US2014308260A1PendingUtilityA1
Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products
Est. expiryOct 7, 2031(~5.2 yrs left)· nominal 20-yr term from priority
Inventors:Bryan T. OronskyJan ScicinskiSusan KnoxWilliam FitchFrans A. KuypersMarcel FensSandra LarkinPedro CabralesChad Brouse
A61N 5/10A61K 31/198A61K 45/06A61K 35/16A61K 31/22A61K 38/1709A61K 47/6445A61K 31/445A61K 31/40A61K 35/18A61K 31/397A61K 31/215A61K 31/12A61K 31/16A61K 31/255A61K 35/14A61K 33/00A01N 1/126Y02A50/30A01N 1/0226
40
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Claims
Abstract
The invention provides methods, compositions, and medical kits comprising a nitrite-reductase promoter, such as an allosteric modulator of hemoglobin, for use in treating medical disorders and preservation of blood products. In one aspect, the invention provides methods, compositions, and medical kits comprising an inorganic nitrite salt and a nitrite-reductase promoter, such as an allosteric modulator of hemoglobin, for use in treating medical disorders, such as cancer, cardiovascular disorders, ischemic conditions, hemolytic conditions, and bacterial infections. Exemplary inorganic nitrite salts include sodium nitrite and arginine nitrite. Exemplary allosteric modulators of hemoglobin described herein include alkyl-substituted and acyl-substituted di-nitroheterocycles.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating or preventing a disorder selected from the group consisting of cancer, a cardiovascular disorder, an ischemic condition, a hemolytic condition, or a bacterial infection, comprising administering to a patient in need thereof a therapeutically effective amount of (i) an inorganic nitrite salt, and (ii) an allosteric modulator of hemoglobin that promotes nitrite reductase activity.
2 . The method of claim 1 , wherein the disorder is cancer.
3 . The method of claim 2 , wherein the cancer is a tumor.
4 . The method of claim 2 or 3 , further comprising exposing the patient to a chemotherapeutic agent or radiation.
5 . The method of claim 1 , wherein the disorder is a cardiovascular disorder.
6 . The method of claim 5 , wherein the cardiovascular disorder is pulmonary hypertension, systemic hypertension, angina, Cardiac Syndrome X, myocardial infarction, peripheral artery disease, or Raynaud's disease.
7 . The method of claim 1 , wherein the disorder is a hemolytic condition.
8 . The method of claim 7 , wherein the hemolytic condition is sickle cell disease.
9 . A method of increasing the amount of nitric oxide produced by hemoglobin in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of (i) an inorganic nitrite salt, and (ii) an allosteric modulator of hemoglobin that promotes nitrite reductase activity.
10 . The method of any one of claims 1 - 9 , wherein the inorganic nitrite salt is an alkali metal nitrite.
11 . The method of any one of claims 1 - 9 , wherein the inorganic nitrite salt is sodium nitrite.
12 . The method of any one of claims 1 - 9 , wherein the inorganic nitrite salt is represented by NO 2 —N(R′) 4 , wherein R′ represents independently for each occurrence hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.
13 . The method of any one of claims 1 - 12 , wherein the allosteric modulator of hemoglobin binds to the beta-cysteine-93 residue of hemoglobin.
14 . The method of any one of claims 1 - 12 , wherein the allosteric modulator of hemoglobin is a compound of Formula I or II, wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3; and
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3.
15 . The method of any one of claims 1 - 12 , wherein the allosteric modulator of hemoglobin is a compound of Formula I-A:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is N or C(H);
R 1 is chloro, bromo, —OS(O) 2 —(C 1 -C 6 alkyl), —OS(O) 2 —(C 1 -C 6 haloalkyl), —OS(O) 2 -(para-methylphenyl), or —OC(O)CF 3 ;
R 2 represents independently for each occurrence hydrogen or methyl; and
y represents independently for each occurrence 1 or 2.
16 . The method of claim 15 , wherein A is N.
17 . The method of claim 15 or 16 , wherein R 1 is bromo.
18 . The method of any one of claims 15 - 17 , wherein y is 1.
19 . The method of any one of claims 1 - 12 , wherein the allosteric modulator of hemoglobin is
or a pharmaceutically acceptable salt or solvate thereof.
