AU8108498A - Method for producing quinazoline-diones in solid phase and use of the same - Google Patents

Description

The solid-phase preparation of quinazolinediones and their use The invention relates to a process for preparing quinazolinedione 5 derivatives and to their use. In classical research looking for active substances, the biological effect of novel compounds has been tested in random screening on the whole organism, for example of the plant or the 10 microorganism. In this case, the biological testing was the limiting factor in contrast to the synthetic chemistry. The situation has changed drastically due to the provision of molecular test systems by molecular and cell biology. 15 A large number of molecular test systems such as receptor binding assays, enzyme assays and cell-cell interaction assays have been and are currently being developed for modern research looking for active substances. Automation and miniaturization of these test systems makes high sample throughput possible. This development 20 allows an ever increasing number of chemicals to be tested in an ever decreasing time for their biological effect in random screening and thus for a possible use as lead structure for an active substance in medicine, veterinary medicine or crop protection. 25 A modern automated test system allows 100,000 or more chemicals to be tested for their biological effect per year in a mass screening. 30 Classical synthetic chemistry has become, through this development, the limiting factor in research looking for active substances. If the capacity of these test systems is to be fully exploited, 35 the efficiency of the chemical synthesis of lead structures for active substances must be considerably increased. Combinatorial chemistry can contribute to this necessary increase in efficiency, in particular when it makes use of automated 40 solid-phase synthetic methods (see, for example, review articles in J. Med. Chem. 37 (1994) 1233 and 1385). Combinatorial chemistry makes it possible to synthesize a wide variety of different chemical compounds, called substance libraries. Solid-phase synthesis has the advantage that by-products and 45 excess reactants can easily be removed, so that elaborate purification of the products is unnecessary. The finished synthetic products can be passed on for mass screening directly, 2 ie. bound to the support, or after cleavage off the solid phase. Intermediates can also be tested in the mass screening. In recent years, solid-phase chemistry has increasingly moved 5 from applications in peptide and nucleotide chemistry (Lebl et al., Int. J. Pept. Prot. Res. 41, 1993: 203, WO 92/00091 and WO 96/00391) toward synthesizing small organic molecules. Numerous reviews, for example Balkenhohl et al. (Angew. Chem. 10 Int. Ed. 108, 1996, 2436 - 2288), Terrett et al. (Tetrahed. Report No. 337 Tetrahedron 51, 1995: 8135) or Ellman et al. (Chem. Rev. 96, 1996: 555) demonstrate this trend. Despite the large number of syntheses which have been developed, however, there is still a great need for novel, high-capacity methods for 15 preparing such compounds, it being very important not least that there be a reliable and wide variability of the building blocks, which must additionally be commercially available or accessible by synthesis with little effort, in order to make automated provision of a large number of compounds possible for the test 20 systems whose capacity is always increasing. It is moreover sensible to aim at biologically active compounds. It is possible by this procedure to reduce considerably the time for identification and optimization of a novel lead structure for 25 active substances. Quinazolinediones are substances sought for synthesis of active substances (Burckthaler et al., J. Am. bull. Assoc. 44, 1956: 545, Hayao et al., J. Med. Chem. 8, 1965: 807 or Kornet et al., 30 J. Pharm. Sci. 72, 1983: 1213). Thus, for example, they form part of CNS-active substances or are used as peptidomimetics or as part of peptidomimetics. Syntheses of this class of substances on polymeric supports have 35 been described in the literature by Buckman et al. (Tetrahedron Lett. 37, 1996: 4439), Gouilleux et al. (Tetrahedron Lett. 37, 1996: 7031) and Gordeev et al. (Tetrahedron Lett. 38, 1997: 1729). The synthesis described by Buckman et al. requires the preparation of a specific starter molecule in a multistage 40 synthesis. Another disadvantage of this process is that the products can be detached from the polymer only under drastically acidic conditions, so that side reactions may occur with acid-labile side chains and lead to contamination of the products. In addition, only a limited number of compounds can be 45 prepared in this way, so that, for example compounds of the type which can be prepared by the novel process, for example products with tert-butyl or tert-butyloxycarbonyl-derivatized heteroatoms, 3 cannot be prepared by this method because these tertiary radicals would be eliminated under the conditions specified by Buckman. In contrast to this, any desired amino carboxylic acid can be employed as starter molecule in the process presented herein. 5 The synthesis described by Gouilleux et al. requires strongly alkaline conditions to carry out the cyclization to the quinazoline with cleavage off the polymer. In contrast to this, the cyclization to the quinazolinedione in the novel process 10 takes place under virtually neutral conditions on the polymer, so that it is also possible to prepare compounds with base-labile side chains, for example esters, or carry out other synthetic steps after cyclization on the polymeric support. 15 A disadvantage of the method described by Gordeev et al. is the use for the synthesis of isocyanates which are not stable on storage and must either be stored with exclusion of moisture in a costly manner or else be prepared immediately before the synthesis. In some cases, the isocyanates must also be purified. 20 Suesse et al. (Monathsh. [sic] Chem. 326, N2, 1984, 342) describe the synthesis of quinazolinediones starting from amino acid esters using isocyanates of the appropriate anthranilic acid derivatives in solution. A disadvantage of this method is that 25 the quinazolinediones synthesized in this way must first be purified to remove by-products and unreacted precursors. It is an object of the present invention to provide a rapid and efficient process for the solid-phase preparation of 30 quinazolinedione derivatives which does not have the abovementioned disadvantages and meets the requirements of combinatorial chemistry. We have found that this object is achieved by a process for 35 preparing quinozalinedione [sic] derivatives of the formula I 0 40 R A1X 3 N OR R 1 R which comprises reacting compounds of the formula II 45 H 2N a& As, (

