Carboxylic acids and the esters thereof, pharmaceutical compositions thereto and processes for the preparation thereof

Abstract

The present invention relates to carboxylic acids and esters of general formula 1

Description

DETAILED DESCRIPTION OF THE INVENTION

[0002] The present invention relates to new carboxylic acids and the esters thereof of general formula 2

[0003] the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.

[0004] In the above general formula I

[0005] R denotes a monounsaturated 5- to 7-membered diaza, triaza or S,S-dioxido-thiadiaza heterocycle,

[0006] while the above-mentioned heterocycles are linked via a nitrogen atom and

[0007] are characterised by a carbonyl group or sulphonyl group each flanked by two nitrogen atoms,

[0008] may be substituted at one or at two carbon atoms by an alkyl, phenyl, pyridinyl, thienyl or 1,3-thiazolyl group, while the substituents may be identical or different,

[0009] and the double bond of one of the above-mentioned unsaturated heterocycles may be fused to a benzene, pyridine or quinoline ring,

[0010] while the phenyl, pyridinyl, thienyl, or 1,3-thiazolyl groups contained in R as well as benzo-, pyrido- and quinolino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, nitro, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, trifluoromethyl, alkoxycarbonyl, carboxy, dialkylamino, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, methylenedioxy, aminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while the substituents may be identical or different,

[0011] Ar denotes a phenyl, 1-naphthyl, 2-naphthyl, tetrahydro-1-naphthyl, tetrahydro-2-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]furyl, 2,3-dihydrobenzo[b]furyl, benzo[b]thienyl, pyridinyl, quinolinyl or isoquinolinyl group,

[0012] while the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, carboxy, dialkylamino, nitro, hydroxy, amino, alkylamino, acetylamino, propionylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,

[0013] Y denotes the methylene or the —NH— group,

[0014] Y1 denotes the carbon or the nitrogen atom,

[0015] X1 denotes the pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, denotes a hydrogen atom or a carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0016] X3 and X4 in each case denote the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0017] with the proviso that at least one but also not more than one of the groups X1, X2, X3 or X4 contains an optionally esterified carboxylic acid function, and

[0018] R1 denotes a group of general formula 3

[0019] wherein

[0020] Y2 denotes the carbon or, if m assumes the value 0, also the nitrogen atom,

[0021] Y3, which is always different from Y1, denotes the carbon or nitrogen atom,

[0022] X2 denotes a group of general formula

CH2CO2R2,  (III)

[0023] wherein

[0024] R2 denotes the hydrogen atom or a C1-5-alkyl group,

[0025] or, if Y2 is the carbon atom, it may also denote the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0026] m denotes the numbers 0 or 1,

[0027] p denotes the numbers 0, 1, 2 or 3 and

[0028] q denotes the numbers 0, 1 or 2,

[0029] while the sum of m, p and q may assume the values 1, 2 or 3,

[0030] or one of the groups (IIb), (IIc) or (IId) 4

[0031] wherein

[0032] X2b, X2c and X2d each denote the hydrogen atom or a carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0033] o denotes the numbers 0, 1, 2 or 3 and

[0034] R3 denotes the hydrogen atom, the fluorine, chlorine or bromine atom, an alkyl, alkoxy, nitro, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, acetyl or cyano group,

[0035] while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 5 carbon atoms and may be straight-chain or branched.

[0036] The present invention relates to racemates, if the compounds of general formula I have only one chiral element. The application also includes, however, the individual diastereomeric pairs of antipodes or the mixtures thereof which are obtained when there is more than one chiral element in the compounds of general formula 1, as well as the individual optically active enantiomers of which the above-mentioned racemates are composed.

[0037] The compounds of general formula I have valuable pharmacological properties, which are based on their selective CGRP-antagonistic properties. The invention further relates to pharmaceutical compositions containing these compounds, the use thereof and the preparation thereof.

[0038] Preferred compounds of the above general formula I are those wherein

[0039] R denotes a monounsaturated 5- to 7-membered diaza, triaza or S,S-dioxido-thiadiaza heterocycle,

[0040] while the above-mentioned heterocycles are linked via a nitrogen atom and

[0041] are characterised by a carbonyl group or sulphonyl group in each case flanked by two nitrogen atoms,

[0042] may be substituted at a carbon atom by a phenyl, pyridinyl, thienyl or 1,3-thiazolyl group,

[0043] and the double bond of one of the above-mentioned unsaturated heterocycles may be fused to a benzene, pyridine or quinoline ring,

[0044] while the phenyl, pyridinyl, thienyl, or 1,3-thiazolyl groups contained in R as well as benzo-, pyrido- and quinolino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, trifluoromethyl, amino, cyano or acetylamino groups, while the substituents may be identical or different,

[0045] Ar denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl or 2,3-dihydrobenzo[b]fur-5-yl group,

[0046] while the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by alkyl groups, alkoxy, trifluoromethyl, nitro, hydroxy, amino, aminocarbonyl, acetyl or cyano groups and the substituents may be identical or different,

[0047] Y denotes the methylene or the —NH— group,

[0048] Y1 denotes the carbon or the nitrogen atom,

[0049] X1 denotes a pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0050] X3 and X4 each denote the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0051] with the proviso that at least one but also not more than one of the groups X1, X2, X3 or X4 contains an optionally esterified carboxylic acid function, and

[0052] R1 denotes a group of general formula 5

[0053] wherein

[0054] Y2 denotes the carbon atom or, if m assumes the value 0, may also denote the nitrogen atom,

[0055] Y3, which is always different from Y1, denotes the carbon or the nitrogen atom,

[0056] X2 denotes a group of general formula

CH2CO2R2,  (III)

[0057] wherein

[0058] R2 denotes the hydrogen atom or a C1-5-alkyl group,

[0059] or, if Y2 is the carbon atom, also denotes the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0060] m denotes the numbers 0 or 1,

[0061] p denotes the numbers 0, 1 or 2 and

[0062] q denotes the numbers 0, 1 or 2,

[0063] while the sum of m, p and q may assume the values 1 or 2,

[0064] or one of the groups 6

[0065] wherein

[0066] X2b and X2d each denote the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol,

[0067] o denotes the numbers 0, 1, 2 or 3 and

[0068] R3 denotes the hydrogen atom, the fluorine, chlorine or bromine atom, a methyl, methoxy, nitro, trifluoromethyl or cyano group,

[0069] while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 4 carbon atoms and may be branched or unbranched,

[0070] the tautomers, the diastereomers, the enantiomers and the salts thereof.

[0071] Particularly preferred compounds of the above general formula I are those wherein

[0072] R denotes a monounsaturated 5- to 7-membered diaza, triaza or S,S-dioxido-thiadiaza heterocycle,

[0073] while the above-mentioned heterocycles are linked via a nitrogen atom and

[0074] are characterised by a carbonyl group or sulphonyl group each flanked by two nitrogen atoms,

[0075] may be substituted at a carbon atom by a phenyl group,

[0076] and the double bond of one of the above-mentioned unsaturated heterocycles may be fused to a benzene, pyridine or quinoline ring,

[0077] while the phenyl groups contained in R as well as benzo-, pyrido- and quinolino-fused heterocycles may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, or cyano groups, while the substituents may be identical or different,

[0078] Ar denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl or 2,3-dihydrobenzo[b]fur-5-yl group,

[0079] while the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, hydroxy or amino groups and the substituents may be identical or different,

[0080] Y denotes the methylene or —NH— group,

[0081] Y1 denotes the carbon or nitrogen atom,

[0082] X1 denotes a pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol,

[0083] X3 and X4 each denote the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol,

[0084] with the proviso that at least one but also not more than one of the groups X1, X2, X3 or X4 contains an optionally esterified carboxylic acid function, and

[0085] R1 denotes a group of general formula 7

[0086] wherein

[0087] Y2 denotes the carbon or, if m assumes the value 0, also denotes the nitrogen atom,

[0088] Y3, which is always different from Y1, denotes the carbon or the nitrogen atom,

[0089] X2 denotes a group of general formula

CH2CO2R2,  (III)

[0090] wherein

[0091] R2 denotes the hydrogen atom or a straight-chain or branched C1-4-alkyl group,

[0092] or, if Y2 is the carbon atom, also denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol,

[0093] m denotes the numbers 0 or 1,

[0094] p denotes the numbers 0, 1 or 2 and

[0095] q denotes the numbers 0, 1 or 2,

[0096] while the sum of m, p and q may assume the values 1 or 2,

[0097] or one of the groups 8

[0098] wherein

[0099] X2b and X2d each denote the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol,

[0100] o denotes the numbers 0, 1 or 2 and

[0101] R3 denotes the hydrogen atom, the fluorine, chlorine or bromine atom, a methyl, methoxy or trifluoromethyl group,

[0102] while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 4 carbon atoms and may be straight-chain or branched,

[0103] the tautomers, the diastereomers, the enantiomers and the salts thereof.

[0104] Most particularly preferred compounds of the above general formula (I) are those wherein

[0105] R denotes the 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl or 3,4-dihydro-2,2-dioxido-2, 1, 3-benzothiadiazin-3-yl group,

[0106] Ar denotes the 3,5-dibromo-4-hydroxyphenyl, 4-amino-3,5-dibromophenyl, 4-bromo-3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 3,4-dibromophenyl, 3-bromo-4,5-dimethylphenyl, 3,5-dibromo-4-methylphenyl, 3-chloro-4-methylphenyl, 3,4-difluorophenyl, 4-hydroxyphenyl, 1-naphthyl, 3,5-dibromo-4-fluorophenyl, 3,5-bis-(trifluoromethyl)-phenyl, 3,4,5-trimethylphenyl, 3-(trifluoromethyl)-phenyl, 3,5-dimethyl-4-methoxyphenyl, 4-amino-3,5-dichlorophenyl, 2,4-bis-(trifluoromethyl)-phenyl, 3,4,5-tribromophenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 4-bromo-3,5-dichlorophenyl, 2-naphthyl, 2,3-dihydrobenzo[b]fur-5-yl, 1,2,3,4-tetrahydro-1-naphthyl or 2,3-dichlorophenyl group,

[0107] Y denotes the methylene or the —NH— group,

[0108] Y1 denotes the carbon or the nitrogen atom,

[0109] X1 denotes a pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, the hydrogen atom, the carboxylic acid or the methoxycarbonyl group and

[0110] R1 denotes a group of general formula 9

[0111] wherein

[0112] Y2 denotes the carbon atom or, if m assumes the value 0, also the nitrogen atom,

[0113] Y3, which is always different from Y1, denotes the carbon or the nitrogen atom,

[0114] X2 denotes a group of general formula

CH2CO2R2,  (III)

[0115] wherein

[0116] R2 denotes the hydrogen atom or a straight-chain or branched C1-4-alkyl group,

[0117] or, if Y2 is the carbon atom, also denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol,

[0118] m denotes the numbers 0 or 1,

[0119] p and q in each case denotes the numbers 0, 1 or 2,

[0120] while the sum of m, p and q may assume the values 1 or 2,

[0121] or one of the groups 10

[0122] wherein

[0123] X2b denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol,

[0124] X2d denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol,

[0125] o denotes the numbers 0, 1 or 2 and

[0126] R3 denotes the hydrogen atom or the trifluoromethyl group,

[0127] while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 4 carbon atoms and may be straight-chain or branched,

[0128] the tautomers, the diastereomers, the enantiomers and the salts thereof.

[0129] The following are mentioned as examples of particularly preferred compounds:

[0130] (1) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetate,

[0131] (2) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetic acid,

[0132] (3) 1,1-dimethylethyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-1-piperidineacetate,

[0133] (4) 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-1-piperidineacetic acid,

[0134] (5) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetate,

[0135] (6) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetic acid,

[0136] (7) ethyl endo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylate,

[0137] (8) endo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylic acid,

[0138] (9) ethyl exo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylate,

[0139] (10) exo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylic acid,

[0140] (11) ethyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-1-piperidineacetate,

[0141] (12) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4-acetate,

[0142] (13) 1′-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4-acetic acid,

[0143] (14) ethyl 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-1-piperidineacetate,

[0144] (15) ethyl 4-{1-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0145] (16) ethyl 4-{1-[3,5-dichloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0146] (17) ethyl 4-{1-[3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0147] (18) ethyl 4-{1-[3-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0148] (19) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0149] (20) ethyl 4-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0150] (21) ethyl 4-{4-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-1-piperazinyl}-1-piperidineacetate,

[0151] (22) 4-{1-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0152] (23) 4-{1-[3,5-dichloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0153] (24) 4-{1-[3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0154] (25) 4-{1-[3-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-4,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0155] (26) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}1-piperazineacetic acid,

[0156] (27) 4-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0157] (28) 4-{4-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-1-piperazinyl}-1-piperidineacetic acid,

[0158] (29) 1,1-dimethylethyl 4-{1-[3,4-difluoro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0159] (30) methyl 1′-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetate,

[0160] (31) ethyl 4-{1-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetate,

[0161] (32) ethyl(R,S)-4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetate,

[0162] (33) methyl 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate,

[0163] (34) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate,

[0164] (35) 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid,

[0165] (36) 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid,

[0166] (37) methyl 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate,

[0167] (38) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate,

[0168] (39) 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylic acid,

[0169] (40) 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylic acid,

[0170] (41) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(R)-[1,4′]bipiperidinyl-2-carboxylate,

[0171] (42) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-(R)-[1,4′]bipiperidinyl-2-carboxylate,

[0172] (43) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(S)-[1,4′]bipiperidinyl-2-carboxylate,

[0173] (44) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-(S)-[1,4′]bipiperidinyl-2-carboxylate,

[0174] (45) 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(R)-[1,4′]bipiperidinyl-2-carboxylic acid,

[0175] (46) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-(R)-[1,4′]bipiperidinyl-2-carboxylic acid,

[0176] (47) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-(S)-[1,4′]bipiperidinyl-2-carboxylic acid,

[0177] (48) 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(S)-[1,4′]bipiperidinyl-2-carboxylic acid,

[0178] (49) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4′-carboxylate,

[0179] (50) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4′-carboxylate,

[0180] (51) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4′-carboxylic acid,

[0181] (52) 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4′-carboxylic acid,

[0182] (53) 1′-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetic acid,

[0183] (54) 4-{1-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetic acid,

[0184] (55) ethyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoate,

[0185] (56) ethyl 3-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoate,

[0186] (57) methyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoate,

[0187] (58) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinylmethyl}-benzoate,

[0188] (59) ethyl 4-{2-[1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl]-ethyl}-benzoate,

[0189] (60) methyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoate,

[0190] (61) methyl 3-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoate,

[0191] (62) ethyl 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoate,

[0192] (63) ethyl 3-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoate,

[0193] (64) methyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoate,

[0194] (65) methyl 4-{2-[1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl]-ethyl}-benzoate,

[0195] (66) methyl 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoate,

[0196] (67) methyl 3-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoate,

[0197] (68) 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoic acid,

[0198] (69) 3-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoic acid,

[0199] (70) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoic acid,

[0200] (71) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinylmethyl}-benzoic acid,

[0201] (72) 4-{2-[1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl]-ethyl}-benzoic acid,

[0202] (73) 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoic acid,

[0203] (74) 3-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoic acid,

[0204] (75) 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoic acid,

[0205] (76) 3-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoic acid,

[0206] (77) 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-terahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoic acid,

[0207] (78) 4-{2-[1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl]-ethyl}-benzoic acid,

[0208] (79) 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoic acid,

[0209] (80) 3-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoic acid,

[0210] (81) ethyl 4-{1-[3-(1-naphthyl)-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-alanyl]-4-piperidinyl}-1-piperazineacetate,

[0211] (82) 4-{1-[3-(1-naphthyl)-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin -3-yl)-1-poperidinyl]carbonyl]-D-alanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0212] (83) methyl 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-5-thiazolecarboxylate,

[0213] (84) methyl 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-4-thiazolecarboxylate,

[0214] (85) 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-5-thiazolecarboxylic acid,

[0215] (86) 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-4-thiazolecarboxylic acid,

[0216] (87) methyl 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-4-thiazolecarboxylate,

[0217] (88) methyl 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-5-thiazolecarboxylate,

[0218] (89) 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin -3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-4-thiazolecarboxylic acid,

[0219] (90) 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin -3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-5-thiazolecarboxylic acid,

[0220] (91) 4-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin -3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-1-piperidineacetic acid,

[0221] (92) 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-1-piperidineacetic acid,

[0222] (93) 1,1-dimethylethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0223] (94) 1,1-dimethylethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0224] (95) ethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0225] (96) ethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate,

[0226] (97) 4-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin- 3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0227] (98) 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid,

[0228] (99) (R,S)-4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0229] (100) (R,S)-4-{1-[2-[(3,5-dibromo-4-fluorophenyl)methyl]-4-[4-(3,4-dihydro -2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0230] (101) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0231] (102) (R,S)-4-{1-[2-[[3,5-bis-(trifluoromethyl)-phenyl]methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0232] (103) (R,S)4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4,5-trimethylphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0233] (104) (R,S)-4-{1-[2-[(3-bromo-4,5-dimethylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0234] (105) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0235] (106) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0236] (107) (R,S)-4-{1-[2-[(4-amino-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro -2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0237] (108) (R,S)-4-{1-[2-[[2,4-bis-(trifluoromethyl)-phenyl]methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0238] (109) (R,S)-4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro -2(1H)-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0239] (110) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4,5-tribromophenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl)-1-piperazineacetic acid,

[0240] (111) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0241] (112) (R,S)-4-(1-[2-[(3,4-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0242] (113) (R,S)-4-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro -2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0243] (114) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0244] (115) (R,S)-4-{1-[2-[(2,3-dihydrobenzo[b]fur-5-yl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0245] (116) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1,2,3,4-tetrahydro-1-naphthyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0246] (117) (R,S)-4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0247] (118) (R,S)-4-{1-[2-[(2,3-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0248] (119) ethyl(R,S)-4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetate,

[0249] (120) (R,S)-4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid,

[0250] (121) (R,S)-4-{4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-piperazinyl}-1-piperidineacetic acid,

[0251] (122) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl) -1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate,

[0252] (123) methyl 1-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate,

[0253] (124) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate,

[0254] (125) methyl 1-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate,

[0255] (126) 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl) 1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid,

[0256] (127) 1-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid,

[0257] (128) ethyl 4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0258] (129) ethyl 4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0259] (130) ethyl 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate,

[0260] (131) ethyl 4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro 3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0261] (132) ethyl 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate,

[0262] (133) ethyl 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate,

[0263] (134) 4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid,

[0264] (135) 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylic acid,

[0265] (136) 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylic acid,

[0266] (137) 4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid,

[0267] (138) ethyl 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate,

[0268] (139) 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylic acid,

[0269] (140) ethyl 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl)-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate,

[0270] (141) ethyl 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate,

[0271] (142) ethyl 4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0272] (143) 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylic acid,

[0273] (144) 4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid,

[0274] (145) 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylic acid,

[0275] (146) 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylic acid,

[0276] (147) ethyl 4-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate,

[0277] (148) ethyl 4-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate,

[0278] (149) 4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di-methyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid,

[0279] (150) ethyl 4-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0280] (151) ethyl 1-{1-[2-[(3,4-dibromophenyl)methyl]4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate,

[0281] (152) ethyl 1-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate,

[0282] (153) ethyl 1-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate,

[0283] (154) ethyl 1-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate,

[0284] (155) ethyl 1-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate,

[0285] (156) 1-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid,

[0286] (157) 1-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di-methyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid,

[0287] (158) 1-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid,

[0288] (159) 1-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid,

[0289] (160) 1-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid,

[0290] (161) ethyl 4-{1-[3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-phenylalanyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0291] (162) 4-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid,

[0292] (163) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-phenylalanyl]-[1,4′]bipiperidinyl-4-acetate,

[0293] (164) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-phenylalanyl]-[1,4′]bipiperidinyl-4-acetic acid,

[0294] (165) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate,

[0295] (166) ethyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate and the salts thereof.

