WO1997049706A1 - 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES - Google Patents

7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES Download PDF

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WO1997049706A1
WO1997049706A1 PCT/EP1997/003115 EP9703115W WO9749706A1 WO 1997049706 A1 WO1997049706 A1 WO 1997049706A1 EP 9703115 W EP9703115 W EP 9703115W WO 9749706 A1 WO9749706 A1 WO 9749706A1
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pyrrolo
phenyl
unsubstituted
substituted
pyrimidin
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PCT/EP1997/003115
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English (en)
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Eva Altmann
Martin Missbach
Leo Widler
Jürgen Klaus MAIBAUM
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Novartis Ag
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Priority to AU31762/97A priority Critical patent/AU3176297A/en
Publication of WO1997049706A1 publication Critical patent/WO1997049706A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds of formula I
  • R is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl or cyclo-lower hydrocarbyl-lower alkyl, unsubstituted or substituted aryl or aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl or hetero-lower cyclyl-lower alkyl;
  • R 2 is hydrogen, lower alkyl or halogen
  • R 3 is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl or cyclo-lower hydrocarbyl-lower alkyl, unsubstituted or substituted aryl or aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl or hetero-lower cyclyl-lower alkyl; and salts thereof.
  • lower denotes a radical having up to and including 7, and especially up to and including 6, carbon atoms.
  • Lower alkyl is, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ferf-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl or methyl.
  • Alkyl is straight-chain or branched.
  • lower alkyl On its own, for example lower alkyl, or as a constituent of other groups, for example lower alkoxy, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl, it may be unsubstituted or mono- or poly- substituted, for example by halogen, hydroxy, lower alkoxy, t ⁇ fluoromethyl or by imidazolyl, and is preferably unsubstituted or substituted by halogen, hydroxy, lower alkoxy, ammo, N- lower alkylamino or by N,N-d ⁇ -lower alkylamino.
  • hetero-substituted alkyl the carbon chain is interrupted by one or more, identical or different hetero atoms, for example by oxygen, sulfur or S(O 2 ), especially oxygen
  • Cyclo-lower hydrocarbyl denotes saturated or mono- or poly-unsaturated carbocyciic rings, preferably having from 3 up to and including 7 ring members, especially 5 or 6 ring mem ⁇ bers, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl.
  • Cyclo-lower hydrocarbyl-lower alkyl is, for example, cyclopentylmethyl, cyclopentenylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexenylethyl
  • Cyclo-lower hydrocarbyl and cyclo-lower hydrocarbyl- lower alkyl may be unsubstituted or mono- or poly-substituted, for example by hydroxy, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkoxy, halo-lower alkyl, halo- lower alkoxy, lower alkoxy-lower alkoxy, ammo-lower alkyl, ammo-lower alkoxy, lower alkylamino-lower alkyl, lower alkylamino-lower alkoxy, N,N-d ⁇ -lower alkylamino-lower alkyl,
  • 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 substituted by one or more, for example from one to three, especially one or two, substi ⁇ tuents from the group consisting of hydroxy, lower alkyl, halo-lower alkyl, (hydroxy or lower alkanoyloxy)-lower alkyl, lower alkoxy-lower alkyl, (hydroxy, lower alkoxy or lower alkanoyl- oxy)-lower alkoxy-lower alkyl, (ammo, lower alkylamino, di-lower alkylamino or lower alkanoylam ⁇ no)-lower alkoxy-lower alkyl, (ammo or lower aikanoylam ⁇ no)-lower alkyl, lower alkylamino-lower al
  • 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.
  • Halogen is, for example, chlorine, bromine or fluorine, but may also be iodine.
  • Hetero-lower cyclyl is a saturated, mono- or poly-unsaturated or aromatic radical having from 3 up to and including 7 ring atoms, especially from 3 up to and including 6 ring atoms, wherein at least one of the ring atoms is a hetero atom, preferably nitrogen, oxygen or sulfur.
  • a hetero atom preferably nitrogen, oxygen or sulfur.
  • aza-lower cycloalkyl and aza-heteroaryl that is to say hetero-lower cyclyl radicals that contain at least one nitrogen ring atom.
  • the hetero atoms may be identical or different; one ring hetero atom is preferred.
  • Hetero-lower cyclyl is, for example, piperidmyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, tetrahydrofuran, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyranyl, thiopyranyl, pyridyl, pyrrolyl or tetrazolyl.
  • the compounds I and their salts may be in the form of one of the possible isomers, for example stereoisomers, diastereoisomers or tautomers, or in the form of a mixture thereof.
  • isomers for example, pure enantiomers, pure diastereo- isomers or, where appropriate, pure tautomers.
  • isomeric mixtures may be in the form of, for example, racemates or diastereoisomeric mixtures.
  • 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 carboxylic 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 phosphoric
  • 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, morpholine, thiomorpholine, piperidine or pyrrolidine.
  • Suitable mono-lower alkylamines are, for example, ethyl- and tert- 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; hydroxy-lower alkyl-lower alkyl-amines are, for example, N,N-dimethylamino- and N,N-diethylamino- 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 internal salt and another part in the form of a normal salt.