R

2 R 0 5 with an N-protected 2-aminobenzoic acid derivative of the formula III 10 R O Q (III)

R

3 NH R '7 R 15 or with an isatoic anhydride derivative of the formula IV 0 20 0IV)

R

3 NH O 25 to give compounds of the formula V 0 30 R4 N A , M 2 R 0

R

3

NH

2 R and then reacting the latter with compounds of the formula VI 35 0 D E(VI), 40 to give compounds of the formula VII 45 . , 5 4 0 R N A 5 -k R2 RI O

R

3 NH O R and subsequently alkylating with compounds of the formula VIII (R 8 -FG) to give compounds of the formula I, 10 where the variables and substituents mentioned in formulae I to VIII have the following meanings: (P) a solid phase 15 (A) 0, NH,

R

1 ' R 2 independently of one another hydrogen, substituted or unsubstituted Ci-C 6 -alkyl, 20 C 3

-C

6 -cycloalkyl, aryl, hetaryl with one or more heteroatoms in the ring system, Ci-C 4 -alkylaryl or Ci-C4-alkylhetaryl with one or more heteroatoms in the ring or R 1 and R 2 together form a ring with 3 to 8 carbon atoms in the ring, 25

R

3 , R 4 independently of one another H, CI-C 8 -alkyl, C2-C 8 -alkenyl, C2-C 8 -alkynyl, aryl, hetaryl, halogen, NR 5

R

6 , OR 6 , SR 6 , COOR 6 , CONR 5

R

6 , nitro, cyano or R 3 and R 4 together form a fused aromatic or 30 aliphatic system,

R

5 H, substituted or unsubstituted Ci-C 8 -alkyl,

C

3

-C

6 -alkenyl, C 3

-C

8 -alkynyl, aryl, C3-C 8 -cycloalkyl with or without one or more heteroatoms in the ring, 35 Ci-C 4 -alkylaryl, Ci-C 4 -alkylhetaryl,

C

1

-C

6 -alkyl-( Z )m-CO-, C3-C6-alkenyl-(Z)m-CO-, aryl-(Z)m-CO-, Ci-C 4 -alkylaryl-(Z)m-CO-, C3-C 8 -cycloalkyl-(Z)m-CO-, Ci-CB-alkyl-SO 2 -, aryl-S0 2 -, Ci-C4-alkylaryl-SO 2 -, 40 R 6 H, substituted or unsubstituted Ci-C 8 -alkyl, C3-C 8 -cycloalkyl, Ci-C4-alkylaryl, Ci-C 4 -alkylhetaryl,

R

7 substituted or unsubstituted Ci-C 6 -alkyl-OCO-,

C

3

-C

6 -alkenyl-OCO-, C3-C 8 -cycloalky-OCO- [sic], 45 Ci-C 4 -alkylaryl-OCO-, 6

R

8 is [sic] substituted or unsubstituted Ci-C 6 -alkyl, Ci-C 4 -alkylaryl, Ci-C 4 -alkylhetaryl with one or more heteroatoms in the ring system 5 (Z) 0, NH (m) 0, 1 X,Y independently of one another 0 to 6, 10 D,E independently of one another imidazolyl, triazolyl, nitrophenyl, halogen, succinimidyl, pentafluorophenolate [sic] or OCC13 15 Q an acid activating group LG a leaving group. The invention additionally relates to the use of the synthesized 20 quinazolinediones in the free state or bound to the solid phase. It is possible to use as solid phase (P) in the novel process the supports known from solid-phase peptide synthesis. Supports which can be used may consist of a large number of materials provided 25 they are compatible with the synthetic chemistry employed. The size of the supports may vary within wide limits depending on the material. Particles in the range from 1 pm to 1.5 cm are preferably used as supports, and particles in the range from 1 FM to 150 pm are particularly preferred for polymeric supports. 30 The support may have any shape, and spherical particles are preferred. The size distribution of the supports may be homogeneous or heterogeneous, and homogeneous particle sizes are preferred. 35 To make it possible to attach the reactant and cleave off the product after the synthesis, the support must be suitably functionalized or provided with a linker which has an appropriate functional group. 40 Suitable polymeric supports are solid phases which have a functional group or a linker so that attachment of other molecules is possible. 45 Examples of suitable and preferred solid phases are polyacrylamides, which may have been crosslinked with polyethylene glycols, and 1-2% crosslinked polystyrenes, which 7 may have been provided with polyethylene glycol spacers. Examples of commercially available polymers which are functionalized appropriately or provided with a linker are PEGA resin, Rink or Sieber resin (amino group), Wang resin and Sasrin resin (hydroxyl 5 group) and trityl- or chlorotrityl-resin or Merrifield resin (active halogen group), and appropriately modified Tentagel resins. After completion of the synthesis, the product can be cleaved off 10 the solid phase in a manner known to the skilled worker. The cleavage off the polymer can take place under acidic or basic conditions or else under the action of light, so that appropriate reaction conditions are available for molecules with sensitive 15 side chains.

