
US6001839A (en) * 1997-03-19 1999-12-14 Basf Aktiengesellschaft Substituted 4-amino-7H-pyrrolo [2,3,-d]-pyrimidines as PTK inhibitors
WO1998041525A1 (fr) * 1997-03-19 1998-09-24 Basf Aktiengesellschaft Pyrrolo [2,3] pyrimidines et leur utilisation comme inhibiteurs de la tyrosine kinase
US6294532B1 (en) 1997-08-22 2001-09-25 Zeneca Limited Oxindolylquinazoline derivatives as angiogenesis inhibitors
US7687507B2 (en) 1998-06-19 2010-03-30 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6635762B1 (en) 1998-06-19 2003-10-21 Pfizer Inc. Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use
US7569569B2 (en) 1998-06-19 2009-08-04 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6610847B2 (en) 1998-06-19 2003-08-26 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6890929B2 (en) 1998-06-19 2005-05-10 Pfizer, Inc. Pyrrolo [2,3-D] pyrimidine compounds
AU753555C (en) * 1998-09-18 2003-07-03 Abbott Gmbh & Co. Kg Pyrrolopyrimidines as protein kinase inhibitors
US6713474B2 (en) 1998-09-18 2004-03-30 Abbott Gmbh & Co. Kg Pyrrolopyrimidines as therapeutic agents
AU753555B2 (en) * 1998-09-18 2002-10-24 Abbott Gmbh & Co. Kg Pyrrolopyrimidines as protein kinase inhibitors
WO2000017203A1 (fr) * 1998-09-18 2000-03-30 Basf Aktiengesellschaft Pyrrolopyrimidines utilisees comme inhibiteurs de proteines kinases
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7071199B1 (en) 1999-09-17 2006-07-04 Abbott Gmbh & Cco. Kg Kinase inhibitors as therapeutic agents
US6660744B1 (en) 1999-09-17 2003-12-09 Abbott Gmbh & Co. Kg Pyrazolopyrimidines as therapeutic agents
US7173038B1 (en) 1999-11-05 2007-02-06 Astrazeneca Ab Quinazoline derivatives as VEGF inhibitors
US9040548B2 (en) 1999-11-05 2015-05-26 Astrazeneca Ab Quinazoline derivatives as VEGF inhibitors
US10457664B2 (en) 1999-11-05 2019-10-29 Genzyme Corporation Quinazoline derivatives as VEGF inhibitors
US6627754B2 (en) 1999-12-10 2003-09-30 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US7265221B2 (en) 1999-12-10 2007-09-04 Pfizer, Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6956041B2 (en) 1999-12-10 2005-10-18 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US7842699B2 (en) 1999-12-10 2010-11-30 Pfizer Inc. Pyrrolo[2,3-D]pyrimidine compounds
US7091208B2 (en) 1999-12-10 2006-08-15 Pfizer Inc. Pyrrolo[2,3-D]pyrimidine compounds
US7601727B2 (en) 1999-12-10 2009-10-13 Pfizer, Inc. Pyrrolo[2,3-d]pyrimidine compounds
USRE41783E1 (en) 1999-12-10 2010-09-28 Pfizer Inc. Pyrrolo[2,3-D]pyrimidine compounds
WO2001072751A1 (fr) * 2000-03-29 2001-10-04 Knoll Gesellschaft Mit Beschraenkter Haftung Pyrrolopyrimidines utilisees comme inhibiteurs de tyrosine kinases
US7160889B2 (en) 2000-04-07 2007-01-09 Astrazeneca Ab Quinazoline compounds
US6962993B2 (en) 2000-06-26 2005-11-08 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US6696567B2 (en) 2000-06-26 2004-02-24 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US7192963B2 (en) 2000-06-26 2007-03-20 Pfizer Inc Pyrrolo[2,3-d]pyrimidine compounds
US7326699B2 (en) 2001-05-14 2008-02-05 Novartis Ag 4-Amino-5-phenyl-7-cyclobutyl-pyrrolo(2,3-d)pyrimidine derivatives
US7432370B2 (en) 2001-05-31 2008-10-07 Pfizer Inc. Chiral salt resolution
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
US8119649B2 (en) 2001-08-10 2012-02-21 Novartis Ag Use of c-Src inhibitors alone or in combination with STI571 for the treatment of leukaemia
EP2258371A1 (fr) 2001-08-10 2010-12-08 Novartis AG Utilisation d'inhibiteurs c-Src seuls ou en combinaison avec STI571 pour le traitement de leucemies
US8268837B2 (en) 2001-08-10 2012-09-18 Novartis Ag Use of c-Src inhibitors alone or in combination with STI571 for the treatment of leukaemia
EP2308855A1 (fr) 2002-03-15 2011-04-13 Novartis AG Dérivés de 2,4-Diaminopyrimidine
CN100413867C (zh) * 2002-11-12 2008-08-27 诺瓦提斯公司 4-氨基-5-苯基-7-环己基-吡咯并[2,3-d]嘧啶衍生物
WO2004043962A1 (fr) * 2002-11-12 2004-05-27 Novartis Ag Derives de 4-amino-5-phenyl-7-cyclohexyl-pyrrolo[2,3-d]pyrimidine
US7250420B2 (en) 2002-11-26 2007-07-31 Pfizer Inc. Method of treatment of transplant rejection
