In the claims:
1. A luminophore comprising a donor portion (D) in close association with an acceptor portion (A) sufficient for resonant energy transfer from D to A, wherein upon excitation by external electromagnetic radiation of a wavelength shorter than 1, said luminophore emits luminophore radiation of a wavelength longer than 1, which is in the range of about 400 to about 1200 nm with an emission lifetime 1 and a quantum yield Q1,
wherein when D is not in said close association with A, it absorbs radiation of a wavelength 2 shorter than 1 and thereafter emits radiation with a quantum yield Q2 less than about 0.2,
wherein when said donor portion D is in said close association with A and is excited by electromagnetic radiation of wavelength shorter than 1, it resonantly transfers energy to said acceptor portion A which then resonantly emits said luminophore radiation, and wherein said quantum yield Q1 is substantially greater than Q2.
2. A luminophore of claim 1, which is a chemical compound wherein D is covalently linked to A.
3. A luminophore of claim 1, wherein each of D and A are bound to separate molecules which can interact in solution to form said close association.
4. A luminophore of claim 1, wherein said luminophore radiation has a wavelength of 550 to 1000 nm.
5. A luminophore of claim 4, wherein the emission lifetime 1 is 25 ns to 100 s.
6. A luminophore of claim 5, wherein said luminophore emission has a quantum yield Q1 of about 1.
7. A luminophore of claim 6, wherein at least one of D and A comprises a functional group by which it can be covalently bonded to another compound.
8. A compound of the formula
D-L-A
wherein D is a donor metal ligand complex having a quantum yield less than about 0.2 for emissions in the wavelength range greater than about 400 nm;
A is an acceptor of energy resonantly transferred from D which is then emitted in the wavelength range of about 400 to about 1200 nm; and
L is a spacer of a length effective for resonant energy transfer between D and A.
9. A compound of claim 2, further comprising a functional group by which it can be covalently bonded to another compound.
10. In a chemical compound marked with a covalently bonded detectable label, the improvement wherein the label is a compound of claim 9.
11. A method of labeling a chemical compound comprising covalently bonding thereto a compound of claim 9.
12. In a method of identifying a chemical species in a mixture of compounds comprising detecting radiation emitted by said chemical species, the improvement wherein said chemical species is a compound of claim 10.
13. A method of providing a probe which emits luminophore radiation of a wavelength 1 in the range of about 400 nm to about 1200 nm with a high quantum yield Q1 and a half-life greater than about 25 ns, comprising placing a donor molecule D, which per se emits radiation of a wavelength less than 1 with a quantum yield substantially lower than Q1, in close association with an acceptor molecule A sufficient for resonant energy transfer from D to A, as a result of which D resonantly transfers energy to A and A emits said luminophore radiation.
14. A compound of claim 8, wherein D is a transition metal ligand complex.
15. A compound of claim 14, wherein said transition metal is Re, Ru, Os or Ir.
16. A luminophore of claim 1, wherein D is a transition metal ligand complex.
17. A luninophore of claim 1, wherein said quantum yield Q2 is about 0.1.
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 compound of formula I
wherein
R1 is hydroxy or NR\u2032R\u2033;
R\u2032 and R\u2033 are each independently hydrogen, lower alkyl, cycloalkyl, or together with the N-atom to which they are attached form a heteroalkyl ring;
R2 is hydrogen, lower alkyl, lower alkoxy, halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano or S(O)2-lower alkyl;
R3 is, \u2014(CH2)m-aryl optionally substituted by halogen, or \u2014(CH2)m-cycloalkyl;
R4 and R5 are each independently
hydrogen,
lower alkyl substituted by halogen,
\u2014(CR2)m-aryl or \u2014(CR2)m-heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, lower alkyl, lower alkyl substituted by halogen, cyano, hydroxy, NR\u2032R\u2033 and lower alkoxy substituted by halogen,
\u2014(CR2)m-cycloalkyl optionally substituted by hydroxy or by aryl,
a heteroalkyl ring optionally substituted by \u2550O or \u2014(CR2)m-aryl, or
R4 and R5 together with the N-atom to which they are attached form a heterocyclic ring system optionally substituted by lower alkyl, aryl or halogen-substituted aryl,
each R is independently hydrogen, lower alkyl or lower alkyl substituted by hydroxyl;
n is 1 or 2; and
m is 0, 1 or 2;
or a pharmaceutically active salt, a racemic mixture, an enantiomer, an optical isomer or a tautomeric form thereof.
2. The compound of claim 1, wherein R3 is \u2014(CH2)m-aryl wherein m is 1 and wherein one of R4 or R5 is \u2014(CH2)m-heteroaryl optionally substituted by methyl wherein m is 0 or 1.
3. The compound of claim 2, selected from the group consisting of
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid (pyridin-3-ylmethyl)-amide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid (pyridin-3-ylmethyl)-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid (furan-2-ylmethyl)-amide; and
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl) -piperidine-4-carboxylic acid (1-methyl-1H-pyrazol-4-yl)-amide.
4. The compound of claim 1, wherein R3 is \u2014(CH2)m-aryl optionally substituted by halogen wherein m is 1 and one of R4 or R5 is \u2014(CH2)m-phenyl wherein m is 1.