[0296] The compounds of general formula I are prepared by methods known in principle. The following methods have proved particularly suitable for preparing the compounds of general formula I according to the invention:

[0297] In order to prepare compounds of general formula (I) wherein Y denotes the NH group and neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined:

[0298] reacting piperidines of general formula 11

[0299] wherein

[0300] R is as hereinbefore defined, with carbonic acid derivatives of general formula 12

[0301] wherein

[0302] X5 denotes a nucleofugic group, preferably the 1H-imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy or the 2,5-dioxopyrrolidin-1-yloxy group,

[0303] and with primary amines of general formula 13

[0304] wherein

[0305] neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined.

[0306] The fundamentally two-step reactions are normally carried out as one-pot processes, in which, preferably, in the first step, one of the two components (IV) or (VI) is reacted with equimolar amounts of the carbonic acid derivative of general formula (V) in a suitable solvent at lower temperature, then at least equimolar amounts of the other component (IV) or (VI) are added and the reaction is completed at a higher temperature. The reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonate) of a tertiary base, for example triethylamine, N-ethyldiisopropylamine, pyridine, 1,5-diaza-bicyclo-[4,3,0]-non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]-undec-7-ene. The solvents used, which should be anhydrous, may be for example tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, while if bis-(trichloromethyl)-carbonate is used as the carbonyl component anhydrous chlorohydrocarbons, for example dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The reaction temperatures for the first reaction step are between −30° C. and +25° C., preferably-5° C. and +10° C., for the second reaction step between +15° C. and the boiling temperature of the solvent used, preferably between +20° C. and +70° C. (cf. also: H. A. Staab and W. Rohr, “Synthesen mit heterocyclischen Amiden (Azoliden)”, Neuere Methoden der Präparativen Organischen Chemie, Volume V, p. 53-93, Verlag Chemie, Weinheim/Bergstr., 1967; P. Majer and R. S. Randad, J. Org. Chem. 59, p.1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, Tetrahedron Letters 24 (42), 4569-4572 (1983)).

[0307] b) In order to prepare compounds of general formula (I) wherein Y denotes the CH2 group and neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined:

[0308] Coupling a carboxylic acid of general formula 14

[0309] wherein

[0310] neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined,

[0311] with a piperidine of general formula 15

[0312] wherein

[0313] R has the meanings given hereinbefore.

[0314] The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N-N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably −20 and +25° C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.

[0315] The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula (I) (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the carboxylic acid of general formula (VII) which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process, using the above-mentioned solvents and at temperatures between −20 and +25° C., preferably 0° C. and +25° C.

[0316] c) In order to prepare compounds of general formula (I) wherein Y denotes the CH2 group and neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined:

[0317] Coupling a compound of general formula 16

[0318] wherein

[0319] neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined, and Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, a C1-10-alkylsulphonyloxy group, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, while the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted in the carbon skeleton by 1 or 2 methyl groups, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzo-triazol-1-yloxy or azide group,

[0320] with a piperidine of general formula 17

[0321] wherein

[0322] R is as hereinbefore defined.

[0323] The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably −10° C. and +30° C., and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.

[0324] d) In order to prepare compounds of general formula (I) wherein neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined:

[0325] Coupling a carboxylic acid of general formula 18

[0326] wherein

[0327] Ar, R and Y are as hereinbefore defined,

[0328] with a cyclic secondary amine of general formula 19

[0329] wherein

[0330] neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise the groups are as hereinbefore defined.

[0331] The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N-N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably −20 and +25° C. If necessary, N-ethyl-diisopropylamine (DIEA) (Hünig base) is preferably used as an additional auxiliary base.

[0332] The so-called anhydride process is used as a further coupling method for synthesising compounds of general formula (I) (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27). The Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride of the carboxylic acid of general formula (IX) which is to be coupled and monoisobutyl carbonate is obtained, using isobutyl chlorocarbonate in the presence of bases such as 4-methyl-morpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines of general formula (X) are carried out in a one-pot process, using the above-mentioned solvents and at temperatures between −20 and +25° C., preferably 0° C. and +25° C.

[0333] e) In order to prepare compounds of general formula (I) wherein neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise all groups are as hereinbefore defined:

[0334] Coupling a compound of general formula 20

[0335] wherein

[0336] Ar, R and Y are as hereinbefore defined and Nu denotes a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, a C1-10-alkylsulphonyloxy group, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, while the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted in the carbon skeleton by 1 or 2 methyl groups, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,

[0337] with a cyclic secondary amine of general formula 21

[0338] wherein

[0339] neither X1 nor X3 nor X4 nor R1 contains a free carboxylic acid function, but otherwise the groups are as hereinbefore defined.

[0340] The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably −10° C. and +30° C., and optionally in the presence of solvents. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or caesium carbonate, alkali metal acetates, e.g. sodium or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as the auxiliary bases, water may also be added to the reaction mixture as cosolvent.

[0341] f) In order to prepare compounds of general formula (I) wherein X1, X3, X4 or R1 contains a free carboxylic acid function, but otherwise all the groups are as hereinbefore defined:

[0342] hydrolysis of carboxylic acid esters of general formula (I), wherein either X1 or X3 or X4 or R1 contains a carboxylic acid ester function and all the other groups are as hereinbefore defined. The hydrolysis may be carried out with acid or alkaline catalysis under the conditions familiar to those skilled in the art. Acid-catalysed hydrolysis takes place in the presence of strong organic or inorganic acids, for example methanesulphonic acid, p-toluenesulphonic acid, hydrochloric acid, hydrobromic acid or sulphuric acid, preferably in the presence of water-miscible solvents, for example methanol, ethanol or 1,4-dioxane, and at temperatures between 0° C. and the boiling temperature of the hydrolysis mixture. It is advantageous to carry out alkaline saponification of the carboxylic acid esters of general formula (I), optionally also in the presence of water-miscible cosolvents. To do this, at least 1 equivalent, based on the particular carboxylic acid ester, of an inorganic base such as aqueous lithium hydroxide solution, sodium, potassium or barium hydroxide solution is used. Suitable temperatures are between 0° C. and 50° C., room temperature being preferred. The desired acid can be released from the salt initially obtained by acidification in known manner.

[0343] The new carboxylic acids and carboxylic acid esters of general formula (I) according to the invention contain one or more chiral centres. If for example there are two chiral centres the compounds may occur in the form of two pairs of diastereomeric antipodes. The invention covers the individual isomers as well as the mixtures thereof.

[0344] The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.

[0345] Racemates covered by general formula (I) may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or (−)-monomethyl tartrate or (+)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine or (S)-brucine.

[0346] According to a conventional method of separating isomers, the racemate of a compound of general formula (I) is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is shows a sufficient difference in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. dilute hydrochloric acid or aqueous methanesulphonic acid, and in this way the corresponding free compound is obtained in the (+) or (−) form.

[0347] The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula I may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.

[0348] The starting compounds of general formula (IV) may be obtained, if they are not known from the literature or even commercially available, according to the processes described in WO 98/11128 and DE 199 52 146. The starting compounds of general formula (V) are commercially available. Compounds of general formula (VI) may be obtained by methods familiar to the peptide chemist from protected phenylalanines and amines of general formula (X). The starting compounds of general formula (VII) are obtained for example by reacting cyclic secondary amines of general formula (X) with 2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids and subsequently hydrolytically cleaving the alkyl group. The 2-(alkoxycarbonylmethyl)-3-aryl-propanoic acids required may be prepared analogously to methods known from the literature (Saul G. Cohen and Aleksander Milovanovic, J. Am. Chem. Soc. 90, 3495-3502 [1968]; Hiroyuki Kawano, Youichi Ishii, Takao lkariya, Masahiko Saburi, Sadao Yoshikawa, Yasuzo Uchida and Hidenori Kumobayashi, Tetrahedron Letters 28, 1905-8 [1987]). Carboxylic acids of general formula IX have been described in WO 98/11128 or may be prepared using the methods described therein from generally available starting materials. The cyclic secondary amines of general formula (X) may be synthesised from compounds of general formula 22

[0349] wherein PG denotes a cleavable protective group, for example by hydrogenolysis of a phenylmethyl group. The preliminary products for synthesising the compounds of general formula (XII) are obtainable from starting materials which are commercially available or easily obtained by common methods. Finally, the starting compounds of general formulae VIII and XI may be prepared from the corresponding carboxylic acids (VII) or (IX) using known standard methods.

[0350] The compounds of general formula I obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids. Suitable acids include for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.

[0351] Moreover, the new compounds of formula (I), if they contain a carboxylic acid function, may if desired be converted into the addition salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable addition salts thereof. Suitable bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

[0352] The new compounds of general formula I and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies. The compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.

[0353] The following experiments were carried out to demonstrate the affinity of the compounds of general formula I for human CGRP-receptors and their antagonistic properties:

[0354] A. Binding Studies With SK-N-MC Cells (Expressing the Human CGRP Receptor)

[0355] SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer mixed with 0.02% EDTA, and isolated by centrifuging. After resuspension in 20 ml of “Balanced Salts Solution” [BSS (in mM): NaCl 120, KCl 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100×g and resuspended in BSS. After the number of cells has been determined, the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000×g. The supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40 enriched with 1% bovine serum albumin and 0.1% bacitracin), and resuspended (1 ml/1000000 cells). The homogenised product is frozen at −80° C. The membrane preparations are stable for more than 6 weeks under these conditions.

[0356] After thawing, the homogenised product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 μl of the homogenised product are incubated for 180 minutes at ambient temperature with 50 pM 125I-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 μl. The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 μM human CGRP-alpha during incubation.

[0357] The concentration binding curves are analysed using computer-aided non-linear curve matching.

[0358] The compounds of general formula (I) show IC50 values ≦10000 nM in the test described.

[0359] B. CGRP Antagonism in SK-N-MC Cells

[0360] SK-N-MC cells (1 million cells) are washed twice with 250 μl incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 μl) as agonist in increasing concentrations (10−11 to 10−6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.

[0361] Intracellular cAMP is then extracted by the addition of 20 μl of 1 M HCl and centrifugation (2000×g, 4° C., for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at −20° C.

[0362] The cAMP contents of the samples are determined by radioimmunoassay (Messrs. Amersham) and the pA2 values of antagonistically acting substances are determined graphically.

[0363] The compounds of general formula (I) exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range between 10−11 and 10−5 M.

[0364] In view of their pharmacological properties the compounds of general formula I and the salts thereof with physiologically acceptable acids are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches. Moreover, the compounds of general formula I also have a positive effect on the following diseases: “complex regional pain syndrome”, non-insulin-dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridium toxin, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory diseases of the joints (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and resultant reduced blood supply to the tissues, e.g. shock and sepsis. The symptoms of menopausal hot flushes caused by vasodilatation and increased blood flow in oestrogen-deficient women are favourably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects. In addition, the compounds according to the invention have a general pain-relieving effect.

[0365] The dosage required to achieve a corresponding effect is conveniently 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, when administered intravenously or subcutaneously, and 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight when administered orally, nasally or by inhalation, 1 to 3× a day in each case.

[0366] For this purpose, the compounds of general formula I prepared according to the invention may be formulated with other active substances such as e.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anticonvulsants, histamine-H1 receptor antagonists, antimuscarinics, β-blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT1D agonists or other anti-migraine agents, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.

[0367] Thus other active substances which may be used for the combinations mentioned above include for example meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenyloin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT1D agonists such as e.g. naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan. The dosage for these active substances is expediently ⅕ of the lowest usually recommended dose to {fraction (1/1)} of the normally recommended dose, i.e. for example 20 to 100 mg of sumatriptan.

[0368] The invention further relates to the use of the compounds of general formula (I) as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as in RIA and ELISA assays, after suitable radioactive labelling, for example by direct labelling with 125I or 131I or by tritiation of suitable precursors, for example by replacing halogen atoms with tritium, and as a diagnostic or analytical aid in neurotransmitter research.

[0369] The Examples that follow are intended to illustrate the invention more fully:

[0370] Preliminary Remarks:

[0371] The compounds were prepared in some cases by conventional methods of synthesis and in other cases using methods of combined chemistry.

[0372] The automatic synthesiser used was the ASW2000 machine made by Chemspeed Ltd., Rheinstraβe 32, CH-4302 Augst, Switzerland.

[0373] As a rule, IR, 1H-NMR and/or mass spectra have been obtained for all the compounds prepared by conventional methods. Unless otherwise stated, Rf values were obtained using ready-made silica gel TLC plates 60 F254 (E. Merck, Darmstadt, Item no.1.05714) without chamber saturation. If no detailed information is given as to the configuration, it is not clear whether it is a pure enantiomer or whether partial or even complete racemisation has occurred. The following eluants or eluant mixtures were used for the chromatography:

[0374] EI A=ethyl acetate/methanol 100/5 v/v

[0375] EI B=ethyl acetate/methanol 9/1 v/v

[0376] EI C=ethyl acetate/methanol/conc. ammonia 80/20/1 v/v/v

[0377] EI D=dichloromethane/cyclohexane/methanol/conc.ammonia 70/15/15/2 v/v/v/v

[0378] EI E=ethyl acetate/glacial acetic acid 99/1 v/v

[0379] EI F=ethyl acetate/methanol/glacial acetic acid 90/10/1 v/v/v

[0380] EI G=dichloromethane/methanol/conc. ammonia 90/9/1 v/v/v

[0381] EI H=petroleum ether/ethyl acetate 4/6 v/v

[0382] EI I=dichloromethane/methanol/glacial acetic acid 90/10/2.5 v/v/v

[0383] EI K=dichloromethane/isopropanol 9/1 v/v

[0384] EI M=dichloromethane/methanol/conc. ammonia 75/25/5 v/v/v

[0385] EI N=dichloromethane/ethyl acetate 1/1 v/v

[0386] EI 0=dichloromethane/methanol 9/1 v/v

[0387] EI P=dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 60/16/5/5/0.6 v/v/v/v/v

[0388] EI Q=dichloromethane/methanol/conc. ammonia 80/20/2 v/v/v

[0389] EI R=dichloromethane/methanol/glacial acetic acid 80/20/1 v/v/v

[0390] EI S=dichloromethane/methanol 9/1 v/v (Alox TLC plates [E. Merck, Darmstadt])

[0391] EI T=dichloromethane/methanol/glacial acetic acid 70/30/3 v/v/v

[0392] EI U=ethyl acetate/petroleum ether 2/1 v/v

[0393] EI V=ethyl acetate/petroleum ether 1/4 v/v

[0394] EI W=ethyl acetate/petroleum ether 3/7 v/v

[0395] EI X=petroleum ether/ethyl acetate/glacial acetic acid 8/2/0.5 v/v/v

[0396] EI Y=ethyl acetate/petroleum ether 1/9 v/v

[0397] EI Z=toluene/petroleum ether/ethyl acetate 5/5/2 v/v/v

[0398] EI AA=ethyl acetate/petroleum ether/triethylamine 5/5/0.1 v/v/v

[0399] EI BB=dichloromethane/methanol 3/1 v/v (Alox TLC plates [E. Merck, Darmstadt])

[0400] EI DD=ethyl acetate/methanol/conc. ammonia 70/30/3 v/v/v

[0401] EI EE=dichloromethane/ethanol 9/1 v/v

[0402] EI FF=dichloromethane/ethanol 50/1 v/v

[0403] EI GG=dichloromethane/ethanol 40/1 v/v

[0404] EI HH=dichloromethane/methanol 5/1 v/v

[0405] EI II=ethyl acetate/methanol/conc. ammonia 90/10/1 v/v/v

[0406] EI KK=ethyl acetate/methanol/conc. ammonia 60/40/4 v/v/v

[0407] EI LL=ethyl acetate/methanol/conc. ammonia 50/50/5 v/v/v

[0408] EI MM=ethyl acetate/cyclohexane 1/1 v/v

[0409] EI NN=ethyl acetate/cyclohexane 2/8 v/v

[0410] EI OO=dichloromethane/methanol/conc. ammonia 70/30/3 v/v/v

[0411] The following abbreviations are used in the description of the test:

[0412] mp.: melting point

[0413] (Z): (decomposition)

[0414] DIEA: N,N-diisopropylethylamine

[0415] Boc: (1,1-dimethylethoxy)carbonyl

[0416] TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

[0417] HOBt: 1-hydroxybenzotriazole-hydrate

[0418] CDT: 1,1′-carbonyldi-(1,2,4-triazole)

[0419] PyBroP: bromo-tris-pyrrolidino-phosphonium hexafluorophosphate

[0420] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate

[0421] THF: tetrahydrofuran

[0422] DMF: dimethylformamide

[0423] EE: ethyl acetate

[0424] PE: petroleum ether

[0425] LM: solvent

[0426] ZT room temperature

[0427] Ser. no: serial no.

[0428] The meanings of the symbols consisting of letters and numbers used in the Examples are shown in the following summary: 2324252627282930313233343536

[0429] A. Preparation of Intermediate Compounds

EXAMPLE A1

[0430] (R,S)-3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-phenylalanine

[0431] 150 ml 1M sodium hydroxide solution were added to the solution of 20.0 g (0.033 mol) (R,S)-3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-phenylalanine ethyl ester in 500 ml of ethanol and the mixture was then stirred for 3.5 hours at room temperature. The solvent was eliminated using the rotary evaporator and the residue was acidified with 1 M hydrochloric acid. The precipitated precipitate was suction filtered, washed thoroughly with water and dried at 70° C. in the circulating air dryer. 10.0 g (52% of theory) of the desired colourless crystalline substance were obtained, Rf 0.62 (EI M).

