Substituted tetrahydropyrane derivatives, method for...

Details Substituted tetrahydropyrane derivatives, method for... Substituted tetrahydropyrane derivatives, method for...

2000-04-25

2004-06-29

Wilson, James O. (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S016800, C536S017700

Reexamination Certificate

active

06756489

ABSTRACT:

This application is the National Stage filed under 35 USC 371 of PCT/EP98/05025, filed Aug. 7, 1998.
The invention relates to substituted tetrahydropyran derivatives, processes for their preparation, their use as a pharmaceutical or diagnostic and pharmaceutical comprising them.
Peptides and peptide mimetics are a valuable aid for the discovery of new lead structures and the identification of potential active compounds. By fixing side chains in a rigid structure (scaffold), it is hoped, in comparison with the conformationally more flexible peptide chain, for an increase in the affinity of this conformationally fixed ligand for the receptor.
Very different structural units are already finding use as peptide mimetics.
Owing to their polyvalency and their defined spatial arrangement, carbohydrate units should be particularly highly suitable as structural units for peptide mimetics.
Thus, it has recently been shown that a specific monosaccharide mimics, as a conformationally fixed structure, the spatial arrangement of a certain cyclopeptide, somatostatin (K. C. Nicolaou, J. I. Trujillo, K. Chibale, Tetrahedron 1997, 53, 8751-8778).
In this connection, starting from a glucose derivative having standard protective groups, a restricted variation of the simply accessible anomeric hydroxyl function and the C-6 hydroxyl function was carried out. The synthesis strategy described there starts from already known sugar units and is restricted by the protective group:strategy to a narrow application range of somatostatin. At the same time, the method is not transferable to the targeted variation of the structural unit by solid-phase synthesis.
The previous syntheses of carbohydrate derivatives in solution or in the form of substance libraries on a solid phase concentrated, in particular, on the synthesis of oligosaccharides or glycopeptides (L. DeNapoli et al., Tetrahedron Letters 1996, 37, 5007-5010; S. J. Danishefsky et al., Science 1995, 269, 202-204, J. J. Krepinski et al., J. Am. Chem. Soc., 1991, 113, 5095-5097).
Compounds synthesized from oligosaccharide or glycopeptide units are, however, of only very restricted use for the discovery of lead structures or as potential active compounds on account of their complexity.
Restriction to a monosaccharide as a structural unit, however, combines the positive property of the defined spatial arrangement of the ligands with a low complexity, low molecular weight, low toxicity and further properties which are of importance for potential active compounds.
On account of the polyvalency of the monosaccharides, targeted synthesis of selectively functionalized monosaccharides—both in solution and on the solid phase—causes great difficulties.
Variously protected carbohydrate units are likewise known as a result of the various studies on carbohydrate chemistry (see R. R. Schmidt, Pure & Appl. Chem. 1989, 61, 1257). In the intermediates described there, the hydroxyl groups are temporarily blocked more or less selectively by protective groups which are then deprotected for linkage with other protective groups, as a result of which the synthesis of di- or oligosaccharides takes place.
These intermediates or the polysugars synthesized therefrom are, however, of only restricted use for specific lead structure discovery and as potential active compounds. In some cases, these structures are relatively labile and thus not resistant to degradation or cleavage.
The linkers and activation strategies developed for the preparation of the abovementioned polysaccharides or glycopeptides (D. Kahne et al., J. Am. Chem. Soc. 1994, 116, 6953-6954) are also not generally transferable to the preparation of selectively polysubstituted monosaccharide compounds.