20 . The method of any one of claims 1 - 12 , wherein the allosteric modulator of hemoglobin is selected from the group consisting of S-nitroso-N-acetylcysteine, S-nitrosocysteinylglycine, S-nitrosocysteine, S-nitrosohomocysteine, a metal nitrosyl complex, an S-nitro compound, an S-nitroso compound, a thionitrite, a diazeniumdiolate, 4-pyridylmethyl chloride, an alkoxyalkylchloride, dimethoxymethane, N-(hydroxymethyl)acetamide, triphenylmethyl chloride, acetyl chloride, 2-chloroacetic acid, acetic anhydride, a haloacetamide, a haloacetate, benzyl chloride, benzoyl chloride, di-tert-butyl dicarbonate, p-hydroxyphenacyl bromide, p-acetoxybenzyl chloride, p-methoxybenzyl chloride, tetrahydropyran, acetamidohydroxymethane, acetone, bis-carboethoxyethene, tert-butoxycarbonyl chloride, alkyl isocyanate, alkoxyalkyl isocyanate, a derivatized dextran, a (polyethylene glycol)-maleimide, 2,4-dinitrophenyl fluoride, and 2,2,2-trichloroethoxycarbonyl.
21 . The method of any one of claims 1 - 20 , wherein the inorganic nitrite salt is administered at a daily dosage of about 0.1 μg/kg to about 10 mg/kg.
22 . The method of any one of claims 1 - 21 , wherein the inorganic nitrite salt is administered orally.
23 . The method of any one of claims 1 - 22 , wherein the allosteric modulator of hemoglobin is administered at a dosage sufficient to cause a ten percent increase in the rate at which hemoglobin converts nitrite to nitric oxide in vivo.
24 . The method of any one of claims 1 - 23 , wherein the allosteric modulator is administered within about 1 hour after administration of the inorganic nitrite salt.
25 . A pharmaceutical composition comprising (i) an inorganic nitrite salt, and (ii) an allosteric modulator of hemoglobin that promotes nitrite reductase activity.
26 . The pharmaceutical composition of claim 25 , wherein the inorganic nitrite salt is an alkali metal nitrite.
27 . The pharmaceutical composition of claim 25 , wherein the inorganic nitrite salt is sodium nitrite.
28 . The pharmaceutical composition of claim 25 , wherein the inorganic nitrite salt is represented by NO 2 —N(R′) 4 , wherein R′ represents independently for each occurrence hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl.
29 . The pharmaceutical composition of any one of claims 25 - 28 , wherein the allosteric modulator of hemoglobin binds to the beta-cysteine-93 residue of hemoglobin.
30 . The pharmaceutical composition of any one of claims 25 - 28 , wherein the allosteric modulator of hemoglobin is a compound of Formula I or II, wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3; and
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3.
31 . The pharmaceutical composition of any one of claims 25 - 28 , wherein the allosteric modulator of hemoglobin is a compound of Formula I-A:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is N or C(H);
R 1 is chloro, bromo, —OS(O) 2 —(C 1 -C 6 alkyl), —OS(O) 2 —(C 1 -C 6 haloalkyl), —OS(O) 2 -(para-methylphenyl), or —OC(O)CF 3 ;
R 2 represents independently for each occurrence hydrogen or methyl; and
y represents independently for each occurrence 1 or 2.
32 . The pharmaceutical composition of claim 31 , wherein A is N.
33 . The pharmaceutical composition of claim 31 or 32 , wherein R 1 is bromo.
34 . The pharmaceutical composition of any one of claims 31 - 33 , wherein y is 1.
35 . The pharmaceutical composition of any one of claims 25 - 28 , wherein the allosteric modulator of hemoglobin is
or a pharmaceutically acceptable salt or solvate thereof.
