Lactam-aldehyde compound and process of preparing same

Details Lactam-aldehyde compound and process of preparing same Lactam-aldehyde compound and process of preparing same

2002-03-07

2003-10-28

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S266000, C549S321000, C549S322000

Reexamination Certificate

active

06639075

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a lactam-aldehyde compound and a process of preparing same. The present invention is also directed to a lactone-imine compound useful as a precursor of the lactam-aldehyde compound and a process of preparing same.
The present inventors have proposed a 3,5-dioxa-12-azawurtzitane compound represented by the following formula (IV):
wherein R
1
represents an alkyl group, R
3
represents a group which, together with a —CH(NH
2
)COOH group, constitutes an &agr;-amino acid of the formula R
3
CH(NH
2
)COOH and which may contain one or more substituents and R
4
represents a hydroxyl group or a group obtained by removing a hydrogen atom of the terminal amino group of an oligo- or polypeptide or a polyamino acid (EP-A-1153926 and U.S. patent application Ser. No. 09/733,063).
The 3,5-dioxa-12-azawurtzitane compound does not have any site into which other functional groups may be introduced.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a lactam-aldehyde compound having a lactam site and a formyl group into which other functional groups may be introduced.
Another object of the present invention is to provide a compound of the above-mentioned type which has a structure similar to an amino acid or a polypeptide.
It is a further object of the present invention to provide a process for the production of the above lactam-aldehyde compound.
It is yet a further object of the present invention to provide a lactone-imine compound which is useful as a precursor of the above lactam-aldehyde compound.
In accordance with one aspect of the present invention, there is provided a lactam-aldehyde compound represented by the following formula (I):
wherein R
1
represents an alkyl group, R
2
represents an organic group.
In another aspect, the present invention provides a lactam-aldehyde compound as claimed in claim 1, and represented by the following formula (II)
wherein R
1
is as defined above, R
3
is an amino acid side chain group and R
4
is a hydroxyl group or a peptide chain.
The present invention also provides a lactone-imine compound represented by the following formula (III):
wherein R
1
is as defined above, R
3
is an amino acid side chain group and R
4
is a hydroxyl group or a peptide chain.
The present invention further provides a process for the production of a lactam-aldehyde compound of the following formula (II):
wherein R
1
represents an alkyl group, R
3
is an amino acid side chain group and R
4
is a hydroxyl group or a peptide chain, said process comprising subjecting a lactone-imine compound to an isomerization reaction, said lactone-imine compound being represented by the following formula (III):
wherein R
1
, R
3
and R
4
are as defined above.
The present invention further provides a process for the production of a lactone-imine compound of the following formula (III):
wherein R
1
represents an alkyl group, R
3
is an amino acid side chain group and R
4
is a hydroxyl group or a peptide chain, said process comprising subjecting a 3,5-dioxa-12-azawurtzitane compound to molecular rearrangement, said 3,5-dioxa-12-azawurtzitane compound being represented by the following formula (IV):
wherein R
1
represents an alkyl group, R
3
is an amino acid side chain group and R
4
is a hydroxyl group or a peptide chain.
In the present specification and claims, the three R
1
s bonded to the carbon atoms of the lactam-aldehyde compound of the formula (I) or (II) may be the same or different alkyl groups.
The new class of lactam-aldehyde compounds of the present invention have a lactam site and a formyl group into which other functional groups may be introduced and are able to possess a structure similar to an amino acid or a polypeptide. Therefore, the compounds of the present invention will be utilizable for various applications, for example, as a molecular recognition agent for use in neurotransmission studies, an intermediate for a protein-resembling compound, a surfactant, a protective group and a host-guest complex for use as a sensor.