[0432] IR (KBr): 1705, 1645 cm−1 (C═O)

[0433] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	IR [cm−1]	mp. [° C.]
N1	B6	OH	from N1—CO—B6—OEt	96			ESI: (M − H)− = 527/	1630, 1701	173-175
			with aq. 1M NaOH, then				529 (Br)	(C═O)
			aq. 1M HCl
N1	B7	OH	from N1—CO—B7—OEt	62	D	0.19		1705	colourless
			with aq. 1M NaOH, then					(C═O)	crystals
			aq. 1M HCl
N1	B10	OH	from N1—CO—B10—OMe	79			ESI: (M + Na)+ = 481		colourless
			with aq. 1M NaOH, then						crystals
			aq. 1M HCl
N1	B11	OH	from N1—CO—B11—OMe	61			ESI: (M + H)+ = 439		colourless
			with aq. 1M LiOH, then						crystals
			aq. citric acid
N1	B3	OH	from N1—CO—B3—OEt	95					colourless
			with aq. 1M LiOH, then						crystals
			aq. citric acid
N1	B4	OH	from N1—CO—B4—OEt	96	B	0.12	ESI: (M − H)− = 503/		colourless
			with aq. 1M NaOH, then				505/507		crystals
			aq. 1M HCl				(Cl2)
N1	B12	OH	from N1—CO—B12[α-	100	G	0.11	ESI: (M − H)− = 594/		colourless
			CO2Et]-OEt with aq.				596/598		crystals
			40% NaOH, then aq. 5M				(Br2)
			HCl
N1	B15	OH	from N1—CO—B15[α-	46	F	0.60	ESI: (M − H)− = 462;	1647	colourless
			CO2Et]-OEt with aq. 1M				(M + H)+ = 464	(C═O)	crystals
			NaOH, then aq. 1M HCl
N1	B16	OH	from N1—CO—B16[α-	100	F	0.49	ESI: (M − H)− = 526	1645	colourless
			CO2Et]-OEt with aq. 1M					(C═O)	crystals
			NaOH, then aq. 1M HCl
N1	B19	OH	from N1—CO—B19[α-	50					colourless
			CO2Et]-OEt with aq. 1M						crystals
			NaOH, then aq. 1M HCl
N1	B20	OH	from N1—CO—B20[α-	55	D	0.23	M+ = 557; ESI:		colourless
			CO2Et]-OEt with aq. 1M				(M − H)− = 556		crystals
			NaOH, then aq. 1M HCl
N1	B22	OH	from N1—CO—B22[α-	91	D	0.25	ESI: (M − H)− = 654/	1641	colourless
			CO2Et]-OEt with aq. 1M				656/658/660	(C═O)	crystals
			NaOH, then aq. 1M HCl				(Br3)
N1	B25	OH	from N1—CO—B25[α-	62	F	0.4	no M+,	1726,	colourless
			CO2Et]-OEt with aq. 1M				decomposition	1705, 1641	crystals
			KOH, then aq. 1M HCl				compatible	(C═O)
							with structure
N1	B27	OH	from N1—CO—B27[α-	87	F	0.55			colourless
			CO2Et]-OEt with aq. 1M						crystals
			NaOH, then aq. 1M HCl
N1	B29	OH	from N1—CO—B29[α-	100	D	0.46	no M+,	1640	colourless
			CO2Et]-OEt with KOH,				decomposition	(C═O)	crystals
			then aq. 10M HCl				compatible
							with structure
N1	B21	OH	from N1—CO—B21[α-	71	D	0.16	no M+,	1724, 1643	colourless
			CO2Et]-OEt with 1M				decomposition	(C═O)	crystals
			NaOH, then aq. 1M HCl				compatible
							with structure
N1	B8	OH	from N1—CO—B8—OEt	90	Q	0.23		1730, 1665	colourless
			with 1M NaOH, then aq.					(C═O)	crystals
			1M HCl
N1	B30	OH	from N1—CO—B30[α-	100	F	0.45	ESI: (M − H)− = 576/		colourless
			CO2Et]-OEt with 1M				578/580		crystals
			NaOH, then aq. 1M HCl				(Br2)
N1	B23	OH	from N1—CO—B23—OMe	96
			with 1M NaOH, then aq.
			1M HCl
N1	B24	OH	from N1—CO—B24[α-	98	F	0.29			colourless
			CO2Et]-OEt with 1M						crystals
			NaOH, then aq. 1M HCl
N6	B21	OH	from N6—CO—B21[α-	89			ESI: (M − H)− = 626/		colourless
			CO2Et]-OEt with 1M				628/630		crystals
			NaOH, then aq. 1M HCl				(Br2)
N2	B2	OH	from N2—CO—B2—OMe	96	M	0.49	ESI: (M − H)− = 606/	1724, 1660	colourless
			with 1M LiOH, then aq.				608/610	(C═O)	crystals
			1M HCl				(Br2)

EXAMPLE A2

[0434] 3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanine ethyl ester

[0435] 9.7 g (0.056 Mol) CDT were added to an ice-cooled suspension of 18.0 g (0.051 Mol) (R,S)-3,4-dibromo-phenylalanine ethyl ester in 300 ml THF. The reaction mixture was then stirred for 1 hour at 0° C. and 1 hour at ambient temperature and then combined with 11.9 g (0.051 mol) 3-(4-piperidinyl)-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one. The mixture was refluxed for 4 hours and left to stand overnight at ambient temperature. The reaction mixture was concentrated by evaporation using the rotary evaporator, the residue was combined with 300 ml aqueous sodium hydrogen carbonate solution and stirred for 30 minutes. The aqueous solution was decanted off, the residue was combined with 150 ml of ethanol and refluxed. After cooling the white solid obtained was suction filtered, washed with ethanol and dried at 50° C. 20.0 g (64% of theory) of the product were obtained, with an Rf value of 0.68 (EI D).

[0436] IR (KBr): 1734, 1680,1662 (C═O) cm−1

[0437] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	IR [cm−1]	mp. [° C.]
N1	B6	OEt	from N1—H, CDT and H—	90	B	0.67	M+ = 557	1732, 1662	colourless
			B6—OEt in THF					(C═O)	crystals
N1	B7	OEt	from N1—H, CDT and H—	100	D	0.45			colourless
			B7—OEt in THF						crystals
N1	B11	OMe	from N1—H, CDT, H—B11—	97			ESI:
			OMe * HCl and DIEA in				(M − H)− = 471
			THF
N1	B10	OMe	from N1—H, CDT, H—B10—	63	G	0.55	ESI:
			OMe * HCl and DIEA in				(M + H)+ = 453
			THF
N1	B3	OEt	from N1—H, CDT, H—B3—	92				1739,	colourless
			OEt * HCl and NEt3 in					1682, 1664	crystals
			THF/DMF 2/1 v/v					(C═O)
N1	B4	OEt	from N1—H, CDT and H—	73	B	0.50	ESI:	3402 (NH);	200-202
			B4—OEt in THF				(M + H)+ = 533	1741,
								1680, 1662
								(C═O)
N1	B8	OEt	from N1—H, CDT and H—	72			M+ = 498/500	1736, 1664	colourless
			B8—OEt in THF				(Cl)	(C═O)	crystals
N2	B2	OMe	from N2—H, CDT and H—	96	D	0.76	ESI: (M − H)− = 620/	1728, 1664	colourless
			B2—OMe * HCl and DIEA				622/624	(C═O)	crystals
			in THF				(Br2);
							(M + Na)+ = 644/
							646/
							648 (Br2)

EXAMPLE A3

[0438] Ethyl 2-[(3,5-dibromo-4-fluoro-phenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-4-oxobutanoate

[0439] The mixture of 4.39 g (0.019 mol) 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone, 9.25 g (0.019 mol) β,β-bis-(ethoxycarbonyl)-3,5-dibromo-4-fluoro-benzenebutanoic acid, 6.08 g (0.019 mol) TBTU, 6.9 ml (0.05 mol) triethylamine, 200 ml THF and 70 ml DMF was stirred overnight at room temperature. The solvents were eliminated in vacuo and the residue combined with dichloromethane and 10% aqueous citric acid solution. The organic phase was separated off, extracted with sodium hydrogen carbonate solution and dried over sodium sulphate. After elimination of the desiccant and solvent the residue was combined with tert-butylmethylether and the precipitated solid substance was suction filtered. 11.0 g (83% of theory) of the desired product were obtained, mp=167-170°.

[0440] IR (KBr): 1734,1662 (C═O) cm−1

[0441] ESI-MS: (M+H)+696/698/700 (Br2)

[0442] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	IR [cm−1]	mp. [° C.]
N1	B15[α-	OEt	from N1—H,	89	AcOEt	0.7		1734,	colourless
	CO2Et]		HO2C—B15[α-					1666	crystals
			CO2Et]-OEt,					(C═O)
			TBTU, HOBt and
			NEt3 in
			THF/DMF
			220/70 v/v
N1	B16[α-	OEt	from N1—H,	72	AcOEt	0.33	ESI: (M + H)+ = 628/	1739,	189-191
	CO2Et]		HO2C—B16[α-				630	1653
			CO2Et]-OEt,				(Br)	(C═O)
			TBTU and NEt3
			in THF/DMF
			150/50 v/v
N1	B20[α-	OEt	from N1—H,	100	D	0.73	M+ = 657	1736,	colourless
	CO2Et]		HO2C—B20[α-					1668,	viscous oil
			CO2Et]-OEt,					1649
			TBTU, HOBt and					(C═O)
			DIEA in
			THF/H2O 10/1 v/v
N1	B22[α-	OEt	from N1—H,	88	D	0.78		1734,	colourless
	CO2Et]		HO2C—B22[α-					1668	crystals
			CO2Et]-OEt,					(C═O)
			TBTU, HOBt and
			DIEA in
			THF/H2O 10/1 v/v
N1	B25[α-	OEt	from N1—H,	83	AcOEt	0.55	M+ = 667/	1728,	colourless
	CO2Et]		HO2C—B25[α-				669/671/	1664,	viscous oil
			CO2Et]-OEt,				673 (BrCl2)	1645
			TBTU, HOBt and					(C═O)
			DIEA in
			THF/H2O 10/1 v/v
N1	B27[α-	OEt	from N1—H,	88	AcOEt	0.56		1732,	colourless
	CO2Et]		HO2C—B27[α-					1668	crystals
			CO2Et]-OEt,					(C═O)
			TBTU and NEt3
			in THF/DMF
			250/10 v/v
N1	B29[α-	OEt	from N1—H,	87	D	0.79		1753,
	CO2Et]		HO2C—B29[α-					1728,
			CO2Et]-OEt,					1660
			TBTU, HOBt and					(C═ 0)
			DIEA in
			THF/H2O 10/1 v/v
N1	B21[α-	OEt	from N1—H,	75	D	0.74			colourless
	CO2Et]		HO2C—B21[α-						crystals
			CO2Et]-OEt,
			TBTU, HOBt and
			DIEA in
			THF/H2O 10/1 v/v
N1	B30[α-	OEt	from N1—H,	93	F	0.90	ESI: (M + H)+ = 678/		colourless
	CO2Et]		HO2C—B30[α-				680/682		crystals
			CO2Et]-OEt,				(Br2)
			TBTU, HOBt and
			DIEA in
			THF/H2O 10/1 v/v
N1	B23	OMe	from N1—H,	100
			HO2C—B23—OMe,
			TBTU, HOBt and
			NEt3 in THF
N1	B24[α-	OEt	from N1—H,	95	D	0.82			colourless
	CO2Et]		HO2C—B24[α-						crystals
			CO2Et]-OEt,
			TBTU, HOBt and
			DIEA in
			THF/H2O 10/1 v/v
N6	B21[α-	OEt	from N6—H,	86	AcOEt	0.9	M+ = 727/	1734	colourless
	CO2Et]		HO2C—B21[α-				729/731	(C═O)	viscous oil
			CO2Et]-OEt,				(Br2)
			TBTU, HOBt and
			NEt3 in
			THF/DMF 5/1 v/v

EXAMPLE A4

[0443] (R,S)-3,4-dibromo-phenylalanine ethyl ester

[0444] The mixture of 37.40 g (0.140 mol) N-(diphenylmethylene)-glycine ethyl ester, 55.0 g (0.167 mol) (3,4-dibromophenyl)-methylbromide, 6.40 g (0.020 mol) tetrabutylammonium bromide, 57.80 g (0.35 mol) potassium carbonate sesquihydrate and 1000 ml acetonitrile was refluxed for 15 hours. The solid was filtered off, the mother liquor was concentrated by evaporation in vacuo. The residue was taken up in 400 ml diethyl ether and after the addition of 200 ml semiconcentrated hydrochloric acid stirred for 1 hour at room temperature. The organic phase was separated off, the aqueous phase was washed twice more with 50 ml diethyl ether, then neutralised with solid sodium hydrogen carbonate while being cooled externally with ice and exhaustively extracted with ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulphate, filtered and evaporated down in vacuo. The product was obtained as a light brown oil.

[0445] Yield: 33.0 g (67% of theory). Rf 0.65 (EI D).

[0446] IR (KBr): 1734 (C═O) cm−1

[0447] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	IR [cm−1]	mp. [° C.]
H	B6	OEt	from Ph2C═NCH2CO2Et	60			ESI: (M + H)+ = 300/	1738	colourless
			and 3-Br-4,5-Me2—C6H2—				302	(C═O)	oil
			CH2Br				(Br)
H	B7	OEt	from Ph2C═NCH2CO2Et	60	P	0.75		1738	colourless
			and 3,5-Br2-4-Me—C6H2—					(C═O)	oil
			CH2Br
H	B4	OEt	from Ph2C═NCH2CO2Et	70	B	0.73	ESI: (M + H)+ = 276/	1728	colourless
			and 3,5-Cl2-4-Me—C6H2—				278/280	(C═O)	crystals,
			CH2Br				(Cl2)		mp. 44-46
H	B8	OEt	from Ph2C═NCH2CO2Et	83	O	0.46		1736
			and 3-Cl-4-Me—C6H3—					(C═O)
			CH2Cl

EXAMPLE A5

[0448] (R,S)-3,4-difluorophenylalanine methyl ester hydrochloride

[0449] 4.0 ml saturated methanolic hydrogen chloride solution were added to a suspension of 0.5 g (2.485 mmol) of 3,4-difluorophenylalanine in 10 ml of methanol and the mixture was stirred for 4 hours at room temperature. It was then evaporated down in vacuo, another 10 ml of methanol were added to the residue and the solvent was distilled off again in vacuo. 0.6 g (96% of theory) of colourless crystals were obtained, Rf 0.7 (EI dichloromethane).

[0450] ESI-MS: (M+H)+=216

EXAMPLE A6

[0451] β,β-bis-(ethoxycarbonyl)-3,5-dibromo-4-fluoro-benzene-butanoic acid

[0452] 70 ml trifluoroacetic acid were added dropwise to an ice-cooled solution of 13.1 g (0.037 mol) 1,1-dimethylethyl β,β-bis-(ethoxycarbonyl)-3,5-dibromo-4-fluoro-benzenebutanoate in 450 ml dichloromethane, the cooling was removed, the mixture was stirred overnight at ambient temperature and then evaporated down in vacuo. The residue was dried twice by coevaporation with petroleum ether, triturated with petroleum ether, suction filtered and dried in vacuo. 9.3 g (79% of theory) of colourless crystals were obtained.

[0453] IR (KBr): 1707 (C═O) cm−1

[0454] ESI-MS: (M−H)-=481/483/485 (Br2)

[0455] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	IR [cm−1]	mp. [° C.]
HO	B15[α-	OEt	from (H3C)3CO2C—	81	V	0.1		1709 (C═O)
	CO2Et]		B15[α-CO2Et]-OEt
			and TFA in CH2Cl2
HO	B16[α-	OEt	from (H3C)3CO2C—	100				1738 (C═O)	colourless
	CO2Et]		B16[α-CO2Et]-OEt						viscous oil
			and TFA in CH2Cl2
HO	B20[α-	OEt	from (H3C)3CO2C—	77	V	0.24		3321 (OH);	colourless
	CO2Et]		B20[α-CO2Et]-OEt					1714	crystals
			and TFA in CH2Cl2					(C═O);
								1161, 1124
								(CF3)
HO	B22[α-	OEt	from (H3C)3CO2C—	69	W	0.21		1736 (C═O)	colourless
	CO2Et]		B22[α-CO2Et]-OEt						crystals
			and TFA in CH2Cl2
HO	B25[α-	OEt	from (H3C)3CO2C—	72				1730, 1711	colourless
	CO2Et]		B25[α-CO2Et]-OEt					(C═O)	viscous oil
			and TFA in CH2Cl2
HO	B27[α-	OEt	from (H3C)3CO2C—	93				1736 (C═O)
	CO2Et]		B27[α-CO2Et]-OEt
			and TFA in CH2Cl2
HO	B24[α-	OEt	from (H3C)3CO2C—	68	X	0.28		1709 (C═O)	colourless
	CO2Et]		B24[α-CO2Et]-OEt						crystals
			and TFA in CH2Cl2
HO	B19[α-	OEt	from (H3C)3CO2C—	46
	CO2Et]		B19[α-CO2Et]-OEt
			and TFA in CH2Cl2
HO	B30[α-	OEt	from (H3C)3CO2C—	81			ESI: (M − H)− = 463/		colourless
	CO2Et]		B30[α-CO2Et]-OEt				465/467		crystals
			and TFA in CH2Cl2				(Br2)
HO	B24[α-	OEt	from (H3C)3CO2C—	54			ESI: (M − H)− = 375/		colourless
	CO2Et]		B24[α-CO2Et]-OEt				377/379		crystals
			and TFA in CH2Cl2				(Cl2)

EXAMPLE A7

[0456] 1,1-dimethylethyl 3,5-dibromo-4-fluoro-β,β-bis-(ethoxycarbonyl)-benzenebutanoate

[0457] 0.64 g (0.0266 mol) 95% sodium hydride were added to the solution of 6.69 g (0.024 mol) diethyl [(1,1-dimethylethoxy-carbonyl)methyl]-malonate in 170 ml anhydrous tetrahydrofuran while cooling externally with ice water. After one hour's stirring a solution of 8.35 g (0.024 mol) 3,5-dibromo-4-fluorobenzylbromide in 30 ml of tetrahydrofuran was added dropwise thereto while maintaining a reaction temperature of 0 to +5° C. and the mixture was then allowed to come up to room temperature within 14 hours. The reaction mixture was freed from solvent in vacuo, the residue was combined with 200 ml 10% citric acid and exhaustively extracted with tert.-butylmethylether. After working up in the usual way the combined extracts yielded 13.1 g (100% of theory) of a colourless oil, Rf=0.14

[0458] (EI Y), which was used in the next step without any purification.

[0459] IR (KBr): 1732 (C═O) cm−1

[0460] ESI-MS: (M+Na)+=561/563/565 (Br2)

[0461] The following compounds of general formula N-B-C were prepared analogously:

				%				IR
N	B	C	Remarks	yield	EI	Rf	MS	[cm−1]	mp. [° C.]
Me3CO	B15[α-	OEt	from (H3C)3COCO—	100	V	0.6			colourless
	CO2Et]		CH2C(CO2Et)2,						oil
			3,4,5-Me3—
			C6H2CH2Br and
			NaH in THF
Me3CO	B16[α-	OEt	from (H3C)3COCO—	67	CH2Cl2	0.71		1736	colourless
	CO2Et]		CH2C(CO2Et)2,					(C═O)	oil
			3Br-4,5-Me2—
			C6H2CH2Br and
			NaH in THF
Me3CO	B20[α-	OEt	from (H3C)3COCO—	100	V	0.72	no M+;	1736
	CO2Et]		CH2C(CO2Et)2, 2,4-				(M − C4H8)+ = 444	(C═O)
			(CF3)2—C6H2CH2Br
			and NaH in THF
Me3CO	B22[α-	OEt	from (H3C)3COCO—	91	W	0.78		1734	colourless
	CO2Et]		CH2C(CO2Et)2,					(C═O)	oil
			3,4,5Br3—
			C6H2CH2Br and
			NaH in THF
Me3CO	B25[α-	OEt	from (H3C)3COCO—	100	Y	0.75			colourless
	CO2Et]		CH2C(CO2Et)2, 4-						viscous oil
			Br-3,5Cl2—
			C6H2CH2Br and
			NaH in THF
Me3CO	B27[α-	OEt	from (H3C)3COCO—	58	Y	0.31	M+ = 406	1734
	CO2Et]		CH2C(CO2Et)2, 3,4					(C═O)
			(CH2)2O—
			C6H3CH2Br and
			NaH in THF
Me3CO	B29[α-	OEt	from (H3C)3COCO—	89	X	0.49		1736	colourless
	CO2Et]		CH2C(CO2Et)2,					(C═O)	oil
			2,3Cl2—C6H3CH2Cl
			and NaH in THF
Me3CO	B19[α-	OEt	from (H3C)3COCO—	88					colourless
	CO2Et]		CH2C(CO2Et)2,						oil
			4NH4-3,5Cl2—
			C6H2CH2Br and
			NaH in THF

EXAMPLE A8

[0462] 3,4-dimethoxy-β-(methoxycarbonyl)-benzenebutanoic acid

[0463] The solution of 58.0 g (0.205 mol) 4-[(3,4-dimethoxyphenyl]-3-(methoxycarbonyl)-3-butenoic acid in 500 ml of methanol was hydrogenated at 5 bar hydrogen in the presence of 3.0 g 10% platinum/activated charcoal until the uptake of hydrogen had ended. After working up in the usual way 26.0 g (46% of theory) of colourless crystals were obtained, mp=104-107° C.

[0464] The following compound of general formula N-B-C was obtained analogously:

				%			mp.
N	B	C	Remarks	yield	EI	Rf	[° C.]
HO	B26	OMe	from 4-(2-naphthyl)-3-		X	0.85
			(methoxycarbonyl)-3-
			butenoic acid,
			H2 and Pd—C in MeOH

EXAMPLE A9

[0465] 4-[(3,4-dimethoxy-phenyl]-3-(methoxycarbonyl)-3-butenoic acid

[0466] 26.6 ml (0.2 mol) dimethyl succinate were added to a freshly prepared solution of 4.6 g (0.2 mol) sodium in 250 ml anhydrous methanol and after one hour's stirring at room temperature the solution of 33.3 g (0.2 mol) 3,4-dimethoxybenzaldehyde in 100 ml anhydrous methanol was added dropwise. Then the mixture was refluxed for 6 hours, the methanol was eliminated in vacuo and the bottom remaining was maintained at a reaction temperature of 80° C. for 30 minutes. The viscous slurry obtained was taken up in 500 ml of water, acidified with 20% aqueous citric acid solution and the resulting mixture was exhaustively extracted with ethyl acetate. The combined ethyl acetate extracts were in turn extracted five times with 5% aqueous ammonia solution. The ammoniacal extracts were carefully acidified with 20% aqueous citric acid solution and then exhaustively extracted with ethyl acetate. These extracts were washed with water, dried over sodium sulphate and freed from the solvent in vacuo. The crude product (quantitative yield) was further reacted without purification.