US7429596B2 (en) * 2003-06-20 2008-09-30 The Regents Of The University Of California 1H-pyrrolo [2,3-D] pyrimidine derivatives and methods of use thereof
US7459554B2 (en) 2003-10-15 2008-12-02 Osi Pharmaceuticals, Inc. Imidazopyrazine tyrosine kinase inhibitors
EP2305682A1 (fr) 2004-04-02 2011-04-06 OSI Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de la protéine kinase à anneau bicyclique substitué en 6,6
US7534797B2 (en) 2004-04-02 2009-05-19 Osi Pharmaceuticals, Inc. 6,6-Bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8101613B2 (en) 2004-04-02 2012-01-24 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8367826B2 (en) 2004-04-02 2013-02-05 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
EP2308879A1 (fr) 2004-04-02 2011-04-13 OSI Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de la protéine kinase à anneau bicyclique substitué en 6,6
US7820662B2 (en) 2004-04-02 2010-10-26 Osi Pharmaceuticals, Inc. 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8653268B2 (en) 2004-04-02 2014-02-18 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
US8735405B2 (en) 2004-04-02 2014-05-27 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
JP4842929B2 (ja) * 2004-05-27 2011-12-21 ファイザー・プロダクツ・インク 癌治療に有用なピロロピリミジン誘導体
EP2409969A1 (fr) 2004-06-24 2012-01-25 Novartis AG Dérivés d'urée de pyrimidine en tant qu'inhibiteurs de kinase
EP2418205A1 (fr) 2004-06-24 2012-02-15 Novartis AG Dérivés d'urée de pyrimidine en tant qu'inhibiteurs de kinase
WO2006012422A1 (fr) 2004-07-20 2006-02-02 Osi Pharmaceuticals, Inc. Imidazotriazines comme inhibiteurs de la tyrosine kinase
US7741324B2 (en) 2004-07-20 2010-06-22 Osi Pharmaceuticals, Inc. Imidazotriazines as protein kinase inhibitors
US7465726B2 (en) 2004-08-02 2008-12-16 Osi Pharmaceuticals, Inc. Substituted pyrrolo[2.3-B]pyridines
US9512125B2 (en) 2004-11-19 2016-12-06 The Regents Of The University Of California Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents
US7566721B2 (en) 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
WO2007035744A1 (fr) 2005-09-20 2007-03-29 Osi Pharmaceuticals, Inc. Marqueurs biologiques predictifs d'une reaction anticancereuse aux inhibiteurs kinase du recepteur du facteur de croissance 1 analogue a l'insuline
EP2372363A1 (fr) 2005-09-20 2011-10-05 OSI Pharmaceuticals, Inc. Marqueurs biologiques prédictifs d'une réaction anticancéreuse aux inhibiteurs kinase du récepteur du facteur de croissance 1 analogue à l'insuline
WO2007064993A2 (fr) 2005-12-02 2007-06-07 Osi Pharmaceuticals, Inc. Inhibiteurs bicycliques de la proteine kinase
US7648987B2 (en) 2005-12-02 2010-01-19 Osi Pharmaceuticals, Inc. Bicyclic protein kinase inhibitors
US8575164B2 (en) 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
WO2007079164A3 (fr) * 2005-12-29 2007-09-27 Abbott Lab Inhibiteurs de protéines kinases
JP2014088397A (ja) * 2005-12-29 2014-05-15 Abbvie Inc タンパク質キナーゼ阻害薬
US7625880B2 (en) 2006-01-13 2009-12-01 Pharmacyclics, Inc. Inhibitors of tyrosine kinases and uses thereof
US8067395B2 (en) 2006-01-13 2011-11-29 Pharmacyclics, Inc. Inhibitors of tyrosine kinases and uses thereof
US7585868B2 (en) 2006-04-04 2009-09-08 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines as kinase antagonists
US8642604B2 (en) 2006-04-04 2014-02-04 The Regents Of The University Of California Substituted pyrazolo[3,2-d]pyrimidines as anti-cancer agents
US9493467B2 (en) 2006-04-04 2016-11-15 The Regents Of The University Of California PI3 kinase antagonists
WO2007116025A3 (fr) * 2006-04-07 2007-12-13 Novartis Ag Utilisation d'inhibiteurs de c-src en combinaison avec un composé pyrimidylaminobenzamide pour traiter la leucémie
WO2007115620A3 (fr) * 2006-04-07 2007-11-29 Merck Patent Gmbh Nouveaux composés de cyclobutyle en tant qu'inhibiteurs de kinase
US8957079B2 (en) 2006-09-22 2015-02-17 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8399470B2 (en) 2006-09-22 2013-03-19 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US9181257B2 (en) 2006-09-22 2015-11-10 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US8088781B2 (en) 2006-09-22 2012-01-03 Pharmacyclics, Inc. Inhibitors of brutons tyrosine kinase