R

1 and R 2 in the compounds of the formulae I, II, V, VII and IX are, independently of one another,hydrogen, substituted or unsubstituted Ci-C 6 -alkyl, C 3

-C

8 -cycloalkyl, aryl, hetaryl with 20 one or more heteroatoms in the ring system, Ci-C 4 -alkylaryl or Ci-C 4 -alkylhetaryl with one or more heteroatoms in the ring or R1 and R 2 together form a ring with 3 to 8 carbon atoms in the ring, where 25 - alkyl is branched or unbranched Ci-C 6 -alkyl such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 30 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 35 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl; - cycloalkyl is branched or unbranched C 3

-C

8 -cycloalkyl chains [sic] with 3 to 7 carbon atoms in the ring which may contain one or more hetero atoms such as S, N or 0, such as 40 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methyl-2-ethylcyclopropyl or cyclooctyl; 45 - aryl is phenyl, naphthyl or biphenyl [sic]; 9 alkenyl is branched or unbranched C 2

-C

8 -alkenyl such as ethenyl, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 5 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1 propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 10 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1 pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2 pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3 15 pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl 2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl 1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 20 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl 2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, .1,1,2-trimethyl-2-propenyl, 1-ethyl-1 25 methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2 methyl-2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl or 7-octenyl, 30 - alkynyl is branched or unbranched C 2

-C

8 -alkynyl such as ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, 35 n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 40 3-methyl-pent-1-yn-1-yl, 3-methyl-pent-1-yn-3-yl, 3-methyl-pent-1-yn-4-yl, 3-methyl-pent-1-yn-5-yl, 4-methyl-pent-1-yn-1-yl, 4-methyl-pent-2-yn-4-yl 4-methyl-pent-2-yn-5-yl, heptynyl or octynyl 45 - aryl is phenyl, naphthyl or biphenyl [sic]; 10 - hetaryl is a simple or fused aromatic ring system with one or more heteroaromatic 3- to 8-membered rings, which may contain one or more heteroatoms such as S, N or 0, 5 - is halogen, NR 5

R

6 , OR 6 , SR 6 , COOR 6 , CONR 5

R

6 , nitro, cyano or R3 and R 4 together form a fused aromatic or aliphatic system. [sic] All said radicals R 3 or R 4 may be unsubstituted or substituted by 10 one or more of the radicals mentioned under R 3 ,

R

5 in the compounds [sic] NR 5

R

6 or CONR 5

R

6 is hydrogen or substituted or unsubstituted Ci-C 8 -alkyl, C 3

-C

6 -alkenyl,

C

3

-C

8 -alkynyl, aryl, C 3

-C

8 -cycloalkyl with or without one or more 15 heteroatoms in the ring, Ci-C 4 -alkylaryl, Ci-C 4 -alkylhetaryl, Ci-C6-alkyl-(Z)m-CO-, C3-C6-alkenyl-(Z)m-CO-, aryl-(Z)m-CO-,

C

1

-C

4 -alkylaryl-(Z)m-CO-, C 3

-C

8 -cycloalky-(Z)m-CO- [sic], Ci-C 8 -alkyl-SO 2 -, aryl-S0 2 -, Ci-C 4 -alkylaryl-SO 2 -, where in the aforementioned names such as alkyl, alkenyl, aryl or in the 20 formulae - alkyl is branched or unbranched Ci-C 4 -alkyl, Ci-C 6 -alkyl or Ci-C 8 -alkyl, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, 25 n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 30 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl or octyl; 35 - alkenyl is branched or unbranched C 2

-C

6 -alkenyl such as ethenyl, propenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 40 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 45 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl- 11 2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1, 3-dimethyl-3-butenyl, 2, 2-dimethyl-3-butenyl, 2, 3-dimethyl 2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-2-butenyl, 5 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1 methyl-2-propenyl or 1-ethyl-2-methyl-2-propenyl, - alkynyl is branched or unbranched C 3

-C

8 -alkynyl such as 10 n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-2-yl, 4-methyl-pent-2-yn-4-yl, 4-methyl-pent-2-yn-5-yl, heptynyl or octynyl; 15 - aryl is phenyl, naphthyl or biphenyl [sic]; - cycloalkyl is branched or unbranched C 3

-C

8 -cycloalkyl chains [sic] with 3 to 7 carbon atoms in the ring, which may contain one or more heteroatoms such as S, N or 0, such as 20 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methyl-2-ethylcyclopropyl or cyclooctyl; 25 - alkylaryl is branched-chain or straight-chain Ci-C 4 -alkylphenyl or Ci-C 6 -alkylnaphthyl such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 30 1,1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl [sic], 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl or 1,1-dimethylethylnaphthyl, 35 alkylhetaryl is branched-chain or straight-chain Ci-C 4 -alkylhetaryl which [lacuna] simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings, which may contain one or more heteroatoms such as S, N or 0, 40 - Z is 0, NH and m is 0 and 1.

R

6 in the compounds [sic] NR 5

R

6 , OR 6 , SR 6 , COOR 6 or CONR 5

R

6 is hydrogen or substituted or unsubstituted Ci-C-alkyl, 45 C 3

-C

8 -cycloalkyl, Ci-C 4 -alkylaryl, Ci-C 4 -alkylhetaryl, where 12 - alkyl is branched or unbranched Ci-C 6 -alkyl such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 5 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 10 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl; - cycloalkyl is branched or unbranched C3-C 8 -cycloalkyl chains [sic] with 3 to 7 carbon atoms in the ring which may contain 15 one or more heteroatoms such as S, N or 0, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclopropyl, 20 1-methyl-2-ethylcyclopropyl or cyclooctyl; - alkylaryl is branched-chain or straight-chain Ci-C 4 -alkylphenyl or Ci-C 6 -alkylnaphthyl such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 25 1-methylpropylphenyl, 2-methylpropylphenyl, 1,1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl [sic], 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl, 1,1-dimethylethylnaphthyl or methyl-9-fluorenyl [sic], 30 - alkylhetaryl is branched-chain or straight-chain Ci-C4-alkylhetaryl which [lacuna] simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings, which may contain one or more heteroatoms such as S, N 35 or O. All said radicals R 5 or R 6 may be unsubstituted or substituted by one or more of the radicals mentioned under R 3 . 40 R 7 in the compounds of the formula III is substituted or unsubstituted Ci-C 6 -alkyl-OCO-, C 3

