The present invention relates to diazepanes, a process for their production, their use as a pharmaceutical and pharmaceutical preparations containing them.
More particularly the present invention provides a compound of formula I 
wherein
n is 1, 2 or 3,
R1 is H, C1-4 alkyl; aryl; or aryl-C1-4alkyl,
Y is C1-4alkylene; xe2x80x94COxe2x80x94C1-4alkylene; xe2x80x94COxe2x80x94C2-5alkenylene; xe2x80x94COxe2x80x94NHxe2x80x94; xe2x80x94COxe2x80x94C1-3alkylexe2x80x94NHxe2x80x94; or xe2x80x94COxe2x80x94Oxe2x80x94,
R2 is an aromatic or heteroaromatic residue, each being optionally substituted by CF3, halogen, OH, C1-4alkoxy, amino, mono- or di-C1-4alkyl substituted amino, phenyl, benzyl or C1-4alkyl optionally substituted by amino,
R3 is the side chain present on the Cxcex1 of an a-amino acid,
R4 is biphenylyl; or benzyl, hydroxy-benzyl, xcex1- or xcex2-naphthyl-methyl, 5,6,7,8-tetrahydro-xcex2-naphthyl-methyl or indolyl-methyl, each being optionally substituted on the ring by CF3, halogen, OH, C1-4alkoxy, amino, mono- or di-C1-4alkyl substituted amino, phenyl, benzyl or C1-4alkyl optionally substituted by amino,
X is xe2x80x94CN; xe2x80x94NR5R6; or xe2x80x94Oxe2x80x94R8 
R5 is H, C1-6alkyl, aryl or aryl-C1-4alkyl,
R6 is H or C1-6alkyl and
R8 is H, C1-4alkyl, aryl or aryl-C1-4alkyl,
in free form or in salt form.
Alkyl may be linear or branched. When alkyl is substituted by amino, it is preferably monosubstituted, more preferably terminally substituted. Aryl may be, e.g., optionally substituted phenyl, naphthyl or dihydro- or tetrahydro-naphthyl. Aryl-C1-4alkyl may be, e.g., phenyl-Cl4alkyl, e.g. benzyl, optionally substituted on the ring. Examples of substitutents are, e.g., halogen, OH, CF3 or NH2. Preferably aryl and aryl-C1-4alkyl are unsubstituted.
Halogen may be F, Cl or Br.
When R2 is an aromatic residue, it may be phenyl, naphthyl, dihydro- or tetrahydro-naphthyl or biphenylyl. Suitable heteroaromatic residues as R2 include, e.g., pyridyl, quinolyl, isoquinolyl, dihydro-, tetrahydro-quinolyl or -isoquinolyl, e.g., 1,2,3,4-tetrahydro-quinolyl, benzo-thienyl, indolyl or pyridyl-phenyl. By optionally substituted tetrahydro-quinolyl or indolyl is also meant tetrahydroquinolyl or indolyl wherein the nitrogen is substituted, e.g., by C1-4alkyl, e.g., methyl or ethyl. When substituted, R2 may be mono- or polysubstituted, e.g., disubstituted.
The xcex1-amino acid or aromatic xcex1-amino acid from which is derived the side chain present on the Cxcex1 as R3, may be natural or non natural. Suitable examples as R3 include, e.g., propyl, isopropyl, butyl, isobutyl, 1-methyl-propyl, phenyl, benzyl or aminobutyl.
By optionally ring substituted indolyl as R4 is also meant indolyl wherein the nitrogen is substituted, e.g., by C1-4alkyl, e.g. methyl or ethyl, or benzyl.
The compounds of formula I may exist in free form or in salt form, e.g., addition salts with, e.g., organic or inorganic acids, for example, hydrochloric acid, acetic acid, or salts obtainable when R8 is H as salts with a base, e.g., alkali salts such as sodium or potassium, or substituted or unsubstituted ammonium salts.
It will be appreciated that the compounds of formula I may exist in the form of optical isomers, racemates or diastereoisomers as well as in the form of cis or trans conformers. For example, the carbon atom bearing the substituent R3 or R4, respectively, is asymmetric and may have the D- or L-configuration. For example, the carbon atom bearing R4 has preferably the D-configuration when R4 is xcex1-naphthyl-methyl; it preferably has the L-configuration when R4 is xcex2-naphthyl-methyl. It is to be understood that the present invention embraces all enantiomers and conformers and their mixtures. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms as mentioned above.
