Peptides

Details Peptides Peptides

1998-12-09

2003-09-09

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

6 to 7 amino acid residues in defined sequence

C530S327000, C530S328000, C530S330000, C530S317000, C514S015800, C514S016700, C514S017400, C514S018700

Reexamination Certificate

active

06617425

ABSTRACT:

Many naturally occurring, biologically active compounds are proteins or peptides based upon &agr;-amino acids (i.e. sequences of &agr;-amino acids in which the &agr;-carboxyl group of one amino acid is joined by an amide bond to the &agr;-amino group of the adjacent amino acid). In recent years an approach to the discovery of new pharmaceutically active drugs has been to synthesise libraries of peptides and then to assay for compounds within the library which have a desired activity, such as a desired binding activity. However, &agr;-amino acid peptides are not altogether satisfactory for pharmaceutical uses, in particular because they are often poorly absorbed and subject to proteolytic degradation in vivo.
We have now synthesised new peptides based on &bgr;-amino acids and have found that these peptides have unexpected and desirable properties.
Accordingly the present invention provides a &bgr;-peptide comprising 2 or more different &bgr;-amino acid residues.
For the purposes of the present description a &bgr;-peptide comprises a sequence of 2 or more &bgr;-amino acid residues in which the &agr;-carboxyl group of one amino acid is joined by an amide bond to the &bgr;-amino group of the adjacent amino acid. The &bgr;-peptides of the invention may comprise any number of amino acid residues, though conveniently comprise from 2 to 11, preferably from 4 to 7, especially 5 or 6, &bgr;-amino acid residues.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The &bgr;-amino acid residues of the &bgr;-peptides of the invention are characteristically &bgr;-amino-n-propionic acid derivatives, typically further substituted at the &agr;- and/or &bgr;-carbon atoms and may be further substituted, e.g. at the N-terminal amino nitrogen atom. The &agr;-, &bgr;- and and amino substituents may include substituents containing from 1 to 43 carbon atoms optionally interrupted by up to 4 hetero atoms, selected from O, N or S, optionally containing a carbonyl (i.e. —C(O)—) group, and optionally further substituted by up to 6 substituents selected from halo, NO
2
, —OH, C
1-4
alkyl, —SH, —SO
3
, —NH
2
, C
1-4
acyl, C
1-4
acyloxy, C
1-4
alkylamino, C
1-4
dialkylamino, trihalomethyl, —CN, C
1-4
alkylthio, C
1-4
alkylsulfinyl, or C
1-4
alkylsulfonyl. Conveniently, the &agr;-, &bgr;- and amino substituents may include any of those substituents defined below as the “R” substituents of formula I. For example, the &agr;- and &bgr;-substituents may be selected from the group comprising the substituents which are present on the &agr;-carbon atoms of &agr;-amino acids, e.g. —H, —CH
3
, —CH(CH
3
)
2
, —CH
2
—CH(CH
3
)
2
, —CH(CH
3
)CH
2
CH
3
, —CH
2
-phenyl, CH
2
-pOH-phenyl, —CH
2
-indole, —CH
2
—SH, —CH
2
—CH
2
—S—CH
3
, —CH
2
OH, —CHOH—CH
3
, —CH
2
—CH
2
—CH
2
—CH
2
—NH
2
, —CH
2
—CH
2
—CH
2
—NH—C(NH)NH
2
, —CH
2
-imidazole, —CH
2
—COOH, —CH
2
—CH
2
-COOH, —CH
2
—CONH
2
, —CH
2
—CH
2
-CONH
2
or together with an adjacent —NH group forms a proline amino acid residue.
The &bgr;-peptides of the invention preferably comprise only &bgr;-amino acid residues. However, the invention includes &bgr;-peptides, for instance longer &bgr;-peptides, e.g. comprising 7 or more acid residues, which contain one or a few, e.g. 1 or 2, acid residues which are not &bgr;-amino acids, e.g. &agr;- or &ggr;-amino acids, or an &agr;-, &bgr;- or &ggr;-hydroxycarboxlic acids. For example, a non-&bgr;-amino acid may be present in the &bgr;-peptide at a junction or transition region between two sequences of &bgr;-amino acid residues.
Characteristically substitutents present on the &agr;- and/or &bgr;-carbon atoms of the &bgr;-amino acid residues are in the radial orientation with respect to the peptide chain.
Preferably the present invention provides a compound of formula I
wherein
each R is H, —R
5
, —OR
5
, —C(O)R
5
, —R
5
C(O)R
6
, —C(O)OR
5
, —R
5
C(O)OR
6
, —R
5
OC(O)R
6
, —R
5
OC(O)OR
6
, —R
5
NR
6