5. The compound of claim 4, selected from the group consisting of
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-(4-fluoro-benzyl)-piperidine-4-carboxylic acid benzylamide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-dimethylamino-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-cyclopropylamino-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(7-chloro-6-fluoro-4-hydroxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzyl-methyl-amide;
4-benzyl-1-(4-hydroxy-6-isopropoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(6-fluoro-4-hydroxy-7-methoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(7-difluoromethoxy-4-hydroxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide; and
4-benzyl-1-(4-hydroxy-7-methoxy-6-methyl-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide.
6. The compound of claim 4, selected from the group consisting of
4-benzyl-1-(4-hydroxy-6-isopropoxy-7-methoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-hydroxy-7-isopropoxy-6-methoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(6-chloro-4-hydroxy-7-methoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(6-difluoromethoxy-7-ethoxy-4-hydroxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-hydroxy-7-methoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-hydroxy-7-isopropoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(6-cyano-4-hydroxy-7-methoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-benzyl-1-(4-hydroxy-7-trifluoromethyl-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide; and
4-benzyl-1-(4-hydroxy-7-trifluoromethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide.
7. The compound of claim 1, wherein R3 is \u2014(CH2)m-aryl wherein m is 1 and one of R4 or R5 is \u2014(CH2)m-aryl wherein m is 0 and wherein aryl is other than phenyl optionally substituted by hydroxy or halogen.
8. The compound of claim 7, selected from the group consisting of
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid indan-2-ylamide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid (1-hydroxy-indan-2-yl)-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid ((1S,2S)-2-hydroxy-indan-1-yl)-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid indan-1-ylamide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid indan-2-ylamide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid indan-2-yl-methyl-amide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide;
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid (5-chloro-1-hydroxy-indan-2-yl)-amide; and
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid (1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide.
9. The compound of claim 1, wherein R3 is \u2014(CH2)m-aryl wherein m is 1 and one of R4 or R5 is \u2014(CR2)m-aryl optionally substituted by OCHF2, Cl, or N(CH3)2 wherein m is 1.
10. The compound of claim 9, selected from the group consisting of
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid 4-difluoromethoxy-benzylamide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid 1-(4-chloro-phenyl)-ethyl-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid 4-dimethylamino-benzylamide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid 3,4-dichloro-benzylamide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide;
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid ((R)-1-phenyl-ethyl)-amide; and
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidine-4-carboxylic acid ((R)-1-phenyl-propyl)-amide.
11. The compound of claim 1, wherein R3 is \u2014(CH2)m-aryl wherein m is 1 and one of R4 or R5 is a heteroalkyl ring optionally substituted by phenyl.
12. The compound of claim 11, which compound is
1-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-4-benzyl-piperidin-4-yl-(2-phenyl-pyrrolidin-1-yl)-methanone.
13. The compound of claim 1, wherein R3 is \u2014(CH2)m-aryl wherein m is 1 and one of R4 or R5 is \u2014(CH2)m-cycloalkyl wherein m is 0 or 1.
14. The compound of claim 13, selected from the group consisting of
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid cyclopentylamide and
4-benzyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid cyclobutylmethyl-amide.
15. The compound of claim 1, wherein R3 is \u2014(CH2)m-cycloalkyl and one of R4 or R5 is \u2014(CH2)m-aryl wherein m is 0 or 1.
16. The compound of claim 15, selected from the group consisting of
4-cyclopropylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-cyclopropylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzyl-methyl-amide;
4-cyclobutylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzylamide;
4-cyclobutylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid benzyl-methyl-amide;
4-cyclobutylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid (1,2,3,4-tetrahydro-naphthalen-2-yl)-amide; and
4-cyclobutylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid indan-2-ylamide.
17. The compound of claim 1, wherein R3 is \u2014(CH2)m-cycloalkyl and one of R4 or R5 is \u2014(CH2)m-cycloalkyl wherein m is 0.
18. The compound of claim 17, which compound is
4-cyclobutylmethyl-1-(4-hydroxy-6,7-dimethoxy-quinazolin-2-yl)-piperidine-4-carboxylic acid cyclopentylamide.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
R1 is hydroxy or NR\u2032R\u2033;
R\u2032 and R\u2033 are each independently hydrogen, lower alkyl, cycloalkyl, or together with the N-atom to which they are attached form a heteroalkyl ring;
R2 is hydrogen, lower alkyl, lower alkoxy, halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano or S(O)2-lower alkyl;
R3 is, \u2014(CH2)m-aryl optionally substituted by halogen, or \u2014(CH2)m-cycloalkyl;
R4 and R5 are each independently
hydrogen,
lower alkyl substituted by halogen,
\u2014(CR2)m-aryl or \u2014(CR2)m-heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents selected from halogen, lower alkyl, lower alkyl substituted by halogen, cyano, hydroxy, NR\u2032R\u2033 and lower alkoxy substituted by halogen,
\u2014(CR2)m-cycloalkyl optionally substituted by hydroxy or by aryl,
a heteroalkyl ring optionally substituted by \u2550O or \u2014(CR2)m-aryl, or
R4 and R5 together with the N-atom to which they are attached form a heterocyclic ring system optionally substituted by lower alkyl, aryl or halogen-substituted aryl,
each R is independently hydrogen, lower alkyl or lower alkyl substituted by hydroxyl;
n is 1 or 2; and
m is 0, 1 or 2;
or a pharmaceutically active salt, a racemic mixture, an enantiomer, an optical isomer or a tautomeric form thereof and a pharmaceutically acceptable carrier.