1. A method for representing flow with a medical imaging system, the method comprising using the medical imaging system to perform the steps of:
(a) assigning first display values to each of a first plurality of spatial locations of a first image;
(b) tracking a flow direction and magnitude for each of the first plurality of spatial locations;
(c) identifying a second plurality of spatial locations as a function of the flow directions and magnitudes, the second plurality of spatial locations corresponding to locations in a second image; and
(d) assigning second display values of the second image to each of the second plurality of spatial locations as a function of the first display values of the first image such that the second display values have a perceived similarity to the first display values but shifted spatially between the first and second images.
2. The method of claim 1 wherein (a) comprises generating a first pattern for the first plurality of spatial locations for a first image, the first plurality of spatial locations associated with flow, and (d) comprises generating a second pattern for the second plurality of spatial locations for a second image, the second plurality of spatial locations associated with flow, each of the second plurality of spatial locations of the second pattern responsive to the first pattern shifted by the flow direction and magnitude for each of first plurality of spatial locations.
3. The method of claim 1 wherein (a) comprises assigning as a function of a random field with a normal distribution.
4. The method of claim 1 wherein (a) and (d) comprise assigning at least one characteristic of the first and second display values as modulated gray scale values, color, hue or combinations thereof.
5. The method of claim 4 further comprising:
(e) modulating the first and second display values also as a function of B-mode signals, color flow signals, or combinations thereof.
6. The method of claim 1 wherein (d) comprises assigning the second display values as a weighted combination of the first display values and a pattern function.
7. A method for representing flow with a medical imaging system, the method comprising using the medical imaging system to perform the steps of:
(a) generating a first pattern for a plurality of pixels associated with flow for a first image;
(b) determining a spatial offset between the first image and a second image as a function of the flow;
(c) generating a second pattern for the pixels associated with flow for the second image, the second pattern determined as a function of the first pattern, the second pattern being positioned in the second image as a function of the spatial offset; and
(d) determining a flow direction and magnitude for each of the plurality of pixels;
wherein (c) comprises generating the second pattern as a function of the flow direction and magnitude.
8. The method of claim 7 wherein (a) comprises generating the first pattern with a normal distribution with a width of the distribution being a function of a variance of flow.
9. The method of claim 7 wherein (a) comprises modulating gray scale values of pixel display values for the plurality of pixels.
10. The method of claim 9 further comprising:
(d) modulating a color of the pixel display values for the plurality of pixels as a function of a flow characteristic.
11. The method of claim 9 further comprising:
(d) modulating the gray scale pixel display values also as a function of B-mode signals for the plurality of pixels.
12. The method of claim 7 wherein (c) comprises generating the second pattern as representing movement of the first pattern.
13. The method of claim 7 wherein (a) and (c) comprise indicating a direction of flow with a shift of the first pattern to a different position, the second pattern including information from the shifted first pattern.
14. The method of claim 7 wherein (a) and (c) comprise indicating a magnitude of flow with a shift of the first pattern to a different position, the second pattern including information from the shifted first pattern.
15. A system for representing flow in medical imaging, the system comprising:
a processor operable to generate an at least partially persistent pattern in each of at least two images representing a region of a patient, the persistent pattern shifted, in a second of the images as compared to a first of the images, as a function of flow direction, flow magnitude or combinations thereof in the first of the images, the processor operable to calculate a second pattern in the second of the images as a function of a first pattern in the first of images; and
a display operable to display the at least two images;
wherein the processor is operable to assign the first pattern to each of a first plurality of spatial locations in the first of the at least two images, to track a flow direction and magnitude for each of the first plurality of spatial locations, to identify a second plurality of spatial locations as a function of the flow direction and magnitude, and to assign second display values to each of the second plurality of spatial locations in the second of the at least two images as a function of the first display values.
