1. An optical amplifier arrangement for amplifying input signals within a predetermined wavelength band including an optical amplifier (10), means (21, 40) for measuring the input power to the optical amplifier, means (31, 40) for measuring the output power from the amplifier, and means (40) for determining total amplifier gain from said input and output powers, characterised by means (50) for determining the degree of variation of gain with wavelength using a predetermined relationship between total gain and the slope of gain with wavelength.
2. An arrangement as claimed in claim 2, characterised in that said predetermined relationship models the slope of gain with wavelength against the deviation of actual amplifier gain from a known optimal gain value at which amplifier gain is substantially equal for all wavelengths in said wavelength band, and including means (50) for determining the deviation of said determined gain from said optimal gain value.
3. An arrangement as claimed in claim 1 or 2, characterised by means (70, 50) for measuring the temperature of said optical amplifier (20), and means (50) for determining the optimal gain of the amplifier from a predetermined relationship between the optimal gain of the amplifier and amplifier temperature prior to determining the gain slope with wavelength.
4. An arrangement as claimed in any one of claims 1 to 3, characterised in that said predetermined relationship is specific to said optical amplifier.
5. An arrangement as claimed in any one of claims 1 to 3, characterised in that said predetermined relationship is specific to a class of optical amplifiers.
6. An optical amplifying device including first (100) and second (110) optical amplifiers and attenuating means (120) connected between said first and second optical amplifiers, characterised by means (130) for measuring the gain of each amplifier, means (130) for determining for each optical amplifier the degree of variation of gain with wavelength using a predetermined relationship between total amplifier gain and the slope of gain with wavelength, means (130) for adjusting the pump power to said first amplifier (100) andor the attenuation of said attenuator (130) andor the pump power to said second optical amplifier (120) to adjust the gain of at least one of said amplifiers.
7. A device as claimed in claim 6, characterised in that said predetermined relationship models the slope of gain with wavelength against the deviation of actual amplifier gain from an optimal gain value at which amplifier gain is substantially equal for all wavelengths in said wavelength band, wherein said adjusting means (130) are arranged to alter the pump power to said amplifiers (100, 110) and or the attenuation of said attenuator (130) to minimise the deviation of said measured gain from said optimal gain value for each amplifier.
8. A device as claimed in claim 6 or 7, characterised by means (70) for measuring the temperature of said optical amplifiers (100, 110), and means for determining the optimal gain of the amplifiers from a predetermined relationship between the optimal gain of the amplifier and amplifier temperature prior to determining the gain slope with wavelength.
9. An optical transmission link of an optical fibre network adapted to carry wavelength division multiplexed signals, said link including an optical fibre for carrying traffic data in at least one direction and at least one optical amplifier coupled to said optical fibre for amplifying the signal power of said traffic data, characterised in that said amplifier includes means for measuring total amplifier gain and means for determining the degree of variation of gain with wavelength from a predetermined relationship between total amplifier gain and the slope of gain with wavelength.
10. A transmission link as claimed in claim 9, characterised by a control channel (140) coupled to said at least one amplifier for carrying information relating to the determined degree of variation of gain with wavelength.
11. A transmission link as claimed in claim 10, characterised by controllable wavelength dependent attenuating means coupled to said optical fibre and said control channel (140), said attenuating means being adapted to attenuate select wavelengths of the traffic data in response to information relating to the determined degree of variation of gain with wavelength received via said control channel (140).
12. A link as claimed in claim 11, characterised in that said wavelength dependent attenuating means include an amplifying device having first and second optical amplifiers,
an attenuator connected between said first and second optical amplifiers,
means for determining for each optical amplifier the degree of variation of gain with wavelength from a predetermined relationship between total amplifier gain and the slope of gain with wavelength and means for controlling the attenuation of said attenuator andor the gain of said second optical amplifier to generate a signal at the output of said device having a specified degree of variation of gain with wavelength.
13. A link as claimed in claim 12, characterised in that said attenuator (120) is adapted to apply wavelength dependent attenuation to said traffic data.
14. A link as claimed in any one of claims 9 to 13, characterised in that said predetermined relationship models the slope of gain with wavelength against the deviation of actual amplifier gain from a known optimal gain value at which amplifier gain is substantially equal for all wavelengths in said wavelength band, said amplifier including means (50) for determining the deviation of said determined gain from said optimal gain value.