C(O)R
7
, —R
5
C(O)NR
6
R
7
, —C(O)NR
6
R
7
, —R
5
OC(O)NR
6
R
7
, —R
5
NR
6
C(O)NR
7
R
8
, —R
5
NR
6
C(O)OR
7
, —R
5
—O—R
6
, —R
5
—NR
6
R
7
, —R
5
—S—R
6
, —R
5
SO
m
—R
6
, —R
5
OR
6
—O—R
7
, —R
5
NR
6
R
7
—O—R
8
, —R
5
SO
m
R
6
—O—R
7
, —C(O)R
5
—O—R
6
, —C(O)OR
5
—O—R
6
, —R
5
C(O)R
6
—O—R
7
, —R
5
C(O)OR
6
—O—R
7
, —R
5
OC(O)R
6
—O—R
7
, —R
5
OC(O)OR
6
—O—R
7
, —R
5
NR
6
C(O)R
7
—O—R
8
, —C(O)NR
5
R
6
—O—R
7
, —R
5
C(O)NR
6
R
7
—O—R
8
, —R
5
OC(O)NR
6
R
7
—O—R
8
, —R
5
NR
6
C(O)NR
7
R
8
—O—R
9
, —R
5
NR
6
C(O)OR
7
—O—R
8
, —R
5
OR
6
—S—R
7
, —R
5
NR
6
R
7
—S—R
8
, —R
5
SO
m
R
6
—S—R
7
, —C(O)R
5
—S—R
6
, —C(O)OR
5
—S—R
6
, —R
5
C(O)R
6
—S—R
7
, —R
5
C(O)OR
6
—S—R
7
, —R
5
OC(O)R
6
—S—R
7
, —R
5
OC(O)OR
6
—S—R
7
, —R
5
NR
6
C(O)R
7
—S—R
8
, —C(O)NR
5
R
6
—S—R
7
, —R
5
C(O)NR
6
R
7
—S—R
8
, —R
5
OC(O)NR
6
R
7
—S—R
8
, —R
5
NR
6
C(O)NR
7
R
8
—S—R
9
, —R
5
NR
6
C(O)OR
7
—S—R
8
, —R
5
OR
6
—NR
7
R
8
, —R
5
NR
6
R
7
—NR
8
R
9
, —R
5
SO
m
R
6
—NR
7
R
8
, —C(O)R
5
—NR
6
R
8
, —C(O)OR
5
—NR
6
R
8
, —R
5
C(O)R
6
—NR
7
R
8
, —R
5
C(O)OR
6
—NR
7
R
8
, —R
5
OC(O)R
6
—NR
7
R
8
, —R
5
OC(O)OR
6
—NR
7
R
8
, —R
5
NR
6
C(O)R
7
—NR
8
R
9
, —C(O)NR
5
R
6
—NR
7
R
8
, —R
5
C(O)NR
6
R
7
—NR
8
R
9
, —R
5
OC(O)NR
6
R
7
—NR
8
R
9
, —R
5
NR
6
C(O)NR
7
R
8
—NHR
9
or —R
5
NR
6
C(O)OR
7
—NR
8
R
9′
,
where R
5
, R
6
, R
7
, R
8
and R
9
are each independently C
1-10
alkyl, C
1-10
alkenyl, C
1-10
alkynyl, C
6-10
aryl, C
6-14
aralkyl, C
6-14
aralkenyl or C
6-14
aralkynyl and m is 1,2,3 or 4; and where R
5
R
6
, R
7
, R
8
and R
9
are each unsubstituted or substituted with up to 6 substituents selected from halo, NO
2
, —OH, C
1-4
alkyl, —SH, —SO
3
, —NH
2
, C
1-4
acyl, C
1-4
acyloxy, C
1-4
alkylamino, C
1-4
dialkylamino, trihalomethyl, —CN, C
1-4
alkylthio, C
1-4
alkylsulfinyl, or C
1-4
alkylsulfonyl, provided that all the R substituents are not identical, or R forms a cyclic structure , e.g. a carbocyclic or heterocyclic ring, with itself, with R
3
or with the carbonyl group attached to the immediately adjacent nitrogen atom;
R
1
and R
2
, which may be the same or different, are H, an N-protecting group or as defined above for R, or R
1
and R
2
are linked together in a 3 to 7 membered heterocyclic ring structure, or either R
1
or R
2
together with OX signify an amide bond;
each R
3
, which may be the same or different, is as defined above for R, or R
3
forms a cyclic structure , e.g. a carbocyclic or heterocyclic ring, with itself, with R or with the nitrogen atom of its &bgr;-amino acid residue,
provided that R and R
3
are not both H;
X is H, an O-protecting group or as defined above for R, except that X is not —OR
5
, or OX together with R
1
or R
2
signify an amide bond;
n is 1,2,3,4,5,6,7,8,9, or 10.
The &bgr;-peptides of the invention, and in particular the compounds of formula I, are hereinafter referred to as the compounds of the invention.
Characteristically when R and R
3
are not H, R and R
3
are in the radial orientation with respect to the peptide chain.
Typically when R or R
3
form a cyclic structure, the cyclic structure is a 3 to 7 membered cyclic structure.
Preferably n is 4, 5, 6 or 7 or more preferably n is 5 or 6.
Thus in preferred embodiments the invention provides a compound of formula II or a compound of formula III
wherein R, R
1
, R
2
, R
3
and X are as defined above.
When R
1
and R
2
are linked together in a ring structure the structure is optionally substituted as for R
5
etc. above and may be fused with one or more rings such as phenyl rings. For example the R
1
and R
2
ring system may be a piperidine or pyridine ring system.
When either R
1
or R
2
together with OX signify an amide bond, i.e. when the compounds of formula I are cyclic compounds, n is preferably at least 2.
In the present description unless otherwise indicated terms such as “compounds of the invention” embrace the compounds in salt form as well as in free base form and also when the compounds are attached to a solid phase. Where a basic substituent such as an amine substituent is present, the salt form may be a double acid addition salt, for example a dihydrochloride.
The term halogen includes F, Cl, Br and I, preferably F and Cl.
Suitable N-p

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