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 method for treating an individual suffering form a pathological conditions which is ameloriated by supression of CD4+-T-cell-mediated immune response, other than a condition resulting from viral infection which comprises the steps of administering to the individual a therapeutically effective amount of a triaza macrocyclic compound having the formula:
or a pharmaceutically acceptable salt or solvate thereof wherein:
W represents a bridge carbon which is unsubstituted or which is bonded directly or indirectly to one or two polar or non-polar side group substituents selected from the group consisting of double-bonded carbon (\u2550C(H)2 or \u2550C(R)2), double bonded oxygen (\u2550O), hydroxyl, alkyl of about one to 10 carbons alkenyl of about two to 10 carbons (preferably of 2 to 6 carbon atoms); a substituted alkyl group carrying a charged substituent, such as an \u2014S(R\u2033)2+, an \u2014N(R\u2033)3+, a \u2014PR3+, or an \u2014OSO3\u2212 group, alkoxy of about one to 10 carbons; aryl of about 6 to 12 carbons; halogen, methyl halogen(\u2014CT3, \u2014CHT2, or \u2014CH2T), methylene halide (\u2550CT2); optionally substituted epoxide (or oxirane); acyl (\u2014CO\u2014R); (\u2014CO2\u2014R); CH2OH and hydrogen; where halogen is F, Cl, I or Br; T, independently of other T, is F, Cl, I or Br, but preferably all T are the same halogen; R, independently of other R1 is an optionally substituted alkyl of about one to 10 carbons (preferably of one to 6 carbon atoms), an optionally substituted alkenyl group of about 2 to 10 carbon atoms or an optionally substituted aryl group of about 6 to 12 carbons and R\u2033 is a hydrogen or an alkyl group having from one to 10 carbon atoms and W may be bonded to one hydrogen and one polar or non-polar group;
X and Y independently represent an optionally substituted aryl group (Ar), an optionally substituted alkyl group having from one to 10 carbon atoms, or an optionally substituted alkenyl group having from 2 to 10 carbon atoms attached to the triaza macrocycle through an optional linker group L; where the linker group L can be sulfonyl (\u2014SO2\u2014), \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH)\u2014, \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, carboxy (\u2014OCO\u2014), carbonyl (\u2014CO\u2014), or alkyl (e.g., \u2014(CH2)n\u2014 where n is 1 or 2-; where Ar comprises at least one aromatic homocyclic or heterocyclic ring having from five to seven members; wherein the Ar ring can be substituted with one or more non-hydrogen substituent groups. Ar group substituents include one or more halogens, one or more \u2014CN; one or more \u2014SO3, \u2014SH, \u2014SR or \u2014S\u2014OR groups; one or more trihalomethyl groups; one or more NO, one or more NO2, one or more NH2, NHR or N(R)2 groups; one or more alkyl groups, one or more alkoxy groups, one or more hydroxyl groups, one or more acyl groups (\u2014COH or \u2014CO\u2014R), one or more acid or ester groups (\u2014CO2H or \u2014CO2R, respectively), where and R, independently of other R, is an alky of about one to 10 carbons or an aryl group of about 7 to 10 carbons and wherein X and Y are not both an alkyl group;
Z represents a hydrogen, or optionally substituted aryl, alkyl or alkenyl groups attached to the triaza macrocycle though a linking group L3, wherein the aryl, alkyl and alkenyl groups and the linking group of Z are as described under X and Y variables above;
C labeled with subscripts a-d in formula I represent carbon bridges, preferably alkylene bridges, between nitrogens, these carbon bridges, the length of which is defined by the values of subscripts a-d and e, may all be the same length or may differ in length, each bridges may be composed entirely of saturated alkyl groups, or one or more bridges may contain one or more double or triple bonds between carbons, additionally one or more bridge carbons can be optionally substituted with one or more polar groups, for example, halogens or hydroxy groups, and additionally aromatic, non-aromatic rings or both may be fused to one or more of the carbon atom bridges; and
a and d, independently, represent a number from zero to 10; b and c, independently, represent a number from one to 10; and e represents a number from zero to three.
2. The method of claim 1 wherein e is 1 and W is double-bonded carbon (\u2550C(H)2 or \u2550C(R)2), a double bonded oxygen (\u2550O), a methylene halide, or a carbon bonded to one or two groups selected from hydrogen, hydroxyl, alkyl groups of about one to 10 carbons, alkenyl groups of about two to 10 carbons, a substituted alkyl group carrying a charged substituent, alkoxy groups of about one to 10 carbons; aryl groups of about 6 to 12 carbons; halogens, methyl, an optionally substituted epoxide (or oxirane); acyl (\u2014CO\u2014R); (\u2014CO2\u2014R); and CH2OH; where the halogen is F, Cl, I or Br; and R independently of other R, is an optionally substituted alky of about one to 10 carbons, an optionally substituted alkenyl group of about 2 to 10 carbon atoms or an optionally substituted aryl group of about 6 to 12 carbons and R\u2033 is a hydrogen or an alkyl group having from one to 10 carbon atoms.
3. The method of claim 2 wherein W is \u2550C(H)2 or \u2550C(R)2, or a methylene halide.
4. The method of claim 1 wherein and Y independently represent an optionally substituted aryl group attached to the triaza macrocycle through an optional linker group L; where the linker group L can be \u2014SO2\u2014, \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH), \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, \u2014OCO\u2014, \u2014CO\u2014, or alkyl.