15. A link as claimed in any one of claims 9 to 14, characterised by means (70, 50) for measuring the temperature of said optical amplifier (20), and means (50) for determining the optimal gain of the amplifier from a predetermined relationship between the optimal gain of the amplifier and amplifier temperature prior to determining the gain slope with wavelength.
16. A method for determining the degree of variation of gain with wavelength applied to optical WDM signals amplified in an optical amplifier, including: measuring the total power output by the amplifier, measuring the total power input to the amplifier, calculating the total amplifier gain, characterised by using a predetermined relationship between total gain and degree of variation of gain with wavelength, determining the wavelength dependent variation for the calculated total gain.
17. A method as claimed in claim 16, characterised by determining the deviation of said calculated gain from a predetermined optimal gain value for said amplifier and using a predetermined relationship between the deviation from said optimal gain and the degree of variation of gain with wavelength to determine the wavelength dependent variation for the calculated gain.
18. A method as claimed in claim 16 or 17, characterised by determining factors that affect the value of optimal gain, such as temperature, and adjusting the optimal gain in accordance with said determined factors prior to determining the wavelength dependent variation for the calculated gain.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
What is claimed is:
1. A combination comprising a polypeptide comprising the modulating sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
41
wherein:
X is of from 1 to 7 atoms other than hydrogen and is oxygen, sulfur bonded to 0 to 2 oxygen atoms, amino and alkyl substituted amino;
n is 0 or 1;
R1 is hydrogen or an organic group of from 1 to 12 carbon atoms and from 0 to 6 heteroatoms, which are chalcogen, nitrogen, and halogen consisting of an aliphatic group of from 1 to 6 carbon atoms having from 0 to 2 sites of unsaturation, non-oxo-carbonyl and the nitrogen and sulfur derivatives thereof, alicyclic having from 0 to 2 sites of unsaturation, aryl, heterocyclic and combinations thereof, where the cyclic structures may have from 1 to 2 rings;
R2 is hydrogen, a heterofunctionality having nitrogen andor chalcogen bonded to annular carbon, a heterofunctionality having nitrogen andor chalcogen bonded to annular carbon to which is substituted with an organic group of from 1 to 10 carbon atoms, aryl, alkaryl, aralkyl and aralkenyl of from 5 to 10 carbon atoms, aroyl of from 6 to 10 carbon atoms, or an organic group bonded through a carbon atom of from 1 to 12 carbon atoms having from 1 to 4, as described above for R1;
R3 is hydrogen or an organic group of from 1 to 10 carbon atoms and from 0 to 4 chalcogen and nitrogen heteroatoms;
R4 is hydrogen or alkyl and substituted alkyl of from 1 to 6 carbon atoms, where the substituents are oxy, amino and halo;
with the proviso that R3 and R4 can be taken together to form a ring with the annular atoms to which they are attached of from 4 to 10 annular atoms and forming from 1 to 2 rings, where the annular atoms are unsubstituted or substituted with halo, alkyl of from 1 to 3 carbon atoms, oxy of from 0 to 3 carbon atoms, thio of from 0 to 3 carbon atoms and amino of from 0 to 4 carbon atoms;
42
wherein:
p is 0, 1 or 2; and
R5 is a group having from 1 to 3 atoms other than hydrogen and is oxy, thio, amino, nitro, cyano, and alkyl;
43
wherein:
Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
R6 is H or alkyl of from 1-3 carbon atoms;
R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
V is an aryl group having 6 annular members comprising 0 to 2 nitrogen atoms and the remainder carbon atoms
U is a substituent group of from 0 to 5 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, halo, and alkyl; and
u is 0 to 3; and
44
wherein:
Y is oxygen, sulfur, NH, (alkyl of from 1 to 3 carbon atoms, H) or H2
R7 is hydrogen or an organic group of from 1 to 12 carbon atoms and 0 to 4 heteroatoms;
R8 is hydrogen, an aliphatic group of from 1 to 6 carbon atoms or a heterocycle of from 5 to 6 annular members and from 1 to 2 heteroannular members that are oxygen, nitrogen or sulfur; and
R9, R10, R13, R14, R15 and R16 are the same or different and are hydrogen or an organic radical of from 1 to 12 carbon atoms or a heterosusbtituent of from 1 to 3 heteroatoms;
R11 and R12 are the same or different and are hydrogen or an organic group of from 1 to 12 carbon atoms.