US9206189B2 (en) 2006-09-22 2015-12-08 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
US9212185B2 (en) 2006-09-22 2015-12-15 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9409911B2 (en) 2006-09-22 2016-08-09 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
US8008309B2 (en) 2006-09-22 2011-08-30 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8883435B2 (en) 2006-09-22 2014-11-11 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8158786B2 (en) 2006-09-22 2012-04-17 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8232280B2 (en) 2006-09-22 2012-07-31 Pharmacyclics, Inc. Inhibitors of bruton'S tyrosine kinase
US8236812B2 (en) 2006-09-22 2012-08-07 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US7732454B2 (en) 2006-09-22 2010-06-08 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8759516B2 (en) 2006-09-22 2014-06-24 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US9133201B2 (en) 2006-09-22 2015-09-15 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US7960396B2 (en) 2006-09-22 2011-06-14 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US9133202B2 (en) 2006-09-22 2015-09-15 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US9266893B2 (en) 2006-09-22 2016-02-23 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9133198B2 (en) 2006-09-22 2015-09-15 Pharmacyclics Llc Inhibitors of bruton'S tyrosine kinase
US8952015B2 (en) 2006-09-22 2015-02-10 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8476284B2 (en) 2006-09-22 2013-07-02 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US9127012B2 (en) 2006-09-22 2015-09-08 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8754091B2 (en) 2006-09-22 2014-06-17 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8748438B2 (en) 2006-09-22 2014-06-10 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8497277B2 (en) 2006-09-22 2013-07-30 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8501751B2 (en) 2006-09-22 2013-08-06 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8748439B2 (en) 2006-09-22 2014-06-10 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8552010B2 (en) 2006-09-22 2013-10-08 Pharmacyclics, Inc. Inhibitors of Bruton'S tyrosine kinase
US8741908B2 (en) 2006-09-22 2014-06-03 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8563563B2 (en) 2006-09-22 2013-10-22 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8735403B2 (en) 2006-09-22 2014-05-27 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US7514444B2 (en) 2006-09-22 2009-04-07 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8975266B2 (en) 2006-09-22 2015-03-10 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US7825118B2 (en) 2006-09-22 2010-11-02 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US8735404B2 (en) 2006-09-22 2014-05-27 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US9193735B2 (en) 2006-09-22 2015-11-24 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US8703780B2 (en) 2006-09-22 2014-04-22 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8658653B2 (en) 2006-09-22 2014-02-25 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8691546B2 (en) 2006-09-22 2014-04-08 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US8697711B2 (en) 2006-09-22 2014-04-15 Pharmacyclics, Inc. Inhibitors of bruton'S tyrosine kinase
US9556182B2 (en) 2007-03-28 2017-01-31 Pharmacylics LLC Inhibitors of Bruton's tyrosine kinase
US8809273B2 (en) 2007-03-28 2014-08-19 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase
US9181263B2 (en) 2007-03-28 2015-11-10 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
US9139591B2 (en) 2007-03-28 2015-09-22 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
US8940750B2 (en) 2007-03-28 2015-01-27 Pharmacyclics, Inc. Inhibitors of bruton's tyrosine kinase
US9079908B2 (en) 2007-03-28 2015-07-14 Pharmacyclics, Inc. Inhibitors of Bruton'S tyrosine kinase