5. The method of claim 4 wherein L is \u2014SO2\u2014.
6. The method of claim 5 wherein X and Y are selected from tosyl groups or dansyl groups.
7. The method of claim 1 wherein Z is an optionally substituted aryl, alkyl or alkenyl group attached to the triaza macrocycle though a linking group L3 selected from the groups consisting of \u2014SO2\u2014, \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH)\u2014, \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, \u2014OCO\u2014, \u2014CO\u2014, or alkyl.
8. The method of claim 7 wherein L3 is an alkyl, \u2014CO\u2014 or \u2014OCO\u2014 group.
9. The method of claim 7 wherein Z is a benzyl groups a methylene cyclohexane group or a methylene cyclohexene group.
10. The method of claim 1 wherein a, d and e are all 1 and b and c are 3.
11. The method of claim 1 wherein the pathological condition is an autoimmune disorder or a chronic inflammatory disease.
12. The method of claim 1 wherein the pathological condition is graft-versus host disease or transplant rejection.
13. The method of claim 1 wherein the pathologic condition is rheumatoid arthritis, type I-diabetesmellitus, autoimmune demyelinating diseases such as multiple sclerosis, inflammatory bowel disease syndrome, psoriasis, discoid lupus erythematosus, systemic lupus erythematosus (SLE),adult respiratory distress syndrome, cardiovascular atherosclerosis, leukocytosis, or asthma.
14. A method for downregulating CD4 expression on T cells by exposing the T cells to an amount of a triaza compound of formula:
or a pharmaceutically acceptable salt or solvate thereof that is effective for down-regulating expression of CD4
wherein:
W represents a bridge carbon which is unsubstituted or which is bonded directly or indirectly to one or two polar or non-polar side group substituents selected from the group consisting of double-bonded carbon (\u2550C(H)2 or \u2550C(R)2), double bonded oxygen (\u2550O), hydroxyl, alkyl of about one to 10 carbons alkenyl of about two to 10 carbons (preferably of 2 to 6 carbon atoms); a substituted alkyl group carrying a charged substituent, such as an \u2014S(R\u2033)2+, an \u2014N(R\u2033)3+, a \u2014PR3+, or an \u2014OSO3\u2212 group, alkoxy of about one to 10 carbons; aryl of about 6 to 12 carbons; halogen, methyl halogen(\u2014CT3, \u2014CHT2, or \u2014CH2T), methylene halide (\u2550CT2); optionally substituted epoxide (or oxirane); acyl (\u2014CO\u2014R); (\u2014CO2\u2014R); CH2OH and hydrogen; where halogen is F, Cl, I or Br; T, independently of other T, is F, Cl, I or Br, but preferably all T are the same halogen; R, independently of other R, is an optionally substituted alky of about one to 10 carbons (preferably of one to 6 carbon atoms), an optionally substituted alkenyl group of about 2 to 10 carbon atoms or an optionally substituted aryl group of about 6 to 12 carbons and R\u2033 is a hydrogen or an alkyl group having from one to 10 carbon atoms and W may be bonded to one hydrogen and one polar or non-polar group;
X and Y independently represent an optionally substituted aryl group (Ar), an optionally substituted alkyl group having from one to 10 carbon atoms, or an optionally substituted alkenyl group having from 2 to 10 carbon atoms attached to the triaza macrocycle through an optional linker group L; where the linker group L can be sulfonyl (\u2014SO2\u2014), \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH), \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, carboxy (\u2014OCO\u2014), carbonyl (\u2014CO\u2014), or alkyl (e.g., \u2014(CH2)n\u2014 where n is 1 or 2-; where Ar comprises at least one aromatic homocyclic or heterocyclic ring having from five to seven members; wherein the Ar ring can be substituted with one or more non-hydrogen substituent groups. Ar group substituents include one or more halogens, one or more \u2014CN; one or more \u2014SO3, \u2014SH, \u2014SR or \u2014S\u2014OR groups; one or more trihalomethyl groups; one or more NO, one or more NO2, one or more NH2, NHR or N(R)2 groups; one or more alkyl groups, one or more alkoxy groups, one or more hydroxyl groups, one or more acyl groups (\u2014COH or \u2014CO\u2014R), one or more acid or ester groups (\u2014CO2H or \u2014CO2R, respectively), where and R, independently of other R, is an alky of about one to 10 carbons or an aryl group of about 7 to 10 carbons and wherein X and Y are not both an alkyl group;
Z represents a hydrogen, or optionally substituted aryl, alkyl or alkenyl groups attached to the triaza macrocycle though a linking group L3, wherein the aryl, alkyl and alkenyl groups and the linking group of Z are as described under X and Y variables above;
C labeled with subscripts a-d in formula I represent carbon bridges, preferably alkylene bridges, between nitrogens, these carbon bridges, the length of which is defined by the values of subscripts a-d and e, may all be the same length or may differ in length, each bridges may be composed entirely of saturated alkyl groups, or one or more bridges may contain one or more double or triple bonds between carbons, additionally one or more bridge carbons can be optionally substituted with one or more polar groups, for example, halogens or hydroxy groups, and additionally aromatic, non-aromatic rings or both may be fused to one or more of the carbon atom bridges; and
a and d, independently, represent a number from zero to 10; b and c, independently, represent a number from one to 10; and e represents a number from zero to three.