[0467] The following compounds of general formula N-B-C were obtained analogously:

				%
N	B	C	Remarks	yield	EI	Rf
4-(2-naphthyl)-3-	from 2-naphthaldehyde,	65	X	0.8
(methoxycarbonyl)-	dimethyl succinate and
3-butenoic acid	NaOMe in MeOH

EXAMPLE A10

[0468] Methyl [1,4′]bipiperidinyl-4-acetate

[0469] The solution of 0.669 g (2.024 mmol) of methyl 1′-phenylmethyl-[1,4′]bipiperidinyl-4-acetate in 20 ml of methanol was hydrogenated at a pressure of 5 bar after the addition of 100 mg of 10% palladium on charcoal until the uptake of hydrogen had ended. The catalyst was filtered off, the filtrate was freed from solvent, the residue was taken up in 20 ml THF, the solution obtained was filtered and evaporated down again. The residue was used without further purification. Colourless oil.

[0470] Yield: 490 mg (100% of theory).

[0471] ESI-MS: (M+H)+=241 (M+Na)+=253

[0472] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	mp. [° C.]
H	—	C5	from PhCH2—C5, H2	100	G	0.22	ESI: (M + H)+ = 241;	colourless
			and Pd/C in MeOH				(M + Na)+ = 253	oil
H	—	C12	from PhCH2—C12, H2	98	D	0.17	ESI: (M + H)+ = 284	colourless
			and Pd/C in EtOH					crystals
H	—	C9	from PhCH2—C9, H2	78	O	0.1		colourless
			and Pd/C in EtOH					oil
H	—	C3	from PhCH2—C3, H2	99			ESI: (M + H)+ = 284;	colourless
			and Pd/C in MeOH				(M + Na)+ = 306	oil
H	—	C1	from PhCH2—C1, H2	97	M	0.38	ESI: (M + H)+ = 256
			and Pd/C in EtOH
H	—	C14	from PhCH2—C14, H2	79	G	0.14	ESI: (M + H)+ = 213	colourless
			and Pd/C in MeOH					crystals
H	—	C16	from PhCH2—C16, H2	67	G	0.16	ESI: (M + H)+ = 213	colourless
			and Pd/C in MeOH					crystals
H	—	C19	from PhCH2—C19, H2	100	G	0.20	ESI: (M + H)+ = 227	colourless
			and Pd/C in MeOH					oil
H	—	C22	from PhCH2—C22, H2	100	C	0.06	ESI: (M + H)+ = 227	colourless
			and Pd/C in MeOH					crystals
H	—	C26	from PhCH2—C26, H2	100				colourless
			and Pd/C in MeOH					crystals
H	—	C28	from methyl 4-[(1-	70	S	0.4		colourless
			phenylmethyl)-1,2,3,6-					crystals
			tetrahydro-4-
			pyrididinyl]-benzoate,
			H2 and Pd/C in MeOH
H	—	C18	acetate, from PhCH2—	88	G	0.20	ESI: (M + H)+ = 227	colourless
			C18, H2 and Pd/C in					viscous oil
			MeOH
H	—	C7	from PhCH2—C7, H2	92	O	0.15	ESI: (M + H)+ = 241;	colourless
			and Pd/C in EtOH				(M + Na)+ = 263	oil
H	—	C50	from PhCH2—C50, H2	100	KK	0.21	ESI: (M + H)+ = 256	colourless
			and Pd(OH)2					viscous oil
			(Pearlman's catalyst)
			in EtOH
ethyl 4-	from ethyl 1-	99		colourless
methyl-2-	(phenylmethyl)-4-			oil
piperazine-	methyl-2-
carboxylate	piperazinecarboxylate,
	H2 and Pd(OH)2
	(Pearlman's catalyst)
	in EtOH
H	—	C46	from PhCH2—C46, H2	100	DD	0.24	ESI: (M + H)+ = 256	colourless
			and Pd(OH)2					viscous oil
			(Pearlman's catalyst)
			in EtOH
H	—	C45	from PhCH2—C45, H2	100	LL	0.1	ESI: (M + H)+ = 256	colourless
			and Pd(OH)2					oil
			(Pearlman's catalyst)
			in EtOH
ethyl 2-	from ethyl 1,4-bis-	100	MM	0.2	ESI: (M + H)+ = 159
piperazine-	(phenylmethyl)-2-
carboxylate	piperazinecarboxylate,
	H2 and 10% Pd/C in
	EtOH

EXAMPLE A11

[0473] Methyl 1′-(phenylmethyl)-[1,4′]bipiperidinyl-4-acetate

[0474] 4.0 ml glacial acetic acid and 20 g of molecular sieve 3 Å were added to a mixture of 4.549 ml (24.54 mmol) of 1-(phenylmethyl)-4-piperidinene, 4.753 g (24.54 mmol) of methyl 4-piperidineacetate hydrochloride and 40 ml of THF, the mixture was stirred for 2 hours at room temperature, cooled to 0° C. and while this temperature was maintained a total of 6.358 g (30.0 mmol) of sodium triacetoxyborohydride were added in small batches within 8 hours. Then the resulting mixture was stirred for another 16 hours at room temperature. The mixture was made alkaline with sodium hydrogen carbonate, extracted exhaustively with ethyl acetate, the combined extracts were dried over sodium sulphate and the evaporation residue was chromatographed on silica gel using first 30/1 dichloromethane/methanol, then 20/1, and finally 10/1 as eluants. Working up the appropriate fractions yielded 1.804 g (22% of theory) of a readily mobile oil which set overnight into colourless crystals. Rf=0.56 (EI B).

[0475] ESI-MS: (M+H)+=331.

[0476] The following compounds of general formula N-B-C were prepared analogously:

N	B	C	Remarks	% yield	EI	Rf	MS	mp. [° C.]
PhCH2	—	C7 + C9	from 1-(phenylmethyl)-	cis: 14.7 + trans:	AA	cis:	cis: ESl:	colourless
			piperazine, ethyl 4-	13.8 + cis/		0.40;	(M + H)+ = 331;	liquids
			oxocyclohexane-	trans:		trans:	(M + Na)+ = 353;
			carboxylate and	5.8		0.30	trans:
			Na(CN)BH3/AcOH in				ESI: (M + H)+ = 331
			MeOH at pH 5-6;
			separation of the two
			diastereomers on silica
			gel, El dichloromethane/
			MeOH 30/1 v/v
PhCH2	—	C3	from 1-(phenylmethyl)-	58	O	0.67	ESI: (M + H)+ = 374;	colourless
			piperazine, 1,1-				(M + Na)+ = 396	crystals
			dimethylethyl 4-oxo-1-
			piperidineacetate and
			Na(CN)BH3/AcOH in
			MeOH at pH 5-6
4-[1-(phenylmethyl)-4-	from 1-(phenylmethyl)-4-	100	D	0.60	ESI: (M + H)+ = 360;	colourless
piperidinyl]-1-(1,1-	piperidinene, 1-(1,1-				(M + Na)+ = 382;	oil
dimethylethoxycarbonyl)-	dimethylethoxycarbonyl)-				(2M + Na)+ = 741
piperazine	piperazine and
	NaBH(OAc)3/AcOH in
	THF
PhCH2	—	C14	from 1-(phenylmethyl)-4-	51	G	0.50	ESI: (M + H)+ = 303	colourless
			piperidinene, L-proline					oil
			methyl ester
			hydrochloride and
			NaBH(OAc)3/AcOH in
			THF
PhCH2	—	C16	from 1-(phenylmethyl)-4-	54	G	0.50	ESI: (M + H)+ = 303;	colourless
			piperidinene, D-proline				(M + Na)+ = 325	oil
			methyl ester
			hydrochloride and
			NaBH(OAc)3/AcOH in
			THF
PhCH2	—	C19	from 1-(phenylmethyl)-4-	51	G	0.40	ESI: (M + H)+ = 317;	colourless
			piperidinene, L-				(M + Na)+ = 339	oil
			homoproline methylester
			hydrochloride [Bachem]
			and NaBH(OAc)3 in
			CH2Cl2
PhCH2	—	C18	from 1-(phenylmethyl)-4-	57	G	0.40	ESI: (M + H)+ = 317	colourless
			piperidinene, D-					viscous
			homoproline methylester					oil
			hydrochloride [Bachem]
			and NaBH(OAc)3 in
			CH2Cl2
PhCH2	—	C50	from 1-(phenylmethyl)-4-	22	DD	0.84	ESI: (M + H)+ = 346
			piperidinene, ethyl 4-
			methyl-2-
			piperazinecarboxylate
			and NaBH(OAc)3 in THF
PhCH2	—	C46	from 1-methyl-4-	100	C	0.53	ESI: (M + H)+ = 346	colourless
			piperidinene, ethyl bis-					oil
			(trifluoroacetate) 1-
			(phenylmethyl)-2-
			piperazinecarboxylate-
			and NaBH(OAc)3 in THF
PhCH3	—	C45	from 1-(phenylmethyl)-4-	100	C	0.41	M+ = 345	colourless
			piperidinene, ethyl bis-					oil
			(trifluoroacetate) 1-
			methyl-2-
			piperazinecarboxylate
			and NaBH(OAc)3 in THF
Boc	—	C44	from 1-methyl-4-	57	C	0.46	ESI: (M + H)+ = 356	colourless
			piperidinene, ethyl -bis-					viscous
			(trifluoroacetate) 4-(1,1-					oil
			dimethylethoxycarbonyl)-
			2-piperazinecarboxylate
			and NaBH(OAc)3 in THF

EXAMPLE A12

[0477] Ethyl 4-[1-(phenylmethyl)-4-piperidinyl]-1-piperazineacetate

[0478] 3.5 ml (19.892 mmol) of DIEA were added to a suspension of 2.0 g (3.325 mmol) of 1-(phenylmethyl)-4-(1-piperazinyl)-piperidine-tris-(trifluoroacetate) in 50 ml dichloromethane and the mixture was stirred for 10 minutes at room temperature. Then 0.38 ml (3.365 mmol) of ethyl bromoacetate were added and the mixture was stirred overnight at room temperature. The reaction mixture was extracted four times with 50 ml of water, dried over sodium sulphate and concentrated by evaporation. 0.70 g (61% of theory) of the desired product were obtained, Rf 0.63 (EI D) and

[0479] ESI-MS: (M+H)+=346.

[0480] The following compound of general formula N-B-C was obtained analogously:

				%
N	B	C	Remarks	yield	EI	Rf	MS	mp. [° C.]
PhCH2	—	C12	from 1-(phenylmethyl)-4-	65	D	0.51	ESI: (M + H)+ = 374;	colourless
			(1-piperazinyl)-				(M + Na)+ = 396	crystals
			piperidine-tris-
			(trifluoroacetate), 1,1-
			dimethylethyl
			bromoacetate and
			K2CO3 in CH3CN

EXAMPLE A13

[0481] 1-(phenylmethyl)-4-(1-piperazinyl)-piperidine-tris-(trifluoroacetate)

[0482] The mixture of 77.6 g (0.216 mol) 4-[1-(phenylmethyl)-4-piperidinyl]-1-(1,1-dimethylethoxycarbonyl)-piperazine, 150 ml (1.941 mol) trifluoroacetic acid and 450 ml dichloromethane was refluxed for 1 hour and then stirred for 2 hours at room temperature. The solvent was distilled off, the residue triturated with diethyl ether, suction filtered and dried in the air. 119.0 g (92% of theory) of colourless crystals were obtained, Rf 0.20 (EI D) and

[0483] ESI-MS: (M+H)+=260

[0484] The following compounds of general formula N-B-C were prepared analogously:

				%
N	B	C	Remarks	yield	EI	Rf	MS	mp. [° C.]
H	—	C29	from ethyl 4-[[1-(1,1-	89	BB	0.70		colourless
			dimethylethoxycarbonyl)-					crystals
			4-piperidinyl]methyl]-
			benzoate and TFA in
			CH2Cl2
H	—	C44	from ethyl 4-(1,1-	100	DD	0.11	M+ = 255	colourless
			dimethylethoxycarbonyl)-					viscous oil
			1-(1-methyl-4-piperidinyl)-
			2-piperazinecarboxylate
			and TFA in CH2Cl2
ethyl-bis-	from ethyl 4-(1,1-	100	AcOEt	0.00	ESI:	colourless
(trifluoroacetate)	dimethylethoxycarbonyl)-				(M + H)+ = 249	oil
1-(phenylmethyl)-	1-(phenylmethyl)-2-
2-piperazine-	piperazinecarboxylate
carboxylate	and TFA in CH2Cl2
ethyl-bis-	from ethyl 4-(1,1-	100	DD	0.16	ESI:	colourless
(trifluoroacetate)1-	dimethylethoxycarbonyl)-				(M + H)+ = 173	viscous oil
methyl-2-	1-methyl-2-
piperazine-	piperazinecarboxylate
carboxylate	and TFA in CH2Cl2

EXAMPLE A14

[0485] methyl 1′-(phenylmethyl)-[1,4′]bipiperidinyl-4′-carboxylate

[0486] 1.124 g (3.5 mmol) of TBTU and 1.0 ml (7.175 mmol) of triethylamine were added to the solution of 1.0 g (3.307 mmol) of 1′-(phenylmethyl)-[1,4′]bipiperidinyl-4′-carboxylic acid in 30 ml DMF, the mixture was stirred for 20 minutes at room temperature, then 20 ml of methanol were added and the mixture was stirred for a further 3 hours at ambient temperature. The mixture was concentrated by evaporation, the residue was taken up in 50 ml of ethyl acetate and filtered. The filtrate was evaporated down, the residue purified by column chromatography on silica gel, initially using ethyl acetate, then ethyl acetate mixed with up to 5% methanol/conc. ammonia (9/1 v/v) as eluant. 0.231 g (22% of theory) of colourless crystals were obtained, mp. 84.7° C. and Rf 0.73 (EI F).

[0487] ESI-MS: (M+H)+=317

EXAMPLE A15

[0488] Methyl 3-(4-piperidinyl)-benzoate-hydrochloride

[0489] The mixture of 500 mg (2.069 mmol) of 3-(4-piperidinyl)-benzoic acid-hydrochloride and 10 ml saturated methanolic hydrogen chloride solution was stirred overnight at room temperature. The reaction mixture was concentrated by evaporation in vacuo, the residue was stirred with 3 ml isopropanol, suction filtered, washed with diethyl ether and dried at 60° C. in the circulating air dryer. 390 mg (74% of theory) of colourless crystals were obtained, Rf 0.34 (EI D).

[0490] IR (KBr): 1728 (C═O) cm−1

[0491] ESI-MS: (M+H)+=220;

[0492] (M+Cl+HCl)=290/292/294 (Cl2)

[0493] The following esters of general formula N-B-C were obtained analogously:

				%				IR	mp.
N	B	C	Remarks	yield	EI	Rf	MS	[cm−1]	[° C.]
H	—	C31	dihydrochloride; from	76	D	0.58	ESI: (M + H)+ = 289;	1722	colourless
			H-C38 [BAYER],				(M + Cl + HCl)− =	(C═O)	crystals
			MeOH and HCl				359/361/363
							(Cl2)
PhCH2	—	C41	from PhCH2-C43,	52	D	0.88	ESI: (M + H)+ = 318;
			MeOH and HCl				(M + Na)+ = 340;
							(2M + Na)+ = 657
methyl 2-	from 2-	100	D	0.59	ESI: (M + H)+ = 159;
aminothiazole-5-	aminothiazole-5-				(M − H)− = 157
carboxylate	carboxylic acid,
hydrochloride	MeOH and HCl
methyl 4-[1-	from 4-[1-	85			ESI: (M + H)+ = 308	1707
(phenylmethyl)-	(phenylmethyl)-					(C═O)
1,2,3,6-tetrahydro-4-	1,2,3,6-tetrahydro-4-
pyridinyl]-benzoate	pyridinyl]-benzoic
	acid, MeOH and HCl

EXAMPLE A16

[0494] 1′-(phenylmethyl)-[1,4′]bipiperidinyl-4′-carboxylic acid

[0495] A total of 5.0 g (17.642 mmol) of 1′-(phenylmethyl)-[1,4′]bipiperidinyl-4′-carbonitrile were added in small batches to 15 ml of conc. sulphuric acid. After the nitrile had dissolved, the mixture was stirred for a further 3 hours at room temperature, then ml of water were added and the mixture was refluxed for 15 hours. The cooled mixture was stirred into 50 ml ice water and adjusted to pH 7 with conc. ammonia. The precipitate was suction filtered, washed with a little water, stirred with 10 ml dichloromethane, suction filtered again, then dried in vacuo. 1.56 g (29% of theory) of colourless crystals were obtained, Rf 0.0 (EI DD).

[0496] ESI-MS: (M+H)=303

EXAMPLE A17

[0497] Ethyl 3-(1-piperazinyl)-benzoate

[0498] 30 ml of a saturated solution of hydrogen bromide in glacial acetic acid was added dropwise at room temperature to the solution of 18.5 g (0.055 mol) ethyl 3-[4-(phenylmethoxycarbonyl)-1-piperazinyl]-benzoate in 30 ml glacial acetic acid and stirred for a further 4 hours at room temperature. 300 ml diethyl ether were added to the mixture, the precipitate formed was then suction filtered, washed thoroughly with diethyl ether and dried in the air.

[0499] Yield 17.8 g (82% of theory). Colourless crystals, mp. 226° C. (Z) and Rf 0.24 (EI EE).

[0500] C13H18N2O2*2 HBr (396.13) Calc.: C, 39.42H, 5.09N, 7.07 Br, 40.34 Found: 39.27 5.06 7.15 40.35

EXAMPLE A18

[0501] Ethyl 3-[4-(phenylmethoxycarbonyl)-1-piperazinyl]-benzoate

[0502] At intervals of 16 hours 15.0 g (a total of 0.176 mol) of benzyl chlorocarbonate were added twice to the solution of 26.0 g (0.08 mol) ethyl 3-[4-(phenylmethyl)-1-piperazinyl]-benzoate in 260 ml dichloromethane and the mixture was stirred for a total of 32 hours at room temperature. The solvent was eliminated in vacuo, the residue purified by column chromatography on silica gel using dichloromethane as eluant. 18.8 g (70% of theory) of a colourless oil were obtained, Rf 0.67 (EI FF).

EXAMPLE A19

[0503] Ethyl 3-[4-(phenylmethyl)-1-piperazinyl]-benzoate-hydriodide

[0504] The mixture of 53.6 g (0.2 mol) N,N-bis-(2-chlorethyl)-benzenemethanamine-hydrochloride, 40.2 g (0.2 mol) ethyl 3-aminobenzoate-hydrochloride, 30.0 g (0.2 mol) sodium iodide, 20.0 g sodium carbonate and 11 of n-propanol was refluxed for 2 hours. The mixture was cooled to 80° C., a further 15 g of sodium carbonate were added slowly and the mixture was refluxed for another 2 hours. After cooling to 80° C. the remaining sodium carbonate from a total amount of 53.0 g (0.5 mol) was added and again the mixture was refluxed for 2 hours. It was left to cool, the insoluble salts were filtered off and the filtrate was evaporated down in vacuo. The residue was taken up in 200 ml dichloromethane, the dichloromethane solution was washed twice with 50 ml 1 N hydrochloric acid, then concentrated by evaporation. After being recrystallised from ethanol the residue remaining yielded 43.0 g (48% of theory) of colourless crystals, mp. 180-182° C. and Rf=0.62 (EI GG).