US9359349B2 (en) 2007-10-04 2016-06-07 Intellikine Llc Substituted quinazolines as kinase inhibitors
US9655892B2 (en) 2008-01-04 2017-05-23 Intellikine Llc Certain chemical entities, compositions and methods
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
US11433065B2 (en) 2008-01-04 2022-09-06 Intellikine Llc Certain chemical entities, compositions and methods
US8785456B2 (en) 2008-01-04 2014-07-22 Intellikine Llc Substituted isoquinolin-1(2H)-ones, and methods of use thereof
US8703777B2 (en) 2008-01-04 2014-04-22 Intellikine Llc Certain chemical entities, compositions and methods
US9216982B2 (en) 2008-01-04 2015-12-22 Intellikine Llc Certain chemical entities, compositions and methods
WO2009098715A2 (fr) 2008-01-11 2009-08-13 Natco Pharma Limited Nouveaux dérivés de pyrazolo [3, 4 -d] pyrimidine en tant qu’agents anticancéreux
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US9637492B2 (en) 2008-03-14 2017-05-02 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US8481733B2 (en) 2008-05-19 2013-07-09 OSI Pharmaceuticals, LLC Substituted imidazopyr- and imidazotri-azines
US9828378B2 (en) 2008-07-08 2017-11-28 Intellikine Llc Kinase inhibitors and methods of use
US9629843B2 (en) 2008-07-08 2017-04-25 The Regents Of The University Of California MTOR modulators and uses thereof
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US9107924B2 (en) 2008-07-16 2015-08-18 Pharmacyclics, Inc. Inhibitors of Bruton'S tyrosine kinase for the treatment of solid tumors
US9278100B2 (en) 2008-07-16 2016-03-08 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors
US9795605B2 (en) 2008-07-16 2017-10-24 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase for the treatment of solid tumors
US8883803B2 (en) 2008-07-16 2014-11-11 Pharmacyclics, Inc. Inhibitors of Bruton's tyrosine kinase for the treatment of solid tumors
US8133899B2 (en) 2008-08-20 2012-03-13 Pfizer Inc. Pyrrolo[2,3-d]pyrimidine compounds
US9161939B2 (en) 2008-08-20 2015-10-20 Zoetis Services Llc Pyrrolo[2,3-d]pyrimidine compounds
US9271981B2 (en) 2008-08-20 2016-03-01 Zoetis Services Llc Pyrrolo[2,3-D]pyrimidine compounds
US8987283B2 (en) 2008-08-20 2015-03-24 Zoetis Llc Pyrrolo[2,3-D]pyrimidine compounds
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
US9790228B2 (en) 2008-09-26 2017-10-17 Intellikine Llc Heterocyclic kinase inhibitors
US9296742B2 (en) 2008-09-26 2016-03-29 Intellikine Llc Heterocyclic kinase inhibitors
US8697709B2 (en) 2008-10-16 2014-04-15 The Regents Of The University Of California Fused ring heteroaryl kinase inhibitors
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
WO2010099139A2 (fr) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Thérapie anti-cancer combinée
WO2010099137A2 (fr) 2009-02-26 2010-09-02 Osi Pharmaceuticals, Inc. Procédés in situ pour surveiller l'état emt de cellules tumorales in vivo
WO2010099138A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Procédés pour l'identification d'agents qui inhibent les cellules tumorales de type mésenchymateuses ou leur formation
WO2010099364A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
WO2010099363A1 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Méthodes d'identification d'agents qui inhibent les cellules cancéreuses mésenchymateuses ou leur formation
US8513415B2 (en) 2009-04-20 2013-08-20 OSI Pharmaceuticals, LLC Preparation of C-pyrazine-methylamines
US8785454B2 (en) 2009-05-07 2014-07-22 Intellikine Llc Heterocyclic compounds and uses thereof
US9315505B2 (en) 2009-05-07 2016-04-19 Intellikine Llc Heterocyclic compounds and uses thereof
US8569323B2 (en) 2009-07-15 2013-10-29 Intellikine, Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9522146B2 (en) 2009-07-15 2016-12-20 Intellikine Llc Substituted Isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
WO2011029915A1 (fr) 2009-09-10 2011-03-17 Novartis Ag Dérivés éthers d'hétéroaryles bicycliques
US8980899B2 (en) 2009-10-16 2015-03-17 The Regents Of The University Of California Methods of inhibiting Ire1