36 . The pharmaceutical composition of any one of claims 25 - 28 , wherein the allosteric modulator of hemoglobin is S-nitroso-N-acetylcysteine, S-nitrosocysteinylglycine, S-nitrosocysteine, S-nitrosohomocysteine, a metal nitrosyl complex, an S-nitro compound, an S-nitroso compound, a thionitrite, a diazeniumdiolate, 4-pyridylmethyl chloride, an alkoxyalkylchloride, dimethoxymethane, N-(hydroxymethyl)acetamide, triphenylmethyl chloride, acetyl chloride, 2-chloroacetic acid, acetic anhydride, a haloacetamide, a haloacetate, benzyl chloride, benzoyl chloride, di-tert-butyl dicarbonate, p-hydroxyphenacyl bromide, p-acetoxybenzyl chloride, p-methoxybenzyl chloride, tetrahydropyran, acetamidohydroxymethane, acetone, bis-carboethoxyethene, tert-butoxycarbonyl chloride, alkyl isocyanate, alkoxyalkyl isocyanate, a derivatized dextran, a (polyethylene glycol)-maleimide, 2,4-dinitrophenyl fluoride, and 2,2,2-trichloroethoxycarbonyl.
37 . A kit for treating a medical disorder, comprising (i) an inorganic nitrite salt, (ii) an allosteric modulator of hemoglobin, and (iii) instructions for using the kit to treat a medical disorder.
38 . A method of treating a patient suffering from reduced blood volume, comprising administering to a patient in need thereof a blood product by injection and a therapeutic agent selected from the group consisting of an organonitro compound of Formula I, organonitro compound of Formula II, hemoglobin conjugate of Formula III, hemoglobin conjugate of Formula IV, and an erythrocyte cell that has been exposed to an organonitro compound of Formula I or II; wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3;
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3;
Formula III is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
m and p are independently 1, 2, or 3;
n is 0, 1, 2, or 3;
x is 1, 2, or 3; and
z is an integer from 1 to 10; and
Formula IV is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
t is an integer in the range from 1 to 12;
x is 1, 2, or 3; and
z is an integer from 1 to 10.
39 . The method of claim 38 , wherein the patient suffering from reduced blood volume is suffering from hemorrhagic shock.
40 . A method of performing a blood transfusion to a patient, comprising administering to a patient in need thereof a blood product by injection and a therapeutic agent selected from the group consisting of an organonitro compound of Formula I, organonitro compound of Formula II, hemoglobin conjugate of Formula III, hemoglobin conjugate of Formula IV, and an erythrocyte cell that has been exposed to an organonitro compound of Formula I or II, wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3;
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3;
Formula III is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
m and p are independently 1, 2, or 3;
n is 0, 1, 2, or 3;
x is 1, 2, or 3; and
z is an integer from 1 to 10; and
Formula IV is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
t is an integer in the range from 1 to 12;
x is 1, 2, or 3; and
z is an integer from 1 to 10.
41 . The method of any one of claims 38 - 40 , wherein the blood product comprises erythrocyte cells.
42 . The method of any one of claims 38 - 41 , wherein the blood product comprises blood plasma.
43 . The method of any one of claims 38 - 42 , wherein the blood product and organonitro compound are administered to the patient concurrently.
44 . The method of any one of claims 38 - 42 , wherein the blood product is administered to the patient separately from the therapeutic agent.
45 . The method of any one of claims 38 - 42 , wherein the patient receives, by intravenous injection, a single composition comprising blood product and the therapeutic agent.
46 . The method of any one of claims 38 - 45 , further comprising administering an alkali metal nitrite to the patient.
47 . The method of any one of claims 38 - 45 , further comprising administering sodium nitrite to the patient.
48 . A method of treating a patient suffering from anemia, comprising administering to a patient in need thereof a therapeutic agent selected from the group consisting of an organonitro compound of Formula I, organonitro compound of Formula II, hemoglobin conjugate of Formula III, hemoglobin conjugate of Formula IV, and an erythrocyte cell that has been exposed to an organonitro compound of Formula I or II; wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3;
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3;
Formula III is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
m and p are independently 1, 2, or 3;
n is 0, 1, 2, or 3;
x is 1, 2, or 3; and
z is an integer from 1 to 10; and
Formula IV is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
t is an integer in the range from 1 to 12;
x is 1, 2, or 3; and
z is an integer from 1 to 10.
49 . The method of claim 48 , further comprising administering a blood product to the patient by injection.
50 . The method of claim 49 , wherein the blood product comprises erythrocyte cells.
51 . The method of claim 49 or 50 , wherein the blood product comprises blood plasma.
52 . The method of any one of claims 49 - 51 , wherein the blood product and organonitro compound are administered to the patient concurrently.
53 . The method of any one of claims 49 - 51 , wherein the blood product is administered to the patient separately from the therapeutic agent.