2. A combination according to claim 1, wherein said polypeptide and said non-peptide organic molecule are complexed at the modulating domain of EPO-R.
3. A combination according to claim 2, wherein said polypeptide is EPO-R bound to a cellular membrane.
4. A combination comprising a polypeptide comprising the modulating domain sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
45
wherein:
X is of from 1 to 3 atoms other than hydrogen and is oxygen, sulfur bonded to 0 to 2 oxygen atoms, amino and alkyl substituted amino;
n is 0 or 1;
R1 is a lower alkyl group of 1 to 3 carbon atoms or an organic group having a six annular membered aromatic group having from 0 to 3 substituents, where the substituents are halo, lower alkyl of from 1 to 3 carbon atoms, nitro, trihalomethyl, and is either directly bonded to X or bonded through a linking group of from 1 to 4 carbon, nitrogen, or chalcogen atoms in the chain, being particularly carbon and nitrogen, and there being from 0 to 2 heteroatoms in the chain, where heteroatoms are bonded solely to carbon and hydrogen, or_-acetamidinyl having from 0 to 1 NOH;
R2 is hydrogen, amino of 0 to 3 carbon atoms, oxy of from 0 to 3 carbon atoms, a heterofunctionality having nitrogen or chalcogen bonded to annular carbon to which is substituted an organic group of from 1 to 10 carbon atoms and from 0 to 3 heteroatoms;
R3 is hydrogen or an organic group of from 1 to 10 carbon atoms and from 0 to 4 chalcogen and nitrogen heteroatoms;
R4 is hydrogen, alkyl or substituted alkyl of from 1 to 6 carbon atoms, where the substituents are oxy, amino and halo;
with the proviso that R3 and R4 can be taken together to form a ring with the annular atoms to which they are attached of from 4 to 10 annular atoms and forming from 1 to 2 rings, where the annular atoms are unsubstituted or substituted with halo, alkyl of from 1 to 3 carbon atoms, oxy of from 0 to 3 carbon atoms, thio of from 0 to 3 carbon atoms and amino of from 0 to 4 carbon atoms.
5. A combination according to claim 4, wherein R3 is hydrogen or an organic group of from 1 to 8 carbon atoms and 0 to 4 chalcogen, nitrogen and halo heteroatoms.
6. A combination according to claim 5, wherein R3 is cyclopropylmethylamino.
7. A combination according to claim 5, wherein R3 is H.
8. A combination according to claim 4, wherein R1 is a six annular membered aromatic group having from 0 to 3 substituents, where the substituents are halo, lower alkyl of from 1 to 3 carbon atoms, nitro, trihalomethyl, and is either directly bonded to X or bonded through a linking group of from 1 to 4 carbon, nitrogen, or chalcogen atoms in the chain.
9. A combination according to claim 4, wherein R4 is methyl.
10. A combination according to claim 4, wherein R4 is H.
11. A combination comprising a polypeptide comprising the modulating sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
46
wherein:
Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
R6 is H or alkyl of from 1-3 carbon atoms;
R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
V is a phenyl group;
U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen; and u is 0 to 3.
12. A combination according to claim 11, wherein Y is SO2, V is phenyl, R7 is Cl and u is 0.
13. A combination comprising a polypeptide comprising the modulating domain sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
47
wherein:
R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain or N-hydroxyamidinyl;
R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo, _CH3-halobenzene, where halo is F or Cl. A method for modulating the activity of EPO-R present as a cell membrane component comprising:
forming a complex by bringing together the members of the combination of claim 13 under complex forming conditions, where said polypeptide is EPO-R.
14. A method for modulating the activity of EPO-R present as a cell membrane component comprising:
forming a complex by bringing together the members of the combination of claim 13 under complex forming conditions, where said polypeptide is EPO-R.