WO2011064211A1 (fr) 2009-11-25 2011-06-03 Novartis Ag Dérivés hétérocycliques d'hétéroaryles bicycliques à 6 cycles benzéniques accolés de benzène contenant de l'oxygène
WO2011109572A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011109584A2 (fr) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de kinase du récepteur du facteur de croissance insulinique 1
WO2011112666A1 (fr) 2010-03-09 2011-09-15 OSI Pharmaceuticals, LLC Thérapie anticancéreuse combinatoire
US8604032B2 (en) 2010-05-21 2013-12-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US9181221B2 (en) 2010-05-21 2015-11-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US9738644B2 (en) 2010-05-21 2017-08-22 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US9125889B2 (en) 2010-06-03 2015-09-08 Pharmacyclics, Inc. Use of inhibitors of Bruton's tyrosine kinase (Btk)
US9801883B2 (en) 2010-06-03 2017-10-31 Pharmacyclics Llc Use of inhibitors of bruton's tyrosine kinase (Btk)
US11672803B2 (en) 2010-06-03 2023-06-13 Pharmacyclics Llc Use of inhibitors of Brutons tyrosine kinase (Btk)
US10751342B2 (en) 2010-06-03 2020-08-25 Pharmacyclics Llc Use of inhibitors of Bruton's tyrosine kinase (Btk)
US10653696B2 (en) 2010-06-03 2020-05-19 Pharmacyclics Llc Use of inhibitors of bruton's tyrosine kinase (BTK)
US10478439B2 (en) 2010-06-03 2019-11-19 Pharmacyclics Llc Use of inhibitors of bruton's tyrosine kinase (Btk)
US10004746B2 (en) 2010-06-03 2018-06-26 Pharmacyclics Llc Use of inhibitors of Bruton's tyrosine kinase (Btk)
US10004745B2 (en) 2010-06-03 2018-06-26 Pharmacyclics Llc Use of inhibitors of Bruton'S tyrosine kinase (Btk)
US9801881B2 (en) 2010-06-03 2017-10-31 Pharmacyclics Llc Use of inhibitors of bruton's tyrosine kinase (BTK)
US8999999B2 (en) 2010-06-03 2015-04-07 Pharmacyclics, Inc. Use of inhibitors of Bruton's tyrosine kinase (Btk)
US8754090B2 (en) 2010-06-03 2014-06-17 Pharmacyclics, Inc. Use of inhibitors of bruton's tyrosine kinase (Btk)
US9814721B2 (en) 2010-06-03 2017-11-14 Pharmacyclics Llc Use of inhibitors of bruton'S tyrosine kinase (BTK)
US10016435B2 (en) 2010-06-03 2018-07-10 Pharmacyclics Llc Use of inhibitors of Bruton's tyrosine kinase (Btk)
WO2011157793A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle
WO2011157787A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution biphényle
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9388183B2 (en) 2010-11-10 2016-07-12 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10550122B2 (en) 2011-01-10 2020-02-04 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof
USRE46621E1 (en) 2011-01-10 2017-12-05 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US9840505B2 (en) 2011-01-10 2017-12-12 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof
US11312718B2 (en) 2011-01-10 2022-04-26 Infinity Pharmaceuticals, Inc. Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
US9290497B2 (en) 2011-01-10 2016-03-22 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
WO2012116040A1 (fr) 2011-02-22 2012-08-30 OSI Pharmaceuticals, LLC Marqueurs biologiques prédictifs d'une réponse anticancéreuse aux inhibiteurs de la kinase du récepteur du facteur de croissance 1 analogue à l'insuline dans le carcinome hépatocellulaire
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
WO2012120469A1 (fr) 2011-03-08 2012-09-13 Novartis Ag Composés hétéroaryliques bicycliques de type fluorophényle
CN103492390A (zh) * 2011-03-08 2014-01-01 诺瓦提斯公司 氟苯基双环杂芳基化合物
EP3597761A1 (fr) 2011-03-09 2020-01-22 Richard G. Pestell Lignées de cellules du cancer de la prostate, signatures géniques et leurs utilisations
WO2012122499A2 (fr) 2011-03-09 2012-09-13 Pestell Richard G Lignées de cellules du cancer de la prostate, signatures géniques et leurs utilisations
US10952415B2 (en) 2011-03-09 2021-03-23 Richard G. Pestell Prostate cancer cell lines, gene signatures and uses thereof
WO2012149014A1 (fr) 2011-04-25 2012-11-01 OSI Pharmaceuticals, LLC Utilisation de signatures de gènes de tem dans la découverte de médicaments contre le cancer, diagnostics et traitement du cancer