-C

6 -alkenyl-OCO-,

C

3

-C

8 -cycloalky-OCO- [sic], Ci-C4-alkylaryl-OCO-, where in the aforementioned names such as alkyl, alkenyl, aryl or in the formulae 45 13 - alkyl is branched or unbranched Ci-C 4 -alkyl or Ci-C 6 -alkyl, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 5 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 10 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl; - alkenyl is branched or unbranched C 3

-C

6 -alkenyl such as 15 propenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 20 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 25 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl 2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl 30 2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1 methyl-2-propenyl or 1-ethyl-2-methyl-2-propenyl, 35 - cycloalkyl is branched or unbranched C 3

-C

8 -cycloalkyl chains [sic] with 3 to 7 carbon atoms in the ring, which may contain one or more heteroatoms such as S, N or 0, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-methylcyclopropyl, 1-ethylcyclopropyl, 40 1-propylcyclopropyl, 1-butylcyclopropyl, 1-pentylcyclopropyl, 1-methyl-1-butylcyclopropyl, 1,2-dimethylcyclopropyl, 1-methyl-2-ethylcyclopropyl or cyclooctyl; - alkylaryl is branched-chain or straight-chain 45 Ci-C 4 -alkylphenyl or Ci-C 6 -alkylnaphthyl such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 1-methylpropylphenyl, 2-methylpropylphenyl, 14 1,1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl [sic], 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl, 1,1-dimethylethylnaphthyl or 9-methylfluorenyl. 5 RO in the compounds of the formulae I or VIII is substituted or unsubstituted Ci-C 6 -alkyl, Ci-C 4 -alkylaryl, Ci-C 4 -alkylhetaryl with one or more heteroatoms in the ring system, where 10 - alkyl is branched or unbranched Ci-C 6 -alkyl such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 15 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 20 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl; - alkylaryl is branched-chain or straight-chain Ci-C 4 -alkylphenyl or Ci-C 6 -alkylnaphthyl such as methylphenyl, ethylphenyl, propylphenyl, 1-methylethylphenyl, butylphenyl, 25 1-methylpropylphenyl, 2-methylpropylphenyl, 1,1-dimethylethylphenyl, methylnaphthyl, ethylnaphthyl, propynaphthyl [sic], 1-methylethylnaphthyl, butylnaphthyl, 1-methylpropylnaphthyl, 2-methylpropylnaphthyl, 1,1-dimethylethylnaphthyl or 9-methylfluorenyl, 30 - alkylhetaryl is branched-chain or straight-chain Ci-C 4 -alkylhetaryl which [lacuna] simple or fused aromatic ring systems with one or more heteroaromatic 3- to 8-membered rings, which may contain one or more heteroatoms such as S, N 35 or 0. R9 in the compounds of the formula IX is hydrogen or the radicals defined under R 8 . 40 G in the formula IX is NR 10

R

11 or OR 11 , where R 10 and R 11 are, independently of one another, the radicals defined under R 6 . All said radicals R 7 , R 8 , R 9 , R 1 0 or R 11 may be unsubstituted or substituted by one or more of the radicals mentioned under R 3 . 45 15 The novel process for preparing quinazolinedione derivatives is advantageously carried out in a reaction sequence (scheme I) Scheme I: Reaction sequence for the novel process e- (IV) 5 R R 3 NHtO 10 * 0

H

2 NkY r P Nf 1.0 H2N A R AH (3 NH (VI) R 20 2.Elimination of R 7 4R 0 25 R A (VII)

R

8 -FG (VIII) 30 0A R (I) 35 The starting compounds of the formula II in scheme I are obtained from the functionalized polymers by reactions with suitably protected amino acids (Sieber, Tetrahedron Lett. 28, 1987: 6147) or are commercially available in the form of suitably protected derivatives (Novabiochem), advantageous protective groups being 40 trityl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, nitroveratryloxycarbonyl. Processes for preparing the starting compounds are sufficiently well known to the skilled worker so that reference may be made here only to the appropriate [lacuna] (Fields et al., Int. J. Peptide Protein Res. 45 35, 1990: 161, Muller in Houben Weyl, Methoden d. org. Chem. Vol. XV, pp. 20 - 906 Thieme Verlag Stuttgart, 1974, Kocienski et al. Org. Synth. 1905: 2315 and Protecting Groups Thieme Verlag, 1994, 16 Novabiochem Catalog & Peptide Synthesis Handbook 1987/1988 Synthesis Notes, Novabiochem Combinatorial Chemistry Catalog & Solid Phase Organic Chemistry Handbook 1987). 5 Further reaction to give the required compounds of the formula (V) are [sic] possible in several ways. It is preferred to react an N-protected aminobenzoic acid derivative (III) with compounds of the formula (II), and then to 10 remove the R 7 protective group (scheme II). Scheme II: Synthesis with aminobenzoic [lacuna] derivatives 15 H2N A,

R

2 R 0 R 4 O R 1. i(III) 20R 203 NH RR R 2. Elimination of R 7 25 R3 NH R1 300 30 R H The reaction to give the compounds of the formula V with activated aminobenzoic acid derivatives is advantageously carried 35 out with the appropriate previously prepared acid chlorides or the fluorides which have been generated in situ, used for this is, for example, TFFH or cyanuric fluoride, or with the bromides, this is obtained by adding, for example, PyBrop (bromotrispyrrolidinophosphonium hexafluorophosphate), or with an 40 active ester method which is known to the skilled worker, for example with the addition of HOBT (hydroxybenzotriazole) or HOAT and a uronium salt, mentioning here only TBTU (2-( lH-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium tetrafluoroborate) or HOAT as representative, or with the 45 addition of carbodiimide/HOBT or pentafluoropheno [sic]. These reactions require no further explanation because they are sufficiently well known to the skilled worker and may be referred 17 to in the abovementioned specialist literature (Fields et al., etc.). The abovementioned aminobenzoic acid-activating groups may be mentioned as examples of the acid-activating group Q. 5 Suitable and advantageous as protective group R 7 for the amino acid are trityl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, benzyloxycarbonyl, nitroveratryloxycarbonyl. The methods for cleaving off these protective groups are known to the skilled worker and likewise require no further explanation and can 10 likewise be referred to in the abovementioned literature. As an alternative to the reaction with activated, protected aminobenzoic acid derivatives and subsequent removal of the protective group, compounds of the formula (V) can also be 15 obtained by reacting compounds of the formula (II) with isatoic anhydrides of the formula (IV) (scheme III). Scheme III: Synthesis with isatoic anhydrides 20