In the compounds of formula I, the following significances are preferred individually or in any sub-combination:
1. n=2
2. Y is xe2x80x94CH2xe2x80x94; xe2x80x94COxe2x80x94CH2xe2x80x94; xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94; xe2x80x94COxe2x80x94NHxe2x80x94; xe2x80x94COxe2x80x94CH2xe2x80x94NHxe2x80x94; or xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94;
3. R1 is C1-4alkyl, preferably methyl or ethyl, more preferably methyl;
4. R1 is C1-4alkyl, preferably as indicated, and the carbon atom bearing it has the R- configuration;
5. R2 is phenyl; phenyl substituted as indicated above, e.g. as indicated in the examples; naphthyl; pyridyl, preferably 2-, 3- or 4-pyridyl; pyridyl-phenyl; quinolyl, isoquinolyl, tetrahydro-quinolyl or substituted quinolyl or isoquinolyl, preferably 2-,4-, 6- or 8- quinolyl, optionally substituted as indicated above, e.g. as in the examples below;
6. R2 is quinolyl or isoquinolyl; or substituted quinolyl or isoquinolyl, e.g., by OH, OCH3 or phenyl; preferably quinolyl;
7. R3 is isopropyl; n-butyl; isobutyl; or phenyl;
8. R4 is xcex1- or xcex2-naphthyl-methyl;
9. R4 is xcex2-naphthyl-methyl and the carbon atom bearing R4 has the L-(S)-configuration;
10. R4 is xcex2-naphthyl-methyl and the carbon atom bearing R4 has the D-(R)-configuration;
11. X is xe2x80x94NR5R6;
12. R5 is H; C1-3alkyl; or benzyl;
13. R6 is H or CH3, preferably H.
The present invention also includes a process for the production of a compound of formula I, which process comprises appropriately substituting a corresponding compound of formula II as defined below, e.g.,
a) for the production of a compound of formula I wherein Y is xe2x80x94COxe2x80x94C1-4alkylene or xe2x80x94COxe2x80x94C2-5alkenylene, reacting a compound of formula II 
wherein R1, R3, R4, X and n are as defined above, with a compound of formula IIIa
R2xe2x80x94Yxe2x80x2xe2x80x94OHxe2x80x83xe2x80x83IIIa
wherein R2 is as defined above and Yxe2x80x2 is xe2x80x94COxe2x80x94C1-4alkylene or xe2x80x94COxe2x80x94C2-5alkenylene or a functional derivative thereof;
b) for the production of a compound of formula I wherein Y is C1-4alkylene, reacting a compound of formula II above, with a compound of formula IIIb:
R2xe2x80x94Yxe2x80x3xe2x80x94CHOxe2x80x83xe2x80x83IIIb
wherein R2 is as defined above and Yxe2x80x3 is a direct bond or C1-3alkylene, under reducing conditions;
c) for the production of a compound of formula I wherein Y is xe2x80x94COxe2x80x94NHxe2x80x94 or xe2x80x94COxe2x80x94C1-3-alkylene-NH, reacting a compound of formula II above with a compound of formula IIIc:
X1xe2x80x94COxe2x80x94Yxe2x80x2xe2x80x3xe2x80x94X2xe2x80x83xe2x80x83IIIc
wherein Yxe2x80x2xe2x80x3 is xe2x80x94COxe2x80x94NH or xe2x80x94COxe2x80x94C1-3alkylene-NH and each of X1 and X2 is a leaving group, e.g., Br, and subsequently reacting the resulting compound with R2xe2x80x94NH2; and
d) for the production of a compound of formula I wherein Y is xe2x80x94COxe2x80x94NHxe2x80x94, reacting a compound of formula II with R2xe2x80x94Nxe2x95x90Cxe2x95x90O, and, where required, converting the resulting compound of formula I obtained in free form to a salt form or vice versa.
A functional derivative of a compound of formula IIIa includes, e.g., a halide, ester or anhydride.
Process step a) may be carried out according to known acylation methods, e.g., in liquid phase or in solid phase. The latter case may particularly be suitable for the preparation of a compound of formula I wherein X is NR5R6: in such a case, the compound of formula II is attached to a resin, e.g., a commercially available resin, e.g. by NH. Once acylation is complete, the desired compound of formula I is cleaved from the resin, e.g., by acidic hydrolysis.
Process step b) may be carried out according to known methods, in the presence of a reducing agent, e.g., NaCNBH3. Process steps c) and d) may be performed according to known methods.
The compounds of formula II may be produced, e.g., by cyclisation of a compound of formula IV: 
wherein R1, R3, R4, X and n are as defined above and Z is an amino protecting group,
in the presence of a reducing agent.
Suitable reducing agents include, e.g., NaCNBH3, Na BH(CH3COO)3, or Na triacetoxy borohydride. The compounds of formula II may be prepared in liquid or solid phase. In the latter case, the compound of formula IV is attached to a resin by an appropriate group Xxe2x80x2, e.g. NH. Suitable N-protecting groups may be, e.g., as disclosed in xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d T. W. Greene, J. Wiley and Sons NY(1981), 219-287, e.g., alcoxycarbonyl such as methoxycarbonyl or t-butyloxycarbonyl, allyloxy-carbonyl, arylmethoxycarbonyl such as Fmoc, or benzyloxycarbonyl.
Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed hereafter.