  • Pharmaceutically unacceptable salts are also included, since they can be used, for example, for the isolation and/or purification of free compounds I and the pharmaceutically acceptable salts thereof.
  • the compounds 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 ⁇ M [test description: K. Farley et al., Anal. Biochem. 203 (1992) 151-157; purified enzyme - as described in N. B. Lydon er a/., Biochem. J. 287 (1992) 985-
  • 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 absorption 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 In that test, 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 ovanectomy in rats [the "Hock model" is described, for example, in Metab. Bone
  • 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 .
  • the com ⁇ pounds of formula I are useful in the treatment of benign or malignant tumours that are responsive to inhibition of tyrosine protein kinase pp60 c"src , such as breast cancer (mammary carcinoma) or intestinal cancer (colon carcinoma). They are capable of effecting tumour regression and of preventing the formation of tumour metastases and the growth of micrometastases.
  • the compounds of formula I are also useful in the treatment of cardio ⁇ vascular disorders, such as thrombosis.
  • the compounds of formula I also inhibit the activity of other non-receptor tyrosine protein kmases, 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 kmases, 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-1 , Kit, VEGF and FGF.
  • other non-receptor tyrosine protein kmases 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 protein kmases,
  • 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)prol ⁇ ferat ⁇ ve diseases, such as psoriasis, tumours, carcinomas and leukaemias, 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 preferably to compounds of formula I wherein
  • R is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl;
  • R 2 is hydrogen, lower alkyl or halogen
  • R 3 is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, unsubstituted or substituted aryl or aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl; and salts thereof
  • the invention relates especially to compounds of formula I wherein
  • R is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl;
  • R 2 is hydrogen, lower alkyl or halogen
  • R 3 is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, or unsubstituted or substituted aryl; and salts thereof.
  • the invention relates more especially to compounds of formula I wherein
  • R is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl;
  • R 2 is hydrogen
  • R 3 is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, or unsubstituted or substituted aryl; and salts thereof.
  • the invention relates most especially to compounds of formula I wherein
  • Ri is unsubstituted or substituted lower alkyl or hetero-substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, unsubstituted or substituted aryl, unsubstituted or substituted aryl-lower alkyl, or unsubstituted or substituted hetero-lower cyclyl;
  • R 2 is hydrogen
  • R 3 is unsubstituted or substituted lower alkyl, unsubstituted or substituted cyclo-lower hydrocarbyl, or unsubstituted or substituted aryl; and pharmaceutically acceptable salts thereof.
  • the invention relates especially to the specific compounds described in the Examples and to salts thereof.
  • the compounds of formula I can be prepared in a manner known perse, for example by a) subjecting a compound of formula II wherein
  • R,, R 2 and R 3 are as defined above, and R 4 is lower alkyl, to a ring-closure reaction, with the formation of the pyrimidine ring, to give a compound of formula III
  • R 1 t R 2 and R 3 are as defined above, to a ring-closure reaction with the formation of the pyrimidine ring; or
  • R 2 and R 3 are as defined above, with a compound of formula VI wherein Ri is as defined above and X is a leaving group;
  • Suitable cyclisation reagents are the sequence 1. N,N-di-lower alkylformamide di-lower alkyl acetal and 2. ammonia.
  • Preferred N,N-di-lower alkylformamide di-lower alkyl acetals are di-lower alkyl acetals of N,N-dimethylformamide, especially N,N-di-lower alkylformamide dineopentyl acetal.
  • the reaction of compounds of formula II is preferably effected at elevated tempera ⁇ tures, for example at the reflux temperature of the reaction mixture.
  • the reaction can be carried out with or without solvent, but preferably takes place in an aprotic solvent or solvent mixture.
  • the resulting dialkylamino-methyleneaminoalkoxycarbonyl-pyrroles are then cyclised with ammonia to form a compound of formula III.
  • the latter reaction is preferably effected in a polar solvent or solvent mixture in a bomb tube at ambient temperature or slightly elevated temperature whereby also one of the reactants may serve as solvent or component of a solvent mixture.
  • the 4-oxo group can then be replaced in a manner known per se by halogen, especially chlorine, by reaction with a phosphorus oxytrihalide, prefer ⁇ ably phosphorus oxytrichloride.
  • the reaction can be carried out with or without solvent, but preferably takes place without solvent at distinctly elevated temperature, for example at 100°C to 120°C.
  • the 4-halide can be replaced by -NH 2 by treating the reaction product with ammonia. That reaction is generally carried out at relatively high temperatures, for example at 130°C in an autoclave.
  • the compounds of formula II are preferably prepared using one of the known methods of pyrrole synthesis. They are obtained, for example, by cyclising a compound of formula I la
  • a base for example sodium ethanolate/ethanol.
  • Process (b) corresponds to the cyclisation known perse of 2-am ⁇ no-3-cyano-pyrroles to 4-am ⁇ no-pyrrolo[2,3-d]pyr ⁇ m ⁇ d ⁇ nes.
  • Suitable cyclisa ⁇ tion reagents are, for example, (1) formamide or (2) 1. trialkyi orthoformate/2. ammonia.