US9862722B2 (en) 2011-07-13 2018-01-09 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US9605003B2 (en) 2011-07-19 2017-03-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8969363B2 (en) 2011-07-19 2015-03-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9718815B2 (en) 2011-07-19 2017-08-01 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9115141B2 (en) 2011-08-29 2015-08-25 Infinity Pharmaceuticals, Inc. Substituted isoquinolinones and methods of treatment thereof
US8785470B2 (en) 2011-08-29 2014-07-22 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9546180B2 (en) 2011-08-29 2017-01-17 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9895373B2 (en) 2011-09-02 2018-02-20 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9321772B2 (en) 2011-09-02 2016-04-26 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9273051B2 (en) 2011-12-30 2016-03-01 Pharmacyclics Llc Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
US9546172B2 (en) 2011-12-30 2017-01-17 Pharmacyclics Llc Pyrazolo[3,4-d]pyrimidine and pyrazolo[2,3-d]pyrimidine compounds as kinase inhibitors
US8377946B1 (en) 2011-12-30 2013-02-19 Pharmacyclics, Inc. Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
WO2013152252A1 (fr) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Polythérapie antinéoplasique
US9255108B2 (en) 2012-04-10 2016-02-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9453836B2 (en) 2012-05-14 2016-09-27 Richard G. Pestell Use of modulators of CCR5 in the treatment of cancer and cancer metastasis
US11633397B2 (en) 2012-05-14 2023-04-25 Richard G. Pestell Use of modulators of CCR5 in the treatment of cancer and cancer metastasis
US9713617B2 (en) 2012-06-04 2017-07-25 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10106548B2 (en) 2012-06-04 2018-10-23 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10294231B2 (en) 2012-06-04 2019-05-21 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10294232B2 (en) 2012-06-04 2019-05-21 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US9828383B1 (en) 2012-06-04 2017-11-28 Pharmacyclic s LLC Crystalline forms of a bruton's tyrosine kinase inhibitor
US9296753B2 (en) 2012-06-04 2016-03-29 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10125140B1 (en) 2012-06-04 2018-11-13 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
US10266540B2 (en) 2012-06-04 2019-04-23 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10065968B2 (en) 2012-06-04 2018-09-04 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
US10961251B1 (en) 2012-06-04 2021-03-30 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US9540382B2 (en) 2012-06-04 2017-01-10 Pharmacyclics Llc Crystalline forms of a Bruton's tyrosine kinase inhibitor
US10752634B2 (en) 2012-06-04 2020-08-25 Pharmacyclics Llc Crystalline forms of a brutons tyrosine kinase inhibitor
US9725455B1 (en) 2012-06-04 2017-08-08 Pharmacyclics Llc Crystalline forms of a bruton's tyrosine kinase inhibitor
US9527847B2 (en) 2012-06-25 2016-12-27 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US10954567B2 (en) 2012-07-24 2021-03-23 Pharmacyclics Llc Mutations associated with resistance to inhibitors of Bruton's Tyrosine Kinase (BTK)
US10822340B2 (en) 2012-09-26 2020-11-03 The Regents Of The University Of California Substituted imidazolopyrazine compounds and methods of using same
US11613544B2 (en) 2012-09-26 2023-03-28 The Regents Of The University Of California Substituted imidazo[1,5-a]pyrazines for modulation of IRE1
US10131668B2 (en) 2012-09-26 2018-11-20 The Regents Of The University Of California Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US9540385B2 (en) 2012-11-15 2017-01-10 Pharmacyclics Llc Pyrrolopyrimidine compounds as kinase inhibitors
US9096604B2 (en) 2012-11-15 2015-08-04 Pharmacyclics, Inc. Pyrrolopyrimidine compounds as kinase inhibitors
US9834575B2 (en) 2013-02-26 2017-12-05 Triact Therapeutics, Inc. Cancer therapy
