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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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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phenyl
lower alkyl
amino
formula
compound
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PCT/EP1997/000350
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English (en)
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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).

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