  • the cyclisation of compounds of formula IV with formamide is preferably carried out at elevated temperature, for example at 160°C, and advantageously with the addition of a small amount of dimethylformamide and formic acid.
  • the reaction of compounds of formula IV with trialkyi orthoformate to give the corresponding alkoxy formimidates formed as intermediates norm ⁇ ally takes place at less elevated temperatures, for example at from 80 to 140°C
  • the reac ⁇ tion of the latter with ammonia can then be carried out generally at relatively low tempera ⁇ tures, for example at ambient temperature.
  • the cyclisation then takes place preferably with base catalysis, especially using sodium ethanolate/ethanol, once again at elevated tem ⁇ perature, for example at the reflux temperature of the reaction mixture.
  • Suitable leaving groups are, for example, methanesulfonates or p-toluenesulf- onates of hydroxy compounds and halogen.
  • the preparation of suitable pyrrolo[3,2-d]- py ⁇ midmes of formula V is known from the literature or can be carried out analogously to the methods described in the literature.
  • the reaction of compounds of formula V with compounds of formula VI is carried out in a manner known per se. For example, a methane- sulfonate of formula VI is reacted with a pyrrolo[3,2-d]pyr ⁇ m ⁇ d ⁇ ne of formula V in the presence of a base, for example potassium carbonate.
  • the reaction is preferably carried out at elevated temperature, for example at from 50°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 V and VI 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.
  • halo-lower alkyl e.g. chloromethyl
  • halo-lower alkyl e.g. chloromethyl
  • Hydroxy can be reacted, for example, with unsubstituted or substituted halo-lower alkanes, yielding unsubstituted or substituted lower alkoxy. Hydroxy can, for example, also be reacted first with a di-halo-lower alkane, for example 1 -bromo-2-chloroethane, yielding ⁇ -halo-lower alkoxy; the latter can be reacted in a manner analogous to that described above with unsubstituted or substititued lower alkanols, lower alkanethiols or lower alkyl ⁇ amines 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.
  • a di-halo-lower alkane for example 1 -bromo-2-chloroethan
  • mercapto can also be alkylated as described in the preceding paragraph.
  • Lower alkylthio groups can be converted by controlled 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 alkanoylar ⁇ ino and lower alkanoyloxy groups, respectively.
  • Carboxylic acid radicals can be converted in accordance with known derivatisation methods, such as esterification or amide formation, into carboxylic acid derivatives, such as lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di-lower alkylamino ⁇ carbonyl, cyano or amidino.
  • carboxylic acid derivatives can also be converted into free carboxylic acids, for example by hydrolysis.
  • hydroxy groups can be esterified with organic or inorganic acids or etherified with alcohols or organic halides or they can be removed by reduction.
  • any of the intermediates contain troublesome reactive groups, for example carboxy, hydroxy, mercapto or amino groups, those groups can be protected temporarily by readily removable protecting groups.
  • suitable protecting groups their introduction and their removal are known perse and are described, for example, in J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London, New York 1973 and, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York et al., 1991 , or also in PJ. Kocienski, Protecting Groups, Thieme, Stuttgart, New York 1994.
  • Salts of compounds I can be prepared in a manner known per se.
  • acid addition salts of compounds I are obtained by treatment with a suitable acid or a suitable ion exchange reagent and salts with bases by treatment with a suitable base or a suitable ion exchange 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 per se into other salts of compounds 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 suitable 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 chloride, is insoluble and thus precipitates from the reaction mixture.
  • a salt of an inorganic acid such as a hydrochloride
  • a suitable metal salt such as a sodium, barium or silver salt
  • 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 approp ⁇ ate 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
  • isome ⁇ c mixtures may be in the form of, for example, diastereoisomenc mixtures.
  • Isome ⁇ c 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 manner, for example on the basis of the physico-chemical differences between the con ⁇ stituents in known manner by fractional crystallisation, distillation and/or chromatography
  • 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 materiai and the remaining steps are carried out or a starting material is used in the form of a derivative or salt or, especially, is formed under the reaction conditions.
  • 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 preparation.
  • 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 pharmacological active ingredient on its own or together with customary pharmaceutical excipients.
  • the pharmaceutical compositions comprise (in percent by weight) for example from approximately 0.001 % to 100 %, preferably from approximately 0.1 % to approxi ⁇ mately 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 ampoules. They are prepared in a manner known perse, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising procedures.
  • pharmaceutical compositions for oral administration can be obtained by combining the active 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 dragee cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methyl- cellulose and/or polyvinylpyrrolidone, and, 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 tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes using, for example, corn
  • Excipients are especially flow conditioners and lubricants, 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, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • compositions are hard gelatin capsules, and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the hard gelatin 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 rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material.
  • Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal 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 sesame oil, or synthetic fatty acid esters, for example ethyl ol ⁇ ate or triglycerides
  • 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 tinctures having an aqueous-ethanolic base and may comprise other customary pharma ⁇ ceutical excipients, such as preservatives.
  • the pharmaceutical compositions for local administration are prepared in a manner known per se by mixing the active ingredient with the pharmaceutical excipients, for example by dissolving or suspending the active ingred ⁇ ient in the base or in a portion thereof, if necessary.