H

2 N AI R 2 R 0 25 R4 (IV)

R

3 NH O 30 R4 O N & P | Y X(V) 35 2RI O

R

3

NH

2 R The reaction is carried out in a solvent, preferably in aprotic, organic solvents such as toluene, DMF (dimethylformamide), NMP 40 (N-methylpyrrolidone) or higher homologs of halogenated hydrocarbons, preferably in DMF or DMSO (dimethyl sulfoxide), reacting from 1 to 10 equivalents (=Eq), preferably from 1 to 3 Eq, of the compound IV with the polymer-bound compounds at a temperature in the range from -40 to + 250'C, preferably from 50 45 to + 200 0 C, particularly preferably + 100 to + 150 0

C.

18 Reactions leading to compounds of the formula VII are then [lacuna] with the addition of phosgene or phosgene equivalents of the formula (VI), of which diphosgene, triphosgene, nitrophenyl chloroformate, dinitrophenyl carbonate may be mentioned here as 5 representatives and without intending to make a restriction; triphosgene is preferred, which is reacted in a solvent, preferably in a moderately polar solvent such as CH 2 Cl 2 , CHCl 3 or higher homologs of halogenated hydrocarbons, toluene, benzene, NMP or THF, with the polymer-bound compounds at from 0 0 C to 40 0 C, 10 preferably from 10 to 40 0 C, particularly preferably from 15 to 25 0 C, and very particularly preferably at 20*C (scheme IV). Scheme IV: Cyclization 15 4 0 RN Y2 R O 3 NH RR0 20 R 2 0 25 D E 25 (VI) 304 0 30 R NA, NP (VII) Y2 R O

R

3 NH O R 35 D in the compounds of the formula (VI) is, for example, a nucleofugic group which makes the cyclization possible. Nucleofugic groups which may be mentioned are leaving groups such as halogen such as Br or Cl or groups such as 40 0 N N-N R 5 --- N -N -NI _-OCC1 3 -0 Q 45 0 m = 1 to 5 R5 = H, Cl, Br, F, N02.

19 E in the compounds of the formula VI has the meaning stated for D and can be identical to or different from D. These compounds can be characterized directly on the polymer by 5 special NMR techniques as described, for example, in Wehler, J., Westman, J. Tetrahedron Lett. (1996) 4771 and the literature cited therein; however, this method cannot be applied to all polymers so that it is advantageous to cleave off the molecules for characterization. The compounds obtained in this way are 10 soluble in organic solvents and can be characterized by NMR, HPLC and/or HPLC/MS. Further derivatization of compounds of the formula VII with R 8 to give compounds of the formula I is possible, for example, by 15 treatment with a base and a compound R 8 -FG (VIII) which is amenable to nucleophilic substitutions (scheme V). Suitable bases are inorganic carbonates (K 2 C0 3 , Na 2

CO

3 ), NaH, possibly with addition of a crown ether, and strong amine bases such as tetramethylguanidine, diazabicycloundecene, Schwesinger bases and 20 the lithium, sodium or potassium compounds of lower alcohols such as methanol, ethanol, tert-butanol. It is furthermore possible to employ strong non-nucleophilic bases such as LDA (lithium diisopropylamide), LiHMDS (lithium hexamethyldisiliazide [sic]), KHMDS (potassium hexamethyldisilazide), NAHMDS [sic] (sodium 25 hexamethyldisilazide). Scheme V: Alkylation 30 4 O RNA

R

3 NH OR R 0 35

R

8 -FG (VIII) 40 R4 O 45 Y (I) 3 N O 2 R R 18

R

20 Solvents which are suitable and advantageous are aprotic organic solvents such as diethyl eter [sic], THF, dioxane or toluene. Suitable alkylating agents (VIII) for alkylating the nitrogen and 5 as leaving group (FG) are in principle all alkylating agents such as alkyl chlorides, bromides or iodides, sulfonic esters such as nosylates, brosylates, mesylates, tosylates, triflates, tresylates or nonaflates or sulfuric esters such as dimethyl sulfate or quaternary ammonium salts such as trialkylammonium. 10 For reasons of cost, the alkyl halides or, in some cases, the quaternary ammonium salts are preferred. The reaction is typically carried out by adding from 0.5 to 10 eq, preferably 1 to 5 eq, of the base to the compounds of the 15 formula VII in THF at from -80 0 C to + 25 0 C, preferably from -20 to 0*C, under a protective gas and, after lengthy incubation, reacting with from 5 to 40 eq, preferably 15 to 30 eq, of the alkylating reagent R 8 -FG. To achieve complete conversion, it may be advantageous to repeat this procedure several times. 20 The linkages (= A-P) used for attachment to the polymer are of such a nature that, under suitable conditions, cleavage of the compounds of the formula I or VII off the solid phase is possible (see scheme VI). 25 Scheme VI: Cleavage off the solid phase 0 30 R A 3 N OR 2 R 0 R 19 R 35 H+,-OH