54 . The method of any one of claims 49 - 51 , wherein the patient receives, by intravenous injection, a single composition comprising blood product and the therapeutic agent.
55 . The method of any one of claims 48 - 54 , further comprising administering an alkali metal nitrite to the patient.
56 . The method of any one of claims 48 - 54 , further comprising administering sodium nitrite to the patient.
57 . The method of any one of claims 38 - 56 , wherein the therapeutic agent is an organonitro compound of Formula I.
58 . The method of any one of claims 38 - 56 , wherein the therapeutic agent is an erythrocyte cell that has been exposed to an organonitro compound of Formula I, and said therapeutic agent is administered by injection.
59 . The method of claim 57 or 58 , wherein A 1 is —C(O)—, and A 2 is N.
60 . The method of any one of claims 38 - 59 , wherein R 1 is bromo.
61 . The method of any one of claims 38 - 60 , wherein n is 0, and m is 2.
62 . The method of any one of claims 38 - 58 , wherein the therapeutic agent is
or a pharmaceutically acceptable salt thereof.
63 . The method of any one of claims 38 - 56 , wherein the therapeutic agent is a hemoglobin conjugate of Formula III, and said therapeutic agent is administered by injection.
64 . The method of claim 63 , wherein A 1 is —C(O)— and A 2 is N.
65 . The method of claim 63 or 64 , wherein n is 0, and m is 2.
66 . The method of any one of claims 38 - 56 , wherein the therapeutic agent is
or a pharmaceutically acceptable salt thereof, wherein z is an integer from 1 to 10.
67 . A method of preserving an isolated blood product, comprising exposing the isolated blood product to an agent selected from the group consisting of an organonitro compound of Formula I, organonitro compound of Formula II, hemoglobin conjugate of Formula III, hemoglobin conjugate of Formula IV, and an erythrocyte cell that has been exposed to an organonitro compound of Formula I or II, wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3;
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3;
Formula III is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
m and p are independently 1, 2, or 3;
n is 0, 1, 2, or 3;
x is 1, 2, or 3; and
z is an integer from 1 to 10; and
Formula IV is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
t is an integer in the range from 1 to 12;
x is 1, 2, or 3; and
z is an integer from 1 to 10.
68 . The method of claim 67 , wherein the isolated blood product is whole blood.
69 . The method of claim 67 , wherein the isolated blood product comprises erythrocyte cells.
70 . The method of claim 67 , wherein the isolated blood product is erythrocyte cells.
71 . The method of any one of claims 67 - 70 , further comprising exposing the isolated blood product to an alkali metal nitrite.
72 . The method of any one of claims 67 - 70 , further comprising exposing the isolated blood product to sodium nitrite.
73 . The method of any one of claims 67 - 72 , wherein the agent is an organonitro compound of Formula I.
74 . The method of any one of claims 67 - 72 , wherein the agent is an erythrocyte cell that has been exposed to an organonitro compound of Formula I.
75 . The method of claim 73 or 74 , wherein A 1 is —C(O)—, and A 2 is N.
76 . The method of any one of claims 67 - 75 , wherein R 1 is bromo.
77 . The method of any one of claims 67 - 76 , wherein n is 0, and m is 2.
78 . The method of any one of claims 67 - 72 , wherein the agent is
or a pharmaceutically acceptable salt thereof.
79 . The method of any one of claims 67 - 72 , wherein the agent is a hemoglobin conjugate of Formula III.
80 . The method of claim 79 , wherein A 1 is —C(O)—, and A 2 is N.
81 . The method of claim 79 or 80 , wherein n is 0, and m is 2.
82 . The method of any one of claims 67 - 72 , wherein the agent is
or a pharmaceutically acceptable salt thereof, wherein z is an integer from 1 to 10.