  • the active ingredient is normally dissolved therein prior to emulsification; in order to prepare suspensions in which the active ingredient 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.
  • the following Examples are intended to illustrate the invention described hereinbefore, but without limiting the invention thereto.
  • M.p.: melting point
  • CDCI 3 deuterochloroform
  • DMSO-d 6 hexadeuterodimethyl sulfoxide
  • CD 3 OD deuteromethanol
  • C 2 D 2 CI 4 deuterotetrachloroethane
  • Example 1 5-lsopropyl-7-phenyl-5H-pyrrolof3.2-d]pyrimidin-4-ylamine 0.252 g of 4-chloro-5-isopropyl-7-phenyl-5H-pyrrolo[3,2-d]pyrimidine is stirred in a bomb tube with 15 ml of ammonia at 130°C for 24 hours. The ammonia is evaporated off and the residue is purified by flash chromatography (methylene chloride/methanol 10:0.4). M.p.: 96-98°C.
  • Example 3 5-(2-Methoxy-ethoxymethyl)-7-phenyl-5H-Pyrrolof3.2-d]pyrimidin-4-ylamine M.p.: 161 -162°C.
  • Example 4 5-f2-(2-Methoxy-ethoxy)-ethyl1-7-phenyl-5H-pyrrolof3.2-dlpyrimidin-4-ylamine M.p.: 150-151 °C. 'H-NMR (CDCI 3 , ppm): 8.5 (s, 1H), 8.05 (m, 2H), 7.45 (m, 3H), 7.2 (s, 1H), 5.8 (s, 2H), 4.55 (t, 2H), 3.95 (t, 2H), 3.62 (m, 2H), 3.48 (m, 2H), 3.3 (s, 3H).
  • f(3-Nitrilo-2-phenyl-propenyl)-phenyl-aminol-acetic acid ethyl ester 4.48 g of phenyl- ammo-acetic acid ethyl ester, 3.60 g of ⁇ -formyl-phenylacetonitrile and 0.100 g of toluenesulfonic acid are dissolved in 200 ml of toluene and stirred under reflux using a water separator for 1.5 hours. The reaction mixture is cooled to room temperature and concentrated by evaporation using a rotary evaporator, and the residue is dried under a high vacuum.
  • Phenylammo-acetic acid ethyl ester (CAS Re ⁇ .No.: 2216-92-4] ⁇ s prepared according to W.K. Anderson et al., J. Med. Chem. 1989, 32, page 1 19.
  • Example 7 The following Examples are prepared analogously to Example 7 using the variously substituted phenylaminoacetic acid ethyl ester or benzylaminoacetic acid ethyl ester and the appropriate ⁇ -formyl-acetonitrile derivative as starting materials.
  • Example 12 3-(4-Amino-7-phenyl-pyrrolof3.2-d1pyrimidin-5-yl)-phenol
  • Example 13 7-[4-(2-Benzyloxy-ethoxy)-phenyl1-5-phenyl-5H-pyrrolo[3.2-d1pyrimidin-4- ylamine
  • Example 14 2-f4-(4-Amino-5-phenyl-5H-Pyrrolor3.2-dlpyrimidin-7-y ⁇ -phenoxyl-ethanol ⁇ -NMR (DMSO-d 6 , ppm): 8.32 (s, 1H), 8.15 (m, 3H), 7.60 (m, 6H), 7.0 (d, 2H), 6.8 (s, 2H), 4.89 (t, 1 H), 4.0 (t, 2H), 3.72 (m, 2H). M.p.: 190-192°C.
  • the oily residue is pre-purified by flash chromatography (hexane/ethyl acetate 10:1). Unreacted N-(3-methoxy- phenyl)glycine ethyl ester is then substantially removed from the resulting crude product by bulb tube distillation (170-180°C/0.06 mbar). The crude title compound is obtained in the form of a coloured oil.
  • Example 17 7-Cvclohexyl-5-(3-methoxy-phenvO-5H-pyrrolof3.2-d]pyrimidin-4-ylamine
  • a solution of 0.22 g of 7-cyclohex-1-enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4- ylamine in 10 ml of methanol is hydrogenated in the presence of 0.025 g of Pd/C (10 %) at room temperature under normal pressure for 3 days.
  • the reaction mixture is filtered over Celite 545 and the crude product obtained after concentration of the filtrate is purified by flash chromatography (methylene chloride/methanol 97:3).
  • 0.27 ml of boron tribromide is added in portions in the course of 15 minutes at 0-5°C to a solution of 0.30 g of 7-cyclohex-1-enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyr ⁇ m ⁇ din-4- ylamine in 10 ml of methylene chloride and, after 2.5 hours, a further 0.27 ml of boron tribromide is added. Stirring is then carried out for a further hour, 1.5 ml of water are then added dropwise and the mixture is stirred at 0-5°C for 30 minutes.
  • the crude product obtained after customary working-up is purified by flash chromatography (methylene chlonde/methanol 95:5).
