Amino acid derivatives and methods of making the same

Details Amino acid derivatives and methods of making the same Amino acid derivatives and methods of making the same

2002-06-21

2003-07-08

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S567000, C558S441000, C558S445000, C564S502000, C564S511000

Reexamination Certificate

active

06590106

ABSTRACT:

BACKGROUND OF THE INVENTION
A peptide mimetic is a compound which has sufficient structural similarity to a peptide so that the desirable properties of the peptide are retained by the mimetic. For example, peptide mimetics are already being used as protease inhibitors for treating HIV infection, as disclosed in Tung, et al., WO 94/05639, Vazquez, et al., WO 94/04491, Vazquez, et al., WO 94/10134 and Vaquez, et al., WO 94/04493. The entire relevant teachings of these publications are incorporated herein by reference. To be useful as a drug, a peptide mimetic should retain the biological activity of a peptide, but also have one or more properties which are improved compared with the peptide which is being mimicked. For example, some peptide mimetics are resistant to hydrolysis or to degradation in vivo. One strategy for preparing a peptide mimetic is to replace one or more amino acid residues in a peptide with a group which is structurally related to the amino acid residue(s) being replaced and which can form peptide bonds. The development of new amino acid derivatives which can be used to replace amino acid residues in peptides will advance the development of new peptide mimetic drugs.
Combinatorial libraries have great utility for identifying leads in drug discovery. The “Ugi” reaction, shown schematically below, is commonly used to generate combinatorial libraries
The ability to identify new, structurally diverse compounds which can participated in the Ugi reaction are needed to identify new drug leads from combinatorial libraries which are constructed using the this reaction.
SUMMARY OF THE INVENTION
The present invention includes novel isonitriles, diisonitriles, triamines, oxazolidines, oxazolines and imidazoles, and methods of preparing these novel compounds.
One embodiment of the present invention is a compound represented by Structural Formula I:
or salts thereof.
In Structural Formula I, R
1
is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. Preferably, R
1
is an amino acid side-chain or a protected amino acid side-chain.
R
2
is —NR
5
R
6
or —N≡
+
C
−
.
Alternatively, R
1
and R
2
, taken together with the methine group to which they are bonded, are a moiety represented by the following structural formula:
R
3
is —NH
2
, —OH, —OC(O)H or —OR
9
.
R
4
is —N
+
≡C
−
, —NH
2
, or —NO
2
.
R
5
, R
6
and R
7
, are each, independently, —H or an amine protecting group.
R
8
is —H, —OH or —OR
9
.
R
9
is an alcohol protecting group.
One embodiment of the present invention is an isonitrile represented by Structural Formula II:
Isonitriles represented by Structural Formula II are prepared by dehydrating a N-alkyl formamide represented by Structural Formula III:
The N-alkyl formamide of Structural Formula m is prepared by formylating a starting material represented by Structural Formula IV:
In Structural Formulas II, III and IV, R
1
, R
2
, and R
3
are defined as in Structural Formula I. In a preferred embodiment, R
1
is benzyl, sec-butyl, the side-chain of tryptophan, —(CH
2
)
4
—NH(t-butoxycarbonyl), —CH
2
COO(t-butyl), —CH(O-benzyl)—CH
3
, or —(CH
2
)
2
—S—CH
3
; and R
3
is —OCH(O).
Another embodiment of the present invention is a 2-hydroxypropyl isonitrile represented by Structural Formula V:
Isonitriles represented by Structural Formula V are prepared by reacting a trialkylsilyl cyanide and ZnI
2
with a starting compound represented by Structural Formula VI:
In Structural Formulas V and VI, R
1
and R
2
are as described form Structural Formula I.
Another embodiment of the present invention is a 2-amino-1-nitropropane represented by Structural Formula VII:
The 2-amino-1-nitropropanes represented by Structural Formula VII are prepared by reducing an oxime ether of a compound represented by Structural Formula VIII:
In Structural Formulas VII and VIII, R
1
and R
2
are as described for Structural Formula I. R
18
is an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. Preferably R
18
is a C1-C3 alkyl group.
Another embodiment of the present invention is an imidazole represented by Structural Formula IX:
Imidazoles represented by Structural Formula IX are prepared by reacting an aliphatic carboxylic acid and an ammonium salt of the aliphatic carboxylic acid with a compound represented by Structural Formula X:
In Structural Formulas IX and X, R
2
, and R
22
are each, independently, —H, an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. R
21
, is preferably a C1-C4 straight chain or branched alkyl group. R
22
is preferably an aliphatic side-chain of a naturally occurring amino acid.
Another embodiment of the present invention is an oxazolidine represented by Structural Formula XI:
R
41
is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R
41
is preferably the side-chain of a naturally occurring amino acid or a protected side-chain of a naturally occurring amino acid.
R
42
is —NR
5
R
6
.
Alternatively, R
41
and R
42
, taken together with the methine group to which they are bonded, form a moiety represented by Structural Formula XII:
R
43
is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R
43
is preferably a C1-C3 alkyl group or substituted alkyl group.
In Structural Formulas XI and XII, R
5
, R
6
, R
7
and R
8
are as described for Structural Formula I. In a preferred embodiment, one of R
5
, and R
6
is —H.
The compounds represented by Structural Formula XI are prepared by reacting a 2-hydroxy-1-propylamine represented by Structural Formula XIII and a compound represented by Structural Formula XIV:
R
41-43
are as described for Structural Formula XI.
X is —CHO, —COOR or —C(═NH)OR. R is an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group. R is preferably a C1-C4 alkyl group.
The compounds of the present invention can be used as reagents in the Ugi reaction or to prepare peptide mimetics, and, consequently, can be used to identify new drug leads. The compounds of the present invention can be obtained in optically pure form from the disclosed methods, if the starting materials are optically pure. Using optically pure reagents in combinatorial reactions such as the Ugi reaction should result in conformationally restricted adducts which can be utilized to map the three-dimensional structure of receptor sites.
DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the method of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.
Compounds represented by Structural Formulas I are derived from amino acid precursors. The amino alcohols can be prepared by a method summarized in Scheme I and described in detail in U.S. Pat. No. 5,475,138, the entire teachings of which are incorporated herein by reference. In Scheme I, R
1
, R
5
and R
6
are as described above. The starting material in Scheme I, compound XV, is an amino acid wherein the amine functionality is protected. The compounds of the present invention represented by Structural Formula I are derived from compound XVIII of Scheme I.
In a preferred embodiment of the present invention, R
5
and R
6
of Structural Formula XVIII are each —H and the alcohol group is protected. This compound is represented by Structural Formula XIX:
Methods for protecting alcohols are known to those skilled in the art and can be found in Greene and Wuts, “Protective Groups in Organic Synthesis, 2
nd
,” John Wiley & Sons (1991). A diamino compound represented by Structural Formula XIX can be formylated to form a compou

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