EXAMPLE A20

[0505] 4-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-benzoic acid

[0506] 25.0 ml (0.04 mol) of a 1.6-molar solution of n-butyl lithium in n-hexane were added dropwise to the solution of 13.13 g (0.040 mol) 4-(4-bromophenyl)-1-(phenylmethyl)-1,2,3,6-tetrahydropyridine in 190 ml of anhydrous THF under an argon atmosphere and while maintaining a reaction temperature of −70 to −60° C. After 30 minutes at −60° C. the mixture was poured, while stirring well, onto 500 g of finely crushed dry ice and the mixture was then left overnight to come up to room temperature. It was diluted with 300 ml diethyl ether and then extracted twice with 100 ml of water. While cooling externally, the combined aqueous extracts were adjusted to pH 7.5 with 2N hydrochloric acid. The precipitate formed was suction filtered, stirred with 50 ml hot methanol and after cooling suction filtered again. After drying in the desiccator 8.3 g (71% of theory) of colourless crystals were obtained, Rf 0.5 (EI HH).

[0507] ESI-MS: (M+H)+=294 (M−H)−=292

EXAMPLE A21

[0508] 4-(4-Bromophenyl)-1-(phenylmethyl)-4-piperidinel

[0509] 62.5 ml (0.1 mol) of a 1.6 molar solution of n-butyl lithium in n-hexane were added dropwise to the solution of 23.591 g (0.10 mol) 1,4-dibromobenzene in 250 ml anhydrous THF while maintaining a reaction temperature of −60 to −50° C. The mixture was stirred for a further 20 minutes at the stated temperature before the solution of 18.926 g (0.10 mol) 1-(phenylmethyl)-4-piperidinene in 50 ml anhydrous THF was added dropwise. The mixture was allowed to warm up to room temperature, then stirred overnight at this temperature, the mixture was then added to ice water and exhaustively extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and saturated saline solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue was recrystallised from diisopropylether. 23.1 g (67% of theory) of colourless crystals were obtained, Rf 0.4 (EI BB).

EXAMPLE A22

[0510] Ethyl 4-[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]methyl]-benzoate The solution of 38.7 g (0.112 mol) 1-(1,1-dimethylethoxycarbonyl)-4-[4-(ethoxy-carbonyl)-phenylmethylene]-piperidine in 350 ml of ethyl acetate was hydrogenated at room temperature and under a pressure of 5 bar in the presence of 4.82 g 10% palladium on charcoal until the uptake of hydrogen had ended. Working up in the usual way yielded 35.8 g (92% of theory) of a colourless oil which was used without any further purification.

EXAMPLE A23

[0511] 1-(1,1-dimethylethoxycarbonyl)-4-[4-(ethoxycarbonyl)-phenylmethylene]-piperidine

[0512] 85.0 ml (0.136 mol) of a 1.6 molar solution of n-butyl lithium in n-hexane was added dropwise to the solution of 19.2 ml (0.135 mol) diisopropylamine in 400 ml anhydrous THF using argon as protective gas and while maintaining a reaction temperature of −20 to −10° C. This temperature was maintained for another 20 minutes and then the solution of 39.35 g (0.131 mol) diethyl [4-(ethoxy-carbonyl)phenyl]-methanephosphonate in 100 ml THF was added dropwise. The mixture was stirred for a further 20 minutes at a temperature between −20 and −10° C., then the solution of 28.1 g (0.131 mol) 1-(1,1-dimethylethoxy-carbonyl)-4-piperidinene in 100 ml THF was added dropwise thereto and the mixture was left overnight to warm up to room temperature. The mixture was stirred into ice water, the resulting mixture was exhaustively extracted with ethyl acetate, the combined extracts were washed with saturated aqueous NaCl solution, dried over sodium sulphate and freed from solvent. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 7/1 v/v as eluant. 38.7 g (86% of theory) of a colourless oil were obtained, which solidified in the presence of petroleum ether to form colourless crystals.

EXAMPLE A24

[0513] Diethyl [4-(ethoxycarbonyl)phenyl]-methanephosphonate

[0514] 55 ml (0.316 mol) triethyl phosphite were placed in a stirring apparatus and pre-heated to an internal temperature of 90° C. The suspension of 60.0 g (0.247 mol) ethyl 4-(bromomethyl)-benzoate in 100 ml dichloromethane was slowly added thereto in small batches, while the ethyl bromide formed and the evaporating dichloromethane were continuously distilled off. Once the quantity of ethyl bromide formed had significantly diminished, the reaction temperature was slowly increased to 140° C. and this temperature was maintained until the formation of ethyl bromide had ended (approx. 2 hours). The excess triethyl phosphite was eliminated in vacuo, the residue was suspended in a little ethyl acetate and purified by column chromatography on silica gel using ethyl acetate/petroleum ether (gradient 1/1→1/0 v/v) as eluant. After working up in the usual way 56.3 g (76% of theory) of the above title compound were obtained in the form of a colourless oil.

EXAMPLE A25

[0515] Ethyl 4-[2-(4-piperidinyl)ethyl]-benzoate

[0516] The solution of 22.0 g (0.076 mol) ethyl 4-[2-(4-pyridinyl)vinyl]-benzoate hydrochloride in 800 ml of ethanol was hydrogenated in the presence of 2 g platinum(IV)-oxide at 3.8 bar hydrogen pressure for 8 hours. Catalyst and solvent were removed, the residue was taken up in 5% hydrochloric acid and extracted twice with 50 ml diethyl ether. The aqueous phase was made alkaline with sodium hydroxide and exhaustively extracted with ethyl acetate. The combined ethyl acetate extracts were washed with saturated saline solution, dried over sodium sulphate and concentrated by evaporation. The oily product obtained (17.0 g, 86% of theory) was used without further purification.

EXAMPLE A26

[0517] Ethyl (E)-4-[2-(4-pyridinyl)vinyl]-benzoate hydrochloride

[0518] A solution of 9.1 g (85.0 mmol) of 4-pyridine-carboxaldehyde and 25.0 g (83.3 mmol) of diethyl [4-(ethoxycarbonyl)phenyl]-methanephosphonate in 150 ml THF was added dropwise to a suspension of 1.87 g (78 mmol) of sodium hydride in 150 ml THF while maintaining a reaction temperature of −10 to 0° C. The mixture was stirred for 35 hours under a nitrogen atmosphere. Then it was distributed between water and diethyl ether, the ethereal phase was dried over sodium sulphate, evaporated down to a volume of approx. 200 ml and combined with ethereal hydrogen chloride solution until the reaction of precipitation had ended. The colourless crystals obtained were suction filtered, washed with diethyl ether and dried in the air.

[0519] Yield: 22.0 g (87% of theory). mp. 215-225° C.

EXAMPLE A27

[0520] Methyl 2-(1-piperazinyl)-thiazole-5-carboxylate

[0521] 10.0 g (116.09 mmol) of anhydrous piperazine were added to a solution of 4.2 g (23.647 mmol) of methyl 2-chlorothiazole-5-carboxylate in 5 ml of ethanol and refluxed for 3 hours. The reaction mixture was combined with saturated aqueous sodium hydrogen carbonate solution and exhaustively extracted with ethyl acetate. The combined organic extracts were washed thoroughly with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 1.8 g (34% of theory) of colourless crystals were obtained, Rf 0.44 (EI D).

EXAMPLE A28

[0522] Methyl 2-chlorothiazole-5-carboxylate

[0523] 20 g of crushed ice were added to a suspension of 14.0 g (71.927 mmol) of methyl 2-aminothiazol-5-carboxylate hydrochloride in 8 ml of conc. hydrochloric acid and while cooling externally a solution of 5.0 g (72.464 mmol) of sodium nitrite in 30 ml of water was added dropwise, while the reaction temperature was kept below 0° C. at all times. After 30 minutes 7.2 g (72.735 mmol) of copper (I) chloride were added, the mixture was stirred for another hour while being cooled and in the following 1½ hours allowed to come slowly up to room temperature. The mixture was exhaustively extracted with diethyl ether, the combined extracts were washed with saturated saline solution, dried over sodium sulphate and evaporated down. 4.3 g (34% of theory) of a colourless oil were obtained, Rf=0.94 (EI D), which was used in the next steps without any further purification.

[0524] MS: M+=177/179 (Cl)

EXAMPLE A29

[0525] Methyl 2-(1-piperazinyl)-thiazole-4-carboxylate hydrochloride

[0526] 4.0 ml (35.973 mmol) of 1-chloroethyl chloroformate were added to an ice-cooled solution of 8.0 g (15.752 mmol) of methyl 2-[4-(phenylmethyl)-1-piperazinyl]-thiazole-4-carboxylate in 60 ml of 1,2-dichloroethane, the mixture was stirred for another 20 minutes at 0° C. and refluxed overnight, before distilling off the solvent. The residue was combined with 60 ml of methanol and refluxed for another 4 hours. The solvent was eliminated in vacuo, the residue was triturated with 3 ml of methanol, then suction filtered. After drying in the vacuum drying cupboard 2.5 g (60% of theory) of colourless crystals were obtained, Rf=0.49 (EI D).

[0527] ESI-MS: (M+H)+=228; (M+Na)+=250

EXAMPLE A30

[0528] 2-[4-(phenylmethyl)-1-piperazinyl]-thiazole-4-carboxylic acid-hydrobromide

[0529] 12.7 g (76.066 mmol) of bromopyruvic acid were added to the solution of 18.0 g (76.482 mmol) of 1-(aminothiocarbonyl)-4-(phenylmethyl)-piperazine in 300 ml of ethanol and refluxed for 3 hours. The mixture was left to stand overnight, the precipitated solid product was separated off by suction filtering and washed with ethanol. After drying 23.0 g (79% of theory) of colourless crystals were obtained, Rf 0.10 (EI D).

[0530] ESI-MS: (M−H)−=302; (M+Na)+=326

EXAMPLE A31

[0531] 1-(aminothiocarbonyl)-4-(phenylmethyl)-piperazine

[0532] 12.596 g (108.247 mmol) of tert.-butyl isothiocyanate were added dropwise to an ice-cooled solution of 19.08 g (108.25 mmol) of 1-(phenylmethyl)-piperazine in 150 ml dichloromethane, while keeping the reaction temperature below +5° C. The mixture was stirred overnight at room temperature, freed from solvent and the residue remaining was boiled for 1½ hours with 100 ml of conc. hydrochloric acid. After cooling, it was neutralised while cooling externally with 12M sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined dichloromethane extracts were dried over sodium sulphate and concentrated by evaporation in vacuo. 25.2 g (99% of theory) of bright yellow crystals were obtained, Rf=0.45 (EI D).

[0533] ESI-MS: (M+H)+=236; (M−H)−=234; (M+Na)+=258

EXAMPLE A32

[0534] Ethyl 4-methyl-1-(phenylmethyl)-2-piperazinecarboxylate

[0535] A solution of 2.2 ml (35.029 mmol) of iodomethane in 50 ml THF was added dropwise at room temperature to a mixture of 15.12 g (31.739 mmol) of ethyl 1-(phenylmethyl)-2-piperazinecarboxylate-bis-(trifluoroacetate), 20 ml DIEA and 250 ml THF and stirred for a further 4 hours at room temperature. The mixture was filtered, the residue was evaporated down in vacuo and chromatographed on a silica gel column using EI II as eluant. After the appropriate fractions had been worked up in the usual way, 2.43 g (29% of theory) of a colourless oil were obtained, which was used in the next steps without further purification.

[0536] The following compounds of general formula N-B-C were prepared analogously:

				%
N	B	C	Remarks	yield	EI	Rf	MS	mp. [° C.]
ethyl 4-(1,1-	from ethyl 4-(1,1-	79	AcOEt	0.58	ESI:	colourless
dimethylethoxycarbonyl)-	dimethylethoxy-				(M + H)+ = 273	oil
1-methyl-2-	carbonyl)-2-
piperazinecarboxylate	piperazinecarboxylate,
	CH3l and DIEA in
	THF
ethyl 4-(1,1-	from ethyl 4-(1,1-	90	NN	0.51	ESI:
dimethylethoxycarbonyl)-	dimethylethoxy-				(M + H)+ = 349
1-(phenylmethyl)-2-	carbonyl)-2-
piperazinecarboxylate	piperazinecarboxylate,
	PhCH2Br and DIEA in
	THF

EXAMPLE A33

[0537] Ethyl 4-(1,1-dimethylethoxycarbonyl)-2-piperazinecarboxylate

[0538] 22.0 g (0.101 mol) di-tert.-butyl pyrocarbonate were added dropwise to a solution of 17.07 g (0.108 mol) ethyl 2-piperazinecarboxylate in 400 ml of ethanol while cooling with ice and the mixture was stirred for a further 3 hours while cooling externally with ice. The solvent was distilled off, lastly in vacuo, and the residue remaining was distributed between water and ethyl acetate. The organic phase was dried over sodium sulphate and evaporated down in vacuo, the residue was purified by column chromatography on silica gel using ethyl acetate/ethanol 95/5 v/v as eluant.

[0539] Yield: 11.798 g (42% of theory) of a colourless solid.

EXAMPLE A34

[0540] Ethyl 1,4-bis-(phenylmethyl)-2-piperazinecarboxylate

[0541] A solution of 56.441 g (217.141 mmol) of ethyl 2,3-dibromopropanoate in 55 ml of toluene was added dropwise to a solution, heated to 40° C., of 52.190 g (217.141 mmol) of N,N′-dibenzylethylenediamine and 60 ml triethylamine in 165 ml of toluene, with vigorous stirring, and stirred for a further 3 hours at a bath temperature of 80° C. The mixture was left to cool, filtered, the filtrates were washed twice with 50 ml of water, then once with 100 ml of saturated saline solution, dried over sodium sulphate and evaporated down in vacuo. 73.4 g (100% of theory) of a colourless viscous oil were obtained, Rf 0.79 (EI MM), which was used without further purification in the following step.

[0542] ESI-MS: (M+H)+=339

[0543] B. Preparation of the Final Compounds

EXAMPLE 1

[0544] Ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetate (Ser. no.1)

[0545] The mixture of 954.048 mg (1.6 mmol) 3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosine, 955.898 mg (1.6 mmol) ethyl 4-(4-piperidinyl)-1-piperazin-acetate, 802.75 mg (2.5 mmol) TBTU, 216.208 mg (1.6 mmol) HOBt, 2.4 ml (14.02 mmol) DIEA and 8 ml THF-DMF-mixture (5/3 v/v) was stirred overnight at ambient temperature. The reaction mixture was stirred into 50 ml of saturated aqueous sodium hydrogen carbonate solution, the precipitated solid was purified by column chromatography on silica gel using EI G as eluant. After the eluates had been worked up in the usual way 283 mg (21% of theory) of a colourless amorphous product were obtained, Rf 0.39 (EI G).

[0546] IR (KBr): 3405(NH, OH); 1731 (C═O) cm−1

[0547] ESI: (M−H)−=830/832/834(Br2); (M+Na)+=854/8561858(Br2)

[0548] The following compounds of general formula N-B-C were prepared analogously:

Ser.					%				IR
no.	N	B	C	Remarks	yield	EI	Rf	MS	[cm−1]	mp. [° C.]
3	N1	B1	C3	from N1—CO—B1—OH,	71	G	0.34	ESI: (M − H)− = 858/	1740	colourless
				H—C3, TBTU, HOBt				860/862 (Br2);	(C═O)	amorphous
				and DIEA in THF				(M + Na)+ = 882/		substance
								884/886 (Br2)
5	N1	B1	C5	from N1—CO—B1—OH,	56	G	0.36	ESI: (M − H)− = 815/		colourless
				H—C5 * 2 CF3CO2H,				817/819 (Br2);		amorphous
				TBTU, HOBt and				(M + Na)+ = 839/		substance
				DIEA in THF				841/843 (Br2)
7	N1	B1	C7	from N1—CO—B1—OH,	53	G	0.37	ESI: (M − H)− = 815/	3421	colourless
				H—C7, TBTU, HOBt				817/819 (Br2);	broad	amorphous
				and DIEA in THF				(M + H)+ = 817/	(NH,	substance
								819/821	OH);
								(Br2);(M + Na)+ = 839/	1726
								841/843 (Br2)	(C═O)
9	N1	B1	C9	from N1—CO—B1—OH,	46	G	0.40	ESI: (M − H)− = 815/		colourless
				H—C9, TBTU, HOBt				817/819 (Br2);		amorphous
				and DIEA in THF				(M + H)+ = 817/		substance
								819/821 (Br2)
11	N1	B1	C11	from N1—CO—B1—OH,	51	G	0.32	ESI: (M − H)− = 830/	3317	colourless
				H—C11, TBTU, HOBt				832/834 (Br2)	broad	amorphous
				and DIEA in THF					(NH,	substance
									OH);
									1738
									(C═O)
12	N2	B2	C5	from N2—CO—B2—OH,	96	G	0.61	ESI: (M + H)+ = 830/	3377	colourless
				H—C5, TBTU, HOBt				832/834;	broad	amorphous
				and DIEA in THF				(M + HCO2)− = 874/	(NH,	substance
								876/878 (Br2)	NH2);
									1734
									(C═O)
14	N2	B2	C11	from N2—CO—B2—OH,	82	G	0.57	ESI: (M + HCO2)− = 889/	3446	colourless
				H—C11, TBTU, HOBt				891/893 (Br2)	broad	amorphous
				and DIEA in THF					(NH,	substance
									NH2);
									1734
									(C═O)
15	N1	B3	C1	from N1—CO—B3—OH,	26			ESI: (M + H)+ = 766/	1669
				H—C1 * 3 CF3CO2H,				768 (Br)	(C═O)
				TBTU, HOBt and
				DIEA in DMF
				(Chemspeed)
16	N1	B4	C1	from N1—CO—B4—OH,	24			ESI: (M + H)+ = 742/
				H—C1 * 3 CF3CO2H,				744/746 (Cl2)
				TBTU, HOBt and
				DIEA in DMF
				(Chemspeed)
17	N1	B5	C1	from N1—CO—B5—OH,	37			ESI: (M + H)+ = 816/
				H—C1 * 3 CF3CO2H,				818/820 (Br2)
				TBTU, HOBt and
				DIEA in DMF
				(Chemspeed)
18	N1	B6	C1	from N1—CO—B6—OH,	26			ESI: (M + Na)+ = 788/
				H—C1 * 3 CF3CO2H,				790 (Br)
				TBTU, HOBt and
				DIEA in DMF
				(Chemspeed)
19	N1	B7	C1	from N1—CO—B7—OH,	18			ESI: (M + Na)+ = 852/
				H—C1 * 3 CF3CO2H,				854/856 (Br2)
				TBTU, HOBt and
				DIEA in DMF
				(Chemspeed)
20	N1	B8	C1	from N1—CO—B8—OH,	13			ESI: (M + H)+ = 708/
				H—C1 * 3 CF3CO2H,				710 (Cl)
				TBTU, HOBt and
				DIEA in DMF
				(Chemspeed)
21	N1	B3	C11	from N1—CO—B3—OH,	26			ESI: (M + Na)+ = 788/
				H—C11, TBTU, HOBt				790 (Br)
				and DIEA in DMF
				(Chemspeed)
29	N1	B9	C12	from N1—CO—B9—OH,	40			ESI: (M + H)+ = 724
				H—C12, TBTU, HOBt
				and DIEA in DMF
				(Chemspeed)
30	N1	B10	C5	from N1—CO—B10—	66	G	0.35	ESI: (M + H)+ = 661	1662	colourless
				OH, H—C5, TBTU,					(C═O)	amorphous
				HOBt and DIEA in						substance
				DMF (Chemspeed)
31	N1	B10	C1	from N1—CO—B10—	22			ESI: (M + H)+ = 676	1734,	colourless
				OH, H—C1, TBTU,					1660	amorphous
				HOBt and DIEA in					(C═O)	substance
				DMF (Chemspeed)
32	N1	B21	C1	from N1—CO—B21—	13			ESI: (M − H)− = 827/	1670	colourless
				OH, H—C1, TBTU				829/831 (Br2);	(C═O)	amorphous
				and NEt3 in				(M + H)+ = 829/		substance
				THF/DMF (10/1 v/v)				831/833 (Br2)
33	N1	B2	C14	from N1—CO—B2—OH,	33	S	0.67	ESI: (M + H)+ = 788/	3435,	184.6
				H—C14, TBTU and				790/792 (Br2);	3373
				NEt3 in THF/DMF				(M + Na)+ = 810/	(NH,
				(1/1 v/v)				812/814 (Br2)	NH2);
									1734,
									1668
									(C═O)
34	N1	B1	C14	from N1—CO—B1—OH,	6	S	0.67	ESI: (M − H)− = 787/	1653	141.9
				H—C14, TBTU and				789/791 (Br2);	(C═O)
				NEt3 in THF/DMF				(M + H)+ = 789/
				(1/1 v/v)				791/793 (Br2)
37	N1	B2	C16	from N1—CO—B2—OH,	53	S	0.67	ESI: (M + H)+ = 788/	3437	colourless
				H—C16, TBTU and				790/792 (Br2)	(NH,	crystals
				NEt3 in THF/DMF					NH2);
				(1/1 v/v)					1653
									(C═O)
38	N1	B1	C16	from N1—CO—B1—OH,	32	S	0.67	ESI: (M + H)+ = 789/	3321	colourless
				H—C16, TBTU and				791/793 (Br2)	(NH,	crystals
				NEt3 in THF/DMF					OH);
				(1/1 v/v)					1662
									(C═O)
41	N1	B2	C18	from N1—CO—B2—OH,	26	G	0.35	ESI: (M + H)+ = 802/		colourless
				H—C18 * AcOH,				804/806 (Br2)		crystals
				TBTU and NEt3 in
				THF/DMF (1/1 v/v)
42	N1	B1	C18	from N1—CO—B1—OH,	35	G	0.47	ESI: (M + H)+ = 803/		colourless
				H—C18 * AcOH,				805/807 (Br2)		crystals
				TBTU and NEt3 in
				THF/DMF (1/1 v/v)
43	N1	B2	C19	from N1—CO—B2—OH,	52	Q	0.73	ESI: (M + H)+ = 802/		colourless
				H—C19, TBTU and				804/806 (Br2);		crystals
				NEt3 in THF/DMF				(M + Na)+ = 824/
				(1/1 v/v)				826/828 (Br2)
44	N1	B1	C19	from N1—CO—B1—OH,	63	Q	0.72	ESI: (M + H)+ = 803/		colourless
				H—C19, TBTU and				805/807 (Br2)		crystals
				NEt3 in THF/DMF
				(1/1 v/v)
49	N1	B1	C22	from N1—CO—B1—OH,	49	G	0.44	ESI: (M − H)− = 801/		colourless
				H—C22, TBTU and				803/805 (Br2)		crystals
				NEt3 in THF/DMF
				(1/1 v/v)
50	N1	B2	C22	from N1—CO—B2—OH,	70	G	0.65	ESI: (M + H)+ = 802/		colourless
				H—C22, TBTU and				804/806 (Br2)		crystals
				NEt3 in THF/DMF
				(1/1 v/v)
55	N1	B1	C26	from N1—CO—B1—OH,	52	D	0.55	ESI: (M − H)− = 809/		colourless
				H—C26, TBTU, HOBt				811/813 (Br2)		crystals
				and DIEA in THF
56	N1	B1	C27	from N1—CO—B1—OH,	54	D	0.56	ESI: (M − H)− = 809/		colourless
				H—C27 * 2 HBr,				811/813 (Br2)		crystals
				TBTU, HOBt and
				DIEA in THF
57	N1	B1	C28	from N1—CO—B1—OH,	33	D	0.56	ESI: (M − H)− = 794/		colourless
				H—C28, TBTU, HOBt				796/798 (Br2)		crystals
				and DIEA in THF
58	N1	B1	C29	from N1—CO—B1—OH,	32	D	0.57	ESI: (M − H)− = 822/		colourless
				H—C29, TBTU, HOBt				824/826 (Br2)		crystals
				and DIEA in THF
59	N1	B1	C30	from N1—CO—B1—OH,	25	D	0.68	ESI: (M − H)− = 836/	1716,	colourless
				H—C30, TBTU, HOBt				838/840 (Br2);	1662	crystals
				and DIEA in THF				(M + Na)+ = 860/	(C═O)
								862/864 (Br2)
60	N1	B1	C31	from N1—CO—B1—OH,	55	D	0.59	ESI: (M − H)− = 863/		colourless
				H—C31 * 2 HCl,				865/867 (Br2)		crystals
				TBTU, HOBt and
				DIEA in THF
61	N1	B1	C32	from N1—CO—B1—OH,	45	D	0.59	ESI: (M − H)− = 794/		colourless
				H—C32 * HCl, TBTU,				796/798 (Br2);		crystals
				HOBt and DIEA in				(M + Na)+ = 818/
				THF				820/822 (Br2)
62	N2	B2	C26	from N2—CO—B2—OH,	62	D	0.81	ESI: (M − H)− = 822/		colourless
				H—C26, TBTU, HOBt				824/826 (Br2);		crystals
				and DIEA in THF				(M + Na)+ = 846/
								848/850 (Br2)
63	N2	B2	C27	from N2—CO—B2—OH,	65	D	0.79	ESI: (M + Na)+ = 846/		colourless
				H—C27 * 2 HBr,				848/850 (Br2)		crystals
				TBTU, HOBt and
				DIEA in THF
64	N2	B2	C28	from N2—CO—B2—OH,	38	D	0.81	ESI: (M − H)− = 807/		colourless
				H—C28, TBTU, HOBt				809/811 (Br2)		crystals
				and DIEA in THF
65	N2	B2	C30	from N2—CO—B2—OH,	54	D	0.87	ESI: (M + Na)+ = 873/		colourless
				H—C30, TBTU, HOBt				875/877 (Br2)		crystals
				and DIEA in THF
66	N2	B2	C31	from N2—CO—B2—OH,	50	D	0.85	ESI: (M + Na)+ = 900/		colourless
				H—C31 * 2 HCl,				902/904 (Br2)		crystals
				TBTU, HOBt and
				DIEA in THF
67	N2	B2	C32	from N2—CO—B2—OH,	52	D	0.88	ESI: (M − H)− = 807/	1723	colourless
				H—C32 * HCl, TBTU,				809/811 (Br2);	(C═O)	crystals
				HOBt and DIEA in				(M + Na)+ = 831/
				THF				833/835 (Br2)
83	N1	B1	C40	from N1—CO—B1—OH,	17	D	0.50	ESI: (M − H)− = 802/		colourless
				H—C40, TBTU, HOBt				804/806 (Br2);		crystals
				and DIEA in THF				(M + Na)+ = 826/
								828/830 (Br2)
84	N1	B1	C41	from N1—CO—B1—OH,	82	D	0.41	ESI: (M − H)− = 802/
				H—C41 * HCl,				804/806 (Br2)
				TBTU, HOBt and
				DIEA in THF
87	N1	B2	C41	from N1—CO—B2—OH,	75	D	0.62	ESI: (M − H)− = 801/
				H—C41 * HCl,				803/805 (Br2)
				TBTU, HOBt and
				DIEA in THF
88	N1	B2	C40	from N1—CO—B2—OH,	62	D	0.52	ESI: (M + Na)+ = 825/
				H—C40, TBTU, HOBt				827/829 (Br2)
				and DIEA in THF
93	N1	B2	C12	from N1—CO—B2—OH,	55	D	0.47	ESI: (M − H)− = 857/	1665	colourless
				H—C12, TBTU, HOBt				859/861 (Br2);	(C═O)	crystals
				and DIEA in THF				(M + H)+ = 859/
								861/863 (Br2);
								(M + Na)+ = 881/
								883/885 (Br2)
94	N2	B2	C12	from N2—CO—B2—OH,	65	D	0.49	ESI: (M − H)− = 871/		colourless
				H—C12, TBTU, HOBt				873/875 (Br2);		crystals
				and DIEA in THF				(M + Na)+ = 895/
								897/899 (Br2)
95	N1	B2	C1	from N1—CO—B2—OH,	57	D	0.68	ESI: (M + H)+ = 831/	1665	colourless
				H—C1, TBTU, HOBt				833/835 (Br2)	(C═O)	crystals
				and DIEA in THF
96	N2	B2	C1	from N2—CO—B2—OH,	58	D	0.72	ESI: (M − H)− = 843/	1658	colourless
				H—C1, TBTU, HOBt				845/847 (Br2);	(C═O)	crystals
				and DIEA in THF				(M + H)+ = 845/
								847/849 (Br2)
119	N1	B30	C1	from N1—CO—B30—	50			ESI: (M + H)+ = 815/		colourless
				OH, H—C1, TBTU,				817/819 (Br2)		crystals
				HOBt and DIEA in
				THF
122	N1	B7	C14	from N1—CO—B7—OH,	26	II	0.44	ESI: (M + H)+ = 787/		colourless
				H—C14, TBTU and				789/791 (Br2)		amorphous
				NEt3 in DMF						substance
123	N1	B8	C14	from N1—CO—B8—OH,	28	C	0.68	ESI: (M + H)+ = 665/		highly
				H—C14, TBTU and				667 (Cl)		viscous oil
				NEt3 in DMF
124	N1	B7	C16	from N1—CO—B7—OH,	20	C	0.80	ESI: (M + H)+ = 787/		highly
				H—C16, TBTU and				789/791 (Br2)		viscous oil
				NEt3 in DMF
125	N1	B8	C16	from N1—CO—B8—OH,	11	II	0.58	ESI: (M + H)+ = 665/		colourless
				H—C16, TBTU and				667 (Cl)		amorphous
				NEt3 in DMF						substance
128	N1	B32	C45	from N1—CO—B32—	4	C	0.45	ESI: (M + H)+ = 703		colourless
				OH, H—C45, TBTU,						solid
				HOBt and NEt3 in						substance
				DMF
129	N1	B30	C45	from N1—CO—B30—	19	C	0.72	ESI: (M + H)+ = 815/		colourless
				OH, H—C45, TBTU				817/819 (Br2)		solid
				and DIEA in THF						substance
130	N1	B30	C44	from N1—CO—B30—	18	C	0.81	ESI: (M + H)+ = 815/		colourless
				OH, H—C44, TBTU				817/819 (Br2)		solid
				and DIEA in THF						substance
131	N1	B21	C45	from N1—CO—B21—	14	C	0.67	ESI: (M + H)+ = 829/		colourless
				OH, H—C45, TBTU				831/833 (Br2)		solid
				and DIEA in THF						substance
132	N1	B21	C44	from N1—CO—B21—	24	C	0.48	ESI: (M + H)+ = 829/		colourless
				OH, H—C44, TBTU				831/833 (Br2)		solid
				and DIEA in THF						substance
133	N1	B30	C46	from N1—CO—B30—	16	C	0.55	ESI: (M + H)+ = 815/		colourless
				OH, H—C46, TBTU				817/819 (Br2)		solid
				and DIEA in THF						substance
138	N1	B21	C46	from N1—CO—B21—	26	Q	0.65	ESI: (M + H)+ = 829/		colourless
				OH, H—C46, PyBroP				831/833 (Br2)		solid
				and DIEA in THF						substance
140	N1	B31	C44	from N1—CO—B31—	22	Q	0.57	ESI: (M + H)+ = 830/		colourless
				OH, H—C44, PyBroP				832/834 (Br2)		solid
				and DIEA in THF						substance
141	N1	B31	C46	from N1—CO—B31—	15	Q	0.47	ESI: (M + H)+ = 830/		colourless
				OH, H—C46, PyBroP				832/834 (Br2)		solid
				and DIEA in THF						substance
142	N1	B31	C45	from N1—CO—B31—	11	Q	0.59	ESI: (M + H)+ = 830/		colourless
				OH, H—C45, PyBroP				832/834 (Br2)		solid
				and DIEA in THF						substance
148	N1	B32	C44	from N1—CO—B32—	24	Q	0.50	ESI: (M + H)+ = 703	1736,	colourless
				OH, H—C44, HATU					1664,	solid
				and DIEA in THF					1637	substance
									(C═O)
149	N1	B32	C46	from N1—CO—B32—	3	Q	0.50	M+ = 702		colourless
				OH, H—C46, HATU						solid
				and DIEA in THF						substance
151	N1	B25	C45	from N1—CO—B25—	10	G	0.38	ESI: (M + H)+ = 805/		colourless
				OH, H—C45, TBTU				807/809 (Cl2)		solid
				and DIEA in THF						substance
152	N1	B30	C50	from N1—CO—B30—	21	G	0.28	ESI: (M + H)+ = 815/		colourless
				OH, H—C50, TBTU				817/819 (Br2)		solid
				and DIEA in THF						substance
153	N1	B21	C50	from N1—CO—B21—	34	G	0.36	ESI: (M + H)+ = 829/	3439	colourless
				OH, H—C50, TBTU				831/833 (Br2)	(NH);	solid
				and DIEA in THF					1738,	substance
									1666,
									1639
									(C═O)
154	N1	B32	C50	from N1—CO—B32—	46	G	0.35	ESI: (M + H)+ = 703	1736,	colourless
				OH, H—C50, TBTU					1660,	solid
				and DIEA in THF					1628	substance
									(C═O)
155	N1	B31	C50	from N1—CO—B31—	30	Q	0.66	ESI: (M + H)+ = 830/	3458	colourless
				OH, H—C50, TBTU				832/834 (Br2)	(NH,	solid
				and DIEA in THF					NH2);	substance
									1734
									(C═O)
156	N1	B25	C50	from N1—CO—B25—	29	Q	0.68	ESI: (M + H)+ = 806/	3439	colourless
				OH, H—C50, TBTU				807/809/811	(NH);	solid
				and DIEA in THF				(Br2, Cl)	1639	substance
									(C═O)
162	N1	B5	C45	from N1—CO—B5—OH,	22	C	0.69	ESI: (M + H)+ = 816/		colourless
				H—C45, TBTU and				818/820 (Br2)		solid
				DIEA in THF/DMF						substance
				(3/1 v/v)
164	N1	B33	C5	from N1—CO—B33—	70	C	0.79	ESI: (M + H)+ = 801/		colourless
				OH, H—C5, TBTU				803/805 (Br2)		solid
				and DIEA in THF						substance
166	N1	B7	C45	from N1—CO—B7—OH,	25	C	0.69	ESI: (M + H)+ = 830/	1738,	colourless
				H—C45, TBTU and				832/834 (Br2)	1660	solid
				DIEA in THF/DMF					(C═O)	substance
167	N1	B7	C50	from N1—CO—B7—OH,	41	C	0.71	ESI: (M + H)+ = 830/	1736,	colourless
				H—C50, TBTU and				832/834 (Br2)	1662	solid
				DIEA in THF/DMF					(C═O)	substance

EXAMPLE 2

[0549] 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazine-acetic acid (Ser. no. 2)

[0550] 0.5 ml of 1 M aqueous sodium hydroxide solution was added to a solution of 85.0 mg (0.102 mmol) of ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazine-acetate in 3.5 ml of methanol at room temperature and the mixture was stirred for 1 hour at a reaction temperature of 40° C. The solvent was eliminated in vacuo and then neutralised while cooling externally with ice by the addition of 0.5 ml 1 M hydrochloric acid. The mixture was left to stand for 2 hours at room temperature before the precipitated crystals were collected. The mother liquor was evaporated down again, the residue was digested with a few drops of water to eliminate inorganic salts, left to stand for 2 hours and then filtered. The combined solids were dried in vacuo, triturated with diethyl ether and yielded 80.0 mg (97% of theory) of colourless crystals.

[0551] ESI-MS: (M+Na)+=826/828/830 (Br2) (M−H)−=802/804/806 (Br2)

[0552] The following compounds of general formula N-B-C were prepared analogously:

Ser.					%
no.	N	B	C	Remarks	yield	EI	Rf	MS	IR [cm−1]	mp. [° C.]
4	N1	B1	C4	from N1—CO—B1—	88	G	0.02	ESI: (M − H)− = 802/		colourless
				C3 with aq. 1M				804/806 (Br2);		crystals
				NaOH, then aq.				(M + Na)+ = 826/
				1M HCl				828/830 (Br2)
6	N1	B1	C6	from N1—CO—B1—	88	G	0.02	ESI: (M − H)− = 801/	3420 (NH,	colourless
				C5 with aq. 1M				803/805 (Br2);	OH), 1734,	crystals
				NaOH, then aq.				(M + H)+ = 803/	1653 (C═O)
				1M HCl				805/807 (Br2);
								(M + Na)+ = 825/
								827/829 (Br2)
8	N1	B1	C8	from N1—CO—B1—	96	G	0.02	ESI: (M − H)− = 787/	3420 (NH,	colourless
				C7 with aq. 1M				789/791 (Br2);	OH), 1709,	crystals
				NaOH, then aq.				(M + Na)+ = 811/	1653 (C═O)
				1M HCl				813/815 (Br2)
10	N1	B1	C10	from N1—CO—B1—	72	G	0.03	ESI: (M − H)− = 787/	3413 (NH,	colourless
				C9 with aq. 1M				789/791 (Br2);	OH), 1707,	crystals
				NaOH, then aq.				(M + Na)+ = 811/	1653 (C═O)
				1M HCl				813/815 (Br2)
13	N2	B2	C6	from N2—CO—B2—	78	G	0.04	ESI: (M − H)− = 814/	3431 (NH,	colourless
				C5 with aq. 1M				816/818 (Br2);	NH2); 1653	crystals
				NaOH, then aq.				(M + H)+ = 816/	(C═O)
				1M HCl				818/820 (Br2);
								(M + HCO2)− = 859/
								861/863 (Br2)
22	N1	B3	C2	from N1—CO—B3—	97			ESI: (M + H)+ = 738/	3425 (NH),	colourless
				C1 with aq. 1M				740 (Br)	1659, 1632	crystals
				NaOH, then aq.					(C═O)
				1M HCl
23	N1	B4	C2	from N1—CO—B4—	99			ESI: (M + Cl)− = 748/	3419 (NH),	colourless
				C1 with aq. 1M				750/752/754	1655, 1628	crystals
				NaOH, then aq.				(Cl2); (M + Na)+ = 736/	(C═O)
				1M HCl				738/740 (Cl2)
24	N1	B5	C2	from N1—CO—B5—	98			ESI: (M + Cl)− = 822/	3419 (NH),	colourless
				C1 with aq. 1M				824/826/828	1655, 1635	crystals
				NaOH, then aq.				(Br2); (M + Na)+ = 810/	(C═O)
				1M HCl				812/814 (Br2)
25	N1	B6	C2	from N1—CO—B6—	98			ESI: (M + Cl)− = 772/	3427 (NH),	colourless
				C1 with aq. 1M				774/776 (Br);	1630 (C═O)	crystals
				NaOH, then aq.				(M + Na)+ = 760/
				1M HCl				762 (Br)
26	N1	B7	C2	from N1—CO—B7—	99			ESI: (M + Cl)− = 836/	3419 (NH),	colourless
				C1 with aq. 1M				838/840/842	1655, 1635	crystals
				NaOH, then aq.				(Br2); (M + Na)+ = 824/	(C═O)
				1M HCl				826/828 (Br2)
27	N1	B8	C2	from N1—CO—B8—	89			ESI: (M + Cl)− = 714/	3419 (NH),	colourless
				C1 with aq. 1M				716/718 (Cl);	1655, 1635	crystals
				NaOH, then aq.				(M + Na)+ = 702/	(C═O)
				1M HCl				704 (Cl)
28	N1	B3	C4	from N1—CO—B3—	97			ESI: (M + Cl)− = 772/	3416 (NH),	colourless
				C11 with aq. 1M				774/776 (Br);	1655, 1635	crystals
				NaOH, then aq.				(M + Na)+ = 760/	(C═O)
				1M HCl				762 (Br)
35	N1	B2	C15	from N1—CO—B2—	78	T	0.46	ESI: (M + Na)+ = 796/	3339 (NH,	colourless
				C14 with aq. 1M				798/800 (Br2)	NH2); 1653	crystals
				LiOH, then aq. 1M					(C═O)
				HCl
36	N1	B1	C15	from N1—CO—B1—	78	T	0.42	ESI: (M − H)− = 773/		colourless
				C14 with aq. 1M				775/779 (Br2);		crystals
				LiOH, then aq. 1M				(M + H)+ = 775/
				HCl				777/779 (Br2);
								(M + Na)+ = 797/
								799/801 (Br2)
39	N1	B2	C17	from N1—CO—B2—	76	T	0.46	ESI: (M − H)− = 772/	3429 (NH,	colourless
				C16 with aq. 1M				774/776 (Br2);	NH2); 1653	crystals
				LiOH, then aq. 1M				(M + Na)+ = 796/	(C═O)
				HCl				798/800 (Br2)
40	N1	B1	C17	from N1—CO—B1—	70	T	0.42	ESI: (M − H)− = 773/	3420 (NH,	colourless
				C16 with aq. 1M				775/777 (Br2);	OH); 1653	crystals
				LiOH, then aq. 1M				(M + Na)+ = 797/	(C═O)
				HCl				799/801 (Br2)
45	N1	B2	C20	from N1—CO—B2—	96			ESI: (M − H)− = 786/		colourless
				C18 with aq. 1M				788/790 (Br2)		crystals
				LiOH, then aq. 1M
				HCl
46	N1	B1	C20	from N1—CO—B1—	97			ESI: (M − H)− = 787/		colourless
				C18 with aq. 1M				789/791 (Br2)		crystals
				LiOH, then aq. 1M
				HCl
47	N1	B1	C21	from N1—CO—B1—	86			ESI: (M − H)− = 787/		colourless
				C19 with aq. 1M				789/791 (Br2)		crystals
				LiOH, then aq. 1M
				HCl
48	N1	B2	C21	from N1—CO—B2—	2			ESI: (M − H)− = 786/		colourless
				C19 with aq. 1M				788/790 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 810/
				HCl				812/814 (Br2)
51	N1	B1	C23	from N1—CO—B1—	12			ESI: (M − H)− = 787/		colourless
				C22 with aq. 1M				789/791 (Br2)		amorphous
				LiOH, then aq. 1M						substance
				HCl
52	N1	B2	C23	from N1—CO—B2—	14			ESI: (M + H)+ = 788/		colourless
				C22 with aq. 1M				790/792 (Br2)		amorphous
				LiOH, then aq. 1M						substance
				HCl
53	N1	B10	C6	from N1—CO—B10—	36			ESI: (M + H)+ = 647		colourless
				C5 with aq. 1M						amorphous
				LiOH, then aq.						substance
				citric acid
54	N1	B10	C2	from N1—CO—B10—	21			ESI: (M + H)+ = 648	1711, 1639	colourless
				C1 with aq. 1M					(C═O)	crystals
				LiOH, then aq.
				citric acid
68	N1	B1	C33	from N1—CO—B1—	77	I	0.51	ESI: (M − H)− = 781/	1655 (C═O)	colourless
				C26 with aq. 1M				783/785 (Br2)		crystals
				LiOH, then aq. 1M
				HCl
69	N1	B1	C34	from N1—CO—B1—	75	I	0.50	ESI: (M − H)− = 781/	1637 (C═O)	colourless
				C27 with aq. 1M				783/785 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 805/
				HCl				807/809 (Br2)
70	N1	B1	C35	from N1—CO—B1—	82	I	0.52	ESI: (M − H)− = 780/		colourless
				C28 with aq. 1M				782/784 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 804/
				HCl				806/808 (Br2)
71	N1	B1	C36	from N1—CO—B1—	76	I	0.54	ESI: (M − H)− = 794/	1658 (C═O)	colourless
				C29 with aq. 1M				796/798 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 818/
				HCl				820/822 (Br2)
72	N1	B1	C37	from N1—CO—B1—	75	I	0.53	ESI: (M − H)− = 808/	1707, 1659	colourless
				C30 with aq. 1M				810/812 (Br2);	(C═O)	crystals
				LiOH, then aq. 1M				(M + Na)+ = 832/
				HCl				834/836 (Br2)
73	N1	B1	C38	from N1—CO—B1—	73	I	0.47	ESI: (M − H)− = 849/		colourless
				C31 with aq. 1M				851/853 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 873/
				HCl				875/877 (Br2)
74	N1	B1	C39	from N1—CO—B1—	68	I	0.49	ESI: (M − H)− = 780/	1711, 1657	colourless
				C32 with aq. 1M				782/784 (Br2)	(C═O)	crystals
				LiOH, then aq. 1M
				HCl
75	N2	B2	C33	from N2—CO—B2—	82	I	0.55	ESI: (M − H)− = 794/		colourless
				C26 with aq. 1M				796/798 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 818/
				HCl				820/822 (Br2)
76	N2	B2	C34	from N2—CO—B2—	76	I	0.54	ESI: (M − H)− = 794/	1709, 1637	colourless
				C27 with aq. 1M				796/798 (Br2);	(C═O)	crystals
				LiOH, then aq. 1M				(M + Na)+ = 818/
				HCl				820/822 (Br2)
77	N2	B2	C35	from N2—CO—B2—	76	I	0.54	ESI: (M − H)− = 793/	1657 (C═O)	colourless
				C28 with aq. 1M				795/797 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 817/
				HCl				819/821 (Br2)
78	N2	B2	C37	from N2—CO—B2—	86	I	0.56	ESI: (M − H)− = 821/		colourless
				C30 with aq. 1M				823/825 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 845/
				HCl				847/849 (Br2)
79	N2	B2	C38	from N2—CO—B2—	77	I	0.56	ESI: (M − H)− = 862/		colourless
				C31 with aq. 1M				864/866 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 886/
				HCl				888/890 (Br2)
80	N2	B2	C39	from N2—CO—B2—	71	I	0.57	ESI: (M − H)− = 793/	1711 (C═O)	colourless
				C32 with aq. 1M				795/797 (Br2)		crystals
				LiOH, then aq. 1M
				HCl
82	N2	B11	C2	from N2—CO—B11—	83			ESI: (M + H)+ = 696		colourless
				C1 with aq. 0.1M						amorphous
				LiOH, then aq.						substance
				0.1M HCl
85	N1	B1	C42	from N1—CO—B1—	97	O	0.12	ESI: (M − H)− = 788/		colourless
				C40 with aq. 0.1M				790/792 (Br2)		crystals
				LiOH, then aq.
				0.1M HCl
86	N1	B1	C43	from N1—CO—B1—	82	O	0.16	ESI: (M − H)− = 788/		colourless
				C41 with aq. 0.1M				790/792 (Br2)		crystals
				LiOH, then aq.
				0.1M HCl
89	N1	B2	C43	from N1—CO—B2—	76	D	0.15	ESI: (M − H)− = 787/		colourless
				C41 with aq. 0.1M				789/791 (Br2)		crystals
				LiOH, then aq.
				0.1M HCl
90	N1	B2	C42	from N1—CO—B2—	86	D	0.16	ESI: (M − H)− = 787/		colourless
				C40 with aq. 0.1M				789/791 (Br2)		crystals
				LiOH, then aq.
				0.1M HCl
91	N1	B2	C4	from N1—CO—B2—	86	M	0.24	ESI: (M − H)− = 801/	1653 (C═O)	colourless
				C11 with aq. 0.1M				803/805 (Br2);		crystals
				LiOH, then aq.				(M + H)+ = 803/
				0.1M HCl				805/807 (Br2)
92	N2	B2	C4	from N2—CO—B2—	69	M	0.31	ESI: (M − H)− = 815/		colourless
				C11 with aq. 0.1M				817/819 (Br2);		crystals
				LiOH, then aq.				(M + Na)+ = 839/
				0.1M HCl				841/843 (Br2)
97	N1	B2	C2	from N1—CO—B2—	61	D	0.06	ESI: (M − H)− = 801803/	1653 (C═O)	colourless
				C1 with aq. 1M				805 (Br2);		crystals
				LiOH, then aq. 1M				(M + Na)+ = 825/
				HCl				827/829 (Br2)
98	N2	B2	C2	from N2—CO—B2—	73	D	0.05	ESI: (M − H)− = 815/		colourless
				C1 with aq. 1M				817/819 (Br2);		crystals
				LiOH, then aq. 1M				(M + H)+ = 817/
				HCl				819/821 (Br2);
								(M + Na)+ = 839/
								841/843 (Br2)
120	N1	B30	C2	from N1—CO—B30—	40			ESI: (M − H)− = 785/		colourless
				C1 with aq. 1M				787/789 (Br2);		amorphous
				NaOH, then aq.				(M + H)+ = 787/		substance
				1M HCl				789/791 (Br2)
121	N1	B30	C4	from N1—CO—B30—	48			ESI: (M − H)− = 785/		colourless
				C11 with aq. 1M				787/789 (Br2);		amorphous
				NaOH, then aq.				(M + H)+ = 787/		substance
				1M HCl				789/791 (Br2)
126	N1	B7	C15	from N1—CO—B7—	77	C	0.00	ESI: (M + H)+ = 773/		colourless
				C14 with aq. 1M				775/777 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
127	N1	B8	C15	from N1—CO—B8—	100	C	0.00	ESI: (M + H)+ = 651/		colourless
				C14 with aq. 1M				657 (Cl)		solid
				LiOH, then aq. 1M						substance
				HCl
134	N1	B30	C47	from N1—CO—B30—	68	KK	0.25	ESI: (M + H)+ = 787/		colourless
				C45 with aq. 1M				789/791 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
135	N1	B30	C48	from N1—CO—B30—	29	KK	0.14	ESI: (M + H)+ = 787/		colourless
				C44 with aq. 1M				789/791 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
136	N1	B30	C49	from N1—CO—B30—	78	KK	0.10	ESI: (M − H)− = 785/		colourless
				C46 with aq. 1M				787/789 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
137	N1	B21	C47	from N1—CO—B21—	81	KK	0.24	ESI: (M + H)+ = 801/		colourless
				C45 with aq. 1M				803/805 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
139	N1	B21	C48	from N1—CO—B21—	51	KK	0.11	ESI: (M + H)+ = 801/		colourless
				C44 with aq. 1M				803/805 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
143	N1	B31	C48	from N1—CO—B31—	74	KK	0.11	ESI: (M + H)+ = 802/		colourless
				C44 with aq. 1M				804/806 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
145	N1	B31	C47	from N1—CO—B31—	72	KK	0.23	ESI: (M + H)+ = 802/		colourless
				C45 with aq. 1M				804/806 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
146	N1	B31	C49	from N1—CO—B31—	62	KK	0.07	ESI: (M + H)+ = 802/		colourless
				C46 with aq. 1M				804/806 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
147	N1	B21	C49	from N1—CO—B21—	92	KK	0.08	ESI: (M + H)+ = 801/		colourless
				C46 with aq. 1M				803/805 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl
150	N1	B32	C47	from N1—CO—B32—	17	KK	0.14	ESI: (M + H)+ = 675		colourless
				C45 with aq. 1M						solid
				LiOH, then aq. 1M						substance
				HCl
157	N1	B21	C51	from N1—CO—B21—	75	Q	0.35	ESI: (M + H)+ = 801/		colourless
				C50 with aq. 1M				803/805 (Br2)		amorphous
				LiOH, then aq. 1M						substance
				HCl
158	N1	B32	C51	from N1—CO—B32—	20	KK	0.13	ESI: (M − H)− = 673;		colourless
				C50 with aq. 1M				(M + H)+ = 675		amorphous
				LiOH, then aq. 1M						substance
				HCl
159	N1	B31	C51	from N1—CO—B31—	91	OO	0.60	ESI: (M + H)+ = 802/		colourless
				C50 with aq. 1M				804/806 (Br2)		amorphous
				LiOH, then aq. 1M						substance
				HCl
160	N1	B25	C51	from N1—CO—B25—	82	Q	0.25	ESI: (M + H)+ = 777/		colourless
				C50 with aq. 1M				779/781/783		amorphous
				LiOH, then aq. 1M				(BrCl2)		substance
				HCl
161	N1	B30	C51	from N1—CO—B30—	73	Q	0.32	ESI: (M + H)+ = 787/		colourless
				C50 with aq. 1M				789/791 (Br2)		amorphous
				LiOH, then aq. 1M						substance
				HCl
163	N1	B25	C47	from N1—CO—B25—	90	KK	0.17	ESI: (M + H)+ = 777/		colourless
				C45 with aq. 1M				779/781/783		amorphous
				LiOH, then aq. 1M				(BrCl2)		substance
				HCl
165	N1	B33	C6	from N1—CO—B33—	78	KK	0.16	ESI: (M + H)+ = 787/		colourless
				C5 with aq. 1M				789/791 (Br2)		solid
				LiOH, then aq. 1M						substance
				HCl

EXAMPLE 3

[0553] Ethyl 4-{1-[3-(1-naphthyl)-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-alanyl]-4-piperidinyl}-1-piperazineacetate (Ser. no. 81)

[0554] A tetrahydrofuran solution (20 ml) of 380.0 mg (0.84 mmol) ethyl 4-{1-[3-(1-naphthyl)-D-alanyl]-4-piperidinyl}-1-piperazineacetate was added dropwise over a period of 40 minutes to a stirred suspension of 149.356 mg (0.91 mmol) CDT in 10 ml of tetrahydrofuran cooled to −5° C. The reaction mixture was then stirred for 1 hour at −5° C. and 1 hour at ambient temperature and combined with the suspension of 206.075 mg (0.84 mmol) 3-(4-piperidinyl)-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 10 ml DMF. In order to obtain a homogeneous mixture, the tetrahydrofuran was distilled off at normal pressure, another 15 ml of DMF were added and the mixture was then heated to 100° C. for 2 hours. The reaction mixture was evaporated down in vacuo, the residue was purified by column chromatography using a gradient method developed in-house using mixtures of dichloromethane, methanol and conc. ammonia on silica gel, the appropriate fractions were triturated with ether and the solid obtained (450.0 mg; 74% of theory) was suction filtered and dried.

[0555] ESI-MS: (M+H)+=724

EXAMPLE 4

[0556] (R,S)-4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid (Ser. no. 99)

[0557] This and the following syntheses were carried out using the Chemspeed ASW2000 synthesising robot (Chemspeed Ltd., Rheinstraβe 32, CH-4302 Augst, Switzerland).

[0558] Mixture:

[0559] AGV 1: 118.862 mg (0.200 mmol) of (R,S)-2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutanoic acid in 3 ml THF;

[0560] AGV 2: 51.073 mg (0.200 mmol) of ethyl 4-(4-piperidinyl)-1-piperazineacetate in 2 ml THF;

[0561] AGV 3: 64.220 mg (0.200 mmol) of TBTU in 2 ml DMF;

[0562] AGV 4: 1.00 ml (1.00 mmol) of triethylamine;

[0563] AGV 5: 1.00 ml 4M sodium hydroxide solution;

[0564] AGV 6: 1.00 ml 4M hydrochloric acid;

[0565] AGV 7: 6 ml THF.

[0566] AGV 1 to 4 were positioned accordingly, then pipetted together by the robot and shaken for 8 hours at room temperature. The reaction mixtures were concentrated by evaporation, each combined with 7 ml of ethyl acetate, the solutions formed were each washed with 10 ml 10% aqueous potassium carbonate solution and with 6 ml of water and again freed from solvent. The residues were each dissolved in AGV 7 and after the addition of AGV 5 stirred for six hours at room temperature. The reaction mixtures were neutralised by the addition of AGV 6, then concentrated by evaporation. The residues obtained were each dissolved in 1.9 ml DMF and placed on a microtitre plate. The samples were in each case separated using an HPLC-MS apparatus (Agilent Technologies, Agilent 1100 Series Modules and Systems for HPLC and LC/MS), the products of interest were collected under mass control. The end products were freeze-dried.:

[0567] Yield: 26.0 mg (15% of theory).

[0568] ESI-MS: (M−H)−=800/802/804 (Br2) (M+H)+=802/804/806 (Br2)

[0569] The following compounds of general formula N-B-C were prepared analogously:

Ser.					%
no.	N	B	C	Remarks	yield	MS
100	N1	B12	C2	coupling of N1—CO—B12—OH with	8	ESI: (M − H)− = 803/805/807
				H—C1 and subsequent		(Br2); (M + H)+ = 805/807/809
				saponification with aq. NaOH		(Br2)
101	N5	B13	C2	coupling of N5—CO—B13—OH with	6	ESI: (M + H)+ = 682
				H—C1 and subsequent
				saponification with aq. NaOH
102	N1	B14	C2	coupling of N1—CO—B14—OH with	6	ESI: (M + H)+ = 767
				H—C1 and subsequent
				saponification with aq. NaOH
103	N1	B15	C2	coupling of N1—CO—B15—OH with	6	ESI: (M + H)+ = 673
				H—C1 and subsequent
				saponification with aq. NaOH
104	N1	B16	C2	coupling of N1—CO—B16—OH with	6	ESI: (M − H)− = 735/737 (Br);
				H—C1 and subsequent		(M + H)+ = 737/739 (Br)
				saponification with aq. NaOH
105	N1	B17	C2	coupling of N1—CO—B17—OH with	10	ESI: (M + H)+ = 699
				H—C1 and subsequent
				saponification with aq. NaOH
106	N1	B18	C2	coupling of N1—CO—B18—OH with	4	ESI: (M + H)+ = 689
				H—C1 and subsequent
				saponification with aq. NaOH
107	N1	B19	C2	coupling of N1—CO—B19—OH with	4	ESI: (M − H)− = 712/714/716
				H—C1 and subsequent		(Cl2); (M + H)+ = 714/716/718
				saponification with aq. NaOH		(Cl2)
108	N1	B20	C2	coupling of N1—CO—B20—OH with	4	ESI: (M + H)+ = 767
				H—C1 and subsequent
				saponification with aq. NaOH
109	N1	B21	C2	coupling of N1—CO—B21—OH with	13	ESI: (M − H)− = 799/801/803
				H—C1 and subsequent		(Br2); (M + H)+ = 801/803/805
				saponification with aq. NaOH		(Br2)
110	N1	B22	C2	coupling of N1—CO—B22—OH with	4	ESI: (M + H)+ = 865/
				H—C1 and subsequent		867/869/871 (Br3)
				saponification with aq. NaOH
111	N1	B23	C2	coupling of N1—CO—B23—OH with	12	ESI: (M + H)+ = 691
				H—C1 and subsequent
				saponification with aq. NaOH
112	N1	B24	C2	coupling of N1—CO—B24—OH with	2	ESI: (M + H)+ = 699/701/703
				H—C1 and subsequent		(Cl2)
				saponification with aq. NaOH
113	N1	B25	C2	coupling of N1—CO—B25—OH with	4	ESI: (M + H)+ = 777/779/781
				H—C1 and subsequent		(Br, Cl2)
				saponification with aq. NaOH
114	N1	B26	C2	coupling of N1—CO—B26—OH with	3	ESI: (M + H)+ = 681
				H—C1 and subsequent
				saponification with aq. NaOH
115	N1	B27	C2	coupling of N1—CO—B27—OH with	4	ESI: (M − H)− = 671; (M + H)+ = 673
				H—C1 and subsequent
				saponification with aq. NaOH
116	N1	B28	C2	coupling of N1—CO—B28—OH with	4	ESI: (M + H)+ = 685
				H—C1 and subsequent
				saponification with aq. NaOH
117	N6	B21	C2	coupling of N6—CO—B21—OH with	3	ESI: (M + H)+ = 837/839/841
				H—C1 and subsequent		(Br2)
				saponification with aq. NaOH
118	N1	B29	C2	coupling of N1—CO—B29—OH with	4	ESI: (M + H)+ = 699/701/703
				H—C1 and subsequent		(Cl2)
				saponification with aq. NaOH

[0570] The Examples that follow describe the preparation of pharmaceutical formulations which contain as active substance any desired compound of general formula (1):

EXAMPLE I

[0571] Capsules for Powder Inhalation Containing 1 mg of Active Ingredient

[0572] Composition:

[0573] 1 capsule for powder inhalationcontains:

active ingredient      1.0 mg
lactose                20.0 mg
hard gelatine capsules 50.0 mg
                       71.0 mg

[0574] Method of Preparation:

[0575] The active ingredient is ground to the particle size required for inhaled substances. The ground active ingredient is homogeneously mixed with the lactose. The mixture is transferred into hard gelatine capsules.

EXAMPLE II

[0576] Inhalable Solution for Respimat® Containing 1 mg of Active Ingredient

[0577] Composition:

1 puff contains:
active ingredient     1.0 mg
benzalkonium chloride 0.002 mg
disodium edetate      0.0075 mg
purified water ad     15.0 μl

[0578] Method of Preparation:

[0579] The active ingredient and benzalkonium chloride are dissolved in water and transferred into Respimat® cartridges.