  • Example 19 5-Phenyl-7-(pyr ⁇ d ⁇ n-3-yl)-5H-pyrrolo[3.2-dlpyr ⁇ mid ⁇ n-4-ylam ⁇ ne
  • a solution of 0.25 g of 5-phenyl-7-(pyridin-3-yl)-5/-/-pyrrolo[3,2-d]pyr ⁇ m ⁇ d ⁇ n-4-ol in 2 ml of phosphoryl chloride is stirred at 120°C for 2 hours.
  • the reaction mixture is concentrated using a rotary evaporator and the residue is dried under a high vacuum.
  • the crude product so obtained is stirred in 15 ml of liquid ammonia at 130°C in an autoclave for 24 hours.
  • Example 21 3-(4-Am ⁇ no-7-r4-(2- ⁇ m ⁇ dazol-1-yl-ethoxy)-phenyll-pyrrolo[3.2-d]pyrimidin-5-yll- phenol
  • Example 22 7-f4-(2-lmidazol-1 -yl-ethoxy)-phenvn-5-(4-methoxy-phenvh-5H-Pyrrolof3.2-dl- pyrimidin-4-ylamine
  • Example 27 7-[4-(2-Amino-ethoxy)-Phenyl1-5-(4-methoxy-phenyl,-5/-/-pyrrolof3.2-dlpyr ⁇ m ⁇ - d ⁇ n-4-ylam ⁇ ne
  • Example 28 7-[4-(2-Am ⁇ no-ethoxy)-phenvn-5-(3-methoxy-phenyl)-5/-/-pyrrolof3.2-dlpy ⁇ m ⁇ - d ⁇ n-4-ylam ⁇ ne
  • Example 30 4-(4-Am ⁇ no-7-(4-[2-(2-hvdroxy-ethylam ⁇ no)-ethoxyl-phenyl)-pyrrolo[3.2-d]- pyr ⁇ m ⁇ d ⁇ n-5-yl-phenol
  • Examole 32 2-2- ⁇ 4-[4-Amino-5-(4-methoxy-phenyl)-5H-pyrrolor3.2-d]pyrimidin-7-yl]-phen- oxy ⁇ -ethylamino)-ethanol
  • Example 46 7-(3.4-Difluoro-cvclopentyl-5-phenyl-5H-pyrrolor3.2-d1pyrimidin-4-ylamine
  • Example 47 3-(4-Amino-5-phenyl-5H-pyrrolo[3.2-d]pyrimidin-7-yl)-cvclohexanol
  • Example 56 1 -f3-(4-Amino-5-phenyl-5/-/-pyrrolor3.2-dlPyrimidin-7-yl)-pyrrolidin-1 -yll- ethanone
  • Example 61 7-(1-Methyl-piperidin-4-v ⁇ -5-phenyl-5/-/-pyrrolof3,2-d1pyrimidin-4-ylamine
  • Example 62 1-f4-(4-Amino-5-phenyl-5H-pyrrolor3.2-dlpyrimidin-7-yl)-piperidin-1-vn- ethanone
  • Example 66 7-(1.1-Dioxo-tetrahvdro-thiophen-3-yl)-5-phenyl-5H-pyrrolo[3.2-dlpyrimidin-4-yl- amine
  • Example 67 7-Cvclopent-1 -enyl-5-(3-fluorophenyl)-5H-pyrrolo[3.2-d]pyrimidin-4-ylamine
  • a solution of 0.07 g of sodium in 10 ml of absolute ethanol is added dropwise to a suspension of 0.81 g of N-[2-cyano-4-cyclopent-1-enyl-1-(3-fluorophenyl)-7H-pyrrolo-3-yl]- formamidme in 3 ml of ethanol and the mixture is stirred overnight at room temperature. It is then heated to reflux over 2 hours and, after cooling, the solvent is removed and the residue is partitioned between water and methylene chloride.
  • Sodium 2-cvclopent-1 -enyl-3-oxido-acrylonitrile 25.2 g of sodium hydride (80 % dispersion in oil) are washed twice with absolute tetrahydrofuran and then suspended in 1000 ml of tetrahydrofuran. 57.1 g of (1-cyclopent-1-enyl)acetonitrile are added and the mixture is heated to 50°C. After 15 minutes, 204 ml of ethyl formate are added with stirring, vigorous gas evolution commencing after a short time. After stirring at 50°C for 1 hour, the coloured suspension is filtered and the precipitate is washed with tetrahydrofuran and dried under a high vacuum.
  • a viscous slurry is obtained, to which 50 ml of toluene are added followed by heating to 80°C. 19.7 g of (3- fluorophenyl)-acetonitrile are then added and the reaction mixture is heated under reflux using a water separator. After 1 hour, the mixture is allowed to cool, the insoluble residue is removed by filtration and the filtrate is concentrated. The oily residue is pre-purified by flash chromatography on silica gel (hexane/ethyl acetate/toluene 6:1 :7).
  • the crude product so obtained is taken up in 40 ml of a saturated solution of ammonia in methanol, diluted with 30 ml of methylene chloride and stirred at room temperature for several days until the reaction comes to a standstill (monitoring by TLC).