The specific synthesis of selectively functionalized monosaccharide derivatives therefore requires the development of a novel, completely orthogonal protective group strategy, which makes it possible to selectively remove the protective groups of all functional groups, the conditions used for this being stable to the conditions of the synthesis sequence. At the same time, these protective groups must guarantee compatibility with all reaction conditions which are necessary for synthesis in solid-phase synthesis. For synthesis on a solid phase, it is furthermore necessary to have available a linker system for linking the monosaccharide unit, preferably via the anomeric center, which is compatible with all reaction conditions and can be selectively activated. Such a strategy makes possible the specific different variation of all functionalities of the monosaccharide unit to give stable final products.
The invention thus relates to compounds of the formula I
in which:
R
1
, R
2
, R
3
, R
4
, R
5
independently of one another are
1. hydrogen;
2. (C
1
-C
12
)-alkyl;
3. (C
2
-C
8
)-alkenyl;
4. (C
2
-C
8
)-alkynyl;
5. (C
1
-C
6
)-alkylene-(C
3
-C
10
)-cycloalkyl;
6. (C
0
-C
6
)-alkylene-(C
6
-C
12
)-aryl; preferably phenyl or benzyl;
7. (C
1
-C
6
)-alkoxy;
8. (C
0
-C
6
)-alkylene-CO—R
8
;
9. (C
1
-C
6
)-alkylene-(C
1
-C
9
)-heteroaryl;
10. carbamoyl;
11. —C(O)NR
6
R
7
;
12. —C(O)OR
6
;
13. a radical defined as in 2.-12., which is mono-, di- or polysubstituted in the alkyl moiety and/or aryl or heteroaryl moiety by a radical from the group consisting of (C
1
-C
6
)-alkyl, NO
2
, CN, halogen, CF
3
or (C
1
-C
6
)-alkoxy;
14. a radical defined as in 6. and 9., which is substituted in the aryl or heteroaryl moiety by one, two or more halogen atoms;
R
6
and R
7
independently of one another are:
1. hydrogen;
2. (C
1
-C
12
)-alkyl;
3. (C
2
-C
8
)-alkenyl;
4. (C
2
-C
8
)-alkynyl;
5. (C
1
-C
6
)-alkylene-(C
3
-C
10
)-cycloalkyl;
6. (C
1
-C
6
)-alkylene-(C
6
-C
12
)-aryl; preferably benzyl;
7. (C
2
-C
6
)-alkyloxy;
8. (C
0
-C
6
)-alkylene-CO—R
8
;
9. (C
1
-C
6
)-alkylene-(C
1
-C
9
)-heteroaryl;
10. (C
0
-C
6
)-alkylene-(C
1
-C
6
)-alkoxy;
11. (C
3
-C
10
)-cycloalkyl;
12. (C
6
-C
12
)-aryl, preferably phenyl;
R
8
is hydrogen, (C
1
-C
6
)-alkyl, (C
6
-C
12
)-aryl or OR
12
;
R
12
is hydrogen, (C
1
-C
6
)-alkyl or (C
6
-C
12
)-aryl; or
R
2
and R
3
together or R
3
and R
4
together or R
4
and R
5
together are
(C
1
-C
3
)-alkylene which can be substituted by 1 or 2 (C
1
-C
3
)-alkyl radicals or optionally substituted (C
6
-C
12
)-aryl radicals;
X is N or O;
with the proviso that R
2
is not —C(O)OR
6
when X is O;
and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which the radicals R
1
, R
2
, R
3
, R
4
and R
5
do not each have the same meaning, and their physiologically tolerable salts.
Preferred compounds of the formula I are furthermore those in which only three of the radicals R
1
, R
2
, R
3
, R
4
, R
5
have the same meaning, and their physiologically tolerable salts.
Particularly preferred compounds of the formula I are those in which only two of the radicals R
1
, R
2
, R
3
, R
4
, R
5
have the same meaning, and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are those in which all radicals R
1
, R
2
, R
3
, R
4
, R
5
have a different meaning, and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which at least one of the radicals R
1
, R
2
, R
3
, R
4
, R
5
is hydrogen, —C(O)NR
6
R
7
, (C
1
-C
8
)-alkyl, (C
0
-C
6
)-alkyl-(C
6
-C
12
)-aryl, preferably phenyl or benzyl; the aryl moiety of the (C
1
-C
6
)-alkyl-(C
6
-C
12
)-aryl radical being unsubstituted or mono-, di- or trisubstituted by (C
1
-C
6
)-alkyl, cyano, nitro, CF
3
, Cl, Br or (C
1
-C
4
)alkoxy, preferably methoxy, and R
6
and R
7
independently of one another are hydrogen, (C
1
-C
4
)-alkyl, benzyl, (C
1
-C
3
)-alkylene-(C
3
-C
7
)-cycloalkyl, (C
1
-C
3
)-alkylene-CO—OR
12
, (C
1
-C
3
)-alkylene-(C
1
-C
3
)-alkoxy, phenyl, optionally substituted by one or two radicals from the group consisting of CF
3
, Cl, Br, F, nitro, cyano; and R
12
is as defined above;
or R
3
and R
4
together or R
4
and R
5
together are —CH
2
— which is substituted by 1 or 2 methyl radicals or optionally substituted phenyl radicals, and the other radica

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