Substituted 2-oxo-1,4-diazacycloalkanes

Details Substituted 2-oxo-1,4-diazacycloalkanes Substituted 2-oxo-1,4-diazacycloalkanes

2000-10-11

2002-06-04

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S492000

Reexamination Certificate

active

06399599

ABSTRACT:

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,
R
1
is H, C
1-4
alkyl; aryl; or aryl-C
1-4
alkyl,
Y is C
1-4
alkylene; —CO—C
1-4
alkylene; —CO—C
2-5
alkenylene; —CO—NH—; —CO—C
1-3
alkyle—NH—; or —CO—O—,
R
2
is an aromatic or heteroaromatic residue, each being optionally substituted by CF
3
, halogen, OH, C
1-4
alkoxy, amino, mono- or di-C
1-4
alkyl substituted amino, phenyl, benzyl or C
1-4
alkyl optionally substituted by amino,
R
3
is the side chain present on the C&agr; of an a-amino acid,
R
4
is biphenylyl; or benzyl, hydroxy-benzyl, &agr;- or &bgr;-naphthyl-methyl, 5,6,7,8-tetrahydro-&bgr;-naphthyl-methyl or indolyl-methyl, each being optionally substituted on the ring by CF
3
, halogen, OH, C
1-4
alkoxy, amino, mono- or di-C
1-4
alkyl substituted amino, phenyl, benzyl or C
1-4
alkyl optionally substituted by amino,
X is —CN; —NR
5
R
6
; or —O—R
8
R
5
is H, C
1-6
alkyl, aryl or aryl-C
1-4
alkyl,
R
6
is H or C
1-6
alkyl and
R
8
is H, C
1-4
alkyl, aryl or aryl-C
1-4
alkyl,
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-C
1-4
alkyl may be, e.g., phenyl-Cl
4
alkyl, e.g. benzyl, optionally substituted on the ring. Examples of substitutents are, e.g., halogen, OH, CF
3
or NH
2
. Preferably aryl and aryl-C
1-4
alkyl are unsubstituted.
Halogen may be F, Cl or Br.
When R
2
is an aromatic residue, it may be phenyl, naphthyl, dihydro- or tetrahydro-naphthyl or biphenylyl. Suitable heteroaromatic residues as R
2
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 C
1-4
alkyl, e.g., methyl or ethyl. When substituted, R
2
may be mono- or polysubstituted, e.g., disubstituted.
The &agr;-amino acid or aromatic &agr;-amino acid from which is derived the side chain present on the C&agr; as R
3
, may be natural or non natural. Suitable examples as R
3
include, e.g., propyl, isopropyl, butyl, isobutyl, 1-methyl-propyl, phenyl, benzyl or aminobutyl.
By optionally ring substituted indolyl as R
4
is also meant indolyl wherein the nitrogen is substituted, e.g., by C
1-4
alkyl, 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 R
8
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 R
3
or R
4
, respectively, is asymmetric and may have the D- or L-configuration. For example, the carbon atom bearing R
4
has preferably the D-configuration when R
4
is &agr;-naphthyl-methyl; it preferably has the L-configuration when R
4
is &bgr;-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 —CH
2
—; —CO—CH
2
—; —CO—CH
2
—CH
2
—; —CO—NH—; —CO—CH
2
—NH—; or —CO—CH═CH—;
3. R
1
is C
1-4
alkyl, preferably methyl or ethyl, more preferably methyl;
4. R
1
is C
1-4
alkyl, preferably as indicated, and the carbon atom bearing it has the R- configuration;
5. R
2
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. R
2
is quinolyl or isoquinolyl; or substituted quinolyl or isoquinolyl, e.g., by OH, OCH
3
or phenyl; preferably quinolyl;
7. R
3
is isopropyl; n-butyl; isobutyl; or phenyl;
8. R
4
is &agr;- or &bgr;-naphthyl-methyl;
9. R
4
is &bgr;-naphthyl-methyl and the carbon atom bearing R
4
has the L-(S)-configuration;
10. R
4
is &bgr;-naphthyl-methyl and the carbon atom bearing R
4
has the D-(R)-configuration;
11. X is —NR
5
R
6
;
12. R
5
is H; C
1-3
alkyl; or benzyl;
13. R
6
is H or CH
3
, 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 —CO—C
1-4
alkylene or —CO—C
2-5
alkenylene, reacting a compound of formula II
wherein R
1
, R
3
, R
4
, X and n are as defined above, with a compound of formula IIIa
R
2
—Y′—OH  IIIa
wherein R
2
is as defined above and Y′ is —CO—C
1-4
alkylene or —CO—C
2-5
alkenylene or a functional derivative thereof;
b) for the production of a compound of formula I wherein Y is C
1-4
alkylene, reacting a compound of formula II above, with a compound of formula IIIb:
R
2
—Y″—CHO  IIIb
wherein R
2
is as defined above and Y″ is a direct bond or C
1-3
alkylene, under reducing conditions;
c) for the production of a compound of formula I wherein Y is —CO—NH— or —CO—C
1-3
-alkylene-NH, reacting a compound of formula II above with a compound of formula IIIc:
X
1
—CO—Y′″—X
2
  IIIc
wherein Y′″ is —CO—NH or —CO—C
1-3
alkylene-NH and each of X
1
and X
2
is a leaving group, e.g., Br, and subsequently reacting the resulting compound with R
2
—NH
2
; and
d) for the production of a compound of formula I wherein Y is —CO—NH—, reacting a compound of formula II with R
2
—N═C═O, 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 NR
5
R
6
: 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., NaCNBH
3
. 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 R
1
, R
3
, R
4
, 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., NaCNBH
3
, Na BH(CH
3
COO)
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 X′, e.g. NH. Suitable N-protecting groups may be, e.g., as disclosed in “Protective Groups in Organic Synthesis,” T. W. Greene, J. Wiley & Sons NY(1981), 219-287, e.g., alcoxycarbonyl such as methoxycarbonyl or t-butyloxycarbonyl, allyloxy-carbonyl, arylmethoxycarbonyl such as Fmoc,

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