  • the reaction mixture is concentrated and the residue is purified by means of flash chromatography on silica gel (methylene chloride/methanol 98:2).
  • the title compound is obtained in the form of a solid.
  • Example 68 7-Cvclopent-1 -enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3.2-d)pyrimidin-4-ylamine
  • the title compound is obtained from 2.96 g of 7-cyclopent-1-enyl-5-(3-methoxyphenyl)-5/-/- pyrrolo[3,2-d]pyrimidin-4-ol in a manner analogous to that described in Examples 1 ) and 1e), after recrystallisation from hexane/ethyl acetate.
  • reaction mixture is then stirred for a further 30 minutes and, after cooling, the precipitate is removed by filtration and the filtrate is washed with saturated sodium hydrogen carbonate solution.
  • the aqueous phase is back-extracted with toluene and the combined organic phases are dried over magnesium suifate and concentrated.
  • the majority of the unreacted N-(3-methoxyphenyl)giycine ethyl ester is removed from the resulting crude product by solid distillation under a high vacuum (0.15 mbar; bath temperature 160-180°C).
  • Example 69 7-Cvclopent-1-enyl-5-(4-methoxyphenv ⁇ -5H-pyrrolor3.2-dlpyrimidin-4-ylamine
  • the title compound is obtained in the form of a solid from 5.1 g of 7-cyclopent-1 -enyl-5-(4- methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol in a manner analogous to that described in Examples 1 ) and 1e), after recrystallisation from methylene chloride/hexane.
  • FAB-MS 307 [M+H] + .
  • Example 70 7-Cyclopent-1 -enyl-5-(3-hvdroxyphenv ⁇ -5H-pyrrolof3.2-d1pyr ⁇ m ⁇ d ⁇ n-4-ylam ⁇ ne 0 47 ml of boron tribromide is added dropwise at 0-5°C, with stirring, to a suspension of 0.5 g of 7-cyclopent-1-enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyr ⁇ m ⁇ d ⁇ n-4-ylam ⁇ ne in 10 ml of methylene chloride. After 45 minutes, a further 0.16 ml of boron tribromide is added and stirring is subsequently carried out for 30 minutes.
  • Example 71 7-Cvclopent-1-enyl-5-(4-hvdroxyphenyl)-5H-pyrrolo[3.2-dlpyr ⁇ mid ⁇ n-4-ylam ⁇ ne
  • the title compound is obtained in the form of a solid from 1.0 g of 7-cyclopent-1-enyl-5-(4- methoxyphenyl)-5H-pyrrolo[3,2-d]pyr ⁇ m ⁇ d ⁇ n-4-ylam ⁇ ne in a manner analogous to that described in Example 70).
  • Example 72 7-Cvclopentyl-5-(4-hvdroxyphenv ⁇ -5H-pyrrolor3.2-d]pyrimidin-4-ylamine
  • a solution of 0.22 g of 7-cyclopent-1-enyl-5-(4-hydroxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4- ylamine in 20 ml of methanol is hydrogenated in the presence of 0.06 g of 10 % palladium- on-carbon for 24 hours at room temperature.
  • the crude product obtained after customary working-up is purified by flash chromatography on silica gel (methylene chloride/methanol 95:5).
  • the title compound is obtained in the form of a solid.
  • Example 73 7-Cvclopentyl-5-(3-hvdroxyphenv ⁇ -5H-pyrrolof3,2-d]pyrimidin-4-ylamine
  • the title compound is obtained in the form of a solid from 0.30 g of 7-cyclopent-1 -enyl-5-(3- hydroxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ylamine in a manner analogous to that described in Example 72).
  • FAB-MS 295 [M+H]+.
  • Example 74 7-Cvclopentyl-5-(3-fluorophenyl)-5H-pyrrolo[3.2-dlPyrimidin-4-ylamine Obtained in the form of a solid from 0.22 g of 7-cyclopent-1-enyl-5-(3-fluorophenyl)-5H- pyrrolo[3,2-d]pyrimidin-4-ylamine in a manner analogous to that described in Example 30), after recrystallisation from methylene chloride/hexane.
  • FAB-MS 297 [M+H]+.
  • Example 75 7-lsopropyl-5-(3-methoxyphenyl)-5H-pyrrolof3.2-dlpyrimidin-4-ylamine Reaction of 2.0 g of 7-isopropyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol in 10 ml of phosphorus oxychloride at 120°C for 2 hours, working-up and further reaction in methanolic ammonia under pressure at 130°C in a manner analogous to that described in Example 19) yield the title compound in the form of a white solid after recrystallisation from 1 :3 hexane/ethyl acetate.
  • f2-Cvano-3-methyl-but-1-enylH3-methoxyphenyl)aminol-acetic acid ethyl ester A mixture of 10.0 g of isovaleronitrile and ethanolic sodium ethanolate solution (2.76 g of sodium in 33 ml of absolute ethanol) in 36 ml of toluene is stirred at 50°C and 40-50 bar pressure under a carbon monoxide atmosphere for 10 hours analogously to a known process (DE 2753322 A1 ). After concentration of the reaction mixture by evaporation and drying under a high vacuum, the crude sodium 2-isopropyl-3-oxido-acrylonitrile is obtained in the form of a beige solid.