83 . An isolated blood product composition, comprising (i) a blood product, and (ii) an agent selected from the group consisting of an organonitro compound of Formula I, organonitro compound of Formula II, hemoglobin conjugate of Formula III, hemoglobin conjugate of Formula IV, and an erythrocyte cell that has been exposed to an organonitro compound of Formula I or II; wherein Formula I is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —(C(R 3 ) 2 ) x C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 1 is halogen, —OS(O) 2 R 5 , or —OC(O)CF 3 ;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
R 5 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
m and p are independently 1, 2, or 3; and
n and x each represent independently for each occurrence 0, 1, 2, or 3;
Formula II is represented by:
or a pharmaceutically acceptable salt or solvate thereof: wherein:
A 1 is —C(O)— or —(C(R 5 ) 2 ) x C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 1 is halogen, —OS(O) 2 R 6 , or —OC(O)CF 3 ;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, or aralkyl;
t is an integer in the range from 1 to 12; and
x represents independently for each occurrence 0, 1, 2, or 3;
Formula III is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
m and p are independently 1, 2, or 3;
n is 0, 1, 2, or 3;
x is 1, 2, or 3; and
z is an integer from 1 to 10; and
Formula IV is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
t is an integer in the range from 1 to 12;
x is 1, 2, or 3; and
z is an integer from 1 to 10.
84 . The composition of claim 83 , wherein the blood product is whole blood.
85 . The composition of claim 83 , wherein the blood product comprises erythrocyte cells.
86 . The composition of claim 83 , wherein the blood product comprises erythrocyte cells and blood plasma.
87 . The composition of claim 83 , wherein the blood product is erythrocyte cells.
88 . The composition of any one of claims 83 - 87 , further comprising an alkali metal nitrite.
89 . The composition of any one of claims 83 - 87 , further comprising sodium nitrite.
90 . The composition of any one of claims 83 - 89 , wherein the agent is an organonitro compound of Formula I.
91 . The composition of any one of claims 83 - 89 , wherein the agent is an erythrocyte cell that has been exposed to an organonitro compound of Formula I.
92 . The composition of claim 90 or 91 , wherein A 1 is —C(O)—, and A 2 is N.
93 . The composition of any one of claims 83 - 92 , wherein R 1 is bromo.
94 . The composition of any one of claims 83 - 93 , wherein n is 0, and m is 2.
95 . The composition of any one of claims 83 - 89 , wherein the agent is
a pharmaceutically acceptable salt thereof.
96 . The composition of any one of claims 83 - 89 , wherein the agent is a hemoglobin conjugate of Formula III.
97 . The composition of claim 96 , wherein A 1 is —C(O)— and A 2 is N.
98 . The composition of claim 96 or 97 , wherein n is 0, and m is 2.
99 . The composition of any one of claims 83 - 89 , wherein the agent is
or a pharmaceutically acceptable salt thereof, wherein z is an integer from 1 to 10.
100 . An isolated hemoglobin conjugate represented by Formula III or IV:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 3 ) 2 ) x —;
A 2 is N or —C(R 4 )—;
R 2 is C 1 -C 6 alkyl;
R 3 and R 4 each represent independently for each occurrence hydrogen or C 1 -C 5 alkyl;
m and p are independently 1, 2, or 3;
n is 0, 1, 2, or 3;
x is 1, 2, or 3; and
z is an integer from 1 to 10; and
Formula IV is represented by:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 1 is —C(O)— or —C(O)(C(R 5 ) 2 ) x —;
A 2 is —N(R 5 )— or —C(R 2 )(R 3 )—;
R 2 and R 3 each represent independently for each occurrence hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 are taken together with the carbon atom to which they are attached to form a 3-6 membered, saturated carbocyclic ring;
R 4 is hydrogen or C 1 -C 6 alkyl;
R 5 represents independently for each occurrence hydrogen or C 1 -C 6 alkyl;
t is an integer in the range from 1 to 12;
x is 1, 2, or 3; and
z is an integer from 1 to 10.
101 . The isolated hemoglobin conjugate of claim 100 , wherein the agent is a hemoglobin conjugate of Formula III.
102 . The isolated hemoglobin conjugate of claim 100 or 101 , wherein A 1 is —C(O)—, and A 2 is N.
103 . The isolated hemoglobin conjugate of any one of claims 100 - 102 , wherein n is 0, and m is 2.
104 . The isolated hemoglobin conjugate of claim 100 , wherein the agent is
or a pharmaceutically acceptable salt thereof, wherein z is an integer from 1 to 10.
105 . The isolated hemoglobin conjugate of claim 104 , wherein the bond depicted to the hemoglobin is a thioether bond to the sulfur atom of the beta-cysteine-93 residue of said hemoglobin.
106 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an isolated hemoglobin conjugate of claim 100 .Cited by (0)
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