NR

10

R

11

-OR

11 or hO [sic] 40 * R NNG (IX) 3 N "O R2 45 R 19

R

21 Examples of suitable conditions in the case where A-P is an ester linkage (eg. Wang or Tentagel resins) or amide linkage (eg. Rink or Sieber resin) strong organic or mineral acids such as trifluoroacetic acid or HCl in organic solvents such as 5 halogenated hydrocarbons, THF, possibly with the addition of cation scavengers such as EDT (1,2-ethanedithiol). The typical procedure is to treat the polymer in a solvent or solvent mixture such as a mixture of 20-99% TFA in CH 2 Cl 2 and 10 water until the A-P linkage has been cleaved, for example for 1 to 3 h, and then to filter off and concentrate the filtered solution. An alternative possibility to this for compounds with an ester 15 linkage to the polymeric support is a basic cleavage off. Suitable and advantageous for this purpose are alkali metal hydroxides such as NaOH and LiOH in the form of their aqueous solutions, possibly with the addition of organic solvents such as THF..The basic cleavage off can also be carried out with 20 simultaneous esterification when, for example, the alkali metal salts of lower alcohols (eg. NaOMe or NaOEt) dissolved in the corresponding alcohol are used as base. Aminolysis, for example with nucleophilic organic primary or 25 secondary amines, also results in the products being cleaved off the resin. Particularly suitable for this are amines such as methylamine, benzylamine etc. in the form of their solutions in aprotic solvents such as toluene or THF. 30 The novel process can be carried out in the described complete sequence starting from compounds of the formula (II) to compounds of the formula (I) via compounds (V) and (VII), and the synthesized compounds (I) can finally be cleaved off the solid support to give compounds of the formula (IX). However, it is 35 also possible for the products at all other intermediate stages of the synthesis to be cleaved off the solid phase. Besides this complete synthesis, however, it is also possible to carry out only some of the steps in the synthesis. For example, 40 the synthesis can be terminated at the stage of compounds (VII) (scheme I) or else the synthesis can be started at the stage of compounds (V) and terminated at the stage of compounds (VII) or (I). 45 An essential step in the novel process is the cyclization using compounds of the formula (VI).

22 The novel process can be carried out in a series of parallel automated synthesis stages. Mixtures of reactants can also be employed in one synthesis stage or parallel synthesis stages. 5 The novel process is very suitable for generating a large number of structurally diverse compounds of the formulae I, VII or IX because the substituents R 1 to R 8 can easily be varied widely, independently of one another. 10 Another advantage of the novel process is that Fmoc-protected anthranilates, which are easy to prepare, can be used for the synthesis. These urethane-protected anthranilates are, on the one hand, obtainable in large amounts in a one-pot reaction without purification and, on the other hand, stable on storage. 15 The preparation of these urethane-protected anthranilates corresponds to the process for preparing the Fmoc-protected amino acids and is disclosed in the literature. 20 Compared with reactions in solution, the reactions on the polymeric support have great advantages. Thus, the products contain considerably fewer impurities, so that chromatographic fractionation is unnecessary. The good yields, the high purity of the cleaved-off products and the simple reaction procedure in the 25 novel process make its use in combinatorial synthesis very attractive. It is a particular advantage of this process, for example, that it is unnecessary to use costly self-prepared polymer-bound starter molecules because low-cost precursors are commercially available and can be used. 30 The process is also particularly suitable for preparing defined mixtures of quinazolinedione derivatives of the formula I, VII or IX. This is done not by starting from a single substance bound to the solid phase, but by binding a mixture, preferably a mixture 35 of known substances and known stoichiometry, to the solid phase. The reactant bound to the solid phase is then reacted with other reactants in the process as described. 40 The advantage of this solid-phase synthesis is the rapid generation of a large number of individual compounds which can subsequently be investigated for their activity in test systems. This large number of individual compounds form substance libraries. 45 23 Tests can be carried out either on previously fractionated substance mixtures or directly on the mixtures. In the second case, a potential active substance is identified after the testing. 5 The invention furthermore relates to the use of the novel process for preparing bound or free quinazolinedione derivatives of the formulae I, VII or IX for generating substance libraries. 10 By this is meant both the above-described generation of quinazolinedione mixtures and the preparation of a large number of single substances of the formulae I, VII or IX, for example by carrying out many similar reactions, with one reactant having been altered in each case, in parallel. 15 Carrying out many similar reactions in parallel makes it possible rapidly to vary systematically all the functional groups in the formulae I, VII or IX. 20 The substance libraries which can be generated in this way can be rapidly tested for a particular activity in mass screening. This greatly speeds up the search for potent active substances. The following examples serve to illustrate the invention further 25 without restricting it in any way. Example 1 0 30 R4 OH R3 N 35 0 0 40 0 N A -1 1. TBTU/HOBT/DiPEA R N A

R

2 Ri 0 2. Piperidine/NMP / 2 Ri 0 45 (3N R (II)

(V)

24 100 mg (about 0.1 mmol) of polymer-bound amino acid (polymer eg. Cl-trityl resin, Wang resin, Rink resin) in 4 ml of NMP in a 5 ml syringe with polypropylene frit and septum were shaken twice with 0.3 mmol of the appropriate 2-N-Fmoc-aminobenzoic acid, 85 pl 5 (0.5 mmol) of diisopropylethylamine, 46 mg (0.3 mmol) of hydroxybenzotriazole and 96 mg (0.3 mmol) of TBTU each time until the ninhydrin test indicated complete conversion. The mixture was filtered with suction and washed twice with 3 ml of N-methylpyrrolidone each time. 10 The polymer was shaken in 3 ml of a 40% strength solution of piperidine in N-methylpyrrolidone for 1/2 h, filtered off with suction, washed with 3 ml of N-methylpyrrolidone and again shaken in 3 ml of a 40% strength solution of piperidine in 15 N-methylpyrrolidone for 1/2 h. The polymer was filtered off with suction and washed three times with 3 ml of N-methylpyrrolidone each time, three times with 3 ml of THF and three times with 3 ml of methylene chloride. 20 0 REN A~ V 2 R 0 R3 NH 2 R 25 (Cl 3

