1. A pro-apoptotic Smac (second mitochondria-derived activator of caspases) peptide mimetic dimeric compound of the general formula M1-L-M2, wherein moieties M1 and M2 are monomeric Smac mimetics and L is a linker covalently linking M1 and M2 in the active dimeric compound.
2. The compound of claim 1 wherein M1 and M2 are identical.
3. The compound of claim 2 wherein M1 is of the formula:
wherein R1 is methyl;
R2 is methyl,
R3 is NH;
R4 is CH;
each of R5 and R8, is selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, and optionally hetero-, optionally substituted aryl; and
R6 and R7 are connected in a 5 membered ring.
4. The compound of claim 3 wherein L is a contiguous chain of between 2 and 200 atoms, having a MW between 20 and 2 KD that can incorporate substitution, heteroatoms, unsaturation and cyclic aromatic and heteroaromatic portions.
5. The compound of claim 4 wherein L covalently links M1 and M2 through R5 or through a 5 membered saturated non-heterocyclic ring represented by R6 and R7.
6. The compound of claim 1, wherein M1-L-M2 is of formula II,
wherein:
R1 and R1\u2032 are selected from hydrogen, optionally substituted methyl, and hydroxyl;
R2 and R2\u2032 are selected from optionally substituted methyl and optionally substituted ethyl;
R3 and R3\u2032 are selected from CH2, NH, O and S;
R4 and R4\u2032 are selected from CH and N;
R5-R8, and R5\u2032-R8\u2032 are selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl, wherein optionally either R6 and R7 as well as R6\u2032 and R7\u2032 or R7 and R8 as well as R7\u2032 and R8\u2032 are connected in 5- to 8-membered rings; and
L is a contiguous chain of between 2 and 200 atoms, having a MW between 20 and 2 KD that can incorporate substitution, heteroatoms, unsaturation and cyclic aromatic and heteroaromatic portions, covalently linking any of R2, R5, R6 or R7, with any of R2\u2032, R5\u2032, R6\u2032 or R7\u2032,
or a pharmaceutically-acceptable salt thereof.
7. The compound of claim 6, wherein R1 and R1\u2032 are selected from hydrogen and methyl.
8. The compound of claim 6, wherein R2 and R2\u2032 are selected from methyl and ethyl.
9. The compound of claim 6, wherein R3 and R3\u2032 are NH.
10. The compound of claim 6, wherein R4 and R4\u2032 are CH.
11. The compound of claim 6, wherein R5 and R5\u2032 are C1-C3 alkyl.
12. The compound of claim 6, wherein R1 and R1\u2032 are selected from hydrogen and methyl, R2 and R2\u2032 are selected from methyl and ethyl, R3 and R3\u2032 are NH, R4 is CH, and R5 and R5\u2032 are C1-C3 alkyl, and L covalently links R5, R6 or R7, with R5\u2032, R6\u2032 or R7\u2032.
13. The compound of claim 6, wherein either R6 and R7 as well as R6\u2032 and R7\u2032 or R7 and R8 as well as R7\u2032 and R8\u2032 are connected in 5- to 8-membered rings.
14. The compound of claim 6, wherein R7 and R8 are connected in a 5- or 6-membered ring.
15. The compound of claim 6, wherein R6 and R7 are connected in a 5- or 6-membered ring.
16. The compound of claim 6, wherein R6 and R7 are connected in a 5-membered ring, and L covalently links the ring with R2\u2032, R5\u2032, R6\u2032 or R7\u2032.
17. The compound of claim 6, wherein R8 comprises a 5- or 6-membered ring.
18. The compound of claim 6, wherein R8 comprises a 5-membered ring, comprising at least one heteroatom, at least one substitution, and at least one unsaturation.
19. The compound of claim 6, wherein R1 and R2, and R1\u2032 and R2\u2032 are connected in 5-membered rings.
20. The compound of claim 6, wherein L is a contiguous chain of between 4 and 100 atoms, and between 40 D and 1 kD.
21. The compound of claim 6, wherein L is an optionally hetero-, optionally substituted dialkynyl radical.
22. The compound of claim 6, wherein L is substituted with a protonated or alkylated amine wherein the compound is a triamine.
23. The compound of claim 6, wherein the dimer is symmetrical about the linker.
24. The compound of claim 6, wherein the dimer is symmetrical.
25. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
26. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, copackaged with instructions describing use of the composition to treat a disease associated with undesirable caspase activity.
27. The pharmaceutical composition of claim 1 comprising a unit dosage of the compound of claim 1.
28. A method of promoting apoptosis of pathogenic mammalian cells, the method comprising the steps of contacting the cells with an effective amount of the compound of claim 1, and detecting a resultant increase in apoptosis of the cells.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A fuel delivery system for a fuel tank in a motor vehicle, comprising a delivery unit, which has a surge chamber and a fuel pump arranged in the latter, and a ventilation system for ventilation during refueling andor operation with a compensating container into which at least one ventilation line opens, wherein the surge chamber and the compensating container are joined into a structural unit.
2. The fuel delivery system as claimed in claim 1, wherein the surge chamber and the compensating container are separate components which are joined to each other by means of a positive-locking connection, preferably with latching and plug-in connections, or by means of a material connection, preferably by bonding or welding.
3. The fuel delivery system as claimed in claim 2, wherein the surge chamber and the compensating container are joined by a frictional latch.
4. The fuel delivery system as claimed in claim 2, wherein the surge chamber and the compensating container are joined by a bonding material.
5. The fuel delivery system as claimed in claim 1, wherein the surge chamber and the compensating container are formed integrally as a single constructional unit.
6. The fuel delivery system as defined in claim 1 or 2, wherein the surge chamber and the compensating container can each be closed with a lid.
7. The fuel delivery system as claimed in claim 1 or 2, wherein the surge chamber and the compensating container are connected via a non-return valve, or via a jet pump.