5. A combination
6. A combination according to claim 5, wherein R3 is cyclopropylmethylamino.
7. A combination according to claim 5, wherein R3 is H.
8. A combination according to claim 4, wherein R1 is a six annular membered aromatic group having from 0 to 3 substituents, where the substituents are halo, lower alkyl of from 1 to 3 carbon atoms, nitro, trihalomethyl, and is either directly bonded to X or bonded through a linking group of from 1 to 4 carbon, nitrogen, or chalcogen atoms in the chain.
9. A combination according to claim 4, wherein R4 is methyl.
10. A combination according to claim 4, wherein R4 is H.
11. A combination comprising a polypeptide comprising the modulating sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
48
wherein:
Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
R6 is H or alkyl of from 1-3 carbon atoms;
R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
V is a phenyl group;
U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen; and
u is 0 to 3.
12. A combination according to claim 11, wherein Y is SO2, V is phenyl, R7 is Cl and u is 0.
13. A combination comprising a polypeptide comprising the modulating domain sequence of the erythropoietin receptor and a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
49
wherein:
R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain or N-hydroxyamidinyl;
R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo, _CH3-halobenzene, where halo is F or Cl.
14. A method for modulating the activity of EPO-R present as a cell membrane component comprising:
forming a complex by bringing together the members of the combination of claim 13 under complex forming conditions, where said polypeptide is EPO-R.
15. A method for modulating the activity of EPO-R comprising:
forming a complex by bringing together the members of the combination of claim 11 under complex forming conditions, where said polypeptide is EPO-R.
16. A compound according to claim 13 and a pharmaceutically acceptable vehicle.
17. A compound according to claim 11 and a pharmaceutically acceptable vehicle.
18. A method of determining the binding affinity of a test compound to the modulating domain of EPO-R, said method comprising:
adding said test compound to a combination according to claim 1 and determining the amount of complex of said combination in the presence of said test compound as compared to the absence of said test compound.
19. A method of inducing a physiological response of EPO-R in a host, said method comprising:
administering to said host a physiologically effective amount of a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
50
wherein:
R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain, N-hydroxyamidinyl;
R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo,_-CH3-halobenzene, where halo is F or Cl; or
51
wherein:
Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
R6 is H or alkyl of from 1-3 carbon atoms;
R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
V is a phenyl group;
U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen; and
u is 0 to 3.
20. A method according to claim 19, wherein said non-peptide organic molecule is of formula 1.
21. A method according to claim 20, wherein X is amino, R2 is o-methyl, p-chlorophenyl-1, R2 is H, R3 is cyclopropylmethylamino and R4 is methyl.
22. A method of modulating the response to a stimulus of hematopoietic or neuronal cells influenced by the binding of EPO to EPO-R, said method comprising:
contacting said cells with an effective amount to modulate said response of a non-peptide organic molecule of from 12 to 36 atoms other than hydrogen, from 9 to 20 carbon atoms, and from 4 to 12 of the heteroatoms chalcogen, nitrogen, halogen, and metal ion of Groups I and II of the periodic chart, and of the formula:
52
wherein:
R1 is alkyl of from 1 to 3 carbon atoms, substituted phenyl having from 0 to 3 substituents that are CH3, Cl, NO2, and CF3 and bonded directly to an annular carbon atom or through a linking group of from 1 to 3 carbon and nitrogen atoms in the chain, N-hydroxyamidinyl;
R2 is CH3, NH2, OH, and aroylamido of from 7 to 8 carbon atoms having from 0 to 2 substituents that are CH3, Cl, NO2, and CF3;
R3 is cycloalkylalkyl of from 4 to 8 carbon atoms, having from 3 to 4 annular atoms, H or carboxy;
R4 is H, lower alkyl of from 1 to 3 carbon atoms or alkoxymethyl of from 2 to 4 carbon atoms;
with the proviso that R3 and R4 may be taken together to define 1,2-dimethylene-_-halo,_-CH3-halobenzene, where halo is F or Cl; or
53
wherein:
Y is 0, S(O)m, wherein m is 0, 1 or 2, amino or CH2;
R6 is H or alkyl of from 1-3 carbon atoms;
R7 is hydrogen, or a group of from 0 to 3 atoms other than hydrogen, and is oxy, thio amino, nitro, cyano, and alkyl;
V is a phenyl group;
U is oxy, thio amino, nitro, cyano, halo, and alkyl and from 0 to 3 atoms other than hydrogen; and
u is 0 to 3.