CO)

2 CO/DIPEA 30 0 35

R

4 N N xjk y p V) 0 ( II) R3 N O R 40 20 mg (0.07 mmol) of triphosgene and then 69 pl (0.4 mmol) of diisopropylamine were added to the compound V obtained by the method in 2 ml of methylene chloride and shaken for 16 h. Filtration with suction was followed by washing three times with 45 3 ml of methylene chloride and drying under reduced pressure. Characterization took place by cleaving off the quinazolinedione (VII) from the polymer and HPLC analysis (Gromsil 80 ODS-7, ' '25 mobile phase: acetonitrile/water 0 to 100%, 15 min.) and/or 13 C-NMR (in DMSO 270 MHz). Cleavage off the resin was carried out under acidic or basic 5 conditions. 100 mg of the polymer were shaken in 3 ml of a 95% by volume solution of trifluoroacetic acid in methylene chloride for 1 h, the polymer was filtered off and the solution was evaporated 10 under reduced pressure. The following compounds were synthesized and cleaved off the polymer under acidic conditions in this way. 15 a) 3-( 1 '-carboxy-3 '-methylbutyl) -quinazoline-2,4-dione 0 0 N H 20 N O Rt = 8.6 min., 25 MS-FAB (M/z) = 276 6 (ppm) = 171.1 (KOOH), 161.7 (C2), 149.7 (Cl), 139.3, 135.3 127.5, 122.7, 115.2, 113.3 (aryl-C), 51.4 (Cl'), 37.2

(KH

2

CH(CH

3

)

2 , 24.8 (CH 2

KH(CH

3

)

2 ), 22.9 (CH 2

CH(CH

3

)

2 ), 21.7 (CH 2

CH(CH

3

)

2

)

30 b) 3-(1'-carboxyethyl)-quinazoline-2,4-dione [sic] 0 O OH 35 O N H N O 40 Rt = 5.3 min, 6 (ppm) = 171.9, 170.4 (OOH), 161.5 (C2), 149.9 (Cl), 139.3, 135.4, 127.5, 122.8, 115.2, 113.1 (aryl-C), 53.5 (Cl'), 49.5

(CH

2

)

45 c) 3-(1'-carboxy-2'-hydroxyethyl)-quinazoline-2,4-dione 26 OH ON OH N O Rt = 2 min, 10 6 (ppm) = 169.4 (OH), 161.8 (C2), 149.9 (Cl), 139.4, 135.1, 127.4, 122.5, 115.0, 113.6 (aryl-C), 58.1 (_CH 2 OH), 53.5 (Cl'). d) 3-(1'-carboxy-2-'methylpropyl)-quinazoline-2,4-dione 15 0 O N H 20 N O Rt = 7.73 min, MS-FAB 25 (M/z) = 262 6 (ppm) = 170.4 (!OOH), 161.7 (C2), 149.9 (Cl), 139.3, 135.4, 127.5, 122.8, 115.2, 113.1 (aryl-C), 57.9 (Cl'), 26.7

(!)CH

3

)

2 ), 22.1 (C(gH 3

)

2 ), 18.7 (C(CH 3

)

2

)

30 e) 3-(l'-carboxy-1'-methylethyl)-quinazoline-2,4-dione 0 N OH 35O N O Rt = 6.3 min, 40 MS-FAB (M/z) = 234 f) 3-( 1 '-carboxy-2 '-methylbutyl) -quinazoline-2,4-dione 45 27 0 5 N H O N 0 Rt = 8.5 min, 10 MS-FAB (M/z) = 262 b (ppm) = 170.4 (!OOH), 161.7 (C2), 149.9 (Cl), 139.3, 135.4, 127.5, 122.8, 115.2, 113.1 (aryl-C), 57.4 (Cl'), 32.6

(C(CH

3

)C

2

H

5 ), 24.5(C-CH 2

H

5 ), 18.0 (CH 3 ), 10.6 (KH 3

)

15 g) 3-(l'-carboxy-2'-phenylethyl)-quinazoline-2,4-dione 0 20 0 N H O N O 25 Rt = 8.5 min, MS-FAB (M/z) = 310 h) 3-(l'-carboxy-3'-thiomethylethyl)-quinazoline-2,4-dione [sic] 30 S 0 N O 35 Rt=7.6 min, MS-FAB (M/z) = 294 40 45 28 i) 3-( 1' -carboxy-2 '-p-hydroxyphenylethyl) -quinazoline-2, 4-dione [ sic] OH 5 0 N H O N O 10 Rt = 6.8 min, MS-FAB (M/z) = 328 j) 3-(1'-carboxy-2'-p-methoxyphenylethyl)-quinazoline-2,4-dione 15 [sic] 0 0 20O N H I N> O N O 25 Rt = 8.4 min, MS-FAB (M/z) = 340 k) 3-(1'-carboxy-2'-p-nitrophenylethyl)-quinazoline-2,4-dione [sic] 30 0 300 35 N H N O Rt = 8.5 min, 40 MS-FAB (M/z) = 355 1) 3-( 3 '-carboxypropyl) -quinazoline-2, 4-dione 0 0 45 N H N O 29 Rt = 6.5 min, MS-FAB (M/z) = 248 m) 3-(1l-carboxypropyl)-quinazoline-2,4-dione 5 0 N H O 10 N 0 Rt = 7.2 min, MS-FAB (M/z) = 248 15 n) 3-(1'-carboxy-5'-pentyl)naphthoquinazoline- 2 ,4-dione [sic]