15. The method of claim 14 wherein e is 1 and W is double-bonded carbon (\u2550C(H)2 or \u2550C(R)2), a double bonded oxygen (\u2550O), a methylene halide, or a carbon bonded to one or two groups selected from hydrogen, hydroxyl, alkyl groups of about one to 10 carbons, alkenyl groups of about two to 10 carbons, a substituted alkyl group carrying a charged substituent, alkoxy groups of about one to 10 carbons; aryl groups of about 6 to 12 carbons; halogens, methyl, an optionally substituted epoxide (or oxirane); acyl (\u2014CO\u2014R); (\u2014CO2\u2014R); and CH2OH; where the halogen is F, Cl, I or Br; and R independently of other R, is an optionally substituted alky of about one to 10 carbons, an optionally substituted alkenyl group of about 2 to 10 carbon atoms or an optionally substituted aryl group of about 6 to 12 carbons and R\u2033 is a hydrogen or an alkyl group having from one to 10 carbon atoms.
16. The method of claim 15 wherein W is \u2550C(H)2 or \u2550C(R)2, or a methylene halide.
17. The method of claim 14 wherein X and Y independently represent an optionally substituted aryl group attached to the triaza macrocycle through an optional linker group L; where the linker group L can be \u2014SO2\u2014, \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH)\u2014, \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, \u2014OCO\u2014, \u2014CO\u2014, or alkyl.
18. The method of claim 17 wherein L is \u2014SO2\u2014.
19. The method of claim 18 wherein X and Y are selected from tosyl groups or dansyl groups.
20. The method of claim 14 wherein Z is an optionally substituted aryl, alkyl or alkenyl group attached to the triaza macrocycle though a linking group L3 selected from the groups consisting of \u2014SO2\u2014, \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH), \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, \u2014OCO\u2014, \u2014CO\u2014, or alkyl.