Other objects, features and advantages of the present invention will be apparent from the detailed description of the preferred embodiments of the invention to follow.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
A lactam-aldehyde compound of the present invention is represented by the above formula (I). In the formula (I), R
1
represents an alkyl group preferably having 1-12 carbon atoms. Illustrative of suitable alkyl groups of R
1
are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and structural isomers thereof.
The symbol R
2
represents an organic group. The organic group is preferably a group represented by the formula —Z—Y in which Z represents a direct bond or an alkylene group and Y represents a group having an active hydrogen. Specific examples of the organic group include carboxyl, carboxyalkyl, amino, aminoalkyl, imidazolyl, imidazolylalkyl, indolyl, indolylalkyl, hydroxyphenyl, hydroxyphenylalkyl, pyridyl, pyridylalkyl, aminophenyl, aminophenylalkyl, hydroxyl, hydroxyalkyl, glycoloyl, glycoloylalkyl, glyceroyl, glyceroylalkyl, mercapto, mercaptoalkyl, carboxyaminoethylenedithio and carboxyaminoethylenedithioalkyl.
Another class of preferred organic group R
2
is represented by —CHR
3
COR
4
where R
3
is an amino acid side chain group and R
4
is a hydroxyl group or a peptide chain.
The term “amino acid side chain group” as used herein refers to the amino acid functional “R” side chains of any amino acid-based compound, including but not limited to any of the known twenty two amino acids, including alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, i.e., the substituents on the amino acid carbon atom located between the amino group and carboxylic acid functionalities of the amino acids such as described above. The amino acid side chain group may contain one or more substituents such as an alkyl group, an acetyl group, an alkoxy group, a benzoxycarbonyl group, a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group and a 1,7,9-trialkyl-3,5-dioxa-12H-azawurtzitan-12-yl group.
The peptide chain R
4
may be an oligopeptide (composed of 2 to 9 amino acids), a polypeptide (composed of 10 or more amino acids, generally 10-100 amino acids) or a polyamino acid (composed of two or more same amino acids) and is linked through a terminal amino group thereof to the carbonyl group of —CHR
3
COR
4
. The amino acids constituting the peptide chain R
4
may be, for example, those as described previously.
Some examples of lactam-aldehyde compounds of the present invention are shown in Table 1 in which R
1
, R
3
and R
4
are the symbols of the formula (II). The lactam-aldehyde compounds of the present invention, however, are of course not limited to those specifically exemplified compounds. For example, the groups R
1
, R
3
and R
4
listed in Table 1 may be arbitrarily selected for any desired combination.
TABLE 1
R
1
R
3
R
4
CH
3
H
(His)
n
CH
3
CH
3
(Gly)
n
CH
3
CH
2
(CH
3
)
2
CH
(Ala)
n
CH
3
CH
2
CH
2
(CH
3
)
2
CHCH
2
(Val)
n
CH
3
(CH
2
)
3
CH
3
CH
2
(CH
3
)CH
(Leu)
n

CH
3
(CH
2
)
4
(Phe)
n

CH
3
(CH
2
)
5
(Tyr)
n

H
(Try)
n

(CH
3
)
2
CH
HOCH
2
(Ser)
n
(CH
3
)
3
C
CH
3
(OH)CH
(Thre)
n
(CH
3
)
2
CHCH
2
HSCH
2
(CySH)
n

(CH
3
)
2
CH(CH
2
)
2
(CyS-SCy)
n

(CH
3
)
3
C(CH
2
)
3
CH
3
SCH
2
CH
2
(Meth)
n
CH
3
CH
2
CH
2
HOOCCH
2
(Asp)
n
CH
3
(CH
2
)
9
HOOCCH
2
CH
2
(Glu)
n
CH
3
H
2
NCH
2
(CH
2
)
3
(Lys)
n
CH
3
HN═C(NH
2
)NH(CH
2
)
3
(Arg)
n

CH
3
OH
In Table 1, n is an integer.
The lactam-aldehyde compounds of the formula (II) may be prepared by subjecting a lactone-imine compound of the above formula (III) to isomerization.
The isomerization may be carried out by dissolving the lactone-imine compound in an aqueous solvent or a hydrophilic polar organic solvent to obtain a solution. The solution is then allowed to

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