  • the crude product is dissolved in about 45 ml of water and adjusted to pH 6 by the addition of 1N hydrochloric acid. Extraction is then carried out with toluene, and the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium suifate and filtered. The filtrate is added to a solution, heated to 50°C, of 8.95 g of N-(3-methoxyphenyl)glycine ethyl ester in 50 ml of toluene, a catalytic amount of p-toluenesulfonic acid is added to the reaction mixture and heating is then carried out under reflux for 1 hour.
  • N-(3-methoxyphenyl)- glycine ethyl ester contained in the crude product are substantially removed by bulb tube distillation at 220°C/5.5 mbar. Further purification by means of flash chromatography on silica gel (hexane/ethyl acetate/toluene 5:1 :5) yields the title compound in the form of an oil.
  • Example 76 5-(3-Hvdroxyphenyl)-7-isopropyl-5r-/-pyrrolo[3.2-dlpyrimidin-4-ylamine 0.5 ml of boron tribromide is added in portions over 20 minutes at 0°C to a solution of 0.5 g of 7-isopropyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ylamine in 30 ml of methylene chloride. The resulting suspension is further stirred at 0-5°C for 2 hours and then, with ice cooling, 10 ml of water are added. The mixture is allowed to warm to room temperature and is subsequently stirred for a further hour.
  • Example 77 7-Cvclopent-3-enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3.2-d]pyrimidin-4-ylamine 2.1 g of 7-cyclopent-3-enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol and 10 ml of phosphorus oxychloride are stirred at 120°C for 2 hours. After concentration of the reaction mixture and drying under a high vacuum, 4-chloro-7-cyclopent-3-enyl-5-(3- methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine is obtained as the crude product.
  • a solution of 10.7 g of the crude product so obtained in 30 ml of water is adjusted to pH 6 with 1N hydrochloric acid and extracted twice with 100 ml of toluene.
  • the combined organic phases are dried over magnesium suifate, filtered and then added, at 50°C, to a solution of 7.15 g of N-(3-methoxyphenyl)glycine ethyl ester in 50 ml of toluene.
  • the reaction mixture is stirred under reflux for 60 minutes and, after cooling, the organic phase is washed with 5 % sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium suifate and concentrated.
  • the residue obtained after bulb tube distillation (210°C/2 mbar) is purified by means of flash chromatography on silica gel (hexane/ethyl acetate/toluene
  • Potassium 2-cvclopent-3-enyl-3-oxido-acrylonitrile 5.0 g of cyclopent-3-enyl-acetonitrile are added, with stirring, to a suspension of potassium hydride (obtained from 28.1 g of potassium hydride 20 % dispersion in oil by washing twice with n-hexane) in 1 :1 diethyl ether/hexane, gas evolution taking place. The brown suspension is stirred at room temperature for 1 hour and then 30.4 ml of ethyl formate are added dropwise over 15 minutes.
  • the initially viscous suspension is stirred at room temperature for 12 hours and then filtered over a glass frit, and the coloured precipitate is washed with a small amount of hexane.
  • the filter residue is dried at 50°C under a high vacuum for 3 hours and is then reacted, without further purification, with N-(3-methoxyphenyl)glyc ⁇ ne ethyl ester as described in Example 44d).
  • the oily residue is purified by means of flash chromatography on silica gel (hexane/ethyl acetate/- toluene, gradient 3:1 :4 to 1:1:4). Reaction of 5.72 g of the resulting product in 150 ml of a saturated ammonia solution in methanol at 40-45°C for 48 hours and subsequent purifi ⁇ cation by means of flash chromatography on silica gel (methylene chlonde/methanol 98:2) yield the title compound in the form of a solid.
  • Example 78 7-Cvclopent-3-enyl-5-(3-hvdro ⁇ yphenyl)-5H-pyrrolo[3.2-d1pyrimid ⁇ n-4-ylam ⁇ ne 0.47 ml of boron tribromide is added dropwise at 0-5 c C over 20 minutes, with stirring, to a solution of 0.5 g of 7-cyclopent-3-enyl-5-(3-methoxyphenyl)-5H-pyrrolo[3,2-d]pyr ⁇ mid ⁇ n-4- ylamme in 30 ml of methylene chloride.
  • the title compound contains 50% 7-[4-(2-chloro-ethoxy)- phenyl]-5-(3-methoxy-phenyl)-5H-pyrrolo[2,3-d]pyr ⁇ m ⁇ d ⁇ n-4-ylam ⁇ ne.
  • Example 83 3-(4-Am ⁇ no-7-r4-(2-hvdroxy-ethoxy)-phenyl]-pyrrolo[3,2-d1pyr ⁇ m ⁇ d ⁇ n-5-ylr-phenol
  • the compound is prepared analogously to Example 81.
  • Example 85 7-(4-[2-(2-Methoxy-ethylam ⁇ no)-ethoxyl-phenyll-5-(3-methoxy-phenyl)-5r-y-pyr- rolof3.2-d1pynm ⁇ d ⁇ n-4-ylam ⁇ ne
  • the compound is prepared analogously to Example 81. M.p.:152 - 154°C.