NH

2 20 0 0 N H 25 N 0 Rt = 4.7 min, MS-FAB (M/z)=341 30 o) 3-(1'-carboxyethyl)-6-iodoquinazoline-2,4-dione 0 35I N ly OH 35OH N O Rt=8.2 min, 40 MS-FAB (M/z)=360 45 30 p) 3- (1'-carboxy-3'-methylbutyl)-6-iodoquinazoline-2,4-dione 0 5 0 I ~z N H N O 10 Rt = 10.1 min. 6 (ppm) = 170.9 (!0OH), 160.5 (C2), 149.5 (Cl), 143.3, 138.9, 135.4, 117.6, 115.4, 85.5 (aryl-C), 51.6 (Cl'), 37.2

(CH

2

CH(CH

3 )2), 24.8 (CH 2

CH(CH

3 )2), 22.9 (CH 2

CH(CH

3 )2), 21.7 (CH 2 CH(!H3)2) 15 q) 3-(1'-carboxyamido-3'-methylbutyl)-quinazoline- 2 ,4-dione [sic] 0 20

NH

2 IIz N N N 25 R- = 7.81 min. MS-FAB (M/z) = 275 3-(1'-carboxy-2'-(3"-N-tert-butyloxycarbonylindolyl)ethyl) quinazoline-2,4-dione [sic] was obtained by basic cleavage off 30 (for base-labile compounds) after synthesis and following instruction [sic]. 100 mg of polymer-bound quinazolinedione of the formula VII were mixed with 3 ml of THF and 1 ml of a 1M solution of LiOH in water 35 and shaken for 4 h. The solution was filtered and mixed with 5 ml of ethyl acetate and 5 ml of concentrated acetic acid, and the phases were separated. Concentration of the organic phase afforded the quinazolinediones of the formula VII 40 45 31 r) 3-(1'-carboxy-2'-(3"-N-tert-butyloxycarbonylindolyl)ethyl) quinazoline-2,4-dione [sic] 5 N 0 0 N OH 10 N O Rt = 10.9 min. MS-FAB (M/z) = 449 15 Example 2 Derivatization of the compounds of the formula VII to give compounds of the formula I. 20 112 mg (about 0.1 mmol) of polymer-bound quinazolinedione VII were suspended in 2 ml of THF under N 2 , and 1 ml (0.5 mmol) of a 0.5 M solution of KHMDS in toluene was added. The suspension was shaken for 2 h and then 0.5 g (3 mmol) of benzyl bromide dissolved in 2 ml of THF was added, and shaking was continued 25 (16 h). After filtration and washing with THF, treatment with KHMDS and benzyl bromide was repeated. The product was detached from the polymer under acidic or basic conditions as described in Example 1. 30 a) 1-Phenylmethyl-3-(1'-carboxy-3'-methybutyl)-quinazoline-2,4 dione [sic] 35 0 N H 0 40 Rt = 11.3 min. MS-FAB (M/z) = 366 45

Claims (7)

1. A process for preparing compounds of the formula I 5 10 R N R 18 R which comprises reacting compounds of the formula II 15 R

2 R 0 20 with an N-protected 2-aminobenzoic acid derivative of the formula III 0 R 4 25 Q R

3 NH R 17 R 30 or with an isatoic anhydride derivative of the formula IV 0 35 R R 3 NH 0 to give compounds of the formula V 40 40 R 1 45 R3 NH 2 R 338/97 UP/Ke 013.06.1997 2 and then reacting the latter with compounds of the formula VI 0 D k(VI), 10 to give compounds of the formula VII 0 15 A isN aR 2 0X (VII) R3b NH O 0R 2R and subsequently alkylating with compounds of the formula 20 VIII (R 8 -FG) to give compounds of the formula I, where the variables and substituents mentioned in formulae I to VIII have the following meanings: 25 (P) a solid phase (A) 0, NH, R 1 , R 2 independently of one another 30 hydrogen, substituted or unsubstituted Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl, aryl, hetaryl with one or more heteroatoms in the ring system, Ci-C 4 -alkylaryl or Ci-C 4 -alkylhetaryl with one or more heteroatoms in the ring or R 1 and R 2 together form a ring with 3 to 8 carbon 35 atoms in the ring, R 3 , R 4 independently of one another H, Ci-C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, aryl, hetaryl, halogen, NR 5 R 6 , OR 6 , SR 6 , COOR 6 , CONR 5 R 6 , nitro, 40 cyano or R 3 and R 4 together form a fused aromatic or aliphatic system, R 5 H, substituted or unsubstituted Ci-C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 8 -alkynyl, aryl, C 3 -C 8 -cycloalkyl with 45 or without one or more heteroatoms in the ring, Ci-C 4 -alkylaryl, Ci-C 4 -alkylhetaryl, C 1 -C 6 -alkyl-(Z)m-CO-, C 3 -C 6 -alkenyl-(Z)m-CO-, aryl-(Z)m-CO-, V 4

4. A process for preparing compounds of the formula VII, which comprises reacting compounds of the formula V with compounds of the formula VI to give compounds of the formula VII, where the formulae and the variables and substituents mentioned in 5 formulae V to VII have the meanings stated in claim 1.

5. The use of a process as claimed in any of claims 1 to 4 for preparing substance libraries. 10

6. A process for preparing substance libraries which comprise a plurality of compounds of the formula IX 0 4 O 15 RN G Y2 R 0 (IX) 3 N O R R i R 20 where R 9 is hydrogen or R 8 , G is NRiOR 11 or OR 11 and RIO and R 11 are, independently of one another, R 6 , and the other variables and substituents R 1 to R 8 have the meanings stated in claim 1, wherein compounds of the formula I or VII are cleaved off the solid phase. 25

7. The use of the substance libraries obtained as claimed in claims 5 or 6 in mass screening. 30 35 40 45