EXAMPLE III

[0580] Inhalable Solution for Nebulisers Containing 1 mg of Active Ingredient

[0581] Composition:

1 vial contains:
active ingredient     0.1 g
sodium chloride       0.18 g
benzalkonium chloride 0.002 g
purified water ad     20.0 ml

[0582] Method of Preparation

[0583] The active ingredient, sodium chloride and benzalkonium chloride are dissolved in water.

EXAMPLE IV

[0584] Propellant Gas-Operated Metering Aerosol Containing 1 mg of Active Ingredient

[0585] Composition:

1 puff contains:
active ingredient 1.0 mg
lecithin          0.1%
propellant gas ad 50.0 μl

[0586] Method of Preparation:

[0587] The micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.

EXAMPLE V

[0588] Nasal Spray Containing 1 mg of Active Ingredient

[0589] Composition:

active ingredient     1.0 mg
sodium chloride       0.9 mg
benzalkonium chloride 0.025 mg
disodium edetate      0.05 mg
purified water ad     0.1 ml

[0590] Method of Preparation:

[0591] The active ingredient and the excipients are dissolved in water and transferred into a suitable container.

EXAMPLE VI

[0592] Injectable Solution Containing 5 mg of Active Substance Per 5 ml

[0593] Composition:

active substance        5 mg
glucose                 250 mg
human serum albumin     10 mg
glycofurol              250 mg
water for injections ad 5 ml

[0594] Preparation:

[0595] Glycofurol and glucose are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.

EXAMPLE VII

[0596] Injectable Solution Containing 100 mg of Active Substance Per 20 ml

[0597] Composition:

active substance                 100 mg
monopotassium dihydrogen phosphate = KH2PO4 12 mg
disodium hydrogen phosphate = Na2HPO4.2H2O 2 mg
sodium chloride                  180 mg
human serum albumin              50 mg
Polysorbate 80                   20 mg
water for injections ad          20 ml

[0598] Preparation:

[0599] Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules.

EXAMPLE VIII

[0600] Lyophilisate Containing 10 mg of Active Substance

[0601] Composition:

Active substance    10 mg
Mannitol            300 mg
human serum albumin 20 mg

[0602] Preparation:

[0603] Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into vials; freeze-dried.

[0604] Solvent for Lyophilisate:

Polysorbate 80 = Tween 80 20 mg
mannitol                  200 mg
water for injections ad   10 ml

[0605] Preparation:

[0606] Polysorbate 80 and mannitol are dissolved in water for injections (Wfl); transferred into ampoules.

EXAMPLE IX

[0607] Tablets Containing 20 mg of Active Substance

[0608] Composition:

active substance   20 mg
lactose            120 mg
maize starch       40 mg
magnesium stearate 2 mg
Povidone K 25      18 mg

[0609] Preparation:

[0610] Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.

EXAMPLE X

[0611] Capsules Containing 20 mg Active Substance

[0612] Composition:

active substance        20 mg
maize starch            80 mg
highly dispersed silica 5 mg
magnesium stearate      2.5 mg

[0613] Preparation:

[0614] Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size for 3 hard gelatine capsules in a capsule filling machine.

EXAMPLE XI

[0615] Suppositories Containing 50 mg of Active Substance

[0616] Composition:

active substance                 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg

[0617] Preparation:

[0618] Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35° C. it is poured into chilled moulds.

EXAMPLE XII

[0619] Injectable Solution Containing 10 mg of Active Substance Per 1 ml

[0620] Composition:

active substance        10 mg
mannitol                50 mg
human serum albumin     10 mg
water for injections ad 1 ml

[0621] Preparation:

[0622] Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.

Claims

1. Carboxylic acids and esters of general formula

2. Carboxylic acids and esters of general formula I according to claim 1, wherein R denotes a monounsaturated 5- to 7-membered diaza, triaza or S,S-dioxido-thiadiaza heterocycle, while the above-mentioned heterocycles are linked via a nitrogen atom and are characterised by a carbonyl group or sulphonyl group in each case flanked by two nitrogen atoms, may be substituted at a carbon atom by a phenyl, pyridinyl, thienyl or 1,3-thiazolyl group, and the double bond of one of the above-mentioned unsaturated heterocycles may be fused to a benzene, pyridine or quinoline ring, while the phenyl, pyridinyl, thienyl, or 1,3-thiazolyl groups contained in R as well as benzo-, pyrido- and quinolino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, trifluoromethyl, amino, cyano or acetylamino groups, while the substituents may be identical or different, Ar denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl or 2,3-dihydrobenzo[b]fur-5-yl group, while the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by alkyl groups, alkoxy, trifluoromethyl, nitro, hydroxy, amino, aminocarbonyl, acetyl or cyano groups and the substituents may be identical or different, Y denotes the methylene or the —NH— group, Y1 denotes the carbon or the nitrogen atom, X1 denotes a pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol, X3 and X4 each denote the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol, with the proviso that at least one but also not more than one of the groups X1, X2, X3 or X4 contains an optionally esterified carboxylic acid function, and R1 denotes a group of general formula 40wherein Y2 denotes the carbon atom or, if m assumes the value 0, may also denote the nitrogen atom, Y3, which is always different from Y1, denotes the carbon or the nitrogen atom, X2 denotes a group of general formula CH2CO2R2,  (III) wherein R2 denotes the hydrogen atom or a C1-5-alkyl group, or, if Y2 is the carbon atom, also denotes the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol, m denotes the numbers 0 or 1, p denotes the numbers 0, 1 or 2 and q denotes the numbers 0, 1 or 2, while the sum of m, p and q may assume the values 1 or 2, or one of the groups 41wherein X2b and X2d each denote the hydrogen atom or the carboxylic acid group optionally esterified with a lower aliphatic alcohol, o denotes the numbers 0, 1, 2 or 3 and R3 denotes the hydrogen atom, the fluorine, chlorine or bromine atom, a methyl, methoxy, nitro, trifluoromethyl or cyano group, while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 4 carbon atoms and may be branched or unbranched, or the tautomers or the diastereomers or the enantiomers or the salts thereof.

3. Carboxylic acids and esters of general formula I according to claim 1, wherein R denotes a monounsaturated 5- to 7-membered diaza, triaza or S,S-dioxido-thiadiaza heterocycle, while the above-mentioned heterocycles are linked via a nitrogen atom and are characterised by a carbonyl group or sulphonyl group each flanked by two nitrogen atoms, may be substituted at a carbon atom by a phenyl group, and the double bond of one of the above-mentioned unsaturated heterocycles may be fused to a benzene, pyridine or quinoline ring, while the phenyl groups contained in R as well as benzo-, pyrido- and quinolino-fused heterocycles may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, or cyano groups, while the substituents may be identical or different, Ar denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl or 2,3-dihydrobenzo[b]fur-5-yl group, while the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, hydroxy or amino groups and the substituents may be identical or different, Y denotes the methylene or —NH— group, Y1 denotes the carbon or nitrogen atom, X1 denotes a pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol, X3 and X4 each denote the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol, with the proviso that at least one but also not more than one of the groups X1, X2, X3 or X4 contains an optionally esterified carboxylic acid function, and R1 denotes a group of general formula 42wherein Y2 denotes the carbon or, if m assumes the value 0, also denotes the nitrogen atom, Y3, which is always different from Y1, denotes the carbon or the nitrogen atom, X2 denotes a group of general formula CH2CO2R2,  (III) wherein R2 denotes the hydrogen atom or a straight-chain or branched C1-4-alkyl group, or, if Y2 is the carbon atom, also denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol, m denotes the numbers 0 or 1, p denotes the numbers 0, 1 or 2 and q denotes the numbers 0, 1 or 2, while the sum of m, p and q may assume the values 1 or 2, or one of the groups 43wherein X2b and X2d each denote the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol, o denotes the numbers 0, 1 or 2 and R3 denotes the hydrogen atom, the fluorine, chlorine or bromine atom, a methyl, methoxy or trifluoromethyl group, while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 4 carbon atoms and may be straight-chain or branched, or the tautomers or the diastereomers or the enantiomers or the salts thereof.

4. Carboxylic acids and esters of general formula I according to claim 1, wherein R denotes the 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl or 3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl group, Ar denotes the 3,5-dibromo-4-hydroxyphenyl, 4-amino-3,5-dibromophenyl, 4-bromo-3,5-dimethylphenyl, 3,5-dichloro-4-methylphenyl, 3,4-dibromophenyl, 3-bromo-4,5-dimethylphenyl, 3,5-dibromo-4-methylphenyl, 3-chloro-4-methylphenyl, 3,4-difluorophenyl, 4-hydroxyphenyl, 1-naphthyl, 3,5-dibromo-4-fluorophenyl, 3,5-bis-(trifluoromethyl)-phenyl, 3,4,5-trimethylphenyl, 3-(trifluoromethyl)-phenyl, 3,5-dimethyl-4-methoxyphenyl, 4-amino-3,5-dichlorophenyl, 2,4-bis-(trifluoromethyl)-phenyl, 3,4,5-tribromophenyl, 3,4-dimethoxyphenyl, 3,4-dichlorophenyl, 4-bromo-3,5-dichlorophenyl, 2-naphthyl, 2,3-dihydrobenzo[b]fur-5-yl, 1,2,3,4-tetrahydro-1-naphthyl or 2,3-dichlorophenyl group, Y denotes the methylene or the —NH— group, Y1 denotes the carbon or the nitrogen atom, X1 denotes a pair of free electrons, if Y1 denotes the nitrogen atom, or, if Y1 is the carbon atom, the hydrogen atom, the carboxylic acid or the methoxycarbonyl group and R1 denotes a group of general formula 44wherein Y2 denotes the carbon atom or, if m assumes the value 0, also the nitrogen atom, Y3, which is always different from Y1, denotes the carbon or the nitrogen atom, X2 denotes a group of general formula CH2CO2R2,  (III) wherein R2 denotes the hydrogen atom or a straight-chain or branched C1-4-alkyl group, or, if Y2 is the carbon atom, also denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol, m denotes the numbers 0 or 1, p and q in each case denotes the numbers 0, 1 or 2, while the sum of m, p and q may assume the values 1 or 2, or one of the groups 45wherein X2b denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol or ethanol, X2d denotes the hydrogen atom or the carboxylic acid group optionally esterified with methanol, o denotes the numbers 0, 1 or 2 and R3 denotes the hydrogen atom or the trifluoromethyl group, while, unless otherwise stated, the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned groups contain 1 to 4 carbon atoms and may be straight-chain or branched, or the tautomers or the diastereomers or the enantiomers or the salts thereof.

5. The following carboxylic acids and esters of general formula I according to claim 1:(1) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetate, (2) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetic acid, (3) 1,1-dimethylethyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-1-piperidineacetate, (4) 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-1-piperidineacetic acid, (5) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetate, (6) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetic acid, (7) ethyl endo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylate, (8) endo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylic acid, (9) ethyl exo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylate, (10) exo-4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-cyclohexanecarboxylic acid, (11) ethyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-1-piperidineacetate, (12) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4-acetate, (13) 1′-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′] bipiperidinyl-4-acetic acid, (14) ethyl 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-1-piperidineacetate, (15) ethyl 4-{1-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (16) ethyl 4-{1-[3,5-dichloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (17) ethyl 4-{1-[3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl) 1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (18) ethyl 4-{1-[3-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (19) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (20) ethyl 4-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (21) ethyl 4-{4-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-1-piperazinyl}-1-piperidineacetate, (22) 4-{1-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (23) 4-{1-[3,5-dichloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (24) 4-{1-[3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (25) 4-{1-[3-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-4,5-dimethyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (26) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (27) 4-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (28) 4-{4-[4-bromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-3,5-dimethyl-D,L-phenylalanyl]-1-piperazinyl}-1-piperidineacetic acid, (29) 1,1-dimethylethyl 4-{1-[3,4-difluoro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (30) methyl 1′-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetate, (31) ethyl 4-{1-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetate, (32) ethyl(R,S)-4-{1-[2-[(3,5-dibromo-4-methyl phenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetate, (33) methyl 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate, (34) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate, (35) 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid, (36) 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid, (37) methyl 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(R)-pyrroidine-2-carboxylate, (38) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate, (39) 1-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylic acid, (40) 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylic acid, (41) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(R)-[1,4′]bipiperidinyl-2-carboxylate, (42) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-(R)-[1,4′]bipiperidinyl-2-carboxylate, (43) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(S)-[1,4′]bipiperidinyl-2-carboxylate, (44) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-(S)-[1,4′]bipiperidinyl-2-carboxylate, (45) 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(R)-[1,4′]bipiperidinyl-2-carboxylic acid, (46) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-(R)-[1,4′]bipiperidinyl-2-carboxylic acid, (47) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-(S)-[1,4′]bipiperidinyl-2-carboxylic acid, (48) 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-(S)-[1,4′]bipiperidinyl-2-carboxylic acid, (49) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4′-carboxylate, (50) methyl 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4′-carboxylate, (51) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4′-carboxylic acid, (52) 1′-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-[1,4′]bipiperidinyl-4′-carboxylic acid, (53) 1′-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-[1,4′]bipiperidinyl-4-acetic acid, (54) 4-{1-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-1-piperazineacetic acid, (55) ethyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoate, (56) ethyl 3-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoate, (57) methyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoate, (58) ethyl 4-{1-[3,5-dibromo-N-[(4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinylmethyl}-benzoate, (59) ethyl 4-{2-[1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl]-ethyl}-benzoate, (60) methyl 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoate, (61) methyl 3-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoate, (62) ethyl 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoate, (63) ethyl 3-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoate, (64) methyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoate, (65) methyl 4-{2-[1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl]-ethyl}-benzoate, (66) methyl 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoate, (67) methyl 3-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoate, (68) 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoic acid, (69) 3-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-benzoic acid, (70) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoic acid, (71) 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinylmethyl}-benzoic acid, (72) 4-{2-[1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl]-ethyl}-benzoic acid, (73) 4-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1%)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoic acid, (74) 3-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-piperidinyl}-benzoic acid, (75) 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoic acid, (76) 3-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-benzoic acid, (77) 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-terahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoic acid, (78) 4-{2-[1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl]-ethyl}-benzoic acid, (79) 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-3-(trifluoromethyl)-benzoic acid, (80) 3-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-benzoic acid, (81) ethyl 4-{1-[3-(1-naphthyl)-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-alanyl]-4-piperidinyl}-1-piperazineacetate, (82) 4-{1-[3-(1-naphthyl)-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-alanyl]-4-piperidinyl}-1-piperazineacetic acid, (83) methyl 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-5-thiazolecarboxylate, (84) methyl 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-4-thiazolecarboxylate, (85) 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-5-thiazolecarboxylic acid, (86) 2-{4-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1-piperazinyl}-4-thiazolecarboxylic acid, (87) methyl 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-4-thiazolecarboxylate, (88) methyl 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-5-thiazolecarboxylate, (89) 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-4-thiazolecarboxylic acid, (90) 2-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-5-thiazolecarboxylic acid, (91) 4-{4-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-1-piperidineacetic acid, (92) 4-{4-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-1-piperazinyl}-1-piperidineacetic acid, (93) 1,1-dimethylethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (94) 1,1-dimethylethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (95) ethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (96) ethyl 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetate, (97) 4-{1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (98) 4-{1-[4-amino-3,5-dibromo-N-[[4-(2-oxo-1,3,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-piperidinyl}-1-piperazineacetic acid, (99) (R,S)-4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (100) (R,S)-4-{1-[2-[(3,5-dibromo-4-fluorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (101) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (102) (R,S)-4-{1-[2-[[3,5-bis-(trifluoromethyl)-phenyl]methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (103) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4,5-trimethylphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (104) (R,S)-4-{1-[2-[(3-bromo-4,5-dimethylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (105) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (106) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (107) (R,S)-4-{1-[2-[(4-amino-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (108) (R,S)-4-{1-[2-[[2,4-bis-(trifluoromethyl)-phenyl]methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (109) (R,S)-4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (110) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4,5-tribromophenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (111) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (112) (R,S)-4-{1-[2-[(3,4-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (113) (R,S)-4-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (114) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (115) (R,S)-4-{1-[2-[(2,3-dihydrobenzo[b]fur-5-yl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (116) (R,S)-4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1,2,3,4-tetrahydro-1-naphthyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (117) (R,S)-4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]4-piperidinyl}-1-piperazineacetic acid, (118) (R,S)-4-{1-[2-[(2,3-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (119) ethyl(R,S)-4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetate, (120) (R,S)-4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-piperazineacetic acid, (121) (R,S)-4-{4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-piperazinyl}-1-piperidineacetic acid, (122) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate, (123) methyl 1-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylate, (124) methyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate, (125) methyl 1-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(R)-pyrrolidine-2-carboxylate, (126) 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid, (127) 1-{1-[3-chloro-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-(S)-pyrrolidine-2-carboxylic acid, (128) ethyl 4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (129) ethyl 4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (130) ethyl 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate, (131) ethyl 4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (132) ethyl 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate, (133) ethyl 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate, (134) 4-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid, (135) 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylic acid, (136) 4-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylic acid, (137) 4-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid, (138) ethyl 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate, (139) 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylic acid, (140) ethyl 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate, (141) ethyl 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate, (142) ethyl 4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (143) 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylic acid, (144) 4-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid, (145) 4-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylic acid, (146) 4-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylic acid, (147) ethyl 4-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-2-piperazinecarboxylate, (148) ethyl 4-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-1-(1-methyl-4-piperidinyl)-3-piperazinecarboxylate, (149) 4-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di-methyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid, (150) ethyl 4-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (151) ethyl 1-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate, (152) ethyl 1-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate, (153) ethyl 1-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate, (154) ethyl 1-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate, (155) ethyl 1-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate, (156) 1-{1-[2-[(3,5-dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid, (157) 1-{1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-di-methyl-4-hydroxyphenyl)methyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid, (158) 1-{1-[2-[(4-amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid, (159) 1-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid, (160) 1-{1-[2-[(3,4-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylic acid, (161) ethyl 4-{1-[3,4-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-phenylalanyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (162) 4-{1-[2-[(4-bromo-3,5-dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylic acid, (163) methyl 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-phenylalanyl]-[1,4′]bipiperidinyl-4-acetate, (164) 1′-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-phenylalanyl]-[1,4′] bipiperidinyl-4-acetic acid, (165) ethyl 4-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-1-methyl-2-piperazinecarboxylate, (166) ethyl 1-{1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-methyl-D,L-phenylalanyl]-4-piperidinyl}-4-methyl-2-piperazinecarboxylate or the salts thereof.

6. Physiologically acceptable salts of the compounds according to one of claims 1 to 5 with inorganic or organic acids or bases inorganic or organic acids or bases.

7. Pharmaceutical compositions containing a compound according to one of claims 1 to 5, optionally together with one or more inert carriers and/or diluents.

8. Pharmaceutical compositions containing a physiologically acceptable salt according to claim 6, optimally together with one or more inert carriers and/or diluents.

9. A method for the acute or prophylactic treatment of headaches comprising administering a pharmaceutical composition according to one of claims 1 to 5.

10. A method for the acute or prophylactic treatment of headaches comprising administering a pharmaceutical composition according to claim 6.

11. A method for treating a disease or syndrome selected from the group consisting of: non-insulin-dependent diabetes mellitus, cardiovascular diseases, morphine tolerance, skin diseases, inflammatory diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilation and resultant reduced circulation of the blood, and pain comprising administering a pharmaceutical composition according to one of claims 1 to 5.

12. A method for treating a disease or syndrome selected from the group consisting of: non-insulin-dependent diabetes mellitus, cardiovascular diseases, morphine tolerance, skin diseases, inflammatory diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilation and resultant reduced circulation of the blood, and pain comprising administering a pharmaceutical composition according to claim 6.

13. A method for the acute or prophylactic treatment of menopausal hot flashes in estrogen-deficient women comprising administering a pharmaceutical composition according to one of claims 1 to 5.

14. A method for the acute or prophylactic treatment of menopausal hot flashes in estrogen-deficient women comprising administering a pharmaceutical composition according to claim 6.