21. The method of claim 20 wherein L3 is an alkyl, \u2014CO\u2014 or \u2014OCO\u2014 group.
22. The method of claim 20 wherein Z is a benzyl groups a methylene cyclohexane group or a methylene cyclohexene group.
23. The method of claim 14 wherein a, d and e are all 1 and b and c are 3.
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective combined amount of one or more triaza macrocycle compounds of formula:
or a pharmaceutically acceptable salt or solvate thereof that is effective for down-regulating expression of CD4
wherein:
W represents a bridge carbon which is unsubstituted or which is bonded directly or indirectly to one or two polar or non-polar side group substituents selected from the group consisting of double-bonded carbon (\u2550C(H)2 or \u2550C(R)2), double bonded oxygen (\u2550O), hydroxyl, alkyl of about one to 10 carbons alkenyl of about two to 10 carbons (preferably of 2 to 6 carbon atoms); a substituted alkyl group carrying a charged substituent, such as an \u2014S(R\u2033)2+, an \u2014N(R\u2033)3+, a \u2014PR3+, or an \u2014OSO3-group, alkoxy of about one to 10 carbons; aryl of about 6 to 12 carbons; halogen, methyl halogen(\u2014CT3, \u2014CHT2, or \u2014CH2T), methylene halide (\u2550CT2); optionally substituted epoxide (or oxirane); acyl (\u2014CO\u2014R); (\u2014CO2\u2014R); CH2OH and hydrogen; where halogen is F, Cl, I or Br; T, independently of other T, is F, Cl, I or Br, but preferably all T are the same halogen; R, independently of other R1 is an optionally substituted alky of about one to 10 carbons (preferably of one to 6 carbon atoms), an optionally substituted alkenyl group of about 2 to 10 carbon atoms or an optionally substituted aryl group of about 6 to 12 carbons and R\u2033 is a hydrogen or an alkyl group having from one to 10 carbon atoms and W may be bonded to one hydrogen and one polar or non-polar group;
X and Y independently represent an optionally substituted aryl group (Ar), an optionally substituted alkyl group having from one to 10 carbon atoms, or an optionally substituted alkenyl group having from 2 to 10 carbon atoms attached to the triaza macrocycle through an optional linker group L; where the linker group L can be sulfonyl (\u2014SO2\u2014), \u2014SO\u2014, \u2014PO\u2014, \u2014PO(OH)\u2014, \u2014PO(H)\u2014, \u2014PO2(OH), \u2014PO2(H)\u2014, \u2014PO3(OH)\u2014, carboxy (\u2014OCO\u2014), carbonyl (\u2014CO\u2014), or alkyl (e.g., \u2014(CH2)n\u2014 where n is 1 or 2-; where Ar comprises at least one aromatic homocyclic or heterocyclic ring having from five to seven members; wherein the Ar ring can be substituted with one or more non-hydrogen substituent groups. Ar group substituents include one or more halogens, one or more \u2014CN; one or more \u2014SO3, \u2014SH, \u2014SR or \u2014S\u2014OR groups; one or more trihalomethyl groups; one or more NO, one or more NO2, one or more NH2, NHR or N(R)2 groups; one or more alkyl groups, one or more alkoxy groups, one or more hydroxyl groups, one or more acyl groups (\u2014COH or \u2014CO\u2014R), one or more acid or ester groups (\u2014CO2H or \u2014CO2R, respectively), where and R, independently of other R1 is an alkyl of about one to 10 carbons or an aryl group of about 7 to 10 carbons and wherein X and Y are not both an alkyl group;
Z represents a hydrogen, or optionally substituted aryl, alkyl or alkenyl groups attached to the triaza macrocycle though a linking group L3, wherein the aryl, alkyl and alkenyl groups and the linking group of Z are as described under X and Y variables above;
C labeled with subscripts a-d in formula I represent carbon bridges, preferably alkylene bridges, between nitrogens, these carbon bridges, the length of which is defined by the values of subscripts a-d and e, may all be the same length or may differ in length, each bridges may be composed entirely of saturated alkyl groups, or one or more bridges may contain one or more double or triple bonds between carbons, additionally one or more bridge carbons can be optionally substituted with one or more polar groups, for example, halogens or hydroxy groups, and additionally aromatic, non-aromatic rings or both may be fused to one or more of the carbon atom bridges; and
a and d, independently, represent a number from zero to 10; b and c, independently, represent a number from one to 10; and e represents a number from zero to three.
25. A triaza macrocylic compound of formula:
or a pharmaceutically acceptable salt or solvate thereof wherein:
X1 and X2 independently can be a charged, polar or non-polar substituent;
the A ring is an optionally substituted phenyl ring, an optionally substituted cyclohexane ring or an optionally substituted cyclohexene ring;
R1 and R2 represent substituents on the central carbon of one of the carbon bridges which independently, can be a hydrogen, hydroxyl, halogen, an optionally substituted alkyl group having one to 10 carbon atoms, an optionally substituted alkenyl group having 2 to 10 carbon atoms; optionally substituted alkoxy of about one to 10 carbons; methyl halogen(\u2014CT3, \u2014CHT2, or \u2014CH2T); epoxide (or oxirane); acyl (\u2014CO\u2014R); ester (\u2014CO2\u2014R); CH2OH and hydrogen; or R1 and R2 together can represent a double-bonded carbon which in turn is bonded to one or two hydrogens andor R\u2032 groups (i.e., \u2550CH2, \u2550CRH, or \u2550C(R)2), methylene halide (\u2550CT2);or a double bonded oxygen (\u2550O). (preferably one to 6 carbon atoms), where halogen is F, Cl, I or Br; T, independently of other T, is F, Cl, I or Br, and
R and R3, independently of other R and R3, is an optionally substituted alkyl, ether or thioether of about one to 10 carbons or an aryl group of about 7 to 10 carbons and wherein the R groups are optionally substituted and two R in the same group can form a cyclic moiety.
26. The compound of claim 25 wherein X1 and X2 are alkyl amines.
27. The compound of claim 26 wherein the A ring is an optionally substituted phenyl ring.
28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of claim 25 in a combined amount that is therapeutically effective.