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US9421208B2 (en) 2013-08-02 2016-08-23 Pharmacyclics Llc Methods for the treatment of solid tumors
US10016434B2 (en) 2013-08-12 2018-07-10 Pharmacyclics Llc Methods for the treatment of HER2 amplified cancer
US9415050B2 (en) 2013-08-12 2016-08-16 Pharmacyclics Llc Methods for the treatment of HER2 amplified cancer
US9724349B2 (en) 2013-08-12 2017-08-08 Pharmacyclics Llc Methods for the treatment of HER2 amplified cancer
US9381246B2 (en) 2013-09-09 2016-07-05 Triact Therapeutics, Inc. Cancer therapy
US9624224B2 (en) 2013-09-30 2017-04-18 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US12152032B2 (en) 2013-10-04 2024-11-26 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10329299B2 (en) 2013-10-04 2019-06-25 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9828377B2 (en) 2013-10-04 2017-11-28 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9359365B2 (en) 2013-10-04 2016-06-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10695350B2 (en) 2013-10-25 2020-06-30 Pharmacyclics Llc Methods of treating and preventing graft versus host disease
US10463668B2 (en) 2013-10-25 2019-11-05 Pharmacyclics Llc Methods of treating and preventing graft versus host disease
US10675286B2 (en) 2014-03-19 2020-06-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US11541059B2 (en) 2014-03-19 2023-01-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9775844B2 (en) 2014-03-19 2017-10-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9885086B2 (en) 2014-03-20 2018-02-06 Pharmacyclics Llc Phospholipase C gamma 2 and resistance associated mutations
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11944631B2 (en) 2014-04-16 2024-04-02 Infinity Pharmaceuticals, Inc. Combination therapies
WO2016016894A1 (fr) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Milieux pour la culture de cellules souches pluripotentes
US9533991B2 (en) 2014-08-01 2017-01-03 Pharmacyclics Llc Inhibitors of Bruton's tyrosine kinase
US20180028537A1 (en) 2014-08-07 2018-02-01 Pharmacyclics Llc Novel Formulations of a Bruton's Tyrosine Kinase Inhibitor
US9545407B2 (en) 2014-08-07 2017-01-17 Pharmacyclics Llc Formulations of a bruton's tyrosine kinase inhibitor
US10941162B2 (en) 2014-10-03 2021-03-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10253047B2 (en) 2014-10-03 2019-04-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
US10828259B2 (en) 2015-03-03 2020-11-10 Pharmacyclics Llc Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
US10213386B2 (en) 2015-03-03 2019-02-26 Pharmacyclics Llc Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
US9655857B2 (en) 2015-03-03 2017-05-23 Pharmacyclics Llc Pharmaceutical formulations of a Bruton's tyrosine kinase inhibitor
US10010507B1 (en) 2015-03-03 2018-07-03 Pharmacyclics Llc Pharmaceutical formulations of a bruton's tyrosine kinase inhibitor
US11247995B2 (en) 2015-09-14 2022-02-15 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US10160761B2 (en) 2015-09-14 2018-12-25 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US11939333B2 (en) 2015-09-14 2024-03-26 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US12384792B2 (en) 2015-09-14 2025-08-12 Twelve Therapeutics, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
US10759806B2 (en) 2016-03-17 2020-09-01 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
US10919914B2 (en) 2016-06-08 2021-02-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US11602534B2 (en) 2017-12-21 2023-03-14 Hefei Institutes Of Physical Science, Chinese Academy Of Sciences Pyrimidine derivative kinase inhibitors
WO2019119486A1 (fr) 2017-12-21 2019-06-27 中国科学院合肥物质科学研究院 Classe d'inhibiteurs de kinase dérivés de pyrimidine
WO2020152686A1 (fr) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Milieux de culture pour cellules souches pluripotentes
US12202834B2 (en) 2019-01-29 2025-01-21 Vationpharma B.V. Solid state forms of oclacitinib maleate
WO2021097256A1 (fr) 2019-11-14 2021-05-20 Cohbar, Inc. Peptides antagonistes de cxcr4

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