  • Example 87 7-(4-[2-(4-Fluoro-benzylam ⁇ no)-ethoxy1-phenyl)-5-(3-methoxy-phenyl)-5/-/-pyr- rolo[3,2-dlpyr ⁇ m ⁇ d ⁇ n-4-ylam ⁇ ne
  • the compound is prepared analogously to Example 81. M.p/ 137 -140°C.
  • Example 91 1-(2-(4-[4-Amino-5-(3-methoxy-phenyl)-ffH-pyrrolor3.2-d]pyrimidin-7-yl]-phen- oxy>-ethyl)-pyrrolidin-3-ol
  • the compound is prepared analogously to Example 81. M.p.: 132 -135°C.
  • the compound is prepared analogously to Example 81. M.p.: 212 - 216°C.
  • the compound is prepared analogously to Example 81. M.p.: 166 - 168°C.
  • the compound is prepared analogously to Example 81. M.p.: 152 -154°C.
  • Example 96 2-2-(4-f4-Am ⁇ no-5-(3-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyr ⁇ mid ⁇ n-7-v ⁇ -phenoxy>- ethylaminoVethanol
  • the compound is prepared analogously to Example 81 . M.p.: 148-151 °C.
  • the compound is prepared analogously to Example 81. M.p.: 164 - 168°C.
  • Example 99 4-f4-Amino-5-(3-hvdroxy-phenyl)-5/-/-pyrrolo[3.2-d1pyrimidin-7-yl]-phenol
  • the compound is prepared analogously to Example 81.
  • Example 100 3-r4-Amino-7-(4-(2-f(2-hvdroxy-ethvO-methyl-amino1-ethoxy)-phenyl)-pyrrolo- f3.2-dlpyrimidin-5-yl1-phenol
  • the compound is prepared analogously to Example 81. M.p.: 212 - 215°C.
  • the compound is prepared analogously to Example 81. M.p.: 212 - 216°C.
  • Example 102 1 -(2-(4-[4-Amino-5-(3-hvdroxy-phenyl)-5/-/-pyrrolo[3.2-dlpyrimidin-7-v ⁇ -phen- oxVf-ethyl)-pyrrolid ⁇ n-3-ol
  • the compound is prepared analogously to Example 81. M.p.: 218 - 222°C.
  • Example 104 2-(2-(3-[4-Amino-5-(3-methoxy-phenyl)-5/-/-pyrrolof3.2-d1pyrimidin-7-yl]-phen- oxy
  • the compound is prepared analogously to Example 81. M.p.: 166 - 168 C C.
  • Example 106 7-f3-(2-lmidazol-1 -yl-ethoxy)-phenv ⁇ -5-(3-methoxy-phenyl)-5/-/-pyrrolo[3.2-d]- pyrimidin-4-ylam ⁇ ne
  • Example 107 5-(3-Methoxy-phenyl)-7-r3-(2-piperaz ⁇ n-1 -yl-ethoxy)-phenv ⁇ -5H-pyrrolor3.2-dl- pyr ⁇ m ⁇ d ⁇ n-4-ylam ⁇ ne hydrochloride
  • Example A Tablets, each comprising 50 mg of active ingredient:
  • composition (10 000 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 O g silicon dioxide (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 mixture is moistened with an ethanohc solution of the gelatin and granulated through a sieve. After drying, the remaining potato starch, the magnesium stearate, the talc and the silicon dioxide 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
  • composition 1000 film-coated tablets
  • active ingredient 100.0 g lactose 100 O g corn starch 70.0 g talc 8.5 g calcium stearate 1.5 g hydroxypropyimethylcellulose 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 corn starch and water (with heating), and granulated.
  • the granules are dried, and the remaining corn 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 hydroxypropyimethylcellul ⁇ ose and the shellac in dichloromethane (final weight of each film-coated tablet: 283 mg).

Abstract

L'invention concerne les pyrrolo[3,2-d]pyrimidines selon la formule (I). Dans cette dernière, R1, R2 et R3 sont tels que définis dans le descriptif. Ces composés présentent des propriétés pharmaceutiques utiles et sont particulièrement efficaces comme inhibiteurs de la tyrosine protéine kinase. Ils peuvent être utilisés chez les animaux à sang chaud dans le traitement des affections osseuses et d'autres maladies qui peuvent être traitées par l'inhibition de la tyrosine protéine kinase.
PCT/EP1997/003115 1996-06-25 1997-06-16 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES WO1997049706A1 (fr)

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US6316464B1 (en) 1997-10-20 2001-11-13 Syntex (U.S.A.) Llc P38 MAP kinase inhibitors
WO2002006223A1 (fr) * 2000-07-13 2002-01-24 Abbott Laboratories Pyrrolidines 1,3-disubstituees et 1,3,3-trisubstituees utilisees comme ligands du recepteur de l'histamine-3 et leurs applications therapeutiques
US6515013B2 (en) 2000-07-13 2003-02-04 Abbott Laboratories 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications
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